AN ABSTRACT OF THE THESIS OF
Heath Eugene Giesbrecht for the degree of Master of Science in
Chemistry on June 19, 2008.
Title: Broadening the Scope of the Modified-Julia Reaction: A Mild and
Stereoselective Method for the Synthesis of (Z)-Configurated α,βUnsaturated Lactones
Abstract approved:
Paul R. Blakemore
An intramolecular variant of the modified-Julia olefination was
demonstrated by the synthesis of α,β-unsaturated lactones in a mild and
(Z)-selective fashion. The lynchpin reagent (benzothiazol-2-sulfonyl)
acetic acid was synthesized in a straightforward fashion in 86% overall
yield from commercially available 2-mercaptobenzothiazole via
conversion to ethyl (benzothiazol-2-ylthio)acetate by base mediated
alkylation with ethyl chloroactetate; saponification of the ester to (1,3benzothiazol-2-ylthio)acetic acid;
and,
oxidation
by
ammonium
molybdate and H2O2 to afford the key sulfonyl acid reagent. Through the
use of an efficient dicyclohexylcarbodiimide coupling reaction, the
acetic acid derivative was condensed with a series of ω-alkenyl
carbinols to form the corresponding ω-alkenyl (benzothiazol-2sulfonyl)acetates in moderate to excellent yields (60 – 94%). The esters
were then subjected to ozonolysis conditions (O3 in CH2Cl2) and, after
subsequent reduction of the ozonide with dimethyl sulfide, the
carboxaldehyde intermediates were immediately subjected to 1,8diazabicycloundec-7-ene in CH2Cl2 (-78 °C to rt) to effect cyclic alkene
formation. Successful production of the α,β-unsaturated lactones was
observed for a variety of ring sizes (7, 12, 13, and 19) in moderate yields
(30 – 45%), but comparable to other methods for lactone synthesis.
Aldol condensation products resulting from the elimination of H2O from
the putative anti-β-alkoxy-benzothiazol-sulfones intermediates were
also obtained from the smaller rings sizes, albeit in low yields (2 – 4%).
The reaction conditions proved to be ideal for these simple substrates.
Significantly, biasing factors such as Thorpe-Ingold effects were not
required to aid macrocyclic lactone formation. The targeted α,βunsaturated
lactones
were
generated
stereoselectively
with
predominantly (Z)-configuration (Z:E ≥ 85:15) in all cases examined.
© Copyright by Heath Eugene Giesbrecht
June 19, 2008
All Rights Reserved
Broadening the Scope of the Modified-Julia Reaction: A Mild
and Stereoselective Method for the Synthesis of (Z)Configurated α,β-Unsaturated Lactones
by
Heath Eugene Giesbrecht
A THESIS
submitted to
Oregon State University
in partial fulfillment of
the requirements for the
degree of
Master of Science
Presented June 19, 2008
Commencement June 2009
Master of Science thesis of Heath Eugene Giesbrecht
presented on June 19, 2008
APPROVED:
Major Professor, Representing Chemistry
Chair of the Department of Chemistry
Dean of the Graduate School
I understand that my thesis will become part of the permanent collection
of Oregon State University libraries. My signature below authorizes
release of my thesis to any reader upon request
Heath Eugene Giesbrecht, Author
ACKNOWLEDGEMENTS
The author would like to express his sincere appreciation to the
following people.
I would first like to thank my advisor Prof. Paul R. Blakemore for his
support and guidance in both my chemistry and other studies during my
stay in Corvallis.
Dr. Jeff Morre for his mass spectroscopic services while at Oregon State
University.
Dr. Rodger Kohnert for his time and assistance with NMR analysis and
instruction.
All of the professors who took the time to teach me organic chemistry as
well as other subjects during my time at the university.
All of my colleagues in the Blakemore Research Group for both
challenging and inspiring me during these four years.
Tartar Foundation for summer funding.
Oregon State University for all the lasting friendships that I have made
during my time here.
Lastly, I would sincerely like to thank those in the Chemistry
Department who stuck by me through the difficult times and always
believed in my abilities even when I would question them.
TABLE OF CONTENTS
Page
1
Synthesis of α,β-Unsaturated Lactones Using
Previously Employed Methods…………………….
1.1
The Modified-Julia-Kocienski Olefination:
Early Development, Mechanistic
Consideration, and Applications…………....
3
Stereoselective Synthesis of α,β-Unsaturated
Esters and Amides via Intermolecular
Modified-Julia Olefination…………………..
15
Recent Applications of the Modified-Julia
Olefination…………………………………..
17
Overview of Projected Study………………..
22
Synthesis of (Benzothiazol-2-sulfonyl) Acetates……
24
1.2
1.3
1.4
2
2.1
Initial Routes to Proposed (Benzothiazol2-sulfonyl) Acetate Intermediates……………
24
Synthesis of (Benzothiazol-2-sulfonyl)
acetic acid…………………………………….
28
DCC Coupling of (Benzothiazol-2-sulfonyl)
acetic acid with ω-Alkenyl Carbinols………...
30
2.4
Direct Synthesis of ω-Alkenyl Carbinols……..
30
2.5
Synthesis of (Benzothiazol-2-sulfonyl) acetate
Esters Using DCC Coupling…………………..
33
α,β-Unsaturated Lactone Formation…………………..
35
3.1
Ozonolysis of ω-Alkenyl Sulfonyl Esters……..
35
3.2
Modified-Julia Reacton of ω-Carboxaldehyde
Sulfonyl Esters…………………………………
38
Conclusion……………………………………………..
44
2.2
2.3
3
4
1
TABLE OF CONTENTS (Continued)
Page
5
Experimental………………………………………....
45
6
References………………………………………........
78
Bibliography………………………………………………..
83
Appendix……………………………………………………
88
LIST OF FIGURES
Figure
1.
2.
3.
Page
Examples of natural products containing α,β–unsaturated
lactones…..………………………………………………
2
Aromatic activators commonly used in the modified-Julia
reaction…………………………………………………..
14
Readily synthesized esters from DCC coupling…………
34
LIST OF TABLES
Table
1.
2.
3.
Page
Influence of counterion and solvent in the stereochemical
course of the coupling reaction…………………………..
6
E-selectivity exhibited for unsaturated (aromatic)
aldehydes …………………………………………………
11
Aldehyde substituent effect on stereoselectivity of alkene
geometry…………………………………………………..
17
LIST OF SCHEMES
Scheme
Page
1.
The modified-Julia olefination with (BT) sulfones………
4
2.
Self-condensation of BT sulfones leading to dimerization
5
3.
Reaction type (a) exemplified……………………………
6
4.
Stereoselective elimination of β-alkoxy-BT-sulfone
intermediates……………………………………………… 8
5.
Mechanism explaining stereochemical outcome of
modified-Julia reaction…………………………………… 9
6.
Cross-over adduct formation……………………………… 10
7.
Substrate dependence in the synthesis of Rapamycin…….. 12
8.
Effect of the heterocyclic activator on the yields of
α,β-unsaturated esters…………………………………….. 15
9.
Stereoselective synthesis of fluorinated olefins…………... 18
10. Additive effect of MgBr2 on alkene geometry……………. 19
11. Synthesis of substituted exoglycals using the
modified-Julia reaction…………………………………… 19
12. Synthesis of vinyl ethers with the modified-Julia reaction.. 20
13. Synthesis of α,β-unsaturated Weinreb amides from
BT-sulfones………………………………………………. 21
14. First published example of an intramolecular
modified-Julia reaction…………………………………… 22
15. Schematic representation of proposed study……………… 22
16. Alkylation of 2-mercaptobenzothiazole…………………... 25
LIST OF SCHEMES (Continued)
Scheme
Page
17. Thermodynamic transesterification of BT-sulfide ………
26
18. Attempts to prepare lynchpin reagent 78 from ester 83….
26
19. Mechanism for the formation of purple betaine
pigment 91……………………………………………….. 28
20. Synthesis of key reagent 78 by oxidation of thioether 88... 29
21. Facile decarboxylation of the lynchpin reagent in high
dielectric constant solvents………………………………. 30
22. General scheme for ester formation……………………… 30
23. Grignard reaction for synthesis of 2° aryl alcohol……….. 31
24. Pentenol 107 synthesis from dimethyl malonate 103……. 32
25. Reduction of undecenoic acid……………………………
32
26. Synthesis of ethereal alcohol 113………………………… 33
27. Initial ester formation through DCC coupling…………… 34
28. General two-step ozonolysis/lactonization protocol……… 35
29. Differences in product distribution due to solvent effects... 36
30. Reduction of ozonide……………………………………... 37
31. 7-membered lactone formation…………………………… 39
32. 12-membered α,β-unsaturated lactone formation………... 40
33. 13-membered α,β-unsaturated lactone formation………... 41
34. 19-membered ethereal α,β-unsaturated lactone formation.. 41
LIST OF SCHEMES (Continued)
Scheme
35. Elimination of labile substrate …………………………..
Page
42
This thesis is dedicated to every individual who has, throughout my life,
inspired me to dream, think, learn, do, teach and especially write.
I dedicate this specifically to my loved ones, family and friends: to those
with whom I can share this occasion, but also to those whom I will
encounter later in existence. You have been my ultimate motivation.
Broadening the Scope of the Modified-Julia Reaction: A
Mild and Stereoselective Method for the Synthesis of (Z)Configurated α,β -Unsaturated Lactones
1. Synthesis of α,β -Unsaturated Lactones Using
Previously Employed Methods
At
present,
few
generally
stereoselective synthesis of
applicable
methods
exist
for
the
α,β-unsaturated lactones, especially
macrocyclic examples. These include, but are not limited to, methods
where the ring closure comes from intramolecular esterification (i.e.,
lactonization)1, others where the alkene is the point of metathesis2, and
other common alkenation reactions3 most often the Horner-WadsworthEmmons reaction4 as well as a variety of other methods5. Some natural
products contain α,β-unsaturated lactones include rhizoxin D6,
dactdyolide7, (+)-latrunculin A8, callystatin A9, (+)-digitoxigenin10, and
phorboxazole A11 (Figure 1).
2
O
O
O
O
O
O
O
O
O
HO
O
O
O
O
H
HN
O
N
OH
S
O
O
2
Dactylolide
1
Rhizoxin D
3
O (+)-Latrunculin A
O
O
O
H
H
HO
OH O
OH
H
5
(+)-Digitoxigenin
4
Callystatin A
OH
O
N
O
Br
OMe
O
MeO
O
N
O
OH
OH
O
O
O
6
Phorboxazole A
Figure 1. Examples of natural products containing α,β–unsaturated
lactones
Many of the protocols used to generate unsaturated lactones involve
harsh conditions not amicable to advanced substrates, or else lengthy
syntheses are needed to arrive at the desired substrates necessary for
lactone formation. In many of these approaches, the selectivity for the
alkene formation lies toward the more stable (E)-isomer and very few
known methods return the (Z)-isomer as the major product. This thesis
describes a novel, convenient way to construct (Z)-configurated α,β–
unsaturated lactones via the modified-Julia alkenation under so called
“Barbier-type” conditions12.
3
1.1 The Modified-Julia-Kocienski Olefination: Early
Development, Mechanistic Consideration, and
Applications
The modified-Julia olefination13 allows for the single-step synthesis of
alkenes from carbonyl compounds and heterocyclic sulfones via a novel
condensation process. The direct synthesis of olefins employing
heterocyclic sulfones was initially described by Sylvestre Julia in 1991
(Scheme 1). The reaction commences with the metallation/deprotonation
of an aryl alkyl benzothiazol-2-yl sulfone 7, the resulting anion 8 acts as
the nucleophilic partner in the reaction manifold. This species
subsequently condenses with a carbonyl compound 9 forming a transient
β-alkoxysulfone intermediate 10. The alkoxide continues along the
reaction pathway, attacking in an intramolecular fashion the electrophilic
C=N bond of the benzothiazole (BT) portion of the molecule. The series
of consecutive reactions results in a putative spirocyclic intermediate 11
that selectively breaks down via an overall Smiles rearrangement14
affording the alkene 14 together with loss of sulfur dioxide 15 and
elimination of metallated benzothiazolone 13.
4
O
O2
S
N
R1
base
H
S
O2
S
Smiles
1
R2
9
H
addition
R
O
rearrangement
2
R
N O
R2
S S
O2
R1
11
N
N
O
2
O
R
R1
S
O
S
12
R1
8
S
10
N
S
7
N
O2
S
O
elimination
S
+
13
R2
+
1
14
R
SO2
15
Scheme 1. The modified-Julia olefination with (BT) sulfones
The reaction is dependent on the relative electrophilicity of the BT
moiety. Due to this limitation, a non-nucleophilic base must be used for
the deprotonation step, thus avoiding attack on the heterocycle.
Unfortunately, in practice, when deprotonation occurs the resulting
anion 17 itself becomes a good nucleophile, and owing to the donoracceptor nature of the BT heterocyle, self-condensation resulting in
homocoupled species 19 can occur (Scheme 2). Reverse addition
(sulfone to the base) does nothing to circumvent this problem. Of course,
this alternative pathway necessarily decreases the overall yield of the
desired reaction. Using “Barbier-type” conditions in which both the BTsulfone and the aldehyde are added together and subsequently subjected
to the action of the base can avert this “dimerization”. This protocol
considerably enhances the chemoselectivity of the reaction due to the
5
higher relative electrophilicity of the aldehyde over the BT-sulfone in a
self-condensation mechanism15. Barbier-conditions typically lead to
yields that are 10-40% higher in the case of simple sulfones, but when
joining together complex substrates, such conditions may be intolerable.
acceptor
O2
S
N
LDA (1.1 eq),
THF, -78 °C
S
O2
S
N
S
16
16
Li
17
donor
Li
SO2Me
N
S
SO2BT
18
-MeSO2Li
N
O2
S
N
S
S
19
Scheme 2. Self-condensation of BT sulfones leading to dimerization
The stereochemical outcome of the one-pot Julia reaction is substrate
controlled, but can also be influenced by reaction conditions. Julia first
systematically studied the effect of structure of both the BT-sulfone and
substrate on product distribution. These reactions can be broken down
into three distinct types: (a) R1 and R2 are saturated (see Scheme 1), (b)
the R1 is unsaturated (i.e., stabilized sulfone anion) and R2 is saturated,
and (c) R1 is saturated and R2 is unsaturated15. Reactions performed
under Barbier conditions, with THF as the solvent and LDA as the base,
showed no stereochemical bias when saturated alkyl-BT-sulfones were
6
metallated in the presence of saturated aldehydes to yield the 1,2disubstitued alkene products (Scheme 3).
nC
BT
O2
S
20
8H17CHO,
LDA, THF,
nC
-78 °C to rt
8H17
21
48%,
E:Z = 49:51
Scheme 3. Reaction type (a) exemplified15
Later studies16 revealed that some stereocontrol is achievable depending
on the reaction conditions. The solvent polarity and counter ion were, in
some instances, shown to affect the E:Z ratio of the resulting products.
For example, in the reaction between the 2-(pentylsulfonyl)benzothiazole 22 and cyclohexane carboxaldehyde, moderate trans
selectivity was observed when the solvent polarity was increased from
toluene to DME and the trend was further enhanced when the counterion
was changed from Li+ to K+ (Table 1).
SO2BT
(a) (Me2Si)2NM
(b) cC6H11CHO
22
E:Z (23)
M
Li
Na
K
23
Reaction Solvent
Toluene
Et2O
THF
DME
50:50
54:46
54:46
49:51
50:50
51:49
66:34
62:38
54:46
70:30
75:25
76:24
Table 1. Influence of counterion and solvent in the stereochemical
course of the coupling reaction
7
The geometry of the resulting alkene mixture depends on the
diastereoselectivity of the initial addition of the BT moiety to the
carbonyl compound. To gain insight into the mechanism, a series of
base-mediated elimination studies was performed on both the syn- and
anti-diastereomers of β-alkoxy-BT-sulfones17. These were made
diastereomerically pure15,17 via the base mediated opening of
stereodefined epoxides by heterocylic thiols followed by subsequent
sulfur oxidation. In cases where R and R’ bore saturated alkyl chains,
both isomers underwent antiperiplanar elimination of the electrofuge and
nucleofuge in the final step, with the syn-isomer 24 reacting much faster
and selectively producing the (Z)-olefin 25 (Scheme 4). The anti-isomer
26 produced the (E)-alkene 27 in a much slower reaction with a
diminished overall yield. Therefore, the poor E:Z selectivity in the
simple examples of the modified Julia reaction can be directly attributed
to the fact that there is little diastereocontrol during the initial addition of
the nucleophile to the aldehyde, reflecting the relative concentrations of
the syn:anti β-alkoxy-BT-sulfone intermediates present in the reaction
mixture.
8
nC
6H13
SO2BT
nC H
6 13
TBAF (10 eq), THF
nC H
6 13
OTBS
6H13
SO2BT
nC H
6 13
25
92%
TBAF (10 eq), THF
OTBS
26
Scheme
4.
6H13
0 to -18 °C, 18 h
24
nC
nC
Stereoselective
0 to -18 °C, 18 h
elimination
nC
nC
6H13
6H13
27
56%
of
β-alkoxy-BT-sulfone
intermediates
The observed stereochemical outcome, yield, and reaction rate can be
rationalized by the substituents R and R’ being in an anti-arrangement
during spirocyclization of the syn-diastereomer 34, but destabilized in
the anti-diastereomer 30 due to the substituents being forced into a
gauche/eclipsed conformation 31 (Scheme 5).
9
O
R
anti
BT
slow
R'
SO2
S
O2S
30
R
O
S
R
O2
28
R'
O
H
H
H
R'
R
-SO2
trans
32
33
H
31
destabilizing
gauche to eclipsed
interactions
O
BT
R'
-BTO-
29
R
syn
H SO
2
BTO
R'
BT
R
N
R'
SO2
fast
S
N
R
O2S
O
BTO
H
H
34
R'
R
R' SO
2
H
H
36
-BTO-
R
R'
-SO2
cis
37
35
Scheme 5. Mechanism explaining stereochemical outcome of modifiedJulia reaction
When investigating the reactions of stabilized-metallated BT-sulfones
with non-conjugated aliphatic aldehydes, it was observed that the
reactions tend to give moderate selectivity of the cis over the trans olefin
to be formed. This drift of stereocontrol was routinely noted in cases
where prenyl- or benzyl-BT-sulfones were used. Where this loss was
observed, equilibration between the hydroxysulfones was proposed to be
the cause of the erosion of selectivity. The components of the reaction
are able to add and then fragment into the resonance stabilized αmetallated sulfones 28 and the aldehyde 29 followed by the re-addition
to the more rapidly forming syn-isomer 34 of the β-alkoxy-BT-sulfone
intermediate.
10
The retroaddition/readdition pathway is therefore attained by metallated
BT-sulfones containing unsaturated substituents (type (b)). The energy
barrier for the anti-isomer 30 of the β-alkoxy-BT-sulfone intermediate to
spirocyclize is evidently higher than for the analogous process from the
syn-isomer during the Smiles rearrangement. This is presumably due to
the gauche/eclipsed interaction of the substituents R and R’ in the
spirocyclization step. As previously described, the syn-diastereomer 34
does react with an increased rate over the anti-diastereomer 30 thus
resulting in the observed product distribution. Giving further credence to
this mechanistic pathway, formation of a cross-over adduct 41 was
observed from the reaction between the metallated anti-β-hydroxybenzyl-BT-sulfone 38 with nitrobenzaldehyde 39 (Scheme 6).
CHO
NO2
OH
Ph
Ph
O2S
38
BT
O2N
39
Ph
LDA, THF
-78 °C to rt
Ph
40
40%,
E:Z = 98:2
Ph
41
60%,
E:Z = 98:2
Scheme 6. Cross-over adduct formation
While stabilized metallated sulfones have a tendency to give cis alkenes
in reactions with simple aliphatic aldehydes; the situation is more
complex in other cases. For example, the reactions of stabilizedmetallated benzyl-BT-sulfones with α-branched aliphatic aldehydes give
(E)-configurated alkenes almost exclusively.
This type of trans
11
selectivity has been observed when using more complex aldehydes
during total synthesis efforts.
The final types of reactions originally investigated by Julia (type (c))
involve the synthesis of conjugated 1,2-disubstituted alkenes from
saturated BT-sulfones and unsaturated aldehydes (Table 2). This class of
reactions is the most synthetically useful due to the high degree of (E)olefin selectivity obtained. The best stereoselectivity was observed in the
reaction between simple BT-sulfones and stabilized, electron rich
aromatic aldehydes 43, although more complex BT-sulfones also gave
rise to similar results15.
CHO
SO2BT
42
R
R
43
44
LDA, THF
-78 °C to rt
alkene
R
yield
E:Z
X
Y
Z
OMe
H
Cl
98%
68%
51%
99:1
94:6
77:23
Table 2. E-selectivity exhibited for unsaturated (aromatic) aldehydes
The first application of the modified-Julia reaction in a total synthesis
was reported in 1996 by Kocienski and co-workers18 who used it to
synthesize the triene portion of rapamycin via both type (b) and type (c)
reactions (Scheme 7). Using LiHMDS as the base to deprotonate
benzothiazolyl sulfone 46, the metallated BT-sulfone was then
12
condensed with aldehyde 45 giving a 68% yield of alkenes in a 19:1 E:Z
ratio. They also observed the substrate dependence of the reaction with
the reaction when aldehyde 48 was condensed with BT-sulfone 49,
opposite olefin geometry was preferred (Z:E = 2.4:1) in a 75% yield.
This second reaction exemplifies that stabilized BT-sulfone anions have
a preferential tendency to give (Z)-configurated products.
OTBS
S
S
O
OMe
BT
CHO
H
S
O2
45
46
M
MN(SiMe3)2, THF,
-78 °C to rt
S
S
O
E:Z
[C21-C22]
yield
47
Li
Na
68%
21%
95:5
78:22
OTBS
OMe
20
H
19
22
21
47
M
MN(SiMe3)2, THF,
-78 °C to rt
E:Z
[C19-C20]
yield
47
Li
Na
K
75%
21%
----
29:71
43:57
18:82
OTBS
S
S
O
OMe
BT
CHO
H
48
S
O2
49
Scheme 7. Substrate dependence in the synthesis of Rapamycin
Also in 1996, while performing a model study of the modified-Julia
olefination for their total synthesis of the natural product (+)-U-
13
10630519, Charette et al., carried out a series of investigations which
confirmed the importance of solvent, temperature, and counter ion on
the alkene ratio. They found that varying these parameters had a
profound effect on the resulting E:Z ratio (Table 3).
TIPSO
N
S
O2
S
52
base
50
TIPSO
O
TIPSO
H
53
51
Conditions
E:Z
NaHMDS, THF
NaHMDS, DME
NaHMDS, DMF
KHMDS, THF
KHMDS, toluene
NaHMDS, Et2O
NaHMDS, toluene
NaHMDS, CH2Cl2
1.1:1
2.4:1
3.5:1
1.2:1
1:3.7
1:7.7
1:10
1:10
Table 3. Solvent effect on E:Z ratio
The modified-Julia olefination was first described using BT-sulfones,
but has since been extended to other heteroaryl sulfones. In fact, any aryl
unit that may support a Smiles rearrangement can potentially be
employed in Julia olefination chemistry, and many other such activators
have now been investigated. Julia himself discovered that pyridine and
pyrimidine heterocyclic sulfones could also mediate the olefination15,17.
From the pyridine series, Julia was able to isolate the 2-pyridyl-βhydroxysulfone intermediates from the reaction mixtures, thus giving
more validity to the proposed mechanism. Later, Kocienski extended the
14
library of heteroarenes that were able to perform the reaction to 1isoquinolinoyl, 1-methyl-2-imiazoyl, 4-methyl-2-imidazoyl, 4-methyl-1,
2, 4-triazol-3-yl, and 1-phenyl-1H-tetrazol-5-yl16. More recently, nonheterocyclic
aromatics
have
been
used,
for
example
bis-
trifluoromethylphenyl20 and hexachlorophenyl21 to affect the modifiedJulia reaction (Figure 2).
N
N
N
N
N
N
N
N
N
N
N
S
BT
N N
N
PYR
CF3
R
PT R = Ph
F3C
BTFP
TBT R = tBu
Figure 2. Aromatic activators commonly used in the modified-Julia
reaction
Since its discovery by Julia, the modified-Julia alkenation reaction has
become one of the more commonly used tools for advanced fragment
linkage in target-directed synthesis22.
15
1.2 Stereoselective Synthesis of α,β -Unsaturated Esters
and Amides via Intermolecular Modified-Julia Olefination
In 2005, Blakemore et al., extended the modified-Julia methodology to
the synthesis of α,β-unsaturated esters23 by condensing a novel BTsulfone reagent, ethyl (benzothiazol-2-ylsulfonyl)acetate (55) with
various aldehydes. The construction of the key reagents in the study was
a two-step straightforward synthesis of the BT- (55), PT- (56), and TBT(57) sulfones from the parent heterocycle.
Act SH
54
(a) EtO2CCH2Cl (1.2 eq),
K2CO3, acetone, 56 °C, 20h
Act
(b) (NH4)6Mo7O24 (5 mol%),
aq. H2O2 (4 eq), EtOH,
0 °C to rt, 40 h
55
56
57
PhCHO (1 eq),
DBU (2eq),
CH2Cl2, rt, 16 h
O2
S
O
OEt
Act
Yield
BT
PT
TBT
71%
57%
35%
O
Ph
OEt
58
Act
Yield
BT
PT
TBT
63%
5%
0%
Scheme 8. Effect of the heterocyclic activator on the yields of α,βunsaturated esters
These reagents were then subjected to the reaction conditions previously
employed for the modified-Julia reaction (NaHMDS, THF, -78 °C to
0°C) in order to assess their ability to participate in the alkenation.
16
Unfortunately, none of the reagents reacted significantly with
benzaldehyde under these reaction conditions. The low reactivity was
not wholly unexpected because of the highly stabilized nature of the
sulfone metallate in this case. However, at elevated temperature (THF,
reflux) trans-ethyl cinnamate 58 was produced in a 62% yield (E:Z >
98:2). The PT- and TBT-sulfones produced little, if any, product when
subjected to the same conditions.
Various bases were then evaluated to perform the reaction at lower
temperatures,
with
the
researchers
settling
on
1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) and anhydrous LiCl. When
reacting under these conditions, product 58 was recovered in a 21%
yield after 20h. Removal of the LiCl from the reaction conditions
improved the yield to 45%. Once less harsh conditions were identified,
the reaction solvent was varied in order to improve yields. Attempting
to use a variety of solvents in the olefination reaction, it was observed
that the ideal medium was dichloromethane where the overall yield was
improved to 88% at 23 °C with DBU as the base (E:Z = 96:4).
Ethyl (benzothiazol-2-ylsulfonyl)acetate (55) was then deprotonated
with DBU in the presence of a number of aldehydes, most giving good
to moderate yields under the optimized conditions (Table 3). When the
BT-sufone 55 was subjected to the reaction conditions and subsequently
aryl aldehydes were added to the mixture, the expected (E)-olefin was
17
preferentially produced when these stabilized aldehydes were used. This
was especially the case when electron deficient aldehydes were used.
The trans stereoselectivity was shown to erode when electron rich aryl
aldehyde substrates were incorporated. The stereoselectivity was
completely reversed when non-stabilized aliphatic aldehydes were
condensed with the key reagent thus selectively producing the (Z)-alkene
geometry. This type of selectivity was expected on the basis of earlier
studies with stabilized sulfone anions (i.e., type (b) reactions, see above).
BT
O2
S
O
O
OEt
55 (2 eq)
H
R
O
DBU (2 eq)
CH2Cl2, rt, 16h
R
59
Aldehyde
4-(NO2)C6H4CHO
2,6-Cl2C6H3CHO
4-(MeO)C6H4CHO
nC H CHO
5 11
Citronellal
OEt
60
Yield (%)
E:Z
89%
83%
93%
41%
64%
>98:2
>98:2
92:8
19:81
30:70
Table 3. Aldehyde substituent effect on stereoselectivity of alkene
geometry
1.3 Recent Applications of the Modified-Julia Olefination
Since the last major review24, the modified-Julia olefination has been
used to access a diverse array of alkenyl functional groups. Of these,
some of the more interesting examples include the synthesis of
fluorinated alkene derivatives25,26. These have been shown to be useful
building blocks for the synthesis of biologically active compounds,
18
selective enzyme inhibitors, and pharmaceutical precursors27. Zajc et al.
showed that vinyl fluorides could be prepared by condensation of a
metallated α-fluoro-BT-sulfone with an appropriate aldehyde or
ketone25. They found that they could affect the stereochemical outcome
of the reaction by varying the reaction conditions. The yields from alkyl,
aryl, and allyl aldehydes were all excellent (87-100%) as were the yields
of substrates with ketone functionalities. Again, it was found that the
stereochemical outcome was affected by varying the reaction conditions
(Scheme 9).
(E : Z = 1 : 11.9)
F
LiHMDS,
O2
S
N
S
61
Ph
DMF-DMPU
(1:1), -78 °C
Ph
63
F
CHO
62
Ph
LiHMDS,
F
THF, -78 °C
(E : Z = 2.2 : 1)
64
Scheme 9. Stereoselective synthesis of fluorinated olefins
In a natural extension of the aforementioned experiments26, Lequeux et
al. were able to synthesize flouroalkenoates 66 and 67 stereoselectively
from the fluoroalkyl-BT-sulfones 65 and the corresponding aldehyde
(Scheme 10). They observed that the olefin geometry was highly
affected by the reaction conditions, including base, temperature, and
additives. The olefination was observed to be most selective with DBU
as the base at -78 to 20 °C over 2 h.
19
F
CO2Et
DBU
H
O2S
N
S
CO2Et
R
RCHO
F
DBU,
65
F
MgBr2
R
CO2Et
H
yield
Z:E
Ph-
none
MgBr2
72%
71%
44:56
92:8
nC
none
MgBr2
57%
87%
31:69
88:12
8H17-
(Z)
67
additive
R
(E)
66
Scheme 10. Additive effect of MgBr2 on alkene geometry
Another more recent application28 using BT-sulfones in the modifiedJulia olefination is the synthesis of enol ethers 70 from lactones 69
constructing tri- and tetrasubstituted exogycals (Scheme 11).
O2S R1
O
N
S
n
O
OR
68
69
LiHMDS, -78 °C,
then DBU
(28-77%),
E-selective
R2
O
n
3
OR R
70
Scheme 11. Synthesis of substituted exoglycals using the modified-Julia
reaction
This reaction is unique in that it is necessary to use DBU as an additive
to promote the elimination from the hemiacetal arising from the
condensation 68 and 69.
20
Vinyl ethers are another functional group easily accessed by the
modified-Julia alkenation29. In 2003, Berthelette et al. accessed these
substrates that are useful in reactions such as Diels-Alder30, Claisen
rearrangements31,
and
aldehyde
homologations32.
The
reaction
conditions are significantly more mild than conventional vinyl ether
syntheses. Both aldehydes and ketones are substrates that can be easily
used in the reaction (Scheme 12). The one limitation of this current
methodology is that the stereoselectivity of the reaction is extremely
poor with the ratio of E:Z isomers usually being approximately equal in
all examples.
O2
S
N
O
S
LiHMDS,
O
R1
R2
R3
THF, -78 °C
45-90%
72
O
R2
R1
R3
R1, R2 = aryl, alkyl
R3 = aryl, akyl, benzyl
73
71
Scheme 12. Synthesis of vinyl ethers with the modified-Julia reaction
α,β-Unsaturated
N-methoxy-N-methyl
amides
have
also
been
synthesized with similar methodology33. In 2006, Manjunath et al.
synthesized a number of these α,β-unsaturated Weinreb amides34 from
the corresponding aldehydes and the BT-sulfone 74 using NaH in THF
(Scheme 13).
21
O2
S
N
S
74
O
N
O
O
NaH, THF,
RCHO
44-72%
R
R = aryl, alkyl, sugar
N
O
75
Scheme 13. Synthesis of α,β-unsaturated Weinreb amides from BTsulfones
Aïssa published an interesting report35 on improved conditions for use of
the modified-Julia olefination to perform the methylenation of aldehydes
and ketones. In this series of experiments, TBT-sulfones 76 were used
exclusively to execute the synthesis. Under two different protocols,
Barbier-type conditions were employed using (a) NaHMDS at -78 °C, or
(b) Cs2CO3 at 70 °C in THF, to return good to excellent yields when
using one or the other of the new methodologies. During this notable
work, the first examples of intramolecular modified-Julia olefination
were achieved (Scheme 14). Aïssa shows three examples of this cyclic
variant with a BT-sulfone-ω-aldehyde 76 as the substrate and 1,4dioxane as the solvent. The best results were observed when the
substrates were added over 15 h by slow-addition syringe pump to a
dioxane/DMF solvent mixture at 100 °C. The modest yields encountered
when working with the larger rings, Aïssa claims, are an entropy issue
counteracting their formation due to the fact no inherently favorable
conformation effect is established in the architecture of the substrates.
22
EtO2C
N
N
O2
S
CO2Et
Cs2CO3,
n
O
EtO2C
dioxane/DMF,
100 °C
N N
CO2Et
n
76
n
yield
1
2
8
91%
32%
56%
(E : Z)
0 : 100
1:1
2:1
77
Scheme 14. First published example of an intramolecular modified-Julia
reaction
1.4 Overview of Projected Study
Cognizant of the widespread occurrence of α,β-unsaturated lactones 81
in a variety of bioactive natural product molecules, and the growing
scope of the modified-Julia reaction, we elected to study an
intramolecular variant of the process directed at this important class of
ester. Requisite ω-sulfonyl carboxaldehydes 80 for the projected study
were envisioned to arise from ω-alkenyl alcohols 79 and sulfonyl acid
78 via esterification and ozonolysis reactions (Scheme 15).
N
HO
O
O2
S
OH
n
79
O2
S
N
S
O
O
S
80
78
base
O
yield?
stereochemistry?
intramolecular
Julia-olefination
O
n
81
Scheme 15. Schematic representation of proposed study
CHO
n
23
The study was divided into three phases. The first phase consisted of the
development of an efficient synthesis of the “lynch-pin” sulfonyl acid
78. This was followed by the study of the esterification reactions from
78, and finally the in situ generation of ω-sulfonyl carboxaldehydes 80
and
subsequent
olefination.
investigation
of
intramolecular
modified-Julia
24
2. Synthesis of (Benzothiazol-2-sulfonyl)acetates
The three routes which were proposed to be investigated that could lead
to the target compounds, BT-sulfonyl acetates, are (a) the thermal
transesterification of 55 using excess alcohol as the solvent; (b) the
carbodiimide coupling reaction of sulfide acid 89 and various ω-alkenyl
carbinols; and (c) the synthesis of (benzothiazol-2-sulfonyl)acetic acid36
(78) and the subsequent coupling of the various ω-alkenyl carbinols with
this reagent. All of the paths were pursued in the course of this research.
2.1 Initial Routes to Proposed (Benzothiazol-2-sulfonyl)acetate Intermediates
Commencing with the condensation of 2-mercaptobenzothiazole (81)
with ethyl chloroacetate (82) under mild basic conditions, this
straightforward reaction produced the resulting ester 83 in a quantitative
yield. An alternate synthetic route was pursued by reacting 81 with
methyl bromoacetate (84) under the same conditions giving ester 85 in a
quantitative yield (Scheme 16).
25
O
Cl
N
SH
S
O
Br
N
SH
81
O
84
OMe
K2CO3, acetone,
56 °C, 19h,
100%
S
N
OEt
S
K2CO3, acetone,
56 °C, 19h,
100%
81
S
82
OEt
83
O
S
N
OMe
S
85
Scheme 16. Alkylation of 2-mercaptobenzothiazole
Base promoted thermal transesterification of the ethyl ester 86 with ωunsaturated straight-chain primary alcohols was then examined (Scheme
17). The reaction conditions for this protocol, though they give the
desired ester, were deemed inefficient and inappropriate for potential
future applications using complex alcohol substrates. This was due to a
number of drawbacks to the transesterification protocol. First, the ωunsaturated alcohol 87 was used as the solvent in a 3 equivalent excess.
Since the alcohol in the reaction will usually be the more advanced
intermediate, using it as the solvent is not advantageous. Also, the
reaction conditions are relatively harsh because of the high temperatures;
many advanced interemediates may not be able to withstand the media.
Finally, only primary alcohols were shown to be able to effect efficient
transesterification. All attempts to perform the reaction with 2° or 3°
alcohols failed. Due to these obvious detriments a new pathway to arrive
at the desired esters was explored.
26
HO
O
S
N
O
87 (3 eq)
OEt
K2CO3, neat, 50 °C, 21 h
65%
S
83
S
N
O
S
88
Scheme 17. Thermodynamic transesterification of BT-sulfide
Proceeding with the knowledge of how to synthesize ethyl
(benzothiazole-2-sulfonyl)acetate (55), the key reagent in the synthesis
of α,β-unsaturated esters from previous work23, the oxidation of 83 was
carried out giving exclusively the oxidized BT-sulfonyl ester 55 in
quantitative yield (Scheme 18).
O2
S
N
O
OH
S
78
1.2 M NaOH,
MeOH, 0 °C to rt
O
S
N
(NH4)6Mo7O24·4H2O
OEt
S
O2
S
N
H2O2 EtOH, 0 °C to rt, 40 h,
100%
55
1.2 M NaOH,
MeOH, 0 °C to rt
90%
1.2 M NaOH, 0 °C to rt
100%
MeOH,
O
S
O
OH
O
N
DCC, DCM,
0 °C, 5 min
S
OEt
S
83
N
O
N
S
S
89
S
90
91
Scheme 18. Attempts to prepare lynchpin reagent 78 from ester 83
27
Unfortunately, attempts to saponify ester 55 failed due to the highly
electrophilic nature of the BT-sulfonyl portion of the molecule. The only
observable product was 2-methoxy-benzothiazole (90); the result of ipso
substitution of a sulfinate nucleofuge, and the desired acid 78 was not an
observed product (NMR).
In lieu of these problems with the synthesis of the acid, another route
was investigated. Starting now from the esters 83 and 85, subjection to
hydrolysis conditions, 1.2 M NaOH in MeOH/H2O mixture, gave the
expected thioether acid 89 as a light yellow powder after the
saponification.
In an attempt to employ existing procedures for ester synthesis, 88 was
then subjected to dicyclohexylcarbodiimide (DCC)37 and the desired
coupling partner alcohol. All attempts to prepare esters from acid 88
were unsuccessful, however, due to the formation of an insoluble purple
pigment upon treatment with DCC. We believe that betaine 91 is the
pigment generated in these experiments. The formation of related
compounds from similar heterocyclic heterocyclic starting materials has
been reported48.
The likely mechanism of formation of the undesired product is
illustrated in scheme 19. The increased electrophilicity of the carbonyl
28
moiety through activation of the acid by DCC induces the facile
nucleophilic attack of N-atom of the heterocyle, thus allowing the
intramolecular self-condensation product consisting of the undesired
purple dye to be the only one observed.
O
S
N
O
H
S
N
·
O
N
N
H
N
O
O
N
O O
S
N
S
95
96
H
S
S
97
S
N
S
N
94
93
HN
O
N · N
O
S
92
89
H
S
N
O
H
N
N
O
98
S
N
S
91
H
N
H
N
O
98
Scheme 19. Mechanism for the formation of purple betaine pigment 91
2.2 Synthesis of (Benzothiazol-2-sulfonyl) acetic acid
Since ester formation from BT-thioether acid 89 was problematic, and
we wanted to avoid a transesterification route to substrates of interest we
elected to synthesize sulfonyl acid 78. Saponification product 89 was
29
subjected to the typical sulfide oxidation conditions, MoVI and H2O2 in
EtOH24, followed by a sodium bisulfite reductive-work up to afford the
desired acid 78 in a 57% yield with the only by-product being the BTmethyl sulfone 99 formed in a 33% yield (Scheme 20).
O
S
N
S
89
(NH4)6Mo7O24·4H2O
OH
H2O2 EtOH, 0 °C to rt, 17 h,
then Na2SO3
O2
S
N
O
S
OH
O2
S
N
S
78
57%
99
33%
Scheme 20. Synthesis of key reagent 78 by oxidation of thioether 88
The acid was found to be shelf stable at ambient temperature over
months and stable under vacuum for 4 weeks. An interesting property of
78 is exhibited when dissolved into solvents with a high dielectric
constant (ie. acetone, DMSO) (Scheme 21). The acid will spontaneously
undergo facile decarboxylation to give 99 in a quantitative yield. The
more polar the solvent, the faster the rate of decarboxylation. When
followed by NMR analysis it takes 66 min for a 10 mg sample to fully
decompose in dimethylsulfoxide and 22 h to fully decarboxylate when
dissolved into acetone. This phenomenon is probably due to
intramolecular deprotonation that could occur through a malonate-like
cyclic transition state where one of the heteroatoms is the base for the
acidic proton.
30
O2
S
N
O
DMSO or Acteone
OH
S
O2
S
N
S
(– CO2), 100%
78
99
Scheme 21. Facile decarboxylation of the lynchpin reagent in high
dielectric constant solvents
2.3 DCC Coupling of (Benzothiazol-2-sulfonyl) acetic acid
with ω -Alkenyl Carbinols
The synthesis of the BT-esters was a straightforward process using
known methods to construct esters (Scheme 22). Although it was the
first time DCC was used to create BT-esters, the methodology for DCC
ester synthesis37 has been well documented on other substrates.
O2
S
N
O
OH
DCC, CH2Cl2
HO
n
S
78
79
rt, 15 h
O2
S
N
O
O
n
S
100
Scheme 22. General scheme for ester formation
2.4 Direct Synthesis of ω -Alkenyl Carbinols
The multi-step synthesis of the various ω-alkenyl carbinols initiated the
construction of the BT-esters. The ω-alkenyl alcohols were synthesized
31
from readily available starting materials using previously reported
methods.
1-Phenyl-2-buten-1-ol (102) was produced in a one-step synthesis
reacting via the addition of the Grignard reagent derived from allyl
bromide (101) to benzaldehyde in excellent yield38.
Br
101
Mg, Et2O,
then PhCHO,
99%
OH
102
Scheme 23. Grignard reaction for synthesis of 2° aryl alcohol
4-Penten-1-ol (107) was assembled through a three-step procedure of
known chemistry from dimethyl malonate (103) (Scheme 24). The
malonate was deprotonated by the action of NaH39 and then to the
resulting anion was added the electrophilic allyl bromide 101 making
olefin 104. The resulting alkene was then subjected to modified-Krapcho
conditions40 thereby dealkoxycarboxylating the malonate to form 105 ωalkenyl methyl ester 106 in a moderate yield. The ester was then reduced
to the desired pentenol 107 by the action of LiAlH4 in excellent yield.
32
O
NaH, THF
0° C to rt, 30 min;
O
O
O
O
O
Br
101
THF, reflux, 15 h
93%
103
O
NaCl, H2O,
O
104
DMSO, reflux,
62%
LiAlH4,
O
105
O
OH
THF, reflux,
94%
107
Scheme 24. Pentenol 107 synthesis from dimethyl malonate 103
10-Undecen-1-ol (109) was constructed quantitatively from the acid 108
by standard reducing conditions using LiAlH4 in diethyl ether41 (Scheme
25).
LiAlH4, Et2O,
O
100 %
HO
108
HO
109
Scheme 25. Reduction of undecenoic acid
Alkenyl ether 113 was assembled via a two-step process starting from
the commercially available 9-decen-1-ol 110. Proceeding through the
alkyl iodide intermediate 111 by the PPh3/imidazole42 substitution
reaction exchanging the hydroxyl group for iodine. This was
subsequently subjected to Williamson ether synthesis43 conditions with
hexadiol 112 and gave an overall yield from the two steps at 31%
(Scheme 26).
33
PPh3,
OH
110
I
I2
111
OH
112
HO
OH
O
NaH, DMF,
31%
113
Scheme 26. Synthesis of ethereal alcohol 113
2.5 Synthesis of (Benzothiazol-2-sulfonyl)acetate Esters
using DCC coupling
Sulfonyl acid 78 proved amenable to standard carbodiimide mediated
esterification and a variety of simple ω-alkenyl sulfonyl esters 100 were
readily prepared from ω-alkenyl carbinols (Scheme 27). The initial
substrate used in the DCC esterification for a proof of concept was the
commercially available 10-decen-1-ol 87. After performing this step
under standard conditions, it was discovered that the reaction gave an
excellent 97% yield and the excess acid was easily removed using a
NaHCO3 wash.
O2
S
N
S
78
O
HO
OH
87
DCC, DCM,
0 °C to rt, 16 h
97%
O2
S
N
O
O
S
Scheme 27. Initial ester formation through DCC coupling
114
34
This methodology was then extended using the aforementioned ωalkenyl alcohols. All proceeded with moderate to excellent yields under
similar conditions depending on the nature of the alcohol (Figure 3).
O
O2
S
N
DCC, CH2Cl2
HO
OH
O2
S
N
n
100
O
O2
S
N
O
S
O
O
S
115
67%
O2
S
N
O
rt, 15 h
79
78
O
S
n
S
O2
S
N
116
60%
O
O2
S
N
O
S
O
O
S
117
100%
114
93%
O2
S
N
O
O
O
S
118
94%
Figure 3. Readily synthesized esters from DCC coupling
The nature of the alcohol played a major role in the efficiency of ester
formation. Primary alcohols were easily esterified through the
carbodiimide procedure, whereas 2° and 3° alcohols gave much lower
yields in relation to their 1° analogues. All of the esters proved to be
extremely shelf-stable and readily available masked aldehyde substrates
for use in the intramolecular synthesis of α,β-unsaturated lactones.
35
3. α,β -Unsaturated Lactone Formation
The synthesis of the desired lactone products was envisioned to proceed
through a two-step process commencing with ozonolysis45 of the
requisite ω-alkenyl sulfonyl esters and then subsequent subjection to the
previously employed reaction conditions for the intermolecular
modified-Julia variant (Scheme 28).
O2
S
N
O
O
n
O3, CH2Cl2:MeOH, 15 min
then
O2
S
N
S
O
O
CHO
n
S
DMS, –78 °C to rt, 16h
80
100
DBU, CH2Cl2,
O
O
–78 °C to rt, 15 h,
n
81
Scheme 28. General two-step ozonolysis/lactonization protocol
3.1 Ozonolysis of ω -Alkenyl Sulfonyl Esters
The ozonolysis reactions applied in this study were the first to be
successfully demonstrated on BT-sulfone containing compounds 100.
Initially, it was believed that the heterocycle might not be able to
withstand the harsh conditions of the ozonolysis. Fortuitously, the
aromatic benzothaizole was found to be unaffected by the typically
36
severe action of ozone in any appreciable amount. The use of simple ωalkenyl sulfonyl esters 100 gave the expected aldehydes 80 in pure form
when subjected to typical ozonolysis conditions with CH2Cl2 as the
common solvent for such reactions. In contrast, when the solvent was
changed to a mixture of CH2Cl2:MeOH (4:1)46, conditions used to avoid
the formation of ozonides and proceeding instead via more easily
reduced α-alkoxy hydroperoxides, the longer chain esters continued to
return the expected aldehyde products, whereas the shorter chain esters
gave methyl acetals exclusively (Scheme 29). When the long chain ωalkenyl sulfonyl esters were subjected to a straight CH2Cl2 medium, the
yields and purification were largely unaffected.
O3, CH2Cl2:MeOH,
40 min,
O2
S
N
then DMS,
–78 °C to rt, 19 h
72%
O
O2
S
N
O
O
O
O
S
119
O
S
115
O3, CH2Cl2,
10 min,
then DMS,
–78 °C to rt, 12 h
59%
O2
S
N
O
O
O
S
120
Scheme 29. Differences in product distribution due to solvent effects
Conditions for the reduction of the ozonide were also investigated
during the course of this research. Both dimethyl sulfide (DMS) and
triphenylphosphine were able to effect the reductive-work up of the
37
trioxolane intermediates equally well, but both reductants had their
drawbacks (Scheme 30). Triphenylphosphine was the faster of the two at
reducing the ozonide, but it was necessary to remove the resulting
triphenylphosphine oxide from the product mixture by column
chromatography.
DMS or PPh3,
O O
O
R
DCM, -78 to rt
121
O
H
R
122
Scheme 30. Reduction of ozonide
DMS, alternatively, was less rapid in reducing the trioxolane
intermediate at 19 hours. Nevertheless, DMS proved to be the ideal
reductant due to the ease of removal of the dimethylsulfoxide (DMSO)
byproduct. Simple evaporation of the excess DMS and the subsequent
washing of its oxidation product DMSO out with excess H2O proved to
be enough to eliminate all extraneous compounds from the mixture save
the desired aldehydes. The DMS reductive-work up conditions also
proved efficient by affording us the opportunity to immediately subject
the labile aldehyde substrate to the cyclization conditions without the
need for chromatography. This was ideal since it had previously been
observed that the carboxaldehyde products would decompose readily on
silica gel even during flash chromatographic methods.
38
During the developmental stages of the ozonolysis reaction, we
considered it a likely possibility that the oxidation conditions may
promote the subsequent alkenation due to the basicity of the reaction
medium. Unfortunately, the desired cyclic lactone products were never
observed by NMR or isolated through chromatographic methods.
3.2 Modified-Julia Reacton of ω -Carboxaldehyde Sulfonyl
Esters
Due to the facile and time dependent decomposition of the ωcarboxaldehyde sulfonyl esters 100 that were produced in the previous
ozonolysis step, it was decided that the crude products should be
immediately subjected to the base mediated cyclization without
purification. The reaction conditions used to effect the alkenation were
similar to those previously employed for intermolecular modified-Julia
olefination
reactions23:
the
relatively
innocuous
base
1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) in CH2Cl2. A variety of ring
sizes were formed in the course of this research. The synthesis of small,
medium, and large α,β-unsaturated lactones 81 each presented their own
problems.
ω-Carboxaldehyde sulfonyl ester 123 was the substrate used for the
synthesis of the 7-member lactone 124 (Scheme 31). When subjected to
the reaction conditions, the small ring was able to close, but it was
39
found, as was expected that the only lactone product that was formed
was the (Z)-isomer 124. Though the stereoselectivity of the reaction is
predicted by the fact that the both the BT-moiety 28 and the aldehyde 29
are unstabilized15, the more compelling argument for the selective nature
of the reaction is due the impossibility of accommodating a trans olefin
into a 7-membered ring. Interestingly, a byproduct isolated in small
amounts was the aldol condensation product 125. This is most likely due
to the fact that the nucleofuge and electrofuge must be in an
antiperiplanar arrangement in order to properly eliminate. Due to the
small ring size, the resulting steric demands disallow the anti-β-alkoxyBT-sulfone 30 intermediate the ability to rotate into the necessary
antiperiplanar conformation that would enable the elimination reaction
to occur. Therefore, the intermediate that would have necessarily led to
the trans-isomer gives instead the resulting aldol product 125.
O2
S
N
O
O
O
O
S
O
DBU (2eq), CH2Cl2,
[7]
O2
S
N
S
-78 to rt, 15h
O
O
[7]
123
124
31%
E:Z = 0:100
125
4%
Scheme 31. 7-membered lactone formation
The next series of products obtained were of the medium/large sized 12membered α,β-unsaturated lactone and its aldol product (Scheme 32).
These were derived from ester 116. This lactone had no predisposed
40
tendency due to steric constraints of ring size to preferentially afford
either of the stereoisomers. Even with this stipulation, the medium size
ring was observed to return the expected product distribution by giving
the (Z)-isomer 37 in an 11:89 ratio, which falls in line with the
previously observed results that type (b)15 intermolecular modified-Julia
reactions afford cis-alkene stereoselectively. Separating and identifying
the pair of olefin isomers, indicating where the alkene protons lay, and
subsequent analysis of the integration values presented in the crude
NMR determined the cis:trans ratio. Also of note was the unexpected
formation of the aldol product 128. In this case ring size was not a factor
in its formation, but it was observed in a diminished ratio as compared to
the 7-membered analogue.
O
O2
S
N
S
O
O
O
O
126
DBU (2eq), CH2Cl2,
O2
S
N
[12]
S
O
O
[12]
-78 to rt, 15h
127
44%
E:Z = 11:89
128
2%
Scheme 32. 12-membered α,β-unsaturated lactone formation
The stereoselectivity of 13-membered α,β-unsaturated lactone 130
formation was observed to be similar olefin ratio to the 12-membered
situation. The product yield was not determined exactly because of
isolation difficulty: the lactone 130 has a tendency to streak through the
41
entirety of the column. The (E:Z) ratio was once again determined by the
integration values of the alkene protons found in the crude NMR.
O
N
O
O
O2
S
N
S
O2
S
S
[13]
DBU (2eq), CH2Cl2,
O
O
O
O
[13]
-78 to rt, 15h
129
130
~45%
E:Z = 17:83
131
0%
Scheme 33. 13-membered α,β-unsaturated lactone formation
The large ring size 19-membered ethereal analogue of the reaction also
went as expected affording the (Z)-isomer 37 from the unstabilized
nature of both the aldehyde and BT-sulfone R groups. None of the aldol
product was observed.
O2
S
N
O
O
O
O
S
DBU (2eq), CH2Cl2,
-78 to rt, 15h
132
O
O2
S
N
O
O
O
S
[19]
[19]
O
O
133
40%
E:Z = 15:85
134
0%
Scheme 34. 19-membered ethereal α,β-unsaturated lactone formation
42
The whole of these examples indicate that the modified-Julia reaction is
able to occur on even the simplest substrates that have no tendency to
entropically cyclize on their own (ie. Thorpe-Ingold effect47) thus adding
to the generality of the method developed.
The final substrate attempted was the substituted ω-carboxaldehyde
sulfonyl ester 135. The product exclusively formed was found to be
trans-cinnamaldehyde 137. This is probably due to facile elimination
following the deprotonation of the methylene group and promoted by the
added stabilization afforded to the structure by the phenyl substituent. It
is of note to recall that the reaction conditions for the lactone formation
are of the most mild that could be encountered, yet none of the 6membered lactone 136 was isolated through chromatography or
observed by spectroscopic analysis.
O2
S
N
S
O
O
O
DBU (2eq), CH2Cl2,
[6]
Ph
-78 to rt, 15h
O
136
0%
135
O
O
H
Ph
137
36%
Scheme 35. Elimination of labile substrate
A variety of other bases were investigated in the process of determining
the ideal reaction conditions, but all proved to be ineffectual in
promoting
the
desired
cyclization.
Other
solvents
besides
dichloromethane were also examined in the course of the research, but
43
again, all gave low product yields in intractable mixtures. Nevertheless,
it was noted that the alkene ratio (E:Z) was consistent with the results
arising from the use of CH2Cl2 as the solvent.
As expected, the varying chain lengths of the ω-carboxaldehyde sulfonyl
esters 100 gave differing results based on the lactone ring size produced,
but most returned modest yields of the expected (Z)-α,β-unsaturated
lactone products 81. Besides the predicted outcomes of modified-Julia
olefinations, cyclic adducts resulting from simple aldol condensation
products were commonly also obtained. Significantly, when isomeric
olefins were allowed by ring size, (Z)-configurated cyclic Julia products
37 predominated, presumably due to the type (b) reaction with
unstabilized substrates. The generality of this method was also shown
due to the nature of the starting materials, which contained no activating
group yet still contained the ability to cyclize to the desired (Z)-lactone.
Base labile substrates proved to be a liability to the universality of the
reaction conditions. It was hypothesized that any 6-membered ring will
not form, but instead will readily eliminate due to the entropic tendency
to release SO2, CO2, benzothiazole and the conjugated aldehyde even in
conditions as mild as those presented with DBU as a relatively weak
base.
44
4. Conclusion
Our results suggest that the modified-Julia reaction is an effective
process for the synthesis of α,β-unsaturated lactones 81, but perhaps less
efficient that the comparable Horner-Wadsworth-Emmons4 based
approaches. In the examples studied, the cyclical nature of the initial βalkoxysulfone intermediates (30, 34) no doubt hindered spirocyclization
(and the ensuing Smiles rearrangement14). Subsequent SO2 elimination,
which usually requires an antiperiplanar arrangement of electrofugal and
nucleofugal groups, would also be less effective (or otherwise
impossible) from certain cyclic intermediates. Presumably, synthetic
fragments leading to natural product molecules will have substituents to
induce them to cyclize even more readily then the unsubstituted
analogues, thereby the yields may well be observed to be higher when
compared to those presented in this thesis.
Interestingly, the examples described by Aïssa35 recently demonstrated
successful intramolecular Julia alkenation under reaction conditions
employing Cs2CO3 to facilitate the reaction.
45
5. Experimental
Laboratory notebook reference: HG-183
O
S
N
O
S
83
C11H11NO2S2
(253.34)
(NH4)6Mo7O24·4H2O (20 mol %),
30% H2O2, EtOH, 0 °C to rt, 40 h
O2
S
N
O
O
S
55
C11H11NO4S2
(285.34)
Ethyl (benzothiazol-2-ylsulfonyl)acetate: To a stirred solution of ethyl
(1,3-benzothiazol-ylthio)acetic acid (5.0 g, 19.8 mmol) in ethanol (260
mL) at rt and solid was allowed to dissolve. To the solution was added
(NH4)6Mo7O24·4H2O (4.4 g, 3.56 mmol) and suspension was cooled to 0
°C. To the reaction mixture was added 30% aq H2O2 (40 mL, 3.55 mol)
in 10 mL portions over 1 min. Reaction was allowed to warm to rt and
stir for 40 h. Suspension was filtered by vacuum and the filtrate was
concentrated in vacuo to afford pink-white solid (5.61 g, 19.8 mmol,
100%): mp = 53-55 °C. Purity of the sample was confirmed by 1H
NMR.
IR (neat) 2989, 1742, 1471, 1342, 1153, 761 cm-1; 1H NMR (300MHz,
CDCl3) δ 8.23 (1H, dd, J = 7.2, 1.8 Hz), 8.03 (1H, td, J = 7.0, 1.9 Hz),
7.63 (2H, td, J = 7.2, 1.5 Hz), 4.56 (2H, s), 4.17 (2H, q, 7.2 Hz), 1.17
(3H, t, 7.2 Hz) ppm; 13C NMR (75 MHz, CDCl3) δ 164.9 (0), 161.6 (0),
46
152.3 (0), 136.9 (0), 128.3 (1), 127.8 (1), 125.4 (1), 122.4 (1), 62.7 (2),
58.8 (2), 13.8 (3) ppm.
Reference:
1) Blakemore, P. R.; Ho, D. K. H.; Nap, W. M. Org. Biomol. Chem.
2005, 3, 1365-8.
Laboratory notebook reference: HG-196
O
S
N
S
OH
(NH4)6Mo7O24·4H2O (0.10 eq),
O2
S
N
O
OH
S
30% aq. H2O2, EtOH,
0 °C to rt, 17 h
89
C9H7NO2S2
(225.29)
78
C9H7NO4S2
(257.29)
(Benzothiazole-2-sulfonyl)acetic acid: To a stirred solution of
(benzothiazol-2-ylsulfanyl)acetic acid (20.0 g, 88.8 mmol) in EtOH (800
mL) at 0 °C was added ammonium molybdate (11.16 g, 9.03 mmol)
solid and allowed for stir for 5min. To the suspension was added 30%
aq. H2O2 (60 mL, 5.33 mol) in 10 mL portions over 1 min. Reaction was
then allowed to warm to room temperature while stirring for 17 h.
Reaction mixture was then cooled to 0 °C and solid was filtered by
vacuum. **Caution: oxidants present. Saturated Na2SO3 solution at 0 °C
was added until oxidants not present. Solution changed color from
yellow to blue while standing. Removed the precipitate formed in the
47
reduction step by vacuum filtration. The pH of the reaction mixture was
1. Suspension was next extracted 5x using CHCl3, organic layers were
then combined and washed with brine until aqueous phase was colorless.
Organic layer was then dried over Na2SO4, and concentrated in vacuo
while not allowing the bath to rise above room temperature to afford the
white solid: mp 131-133 °C (13.0 g, 50.5 mmol, 59%). **1H NMR
indicated that 5% was methyl-benzothiazole sulfone.
IR (KBr) 3410 (br), 2994, 2933, 1725, 1471, 1338, 1166, 1101, 766; 1H
NMR (400 MHz, d6-acetone) δ 8.31 (1H, dd, J = 7.1, 1.5 Hz), 8.24 (1H,
d, J = 7.4 Hz), 7.75 (1H, td, J = 7.2, 1.3 Hz), 7.71 (1H, td, J = 7.2, 1.3
Hz), 4.81 (2H, s) ppm; 13C NMR (75 MHz, d6-acetone) 167.0 (0), 163.4
(0), 153.4 (0), 137.7 (0), 129.1 (1), 128.7 (1), 125.9 (1), 123.9 (1), 59.2
(2) ppm.
Reference:
Naya, A.; Kobayashi, K.; Ishikawa, M.; Ohwaki, K.; Saeki, T.; Noguchi,
K.; Ohtake, N. Chem. Pharm. Bull. 2003, 51, 697-701.
48
Laboratory notebook reference: HG-181
O
K2CO3 (1.2 eq),
N
SH
O
S
Cl
81
C7H5NS2
(167.25)
(1.2 eq)
OEt 82
acetone, 56 °C, 18 h
S
N
O
S
83
C11H11NO2S2
(253.34)
Ethyl (1,3-benzothiazol-2-ylthio)acetate: To a stirred solution of 2mercaptobenzothiazole (80.0 g, 0.478 mol) in acetone (1200 mL) at rt
was added K2CO3 (79.6 g, 0.576 mol) all at once. The solution changed
color from light to dark orange when solid was added. Suspension was
allowed to stir for 15 min at rt. The suspension was then cooled to 0 °C
and to this was added ethylchloroacetate (17.7 g, 54 mL, 0.144 mol) all
at once. The vessel was then fitted with a condenser and set to reflux at
56 °C for 20 h. Solution color changed to yellow with a white precipitate
formed.
Reaction mixture was filtered by vacuum and filtrate was
concentrated in vacuo to afford (121.2 g, 0.478 mol, 100%) of orange
solid. A portion of the product was further purified by recrystallization
using EtOAc to yield the purified ketone as an orange solid: mp 37-40
°C. Purity of the sample was confirmed by 1H NMR.
IR (neat) 2984, 1738, 1462, 1428, 1299, 1157, 1002, 753 cm-1; 1H NMR
(300MHz, CDCl3) δ 7.87 (1H, d, J = 8.1 Hz), 7.77 (1H, d, J = 8.0 Hz),
7.44 (1H, td, J = 7.2, 1.1 Hz), 7.32 (1H, td, J = 7.3, 1.0 Hz), 4.27 (2H, q,
7.1 Hz), 4.19 (2H, s), 1.31 (3H, t, 7.1 Hz) ppm;
13
C NMR (75 MHz,
49
CDCl3) δ 168.4 (0), 164.9 (0), 153.0 (0), 135.6 (0), 126.2 (1), 124.6 (1),
121.8 (1), 121.2 (1), 63.2 (2), 35.3 (2), 14.3 (3) ppm.
Laboratory notebook reference: HG-221
O
K2CO3 (1.2 eq),
N
SH
O
S
Br
81
C7H5NS2
(167.25)
O
S
(1.2 eq)
OMe 84
acetone, 56 °C, 18 h
S
N
85
C10H8NO2S2
(239.31)
Methyl (1,3-benzothiazol-2-ylthio)acetate: To a stirred solution of 2mercaptobenzothiazole (20.0 g, 0.120 mol) in acetone (500 mL) at rt
was added K2CO3 (19.9 g, 0.144 mol) all at once. The solution changed
color from light to dark orange when solid was added. Suspension was
allowed to stir for 15 min at rt. The suspension was then cooled to 0 °C
and to this was added methylbromoacetate (22.0 g, 0.144 mol) all at
once. The vessel was then fitted with a condenser and set to reflux at 56
°C for 18 h. Solution color changed to yellow with a white precipitate
formed.
Reaction mixture was filtered by vacuum and filtrate was
concentrated in vacuo to afford 37.35 g of orange solid. The product was
further purified by recrystallization using EtOAc to yield the purified
thioether (28.48 g, 0.119 mol, 100%) as a off-white solid: mp 70-72 °C.
Purity of the sample was confirmed by 1H NMR.
50
1
H NMR (300MHz, CDCl3) δ 7.86 (1H, d, J = 8.1 Hz), 7.76 (1H, dd, J =
8.0, 0.6 Hz), 7.41 (1H, td, J = 7.7, 1.2 Hz), 7.30 (1H, td, J = 7.6, 1.2 Hz),
4.20 (2H, s), 3.79 (3H, s) ppm;
13
C NMR (100 MHz, CDCl3) δ 168.7
(0), 164.5 (0), 152.7 (0), 135.4 (0), 126.0 (1), 124.4 (1), 121.6 (1), 121.0
(1), 52.8 (2), 34.7 (3) ppm.
Laboratory notebook reference: HG-13
O
S
N
S
83
C11H11NO2S2
(253.34)
O
HO
87
(3 eq)
K2CO3 (0.5 eq), neat,
50 °C, 20.5 h
O
N
S
S
O
88
C19H25NO2S2
(363.54)
(Benzothiazol-2-ylsulfanyl)-acetic acid dec-9-enyl ester: To a stirred
solution of (benzothiazol-2-ylsulfanyl)-acetic acid ethyl ester (5.0 g,
19.76 mmol) in 9-decen-1-ol (10.6 mL, ρ = 0.875, 9.25g, 59.25 mmol)
was added K2CO3 (1.5 g, 10.85 mmol). Heat was then increased from rt
to 50 °C. While stirring vigorously, the reaction was allowed to run for
20.5 h. The suspension was diluted with H2O (100 mL) and extracted
using EtOAc (3x100 mL), dried (Na2SO4), and concentrated in vacuo to
afford orange oil (12.28 g). Reaction mixture was further purified by
column chromatography (10% EtOAc/hexanes) to yield product ester
(4.70 g, 12.9 mmol, 65%) as a yellow oil.
51
IR (neat) 2927, 1738, 1640, 1429, 1002 cm-1; 1H NMR (300MHz,
CDCl3) δ 7.86 (1H, d, J = 8.0 Hz), 7.75 (1H, d, J = 8.0 Hz), 7.41 (1H, t,
7.4 Hz), 7.30 (1H, t, J = 7.6 Hz), 5.83 (1H, ddt, J = 16.8, 9.7, 6.9 Hz),
5.04-4.87 (2H, m), 4.21-4.31 (3H, m), 2.02 (2H, quartet, J = 6.9 Hz)
ppm, 1.75-1.20 (13H, m); 13C NMR (75MHz, CDCl3) δ 167.8 (0), 164.4
(0), 152.5 (0), 138.6 (1), 135.1 (0), 125.7 (1), 124.0 (1), 121.3 (1), 120.7
(1), 113.9 (2), 65.6 (2), 34.7 (2), 33.4 (2), 28.8 (2), 28.7 (2), 28.5 (2),
28.1 (2), 25.4 (2) ppm. ; MS (FAB+) m/z 364 (M+H)+; HRMS (FAB+)
m/z 364.1413 (calcd. for C19H26NO2S2: 364.1405).
Laboratory notebook reference: HG-182
O
S
N
S
83
C11H11NO2S2
(253.34)
O
O
1.5 M NaOH (2.7 eq),
MeOH, 0 °C to rt, 19 h
S
N
OH
S
89
C9H7NO2S2
(225.29)
(1,3-Benzothiazol-2-ylthio)acetic acid: To a stirred solution of ethyl
(1,3-benzothiazol-ylthio)acetic acid (61.0 g, 0.241 mol) in methanol
(800 mL) at 0 °C was added 1.5 M NaOH solution (430 mL, 0.645 mol)
in 20 mL portions. The vessel was then fitted with a condenser and
warm to rt and stir for 20 h. pH of solution was changed from 13 to 2
using 6 M HCl solution. Solution was allowed to stir for 10 min. Upon
stirring color changed to yellow with a white precipitate formed.
52
Reaction mixture was filtered by vacuum and solid was the purified acid
(10.2 g, 45.3 mmol). Filtrate was concentrated in vacuo to afford offwhite solid (51.0 g, 0.226 mol, 94%). A portion of the product was
further purified by recrystallization using MeOH/H2O to yield the
purified ketone as an off-white solid: mp 151-153 °C. Purity of both
samples were confirmed by 1H NMR.
IR (KBr) 2512, 1712, 1454, 1415, 1398, 1170, 1032, 748 cm-1; 1H NMR
(300MHz, d6-DMSO) δ 7.92 (1H, d, J = 8.0 Hz), 7.83 (1H, d, J = 8.1
Hz), 7.53 (1H, td, J = 7.2, 1.2 Hz), 7.43 (1H, td, J = 7.0, 1.1 Hz), 4.03
(2H, s), 1.27 (1H, bs) ppm; 13C NMR (75 MHz, d6-DMSO) δ 169.23 (0),
165.9 (0), 152.5 (0), 134.7 (0), 126.4 (1), 124.5 (1), 121.8 (1), 121.1 (1),
35.0 (2) ppm.
Reference:
1) Naya, A.; Kobayashi, K.; Ishikawa, M.; Ohwaki, K.; Saeki, T.;
Noguchi, K.; Ohtake, N. Chem. Pharm. Bull. 2003, 51, 697-701.
53
Laboratory notebook reference: HG-184
O2
S
N
O
O
S
55
C11H11NO4S2
(285.34)
1.5 M NaOH (3eq),
MeOH, rt, 15 h
O
N
S
90
C8H7NOS
(165.21)
2-Methoxybenzothiazole: To a stirred solution of ethyl (benzothiazol2-ylsulfonyl)acetate (1.00 g, 3.51 mmol) in MeOH (10 mL) at rt was
added 1.5 M NaOH solution (7.0 mL, 10.5 mmol) dropwise over 5 min.
Color changed from light yellow to dark yellow upon addition of base.
The solution was allowed to stir for 15 h. The pH of the reaction mixture
was lowered from 12 to 2 by addition of 6 M HCl (3 mL). Suspension
was extracted 2x using CHCl3, organic layers were then combined and
washed with brine. Organic layer was then dried over Na2SO4, and
concentrated in vacuo to afford the orange oil (653 mg). Crude product
was further purified by column chromatography (eluting with 20%
Et2O/hexanes) to yield the benzothiazole (522 mg, 3.16 mmol, 90%) as a
clear oil.
IR (neat) 2936, 1600, 1540, 1443, 1258, 1220, 1068, 748 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.70 (1H, d, J = 8.3 Hz), 7.63 (1H, dd, J = 7.9, 0.8
Hz), 7.37 (1H, td, J = 7.4, 1.3 Hz), 7.23 (1H, td, J = 7.7, 1.2 Hz), 4.21
(3H, s) ppm;
13
C NMR (75 MHz, CDCl3) δ 173.3 (0), 149.2 (0), 132.0
(0), 125.9 (1), 123.4 (1), 121.2 (1), 120.8 (1), 58.4 (3) ppm.
54
Reference:
Sawhney, S. N; Boykin, D. W. J. Org. Chem. 1979, 44, 1136-42.
Laboratory notebook reference: HG-196
O
S
N
S
OH
(NH4)6Mo7O24·4H2O (0.10 eq),
O2
S
N
S
30% aq. H2O2, EtOH,
0 °C to rt, 17 h
89
C9H7NO2S2
(225.29)
99
C8H7NO2S2
(213.28)
(Benzothiazole-2-sulfonyl)acetic acid: To a stirred solution of
(benzothiazol-2-ylsulfanyl)acetic acid (20.0 g, 88.8 mmol) in EtOH (800
mL) at 0 °C was added ammonium molybdate (11.16 g, 9.03 mmol)
solid and allowed for stir for 5min. To the suspension was added 30%
aq. H2O2 (60 mL, 5.33 mol) in 10 mL portions over 1 min. Reaction was
then allowed to warm to room temperature while stirring for 17 h.
Reaction mixture was then cooled to 0 °C and solid was filtered by
vacuum. **Caution: oxidants present. Saturated Na2SO3 solution at 0 °C
was added until oxidants not present. Solution changed color from
yellow to blue while standing. Removed the precipitate formed in the
reduction step by vacuum filtration. The pH of the reaction mixture was
1. Suspension was next extracted 5x using CHCl3, organic layers were
then combined and washed with brine until aqueous phase was colorless.
Organic layer was then dried over Na2SO4, and concentrated in vacuo
55
while not allowing the bath to rise above room temperature to afford the
white solid: mp °C (6.25 g, 29.3 mmol, 33%).
1
H NMR (300 MHz, d6-DMSO) δ 8.36 (1H, m), 7.63 (1H, d, J = 2.1
Hz), 7.71 (2H, sd, J = 7.2, 1.6 Hz), 3.59 (3H, s) ppm;
13
C NMR (75
MHz, CDCl3) δ 167.3 (0), 151.9 (0), 136.0 (0), 128.1 (1), 127.9 (1),
124.7 (1), 123.5 (1), 42.1 (3) ppm.
Laboratory notebook reference: HG-49
Br
Mg (3 eq),
Et2O, 33 °C, 1.5 h,
OH
then C6H5CHO, 2 h
101
C3H5Br
(120.98)
102
C10H12O
(148.20)
1-Phenyl-3-buten-1-ol: A stirred suspension of Mg (7.05 g, 0.294 mol)
in anhydrous Et2O (250 mL) under argon was added a solution of allyl
bromide (8.30 mL, ρ = 1.43 g/mL, 11.86 g, 98.0 mmol) in anhydrous
Et2O (125 mL). The solution was allowed to reflux at 33 °C for 0.5 h.
Benzaldehyde was added (6.4 mL, ρ = 1.043 g/mL, 6.65 g, 62.7 mmol)
dropwise over 30 min. Reaction was then allowed to stir for 2 h.
Quenched reaction with solution of sat. NH4Cl and solid was then
filtered by vacuum. Solution was extracted 3x using Et2O and dried over
Na2SO4. Suspension was filtered by vacuum and concentrated in vacuo
56
to afford 13.63 g of clear oil. Structure and purity confirmed by 1H
NMR.
1
H NMR (300MHz, CDCl3) δ 7.40-7.25 (5H, m) 5.80 (1H, ddt, J = 17.2,
10.1, 7.0 Hz), 5.21-5.11 (2H, m), 4.71 (1H, t, J = 6.5 Hz), 2.60-2.47
(2H, m), 2.41 (1H, bs, 2.65);
13
C NMR (75MHz, CDCl3) δ 143.8 (0),
134.3 (1), 127.9 (2C, 1), 127.0 (1), 125.7 (2C, 1), 117.2 (1), 73.2 (1),
43.2 (2)
Laboratory notebook reference: HG-73
O
NaH (1.1 eq), THF
0° C to rt, 30 min;
O
O
O
103
C5H8O4
(132.04)
O
O
O
O
Br 101
(1.1 eq)
THF, reflux, 15 h
104
C8H12O4
(172.07)
2-Allyl-malonic acid dimethyl ester: A stirred suspension of NaH
(4.00 g, 166.7 mmol) in anhydrous THF (170 mL) at 0° C under argon
was treated dropwise with a solution of dimethyl malonate (17.3 mL, ρ
= 1.153, 20.0 g, 151.6 mmol) in anhydrous THF (170 mL) over 35 min.
During the addition, the temperature was not allowed to increase over 5
°C. The resulting suspension was stirred for 30 min. Solid NaH was
observed to be consumed during the reaction. A solution of allyl
bromide (13.8 mL, ρ = 1.469, 20.2 g, 166.8 mmol) in THF (170 mL)
was added dropwise over 20 min. Reaction mixture was set to reflux for
57
15 h. During this time a white precipitate was observed to form. Solid
was filtered by vacuum then filtrate was washed with H2O (2x200 mL)
to remove any excess solid. Organic layer was removed, dried (Na2SO4),
and filtered by vacuum. Solution was concentrated in vacuo to afford
24.36 g of yellow oil. A portion of the crude product was purified by
column chromatography (eluting with 0-20% EtOAc/hexanes) to yield
the alkylated ester (24.36 g, 141.6 mmol, 93%) as a colorless oil: IR
(neat) 2954, 1737, 1643, 1437, 1342, 1234, 1191, 1157, 920 cm-1; 1H
NMR (300MHz, CDCl3) δ 5.75 (1H, ddt, J = 17.0, 10.2, 6.9 Hz), 5.12
(1H, dq, J = 18.0, 1.4 Hz), 5.06 (1H, dq, J = 10.4, 1.1 Hz), 3.73 (6H, s),
3.47 (1H, t, J = 7.6 Hz), 2.65 (2H, t, J = 7.2 Hz);
13
C NMR (75MHz,
CDCl3) δ 168 (2C, 0), 134 (2), 117 (1), 53 (2C, 6), 51 (2) 33 (1).
Laboratory notebook reference: HG-80
O
O
O
O
O
NaCl (1.25 eq), H2O (2.00 eq),
DMSO, reflux
104
C8H12O4
(172.07)
O
105
C6H10O2
(114.07)
Pent-4-enoic acid methyl ester: To a stirred solution of 2-allyl-malonic
acid dimethyl ester (24.34 g, 141.5 mmol) in DMSO (40 mL) at reflux
(189 °C) under argon to which was added H2O (5.09 g, 283.0 mmol) and
NaCl (10.34 g, 176.9 mmol) sequentially. Biphasic reaction mixture was
58
allowed to stir for 25 h then diluted with Et2O (150 mL) and the
resulting solution was washed with H2O (6x100 mL). The organic phase
was removed and dried (Na2SO4). Suspension was then filtered by
vacuum and concentrated in vacuo to afford 14.87 g of crude yelloworange oil (Caution: product volatile). This material was then purified by
distillation at atmospheric pressure to yield the methyl ester (9.98 g, 87.5
mmol, 62%) as a colorless oil: bp 96-100 °C. Purity of the sample was
confirmed by 1H NMR.
IR (neat) 2954, 1737, 1643, 1432, 1170, 916 cm-1; 1H NMR (300MHz,
CDCl3) δ 5.83 (1H, ddt, J = 16.5, 10.5, 6.5 Hz), 5.08 (1H, dq, J = 17.5,
1.5 Hz), 5.02 (1H, dq, J = 17.5, 1.1 Hz), 3.70 (3H, s), 2.42 (4H, m) ppm;
13
C NMR (75MHz, CDCl3) δ 173.3 (0), 136.6 (1), 115.5 (2), 51.4 (3),
33.3 (2), 28.8 (2) ppm.
Laboratory notebook reference: HG-81
O
LiAlH4 (0.75 eq),
O
105
C6H10O2
(114.07)
THF, reflux
OH
107
C5H10O
(86.07)
4-Penten-1-ol: A stirred suspension of LiAlH4 (1.00 g, 26.3 mmol) in
anhydrous Et2O (80 mL) at 0° C under argon was treated dropwise with
pent-4-enoic acid methyl ester (4.00 g, 35.1 mmol) solution in
anhydrous Et2O (80 mL) over 15 min at 0° C. Suspension was then
59
heated to reflux (34 °C). After 14 h, reaction was allowed to cool to rt
and was quenched by adding a slurry of Na2SO4/H2O portionwise until
gray color had completely disappeared. Suspension was filtered by
vacuum and the layers were separated. Aqueous layer was extracted
using Et2O (2x15 mL). Organic layers were combined, dried (Na2SO4),
and the resulting suspension was vacuum filtered. Solution was
concentrated in vacuo (Caution: product volatile). The structure and
purity of the resulting alcohol (2.85 g, 33.1 mmol, 94%) was confirmed
by 1H NMR.
IR (neat) 3333, 2938, 2869, 1634, 1553, 1432 cm-1; 1H NMR (300MHz,
CDCl3) δ 5.82 (1H, ddt, J = 17.0, 10.3, 6.9 Hz), 5.05 (1H, dq, J = 17.0,
1.6 Hz), 4.97 (1H, dq, J = 10.0, 1.0 Hz), 3.66 (2H, t, J = 6.5 Hz), 2.14
(2H, quartet, J = 6.0 Hz), 1.67 (2H, quintet, J = 7.0 Hz), 1.52 (1H, bs)
ppm;
13
C NMR (75MHz, CDCl3) δ 138.4 (1), 114.9 (2), 62.2 (2), 31.8
(2), 30.1 (2).
Laboratory notebook reference: HG-213
O
OH LiAlH , Et O,
4
2
108
C11H20O2
(184.28)
33 °C, 16 h
OH
109
C11H22O
(170.29)
10-Undecen-1-ol: To a stirred flask was added LiAlH4 (1.072 g, 28.2
mmol) and diluted into Et2O (40 mL). Suspension was cooled to 0 °C
60
then the 10-undecenoic acid (4.23 g, 23.5 mmol, 2.98 mL)/Et2O (60 mL)
solution was added to the mixture. The reaction was allowed to
gradually heat to 33 °C, then continue reaction for 16 h. Na2SO4/H2O
slurry was added to the reaction vessel until no reaction was observed.
Solid was filtered by vacuum and the resulting solution was
concentrated in vacuo to afford the alcohol (4.00 g, 23.5 mmol, 100%)
as a clear oil: IR (neat) 3330, 2927, 2856, 1647, 1467, 1059, 912 cm-1;
1
H NMR (300MHz, CDCl3) δ 5.81 (1Η, ddt, J = 16.9, 10.3, 6.7 Hz),
5.05-4.87 (2H, m), 3.63 (2H, t, J = 6.6 Hz), 2.03 (2H, quart. J = 6.7 Hz),
1.75-0.02 (14H, m) ppm; 13C NMR (75 MHz, CDCl3) δ 139.1 (1), 114.1
(2), 62.6 (2), 33.8 (2), 32.8 (2), 29.6 (2), 29.5 (2), 29.2 (2), 29.0 (2), 25.8
(2) ppm.
**Note 2 x 2Cs overlap (10 C’s shown)
Reference
1) Riedl, R.; Tappe, R.; Berkessel, A. J. Am. Chem. Soc. 1998, 120,
8894-9000.
61
Laboratory notebook reference: HG-206
N
O2
S
S
HO
O
78
OH (1.2 eq)
N
S
DCC (1.2 eq), THF, 0 °C to rt, 19 h
O2
S
O
O
114
C19H25NO4S2
(395.54)
87
C11H22O
(156.27)
(Benzothiazole-2-sulfonyl)acetic acid 9-decenyl ester: To a flame
dried
flask
purged
with
argon,
was
added
(benzothiazole-2-
sulfonyl)acetic acid (6.80 g, 26.5 mmol) in THF (200 mL) and was
allowed to dissolve at 0 °C. To this solution was added 9-decen-1-ol
(3.93 g, 25.2 mmol, ρ = 0.843, 4.66 mL) neat dropwise over 1 min.
Solution was allowed to stir at 0 °C for 10 min. To this was added N,N’dicyclohexylcarbodiimide (5.72 g, 27.7 mmol) all at once. White
precipitate was observed to form shortly after addition of DCC. Mixture
was allowed to warm to rt. After 19 h, the reaction was stopped. Solid
DCU formed was filtered by vacuum. Concentrated solution in vacuo to
afford crude product (15.84 g) as yellow oil containing white solid. 1H
NMR confirmed product was present as well as DCU. Crude product
was further purified by column chromatography (eluting with 10%
Et2O/hexanes) to yield the ester (9.721 g, 24.57 mmol, 93%) as clear
yellow oil.
IR (neat) 3071, 2929, 2856, 1738, 1639, 1471, 1346, 1157, 912, 761 cm1 1
; H NMR (300 MHz, CDCl3) δ 8.23 (1H, d, J = 8.0 Hz), 8.02 (1H, dd,
62
J = 6.9, 1.5 Hz), 7.65 (1H, td, J = 7.3, 1.4 Hz), 7.61 (1H, td, J = 7.1, 1.4
Hz), 5.81 (1H, ddt, 17.0, 10.2, 6.7 Hz), 5.04-4.89 (2H, m), 4.57 (2H, s),
4.10 (2H, t, J = 6.6 Hz), 2.03 (2H, q, J = 7.0 Hz), 1.59-1.09 (12H, m)
ppm;
13
C NMR (75 MHz, CDCl3) δ 165.0 (0), 161.6 (0), 152.3 (0),
139.0 (1), 136.9 (0), 128.2 (1), 127.7 (1), 125.5 (1), 122.3 (1), 114.2 (2),
66.8 (2), 58.6 (2), 33.7 (2), 29.6 (2), 29.1 (2), 28.9 (2), 28.7 (2), 28.1 (2),
25.5 (2) ppm; MS (FAB+) m/z 396 (M+H)+; HRMS (FAB+) m/z
396.1309 (calcd. for C19H25NO4S2: 396.1303).
Laboratory notebook reference: HG-59
OH
N
S
102
C10H12O
(148.20)
O2
S
O
78
OH (1.2 eq)
DCC (1.2 eq), THF, 0 °C to rt, 19 h
N
S
O2
S
O
O
116
C19H17NO4S2
(387.47)
(Benzothiazole-2-sulfonyl)acetic acid 3-phenyl-3-butenyl ester: To a
flame dried flask purged with argon, was added (benzothiazole-2sulfonyl)acetic acid (416 mg, 1.62 mmol) in THF (15 mL) and was
allowed to dissolve at 0 °C. To this solution was added 1-phenyl-3buten-1-ol (200 mg, 1.35 mmol) neat dropwise over 1 min. Solution was
allowed to stir at 0 °C for 10 min. To this was added N,N’dicyclohexylcarbodiimide (334 mg, 1.62 mmol) all at once. White
precipitate was observed to form shortly after addition of DCC. Mixture
63
was allowed to warm to rt. After 15 h, to the reaction was added the acid
(278 mg) and DCC (222 mg) to ensure completion of reaction. Allowed
reaction to run for 24 h. Solid DCU formed was filtered by vacuum.
Concentrated solution in vacuo to afford crude product (478 mg) as
yellow oil containing white solid. 1H NMR confirmed product was
present as well as DCU. Crude product was further purified by column
chromatography (eluting with 40% EtOAc/hexanes) to yield the ester
(310 mg, 0.810 mmol, 60%) as clear yellow oil.
IR (neat) 3067, 2929, 1738, 1642, 1553, 1471, 1342, 1278, 1148, 757,
731 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.22-8.16 (1H, m), 8.03-7.97
(1H, m), 7.63 (2H, td, J = 7.2, 1.5 Hz), 7.26-7.10 (5H, m), 5.76 (1H, t, J
= 6.9 Hz), 5.65-5.45 (1H, m), 5.03-4.92 (2H, m), 4.60 (2H, s), 2.65-2.40
(2H, m), 1.56 (2H, s) ppm;
13
C NMR (75 MHz, CDCl3) δ 165.0 (0),
160.9 (0), 152.5 (0), 138.3 (0), 137.0 (0), 132.4 (1), 128.5 (1), 128.3 (1),
127.8 (1), 126.6 (1), 125.6 (1), 122.5 (1), 118.7 (2), 78.2 (1), 58.7 (2),
40.2 (2) ppm; MS (CI+) m/z 388; HRMS (CI+) m/z 388.06646 (calcd.
for C19H17O4NS2 : 388.06435).
64
Laboratory notebook reference: HG-69
N
OH
107
C5H10O
(86.07)
O2
S
O
S
OH
(1.2 eq)
N
78
S
DCC (1.2 eq),
THF, 0 °C to rt,
12 h
O2
S
O
O
115
C14H15NO4S2
(325.04)
(Benzothiazole-2-sulfonyl)acetic acid 4-pentenyl ester: To a flame
dried
flask
purged
with
argon,
was
added
(benzothiazole-2-
sulfonyl)acetic acid (9.39 g, 36.5 mmol) in THF (450 mL) and was
allowed to dissolve at 0 °C. To this solution was added 4-penten-1-ol
(2.85 g, 33.1 mmol) neat all at once. Solution was allowed to stir at 0 °C
for 10 min. To this was added DCC (8.18 g, 39.7 mmol) all at once.
White precipitate was observed to form shortly after addition of DCC.
Mixture was allowed to warm to rt. After 12 h, the reaction was stopped.
Solid DCU formed was filtered by vacuum. Concentrated solution in
vacuo to afford crude product (13.65 g) as a clear light yellow oil
containing white solid. 1H NMR confirmed product was present as well
as DCU. Crude product was further purified by column chromatography
(eluting with 25% EtOAc/hexanes) to yield the ester (7.13 g, 21.9 mmol,
66%) as clear yellow oil.
IR (neat) 2933, 1742, 1638, 1342, 1153, 761 cm-1; 1H NMR (300MHz,
CDCl3) δ 8.26-8.00 (1H, m), 8.06-8.20 (1H, m), 7.69-7.58 (2H, m), 5.82
(1H, ddt, J = 15.9, 9.4, 6.5 Hz), 4.98-4.88 (2H, m), 4.58 (2H, s), 4.12
(2H, t, J = 6.6 Hz), 1.97 (2H, quartet, J = 7.1 Hz), 1.68-1.55 (2H, m)
65
ppm; 13C NMR (75MHz, CDCl3) δ 165.0 (0), 161.6 (0), 152.4 (0), 136.8
(1), 128.2 (1), 127.8 (1), 125.5 (1), 122.3 (1), 115.5 (2), 66.1 (2), 58.7
(2), 29.6 (2), 27.3 (2). MS (ES) m/z 326 (M)+; HRMS (ES) m/z
326.05256 (calcd. for C14H16O4NS2 : 326.05208).
Note 1: 1 Carbon not found in 13C spectrum
Laboratory notebook reference: HG-215
N
HO
S
O2
S
O
78
OH (1.01 eq)
DCC (1.02 eq), THF, 0 °C to rt, 20 h
109
C11H22O
(170.29)
N
S
O2
S
O
O
117
C20H27NO4S2
(409.56)
Undec-10-enyl(1,3-benzothiazol-2-ylsulfonyl)acetate: To a flame
dried flask purged with argon, was added 9-decen-1-ol (1.50 g, 8.82
mmol) neat and diluted into THF (80 mL). To this solution, was added
(benzothiazole-2-sulfonyl)acetic acid (2.30 g, 8.95 mmol) and was
allowed to dissolve at 0 °C. Solution was allowed to stir at 0 °C for 10
min. To this was added N,N’-dicyclohexylcarbodiimide (1.86 g, 9.01
mmol) all at once. White precipitate was observed to form shortly after
addition of DCC. Mixture was allowed to warm to rt. After 20 h, the
reaction was stopped. Solid DCU formed was filtered by vacuum. The
mixture was cooled to 0 °C, and the solid filtered again. Ester was
extracted with CH2Cl2 and then washed combined layers with sat.
66
NaHCO3 solution then brine. Dried layers over solid Na2SO4. Filtered
solid and concentrated solution in vacuo to afford crude product as
yellow oil (5.32 g) containing white solid. 1H NMR confirmed product
was present as well as DCU. Crude product was further purified by
column chromatography (eluting with 20% EtOAc/hexanes) to yield the
ester (3.61 g, 8.82 mmol, 100%) as clear yellow oil.
IR (neat) 2925, 2856, 1742, 1639, 1471, 1342, 1277, 1153, 908, 757 cm1
; 1H NMR (300 MHz, CDCl3) δ 8.23 (1H, dd, J = 7.2, 1.8 Hz), 8.03
(1H, dd, J = 7.0, 1.9 Hz), 7.67 (1H, td, J = 7.2, 1.5 Hz), 7.61 (1H, td, J =
7.2, 1.5 Hz), 5.82 (1H, ddt, J = 17.0, 10.2, 6.7 Hz), 5.05-4.89 (2H, m),
4.58 (2H, s), 4.10 (2H, t, J = 6.7 Hz), 2.10-1.98 (2H, m), 1.64-1.08
(13H, m) ppm; 13C NMR (75 MHz, CDCl3) δ 165.1 (0), 161.7 (0), 152.5
(0), 139.2 (1), 137.0 (0), 128.3 (1), 127.8 (1), 125.6 (1), 122.4 (1), 114.2
(2), 66.9 (2), 58.7 (2), 33.8 (2), 29.3 (2), 29.1 (2), 28.9 (2), 28.2 (2), 25.6
(2) ppm; MS (CI+) m/z 410 (M+H)+; HRMS (CI+) m/z 410.14698
(calcd. for C20H28NO4S2: 410.14598).
*Note 2 x 2Cs overlap (18 Cs shown)
67
Laboratory notebook reference: HG-125
N
118
C16H32O2
(256.42)
O
78
OH (1.2 eq)
S
O
HO
O2
S
DCC (1.2 eq), THF, 0 °C to rt, 20 h
O2
S
N
O
O
O
S
118
C25H37NO5S2
(495.69)
9-Decenyloxy-1-hexanyl(1,3-benzothiazol-2-ylsulfonyl)acetate: To a
flame dried flask purged with argon, was added 9-decenyloxy-1-hexanyl
(385 mg, 1.50 mmol) and diluted into THF (10 mL). To this solution,
was added (benzothiazole-2-sulfonyl)acetic acid (464 mg, 1.80 mmol)
and was allowed to dissolve at 0 °C. To this was added N,N’dicyclohexylcarbodiimide (372 mg, 1.80 mmol) all at once. THF volume
was increased to 25 mL. White precipitate was observed to form shortly
after addition of DCC. Mixture was allowed to warm to rt. After 20 h,
the reaction was stopped. Solid DCU formed was filtered by vacuum.
The mixture was cooled to 0 °C, and the solid filtered again. Ester was
extracted with CH2Cl2 and then washed combined layers with sat.
NaHCO3 solution then brine. Dried layers over solid Na2SO4. Filtered
solid and concentrated solution in vacuo to afford crude product as
yellow oil (1.03 g) containing white solid. 1H NMR confirmed product
was present as well as DCU. Crude product was further purified by
68
column chromatography (eluting with 12% EtOAc/hexanes) to yield the
ester (700 mg, 1.41 mmol, 94%) as clear yellow oil.
IR (neat) 2924, 2852, 1742, 1471, 1338, 1273, 1153, 908, 761 cm-1; 1H
NMR (300 MHz, CDCl3) δ 8.25-8.20 (1H, m), 8.05-7.98 (1H, m), 7.67
(2H, td, J = 7.1, 1.5 Hz), 5.82 (1H, ddt, J = 16.9, 10.3, 6.6 Hz), 5.054.89 (2H, m), 4.58 (2H, s), 4.10 (2H, t, J = 6.6 Hz), 2.10-1.98 (2H, m),
1.80-0.50 (24H, m) ppm; 13C NMR (75 MHz, CDCl3) δ 165.1 (0), 161.8
(0), 152.7 (0), 139.3 (1), 137.1 (0), 128.4 (1), 127.9 (1), 125.8 (1), 122.5
(1), 114.2 (2), 67.1 (2), 58.9 (2), 33.9 (2), 29.9 (2), 29.4 (2), 28.9 (2),
29.18 (2), 29.15 (2), 29.0 (2), 28.4 (2), 25.8 (2) ppm
** 4 C’s are hidden in 13C spectrum.
Laboratory notebook reference: HG-70
N
S
O2
S
O2/O3 (XS),
DCM:MeOH,
-78 °C, 10 min,
O
O
115
C14H15NO4S2
(325.04)
then,
DMS (12.8 eq),
12 h to rt
N
S
O2
S
O
O
O
119
C15H19NO6S2
(373.07)
O
(Benzothiazole-2-sulfonyl)acetic acid 4,4-dimethoxy-butyl ester: To a
stirred solution of (benzothiazole-2-sulfonyl)acetic acid pent-4-enyl
ester (174 mg, 534 mmol) in DCM:MeOH (4 mL:1 mL) at -78 °C was
bubbled through gaseous O2/O3. Reaction was allowed to stir for 40 min,
until the solution turned a light-blue color. To this solution was added
69
DMS (0.5 mL, ρ=0.846, 423 mg, 6.81 mmol) and allowed to stir for 12
h. Solution was concentrated in vacuo to afford 219 mg of yellow oil.
The crude material was further purified by column chromatography
(eluted with 25% EtOAc/hexanes) to yield the dimethyl acetal (143 mg,
72%) as yellow oil.
IR (neat) 2937, 2830, 1738, 1471, 1342, 1273, 1153, 761, 727; 1H NMR
(300MHz, CDCl3) δ 8.28-8.22 (1H, m), 8.08-8.02 (1H, m), 7.71-7.60
(2H, m), 4.60 (2H, s), 4.28 (1H, t, J = 5.3 Hz), 4.17 (2H, t, J = 6.1 Hz),
3.29 (6H, s), 1.70-1.50 (4H, m) ppm.
Laboratory notebook reference: HG-71
N
S
O2
S
O3, CH2Cl2,
-78 °C, 15 min,
O
O
115
C14H15NO4S2
(325.40)
then,
DMS to rt 20 h
N
S
O2
S
O
O
O
123
C13H13NO5S2
(327.38)
4-(1,3-Benzothiazol-2-ylsulfonyl)butanal: To a stirred flask was added
(benzothiazol-2-sulfonyl)-acetic acid 4-pentenyl ester (140 mg, 426
µmol) and diluted into DCM (5 mL). Oil and was allowed to stir at rt
until yellow solution was observed. Solution was then cooled to -78 °C
and bubbled through gaseous O3. After 10 min solution became blue and
O3 was stopped. DMS (0.5 mL, 6.81 mmol) was added and reaction
mixture was allowed to warm to rt over 21 h. Solution was concentrated
70
to afford 190 mg of orange oil. Further purified by column
chromatography (eluting with 50% EtOAc/hexanes) to yield the
aldehyde (83 mg, 253 µmol, 59%) as a clear yellow oil: IR (neat) 3449,
2929, 2727, 1742, 1471, 1342, 1237, 1153, 766, 723 cm-1; 1H NMR
(300MHz, CDCl3) δ 9.66 (1Η, t, J = 0.85 Hz), 8.24-8.19 (1H, m), 8.067.99 (1H, m), 7.70-7.57 (2H, m), 4.57 (2H, s), 4.17 (2H, t, J = 6.2 Hz),
2.45 (2H, dt, J = 0.81, 7.2 Hz), 1.98 (2H, quint, J = 6.7 Hz) ppm;
13
C
NMR (100 MHz, CDCl3) δ 200.8 (1), 165.0 (0), 161.6 (0), 152.6 (0),
137.1 (0), 128.6 (1), 128.0 (1), 125.8 (1), 122.6 (1), 65.7 (2), 58.9 (2),
40.1 (2), 20.1 (2) ppm; MS (CI+) m/z 328.1 (M+H)+; HRMS (CI+) m/z
328.03145 (calcd. for C13H14NO5S2: 328.03134).
Laboratory notebook reference: HG-20
O2
S
N
O
O
S
114
C19H25NO4S2
(395.54)
O3, CH2Cl2:MeOH,
-78 °C, 15 min,
then, DMS to rt 20 h
O2
S
N
O
O
S
O
126
C18H23NO5S2
(397.21)
9-Oxonoyl(1,3-benzothiazol-2-ylsulfonyl)acetate: To a stirred flask
was added (benzothiazol-2-sulfonyl)acetic acid 9-decenyl ester (200 mg,
510 µmol) and diluted into DCM:MeOH (4:1) (5 mL). Oil and was
allowed to stir at rt until yellow solution was observed. Solution was
then cooled to -78 °C and bubbled through gaseous O3. After 10 min
71
solution became blue and O3 was stopped. DMS (0.5 mL, 6.81 mmol)
was added and reaction mixture was allowed to warm to rt over 21 h.
Solution was concentrated to afford 249 mg of yellow oil. Further
purified by column chromatography (eluting with 40% EtOAc/hexanes)
to yield the aldehyde (190 mg, 478 µmol, 94%) as a clear white oil:
IR (neat) 2929, 2852, 1742, 1471, 1342, 1153, 761cm-1; 1H NMR
(300MHz, CDCl3) δ 9.76 (1Η, s), 8.22 (1H, d, J = 7.5 Hz), 8.03 (1H, d,
J = 7.2 Hz), 7.63 (2H, ), 4.67 (2H, s), 4.18-4.03 (2H, m), 2.41 (2H, t, J =
6.7 Hz), 1.70-0.01 (12H, m) ppm; 13C NMR (75 MHz, CDCl3) δ 202.9
(1), 171.3 (0), 165.1 (0), 161.7 (0), 152.5 (0), 137.0 (1), 128.3 (1), 127.9
(1), 122.6 (1), 65.7 (2), 58.9 (2), 40.1 (2), 20.1 (2) ppm; MS (CI+) m/z
328.1 (M+H)+; HRMS (CI+) m/z 328.03145 (calcd. for C13H14NO5S2:
328.03134).
Laboratory notebook reference: HG-93
O2
S
N
O
O
DBU (2eq), CH2Cl2,
O
O
S
-78 to rt, 15h
123
C15H17NO5S2
(355.43)
(Z)-6,7-Dihydro-5H-oxepin-2-one:
O
124
C6H8O2
(112.13)
A
stirred
solution
of
1,8-
diazabicyclo[5.4.1]undecene (353 mg, 2.32 mmol) in CH2Cl2 (10 mL) at
-78 °C under argon was treated by dropwise addition with a solution of
72
4-(1,3-benzothiazol-2-ylsulfonyl)butanal (379 mg, 1.16 mmol) in
CH2Cl2 (10 mL) over 15 min. After the addition the solution was
allowed to warm to rt over 15 h and stir at rt for 2 h. The reaction was
then quenched by the addition of 0.375 M HCl solution. Extracted
organic 3x using CH2Cl2 and combined layers. Organic layers were
removed, dried (Na2SO4), and filtered by vacuum. Solution was
concentrated in vacuo to afford 506 mg of light yellow oil (Z:E = 100:0).
Purified product using column chromatography (eluting with 0-50%
EtOAc/hexanes) to yield the a,b-unsaturated lactone (40 mg, 360 mmol,
31%) as an off-white solid. **Unable to completely separate
benzothiazolone side-product, yield derived from NMR analysis.
1
H NMR (300 MHz, CDCl3) δ 6.25 (1H, dt, J = 11.7, 8.8 Hz), 5.81 (1H,
d, 11.7 Hz), 4.19 (2H, t, J = 5.2 Hz), 2.54 (2H, q, J = 8.0 Hz), 1.90-1.77
(2H, m) ppm. HRMS (CI+) m/z 113.06048 (calcd. for C6H9O2:
113.06026).
Laboratory notebook reference: HG-136
N
S
O2
S
O
O
DBU (2.0 eq), CH2Cl2,
-78 °C, 14 h
O
O
126
C18H23NO5S2
(397.51)
(Z)-Oxacyclododec-3-en-2-one:
O
slow addition (0.74 mL/h)
to rt
127
C11H18O2
(182.26)
A
stirred
solution
of
1,8-
diazabicyclo[5.4.1]undecene (67 mg, 440 mmol) in CH2Cl2 (10 mL) at
-78 °C under argon was treated by slow addition (0.74 mL/h) with a
73
solution of 9-oxononyl(1,3-benzothiazol-2-ylsulfonyl)acetate (75 mg,
189 mmol) in CH2Cl2 (10 mL) over 14 h. During the addition the
solution was allowed to warm to rt over 12 h and stir at rt for 2 h. The
reaction was then quenched by the addition of sat. NH4Cl solution and
allowed to stir for 0.5 h. Extracted organic 5x using EtOAc. Organic
layers were removed, dried (Na2SO4), and filtered by vacuum. Solution
was concentrated in vacuo to afford 45 mg of light yellow oil (Z:E =
89:11). Purified product using column chromatography (eluting with 012.5% EtOAc/hexanes) to yield the a,b-unsaturated lactone (15 mg, 82.3
mmol, 44%) as a white solid (mp = 58-60 °C) : IR (KBr) 2916, 2850,
1719, 1701, 1466, 1293, 1237, 830 cm-1; 1H NMR (300 MHz, CDCl3) δ
6.18 (1H, dt, J = 11.7, 8.0 Hz), 5.74 (1H, d, 11.7 Hz), 4.17 (2H, t, J =
5.9 Hz), 2.54 (2H, q, J = 7.4 Hz), 1.67 (2H, quint., J = 11.7 Hz), 1.491.18 (8H, m), 0.94-0.77 (2H, m) ppm;
13
C NMR (75 MHz, CDCl3) δ
167.3 (0), 148.6 (1), 120.9 (1), 64.4 (2), 29.9 (2), 29.5 (2), 29.33 (2),
29.26 (2), 29.1 (2), 29.0 (2), 26.4 (2) ppm; HRMS (CI+) m/z 183.13845
(calcd. for C11H19O2: 183.13851)
Reference:
1) Izbedski, J.; Pawlak, D. Synthesis 1989, 419-23.
74
Laboratory notebook reference: HG-212
O
O2
S
N
O
O3, CH2Cl2,-78 °C, 15 min,
then DMS to rt, 45 min,
O
[13]
O
S
117
C20H27NO4S2
(409.56)
then conc.,
then, DBU (2eq), CH2Cl2,
-78 °C to rt, 15h
130
C12H20O2
(196.29)
Oxacyclotridec-3-en-2-one: A stirred solution of undec-10-enyl(1,3benzothiazol-2-ylsulfonyl)acetate
(276
mg,
0.675
mmol)
in
CH2Cl2:MeOH (4:1, 20 mL) was subjected to O3 for 15 min. Bubbled
argon through solution for 5 min. Then DMS (0.5 mL) was added all ta
once. The resulting solution was allowed to stri at -78 °C for 50 min,
then warmed to rt for 45 min. Solution was concentrated in vacuo.
Concentrate was then diluted into CH2Cl2 (15 mL) and cooled to – 78 °C
under
an
argon
atmosphere.
To
this
was
added
1,8-
diazabicyclo[5.4.1]undecene (206 mg, 1.35 mmol) and allowed the
solution to warm to rt over 3 h. Stirred solution at rt for 30 min, then the
reaction was quenched by the addition of sat. NH4Cl solution and
allowed to stir for 0.5 h. Extracted organic 3x using CH2Cl2, combined
layers and washed with brine. Organic layers were removed, dried
(Na2SO4), and filtered by vacuum. Solution was concentrated in vacuo
to afford 341 mg of light yellow oil (Z:E crude = 83:17). 1H NMR (300
MHz, CDCl3) δ 6.24-6.10 (1H, m), 5.40-4.88 (1H, m), ~ 4.17, ~ 2.54,
~1.67, 1.49-1.18 (m) ppm
75
Laboratory notebook reference: HG-125
O
O2
S
N
S
O
O
O
O
O
DBU (2eq), CH2Cl2,
-78 to rt, 15h
O
133
C17H30O3
(282.42)
132
C24H35NO6S2
(497.67)
(Z)-Oxacyclotridec-3-en-2-one:
diazabicyclo[5.4.1]undecene
A
(37
stirred
mg,
solution
245
of
1,8-
mmol)
and
dimethylaminopyridine (5 mg, 41 mmol) in CH2Cl2 (3 mL) at
-78 °C
under argon was treated by a solution of 9-oxononyloxy-1-hexanyl(1,3benzothiazol-2-ylsulfonyl)acetate (61 mg, 123 mmol) in CH2Cl2 (5 mL)
over 5 h. The solution was then allowed the solution to warm to rt over
13 h. The reaction was quenched by the addition of sat. NH4Cl solution
and allowed to stir for 2 h. Extracted organic 4x using CH2Cl2,
combined layers and washed with brine. Organic layers were removed,
dried (Na2SO4), and filtered by vacuum. Solution was concentrated in
vacuo to afford 52 mg of light yellow oil. Product was further purified
by column chromatography (EtOAc/hexanes) to yield the lactone (13.1
mg, 43%) as a white solid (Z:E = 85:15).
1
H NMR (300 MHz, CDCl3) δ 6.14 (1H, dt, J = 11.6, 7.9 Hz), 5.77 (1H,
d, J = 11.6 Hz), 4.17 (2H, t, J = 5.9 Hz), 2.54 (2H, t, J = 5.6 Hz), 1.80-
76
0.50 (24H, m) ppm; 13C NMR (75 MHz, CDCl3) δ 167.1 (0), 149.0 (1),
120.6 (1), 70.0 (2), 69.8 (2), 64.0 (2), 29.7 (2), 29.4 (2), 29.3 (2), 28.7
(2), 28.6 (2), 28.5 (2), 28.3 (2), 28.2 (2), 28.0 (2), 25.7 (2), 25.5 (2) ppm;
Laboratory notebook reference: HG-64
O2
S
N
S
O
O
DBU (1.5 eq), CH2Cl2,
O
Ph
137
C9H8O
(132.16)
135
C11H23NO5S2
(389.45)
trans-Cinnamaldehyde:
H
-78 to rt, 15h
O
A
stirred
solution
of
1,8-
diazabicyclo[5.4.1]undecene (75 mg, 492 mmol) in CH2Cl2 (10 mL) at
-78 °C under argon was treated dropwise with a solution of 3-phenyl-3oxopropyl(1,3-benzothiazol-2-ylsulfonyl)acetate (131 mg, 328 mmol) in
CH2Cl2 (2 mL) over 10 min. The reaction mixture was allowed to warm
to rt and spin for 28 h. The reaction was then quenched by the addition
of sat. NH4Cl solution and allowed to stir for 0.5 h. Extracted organic 2x
using CH2Cl2. Organic layers were removed, dried (Na2SO4), and
filtered by vacuum. Solution was concentrated in vacuo to afford 93 mg
of light yellow oil. 1H NMR clearly confirmed cinnamaldehyde plus
other byproducts. Crude product was further purified by column
chromatography (eluting with 25% EtOAc/hexanes) to yield the
aldehyde (15.6 mg, 118 mmol, 36%) as clear yellow oil.
77
IR (neat) 3063, 2813, 2731, 1685, 1625, 1451, 1124, 972, 749 cm-1; 1H
NMR (300 MHz, CDCl3) δ 9.71 (1H, d, J = 7.7 Hz), 7.60-7.40 (6H, m),
6.72 (1H, dd, J = 15.9, 7.7 Hz) ppm;
13
C NMR (75 MHz, CDCl3) δ
194.0 (1), 153.1 (1), 134.2 (0), 131.5 (1), 129.4 (1), 128.8 (2C, 1), 128.7
(2C, 1) ppm
78
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88
Appendix
1
H NMR/13C NMR Compound
Spectral Data
N
S
55
O2
S
O
O
89
N
S
55
O2
S
O
O
90
N
S
78
O2
S
O
OH
91
N
S
78
O2
S
O
OH
92
N
S
S
83
O
O
93
N
S
S
83
O
O
94
N
S
85
S
O
O
95
N
S
85
S
O
O
96
S
N
S
88
O
O
97
S
N
S
88
O
O
98
N
S
89
S
O
OH
99
N
S
89
S
O
OH
100
S
90
N
O
101
S
90
N
O
102
S
99
N
O2
S
103
S
99
N
O2
S
104
102
OH
105
102
OH
106
O
O
104
O
O
107
O
O
104
O
O
108
105
O
O
109
105
O
O
110
107
OH
111
107
OH
112
109
OH
113
109
OH
114
S
N
O2
S
O
114
O
115
S
N
O2
S
O
114
O
116
S
N
O
116
O2
S
O
117
S
N
O
116
O2
S
O
118
S
N
O
115
O2
S
O
119
S
N
O
115
O2
S
O
120
S
N
O2
S
117
O
O
121
S
N
O2
S
117
O
O
122
N
S
O2
S
O
118
O
O
123
N
S
O2
S
O
118
O
O
124
S
N
O2
S
O
119
O
O
O
125
S
N
O2
S
123
O
O
O
126
S
N
O2
S
123
O
O
O
127
N
S
O2
S
O
126
O
O
128
N
S
O2
S
O
126
O
O
129
O
124
O
130
O
127
O
131
O
127
O
132
O
130
O
133
O
O
133
O
134
O
O
133
O
135
H
O
137
Ph
136
H
O
137
Ph
137