Manganese-Catalyzed Carbonylation of Alkyl Iodides
By
Felix Alexander Westerhaus
Vordiplom (Chemistry), Philipps-Universitit Marburg, 2006
SUBMITTED TO THE DEPARTMENT OF CHEMISTRY IN PARTIAL
FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF
SCIENCE MASTERS IN ORGANIC CHEMISTRY
AT THE
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
AUGUST 2009
ARCHIVES
© 2009 Massachusetts Institute of Technology. All rights reerve.
Signature of A uthor: ...........................................
.......
.. ...
..
.,.
Department of Chemistry
Certified by:
..........................................................
w..
n
.
........
August 27, 2008
x.
.........
Stephen L. Buchwald
Camille Dreyfus Professor of Chemistry
Academic Advisor
Accepted by: .......
................
Robert W. Field
Chairman, Department Committee on Graduate Students
MASSACHUSETTS
OF TECHNOLOGY
SEP 2 2 2009
[11
LIBRARIES
Palladium Catalyzed Cross-Coupling of Aryl Halides with Zirconocene-Benzyne
Complexes and Manganese Catalyzed Carbonylation of Alkyl Halides
By
Felix Alexander Westerhaus
Vordiplom (Chemistry), Phillips Universitiit Marburg, 2006
Submitted to the Department of Chemistry on August 28, 2009
in Partial Fulfillment for the Degree of Science Masters in Organic Chemistry
ABSTRACT
The palladium-catalyzed cross-coupling of aryl bromides with zirconocene-benzyne
complexes has been investigated by S.L. Buchwald and coworkers. This method allows the
formation of substituted biphenyls and terphenyls, however only two ortho-substituents are
tolerated in this transformation. The studies reportd herein aimed at the synthesis of tri- and
tetra substituted biaryls, since they are important precursors to biaryl phosphine ligands. The
project did not succeed due to stability problems of the formed substituted zirconium biaryl.
A general method for the manganese-catalyzed carbonylation of alkyl iodides while using a
variety of nucleophiles was developed. The method concerns the alkoxy and amino
carbonylation as well as the use of more unconventional nucleophiles such as thiols, azide
and hydride. The method employs alkyl iodides although bromides are also feasible
substrates through in situ Finkelstein reaction with catalytic to substoichiometric amounts of
sodium iodide. The functional group tolerance is high and the conditions for the
transformation are mild using only 40 psi of carbon monoxide pressure and temperatures
between r.t. and 90 'C for more difficult cases.
Thesis Supervisor: Stephen L. Buchwald
Title: Camille Dreyfus Professor of Organic Chemistry
Acknowledgements
I would like to thank my academic advisor Stephen L. Buchwald for his guidance, patience
and understanding during the last two years, my thesis chair Prof. Fu for helping me out.
Special thanks to Ruben and Dr. Surry for their outstanding mentorship, Georgiy and
Debabrata for the enlightening conversations, as well as Dima and Xiaoqiang, being great lab
neighbors.
Of course I would like to thank my family for the unconditional support during the last two
years.
Table of Contents
Chapter 1:
Palladium-Catalyzed Cross-Coupling Reactions of Zirconocene-Benzyne
Complexes with Aryl Bromides
Introduction
Results and Discussion
Conclusions
Experimental
Chapter 2:
Manganese-Catalyzed Carbonylation of Iodoalkanes
Introduction
Results and discussion
Conclusions
Experimental
Appendix A:
Analytical Data
Appendix B:
References
Appendix C:
Curriculum Vitae
Chapter 1:
Palladium-Catalyzed Cross-Coupling Reactions of Zirconocene-Benzyne Complexes
with Aryl Bromides
A. Introduction
Arynes are highly strained and reactive species that undergo a range of synthetically
useful transformations when generated and used in situ, hence a number of methods for their
formation have been developed. 1' 2
Although highly reactive in solution, arynes can be stabilized by electron rich metal
fragments. This stabilization can be attributed to several factors: 1) the aryne is less strained
due to the back bonding of the metal which decreases the order of the triple bond and thus the
bond angle distortion; 2) electropositive metals release electron density into the aryne. This
metallacyclopropane is less strained than all carbon cyclopropanes because the metal based
orbitals can accommodate the small bond in a three-membered ring more easily.
Although there was some early evidence for metal-stabilized benzyne complexes 3 7 the
first isolated complex was described by the Schrock group using a tantalum system (Figure 1
[1]).8 This was followed by Bennett who reported an isolated nickel-benzyne complex
(Figure 1 [2]) 9 and by Buchwald an coworkers who reported the first zirconium stabilized
benzyne complex as the zirconocene benzyne trimethylphosphine adduct (Figure 1 [3]).10
Cp*
Ta-Me
Me
Cy Cy
'p
"cIN<
I
Me
ZrCp 2
PMe 3
Cp*= Me
Me
Me
Me
Figure 1: First examples of isolated benzyne-metal complexes
Zirconocene-benzyne complexes were first generated in the laboratories of Erker by
thermolysis of diaryl zirconocene complexes. I His work was based on related studies using
diaryl titanocene compounds, which also give benzyne complexes upon heating. 12 -13 Erker
established that the mechanism of formation of these metallocenes must proceed via 3abstraction from the aryne compound (Scheme 1).
-K
Cp 2 Zr
-Hc t-- oZrCp2
3-H-Abstraction
b
Scheme 1: Formation of zirconocene-benzyne via P-abstraction
A more synthetically useful method of generating zirconocene-benzyne complexes
was introduced by Buchwald. 14 This method uses zirconocene (methyl) chloride and an
aryllithium species to form the aryl (alkyl) zirconocene which then undergoes 3-abstraction
to form the zirconocene-benzyne complex (Scheme 1).
R
Me
\
P-Abstraction
Li
Cp 2 Zr(1C
CI
Cp 2 Zr
-
IZrCp2
H
- CH44
Me
Scheme 2: Formation of zirconocene-benzyne from zirconocene (methyl) chloride
This protocol was further simplified into a one step procedure to synthesize the
zirconocene-benzyne starting from zirconocene dichloride.' 5 A further advantage is that this
method does not make use of zirconocene (methyl) chloride, which must first be prepared in
a two step process. 16 tert-Butyllithium is added to zirconocene dichloride, which after
rearrangement of the initial adduct gives zirconocene (isobutyl) chloride. This mixture is then
treated with the aryllithium to produce the zirconocene-benzyne as described above (Scheme
3).
t-BuLi
Cp 2ZrCI 2
CP 2Zr-CI
P-hydride
Eliminatio.
n) n
CI
Cp2Zr
neto
H-yrd
R
Re
Li
P-hydride
Insertion
Elimination
P-Abstraction
Cp2ZrNMe
CP 2Zr><Y
Scheme 3: Mechanism of formation of zirconocene-benzyne complex from zirconocene
dichloride
This method allows the functionalization of an aromatic ring in two positions through
C-H activation starting from a monohaloarene. These zirconium complexes show reactivity
towards a wide array of electrophiles and unsaturated molecules. Insertion is highly
regioselective, reaction of unsaturated molecules occurring at the less hindered position. In
particular the insertion of nitriles is of great significance since upon hydrolysis anti-FriedelCrafts-acylation products are obtained (Scheme 4).14,17
R1
R1
R2 CN
ZrCp 2
R
R1
Cp2
Zr
'N--
H2 0
R2
H(E
R2
Scheme 4: meta-acylation of aromatic compounds
Zirconocene-benzyne complexes have also been reported to react with a variety of
other unsaturated systems, such as olefins and alkynes, as well as organometallic species
including boron or gallium reagents, which form heterobimetallic compounds (Scheme 5).1718
R
Cp2
I
OMe
Et2
Et2BOMe
R
CP2
Ph
R
Phh
ZrCp 2
Me 2GaOMe
CP2
Zr
GOMe
/
I
Me 2
PhN
Ph
R
CP2
Zr
rly
-Ph
Scheme 5: Various reactions zirconocene-benzyne can undergo
By quenching the intermediate cyclic- aryl zirconocene species with an electrophile
other than water, such as iodine or sulfur dichloride, polysubstituted aromatic compounds, or
heterocycles can be generated (Scheme 6).15 ' 17
R1
R1
Cp2
Zr
R2
SCI2
R3
R3
R1
R1
Cp2
Zr
1)12
N
2)H 3 0+
]
R2
R2
Scheme 6: Different electrophiles for quenching aryl-zirconocene species
Vinyl zirconocene species are known to be viable partners in palladium or nickel
catalyzed cross-coupling reactions. In this case the zirconocene complex can be easily made
by hydrozirconation of alkynes and can subsequently be coupled with aryl halides (Scheme
7).19
R1
R1
R2
X
Cp2ZrHCI
R
X = CI, Br, I
g
ZrC
cIZrCP 2
Ni/Pd Cat.
Scheme 7: Hydrozirconation and subsequent cross-coupling of vinyl-zirconocene
The Buchwald group has investigated the feasibility of zirconocene-benzyne as a
nucleophile in cross-coupling reactions.20 It was found that these complexes are viable
partners for palladium-catalyzed cross-coupling reactions, producing a variety of useful
biaryls.
[10]
The optimized conditions for the coupling reaction show high regioselectivity for the
transmetalation step, resulting in a method that can produce substituted biaryls in which a
single regioisomer is formed. For toluene-derived benzyne-complexes the best ligand was
DPEPhos, whereas for anisole derived benzyne-complexes DPPF was the superior ligand
(Scheme 8).20
OMe Br
ZrCp 2
Me
R
Br
Z rCp2
R = Me
R =OMe
ZrCp 2
Pd2(dba) 3, DPPF
Z
-PPh
Fe
--
Pd2 (dba) 3 , DPEPhos
PPh 2
2
PPh 2
PPh 2
DPEPhos
DPPF
DPEPhos
Scheme 8: Cross-coupling of zirconocene-benzyne
The use of an appropiate phosphine ligand is crucial to ensure coupling takes place in
a regioselective fashion and prevent the resulting aryl zirconocene species from undergoing a
second transmetalation (Scheme 9).
a
Br
R
Pd Cat.
Scheme 9: The catalytic system reported by Buchwald and coworkers prevents further crosscoupling of the aryl zirconium species
[11]
The proposed mechanism for this transformation consists of oxidative addition to the
aryl bromide followed by transmetalation of the zirconocene-benzyne complex. After
reductive elimination and iodine quench the final product, an ortho-iodo biaryl is formed
(Scheme 10).
Pd(O)Ln
R
Oxidative Addition
Br
SZrCp
2
Ln
Pd. Br
12 (E)
R
Reductive
Elimination
R
Br
Transmetalation
ZrCp 2
R
"
PdLn
ZrCp 2
Scheme 10: Proposed catalytic cycle for zirconocene-benzyne cross-coupling
The scope of the reaction is broad, with numerous functional groups such as ethers
and chlorides as well as protected aldehydes, amines and esters being tolerated (Figure 2).
There are, however, no examples of tri-ortho substituted biaryls being made by this method.
[12]
O
Me
I
MeO
H
/e
77%
H
MeO
2
-6NH
Me
Cl
-
I
Me
I
I
83%
CF 3
84%
44%
MeO
I Me
I OMe
56%
84%
Figure 2: Biaryl iodides synthesized by zirconocene-benzyne cross-coupling
Substituted biaryl iodides are important precursors to modem biaryl phosphine
ligands, thus further developing the reaction to tolerate increased steric bulk in the coupling
partners would be of value. Development of an enantioselective version of this chemistry
21 26
would also be desirable to facilitate the synthesis of chiral ligands. -
i-Pr,
PCy2
-i-Pr
BrettPhos
"PCy2
NMe 2
Me 2 N
CPhos
i-Pr-MOP
Figure 3: Biaryl- and binaphthyl based phosphine ligands
[13]
KenPhos
B. Results and discussion
The cross-coupling reaction of zirconocene-benzyne species with ortho-substituted aryl
halides to form tri- or tetra ortho-substitutedbiaryls was first examined using the conditions
previously reported by Buchwald and coworkers. 2 0 Initial experiments showed that this
system did not give any of the desired cross-coupling products, hence a number of different
biaryl phosphine ligands were examined (Figure 4). Several of these ligands proved effective,
with XPhos giving the highest yields and conversions.
PCy 2
Me2 N
27-29
PCY2
OMe
MeO
PCy 2
i-Pr
i-Pr
i-Pr
DavePhos
SPhos
XPhos
Figure 4: Selection of biaryl phosphine ligands examined
Although the biaryl was formed with good regioselectivity,
after the final
electrophilic quench, using iodine only the protonated biaryl could be recovered. This was
the case for several substrates having different steric and electronic properties (Figure 5).
Quenching the reaction mixture with D 20, DCI (20% in D2 0) in or MeOD did not result in
any deuterium incorporation, showing the proton incorporation occurred before addition of
the electrophile.
[14]
OMe
MeO
H
OMe
OMe
MeO
MeO
H
MeO
Me2N
OMe
Me
H
H
OMe
MeO
Figure 5: Protonated biaryls after cross-coupling reaction
Isolated yields of up to 80% of the protonated biaryl could be obtained, however
without the possibility of further functionalization the method is not useful. There are a
number of possible explanations for the exclusive formation of the protonated compounds: 1)
The reaction of iodine with the biaryl zirconocene species may be significantly slower than
competing protonation. 2) It is possible that adventitous water in the solvent is providing the
proton source, however this is not consistent with formation of the desired iodinated
compound for less hindered substrates. In order to demonstrate that protonation was not a
result of water in the in the reaction vessel, all solvents were carefully dried and tested for
moisture with benzophenone ketal. The reaction was also performed inside the glovebox.
Despite these precautions, protonated material remained the only product. 3) Alternatively
iodine may be too sterically demanding to react with the aryl zirconocene species, thus a
number of other electrophiles were examined. Amongst these were very reactive reagents
such as bromine, iodine or iodine monochloride as well as milder electrophiles such as NCS,
NBS, NIS or dibromoethane. All of these attempts failed to yield any of the desired
halogenated product.
[15]
Since THF is used as a reaction medium for the transformation, there is a possibility
that the proton found in the final product derives from the solvent. A number of alternative
solvents were examined, most of which give poor conversion and yield of the biaryl. When
reaction was carried out in those solvents that gave successful coupling reactions, for
example diethyl ether, the same undesired product was observed. Performing the reaction in
deuterated THF, provided further evidence that the solvent is not acting as a proton source, as
no incorporation of deuterium into the final biaryl product was observed. Using zirconocene
(methyl) chloride instead of in situ generation of the zirconocene iso-butyl chloride gave the
same outcome. Even using the isolated aryl lithium species with zirconocene (methyl)
chloride to generate the benzyne-complex resulted in the same undesired product. Although
tri- and tetra-ortho-susbtitutedbiaryl iodides proved elusive, compounds bearing only two
ortho-substituentscould be successfully synthesized using these reaction conditions (Scheme
11). From these biaryl iodides some novel ligands could be synthesized by simple lithiation
and subsequent addition of a chlorophosphine. These ligands are especially interesting due to
their resemblance to the new BrettPhos 22 series which are highly effective in palladiumcatalyzed cross-coupling reactions (Figure 6), where the methoxy group ortho to the
phosphine seems be of great significance.
OMe
MeO
i-Pr
OMe
PCy2
i-Pr
MeO
i-Pr
i-Pr
P(t-Bu) 2
i-Pr
i-Pr
BrettPhos
t-Bu-BrettPhos
Figure 6: BrettPhos type ligands
[16]
.
1. t-BuLi, THF -78
oC
to rt
PCy 2
1. t-BuLi, THF -78
Me 2 N
2. CI-PPh 2 , 70
0C
0C
75%
MeO.
2. CI-PCy 2 , 70 C 24h
to rt
24h
Me 2N
14% (2 steps)
Scheme 11: Biaryl phosphine ligands synthesized over two steps starting with zirconocenebenzyne cross-coupling
[17]
C. Conclusions
The synthesis of tri- and tetrasubstituted biaryl iodides via palladium-catalyzed
zirconocene-benzyne cross-coupling reaction could not be achieved. Although the initial
palladium-catalyzed
coupling was successful, further functionalization
of the aryl-
zirconocene species using a variety of elctrophiles was unsuccessful. The source of the
proton found in the biaryl could not be identified. It is possible that the proton originates
from cyclopentadienyl rings on the zirconium since other options have been eliminated
(Scheme 12).
OMe
Br
Pd(O)Ln
OMe
MeO
H
Oxidative Addition
ZrCp 2Br
OMe
OMe
MeO.
OMe
H
OMe
Scheme 12: Unknown protonation step in catalytic cycle
[18]
D. Experimental
General Considerations
All reactions were carried out in flame-dried or oven dried (150 'C) glassware under
argon using Schlenk techniques. THF was either distilled or vacuum transferred from sodium
benzophenone ketyl, the solvents were stored in Schlenk flasks with Teflon screw caps.
Alternatively solvents were stored in a glovebox and tested for moisture with sodium
benzophenone ketyl. All anhydrous solvents were purchased from Aldrich Chemical
Company. Tris(dibenzylidenecetone)dipalladium was purchased from Strem Chemicals Inc.
and stored either in the glovebox or in a desiccator. Zirconocene dichloride was a gift from
Boulder Scientific and stored in a glovebox. Iodine was purchased from Mallinckrodt and
stored in a desiccator. All liquid aryl bromides or iodides were distilled from calcium
hydride, stored in the glovebox and filtered through alumina prior to use. Solid substrates
were stored either in the glovebox or in desiccators. Products were generally purified by flash
chromatography on silica gel using the Biotage SP4 system. 'H NMR spectra were recorded
on a Bruker DRX 400 spectrometer in deuterochloroform operating at 400 MHz. 13C NMR
spectra were recorded on a Bruker DRX 400 spectrometer operating at 100 MHz. Chemical
shifts are quoted relative to residual solvent (7.26 ppm for CHC13 ) and coupling constant are
given in Hz to the nearest 0.5 Hz. The following abbreviations are used singularly or in
combination to indicate the multiplicity of signals: s singlet, d doublet, t triplet, q quartet, m
multiplet or br broad. NMR spectra were aquired at 300 K. Infrared spectra were recorded on
a Perkin-Elmer 2000 FT-IR spectrometer as thin films on KBr plates. Selected absorption
maxima (Vmax) are reported in wavenumbers (cm-1). GC analysis were performed on an
[19]
Agilent 6890 equipped with an FID detector and a Hewlett Packard 10 m - 0.2 mm HP-1
capillary column using tetradecane as an internal standard.
R
R'
Flask B
Li
Cp2Zr(
e or
Pd 2 (dba) 3, Ligand
Flask CR'
ZrC
Cp2Zr
R
ZrCp 2Br
Flask A
Scheme 12: General procedure A and B
General procedure A for the synthesis of biaryl iodides using zirconocene (methyl)
chloride:
Three oven dried Schlenk flasks with Teflon screw caps were introduced to the glove
box. Schlenk flask A was charged with zirconocene (methyl) chloride (1.4 equiv) and THF
(0.28 M), Schlenk flask B was charged with the aryl halide A (1.5 equiv) and THF (0.22 M),
Schlenk flask C was charged with Pd 2 (dba) 3 (2 mol%), the phosphine ligand (XPhos, 5
mol%), the second aryl halide B (1 equiv) and THF (0.5 M). All Schlenk flasks were then
removed from the glovebox. To Schlenk flask B containing aryl halide A, n-BuLi (1.5 equiv)
was added dropwise at -78 'C via syringe. The resulting mixture was stirred for 30 min at -78
'C and then allowed to warm to -50 OC. The solution of zirconocene (methyl) chloride in
Schlenk flask A was then added via cannula at -50 oC, the resulting solution was stirred at 50 'C for 30 min. The cold bath was then removed and the mixture was stirred for 1 h,
before it was transferred into Schlenk flask C via cannula. Schenk flask C was then sealed
[20]
and heated to 60 oC for 16-18 h. The reaction mixture was then cooled to -50 oC and a
solution of iodine (3 equiv) in dry THF (1.5 M) and methylene chloride (0.4 M) was added
via cannula. The resulting solution was stirred at 0 oC for 2 h, then warmed to room
temperature and stirred for another 10 h. The reaction mixture was poured into a saturated
solution of sodium thiosulfite and extracted with three portions of diethyl ether. The
combined organic layers were washed with brine and then dried over anhydrous magnesium
sulfate. The resulting solution was filtered through celite and then concentrated under
reduced pressure. The crude product was taken up in methylene chloride and added onto a
biotage samplet. Purification was then performed by flash chromatography on silica gel using
the Biotage SP4 system.
General procedure B for the synthesis of biaryl iodides using zirconocene dichloride:
Three oven-dried Schlenk flasks with teflon screw caps were introduced into the
glove box. Schlenk flask A was charged with zirconocene dichloride (1.5 equiv) and THF
(0.22 M), Schlenk flask B was charged with aryl halide A (1.5 equiv) and THF (0.3 M),
Schlenk flask C was charged with Pd 2 (dba)3 (2 mol%) and the phosphine ligand (5 mol%)
and aryl halide B (1 equiv) in THF (0.5 M). All Schlenk flasks were sealed and removed
from the glove box. To Schlenk flask A containing zirconocene dichloride was added t-BuLi
(1.5 equiv) via syringe at -78 'C, the resulting mixture was stirred for 15 min, then the cold
bath was removed and the reaction mixture was stirred for 75 min. The reaction mixture was
then cooled to -78 "C. To Schlenk flask B containing aryl halide A was added n-BuLi via
syringe under argon flow at -78 "C, the reaction mixture was stirred for 15 min and then
[21]
added to Schlenk flask A at -78 'C via cannula. The reaction was stirred at -78 'C for 15 min,
then at -50 'C for 30 min, after which the cold bath was removed and the reaction mixture
was stirred for another 40 min. The reaction was then transferred to Schlenk flask C
containing the catalyst and aryl halide B via cannula. The resulting mixture was then heated
to 60 'C for 16-18 h. After this period of time the reaction vessel was cooled down to -50 OC
and a solution of iodine (3 equiv) in dry THF (1.5 M) and methylene chloride (0.4 M) was
added via cannula. The resulting solution was stirred at 0 OC for 2 h, then warmed to room
temperature and stirred for another 10 h. The reaction mixture was then poured into an
aqueous saturated solution of sodium thiosulfite. The resulting biphasic mixture was
extracted with diethyl ether three times. The combined organic layers were washed with
brine once and then dried over anhydrous magnesium sulfate. The resulting solution was
filtered through celite and then concentrated in under reduced pressure. The crude product
was taken up in methylene chloride and added onto a biotage samplet. Purification was then
performed on the Biotage system using a gradient of of ethyl acetate in hexanes as an eluant.
OMe
Li
Procedure for isolation of aryllithium species
An oven dried Schlenk flask was evacuated and filled with argon (this sequence was
repeated three times). To this was added 2-bromoanisole (1 equiv, 40 mmol) and dry pentane
(2.7 M, 15 mL) via syringe. Then n-BuLi (1 equiv, 13.3 mL) was added dropwise via syringe
at room temperature. After the 2-lithioanisole precipitates out of solution, the Schlenk flask
was moved into the glovebox. The solid was washed out of the reaction vessel with pentane,
and isolated by filtration. Excess pentane was then removed under reduced pressure in the
[22]
glovebox to give quantitative yield of the desired product. The final product was stored in the
glovebox. 'H NMR (400 MHz, CD 2C12 ) 6: 7.61 (m, 1 H), 7.19 (m, 1 H), 7.17 (m, 1 H), 6.75
(m, 1 H), 3.65 (s, 3 H)
Procedure D for the synthesis of biaryl diphenyl and dicyclohexyl biaryl phoshine ligands:
The biaryliodide (1 equiv) was added to a Schlenk flask which was equipped with a
teflon screw cap, the vessel was evacuated and purged with argon three times. THF (0.1 M)
was added and the reaction cooled to -78 OC. n-BuLi (1.1 equiv, 2.5 M in hexanes) was
added via syringe, the reaction was stirred at -78 'C for 30 min. Then the chloro phosphine
(1.2 equiv) was added to the reaction mixture and stirred for 30 min at -78 'C. The reaction
was then allowed to warm to room temperature and was stirred for a further 10 h. The
reaction vessel was then opened and the resulting crude was washed with brine and back
extracted with ethyl acetate three times. The combined organic layers were dried over
magnesium sulfate and filtered through a pad of silica layered on top of celite eluting with
ethyl acetate. The resulting mixture was then concentrated in vacuo and recrystalized from
methanol with addition of methylene chloride.
OMe
PCy 2
Dicyclohexyl[2-methoxy-6-(2-methoxy)phenyl]phosphane:
MeO
The general procedure D was used, 1.03 mmol (350 mg) of the starting iodide was employed
to yield the desired biaryl in 75% yield (315 mg). 'H NMR (400 MHz, CDC13 ) 6: 7.15-7.05
(m, 2 H), 6.90 (m, 2 H), 6.6 (m, 1 H), 6.4 (m, 2 H), 3.4 (s, 3 H), 3.3 (s, 3 H), 2.5 (m, 2 H),
1.95-0.95 (m, 20 H),
31P
NMR (170 MHz, CDC13 ) 6: 0.003
[23]
OMe
PPh 2
Diphenyl[2-methoxy-6-(2-dimethylamino)phenyl]phosphane:
The general procedure D was used, 2.1 mmol (750 mg) of the crude iodide was employed to
yield the desired biaryl in 14% yield (115 mg) over 2 steps. 1H NMR (400 MHz, CDC13) 6:
OMe
7.6-7.0 (m, 15 H), 6.9 (m, 1 H), 6.5 (m, 1 H), 2.9 (s, 3 H), 2.2 (s, 6 H)
MeO
3-(2,6-dimethoxy)anisole:
OMe
General procedure B was employed to yield the biaryl compound in 78%. 'H NMR (400
MHz, CDCl 3) 6: 7.28 (m, 2 H), 7.14 (m, 1 H), 6.98 (m, 2 H), 6.61 (m, 2 H), 3.72 (s, 3 H),
3.70 (s, 6 H)
[24]
Chapter 2:
Manganese-Catalyzed Carbonylation of Alkyl Halides
A. Introduction
Transition metal-catalyzed reactions have revolutionized organic synthesis in the last 40
years. Increasing interest has focused on reactions of alkyl halides which have previously
proved challenging due to their facility in undergoing undesired P-hydride elimination and
difficulty in undergoing oxidative addition. By the choice of an appropriate ligand, elegant
studies by Fu and coworkers have demonstrated that alkyl halides can participate in a range
of transition-metal catalyzed reactions such as Suzuki, Hiyama and Nehishi couplings which
were until recently limited to aryl electrophiles.30 36 Although the transition metal- catalyzed
carbonylation of aryl halides has been the subject of intensive research due to its industrial
significance. The carbonylation of alkyl halides is far less developed. The conversion of an
alkyl halide to a homologated carbonyl compound, however, is of great utility in the
synthesis of natural products and pharmaceuticals. Present methods for this homologation
rely on the transformation of an alkyl halide to an organometalic compound such as a
Grignard reagent or organolithium, followed by quenching with carbon dioxide and
subsequent interconversion of the resulting carboxylic acid in a separate step. Alternatively,
the alkyl halide may undergo SN2 reaction with cyanide to give the homologated nitrile
followed by hydrolysis to the carboxylic acid, a mthod which, potentially offers much great
functional group tolerance of electrophilic functional groups. Furthermore if the reaction is
[25]
performed in the presence of a suitable nucleophile such as an amine or alcohol the amide or
ester may be accessed in a single synthetic operation.
The carbonylation of an alkyl halide was first reported by Chiusoli using a nickel
catalyst (Scheme 13). 37 The nickel catalyst can perform a carbonylation reaction of an allyl
chloride in presence of an alcohol to produce a 0-y unsaturated ester.
1
Ni(CO) 4
R 'J
Cl
2
R -OH
CO
O
-
R2
R2
COOR
R 1 = Alkyl,
R 2 = Et, n-Bu
Scheme 13: Nickel-catalyzed carbonylation of allyl chlorides
The reaction is believed to proceed via a radical mechanism. The reaction is run at
room temperature under one atmosphere of carbon monoxide with substoichiometric
amounts of nickel carbonyl.
Carboxyalkylation by cobalt was subsequently reported by Heck and Breslow
(Scheme 14).38 By using a cobalt carbonylate ion in the presence of either sodium methoxide
or dicyclohexylethyl amine as base a variety of alkyl halides can be carbonylated. The
reaction can occur over a range of temperatures from 0 oC for methyl iodide and 100 oC for
more difficult substrates such as chlorooctane.
[26]
The reaction requires a high pressure of carbon monoxide
(70 atm) and
substoichiometric to stoichiometric amounts of the cobalt catalyst.
R1-X
R2 -OH
0.2 - 1 equiv NaCo(CO) 4
N(Et)Cy 2 or NaOMe
0
R
RI
OR2
70 atm CO
0-100 OC
R1 = Benzyl, Allyl, Alkyl
R 2 = Me, Et
Scheme 14: Breslow's method for carbonylation
Primary and secondary alkyl halides as well as benzylic and allylic halides and a-halo
acetates could be carbonylated giving the corresponding methyl and ethyl esters in poor to
good yields. The first example of an amino carbonylation of an alkyl halide was also reported
(Table 1).
[27]
R-1
MeOH
0
NaCo(CO) 4
R
70 atm CO
Base, A
Aklyl halide
OMe
Product
Me-I
Yield
MeOAc
0
80%
0
Cl
O
0 -
20%
OMe
NO
0
Br
,
0
OMe
33%
25%
Br
OMe
O
28%
OMe
O
0OMe
OMe
'N
-
9%
0
47%
Cl
co
Table 1: Substrate scope of Breslow's method
The carbonylation of alkyl halides came more into focus in the 1980s and 1990 when
several methods for this transformation were developed using a variety of transition metal
catalysts.
[28]
In the mid- 1980s Alper and coworkers investigated carbonylation reactions of a range
of substrates using several different catalysts. 39-42 In the course of this work a catalyst for the
carbonylation of alkyl halides was found. The system described by Alper employs a
bimetallic catalyst composed of palladium and rhodium (Scheme 15). The source of the
nucleophile are either titanium or zirconium alkoxides as well as borates. The reaction
proceeds under one atmosphere of carbon monoxide at 75 or 150 'C. This method gives
moderate yields for alkyl bromides, but is most efficient for aromatic halides.
Meq
'5
Br
B(On-Bu)3
5.5% Pd(PPh 3)4
8.5% [Rh(HD)CI] 2
8.5% [Rh(HD)CI]2
1 atm CO
150 oC, 12h
O
Me
On-Bu
5
57%
Scheme 15: Combined palladium-rhodium catalyst for carbonylation of alkyl bromides
The Urata group also examined the carbonylation of carbon electrophiles. 43 48
Although most of the studies were focused on aryl iodides and benzylic halides, some alkyl
iodides and perfluoroalkyl iodides were also used as substrates. Urata mainly exploited a
cobalt or palladium catalyst to perform the transformation, although other metals were also
examined. The reaction occurs at 100 oC under 30 - 50 atmospheres of carbon monoxide.
4 5 47
Initially only perfluorinated alkyl iodides were examined for this transformation, "
these are much easier substrates due to the reduced potential to undergo 3-hydride
elimination. Although the desired acids and esters can be synthesized from the starting
iodides in modest yields several side products are also formed in significant amounts. The
base used for the alkoxy carbonylation is triethylamine and the catalyst loading is relatively
high at 20 mol% of cobalt (Scheme 16).
[29]
O
C8F 1
OE t
Me
10% C002(C00)8
I
C8 F1 7
EtOH
Me
50 atm CO
100
0C,
59%
O
24 h
CF
1 7,,OEt
24%
Scheme 16: Cobalt-catalyzed carbonylation of perfluoro alkyl iodides
The palladium system yields less of the isomerized product, but also requires high
pressure and temperature to give good yields (Scheme 17). Double carbonylation is observed
as a side product, and seems to be base dependent for this catalytic system, potassium
fluoride giving the best results for the carboxylation reaction. For the alkoxy carbonylation
triethylamine remains the base of choice.
O
5% Pd(PPh 3)2 CI2
CF17
'
I
Me
Me
ROH
R = Et 88%
-
50 atm CO
100 oC, 24 h
C8F17
OR
R = H 89%
Me
Scheme 17: Palladium-catalyzed carbonylation of perfluoro alkyl iodides
Susbsequently, Urata studied the carbonylation reaction of non-perfluorinated alkyl
iodides. The procedure could be successfully employed for primary alkyl iodides using a
cobalt catalyst. For secondary iodides the palladium catalyst gave the best results. Instead of
43-44
using an inorganic or amine base, molecular sieves are used in this system.
[30]
The reaction conditions remain harsh, requiring high temperature and pressure of
carbon monoxide (Scheme 18). For the palladium system only 2 mol% catalyst is required,
for the cobalt system 20 mol% is used.
0
a
I
2% Pd(PPh 3 )2C12
EtOH
S80%
CO 50 bar
120
0C,
48 h
4AMS
Me
a
7
Il EtOH
10% C02(CO)8
0
--
Me
CO 50 bar
100 0C, 48 h
4AMS
OEt
58%
7
Scheme 18: Palladium- and cobalt-catalyzed carbonylation of non-activated alkyl iodides
These authors later showed that by using tetraalkyl urea solvents the reactions could
be performed in slightly higher yields and without the need for added base (Scheme 19).43,48
It also proved possible to perform the carbonylation of alkyl sulfonates under these condition
by carrying out an in situ Finkelstein reaction (Scheme 20). 43
[31]
O
EtOH
5% Pd(PPh 3)2Cl 2
MeN..
OEt
1
70%
CO 50 bar
100 oC, 24 h
DMPU
Me
H20
7
10% Co 2(CO) 8
CO 50 0(C)8
bar
CO 50 bar
100 oC, 24 h
TMU
NMe
70%
DMPU
O
Me. .NMe
O
Me
OH
N
Me
97% (GC-Yield)
7
N
Me
TMU
Scheme 19: Palladium- and cobalt-catalyzed carbonylation of non-activated alkyl iodides in
tetramethyl ureas as solvents replacing the base
O
10% Co 2 (CO)8
OEt
73%
CO 50 bar
100 oC, 24 h
TMU
10% Co02(CO)8
Ph '
CO 50 bar
100 0C, 24 h
TMU
OEt
61%
Scheme 20: Carbonylation of alkyl tosylates and mesylates via in situ Finkelstein reaction
Watanabe undertook several studies of carbonylation with platinum catalysts
(Scheme 21),49-50 and a range of other metal carbonyls. Platinum catalysts were competent to
convert alkyl iodides to the homologated esters under high pressures and temperatures. The
reaction is run in 1,4-dioxane and the base of choice is potassium carbonate.
[32]
Me
'../I
MeOH
7
0
5% Pt(PPh 3)2 12
OMe
50 atm CO
9 h, 120 oC
68%
7
0
I MeOH
Me
_ 4
Me
5% Pt(PPh 3) 2 12 MeOe
OMe
50 atm CO
76%
Me
9 h, 120 oC
Scheme 21: Platinum-catalyzed carbonylation of alkyl iodides
The same reaction could be also performed at room temperature and atmospheric
carbon monoxide pressure under UV-irradiation (Scheme 22).51 The reactions are run in
THF, potassium carbonate is the optimal base.
Me
IlMeOH
7
No.
1 atm CO
10 h, r.t.
UV 200 W Hg-Lamp
I
Me
Me
MeOH
O
0
5% Pt(CO) 2(PPh 3)2 Me
Me
OMe
76%
OMe
46%
7
5% Pt(CO) 2 (PPh3 )2 Me.
\-'4
'
1 atm CO
Me
10 h, r.t.
UV 200 W Hg-Lamp
0
Scheme 22: Platinum-catalyzed carbonylation of alkl iodides at room temperature using UVirradiation
Although the main focus of Watanabe's work was platinum-catalyzed carbonylation,
various transition other metal complexes were also examined for this transformation (Table
2).51 52
[33]
O
I
MeOH
5% Mx(CO)y
OMe
1 atm CO
20 h, r.t.
UV 200 W Hg-Lamp
Metal
Carbonyl
Yield%
Conversioneld%
Cr 2 (CO)6
Mn 2 (CO)lo
Fe3(CO) 12
C0 2(CO)8
Ni(CO) 4
5(12)
88(100)
33(51)
76(88)
47(49)
Mo(CO) 6
-
Ru 3(CO) 12
RhCI(CO)(PPh 3) 2
Pd 3 (CO)3 (PPh3) 4
8(11)
-
82(100)
42(48)
25(37)
W(CO) 6
Re2(CO)o
Os3(CO)12
IrCI(CO)(PPh 3) 2
Pt(CO) 2(PPh 3)
8(21)
77(87)
67(83)
42(44)
84(87)
Metal
Carbonyl
Yield%
(Conversion%)
Metal
Carbonyl
Yield%
(Conversion%)
(Conversion%)
Table 2: Activity for several transition metal complexes for carbonylation reaction under
UV-irradiation
These authors performed thermal, photochemical and electrochemical investigations
of the mechanism of the carbonylation reaction using manganese carbonyl. 52 For the thermal
variant they discovered that by using sodium tetracarbonyl manganate, alkyl iodides could be
carbonylated at room temperature under only one atmosphere of carbon monoxide.
Cyclohexyl iodide gave the best yields, consistent with other methods. The manganate
catalyst is made from the manganese carbonyl dimer by reaction with sodium amalgam
(Scheme 23).
[34]
O
MeOH
5% Mn 2(CO)0 o
22% (28% Conversion) by GC
OMe
1 atm CO, r.t.
K2CO 3, THF
6h
MeOH
10% NaMn(CO) 5
84% (100% Conversion) by GC
1 atm CO, r.t.
0 OMe
K2CO3, THF
24 h
MeOH
0
10% KMn(CO) 5
OMe
1 atm CO, r.t.
35% (83% Conversion) by GC
K2CO 3 , THF
6h
Scheme 23: Watanabe's studies on manganese-catalyzed carbonylation of alkyl iodides
The rationale behind using the manganate anion comes from the belief that in
photochemical and electrochemical carbonylation reactions this species is formed from the
manganese carbonyl dimer in situ, generating the active catalyst (Scheme 24).52 Several
pentacarbonyl manganates were investigated and showed better activity than their neutral
analogues.
UV irradiation, or
Mn 2(CO)
10
electrolysis
'
Mn(CO)5
Scheme 24: Watanabe's theory on generation of active catalyst for carbonylation reaction
[35]
The reaction is thought to proceed via a radical mechanism based on ESR studies of
the catalytic system (Scheme 25). The fact that no alkyl dimers are formed suggests the
intervention of a tight radical pair. Further evidence for a radical process comes from the
observation that the carbonylation reaction is inhibited by the addition of radical scavengers.
[Mn(CO)n-]
I RH-1
R-Mn(CO)n
R-1
CO
R ""
Mn(CO)n
H-Mn(CO)n]
R'OH
0
R
OR'
Scheme 25: Proposed catalytic cycle for pentacarbonyl manganate-catalyzed carbonylation
reaction 52
A few alternative methods have also been published, for example Dragojlovic and
coworkers have reported a cobalt-catalyzed methoxycarbonylation of bromoalkanes in the
presence of Lewis acids (Scheme 26).53 Secondary and tertiary iodides and bromides can be
[36]
converted to the corresponding methyl esters in good yields. Aryl bromides are also viable
substrates.
O
Br
MeOH
Br
MeOH
e
-Br MeOH
OMe
92%
OMe
8% (mixture of regioisomeres)
Z9-
88%
Me
Conditions:
30-50% Co(acac) 2
1-2 equiv InCI3
MeOH:Acetone 1:3
1 atm CO, 18-48 h
5.5 W low pressure Hg-lamp
Scheme 26: Cobalt-catalyzed carbonylation of alkyl bromides under UV-irradiation in the
presence of a Lewis acid
A molybdenum-based system has been reported by Rolando and coworkers (Scheme
27). 54 By using stoichiometric molybdenum carbonyl both as a catalyst and as the source of
carbon monoxide primary iodides can be converted into the dimerized esters, while diiodides
lactonize under the aqueous reaction conditions. One of the alkyl iodides is apparently
selectively hydrolyzed while the other is carbonylated. The reaction is conducted at reflux in
THF for 20 h, with a fluoride source being essential to activate the system. The
transformation can also be run with catalytic amounts of metal by using one atmosphere
[37]
pressure
of carbon
monoxide.
Yields
are
higher
when
molybdenum
is used
stoichiometrically.
Me
1
5
1 equiv Mo(CO) 6
2 equiv TBAF
O
THF - reflux, 20 h
then FeCI 3
5
6
91% (70% for catalytic system)
2 equiv Mo(CO) 6
2 equiv TBAF
O0
70%
Na(HCO 2 )
THF - reflux, 20 h
Scheme 27: Molybdenum-promoted carbonylation of alkyl iodides with fluoride activation
The photochemical carbonylation of iodides can also be achieved in the absence of a
metal." The reaction presumably proceeds directly through the alkyl radical species. The
method is almost exclusively applicable towards secondary iodides and a variety of alcohol
nucleophiles can be used. For the reaction to proceed, carbon monoxide pressures of between
20 and 55 atmospheres and UV irradiation from a xenon lamp are required (Scheme 28).
0
CO 30 atm
n-Bu,
I
n-Bu
HO
n-Bu
r.t., 15 h
O
73%
n-Bu
K2C003, hexane
Xe-lamp
PhS
CO 50 atm
.
Me
I
EtOH
r.t., 17 h
K2C003, hexane
Xe-lamp
O
PhS
OEt
Me
Scheme 28: Photochemical carbonylation of alkyl iodides
[38]
59%
A palladium-catalyzed oxidative carbonylation of indium reagents has been recently
reported (Table 3).56 Primary and secondary alkyl indium species as well as aryl indium
reagents can be carbonylated in the presence of a palladium SynPhos catalyst and a
stoichiometric oxidant. The reaction is run at 60 OC and 50 psi carbon monoxide. The
functional group tolerance is excellent and the yields are high. The drawback of this method,
however, are the sensitive reagents which must be used in the glovebox.
3-5% PdCI 2(CH 3CN) 2
4% Synphos
O
R 3 -In
0.83 equiv Desyl Chloride
60 0C in n-BuOH
50 psi CO, 24-36 h
R
On-Bu
Product
Alkyl Indium Reagent
Yield
O
On-Bu
(CI
66%
CI
(
In
0_11On-Bu
90%
3
On-Bu
MeOOn-Bu
Table 3: Oxidative carbonylation reaction of alkyl indium reagents
[39]
83%
Despite the attention that the carbonylation of alkyl halides has received over the
previous 40 years, none of these methods has received widespread use in synthetic chemistry.
This is because all of these methods have poor functional group tolerance or require the use
of specialized high-pressure equipment. The goal of this project was to develop a transition
metal catalyst capable of bringing about the carbonylation of alkyl halides using a cheap,
readily handled catalyst in standard laboratory glassware and in the presence of a range of
functional groups, allowing application in complex molecule synthesis.
[40]
B. Results and Discussion
During initial screening the catalytic activity of a number of transition metal complexes
was examined (Figure 7). Several manganese complexes gave promising results, manganese
carbonyl dimer being superior to the other complexes examined.
OC O
OC~
CO
'
MnCO
I
OC lMncCO
CO
OCIMn'CO
CCO
CO
Manganese Carbonyl Dimer
Mn(HCO 2)2
CO
OC InCO
K Mn
K®® I CO
CO
Me
Mn
OC- I CO
CO
Cyclopentadienyl Mangenese
Tricarbonyl
Mn(OAc) 2
MMT
Potassium Pentacarbonyl
Manganate
Mnl2
MnCI2
Figure 7: Manganese complexes and salts examined for carbonylation reaction
lododecane was chosen as a model substrate to optimize and investigate the reactivity
of manganese carbonyl dimer. It was found that the conversion to the homologated ethyl
ester of iododecane with ethanol can be carried out at room temperature under only 20-40 psi
of carbon monoxide pressure (Scheme 29).
Mn 2(CO) 10
Me rI
7
EtOH -
CO, Base
O
Me
7
Et
Scheme 29: Model system for the investigation of manganese-catalyzed carbonylation
reaction
[41]
After examining several bases, potassium carbonate and potassium bicarbonate were
found to be optimal for the transformation. The bases do not have to be stored in a rigorously
dry environment (desiccator or glove box).
"
Me
I
7
0
Mn 2(CO)lo
EtOH
-
Me
CO, Base
Cyclohexane
OEt
7
100
90
80
70
60
6 Conversion
50
40
N Product
a Reduction
30
20
10
0
Li2CO3
MgCO3
Na2CO3
K2CO3
KHCO3
KOH
Table 4: Base screen for manganese-catalyzed carbonylation reaction
The use of excess base slightly lowered the yield. The best conditions were found to
be one equivalent of potassium bicarbonate or half an equivalent of potassium carbonate
(Table 4). Various solvents were screened for the reaction, cyclohexane giving both high
yields and low amounts of reduction of the alkyl electrophile (Table 5).
[42]
I
Mea
7
Mn 2(CO) 10
EtOH
D
-
CO, K2 CO 3
0
Me
7
7
OEt
100 -
90 80 70 -
60
50
40
* Conversion
30
* Product
* Reduction
2010 0-
jI
c~e
e,
eL
~
e
~c~
~
Table 5: Solvent screen for manganese-catalyzed carbonylation reaction
A catalyst loading of 3 mol% manganese carbonyl dimer was found to be optimal
(Table 6).
[43]
Me
I
EtOH
7
0
Mn 2 (CO) 10
-CO, K 2C0
Me
OEt
7
3
Cyclohexane
100
90
80
70
60
i Conversion
50
* Product
40
* Reduction
30
20
10
0
0.50%
1%
2%
4%
3%
5%
6%
Table 6: Screen of catalyst loadings for manganese-catalyzed carbonylation reaction
Higher temperatures were found to increase the rate of the reaction, but also to
increase the amount of dehalogenated product formed. Reduction of the iodoalkane to the
alkane is the main side product of the reaction, which presumably comes about through
radical abstraction of a hydrogen atom from the solvent. As a very minor side product, <1%,
of the branched ester was detected by GC-MS.
[44]
The optimized conditions for the reaction were found to be a catalyst loading of 3
mol% of the manganese dimer in cyclohexane under 40 psi of carbon monoxide, with one
equivalent of potassium bicarbonate (Scheme 30). Five equivalents of the nucleophile
ethanol were present, although when using more valuable nucleophiles this number could be
lowered to between 1.2 and 1.5 equivalents with little reduction in yield.
Me
O
3% Mn 2 (CO) 10
I
EtOH
5 equiv
7
0_
Me
OEt
7
96% GC-Yield
30 psi CO
0.5 equiv K2C03
Cyclohexane
r.t., <12 h
Scheme 30: Optimized system for manganese-catalyzed carbonylation reaction
It was found that the reaction had to be constantly exposed to ambient light in order to
proceed (Scheme 31). Using light of higher intensity or shorter wavelengths (UV) had no
effect on rate or yield of the reaction.
Isolation from any Light
O
Me
Me
OEt
-
Ambient Light
me
MeI
EtOH
7
7
O
w Me
Et
7
Trace Yield
2% Conversion
96% GC-Yield
100% Conversion
Scheme 31: Effects of light on manganese-catalyzed carbonylation reaction
[45]
Having mild conditions in hand, the scope of the reaction with a range of
electrophiles and nucleophiles was explored. It was found that primary, secondary or tertiary
alkyl iodides were viable substrates, reacting with a wide variety of alcohols as the
nucleophilic component. Several functional groups were tolerated in the transformation
including, alkyl bromides and chlorides, aryl chlorides, bromides and iodides as well as
nitriles and carbonyl groups (Table 7).
3% Mn2 (CO) 10
R2-OH
1.2 equiv
R1-l
1 equiv
O
R1 1OR2
40 psi CO
0.5 equiv K2C03
Cyclohexane
r.t., 12-24 h
Alkyl Iodide
Alcohol Nucleophile
Product
Yield
0
r
HO,~
Br
Br
o
64%
0
HO
r
63%
N
HO-
0
67%
O
N
68%
[46]
Alkyl Iodide
3% Mn 2(CO) 10
R2-OH
1.2 equiv
R1 -I
1 equiv
O
R1 "OR
40 psi CO
0.5 equiv K2C03
Cyclohexane
r.t., 12-24 h
Alcohol Nucleophile
2
Product
Yield
86%
I
HO
O
83%
0
85%
al
O
HO
N
O
HO
83%
O
O
0-
62%
O
aI
HO
Cl
seoc
Table 7: Esters generated by manganese-catalyzed carbonylation reaction
[47]
73%
No product resulting from the carbonylation of aryl iodides was observed, the
reaction was completely chemoselective. Tertiary iodides gave lower yields, presumably due
to facile elimination of HI to generate the alkene under basic conditions. Substrates bearing
heterocyclic rings containing nitrogen or sulfur require elevated temperatures. Neopentyl
iodide was a very difficult case, requiring prolonged reaction times to reach full conversion.
For the synthesis of methyl and ethyl esters, the alcohol was used as solvent, giving
very high yields of the corresponding esters (Table 8).
[48]
3% Mn 2(CO)10
R1 -I
1 equiv
R'
40 psi CO
1 equiv KHCO 3
r.t., 8-24 h
OEt
Yield
Product
Solvent
Aklyl Iodide
0
EtOH
0
Me
lI
EtOH
Me
7
Et
93%
OMe
87%
7
Me
MeOH
Me
7
7
0
Oe
OEt
EtOH
84%
0
EtOH
OEt
59%
O
Cl
I
EtOH
4
41
4
EtOH
CI
OEt
0
0
EtO
81%
0oEt
O4__
74%
Table 8: Methyl- and ethyl esters generated using manganese-catalyzed carbonylation
reaction in alcoholic solvents
[49]
Heterocyclic substrates were more difficult and required heating in order for reaction
to occur. Diiodides could be converted to the diester in good yields. Adamantyl iodide was
an easier case, probably because no elimination of HI can take place, in contrast to tert-butyl
iodide. Reaction in ethanol was quite fast, the alkyl iodide was fully converted in less than
eight hours at room temperature. Using alcohols as solvents also had advantages for the
solubility of some compounds.
In addition to alcohols, the use of amines as nucleophiles was also examined, and
found to be successful for the synthesis of primary and secondary amides.
Although a
temperature of 70 'C was required to achieve high yields, a variety of amines bearing either
alkyl or aryl substituents could be employed (Table 9).
[50]
R1-l
3% Mn 2 (CO)10
2
0
3
H-N(R )R
1 equiv
Aklyl Iodide
N(R 2)R3
R
40 psi CO
2 equiv K2C03
70 "C, 24 h
Amine
Product
Yield
O
Me
"I7
7
H-N(n-Bu) 2
H
Me fh7
N(n-Bu) 2
ON
N
84%
I
Me
H2
Me
6
6
H'N
I
93%
I
Me
84%
H2N
H2N
92%
Cl
Me
Me .7
• 7
88%
ON
H-N(n-Bu) 2
N
CN
90%
H
74%
N(n-Bu) 2
Table 9: Amides generated by manganese-catalyzed carbonylation reaction
[51]
The carbonylation reaction was significantly faster than the SN2 reaction of the amine
with the iodide, thus the amide was formed almost exclusively. The SN2 reaction was only
found to be a significant issue when primary iodides were reacted with primary amines.
Although some of the amines were visibly insoluble in cyclohexane, the reaction still
proceeded within 24 hours in excellent yield.
A number of more exotic nucleophiles were also examined. Thiols gave reasonable
yields of the homologated thioesters, although higher temperatures were required (Scheme
32).
Me
1
7
Me
HS
10
3% Mn 2(CO) 10
2 equiv K2C03
40 psi CO
cyclohexane
70
0C,
20 h
0
Me
S
7
Me
10
-60% Uncorrected GC-Yield
Detected by GC-MS
Scheme 32: Generation of thioesters by manganese-catalyzed carbonylation reaction
Preliminary results showed that free amino acids could be used as nucleophiles. An
excess of base was required to deprotonate the free acid. The reaction proceeded in
cyclohexane at elevated temperatures (Scheme 33).
H
O
H2 N
1.5 equiv
O
3% Mn 2 (CO) 10
OH
3 equiv K2C03
40 psi CO
cyclohexane
80 0C, 24 h
OOH
-70% Uncorrected LC-Yield
Detected by LC-MS
I equiv
[52]
Scheme 33: Amino Acids as Nucleophiles for Manganese-Catalyzed Carbonylation Reaction
This process has not been fully explored, the results are based on mass spectrometry
data, however, conversion of the amino acid was good. An excess of cyclohexyl iodide was
used since the amino acid is of greater value.
Azide was also examined as a potential nucleophile for the reaction. By using sodium
azide at temperatures of 70 'C
the intermediate acyl azide underwent Hofmann
rearrangement to form the isocyante. This isocyanate could then be reacted with another
nucleophile such as an alcohol to give the corresponding carbamate (Scheme 34).
0
3% Mn 2 (CO)10
Me7I
7
O0
Me
6",6
N-JNOn-Bu
2 equiv NaN 3
2 equiv K2C03
40 psi CO
cyclohexane
70 oC, 12 h
n-BuOH
70 OC, 8 h
7
in situ Rearrangement
Met,
NCO
7
-50% uncorrected GC-Yield
detected by GC-MS
Scheme 34: Azides as nucleophiles for manganese-catalyzed carbonylation reaction to yield
carbamates
[53]
Preliminary results show that aldehydes could be accessed by adding a hydride source
to the reaction mixture. Silanes proved to give some reactivity in this transformation, the best
was found to be polymethylhydrosiloxane (PMHS) (Scheme 35).
3% Mn 2(CO) 10
Me
0
MeH
l
2 equiv PHMS
40 psi CO
THF
70 oC, 16 h
7
\
PHMS =
Si-O
H
7
MMeI
,e
,H
Si-O SiH
Me
Scheme 35: Generation of aldehydes via manganese-catalyzed carbonylation reaction
It was found that bromides cannot be directly carbonylated using the manganese
catalyst. To circumvent this problem an in situ Finkelstein-reaction was considered. This
method does not only open the possibility of using bromides and chlorides, but could also be
applied to sulfonate leaving groups such as mesylates or tosylates. Interestingly, the
Finkelstein reaction took place in ethanol or methanol under the catalytic conditions (Scheme
36). A temperature of 70 'C was required for the initial Finkelstein reaction to occur. Under
these conditions the manganese-catalyzed carbonylation was faster than the Finkelstein
reaction thus no alkyl iodide was observed when the reaction is quenched at 50% conversion.
Me
Br
7
[Me
EtOH
2 equiv K2 CO 3
1 equiv Nal
40 psi CO
70 0C, 20 h
__
7
Me
7
Scheme 36: Carbonylation reaction of alkyl bromides via in situ Finkelstein reaction
[54]
The yield of the ester was, however, slightly lower than from the direct carbonylation
of iodides, probably because at the higher temperatures employed, more of the reduction side
product is being produced. The iodide was regenerated after the carbonylation reaction and
could be used catalytically (Table 10).
Preliminary results show that mesylates also undergo Finkelstein reaction under these
conditions in ethanol, subsequent carbonylation provided the corresponding ester.
Me
Mn 2(CO) 10
Br
EtOH
7
D
0
Me
CO, K2 C03, MI
7
OEt
100
90
80
70
60
50
* Conversion
40
* Product
30
* Reduction
20
10
n
lc~s~-cl
r
\O
~I~-~ ..~-LI...
iI
IA1501
P~s
CIAO 4a
I
I
---CL.__. -~X- ~
p~Ne
1e
62
I
T
~-~ ~~~~~f~
~R
-- ------7
- ____T--------
)
Table 10: Screen of iodide sources and loadings for manganese-catalyzed carbonylation
reaction in combination with in situ Finkelstein reaction
[55]
It was found that the in situ Finkelstein reaction of secondary bromides or primary
chlorides required even higher temperatures, further reducing the yield of the ester. However,
by forming the alkyl iodide prior to the carbonylation in a one flask, two step process using
one equivalent of sodium iodide, reduction of the alkyl halide could be minimized. The
Finkelstein was carried out in acetone with the starting bromide, sodium iodide and
potassium carbonate all present in the reaction mixture. The reaction was then heated to 70
'C for 12 hours, after which the acetone was removed on the Schlenk line, since it is not a
suitable solvent for the carbonylation reaction. Manganese catalyst as a solution in ethanol
was then added to the reaction, and after application of the standard conditions for
carbonylation the final product was isolated in high yield (Scheme 37).
1 equiv Nal
Me
Br
7
OH Me._BrEt_
2 equiv K2CO 3 Acetone
70
oC,
3% Mn2(CO)10
rMe
7
12 h
K
I
EtOH
EOHOEt
O
Me
7
40 psi CO
70 °C, 20 h
Scheme 37: Two step one pot carbonylation reaction of alkyl bromides
This two step process also allowed for the use of different nucleophiles which could
be added in cyclohexane solution, as opposed to the one step method which only provided
methyl- and ethyl esters.
The mechanism of this reaction has not been explored; Watanabe and coworkers have
proposed a radical mechanism for the pentacarbonyl manganate anion-catalyzed reaction. It
is likely that the manganese carbonyl dimer-catalyzed carbonylation also proceeds via a
radical mechanism. Light is known to dissociate the manganese carbonyl dimer; or to
[56]
labialize carbon monoxide ligands. Studies on methyl manganese pentacarbonyl reveal that
carbon monoxide is inserted via an alkyl migration. Consistent with previous data a catalytic
cycle can be proposed (Scheme 38).
Mn2(CO) 10
I hv
HI- K2C03
SMn(CO) 5
R-1
SET
[ R-I
Mn(CO) 5
R'-I--- Mn(CO)5]
R
,Mn(CO)n -
-Mn(CO) 5J
Oxidative Addition
via Radical Pathway
O
R
[R
OR ,
Alkyl Migration
O0
R
Mn(CO)n
R'OH
0
R
)"
Mn(CO)n
Scheme 38: Proposed catalytic cycle
[57]
C. Conclusions
A general protocol for the carbonylation of alkyl iodides has been developed. The method
may also be applied to alkyl bromides, chlorides or mesylates by generating the iodide in situ
via a Finkelstein reaction. Esters, amides, thioesters, aldehydes and carbamates could be
accessed through this transformation. The reaction conditions are very mild, with reactions
proceeding at room temperature for most substrates, and using a relatively low carbon
monoxide pressure of only 40 psi, which does not require specialized high-pressure
equipment. For methyl and ethyl esters the alcohol itself can serve as the solvent, whilst other
substrates are run in environmentally friendly cyclohexane. Although the catalyst is not
sensitive to moisture, air tends to oxidize the complex over the course of several weeks. In
particular the solvents have to be degassed due to the higher sensitivity of the catalyst
towards oxygen in solution. Overall, both the functional group tolerance and substrate scope
of the method is excellent, with primary, secondary or tertiary alkyl halides producing good
yields in the transformation.
The method is synthetically valuable to due to its ability to convert alkyl iodides into a
variety of the corresponding homologated carbonyl compounds under very mild conditions.
[58]
D. Experimental
General Considerations:
All reactions were carried out in oven-dried glassware using standard Schlenk
techniques. All commercial iodides were filtered through a plug of alumina prior to use. The
solvents, cyclohexane, ethanol and methanol were degassed prior to use. Degassing consisted
of freezing the solvent in liquid nitrogen under vacuum, then thawing the solution while
keeping the vessel closed. This process was repeated once. Liquid reagents were degassed
the same way. Manganese carbonyl was purchased from Strem Chemical and stored in the
glove box. Flash chromatography was performed using the Biotage SP4 system. 1H NMR
spectra were recorded on a Bruker DRX 400 spectrometer in deuterochloroform operating at
400 MHz.
13C
NMR spectra were recorded on a Bruker DRX 400 spectrometer operating at
100 MHz. Chemical shifts are quoted relative to residual solvent (7.26 ppm for CHC13) and
coupling constant are given in Hz to the nearest 0.5 Hz. The following abbreviations are used
singularly or in combination to indicate the multiplicity of signals: s singlet, d doublet, t
triplet, q quartet, m multiplet or br broad. NMR spectra were aquired at 300 K. Infrared
spectra were recorded on a Perkin-Elmer 2000 FT-IR spectrometer as thin films on KBr
plates. Selected absorption maxima (Vmax) are reported in wavenumbers (cm'). GC analysis
were performed on an Agilent 6890 equipped with an FID detector and a Hewlett Packard 10
m - 0.2 mm HP-i capillary column using tetradecane as an internal standard.
[59]
General procedure C for the carbonylation reaction of alkyl iodides:
Into an oven-dried Schlenk flask with Teflon screw cap was added the manganese
carbonyl dimer (3mol%), potassium carbonate (1 equiv) and the alkyl iodide (1 equiv) or
nucleophile (1.2 equiv) if solid. The flask was then sealed, evacuated and charged with argon
three times. Cyclohexane (0.13 M), methanol or ethanol was added via syringe followed by
alkyl iodides (lequiv) or nucleophiles (1.2 equiv). The vessel was then charged with carbon
monoxide (40 psi) through a three way stop cock. The vessel was pressurized and released
into the argon line three times before the final charge. The reaction vessel was then stirred at
the specified temperature until full conversion was achieved as determined by GC analysis.
After the reaction was completed, the reaction was allowed to cool to room temperature and
the pressure carefully released. The reaction mixture was then poured into brine and
extracted with ethyl acetate (3 times). The combined organic layers were dried (MgSO 4),
filtered and concentrated under reduced pressure. The residue was dissolved in methylene
chloride and purified via flash chromatography on silica gel using the Biotage SP4.
Procedure for carbonylation combined with in situ Finkelstein
Into an oven dried Schlenk flask with Teflon screw cap were added the reagents
according to general procedure C. In addition sodium iodide (0.5 equiv) was added to the
reaction mixture. The vessel was then sealed and heated to 70 OC until full conversion was
achieved as determined by GC. The product was worked up and purified according to general
procedure C.
[60]
Procedure for one pot two step Finkelstein followed by carbonylation:
Into an oven dried Schlenk flask with Teflon screw cap were added the alkyl electrophile
(alkyl chloride, alkyl bromide or alkyl mesylate, 1 equiv), sodium iodide (1.05 equiv) and
potassium carbonate (1 equiv). Acetone (0.2 M) was added and the reaction mixture was
stirred until full conversion was achieved. The solvent was then removed on the Schlenk line
and the vessel was evacuated and purged with argon three times. A solution of the
manganese carbonyl (3 mol%) in degassed methanol or ethanol (0.2 M) was added. The
vessel was then charged with carbon monoxide according to general procedure C and the
reaction was then stirred at room temperature for 12 h. The workup and isolation of the final
product was performed according to general procedure C.
Procedure for converting alcohols into iodides:
The alkyl alcohol (primary or secondary, 1 equiv) was dissolved in anhydrous
methylene chloride (0.1 M), then triphenylphosphine (1.2 equiv) and imidazole (2 equiv)
were added to the solution. The reaction was then cooled to 0 oC and iodine (3 equiv) was
added slowly. The cold bath was removed and the reaction mixture was stirred for 1 h. After
this period of time n-propanol (20 equiv) was added and stirring continued for 30 min. The
excess iodine was then slowly quenched with saturated sodium thiosulfate solution. The
reaction mixture was poured into brine and extracted with ethyl acetate (3 times). The
combined organic layers were dried over magnesium sulfate, and filtered through alumina
and concentrated in vacuo. Pentane was added and the resulting suspension filtered through
[61]
alumina, then concentrated and purified via flash chromatography on the Biotage SP4 system
using a gradient of ethyl acetate in hexanes.
Individual Procedures:
0
N
H
N-(3cyanophenyl)cyclohexanecarboxamide:
General Procedure C was employed using cyclohexyl iodide (2 mmol, 260
CN
1 L),
3-
aminobenzonitrile (2.6 mmol, 307 mg) and potassium carbonate (4 mmol, 552 mg) with
following exceptions: The reaction was heated to 70 oC in cyclohexane (15 mL) for 24 h, in
addition to the work up reported in general procedure C the organic phase was washed in 1
M HC1. After Concentration of the combined organic layers the crude was taken up into
methylen chloride and purified via flash chromatography using ethyl acetate in hexanes as an
eluent to yield 411.0 mg (90%) of the desired amide. 'H NMR (400 MHz, CDC13) 8: 7.95 (s,
1H), 7.71 (d, 7.3 Hz, 1 H), 7.39 (m, 2H), 2.25 (m, 1 H), 1.97-1.29 (m, 10 H) 13C NMR (130
MHz, CDC 3) 8: 175.6, 139.3, 129.8, 127.4, 124.2, 123.1, 112.5, 46.3, 29.6, 25.6, 25.5; vmaX
(film) / cm' 3447, 1664
N-(4-chlorophenyl)-N-methylcyclopentanecarboxamide:
N
Me
General Procedure C was employed using cyclopentyl iodide (2 mmol, 231 qL), 3aminobenzonitrile (4 mmol, 660 iL) and potassium carbonate (4 mmol, 552 mg) with
following exceptions: The reaction was heated to 70 'C in cyclohexane (15 mL) for 24 h, In
addition to the work up reported in general procedure C the organic phase was washed in 1
[62]
M HC1. After concentration of the combined organic layers the crude was taken up in
methylene chloride and purified via flash chromatography using ethyl acetate in hexanes as
an eluent to yield 441.0 mg (93%) of the desired amide. 'H NMR (400 MHz, CDCl 3) 6: 7.24
(m,2 H), 7.02 (m,2 H), 3.96 (m,1 H), 3.08 (m,3 H), 2.38 (m,1 H), 1.91 (m,2 H), 1.63-1.09
(m, 10 H), 13 C NMR (130 MHz, CDC13) 6: 176.8, 142.8, 133.4, 129.9, 128.9, 41.9, 37.6,
31.1, 26.2; vmax (film) /cm' 2955, 1655, 1490, 1092, 1014, 840
O
3-iodobenzyl cyclohexanecarboxylate:
°
General Procedure C was employed using cyclohexyl iodide (2 mmol, 260 qL), (3iodophenyl)methanol (2.6 mmol, 340 flL) and potassium bicarbonate (2.6 mmol, 260 mg),
the reaction was run at room temperature in cyclohexane (15 mL) for 24 h, giving the desired
ester in 83% Yield (571 mg). 'H NMR (400 MHz, CDC13) 8: 7.65 (m,2 H), 7.27 (m,1 H),
7.04 (m, 1 H), 4.99 (s, 2 H), 2.32 (m, 1 H), 2.00-1.22 (m, 10 H), 13C NMR (130 MHz,
CDC13) 6: 175.5, 138.6, 137.1, 136.8, 130.3, 127.1, 94.4, 64.8, 43.1, 29.0, 25.8, 25.5; vmax
(film)/ cm' 2932, 1732, 1567, 1164
0
O Et
ethyl adamantane-l-carboxylate:
General procedure C was employed using 1-adamantyl iodide (2 mmol, 525 mg) and
potassium bicarbonate (2 mmol, 200 mg) in ethanol (15 mL). The reaction was run at room
temperature for 12 h yielding the desired ester in 84% (349 mg). 'H NMR (400 MHz, CDCl 3)
[63]
6: 4.00 (m, 2 H), 1.91 (m, 3 H), 1.78 (m, 6 H), 1.61 (m, 6 H), 1.14 (m, 3 H),
13
C NMR (130
MHz, CDCl 3) 6: 177.6, 59.9, 40.5, 38.8, 36.5, 27.9, 14.2; vmax (film) / cm 1' 2907, 1729, 1453,
1235, 1078
0
2-(pyridin-2-yl)ethyl cyclopentanecarboxylate:
N
General procedure C was employed using cyclopentyl iodide (2 mmol, 231 7L), 3-(pyridin2-yl)propan-l-ol (2.6 mmol, 347 r9L) and potassium carbonate (2.6 mmol, 552 mg), the
reaction was run at 70 'C in cyclohexane (15 mL) for 24 h yielding the desired ester in 83%
(363 mg). 'H NMR (400 MHz, CDC13 ) 6: 8.37 (m, 1 H), 7.44 (m, 1 H), 7.00 (m 2 H), 4.29
(m, 2 H), 2.95 (m, 2 H), 2.51 (m, 1 H), 1.65-1.37 (m, 8 H), 13 C NMR (130 MHz, CDC13) 6:
175.9, 157.5, 148.8, 135.7, 122.8, 120.9, 62.7, 43.1, 36.8, 29.3, 25.2; vmax (film) / cm "1 2959,
1730, 1592, 1437, 1182, 756
6-chlorohexyl 3,3-dimethylbutanoate:
I
o
General Procedure C was employed using neopentyl iodide (2 mmol, 265 rqL), 6chlorohexan-l-ol (2.6 mmol, 347 rL) potassium carbonate (2.6 mmol, 552 mg). The reaction
was run at 70 'C in cyclohexane for 24 h, yielding the desired ester in 73% yield (341 mg).
'H NMR (400 MHz, CDC13 ) 6: 4.00 (m, 2 H), 3.47 (m, 2 H), 2.13 (s, 2 H), 2.13-1.33 (m, 8
H), 0.97 (s, 9 H), 13C NMR (130 MHz, CDC13) 6: 171.8, 63.3, 47.5, 44.3, 31.9, 30.1, 29.1,
28.0, 25.9, 24.8; vmax (film) / cm "' 2956, 1732, 1466, 1229, 1131
[64]
O
N
N-hexylcyclohexanecarboxamide:
General procedure C was employed cyclohexyl iodide (2 mmol, 260 iL), octylamine (4
mmol, 660 IL) and potassium carbonate (4 mmol, 552 mg). The reaction was run at 70 oC in
cyclohexane for 24 h yielding the desired amide in 92% (388 mg). In addition to the standard
workup the product was washed with 1 M HC1. 'H NMR (400 MHz, CDC13 ) 6: 5.99 (m,1
H), 3.16 (m,2 H), 2.02 (m,3 H), 1.76-1.21 (m,23 H), 0.81 (m,3 H),
13C
NMR (130 MHz,
CDC13) 6: 176.1, 45.0, 38.9, 31.2, 29.1, 29.0, 28.7, 28.6, 26.3, 25.2, 22.1, 20.4, 13.5; vmax
(film) /cm'1 3300, 1950, 1630
O
N
N,N-dibutylundecanamide:
General procedure C was employed with following additions: the crude reaction mixture was
washed with 1 M HC1. The reaction was setup using iodo decane (2 mmol, 427 rL),
dibutylamine (4 mmol, 676 rqL) and potassium carbonate (4 mmol, 552 mg). The reaction
was run at 70 'C in cyclohexane for 24 h yielding the desired amide in 88% (522 mg). 'H
NMR (400 MHz, CDC13 ) 6: 3.15 (m,2 H), 3.07 (m,2 H), 2.13 (m,2 H), 1.38-1.13 (m,24 H),
0.80 (m,9 H), '3 C NMR (130 MHz, CDC13) 6: 172.0, 47.1, 45.0, 32.5, 31.3, 30.7, 29.4, 29.0,
28.9, 28.7, 24.9, 22.1, 19.7, 19.5, 13.2, 13.0, 12.9; vmax (film) / cm -1 2929, 1645, 1465
O
Methyl undecanoate:
O
General procedure C was employed using iododecane (2mmol, 427 gL), potassium
bicarbonate (2mmol, 200 mg) in methanol (15 mL) as a solvent and nucleophile. The
[65]
reaction was stirred at room temperature for 8 hours to yield the desired ester in 87% (348
mg) yield. 1H NMR (400 MHz, CDC13) 6: 3.59 (s, 3 H), 2.23 (t, 2 H), 1.55 (m, 2 H), 1.20 (m,
15 H), 0.81 (m, 3 H), 13C NMR (130 MHz, CDC13) 6: 173.6, 50.7, 33.5, 31.3, 29.0, 28.9,
28.8, 28.7, 28.6, 24.4, 22.1, 13.5; vmax (film) / cm- 3461, 2926, 1743, 1436, 1170
Ethyl undecanoate:
O
,
0--/
General procedure C was employed using iododecane (2mmol, 427 4L), potassium
bicarbonate (2mmol, 200 mg) in methanol (15 mL) as a solvent and nucleophile. The
reaction was stirred at room temperature for 8 hours to yield the desired ester in 93% (398
mg) yield. 'H NMR (400 MHz, CDC13) 6: 4.08 (q, 2 H), 2.23 (t, 2 H), 1.56 (m, 2 H), 1.21 (m,
17 H), 0.82 (m, 3 H), 13C NMR (130 MHz, CDC13) 8: 173.6, 59.8, 34.1, 29.3, 29.2, 29.1,
29.0, 28.9, 24.8, 22.5, 14.0, 13.8; vmax (film) / cm' 2929, 1739, 1178
N-(tert-butyl)undecanamide:
N
H
General procedure C was employed using iododecane (2mmol, 427 pL), potassium carbonate
(4 mmol, 552 mg) in cyclohexane (15 mL). The reaction was heated to 70 oC for 24 h, in
addition to the general workup, the crude solution was also washed with 1 M HC1, to yield
the desired amide in 84% (405 mg) yield. 'H NMR (400 MHz, CDCl3 ) 6: 5.39 (m, 1 H), 1.98
(q, 2 H), 1.51 (m, 2 H), 1.26-1.17 (m, 22 H), 0.79 (t, 3 H),
13C
NMR (130 MHz, CDC13 ) 6:
172.4, 50.8, 37.5, 31.7, 29.4, 29.3, 29.2, 29.1, 29.0, 28.6, 25.6, 22.5, 13.9; Vmax (film) / cm - 1
3306, 2933, 1700, 1600, 1450, 1350
[66]
O
2-phenoxyethyl cyclohexanecarboxylate:
0
General procedure C was employed using iodocyclohexane
(2mmol, 260 ptL), 2-
phenoxyethanol (2.4 mmol, 299 gL) and potassium carbonate (2.6 mmol, 360 mg) in
cyclohexane (15 mL) to give the desired ester in 86% (427 mg) yield. 'H NMR (400 MHz,
CDC13) 6: 7.27 (m,2 H), 6.90 (m,3 H), 4.39 (m,2 H), 4.13 (m,2 H), 2.33 (m, 1 H), 1.881.24 (m,10 H), 13C NMR (130 MHz, CDC13) 6: 175.9, 158.4, 129.4, 121.0, 114.5, 65.8, 62.4,
42.9, 28.9, 25.6, 25.3
O
2-phenoxyethyl cyclopentanecarboxylate:
O
'O'
General procedure C was employed using iodocyclopentane (2mmol, 231 gL), 2phenoxyethanol (2.4 mmol, 299 jiL) and potassium carbonate (2.6 mmol, 360 mg) in
cyclohexane (15 mL) to give the desired ester in 85% (398 mg) yield. 1H NMR (400 MHz,
CDC13) 6: 7.27 (m,2 H), 6.91 (m,3 H), 4.40 (m,2 H), 4.13 (m,2 H), 2.75 (m,1 H), 1.82 (m,
8 H),
13C
NMR (130 MHz, CDC13) 8: 176.2, 158.0, 129.0, 120.6, 114.1, 65.4, 62.1, 43.2,
29.5, 25.3
0
2-phenoxyethyl pivalate:
O
0O
General procedure C was employed using tert-butyl iodide (2mmol, 238 pgL), 2phenoxyethanol (2.4 mmol, 299 pL) and potassium carbonate (2.6 mmol, 360 mg) in
cyclohexane (15 mL) to give the desired ester in 68% (302 mg) yield. 'H NMR (400 MHz,
CDC13) 6: 7.27 (m,2 H), 6.91 (m,3 H), 4.40 (m,2 H), 4.14 (m,2 H), 1.21 (s, 9 H),
(130 MHz, CDC13) 6: 178.3, 158.1, 129.0, 120.6, 114.2, 65.4, 62.2, 38.3, 26.7
[67]
13C
NMR
0
3-bromobenzyl pivalate:
Br
-
General procedure C was employed using tert-butyl iodide (2mmol, 238 pL), 2-(3bromophenyl)methanol (2.6 mmol, 312 1.L) and potassium carbonate (2.6 mmol, 360 mg) in
cyclohexane (15 mL) to give the desired ester in 64% (364 mg) yield. 1H NMR (400 MHz,
CDC13) 6: 7.44 (m,2 H), 7.21 (m,2 H), 5.02 (s, 2 H), 1.19 (s, 9 H), 13 C NMR (130 MHz,
CDC13) 6: 177.7, 138.3, 130.6, 130.1, 129.6, 125.7, 122.1, 64.6, 38.3, 26.7; vmax (film) / cm2973, 1732, 1572, 1479, 1144, 779, 669
O
Ethyl 3-(thiophen-2-yl)propanoate:
-O.
General procedure C was employed using 2-(2-iodoethyl)thiophene (2mmol, 476 mg),
ehtanol as solvent and nucleophile, and potassium carbonate (4 mmol, 552 mg) in
cyclohexane (15 mL). The reaction was heated to 70 oC for 36 h to give the desired ester in
59% (217 mg) yield. 1H NMR (400 MHz, CDCl 3) 6: 7.21 (m,1 H), 6.95 (m,2 H), 4.11 (m,1
H), 2.94 (m,2 H), 2.59 (m,2 H), 1.21 (m,3 H), 13 C NMR (130 MHz, CDC13) 8: 172.4,
140.4, 127.5, 125.1, 120.1, 60.0, 34.7, 25.0, 13.8
0
3-iodobenzyl pivalate:
OI
General procedure C was employed using tert-butyl iodide (2mmol, 238 pL), 2-(3iodophenyl)methanol (2.6 mmol, 340 pL) and potassium carbonate (2.6 mmol, 360 mg) in
cyclohexane (15 mL) to give the desired ester in 63% (401 mg) yield. 1H NMR (400 MHz,
CDC13) 6: 7.64 (m, 2 H), 7.59 (m,1 H), 7.26 (m,1 H), 4.99 (s, 2 H), 1.19 (s, 9 H), 13C NMR
[68]
(130 MHz, CDC13) 6: 177.5, 138.3, 136.5, 136.0, 129.8, 126.3, 93.9, 64.4, 38.3, 26.7; vmax
(film) / cm' 3439, 1642
O
N
N,N-dibutyl-3,3-dimethylbutanamide:
General procedure C was employed using neopentyl iodide (2 mmol, 265 iiL), potassium
carbonate (XX mmol, XX mg) and dibutylamine (4 mmol, 676 pL ) in cyclohexane (15 mL).
The reaction was heated to 70 oC for 24 h, in addition to the general workup, the crude
solution was also washed with 1 M HC1, to yield the desired amide in XX% (XX mg) yield.
'H NMR (400 MHz, CDC13) 8: 3.13 (m, 4 H), 2.06 (s, 2 H), 1.37 (m, 4 H), 1.17 (m, 4 H),
0.91 (s, 9 H), 0.79 (m, 6 H), 13C NMR (130 MHz, CDCl 3) 6: 171.1, 48.2, 45.4, 44.4, 31.2,
31.0, 29.8, 20.1, 19.8, 13.7, 13.6; vmax (film) / cm' 1 2957, 1641, 1466, 1364
O
Ethyl 7-chloroheptanoate:
O
C
General procedure C was employed using 1-chloro-6-iodohexane (2mmol, 308 gL), ethanol
as solvent and nucleophile and potassium carbonate (2.6 mmol, 360 mg). The reaction was
heated to 70 oC for 24 h to give the desired ester in 81% (311 mg) yield. 1H NMR (400 MHz,
CDC13) 6: 4.03 (m, 2 H), 3.44 (m, 3 H), 3.11 (m, 1 H), 2.21 (m, 2 H), 1.69-1.16 (m, 14 H),
13C
NMR (130 MHz, CDC13) 6: 173.4, 60.0, 44.8, 44.7, 44.0, 33.1, 32.2, 29.6, 28.2, 26.3,
25.6, 24.6, 14.1, 6.6
[69]
O
(tetrahydro-2H-pyran-2-yl)methyl pivalate:
0
General procedure C was employed using tert-butyl iodide (2mmol, 238 jiL), (tetrahydro2H-pyran-2-yl)methanol (2.6 mmol, 294 gL) and potassium carbonate (2.6 mmol, 360 mg) in
cyclohexane (15 mL) to give the desired ester in 67% (268 mg) yield. 1H NMR (400 MHz,
CDC13) 6:3.93 (m,4 H), 3.44 (m , 3 H), 1.78 (m , 2 H), 1.47 (m,9 H), 1.11 (s, 9 H),
13
C NMR
(130 MHz, CDC13) 6: 177.9, 75.0, 67.8, 66.6, 38.2, 27.5, 26.6, 25.3, 22.4; vmax (film) / cm'
3360, 2940, 1732, 1481, 1285, 1167
[70]
Appendix A:
Analytical Data
[71]
bJ
O'ZL
0oi-
L..
{
{
9goL L
sesc -C
oo'0 LC
[72]
eH
o NacCN
6
1,72
1,55
1,52
1,29
1,83
1,93
1,97
2,25
7,38
7,26
7,41
7,74
7,72
7,95
h.
r;
B-
[73]
o
N
H
-
CN
---
---
29,39
25,40
46,10
112,36
127,22
124,05
122,93
S129,66
139, 14
175,47
175,45
6
6
o
{
t O -[
S7-
-
[74]
Me
e
CI
4,99
7,04
7,25
7,61
7,59
7,65
--
1,22
1,61
-- 1,43
S1,40
1,70
S2,32
2,00
---- 1,87
--
001-
-
[75]
IC
Me
__~
25,74
--- 30,65
.-37,12
4 1,45
129,41
128,39
132,97
142,38
176,37
06-0
T;"L
{
684{
t76-0{
00o -
[76]
0
0o
N
V
_____
1,61
1,61
1,43
1,40
1,22
2,00
1,87
1,70
2,32
---------- 4,99
7,04
7,65
7,61
7,59
-- 7,25
--
--
[77]
-&r
28,87
25,60
25,30
42,98
64,68
94,25
136,96
136,64
130,13
126,96
J""~--- 138,49
175,58
ooz
F
{
[78]
---
T-7v--
1, 16
1,63
- 1,93
4,03
4,01
[79]
O
OEt
-
--
13,64
27,41
35,97
--- 39,96
38,25
59,39
177,06
66-0
LO'
{
va-L -{
00.1
[80]
0
\
---
-
1,37
1,48
1,49
1,55
1,64
1,63
1,57
S1,65
-2,51
2,95
2,94
2,52
4,29
7,44
7,43
7,03
7,02
6,98
6,98
8,37
8,37
N)
L
__
[81]
0
N
29,29
25,10
-----
43,11
36,83
62,73
120,95
122,80
135,68
148,77
157,50
175,92
£VS'
{C
9L -1{
oo" -
£6 L [
0I
[82]
j---
----
0,97
1,59
1,42
1,42
1,40
1,35
1,33
2,13
1,72
1,71
3,47
4,00
7,26
>c
[83]
o
CI
31,90
S44,32
47,45
-- 25,93
24,79
27,97
-- 30,14
- 29,09
/-
63,27
171,82
[84]
1,21
0,81
1,76
1,70
1,42
2,02
-
gL" -C
5,99
3,17
3,15
0
---
Loz I
001
7,26
"$;~8:
0
[85]
H
__
13,53
20,44
26,37
25,20
22,09
29,13
29,04
28,74
28,67
3 1,24
44,98
38,91
176,12
P.
_.-
..G = ..
294
-
{
oT
_
_-
.- -6
L
\
\
n
71Z
0,80
1,15
1, 13
1,11
7
1,35
1,35
2,13
3,07
3,15
7,23
i
t
e
t
[87]
0
N
19,67
19,51
22,09
28,74
24,92
28,92
47, 12
44,98
32,52
31,31
30,71
29,35
29,00
-- 28,94
-
- 171,98
9vg~
{E
t " {
oz -C
por
{
00ao -E
[88]
0
O~~
-
--
---
-
0,81
1,20
1,53
1,55
2,23
3,59
7,26
~ce,
ri
o~
~
3
~46~
It~k
.
-.
[89]
0
0~~~~
\:
--
13,49
22,11
28,59
24,38
28,9 1
28,76
28,71
29,00
31,34
33,47
50,74
173,60
wLE
EL'. {
{
LO-7 "1
161-
[90]
0
o
--
-----
0,82
1,21
1,56
2,23
4,08
\-_ 4,06
- 7,26
[91]
o
1__
\- \
13,98
13.84
22,45
28,93
24,75
29,06
29,34
29,25
29,10
31,167
34,11
59,84
173,55
{g!-"
{02
.
com -C
{8!
ssT -E
[92]
0
\\____
1,17
0,79
1,26
~~~U~~UU'Y*~
2,00
1,98
5,39
7,23
__
[93]
H
o
/
/
I
/
29,36
29,29
29, 18
29,09
29,02
28,60
25,61
22,46
13,90
37,48
31,68
50,75
172,41
{
{
9 0 I
92,0
g6u
9(3{
90 -L
ooxI
[94]
0
0
O
OPh
-
j---
-------
2,33
1,88
1,71
1,45
.1,42
1,24
4,39
4,13
6,90
-6,88
7,27
i
____
[95]
C
0
__
0
O Ph
"--
"--
---.-
25,30
28,88
25,64
42,93
62,39
65,82
120,99
114,51
129,39
158,44
175,88
{
ttON -
00'
[96]
eO,-OPh
0
1,67
1,55
1,86
1,79
2,75
4,40
4,14
6,90
7,26
[97]
0
O-0
, O
Ph
--"
--
--
29,52
25,31
43,15
62,12
65,40
120,57
114,09
128,98
158,03
176,17
[98]
1,01
00-6 f{
4,14
4,15
-
6,87
4,39
4,38
.-
6,89
-----
-.
7,26
2,22
OPh
t-6 1
gt .F{
tC
lzz {
-,o
-[O
"a~
[99]
0
O
0-I
,Ph
"---
--
30,83
29,68
47,89
62,35
65,87
121,15
114,63
129,55
158,53
158,48
172,27
{
{
go-
00'6
__
_Ir
__--~IIIIIXX IIX~^I^I~
[100]
0
O -,
OPh
----
1,18
"--. 4,15
4,39
6,90
6,88
7,27
(S.
0eb
"a0~
i
L---------
--
[101]
>
,
0
,_ OPh
-
--
26,65
38,27
--- 62,22
65,38
114,17
120,58
128,99
158,1 1
178,28
178,26
178,21
178,19
[
tL-
oo00
z:
-C
SOwe
[102]
0
OBr
1,19
5,02
--- 7,37
7,21
7,17
0et
I-
[103]
>rk
0
,
Br
-
26,71
38,31
64,57
130,57
130,12
129,62
125,69
122,05
--- 138,25
177,71
9V'- {
9CT
C
004
[104]
0
0Oss
- -----
1,21
2,59
2,94
4,10
---- 6,95
7,21
0ri
IL_
-MR
[105]
o
~___
13,77
25,02
34,70
59,99
120,12
125,11
127,53
140,38
172,36
172,32
172,24
172,40
172,42
6t'6
661
L6s0
00o -C
98e{
1{
-
-
[106]
0
-
-
7,26
1,19
4,99
7,24
.. 7,03
-
7,59
7,57
7,64
0f~
Lba
0k~
---
[107]
0
--
26,73
38,28
64,42
93,88
138,28
136,50
136,03
129,75
126,32
177,52
a~i
99{9
oo --
9V --{
o'-
,"
[108]
0
N
..
0,91
1,17
1,36
1,38
2,06
3,10
3,16
S0,78
S0,81
-
.
I
I
---------
i
_-
-
[109]
N
0O
__~
45,42
44,37
31,17
31,06
29,83
20,12
19,83
13,68
13,60
48,23
-- 171,11
9'Ce
OE {
[110]
CI
0
2,24
3,47
3,15
2,25
3
3,49
3,50
L__
1,41
1,40
1,23
1,21
1,19
1,59
- -1,75
1,73
"--
S--.
S4,07
i--- 4,09
--
CI
[111]
V;-,
1
b---------
ic
ir
I
0
K
a 9: 12
14,09
24,56
25,61
26,33
28, 16
29,55
33,07
32,19
33,98
44,69
59,99
44,77
173,38
0
o' 1
. .
[112]
S-
o
0O
-
1,12
1,44
1,76
1,76
-- 1, 79
-
1,95
3,34
3,34
3,94
3,96
3,95
4,02
--
--
0yO4
4,04
/
r.
r--
7,23
[113]
0
22,43
25,28
26,61
38,22
74,99
67,80
66,55
177,91
o' -
o -c
[01 -c
001o j--
00 1 -C
-"
[114]
OMe
Li
"-"
.
3,65
7,19
7,17
7,17
6:89
6,76
6,74
7,19
7,60
7,59
7,19
7,19
7,61
-o
1o1-:
No
[l -C
l -C
[115s]
C-
3,70
3, 72
6,63
6,61
7,14
7,14
6,98
6,97
6,95
7,28
7,26
7,24
7,23
,14
---------
--- ---------
--------
i .119
, .I jb
[116]
~~--~~---~----------------------
;.T'i7
:i.~jgq
PCy 2
.OMe
0c
N
Cm
[117]
0.003
fw- i -181
a)
0
)
.><j)
-cu4
a
C urren t Data Parameters
NAME
ZXFNO
N
IL;
F2 - Acqiisition Paraneters
D:te
Tire
INSTRUM
PRCBHD
PULPROG
TaDLVENT
NS
z
a)
5
20380512
11i.43
spect
QNP Irn
1,13
zr, 0
6553 6
CED6
7
2
8278.i46 1z
7S
la!
7IDRES
A-
4;
0.126314 Hz
3,9594243 sec
60.400 usec
6.00 usec
30C.0 K
E
TE
1O3000000
D1
sec
TCC
.
Pi
PL
sO1
--.
ChANNEL fL ---14.00 usec
0C.00oH
400.1324710
FO4
£2 - Procecsing parameters
01
65E36
SF
400.130C220
eDIW
Lb
rs
S--+- .
". .
8.0
' ! ..
.
7.5
7.0
-
- I.
....
+.
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
T
I I -,
I
2.0
1.5
"' -
1.0
T7
0.5
ppm
EM
4Hiz
C.30 Hz
0
1.00
N81
I rt?
{
00"1 -c
[119]
C\S-r
--
G
Ct
I
3,35
6,86
6,86
7,17
6,95
7,17
7,18
K
m
[120]
I_
126,81
142,88
5,08
34, 15
123,89
125,15
i-11
--
_-
Appendix B:
References
(1)
Carey, F. A., Sundberg, Richard J. Advanced Organic Chemistry. PartA. Structure
and Mechanism, 2007; Vol. 5.
(2)
The Use of Arynes in Organic Synthesis
Pellissier, H.; Santelli, M. Tetrahedron2003, 59, 2575.
(3)
A Transition-Metal Complex of Benzyne
Gowling, E. W.; Kettle, S. F. A.; Sharples, G. M. Chem Commun 1968, 21.
(4)
Oxidative Addition-Reactions of Triphenylphosphine with DodecacarbonylTriosmium(0) - Benzene-Complexes, Phenyl-Complexes and Related Complexes of Osmium
Bradford, C. W.; Mason, R.; Gainsfor.Gj; Guss, J. M.; Nyholm, R. S.; Ireland, P. R. JChem Soc
Chem Comm 1972, 87.
(5)
Fluxional Behavior of Some Cluster Complexes of Osmium Containing C 6H 4 as
Ligands
Deeming, A. J.; Underhil.M; Nyholm, R. S. JChem Soc Chem Comm 1972, 224.
(6)
Some Benzyme Complexes of Osmium Derived from Dimethylphenylphosphine
or Dimethylphenylarsine
Deeming, A. J.; Kimber, R. E.; Underhil.M JChem Soc Dalton 1973, 2589.
(7)
Metal-Complexes of Small Cycloalkynes and Arynes
Bennett, M. A.; Schwemlein, H. P. Angewandte Chemie-InternationalEdition in English 1989, 28,
1296.
(8)
Synthesis of Monomeric Niobium-Benzyne and Tantalum-Benzyne Complexes
and the Molecular-Structure of Ta(q-5-C5 Mes)(C 6 H4)Me2
Mclain, S. J.; Schrock, R. R.; Sharp, P. R.; Churchill, M. R.; Youngs, W. J. JAm Chem Soc 1979,
101, 263.
(9)
Synthesis and Single-Crystal X-Ray Study of the Mononuclear 'q -2-Benzyne
(Dehydrobenzene) Nickel(0) Complex Ni(q -2-CsH 4)((C6H1 1)2 PCH 2CH 2P(C6 H 1) 2) - Insertion
Reactions with Simple Molecules and X-Ray Crystal-Structure of the Nickelaindan Complex
Ni(CH 2CH2C 6H 4-O)((C6H 11) 2PCH 2CH 2P(C6 H 11) 2)
Bennett, M. A.; Hambley, T. W.; Roberts, N. K.; Robertson, G. B. Organometallics1985, 4, 1992.
(10)
The Trimethylphosphine Adduct of the Zirconocene Benzyne Complex Synthesis, Reactions, and X-Ray Crystal-Structure
Buchwald, S. L.; Watson, B. T.; Huffman, J. C. JAm Chem Soc 1986, 108, 7411.
[121]
(11)
Reaction of Intermediate Zirconocene - Aryne Complexes with C-H Bonds in
Thermolysis of Diarylzirconocenes
Erker, G. J Organomet Chem 1977, 134, 189.
(12)
Thermal-Decomposition of Dicyclopentadienyltitanium(Iv) Diaryl and Dibenzyl
Compounds
Boekel, C. P.; Teuben, J. H.; Deliefde.Hj J Organomet Chem 1974, 81, 371.
(13)
Mechanistic Aspects of Thermal-Decomposition of
Dicyclopentadienyltitanium(Iv)Diaryl Compounds
Boekel, C. P.; Teuben, J. H.; Liefdemeijer, H. J. D. JOrganometChem 1975, 102, 161.
(14)
A General-Method for the Preparation of Zirconocene Complexes of Substituted
Benzynes - In situ Generation, Coupling Reactions, and Use in the Synthesis of
Polyfunctionalized Aromatic-Compounds
Buchwald, S. L.; Watson, B. T.; Lum, R. T.; Nugent, W. A. JAm Chem Soc 1987, 109, 7137.
(15)
Zirconocene(Iso-Butyl) Chloride - In situ Generation of a Zirconocene(Methyl)
Chloride Equivalent for Use in Organic-Synthesis
Barr, K. J.; Watson, B. T.; Buchwald, S. L. Tetrahedron Lett 1991, 32, 5465.
(16)
Sulphur Dioxide Insertion Reactions with Dicyclopentadienyltitanium and
Dicyclopenta-Zirconium Alkyl and Aryl Compounds
Wailes, P. C.; Weigold, H.; Bell, A. P. JOrganomet Chem 1971, 33, 181.
(17)
Group-4 Metal-Complexes of Benzynes, Cycloalkynes, Acyclic Alkynes, and
Alkenes
Buchwald, S. L.; Nielsen, R. B. Chem Rev 1988, 88, 1047.
(18)
Synthesis and Structure of Zirconium Group-13 Heterobimetallic Compounds
Derege, F. M. G.; Davis, W. M.; Buchwald, S. L. Organometallics1995, 14, 4799.
(19)
Novel-Approach to Cross-Coupling Exemplified by Ni-Catalyzed Reaction of
Alkenyl-Zirconium Derivatives with Aryl Halides
Negishi, E. I.; Vanhorn, D. E. Abstr Pap Am Chem S 1977, 173, 123.
(20)
A Combined Zirconocene Benzyne-Palladium Cross-Coupling Route to
Substituted Biphenyls and Terphenyls
Frid, M.; Perez, D.; Peat, A. J.; Buchwald, S. L. JAm Chem Soc 1999, 121, 9469.
(21)
Negishi Coupling of Secondary Alkylzinc Halides with Aryl Bromides and
Chlorides
Han, C.; Buchwald, S. L. JAm Chem Soc 2009, 131, 7532.
(22)
A Highly Active Catalyst for Pd-Catalyzed Amination Reactions: CrossCoupling Reactions Using Aryl Mesylates and the Highly Selective Monoarylation of Primary
Amines Using Aryl Chlorides
Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. JAm Chem Soc 2008, 130, 13552.
(23)
Catalytic Asymmetric Vinylation of Ketone Enolates
Chieffi, A.; Kamikawa, K.; Ahman, J.; Fox, J. M.; Buchwald, S. L. Org Lett 2001, 3, 1897.
[122]
(24)
A Catalytic Asymmetric Suzuki Coupling for the Synthesis of Axially Chiral
Biaryl Compounds
Yin, J. J.; Buchwald, S. L. JAm Chem Soc 2000, 122, 12051.
(25)
Chiral Monodentate Phosphine Ligand Mop for Transition Metal-Catalyzed
Asymmetric Reactions
Hayashi, T. Accounts Chem Res 2000, 33, 354.
(26)
Novel Electron-Rich Bulky Phosphine Ligands Facilitate the PalladiumCatalyzed Preparation of Diaryl Ethers
Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L. JAm Chem Soc
1999, 121, 4369.
(27)
Expanding Pd-Catalyzed C-N Bond-Forming Processes: The First Amidation of
Aryl Sulfonates, Aqueous Amination, and Complementarity with Cu-Catalyzed Reactions
Huang, X. H.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. JAm Chem Soc
2003, 125, 10767.
(28)
A Highly Active Catalyst for Palladium-Catalyzed Cross-Coupling Reactions:
Room-Temperature Suzuki Couplings and Amination of Unactivated Aryl Chlorides
Old, D. W.; Wolfe, J. P.; Buchwald, S. L. JAm Chem Soc 1998, 120, 9722.
(29)
A Rationally Designed Universal Catalyst for Suzuki-Miyaura Coupling
Processes
Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew Chem Int Edit 2004, 43, 1871.
(30)
Intramolecular Heck Reactions of Unactivated Alkyl Halides
Firmansjah, L.; Fu, G. C. JAm Chem Soc 2007, 129, 11340.
(31)
Room-Temperature Hiyama Cross-Couplings of Arylsilanes with Alkyl
Bromides and Iodides
Lee, J. Y.; Fu, G. C. JAm Chem Soc 2003, 125, 5616.
(32)
Room-Temperature Alkyl-Alkyl Suzuki Cross-Coupling of Alkyl Bromides That
Possess Beta Hydrogens
Netherton, M. R.; Dai, C. Y.; Neuschutz, K.; Fu, G. C. JAm Chem Soc 2001, 123, 10099.
(33)
Suzuki Cross-Couplings of Alkyl Tosylates That Possess Beta Hydrogen Atoms:
Synthetic and Mechanistic Studies
Netherton, M. R.; Fu, G. C. Angew Chem Int Edit 2002, 41, 3910.
(34)
Nickel-Catalyzed Cross-Couplings of Organosillicon Reagents with Unactivated
Secondary Alkyl Bromides
Powell, D. A.; Fu, G. C. JAm Chem Soc 2004, 126, 7788.
(35)
Suzuki Cross-Couplings of Unactivated Secondary Alkyl Bromides and Iodides
Zhou, J.; Fu, G. C. JAm Chem Soc 2004, 126, 1340.
(36)
Palladium-Catalyzed Negishi Cross-Coupling Reactions of Unactivated Alkyl
Iodides, Bromides, Chlorides, and Tosylates
[123]
Zhou, J. R.; Fu, G. C. JAm Chem Soc 2003, 125, 12527.
(37)
Reazioni dell'ossido di carbonio: La funzione dem nichelcarbonile in alcune
nuove sintesi.
G. P. Chiusoli, Gazz. Chem. Ital, 1959, 89, 1332
(38)
Carboxyalkylation Reactions Catalyzed by Cobalt Carbonylate Ion
Heck, R. F.; Breslow, D. S. JAm Chem Soc 1963, 85, 2779.
(39)
Rhodium(I) Catalyzed Carbonylation Reactions of Halides and Ethers
Buchan, C.; Hamel, N.; Woell, J. B.; Alper, H. TetrahedronLett 1985, 26, 5743.
(40)
Palladium(O) and Rhodium(I) Catalysis of the Carbonylation of Unactivated
Bromides
Hashem, K. E.; Woell, J. B.; Alper, H. TetrahedronLett 1984, 25, 4879.
(41)
Synthesis of Esters by Rhodium(I) Catalyzed Borate Ester Benzylic Bromide
Carbonylation Reactions
Woell, J. B.; Alper, H. TetrahedronLett 1984, 25, 3791.
(42)
Rhodium and Palladium Catalyzed Carbonylation Reactions with Titanium and
Zirconium Alkoxides
Woell, J. B.; Fergusson, S. B.; Alper, H. J Org Chem 1985, 50, 2134.
(43)
Carbonylation of Alkyl Sulfonates Catalyzed by Cobalt Complexes
Urata, H.; Goto, D.; Fuchikami, T. Tetrahedron Lett 1991, 32, 3091.
(44)
Transition-Metal Complex Catalyzed Carbonylation of Organic Halides in the
Presence of Molecular-Sieves Instead of Base
Urata, H.; Hu, N. X.; Maekawa, H.; Fuchikami, T. TetrahedronLett 1991, 32, 4733.
(45)
Palladium-Catalyzed Double Carbonylation of Alkyl Iodides Bearing
Perfluoroalkyl Group
Urata, H.; Ishii, Y.; Fuchikami, T. TetrahedronLett 1989, 30, 4407.
(46)
A Facile Synthesis of Alpha,Omega-Dicarboxylic Acids Containing
Perfluoroalkylene Groups
Urata, H.; Kinoshita, Y.; Asanuma, T.; Kosukegawa, O.; Fuchikami, T. J Org Chem 1991, 56, 4996.
(47)
Carbonylation of 1-Perfluoroalkyl-Substituted 2-Iodoalkanes Catalyzed by
Transition-Metal Complexes
Urata, H.; Kosukegawa, O.; Ishii, Y.; Yugari, H.; Fuchikami, T. Tetrahedron Lett 1989, 30, 4403.
(48)
Transition-Metal Complex Catalyzed Carbonylation of Organic Halides in
N,N,N',N'-Tetraalkylurea Solution in the Absence of Added Base
Urata, H.; Maekawa, H.; Takahashi, S.; Fuchikami, T. J Org Chem 1991, 56, 4320.
(49)
Platinum Complex-Catalyzed Carbonylations of Organic Iodides Having BetaHydrogens Attached to sp 3 -Carbons
Takeuchi, R.; Tsuji, Y.; Watanabe, Y. J Chem Soc Chem Comm 1986, 351.
[124]
(50)
Platinum Complex Catalyzed Carbonylation of Organic Iodides - Effective
Carbonylation of Organic Iodides Having Beta-Hydrogens on Saturated sp 3 Carbons
Takeuchi, R.; Tsuji, Y.; Fujita, M.; Kondo, T.; Watanabe, Y. J Org Chem 1989, 54, 1831.
(51)
Photochemical Carbonylation of Alkyl Iodides in the Presence of Various MetalCarbonyls
Kondo, T.; Tsuji, Y.; Watanabe, Y. Tetrahedron Lett 1988, 29, 3833.
(52)
Photo Electro and Thermal Carbonylation of Alkyl Iodides in the Presence of
Group-7 and 8-10 Metal-Carbonyl Catalysts
Kondo, T.; Sone, Y.; Tsuji, Y.; Watanabe, Y. JOrganomet Chem 1994, 473, 163.
(53)
Cobalt-Catalyzed Photolytic Methoxycarbonylation of Bromoalkanes in the
Presence of a Lewis Acid
Cash, D.; Combs, A.; Dragojlovic, V. Tetrahedron Lett 2004, 45, 1143.
(54)
Fluoride-Induced Activation of Molybdenum Hexacarbonyl - Formation of
Esters and Lactones from Alkyl Iodides
Imbeaux, M.; Mestdagh, H.; Moughamir, K.; Rolando, C. JChem Soc Chem Comm 1992, 1678.
(55)
Radical Carboxylation: Ester Synthesis from Alkyl Iodides, Carbon Monoxide,
and Alcohols under Irradiation Conditions
Nagahara, K.; Ryu, I.; Komatsu, M.; Sonoda, N. JAm Chem Soc 1997, 119, 5465.
(56)
Palladium-Catalyzed Oxidative Carbonylation of Alkyl and Aryl Indium
Reagents with CO under Mild Conditions
Zhao, Y. S.; Jin, L. Q.; Li, P.; Lei, A. W. JAm Chem Soc 2008, 130, 9429.
(57)
Sir Geoffrey Wilkinson, F. G. A. S., Edward W. Abel Comprehensive
OrganometallicChemistry; Pergamon Press: Oxford, 1982; Vol. 4.
[125]
Appendix C:
Curriculum Vitae
Education
M.S., Organic Chemistry, 2009. MassachusettsInstitute of Technology.
Research Advisor: Professor Stephen L. Buchwald.
Thesis: "Palladium Catalyzed Cross-Coupling of Aryl Halides with ZirconoceneBenzyne Complexes and Manganese Catalyzed Carbonylation of Alkyl Halides".
Vordiplom Chemie, 2006. Philipps-Universitit Marburg
Professional Experience
Graduate Research with Professor Stephen L. Buchwald
Massachusetts Institute of Technology, January 2008 - September 2009
Investigation of Transition
Carbonylation Reactions.
Metal-Catalyzed
Cross-Coupling
and
Undergraduate Research with Professor Stephen L. Buchwald
Massachusetts Institute of Technology, April 2007 - September 2008
Investigation of Transition Palladium-Catalyzed Carbon-Nitrgen CrossCoupling Reactions and Ligand Development.
Teachin experience
MassachusettsInstitute of Technology, September 2007 - May 2008
Taught intermediate organic chemistry and advanced organic laboratory.
[126]