Development of a Copper-catalyzed Amidation-Base-promoted Cyclization
Sequence for the Synthesis of 2-Aryl- and 2-Vinyl-4-quinolones
By
Carrie Preston Jones
B.A. Chemistry
Williams College, 2002
SUBMITTED TO THE DEPARTMENT OF CHEMISTRY IN PARTIAL FULFILLMENT OF
THE REQUIREMENT FOR THE DEGREE OF
MASTER OF SCIENCE IN ORGANIC CHEMISTRY
AT THE
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
SEPTEMBER 2007
@Massachusetts Institute of Technology, 2007
All rights reserved
Signature of A uthor:...... '.
.......
..................................................
Department of Chemistry
June 26, 2007
Certified by: .............. .... ...............
.................
A ccepted by:....... ...........
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f'•l-__.'__~_i
MASSACHUSETTS INSTITUTE
OF TECHNOLOGY
SEP 17 2007
LIBRARIES
___
T'•
.
...............................................
Stephen L. Buchwald
Camille Dreyfus Professor of Chemistry
Academic Advisor
_- ___.L. ..
J.•
.
..
..........................
Robert W. Field
~_--.
..
..
r_'__
]_~__J__
C"IL _ J_
ts
I
Chairman,
Departmen
Development of a Copper-catalyzed Amidation-Base-promoted Cyclization
Sequence for the Synthesis of 2-Aryl- and 2-Vinyl-4-quinolones
By
Carrie Preston Jones
Submitted to the Department of Chemistry
on June 26, 2007 in Partial Fulfillment of the
Requirements for the Degree of Master of Science in
Chemistry
ABSTRACT
A direct two-step method for the preparation of 2-aryl- and 2-vinyl-4-quinolones that utilizes a
copper-catalyzed amidation of ortho-halophenonesfollowed by a base-promoted Camps
cyclization of the resulting N-(2-keto-aryl)amides is described. With Cul, a diamine ligand, and
base as the catalyst system, the amidation reactions proceed in good yields for a range of aryl,
heteroaryl, and vinyl amides. The subsequent Camps cyclization efficiently provides the desired
4-quinolones using the conditions that are described.
Thesis Supervisor : Stephen L. Buchwald
Title: Camille Dreyfus Professor of Chemistry
Acknowledgments
I would like to thank Stephen Buchwald for giving me the great opportunity to do research in his
group and for being so supportive. I would also like to thank the members of the Buchwald
group for all your help. I feel very honored to have met such genuine labmates and I greatly
value the friendships I have made through MIT. I would like to thank my chemistry mentors both
in college (Lee) and at Merck (Ping, Tom, Linus, and James) for their advice and inspiration
even now- I am very grateful for the opportunity I had to work with you. I would like to thank
my family for supporting me through all my endeavors, especially my brother, Kevin, for
emotional support and biweekly lunches, and my friends Karen and Laddie for continual
uplifting and because they too love complaining. Lastly, I want to thank Brian for enduring grad
school and for wanting me to be happy no matter what- your thoughtfulness, humor, and
understanding have been invaluable to me.
Preface
Parts of this thesis have been adapted from the following article co-written by the author.
"Sequential Cu-Catalyzed Amidation-Base-mediated Camps Cyclization: A Two-step Synthesis
of 2-Aryl-4-quinolones from ortho-Halophenones"Jones, C. P.; Anderson, K. W.; Buchwald, S.
L. J Org. Chem. 2007, submitted.
Table of Contents
Development of a Copper-catalyzed Amidation-Base-promoted Cyclization Sequence for the
Synthesis of 2-Aryl- and 2-Vinyl-4-quinolones
I.
Introduction
7
II.
Results and Discussion
15
III.
Experimental Section
23
IV.
References
45
V.
Appendix A: Selected NMR Spectra
49
VI.
Appendix B: Curriculum Vitae
67
I. Introduction
The metal-catalyzed formation of aromatic C-N bonds has become increasingly important in
organic synthesis over the past decade.' Palladium and copper catalyst systems for crosscoupling aryl halides and nitrogen nucleophiles have recently found application in the synthesis
of nitrogen-containing heterocycles. Several efficient methods have been developed in which a
sequential metal-catalyzed C-N bond-forming/cyclization process yields a heterocycle. For
example, Ma has reported a one-pot procedure for synthesizing benzimidazoles in which a Cucatalyzed amination of iodoacetanilides provides an ortho-aminoanilide that can undergo a
thermal or acid-promoted cyclization to the benzimidazole (Scheme 1, eq. 1).2 Similarly, Cucatalyzed aminations of haloenynes with hydrazines and amines followed by hydroamidation
yield pyrazoles or pyrroles, respectively (Scheme 1, eq. 2). 3 2-Naphthyridinones and 2quinolones can be prepared using a Pd-catalyzed amidation/intramolecular aldol condensation
domino synthesis (Scheme 1, eq. 3).4 Indoles 5 and pyrroles 6 have also been synthesized via
similar sequences.
Cul
L-proline
H
N
H
+ R2NH2
RJiO
X
A
or
K2CO3
R1
AOH
DMSO, RT
h2
Synthesis of Benzimidazoles
[
Cul
Cul
DMEDA
Cs2CO3
THIF, 80 OC
B oc-NH
oc-NH
R'
DMEDA
Cs2CO3
X
THF, 80 °C
H2N-Boc
R2X
R3
B
I Boc
R' N
IN-Bo c
R2
DMEDA:
TFA
Me(H)N
R3
R2
N(H)Me
Boc
I
N
R3
R2
Synthesis of Substituted Pyrroles and Pyrazoles
Y
I
Pd 2(dba)3
Xantphos
Cs2CO3
0
R1
O
N
R+
R2N
H
Ar
toluene
100 0C
R1= H, Me, Ph, OR
Y= CH or N
L
YJ
-
N
N R1
O
'
R
jy3
r --- - Y Y
0
(3)
'
Ar
R
R3= H, Me, Ph, OH
Synthesis of 2-Quinolones and 2-Naphthyridinones
Scheme 1. Metal-Catalyzed C-N Bond-formation/Cyclization Methods for the Synthesis of
Heterocycles.
Nitrogen-containing heterocycles are present in a variety of biologically-active compounds that
can be used in a wide range of therapeutic areas.7 Specifically, 4-quinolone derivatives' exhibit
antibacterial activity, and several quinolones, such as oxolinic acid and ciprofloxacin, have
emerged as potent antibiotics (Figure 1).7 More recently certain 2-aryl-4-quinolones and
compounds containing these structures have been studied as potential treatments for a range of
diseases 9 as they exhibit antimitotic, 10 antiplatelet, 9b and antiviral 9r',i activities and have positive
cardiac effects. 9a
0O
OH
Oxolinic Acid
Ciprofloxacin
Figure 1. Structures of 4-Quinolones with Antibiotic Activity.
Multiple methods have been reported for the synthesis of 2-aryl-4-quinolones
"
including two
classical approaches, the Conrad-Limpach and Niementowski reactions." The Conrad-Limpach
synthesis involves the condensation of a P-ketoester with an aniline followed by a high
temperature thermal cyclization (Scheme 2, eq. 1).11a Modifications of the method have
incorporated the use of P-ketoamides and have succeeded in lowering the temperature of the
cyclization by employing polyphosphoric acid (PPA) (Scheme 2, eq. 2). 9f,12 Recently several
groups have reported milder conditions in which Eaton's reagent (P20/MeSO 3H) is used for the
cyclization to 2- or 3-carboxy-4-quinolones at temperatures below 90 oC (Scheme 2, eq. 3).13
This new protocol has not been demonstrated for the synthesis of 2-aryl-4-quinolones.
Conrad-Limpach Reaction
NH
2
0
Ph
2
260 C
+
>>0
OH
[
eOOEt
6
e'-cyclization
Mi
N
Me
( 1)
N
H
Me
Modified Conrad-Limpach Reactions
NH2
Rl.
O
+
I
N
O
R2
A
CO2R
2
H
R
•C
or
R2= OEt or NH2
R3
R1 R(P
PPA
135-150 C
Eaton's Reagent
20 5 /MeSO 3 H)
50-90 °C
N
H
Ph 20
250
OC
0
R
(2)
I(3)
N
H
R3
R2
R2, R3= H or CO 2R
Scheme 2. Conrad-Limpach Reaction and Modifications.
The Niementowski reaction employs the condensation of anthranilic acid with a ketone or an
aldehyde for the synthesis of 4-quinolones (Scheme 3, eq. 1 ).11b Initially when acetophenone was
used in the reaction with anthranilic acid, only a 3-5% yield of the 2-phenyl-4-quinolone was
obtained. The yield was improved to 84% by using the diethyl acetal of acetophenone as the
starting material at high temperature (Scheme 3, eq. 2).14 Even with this improvement, the
temperatures employed in the reaction were still very high. Addressing these harsh reaction
conditions, a new modification of the Niementowski synthesis was recently developed in which
anthranilic acid was converted in situ to an iminoketene that cyclized via a [4n + 2X]
15 However, this
cycloaddition with a ketone to yield the desired 4-quinolones (Scheme 3, eq. 3).
synthetic route requires anthranilic acid derivatives that can withstand reaction with thionyl
chloride. Less traditional syntheses of these compounds16 make use of transition metals,
Niementowski Reaction
0
0
0
OH
+
120-130 °C
2 days
Me
N
NH2
H
3-5% yield
Modified Niementowski Reactions
0
N•
0
Me
OEt
OEt.-
N
O
Et + r
OMe
MOoMe 250 C
NH2
N Me
+ EtOH
I-"
84% yiela
0
OH
SOC 2
O
__L••
O
X
X= CH, N
NH2
NH
H
74-87% yield
Scheme 3. Niementowski Reaction and Modifications.
including palladium-catalyzed carbonylation,' 7 titanium-mediated reductive coupling,'8 and
ruthenium-catalyzed reduction reactions (Scheme 4)."19
Palladium-catalyzed Carbonylative Coupling/Cyclization
PdrC, (PPh•,
+/-'
R
NH2
2I
or
II
PdCl2(dppf)
R2
CO, Et2 NH
R2=
(1)
120 oC
'R2
aryl
49-95% yield
Titanium-mediated Reductive Coupling
TiCI3
Zn
THF
O
I
1. H2 , Pd/C
OAc
2.
,,,
NO2
O
(2)
U
66% yield
569'o yield
Ruthenium-catalyzed Reduction/Cyclization
C
Ru3(CO)12
DIAN-Me
EtOH/H 20
CO, 170 OC
(3)
R
22-60% yield
26-78% yield
Scheme 4. Metal-promoted Syntheses of 4-Quinolones.
The base-promoted cyclization of N-(keto-aryl)amides (the Camps cyclization) 20 has seen
9
widespread utilization for the synthesis of quinolones (Scheme 5 ). cf,10b-f,21 Camps'
O
R
R1
OH
R2
3
Nl**R
base
solvent
A
HO
Scheme 5. Camps Quinolone Synthesis.
N
R3
intramolecular aldol condensation was used in the scalable synthesis of BILN 2061, a drug
candidate for the treatment of Hepatitis C Virus (Scheme 6, eq. 1),9i as well as in the preparation
of the indole-substituted 4-quinolone target for SAR studies aimed at developing potent 5areductase inhibitors (Scheme 6, eq. 2).9c Several different bases and solvents have been employed
in the Camps method for cyclizing N-(keto-aryl)amides and recently a microwave protocol was
reported for the transformation.21d
0
Me
MeO
t-BuOK
DME
A
NH
N
N82%yield
S
Me
1)
Me
Synthesis of BILN (2061)
BILN (2061)
NaOMe
EtOH
t-BuOK
DMF
Me Br
(2)
I
Me
Me
Synthesis of Potential 5c-Reductase Inhibitor
Scheme 6. Pharmaceutical Applications of the Camps Quinolone Synthesis.
Crucial to the utility of the Camps cyclization is the ability to access the N-(keto-aryl)amide
starting materials. Known methods for the syntheses of these Camps precursors comprise
9 or acid chlorides
condensations of o-aminoacetophenones and carboxylic acids"
(Scheme 7, eq.
1
),9h,
10
b-e,21b,22
synthesis and subsequent opening of a benzoxazinone with the dianion of an N-
substituted acetamide (Scheme 7, eq. 2 ),20b,21a or Friedel-Crafts acylations of anilides, which often
result in mixtures of products (Scheme 7, eq. 3 and 4 ). 9i10f2 k1
0
II
=l
R
R2•I
N Me
=,
M,
R
RF
).
R2
NEt 3, THF
NH2
R2= Aryl, Heteroaryl
Amide Formation from Anilines and Acid Chlorides
O
H3C
0
R2 1 c
0
N1
H
SBuLi, -70 -C
O AOH R2Cl
R2
NH
2 R2tlor
Ri
R
N
R2
N-(Keto-aryl)amides through a Benzoxazinone Intermediate
OMe O
OMe
MeO
NH
O1ý
0
Me
CI
SnCI4
1,2-dichloroethan
NH
N
<5%
MeO
NH2
MeCN
BCI3 , AIC13
toluene-CH 2ClI
0 OC to reflux
45-55%
4.2
Friedel-Crafts Acylations for Installing o-Acetyl Groups
Scheme 7. Methods for the Formation of N-(Keto-aryl)amides.
In the next section we describe a simple sequence which employs a copper-catalyzed
amidation reaction of 2-halophenones with aryl, heteroaryl, and vinyl amides as a means to
access N-(keto-aryl)amides and their subsequent Camps cyclizations to 2-aryl- or 2-vinyl-4quinolones. We also demonstrate the ability of these same amidation products to undergo
8 22 23
McMurry titanium-mediated coupling reactions to form indoles as developed by Fiirstner.' , ,
II. Results and Discussion
Considering the established Camps cyclization for the synthesis of 2-aryl-4-quinolones, we
envisioned that a cross-coupling reaction could be applied to prepare the N-(keto-aryl)amide
Camps precursor. Retrosynthetic analysis of the N-(keto-aryl)amides suggested that a metalcatalyzed C-N bond-forming amidation approach could be utilized to install the amide portion of
the compounds using ortho-halophenonesas starting materials (Scheme 8). This approach to the
N-(keto-aryl)amide intermediates would allow easy access to different R3 groups by simply using
diverse aryl (or vinyl) amides.
0
St+
Camos
cyc.i---aio
R22
cyclization
R
'R3
l_
O
catalyzed
Amidation
R3
R2
O
+H
+ 2
2N
R
R3
(X= Br, I)
Scheme 8. Retrosynthetic Analysis of 2-Substituted-4-quinolones.
Based on the Cu(I)-catalyzed amidation of aryl halides in the presence of 1,2-diamine ligands
developed in our group, 24 We focused on the application of this methodology to aryl halides with
ortho-substituted ketones. As a test case, 2-bromoacetophenone was allowed to react with
benzamide using 10 mol% Cul, 20 mol% ligand, and 2 equivalents of K2CO 3 in toluene at 110
'C for 24 hours. In a preliminary screen employing ligands L1-L3, the reaction with L1
proceeded in the highest yield (Table 1, entry 1). We observed that 2-hydroxyacetophenone was
generated from the reaction of 2-bromoacetophenone with traces of water, presumably
introduced into the reaction mixture by moisture in the base. The formation of this by-product
could be suppressed and the yield of the desired product improved by the use of activated
molecular sieves or by a reduction in the reaction temperature to 90 OC (Table 1, entry 4).
N H2
N
.. N(H)Me
Me(H)N
N(H)Me
L1
"N(H)Me
'N(H)Me
"NH2
(+)NH
L3
L2
Figure 2. Diamine Ligands for Cu-catalyzed Amidation Reactions of Aryl Halides.
Table 1. Ligand Screening for Cu-Catalyzed Amidation with Benzamide.
0
benzamide
(1.2 equiv)
Me 20 mol% ligand,
K2C03 (2 equiv)
toluene, 24 h
(1 equv)
(1equiv)
O
M
N"1r
HO
entry ligand Cul (mol%) temp (OC) mol. sieves (5A) GC con,versiona (%) GC yielda(%)
78
c )8
no
110
10
L1
1
54
100
no
110
10
L2
2
75
100
no
110
10
L3
3
100
94
yes
90
10
L1
4
0
3
yes
90
0
L1
5
2
0
yes
0
90
6 none
76
66
yes
90
10
7 none
"GC yields and conversions are the average of two or more runs.
In a series of control experiments, we found that the reaction did not proceed in the absence of
Cul indicating that the amidation reaction does not follow a simple nucleophilic aromatic
substitution mechanism (Table 1, entries 5 and 6).25 The reaction did however yield product in
the absence of ligand (Table 1, entry 7). As reported previously in the Cu-catalyzed synthesis of
biaryl ethers, certain electron-withdrawing groups in the ortho position of the aryl halide have
the ability to coordinate to copper and hasten the Ullmann-type reaction.26 Presumably, in this
amidation reaction the o-accelerating acetyl group had the ability to promote the coupling
without the diamine ligand present. Nevertheless, the diamine ligand did enhance the rate of the
amidation reaction as the ligand-free reaction did not reach completion after 24 hours.
With these reaction conditions in hand, the versatility of the Cu-catalyzed amidation reaction
of 2-bromophenones and 2-iodophenones was explored (Table 2). The substrate scope of the
coupling reaction encompassed 2-halophenones bearing both electron-withdrawing (8-10) and
electron-donating groups (11 and 12). As demonstrated by the use of 2-halopropiophenones, the
amidation reaction also tolerated larger ketone substituents than the methyl group (11 and 12).
The couplings proceeded with heterocyclic amides, including 2-, 3-, and 4-pyridyl amides as
well as 2- and 3-thiophenecarboxamides (3-7, 10, and 12). Both aryl and alkyl vinyl amides
could be cross-coupled (13 and 14), and though the cyclic secondary amide pyrrolidinone reacted
in good yield (15), acyclic secondary amides were not effective coupling partners.
Though most reactions were conducted using the 2-bromophenones, the low reactivity of
picolinamide (5), 2-chlorobenzamide (9), and crotonamide (14) as nucleophiles prompted us to
employ the more active 2-iodophenones as substrates for these couplings. 27'" However, even
with the use of the 2-iodophenone, the yields for the syntheses of 9 and 14 were still only
moderate. The synthesis of 9 from the 2-iodophenone could be accomplished in a one-pot
procedure from the corresponding aryl bromide using a Cu-catalyzed halide exchange reaction2
followed by the Cu-catalyzed amidation reaction (Scheme 9).
Table 2. Cu-catalyzed Amidation of 2-Halophenones.
0
0
10 mol% Cul
20 mol% L
Rl1H2N R3
K2CO 3 (2equiv)
toluene
HO
1.2 equiv molecular sieves (5A)
24 h, 110 0C
product
yield (%)a X
0
0
+
R
1 equiv
(X= Br, I)
product
(1)
86 b
Me
Br
0
Br
Me
Cl
(2)
(8)
78
0
N
F
eN "
yield (%)a
83
(9)
6 7 e,f
(10)
77
HO
HO
0
(3)
N
80c
Me
Br
"NNN
F
N
0HO
0
Me
Me
MeO
Br
Me
Br
HOMe
Br
N
(1N)
0
Me
Nr
MeO
(5)
Me
7 1d
N
(12)
72
(13)
77
(14)
6 8f
(15)
89h
H
0
(6)
81c
Me
Br
9
HO
0
(7)
82
1N
Br
Me
Nl>-Me
HO
O;D
"Isolated yields are the average of two or more runs. bHeated to 90 oC. cWithout molecular
sieves. dHeated for 42 h with K3PO4. eAryl iodide generated in situ from aryl bromide. fWith 2
equiv K3 PO4. gWith 20 mol% L2. hWith 5 mol% Cul, 10 mol% L1.
CI
10 moI% Cul
20 mol% L1
F
toluene
i21
OAh
C
0
-
F
S'
I
llz
O
NH2
K3P0
1-.
4 (2equiv)
toluene
24 h,110 °C
F
N
nH
67%
Scheme 9. Synthesis of 9 via in situ Formation of 2-lodo-4-fluoroacetophenone Followed by
Cu-catalyzed Amidation Reaction.
Having developed a successful method for the synthesis of N-(2-keto-aryl)amides, we focused
on the base-catalyzed Camps cyclization to yield 2-substituted-4-quinolones. The optimal
reaction conditions for the cyclization of N-(2-keto-aryl)amide 6 to 4-quinolone 21 were found to
involve the use of 3-3.5 equivalents of NaOH in dioxane at 110 'C. The conditions proved to be
generally applicable to a wide range of N-(2-keto-aryl)amides providing the appropriate 2substituted-4-quinolones in good to excellent yields (Table 3). The cyclization method was also
effective for the syntheses of more highly substituted quinolones 26 and 27. Notably, when
submitted to the reaction conditions, the pyrrolidinone-coupled substrate 15 provided a more
complex tricyclic pyrrolo-quinolone ring system (29).
The workup of the 4-quinolone compounds was particularly facile as, with the exception of 29,
all the compounds shown in Table 3 could be isolated in pure form without the need to employ
column chromatography; after initial concentration of the organic reaction mixture, the resulting
residue was dissolved in water, and the desired products precipitated upon neutralization.
Table 3. Base-catalyzed Camps Cyclization to 2-Substituted-4-quinolones.
O
NaOH
(3-3.5 equiv)
R1
1,4-dioxane
1-2 h, 110 0C
HO
(1 equiv)
product
starting material
yield (%)a starting material
(16)
.CI (17)
yield (%)a
product
(8)
(23)
(9)
(24)
72
(25)
92
O
(18)
90
(10)
F
N
H
N
O
MI
(4)
(19)
H
88
(11)
K-
0
0
MeO
(5)
N
H
NZ
(20)
88
Me
(27)
86
(13)
(28)
82
(15)
(29)
(12)
N
H
/
0
(6)
(21)
N
S
97
H
(22)
alIsolated
yields are the average of two or more runs. bHeated to 90 'C.
Compound 14 has the ability to cyclize to either 2-vinyl-4-quinolone (30) or 4-methyl-3-vinyl2-quinolone (31) depending on the nature of the base utilized (Scheme 10). With NaOH,
deprotonation occurred at the a position of the ketone followed by the intramolecular aldol
condensation. However, the use of a weaker base (Cs 2CO 3) afforded 31 as the major product via
y-deprotonation of the amide. In both cases, traces of the other isomer were produced, which
could be readily separated by column chromatography on silica gel. Similarly, as Camps
observed, 20 a substrates with accessible protons at the a position of the amide yield a mixture of
4- and 2-quinolones rendering this method unsuitable for use with alkyl amides for the selective
preparation of 2-alkyl-4-quinolones. 30 Unfortunately, the base-dependent selectivity observed for
the synthesis of 30 and 31 was not seen for alkyl amides.
0
NaOH
(1.5 equiv)
Me
1,4-dioxane
h, 110°C
55%
0
a
e
NM
HO
CS2C0
3
(3 equiv)
14-dioxane
S21,4-dioxane
24Mh, 110HN
H0H
14
(30)
Me
H
74%
(31)
Scheme 10. Base-promoted Cyclizations to Synthesize 30 and 31
Finally, the Cu-catalyzed amidation products in Table 2 were submitted to Fiirstner's "instant"
TiCl3/Zn powder conditions'" for the McMurry Ti-promoted coupling reaction to prepare 2- and
3-substituted indoles (Table 4). The yield was low when the obtained indole contained alkyl
substituents in both the 2- and 3-positions (37).
Table 4. Ti-mediated Coupling for the Preparation of Substituted Indoles.
0
S
•
~U
np
.R
2
TiC13 (3.6 equiv)
n powder (7.2 equiv)
DME
H
N-I4R93
H O
(1 equiv)
starting
material
4-28 h, 90 OC
product
Me
(1)
yield (%)a
(35)
67
(36)
71
(37)
35
H
Me
(7)
S
H
Me
(15)
\
"Isolated yields are the average of two or more runs.
In conclusion, we have demonstrated a new two-step synthesis of 2-aryl- and 2-vinyl-4quinolones. The Cu-catalyzed amidation reaction of 2-halophenones offers access to N-(2-ketoaryl)amides that readily undergo base-promoted Camps cyclization to provide the desired 4quinolones. We have also shown the accessibility of 2- and 3-substituted indoles from the N-(2keto-aryl)amides via Ti-mediated reductive coupling. These sequential methods have potential
for application in the synthesis of substituted nitrogen-containing heterocycles.
III. Experimental Section
General Considerations. All reactions were carried out in oven-dried resealable test tubes or
Schlenk tubes under an atmosphere of argon. Potassium carbonate (Mallinckrodt or Aldrich),
potassium phosphate (Riedel-de-Hain), and cesium carbonate (Chemetall) bases were stored in
bulk in a glove box. Quantities of approximately 5 grams were removed from the glove box and
stored in a bench-top desiccator. Sodium hydroxide pellets were crushed using a mortar and
pestle and stored in the bench-top desiccator. Cul was obtained from Strem Chemicals (99.9%
purity). TiCl3 (99.999% purity) and Zn nanosize activated powder were both purchased from
Aldrich and stored and weighed in the glove box. All three diamine ligands (L1, L2, L3) were
obtained from Aldrich and stored in a bench-top desiccator. Amides and aryl halides were
obtained from commercial sources (Aldrich, TCI, Avocado, Acros, Alfa Aesar) and used without
further purification, except for 2-bromo-5-methoxypropiophenone, which was synthesized from
commercially available starting materials as described in the Supporting Information. Toluene
was obtained from J. T. Baker in CYCLE-TAINER kegs which were purged with argon for two
hours and subsequently passed through two columns of neutral alumina and copper(II) oxide
under a pressure of argon for further purification. Anhydrous 1,4-dioxane and DME were
purchased from Aldrich in SureSeal® bottles. Molecular sieves (5A) were obtained as a powder
from Acros and were activated in bulk via flame-drying under vacuum. Silica column
chromatography was performed using a Biotage SP4 Flash Purification System on KP-Sil silica
cartridges.
Compounds were characterized using 'H-NMR,
13C-NMR,
in certain cases, elemental analysis. (Copies of 'H-NMR and
melting point, IR (KBr plate) and,
13
C-NMR spectra are provided in
the Supporting Information for all new compounds and any compounds that did not have
adequate elemental analysis results.) Data of known compounds were compared with existing
literature characterization data and the references are given. All isolated and GC yields reported
in the Results and Discussion are the average of two or more experiments. Elemental Analyses
were conducted by Atlantic Microlabs, Inc., Norcross, GA. NMR spectra were obtained using
Varian 500 MHz, Bruker Advance 400 MHz, or Varian 300 MHz instruments. The chemical
shifts are reported in parts per million (ppm) based on the reference of the deuterated solvent.
Melting points (uncorrected) were measured using a Mel-Temp II capillary apparatus. GC
analysis was performed on an Agilent 6890 instrument with an FID detector and an Agilent 10m
x 0.1mm DB-1 capillary column. GC yields and conversions were reported as referenced to
dodecane as an internal standard.
GC-MS analyses were performed on an Agilent 6850
instrument with an Agilent 5975 inert Mass Selective Detector. IR spectra were measured using
a Perkin-Elmer System 2000 FT-IR. Compounds were applied in a thin film on a KBr pellet.
General Procedure A: Amidation of o-halophenones. An oven-dried resealable test tube
with a Teflon stir bar was charged with amide (1.2 equiv, 0.60 mmol), CuI (10 mol%, 0.05
mmol), base (2 equiv, 1 mmol), and approximately 200 mg activated 5 A molecular sieves. The
test tube was sealed with a rubber septum and evacuated and refilled with Argon through a
syringe needle (this sequence was performed three times). Under argon, o-halophenone (1.0
equiv, 0.50 mmol), N, N'-dimethylethylenediamine (L1) (20 mol%, 0.1 mmol), and toluene (1
mL) were each added via syringe. The rubber septum was then removed and quickly replaced
with a Teflon screw-cap. The test tube was then placed in a preheated oil bath at 110 OC. The
reaction was heated with stirring for 24 h and then cooled to room temperature. The reaction
mixture was partitioned between EtOAc and water and the organic layer separated. The aqueous
layer was extracted with EtOAc and the organic layer combined, dried over magnesium sulfate,
filtered, and concentrated in vacuo to remove solvent. The product was purified by column
chromatography on silica gel with EtOAc and hexane.
N-(2-Acetyl-phenyl)-benzamide (1).31 22 Following General Procedure A, benzamide (76 mg,
0.63 mmol) was coupled with 2-bromoacetophenone (67 pLL, 0.50 mmol) using Cul (9.5 mg,
0.050 mmol), L1 (10.5 pL, 0.985 mmol), K2CO 3 (140 mg, 1.0 mmol), and 200 mg activated 5 A
molecular sieves in anhydrous toluene (1 mL). The reaction was heated to 90 OC for 24 h. 1 was
purified by column chromatography using a hexane-EtOAc 98:2 to 90:10 gradient. 106 mg (88%
yield) of a cream-colored solid were obtained. Mp: 99-100 *C (lit mp: 100 °C (ether)).32 'HNMR (400 MHz, CDCl 3): 8 12.73 (s, 1H), 9.00 (dd, J = 8.5, 1.1 Hz, 1H), 8.08 (m, 2H), 7.98 (dd,
J = 8.0, 1.5 Hz, 1H), 7.64 (m, 1H), 7.55 (m, 3H), 7.18 (ddd, J = 8.5, 7.3, 1.2 Hz, 1H), 2.75 (s,
3H). 13C-NMR (400 MHz, CDCl3): 203.3, 166.1, 141.4, 135.4, 134.8, 132.1, 131.9, 128.9, 127.5,
122.5, 121.9, 120.7, 28.6. IR (neat, cm-'): 3222, 3064, 1679, 1650, 1607, 1585, 1450, 1359,
1313, 1247, 1166, 1099, 1073, 1028, 960, 896, 799, 756, 701, 609. Anal. calcd. for C sH
5 13NO 2:
C, 75.30; H, 5.48. Found: C, 75.10; H, 5.50.
N-(2-Acetyl-phenyl)-3-chlorobenzamide
(2).
Following
General
Procedure
A,
3-
chlorobenzamide (93 mg, 0.60 mmol) was coupled with 2-bromoacetophenone (67 pL, 0.50
mmol) using Cul (9.5 mg, 0.050 mmol), L1 (10.5 pL, 0.985 mmol), K2CO 3 (140 mg, 1.0 mmol),
and 200 mg activated 5 A molecular sieves in anhydrous toluene (1 mL). 2 was purified by
column chromatography using a hexane-EtOAc 98:2 to 90:10 gradient. 112 mg (82% yield) of a
white solid were obtained. Mp: 137-139
oC.
'H-NMR (400 MHz, CDCI3): 8 12.75 (s, 1H), 8.95
(d, J = 8.5 Hz, 1H), 8.07 (s, 1H), 7.98 (dd, J = 8.0, 1.4 Hz, 1H), 7.94 (ddd, J =7.7, 1.7, 1.1 Hz,
1H), 7.65 (m, 1H), 7.55 (ddd, J = 8.0, 2.0, 1.1 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.20 (m, 1H),
2.74 (s, 3H).
13
C-NMR (400 MHz, CDC13): 203.5, 164.7, 141.2, 136.7, 135.5, 135.1, 132.1,
132.0, 130.2, 128.2, 125.3, 122.9, 122.0, 120.8, 28.7. IR (neat, cmn'): 3185, 3068, 2920, 1684,
1644, 1608, 1584, 1523, 1452, 1359, 1315, 1258, 1170, 1076, 965, 904, 851, 798, 755, 739, 721,
611. Anal. calcd. for C sHl
5 2CINO2: C, 65.82; H, 4.42. Found: C, 65.69; H, 4.22.
N-(2-Acetyl-phenyl)-isonicotinamide (3 ).9h Following General Procedure A, isonicotinamide
(73 mg, 0.60 mmol) was coupled with 2-bromoacetophenone (67 RiL, 0.50 mmol) using CuI (9.5
mg, 0.050 mmol), L1 (10.5 pL, 0.985 mmol), and K2 CO 3 (140 mg, 1.0 mmol), in anhydrous
toluene (1 mL). No molecular sieves were added for the synthesis of the title compound. 3 was
purified by column chromatography using a hexane-EtOAc 95:5 to 50:50 gradient. 94 mg (78%
yield) of a cream-colored solid were obtained. Mp: 119-120 'C (lit mp: 116-117
33
oC).
'H-NMR
(400 MHz, CDCl 3): 8 12.91 (s, 1H), 8.96 (dd, J = 8.5, 0.9 Hz, 1H), 8.85 (d, J = 5.3 Hz, 2H), 8.01
(dd, J = 8.0, 1.5 Hz, 1H), 7.91 (dd, J =4.6, 1.6 Hz, 2H), 7.67 (m, 1H), 7.24 (ddd, J = 8.5, 7.3, 1.2
Hz, 1H), 2.75 (s, 3H).
13C-NMR
(300 MHz, CDCl 3): 203.6, 163.9, 150.9, 141.8, 140.7, 135.6,
132.0, 123.3, 122.0, 121.1, 120.8, 28.7. IR (neat, cm-'): 3205, 3120, 3029, 1678, 1645, 1611,
1586, 1535, 1449, 1410, 1362, 1317, 1251, 1161, 1062, 963, 836, 756, 692, 677. Anal. calcd. for
C14H12N20 2: C, 69.99; H, 5.03. Found: C, 69.96; H, 5.09.
N-(2-Acetyl-phenyl)-nicotinamide (4). Following General Procedure A, nicotinamide (73 mg,
0.60 mmol) was coupled with 2-bromoacetophenone (67 pL, 0.50 mmol) using Cul (9.5 mg,
0.050 mmol), L1 (10.5 [LL, 0.985 mmol), K2 CO 3 (140 mg, 1.0 mmol), and 200 mg activated 5 A
molecular sieves in anhydrous toluene (1 mL). 4 was purified by column chromatography using
a hexane-EtOAc 90:10 to 50:50 gradient. 100 mg (83% yield) of a cream-colored solid were
obtained. Mp: 114-116 OC. 'H-NMR (400 MHz, CDCl 3): 8 12.85 (s, 1H), 9.32 (d, J = 2.0 Hz,
1H), 8.96 (dd, J = 8.5, 1.1 Hz, 1H), 8.81 (dd, J = 4.8, 1.5 Hz, 1H), 8.35 (ddd, J =8.0, 2.3, 1.7
Hz, 1H), 8.00 (dd, J = 8.0, 1.6 Hz, 1H), 7.65 (m, 1H), 7.48 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 7.22
(ddd, J = 8.5, 7.4, 1.2 Hz, 1H), 2.75 (s, 3H). 13 C-NMR (300 MHz, CDCl 3): 203.5, 164.2, 152.6,
149.2, 140.9, 135.5, 134.9, 132.0, 130.3, 123.5, 123.0, 121.9, 120.7, 28.6. IR (neat, cm'-1): 3153,
2919, 1678, 1649, 1610, 1588, 1527, 1454, 1420, 1361, 1316, 1252, 1172, 1112, 1022, 963, 896,
827, 758, 717. Anal. calcd. for Cl 4HI 2N20 2: C, 69.99; H, 5.03. Found: C, 69.69; H, 5.04.
N-(2-Acetyl-phenyl)-picolinamide (5). 34 Following General Procedure A, picolinamide (73
mg, 0.60 mmol) was coupled with 2-iodoacetophenone (71 gL, 0.50 mmol) using Cul (9.5 mg,
0.050 mmol), L1 (10.5 pL, 0.985 mmol), K3 PO4 (210 mg, 0.99 mmol), and 200 mg activated 5
A
molecular sieves in anhydrous toluene (1 mL). The reaction was heated for 42 h. 5 was purified
by column chromatography using a hexane-EtOAc 95:5 to 70:30 gradient. 85 mg (71% yield) of
a pale pink solid were obtained. Mp: 109-112 'C (lit mp: 112-112.5 oC). 'H-NMR (400 MHz,
CDCl 3): 8 13.53 (s, 1H), 8.99 (d, J = 8.4 Hz, 1H), 8.76 (d, J = 4.3 Hz, 1H), 8.25 (d, J = 7.8 Hz,
1H), 7.92 (d, J =7.8 Hz, 1H), 7.86 (td, J = 7.7, 1.3 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.45 (m,
1H), 7.13 (t, J = 7.4 Hz, 1H), 2.68 (s, 3H).
13
C-NMR (300 MHz, CDCl3): 202.3, 164.0, 150.5,
148.8, 140.3, 137.5, 134.9, 131.8, 126.5, 123.2, 122.8, 122.8, 121.1, 28.7. IR (neat, cm~'): 3207,
1684, 1656, 1576, 1517, 1451, 1430, 1363, 1312, 1251, 1169, 1111, 1042 997, 961, 900, 818,
757, 693, 610. Anal. calcd. for C14HI 2N20 2: C, 69.99; H, 5.03. Found: C, 69.85; H, 5.18.
N-(2-Acetyl-phenyl)-2-thiophenecarboxamide
(6). 35 Following General Procedure A, 2-
thiophenecarboxamide (76 mg, 0.60 mmol,) was coupled with 2-bromoacetophenone (67 pL,
0.50 mmol) using Cul (9.5 mg, 0.050 mmol), L1 (10.5 [tL, 0.985 mmol), and K2 CO 3 (140 mg,
1.0 mmol) in anhydrous toluene (1 mL). No molecular sieves were utilized in the synthesis of the
title compound. 6 was purified by column chromatography using a hexane-EtOAc 98:2 to 90:10
gradient. 100 mg (82% yield) of a cream-colored solid were obtained. Mp: 131-134 'C (lit mp:
129
oC).
'H-NMR (400 MHz, CDC13): 6 12.74 (s, 1H), 8.90 (dd, J = 8.5, 1.0 Hz, 1H), 7.97 (dd, J
= 8.0, 1.4 Hz, 1H), 7.85 (dd, J = 3.8, 1.1 Hz, 1H), 7.62 (m, 1H), 7.58 (dd, J = 5.0, 1.1 Hz, 1H),
7.17 (m, 2H), 2.74 (s, 3H). 13C-NMR (300 MHz, CDCl3 ): 203.4, 160.7, 141.3, 140.4, 135.4,
132.0, 131.4, 128.8, 128.1, 122.5, 121.5, 120.5, 28.6. IR (neat, cm-'): 3208, 3094, 2919, 1661,
1641, 1608, 1587, 1541, 1450, 1354, 1315, 1247, 1166, 1094, 1029, 960, 863, 811, 754, 731,
610. Anal. calcd. for C13H,,NO 2S: C, 63.65; H, 4.52. Found: C, 63.39; H, 4.40.
N-(2-Acetyl-phenyl)-3-thiophenecarboxamide
(7). Following General Procedure A, 3-
thiophenecarboxamide (76 mg, 0.60 mmol) was coupled with 2-bromoacetophenone (67 ptL,
0.50 mmol) using Cul (9.5 mg, 0.050 mmol), LI (10.5 pL, 0.985 mmol), K2CO 3 (140 mg, 1.0
mmol), and 200 mg activated 5 A molecular sieves in anhydrous toluene (1 mL). 7 was purified
by column chromatography using a hexane-EtOAc 98:2 to 90:10 gradient. 97 mg (79% yield) of
a white solid were obtained. Mp: 90-93 OC. 1H-NMR (400 MHz, CDCl3): 8 12.63 (s, 1H), 8.93
(dd, J = 8.5, 1.1 Hz, 1H), 8.16 (dd, J = 3.0, 1.4 Hz, 1H), 7.97 (dd, J = 8.0, 1.5 Hz, 1H), 7.69 (dd,
J =5.1, 1.3 Hz, 1H), 7.62 (m, 1H), 7.41 (dd, J = 5.1, 3.0 Hz, 1H), 7.16 (ddd, J = 8.5, 7.3, 1.2 Hz,
1H), 2.73 (s, 3H). 13C-NMR (300 MHz, CDCl 3): 203.4, 161.6, 141.5, 138.4, 135.5, 132.0, 129.6,
126.8, 126.5, 122.4, 121.6, 120.6, 28.7. IR (neat, cm'): 3218, 3110, 2924, 1677, 1650, 1607,
1585, 1531, 1451, 1358, 1314, 1254, 1207, 1166, 1102, 1072, 1021, 961, 865, 838, 818, 757,
741, 610. Anal. calcd. for C1 3H1 INO2S: C, 63.65; H, 4.52. Found: C, 63.58; H, 4.41.
N-(6-Acetyl-3-fluoro-phenyl)-benzamide (8). Following General Procedure A, benzamide
(76 mg, 0.63 mmol) was coupled with 2-bromo-4-fluoroacetophenone (109 mg, 0.502 mmol)
using Cul (9.5 mg, 0.050 mmol), L1 (10.5 pL, 0.985 mmol), K2CO 3 (140 mg, 1.0 mmol), and
200 mg activated 5 A molecular sieves in anhydrous toluene (1 mL). 8 was purified by column
chromatography using a hexane-EtOAc 95:5 to 90:10 gradient. 101 mg (79% yield) of a white
solid were obtained. Mp: 123-126 'C. 1H-NMR (400 MHz, CDCI3): 8 12.91 (s, 1H), 8.78 (dd, J
= 12.1, 2.6 Hz, 1H), 8.05 (m, 2H), 7.94 (dd, J = 8.9, 6.3 Hz, 1H), 7.55 (m, 3H), 6.81 (m, 1H),
2.67 (s, 3H). 13C-NMR (300 MHz, CDCl3): 202.0, 166.5 (d,JcF = 255 Hz), 166.2, 144.0 (d, Jcr=
13 Hz), 134.4 (d, JCF = 11 Hz), 132.4, 130.2, 129.0, 127.6, 118.5 (d, JcF = 3 Hz), 109.8 (d, JC =
23 Hz), 107.8 (d, JCF = 28 Hz), 28.6. IR (neat, cm-1): 3175, 1678, 1644, 1602, 1536, 1495, 1361,
1318, 1264, 1250, 1134, 992, 873, 806, 763, 706. Anal. calcd. for C ,H,
5 2FNO2: C, 70.03; H,
4.70. Found: C, 69.86; H, 4.49.
N-(6-Acetyl-3-fluoro-phenyl)-2-chlorobenzamide
(9). An oven-dried resealable test tube
with a Teflon stir bar was charged with Cul (9.5 mg, 0.050 mmol) and Nal (150 mg, 1.0 mmol).
The test tube was covered with a rubber septum and evacuated and refilled with argon three
times through a syringe needle. Under argon, 2-bromo-4-fluoroacetophenone (109 mg, 0.502
mmol), N, N'-dimethylethylenediamine (Ll) (10.5 pL, 0.985 mmol), and toluene (1 mL) were
each added via syringe. The rubber septum was then removed and quickly replaced with a Teflon
screw-cap. The test tube was then placed in a preheated oil bath, at 110 *C. The reaction was
heated with stirring for 24 h at which point it was cooled to room temperature. Next, 2chlorobenzamide (93 mg, 0.60 mmol) and K3PO4 (210 mg, 0.99 mmol) were added quickly to
the reaction mixture. The test tube was re-capped and the reaction was heated with stirring in the
oil bath at 110 *C. After 24 h, the reaction was cooled to room temperature. The reaction mixture
was partitioned between ethyl acetate and water and the organic layer was extracted. A second
portion of ethyl acetate was used to wash the water layer and was extracted and combined with
the first layer. The organic layers were dried over magnesium sulfate, filtered, and concentrated
in vacuo to remove solvent. 9 was purified by column chromatography with a hexane-EtOAc
95:5 to 90:10 gradient. 97 mg (66% yield) of a beige solid were obtained. Mp: 105-108 °C. 'H-
NMR (400 MHz, CDCl3 ): 8 12.42 (s, 1H), 8.74 (dd, J = 11.9, 2.6 Hz, 1H), 7.95 (dd, J = 8.9, 6.3
Hz, 1H), 7.62 (dd, J = 7.5, 1.8 Hz, 1H), 7.41 (m,3H), 6.85 (dd, J = 10.0, 7.4, 2.6 Hz, 1H), 2.63
(s, 3H).
13C-NMR
(300 MHz, CDCl3 ): 201.6, 166.4 (d, JcF = 255 Hz), 166.2, 143.2 (d, JCF = 13
Hz), 135.8, 134.3 (d, JcF= 11 Hz), 131.8, 131.4, 130.8, 129.4, 127.3, 118.8 (d, JcF= 3 Hz), 110.3
(d, JcF = 22 Hz), 108.1 (d, JcF = 28 Hz), 28.7. IR (neat, cm'): 3113, 1691, 1655, 1592, 1524,
1449, 1359, 1317, 1291, 1248, 1171, 1129, 1104, 1047, 993, 956, 871, 805, 784, 744, 715. Anal.
calcd. for C15H,,CIFNO2: C,61.76; H, 3.80. Found: C,61.55; H, 3.77.
N-(6-Acetyl-3-fluoro-phenyl)-nicotinamide
(10).
Following
General
Procedure
A,
nicotinamide (73 mg, 0.60 mmol) was coupled with 2-bromo-4-fluoroacetophenone (109 mg,
0.502 mmol) using Cul (9.5 mg, 0.050 mmol), L1 (10.5 pL, 0.985 mmol), K 2CO 3 (140 mg, 1.0
mmol), and 200 mg activated 5 A molecular sieves in anhydrous toluene (1 mL). 10 was purified
by column chromatography using a hexane-EtOAc 95:5 to 50:50 gradient. 97 mg (75% yield) of
a white solid were obtained. Mp: 165-167 oC. 'H-NMR (400 MHz, CDCl 3): 8 13.04 (s, 1H), 9.30
(s, br, 1H), 8.81 (s, br, 1H), 8,74 (dd, J = 11.9, 2.7 Hz, 1H), 8.32 (d, J =8.0 Hz, 1H), 7.99 (dd, J
= 8.9, 6.2 Hz, 1H), 7.47 (dd, J = 7.7, 4.7 Hz, 1H), 6.87 (ddd, J = 10.0, 7.4, 2.6 Hz, 1H), 2.70 (s,
3H).
13C-NMR
(300 MHz, CDCl 3): 203.2, 166.5 (d, JcF = 256 Hz), 164.5, 153.0, 149.2, 143.6 (d,
Jc,= 13 Hz), 135.0, 134.5 (d, JcF= 11 Hz), 130.0, 123.7, 118.6 (d, JcF= 3 Hz), 110.3 (d, JcF =
23 Hz), 108.0 (d, Jc = 28 Hz), 28.7. IR (neat, cm-'): 3116, 2921, 1687, 1651, 1606, 1589, 1532,
1460, 1419, 1368, 1320, 1299, 1278, 1261, 1251, 1169, 1143, 1110, 1025, 994, 960, 882, 863,
824, 811, 779, 765, 718. Anal. calcd. for C 14Hj 1FN20 2 : C, 65.11; H, 4.29. Found: C, 65.01; H,
4.10.
N-(4-Methoxy-6-propioyl-phenyl)-3-chlorobenzamide
(11). Following General Procedure
A, 3-chlorobenzamide (93 mg, 0.60 mmol) was coupled with 2-bromo-5-methoxypropiophenone
(122 mg, 0.502 mmol) using Cul (9.5 mg, 0.050 mmol), Li (10.5 pL, 0.985 mmol), K2CO 3 (140
mg, 1.0 mmol), and 200 mg activated 5 A molecular sieves in anhydrous toluene (1 mL). 11 was
purified by column chromatography using a hexane-EtOAc 95:5 to 90:10 gradient. 107 mg (68%
yield) of a pale yellow solid were obtained. Mp: 112-114 °C. 'H-NMR (400 MHz, CDCl 3): 6
12.43 (s, 1H), 8.85 (d, J = 9.2 Hz, 1H), 8.04 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.49 (m, 3H), 7.18
(dd, J = 9.2, 3.0 Hz, 1H), 3.86 (s, 3H), 3.08 (q, J = 7.2 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H). 13CNMR (300 MHz, CDCI3): 205.5, 164.2, 154.6, 136.8, 135.1, 134.4, 131.8, 130.1, 128.1, 125.1,
122.9, 122.4, 119.9, 116.1, 55.7, 33.3, 8.6. IR (neat, cm-'): 3221, 3087, 2986, 2968, 2947, 2915,
2838, 1668, 1651, 1642, 1615, 1572, 1531, 1454, 1423, 1383, 1320, 1291, 1265, 1252, 1195,
1176, 1050, 973, 836, 817, 730. Anal. calcd. for C17H16CINO3: C, 64.26; H, 5.08. Found: C,
64.07; H, 5.02.
N-(4-Methoxy-6-propioyl-phenyl)-2-thiophenecarboxamide
(12).
Following
General
Procedure A, 2-thiophenecarboxamide (76 mg, 0.60 mmol) was coupled with 2-bromo-5methoxypropiophenone (122 mg, 0.502 mmol) using Cul (9.5 mg, 0.050 mmol), L1 (10.5 VLL,
0.985 mmol), K2CO3 (140 mg, 1.0 mmol), and 200 mg activated 5 A molecular sieves in
anhydrous toluene (1 mL). 12 was purified by column chromatography using a hexane-EtOAc
95:5 to 90:10 gradient. 107 mg (74% yield) of a yellow solid were obtained. Mp: 153-155 °C.
'H-NMR (400 MHz, CDCl 3): 8 12.45 (s, 1H), 8.81 (d, J = 9.2 Hz, 1H), 7.82 (dd, J = 3.8, 1.1 Hz,
1H), 7.56 (d, J = 5.0, 1.1 Hz, 1H), 7.46 (d, J = 2.9 Hz, 1H), 7.17 (m, 2H), 3.86 (s, 3H), 3.10 (q, J
= 7.2 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H).
13C-NMR
(300 MHz, CDCl3): 205.5, 160.4, 154.4,
140.7, 134.6, 131.0, 128.4, 128.0, 122.5, 122.2, 120.1, 116.0, 55.7, 33.3, 8.5. IR (neat, cm1-):
3216, 2983, 2911, 2830, 1643, 1616, 1595, 1521, 1420, 1352, 1314, 1287, 1261, 1192, 1175,
1056, 1044, 971, 826, 729. Anal. calcd. for C15HisNO 3S: C, 62.26; H, 5.23. Found: C, 62.06; H,
5.20.
36 Following General Procedure
N-(2-Acetyl-phenyl)-cinnamamide (13).
A, cinnamamide (88
mg, 0.60 mmol) was coupled with 2-bromoacetophenone (67 pL, 0.50 mmol) using Cul (9.5 mg,
0.050 mmol), rac trans-1,2-dimethyl-diamino-cyclohexane (L2) (15.8 pL, 0.100 mmol), K 2CO 3
(140 mg, 1.0 mmol), and 200 mg activated 5
A molecular
sieves in anhydrous toluene (1 mL).
The reaction was heated for 25 h. 13 was purified by column chromatography using a hexaneEtOAc 98:2 to 90:10 gradient. 106 mg (80% yield) of a cream-colored solid were obtained. Mp:
90-93 °C (lit mp: 89.5-90.5 oC). 'H-NMR (400 MHz, CDCl 3): 8 12.06 (s, 1H), 8.92 (d, J = 8.5
Hz, 1H), 7.94 (dd, J = 8.0, 1.1 Hz, 1H), 7.76 (d, J = 15.6 Hz, IH), 7.61 (m,3H), 7.41 (m,3H),
7.16 (t, J = 7.2 Hz, 1H), 6.64 (d, J = 15.6 Hz, 1H), 2.71 (s, 3H). 13C-NMR (300 MHz, CDCl 3):
203.2, 165.1, 142.4, 141.5, 135.5, 134.8, 132.0, 130.2, 129.1, 128.3, 122.6, 122.3, 121.9, 121.1,
28.9. IR (neat, cm-'): 3224, 3109, 3061, 3027, 1685, 1652, 1629, 1606, 1585, 1524, 1358, 1332,
1295, 1248, 1162, 975, 855, 757, 679, 614. Anal. calcd. for C17H, 5NO2 : C, 76.96; H, 5.70.
Found: C, 76.89; H, 5.65.
N-(2-Acetyl-phenyl)-crotonamide (14). Following General Procedure A, crotonamide (51
mg, 0.60 mmol) was coupled with 2-iodoacetophenone (71 pL, 0.50 mmol) using Cul (9.5 mg,
0.050 mmol), L1 (10.5 pL, 0.985 mmol), K 3PO4 (210 mg, 0.99 mmol), and 200 mg activated 5
A
molecular sieves in anhydrous toluene (1 mL). The reaction was heated at 110 OC for 24 h. 14
was purified by column chromatography using a hexane-EtOAc 98:2 to 90:10 gradient. 73 mg
(71% yield) of a beige solid were obtained. Mp: 80-83 *C. 'H-NMR (400 MHz, CDCl 3): 8 11.84
(s, 1H), 8.85 (dd, J = 8.5, 1.1 Hz, 1H), 7.92 (dd, J = 8.0, 1.6 Hz, 1H), 7.57 (m,1H), 7.12 (ddd, J
=8.5, 7.4, 1.2 Hz, 1H), 6.99 (dq, J = 15.3, 6.9 Hz,1H), 6.04 (dq, J = 15.3, 1.7 Hz, 1H), 2.69 (s,
3H), 1.94 (dd, J = 6.9, 1.7 Hz, 3H). 13C-NMR (300 MHz, CDCl 3): 203.0, 165.0, 141.4, 141.3,
135.2, 131.8, 126.9, 122.3, 121.7, 120.8, 28.7, 18.0. IR (neat, cm-): 3208, 2915, 1686, 1643,
1607, 1585, 1523, 1453, 1358, 1331, 1298, 1286, 1250, 1188, 1166, 960, 928, 825, 757, 675.
Anal. calcd. for C12H13NO 2: C, 70.92; H,6.45. Found: C, 71.03; H, 6.45.
1-(2-Acetyl-phenyl)-pyrrolidin-2-one
(15).37
Following
General
Procedure
A, 2-
pyrrolidinone (46 ipL, 0.61 mmol) was coupled with 2-bromoacetophenone (67 pL, 0.50 mmol)
using Cul (4.8 mg, 0.025 mmol, 5 mol%), L1 (5.3 gpL, 0.050 mmol, 10 mol%), K 2CO 3 (140 mg,
1.0 mmol), and 200 mg activated 5 A molecular sieves in anhydrous toluene (1 mL). The
reaction was heated at 90 OC for 25 h. 15 was purified by column chromatography using a
hexane-EtOAc 50:50 to 0:100 gradient. 87 mg (86% yield) of a white solid were obtained. Mp:
89-91 *C (lit mp: 88-89
oC). 1H-NMR
(300 MHz, CDCl3): 8 7.57 (dd, J = 7.7, 1.6 Hz, 1H), 7.43
(m,1H), 7.29 (m,1H), 7.17 (d, J =7.9 Hz, 1H), 3.82 (t, J = 7 Hz, 2H), 2.52 (s, 3H), 2.44 (t, J = 8
Hz, 2H), 2.15 (m,2H). 13C-NMR (300 MHz, CDCl 3): 200.6, 175.0, 136.8, 135.9, 131.9, 128.2,
126.8, 125.9, 50.9, 31.8, 28.6, 18.8. IR (neat, cm-'): 3361, 2999, 2958, 2902, 1693, 1598, 1575,
1488, 1453, 1402, 1358, 1324, 1257, 1238, 1167, 1146, 1101, 1020, 968, 776, 656. Anal. calcd.
for C12HI3NO 2: C, 70.92; H, 6.45. Found: C, 70.86; H, 6.52.
General Procedure B: Base-promoted Cyclization to 2-Aryl-4-Quinolones. A resealable
oven-dried test tube with Teflon stir bar was charged with N-(keto-aryl)amide (1 equiv) obtained
in step one and crushed NaOH (3-3.5 equiv). Anhydrous 1,4-dioxane was added via syringe such
that the reaction mixture was 0.1M in concentration. The test tube was then sealed with a Teflon
screw-cap and the reaction was placed in a preheated oil bath at 110 OC. The reaction mixture
was stirred for 1-2 h and then removed from the oil bath and allowed to cool to room
temperature. The reaction mixture was then dissolved in ethanol and transferred to a round
bottom flask in which it was concentrated in vacuo to remove solvent. Next, a small amount of
water and a large amount of hexane were added to the flask and the flask was sonicated for
approximately two minutes. The biphasic mixture was neutralized to pH -7 with IM HCI and
saturated NaHCO 3 solutions. Solid precipitated out of the water layer and the heterogeneous
mixture was filtered through a Buchner funnel. The solid powder was rinsed with copious
amounts of hexane and minimal water. The solid was collected and transferred to a vial with
ethanol and concentrated in vacuo to remove residual solvent. In some cases, the hexane rinses
during filtration did not completely wash away the alkyl residue and the 'H-NMR showed
contamination. Further purification involved a more extensive hexane wash in which hexane was
added to the vial containing the compound and the mixture was sonicated. The solid was
allowed to settle, and then the hexane was carefully removed via pipette. Hexane was added and
removed twice more before the product was dried in vacuo.
2-Phenyl-4-quinolone (1 6 ).17b Following General Procedure B, 1 (98 mg, 0.41 mmol) was
cyclized using NaOH (49 mg, 1.2 mmol) in 1,4-dioxane (4.1 mL). The reaction was heated for 1
h at 110 'C. After work-up and filtration, 87 mg (96% yield) of a beige solid were obtained. Mp:
247-250 *C (ethanol) (lit mp: 254 oC). 1 2a 'H-NMR (400 MHz, CD 3OD/CDCl 3): 8 8.26 (d, J = 8.1
Hz, 1H), 7.69 (m, 4H), 7.52 (m, 3H), 7.38 (m, 1H), 6.56 (s, 1H). ' 3C-NMR (400 MHz,
CD 3OD/CDCl 3): 180.3, 153.0, 141.5, 135.0, 133.3, 131.6, 129.9, 128.2, 125.7, 125.4, 125.1,
119.4, 108.4. IR (neat, cm-'): 3067, 2962, 1635, 1594, 1581, 1546, 1502, 1472, 1450, 1431,
1355, 1320, 1255, 1139, 839, 798, 771, 753, 689, 670.
2-(3'-Chlorophenyl)-4-quinolone (17). Following General Procedure B, 2 (107 mg, 0.39
mmol) was cyclized using NaOH (47 mg, 1.2 mmol) in 1,4-dioxane (3.9 mL). The reaction was
heated for 1 h at 110 *C. After work-up and filtration, 96 mg (96% yield) of a cream-colored
solid were obtained. Mp: >260 'C. 'H-NMR (400 MHz, CD 3OD/CDCl 3): 8 8.26 (m,1H), 7.76
(m, 1H), 7.67 (m, 3H), 7.50 (m, 2H), 7.40 (m, 1H), 6.55 (s, 1H).
13C-NMR
(500 MHz,
CD 3OD/CDCl3): 180.4, 151.4, 141.6, 137.0, 135.9, 133.5, 131.5, 131.4, 128.3, 126.7, 125.8,
125.6, 125.3, 119.5, 108.7. IR (neat, cm-): 2193, 1604, 1572, 1558, 1503, 1445, 1350, 841, 769,
757, 705.
2-(4'-Pyridyl)-4-quinolone (1 8).9h Following General Procedure B, 3 (63 mg, 0.26 mmol) was
cyclized using NaOH (31 mg, 0.78 mmol) in 1,4-dioxane (2.6 mL). The reaction was heated for
2 h at 110 'C. After work-up and filtration, 52 mg (90% yield) of a beige solid were obtained.
Mp: >260 'C. 1H-NMR (400 MHz, CD 3OD/CDCl3): 6 8.71 (d, J = 5.0 Hz, 2H), 8.27 (dt, J = 8.2,
1.1 Hz, 1H), 7.70 (m,4H), 7.39 (m, 1H), 6.60 (s, 1H).
13C-NMR
(500 MHz, CD3OD/CDCl 3):
180.1, 150.6, 149.2, 143.2, 141.5, 133.5, 125.7, 125.6, 125.3, 122.8, 119.4, 109.0. IR (neat, cm
1): 3066,2968, 1635, 1591, 1567, 1536, 1506, 1444, 1358, 1259, 1143, 821, 796,769,675.
2-(3'-Pyridyl)-4-quinolone (19). Following General Procedure B,4 (81 mg,0.34 mmol) was
cyclized using NaOH (41 mg,1.0 mmol) in1,4-dioxane (3.4 mL). The reaction was heated for I
h at 110 *C. After work-up and filtration, 66 mg (88% yield) of a beige solid were obtained. Mp:
>260
oC. 1H-NMR
(400 MHz, CD 3OD/CDC13): 6 8.90 (dd, J = 2.4, 0.8 Hz, 1H), 8.68 (dd, J =
4.9, 1.6 Hz, 1H), 8.28 (m,1H), 8.13 (ddd, J = 8.0, 2.4, 1.6 Hz, 1H), 7.66 (m,2H), 7.55 (ddd, J =
8.0, 4.9, 0.8 Hz, 1H), 7.40 (m,1H), 6.54 (s, 1H). 13C-NMR (500 MHz, CD3OD/CDCI3): 180.1,
151.5, 149.2, 148.3, 141.4, 136.6, 133.4, 131.5, 125.8, 125.5, 125.2, 125.0, 119.2, 109.0. IR
(neat, cm'): 3090, 2966, 1637, 1602, 1578, 1548, 1509, 1442, 1384, 1356, 1024, 801, 749, 704.
2-(2'-Pyridyl)-4-quinolone (20).15 Following General Procedure B, 5 (89 mg,0.37 mmol) was
cyclized using NaOH (44 mg, 1.1 mmol) in 1,4-dioxane (3.7 mL). The reaction was heated for 1
h at 110 *C. After work-up and filtration, 71 mg (86% yield) of a beige solid were obtained.
Decomposition: 232-234 'C (ethanol). 'H-NMR (400 MHz, CD 3OD/CDCl 3): 8 8.77 (ddd, J =
4.8, 1.7, 1.0 Hz, 1H), 8.27 (ddd, J = 8.3, 1.5, 0.6 Hz, 1H), 8.09 (d, J = 8.1 Hz, 1H), 7.97 (td, J =
7.6, 1.8 Hz, 1H), 7.78 (ddd, J = 8.5, 1.1, 0.6 Hz, 1H), 7.71 (m,1H), 7.50 (ddd, J = 7.6, 6.9, 1.2
Hz, 1H), 7.41 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 6.98 (s, 1H).
13
C-NMR (500 MHz,
CD3OD/CDCl 3): 181.0, 150.2, 149.8, 147.7, 140.7, 138.7, 133.6, 126.4, 125.9, 125.8, 125.2,
122.3, 119.7, 106.6. IR (neat, cm-'): 3063, 1627, 1603, 1573, 1516, 1477, 1384, 1355, 1321,
1254, 1138, 1022, 995, 781, 760, 692. Anal. calcd. for C 14H10N20: C, 75.66; H, 4.54. Found: C,
75.45; H, 4.53.
2-(2'-Thiophenyl)-4-quinolone (21).9a Following General Procedure B, 6 (97 mg,0.40 mmol)
was cyclized using NaOH (48 mg, 1.2 mmol) in 1,4-dioxane (4.0 mL). The reaction was heated
for 1 h at 110 'C. After work-up, filtration, and a hexane wash, 88 mg (97% yield) of a beige
solid were obtained. Mp: >260 'C (lit mp: >300
oC).21d
'H-NMR (400 MHz, CD30D/CDC13): 8
8.22 (ddd, J = 8.2, 1.4, 0.6 Hz, 1H), 7.76 (dd, J = 3.8, 1.1 Hz, 1H), 7.66 (m,2H), 7.57 (dd, J =
5.1, 1.1 Hz, 1H), 7.36 (ddd, J = 8.1, 6.7, 1.4 Hz, 1H), 7.19 (dd, J = 5.1, 3.8 Hz, 1H), 6.60 (s,
1H).
13
C-NMR (500 MHz, CD 3OD/CDCl 3): 179.9, 146.0, 141.1, 136.8, 133.2, 130.0, 129.1,
128.5, 125.6, 125.3, 124.8, 118.9, 107.3. IR (neat, cm-): 3058, 2184, 1598, 1557, 1503, 1443,
1347, 1256, 1136, 857, 824, 768, 756, 697.
2-(3'-Thiophenyl)-4-quinolone (22). Following General Procedure B, 7 (67 mg,0.27 mmol)
was cyclized using NaOH (33 mg, 0.83 mmol) in 1,4-dioxane (2.7 mL). The reaction was heated
for 2 h at 110 *C. After work-up and filtration, 57 mg (92% yield) of a beige solid were obtained.
Mp: >260 'C (CDCl3/CD3OD). 'H-NMR (400 MHz, CD 3OD/CDCl 3): 8 8.23 (d, J = 8.0 Hz, 1H),
8.01 (s, 1H), 7.63 (m, 2H), 7.55-7.33 (m, 3H), 6.61 (s,
1H).
13C-NMR
(500 MHz,
CD3OD/CDCl3 ): 180.7, 147.8, 141.6, 136.2, 133.5, 128.6, 127.2, 126.9, 125.9, 125.7, 125.2,
119.4, 107.6. IR (neat, cm-'): 3069, 2926, 1633, 1593, 1552, 1508, 1470, 1440, 1428, 1369,
1350, 1313, 1142, 1022, 830, 757, 694.
7-Fluoro-2-phenyl-4-quinolone (23). 9f Following General Procedure B, 8 (76 mg, 0.29 mmol)
was cyclized using NaOH (35 mg, 0.88 mmol) in 1,4-dioxane (2.9 mL). The reaction was heated
for 2 h at 110 °C. After work-up and filtration, 63 mg (89% yield) of a cream-colored solid were
obtained. Mp: >260 oC. 'H-NMR (400 MHz, CD 3OD/CDCl 3): 6 8.27 (dd, J = 9.1, 6.1 Hz, 1H),
7.72 (m, 2H), 7.52 (m, 3H), 7.36 (dd, J = 9.8, 2.4 Hz, 1H), 7.10 (ddd, J = 10.7, 8.3, 2.4 Hz, 1H),
6.53 (s, 1H).
13
C-NMR (500 MHz, CD 3OD/CDCI3/CD 2CI2): 179.8, 166.1 (d, JCF = 252 Hz),
153.6, 143.1 (d, JcF = 13 Hz), 134.9, 131.7, 130.0, 129.0 (d, JCF = 10 Hz), 128.2, 122.4 (d, JcF =
1.7 Hz), 114.1 (d, JCF = 24 Hz), 108.6, 104.6 (d, JcF = 25 Hz). IR (neat, cm-'): 3255, 3159, 3117,
3082, 3005, 1641, 1602, 1583, 1542, 1509, 1469, 1425, 1367, 1295, 1253, 1162, 1132, 1092,
869, 840, 816, 771,744,696.
2-(2'-Chlorophenyl)-7-fluoro-4-quinolone (24). Following General Procedure B, 9 (73 mg,
0.25 mmol) was cyclized using NaOH (30 mg, 0.75 mmol) in 1,4-dioxane (2.5 mL). The reaction
was heated for 2 h at 110 OC. After work-up and filtration, 50 mg (73% yield) of a beige solid
were obtained. Decomposition: 252-256 °C (ethanol). 'H-NMR (400 MHz, CD3OD/CDCl3): 6
8.30 (dd, J = 9.0, 6.0 Hz, 1H), 7.53 (m, 1H), 7.44 (m, 3H), 7.22 (dd, J = 9.6, 2.4 Hz, 1H), 7.11
(ddd, J = 10.8, 8.2, 2.1 Hz, 1H), 6.31 (s, 1H).
13C-NMR
(500 MHz, CD 3OD/CDCl3): 179.4,
165.8 (d, JcF = 252 Hz), 150.9, 142.4 (d, JCF = 13 Hz), 134.2, 133.2, 132.1, 131.3, 130.8, 128.9
(d, JCF = 11 Hz), 127.8, 122.2, 114.1 (d, JcF = 24 Hz), 111.1, 104.2 (d, JcF= 25 Hz). IR (neat, cm
1): 3070, 1642, 1606, 1589, 1551, 1513, 1462, 1259, 1162, 1129, 966, 873, 822, 753, 732.
7-Fluoro-2-(3'-pyridyl)-4-quinolone (25). Following General Procedure B, 10 (85 mg, 0.33
mmol) was cyclized using NaOH (40 mg, 1.0 mmol) in 1,4-dioxane (3.3 mL). The reaction was
heated for 1 h at 110 *C. After work-up and filtration, further purification was needed so a
hexane wash was performed. Upon drying, 87 mg (96% yield) of a beige solid were obtained.
Mp: >260 'C (CDCl 3/CD 3OD). 'H-NMR (400 MHz, CD 3OD/CDCl 3): 6 8.93 (s, br, 1H), 8.72 (s,
br, 1H), 8.29 (dd, J = 9.0, 6.0 Hz, 1H), 8.14 (d, J = 8.1 Hz, 1H), 7.58 (s, br, 1H), 7.34 (dd, J =
9.6, 2.4 Hz, 1H), 7.13 (ddd, J = 10.7, 8.3, 2.4 Hz, 1H), 6.52 (s, 1H). ' 3C-NMR (500 MHz,
CD 3OD/CDCl 3): 179.4, 166.1 (d, JcF = 252 Hz), 151.7, 150.2, 148.4, 143.5, 136.7, 131.8, 129.0
(d, JCF = 10 Hz), 125.2, 122.5 (d, JcF = 1.2 Hz), 114.4 (d, JcF = 24 Hz), 109.2, 104.8 (d, JcF = 25
Hz). IR (neat, cm-'): 3079, 2921, 2306, 2266, 1636, 1605, 1579, 1568, 1543, 1515, 1467, 1427,
1259, 1213, 1090, 852, 805, 703.
2-(3'-Chlorophenyl)-6-methoxy-3-methyl-4-quinolone (26). Following General Procedure
B, 11 (66 mg, 0.21 mmol) was cyclized using NaOH (29 mg, 0.73 mmol) in 1,4-dioxane (2.1
mL). The reaction was heated for 2 h at 110 OC. After work-up and filtration, 57 mg (91% yield)
of a beige crystalline solid were obtained. Mp: >260 °C. 'H-NMR (400 MHz, CD 3OD/CDCl3): 8
7.67 (d, J = 2.9 Hz, 1H), 7.46 (m, 4H), 7.37 (m, 1H), 7.24 (dd, J = 9.1, 2.9 Hz, 1H), 3.90 (s, 3H),
2.03 (s, 3H).
13
C-NMR (500 MHz, CD 3OD/CDCl 3): 178.9, 157.5, 148.1, 137.8, 135.4, 135.4,
131.0, 130.5, 129.7, 128.2, 125.3, 124.4, 120.6, 115.9, 104.3, 56.1, 12.8. IR (neat, cm '): 3078,
2957, 1582, 1544, 1501, 1380, 1294, 1229, 1190, 1158, 1097, 1032, 848, 812, 768, 736, 714.
Anal. calcd. for C17H14CINO 2 : C, 68.12; H, 4.71. Found: C, 68.08; H, 4.73.
6-Methoxy-3-methyl-2-(2'-thiophenyl)-4-quinolone (27). Following General Procedure B,
12 (84 mg, 0.29 mmol) was cyclized using NaOH (41 mg, 1.0 mmol) in 1,4-dioxane (2.9 mL).
The reaction was heated for 1 h at 110 OC. After work-up and filtration, 73 mg (92% yield) of a
pale yellow solid were obtained. Mp: >260 °C (CDCl 3/CD3OD).
1H-NMR
(400 MHz,
CD 3OD/CDCl 3): 8 7.65 (d, J = 2.9 Hz, 1H), 7.58 (dd, J = 5.1, 1.2 Hz, 1H), 7.49 (d, J = 9.1 Hz,
1H), 7.33 (dd, J = 3.6, 1.2 Hz, 1H), 7.23 (dd, J = 9.1, 2.9 Hz, 1H), 7.18 (dd, J = 5.1, 3.6 Hz,
1H), 3.90 (s, 3H), 2.18 (s, 3H). '3C-NMR (500 MHz, CD3OD/CDCl 3): 178.9, 157.8, 143.2, 136.1,
135.7, 130.7, 129.4, 128.4, 125.5, 124.6, 120.8, 117.2, 104.4, 56.1, 13.1. IR (neat, cm-1): 2951,
1589, 1541, 1488, 1439, 1375, 1256, 1228, 1161, 1026, 850, 822.7, 768, 708, 692. Anal. calcd.
for C15H 13NO 2 S: C, 66.40; H,4.83. Found (Recrystallized from CDCI3/CD 3OD): C, 66.18; H,
4.74.
2-Styryl-4-quinolone (28).38 Following General Procedure B, 13 (101 mg, 0.38 mmol) was
cyclized using NaOH (46 mg, 1.2 mmol) in 1,4-dioxane, (3.8 mL). The reaction was heated for 3
h at 90 *C. After work-up and filtration, 77 mg (82% yield) of an orange-yellow solid were
obtained. Mp: >260 'C (lit mp: 279 °C). 'H-NMR (400 MHz, CD 3OD/CDCl 3): 6 8.22 (ddd, J =
8.2, 1.4, 0.6 Hz, 1H), 7.58 (m,5H), 7.38 (m,4H), 6.96 (d, J = 16.5 Hz, 1H), 6.55 (s, 1H).' 3 C-
NMR (400 MHz, CD 3OD/CDCI3): 180.0, 149.5, 141.0 137.5, 136.0, 133.1, 130.3, 129.6, 128.1,
125.6, 125.6, 124.8, 121.5, 118.8, 107.0. IR (neat, cm-'): 3059, 2040, 1621, 1590, 1547, 1494,
1436, 1246, 1138, 959, 752, 686.
37 Following General Procedure B, 15
2,3-Dihydro-pyrrolo[1,2-a]quinolin-5(1H)-one (29).
(71 mg,0.35 mmol) was cyclized using NaOH (49 mg,1.2 mmol) in 1,4-dioxane (3.5 mL). The
reaction was heated for 1 h at 110 OC. After the reaction was cooled to room temperature, it was
transferred into a round bottom flask with ethanol. The solvent was removed in vacuo and water
was added. The solution was neutralized to pH ~7 with IM HCI and saturated NaHCO 3 solutions
and then the water was removed in vacuo. The title compound was purified by silica column
chromatography using a EtOAc-MeOH 100:0 to 95:5 gradient. After the product was collected
and concentrated, a hexane wash was performed. 60 mg (93% yield) of a beige solid were
obtained. Mp: 167-173 °C (lit mp: 173-174 0C). 'H-NMR (400 MHz, CD 3OD/CDCl3): 6 8.24 (d,
J = 8.5, 1.5 Hz, 1H), 7.64 (ddd, J = 8.5, 7.1, 1.5 Hz, 1H), 7.36 (m,2H), 6.19 (s, 1H), 4.26 (t, J =
7.3 Hz, 2H), 3.15 (t, J = 7.6 Hz, 2H), 2.10 (m,2H).
13C-NMR
(400 MHz, CD 3OD/CDCI 3):
179.3, 157.8, 139.1, 133.0, 126.5, 125.8, 124.6, 116.7, 105.0, 51.3, 32.4, 21.4. IR (neat, cm-t):
3480 (br), 3388 (br), 2964, 2895, 1625, 1599, 1558, 1503, 1473, 1430, 1310, 1267, 1167, 1151,
1073, 1030,962, 840,787,759, 671, 621.
2-(l'-Propenyl)-4-quinolone (30).39 Following General Procedure B, 14 (84 mg,0.41 mmol)
was cyclized using NaOH (25 mg, 0.63 mmol, 1.5 equiv) in 1,4-dioxane (4.1 mL). The reaction
was heated for 1 h at 110 OC. After the reaction was cooled to room temperature, it was
transferred into a round bottom flask with ethanol. The solvent was removed in vacuo and water
was added. The solution was neutralized to pH -7 with IM HCI and saturated NaHCO 3 solutions
and then the water was removed in vacuo. The title compound was purified by silica column
chromatography using a hexane-EtOAc 50:50 to 0:100 gradient. After the product was collected
and concentrated, a hexane wash was performed. 42 mg (54% yield) of a pale yellow solid were
obtained. Decomposition: 240-244 'C (lit decomposition: 210 oC). 'H-NMR (400 MHz,
CD 3OD/CDCl 3): 8 8.17 (d, J = 7.9 Hz, 1H), 7.54 (m,2H), 7.28 (m, 1H), 6.68 (m,1H), 6.32 (s,
1H), 6.24 (dd, J = 15.9, 1.5 Hz, 1H), 1.91 (dd, J = 6.7, 1.4 Hz, 3H).
13
C-NMR (500 MHz,
CD 3OD/CDCl 3): 180.0, 149.6, 140.7, 136.4, 132.8, 125.5, 125.4, 125.2, 124.6, 118.7, 106.1,
19.2. IR (neat, cm-'): 3061, 2916, 2773, 2189, 2115, 1596, 1549, 1499, 1442, 1354, 1326, 1249,
1138, 961, 835, 756.
4-Methyl-3-vinyl-2-quinolone (31).40 Following a slight modification of General Procedure B,
14 (94 mg,0.46 mmol) was cyclized using Cs2CO 3 (450 mg, 1.4 mmol) in 1,4-dioxane (4.6 mL).
The reaction was heated for 24 h at 110 oC. After the reaction was cooled to room temperature, it
was transferred into a round bottom flask with ethanol. The solvent was removed in vacuo and
water was added. The solution was neutralized to pH ~ 7 with IM HCI and saturated NaHCO 3
solutions and then the water was removed in vacuo. The title compound was purified by silica
column chromatography using a hexane-EtOAc 75:25 to 100:0 gradient. After the product was
collected and concentrated, a hexane wash was performed. 65 mg (76% yield) of a pale yellow
solid were obtained. Decomposition: >150 °C (lit mp: 203-205 0C). 'H-NMR (400 MHz,
CD 3OD/CDCI3): 6 7.73 (dd, J = 8.2, 0.9 Hz, 1H), 7.44 (m, 1H), 7.28 (dd, J = 8.2, 0.7 Hz, IH),
7.21 (m,1H), 6.76 (dd, J = 17.8, 11.7 Hz, 1H), 5.77 (dd, J = 17.8, 2.1 Hz, 1H), 5.64 (dd, J =
11.7, 2.1 Hz, 1H), 2.55 (s, 3H). 13C-NMR (400 MHz, CD 3OD/CDC13): 163.3, 145.3, 137.4,
131.2, 130.7, 128.3, 125.7, 123.3, 122.5, 121.7, 116.3, 16.3. IR (neat, cm-): 2944, 2845, 1648,
1603, 1551, 1503, 1431, 1380, 1270, 919, 747, 664. Anal. calcd. for C12H11NO: C, 77.81; H,
5.99. Found: C: 77.70, H: 5.96.
N-(2-Acetyl-phenyl)-n-hexanamide (32). Following General Procedure A, hexanamide (138
mg, 1.20 mmol) was coupled with 2-iodoacetophenone (141 mL, 1.00 mmol) using Cul (9.5 mg,
0.050 mmol), L1 (10.5 giL, 0.100 mmol), K3PO4 (425 mg, 2.0 mmol), and 400 mg activated 5 A
molecular sieves in anhydrous toluene (2 mL). The title compound was purified by column
chromatography using a 5-10% ethyl acetate/hexane gradient. 187 mg (80% yield) of a clear,
yellow oil were obtained. 'H-NMR (400 MHz, CDCl 3): 6 11.68 (s, 1H), 8.73 (dd, J = 8.5, 1.1
Hz, 1H), 7.82 (dd, J = 8.0, 1.5 Hz, 1H), 7.47 (m,1H), 7.03 (m,1H), 2.60 (s, 3H), 2.37 (t, J = 7.4
Hz, 2H), 1.70 (m,2H), 1.32 (m,4H), 0.86 (m,3H).
13C-NMR
(300 MHz, CDCl3): 202.8, 172.7,
141.2, 135.1, 131.7, 122.1, 121.6, 120.6, 38.7, 31.4, 31.4, 28.6, 25.2, 22.4, 22.4, 14.0. IR (neat,
cm-'): 3253, 2957, 2931, 2861, 1699, 1653, 1607, 1585, 1521, 1451, 1360, 1311, 1298, 1248,
1163, 1092, 1022, 962, 756, 606. Anal. calcd. for C,4HI 9NO 2: C, 72.07; H: 8.21. Found: C,
72.23; H, 8.26.
3-n-Butyl-4-methyl-2-quinolone
(33)41
and 2-n-Pentyl-4-quinolone (34)." Following
General Procedure B, 32 (82 mg, 0.35 mmol) was cyclized using NaOH (42 mg, 3 equiv.) in 1,4dioxane (3.5 mL). The reaction was heated for 1 h at 110 OC. After the reaction was cooled to
room temperature, ethanol was added to dissolve all solid and the reaction mixture was loaded
directly onto a Biotage samplet. The samplet was dried with gentle heating. The title compounds
were purified by silica column chromatography using a hexane-EtOAc 75:25 to 0:100 gradient
followed by a EtOAc-MeOH 100:0 to 95:5 gradient. 33 eluted faster than 34 under these
conditions. After the products were collected and concentrated, hexane washes were performed
on both compounds. 17 mg (23% yield) of 33 were obtained as a white solid. Mp: 171-173 'C
(lit mp: 170-171 °C). 'H-NMR (400 MHz, CDCl 3): 8 11.99 (s, br, 1H), 7.70 (dd. J = 8.2, 0.9 Hz,
1H), 7.46 (m, 1H), 7.38 (m, 1H), 7.21 (m, 1H), 2.83 (t, J = 7.3 Hz, 2H), 2.51 (s, 3H), 1.52 (m,
4H), 0.99 (t, J = 7.2 Hz, 3H). 13C-NMR (400 MHz, CDCl 3): 164.1, 143.2, 137.0, 131.9, 129.3,
124.4, 122.3, 121.3, 116.2, 31.5, 26.9, 23.2, 15.3, 14.3. IR (neat, cm-'): 2946, 2860, 1654, 1611,
1562, 1503, 1428, 1394, 1274, 1182, 1158, 1097, 1032, 905, 747, 706, 667, 613. 37 mg (49%
yield) of 34 were obtained as a white solid. Mp: 142-145 °C (lit mp: 141-142 °C). 1H-NMR (400
MHz, CDCl 3): 8 13.02 (s, 1H), 8.38 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.60 (t, J = 7.1
Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 6.28 (s, 1H), 2.72 (t, J = 7.5 Hz, 2H), 1.71 (m, 2H), 1.22 (m,
4H), 0.78 (t, J = 6.8 Hz, 3H). ' 3C-NMR (400 MHz, CDCl 3): 179.0, 156.0, 141.0, 131.9, 125.2,
123.8, 119.0, 108.2, 34.5, 31.5, 29.1, 22.5, 14.0. IR (neat, cm-'): 3250, 3065, 2956, 2930, 2871,
1639, 1595, 1552, 1505, 1472, 1444, 1355, 1322, 1249, 1176, 1138, 1111, 844, 761, 675.
General Procedure C: McMurry-Type Coupling to Form Indoles.' 8 In a glove box, TiCl3
(1.8 mmol, 3.6 equiv.) and Zn powder (3.6 mmol, 7.2 equiv.) were weighed into an oven-dried
Schlenk tube with a Teflon-coated stir bar. The Schlenk tube was capped with a rubber septum
and removed from the glove box. Outside of the glove box, the Schlenk tube was evacuated and
refilled with Argon twice. While still under a stream of Argon, the rubber septum was removed
and the N-(keto-aryl)amide (0.5 mmol, 1 equiv.) was added quickly to the Schlenk tube. The
Schlenk tube was recapped with the septum and evacuated and refilled with Argon three more
times. Anhydrous DME was added via syringe and the rubber septum was replaced with a Teflon
Schlenk cap. The reaction was placed in a preheated oil bath at 90 'C, and the reaction was
heated with stirring for 4-28 h, monitored by TLC. The reaction mixture was allowed to cool to
room temperature and filtered through a pad of silica gel with copious amounts of EtOAc. The
filtrate was concentrated in vacuo, and the crude material was purified via silica gel column
chromatography using a hexane-EtOAc 100:0 to 92:8 gradient.
3-Methyl-2-phenylindole (35).22 Following General Procedure C, 1 (119.6 mg, 0.50 mmol)
underwent an intramolecular coupling using TiCl3 (280 mg, 1.8 mmol) and Zn powder (235 mg,
3.6 mmol) in DME (6.0 mL). The reaction was heated for 28 h at 90 OC. After filtration and
column chromatography, 71 mg (69% yield) of a pale yellow solid were obtained. Mp: 88-92 °C
(lit mp. 90-92 °C). 'H-NMR (400 MHz, CDCl3): 8 8.03 (s, br, 1H), 7.61 (m,3H), 7.50 (m,2H),
7.38 (m,2H), 7.23 (m, 1H), 7.17 (m, 1H), 2.49 (s, 3H).
13C-NMR
(400 MHz, CDCI3): 136.1,
134.3, 133.6, 130.3, 129,1, 128.0, 127.6, 122.6, 119.8, 119.3, 111.0, 108.9, 9.9. IR (neat, cm1'):
3448, 3421, 3056,2914,2862, 1603, 1458, 1445, 1332, 1306, 1235, 1074,918, 770, 739,700.
3-Methyl-2-(3'-thiophenyl)-indole (36). Following General Procedure C, 7 (122.7 mg, 0.50
mmol) underwent an intramolecular coupling using TiCl3 (280 mg, 1.8 mmol) and Zn powder
(235 mg, 3.6 mmol) in DME (6.0 mL). The reaction was heated for 16 h at 90 OC. After filtration
and column chromatography, 75 mg (70% yield) of a beige solid were obtained. Mp: 92-95 °C.
1H-NMR
(400 MHz, CDCl3): 6 7.77 (s, br, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.34 (dd, J = 4.6, 3.4
Hz, 1H), 7.24 (m, 3H), 7.13 (m, 3H), 2.39 (s, 3H). 13 C-NMR (400 MHz, CDCl3): 135.7, 134.2,
130.0, 130.0, 126.7, 126.3, 122.4, 121.3, 119.7, 119.0, 110.8, 108.6, 9.87. IR (neat, cm-1): 3417,
3100, 3056, 2916, 2862, 1461, 1350, 1332, 1291, 1240, 1206, 1153, 1118, 1090, 1025, 1007,
865, 781, 741, 683, 619. Anal. calcd. for C13 HINS: C, 73.20; H, 5.20. Found: C, 73.33; H, 5.30.
2,3-Dihydro-9-methyl-lH-pyrrolo[1,2-a]indole
(37).43 Following General Procedure C, 15
(101.6 mg, 0.50 mmol) underwent an intramolecular coupling using TiCl3 (280 mg, 1.8 mmol)
and Zn powder (235 mg, 3.6 mmol) in DME (6.0 mL). The reaction was heated for 4.5 h at 90
'C. After filtration and column chromatography, 29 mg (34% yield) of a colorless oil were
obtained. Note: Title compound readily decomposes even at low temperature. 'H-NMR (400
MHz, CDCl3): 6 7.54 (d, J = 7.4 Hz, 1H), 7.25 (m, 1H), 7.14 (m, 2H), 4.06 (t, J = 6.9 Hz, 2H),
2.98 (t, J = 7.5 Hz, 2H), 2.63 (m, 2H), 2.32 (s, 3H). 13C-NMR (400 MHz, CDCl 3): 141.5, 133.3,
132.7, 120.1, 118.5, 118.5, 109.3, 100.8, 43.7, 28.0, 23.1, 9.2.
2-Bromo-5-methoxypropiophenone. 44'45 2-Bromo-5-methoxybenzoyl chloride (1.91 g, 7.67
mmol) was added to a flame-dried round bottom flask. The flask was covered with a rubber
septum and then evacuated and refilled with Argon three times. Anhydrous THF (20 mL) was
added via syringe and the reaction mixture was cooled to -78 'C. Ethyl magnesium bromide (3M
in ether) was added drop-wise over approximately 30 minutes. Then the reaction mixture was
allowed to warm to room temperature and was stirred for 20 h at which point saturated
ammonium chloride was added. The organic layer was extracted and concentrated. Then it was
partitioned between ether and water. The ether layer was extracted and then washed once more
with water. The organic layer was dried over MgSO 4, filtered, and concentrated to dry. The title
compound was purified by silica column chromatography using a hexane-EtOAc 100:0 to 90:10
gradient. 1.37 g (74% yield) of a clear, yellow oil were obtained. 'H-NMR (300 MHz, CDCl 3): 6
7.47 (dd, J = 8.6, 0.5 Hz, 1H), 6.85 (m, 2H), 3.81 (s, 3H), 2.93 (q, J = 7.2 Hz, 2H), 1.21 (t, J =
7.2 Hz, 3H). 13C-NMR (400 MHz, CDCl3): 204.7, 158.8, 142.6, 134.2, 117.1, 113.6, 108.5, 55.5,
35.9, 8.0. IR (neat, cm-'): 3073, 2977, 2939, 2905, 2840, 1705, 1592, 1569, 1467, 1405, 1345,
1290, 1241, 1198, 1175, 1090, 1051, 1027, 967, 874, 846, 816.
IV. References
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Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; pp 699-760. (b) Hartwig, J. F.
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2. Zou, B.; Yuan, Q.; Ma, D. Angew. Chem. Int. Ed. 2007, 46, 2598-2601.
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6. Rodriguez Rivero, M.; Buchwald, S. L. Org. Lett. 2007, 9, 973-976.
7. Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R. Heterocycles and Health. in
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8. It is known that 4-quinolines have two tautomeric forms and can be drawn as either the 4hydroxyquinolines in the enol-form or as 4-quinolones in the keto-form (Scheme 5). Both forms
are important in understanding the characterization data and the chemical reactivity of such
compounds. However, it is believed that in the solid state, as well as in many solvents, these
compounds exist primarily in the keto-form. Therefore, for the purposes of this publication, we
will refer to and draw the products as 4-quinolones. For discussions on the tautomerization of
hydroxyquinolines: (a) Reitsema, R. H. Chem. Rev. 1948, 43, 43-68. (b) Katritzky, A. R.;
Lagowski, J. M. Prototropic Tautomerism of Heteroaromatic Compounds: II. Six-Membered
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2563-2567.
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Juang, J.-P.; Lin, Y.-T.; Wu, T.-S.; Chang, J.- J.; Lednicer, D.; Paull, K. D.; Lin, C. M.; Hamel,
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Bernstein, J. I.; Barrett, J. F.; Ohemeng, K. A.; Eur. J. Med. Chem. 1999, 34, 381-387. (e) Xia,
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2001, 44, 3932-3936. (f) Hadjeri, M.; Peiller, E.-L.; Beney, C.; Deka, N.; Lawson, M. A.;
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Hlavaic, J.; Wiedermannovai, I.; Lycka, A.; Bertolasi, V. J. Heterocyclic Chem. 2004, 41, 375379. (h) Lai, Y.-Y.; Hung, L.-J.; Lee, K.-H.; Xiao, Z.; Bastow, K. F.; Yamori, T.; Kuo, S.-C.
Bioorg. Med. Chem. 2005, 13, 265-275. (i) Ferlin, M. G.; Chiarelotto, G.; Gasparotto, V.; Via, L.
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Gasparotto, V.; Castagliuolo, I.; Chiarelotto, G.; Pezzi, V.; Montanaro, D.; Brun, P.; Palu, G.;
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11. (a) Li, J. J. Conrad-Limpach Reaction in Name Reactions: A Collection of Detailed
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M.; Sarau, H. M.; Farina, C.; Medhurst, A. D.; Grugni, M.; Rveglia, L. F.; Schmidt, D. B.;
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13. (a) Dorow, R. L.; Herrinton, P. M.; Hohler, R. A.; Maloney, M. T.; Mauragis, M. A.;
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10, 493-499. (b) Zewge, D.; Chem, C.-Y.; Deer, C.; Dormer, P. G.; Hughes, D. L. J. Org. Chem.
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18. Fiirstner, A.; Hupperts, A.; Ptock, A.; Janssen, E. J. Org. Chem. 1994, 59, 5215-5229.
19. Tollari, S.; Cenini, S.; Ragaini, F.; Cassar, L. J. Chem. Soc., Chem. Commun. 1994, 17411742.
20. (a) Camps, R. Chem. Ber. 1899, 32, 3228-3234. (b) Pflum, D. A. Camps Quinolinol
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(b) Dubroeucq, M.-C.; Bains, E. L.; Paris, J.-M.; Marne, V. S.; Renault, C.
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25. References indicating catalyst-free amination reactions:
Riermeier, T. H.; Tillack, A. J. Org. Chem. 2001, 66, 1403-1412.
A.; Zhang, F.-M.; Tu, Y.-Q. Org. Lett. 2003, 5, 3515-3517.
Verstappen, M. H.; Schmieder-van de Vondervoort, L.; Sereinig,
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(a) Beller, M.; Breindl, C.;
(b) Shi, L.; Wang, M.; Fan, C.(c) De Lange, B.; LambersN.; de Rijk, R.; de Vries, A. H.
26. (a) Lindley, J. Tetrahedron 1984, 40, 1433-1456. (b) Nicolaou, K. C.; Boddy, C. N. C.;
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27. Aryl iodides: were found to be better starting materials for the more difficult Cu-catalyzed
amidation reactions of 2-halophenones with alkyl amides, which are not discussed in this
publication due to their problematic reactivity in the Camps cyclization.
28. K3PO4 was employed for reactions with 2-iodophenones due to the superiority of K3PO4 for
the facilitation of Cu-catalyzed amidation with aryl iodides reported in our earlier work
(Reference 24b).
29. (a) Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 14844-14845. (b) Antilla, J.
C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69, 5578-5587.
30. For example, N-(2-acetyl-phenyl)-n-hexanamide (32) cyclized to afford 25% of 4-methyl3-n-butyl-2-quinolone (33) and 49% of 2-n-pentyl-4-quinolone (34).
31. (a) Gribble, G. W.; Bousquet, F. P. Tetrahedron 1971, 27, 3785-3794. (b) Mudry, C. A.;
Frasca, A. R. Tetrahedron1973, 29, 603-613.
32. Grammaticakis, P. Bull. Soc. Chim. Fr. 1953, 93-99.
33. Shirakawa, N.; Tomioka, H.; Koizumi, M.; Takeuchi, M.; Sugiyama, H.; Okada, M.;
Yoshimoto, M.; Iwane, Y.; Murakami, Y. Isonicotinanilide Derivatives, Process for Preparing
the Same and Plant Growth Regulator Containing the Same. Eur. Pat. Appl. 48998, 1982.
34. Soloshonok, V. A.; Cai, C.; Hruby, V. J.; Meervelt, L. V.; Yamazaki, T. J. Org. Chem.
2000, 65, 6688-6696.
35. Amino ph6nones, leur preparation et leur utilization en therapeutique. Fr. Patent 2121391,
1972.
36. Ktivendi, A.; Kircz, M. Chem. Ber. 1965, 98, 1049-1059.
37. MShrle, H.; Gerloff, J. Arch. Pharm. 1979, 312, 219-230.
38. (a) Troger, J.; Dunker, E. J. Prakt. Chem. 1925, 109, 88-123. (b) Jayabalan, L.;
Shanmugam, P. Synthesis 1991, 217-220.
39. (a) Gottstein, W. J.; Roberts, H.; Wells, I. C.; Cheney, L. C. J. Org. Chem. 1964, 29, 30653067. (b) Cheney, L. C.; Gottstein, W. J. Cinchoninic Acids and Use in Process for Quinolinols.
US Patent 3301859, 1967.
40. Shanmugam, P.; Lakshminarayana, P. Tet. Lett. 1971, 25, 2323-2324.
41. Searles, A. L.; Lindwall, H. G. J. Am. Chem. Soc. 1946, 68, 988-990.
42. Back, T. G.; Parvez, M.; Wulff, J. E. J. Org. Chem. 2003, 68, 2223-2233.
43. (a) Lee, J.; Ha, J. D.; Cha, J. K. J. Am. Chem. Soc. 1997, 119, 8127-8128. (b) Ishikura, M.;
Ida, W.; Yanada, K. Tetrahedron2006, 62, 1015-1024.
44. Fleming, I.; Woolias, M. J. Chem. Soc., Perkin Trans. 1 1979, 3, 829-837.
45. Procedure for the synthesis of 2-bromo-5-methoxypropiophenone was modified from the
procedure for the synthesis of o-bromopropiophenone in Wang, S.; Morrow, G. W.; Swenton, J.
S. J. Org. Chem. 1989, 54, 5364-5371.
V. Appendix A: Selected NMR Spectra
CD 30D
Current rate Paramaters
iNAMS
0-2-20
ExPNO
1
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1
(16)
F2 - Acquisltion Parameters
Datae
20061201
Time
1it.0
Wsrauft
spect
PWOXIID
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66536
SOLVENT
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1,
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VI. Appendix B: Curriculum Vitae
472 Cambridge St. Apt. 3
Cambridge, MA 02141
Phone: 908-304-4781
E-mail: carriepionesciAAmail.com
Carrie Preston Jones
Objective
An intellectually challenging position which utilizes my creativity, enthusiasm, and analytical and
problem-solving skills
Education
September 2005-present
Massachusetts Institute of Technology, Cambridge, MA
Master of Science/Organic Chemistry
(Expected Sept. 2007)
* Teaching Award 2006
* MIT Presidential Fellow 2005-2006
* Completed Master's thesis: Development ofa Copper-catalyzedAmidation-Base-promoted
Cyclization Sequence for the Synthesis of 2-Aryl- and 2- Vinyl-4-quinolones
September 1998-June 2002
Williams College, Williamstown, MA
Bachelor of Arts/Chemistry
June 2002
*Highest Honors, Magna Cum Laude, Phi Beta Kappa, Sigma Xi
-Chemistry GPA: 3.89; Career GPA: 3.78
*Received ACS Connecticut Valley Section 2002 Achievement Award
*Received 1999 CRC Press First-Year Chemist Achievement Award
*Dean's List for all eight semesters
-Completed year-long chemistry research thesis: MetallomesogenicPlatinum Complexes with
2,2 '-Bipyridyl-BasedLigands: ProgressTowards 1-D Conductive Materials
Work
Experience
January 2006-present
Buchwald Lab, MIT
Lab Research Assistant
-Developed a copper-catalyzed method for the synthesis of nitrogen heterocycles: 2-aryl-4quinolones.
*Research culminated in written thesis (above) and publication (below) and involved regular
presentations at group meetings
September 2005-December 2005
MIT, Cambridge, MA
Teaching Assistant
*Held biweekly recitations and office hours for Course 5.13: Organic Chemistry (2 nd semester),
graded problem sets and exams
Merck & Co., Inc., Rahway, NJ
April 2003-July 2005
Chemist
*Worked in Medicinal Chemistry department performing organic synthesis of small molecules for
drug discovery
*Received promotion in Spring 2005
*Presented work at Merck's annual Associate Research Symposium (June 2005)
September 2002-January 2003
Substitute Teacher
Waynflete School, Portland, ME
June 2001-May 2002
Inorganic Chemistry Lab, Williams College
Lab Research Assistant
*Performed organic syntheses and scale-ups of bipyridyl-based ligands and inorganic syntheses of
Pt-coordinated complexes
*Research culminated in written thesis (above) and included two oral presentations
Publications "Sequential Cu-Catalyzed Amidation-Base-mediated Camps Cyclization: A Two-step Synthesis of
2-Aryl-4-quinolones from ortho-Halophenones."Jones, C. P., Anderson, K. W., Buchwald, S. L.
Manuscript submitted.
"A Highly Activated Catalyst System for the Heteroarylation of Acetone." Liu, P., Lanza, T. J.,
Jewell, J. P., Jones, C.P., Hagmann, W. K., Lin, L. S. TetrahedronLett. 2003, 44, 8869-8871.
"Mesomorphic Properties of Novel 2,2'-Bipyridines and Their Metal Complexes." Park, L. Y.,
Fulmer, S. L., Hensley, L. A., Jones, C. P., McGehee, E. A., Scroggins, S. T., Walrod, M. D.
Manuscript submitted.
Skills
Computer Proficiency: Microsoft Office, ChemDraw, Mac and PC systems; Chemistry
Instrumentation: NMR, GC, GC-MS, LC-MS, HPLC, IR, silica chromatography, DSC, polarized
optical microscopy, microwave