Investigation of the asymmetric Birch reduction-alkylation of a chiral 5-arylbenzamide containing a carbamate group

Article abstract of DOI:10.1016/j.tetlet.2006.02.093

The synthesis and asymmetric Birch reduction-alkylation of chiral benzamide 17 are described. Birch reductive alkylation of benzamide 17 was optimized to give the corresponding cyclohexa-1,4-diene products in 66-78% isolated yield and with high diastereoselectivity (dr: >98:2). The effects of performing the reduction in the presence and in the absence of tert-butyl alcohol are discussed.

Full text of DOI:10.1016/j.tetlet.2006.02.093

Tetrahedron Letters 47 (2006) 2739–2742
Investigation of the asymmetric Birch reduction–alkylation
of a chiral 5-arylbenzamide containing a carbamate group
Agustin Casimiro-Garcia* and Arthur G. Schultzz
Department of Chemistry, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
Received 2 February 2006; revised 13 February 2006; accepted 14 February 2006
Available online 3 March 2006
Abstract—The synthesis and asymmetric Birch reduction–alkylation of chiral benzamide 17 are described. Birch reductive alkylation
of benzamide 17 was optimized to give the corresponding cyclohexa-1,4-diene products in 66–78% isolated yield and with high dia-
stereoselectivity (dr: >98:2). The effects of performing the reduction in the presence and in the absence of tert-butyl alcohol are
discussed.
Ó 2006 Elsevier Ltd. All rights reserved.
1) Li, NH3,
THF,
t-BuOH,
-78 oC
The asymmetric Birch reductive alkylation of chiral
CO2Me
OMe
nonracemic benzoic acid derivatives has demonstrated
ample utility for the synthesis of a variety of natural
products.1 In these applications, chiral 2-alkoxy-, 2-
alkyl-, 2-aryl-, and 2-trialkylsilyl-benzamides have been
efficiently converted into a variety of optically active
cyclohexa-1,4-diene derivatives. Our continuous interest
in the application of the Birch reductive alkylation as
the key strategic element in natural product synthesis
has recently led us to investigate new synthetic methods
toward vindoline (1). This highly functionalized alkaloid
has important medicinal interest because of its biosyn-
thetic and synthetic role as a precursor of the anticancer
drugs vincristine and vinblastine.2 In addition, vindoline
has attracted the attention of numerous research groups,
and both racemic3 and asymmetric4 total syntheses have
been reported. Our initial work in this area consisted in
the disclosure of an efficient racemic synthesis of the tri-
cyclic core structure of vindoline.5 Important features of
this work include the elaboration of ring C of vindoline
by means of a Birch reductive alkylation of 5-phenyl-
benzoic acid derivative 2 to cyclohexadiene 3 and an
intramolecular 1,3-dipolar cycloaddition of azido di-
enone 4 that was used for the construction of ring D
of 1 (Scheme 1).
CO2Me
OMe
N3
2) I(CH2)3N3
PhH, reflux
2
3, 92%
PDC, t-BuO2H
PhH, celite
N
H
CO2Me
N3
CO2Me
OMe
O
O
OMe
4, 62%
4 steps
N
E
D
O
N
H
A
B
N
C
MeO
OAc
CO2Me
OH
CO2Me
OMe
H
Me
O
1
Scheme 1. Racemic synthesis of tricylic core structure of vindoline.
As an extension to our initial studies, and with the aim
of investigating conditions for the development of an
asymmetric total synthesis of (+)-vindoline, the Birch
reduction–alkylation of chiral benzamide 6 was planned
(Scheme 2). Following the chemistry developed in our
earlier studies, it was envisioned that Birch reduction
of 6 and alkylation of the corresponding enolate with
3-azido-1-iodopropane would provide diene 5 that repre-
sents an advanced intermediate for the construction of
*
Corresponding author at present address: Department of Chemistry,
Pfizer Global Research and Development, Michigan Laboratories,
2800 Plymouth Road, Ann Arbor, MI 48015, USA. Tel.: +1 (734)
622 2142; fax: +1 (734) 622 3909; e-mail: agustin.casimiro-garcia@
pfizer.com
z Deceased January 20, 2000.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.093

2740
A. Casimiro-Garcia, A. G. Schultz / Tetrahedron Letters 47 (2006) 2739–2742
intermediate would provide useful information about
N
H
the feasibility of this step. After examination of a variety
of biaryl coupling techniques, the Suzuki cross-coupling
was selected as the most efficient alternative for the
preparation of 14.9 The preferred synthetic route departs
from 4-methoxy-2-nitroaniline (9) and iodosalicylate 12
(Scheme 4). Nitroaniline 9 is transformed into bromo-
anisole 1010 via a Sandmeyer reaction in 85% yield fol-
lowing conditions described by Stille and co-workers.11
Iron–acetic acid reduction of nitroanisole 10 was fol-
lowed by reaction of the aniline with methyl chlorofor-
mate in the presence of potassium carbonate to afford
bromide 11 in 92% overall yield.
(+)-Vindoline
MeO
N
O
H
Me
OR
RO
N
MeO
MeO
O
N3
N
MeO2CHN
MeO2CHN
O
OMe
OMe
5
6
Scheme 2. Proposed disconnection of (+)-vindoline.
Evaluation of a variety of arylboronic acids and esters
for the Suzuki coupling led to the selection of pinacol-
boronate ester 13 as the most suitable coupling partner.
This compound was prepared using the methodology re-
ported by Murata and Masuda.12 Iodosalicylate 1213
was reacted with pinacolborane and triethylamine in
the presence of PdCl2(PPh3)2 to give boronate ester 13
in 84% yield. Cross-coupling between bromide 11 and
13 was achieved using Pd(PPh3)4 and 2 M Na2CO3 in
DME at 80 °C to give ester 14 in 97% isolated yield.
Potassium cyanide-catalyzed ester hydrolysis afforded
carboxylic acid 15 in 92% yield. As discussed above, pre-
vious work with the asymmetric Birch reductive alkyl-
ation of chiral 5-arylbenzamides (e.g., benzamide 7)
rings D and E of (+)-vindoline. The quaternary center
created during the asymmetric Birch reduction–alkyl-
ation step would direct the stereochemistry in subse-
quent transformations en route to (+)-1. The selection
of chiral benzamide 6 for this study was based on the
opportunity to incorporate early a 5-aryl substituent
that contains all the functionality required for the con-
struction of the indole ring (rings A and B) of vindoline.
The early incorporation of the aromatic substituent in
the synthesis of aspidosperma alkaloids has received
considerable attention from different groups.6 There
was limited information about the asymmetric Birch
reduction–alkylation of highly substituted chiral benz-
amide derivatives like 6. Previous studies carried out in
our laboratories showed that Birch reduction–alkylation
of benzamide 7 gave cyclohexadiene 8 in 78% isolated
yield and with a diastereomer ratio of 98:2 (Scheme
3).7 The reasonable asymmetric control established with
this prototype model gave support to continue with the
proposed study. The selection of the protecting group
for the prolinol chiral auxiliary in benzamide 6 would
be determined based on ease of synthesis and compati-
bility with subsequent steps. The effect of the carbamate
group on the Birch reduction–alkylation was not com-
pletely known when this study was undertaken. Based
on our previous experience with the Birch reduction–
alkylation of anthranilic acid derivatives containing an
ionizable NH group,8 as is the case of benzamide 6,
the carbamate group was expected to serve as a potential
proton donor for the protonation of the radical anion
formed after the initial first electron transfer. In this
communication, the results of our studies of the asym-
metric Birch reductive alkylation are described.
MeO
MeO
MeO
a
b
NH2
Br
Br
NO2
NO2
NHCO2Me
9
10
11
OMe
O
B
CO2Me
I
CO2Me
OMe
O
NHCO2Me
CO2Me
c
d
OMe
12
13
14
OMe
e
OMe
OMe
OMOM
N
H
16
f
The initial efforts of this study were directed at develop-
ing an efficient synthesis of ester 14. This intermediate
would not only serve as a precursor of the desired chiral
benzamide, but also Birch reductive alkylation of this
NHCO2Me
CO2H
NHCO2Me
N
OMe
OMe O
17
OMOM
15
MeO
N
MeO
1) K, NH3,
THF, t-BuOH,
-78 oC
2) MeI
O
O
Scheme 4. Synthesis of benzamide 17. Reagents and conditions: (a) (i)
HBr, H2O, 1,4-dioxane, reflux, (ii) NaNO2, H2O, 0 °C, (iii) CuBr, HBr,
0–60 °C, 85%; (b) (i) Fe, EtOH, AcOH, reflux, (ii) MeOCOCl, K2CO3,
acetone, reflux, 92%; (c) pinacolborane, PdCl2(PPh3)2, Et3N, 1,4-
dioxane, 80 °C, 84%; (d) 11, Pd(PPh3)4, 2 M Na2CO3, DME, 80 °C,
97%; (e) K2CO3, KCN (0.2 equiv), THF-MeOH–H2O, 80 °C, 36 h,
92%; (f) (i) (COCl)2, cat. DMF, CH2Cl2, (ii) 16, Et3N, À70 °C to rt,
87%.
Me
N
OMe
OMe
OMe
OMe
7
8, 78% yield
dr: 98:2
Scheme 3. Asymmetric Birch reductive alkylation of benzamide 7.

A. Casimiro-Garcia, A. G. Schultz / Tetrahedron Letters 47 (2006) 2739–2742
2741
was performed using (S)-2-methoxymethyl-pyrrolidine
as the chiral auxiliary. However, (S)-2-methoxymeth-
oxymethyl-pyrrolidine 1614 was identified as the pre-
ferred chiral auxiliary for this study based on the
simplicity for its removal and compatibility with later
transformations.15 In addition, the ratio of diastereo-
mers obtained with these two chiral auxiliaries was iden-
tical when they were compared in the Birch reductive
alkylation of benzamide derivatives.16 The incorpora-
tion of the chiral auxiliary was accomplished by first
reacting carboxylic acid 15 with oxalyl chloride and cat-
alytic DMF to afford the corresponding acid chloride.
Without isolation, the acid chloride was reacted with
prolinol ether 16 and triethylamine at low temperature
to give benzamide 17 in 87% isolated yield.
aryl substituent has a strong effect on the yield of the
cyclohexadiene product. No optimization of the Birch
reductive alkylation of ester 14 was attempted.
The asymmetric Birch reduction–alkylation of benzam-
ide 17 was explored next and the results are summarized
in Table 1. This reaction was first performed using
potassium (7 equiv) in the presence of t-BuOH (1 equiv)
in NH3–THF at À78 °C followed by quenching excess
metal with piperylene. The enolate was reacted with 3-
azido-1-iodopropane to afford 19 in only 30% yield (en-
try 1). Reducing the amount of potassium to 6.0 equiv
furnished a modest improvement in the yield of 19 (en-
try 2). Further investigation of the Birch reduction con-
ditions led to performing the reaction in the absence of
t-BuOH (entry 3) and to our delight, a drastic increase in
the yield of 19 (70%) was achieved while using a similar
amount of potassium (5.2 equiv) for the reduction. The
optimal conditions (entry 4) involved performing the
reduction of 17 with 3.7 equiv of potassium, in the
absence of t-BuOH, in THF/NH3 at À78 °C for 3 h
followed by addition of piperylene and then 3-azido-1-
iodopropane to provide 19 in 78% yield. This reaction
has been performed in multi-gram scale under these con-
ditions to provide 19 in 74–78% isolated yield.
The Birch reduction–alkylation of ester 14 was investi-
gated first (Scheme 5). Birch reduction of ester 14 with
lithium (3.2 equiv) in the presence of t-BuOH (1 equiv)
in NH3–THF at À78 °C followed by addition of piperyl-
ene (1,3-pentadiene) to consume excess metal and
alkylation with 3-azido-1-iodopropane17 afforded cyclo-
hexadiene 18 in 49% isolated yield. As previously dis-
cussed, Birch reduction–alkylation of 5-phenylbenzoic
acid derivative 2 proceeded in high yield (92%). There-
fore, it appears that the functionality present in the 5-
The asymmetric Birch reduction–alkylation of benz-
amide 17 to cyclohexadiene 20 was also investigated
and a similar effect was observed when the reaction
was carried out in the absence of t-BuOH. Reduction
of 17 with potassium (4 equiv) in the presence of t-BuOH
(1 equiv) followed by addition of piperylene and alkyl-
ation with iodoethane led to 20 in 46% yield (Table 1, en-
try 5). A modest, but noticeable increase in the yield of
cyclohexadiene 20 (66%) was obtained by carrying out
the reduction with 4.8 equiv of potassium in the absence
of t-BuOH (entry 6). The results from these experiments
indicate that the reduction of 17 is best performed in
the absence of tert-butyl alcohol. Changes in the amount
OMe
OMe
1) Li, NH3/THF
t-BuOH,
NHCO2Me
CO2Me
NHCO2Me
-78 oC
2) Piperylene
3) I(CH2)3N3
N3
CO2Me
OMe
OMe
14
18, 49% yield
Scheme 5. Birch reductive alkylation of ester 14.
Table 1. Asymmetric Birch reduction–alkylation of benzamide 17
OMe
OMe
Conditions
Table 1
NHCO2Me
NHCO2Me
N
R
N
OMe O
OMOM
OMe O
OMOM
19 R = CH2CH2CH2N3
20 R = CH2CH3
17
Entry
RX
Conditionsa
Product
Yield (%)
Potassium (equiv)
t-BuOH (equiv)
1
2
3
4
5
6
I(CH2)3N3
I(CH2)3N3
I(CH2)3N3
I(CH2)3N3
EtI
7.0
6.0
5.2
3.7
4.0
4.8
1
1
0
0
1
0
19
19
19
19
20
20
30
40
70
78
46
66
EtI
a General reaction conditions: Benzamide 17 in NH3–THF was reacted with K (n equiv), t-BuOH (n equiv) at À78 °C for 3 h; piperylene was added
followed by RX.

2742
A. Casimiro-Garcia, A. G. Schultz / Tetrahedron Letters 47 (2006) 2739–2742
3. Racemic total synthesis: (a) Ando, M.; Buchi, G.;
¨
Ohnuma, T. J. Am. Chem. Soc. 1975, 97, 6880; (b)
Kutney, J. P.; Bunzli-Trepp, U.; Chan, K. K.; de Souza, J.
P.; Fujise, Y.; Honda, T.; Katsube, J.; Klein, F. K.;
Leutwiller, A.; Morehead, S.; Rohr, M.; Worth, B. R. J.
Am. Chem. Soc. 1978, 100, 4220; (c) Andriamialisoa, R.
Z.; Langlois, N.; Langlois, Y. J. Org. Chem. 1985, 50, 961;
Formal racemic total synthesis: (d) Ban, Y.; Sekine, Y.;
Oishi, T. Tetrahedron Lett. 1978, 151; (e) Takano, S.;
Shishido, K.; Matsuzaka, J.; Sato, M.; Ogasawara, K.
Heterocycles 1979, 13, 307; (f) Danieli, B.; Lesma, G.;
Palmisano, G.; Riva, R. J. Chem. Soc., Chem. Commun.
1984, 909; (g) Danieli, B.; Lesma, G.; Palmisano, G.; Riva,
R. J. Chem. Soc., Perkin Trans. 1 1987, 155; (h) Zhou, S.;
Bommezijn, S.; Murphy, J. A. Org. Lett. 2002, 4, 443.
4. (a) Feldman, P. L.; Rapaport, H. J. Am. Chem. Soc. 1987,
109, 1603; (b) Kuehne, M. E.; Podhorez, D. E.; Mulamba,
T.; Bornmann, W. G. J. Org. Chem. 1987, 52, 347; (c)
Kobayashi, S.; Ueda, T.; Fukuyama, T. Synlett 2000, 883;
(d) Choi, Y.; Ishikawa, H.; Velcicky, J.; Elliott, G. I.;
Miller, M. M.; Boger, D. L. Org. Lett. 2005, 7, 4539.
5. Guo, Z.; Schultz, A. G. Tetrahedron Lett. 2004, 45, 919.
6. (a) Angle, S. R.; Fevig, J. M.; Knight, S. D.; Marquis, R.
W.; Overman, L. E. J. Am. Chem. Soc. 1993, 115, 3966; (b)
Bonjoch, J.; Sole, D.; Bosch, J. J. Am. Chem. Soc. 1995,
117, 11017; (c) Toczko, M. A.; Heathcock, C. H. J. Org.
Chem. 2000, 65, 2642.
N3
MOMO
MeO
PDC/t-BuO2H
celite, PhH
O
19
N
MeO2CHN
O
OMe
21, 73% yield
dr: >98:2
Scheme 6. Synthesis of cyclohexadienone 21.
of potassium used for the reduction leads only to a mod-
est improvement in the yield of the product. As dis-
cussed earlier, the acidic NH moiety of the carbamate
group of 17 was expected to serve as the proton source
for the protonation of the radical anion formed after
the initial first electron transfer. The results of this study
support this role. The dianion obtained after transfer
of a second electron would undergo reaction with alkyl
halides and protonation with NH4Cl. The participation
of the NH group of 17 in the protonation step is in
agreement with our previous results with other sub-
strates containing ionizable NH groups.8 However, it
is important to note that this is the first report of an
asymmetric Birch reductive alkylation of a chiral benz-
amide performed in the absence of t-BuOH that pro-
vides synthetically useful yields of the cyclohexadiene
product.18
7. (a) Khim, S.-K.; Dai, M.; Zhang, X.; Chen, L.; Pettus, L.;
Thakkar, K.; Schultz, A. G. J. Org. Chem. 2004, 69,
7728; (b) Thakkar, K. Rensselaer Polytechnic Institute,
unpublished results.
The diastereoselectivity of the Birch reductive alkylation
was determined after conversion of diene 19 to cyclo-
hexadienone 21. Bisallylic oxidation of 19 with PDC,
t-BuO2H, and celite gave 21 in 73% isolated yield
(Scheme 6). The diastereomeric ratio of 21 was deter-
mined to be >98:2 by HPLC comparison to a 1:1 mix-
ture of diastereomers prepared from the racemic ester
18.
8. (a) Schultz, A. G.; McCloskey, P. J.; Sundararaman, P.
Tetrahedron Lett. 1985, 26, 1619; (b) Schultz, A. G.;
McCloskey, P. J.; Court, J. J. J. Am. Chem. Soc. 1987,
109, 6493.
9. (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron
Lett. 1979, 36, 3437; (b) Miyaura, N.; Suzuki, A. Chem.
Rev. 1995, 95, 2457; (c) Suzuki, A. J. Organomet. Chem.
1999, 576, 147.
10. Rudisill, D. E.; Stille, J. K. J. Org. Chem. 1989, 54, 5856.
11. Krolski, M.; Renaldo, A. F.; Rudisill, D. E.; Stille, J. K. J.
Org. Chem. 1988, 53, 1170.
Acknowledgments
12. (a) Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y. J.
Org. Chem. 2000, 65, 164; (b) Murata, M.; Watanabe, S.;
Masuda, Y. J. Org. Chem. 1997, 62, 6458.
13. Bergman, J. J.; Griffith, E. A. H.; Robertson, B. E.;
Chandler, W. D. Can. J. Chem. 1973, 51, 162.
14. For the preparation of this chiral auxiliary, see: Tamura,
R.; Watabe, K.-i.; Ono, N.; Yamamoto, Y. J. Org. Chem.
1992, 57, 4895.
This work was supported by the National Institutes of
Health (GM 33061). A.C.-G. thanks Professor Mark
P. Wentland for his helpful discussions and Dr. Noel
A. Powell for proofreading this manuscript.
15. For the use of this chiral auxiliary in other applications of
the Birch reductive alkylation, see: (a) Schultz, A. G.;
Puig, S. J. Am. Chem. Soc. 1985, 50, 915; (b) McCloskey,
P. J.; Schultz, A. G. Heterocycles 1987, 25, 437; (c)
Schultz, A. G.; Macielag, M.; Podhorez, D. E.; Suhadol-
nik, J. C. J. Org. Chem. 1988, 53, 2456.
16. Schultz, A. G.; Sundararaman, P.; Macielag, M.; Lavieri,
F. P.; Welch, M. Tetrahedron Lett. 1985, 26, 4575.
17. Conrad, P. C.; Kwiatkowski, P. L.; Fuchs, P. L. J. Org.
Chem. 1987, 52, 586.
Supplementary data
Experimental procedures and analytical data for new
compounds. Supplementary data associated with this
article can be found, in the online version, at doi:
10.1016/j.tetlet.2006.02.093.
References and notes
18. During the early development of this methodology, it was
observed that Birch reduction of N,N-dimethylbenzamide
with lithium in NH3–THF at À33 °C in the absence of t-
BuOH gave benzaldehyde and benzyl alcohol as the major
reaction products. For more details, see: Schultz, A. G.;
Macielag, M. J. Org. Chem. 1986, 51, 4983.
1. (a) Schultz, A. G. Chem. Commun. 1999, 14, 1263; (b)
Schultz, A. G. J. Chin. Chem. Soc. 1994, 41, 487; (c)
Schultz, A. G. Acc. Chem. Res. 1990, 23, 207.
2. Gorman, M.; Neuss, N.; Biemann, K. J. Am. Chem. Soc.
1962, 84, 1058.