Synthesis of 4-substituted 1,5-dihydropyrrol-2-ones and 5,6-dihydro-1H-pyridin-2-ones by Negishi cross-coupling reactions: Short access to the antidepressant (±)-rolipram

Article abstract of DOI:10.1055/s-2007-982553

A straightforward access to the title compounds was established by Pd-catalyzed Negishi cross-coupling reactions of the readily available bromides 3 and 6 with various functionalized zinc reagents (71-97% yield). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-982553

LETTER
1557
Synthesis of 4-Substituted 1,5-Dihydropyrrol-2-ones and 5,6-Dihydro-1H-
pyridin-2-ones by Negishi Cross-Coupling Reactions: Short Access to the
Antidepressant ( )-Rolipram
4
-Substituted Dihy
o
dropyrrolone
m
s and Dihydropyrid
i
inonesnik Albrecht, Thorsten Bach*
Lehrstuhl für Organische Chemie I, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany
Fax +49(89)28913315; E-mail: thorsten.bach@ch.tum.de
Received 18 April 2007
O
Abstract: A straightforward access to the title compounds was
(COBr)2, DMF
established by Pd-catalyzed Negishi cross-coupling reactions of the
readily available bromides 3 and 6 with various functionalized zinc
reagents (71–97% yield).
N
n
PG
CH2Cl2
TFA
6
4
5
3
O
84%
50%
99%
99%
7
8
n = 1
n = 2
PG = Boc
PG = t-Bu
Key words: catalysis, cross-coupling, heterocycles, lactams, palla-
dium, zinc
Scheme 1 Preparation of the bromides 3–6
Despite the fact that the title compounds 1 and 2 (cf.
Figure 1) represent valuable intermediates1 for the con-
struction of more complex nitrogen heterocycles, there is
no general access, which allows for variation of the C4-
substituent.2 We became interested in these compounds
because the w-alkenyl-substituted derivatives appeared to
be suitable precursors for [2+2]-photocycloaddition reac-
tions. The introduction of the R group by a cross-coupling
reaction3 at the corresponding 4-halo precursors stroke us
as a versatile and extremely flexible route towards 4-sub-
stituted 1,5-dihydropyrrol-2-ones and 5,6-dihydro-1H-
pyridin-2-ones.4 In this communication we report on our
preliminary experiments in this area focusing on reactions
of the 4-bromo-substituted heterocycles 3–6 (Figure 1,
PG = protecting group).
added to a solution of the substrate and of (COBr)2 in
CH2Cl2 was not applicable, neither could DMF be used in
catalytic amounts. Deprotection was performed either in
refluxing trifluoroacetic acid (TFA) for dihydro-1H-pyri-
dinone 4 or with TFA at ambient temperature in CH2Cl2
for dihydropyrrolone 6.
An optimization of the cross-coupling reactions was con-
ducted with bromide 4 and butyl zinc bromide as nucleo-
phile (cf. Table 1).
The organozinc reagent was generated from butyl lithium
and zinc bromide (THF as solvent) or from butyl bromide
and activated zinc9 (DMA as solvent). Ligandless condi-
tions (entries 1, 3, 4) and the use of standard catalysts (en-
tries 2 and 5) gave moderate to good results. A ligand
variation revealed the superiority of triphenylarsane and
RuPhos (2-dicyclohexylphosphino-2¢¢, 6¢¢-diisopropoxy-
1,1¢¢-biphenyl) as ligands (entries 6 and 7).10 By changing
the solvent from THF to DMA a slight increase in yield
was observed (entry 7 vs. entry 8). While the Pd2(dba)3/
RuPhos catalyst allowed a reduction of the catalyst
loading the conversion decreased with Pd2(dba)3/AsPh3 as
the catalyst (entries 9 and 10).11
O
O
O
PG
N
NH
N
PG
n
R
Br
Br
1
2
5
6
PG = H
PG = Boc
n = 1
n = 2
3
4
PG = H
PG = t-Bu
Figure 1 Structures of the 4-substituted title compounds 1, 2, and of
their 4-bromosubstituted precursors 3–6
With optimum conditions in hand we applied the cross-
coupling to the bromides 3, 5, and 6. While the unprotect-
ed dihydropyridinone 3 performed as well as its tert-bu-
tyl-protected analogue, the reactions with compound 5
proceeded sluggishly. Reactions remained incomplete
and overall yields were moderate at best. We were there-
fore delighted to observe a smooth conversion with the N-
Boc-protected compound 6. Since the N-deprotection of
Boc is in contrast to the N-deprotection of tert-butyl facile
(vide infra) we considered the fact that we had to use 6 in-
stead of 5 not to be a significant drawback. Various orga-
nozinc reagents were prepared and tested in the cross-
coupling with bromides 3 and 6 (Scheme 2, Table 2).
The starting materials were accessible from the known
b-ketolactams 75 and 8,6 which were transformed into the
bromides 4 and 6 by treatment with oxalyl bromide and
DMF in dichloromethane (Scheme 1).
It was crucial for the success of the reaction to preform the
Vilsmeier reagent and to add the substrate subsequently.7
The conventional procedure,8 according to which DMF is
SYNLETT 2007, No. 10, pp 1557–1560
1
8
.0
6
.2
0
0
7
Advanced online publication: 07.06.2007
DOI: 10.1055/s-2007-982553; Art ID: G12707ST
© Georg Thieme Verlag Stuttgart · New York

1558
D. Albrecht, T. Bach
LETTER
Table 1 Optimization of the Negishi Cross-Coupling Using
Bromide 4 and Butyl Zinc Bromide as the Reagent
Table 2 Negishi Cross-Coupling Reactions of Bromides 3 and 6
with the Organozinc Reagents 10
O
O
ZnBr
Entry
1
Substratea RZnX
Procedureb Product Yield (%)c
(2 equiv)
t-Bu
t-Bu
N
N
cat., r.t., 14 h
(solvent)
3
6
3
6
3
6
3
6
3
6
3
6
3
6
3
6
10a
10a
10b
10b
10c
10c
10d
10d
10e
10e
10f
A
A
A
A
A
A
A
A
A
A
A
A
B
B
C
C
2a
11a
2b
97
88
96
82
90
82
84
75
95
73
77
80
76
73
91
72
Br
Bu
2
4
9a
3
Entry Cat.a
c (mol%) Solvent
Yield (%)b
4
11b
2c
1
2
PdCl2(MeCN)2
Pd(PPh3)4
10
10
10
10
10
10
10
10
5
THF
THF
THF
THF
THF
THF
THF
DMA
DMA
DMA
23
40
54
68
77
93
94
96
97
49
5
6
11c
2d
3
PdCl2(PhCN)2
7
c
4
Pd2(dba)3
8
11d
2e
5
PdCl2(dppf)d
9
6
Pd2(dba)3/AsPh3
Pd2(dba)3/RuPhose
Pd2(dba)3/RuPhos
Pd2(dba)3/RuPhos
Pd2(dba)3/AsPh3
10
11
12
13
14
15
16
11e
2f
7
8
10f
11f
2g
9
10g
10g
10h
10h
10
5
11g
2h
a All reactions were conducted at a substrate concentration of 0.1 mM
using 2 equiv of butyl zinc bromide at ambient temperature in the
indicated solvent.
b Yield of isolated product.
11h
c dba = dibenzylideneacetone.
a All reactions were conducted at a substrate concentration of 0.05–
0.07 mM in DMA as the solvent at ambient temperature.
b For the preparation of the zinc reagents three different procedures
were used: A: Zn [I2], 80 °C, 3 h (DMA). B: Zn [I2], 50 °C, 1.5 h
(DMA). C: Zn [C2H4Br2, TMSCl], r.t., 1.5 h (DMA).
c Yield of isolated product.
d dppf = bis(diphenylphosphino)ferrocene.
e RuPhos = 2-dicyclohexylphosphino-2¢¢,6¢¢-diisopropoxy-1,1¢¢-bi-
phenyl.
O
O
In most cases the zincation was performed on the corre-
sponding bromide (X = Br) according to the procedure by
Huo (procedure A, Table 2).9 Zinc reagent 10g was pre-
pared from the corresponding iodide (X = I) at lower tem-
perature than applied in procedure A (procedure B). The
thiazolyl reagent 10h was obtained from the bromide
(X = Br). In this case the procedure described by Knochel
et al. was followed (procedure C).12 The cross-coupling
reactions proceeded at ambient temperature within 14
hours. Yields were very good to excellent (72–97%) for
all reagents tested. The compatibility with functional
groups was demonstrated for alkenyl (Table 2, entries 3,
4) for cyano (entries 5, 6), for chloro (entries 7, 8), for
phthaloyl (Phth, entries 9, 10), for alkoxycarbonyl (entries
11, 12) and for NHBoc (entries 13, 14). The catalyst
Pd2(dba)3 was used in 5 mol%, the ligand RuPhos in 20
mol%. A further decrease of the catalyst loading resulted
in incomplete conversions. By using 2.5 mol% of
Pd2(dba)3 and 10 mol% RuPhos, for example, we ob-
served the formation of 2a from bromide 3 and butyl zinc
bromide (10a) but the yield was reduced to 80%.
NH
NH
RZnX (10)
[Pd2(dba)3/RuPhos]
25 °C (DMA)
Br
R
3
2
O
O
see table 2
N
Boc
N
Boc
Br
R:
R
6
11
NC
a
b
c
Cl
PhthN
d
e
NHBoc
O
t-BuOOC
N
S
10
BnOOC
t-Bu
O
f
g
h
Scheme 2 Negishi cross-coupling reactions of bromides 3 and 6
with various organozinc reagents RZnX (10)
Synlett 2007, No. 10, 1557–1560 © Thieme Stuttgart · New York

LETTER
4-Substituted Dihydropyrrolones and Dihydropyridinones
1559
N-Boc deprotection of products 11 turned out to be facile. lactam.22 Finally, conjugate reduction by hydrogenation
Treatment of product 11b with TFA in dichloromethane with palladium on charcoal delivered racemic rolipram
for example gave the desired 4-substituted 1,5-dihydro- (rac-14) in a yield of 93%.23
pyrrol-2-one in 99% yield. The same deprotection condi-
tions are applicable to all other products 11 (vide infra).
The method consequently allows to obtain a broad variety
of 4-substituted products 1 and 2. For the 1,5-dihydropyr-
rol-2-ones Boc protection is required in the cross-cou-
pling step while 5,6-dihydro-1H-pyridin-2-ones are
available directly in unprotected form. If desired, the tert-
butyl group can be employed in the latter case. Deprotec-
tion conditions are harsh, however, and require refluxing
In summary, we have developed a conjugate substitution
protocol by Pd-catalyzed Negishi cross-coupling that
allows for the formation of five- and six-membered a,b-
unsaturated lactams possessing a single substituent in the
4-position. Finally, this method has been successfully
applied to an effective and brief approach to the anti-
depressant agent ( )-rolipram.
Acknowledgment
trifluoroacetic acid for one hour.
This project was supported by the Fonds der Chemischen Industrie
(FCI) and the Deutsche Forschungsgemeinschaft. D.A. is grateful
to the FCI for a Kekulé scholarship and for support by the Studien-
stiftung des Deutschen Volkes.
Finally, we demonstrated the synthetic potential of the
conjugate substitution by Negishi cross-coupling reaction
in a short-step synthesis of (R,S)-4-(3-cyclopentyloxy-4-
methoxyphenyl)pyrrolidin-2-one (rolipram, rac-14,
Scheme 3). Rolipram (rac-14) was initially developed as
an antidepressant13 drug by Schering.14 It has been shown References and Notes
to be a potent and selective inhibitor of phosphodiesterase
(1) Reviews on 1,5-dihydropyrrol-2-ones and 5,6-dihydro-1H-
type IV (PDE IV),15 the main enzyme regulating the con-
centration of cyclic adenosine 3¢,5¢-monophosphate
(cAMP).16 Inhibition of PDE IV has been rapidly recog-
nized as a promising therapeutic target for the treatment of
a number of disorders such as multiple sclerosis, coronary
failure, asthma, pulmonary diseases, and diabetes.17
Both enantiomers are known to be active against PDE IV
with the R-(–)-enantiomer being primarily responsible for
the pharmacological effects.13a,18 The industrial synthesis
of rac-14 and resolution of the enantiomers either by
chromatography13,19,21q or by classical (enzymatic)
resolution of an intermediate in the synthesis20 has been
reported. Due to the importance of rolipram as a drug and
as a pharmacological probe, a general approach to 14 and
new derivatives thereof is desirable and useful.21
pyridin-2-ones: (a) Rio, G.; Masure, D. Bull. Soc. Chim. Fr.
1972, 12, 4598. (b) Egorova, A. Y.; Timofeeva, Z. Y. Chem.
Heterocycl. Compd. (N.Y.) 2004, 10, 1243. (c) Smith, M. B.
Science of Synthesis, Vol. 21; Weinreb, S. M., Ed.; Thieme:
Stuttgart, 2005, 647–711. (d) Fisyuk, A. S.; Poendaev, N. V.
In Targets in Heterocyclic Systems, Vol. 5; Attanasi, O. A.;
Spinelli, D., Eds.; Società Chimica Italiana: Roma, 2005,
271.
(2) Individual methods (see also ref. 4) for 4-substituted 1,5-
dihydropyrrol-2-ones, see: (a) Barluenga, J.; Fañanás, F. J.;
Foubelo, F.; Yus, M. Tetrahedron Lett. 1988, 29, 4859.
(b) Corriu, R. J. P.; Bolin, G.; Iqbal, J.; Moreau, J. J. E.;
Vernhet, C. Tetrahedron 1993, 49, 4603. (c) Li, W.-R.; Lin,
S. T.; Hsu, N.-M.; Chern, M.-S. J. Org. Chem. 2002, 67,
4702. (d) Lautens, M.; Han, W.; Liu, J. H.-C. J. Am. Chem.
Soc. 2003, 125, 4028. (e) Verniest, G.; Boterberg, S.;
Bombeke, F.; Stevens, C. V.; De Kimpe, N. Synlett 2004,
1059.
1. t BuLi (THF)
2. ZnBr2 (THF)
3. 6, DMA
(3) Review on Pd-catalyzed conjugate substitution reactions:
Negishi, E.-i.; Dumond, Y. Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-i., Ed.; Wiley:
New York, 2002, 767–789.
HO
Br
4 steps21s
O
[Pd2(dba)3, RuPhos]
(4) A 4-stannylated N-Boc-protected 1,5-dihydropyrrol-2-one
has been used as nucleophile in Stille cross-coupling
reactions: (a) Reginato, G.; Capperucci, A.; Degl’Innocenti,
A.; Mordini, A.; Pecchi, S. Tetrahedron 1995, 51, 2129.
(b) Santos, M. M. M.; Lobo, A. M.; Prabhakar, S.; Marques,
M. M. B. Tetrahedron Lett. 2004, 45, 2347.
(5) Li, W.-R.; Lin, S. T.; Hsu, N.-M.; Chern, M.-S. J. Org.
Chem. 2002, 67, 4702.
(6) Oda, R.; Takashima, S.; Okano, M. Bull. Chem. Soc. Jpn.
1962, 35, 1843.
MeO
71%
MeO
12
13
O
O
1. TFA (CH2Cl2)
2. H2 [Pd/C]
EtOH
N
Boc
NH
O
O
89%
(7) Typical Procedure for the Bromide Formation with
Oxalyl Bromide
MeO
MeO
11i
rac-14
To a solution of DMF (6.4 mL, 82.3 mmol) in dry CH2Cl2
(100 mL) oxalyl bromide (6.8 mL, 73.4 mmol) was added
slowly at 0 °C. The reaction mixture was stirred at this
temperature until gas formation ceased. Then, 1-tert-butyl-
piperidine-2,4-dione (8, 5.24 g, 31.0 mmol) dissolved in dry
CH2Cl2 (50 mL) was added to the solution at 0 °C. The
reaction mixture was stirred for 1 h at 0 °C and for 1 h at r.t.
After neutralization with sat. aq NaHCO3 solution, H2O (20
mL) and CH2Cl2 (20 mL) were added. The layers were
separated and the aqueous layer was extracted with CH2Cl2
Scheme 3 Synthesis of ( )-rolipram (rac-14)
Our own synthesis was based on the readily available bro-
mide 13, which is available in four steps from guaiacol
(12).21s Zincation and subsequent cross-coupling deliv-
ered product 11i in 71% yield. N-Boc deprotection pro-
vided in 95% yield the corresponding unsaturated
Synlett 2007, No. 10, 1557–1560 © Thieme Stuttgart · New York

1560
D. Albrecht, T. Bach
LETTER
(18) Barluenga, J.; Fernández-Rodríguez, M. A.; Aguilar, E.;
Fernández-Marí, F.; Salinas, A.; Olano, B. Chem. Eur. J.
2001, 7, 3533.
(19) (a) Blaschke, G. J. Liq. Chromatogr. 1986, 9, 341.
(b) Kuesters, E.; Spoendlin, C. J. Chromatogr., A 1996, 737,
333.
(3 × 20 mL). The organic layers were combined, washed
with sat. aq NaCl solution (20 mL) and dried over MgSO4.
After filtration the solvent was evaporated under reduced
pressure. After purification by flash chromatography
(pentane–EtOAc, 9:1) 4-bromo-1-tert-butyl-5,6-dihydro-
1H-pyridin-2-one (4, 5.98 g, 25.9 mmol, 84%) was obtained
as colorless liquid. Rf = 0.25 (cyclohexane–EtOAc, 9:1). IR
(film): nmax = 2974, 2868, 1652, 1625, 1461, 1411, 1364,
1352, 1319, 1258, 1242 cm–1. 1H NMR (360 MHz, CDCl3):
d = 1.40 (s, 9 H), 2.68 (dt, 3J = 6.8 Hz, 4J = 1.4 Hz, 2 H), 3.44
(t, 3J = 6.8 Hz, 2 H), 6.17 (t, 4J = 1.4 Hz, 1 H) ppm. 13C NMR
(90.6 MHz, CDCl3): d = 28.6 (q), 35.6 (t), 42.2 (t), 57.0 (s),
129.5 (d), 135.7 (q), 164.3 (s) ppm. HMRS (EI): m/z calcd
for C8H11BrNO [M – CH3]+: 216.0024; found: 216.0019.
Anal. Calcd for C9H14BrNO: C, 46.57; H, 6.08; N, 6.03.
Found: C, 46.53; H, 6.07; N, 6.12.
(20) Petzoldt, K.; Schmiechen, R.; Hamp, K. DE 3921593, 1991;
Chem. Abstr. 1991, 114, 143134.
(21) For previous syntheses of rolipram, see: (a) Mulzer, J.;
Zuhse, R.; Schmiechen, R. Angew. Chem., Int. Ed. Engl.
1992, 31, 870. (b) Meyers, A. I.; Snyder, L. J. Org. Chem.
1993, 58, 36. (c) Baures, P. W.; Egglestone, D. S.; Erhard,
K. F.; Cieslinski, L. B.; Torphy, T. J.; Christensen, S. B. J.
Med. Chem. 1993, 36, 3274. (d) Mulzer, J. J. Prakt. Chem.
1994, 336, 287. (e) Braun, M.; Opdenbusch, K.; Unger, C.
Synlett 1995, 1174. (f) Honda, T.; Ishikawa, F.; Kanai, K.;
Sato, S.; Kato, D.; Tominaga, H. Heterocycles 1996, 42,
109. (g) Langlois, N.; Wang, H.-S. Synth. Commun. 1997,
27, 3133. (h) Diaz, A.; Siro, J. G.; García-Navío, J. L.;
Vaquero, J. J.; Alvarez-Builla, J. Synthesis 1997, 559.
(i) Demnitz, J.; LaVecchia, L.; Bacher, E.; Keller, T. H.;
Müller, T.; Schürch, F.; Weber, H.-P.; Pombo-Villar, E.
Molecules 1998, 3, 107. (j) Anada, M.; Mita, O.; Watanabe,
H.; Kitagaki, S.; Hashimoto, S. Synlett 1999, 1775.
(k) Barluenga, J.; Fernández-Rodríguez, M. A.; Aguilar, E.;
Fernández-Marí, F.; Salinas, A.; Olano, B. Chem. Eur. J.
2001, 7, 3533. (l) Itoh, K.; Kanemasa, S. J. Am. Chem. Soc.
2002, 124, 13394. (m) Barnes, D. M.; Ji, J.; Fickes, M. G.;
Fitzgerald, M. A.; King, S. A.; Morton, H. E.; Plagge, F. A.;
Preskill, M.; Wagaw, S. H.; Wittenberger, S. J.; Zhang, J. J.
Am. Chem. Soc. 2002, 124, 13097. (n) Yoon, C. H.; Nagle,
A.; Chen, C.; Gandhi, D.; Jung, K. W. Org. Lett. 2003, 5,
2259. (o) Chang, M.-Y.; Sun, P.-P.; Chen, S.-T.; Chang, N.-
C. Heterocycles 2003, 60, 1865. (p) Becht, J.-M.; Meyer,
O.; Helmchen, G. Synthesis 2003, 2805. (q) Garcia, A. L.
L.; Carpes, M. J. S.; de Oca, A. C. B. M.; dos Santos, M. A.
G.; Santana, C. C.; Correia, C. R. D. J. Org. Chem. 2005, 70,
1050. (r) Tonogaki, K.; Itami, K.; Yoshida, J. J. Am. Chem.
Soc. 2006, 128, 1464. (s) Paraskar, A. S.; Sudalai, A.
Tetrahedron 2006, 62, 4907.
(8) Jas, G. Synthesis 1991, 965.
(9) Huo, S. Org. Lett. 2003, 5, 423.
(10) Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126,
13028.
(11) Representative Cross-Coupling Procedure
To a solution of Pd2(dba)3 (20 mg, 22.7 mmol) and RuPhos
(40 mg, 90.8 mmol) in dry dimethylacetamide (2 mL) 4-
bromo-1-tert-butyl-5,6-dihydro-1H-pyridin-2-one (4, 105
mg, 0.454 mmol) was added at r.t. After stirring for 10 min
a solution of the organozinc reagent (0.903 mmol) prepared
according to procedure A was added at once. After the
reaction mixture was stirred at r.t. for 14 h the solvent was
removed under reduced pressure. Purification by flash
chromatography (pentane–EtOAc, 19:1) yielded 4-butyl-1-
tert-butyl-5,6-dihydro-1H-pyridin-2-one (9a, 92.0 mg,
0.441 mmol, 97%) as a colorless liquid. Rf = 0.18
(cyclohexane–EtOAc, 9:1). 1H NMR (360 MHz, CDCl3): d
= 0.85 (t, 3J = 7.2 Hz, 3 H), 1.44–1.21 (m, 13 H), 2.07 (t,
3J = 7.5 Hz, 2 H), 2.13 (t, 3J = 6.6 Hz, 2 H), 3.31 (t, 3J = 6.6
Hz, 2 H), 5.55 (s, 1 H) ppm. 13C NMR (62.9 MHz, CDCl3):
d = 13.8 (q), 22.3 (t), 28.7 (q), 28.8 (t), 29.2 (t), 35.5 (t), 41.8
(t), 56.3 (s), 122.4 (d), 153.3 (s), 167.1 (s) ppm. HMRS (EI):
m/z calcd for C13H23NO: 209.1780; found: 209.1782. Anal.
Calcd for C13H23NO: C, 74.59; H, 11.07; N, 6.69. Found: C,
74.22; H, 11.30; N, 6.55.
(22) Representative Deprotection Procedure
(12) Prasad, A. S. B.; Stevenson, T. M.; Citineni, J. R.; Nyzam,
V.; Knochel, P. Tetrahedron 1997, 53, 7237.
4-(3-Cyclopentyloxy-4-methoxy-phenyl)-2-oxo-2,5-
dihydro-pyrrole-1carboxylic acid tert-butyl ester (11i, 36
mg, 96.4 mmol) was dissolved in CH2Cl2 (2 mL) at r.t. and
TFA (37 ml, 482 mmol) was added. After the reaction mixture
was stirred at r.t. for 30 min the solvent and TFA were
removed under reduced pressure. Purification by flash
chromatography (EtOAc–MeOH, 9:1) yielded 4-(3-
cyclopentyloxy-4-methoxy-phenyl)-1,5-dihydro-pyrrol-2-
one (25.0 mg, 91.5 mmol, 95%) as colorless crystals.
Rf = 0.55 (EtOAc–MeOH, 9:1); mp 203–205 °C. 1H NMR
(360 MHz, CDCl3): d = 1.60–1.63 (m, 2 H), 1.81–1.95 (m, 6
H), 3.87 (s, 3 H), 4.37 (s, 2 H), 4.76–4.80 (m, 1 H), 6.29 (s,
1 H), 6.85 (d, 3J = 8.4 Hz, 1 H), 7.01–7.04 (m, 2 H), 7.14 (s,
br, 1 H) ppm. 13C NMR (90.6 MHz, CDCl3): d = 24.2 (t),
32.9 (t), 48.5 (t), 56.2 (q), 81.0 (d), 111.9 (d), 112.8 (d),
118.2 (d), 119.2 (d), 124.9 (s), 148.1 (s), 152.3 (s), 157.9 (s),
175.8 (s) ppm. HMRS (EI): m/z calcd for C16H19NO3:
273.1365; found: 273.1361.
(13) (a) Baures, P. W.; Egglestone, D. S.; Erhard, K. F.;
Cieslinski, L. B.; Torphy, T. J.; Christensen, S. B. J. Med.
Chem. 1993, 36, 3274. (b) Sommer, N.; Loeschmann, P. A.;
Northoff, G. H.; Weller, M.; Steinbrecher, A.; Steinbach, J.
P.; Richtenfels, R.; Meyermann, R.; Reithmueller, A.;
Fontana, A.; Dichgans, J.; Martin, R. Nat. Med. 1995, 1,
244. (c) Nibuya, M.; Nestler, E. J.; Duman, R. S. J.
Neurosci. 1996, 16, 2365. (d) Seika, M. Drugs Future 1998,
23, 108; and references therein.
(14) Schmiechen, R.; Horowski, R.; Palenschat, D.; Paschelke,
G.; Wachtel, H.; Kehr, W. US 4193926, 1976; Chem. Abstr.
1976, 84, 30878.
(15) Wachtel, H. J. Pharm. Pharmacol. 1983, 35, 440.
(16) Beavo, J. A.; Reifsnyder, D. H. Trends Pharm. Sci. 1990, 11,
150.
(17) (a) Marivet, M. C.; Bourguignon, J.-J.; Lugnier, C.; Mann,
A.; Stoclet, J.-C.; Wermuth, C.-G. J. Med. Chem. 1989, 32,
1450. (b) Doherthy, A. M. Curr. Opin. Chem. Biol. 1999, 3,
466. (c) Burnouf, C.; Pruniaux, M.-P.; Szilagyi, C. M. Annu.
Rep. Med. Chem. 1998, 33, 91.
(23) For catalytic enantioselective conjugate reductions of five-
membered lactams, see: Hughes, G.; Kimura, M.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11253.
Synlett 2007, No. 10, 1557–1560 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.