Diastereoselective Ugi reaction without chiral amines: the synthesis of chiral pyrroloketopiperazines

Article abstract of DOI:10.1016/j.tet.2007.01.056

The three-component Ugi reaction with chiral 2-(2-formyl-1H-pyrrol-1-yl)acetic acids prepared from natural l-aminoacids was investigated. The reaction opens a new route to chiral substituted pyrroloketopiperazines. One of the first examples of an asymmetric Ugi reaction without chiral amines is described. The reaction proceeds with moderate diastereoselectivity to give the target compounds in good yields. The scope and limitation of the approach are discussed.

Full text of DOI:10.1016/j.tet.2007.01.056

Tetrahedron 63 (2007) 3031–3041
Diastereoselective Ugi reaction without chiral amines: the
synthesis of chiral pyrroloketopiperazines
*
Valentine G. Nenajdenko, Alexander L. Reznichenko and Elizabeth S. Balenkova
Department of Chemistry, Moscow State University, 119899 Moscow, Russia
Received 24 October 2006; revised 16 January 2007; accepted 25 January 2007
Available online 30 January 2007
Abstract—The three-component Ugi reaction with chiral 2-(2-formyl-1H-pyrrol-1-yl)acetic acids prepared from natural L-aminoacids was
investigated. The reaction opens a new route to chiral substituted pyrroloketopiperazines. One of the first examples of an asymmetric Ugi
reaction without chiral amines is described. The reaction proceeds with moderate diastereoselectivity to give the target compounds in
good yields. The scope and limitation of the approach are discussed.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
are of interest because 1,2,3,4-tetrahydropyrrolo[1,2-a]pyr-
azines can serve as effective aldol protease inhibitors.8
The four-component Ugi reaction is of considerable interest
owing to its exceptional synthetic efficiency and is widely
used, especially in the field of modern combinatorial and
medical chemistry.1 This is most evident in the application
towards multicomponent heterocyclisations. The three-com-
ponent Ugi reaction wherein one component is a bifunctional
building blocks is an effective strategy for the one-pot syn-
thesis of various heterocyclic systems and the efficiency of
bifunctional blocks containing various combinations of the
four functional groups acting in the Ugi reaction has been
shown.2
2. Results and discussion
Chiral 2-(2-formyl-1H-pyrrol-1-yl)acetic acids were pre-
pared from natural L-aminoacids: alanine, phenylalanine,
leucine, valine and isoleucine (Scheme 1). The hydrochlo-
ride salts of a-aminoacid ethyl esters reacted with 2,5-
diMeO-THF to afford the corresponding chiral pyrroles
(1–5) in good yields. Subsequent Vilsmeier-type formyla-
tion and basic hydrolysis under mild conditions led to the de-
sired formylacids 11–15 in high yields. The optical rotatory
power of acid 13 was identical to that described in litera-
ture.9 In addition, the absence of racemisation during the
ester hydrolysis was confirmed by an alternative transforma-
tion using TMSI.10 The optical rotations for formylacids
11, 12 and 14 were identical for the two independent
methods.
It is noteworthy that there is, to date, no general solution for
the problem of the stereocontrol in the Ugi reaction. The
only way to achieve an appropriate stereoinduction for the
new stereocentre is to use a chiral amine.3 In contrast, chiral
acids, isocyanides and carbonyl compounds give poor4 in-
duction or even epimerisation5 of the starting chiral stereo-
centre. Bifunctional chiral amines have been reported as
stereoselective precursors for the Ugi synthesis of a-amino-
acids6 and substituted diketopiperazines.7 We proposed that
chiral bifunctional amine-free blocks would also be effective
in an asymmetric Ugi reaction. Reaction of chiral 2-(2-for-
myl-1H-pyrrol-1-yl)acetic acids obtained from enantiomeri-
cally pure natural aminoacids with isocyanides and amines
would provide a novel route to chiral substituted 3-oxo-
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines. Thesecompounds
Model acid 11 has been chosen to study the influence of the
isocyanide and amine component on yield and diastereo-
selectivity of the Ugi reaction (Scheme 2). Recently, it was
reported that achiral, unsubstituted 2-(2-formyl-1H-pyrrol-
1-yl)acetic acid 16 gives the corresponding substituted pyr-
roloketopiperazines in moderate to good yields when reacted
with isocyanides and primary amines.11 We found that opti-
mal conditions for the reaction of 11 with isocyanides and
primary amines require the use of MeOH as solvent at
40 ꢀC. In contrast, aprotic polar and non-polar solvents
(PhH, CH3CN, CHCl3) gave unsatisfactory, low yields of
the desired products.
* Corresponding author. Tel.: +7 495 939 2276; fax: +7 495 932 8846;
e-mail: nen@acylium.chem.msu.ru
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.056

3032
V. G. Nenajdenko et al. / Tetrahedron 63 (2007) 3031–3041
OMe
O
O
O
O
R1
O
R1
R1
O
OEt
POCl3
R1
OEt
O
OH
O
MeO
OEt
NH3Cl
SOCl2
EtOH
NaOH/MeOH
or TMSI
R1
N
N
N
OH
AcOH, AcONa
DMF
NH2
100%
58-69%
1-5
95-98%
11-15
75-82%
6-10
Scheme 1.
O
O
R2
N
O
O
R2
N
O
R2
N
H3C
R3
O
R1
R3
O
R3
O
R2NH2, R3NC
MeOH, 40 °C
OH
N
H
R2NH2, R3NC
MeOH, 40 °C
OH
N
H
N
H
+
N
N
N
R1
N
CH3
N
R1
O
O
11
Scheme 3.
Scheme 2.
The reaction is quite general and we found no other restric-
tion on the structure of the reagents participating in the pro-
cess. A number of substituted heterocycles were prepared
using benzylamine as the amine moiety; this allows the pos-
sibility of subsequent removal of the amine protecting group.
The influence of amine structure on the diastereoselectivity
is very low and the most important factor effecting the ratio
of diastereomers is the structure of starting formylacids.
We have found that the reaction is general and applicable for
various amines and isocyanides (Table 1). The only excep-
tion is the sterically hindered tert-butylamine. For the other
examples, target products were obtained in good yields;
unfortunately, low diastereoselectivity was observed in all
cases. Thus, the reaction appears almost insensitive to the
nature of amine and isocyanide components.
We proposed that the use of 2-(2-formyl-1H-pyrrol-1-yl)-
acetic acids with more sterically hindered substituents
should improve the diastereoselectivity of the reaction.
Thus, we were delighted to find that the diastereoselectivity
of the reaction is sensitive to the nature of substituent in the
molecule of the formylacid (Table 2). 2-(2-Formyl-1H-pyr-
rol-1-yl)acetic acids bearing bulky substituents such as i-Pr
or s-Bu could serve as most efficient asymmetric inductors
for this reaction. The diastereoselectivity obtained (d.r.w3:1)
represents first examples of asymmetric Ugi reaction with-
out a chiral amine. It is noteworthy that the target hetero-
cycles were separated by column chromatography and could
be isolated as single diastereomers in most cases (Scheme 3).
In spite of the high effectiveness of Ugi reaction this four-
component transformation is really a complex process. It
is known that multicomponent reactions proceed through
a number of reversible steps. In the case of the Ugi reaction
the final step, the formation of amide, is irreversible. The
general scheme of the Ugi process includes the initial forma-
tion of an iminium salt.12,13 Subsequent reaction of iminium
salt (Scheme 4) with isocyanide then gives a diastereomeric
mixture of the target pyrroloketopiperazines. We proposed
that if the reaction is a thermodynamically controlled pro-
cess the energy of final products will play critical role in
the diastereoselectivity of the process.
R2
R2
N
R1
C
R1
O
R1
O
O
O
N
N
N
N
Table 1
+
O
NH
NH
R2
N
O
Entry
R2
R3
No.
Yield, %
d.r.
H
N
1
2
3
4
5
6
7
4-MeOPh
2-Furylmethyl
i-Pr
t-Bu
Bn
t-Bu
t-Bu
t-Bu
t-Bu
Bn
17
18
19
—
20
21
22
62
58
59
0
68
70
74
1.7:1
1.9:1
1.7:1
—
1.8:1
1.7:1
1.6:1
R1=Ph, i-Pr
(1S,4S)
(1R,4S)
Scheme 4.
Bn
4-MeOPh
t-Bu
4-BrPh
This statement can be illustrated by semiempirical calcula-
tions for both diastereoisomers of compound 19. PM3 calcu-
lations showed that the major trans-isomer 19a is only
0.6 kcal/mol more stable than minor cis-isomer. Such small
differences in the stability of cis- and trans-isomer of target
products can be explained to be due to structural peculiari-
ties of substituted pyrroloketopiperazines. Due to the con-
densed nature of target heterocycle and the presence of an
amide component, the piperazine ring is almost planar. As
a result of this, low difference in energies of two diastereo-
mers leads to moderate diastereoselectivity of the reaction.
Table 2
Entry
R1
R2
R3
No.
Yield, %
d.r.
1
2
3
4
5
6
7
8
Bn
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
Bn
Bn
Bn
Bn
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Et
23
24
25
26
27
28
29
30
31
32
33
62
59
68
67
66
68
60
70
63
68
61
1.9:1
2.2:1
2.9:1
3.2:1
2.2:1
2.3:1
2.8:1
3.1:1
2.1:1
2.3:1
3.1:1
i-Bu
i-Pr
s-Bu
Bn
i-Bu
i-Pr
s-Bu
Bn
The absolute configuration of the target pyrroloketopiper-
azines was established via NOESY H NMR analysis of
1
9
10
11
2-Furylmethyl
Bn
Bn
i-Bu
s-Bu
both stereoisomers of compounds 24 and 27. Interaction be-
tween tert-butyl and CH-protons of benzyl or isobutyl group,
Et

V. G. Nenajdenko et al. / Tetrahedron 63 (2007) 3031–3041
3033
observed in minor stereoisomers (24b and 27a, respectively)
illustrates that more stable (1S,4S)-isomer is the major prod-
uct of the Ugi reaction (Scheme 4).
Chemical shifts are recorded relative to TMS as an internal
standard and are given in d values. Optical rotations were
measured with a Perkin–Elmer 341 polarimeter. Merck
60F254 plates were used for analytical TLC. Column chro-
matography was performed on a silica gel (60–230 mesh,
Merck). All starting materials are commercially available.
To confirm our proposal that structural motif of pyrroloketo-
piperazines is responsible for moderate diastereoselectivity
of Ugi reaction we decided to investigate the influence of
chiral amines as asymmetric inductors. As it was noted pre-
viously, the use of chiral amines is still the only ability to
obtain an appropriate induction (up to 90% ee) in the Ugi
reaction. Achiral 2-(2-formyl-1H-pyrrol-1-yl)acetic acid
16 (derivative of glycine) reacted with chiral (1R)-1-phenyl-
ethylamine to give the corresponding heterocycle 34 with
the lowest diastereoselectivity observed from the variety of
reactions we have investigated. In the case of reaction with
substituted formylacids 11 and 13 no significant improve-
ment in diastereoselectivity was observed. The R-enantio-
mer of phenylethylamine is more effective asymmetric
inductor than S-enantiomer (matched stereochemistry
(Table 3)). However, chiral amines do not change the dia-
stereoselectivity dramatically, as observed in the traditional
variant of the Ugi reaction. We believe that this is due to the
almost flat geometry of the target pyrroloketopiperazines
(Scheme 5).
2-(2-Formyl-1H-pyrrol-1-yl)acetic acid 16 was prepared
according to the literature procedure.14
4.1.1. Ethyl (1H-pyrrol-1-yl)acetates. To a stirred suspen-
sion of 1.0 mol a-aminoacid in 700 mL of ethanol, SOCl2
(110 mL, 1.5 mol) was added dropwise and the mixture
was stirred under reflux for 5 h. The solvent was removed
in vacuo, the residue was suspended in a solution of
NaOAc (150 g, 1.1 mol) and 2,5-dimethoxytetrahydrofuran
(140 mL, 1.0 mol) in 800 mL of AcOH added. The mixture
was stirred at 80 ꢀC for an appropriate time (0.5–1.5 h, TLC
monitoring) before the solvent was evaporated, the residue
was dissolved in water (1 L) and extracted with ether
(2ꢁ200 mL). The combined organic layers were dried
(Na2SO4), concentrated in vacuo and the residue was puri-
fied by vacuum distillation or by flash chromatography on
silica gel (CH2Cl2).
O
R2
N
O
4.1.1.1. Ethyl (2S)-2-(1H-pyrrol-1-yl)propionate (1).
Yield 57%, colourless oil. Rf 0.80 (CH2Cl2). Bp 70–74 ꢀC
(1 Torr). [a]2D0 22.4 (c 0.10, CHCl3). nmax (Nujol): 2920,
O
R2
N
t-Bu
+
O
R1
t-Bu
O
N
H
R2NH2, t-BuNC
OH
N
H
N
MeOH, 40 °C
1
1740 cmꢂ1. H NMR (CDCl3) d: 6.76–6.74 (m, 2H), 6.19–
N
R1
N
R1
O
6.17 (m, 2H), 4.74 (q, J¼7.2 Hz, 1H), 4.17 (q, J¼7.2 Hz,
2H, OCH2), 1.71 (d, J¼7.2 Hz, 3H, CH3), 1.24 (t,
J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3) d: 171.2, 119.6,
108.4, 61.5, 57.0, 18.2, 14.0. Anal. Calcd: C, 64.65; H,
7.84. Found: C, 64.85; H, 7.88%.
Scheme 5.
Table 3
Entry
R1
R2
No.
Yield, %
d.r.
1
2
3
4
5
6
7
H
(1R)-PhEt
(1R)-PhEt
(1S)-PhEt
(1R)-PhEt
(1S)-PhEt
(1R)-PhEt
(1S)-PhEt
34
35
36
37
38
39
40
67
66
64
65
63
65
62
1.3:1
1.9:1
1.8:1
2.7:1
2.4:1
4.0:1
3.6:1
4.1.1.2. Ethyl (2S)-2-(1H-pyrrol-1-yl)-3-phenylpropa-
noate (2). Yield 67%, yellow oil. Rf 0.83 (CH2Cl2). [a]D20
CH3
CH3
i-Bu
i-Bu
s-Bu
s-Bu
1
42.9 (c 0.16, CHCl3). nmax (Nujol): 2940, 1745 cmꢂ1. H
NMR (CDCl3) d: 7.27–7.21 (m, 3H), 7.06–7.04 (m, 2H),
6.76–6.74 (m, 2H), 6.16–6.14 (m, 2H), 4.75 (t, J¼7.8 Hz,
CH), 4.18–4.13 (m, 2H, CH2), 3.42 (dd, J1¼13.9 Hz,
J2¼6.8 Hz, 1H), 3.26 (dd, J1¼3.9 Hz, J2¼6.8 Hz, 1H),
1.20 (t, J¼7.1 Hz, 3H, CH3). 13C NMR (CDCl3) d: 170.0,
136.3, 128.8, 128.4, 126.9, 120.0, 108.5, 63.6, 61.5, 39.5,
13.9. Anal. Calcd: C, 69.12; H, 5.39. Found: C, 69.04; H,
5.31%.
3. Conclusion
In conclusion, we have described a novel effective approach
to chiral substituted pyrroloketopiperazines via a three-com-
ponent Ugi reaction with chiral 2-(2-formyl-1H-pyrrol-1-
yl)acetic acids. The reaction proceeds smoothly to give the
products as a mixture of diastereomers (d.r., up to 4:1), which
can be easily separated and isolated in individual form in
most cases. The low diastereoselectivity observed can be
explained by the almost planar structure of the heterocyclic
fragment in the target molecules. The use of chiral amines
does not improve the diastereoselectivity significantly due
to the structural peculiarities of pyrroloketopiperazines.
4.1.1.3. Ethyl (2S)-4-methyl-2-(1H-pyrrol-1-yl)penta-
noate (3). Yield 62%, colourless oil. Rf 0.82 (CH2Cl2). Bp
91–96 ꢀC (1 Torr). [a]D20 9.4 (c 0.10, CHCl3). nmax (Nujol):
2920, 1740 cmꢂ1. 1H NMR (CDCl3) d: 6.76–6.74 (m, 2H),
6.18–6.16 (m, 2H), 4.64 (dd, J1¼9.9 Hz, J2¼6.1 Hz, 1H),
4.17 (q, J¼7.8 Hz, 2H, OCH2), 2.02–1.86 (m, 2H, CH2),
1.45–1.38 (m, 1H, CH), 1.25 (t, J¼7.8 Hz, 3H, CH3), 0.94
(d, J¼6.8 Hz, 3H, CH3), 0.91 (d, J¼6.8 Hz, 3H, CH3). 13C
NMR (CDCl3) d: 171.1 (COO), 120.0, 108.3, 61.4, 60.2,
41.5, 24.5, 22.7, 21.6, 14.0. Anal. Calcd: C, 68.87; H,
9.15. Found: C, 68.95; H, 9.20%.
4. Experimental
4.1. General
4.1.1.4. Ethyl (2S)-3-methyl-2-(1H-pyrrol-1-yl)buta-
noate (4). Yield 68%, yellow oil. Rf 0.82 (CH2Cl2). Bp
90–94 ꢀC (1 Torr). [a]D20 8.2 (c 0.10, CHCl3). nmax (Nujol):
2920, 1740 cmꢂ1. 1H NMR (CDCl3) d: 6.79–6.77 (m, 2H),
NMR spectra were recorded on a Bruker VRX-400 at
400 MHz for 1H NMR and 100 MHz for 13C NMR.

3034
V. G. Nenajdenko et al. / Tetrahedron 63 (2007) 3031–3041
6.16–6.14 (m, 2H), 4.23–4.13 (m, 2H, CH2), 4.09 (d,
J¼10.2 Hz, 1H, CH), 2.45–2.36 (m, 1H, CH), 1.26 (t,
J¼7.1 Hz, 3H, CH3), 0.99 (d, J¼6.5 Hz, 3H, CH3), 0.74
(d, J¼6.6 Hz, 3H, CH3). 13C NMR (CDCl3) d: 170.5,
120.3, 108.2, 67.5, 61.2, 37.7, 24.6, 15.5, 15.0. Anal. Calcd:
C, 67.66; H, 8.78. Found: C, 67.93; H, 8.70%.
(t, J¼7.3 Hz, 3H, CH3), 0.90 (d, J¼6.6 Hz, 3H, CH3), 0.88
(d, J¼6.6 Hz, 3H, CH3). 13C NMR (CDCl3) d: 179.6
(CHO), 171.0 (CO2), 131.6, 129.5, 125.4, 110.3, 61.4,
57.5, 41.2, 24.6, 22.8, 21.3, 14.0. Anal. Calcd: C, 65.80;
H, 8.07. Found: C, 66.05; H, 8.15%.
4.1.2.4. Ethyl (2S)-3-methyl-2-(2-formyl-1H-pyrrol-1-
yl)butanoate (9). Yield 65%, yellow oil. Rf 0.11 (CH2Cl2).
[a]2D0 10.1 (c 0.10, CHCl3). nmax (Nujol): 2950, 1740,
1690 cmꢂ1. 1H NMR (CDCl3) d: 9.51 (s, 1H, CHO), 7.40–
7.38 (m, 1H), 6.91–6.89 (m, 1H), 6.29 (t, J¼3.1 Hz, 1H),
5.95 (d, J¼9.4 Hz, 1H, CH), 4.25–4.12 (m, 2H, OCH2),
2.42–2.35 (m, 1H, CH), 1.25 (t, J¼7.2 Hz, 3H, CH3), 0.99
(d, J¼6.7 Hz, 3H, CH3), 0.77 (d, J¼6.7 Hz, 3H, CH3).
13C NMR (CDCl3) d: 179.8 (CHO), 170.6 (CO2), 131.9,
130.0, 125.3, 110.6, 63.8, 61.3, 33.0, 19.1, 18.5, 14.0.
Anal. Calcd: C, 64.55; H, 7.67. Found: C, 64.59; H, 7.56%.
4.1.1.5. Ethyl (2S,3R)-3-methyl-2-(1H-pyrrol-1-yl)-
pentanoate (5). Yield 68%, yellow oil. Rf 0.82 (CH2Cl2).
Bp 115–118 ꢀC (1 Torr). [a]D20 9.7 (c 0.10, CHCl3). nmax
1
(Nujol): 2940, 1740 cmꢂ1. H NMR (CDCl3) d: 6.79–6.77
(m, 2H), 6.16–6.14 (m, 2H), 4.23–4.13 (m, 3H, CH2, CH),
2.25–2.15 (m, 1H, CH), 1.27 (t, J¼7.1 Hz, 3H, CH3), 1.19–
1.10 (m, 1H, CH), 0.96 (d, J¼6.8 Hz, 3H, CH3), 0.82 (t,
J¼7.1 Hz, 3H, CH3). 13C NMR (CDCl3) d: 170.5, 120.3,
108.2, 67.5, 61.2, 37.8, 24.7, 15.5, 14.0, 10.5. Anal. Calcd:
C, 68.87; H, 9.15. Found: C, 68.93; H, 9.22%.
4.1.2. Ethyl (2-formyl-1H-pyrrol-1-yl)acetates. POCl3
(50 mL, 0.55 mol) was added dropwise to a stirred DMF
(150 mL, 1.5 mol) at 0 ꢀC. The reaction mixture was then
stirred for a further 0.5 h at 0 ꢀC. A solution of 0.5 mol of
the corresponding ethyl (1H-pyrrol-1-yl)acetate in 100 mL
CH2Cl2 was added dropwise at 0 ꢀC. The mixture was stirred
4 h at rt then poured into a solution of NaOAc (270 g, 2 mol)
in water (500 mL). The mixture was stirred for 3 h, then
diluted with water (1 L) and extracted with CH2Cl2
(3ꢁ200 mL). The combined extracts were dried (Na2SO4),
the solvent was removed in vacuo and the residue was puri-
fied with flash chromatography (CH2Cl2).
4.1.2.5. Ethyl (2S,3R)-3-methyl-2-(2-formyl-1H-pyr-
rol-1-yl)pentanoate (10). Yield 68%, yellow oil. Rf 0.12
(CH2Cl2). [a]2D0 38.5 (c 0.10, CHCl3). nmax (Nujol): 2930,
1740, 1680 cmꢂ1. 1H NMR (CDCl3) d: 9.49 (s, 1H, CHO),
7.39–7.37 (m, 1H), 6.90–6.88 (m, 1H), 6.27 (t, J¼3.1 Hz,
1H), 5.99 (d, J¼9.6 Hz, 1H, CH), 4.25–4.09 (m, 2H,
OCH2), 2.18–2.11 (m, 1H, CH), 1.24 (t, J¼7.0 Hz, 3H,
CH3), 1.18–1.10 (m, 1H), 1.07–0.99 (m, 1H), 0.95 (d,
J¼6.7 Hz, 3H, CH3), 0.79 (t, J¼7.4 Hz, 3H, CH3). 13C
NMR (CDCl3) d: 179.8 (CHO), 170.8 (COO), 132.0,
130.0, 125.4, 110.6, 62.9, 61.3, 39.0, 24.9, 15.4, 14.1,
10.6. Anal. Calcd: C, 65.80; H, 8.07. Found: C, 65.93; H,
8.00%.
4.1.2.1. Ethyl (2S)-2-(2-formyl-1H-pyrrol-1-yl)propio-
nate (6). Yield 57%, colourless oil. Rf 0.11 (CH2Cl2).
[a]2D0 ꢂ74.0 (c 0.19, CHCl3). nmax (Nujol): 2920, 1740,
1680 cmꢂ1. 1H NMR (CDCl3) d: 9.49 (s, 1H, CHO), 7.17–
7.15 (m, 1H), 6.97–6.95 (m, 1H), 6.29 (t, J¼3.2 Hz, 1H),
5.85 (q, J¼7.3 Hz, 1H, CH), 4.17 (q, J¼7.1 Hz, 2H, CH2),
1.72 (d, J¼7.3 Hz, 3H, CH3), 1.23 (t, J¼7.1 Hz, 3H, CH3).
13C NMR (CDCl3) d: 179.6 (CHO), 171.1 (CO2), 131.5,
128.7, 125.4, 110.1, 61.5, 55.3, 17.7, 14.0. Anal. Calcd: C,
61.53; H, 6.71. Found: C, 61.74; H, 6.82%.
4.1.3. (2-Formyl-1H-pyrrol-1-yl)acetic acids. To a stirred
solution of corresponding ethyl (2-formyl-1H-pyrrol-1-yl)-
acetate (0.2 mol) in methanol (200 mL), a solution of NaOH
(8.8 g, 0.22 mol) in water (100 mL) was added dropwise.
The reaction mixture was stirred 4–6 h at rt (TLC monitor-
ing). The reaction mixture was then diluted with water
(200 mL), acidified with HCl (5%) to pH 3–4 and the prod-
uct was extracted with ether (2ꢁ100 mL). The combined
organic extracts were dried (Na2SO4) and the ether was
removed in vacuo to give the target acid.
4.1.2.2. Ethyl (2S)-2-(2-formyl-1H-pyrrol-1-yl)-3-phe-
nylpropionate (7). Yield 67%, yellow needle crystals. Rf
0.13 (CH2Cl2). Mp 42 ꢀC. [a]D20 0.8 (c 0.10, CHCl3). nmax
(Nujol): 2950, 1740, 1685 cmꢂ1. 1H NMR (CDCl3) d: 9.42
(s, 1H, CHO), 7.21–7.16 (m, 3H), 7.05–6.99 (m, 3H),
6.89–6.87 (m, 1H), 6.19 (t, J¼3.1 Hz, 1H), 6.10–6.03
(m, 1H, CH), 4.19 (q, J¼7.1 Hz, 2H, OCH2), 3.51 (dd,
J1¼14.2 Hz, J2¼5.7 Hz, 1H), 3.27 (dd, J1¼14.2 Hz,
J2¼9.6 Hz, 1H), 1.21 (t, J¼7.1 Hz, 3H, CH3). 13C NMR
(CDCl3) d: 179.4 (CHO), 169.8 (CO2), 136.0, 131.3,
130.5, 128.9, 128.7, 128.3, 126.8, 125.5, 110.1, 61.7
(OCH2), 39.1 (CH2), 14.00 (CH3). Anal. Calcd: C, 70.83;
H, 6.32. Found: C, 71.05; H, 6.51%.
4.1.3.1. (2S)-2-(2-Formyl-1H-pyrrol-1-yl)propionic
acid (11). Yield 97%, yellow needle crystals. Rf 0.41
(CH3OH–CH2Cl2 1:4). Mp 81–84 ꢀC. [a]D20 67.1 (c 0.10,
1
CHCl3). nmax (Nujol): 3100–3300, 1720, 1690 cmꢂ1. H
NMR (DMSO-d6) d: 12.9 (br s, 1H, COOH), 9.45 (s,
CHO), 7.44–7.42 (m, 1H), 7.07–7.05 (m, 1H), 6.26 (t,
J¼3.1 Hz, 1H), 5.61 (q, J¼7.3 Hz, 1H), 1.63 (d, J¼
7.3 Hz, 3H, CH3). 13C NMR (CDCl3) d: 180.1 (CHO),
175.9 (CO2), 131.4, 129.2, 126.1, 110.5, 55.3, 17.5. Anal.
Calcd: C, 57.48; H, 5.43. Found: C, 57.51; H, 5.39%.
4.1.3.2. (2S)-2-(2-Formyl-1H-pyrrol-1-yl)-3-phenyl-
propionic acid (12). Yield 97%, yellow needle crystals. Rf
0.45 (CH3OH–CH2Cl2 1:4). Mp 89 ꢀC. [a]D20 11.5 (c 0.10,
4.1.2.3. Ethyl (2S)-4-methyl-2-(2-formyl-1H-pyrrol-
1-yl)pentanoate (8). Yield 62%, colourless oil. Rf 0.11
(CH2Cl2). [a]2D0 12.2 (c 0.07, CHCl3). nmax (Nujol): 2930,
1750, 1690 cmꢂ1. 1H NMR (CDCl3) d: 9.49 (s, 1H, CHO),
7.19–7.17 (m, 1H), 6.93–6.91 (m, 1H), 6.29 (t, J¼3.2 Hz,
1H), 6.05 (t, J¼7.1 Hz, 1H, CH), 4.15 (q, J¼7.1 Hz, 2H,
OCH2), 1.95 (m, 2H, CH2), 1.43–1.33 (m, 1H, CH), 1.22
1
CHCl3). nmax (Nujol): 3100–3300, 1720, 1680 cmꢂ1. H
NMR (CDCl3) d: 10.7 (br s, 1H, COOH), 9.40 (s, 1H,
CHO), 7.21–7.16 (m, 3H), 7.00–6.92 (m, 4H), 6.19 (t,
J¼3.1 Hz, 1H), 6.07–5.97 (m, 1H, CH), 3.59 (dd, J1¼
14.4 Hz, J2¼4.8 Hz, 1H), 3.31 (dd, J1¼14.4 Hz, J2¼
10.4 Hz, 1H). 13C NMR (CDCl3) d: 179.9 (CHO), 174.3

V. G. Nenajdenko et al. / Tetrahedron 63 (2007) 3031–3041
3035
(CO2), 135.8, 131.6, 131.0, 128.8, 128.4, 126.9, 126.5, 110.4,
38.3 (CH2). Anal. Calcd: C, 69.12; H, 5.39. Found: C, 69.51;
H, 5.56%.
134.4, 134.0, 128.6, 128.2, 123.3, 121.6, 118.6, 117.7,
109.8, 109.0, 104.2, 103.7, 64.0, 63.7, 55.7, 55.4, 54.5,
51.9, 28.4, 22.3, 15.79. Anal. Calcd: C, 67.58; H, 7.09.
Found: C, 67.74; H, 7.22%.
4.1.3.3. (2S)-4-Methyl-2-(2-formyl-1H-pyrrol-1-yl)-
pentanoic acid (13). Yield 98%, yellow needle crystals. Rf
0.43 (CH3OH–CH2Cl2 1:4). Mp 76–78 ꢀC. [a]D20 12.2 (c
4.1.4.2. (4S)-2-(2-Furylmethyl)-N-(tert-butyl)-4-methyl-
3-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-1-carbox-
amide (18). Mixture of (1R)/(1S) isomers 1.6:1. Yield 58%,
yellow oil. Rf 0.16 (CH3CN–CH2Cl2 1:20). nmax (Nujol):
3100–3200, 1705 cmꢂ1. 1H NMR (CDCl3) signals of major
isomer d: 7.31–7.29 (m, 1H), 6.70–6.68 (m, 1H), 6.29–6.26
(m, 2H), 6.16 (t, J¼3.0 Hz, 1H), 6.06–6.04 (m, 1H), 5.69
(br s, 1H, NH), 5.16 (d, J¼15.7 Hz, 1H), 4.93 (s, 1H), 4.74
(q, J¼6.8 Hz, 1H), 4.30 (d, J¼15.7 Hz, 1H), 1.79 (d,
J¼6.7 Hz, 3H), 1.25 (s, 9H, t-Bu), signals of minor isomer
d: 6.61–6.59 (m, 1H), 6.70–6.68 (m, 1H), 6.29–6.26 (m,
2H), 6.19 (t, J¼3.0 Hz, 1H), 6.02–6.00 (m, 1H), 5.78 (br s,
1H, NH), 5.39 (d, J¼15.7 Hz, 1H), 4.97 (s, 1H), 4.21 (d, J¼
15.7 Hz, 1H), 1.69 (d, J¼6.7 Hz, 3H), 1.27 (s, 9H, t-Bu),
other signals are overlapped by signals of major isomer.
13C NMR (CDCl3) d: 168.6, 168.4, 167.3, 149.5, 149.4,
142.7, 142.6, 110.5, 110.4, 109.8, 109.7, 109.6, 109.1,
104.5, 104.3, 58.8, 58.2, 55.3, 53.8, 51.8, 51.7, 42.6, 42.3,
28.5, 28.4, 21.8, 21.83, 16.1. Anal. Calcd: C, 65.63; H,
7.04. Found: C, 67.74; H, 7.22%.
0.10, CHCl3). nmax (Nujol): 3100–3300, 1710, 1690 cmꢂ1
.
1H NMR (CDCl3) d: 10.7 (br s, 1H, COOH), 9.48 (s, 1H,
CHO), 7.17–7.15 (m, 1H), 6.98–6.96 (m, 1H), 6.31 (t,
J¼3.1 Hz, 1H), 6.08–6.02 (m, 1H, CH), 2.01 (t, J¼7.4 Hz,
2H, CH2), 1.45–1.38 (m, 1H, CH), 0.92–0.88 (m, 6H,
1
2CH3). Optical rotatory power and H NMR are similar to
that described in literature.9
4.1.3.4. (2S)-3-Methyl-2-(2-formyl-1H-pyrrol-1-yl)-
butanoic acid (14). Yield 98%, yellow needle crystals. Rf
0.43 (CH3OH–CH2Cl2 1:4). Mp 90 ꢀC. [a]D20 8.2 (c 0.10,
CHCl3). nmax (Nujol): 3100–3300, 1720, 1680 cmꢂ1. 1H NMR
(CDCl3) d: 9.6 (br s, 1H, COOH), 9.49 (s, 1H, CHO),
7.34–7.32 (m, 2H), 6.97–6.95 (m, 1H), 6.31 (t, J¼3.1 Hz,
1H), 5.91 (d, J¼9.1 Hz, 1H), 2.48–2.39 (m, 1H), 1.04 (d,
J¼6.7 Hz, 3H, CH3), 0.81 (d, J¼6.8 Hz, 3H, CH3). 13C
NMR (CDCl3) d: 180.2 (CHO), 174.7 (CO2), 131.9, 130.8,
126.1, 110.9, 64.2, 32.3, 19.2 (CH3), 18.6 (CH3). Anal.
Calcd: C, 76.55; H, 8.57. Found: C, 76.21; H, 8.39%.
4.1.4.3. (1S,4S)-N-(tert-Butyl)-2-isopropyl-4-methyl-3-
oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-1-carbox-
amide (19a). Yield 37%, yellow oil. Rf 0.20 (CH3CN–
CH2Cl2 1:20). [a]D20 56.47 (c 0.05, CHCl3). nmax (Nujol):
4.1.3.5. (2S,3R)-3-Methyl-2-(2-formyl-1H-pyrrol-1-yl)-
pentanoic acid (15). Yield 96%, white needle crystals. Rf
0.42 (CH3OH–CH2Cl2 1:4). Mp 67–68 ꢀC. [a]D20 4.0 (c
0.10, CHCl3). nmax (Nujol): 3100–3300, 1720, 1680 cmꢂ1
.
3100–3200, 1700 cmꢂ1 1H NMR (CDCl3) d: 6.71–6.69
.
1H NMR (CDCl3) d: 10.8 (br s, 1H, COOH), 9.48 (s, 1H,
CHO), 7.34–7.32 (m, 2H), 6.97–6.95 (m, 1H), 6.31 (t,
J¼3.1 Hz, 1H), 6.01 (d, J¼9.1 Hz, 1H), 2.26–2.15 (m,
1H), 1.27–1.18 (m, 1H), 1.12–1.01 (m, 4H), 0.83 (t,
J¼7.3 Hz, 3H, CH3). 13C NMR (CDCl3) d: 180.2 (CHO),
175.0 (CO2), 131.8, 130.8, 126.3, 110.9, 63.2, 38.3, 25.0,
15.5 (CH3), 10.8 (CH3). Anal. Calcd: C, 63.14; H, 7.23.
Found: C, 62.91; H, 7.39%.
(m, 1H), 6.15 (t, J¼3.0 Hz, 1H), 6.08–6.06 (m, 1H), 5.75
(br s, 1H, NH), 4.91 (s, 1H), 4.84–4.78 (m, 2H), 1.77 (d,
J¼7.1 Hz, 3H), 1.26 (s, 9H, t-Bu), 1.18 (d, J¼6.8 Hz, 3H),
1.15 (d, J¼6.8 Hz, 3H). 13C NMR (CDCl3) d: 168.7,
168.5, 123.9, 117.3, 108.8, 103.8, 54.9, 54.2, 51.7, 46.3,
28.5, 19.9, 19.5, 15.3. Anal. Calcd: C, 65.95; H, 8.65. Found:
C, 70.90; H, 7.62%.
4.1.4.4. (1R,4S)-N-(tert-Butyl)-2-isopropyl-4-methyl-
3-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-1-carbox-
amide (19b). Yield 22%, yellow oil. Rf 0.13 (CH3CN–
CH2Cl2 1:20). [a]D20 38.2 (c 0.05, CHCl3). nmax (Nujol):
4.1.4. 3-Oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-1-
carboxamides. A solution of (2-formyl-1H-pyrrol-1-yl)ace-
tic acid (1 mmol), amine (1 mmol) and isocyanide (1 mmol)
in methanol (2 mL) was stirred at 40 ꢀC for an appropriate
time (12–20 h, TLC monitoring). The solvent was then evap-
orated in vacuo and the residue was purified by column chro-
matography (CH2Cl2–CH3CN).
3100–3200, 1695 cmꢂ1 1H NMR (CDCl3) d: 6.58–6.56
.
(m, 1H), 6.17 (t, J¼3.0 Hz, 1H), 6.11 (br s, 1H, NH),
6.05–6.03 (m, 1H), 5.02 (s, 1H), 4.78–4.66 (m, 2H), 1.77
(d, J¼7.1 Hz, 3H), 1.27 (s, 9H, t-Bu), 1.18 (d, J¼6.8 Hz,
3H), 1.17 (d, J¼6.8 Hz, 3H). 13C NMR (CDCl3) d: 168.7,
168.6, 122.2, 118.1, 109.5, 103.4, 55.6, 55.4, 51.5, 46.7,
28.3, 22.0, 19.8, 19.4. Anal. Calcd: C, 65.95; H, 8.65. Found:
C, 70.90; H, 7.62%.
4.1.4.1.
(4S)-2-(4-Methoxyphenyl)-N-(tert-butyl)-4-
methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-
1-carboxamide (17). Mixture of (1R)/(1S) isomers 1.9:1.
Yield 62%, yellow oil. Rf 0.16 (CH3CN–CH2Cl2 1:20).
1
nmax (Nujol): 3100–3200, 1700 cmꢂ1. H NMR (CDCl3)
4.1.4.5.
(4S)-N,2-Dibenzyl-4-methyl-3-oxo-1,2,3,4-
signals of major isomer d: 7.20 (d, J¼9.0 Hz, 2H), 6.89 (d,
J¼9.0 Hz, 2H), 6.79–6.77 (m, 1H), 6.22 (t, J¼3.0 Hz,
1H), 6.08–6.06 (m, 1H), 5.46 (br s, 1H, NH), 5.06 (s, 1H),
4.98 (q, J¼6.7 Hz, 1H), 3.79 (s, 3H, OCH3), 1.81 (d,
J¼6.7 Hz, 3H), 1.23 (s, 9H, t-Bu), signals of minor isomer
d: 6.68–6.66 (m, 1H), 6.25 (t, J¼3.0 Hz, 1H), 6.03–6.01
(m, 1H), 5.52 (br s, 1H, NH), 5.10 (s, 1H), 4.84 (q,
J¼6.7 Hz, 1H), 1.85 (d, J¼6.7 Hz, 3H), other signals are
observed by the signals of the major isomer. 13C NMR
(CDCl3) d: 169.1, 169.0, 167.7, 167.5, 158.9, 158.8, 158.8,
tetrahydropyrrolo[1,2-a]pyrazine-1-carboxamide (20).
Mixture of (1R)/(1S) isomers 1.8:1. Yield 68%, white amor-
phous solid. Rf 0.18 (CH3CN–CH2Cl2 1:20). nmax (Nujol):
3100–3200, 1700 cmꢂ1. 1H NMR (CDCl3) signals of major
isomer d: 7.29–7.11 (m, 10H), 6.78–6.72 (m, 2H), 6.23 (t,
J¼3.0 Hz, 1H), 6.04–6.02 (m, 1H), 5.32 (d, J¼15.1 Hz,
1H), 5.03 (s, 1H), 4.82 (q, J¼6.8 Hz, 1H), 4.39–4.28 (m,
2H), 4.08 (d, J¼15.1 Hz, 1H), 1.77 (d, J¼6.8 Hz, 3H),
signals of minor isomer d: 6.64–6.62 (m, 1H), 6.02–6.00
(m, 1H), 5.48 (d, J¼15.1 Hz, 1H), 5.04 (s, 1H), 4.67 (q,

3036
V. G. Nenajdenko et al. / Tetrahedron 63 (2007) 3031–3041
J¼6.8 Hz, 1H), 3.97 (d, J¼15.1 Hz, 1H), 1.72 (d, J¼6.8 Hz,
3H), other signals are observed by the signals of the major
isomer. 13C NMR (CDCl3) d: 169.3, 169.1, 168.4, 168.2,
137.51, 137.47, 135.5, 135.4, 128.61, 128.57, 128.3,
128.2, 127.74, 127.70, 127.50, 127.46, 127.41, 127.37,
122.2, 120.6, 118.5, 117.6, 109.8, 109.2, 104.7, 104.4,
57.9, 57.6, 55.1, 53.9, 53.9, 49.7, 49.3, 43.7, 43.6, 22.0,
16.3. Anal. Calcd: C, 73.97; H, 6.21. Found: C, 73.90; H,
6.32%.
7.29–7.25 (m, 5H), 7.09–7.06 (m, 2H), 6.92 (d, J¼9.1 Hz,
2H), 6.08–6.06 (m, 1H), 5.99 (t, J¼3.0 Hz, 1H), 5.78–5.76
(m, 1H), 5.55 (br s, 1H, NH), 4.18 (s, 1H), 4.8, 7 (dd,
J1¼10.8 Hz, J2¼3.7 Hz, 1H), 3.80 (s, 3H, OCH3), 3.59
(dd, J1¼13.7 Hz, J2¼3.7 Hz, 1H), 3.39 (dd, J1¼13.7 Hz,
J2¼10.8 Hz, 1H), 1.29 (s, 9H, t-Bu). 13C NMR (CDCl3) d:
168.1, 158.8, 137.4, 134.1, 129.8, 128.4, 126.8, 121.6,
120.4, 114.5, 108.4, 63.5, 62.5, 55.3, 51.7, 42.0, 28.3.
Anal. Calcd: C, 72.37; H, 6.77. Found: C, 72.09; H, 6.47%.
4.1.4.6. (4S)-2-Benzyl-N-(tert-butyl)-4-methyl-3-oxo-
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-1-carboxamide
(21). Mixture of (1R)/(1S) isomers 1.7:1. Yield 70%, yellow
oil. Rf 0.18 (CH3CN–CH2Cl2 1:20). nmax (Nujol): 3100–
3200, 1710 cmꢂ1. 1H NMR (CDCl3) signals of major isomer
d: 7.32–7.21 (m, 5H), 6.75–6.73 (m, 1H), 6.17 (t, J¼3.0 Hz,
1H), 5.96–5.94 (m, 1H), 5.31 (d, J¼15.2 Hz, 1H), 5.82 (br s,
1H, NH), 4.77 (q, J¼6.7 Hz, 1H), 4.71 (s, 1H), 4.17 (d,
J¼15.2 Hz, 1H), 1.72 (d, J¼6.7 Hz, 3H), 1.23 (s, 9H,
t-Bu), signals of minor isomer d: 6.66–6.64 (m, 1H), 6.20
(t, J¼3.0 Hz, 1H), 5.94–5.92 (m, 1H), 5.62 (d, J¼15.7 Hz,
1H), 5.49 (br s, 1H, NH), 4.82 (q, J¼6.7 Hz, 1H), 4.76 (s,
1H), 4.10 (d, J¼15.7 Hz, 1H), 1.84 (d, J¼6.7 Hz, 3H,
CH3), 1.26 (s, 9H, t-Bu), other signals are observed by the
signals of the major isomer. 13C NMR (CDCl3) d: 169.0,
168.9, 167.4, 167.3, 135.8, 135.6, 128.7, 128.3, 127.7,
122.6, 121.2, 118.5, 117.5, 109.8, 109.1, 104.4, 104.2,
58.6, 58.0, 55.3, 53.9, 49.7, 49.4, 28.44, 21.92, 16.4. Anal.
Calcd: C, 70.77; H, 7.42. Found: C, 70.90; H, 7.62%.
4.1.4.10. (1S,4S)-4-Benzyl-N-(tert-butyl)-2-(4-methoxy-
phenyl)-3-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-
1-carboxamide (23b). Yield 41%, yellow oil. Rf 0.11
(CH3CN–CH2Cl2 1:20). [a]2D0 22.4 (c 0.05, CHCl3). nmax
(Nujol): 3100–3200, 1700 cmꢂ1 1H NMR (CDCl3) d:
.
7.28–7.25 (m, 1H), 7.21–7.17 (m, 2H), 6.84–6.80 (m, 5H),
6.76–6.72 (m, 2H), 6.29 (t, J¼3.0 Hz, 1H), 5.91–5.89 (m,
1H), 5.34 (br s, 1H, NH), 5.23–5.21 (m, 1H), 4.27 (s, 1H),
3.76 (s, 3H, OCH3), 3.47 (dd, J1¼13.9 Hz, J2¼3.9 Hz,
1H), 3.37 (dd, J1¼13.9 Hz, J2¼11.1 Hz, 1H), 1.04 (s, 9H,
t-Bu). 13C NMR (CDCl3) d: 167.2, 166.7, 158.6, 135.0,
132.3, 129.5, 128.2, 128.0, 127.3, 122.7, 117.7, 114.1,
110.2, 103.7, 63.2, 55.3, 51.3, 41.0, 28.0. Anal. Calcd: C,
72.37; H, 6.77. Found: C, 72.29; H, 6.54%.
4.1.4.11. (1S,4S)-N-(tert-Butyl)-4-isobutyl-2-(4-meth-
oxyphenyl)-3-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyr-
azine-1-carboxamide (24a). Yield 40%, yellow oil. Rf 0.35
(CH3CN–CH2Cl2 1:20). [a]2D0 12.6 (c 0.05, CHCl3). nmax
(Nujol): 3100–3200, 1705 cmꢂ1. 1H NMR (CDCl3) d: 7.27
(d, J¼8.9 Hz, 2H), 7.89 (d, J¼8.9 Hz, 2H), 6.68–6.66 (m,
1H), 6.23 (t, J¼3.0 Hz, 1H), 6.12–6.10 (m, 1H), 5.65 (br s,
1H, NH), 5.17 (s, 1H), 4.75 (dd, J1¼8.4 Hz, J2¼6.3 Hz,
1H), 3.79 (s, 1H, OCH3), 1.98–1.92 (m, 2H, CH2), 1.90–
1.82 (m, 1H), 1.24 (s, 9H, t-Bu), 1.02 (d, J¼6.5 Hz, 3H,
CH3), 0.96 (d, J¼6.5 Hz, 3H, CH3). 13C NMR (CDCl3) d:
168.7, 167.3, 158.7, 134.5, 128.6, 122.4, 119.6, 114.4,
109.4, 104.5, 63.2, 59.1, 55.4, 51.7, 44.4, 28.4, 24.8, 23.0,
21.6. Anal. Calcd: C, 69.49; H, 7.86. Found: C, 69.90; H,
7.98%.
4.1.4.7.
(1S,4S)-N-(4-Bromophenyl)-2-(4-methoxy-
phenyl)-4-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]-
pyrazine-1-carboxamide (22a). Yield 46%, yellow oil. Rf
0.20 (CH3CN–CH2Cl2 1:20). [a]2D0 24.6 (c 0.05, CHCl3).
nmax (Nujol): 3100–3200, 1690 cmꢂ1. 1H NMR (CDCl3) d:
7.30 (d, 2H, J¼8.6 Hz), 7.18 (d, 2H, J¼8.6 Hz), 7.10 (d,
2H, J¼9.2 Hz), 6.79 (t, J¼3.0 Hz, 1H), 6.74 (d, 2H,
J¼9.2 Hz), 6.25–6.23 (m, 2H), 5.37 (s, 1H), 5.01 (q, 1H,
J¼6.9 Hz), 3.69 (s, 3H, OCH3), 1.79 (d, J¼6.9 Hz, 3H,
CH3). 13C NMR (CDCl3) d: 170.0, 166.7, 159.0, 136.4,
134.1, 131.8, 128.1, 122.5, 121.4, 118.1, 117.3, 114.7,
109.4, 105.1, 63.5, 55.4, 54.6, 15.5. Anal. Calcd: C, 58.16;
H, 4.44. Found: C, 57.90; H, 4.47%.
4.1.4.12. (1R,4S)-N-(tert-Butyl)-4-isobutyl-2-(4-meth-
oxyphenyl)-3-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyr-
azine-1-carboxamide (24b). Yield 18%, yellow oil. Rf 0.11
(CH3CN–CH2Cl2 1:20). [a]2D0 21.3 (c 0.05, CHCl3). nmax
(Nujol): 3100–3200, 1700 cmꢂ1. 1H NMR (CDCl3) d: 7.19
(d, J¼8.9 Hz, 2H), 6.90 (d, J¼8.9 Hz, 2H), 6.75–6.73
(m, 1H), 6.22 (t, J¼3.1 Hz, 1H), 6.06–6.04 (m, 1H), 5.37
(br s, 1H, NH), 5.21 (s, 1H), 4.80 (t, J¼5.5 Hz, 1H), 3.79
(s, 1H, OCH3), 2.16–2.01 (m, 2H, CH2), 1.86–1.76 (m,
1H), 1.17 (s, 9H, t-Bu), 0.93 (d, J¼6.7 Hz, 3H, CH3), 0.90
(d, J¼6.7 Hz, 3H, CH3). 13C NMR (CDCl3) d: 168.9,
167.3, 158.7, 133.5, 128.1, 122.6, 118.4, 114.4, 109.2,
104.4, 63.7, 57.7, 55.4, 51.7, 40.9, 28.3, 28.4, 24.9, 22.8,
22.5. Anal. Calcd: C, 69.49; H, 7.86. Found: C, 64.86; H,
7.95%.
4.1.4.8.
(1R,4S)-N-(4-Bromophenyl)-2-(4-methoxy-
phenyl)-4-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]-
pyrazine-1-carboxamide (22b). Yield 28%, yellow oil. Rf
0.13 (CH3CN–CH2Cl2 1:20). [a]2D0 ꢂ12.0 (c 0.04, CHCl3).
1
nmax (Nujol): 3100–3200, 1700 cmꢂ1. H NMR (CDCl3)
d: 6.58–6.56 (m, 1H), 6.17 (t, J¼3.0 Hz, 1H), 6.11 (br s,
1H, NH), 6.05–6.03 (m, 1H), 5.02 (s, 1H), 4.78–4.66 (m,
2H), 1.77 (d, J¼7.1 Hz, 3H), 1.27 (s, 9H, t-Bu), 1.18
(d, J¼6.8 Hz, 3H), 1.17 (d, J¼6.8 Hz, 3H). 13C NMR
(CDCl3) d: 169.9, 166.6, 159.1, 136.5, 133.7, 131.7, 128.4,
121.4, 120.7, 119.0, 114.7, 110.2, 104.5, 63.8, 55.9, 55.4,
22.3. Anal. Calcd: C, 58.16; H, 4.44. Found: C, 58.03; H,
4.30%.
4.1.4.13. (1R,4S)-2-(4-Methoxyphenyl)-N-(tert-butyl)-
4-isopropyl-3-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyr-
azine-1-carboxamide (25a). Yield 60%, yellow amorphous
solid. Mp 68–70 ꢀC. Rf 0.28 (CH3CN–CH2Cl2 1:20). [a]2D0
4.1.4.9. (1R,4S)-4-Benzyl-N-(tert-butyl)-2-(4-methoxy-
phenyl)-3-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-
1-carboxamide (23a). Yield 21%, yellow oil. Rf 0.31
(CH3CN–CH2Cl2 1:20). [a]2D0 18.27 (c 0.05, CHCl3). nmax
5.3 (c 0.05, CHCl3). nmax (Nujol): 3100–3200, 1710 cmꢂ1
.
(Nujol): 3100–3200, 1700 cmꢂ1
.
1H NMR (CDCl3) d:
1H NMR (CDCl3) d: 7.34 (d, J¼8.8 Hz, 2H), 6.93 (d,

V. G. Nenajdenko et al. / Tetrahedron 63 (2007) 3031–3041
3037
J¼8.8 Hz, 2H), 6.71–6.69 (m, 1H), 6.24 (t, J¼3.0 Hz, 1H),
6.19–6.17 (m, 1H), 5.80 (br s, 1H, NH), 5.26 (s, 1H), 4.29
(d, J¼9.2 Hz, 1H), 3.81 (s, 3H, CH3), 2.28–2.19 (m, 1H),
1.25 (s, 9H, t-Bu), 1.21 (d, J¼6.7 Hz, 3H, CH3), 0.98 (d,
J¼6.9 Hz, 3H, CH3). 13C NMR (CDCl3) d: 167.6, 167.3,
134.9, 128.7, 122.9, 121.1, 114.4, 109.0, 105.0, 67.5, 62.8,
55.4, 51.6, 32.9, 28.9 (t-Bu), 20.1, 19.9. Anal. Calcd: C,
68.90; H, 7.62. Found: C, 68.96; H, 7.74%.
5.75–5.73 (m, 1H), 5.71 (br s, 1H, NH), 5.64 (d,
J¼15.2 Hz, 1H), 4.85 (s, 1H), 4.81 (dd, 1H, J1¼11.1 Hz,
J2¼3.5 Hz), 4.24 (d, 1H, J¼15.2 Hz), 3.50 (dd, 1H,
J1¼13.6 Hz, J2¼11.1 Hz), 1.32 (s, 9H, t-Bu). 13C NMR
(CDCl3) d: 167.8, 167.5, 137.0, 135.7, 129.7, 128.8, 128.5,
128.3, 127.7, 127.0, 121.2, 120.6, 108.5, 104.7, 62.3, 57.6,
51.8, 49.9, 42.5, 28.5. Anal. Calcd: C, 75.15; H, 7.03. Found:
C, 75.32; H, 7.14%.
4.1.4.14. (1S,4S)-2-(4-Methoxyphenyl)-N-(tert-butyl)-
4-isopropyl-3-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyr-
azine-1-carboxamide (25b). Yield 18%, yellow amor-
phous solid. Mp 78–79 ꢀC. Rf 0.19 (CH3CN–CH2Cl2
1:20). [a]2D0 29.14 (c 0.05, CHCl3). nmax (Nujol): 3100–
4.1.4.18.
(1S,4S)-2,4-Dibenzyl-N-(tert-butyl)-3-oxo-
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-1-carboxamide
(27b). Yield 45%, yellow oil. Rf 0.15 (CH3CN–CH2Cl2
1:20). [a]2D0 33.14 (c 0.05, CHCl3). nmax (Nujol): 3100–
3200, 1690 cmꢂ1. 1H NMR (CDCl3) d: 7.26–7.15 (m, 4H),
7.08–7.04 (m, 2H), 6.83–6.78 (m, 3H), 6.70–6.67 (m, 2H),
6.24 (t, J¼3.0 Hz, 1H), 5.87–5.85 (m, 1H), 5.36 (d,
J¼15.2 Hz, 1H), 5.26 (br s, 1H, NH), 5.17–5.14 (m, 1H),
3.71 (d, J¼15.2 Hz, 1H), 3.55–3.43 (m, 2H), 1.23 (s, 9H,
t-Bu). 13C NMR (CDCl3) d: 167.2, 167.9, 135.4, 135.1,
129.4, 128.5, 128.3, 128.2, 127.5, 126.9, 121.9, 117.8,
110.1, 103.9, 59.5, 58.7, 51.8, 48.3, 40.1, 28.3. Anal. Calcd:
C, 75.15; H, 7.03. Found: C, 75.41; H, 7.10%.
1
3200, 1695 cmꢂ1. H NMR (CDCl3) d: 7.19 (d, J¼8.8 Hz,
2H), 6.92 (d, J¼8.8 Hz, 2H), 6.70–6.68 (m, 1H), 6.24 (t,
J¼3.0 Hz, 1H), 6.07–6.05 (m, 1H), 5.43 (s, 1H), 5.80
(br s, 1H, NH), 5.26 (d, J¼9.2 Hz, 1H), 4.74 (s, 1H), 3.79
(s, 3H, CH3), 2.55–2.44 (m, 1H), 1.09 (s, 9H, t-Bu), 1.05
(d, J¼6.7 Hz, 3H, CH3), 0.98 (d, J¼6.9 Hz, 3H, CH3). 13C
NMR (CDCl3) d: 168.1, 167.6, 158.6, 132.3, 128.7, 122.5,
120.4, 113.5, 108.6, 104.7, 67.0, 64.3, 54.8, 51.5, 34.6,
28.7 (t-Bu), 18.5, 17.3. Anal. Calcd: C, 68.90; H, 7.62.
Found: C, 68.99; H, 7.56%.
4.1.4.19. (1S,4S)-2-Benzyl-N-(tert-butyl)-4-isobutyl-3-
oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-1-carbox-
amide (28a). Yield 52%, yellow oil. Rf 0.32 (CH3CN–
CH2Cl2 1:20). [a]D20 40.74 (c 0.05, CHCl3). nmax (Nujol):
4.1.4.15. (1S,4S)-N-(tert-Butyl)-2-(4-methoxyphenyl)-
4-[(1R)-1-methylpropyl]-3-oxo-1,2,3,4-tetrahydropyrrolo-
[1,2-a]pyrazine-1-carboxamide (26a). Yield 51%, yellow
oil. Rf 0.31 (CH3CN–CH2Cl2 1:20). [a]2D0 10.25 (c 0.05,
3100–3200, 1700 cmꢂ1 1H NMR (CDCl3) d: 7.30–7.25
.
(m, 3H), 7.21–7.19 (m, 2H), 6.64–6.62 (m, 1H), 6.17
(t, J¼3.0 Hz, 1H), 6.00–5.98 (m, 1H), 5.65 (br s, 1H, NH),
5.63 (d, J¼15.3 Hz, 1H), 4.81 (s, 1H), 4.73 (dd, J1¼
9.1 Hz, J2¼4.9 Hz, 1H), 4.29 (d, J¼15.3 Hz, 1H), 1.86–
1.75 (m, 2H, CH2), 1.73–1.68 (m, 1H), 1.25 (s, 9H, t-Bu),
1.02 (d, J¼5.8 Hz, 3H, CH3), 0.94 (d, J¼6.1 Hz, 3H,
CH3). 13C NMR (CDCl3) d: 168.5, 167.4, 135.9, 128.7,
128.2, 127.6, 119.6, 109.4, 104.9, 58.6, 57.2, 51.6, 49.9,
44.2, 28.4, 24.6, 22.9, 21.5. Anal. Calcd: C, 72.41; H,
8.19. Found: C, 72.40; H, 8.28%.
1
CHCl3). nmax (Nujol): 3100–3200, 1700 cmꢂ1. H NMR
(CDCl3) d: 7.31 (d, J¼8.8 Hz, 2H), 6.91 (d, J¼8.9 Hz,
2H), 6.69–6.67 (m, 1H), 6.22 (t, J¼3.0 Hz, 1H), 6.17–6.15
(m, 1H), 5.79 (br s, 1H, NH), 5.25 (s, 1H), 4.34 (d,
J¼9.0 Hz, 1H), 3.79 (s, 3H, OCH3), 2.04–1.95 (m, 1H),
1.59–1.52 (m, 1H), 1.23 (s, 9H, t-Bu), 1.14 (d, J¼6.7 Hz,
3H), 0.88 (t, J¼7.0 Hz, 3H, CH3). 13C NMR (CDCl3) d:
167.6, 167.0, 158.5, 134.7, 128.6, 122.8, 120.6, 114.2,
109.0, 104.9, 65.7, 62.7, 55.3, 51.4, 39.0, 28.2, 25.8, 15.6,
10.5. Anal. Calcd: C, 69.49; H, 7.86. Found: C, 69.48; H,
8.07%.
4.1.4.20. (1R,4S)-2-Benzyl-N-(tert-butyl)-4-isobutyl-3-
oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-1-carbox-
amide (28b). Yield 23%, yellow oil. Rf 0.13 (CH3CN–
CH2Cl2 1:20). [a]D20 31.2 (c 0.05, CHCl3). nmax (Nujol):
4.1.4.16. (1R,4S)-N-(tert-Butyl)-2-(4-methoxyphenyl)-
4-[(1R)-1-methylpropyl]-3-oxo-1,2,3,4-tetrahydropyrrolo-
[1,2-a]pyrazine-1-carboxamide (26b). Yield 16%, yellow
oil. Rf 0.11 (CH3CN–CH2Cl2 1:20). [a]2D0 37.03 (c 0.05,
3100–3200, 1710 cmꢂ1 1H NMR (CDCl3) d: 7.33–7.23
.
(m, 5H), 6.69–6.67 (m, 1H), 6.16 (t, J¼3.1 Hz, 1H), 5.96–
5.94 (m, 1H), 5.50 (d, J¼15.1 Hz, 1H), 5.37 (br s, 1H,
NH), 4.78–4.73 (m, 2H), 4.00 (d, J¼15.1 Hz, 1H), 2.12–
2.02 (m, 2H, CH2), 1.81–1.70 (m, 1H), 1.27 (s, 9H, t-Bu),
0.90 (d, J¼6.7 Hz, 3H, CH3), 0.83 (d, J¼6.7 Hz, 3H,
CH3). 13C NMR (CDCl3) d: 168.7, 167.3, 135.9, 128.7,
128.5, 127.8, 121.8, 118.1, 109.2, 104.3, 59.2, 57.0, 51.8,
48.9, 41.1, 28.4, 24.8, 22.9, 22.3. Anal. Calcd: C, 72.41;
H, 8.19. Found: C, 72.45; H, 8.30%.
1
CHCl3). nmax (Nujol): 3100–3200, 1710 cmꢂ1. H NMR
(CDCl3) d: 7.18 (d, J¼8.8 Hz, 2H), 6.91 (d, J¼8.9 Hz,
2H), 6.71–6.69 (m, 1H), 6.24 (t, J¼3.0 Hz, 1H), 6.06–6.05
(m, 1H), 5.40 (s, 1H), 5.32 (br s, 1H, NH), 4.81 (d,
J¼3.0 Hz, 1H), 3.79 (s, 3H, OCH3), 2.25–2.17 (m, 1H),
1.67–1.61 (m, 1H), 1.31–1.25 (m, 1H), 1.10 (s, 9H, t-Bu),
0.99 (d, J¼6.7 Hz, 3H), 0.93 (t, J¼7.0 Hz, 3H, CH3). 13C
NMR (CDCl3) d: 167.8, 166.8, 158.7, 132.5, 128.1, 122.5,
119.0, 114.3, 109.5, 104.4, 63.8, 63.4, 55.5, 51.6, 42.3,
28.2, 25.3, 15.4, 11.9. Anal. Calcd: C, 69.49; H, 7.86. Found:
C, 69.34; H, 8.17%.
4.1.4.21. (4S)-2-Benzyl-N-(tert-butyl)-4-isopropyl-3-
oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-1-carbox-
amide (29). Mixture of (1R)/(1S) isomers 2.8:1. Yield 60%,
yellow oil. Rf 0.18 (CH3CN–CH2Cl2 1:20). nmax (Nujol):
3100–3200, 1700 cmꢂ1. 1H NMR (CDCl3) signals of major
isomer d: 7.35–7.24 (m, 5H), 6.65–6.63 (m, 1H), 6.19 (t,
J¼3.0 Hz, 1H), 6.01–5.99 (m, 1H), 5.57 (d, J¼14.7 Hz,
1H), 5.34 (br s, 1H, NH), 4.83 (s, 1H), 4.53 (d, J¼2.7 Hz,
1H), 3.98 (d, J¼14.7 Hz, 1H), 2.54–2.45 (m, 1H), 1.32 (s,
4.1.4.17. (1R,4S)-2,4-Dibenzyl-N-(tert-butyl)-3-oxo-
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-1-carboxamide
(27a). Yield 21%, yellow oil. Rf 0.35 (CH3CN–CH2Cl2
1:20). [a]2D0 12.74 (c 0.05, CHCl3). nmax (Nujol): 3100–
3200, 1700 cmꢂ1. 1H NMR (CDCl3) d: 7.30–7.21 (m, 8H),
7.04–7.01 (m, 2H), 5.99–5.97 (m, 1H), 5.94 (t, J¼3.0 Hz),

3038
V. G. Nenajdenko et al. / Tetrahedron 63 (2007) 3031–3041
9H, t-Bu), 0.95 (d, J¼7.1 Hz, 3H, CH3), 0.76 (d, J¼6.8 Hz,
3H, CH3), signals of minor isomer d: 7.22–7.19 (m, 2H),
6.67–6.65 (m, 1H), 6.03–6.01 (m, 1H), 5.83 (br s, 1H,
NH), 5.68 (d, J¼15.7 Hz, 1H), 4.44 (d, J¼15.7 Hz, 1H),
4.31 (d, J¼8.6 Hz, 1H), 2.15–2.07 (m, 1H), 1.25 (s, 9H,
t-Bu), 1.15 (d, J¼6.8 Hz, 3H, CH3), 0.91 (d, J¼6.8 Hz,
3H, CH3), other signals observed by the signals of the major
isomer. 13C NMR (CDCl3) d: 168.0, 167.54, 167.45, 167.2,
136.0, 135.9, 129.1, 128.6, 128.2, 127.9, 127.6, 122.3, 121.9,
120.9, 119.0, 109.3, 109.1, 105.3, 104.4, 66.6, 63.7, 60.3,
56.8, 51.8, 51.5, 50.2, 48.2, 35.5, 33.0, 28.4, 28.2, 19.9,
19.6, 19.3, 17.3. Anal. Calcd: C, 71.90; H, 7.95. Found: C,
71.90; H, 8.01%.
(CH3CN–CH2Cl2 1:20). [a]2D0 29.16 (c 0.05, CHCl3). nmax
(Nujol): 3100–3200, 1700 cmꢂ1 1H NMR (CDCl3) d:
.
7.33–7.28 (m, 5H), 6.63–6.61 (m, 1H), 6.17 (t, J¼3.0 Hz,
1H), 5.98–5.96 (m, 1H), 5.55 (d, J¼14.7 Hz, 1H), 5.37
(br s, 1H, NH), 4.80 (s, 1H), 4.71 (d, J¼2.9 Hz, 1H), 3.93
(d, J¼14.7 Hz, 1H), 2.20–2.14 (m, 1H), 1.52–1.54 (m,
1H), 1.30 (s, 9H, t-Bu), 1.14–1.06 (m, 1H), 0.86 (t,
J¼7.3 Hz, 3H, CH3), 0.82 (d, J¼6.8 Hz, 3H, CH3). 13C
NMR (CDCl3) d: 167.3, 149.4, 142.3, 134.9, 129.1, 128.1,
126.9, 121.9, 117.8, 110.5, 110.1, 109.8, 103.9, 60.0, 58.8,
51.9, 41.3, 40.5, 28.4. Anal. Calcd: C, 71.09; H, 6.01. Found:
C, 71.21; H, 6.09%.
4.1.4.26. (1S,4S)-2-Benzyl-N-ethyl-4-isobutyl-3-oxo-
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-1-carboxamide
(32a). Yield 47%, yellow oil. Rf 0.30 (CH3CN–CH2Cl2
1:20). [a]2D0 26.08 (c 0.05, CHCl3). nmax (Nujol): 3100–
3200, 1700 cmꢂ1. 1H NMR (CDCl3) d: 7.29–7.18 (m, 5H),
6.64–6.62 (m, 1H), 6.17 (t, J¼3.0 Hz, 1H), 6.04–6.00 (m,
2H), 5.61 (d, J¼15.2 Hz, 1H), 4.90 (s, 1H), 4.74–4.70 (m,
1H), 4.22 (d, J¼15.2 Hz, 1H), 3.24–3.17 (m, 2H), 1.87–
1.72 (m, 3H), 1.06–1.01 (m, 6H), 0.92 (d, J¼5.9 Hz, 3H,
CH3). 13C NMR (CDCl3) d: 168.5, 168.2, 135.7, 128.7,
128.3, 127.7, 121.3, 119.7, 109.3, 105.0, 58.4, 56.7, 49.7,
44.3, 34.8, 24.6, 22.9, 21.4, 14.6. Anal. Calcd: C, 71.36;
H, 7.70. Found: C, 71.18; H, 7.65%.
4.1.4.22.
(1S,4S)-2-Benzyl-N-(tert-butyl)-4-[(1R)-1-
methylpropyl]-3-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyr-
azine-1-carboxamide (30a). Yield 53%, yellow oil. Rf 0.30
(CH3CN–CH2Cl2 1:20). [a]2D0 8.11 (c 0.05, CHCl3). nmax
(Nujol): 3100–3200, 1690 cmꢂ1 1H NMR (CDCl3) d:
.
7.29–7.23 (m, 3H), 7.21–7.17 (m, 2H), 6.64–6.62 (m, 1H),
6.17 (t, J¼3.0 Hz, 1H), 6.00–5.98 (m, 1H), 5.82 (br s, 1H,
NH), 5.64 (d, J¼15.3 Hz, 1H), 4.84 (s, 1H), 4.45–4.40 (m,
2H), 1.92–1.84 (m, 1H), 1.54–1.47 (m, 1H), 1.24 (s, 9H,
t-Bu), 1.18–1.11 (m, 1H), 1.08 (d, J¼6.8 Hz, 3H, CH3),
0.87 (t, J¼7.3 Hz, 3H, CH3). 13C NMR (CDCl3) d: 167.42,
167.40, 136.1, 128.7, 128.2, 127.6, 122.3, 120.6, 109.2,
105.3, 65.3, 57.0, 51.5, 50.2, 39.4, 28.3, 25.6, 15.7, 10.8.
Anal. Calcd: C, 72.41; H, 8.19. Found: C, 72.18; H, 7.99%.
4.1.4.27. (1R,4S)-2-Benzyl-N-ethyl-4-isobutyl-3-oxo-
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-1-carboxamide
(32b). Yield 21%, yellow oil. Rf 0.11 (CH3CN–CH2Cl2
1:20). [a]2D0 19.50 (c 0.05, CHCl3). nmax (Nujol): 3100–
3200, 1710 cmꢂ1. 1H NMR (CDCl3) d: 7.30–7.20 (m, 5H),
6.69–6.67 (m, 1H), 6.16 (t, 1H, J¼3.0 Hz), 5.98–5.96 (m,
1H), 5.86 (br s, 1H, NH), 5.47 (d, J¼15.2 Hz, 1H), 4.89
(s, 1H), 4.77–4.75 (m, 1H), 4.00 (d, J¼15.2 Hz, 1H),
3.23–3.13 (m, 2H), 2.14–2.03 (m, 2H), 1.79–1.72 (m, 1H),
1.04 (t, J¼7.3 Hz, 3H, CH3), 0.89 (d, J¼5.9 Hz, 3H, CH3),
0.81 (d, J¼5.9 Hz, 3H, CH3). 13C NMR (CDCl3) d:
168.7, 168.2, 135.8, 128.7, 128.5, 127.8, 121.7, 118.2,
109.3, 104.6, 58.5, 57.0, 49.1, 40.8, 34.8, 25.0, 22.8, 22.3,
14.5. Anal. Calcd: C, 71.36; H, 7.70. Found: C, 71.21; H,
7.60%.
4.1.4.23.
(1R,4S)-2-Benzyl-N-(tert-butyl)-4-[(1R)-1-
methylpropyl]-3-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyr-
azine-1-carboxamide (30b). Yield 16%, yellow oil. Rf 0.11
(CH3CN–CH2Cl2 1:20). [a]2D0 44.85 (c 0.04, CHCl3). nmax
(Nujol): 3100–3200, 1700 cmꢂ1 1H NMR (CDCl3) d:
.
7.33–7.28 (m, 5H), 6.63–6.61 (m, 1H), 6.17 (t, J¼3.0 Hz,
1H), 5.98–5.96 (m, 1H), 5.55 (d, J¼14.7 Hz, 1H), 5.37
(br s, 1H, NH), 4.80 (s, 1H), 4.71 (d, J¼2.9 Hz, 1H), 3.93
(d, J¼14.7 Hz, 1H), 2.20–2.14 (m, 1H), 1.52–1.54 (m,
1H), 1.30 (s, 9H, t-Bu), 1.14–1.06 (m, 1H), 0.86 (t,
J¼7.3 Hz, 3H, CH3), 0.82 (d, J¼6.8 Hz, 3H, CH3). 13C
NMR (CDCl3) d: 167.7, 167.3, 136.0, 129.0, 128.6, 127.9,
121.9, 118.5, 109.5, 104.2, 62.6, 60.3, 51.8, 48.3, 42.5,
28.4, 25.2, 15.3, 12.0. Anal. Calcd: C, 72.41; H, 8.19. Found:
C, 72.48; H, 8.07%.
4.1.4.28. (1S,4S)-2-Benzyl-N-ethyl-4-[(1R)-1-methyl-
propyl]-3-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-
1-carboxamide (33a). Yield 46%, yellow oil. Rf 0.30
(CH3CN–CH2Cl2 1:20). [a]2D0 22.4 (c 0.05, CHCl3). nmax
4.1.4.24. (1R,4S)-4-Benzyl-N-(tert-butyl)-2-(2-furyl-
methyl)-3-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-
1-carboxamide (31a). Yield 20%, yellow oil. Rf 0.30
(CH3CN–CH2Cl2 1:20). [a]2D0 ꢂ18.30 (c 0.05, CHCl3).
nmax (Nujol): 3100–3200, 1690 cmꢂ1. 1H NMR (CDCl3) d:
7.32–7.30 (m, 1H), 7.27–7.23 (m, 3H), 7.01–6.98 (m, 2H),
6.32–6.28 (m, 2H), 6.06–6.04 (m, 1H), 5.94 (t, J¼3.1 Hz,
1H), 5.83 (br s, 1H, NH), 5.72–5.70 (m, 1H), 5.43 (d, J¼
15.7 Hz, 1H), 5.02 (s, 1H), 4.77–4.73 (m, 1H), 4.36 (d, J¼
15.7 Hz, 1H), 3.48–3.44 (m, 1H), 3.05–3.00 (m, 1H), 1.34
(s, 9H, t-Bu). 13C NMR (CDCl3) d: 167.5, 167.4, 149.5,
142.7, 136.9, 129.6, 128.5, 127.0, 121.2, 120.6, 110.4,
109.8, 108.5, 104.9, 62.2, 57.9, 51.8, 42.8, 41.5, 28.5. Anal.
Calcd: C, 71.09; H, 6.01. Found: C, 71.25; H, 6.19%.
(Nujol): 3100–3200, 1700 cmꢂ1 1H NMR (CDCl3) d:
.
7.28–7.23 (m, 3H), 7.21–7.16 (m, 2H), 6.65–6.63 (m, 1H),
6.18 (t, J¼3.0 Hz, 1H), 6.02–6.00 (m, 1H), 5.96 (br s, 1H,
NH), 5.69 (d, J¼15.3 Hz, 1H), 4.89 (s, 1H), 4.43–4.39 (m,
2H), 3.24–3.17 (m, 2H), 1.87–1.80 (m, 1H), 1.51–1.42 (m,
1H), 1.16–1.01 (m, 7H), 0.85 (t, J¼7.6 Hz, 3H, CH3). 13C
NMR (CDCl3) d: 168.4, 167.4, 136.0, 128.7, 128.3, 127.6,
121.9, 120.9, 109.2, 105.5, 65.3, 56.2, 50.0, 39.5, 34.7,
25.6, 15.8, 14.6, 10.9. Anal. Calcd: C, 71.36; H, 7.70. Found:
C, 71.19; H, 7.79%.
4.1.4.29. (1R,4S)-2-Benzyl-N-ethyl-4-[(1R)-1-methyl-
propyl]-3-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-
1-carboxamide (33b). Yield 15%, yellow oil. Rf 0.11
(CH3CN–CH2Cl2 1:20). [a]2D0 34.92 (c 0.05, CHCl3). nmax
4.1.4.25. (1S,4S)-4-Benzyl-N-(tert-butyl)-2-(2-furyl-
methyl)-3-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-
1-carboxamide (31b). Yield 43%, yellow oil. Rf 0.11
(Nujol): 3100–3200, 1700 cmꢂ1 1H NMR (CDCl3) d:
.

V. G. Nenajdenko et al. / Tetrahedron 63 (2007) 3031–3041
3039
7.33–7.27 (m, 5H), 6.65–6.63 (m, 1H), 6.18 (t, J¼3.0 Hz,
1H), 5.99–5.97 (m, 1H), 5.63 (br s, 1H, NH), 5.52 (d,
J¼15.3 Hz, 1H), 4.94 (s, 1H), 4.70 (d, J¼3.0 Hz, 1H),
3.95 (d, J¼15.3 Hz, 1H), 3.28–3.20 (m, 2H), 2.21–2.14
(m, 1H), 1.51–1.45 (m, 1H), 1.16–1.10 (m, 1H), 1.06 (t,
3H, J¼7.2 Hz, CH3), 0.87 (t, 3H, J¼7.6 Hz, CH3), 0.81 (d,
3H, J¼7.0 Hz, CH3). 13C NMR (CDCl3) d: 168.3, 167.5,
135.8, 129.0, 128.6, 128.0, 121.7, 118.5, 109.6, 104.5,
62.5, 59.6, 48.5, 42.5, 34.7, 25.3, 15.2, 14.4, 12.0. Anal.
Calcd: C, 71.36; H, 7.70. Found: C, 71.28; H, 7.75%.
(CH3CN–CH2Cl2 1:20). [a]2D0 46.74 (c 0.05, CHCl3). nmax
(Nujol): 3100–3200, 1700 cmꢂ1 1H NMR (CDCl3) d:
.
7.47–7.44 (m, 2H), 7.33–7.29 (m, 3H), 6.64–6.62 (m, 1H),
6.19 (t, J¼3.2 Hz, 1H), 6.00 (q, J¼7.1 Hz, 1H), 6.00–5.98
(m, 1H), 4.87 (br s, 2H), 4.81 (q, J¼7.3 Hz, 1H), 1.83 (d,
J¼7.1 Hz, 3H, CH3), 1.58 (d, J¼7.2 Hz, 3H, CH3), 0.98
(s, 9H, t-Bu). 13C NMR (CDCl3) d: 169.0, 167.5, 138.5,
128.9, 128.6, 128.1, 127.2, 124.4, 117.2, 108.6, 103.6,
55.8, 54.2, 52.0, 51.2, 28.2, 16.4, 14.9. Anal. Calcd: C,
71.36; H, 7.70. Found: C, 71.32; H, 7.80%.
4.1.4.30. (4S)-N-(tert-Butyl)-3-oxo-2-[(1R)-1-phenyl-
ethyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-1-carbox-
amide (34). Mixture of (1R)/(1S) isomers 1.3:1. Yield 67%,
white amorphous solid. Mp 80 ꢀC. Rf 0.14 (CH3CN–CH2Cl2
4.1.4.34. (1R,4S)-N-(tert-Butyl)-4-methyl-3-oxo-2-[(1S)-
1-phenylethyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-
1-carboxamide (36b). Yield 23%, yellow oil. Rf 0.24
(CH3CN–CH2Cl2 1:20). [a]2D0 19.3 (c 0.05, CHCl3). nmax
1:20). nmax (Nujol): 3100–3200, 1705 cmꢂ1
.
1H NMR
(Nujol): 3100–3200, 1695 cmꢂ1 1H NMR (CDCl3) d:
.
(CDCl3) signals of major isomer d: 7.44–7.40 (m, 2H),
7.35–7.22 (m, 3H), 6.61–6.59 (m, 1H), 6.11 (t, J¼3.0 Hz,
1H), 6.04 (q, J¼7.1 Hz, 1H), 5.84–5.82 (m, 1H), 5.43
(br s, 1H, NH), 4.95 (d, J¼16.4 Hz), 4.62 (d, J¼16.4 Hz),
1.56 (d, J¼7.1 Hz, 3H, CH3), 1.27 (s, 9H, t-Bu), signals of
minor isomer d: 6.60–6.58 (m, 1H), 5.97–5.95 (m, 1H),
J¼6.8 Hz, 1H), 4.94 (d, J¼16.4 Hz), 4.71 (br s, 1H, NH),
4.68 (s, 1H), 4.58 (d, J¼16.4 Hz), 1.49 (d, J¼7.1 Hz, 3H,
CH3), 0.92 (s, 9H, t-Bu), other signals are observed by the
signals of the major isomer. 13C NMR (CDCl3) d: 168.7,
167.6, 166.6, 166.3, 139.8, 139.4, 138.3, 129.2, 128.8,
128.7, 128.2, 127.7, 127.3, 123.8, 123.0, 119.5, 109.1,
103.4, 103.3, 55.8, 55.7, 51.8, 51.7, 51.4, 51.2, 50.1, 49.7,
28.5, 28.2, 16.5, 15.8. Anal. Calcd: C, 70.77; H, 7.42. Found:
C, 70.70; H, 7.44%.
7.47–7.44 (m, 2H), 7.37–7.32 (m, 3H), 6.62–6.60 (m, 1H),
6.20 (t, J¼3.2 Hz, 1H), 6.00 (q, J¼7.1 Hz, 1H), 5.99–5.97
(m, 1H), 4.87–4.78 (m, 3H), 1.84 (d, J¼7.1 Hz, 3H, CH3),
1.56 (d, J¼7.3 Hz, 3H, CH3), 0.98 (s, 9H, t-Bu). 13C NMR
(CDCl3): 169.0, 167.3, 138.3, 129.2, 128.6, 128.2, 127.5,
122.4, 118.2, 109.6, 103.5, 56.5, 55.9, 53.1, 51.2, 28.2,
21.9, 16.9. Anal. Calcd: C, 71.36; H, 7.70. Found: C,
71.34; H, 7.85%.
4.1.4.35. (1S,4S)-N-(tert-Butyl)-4-isobutyl-3-oxo-2-[(1R)-
1-phenylethyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-
1-carboxamide (37a). Yield 47%, yellow oil. Rf 0.33
(CH3CN–CH2Cl2 1:20). [a]2D0 37.3 (c 0.05, CHCl3). nmax
(Nujol): 3100–3200, 1700 cmꢂ1. 1H NMR (CDCl3) d: 7.43–
7.40 (m, 2H), 7.35–7.29 (m, 3H), 6.57–6.55 (m, 1H), 6.16 (t,
J¼3.1 Hz, 1H), 6.08–6.06 (m, 1H), 5.83 (q, J¼7.0 Hz, 1H),
5.05 (br s, 1H, NH), 4.93 (s, 1H), 4.68 (t, J¼7.0 Hz, 1H),
1.88–1.83 (m, 2H, CH2), 1.58 (d, J¼7.0 Hz, 3H, CH3), 1.04
(d, J¼6.0 Hz, 3H, CH3), 0.98 (s, 9H, t-Bu), 0.91 (d,
J¼6.1 Hz, 3H, CH3). 13C NMR (CDCl3) d: 169.1, 167.1,
138.8, 128.8, 128.7, 128.2, 122.8, 119.0, 109.3, 104.5,
59.0, 56.7, 54.6, 51.2, 44.5, 28.1, 24.9, 23.0, 21.4, 17.1.
Anal. Calcd: C, 72.88; H, 8.41. Found: C, 72.65; H, 8.30%.
4.1.4.31. (1S,4S)-N-(tert-Butyl)-4-methyl-3-oxo-2-[(1R)-
1-phenylethyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-
1-carboxamide (35a). Yield 44%, yellow oil. Rf 0.33
(CH3CN–CH2Cl2 1:20). [a]2D0 26.75 (c 0.05, CHCl3). nmax
(Nujol): 3100–3200, 1700 cmꢂ1 1H NMR (CDCl3, d:
.
7.47–7.44 (m, 2H), 7.33–7.29 (m, 3H), 6.64–6.62 (m, 1H),
6.20 (t, J¼3.2 Hz, 1H), 6.00 (q, J¼7.1 Hz, 1H), 6.00–5.98
(m, 1H), 4.87 (br s, 2H), 4.81 (q, J¼7.3 Hz, 1H), 1.84 (d,
J¼7.1 Hz, 3H, CH3), 1.58 (d, J¼7.3 Hz, 3H, CH3), 0.98
(s, 9H, t-Bu). 13C NMR (CDCl3) d: 169.0, 167.5, 138.5,
128.9, 128.6, 128.1, 127.2, 124.4, 117.2, 108.6, 103.7,
55.6, 54.4, 52.1, 51.2, 28.2, 16.4, 14.9. Anal. Calcd: C,
71.36; H, 7.70. Found: C, 71.45; H, 7.68%.
4.1.4.36. (1R,4S)-N-(tert-Butyl)-4-isobutyl-3-oxo-2-[(1R)-
1-phenylethyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-
1-carboxamide (37b). Yield 18%, yellow oil. Rf 0.13
(CH3CN–CH2Cl2 1:20). [a]2D0 35.14 (c 0.05, CHCl3). nmax
(Nujol): 3100–3200, 1710 cmꢂ1 1H NMR (CDCl3) d:
.
7.32–7.21 (m, 5H), 6.73–6.71 (m, 1H), 6.10 (t, J¼3.1 Hz,
1H), 5.94 (q, J¼7.0 Hz, 1H), 5.82–5.80 (m, 1H), 5.28
(br s, 1H, NH), 4.86 (t, J¼4.7 Hz, 1H), 4.45 (s, 1H), 2.33–
2.26 (m, 1H), 2.21–2.15 (m, 1H), 1.96–1.89 (m, 1H), 1.57
(d, J¼7.0 Hz, 3H, CH3), 1.25 (s, 9H, t-Bu), 0.96 (d,
J¼6.7 Hz, 3H, CH3), 0.99 (d, J¼6.5 Hz, 3H, CH3). 13C
NMR (CDCl3) d: 169.0, 168.7, 139.7, 128.7, 127.6, 127.3,
123.5, 118.0, 108.7, 103.5, 57.3, 56.1, 52.6, 51.7, 38.8,
28.4, 25.4, 22.8, 22.7, 15.9. Anal. Calcd: C, 72.88; H,
8.41. Found: C, 72.60; H, 8.26%.
4.1.4.32. (1R,4S)-N-(tert-Butyl)-4-methyl-3-oxo-2-[(1R)-
1-phenylethyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-
1-carboxamide (35b). Yield 22%, yellow oil. Rf 0.24
(CH3CN–CH2Cl2 1:20). [a]2D0 43.25 (c 0.05, CHCl3). nmax
(Nujol): 3100–3200, 1690 cmꢂ1 1H NMR (CDCl3) d:
.
7.47–7.44 (m, 2H), 7.37–7.32 (m, 3H), 6.62–6.60 (m, 1H),
6.20 (t, J¼3.2 Hz, 1H), 6.00 (q, J¼7.1 Hz, 1H), 5.99–5.97
(m, 1H), 4.87–4.78 (m, 3H), 1.84 (d, J¼7.1 Hz, 3H, CH3),
1.56 (d, J¼7.3 Hz, 3H, CH3), 0.98 (s, 9H, t-Bu). 13C NMR
(CDCl3) d: 169.0, 167.3, 138.3, 129.2, 128.6, 128.2, 127.5,
122.4, 118.2, 109.6, 103.5, 56.5, 55.9, 53.1, 51.2, 28.2,
21.9, 16.9. Anal. Calcd: C, 71.36; H, 7.70. Found: C,
71.39; H, 7.67%.
4.1.4.37. (1S,4S)-N-(tert-Butyl)-4-isobutyl-3-oxo-2-[(1S)-
1-phenylethyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-
1-carboxamide (38a). Yield 44%, yellow oil. Rf 0.33
(CH3CN–CH2Cl2 1:20). [a]2D0 40.6 (c 0.05, CHCl3). nmax
4.1.4.33. (1S,4S)-N-(tert-Butyl)-4-methyl-3-oxo-2-[(1S)-
1-phenylethyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-
1-carboxamide (36a). Yield 41%, yellow oil. Rf 0.33
(Nujol): 3100–3200, 1700 cmꢂ1 1H NMR (CDCl3) d:
.
7.31–7.19 (m, 5H), 6.58–6.56 (m, 1H), 6.16 (t, J¼3.3 Hz,
1H), 6.97 (q, J¼7.3 Hz, 1H), 5.85–6.83 (m, 1H), 5.49

3040
V. G. Nenajdenko et al. / Tetrahedron 63 (2007) 3031–3041
(br s, 1H, NH), 4.70 (t, J¼7.0 Hz, 1H), 4.57 (s, 1H), 1.96–
1.86 (m, 3H), 1.59 (d, J¼7.3 Hz, 3H, CH3), 1.26 (s, 9H,
t-Bu), 1.02 (d, J¼6.3 Hz, 3H, CH3), 0.95 (d, J¼6.3 Hz,
3H, CH3). 13C NMR (CDCl3) d: 169.0, 168.1, 139.7,
128.6, 127.7, 127.4, 122.7, 119.2, 109.1, 103.7, 58.7, 55.8,
52.8, 51.5, 44.7, 28.3, 24.8, 23.0, 21.5, 16.6. Anal. Calcd:
C, 72.88; H, 8.41. Found: C, 72.55; H, 8.44%.
4.30 (d, J¼7.5 Hz, 1H), 2.01–1.91 (m, 1H, CH), 1.60 (d,
J¼7.0 Hz, 3H, CH3), 1.57–1.47 (m, 1H), 1.28 (s, 9H,
t-Bu), 1.22–1.12 (m, 4H), 0.86 (t, J¼6.1 Hz, 3H, CH3).
13C NMR (CDCl3) d: 169.1, 167.1, 138.8, 128.8, 128.7,
128.2, 122.8, 119.0, 109.3, 104.5, 59.0, 56.7, 54.6, 51.2,
44.5, 28.1, 24.9, 23.0, 21.4, 17.1. Anal. Calcd: C, 72.88;
H, 8.41. Found: C, 72.69; H, 8.37%.
4.1.4.38. (1R,4S)-N-(tert-Butyl)-4-isobutyl-3-oxo-2-[(1S)-
1-phenylethyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-
1-carboxamide (38b). Yield 19%, yellow oil. Rf 0.13
(CH3CN–CH2Cl2 1:20). [a]2D0 110.3 (c 0.05, CHCl3). nmax
4.1.4.42. (1R,4S)-N,N-(tert-Butyl)-4-[(1R)-1-methyl-
propyl]-3-oxo-2-[(1S)-1-phenylethyl]-1,2,3,4-tetrahydro-
pyrrolo[1,2-a]pyrazine-1-carboxamide (40b). Yield 14%,
yellow oil. Rf 0.13 (CH3CN–CH2Cl2 1:20). [a]2D0 28.64 (c
(Nujol): 3100–3200, 1690 cmꢂ1
.
1H NMR (CDCl3) d:
0.05, CHCl3). nmax (Nujol): 3100–3200, 1700 cmꢂ1 1H
.
7.45–7.42 (m, 2H), 7.35–7.28 (m, 3H), 6.71–6.69 (m, 1H),
6.12 (t, J¼3.1 Hz, 1H), 6.00–5.93 (m, 2H), 4.83 (t,
J¼5.1 Hz, 1H), 4.75 (br s, 1H, NH), 4.45 (s, 1H), 2.32–
2.25 (m, 1H), 2.10–2.03 (m, 1H), 1.98–1.92 (m, 1H), 1.51
(d, J¼7.1 Hz, 3H, CH3), 0.97–0.92 (m, 15H). 13C NMR
(CDCl3) d: 169.0, 168.1, 139.7, 128.6, 127.7, 127.4, 122.7,
119.2, 109.1, 103.7, 58.7, 55.8, 52.8, 51.5, 44.7, 28.3,
24.8, 23.0, 21.5, 16.6. Anal. Calcd: C, 72.88; H, 8.41. Found:
C, 72.65; H, 8.38%.
NMR (CDCl3) d: 7.37–7.22 (m, 2H), 7.25–7.19 (m, 3H),
6.62–6.64 (m, 1H), 6.13 (t, J¼3.1 Hz, 1H), 5.90 (q,
J¼7.0 Hz, 1H), 5.98–5.96 (m, 1H), 5.35 (br s, 1H, NH),
4.63 (s, 1H), 4.30 (d, J¼7.5 Hz, 1H), 2.01–1.91 (m, 1H,
CH), 1.55 (d, J¼7.0 Hz, 3H, CH3), 1.55–1.46 (m, 1H),
1.22–1.12 (m, 4H), 1.14 (s, 9H, t-Bu), 0.87 (t, J¼6.1 Hz,
3H, CH3). 13C NMR (CDCl3) d: 169.1, 168.9, 134.0,
128.7, 127.5, 127.2, 123.7, 118.0, 108.2, 104.0, 56.9, 56.1,
52.6, 51.7, 38.8, 28.3, 24.9, 22.8, 22.7, 16.0. Anal. Calcd:
C, 72.88; H, 8.41. Found: C, 72.79; H, 8.30%.
4.1.4.39. (1S,4S)-N-(tert-Butyl)-4-[(1R)-1-methylpropyl]-
3-oxo-2-[(1R)-1-phenylethyl]-1,2,3,4-tetrahydropyrrolo-
[1,2-a]pyrazine-1-carboxamide (39a). Yield 52%, yellow
oil. Rf 0.29 (CH3CN–CH2Cl2 1:20). [a]2D0 20.1 (c 0.05,
Acknowledgements
Financial support from Russian Science Support Foundation
is gratefully acknowledged. The authors also thank Dr. A. S.
Shashkov for the NMR spectra and Dr. B. V. Lokshin for the
optical rotation measurements.
1
CHCl3). nmax (Nujol): 3100–3200, 1705 cmꢂ1. H NMR
(CDCl3) d: 7.35–7.26 (m, 2H), 7.24–7.20 (m, 3H), 6.62–
6.64 (m, 1H), 6.12 (t, J¼3.1 Hz, 1H), 5.96 (q, J¼7.0 Hz,
1H), 5.88–5.86 (m, 1H), 5.65 (br s, 1H, NH), 4.63 (s, 1H),
4.30 (d, J¼7.5 Hz, 1H), 2.01–1.91 (m, 1H, CH), 1.60 (d,
J¼7.0 Hz, 3H, CH3), 1.57–1.47 (m, 1H), 1.28 (s, 9H,
t-Bu), 1.22–1.12 (m, 4H), 0.86 (t, J¼6.1 Hz, 3H, CH3).
13C NMR (CDCl3) d: 169.2, 167.0, 138.9, 128.5, 128.6,
128.3, 122.4, 118.6, 109.4, 104.5, 59.0, 56.7, 54.6, 51.2,
44.5, 28.1, 24.9, 23.2, 21.4, 17.0. Anal. Calcd: C, 72.88;
H, 8.41. Found: C, 72.71; H, 8.36%.
References and notes
1. For recent reviews on the Ugi reaction and other isocyanide-
based multicomponent reactions, see: (a) Multicomponent
Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH:
€
Weinheim, 2005; (b) Domling, A. Chem. Rev. 2006, 106, 17–
89; (c) Mironov, M. A. QSAR Comb. Sci. 2006, 25, 423–431;
€
(d) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39,
3168–3210.
4.1.4.40. (1R,4S)-N-(tert-Butyl)-4-[(1R)-1-methylpropyl]-
3-oxo-2-[(1R)-1-phenylethyl]-1,2,3,4-tetrahydropyrrolo-
[1,2-a]pyrazine-1-carboxamide (39b). Yield 13%, yellow
oil. Rf 0.14 (CH3CN–CH2Cl2 1:20). [a]2D0 46.25 (c 0.05,
2. (a) Zhang, J.; Jacobson, A.; Rusche, J. R.; Herlihy, W. J. Org.
Chem. 1999, 64, 1074–1076; (b) Zhu, J. Eur. J. Org. Chem.
2003, 68, 1133–1144.
1
CHCl3). nmax (Nujol): 3100–3200, 1700 cmꢂ1. H NMR
(CDCl3) d: 7.37–7.22 (m, 2H), 7.25–7.19 (m, 3H), 6.62–
6.64 (m, 1H), 6.13 (t, J¼3.1 Hz, 1H), 5.90 (q, J¼7.0 Hz,
1H), 5.98–5.96 (m, 1H), 5.35 (br s, 1H, NH), 4.63 (s, 1H),
4.30 (d, J¼7.5 Hz, 1H), 2.01–1.91 (m, 1H, CH), 1.55 (d,
J¼7.0 Hz, 3H, CH3), 1.55–1.46 (m, 1H), 1.22–1.12 (m,
4H), 1.14 (s, 9H, t-Bu), 0.87 (t, J¼6.1 Hz, 3H, CH3). 13C
NMR (CDCl3) d: 169.1, 168.9, 134.0, 128.7, 127.5, 127.4,
123.7, 118.0, 108.2, 103.8, 56.9, 56.5, 52.6, 52.0, 39.0,
28.3, 25.0, 22.8, 22.7, 16.0. Anal. Calcd: C, 72.88; H,
8.41. Found: C, 72.62; H, 8.34%.
3. (a) Martquarding, D.; Hoffman, P.; Heitzer, H.; Ugi, I. J. Am.
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1
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