A convenient preparation of diastereomerically pure, diversely substituted piperazine-2,5-diones from n-protected -amino acids

Article abstract of DOI:10.1055/s-0029-1218829

The products of the Ugi reaction of various N-tert-butoxycarbonyl-protected -amino acids, aldehydes, amines and tert-butyl isocyanide, after tert-butoxycarbonyl deprotection, undergo efficient microwave-assisted cyclization in acetic acid to give diastereomerically pure, racemic piperazine-2,5-diones. The formation of a single diastereomer is rationalized via an enolization equilibration process in acetic acid at high temperature which enriches the product mixture in the more stable diastereomer. The relative stereochemistry of the products are confirmed by NOESY experiments and are consistent with molecular mechanics calculations. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1218829

PAPER
2527
A Convenient Preparation of Diastereomerically Pure, Diversely Substituted
Piperazine-2,5-diones from N-Protected a-Amino Acids
Preparationof
D
iastere
i
omeric
k
allyPure
P
ip
h
erazine-2,5-
a
diones il Nikulnikov,a,b Alexei Shumsky,b Mikhail Krasavin*a,b
a
Science and Education Center ‘Innovative Research’, Yaroslavl State Pedagogical University, Yaroslavl 150000, Russian Federation
Chemical Diversity Research Institute, 2a Rabochaya St., Khimki, Moscow Region 141400, Russian Federation
Fax +7(495)6269780; E-mail: myk@chemdiv.com
b
Received 22 March 2010
lowing deprotection), in good yields, of Ugi multicompo-
nent reaction products derived from N-tert-
butoxycarbonyl-protected a-amino acids and n-butyl iso-
cyanide (n-BuNC).5 Notably, the products resulting from
Abstract: The products of the Ugi reaction of various N-tert-but-
oxycarbonyl-protected a-amino acids, aldehydes, amines and tert-
butyl isocyanide, after tert-butoxycarbonyl deprotection, undergo
efficient microwave-assisted cyclization in acetic acid to give dia-
stereomerically pure, racemic piperazine-2,5-diones. The formation chiral N-tert-butoxycarbonyl-protected a-amino acids
of a single diastereomer is rationalized via an enolization equilibra-
were obtained as 1:1 mixtures of diastereomers
tion process in acetic acid at high temperature which enriches the
(Scheme 2). Herein, we report on the preparation of dia-
product mixture in the more stable diastereomer. The relative ste-
stereomerically pure piperazine-2,5-diones via a similar
reochemistry of the products are confirmed by NOESY experiments
microwave-assisted protocol involving intramolecular cy-
and are consistent with molecular mechanics calculations.
clization onto a tert-butyl amide unit in glacial acetic acid.
Key words: piperazine-2,5-diones, Ugi multicomponent reaction,
post-Ugi modification, microwave-assisted, enolization
R1
R1
O
O
N
R2
O
H
N
N
N
AcOH
N
R2
N
NH
R3
(a)
Strategic incorporation of potentially reactive functional-
ities into the structure of any two components of the Ugi
multicomponent reaction (U-MCR) provides dipeptoid
templates that can undergo further complexity-generating
transformations. Such premeditated post-Ugi modifica-
tion processes have served1 as a rich source of diverse het-
erocyclic compounds that would otherwise be
inaccessible, or require tedious synthetic elaboration by
alternative preparative strategies.
O
MW, 20 min, 180 °C
R3
R1
R1
O
H
H
O
R2
O
N
N
N
N
R2
AcOH
N
(b)
O
MW, 20 min, 180 °C
R3
R3
Scheme 1 Examples of microwave-assisted cyclization of Ugi reac-
tion derived tert-butyl amides containing (a) pyrazole,2 and (b)
indole3 moieties
Previously, we described post-Ugi multicomponent cy-
clization of Ugi reaction products containing a pyrazole-
3-carboxylic acid2 or an indole-2-carboxylic acid resi-
due,3 under microwave irradiation in glacial acetic acid. In
this procedure, tert-butyl isocyanide (t-BuNC) manifested
itself as a convertible isocyanide in the preceding Ugi re-
action as the resulting terminal tert-butyl amide was con-
verted, intramolecularly, into an N-acyl azole moiety
(Scheme 1). Clearly, tert-butyl isocyanide serves as an at-
tractive, low-cost alternative to other convertible isocya-
nides described in the literature.4 This consideration
prompted us to investigate cyclizations of Ugi reaction de-
rived tert-butyl amides with other nitrogen nucleophiles
under similar conditions.
A set of 12 dipeptoids, 2a–l, was prepared via the Ugi re-
action of various N-tert-butoxycarbonyl-protected amino
acids 1, aldehydes and amines with tert-butyl isocyanide.
In all cases, the crude products 2 were at least 80% pure
according to LC–MS analysis.6 Without further purifica-
tion, we next attempted the microwave-assisted cycliza-
tion of dipeptoids 2 in glacial acetic acid. Disappointingly,
these conditions were insufficiently acidic to enable effi-
cient removal of the tert-butoxycarbonyl group, and sig-
nificant amounts of the starting materials 2, along with
minor unidentified impurities, were recovered after heat-
ing in a microwave oven at 180 °C for 90 minutes. Pro-
longed heating (up to three hours) or higher temperatures
(200–220 °C) resulted in the accumulation of more impu-
rities. Therefore, it was decided to deprotect dipeptoids 2
prior to submitting them to the microwave-assisted cy-
clization step. To our delight, the respective free-base
deprotected products underwent clean cyclization into the
target piperazine-2,5-diones 3 (Scheme 3). Surprisingly,
in all cases, the crude 1H NMR spectra of the products ex-
hibited only one set of signals thereby confirming the for-
An opportunity for such a cyclization exists if, for exam-
ple, N-tert-butoxycarbonyl-protected a-amino acids are
used in combination with tert-butyl isocyanide to con-
struct dipeptoid products via the Ugi multicomponent re-
action. Indeed, during the course of our investigations,
Hulme reported the microwave-assisted cyclization (fol-
SYNTHESIS 2010, No. 15, pp 2527–2532
x
x.
x
x
.
2
0
1
0
Advanced online publication: 18.06.2010
DOI: 10.1055/s-0029-1218829; Art ID: P04510SS
© Georg Thieme Verlag Stuttgart · New York

2528
M. Nikulnikov et al.
PAPER
PhCH2CH2CHO
i-BuNH2
O
O
O
O
H
n-BuNC
R
10% TFA in DCE
R
O
N
HN
OH
N
n-Bu
MeOH
MW, 90 °C, 10 min
MW, 120 °C, 20 min
N
O
NH
O
NH
O
R
O
(a) R = Me, 47% (2 steps), dr = 1:1
(b) R = Bn, 51% (2 steps), dr = 1:1
Scheme 2 In situ deprotection and microwave-assisted cyclization of Ugi reaction products containing natural amino acid components as de-
scribed by Hulme5
R2
R1
O
N
O
O
OH
R2
N
O
O
1
R1
N
R1
R2
R3
R4
O
R4
MeOH
1) HCl in 1,4-dioxane (3 M)
N
N
C–
H2N R3
+
H
O
60 °C, 16 h
N
N
2) AcOH, MW, 90 min, 180 °C
O
O
R3
O
H
R4
(
)-3
2
single diastereomer!
Scheme 3 Three-step preparation of diastereomerically pure piperazine-2,5-diones 3
mation of only one of the two possible diastereomers tography or by crystallization, in similar yields over the
during the cyclization. Analytically and diastereomerical- three steps (Table 1).
ly pure compounds 3a–l were obtained, either by chroma-
Table 1 Ugi Multicomponent Reaction Templates 2 and Cyclization Products 3
Products
Amino acid 1
R3
R4
LC–MS 2, m/z [M + H+] Yield of 3 (%)
46a
42a
50a
44a
50a
41a
43a
N
O
2a/3a
462.5
488.6
538.4
476.7
502.2
544.4
580.3
MeO
*
*
*
*
*
*
O
O
OH
OH
O
N
O
2b/3b
2c/3c
2d/3d
2e/3e
2f/3f
*
O
O
*
N
O
MeO
OH
O
O
O
O
O
O
MeO
O
N
O
*
OH
OH
OH
OH
O
O
O
O
*
*
N
O
O
N
O
*
*
*
2g/3g
N
O
MeO
Synthesis 2010, No. 15, 2527–2532 © Thieme Stuttgart · New York

PAPER
Preparation of Diastereomerically Pure Piperazine-2,5-diones
2529
Table 1 Ugi Multicomponent Reaction Templates 2 and Cyclization Products 3 (continued)
Products
Amino acid 1
R3
R4
LC–MS 2, m/z [M + H+] Yield of 3 (%)
*
*
45b
52b
HN
O
2h/3h
498.7
560.6
*
*
MeO
OH
O
O
H
N
2i/3i
O
MeO
O
OH
O
*
*
*
2j/3j
2k/3k
2l/3l
526.3
540.5
540.3
41b
45b
39b
HN
O
*
*
*
MeO
MeO
MeO
O
OH
OH
OH
O
O
O
HN
O
O
HN
O
O
a Yield of isolated product after chromatography.
b Yield of isolated product after crystallization.
OH
corresponding to two diastereomers of 3 were observed in
the complex H NMR spectrum of the reaction mixture
R1
R2
R3
R4
1
N
(the conversion at this point was <10%). It was noted that
the piperazine-2,5-dione products 3a, 3b, 3h and 3j–l, de-
rived from optically pure amino acids, were not optically
active. Indeed, we monitored the optical rotation en route
to 3h and established that the product was not optically ac-
tive (Scheme 5). This would appear to be consistent with
the proposed enolization and equilibration.
N
O
O
O
O
O
R1
R2
R3
R4
R1
R2
R3
N
N
4
N
N
R4
O
R1
R2
R3
R4
N
(
)-3
initially formed
diastereomeric
mixture
N
single diastereomer!
OH
The trans stereochemistry of the products 3a–l was estab-
lished based on their NOESY spectra (see Figure 1 for
representative examples). Interestingly, when the energies
of the MM2 minimized8 conformations of cis- and trans-
3 were compared, no significant difference was observed
in the majority of cases; this is probably due to the piper-
azine-2,5-dione ring being nearly planar. However, in
some cases (products 3a, 3b, 3g and 3i), the calculated en-
ergy preference toward the trans isomer was >20 kcal/
mol, which is consistent with the proposed equilibration
of the diastereomeric mixture into a single trans isomer.
5
Scheme 4 Possible enolization and equilibration leading to the for-
mation of a single diastereomer of product 3
The observed formation of single diastereomers of com-
pounds 3a–l can be rationalized through enolization of the
initially formed diastereomeric mixture in glacial acetic
acid, on prolonged heating, and its equilibration via the
enol form 4 (and possibly also 5) into a single, more stable
diastereomer (Scheme 4). Indeed, when the microwave-
assisted cyclization was stopped after 10 minutes, signals
Me
O
O
O
O
H
1) HCl in 1,4-dioxane (3 M)
2) basic workup
N
N
OH
4-MeOC6H4CH2NH2
N
HN
O
NH
O
NH
O
3) AcOH, MW 90 min, 180 °C
PhCHO, t-BuNC
MeOH, 60 °C, 16 h
O
O
O
[α] –18.5
3h
[α] +0.6
(AcOH, c = 2)
2h
Lit.7 [α] –26.0
O
Me
(AcOH, c = 2)
Scheme 5 Loss of optical activity during the preparation of 3h
Synthesis 2010, No. 15, 2527–2532 © Thieme Stuttgart · New York

2530
M. Nikulnikov et al.
PAPER
tography on silica gel [10→40% CH2Cl2 in hexanes (compounds
3a–g)] or by crystallization [i-PrOH (compounds 3h–l)] to afford
analytically pure piperazine-2,5-diones 3.
Me
O
O
NOE
NOE
H
H
O
O
H
H
N
N
( )-(3R,8aS)-2-(2-Methoxyethyl)-3-phenylhexahydropyrro-
lo[1,2-a]pyrazine-1,4-dione (3a)
Yield: 46%; white solid; mp 119–121 °C.
1H NMR (300 MHz, DMSO-d6): d = 7.46–7.28 (m, 5 H), 5.18 (s, 1
H), 4.16 (t, J = 7.9 Hz, 1 H), 3.89 (dt, Jd = 14.0 Hz, Jt = 5.2 Hz, 1
H), 3.63–3.36 (m, 3 H), 3.33–3.22 (m, 1 H), 3.19 (s, 3 H), 3.16–3.04
(m, 1 H), 2.19 (m, 1 H), 2.04–1.71 (m, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 167.4, 163.2, 135.5, 128.9,
128.1, 126.0, 69.4, 66.1, 57.9, 57.6, 45.2, 43.9, 29.0, 21.7.
LC–MS: m/z = 289 [M + H+].
N
N
H
H
O
O
3f
3a
Me
O
NOE
H
H
O
N
N
H
H
O
3k
Anal. Calcd for C16H20N2O3: C, 66.65; H, 6.99; N, 9.72. Found: C,
66.73; H, 7.07; N, 9.77.
Figure 1 Examples of the relative stereochemistries of 3 assigned
based on through-space interactions observed in NOESY spectra
( )-(3R,8aS)-3-Phenyl-2-(tetrahydrofuran-2-ylmethyl)hexahy-
dropyrrolo[1,2-a]pyrazine-1,4-dione (3b)
In conclusion, we have developed a convenient protocol
for the preparation of diastereomerically pure trans-piper-
azine-2,5-diones 3 via the Ugi reaction of various N-tert-
butoxycarbonyl-protected a-amino acids, aldehydes,
amines and tert-butyl isocyanide, deprotection and micro-
wave-assisted cyclization. This method extends the utility
of tert-butyl isocyanide as a convertible isocyanide for the 128.2, 126.0, 77.5, 67.3, 66.3, 57.5, 48.4, 45.2, 29.1, 28.8, 24.7,
design of Ugi reaction products intended for post-Ugi cy-
clizations, specifically, under microwave irradiation in
acetic acid.
Yield: 42%; white solid; mp 133–135 °C.
1H NMR (300 MHz, DMSO-d6): d = 7.46–7.28 (m, 5 H), 5.30 (d,
J = 11.5 Hz, 1 H), 4.17 (t, J = 8.0 Hz, 1 H), 4.06–3.90 (m, 2 H),
3.81–3.49 (m, 3 H), 3.34–3.22 (m, 1 H), 2.76–2.63 (m, 1 H), 2.34–
2.19 (m, 1 H), 2.04–1.69 (m, 6 H), 1.53–1.37 (m, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 167.4, 163.2, 135.3, 128.9,
21.7.
LC–MS: m/z = 315 [M + H+].
Anal. Calcd for C18H22N2O3: C, 68.77; H, 7.05; N, 8.91. Found: C,
68.69; H, 6.98; N, 8.83.
All reactions were run in oven-dried glassware under an N2 atm.
Melting points were obtained with a Buchi B-520 melting point ap-
paratus and are uncorrected. Analytical TLC was performed using
F254 silica gel plates (EM Separations Technology). Compounds
were visualized using short-wavelength UV light. Column chro-
matographic separations were carried out on Merck silica gel (70–
( )-(3R,9aS)-2-(4-Methoxybenzyl)-3-phenyltetrahydro-2H-py-
rido[1,2-a]pyrazine-1,4(3H,6H)-dione (3c)
Yield: 50%; white solid; mp 168 °C (dec.).
1H NMR (300 MHz, DMSO-d6): d = 7.45–7.20 (m, 5 H), 7.07 and
6.87 (ABq, J = 7.3 Hz, 4 H), 5.07 (d, J = 14.5 Hz, 1 H), 4.78 (s, 1
H), 4.38–4.16 (m, 2 H), 3.75 (s, 3 H), 3.49 (d, J = 14.4 Hz, 1 H),
2.63–2.52 (m, 1 H), 2.45–2.29 (m, 1 H), 1.96–1.81 (m, 1 H), 1.74–
1.25 (m, 4 H).
13C NMR (75 MHz, DMSO-d6): d = 165.7, 162.7, 158.7, 137.4,
129.5, 129.2, 128.9, 128.4, 127.7, 127.4, 127.2, 114.0, 62.3, 56.9,
55.0, 45.8, 41.7, 31.5, 23.9, 23.4.
1
230 mesh). H NMR and 13C NMR spectra were recorded on a
Bruker DPX-300 spectrometer in DMSO-d6 using TMS as the inter-
nal standard. LC–MS analyses were obtained using a PE SCIEX
API 150EX mass spectrometer following separation on a Shimadzu
LC-10AD liquid chromatography system equipped with a Shimadzu
SP D-10A UV-Vis detector (254 nm) and a Sedex 75 ELSD detec-
tor. Elemental analyses were recorded at the Research Institute for
Chemical Crop Protection (Moscow, Russia) using a Carlo Erba
Strumentazione 1106 analyzer. All solvents and reagents were ob-
tained from commercial sources and were used without purification.
LC–MS: m/z = 365 [M + H+].
Anal. Calcd for C22H24N2O3: C, 72.51; H, 6.64; N, 7.69. Found: C,
72.60; H, 6.71; N, 7.75.
Piperazine-2,5-diones 3a–l; Typical Procedure
( )-(3R,9aS)-2-(2-Methoxyethyl)-3-phenyltetrahydro-2H-pyri-
do[1,2-a]pyrazine-1,4(3H,6H)-dione (3d)
Yield: 44%; white solid; mp 139–141 °C.
1H NMR (300 MHz, DMSO-d6): d = 7.45–7.26 (m, 5 H), 5.11 (s, 1
H), 4.36 (dt, Jd = 13.2 Hz, Jt = 2.0 Hz, 1 H), 4.13 (dd, J = 11.5 Hz,
J = 3.3 Hz, 1 H), 3.86 (dt, Jd = 14.0 Hz, Jt = 5.5 Hz, 1 H), 3.52–3.41
(m, 1 H), 3.40–3.30 (m, 1 H), 3.21 (s, 3 H), 2.82–2.70 (m, 1 H),
2.63–2.53 (m, 1 H), 2.41–2.28 (m, 1 H), 1.96–1.83 (m, 1 H), 1.74–
1.63 (m, 1 H), 1.53–1.26 (m, 3 H).
The syntheses reported herein were performed on 10 mmol scale.
Equimolar amounts of an aldehyde and an amine were dissolved in
MeOH (20 mL) and the mixture was stirred for 10 min at 60 °C. N-
Boc-a-amino acid 1 (1 equiv) and t-BuNC (1 equiv) were added and
stirring was continued at 60 °C for 16 h. The solvent was evaporated
and the residue was dissolved in a 3 M soln of HCl in 1,4-dioxane
(20 mL). After stirring at r.t. for 10 h, the volatiles were removed in
vacuo and the residue was partitioned between CH2Cl2 (20 mL) and
10% aq NaHCO3 soln (20 mL). The organic layer was separated,
dried over anhyd Na2SO4, filtered and concd. The residue was dis-
solved in glacial AcOH (5 mL) and the resulting soln was placed in
a microwave reactor tube and heated at 180 °C for 90 min using a
Biotage Initiator™ microwave synthesizer operating at 100 W.
Upon cooling, the solvent was removed in vacuo (using GeneVac®
equipment) and the residue again subjected to basic aqueous work-
up (vide supra). The crude product was purified by column chroma-
13C NMR (75 MHz, DMSO-d6): d = 165.6, 162.9, 138.0, 128.7,
128.3, 127.4, 68.9, 63.8, 58.0, 56.7, 43.1, 41.6, 31.3, 23.9, 23.4.
LC–MS: m/z = 303 [M + H+].
Anal. Calcd for C17H22N2O3: C, 67.53; H, 7.33; N, 9.26. Found: C,
67.58; H, 7.43; N, 9.32.
Synthesis 2010, No. 15, 2527–2532 © Thieme Stuttgart · New York

PAPER
Preparation of Diastereomerically Pure Piperazine-2,5-diones
2531
( )-(3S,9aR)-3-Phenyl-2-(tetrahydrofuran-2-ylmethyl)tetrahy-
dro-2H-pyrido[1,2-a]pyrazine-1,4(3H,6H)-dione (3e)
Yield: 50%; white solid; mp 149–150 °C.
( )-(3R,6S)-1-(4-Methoxybenzyl)-3,6-diphenylpiperazine-2,5-
dione (3i)
Yield: 52%; white solid; mp 164 °C (dec.).
1H NMR (300 MHz, DMSO-d6): d = 7.46–7.23 (m, 5 H), 5.20 (d,
J = 22.1 Hz, 1 H), 4.41–4.29 (m, 1 H), 4.19–4.08 (m, 1 H), 4.06–
3.86 (m, 2 H), 3.81–3.55 (m, 2 H), 2.65–2.53 (m, 1 H), 2.43–2.30
(m, 1 H), 2.02–1.25 (m, 10 H).
1H NMR (300 MHz, DMSO-d6): d = 8.45 (d, J = 6.2 Hz, 1 H), 7.50–
7.10 (m, 10 H), 7.04 (t, J = 6.5 Hz, 2 H), 6.87 (t, J = 9.0 Hz, 2 H),
5.36–5.24 (m, 1 H), 5.11 (t, J = 16.0 Hz, 1 H), 4.92 (s, 1 H), 3.76 (s,
3 H), 3.59 (d, J = 14.7 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 166.4, 163.0, 137.9, 128.8,
128.3, 127.4, 75.5, 67.0, 63.6, 56.9, 47.4, 45.6, 41.5, 31.7, 28.0,
25.3, 23.9.
13C NMR (75 MHz, DMSO-d6): d = 165.7, 165.4, 164.9, 158.7,
139.0, 137.8, 136.6, 135.4, 129.5, 129.0, 128.3, 128.1, 127.7, 127.2,
126.8, 126.3, 114.0, 63.1, 62.4, 58.0, 55.0, 46.6.
LC–MS: m/z = 329 [M + H+].
LC–MS: m/z = 387 [M + H+].
Anal. Calcd for C19H24N2O3: C, 69.49; H, 7.37; N, 8.53. Found: C,
69.53; H, 7.42; N, 8.62.
Anal. Calcd for C24H22N2O3: C, 74.59; H, 5.74; N, 7.25. Found: C,
74.68; H, 5.81; N, 7.30.
( )-(3S,9aR)-3-(4-Isopropylphenyl)-2-(tetrahydrofuran-2-yl-
methyl)tetrahydro-2H-pyrido[1,2-a]pyrazine-1,4(3H,6H)-di-
one (3f)
( )-(3R,6S)-3-Isopropyl-1-(4-methoxybenzyl)-6-phenylpipera-
zine-2,5-dione (3j)
Yield: 41%; white solid; mp 140–143 °C.
Yield: 41%; white solid; mp 159 °C (dec.).
1H NMR (300 MHz, DMSO-d6): d = 7.78 (s, 1 H), 7.46–7.25 (m, 5
H), 7.10 and 6.88 (ABq, J = 8.5 Hz, 4 H), 5.16 (d, J = 14.5 Hz, 1 H),
4.77 (s, 1 H), 4.07 (s, 1 H), 3.76 (s, 3 H), 3.52 (d, J = 14.7 Hz, 1 H),
2.48–2.40 (m, 1 H), 1.03 (d, J = 7.1 Hz, 3 H), 0.94 (d, J = 6.9 Hz, 3
H).
1H NMR (300 MHz, DMSO-d6): d = 7.31–7.14 (m, 4 H), 5.16 (d,
J = 21.5 Hz, 1 H), 4.41–4.29 (m, 1 H), 4.16–3.85 (m, 3 H), 3.81–
3.54 (m, 2 H), 2.94–2.85 (m, 1 H), 2.66–2.53 (m, 1 H), 2.44–2.29
(m, 1 H), 2.05–1.32 (m, 10 H), 1.22 (d, J = 6.9 Hz, 6 H).
13C NMR (75 MHz, DMSO-d6): d = 166.4, 165.5, 163.1, 148.5,
135.2, 127.0, 77.3, 75.6, 67.1, 63.8, 63.3, 56.7, 47.4, 45.5, 41.5,
33.0, 31.6, 28.4, 25.0, 23.7.
13C NMR (75 MHz, DMSO-d6): d = 166.1, 158.7, 136.5, 129.3,
128.9, 128.4, 128.0, 127.0, 114.0, 62.7, 58.4, 55.0, 46.2, 30.9, 18.0,
16.2.
LC–MS: m/z = 371 [M + H+].
LC–MS: m/z = 353 [M + H+].
Anal. Calcd for C22H30N2O3: C, 71.32; H, 8.16; N, 7.56. Found: C,
71.44; H, 8.26; N, 7.61.
Anal. Calcd for C21H24N2O3: C, 71.57; H, 6.86; N, 7.95. Found: C,
71.64; H, 6.96; N, 7.84.
( )-(3S,9aR)-3-(4-Isopropylphenyl)-2-(4-methoxybenzyl)tetra-
hydro-2H-pyrido[1,2-a]pyrazine-1,4(3H,6H)-dione (3g)
Yield: 43%; white solid; mp 173 °C (dec.).
( )-(3R,6S)-3-Isobutyl-1-(4-methoxybenzyl)-6-phenylpipera-
zine-2,5-dione (3k)
Yield: 45%; white solid; mp 139–141 °C.
1H NMR (300 MHz, DMSO-d6): d = 7.26 and 7.18 (ABq, J = 8.0
Hz, 4 H), 7.08 and 6.87 (ABq, J = 8.3 Hz, 4 H), 5.05 (d, J = 14.8 Hz,
1 H), 4.71 (s, 1 H), 4.36–4.24 (m, 2 H), 3.73 (s, 3 H), 3.40 (d,
J = 14.8 Hz, 1 H), 2.89 (sept, J = 6.9 Hz, 1 H), 2.59–2.52 (m, 1 H),
2.36 (d, J = 12.2 Hz, 1 H), 1.87 (d, J = 12.2 Hz, 1 H), 1.70–1.25 (m,
4 H), 1.20 (d, J = 6.9 Hz, 6 H).
13C NMR (75 MHz, DMSO-d6): d = 165.7, 162.8, 158.6, 148.6,
134.8, 129.2, 127.8, 127.3, 126.7, 114.0, 62.0, 56.8, 55.0, 45.8,
41.6, 33.1, 31.5, 23.9, 23.7, 23.4.
1H NMR (300 MHz, DMSO-d6): d = 7.95 (s, 1 H), 7.45–7.24 (m, 5
H), 7.10 and 6.87 (ABq, J = 8.4 Hz, 4 H), 5.13 (d, J = 14.7 Hz, 1 H),
4.79 (s, 1 H), 4.11 (t, J = 5.2 Hz, 1 H), 3.76 (s, 3 H), 3.60 (d, J = 14.7
Hz, 1 H), 1.99–1.79 (m, 2 H), 1.74–1.61 (m, 1 H), 0.89 (d, J = 5.8
Hz, 6 H).
13C NMR (75 MHz, DMSO-d6): d = 167.1, 165.6, 158.7, 136.1,
129.4, 128.9, 128.3, 128.0, 126.9, 114.0, 63.0, 55.0, 51.8, 46.4,
23.6, 22.8, 22.2.
LC–MS: m/z = 367 [M + H+].
LC–MS: m/z = 407 [M + H+].
Anal. Calcd for C22H26N2O3: C, 72.11; H, 7.15; N, 7.64. Found: C,
72.10; H, 7.19; N, 7.70.
Anal. Calcd for C25H30N2O3: C, 73.86; H, 7.44; N, 6.89. Found: C,
73.77; H, 7.50; N, 6.78.
( )-(3R,6S)-3-sec-Butyl-1-(4-methoxybenzyl)-6-phenylpipera-
zine-2,5-dione (3l)
Yield: 39%; white solid; mp 149–152 °C.
( )-(3S,6R)-1-(4-Methoxybenzyl)-3-methyl-6-phenylpipera-
zine-2,5-dione (3h)
Yield: 45%; beige solid; mp 127–129 °C.
1H NMR (300 MHz, DMSO-d6): d = 8.09 and 8.17 (2 × br s, 1 H),
7.47–7.26 (m, 5 H), 7.10 (dd, J = 8.7 Hz, J = 2.0 Hz, 2 H), 6.89 (d,
J = 8.2 Hz, 2 H), 5.17 (d, J = 14.3 Hz, 1 H), 4.72 (d, J = 3.8 Hz, 1
H), 4.18 (d, J = 11.1 Hz, 1 H), 3.74 (s, 3 H), 3.41 (d, J = 14.8 Hz, 1
H), 2.30–2.06 (m, 1 H), 1.50–1.25 (m, 2 H), 1.01–0.76 (m, 6 H).
1H NMR (300 MHz, DMSO-d6): d = 8.38 (s, 1 H), 7.47–7.25 (m, 5
H), 7.13 and 6.89 (ABq, J = 8.2 Hz, 4 H), 5.14 (d, J = 14.3 Hz, 1 H),
4.79 (s, 1 H), 4.27–4.15 (m, 1 H), 3.74 (s, 3 H), 3.59 (d, J = 14.4 Hz,
1 H), 1.37 (d, J = 6.6 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 167.6, 165.7, 158.7, 135.7,
129.3, 128.9, 128.3, 128.1, 126.6, 114.0, 63.4, 55.0, 48.8, 46.6,
17.9.
13C NMR (75 MHz, DMSO-d6): d = 166.3, 166.0, 165.9, 158.7,
136.6, 129.4, 128.9, 128.4, 128.0, 127.0, 114.0, 62.7, 58.0, 56.9,
55.0, 46.2, 37.8, 24.6, 24.0, 14.8, 13.6, 12.0.
LC–MS: m/z = 325 [M + H+].
LC–MS: m/z = 367 [M + H+].
Anal. Calcd for C19H20N2O3: C, 70.35; H, 6.21; N, 8.64. Found: C,
70.40; H, 6.23; N, 8.57.
Anal. Calcd for C22H26N2O3: C, 72.11; H, 7.15; N, 7.64. Found: C,
72.20; H, 7.24; N, 7.59.
Synthesis 2010, No. 15, 2527–2532 © Thieme Stuttgart · New York

2532
M. Nikulnikov et al.
PAPER
(4) For selected reports on convertible isocyanides, see:
Acknowledgment
(a) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc.
1995, 117, 7842. (b) Rikimaru, K.; Yanagisawa, A.; Kan,
T.; Fukuyama, T. Synlett 2004, 41. (c) Isaacson, J.; Gilley,
C. B.; Kobayashi, Y. J. Org. Chem. 2007, 72, 3913.
(d) Blackburn, C.; Guan, B. Tetrahedron Lett. 2000, 41,
1495.
This research was supported by the Federal Agency for Science and
Innovation
02.740.11.0092). We are grateful to Dr. Pavel Kislitsyn of CDRI for
his help in measuring the optical rotations, and Dr. Yan Ivanenkov
of CDRI for performing Molecular Mechanics calculations.
(Russian
Federation
Government
Contract
(5) Hulme, C.; Chapetta, S.; Dietrich, J. Tetrahedron Lett. 2009,
50, 4054.
References
(6) The 1H NMR spectra (300 MHz, DMSO-d6) of the crude
products 2 displayed strongly broadened signals when run at
ambient temperature, most likely, due to restricted amide
bond rotation. On running some of the spectra at increased
temperature (314 K), it was possible to confirm that products
2 were obtained as equal mixtures of diastereomers, as
would be expected from the non-diastereoselective course of
the Ugi reaction.
(1) For a comprehensive review, see: (a) Akritopoulou-Zanze,
I.; Djuric, S. W. Heterocycles 2007, 73, 125. (b) Wu, J.;
Yong, J.; Dai, W.-M. Synlett 2009, 1162. (c) Hulme, C.;
Chapetta, S.; Griffith, C.; Lee, Y.-S.; Dietrich, J.
Tetrahedron Lett. 2009, 50, 1939. (d) Erb, W.; Neuville, L.;
Zhu, J. J. Org. Chem. 2009, 74, 3109. (e) Basso, A.; Banfi,
L.; Guanti, G.; Riva, R. Org. Biomol. Chem. 2009, 7, 253.
(2) Nikulnikov, M.; Tsirulnikov, S.; Kysil, V.; Ivachtchenko,
A.; Krasavin, M. Synlett 2009, 260.
(7) Sigma-Aldrich chemistry products catalogue:
www.sigmaaldrich.com.
(8) Molecular mechanics (MM2) calculations were performed
using ChemBio3D Ultra 11.0, CambridgeSoft.
(3) Nikulnikov, M.; Krasavin, M. Poster Abstract 18, 4th
International Conference on Multi-Component Reactions
and Related Chemistry, Ekaterinburg, 24–28 May, 2009.
Synthesis 2010, No. 15, 2527–2532 © Thieme Stuttgart · New York