Ugi four-component reaction with tandem deprotection, cyclization and pictet-spengler reaction: A concise route to N-fused polycyclic indoledi-ketopiperazine alkaloid analogues

Article abstract of DOI:10.1055/s-0033-1338707

Aza-fused polycyclic indolediketopiperazine alkaloids are of potential interest due to their broad range of biological activities. Traditionally, a number of methods have been used to generate N-fused polycyclic indolediketopiperazine skeletons, but the need to develop novel, concise methods with which to modify the substitution pattern continues. Herein, we describe the two-step formation of N-fused polycyclic indolediketopiperazine alkaloid analogues by the application of the Ugi four-component reaction with tandem deprotection, cyclization and Pictet-Spengler reaction. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1338707

LETTER
▌1291
lUettgeri Four-Component Reaction with Tandem Deprotection, Cyclization and
Pictet–Spengler Reaction: A Concise Route to N-Fused Polycyclic Indoledi-
ketopiperazine Alkaloid Analogues
Indolediketopiperazine Alkaloid Analogues
Vikas Tyagi, Shahnawaz Khan, Prem M. S. Chauhan*
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, 226 001, India
E-mail: premsc58@hotmail.com; E-mail: prem_chauhan_2000@yahoo.com
Received: 19.03.2013; Accepted after revision: 12.04.2013
vasodilator amauromine (5) and the insecticidal
Abstract: Aza-fused polycyclic indolediketopiperazine alkaloids
okaramine C (6) also possess the N-fused indolediketo-
are of potential interest due to their broad range of biological activ-
piperazine as a key structural motif.2
ities. Traditionally, a number of methods have been used to generate
N-fused polycyclic indolediketopiperazine skeletons, but the need
to develop novel, concise methods with which to modify the substi-
tution pattern continues. Herein, we describe the two-step formation
skeleton, novel, concise methods with which to modify
of N-fused polycyclic indolediketopiperazine alkaloid analogues by
the application of the Ugi four-component reaction with tandem de-
Although a number of methods have been developed to
generate the N-fused polycyclic indolediketopiperazine
the substitution pattern remain in strong demand.3
protection, cyclization and Pictet–Spengler reaction.
Over the past few decades, isocyanide-based multicompo-
nent reactions (IMCRs) followed by other synthetic trans-
formations have attracted considerable attention because
that approach can allow the construction of complex mol-
ecules in a small number of steps, usually from readily ob-
tainable starting materials.4 Recently, combination of the
isocyanide-based Ugi-MCR and the Pictet–Spengler reac-
tion has emerged as a promising strategy for the creation
of highly diverse natural-product-like compounds
(Scheme 1).5 We have also reported the synthesis of N-
fused polycyclic heterocycles through Ugi type MCR fol-
lowed by acid-catalyzed tandem de-tert-butylation and
Pictet–Spengler reaction (Scheme 1).6
Key words: alkaloids, Ugi reaction, tandem reactions, deprotec-
tion, cyclization, Pictet–Spengler reaction
Polycyclic indole alkaloids containing the aza-fused di-
ketopiperazine motif are highly significant in view of their
widespread biological activities and have therefore
attracted considerable attention.1 For example,
Fumitremorgine C (1) and Demethoxyfumitremorgine C
(2), both isolated from Aspergillus fumigates, show anti-
fungal activity and enhance the cytotoxicity of several an-
ticancer agents in vitro (Figure 1). Tadalafil (3) and its
analogue 4 exhibit antimalarial activity, and the potent
Me
O
N
O
O
H
N
N
H
H
H
N
H
N
H
O
H
N
O
O
N
H
N
H
N
MeO
H
2
O
1
O
3
N
O
H
O
HO
NH
N
H
H
O
N
H
N
H
H
N
N
N
O
O
H
N
NH
N
H
H
N
O
5
H
6
O
O
4
Figure 1 Representative N-fused indolediketopiperazine alkaloids
SYNLETT 2013, 24, 1291–1297
Advanced online publication: 08.05.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338707; Art ID: ST-2013-D0247-L
© Georg Thieme Verlag Stuttgart · New York

1292
V. Tyagi et al.
LETTER
EI Kaim et al.
O
CHO
NO2
MeO
MeO
COOH
NH2
8
N
N
O
9
+
MeO
NC
O
12
10
MeO
H2N
O2N
11
Domling et al.
OMe
X
O
+
N
OHC
COOH
+
n
NC
OMe
15
n
14
13
N
X = (CH2)n, n = 2, 3
X
O
16
Miranda et al.
R2
OMe
OMe
R1
H
O
NH2
Me
N
R2
18
17
N
+
NHBoc
HO
O
R3NC
19
HN
R3
O
O
21
R1
20
our recent approach
X
N
CHO
Ugi-type
MCR
acid-catalyzed tandem
debutylation–Pictet–Spengler
N
N
N
X
+
N
N
NH2
HN
25
23
22
CN
24
26
Scheme 1 Sequential Ugi and Pictet–Spengler reactions for the synthesis of N-fused polycyclic heterocycles
Based on our interest in the synthesis of biologically im- volves tandem deprotection, cyclization and Pictet–
portant heterocycles through IMCRs with other synthetic Spengler reaction. To the best of our knowledge, there is
transformations,7 we turned our attention towards the syn- no report available on this type of tandem cyclization se-
thesis of diverse N-fused polycyclic indolediketopipera- quence.
zine alkaloid analogues using the Ugi-MCR followed by
tandem deprotection, cyclization and Pictet–Spengler re-
actions. An interesting feature of this methodology in-
We envisaged that the product 31 (Scheme 2) might be
constructed by the Ugi four-component condensation of
R1
HN
R1
HN
O
COOH
Boc
O
N
O
COOEt
O
COOEt
N
N
H
NH
H2N
R1
Boc
N
N
H
30
27
N
O
+
H
31
N
O
NC
H
+
28
H
H
R2
29
R2
CHO
33
32
Scheme 2 Retrosynthetic analysis
Synlett 2013, 24, 1291–1297
© Georg Thieme Verlag Stuttgart · New York

LETTER
Indolediketopiperazine Alkaloid Analogues
1293
R1
HN
COOH
Boc
O
COOEt
O
N
N
H
COOEt
H2N
Ugi-MCR
27
NH
N
H
30
+
Boc
O
NC
N
H
R1
H
H
31
31a R1 = t-Bu 89%
31b R1 = Cy 84%
28
29
Scheme 3 Four-component Ugi reaction
N-Boc protected tryptophan 30, amine 27, aldehyde 29, 4), we selected Ugi intermediate 31a and 4-chlorobenzal-
and isocyanide 28. The Ugi product 31 can undergo tan- dehyde 32a as a model system. Initially, we applied our
dem deprotection/cyclization/Pictet–Spengler reactions previously optimized acidic conditions (10% TFA in DCE
with aldehydes 32 under the acidic conditions to generate at reflux) but, unfortunately, product 33a was only formed
N-fused polycyclic indolediketopiperazine alkaloid in low yield, with deprotected and cyclized product 34a
analogues.
being furnished in very good yield (Table 1, entry 4). In-
terestingly, when these acidic conditions were applied un-
der the microwave irradiation, product 33a was formed in
61% yield (Table 1, entry 6). The product 33a was formed
as a mixture of two diastereomers, the trans-diastereomer
being strongly preferred over the cis-diastereomer, and
the major product was separated by column chromatogra-
phy on silica gel. The stereochemical assignment of these
diastereomers was achieved on the basis of NOE experi-
ments (see the Supporting Information).8
To test the feasibility of the proposed methodology to-
wards the synthesis of N-fused polycyclic indolediketopi-
perazine alkaloid analogues, Ugi-4CR of N-Boc protected
L-tryptophan (30), formaldehyde 29, and glycine ester 27
with two different isocyanides 28 was considered
(Scheme 3). Initially, the Ugi reaction was carried out at
room temperature, and it was found that the reaction re-
quired 24 hours to reach the completion, however, the re-
action was complete within 30–35 minutes when
performed at 60 °C using microwave irradiation; the We next explored the ability of Ugi intermediates 31a and
products 31a and 31b were furnished in 89 and 84% 31b to undergo tandem deprotection, cyclization and
yields, respectively (Scheme 3).
Pictet–Spengler reaction with a variety of aldehydes
32a–j (Table 2).9 The reaction proceeded smoothly with
electron-rich benzaldehydes (Table 2, entry 1–9), whereas
To optimize the acidic conditions for the tandem deprot-
ection, cyclization and Pictet–Spengler reaction (Scheme
Table 1 Optimization of Acidic Conditions for the Tandem Cyclization Reactiona
HN
HN
HN
O
O
O
N
O
O
N
O
CHO
N
COOEt
+
N
HN
acidic conditions
O
NH
Boc
O
+
N
H
N
H
N
Cl
34a
H
31a
32a
Cl
33a
Entry
Solvent
TFA (%)
Yield 33a (%)
Yield 34a (%)
1
CH2Cl2
CH2Cl2
DCE
5
10
5
trace
18
39
2
43
3
trace
23
46
4
DCE
10
10
10
51
5
THF
14
32
6b
DCE
61
trace
a Reaction conditions: 31a (1 equiv), 32a (1.2 equiv).
b Reaction conditions: microwave irradiation, 90 °C, 15 min.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1291–1297

1294
V. Tyagi et al.
LETTER
R1
HN
R1
O
HN
O
N
O
CHO
O
N
N
tandem cyclization
COOEt
O
+
NH
Boc
R2
N
H
32
N
H
R2
31
33
Scheme 4 Tandem cyclization reaction using Ugi-MCR synthesized precursors
the use of electron-withdrawing benzaldehydes did not af- tion and Pictet–Spengler reaction. This synthetic strategy
ford the desired Pictet–Spengler products and instead led has the advantages of fewer reaction steps, good yields,
only to deprotection and cyclization to afford products and operational simplicity, ultimately leading to N-fused
34a and 34b (Table 2, entries 10–12).
polycyclic indolediketopiperazine alkaloid analogues
with diverse substitution patterns, with the trans-isomers
being formed with high stereoselectivity. Biological
screenings of the synthesized compounds are in progress
in our lab and will be reported in due course.
In summary, we have described a two-step protocol for
the synthesis of N-fused polycyclic indolediketopipera-
zine alkaloid analogues by application of the Ugi four-
component reaction with tandem deprotection, cycliza-
Table 2 Scope of the Two-Step Reaction Protocola
Entry
1
Ugi intermediate 31
Aldehyde 32
Cyclized product 33
Yield (%)b
61
HN
O
Cl
CHO
HN
O
O
N
H
N
O
32a
COOEt
N
NH
H
O
Boc
N
H
N
H
31a
31a
Cl
33a
2
54
CHO
HN
O
O
H
N
32b
N
H
O
N
H
33b
3
31a
47
HN
O
Cl
CHO
O
H
N
Cl
32c
N
H
O
N
H
Cl
Cl
33c
Synlett 2013, 24, 1291–1297
© Georg Thieme Verlag Stuttgart · New York

LETTER
Indolediketopiperazine Alkaloid Analogues
1295
Table 2 Scope of the Two-Step Reaction Protocola (continued)
Entry
4
Ugi intermediate 31
Aldehyde 32
Cyclized product 33
Yield (%)b
39
31a
HN
F
CHO
CHO
CHO
O
H
H
H
N
N
N
O
33d
N
N
N
H
H
H
O
F
N
H
33d
5
31a
42
HN
O
Cl
O
F
33e
O
N
H
F
Cl
33e
6
31a
57
HN
O
O
33f
O
N
H
33f
7
31a
60
CHO
HN
O
O
H
N
33g
N
H
O
N
H
33g
8
32c
43
HN
O
HN
O
O
N
H
N
O
COOEt
N
NH
H
O
Boc
N
H
N
H
Cl
31b
Cl
33h
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1291–1297

1296
V. Tyagi et al.
LETTER
Table 2 Scope of the Two-Step Reaction Protocola (continued)
Entry
9
Ugi intermediate 31
Aldehyde 32
Cyclized product 33
Yield (%)b
47
31b
MeO
CHO
HN
O
O
H
N
32h
N
H
O
N
H
OMe
33i
10
31b
69
O2N
CHO
HN
O
O
32i
N
H
N
H
O
N
H
34a
11
31a
32i
67
HN
O
O
N
H
N
H
O
N
H
34b
34a
12
31a
65
NC
CHO
32j
a Reaction conditions: Ugi intermediate 31 (1 equiv), aldehyde 32 (1.2 equiv), 90 °C, microwave, 15 min.
b Yield of separated trans-isomer.
Eskeland, R.; Roemer, E.; Imhof, A. Nat. Chem. Biol. 2005,
1, 143. (e) Zhang, Y.-X.; Chen, Y.; Guo, X.-N.; Zhang, X.-
W.; Zhao, W.-M.; Zhong, L.; Zhou, J.; Xi, Y.; Lin, L.-P.;
Ding, J. Anti-Cancer Drugs 2005, 16, 515. (f) Kato, N.;
Suzuki, H.; Takagi, H.; Asami, Y.; Kakeya, H.; Uramoto,
M.; Usui, T.; Takahashi, S.; Sugimoto, Y.; Osada, H.
ChemBioChem 2009, 10, 920. (g) Barrow, J. C.; Musza, L.
L.; Cooper, R. Bioorg. Med. Chem. Lett. 1995, 5, 377.
(h) Popp, J. L.; Musza, L. L.; Barrow, C. J.; Rudewicz, P. J.;
Houck, D. R. J. Antibiot. 1994, 47, 411. (i) Oleynek, J. J.;
Sedlock, D. M.; Barrow, C. J.; Appell, K. C.; Casiano, F.;
Haycock, D.; Ward, S. J.; Kaplita, P.; Gillum, A. M. J.
Antibiot. 1994, 47, 399. (j) Sedlock, D. M.; Barrow, C. J.;
Brownell, J. E.; Hong, A.; Gillum, A. M.; Houck, P. R. J.
Antibiot. 1994, 47, 391. (k) Shigematsu, N.; Hayashi, K.;
Kayakiri, N.; Takase, S.; Hashimoto, M.; Tanaka, H. J. Org.
Chem. 1993, 58, 170. (l) Vaught, J. L. Life Sci. 1988, 43,
1419. (m) Pernow, B. Pharmacol. Rev. 1983, 35, 85.
Acknowledgment
V.T. and S.K. are grateful to the University Grant Commission,
New Delhi, for financial support in the form of SRF. The authors
also acknowledge SAIF-CDRI for providing spectroscopic and
analytical data. The CDRI communication number is 8434.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
References and Notes
(1) (a) Movassaghi, M.; Schmidt, M. A.; Ashenhurst, J. A.
Angew. Chem. Int. Ed. 2008, 47, 1485. (b) Springer, J. P.;
Dchi, G. B.; Kobbe, B.; Demain, A. L.; Clardy, J.
Tetrahedron Lett. 1977, 2403. (c) Barrow, C. J.; Cai, P.;
Snyder, J. K.; Sedlock, D. M.; Sun, H. H.; Cooper, R. J. Org.
Chem. 1993, 58, 6016. (d) Greiner, D.; Bonaldi, T.;
Synlett 2013, 24, 1291–1297
© Georg Thieme Verlag Stuttgart · New York

LETTER
Indolediketopiperazine Alkaloid Analogues
1297
(2) (a) Kodato, S.; Nakagawa, M.; Hongu, M.; Kawate, T.;
Tohru, H. Tetrahedron 1988, 44, 359. (b) Limbach, M.;
Surayakanta, D.; Janssen, A.; Es-Sayed, M.; Magull, J. M.;
de Meijere, A. Eur. J. Org. Chem. 2005, 610. (c) Daugan,
A.; Grondin, P.; Ruault, C.; Le Monnier de Gouville, A.-C.;
Coste, H.; Linget, J. M.; Kirilovsky, J.; Hyafil, F.;
(f) Cano-Herrera, M.-A.; Miranda, L. D. Chem. Commun.
2011, 47, 10770. (g) Liu, H.; William, S.; Herdtweck, E.;
Botros, S.; Dömling, A. Chem. Biol. Drug Des. 2012, 79,
470. (h) Lesma, G.; Cecchi, R.; Crippa, S.; Giovanelli, P.;
Meneghetti, F.; Musolino, M.; Sacchetti, A.; Silvani, A.
Org. Biomol. Chem. 2012, 10, 9004.
Labaudinière, R. J. Med. Chem. 2003, 46, 4533. (d) Beghyn,
T. B.; Charton, J.; Leroux, F.; Laconde, G.; Bourin, A.; Cos,
P.; Maes, L.; Deprez, B. J. Med. Chem. 2011, 54, 3222.
(e) Takase, S.; Iwami, M.; Ando, T.; Okamoto, M.; Yoshida,
K.; Horiai, H.; Kohsaka, M.; Aoki, H.; Imanaka, H. J.
Antibiot. 1984, 37, 1320. (f) Hayashi, H.; Fujiwara, T.;
Murao, S.; Arai, M. Agric. Biol. Chem. 1991, 55, 3143.
(3) (a) Schkeryantz, J. M.; Woo, J. C. G.; Siliphaivanh, P.;
Depew, K. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1999,
121, 11964. (b) Coste, A.; Toumi, M.; Wright, K.;
Razafimahaléo, V.; Couty, F.; Marrot, J.; Evano, G. W. Org.
Lett. 2008, 10, 3841. (c) Wang, H.; Usui, T.; Osada, H.;
Ganesan, A. J. Med. Chem. 2000, 43, 1577. (d) Zhao, L.;
May, J. P.; Huang, J.; Perrin, D. M. Org. Lett. 2012, 14, 90.
(4) (a) Ma, Z.; Xiang, Z.; Luo, T.; Lu, K.; Xu, Z.; Chen, J.;
Yang, Z. J. Comb. Chem. 2006, 8, 69. (b) Ilyin, A.; Kysil,
V.; Krasavin, M.; Kurashvili, I.; Ivachtchenko, A. V. J. Org.
Chem. 2006, 71, 9544. (c) Riva, R.; Banfi, L.; Basso, A.;
Cerulli, V.; Guanti, G.; Pani, M. J. Org. Chem. 2010, 15,
5134. (d) Guchhait, S. K.; Madaan, C. Org. Biomol. Chem.
2010, 8, 3631. (e) Erb, W.; Neuville, L.; Zhu, J. J. Org.
Chem. 2009, 74, 3109. (f) El Kaïm, L.; Gizzi, M.; Grimaud,
L. Org. Lett. 2008, 10, 3417. (g) Sunderhaus, J. D.;
(6) Tyagi, V.; Khan, S.; Bajpai, V.; Gauniyal, H. M.; Kumar, B.;
Chauhan, P. M. S. J. Org. Chem. 2012, 77, 1414.
(7) (a) Tyagi, V.; Khan, S.; Giri, A.; Gauniyal, H. M.; Sridhar,
B.; Chauhan, P. M. S. Org. Lett. 2012, 14, 3126. (b) Sharma,
M.; Pandey, S.; Chauhan, K.; Sharma, D.; Kumar, B.;
Chauhan, P. M. S. J. Org. Chem. 2012, 77, 929. (c) Porwal,
S.; Chauhan, S. S.; Chauhan, P. M. S.; Shakya, N.; Verma,
A.; Gupta, S. J. Med. Chem. 2009, 52, 5793. (d) Sharma, R.;
Pandey, A. K.; Chauhan, P. M. S. Synlett 2012, 23, 2209.
(e) Pandey, S.; Khan, S.; Singh, A.; Gauniyal, H. M.;
Kumar, B.; Chauhan, P. M. S. J. Org. Chem. 2012, 77,
10211. (f) Tyagi, V.; Khan, S.; Chauhan, P. M. S.
Tetrahedron Lett. 2013, 54, 1279.
(8) See the Supporting Information.
(9) Synthesis of Ugi Products 31a and 31b; General
Procedure: To a solution of N-Boc protected L-tryptophan
30 (1 mmol), glycine ester 27 (1 mmol), and
paraformaldehyde 29 (1.2 mmol) in methanol (3 mL) was
added isocyanide 28 (1 mmol) in a 10 mL reaction glass vial
containing a stirring bar. The vial was sealed tightly with a
Teflon cap and placed in a microwave cavity (33 W) for 30
min at a pre-selected temperature of 60 °C. After completion
of the reaction (indicated by TLC), the solvent was
evaporated under reduced pressure and the residue was
purified by flash column chromatography on silica gel
(hexane–EtOAc) to afford the corresponding products.
Synthesis of Cyclized Products 33a–i; General
Procedure: The Ugi-4CR products (1 mmol) were
dissolved in 10% TFA in DCE (3 mL) and the corresponding
aromatic aldehydes (1.5 mmol) were added in a 10 mL
reaction glass vial containing a stirring bar, the vial was
sealed tightly with a Teflon cap and placed in a microwave
cavity for 15 min at a pre-selected temperature of 90 °C. The
progress of the reaction was monitored by TLC. Upon
completion, the reaction mixture was evaporated and the
residue was neutralized with saturated NaHCO3, extracted
with EtOAc (20 mL) and the combined organic layer was
washed with water (10 mL) and dried over sodium sulfate.
EtOAc was removed under reduced pressure and the crude
material was purified by column chromatography (CHCl3–
MeOH) to afford the cyclized products 33a–i in 61–39%
yield.
Dockendorff, C.; Martin, S. F. Org. Lett. 2007, 9, 4223.
(h) El Kaïm, L.; Grimaud, L.; Wagschal, S. J. Org. Chem.
2010, 75, 5343. (i) Bonnaterre, F.; Bois-Choussy, M.; Zhu,
J. Org. Lett. 2006, 19, 4351. (j) Hulme, C.; Ma, L.; Romano,
J. J.; Morton, G.; Tang, S.-Y.; Cherrier, M.-P.; Choi, S.;
Salvino, J.; Labaudinière, R. Tetrahedron Lett. 2000, 41,
1889. (k) Gracias, V.; Moore, J. D.; Djuric, S. W.
Tetrahedron Lett. 2004, 45, 417. (l) Zhu, J. Eur. J. Org.
Chem. 2003, 1133. (m) El Kaïm, L.; Grimaud, L.; Pravin, P.
Org. Lett. 2012, 14, 476. (n) Zhu, D.; Xia, L.; Pan, L.; Li, S.;
Chen, R.; Mou, Y.; Chen, X. J. Org. Chem. 2012, 77, 1386.
(o) Kulsi, G.; Ghorai, A.; Chattopadhyay, P. Tetrahedron
Lett. 2012, 53, 3619. (p) Ramazani, A.; Rezaei, A. Org. Lett.
2010, 12, 2852. (q) Balalaie, S.; Bararjanian, M.;
Hosseinzadeh, S.; Rominger, F.; Bijanzadeh, H. R.; Wolf, E.
Tetrahedron 2011, 67, 7294. (r) Tsaloev, A.; Ilyin, A.;
Tkachenko, S.; Ivachtchenko, A.; Kravchenko, D.;
Krasavin, M. Tetrahedron Lett. 2011, 52, 800. (s) Welsch, S.
J.; Umkehrer, M.; Ross, G.; Kolb, J.; Burdack, C.;
Wessjohann, L. A. Tetrahedron Lett. 2011, 52, 6295.
(t) Santra, S.; Andreana, P. R. J. Org. Chem. 2011, 76, 2261.
(u) Sanudo, M.; García-Valverde, M.; Marcaccini, S.;
Torroba, T. Tetrahedron 2012, 68, 2621.
Spectroscopic Data for 33a: Yield: 61%; solid. 1H NMR
(300 MHz, CDCl3): δ = 8.14 (s, 1 H), 7.56 (d, J = 7.2 Hz,
1 H), 7.34–7.15 (m, 7 H), 7.05 (s, 1 H), 5.69 (s, 1 H), 4.55–
3.98 (m, 4 H), 3.74–3.51 (m, 2 H), 3.09 (t, J = 12.3 Hz, 1 H),
1.37 (s, 9 H); 13C NMR (75 MHz, CDCl3): δ = 166.5, 166.1,
162.2, 137.0, 136.7, 135.2, 130.4, 129.4, 126.5, 123.2,
120.5, 118.8, 111.5, 109.5, 52.8, 52.2, 51.7, 51.2, 50.4, 29.1,
27.8; HRMS (ESI): m/z [M + H]+ calcd for C26H28ClN4O3:
479.1850; found: 479.1842.
(5) (a) Wang, W.; Ollio, S.; Herdtweck, E.; Dömling, A. J. Org.
Chem. 2011, 76, 637. (b) Wang, W.; Herdtweck, E.;
Dömling, A. Chem. Commun. 2010, 46, 770. (c) Liu, H.;
Dömling, A. J. Org. Chem. 2009, 74, 6895. (d) Cao, H.; Liu,
H.; Dömling, A. Chem. Eur. J. 2010, 16, 12296. (e) El Kaïm,
L.; Gageat, M.; Gaultier, L.; Grimud, L. Synlett 2007, 500.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1291–1297