Two novel diastereoselective three-component reactions of alkenes or 3,4-dihydro-(2H)-pyran with urea/thiourea-aldehyde mixtures: [4 + 2] cycloaddition vs Biginelli-type reaction

Article abstract of DOI:10.1021/ol060874b

Two novel diastereoselective three-component reactions of alkenes or 3,4-dihydro-(2H)-pyran with urea/thiourea-aldehyde mixtures are described.

Full text of DOI:10.1021/ol060874b

ORGANIC
LETTERS
2006
Vol. 8, No. 12
2599-2602
Two Novel Diastereoselective
Three-Component Reactions of Alkenes
or 3,4-Dihydro-(2H)-pyran with
Urea/Thiourea−Aldehyde Mixtures:
[4 2] Cycloaddition vs Biginelli-Type
+
Reaction
Yulin Zhu,† Shenlin Huang,† Jieping Wan,† Lei Yan,† Yuanjiang Pan,*,† and
Anxin Wu*,‡
Department of Chemistry, Zhejiang UniVersity, Hangzhou 310027, P.R. China, and
Key Laboratory of Pesticide and Chemical Biology of Ministry of Education,
Central China Normal UniVersity, Wuhan 430079, P.R. China
panyuanjiang@zju.edu.cn; chwuax@mail.ccnu.edu.cn
Received April 11, 2006
ABSTRACT
Two novel diastereoselective three-component reactions of alkenes or 3,4-dihydro-(2H)-pyran with urea/thiourea−aldehyde mixtures are described.
Numerous classical multicomponent reactions1 (MCRs)
employ the in situ condensation of aldehydes, amines, or
amides to give reactive imine or enamine derivatives, which
subsequently react with other different components in pro-
cesses such as the Mannich reaction,2 the Strecker reaction,3
and the Biginelli reaction4 to name but a few. It is also well-
known that N-acylimines are valuable partners in cycload-
dition reactions,5 acting as dienophiles6 or dienes7 in [4 +
2] cycloadditions.
It was found that the intermediary N-acyliminium ions
undergo a hetero [4 + 2] cycloaddition with alkynes. In light
of this, we considered that the analogous mechanism might
be utilized for alkenes instead of alkynes (Scheme 1). Herein,
we report two three-component reactions of alkenes or 3,4-
dihydro-(2H)-pyran with urea/thiourea-aldehyde mixtures.
(1) (a) Do¨mling, A.; Ugi, I.Angew. Chem., Int. Ed. 2000, 39, 3168. (b)
Kappe, C. O. Acc. Chem. Res. 2000, 33, 879. (c) Simon, C.; Constantieux,
T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 4957. (d) Bienayme´, H.; Hulme,
C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321. (e) Jacobi von
Wangelin, A.; Neumann, H.; Go¨rdes, D.; Klaus, S.; Stru¨bing, D.; Beller,
M.Chem. Eur. J. 2003, 9, 4286.
(2) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K.Angew. Chem., Int.
Ed. 2004, 43, 1566.(b) Gommermann, N.; Koradin, C.; Polborn, K.;
Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 5763.(c) Notz, W.; Tanaka,
F.; Watanabe, S.; Chowdari, N. S.; Turner, J. M.; Thayumanaran, R.; Barbas,
C. F. J. Org. Chem. 2003, 68, 9624.
We recently disclosed a novel three-component, one-
pot reaction8 involving alkynes, urea or thiourea, and alde-
hydes.
† Zhejiang University.
‡ Central China Normal University.
10.1021/ol060874b CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/19/2006

Scheme 1
Table 1. Multicomponent Reaction of Aryl Alkenes, Urea or
Thioureas, and Aryl Aldehydes for the Synthesis of 4a-na,b
entry
R1
X
R2
product yieldc (%)
1
2
3
4
5
6
7
8
C6H5
C6H5
4-CH3C6H4
4-CH3OC6H4
2-FC6H4
4-CH3C6H4
4-CH3C6H4
2-FC6H4
S
S
S
S
S
O
S
S
4-CH3C6H4
C6H5
C6H5
C6H5
C6H5
C6H5
4-CH3C6H4
4-CH3C6H4
4a
4b
4c
4d
4e
4f
91
79
92
88
85
78
88
87
4g
4h
a While we tried as many reactions with urea as thiourea, only
benzaldehyde proceeded smoothly with urea and styrene to give the
corresponding product. More details about this kind of reactions may be
described on the basis of further study. b Reaction conditions: 1 (5 mmol),
2 (5 mmol), and 3 (6 mmol), TMSCl (5 mmol), DMF/CH3CN (1.5 mL/3
mL), reflux, 10 h. c Isolated yields.
We initiated our studies by subjecting benzaldehyde (1a),
styrene (2a), and thiourea to TMSCl in CH3CN/DMF (2/1)
at reflux temperature, which afforded 2-amino-4-phenyl-6-
p-tolyl-5,6-dihydro-4H-1,3-thiazin-3-ium chloride 4a in 91%
yield (Table 1, entry 1). Only the cis diastereomer (with
respect to R1 and R2) was observed as determined by NOE
experiments and X-ray crystallography (Figure 1).
Because of its great facility and low cost, we proceeded
to examine the scope of this transformation with various
aromatic aldehydes, aromatic alkenes, and urea or thiourea
(Table 1). All products were isolated as single cis diaster-
eomers. The regioselectivity of the [4 + 2] cycloaddition of
both the N-acyliminium ion and N-thioacyliminium processes
with an alkene is well documented.5,7 Encouraged by the
results obtained from the reaction with alkenes, we turned
our attention to 3,4-dihydro-(2H)-pyran 5. To our surprise,
3,4-dihydro-(2H)-pyran 5 did not follow the same rules as
alkenes. However, the reaction of 5 with urea and 4-meth-
ylbenzaldehyde proceeded smoothly to deliver 4-p-tolyl-
hexahydro-1H-pyrano[2,3-d]pyrimidin-2(8aH)-one 6a in 86%
yield (Table 2, entry 1). Although three chiral centers are
created, only one diastereomer is formed in a highly selective
way (Figure 2).9
To test this type of MCR, the scope of the reaction
was investigated with various aromatic aldehydes and urea
or thiourea under the same protocol. All reactions proceeded
smoothly to provide corresponding hexahydro-4-phenyl-1H-
pyrano[2,3-d]pyrimidin-2(8aH)-ones or hexahydro-4-phenyl-
1H-pyrano[2,3-d]pyrimidine-2(8aH)-thiones (Table 2).
Scheme 2 shows a possible mechanism for this Biginelli-
type reaction, which is based on the mechanism suggested
by Overman.10 The formation of 6 is considered to be a
stepwise cyclocondensation of 3,4-dihydro-(2H)-pyran 5 with
the N-acyliminium ion intermediate 10 generated from an
aldehyde and urea. The stepwise nature of this cyclocon-
densation contrasts with the first hetero Diels-Alder reaction
of N-acyliminium ion intermediate 10. As shown in Scheme
(3) (a) Li, J.; Jiang, W. Y.; Han, K. L.; He, G. Z.; Li, C.J. Org. Chem.
2003, 68, 8786. (b) Davis, F. A.; Prasad, K. R.; Carroll, P. J. J. Org. Chem.
2002, 67, 7802. (c) Yet, L. Angew. Chem., Int. Ed. 2001, 40, 875. (d)
Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2000,
39, 1279.
(4) (a) Shimokawa, J.; Shirai, K.; Tanatani, A.; Hashimoto, Y.; Nagasawa,
K.Angew. Chem., Int. Ed. 2004, 43, 1559. (b) Yadav, J. S.; Reddy, B. V.
S.; Sridar, P.; Reddy, J. S. S.; Nagaiah, K.; Lingaiah, N.; Saiprasad, P. S.
Eur. J. Org. Chem. 2004, 3, 552. (c) Cohen, F.; Collins, S. K.; Overman,
L. E. Org. Lett. 2003, 5, 4485. (d) Dondoni, A.; Massi, A.; Minghini, E.;
Sabbatini, S.; Bertolasi, V. J. Org. Chem. 2003, 68, 6172.
(5) Weinreb, S. M.; Scola, P. M.Chem. ReV. 1989, 89, 1525 and
references therein.
(6) (a) Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology
in Organic Synthesis; Academic Press: San Diego, 1987; Chapter 2. (b)
Weinreb, S. M. Acc. Chem. Res. 1985, 18, 16. (c) Kametani, T.; Hibino, S.
AdV. Heterocycl. Chem. 1987, 42, 245.
(7) (a) Schmidt, R. R. Synthesis 1972, 333. (b) Murai, T.; Sano,
H.; Kawai, H.; Aso, H.; Shibahara, F. J. Org. Chem. 2005, 70, 8148. (c)
Gizecki, P.; Dhal, R.; Toupet, L.; Dujardin, G. Org. Lett. 2000, 2, 585. (d)
Katritzky, A. R.; Ghiviriga, I.; Chen, K.; Tymoshenko, D. O.; Abdel-Fattah,
A. A. A. J. Chem. Soc., Perkin Trans. 2 2001, 530. (e) Gizecki, P.;
Dhal, R.; Poulard, C.; Gosselin, P.; Dujardin, G. J. Org. Chem. 2003, 68,
4338.
Figure 1. X-ray crystal structure of compound 4a.
(8) Huang, S.; Pan, Y.; Zhu, Y.; Wu, A.Org. Lett. 2005, 7, 3797.
2600
Org. Lett., Vol. 8, No. 12, 2006

Scheme 2. Proposed Mechanism of the Cyclocondensation
Table 2. Multicomponent Reaction of 3,4-Dihydro-(2H)-pyran,
Urea or Thioureas, and Aryl Aldehydes for the Synthesis of
6a-na
entry
R1
X
product
yieldb (%)
1
2
3
4
5
6
7
8
9
4-CH3C6H4
C6H5
4-CH3OC6H4
4-ClC6H4
C6H5
O
O
O
O
S
S
S
S
S
S
S
6a
6b
6c
6d
6e
6f
6g
6h
6i
86
89
79
92
86
89
83
80
84
90
87
2-FC6H4
4-CH3C6H4
4-CH3OC6H4
4-FC6H4
2-CH3OC6H4
3-NO2C6H4
10
11
6j
6k
a Reaction conditions: 1 (5 mmol), 5 (5 mmol), and 3 (6 mmol),
TMSCl (5 mmol), DMF/CH3CN (1.5 mL/3 mL), reflux, 10 h. b Isolated
yields.
2, initial addition of 5 to 10 in an exo fashion would lead to
one limiting reactive conformer of the intermediate 2,3,4,5-
tetrahydropyrylium 8. On the other hand, endo addition of
5 to 10 would lead to reactive intermediate 2,3,4,5-tetrahy-
dropyrylium conformer 9. The severe steric interaction
between the tetrahydropyrylium cycle and urea group
disfavors the reaction via 9, and the observed product 6 arises
from the trapping of intermediate 8.
In conclusion, we have developed two new multicompo-
nent reactions; the first reaction constitutes a facile syn-
thesis of 2-amino-5,6-dihydro-4H-1,3-thiazin-3-ium chloride
salts11 or 2-amino-5,6-dihydro-4H-1,3-oxazin-3-ium chloride
salts,12 while the second one is a simple three-component
process leading to hexahydro-4-phenyl-1H-pyrano[2,3-d]py-
rimidin-2(8aH)-ones or hexahydro-4-phenyl-1H-pyrano[2,3-
d]pyrimidine-2(8aH)-thiones. Further determination of the
scope and limitations of this process is still under investiga-
tion.
(9) (a) Yan, L.; Zhu, Y.; Pan, Y. Acta Crystallogr. 2005, E61, o1049.
(b) Yan, L.; Zhu, Y.; Pan, Y. Acta Crystallogr. 2005, E61, o1228.
(10) Overman, L. E.; Wolfe, J. P. J. Org. Chem. 2001, 66, 3167.
(11) Several methods for the synthesis of 4H-5,6-dihydro-1,3-thiazine
derivatives: Nishio, T.; Konno, Y.; Ori, M.; Sakamoto, M. Eur. J. Org.
Chem. 2001, 3553 and references therein.
(12) Recent examples of 4H-5,6-dihydro-1,3-oxazine dirivatives as key
intermediates: (a) Liu, S.; Muller, J. F. K.; Neuburger, M.; Schaffner, S.;
Zehnder, M. HelV. Chim. Acta 2000, 83, 1256. (b) Kuznestsov, V. V.;
Brusilovskii, Y. E. Chem. Heterocycl. Commun. 2001, 37, 574. (c) Nakajima,
N.; Saito, M.; Kudo, M.; Ubukata, M. Tetrahedron 2002, 58, 3579. (d)
Gaulon, C.; Gizecki, P.; Dhal, R.; Dujardin, G. Synlett 2002, 952. (e)
Nakajima, N.; Isobe, T.; Irisa, S.; Ubukata, M. Heterocycles 2003, 59, 107.
(f) Palko, M.; Hetenyi, A.; Fueloep, F. J. Heterocycl. Chem. 2004, 41, 69.
(g) Tse, M. K.; Doebler, C.; Bhor, S.; Klawonn, M.; Maegerlein, H. H.;
Beller, M. Angew. Chem., Int. Ed. 2004, 43, 5255.
Figure 2. X-ray crystal structure of compounds 6a and 6j.
Org. Lett., Vol. 8, No. 12, 2006
2601

Acknowledgment. This work was supported by the
NSFC of China (20472073).
lographic information file (CIF) for 4a. This material is
available free of charge via the Internet at http://
pubs.acs.org.
Supporting Information Available: Experimental pro-
cedures and spectral data for all compounds and crystal-
OL060874B
2602
Org. Lett., Vol. 8, No. 12, 2006