Microwave-assisted rapid and selective synthesis of cis- and trans-2,4,5-triarylimidazolines from aromatic aldehydes

Article abstract of DOI:10.1055/s-2003-39906

Microwave irradiation of a mixture of aromatic aldehydes and hexamethyldisilazane in the presence of a solid catalyst such as alumina afforded methanediamines which were efficiently converted to either cis- or trans-2,4,5-triarylimidazolines depending on the base used. A one-pot selective synthesis of cis- and transimidazolines from aromatic aldehydes was achieved under microwave irradiation.

Full text of DOI:10.1055/s-2003-39906

LETTER
1117
Microwave-Assisted Rapid and Selective Synthesis of cis- and trans-2,4,5-
Triarylimidazolines from Aromatic Aldehydes
M
icrowave-Assist
i
e
d
Ra
p
t
o
elective Syn
s
thesis of
c
is
-
a
ndtran
i
s
-2,4,5-Triary
U
limidazolinesfrom
c
Aromatic
h
A
ldehydes ida,a Hirofumi Tanikoshi,a Shuichi Nakamura,a Paidi Yella Reddy,b Takeshi Toru*a
a
Department of Applied Chemistry, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan
b
AISIN COSMOS R&D Co., Ltd., Kariya, Aichi 448-8650, Japan
Fax +81(52)7355217; E-mail: toru@ach.nitech.ac.jp
Received 4 April 2003
tive than silica gel, and a high yield of 2a was achieved on
addition of a small amount of alumina (entries 3 and 4).11
Bentonite and montmorillonite K-10 also afforded 2a but
in lower yields (entries 5 and 6).
Abstract: Microwave irradiation of a mixture of aromatic alde-
hydes and hexamethyldisilazane in the presence of a solid catalyst
such as alumina afforded methanediamines which were efficiently
converted to either cis- or trans-2,4,5-triarylimidazolines depend-
ing on the base used. A one-pot selective synthesis of cis- and trans-
imidazolines from aromatic aldehydes was achieved under micro-
wave irradiation.
(Me3Si)2NH (1.5 equiv)
solid catalyst
Ph
PhCHO
N
N
Key words: microwave, imidazoline, methanediamine, hexameth-
yldisilazane, solvent-free
microwave, 5 min
1a
Ph
Ph
2a
Ph
Diarylethylenediamines and their derivatives, which can
serve as important chiral ligands1 and biologically active
compounds,2 are obtainable from trans-2,4,5-triarylimi-
dazolines.3 trans-Triarylimidazolines are prepared by
isomerization of the corresponding cis isomers, which can
be obtained from aromatic aldehydes through N,N¢-
(Me3Si)2NH (1.5 equiv)
N
NH
Ph
conventional heating, 6 h
Ph
3a
Scheme 1
bis(arylmethylidene)arylmethanediamines.
Prolonged
Table 1 Reaction of Benzaldehyde 1a with HMDS under Micro-
heating is needed to form methanediamines from aromatic
aldehydes; for example, it takes over one week to prepare
wave Irradiationa
methanediamines with ammonia4 and several hours by Entry
Solid catalyst
–
Weight Ratiob
Yield of 2a (%)
heating aldehydes with hexamethyldisilazane (HMDS) in
1
0
0
79
94
89
26
45
the presence of a Lewis acid5 or without a Lewis acid un-
der solvent-free conditions.6 Recently, a one-pot synthesis
2
silica gel
alumina
alumina
bentonite
K-10
5.0
0.5
5.0
5.0
5.0
of triphenyl- and tris(2-pyridyl)imidazolines has been re-
3
ported in the reaction of aromatic aldehydes with HMDS
and LiBr in DMSO.7 Independently, we have found a one-
4
step synthesis of triarylimidazolines on treatment of aro-
matic aldehydes with HMDS without a solvent.8 Studying
5
this synthesis under microwave irradiation,9 we found that
6
the reaction was greatly accelerated. We now report a rap-
a The mixture was irradiated for 5 min.
id, convenient and selective synthesis of methanedi-
amines as well as cis- and trans-triarylimidazolines from
aromatic aldehydes with HMDS under microwave irradi-
ation.
b Weight ratio of the solid catalyst to 1a.
Thus, the above reaction under microwave irradiation did
not afford cis-imidazoline 3a but gave methanediamine
2a.12 This is in contrast with the results that cis-imidazol-
ines 3 are obtained directly from aldehydes by the conven-
tional heating.8 Methanediamines are known to cyclize to
imidazolines by the action of a base such as phenyllithi-
um,13 t-BuOK,14 or sodium alkoxides.3,7 We examined
microwave irradiation in the presence of bases. Methane-
diamine 2a was isolated by recrystallization of the crude
product obtained in the irradiation of aldehyde 1a,
HMDS, and alumina for 5 minutes. Indeed, irradiation
of 2a for 5 minutes with 1.0 equivalent of NaOMe in
methanol gave cis-imidazoline 3a in 55% yield (Table 2,
When a mixture of benzaldehyde 1a and HMDS was ir-
radiated with microwave, no reaction occurred (Table 1,
entry 1). The reaction proceeded to give N,N¢-bis(phenyl-
methylidene)phenylmethanediamine 2a on addition of
5.0-fold excess amount of silica gel10 to a mixture of 1a
and 1.5 equivalents of HMDS without using a solvent
(Scheme 1). The irradiation for 5 minutes afforded 2a in
79% yield (entry 2). Alumina was found to be more effec-
Synlett 2003, No. 8, Print: 24 06 2003.
Art Id.1437-2096,E;2003,0,08,1117,1120,ftx,en;U06103ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

1118
H. Uchida et al.
LETTER
entry 1). The reaction in the presence of 1.0 equivalent of alumina was irradiated for 5 minutes, when methanedi-
t-BuOK in t-BuOH gave cis-3a exclusively in 78% yield amine 2a was formed, and then, without isolation, was
after irradiation for 2 minutes (entry 2). The reaction with added 1.0 equivalent of DBN (the equivalency is based on
0.1 equivalents of t-BuOK gave the trans-imidazoline 2a assumed to be formed in 100% yield). When micro-
trans-3a predominantly in high yield (entry 3). When wave irradiation was continued for an additional 5 min-
the mixture was irradiated for 5 minutes with t-BuOK/t- utes, cis-imidazoline cis-3a was obtained in 85% yield
BuOH, trans-3a was obtained exclusively (entry 4).15 The (entry 1).16 Under these conditions, formation of trans-3a
reaction performed in the presence of DBN without a sol- was not observed although cyclization of 2a with DBN
vent afforded cis-3a in high yield (entry 5). DBU also af- gave a mixture of cis- and trans-3a (Table 2, entry 6).
forded cis-3a exclusively when the reaction was carried This is because the reaction starting with 1a was per-
out with 1.0 equivalent of DBU for 2 minutes (entry 8). formed in the presence of alumina even in the cyclization
Several reaction conditions using DBU were examined as step. Benzaldehydes having various substituents also gave
shown in Table 2, and trans-3a was found to be formed cis-imidazolines in high yields. It should be noted that
exclusively in high yield when the mixture was irradiated both p-anisaldehyde (1e) and p-dimethylaminobenzalde-
in the presence of 10.0 equivalents of DBU for 5 minutes hyde (1f) yielded cis-imidazolines cis-3e and cis-3f in
(entry 12).
high yields, respectively (entries 5 and 6), since the con-
ventional thermal reaction of 1e with HMDS affords cis-
3e only on addition of chlorotrimethylsilane and that of 1f
does not afford 3f at all even with chlorotrimethylsilane.8
We next examined a one-pot synthesis of imidazolines 3
from aromatic aldehydes 1. Since irradiation of a mixture
of 1a, HMDS, alumina, and DBN afforded neither 2a nor
3a, we decided to add a base after the formation of meth- We also studied a selective one-pot synthesis of trans-im-
anediamine 2a. The results are shown in Table 3. A mix- idazoline trans-3 from 1. Isomerization of cis-3 to trans-3
ture of 1a, 1.5 equivalents of HMDS and 50 wt% of depends on the base added for the cyclization as well as
on the irradiation time as shown in Table 4. As previously
shown in Table 3 (entry 1), after irradiation for 5 minutes,
Table 2 Selective Formation of cis-3a and trans-3a from Meth-
further irradiation with 1.0 equivalent of DBN gave cis-3a
anediamine 2a with Bases
exclusively. Prolonged irradiation with DBN also gave
Ph
Ph
Ph
only cis-3a (Table 4, entry 1). Although irradiation with
1.0 equivalent of DBU for 5 minutes gave cis-3a (entry 2),
use of an excess amount of DBU increased the formation
of trans-3a, but it still could not avoid the formation of
cis-3a (entries 3, 4, 5 and 6), these results being in contrast
to the exclusive formation of trans-3a from cis-3a
(Table 2, entry 12). The selective formation of trans-3a
was achieved by irradiation with 3.0 equivalents of t-
BuOK in t-BuOH, although the yields were moderate
(entries 8 and 9). From the rather lower yield of 3a
with t-BuOK/t-BuOH, it was assumed that 2a was
hardly removed from the alumina face in t-BuOH. In-
deed, t-BuOK/DMF improved the yield of trans-3a (entry
10). Finally, a mixed base, t-BuOK/DBU, was found to be
the most effective to give trans-3a (entry 11).17 Under
similar reaction conditions, aldehydes 1b,d,e gave the
corresponding trans-imidazolines trans-3b,d,e selec-
tively in good yields (entries 12–14).
base
N
NH
N
NH
N
N
and/or
microwave
Ph
Ph
Ph
cis-3a
Ph
Ph
trans-3a
Ph
2a
Entry Base
Equiv
Time
(min)
cis:trans Yield
(%)
1
2
MeONa/MeOH
t-BuOK/t-BuOH
t-BuOK/t-BuOH
t-BuOK/t-BuOH
DBN
1.0
1.0
0.1
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
10.0
5
2
>98:2
>98:2
25:75
2:>98
>98:2
50:50
39:61
>98:2
25:75
6:94
55
78
86
96
98
96
94
96
88
78
96
83
3
5
4
5
5
2
6
DBN
5
7
DBN
10
2
In summary, a rapid, solvent-free, and selective synthesis
of cis- and trans-2,4,5-triarylimidazolines was achieved
by microwave irradiation of a mixture of aromatic alde-
hydes and HMDS in the presence of alumina and subse-
quently by further irradiation in the addition of a base.
8
DBU
9
DBU
5
10
11
12
DBU
10
5
DBU
25:75
2:>98
DBU
5
Acknowledgment
This work was partly supported by a Grant-in-Aid for Scientific Re-
search on Priority Areas (A) ‘Exploitation of Multi-Element Cyclic
Molecules’ (No. 14044040) from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
Synlett 2003, No. 8, 1117–1120 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Microwave-Assisted Rapid and Selective Synthesis of cis- and trans-2,4,5-Triarylimidazolines
1119
Table 3 Reactions of Aromatic Aldehydes 1a–h with DBN under Microwave Irradiation
Ar
Ar
(Me3Si)2NH (1.5 equiv)
alumina
base (1.0 equiv)
microwave
N
NH
Ar
ArCHO
N
N
microwave
step A
Ar
Ar
Ar
step B
1a–h
2a–h
3a–h
Entry Ar
Aldehyde
Base
Irradiation time
step A (min)
Product
Yield (%)
step B (min)
5
1
1a
1b
1c
1d
1e
1f
DBN
DBN
DBU
DBU
DBU
DBU
DBU
DBU
5
10
10
10
10
10
5
3a
3b
3c
3d
3e
3f
85
83
83
82
86
82
70
59
2
3
1
Cl
3
Br
4
5
Me
5
6
7
8
10
10
5
MeO
(Me)2N
1g
1h
3g
3h
O
S
5
5
(3) (a) Saigo, K.; Kubota, N.; Takebayashi, S.; Hasegawa, M.
Bull. Chem. Soc. Jpn. 1986, 59, 931. (b) Corey, E. J.;
Kühnle, F. N. M. Tetrahedron Lett. 1997, 38, 8631.
(4) (a) Laurent, M. A. Annals 1837, 21, 130. (b) Kamal, A.;
Ahmad, A.; Qureshi, A. A. Tetrahedron 1963, 19, 869.
(5) (a) Nishiyama, K.; Saito, M.; Oba, M. Bull. Chem. Soc. Jpn.
1988, 61, 609. (b) Grigor’ev, S. V.; Voronkov, M. G.;
Mirskov, R. G.; Rakhlin, V. I. Russ. J. Gen. Chem. (Engl.
Transl.) 2001, 71, 149.
(6) Reddy, P. Y.; Shimizu, M.; Higashi, K.; Shimizu, T.; Toru,
T. Arkivoc 2001, 8, 111.
(7) Mistryukov, E. A. Mendeleev Commun. 2001, 29.
(8) Uchida H.; Shimizu, T.; Reddy, P. Y.; Nakamura, S.; Toru,
T. Synthesis 2003, in press.
(9) (a) Caddick, S. Tetrahedron 1995, 38, 10403. (b) Loupy, A.
Microwave in Organic Synthesis; Wiley: Weinheim, 2002.
(10) For reviews of microwave-assisted reactions with solid
catalysts, see (a) Verma, R. S. Green Chemistry 1999, 1, 43.
(b) Loupy, A. Microwave in Organic Synthesis; Wiley:
Weinheim, 2002, Chap. 10, 345–378.
(11) Basic, acidic, and neutral alumina showed similar results.
(12) Irradiation in the presence of silica gel for 10 min gave 3a in
44% yield together with 2a and other unidentified products,
whereas formation of 3a was not observed in the irradiation
with alumina for 10 min.
References
(1) See for example: (a) Corey, E. J.; Huang, H. C. Tetrahedron
Lett. 1989, 30, 5235. (b) Corey, E. J.; Imwinkelried, R.;
Pikul, S.; Xing, Y. B. J. Am. Chem. Soc. 1989, 111, 5493.
(c) Corey, E. J.; Yu, C. M.; Kim, S. S. J. Am. Chem. Soc.
1989, 111, 5495. (d) Corey, E. J.; DaSilva, J. P.; Virgil, S.;
Yuen, P. W.; Conneell, R. D. J. Am. Chem. Soc. 1989, 111,
9243. (e) Corey, E. J.; Yu, C. M.; Lee, D.-H. J. Am. Chem.
Soc. 1990, 112, 878. (f) Zhang, W.; Loebatch, J.; Wilson, S.
R.; Jacobsen, E. N. J. Am. Chem. Soc. 1990, 112, 2801.
(g) Corey, E. J.; Kim, S. S. J. Am. Chem. Soc. 1990, 112,
4976. (h) Zhang, W.; Jacobsen, E. N. J. Org. Chem. 1991,
56, 2296. (i) Corey, E. J.; Imai, N.; Pikul, S. Tetrahedron
Lett. 1991, 32, 7517. (j) Corey, E. J.; Sarshar, S.; Bordner, J.
J. Am. Chem. Soc. 1992, 114, 7938. (k) Corey, E. J.;
Sarshar, S.; Lee, D.-H. J. Am. Chem. Soc. 1994, 116, 12089.
(l) Corey, E. J.; Letavic, M. A. J. Am. Chem. Soc. 1995, 117,
9616. (m) Corey, E. J.; Sarshar, S.; Azimioara, M. D.;
Newbold, R. C.; Noe, M. C. J. Am. Chem. Soc. 1996, 118,
7851. (n) Evans, D. A.; Nelson, S. G. J. Am. Chem. Soc.
1997, 119, 6452.
(2) (a) Greenhill, J. V.; Lue, P. Prog. Med. Chem. 1993, 30,
203. (b) Bousquet, P.; Feldman, J. Drugs 1999, 58, 799.
(c) Gilman, A. G.; Goodman, L. S. In The Pharmacological
Basis of Therapeutics, 10th ed.; Macmillan and Co.: New
York, 2001, Chap. 10, 215–268.
(13) Hunter, D. H.; Sim, S. K. J. Am. Chem. Soc. 1969, 91, 6202.
(14) (a) Hunter, D. H.; Sim, S. K. Can. J. Chem. 1972, 50, 669.
(b) Hunter, D. H.; Sim, S. K. Can. J. Chem. 1972, 50, 678.
Synlett 2003, No. 8, 1117–1120 ISSN 1234-567-89 © Thieme Stuttgart · New York

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LETTER
Table 4 One-pot Preparation of trans-Triarylimidazolines trans-3 from Aromatic Aldehydes 1
Ar
Ar
(Me3Si)2NH (1.5 eq.)
alumina
base
N
NH
Ar
ArCHO
N
N
microwave, 5 min
microwave
Ar
Ar
Ar
1a,b,d,e
2a,b,d,e
trans-3a,b,d,e
Entry
1
Aldehyde
1a
Base
Equiv
1.0
Time (min)
Product
3a
cis:trans
>98:2
>98:2
80:20
70:30
37:63
33:67
>98:2
2:>98
2:>98
2:>98
2:>98
2:>98
2:>98
2:>98
Yield (%)
DBN
DBU
DBU
DBU
DBU
DBU
10
5
87
84
86
85
86
57
45
57
69
71
81
68
78
63
2
1a
1.0
3a
3
1a
1.0
10
5
3a
4
1a
5.0
3a
5
1a
5.0
10
5
3a
6
1a
20.0
3a
7
1a
t-BuOK/t-BuOH
t-BuOK/t-BuOH
t-BuOK/t-BuOH
t-BuOK/DMF
t-BuOK/DBU
t-BuOK/DBU
t-BuOK/DBU
t-BuOK/DBU
0.9/4.3
3.0/14.4
3.0/14.4
3.0/12.3
1.0/1.0
1.0/1.0
1.0/1.0
2.0/2.0
5
3a
8
1a
5
3a
9
1a
10
5
3a
10
11
12
13
14
1a
3a
1a
5
3a
1ba
1da
1ea
5
3b
3d
3e
5
10
a The mixture was first irradiated for 10 min to form methanediamines.
(15) Irradiation of cis-3a with 1.0 equiv of t-BuOK/t-BuOH for 5
min gave trans-3a quantitatively.
(16) Typical Procedure for Preparation of cis-2,4,5-
Triphenylimidazoline (cis-3a) from 1a.
was filtered and washed with CH2Cl2. The obtained organic
solution was concentrated under vacuum to leave a residue,
which was purified by silica gel column chromatography
(hexane/EtOAc 9:1) to give 164 mg (85%) of cis-3a.
(17) Typical Procedure for Preparation of trans-2,4,5-
Triphenylimidazoline (trans-3a) from 1a.
A mixture of benzaldehyde 1a (209 mg, 1.97 mmol), HMDS
(620 mL, 480 mg, 2.95 mmol), and basic alumina (100 mg,
Wako Pure Chemical Industries Ltd., column
chromatography grade, 200 mesh, pH 9.0–11.0) was
charged in a test tube equipped with a cooler. The mixture
was irradiated under argon atmosphere for 5 min in a
microwave oven (500 W, 2450 MHz). Then, DBU (100 mL,
105 mg, 0.69 mmol) was added and the mixture was
irradiated for an additional 5 min. After cooling, alumina
A mixture of 1a (209 mg, 1.97 mmol), HMDS (620 mL, 480
mg, 2.95 mmol) and, basic alumina (100 mg) was irradiated
for 5 min, and then, t-BuOK (77 mg, 0.69 mmol) and DBU
(100 mL, 105 mg 0.69 mmol) were added to the mixture
which was further irradiated for an additional 5 min. Work-
up and purification as described above gave 159 mg (81%)
of trans-3a.
Synlett 2003, No. 8, 1117–1120 ISSN 1234-567-89 © Thieme Stuttgart · New York