Preparation and diels-alder chemistry of 4-vinylimidazoles

Article abstract of DOI:10.1021/jo0626008

(Chemical Equation Presented) Various 4-vinylimidazole derivatives have been prepared from the corresponding 4-iodoimidazoles or from urocanic acid. Several methods for the elaboration of these vinylimidazoles and their Diels-Alder reactions are reported. All of the vinylimidazoles prepared in the course of this study react with N-phenylmaleimide quite readily with mild thermal activation providing a single cycloadduct, in most cases the initial, nonaromatic adduct. With more electron rich substrates, there is a tendency for these initial cycloadducts to undergo aromatization, ene reaction, and oxidation although this can be circumvented to a large extent by the choice of reaction conditions. Limited reactions were observed with other dienophiles, providing the expected cycloadducts in most cases, although an abnormal adduct was obtained in one case with dimethyl acetylene dicarboxylate. These substrates also participate in regioselective Diels-Alder reactions with monoactivated dienophiles, but require fairly forcing conditions, thus only providing the aromatized cycloadducts in modest yields. An investigation of substituent effects at the 2-position of the imidazole moiety was undertaken, in which electron-donating and weakly electron-withdrawing substituents are tolerated. In addition, several substrates with terminally substituted vinyl moieties have been investigated.

Full text of DOI:10.1021/jo0626008

Preparation and Diels-Alder Chemistry of 4-Vinylimidazoles
Carl J. Lovely,* Hongwang Du, Rasapalli Sivappa, Manojkumar R. Bhandari, Yong He, and
H. V. Rasika Dias*
Department of Chemistry and Biochemistry, P.O. Box 19065, The UniVersity of Texas at Arlington,
Arlington, Texas 76019
loVely@uta.edu; dias@uta.edu
ReceiVed December 18, 2006
Various 4-vinylimidazole derivatives have been prepared from the corresponding 4-iodoimidazoles or
from urocanic acid. Several methods for the elaboration of these vinylimidazoles and their Diels-Alder
reactions are reported. All of the vinylimidazoles prepared in the course of this study react with
N-phenylmaleimide quite readily with mild thermal activation providing a single cycloadduct, in most
cases the initial, nonaromatic adduct. With more electron rich substrates, there is a tendency for these
initial cycloadducts to undergo aromatization, ene reaction, and oxidation although this can be circumvented
to a large extent by the choice of reaction conditions. Limited reactions were observed with other
dienophiles, providing the expected cycloadducts in most cases, although an abnormal adduct was obtained
in one case with dimethyl acetylene dicarboxylate. These substrates also participate in regioselective
Diels-Alder reactions with monoactivated dienophiles, but require fairly forcing conditions, thus only
providing the aromatized cycloadducts in modest yields. An investigation of substituent effects at the
2-position of the imidazole moiety was undertaken, in which electron-donating and weakly electron-
withdrawing substituents are tolerated. In addition, several substrates with terminally substituted vinyl
moieties have been investigated.
Introduction
noimidazoles can function as 2π-components in inverse electron
demand DA reactions (both inter- and intramolecular variants
are known), providing expedient approaches to imidazopyridine
derivatives.6,7 It has been reported by Yamazaki that imidazoles
can react with electron-deficient acetylenes in DA reactions
leading to the formation of pyrroles.8 In a rare example, Wuonala
and co-workers have reported one example of an intramolecular
DA reaction of an imidazole in which it acts as a 4π-component,
although ultimately the imidazole moiety does not remain intact
in the product.9 More recently, Romo and co-workers have
reported several examples of DA reactions of vinylimidazol-
The Diels-Alder (DA) reaction continues to play a central
role in many natural product total syntheses and in the
construction of a large number of molecules of biological
interest.1,2 This reaction has been extensively investigated since
its discovery and a large number of variants are known,1 ranging
from the all-carbon version to a number of heteroatom-based
examples.3 Many common heterocycles participate in this
reaction, but unlike furan4 and pyrrole5 which react with various
dienophiles to provide the expected adducts, there are limited
examples of imidazoles participating in DA chemistry. Snyder
and co-workers have demonstrated that electron-rich 2-ami-
(6) (a) Neipp, C.; Ranslow, P. B.; Wan, Z.; Snyder, J. K. Tetrahedron
Lett. 1997, 38, 7491. (b) Wan, Z.; Snyder, J. K. Tetrahedron Lett. 1997,
38, 7495. (c) Wan, Z.-K.; Woo, G. H. C.; Snyder, J. K. Tetrahedron 2001,
57, 5497. (d) Lahue, B. R.; Wan, Z.-K.; Snyder, J. K. J. Org. Chem. 2003,
68, 4345. (e) Lahue, B. R.; Lo, S.-M.; Wan, Z. K.; Woo, G. H. C.; Snyder,
J. K. J. Org. Chem. 2004, 69, 7171.
(1) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis,
G. Angew. Chem., Int. Ed. 2002, 41, 1668.
(2) Takao, K.; Munakata, R.; Tadano, K. Chem. ReV. 2005, 105, 4779.
(3) Heintzelman, G. R.; Meigh, I. R.; Mahajan, Y. R.; Weinreb, S. M.
Org. React. 2005, 65, 141.
(7) Xu, Y.-z.; Yakushijin, K.; Horne, D. A. J. Org. Chem. 1996, 61,
9569.
(4) Kappe, C. O.; Murphee, S. S.; Padwa, A. Tetrahedron 1997, 53,
14179.
(5) Lipshutz, B. H. Chem. ReV. 1986, 86, 795.
(8) Yamazaki, C.; Katayama, K.; Suzuki, K. J. Chem. Soc., Perkin Trans.
2 1990, 3085.
(9) Wuonola, M. A.; Smallheer, J. M. Tetrahedron Lett. 1992, 33, 5697.
10.1021/jo0626008 CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/11/2007
J. Org. Chem. 2007, 72, 3741-3749
3741

Lovely et al.
FIGURE 2. Proposed biosynthesis of Scheuer and Kinnel (7 + 8 f
10) and Romo’s modification (7 f 9 + 8 f 10).
which might be expected to be a better dienophile than 7.10c
Subsequent rearrangement of the DA adduct 10, presumably
triggered by a chloroperoxidase, leads to ring contraction and
formation of the spiro fusion of the imidazole and the cyclo-
pentane ring, and assembly of the stereochemically and func-
tional group rich cyclopentyl E-ring. Although there was no
experimental basis for this biosynthetic proposal, it suggested
a strategically appealing cycloaddition-rearrangement approach
to the congested cyclopentane ring found in 4 and other related
marine natural products, konbu’acidin (3),17 styloguanidine
(4),14,18 axinellamine A (5),19,20 and massadine (6) depicted in
Figure 1.21 However, if this general approach were to be viable,
it required establishing whether vinylimidazoles would partici-
pate in DA chemistry in a general sense, and further, it
necessitated the development of reliable synthetic procedures
for the assembly and functionalization of vinylimidazoles. When
we initiated this research program only two reports,22,23 contain-
ing a total of three examples, existed in the literature describing
the DA chemistry of vinylimidazoles as 4π-components. These
reports were of very limited scope and did not provide any
indication of stereochemical or regiochemical outcome of this
type of reaction. Furthermore, in the most closely related work
to that envisioned, Walters and Lee describe the reaction of
two 5-vinylimidazoles with N-phenylmaleimide (NPM).22 Al-
though both reactions proceeded, they were moderately efficient
(∼40%) and provide only the aromatized adduct, rather than
the initial adduct, which was required as a substrate for
investigation of “biomimetic” rearrangement (10 f 2, Figure
2). A more recent report indicated that the primary adduct could
be obtained, but this example employed the highly reactive
N-phenyl-1,3,4-triazoline-2,5-dione (PTAD) as dienophile.23 It
FIGURE 1. Oroidin and biogenetically derived alkaloids.
2-ones in their studies toward several oroidin-derived alkaloids.10
On the basis of this general paucity of examples of imidazoles
participating in DA chemistry, the significance of the imidazolyl
moiety in medicinal chemistry11 and its presence in several
classes of natural products (e.g., Figure 1),12 there appeared to
be a significant opportunity to develop this area of synthetic
chemistry.
Our own interest in the DA chemistry of imidazoles was
stimulated by a report on the isolation of the oroidin-derived
marine alkaloid (1a-c),13 palau’amine (2) by Scheuer and
Kinnel, in which they propose a biosynthesis of the natural
product involving a DA reaction of a vinylimidazole derivative
(Figure 2, 7 + 8 f 10).14-16 Quite recently, Romo and co-
workers have suggested that the DA substrate may in fact be
iminium ion 9 resulting from scission of the N9-C10 bond,
(10) (a) Dilley, A. S.; Romo, D. Org. Lett. 2001, 3, 1535. (b) Dransfield,
P. J.; Wang, S.; Dilley, A. S.; Romo, D. Org. Lett. 2005, 7, 1679. (c)
Dransfield, P. J.; Dilley, A. S.; Wang, S.; Romo, D. Tetrahedron 2006, 62,
5223. (d) Wang, S.; Dilley, A. S.; Poullennec, K. G.; Romo, D. Tetrahedron
2006, 62, 7155.
(11) De Luca, L. Curr. Med. Chem. 2006, 13, 1.
(12) Jin, Z. Nat. Prod. Rep 2006, 23, 464.
(13) Hoffmann, H.; Lindel, T. Synthesis 2003, 1753.
(14) (a) Kinnel, R. B.; Gehrken, H. P.; Scheuer, P. J. J. Am. Chem. Soc.
1993, 115, 3376. (b) Kinnel, R.; Gehrken, H.-P.; Swali, R.; Skoropowski,
G.; Scheuer, P. J. J. Org. Chem. 1998, 63, 3281.
(15) (a) McAlpine, I. J.; Armstrong, R. W. J. Org. Chem. 1996, 61, 5674.
(b) Overman, L. E.; Rogers, B. N.; Tellew, J. E.; Trenkle, W. C. J. Am.
Chem. Soc. 1997, 119, 7159. (c) Belanger, G.; Hong, F.-T.; Overman, L.
E.; Rogers, B. N.; Tellew, J. E.; Trenkle, W. C. J. Org. Chem. 2002, 67,
7880. (d) Katz, J. D.; Overman, L. E. Tetrahedron 2004, 60, 9559. (e)
Koenig, S. G.; Miller, S. M.; Leonard, K. A.; Lowe, R. S.; Chen, B. C.;
Austin, D. J. Org. Lett. 2003, 5, 2203. (f) Garrido-Hernandez, H.; Nakadai,
M.; Vimolratana, M.; Li, Q.; Doundoulakis, T.; Harran, P. G. Angew. Chem.,
Int. Ed. 2005, 44, 765. (g) Tan, X.; Chen, C. Angew. Chem., Int. Ed. 2006,
45, 4345. (h) Nakadai, M.; Harran, P. G. Tetrahedron Lett. 2006, 47, 3933.
For a review see: Jacquot, D. E. N.; Lindel, T. Curr. Org. Chem. 2005, 9,
1551.
(17) Kobayashi, J.; Suzuki, M.; Tsuda, M. Tetrahedron 1997, 53, 15681.
(18) Kato, T.; Shizuri, Y.; Izumida, H.; Yokoyama, A.; Endo, Y.
Tetrahedron Lett. 1995, 36, 2133.
(19) Urban, S.; de Almeida Leone, P.; Carroll, A. R.; Fechner, G. A.;
Smith, J.; Hooper, J. N. A.; Quinn, R. J. J. Org. Chem. 1999, 64, 731.
(20) Starr, J. T.; Koch, G.; Carreira, E. M. J. Am. Chem. Soc. 2000,
112, 8793.
(21) Nishimura, S.; Matsunaga, S.; Shibazaki, M.; Suzuki, K.; Furihata,
K.; van Soest, R. W. M.; Fusetani, N. Org. Lett. 2003, 5, 2255.
(22) Walters, M. A.; Lee, M. D. Tetrahedron Lett. 1994, 35, 8307.
(23) Deghati, P. Y. F.; Wanner, M. J.; Koomen, G.-J. Tetrahedron Lett.
1998, 39, 4561.
(16) Al Mourabit, A.; Potier, P. Eur. J. Org. Chem. 2001, 237.
3742 J. Org. Chem., Vol. 72, No. 10, 2007

Preparation of 4-Vinylimidazoles
FIGURE 4. Synthetic approach to 4-vinylimidazoles.
the known 4-vinylimidazole 16 in good yield.28 We were
delighted to find that when this substrate was reacted with NPM
in benzene at reflux two cycloadducts were formed and could
be isolated by column chromatography in 63% and 8% yield,
1
respectively. Analysis of the H NMR data indicated that the
products were the required initial adduct 17 (major), as a single
diastereomer, and the corresponding aromatic (minor) derivative
18. A survey of various solvents indicated that the initial adduct
was favored in lower boiling solvents, and indeed was the only
isolated product in dichloromethane and chloroform. Notably,
in the higher boiling solvents significant or complete decom-
position occurred; presumably this is due to loss of the trityl
group. Although encouraged by these preliminary experiments,
the N-trityl protecting group was not viewed as being optimal
for our long-term goals in total synthesis; therefore we evaluated
other N-substituents on the efficiency of the DA reaction.
FIGURE 3. Comparison of 4- and 5-vinylimidazoles.
has also been reported that 4-vinylimidazoles can function as
dienophiles in the DA reaction, although this was a very limited
study.24,25 After our initial reports, Ohta described the dimer-
ization reactions of several 5-vinylimidazoles, which were
moderately efficient and were employed in an approach to
ageliferin-type molecules.26 Quite recently, Lindel and co-
workers have reported some intermolecular reactions of oroidin
derivatives with NPM.25 Herein, we describe in full our
investigation of the synthesis and intermolecular DA chemistry
of 4-vinylimidazoles.27
Although the literature reports with 5-vinylimidazoles 5-11
provided encouraging precedent for the proposed first step in
an approach to palau’amine (2), the inability to obtain the initial
cycloadduct (enamine, 5-12) even with the reactive all-carbon
dienophile NPM was of some concern (Figure 3).22,23 However,
on the basis of our analysis of the products from the Diels-
Alder reaction, it appeared that the isomeric 4-vinylimidazole
4-11 might provide a more realistic opportunity to access the
initial adducts 4-12. The justification for this relatively simple
modification lay in the observation that the diene was cross-
conjugated and thus the initial cycloadducts 4-12 would be
conjugated and therefore might be expected to be more stable,
potentially less likely to rearomatize, and possibly react under
milder reaction conditions thereby preventing aromatization.
To establish the general viability of the DA chemistry with
4-vinylimidazoles, the known 1-trityl-4-vinylimidazole (16) was
prepared, although not via the reported Wittig route.28 Imidazole
was polyiodinated by treatment with a solution of iodine in
aqueous KI under basic conditions, and the resulting mixture
of di- and triiodoimidazole 14 was treated with an aqueous
ethanolic solution of Na2SO3 to provide 4(5)-iodoimidazole.29
Reaction with trityl chloride provides the corresponding pro-
tected 4-iodoimidazole 15,30 which was subjected to a Stille
cross-coupling reaction with tributylvinylstannane, producing
To address the influence of the N-protecting group, an
efficient approach to 4-vinylimidazoles needed to be identified
that ultimately would permit the greatest amount of flexibility
in terms of incorporating a number of different substituents on
nitrogen (protecting groups), at C2 (particularly for the introduc-
tion of an amine or amino surrogate), and on the vinyl moiety.
On the basis of this set of prerequisites, the general approach
outlined in Figure 4 evolved in which the fully substituted
derivative 19 would be prepared from the parent substrate 20
by C2-functionalization.31 Vinylimidazole 20 would be as-
sembled via an appropriate cross-coupling reaction from the
corresponding 4-haloimidazole,32 which in turn would be derived
from the halogenation and protection of imidazole.
N-Protecting Group. The first issue that required attention
was the efficient preparation of the protected 4-iodoimidazole
derivatives. While the introduction of the bulky trityl group
could be achieved directly from the 4(5)-iodoimidazole (Scheme
1), this approach was not anticipated as being generally
applicable for the preparation of other derivatives. While this
was not true for the synthesis of the known tosyl derivative
21a (Scheme 2), other derivatives provided mixtures of 4- and
5-iodoimidazoles. For example, 4(5)-iodoimidazole provided a
2:1 mixture, albeit separable, of the corresponding 4- and
5-iodoimidazoles, 21e and 24e (Scheme 2).33 To circumvent
this problem, two approaches to the selective syntheses of the
4-iodo derivatives were developed. The first involved the
preparation of the N-substituted 4,5-diiodo derivatives 26b-f
from 25,34 which were then selectively deiodinated in the
5-position by treatment with EtMgBr, followed by protonation
of the thus formed Grignard to afford the corresponding
4-iodoimidazoles 21b-f (Scheme 3).34,35 An alternative ap-
proach was developed later that involved isomerization of the
(24) Kosaka, K.; Maruyama, K.; Nakamura, H.; Ikeda, M. J. Heterocycl.
Chem. 1991, 28, 1941.
(25) Poverlein, C.; Breckle, G.; Lindel, T. Org. Lett. 2006, 8, 819.
(26) (a) Kawasaki, I.; Sakaguchi, N.; Fukushima, N.; Fujioka, N.;
Nikaido, F.; Yamashita, M.; Ohta, S. Tetrahedron Lett. 2002, 43, 4377. (b)
Kawasaki, I.; Sakaguchi, N.; Khadeer, A.; Yamashita, M.; Ohta, S.
Tetrahedron 2006, 62, 10182.
(27) (a) Lovely, C. J.; Du, H.; Dias, H. V. R. Org. Lett. 2001, 3, 1319.
(b) Lovely, C. J.; Du, H.; Dias, H. V. R. Heterocycles 2003, 60, 1. (c)
Lovely, C. J.; Du, H.; He, Y.; Dias, H. V. R. Org. Lett. 2004, 6, 735. For
intramolecular variants see: (d) He, Y.; Chen, Y.; Wu, H.; Lovely, C. J.
Org. Lett. 2003, 5, 3623. For a review of our efforts see: (e) He, Y.; Du,
H.; Sivappa, R.; Lovely, C. J. Synlett 2006, 965.
(31) Kirk, K. L. J. Org. Chem. 1978, 43, 4381.
(32) Schnu¨rch, M.; Flasik, R.; Khan, A. F.; Spina, M.; Mihovilovic, M.
D.; Stanetty, P. Eur. J. Org. Chem. 2006, 3283.
(28) Kokosa, J. M.; Szafasz, R. A.; Tagupa, E. J. Org. Chem. 1983, 48,
3605.
(29) Naidu, M. S. R.; Bensusan, H. B. J. Org. Chem. 1968, 33, 1307.
(30) Kirk, K. L. J. Heterocycl. Chem. 1985, 57, 57.
(33) Pilarski, B. Liebigs Ann. Chem. 1983, 1078.
(34) El Borai, M. M.; A. H.; Anwar, M.; Abdel Hay, F. I. Pol. J. Chem.
1981, 55, 1659.
(35) Lipshutz, B. H.; Hagen, W. Tetrahedron Lett. 1992, 33, 5865.
J. Org. Chem, Vol. 72, No. 10, 2007 3743

Lovely et al.
SCHEME 1
SCHEME 2
SCHEME 3
TABLE 1. Solvent Dependence on Isolated Product Yield
solvent
enaminec
17/%
imidazolec
18/%
entry
(reaction time/h)a
1
2
3
4
5
6
xylene (1)
toluene (3)
benzene (12)
benzene (30)b
chloroform (24)
dichloromethane
0
52
63
60
84
52
0
8
8
3
0
0
a A solution containing 1.0 equiv of 16 and 2.5 equiv of NPM in the
indicated solvent (3 mL) was heated at reflux for the indicated time. b 1.3
equiv of NPM was employed. c These are isolated yields of chromatographi-
cally purified products.
TABLE 2. Yields in Protection and Deiodination
PG
26/%
21/%
27/%
Ts
a
b
c
d
e
f
92
52
79
76
90
30
MOM
SO2NMe2
SEM
Bn
89
62
91
90
93
90
54
80
93
87
initially formed mixture of 4- and 5-iodo derivatives,36 although
the approach described in Scheme 3 is more convenient for
large-scale preparations. With the 4-iodoimidazoles in hand, it
was found that they participate smoothly in the Stille cross-
coupling reaction with vinyl(tributyl)stannane to provide the
corresponding vinylimidazoles 27a-f in moderate to excellent
yield.37 The Me- and MOM-derivatives, 27b and 27f, were
somewhat water soluble, leading to loss of material during the
aqueous workups employed.
These vinylimidazoles 27a-f were subjected to the DA
reaction with NPM in either CH2Cl2 or PhH, and in general
terms, the outcomes can be divided into two groups. Substrates
possessing an electron-withdrawing group on nitrogen 27a-d
provide a single cycloadduct, the initial adduct 29a-d, in
generally good isolated yield (Table 3, Scheme 4). As far as
can be determined, a single stereoisomer is formed which, based
on an X-ray crystal structure (Figure S1 in the Supporting
Information) of the Ts-protected derivative 29a, derives from
an endo transition state (28, Scheme 4). NOESY experiments
on the remaining derivatives, as well as the broadly similar 1H
NMR spectra, suggested that the other cycloadducts shared a
common stereochemical framework.
Me
and others including the ene product 31e38 and the bis DA
adduct 33e (see Figure S2 in the Supporting Information for an
X-ray structure). Purification of these products by chromatog-
raphy, particularly 29e, was difficult due to aromatization to
30e, even with pretreatment of silica gel with triethylamine
(Table 4, entry 1). However, it was found that allowing the
reaction to run for shorter periods limited the formation of these
other adducts, and so 29e could be readily purified by trituration
of the crude reaction mixture (Table 4, entry 2). The aromatized
product 30e can be obtained as the only product by the addition
of p-TsOH (Table 4, entry 3). If the reaction was conducted in
toluene and allowed to proceed until all of 29e was consumed
then 30e could be obtained (Table 4, entry 4), although it was
accompanied by the formation of 31e and 33e. The ene adduct
arises through addition of the excess NPM to the electron-rich
enamine, and reaction via this manifold then permits rearoma-
tization of the imidazole fragment. The bis DA adduct results
from oxidation of 29e to the cyclic vinylimidazole 32e, which
undergoes a second endo selective DA reaction with NPM. We
were curious as to the identity of the oxidant in this reaction;
our initial suspicion was that it was dissolved oxygen as addition
of BHT (Table 4, entry 6) prevented the oxidation (as did
degassing the solvent by bubbling nitrogen through the reaction
mixture prior to heating), although some 31e was still observed
in this case. Further evidence in support of this hypothesis arose
The more electron rich derivatives, the Bn- and Me-substrates
27e and 27f, provided a more diverse collection of adducts that
depended to a large extent on the precise reaction conditions
employed (Table 4). Initial experiments with the Bn-derivative
provided relatively complex mixtures of products including the
anticipated initial adduct 29e, the aromatized derivative 30e,
(36) He, Y.; Chen, Y.; Du, H.; Schmid, L. A.; Lovely, C. J. Tetrahedron
Lett. 2004, 45, 5529.
(37) (a) Cliff, M. D.; Pyne, S. G. J. Org. Chem. 1995, 60, 2378. (b)
Cliff, M. D.; Pyne, S. G. Tetrahedron 1996, 52, 13703. (c). Cliff, M. D.;
Pyne, S. G. J. Org. Chem. 1997, 62, 10238.
(38) The relative stereochemistry of this product is assumed by analogy
to the two related adducts 31f and 51 for which X-ray crystal structures
were determined.
3744 J. Org. Chem., Vol. 72, No. 10, 2007

Preparation of 4-Vinylimidazoles
SCHEME 4
SCHEME 5
TABLE 3. Yields for the Cycloaddition Reactionsa
entry
1
R
29
a
solventa
time/h
yield/%
Ts
PhH
27
48
2.5
17
9
48
5
6
80
89
70
86
93
94
85
78
2
3
4
MOM
b
c
PhH
PhH
PhH
SO2NMe2
SEM
d
a A solution containing 1.0 equiv of 27a-d and 2.5 equiv of NPM in
the indicated solvent (3 mL) was heated at reflux for the indicated time.
TABLE 4. Yields and Product Distributions of DA Reactions of
27e and 27f with NPMa
entry PG
solvent temp/°C time/h 29/% 30/% 31/% 33/%
1
2
3
4
5
6
7
8
9
Bn 27e CH2Cl2
50
50
50
90
90
90
90
50
50
50
90
14
10
80b
88
9
SCHEME 6
Bn 27e CH2Cl2
Bn 27e CH2Cl2
Bn 27e PhH
Bn 27e PhH
Bn 27e PhH
Bn 27e PhH
Me 27f CH2Cl2
Me 27f CH2Cl2
18c
21d
21e
21f
21g
80
18
75
74
32
39h
21
76
46
18
19
28
19
3.5
21
36
24
13
10 Me 27f CH2Cl2
11 Me 27f PhH
6d
15
The Me-derivative behaved somewhat similarly to 27e in that
mixtures of products were obtained containing the primary
adduct 29f, the aromatized adduct 30f, and the ene adduct 31f.
Unlike the Bn-derivative 29e, the initial adduct 29f was never
obtained free of the aromatic adduct 30f, and so typically the
reaction was allowed to proceed until 29f had been totally
consumed. Under these conditions a mixture of the aromatized
adduct and the ene adduct was obtained. The relative stereo-
chemistry of the ene adduct was determined via X-ray crystal-
lography (Figure S3 in the Supporting Information). Interest-
ingly, none of the analogous bis DA adduct (cf., 33e) was
obtained with this substrate. Conceivably, the smaller methyl
group renders rearomatization more facile than the benzyl-
protected analogue due to reduced steric crowding with the
pyrrolidine moiety derived from NPM and so conversion of 29f
to 30f and 31f occurs faster than oxidation to the corresponding
cyclic vinylimidazole.
As noted above, our initial synthesis of vinylimidazole 27e
proceeded via a nonselective synthesis of the corresponding
4-iodoimidazole 21e (Scheme 2). This approach provided
significant quantities of the isomeric 5-iodoimidazole 24e, which
allowed the preparation of the corresponding 5-vinylimidazole
37 (Scheme 6). We found this to be a less effective diene, as
on reaction with NPM in benzene for 24 h at 90 °C the
aromatized cycloadduct was formed in 28% yield, with the
material balance being largely unreacted starting materials. This
result is in accord with the observations of Walters and Lee
discussed above.22
a A solution containing 1.0 equiv of 27a-d and 2.5 equiv of NPM in
the indicated solvent (3 mL) was heated at reflux for the indicated time.
b Contaminated with a few percent of the aromatic product 30e. c 30 mol
% p-TsOH. d Reaction was allowed to run until all of 29e or 29f was
consumed to assist in product isolation. e The reaction was run in the
presence of catechol (30 mol %). f The reaction was run in the presence of
BHT (30 mol %). g Oxygen was bubbled through the reaction prior to
heating. h Overall yield from 27f after treatment of the “purified” enamine
with p-TsOH.
from an effort to increase the quantity of the bis adductsair
was bubbled through a mixture of 27e and NPM prior to
subjecting it to the DA reaction under otherwise analogous
conditions (Table 4, entry 7).39 Surprisingly (initially at least)
in addition to the aromatized adduct 30e and the bis DA product
33e, the major byproduct from a fairly complex mixture of
products was an ca. 1:1 mixture of epimeric 4-hydroxy
derivatives 34e and 35e (28%).40 In control reactions, both 29e
and 30e were subjected independently to the DA reaction
conditions in the presence of NPM. Only 29e led to the
formation of new products providing 30e (56%), the bis adduct
33e (16%), the ene product 31e (9%), and an epimeric mixture
of 34e and 35e (9%). Further, it was found that by heating a
solution of 29e in benzene until it was completely consumed
several products were isolated including the fully aromatized
adduct 36e and the cyclic vinylimidazole 32e, in addition to
34e/35e and 30e.
(39) (a) Noland, W. E.; Konkel, M. J.; Tempesta, M. S.; Cink, R. D.;
Powers, D. M.; Schlemper, E. O.; Barnes, C. L. J. Heterocycl. Chem. 1993,
38, 183. (b) Pfeuffer, L.; Pindur, U. HelV. Chem. Acta 1987, 70, 1419.
(40) We have independently prepared both of these alcohols from 29e,
see ref 26c
It is notable that these cycloaddition reactions take place under
exceedingly mild reaction conditions considering that the initial
step involves dearomatization of the imidazole, albeit with a
J. Org. Chem, Vol. 72, No. 10, 2007 3745

Lovely et al.
SCHEME 7
FIGURE 5. Possible regioisomeric cycloaddition transition states.
Information). However, this is a very sluggish reaction, requiring
a large excess of the dienophile (10 equiv total) and extended
reaction times (10 days). 27e also reacts with dimethyl acetylene
dicarboxylate (DMAD), however, via a manifold other than the
expected DA pathway. In this case, a bis addition adduct is
obtained, which results from a net [2 + 2 + 2] cycloaddition
similar to the reaction observed with simple alkyl imidazoles.45
In addition a [1,5]-hydride shift occurs to then provide the
observed adduct 41e. A cross-peak observed in a NOESY
experiment between the signals due to H5 and H9 is consistent
with the formation of this constitutional isomer. The DMAS-
protected derivative 27c reacts quite nicely with maleic anhy-
dride, providing the expected adduct 42c. This derivative also
reacts with methyl acrylate to afford 39c, but less efficiently
than the corresponding Bn-derivative 27e, which is apparently
due to thermal decomposition. Some reaction was observed with
acrylonitrile; however, there was substantial decomposition and
other side reactions that precluded complete purification and
rigorous characterization. A similar result was obtained with
the MOM-derivative 27b, again leading to the formation of a
single regioisomer 39b with methyl acrylate.
reactive dienophile. For comparative purposes, styrene deriva-
tives require substantially higher reaction temperatures and
longer reaction times.41 A second feature worth noting was the
general ability to isolate the initial cycloadduct 29a-e from
reaction with NPM with all but the methyl derivative 27f, which
was not reported with the corresponding 5-isomer, either in
published examples22 or by us (e.g., with 37). We suspect that
several factors contribute to this observation. First, as alluded
to in the introduction, the cycloadducts are conjugated, which
presumably confers additional stability on these products
compared to the 5-isomer. Second, on converting from the initial
adduct to the aromatized isomer (29a-e f 30a-e), there is an
overall flattening out of the structure, which increases, presum-
ably, the steric interaction between the imidazole N-substituent
and pyrrolidine moiety, representing a barrier to isomerization.
Third, in the cases of substrates with an electron-withdrawing
N-substituent, the imidazole nitrogen lone pair (N1) is tied up
(either through inductive or resonance effects), thereby prevent-
ing its ready incorporation in the aromatic sextet, and thus the
driving force for aromatization is attenuated.
Other Dienophiles. One of the earliest variables that we
investigated was the generality of the cycloaddition with respect
to dienophiles other than NPM. To assess this, we evaluated
three vinylimidazoles: the Bn-derivative 27e (electron rich),
MOM-derivative 27b (moderately electron poor), and DMAS-
derivative 27c (highly electron poor). It was anticipated that
this group of vinylimidazoles would offer a spectrum of
reactivities, which in turn would provide a framework for the
eventual use of this reaction in total synthesis endeavors vis a`
vis guiding the choice of protecting group.42 Only the successful
examples from these experiments are summarized in Scheme
7.43 The most broadly reactive substrate was the Bn-protected
derivative 27e as it undergoes Diels-Alder reactions with
several of these common dienophiles. With methyl acrylate and
acrylonitrile, the anticipated adducts 39e and 40e were obtained,
and each was isolated as a single regioisomer.44 In the case of
the acrylate derivative 39e, the regiochemistry was confirmed
through an X-ray analysis (Figure S4 in the Supporting
The regiochemistry observed in cycloadditions with nonsym-
metric dienophiles is similar to that observed with other vinyl
heterocycle derivatives in which the electron-withdrawing
substituent ends up proximal to the heteroaromatic system.46-48
This result can be understood in terms of a nonsynchronous
transition state in which bonding is more developed with the
vinyl moiety than the imidazole 43 (Figure 5), leading to the
development of positive character at the benzylic position, which
is stabilized by the electron-rich imidazole nucleus. Cycload-
dition via the alternate regiochemistry would require loss of
aromaticity, although the developing positive charge could be
stabilized by N1 through resonance.
C2-Substituents. One of the long-term goals for this
chemistry included its application in synthetic approaches to
several of the oriodin family of alkaloids (Figure 1). A cursory
glance at the members of this family reveals the presence of a
2-amino moiety in most examples (oxo in the remainder), and
thus to have utility in this application, the DA reaction must be
tolerant of a 2-amino group (or surrogate) on the substrates.
Therefore, we set out to explore the influence of 2-substituents
in general on the Diels-Alder reaction. While our manuscript
was in preparation, Lindel and co-workers reported some
examples of DA reactions with oroidin and some closely related
congeners which possess a 2-amino substituent.25 All of our
initial experiments were carried out in the Bn-series as a result
of the utility of this protecting group in the subsequent oxidative
(41) Wagner-Jauregg, T. Synthesis 1980, 779.
(42) Although part of the motivation for this component of the study
was to establish protecting group flexibility, we have subsequently
discovered that in the oxidative rearrangement chemistry, strongly electron-
withdrawing substituents are not tolerated, see ref 26c.
(43) Several common dienophiles, including methyl propriolate, dimethyl
fumarate, and dimethyl maleate, were investigated and did not participate
in a Diels-Alder reaction.
(44) We cannot unequivocally exclude the formation of the alternative
regioisomer in this or related cases as these reactions occur under rather
harsh reaction conditions, which leads to decomposition, and so it is
conceivable that the other isomer is formed in small amounts and is not
observed in the NMR spectra of the crude reaction mixtures, or isolated
from them.
(45) Acheson, R. M.; Foxton, M. W.; Abbott, P. J.; Mills, K. R. J. Chem.
Soc. C 1967, 2218.
(46) Kusurkar, R. S.; Bhosale, D. K. Synth. Commun. 1990, 20, 101.
(47) Jones, R. A.; Marriot, M. T. P.; Rosenthal, W. P.; Arques, J. S. J.
Org. Chem. 1980, 45, 4515.
(48) Abarca, B.; Ballesteros, R.; Enriquez, E.; Jones, G. Tetrahedron
1987, 43, 269.
3746 J. Org. Chem., Vol. 72, No. 10, 2007

Preparation of 4-Vinylimidazoles
SCHEME 8
conditions, the 2-Me-substituted derivative behaved similarly
to the unsubstituted case (Scheme 8), providing the initial adduct
49, the aromatized adduct 50, and the ene adduct 51 (for X-ray,
Figure S5 in the Supporting Information). Similarly to the parent
case 27e, the initial adduct could not be completely purified by
column chromatography due to aromatization, and so to aid
purification the reaction was allowed to proceed until all of this
initial adduct had converted to 50 and 51. The 2-methyl
derivative also undergoes cycloaddition with methyl acrylate,
providing 52 in reasonable yield (Scheme 8), although harsh
reaction conditions are required, similar to the parent substrate
27e. The carboxyethyl-containing derivative 53 did not partici-
pate in the DA reaction with NPM in any of the reactions
attempted; however, the 2-azido derivative 54 did undergo
cycloaddition, provided that the reaction temperature was
moderated to 45 °C (Scheme 9), while at higher temperatures
complex mixtures of products are formed. In the case of 54,
1
the H NMR spectrum of the crude reaction mixture indicated
that the initial adduct 55 was the only product, but we were
unable to fully purify this compound by column chromatography
due to isomerization to the aromatic derivative 56. It was found
that the initial adduct 55 could be obtained in reasonable yield
and purity by trituration of the crude reaction mixture. The
cycloaddition reaction of the 2-azido derivative shows interesting
chemoselectivitysat least at 45 °C, only reaction with the
vinylimidazole and NPM is observed and apparently no [3 +
2] cycloaddition of the azide subunit was observed.
SCHEME 9
The 2-azido derivative 54 also served as a precursor for the
preparation of several 2-amino derivatives which were obtained
via NaBH4 reduction providing the amine 58 (Scheme 10). The
amine was then protected with BOC2O in the presence of
TMEDA affording 59 or with a phthaloyl group on treatment
with the modified Nefkens reagent affording 60 (Scheme 10).53
This selective protection in the former case is worthy of note,
and although the precise role of TMEDA is not clear, in its
absence both acylation of the amino group and the imidazole
N3 occurs.54 Vinylimidazole 60 participated in the cycloaddition,
but the reaction was extremely sluggish requiring heating at
120 °C, whereas both the BOC-protected 59 and the free amino
derivative 58 engaged in the cycloaddition quite readily. The
BOC-protected substrate 59 provided the initial adduct 61 in
excellent yield on heating at 60 °C, whereas the phthaloyl
substrate 58 provided the aromatic derivative 64 (plus a small
quantity of the ene adduct 63) at room temperature, provided
only 1.0 equiv of NPM was employed. In contrast, when the
reaction was conducted at room temperature, under standard
conditions, 2.5 equiv of NPM, a cycloaddition occurred, but
this was followed by an ene reaction with excess NPM, leading
to the formation of 63 only. There is a fairly clear-cut correlation
between the electron density of the vinylimidazole and the
relative reactivity. The most electron rich derivative 58 reacts
rapidly at room temperature, whereas the least electron rich
derivative 60 requires heating at elevated temperature, which
leads to rearomatization.
rearrangement chemistry.49 Two approaches to the construction
of the requisite 4-substituted imidazoles were employed,
depending on the nature of the 2-substituent. The 2-methyl
derivative 48 was prepared from the known 4(5)-iodoimidazole
4650 by benzylation (3.8:1.0 mixture of separable 4- and
5-isomers) and Stille cross-coupling of the resulting 4-iodoimi-
dazole 47 with vinylstannane (Scheme 8). The other derivatives
were prepared from 27e by metalation (n-BuLi) and electrophilic
trapping with Mander’s reagent (EtO2CCN), or TsN3,51 provid-
ing the corresponding 2-ethyl ester (53) and 2-azide (54) in good
yield (Scheme 9). At the outset, we were somewhat apprehensive
about the viability of this direct metalation approach in these
benzyl protected imidazole derivatives, as it had been previously
shown that lateral lithiation occurs in N-benzyl benzimidazoles.52
In the event, however, our concerns were unfounded with 27e
and the metalation proceeded uneventfully, and as best we could
tell with high selectivity at the 2-position.
Each of these substrates was then subjected to a Diels-Alder
reaction with NPM, initially in PhH at 90 °C. Under these
Vinyl Substitution. Three examples incorporating substitu-
tion on the terminus of the vinyl moiety were prepared and
(49) As part of general studies toward the oroidin family of natural
products, we have found that reasonably electron rich tetrahydrobenzimi-
dazoles can be converted into the corresponding spiro fused imidazolones
through an oxidative rearrangement, therefore the reactivity of these benzyl-
protected derivatives was investigated first.
(53) Einhorn, C.; Einhorn, J.; Marcadal-Abbadi, C. Synth. Commun. 2001,
31, 741.
(50) Cliff, M. D.; Pyne, S. G. Synthesis 1994, 681.
(51) Kawasaki, I.; Taguchi, Y.; Yamashita, M.; Ohta, S. Heterocycles
1996, 43, 1375.
(52) (a) Cuberes, M. R.; Moreno-Manas, M.; Trius, A. Synthesis 1985,
302. (b) Moreno-Manas, M.; Bassa, J.; Llado, N.; Pleixats, R. Heterocycles
1990, 27, 673.
(54) (a) Koyanagi, K.; Tsucha, S. Preparation of (alkoxycarbonylamino)-
heterocycles. Jpn Kokai Tokkyo Koho 93 164,438; Chem. Abstr. 1995, 122,
265365. (b) Koyanagi, K.; Tsucha, S. Method for Preparation of N-
Heterocyclylurethane. Jpn Kokai Tokkyo Koho 93 164,378; Chem. Abstr.
1995, 122, 290878.
J. Org. Chem, Vol. 72, No. 10, 2007 3747

Lovely et al.
SCHEME 10
SCHEME 11
SCHEME 12
evaluated in the DA reaction. In this case urocanic acid, which
is commercially available, or can be prepared in excellent yield
from histidine, was utilized as the starting material. Conversion
of the acid into the methyl ester55 through standard Fischer
esterification conditions and subsequent protection with either
BnCl or DMASCl provided the corresponding derivatives 66a56
and 66b in good yields and selectivities (Scheme 11). Reduction
of the ester to the alcohol with DIBAL proceeded efficiently,56
and then the resulting alcohol was protected as the silyl ether.
Alternatively, allylic oxidation of 67a with MnO2, followed by
treatment with benzylamine and then NaBH4 provided the allylic
amine, which can be protected with BOC2O to provide 75
(Scheme 12). Perhaps not unexpectedly, each of these substrates
smoothly underwent cycloaddition with NPM to provide the
enamines 69a and 69b with short reaction times, or the
aromatized adducts 70 and 76 on extended reaction times.
Formation of the ene adduct 71 also resulted when the reaction
was conducted in benzene at reflux, but this could be readily
separated. Each of these more elaborate adducts was obtained
as a single stereoisomer, again derived from an endo transition
state.
(55) Pirrung, M. C.; Pei, T. J. Org. Chem. 2000, 65, 2229.
(56) Greig, I. R.; Tozer, M. J.; Wright, P. T. Org. Lett. 2001, 3, 369.
3748 J. Org. Chem., Vol. 72, No. 10, 2007

Preparation of 4-Vinylimidazoles
In summary, we have developed synthetic approaches for the
construction of a number of 4-vinylimidazoles with high levels
of selectivity. 2-Substituted systems can be prepared either from
the corresponding 2-substituted imidazoles or by lithiation of
the 2-position and trapping with appropriate electrophiles. These
vinylimidazoles smoothly participate in Diels-Alder reactions
with NPM through the anticipated pathway under reasonably
mild conditions; however, other doubly activated dienophiles
generally do not react well (e.g., dimethyl fumarate, dimethyl
maleate) or do not react via the Diels-Alder manifold (DMAD).
All of these reactions with NPM are stereoselective, providing
a single stereoisomer that appears to be derived from an endo
transition state. Monoactivated dienophiles do react, but require
considerably more forcing conditions, which leads to attenuated
yields as a result of competitive substrate decomposition. Despite
the lower reactivity, these reactions are regioselective, leading
to the construction of 7-substituted tetrahydrobenzimidazole
derivatives.
Acknowledgment. This research has been supported by the
University of Texas at Arlington, the Texas Higher Education
Coordinating Board-Advanced Research Program (ARP-003656-
0004-1999), The Robert A. Welch Foundation (Y-1362 (C.J.L.)
and Y-1289 (H.V.R.D.)), and the National Institutes of Health
(GM065503). NMR spectrometers employed in this work were
purchased in part with support from the NSF (CHE-0234811
and CHE-9601771).
Supporting Information Available: Experimental procedures
and spectroscopic data for all new compounds, copies of 1H NMR
and 13C NMR spectra for compounds (17, 18, 21d, 27b,d,e, 29d,
31e, 30f, 39b,c, 40e, 41e, 52-56, 58-64, 68b, 72, 74, 75) lacking
combustion analysis and CIF files for compounds 29a, 31f, 33e,
39e, and 51. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO0626008
J. Org. Chem, Vol. 72, No. 10, 2007 3749