Synthesis of fused bicyclic imidazoles by ring-closing metathesis

Article abstract of DOI:10.1016/S0040-4039(02)02864-2

The preparation of a number of dienylimidazole via chemoselective metal-halogen exchange and their utility in ring-closing metathesis is described. Essentially all regioisomeric permutations participate in metathesis with the notable exception of 4-vinyl-

Full text of DOI:10.1016/S0040-4039(02)02864-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1379–1382
Synthesis of fused bicyclic imidazoles by ring-closing metathesis
Yingzhong Chen, H. V. Rasika Dias† and Carl J. Lovely*
Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, USA
Received 18 December 2002; accepted 19 December 2002
Abstract—The preparation of a number of dienylimidazole via chemoselective metal–halogen exchange and their utility in
ring-closing metathesis is described. Essentially all regioisomeric permutations participate in metathesis with the notable exception
of 4-vinyl-5-allylimidazoles, provided that the imidazole N3 atom is protonated. © 2003 Elsevier Science Ltd. All rights reserved.
Olefin metathesis has continued to evolve over the past
few years as an extremely useful transformation in
organic synthesis.1 The development of robust and
commercially available transition metal catalysts (e.g. 1
and 2, inter alia) has permitted a thorough investigation
of the scope and limitations of this reaction. Of the
various modes of olefin metathesis, the intramolecular
variant (ring-closing metathesis (RCM)) has received a
significant amount of attention with this reaction being
employed for the construction of numerous carbocyclic
and heterocyclic systems. However, despite this activity,
there appear to be no reports of the application of this
transformation to imidazole containing systems,
although hydantoins2 and very recently 2-amino-5-
imidazolones3 have been investigated. As a continua-
tion of our program to develop methods for the
elaboration of simple imidazoles,4 we now wish to
report our studies on the RCM reactions of imidazole
derivatives.
the complex catalytically inert or attenuating the reac-
tivity.5 The second issue related to the possibility of the
formation of stable carbene complexes with vinylimida-
zoles similar to that observed by the Grubbs’ group
with N-vinylimidazole in some early work on ruthe-
nium alkylidene complexes.6,7 Conceivably the use of
electron-withdrawing substituents on the imidazole
might alleviate the first problem, whereas the validity of
the second issue could only be established
experimentally.
Our studies commenced with the preparation of diene 6
which was to serve as a precursor to allylic alcohol (8a)
which was required as a key intermediate en route to
the oroidin-derived marine alkaloid, agelastatin A
(3).8,9 The known dimethylsulfamoyl protected
diiodoimidazole (4) served as the starting material for
the preparation of 6.10 Thus treatment of 4 with
EtMgBr followed by reaction with N-methyl-N-2-
pyridylformamide provided the corresponding aldehyde
(5) in 70% yield.10,11 Stille cross-coupling of 5 with
tributylvinylstannane, followed by treatment with
CH2ꢀCHMgBr gave 6. With this alcohol in hand it was
treated with Grubbs’ first generation catalyst 1 in
CH2Cl2 at reflux, disappointingly however, no metathe-
sis products were obtained. Only methyl and ethyl
ketone products, resulting from fragmentation and
rearrangement, were obtained in low yields.12 Since
these types of reaction pathways have been observed
with allylic alcohols previously, the alcohol was pro-
tected as the TBS ether and reevaluated in the RCM
reaction with the same catalyst but to no avail. It has
been reported that the newer second-generation
Grubbs’ catalyst (2) can offer improved performance
over 1 in both reactivity and functional group toler-
ance.13 However, on reacting 6 or 7 with 2 no evidence
for cyclization was obtained. As mentioned above, one
At the outset of this work there were two issues of
concern regarding the viability of metathesis reactions
involving imidazoles. In particular was the possibility of
imidazole ligation through donation of the N3-lone
pair to the transition metal, either potentially rendering
* Corresponding author. Tel.: +1-817-272-5446; fax: +1-817-272-3808;
e-mail: lovely@uta.edu
† For correspondence regarding the X-ray crystal structure. Tel.:
+1-817-272-3813; fax: +1-817-272-3808; e-mail: dias@uta.edu
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02864-2

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Y. Chen et al. / Tetrahedron Letters 44 (2003) 1379–1382
of the potential problems with imidazole substrates in
metathesis reactions is the possibility of ligation via N3
with the ruthenium alkylidene, rendering the catalyst
inactive. Thus attempts were made to circumvent this
issue by protonating the offending nitrogen by treating
the metathesis substrates (6 or 7) with p-TsOH prior to
introduction of 1 or 2. Unfortunately this also did not
lead to successful metathesis, rather allylic transposition
occurred. To prevent this rearrangement, a substrate
lacking the hydroxy group (i.e. 8c) was prepared from 4
via metallation (I“MgX), transmetallation (MgX“
Cu) and then allylation to provide 9 (Scheme 1, Table 1,
mation around the imidazole nucleus. Initially, the effect
of substitution on the 4-allyl moiety was investigated.
Thus the methallyl substituted derivative (13, Table 1,
entry 2) and the allylic alcohol (15, Table 1, entry 3) were
prepared and evaluated. Each substrate participated in
the metathesis reaction with reasonable efficiency. The
methallyl substrate provided the non-conjugated dibenz-
imidazoles (14), the structure of which was confirmed
through an X-ray analysis of the product (Fig. 1). As can
be seen in Table 1 (entry 3), the allylic alcohol provides
benzimidazole (16), in which the initial product under-
goes elimination of water.
entry 1).14 Stille cross coupling of
9 with tri-
butylvinylstannane gave the required metathesis sub-
strate (10) which unfortunately did not cyclize on
exposure to either 1 or 2 as the free base or as the
imidazolium salt.
One of the key variables investigated was the necessity
for an electron-withdrawing N1-substituent, accordingly
the benzyl-protected analog was prepared. Starting from
the benzyl 4,5-diiodo derivative (17),4b two sequential
metallation and substitution reactions provided the
required substrate (19, Table 1, entry 4). After protona-
tion with p-TsOH and introduction of the ruthenium
carbene 2, we were delighted to find that this substrate
participated in metathesis to provide the corresponding
cyclized product (20) in 87% yield. The methallyl-substi-
tuted derivative (21, Table 1, entry 5) was prepared and
it engaged in metathesis very efficiently to provide 22, the
identity of which was confirmed by X-ray analysis (Fig.
2). As a result of these observations, the implication was
that essentially any mode of linkage around the imidazole
nucleus should be amenable to metathesis. Accordingly,
substrates linked at other positions were prepared and
investigated. The N-allyl systems (24, 26, 31) were
constructed by N-allylation of 4,5-diiodoimidazole or
2,4,5-tribromoimidazole15 and then metallation and
electrophilic trapping with allyl bromide (24 and 31,
Table 1, entries 6 and 9) or acetaldehyde (dehydration
then provided the allyl–vinyl system, 26, Table 1, entry
7). Intriguingly, all of these substrates participated in
metathesis after protonation and introduction of the
catalyst, even 26. This latter result (Table 1, entry 7) is
particularly striking given that the corresponding 4,5-
linked congener did not provide the cyclic product. At
this point, we have no definitive explanation for this
observation, although steric effects through the 4-iodo
substituent may be important since its removal from 26
provides a substrate (27, Table 1, entry 8) that partici-
pates in metathesis but with reduced efficiency (Scheme
2).
We were concerned that the failure of these substrates to
undergo metathesis might arise from the formation of
stable metallacarbenes as had been observed previously
with N-vinylimidazole, therefore, we decided to investi-
gate diallyl systems in which the ring nitrogens can no
longer interact with the alkene. Access to such substrates
required only minor modifications of the sequence previ-
ously employed. Thus, metallation of 9 (I“MgX),
transmetallation (MgX“Cu) and allylation provided the
diallyl substrate (11, Table 1, entry 1). When this was
subjected to metathesis with 1, no evidence for cycliza-
tion was observed, formation and metathesis of the
imidazolium salt was unsuccessful. On the other hand,
metathesis of 11 with 2 led to successful cyclization, albeit
in 22% yield. However, on preparation (1.1 equiv.
p-TsOH) and metathesis of the imidazolium ion from 11,
the dihydrobenzimidazole (12) was obtained in 77%
yield. With the identification of suitable conditions we set
out to identify the scope and limitations of this transfor-
Scheme 1. Reagents and conditions: (a) EtMgBr, CH2Cl2, then
2-PyN(CHO)Me, 70%; (b) CH2ꢀCHSnBu3, Pd2dba3, PPh3,
DMF, 90°C, 97%; (c) CH2ꢀCHMgBr, THF, 56%; (d) 5–50
mol% 1 or 2, CH2Cl2, reflux; (e) TBSCl, DMF, imidazole, 84%;
(f) see Table 1 (g); CH2ꢀCHSnBu3, Pd2dba3, PPh3, DMF, 90°C,
99%.
Figure 1. X-Ray crystal structure of RCM product 14.

Y. Chen et al. / Tetrahedron Letters 44 (2003) 1379–1382
1381
Scheme 2.
Table 1.
In summary, efficient syntheses of a number of dienyl
imidazoles have been developed that rely on chemoselec-
tive metallation–electrophile capture sequences. These
substrates participate in RCM reactions with Grubbs’
second generation ruthenium carbene catalysts provided
that the imidazole N3 atom is protonated. Apparently,
only 4,5-allyl vinyl systems do not participate in the
metathesis reaction. Further extensions and application
of this transformation to natural product total syntheses
are under way and will be reported in due course.

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Y. Chen et al. / Tetrahedron Letters 44 (2003) 1379–1382
J. Am. Chem. Soc. 2002, 124, 9060; (c) Baron, E.; O’Brien,
P.; Towers, T. D. Tetrahedron Lett. 2002, 43, 723.
10. Carver, D. S.; Lindell, S. D.; Saville-Stones, E. A. Tetra-
hedron 1997, 53, 14481.
11. Comins, D.; Meyers, A. I. Synthesis 1978, 403.
12. (a) Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 1123; (b)
Gurjar, M. K.; Yakambram, P. Tetrahedron Lett. 2001, 42,
3633.
13. (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org.
Lett. 1999, 1, 953; (b) See also: Paquette, L. A.; Efremov,
I. J. Am. Chem. Soc. 2001, 123, 4492.
14. (a) Dehmel, F.; Abarbri, M.; Knochel, P. Synlett 2000, 345;
(b) Abarbri, M.; Thibonnet, J.; Be´rillon, L.; Dehmel, F.;
Rottla¨nder, M.; Knochel, P. J. Org. Chem. 2000, 65, 4618.
15. Stensio, K.; Wahlberg, K.; Wahren, R. Acta Chem. Scand.
1973, 27, 22.
16. General procedure: An ethereal solution of EtMgBr (3 M,
14.3 mL, 42.9 mmol) was added dropwise to a magnetically
stirred solution of 17 (16.00 g, 39.9 mmol) in CH2Cl2 (160
mL) at room temparature. After stirring at room temper-
ature for 30 min, a THF solution of CuCN·2LiCl (1 M,
39.0 mL, 39.9 mmol) was added, followed by cooling to
−30°C. Allyl bromide (3.67 mL, 42.6 mmol) was added by
syringe and then the reaction mixture was warmed to 0°C
and stirred for 4 h. The reaction was quenched by the
addition of half saturated aqueous NH4Cl containing 2%
concentrated NH3 and stirring for 20 min. The resulting
blue solution was extracted with CH2Cl2 (×2), the combined
extracts were dried (MgSO4) and concentrated. The residue
was purified by flash chromatography (SiO2, hexane/
Figure 2. X-Ray structure of RCM product 22.
Acknowledgements
This work was supported by the Robert A. Welch
Foundation (CJL Y-1362; HVRD Y-1289), and the
Texas Higher Education Coordinating Board–Advanced
Research Program (003656-0004-1999). The NSF (CHE-
9601771) is thanked for partial funding of the purchase
of a 500 MHz NMR spectrometer employed in this work.
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1
EtOAc, 1:1) to afford 17 (9.67 g, 77%) as a yellow oil. H
NMR (500 MHz, CDCl3): l=3.22 (ddd, 2H, J=1.5, 1.8,
5.9 Hz), 4.93 (ddt, 1H, J=1.5, 1.8, 17.2 Hz), 5.04 (ddt, 1H,
J=1.5, 1.5, 10.3 Hz), 5.06 (s, 2H), 5.70 (ddt, 1H, J=5.9,
10.3, 17.2 Hz), 7.02–7.06 (m, 2H), 7.27–7.35 (m, 3H), 7.45
(s, 1H); 13C NMR (125 MHz, CDCl3): l=29.1, 49.6, 85.2,
116.9, 127.0, 128.4, 129.2, 131.5, 133.5, 135.5, 139.4; IR
(CHCl3, cm−1): 3080, 3031, 2978, 2906, 1638, 1486, 1230,
1163, 976, 919, 722; EIMS (m/z): 65, 148, 275 (100%), 303,
324 (M+), 325 (M++1); Anal. calcd for C13H13IN2: C, 48.17;
H, 4.04; N, 8.64. Found: C, 48.03; H, 4.27; N, 8.73.
17. Generalprocedure:Diallylimidazole19(300mg, 1.26mmol)
and p-TsOH (264 mg, 1.39 mmol) were dissolved in CH2Cl2
(12.6 mL) and heated at reflux for 30 min. After cooling
to room temperature Grubbs’ catalyst (2, 53 mg, 0.062
mmol) was added and then the mixture was heated to reflux
for 60 min. After cooling to room temperature, the solvent
was removed by rotary evaporation and aqueous NaHCO3
solution was added to the residue. After the addition of solid
K2CO3 to make the solution basic, that organic components
were extracted with CH2Cl2. The organic solution was dried
(MgSO4) and concentrated to afford the crude product,
which was purified by flash chromatography (SiO2, hexane/
EtOAc, 1:4) to afford 20 (230 mg, 87%) as a colorless solid.
Mp: 140.0–140.5°C; 1H NMR (500 MHz, CDCl3): l=3.06
(m, 2H), 3.32 (m, 2H), 5.01 (s, 2H), 5.72 (m, 1H), 5.89 (m,
1H), 7.04–7.08 (m, 2H), 7.24–7.33 (m, 3H), 7.46 (s, 1H);
13C NMR (125 MHz, CDCl3): l=23.0, 26.7, 48.7, 122.1,
125.9, 126.9, 128.1, 129.0, 134.5, 136.1, 136.5; IR (KBr,
cm−1): 3089, 3030, 2871, 2835, 1651, 1594, 1493, 1438, 1364,
1234, 1178, 951, 900, 826, 736, 680, 456; EIMS (m/z): 65,
91, 119, 172, 210 (M+), 211 (M++1, 100%). Anal. calcd for
C14H14N2: C, 79.97; H, 6.71; N, 13.32. Found: C, 79.73;
H, 6.71; N, 12.97.
9. For synthetic studies, see: (a) Stien, D.; Anderson, G. T.;
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