Synthesis of trisubstituted imidazoles by palladium-catalyzed cyclization of O-pentafluorobenzoylamidoximes: Application to amino acid mimetics with a C-terminal imidazole

Article abstract of DOI:10.1021/ol047628p

(Chemical Equation Presented) 1-Benzyl-4-methylimidazoles with a range of substituents at the 2-position are prepared from O-pentafluorobenzoylamidoximes on treatment with catalytic amounts of Pd(PPh₃)₄ and triethylamine. The sequenc

Full text of DOI:10.1021/ol047628p

ORGANIC
LETTERS
2005
Vol. 7, No. 4
609-611
Synthesis of Trisubstituted Imidazoles
by Palladium-Catalyzed Cyclization of
O-Pentafluorobenzoylamidoximes:
Application to Amino Acid Mimetics
with a C-Terminal Imidazole
Shazia Zaman, Kitamura Mitsuru,† and Andrew D. Abell*
Department of Chemistry, UniVersity of Canterbury, PriVate Bag 4800,
Christchurch, New Zealand, and Department of Chemistry, Graduate School of
Science, The UniVersity of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan
andrew.abell@canterbury.ac.nz
Received November 17, 2004
ABSTRACT
1-Benzyl-4-methylimidazoles with a range of substituents at the 2-position are prepared from O-pentafluorobenzoylamidoximes on treatment
with catalytic amounts of Pd(PPh3)4 and triethylamine. The sequence provides access to optically active amino acid mimetics with a C-terminal
imidazole.
Imidazoles are an important class of heterocycle with an
ability to behave as ligands in metalloenzymes1 and non-
natural metal complexes.2 They are components of a number
of highly significant biomolecules, including the essential
amino acid histidine (and related compounds), biotin, and
the pilocarpine alkaloids.3 An imidazole ring has also been
used as a component of nonnatural cyclic peptides4 and as a
stable ester isostere for use in peptidomimetics.5,6 As such,
a good deal of interest exists in developing new and efficient
methods for the synthesis and functionalization of imid-
azoles: 2-functionalized imidazoles are typically prepared
by metalation of an imidazole followed by reaction with an
electrophile7 (e.g., an aldehyde or isocynate) or, more
recently, by reaction of an azolium ylide with a reactive
carbonyl.8
In this paper, we present a new synthesis of 2-substituted
1-benzyl-4-methylimidazoles based on a palladium(0)-
catalyzed amino Heck reaction (an electrophilic amination
sequence) of amidoximes and the application of this meth-
odology to the preparation of amino acid mimetics containing
a C-terminal imidazole; see 12a-c. Mimetics of this type
† The University of Tokyo.
(1) Vallee, B. L.; Auld, D. S. Biochemistry 1990, 29, 5647.
(2) Omotowa, B. A.; Shreeve, J. M. Organometallics 2004, 23, 783. Liu,
J.; Zhao, Y.; Zhou, Y.; Li, L.; Zhang, T. Y.; Zhang, H. Org. Biomol. Chem.
2003, 1, 3227.
(3) Grimmett, M. R. In ComprehensiVe Heterocyclic Chemistry II:
Katritzky, A. R.; Ress, C. W.; Scriven, E. F. V., Eds.; Pergamon Press:
Oxford, 1996: Vol. 3, pp 77-220.
(4) Haberhauer, G.; Rominger, F. Eur. J. Org. Chem. 2003, 3209.
(5) Von Geldern, T. W.; Kester, J. A.; Bal, R.; Wu-Wong, J. R.; Chiou,
W.; Dixon, D. B.; Opgenorth, T. J. J. Med. Chem. 1996, 39, 968. Predgen,
L. N.; Mokhallalati, M. K.; Mcguire, M. A. Tetrahedron Lett. 1997, 38,
1275.
(6) Dhanak, D.; Christmann, L. T.; Darcy, M. G.; Keenan, R. M.; Knight,
S. D.; Lee, J.; Ridgers, L. H.; Sarau, H. M.; Shah, D. H.; White, J. R.;
Zhang, L. Bioorg. Med. Chem. Lett. 2001, 11, 1445.
(7) Pinkerton, F. H.; Thames, S. F. J. Heterocycl. Chem. 1972, 9, 67.
(8) Hlasta, D. J. Org. Lett. 2001, 3, 157. Deng, Y.; Hlasta, D. J.
Tetrahedron Lett. 2002, 43, 189.
10.1021/ol047628p CCC: $30.25
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Published on Web 01/19/2005

are known, being prepared by reaction of an optically active
aldehyde derivative of an amino acid with NH3 in 40%
glyoxal and DMF.5 However, problems with racemization
have been noted with this method.6 This is, to our knowledge,
the first report of an imidazole synthesis based on a metal-
catalyzed C-N bond formation reaction. Related methodol-
ogy has been reported for the preparation of pyrroles and a
number of azaheterocycles, including azaazulenes, spiroimines,
and pyridinium derivatives.9-11
the same isomer of 4b, as per the in situ experiment. The
hydroxamoyl chloride 3c, prepared as an E/Z mixture (6:5)
from glycine methyl ester hydrochloride,15 was also reacted
with allyl benzylamine in DMF to give 4c (75%) as a 6:5
mixture of isomers (Scheme 1).
The key substrates for the amino Heck reactions (5a-c)
were then prepared by reacting the samples of (E)-4a, (E)-
4b, and (E/Z)-4c (isomer ratio of 6:5) with TEA and
pentafluorobenzoyl chloride in DCM at 0 °C to give (E)-5a
and (E)-5b as single isomers and (E/Z)-5c (isomer ratio of
4:1) in 83, 87, and 88% yields, respectively. An N,O-
pentafluorobenzoyloxime was chosen for use in the subse-
quent amino Heck sequence since this group is known to
suppress the competing Beckman rearrangement.10
We first demonstrated the feasibility of the methodology
using simple amidoximes as depicted in Scheme 1. Reaction
Scheme 1a
The N,O-pentafluorobenzoyl amidoximes 5a,b were treated
with 10 mol % Pd(PPh3)4 and 5 equiv of TEA in DMF, at
80 °C for 30 min, to give the desired imidazoles 6a,b in 72
and 70% yields, respectively. The amino Heck cyclization
of 5c was slower. Its consumption (as determined by TLC)
required 3 h at 80 °C, and the desired imidazole 6c was
isolated in 30% yield. The lower yield in this case is unlikely
to be linked to the presence of two isomers of the substrate
5c, since the outcome of other amino Heck reactions are
reported to be independent of the geometry of the substrate
oxime.10,11 The amino Heck cyclizations of 5a-c are thought
to proceed by oxidative addition of Pd(0) to the N-O bond
to give an alkylideneaminopalladium(II) intermediate.16
Olefin insertion into this species, followed by elimination
of palladium hydride gives a dihydroimidazole, which finally
isomerizes under the reaction conditions to the imidazole.
With the simple imidazoles 6 in hand, we next set about
extending the methodology to amino acid-based examples;
see 12 in Scheme 2. As mentioned earlier, an imidazole has
a Key: a, R ) PhCH2; b, R ) Ph(CH2)2; c, R ) CO2Me.
of aldehydes 1a and 1b with hydroxylamine in the presence
of pyridine gave the aldoximes, (E/Z)-2a12 (75%, 1:1) and
(E/Z)-2b13 (72%, 3:2), respectively. These were then sepa-
rately treated with NCS, in dry DMF at 70 °C, to give the
corresponding hydroxamoyl chlorides 3a and 3b, which were
not isolated but simply coupled, in situ, with allyl benzyl-
amine in DMF to give 4a (63%) and 4b (61%), respectively,
as single isomers, tentatively assigned the (E)-configuration.14
In a separate experiment, 2b was treated with NCS and the
crude product analyzed by 1H NMR to show 3b as a single
isomer, which was isolated in 87% yield, characterized, and
tentatively assigned the (E)-configuration.14 This sample of
3b was then reacted with allyl benzylamine in DMF to give
Scheme 2a
(9) Kitamura, M.; Narasaka, K. Chem. Record 2002, 2, 268. Kitamura,
M.; Chiba, S.; Saku, O.; Narasaka, K. Chem. Lett. 2002, 606. Tsutsui, H.;
Narasaka, K. Chem. Lett. 1999, 45. Tsutsui, H.; Narasaka, K. Chem. Lett.
2001, 526.
(10) Tsutsui, H.; Narasaka, K.; Kitamura, M. Bull. Chem. Soc. Jpn. 2002,
75, 1451.
(11) Zaman, S.; Kitamura, M.; Narasaka, K. Bull. Chem. Soc. Jpn. 2003,
76, 1055.
(12) Boucher, J.-L.; Delaforge, M.; Mansuy, D. Biochemistry 1994, 33,
7811.
(13) Lam, P. Y. S.; Adams, J. J.; Clark, C. G.; Calhoun, W. J.; Luettgen,
J. M.; Knabb, R. M.; Wexler, R. R. Bioorg. Med. Chem. Lett. 2003, 13,
1795.
a Key: a, R ) PhCH2; b, R ) Me; c, R ) CH2CHMe2.
(14) It has been noted that O-alkyl hydroxamoyl chlorides isomerize to
the thermodynamically stable (E)-isomer and that these react stereospecifi-
cally to give an (E)-amidoxime (Johnson, J. E.; Nalley, E. A.; Kunz, Y.
K.; Springfield, J. R. J. Org. Chem. 1976, 41, 252. Johnson, J. E.; Todd, S.
L.; Dutson, S. M.; Ghafouripour, A.; Alderman, R. M.; Hotema. M. R. J.
Org. Chem. 1992, 57, 4648). Note that the substituent priorities of 2 and
3/4 are different such that the respective (E)-isomers have opposite relative
configurations.
been used in this context as a stable ester isostere at the
C-terminus of a peptidomimetic.5,6 The key starting aldehydes
7a-c were prepared by DIBALH reduction of (S)-N-Boc-
610
Org. Lett., Vol. 7, No. 4, 2005

Phe-OMe, (S)-N-Boc-Ala-OMe, and (S)-N-Boc-Leu-OMe,
NMR of the crude product revealed a turnover of 90-95%
in all cases; however, the isolated yields are some what
lowered by difficulties in removing the triphenylphosphine
oxide byproduct. Finally, the N-Boc group of the Phe-based
imidazole 12a was removed on treatment with 1 N HCl, and
the resulting free amine coupled with (S)-Boc-Ala under
respectively. Treatment of each of these aldehydes with
17
hydroxylamine hydrochloride in the presence of Na2CO3
gave the (E/Z)-R-amino aldoximes 8a (79%, 2:1), 8b (72%,
3:1), and 8c (83%, 3:2), which were purified by column
chromatography and recrystallization.18 A one-pot treatment
of these oximes with NCS, as for 2 in Scheme 1, gave the
hydroxamoyl chlorides 9a-c, which were reacted in situ with
allyl benzylamine to give the amidoximes 10a-c as mixtures
of isomers.18
1
standard conditions to give 13 (>95% de by H and 13C
NMR), thus suggesting that little or no racemization had
occurred in the preparation of the imidazole.
In summary, new methodology has been developed for
the synthesis of 1-benzyl-4-methylimidazoles with a range
of substituents at the 2-position based upon a palladium-
mediated amino Heck reaction of an amidoxime, itself
derived from the corresponding aldehyde. The sequence is
simple and efficient and can be used to prepare optically
active amino acid mimetics containing a C-terminal imid-
azole.
Treatment of separate samples of 10a-c with TEA and
pentafluorobenzoyl chloride, as for 4, gave single isomers
of the substrates for the amino Heck reaction, 11a-c in 61,
63, and 31% yields, respectively.18 These were then subjected
to the amino Heck reaction conditions to give the C-terminal
amino acid mimetics 12a-c in good yield. In particular, the
(S)-Phe- and (S)-Leu-based amidoximes 11a and 11c cyclized
smoothly in 1 h to give the optically active imidazole
derivatives 12a (70%) and 12c (56%), while (S)-Ala-based
12b was isolated in 68% yield after a comparatively shorter
Acknowledgment. We thank Professor Koichi Narasaka
(University of Tokyo, Japan) and Dr. Owen Curnow
(University of Canterbury, Christchurch, New Zealand) for
their useful suggestions.
1
reaction time of 30 min. The reactions work well, and H
(15) Abbott, S. D.; Lane-Bell, P.; Sidhu, K. P. S.; Vederas, J. C. J. Am.
Chem. Soc. 1994, 116, 6513.
(16) Related radical cyclization has been reported; see: Gennet, D.; Zard,
S. Z.; Zhang, H. Chem. Commun. 2003, 1870.
(17) Chung, Y. J.; Ryu, E. J.; Keum, G.; Kim, H. Bioorg. Med. Chem.
1996, 4, 209.
(18) Assignment of isomers is ambiguous and, in any event, unimportant
since both react in the subsequent amino Heck reactions. However, the
literature suggests that for the amidoximes, the (Z)-isomer would be major
(Sauve, G.; Rao, V. S.; Lajoie, G.; Belleau, B. Can. J. Chem. 1985, 63,
3089).
Supporting Information Available: General methods of
preparation and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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