Synthesis of 2-imidazolones and 2-iminoimidazoles

Article abstract of DOI:10.1021/ol2022438

Convenient methods for the direct conversion of imidazolium salts to the corresponding 2-imidazolone or 2-imino imidazole derivatives have been developed. Treatment of the salt with commercial bleach leads to effective oxidation at C2 and the formation of the corresponding imidazolone. Alternatively, treatment of the salt with an N-chloro amide affords the corresponding protected 2-amino derivative in good yield.

Full text of DOI:10.1021/ol2022438

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5736–5739
Synthesis of 2-Imidazolones and
2-Iminoimidazoles
Heather M. Lima and Carl J. Lovely*
Department of Chemistry and Biochemistry, The University of Texas at Arlington,
Arlington, Texas 76019, United States
lovely@uta.edu
Received August 18, 2011
ABSTRACT
Convenient methods for the direct conversion of imidazolium salts to the corresponding 2-imidazolone or 2-imino imidazole derivatives have been
developed. Treatment of the salt with commercial bleach leads to effective oxidation at C2 and the formation of the corresponding imidazolone.
Alternatively, treatment of the salt with an N-chloro amide affords the corresponding protected 2-amino derivative in good yield.
A large number of natural products, most notably those
of the Leucetta (e.g., 1À3)1À3 and the oroidin families of
alkaloids (e.g., 4 and 5),4 have been identified that contain
either a 2-aminoimidazole or a 2-imidazolone moiety.5,6 In
the context of our approaches to these molecules,7 we have
generally adopted a strategy that involves the functionali-
zation of pre-existing imidazoles, with the late-stage intro-
duction of the 2-amino group, rather than the de novo
construction of the heterocycle.7
in a number of different settings both for us12 and for other
investigators,13 including en route to modestly complex
natural products (Figure 1).
Typically, the C2-amine is introduced via the azide,
which in turn is incorporated via lithiation at C2, followed
by reaction with TsN3 or TrisN3,8,9 whereas the corre-
sponding carbonyl moiety can be introduced by oxidation
10
of the organometallic with a peroxide such as (TMSO)2
or (PhCO2)2.11 This type of strategy has worked very well
(1) Akee, R.; Carroll, T. R.; Yoshida, W. Y.; Scheuer, P. J.; Stout,
T. J.; Clardy, J. J. Org. Chem. 1990, 55, 1944–1946.
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497–498.
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(4) D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Ribes, O.; Pusset, J.;
Leroy, S.; Pietra, F. J. Chem. Soc., Chem. Commun. 1993, 1305–1306.
(5) Koswatta, P. B.; Lovely, C. J. Nat. Prod. Rep. 2011, 28, 511–528.
(6) Forte, B.; Malgesini, B.; Piutti, C.; Quartieri, F.; Scolaro, A.;
Papeo, G. Mar. Drugs 2009, 7, 705–753.
(7) He, Y.; Du, H.; Sivappa, R.; Lovely, C. J. Synlett 2006, 965–992.
(8) Lindel, T.; Hochguertel, M. J. Org. Chem. 2000, 65, 2806–2809.
(9) Kawasaki, I.; Taguchi, N.; Yoneda, Y.; Yamashita, M.; Ohta, S.
Heterocycles 1996, 43, 1375–1379.
Figure 1. 2-Imidazolone natural product.
Recently, however, in the context of total syntheses of
kealiiquinone (1)1,11 and the 2-amino congener 2,2 we
found that this metalationÀelectrophile quench approach
failed (Scheme 1).14 Specifically, the advanced intermediate
(10) Lipshutz, B. H.; Huff, B.; Hagen, W. Tetrahedron Lett. 1988, 29,
3411–3414.
(11) Kawasaki, I.; Taguchi, N.; Yamashita, M.; Ohta, S. Chem.
Pharm. Bull. 1997, 45, 1393–1398.
r
10.1021/ol2022438
Published on Web 10/12/2011
2011 American Chemical Society

synthesis of several Leucetta alkaloids.15 They have de-
monstrated that 2-thio-substituted imidazoles 8 can be
converted into imidazolones 11 via hydrolysis of the
corresponding imidazolium salt 9 (X = SPh) presumably
via 10 (Scheme 2).16 While this chemistry appears to work
quite well, it does require the prefunctionalization of the
imidazole by C2-metalation and treatment with (PhS)2
(12f8, Scheme 2). This requirement adds a step and there
are issues associated with odor. In our own setting, appli-
cation of this chemistry was not considered attractive given
the apparent sensitivity of 6 to metalation or the prospect
ofintroducing the thiomoietyatthe outset of the sequence.
From a mechanistic perspective, the Ohta chemistry can be
viewed as proceeding via the amidinium species 9, where
the thiophenyl moiety serves as a leaving group. Addition
of water, loss of the thiophenyl group and deprotonation
of the hydroxyl moiety then provides the imidazolone. We
speculated that perhaps this process could be generalized,
such that as long as there was an appropriate leaving group
at C2 and that an imidazolium salt was employed, the
hydrolysis reaction should proceed in a mechanistically
similar fashion. Furthermore, there was no reason to
suppose that the order of the reactions could not be inter-
changed such that the imidazolium salt 13 could be pre-
pared first and then advantage could be taken of the
relative ease of C2-deprotonation to form the carbene.17
Subsequent reaction of the carbene 14 with a suitable
electrophile to provide the amidinium species 9, followed
by hydrolysis would lead to the formation of the imidazo-
lone, that is, 12f13f9f11, in a one pot process from 13
(Scheme 2).16 Herein, we describe the development of an
approach using a halonium source to activate the C2
position and subsequent basic hydrolysis.
Scheme 1. Attempted C2-Functionalization of an Advanced
Kealiiquinone Intermediate
6 was in hand, and we had anticipated that C2-lithiation and
then trapping with (TMSO)2 or TsN3 would provide kea-
liiquinone (1) or 2-amino-2-deoxykealiiquinone (2) (after
reduction), respectively.
This failure to complete these syntheses was immensely
disappointing given that it occurred at such a late stage of
the sequence. Accordingly, we set out to identify potential
solutions to the problem of introducing the C2 substituent
onto these and related substrates.
Scheme 2. AdditionÀElimination Pathways to Imidazolones
Given that our initial application of this chemistry
would be directed toward the total synthesis of kealiiqui-
none (1), we examined benzimidazole derivatives as sub-
strates. After some preliminary scouting experiments on
two imidazolium salts 15a and 15b18 with bases (NaH,19
NaOH, Na2CO3, and K2CO3) and NCS, we settled on
using either aqueous NaOH, NCS or Na2CO3, NCS in
THF, from the four conditions examined (Table 1). Occa-
sionally, with the stronger base we observed some hydro-
lysis (entries 3À5, Table 2) of the imidazolium salt and
other unidentified side product formation rather than
oxidation. This method was extended to include simple
imidazoles in addition to benzimidazoles. The reaction is
effective at producing the imidazolones in yields between
36 and 86%, and various combinations of nitrogen sub-
stituents are tolerated, including Bn, MOM, SEM and
PMB (Table 2, Method A or B)). These yields are similar to
As a result of this roadblock, we sought to develop a
method for the direct functionalization at the C2-position
that avoided metalation with strong (and potentially
nucleophilic) bases. The Ohta group has been a significant
contributor to the development of methods for the ela-
boration of simple imidazoles in the context of the total
(12) (a) Mukherjee, S.; Sivappa, R.; Yousufuddin, M.; Lovely, C. J.
Org. Lett. 2010, 12, 4940–4943. (b) Koswatta, P.; Lovely, C. J. Chem.
Commun. 2010, 46, 2148–2150. (c) Mukherjee, S.; Sivappa, R.; Yousu-
fuddin, M.; Lovely, C. J. Synlett 2010, 817–821. (d) Koswatta, P.;
Lovely, C. J. Tetrahedron Lett. 2010, 51, 164–166. (e) Bhandari,
M. K.; Sivappa, R.; Lovely, C. J. Org. Lett. 2009, 11, 1535–1538. (f)
Koswatta, P. B.; Sivappa, R.; Dias, H. V. R.; Lovely, C. J. Synthesis
2009, 2970–2982. (g) Koswatta, P. B.; Lovely, C. J. Tetrahedron Lett.
2009, 50, 4998–5000. (h) Koswatta, P. B.; Sivappa, R.; Dias, H. V. R.;
Lovely, C. J. Org. Lett. 2008, 10, 5055–5058.
(13) Jacobi, N.; Lindel, T. Eur. J. Org. Chem. 2010, 5415–5425.
(14) Lima, H. M.; Sivappa, R.; Yousuffudin, M.; Lovely, C. J. 2011,
unpublished results.
(15) (a) Ohta, S.; Tsuno, N.; Nakamura, S.; Taguchi, N.; Yamashita,
M.; Kawasaki, I.; Fujieda, M. Heterocycles 2000, 53, 1939–1955.
(b) Kawasaki, I.; Sakaguchi, N.; Khadeer, A.; Yamashita, M.; Ohta,
S. Tetrahedron 2006, 62, 10182–10192. (c) Nakamura, S.; Kawasaki, I.;
Kunimura, M.; Matsui, M.; Noma, Y.; Yamashita, M.; Ohta, S. J.
Chem. Soc., Perkin Trans. 1 2002, 1061–1066.
(16) Nakamura, S.; Tsuno, N.; Yamashita, M.; Kawasaki, I.; Ohta,
S.; Ohishi, Y. J. Chem. Soc., Perkin Trans. 1 2001, 429–436.
(17) (a) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719–3726.
(b) Ennis, E.; Handy, S. T. Curr. Org. Synth. 2007, 4, 381–389.
(18) These two substrates were chosen initially as they represented
models for advanced intermediates in total syntheses projects underway
in our lab.
(19) In this case, the reaction was performed through the sequential
addition of NaH followed by stirring, the addition of NCS followed by
stirring and then the addition of water.
Org. Lett., Vol. 13, No. 21, 2011
5737

those reported by Ohta and co-workers via the 2-thioben-
zimidazole derivatives.16
Table 2. Substrate Screena
Table 1. Preliminary Base Screen
While these procedures worked reasonably well, it oc-
curred to us that the same transformation might be
accomplished through the addition of household bleach
(NaOCl), which could serve as both the base and as the
source of a chloronium ion. Accordingly, we were de-
lighted to observe that treatment of the substrates in
Table 2 (Method C) with bleach at 0 °C resulted in the
smooth conversion into the corresponding imidazolones in
excellent yield and purity. In some cases, we found that
yields were improved and chlorination side reactions were
minimized by the reduction of the amount of bleach and
addition of NaOH (Method D).
From the substrates depicted in Table 2, it can be
observed that most of the imidazolones are relatively
simple, and in reality for our purposes we needed this
chemistry to be successful on more elaborate substrates. In
the context of our kealiiquinone endeavors, imidazolium
salt 1714 containing a lactone moiety was available, and
thus we subjected it to the oxidation chemistry. Gratify-
ingly, this substrate underwent oxidation to provide the
corresponding imidazolone in good yield upon treatment
with bleach (Scheme 3).
At this stage, we do not know whether this reaction
proceeds mechanistically via carbene 14 as depicted in
Scheme 2 or whether the alternative mechanism outlined
in Scheme 4 is more likely. Related observations of nu-
cleophilic substitution of 2-haloimidazolium salts have
been reported in the literature.20,21 While these observa-
tions do not prove that the 2-chloroimidazolium salt is
a Condition A = 1 M Na2CO3, NCS, THF; Condition B = 2 M
NaOH, NCS, Condition C = 10 equiv, NaOCl, THF, rt; Condition D =
1 equiv, NaOCl, NaOH, THF, rt.
formed in the course of the oxidation, they demonstrate
that it is a competent intermediate in this chemistry. In the
latter case, hydoxide adds to the imidazolium salt 15 to
form 19.22 O-Chlorination and then base-induced elimina-
tionof HCl from 20resultsinthe formation ofthe carbonyl
(20) Wamhoff, H.; Kleimann, W.; Kunz, G.; Theis, C. H. Angew.
Chem. 1981, 93, 601–602.
(21) Kitamura, M.; Yano, M.; Tashiro, N.; Miyagawa, S.; Sando,
(22) Medvedeva, M. M.; Pozharskii, A. F. Khim. Get. Soed. 1982,
M.; Okauchi, T. Eur. J. Org. Chem. 2011, 458–462.
1086–1088.
5738
Org. Lett., Vol. 13, No. 21, 2011

Scheme 5. Introduction of a 2-Imino Moiety
Scheme 3. C2-Oxidation of an Advanced Kealiiquinone Inter-
mediate
Scheme 4. Possible Mechanistic Pathways for Imidazolium Salt
Oxidation
the tosyl group is not always easy to remove and thus we
briefly examined other N-chloroamides (prepared in situ
from the corresponding carbamates by treatment with
t-BuOCl).23 Both the benzimidazole 15a and simple im-
idazole derivative 15h undergo amination with both the
benzyl and t-butyl chlorocarbamate providing the corre-
sponding imino derivative in good yields (Scheme 5).24,25
In summary, we have discovered a convenient procedure
for the direct conversion of imidazolium salts to imidazo-
lones by treatment with NCS/aqueous base or hypochlor-
ite. A range of substrates participate in this chemistry,
including benzimidazole, simple imidazole derivatives and
more elaborate benzimidazole derivatives. Similarly, the
use of N-chloro amides allows the incorporation of a
2-amino substituent. This process occurs at room tempera-
ture or below and avoids the use of strong bases and
transition metal catalysts. Current investigations are di-
rected toward determining the mechanistic details, extend-
ing the scope of this chemistry and applying it in the total
synthesis of various alkaloids.
moiety. Alternatively, with hypochlorite ion (either pro-
duced in situ or added directly), this may give species 20
directly, which upon base-induced elimination provides
the corresponding imidazolone.
While the mechanistic details of this reaction remain
unclear pending further investigation, we reasoned that
other reagents that contain a nucleophilic site and an
appropriately positioned leaving group may also partici-
pateinthischemistry. Specifically, itwashypothesizedthat
N-chloro amides would permit the direct introduction of
an amino moiety. We were delighted to observe that upon
treatment of imidazolium salt 15a with chloramine-T the
imino imidazole 21 was formed in 55% yield (Scheme 5).
Increasing the equivalents of chloramine-T to 2.2 improved
the yield of 21 to 95%. While this result was encouraging,
Acknowledgment. This work was supported by the
Robert A. Welch Foundation (Y-1362) and the NIH
(GM065503). The NSF (CHE-0234811, CHE-0840509) is
thanked for partial funding of the purchases of the NMR
spectrometers used in this work.
(23) Tsuruoka, R.; Nagamachi, T.; Murakami, Y.; Komatsu, M.;
Minakata, S. J. Org. Chem. 2009, 74, 1691–1697.
Supporting Information Available. Detailed experimen-
tal procedures, characterization data and copies of
1H and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(24) Ohta has demonstrated that 2-thio imidazolium salts undergo
substitution with carbamate anions to provide the corresponding 2-imi-
noimidazole, see: Kawasaki, I.; H., N.; Yanagitani, S.; Kakuno, A.;
Yamashita, M.; Ohta, S. J. Chem. Soc., Perkin Trans. 1 2001, 3095–3099.
(25) For a recent review of direct methods for the C2-amination of
azoles, see: Zhang, M. Synthesis 2011, 10.1055/s-0030-1260231.
Org. Lett., Vol. 13, No. 21, 2011
5739