Oxidative reactions of tetrahydrobenzimidazole derivatives with N-sulfonyloxaziridines

Article abstract of DOI:10.1016/j.tetlet.2007.06.088

An investigation of the utility of N-sulfonyloxaziridines to effect the oxidative rearrangement of tetrahydrobenzimidazoles to spiro fused 5-imidazolones is reported. In addition to the anticipated rearrangement manifold, it was found that 2-amino substit

Full text of DOI:10.1016/j.tetlet.2007.06.088

Tetrahedron Letters 48 (2007) 5771–5775
Oxidative reactions of tetrahydrobenzimidazole derivatives with
N-sulfonyloxaziridines
Rasapalli Sivappa, Panduka Koswatta and Carl J. Lovely*
Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, United States
Received 3 May 2007; revised 15 June 2007; accepted 18 June 2007
Available online 23 June 2007
Abstract—An investigation of the utility of N-sulfonyloxaziridines to effect the oxidative rearrangement of tetrahydrobenzimidaz-
oles to spiro fused 5-imidazolones is reported. In addition to the anticipated rearrangement manifold, it was found that 2-amino
substituted derivatives afford products resulting from rearrangement, or alternatively from addition of methanol or water depending
on the nature of the N-substituents and reaction conditions.
Ó 2007 Elsevier Ltd. All rights reserved.
As part of a broader investigation of the chemistry of
imidazoles,1 we recently reported a novel rearrangement
reaction of tetrahydrobenzimidazoles (THB’s, 1) leading
to the formation of spiro fused 5-imidazolones 2 upon
treatment with dimethyldioxirane (DMDO, 1!2,
Scheme 1).2–5 While no detailed mechanistic studies
were conducted, the reaction was formulated as pro-
ceeding via epoxide 3 in analogy with the corresponding
rearrangement of N-acyl indoles with DMDO.6,7 Subse-
quent ring opening of intermediate 3 leads to the forma-
tion of the more stable zwitterion 4, which rearranges
via a pinacol-type process to provide 2. While this chem-
istry was quite satisfactory in most respects, there were
practical aspects of this reaction that rendered it some-
what inconvenient, particularly for small scale scouting
experiments. Chief among the deficiencies was the need
to prepare isolated DMDO solutions, which often were
of variable concentration and would contain trace (and
variable) amounts of water. Therefore, we sought to
identify alternative oxidants that would effect this rear-
rangement. Among several possibilities, Davis’ reagents,
N-sulfonyloxaziridines,8,9 attracted our attention as they
share many common characteristics with dioxiranes,
therefore it occurred to us that this class of reagent
may offer a shelf-stable alternative to DMDO. These
reagents are readily accessible by oxidation of the
N-sulfonylimine, which in turn can be obtained from
condensation of the corresponding benzaldehyde deriv-
ative and a sulfonamide.10
Me
O
O
O
Me
N
N
PG
N
N
PG
1
2
Me
Me
Me
Me
O
O
Pinacol-like
rearrangement
In our previously reported studies,2 it was found that the
THB 1 needed to be reasonably electron rich for this
reaction to occur, and so in preliminary experiments,
the Me-substituted THB 1a was employed. After a few
test reactions, we were delighted to find that exposure
of 1a to 2.0 equiv of phenyl sulfonyloxaziridine 5 in
CHCl3 led to a smooth rearrangement reaction,11 pro-
viding the spiro fused 5-imidazolone 2a in 82% yield
(Table 1, entry 1). Interestingly, in addition to the major
rearrangement product, a small amount of a second
product was isolated in ꢀ2% yield. It was clear from
the NMR data and HRMS analysis that this byproduct
contained fragments derived from the oxaziridine. A
O
N
N
N
N
O
O
PG
PG
3
4
Scheme 1.
*
Corresponding author. Tel.: +817 272 5446; fax: +817 272 3808;
e-mail: lovely@uta.edu
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.088

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R. Sivappa et al. / Tetrahedron Letters 48 (2007) 5771–5775
Table 1. Conditions and yields for oxidative rearrangement of various THB derivatives
Entry
PG
X
Substrate
Conditions
Product
Yield/%
1
2
3
4
5
6
Me
Bn
MOM
SEM
DMAS
Bn
H
H
H
H
1a
1b
1c
1d
1e
1f
CHCl3, rt, 4 h, 5
CHCl3, rt, 4 h, 5
CH2Cl2, 40 °C, 26 h, 5
2a
2b
2c
2d
2e
2f
82
80
50
60
NR
56
CHCl3, rt, 16 h, 5
a
H
CO2Me
CHCl3, 40 °C, 24 h, 6
a No rearrangement was observed with either 5 or 6 at temperatures up to 60 °C.
clue to the identity of this product was found in a study
by Dmitrienko of the utility of N-sulfonyloxaziridines as
oxygen transfer agents with indoles.9,12 Instead of the
desired oxindoles, formal [3+2] oxaziridine–alkene cyclo-
adducts (across the indole 2,3-bond) were isolated as
the major products (diastereomeric mixture) when sim-
Given the success of this initial reaction we began to
investigate the scope and limitations of this reaction.
In the course of our earlier DMDO study,2 we had
assembled a collection of THB derivatives that differed
in the nature of the N-substituent 1a–e and the C2 sub-
stituent 1f. These were investigated in the rearrangement
chemistry with Davis’ reagents (Ar = Ph, 5 or Ar = p-
NO2C6H4, 6) and the outcome of this investigation is re-
ported in Table 1 (entries 2–6).14 As can be seen, the
rearrangement proceeds with the same types of sub-
strates that undergo reaction with DMDO, and simi-
larly, the same set of unreactive substrates fail to
rearrange, including the DMAS-protected (DMAS =
Me2NSO2) derivative 1e.2 For the more electron defi-
cient substrates, heating was required to effect rear-
rangement (Table 1, 1c, entry 3), and in some cases
the more reactive oxaziridine (Ar = 4-NO2C6H4, 6)
was required (Table 1, 1e, entry 6). We also investigated
the reaction of unsubstituted tetrahydrobenzimidazole,
that is, PG = H and found that it reacts with both
Davis’ reagents (5, Ar = Ph or 6, Ar = 4-NO2C6H4),
but provides the addition product 9a or 9b as a separa-
ble mixture of as yet unassigned diastereomers, rather
than rearrangement products.
ple benzaldehyde-derived oxaziridines were used.12,13
A
similar adduct 8a is formed in this case through net
addition of the oxaziridine across the imidazole 4,5-
bond. Although the relative stereochemistry of the benz-
ylic center awaits assignment, the regiochemistry of the
adduct has been proposed based on the putative mecha-
nism of formation (Scheme 2). The isolation of 8a has
implications for the mechanism of this rearrangement
reaction. As described above in Scheme 1, the
DMDO-mediated rearrangement was proposed to pro-
ceed via 3a,7a-epoxide 3, which opens to form 4, and
then rearranges.2 The isolation of 8a when an N-
sulfonyloxaziridine is employed suggests an alternative
mechanistic pathway involving the direct formation of
zwitterion 5, and then either elimination of imine and
rearrangement to spiro imidazolone (7!2, Scheme 2),
or intramolecular trapping to generate 8 (7!8, Scheme
2). While extrapolation of this mechanistic proposal to
the DMDO-mediated process should be made with cau-
tion, the direct formation of the zwitterionic intermedi-
ate 4 (or the corresponding DMDO adduct related to 7)
cannot be ruled out on the basis of the experimental
data available.6
One major deficiency of the DMDO-mediated rear-
rangements was application of this reaction to 2-amino
substituted derivatives.15 It was our intention to use this
transformation in approaches to a variety of marine nat-
ural products in the oroidin and related families.1,15,16
Therefore, we decided to investigate the use of Davis’
reagents with substrates of this type. Since Davis’ re-
agent led to rearrangement of the benzyl-protected
THB and as some of our on-going total synthesis efforts
utilized benzyl-protected derivatives, we prepared both
the 2-azido, and the N-phthalimidoyl derivatives 10
and 14, respectively, for investigation. The 2-azido
derivative 10 was obtained by lithiation of 1b at C2, fol-
lowed by treatment with TsN3. NaBH4 reduction of 10
and treatment 12 with the modified Nefkens’ reagent
provided phthalimide derivative 14 (Scheme 3).17 We
had found in our initial studies with Davis’ reagent that
the DMAS-protected THB 1e did not undergo rear-
rangement, but we speculated that if the electron density
of the imidazole moiety could be increased, a rearrange-
ment might ensue. Accordingly, the 2-amino derivative
15 was prepared as above via metalation and trapping
with TsN3 providing the 2-azido congener 11 (Scheme
3), which was easily reduced to amine 13, which in turn
was protected with a phthaloyl moiety on treatment
with Nefkens’ reagent, providing 15.
O
N SO2Ph
H
Ar
O
N
N
PG
Ar
X
N
5: Ar = Ph
6: Ar = 4-NO2Ph
N
PG
X
2a-f
1a-f
PhSO2N
SO2Ph
N
N
N
N
5 or 6
Ar
O
N
PG
O
Ar
NSO2Ph
PG
8a: PG = Me, Ar = Ph, 2%
8b: PG = Bn, Ar = Ph, ~2%
7
9a: PG = H, Ar = Ph, 12
& 32%
9b: PG = H, Ar = 4-NO2Ph, 32 & 30%
Scheme 2.

R. Sivappa et al. / Tetrahedron Letters 48 (2007) 5771–5775
5773
both 10 and 14 underwent smooth rearrangement to
the corresponding 5-imidazolones 16 and 17 (Scheme
4), respectively (Table 2, entries 1 and 2). Unfortunately,
this was not the case with the DMAS derivatives as
neither the protected substrate 15 nor the azide 11
rearranged (Table 2, entries 4 and 5), however, we
discovered that when the 2-amino derivative 13 was
reacted with oxaziridine 6 in methanol a rapid reaction
occurred, but not the anticipated rearrangement to a
5-imidazolone.18 On isolation of the product it was clear
from the NMR data that it contained a methoxy group,
and the typical signal due to the imidazolone carbonyl in
the 13C NMR spectrum at around dC = 180 ppm was
N
N
1.
n-BuLi, THF
N
N
N3
2. TsN3, -78 °C
PG
PG
1b: PG = Bn
1e: PG = DMAS
10: PG = Bn, 60%
11: PG = DMAS, 85%
O
S N
O
Me
NaBH4,
MeOH,
0 °C
DMAS =
Me
O
NBOC
N
N
N
O
H2N
PhthN
N
PG
K2CO3, CH2Cl2
PG
O
N SO2Ph
12: PG = Bn, 98%
13: PG = DMAS, 100%
14: PG = Bn, 90%
15: PG = DMAS, 87%
O
H
Ar
N
N
PG
X
N
Scheme 3.
N
PG
X
10-15
16-18
Gratifyingly, on treatment of the benzyl-protected deriv-
Scheme 4.
atives with the nitrophenyl substituted oxaziridine 6,
Table 2. Oxidation products of 2-azaimidazole derivatives
Entry
PG
X
Substrate
Conditions
Product (%)
O
Bn
N
N
1
Bn
N3
10
CHCl3, 35 °C, 24 h, 6
CHCl3, 35 °C, 24 h, 6
MeOH, rt, 4 h, 5
N3
16 (70)
O
Bn
N
2
3
Bn
Bn
NPhth
14
N
PhthN
17 (40)
O
Bn
N
N
NH2
12
H2N
18 (59)
a
a
4
5
DMAS
DMAS
N3
11
15
NR
NR
NPhth
OMe
OH
H
O
N S
O
N
N
6
DMAS
NH2
13
MeOH, rt, 4 h, 6
N
H
19 (68)
OH
H
N
O
N S N
O
7
DMAS
NH2
13
H2O, acetone, rt, 4 h, 5
N
H
OH
20 (70)
a No rearrangement was observed with either 5 or 6 at temperatures up to 60 °C.

5774
R. Sivappa et al. / Tetrahedron Letters 48 (2007) 5771–5775
absent.2 The NMR and MS data pointed to the forma-
tion of the hydroxy methyl ether 21 (Scheme 5), in which
the stereochemistry was assigned on the basis of metha-
nol trapping the (incipient) carbocation on the opposite
face from the oxaziridine approach.19 Subsequently, an
X-ray structure determination proved that both our ste-
reochemical proposal and our constitutional assignment
were incorrect. The methoxy and hydroxy groups were
in fact cis to one another and there was a net migration
of the DMAS moiety to the exocyclic nitrogen. Presum-
ably, the locus of the N-protecting group changes as a
result of a ring opening/reclosure sequence via 24 de-
picted in Scheme 5. We cannot distinguish at this time
whether the initial formation of the expected adduct
21 occurs, and that this rearranges to form the observed
adduct 19, or the formation of the cis isomer 23 occurs,
which then rearranges to 19. It was also found that a
similar reaction could be performed in aqueous acetone,
leading to the formation of a dihydroxylation product
(Table 2, 20, entry 7). The constitution was assigned
on the basis of the 13C NMR spectrum, in which only
five unique carbon signals were observed. The stereo-
chemical assignment is by analogy to 19.20 As the
DMAS-derivative 15 underwent an addition reaction,
we wanted to establish whether the Bn-derivative 12 also
underwent this same type of transformation. Interest-
ingly, and in contrast, subjection of 12 to the same reac-
tion conditions led to rearrangement, rather than
addition, providing the imidazolone 16 (Table 2, entry
3).
imine) and rearrangement. On the other hand, with
the more electron deficient system 13, presumably the
zwitterion 19 is relatively unstable, and is heavily sol-
vated leading to trapping of the carbocation with
methanol.
In summary, aryl N-sulfonyloxaziridines are effective re-
agents for the oxidative rearrangement of tetrahydro-
benzimidazoles to the corresponding spiro fused 5-
imidazolones or in some cases to bis addition products.
Although we are still investigating this chemistry, there
are some fairly subtle effects in play here that lead to
various outcomes depending on the nature of the 2-sub-
stituent and the solvent employed. Also of note is the
fact that a free amine can be tolerated with these sub-
strates leading to either rearrangement or addition of
solvent depending upon the N1 protecting group. These
reagents provide a shelf-stable alternative to DMDO,
which has to be prepared in isolated form to effect this
rearrangement.2 We are continuing to explore the utility
of Davis’ reagents to effect oxidation reactions of imid-
azole-containing substrates and its use in total synthesis
efforts.
Acknowledgments
Professor H. V. Rasika Dias is gratefully acknowledged
for obtaining and solving the X-ray structure of com-
pound 19. This work was supported by the Robert A.
Welch Foundation (Y-1362)
and the NIH
This spectrum of reactivity is interesting and presumably
reflects the relative stabilities of the zwitterionic interme-
diate 5. In the case of 12, this is highly electron rich and
so the carbocationic center is quite stable (via delocaliza-
tion of the amine lone pair), which in turn permits col-
lapse of the carbinolamine (with expulsion of the
(GM065503). The NSF (CHE-9601771, CHE-0234811)
is thanked for partial funding of the purchases of the
NMR spectrometers used in this work.
References and notes
1. He, Y.; Du, H.; Sivappa, R.; Lovely, C. J. Synlett 2006,
965.
2. Lovely, C. J.; Du, H.; He, Y.; Dias, H. V. R. Org. Lett.
2004, 6, 735.
OMe
N
N
N
6, MeOH
H2N
H2N
rt, 68%
N
OH
DMAS
DMAS 13
3. A similar type of rearrangement occurs on treatment of
tetrahydrobenzimidazoles with singlet oxygen in the pres-
ence of base, see: (a) Bernhart, C. A.; Perreaut, P. M.;
Ferrari, B. P.; Muneaux, Y. A.; Assens, J. L. A.; Clement,
J.; Haudricourt, F.; Muneaux, C. F.; Taillades, J. E.;
Vignal, M.-A.; Gougat, J.; Guiraudou, P. R.; Lacour, C.
A.; Roccon, A.; Cazaubon, C. F.; Breliere, J.-C.; Le Fur,
G.; Nisato, N. J. Med. Chem. 1993, 36, 3371; (b) Kimura,
M.; Lu, G.; Iga, H.; Tsunenaga, M.; Zhang, Z.; Hu, Z.
Tetrahedron Lett. 2007, 48, 3109.
21
MeOH
OMe
H
N
DMASN
N
N
H
H2N
OH
N
O-
22
19
DMAS
4. The Chen lab has reported a similar oxidative rearrange-
ment of imidazolones using MCPBA, see: Tan, X.; Chen,
C. Angew. Chem., Int. Ed. 2006, 45, 4345.
MeOH
5. Romo and co-workers have reported several examples of
reactions of imidazolones with DMDO, however these
rearrange via an alternate pathway providing allylic
alcohols, which on treatment with NCS rearrange to spiro
imidazolones, see: (a) Dilley, A. S.; Romo, D. Org. Lett.
2001, 3, 1535; (b) Dransfield, P. J.; Wang, S.; Dilley, A.;
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.
OMe
H
N
OMe
N
H2N
H2N
DMASN
N
O
O
H
DMAS
B
24
23
Scheme 5.

R. Sivappa et al. / Tetrahedron Letters 48 (2007) 5771–5775
5775
6. (a) Zhang, X.; Foote, C. S. J. Am. Chem. Soc. 1993, 115,
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13. It has recently been demonstrated that N-sulfonyloxazir-
idines undergo a [3+2] cycloaddition reaction with olefins
in the presence of CuX, see: Michaelis, D. J.; Shaffer, C. J.;
Yoon, T. P. J. Am. Chem. Soc. 2007, 129, 1866.
14. The [3+2] adduct 6b was obtained with 1b, but we were
unable to fully purify this material to determine an
accurate yield, but it was of the same order as 1a.
15. He, Y. Ph.D. Dissertation, 2004, The University of Texas
at Arlington.
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Lavilla, R.; Baron, X.; Coll, O.; Gullon, F.; Masdeu, C.;
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9. While this manuscript was in preparation, the Williams
lab reported that N-sulfonyloxaziridines can be utilized in
the oxidative rearrangement of indoles to spiro oxindoles,
see: (a) Grubbs, A. W.; Artman, G. D., III; Tsukamoto,
S.; Williams, R. M. Angew. Chem., Int. Ed. 2007, 46, 2257;
(b) Greshock, T. J.; Grubbs, A. W.; Tsukamoto, S.;
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11. Other solvents were investigated including CH2Cl2,
MeCN, PhH, and MeOH, but CHCl3 was generally
superior.
17. Einhorn, C.; Einhorn, J.; Marcadal-Abbadi, C. Synth.
Commun. 2001, 31, 741.
18. An initial experiment conducted in chloroform indicated
that
a reaction occurred as the starting material
was consumed, but no characterizable products were
isolated.
19. A related adduct was obtained by Horne and co-workers
on treatment of the 2-aminoimidazoles with NCS and
methanol, in which the two newly installed methoxy
groups were trans to one another. Olafson, A.; Yakushijin,
K.; Horne, D. A. J. Org. Chem. 1998, 63, 1248.
20. Baran and co-workers reported the oxidation of one of the
2-aminoimidazole moieties in ageliferin with peracetic acid
leading to the formation of the dihydroxylated derivative.
Subsequent treatment with NaHCO3 led to the formation
of the spiro fused imidazolone, see: O’Malley, D. P.; Li,
K.; Maue, M.; Zografos, A.; Baran, P. S. J. Am. Chem.
Soc. 2007, 129, 4762.
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