Late-stage diversification of chiral N-heterocyclic-carbene precatalysts for enantioselective homoenolate additions

Article abstract of DOI:10.1002/asia.201000617

A library of chiral triazolium salts has been prepared by late-state diversification of a triazolium amine salt. By utilizing a primary amine as a functional handle, a single triazolium salt can be transformed into a variety of chiral N-heterocyclic carbene precatalysts. This approach makes the preparation of chiral N-heterocyclic carbenes possible by a single-step modification of a triazolium salt, rather than the usual need for multistep organic synthesis and challenging heterocycle formation for each member of a catalyst library. We have screened these catalysts for control of diastereo- and enantioselectivity in a γ-lactam-forming reaction between α,β-unsaturated aldehydes and cyclic ketimines. Saving the best for last: Enantioselective homoenolate additions have been hindered by the challenge of synthesizing N-mesityl-substituted azolium salts. A library of pyrrole-functionalized chiral triazolium salts was prepared by direct modification of the preformed azolium core. Copyright

Full text of DOI:10.1002/asia.201000617

FULL PAPERS
DOI: 10.1002/asia.201000617
Late-Stage Diversification of Chiral N-Heterocyclic-Carbene Precatalysts for
Enantioselective Homoenolate Additions
Pinguan Zheng, Chenaimwoyo A. Gondo, and Jeffrey W. Bode*[a]
Dedicated to Professor Eiichi Nakamura on the occasion of his 60th birthday
Abstract: A library of chiral triazolium
salts has been prepared by late-state di-
versification of a triazolium amine salt.
By utilizing a primary amine as a func-
tional handle, a single triazolium salt
can be transformed into a variety of
chiral N-heterocyclic carbene precata-
lysts. This approach makes the prepara-
tion of chiral N-heterocyclic carbenes
possible by a single-step modification
of a triazolium salt, rather than the
usual need for multistep organic syn-
thesis and challenging heterocycle for-
mation for each member of a catalyst
library. We have screened these cata-
lysts for control of diastereo- and enan-
tioselectivity in a g-lactam-forming re-
action between a,b-unsaturated alde-
hydes and cyclic ketimines.
Keywords: carbenes · asymmetric
catalysis · heterocycles · homoeno-
lates · N-heterocyclic carbenes
Introduction
Unlike the increasingly mild and general methods for eno-
late generation,[4] the majority of protocols for the use of ho-
moenolates require harsh conditions and strong reagents,
which limits both their synthetic appeal and their options
for the development of catalytic, enantioselective variants.
In 2004, both our group[5] and that of Glorius[6] independ-
ently reported the first catalytic method for the generation
of homoenolate equivalents by the combination of a,b-unsa-
turated aldehydes and a N-heterocyclic carbene (NHC) cat-
alyst. This mild and simple protocol catalytically generates
homoenolates at ambient temperature without the need for
stoichiometric additives or exclusion of water. Following our
initial report on the use of this chemistry for the preparation
of g-lactones, NHC-catalyzed homoenolate formation has
been extended to the synthesis of g-lactams and related het-
erocycles,[7] spiro g-butyrolactones,[8] and pyridazinones[9]
(see Scheme 1). Similar conditions and catalysts can be used
to prepare cyclopentenes and cyclopentane derivatives in
good yield and with high enantioselectivity, but more-com-
plex mechanisms, rather than a simple homoenolate equiva-
lent, may be involved in those processes.[10]
Homoenolates are synthetically important reactive species
for the construction of both linear and cyclic stereochemical
assemblies. In contrast to their enolate counterparts, which
can be generated under a larger number of catalytic and sto-
ichiometric conditions, there are relatively few general
methods for the preparation of homoenolates and their ad-
dition to suitable electrophiles. The first general stoichio-
metric methodology for homoenolate additions was pio-
neered by Nakamura, Kuwajima et al.[1] who demonstrated
that cyclopropane silyl hemiketals serve as homoenolate
equivalents under strong Lewis acid catalysis. Other advan-
ces in the preparation of homoenolates under stoichiometric
conditions include Hoppeꢀs g-deprotonation of carbamates
facilitated by (À)-sparteine[2] and a single report on the use
of a b-trimethylsilyl ester[3] as a homoenolate precursor.
[a] Dr. P. Zheng, C. A. Gondo, Prof. Dr. J. W. Bode+
Roy and Diana Vagelos Laboratories
Department of Chemistry
University of Pennsylvania
Philadelphia, PA 19104 (USA)
[+] Present address:
The most synthetically valuable products obtained from
NHC-catalyzed homoenolate generation are arguably the g-
lactone and g-lactam products. These two structural motifs
feature prominently in several classes of biologically active
natural products and pharmaceuticals. For example, g-lac-
tams constitute the core of natural products, including clau-
senamide,[11] salinosporamide,[12] and the polychlorinated
Laboratorium fꢁr Organische Chemie
ETH-Zꢁrich, Wolfgang Pauli Strasse 10, Zꢁrich 8093 (Switzerland)
E-mail: bode@org.chem.ethz
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000617.
614
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Chem. Asian J. 2011, 6, 614 – 620

various pendant groups, includ-
ing pyrroles, thioureas, and ter-
tiary amines, to quickly gener-
ate a small library of chiral azo-
lium salts. These precursors to
chiral NHC catalysts were
screened for enantioselectivity
against a particularly challeng-
ing g-lactam formation that
used saccharine-derived keti-
mines as electrophiles.
Results and Discussion
Scheme 1. Selected NHC-catalyzed homoenolate additions of enals to various electrophiles.
Ongoing work from our labora-
tory has employed chiral bicy-
dysidamides.[13] NHC-catalysis offers a direct, one-step route
to the core of a number of these molecules. However, these
protocols largely remain limited to racemic products; de-
spite considerable effort, there have been few successful re-
ports of highly enantioselective NHC-catalyzed syntheses of
g-lactones and g-lactams through NHC-catalyzed homoeno-
late generation.[14] This is surprising because other reaction
manifolds promoted by NHC-catalysts, such as benzoin[15]
and Stetter reactions,[16] formal cycloadditions,[17] and proto-
Scheme 2. Late-stage modification of 1.
nation reactions,[18] may be effected with high enantioselec-
tivity by using a number of chiral catalysts.[19]
The difficulty in identifying superior catalysts for NHC-
catalyzed g-lactam and g-lactone formation lies partly in the
synthetic complexity of preparing chiral NHCs or, more pre-
cisely, their azolium-salt precursors.[15d,20,21] The best catalysts
often require numerous steps for their preparation, many of
which require re-optimization after even modest changes in
the structures. The relatively harsh conditions needed for
the formation of the imidazolium or triazolium ring limit
the choice of pendant functionality compatible with the
known synthetic protocols. This limitation is particularly
true for the formation of azolium salts bearing sterically hin-
dered N-mesityl groups, which have been shown to be essen-
tial for most NHC-promoted homoenolate reactions. In
seeking to further the development of chiral NHC catalysts,
we sought an approach for the late-stage variation of the
catalyst structure by elaborations after the installation of the
azolium ring. Similar late-stage modifications have proven
to be highly effective in the synthesis and screening of other
catalyst types, including ligands for transition-metal-cata-
lyzed reactions[22] and thioureas.[23] This approach, however,
has seen less use with chiral azoliums or NHC-carbene li-
gands, owing to potential difficulties of synthetic manipula-
tions and purifications of molecules containing the azolium
salts.
clic triazolium salts similar to those originally prepared by
Knight and Leeper[21] in asymmetric benzoin and Stetter re-
actions. Subsequent efforts by Rovis and co-workers[25] and
Enders and Han[20] have improved the synthesis of these
structures, and provide catalysts that offer excellent enantio-
selectivity in reactions that occur through acyl anion equiva-
lents. In our studies that required an N-mesityl moiety on
the triazolium ring, we often found that bicyclic precata-
lyst 7, derived from (S)-phenylalanine, gave the best results,
albeit still with suboptimal levels of stereoselectivity. Un-
fortunately, modification of the benzyl group was a long and
costly process that required the prior synthesis of the corre-
sponding enantiopure amino acid followed by seven steps
for each catalyst derivative. For example, the naphthyl-con-
taining triazolium 6 was prepared over seven steps from the
commercially available, but rather expensive, unnatural
amino acid 2 (Scheme 3). The same—or similar—procedures
were used for the preparation of several other triazolium
precatalysts (7–20), some of which were previously reported
by ourselves or others. To confirm that epimerization did
not occur during this sequence, triazolium salt 7 and its
enantiomer were prepared with the chiral counteranion (S)-
(+)-binaphthyl-2,2’-diyl phosphate.[26] The resulting diaste-
reomeric salts had distinctly different 1H NMR and
13C NMR spectra.
Herein, we report the preparation of N-mesityl-substitut-
ed triazolium 1, which contains a chiral aminomethyl func-
tionality that is poised for further elaboration (Scheme 2).[24]
This synthetic handle was exploited in the introduction of
In seeking less-expensive starting materials and a route
amenable to late-stage modification, ideally following the in-
troduction of the N-mesityl moiety and the completion of
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J. Bode et al.
FULL PAPERS
give esters afford products that
were not always stable to the
conditions of NHC-catalyzed
reactions. Therefore, we target-
ed the chiral aminomethyl-sub-
stituted triazolium 1, which we
believed could be elaborated by
reactions at the primary amine
as the final step in the precata-
lyst synthesis (see Scheme 4).
Our synthesis began from
readily available (S)-pyrogluta-
mic acid methyl ester 21. Selec-
tive reduction of the ester to
the primary alcohol followed by
mesylation and displacement
with sodium azide afforded 23,
a sequence previously reported
by Bateman et al.[29] In an anal-
ogy to the protocol described
by Knight and Leeper[21] and
ourselves,[30] 23 was methylated
with Meerweinꢀs salt to give
neutral imidate 24 in 85%
yield. Condensation with N-me-
sitylhydrazine hydrochloride af-
forded 26, which was further
used without purification to
generate N-mesityl triazolium
chloride 27. In our hands, re-
duction of the azide to the
amine was best effected by zinc
metal in aqueous ethanol fol-
lowed by careful workup to
separate the hydrochloride salt
of the product from unreacted
zinc metal. These procedures
could be executed on a 5–10
gram scale, although care in the
final azide reduction was neces-
sary.
Conversion
of
primary
amines into pyrroles by the
Paal–Knorr reaction was partic-
ularly valuable in the combina-
torial synthesis of chiral cata-
lysts, and we chose this reaction
for our initial elaborations
(Scheme 5).[23] Although the
Scheme 3. Chiral triazolium salts synthesized by our group or others and used in this study. DCC=N,N’-dicy-
clohexylcarbodiimide, DMAP=4-dimethylaminopyridine, Meldrumꢀs acid=2,2-dimethyl-1,3-dioxane-4,6-
dione, Boc=tert-butoxycarbonyl, TFA=trifluoroacetic acid. For previous syntheses of 7-8 and 10,[10b] 11,[28]
12,[27] and 20[20] see references, respectively.
the triazolium ring, we wanted to prepare a structure with a
suitable synthetic handle. Earlier work in our group on
chiral carboxylic acid 28 established the viability of such a
route, but was plagued by epimerization of the chiral center.
Azolium precatalyst 29, which bears a primary alcohol, has
also been prepared, but simple derivatization reactions to
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Chem. Asian J. 2011, 6, 614 – 620

Late-Stage Diversification of Chiral N-Heterocyclic Carbene Precatalysts
Scheme 4. Synthesis of 1 from (S)-methyl pyrroglutamate. Ms=methanesulfonyl, DMF=N,N-dimethylformamide, Mes=mesityl.
use of the azolium salt initially complicated the reactions
and isolations, successful procedures were identified after
some experimentation. For bisACTHNUTRGNEUGN(ketones), the optimal condi-
tions employed one equivalent of HCl in methanol, and pro-
vided products 30–34 in 23–29% yield. However, the same
conditions applied to 1,4-ketoaldehydes only resulted in de-
composition of the starting materials. A survey of other con-
ditions for the Paal–Knorr synthesis led to an improved pro-
cedure that employs acetic acid to afford the desired prod-
ucts 35–38 in 39–67% yield. Other modifications of primary
amine 1 were conversion into thiourea 39 by reaction with
an isothiocyanate, as well as dimethylation to give 40
(Scheme 6).
Scheme 6. Other chiral-amine derivatives prepared from 1.
In 2008, we reported the direct annulation of a,b-unsatu-
rated aldehydes with ketimines derived from saccharine
(Scheme 7) to give g-lactams.[7d] Our preliminary studies
showed that the catalyst structure had a profound effect on
the stereochemical outcome. In-
terestingly, the azolium precata-
lysts that gave the highest enan-
tioselectivities gave the poorest
diastereoselectivity. Chiral var-
iants 42, 43, and 44 gave rise to
the g-lactams with excellent
diastereoselectivity in transfor-
mations that favored the cis
isomer.
As an initial test of our cata-
lyst library, which consisted of
the compounds shown in
Schemes 3 and 5, we screened
these azolium salts for their
ability to promote the g-lactam-
forming annulation between
cinnamaldehyde and phenyl-
substituted saccharine deriva-
tive 46 (Table 1). For initial
work, we selected conditions
employing 5–10 mol% of the
catalyst and 20 mol% DBU at
258C in dichloromethane. The
conversion into the product,
diastereoselectivity, and enan-
tioselectivity of the major cis
diastereomer were directly as-
Scheme 5. Paal–Knorr synthesis of pyrrole-functionalized precatalysts. Ac=acetyl.
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J. Bode et al.
FULL PAPERS
um precatalysts bearing the N-
mesityl moiety and various sub-
stituted pyrrolidine rings gave
similar results despite consider-
able changes in the size of the
pendant group (Table 1, en-
tries 1–5). Variation of the tria-
zolium N-substituted (Table 1,
entries 6–13) gave similar enan-
tioselectivity but lowered the
conversion and diastereoselec-
tivity. With the exception of 11,
the perfluorophenyl-substituted
Scheme 7. Previous attempts at enantioselective g-lactam formation by triazolium-catalyzed homoenolate addi-
tions to saccharine-derived ketimines. DBU=1,8-diazabicycloACTHNUTRGNEU[GN 5.4.0]undec-7-ene.
triazolium compounds were in-
effective as catalysts. These
electron-deficient azoliums are
usually poor catalysts for NHC-catalyzed reac-
tions that occur through homoenolate equiva-
lents.[10b]
Table 1. Screening of chiral-azolium catalysts for enantioselective annu-
lation of cinnamaldehyde and ketimine 46.
We were pleased to find that the pyrrole-sub-
stituted triazolium salts (entries 14–22) were ef-
fective catalysts because these structural motifs
have not previously been employed in NHC-cat-
alyzed processes. Although they did not offer im-
proved selectivity in this (particularly challeng-
ing) case, their synthetic availability and late-
stage diversification should prove valuable in
other enantioselective reactions promoted by this
class of catalysts.
Entry
Catalyst
Conversion [%][a]
d.r.[b]
ee [%] (major)
1
2
3
4
5
6
7
8
6[c]
7[c]
61
57
100
100
87
98
10
n.r.
10
70
70
51
17
89
98
100
19
n.r.
41
96
13:1
24:1
13:1
5:1
3:1
12:1
nd
53
57
52
34
42
58
42
8[c]
9[c]
10[c]
11[c]
12[c]
13[c]
14[c]
15[c]
16[c]
19[c]
20[c]
30[d}
31[d}
32[d}
33[d}
34[d}
35[d}
36[d}
37[d}
38[d}
39[c}
40[c}
Conclusions
9
nd
3:1
2:1
3:1
5:1
6:1
7:1
5:1
10:1
–
9:1
13:1
–
8:1
2:1
8:1
28
38
41
61
56
25
23
23
23
–
45
55
–
53
27
43
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
We have described the preparation of a number
of novel triazolium precatalysts for NHC-cata-
lyzed reactions. We disclosed the preparation of
N-mesityl-substituted triazolium amine 1 and its
late-stage, one-step conversion into various pyr-
role-substituted precatalysts by Paal–Knorr syn-
thesis on the intact triazolium salt. The success of
this reaction as the last step in the synthetic se-
quence suggests that further functionalization of
the amine or other functional groups will be pos-
sible, which should aid the rapid generation of
structurally diverse libraries of chiral NHC cata-
lysts and ligands.
n.r.
80
100
100
[a] Relative conversion determined with SFC. Direct comparison of the
area under the peak for 46, the limiting reagent, versus the combined
areas of 47 and 48. [b] Diastereomeric ratio determined by direct com-
parison of the area of the two enantiomers of 47 and 48. [c] 5 mol% cata-
lyst used [d] 10 mol% catalyst used.
Experimental Section
Preparation of (S)-5-(azidomethyl)-2-mesityl-6,7-dihydro-
5H-pyrrolo
[2,1-c]
E
A
sayed by supercritical fluid chromatography (SFC) with
chiral columns.
Despite a wide scope in the appendages of the azolium
catalysts, this annulation reaction was remarkably intransi-
gent to improved enantioselectivity, with no catalysts giving
greater than 70% enantiomeric excess (ee). Chiral triazoli-
flame-dried 1 L round-bottomed flask was charged with a magnetic stir-
rer bar, (S)-5-(azidomethyl)-2-pyrrolidone (23, 6.0 g, 43 mmol, 1.0 equiv),
CH2Cl2 (300 mL), and trimethyloxonium tetrafluoroborate (7.0 g,
47 mmol, 1.1 equiv). The tan mixture was stirred at ambient temperature
under an atmosphere of nitrogen for 17 h. The solution was cooled to
08C and quenched by the slow, portionwise addition of NaHCO3 (satu-
rated aqueous, 300 mL) over a period of 1.5 h; stirring was maintained
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Late-Stage Diversification of Chiral N-Heterocyclic Carbene Precatalysts
for an additional 1 h. The biphasic mixture was transferred to a separato-
ry funnel, and the organic phase was isolated, dried over Na2SO4, filtered,
and concentrated to afford the crude iminoether (5.6 g, 85%) as a brown
oil, which was used without further purification. A flame-dried 500 mL
round-bottomed flask was charged with the crude iminoether (5.5 g,
35 mmol, 1.0 equiv), a magnetic stirrer bar, 2- mesitylhydrazinium chlo-
ride[30] (6.6 g, 35 mmol, 1.0 equiv), and MeOH (140 mL), which resulted
in a deep-red–orange solution that was stirred at 508C under an atmos-
phere of nitrogen for 1 h. The reaction was allowed to cool to ambient
temperature, and then concentrated under reduced pressure to afford the
hydrazone as a crude orange solid. The crude material was suspended in
EtOAc and placed in a sonicating bath for 30 minutes. The light-orange
precipitate (recovered 2-mesitylhydrazinium hydrochloride) was removed
by suction filtration. The filtrate was concentrated under reduced pres-
sure to afford crude hydrazone 26 (8.7 g, 79%) as an orange foam. Trie-
thylorthoformate (38 mL, 280 mmol, 10 equiv), chlorobenzene (28 mL),
and anhydrous HCl (4m in 1,4-dioxane, 7.0 mL, 28 mmol, 1.0 equiv) were
added to the round-bottomed flask that contained the crude hydrazone.
The reaction vessel was equipped with a water-jacketed condenser, and
stirred at 1008C for 50 min under an atmosphere of nitrogen. The brown
solution was allowed to cool to ambient temperature and concentrated
under reduced pressure. The crude brown solid was purified by flash
column chromatography on silica gel (gradient elution, CH2Cl2/acetone,
10:1 to 5:1 to 2:1 to 1:1) to give the title compound (4.45 g, 50%) as a
1H), 2.79–2.82 (m, 1H), 2.50–2.51 (m, 1H), 2.36 (s, 3H), 2.18 (s, 3H),
2.04 ppm (s, 6H); 13C NMR (125 MHz, MeOD): d=164.3, 143.5, 136.3,
134.9, 134.6, 133.2, 132.4, 130.6, 130.1, 129.3, 128.5, 111.5, 109.3, 62.1,
46.9, 31.5, 22.0, 21.1, 17.4, 13.3 ppm; HRMS (ESI): m/z calcd for
C26H29N4+: 397.2392 [M]+, found: 397.2374.
Acknowledgements
This work was supported by the National Science Foundation (CHE-
0449587) and the National Institutes of Health (GM-079339). Unrestrict-
ed support from Bristol Myers Squibb and Roche is gratefully acknowl-
edged. We thank Justin Struble for preliminary work on the preparation
of 1, Yoonjoo Kim for work on 28, and Juthanat Kaeobamrung for work
on 29.
[1] a) E. Nakamura, I. Kuwajima, S. Aoki, K. Seyika, H. Oshino, J. Am.
Chem. Soc. 1987, 109, 8056–8066; b) E. Nakamura, I. Kuwajima, J.
Am. Chem. Soc. 1984, 106, 3368–3370; c) H. Oshino, E. Nakamura,
I. Kuwajima, J. Org. Chem. 1985, 50, 2802; d) E. Nakamura, I. Ku-
wajima, Tetrahedron Lett. 1986, 27, 83–86.
[2] M. Seppi, R. Kalkofen, J. Reupohl, R. Frçhlich, D. Hoppe, Angew.
Chem. 2004, 116, 1447–1451; Angew. Chem. Int. Ed. 2004, 43, 1423–
1427.
[3] E. DiMauro, A. J. Fry, Tetrahedron Lett. 1999, 40, 7945–7949.
[4] R. Mahrwald, D. A. Evans in Modern Aldol Reactions (Eds.: R.
Mahrwald), Wiley-VCH, 2004.
[5] S. S. Sohn, E. L. Rosen, J. W. Bode, J. Am. Chem. Soc. 2004, 126,
8126–8127.
tan powder. [a]2D0 =1.47 (c=8.23, MeOH); IR
ACHTUNGTNER(NUNG KBr): n˜ =2919, 2108, 1586,
1442, 1388, 1331, 1290, 1037, 854 cmÀ1 1H NMR (500 MHz, [D6]DMSO):
;
d=10.77 (s, 1H,), 7.16 (s, 2H), 5.03 (s, 1H), 4.18–4.12 (m, 1H), 3.95–3.94
(m, 1H), 3.34–3.18 (m, 3H), 2.96–2.89 (m, 1H), 2.37 (s, 3H), 2.08 ppm (s,
6H); 13C NMR (125 MHz, [D6]DMSO): d=162.7, 141.8, 141.2,
134.8,131.9, 129.3, 59.5, 52.0, 30.0, 21.3, 20.7, 16.9 ppm; HRMS (ESI): m/z
calcd for C15H19N6+: 283.1666 [M]+, found: 283.1671.
Preparation of (S)-5-(aminomethyl)-2-mesityl-6,7-dihydro-5H-pyrrolo-
ACHTUNGTRENNUNG[2,1-c]ACHTUNGTRENNUNG[1,2,4]triazol-2-ium chloride (1): NH4Cl (0.847 g, 13.0 mmol,
[6] C. Burstein, F. Glorius, Angew. Chem. 2004, 116, 6331–6334;
Angew. Chem. Int. Ed. 2004, 43, 6205–6208.
1.3 equiv) and Zn powder (1.39 g, 25.9 mmol, 2.3 equiv) were added to a
solution of 27 (3.18 g, 9.97 mmol, 1.0 equiv) in EtOH/H2O (3:1, 10 mL).
Vigorous stirring was maintained for 1 h at ambient temperature. Di-
methyl sulfoxide (DMSO, 10 mL) was added, and the insoluble solids
were removed by suction filtration and washed with DMSO (5 mL). A
magnetic stirrer bar was added to the filtrate, and Et2O (100 mL) was
added with vigorous stirring, which resulted in the formation of an oil. To
induce product precipitation, EtOH (20 mL) was added with vigorous
stirring. The heterogeneous mixture was placed in an ultrasound bath
until all traces of the initially formed oil had dissolved. The resultant pre-
cipitate was collected by suction filtration and washed with EtOAc to
afford the title compound (1.85 g, 64%) as a white powder. Note: the
[7] a) M. He, J. W. Bode, Org. Lett. 2005, 7, 3131–3134; b) M. He, J.
Struble, J. W. Bode, J. Am. Chem. Soc. 2006, 128, 8418–8420; c) M.
He, J. W. Bode, J. Am. Chem. Soc. 2008, 130, 418–419; d) M.
Rommel, T. Fukuzumi, J. W. Bode, J. Am. Chem. Soc. 2008, 130,
17266–17267.
[8] V. Nair, S. Vellalath, M. Poonoth, R. Mohan, E. Suresh, Org. Lett.
2006, 8, 507–509.
[9] A. Chan, K. A. Scheidt, J. Am. Chem. Soc. 2007, 129, 5334–5335.
[10] a) P.-C. Chiang, J. Kaeobamrung, J. W. Bode, J. Am. Chem. Soc.
2007, 129, 3520–3521; b) P.-C. Chiang, M. Rommel, J. W. Bode, J.
Am. Chem. Soc. 2009, 131, 8714–8718.
[11] Y. R. Chen, M. H. Yang, L. Huang, G. T. Liu, U. Benz, Ger. Offen.
DE 3431257A1 19860306, 1986.
[12] H. R. Feling, G. O. Buchanan, T. J Mincer, C. A. Kauffman, P. R.
Jensen, W. Fenical, Angew. Chem. 2003, 115, 369–371; Angew.
Chem. Int. Ed. 2003, 42, 355–357.
[13] P. Sauleau, P. Retailleau, J. Vacelet, M.-L. Bourguet-Kondracki, Tet-
rahedron 2005, 61, 955–963.
[14] a) Y. Li, Z-A. Zhao, H. He, S-L. You, Adv. Synth. Catal. 2008, 350,
1885–1890; b) Y. Matsuoka, Y. Ishida, K. Saigo, Tetrahedron Lett.
2008, 49, 2985–2989; c) B. Cardinal-David, D. E. A. Raup, K. A.
Scheidt, J. Am. Chem. Soc. 2010, 132, 5345–5347.
[15] a) D. Enders, K. Breuer, J. H. Teles, Helv. Chim. Acta 1996, 79,
1217–1221; b) D. Enders, U. Kallfass, Angew. Chem. 2002, 114,
1822–1824; Angew. Chem. Int. Ed. 2002, 41, 1743–1745; c) H. Taki-
kawa, Y. Hachisu, J. W. Bode, K. Suzuki, Angew. Chem. 2006, 118,
3572–3574; Angew. Chem. Int. Ed. 2006, 45, 3492–3494; d) D.
Enders, O. Niemeier, T. Balensiefer, Angew. Chem. 2006, 118, 1491–
1495; Angew. Chem. Int. Ed. 2006, 45, 1463–1467.
[16] a) M. S. Kerr, J. R. deAlaniz, T. Rovis, J. Am. Chem. Soc. 2002, 124,
10298–10299; b) M. S. Kerr, T. Rovis, J. Am. Chem. Soc. 2004, 126,
8876–8877; c) J. R. deAlaniz, T. Rovis, J. Am. Chem. Soc. 2005, 127,
6284–6289; d) J. R. deAlaniz, T. Rovis, Synlett 2009, 8, 118–1207.
[17] a) M. He, J. R. Struble, J. W. Bode, J. Am. Chem. Soc. 2006, 128,
8148–8150; b) M. He, G. J. Uc, J. W. Bode, J. Am. Chem. Soc. 2006,
product may contain some inorganic salts (ZnCl and NH4Cl). IR
ACHTUNGTRNE(NUNG KBr):
n˜ =3434, 3330, 3252, 3049, 2992, 1588, 1402, 1234, 1134, 1023, cmÀ1
;
1H NMR (500 MHz, [D6]DMSO): d=7.05 (s, 2H), 4.60 (q, 1H, J=
8.5 Hz), 3.36–3.14 (m, 2H), 3.06 (dd, 1H, J=16.5, 9.0 Hz), 2.75–2.71 (m,
2H), 2.40–2.34 (m, 1H), 2.32 (s, 3H), 2.08 (s, 3H), 1.99 ppm (s, 3H);
13C NMR (125 MHz, [D6]DMSO): d=172.9, 160.0, 139.4, 135.4, 134.9,
128.7, 128.6, 57.0, 44.8, 31.7, 30.7, 21.2, 20.7, 17.2, 17.0 ppm; HRMS
(ESI): m/z calcd for C15H21N4+: 257.1761 [M]+, found: 257.1746.
General Procedure for the Paal–Knorr Pyrrole Synthesis/Preparation of
(S)-2-mesityl-5-((2-methyl-5-phenyl-1H-pyrrol-1-yl)methyl)-6,7-dihydro-
5H-pyrrolo
0.34 mmol, 1.0 equiv) and anhydrous HCl (85 mL, 4.0m in dioxane,
1.0 equiv) were added to solution of 1-phenylpentane-1,4-dione
ACHTUNGTRENNUNG[2,1-c]ACHTUNGTRENNUNG[1,2,4]triazol-2-ium chloride (30): Compound 1 (100 mg,
a
(59.8 mg, 0.34 mmol, 1.0 equiv) in MeOH (0.2m, 1.7 mL) under an atmos-
phere of nitrogen. The resulting mixture was stirred at 508C for 10 h, and
then cooled to room temperature and concentrated in vacuo. The crude
mixture was purified by flash chromatography on silica gel (5% MeOH/
CH2Cl2) to afford 30 (33.8 mg, 23% yield) as a yellow foam. m.p.: 132–
1338C; [a]2D0 =74.14 (c=2.53, MeOH); IR
1513, 1476, 1445, 1396, 1308, 1194, 756, 732, 702 cmÀ1
N
;
(500 MHz, MeOD): d=7.50 (d, J=7.0 Hz, 2H), 7.44 (t, J=7.7 Hz, 2H),
7.34 (t, J=7.2 Hz, 1H), 7.10 (s, 2H), 6.18 (d, J=3.5 Hz, 1H), 5.97 (d, J=
3.0 Hz, 1H), 4.76 (dd, J=14.5, 5.5 Hz, 1H), 4.69–4.70 (m, 1H), 4.45 (dd,
J=15.0, 10 Hz, 1H), 3.31–3.34 (m, 1H), 3.18 (ddd, J=17.5, 9.5, 4.7 Hz,
Chem. Asian J. 2011, 6, 614 – 620
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
619

J. Bode et al.
FULL PAPERS
128, 15088–15089; c) M. He, B. J. Beahm, J. W. Bode, Org. Lett.
2008, 10, 3817–3820.
many NHC-catalyzed reactions, and the conversion of the amine
into pyrroles.
[18] a) H. U. Vora, T. Rovis, J. Am. Chem. Soc. 2010, 132, 2860–2861;
b) N. T. Reynolds, T. Rovis, J. Am. Chem. Soc. 2005, 127, 16406–
16407; c) X.-N. Wang, H. Lv, X.-L. Huang, S. Ye, Org. Biomol.
Chem. 2009, 7, 346–350.
[19] For a review, see: D. Enders, O. Niemeier, A. Henseler, Chem. Rev.
2007, 107, 5606–5655.
[25] a) M. Kerr, J. R. deAlaniz, T. Rovis, J. Org. Chem. 2005, 70, 5725–
5728; b) H. U. Vora, S. P. Lathrop, N. T. Reynolds, M. S. Kerr, J. R.
deAlaniz, T. Rovis, Org. Synth. 2010, 87, 350–361.
[26] a) J. Jacques, C. Fouquey, Org. Synth. 1989, 67, 1–10; b) For a
recent review, see: J. Lacour, D. Moraleda, Chem. Commun. 2009,
7073–7089.
[20] D. Enders, J. Han, Tetrahedron: Asymmetry 2008, 19, 1367–1371.
[21] R. L. Knight, F. J. Leeper, J. Chem. Soc. Perkin Trans. 1 1998, 1891–
1893.
[22] M. C. Perry, X. Cui, M. T. Powell, D. H. Hou, J. H. Reibenspies, K.
Burgess, J. Am. Chem. Soc. 2003, 125, 113–123.
[23] C. Uyeda, E. N. Jacobsen, J. Am. Chem. Soc. 2008, 130, 9228–9229.
[24] During the course of this work, Waser and co-workers reported a
similar strategy for late-stage modification of chiral triazolium salts
by formation of ureas and thioureas from a similar amine: J. B.
Brand, J. I. O. Siles, J. Waser, Synlett 2010, 881–884. Our work dif-
fers in the use of an N-mesityl substituent, which is essential for
[27] D. A. DiRocco, K. M. Oberg, D. M. Dalton, T. Rovis, J. Am. Chem.
Soc. 2009, 131, 10872–10874.
[28] Q. Liu, S. Perreault, T. Rovis, J. Am. Chem. Soc. 2008, 130, 14066–
14067.
[29] L. Bateman, S. Breeden, P. OꢀLeary, Tetrahedron: Asymmetry 2008,
19, 391386.
[30] J. R. Struble, J. W. Bode, Org. Synth. 2010, 87, 362–376.
Received: August 30, 2010
Published online: December 22, 2010
620
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Chem. Asian J. 2011, 6, 614 – 620