Sequential one-pot and three-component reactions of an N-heterocyclic carbene to form 4-(1,2,4-triazol-5-ylidene)pyrrolidine-2,5-diones: A tandem umpolung/annulation sequence via deoxy-Breslow intermediates

Article abstract of DOI:10.1016/j.tet.2012.08.076

The tandem sequence of the umpolung of α,β-unsaturated esters by an N-heterocyclic carbene (NHC) followed by annulation is demonstrated. The deoxy-Breslow intermediates are selectively generated from the reaction of NHC with methyl methacrylate, dimethyl itaconate, or methyl crotonate. Subsequently, they undergo annulation with isocyanates to give 4-(1,2,4-triazol-5-ylidene) pyrrolidine-2,5-diones in good isolated yields. In addition, the stoichiometric three-component reaction of NHC, methyl methacrylate, and phenyl isocyanate proceeded, accompanied by the formation of the 1:2 adduct of NHC with phenyl isocyanate.

Full text of DOI:10.1016/j.tet.2012.08.076

Tetrahedron 68 (2012) 9836e9841
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Sequential one-pot and three-component reactions of an N-heterocyclic carbene
to form 4-(1,2,4-triazol-5-ylidene)pyrrolidine-2,5-diones: a tandem umpolung/
annulation sequence via deoxy-Breslow intermediates
*
Shin-ichi Matsuoka , Yusuke Tochigi, Koji Takagi, Masato Suzuki
Department of Materials Science and Engineering, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya 466-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 July 2012
Received in revised form 24 August 2012
Accepted 25 August 2012
Available online 2 September 2012
The tandem sequence of the umpolung of a,b-unsaturated esters by an N-heterocyclic carbene (NHC)
followed by annulation is demonstrated. The deoxy-Breslow intermediates are selectively generated
from the reaction of NHC with methyl methacrylate, dimethyl itaconate, or methyl crotonate. Sub-
sequently, they undergo annulation with isocyanates to give 4-(1,2,4-triazol-5-ylidene)pyrrolidine-2,5-
diones in good isolated yields. In addition, the stoichiometric three-component reaction of NHC,
methyl methacrylate, and phenyl isocyanate proceeded, accompanied by the formation of the 1:2 adduct
of NHC with phenyl isocyanate.
Keywords:
N-Heterocyclic carbene
Sequential one-pot reaction
Three-component reaction
Umpolung
Ó 2012 Elsevier Ltd. All rights reserved.
Deoxy-Breslow intermediate
1. Introduction
forming reactions. In contrast, the NHC-catalyzed umpolung of
activated olefins is far less developed. Fu et al. first demonstrated
N-Heterocyclic carbenes1 (NHCs), due to their strong electron
donating ability,2 readily react with various unsaturated electro-
philes to generate zwitterionic adducts.3 While the adducts of NHC
with carbon dioxide,4 carbon disulfide,1b-d,5 and isothiocyanates1b-
the umpolung reaction of a,b-unsaturated carbonyl compounds via
the deoxy-Breslow intermediate.8a We8b and Glorius8c extended
this concept to the intermolecular bond forming reaction between
b
-carbons of methacrylates. Scheidt used the umpolung process for
are relatively stable and isolable, those with aldehydes,7 acti-
the rearrangement of vinyl sulfones8d and the related Rau-
d,6
vated olefins,1,8,9 and isocyanates1b,10 readily undergo proton
transfer generating Breslow7,11 or deoxy-Breslow8,12 intermediates,
or the further addition to the electrophile. Since the first report by
Nair,13a the nucleophilic reactivity of NHCs has been extended to
three-component reactions.13 Specifically, NHCs selectively and
sequentially react with two kinds of electrophiles (combinations of
aldehydes,13a-d,h-j activated acetylenes,13a-f,h-j ketenes,13e,f allenoa-
tes,13g,i and isothiocyanates13g) to yield a variety of complex mol-
ecules, such as furan and furanone derivatives, in one pot. The
three-component reaction may allow us to understand the re-
activity of various adducts formed by NHCs and electrophiles.
NHC catalysis can offer new opportunities for the discovery of
reactions, in particular, the umpolung of aldehydes.7 Indeed, Bre-
slow intermediates, the acyl anion and homoenolate equivalents,
react with various electrophiles leading to widespread bond
huteCurrier reaction.8e The NHC-catalyzed umpolung of activated
olefins is a promising procedure to introduce electrophiles at the b-
carbons, thereby creating a new field of NHC catalysis. However,
electrophiles are now limited to alkyl halides,8a tosylate,8a and
electron-deficient alkenes.8b-e In this context, to expand the scope,
we examined the reactions of the deoxy-Breslow intermediates
with other electrophiles. Herein we report the sequential one-pot
and three-component reactions of NHC,
a,b-unsaturated esters,
and isocyanates that involve the tandem umpolung/annulation
sequence.
2. Results and discussion
2.1. Sequential one-pot reaction
We have previously reported the dimerization of methacrylates
catalyzed by the isolated NHC (1) and detected the deoxy-Breslow
intermediate (2) by electrospray ionization mass spectrometry
(Scheme 1).8b In contrast, Glorius and co-workers used the in situ
* Corresponding author. E-mail address: matsuoka.shinichi@nitech.ac.jp
(S. Matsuoka).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.08.076

S. Matsuoka et al. / Tetrahedron 68 (2012) 9836e9841
9837
generated species, 1, for the same reaction and isolated its corre-
sponding HClO4 adduct.8c Recently, Chen isolated the deoxy-
Breslow intermediate derived from another NHC, imidazolium-2-
ylidene, and MMA.9e When compared to the Breslow in-
termediates, the deoxy-variants are relatively stable.
Scheme 2. The direct synthesis of 4a from 1 and 5.
feed ratio (entries 10 and 11). Compounds 4aef show a single set of
13C NMR signals, indicating that there are no diastereomers ob-
served on the NMR timescale. It is reasonable to assume that the
interconversion between 4 and 40 allows the free rotation of the
CeC bond formed from the carbene carbon and b-carbon of MMA
(Scheme 1).12,16
We next examined the reaction of dimethyl itaconate (DMI),
a substitute for MMA, as the two distinct methoxy carbonyl groups
show promise for interesting reactivity. The analogous reaction
proceeded to give a three-component product in 94% yield. Al-
though there are two possible structural isomers,
6 and 7
(Scheme 3), the 1H and 13C NMR spectra indicated a single product.
Compared to the 13C NMR data of 4aef, similar resonances corre-
sponding to the five-membered ring were observed.17 In addition,
the 2D INADEQUATE NMR spectrum showed a key correlation of
the tertiary carbon (C3) with the imide carbonyl carbon (C2),18
which does not appear in the six-membered ring of 7, thereby
identifying the structure of 6 (See Supplementary data).
Scheme 1. The sequential one-pot reaction of 1, methyl methacrylate (MMA), and
isocyanates.
We first carried out the reaction of 1 with an equimolar amount
of MMA in 1,2-dimethoxyethane at 80 ꢀC for 10 min followed by the
addition of HCl in methanol. The HCl adduct 3 was selectively
formed and isolated in 80% yield, suggesting the selective genera-
tion of 2 without the further conjugate addition to MMA (Scheme
1). The addition of phenyl isocyanate (PhNCO) to 2 generated in
situ produced 4a in good yields (Table 1, entries 1 and 2).14 Mech-
anistically, the umpolung b-carbon of 2 has sufficient nucleophi-
licity to attack the electrophilic carbon of PhNCO, followed by the
ring closure and elimination of methanol. When the reaction time
of 1 with MMA was extended to 8 h before the addition of PhNCO,
the yield of 4a decreased to 38% (entry 3), suggesting a de-
composition of 2 during the prolonged reaction time. The reaction
of 2 with PhNCO at 40 ꢀC lowered the yield to 31% (entry 4), and no
product was observed at 0 ꢀC (entry 5). As an alternative pathway,
the reaction of 1 with an equimolar amount of 5 at 80 ꢀC directly
produced 4a in 70% yield through the conjugate addition and
subsequent proton transfer (Scheme 2).15
Scheme 3. The sequential one-pot reaction of 1, dimethyl itaconate (DMI), and PhNCO.
The arrows and bold lines in 6 indicate the key HMBC and INADEQUATE correlations,
respectively.
Given that the above reactions using MMA and DMI involved the
abstraction of b-protons, we then turned our attention to the b-
substituted olefin methyl crotonate (MCr). The reaction of 1 with
MCr at 80 ꢀC followed by the addition of HCl gave the HCl adduct (9)
through the corresponding deoxy-Breslow intermediate (8)
(Scheme 4). When 8, generated in situ, was subsequently reacted
with PhNCO, compounds 4a and 13 were unexpectedly obtained.
The yield of 13 increased with excess PhNCO (Table 2). The for-
mation of 13 suggests that the enolate (12) is an intermediate.
Mechanistically, the tandem umpolung/annulation sequence gen-
erates the intermediary species 10, as in the case of MMA. Since the
Table 1
The sequential one-pot reaction of 1, MMA, and isocyanatesa
Entry
RNCO
R
Temp (ꢀC)b
Yield (%)c
Equiv
1
Ph
Ph
Ph
Ph
1
3
1
1
1
1
1
1
1
1
3
80
80
80
40
0
80
80
80
80
80
80
75
81
38
31
<1
87
76
72
73
22
26
2
3d
4
5
6
7
8
9
10
11
Ph
4-ClC6H4
4-MeOC6H4
4-NO2C6H4
n-Bu
t-Bu
t-Bu
b-carbon of 10 is quaternary, the methoxide anion generated in situ
abstracts the -proton to give 12. The proton transfer of 12 pro-
a
duces 4a, while the further addition of 12 to PhNCO followed by the
proton transfer resulted in 13. There are two possible pathways for
the transformation of 10 to 12: (i) an intramolecular 1,2-migration
of triazolinium ring via the three-membered ring 11; or (ii) liber-
ation of 1 and 5 followed by the intermolecular conjugate addition
of 1 to the less hindered olefinic carbon of 5. To gain a mechanistic
insight into this process, the one-feed three-component reaction of
1, 5, and PhNCO was performed (Table 3). The stoichiometric re-
action gave 4a and 14 in 36% and 50% yields, respectively, without
forming 13 (entry 1). In the presence of an excess of PhNCO, 14 was
selectively obtained (entry 2). Given these results, if 10 liberated 1
and 5, 14 would be formed instead of 13 by the reaction of the
regenerated 1 with PhNCO. However, this was not the case.
a
1 (0.46 mmol), MMA (0.46 mmol), in 1,2-dimethoxyethane (0.9 mL). The re-
action of 1 with MMA was carried out at 80 ꢀC for 10 min, followed by the reaction
with RNCO for 8 h.
b
Temperature of the reaction of 2 with RNCO.
Isolated yields of 4aef.
The reaction of 1 and MMA was carried out for 8 h.
c
d
The aromatic isocyanates bearing electron-withdrawing and
donating substituents at the para position and n-butyl isocyanate
gave the products (4aee) in good yields (entries 6e9); whereas the
bulky tert-butyl isocyanate reduced the yield, even at an increased

9838
S. Matsuoka et al. / Tetrahedron 68 (2012) 9836e9841
Therefore, we reason that the transformation of 10 to 12 takes place
intramolecularly via 11 without the liberation of 1 and 5.
2.2. Three-component reaction
The sequential one-pot reactions were found to be highly se-
lective, leading us to examine the one-feed three-component re-
action of 1, MMA, and PhNCO (Table 4). Although 14 was exclusively
obtained at 40 ꢀC (entry 1), the reaction at 80 ꢀC gave 4a and 14 in
31% and 37% yields, respectively, (entry 2). Increasing the MMA feed
ratios to 2 and 10 neither increased the yield of 4a, nor gave the
MMA dimer or oligomers (entries 3 and 4). Alternatively, the ad-
dition of only 2 equiv of PhNCO led to the exclusive formation of 14
even in the presence of an excess amount of MMA (entries 5 and 6).
Table 4
Three-component reaction of NHC (1) or its precursor (15), MMA, and PhNCOa
Entry
NHC
NHC:MMA:PhNCO (equiv)
Temp (ꢀC)
Yield (%)b
4a
14c
1
2
3
4
5
6
7
8
1
1
1
1
1
1
15
15
1:1:1
1:1:1
1:2:1
1:10:1
1:2:2
1:10:2
1:1:1
1:2:2
40
80
80
80
80
80
80
80
<1
31
25
21
<1
<1
38
<1
50 (>99)
37 (74)
41 (82)
42 (84)
94 (94)
>99 (>99)
33 (66)
>99 (>99)
Scheme 4. The sequential one-pot reaction of 1, methyl crotonate (MCr), and PhNCO.
The proposed 1,2-migration mechanism of triazolinium ring (10/12).
Table 2
a
The sequential one-pot reaction of 1, MCr, and PhNCOa
1 or 15 (0.46 mmol), in 1,2-dimethoxyethane (0.9 mL) for 8 h.
Isolated yields calculated based on NHC.
The values in parentheses indicate the yields calculated based on PhNCO.
b
c
Entry
PhNCO (equiv)
Yield (%)b
4a
13c
This effect of the stoichiometry can be mechanistically
1
2
1
10
24
11
11 (22)
50
explained as follows. The NHC 1 quickly adds to PhNCO to quanti-
tatively generate the zwitterion, 16 (Scheme 5). In the presence of
more than 2 equiv of PhNCO, 16 readily reacts further with PhNCO
to yield 14. In the case of an equimolar amount of PhNCO, com-
pound 1 and PhNCO were partially regenerated from 16, and the
PhNCO was consumed by the reaction with 2 or 16. The regenerated
species 1 then reacted with MMA and PhNCO to yield 4a.
a
1 (0.46 mmol), MCr (0.46 mmol), in 1,2-dimethoxyethane (0.9 mL) at 80 ꢀC. The
reaction of 1 with MCr was carried out for 10 min, followed by the reaction with
RNCO for 8 h.
b
Calculated by 1H NMR spectra based on 1.
The value in parenthesis indicates the yield calculated based on PhNCO.
c
Table 3
Three-component reaction of 1, 5, and PhNCOa
Scheme 5. Three-component reaction of 1, MMA, and PhNCO through the equilibrium
between 1 and 16.
Entry
1:5:PhNCO (equiv)
Yield (%)b
4a
14c
13
This reaction similarly proceeded using the methanol adduct of
1 (15) instead of the isolated 1, and the same effect of the stoichi-
ometry was observed (entries 7 and 8). In addition, 15 was found to
react with PhNCO, even at room temperature, to quantitatively give
14, suggesting that 16 was generated in situ under these conditions.
1
2
1:1:1
1:1:9
36
<1
50 (>99)
>99
<1
<1
a
1 (0.46 mmol), 5 (0.46 mmol), in 1,2-dimethoxyethane (0.9 mL) at 80 ꢀC for 8 h.
Isolated yields calculated based on 1.
The value in parenthesis indicates the isolated yield calculated based on PhNCO.
b
c

S. Matsuoka et al. / Tetrahedron 68 (2012) 9836e9841
9839
Therefore, 15 is regarded as a masked precursor of 1 and similarly
used for this transformation.
HDMS tandem quadrupole orthogonal acceleration time-of-flight
instrument equipped with a Z-spray nanoelectrospray ionization
source. Infrared spectra were recorded on a FT/IR-460 Plus spec-
trometer equipped with a ZnSe crystal ATR accessory.
2.3. Reactions using phenyl isothiocyanate (PhNCS)
4.2. Synthesis of 3 and 9
PhNCS also underwent the sequential one-pot reaction to give
a product (17 or 18) in 86% yield (Scheme 6), however, it was poorly
soluble in common organic solvents.19 On the other hand, the
attempted three-component reaction gave the zwitterionic product
19 without forming 17 or 18 (Scheme 7). This result is in sharp
contrast to that observed with PhNCO. Previously, Enders reported
the stability and reactivity of 16 and 19.1b Indeed, 16 was not iso-
lable, while 19 was quite stable. Thus, we reason that there is an
equilibrium between 1 and 16 and not between 1 and 19, thereby
not yielding the three-component products from PhNCS.
To the solution of
1 (150 mg, 0.46 mmol) in 1,2-
dimethoxyethane (0.9 mL), MMA (47.1 mg, 0.47 mmol) was
added. After the reaction stirred at 80 ꢀC for 10 min, HCl in meth-
anol (5.0 mL, 0.46 mol/L) was added, and the reaction mixture was
stirred at room temperature for 3 h. The crude product was purified
by silica gel column chromatography using chloroform/methanol as
the eluent to give 3 (158 mg, 0.36 mmol) in 80% yield. 9 was ob-
tained in 90% yield from the analogous procedure with MCr.
4.2.1. 5-(3-Methoxy-2-methyl-3-oxopropyl)-1,3,4-triphenyl-4H-
1,2,4-triazol-1-ium chloride (3). Mp¼225e227 ꢀC; 1H NMR
(600 MHz, CDCl3):
d
8.21 (m, 3H), 7.98 (d, 1H, J¼6.9 Hz), 7.95e7.28
(m, 12H), 4.08 (dd, 1H, J¼16.1 Hz, 5.0 Hz), 3.54 (s, 3H), 3.22 (dd, 1H,
J¼16.1 Hz, 11.5 Hz), 2.27 (m, 1H), 1.00 (d, 3H, J¼7.2 Hz); 13C NMR
(150 MHz, CDCl3):
d 174.0, 154.8, 152.8, 135.2, 131.9, 131.7, 131.7,
Scheme 6. The sequential one-pot reaction of 1, MMA, and PhNCS.
131.4, 130.5, 130.4, 129.9, 129.2,128.7,128.2,128.0,126.4, 122.7, 52.3,
35.7, 29.5, 17.2; HRMS (ESI) calcd for C25H24ClN3O2 [MꢁCl]þ:
398.1868, found: 398.1866; IR (neat, cmꢁ1): 3051, 1735, 1553, 1506,
1459, 1198, 928, 767, 731, 638.
4.2.2. 5-(4-Methoxy-4-oxobutan-2-yl)-1,3,4-triphenyl-4H-1,2,4-
triazol-1-ium chloride (9). Mp¼120e122 ꢀC; 1H NMR (600 MHz,
CDCl3):
d 8.16e8.01 (m, 4H), 7.68e7.47 (m, 8H), 7.41e7.32 (m, 2H),
7.25 (t, 2H, J¼7.6 Hz), 3.61 (s, 3H), 3.59 (m, 1H), 2.96 (dd, 1H,
J¼8.4 Hz, 17.5 Hz), 2.33 (dd, 1H, J¼7.6 Hz, 17.5 Hz), 1.47 (d, 3H,
Scheme 7. The attempted three-component reaction of 1, MMA, and PhNCS.
J¼7.2 Hz); 13C NMR (150 MHz, CDCl3):
d 171.1, 156.3, 153.5, 135.2,
131.7, 131.7, 131.6, 131.3, 130.1, 130.1, 129.7, 129.7, 128.6, 128.4, 128.4,
127.4, 122.8, 52.0, 36.9, 28.0, 18.3; HRMS (ESI) calcd for
C25H24ClN3O2 [MꢁCl]þ: 398.1868, found: 398.1895; IR (neat, cmꢁ1):
3051, 2951, 1732, 1504, 1362, 1198, 1178, 926, 764, 724, 693.
3. Conclusions
We have demonstrated the sequential one-pot and three-
component reactions that feature the unique tandem umpolung/
annulation sequences. The deoxy-Breslow intermediates from
MMA or DMI react with isocyanates to give compounds 4aef and 6
in good yields. Unexpectedly, 4a was also obtained from MCr
through the tandem sequence and intramolecular migration. These
reactions are the first intermolecular reactions of the deoxy-
Breslow intermediates with electrophiles other than activated
olefins. It should also be noted that the stoichiometric three-
component reaction of 1, MMA, and PhNCO is the first multicom-
ponent reaction of NHC via umpolung. Further study of reactions of
the deoxy-Breslow intermediates with other electrophiles is now in
progress.
4.3. General procedure for the sequential one-pot reaction
(4aef, 6)
To the solution of
1 (150 mg, 0.46 mmol) in 1,2-
dimethoxyethane (0.9 mL), MMA (45.6 mg, 0.46 mmol) was
added. After the reaction stirred for 10 min at 80 ꢀC, PhNCO
(53.3 mg, 0.45 mmol) was then added, and the reaction solution
was stirred for 8 h. An excess amount of ethyl acetate was added to
the solution, and the precipitated 4a (162 mg, 0.33 mmol, 75%) was
collected by filtration. Compounds 4bef and 6 were obtained from
the analogous procedure.
4.3.1. 3-Methyl-1-phenyl-4-(1,3,4-triphenyl-1H-1,2,4-triazol-5(4H)-
4. Experimental section
4.1. General
ylidene)pyrrolidine-2,5-dione (4a). Mp¼257e258 ꢀC; 1H NMR
(600 MHz, CDCl3):
d
7.68 (d, 2H, J¼7.6 Hz), 7.52e7.45 (m, 5H),
7.43e7.36 (m, 4H), 7.32e7.27 (m, 6H), 7.18 (t, 1H, J¼7.6), 7.13 (d, 2H
J¼7.9 Hz), 2.81 (q, 1H, J¼7.0 Hz), 1.16 (d, 3H, J¼7.0 Hz); 13C NMR
All reactions were performed under nitrogen atmosphere using
standard Schlenk techniques. MMA, MCr, DMI, and 1,2-
dimethoxyethane were distilled from CaH2 under reduced pres-
sure before use. Other chemicals were used as received. Melting
points were measured on a Yanaco micro melting point apparatus.
1H and 13C NMR spectra were recorded on Bruker Avance-600
(600 MHz for 1H, 150 MHz for 13C) or Avance III 500 MHz
(500 MHz for 1H, 125 MHz for 13C) spectrometers. Chemical shifts
were referenced internally to tetramethylsilane (0.0 ppm for 1H), or
CDCl3 resonance (77.1 ppm for 13C). Electrospray ionization mass
spectrometry (ESI-MS) was performed on a Waters Synapt G2
(150 MHz, CDCl3): d 177.7, 164.6, 151.1, 150.2, 139.3, 135.0, 133.4,
130.9, 130.0, 129.9, 129.2, 129.1, 128.6, 128.6, 128.2, 126.9, 126.6,
124.8, 123.3, 70.4, 39.0, 18.4; HRMS (ESI) calcd for C31H24N4O2
[MþH]þ: 485.1978, found: 485.1970; IR (neat, cmꢁ1): 1720, 1667,
1532, 1492, 1376, 1274, 1122, 1099, 691.
4.3.2. 1-(4-Chlorophenyl)-3-methyl-4-(1,3,4-triphenyl-1H-1,2,4-
triazol-5(4H)-ylidene)pyrrolidine-2,5-dione (4b). The crude product
was purified by silica gel column chromatography using chloro-
form/ethyl acetate as the eluent. Mp¼231e233 ꢀC; 1H NMR
(600 MHz, CDCl3):
d
7.66 (d, 2H, J¼7.7 Hz), 7.52e7.43 (m, 5H),

9840
S. Matsuoka et al. / Tetrahedron 68 (2012) 9836e9841
7.42e7.34 (m, 4H), 7.31e7.21 (m, 6H), 7.11 (d, 2H, J¼8.4 Hz), 2.79 (q,
1H, J¼7.0 Hz), 1.15 (d, 3H, J¼7.0 Hz); 13C NMR (150 MHz, CDCl3):
[MþH]þ: 543.2032, found: 543.2032; IR (neat, cmꢁ1): 3066, 1731,
1668, 1531, 1493, 1387, 1122, 907, 725, 690.
d
177.4, 163.9, 151.0, 150.2, 139.1, 134.7, 132.2, 131.9, 130.9, 130.0,
129.8, 129.1, 129.0, 128.6, 128.6, 128.5, 128.2, 127.6, 124.5, 123.2,
69.9, 38.9, 18.3; HRMS (ESI) calcd for C31H23ClN4O2 [MþH]þ:
519.1588, found: 519.1589; IR (neat, cmꢁ1): 1721, 1666, 1531, 1490,
1374, 1363, 1275, 1090, 835, 706, 690.
4.4. General procedure for the three-component reaction
The mixture of MMA (47.0 mg, 0.47 mmol) and PhNCO (54.1 mg,
0.45 mmol) in 1,2-dimethoxyethane (0.9 mL) was added to 1
(150 mg, 0.46 mmol) at 80 ꢀC. The mixture was stirred for 8 h. An
excess amount of ethyl acetate was added to the solution, and
precipitated 4a (67.4 mg, 0.14 mmol, 31%) was collected by filtra-
tion. The filtrate was concentrated under reduced pressure, and the
residual solution was then poured into hexane. The precipitated 14
(89.9 mg, 0.17 mmol, 37%) was collected by filtration.
4.3.3. 1-(4-Methoxyphenyl)-3-methyl-4-(1,3,4-triphenyl-1H-1,2,4-
triazol-5(4H)-ylidene)pyrrolidine-2,5-dione (4c). Mp¼259e260 ꢀC;
1H NMR (600 MHz, CDCl3):
d
7.67 (d, 2H, J¼7.8 Hz), 7.52e7.23 (m,
13H), 7.04 (d, 2H, J¼8.6 Hz), 6.83 (d, 2H, J¼8.6 Hz), 3.73 (s, 3H), 2.79
(q, 1H, J¼7.0 Hz), 1.15 (d, 3H, J¼7.0 Hz); 13C NMR (150 MHz, CDCl3):
d
177.9, 164.8, 158.3, 151.0, 150.0, 139.2, 134.9, 130.8, 129.9, 129.8,
129.1, 129.1, 128.6, 128.0, 127.7, 126.2, 124.7, 123.2, 1134.0, 70.4, 55.3,
28.9, 18.3; HRMS (ESI) calcd for C32H26N4O3 [MþH]þ: 515.2083,
found: 515.2080; IR (neat, cmꢁ1): 1719, 1666, 1538, 1510, 1494, 1257,
1083, 708, 693.
Acknowledgements
We thank Professor Akihiro Yoshino and Masato Taki at Nagoya
Institute of Technology for the 2D INADEQUATE NMR measure-
ment. We also thank Dr. Jillian Hatnean at University of Toronto for
careful reading of the manuscript.
4.3.4. 3-Methyl-1-(4-nitrophenyl)-4-(1,3,4-triphenyl-1H-1,2,4-
triazol-5(4H)-ylidene)pyrrolidine-2,5-dione (4d). The crude product
was purified by silica gel column chromatography using dichloro-
methane/ethyl acetate as the eluent. Mp¼223e224 ꢀC; 1H NMR
Supplementary data
(600 MHz, CDCl3):
d
8.14 (d, 2H, J¼9.2 Hz), 7.68 (d, 2H, J¼7.7 Hz),
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.08.076.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
7.56e7.39 (m, 11H), 7.31 (d, 4H, J¼4.3 Hz), 2.82 (q, 1H, J¼7.1 Hz), 1.17
(d, 3H, J¼7.1 Hz); 13C NMR (150 MHz, CDCl3):
d 177.1, 163.0, 151.2,
150.5, 145.2, 139.5, 138.9, 134.6, 131.1, 130.2, 129.9, 129.3, 129.1,
128.6, 128.5, 126.2, 124.4, 123.8, 123.4, 69.4, 39.0, 18.4; HRMS (ESI)
calcd for C31H23N5O4 [MþH]þ: 530.1828, found: 530.1827; IR (neat,
cmꢁ1): 1733, 1674, 1533, 1493, 1339, 1125, 822, 742, 708, 694.
References and notes
1. For seminal studies of NHC 1 by Enders, see: (a) Enders, D.; Breuer, K.; Raabe,
G.; Runsink, J.; Teles, J. H.; Melder, J.-P.; Ebel, K.; Brode, S. Angew. Chem., Int. Ed.
Engl. 1995, 34, 1021e1023; (b) Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H.
Liebigs Ann. 1996, 2019e2028; (c) Enders, D.; Breuer, K.; Teles, J. H.; Ebel, K. J.
Prakt. Chem. 1997, 339, 397e399; (d) Enders, D.; Breuer, K.; Kallfass, U.; Ba-
lensiefer, T. Synthesis 2003, 1292e1295.
4.3.5. 1-n-Butyl-3-methyl-4-(1,3,4-triphenyl-1H-1,2,4-triazol-5(4H)-
ylidene)pyrrolidine-2,5-dione (4e). The crude product was purified
by silica gel column chromatography using chloroform/ethyl ace-
tate as the eluent. Mp¼200e202 ꢀC; 1H NMR (600 MHz, CDCl3):
2. (a) Maji, B.; Breugst, M.; Mayr, H. Angew. Chem., Int. Ed. 2011, 50, 6915e6919; (b)
d
7.62 (d, 2H, 7.5 Hz), 7.48e7.41 (m, 5H), 7.39e7.32 (m, 4H), 7.28 (s,
€
Droge, T.; Glorius, F. Angew. Chem., Int. Ed. 2010, 49, 6940e6952; (c) Domingo,
ꢀ
4H), 3.30 (t, 2H, J¼6.7 Hz), 2.61 (q, 1H, J¼6.7 Hz), 1.36 (m, 2H), 1.15
L. R.; Aurell, M. J.; Arno, M. Tetrahedron 2009, 65, 3432e3440.
(m, 2H), 1.07 (d, 3H, J¼6.7 Hz), 0.82 (t, 3H, J¼7.1 Hz); 13C NMR
3. For reviews, see: (a) Nair, V.; Bindu, S.; Sreekumar, V. Angew. Chem., Int. Ed.
2004, 43, 5130e5135; (b) Kirmse, W. Eur. J. Org. Chem. 2005, 237e260; (c)
Delaude, L. Eur. J. Inorg. Chem. 2009, 1681e1699.
(150 MHz, CDCl3):
d 178.5, 165.7, 150.7, 149.4, 139.3, 134.9, 130.6,
129.7, 129.6, 128.9, 128.9, 128.4, 127.7, 124.7, 122.9, 70.9, 38.7, 37.3,
30.3, 19.8, 18.1, 13.7; HRMS (ESI) calcd for C29H28N4O2 [MþH]þ:
465.2290, found: 465.2290; IR (neat, cmꢁ1): 2960, 2930, 1714, 1659,
1537, 1494, 1445, 1271, 1032, 691.
4. For selected examples, see: (a) Kuhn, N.; Steimann, M.; Weyers, G. Z. Natur-
forsch., Teil B 1999, 54, 427e433; (b) Holbrey, J. D.; Reichert, W. M.; Tkatchenko,
I.; Bouajila, E.; Walter, O.; Tommasi, I.; Rogers, R. D. Chem. Commun. 2003,
28e29; (c) Duong;, H. A.; Tekavec, T. N.; Arif, A. M.; Louie, J. Chem. Commun.
2004, 112e113; (d) Tommasi, I.; Sorrentino, F. Tetrahedron Lett. 2006, 47,
6453e6456; (e) Zhou, H.; Zhang, W.-Z.; Wang, Y.-M.; Qu, J.-P.; Lu, X.-B. Mac-
romolecules 2009, 42, 5419e5421; (f) Van Ausdall, B. R.; Glass, J. L.; Wiggins, K.
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Suresh, C. H. J. Org. Chem. 2012, 77, 1087e1094.
4.3.6. 1-tert-Butyl-3-methyl-4-(1,3,4-triphenyl-1H-1,2,4-triazol-
5(4H)-ylidene)pyrrolidine-2,5-dione (4f). The crude product was
purified by silica gel column chromatography using chloroform/
ethyl acetate as the eluent. Mp¼88e90 ꢀC; 1H NMR (600 MHz,
5. For selected examples, see: (a) Kuhn, N.; Bohnen, H.; Henkel, G. Z. Naturforsch.,
Teil B 1994, 49, 1473e1480; (b) Kuhn, N.; Niquet, E.; Steimann, M.; Walker, I. Z.
€
Naturforsch., Teil B 1999, 54, 1181e1187; (c) Faust, R.; Gobelt, B. Chem. Commun.
CDCl3):
d
7.61 (d, 2H, J¼7.8 Hz), 7.48e7.25 (m, 5H), 2.52 (q, 1H,
2000, 919e920; (d) Delaude, L.; Demonceau, A.; Wouters, J. Eur. J. Inorg. Chem.
2009, 1882e1891.
J¼6.9 Hz), 1.40 (s, 9H), 0.99 (d, 3H, J¼6.8 Hz); 13C NMR (150 MHz,
6. (a) Cheng, Y.; Liu, M.-F.; Fang, D.-C.; Lei, X.-M. Chem.dEur. J. 2007, 13,
4282e4292; (b) Liu, M.-F.; Wang, B.; Cheng, Y. Chem. Commun. 2006,
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Y. G.; Cheng, Y. Chem. Commun. 2007, 5087e5089; (f) Li, J.-Q.; Liao, R.-Z.; Ding,
W.-J.; Cheng, Y. J. Org. Chem. 2007, 72, 6266e6269; (g) Cheng, Y.; Kang, Z.-M.;
Ma, Y.-G.; Peng, J.-H.; Liu, M.-F. Tetrahedron 2008, 64, 7362e7368; (h) Cheng, Y.;
Wang, B.; Wang, X.-R.; Zhang, J.-H.; Fang, D.-C. J. Org. Chem. 2009, 74,
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Hall, C. D.; Steel, P. J. J. Org. Chem. 2011, 76, 4082e4087; (l) Chia, E. Y.; Naeem, S.;
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CDCl3):
d 179.3, 167.7, 150.8, 149.2, 139.6, 135.3, 130.7, 129.6, 129.6,
129.1, 128.9, 128.9, 128.9, 128.5, 128.4, 127.9, 127.4, 125.0, 122.8, 71.8,
56.5, 39.2, 29.0, 18.5; HRMS (ESI) calcd for C29H28N4O2 [MþH]þ:
465.2290, found: 465.2290; IR (neat, cmꢁ1): 2960, 2924, 2853,1718,
1661, 1495, 1255, 1102, 1017, 702, 690.
4.3.7. Methyl 2-(2,5-dioxo-1-phenyl-4-(1,3,4-triphenyl-1H-1,2,4-
triazol-5(4H)-ylidene)pyrrolidin-3-yl)acetate (6). The crude prod-
uct was purified by silica gel column chromatography using chlo-
roform/ethyl acetate as the eluent. Mp¼186e188 ꢀC; 1H NMR
(600 MHz, CDCl3):
d
7.67 (d, 2H, J¼7.6 Hz), 7.52e7.12 (m, 18H), 3.65
7. For reviews of NHC-catalyzed umpolung reactions of aldehyde, see: (a) Enders,
D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534e541; (b) Enders, D.; Niemeier,
(s, 3H), 3.05 (dd, 1H, J¼3.5 Hz, 5.4 Hz), 2.79 (dd, 1H, J¼3.5 Hz,
15.6 Hz), 2.30 (dd, 1H, J¼2.3 Hz, 15.6 Hz); 13C NMR (150 MHz,
ꢀ
O.; Henseler, A. Chem. Rev. 2007, 107, 5606e5655; (c) Marion, N.; Díez-Gonzalez,
S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988e3000; (d) Nair, V.; Vellalath,
S.; Babu, B. P. Chem. Soc. Rev. 2008, 37, 2691e2698; (e) Phillips, E. M.; Chan, A.;
Scheidt, K. A. Aldrichimica Acta 2009, 42, 54e66; (f) Moore, J. L.; Rovis, T. Top.
Curr. Chem. 2010, 291, 77e144; (g) Vora, H. U.; Rovis, T. Aldrichimica Acta 2011,
CDCl3):
d 175.8, 171.2, 164.9, 151.1, 149.7, 139.0, 134.8, 133.5, 130.9,
130.1, 129.7, 129.2, 129.1, 128.6, 128.6, 128.3, 127.0, 126.6, 124.6,
123.5, 66.5, 51.7, 40.7, 36.1; HRMS (ESI) calcd for C33H26N4O4

S. Matsuoka et al. / Tetrahedron 68 (2012) 9836e9841
9841
€
44, 3e11; (h) Biju, A. T.; Kuhl, N.; Glorius, F. Acc. Chem. Res. 2011, 44, 1182e1195;
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Smith, S. W.; Powell, D. A.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 1472e1473; (b)
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14. The analogous reaction using 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene
did not proceed.
10. (a) Takamizawa, A.; Hirai, K.; Matsumoto, S.; Ishiba, T. Chem. Pharm. Bull. 1968,
15. The analogous reactions of 1 with maleimides, see: Ref. 1b.
16. For the similar interconversions, see: (a) Furstner, A.; Alcarazo, M.; Goddard, R.;
€
16, 2130e2136; (b) Takamizawa, A.; Hirai, K.; Matsumoto, S.; Ishiba, T. Chem.
€
Pharm. Bull. 1969, 17, 462e466; (c) Regitz, M.; Hocker, J.; Schossler, W.; Weber,
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€
B.; Liedhegener, A. Justus Liebigs Ann. Chem. 1971, 748, 1e19; (d) Schossler, W.;
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17. The 13C NMR chemical shifts of C-2, 3, 4, and 5 of 6 are 175.8, 40.7, 66.5, 164.
9 ppm, respectively, and the corresponding peaks of 4aef are observed within
177.1e179.3, 38.6e39.1, 69.4e71.8, 163.0e167.7 ppm.
18. The signals of three carbonyl carbons (C-2, 5, 7) of 6 were assigned by HMBC
experiments (See Scheme 3 and Supplementary data).
12. The deoxy-Breslow intermediates were also obtained from the reaction of NHC
19. The characterization was limited to 1H NMR, ESI-MS, and IR. We have been
unsuccessful in obtaining a suitable single crystal for X-ray analysis to date, and
thus, the chemical structure (17 or 18) could not be determined.
€
with alkyl halides, see: (a) Knappke, C. E. I.; Neudorfl, J. M.; Jacobi von Wan-
gelin, A. Org. Biomol. Chem. 2010, 8, 1695e1705; (b) Knappke, C. E. I.; Arduengo,