NHC-catalyzed enantioselective [2 + 2] and [2 + 2 + 2] cycloadditions of ketenes with isothiocyanates

Article abstract of DOI:10.1021/ol202688h

The enantioselective N-heterocyclic carbene-catalyzed formal [2 + 2] and [2 + 2 + 2] cycloaddition of ketenes and isothiocyanates were developed. Reaction with N-aryl isothiocyanates at room temperature favors the [2 + 2] cycloaddition, while reaction wit

Full text of DOI:10.1021/ol202688h

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6382–6385
NHC-Catalyzed Enantioselective [2 þ 2]
and [2 þ 2 þ 2] Cycloadditions of Ketenes
with Isothiocyanates
Xiao-Na Wang, Li-Tao Shen, and Song Ye*
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular
Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences,
Beijing 100190, China
songye@iccas.ac.cn
Received October 6, 2011
ABSTRACT
The enantioselective N-heterocyclic carbene-catalyzed formal [2 þ 2] and [2 þ 2 þ 2] cycloaddition of ketenes and isothiocyanates were
developed. Reaction with N-aryl isothiocyanates at room temperature favors the [2 þ 2] cycloaddition, while reaction with N-benzoyl
isothiocyanates at ꢀ40 °C favors the [2 þ 2 þ 2] cycloaddition.
The cycloaddition reactions of ketenes are powerful
tools for the construction of various cyclic compounds.1,2
During the past few years, we demonstrated that N-hetero-
cyclic carbenes (NHCs)3 are efficient catalysts for cycload-
dition reactions of ketenes with carbonyl compounds,
imines, heterodienes, oxaziridines, carbon disulfide, and
N-sulfinylanilines.4,5 Because of their easy availability and
diverse reactions, isothiocyanates are widely utilized, espe-
cially in the synthesis of heterocycles.6,7 In 1965, Winberg
et al. reported the reaction of NHCs with isothiocyanates
to form stable adducts.8 Recently, Cheng et al. have
successfully developed this process for the synthesis of a
(1) For reviews, see: (a) Orr, R. K.; Calter, M. A. Tetrahedron 2003,
59, 3545–3565. (b) Fu, G. C. Acc. Chem. Res. 2004, 37, 542–547. (c)
Tidwell, T. T. Angew. Chem., Int. Ed. 2005, 44, 5778–5785. (d) Paull,
D. H.; Weatherwax, A.; Lectka, T. Tetrahedron 2009, 65, 6771–6803.
(2) For recent examples, see: (a) Cabrera, J.; Hellmuth, T.; Peters, R.
J. Org. Chem. 2010, 75, 4326–4329. (b) Morris, K. A.; Arendt, K. M.;
Oh, S. H.; Romo, D. Org. Lett. 2010, 12, 3764–3767. (c) Mondal, M.;
Ibrahim, A. A.; Wheeler, K. A.; Kerrigan, N. J. Org. Lett. 2010, 12,
1664–1667. (d) Kull, T.; Cabrera, J.; Peters, R. Chem.;Eur. J. 2010, 16,
9132–9139. (e) Dochnahl, M.; Fu, G. C. Angew. Chem., Int. Ed. 2009, 48,
2391–2393. (f) Sereda, O.; Blanrue, A.; Wilhelm, R. Chem. Commun.
2009, 1040–1042.
(3) For reviews on NHC catalysis, see: (a) Enders, D.; Balensiefer, T.
Acc. Chem. Res. 2004, 37, 534–541. (b) Enders, D.; Niemeier, O.;
Henseler, A. Chem. Rev. 2007, 107, 5606–5655. (c) Moore, J. L.; Rovis,
T. Top. Curr. Chem. 2010, 291, 77–144.
(4) (a) Zhang, Y.-R.; He, L.; Wu, X.; Shao, P.-L.; Ye, S. Org. Lett.
2008, 10, 277–280. (b) Wang, X.-N.; Shao, P.-L.; Lv, H.; Ye, S. Org. Lett.
2009, 11, 4029–4031. (c) Wang, X.-N.; Zhang, Y.-Y.; Ye, S. Adv. Synth.
Catal. 2010, 352, 1892–1895. (d) Shao, P.-L.; Chen, X.-Y.; Ye, S. Angew.
Chem., Int. Ed. 2010, 49, 8412–8416. (e) Zhang, Y.-R.; Lv, H.; Zhou, D.;
Ye, S. Chem.;Eur. J. 2008, 14, 8473–8476. (f) Jian, T.-Y.; Shao, P.-L.;
Ye, S. Chem. Commun. 2011, 47, 2381–2383. (g) Jian, T.-Y.; He, L.;
Tang, C.; Ye, S. Angew. Chem., Int. Ed. 2011, 50, 9104–9107.
(5) Smith et al. have also independently reported an NHC-catalyzed
reaction of ketenes: (a) Duguet, N.; Campbell, C. D.; Slawin, A. M. Z.;
ꢀ
Smith, A. D. Org. Biomol. Chem. 2008, 6, 1108–1113. (b) Concellon, C.;
Duguet, N.; Smith, A. D. Adv. Synth. Catal. 2009, 351, 3001–3009.
(6) For reviews, see: (a) Mukerjee, A. K.; Ashare, R. Chem. Rev.
1991, 91, 1–24. (b) Sommen, G. Synlett 2004, 1323–1324. (c) Ozaki, S.
Chem. Rev. 1972, 72, 457–496.
(7) For recent examples of enantioselective reaction with isothiocya-
nates, see: (a) Cao, Y.; Jiang, X.; Liu, L.; Shen, F.; Zhang, F.; Wang, R.
Angew. Chem., Int. Ed. 2011, 50, 9124–9127. (b) Lu, G.; Yoshino, T.;
Morimoto, H.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed.
2011, 50, 4382–4385. (c) Chen, X.; Dong, S.; Qiao, Z.; Zhu, Y.; Xie, M.;
Lin, L.; Liu, X.; Feng, X. Chem.;Eur. J. 2011, 17, 2583–2586. (d) Jiang,
X.-X.; Cao, Y.-M.; Wang, Y.-Q.; Liu, L.-P.; Shen, F.-F.; Wang, R. J.
Am. Chem. Soc. 2010, 132, 15328–15333. (e) Chem, X.; Zhu, Y.; Qiao,
Z.; Xie, M.; Lin, L.; Liu, X.; Feng, X. Chem.;Eur. J. 2010, 16, 10124–
10129. (f) Vecchione, M. K.; Li, L.; Seidel, D. Chem. Commun. 2010, 46,
4604–4606. (g) Yoshino, T.; Morimoto, H.; Lu, G.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 17802–17803. (h) Li, L.;
Ganesh, M.; Seidel, D. J. Am. Chem. Soc. 2009, 131, 11648–11649. (i)
Willis, M. C.; Cutting, G. A.; Piccio, V. J.-D.; Durbin, M. J.; John, M. P.
Angew. Chem., Int. Ed. 2005, 44, 1543–1545.
(8) (a) Winberg, H. E.; Coffman, D. D. J. Am. Chem. Soc. 1965, 87,
2776–2777. (b) Delaude, L. Eur. J. Inorg. Chem. 2009, 1681–1699.
r
10.1021/ol202688h
Published on Web 11/15/2011
2011 American Chemical Society

wide range of heterocycles.9 Very recently, Yadav et al.
reported the NHC-catalyzed [2 þ 2] cycloaddition of
isothiocyanates and nitroolefins.10,11 In this paper, we
report an NHC-catalyzed enantioselective reaction of ketenes
with isothiocyanates for the synthesis of 4-thioxo-2-azeti-
dinones (thioxo-β-lactams), which are potential synthons
for bioactive heterocycles,12 such as sulfur-containing
β-lactam antibiotics.13 Although 4-thioxo-2-azetidinones
have been prepared from degradation of penicillin since
1976,14 to the best of our knowledge, the enantioselective
synthesis of this key motif remains unrealized.
Initially, we found that the reaction of ketene 1a and N-
phenyl isothiocyanate gave the desired 4-thioxo-2-azetidi-
none 3a in 13% yield with 75% ee in the presence of NHC
A10, generated freshly from NHC precursor A1 and
Cs2CO3, at room temperature (Scheme 1). Encouraged
by this result, several isothiocyanates were then
screened. Reaction with N-p-chlorophenylisothiocya-
nates gave the desired product 4a in 25% yield with
70% ee. The yield was increased to 69% albeit with
39% ee when N-p-nitrophenyl isothiocyanate was used.
Reaction of N-benzoyl isothiocyanate gave no desired
cycloadduct but a complex mixture.
better yield and enantioselectivity were realized when the
reaction was carried out in dilute solution (entries 1ꢀ5).
Several NHC precursors A2-A5, derived from L-pyroglu-
tamic acid were then tested for the reaction. NHC pre-
cursor A2 with an N-phenyl group led to a decreased yield
with moderate enantioselectivity (entry 6), while NHC
precursors A3ꢀA4 with an N-benzyl group showed better
enantioselectivity but decreased yield (entries 7 and 8).
NHC precursor A5witha freehydroxyl group affordedthe
cycloadduct 5a in 73% with 96% ee (entry 9). NHC
precursor B, derived from chiral indanol, resulted in low
yield and enantioselectivity (entry 10). The yield was
improved when excess ketene (2.5 equiv) was used and
added via a syringe pump (entries 11 and 12). Unex-
pectedly, a [2 þ 2 þ 2] cycloadduct 7a was observed,
along with the normal [2 þ 2] cycloadduct 5a, when the
reaction temperature was lowed to ꢀ10 or ꢀ40 °C
(entries 13 and 14)
Table 1. Condition Optimization of [2 þ 2] Cycloaddition
Scheme 1. Screening of Isothiocyanates
entry
precat.
DCM (x mL)
T (°C)
yielda (%)
eeb
39
1
A1
A1
A1
A1
A1
A2
A3
A4
A5
B
5
2.5
10
15
20
15
15
15
15
15
15
15
15
5
rt
rt
69
2
60
33
3
rt
70
52
4
rt
96
55
5
rt
91
57
6
rt
74
55
7
rt
75
85
8
rt
66
83
The reaction of ketene 1a and N-p-nitrophenyl isothio-
cyanate (2c) was optimized (Table 1). It is interesting that
9
rt
73
96
10
11c
12c,d
13
14
rt
31
ꢀ33
96
A5
A5
A5
A1
rt
76
(9) (a) Liu, M.-F.; Wang, B.; Cheng, Y. Chem. Commun. 2006, 1215–
1217. (b) Cheng, Y.; Liu, M.-F.; Fang, D.-C.; Lei, X.-M. Chem.;Eur. J.
2007, 13, 4282–4292. (c) Zhu, Q.; Liu, M.-F.; Wang, B.; Cheng, Y. Org.
Biomol. Chem. 2007, 5, 1282–1286. (d) Wang, B.; Li, J.-Q.; Cheng, Y.
Tetrahedron Lett. 2008, 49, 485–489.
(10) Awasthi, C.; Yadav, L. S. Synlett. 2010, 1783–1788.
(11) The NHC-catalyzed cyclotrimerization of isocyanates was re-
ported: Duong, H. A.; Cross, M. J.; Louie, J. Org. Lett. 2004, 6, 4679–
4681.
rt
80
97
ꢀ10
60 (6)e
<10 (18)e
97 (96)e
42 (71)e
ꢀ40
a Isolated yield. b Deterninded by chiral HPLC. c Ketene 1a was
added via a syringe pump over 3 h. d 2.5 mmol of ketene 1a was used.
e Yield and ee of 7a were showed in parentheses.
(12) Bachi, M. D.; Goldberg, O.; Gross, A.; Vaya, J. J. Org. Chem.
1980, 45, 1481–1485.
(13) (a) Chemistry and Biology of β-Lactam Antibiotics; Morin, R. B.,
Gorman, M., Eds.; Academic Press: New York, 1982; Vols. 1ꢀ3. (b) Lysek,
R.; Borsuk, K.; Furman, B.; Kaluza, Z.; Kazimierski, A.; Chmielewski,
M. Curr. Med. Chem. 2004, 11, 1813–1835. (c) Buynak, J. D. Curr. Med.
Chem. 2004, 11, 1951–1967.
(14) (a) Chou, T. S.; Koppel, G. A.; Dorman, D. E.; Paschal, J. W.
J. Am. Chem. Soc. 1976, 98, 7864–7865. (b) Bachi, M. D.; Vaya, J. J. Am.
Chem. Soc. 1976, 98, 7825–7826. (c) Brandt, A.; Bassignani, L.; Re, L.
Tetrahedron Lett. 1976, 17, 3975–3978. (d) Bachi, M. D.; Goldberg, O.;
Gross, A.; Vaya, J. J. Org. Chem. 1980, 45, 1477–1481.
A variety of aryl(alkyl)ketenes were tested under the
optimized conditions for the [2 þ 2] cycloaddition (Table 2).
Both aryl(alkyl)ketenes with electron-withdrawing groups
(Ar = 4-Cl, 4-BrC6H4) and with electron-donating groups
(Ar = 4-Me, 4-MeOC6H4) worked well to give the corre-
sponding 4-thioxo-2-azetidinones 5 in good yields with
high enantioselectivities (entries 2ꢀ5). The ketene 1f with
an m-chlorophenyl group worked well for the reaction, but
Org. Lett., Vol. 13, No. 24, 2011
6383

ketene 1g with an o-chlorophenyl group did not (entries 6
and 7). The ketenes with methyl, n-propyl, and n-butyl
groups all worked well, affording the desired cycloadducts
in high yields with high enantioselectivities (entries 8ꢀ10).
However, ketene 1k with isopropyl group gave no cycload-
duct under the current reaction conditions (entry 11).
Table 3. Condition Optimization of the [2 þ 2 þ 2] Cycloaddi-
tion
Table 2. NHC-Catalyzed [2 þ 2] Cycloaddition
entry
1a:2d
solvent
T (°C)
yielda (%)
eeb (%)
1
1.5:1
1.5:1
1.5:1
1.5:1
1:1.5
2.5:1
2.5:1
2.5:1
2.5:1
2.5:1
DCM
DCM
toluene
CH3CN
DCM
DCM
DCM
DCM
DCM
DCM
rt
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ40
ꢀ60
ꢀ40
ꢀ40
mixture
40
/
86
87
46
77
73
83
84
85
83
2
3
21
4
15
5
21
entry
1 (Ar, R)
1a, Ph, Et
5
time (h) yielda (%) eeb (%)
6
40
7
60
1
2
5a
5b
5c
5d
21
21
80
75
97
97
95
93
93
96
/
8
39
1b, 4-ClC6H4, Et
1c, 4-BrC6H4, Et
1d, 4-MeC6H4, Et
9c
10d
72
3
27
62
64
4
22
65
5
1e, 4-MeOC6H4, Et 5e
141
39
63
a Isolated yield. b Determined by HPLC. c 2.5 mL of DCM was used.
d 1.5 mL of DCM was used.
6
1f, 3-ClC6H4, Et
1g, 2-ClC6H4, Et
1h, Ph, Me
5f
70
7
5g
5h
5i
61
NR
78
8
15
92
93
92
/
9
1i, Ph, n-Pr
20
81
10
11
1j, Ph, n-Bu
5j
10
85
1k, 4-ClC6H4, i-Pr
5k
125
NR
a Isolated yield. b Determined by HPLC. NR = no reaction.
Table 4. NHC-Catalyzed [2 þ 2 þ 2] Cycloaddition
We then turned our attention to the possible [2 þ 2 þ 2]
cycloaddition (Table 3). It is interesting that although the
reaction with N-benzoylisothiocyanate gave a complex mix-
ture at room temperature, the corresponding [2 þ 2 þ 2]
cycloadduct 8a was isolated in 40% yield with 86% ee
without the observation of [2 þ 2] cycloadduct when the
reaction was carried out at ꢀ10 °C (entries 1 and 2).
Solvent screening revealed that no improvement was made
in toluene or acetonitrile (entries 3 and 4). Reaction tem-
perature (ꢀ10 to ꢀ60 °C) and dosage of the ketene had
strong impact on the yield of the reactions (entries 5ꢀ8). A
little excess of ketene (1a:2d = 2.5:1) and lowing the
reaction temperature to ꢀ40 °C gave cycloadduct 8a in
60% yield with 83% ee (entry 7). Further experiments
showed that concentration could also alter the yield of the
reaction (entries 7, 9ꢀ10). Moderately concentrated solu-
tion ([1a] = 1.0 M) benefited the reaction, giving cycload-
duct 8a in 72% yield with 85% ee (entry 9).
entry
1 (Ar, R)
1a, Ph, Et
8
time (h) yielda (%) eeb (%)
1
8a
8b
8d
45
53
41
78
39
50
38
51
31
113
72
62
86
75
78
67
61
/
2
1b, 4-ClC6H4, Et
1d, 4-MeC6H4, Et
3
71
4
1e, 4-MeOC6H4, Et 8e
54
5c
6d
7
1f, 3-ClC6H4, Et
1g, 2-ClC6H4, Et
1h, Ph, Me
8f
50
8g
8h
8i
NR
60
77
81
79
/
8
1i, Ph, n-Pr
65
9
10d
1j, Ph, n-Bu
8j
66
1k, 4-ClC6H4, i-Pr
8k
NR
a Isolated yield. b Determined by HPLC. c Reaction was carried out
at ꢀ10 °C. d No reaction occurred at ꢀ40 °C or room temperature.
Several ketenes were then tested for the [2 þ 2 þ 2]
cycloaddition reaction with N-benzoyl isothiocyanate,
which showed similar scope as the [2 þ 2] cycloaddition
reaction with N-p-nitrophenyl isothiocyanate (Table 4).
Both electron-withdrawing substituents and electron-
donating substituents were tolerable for the aryl(alkyl)-
ketenes (entries 2ꢀ5). However, ketene 1g with a 2-chloro-
phenyl group gave no cycloadduct (entry 6). The
ketenes with methyl, n-propyl, and n-butyl groups all
worked well, but ketene 1k with isopropyl group did
not(entries 7ꢀ10).
Both the structures of [2 þ 2] cycloadduct 5h and [2 þ
2 þ 2] cycloadduct 7a were unambiguously established by
X-ray analysis of their crystals (Figures S1 and S3, Sup-
porting Information).15
The resulted highly functionalized cycloadducts offer
many opportunity of chemical transformations. For exam-
ple, alcoholysis of the cycloadduct 5a gave the ring-opening
(15) See the Supporting Information for details.
6384
Org. Lett., Vol. 13, No. 24, 2011

which reacts with isothiocyanate to give intermediate
B. Intermediate B may collapse via an intramolecu-
lar N-addition to azolium acyl to furnish [2 þ 2] cyclo-
adducts 5 and regenerates NHC (pathway a). However,
when the isothiocyanate with N-benzoyl is employed
the intermediate B is stabilized with resonant structure
B3, which facilitates the S-addition to the second
molecule of ketene to generate intermediate C at low
temperature (pathway b). Intermediate C collapses via
an intramolecular O-addition to azolium acyl to fur-
nish [2 þ 2 þ 2] cycloadducts 8 and regenerates NHC.
Control experiments revealed that [2 þ 2] cycloadduct
could not be transformed to [2 þ 2 þ 2] cycloadduct in
the presence of ketene under the reaction condition of
[2 þ 2 þ 2] cycloaddition.15
Scheme 2. Plausible Reaction Pathways
In summary, the enantioselective N-heterocyclic car-
bene-catalyzed formal [2 þ 2] and [2 þ 2 þ 2] cycloaddi-
tions of ketenes and isothiocyanates were developed.
Reaction with N-arylisothiocyanates at room tem-
perature favors the [2 þ 2] cycloaddition to give the
4-thioxo-2-azetidinones (thioxo-β-lactams) in good
yields with high enantioselectivities, while reaction
with N-benzoyl isothiocyanates at ꢀ40 °C favors
the [2 þ 2 þ 2] cycloaddition to give the corresponding
1,3-oxathian-6-ones in good yields with good enan-
tioselectivities. The resulted optically active cycload-
ducts are potentially useful for the synthesis of sulfur-
containing heterocycles, particularly the β-lactam
antiobiotics.
compound 9 in 78% yield without apparent erosion of
enantiopurity (eq 1).
Acknowledgment. Financial support from National
Natural Science Foundation of China (No. 20872143,
20932008), the Ministry of Science and Technology of
China (2011CB808600), and the Chinese Academy of
Sciences is gratefully acknowledged.
Supporting Information Available. Experimental pro-
cedures, compound characterization and X-ray data
for cycloadducts 5h and 7a (CIF). This material is avail-
able free of charge via the Internet at http://pubs.acs.
org.
The plausible reaction pathways are depicted in Scheme 2.
The addition of NHC to ketenes generates intermediate A,
Org. Lett., Vol. 13, No. 24, 2011
6385