cycloadduct 3aa could be obtained in very high yields with
excellent enantioselectivities even when utilizing as little as
1 mol% of either 4a’ or 5’ as the catalyst (Table 1, entries 9
and 10).
(cycloheptylidenemethanone) resulted in the desired cyclo-
adduct in very good yield albeit with a very low ee value
(entry 13).
Other N-sulfinylanilines, 2b–2e, having both electron-
donating (4-Me, 4-MeOC6H4) and electron-withdrawing
groups (4-Cl, 4-FC6H4) worked as well as N-sulfinylaniline
2a (Table 2, entries 14–17). In addition, the sulfinylanilines
2 f–2h having 2-substituted aryl groups (2-MeO, 2-Cl, 2-
FC6H4) also worked very well, thus giving the cycloadducts in
good yields with 91–99% ee (entries 18–20).
With the optimized reaction conditions in hand, a variety
of ketenes and N-sulfinylanilines were tested for the reaction
(Table 2). Both aryl(ethyl)ketenes with electron-donating
groups (4-Me, 4-MeOC6H4) and those with electron-with-
drawing groups (4-Br, 4-ClC6H4) worked very well for the
reactions catalyzed by either 4a’ or 5’, thus affording the
cycloadducts in very good yields with excellent enantioselec-
tivities (entries 1–5). The reaction of 3-chlorophenyl-
(ethyl)ketene (1 f) catalyzed by 1 mol% of 4a’ led to some
decreased enantioselectivity, and 10 mol% of 4a’ is required
for the reaction of 2-chlorophenyl(ethyl)ketene (1g) to
achieve high enantioselectivity (entries 6 and 7). It is inter-
esting that 1 mol% of 5’ worked well for the reactions of the
ketenes 1 f and 1g (entries 6 and 7); the lower loading of 5
may result from the smaller steric bulk of the NHC 5’ relative
to 4a’. Phenyl(alkyl)ketenes 1h, 1i, and 1j with methyl, n-
propyl, and n-butyl groups, respectively, worked very well
(entries 8–10). Again, the sterically crowed ketene 1k having
an isobutyl group showed somewhat decreased enantioselec-
tivity (entry 11). The reaction of diphenylketene (1l) cata-
lyzed by 5’ gave the desired cycloadduct in 81% yield with
82% ee, whereas the reaction catalyzed by 4a’ resulted in very
low yield and selectivity (entry 12). The cyclic ketene 1m
The relative and absolute structure of thiazetidinone
oxide (À)-3ha was unambiguously established by X-ray
analysis of its crystal.[14]
The highly functional cycloadducts 3 afford many possi-
bilities for chemical transformations (Scheme 2). As
expected, the 3-oxo-b-sultam 6aa could be obtained in 95%
yield with 98% ee by the oxidation of the cycloadduct 3aa,[15]
and alcoholysis of 6aa gave the sulfate 7aa in good yield
(Scheme 2, steps a and b).[1e] Aminolysis of the cycloadduct
3aa with pyrrolidine gave the sulfonamide 8aa (Scheme 2,
step c).[16] Reductive ring-opening with DIBAL-H afforded a-
mercapto amides 9aa, 9ha, and 9ae in good yields with
excellent enantioselectivities at À788C (Scheme 2, step d).[17]
It is interesting that the 1,2-mercapto amine resulted in good
yield as the reductive reaction was carried out at room
temperature (Scheme 2, step e).
Although the noncatalytic [2+2] cycloaddition reaction of
ketenes with sulfur dioxide,[18]
sulfur diimides,[2c] or N-sulfinylani-
lines[2a,b] have been reported, we
Table 2: Enantioselective [2+2] cycloaddition of ketenes and N-sulfinylanilines by NHC 4a’ or 5’.
have not observed the noncatalytic
background [2+2] cycloaddition
reaction of ketenes and N-sulfiny-
laniline at À788C. Controlled
experiments without the addition
of ketenes revealed that no reaction
of N-sulfinylaniline occurred in the
presence of 10 mol% or 1 equiva-
lent of 4a’ at À788C.[19] Based on
these observations and our previ-
ously established reactivity of
NHCs towards ketenes, we propose
that the catalytic cycle is initiated by
the addition of the NHC to the
ketene to give enolate B, which
reacts with N-sulfinylanilines 2 to
afford adduct C (Scheme 3). Ring
closure of adduct C gives the final
product 3 and regenerates the cata-
lyst.
In summary, the enantioselec-
tive N-heterocyclic carbene cata-
lyzed [2+2] cycloaddition of
ketenes and N-sulfinylanilines was
developed. Both enantiomers of the
cycloadduct of 1,2-thiazetidin-3-one
1-oxides were obtained in very good
yields with excellent enantioselec-
tivities using only 1 mol% of the
Entry 1 (Ar1, R)
2 (Ar2)
Reaction using 4a’[a]
Reaction using 5’[a]
(+)-3
Yield ee
(À)-3
Yield ee
[%][b] [%][c]
[%][b] [%][c]
1
1a (Ph, Et)
2a (Ph)
2a
(+)-3aa 95
(+)-3ba 88
(+)-3ca 93
(+)-3da 93
(+)-3ea 89
(+)-3 fa 81
(+)-3ga 81[d]
(+)-3ha 91
99
95
98
94
99
81
93[d]
98
97
97
80
3
(À)-3aa
(À)-3ba
(À)-3ca
(À)-3da
(À)-3ea
(À)-3 fa
(À)-3ga
(À)-3ha
(À)-3ia
(À)-3ja
(À)-3ka
(À)-3la
94
91
91
93
87
87
73
93
95
96
81
81
99
93
98
94
97
92
88
98
94
96
88
82
16
91
99
99
99
99
95
98
2
1b (4-MeC6H4, Et)
3
1c (4-MeOC6H4, Et) 2a
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
1d (4-BrC6H4, Et)
1e (4-ClC6H4, Et)
1 f (3-ClC6H4, Et)
1g (2-ClC6H4, Et)
1h (Ph, Me)
1i (Ph, n-Pr)
1j (Ph, nBu)
1k (Ph, iBu)
1l (Ph, Ph)
1m (-(CH2)6-)
1a (Ph, Et)
1a
2a
2a
2a
2a
2a
2a
2a
2a
(+)-3ia
(+)-3ja
93
94
(+)-3ka 86
2a
2a
3la
3ma
13
91
3
(À)-3ma 93
2b (4-MeC6H4)
2c (4-MeOC6H4) (+)-3ac 90
2d (4-ClC6H4)
2e (4-FC6H4)
2 f (2-MeOC6H4) (+)-3af
(+)-3ab 81
98
99
99
99
98
91
97
(À)-3ab
(À)-3ac
(À)-3ad
(À)-3ae
(À)-3af
(À)-3ag
(À)-3ah
83
87
86
91
87
83
87
1a
1a
1a
1a
(+)-3ad 89
(+)-3ae 88
79
2g (2-ClC6H4)
2h (2-FC6H4)
(+)-3ag 81
(+)-3ah 84
1a
[a] The NHCs 4a’ and 5’ were freshly generated from the precatalysts 4a and 5 (1 mol%), respectively, in
the presence of Cs2CO3 (2 mol%) at room temperature after 30 min, and then used immediately.
[b] Yield of the isolated product. [c] Determined by HPLC methods using a chiral stationary phase.
[d] Reaction catalyzed by 10 mol% of NHC 4a’.
Angew. Chem. Int. Ed. 2011, 50, 9104 –9107
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9105