Enantioselective synthesis of Aza-β-lactams via NHC-catalyzed [2 + 2] cycloaddition of ketenes with diazenedicarboxylates

Article abstract of DOI:10.1021/jo901656q

(Chemical Equation Presented) N-Heterocyclic carbenes were found to be efficient catalysts for the formal [2 + 2] cycloaddition of aryl-(alkyl)ketenes and diazenedicarboxylates to give the corresponding aza-β-lactams in good yields with up to 91% ee. The

Full text of DOI:10.1021/jo901656q

pubs.acs.org/joc
SCHEME 1. [2 þ 2] and [4 þ 2] Cycloadditions Reported
Enantioselective Synthesis of Aza-β-lactams via
NHC-Catalyzed [2 þ 2] Cycloaddition of Ketenes
with Diazenedicarboxylates
Xue-Liang Huang, Xiang-Yu Chen, 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 July 30, 2009
contributors for the synthesis and application of aza-β-
lactams.6 Recently, Berlin and Fu reported the first enantio-
selective [2 þ 2] cycloaddition of ketenes with diazenedicar-
boxylates catalyzed by their planar-chiral 4-pyrrolidino-
pyridine derivatives (Scheme 1a).7 Interestingly, we found
that the reaction of ketenes and N-benzoyldiazenes catalyzed
by chiral N-heterocyclic carbenes (NHCs) gave predomi-
nately the formal [4 þ 2] cycloaddition of ketenes in high
yield with good enantioselectivities (Scheme 1b).8
The two reaction modes ([4 þ 2] and [2 þ 2]) prompt us to
think whether the catalysts or the different substituents of
diazenes control the reaction modes. To answer this ques-
tion, two more experiments were carried out. It was found
that NHC 2a0, generated freshly from the precursor 2a and
Cs2CO3, could catalyze the reaction of phenyl(ethyl)ketene
(3a) and diethyl diazenedicarboxylate (4a) to give [2 þ 2]
cycloaddition product in 38% yield with 87% ee, and no
[4 þ 2] cycloaddition product was detected (Scheme 2a). The
other experiment showed that DMAP-catalyzed reaction of
ketene 3a and N-phenyl-N0-benzoyldiazene gave the [4 þ 2]
cycloaddition product (Scheme 2b).
N-Heterocyclic carbenes were found to be efficient
catalysts for the formal [2 þ 2] cycloaddition of aryl-
(alkyl)ketenes and diazenedicarboxylates to give the cor-
responding aza-β-lactams in good yields with up to 91%
ee. The N-substituent (carboxylate vs benzoyl) of dia-
zenes played an important role to control the reaction
modes (formal [2 þ 2] vs [4 þ 2] cycloaddtions).
As the aza analogues of β-lactams, aza-β-lactams show
some interesting biological activities1 and are useful inter-
mediates for the synthesis of R-amino acids and heterocyclic
compounds.2 In 1925, Ingold and Weaver reported the first
[2 þ 2] cycloaddition of ketenes and diazenes to give aza-β-
lactams.3-5 Lately, Taylor and co-workers were the main
(1) (a) Morioka, H.; Takezawa, M.; Shibai, H.; Okawara, T.; Furukawa,
M. Agric. Biol. Chem. 1986, 50, 1757–1764. (b) Abdel-Ghaffar, S. A.;
Mpango, G. B.; Ismail, M. A.; Nanyonga, S. K. Boll. Chim. Farm. 2002,
141, 389–393.
For the reactions catalyzed by NHC, the reaction mode is
changed from [4 þ 2] to [2 þ 2] when the diazene is changed
from N-benzoyldiazene to diazenedicarboxylate (Scheme 1b vs
(2) For reviews of the synthesis of R,R-disubstituted R-amino acids, see:
€
(a) Vogt, H.; Brase, S. Org. Biomol. Chem. 2007, 5, 406–430. (b) Cativiela, C.;
Diaz-de-villegas, M. D. Tetrahedron: Asymmetry 2007, 18, 569–623.
(3) Ingold, C. K.; Weaver, S. D. J. Chem. Soc. 1925, 127, 378–387.
(4) For reviews of ketene chemistry, see: (a) Tidwell, T. T. Ketenes; Willey-
Interscience: New York, 2006. (b) Tidwell, T. T. Angew. Chem., Int. Ed. 2005, 44,
5778–5 785. (c) Tidwell, T. T. Eur. J. Org. Chem. 2006, 563–576.
(5) For selective examples of R-amination of carbonyl compounds, see:
(a) List, B. J. Am. Chem. Soc. 2002, 124, 5656–5657. (b) Bogevig, A.; Juhl, K.;
Kumaragurubaran, N.; Zhuang, W.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2002, 41, 1790–1793. (c) Kumaragurubaran, N.; Juhl, K.; Zhuang, W.;
Bogevig, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2003, 125, 6254–6255.
(d) Marigo, M.; Juhl, K.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42,
1367–1369. (e) Saaby, S.; Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004,
126, 8120–8121. (f) Hasegawa, Y.; Watanabe, W.; Gridnev, I. D.; Ikariya, T.
J. Am. Chem. Soc. 2008, 130, 2158–2159. (g) He, R.; Wang, X.; Hashimoto,
T.; Maruoka, K. Angew. Chem., Int. Ed. 2008, 47, 9466–9468.
(6) (a) Taylor, E. C.; Clemens, R. J.; Davies, H. M. L.; Haley, N. F. J. Am.
Chem. Soc. 1981, 103, 7659–7660. (b) Taylor, E. C.; Davies, H. M. L.;
Clemens, R. J.; Yanagisawa, H.; Haley, N. F. J. Am. Chem. Soc. 1981, 103,
7660–7661. (c) Taylor, E. C.; Haley, N. F.; Clemens, R. J. J. Am. Chem. Soc.
1981, 103, 7743–7752. (d) Taylor, E. C.; Clemens, R. J.; Davies, H. M. L. J.
Org. Chem. 1983, 48, 4567–4571. (e) Taylor, E. C.; Davies, H. M. L.; Lavell,
W. T.; Jones, N. D. J. Org. Chem. 1984, 49, 2204–2208. (f) Taylor, E. C.;
Davies, H. M. L.; Hinkle, J. S. J. Org. Chem. 1986, 51, 1530–1536. (g) Taylor,
E. C.; Davies, H. M. L. J. Org. Chem. 1986, 51, 1537–1540. (h) Taylor, E. C.;
Hinkle, J. S. J. Org. Chem. 1987, 52, 4107–4110.
(7) Berlin, J. M.; Fu, G. C. Angew. Chem., Int. Ed. 2008, 47, 7048–7050.
(8) Huang, X.-L.; He, L.; Shao, P.-L.; Ye, S. Angew. Chem., Int. Ed. 2009,
48, 192–195.
DOI: 10.1021/jo901656q
r
Published on Web 09/01/2009
J. Org. Chem. 2009, 74, 7585–7587 7585
2009 American Chemical Society

Huang et al.
JOCNote
SCHEME 2. Control Experiments
TABLE 1. Chiral NHCs Screeninga
entry
2 (Ar1, Ar2, R) or 8
2a: Ph, Ph, TBS
2b: Ph, Ph, TMS
2c: Ph, PMP, TBS
2d: Ph, Mes, TMS
2e: Ph, Ph, H
2f: 3,5-(CF3)2C6H3, Ph, H
2g: 3,5-(CF3)2C6H3, PMP, H
2h: Ph, Mes, H
2h: Ph, Mes, H
8
yield (%)b
ee (%)c
Scheme 2a). For the reaction catalyzed by pyridine derivatives,9
change of the diazenes also led to the change of reaction modes
(Scheme 1a vs Scheme 2b). In other words, the reaction of
ketenes and diazenedicarboxylates, catalyzed by either pyridine
derivative (Scheme 1a) or NHC (Scheme 2a) gave the [2 þ 2]
cycloaddition product, whereas the reaction of ketenes and
N-benzoyldiazenes, catalyzed by either NHC (Scheme 1b) or
DMAP (Scheme 2b), gave the [4 þ 2] cycloaddition product.
Thus, we conclude that the different reaction modes are pre-
dominantly controlled by the different substituents of the
diazenes.10 The different behaviors of carbonyl groups of
benzoyl and carboxylate may contribute to the two different
reaction modes.
1
2
3
4
5
6
7
8
88
94
88
53
43
69
71
26
26
48
85
88
84
68
8
59
58
-70d
-87d
-88d
9e
10
a
NHCs 20 and 80 were generated from the NHC precursor 2 and 8 with
Cs2CO3 in THF at room temperature in 10 min and used immediately.
bIsolated yields. cDeterimined by chiral HPLC. dent-5a was obtained as
the major enantiomer. eToluene was used as the solvent.
Encouraged by these results, we decided to investigate the
NHC-catalyzed [2 þ 2] cycloaddition of ketenes with diaze-
nedicarboxylates to synthesize optically active aza-β-lac-
tams. A series of NHCs were then tested for reactions
(Table 1). Interestingly, when the reaction was carried out
in dichoromethane (the solvent of choice in Fu’s work), the
yield was increased to 88% with 85% ee (Table 1, entry 1 vs
Scheme 2a). Unexpectedly, the reaction catalyzed by less
sterically hindered NHC 2b0 with a TMS protective group
gave the aza-β-lactams in very good yield with slightly better
enantioselevtivity than with NHC 2a0 (entry 2 vs entry 1).
Installing an electron-donationg group gives NHC 2c0
(Ar2 = p-methoxylphenyl), which showed similar result as
with NHC 2a0 (entry 3). The reaction catalyzed by NHC 2d0
(Ar2 = mesityl) led to low yield and enantioselectivity (entry 4).
A series of N-heterocyclic carbenes (2e0-h0) with a free
hydroxyl group were then tested.11 NHC 2e0 did catalyze this
cycloaddition, but with little asymmetric induction (Table1,
entry 5). Both NHC 2f0 and 2g0 catalyzed the reaction with
improved results (entries 6 and 7). The enantioselectivity
could be switched when NHC 2h0 was employed, but low
yield resulted (entries 8 and 9).8 The reaction catalyzed by
Rovis’ catalyst 8012 also afforded the desired product in 48%
yield with 88% ee (entry 10).
TABLE 2. Optimization of Conditions for the Formal [2 þ 2]
a
Cycloaddition of 3a and 4a catalyzed by NHC 2b0
entry
conditions
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
CH2Cl2, rt
CH3CN, rt
THF, rt
toluene, rt
CHCl3, rt
ClCH2CH2Cl, rt
CH2Cl2, 0 °C
CH2Cl2/THF (9:1), rt
CH2Cl2/ether (9:1), rt
CH2Cl2/toluene (9:1), rt
CH2Cl2/toluene (9:1), rt
CH2Cl2/toluene (9:1), rt
CH2Cl2/toluene (9:1), rt
94
78
81
81
88
79
69
91
91
90
93
93
87
88
83
86
85
84
85
87
90
89
90
89
91
89
9
10
11d
12d,e
13e,f
a
Ketene 3a (0.75 mmol), diazene 4a (0.5 mmol), NHC precursor 2b
(0.1 mmol), and Cs2CO3 (0.1 mmol) were employed. bIsolated yields.
cDeterimined by chiral HPLC. dNHC precursor 2b (0.05 mmol) and
Cs2CO3 (0.05 mmol) were used. eKetene 3a was added by syringe pump
over 1 h. fNHC precursor 2b (0.025 mmol) and Cs2CO3 (0. 025 mmol)
were used.
enantioselectivity (entry 7). When the reaction was run in
dichloromethane with other co-solvents, the high yields were
retained and slightly better enantioselectivities were achieved
(entries 8-10). Slow addition of the solution of ketene 3a by
a syringe pump showed some benefits for the enantioselec-
tivity (entry 11 vs 12). Reactions with 10 or 5 mol % NHC
loading also gave the desired product in good yields with
good enantioselectivities (entries 11 and 12).
A variety of ketenes with different steric and electronic
properties were then examined (Table 3). Ketenes bearing an
electron-donating group (4-Me or 4-MeO) on the phenyl ring
gave the desired aza-β-lactacm in a slightly decreased yield
with moderate to good enantiomeric excess (entries 2 and 3).
When an electron-withdrawing group (Cl or Br) was intro-
duced at the para or meta position on the phenyl ring, the
Further solvent screening revealed that reaction in di-
chloromethane was better than in acetonitrile, THF, and
toluene (Table 2, entries 1-6). Lowering the tempera-
ture had no positive impact on either the yield or the
(9) DMAP (N,N-dimethylpyridin-4-amine) was used as the simplified
achiral catalyst of pyridine derivative 1, for its read availability.
(10) Reaction conditions such as solvents also showed some influence on
the formation of [2 þ 2] or [4 þ 2] cycloaddition product. See ref 8 and its
Supporting Information for detail.
(11) (a) He, L.; Zhang, Y.-R.; Huang, X.-L.; Ye, S. Synthesis 2008, 17,
2825–2829. (b) Lv, H.; Zhang, Y. -R.; Huang, X.-L.; Ye, S. Adv. Synth. Catal.
2008, 350, 2715–2718.
(12) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Org. Chem. 2005, 70,
5725–5728.
7586 J. Org. Chem. Vol. 74, No. 19, 2009

Huang et al.
JOCNote
TABLE 3. Enantioselective Formal [2 þ 2] Cycloaddition of Ketenes
with Diazenedicarboxylates
entry
3 (Ar, R)
a: Ph, Et
b: 4-MeC6H4, Et
4 (R0)
5
yield (%)a ee (%)b
1
2
3
4
5
6
7
8
a: Et
a: Et
aa
ba
ca
da
ea
fa
93
74
95
90
93
90
52
65
84
83
92
93
93
88
67
91
91
81
65
90
c: 4-MeOC6H4, Et a: Et
d: 4-ClC6H4, Et
e: 4-BrC6H4, Et
f: 3-ClC6H4, Et
g: 2-ClC6H4, Et
h: Ph, Me
i: Ph, n-Pr
j: Ph, n-Bu
k: 4-ClC6H4, n-Bu a: Et
l: 4-ClC6H4, i-Pr
m: Bn, Et
a: Ph, Et
a: Ph, Et
a: Ph, Et
a: Et
a: Et
a: Et
a: Et
a: Et
a: Et
a: Et
91
90
ent-ga
ha
-57c
79
9
ia
91
89
FIGURE 1. Proposed catalytic cycle.
10
11
12
13
14
15
16
a
ja
ka
ent-la
mad
ab
90
control the reaction modes (formal [2 þ 2] vs [4 þ 2] cyclo-
a: Et
a: Et
b: Me
c: i-Pr
d: t-Bu ad
-35c
33
addtions).
85
89
91
ac
Experimental Section
General Procedure for the [2 þ 2] Cycloaddtion of Ketenes with
Diazenedicarboxylates Catalyzed by NHC. To a solution of
NHC 2b0, which was generated freshly from the NHC precursor
2b (26.4 mg, 0.05 mmol) and Cs2CO3 (16.3 mg, 0.05 mmol) in
dichloromethane/toluene (v/v, 9:1, 3 mL) at room temperature
for 10 min, was added diazenedicarboxylate 4a (87.1 mg,
0.5 mmol). A solution of phenyl(ethyl)ketene 3a (109.6 mg,
0.75 mmol) in dichloromethane/toluene (v/v, 9:1, 2 mL) was
added by a syringe pump over 1 h. After stirring for another 1 h
at room temperature, the reaction mixture was diluted with
diethyl ether and passed through a short silica gel pad. The
solvent was removed under reduced pressure, and the residue
was purified by flash chromatography on silica gel to give
the desired product (5aa). Yield: 148 mg (93%); Rf = 0.23
Isolated yields. bDeterimined by chiral HPLC. cThe minus ee value
indicates that an opposite enantioselectivity is observed. dThe absolute
stereochemistry of 5ma was not determined.
corresponding adduct was obtained in excellent yield with
very high ee value (entries 4-6). Ethyl(2-chlorophenyl)-
ketene worked well under the standard condition and
afforded ent-5ga in 52% yield with 57% ee (entry 7).
Ketenes with methyl, n-propyl, and n-butyl groups afforded
the products in good yields with high enantioselecti-
vities (entries 8-11). A ketene with an isopropyl substi-
tuent also proved to be a suitable substrate for this reaction
and gave the product in 93% yield with opposite enantios-
electivity (entry 12). The reaction of dialkylketene 3m
gave the cycloaddition adduct in 93% yield with 33% ee
(entry 13).
Several other dialkyl diazenedicarboxylates were then
examined. All of the dimethyl, diisoproyl, and di(tert-butyl)
diazenedicarboxylates worked well for the formal [2 þ 2]
cycloaddition reaction (Table 3, entries 1, 14-16).
A proposed catalytic cycle for this NHC-catalyzed reac-
tion is depicted in Figure 1. NHC attacks ketene to give
triazolium enolate 9. Nucleophilic addition of the enolate 9
to diazenedicarboxylate generates zwitterionic intermediates
10, followed by an intramolecular cyclization to give the
formal [2 þ 2] cycloaddition adducts 5 and regenerate the
catalyst.
(petroleum ether/diethyl ether, 5:1); colorless oil; [R]25 -19.0
D
1
(c 0.5, CHCl3). H NMR (300 MHz, CDCl3) δ 7.49-7.46 (m,
2H), 7.34-7.25 (m, 3H), 4.30-4.23 (m, 2H), 2.35-2.30 (m, 1H),
2.23-2.18 (m, 1H), 1.30-1.25 (m, 3H), 1.13 (t, J = 7.0 Hz, 3H),
1.00 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 164.5,
157.4, 147.8, 134.9, 128.8, 128.5, 126.0, 90.3, 64.0, 63.2, 28.4,
14.1, 14.0, 8.4. HPLC analysis: 91% ee [Daicel CHIRALPAK
OD-H column; 20 °C, 254 nm, 1.0 mL/min; solvent system,
2-propanol/hexane = 5:95; tR = 10.1 min (minor), 14.0 min
(major)].
Acknowledgment. This paper is dedicated to Professor Li-
Xin Dai on the occasion of his 85th birthday. Financial
support from National Science Foundation of China
(20602036, 20872143), the Ministry of Science and Technol-
ogy of China (2009ZX09501-018), and the Chinese Academy
of Sciences is greatly acknowledged.
In summary, highly enantioselective synthesis of aza-β-
lactams was realized by the N-heterocyclic carebenes-cata-
lyzed formal [2 þ 2] cycloaddition of alkylarylketenes
and diazenedicarboxylates. The N-substituent (carboxylate
vs benzoyl) of the diazenes plays an important role to
Supporting Information Available: Experimental proce-
dures and characterization data for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 74, No. 19, 2009 7587