[4+2] Cycloaddition of ketenes with N-benzoyldiazenes catalyzed by N-heterocyclic carbenes

Article abstract of DOI:10.1002/anie.200804487

(Chemical Equation Presented) Enantioselectivity switch: A catalytic enantioselective [4+2] cycloaddition reaction of alkylarylketenes with N-aryl-N′-benzoyldiazenes or N,N′-dibenzoyldiazenes to give 1,3,4-oxadiazin-6-ones 1 was developed by employing N-h

Full text of DOI:10.1002/anie.200804487

Communications
DOI: 10.1002/anie.200804487
Asymmetric Catalysis
[4+2] Cycloaddition of Ketenes with N-Benzoyldiazenes Catalyzed by
N-Heterocyclic Carbenes**
Xue-Liang Huang, Lin He, Pan-Lin Shao, and Song Ye*
Table 1: Cycloaddition of ketenes with N-aryl-N’-benzoyldiazenes cata-
The cycloaddition reactions of ketenes are useful approaches
to heterocyclic compounds.[1] Recently, N-heterocyclic car-
benes (NHCs)[2] were found to be efficient catalysts for the
[2+2] ketene/imine,[3] ketene/aldehyde,[4] and [4+2] ketene/
enone[5] cycloaddition reactions. Herein we report an unpre-
cedented enantioselective [4+2] cycloaddition reaction of
ketenes with N-benzoyldiazenes catalyzed by chiral NHCs to
give 1,3,4-oxadiazin-6-ones.[6] In addition to its potential
biological activity,[7] this heterocycle is highly functionalized
and is a useful intermediate in organic synthesis.[8] For an
example, it can be regarded as the masked a,a-disubstituted
amino acid derivative.[9] Interestingly, Berlin and Fu reported
a [2+2] cycloaddition of ketenes with N,N’-dimethoxycarbo-
nyldiazenes catalyzed by their planar-chiral 4-pyrrolidinopyr-
idine derivatives [Eq. (1)].[10,11] The different mode of reac-
tion ([4+2] versus [2+2] cycloaddition) prompted us to report
our results herein.[12]
lyzed by NHC.[a,b]
Entry 1 (Ar, R)
2 (R1, R2)
3
Yield ee
[%][c] [%][d]
1
1a (Ph, Et)
1b (4-MeC6H4, Et)
1b (4-MeC6H4, Et)
2a (Ph, Ph)
2a (Ph, Ph)
2a (Ph, Ph)
3aa 93
3ba 79
3ba 64
3ca 88
3da 92
3ea 90
94
90
79
93
91[e]
90
–
2[b]
3
4
5
6
1c (4-MeOC6H4, Et) 2a (Ph, Ph)
1d (4-ClC6H4, Et)
1e (4-BrC6H4, Et)
1 f (2-ClC6H4, Et)
2a (Ph, Ph)
2a (Ph, Ph)
2a (Ph, Ph)
7[b]
8
3 fa
3ga
0
0
1g (1-naphthyl, Et) 2a (Ph, Ph)
–
9
10
1h (PhCH2, Et)
1i (Ph, Me)
2a (Ph, Ph)
2a (Ph, Ph)
2a (Ph, Ph)
2b (Ph, 4-ClC6H4)
2c (Ph, 4-MeC6H4)
3ha 75
3ia 85
3ja 69
3ab 92
3ac 82
8
89
90
94
84
83
11[b] 1j (Ph, nPr)
12
13
14
1a (Ph, Et)
1a (Ph, Et)
1a (Ph, Et)
2d (4-MeOC6H4, Ph) 3ad 57
[a] The NHCs 4’ were freshly generated from precatalysts 4 with Cs2CO3
in THF (2 mL) at RT for 10 min, followed by the addition of diazene and
slow addition of the ketene by using a syringe pump over a 1 h period.
[b] Precatalyst 4a used for entries 2, 7, and 11, and 4b for other entries.
[c] Yields of isolated products. [d] Determined by chiral HPLC analysis.
[e] The absolute configuration was determined by X-ray crystallography.
TBS=tert-butyldimethylsilyl.
After the initial investigation and the optimization of the
reaction conditions,[13] we found that in the presence of
10 mol% of NHC 4a’ or 4b’, generated from the correspond-
ing NHC precursor 4a or 4b with Cs2CO3,[14] a variety of
ketenes and N-aryl-N’-benzoyldiazenes 2 could react to give
the corresponding [4+2] cycloaddition products in good
yields with good enantioselectivities (Table 1). Alkylarylke-
tenes with both electron-donating (1b and 1c) and electron-
withdrawing groups (1d and 1e) worked well (Table 1,
entries 1–6). However, neither (2-chlorophenyl)ethylketene
(1 f) nor (1-naphthyl)ethylketene (1g) led to product
(Table 1, entries 7 and 8). The reaction of benzylethylketene
(1h) gave the cycloaddition product in good yield but with
very little enantioselectivity (Table 1, entry 9), and high
enantioselectivities were obtained for the reaction of phenyl-
methylketene (1i) and phenylpropylketene (1j; Table 1,
entries 10 and 11). Both electron-donating and electron-
withdrawing groups on the diazene are tolerated (Table 1,
entries 12–14). Interestingly, precatalyst 4a is better than 4b
in some cases (Table 1, entry 2 versus 3).
[*] X.-L. Huang, L. He, P.-L. Shao, Prof. Dr. S. Ye
Beijing National Laboratory for Molecular Sciences, Research
Center of Chemical Biology, Institute of Chemistry
Chinese Academy of Sciences, Beijing 100190 (China)
Fax: (+86)10-6255-4449
To expand the scope of the diazenes for this reaction,
N,N’-dibenzoyldiazene (5a) was investigated. After the
optimization of the reaction conditions,[13] it was found that
a wide variety of alkylarylketenes worked well for the
reaction with N,N’-dibenzoyldiazene (5a; Table 2). Both
electron-rich and electron-deficient alkylarylketenes afforded
E-mail: songye@iccas.ac.cn
[**] We are grateful to the Chinese Academy of Sciences and the Natural
Sciences Foundation of China (No 20602036) for the financial
support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804487.
192
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Chemie
Table 2: Cycloaddition of ketenes with N,N’-dibenzoyldiazenes catalyzed
Table 3: Switching of enantioselectivity.
by NHC.[a]
Entry
1 (Ar, R)
6
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1a (Ph, Et)
6aa
6ba
6ca
6da
6ea
6ka
ent-6 fa
ent-6ga
6ja
70
55
62
78
74
32
36
27
79
85
55
38
63
97
90
73
95
97
1b (4-MeC6H4, Et)
1c (4-MeOC6H4, Et)
1d (4-ClC6H4, Et)
1e (4-BrC6H4, Et)
1k (3-ClC6H4, Et
1 f (2-ClC6H4, Et)
1g (1-naphthyl, Et)
1j (Ph, nPr)
1l (4-ClC6H4, nBu)
1m (4-ClC6H4, iPr)
1h (PhCH2, Et)
1a (Ph, Et)
Entry
7, mol%,[a] solvent
Yield [%][b]
ee [%][c,d]
1
2
3
4
5
6
7
7a, 20, THF
7b, 20, THF
7c, 20, THF
7d, 20, THF
7c, 20, CH2Cl2
7c, 20, toluene
7c, 10, toluene
7c, 10, toluene
7c, 10, THF
40
46
86
55
18
79
76
52
62
84
90
72
À63[d]
À76[d]
96
À92
À64
À90
À96
À94
À89
À88
9
10
11
12
13[e]
6la
ent-6ma
6ha
94
À64[d]
8[e]
9[e]
3
6aa
95
[a] The amount of Cs2CO3 used was the equivalent to the mol% of the
precatalyst used for each reaction. [b] Yields of isolated products.
[c] Determined by chiral HPLC analysis. [d] ent-3aa was obtained as the
major enantiomer for entries 3–9. [e] Ketenes were added by using a
syringe pump over a 1 h period.
[a] See note [a] in Table 1. [b] Yields of isolated products. [c] Determined
by HPLC analysis. [d] Opposite enantioselectivity is observed. [e] 1a
(7.5 mmol) and 5a (5.0 mmol) was employed.
the [4+2] cycloaddition reaction products in good yields with
good to high enantioselectivities (Table 2, entries 1–5). The
reaction using (3-chlorophenyl)ethylketene (1k) resulted in a
low yield and decreased enantioselectivity (Table 2, entry 6).
Notably, ketenes with bulky substituents (1 f, 1g), which did
not work for the reaction with N-phenyl-N’-benzoyldiazene
(2a), worked in the reaction with N,N’-dibenzoyldiazene (5a)
albeit in low yield and with the opposite enantioselectivity
(Table 2, entries 7 and 8). Ketenes with n-propyl (1j) and
n-butyl (1l) groups afforded the products in good yields with
highly enantioselectivities (Table 2, entries 9 and 10). How-
ever, a ketene having an isopropyl group (1m) gave the
product in low yield and with the opposite enantioselectivity
(Table 2, entry 11). The reaction of benzylethylketene (1h)
gave the cycloaddition product in low yield with very low
enantioselectivity (Table 2, entry 12). Notably, the good yield
and high enantioselectivity for the reaction between 1a and
5a were maintained when the reaction was scaled up to
5.0 mmol (Table 2, entry 13).
(Table 3, entry 7), and the slow addition of the ketene had
no positive impact on the reaction (Table 3, entries 8 and 9).
The switch in enantioselectivity to give ent-3 by employing
NHC precursor 7c was also observed for the reaction of
several other ketenes and N-aryl-N’-benzoyldiazenes
(Table 4, entries 1–8). However the reaction of ketene and
N,N’-dibenzoyldiazene catalyzed by 7c gave ent-6aa in low
yield with moderate enantioselectivity (Table 4, entry 9).
The 1,3,4-oxadiazin-6-one 3aa reacted with methanol to
give the ring-opening product a,a-disubstituted a-amino acid
derivative 8 in 99% yield with high enantiopurity [Eq. (2)].
The NHC-catalyzed [4+2] cycloadditions of ketenes with
diazenes are possibly initiated by the nucleophilic addition of
the NHC to the ketene to give triazolium enolate 9 (Figure 1),
Table 4: Synthesis of ent-3/6 catalyzed by NHC 7c’.
Recently, we found that the silyl group on NHC pre-
cursors 4 could be removed and to furnish the NHC
precursors 7 with a free hydroxy group.[15] NHC precursors
7a–c were therefore synthesized and tested as precatalysts
(Table 3). Oxadiazinone 3aa was obtained as the major
enantiomer with a slightly decreased enantioselectivity when
7a and 7b were used (Table 3, entries 1–2). However, it is
very interesting that the enanitoselectivity was totally
switched and a À92% ee was achieved when NHC precatalyst
7c (Ar1 = Ph, Ar2 = Mes, R = H) was employed (Table 3,
entry 3). Additional experiments showed that NHC precata-
lyst 7d (Ar1 = Ph, Ar2 = Mes, R = TMS) could also switch the
enantioselectivity but with a lower ee value (Table 3, entry 4).
Solvent screening revealed that toluene is a good choice
(Table 3, entries 5–6). Reducing the loading of catalyst to
10 mol% led to decreased yield and enantioselectivity
Entry 1 (Ar, R)
2/5 (R1, R2)
ent-3/6 Yield ee
[%][b] [%][c]
1
2
3
4
5
6
7
8
9
1a (Ph, Et)
1b (4-MeC6H4, Et)
1c (4-MeOC6H4, Et) 2a (Ph, Ph)
1e (4-BrC6H4, Et)
1i (Ph, Me)
1j (Ph, nPr)
1a (Ph, Et)
1a (Ph, Et)
1a (Ph, Et)
2a (Ph, Ph)
2a (Ph, Ph)
ent-3aa 79
ent-3ba 78
ent-3ca 85
ent-3ea 61
ent-3ia 47
ent-3ja 76
À96
À95
À95
À76
À86
À90
À97
À88
À50
2a (Ph, Ph)
2a (Ph, Ph)
2a (Ph, Ph)
2b (Ph, 4-ClC6H4) ent-3ab 89
2c (Ph, 4-MeC6H4) ent-3ac 76
5a (PhCO, Ph)
ent-6aa 25
[a] Yields of isolated products. [b] Determined by HPLC analysis.
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Communications
For the reactions catalyzed by NHC 7c’, the perpendicular
TS B is favored and gives ent-3 and ent-6 as the major
enantiomer (Table 4). For the reactions of ketenes with bulky
substituents catalyzed by NHC 4a’, the coplanar TS A cannot
be maintained, so the opposite enantioselectivity is observed
(Table 2, entries 7, 8, and 11).
which reacts with the diazene by an inverse electron demand
In conclusion, an unprecedented catalytic enantioselec-
tive [4+2] cycloaddition of alkylarylketenes with N-aryl-N’-
benzoyldiazenes or N,N’-dibenzoyldiazenes to give 1,3,4-
oxadiazin-6-ones was developed by employing NHC catalysts.
The enantioselectivities could be switched for most reactions
by adjusting the substitutents in the NHC catalysts. The ready
availability of the NHC precatalysts and highly and switch-
able enantioselectivities of the reaction make it potential
useful to synthesize the 1,3,4-oxadiazin-6-one heterocycles.
Diels–Alder reaction to give the [4+2] cycloaddition adduct
10. Subsequent elimination of the NHC furnishes the
corresponding 1,3,4-oxadiazin-6-ones and regenerates the
NHC catalyst.[16]
Experimental Section
General Procedure (Table 1): Trazolium salt 4b (33.5 mg, 0.05 mmol)
and anhydrous Cs2CO3 (16.3 mg, 0.05 mmol) was added to an oven-
dried 50 mL Schlenk tube equipped with a stir bar. This tube was
closed with a septum, evacuated, and back-filled with argon. Freshly
distilled THF (2 mL) was added to the reaction mixture and then
stirred for 10 min at room temperature. N-Benzoyl-N’-phenyldiazene
(105 mg, 0.5 mmol) was then added, affording a red solution. A
solution of phenylethylketene (109.6 mg, 0.75 mmol) in THF (2 mL)
was added slowly by using a syringe pump over a period of 1 h
(2 mLhÀ1). After the addition of the ketene, the red color disap-
peared, and the heterogeneous mixture was then diluted with THF
(1 mL, 0.1m) and stirred for 1 h hour ensure the complete consump-
tion of diazene. The 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 chromatography on
silica gel (Et2O/petroleum ether, typically 1:200) to give the desired
product.
Figure 1. Possible catalytic cycle.
(R)-5-ethyl-2,4,5-triphenyl-4,5-dihydro-1,3,4-oxadiazin-6-one
(3aa): 166 mg (93%), Rf = 0.41 (petroleum ether/diethyl ether, 50:1);
white solid, mp 118–1208C, [a]2D5 = À496.2 degcm3 gÀ1 dmÀ1 (c =
0.5 gcmÀ3, CHCl3). 1H NMR (300 MHz, CDCl3): d = 7.80–7.77 (m,
2H), 7.37–6.95 (m, 13H), 2.98–2.86 (m, 1H), 2.50–2.38 (m, 1H),
0.82 ppm (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d = 163.8,
144.5, 138.2, 137.6, 129.7, 129.4, 129.1, 128.7, 128.5, 128.3, 127.0, 125.2,
The X-ray crystallographic structures of NHC precursors
4a and 7c revealed that the N-phenyl group is coplanar with
the triazole in NHC precursor 4a, whereas the N-mesityl
group is perpendicular to the triazole in NHC precursor 7c.[17]
On the basis of the structural difference between 4a and 7c
and the enantioselectivites observed, two possible transition
states are proposed (Figure 2). In transition state A (TS A),
NHC–ketene adduct 9 is in a coplanar conformation in which
the N-phenyl group of NHC, the triazole, and the enloate are
coplanar. In transition state B (TS B), NHC–ketene adduct 9
is in a perpendicular conformation in which both the
N-mesityl group and the enolate are perpendicular to the
triazole. For the reaction of most ketenes catalyzed by NHC
4a’ and 4b’, coplanar TS A is favored to give cycloaddition
products 3 and 6 as the major enantiomer (Tables 1 and 2).
=
123.8, 122.0, 70.8, 27.4, 9.0 ppm; IR (KBr): n˜ = 3060, 1777 (s, C O),
1640 (m, C N), 1596, 1494, 767, 759, 747 cmÀ1; EIMS: m/z (%): 356
=
(37.0), 146 (100); HRMS (EI): m/z calcd for C23H20N2O2 [M+]:
356.1525; found: 356.1527; HPLC analysis: 94% ee (Daicel CHIR-
ALPAK AD-H column; 208C, 332 nm, 1.0 mLminÀ1; solvent system:
2-propanol/hexane = 1:99; retention times: 6.4 min (minor), 12.9 min
(major)).
Received: September 11, 2008
Published online: November 28, 2008
Keywords: carbenes · cycloaddition · enantioselectivity ·
.
ketenes · synthetic methods
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Chemie
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