Intramolecular N-H insertion of α-diazocarbonyls catalyzed by Cu(acac)2: An efficient route to derivatives of 3-oxoazetidines, 3-oxopyrrolidines and 3-oxopiperidines

Article abstract of DOI:10.1039/a903722e

Cu(acac)₂ was found to be an efficient catalyst for the intramolecular N-H insertion by carbenoids. The competitive intramolecular C-H insertion by carbenoids is not a problem in the diazo decomposition reaction with Cu(acac)₂ as catalyst. The reaction provided derivatives of 3-oxoazetidine, 3-oxopyrrolidine and 3-oxopiperidine in moderate to good yields.

Full text of DOI:10.1039/a903722e

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Intramolecular N–H insertion of ꢀ-diazocarbonyls catalyzed by
Cu(acac)2: An efficient route to derivatives of 3-oxoazetidines,
3-oxopyrrolidines and 3-oxopiperidines
Jianbo Wang,* Yihua Hou and Peng Wu
Department of Chemistry, Peking University, Beijing 100871, People’s Republic of China
Received (in Cambridge) 10th May 1999, Accepted 30th June 1999
Cu(acac)2 was found to be an efficient catalyst for the intramolecular N–H insertion by carbenoids. The competitive
intramolecular C–H insertion by carbenoids is not a problem in the diazo decomposition reaction with Cu(acac)2 as
catalyst. The reaction provided derivatives of 3-oxoazetidine, 3-oxopyrrolidine and 3-oxopiperidine in moderate to
good yields.
devoid of unnecessary functionality. Three typical amino-
Introduction
protecting groups, p-tolylsulfonyl (Ts), tert-butoxycarbonyl
Along with the intramolecular C–H insertion reactions by
(Boc), and benzyloxycarbonyl (Cbz), were selected in order to
carbenoids, intramolecular N–H insertion reactions of α-diazo-
investigate the effect of protecting group on the N–H insertion.
carbonyl substrates catalyzed by metal complex have received
The diazo substrates 3a–g were prepared from corresponding
considerable attention in recent years.1 This type of insertion
amino acids 2a–g according to the known procedure.8,9 Diazo
reaction has been shown to be a mild and efficient route to
4-, 5-, and 6-membered aza rings. A frequently cited example
of this powerful approach is the Merck industrial synthesis of
decomposition by a catalytic amount of Cu(acac)2 was per-
formed by adding the α-diazocarbonyl substrate in benzene to a
refluxing benzene solution containing 10% (mol) Cu(acac)2.
Upon completion of the reaction as indicated by TLC, the mix-
the bicyclic β-lactam thienamycin, in which the intramolecular
N–H insertion by RhII-carbenoid is the key step.2 The corre-
ture of products was subjected to column chromatography with
sponding asymmetric N–H insertion was early exploited with a
silica gel and the structure of the product was established by
chiral-auxiliary approach,3 and recent efforts in this area are
spectroscopic analysis. As shown in Scheme 1, for diazo sub-
concentrated on the application of chiral RhII catalysts.4
Although N–H insertions by metallocarbenoids were origin-
O
O
O
ally promoted by copper-mediated diazo decomposition,3,5
most of the intramolecular N–H insertions recently reported
are based on RhII-catalyzed diazo decomposition, particularly
with Rh2(OAc)4 as the catalyst.4,6 RhII complexes have been
extensively used in diazo decomposition, and they have been
shown to be the most efficient catalysts in intramolecular C–H
insertions as well as in cyclopropanations. Despite great success
demonstrated by RhII catalysts, their application in intra-
molecular N–H insertion has been limited by the competing
C–H insertion,4,6b,7 which is a very easily accomplished RhII-
mediated reaction. For example, Rapoport reported that intra-
molecular C–H insertion, which led to the formation of
5-membered carbocycles, was a significant by-product in the
synthesis of 3-oxopiperidine by Rh2(OAc)4-catalyzed intra-
molecular carbenoid N–H insertion.6b McKervey also recently
reported the competing C–H insertion in asymmetric intra-
molecular N–H insertions by a chiral RhII complex.4 This
possible side reaction may be the reason that the intramolecular
N–H insertion by carbenoids has still not been widely applied
in the synthesis of molecules with complicated structures,
except for the β-lactams syntheses by RhII-carbene intra-
molecular N–H insertion in which the reaction occurs in a con-
formationally restricted ring system. To avoid the complexity
caused by this side reaction, it would be desirable to look for
other metal complexes which can efficiently promote intra-
molecular N–H insertion but not C–H insertion. We report in
this paper our investigation on the intramolecular N–H inser-
tion catalyzed by copper(II) acetylacetonate [Cu(acac)2]. The
results suggest that this catalyst can efficiently promote intra-
molecular N–H insertions.
H2N(CH2)nCOH
Y-NH(CH2)nCOH
Y-NH(CH2)nCCHN2
3a n = 1, Y = Ts
3b n = 2, Y = Ts
3c n = 1, Y = Cbz
3d n = 2, Y = Cbz
3e n = 3, Y = Cbz
3f n= 4, Y = Cbz
3g n = 1, Y = Boc
1
2a n = 1,Y = Ts
2b n = 2,Y = Ts
2c n = 1,Y = Cbz
2d n = 2,Y = Cbz
2e n = 3,Y = Cbz
2f n= 4, Y = Cbz
2g n = 1,Y = Boc
n = 1, 2, 3, 4
O
Cu(acac)2,
0.1 mol equiv.
O
Y-NH(CH2)nCCHN2
(
)
n
N
PhH, reflux
Y
3a n = 1,Y = Ts
3b n = 2,Y = Ts
3c n = 1,Y = Cbz
3d n = 2,Y = Cbz
3e n = 3,Y = Cbz
3f n = 4,Y = Cbz
3g n = 1,Y = Boc
4a n = 1, Y = Ts, 54 %
4b n = 2, Y = Ts, 55 %
4c n = 1, Y = Cbz, 32 %
4d n = 2, Y = Cbz, 62 %
4e n = 3, Y = Cbz, 76 %
4f n = 4, Y = Cbz, complex mixture
4g n = 1, Y = Boc, complex mixture
Scheme 1
strates with N-tosyl or N-Cbz protecting group 3a–e, the intra-
molecular N–H insertion was the major reaction pathway,
leading to the formation of 3-oxoazetidine, 3-oxopyrrolidine
and 3-oxopiperidine systems in moderate to good yields. It is
noteworthy that in diazo substrate 3e there is the possibility of a
competing intramolecular C–H insertion to give a 5-membered
carbocycle. Nevertheless, the N–H insertion product was
isolated as the only major product, thus suggesting that
Cu(acac)2-mediated carbenoids can selectively promote N–H
insertion. While the formation of 4-, 5- and 6-membered aza
rings is a simple procedure, it was observed that the formation
of a seven-membered ring in this reaction was difficult, as shown
by the Cu(acac)2-catalyzed diazo decomposition of 3f. On
the other hand, the diazo substrates with an N-Boc protecting
Results and discussion
First, we investigated the simple diazocarbonyl substrates
J. Chem. Soc., Perkin Trans. 1, 1999, 2277–2280
2277

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group yielded inseparable complex mixtures, suggesting that
amino protecting groups have a marked influence over the
reaction.
O
Cu(acac)2,
(
)
n
O
HNY
0.1 mol equiv.
H
R
N
Y
PhCH=CH2 (10 equiv.)
PhH, reflux
Cu(acac)2 has been widely used to promote cyclopropan-
ation by carbenoids.1 The application of this catalyst in
carbenoid X–H (X = C, N, O, S) insertion is rare. Hon et al.
reported intramolecular C–H insertion using Cu(acac)2 as the
catalyst.10 Intermolecular O–H insertion of a α-diazo ketone
catalyzed by Cu(acac)2 has been recently investigated by
Ohfune’s group.11 However, to the best of our knowledge,
Cu(acac)2 has not been reported to promote intramolecular
carbenoid N–H insertion,12 and so our results seem to be the
first example of this.
To examine whether Cu(acac)2-catalyzed N–H insertion
could be extended to diazo substrates with other functionality
or alkyl substituents, the diazocarbonyl compounds 8–10 and
17–19 were prepared from the corresponding optically pure
α- and β-amino acids 5–7 and 14–16, respectively.8 For the
diazo substrates derived from α-amino acids, the Cu(acac)2-
catalyzed reaction gave corresponding N–H-insertion prod-
ucts 11, 12 and 13 in 34, 45 and 57% yield, respectively (Scheme
2). In the reaction of diazo substrate 10 derived from
R
(
)
n
CHN2
3a n = 0, Y = Ts, R = H
3b n = 1, Y = Ts, R = H
3e n = 2, Y = Cbz, R = H
8 n = 0, Y = Ts, R = Me
4a n = 0, Y = Ts, R = H, 74 %
4b n = 1, Y = Ts, R = H, 61 %
4e n = 2, Y = Cbz, R = H, 52 %
11 n = 0, Y = Ts, R = Me, 70 %
12 n = 0, Y = Ts, R = PhCH2, 69 %
13 n = 0, Y = Ts, R = MeSCH2CH2, 48 %
9 n = 0, Y = Ts, R = PhCH2
10 n = 0, Y = Ts, R = MeSCH2CH2
Scheme 4
products. The detailed mechanism of this styrene effect is not
clear.
Lastly, we examined the corresponding intermolecular
carbenoids N–H insertion catalyzed by Cu(acac)2. As shown
in Scheme 5, diazoacetophenone 23 was decomposed by
O
O
Cu(acac)2,
0.1 mol equiv.
Y
PhCCHN2
+
PhNH-Y
PhCCH2N
PhCH3, reflux
Ph
25a,Y = Me, 28 %
25b,Y = Ac, 58 %
25c,Y =Ts,
23
24a,Y = Me
24b,Y = Ac
24c, Y =Ts
O
HNTs
Cu(acac)2,
HNTs
inseparable mixture
0.1 mol equiv.
CHN2
OH
R
R
N
PhH, reflux
Scheme 5
R
O
Ts
O
Cu(acac)2 in the presence of N-methylaniline 24a, acetanilide
24b and N-tosylaniline 24c, respectively. The corresponding
N–H-insertion products were indeed isolated as major products
from the reaction with N-methylaniline and acetylanilide, albeit
in comparatively low yields. The reaction with N-tosylaniline,
however, gave an inseparable mixture.
In conclusion, we have demonstrated that Cu(acac)2-
mediated carbenoids intramolecular N–H insertion is an effi-
cient and chemoselective approach for the construction of
azetidines, pyrrolidines and piperidines. Although the yields
were only moderately high, the competing C–H intramolecular
insertion was not a problem in the Cu(acac)2-catalyzed reac-
tion. Thus, the readily available and inexpensive Cu(acac)2
can be a choice as the catalyst in carbenoid intramolecular
N–H insertions.
8 R = Me
9 R = PhCH2
10 R = MeSCH2CH2
5 R = Me
6 R = PhCH2
7 R = MeSCH2CH2
11 R = Me, 34 %
12 R = PhCH2, 45 %
13 R = MeSCH2CH2, 57 %
Scheme 2
-methionine, the possible C–H insertion into the C–H bond
adjacent to the methylthio group was not observed.
Similarly, the optically active 2-substituted 3-oxopiperidines
20–22 were obtained in the Cu(acac)2-catalyzed reaction of the
diazo substrates 17–19 derived from β-amino acids 14–16
(Scheme 3). Again, intramolecular C–H-insertion products
O
Cu(acac)2,
0.1 mol equiv.
HNTs
O
HNTs
O
H
R
PhH, reflux
N
R
OH
R
CHN2
Experimental
Ts
14 R = Me
15 R = PhCH2
16 R = MeSCH2CH2
17 R = Me
18 R = PhCH2
19 R = MeSCH2CH2
20 R = Me, 52 %
21 R = PhCH2, 61 %
22 R = MeSCH2CH2, 43 %
Mps were recorded with a Yanaco micro melting point
apparatus and are uncorrected. All reactions with air- and
moisture-sensitive components were performed under a nitro-
gen atmosphere in a flame-dried reaction flask, and the com-
ponents were added via syringe. All solvents were distilled prior
to use. The distillation range of petroleum spirit is 30–60 ЊC.
MeOH and CH2Cl2 were freshly distilled from CaH2 before use.
THF was distilled from sodium. For chromatography, 100–200
mesh silica gel (Qingdao Haiyang Chemical Factory, Qingdao,
China) was employed. For preparative TLC, 10–40 µm silica
gel GF254 (Qingdao Haiyang Chemical Factory, Qingdao,
China) was used. Recrystallization was from petroleum spirit–
Scheme 3
were not observed in these cases. The result with diazo substrate
18 indicates that a phenyl group, which can possibly react
with RhII-carbene, remains intact in the Cu(acac)2-catalyzed
reaction.
The intramolecular N–H-insertion reactions under Cu(acac)2
catalysis conditions were further investigated by the competi-
tion reaction with intermolecular cyclopropanation, since this
catalyst has been most frequently used in cyclopropanation
by carbenoids. Thus, as shown in Scheme 4, the Cu(acac)2-
catalyzed diazo decomposition was performed in the presence
of an excess of styrene. To our surprise, the formation of cyclo-
propanation products was not observed in all cases; the intra-
molecular N–H-insertion products were again isolated as the
major products. Interestingly, compared with the results shown
in Schemes 2 and 3 in which the corresponding Cu(acac)2 reac-
tions were run in the absence of styrene, the presence of styrene
seems to have an influence over the yields of the N–H-insertion
products. For the diazo substrates 3a, 3b, 8 and 9, the presence
of styrene markedly increases the yield of the N–H-insertion
1
ethyl acetate. H and 13C NMR spectra were recorded at 200
MHz and 50 MHz with a Varian Mercury 200 spectrometer,
and chemical shifts are reported in ppm using tetramethyl-
silane as internal standard. J-Values are given in Hz. IR spectra
were recorded with a Nicolet 5MX-S infrared spectrometer.
Mass spectra were obtained on a VG ZAB-HS mass spectro-
meter. Elemental analyses were performed in the Institute of
Chemistry, Chinese Academy of Sciences. Optical activities
were measured on a Perkin-Elmer 291 polarimeter, and [α]D-
values are given in units of 10Ϫ1 deg cm2 gϪ1
.
Diazomethane solution in dry diethyl ether was prepared
from N-methyl-N-nitrosourea.13 Copper(II) acetylacetonate
2278
J. Chem. Soc., Perkin Trans. 1, 1999, 2277–2280

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[Cu(acac)2] was prepared from copper(II) sulfate and acetyl-
acetone according to a literature procedure.14
6.58; N, 21.09%); νmax(KBr)/cmϪ1 3296 (NH), 2979, 2114
(CHN ), 1704 (C᎐O), 1625, 1537, 1369, 1279, 1251; δ 1.45
᎐
2
H
The experimental procedure and the analytical data for
N-tosyl-protected α-diazocarbonyl compounds have been
reported in our previous paper.8 The N-Cbz- and N-Boc-
protected α-diazocarbonyl compounds were prepared from the
corresponding N-protected amino acids according to literature
procedure.9
(9 H, s, CH3), 3.90 (2 H, d, J 4.4, CH2), 5.34 (1 H, br s, CHN2),
5.45 (1 H, br s, NH); δC 28.24, 47.79, 53.32, 80.05, 155.50,
196.89; m/z (EI) 144 (3%), 130 (9), 126 (32), 115 (44), 69 (32), 57
(33), 41 (100); m/z (FAB) 200 [(M ϩ 1)ϩ, 13%], 144 (42), 116
(58), 73 (30), 57 (100).
General procedure for the Cu(acac)2-catalyzed diazo compound
decomposition in benzene
General procedure for the preparation of diazo ketones 3c–g
The N-protected amino acid 2c–g (1.0 mmol) was dissolved in
anhydrous diethyl ether (4 cm3) and anhydrous THF (4 cm3).
The solution was cooled to Ϫ20 ЊC under N2 atmosphere. Tri-
ethylamine (0.14 cm3, 1.0 mmol) and isobutyl chloroformate or
benzyl chloroformate (1.0 mmol) were added and the mixture
was stirred for 30 min, and then the temperature of the reaction
was allowed to rise to Ϫ10 ЊC. A solution of diazomethane (≈2
mmol) in diethyl ether was added dropwise. The mixture was
stirred for 4 h, during which the temperature slowly rose to
20 ЊC. Excess of diazomethane was removed by bubbling
the reaction mixture with N2. The solvent was removed by
evaporation and the residue was dissolved in diethyl ether. The
ethereal solution was washed successively with water, 10%
aq. NaHCO3, and saturated aq. NaCl, and then dried over
anhydrous MgSO4. Removal of the drying agent and the sol-
vent gave a crude product, which was purified by silica gel
column chromatography with petroleum spirit–ethyl acetate as
the eluent.
The diazo compound (0.3 mmol) in anhydrous benzene (6 cm3)
was added dropwise during 1.5 h to a refluxing solution of
Cu(acac)2 (8 mg, 0.03 mmol) in benzene (15 cm3) under nitro-
gen atmosphere. The reflux was continued for another 1.5 h
after addition. After cooling of the reaction mixture to room
temperature, the solvent was removed by evaporation and
the crude residue was subjected to silica gel column chrom-
atography with petroleum spirit–ethyl acetate as eluent. The
structures of N-tosylazetidin-3-one 4a and its 4-substituted
derivatives 11, 12 and 13 were confirmed with the samples
obtained from our previous investigation.8
N-Tosylpyrrolidin-3-one 4b. 55%; mp 121–122 ЊC (lit.,15
122–123 ЊC); νmax(KBr)/cmϪ1 3442, 1752 (C᎐O), 1430, 1339,
᎐
1156; δH 2.54 (3 H, s, CH3), 2.50 (2 H, d, J 7.6, CH2), 3.48 (2 H,
s, CH2), 2.49 (2 H, t, J 7.6, CH2), 7.37 (2 H, d, J 8.2, 4-MeC6H4),
7.72 (2 H, d, J 8.2, 4-MeC6H4); δC 21.51, 37.11, 44.95, 53.63,
127.88, 129.86, 129.95, 144.43, 208.17.
N-(Benzyloxycarbonyl)azetidin-3-one 4c. 32%; oil; νmax(KBr)/
cmϪ1 3360, 2925, 1827 (C᎐O), 1709 (C᎐O), 1497, 1409, 1354,
1205; δH 4.78 (4 H, s, CH2), 5.16 (2 H, s, CH2O), 7.37 (5 H, s,
C6H5); δC 67.71, 71.28, 128.22, 128.39, 128.59, 136.58, 156.10,
200.45; m/z (EI) 205 (Mϩ, 27%), 179 (15), 151 (8), 107 (100), 91
(93) (Found: Mϩ, 205.0738. C11H11NO3 requires M, 205.0748).
Diazo-(N-benzyloxycarbonylglycyl)methane 3c. Mp 68–69 ЊC;
νmax(KBr)/cmϪ1 3426, 3296 (NH), 3089, 2107 (CHN2), 1697,
1649, 1561, 1381; δH 3.97 (2 H, d, J 4.8, NHCH2), 5.12 (2 H, s,
PhCH2), 5.37 (1 H, br s, CHN2), 5.54 (1 H, br s, NH), 7.35 (5 H,
m, C6H5); δC 48.05, 53.57, 67.05, 128.01, 128.15, 128.46, 136.11,
156.25, 190.09; m/z (EI) 233 (Mϩ, 2%), 205 [(M Ϫ N2)ϩ, 10], 120
(16), 107 (100), 91 (71) [Found: (M Ϫ N2)ϩ, 205.0737. C10H11-
NO3 requires m/z, 205.0738].
᎐
᎐
N-(Benzyloxycarbonyl)pyrrolidin-3-one 4d. 62%; oil; νmax
-
(KBr)/cmϪ1 2923, 1760 (C᎐O), 1706 (C᎐O), 1422, 1360, 1173,
᎐
᎐
1106; δH 2.53 (2 H, t, J 7.8, CH2CO), 3.75 (2 H, s, CH2NHCbz),
3.78 (2 H, t, J 7.8, CH2NHCbz), 5.10 (2 H, s, PhCH2), 7.29
(5 H, s, C6H5); δC 29.65, 42.62, 52.46, 67.27, 128.03, 128.19,
128.52, 136.31, 156.40, 209.53; m/z (EI) 219 (Mϩ, 72%), 191
[(M Ϫ CO)ϩ, 8], 146 (12), 128 [(M Ϫ C6H5CH2)ϩ, 7], 91 (100)
[Found: Mϩ, 219.0897. C12H13NO3 requires M, 219.0895].
Diazo-(N-benzyloxycarbonyl-ꢁ-alanyl)methane 3d. Oil; νmax
-
(KBr)/cmϪ1 3353 (NH), 3082, 2110 (CHN2), 1687, 1626, 1532,
1390, 1259; δH 2.65 (2 H, m, CH2CO), 3.48 (2 H, q, J 5.8,
NHCH2), 5.08 (2 H, s, CH2), 5.25 (1 H, br s, CHN2), 5.37 (1 H,
br s, NH), 7.34 (5 H, s, C6H5); δC 36.43, 40.11, 55.01, 66.60,
127.97, 128.45, 136.45, 156.28, 179.21, 193.19; m/z (EI) 233
[(M Ϫ N2)ϩ, 2%], 142 (7), 127 (14), 107 (100), 91 (51) [Found:
(M Ϫ N2)ϩ, 219.0891. C12H13NO3 requires m/z, 219.0882].
N-(Benzyloxycarbonyl)piperidin-3-one 4e. 76%; oil; νmax
-
(KBr)/cmϪ1 3377, 2955, 1705 (C᎐O), 1425, 1265, 1114, 1010; δ
᎐
H
2.00 (2 H, m, CH2), 2.46 (2 H, t, J 6.7, CH2), 3.65 (2 H, d, J 6.0,
1-Diazo-5-(benzyloxycarbonylamino)pentan-2-one 3e. Mp
31–32 ЊC; νmax(KBr)/cmϪ1 3333 (NH), 3089, 2943, 2107
CH2N), 4.07 (2 H, s, CH2N), 5.14 (2 H, s, CH2N), 7.34 (5 H, s,
C5H5); δC 22.16, 38.00, 42.08, 53.90, 67.42, 127.92, 128.10,
128.25, 136.21, 155.07, 205.10; m/z (EI) 233 (Mϩ, 32%), 203
(51), 127 (10), 91 (100) [Found: Mϩ, 233.1055. C13H15NO3
requires M, 233.1051].
(CHN ), 1709 (C᎐O), 1633, 1533, 1375, 1255, 1141; δ 1.83
᎐
2
H
(2 H, m, CH2), 2.35 (2 H, br t, J 5.2, CH2CO), 3.21 (2 H, q,
J 6.6, CH2NH), 5.08 (2 H, s, CH2O), 5.12 (1 H, br s, CHN2),
5.26 (1 H, br s, NH), 7.34 (5 H, s, C6H5); δC 25.02, 37.57, 40.37,
54.54, 66.51, 127.75, 127.98, 128.39, 136.50, 156.48, 194.31; m/z
(EI) 233 [(M Ϫ N2)ϩ, 3%], 142 [(M Ϫ C6H5CH2 Ϫ N2)ϩ, 17],
127 (15), 107 (100) [Found: (M Ϫ N2)ϩ, 233.1067. C13H15NO3
requires m/z, 233.1051].
(5S)-5-Methyl-N-tosylpyrrolidin-3-one 20. 52%; mp 98–99 ЊC
(Found: C, 57.17; H, 5.79; N, 5.35. C12H15NO3S requires C,
56.90; H, 5.97; N, 5.53%); [α]D20 Ϫ63.9 (c 0.61, CH2Cl2);
νmax(KBr)/cmϪ1 3429, 1761, 1715, 1642, 1438, 1345, 1157; δH
1.37 (3 H, d, J 6.4, CH3), 2.17 (1 H, m, CH2), 2.40 (1 H, d, J 8.4,
CH2), 2.44 (3 H, s, CH3C6H4), 3.70 (2 H, s, CH2), 4.24 (1 H, m,
MeCHNTs), 7.34 (2 H, d, J 8.2, MeC6H4), 7.73 (2 H, d, J 8.2,
MeC6H4); δC 21.55, 21.87, 44.98, 53.13, 53.63, 115.99, 127.38,
130.02, 144.19, 209.13; m/z (EI) 253 (Mϩ, 12%), 238
[(M Ϫ Me)ϩ, 22], 184 (40), 155 (100), 91 (95).
1-Diazo-6-(benzyloxycarbonylamino)hexan-2-one 3f. Mp 35–
36 ЊC; νmax(KBr)/cmϪ1 3355 (NH), 2948, 2104 (CHN2), 1691
(C᎐O), 1626, 1525, 1385, 1258; δH 1.58 (4 H, m, 2 × CH2), 2.34
᎐
(2 H, br d, J 6.4, CH2), 3.20 (2 H, m, CH2N), 4.92 (1 H, br s,
NH), 5.08 (2 H, s, CH2O), 5.23 (1 H, s, CHN2), 7.34 (5 H, s,
C6H5); δC 21.76, 29.33, 33.29, 40.46, 54.34, 66.57, 128.02,
128.44, 128.44, 136.55, 156.42, 194.65; m/z (EI) 247
[(M Ϫ N2)ϩ, 3%], 174 (4), 141 (8), 91 (100) [Found: (M Ϫ N2)ϩ,
247.1213. C14H17NO3 requires m/z, 247.1208].
(5S)-5-Benzyl-N-tosylpyrrolidin-3-one 21. 61%; mp 122–
123 ЊC (Found: C, 65.42; H, 5.68; N, 4.06. C18H19NO3S requires
C, 65.63; H, 5.81; N, 4.25%); [α]D20 Ϫ50.6 (c 0.6, CH2Cl2);
νmax(KBr)/cmϪ1 3439, 1754 (C᎐O), 1635, 1438, 1156; δ 2.25
Diazo-(N-tert-butoxycarbonylglycyl)methane 3g. Oil (Found:
᎐
H
C, 47.93; H, 6.45; N, 21.01. C8H13N3O3 requires C, 48.23; H,
(2 H, m, PhCH2), 2.43 (3 H, s, CH3), 2.85 (1 H, dd, J 13.6, 4.8,
J. Chem. Soc., Perkin Trans. 1, 1999, 2277–2280
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CH2), 3.12 (1 H, dd, J 13.6, 4.1, CH2), 3.46 (1 H, d, J 18.8,
CH2), 3.69 (1 H, d, J 18.8, CH2), 4.49 (1 H, m, CHN), 7.12–7.30
(5 H, m, C6H5), 7.32 (2 H, d, J 8.2, 4-MeC6H4), 7.73 (2 H, d,
J 8.2, 4-MeC6H4); δC 21.51, 41.61, 41.91, 53.14, 58.43, 127.09,
127.21, 128.74, 129.71, 130.07, 135.07, 135.97, 144.20, 209.04;
m/z (FAB) 330 [(M ϩ 1)ϩ, 23%], 274 (7), 238 (13), 184 (8), 155
(42), 91 (100).
The reaction with N-tosylaniline 24c gave an inseparable
mixture.
Acknowledgements
Financial support by the Ministry of Education of China
(Excellent Young Teacher’s Foundation to J. W.) and NSFC
(Grant No. 29702002) is gratefully acknowledged.
(5R)-5-[2-(Methylthio)ethyl]-N-tosylpyrrolidin-3-one
22.
43%; mp 71–72 ЊC (Found: C, 54.03; H, 6.09; N, 4.14. C14H19-
References
NO3S2 requires C, 53.65; H, 6.11; N, 4.47%); [α]D20 Ϫ29.4 (c 0.61,
CH2Cl2); νmax(KBr)/cmϪ1 3438, 2920, 1754 (C᎐O), 1632, 1436,
1 (a) M. P. Doyle, M. A. McKervey and T. Ye, Modern Catalytic
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᎐
1349, 1156; δH 1.60–2.38 (4 H, m, CH2), 2.14 (3 H, s, CH3), 2.44
(3 H, s, CH3), 2.60 (2 H, m, CH2), 3.67 (1 H, d, 19.2, CH2), 3.82
(1 H, d, J 19.2, CH2), 4.36 (1 H, m, NHCH), 7.35 (2 H, d, J 8.2,
4-MeC6H4), 7.74 (2 H, d, J 8.2, 4-MeC6H4); δC 15.45, 21.52,
30.14, 34.84, 42.29, 52.88, 56.64, 127.30, 130.15, 135.20, 144.37,
290.50; m/z (EI) 313 (Mϩ, 3%), 238 [(M Ϫ MeSCH2CH2)ϩ, 8],
159 (18), 158 (100), 110 (42), 91 (98).
The Cu(acac)2-catalyzed decomposition of diazoacetophenone in
the presence of aniline derivatives
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The N-substituted aniline 24a–c (5 mmol) was dissolved in dry
toluene (20 cm3). To the solution was added Cu(acac)2 (26 mg,
0.1 mmol) and the mixture was heated under reflux. Diazo-
acetophenone 23 (146 mg, 1 mmol) in toluene (8 cm3) was
added dropwise. The reflux was continued until the disappear-
ance of the starting material as indicated by TLC. The reaction
mixture was cooled and toluene was removed under reduced
pressure to leave a crude product, which was purified by column
chromatography with petroleum spirit–ethyl acetate (8:1) as
eluent.
2-[Methyl(phenyl)amino]acetophenone 25a was isolated in
28% yield when N-methylaniline 24a was used. For 25a: most of
this molecule exists in its enol form in solution. Mp 118–120 ЊC
(Found: C, 79.80; H, 6.30; N, 5.92. C15H15NO requires C, 79.97;
H, 6.71; N, 6.22%); νmax(KBr)/cmϪ1 3437, 2924, 1664, 1600,
1497, 1442, 1272, 1114; δH 2.57 (3 H, s, CH3), 6.07 (1 H, s,
5 P. Yates, J. Am. Chem. Soc., 1952, 74, 5376; T. Saegusa, Y. Ito,
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8 J. Wang and Y. Hou, J. Chem. Soc., Perkin Trans. 1, 1998, 1919.
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12 S. B. Singh and K. N. Mehrotra, Can. J. Chem., 1981, 59, 2475.
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C᎐CH), 6.70–6.79 (3 H, m, C H ), 7.15–7.53 (5 H, m, C H ),
᎐
6
5
6
5
7.90–7.97 (2 H, m, C6H5); δC 34.05, 61.22, 113.35, 117.68,
128.35, 128.54, 128.99, 129.17, 133.29, 148.15, 198.88; m/z
(EI) 225 (Mϩ, 9%), 120 (100), 106 [(M Ϫ C6H5COCH2)ϩ, 95],
77 (81).
2-[Acetyl(phenyl)amino]acetophenone 25b was isolated in
58% yield when acetanilide 24b was used. For 25b: mp 67–69 ЊC
(Found: C, 75.87; H, 5.94; N, 5.11. C16H15NO2 requires C,
75.87; H, 5.97; N, 5.53%); νmax(KBr)/cmϪ1 3434, 1703, 1672,
1592, 1446, 1376, 1224; δH 1.96 (3 H, s, CH3), 5.47 (2 H, s, CH2),
6.70–6.72 (2 H, m, C6H5), 7.00–7.02 (1 H, m, C6H5), 7.20–7.30
(2 H, m, C6H5), 7.46–7.58 (3 H, m, C6H5), 7.93–8.07 (2 H, m,
C6H5); δC 15.73, 67.27, 120.88, 123.06, 127.75, 128.66, 128.88,
133.44, 134.92, 148.16, 160.09, 193.89; m/z (EI) 253 (Mϩ, 13%),
180 (100), 118 (46), 105 (66), 77 (84).
14 D. P. Graggon, J. Inorg. Nucl. Chem., 1960, 14, 161.
15 V. G. Kartser and M. A. Sipyagin, Zh. Org. Khim., 1979, 15, 2603;
J. Org. Chem. USSR (Engl. Transl.), 1979, 15, 2353.
Paper 9/03722E
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J. Chem. Soc., Perkin Trans. 1, 1999, 2277–2280