One-pot regioselective synthesis of β-lactams by a tandem Ugi 4CC/SN cyclization

Article abstract of DOI:10.1016/j.tet.2014.04.033

β-Lactam scaffold was fabricated regioselectively by a facile one-pot base-mediated synthesis. The reactions of bromoacetic acid 1, primary amines 2, isocyanides 3, and arylglyoxals 4 produced 2-aroyl-4-oxoazetidine-2-carboxamides 6 in good yields via a one-pot tandem Ugi condensation and intramolecular C-alkylation at room temperature in the presence of Cs₂CO ₃.

Full text of DOI:10.1016/j.tet.2014.04.033

Tetrahedron 70 (2014) 3647e3652
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One-pot regioselective synthesis of
SN cyclization
b-lactams by a tandem Ugi 4CC/
,
b
,
,
b
,
,
*
Xiao-Hua Zeng a y, Hong-Mei Wang a y, Yan-Mei Yan a, Lei Wu a, Ming-Wu Ding a
a Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Central China Normal University, Wuhan 430079, PR China
b Institute of Medicinal Chemistry, Hubei University of Medicine, Shiyan 442000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
b
-Lactam scaffold was fabricated regioselectively by a facile one-pot base-mediated synthesis. The re-
Received 10 December 2013
Received in revised form 3 April 2014
Accepted 10 April 2014
actions of bromoacetic acid 1, primary amines 2, isocyanides 3, and arylglyoxals 4 produced 2-aroyl-4-
oxoazetidine-2-carboxamides 6 in good yields via a one-pot tandem Ugi condensation and intra-
molecular C-alkylation at room temperature in the presence of Cs2CO3.
Available online 18 April 2014
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
b
-keto acids, amines with isonitriles have been reported to give
b-
lactam derivatives as well.12
Multicomponent reactions (MCRs) are useful tool for diversity-
oriented and complexity-generating synthesis of various hetero-
cycles with novel properties.1 The Ugi reaction is an effective and
atom-economical multicomponent reaction, which assembled al-
dehyde (or ketone), amine, isonitrile, and carboxylic acid to afford
In our previous work, we described a direct synthesis of 5-
oxopyrrolidine-2-carboxamides by a Ugi reaction of BayliseHill-
man acids, primary amines, arylglyoxals, and isocyanides.13 We
envisioned that if
BayliseHillman acid, the above approach might produce
6, piperazine-2,5-diones or 2H-1,4-oxazin-3(4H)-ones
intramolecular C-, N-, or O-alkylation (Scheme 1). It was reported
that piperazine-2,5-diones or -lactams were obtained by Ugi re-
action and subsequent intramolecular N- or C-alkylation in the
a
-bromocarboxylic acid 1 was used instead of
-lactams
by
b
a
significantly
more complex
a
-acylamino-carboxamide
7
8
adduct that has received increased attention in view of its utility in
the synthesis of nitrogen heterocyclic compounds.2
b
The
structure of several antibiotic families. After the discovery of
lactam antibiotics, the past few decades have witnessed notable
growth in the field of -lactam chemistry, especially the -lactams
with electron-withdrawing substituents on their 3- and/or 4-
position(s).3 Apart from their clinical use as antibacterial agents,
b-lactam, as a four-membered heterocyclic ring, is the core
b
-
presence of potassium hydroxide, starting from a-chloroacetic acid,
aldehyde, amine, and isocyanides.10b,14 The regioselectivity of the
above approach was related to the aldehyde used.15 Continuing our
interest in I-MCR mediated synthesis of heterocycles,16 we wish to
disclose herein a one-pot regioselective synthesis of previously
b
b
p
some
b
-lactams have also been utilized as therapeutic agents for
seldom reported 2-acyl-b-lactam-2-carboxamides by a tandem Ugi
4CC/SN cyclization of bromoacetic acid, primary amine, arylglyoxal,
and isocyanide.
cholesterol absorption inhibitor,4 and as a potent mechanism based
inhibitor of several enzymes like chymase,5 leukocyte elastase,6
and human cytomegalovirus protease.7 These compounds have
also been used as intermediate in the preparation of various het-
erocyclic compounds with biological significance.8
2. Results and discussion
There are many known methods for synthesis of
Ugi four-component condensation is also used to prepare
by reactions between
-amino acids, aldehydes, and isocyanides.10
b
-lactams.9 The
-lactams
Initially, we selected the bromoacetic acid 1, tert-butylamine 2a,
4-chlorophenylglyoxal 3a, and cyclohexylisocyanide 4a as the re-
actants (Scheme 2). When the bromoacetic acid 1a, 4-
chlorophenylglyoxal 2a, tert-butylamine 3a, and cyclo-
hexylisocyanide 4a was stirred in methanol at room temperature
for 24 h, the 2-acyl-4-oxoazetidine-2-carboxamide derivative 6a
was directly obtained albeit in low yield (31%, Table 1, entry 1). The
expected Ugi product 5a was also isolated from the reaction mix-
ture (18%) and 1H NMR analysis of 5a revealed that it existed ex-
clusively as the enol form. Similar to our previous report, the
detection of reaction mixture revealed that the pH of the solution
b
b
Some b-lactams have been even obtained by the Passerini or Ugi
reaction and subsequent post-condensations.11 Ugi-type reaction of
* Corresponding author. Tel.: þ86 15327200455; fax: þ86 27 67862041; e-mail
addresses: mwding@mail.ccnu.edu.cn, dmw10@126.com (M.-W. Ding).
y
X.H. Zeng and H.M. Wang are first coauthors and contributed equally to this
work.
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.04.033

3648
X.-H. Zeng et al. / Tetrahedron 70 (2014) 3647e3652
Table 1
R1NH2
O
BrCH2COOH
Optimization of the reaction conditions about 6a
Br
R1
2
N
O
1
Base
Entry
Base
Condition
Product
Yielda (%)
OH
+
1
2
3
4
5
d
rt/24 h
rt/12 h
rt/12 h
rt/12 h
rt/12 h
6a (5a)
6a
31 (18)
69
O
Ar
MeOH
R2HN
Ar
K2CO3
NaHCO3
NEt3
R2NC
6a
71
CHO
6a
65
5
4
3
Cs2CO3
6a
84
a
Isolated yields.
path a
path c
path b
2,5-dione 7 or 2H-1,4-oxazin-3(4H)-one 8 shown in Scheme 1) was
isolated from the reaction mixture.
O
O
O
Br
R1
Br
R1
Br
R1
With the optimized condition, various bromoacetic acid 1,
amine 2, arylglyoxal 3, and isocyanide 4 were employed for the
reaction, utilizing Cs2CO3 as a base to adjust the pH of the solution
to 6 during the reaction process (Scheme 3). In preparation of
compounds 6ae6h (Table 2, when R1 is t-Bu), the reactions pro-
N
N
N
OH
OH
O
NHR2
R2HN
R2HN
HO
Ar
Ar
O
Ar
O
ceeded similarly to give the corresponding
77e93% yield. As the above approach was applied to prepare
compounds 6ie6s (Table 2), the initially formed Ugi products 5ie5s
cyclized more slowly but also gave the corresponding
6ie6s in 58e83% yield.
b-lactams 6ae6h in
-HBr
-HBr
-HBr
O
O
O
O
O
R1
b
-lactams
R1
N
R1
N
O
N
O
O
N
O
Ar
NHR2
R2
Ar NHR2
R1NH2
Ar
BrCH2COOH
O
Br
R1
8
6
7
1
2
N
O
Base
OH
+
Scheme 1. Proposed tandem Ugi 4CC/SN cyclization.
O
MeOH
R2HN
Ar
R2NC
Ar
CHO
decreased from 7 to 4 during the reaction process and reached the
minimum in 4 h, after which the reaction took place slowly ac-
companying side reactions. This evidence implies that the intra-
molecular substitution reaction of intermediate 5a occurs even
under acidic condition with release of HBr, which resulted in the
change of pH value of the reaction mixture. Finally when a base was
added to adjust the pH of the solution to 6 during the reaction
process, good yields of 6a were reached (Table 1, entry 2e5). The
best result was obtained as Cs2CO3 was used as a base (Table 1,
entry 5). This is probably due to its stronger basicity and good
solubility in the solvent. Although intramolecular ring-closure
competition between four-membered and six-membered ring is
generally accepted to lead to six-membered ring, the above re-
3
4
5
O
O
R1
N
O
-HBr
Ar
NHR2
6
Scheme 3. Preparation of compounds 6ae6s.
Table 2
Preparation of compounds 6ae6s
Ar
R1
R2
Yielda (%)
action produced four-membered
b-lactams 6 with high regiose-
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
6s
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
4-NO2C6H4
4-ClC6H4
4-NO2C6H4
4-BrC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
i-Pr
n-Pr
i-Pr
n-Pr
i-Pr
i-Pr
c-C6H11
t-Bu
84
93
90
85
82
77
79
80
83
73
78
77
74
72
74
71
63
68
58
lectivity and no other possible six-membered product (piperazine-
t-Bu
t-Bu
c-C6H11
n-Bu
O
Br
BrCH2COOH
n-Bu
n-Bu
t-Bu
t-Bu
t-Bu
t-Bu
NH2
2a
N
O
OH
Cl
1
Base
HN
+
MeOH
O
Cl
NC
CHO
c-C6H11
c-C6H11
t-Bu
c-C6H11
t-Bu
4a
3a
5a
4-ClC6H4
C6H5
4-CH3C6H4
C6H5
4-CH3C6H4
O
t-Bu
N
O
c-C6H11
a
Isolated yields.
O
-HBr
NH
Cl
As shown in Table 2, the yields of the products were related to
the R1 group of amine 2. When various aliphatic amines were used,
6a
the reaction produced
b-lactams 6 in good to high yields (71e93%,
Scheme 2. Preparation of compound 6a.
Table 2, compounds 6ae6n). However, as the aromatic amine was

X.-H. Zeng et al. / Tetrahedron 70 (2014) 3647e3652
3649
utilized, moderate yields of the products 6oe6s were obtained
(58e74%, Table 2). The formation of the -lactams 6 can be ratio-
nalized in terms of an initial Ugi reaction to give the adduct 5,
Mercury 600 or 400 spectrometer and resonances relative to TMS.
Elementary analyses were taken on a Vario EL III elementary
analysis instrument. The X-ray diffraction data were collected on
b
which directly undergoes intramolecular nucleophilic substitution
a Bruker SMART AXS CCD diffractometer, Mo K
a
, 2
q
¼1.86e27.50ꢁ.
to give the four-membered
b-lactams 6 over the six-membered
piperazine-2,5-dione or 2H-1,4-oxazin-3(4H)-one through the
enol form of intermediate 5. The high regioselectivity of the re-
action is probably owing to that the intramolecular C-alkylation of
intermediate 5 occurs under acidic condition, in which N- or O-
alkylation of intermediate 5 is avoided.
4.2. One-pot synthesis of 4-oxoazetidine-2-carboxamide 6
4.2.1. 1-(tert-Butyl)-2-(4-chlorobenzoyl)-N-cyclohexyl-4-
oxoazetidine-2-carboxamide (6a). A mixture of the bromoacetic acid
1 (0.14 g, 1 mmol), tert-butylamine 2a (R1¼t-Bu, 0.07 g, 1 mmol), and
4-chlorophenylglyoxal 3a (Ar¼4-ClC6H4, 0.17 g, 1 mmol) was stirred
in methanol (5 mL) at room temperature for 10 min, then cyclo-
hexylisocyanide 4a (R2¼c-C6H11, 0.11 g, 1 mmol) was added to the
solution. The mixture was stirred at room temperature and the pH
value of the solution was adjusted to 6 using Cs2CO3 during the re-
action process. After stirring for 12 h, the mixture was chilled and the
resulted solid was then filtered, recrystallized from ether to give
product 6a as white solid (0.33 g, 84%), mp 189e190 ꢁC; 1H NMR
Compounds 6aes were confirmed by their spectral data. For
example, the 1H NMR spectrum of 6a shows two doublets at 3.57
and 3.00 ppm due to the CH2 of the b-lactam ring. The signals of
CONHCH are found at 6.94 ppm and 3.82 ppm as doublets and
multiplets, respectively. The signals of other CH2 and CH3 appear at
1.95e1.13 ppm as multiplets. The signals attributable to the AreHs
are found at 7.73 and 7.43 ppm as two doublets. The 13C NMR
spectrum data in 6a showed the signals of C]O and CON carbon at
194.6, 168.1, and 164.7 ppm. The quaternary carbon of the
b
-lactam
(CDCl3, 600 MHz)
d
(ppm) 7.73 (d, J¼8.4 Hz, 2H, AreH), 7.43 (d,
ring absorbs at 69.3 ppm. The MS spectrum of 6a shows molecular
ion peak and MþꢀCONHC6H11 at m/z 390 and 264 with 4% and 33%
abundance. Furthermore a single crystal for 6i was obtained from
the CH2Cl2/ethanol solution of 6i, and X-ray structure analysis
verified the proposed structure (Fig. 1).
J¼8.4 Hz, 2H, AreH), 6.94 (d, J¼7.2 Hz, 1H, NH), 3.82e3.81 (m, 1H,
NCH), 3.57 (d, J¼14.4 Hz, 1H, CHa2), 3.00 (d, J¼14.4 Hz, 1H, CH2b),
1.95e1.13 (m, 19H, 5CH2 and 3CH3); 13C NMR (CDCl3, 150 MHz)
d
(ppm) 194.6, 168.1, 164.7, 139.9, 132.8, 130.2, 128.8, 69.3, 56.9, 49.1,
46.9, 32.6, 27.9, 25.3, 24.9. MS (m/z, %) 390 (Mþ, 4), 264 (33), 209 (46),
139 (61), 113 (69), 57 (100). Anal. Calcd for C21H27ClN2O3: C, 64.52; H,
6.96; N, 7.17. Found: C, 64.68; H, 7.18; N, 7.11.
4.2.2. N,1-Di-tert-butyl-2-(4-chlorobenzoyl)-4-oxoazetidine-2-
carboxamide (6b). Operation as above with tert-butylisocyanide 4b
(0.08 g, 1 mmol), compound 6b (0.34 g, 93%) was also isolated as
white solid. Mp: 224e226 ꢁC; 1H NMR (CDCl3, 400 MHz)
d (ppm)
7.74 (d, J¼8.4 Hz, 2H, AreH), 7.43 (d, J¼8.4 Hz, 2H, AreH), 6.35 (s,
1H, NH), 3.52 (d, J¼14.8 Hz, 1H, CHa2), 3.01 (d, J¼14.4 Hz, 1H, CH2b),
1.50 (s, 9H, 3CH3), 1.38 (s, 9H, 3CH3); 13C NMR (CDCl3, 150 MHz)
d
(ppm) 194.8,168.1,164.6,139.9,132.9,130.3,128.8, 69.9, 56.8, 52.4,
47.2, 28.3, 27.9; MS (m/z, %) 364 (Mþ, 2), 264 (32), 209 (63),139 (50),
113 (63), 57 (100). Anal.Calcd for C19H25ClN2O3: C, 62.54; H, 6.91; N,
7.68. Found: C, 62.51; H, 7.11; N, 7.49.
4.2.3. 2-(4-Bromobenzoyl)-N,1-di-tert-butyl-4-oxoazetidine-2-
carboxamide (6c). Operation as above with 4-bromophenylglyoxal 3b
(Ar¼4-BrC6H4, 0.21 g, 1 mmol), compound 6c (0.37 g, 90%) was also
isolated as white solid. Mp: 219e220 ꢁC; 1H NMR (CDCl3, 600 MHz)
d
(ppm) 7.66 (d, J¼8.4 Hz, 2H, AreH), 7.60 (d, J¼8.4 Hz, 2H, AreH),
6.38 (s, 1H, NH), 3.52 (d, J¼14.4 Hz, 1H, CHa2), 3.01 (d, J¼15.0 Hz, 1H,
Fig. 1. ORTEP drawing of 6i with 50% probability thermal ellipsoids (with only one
CHb2), 1.49 (s, 9H, 3CH3), 1.38 (s, 9H, 3CH3); 13C NMR (CDCl3, 150 MHz)
enantiomer shown).
d
(ppm) 195.0, 168.1, 164.5, 133.2, 131.8, 130.4, 128.8, 69.8, 56.8, 52.4,
47.4, 28.3, 27.8. MS (m/z, %) 408 (Mþ, 3), 308 (30), 253 (63), 169 (42),
155 (12), 113 (68), 57 (100); Anal. Calcd for C19H25BrN2O3: C, 55.75; H,
6.16; N, 6.84. Found: C, 55.63; H, 6.32; N, 6.58.
3. Conclusion
we have developed a simple synthesis of b-lactams with two p
electron-withdrawing substituents on their 4-position via a regio-
selective one-pot Ugi 4CC/SN cyclization. Due to the mild reaction
condition, good yields, and easily accessible starting material, we
think that this new synthetic approach discussed here has the
potential in synthesis of various 2-acyl-b-lactam-2-carboxamides,
which are of considerable interest as potential biological active
compounds or pharmaceuticals.
4.2.4. N,1-Di-tert-butyl-2-(4-nitrobenzoyl)-4-oxoazetidine-2-
carboxamide (6d). Operation as above with 4-nitrophenylglyoxal
3c (Ar¼4-NO2C6H4, 0.18 g, 1 mmol), compound 6d (0.32 g, 85%)
was also isolated as white solid. Mp: 208e209 ꢁC, lit.17 209e211 ꢁC;
1H NMR (DMSO-d6, 600 MHz)
d (ppm) 8.35 (s, 1H, NH), 8.32 (d,
J¼8.4 Hz, 2H, AreH), 7.94 (d, J¼8.4 Hz, 2H, AreH), 3.80 (d,
J¼15.0 Hz, 1H, CHa2), 3.04 (d, J¼15.0 Hz, 1H, CH2b), 1.41 (s, 9H, 3CH3),
1.30 (s, 9H, 3CH3); 13C NMR (DMSO-d6, 150 MHz)
d (ppm) 195.2,
4. Experimental
4.1. General
168.6, 164.2, 149.6, 139.2, 129.6, 123.7, 70.4, 55.5, 51.6, 46.1, 28.0,
27.6. MS (m/z, %) 375 (Mþ, 2), 275 (46), 220 (100), 113 (41), 57 (88).
Anal. Calcd for C19H25N3O5: C, 60.79; H, 6.71; N, 11.19. Found: C,
60.63; H, 6.59; N, 11.45.
Melting points were determined using a X-4 model apparatus
and were uncorrected. MS were measured on a Finnigan Trace MS
spectrometer. NMR were recorded in CDCl3 or DMSO-d6 on a Varian
4.2.5. 1-(tert-Butyl)-N-cyclohexyl-2-(4-nitrobenzoyl)-4-
oxoazetidine-2-carboxamide (6e). Operation as above with

3650
X.-H. Zeng et al. / Tetrahedron 70 (2014) 3647e3652
cyclohexylisocyanide (0.11 g, 1 mmol), compound 6e (0.33 g, 82%)
was also isolated as white solid. Mp: 229e230 ꢁC; 1H NMR (CDCl3,
C18H23ClN2O3: C, 61.62; H, 6.61; N, 7.98. Found: C, 61.77; H, 6.71; N,
7.71.
600 MHz)
d
(ppm) 8.30 (d, J¼8.4 Hz, 2H, AreH), 7.95 (d, J¼8.4 Hz,
2H, AreH), 6.91 (br, 1H, NH), 3.81e3.79 (m, 1H, NCH), 3.57 (d,
4.2.10. 2-(4-Bromobenzoyl)-N-(tert-butyl)-4-oxo-1-propylazetidine-
2-carboxamide (6j). Operation as above with n-propylamine
(0.06 g, 1 mmol) and 4-bromophenylglyoxal 3b (Ar¼4-BrC6H4,
0.21 g, 1 mmol), compound 6j (0.29 g, 73%) was also isolated as
J¼14.4 Hz, 1H, CHa2), 3.06 (d, J¼15.0 Hz, 1H, CHb2), 1.95e1.16 (m, 19H,
5CH2 and 3CH3); 13C NMR (CDCl3, 150 MHz)
d (ppm) 194.3, 168.1,
164.4,149.9,139.3,129.7,123.5, 69.3, 57.0, 49.7, 48.7, 46.4, 28.4, 27.4,
24.7. MS (m/z, %) 401 (Mþ, 4), 275 (31), 251 (24), 220 (63), 113 (54),
57 (100). Anal. Calcd for C21H27N3O5: C, 62.83; H, 6.78; N, 10.47.
Found: C, 62.92; H, 6.93; N, 10.24.
white solid. Mp: 150e152 ꢁC; 1H NMR (CDCl3, 600 MHz)
d (ppm)
7.73 (d, J¼8.4 Hz, 2H, AreH), 7.63 (d, J¼7.8 Hz, 2H, AreH), 5.68 (s,
1H, NH), 3.74 (d, J¼14.4 Hz, 1H, CHa2), 3.50e3.36 (m, 2H, NCH2), 3.16
(d, J¼14.4 Hz, 1H, CHb2), 1.77e1.69 (m, 2H, CH2), 1.31 (s, 9H, 3CH3),
4.2.6. 1-(tert-Butyl)-N-butyl-2-(4-chlorobenzoyl)-4-oxoazetidine-2-
carboxamide (6f). Operation as above with 4-chlorophenylglyoxal
3a (Ar¼4-ClC6H4, 0.17 g, 1 mmol) and n-butylisocyanide (0.08 g,
1 mmol), compound 6f (0.28 g, 77%) was also isolated as white
0.95 (t, J¼7.2 Hz, 3H, CH3); 13C NMR (CDCl3,150 MHz)
d (ppm) 195.3,
165.8, 165.6, 132.6, 132.2, 130.1, 129.6, 68.8, 52.7, 46.0, 45.0, 28.4,
21.9, 11.5; MS (m/z, %) 394 (Mþ, 2), 294 (62), 209 (61), 183 (50), 155
(100), 57 (36). Anal. Calcd for C18H23BrN2O3: C, 54.69; H, 5.86; N,
7.09. Found: C, 54.63; H, 6.00; N, 6.91.
solid. Mp: 159e160 ꢁC; 1H NMR (CDCl3, 600 MHz)
d (ppm) 7.73 (d,
J¼8.4 Hz, 2H, AreH), 7.43 (d, J¼8.4 Hz, 2H, AreH), 7.35 (s, 1H, NH),
3.59 (d, J¼14.4 Hz, 1H, CHa2), 3.39e3.25 (m, 2H, NCH2), 3.00 (d,
J¼15.0 Hz, 1H, CHb2), 1.55e1.53 (m, 2H, CH2), 1.48 (s, 9H, 3CH3),
1.37e1.33 (m, 2H, CH2), 0.92 (t, J¼7.2 Hz, 3H, CH3); 13C NMR (CDCl3,
4.2.11. N-(tert-Butyl)-1-isopropyl-2-(4-nitrobenzoyl)-4-
oxoazetidine-2-carboxamide (6k). Operation as above with iso-
propylamine (0.06 g, 1 mmol) and 4-nitrophenylglyoxal 3c (Ar¼4-
NO2C6H4, 0.18 g, 1 mmol), compound 6k (0.28 g, 78%) was also
isolated as white solid. Mp: 207e208 ꢁC; 1H NMR (CDCl3, 600 MHz)
150 MHz) d (ppm) 194.5, 169.0, 165.0, 139.9, 132.7, 130.2, 128.8, 69.1,
56.9, 46.7, 39.9, 31.0, 27.9, 20.1, 13.6. MS (m/z, %) 364 (Mþ, 4), 250
(8), 225 (37), 209 (21), 139 (47), 113 (38), 57 (100). Anal. Calcd for
d
(ppm) 8.33 (d, J¼8.4 Hz, 2H, AreH), 8.03 (d, J¼7.6 Hz, 2H, AreH),
C
19H25ClN2O3: C, 62.54; H, 6.91; N, 7.68. Found: C, 62.29; H, 6.93; N,
6.60 (s, 1H, NH), 3.78e3.74 (m, 1H, NCH), 3.71 (d, J¼14.4 Hz, 1H,
CHa2), 3.09 (d, J¼14.4 Hz, 1H, CH2b), 1.55 (d, J¼6.6 Hz, 3H, CH3), 1.43
(d, J¼6.6 Hz, 3H, CH3), 1.37 (s, 9H, 3CH3); 13C NMR (CDCl3, 150 MHz)
7.75.
4.2.7. 1-(tert-Butyl)-N-butyl-2-(4-nitrobenzoyl)-4-oxoazetidine-2-
carboxamide (6g). Operation as above with 4-nitrophenylglyoxal
3c (Ar¼4-NO2C6H4, 0.18 g, 1 mmol), compound 6g (0.30 g, 79%)
was also isolated as white solid. Mp: 166e167 ꢁC. 1H NMR (CDCl3,
d (ppm) 194.5,166.4,164.3,150.3,138.5,129.7,123.7, 68.7, 52.6, 49.0,
48.0, 28.4, 28.0, 21.6; MS (m/z, %) 361 (Mþ, 2), 261 (100), 219 (18),
177 (93), 113 (32), 57 (32). Anal. Calcd for C18H23N3O5: C, 59.82; H,
6.41; N, 11.63. Found: C, 59.74; H, 6.53; N, 11.81.
600 MHz):
d d (ppm) 8.29
183e185 ꢁC; 1H NMR (CDCl3, 400 MHz)
(d, J¼6.4 Hz, 2H, AreH), 7.94 (d, J¼7.2 Hz, 2H, AreH), 7.57 (s, 1H,
NH), 3.62 (d, J¼14.0 Hz, 1H, CH2a), 3.39e3.29 (m, 2H, NCH2), 3.04 (d,
J¼14.0 Hz, 1H, CHb2), 1.82e1.39 (m, 13H, 2CH2 and 3CH3), 0.94 (t,
4.2.12. N-(tert-Butyl)-2-(4-chlorobenzoyl)-4-oxo-1-propylazetidine-
2-carboxamide (6l). Operation as above with n-propylamine
(0.06 g, 1 mmol) and 4-chlorophenylglyoxal 3a (Ar¼4-ClC6H4,
0.17 g, 1 mmol), compound 6l (0.27 g, 77%) was also isolated as
J¼4.4 Hz, 3H, CH3); 13C NMR (CDCl3, 150 MHz)
d (ppm) 194.1, 168.9,
164.7, 149.9, 139.2, 129.7, 123.4, 69.2, 57.0, 30.9, 28.3, 27.3, 20.1, 14.0,
13.1; MS (m/z, %) 375 (Mþ, 11), 261 (17), 225 (55), 169 (78), 113 (28),
57 (100). Anal. Calcd for C19H25N3O5: C, 60.79; H, 6.71; N, 11.19.
Found: C, 60.78; H, 6.85; N, 11.14.
white solid. Mp: 162e163 ꢁC; 1H NMR (CDCl3, 400 MHz)
d (ppm)
7.81 (d, J¼8.4 Hz, 2H, AreH), 7.46 (d, J¼8.4 Hz, 2H, AreH), 5.53 (s,
1H, NH), 3.75 (d, J¼14.8 Hz, 1H, CHa2), 3.48e3.37 (m, 2H, NCH2), 3.17
(d, J¼14.4 Hz, 1H, CHb2), 1.78e1.59 (m, 2H, CH2), 1.31 (s, 9H, 3CH3),
0.95 (t, J¼7.2 Hz, 3H, CH3); 13C NMR (CDCl3,150 MHz)
d (ppm) 194.9,
4.2.8. 2-(4-Bromobenzoyl)-1-(tert-butyl)-N-butyl-4-oxoazetidine-2-
carboxamide (6h). Operation as above with 4-bromophenylglyoxal
3b (Ar¼4-BrC6H4, 0.21 g, 1 mmol), compound 6h (0.33 g, 80%) was
also isolated as white solid. Mp: 149e150 ꢁC; 1H NMR (CDCl3,
165.8, 165.7, 140.7, 132.0, 130.1, 129.1, 68.7, 52.6, 45.9, 27.8, 21.8, 12.0,
11.2; MS (m/z, %) 350 (Mþ, 2), 250 (100), 166 (90), 139 (79), 111 (21),
57 (28). Anal. Calcd for C18H23ClN2O3: C, 61.62; H, 6.61; N, 7.98.
Found: C, 61.67; H, 6.75; N, 7.86.
400 MHz)
d
(ppm) 7.66 (d, J¼7.6 Hz, 2H, AreH), 7.60 (d, J¼7.6 Hz,
2H, AreH), 6.95 (s, 1H, NH), 3.56 (d, J¼14.4 Hz, 1H, CHa2), 3.38e3.27
(m, 2H, NCH2), 3.02 (d, J¼14.4 Hz, 1H, CHb2), 1.53e1.33 (m, 13H, 2CH2
and 3CH3), 0.92 (t, J¼6.8 Hz, 3H, CH3); 13C NMR (CDCl3, 150 MHz)
4.2.13. 2-(4-Bromobenzoyl)-N-cyclohexyl-1-isopropyl-4-
oxoazetidine-2-carboxamide (6m). Operation as above with iso-
propylamine (0.06 g, 1 mmol), cyclohexylisocyanide (0.11 g,
1 mmol), and 4-bromophenylglyoxal 3b (Ar¼4-BrC6H4, 0.21 g,
1 mmol), compound 6m (0.31 g, 74%) was also isolated as white
d
(ppm) 194.4, 168.9, 165.0, 133.0,131.8, 130.0, 128.4, 69.1, 56.8, 30.9,
28.3, 27.3, 20.0, 13.9, 13.1; MS (m/z, %) 408 (Mþ, 4), 250 (95), 139
(100), 113 (46), 43 (35). Anal. Calcd for C19H25BrN2O3: C, 55.75; H,
6.16; N, 6.84. Found: C, 55.63; H, 6.24; N, 6.67.
solid. Mp: 199e200 ꢁC; 1H NMR (CDCl3, 600 MHz)
d (ppm) 7.69 (d,
J¼8.4 Hz, 2H, AreH), 7.61 (d, J¼8.4 Hz, 2H, AreH), 6.52 (d, J¼7.6 Hz,
1H, NH), 3.80e3.70 (m, 3H, 2NCH and CHa2), 3.03 (d, J¼14.4 Hz, 1H,
CH2b), 1.96e1.07 (m, 16H, 5CH2 and 2CH3); 13C NMR (CDCl3,
4.2.9. N-(tert-Butyl)-2-(4-chlorobenzoyl)-1-isopropyl-4-
oxoazetidine-2-carboxamide (6i). Operation as above with iso-pro-
pylamine (0.06 g, 1 mmol), 4-chlorophenylglyoxal 3a (Ar¼4-
ClC6H4, 0.17 g, 1 mmol), and tert-butylisocyanide 4b (0.08 g,
1 mmol), and stirring for 24 h, compound 6i (0.29 g, 83%) was also
isolated as white solid. Mp: 209e210 ꢁC; 1H NMR (CDCl3, 600 MHz)
150 MHz) d (ppm) 194.8, 165.8, 164.7, 132.3, 132.2, 129.9, 129.3, 68.1,
49.8, 49.0, 48.0, 25.1, 24.5, 21.5, 21.1; MS (m/z, %) 420 (Mþ, 2), 294
(50), 209 (49), 155 (100), 111 (26), 43 (28). Anal.Calcd for
C20H25BrN2O3: C, 57.01; H, 5.98; N, 6.65. Found: C, 57.05; H, 6.17; N,
6.88.
d
(ppm) 7.80 (d, J¼7.2 Hz, 2H, AreH), 7.46 (d, J¼7.2 Hz, 2H, AreH),
6.93 (s, 1H, NH), 3.75 (d, J¼13.8 Hz, 1H, CHa2), 3.71e3.67 (m, 1H,
NCH), 3.30 (d, J¼14.4 Hz, 1H, CHb2), 1.55 (d, J¼6.6 Hz, 3H, CH3), 1.40
(d, J¼6.6 Hz, 3H, CH3), 1.32 (s, 9H, 3CH3); 13C NMR (CDCl3, 150 MHz)
4.2.14. N-Cyclohexyl-1-isopropyl-2-(4-nitrobenzoyl)-4-oxoazetidine-
2-carboxamide (6n). Operation as above with 4-nitrophenylglyoxal
3c (Ar¼4-NO2C6H4, 0.18 g, 1 mmol), compound 6n (0.28 g, 72%) was
also isolated as white solid. Mp: 190e192 ꢁC; 1H NMR (CDCl3,
d
(ppm) 194.9, 165.7, 164.7, 140.6, 131.9, 130.0, 129.9, 129.2, 129.1,
68.8, 52.6, 49.0, 48.2, 28.4, 27.8, 21.5, 21.1, 20.4; MS (m/z, %) 350 (Mþ,
600 MHz)
d
(ppm) 8.32 (d, J¼8.4 Hz, 2H, AreH), 8.01 (d, J¼8.4 Hz,
4), 250 (95), 139 (100), 113 (46), 43 (35). Anal. Calcd for
2H, AreH), 6.91 (s, 1H, NH), 3.80e3.77 (m, 2H, 2NCH), 3.71 (d,

X.-H. Zeng et al. / Tetrahedron 70 (2014) 3647e3652
3651
J¼14.4 Hz, 1H, CHa2), 3.11 (d, J¼14.4 Hz, 1H, CHb2), 1.94e1.13 (m, 16H,
J¼7.6 Hz, 2H, AreH), 7.60 (d, J¼8.4 Hz, 2H, AreH), 7.36 (d, J¼6.8 Hz,
2H, AreH), 7.09 (d, J¼7.2 Hz, 2H, AreH), 6.45 (br,1H, NH), 3.82e3.78
(m, 2H, NCH and CHa2), 3.35 (d, J¼14.8 Hz,1H, CH2b), 2.32 (s, 3H, CH3),
5CH2 and 2CH3); 13C NMR (CDCl3, 150 MHz)
d (ppm) 194.4, 166.3,
164.4,150.4,138.6,129.6,123.8, 68.1, 49.2, 48.6, 45.7, 32.5, 24.9, 21.4,
20.8; MS (m/z, %) 387 (Mþ, 3), 262 (100), 177 (81), 155 (62), 111 (26),
43 (30). Anal. Calcd for C20H25N3O5: C, 62.00; H, 6.50; N, 10.85.
Found: C, 61.85; H, 6.74; N, 10.72.
1.81e0.90 (m,10H, 5CH2); 13C NMR (CDCl3,100 MHz)
d (ppm) 193.2,
165.9, 162.5, 134.7, 134.4, 132.6, 131.7, 130.3, 129.1, 128.8, 118.6, 68.6,
49.2, 47.2, 32.1, 25.0, 24.6, 20.8; MS (m/z, %) 468 (Mþ,1), 343 (7), 284
(89), 203 (100), 118 (32), 91 (21). Anal. Calcd for C24H25BrN2O3: C,
61.41; H, 5.37; N, 5.97. Found: C, 61.16; H, 5.49; N, 5.81.
4.2.15. N-tert-Butyl-2-(4-chlorobenzoyl)-1-(4-chlorophenyl)-4-
oxoazetidine-2-carboxamide (6o). Operation as above with 4-
chlorophenylamine (0.13 g, 1 mmol), tert-butylisocyanide (0.08 g,
1 mmol), and 4-chlorophenylglyoxal 3a (Ar¼4-ClC6H4, 0.17 g,
1 mmol), compound 6o (0.31 g, 74%) was also isolated as white
4.3. Isolation of 2-(2-bromo-N-tert-butylacetamido)-3-(4-
chlorophenyl)-N-cyclohexyl-3-oxopropanamide 5a
solid. Mp: 164e165 ꢁC; 1H NMR (CDCl3, 600 MHz)
d (ppm)
A mixture of the bromoacetic acid 1a (0.14 g, 1 mmol), tert-
butylamine 2a (R1¼t-Bu, 0.07 g, 1 mmol), and 4-chlorophenyl
glyoxal 3a (Ar¼4-ClC6H4, 0.17 g, 1 mmol) was stirred in methanol
(5 mL) at room temperature for 10 min, then cyclohexylisocyanide
4a (R2¼c-C6H11, 0.11 g, 1 mmol) was added to the solution. The
mixture was stirred at room temperature for 24 h and was chilled.
The solution was condensed and the residue was chromatagraphed
to give product 5a as white solid (0.085 g, 18%). Mp: 161e162 ꢁC; 1H
7.80e7.24 (m, 8H, AreH), 6.50 (s, 1H, NH), 3.84 (d, J¼15.0 Hz, 1H,
CHa2), 3.35 (d, J¼15.0 Hz, 1H, CH2b), 1.27 (s, 9H, 3CH3); 13C NMR
(CDCl3, 150 MHz)
d (ppm) 193.1, 165.5, 162.7, 140.6, 135.4, 131.9,
130.5, 130.4, 129.1, 128.9, 120.3, 69.8, 52.8, 47.5, 28.2; MS (m/z, %)
418 (Mþ, 4), 318 (25), 279 (100), 262 (25), 139 (95), 111 (29), 57 (37).
Anal. Calcd for C21H20Cl2N2O3: C, 60.15; H, 4.81; N, 6.68. Found: C,
60.08; H, 4.72; N, 6.54.
NMR (CDCl3, 600 MHz) d (ppm) 15.48 (s, 1H, OH), 7.41 (s, 4H, AreH),
4.2.16. 2-(4-Chlorobenzoyl)-N-cyclohexyl-1-phenyl-4-oxoazetidine-
2-carboxamide (6p). Operation as above with phenylamine (0.09 g,
1 mmol) and cyclohexylisocyanide (0.11 g, 1 mmol), compound 6p
(0.29 g, 71%) was also isolated as white solid. Mp: 171e172 ꢁC; 1H
5.78 (d, J¼7.8 Hz, 1H, NH), 4.24e4.18 (m, 2H, CH2), 3.91e3.86 (m,
1H, NCH), 2.02e1.23 (m, 10H, CH2), 1.16 (s, 9H, 3CH3); 13C NMR
(CDCl3, 150 MHz)
d (ppm) 170.2, 169.7, 168.3, 136.9, 132.4, 129.3,
128.8, 107.4, 61.8, 49.2, 32.8, 30.2, 28.7, 27.8, 24.4.; MS (m/z, %) 470
(Mþ, 2), 346 (33), 139 (61), 111 (69), 57 (100). Anal. Calcd for
C21H28BrClN2O3: C, 53.46; H, 5.98; N, 5.94. Found: C, 53.72; H, 6.06;
N, 5.78.
NMR (CDCl3, 400 MHz)
d
(ppm) 7.84 (d, J¼8.4 Hz, 2H, AreH),
7.52e7.16 (m, 6H, AreH), 6.18 (br, 1H, NH), 3.90e3.69 (m, 2H, NCH
and CHa2), 3.40 (d, J¼15.2 Hz, 1H, CH2b), 1.77e0.87 (m, 10H, 5CH2);
13C NMR (CDCl3, 100 MHz)
d (ppm) 193.1, 165.8, 162.8, 140.3, 136.9,
132.3, 130.5, 128.9, 128.8, 125.3, 118.9, 69.0, 49.3, 47.5, 32.3, 25.1,
24.7; MS (m/z, %) 410 (Mþ, 2), 271 (94), 262 (25), 189 (100), 139 (53),
104 (44). Anal. Calcd for C23H23ClN2O3: C, 67.23; H, 5.64; N, 6.82.
Found: C, 67.07; H, 5.71; N, 6.58.
5. Crystallographic material
Compound 6i: formula C18H23ClN2O3, colorless crystal. The
ꢀ
crystal is of triclinic, space group P-1 with a¼6.8083(17) A,
3
ꢀ
ꢁ
ꢀ
ꢀ
b¼11.074(3) A, c¼12.607(3) A,
b
¼83.901(4) , V¼929.3(4) A , Z¼2,
Dc¼1.254 g/cm3, F(000)¼372,
m
¼0.223 mmꢀ1
,
R¼0.0636 and
4.2.17. N-tert-Butyl-2-(4-chlorobenzoyl)-1-p-tolyl-4-oxoazetidine-2-
carboxamide (6q). Operation as above with 4-methylphenylamine
(0.11 g, 1 mmol) and tert-butylisocyanide (0.08 g, 1 mmol), com-
pound 6q (0.25 g, 63%) was also isolated as white solid. Mp:
wR¼0.2016 for 3228 observed reflections with I>2
s(I0). Crystallo-
graphic data for 6i have been deposited in the Cambridge Crystal-
lographic Data Center as supplementary publication
131e132 ꢁC; 1H NMR (CDCl3, 400 MHz)
2H, AreH), 7.45e7.38 (m, 4H, AreH), 7.10 (d, J¼8.4 Hz, 2H, AreH),
6.28 (s, 1H, NH), 3.84 (d, J¼15.2 Hz, 1H, CHa2), 3.32 (d, J¼14.8 Hz, 1H,
CHb2), 2.32 (s, 3H, CH3), 1.23 (s, 9H, 3CH3); 13C NMR (CDCl3,
d
(ppm) 7.82 (d, J¼8.8 Hz,
number CCDC975513. Copies of the data may be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK (fax: þ44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
100 MHz)
d (ppm) 193.6, 165.6, 162.9, 140.4, 135.4, 134.2, 132.2,
Acknowledgements
130.5,129.5,129.0,120.0, 70.0, 52.6, 47.3, 28.2, 20.9; MS (m/z, %) 398
(Mþ, 4), 298 (24), 259 (100), 203 (89), 139 (67), 91 (32), 57 (28).
Anal. Calcd for C22H23ClN2O3: C, 66.24; H, 5.81; N, 7.02. Found: C,
66.17; H, 5.93; N, 7.23.
We gratefully acknowledge financial support of this work by the
National Natural Science Foundation of China (No. 21172085,
21032001).
4.2.18. N-tert-Butyl-2-(4-chlorobenzoyl)-1-phenyl-4-oxoazetidine-
2-carboxamide (6r). Operation as above with phenylamine (0.09 g,
1 mmol), compound 6r (0.26 g, 68%) was also isolated as white
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.04.033.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
solid. Mp: 159e160 ꢁC; 1H NMR (CDCl3, 400 MHz)
d (ppm) 7.83 (d,
J¼6.8 Hz, 2H, AreH), 7.53e7.17 (m, 7H, AreH), 6.10 (br,1H, NH), 3.85
(d, J¼14.8 Hz, 1H, CHa2), 3.35 (d, J¼14.8 Hz, 1H, CHb2), 1.21 (s, 9H,
3CH3); 13C NMR (CDCl3, 100 MHz)
d (ppm) 193.3, 165.7, 162.9, 140.2,
136.8, 132.1, 130.4, 128.9, 128.8, 125.3, 119.2, 69.8, 52.6, 47.3, 28.1;
MS (m/z, %) 384 (Mþ, 2), 284 (58), 245 (100), 189 (82), 139 (94), 77
(32), 57 (44). Anal. Calcd for C21H21ClN2O3: C, 65.54; H, 5.50; N, 7.28.
Found: C, 65.78; H, 5.41; N, 7.11.
References and notes
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ꢁ
ꢁ~
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