Synthesis of α-methylene-β-lactams via PPh3-catalyzed umpolung cyclization of propiolamides

Article abstract of DOI:10.1021/jo502265a

We report herein a facile synthesis of α-methylene-β-lactams. Thus, under the catalysis of triphenylphosphine, a number of 2-propiolamidoacetates or α-propiolamido ketones in refluxing ethanol underwent umpolung cyclization to afford the corresponding 4-s

Full text of DOI:10.1021/jo502265a

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Note
Synthesis of alpha-Methylene-beta-Lactams via PPh3-
Catalyzed Umpolung Cyclization of Propiolamides
Lin Zhu, Yan Xiong, and Chaozhong Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502265a • Publication Date (Web): 20 Nov 2014
Downloaded from http://pubs.acs.org on November 26, 2014
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Synthesis of αꢀMethyleneꢀβꢀLactams via PPh3ꢀ
Catalyzed Umpolung Cyclization of Propiolamides
Lin Zhu,a Yan Xiong,b and Chaozhong Li *, a, b
a Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, P. R.
China, and b Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, P. R. China
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ABSTRACT: We report herein a facile synthesis of αꢀmethyleneꢀβꢀlactams. Thus under the catalysis of
triphenylphosphine, a number of 2ꢀpropiolamidoacetates or αꢀpropiolamido ketones in refluxing ethanol
underwent umpolung cyclization to afford the corresponding 4ꢀsubstituted 3ꢀmethyleneazetidinꢀ2ꢀones
in high yields.
βꢀLactams are an intensively studied family of heterocycles primarily because of their biological
activity.1 For example, βꢀLactam antibiotics such as penicillins and cephalosporins have occupied a
central role in the fight against pathogenic bacteria. αꢀMethyleneꢀβꢀlactams (1) are important structural
motifs widely embedded in βꢀlactam antibiotics such as βꢀlactamase inhibitors asparenomycin A and 6ꢀ
(acetylmethylene)penicillanic acid.2 In the meantime, they are also versatile synthetic intermediates
owing to the unique combination of fourꢀmembered ring and α,βꢀunsaturated amide moiety. A number
of methods have thus been developed for their synthesis,3, 4 including βꢀelimination of 3ꢀsubstituted
azetidinꢀ2ꢀones, [2+2] cycloaddition of allenes with isocyanates, transitionꢀmetalꢀcatalyzed
carbonylation of 2ꢀhaloallylamines or 2ꢀmethyleneaziridines, and palladiumꢀcatalyzed direct oxidative
carbonylation of Nꢀallylamines very recently reported by Lei et al4n. However, these methods suffer from
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either limited scope of application or harsh experimental conditions. Therefore, the development of
simple, economic, efficient and general methods is certainly highly desirable. As our continuous interest
in the construction of fourꢀmembered rings,5 we report herein the facile synthesis of αꢀmethyleneꢀβꢀ
lactams via phosphineꢀcatalyzed cyclization of propiolamides.
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Nucleophilic phosphine organocatalysis has been demonstrated to be a versatile tool in organic
synthesis.6, 7 In particular, the zwitterionic species generated from the conjugated addition of tertiary
phosphines to activated carbon–carbon multiple bonds serve as important intermediates in the synthesis
of carboꢀ or heterocyclic compounds.6f We envisioned that this strategy might be applied into the
synthesis of βꢀlactams from propiolamides such as ethyl 2ꢀ(Nꢀbenzylpropiolamido)acetate (2a). As
proposed in Figure 1, the conjugated addition of a tertiary phosphine to 2a should generate the
zwitterionic intermediate A, which might undergo 1,4ꢀproton migration to give αꢀester anion B. The
intermediate B might undergo intramolecular conjugated addition in a 4ꢀexo mode to afford βꢀlactam
intermediate C. The subsequent 1,2ꢀproton migration (to give D) followed by βꢀelimination might
furnish αꢀmethyleneꢀβꢀlactam 3a as the final product and regenerate the tertiary phosphine, which enters
into the next catalytic circle. Nevertheless, the risk of this plan is obvious in that 2a might undergo
direct intramolecular conjugated addition in a 5ꢀendo mode to produce the corresponding γꢀlactam.
We then used amide 2a as the model substrate to explore the above possibility. After the screening of
a few typical experimental conditions (Table 1),8 we were delighted to find that, with the catalysis of
PPh3 (10 mol %), the reaction of 2a in refluxing ethanol for 12 h afforded the expected αꢀmethyleneꢀβꢀ
lactam 3a in 70% isolated yield (entry 4, Table 1). No corresponding γꢀlactam could be detected. To the
best of our knowledge, this is the first example of fourꢀmembered ring synthesis via nucleophilic
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phosphine organocatalysis. The cyclization also proceeded at rt, but in a much slower rate with a large
portion (> 50%) of 2a recovered. However, when the catalyst PPh3 was switched to PBu3, only a trace
amount of 3a could be detected, while the conjugated addition of ethanol to 2a prevailed to give the
corresponding enol ether (entry 6, Table 1).9
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Figure 1. Proposed mechanism for the synthesis of βꢀlactam 3a.
Table 1. Optimization of Reaction Conditions
catalyst
(mol %)
yield
(%)b
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entrya
additive (mol%)
solvent/temp
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2
3
4
5
6
PPh3 (50)
PPh3 (50)
PPh3 (20)
PPh3 (10)
PPh3 (10)
PBu3 (10)
AcOH (50)/AcONa (50)
PhMe, 100 oC
PhMe, 100 oC
PhMe, 100 oC
EtOH, 80 oC
EtOH, rt
PhOH (100)
EtOH (100)
none
21
trace
70
none
26
none
EtOH, 80 oC
trace
a Conditions: 2a (0.2 mmol), solvent (8 mL), 12 h. b Isolated yield based on 2a.
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A number of propiolamides were then subjected to the above optimized conditions (entry 4, Table 1),
and the results are summarized in Table 2. In all cases, only the expected βꢀlactams were achieved while
no γꢀlactams could be detected. Esters 2b–2h with Nꢀalkyl or Nꢀaryl substituent, which were readily
prepared from the condensation of propiolic acid with glycine derivatives, underwent cyclization
smoothly to give the corresponding lactams 3b–3h in good to excellent yields. In particular, ester 2d
with a bulky Nꢀtertꢀbutyl group afforded βꢀlactam 3d in almost quantitative yield. On the other hand, the
analogous NH amide failed to give any cyclized product (not shown). These Nꢀsubstituent effects should
be attributed to the preferred Zꢀconformations of amide bonds. While the cyclization of 2d requires the
Zꢀconformation, which is also the predominant conformation for 2d, the cyclization of the analogous
NH amide requires the much unfavorable Eꢀconformation. Other than αꢀamino esters, αꢀamino ketones
are also excellent substrates for the synthesis of βꢀlactams. αꢀMethyleneꢀβꢀlactams 3i–3o were thus
obtained in high yields from the corresponding αꢀamino ketones 2i–2o. With αꢀAmino nitrile 2p as the
substrate, the cyclization also proceeded smoothly. Nevertheless, the cyano group was further converted
to the ethyl ester group under the experimental conditions. The optically pure substrate 2q derived from
(R)ꢀ1ꢀphenylethanamine was also tested. The product 3q was achieved in 86% yield. However, no
diastereoselectivity was observed. The above reactions gave 4ꢀmonosubstituted 3ꢀmethyleneazetidinꢀ2ꢀ
ones. To explore the synthesis of 4,4ꢀdisubstituted derivatives, propiolamides 2r and 2s were prepared
and subjected to the optimized reaction conditions. Indeed, the expected products 3r and 3s were
obtained, albeit in lower yields. The decreased yields might be rationalized by the increased steric
hindrance in the 4ꢀexo cyclization step (from B to C). In addition, the cyclization now requires the
unfavorable Eꢀconformations.
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To further examine the scope and limitation of the above method, malonate 4 was prepared and tested
under the optimized conditions (Equation 1). Surprisingly, γꢀlactam 5 was obtained in 90% yield while
no βꢀlactam could be detected, presumably because the malonate was more reactive than PPh3 towards
the activated C – C triple bond.
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Table 2. Synthesis of αꢀMethyleneꢀβꢀlactams
4
5
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8
time
(h)
yield
(%)
entry
substrate
O
product
R1
O
N
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N
R1
CO2R2
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CO2R2
3a
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
(R1 = Bn, R2 = Et)
(R1 = Ph, R2 = Et)
(R1 = i-Bu, R2 = Et)
(R1 = t-Bu, R2 = Et)
12
20
8
70
47
82
95
72
66
75
70
3b
3c
3d
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(R1 = 4-Me-C6H4CH2, R2 = Et)
(R1 = 4-MeO-C6H4CH2, R2 = Et) 3f
(R1 = 4-CF3-C6H4CH2, R2 = Et)
3e
18
18
12
12
2g
2h
3g
3h
(R1 = Bn, R2 = t-Bu)
O
N
R1
O
R2
N
R2
R1
O
O
9
2i
(R1 = R2 = Ph)
3i
12
12
12
8
92
80
77
82
78
82
81
10
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12
13
14
15
2j
(R1 = 4-Me-C6H4, R2 = Ph)
(R1 = 4-Cl-C6H4, R2 = Ph)
(R1 = 4-MeO-C6H4, R2 = Ph)
(R1 = R2 = 4-Cl-C6H4)
3j
2k
2l
3k
3l
2m
3m
12
12
12
2n (R1 = 4-Cl-C6H4, R2 = 4-MeO-C6H4) 3n
2o
(R1 = 4-Cl-C6H4, R2 = Me)
3o
O
O
iBu
N
16
3c
12
70
2p
CN
N
iBu
CO2Et
O
O
O
Ph
3q
N
N
N
CO2Et
17
18
2q
12
20
86
38
Ph
CO2Et
Bn
O
2r
3r
N
Bn
O
O
N
O
O
Bn
19
2s
3s
24
35
N
CO2Et
CO2Et
Bn
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To provide more evidence on the proposed mechanism, we carried out the reaction of 2j in EtOD (Eq
2). Interestingly, trideuterated product 6 was obtained. This result suggests that the intermediates A–D
have relatively long lifetimes to allow the H/D exchange, which in turn supports our proposed
mechanism.
In conclusion, we have successfully developed a new protocol for the synthesis of αꢀmethyleneꢀβꢀ
lactams via triphenylphosphineꢀcatalyzed umpolung cyclization of propiolamides under mild and metalꢀ
free conditions. The ready availability of propriolamides and easy operation of this transformation
should encourage its further application in organic synthesis.
Experimental Section
General Information. Melting points were measured with a melting point instrument and were
1
uncorrected. H and 13C NMR spectra were recorded using a 400 MHz NMR spectrometer. The
chemical shifts are referenced to CDCl3 (signals at 7.26 and 77.0 ppm, respectively) with TMS as the
internal standard. IR spectra were obtained either as potassium bromide pellets or as liquid films
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between two potassium bromide pellets with a spectrometer. Highꢀresolution mass spectrometry (HRMS)
was performed on a TOF MS instrument with an ESI source.
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Ethyl 2ꢀ(Nꢀbenzylpropiolamido)acetate (2a). Typical procedure. To a solution of propiolic acid
(818 mg, 11 mmol) in CH2Cl2 (40 mL) was added DCC (2.35 g, 11 mmol) and DMAP (136 mg, 1.1
9
o
mmol) at ꢀ30 C. The solution of ethyl 2ꢀ(benzylamino)acetate (1.93 g, 10 mmol) in CH2Cl2 (10 mL)
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was then added dropwise. The reaction mixture was stirred at rt for 24 h and then filtered by Celite.
After removal of the solvent under reduced pressure, the crude product was purified by column
chromatography on silica gel with hexane/ethyl acetate (5:1, v:v) as the eluent to give the pure 2a as a
colorless oil. Yield: 2.20 g (90%). 1H NMR (400 MHz, CDCl3): δ 7.22ꢀ7.38 (m, 5H), 4.90/4.67 (2s, 2H),
4.19/3.99 (2s, 2H), 4.11ꢀ4.19 (m, 2H), 3.30/3.24 (2s, 1H), 1.21ꢀ1.26 (m, 3H); 13C NMR (100 MHz,
CDCl3): δ 168.5/168.1, 154.1/153.9, 135.4/135.2, 128.9/128.8, 128.6/128.3, 128.0/127.8, 80.2/79.9,
75.4/75.2, 61.6/61.4, 53.3/49.4, 48.7/45.2, 14.1; IR (neat): ν (cmꢀ1) 3241, 2983, 2938, 2106, 1746, 1642,
1431, 1199, 1026, 737, 699; ESIꢀMS: (m/z) 268.1 (M++Na); HRMS calcd for C14H16NO3 (M+H):
246.1125, found 246.1122.
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Ethyl 2ꢀ(Nꢀphenylpropiolamido)acetate (2b). Yellow solid (1.80 g, 78%): mp 69–71 °C. H NMR
(400 MHz, CDCl3): δ 7.28ꢀ7.42 (m, 5H), 4.65/4.42 (2s, 2H), 4.16ꢀ4.27 (m, 2H), 3.30/2.89 (2s, 1H), 1.26
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 168.6/168.0, 153.5/153.2, 141.5/140.3, 129.3,
128.7, 128.1, 80.5/80.2, 75.8, 61.8/61.5, 50.6, 14.1; IR (KBr): ν (cmꢀ1) 3246, 2984, 2940, 2106, 1746,
1643, 1594, 1381, 1201, 1020, 749, 697; ESIꢀMS: (m/z) 254.1 (M++Na); HRMS calcd for C13H14NO3
(M+H): 232.0968, found 232.0972.
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Ethyl 2ꢀ(Nꢀisobutylpropiolamido)acetate (2c). Yellow oil (1.80 g, 85%). H NMR (400 MHz,
CDCl3): δ 4.30/4.08 (2s, 2H), 4.16ꢀ4.27 (m, 2H), 3.47/3.27 (2d, J = 7.6/6.0 Hz, 2H), 3.26/3.21 (2s, 1H),
1.88ꢀ1.96 (m, 1H), 1.26ꢀ1.323 (m, 3H), 0.97/0.91 (2d, J = 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ
168.7/168.1, 154.2/154.1, 79.8/79.2, 75.6/75.5, 61.6/61.3, 57.3/53.3, 51.0/46.8, 27.4/26.7, 20.0/19.8,
14.1/14.0; IR (neat): ν (cmꢀ1) 3230, 2963, 2105, 1749, 1635, 1462, 1432, 1200, 1141, 1024; ESIꢀMS:
(m/z) 234.1 (M++Na); HRMS calcd for C11H17NNaO3 (M+Na): 234.1101, found 234.1097.
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Ethyl 2ꢀ(Nꢀ(tertꢀbutyl)propiolamido)acetate (2d). Colorless oil (1.50 g, 71%). 1H NMR (400 MHz,
CDCl3): 4.41 (br s, 2H), 4.23 (q, J = 6.8 Hz, 2H), 3.30/2.99 (2s, 1H), 1.60/1.43 (2s, 9H), 1.29 (t, J = 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) (predominant rotamer): δ 170.0, 154.4, 77.24, 77.16, 61.6, 58.2,
49.1, 28.1, 14.1; IR (neat): ν (cmꢀ1) 2981, 2342, 2100, 1751, 1648, 1593, 1383, 1195; ESIꢀMS: (m/z)
234.1 (M++Na); HRMS calcd for C11H17NNaO3 (M+Na): 234.1101, found 234.1104.
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Ethyl 2ꢀ(Nꢀ(4ꢀmethylbenzyl)propiolamido)acetate (2e). Yellow oil (2.23 g, 86%). H NMR (400
MHz, CDCl3): δ 7.15/7.12 (2s, 2H), 4.85/4.62 (2s, 2H), 3.97ꢀ4.17 (m, 4H), 3.33/3.26 (2s, 1H), 2.33/2.31
(2s, 3H), 1.20ꢀ1.26 (m, 3H); 13C NMR (100 MHz, CDCl3): δ 168.5/168.1, 154.1/153.8, 138.0/137.7,
132.4/132.2, 129.6/129.4, 128.6/127.9, 80.3/79.9, 75.4/75.3, 61.6/61.3, 53.0/49.2, 48.3/45.0, 21.1, 14.1;
IR (neat): ν (cmꢀ1) 3243, 2981, 2935, 2105, 1745, 1640, 1432, 1197, 1023, 755; ESIꢀMS: (m/z) 282.1
(M++Na); HRMS calcd for C15H18NO3 (M+H): 260.1281, found 260.1279.
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Ethyl 2ꢀ(Nꢀ(4ꢀmethoxybenzyl)propiolamido)acetate (2f). Yellow oil (2.42 g, 88%). H NMR (400
MHz, CDCl3): δ 7.15ꢀ7.21 (m, 2H), 6.84ꢀ6.90 (m, 2H), 4.84/4.61 (2s, 2H), 3.98ꢀ4.19 (m, 4H), 3.80/3.78
(2s, 3H), 3.33/3.24 (2s, 1H), 1.21ꢀ1.27 (m, 3H); 13C NMR (100 MHz, CDCl3): δ 168.5/168.1,
159.6/159.4, 154.0/153.7, 130.0/129.3, 127.3/127.1, 114.3/114.2, 80.2/79.7, 75.4/75.3, 61.6/61.3,
55.3/55.2, 52.7/40.1, 48.0/44.9, 14.1; IR (neat): ν (cmꢀ1) 3245, 2980, 2937, 2105, 1745, 1638, 1612,
1513, 1437, 1249, 1198, 1028; ESIꢀMS: (m/z) 298.1 (M++Na); HRMS calcd for C15H18NO4 (M+H):
276.1230, found 276.1232.
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Ethyl 2ꢀ(Nꢀ(4ꢀ(trifluoromethyl)benzyl)propiolamido)acetate (2g). Yellow oil (2.57 g, 82%). H
NMR (400 MHz, CDCl3): δ 7.64/7.60 (2d, J = 8.0 Hz, 2H), 7.43/7.39 (2d, J = 8.0 Hz, 2H), 4.99/4.75
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(2s, 2H), 4.24/4.02 (2s, 2H), 4.14ꢀ4.24 (m, 2H), 3.30/3.25 (2s, 1H), 1.22ꢀ1.27 (m, 3H); C NMR (100
MHz, CDCl3): δ 168.3/167.9, 154.3/154.0, 139.7/139.5, 130.4 (q, J = 32.8 Hz), 128.7/128.0,
125.9/125.7 (2q, J = 4.4 Hz), 124.0/123.9 (2q, J = 270.5 Hz), 80.4/80.2, 75.1/74.9, 61.8/61.5, 52.9/49.7,
48.5/45.5, 14.0; IR (neat): ν (cmꢀ1) 3242, 2986, 2940, 2107, 1746, 1642, 1416, 1326, 1201, 1166, 1124,
1067; ESIꢀMS: (m/z) 336.1 (M++Na); HRMS calcd for C15H15NO3F3 (M+H): 314.0999, found
314.0998.
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tertꢀButyl 2ꢀ(Nꢀbenzylpropiolamido)acetate (2h). White solid (2.43 g, 89%): mp 71–73 °C. H
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NMR (400 MHz, CDCl3): δ 7.23ꢀ7.37 (m, 5H), 4.89/4.67 (2s, 2H), 4.07/3.91 (2s, 2H), 3.20/3.14 (2s,
1H), 1.44/1.43 (2s, 9H); 13C NMR (100 MHz, CDCl3): δ 167.5/167.2, 154.2/153.9, 135.6/135.4,
128.9/128.8, 128.7/128.0, 128.2/127.8, 82.6/82.2, 79.8/79.2, 75.5/75.4, 53.3/50.2, 48.8/45.8, 28.0; IR
(KBr): ν (cmꢀ1) 3238, 2980, 2935, 2105, 1741, 1643, 1431, 1369, 1221, 1155, 748, 699; ESIꢀMS: (m/z)
296.1 (M++Na); HRMS calcd for C16H20NO3 (M+H): 274.1438, found 274.1443.
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Nꢀ(2ꢀOxoꢀ2ꢀphenylethyl)ꢀNꢀphenylpropiolamide (2i). White solid (2.03 g, 77%): mp 84–86 °C. H
NMR (400 MHz, CDCl3): δ 7.94 (d, J = 7.6 Hz, 2H), 7.36ꢀ7.59 (m, 8H), 5.36/5.18 (2s, 2H), 3.04/2.87
(2s, 1H); 13C NMR (100 MHz, CDCl3) (predominant rotamer): δ 192.3, 153.3, 141.8, 134.8, 133.8,
129.3, 128.9, 128.6, 128.3, 128.0, 80.5, 76.0, 55.7; IR (KBr): ν (cmꢀ1) 2106, 1695, 1647, 1593, 1493,
1409, 1387, 1230, 759, 699, 688; ESIꢀMS: (m/z) 286.1 (M++Na); HRMS calcd for C17H13NNaO2
(M+Na): 286.0838, found 286.0842.
Nꢀ(2ꢀOxoꢀ2ꢀphenylethyl)ꢀNꢀ(pꢀtolyl)propiolamide (2j). White solid (2.08 g, 75%): mp 120–122 °C.
1H NMR (400 MHz, CDCl3): δ 7.91ꢀ7.96 (m, 2H), 7.56ꢀ7.62 (m, 1H), 7.44ꢀ7.52 (m, 2H), 7.34 (d, J =
8.4 Hz, 2H), 7.18ꢀ7.23 (m, 2H), 5.34/5.15 (2s, 2H), 3.03/2.87 (2s, 1H), 2.36/2.32 (2s, 3H); 13C NMR
(100 MHz, CDCl3) (predominant rotamer): δ 192.3, 153.4, 139.2, 138.6, 134.9, 133.8, 129.9, 128.8,
128.1, 128.0, 80.3, 76.1, 55.8, 21.2; IR (KBr): ν (cmꢀ1) 2103, 1697, 1687, 1635, 1510, 1418, 1390, 1221,
981, 757, 738, 686, 599; ESIꢀMS: (m/z) 300.1 (M++Na); Anal. Calcd for C18H15NO2: C, 77.96; H, 5.45;
N, 5.05; Found: C, 77.91; H, 5.42; N, 5.11.
Nꢀ(4ꢀChlorophenyl)ꢀNꢀ(2ꢀoxoꢀ2ꢀphenylethyl)propiolamide (2k). White solid (2.26 g, 76%): mp
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147–149 °C. H NMR (400 MHz, CDCl3): δ 7.89ꢀ7.95 (m, 2H), 7.29ꢀ7.59 (m, 7H), 5.34/5.13 (2s, 2H),
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3.06/2.91 (2s, 1H); C NMR (100 MHz, CDCl3) (predominant rotamer): δ 192.0, 153.1, 140.2, 134.6,
134.4, 133.9, 129.8, 129.5, 128.8, 127.9, 80.8, 75.7, 55.5; IR (KBr): ν (cmꢀ1) 2102, 1692, 1651, 1492,
1417, 1321, 1225, 1012; ESIꢀMS: (m/z) 320.0 (M++Na); HRMS calcd for C17H12ClNNaO2 (M+Na):
320.0449, found 320.0461.
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Nꢀ(4ꢀMethoxyphenyl)ꢀNꢀ(2ꢀoxoꢀ2ꢀphenylethyl)propiolamide (2l). White solid (2.14 g, 73%): mp
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125ꢀ127 °C. H NMR (400 MHz, CDCl3): δ 7.89ꢀ7.95 (m, 2H), 7.25ꢀ7.59 (m, 5H), 6.76ꢀ6.89 (m, 2H),
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5.35/5.13 (2s, 2H), 3.78/3.73 (2s, 3H), 3.09/2.92 (2s, 1H); C NMR (100 MHz, CDCl3) (predominant
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rotamer): δ 192.4, 159.5, 153.6, 134.9, 134.5, 133.8, 129.6, 128.8, 128.0, 114.4, 80.5, 76.1, 55.9, 54.5;
IR (KBr): ν (cmꢀ1) 2931, 2106, 1700, 1641, 1511, 1221, 1031, 839, 754, 737, 690; ESIꢀMS: (m/z) 316.1
(M++Na); HRMS calcd for C18H15NNaO3 (M+Na): 316.0944, found 316.0938.
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Nꢀ(4ꢀChlorophenyl)ꢀNꢀ(2ꢀ(4ꢀchlorophenyl)ꢀ2ꢀoxoethyl)propiolamide (2m). White solid (2.39 g,
72%): mp 126ꢀ128 °C. 1H NMR (400 MHz, CDCl3): δ 7.85ꢀ7.91 (m, 2H), 7.29ꢀ7.49 (m, 6H), 5.29/5.09
(2s, 2H), 3.01/2.91 (2s, 1H); 13C NMR (100 MHz, CDCl3) (predominant rotamer): δ 191.1, 153.1,
140.4, 140.1, 134.6, 133.0, 129.8, 129.6, 129.4, 129.2, 80.9, 75.6, 55.4; IR (KBr): ν (cmꢀ1) 2109, 1704,
1641, 1590, 1489, 1381, 1315, 1220, 1090, 983, 819; ESIꢀMS: (m/z) 354.0 (M++Na); HRMS calcd for
C17H11Cl2NNaO2 (M+Na): 354.0059, found 354.0067.
Nꢀ(4ꢀChlorophenyl)ꢀNꢀ(2ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀoxoethyl)propiolamide (2n). White solid (2.39 g,
73%): mp 90ꢀ92 °C. 1H NMR (400 MHz, CDCl3): δ 7.83ꢀ7.91 (m, 2H), 7.37 (d, J = 7.2 Hz, 2H), 7.30 (d,
J = 8.4 Hz, 2H), 6.86ꢀ6.92 (m, 2H), 5.28/5.07 (2s, 2H), 3.81/3.79 (2s, 3H), 3.08/2.92 (2s, 1H); 13C NMR
(100 MHz, CDCl3): δ 191.4/190.6, 164.3/164.1, 154.0/153.1, 140.4/139.3, 134.3/133.1, 130.3, 129.8,
129.4/129.3, 128.2/127.7, 114.3/114.1, 80.8/79.9, 75.9, 58.1/55.6, 55.2; IR (KBr): ν (cmꢀ1) 2111, 1686,
1648, 1602, 1492, 1237, 1176, 1011, 977; ESIꢀMS: (m/z) 350.1 (M++Na); HRMS calcd for
C18H14ClNNaO3 (M+Na): 350.0554, found 350.0560.
Nꢀ(4ꢀChlorophenyl)ꢀNꢀ(2ꢀoxopropyl)propiolamide (2o). White solid (1.93 g, 82%): mp 110ꢀ112 °C.
1H NMR 400 MHz, CDCl3): δ 7.22ꢀ7.39 (m, 4H), 4.70/4.48 (2s, 2H), 3.18/2.89 (2s, 1H), 2.120/2.16 (2s,
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3H); C NMR (100 MHz, CDCl3) (predominant rotamer): δ 200.7, 152.9, 140.1, 134.5, 129.6, 129.5,
80.8, 75.5, 58.5, 27.1; IR (KBr): ν (cmꢀ1) 3238, 2108, 1736, 1635, 1493, 1427, 1383, 1319, 1176, 753,
721; ESIꢀMS: (m/z) 236.1 (M++H); HRMS calcd for C12H11ClNO2 (M+H): 236.0473, found 236.0471.
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Nꢀ(Cyanomethyl)ꢀNꢀisobutylpropiolamide (2p). Yellow oil (1.38 g, 84%). H NMR (400 MHz,
CDCl3): δ 4.48/4.23 (2s, 2H), 3.26ꢀ3.46 (m, 3H), 1.91ꢀ2.00 (m, 1H), 0.90/0.85 (2d, J = 6.8 Hz, 6H); 13C
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NMR (100 MHz, CDCl3): δ 153.7/153.2, 114.7/114.9, 81.2/81.5, 74.7/74.5, 56.9/52.7, 33.0/37.8,
27.1/26.5, 19.8/19.6; IR (neat): ν (cmꢀ1) 3247, 2965, 2109, 1637, 1430, 1255, 1145, 742; ESIꢀMS: (m/z)
187.1 (M++Na); HRMS calcd for C9H12N2NaO (M+Na): 187.0842, found 187.0847.
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(R)ꢀEthyl 2ꢀ(Nꢀ(1ꢀphenylethyl)propiolamido)acetate (2q). Yellow oil (2.10 g, 81%). 1H NMR (400
MHz, CDCl3): δ 7.29ꢀ7.39 (m, 5H), 5.99/5.85 (2q, J = 7.2 Hz, 1H), 3.97ꢀ4.16 (m, 3H), 3.83/3.53 (2d, J
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= 16.8 Hz, 1H), 3.23/3.07 (2s, 1H), 1.65/1.51 (2d, J = 7.2 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H); C NMR
(100 MHz, CDCl3): δ 168.9/168.1, 154.3/153.5, 138.8/138.7, 128.7/128.6, 128.1/128.0, 127.7/127.1,
79.9/78.9, 75.8/75.4, 61.5/61.2, 56.8/51.2, 46.3/43.2, 17.3/15.9, 14.0; IR (neat): ν (cmꢀ1) 3244, 2980,
2105, 1749, 1636, 1541, 1457, 1200, 1027; ESIꢀMS: (m/z) 282.1 (M++Na); HRMS calcd for C15H18NO3
(M+H): 260.1281, found 260.1279.
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NꢀBenzylꢀNꢀ(2ꢀoxocyclohexyl)propiolamide (2r). Yellow oil (1.79 g, 70%). H NMR (400 MHz,
CDCl3): δ 7.18ꢀ7.35 (m, 5H), 5.20/5.13 (2d, J = 16.4 Hz, 1H), 4.92/4.68 (2dd, J = 12.0, 6.0 Hz, 1H),
4.54/4.02 (2d, J = 16.4 Hz, 1H), 3.26/3.11 (2s, 1H), 2.45ꢀ2.58 (m, 1H), 2.26ꢀ2.42 (m, 1H), 1.57ꢀ1.98 (m,
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6H); C NMR (100 MHz, CDCl3): δ 205.5/204.5, 154.7/154.5, 137.8/137.5, 128.7/128.5, 127.6/127.1,
127.0/126.8, 80.2/79.4, 76.0/75.9, 67.5/63.2, 51.9/47.6, 41.3/41.2, 32.9/31.2, 26.2/25.9, 24.8/24.6; IR
(neat): ν (cmꢀ1) 2935, 2103, 1720, 1631, 1414, 1123, 1021; ESIꢀMS: (m/z) 278.1 (M++Na); HRMS calcd
for C16H17NNaO2 (M+Na): 278.1152, found 278.1159.
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Ethyl 2ꢀ(Nꢀbenzylpropiolamido)propanoate (2s). Yellow oil (1.84 g, 71%). H NMR (400 MHz,
CDCl3): δ 7.21ꢀ7.38 (m, 5H), 5.08/4.42 (2q, J = 7.2 Hz, 1H), 4.97/4.81 (2d, J = 16.4 Hz, 1H), 4.78/4.45
(2d, J = 16.0 Hz, 1H), 3.90ꢀ4.13 (m, 2H), 3.23/3.14 (2s, 1H), 1.43/1.31 (2d, J = 7.2 Hz, 3H), 1.16ꢀ1.22
(m, 3H); 13C NMR (100 MHz, CDCl3): δ 170.8/170.5, 154.5/153.8, 137.1/136.4, 128.7/128.4,
127.9/127.4, 127.8/127.6, 80.1/79.3, 75.9/75.6, 61.7/61.3, 57.0/53.8, 52.4/46.6, 16.1/14.5, 14.0; IR
(neat): ν (cmꢀ1) 3245, 2986, 2105, 1739, 1638, 1429, 1221, 1112, 730, 698; ESIꢀMS: (m/z) 282.1
(M++Na); HRMS calcd for C15H18NO3 (M+H): 260.1281, found 260.1280.
Diethyl 2ꢀ(Nꢀbenzylpropiolamido)malonate (4).10 Yellow oil (2.32 g, 73%). H NMR (400 MHz,
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CDCl3): δ 7.18ꢀ7.35 (m, 5H), 5.65/5.15 (2s, 1H), 4.98/4.81 (2s, 2H), 4.02ꢀ4.10 (m, 2H), 3.87ꢀ3.96 (m,
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2H), 3.37/3.31 (2s, 1H), 1.14 (t, J = 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 165.4/165.1,
154.5/154.3, 136.1/135.4, 128.5/128.2, 127.9/127.4, 127.8/127.6, 81.3/81.1, 75.0/74.7, 63.9/62.5,
62.2/60.0, 52.4/48.0, 13.7.
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Ethyl 1ꢀbenzylꢀ3ꢀmethyleneꢀ4ꢀoxoazetidineꢀ2ꢀcarboxylate (3a). Typical procedure. To the
solution of 2a (49 mg, 0.2 mmol) in absolute EtOH (8 mL) was added PPh3 (5.2 mg, 0.02 mmol). The
solution was stirred at reflux for 12 h. The resulting mixture was then cooled down to rt and
concentrated in vacuo. The residue was purified by column chromatography on silica gel with
hexane/EtOAc (10:1, v:v) as the eluent to get the pure product 3a as a colorless oil. Yield: 35 mg (70%).
1H NMR (400 MHz, CDCl3): δ 7.17ꢀ7.29 (m, 5H), 5.70 (t, J = 1.6 Hz, 1H), 5.25 (t, J = 1.6 Hz, 1H),
4.88 (d, J = 14.8 Hz, 1H), 4.28 (s, 1H), 4.24 (d, J = 15.2 Hz, 1H), 4.06ꢀ4.20 (m, 2H), 1.19 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 168.6, 162.5, 144.9, 134.8, 128.9, 128.5, 128.0, 110.6, 61.7, 58.8,
45.4, 14.1; IR (neat): ν (cmꢀ1) 1764, 1496, 1455, 1383, 1203, 1107, 1028, 928, 702; ESIꢀMS: (m/z) 268.1
(M++Na); HRMS calcd for C14H15NNaO3 (M+Na): 268.0944, found 268.0944.
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Ethyl 3ꢀmethyleneꢀ4ꢀoxoꢀ1ꢀphenylazetidineꢀ2ꢀcarboxylate (3b). Yellow solid (22 mg, 47%): mp
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70–72 °C. H NMR (400 MHz, CDCl3): δ 7.32ꢀ7.37 (m, 4m), 7.10ꢀ7.15 (m, 1H), 5.92 (t, J = 2.0 Hz,
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NMR (100 MHz, CDCl3): δ 168.0, 159.4, 143.7, 137.3, 129.3, 124.7, 116.7, 111.9, 62.1, 59.8, 14.1; IR
(KBr): ν (cmꢀ1) 1753, 1598, 1502, 1369, 1198, 1122, 1023, 754; ESIꢀMS: (m/z) 254.1 (M++Na); HRMS
calcd for C13H14NO3 (M+H): 232.0968, found 232.0974.
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Ethyl 1ꢀisobutylꢀ3ꢀmethyleneꢀ4ꢀoxoazetidineꢀ2ꢀcarboxylate (3c). Colorless oil (35 mg, 82%). H
NMR (400 MHz, CDCl3): δ 5.71 (t, J = 1.6 Hz, 1H), 5.28 (t, J = 1.2 Hz, 1H), 4.53 (s, 1H), 4.16ꢀ4.29 (m,
2H), 3.36 (dd, J = 14.0, 8.4 Hz, 1H), 3.07 (1H, dd, J = 14.0, 6.4 Hz, 1H), 1.86ꢀ1.94 (m, 1H), 1.28 (t, J =
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7.2 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H); C NMR (100 MHz, CDCl3): δ 168.8,
163.0, 145.1, 109.9, 61.7, 60.3, 49.2, 27.5, 20.4, 20.3, 14.1; IR (neat): ν (cmꢀ1) 2961, 2934, 2873, 1763,
1467, 1387, 1295, 1198, 1078, 1028; ESIꢀMS: (m/z) 234.2 (M++Na); HRMS calcd for C11H17NNaO3
(M+Na): 234.1101, found 234.1101.
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Ethyl 1ꢀ(tertꢀbutyl)ꢀ3ꢀmethyleneꢀ4ꢀoxoazetidineꢀ2ꢀcarboxylate (3d). Colorless oil (40 mg, 95%).
1H NMR (400 MHz, CDCl3): δ 5.66 (t, J = 1.6 Hz, 1H), 5.18 (t, J = 1.6 Hz, 1H), 4.53 (s, 1H), 4.15ꢀ4.29
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(m, 2H), 1.36 (s, 9H), 1.27 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3): δ 169.9, 161.9, 144.5,
108.9, 61.7, 59.0, 54.4, 27.8, 14.1; IR (neat): ν (cmꢀ1) 2980, 1754, 1463, 1370, 1354, 1313, 1189, 1111,
1033, 929; ESIꢀMS: (m/z) 234.1 (M++Na); HRMS calcd for C11H17NNaO3 (M+Na): 234.1101, found
234.1103.
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Ethyl 1ꢀ(4ꢀmethylbenzyl)ꢀ3ꢀmethyleneꢀ4ꢀoxoazetidineꢀ2ꢀcarboxylate (3e). Colorless oil (37 mg,
72%). 1H NMR (400 MHz, CDCl3): δ 7.11ꢀ7.16 (m, 4H), 5.75 (t, J = 1.6 Hz, 1H), 5.30 (s, 1H), 4.91 (d,
J = 14.8 Hz, 1H), 4.32 (s, 1H), 4.14ꢀ4.27 (m, 3H), 2.32 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 168.7, 162.5, 144.9, 137.8, 131.7, 129.6, 128.5, 110.5, 61.7, 58.7, 45.1, 21.1, 14.1; IR
(neat): ν (cmꢀ1) 1766, 1516, 1382, 1203, 1101, 1027, 924, 795; ESIꢀMS: (m/z) 282.1 (M++Na); HRMS
calcd for C15H17NNaO3 (M+Na): 282.1101, found 282.1100.
Ethyl 1ꢀ(4ꢀmethoxybenzyl)ꢀ3ꢀmethyleneꢀ4ꢀoxoazetidineꢀ2ꢀcarboxylate (3f). Colorless oil (36 mg,
66%). 1H NMR (400 MHz, CDCl3): δ 7.16 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 5.74 (t, J = 1.6
Hz, 1H), 5.29 (t, J = 1.6 Hz, 1H), 4.88 (d, J = 14.8 Hz, 1H), 4.31 (s, 1H), 4.16ꢀ4.25 (m, 3H), 3.78 (s,
3H), 1.26 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 168.7, 162.4, 159.4, 144.8, 129.9, 126.8,
114.3, 110.4, 61.7, 58.6, 55.3, 44.8, 14.1; IR (neat): ν (cmꢀ1) 2982, 1763, 1612, 1514, 1443, 1382, 1247,
1100, 1030, 924, 820; ESIꢀMS: (m/z) 298.0 (M++Na); HRMS calcd for C15H17NNaO4 (M+Na):
298.1050, found 298.1050.
Ethyl 3ꢀmethyleneꢀ4ꢀoxoꢀ1ꢀ(4ꢀ(trifluoromethyl)benzyl)azetidineꢀ2ꢀcarboxylate (3g). Colorless oil
(47 mg, 75%). 1H NMR (400 MHz, CDCl3): δ 7.57 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 5.77 (t,
J = 1.6 Hz, 1H), 5.34 (t, J = 1.2 Hz, 1H), 4.92 (d, J = 15.6 Hz, 1H), 4.40 (d, J = 16.0 Hz, 1H), 4.38 (s,
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1H), 4.10ꢀ4.24 (m, 2H), 1.22 (t, J = 6.8 Hz, 3H); C NMR (100 MHz, CDCl3): δ 168.4, 162.5, 144.7,
139.2, 130.3 (q, J = 32.8 Hz), 128.7, 125.8 (q, J = 4.4 Hz), 123.9 (q, J = 270.5 Hz), 111.2, 61.8, 59.1,
45.0, 14.0; IR (neat): ν (cmꢀ1) 2983, 2361, 2340, 1767, 1620, 1384, 1326, 1121, 1066, 1020, 926; ESIꢀ
MS: (m/z) 336.0 (M++Na); HRMS calcd for C15H14F3NNaO3 (M+Na): 336.0818, found 336.0810.
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tertꢀButyl 1ꢀbenzylꢀ3ꢀmethyleneꢀ4ꢀoxoazetidineꢀ2ꢀcarboxylate (3h). Yellow solid (38 mg, 70%):
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mp 73–75 °C. H NMR (400 MHz, CDCl3): δ 7.24ꢀ7.37 (m, 5H), 5.75 (t, J = 2.0 Hz, 1H), 5.29 (br s,
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1H), 4.94 (d, J = 14.8 Hz, 1H), 4.31 (d, J = 14.8 Hz, 1H), 4.25 (1H, s), 1.46 (s, 9H); 13C NMR (100
MHz, CDCl3): δ 167.8, 162.6, 145.2, 134.9, 128.9, 128.5, 128.0, 110.1, 82.8, 59.4, 45.3, 28.0; IR (KBr):
ν (cmꢀ1) 2979, 1768, 1740, 1370, 1152, 1108, 701; ESIꢀMS: (m/z) 296.1 (M++Na); HRMS calcd for
C16H19NNaO3 (M+Na): 296.1257, found 296.1263.
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4ꢀBenzoylꢀ3ꢀmethyleneꢀ1ꢀphenylazetidinꢀ2ꢀone (3i). White solid (48 mg, 92%): mp 193–195 °C. 1H
NMR (400 MHz, CDCl3): δ 8.07 (d, J = 7.6 Hz, 2H), 7.70 (t, J = 7.2 Hz, 1H), 7.58 (t, J = 7.6 Hz, 2H),
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7.30ꢀ7.25 (m, 4H), 7.09ꢀ7.13 (m, 1H), 5.95 (s, 1H), 5.90 (d, J = 1.6 Hz, 1H), 5.26 (s, 1H); C NMR
(100 MHz, CDCl3): δ 191.3, 159.2, 144.0, 137.6, 134.6, 134.5, 129.3, 129.2, 128.7, 124.6, 117.1, 111.9,
64.1; IR (KBr): ν (cmꢀ1) 1764, 1682, 1596, 1505, 1494, 1377, 1229, 1116, 764, 750, 691. ESIꢀMS: (m/z)
286.0 (M++Na); HRMS calcd for C17H13NNaO2 (M+Na): 286.0838, found 286.0841.
4ꢀBenzoylꢀ3ꢀmethyleneꢀ1ꢀ(pꢀtolyl)azetidinꢀ2ꢀone (3j). White solid (44 mg, 80%): mp 120–122 °C.
1H NMR (400 MHz, CDCl3): δ 8.06 (d, J = 7.6 Hz, 2H), 7.69 (t, J = 7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz,
2H), 7.24 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 5.91 (s, 1H), 5.88 (t, J = 2.0 Hz, 1H), 5.24 (d, J =
2.0 Hz, 1H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 191.5, 159.0, 144.1, 135.1, 134.7, 134.4,
134.3, 129.7, 129.2, 128.6, 117.0, 111.5, 64.1, 21.0; IR (KBr): ν (cmꢀ1) 1759, 1683, 1515, 1379, 1228,
1124, 932, 814, 699; ESIꢀMS: (m/z) 300.1 (M++Na); HRMS calcd for C18H16NO2 (M+H): 278.1176,
found 278.1174.
4ꢀBenzoylꢀ1ꢀ(4ꢀchlorophenyl)ꢀ3ꢀmethyleneazetidinꢀ2ꢀone (3k). White solid (46 mg, 77%): mp 124–
126 °C. 1H NMR (400 MHz, CDCl3): δ 8.06 (d, J = 7.8 Hz, 2H), 7.71 (t, J = 7.2 Hz, 1H), 7.59 (t, J = 8.0
Hz, 2H), 7.29 (s, 4H), 5.92ꢀ5.94 (m, 2H), 5.28 (t, J = 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ
191.0, 159.0, 143.8, 136.1, 134.7, 134.4, 129.6, 129.4, 129.3, 128.7, 118.3, 112.5, 64.2; IR (KBr): ν (cmꢀ
1) 1746, 1691, 1595, 1494, 1383, 1128, 1089, 923, 826; ESIꢀMS: (m/z) 320.1 (M++Na); HRMS calcd for
C17H12ClNNaO2 (M+Na): 320.0449, found 320.0456.
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4ꢀBenzoylꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀmethyleneazetidinꢀ2ꢀone (3l). White solid (48 mg, 82%): mp
127–129 °C. 1H NMR (400 MHz, CDCl3): δ 8.06 (d, J = 8.4 Hz, 2H), 7.69 (t, J = 7.6 Hz, 1H), 7.58 (t, J
= 8.0 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 9.2 Hz, 2H), 5.90 (s, 1H), 5.87 (d, J = 2.4 Hz, 1H),
5.23 (t, J = 2.0 Hz, 1H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 191.7, 158.8, 156.6, 144.2, 134.6,
134.5, 131.2, 129.3, 128.6, 118.4, 114.5, 111.3, 64.2, 55.5; IR (KBr): ν (cmꢀ1) 1746, 1686, 1513, 1446,
1387, 1297, 1251, 1236, 828, 765; ESIꢀMS: (m/z) 316.0 (M++Na); HRMS calcd for C18H15NNaO3
(M+Na): 316.0944, found 316.0954.
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4ꢀ(4ꢀChlorobenzoyl)ꢀ1ꢀ(4ꢀchlorophenyl)ꢀ3ꢀmethyleneazetidinꢀ2ꢀone (3m). White solid (52 mg,
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78%): mp 166–168 °C. H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.8 Hz, 2H), 7.54 (t, J = 8.8 Hz,
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2H), 7.22ꢀ7.27 (m, 4H), 5.90 (t, J = 2.0 Hz, 1H), 5.83 (s, 1H), 5.23ꢀ5.24 (m, 1H); C NMR (100 MHz,
CDCl3): δ 190.0, 158.8, 143.5, 141.4, 135.9, 132.6, 129.9, 129.7, 129.6, 129.3, 118.2, 112.6, 64.1; IR
(KBr): ν (cmꢀ1) 1747, 1690, 1587, 1493, 1378, 1322, 1228, 1125, 1092, 997, 827, 794; ESIꢀMS: (m/z)
354.1 (M++Na); HRMS calcd for C17H11Cl2NNaO2 (M+Na): 354.0059, found 354.0063.
1ꢀ(4ꢀChlorophenyl)ꢀ4ꢀ(4ꢀmethoxybenzoyl)ꢀ3ꢀmethyleneazetidinꢀ2ꢀone (3n). White solid (54 mg,
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82%): mp 170–172 °C. H NMR (400 MHz, CDCl3): δ 8.03 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.0 Hz,
4H), 7.04 (d, J = 9.2 Hz, 2H), 5.88ꢀ5.90 (m, 2H), 5.27 (dd, J = 0.8, 1.6 Hz, 1H), 3.91 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 189.3, 164.7, 159.1, 144.1, 136.1, 131.0, 129.4, 129.2, 127.3, 118.2, 114.5, 112.1,
64.0, 55.7; IR (KBr): ν (cmꢀ1) 2919, 1748, 1679, 1603, 1497, 1382, 1262, 1244, 1180, 1094, 834, 805;
ESIꢀMS: (m/z) (M++Na) 350.0; HRMS calcd for C18H14ClNNaO3 (M+Na): 350.0554, found 350.0548.
4ꢀAcetylꢀ1ꢀ(4ꢀchlorophenyl)ꢀ3ꢀmethyleneazetidinꢀ2ꢀone (3o). White solid (38 mg, 81%): mp 182–
184 °C. 1H NMR (400 MHz, CDCl3): δ 7.30ꢀ7.33 (m, 2H), 7.23ꢀ7.26 (m, 2H), 5.98 (t, J = 1.6 Hz, 1H),
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5.45 (dd, J = 1.2, 2.4 Hz, 1H), 4.84 (t, J = 1.6 Hz, 1H), 2.16 (s, 3H); C NMR (100 MHz, CDCl3): δ
203.5, 159.3, 143.1, 135.8, 130.0, 129.6, 117.6, 113.3, 66.9, 24.9; IR (KBr): ν (cmꢀ1) 2923, 1741, 1720,
1497, 1387, 1172, 1093, 940, 826, 635; ESIꢀMS: (m/z) (M++Na) 258.2; HRMS calcd for
C12H10ClNNaO2 (M+Na): 258.0292, found 258.0289.
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Ethyl 3ꢀmethyleneꢀ4ꢀoxoꢀ1ꢀ((R)ꢀ1ꢀphenylethyl)azetidineꢀ2ꢀcarboxylate (3q). This compound was
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obtained as a mixture of two inseparable stereoisomers in ~1:1 ratio (45 mg, 86%). Colorless oil. H
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NMR (400 MHz, CDCl3): δ 7.23ꢀ7.32 (m, 5H), 5.69/5.67 (2t, J = 1.6 Hz, 1H), 5.21/5.18 (2t, J = 2.4 Hz,
1H), 5.07/4.73 (2q, J = 6.8/7.6 Hz, 1H), 4.30/3.23 (2t, J = 1.6 Hz, 1H), 4.03ꢀ4.18 (m, 2H), 1.78/1.63 (2d,
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J = 7.6/6.8 Hz, 3H), 1.20/1.15 (2t, J = 6.8/7.2 Hz, 3H); C NMR (100 MHz, CDCl3): δ 169.1/168.8,
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162.5, 144.5/144.4, 140.7/139.1, 128.8, 128.0/127.9, 127.2/126.8, 110.0, 61.7/61.6, 59.3/59.0,
55.6/52.4, 20.2/18.8, 14.0; IR (neat): ν (cmꢀ1) 2982, 2933, 1751, 1456, 1373, 1303, 1196, 1029, 927,
765, 702; ESIꢀMS: (m/z) (M++Na) 282.0; HRMS calcd for C15H17NNaO3 (M+Na): 282.1101, found
282.1099.
1ꢀBenzylꢀ3ꢀmethyleneꢀ1ꢀazaspiro[3.5]nonaneꢀ2,5ꢀdione (3r). Yellow solid (19 mg, 38%): mp 101–
103 °C. 1H NMR (400 MHz, CDCl3): δ 7.25ꢀ7.33 (m, 5H), 5.74 (d, J = 2.4 Hz, 1H), 5.36 (d, J = 2.4 Hz,
1H), 5.02 (d, J = 15.2 Hz, 1H), 4.32 (d, J = 15.6 Hz, 1H), 2.58ꢀ2.63 (m, 1H), 2.44 (td, J = 14.4, 6.4 Hz,
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1H), 2.06ꢀ2.12 (m, 1H), 1.52ꢀ1.88 (m, 5H); C NMR (100 MHz, CDCl3): δ 205.6, 161.8, 151.1, 137.0,
128.6, 128.4, 127.7, 108.7, 75.0, 44.9, 41.3, 36.5, 25.9, 23.4; IR (KBr): ν (cmꢀ1) 2941, 1755, 1716, 1496,
1454, 1385, 1112, 791, 703; ESIꢀMS: (m/z) 278.2 (M++Na); HRMS calcd for C16H17NNaO2 (M+Na):
278.1152, found 278.1150.
Ethyl 1ꢀbenzylꢀ2ꢀmethylꢀ3ꢀmethyleneꢀ4ꢀoxoazetidineꢀ2ꢀcarboxylate (3s). Colorless oil (18 mg,
35%). 1H NMR (400 MHz, CDCl3): δ 7.26ꢀ7.33 (m, 5H), 5.68 (d, J = 2.0 Hz, 1H), 5.25 (d, J = 2.0 Hz,
1H), 4.78 (d, J = 15.2 Hz, 1H), 4.41 (d, J = 15.2 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 1.36 (s, 3H), 1.21 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 170.9, 162.5, 150.9, 136.0, 128.8, 128.7, 127.8, 108.7,
67.6, 61.8, 44.7, 20.1, 14.0; IR (neat): ν (cmꢀ1) 1762, 1738, 1605, 1455, 1375, 1262, 1121, 1020, 927,
702; ESIꢀMS: (m/z) 282.1 (M++Na); HRMS calcd for C15H17NNaO3 (M+Na): 282.1101, found
282.1105.
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Diethyl 1ꢀbenzylꢀ5ꢀoxoꢀ1Hꢀpyrroleꢀ2,2(5H)ꢀdicarboxylate (5).10 Yellow oil (57 mg, 90%); H
NMR (400 MHz, CDCl3): δ 7.19ꢀ7.27 (m, 5H), 7.13 (d, J = 6.0 Hz, 1H), 6.37 (d, J = 6.0 Hz, 1H), 4.88
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(s, 2H), 3.94 (q, J = 7.2 Hz, 4H), 1.11 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 171.3, 165.1,
142.9, 137.2, 128.9, 128.2, 127.5, 127.1, 76.0, 62.8, 44.9, 13.7.
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4ꢀBenzoylꢀ4ꢀdeuteroꢀ3ꢀ(dideuteromethylene)ꢀ1ꢀ(pꢀtolyl)azetidinꢀ2ꢀone (6). White solid (36 mg,
65%): mp 122–124 °C. 1H NMR (400 MHz, CDCl
7.56 (t, J = 7.2 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 2.29 (s, 3H); 13C NMR (100
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): δ 8.05 (d, J = 7.2 Hz, 2H), 7.68 (t, J = 7.2 Hz, 1H),
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MHz, CDCl ): δ 191.5, 159.0, 143.8, 135.1, 134.55, 134.46, 134.2, 129.7, 129.2, 128.6, 116.9, 111.1
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(qunit, J = 25.0 Hz), 63.6 (t, J = 23.5 Hz), 21.0; IR (KBr): ν (cmꢀ1) 2923, 1746, 1690, 1516, 1382, 1272,
1170, 920, 691; ESIꢀMS: (m/z) 281.2 (M++H); HRMS calcd for C18H12D3NO2 (M+Na): 303.1183, found
303.1177.
SUPPORTING INFORMATION
1H and 13C NMR spectra of all compounds (PDF). This material is available free of charge via the
Internet at: http//pubs.acs.org./
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: clig@mail.sioc.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This project was supported by the National Natural Science Foundation of China (Grants 21228202,
21272259, 21290180, 21472220 and 21361140377) and by the National Basic Research Program of
China (973 Program) (Grant 2011CB710805).
REFERENCES
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Graphic Abstract
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