A facile synthesis of 4-gem-difluoromethylene β-lactam and its derivatives from BrCF2CF2Br

Article abstract of DOI:10.1016/j.jfluchem.2006.05.024

4-Bromodifluoromethyl β-lactams 2 are prepared from the commercial available BrCF₂CF₂Br in overall five-step reaction procedure. Under the radical reaction conditions (Bu₃SnH/AIBN), compound 2 reacted with alkenes affording to the corresponding addition product difluoromethylene β-lactams 7. In the absence of alkenes, it can be converted into the corresponding difluoromethyl β-lactam 6 in almost quantitative yield. Furthermore, allylic stannic reagent Bu₃SnCH₂CH{double bond, long}CH₂ reacted with 2 under the same reaction conditions gave the allylic addition product 8.

Full text of DOI:10.1016/j.jfluchem.2006.05.024

Journal of Fluorine Chemistry 127 (2006) 1195–1203
www.elsevier.com/locate/fluor
A facile synthesis of 4-gem-difluoromethylene b-lactam and
its derivatives from BrCF2CF2Br
Hui Wang a,1, Shifa Zhu b,1, Chunhui Xing b, Wan Pang b,
Qinying Deng a, , Shizheng Zhu
*
b,**
a School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, PR China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 20032, PR China
Received 7 April 2006; received in revised form 29 May 2006; accepted 30 May 2006
Available online 15 June 2006
Abstract
4-Bromodifluoromethyl b-lactams 2 are prepared from the commercial available BrCF2CF2Br in overall five-step reaction procedure. Under
the radical reaction conditions (Bu3SnH/AIBN), compound 2 reacted with alkenes affording to the corresponding addition product difluor-
omethylene b-lactams 7. In the absence of alkenes, it can be converted into the corresponding difluoromethyl b-lactam 6 in almost quantitative
yield. Furthermore, allylic stannic reagent Bu3SnCH2CH CH2 reacted with 2 under the same reaction conditions gave the allylic addition
product 8.
# 2006 Elsevier B.V. All rights reserved.
Keywords: Bromodifluoromethyl; Difluomethyl; Difluoromethylene; b-Lactam; Free radical
1. Introduction
BrCF2-containing building blocks are one of the most used and
important origins of the gem-difluoromethylene. b-Lactams are
very important structures existing widely in various antibiotics
and natural products [5]. A series of methodologies to prepare
this structure have been established [6]. a-Gem-difluoromethy-
lene lactam can be easily prepared from the reaction of ethyl
bromodifluoroacetate and imines. 4-Gem-difluoro-methylene
lactams, to our knowledge, however, do not be synthesized up
to now.
The field of fluoroorganic chemistry has grown tremendously
inrecent years, andfluorochemicalshave permeated nearly every
aspect of our daily lives [1]. Incorporation of fluorine atoms into
an organic molecule sometimes adds an unexpected quality to
organic molecules [1]. It led to the discovery of potent medicinal
agents and development of original methods of preparation [2].
Among them, gem-difluoro compounds have been the subject of
an important area of research as the CF2/CH2 transposition has
been recognized as a valuable tool in the blockage of metabolic
processes. Replacement of various functional groups by a gem-
difluoromethylene group has generated potent transition-state-
type inhibitors [3]. The preparation of gem-difluoromethylene
substituted molecules falls broadly into two classes. The first
involves direct gem-difluorination, [4] and the second draws
from the construction of molecules derived from CF2-synthons.
2. Results and discussion
Following we report a facile method to synthesize this kind
of 4-gem-difluoromethylene lactams 1 from the commercial
available BrCF2CF2Br.
The 4-gem-difluoromethylene containing lactams 1 can be
synthesized from the corresponding g-bromo-difluoromethyl
lactam 2 through the radical initiation reactions, as delineated
in Scheme 1. Intramolecular cyclizations of the b-amino ester 3
can afford to the BrCF2-containing b-lactams 2. Dehydro-
fluorination of the ester 5, followed by substituion of the
fluorine with amines, and reduction of the imines by NaBH4
will give the b-amino ester 3. The ester 5 can be prepared from
* Corresponding author.
** Corresponding author. Fax: +86 21 64166128.
E-mail address: zhusz@mail.sioc.ac.cn (S. Zhu).
1
These authors contributed equally to this work.
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.05.024

1196
H. Wang et al. / Journal of Fluorine Chemistry 127 (2006) 1195–1203
Scheme 1.
the commercial available BrCF2CF2Br in a two-step procedure
[7].
closures of the b-amino esters 3 using methylmagnesium
bromide to deprive the hydrogen on the nitrogen atom smoothly
lead to the desired BrCF2-containing b-lactams in good yields,
respectively (Scheme 4).
Synthesis efforts towards 1 commenced with reaction of
BrCF2CF2Br and ethyl vinyl ether giving ester 5 over two steps
after the reported procedure (Scheme 2) [7].
Their structures were further determined by spectrum
methods and elemental analysis, while the compound 2b
was also further confirmed by X-ray diffraction (Fig. 1).
It is interesting that the b-lactam ring, methoxyl and phenyl
ring are nearly coplanar, the torsion angle is only 58. We early
reported that there exist halogen-bonding interactions between
the carbonyl oxygen atom and the bromine atom on the
bromodifluoromethyl [9]. Therefore, we also want to know if
there are similar halogen bonding interactions between the
bromine atom and the amide oxygen atom in the structure of 2b.
However, no intermolecular halogen bonding interactions but
Dehydrohalogenation of 5 with Et3N in refluxing CH2Cl2,
followed by substitution of the fluorine with the aromatic
amines give the desired imines 4 together with its tautomer
enamine 40. NaBH4 in EtOH can easily reduce these two
tautomers at room temperature in good yields. Except the
desired reduced product amines, two byproducts, 3a0 and 3b0,
are also isolated (Scheme 3).
As we all know, b-lactams can be efficiently synthesized
from the corresponding b-amino esters through the nucleo-
philic reaction in the presence of Grignard’s reagent [8]. Ring
Scheme 2.
Scheme 3.

H. Wang et al. / Journal of Fluorine Chemistry 127 (2006) 1195–1203
1197
Scheme 5.
Scheme 4.
Table 1
The data for the hydrogen bonding interactions for compound 2b
˚
Distance (A)
Hydrogen bonding
Angle (8)
C(10)–H(7)ꢀ ꢀ ꢀF(2) (intramolecular)
C(3)–H(2)ꢀ ꢀ ꢀBr(1) (intramolecular)
C(6)–H(4)ꢀ ꢀ ꢀO(1) (intramolecular)
C(7)–H(5)ꢀ ꢀ ꢀO(1) (intermolecular)
2.438
2.932
2.486
2.495
136.13
107.09
123.71
155.98
Scheme 6.
Bu3SnH/AIBN involved the radical cleavage of the C–Br bond
in the BrCF2-containing b-lactam 2. Treatment of 2b with
Bu3SnH/AIBN in refluxing benzene at 80 8C for 8 h gave only
trace of difluoromethyl b-lactam 6. Raising the temperature did
not enhance the yield obviously. Further experimental tries
turned out that it was inert to the other free radical initiating
conditions, such as CrCl3/Fe, Cp2TiCl/Fe, NaS2O4/NaHCO3,
CuCl/ethanolamine and Pd [11], etc. (Scheme 5).
intramolecular hydrogen bondings was found (Fig. 1). The
distances and angles of the hydrogen bonding interactions in
the compound 2b are listed in Table 1. There are weak hydrogen
bonding interactions between the hydrogen atoms on the phenyl
ring and fluorine and oxygen atoms. Furthermore, there also
exist close intramolecular Brꢀ ꢀ ꢀH contacts, which forming five-
membered ring, although the hydrogen bonding interaction is
rather weak according to its contacting distance and angle
Hu reported that the BrCF2-moiety is fairy stable when it
was not activated by the a-substituted electron-withdrawing
group, such as C C double bonds, carbonyl, etc. [10]. It is
difficult to break the C–Br bond using the common radical
initiating reagents. It was consisted with our experimental
results. Hu developed a method, in which the unactivated
CF2Br-containing compounds could react with alkenes to give
the adducts promoted by Co(III)/Zn system [12]. However, the
catalyst Co(III)/Zn is difficult to avail.
˚
(2.932 A, 107.09). To the best of our knowledge, there are few
examples that the hydrogen on methylene or methyl involved in
a hydrogen bond [10]. It was also found from the packing
diagram of 2b that the hydrogen atom H(5) on the phenyl ring
involved in the intermolecular hydrogen bonding interactions to
the amide oxygen atom O(1) (Fig. 1b). The intermolecular
hydrogen bonding interactions dimerize two molecules to form
a 10-atom constituted cavity (Fig. 1b).
As mentioned above, Bu3SnH/AIBN is one of the most
classical and efficient radical initiating systems in the field of
radical reaction of the halogen compounds and alkenes.
Uneyama reported that Bu3SnH/AIBN could mediate the
radical cleavage of the C–Br bond of the unactivated CF2Br
moiety in a pressed sealed-tube [13]. Under the similar reaction
conditions, the starting material 2b was completely disappear-
ing overnight at 110 8C in a sealed tube when Bu3SnH/AIBN
With the BrCF2-containing b-lactam 2 in hand, we then
explored its further chemical transformation. b-Lactam 2 is a
useful fluorinated synthetic building block to synthesize CF2-
containing b-lactams through the radical reaction conditions to
break the C–Br bond.
It is well know that Bu3SnH/AIBN is the most used free
radical initiating system. Therefore, we initially explored
Fig. 1. The X-ray structure of 2b.

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H. Wang et al. / Journal of Fluorine Chemistry 127 (2006) 1195–1203
Scheme 7.
Table 2
The reaction of 2b and alkenes initiated by Bu3SnH and AIBNa
induce allyl into the organic molecules through radical
reactions initiated by AIBN. When Bu3SnCH2CH CH2 was
used to react with 2b under the same reaction conditions,
desired allylic addition product 8 was obtained in 25%,
together with the reduction product 6 in 30% (Table 2, entry 8)
(Scheme 7).
Entry
CH2 CHR (R
)
Products
Yield (%)b of products
c
1
2
3
4
5
6
7
8
6
98
COOEt
COOMe
CN
7a/6
7b/6
7c/6
7d/6
7f/6
7e/6
8/6
36/64
44/53
38/62
48/21
17/50
77/0
COCH3
OEt
3. Conclusions
Ph
d
In summary, difluoromethylene containing b-lactams 2 are
prepared started from the commercial available BrCF2CF2Br
in overall five-step reaction procedure. The compound 2 is a
useful fluorinated synthetic building block to synthesize CF2-
containing b-lactams through the radical reaction conditions
to break the C–Br bond. Although the difluoromethylene
containing b-lactams 2 is relative stable molecule to the
common radical reaction conditions, it still can react with
alkenes under the radical reaction conditions (Bu3SnH/AIBN)
in the sealed tube giving the desired addition product in
moderate to good yields. And in the absence of alkenes, under
the same reaction conditions, 4-bromodifluoromethyl b-
lactams 2b can be reduced to the corresponding difluoro-
methyl b-lactam 6 in nearly quantitative yield. Furthermore,
allylic stannic reagent Bu3SnCH2CH CH2 reacted with 2
under the same reaction conditions gave the allylic addition
product 8.
25/31
a
All reaction were run in a sealed tube at 110 8C overnight using benzene as
the solvent.
b
c
d
Isolated yield.
No alkenes were added.
Using Bu3SnCH2CH CH2 in stead of alkenes and Bu3SnH.
was used to initiate the reaction and benzene as the solvent. The
reduction product 6 was isolated in almost quantitative yield
(Scheme 6).
Promotion by the above success, we further explore its
addition reactions with kinds of alkenes. Experiments results
showed that b-lactams 2 could react with both electron rich and
poor alkenes. But in most cases, the reduction product 6 was
obtained as the major product. It was inevitable to form the
undesired reduced byproduct 6, even under strict water-free
conditions (Table 2).
Due to the strong electron-withdrawing properties of the
fluorine atoms, the difluoromethylene radical derived from 2b
should be highly reactive. There existed two competitive
reactions as to the radical generated from 2b, addition to
alkenes to lead to the difluorinemethylene b-lactams 7, and
directly depriving the hydrogen atom on Bu3SnH to produce
the reduced product 6. In all cases, product 6 was isolated as the
main product except in the case of styrene as the reactant, in
which no reduced product was detected and the addition
product 7e was obtained as the sole product in 77% yield. We
cannot account for this finding at this time (Table 2, entries 1–
7). Bu3SnCH2CH CH2 was often used as an allylic reagent to
4. Experimental
Melting points were measured in Temp-Melt apparatus and
were uncorrected. NMR spectra were taken at 300 MHz (for 1H
NMR), 75.3 MHz (for 13C NMR) and 282 MHz (for 19F NMR)
in CDCl3 with Me4Si and CFCl3 (with upfield negative) as the
internal and external standards, respectively. IR spectra were
obtained using an FTIR spectrometer and only major peaks
are reported in cmꢁ1. Mass spectra were recorded by the
EI method. Thin-layer chromatography was performed on
pre-coated silica gel 60 F254 analytical plates.

H. Wang et al. / Journal of Fluorine Chemistry 127 (2006) 1195–1203
1199
4.1. Typical procedure for preparation of 4 and 40
3 mmol of the mixture of enamine and imines 4 and 40, 228 mg
(6 mmol) of NaBH4, and 30 ml of ethanol. The mixture was
stirred under nitrogen atmosphere in ice water bath until TLC
indicated the disappearance of the compounds 4 and 40. The
mixture was washed with water and extracted with CH2Cl2. The
combined organic layers were dried over MgSO4, filtered, and
concentrated. The crude product was purified by flash
chromatography on silica gel.
A mixture of 5 mmol of 2,2-dihydropolyfluoroalkante,
7.5 mmol of aniline, 15 mmol Et3N and 5 ml CH3CN was
stirred at 70 8C for 6 h. The mixture was then neutralized
with aqueous of 1N HCl solution and extracted with ether.
The ethereal layer was washed with brine and dried over
anhydrous Na2SO4. After removal of the solvent, the residue
was purified by column chromatography using ether and
ethyl acetate as the eluant to give the mixture of enamine and
imine.
4.4. 4-Bromo-4,4-difluoro-3-phenylamino-butyric acid
ethyl ester (3a)
4.2. 4-Bromo-4,4-difluoro-3-(4-methoxy-phenylamino)-
but-2-enoic acid ethyl ester (4b)
The product, a pale yellow solid, was isolated in 60%
(yield); mp: 19–20 8C; [Found (HRMS): 321.0175,
C12H14O2BrF2N requires 321.0261]; nmax (KBr)/cmꢁ1
3387, 1733, 1604, 1515, 1499, 1278, 1263, 1182, 1110;
dH (in CDCl3) 7.11–7.06 (m, 2H), 6.72–6.61 (m, 3H), 4.51–
4.38 (m, 1H), 4.00 (q, J = 7.2, 2H), 3.86 (d, J = 9.0, 1H), 2.81
(1H, A part of a AB-d system, J = 4.2, JAB = 15.6), 2.51 (1H,
B part of a AB-d system, J = 9.3, JAB = 15.6), 1.06 (3H,
J = 7.2, t); dC (in CDCl3) 13.0, 35.7, 59.0 (t, JCF = 23.3),
60.3, 113.1, 118.4, 124.2 (t, JCF = 312.6), 128.3, 144.7,
168.3; dF (in CDCl3) ꢁ53.2 (1F, A part of a AB-d system,
J = 8.5, JAB = 161.6), ꢁ53.5 (1F, B part of a AB-d system,
J = 5.9, JBA = 161.6); MS (EI): m/z (%) = 321 (M+, 17), 192
(100), 104 (62), 77 (19).
The product, a pale yellow solid, was isolated in 60%
(yield); mp: 36–37 8C; (Found: C, 44.68; H, 4.19; N, 3.89. Calc.
for C13H14O3BrF2N: C, 44.70; H, 4.01; N, 4.01%); nmax (KBr)/
cmꢁ1 3246, 3183, 2981, 2964, 2934, 2839, 1903, 1665, 1620,
1518, 1270, 1197, 1167, 1139, 1111; dH (in CDCl3) 9.70 (s,
1H), 7.20 (d, J = 8.4, 2H), 6.89–6.85 (m, 2H), 5.26 (m, 1H),
4.21 (q, 2H, J = 7.2), 3.82 (s, 3H), 1.32 (t, 3H); dC (in CDCl3)
14.3, 55.4, 60.0, 85.6, 113.2, 113.8 (t, JCF = 349.2), 129.3,
130.6, 153.4 (t, JCF = 22.7), 158.5, 169.8; dF (in CDCl3) ꢁ48.1
(s, 2F); MS (EI): m/z (%) = 349 (M+, 27), 303 (29), 174 (100),
146 (15), 122 (3), 77 (7).
4.3. 4-Bromo-4,4-difluoro-3-(4-methoxy-phenylimino)-
butyric acid ethyl ester (4b0)
4.5. 4,4-Difluoro-3-phenylamino-butyric acid ethyl ester
(3a0)
The product, a yellow oil, was isolated in 35% (yield);
[Found (HRMS): 349.0126, C13H14O3BrF2N requires
349,0125]; nmax (neat)/cmꢁ1 2983, 2838, 1739, 1669,
1605, 1580, 1505, 1297, 1247, 1197, 1136; dH (in CDCl3)
6.89 (s, 4H), 4.15 (q, J = 6.9, 2H), 3.78 (s, 3H), 3.53 (s, 3H),
1.24 (t, J = 6.9, 2H); dC (in CDCl3) 14.0, 33.8, 55.4, 62.0,
The product, a pale yellow oil, was isolated in 11% (yield);
[Found (EI): 223.1012, C12H15O2F2N requires 223.1009]; nmax
(neat)/cmꢁ1 3390, 2984, 1732, 1604, 1514, 1499, 1377, 1284,
1258, 1189, 1141; dH (in CDCl3) 7.16–7.09 (m, 2H), 6.72–6.60
(m, 3H), 5.84 (dt, J = 2.4, JAB = 56.1, 1H,), 4.17–4.12 (m, 1H),
4.05 (q, J = 7.2, 2H,), 3.86 (d, J = 10.2, 1H), 2.65 (1H, A part of
a AB-d system, J = 7.9, JAB = 15.9), 2.51 (1H, B part of a AB-d
system, J = 7.2, JAB = 15.9), 1.16 (t, J = 7.2, 3H); dC (in CDCl3)
13.2, 32.4, 51.7 (t, JCF = 23.0), 60.2, 112.9, 114.1 (t,
114.4, 116.7(t,
J
JCF = 307.8), 120.7, 139.6, 156.1 (t,
CF = 24.7), 157.3, 166.7; dF (in CDCl3) ꢁ55.9 (s, 2F); MS
(EI): m/z (%) = 349 (M+, 18), 262 (2), 242 (2), 220 (100), 174
(20), 77 (7).
J
CF = 246.4),118.1, 128.6, 145.0, 169.8; dF (in CDCl3)
4.3.1. General procedure for the preparation of the 2-
amino acetate 3
A dry flask, 100 ml, 2-necked, fitted with a refluxed
condenser, gas inlet, and magnetic stirrer, was charged with
ꢁ125.5 (1F, A part of a AB-d system, J = 7.9, JAB = 282.0),
ꢁ130.3 (1F, B part of a AB-d system, J = 9.6, JBA = 282.0); MS
(EI): m/z (%) = 243 (M+, 55), 192 (100), 156 (62), 118 (32), 104
(95), 77 (32).

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H. Wang et al. / Journal of Fluorine Chemistry 127 (2006) 1195–1203
4.6. 4-Bromo-4,4-difluoro-3-(4-methoxy-phenylamino)-
butyric acid ethyl ester (3b)
The product, a colorless needle crystal, was isolated in 74%
(yield); mp: 84–86 8C; [Found (EI): 274.9755, C10H8OBrF2N
requires 274.9757]; nmax (KBr)/cmꢁ1 3095, 2987, 1764, 1599,
1502, 1459, 1418, 1375, 1352, 1294, 1260, 1218, 1202, 1127,
1095; dH (in CDCl3) 7.45–7.16 (m, 5H), 4.65 (dq, J = 3.4, 5.8,
12.6, 1H), 3.40 (1H, A part of a AB-d system, J = 5.7,
JAB = 15.6), 3.18 (1H, B part of a AB-d system, J = 2.4,
JAB = 15.6); dC (in CDCl3) 40.7, 57.0 (t, JCF = 24.5), 117.7,
The product, a colorless solid, was isolated in 90% (yield);
mp: 36–8 8C; (Found: C, 44.52; H, 4.50; N, 3.90. Calc. for
C13H16O3BrF2N: C, 44.19; H, 4.50; N, 4.00%); nmax (KBr)/
cmꢁ1 3368, 3006, 2961, 2937, 1721, 1623, 1532, 1510, 1285,
1252, 1192, 1180, 1100; dH (in CDCl3) 6.82–6.73 (m, 4H), 4.14
(q, J = 7.2, 2H), 3.76 (s, 3H), 3.67 (d, J = 8.4, 2H), 2.91 (1H, A
part of a AB-d system, J = 3.9, JAB = 15.6), 2.61 (1H, B part of
a AB-d system, J = 9.5, JBA = 15.6), 1.24 (t, J = 7.2, 3H), 1.03
(br, 1H); dC (in CDCl3) 14.1, 36.8, 55.6, 61.3, 61.4 (t,
122.4 (t, JCF = 307.8), 125.2, 129.2, 136.6, 162.6; dF (in CDCl3)
ꢁ50.7 (1F, A part of a AB system, J = 164.7), ꢁ57.7 (1F, B part
of a AB-d system, J = 164.7); MS (EI): m/z (%) = 275 (M+, 22),
146 (8), 119 (34), 104 (100), 77 (79).
4.9. 4-(Bromo-difluoro-methyl)-1-(4-methoxy-phenyl)-
azetidin-2-one (2b)
J
CF = 22.9), 114.8, 115.9, 125.5 (t, JCF = 313.0), 139.6, 153.4,
169.5; dF (in CDCl3) ꢁ53.4 (s); MS (EI): m/z (%) = 353 (M+,
23), 222 (100), 148 (50), 134 (42), 77 (9).
The product, a pale yellow solid, was isolated in 82%
(yield); mp: 100–101 8C; (Found: C, 43.25; H, 3.33; N, 4.44.
Calc. for C13H16O3BrF2N: C, 43.28; H, 3.28; N, 4.59%); nmax
(KBr)/cmꢁ1 2953, 1747, 1588, 1516, 1385, 1300, 1241, 1183,
1120, 1026; dH (in CDCl3) 7.36–7.31 (m, 2H), 6.91–6.85 (m,
2H), 4.61–4.53 (m, 1H), 3.79 (s, 3H), 3.33 (1H, A part of a AB-
d system, J = 5.4, JAB = 15.0), 3.12 (1H, B part of a AB-d
system, J = 2.1, JBA = 15.0); dC (in CDCl3) 40.6, 55.5, 57.4 (t,
4.7. 4-Bromo-4,4-difluoro-3-(4-methoxy-phenylamino)-
butan-1-ol (3b0)
J
CF = 26.1), 114.4, 119.8, 122.5 (t, JCF = 308.2), 129.8, 157.1,
162.4; dF (in CDCl3) ꢁ50.8 (1F, A part of a AB-d system,
AB = 172.3), ꢁ57.7 (1F, B part of a AB-d system, J = 14.4,
BA = 172.3); MS (EI): m/z (%) = 307 (M+ + 2, 35), 305 (M+,
The product, a brown solid, was isolated in 9.0% (yield); mp:
74–76 8C; (Found: C, 43.00; H, 4.40; N, 4.50. Calc. for
C13H16O3BrF2N: C, 42.72; H, 4.50; N, 4.50%); nmax (KBr)/
cmꢁ1 3457, 3340, 2968, 2912, 2893, 2838, 1619, 1512, 1261,
1238,1104;dH (inCDCl3)6.83–6.70(m,4H),4.10–4.00(br,1H),
3.86–3.84 (br, 2H), 3.76 (s, 3H), 3.54 (d, J = 9.6, 2H), 2.26–2.16
(m,1H),2.04(b,1H),1.78–1.67(m,1H);dC (inCDCl3)33.7,55.7,
58.9, 61.5 (t, JCF = 22.2), 114.9, 115.6, 127.0 (t, JCF = 314.1),
140.3, 153.2; dF (in CDCl3) ꢁ52.3 (m, 2F); MS (EI): m/z
(%) = 309 (M+, 19), 180 (100), 162 (24), 134 (21), 107 (7).
Typical procedure for the preparation of b-lactams 2: To a
dry ice-acetone cooled flask, charged with 16.5 mmol amine 3
and 33 ml dry THF, was added dropwise 5.5 ml CH3MgBr ether
solution (3 mol/l). After the reaction was completed monitored
by the use of TLC, saturated NH4Cl solution was added. Then it
was extracted with ether, the organic phase was dried over
MgSO4, purified with flash chromatography on silica gel.
J
J
35), 184 (89), 149 (33), 134 (100), 77 (48).
4.10. X-ray data of 7b
C11H10NO2BrF2: MW = 306.11, triclinic, space group:
˚
P-1, a = 10.062(4), b = 10.2297(2), c = 5.937(3) A; a =
103.81(3)8, b = 95.42(4)8, g = 87.45(3)8; V = 590.6(4)A3,
Z = 2, Dc = 1.721 g/cm, F(0 0 0) = 304.00. Radiation, Mo Ka
˚
˚
(l = 0.71069 A). Crystal dimensions, 0.15 mm ꢂ 0.20 mm ꢂ
0.30 mm. Intensity data were collected at 293(1) K with a Bruker
P4 four-circle diffractometer with graphite monochromator and
˚
Mo Ka radiation (l = 0.71069 A). A total of 5696 independent
reflection were measured in range 12.328 < 2u < 19.998. The
structure was solved by heavy-atom Patterson methods 2 and
expanded using Fourier techniques 3. The non-hydrogen atoms
were refined anisotropically. Hydrogen atoms were refined iso-
tropically. The final cycle of full-matrix least-squares refinement
4 on F2 was based on 1264 observed reflections and 195 variable
parametersandconverged(largestparametershift was0.00times
its esd) with unweighted and weighted agreement factors of:
4.8. 4-(Bromo-difluoro-methyl)-1-phenyl-azetidin-2-one
(2a)
R1 ¼ SkFoj ꢁ jFck=SjFoj ¼ 0:047;
wR2 ¼ ½SðwðFo2 ꢁ Fc2Þ Þ=SwðFo2Þ ꢃ ¼ 0:092
1=2
2
2

H. Wang et al. / Journal of Fluorine Chemistry 127 (2006) 1195–1203
1201
The standard deviation of an observation of unit weight5 was
2
The product, a colorless solid, was isolated in 37% (yield);
mp: 75–77 8C; (Found: C, 58.73; H, 5.95; N, 4.20. Calc. for
C13H16O3BrF2N: C, 58.71; H, 5.85; N, 4.28%); nmax (KBr)/
cmꢁ1 3490, 2982, 2964, 2938, 1732, 1613, 1517, 1464, 1443,
1386, 1111, 829; dH (in CDCl3) 7.39–7.27 (m, 2H), 6.90–6.86
(m, 2H), 4.39–4.35 (m, 1H), 4.14 (q, J = 7.2, 2H), 3.79 (s, 3H),
3.28 (1H, A part of a AB-d system, J = 6.0, JAB = 15.3),
3.16(1H, B part of a AB-d system, J = 2.4, JBA = 15.3), 2.57
(2H, t, J = 7.8), 2.29–2.18 (m, 2H), 1.25 (t, J = 7.2, 3H); dC (in
CDCl3) 14.1, 26.1 (t, JCF = 4.21), 28.3 (t, JCF = 23.79), 38.7,
53.9 (t, JCF = 30.65), 55.5, 61.0, 114.3, 119.6, 122.5 (t,
0.89. Unit weights were used. Plots of SwðjFoj ꢁ jFcjÞ versus
jFoj, reflection order in data collection, sin q/l and various
classes of indices showed no unusual trends. The maximum and
minimum peaks on the final difference Fourier map corre-
ꢁ
3
˚
sponded to 0.60 and ꢁ0.62 e /A , respectively.
Neutral atom scattering factors were taken from Cromer and
Waber6. Anomalous dispersion effects were included in Fcalc7;
the values for Df0 and Df00 were those of Creagh and McAuley8.
The values for the mass attenuation coefficients are those of
Creagh and Hubbell9. All calculations were performed using the
CrystalStructure, 11 crystallographic software package.
J
CF = 244.42), 130.5, 156.7, 163.3, 171.9; dF (in CDCl3)
ꢁ105.6 (1F, A part of a AB-d system, J = 252.7), ꢁ106.9 (1F, B
part of a AB-d system, J = 258.3); MS (EI): m/z (%) = 327 (M+,
100), 299 (3), 282 (53), 240 (54), 221 (55), 175 (45.7), 134
(100), 77 (18).
4.11. 4 -Difluoro-methyl-1-(4-methoxy-phenyl)-azetidin-2-
one (6)
4.13. Methyl 4,4-Difluoro-4-[1-(4-methoxy-phenyl)-4-oxo-
azetidin-2-yl]-butyrate (7b)
A sealed tube, charged with 153 mg (0.5 mmol) 2b, Bu3SnH
(291 mg, 1 mmol), AIBN (16 mg, 0.1 mmol) and benzene
(2 ml), was immersed in the oil bath with the temperature
maintaining about 110 8C overnight. Cooled to room tempera-
ture, the sealed was open, and saturated KF solution (4 ml) was
added and stir for another hour an hour. Then the mixture was
extracted with ether and dried over MgSO4, purified with flash
chromatography on silica gel to give the desired product in
almost quantitative yield.
The product, a colorless solid, was isolated in 44% (yield);
mp: 91–93 8C; (Found: C, 57.25; H, 5.57; N, 4.27. Calc. for
C13H16O3BrF2N: C, 57.50; H, 5.47; N, 4.47%); nmax (KBr)/
cmꢁ1 3475, 2947, 2957, 2842, 1755, 1736, 1515, 1448, 1386,
1119, 833; dH (in CDCl3) 7.38–7.27 (m, 2H), 6.89–6.86 (m,
2H), 4.42–4.34 (m, 1H), 3.79 (s, 3H), 3.69 (s, 3H), 3.25 (1H, A
part of a AB-d system, J = 6.3, JAB = 15.3), 3.01 (1H, B part of
a AB-d system, J = 2.4, JBA = 15.3), 2.58 (t, J = 8.1, 2H), 2.33–
2.12 (m, 2H); dC (in CDCl3) 25.9 (t, JCF = 4.06), 28.3 (t,
The procedure is similar for the preparation 4-gem-
difluoromethylene b-lactams when using alkenes to trap the
radical.
The product, a colorless solid, was isolated in 98% (yield);
mp: 65–67 8C; (Found: C, 58.08; H, 4.98; N, 5.86. Calc. for
C13H16O3BrF2N: C, 58.15; H, 4.85; N, 6.17%); nmax (KBr)/cmꢁ1
3117, 1770, 1345, 1301, 814; dH (in CDCl3) 7.38–7.27 (m, 2H),
6.89–6.86 (m, 2H), 6.03 (td, J1 = 3.9, J2 = 55.2, 1H), 4.31(br,
1H), 3.79(s, 3H), 3.28–3.05(m, 2H); dC (in CDCl3) 37.5, 51.3,
55.5 (t, JCF = 27.3), 114.4, 114.5 (t, JCF = 244.0), 118.7, 130.6,
156.6, 162.9; dF (in CDCl3) ꢁ125.5 (1F, A part of a AB-d system,
J = 55.3, JAB = 293.6), ꢁ123.3 (1F, B part of a AB-d system,
J = 54.7, JBA = 293.6); MS (EI): m/z (%) = 227 (M+, 33), 185
(29), 149 (11), 134 (100), 107 (12), 92 (11), 77 (22).
J
CF = 24.10), 38.7, 52.1, 53.9 (t, JCF = 30.12), 55.5, 114.3,
119.6, 122.4 (t, JCF = 244.50), 130.5, 156.8, 163.3, 172.3; dF (in
CDCl3) ꢁ105.7 (1F, A part of a AB-m system, J = 252.7),
ꢁ106.7(1F, B part of a AB-d system, J = 226.7); MS (EI): m/z
(%) = 313 (M+, 100), 282 (11), 207 (20), 175 (14), 134 (90), 77
(9).
4.14. 4,4-Difluoro-4-[1-(4-methoxy-phenyl)-4-oxo-
azetidin-2-yl]-butyronitrile (7c)
4.12. Ethyl 4,4-Difluoro-4-[1-(4-methoxy-phenyl)-4-oxo-
azetidin-2-yl]-butyrate (7a)
The product, a colorless solid, was isolated in 38% (yield);
mp: 83–85 8C; (Found: C, 59.96; H, 5.06; N, 9.97. Calc. for
C13H16O3BrF2N: C, 60.00; H, 5.03; N, 10.00%); nmax (KBr)/
cmꢁ1 3467, 2999, 1759, 1514, 1377, 1256; dH (in CDCl3) 7.36–
7.27 (m, 2H), 6.92–6.87 (m, 2H), 4.47–4.39 (m, 1H), 3.80 (s,

1202
H. Wang et al. / Journal of Fluorine Chemistry 127 (2006) 1195–1203
3H), 3.30 (1H, A part of a AB-d system, J = 6.3, JAB = 15.6),
3.17 (1H, B part of a AB-d system, J = 1.8, JBA = 15.6), 2.62 (t,
J = 7.5, 2H), 2.34–2.12 (m, 2H); dC (in CDCl3) 9.95 (t,
4.17. 2-(1,1-Difluoro-3-phenyl-propyl)-1-(4-methoxy-
phenyl)-azetidine (7f)
J
CF = 5.7), 29.32 (t, JCF = 4.2), 38.64, 53.611 (t, JCF = 35.09),
114.5, 118.0, 119.6, 121.4 (t, JCF = 245.80), 129.8, 157.0,
162.9; dF (in CDCl3) ꢁ105.3 (1F, A part of a AB-d system,
J
AB = 251.3), ꢁ107.7 (1F, B part of a AB-d system,
J
BA = 251.3); MS (EI): m/z (%) = 280 (M+, 15), 238 (16),
149 (22), 134 (100), 77 (37), 69 (3).
The product, a colorless solid, was isolated in 76%
(yield); mp: 108–110 8C; [Found (ES): 331.1396,
C19H19F2NO2 requires 331.1384]; nmax (KBr)/cmꢁ1 3478,
3026, 2926, 1784, 1513, 1386, 1242, 698; dH (in CDCl3)
7.44–6.90 (m, 9H), 4.41–4.37 (m, 1H), 3.81 (s, 3H), 3.22
(1H, A part of a AB-d system, J = 6.0, JAB = 15.3), 3.03 (1H,
B part of a AB-d system, J = 2.4, JBA = 15.3), 2.91 (t, J = 8.1,
2H), 2.27–2.13 (m, 2H); dC (in CDCl3) 27.3 (t, JCF = 4.59),
35.1 (t, JCF = 24.10), 38.7, 54.04 (t, JCF = 30.72), 55.5,
114.4, 119.7, 122.7 (t, JCF = 196.16), 126.5, 127.7, 128.3,
130.7, 139.9, 156.8, 163.5; dF (in CDCl3) ꢁ105.3 (1F, A part
of a AB-d system, JCF = 253.0), ꢁ106.2 (1F, B part of
a AB-d system, JCF = 252.4); MS (EI): m/z (%) = 331
(M+, 100), 225 (67), 185 (46), 170 (8), 134 (22), 91 (16),
77 (6).
4.15. 5,5-Difluoro-5-[1-(4-methoxy-phenyl)-azetidin-2-yl]-
pentan-2-one (7d)
The product, a colorless solid, was isolated in 21% (yield);
mp: 122–124 8C; [Found (ES): 297.1193, C15H17F2NO3
requires 297.1176]; nmax (KBr)/cmꢁ1 3476, 2969, 2937,
2842, 1742, 1716, 1515, 1380, 841; dH (in CDCl3) 7.37–7.33
(m, 2H), 6.90–6.84 (m, 2H), 4.39–4.32 (m, 1H), 3.78 (s, 3H),
3.69 (s, 3H), 3.23(1H, A part of a AB-d system, J = 6.0,
J
AB = 15.3), 3.00 (1H, B part of a AB-d system, J = 3.0,
BA = 15.3), 2.70 (t, J = 7.2, 2H), 2.22–2.10 (m, 3H); dC (in
CDCl3) 26.8 (t, JCF = 23.87), 30.0, 34.8, 38.7, 54.0 (t,
CF = 29.52), 55.5, 114.3, 119.6 (t, JCF = 244.20), 130.5,
J
4.18. 4-(1,1-Difluoro-but-3-enyl)-1-(4-methoxy-phenyl)-
azetidin-2-one (8)
J
156.7, 163.4, 206.0; dF (in CDCl3) ꢁ105.2 (1F, A part of a
AB-d system, JCF = 249.3), ꢁ106.9 (1F, B part of a AB-d
system, JCF = 251.3); MS (EI): m/z (%) = 297 (M+, 91), 191
(43), 149 (22),134 (100), 77 (15).
4.16. 2-(3-Ethoxy-1,1-difluoro-propyl)-1-
(4-methoxy-phenyl)-azetidine (7e)
The product, a colorless solid, was isolated in 25%
(yield); mp: 52–54 8C; (Found: C, 62.91; H, 5.73; N, 5.23.
Calc. for C13H16O3BrF2N: C, 62.91; H, 5.66; N, 5.24%);
nmax (KBr)/cmꢁ1 3484, 2967, 2957, 2843, 1760, 1512, 1384,
1115, 831; dH (in CDCl3) 7.41–7.35 (m, 2H), 6.91–6.86(m,
2H), 5.89(m, 1H), 5.27 (m, 2H), 4.42–4.34 (m, 1H), 3.80 (s,
3H), 3.21 (1H, A part of a AB-d system, J = 6.0, JAB = 15.3),
3.03 (1H, B part of a AB-d system, J = 2.7, JBA = 15.3),
2.74–2.60 (m, 2H), 2.33-2.12 (m, 2H); dC (in CDCl3) 38.2,
38.7 (m), 53.7 (t, JCF = 30.35), 55.5, 114.3, 119.8, 121.5,
121.9 (t, JCF = 244.8), 127.6, 130.6, 156.8, 163.4; dF (in
CDCl3) ꢁ102.9 (1F, A part of a AB-d system, 253.5), ꢁ104.5
(1F, B part of a AB-d system, J = 252.7); MS (EI): m/z
(%) = 267 (M+, 100), 225 (25), 204 (48), 160 (4), 149 (18),
134 (89), 77 (17).
The product, a pale yellow oil was isolated in 17% (yield);
[Found (ES): 299.1287, C15H19F2NO3 requires 299.1333]; nmax
(KBr)/cmꢁ1 2974, 2877, 1762, 1514, 1382, 1247, 1117; dH (in
CDCl3) 7.42–6.90 (m, 2H), 6.90–6.85 (m, 2H), 4.55–4.46 (m,
1H), 3.80 (s, 3H), 3.68–3.60 (m, 2H), 3.54–3.47 (m, 2H), 3.19
(1H, A part of a AB-d system, J = 5.7, JAB = 15.6), 3.00 (1H, B
part of a AB-d system, J = 3.0, JBA = 15.6), 2.27–2.12 (m, 2H),
1.30–1.19 (m, 3H); dC (in CDCl3) 15.06, 29.69, 34.66 (t,
J
CF = 39.61), 38.73 (t, JCF = 4.07), 54.02 (t, JCF = 28.76),
63.56, 66.58, 114.26, 119.9, 122.5 (t, JCF = 244.05), 130.8,
156.7, 163.7; dF (in CDCl3) ꢁ103.0 (1F, A part of a AB-d
system, JCF = 248.4), ꢁ106.8 (1F, B part of a AB-d system,
Acknowledgement
J
CF = 254.4); MS (EI): m/z (%) = 299 (M+, 100), 193 (29), 185
The authors thank the National Natural Science Foundation
of China (NNSFC) (Nos. 20372077 and 20472106).
(100), 176 (15), 149 (34), 134 (60), 77 (13).

H. Wang et al. / Journal of Fluorine Chemistry 127 (2006) 1195–1203
1203
(b) L. Ghosez, S. Marchand-Brynaert, in: B.M. Trost, I. Fleming (Eds.),
Comprehensive Organic Synthesis, vol. 5, Pergamon, Oxford, UK, 1991,
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