Remarkable ketene substituent dependent effect of photo irradiation on the diastereoselectivity in the Staudinger reaction

Article abstract of DOI:10.1016/j.tetlet.2011.12.003

Controlling diastereoselectivity is a challenging issue in the Staudinger reaction. The influence of ultraviolet irradiation on the stereoselectivity in the Staudinger reaction has been investigated. The results indicate that ultraviolet irradiation is on

Full text of DOI:10.1016/j.tetlet.2011.12.003

Tetrahedron Letters 53 (2012) 786–789
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Remarkable ketene substituent dependent effect of photo irradiation
on the diastereoselectivity in the Staudinger reaction
⇑
Zhanhui Yang, Jiaxi Xu
State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry, Faculty of Science, Beijing University of Chemical Technology,
Beijing 100029, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Controlling diastereoselectivity is a challenging issue in the Staudinger reaction. The influence of ultravi-
olet irradiation on the stereoselectivity in the Staudinger reaction has been investigated. The results indi-
cate that ultraviolet irradiation is one of the most important means to regulate the diastereoselectivity of
the products in the Staudinger reaction, whatever ketenes were generated from diazomethyl ketones or
from substituted acetyl chlorides in the presence of triethylamine. However, the regulation is dependent
on the ketene substituents obviously. Ultraviolet irradiation can even reverse the diastereoselectivity for
the reactions involving ketenes without strong electron-donating substituents.
Received 1 August 2011
Revised 11 November 2011
Accepted 2 December 2011
Available online 8 December 2011
Keywords:
Acyl chloride
Imine
Ó 2011 Elsevier Ltd. All rights reserved.
Photoirradiation
Staudinger cycloaddition
Stereoselectivity
The Staudinger reaction, also called the ketene–imine cycload-
dition or Staudinger cycloaddition, is one of the most useful meth-
ods for the synthesis of b-lactam derivatives,1 the key structural
element of the most widely employed class of b-lactam antibiotics,
because of abundant and structurally diverse imine and ketene
sources. It is well known that the stereostructure of b-lactam ele-
ment of the antibiotics plays an important role in their biological
activities.2 Thus, it is still a challenge to prepare b-lactam deriva-
tives with desired and special stereostructures.1b,e It has been illus-
trated that the diastereoselectivity in the Staudinger reactions is
governed by the ketene and imine substituents3 and impacted only
by the reaction temperature4 and the addition sequence of the
reactants, rather than other reaction conditions, such as the ketene
generation fashion, solvent, additive (including metals and bases),5
microwave irradiation,6 etc. Our recent investigation results reveal
that the electron-donating ketene substituents, electron-with-
drawing imine substituents, and more steric bulky imine N-sub-
stituents favor the formation of cis-b-lactams, adversely, the
electron-deficient ketene substituents, electron-rich imine substit-
uents, and less steric imine N-substituents favor the formation of
trans-b-lactams. The competition between the direct ring closure
and the iminium isomerization of the zwitterionic intermediates
generated from ketenes and imines in the reactions controls the
diastereoselectivity.3 Higher reaction temperature and first mixing
imines and acyl chlorides followed by the addition of tertiary
amine results in the predominant formation of trans-b-lactams.4,5
Our previous investigation suggested that the photo irradiation
did not impact the diastereoselectivity in the Staudinger reaction
involving phenyl diazothioacetate as the ketene precursor with
an exceptional example of the reaction involving N-4-nitrobenzyl-
idene isopropylamine.3 But our recent examples indicate that a
mixture of cis- and trans-b-lactams, even trans-b-lactams as major
products, were obtained in the photo Staudinger reaction of alkyl/
aryl diazacetates and imines although thermal Staudinger reac-
tions of alkoxy/aryloxyacetyl chlorides and imines generally pro-
duce cis-b-lactams as sole or major products.7 This implies that
photo irradiation may regulate the diastereoselectivity in the Stau-
dinger reaction and the effect may be dependent on the ketene
substituents. Although several photo Staudinger reactions have
been reported,8,9 the detailed comparison of the diastereoselectiv-
ity of the Staudinger reactions under thermal and photo irradiation
conditions has seldom been investigated,3 especially for the Stau-
dinger reactions with different ketenes. This prompts us to investi-
gate the influence of photo irradiation on the diastereoselectivity
in the reaction in detail. Both experimental and theoretical investi-
gations indicate that the isomerization of imines and/or the imin-
ium moiety in the zwitterionic intermediates can adjust the
diastereoselectivity.3,10 It was reported that ultraviolet light can
isomerize (E)-imines and iminiums into (Z)-imines and (Z)-imini-
ums and heating can convert (Z)-imines and iminiums to their
(E)-isomers.11,12 Thus, we assumed that ultraviolet light can regu-
late the diastereoselectivity in the Staudinger reactions through
⇑
Corresponding author. Tel./fax: +86 10 6443 5565.
E-mail address: jxxu@mail.buct.edu.cn (J. Xu).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.003

Z. Yang, J. Xu / Tetrahedron Letters 53 (2012) 786–789
787
transforming (E)-imines and iminiums of the zwitterionic interme-
H
H
N
H
H
N
R1
O
Ph
Ph
R1
O
Ph
+
Ph
diates to their (Z)-isomers. Herein, we present the results on the
regulation of the diastereoselectivity in the Staudinger reactions
with ultraviolet irradiation. This will provide a novel method to
regulate the diastereoselectivity in the synthesis of b-lactams via
the Staudinger reaction.
O
20 °C
+
+
R1
CH2Cl2
N
N
Cl
Ph
Ph
Ph
( )-cis
R1 = Et
cis:trans = 100:0
R1 = Ph cis:trans = 100:0
( )-trans
The Wolff rearrangement of diazomethyl ketones and the elimi-
nation of substituted acetyl chlorides in the presence of a tertiary
amine are the two main pathways to generate ketenes.13 We first
compared the diastereoselectivities between the thermal and photo
reactions of diazomethyl ketones and imines (Scheme 1). The ther-
mal reactions of diazoacetone and diazoacetophenone with N-ben-
zylideneaniline were conducted, respectively, in 1 mmol scale at
140 °C because the diazomethyl ketones cannot undergo Wolff rear-
rangement below 130 °C,3 giving rise to a mixture of cis- and trans-b-
lactams and trans-b-lactams as major products in each of the reac-
tions although higher temperature favors the formation of trans-b-
lactams. The ratio of cis/trans-products was determined by 1H
NMR analysis of the reaction mixture. The same reactions were also
carried out at 0 °C under UV photo irradiation. However, the photo
reactions produced trans-b-lactams as sole products for each of
the reactions although lower temperature predominates in the for-
mation of cis-b-lactams for thermal reactions. The results indicate
that ultraviolet irradiation is advantageous to the formation of
trans-b-lactams for the Staudinger reactions with diazomethyl ke-
tones as the ketene precursors. To explore the influence of the imine
substituents, the reaction of diazoacetophenone and N-(4-nitroben-
zylidene) isopropylamine was conducted at 140 and at 0 °C under
photo irradiation, respectively, producing a mixture of cis- and
trans-b-lactams in 47:53 and 43:57 for cis- and trans-b-lactams.
The results indicate that photo irradiation shows slight influence
on the diastereoselectivity in the Staudinger reaction involving ket-
enes with weak electron-donating substituents. The small stereose-
lective difference may attribute to the different reaction
temperature.
H
H
H
H
R1
Ph
Ph
hv
20 °C
Ph
O
R1
Ph
+
N2
R1
N
N
CH2Cl2
O
O
Ph
( )-cis
R1 = OEt
R1 = OPh cis:trans = 33:67
( )-trans
cis:trans = 24:76
Scheme 2. Stereoselectivity in reactions of ethoxy/phenoxyacetyl chlorides and
ethyl/phenyl diazoacetates with N-benzylidene aniline.
Finally, we conducted the Staudinger reactions with substituted
acetyl chlorides as the ketene precursors under both thermal and
photo irradiation conditions at the same reaction temperatures be-
cause it is unpractical to perform the Staudinger reactions of dia-
zomethyl ketones at the same temperatures under thermal and
photo irradiation conditions. To observe the effect of ultraviolet
irradiation on the diastereoselectivity obviously, we selected the
imines with C-electron-rich substituents for the ketenes with elec-
tron-donating substituents and the imines with C-electron-defi-
cient substituents for the ketenes with electron-withdrawing
substituents. The results are summarized in Table 1. The yields
and ratios of cis/trans-products were determined by 1H NMR anal-
ysis of the reaction mixture with dimethyl maleate as an internal
standard for the determination of the product yields. The ratios
of cis/trans-products were determined on the basis of integrals of
the protons on C3 and C4 of the b-lactam ring. The reactions with
phenylacetyl chloride only produced products in 1–2% yield at 0
and 20 °C. Thus, the data for these reactions are not shown in Table
1. The results indicate that ultraviolet irradiation improves the ra-
tios of trans-b-lactams for all parallel reactions (the same reaction
at the same temperature). For the same reaction, the highest ratio
of trans-b-lactams was obtained at low temperature under ultravi-
olet irradiation. The diastereoselective difference at the same tem-
perature depends obviously on the ketene substituents. The
ketenes with strong electron-donating substituents show less ster-
eoselective differences between thermal and photo reactions at the
same temperature than those with weak electron-donating and
electron-withdrawing substituents.
In order to further confirm the effect of photo irradiation on the
diastereoselectivity of Staudinger reaction, an array of experiments
was conducted at 0 °C by employing the selected acyl chlorides
with different N-substituted imines in the presence of triethyl-
amine. The results are summarized in Table 2. In the way that
was expected, the photo irradiation reverses the cis/trans ratios,
compared with the thermal reactions, providing the trans-b-lac-
tams as the major or exclusive products. These results indicate that
the effect of photo irradiation on the diastereoselectivity in the
Staudinger reaction does exist in most cases, which, however, al-
ways has been interfered by the effect of substituents on both ket-
enes and imines, the effect of temperature, and other factors.
The influence of temperature on the diastereoselectivity was
investigated previously in the Staudinger reaction.4 The results re-
vealed that trans-products increase with increase of temperature in
the temperature range studied. However, an adverse tendency was
observed under photo irradiation conditions. That is, trans-prod-
ucts decrease with increasing temperature under ultraviolet irradi-
ation. How do we explain the different effects of temperature on
Secondly, we examined the Staudinger reaction involving ketene
with strong electron-donating substituents. Ethoxy/phenoxyacetyl
chlorides reacted with N-benzylidene aniline in dichloromethane at
20 °C to give rise to cis-b-lactams as sole products. However, ethyl/
phenyl diazoacetates reacted with N-benzylidene aniline in dichlo-
romethane at 20 °C under photo irradiation to yield a mixture of cis-
and trans-b-lactams in 24:76 and 33:67, respectively, for cis-and
trans-b-lactams7 (Scheme 2). The results illustrate that photo irra-
diation shows certain influence on the diastereoselectivity in the
Staudinger reaction involving ketenes with strong electron-donat-
ing substituents.
We have compared the thermal and photo Staudinger reactions
involving ketenes with electron-withdrawing substituents, such as
ethoxycarbonyl recently. Trans-b-lactams were obtained in each of
the cases.14
H
H
N
H
H
N
R1
O
R2
R3
R1
O
R2
R3
R2
O
+
+
N2
R1
N
R3
( )-cis
( )-trans
R1 = Me, R2 = R3 = Ph
140 °C, xylene cis:trans = 5:95
0 °C, hv, CH2Cl2 cis:trans = 0:100
140 °C, xylene cis:trans = 6:94
0 °C, hv, CH2Cl2 cis:trans = 0:100
R
R
1 = R2 = R3 = Ph
1 = Ph, R2 = 4-O2NPh 140 °C, xylene cis:trans = 47:53
R3 = iPr
0°C, hv, CH2Cl2 cis:trans = 43:57
Scheme 1. Stereoselectivity in reactions of a-diazomethyl ketones and imines.

788
Z. Yang, J. Xu / Tetrahedron Letters 53 (2012) 786–789
Table 1
Comparison between the thermal and photo Staudinger reactions of substituted acetyl chlorides and imines
R
R
R
H
H
N
H
H
N
R1
O
O
R1
O
Et3N, CH2Cl2
or hv
R1
+
+
Cl
N
( )-trans
( )-cis
Cis:trans-b-lactamsa
Substitution
Conditions
R1 = PhO, R = MeO
hv
R1 = PhthN, R = MeO
hv
R1 = Cl, R = NO2
R1 = Me, R = NO2
hv
R1 = Ph, R = NO2
D hv
D
D
D
hv
D
0 °C
20 °C
40 °C
69:31
89:11
100:0
68:32
78:22
90:10
100:0
85:15
87:13
0:100
30:70
44:56
94:6
92:8
99:1
13:87
44:56
52:48
100:0
100:0
99:1
0:100
11:89
13:87
N.R.
N.R.
88:12
N.R.
N.R.
57:43
a
Determined by 1H NMR spectra of the crude reaction mixture and data given here are the average values derived from at least two independent experimental runs with
less than 4% difference.
bN.R. indicates no reaction occurs.
Table 2
Diastereoselectivities in the thermal and photo Staudinger reactions of substituted acetyl chlorides with different N-substituted imines at 0 °C
R
R
R
H
H
N
H
H
N
R1
O
O
R1
O
Et3N, CH2Cl2
or hv, 0°C
R1
+
+
Cl
R3
N
R3
R3
( )-trans
( )-cis
Diastereoselectivity
Substitution
Cis/transa
R1 = PhthN, R = MeO
hv
R1 = Cl, R = NO2
R1 = Me, R = NO2
Reaction conditions
D
D
hv
D
hv
R3
=
nPr
76:24
90:10
0:100
83:17
23:77
35:65
0:100
28:72
92:8
96:4
N.R.b
100:0
26:74
8:92
0:100
5:95
100:0
98:2
70:30
100:0
16:84
0:100
3:97
R3 = cHex
R3 = Ph
R3 = Bn
79:21
a
Determined by 1H NMR spectra of the crude reaction mixture and data given here are the average values derived from at least two independent experimental runs with
less than 4% difference.
b
N.R. indicates no reaction occurs.
the diastereoselectivity under thermal and photo conditions? It has
been documented that (E)-imines and (E)-iminiums predominantly
convert to (Z)-imines and (Z)-iminiums under ultraviolet condi-
tions, while (Z)-imines and (Z)-iminiums favorably isomerize to
their stable (E)-isomers under heating.11,12 Thus, for imines,
although photo irradiation favorably converts (E)-imines to (Z)-
imines, the concentration of (Z)-imines at lower temperature is
higher than that at higher temperature under ultraviolet irradia-
tion, and for iminiums, (E)-iminiums B predominantly convert to
(Z)-iminiums A under ultraviolet conditions at lower temperature,
leading to more trans-products at lower temperature than at high-
er temperature (Scheme 3).
photo Staudinger reactions produce more trans-b-lactams than
the corresponding thermal Staudinger reactions at the same
temperature.
In summary, the influence of ultraviolet irradiation on the diaste-
reoselectivity in the Staudinger reaction has been investigated via
reactions of diazomethyl ketones, diazoacetates, and substituted
acetyl chlorides with different imines. The results indicate that
ultraviolet irradiation is one of the most important means to regu-
late the diastereoselectivity of the products in the Staudinger reac-
tion, whatever the ketenes are generated from diazomethyl
ketones, from diazoacetates, or from substituted acetyl chlorides
in the presence of triethylamine. However, the regulation is depen-
dent on the ketene substituents obviously. Ultraviolet irradiation
can even reverse the diastereoselectivity for the reactions involving
ketenes without strong electron-donating substituents. The current
results provide a novel method to regulate the diastereoselectivity
When (E)-imines convert to (Z)-imines under ultraviolet condi-
tions, (Z)-imines attack ketenes more favorably than (E)-imines to
generate intermediates B directly, which undergo a conrotatory
ring closure to produce trans-b-lactams. This is the reason why

Z. Yang, J. Xu / Tetrahedron Letters 53 (2012) 786–789
789
R2
H
H
N
R2
R3
R1
R1
H
H
R1
O
R2
H
H
conrotate
+
N+
R3
C
O
N
-O
Et3N
O
R3
A
β
( )-cis- -lactam
(E)-imine
R1
hv
hv
Cl
Et3N
H
H
N
R2
R3
R1
O
R1
H
R1
H
R2
H
R2
R3
H
conrotate
+
C
O
N+
R3
N
-O
β
( )-trans- -lactam
B
(Z)-imine
Scheme 3. Reaction process of substituted acetyl chlorides and imines in the presence of triethylamine under ultraviolet irradiation.
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configurations.
Acknowledgments
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The project was supported by the National Natural Science
Foundation of China (Nos. 20772005 and 20472005), specialized
Research Fund for the Doctoral Program of Higher Education, Min-
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Supplementary data
Supplementary data (full experimental procedures for the reac-
tions along with relevant spectra of products) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.12.003.
References and notes
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