Microwave-assisted tandem nucleophilic substitution-Wittig reaction of α-hypervalent iodine functionalized phosphonium ylide

Article abstract of DOI:10.1055/s-2002-34893

Under microwave irradiation conditions the tandem nucleophilic substitution-Wittig reaction of α-hypervalent iodine functionalized phosphonium ylide can occur readily to afford α-heteroatom substituted-α,β-unsaturated enoates in good yields stereo-selecti

Full text of DOI:10.1055/s-2002-34893

LETTER
1895
Microwave-Assisted Tandem Nucleophilic Substitution–Wittig Reaction of
-Hypervalent Iodine Functionalized Phosphonium Ylide
M
icrowave-Assist
i
e
d
T
and
a
e
m
Nucleo
o
philic
W
ittig
c
Reactionshun Yu,a,b Xian Huang*a,b
a
Department of Chemistry, Zhejiang University (Campus XiXi), Hangzhou 310028, P. R. China
b
State Key Laboratory of Organoelemental Chemistry, Nangkai University, Tianjin, 300071, P. R. China
Fax +86(571)88807077; E-mail: huangx@mail.hz.zj.cn
Received 20 August 2002
Bu4NBr (2a). We optimized the reaction conditions, and
the results are summarized in Table 1. Within 3 min the
reaction in DMF afforded -bromosubstituted phosphoni-
um ylide 3 with high yield, so DMF was the optimal sol-
vent.9 We also observed the Wittig reaction of 3 with
benzaldehyde under microwave irradiation conditions to
give -bromo , -unsaturated enoates 4a in 83% yield
(Scheme 1). While both of the above reactions were per-
formed under conventional reaction conditions, the reac-
tion times were much longer, i.e. 14 h and 12 h
respectively.
Abstract: Under microwave irradiation conditions the tandem nu-
cleophilic substitution-Wittig reaction of -hypervalent iodine
functionalized phosphonium ylide can occur readily to afford -het-
eroatom substituted- , -unsaturated enoates in good yields stereo-
selectively.
Keywords: microwave irradiation conditions -hypervalent iodine
functionalized phosphonium ylide, umpolung ylides, tandem reac-
tion
Since the appearance of the first paper1 on the application
of microwave irradiation in organic synthesis, the field
has seen a steady growth to the point where a variety of
transformations are now possible with microwave heat-
ing.2 Carrying out reactions using microwave irradiation,
as opposed to conventional heating, has the major advan-
tage of shorter reaction time.
+
IPh
Br
-
mw irradiation
DMF, 3 min
BF4
Ph3P
+ Bu4NBr
Ph3P
CO2Et
CO2Et
1
2a
3
Ph
H
Br
Br
mw irradiation
DMF, 3 min
Ph3P
+
PhCHO
Our research group has been interested in the application
of microwave to organic synthesis for years, and we firstly
explored the Wittig reaction under microwave irradia-
tion.3 Wittig reaction plays an important role in synthetic
organic chemistry for the construction of carbon-carbon
double bond.4 The research on -heteroatom substituted
ylide is an important aspect in ylide chemistry.5 Recently,
there are considerable current interest and research activ-
ity in hypervalent iodine compounds, which have been
demonstrated that hypervalent iodine is a versatile reagent
in organic synthesis.6 When hypervalent iodine group is
connected with an unsaturated carbon-carbon bond, the
connected carbon can be attacked by nucleophiles.7 In
view of this, the polarity of -carbon in ylide may be re-
versed through introducing hypervalent iodine group at -
carbon of an ylide, which enables the umpolung ylide to
react with nucleophiles.
CO2Et
CO2Et
4a
3
Scheme 1
Table 1 The Reaction of -Hypervalent Iodine Functionalized
Phosphonium Ylide with Bu4NBr under Microwave Irradiation Con-
ditions (3 min)
Solvent
CHCl3
84
CH3CN
79
DMF
94
C2H5OH C6H6
47 19
Yield (%)
We further investigated the reaction of 1 with aldehydes
under the same reaction conditions but unfortunately no
reaction was observed. Considering the above facts, we
designed the following tandem nucleophilic substitution-
Wittig reaction (Scheme 2).10 Under microwave irradia-
tion conditions in DMF the reaction completed in no more
than 5 min to give -halo- , -unsaturated enoates 4 ste-
reoselectively with good yields.11 Although the products
can be similarly synthesized under conventional condi-
tions, microwave irradiation conditions significantly re-
duced the reaction time from hours to several minutes
with a slight improvement in the isolated yields. No
changes were observed about the effects of microwave ir-
radiation on stereoselectivity. The results of tandem reac-
tion of -hypervalent iodine functionalized ylide are listed
in Table 2.
Although the synthesis of -hypervalent iodine function-
alized phosphonium ylides have been reported, few appli-
cations have appeared.8 In order to increase the utility of
these reagents, now we wish to report the reaction of -hy-
pervalent iodine functionalized phosphonium ylide under
microwave irradiation.
At first we examined the substitution reaction of -hyper-
valent iodine functionalized phosphonium ylide (1) and
Synlett 2002, No. 11, Print: 29 10 2002.
Art Id.1437-2096,E;2002,0,11,1895,1897,ftx,en;U06102ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1896
X. Yu, X. Huang
LETTER
+
In conclusion, we have demonstrated a simple and rapid
procedure for the synthesis of (Z)- -heteroatom- , -un-
saturated enoates stereoselectively in moderate to high
yields under microwave irradiation conditions through the
tandem reaction of nucleophilic substitution-Wittig reac-
tion of -hypervalent iodine functionalized phosphonium
ylide. The present work on umpolung ylides also enriches
the contents of ylide chemistry. Further studies on the um-
polung ylides and its application in organic synthesis are
still in progress in our laboratory.
IPh
R
H
X
-
mw irradiation
DMF
BF4
Ph3P
+
+
Bu4NX
RCHO
CO2Et
CO2Et
1
2
4
Z/E=84/16 -- 93/7
X=Cl-, Br-, I-,
Scheme 2
Thioethers are useful heteroatom functional groups in or-
ganic synthesis, and thiophenyl anions are easy avail-
able.12 Thus we used the thiophenyl anion as a nucleophile
to the above tandem reaction to develop a methodology
for the synthesis of -thiophenyl- , -unsaturated enoates.
By similar procedure of adding the solution of thiophenyl
sodium in MeOH to a mixture of 1 and aldehydes in DMF
under microwave irradiation conditions, we found this
procedure occurred smoothly (Scheme 3) and obtained
satisfying results (Table 2). These results show that -hy-
pervalent iodine functionalized phosphonium ylide as
umpolung ylide has versatility.
Acknowledgement
Project No. 29972036 was supported by the National Natural Sci-
ence Foundation of China.
References
(1) (a) Gedye, R.; Smith, F.; Westaway, K.; Humera, A.;
Baldisera, L.; Laberge, L.; Roussel, J. Tetrahedron Lett.
1986, 27, 279. (b) Giguere, R. J.; Bray, T. L.; Duncan, S. M.;
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(2) For reviews, see: (a) Majetich, G.; Wheless, K. In
Microwave-Enhanced Chemistry Fundamentals, Sample
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J., Eds.; American Chemical Society: Washington DC,
1997, 455–505. (b) Caddick, S. Tetrahedron 1995, 51,
10403.
+
IPh
R
H
SPh
-
mw irradiation
DMF
BF4
Ph3P
PhS-Na+
+
+
RCHO
CO2Et
CO2Et
1
5
6
(3) (a) Xu, C. D.; Chen, G. Y.; Huang, X. Chinese Chem. Lett.
1995, 6, 467. (b) Xu, C. D.; Chen, G. Y.; Huang, X. Org.
Prep. Proc. Int. 1995, 27, 559. (c) Xu, C. D.; Chen, G. Y.;
Huang, X. Synth. Commun. 1995, 25, 2229.
Z/E=84/16 -- 90/10
Scheme 3
Table 2 Results of Tandem Reaction of -Hypervalent Iodine Functionalized Ylides under Microwave Irradiation
Entry
1
Nu-
Br–
Br–
Br–
Br–
Cl–
Cl–
Cl–
I–
R
Product
4a
Timea
3 (20)
2 (8)
Yield (%)a,b
85 (71)
97 (97)
78 (70)
76 (67)
92 (92)
94 (94)
84 (78)
92 (90)
91 (89)
68 (61)
89 (82)
81 (74)
84 (78)
Ratio(Z/E)b,c
89:11(89:11)
86:14 (85:15)
90:10 (90:10)
89:11 (89:11)
92:8 (91:9)
C6H5
2
p-NO2C6H4
p-CH3OC6H4
CH3CH2CH2
p-ClC6H4
p-NO2C6H4
C6H5
4b
4d
4e
3
5 (24)
5 (32)
2 (10)
2 (8)
4
5
4f
6
4g
85:15 (84:16)
89:11 (89:11)
84:16 (86:14)
91:9 (82:8)
7
4h
4i
5 (24)
2 (10)
2 (12)
5 (32)
2 (8)
8
p-NO2C6H4
p-ClC6H4
CH3CH2CH2
p-NO2C6H4
C6H5
9
I–
4j
10
11
12
13
I–
4k
6a
88:12 (88:12)
90:10 (91:9)
84:16 (84:16)
88:12 (87:13)
PhS–
PhS–
PhS–
6b
6c
3 (19)
2 (12)
p-ClC6H4
a The number in brackets refers to conventional heating methods.
b Ylides of products based on the aldehyde and the products were identified by mp, 1H NMR, MS, and IR spectra.
c Established using 1H NMR.11
Synlett 2002, No. 11, 1895–1897 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Microwave-Assisted Tandem Nucleophilic Wittig Reaction
1897
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1123.
(10) General procedure for the synthesis of product under
microwave irradiation conditions:
To a solution of -hypervalent iodine functionalized
phosphonium ylide (2.0 mmol) and aldehyde (2.0 mmol) in
anhydrous DMF was added the anions of nuleophiles (2.5
mmol), and the mixture was irradiated in a modified
domestic microwave oven for a few minutes. The reaction
mixture was poured into ice-cold water and extracted with
ethyl acetate (3 20 mL), the organic layer was dried with
Na2SO4. Removal of the solvent followed by column
chromatography (ethyl acetate/hexane) of the crude product
yielded (Z)- -heteroatom- , -unsaturated enoates.
General procedure under conventional conditions:
Under N2, to a solution of -hypervalent iodine functional-
ized phosphonium ylide (2.0 mmol) (2.5 mmol) and
aldehyde (2.0 mmol) in anhydrous DMF was added the
anions of nuleophiles, the mixture was reacted under room
temperature for 8–32 hours. After completion of the
reaction, the following procedure was the same as above.14
(11) The ratio of Z/E was determined by the 1H NMR spectra. It
was reported that the signal of vinyl and the methyl proton in
ester of Z-type -heteroatom substituted- ,-unsaturated
enoates were in lower field than that of the corresponding E
compounds. For example, 1H NMR spectrum shows that the
chemical shifts of vinyl and the methyl in ester proton of
Z-type ethyl 2-bromo-3-(4-methoxyphenyl)-2-propenoate
are 7.80 ppm and 1.35 ppm, respectively. While the
corresponding chemical shifts of the E-type ethyl 2-bromo-
3-(4-methoxyphenyl)-2- propenoate compound are 7.07
ppm and 1.23 ppm, respectively.12 The result is in
accordance with our research.
(7) Ochiai, M. J. Organomet. Chem. 2000, 611, 494.
(8) Moriarty, R. M.; Prakash, I.; Prakash, O.; Freeman, W. J.
Am. Chem. Soc. 1984, 106, 6082.
(9) Typical procedure for the synthesis of -bromo-
substituted phosphonium ylide 3 under microwave
irradiation conditions:
To a solution of -hypervalent iodine functionalized
phosphonium ylide in DMF was added Bu4NBr, and the
mixture was irradiated in a modified domestic microwave
oven (National, power max. 750 W) for 3 min. The reaction
mixture was poured into ice-cold water and extracted with
benzene (4 20 mL), the organic layer was dried with
Na2SO4. The solvent was evaporated to obtain a solid.
Crystallization of this solid from acetone-hexane gave the
pure -bromosubstituted phosphonium ylide 3. mp155–156
°C (lit.13 Mp 157–158 °C)
(12) (a) Ohno, A.; Oae, S. Organic Chemistry of Sulfur; Oae, S.,
Ed.; Plenum: New York, 1976. (b)Metzner, P.;Thuillier, A.
Sulfur Reagents in Organic Synthesis; Academic Press:
London, U.K., 1994.
(13) Denny, D. B.; Ross, K. W. J. Org. Chem. 1962, 27, 998.
(14) Le Menn, J.-C.; Sarrazin, J.; Tallec, A. Can. J. Chem. 1989,
67, 1332.
Synlett 2002, No. 11, 1895–1897 ISSN 0936-5214 © Thieme Stuttgart · New York