[1,2]-Wittig rearrangement of (benzyloxy)acetamides

Article abstract of DOI:10.1055/s-2008-1078268

[1,2]-Wittig rearrangement of (benzyloxy)acetamides can lead to substituted α-hydroxyamides in good yields and good diastereoselectivity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078268

LETTER
2345
[1,2]-Wittig Rearrangement of (Benzyloxy)acetamides
[
1,2]-Wittig Re
a
h
rrangement
o
of (Benzylox
m
y)acetamide
s
as Hameury,a Jérôme Guillemont,b Luc Van Hijfte,b Véronique Bellosta,*a Janine Cossy*a
a
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 Rue Vauquelin, 75231 Paris Cedex 05, France
Fax +33(1)40794660; E-mail: janine.cossy@espci.fr
Tibotec, a Division of Janssen-Cilag SAS, Janssen-Cilag Research Center, Campus de Maigremont, 27106 Val de Reuil, France
b
Received 2 May 2008
•
Li
R
R
Abstract: [1,2]-Wittig rearrangement of (benzyloxy)acetamides
can lead to substituted a-hydroxyamides in good yields and good
diastereoselectivity.
Li
•
•
•
O
Z
LiO
Z
LiO
Z
RO
Z
R
A
B
C
D
Key words: [1,2]-Wittig rearrangement, amides, phase-transfer
Scheme 1
catalysis
OH R3
N
O
base
The [1,2]-Wittig rearrangement is the transformation of a-
lithiated ethers of type A into lithium alkoxides of type D
(Scheme 1).1 This rearrangement has been reviewed many
times2 and due to intensive mechanistic studies since its
discovery in 1942, it is now accepted that the rearrange-
ment proceeds via an intramolecular radical dissociation–
recombination process through species B and C.3 During
the reaction, the stereochemical information is essentially
retained with retention of configuration at the migrating
carbon and through inversion at the lithium-bearing termi-
nus. Under chelated conditions, retention occurs at the
two carbons.4
Ar
O
R3
Ar
R2
N
R1
R2
R1
O
E
F
Scheme 2
Table 1 Synthesis of (Benzyloxy)acetamides 3a–j
O
R2
R2
Br
N
O
N
2
OH
O
n-Bu4NHSO4
35% aq NaOH
toluene, r.t.
R1
1a–j
R1
3a–j
Applications of the [1,2]-Wittig rearrangement in synthe-
sis have been limited because of the low yields in the re-
arranged product and the harsh conditions required.5
[1,2]-Wittig rearrangements of substituted ethers of type
A in which Z is an electron-withdrawing group, such as a
ketone,6 ester,7 cyano,8 imidazolium, or benzyl-
imidazolium9 group, have been reported. Furthermore, the
rearrangements of (diarylmethoxy)acetamides,10 a-alk-
oxycarbamides,11 and a-benzyloxylactams12 have been
studied. We would like to report herein the [1,2]-Wittig
rearrangement of (benzyloxy)acetamides of type E in or-
der to have access to substituted a-hydroxyamides of type
F (Scheme 2).
Entry
R1
R2
3
Yield (%)
1
2
Me
H
3a
3b
3c
3d
3e
3f
75
73
69
65
68
79
74
59
74
65
Me
4-Me
3
Me
4-OMe
4
Me
3,4-(OMe)2
5
Me
4-NO2
6
CH2CH=CH2
(CH2)2CH=CH2
n-Bu
H
H
H
H
H
7
3g
3h
3i
The synthesis of (benzyloxy)acetamides has been
achieved by etherification of benzylic alcohols 1a–j (1.1
equiv) by bromoacetylpyrrolidine (2, 1 equiv) under
phase-transfer conditions using tetra-n-butylammonium
hydrogenosulfate (20 mol%) in a heterogeneous mixture
of 35% aqueous NaOH solution and toluene in a 1:1 ratio,
at room temperature.13,14 The corresponding ethers 3a–j
were obtained in 59–79% yield. The results are reported
in Table 1.
8
9
cyclopropyl
Ph
10
3j
(Benzyloxy)acetamides 3a–k were deprotonated by treat-
ment with LiHMDS (2.5 equiv) at –30 °C, and by raising
up the temperature to 0 °C, the subsequent [1,2]-Wittig re-
arrangement of the resulting amide enolate proceeded
smoothly to produce hydroxyamides 4a–k in modest to
good yields (35-67%), with modest to good diastereose-
lectivity in favor of the syn diastereomer (2.1:1 to 5.9:1,
Table 2).15 It is worth noting that the R2 substituent
present on the aromatic ring has no influence on the dia-
SYNLETT 2008, No. 15, pp 2345–2347
1
5
.0
9
.2
0
0
8
Advanced online publication: 21.08.2008
DOI: 10.1055/s-2008-1078268; Art ID: G16108ST
© Georg Thieme Verlag Stuttgart · New York

2346
T. Hameury et al.
LETTER
Table 2 Deprotonation of (Benzyloxy)acetamides 3a–k
Table 3 Competitive ortho-[2,3]-Wittig Rearrangement
R2
R
R1
O
O
O
R2
LiHMDS
LiHMDS
O
N
O
O
4 +
N
N
N
THF
–30 to 0 °C
THF
–30 to 0 °C
OH
R1
R
OH
3
3a–k
4a–k
5
Entry R1
R2
H
4
syn/anti
Yield (%)
Entry
R
Yield of 4 (%)
Yield of 5 (%)
1
2
3
4
5
Me
Me
Me
Me
Me
4a 2.7:1
4b 2.1:1
63
56
64
35
1
2
3
Me
63
51
46
15
26
24
4-Me
CH2CH=CH2
(CH2)2OTBS
4-OMe
4c
3:1
3,4-(OMe)2 4d 2.8:1
Me
O
4-NO2
complex mixture of
products
Me
OH
N
LiNH2⋅BH3
6
7
CH2CH=CH2
(CH2)2CH=CH2
n-Bu
H
H
H
H
H
H
4f
4.3:1
51
63
46
62
67
46
OH
OH
THF, r.t.
69%
4a
6a
4g 5.2:1
4h 5.9:1
8
O
OH
9
cyclopropyl
Ph
4i
4j
5.7:1
–
N
LiNH2⋅BH3
10
11
OH
THF, r.t.
80%
OH
6f
4f
(CH2)2OTBS
4k 3:1
TBSCl, Et3N
DMAP, CH2Cl2, r.t.
84%
stereoselectivity of the [1,2]-Wittig rearrangement. How-
ever, the presence of an aromatic nitro group (amide 3e,
Table 2, entry 5) led to a complex mixture of products.
Furthermore, the diastereomeric ratio increased with the
size of the R1 group at the benzylic position (4a–d vs 4f–
k, Table 2).
OTBS
OH
7f
The observed diastereomeric ratio for the products ob-
tained after the rearrangement is the result of the rear-
rangement itself, as the treatment of syn compounds 4
with LiHMDS under the same conditions did not produce
any modification of the diastereomeric ratio. The rear-
rangement proceeds via a diradical intermediate, and the
recombination step is diastereoselective.5b,e,11,16
Scheme 3
scribed in the literature.19 By comparison of the NMR data
of 6a and 7f with those described in the literature, the syn
relative stereochemistry between the hydroxy and alkyl
groups was attributed.19,20
The modest yields obtained may be due to a competitive
ortho-[2,3]-Wittig rearrangement, that led to compounds
5 in 15–25% yields (Table 3). The ortho-[2,3]-Wittig re-
arrangement has already been described as a side reaction
of the [1,2]-Wittig rearrangement of (benzyl-
oxy)ethers.12,17 It could proceed via a concerted anionic
[2,3]-rearrangement or via the delocalization of the ben-
zylic radical into the aromatic ring before the recombina-
tion step.
Similarities between the different hydroxyamides 4 were
observed by analysis of the 1H NMR data in term of chem-
ical shift,21 and coupling constants between the benzylic
proton and the proton at the a-position of the amide (ma-
3
jor diastereomer J = 4.6–6.4 Hz, minor diastereomer
3J = 3.1–4.7 Hz, with 3Jmajor > 3Jminor).22 On the basis of the
chemical correlations obtained for compounds 6a and 7f,
as well as the 1H NMR observations, a syn stereochemis-
try for all the major isomers coming from the [1,2]-Wittig
rearrangement, was assigned by analogy.
The relative syn stereochemistry of the major isomers 4a
and 4f, obtained, respectively, from the [1,2]-Wittig rear-
rangement of compounds 3a and 3f, was assigned after
their conversion into known diols (Scheme 3). Com-
pounds syn-4a and syn-4f were converted into 1,2-diols
6a and 6f, respectively, by treatment with LiNH2·BH3.18
Compound 6f was transformed into the corresponding
monosilylated ether 7f, as this latter product was de-
In conclusion, we have succeeded in the development of
[1,2]-Wittig rearrangement of (benzyloxy)acetamides,
which can produce substituted a-hydroxyamides with
good diastereomeric ratio when a sterically hindered sub-
stituent is present at the benzylic position.
Synlett 2008, No. 15, 2345–2347 © Thieme Stuttgart · New York

LETTER
[1,2]-Wittig Rearrangement of (Benzyloxy)acetamides
2347
n-Bu4NHSO4 (0.2 mmol) and a 35% aq NaOH solution (15
mL). The mixture was then stirred vigorously at r.t., and the
reaction was monitored by TLC. After 3–4 h, H2O (20 mL)
and Et2O (20 mL) were added at 0 °C. The aqueous layer
was extracted with Et2O (5 × 30 mL), and the combined
organic layers were washed with sat. aq NH4Cl soln (50
mL), dried over MgSO4, and concentrated in vacuo. The
crude residue was purified on SiO2 (PE–EtOAc) to
afford(benzyloxy)acetamide 3. Amide 3k with
Acknowledgment
Tibotec, a division of Janssen-Cilag SAS, is greatly acknowledged
for financial support (Grant to T. H.).
References and Notes
(1) Wittig, G.; Löhmann, L. Liebigs Ann. Chem. 1942, 550, 260.
(2) (a) Marshall, J. A. In Comprehensive Organic Synthesis,
Vol. 3; Trost, B. M.; Fleming, I., Eds.; Pergamon: London,
1991, 975. (b) Tomooka, K.; Yamamoto, H.; Nakai, T.
Liebigs Ann./Recl. 1997, 1275.
(3) Schöllkopf, U. Angew. Chem., Int. Ed. Engl. 1970, 9, 763.
(4) (a) Maleczka, R. E. Jr.; Geng, F. J. Am. Chem. Soc. 1998,
120, 8551. (b) Tomooka, K.; Igarashi, T.; Nakai, T.
Tetrahedron 1994, 50, 5927. (c) Gärtner, P.; Letschnig,
M. F.; Knollmüller, M.; Völlenkle, H. Tetrahedron:
Asymmetry 1999, 10, 4811.
(5) Synthetic applications of [1,2]-Wittig rearrangement:
(a) Schreiber, S. L.; Goulet, M. T.; Schulte, G. J. Am. Chem.
Soc. 1987, 109, 4718. (b) Schreiber, S. L.; Goulet, M. T.
Tetrahedron Lett. 1987, 28, 1043. (c) Grindley, T. B.;
Wickramage, C. J. Carbohydr. Chem. 1988, 7, 661.
(d) Yadav, J. S.; Ravishankar, R. Tetrahedron Lett. 1991, 32,
2629. (e) Tomooka, K.; Kikuchi, M.; Igawa, K.; Suzuki, M.;
Keong, P.-H.; Nakai, T. Angew. Chem. Int. Ed. 2000, 39,
4502.
R1 = (CH2)2OTBS (Table 2, entry 11) was obtained from
amide 3f (Table 1, entry 6) by using the following sequence:
1) O3, MeOH, –78 °C then Ph3P, CH2Cl2, –78 °C to r.t.; 2)
NaBH4, EtOH, 0 °C; 3) TBSCl, Et3N, DMAP, CH2Cl2, 0 °C
(60% over 3 steps).
(15) Representative Procedure for the [1,2]-Wittig
Rearrangement of (Benzyloxy)acetamides 3
To a solution of(benzyloxy)acetamide 3 (0.2 mmol) in THF
(3 mL), at –30 °C, was added dropwise a 1 M solution of
LiHMDS in THF (2.5 equiv). The reaction mixture was then
warmed to 0 °C over 2–3 h, before being hydrolyzed with
sat. aq NH4Cl soln (10 mL). The aqueous layer was then
extracted with Et2O (3 × 20 mL). The combined organic
layers were dried over MgSO4, and concentrated in vacuo.
The crude residue was purified on SiO2 (PE–EtOAc) to
afford a-hydroxyamide 4.
(16) Tomooka, K.; Yamamoto, H.; Nakai, T. J. Am. Chem. Soc.
1996, 118, 3317.
(17) (a) Schöllkopf, U.; Fellenberger, K.; Rizk, M. Liebigs Ann.
Chem. 1970, 734, 106. (b) Tomooka, K.; Harada, M.; Hanji,
T.; Nakai, T. Chem. Lett. 2000, 1394.
(18) (a) Myers, A. G.; Yang, B. H.; Kopecky, D. J. Tetrahedron
Lett. 1996, 37, 3623. (b) Myers, A. G.; Yang, B. H.; Chen,
H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am.
Chem. Soc. 1997, 119, 6496.
(6) (a) Curtin, D. Y.; Leskowitz, S. J. Am. Chem. Soc. 1951, 73,
2633. (b) Curtin, D. Y.; Proops, W. R. J. Am. Chem. Soc.
1954, 76, 494. (c) Paquette, L. A.; Zeng, Q. Tetrahedron
Lett. 1999, 40, 3823. (d) Vilotijevic, I.; Yang, J.; Hilmey,
D.; Paquette, L. A. Synthesis 2003, 1872.
(7) Beaudoin Bertrand, M.; Wolfe, J. P. Org. Lett. 2006, 8,
4661.
(19) Tanaka, T.; Hiramatsu, K.; Kobayashi, Y.; Ohno, H.
(8) Cast, J.; Stevens, T. S.; Holmes, J. J. Chem. Soc. 1960, 3521.
(9) Miyashita, A.; Matsuoka, Y.; Suzuki, Y.; Iwamoto, K.-I.;
Higashino, T. Chem. Pharm. Bull. 1997, 45, 1235.
(10) Van der Stelt, C.; Heus, W. J.; Haasjes, A. Recl. Trav. Chim.
Pays-Bas 1973, 92, 493.
(11) Kitagawa, O.; Momose, S.-I.; Yamada, Y.; Shiro, M.;
Taguchi, T. Tetrahedron Lett. 2001, 42, 4865.
(12) Garbi, A.; Allain, L.; Chorki, F.; Ourévitch, M.; Crousse, B.;
Bonnet-Delpon, D.; Nakai, T.; Bégué, J.-P. Org. Lett. 2001,
3, 2529.
(13) Barbazanges, M.; Meyer, C.; Cossy, J. Org. Lett. 2007, 9,
3245.
(14) Representative Procedure for the Preparation of
(Benzyloxy)acetamides 3
Tetrahedron 2005, 61, 6726.
(20) (a) Lesuisse, D.; Berchtold, G. A. J. Org. Chem. 1988, 53,
4992. (b) Coghlan, D. R.; Hamon, D. P. G.; Massy-
Westropp, R. A.; Slobedman, D. Tetrahedron: Asymmetry
1990, 1, 299. (c) Park, J.; Pedersen, S. F. Tetrahedron 1992,
48, 2069.
(21) Similarities in term of chemical shift between the different
hydroxyamides 4 were particularly relevant for the proton at
the a-position of the amide, for which dmajor < dminor in all
cases.
(22) In all cases 3Jmajor > 3Jminor except for hydroxyamide 4i
(Table 2, entry 9). For compound 4i, 3Jmajor = 4.3 Hz and
3Jminor = 5.0 Hz. Therefore, the syn stereochemistry
remained ambiguous in this latter case.
To a solution of alcohol 1 (1.1 mmol) and bromoacetyl-
pyrrolidine (2, 1 mmol) in toluene (15 mL), at r.t., was added
Synlett 2008, No. 15, 2345–2347 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.