A general, polymer-supported acid catalyzed hetero-Michael addition

Article abstract of DOI:10.1055/s-2003-39292

Hetero-Michael additions of nitrogen, oxygen and sulfur nucleophiles to α,β-unsaturated ketones were efficiently catalyzed by Nation SAC-13 perfluorinated resinsulfonic acid.

Full text of DOI:10.1055/s-2003-39292

1
070
LETTER
A General, Polymer-Supported Acid Catalyzed Hetero-Michael Addition
P
T
olymer-Suppo
o
b
talyzed
H
ete
i
ro-Mic
a
hael
A
dditi
s
on C. Wabnitz, Jin-Quan Yu, Jonathan B. Spencer*
Cambridge University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK
Fax +44(1223)336362; E-mail: jbs20@cam.ac.uk
Received 7 April 2003
Encouraged by the recent discovery that bis(trifluoro-
Abstract: Hetero-Michael additions of nitrogen, oxygen and sulfur
nucleophiles to a,b-unsaturated ketones were efficiently catalyzed
methanesulfon)imide is superior to transition metal cata-
lysts in the hetero-Michael addition of weakly basic
®
by Nafion SAC-13 perfluorinated resinsulfonic acid.
7
nucleophiles such as carbamates and alcohols, we exam-
Key words: hetero-Michael additions, heterogeneous catalysis,
®
ined the use of polymer-supported acids in the addition of
enones, polymer-support, Nafion
benzyl carbamate (CbzNH ) to a,b-unsaturated ketones.
2
®
Whilst Dowex -50W cation-exchange resins were not ef-
fective, we were pleased to discover high catalytic activity
Polymer-supported catalysts have attracted much atten-
tion in organic synthesis owing to easy workup proce-
dures and minimization of cost and waste generation due
to reuse and recycling of the catalysts. Therefore it is not
surprising that applications are covering an ever-increas-
ing part of the spectrum of organic transformations.1
®
with polystyrene-based Amberlyst -15 and with solid
®
perfluorinated resinsulfonic acids (Nafion -H), which are
the strongest class of polymer-supported acids commer-
8
®
cially available. Nafion SAC-13, a silica nanocomposite
with greatly increased surface area and higher reactivity
®
®
compared to conventional Nafion -H beads (Nafion NR-
5
9
In our ongoing research towards synthetically facile and
environmentally friendly routes for the construction of
b-heteroatom substituted carbonyl compounds we real-
ized that no general procedures using polymer-supported
catalysts exist in this field. Although numerous methods
for Mannich and aldol reactions using resin-bound cata-
lysts have been reported, they often involve strong bases
0) was chosen as a standard catalyst. Due to increasing
environmental concerns associated with the use of chlori-
nated media, CH CN was selected as a solvent, although
3
similar reaction rates were observed in CH Cl and
2
2
CHCl3.
The results of the aza-Michael addition of benzyl carbam-
ate to a series of a,b-unsaturated ketones are summarized
in Table 1.10 Good yields were obtained with vinyl ke-
tones (entries 1,2) and disubstituted enones (entries 3–5).
Increased steric hindrance led to lower yields (entries 6, 7)
and enones bearing additional a-substituents could not be
converted. Aniline, representing a class of more nucleo-
philic nitrogen species, could also be used and the addi-
tion product with methyl vinyl ketone was isolated in
excellent yield (entry 8).
2
for stoichiometric preparation of pre-activated enolates,
3
metal salts which are not always easy to remove, or they
suffer from side reactions such as elimination of water
4
from the reaction products. The alternative strategy to
create the desired functionalities is the Michael addition
of heteroatom nucleophiles to a,b-unsaturated carbonyl
compounds (Scheme 1). This methodology has been rou-
tinely applied to additions of thiols where polymer-sup-5
ported base catalysts have been found to be effective.
Surprisingly, although heterogeneous catalysts play a key
role in industrial olefin hydroalkoxylations and hydro-
aminations, only very few examples of solid catalysts
have been reported for the closely related oxa- and aza-
Oxygen nucleophiles, which are very difficult to use in
1
1
hetero-Michael additions, were found to be considerably
less reactive than carbamates under the same conditions.
Only moderate yields were obtained after prolonged reac-
tion times with benzyl alcohol and methanol as nucleo-
philes (entries 9, 10).
6
Michael reactions.
R3
O
XR
In contrast, additions of benzyl mercaptan proceeded
rapidly in the presence of Nafion SAC-13. Terminal, di-
substituted and trisubstituted enones could be used and
good yields of the corresponding benzyl sulfides were
obtained (entries 11–13).
O
HX-R
®
R1
R3
R1
R2
polymer-
supported catalyst
R2
X = NH, O, S
®
It should be noted that the amount of Nafion SAC-13
Scheme 1 Polymer-supported hetero-Michael addition
used in these reactions corresponds to a catalyst loading of
just 0.7% based on the number of acid functionalities
present in the polymer.12 Substrates other than ketones
were less reactive under these conditions and only slug-
gish conversion was observed with acetacrylimide (entry
Synlett 2003, No. 7, Print: 02 06 2003.
Art Id.1437-2096,E;2003,0,07,1070,1072,ftx,en;D08603ST.pdf.
1
4). However, in order to compare catalyst efficiency to
procedures involving homogeneous transition metal salts
©
Georg Thieme Verlag Stuttgart · New York

LETTER
Polymer-Supported Acid Catalyzed Hetero-Michael Addition
1071
®
Table 1 Nafion SAC-13 Catalyzed Hetero-Michael Addition of
Nitrogen, Oxygen and Sulfur Nucleophiles to a,b-Unsaturated Ke-
tones
These examples demonstrate that the convenient synthe-
sis of benzyloxycarbonyl or benzyl protected amino, oxy
and thio functionalities can be achieved by the use of a
single solid catalyst. Byproducts arising from acid-medi-
ated breakdown reactions of the reactants or products
were not observed in the presence of polymer-supported
acids, once more underlining the great potential of this
method.
R1
R2
R3
Entry
RXH
Time/h Yield
%)
(
1
2
3
4
5
6
7
8
9
Me
Et
H
H
Cbz-NH2
12
12
12
12
24
12
12
12
72
72
1
83
65
93
78
99
48
62
98
67
33
81
98
95
30
H
H
Cbz-NH2
In summary, the first general method for hetero-Michael
reactions of nitrogen, oxygen and sulfur nucleophiles us-
ing a highly active polymer-supported acid catalyst,
Et
Me
Me
Et
H
Cbz-NH2
Cbz-NH2
Cbz-NH2
Cbz-NH2
Cbz-NH2
Ph-NH2
Bn-OH
Me
Ph
H
®
Nafion SAC-13, has been developed. Efficient catalyst
H
regeneration and simple workup are advantages of this
procedure. Further studies will focus on the development
of resin-bound Brønsted superacids17 in order to exceed
current levels of catalyst activity and on the extension of
the reaction scope.
Me
Me
Me
Me
Ph
i-Pr
Me
H
H
Me
H
H
H
Acknowledgment
1
1
1
1
1
0a
Et
H
MeOH
We thank Dr Christian Stark for helpful discussions. Financial
support (T. C. W.) by the Fonds der Chemischen Industrie, the
Studienstiftung des deutschen Volkes and St. John’s College,
Cambridge, is gratefully acknowledged.
1
Et
H
H
Bn-SH
2
Et
Me
Me
H
H
Bn-SH
1
3
Me
AcNH
Me
H
Bn-SH
3
References
4
Cbz-NH2
72
(
1) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.;
Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.;
Storer, R. I.; Taylor, S. J. J. Chem. Soc., Perkin Trans. 1
2000, 3815.
1
5b
AcNH
H
H
Cbz-NH2
12
81
a
MeOH as solvent.
b
®
(2) Recent examples: (a) Nagayama, S.; Kobayashi, S. Angew.
Chem. Int. Ed. 2000, 39, 567. (b) Kobayashi, S.; Nagayama,
S. Synlett 1997, 653. (c) Kobayashi, S.; Nagayama, S. J.
Am. Chem. Soc. 1998, 120, 2985.
205 mg (10 mol%) Nafion SAC-13 were used (see text).
or acids,7,13 catalyst loadings of 10% (based on acid
groups present) were examined and unprecedented levels
of activity were observed (entry 15), exceeding those
(
3) Villemin, D.; Martin, B. J. Chem. Res. 1994, 146.
(4) Sercheli R., Ferreira A. L. B., Guerreiro M. C., Vargas R.
M., Sheldon R. A., Schuchardt U.; Tetrahedron Lett.; 1997,
1
4
38: 1325.
attained with homogeneous catalysts.
(
(
5) Recent developments: (a) Choudary, B. M.; Kantam, M. L.;
Reddy, C. R. V.; Rao, K. K.; Figueras, F. J. Mol. Cat. A
1999, 146, 279. (b) Zahouily, M.; Abrouki, Y.; Rayadh, A.;
Sebti, S.; Dhimane, H.; David, M. Tetrahedron Lett. 2003,
Apart from reactivity, reusability is also a crucial issue
with polymer-supported catalysts. Investigations carried
out on the addition of benzyl carbamate to 4-hexen-3-one
revealed a sharp drop in activity when the resin was re-
used directly (Scheme 2). However, the catalyst could be
regenerated easily with aqueous acid and only a minor
loss of reactivity was observed when the reaction was
44, 2463.
6) (a) Pelletier, S. W.; Venkov, A. P.; Finer-Moore, J.; Mody,
N. Tetrahedron Lett. 1980, 21, 809. (b) Cornelis, A.;
Laszlo, P. Synlett 1994, 155. (c) Shaikh, N. S.; Deshpande,
V. H.; Bedekar, A. V. Tetrahedron 2001, 57, 9045.
1
5,16
carried out ten times with the same catalyst.
(
3
d) Sundararajan, G.; Prabagaran, N. Org. Lett. 2001, 3,
89. (e) Bartoli, G.; Bosco, M.; Marcantoni, E.; Petrini, M.;
Sambri, L.; Torregiani, E. J. Org. Chem. 2001, 66, 9052.
O
H NCbz
O
H NCbz
2
(
(
f) Lorette, N. B. J. Org. Chem. 1958, 23, 937.
g) Kabashima, H.; Katou, T.; Hattori, H. Appl. Cat. A 2001,
Nafion® SAC-13
214, 121.
initial yield: 93 %
(
(
7) Wabnitz, T. C.; Spencer, J. B. Org. Lett. 2003, 5, in press.
8) (a) Olah, G. A.; Iyer, P. S.; Prakash, G. K. S. Synthesis 1986,
CH3CN, 12–16 h, r.t.
5
13. (b) Harmer, M. A.; Sun, Q. Appl. Cat. A 2001, 221, 45.
yield without regeneration: 42 %
(
9) (a) Török, B.; Kiricsi, I.; Molnar, A.; Olah, G. A. J. Cat.
2000, 193, 132. (b) Heidekum, A.; Harmer, M. A.;
Hoelderich, W. F. J. Cat. 1999, 181, 217.
yields after up to 9 successive regenerations: 85 % - 90 %
Scheme 2 Regeneration of Nafion SAC-13
Synlett 2003, No. 7, 1070–1072 ISSN 1234-567-89 © Thieme Stuttgart · New York

1
072
T. C. Wabnitz et al.
LETTER
®
(
10) Experimental procedure: Enone (0.25 mmol) and
(15) Catalyst regeneration: Spent Nafion SAC-13 was stirred
over 6 N HCl (0.5 mL) overnight. After filtration, the
catalyst was dried in vacuo for 20 h and reused.
nucleophile (0.375 mmol, 1.5 equiv.) were dissolved in
®
CH CN (0.5 mL) and stirred over Nafion SAC-13 (15 mg,
6
3
–1
0 g·mol ) at room temperature. The reaction was
(16) Analytical data for 5-(benzyloxycarbonylamino)hexan-3-
1
monitored by TLC and the product was isolated by
preparative TLC after filtering off the catalyst.
one: H NMR (400 MHz, CDCl ): d = 1.00 (t, J = 7.3 Hz, 3
H), 1.19 (d, J = 6.7 Hz, 3 H), 2.38 (q, J = 7.3 Hz, 2 H), 2.53
(dd, J = 5.9 Hz, 15.7 Hz, 1 H), 1.65 (dd, J = 4.8 Hz, 15.7 Hz,
1 H), 4.00–4.10 (m, 1 H), 5.05 (s, 2 H), 5.33 (br, 1 H), 7.22–
7.38 (m, 5 H). C NMR (100 MHz, CDCl ): d = 7.9, 20.9
(CH ), 36.9 (CH ), 44.3 (CH), 48.2, 66.9 (CH ), 128.4,
3
(11) Hayashi, Y.; Nishimura, K. Chem. Lett. 2002, 296.
®
(12) The ion exchange capacity of Nafion SAC-13 is 0.12
mmolg–1 according to ref.
9b
13
3
(
13) (a) Gaunt, M. J.; Spencer, J. B. Org. Lett. 2001, 3, 25.
3
2
2
(
4
b) Wabnitz, T. C.; Spencer, J. B. Tetrahedron Lett. 2002,
3, 3891. (c) Kobayashi, S.; Kakumoto, K.; Sugiura, M.
128.7, 129.9 (Ar-C), 137.0 (ipso-Ar-C), 156.0, 210.5 (C=O).
–
1
IR (neat, film): cm 3323, 3061, 2975, 1706, 1680, 1534,
1254. HRMS [+ESI]: calc. 272.1263, found: 272.1250
Org. Lett. 2002, 4, 1319.
+
(
14) Only sluggish conversion was observed with acetacrylimide
and benzyl carbamate: 34% yield (48 h) with
([C H NO Na] ). Mp: 55–57 °C.
1
4
19
3
(17) Ishihara, K.; Hasegawa, A.; Yamamoto, H. Angew. Chem.
Int. Ed. 2001, 40, 4077.
7
Pd(CH CN) (BF ) ; 84% yield (72 h) with Tf NH (see ref. ).
3
4
4 2
2
Synlett 2003, No. 7, 1070–1072 ISSN 1234-567-89 © Thieme Stuttgart · New York