Palladium catalyzed alkoxy- and aminocarbonylation of vinyl tosylates

Article abstract of DOI:10.1021/ol200744s

Chemical equations presented. The palladium catalyzed alkoxycarbonylation and aminocarbonylation of vinyl tosylates are described. A variety of ketone and aldehyde derived vinyl tosylates may be carbonylated in the presence of primary, secondary, and tert

Full text of DOI:10.1021/ol200744s

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2495–2497
Palladium Catalyzed Alkoxy- and
Aminocarbonylation of Vinyl Tosylates
Diana C. Reeves,* Sonia Rodriguez, Heewon Lee, Nizar Haddad,
Dhileepkumar Krishnamurthy, and Chris H. Senanayake
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900
Ridgebury Road/P.O. Box 368, Ridgefield, Connecticut 06877-0368, United States
diana.reeves@boehringer-ingelheim.com
Received March 20, 2011
ABSTRACT
The palladium catalyzed alkoxycarbonylation and aminocarbonylation of vinyl tosylates are described. A variety of ketone and aldehyde derived
vinyl tosylates may be carbonylated in the presence of primary, secondary, and tertiary alcohols, or primary and secondary amines, to provide the
corresponding esters and amides in good yields. The alkoxycarbonylation was applied to a short synthesis of isoguvacine.
The palladium catalyzed alkoxy- or aminocarbonyla-
tion of vinyl electrophiles is a useful route to R,β-unsatu-
rated esters and amides. The reactions were first described
by Heck in 1974 for vinyl bromide and iodide substrates.1
The carbonylation of vinyl triflates was later developed by
Cacchi and co-workers.2 The use of vinyl chlorides has also
been investigated, though less extensively.1b,3 Larhed and
co-workers recently reported the palladium catalyzed ami-
nocarbonylation of vinyl phosphates under microwave
conditions using Mo(CO)6 as the CO source.4 The alkoxy-
carbonylation of aryl arenesulfonates was first reported in
2006 by Cai and co-workers.5 Recently Buchwald and co-
workers reported the alkoxycarbonylation ofaryl tosylates
and mesylates at atmospheric pressure of CO using a
Pd(OAc)2/dcpp catalyst system.6 While various cross-cou-
pling reactions employing vinyl tosylates have been re-
ported, the carbonylation of these compounds has not
previously been described.7 Vinyl tosylates are attractive
alternatives to conventional vinyl electrophiles due to their
simple one-step synthesis from ketone or aldehyde pre-
cursors and their generally high crystallinity which simpli-
fies isolation and handling. In addition, the reagent used to
prepare vinyl tosylates (Ts2O) is cheaper than the reagent
used to prepare vinyl triflates [PhN(Tf)2]. Herein we
describe our results on the development of a practical
process for the alkoxy- and aminocarbonylation of vinyl
tosylates.
Our initial screening of reaction conditions focused on
the alkoxycarbonylation of tosylate 1 with 1-pentanol to
give ester 2 (Table 1). A survey of various bidentate
phosphine ligands was done, as well as a comparison of
commercially available preformed palladium complexes
with the corresponding Pd(OAc)2/ligand combination.
Phosphines containing a 3-carbon tether (dppp, skewphos,
dcpp) gave the best results (entries 2À5). Introducing a
slight increase of steric constraint (e.g., methyl groups on
the carbons adjacent to phosphorus) improves the catalyst
performance (entries 3 and 5) while an increased bite angle
is detrimental (entry 8). Thus the overall efficiency trend is
skewphos > dcpp > dppp > dppb > dppf > dppe for the
same catalyst loading (5 mol %). These observations are in
agreement with previously reported data for Pd-catalyzed
(1) (a) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974,
39, 3318. (b) Schoenberg, A.; Heck, R. F. J. Org. Chem. 1974, 39, 3327.
(2) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1985, 26,
1109.
(3) Nicholas, P. P. J. Org. Chem. 1987, 52, 5266.
(4) Lagerlund, O.; Mantel, M. L. H.; Larhed, M. Tetrahedron 2009,
65, 7646.
(5) Cai, C.; Rivera, N. R.; Balsells, J.; Sidler, R. R.; McWilliams,
J. C.; Schults, C. S.; Sun., Y. Org. Lett. 2006, 8, 5161.
(6) Munday, R. H.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem.
Soc. 2008, 130, 2754.
(7) For other Pd-catalyzed reactions of vinyl tosylates, see: (a) Huffman,
M. A.; Yasuda, N. Synlett 1999, 471. (b) Baxter, J. M.; Steinhuebel, D.;
Palucki, M.; Davies, I. W. Org. Lett. 2005, 7, 215. (c)Wu, J.;Zhu, Q.;Wang,
L.; Fathi, R.; Yang, Z. J. Org. Chem. 2003, 68, 670. (d) Klapars, A.;
Campos, K. R.; Chen, C.; Volante, R. P. Org. Lett. 2005, 7, 1185. (e)
Reeves, D. C.; Rodriguez, S.; Lee, H.; Haddad, N.; Krishnamurthy, D.;
Senanayake, C. H. Tetrahedron Lett. 2009, 50, 2870.
r
10.1021/ol200744s
2011 American Chemical Society
Published on Web 04/13/2011

alkoxycarbonylation of alkenes8 and carbonylation of aryl
halides (dppp > dppb > dppe > dppm).9 The commer-
cially available complex PdCl2(dppf) performed well
(entry 6), although reducing the catalyst loading signifi-
cantly decreased the yield (entries 7 and 11). In the case of
skewphos, however, the catalyst loading could be reduced
to 1 mol % without loss of performance. From a cost analysis
standpoint, even in enantiopure form, skewphos is prefer-
(entries 13 and 14) were found to be competent sub-
strates. The geometric integrity of enol tosylates was
preserved during the carbonylation reaction (entries 12
and 13). The reaction could also be performed on hetero-
cyclic substrates (entries 15À17).
Table 2. Pd-Catalyzed Alkoxycarbonylation of Vinyl Tosylatesa
able to dcpp 2HBF4. Finally, decreasing the CO pressure
from 100 to 50psi resultedin a slight loss inyield (entry 13).
3
Table 1. Catalyst and Ligand Screening Results
Pd cat.
(mol %)
press yield
entry
catalyst
liganda
(psi)
(%)b
1
PdCl2(dppe)
PdCl2(dppp)
Pd(OAc)2
À
À
5.0
5.0
5.0
5.0
2.5
10
100
100
100
100
100
100
100
100
100
100
100
200
50
40
86
99
97
95
92
78
80
99
99
50
31
91
2
3
skewphosc
skewphos
4
PdCl2
d
5
Pd(OAc)2
dcpp 2HBF4
3
6
PdCl2(dppf)
Pd(OAc)2
À
7
dppf
5.0
5.0
2.5
1.0
5.0
5.0
5.0
8
PdCl2(dppb)
Pd(OAc)2
À
9
skewphos
skewphos
À
10
11
12
13
Pd(OAc)2
PdCl2(dppf)
PdCl2(dppf)
Pd(OAc)2
À
skewphos
a L/Pd ratio = 2. b HPLC assay yield. c 2,4-Bis(diphenylphosphino)-
pentane. d 1,3-Bis(dicyclohexylphosphino)propane 2HBF4.
3
The substrate scope of the alkoxycarbonylation reaction
was explored with respect to vinyl tosylate and alcohol
(Table 2). Using β-tetralone derived tosylate 1, various
alcohols were surveyed (entries 1À6). Primary, secondary,
and tertiary alcohols all gave good yields of ester products.
Full substitution of the vinyl tosylate olefin was tolerated
(entries 8 and 11). Aldehyde-derived vinyl tosylates
a For experimental details see the Supporting Information. b Isolated
yields. c E/Z = 10:1. d E/Z = 13:1. e E/Z = 2.4:1. f E/Z = 4:1.
(8) (a) Dierkes, P.; Van Leeuwen, P. W. N. M. J. Chem. Soc., Dalton
Trans. 1999, 1519. (b) Van Leeuwen, P. W. N. M.; Freixa, Z. Bite Angle
Effects of Diphosphines in carbonylation Reactions. In Modern Carbo-
nylation Methods; Kollar, L., Ed.; Wiley: Weinheim, 2008; pp 1À25 and
references cited therein.
(9) Albaneze-Walker, J.; Bazaral, C.; Leavey, T.; Dormer, P. G.;
Murry, J. A. Org. Lett. 2004, 6, 2097.
We next examined the aminocarbonylation of vinyl
tosylates. Direct application of the conditions developed
for alkoxycarbonylation to carbonylation in the presence
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Org. Lett., Vol. 13, No. 9, 2011

ofamines was foundtogivegood yields of R,β-unsaturated
amide products. The scope of the aminocarbonylation
reaction is given in Table 3.
In addition to alkyl amines, aniline could be employed to
giveanN-phenylamideinhighyield (entry 9). Thereaction
was also applied to a hydrazine to provide an acyl hydra-
zine in moderate yield (entry 11).
Isoguvacine is a potent γ-amino butyric acid (GABA)
agonist which has attracted interest as a potential treat-
ment for psychiatric and neurological disorders.10 We
applied the vinyl tosylate alkoxycarbonylation to a short
synthesis of isoguvacine (Scheme 1). Beginning with com-
mercially available N-Boc 4-piperidone 41, treatment with
KHMDS and subsequent trapping with Ts2O gave the
vinyl tosylate 24 in 63% yield. Carbonylation in the
presence of tert-butanol gave the ester 25 in 78% yield.
Finally, simultaneous deprotection of the tert-butyl ester
and the Boc group was accomplished with HCl in dioxane.
Isoguvacine was isolated as its HCl salt in 97% yield. This
three-step synthesis of isoguvacine is an improved alter-
native to previous syntheses of this compound in terms of
overall yield and number of steps (48% overall yield, 3
steps vs 8% overall yield, 6 steps).11
Table 3. Pd-Catalyzed Aminocarbonylation of Vinyl Tosylatesa
Scheme 1. Vinyl Tosylate Alkoxycarbonylation in the Synthesis
of Isoguvacine
In summary, we have demonstrated the first alkoxy- and
aminocarbonylation of vinyl tosylates, a one carbon
homologation method. The simple one-step synthesis of
vinyl tosylates from ketones or aldehydes makes them an
attractive alternative to vinyl halides or triflates. The
alkoxycarbonylation is tolerant of a diverse set of enol
tosylate and alcohol reactants and provides the ester
products in good yields. The same reaction conditions
may be applied to aminocarbonylation. Primary, second-
ary, and arylaminesreact togivethe corresponding amides
in good yields. Hydrazines may also be used and provide
acyl hydrazines in moderate yields. The alkoxycarbonyla-
tion reaction was demonstrated in a three-step synthesis of
the GABA agonist isoguvacine.
a For experimental details, see the Supporting Information. b Iso-
lated yields. c E/Z = 10:1. d E/Z g 10:1.
Both primary and secondary amines reacted smoothly.
Full substitution of the vinyl tosylate was tolerated (entry 7).
Supporting Information Available. Experimental pro-
cedures, characterization data, and copies of 1H and 13
C
(10) Falch, E.; Krogsgarrd-Larsen, P. J. Med. Chem. 1981, 24, 285.
(11) (a) Chang, M.-Y.; Chen, S.-T.; Chang, N.-C. Heterocycles 2002,
57, 2321. (b) Chang, M.-Y.; Chen, C.-Y.; Tasi, M.-R.; Tseng, T.-W.;
Chang, N.-C. Synthesis 2004, 840.
NMR spectra for all products and unknown substrates.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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