A complementary method to obtain N-acyl enamides using the Heck reaction: Extending the substrate scope for asymmetric hydrogenation

Article abstract of DOI:10.1016/j.tetlet.2004.10.063

A series of N-acyl enamides were prepared using the Heck reaction. Asymmetric hydrogenation provided protected amines in up to 99% ee. A method to prepare N-acyl enamides is reported that is complementary to the existing protocols. Heck reaction of a vari

Full text of DOI:10.1016/j.tetlet.2004.10.063

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9277–9280
A complementary method to obtain N-acyl enamides
using the Heck reaction: extending the substrate
scope for asymmetric hydrogenation
Paul Harrison and Graham Meek*
Dowpharma, Chirotech Technology Ltd, a subsidiary of The Dow Chemical Company, 321 Cambridge Science Park,
Milton Road, Cambridge CB4 0WG, UK
Received 19 August 2004; revised 7 October 2004; accepted 12 October 2004
Available online 22 October 2004
Abstract—A method to prepare N-acyl enamides is reported that is complementary to the existing protocols. Heck reaction of a
variety of aryl trifluoromethanesulfonates with commercially available N-vinylacetamide occurred in a highly regioselective fashion
to provide these valuable synthetic intermediates. This method permits the formation of N-acyl enamides containing functionality
that would not be tolerated by the existing methods. Asymmetric hydrogenation using [diphosphine RhCOD]BF4 complexes pro-
vided optically active protected amines in up to 99% ee. De-acylation occurs without affecting the amine enantiopurity.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Enantiomerically pure amines are valuable building
blocks for organic synthesis and serve as resolving
agents, chiral auxiliaries and ligands for many useful
transformations. Consequently, methods to obtain
amines of high enantiomeric purity are of considerable
interest. Although there has been considerable progress
in the enantioselective reduction of imines,1 the asym-
metric hydrogenation of N-acyl enamides to produce
amines of high enantiopurity is still widely practiced.
This indirect method to obtain optically active amines
is favoured by a number of factors such as a range of
preparative methods for forming N-acyl enamides,2 sub-
strate stability and the tolerance of E/Z mixtures in
highly efficient catalytic asymmetric hydrogenations.3
Although there are several efficient methods for the forma-
tion of N-acyl enamides (Fig. 1), they suffer from harsh
reaction conditions or the use of reagents and substrates
that preclude the incorporation of certain functional
N(H)Ac
OTf
CN
AcNH2,
MeMgBr,
R
R
R
Pd(0)
Ac2O
ref. 2a
ref. 2b
Ac2O,
Fe
ref.2c
OH
N
R
Figure 1. Existing methods to prepare aryl N-acyl enamides.
Keywords: N-Acyl enamides; Heck reaction; Asymmetric hydrogenation.
*
Corresponding author. Tel.: +44 1223 728010; fax: +44 1223 506701; e-mail: gmeek@dow.com
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.063

9278
P. Harrison, G. Meek / Tetrahedron Letters 45 (2004) 9277–9280
groups such as ketones, esters and nitriles. We herein
report a complementary method for producing N-acyl
enamides. Furthermore, we also describe the asymmetric
hydrogenation of these substrates.
access to non-alkyl substituted primary amines after a
simple deprotection.
Consistent with the original report on the Heck reaction
of aryl trifluoromethanesulfonates with unsymmetrical
olefins, high regioselectivity was observed.5 Analysis of
The existing methods to obtain aryl N-acyl enamides
rely on the presence of functionality that is converted
into the enamide unit. An alternative approach to con-
struct this class of compound is based on the functionalis-
ation of a pre-existing N-acyl enamide (Fig. 2). This
approach involves the regioselective coupling of the N-
acyl enamide unit to an activated aryl species.
1
the crude reaction products by H NMR spectroscopy
indicated >19:1 ratio of regioisomers in the majority
of cases and the minor regioisomer could be easily re-
moved by flash column chromatography or solvent slurry.
Replacement of DPPP with triphenylphosphine did not
result in any observable Heck reaction, which is consis-
tent with the previous results.5
N(H)Ac
R'
This method works well for the preparation of aryl-N-
acyl enamides, which are obtained in moderate to good
yields. No optimisation was carried-out and all the Heck
reactions were performed under the originally reported
conditions. The low yield observed with the para-bromo
substituted trifluoromethanesulfonate can be under-
stood in terms of the similar reactivity of the bromide
and trifluoromethanesulfonate functionalities towards
palladium insertion (entry 6).7 Recent improvements in
the field of palladium catalysed cross-coupling reactions
of aryl chlorides8 renders the chloro-substituted prod-
ucts particularly useful (entries 4 and 7). Although not
examined in this study, further functionalisation of the
N-acyl enamides obtained could be envisaged.
N(H)Ac
R'
X
R
+
R
R''
R''
Figure 2. Approach to N-acyl enamides.
A series of aryl trifluoromethanesulfonates containing a
variety of pendant functional groups were prepared
from commercially available phenols under standard
conditions.4 Purification was achieved by distillation
or solvent slurry. Highly regioselective Heck reactions
with tertiary N-vinylacetamides have been reported by
Cabri et al.5 and Larhed and co-workers.6 The condi-
tions described by Cabri et al. were extended to commer-
cially available N-vinylacetamide (Table 1), allowing
The limitations of this method were demonstrated by
the lack of reaction observed under these conditions
with a number of substrates. The enol trifluoromethane-
sulfonates derived from ethyl acetoacetate decomposed
under the reaction conditions whilst reaction with
methyl 3-acetylaminoacrylate only resulted in isomerisa-
tion of the olefin geometry. Aryl trifluoromethanesulfo-
nates containing nitro groups in the meta or para
positions were not reactive under the conditions
employed.
Table 1. Heck reactions to provide N-acyl enamides
Ac(H)N
N(H)Ac
R OTf
R
Pd(OAc)2 (1 mol%)
DPPP (1.1 mol%)
Et3N (1.2 eq), DMF
100 ˚C
The asymmetric hydrogenation of the N-acyl enamides
obtained was examined using a selection of [diphosphine
RhCOD]BF4 complexes and the catalyst providing the
highest enantioselectivity for each substrate was identi-
fied (Table 2). The diphosphines studied were Me-
DuPhos, Et-DuPhos, Me-BPE, Et-BPE and Ph-BPE.
These initial reactions were performed using 0.1mol%
of the rhodium complex.
Entry
1
R-OTf
Yielda (%)
62
Cl
OTf
Cl
MeO2C
OTf
OTf
2
3
69
40
In all cases, with the exception of the ortho-chloro sub-
stituted aryl N-acyl enamide (entry 7), excellent conver-
sions and enantioselectivities were observed. The
absolute stereochemistry of the amines obtained has
been tentatively assigned based upon the well-docu-
mented behaviour of the DuPhos and BPE ligand fam-
ily.3 For substrates containing a ketone, the Lewis
acidic catalysts can promote ketal formation and the
addition of water as a co-solvent is necessary in order
to prevent the formation of this by-product (entry 3).
It is notable that in many cases the recently introduced
Ph-BPE9 was identified as the optimal ligand and with
several of the substrates this provided far superior
results compared to the alternatives examined.
O
OTf
OTf
OTf
4
5
6
64
55
24
63
Cl
NC
Br
OTf
Cl
7
a Isolated yield.

P. Harrison, G. Meek / Tetrahedron Letters 45 (2004) 9277–9280
9279
Table 2. Asymmetric hydrogenation of aryl N-acyl enamides
N(H)Ac
N(H)Ac
*
H2 (10 bar)
[L Rh COD]BF4 (0.1 mol%)
MeOH
R
R
Entry
R
L
Temp (ꢁC)
Conv. (%)a
ee (%)b,c
1
3,4-Cl2
3-CO2Me
4-COMe
4-Cl
(S,S)-Et-DuPhos
(S,S)-Ph-BPE
(S,S)-Et-DuPhos
(S,S)-Ph-BPE
(S,S)-Ph-BPE
(S,S)-Ph-BPE
(S,S)-Et-BPE
40
40
30
40
40
40
40
>98
>98
>98
>98
>98
>98
86
98 (S)
98 (R)
97 (S)
99 (R)
99 (R)
99 (R)
85 (S)
2
3d
4
5
4-CN
4-Br
2-Cl
6
7
a Determined by 1H NMR spectroscopy.
b Determined by HPLC or GC (for details see supplementary data).
c Absolute stereochemistry tentatively assigned (see text).
d Water used as co-solvent (10% v/v).
N(H)Ac
N(H)Ac
NH2.HCl
Cl
Cl
Cl
Cl
a
b
Cl
Cl
3,97% ee
2.HCl, >98% ee
1
Cl
Cl
P
N
H
OH
O
HO
CGP-55845
Scheme 1. Synthesis of 2ÆHCl, a potential intermediate to CGP-55845. Reagents and conditions: (a) [(S,S)-Et-DuPhos RhCOD]BF4 (0.02mol%), H2
(10bar), MeOH, 40ꢁC; (b) 6M HCl, EtOH, 100ꢁC, 86% overall.
In order to evaluate the synthetic potential of this meth-
odology and encouraged by the screening results
obtained, the enantioselective hydrogenation of the N-
acyl enamide 1 leading to (S)-1-(3,4-dichlorophenyl)ethyl-
amine 2 was examined in more detail (Scheme 1). This
amine is a potential intermediate to CGP-55845, a
GABA-B antagonist that is under investigation by
Novartis as a potential treatment for epilepsy.10 Although
we determined that the highest enantioselectivity was
provided by a catalyst containing (S,S)-Et-DuPhos
(Table 2, entry 1), there was little distinction between
the enantioselectivity associated with this ligand and the
others examined for this substrate. However, determina-
tion of the relative rates of hydrogenation indicated that
the catalyst containing (S,S)-Et-DuPhos was by far the
most active of those examined. The asymmetric hydro-
genation was therefore scaled-up and 3 was obtained
in a quantitative fashion with 97% ee when performed
using 0.02mol% of [(S,S)-Et-DuPhos RhCOD]BF4. At
a hydrogen pressure of 10bar, a temperature of 40ꢁC
and concentration of 0.3M, the hydrogenation was
complete within 80min.
the salt 2ÆHCl resulted in a small increase in the
enantiopurity.
In summary, we have reported a method for producing
N-acyl enamides that is complementary to the existing
methods. This method is compatible with the presence
of functional groups such as ketones, esters and nitriles
that are not tolerated by the existing methods illustrated
in Figure 1. This method introduces substituted phenols
as an alternative source of functionalised N-acyl ena-
mides. Asymmetric hydrogenation using [diphosphine
RhCOD]BF4 complexes provided optically active
amines in up to 99% ee. In many cases the optimal
diphosphine was demonstrated to be the recently intro-
duced Ph-BPE. The value of this chemistry was demon-
strated by the synthesis of an intermediate to a potential
drug candidate. Asymmetric hydrogenation catalysed by
[(S,S)-Et-DuPhos RhCOD]BF4 proceeded with excel-
lent enantioselectivity (97% ee) and was followed by ace-
tate hydrolysis, which occurred with no detectable effect
upon the enantiopurity. The combination of N-acyl ena-
mide formation and asymmetric hydrogenation offers a
powerful way to access a wide variety of highly enantio-
merically enriched amines.
Treatment of 3 with 6M hydrochloric acid in refluxing
ethanol provided the hydrochloride salt of 2 in 86%
overall yield from the N-acyl enamide 1.11 The enantio-
purity was determined to be >98% ee, indicating that
although these deprotection conditions are rela-
tively harsh, no racemisation occurs. Formation of
Acknowledgements
We thank Dr. Ian Lennon for useful discussions.

9280
P. Harrison, G. Meek / Tetrahedron Letters 45 (2004) 9277–9280
provides the alternative regioisomer: de Vries, A. M. H.;
Supplementary data
Mulders, J. M. C. A.; Mommers, J. H. M.; Henderickx,
H. J. W.; de Vries, J. G. Org. Lett. 2003, 5, 3285–
3288.
Analytical methods for determination of the enantio-
purity of the acylamines are available in the supplemen-
tary data accompanying this paper, in the online
version, at doi:10.1016/j.tetlet.2004.10.063.
8. For a review of palladium catalysed coupling reactions of
aryl chlorides, see: Littke, A. F.; Fu, G. C. Angew. Chem.,
Int. Ed. 2002, 41, 4176–4211.
9. Pilkington, C. J.; Zanotti-Gerosa, A. Org. Lett. 2003, 5,
1273–1275.
References and notes
10. Mickel, S. J. E.P. Patent 543 780, 1993; Chem. Abstr. 1993,
119, 203630.
11. Experimental procedure: the N-acyl enamide 1 (6.35g,
27.6mmol) and methanol (80mL) were charged to a glass
liner and secured in a 300mL Parr pressure reactor. The
vessel was charged with nitrogen to a pressure of 10bar,
stirred (800rpm) and after 15min vented. The mixture was
heated to 40ꢁC and the nitrogen charge-vent cycle
1. (a) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069–
1094; (b) Ringwald, M.; Sturmer, R.; Brintzinger, H. H. J.
¨
Am. Chem. Soc. 1999, 121, 1524–1527; (c) Abdur-Rashid,
K.; Lough, A. J.; Morris, R. H. Organometallics 2000, 19,
2655–2657; (d) Cobley, C. J.; Henschke, J. P. Adv. Synth.
Catal. 2003, 345, 195–201.
repeated twice. Stirring was stopped and
a freshly
2. (a) Wallace, D. J.; Klauber, D. J.; Chen, C.-Y.; Volante,
R. P. Org. Lett. 2003, 5, 4749–4752; (b) Padwa, A.; Akiba,
M.; Cohen, L. A.; MacDonald, G. J. J. Org. Chem. 1983,
48, 695–703; (c) Burk, M. J.; Casy, G.; Johnson, N. B. J.
Org. Chem. 1998, 63, 6084–6085.
prepared solution of [(S,S)-Et-DuPhos RhCOD]BF4 in
deoxygenated methanol (5mL of a 0.0011M solution,
0.0055mmol) was then added. The vessel was charged with
hydrogen to a pressure of 10bar and subsequently vented.
This hydrogen charge-vent cycle was repeated twice and
the vessel was then charged with hydrogen to a pressure of
10bar and stirring initiated. The hydrogen pressure was
maintained between 8.3 and 10bar and once consumption
ceased, the vessel was vented and the mixture concentrated
in vacuo to provide the amine 3, which was used without
further purification. Hydrochloric acid (45mL of a 6M
solution in water, 270mmol) was added to a solution of
the amine 3 in ethanol (15mL). After heating at reflux for
17h further hydrochloric acid (15mL of a 6M solution in
water, 90mmol) was added and heating was continued for
a further 4h. The mixture was concentrated in vacuo and
the residue was redissolved in ethanol (60mL) and
concentrated in vacuo. This procedure was repeated
twice and the residue was then slurried in dichloro-
methane/MTBE (50mL, 1:3 v/v). Isolation by filtration
followed by drying in vacuo (40ꢁC, 35mbar) provided
2ÆHCl as an off-white solid (5.34g, 86% overall). 1H
NMR d (400MHz, DMSO) 8.41 (2H, br s), 7.68 (1H, s),
7.56 (1H, d, J 8Hz), 7.35 (1H, d, J 8Hz), 4.28 (1H, q, J
6Hz) and 1.32 (3H, d, J 6Hz). 2ÆHCl (4mg) was dissolved
in MTBE (2mL) and washed with 2M NaOH (2mL). GC
analysis of the MTBE solution indicated >98% ee (Chirasil
Dex-CB, Helium (20psi), 100ꢁC for 30min ramped to
200ꢁC at 5ꢁC/min, (S)-2ÆHCl: 40.5min, (R)-2ÆHCl:
40.4min).
3. Burk, M. J.; Wang, Y. M.; Lee, J. R. J. Am. Chem. Soc.
1996, 118, 5142–5143.
4. Representative procedure: trifluoromethanesulfonic anhy-
dride (17.1mL, 101mmol) was added in a dropwise
manner, at a rate such that the temperature did not
exceed 15ꢁC, to a stirred solution of 3,4-dichlorophenol
(15.0g, 92.0mmol) and triethylamine (15.9mL, 120mmol)
in dichloromethane (100mL) under a nitrogen atmos-
phere. Once the addition was complete the mixture was
warmed to room temperature. After 18h, the mixture was
diluted with MTBE (150mL), sequentially washed with
saturated ammonium chloride solution (2 · 100mL), 2M
sodium carbonate (2 · 100mL) and brine (100mL). The
organic phase was dried (MgSO4), filtered and the filtrate
concentrated in vacuo to provide 3,4-dichloro-1-tri-
fluoromethanesulfonyloxy-benzene as a light yellow liquid
(27.8g), which was used in the next step without further
purification. 1H NMR d (400MHz, CDCl3) 7.55 (1H, d, J
8Hz), 7.42 (1H, d, J 2Hz), 7.17 (1H, dd, J 8 and 2Hz); 19
NMR d (376MHz, CDCl3) À73.
F
5. Cabri, W.; Candiani, I.; Bedeschi, A. J. Org. Chem. 1992,
57, 3558–3563.
6. Andappan, M. M. S.; Nilsson, P.; von Schenck, H.;
Larhed, M. J. Org. Chem. 2004, 69, 5212–5218.
7. There is one previous report of N-vinylacetamide
being used in Heck reactions with aryl bromides, which