Palladium-Catalyzed Amidation of Enol Triflates: A New Synthesis of Enamides

Article abstract of DOI:10.1021/ol035959g

(Matrix presented) The palladium-catalyzed coupling of a range of enol triflates with amides, carbamates, and sulfonamides has been developed. This offers a simple and widely applicable synthesis of enamides, which may not be readily available by other me

Full text of DOI:10.1021/ol035959g

ORGANIC
LETTERS
2003
Vol. 5, No. 24
4749-4752
Palladium-Catalyzed Amidation of Enol
Triflates: A New Synthesis of Enamides
Debra J. Wallace,* David J. Klauber, Cheng-yi Chen, and Ralph P. Volante
Department of Process Research, Merck Research Laboratories, P. O. Box 2000,
Rahway, New Jersey 07065
debra_wallace@merck.com
Received October 7, 2003
ABSTRACT
The palladium-catalyzed coupling of a range of enol triflates with amides, carbamates, and sulfonamides has been developed. This offers a
simple and widely applicable synthesis of enamides, which may not be readily available by other means.
In recent years there has been a surge of interest in the
palladium-catalyzed C-N bond-forming reactions of aryl
halides with amines and amides.1-3 These reactions can
proceed under mild conditions and are compatible with a
range of substrates, offering improvements over traditional
methods. For many palladium-catalyzed reactions, enol
triflates can also function as reactive coupling partners;4
however, this has only recently been extended to C-N bond-
forming reactions with the amination of a simple enol triflate
to afford an enamine.5 The related amidation of an enol
triflate would constitute a straightforward synthesis of
enamides, which are valuable substrates for asymmetric
hydrogenation reactions and hence for the synthesis of
optically pure amines (Scheme 1).
be prepared,6 the synthesis of highly substituted enamides
in an efficient and stereoselective manner is more challeng-
ing.7 The palladium- or copper-mediated amidation of a vinyl
halide appeared attractive;8 however, the controlled produc-
tion of these substrates would also present a challenge. In
contrast, the selective formation of a single enol triflate from
a ketone may rely on simple kinetic vs thermodynamic
control in the enolate formation step and can be tuned by
judicious choice of base and solvent combinations. To the
best of our knowledge, no amidations of enol triflates have
been reported, and in this paper we describe our initial studies
on this useful reaction.
(2) (a) Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609. (b)
Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 7217. (c) Hartwig,
J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman,
L. M. J. Org. Chem. 1999, 64, 5575. (d) Stambuli, J. P.; Kuwano, R.;
Hartwig, J. F. Angew. Chem., Int. Ed. 2002, 41, 4746.
(3) (a) Reddy, N. P.; Tanaka, M. Tetrahedron Lett. 1997, 38, 4807. (b)
Kim, Y. M.; Yu, S. J. Am. Chem. Soc. 2003, 125, 1697.
Scheme 1
(4) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b) Scott,
W. J.; McMurray, J. E. Acc. Chem. Res. 1988, 21, 47.
(5) Willis, M. C.; Brace, G. N. Tetrahedron Lett. 2002, 43, 9085. See
also Hicks, F. A.; Brookhardt, M. Org. Lett. 2000, 2, 219.
(6) Burk, M. J.; Casy, G.; Johnson, N. B. J. Org. Chem. 1998, 63, 6084.
(7) For stereocontrolled synthesis of 1,2-disubstituted enamides, see: (a)
Furstner, A.; Brehm, C.; Cancho-Grande, Y. Org. Lett. 2001, 3, 3955. (b)
Snider, B. B.; Song, F. Org. Lett. 2000, 2, 407 and references therein. For
stereoselective preparation of trisubstituted enamides, see: Tanaka, R.;
Hirano, S.; Urabe, H.; Sato, F. Org. Lett. 2003, 5, 67 and references
therein.
(8) For copper-catalyzed amidations of vinyl halides, see: (a) Jiang, L.;
Job, G. E.; Klapars, A.; Buchwald, S. L Org. Lett. 2003, 5, 3667. (b) Shen,
R.; Porco, J. A. Jr. Org. Lett. 2000, 2, 1333. (c) Ogawa, T.; Kiji, T.; Hayami,
K.; Suzuki, H. Chem. Lett. 1991, 1443. For a palladium-catalyzed
intramolecular reaction, see: Kozawa, Y.; Mori, M. Tetrahedron Lett. 2002,
43, 111.
With regard to a recent drug discovery program at Merck,
a stereodefined trisubstituted enamide was required for
hydrogenation studies. While 1,1-disubstituted enamides can
(1) (a) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 7215. (b) Marcoux, J.-F.; Wagaw, S.; Buchwald, S. L. J. Org.
Chem. 1997, 62, 1568. (c) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem.
1997, 62, 6066. (d) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem.
Soc. 1998, 120, 9722. (e) Old, D. W.; Harris, M. C.; Buchwald, S. L. Org.
Lett. 2000, 2, 1403. (f) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101.
10.1021/ol035959g CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/07/2003

Table 1. Optimization of Coupling Conditions
ligand
palladium
solvent
base
temp
time
conversion
ratioa
Xantphos
Xantphos
Xantphos
Xantphos
PCy3
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
THF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
KOtBu
iPr2NEt
80 °C
rt
16 h
6 h
>95
75
85
>95
0
45:55
92:8
rt
8 h
94:6
rt
20 h
16 h
16 h
16 h
6 h
45:55
rt
BINAP
35 °C
35 °C
rt
16
0
46:54
93:7
dppf
Xantphos
Xantphos
Xantphos
67
0b
dioxane
dioxane
rt
3 h
35 °C
16 h
0
a HPLC ratio of 2a:2b. b Starting material converted to alkyne
The readily accessible enol triflate 1, along with acetamide,
was chosen to screen reaction conditions, and initially
the procedure developed by Buchwald1f for the amidation
of aryl halides was examined [Pd(OAc)2, Xantphos,9 and
Cs2CO3 in 1,4-dioxane at 80 °C]. After 8 h, complete
conversion of the enol triflate to a 1:1 mixture of two new
products was observed, and after chromatographic separa-
tion, these were identified as the two isomeric enamides 2a
and 2b.10 This indicated that the coupling was indeed a
viable process but also suggested that isomerization of the
enol triflate or product had taken place during the reaction.
Indeed, resubjection of either of the purified enamides to
the reaction conditions afforded a 1:1 mixture of isomers.
Lowering the temperature to 40-50 °C led to slower
isomerization, and at room temperature the enamides were
relatively stable to the reaction conditions. Hence, for
successful implementation, amidation at room temperature
would be required. On the basis of this, a number of
palladium sources, ligands, bases, and solvents were screened
for this reaction
As can be seen from Table 1, running the reaction at room-
temperature allowed for moderate conversion with minimal
isomerization and a change of palladium source to Pd2(dba)3
gave a 94:6 ratio of enamide isomers with high conversion
after 8 h. Even at these temperatures product equilibration
still occurred after prolonged reaction times. The use of
ligands other than Xantphos (PCy3, BINAP, dppf) was not
successful, with only BINAP providing any of the desired
product. Changing the solvent had only a minor effect;
however, Cs2CO3 was found to be the optimal base. Amine
bases did not promote the reaction, and the use of KOtBu
afforded solely the corresponding alkyne.
With a viable coupling procedure in hand, attention was
turned to the generality of the process and the couplings of
a range of structurally diverse enol triflates with different
amides were studied (Table 2). Where enamide equilibration
was not possible, reactions were run at 50 °C and, as
anticipated, this higher reaction temperature allowed for
complete consumption of starting material without detri-
mental side reactions.
The coupling was found to be compatible with primary
aliphatic and aromatic amides, including the hindered trim-
ethylacetamide and adamantanecarboxamide (entries 4 and
5), and also with functionalized amides (entry 6).11 In the
case of secondary amides, good yields were obtained with
the cyclic 2-pyrrolidinone (entry 7), but N-methylbenzamide
did not react with either enol triflate 3 or 4. This may be
due to steric constraints, as a similar lack of reactivity for
secondary amides has been observed in related reactions.1f
The high yields obtained for the couplings of primary amides
can also be attributed to the lack of reactivity of the
secondary amide product to further coupling. The hindered
enol triflate 5 required higher reaction temperatures, reaching
only 80% conversion after 20 h at 80 °C (entry 8). Some
form of enol triflate activation by electron-withdrawing
substituents or conjugation appeared to be necessary, as enol
(11) General Procedure for Palladium-Catalyzed Amidation Reaction:
Synthesis of Enamide 11. To a solution of enol triflate 3 (255 mg, 0.832
mmol) in dioxane (5.0 mL) at room temperature was added Cs2CO3 (379
mg, 1.16 mmol), trimethylacetamide (109 mg, 1.08 mmol), Xantphos (43.6
mg, 0.075 mmol), and Pd2(dba)3 (23.0 mg, 0.025 mmol). The mixture was
degassed and stirred at 50 °C for 9 h after which time complete conversion
was obtained. The mixture was filtered, concentrated, and purified by flash
column chromatography (toluene) to give the desired enamide (214 mg,
96%): mp ) 96-98 °C; IR (CHCl3 solution) 3252, 2920, 1650, 1645,
1510, cm-1; 1H (400 MHz, CDCl3) δ 7.37 (dd, J ) 7.9, 1.4 Hz, 2H), 7.27
(tt, J ) 7.9, 1.4 Hz, 1H) 7.19 (dd, J ) 7.9, 1.4 Hz, 2H), 6.73 (s, 1H), 2.64
(m, 2H), 2.35 (m, 2H), 1.76 (m, 4H), 1.00 (s, 9H); 13C (100.6 MHz, CDCl3)
δ 176.3, 140.8, 130.9, 128.6, 128.1, 127.0, 125.6, 39.0, 30.7, 27.6, 27.3,
22.8, 22.7; LCMS 258 (MH+, 80), 174 (80), 157 (100); HRMS C17H23NO
(MH+) theory 258.1858, measured 258.1851.
(9) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M. Organometallics 1995, 14, 3081.
(10) New compounds were fully characterized by 1H, 13C, IR, and HRMS
and/or elemental analysis.
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Org. Lett., Vol. 5, No. 24, 2003

Table 2. Coupling of Various Enol Triflates and Amidesa
a Reagents and conditions: enol triflate 1.0 equiv, amide 1.2 equiv, Cs2CO3 1.4 equiv, Pd2(dba)3 3 mol %, Xantphos 9 mol %, 0.2 M in dioxane, 50 °C,
8-14 h. b Isolated yield after chromatography. c At room temperature. d Using KOtBu. e At 80 °C.
triflate 6 did not react with acetamide or benzamide (entry
9) and only trace amounts of product were isolated from the
reaction of enol triflate 7 with 2-pyrolidinone (entry 10). In
substrates where elimination to alkynes or allenes was not
possible, KOtBu could be employed as an alternative base.
With enol triflate 3, shorter reaction times were required with
the soluble base compared to Cs2CO3 (entry 3); however,
competing hydrolysis to the starting ketone lowered yields
with enol triflate 4 (entry 11).
While amides are the most commonly employed nitrogen
protecting group for enamide hydrogenation reactions, the
harsh conditions required to remove these groups can limit
substrate compatibility. With this in mind, C-N bond-
forming reactions were studied with other readily available
nitrogen compounds. Both tert-butyl and benzyl carbamate
underwent coupling reactions with enol triflate 3 in high yield
(entries 12 and 13); however, the less nucleophilic p-
toluenesulfonamide could only be coupled with the highly
reactive enol triflate 4 (entry 14).12
The presence of an aryl bromide in either coupling partner
did not interfere with the desired reaction under the above
conditions. For example, the coupling of enol triflate 3 or 4
with 2-bromobenzamide at 50 °C afforded solely the product
resulting from amidation of the enol triflate with no polym-
(12) While a conjugate addition/elimination pathway could operate for
this enol triflate, we feel that this is unlikely due to the lack of reactivity
in the absence of palladium (<5% conversion after 24 h). We thank a referee
for alerting us to this possibility.
Org. Lett., Vol. 5, No. 24, 2003
4751

isomerization, but no coupling with the aryl bromide group
was observed at this temperature.
Scheme 2a
In conclusion, we have demonstrated that the palladium-
catalyzed amidation of activated enol triflates to afford
enamides is a viable procedure for the synthesis of a range
of cyclic and acyclic enamides. The reactions proceed under
mild conditions that would be compatible with a range of
functionality. Selective coupling of an enol triflate in the
presence of aryl bromides can be achieved. Carbamates, and
in some cases sulfonamides, can also be coupled efficiently.
Where enamide equilibration can occur, control of reaction
temperature allowed for stereoselective synthesis of the
required enamides.
a Reagents and conditions: (a) Cs2CO3 1.4 equiv, Pd2(dba)3 3
mol %, Xantphos 9 mol %, dioxane, 50 °C, 16 h. b Acetamide 1.3
equiv, Cs2CO3 1.4 equiv, Pd2(dba)3 3 mol %, Xantphos 9 mol %,
dioxane, 23 °C, 9 h.
Acknowledgment. We thank Tom Novak for the high-
resolution mass spectral data, Brenda Pipik for elemental
analysis, and Jingjun Yin for preparation of Xantphos.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
erization of the bromobenzamide or subsequent Heck reaction
of the product (Scheme 2). Coupling of acetamide with enol
triflate 21 at room temperature gave an 83% yield of the
product from reaction of the enol triflate. Increasing the
reaction temperature to 50 °C resulted in some alkene
OL035959G
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Org. Lett., Vol. 5, No. 24, 2003