A facile and mild synthesis of enamides using a gold-catalyzed nucleophilic addition to allenamides

Article abstract of DOI:10.1021/ol1001494

Chemical Equation Presentation A mild and facile synthesis of enamides has been developed, based on nucleophilic addition of electron-rich aromatic and heteroaromatics to an allenamide unit catalyzed by a gold salt. Yields for the transformation were 29-98%.

Full text of DOI:10.1021/ol1001494

ORGANIC
LETTERS
2010
Vol. 12, No. 5
1128-1131
A Facile and Mild Synthesis of
Enamides using a Gold-Catalyzed
Nucleophilic Addition to Allenamides
Marc C. Kimber*
Department of Chemistry, Loughborough UniVersity, Leicestershire LE11 3TU, U.K.
M.C.Kimber@lboro.ac.uk
Received January 20, 2010
ABSTRACT
A mild and facile synthesis of enamides has been developed, based on nucleophilic addition of electron-rich aromatic and heteroaromatics
to an allenamide unit catalyzed by a gold salt. Yields for the transformation were 29-98%.
Enamides have become an increasingly valuable and hence
topical functional group within the synthetic community.1
They are contained in a number of natural product frame-
works such as the chondriamides and salicylihalamides and
within cyclic peptides. They have also been used as asym-
metric synthetic precursors within the context of heterocyclic
and amine synthesis.2 The unique reactivity that enamides
display has led to the development of a number of general
and E/Z selective syntheses. To date the synthesis of
enamides has often been centered around condensation of
an amide equivalent with the corresponding carbonyl fun-
tionality.3 However more elaborate and novel methods such
as organocuprate addition to isocyanates,4 acylation of
in situ prepared imines5 and an N-acylation/Peterson elimina-
tion process6 have also been developed. Complementing
these methods, a number of transition-metal-catalyzed ap-
proaches based on C-N bond-forming reactions (Pd, Cu),7
isomerizations of allyl amides (Fe, Rh, Ru),8 addition of
amides to alkynes (Ru), organometallic additions to ynamides
(Rh),9 Heck couplings (Pd),10 co-oligomerization of N-vinyl
amides (Ru),11 and oxidative conjugate additions (Pd)12 have
also been reported (Scheme 1).
In the synthesis of enamides the relationship between
enamides and allenamides, both of which contain the desired
sp2 carbon attached directly to the amide, has yet to be fully
exploited. Allenamides represent a fascinating and versatile
functional group whose chemical utility has been exploited
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10.1021/ol1001494  2010 American Chemical Society
Published on Web 02/09/2010

vinylimidazolidinones23b Via a 5-exo-tet mechanism in each
case. However, for the intermolecular gold-catalyzed addition
of nucleophiles to activated allenamides there have been no
reports to our knowledge.26
Scheme 1. Transition Metal Strategies in Enamide Synthesis
In the intermolecular addition there is an issue of regi-
oselectivity (Scheme 2). Addition of the nucleophile to the
terminal carbon of the gold-activated allenamide 1 would
potentially deliver enamide 2; alternatively, addition to the
carbon adjacent to the nitrogen would deliver the allylic
amine 3. In this study we wished to explore this regioselec-
tivity issue Via the addition of carbon nucleophiles to an
activated allenamide. To activate the allenamide we have
chosen to utilize gold salts, and the attacking nucleophiles
that we selected for the study would be electron-rich
aromatics and heteroaromatics, which we expect to add to
the activated allenamides Via a Friedel-Crafts-type mech-
anism.
by a number of groups.13 The chemistry in which allenamides
have participated include radical cyclizations,14 tandem
epoxidation/cycloadditions,15 Pauson-Khand cyclizations,16
[4 + 2]17 and [4 + 3]18 cycloadditions, acid-catalyzed
cyclizations/rearrangements,19 palladium-mediated transfor-
mations,20 cyclopropanations,21 base-catalyzed CO2 cap-
ture,22 and finally, gold-mediated transformations.23
The use of gold salts for the activation of allenamides is
an attractive concept as it would negate the use of acidic
conditions for allenamide activation24 and would therefore
be more functional group tolerant.25 It is in this class of
reactions, catalyzed by gold salts, in which we thought we
could make a contribution within the context of direct
intermolecular arylations (Scheme 2).
Scheme 3. Synthesis of Allenamides 5a,b
Our test substrate for this study would be the allenamide
5a, which was convieniently synthesized in 2 steps using
the method of Wei et al. (Scheme 3).27 With 5a in hand, a
trial reaction with 1-methylindole, 6a, in the presence of 5
mol % of in situ prepared AuPPh3OTf in CH2Cl2 was
performed (Scheme 4).
Scheme 2. Intermolecular Gold Addition to Allenmamides
To our delight the starting material was consumed within
30 min, and a new product was detected by TLC. This was
subsequently isolated and shown to be the indole enamide
1
7a by a combination of H and 13C NMR and IR spectros-
copy (Scheme 4). The spectroscopic data for 7a show, inter
(20) Beccalli, E. M.; Broggini, G.; Clerici, F.; Galli, S.; Kammerer, C.;
Rigamonti, M.; Sottocornola, S. Org. Lett. 2009, 11, 1563. Fuwa, H.; Sasaki,
M. Org. Biomol. Chem. 2007, 5, 2214. Ma, S.; Gu, Z.; Yu, Z. J. Org. Chem.
2005, 70, 6291.
To date there have only been two reports of gold-catalyzed
cyclization of allenamides, and in both cases the attacking
nucleophile has been intramolecular and a heteroatom,
forming either 2,5-disubstituted dihydrofurans23a or
(21) Lu, T.; Hayashi, R.; Hsung, R. P.; DeKorver, K. A.; Lohse, A. G.;
Song, Z.; Tang, Y. Org. Biomol. Chem. 2009, 7, 3331.
(22) Chen, G.; Fu, C.; Ma, S. Org. Lett. 2009, 11, 2900.
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(b) Manzo, A. M.; Perboni, A. D.; Broggini, G.; Rigamonti, M. Tetrahedron
Lett. 2009, 50, 4696.
(13) Wei, L.-L.; Xiong, H.; Hsung, R. P. Acc. Chem. Res. 2003, 36,
773.
(14) Shen, L.; Hsung, R. P. Org. Lett. 2005, 7, 775.
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Rameshkumar, C.; Hsung, R. P. Angew. Chem., Int. Ed. 2004, 43, 615.
(16) Anorbe, L.; Poblador, A.; Domy´nguez, G.; Perez-Castells, J.
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Garcy´a, A.; Saa, C.; Domy´nguez, D. Tetrahedron Lett. 2007, 48, 2741.
Kinderman, S. S.; Wekking, M. M. T.; Maarseveen, J. H.; Schoemaker,
H. E.; Hiemstra, H.; Rutjes, F. P. J. T. J. Org. Chem. 2005, 70, 5519.
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Hashmi, A. S. K. Chem. ReV. 2007, 107, 3180. Arcadi, A. Chem. ReV.
2008, 108, 3266.
´
Tetrahedron Lett. 2004, 45, 4441. Gonza´lez-Go´mez, A.; An˜orbe, L.;
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A. G.; Hsung, R. P. Org. Lett. 2009, 11, 3430.
(26) One reviewer kindly pointed out that the intermolecular addition
of HCl to a pyrazol-allene giving the pyrazol-allylchloride has been reported,
Baikalova, L. V.; Zyryanova, I. A.; Tarasova, O. A.; Chipanina, N. N.;
Shmidt, E. Yu.; Kashik, T. V.; Afonin, A. V.; Sinegovskaya, L. M.;
Vashchenko, A. V.; Trofimov, B. A. Russ. J. Gen. Chem. 2003, 73, 1634.
(27) Wei, L.-L.; Mulder, J. A.; Xiong, H.; Zificsak, C. A.; Douglas,
C. J.; Hsung, R. P. Tetrahedron 2001, 57, 459.
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Org. Lett., Vol. 12, No. 5, 2010
1129

alia, a doublet at 6.80 (J ) 14.4 Hz), double triplets at 5.01
(J ) 14.4 and 6.8), and a doublet at 3.51 (J ) 6.8 Hz), as
well as an absorbance at 1671 cm-1 in the IR spectrum, all
indicative of an E-enamide. This result confirmed that
addition of the indole nucleophile occurs at the terminus of
the activated allenamide as opposed to the carbon adjacent
to the nitrogen.
Scheme 5. Enamides Synthesized from 5a
Scheme 4
While the yield for this transformation was adequate, we
next set out to optimize our reaction conditions, the results
of which are summarized in Table 1.
Table 1. Intermolecular Arylation of Allenamide 5a with
N-Methylindole 6aa
equivalents
timeb
(h)
conversionc
[% yield]
entry
catalyst
of 6a
1
2
3
PPh3AuOTf
PPh3AuOTf
PPh3AuOTf
AgOTf
TFA
PPh3Au(NTf2)
2.00
1.50
1.05
1.05
1.05
1.05
1.05
0.5
0.5
0.5
16
2.0
0.5
1.0
100 [82]
100
100
0
42
4d
5e
6
100 [83]
95
a Yield is based on 2 equiv of 10.
7f
PPh3Au(NTf2)
a Reactions run with 5.0 mol % of catalyst in CH2Cl2 at room temperature
unless otherwise stated. b Determined by disapperance of 5a by TLC analysis
unless otherwise stated. c Conversion was determined by 1H NMR; isolated
yield in brackets. d No consumption of starting material was seen after 16 h.
e 1 equiv of acid relative to 5a. f 1.0 mol % of catalyst.
With optimized conditions for the arylation determined,
the scope of this transformation was then explored (Scheme
5). N-Methylindole 6a and indole 6b reacted with allenamide
5a to give the enamides 7a and 7b in good yields (entries 1
and 2). 3-Methylindole 8 gave the 2-substituted enamide 7c
in modest yield with the remaining mass balance being
accounted for by the N-substituted enamide (entry 3).29 This
is where reaction has occurred through the indole NH and
suggests that intermolecular enamide synthesis is attainable
using heteroatoms. While anisole failed to add to allenamide
5a, the more electron-rich 1,3,5-trimethoxy benzene 9 added
in good yield to give 7d (entry 4). N-Methyl pyrrole 10 gave
a mixture of the mono- and disubstituted enamides 7e and
7f in modest yields (entry 5). Increasing the amount of 10
relative to allenamide 5a to 2 equiv gave exclusively the
disubstituted enamide 7f in an excellent yield of 88%. Based
on the result from using indole 8, tetrahydrocarbozole 11
gave exclusively the N-substituited enamide 7g in a yield of
78% (entry 6). Finally, addition of 2-methyl furan 12 gave
Variation of the number of equivalents of 6a from 2.0 to
1.05 had no effect on conversion to the desired product,
indicating that the reaction could be essentially carried out
with equimolar amounts of the two reactants (entries 1, 2,
and 3, respectively). Conducting the reaction in the presence
of only AgOTf had no effect on the reaction with starting
material being recovered (entry 4). TFA did promote the
reaction, as expected;28 however, the conversion was low
compared to the gold-catalyzed examples possibily due to
product degradation, and significantly the rate of reaction
was lower. Altering the gold source counterion from OTf to
(NTf2) had no effect on the reaction (entry 6); also, lowering
the amount of gold catalyst from 5 to 1 mol % had little
effect on conversion but did result in increased reaction times
(entry 7).
(28) Navarro-Vazquez, A.; Rodry´guez, D.; Marty´nez-Esperon, M. F.;
Garcy´a, A.; Saa, C.; Domy´nguez, D. Tetrahedron Lett. 2007, 48, 2741.
(29) See structure 22 in Supporting Information for physical data.
Org. Lett., Vol. 12, No. 5, 2010
1130

the amide 13 in a modest yield, presumably due to a second
addition of 12 to the initially formed enamide (entry 7).30
Chiral allenamide 5b was coupled to 6a, 6b, 9, and 10
under the same catalytic gold conditions (Scheme 6). The
yields mirrored that of the achiral allenamide 5a, and
significantly, all enamides 14a-e were delivered with no
racemization of the stereogenic center (entries 1-4).
Scheme 7. Plausible Mechanism
Scheme 6. Enamides Derived from Chiral 5b
In summary, we have demonstrated for the first time that
the intermolecular gold-catalyzed addition of electron-rich
aromatics and heteroaromatics to activated allenamides is
regioselective and high yielding. This method delivers the
desired enamides under very mild conditions, with no
exclusion of air during the reaction and in very short reaction
times as compared to many of the Pd, Ru, Rh, and Cu
coupling methods. The use of this transformation in further
intermolecular transformations, multicomponent reactions,
and natural product synthesis will be reported on in due
course.
a Yield is based on 2 equiv of 10.
A plausible mechanism for this transformation is presented
in Scheme 7. Initial Au complexation to 5a could be Via
pathway A or B; however, pathway A could be energetically
unfavorable as a result of the formation of a primary
carbocation 17. However, both pathways A and B deliver
the key intermediate conjugated acyliminium 19 that can
undergo 1,4-addition by a nucleophile giving 20. This then
subsequently undergoes protodemetalation giving the ena-
mide 21.
Acknowledgment. The author thanks Loughborough
University for financial support and Dr. Mark Edgar (Depart-
ment of Chemistry, Loughborough University) for NMR
analysis.
Supporting Information Available: Experimental pro-
cedures, NMR spectra and characterization for all new
materials. This material is available free of charge via the
Internet at http://pubs.acs.org.
(30) The 1H NMR spectra does indicate a small amount of the enamide
is formed during the reaction; see Supporting Information.
OL1001494
Org. Lett., Vol. 12, No. 5, 2010
1131