A palladium-catalyzed regio- and stereoselective four-component coupling reaction

Article abstract of DOI:10.1021/jo0484068

(Chemical Equation Presented) Pd(PPh₃)₄ catalytically assembles sulfenamide, alkyne, carbon monoxide, and diphenyl diselenide regio- and stereoselectively in a one-pot four-component coupling reaction to yield (Z)-β-selenyl acrylamid

Full text of DOI:10.1021/jo0484068

A Palladium-Catalyzed Regio- and Stereoselective
Four-Component Coupling Reaction
Daniel J. Knapton and Tara Y. Meyer*
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
tmeyer@pitt.edu
Received September 9, 2004
Pd(PPh3)4 catalytically assembles sulfenamide, alkyne, carbon monoxide, and diphenyl diselenide
regio- and stereoselectively in a one-pot four-component coupling reaction to yield (Z)-â-selenyl
acrylamides. The reaction proceeds in good to excellent yields (60-95%) and is tolerant of a range
of functional groups on both the nitrogen of the sulfenamide and the alkyne. Moderate selectivities
ranging from 4:1 to 7:1 â-selenyl to â-sulfenyl acrylamide have been observed despite the initial
concentration of 2:1 selenium to sulfur in the reaction. The chalcogeno selectivity was found to
depend directly on CO pressure; increased pressure decreased selectivity for selenium over sulfur.
Introduction
actions. These assembly processes have several common
aspects that enhance their utility including (1) high
selectivity for the synthesis of one isomeric form of a
single product, (2) tolerance of structural diversity on one
or more of the reagents, and (3) the formation of at least
one C-C bond.
As previously communicated, we have developed a new
palladium-mediated four-component coupling reaction for
the synthesis of â-selenyl acrylamides (Scheme 1).13 This
reaction satisfies the above-mentioned criteria in that it
produces high yields of a single regio- and stereoisomer,
there is considerable diversity available in both the
alkyne and sulfenamide (PhS-NR2) reagents, and one
C-C bond as well as two C-heteroatom bonds (C-N,
C-Se) is formed. In addition, the reaction yields a
product with two reactive functionalities available for
subsequent modification: an R,â-unsaturated amide and
a vinylic pseudohalide group, PhSe-.14 It should be noted
The development of one-pot multicomponent coupling
reactions has provided a rapid and elegant means for the
preparation of complex molecular architectures from
simple and diverse building blocks.1-3 The attraction to
the synthetic chemist lies in the multitude of advantages
that include higher yields than almost any sequential
synthesis to the same target, a single purification step,
and easy adaptation to combinatorial synthetic schemes.4-6
Well-known examples include the Ugi four-component
reaction,7 as well as the Hantzch,8 Biginelli,9 Mannich,10
Passerini,11 and Bucherer-Bergs12 three-component re-
* To whom correspondence should be addressed. Phone: 412-624-
0838. Fax: 412-624-8611.
(1) Montgomery, J. Acc. Chem. Res. 2000, 33, 467.
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J. 2000, 6, 3321.
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(6) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
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10.1021/jo0484068 CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/12/2005
J. Org. Chem. 2005, 70, 785-796
785

Knapton and Meyer
SCHEME 1
PhSe group is more highly precedented using the easily
handled (PhSe)2.23 The PhSe-SePh bond is easily cleaved
by palladium, and it is known that Pd-SePh groups are
capable of migratory insertion, a key reaction in our
system.15h It is important to note that the reactions
mixtures do not contain significant quantities of thiols
or selenols and, therefore, are not particularly odiferous.
To the best of our knowledge, no simple or general
methodology exists for the synthesis of the â-selenyl
acrylamides despite the wealth of knowledge regarding
the preparation and reactivity of the corresponding vinyl
chalcogenides.14e,23,24 The most common preparation of
â-selenyl acrylamides involves the initial synthesis of
â-functionalized acrylates from the hydrochalcogenation
of preformed alkynoic esters. The acrylamide derivatives
are then prepared in subsequent steps by simple con-
densation methods. This approach, though effective,
requires several steps and generally involves the use of
the noxious chalcogenols.25
Recently, new methodology for the preparation of the
related â-sulfenyl acrylates and â-telluryl acrylamides
has been reported.26,27 The former has been prepared via
the palladium-catalyzed thioesterification of alkynes and
the latter via the photoinduced group-transfer radical
addition of tellurylcarbamates to aromatic acetylenes.
Neither has yet been extended to include â-selenyl
acrylamides. Other less common methods for the prepa-
ration of â-chalcogenyl acrylamides exist but are limited
by low yield, substrate specificity, and R rather than â
substitution of the chalcogen.15e,25,28
that few multicomponent couplings give products with
more than one reactive functionality and, although metal-
catalyzed multicomponent coupling reactions1,2,15 are
well-known, they are generally limited to three compo-
nents with the corresponding four-component reactions16
being far more rare.
An unusual pair of heteroatom delivery agents are used
in our system, PhS-NR2 and (PhSe)2. Sulfenamides
represent an alternative to the traditional NR2 delivery
agents, namely, amines and silylamines. Despite the need
for their preparation, sulfenamides are easily synthesized
in one step from commercially available starting materi-
als, and neither they nor their starting materials are
noxious.17 Although not commonly encountered, sulfena-
mides have found some synthetic utility. For example,
Kuniyasu and co-workers found them to be quite useful
in the production of thiocarbamates in the palladium-
catalyzed azathiolation of carbon monoxide,18a and more
recently, Kondo and co-workers have prepared polyfunc-
tionalized alkenes via the ruthenium-mediated addition
of sulfenamides to alkynes.18b In addition, a specific class
of sulfenamide, 4′-nitrobenzenesulfenanalide (NBSA), has
been found to be an effective reagent for the amidino-
and amidosulfenylation,19 aminosulfenylation,20,21 and
bromosulfenylation22 of alkenes. The introduction of the
In this paper, we present a full study of the â-selenyl
acrylamide-forming reaction, including reactant general-
ity, mechanism, and the selective partitioning of selenium
and sulfur in the reaction products. The effect of two-
and three-component side reactions on the overall forma-
tion of the â-selenyl acrylamides is also considered.
(14) For manipulations of the PhSe- group see: (a) Huang, X.; Ma,
Y. Synthesis 1997, 417. (b) Huang, X.; Ma, Y. Synth. Commun. 1997,
27, 2407. (c) Comasseto, J. V.; Lo, W. L.; Petragnani, N. Tetrahedron
1997, 53, 7445. (d) Denis, J. N.; Krief, A. Tetrahedron Lett. 1982, 23,
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Org. Chem. 2004, 69, 1075. (d) Fruehauf, H. W. Chem. Rev. 1997, 97,
523. (e) Huang, X.; Sun, A. J. Org. Chem. 2000, 65, 6561. (f) Kamijo,
S.; Jin, T.; Huo, Z.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 7786.
(g) Kawakami, J.; Mihara, M.; Kamiya, I.; Takeba, M.; Ogawa, A.;
Sonoda, N. Tetrahedron 2003, 59, 3521. (h) Kuniyasu, H.; Ogawa, A.;
Miyazaki, S.; Ryu, I.; Kambe, N.; Sonoda, N. J. Am. Chem. Soc. 1991,
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Z.; Wei, C.; Chen, L.; Varma, R.; Li, C.-J. Tetrahedron Lett. 2004, 45,
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Commun. 2002, 1284. (m) Nishiyama, Y.; Tokunaga, K.; Kawamatsu,
H.; Sonoda, N. Tetrahedron Lett. 2002, 43, 1507. (n) Ogawa, A.; Takeba,
M.; Kawakami, J.; Ryu, I.; Kambe, N.; Sonoda, N. J. Am. Chem. Soc.
1995, 117, 7564. (o) Ogawa, A.; Kuniyasu, H.; Sonoda, N.; Hirao, T. J.
Org. Chem. 1997, 62, 8361. (p) Olivi, N.; Spruyt, J. P.; Alami, M.; Brion,
J. D. Tetrahedron Lett. 2004, 45, 2607. (q) Patel, S. J.; Jamison, T. F.
Angew. Chem., Int. Ed. 2003, 42, 1364. (r) Rao, I. N.; Prabhakaran, E.
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J. Org. Chem. 2000, 65, 4138. (z) Zhao, L.; Lu, X. Org. Lett. 2002, 4,
3903.
Results and Discussion
The reaction of S-phenyl-N-dimethyl sulfenamide,
PhSNMe2 (1), with 1-pentyne, CO, and diphenyl disele-
nide (2) was catalyzed by 4.0% Pd(PPh3)4 (3) in benzene
at 85 °C for 168 h to yield the â-selenyl acrylamide (Z)-
3-phenylselenyl-hex-2-enoic acid dimethylamide (4) in
84% isolated yield based on sulfenamide (Scheme 2). As
(19) Benati, L.; Montevecchi, P. C.; Spagnolo, P. J. Chem. Soc.,
Perkin Trans. 1 1987, 2815.
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A.; Nishi, Y.; Mitsudo, T. Tetrahedron Lett. 2004, 45, 1469.
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2001, 3, 2085.
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786 J. Org. Chem., Vol. 70, No. 3, 2005

Regio- and Stereoselective Coupling Reaction
SCHEME 2
With respect to a variety of functionalized alkynes, the
reaction proceeded in good to excellent yields (Table 1).
Simple aliphatic alkynes such as 1-pentyne and 1-decyne
reacted to yield acrylamide as well as alkynes substituted
with cyano, halogen, ester, and dialkylamine function-
alities. Internal alkynes as well as hydroxy-substituted
alkynes were found to be unreactive (entries 6 and 4).
Propargyl alcohols have been reported to undergo in-
tramolecular lactonization under similar conditions, but
no lactone product was observed upon workup of the
reaction involving 5-hydroxy-1-pentyne.15o Notably, phen-
yl acetylene was found to be unreactive for acrylamide
formation with catalyst 3 but was partially converted to
acrylamide in low yield with (PPh3)2PdCl2 (entry 5). In
addition, the conjugated alkyne, 3-methyl-butyn-3-ene,
was also found to be unreactive under Pd(0) catalysis but
was observed in trace quantities under (PPh3)2PdCl2
catalysis (entry 10).
One of the more surprising aspects of this reaction is
that sulfenamide proved to be a better source of the NR2
group than the more traditional sources, simple amines
and silylamines. Both diethylamine (29) and N,N-di-
methyltrimethylsilylamine (30) were found to produce
â-selenyl acrylamide under typical reaction conditions but
in significantly reduced yields relative to sulfenamide
(Table 2).
Mechanism. Coupling the mechanistic work on the
reactivity of transition metals with diaryl dichalcogenides
published by others with our own observations, it seems
reasonable to propose that the formation of â-selenyl
acrylamides proceeds according to the following catalytic
cycle (Figure 1).13,15h,o,18,30,31 The loss of phosphine to give
a coordinatively unsaturated Pd species is followed by
oxidative addition (I) of diphenyl diselenide to generate
a Pd(II) diselenolate species that stereoselectively inserts
alkyne via cis-selenopalladation (II) to yield a vinyl
palladium selenolate. Selective CO insertion into the
palladium-carbon bond (III) gives a transient pal-
ladium-acyl intermediate that can then react with
sulfenamide via σ-bond metathesis (IV) to yield â-selenyl
acrylamide and a mixed palladium thiolate selenolate
species. The catalyst can then re-enter the cycle either
by reductive elimination (V) or by direct insertion of
alkyne (VI) into either the Pd-SPh or Pd-SePh bond.
As this reaction involves the assembly of four compo-
nents, we were particularly interested in determining the
degree to which two- and three-component side reactions
were contributing to the overall reaction mixture and if
any of the resulting byproducts were, in fact, mechanisti-
cally relevant. As such, a detailed analysis of the reaction
mixture resulting from the preparation of acrylamide 4
was undertaken. Although acrylamide 4 was isolated in
84% yield based on sulfenamide, it was found to comprise
only 47.5% of the final reaction mixture. A complete
previously reported,13 the reaction proceeded with 100%
regiospecificity for placing selenium in the â-position and
100% stereoselectivity for yielding only the Z isomer as
determined by both H NMR and NOE difference spec-
troscopy.
1
Optimization experiments were carried out to deter-
mine the ideal catalyst and solvent system for the
reaction. For aliphatic alkynes, Pd(PPh3)4 was identified
as the only active catalyst as Pd2dba3, (dppf)2PdCl2,
(PPh3)2PdCl2, (AsPh3)2PdCl2, Pd(OAc)2, PdCl2, Pt(PPh3)4,
and ClRh(PPh3)3 produced only trace or no â-selenyl
acrylamide. Interestingly, for phenyl acetylene, only
(PPh3)2PdCl2 was found to be active;29 the use of
Pd(PPh3)4, (AsPh3)2PdCl2, and (dppf)2PdCl2 resulted in
trace or no â-selenyl acrylamide product. Benzene was
found to be the solvent of choice, but only a moderate
decrease in yield was observed in toluene, acetonitrile,
and methylene chloride.
The best yields of acrylamide were obtained at
150-170 h of reaction at 80-85 °C in the presence of
3-5% of palladium with an optimal stoichiometry of 1
equiv of sulfenamide and diphenyl diselenide to 1.5 equiv
of alkyne. The long reaction times were found to be
necessary to obtain the highest yields of â-selenyl acryl-
amide as, for example, an increase in isolated yield of
55-84% was observed upon increasing the reaction time
from 68 to 168 h for the preparation of acrylamide 4.
Attempts to reduce the reaction time by either increasing
temperature or CO pressure resulted in a decreased yield
of â-selenyl acrylamide with a concomitant increase in
undesired byproducts.
As can be seen in Table 1, the reaction can deliver a
variety of NR2 groups to the product. Both simple dialkyl-
and allyl-functionalized sulfenamides, PhSNEt2 (5) and
PhSN(allyl)Me (6), were found to react with 1-pentyne
to give â-selenyl acrylamides in 70 and 82% isolated
yields, respectively (entries 7 and 14). An increase in
catalyst loading to 8% palladium was necessary for
reactions with benzyl- and diallyl-functionalized sulfen-
amides, PhSN(Bn)Me (7) and PhSN(allyl)2 (8), to obtain
excellent GC yields of acrylamide, 95 and 85% in the case
of 1-pentyne, respectively (entries 11 and 15). N-benzyl-
functionalized sulfenamides can be used with a lower
catalyst loading, but such reactions were observed to
proceed in lower yields in some cases (entries 12 and
13). Not surprisingly, neither a primary sulfenamide,
PhSN(H)Me (9), nor a sterically encumbered sulfen-
amide, PhSN(iPr)2 (10), yielded acrylamide (entries 16
and 17) as both have been reported to be inactive toward
the related palladium-catalyzed azathiolation of CO.18
Attempts to prepare a primary â-selenyl acrylamide via
TMS protection of a sulfenamide also failed; couplings
attempted with PhSN(Bn)TMS (11) resulted in a complex
mixture of products (entry 18).
(30) (a) Ananikov, V. P.; Beletskaya, I. P.; Aleksandrov, G. G.;
Eremenko, I. L. Organometallics 2003, 22, 1414. (b) Ananikov, V. P.;
Beletskaya, I. P. Dokl. Chem. 2003, 389, 81. (c) Ananikov, V. P.;
Kabeshov, M. A.; Beletskaya, I. P. Dokl. Chem. 2003, 390, 112. (d)
Beletskaya, I. P.; Moberg, C. Chem. Rev. 1999, 99, 3435. (e) Han, L.-
B.; Tanaka, M. Chem. Commun. 1999, 395.
(31) Although it is likely that some of the catalytically active metal
complexes are binuclear, we have not specifically addressed this
question and thus represent all metal species as monomeric. For
discussions regarding nuclearity in palladium-catalyzed Se-Se bond
additions to alkynes see: Ananikov, V. P.; Beletskaya, I. P.; Aleksan-
drov, G. G.; Eremenko, I. L. Organometallics 2003, 22, 1414.
(29) For the reactivity of phenyl acetylene towards carbonylative
addition under Pd catalysis see: Kuniyasu, H.; Ogawa, A.; Miyazaki,
S.; Ryu, I.; Kambe, N.; Sonoda, N. J. Am. Chem. Soc. 1991, 113, 9796.
J. Org. Chem, Vol. 70, No. 3, 2005 787

Knapton and Meyer
TABLE 1. Palladium-Catalyzed Preparation of â-Selenyl Acrylamides
a (PPh3)2PdCl2. b GC yield. c 8% Pd(PPh3)4.
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Regio- and Stereoselective Coupling Reaction
TABLE 2. Effect of the NR2 Source on the Preparation
TABLE 3. Complete Product Distribution for the
Four-Component Coupling Reaction
of â-Selenyl Acrylamides
a GC yield.
SCHEME 3
FIGURE 1. Initially proposed catalytic cycle.
analysis of all products is presented in Table 3. Before
discussing the byproducts arising from the two- and
three-component reactions, it must be emphasized that,
since under the reaction conditions all three diaryl
dichalcogenides are present (2, 31, and 32), one might
expect that all classes of products would be present as
both S and Se derivatives. Particularly important to the
understanding of the reaction mechanism is not only the
presence of the sulfur analogue (33) of the major product
4 but also the relative ratio of these two products.
Selectivity is discussed later in the paper.
Not surprisingly, evidence was found for the two- and
three-component side reactions shown in Scheme 3.
These reactions have been reported and studied exten-
sively by Kuniyasu, Ogawa, Sonoda, and Kurosawa.15h,18
Byproducts 34 and 35 are indicative of simple dichalco-
genation of alkyne (eq 2, Scheme 3). The presence of
byproducts 36 and 37 is consistent with azaselenolation
and azathiolation of CO (eq 3, Scheme 3). The byproducts
(38, 39) present in the largest quantities are those
resulting from the carbonylative addition of the diaryl
dichalcogenides to alkyne (eq 4, Scheme 3). Although
these two byproducts comprise nearly 20% of the reaction
mixture, it must be remembered that sulfenamide is the
limiting reagent under our optimized reaction conditions
and that the reactions described by eqs 2 and 4 will
continue to occur after all sulfenamide has been con-
sumed. As a result, compounds 38 and 39 are expected
byproducts even in high-yielding reactions. Trace sele-
nium triphenyl phosphine (40) and diphenyl selenide (41)
were also observed in the final reaction mixture with the
latter most likely arising from the aryl-group exchange
between phosphine and diphenyl diselenide.32
J. Org. Chem, Vol. 70, No. 3, 2005 789

Knapton and Meyer
TABLE 4. Reactivity of Dichalcogenated Byproducts
Toward Acrylamide Formation
SCHEME 5
TABLE 5. Reactivity of the Carbonylative Addition
Byproducts Toward Acrylamide Formation
a GC yield.
SCHEME 4
a GC yield.
because only the Z isomer of the four-component product
is produced.27
The final class of byproducts, those that arise from the
carbonylative addition of the dichalcogenides to the
alkyne (eq 4, Scheme 3), do appear to have a potentially
significant role in the overall four-component reaction.
We suspected that this might be the case based on the
previously reported reactivity of sulfenamides with
thioesters (Scheme 5).33
Selenium carbonylative addition product (43) was
prepared and reacted with sulfenamides 1 and 5 in the
presence and absence of catalyst 3. In all cases, complete
conversion to the â-selenyl acrylamides 4 and 17 was
observed. In addition, the reaction of sulfenamide 5 with
the cyano-functionalized sulfur carbonylative addition
product (44) also yielded â-sulfenyl acrylamide (45)
quantitatively in the absence of catalyst 3 (Table 5). It
can be concluded then that the reaction of the carbony-
lative addition byproducts with sulfenamide is facile and
a contributing factor to the production of acrylamide in
the reaction.
On the basis of these mechanistic studies, we propose
the following revision of the catalytic cycle (Figure 2).
We have added steps VII and VIII to acknowledge the
fact that significant product formation may arise from
this alternative pathway. The key factor, which we have
not been able to determine unequivocally, is the relative
rates of reductive elimination (VII) of the palladium-
acyl intermediate vs the proposed σ-bond metathesis (IV)
of sulfenamide with the palladium-acyl intermediate.
We have chosen not to include the pathway that involves
the initial formation of selenocarbamate (eq 3, Scheme
3) since the low yields obtained under the control condi-
tions (Scheme 4) suggest that this is not a significant
pathway in the overall four-component reaction.
Given that the two- and three-component byproducts
were present in the reaction mixtures, we thought it
important to determine if any of them could be interme-
diates in the production of the four-component product.
Both selenium and sulfur addition products 34 and 35
were prepared and reacted under 0.5 atm of initial CO
pressure with sulfenamide 1 in the presence of catalytic
amounts of palladium to determine if the products of
dichalcogenation (eq 2, Scheme 3) lay along the reaction
pathway towards acrylamide formation. GC analysis of
the final reaction mixtures showed no acrylamide prod-
ucts, even in the presence of 50% catalyst 3 (Table 4). It
can be concluded then that the formation of addition
products such as 34 and 35 is essentially irreversible and
that they do not contribute to acrylamide formation.
With respect to the reactivity of the two-component
products arising from azathiolation and azaselenolation
toward acrylamide formation (Scheme 3, eq 3), we have
found that a small percentage of thiocarbamate 37 can
be converted to â-sulfenyl acrylamide 33 upon reaction
with alkyne in the presence of catalytic amounts of
catalyst 3 (Scheme 4). On the basis of this finding, it
seems likely then that selenocarbamate 36 is also active
to a small degree for producing â-selenyl acrylamide 4.
The most likely explanation is that the chalcogenocar-
bamates can oxidatively re-add to palladium, insert al-
kyne, and reductively eliminate to give the four-compo-
nent product. A radical-type mechanism similar to the
one encountered in the photoinduced preparation of
â-telluryl acrylamides can be envisioned, but is unlikely
(32) Jones, W. D.; Reynolds, K. A.; Sperry, C. K.; Lachicotte, R. J.;
Godleski, S. A.; Valente, R. R. Organometallics 2000, 19, 1661.
(33) Parfenov, E. A.; Fomin, V. A. Zh. Obshch. Khim. 1981, 51, 1129.
790 J. Org. Chem., Vol. 70, No. 3, 2005

Regio- and Stereoselective Coupling Reaction
SCHEME 6
SCHEME 7
FIGURE 2. Revised catalytic cycle.
experiment involving the reaction of stoichiometric
amounts of 1-pentyne, diphenyl diselenide, and diphenyl
disulfide in the presence of catalytic palladium was
conducted for 1 day at 85 °C (Scheme 6). GC analysis of
the final reaction mixture showed that the all-selenium
and -sulfur dichalcogenated products, 34 and 35, were
formed in a 1:1 ratio. Small amounts of the mixed
selenium and sulfur addition products, (47) and (48),
were also observed, again in a 1:1 ratio. These results
strongly indicate that there is no kinetic preference for
alkyne insertion into Pd-SePh over Pd-SPh.
We have identified an alternative explanation for the
absence of the mixed carbonylative addition regioisomer
46. It appears that the selenium carbonylative addition
products such as 43 are preferentially converted into
their corresponding thioesters in the presence of diphenyl
disulfide. For example, the mixed byproduct 39 can be
produced in amounts similar to those encountered in the
preparation of â-selenyl acrylamide 4 by the simple
reaction of diphenyl disulfide with the selenium carbo-
nylative addition product 43 (Scheme 7). This reaction
also explains the absence of derivative 43, which to this
point was not satisfactorily accounted for on the basis of
our revised mechanistic proposal (Figure 2).
An intriguing result relevant to the discussion of
selectivity was obtained when attempts were made to
extend the methodology to give the related â-sulfenyl
acrylamides. Surprisingly, we found that the acrylamide
products could not be produced in significant yield by
repeating the reactions with added diphenyl disulfide in
place of diphenyl diselenide. Only upon increasing the
initial CO pressure from 0.5 to 28 atm and by adding
excess alkyne were we able to obtain good yields of
â-sulfenyl acrylamide relative to sulfenamide (Scheme 8).
FIGURE 3. Potential carbonylative addition byproducts.
Selectivity. One of the more fascinating aspects of the
reaction is the selective formation of â-selenyl acrylamide
over â-sulfenyl acrylamide. Analysis of several reaction
mixtures arising from the synthesis of â-selenyl acryl-
amide 4 yielded selectivities ranging from 4:1 to 7:1
selenium to sulfur acrylamide product 33. Significantly,
these observed selectivities were much larger than we
expected on the basis of the initial 2:1 ratio of selenium
to sulfur in the reaction mixture.
We have determined that the observed selectivity is
not due to a difference in the insertion rate of alkyne into
the Pd-SePh and Pd-SPh bonds. We had initially
suspected this possibility as it would be consistent with
our observation that, while the reaction mixture con-
tained the mixed chalcogeno-carbonylative addition prod-
uct 39, we never observed the reverse-substituted regio-
isomer (46) (Figure 3). Such a distribution of products
would be expected if alkyne preferentially inserted into
Pd-SePh whenever the catalyst bore both SePh and SPh
groups.
This unexpected difference in reactivity between sulfur
and selenium led us to examine the potential effect of
To address this question of selective selenopallada-
tion versus thiopalladation of the alkyne, a competition
J. Org. Chem, Vol. 70, No. 3, 2005 791

Knapton and Meyer
SCHEME 8
SCHEME 9
FIGURE 4. Potential chelation of the vinyl selenoether
intermediates.
SCHEME 11
favored than the corresponding carbonylative addition of
diphenyl diselenide at low CO pressure.
SCHEME 10
We believe that the difference in rates likely corre-
sponds to the differences in chelation strengths of the
seleno- and sulfidoethers. Selenoethers exhibit much
higher binding constants to mid-valent metals than
sulfidoethers because of both selenium’s lower electro-
negativity and its larger, more diffuse valence orbitals.
Thus, selenium is more likely to bind to palladium to
form a four-membered- and/or a five-membered-ring
chelate than is sulfur (Figure 4).34 Chelation may facili-
tate the rate of formation of carbonylated product either
by creating a crowded coordination sphere or by inhibit-
ing the deinsertion of CO. In any case, the seleno-favoring
effect must be significant, given that the vinyl sulfido-
ether would ordinarily be expected to be faster at
migratory insertion on the basis of simple nucleophilicity
arguments. Negative hyperconjugation with selenium
would be expected to more effectively delocalize the
negative charge on the anionic vinyl ligand, disfavoring
migration to CO relative to the sulfur analogue.35
Finally, in addition to the effect of CO pressure on
determining reaction selectivity, the concentrations of
both diphenyl disulfide and diphenyl diselenide in the
reaction mixture should also play an important role as
the concentration of diphenyl disulfide is expected to
increase and the concentration of diphenyl diselenide is
expected to decrease with reaction time. To address this
effect of chalcogen concentration, a detailed 1H NMR
experiment in which the concentrations of both selenium-
and sulfur-containing acrylamides 4 and 33 were mea-
sured as a function of time (Scheme 11). As expected, the
best selectivity for the formation of 4 over 33 was
observed early in the reaction, but this selectivity was
observed to decrease slowly over time as the reaction
progressed to consume sulfenamide 1 and, consequently,
produce diphenyl disulfide and acrylamide 33.
CO pressure on acrylamide reaction selectivity. Increas-
ing the CO pressure in reactions that previously gave at
least 4:1 selectivity for â-selenyl acrylamides to â-sulfenyl
acrylamides resulted in a complete loss of selectivity
(Scheme 9). Presumably, at this higher pressure, the CO
insertion step ceases to be rate determining, and there-
fore, any inherent rate differences between the Se and S
derivatives become irrelevant to product distribution.
It seemed logical to hypothesize that the variation
between the sulfur and selenium acrylamide-forming
reactions at low CO pressure could be due to the dif-
ferential activity of the chalcogens toward carbonylative
addition. This idea was tested further by examining the
carbonylative addition of diphenyl disulfide and diphenyl
diselenide to 1-pentyne under conditions similar to those
of the acrylamide-producing reactions (Scheme 10). The
carbonylative addition of diphenyl disulfide to 1-pentyne
was found to produce a near-quantitative yield of only
the simple addition product 35; only trace amounts of
the carbonylative addition product 38 were present. In
contrast, the selenium carbonylative addition product 43
was the major product obtained with only small amounts
of the addition product 34 present under the same
reaction conditions. It thus appears that the carbonyla-
tive addition of diphenyl disulfide to the alkyne is less
On the basis of our findings, we believe that two major
factors contribute to the observed selective formation of
â-selenyl acrylamides over â-sulfenyl acrylamides are (1)
(34) Levason, W.; Orchard, S. D.; Reid, G. Coord. Chem. Rev. 2002,
225, 159.
(35) Mo, Y.; Schleyer, P. v. R.; Wu, W.; Lin, M.; Zhang, Q.; Gao, J.
J. Phys. Chem. A 2003, 107, 10011.
792 J. Org. Chem., Vol. 70, No. 3, 2005

Regio- and Stereoselective Coupling Reaction
6-Cyano-(Z)-1,2-bis(phenylseleno)-1-pentene (42): 1H
NMR (300 MHz, C6D6) δ 0.97 (m, J1 ) J2 ) 7.0 Hz, 2 H), 1.51
(t, J ) 7.0 Hz, 2 H), 1.98 (t, J ) 7.0 Hz, 2 H), 6.88-7.88 (m, 11
H); MS (EI) m/z 407 (M+), 314, 250, 233, 157, 129, 115, 77
(base).
an initially small concentration of diphenyl disulfide (or
PhS-SePh) and (2) the favorable insertion of CO into
vinyl â-selenoethers relative to vinyl â-sulfidoethers at
low CO pressure.
(Z)-1,3-Bis(phenylthio)-2-hexen-1-one (38): 1H NMR
(300 MHz, C6D6) δ 0.46 (t, J ) 7.3 Hz, 3 H), 1.09 (m, J1 ) J2
) 7.6 Hz, 2 H), 1.81 (t, J ) 7.4 Hz, 2 H), 6.22 (s, 1 H), 6.83-
7.73 (m, 10 H); 13C NMR (75 MHz, C6D6) δ 13.3, 22.8, 38.4,
117.9, 127.2, 128.7, 129.1, 129.2, 129.3, 135.1, 135.9, 137.4,
160.9, 183.5; MS (EI) m/z 314 (M+), 205 (base), 176, 109, 91,
77, 65.
Conclusions
In conclusion, we have developed a high-yielding
method for the formation of regio- and stereodefined
â-selenyl and â-sulfenyl acrylamides via a palladium-
catalyzed four-component coupling reaction in which one
C-C bond and two carbon-heteroatom bonds are formed.
From a synthetic standpoint, the reaction exhibits excel-
lent tolerance for a wide variety of substituents on both
the nitrogen of the sulfenamide and alkyne. In addition,
the versatility of the chalcogens as pseudo-halides coupled
with the presence of the R,â-unsaturated amide func-
tionality makes the â-chalcogenyl acrylamides syntheti-
cally attractive targets.14
(Z)-1,3-Bis(phenylseleno)-2-hexen-1-one (43): 1H NMR
(300 MHz, C6D6) δ 0.43 (t, J ) 7.3 Hz, 3 H), 1.06 (m, J1 ) J2
) 7.6 Hz, 2 H), 1.84 (t, J ) 7.5 Hz, 2 H), 6.53 (s, 1 H), 6.86-
7.76 (m, 10 H); 13C NMR (75 MHz, C6D6) δ 13.3, 23.2, 39.6,
122.6, 129.6, 131.3, 132.5, 133.1, 133.3, 133.5, 136.2, 137.5,
162.2, 186.3; MS (EI) m/z 253 (M+ - SePh) (base), 157, 91,
77, 65.
6-Cyano-(Z)-1,3-bis(phenylthio)-2-hexen-1-one (44): 1H
NMR (300 MHz, C6D6) δ 0.95 (m, J1 ) J2 ) 6.9 Hz, 2 H), 1.20
(t, J ) 6.9 Hz, 2 H), 1.76 (t, J ) 6.8 Hz, 2 H), 6.07 (s, 1 H),
6.90-7.73 (m, 10 H); MS (EI) m/z 230 (M+ - SPh)(base), 189,
109, 77, 65, 51.
Experimental Section
N-Dimethyl Phenyl Selenocarbamate (36). To a glass
bomb in a nitrogen-filled glovebox were added sulfenamide 1
(43.0 mg, 0.28 mmol), (PhSe)2 2 (64.0 mg, 0.20 mmol), 5.5%
chlorocarbonylbis(triphenylphosphine) rhodium (8.0 mg, 11.0
µmol), and benzene (4.0 mL). The reaction was charged with
0.5 atm of CO gas and heated for 64 h at 85 °C with stirring.
The resultant solution was degassed, filtered through Celite,
and reduced in vacuo. The crude reaction mixture was partially
purified via column chromatography using 5% ethyl acetate/
hexanes and methanol to yield N-dimethyl phenyl selenocar-
bamate (36). 1H NMR (300 MHz, C6D6) δ 2.44 (br s, 6 H), 6.83-
7.75 (m, 5 H); MS (EI) m/z (M+), 229, 157, 77, 72 (base), 65.
N-Dimethyl Phenyl Thiocarbamate (37). According to
the method of Kuniyasu et al.,18 to a stainless steel reaction
vessel with glass insert in a nitrogen-filled glovebox were
added sulfenamide 1 (40.0 mg, 0.26 mmol), 5.6% catalyst 3
(13.0 mg, 11.2 µmol), and pyridine (2 mL). The reaction was
charged with 28 atm of CO gas and heated for 24 h at 90 °C
with stirring. The resultant solution was degassed, filtered
through Celite, and reduced in vacuo. The crude reaction
mixture was purified by column chromatography using hex-
anes and methanol to yield the red oil (37) (38.0 mg, 0.21
mmol) in 80% yield: 1H NMR (300 MHz, C6D6) δ 2.27 (br s, 6
H), 6.83-7.75 (m, 5 H); MS (EI) m/z 181 (M+), 109, 77, 72
(base), 65.
(Z)-3-Phenylselenyl-hex-2-enoic Acid Dimethylamide
(4). To a glass bomb in a nitrogen-filled glovebox were added
(PhSe)2 2 (63.0 mg, 0.20 mmol), sulfenamide 1 (29.0 mg, 0.19
mmol), 1-pentyne (30.0 µL, 0.30 mmol), 4.5% catalyst 3 (10.0
mg, 8.6 µmol), and benzene (1.5 mL). The reaction was charged
with 0.5 atm of CO gas and heated for 168 h at 85 °C with
stirring. The resultant orange solution was degassed, filtered
through Celite, and reduced in vacuo to yield a red, viscous
oil. The crude reaction mixture was purified via column
chromatography using 5% ethyl acetate/hexanes, 20% ethyl
acetate/hexanes, ethyl acetate to yield the orange oil (Z)-3-
phenylselenyl-hex-2-enoic acid dimethylamide (4) (47.5 mg,
0.16 mmol) in 84% yield. The following percentages of byprod-
ucts in the final reaction mixture were determined by GC using
the internal standards method (hexamethylbenzene) and were
identified either by comparison to independently prepared
standards or by isolation from column chromatography: (PhSe)2
2, 17.0%; (Z)-3-phenylselenyl-hex-2-enoic acid dimethylamide
4, 47.5%; (PhS)2 31, 0.3%; PhS-SePh 32, trace; (Z)-3-phenyl-
sulfenyl-hex-2-enoic acid dimethylamide 33, 6.8%; (Z)-1,2-bis-
(phenylseleno)-1-pentene 34, 2.7%; (Z)-1,2-bis(phenylthio)-1-
pentene 35, trace; N-dimethyl phenyl selenocarbamate 36,
3.4%; N-dimethyl phenyl thiocarbamate 37, 0.1%; (Z)-1,3-bis-
S-Phenyl-N-dimethyl-sulfenamide (1): 1H NMR (300
MHz, C6D6) δ 2.53 (s, 6 H), 6.93-7.37 (m, 5 H); 13C NMR (75
MHz, C6D6) δ 48.3, 127.1, 128.8, 129.9, 137.2; MS (EI) m/z 153
(M+), 138, 109, 77, 65.
S-Phenyl-N-diethyl-sulfenamide (5): 1H NMR (300 MHz,
C6D6) δ 1.08 (t, J ) 7.0 Hz, 6 H), 2.79 (q, J ) 7.0 Hz, 4 H),
6.92-7.35 (m, 5 H); 13C NMR (75 MHz, C6D6) δ 13.8, 53.4,
125.0, 125.5, 128.8, 142.1; MS (EI) m/z 181 (M+), 166, 109, 77,
65.
S-Phenyl-N-allyl-N-methyl-sulfenamide (6): 1H NMR
(300 MHz, C6D6) δ 2.59 (s, 3), 3.34 (d, J ) 6.4 Hz, 2 H), 4.98
(m, 2 H), 5.79 (dtd, J ) 10.0, 7.0, 2.4 Hz, 1 H), 6.93-7.36 (m,
5 H); 13C NMR (75 MHz, C6D6) δ 45.2, 63.3, 117.1, 126.4, 127.6,
128.7, 135.4; MS (EI) m/z 179 (M+), 138, 109, 77, 65.
S-Phenyl-N-benzyl-N-methyl-sulfenamide (7): 1H NMR
(300 MHz, C6D6) δ 2.51 (s, 3 H), 3.87 (s, 2 H), 6.95-7.35 (m,
10 H); 13C NMR (75 MHz, C6D6) δ 45.2, 65.1, 127.0, 128.6,
128.7, 128.9, 138.2, 138.8; MS (EI) m/z 229 (M+), 138, 109, 91,
77, 65.
S-Phenyl-N-diallyl-sulfenamide (8): 1H NMR (300 MHz,
C6D6) δ 3.44 (d, J ) 6.4 Hz, 4 H), 5.04 (m, 4 H), 5.83 (dtd, J )
10.5, 6.4, 2.6 Hz, 2 H), 6.92-7.35 (m, 5 H); 13C NMR (75 MHz,
C6D6) δ 60.9, 117.5, 126.1, 128.9, 135.6, 140.6; MS (EI) m/z
205 (M+), 164, 109, 77, 65, 41.
S-Phenyl-N-methyl-sulfenamide (9): 1H NMR (300 MHz,
C6D6) δ 2.24 (br s, 1 H), 2.42 (d, J ) 17.4 Hz, 3 H), 6.93-7.35
(m, 5); 13C NMR (75 MHz, C6D6) δ 38.4, 123.8, 125.2, 128.8,
129.1, 141.7; MS (EI) m/z 139 (M+), 124, 109, 97, 65.
S-Phenyl-N-diisopropyl-sulfenamide (10): 1H NMR
(300 MHz, C6D6) δ 1.07 (d, J ) 6.4 Hz, 12 H), 3.12 (hpt, J )
6.5 Hz, 2 H), 6.89-7.36 (m, 5 H); 13C NMR (75 MHz, C6D6) δ
21.9, 55.8, 122.1, 124.4, 128.6, 146.4; MS (EI) m/z 209 (M+),
194, 152, 109, 77, 65.
S-Phenyl-N-trimethylsilyl-N-benzyl-sulfenamide
(11): 1H NMR (300 MHz, C6D6) δ 0.80 (s, 9 H), 3.55 (s, 2 H),
7.07-7.19 (m, 10 H); MS (EI) m/z 215 (M+ - TMS), 109, 91
(base), 77, 65, 51.
(Z)-1,2-Bis(phenylseleno)-1-pentene (34): 1H NMR (300
MHz, C6D6) δ 0.69 (t, J ) 7.3 Hz, 3 H), 1.41 (m, J1 ) J2 ) 7.4
Hz, 2 H), 2.14 (t, J ) 7.2 Hz, 2 H), 6.86-7.75 (m, 11 H); MS
(EI) m/z 382 (M+), 314, 183, 157, 143, 129, 115, 91, 77 (base),
65.
(Z)-1,2-Bis(phenylthio)-1-pentene (35): 1H NMR (300
MHz, C6D6) δ 0.70 (t, J ) 7.3 Hz, 3 H), 1.43 (m, J1 ) J2 ) 7.4
Hz, 2 H), 2.10 (t, J ) 7.5 Hz, 2 H), 6.49 (s, 1 H), 6.85-7.73 (m,
10 H); MS (EI) m/z 286 (M+) (base), 177, 167, 147, 135, 109,
91, 77, 65.
J. Org. Chem, Vol. 70, No. 3, 2005 793

Knapton and Meyer
(phenylthio)-2-hexen-1-one 38, 10.3%; 3-phenylselenyl-hex-2-
enoic acid S-phenyl ester 39, 11.1%; SePPh3 40, trace; PhSePh
41, trace. The E/Z ratio was determined by NOE difference
and 1H NMR spectroscopy (E/Z ) 0/100). 4: 1H NMR (300
MHz, C6D6) δ 0.61 (t, J ) 7.3 Hz, 3 H), 1.34 (m, J1 ) J2 ) 7.5
Hz, 2 H), 2.16 (t, J ) 7.4 Hz, 2 H), 2.31 (s, 3 H), 2.69 (s, 3 H),
6.29 (s, 1 H), 6.92-7.62 (m, 5 H); 13C NMR (75 MHz, C6D6) δ
13.4, 23.5, 34.9, 36.5, 40.1, 114.3, 128.5, 128.9, 130.6, 137.7,
157.5, 166.6; IR (NaCl) 3070, 2887, 2325, 1960, 1815, 1633
(CdO), 1438, 1034, 674 cm-1; MS (EI) m/z 297 (M+), 253, 157,
140 (base), 72. HRMS calcd for C14H19NOSe 297.063927, found
297.063185. Anal. calcd for C14H19NOSe: C, 56.55; H, 6.39;
N, 4.71. Found: C, 56.90; H, 6.44; N, 4.67. 33: 1H NMR (300
MHz, C6D6) δ 0.65 (t, J ) 7.4 Hz, 3 H), 1.36 (m, J1 ) J2 ) 7.4
Hz, 2 H), 2.03 (t, J ) 7.3 Hz, 2 H), 2.44 (s, 3 H), 2.71 (s, 3 H),
5.98 (s, 1 H), 6.90-7.42 (m, 5 H); MS (EI) m/z 249 (M+), 205,
176, 140 (base), 109, 72. 39: 1H NMR (300 MHz, C6D6) δ 0.45
(t, J ) 7.3 Hz, 2 H), 1.10 (m, J1 ) J2 ) 7.5 Hz, 2 H), 1.92 (t, J
) 7.4 Hz, 2 H), 6.55 (s, 1 H), 6.89-7.56 (m, 10 H); 13C NMR
(75 MHz, C6D6) δ 13.3, 23.5, 39.7, 120.1, 127.4, 128.8, 129.1,
129.4, 131.2, 133.3, 135.9, 137.1, 163.0, 184.7; MS (EI) m/z 362
(M+), 253 (base), 157, 109, 91, 77, 65.
spectroscopy (E/Z ) 0/100). 1H NMR (300 MHz, C6D6) δ 0.59
(t, J ) 7.3 Hz, 3 H), 0.77 (br s, 3 H), 0.99 (br s, 3 H), 1.33 (m,
J1 ) J2 ) 7.3 Hz, 2 H), 2.18 (t, J ) 7.0 Hz, 2 H), 2.84 (br s, 2
H), 3.26 (br s, 2 H), 6.37 (s, 1 H), 6.94-7.00 (m, 3 H), 7.61-
7.63 (m, 2 H); 13C NMR (75 MHz, C6D6) δ 13.4, 13.6, 14.8, 23.6,
40.1, 40.7, 42.1, 114.0, 128.5, 128.9, 130.8, 137.8, 157.8, 166.0;
MS (EI) m/z 325 (M+), 253, 168 (base), 157, 100. HRMS calcd
for C16H23NOSe 325.094576, found 325.094485.
6-Cyano-(Z)-3-phenylselenyl-hex-2-enoic Acid Dieth-
ylamide (18). Following the general procedure, 6-cyano-(Z)-
3-phenylselenyl-hex-2-enoic acid diethylamide (18) (55.0 mg,
0.16 mmol) was prepared in 80% yield. The E/Z ratio was
determined by 1H NMR and NOE difference spectroscopy (E/Z
1
) 0/100). H NMR (300 MHz, C6D6) δ 0.83 (t, J ) 6.9 Hz, 3
H), 0.98 (t, J ) 6.9 Hz, 3 H), 1.09 (m, J1 ) J2 ) 7.0 Hz, 2 H),
1.30 (t, J ) 7.0 Hz, 2 H), 2.17 (t, J ) 7.1 Hz, 2 H), 2.85 (q, J
) 6.9 Hz, 2 H), 3.24 (q, J ) 6.9 Hz, 2 H), 6.41 (s, 1 H), 6.90-
7.03 (m, 3 H), 7.45-7.47 (m, 2 H); 13C NMR (75 MHz, C6D6) δ
13.5, 14.8, 15.2, 24.8, 36.2, 40.7, 42.1, 115.9, 118.9, 129.1, 130.2,
137.4, 154.5, 165.5; MS (EI) m/z 350 (M+), 278, 193 (base), 157,
77, 72. HRMS calcd for C17H22N2OSe 350.089092, found
350.089734.
6-Cyano-(Z)-3-phenylselenyl-hex-2-enoic Acid Dimeth-
ylamide (12). Following the general procedure, with the
exception of heating for only 115 h, 6-cyano-(Z)-3-phenylsele-
nyl-hex-2-enoic acid dimethylamide (12) (45.0 mg, 0.14 mmol)
was prepared in 70% yield. The E/Z ratio was determined by
NOE difference and H NMR spectroscopy (E/Z ) 0/100). H
NMR (300 MHz, C6D6) δ 1.15 (m, J1 ) J2 ) 7.2 Hz, 2 H), 1.34
(t, J ) 7.0 Hz, 2 H), 2.15 (t, J ) 7.2 Hz, 2 H), 2.36 (s, 3 H),
2.68 (s, 3 H), 6.34 (s, 1 H), 6.93-7.07 (m, 3 H), 7.46-7.48
(m, 2 H); 13C NMR (75 MHz, C6D6) δ 15.3, 25.0, 34.9, 36.3,
36.6, 116.0, 119.0, 129.2, 130.0, 137.3, 154.3, 166.3; MS (EI)
m/z 322 (M+), 278, 165 (base), 157, 77, 72. HRMS calcd for
C15H18N2OSe 322.058553, found 322.058434.
4-Dimethylamino-(Z)-3-phenylselenyl-hex-2-enoic Acid
Diethylamide (19). Following the general procedure, 4-(di-
methylamino)-(Z)-3-phenylselenyl-hex-2-enoic acid diethyl-
amide (19) was prepared in 85% GC yield. The E/Z ratio was
determined by H NMR (E/Z ) 0/100). H NMR (300 MHz,
C6D6) δ 0.79 (t, J ) 6.7 Hz, 3 H), 0.99 (t, J ) 6.7 Hz, 3 H), 1.87
(s, 6 H), 2.35 (s, 1 H), 2.68 (s, 1 H), 2.90 (q, 2 H), 3.27 (q, 2 H),
6.87 (s, 1 H) 6.90-7.08 (m, 3 H), 7.68-7.77 (m, 2 H); MS (EI)
m/z 340 (M+), 219, 183, 157, 82, 72, 58 (base).
(Z)-4-Methyl-3-phenylselenyl-penta-2,4-dienoic Acid
Diethylamide (20). Following the general procedure, with the
exception of using 6.0% (PPh3)2PdCl2, (Z)-4-methyl-3-phenylse-
lenyl-penta-2,4-dienoic acid diethylamide (20) was detected in
trace amounts by GC and GC-MS.
(Z)-3-Phenylselenyl-hex-2-enoic Acid Methylbenzyl-
amide (21). Following the general procedure, with the excep-
tion of running in the presence of 8% catalyst 3, (Z)-3-
phenylselenyl-hex-2-enoic acid methylbenzylamide (21) was
prepared in 95% GC yield. The E/Z ratio was determined by
1H NMR (E/Z ) 0/100). Two distinct rotamers were observed
by 1H and 13C NMR at room temperature. 1H NMR (300 MHz,
C6D6) δ 0.49 (t, J ) 7.1 Hz, 3 H), 0.60 (t, J ) 7.0 Hz, 3 H), 1.34
(m, 4 H), 2.07 (t, J ) 7.1 Hz, 2 H), 2.19 (t, J ) 7.2 Hz, 2 H),
2.39 (s, 3 H), 2.81 (s, 3 H), 4.06 (s, 2 H), 4.51 (s, 2 H), 6.35 (s,
1 H), 6.42 (s, 1 H), 6.95-7.69 (m, 20 H); 13C NMR (75 MHz,
C6D6) δ 13.3, 13.4, 23.5, 23.6, 33.6, 34.2, 39.9, 40.2, 50.8, 53.2,
113.9, 130.5, 132.3, 132.4, 134.5, 137.7, 138.4, 158.9, 159.1,
166.8, 167.2; MS (EI) m/z 373 (M+), 296, 253, 216 (base), 157,
120, 91, 77, 65.
1
1
1
1
Acetic Acid 5-Dimethylcarbamoyl-(Z)-4-phenylselenyl-
pent-4-enyl Ester (13). Following the general procedure, with
the exception of heating for only 115 h, acetic acid 5-dimeth-
ylcarbamoyl-(Z)-4-phenylselenyl-pent-4-enyl ester (13) (53.3
mg, 0.15 mmol) was prepared in 72% yield. The E/Z ratio was
determined by NOE difference and 1H NMR spectroscopy (E/Z
1
) 0/100). H NMR (300 MHz, C6D6) δ 1.54 (m, J1 ) J2 ) 7.1
Hz, 2 H), 1.58 (s, 3 H), 2.21 (t, J ) 7.3 Hz, 2 H), 2.35 (s, 3 H),
2.68 (s, 3 H), 3.73 (t, J ) 6.4 Hz, 2 H), 6.33 (s, 1 H), 6.93-6.99
(m, 3 H), 7.55-7.57 (m, 2 H); 13C NMR (75 MHz, C6D6) δ 20.5,
29.3, 34.6, 35.0, 36.5, 63.1, 114.8, 129.0, 130.3, 137.7, 156.3,
166.6, 170.0; MS (EI) m/z 355 (M+), 269, 198 (base), 157, 138,
111, 72, 43. HRMS calcd for C16H21NO3Se 355.069892, found
355.068664.
6-Hydroxy-(Z)-3-phenylselenyl-hex-2-enoic Acid Di-
methylamide (14). Following the general procedure, with the
exception of heating for only 50 h, the formation of 6-hydroxy-
(Z)-3-phenylselenyl-hex-2-enoic acid dimethylamide (14) was
not detected by GC-MS.
6-Chloro-(Z)-3-phenylselenyl-hex-2-enoic Acid Ben-
zylmethylamide (22). Following the general procedure,13
with the exception of heating for 64 h at 78 °C, 6-chloro-(Z)-
3-phenylselanyl-hex-2-enoic acid benzylmethylamide (22) (50.0
mg, 0.12 mmol) was prepared in 60% yield. The E/Z ratio was
determined by NOE difference and 1H NMR spectroscopy (E/Z
N,N-Dimethyl-3-phenyl-3-phenylselenyl Acrylamide
(15). Following the general procedure, with the exception of
using 6.0% (PPh3)2PdCl2, N,N-dimethyl-3-phenyl-3-phenylse-
lenyl-acrylamide (15) (12.0 mg, 0.04 mmol) was prepared in
30% yield. The E/Z ratio was determined by 1H NMR
) 0/100). Two distinct rotamers were observed by 1H and 13
C
1
NMR at room temperature. H NMR (300 MHz, C6D6) δ 1.44
(m, J1 ) J2 ) 7.5 Hz, 2 H), 1.54 (m, J1 ) J2 ) 7.1 Hz, 2 H),
2.19 (t, J ) 7.0 Hz, 2 H), 2.30 (t, J ) 7.3 Hz, 2 H), 2.38 (s, 3
H), 2.80 (m, 5 H), 2.91 (t, J ) 7.0 Hz, 2 H), 4.05 (s, 2 H), 4.50
(s, 2 H), 6.38 (s, 1 H), 6.46 (s, 1 H), 6.94-7.55 (m, 20 H); 13C
NMR (75 MHz, C6D6) δ 32.2, 32.4, 33.7, 34.2, 34.9, 35.1, 43.4,
43.7, 50.8, 53.3, 115.1, 115.2, 126.6, 130.1, 137.5, 138.2, 156.5,
156.8, 166.5, 167.1; MS (EI) m/z 407 (M+), 287, 250 (base), 157,
91, 77, 65. HRMS calcd for C20H22NOClSe 407.057262, found
407.055513.
1
spectroscopy (E/Z ) 100). H NMR (300 MHz, C6D6) δ 2.34
(s, 3 H), 2.70 (s, 3 H), 6.48 (s, 1 H), 6.74-7.27 (m, 10 H); MS
(EI) m/z 331 (M+), 287, 254, 157, 72 (base).
(Z)-2-Methyl-3-phenylselenyl-but-2-enoic Acid Dimeth-
ylamide (16). Following the general procedure, with the
exception of heating for only 50 h, the formation of (Z)-2-
methyl-3-phenylselenyl-but-2-enoic acid dimethylamide (16)
was not detected by GC-MS.
(Z)-3-Phenylselenyl-hex-2-enoic Acid Diethylamide
(17). Following the general procedure, with the exception of
heating for 140 h, (Z)-3-phenylselenyl-hex-2-enoic acid dieth-
ylamide (17) (46.0 mg, 0.14 mmol) was prepared in 70% yield.
The E/Z ratio was determined by NOE difference and 1H NMR
(Z)-3-Phenylselenyl-undec-2-enoic Acid Benzylmeth-
ylamide (23). Following the general procedure,13 with the
exception of heating for 64 h at 78 °C, (Z)-3-phenylselenyl-
undec-2-enoic acid benzylmethylamide (23) (50.5 mg, 0.11
794 J. Org. Chem., Vol. 70, No. 3, 2005

Regio- and Stereoselective Coupling Reaction
mmol) was prepared in 60% yield. The E/Z ratio was deter-
The Preparation of Acrylamide 12 from Amine 30.
Following the procedure stated above, 6-cyano-(Z)-3-phenylse-
lenyl-hex-2-enoic acid dimethylamide 12 was prepared in 40%
GC yield.
1
mined by H NMR spectroscopy (E/Z ) 0/100). Two distinct
rotamers were observed by 1H and 13C NMR at room temper-
ature. The rotamers were resolved into one species at 350 K.
1H NMR (300 MHz, C6D6) δ 0.87 (t, J ) 6.9 Hz, 6 H), 1.03-
1.40 (m, 24 H), 2.19 (t, J ) 7.1 Hz, 2 H), 2.28 (t, J ) 7.3 Hz,
2 H), 2.41 (s, 3 H), 2.81 (s, 3 H), 4.09 (s, 2 H), 4.52 (s, 2 H),
6.42 (s, 1 H), 6.48 (s, 1 H), 6.94-7.73 (m, 20 H); 13C NMR (75
MHz, d8-tol) δ 14.4, 23.1, 29.6, 30.5, 30.7, 32.3, 33.6, 34.2, 38.3,
38.5, 50.8, 53.4, 113.6, 113.7, 130.7, 131.6, 132.3, 132.5, 133.6,
133.9, 134.6, 135.0, 138.5, 159.2, 159.6, 167.1, 167.7; MS (EI)
m/z 443 (M+), 323, 286 (base), 157, 120, 91, 77, 65.
The Attempted Preparation of Acrylamide 4 from Bis-
(arylseleno)-1-alkene 34 and Sulfenamide 1. To a glass
bomb in a nitrogen-filled glovebox were added bis(phenylse-
leno)-1-alkene 34 (45.8 mg, 0.12 mmol), sulfenamide 1 (19.1
mg, 0.12 mmol), 9.0% of catalyst 3 (12.5 mg, 10.8 µmol), and
benzene (2.5 mL). The reaction was charged with 0.5 atm of
CO gas and heated for 72 h at 90 °C with stirring. The
resultant solution was degassed, filtered through Celite, and
analyzed by GC and GC-MS. Acrylamide 4 was not detected.
The Attempted Preparation of Acrylamide 33 from
Bis(phenylthio)-1-alkene 35 and Sulfenamide 1. Follow-
ing the general procedure stated above, the formation of
acrylamide 33 was not detected.
The Attempted Preparation of Acrylamide 18 from
Bis(phenylseleno)-1-alkene 42 and Sulfenamide 5 in the
Presence of Substoichiometric Pd. Following the general
procedure, with the exception of heating for 144 h in the
presence of 50% catalyst 3, the formation of acrylamide 18 was
not detected.
The Preparation of Acrylamide 33 from Thiocarbam-
ate 37 and 1-Pentyne. To a glass bomb in a nitrogen-filled
glovebox were added thiocarbamate 37 (38.0 mg, 0.21 mmol),
1-pentyne (20 µL, 0.20 mmol), 5% of catalyst 3, and benzene
(2.0 mL). The reaction was heated for 96 h at 85 °C with
stirring. The resultant solution was filtered through Celite and
analyzed by GC-MS and GC. A 4.5% GC yield of acrylamide
33 was observed.
The Preparation of Acrylamide 4 from Phenylseleno-
2-alken-1-one 43 and Sulfenamide 1 in the Presence of
Catalytic Pd. To a glass bomb in a nitrogen-filled glovebox
were added phenylseleno-2-alkenone 43 (73.8 mg, 0.18 mmol),
sulfenamide 1 (28.0 mg, 0.18 mmol), 4.0% of catalyst 3 (8.3
mg, 7.2 µmol), and benzene (2.5 mL). The reaction was heated
for 96 h at 75 °C with stirring. The reaction was filtered
through Celite and analyzed by GC-MS and GC. A 100% GC
yield of acrylamide 4 was observed.
(Z)-3-Phenylselenyl-hex-2-enoic Acid Allylmethyl-
amide (24). Following the general procedure, with the excep-
tion of heating for 126 h, (Z)-3-phenylselenyl-hex-2-enoic acid
allylmethylamide (24) (57.0 mg, 0.18 mmol) was prepared in
82% yield. The E/Z ratio was determined by NOE difference
1
and H NMR spectroscopy (E/Z ) 0/100). Two distinct rota-
mers were observed by 1H and 13C NMR at room temperature.
1H NMR (300 MHz, C6D6) δ 0.59 (m, 6 H), 1.22 (br s, 4 H),
2.16 (m, 4 H), 2.45 (s, 3 H), 2.78 (s, 3 H), 3.40 (m, 2 H), 3.92
(m, 2 H), 4.91 (m, 4 H), 5.40 (m, 1 H), 5.60 (m, 1 H), 6.35 (s, 2
H), 6.88-6.99 (m, 6 H), 7.58-7.62 (m, 4 H); 13C NMR (75 MHz,
C6D6) 13.4, 23.6, 33.5, 34.2, 40.1, 50.0, 52.0, 114.0, 116.0, 116.9,
130.5, 133.5, 134.1, 137.8, 158.0, 158.6, 166.4, 166.9; MS (EI)
m/z 323 (M+), 253, 166 (base), 157, 77, 41. HRMS calcd for
C16H21NOSe 323.079852, found 323.078835.
(Z)-3-Phenylselenyl-hex-2-enoic Acid Diallylamide (25).
Following the general procedure, with the exception of running
in the presence of 10% catalyst 3, (Z)-3-phenylselenyl-hex-2-
enoic acid diallylamide (25) was prepared in 85% GC yield.
The E/Z ratio was determined by NOE difference and 1H NMR
spectroscopy (E/Z ) 0/100). 1H NMR (300 MHz, C6D6) δ 0.57
(t, J ) 7.3 Hz, 3 H), 1.31 (m, J1 ) J2 ) 7.4 Hz, 2 H), 2.15 (t, J
) 7.4 Hz, 2 H), 3.55 (s, 2 H), 4.00 (d, J ) 5.3 Hz, 2 H), 4.94 (m,
4 H), 5.44 (m, 1 H), 5.73 (m, 1 H), 6.38 (s, 1 H), 6.95-7.81 (m,
5 H); 13C NMR (75 MHz, C6D6) δ 13.4, 21.4, 23.5, 40.1, 48.4,
49.1, 113.8, 116.1, 117.1, 130.5, 131.7, 132.3, 133.5, 133.9,
137.8, 159.2, 166.7; MS (EI) m/z 349 (M+), 272, 253, 192 (base),
157, 77, 41. HRMS calcd for C18H23NOSe 349.093142, found
349.094485.
The Preparation of Acrylamide 17 from Phenylseleno-
2-alken-1-one 43 and Sulfenamide 5 in the Absence of
Catalyst. To a glass bomb in a nitrogen-filled glovebox were
added phenylseleno-2-alkenone 43 (74.0 mg, 0.18 mmol),
sulfenamide 5 (33.0 mg, 0.18 mmol), and benzene (2.5 mL).
The reaction was heated for 96 h at 75 °C with stirring. The
reaction was filtered through Celite and analyzed by GC-MS
and GC. A 100% GC yield of acrylamide 17 was observed.
The Preparation of Acrylamide 45 from Phenylthio-
2-alken-1-one 44 and Sulfenamide 5 in the Absence of
Catalyst. To a glass bomb in a nitrogen-filled glovebox were
added phenylthio-2-alken-1-one 44 (27.6 mg, 0.12 mmol),
sulfenamide 5 (23.0 mg, 0.12 mmol), and benzene (2.5 mL).
The reaction was heated for 70 h at 90 °C with stirring. The
resultant orange solution was filtered through Celite and
reduced in vacuo to yield a viscous oil. GC analysis showed
the yield of acrylamide (45) to be 100%. The crude reaction
mixture was purified via column chromatography using 5%
ethyl acetate/hexanes, 20% ethyl acetate/hexanes, and ethyl
acetate to yield the orange oil 6-cyano-(Z)-3-phenylsulfenyl-
hex-2-enoic acid diethylamide 45 (37.0 mg, 0.11 mmol) in 92%
(Z)-3-Phenylselenyl-hex-2-enoic Acid Methylamide (26).
Following the general procedure, with the exception of heating
for only 70 h, the formation of (Z)-3-phenylselenyl-hex-2-enoic
acid methylamide (26) was not detected by GC-MS.
(Z)-3-Phenylselenyl-hex-2-enoic Acid Diisopropyl-
amide (27). Following the general procedure, with the excep-
tion of heating for only 50 h, the formation of (Z)-3-phenylse-
lenyl-hex-2-enoic acid diisopropylamide (27) was not detected
by GC-MS.
6-Cyano-3-phenylselenyl-hex-2-enoic Acid Phenylsul-
fanylethylamide (28a) and 6-Cyano-3-phenylselenyl-hex-
2-enoic Acid Trimethylsilylamineethylamide (28b). Fol-
lowing the general procedure, the formation of 6-cyano-3-
phenylselenyl-hex-2-enoic acid phenylsulfanylethylamide
(28a) and 6-cyano-3-phenylselenyl-hex-2-enoic acid trimeth-
ylsilylamineethylamide (28b) was observed by GC-MS. 28a:
MS (EI) m/z 384 (M+ - SPh), 278, 227, 157, 91, 77, 65, 51.
28b: MS (EI) m/z 384 (M+ - TMS), 342, 278, 227, 157, 91, 77,
65, 51.
The Preparation of Acrylamide 18 from Amine 29. To
a glass bomb in a nitrogen-filled glovebox were added (PhSe)2
2 (65.0 mg, 0.21 mmol), 5-cyano-1-pentyne (32.0 µL, 0.30
mmol), 4.7% of catalyst 3 (11.5 mg, 9.9 µmol), and benzene
(2.5 mL). The glass bomb was sealed, transferred to a vacuum
line, and placed under nitrogen where amine 29 (21 µL, 0.2
mmol) was added. The reaction was charged with 0.5 atm of
CO gas and heated for 138 h at 90 °C with stirring. The
resultant solution was degassed, filtered through Celite, and
analyzed by GC and GC-MS. The GC yield of 6-cyano-(Z)-3-
phenylselenyl-hex-2-enoic acid diethylamide 18 was deter-
mined to be 40%.
1
yield. H NMR (300 MHz, C6D6) δ 0.82 (t, J ) 6.7 Hz, 3 H),
1.01 (t, J ) 6.7 Hz, 3 H), 1.12 (m, J1 ) J2 ) 7.0 Hz, 2 H), 1.33
(t, J ) 7.0 Hz, 2 H), 2.00 (t, J ) 7.0 Hz, 2 H), 2.91 (q, J ) 6.9
Hz, 2 H), 3.27 (q, J ) 6.8 Hz, 2 H), 6.07 (s, 1 H), 6.90-6.93
(m, 3 H), 7.28-7.30 (m, 2 H); 13C NMR (75 MHz, C6D6) δ 13.4,
14.7, 15.2, 24.0, 34.9, 39.9, 42.3, 118.9, 121.3, 129.2, 133.4,
134.1, 146.2, 165.0; MS (EI) m/z 302 (M+), 230, 193 (base), 109,
100, 77, 65, 51.
The Palladium-Catalyzed Reaction of 1-Pentyne with
(PhS)2 and (PhSe)2. To a glass bomb in a nitrogen-filled
glovebox were added (PhS)2 31 (65.4 mg, 0.30 mmol), (PhSe)2
J. Org. Chem, Vol. 70, No. 3, 2005 795

Knapton and Meyer
2 (94.2 mg, 0.30 mmol), 1-pentyne (30.0 µL, 0.30 mmol), 4.5%
of catalyst 3 (17.0 mg, 14.7 µmol), and benzene (3 mL). The
reaction was heated for 24 h at 90 °C with stirring. The
resultant solution was filtered through Celite and analyzed
by GC-MS and GC. (Z)-1,2-Bis(phenylseleno)-1-pentene 34
and (Z)-1,2-bis(phenylthio)-1-pentene 35 were both detected
in 27.0% GC yield. (Z)-1-phenylthio-2-phenylseleno-1-pentene
(47) and (Z)-1-phenylseleno-2-phenylthio-1-pentene (48) were
also observed in 17 and 20% yields, respectively, by GC.
The Reaction of Phenylseleno-2-hexen-1-one 43 with
(PhS)2. To a glass bomb were added phenylseleno-2-hexen-1-
one 43 (61.5 mg, 0.15 mmol), (PhS)2 31 (34.5 mg, 0.16 mmol),
and benzene (2 mL). The reaction was heated for 48 h at 90
°C with stirring. The reaction was filtered through Celite and
analyzed by GC-MS and GC. A 5.3% GC yield of 3-phenylse-
lenyl-hex-2-enoic acid S-phenyl ester 39 (0.008 mmol) was
observed. Trace amounts of diaryl dichalcogenide 32 were also
observed.
6-Cyano-(Z)-3-phenylsulfenyl-hex-2-enoic Acid Dieth-
ylamide (45). To a stainless steel reaction vessel with glass
insert in a nitrogen-filled glovebox were added (PhS)2 31 (13.0
mg, 0.06 mmol), sulfenamide 5 (18.5 mg, 0.11 mmol), 5-cyano-
1-pentyne (32.0 µL, 0.30 mmol), 4.0% of catalyst 3 (5.0 mg,
4.3 µmol), and benzene (2.0 mL). The reaction was charged
with 28 atm of CO gas and heated for 65 h at 110 °C with
stirring. The resultant solution was degassed, filtered through
Celite, and reduced in vacuo to yield a viscous oil. The crude
reaction mixture was purified via column chromatography
using 5% ethyl acetate/hexanes, 20% ethyl acetate/hexanes,
and ethyl acetate to yield the orange oil 6-cyano-(Z)- 3-phen-
ylsulfenyl-hex-2-enoic acid diethylamide 45 (20.0 mg, 0.07
mmol) in 64% yield. Spectral data match those obtained in
prior experiments.
analyzed by GC. A 25% GC yield of both acrylamides 18 and
45 was observed.
The Comparative Carbonylative Additions of (PhS)2
and (PhSe)2 to 1-pentyne. (a) To a glass bomb in a nitrogen-
filled glovebox were added (PhS)2 31 (43.0 mg, 0.20 mmol),
1-pentyne (25.0 µL, 0.25 mmol), 6.2% of catalyst 3 (14.5 mg,
12.5 µmol), and benzene (2.0 mL). The reaction was charged
with 0.5 atm of CO gas and heated for 94 h at 90 °C with
stirring. The resultant solution was degassed, filtered through
Celite, and analyzed by GC-MS and GC. Phenylthio-2-hexen-
1-one 38 and bis(phenylthio)-1-pentene 35 were detected in
GC yields of 4.7 and 95%, respectively. (b) Following the
general procedure stated above, phenylseleno-2-hexen-1-one
43 and bis(phenylseleno)-1-pentene 34 were detected in GC
yields of 75 and 7%, respectively.
The 1H NMR Analysis of Reaction Selectivity. To a
screw-top NMR tube in a nitrogen-filled glovebox were added
0.1 mL of a 0.0203 M C6D6 solution of sulfenamide 1, 0.1 mL
of a 0.02 M C6D6 solution of (PhSe)2 2, 0.15 mL of a 0.02 M
C6D6 solution of 1-pentyne, 0.1 mL of a 0.01 M C6D6 solution
of catalyst 3, and 0.1 mL of a 0.115 M C6D6 solution of anisole
standard. The reaction was charged with CO gas and heated
1
to 80 °C. The reaction was monitored by H NMR every 24 h
for 6 days. Integrated areas were used to determine the
relative amounts of both selenium and sulfur acrylamide
products 4 and 33. The product ratio of 4:33 after 3 h reaction
and every 24 h is as follows: 100:1, 6:1, 4.5:1, 3.3:1, 3.2:1, 4:1,
3.5:1.
Acknowledgment. We thank the National Science
Foundation (CHE-0091400) and the University of Pitts-
burgh for financial support. We also thank Dr. Fu-Tyan
1
Lin and Dr. Kasi Somayajula for assistance with H,
The High-Pressure Preparation of Acrylamides 18
and 45 from 5-Cyano-1-pentyne and Sulfenamide 5. To
a stainless steel reaction vessel with glass insert in a nitrogen-
filled glovebox were added (PhSe)2 2 (63.0 mg, 0.20 mmol),
sulfenamide 5 (36.7 mg, 0.20 mmol), 5-cyano-1-pentyne (32.0
µL, 0.30 mmol), 4.9% of catalyst 3 (11.5 mg, 9.9 µmol), and
xylenes (2.5 mL). The reaction was charged with 28 atm of
CO gas and heated for 67 h at 85 °C with stirring. The
resultant solution was degassed, filtered through Celite, and
13C NMR, and mass spectral analysis. This research was
supported by NSF award CHE-0091400.
Supporting Information Available: General procedures,
including the synthesis of sulfenamides. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO0484068
796 J. Org. Chem., Vol. 70, No. 3, 2005