Palladium-catalyzed tandem bis-allylation of isocyanates

Article abstract of DOI:10.1021/ol015545s

matrix presented A tandem bis-allylation of p-toluenesulfonyl isocyanate can be achieved by palladium-catalyzed three-component coupling reaction with allylstannanes and allyl chlorides. A high level of regioselectivity can be obtained by the appropriate choice of the allylic substituents. The reaction mechanism and the regiochemistry of the reaction can be explained by formation of an amphoteric bis-allylpalladium intermediate. This bis-allylpalladium intermediate undergoes an initial electrophilic attack on one of the allyl moieties followed by a nucleophilic attack on the other.

Full text of DOI:10.1021/ol015545s

ORGANIC
LETTERS
2001
Vol. 3, No. 6
909-912
Palladium-Catalyzed Tandem
Bis-allylation of Isocyanates
Niclas Solin, Sanjay Narayan, and Ka´lma´n J. Szabo´*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm UniVersity,
SE-106 91, Stockholm, Sweden
kalman@organ.su.se
Received January 10, 2001
ABSTRACT
A tandem bis-allylation of p-toluenesulfonyl isocyanate can be achieved by palladium-catalyzed three-component coupling reaction with
allylstannanes and allyl chlorides. A high level of regioselectivity can be obtained by the appropriate choice of the allylic substituents. The
reaction mechanism and the regiochemistry of the reaction can be explained by formation of an amphoteric bis-allylpalladium intermediate.
This bis-allylpalladium intermediate undergoes an initial electrophilic attack on one of the allyl moieties followed by a nucleophilic attack on
the other.
Isocyanates have proven to be useful and versatile reagents
in allylpalladium chemistry.1,2 These reagents have been used
extensively in palladium-catalyzed ring-opening cyclization1
of vinylaziridines and vinyl epoxides, as well as in telom-
erization of butadiene.2 A common feature of these reactions
is that an initial electrophilic attack of the carbonyl carbon
of the isocyanate generates an anionic species, which
performs a nucleophilic attack on the (η3-allyl)palladium
intermediate of the catalytic transformation. We have now
found that toluenesulfonyl isocyanate (1) undergoes a similar
type of reaction with allylstannanes and allyl chlorides in
the presence of catalytic amounts of palladium (Scheme 1).
for 15 min at room temperature under an Ar atmosphere.
Thereafter, allylstannane (0.38 mmol) was added and this
mixture was stirred for 5 min. After addition of Ts-NCO
(0.32 mmol), the reaction mixture was stirred for the
temperatures and times listed in Table 1. The reaction
mixture was then diluted with ether and treated with a
saturated KF solution. After filtration through Celite, the
organic phase was washed with water and brine, dried over
MgSO4, and concentrated. The products 4-9 were isolated
by silica gel chromatography using a pentane-ether eluent.
The reaction was relatively fast (entries 1-2) with
unsubstituted allyls (2a and 3a), while in the presence of
alkyl substituents (3b-e) a higher reaction temperature (60
°C) and a longer reaction time (3-8 h) had to be employed
(entries 3-7). A shorter reaction time or lower temperature
using 3b-e as the allyl chloride component provided a
considerable amount of the mono-allylated product after
workup. On the other hand, a reaction temperature over 60
°C led to allylic rearrangement of the product. Using other
catalyst sources, such as PdCl2(PhCN)2, did not improve the
Scheme 1
(1) (a) Butler, D. C. D.; Inman, G. A.; Alper, H. J. Org. Chem. 2000,
65, 5887. (b) Larksarp, C.; Alper, H. J. Am. Chem. Soc. 1997, 119, 3709.
(c) Baeg, J. O.; Bensimon, C.; Alper, H. J. Am. Chem. Soc. 1995, 117,
4700. (d) Trost, B. M.; Van Venkren, D. L. J. Am. Chem. Soc. 1993, 115,
444. (e) Trost, B. M.; Sudhakar, A. R. J. Am. Chem. Soc. 1988, 110, 7933.
(f) Trost, B. M.; Sudhakar, A. R. J. Am. Chem. Soc. 1987, 109, 3792. (g)
Hayashi, T.; Yamamoto, A.; Ito, Y.; Tetrahedron Lett. 1988, 29, 99.
(2) Ohno, K.; Tsuji, J. Chem. Commun. 1971, 247.
In this process both the carbon and the nitrogen atoms of
isocyanate 1 can be alkylated regioselectively with different
allyl moieties (Table 1) in good yield.
In a typical reaction the corresponding allyl chloride (0.38
mmol) and Pd(PPh3)4 (5 mol %) in THF (1 mL) were stirred
10.1021/ol015545s CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/28/2001

authors3b found that benzyne derivatives also undergo three-
component coupling with 2a,b and 3a or 3e. Nicholas and
co-workers4 performed a similar coupling reaction using
carbon dioxide in place of benzyne. Thus, the present reaction
(Scheme 1) can be considered as a new extension of the
palladium-catalyzed three-component coupling reaction using
an isocyanate as the substrate (entries 1 and 6). An important
feature of the tosyl isocyanate based coupling reactions is
that a very high regioselectivity can be achieved when
terminally alkylated allyl chlorides (R2, R3 * H) are
employed (entries 3-5 and 7). In previous publications3,4 it
was pointed out that using different substituent patterns on
the allyl chloride and allystannane components leads to
formation of regioisomer mixtures. For example, when 2a
and 3e are reacted with benzyne or CO2, an almost statistical
mixture of diallylated products is formed, including all
possible homo- and cross-coupling products.3b,4 We have also
found that in the three-component coupling reaction of 1,
2a, and 3e, a mixture of two different regioisomers and
homo-coupling products 4 and 8 was formed (Scheme 3). A
Table 1. Palladium-Catalyzed Three-Component Reaction of
TsNCO, Allylstannanes 2a,b, and Allyl Chlorides 3a-ea
Scheme 3
similar reaction mixture was obtained when a more bulky
allylstannane, 2b, and the unsubstituted allyl chloride 3a are
employed. Clearly, the presence of alkyl substituents at both
the C1 and C3 positions in the allyl chloride component (3b-
d) is a prerequisite of the high regioselectivity. Furthermore,
by using 3b-d in this process the formation of the homo-
coupling products (e.g., 4 and 8) can be completely avoided.
Mechanistic Considerations. Yamamoto and co-workers5
have shown that reaction of 2a with (η3-allyl)palladium
complexes, such as 10, leads to formation of bis-allylpalla-
dium species (11). In contrast to mono-allylpalladium
complexes, bis-allylpalladium complexes are nucleophilic
and react readily with electrophiles.5-7 Furthermore, it has
been demonstrated5 that under catalytic conditions bis-
allylpalladium complexes may undergo an initial electrophilic
attack on one of the allyl moieties followed by a nucleophilic
attack on the other. Accordingly, a plausible mechanism of
the catalytic cycle is given in Scheme 4. The first step is an
oxidative addition of the palladium(0) catalyst to allyl
a Unless otherwise stated the reactions were conducted in THF using 5
mol % of Pd(PPh3)4. b Temperature (°C)/reaction time (h). c Isolated yield.
d 5 mol % of PdCl2(PhCN)2 and 10 mol % of PPh3 were used as catalyst.
e cis/trans ratio 1:5.
yield of the reaction (entry 2). Only the unchanged starting
material could be recovered, when 1,3-dialkyl-substituted
allylstannanes were employed in place of 2a,b.
Phenyl and nitrophenyl isocyanates reacted more slug-
gishly than 1, and the catalytic reaction was stopped after
mono-allylation of the reagent (Scheme 2).
Scheme 2
(3) (a) Nakamura, H.; Shim, J.-G.; Yamamoto, Y. J. Am. Chem. Soc.
1997, 119, 8113. (b) Yoshikawa, E.; Radhakrishnan, K. V.; Yamamoto, Y.
Tetrahedron Lett. 2000, 41, 729.
(4) Franks, R. J.; Nicholas, K. M. Organometallics 2000, 19, 1458.
(5) Nakamura, H.; Iwama, H.; Yamamoto, Y. J. Am. Chem. Soc. 1996,
118, 6641.
(6) (a) Tsuji, J. Palladium Reagents and Catalysis: InnoVations in
Organic Synthesis; Wiley: New York, 1995, Chapter 3. (b) Benn, R.; Jolly,
P. W.; Mynott, R.; Raspel, B.; Schenker, G.; Schick, K.-P.; Schrot, G.
Organometallics 1985, 4, 1945.
(7) (a) Szabo´, K. J. Chem. Eur. J. 2000, 6, 4413. (b) Solin, N.; Narayan,
S.; Szabo´, K. J. J. Org. Chem. 2001, 66.
Analogous palladium-catalyzed three-component coupling
reactions using allylstannane (2a) and allyl chloride (3a) have
recently been applied to diallylation of benzylidenemalonitrile
and its congeners by Yamamoto and co-workers.3a These
910
Org. Lett., Vol. 3, No. 6, 2001

Scheme 4
Scheme 5
the electrophilic and nucleophilic attack on the unsubstituted
allyls is probably very fast. However, when 3b-d is
employed, the nucleophilic attack on the η3-allyl moiety
bearing bulky alkyl substituents slows down the reaction
(entries 3-5 and 7).
As mentioned above, the catalytic reaction does not
proceed with 1,3-dialkyl-substituted allylstannane derivatives.
This is probably due to the fact that the transmetalation of
10 with bulky allylstannanes is more difficult than the
corresponding transmetalation with 2a,b (cf. 10 f 11 in
Scheme 4). The lower electrophilicity of phenyl isocyanate
(Scheme 2) compared to 1 explains the observation that the
reaction is more sluggish with Ph-NCO than with Ts-NCO.
The high reactivity of the η1-coordinated allyl moiety
toward isocyanates can also be demonstrated by quantum
chemical molecular modeling. Density functional calcula-
tions8 indicate that electrophilic attack on the η1 moiety of
the bis-allylpalladium intermediate (Scheme 6) proceeds with
chloride, which results in mono-allylpalladium complex 10.
This complex reacts with allylstannanes, giving a bisallylpal-
ladium complex5 (11).
In the presence of phosphine ligands (L ) PPh3) this
complex coordinates one of the allyl groups in an η1-fashion
(11b).7 Recent mechanistic studies showed7 that the η1-allyl
moiety in bis-allylpalladium complexes is highly reactive
toward electrophiles. Thus, the η1-allyl moiety of 11b
undergoes electrophilic attack by the carbonyl carbon of 1,
affording a mono-allylpalladium complex and an allylated
N-nucleophile (12). The second allylation reaction involves
a nucleophilic attack by this N-nucleophile on the allyl
moiety of the mono-allylpalladium intermediate. This nu-
cleophilic attack regenerates the palladium(0) catalyst and
provides the bis-allylated isocyanate derivative (e.g., 4)
product.
Scheme 6
In the case of substituted allyls, the above reaction may
result in two (entries 3 and 7) or four regioisomers (entries
4-5) depending on the location of the initial electrophilic
attack and on the regioselectivity of the subsequent nucleo-
philic attack. The structure of the single regioisomers
obtained clearly indicates that the electrophilic attack takes
place on the unsubstituted allyl moiety of the bis-allylpal-
ladium intermediate. This can be explained by the fact that
the substituent effects of the alkyl groups depend on the
coordination state (η1- vs η3-coordination) of the allyl moiety
in the bis-allylpalladium intermediate. Theoretical calcula-
tions show7 that the η3-dimethyl-substituted complex (13a)
is more stable than its η1-dimethyl-substituted (13b) coun-
terpart (Scheme 5). Furthermore, the activation barrier of
the electrophilic attack is lower for 13a than for 13b.7b The
formation of 6 and 7 alone indicates that even the nucleo-
philic attack of the monoallylpalladium complex (cf. 12) is
highly regioselective.
a remarkably low activation energy (11.7 kcal/mol). This
activation barrier is in the range of the corresponding
activation energies calculated for electrophilic attack by
formaldehyde (7.2 kcal/mol) and acrylonitrile (14.2 kcal/
mol).7 It was shown that various derivatives of these species,
such as benzaldehyde and benzylidenemalonitrile, react
(8) The geometries were fully optimized employing a Becke-type9 three-
parameter density functional model B3PW91 using a doubleú(DZ)+P basis
constructed from the LANL2DZ basis augmented by one set of d-
polarization functions on the heavy atoms. For further details see refs 7a,b.
The mild conditions and short reaction time for the three-
component coupling of 2a, 3a, and 1 (entry 1) indicate that
Org. Lett., Vol. 3, No. 6, 2001
911

readily with bis-allylpalladium intermediates occurring in
palladium-catalyzed two- or three-component coupling
reactions.3a,5
high regioselectivity can be achieved using 3b-e as allyl
chloride component. The reactivity of 1 and the regioselec-
tivity of the allylation reaction can be rationalized on the
basis of the formation of a bis-allylpalladium intermediate
in the catalytic transformation.
Transition state structure 14 reveals two important factors
which facilitate the electrophilic attack on bis-allylpalladium
complex 11b: (i) the hyperconjugative interactions10 in the
η1-moiety, as shown by the C1-C2-C3-Pd torsional angle
τ (88.6°),7 and (ii) the electrostatic interactions between the
palladium atom and the nitrogen atom of HNCO. Electron-
withdrawing substituents, such as a tosyl group, on the
nitrogen increase the electrophilicity of the carbonyl carbon
of the isocyanate, which is expected to lower the activation
barrier of the electrophilic attack.
Acknowledgment. This work was supported by the
Swedish Natural Science Council (NFR) and the paralell-
datorcenrum at the Royal Institute of Technology, Sweden.
The financial support of The Wenner-Gren Foundations for
a postdoctoral fellowship to S.N. is gratefully acknowledged.
Supporting Information Available: Characterization and
13C NMR spectra of products 4-9. This material is available
free of charge via the Internet at http://pubs.acs.org.
In summary, we have shown that 1 can be allylated on
both the carbon and nitrogen atoms of the isocyanate
functionality in palladium-catalyzed three-component cou-
pling with allylstannanes and allyl chlorides.11 A remarkably
OL015545S
(9) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
(10) These hyperconjugative interactions occur between the π* and the
dσ(Pd-C) MOs in the η1-allyl moiety. This hyperconjugation is most
intensive when τ ) 90°, since this torsional angle ensures an optimal orbital
overlap between π* and dσ(Pd-C).7
(11) After preparation of this Letter, we found a very recent, independent
study by Yamamoto and co-workers including the coupling reaction of 2a,
3a, and Ts-NCO (Table 1, entry 1). Nakamura, H.; Aoyagi, K.; Shim, J.-
G.; Yamamoto, Y. J. Am. Chem. Soc. 2001, 123, 372.
912
Org. Lett., Vol. 3, No. 6, 2001