Palladium-catalyzed coupling of allyl acetates with aldehyde and imine electrophiles in the presence of bis(pinacolato)diboron

Article abstract of DOI:10.1021/ol035052i

(Matrix presented) An efficient one-pot procedure was developed for palladium-catalyzed electrophilic substitution of allyl acetates (2a-h) in the presence of bis(pinacolato)diboron (1). These reactions proceed with an excellent regioselectivity and with a remarkably high stereoselectivity. The catalytic transformations take place via palladium-catalyzed formation of allyl boronates, which subsequently react with aldehyde (3) and sulfon-imine (4) electrophiles to afford homoallylic alcohols (5a-h) and amines (6a-d), respectively. A particularly interesting mechanistic feature is that the allylic substitution of the transient allyl boronate with sulfon-imine requires palladium catalysis. This finding indicates that the formation of the homoallylic amine derivatives (6a-d) involves bis-allylpalladium intermediates.

Full text of DOI:10.1021/ol035052i

ORGANIC
LETTERS
2
003
Vol. 5, No. 17
065-3068
Palladium-Catalyzed Coupling of Allyl
Acetates with Aldehyde and Imine
Electrophiles in the Presence of
Bis(pinacolato)diboron
3
Sara Sebelius, Olov A. Wallner, and K a´ lm a´ n J. Szab o´ *
Stockholm UniVersity, Arrhenius Laboratory, Department of Organic Chemistry,
SE-106 91, Stockholm, Sweden
kalman@organ.su.se
Received June 11, 2003
ABSTRACT
An efficient one-pot procedure was developed for palladium-catalyzed electrophilic substitution of allyl acetates (2a−h) in the presence of
bis(pinacolato)diboron (1). These reactions proceed with an excellent regioselectivity and with a remarkably high stereoselectivity. The catalytic
transformations take place via palladium-catalyzed formation of allyl boronates, which subsequently react with aldehyde (3) and sulfon-imine
(4) electrophiles to afford homoallylic alcohols (5a−h) and amines (6a−d), respectively. A particularly interesting mechanistic feature is that
the allylic substitution of the transient allyl boronate with sulfon-imine requires palladium catalysis. This finding indicates that the formation
of the homoallylic amine derivatives (6a−d) involves bis-allylpalladium intermediates.
Palladium catalysis offers an attractive synthetic approach
for stereo- and regioselective allylation of electrophilic
substrates. These reactions usually proceed in two consecu-
However, less reactive species such as transient trialkyl-allyl
stannanes require a second palladium-catalyzed step to
accomplish the allylation of the electrophile. The organo-
1
3
tive steps. The first step is a palladium-catalyzed formation
metallic reagents employed in these reactions have to comply
with two important requirements: (1) they must be compat-
ible with several reactive functionalities to ensure a broad
synthetic scope for the catalytic transformations, and (2) the
transient allylmetal compound must undergo highly regio-
and stereoselective coupling with the electrophile.
of an allylmetal species from allyl halides or allyl acetates
and an organometallic reagent2 (such as SnCl
,3
2 2 3
, ZnEt , Et B,
(
SnMe
3 2
) , etc.). Usually, the allyl-metal intermediates are
2
sufficiently reactive for direct coupling with electrophiles.
(
(
1) Marshall, J. A. Chem. ReV. 2000, 100, 3163.
2) (a) Tamaru, Y. J. Organomet. Chem. 1999, 576, 215. (b) Ma-
We have now found that bis(pinacolato)diboron (1) is an
organometallic reagent that largely satisfies the above
requirements. Thus, functionalized allyl acetates (2) could
be reacted with aldehyde (3) or imine (4) electrophiles in
suyamama, Y.; Kinugawa, N.; Kurusu, Y. J. Org. Chem. 1987, 52, 3702.
c) Shimizu, M.; Kimuro, M.; Tanaka, S.; Tamaru, Y. Tetrahedron Lett.
988, 39, 609. (d) Takahara, J. P.; Masuyama, Y.; Kurusu, Y. J. Am. Chem.
Soc. 1992, 114, 2577. (e) Kimura, M.; Kiyama, I.; Tomizawa, T.; Horino,
Y. Tanaka, S.; Tamaru, Y. Tetrahedron Lett. 1999, 40, 6795. (f) Tamaru,
Y.; Goto, S.; Tanaka, A.; Shizimu, M.; Kimura, M. Angew. Chem., Int. Ed.
Engl. 1996, 35, 878.
(
1
the presence of 1 and catalytic amounts of Pd
affording the corresponding homoallylic alcohol (5) or amine
6) products with high regio- and stereoselectivity (Scheme
1 and Table 1).
2 3
(dba)
(
(3) (a) Wallner, O. A.; Szab o´ , K. J. Org. Lett. 2002, 4, 1563. (b) Wallner,
O. A.; Szab o´ , K. J. J. Org. Chem. 2003, 68, 2934.
1
0.1021/ol035052i CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/19/2003

Scheme 1
Table 1. Pd-Catalyzed Allylic Substitution of Allyl Acetates
2a-h in the Presence of Bis(pinacolato)diboron
In a typical reaction, the corresponding electrophile 3 or
4
(0.30 mmol) and Pd
dissolved in DMSO (3 mL). Thereafter, the allylic substrate
a-h (0.36 mmol) was added, and this mixture was stirred
2 3
(dba) (6 mol % palladium) were
2
for 10 min at room temperature under Ar. After addition of
diboron reagent 1 (0.36 mmol), the reaction mixture was
stirred at the allotted temperatures and times listed in Table
1. The products (5, 6) were isolated by column chromatog-
raphy using a pentane-EtOAc eluent.
The reactions usually could be carried out under mild
conditions at room temperature or at slightly elevated
temperatures (40 °C). The synthetic scope of the reaction is
broad due to a high level of functional group tolerance. Many
2 2
functionalities, including NO , COOEt, OAc, and CONH ,
remained unchanged under the applied reaction conditions.
A particularly attractive feature of this catalytic transforma-
tion is that nitro-benzaldehyde (3) can be used as a coupling
component. Under the applied reaction conditions, 3 resists
both Cannizzaro reaction and change of the nitro functional-
ity, which may take place under basic conditions and on
using low-valent metals.4 The catalytic transformations
proceeded with very high regioselectivity, affording the
branched allylic isomer. The diastereoselectivity of the
reactions is also remarkably high. In several cases (entries
a,b
2, 7, 8, and 10), only a single diastereomer was formed. It
is interesting to note that recent publications on synthesis
of analogues of 5g (entry 7) and 5h (entry 8) particular-
ly emphasized the difficulties concerning the highly
stereoeselective preparation of these types of com-
4
a,c
pounds.
When high reaction temperatures (> 60 °C) were em-
ployed, amorphous palladium(0) was precipitated from the
reaction mixture, thereby deactivating the catalyst. We have
tried to stabilize the catalyst by addition of various phos-
3 3
phines (e.g., PPh and P(OPh) ) or activated alkenes (e.g.,
a
All reactions were conducted in DMSO in the presence of 1 using 6
maleic anhydride and COD). However, these additives
strongly retarded or inhibited the catalytic process. It was
found that precipitation of palladium black could be sup-
pressed most efficiently by lowering the reaction temperature
and by elongation of the reaction time.
mol % Pd catalyst. The allotted temperatures and times are given in °C/h.
b
c
Diastereomer ratio (anti/syn) determined by 1H NMR spectroscopy.
Isolated yield. d Major diastereomer has anti configuration.
4a-d
e
Major
9a,b
diastereomer has syn configuration. Bs ) benzenesulfonyl; s.d. ) single
diastereomer
5
a
Mechanistic Aspects. Miyaura and co-workers have
shown that allyl acetates react with diboron reagent 1 in a
palladium-catalyzed transformation affording allyl boronates
eq 1). It was found that this catalytic transformation is
5
a
(
(
4) (a) Lombardo, M.; Morganti, S.; Trombini, C. J. Org. Chem. 2003,
6
8, 997. (b) Parra, M.; Mestres, R.; Aparicio, D.; Durana, N.; Rubiales, G.
(5) (a) Ishiyama, T.; Ahiko, T.-a.; Miyaura, N. Tetrahedron Lett. 1996,
J. Chem. Soc., Perkin Trans. 1 1989, 327. (c) Goldberg, S. D.; Grubbs, R.
H. Angew. Chem., Int. Ed. 2002, 41, 807. (d) Batey, R. A.; Thadani, A. N.;
Smil, D. V.; Lough, A. J. Synthesis 2000, 990.
6889. (b) Yamammoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207. (c)
Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1982, 21, 555. (d) Brown,
H. C.; Racherla, U. S.; Pellechia, P. J. J. Org. Chem. 1990, 55, 1868.
3066
Org. Lett., Vol. 5, No. 17, 2003

However, when the conversion exceeds 50%, the catalytic
transformation of 2a is faster in the presence of 3 than in
the absence of it. This indicates that accumulation of allyl
boronate 8 inhibits the catalytic process.
It is well-known that homocoupling product 7 readily
6
Figure 1. Palladium-catalyzed transformation of 2a in the presence
b) and absence (9) of aldehyde 3.
7
a,b
forms from bis-allylpalladium complexes.
Therefore,
(
appearance of the allyl-allyl coupling product (7) in the
absence of aldehyde 3 indicates that a bis-allylpalladium
intermediate (10) is generated under catalytic conditions (eq
).
The possible intermediacy of bis-allylpalladium complex
0 in the above-presented catalytic process (Scheme 1) is
usually accompanied by formation of the allyl-allyl coupling
product 7.
3
1
also indicated by the reactions involving imine 4 (entries
9
-12). In contrast to aldehyde 3, sulfon-imine 4 cannot be
allylboronated with 8 in the absence of palladium catalyst
(eq 2). Accordingly, the boron atom does not exert an internal
Lewis acid reactivity as in the reactions with aldehyde types
It is reasonable to assume that the first step of the above-
presented allylic substitution reaction (Scheme 1) is pal-
ladium-catalyzed formation of the transient allyl boronate.
However, it is interesting to note that allyl-allyl coupling
products (such as 7) were not observed in any of the reactions
presented in Table 1. It is well established that allyl boronates
5
c
of substrates. On the other hand, we have found that in the
presence of Pd (dba) catalyst, allyl boronate 8 smoothly
2
3
reacts with 4 affording 6a. A similar reactivity was reported
for palladium-catalyzed allylic substitution of trialkyl-allyl
3
,8
undergo direct allylboration with aldehydes and other
stannanes with aldehydes and imines. In these reactions,
the bis-allypalladium intermediate (10) is formed from allyl
stannanes and 9 (cf. eq 3).
electrophiles.5
b-d
In these reactions, the carbonyl group of
the aldehyde coordinates to the boron atom, which reacts as
5c
an internal Lewis acid due to its low-lying vacant p
Indeed, allyl boronate 8 smoothly reacted with aldehyde 3
eq 2) under the applied reaction conditions (Scheme 1) in
π
-orbital.
It was shown that bis-allylpalladium complexes readily
react with electrophiles under catalytic conditions.3 Al-
though the catalytic allylic substitution via bis-allylpalladium
complexes is a well-known reaction for trialkyl-allyl stan-
nanes, as far as we know, this is the first study reporting a
similar reactivity for allyl boronates.
,7,8
(
the absence of palladium catalyst. Accordingly, the catalytic
allylic substitution of allyl acetates (2a-h) with aldehyde 3
can be considered as a palladium-catalyzed formation of
transient allyl boronates followed by direct coupling with
the electrophile (i.e., 3).
The high stereoselectivity is a synthetically useful feature
of the presented allylic substitution reaction. The reactions
with aldehyde 3 selectively provide (entries 2-8) the anti
diastereomer. This stereoselectivity can be explained by the
selective formation of the trans isomer of the allyl boronate
intermediate in the initial palladium-catalyzed step. The
subsequent reaction of the trans-allyl boronates with alde-
5c
hydes leads to formation of the anti diastereomer. The major
diastereomer formed in the reactions with sulfon-imine 4 has
syn configuration. A similar syn diastereoselectivity was
reported for the formation of 6b from 4 and cinnamyl
Performing the reaction as a one-pot sequence has several
advantages. (1) Isolation of the reactive allyl boronate
intermediates (entries 5-8) can be avoided. (2) Allyl-allyl
coupling does not take place in the presence of electrophiles.
9a
bromide in indium- and zinc-mediated reactions. Although
understanding the mechanism of the stereochemistry requires
further studies, we believe that the nature of the steric and
(
3) The palladium-catalyzed conversion of allyl acetate (2a)
is faster in the presence of 3 than in the parent reaction (eq
). To further explore feature 3, we have studied the rate of
1
(
7) (a) Nakamura, H.; Bao, M.; Yamamoto, Y. Angew. Chem., Int. Ed.
001, 40, 3208. (b) Goliaszewski, A.; Schwartz, J. Tetrahedron 1985, 41,
5779.
consumption of 2a in the presence and in the absence of
2
6
aldehyde 3 (Figure 1). In the beginning of the reaction (t <
(
8) (a) Nakamura, H.; Iwama, H.; Yamamoto, Y. J. Am. Chem. Soc. 1996,
10 min) the rate of conversion of 2a does not depend on 3.
1
18, 6641.(b) Nakamura, H.; Aoyagi, K.; Shim, J.-G., Yamamoto, Y. J.
Am. Chem. Soc. 2001, 123, 372. (c) Solin, N.; Narayan, S.; Szab o´ , K. J. J.
Org. Chem. 2001, 66, 1686. (d) Solin, N.; Narayan, S.; Szab o´ , K. J. Org.
Lett. 2001, 3, 909.
(
6) These reactions were performed in the presence of 1 and a catalytic
amount of Pd2(dba)3 in DMSO-d6 at 50 °C.
Org. Lett., Vol. 5, No. 17, 2003
3067

electronic interactions governing the stereoselection can be
similar in the indium-mediated and in the present palladium-
catalyzed process.9a
In summary, we have shown that aldehyde (3) and sulfon-
imine (4) electrophiles can be allylated by allyl acetates in
boronate to afford homoallylic alcohols as products. How-
ever, the reaction of sulfon-imine 4 with the allyl-boronate
intermediate requires palladium catalysis, indicating that bis-
allylpalladium intermediates may be involved in the reaction.
2 3
the presence of 1 and a catalytic amount of Pd (dba) . The
Acknowledgment. This work was supported by the
Swedish Research Council (VR).
catalytic reaction proceeds with a remarkable high regio- and
stereoselectivity providing the branched allylic isomer.
Mechanistic studies show that the first step of the reaction
is a palladium-catalyzed formation of transient allyl bor-
onates. Subsequently, aldehyde 3 reacts directly with the allyl
Supporting Information Available: Characterization and
C NMR spectra of new compounds 5g, 5h, and 6d. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
3
(9) (a) Lu, W.; Chan, T. H. J. Org. Chem. 2000, 65, 8589. (b) Ruano, J.
L. G.; Fern a´ ndez, I.; del Prado Catalina, M.; Hermoso, J. A.; Sanz-Aparicio,
J.; Mart ´ı nez-Ripoll, M. J. Org. Chem. 1998, 63, 7157.
OL035052I
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Org. Lett., Vol. 5, No. 17, 2003