Allylations of chelated enolates using dienyl substrates

Article abstract of DOI:10.1021/ol702865q

Isomerization-free reactions of dienyl carbonates (1-3) with chelated amino acid ester enolates at -78 °C provide important information concerning the mechanism of these dienylations. The formation of regioisomeric products can be explained by competing S

Full text of DOI:10.1021/ol702865q

ORGANIC
LETTERS
2008
Vol. 10, No. 3
501-504
Allylations of Chelated Enolates Using
Dienyl Substrates
Sankar Basak and Uli Kazmaier*
UniVersita¨t des Saarlandes, Institut fu¨r Organische Chemie, Im Stadtwald, Geb. 23.2,
D-66123 Saarbru¨cken, Germany
u.kazmaier@mx.uni-saarland.de
Received November 27, 2007
ABSTRACT
Isomerization-free reactions of dienyl carbonates (1−3) with chelated amino acid ester enolates at
−78
°
C provide important information
concerning the mechanism of these dienylations. The formation of regioisomeric products can be explained by competing SN2/SN2
′ reactions,
and the product distribution can be influenced by proper choice of the reaction conditions.
π-Allyl palladium complexes play an important role in
modern organic synthesis.1 With respect to the different
synthetic applications, the allylic alkylation is probably the
most popular application.2 Herein, a π-allyl complex is
attacked by a nucleophile such as an amine or a stabilized
carbanion (in general malonate). Starting from the isomeric
substrates A1 and A2 (Scheme 1) π-allyl palladium complex
B1 is formed via nucleophilic attack of Pd0.3 A nucleophile
can react with this allyl complex at both allylic positions. In
general, attack on π-allyl palladium complexes occurs at the
sterically least hindered position, giving rise to linear
substitution product C1.2 According to this simplified model,
one should expect the same product distribution, independent
of the substrate (A1 or A2) used, as long as the same π-allyl
intermediate B1 is formed. Interestingly, this is not always
true. Quite often, a higher ratio of branched product C2 is
formed if the branched substrate A2 is used.4 This so-called
“memory effect” was investigated carefully and probably has
several origins.5 Besides the “chloride effect”,6 the conforma-
(1) (a) Hegedus, L. S. Organische Synthese mit U¨ bergangsmetallen;
VCH: Weinheim, Germany, 1995. (b) Kazmaier, U.; Pohlman, M. Cross
Coupling Reactions Via π-Allyl Intermediates. In Metal Catalyzed C-C
and C-N Coupling Reactions; de Meijere, A., Diederich F., Eds.; Wiley-
VCH: Weinheim, Germany, 2004; pp 531-583 and references cited therein.
(2) (a) Consiglio, G.; Waymouth, R. M. Chem. ReV. 1989, 89, 257-
276. (b) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395-422.
(c) Helmchen, G. J. Organomet. Chem. 1999, 576, 203-214. (d) Pfaltz,
A.; Lautens, M. In ComprehensiVe Asymmetric Catalysis I-III; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; pp 833-
884. (e) Acemoglu, L.; Williams, J. M. J. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-I., de Meijere, A., Eds.; John
Wiley: New York, 2002; Vol. 2, pp 1689-1705. (f) Tsuji, J. In Handbook
of Organopalladium Chemistry for Organic Synthesis; Negishi, E.-I., de
Meijere, A., Eds.; John Wiley: New York, 2002; Vol. 2, pp 1669-1688.
(g) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921-2944. (h)
Trost, B. M.; Jiang, C. Org. Lett. 2003, 5, 1563-1565. (i) Trost, B. M.;
Xu, J. J. Am. Chem. Soc. 2005, 127, 2846-2847. (j) Trost, B. M.; Brennan,
M. K. Org. Lett. 2006, 8, 2027-2030.
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10.1021/ol702865q CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/10/2008

in the presence of Pd catalysts,9 while in tungsten-catalyzed
reactions, the branched product F2 was the major one.10 The
same regioselectivity can also be observed with other transi-
tion metals, such as molybdenum11 or iridium.12 In principle,
the product formation can be explained by a π-allyl palladium
intermediate E1, but detailed studies by Trost13 and Ba¨ck-
vall14 indicated that the situation is much more complex.
For example, if branched substrate D2 was reacted, the
linear product F1 was also the major one besides F2. This
is quite surprising because D2 can form π-allyl complexes
E1 and E3, as well, and therefore all three products F1-F3
can be expected. In addition, D2 should be able to form an
anti-vinyl allyl complex,7 analogue to B2 (not shown here
for clarity reasons), which should favor the formation of F2.4b
In contrast, substrate D3, which should deliver F2 and F3
via intermediate E3, gave rise to a mixture of products F1-
F3, while F2 was the major one. These results can be
explained by an isomerization of the π-allyl intermediates
via E2,13 although the different product distribution is
surprising. As an alternative, the formation of F1 from E3
can also be explained by an allylation under SN2′ conditions.
Unfortunately, under the standard reaction conditions used
for malonate allylations/dienylations, no differentiation be-
tween the mechanistic pathways can be made because under
these conditions isomerization is rather fast.13 On the other
hand, if it is possible to suppress these isomerizations, one
should be able to obtain important information about the
mechanism of these dienylations.
Scheme 1. Detailed Mechanism of Pd-Catalyzed Allylic
Alkylation and Dienylation
tion of the allylic substrate in the ionization step also plays
a crucial role because substrates of type A2 can ionize not
only to the syn-complex B1 but also to the anti-complex
B2, as well.7 The higher ratio of branched product C2 can
be explained by a higher reactivity of the anti-position in
complex B2 compared to the syn-position in complex B1.4b,8
This effect is relatively strong in reactions with small
substituents (e.g., R ) CH3). The anti-complex B2 is also
formed from the (Z)-substrate A3.
A more complex situation is when the higher unsaturated
compounds such as dienyl substrates D are reacted. In
dienylations of amines and malonates with linear substrates
such as D1, the linear product F1 was formed preferentially
For several years, our group has been investigating allylic
alkylations of amino acids15 and peptides.16 These substrates
are able to form highly reactive chelated enolates which allow
allylic alkylations at -78 °C. At this temperature, isomer-
ization processes can be suppressed efficiently.17 This is also
(9) (a) Trost, B. M.; Keinan, E. J. Org. Chem. 1979, 44, 3451-3457.
(b) Trost, B. M.; Keinan, E. J. Am. Chem. Soc. 1978, 100, 7779-7781. (c)
Andersson, P. G.; Ba¨ckvall, J. E. J. Org. Chem. 1991, 56, 5349-5353.
(10) Trost, B. M.; Lautens, M.; Hung, M.-H.; Carmichael, C. S. J. Am.
Chem. Soc. 1984, 106, 7641-7643.
(11) Trost, B. M.; Hildbrand, S.; Dogra, K. J. Am. Chem. Soc. 1999,
121, 10416-10417.
(12) (a) Takeuchi, R.; Tanabe, K. Angew. Chem. 2000, 112, 2051-2054.
(b) Lipowsky, G.; Helmchen, G. Chem. Commun. 2004, 116-117. (c)
Lipowski, G.; Miller, N.; Helmchen, G. Angew. Chem 2004, 116, 4695-
4698; Angew. Chem., Int. Ed. 2004, 43, 4595-4597.
(13) (a) Trost, B. M.; Bunt, R. C. Tetrahedron Lett. 1993, 34, 7513-
7616. (b) Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1998, 120, 70-79.
(14) Nilsson, Y. I. M.; Andersson, P. G.; Ba¨ckvall, J.-E. J. Am. Chem.
Soc. 1993, 115, 6609-6613.
(15) (a) Kazmaier, U.; Zumpe, F. L. Angew. Chem. 1999, 111, 1572-
1574; Angew. Chem., Int. Ed. 1999, 38, 1468-1470. (b) Kazmaier, U.;
Maier, S.; Zumpe, F. L. Synlett 2000, 1523-1535. (c) Weiss, T. D.;
Helmchen, G.; Kazmaier, U. Chem. Commun. 2002, 1270-1271. (d)
Kazmaier, U. Curr. Org. Chem. 2003, 317-328. (e) Kazmaier, U.; Stolz,
D. Angew. Chem. 2006, 118, 3143-3146; Angew. Chem., Int. Ed. 2006,
45, 3072-3075 and references cited therein.
(16) (a) Kazmaier, U.; Deska, J.; Watzke, A. Angew. Chem. 2006, 118,
4973-4976; Angew. Chem., Int. Ed. 2006, 45, 4855-4858. (b) Deska, J.;
Kazmaier, U. Angew. Chem. 2007, 119, 4654-4657; Angew. Chem., Int.
Ed. 2007, 46, 4570-4573. (c) Deska, J.; Kazmaier, U. Chem.sEur. J. 2007,
13, 6204-6211.
(17) (a) Kazmaier, U.; Zumpe, F. L. Angew. Chem. 2000, 112, 805-
807; Angew. Chem., Int. Ed. 2000, 39, 802-804. (b) Kazmaier, U.; Zumpe,
F. L. Eur. J. Org. Chem. 2001, 4067-4076. (c) Kazmaier, U.; Pohlman,
M. Synlett 2004, 623-626. (d) Kazmaier, U.; Pohlmann, M.; Lindner, T.
J. Org. Chem. 2004, 69, 6909-6912. (e) Kazmaier, U.; Lindner, T. Angew.
Chem. 2005, 117, 3368-3371; Angew. Chem., Int. Ed. 2005, 44, 3303-
3306. (f) Lindner, T.; Kazmaier, U. AdV. Synth. Catal. 2005, 347, 1687-
1695. (g) Kazmaier, U.; Kra¨mer K. J. Org. Chem. 2006, 71, 8950-8953.
(5) (a) Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1996, 118, 235-
236. (b) Lloyd-Jones, G. C.; Stephen, S. C. Chem.sEur. J. 1998, 4, 2539-
2549. (c) Poli, G.; Scolastico, C. Chemtracts 1999, 12, 837-845. (d) Lloyd-
Jones, G. C.; Stephen, S. C.; Murray, M.; Butts, C. P.; Vyskocil, S.;
Kocovsky, P. Chem.sEur. J. 2000, 6, 4348-4357. (e) Lloyd-Jones, G. C.
Synlett 2001, 161-183. (f) Fairlamb, I. J. S.; Lloyd-Jones, G. C.; Vyskocil,
S.; Kocovsky, P. Chem.sEur. J. 2002, 8, 4443-4453. (g) Gouriou, L.;
Lloyd-Jones, G. C.; Vyskovil, S.; Kocovsky, P. J. Organomet. Chem. 2003,
687, 525-537. (h) Lussem, B. J.; Gais, H.-J. J. Org. Chem. 2004, 69, 4041-
4052. (i) Faller, J. W.; Sarantopoulos, N. Organometallics 2004, 23, 2179-
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Walter, O.; Zsolnai, L. Tetrahedron Lett. 1994, 35, 1523-1526. (b) Brown,
J. M.; Hulmes, D. I.; Guiry, P. J. Tetrahedron 1994, 50, 4493-4506. (c)
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Jones, G. C.; Stephen, S. C. Chem. Commun. 1998, 2321-2322. (e)
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P.-O. AdV. Synth. Catal. 2007, 349, 2631-2640.
(8) The syn/anti-terminology was used to describe the relative orientation
of the substituents at the allylic position relative to the hydrogen at the
central position of the π-allyl Pd complex.
502
Org. Lett., Vol. 10, No. 3, 2008

true with terminal π-allyl palladium complexes of type B,
which provided important information concerning the already
mentioned memory effect.18 Therefore, we decided to
investigate these chelated enolates also in reactions of dienyl
substrates 1-3 (Table 1). These substrates were chosen to
also here the linear product was the preferred one (entry 2).
Interestingly, besides 4 also the E/Z-isomer 4′ was observed
in significant amount (36% of the linear product).
Table 1. Dienylation of Chelated Enolate G
The significant amount of 5 probably results from the
memory effect and can be explained by the reaction
mechanism (Scheme 2). Substrate 2 can undergo ionization
Scheme 2. Formation of Isomeric Products 4-6 from Dienyl
Substrate 2
dr (anti:syn)
reaction
entry substrate conditions
yield
(%)
ratio
4:5:6
5
6
1
2
3
4
5
6
1
2
3
1
2
3
-78 °C, 16 h 92 55:22:23 97:3 65:35
-78 °C, 16 h 64 54a:31:15 90:10 33:67
-78 °C, 16 h 87 36:13:51 95:5 50:50
rt
rt
rt
83 37:20:43 92:8 61:39
25 35b:16:49 88:12 42:58
41 31:12:57 94:6 35:65
a Product contains 36% (E/Z)-isomer 4′ (GC). b Product contains 12%
isomer 4′ (GC).
get results which can directly be compared to those obtained
with the malonates. According to Scheme 1, substrates 1-3
should lead to products 4-6, while the product distribution
should depend on the relative ratio of the allylic complexes
E1-E3 (R ) Me). To suppress the isomerization as much
as possible, we used an excess of enolate to speed up the
nucleophilic substitution. As substrates, the corresponding
carbonates were used, which are more reactive than the
(commonly used) acetates. The reactions were carried out
at -78 °C, a temperature which allowed isomerization-free
reactions with “normal” allylic substrates. In the reaction of
linear substrate 1, as expected, the linear product 4 was
formed preferentially as pure (E/E)-isomer. But in contrast
to the results obtained by Trost and Ba¨ckvall,9 the branched
products 5 and 6 were obtained in a comparable amount as
a 1:1 mixture (Table 1, entry 1).19 5 ws formed in nearly
diastereomerically pure form (97% ds) while 6 was obtained
as a 2:1 isomeric mixture. Especially the high ratio of 5 was
surprising, because its formation can only be explained by
a) a partial isomerization, or b) a significant participation of
a SN2′ attack. Therefore, we next switched to substrate 2.
Under identical reaction conditions, the yield was lower, but
from two different conformations,7 which results in the
formation of the two π-allyl complexes H1 (syn/syn-
complex) and H2 (anti/syn-complex), while H1 is the
thermodynamically favored one. Therefore, at higher tem-
perature, where both complexes are in equilibrium, this
complex should be enriched. Both complexes can be attacked
at both allylic positions (a, b), as well as in a SN2′ fashion
(c). Nucleophilic attacks a and a′ both provide the same
product 5, while the attacks b/c and b′/c′ give rise to the
isomeric products. This might be an explanation for the
relatively high amount of 5 obtained. The formation of 6 is
the result of attack b on H1, and the isomeric product 6′
with a (Z)-double bond was not observed. This is in good
agreement with observations made by the Akermark group4b
that the anti-position (a′) of syn/anti-complexes is the
significantly more reactive one. In the dienyl complexes
investigated here, the SN2′ attack at the terminal position
(c′) is obviously the preferred one. This also explains the
relatively high amount of (E/Z)-product 4′.
It also indicates that complexes H1 and H2 are formed in
comparable amounts and that isomerization of the complexes
under the reaction conditions used is relatively slow, at least
in comparison to nucleophilic attack of the enolate. However,
if the isomerization of the complexes H1 and H2 is very
slow, one can also exclude an interconversion of the allyl
complexes E1 and E3 (via E2).
(18) Kazmaier, U.; Stolz, D.; Kra¨mer, K.; Zumpe, F. Chem.sEur. J.
2007, 13, early view (http://dx.doi.org/10.1002/chem.200701332).
(19) The preferred formation of branched products was also observed
in the presence of chiral ferrocenyl ligands: Zheng, W.-H.; Sun, N.; Hou,
X.-L. Org. Lett. 2005, 7, 5151-5154.
Org. Lett., Vol. 10, No. 3, 2008
503

Table 2. Dienylations of Chelated Enolates G with Various Substrates 7
dr (anti:syn)
reaction
yield
ratio
entry
substrate
R
conditions
(%)
8:9:10
8
9
10
1
2
3
4
5
7a
7b
7b
7c
7c
Me
Et
Et
Ph
Ph
-78 °C to rt, 16 h
-78 °C to rt, 16 h
rt
-78 °C to rt, 16 h
rt
89
85
60
96
45
91a:0:9
92:8
91:9
77:23
87:13
84:16
76:15b:8
48:15:37
78:12:10
49:5:46
>97:3
92:8
>97:3
>97:3
50:50
50:50
56:44
63:37
a Product contains 10% (E/Z)-isomer 8a′ (GC). b Product contains 2% (E/Z)-isomer 9′ (GC).
Therefore, we turned our attention to the branched
substrate 3 which on ionization should give rise to these two
allyl complexes. In high yield, the branched product 6 was
obtained preferentially. This is also quite reasonable because
6 can be formed from both allyl complexes (E1 and E3). In
addition, a significant memory effect might participate.
Obviously, 6 is the thermodynamic product and 4 the kinetic
one. This observation is in contrast to the results obtained
with amines and malonates.9,14 To prove this assumption,
we carried out the reactions also at room temperature (entries
4-6), conditions where the π-allyl complexes should be
more or less in an equilibrium. Indeed, under these condi-
tions, the relative amount of 6 could be increased on cost of
the linear product 4. In these cases, the yield obtained was
significantly lower, caused by a higher degree of side
reactions.
To illustrate that these results can also be transferred to
other dienyl systems, we investigated the reaction of several
other substrates 7 (Table 2). The dimethylated compound
7a has the big advantage that only two products (8 ) 9) are
obtained. Also, with this substrate, 10% of the (E/Z)-isomer
8′ was obtained (Table 2, entry 1). By increasing the sterical
size of the substituent R, the ratio of SN2′ attack at this
position decreases and, as a result of that, also the relative
amount of (E/Z)-isomer. No (E/Z)-isomer at all was formed
from the phenyl-substituted derivative 7c.
If the reactions were carried out at room temperature, the
yield was lower because of side reactions and also the
diastereoselectivity decreased, but again, the amount of non-
conjugated product 10 increased, supporting the assumption
that the deconjugated product is the thermodynamic one.
In conclusion, we have shown that in dienylations of
chelated enolates isomerization processes of the palladium
complexes involved can be suppressed and that the formation
of isomeric products is the result of competing SN2/SN2′
reactions. By choosing proper reaction conditions (kinetic
or thermodynamic control), the product ratio can be ma-
nipulated, at least in part. Further investigations, especially
on the chirality transfer from optically active substrates, are
currently in progress.
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft (Ka880/6 and Ka880/8)
and by the Fonds der Chemischen Industrie. S.B. is thankful
to the Alexander von Humboldt Foundation for a postdoctoral
fellowship.
Supporting Information Available: Analytical and
spectroscopic data of dienylation products 4-6 and 8-10.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL702865Q
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Org. Lett., Vol. 10, No. 3, 2008