Palladium-catalyzed regio-, diastereo-, and enantioselective benzylic allylation of 2-substituted pyridines

Article abstract of DOI:10.1021/ja904441a

(Chemical Equation Presented) We report a new method for the highly regio-, diastereo-, and enantioselective palladiumcatalyzed allylic alkylation of 2-substituted pyridines that allows for the formation of homoallylic stereocenters containing alkyl, aryl

Full text of DOI:10.1021/ja904441a

Published on Web 07/31/2009
Palladium-Catalyzed Regio-, Diastereo-, and Enantioselective Benzylic
Allylation of 2-Substituted Pyridines
Barry M. Trost* and David A. Thaisrivongs
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received June 1, 2009; E-mail: bmtrost@stanford.edu
Table 1. AAA Reactions with 2-Substituted Pyridyl Nucleophilesa
The development of palladium-catalyzed asymmetric allylic
alkylations (AAAs) continues to be a productive area of research.1
Still, there are only a few examples of such reactions that form an
adjacent stereocenter diastereoselectively, and these are almost
exclusively limited to enolate nucleophiles.2 This narrow substrate
scope reflects the inherent challenge of simultaneously forming
vicinal stereocenters selectively. After reporting a method for
employing 2-methylpyridines in palladium-catalyzed AAAs,3 we
wondered whether an analogous reaction with higher-order 2-sub-
stituted pyridines could be effected in a diastereo- and enantiose-
lective fashion (Scheme 1, A). We hypothesized that, upon
coordination of the pyridyl nitrogen atom with BF3, benzylic
deprotonation would provide a nucleophile that would exist as a
single geometric isomer because of the steric demands imposed
by the Lewis acid. If such control were possible, alkylation products
might be obtained with both high diastereo- and enantiocontrol.
Scheme 1. Reaction Hypothesis and Initial Result
a Yield reflects combined isolated yield of both diastereomers; dr and
ee determined by 1H NMR analysis of the crude reaction mixture and
chiral HPLC, respectively.
Unfortunately, when 2-ethylpyridine (1) was reacted with allylic
carbonate 2 under the previously optimized conditions,3 1H NMR
revealed no desired product and partial decomposition of 2 (Scheme
1, B). Replacing the tert-butyl carbonate ester with the more robust
pivalate ester provided an electrophile that was completely stable
to the reaction conditions, and with this substrate the desired
alkylation product (3a) could be obtained in 15% yield, >19:1 dr,
and 95% ee. Although the reaction conversion was low, the
excellent diastero- and enantioselectivity validated our hypothesis.
Disappointingly, higher yields could not be obtained by heating
the reaction or by using other strong bases (e.g., LiTMP, t-BuOK,
KHMDS, or n-BuLi).
The breakthrough came when a single equivalent of n-BuLi was
added to the nucleophilic complex generated with 3 equiv of
LiHMDS; under these conditions, 3a was now isolated in 85% yield,
>19:1 dr, and 94% ee. Presumably, the introduction of n-BuLi
quantitatively deprotonates the equivalent of HMDS formed in the
initial deprotonation event, driving the reaction to completion.
Other 2-substituted pyridines that underwent reaction with
cyclohex-2-enyl pivalate were identified (Table 1). A range of
2-alkyl and 2-aryl substituted pyridines performed well, as did the
corresponding five-membered ring electrophile (see 3b). Large
substituents generally provided the highest level of stereocontrol;
for example, 2-(naphthalene-2-ylmethyl)-pyridine gave 3g in 90%
yield, >19:1 dr, and 98% ee.4 Heteroaryl substitution was also
tolerated (3h), as was an aryl bromide (3i), which did not undergo
oxidative addition by palladium(0) or lithium-halogen exchange
with n-BuLi. Finally, a nitrogen-containing stereocenter could also
be established (3j).5 The relative and absolute stereochemistry of
the products was assigned by analogy to 3d, which was bromocy-
clized to provide single crystals of the corresponding pyridinium
cation suitable for X-ray diffraction (Scheme 2).6
The alkylation is sensitive to the steric nature of the nucleophile.
When additional substituents were placed at either the benzylic (e.g.,
2-isopropylpyridine) or homobenzylic (e.g., 2-neopentylpyridine)
positions, no desired product was observed. Conversely, if the
2-pyridyl substituent is insufficiently sterically demanding for the
two possible geometric configurations of the nucleophile to be
adequately differentiated, the product is formed with low diaste-
reocontrol (e.g., when 2-(methoxymethyl)pyridine was employed,
the product was obtained in 78% yield but 3:2 dr).
9
12056 J. AM. CHEM. SOC. 2009, 131, 12056–12057
10.1021/ja904441a CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Bromocyclization of 3d
recognition, a single enantiomer of ligand is capable of converting
both “matched” and “mismatched” substrate to product.
Table 3. AAA Reactions with Deuterated Substrate 9
entry
ligand
10:11a
yield (%)b
drc
ee (%)d
1
2
3
(S,S)- + (R,R)-L1
(S,S)-L1
(R,R)-L1
1:19
1:1
1:1
97
93
99
9:1
9:1
9:1
-
+90
-91
The reaction is not limited to cyclic electrophiles. Indeed, when
2-benzylpyridine (4) was reacted with pivalate 5, linear product 7
was obtained in 74% yield and 89% ee (Table 2, entry 1).
Unexpectedly, when the reaction was instead conducted with
regioisomeric pivalate 6, a mixture of linear and branched products
(7 and 8) was formed (entry 2). This is an example of the “memory
effect,” in which the regiochemistry of the electrophile influences
the regiochemistry of the product.7 When the reaction was
performed with 5 in benzene with L2, the linear product was again
formed, but with little enantiocontrol (entry 3). However, with 6,
the branched product could be obtained in 64% yield and 63% ee8
(entry 4). Thus either regioisomeric product may be obtained
exclusively by choosing the appropriate allylic ester and ligand.
a Determined by 1H NMR of the product mixture. b Combined
isolated yield of both regioisomers. c Determined by 1H NMR of the
crude reaction mixture. d Determined by chiral HPLC.
In summary, we have reported a new method for the highly
regio-, diastereo-, and enantioselective allylic alkylation of 2-sub-
stituted pyridines. Investigations of the reaction mechanism, the
role of lithium aggregates, and applications of this strategy to other
nucleophilic classes are ongoing.
Acknowledgment. We thank the National Science Foundation
and the National Institutes of Health (GM13598) for supporting
our programs and Johnson Matthey for palladium salts. Dr. Victor
G. Young, Jr. (X-ray Crystallographic Laboratory, University of
Minnesota) is gratefully acknowledged for XRD analysis.
Table 2. “Memory Effect” Observed with Linear Electrophilesa
Note Added after ASAP Publication. A word was inadvertently
omitted from the title in the version published ASAP July 31, 2009.
The corrected version was published August 7, 2009.
Supporting Information Available: Experimental procedures and
analytical data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
entry
substrate
ligand
solvent
7:8b
yield (%)c
ee (%)d
References
1
2
5
6
L1
L1
dioxane
dioxane
>19:1
74
71
89
7:64
8:17
3.6
1:1.6
(1) (a) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921. (b) Lu, Z.;
Ma, S. Angew. Chem., Int. Ed. 2008, 47, 258.
3
4
5
6
L2
L2
PhH
PhH
>19:1
<1:19
32
64
(2) Ketones: (a) Braun, B.; Laicher, F.; Meier, T. Angew. Chem. 2000, 112,
3637. (b) Trost, B. M.; Schroeder, G. M. Chem.sEur. J. 2004, 11, 174. (c)
Trost, B. M.; Xu, J.; Reichle, M. J. Am. Chem. Soc. 2007, 129, 282. (d)
Zheng, W.-H.; Zheng, B.-H.; Zhang, Y.; Hou, X.-L. J. Am. Chem. Soc. 2007,
129, 7718. (e) Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2008,
130, 11852ꢀ-keto esters: (f) Trost, B. M.; Sacchi, K. L.; Schroeder, G. M.;
Asakawa, N. Org. Lett. 2002, 4, 3427. Imino esters: (g) Baldwin, I. C.;
Williams, J. M. J. Tetrahedron: Asymmetry 1995, 6, 1515. (h) Nakoji, M.;
Kanayama, T.; Okino, T.; Takemoto, Y. J. Org. Chem. 2002, 67, 7418. Aza-
lactones: (i) Trost, B. M.; Ariza, X. Angew. Chem., Int. Ed. Engl. 1997, 36,
2635. (j) Trost, B. M.; Lee, C. B. J. Am. Chem. Soc. 1998, 120,
6818. Nitroalkanes: (k) Trost, B. M.; Surivet, J.-P. J. Am. Chem. Soc. 2000,
122, 6291.
63
a Reactions run under standard conditions. b Determined by 1H NMR
of the crude reaction mixture. c Combined isolated yield of both
regioisomers. d Determined by chiral HPLC.
To assess whether such an effect was occurring with cyclic
electrophiles, deuterated substrate 9 was prepared (Table 3). When
the reaction was conducted with 4 and a racemic ligand, regioisomer
11 was obtained with high selectivity (entry 1), while nonracemic
ligands gave an equal mixture of 10 and 11 (entries 2 and 3). These
results show the following: (1) no “memory effect” is operative,
since no bias for nucleophilic attack is observed with the (S,S)- or
(R,R)-ligand alone; (2) when placed in competition, each ligand is
able to perform a near-perfect kinetic resolution of the electrophile,
since each reacts fastest with the enantiomer of 9 for which it is
“matched” (providing 11 as the common product of “matched”
ionization pathways); and (3) despite this high degree of chiral
(3) Trost, B. M.; Thaisrivongs, D. A. J. Am. Chem. Soc. 2008, 130, 14092.
(4) Interestingly, the 1-naphthyl analog of 3g could be obtained in 100% con-
version by 1H NMR but only 2:1 dr.
(5) No reaction was observed with the unmethylated carbamate or the corre-
sponding phthalimide-protected aminopyridine.
(6) (a) Szychowski, J.; Wro´bel, J. T.; Leniewski, A. Bull. Acad. Pol. Sci., Ser.
Sci. Chim. 1980, 28, 9. (b) Waetzig, S. R.; Tunge, J. A. J. Am. Chem. Soc.
2007, 129, 4138.
(7) (a) Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1998, 120, 70. (b) Lloyd-
Jones, G. C.; Stephen, S. C. Chem.sEur. J. 1998, 4, 2539.
(8) No racemization was observed under the reaction conditions.
JA904441A
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