Catalytic SN2′-selective substitution of allylic chlorides with arylboronic esters

Article abstract of DOI:10.1021/ol101171v

(Figure Presented) A copper-catalyzed S_N2′-selective arylation of allylic chlorides has been achieved using arylboronic esters as nucleophiles. Arylation products were obtained in high yield with a variety of allylic chlorides and arylboronic e

Full text of DOI:10.1021/ol101171v

ORGANIC
LETTERS
2010
Vol. 12, No. 14
3216-3218
Catalytic SN2′-Selective Substitution of
Allylic Chlorides With Arylboronic
Esters
Aaron M. Whittaker, Richard P. Rucker, and Gojko Lalic*
Department of Chemistry, UniVersity of Washington, Seattle, Washington 98195
lalic@chem.washington.edu
Received May 20, 2010
ABSTRACT
A copper-catalyzed SN2′-selective arylation of allylic chlorides has been achieved using arylboronic esters as nucleophiles. Arylation products
were obtained in high yield with a variety of allylic chlorides and arylboronic esters in the presence of a wide range of functional groups. A
mechanism is proposed on the basis of the results of stoichiometric experiments and the isolation of the proposed intermediate.
Since its discovery in 1969,1 the copper-catalyzed allylic
alkylation has been a subject of intense study and as a result
has been developed into a valuable tool for organic synthesis.
With a broad range of substrates, highly efficient SN2′-
selective formation of a new carbon-carbon bond can be
achieved, while a number of variants allow enantioselective
formation of both tertiary and quaternary stereocenters.2 In
contrast to the large number of reports of copper-catalyzed
allylic alkylations, allylic substitutions with sp2-hybridized
carbon nucleophiles remain a formidable challenge. Hoveyda
et al. have only recently reported the first general allylic
alkenylation.3 Furthermore, there is still no general SN2′-
selective allylic arylation, despite the progress recently made
using copper,4 iridium,5 and palladium6 catalysts. The major
limitation remains the poor regioselectivity in reactions of
primary electrophiles.
arylboronic esters as nucleophiles. We also present results
of the preliminary study of the reaction mechanism.
One of the major problems in developing a copper-
catalyzed SN2′-selective allylic arylation reaction is the
predominant formation of SN2 products (3), generally
observed in reactions of primary allylic electrophiles (1) (eq
1).5 It has been proposed that the observed selectivity is a
result of the low reactivity of arylcopper complexes, together
with the facile formation of more reactive diaryl cuprates
(4) in the presence of excess aryl nucleophile (2).7 This
proposal is supported by the fact that in stoichiometric
(4) (a) Kacprzynski, M. A.; May, T. L.; Kazane, S. A.; Hoveyda, A. H.
Angew. Chem., Int. Ed. 2007, 46, 4554–4558. (b) Selim, K.; Yamada, K.;
Tomioka, K. Chem. Commun. 2008, 5140–5142. (c) Selim, K. B.;
Matsumoto, Y.; Yamada, K.; Tomioka, K. Angew.Chem., Int. Ed. 2009,
48, 8733–8735. (d) Ohmiya, H.; Yokobori, U.; Makida, Y.; Sawamura, M.
J. Am. Chem. Soc. 2010, 132, 2895–2897. (e) Ohmiya, H.; Yokokawa, N.;
Sawamura, M. Org. Lett. 2010, 12, 2438–2440. (f) Piarulli, U.; Daubos,
P.; Claverie, C.; Roux, M.; Gennari, C. Angew. Chem., Int. Ed. 2003, 42,
234–236. (g) Demel, P.; Keller, M.; Breit, B. Chem.sEur. J. 2006, 12,
6669–6683.
In this paper, we report SN2′-selective allylic arylation of
primary allylic electrophiles using a copper(I) catalyst and
(1) Ronal, P.; To¨kes, J. T.; Crabee´, P. J. Chem. Soc. D 1969, 8, 43–44.
(2) Recent reviews of the copper-catalyzed allylic substitution reactions:
(a) Alexakis, A.; Ba¨ckvall, J. E.; Krause, N.; Pa`mies, O.; Die´guez, M. Chem.
ReV. 2008, 108, 2796–823. (b) Falciola, C. A.; Alexakis, A. Eur. J. Org.
Chem. 2008, 3765–3780.
(5) Polet, D.; Rathgeb, X.; Falciola, C. A.; Langlois, J. B.; El Hajjaji,
S.; Alexakis, A. Chem.sEur. J. 2009, 15, 1205–1216.
(6) Ohmiya, H.; Makida, Y.; Li, D.; Tanabe, M.; Sawamura, M. J. Am.
Chem. Soc. 2009, 131, 17276–17277.
(7) (a) Ba¨ckvall, J. E.; Sellen, M.; Grant, B. J. Am. Chem. Soc. 1990,
112, 6615–6621. (b) Ba¨ckvall, J. E.; Persson, E. S.; Bombrun, A. J. Org.
Chem. 1994, 59, 4126–4130.
(3) Lee, Y.; Akiyama, K.; Gillingham, D. G.; Brown, M. K.; Hoveyda,
A. H. J. Am. Chem. Soc. 2008, 130, 446–447.
10.1021/ol101171v  2010 American Chemical Society
Published on Web 06/18/2010

reactions arylcopper complexes (7) provide a substitution
product with a high SN2′ selectivity, while the preformed
diaryl cuprates provide a mixture of products.7,8
alkoxide18 (Table 1, entries 9 and 10). Overall, the best
results were obtained using reaction conditions described in
entry 8 for electron-rich boronic esters and in entry 10 for
electron-poor boronic esters.
With the optimized reaction conditions in hand, we
explored the reactivity of various arylboronic esters. The
reaction can be successfully performed in the presence of a
variety of functional groups, including formyl and nitro
groups, which are not compatible with previously described
copper-catalyzed allylic substitution reactions (Table 2).
We reasoned that the formation of diaryl cuprates could
be prevented if less reactive arylboronic esters were used as
nucleophiles (eq 2). This approach is particularly appealing
considering the availability, stability, and excellent functional
group compatibility of arylboronic esters.9 Furthermore,
when we started the project there were no examples of
organoboron compounds being used in copper-catalyzed
allylic alkylation or arylation reactions.10,11
Table 2. Arylboronic Esters in Allylic Arylation Reaction
entrya
Ar
alkoxide
SN2′/SN2b yieldc (%)
In preliminary screening experiments, we discovered that
the SN2′-selective addition of 8a to 1-chloro-2-hexene (9)
can be achieved using copper(I) complexes 10a-d as
catalysts in the presence of a stoichiometric amount of KO-
t-Bu. The best SN2′ selectivity12 was obtained with 10a, while
catalysts 10b-d provided a higher rate13 and lower selectiv-
ity. Both the alkoxide and the copper catalyst were necessary
for an efficient reaction.14 Interestingly, allylic arylation of
9 with phenyl Grignard and 10a as a catalyst resulted in
exclusive formation of the product of SN2 reaction, in
agreement with previously published results.15
1
2
3
4
5
6
7
4-MeOPh (8c)
4-(CHO)Ph (8b) NaO-t-Pent
4-CF3Ph (8d)
4-NO2Ph (8e)
3-NO2Ph (8f)
4-BrPh (8g)
KO-t-Bu
58:1
20:1
24:1
13:1
10:1
32:1
24:1
85
97
75
92
66
78
85
NaO-t-Pent
NaO-t-Pent
NaO-t-Pent
KO-t-Bu
2,6-Me2Ph (8h)
KO-t-Bu
a All reactions were performed on 0.5 mmol scale. b Determined by
GC analysis. c Yield of isolated products.
Furthermore, we observed a direct correlation between the
electron-donating ability of the aryl substituents and the
regioselectivity. Steric properties of the boronic ester, on
the other hand, had little effect on the reaction outcome, as
demonstrated by the reaction of the ortho,ortho-disubstituted
arylboronic ester 8h.
In the process of reaction optimization, we discovered that
the highest selectivity is obtained with readily available 10e16
as a catalyst in 1,4-dioxane (Table 1, entry 5).13,17 Among
The scope of the allylic arylation was further explored in
reactions of a variety of allylic chlorides. It was discovered
that both E- and Z-substituted electrophiles can be used in
the reaction with similar success (Table 3, entries 1 and 2).
Azides, nitriles, chlorides, and TBS-protected alcohols are
all compatible with the reaction conditions, further demon-
strating the exceptional functional group tolerance of the
Table 1. Reaction Optimization
(8) For a recent theoretical study, see: Yoshikai, N.; Zhang, S.;
Nakamura, E. J. Am. Chem. Soc. 2008, 130, 12862–12863.
(9) Hall, D. G. Boronic Acids; Wiley-VCH: Weinheim, 2005.
(10) For an early report of a stoichiometric reaction using trialkylborates,
see: Miyaura, N.; Itoh, M.; Suzuki, A. Bull. Chem. Soc. Jpn. 1977, 50,
2199–2200.
(11) See ref 4d,e for two recent reports.
(12) Reaction of 8a and 3-chloro-1-butene under the same reaction
conditions afforded SN2′ product as the exclusive product of the re-
action.
(13) See the Supporting Information for details.
a 8a, Ar ) 4-MePh; 8b, Ar ) 4-(CHO)Ph; B(pin) ) pinacol boron.
(14) In the absence of base with 10e as the catalyst, product was obtained
in 8% yield, while in the absence of catalyst the yield was less than 5%.
(15) Tominaga, S.; Oi, Y.; Kato, T.; An, D. K.; Okamoto, S. Tetrahedron
Lett. 2004, 45, 5585–5588.
b Determined by GC analysis.
(16) Compound 10e is prepared in one step from the commercially
available IMes·HCl. See the Supporting Information for details.
(17) Addition of water was not beneficial as in the copper-catalyzed
arylation of internal alkenes with aryboronic esters, recently reported by
Sawamura (ref 4e).
the alkali tert-butoxides, potassium alkoxide provided the
highest yield. With electron-poor boronic esters, such as 8b,
both sodium and potassium alkoxides could be successfully
used, with slightly better selectivity obtained with sodium
(18) Sodium tert-pentoxide and sodium tert-butoxide provide the same
result.
Org. Lett., Vol. 12, No. 14, 2010
3217

Table 3. Allylic Chlorides in Allylic Arylation Reaction
Scheme 1. Proposed Mechanism and Stoichiometric Reactions
the product of transmetalation (11) from a stoichiometric
reaction of 10e and 8a (Scheme 1, eq 5) and provide direct
evidence for the transmetalation from boron to copper(I).19,20
The isolation of 11 also allowed us to investigate the potential
role of this complex in the second step of the proposed
catalytic cycle.
A stoichiometric reaction of 11 and 9 resulted in the
formation of the expected product within seconds, in good
yield and with selectivity comparable to the selectivity
obtained in a catalytic reaction (Scheme 1, eq 6). Further-
more, 11 is a competent catalyst and can be used instead of
10e. Together, these results support the idea that the
arylcopper intermediate is the reactive nucleophile respon-
sible for the selectivity observed in catalytic reactions.
Finally, in the last step of the catalytic cycle, copper(I)
alkoxide is regenerated from copper(I) chloride and KO-t-
Bu in a well-precedented transformation.21
a All reactions were performed on 0.5 mmol scale. b Determined by
GC analysis of pure products. c Yield of isolated products. d KO-t-Bu was
used.
reaction. Finally, cyclic and aryl-substituted allylic chlorides
are also suitable substrates for allylic arylation (entries 6-8).
In addition to allylic arylation, we discovered that orga-
noboron reagents can also be used as nucleophiles in copper-
catalyzed alkenylation and alkylation of primary allylic
electrophiles. With pentenyl boronic ester, the alkenylation
product is obtained in good yield and excellent selectivity
(eq 3). Allylic alkylation, on the other hand, can be
accomplished using trialkylboranes formed in situ from an
alkene and 9-BBN (eq 4). The hydroboration-allylic alky-
lation sequence allows highly efficient and selective one-
pot coupling of terminal alkenes and allylic chlorides.
In conclusion, we have developed the first general SN2′-
selective allylic arylation reaction using a copper(I) catalyst
and arylboronic esters as nucleophiles. The reaction has a
broad substrate scope and can be performed in the presence
of a variety of functional groups including formyl, car-
bomethoxy, nitrilo, azido, chloro, bromo, and nitro groups.
Acknowledgment. This work was supported by the
University of Washington.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL101171V
(19) Ohishi, T.; Nishiura, M.; Hou, Z. Angew. Chem., Int. Ed. 2008,
In an attempt to provide a better understanding of the
source of the observed SN2′ selectivity, we studied the
mechanism of the reaction, with the catalytic cycle presented
in Scheme 1 as a working hypothesis. We were able to isolate
47, 5792–5795
.
(20) No attempt was made to optimize the reactions conditions used in
preparation of 11.
(21) Mankad, N. P.; Laitar, D. S.; Sadighi, J. P. Organometallics 2004,
23, 3369–3371.
3218
Org. Lett., Vol. 12, No. 14, 2010