Stereoconvergent amine-directed alkyl-alkyl Suzuki reactions of unactivated secondary alkyl chlorides

Article abstract of DOI:10.1021/ja203560q

A new family of stereoconvergent cross-couplings of unactivated secondary alkyl electrophiles has been developed, specifically, arylamine-directed alkyl-alkyl Suzuki reactions. This represents the first such investigation to be focused on the use of alkyl

Full text of DOI:10.1021/ja203560q

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Stereoconvergent Amine-Directed AlkylÀAlkyl Suzuki
Reactions of Unactivated Secondary Alkyl Chlorides
Zhe Lu, Ashraf Wilsily, and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S Supporting Information
b
alkylÀalkyl Suzuki reaction. We recognized that attenuating the
nucleophilicity of the amine toward the halide might also diminish
the likelihood that the amine would serve as a directing group and
that only a single example of an enantioselective cross-coupling
of an unactivated secondary alkyl chloride had been described.5b
When we applied the conditions that we had developed earlier
for enantioselective Suzuki reactions of homobenzylic bromides5a to
the cross-coupling of a secondary chloride bearing a pendant
arylamine, we obtained a promising lead (eq 2; 70% ee, 58%
yield). Optimization of the reaction parameters, primarily through
the use of C2-symmetric 1,2-diamine 1,13 provided a method
that furnishes the desired alkylÀalkyl coupling product with
improved enantioselectivity and yield (Table 1, entry 1).
ABSTRACT: A new family of stereoconvergent cross-cou-
plings of unactivated secondary alkyl electrophiles has been
developed, specifically, arylamine-directed alkylÀalkyl Suzuki
reactions. This represents the first such investigation to be
focused on the use of alkyl chlorides as substrates. StructureÀ
enantioselectivity studies are consistent with the nitrogen, not
the aromatic ring, serving as the primary site of coordination of
the arylamine to the catalyst. The rate law for this asymmetric
cross-coupling is compatible with transmetalation being the
turnover-limiting step of the catalytic cycle.
lkylÀalkyl couplings are among the most challenging of
A
cross-coupling processes, due in part to the potential for
intermediates in the catalytic cycle to undergo β-hydride elim-
ination and other undesired reactions.1,2 The development of
highly versatile methods will likely have a substantial impact on
organic synthesis,3 particularly if carbonÀcarbon bond forma-
tion can be accomplished enantioselectively. We have recently
begun to pursue this objective with both activated and unac-
tivated secondary alkyl electrophiles.4À6 Asymmetric cross-couplings
of unactivated substrates have proved to be especially difficult,
and to date only two families of halides have undergone coupling
in good ee (homobenzylic bromides5a and acylated bromohy-
drins (and one chlorohydrin)5b). In each instance, a functional
group proximal to the electrophilic site (an aryl substituent or a
carbonyl oxygen) is likely interacting with the chiral catalyst in the
stereochemistry-determining step of the reaction.7
Under our optimized conditions, an array of stereoconvergent
arylamine-directed alkylÀalkyl Suzuki couplings of unactivated
secondary chlorides can be achieved with good enantioselectivity
(Table 1).14 The aromatic ring of the arylamine can be un-
(entries 1À3), para- (entries 4À6), meta- (entries 7À9), or
ortho-substituted (entry 10). Furthermore, it can be fused to
another ring (entries 11 and 12). Suzuki reactions of more
hindered electrophiles (e.g., entries 2, 3, and 10) sometimes
proceed in moderate ee or yield. Functional groups such as
ethers, acetals, and aryl fluorides are compatible with the cross-
coupling conditions.15 Although this method was developed for
asymmetric Suzuki couplings of unactivated secondary alkyl
chlorides, we have determined that it can be applied without
modification to the cross-coupling of an alkyl bromide in good ee
and yield (eq 3).
Because a wide array of molecules possess nitrogen-containing
functional groups, including bioactive compounds such as alkaloids,8
we sought the development of an amine-directed method for the
asymmetric alkylÀalkyl cross-coupling of unactivated electrophiles.9
In this report, we describe the achievement of this objective,
specifically, stereoconvergent Suzuki reactions10 of racemic second-
ary alkyl chlorides that bear proximal arylamines (eq 1).
The spatial relationship between the arylamine and the
chloride is important for obtaining good enantioselectivity. Thus,
if an additional methylene unit is introduced between the aryl-
amine and the chloride (3), then the cross-coupling product is
generated with essentially no ee (<5%). Furthermore, a secondary
The potential of β-halo trialkylamines to cyclize (e.g., nitrogen
mustards11) led us to focus on arylamines as the directing group12
and chlorides as the leaving group for our desired asymmetric
Received: April 18, 2011
Published: May 10, 2011
r
2011 American Chemical Society
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Table 1. Stereoconvergent Amine-Directed AlkylÀAlkyl
Suzuki Reactions of Unactivated Secondary Alkyl Chlorides
(for the reaction conditions, see eq 1)a
cross-coupling with very modest ee (cf. 7), comparable to a substrate
that lacks an amino substituent altogether (8).17 Collectively,
these data are consistent with our new Suzuki couplings being
nitrogen-directed processes. They therefore complement the only
two previous examples of asymmetric cross-couplings of unac-
tivated alkyl electrophiles, which are directed by carbon- (aromatic
ring)5a and oxygen-based (carbonyl)5b functional groups.
To date, the rate law has not been determined for any
enantioselective cross-coupling of an unactivated secondary alkyl
halide. For the Suzuki reaction of an arylamine-containing
secondary chloride (entry 1 of Table 1), we have established
that the rate law is first order in the catalyst and in the organo-
borane but zeroth order in the electrophile,18 which is consistent
with a catalytic cycle in which transmetalation is the turnover-
limiting step (e.g., Scheme 119). In a competition experiment, the
catalyst cross-couples an alkyl bromide in preference to a chloride
with very high selectivity (eq 4), indicating that, if complexation
of the amine to nickel precedes oxidative addition, the complexa-
tion is likely reversible vis-ꢀa-vis oxidative addition.20 The data
illustrated in eq 5 are further consistent with the suggestion that
the arylamine does not play a dominant role in determining
relative reactivity in these Suzuki couplings of alkyl halides.
a All data are the average of two experiments. b Yield of purified product.
c Catalyst loading: 20% NiBr2•diglyme, 24% 1.
alkyl chloride that bears a conformationally constrained aryla-
mine (4) couples with only modest enantioselectivity.16
In summary, a new family of stereoconvergent cross-couplings
of unactivated secondary alkyl electrophiles has been developed.
These nitrogen-directed enantioselective Suzuki reactions repre-
sent the third example of such processes, complementing pre-
vious reports of couplings directed by carbon- (arenes) and
oxygen-based functional groups, as well as the first investigation
focused on the use of unactivated alkyl chlorides as substrates.
StructureÀenantioselectivity studies indicate that the likely
primary site of coordination of the arylamine to the catalyst is
the nitrogen, not the aromatic ring. The rate law for an asymmetric
We hypothesize that the effective asymmetric induction in the
Suzuki cross-couplings illustrated in Table 1 arises from com-
plexation of the arylamine to the chiral nickel catalyst in the
stereochemistry-determining step of the catalytic cycle. In order
to gain insight into whether this interaction is primarily through
the aromatic ring5a or through the nitrogen12 of the arylamine,
we examined enantioselective Suzuki reactions of arylamines
5 and 6. We determined that these electrophiles undergo
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Scheme 1. Outline of a Possible Pathway for a Nickel-
Catalyzed Cross-Coupling of a Simple Unactivated Alkyl
Electrophile
Chem. Soc. 2010, 132, 11027–11029. (d) Multigram reactions: Lou, S.;
Fu, G. C. Org. Synth. 2010, 87, 317–329; Lou, S.; Fu, G. C. Org. Synth.
2010, 87, 330–338.
(5) For enantioselective cross-couplings of unactivated secondary
alkyl electrophiles, see: (a) Saito, B.; Fu, G. C. J. Am. Chem. Soc. 2008,
130, 6694–6695. (b) Owston, N. A.; Fu, G. C. J. Am. Chem. Soc. 2010,
132, 11908–11909.
(6) For leading references on enantioselective cross-couplings of
secondary alkyl electrophiles, see: Glorius, F. Angew. Chem., Int. Ed.
2008, 47, 8347–8349.
(7) For reviews of “directed” reactions, see: (a) Hoveyda, A. H.;
Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307–1370. (b) Rousseau,
G.; Breit, B. Angew. Chem., Int. Ed. 2011, 50, 2450–2494.
(8) The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.; Elsevier:
San Diego, 2010.
(9) For a review of methods for the enantioselective synthesis of
amines, see: Chiral Amine Synthesis; Nugent, T. C., Ed.; WileyÀVCH:
Weinheim, Germany, 2010.
(10) (a) The Suzuki reaction is the most broadly used cross-coupling
process. For reviews, see ref 2. (b) For a pioneering study of alkylÀalkyl
Suzuki cross-couplings, see: Ishiyama, T.; Abe, S.; Miyaura, N.; Suzuki,
A. Chem. Lett. 1992, 691–694.
cross-coupling of an unactivated alkyl electrophile has been
determined for the first time, and the data are consistent with
transmetalation being the turnover-limiting step of the cata-
lytic cycle. Additional catalyst-development and mechanistic
investigations of enantioselective alkylÀalkyl cross-couplings
are underway.
(11) Koller, M.; Szinicz, L. In Clinical Toxicological Analysis;
K€ulpmann, W.-R., Ed.; WileyÀVCH: Weinheim, Germany, 2009; Vol.
2, pp 679À743.
’ ASSOCIATED CONTENT
(12) (a) We are aware of only one report of a metal-catalyzed
asymmetric reaction that is directed by a tertiary arylamine (Khan, H. A.;
Kou, K. G. M.; Dong, V. M. Chem. Sci. 2011, 2, 407–410); the paucity of
such processes may be due in part to the diminished Lewis basicity of the
nitrogen as a result of delocalization of the “lone pair”. (b) For an
example of a catalytic enantioselective reaction that is directed by a
secondary arylamine, wherein the proton is lost during binding, see:
Worthy, A. D.; Joe, C. L.; Lightburn, T. E.; Tan, K. L. J. Am. Chem. Soc.
2010, 132, 14757–14759.
S
Supporting Information. Experimental procedures and
b
compound characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
gcf@mit.edu
(13) (a) The synthesis of racemic diamine 1 has been described:
Alexakis, A.; Aujard, I.; Mangeney, P. Synlett 1998, 873–874. (b) The
synthesis of enantiopure diamine 1 has not been reported, but it is
readily prepared through the method of Chin: Chin, J.; Mancin, F.;
Thavarajah, N.; Lee, D.; Lough, A.; Chung, D. S. J. Am. Chem. Soc. 2003,
125, 15276–15277. (c) Kim, H.; So, S. M.; Chin, J.; Kim, B. M.
Aldrichimica Acta 2008, 41, 77–88.
(14) Notes: (a) During the course of an asymmetric cross-coupling,
the unreacted electrophile remains racemic, and the ee of the product is
constant. (b) The stereoconvergent Suzuki reaction illustrated in entry 1
of Table 1 proceeds: in 88% ee and 86% yield on a gram scale (1.2 g of
product); in 88% ee and 74% yield with 5% NiBr2•diglyme/6% 1. (c)
Under the standard cross-coupling conditions: essentially no carbonÀ
carbon bond formation is observed in the absence of NiBr2•diglyme or
ligand 1; the presence of an ortho or a strongly electron-withdrawing
substituent on the arylamine generally leads to lower ee and/or yield; the
use of TBME or Et2O as the solvent results in formation of the cross-
coupling product in comparable ee but somewhat diminished yield
(65À70%); a small amount of unreacted alkyl halide is sometimes observed.
(15) (a) For leading references to nickel-catalyzed Suzuki reactions
of aryl ethers, see: Yu, D.-G.; Li, B.-J.; Shi, Z.-J. Acc. Chem. Res. 2010,
43, 1486–1495. (b) For examples of nickel-catalyzed Suzuki reactions of
aryl fluorides (perfluorinated arenes), see: Schaub, T.; Backes, M.;
Radius, U. J. Am. Chem. Soc. 2006, 128, 15964–15965.
’ ACKNOWLEDGMENT
This study is dedicated to the memory of Prof. David Y. Gin.
Support has been provided by the National Institutes of Health
(National Institute of General Medical Sciences, Grant R01-
GM62871), Eli Lilly (fellowship to Z.L.), and the Martin Family
Society of Fellows for Sustainability (fellowship to Z.L.).
’ REFERENCES
(1) For leading references on metal-catalyzed cross-coupling reac-
tions of alkyl electrophiles, see: Rudolph, A.; Lautens, M. Angew. Chem.,
Int. Ed. 2009, 48, 2656–2670.
(2) For reviews of metal-catalyzed cross-coupling reactions, see: (a)
Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich, F.,
Eds.; WileyÀVCH: New York, 2004. Denmark, S. E. (p 191):
“AlkylÀalkyl cross-coupling reactions have historically been the most
difficult to realize.” (b) Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E.-i., Ed.; Wiley Interscience: New York,
2002.
(3) (a) For examples of applications of alkylÀalkyl Suzuki cross-
couplings in the total synthesis of natural products, see: Keaton, K. A.;
Phillips, A. J. Org. Lett. 2007, 9, 2717–2719. Griggs, N. D.; Phillips, A. J.
Org. Lett. 2008, 10, 4955–4957. (b) For examples of applications of
alkylÀalkyl Negishi cross-couplings in the synthesis of C-alkyl
glycosides, see: Gong, H.; Gagnꢁe, M. R. J. Am. Chem. Soc. 2008, 130,
12177–12183.
(4) For enantioselective cross-couplings of activated secondary alkyl
electrophiles, see: (a) An initial study: Fischer, C.; Fu, G. C. J. Am. Chem.
Soc. 2005, 127, 4594–4595. (b) Work by others: Caeiro, J.; Sestelo, J. P.;
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investigation and leading references: Lundin, P. M.; Fu, G. C. J. Am.
(16) The coupling partner for electrophiles 3 and 4: (9-BBN)-
(CH2)3(p-anisyl).
(17) The coupling partner for electrophiles 5À8: (9-BBN)(CH2)3-
(o-anisyl).
(18) In contrast, for a nonasymmetric cross-coupling of an unac-
tivated secondary alkyl chloride, the rate is dependent on the concentra-
tion of the electrophile: Lu, Z.; Fu, G. C. Angew. Chem., Int. Ed. 2010,
49, 6676–6678.
(19) For a related mechanistic proposal for Ni/terpyridine-catalyzed
Negishi cross-couplings, see: (a) Jones, G. D.; Martin, J. L.; McFarland,
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(20) We speculate that oxidative addition of the electrophile pro-
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form a metalacycle.
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