Asymmetric alkyl-alkyl cross-couplings of unactivated secondary alkyl electrophiles: Stereoconvergent suzuki reactions of racemic acylated halohydrins

Article abstract of DOI:10.1021/ja105924f

A method for asymmetric alkyl-alkyl Suzuki reactions of unactivated secondary alkyl electrophiles, specifically, cross-couplings of racemic acylated halohydrins with alkylborane reagents, has been developed. A range of protected bromohydrins, as well as a protected chlorohydrin and a homologated bromohydrin, are coupled in good ee by a catalyst derived from commercially available components.

Full text of DOI:10.1021/ja105924f

Published on Web 08/11/2010
Asymmetric Alkyl-Alkyl Cross-Couplings of Unactivated Secondary Alkyl
Electrophiles: Stereoconvergent Suzuki Reactions of Racemic Acylated Halohydrins
Nathan A. Owston and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received July 5, 2010; E-mail: gcf@mit.edu
Abstract: A method for asymmetric alkyl-alkyl Suzuki reactions
of unactivated secondary alkyl electrophiles, specifically, cross-
couplings of racemic acylated halohydrins with alkylborane reagents,
has been developed. A range of protected bromohydrins, as well
as a protected chlorohydrin and a homologated bromohydrin, are
coupled in good ee by a catalyst derived from commercially available
components.
During the past several years, there have been substantial advances
in the development of methods for metal-catalyzed cross-couplings
of secondary alkyl electrophiles.1 Furthermore, a number of catalytic
enantioselective processes have been described; however, with one
exception (homobenzylic bromides), this progress has been limited to
couplings of actiVated electrophiles (e.g., R-halocarbonyl compounds,
benzylic halides, allylic halides, and propargylic halides).2-4
The ability to achieve asymmetric carbon-carbon bond formation
with a wide range of unactiVated halides would greatly enhance the
utility of cross-couplings of alkyl electrophiles in organic synthesis.
In this report, we describe a method for enantioselective Suzuki
reactions5 of a new family of unactivated secondary alkyl electrophiles,
acylated halohydrins (eq 1).
Table 1. Asymmetric Alkyl-Alkyl Suzuki Reactions of Unactivated
Alkyl Electrophiles: Racemic Acylated Bromohydrinsa
entry
variation from the “standard” conditions
ee (%)
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
none
no NiBr2 ·diglyme
no (S,S)-1
94
-
80
<2
<2
<2
18
38
47
67
79
61
37
66
79
71
81
-
no KOt-Bu
-
conditions in eq 2 (rt)
Ni(cod)2, instead of NiBr2 ·diglyme
(S,S)-2, instead of (S,S)-1
i-BuOH, instead of n-hexanol
TBME, instead of i-Pr2O
1.5 equiv of alkylborane
5% NiBr2 ·diglyme, 6% (S,S)-1
PG ) CONEt2
94
94
91
95
90
94
94
87
91
95
83
PG ) CONMePh
In 2008, we established that homobenzylic bromides serve as
suitable substrates for nickel-catalyzed asymmetric Suzuki reactions,
thereby furnishing the first examples of enantioselective cross-couplings
of unactivated secondary alkyl electrophiles (eq 2).2 Although this study
provided proof-of-principle for such processes, homobenzylic halides
are a relatively uncommon substructure in organic molecules. We were
therefore intrigued by our observation that low enantioselectivity is
obtained when an ether is present in the R substituent of the electrophile
(eq 2: 40% ee for R ) CH2OBn, Ar ) Ph, and R1 ) n-Hex). We
speculated that this anomalous result might be a manifestation of
coordination of the ether oxygen to the nickel catalyst.
In view of the pervasiveness of oxygen-containing functional groups
in organic molecules, we decided to pursue the possibility that this
interaction could be exploited in the development of a method for the
asymmetric cross-coupling of oxygenated, unactivated electrophiles.
After a series of optimization studies, we determined that a racemic
acylated bromohydrin can be coupled with an alkylborane by a chiral
nickel/diamine catalyst (both components are commercially available
and can be handled in air) in good ee and yield at room temperature
(entry 1 of Table 1; 94% ee and 80% yield).
PG ) CONPh2
PG ) COAr (Ar ) p-anisyl)
a All data are the average of two experiments. b The yield was
determined by GC analysis versus a calibrated internal standard.
Suzuki reaction. In the absence of NiBr2 ·diglyme, ligand 1, or KOt-
Bu, essentially no cross-coupling is observed (entries 2-4). The
conditions that were developed for asymmetric Suzuki couplings of
homobenzylic bromides (eq 2) furnish only a small amount of product
(18% yield; entry 5), due to the inferiority of Ni(cod)2, ligand 2, and
i-BuOH, relative to NiBr2 ·diglyme, ligand 1, and n-hexanol (entries
6-8). TBME can be employed in place of i-Pr2O as the solvent, at
the expense of a slight erosion in ee (entry 9). Use of less alkylborane
or catalyst results in a lower yield (entries 10 and 11). Other acyl
protecting groups can be utilized, although there is a modest erosion
in enantioselectivity and/or yield (entries 12-15).
We have examined the scope of this catalytic asymmetric alkyl-alkyl
cross-coupling with respect to both the electrophilic and the nucleo-
philic partner (Table 2).6 In the case of the racemic electrophile, for R
substituents that range in size from methyl to isobutyl, the Suzuki
reaction proceeds with uniformly good ee (g90% ee; entries 1-10).
Table 1 provides information about the effect of a number of
reaction parameters on the efficiency of this new stereoconvergent
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11908 J. AM. CHEM. SOC. 2010, 132, 11908–11909
10.1021/ja105924f  2010 American Chemical Society

C O M M U N I C A T I O N S
In addition, an array of alkylboranes serve as suitable nucleophiles,
including substrates that bear a silyl ether (entry 3), an aryl alkyl ether
(entry 4), an acetal (entry 6), and an aryl fluoride (entries 7 and 10).7
Table 2. Asymmetric Alkyl-Alkyl Suzuki Cross-Couplings of
Racemic Acylated Bromohydrins: Scope (for the reaction conditions,
see eq 1)a
in good ee by a catalyst derived from commercially available
components. This investigation is only the second report of an
asymmetric cross-coupling of an unactivated secondary alkyl electro-
phile, and it represents an advance with respect to utility, enantiose-
lectivity, and versatility. Additional efforts to develop useful new
coupling reactions of alkyl electrophiles are underway.
Acknowledgment. We thank Angelika Bruckmann for prelimi-
nary studies. Support has been provided by the National Institutes of
Health (National Institute of General Medical Sciences, Grant R01-
GM62871).
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) For leading references, see: Rudolph, A.; Lautens, M. Angew. Chem., Int.
Ed. 2009, 48, 2656–2670.
(2) For a report on catalytic asymmetric cross-couplings of unactiVated secondary
alkyl electrophiles, see: Saito, B.; Fu, G. C. J. Am. Chem. Soc. 2008, 130,
6694–6695. (Suzuki alkylations of homobenzylic bromides)
(3) For reports on catalytic asymmetric cross-couplings of actiVated secondary
alkyl electrophiles, see: (a) Negishi alkylations of R-bromoamides: Fischer,
C.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 4594–4595. (b) Negishi
alkylations of 1-haloindanes: Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2005,
127, 10482–10483. (c) Negishi alkylations of allylic chlorides: Son, S.; Fu,
G. C. J. Am. Chem. Soc. 2008, 130, 2756–2757. (d) Hiyama arylations and
vinylations of R-bromoesters: Dai, X.; Strotman, N. A.; Fu, G. C. J. Am.
Chem. Soc. 2008, 130, 3302–3303. (e) Negishi arylations of propargylic
halides: Smith, S. W.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 12645–
12647. (f) Couplings of alkynylindiums with benzylic bromides: Caeiro, J.;
Perez Sestelo, J.; Sarandeses, L. A. Chem.sEur. J. 2008, 14, 741–746. (g)
Negishi arylations of R-bromoketones: Lundin, P. M.; Esquivias, J.; Fu, G. C.
Angew. Chem., Int. Ed. 2009, 48, 154–156. (h) Kumada arylations of
R-bromoketones: Lou, S.; Fu, G. C. J. Am. Chem. Soc. 2010, 132, 1264–
1266. (i) Zirconium Negishi alkenylations of R-bromoketones: Lou, S.; Fu,
G. C. J. Am. Chem. Soc. 2010, 132, 5010–5011. (j) Suzuki arylations of
R-haloamides: Lundin, P. M.; Fu, G. C. J. Am. Chem. Soc., ASAP (DOI:
10.1021/ja105148g).
a All data are the average of two experiments. b Yield of purified
product. c 15% NiBr2 ·diglyme and 18% (S,S)-1 were used.
This new stereoconvergent method is effective for asymmetric
alkyl-alkyl Suzuki reactions not only of racemic acylated bromohy-
drins but also of chlorohydrins (eq 3); this represents the first example
of an enantioselective cross-coupling of an unactivated secondary alkyl
chloride. The carbamate protecting group can be cleaved in very good
yield without eroding the ee (eq 4).
(4) For overviews and leading references, see: (a) Glorius, F. Angew. Chem.,
Int. Ed. 2008, 47, 8347–8349. (b) Reference 1.
(5) The Suzuki reaction is perhaps the most widely used cross-coupling process.
For leading references, see: (a) Metal-Catalyzed Cross-Coupling Reactions;
de Meijere, A., Diederich, F., Eds.; Wiley-VCH: New York, 2004. (b)
Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
E.-i., Ed.; Wiley Interscience: New York, 2002.
(6) Notes: (a) During the course of a cross-coupling, no kinetic resolution of the
secondary alkyl bromide is detected, and the ee of the product is constant. (b)
On a gram-scale, the reaction illustrated in entry 1 of Table 2 proceeds in 95%
ee and 76% yield. (c) In preliminary experiments under our standard conditions,
an alkylboronic acid and a secondary alkyl-(9-BBN) reagent were not suitable
cross-coupling partners, and the reaction of a hindered (R ) i-Pr) and of an
ether-containing (R ) CH2OMe) electrophile proceeded in good ee (>90%) but
low yield (∼30%) even in the presence of 15% NiBr2 ·diglyme/18% ligand 1.
(d) Except in the case of entries 8 and 9 of Table 2 (20-30% recovered starting
material; heating was not beneficial), little or no starting material remained when
these cross-couplings were terminated. Hydrodebromination of the electrophile
was observed as a side reaction. (e) For a proposed mechanism for Ni/terpyridine-
catalyzed Negishi cross-couplings of unactivated alkyl electrophiles, see: Jones,
G. D.; Martin, J. L.; McFarland, C.; Allen, O. R.; Hall, R. E.; Haley, A. D.;
Brandon, R. J.; Konovalova, T.; Desrochers, P. J.; Pulay, P.; Vicic, D. A. J. Am.
Chem. Soc. 2006, 128, 13175–13183. Lin, X.; Phillips, D. L. J. Org. Chem.
2008, 73, 3680–3688.
(7) For examples of nickel-catalyzed cross-couplings of aryl fluorides, see: (a) Kiso,
Y.; Tamao, K.; Kumada, M. J. Organomet. Chem. 1973, 50, C12–C14. (b)
Bo¨hm, V. P. W.; Gsto¨ttmayr, C. W. K.; Weskamp, T.; Herrmann, W. A.
Angew. Chem., Int. Ed. 2001, 40, 3387–3389. (c) Ackermann, L.; Born, R.;
Spatz, J. H.; Meyer, D. Angew. Chem., Int. Ed. 2005, 44, 7216–7219. (d)
Yoshikai, N.; Mashima, H.; Nakamura, E. J. Am. Chem. Soc. 2005, 127,
17978–17979.
We have begun to investigate asymmetric Suzuki reactions of
homologues of the acylated halohydrin electrophiles described above.
In an initial study, we determined that, under the conditions optimized
for bromohydrins, we obtain promising ee and yield for the cross-
coupling of a racemic acylated homologue (eq 5).8 Importantly, simply
by modifying the structure of the ligand, the desired stereoconvergent
alkyl-alkyl Suzuki coupling can be accomplished with very good
enantioselectivity (eq 5; ligand 2 is commercially available).
In summary, we have developed a method for asymmetric alkyl-alkyl
Suzuki reactions of unactivated secondary alkyl electrophiles, specif-
ically, cross-couplings of racemic acylated halohydrins with alkylbo-
rane reagents. A range of protected bromohydrins, as well as a
protected chlorohydrin and a homologated bromohydrin, are coupled
(8) In contrast, in the case of the other example of an asymmetric cross-coupling
of an unactivated secondary alkyl electrophile (ref 2), the reaction of a
homologue proceeded in low ee (14%).
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