Stille cross-couplings of unactivated secondary alkyl halides using monoorganotin reagents

Article abstract of DOI:10.1021/ja0436300

The first catalyst that achieves Stille cross-couplings of secondary (as well as primary) alkyl halides has been developed. The method employs easily handled and inexpensive catalyst components (NiCl₂ and 2,2′-bipyridine) and, through the use of monoorganotin reagents, avoids the formation of toxic and difficult-to-remove triorganotin side products. Copyright

Full text of DOI:10.1021/ja0436300

Published on Web 12/23/2004
Stille Cross-Couplings of Unactivated Secondary Alkyl Halides Using
Monoorganotin Reagents
David A. Powell, Toshihide Maki, and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received October 20, 2004; E-mail: gcf@mit.edu
The Stille cross-coupling reaction1 is a very powerful method for
the construction of new carbon-carbon bonds that has found appli-
cation in disciplines ranging from natural-products synthesis (e.g.,
chloropeptin I2 and apoptolidin3) to materials science (e.g., conduct-
ing polymers4). A significant impediment to even more widespread
use of this process is the toxicity of triorganotin compounds (R3-
SnX),5 which are the usual stoichiometric side products of Stille
reactions. A second practical issue is the difficulty that is often
encountered in separating R3SnX from the desired cross-coupling
adduct. A few clever approaches to circumventing these problems
have been described, but none has yet found general use.6
Of course, one simple way to avoid trialkyltin-related issues is to
employ an organotin coupling partner that does not generate R3SnX
as a side product. In fact, a few groups have reported Stille reactions
of monoorganotin compounds.7 The tin-based products of such
processes are inorganic species that generally do not suffer from
the purification and toxicity problems common to triorganotins.8
Recently, we and others have devoted considerable effort to ex-
panding the scope of palladium- and nickel-catalyzed coupling reac-
tions to include unactivated, â-hydrogen-containing alkyl halides
as partners.9 A particularly synthetically useful, although challenging
(due to slow oxidative addition and facile â-hydride elimination),
objective is the cross-coupling of secondary alkyl halides. To date,
progress with this family of substrates has been limited to couplings
with organozinc,10 -boron,11 -silicon,9c and -magnesium12 reagents.13
In this communication, we establish that a new family of partners,
organotin compounds, can be cross-coupled with secondary alkyl
halides (eq 1); monoorganotin reagents are the substrates of choice
for this nickel-catalyzed process.
Table 1. Impact of Reaction Parameters on the Cross-Coupling of
Cyclohexyl Bromide with PhSnCl3
entry
variation from the “standard conditions”
yielda (%)
1
2
3
4
5
6
7
8
9
none
no NiCl2
83
<5
<5
10% Pd(OAc)2 or Pd2(dba)3 [instead of NiCl2]
10% Ni(cod)2, NiBr2, or NiBr2‚diglyme [instead of NiCl2]
no 2,2′-bipyridine
15% bathophenanthroline [instead of 2,2′-bipyridine]
no KOt-Bu
5.0 equiv of KOt-Bu [instead of 7.0 equiv]
i-BuOH [instead of t-BuOH/i-BuOH]
t-BuOH [instead of t-BuOH/i-BuOH]
KOi-Bu in i-BuOH [instead of KOt-Bu in
t-BuOH/i-BuOH]
82-86
<5
33
<5
55
76
<5
61
10
11
12
13
5% NiCl2, 7.5% 2,2′-bipyridine [instead of 10% NiCl2,
15% 2,2′-bipyridine]
room temperature [instead of 60 °C]
69
<5
a Determined by GC analysis versus a calibrated internal standard
(average of two experiments).
Table 2. Stille Cross-Couplings of Secondary Alkyl Bromides with
Aryltrichlorotin Reagents (eq 1)
Unfortunately, the conditions that had previously been described
for Negishi,10 Suzuki,11 and Hiyama9c couplings of secondary alkyl
halides were ineffective for the corresponding Stille reactions.
However, we determined that 10% NiCl2/15% 2,2′-bipyridine, in
the presence of KOt-Bu, catalyzes the cross-coupling of cyclohexyl
bromide with PhSnCl3 in good yield (Table 1, entry 1).
Essentially none of the desired carbon-carbon bond formation is
observed in the absence of NiCl2 (Table 1, entry 2) or in the pres-
ence of a range of palladium complexes (entry 3). Other nickel
complexes can furnish reactivity that is comparable to NiCl2 (entry
4); for the studies described below, we chose to use NiCl2, since it
is air-stable and inexpensive.14
a Isolated yield (average of two experiments). b Catalyst: 20% NiCl2/
30% 2,2′-bipyridine. The unpurified product was a 96:4 trans/cis mixture.
The reported yield is for the diastereomerically pure trans isomer.
If 2,2′-bipyridine is omitted, cross-coupling does not occur (entry
5), and other bipyridine-based ligands that we have explored have
proved to be less effective (e.g., entry 6). The stoichiometry of KOt-
Bu and the solvent have a significant impact on reaction efficiency
(entries 7-11);15 from the standpoint of convenience, it is worth
noting that commercially available KOi-Bu in i-BuOH provides a
useful amount of product (entry 11). Decreasing the catalyst loading
leads to a somewhat diminished yield (entry 12), and virtu-
ally no cross-coupling is observed at room temperature (entry 13).
NiCl2/2,2′-bipyridine catalyzes a range of couplings of secondary
alkyl bromides with aryltrichlorotin reagents (Table 2);16 thus, both
cyclic and acyclic bromides can be cross-coupled with a sterically
and electronically diverse set of organotin compounds. The same
catalyst system can also be applied directly to Stille reactions of
9
510
J. AM. CHEM. SOC. 2005, 127, 510-511
10.1021/ja0436300 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Stille Cross-Couplings of Primary and Secondary Alkyl
Bromides and Iodides with Aryltrichlorotin Reagents (eq 1)
lowship to D.A.P.), Merck, and Novartis. We thank Luke Fir-
mansjah for assistance with X-ray crystallography.
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 reviews, see: (a) Kosugi, M.; Fugami, K. In Handbook of Organo-
palladium Chemistry for Organic Synthesis; Negishi, E.-i., Ed.; Wiley-
Interscience: New York, 2002; pp 263-283. (b) Mitchell, T. N. In Metal-
Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: New York, 1998; Chapter 4. (c) Farina, V.; Krishnamurthy,
V.; Scott, W. J. Org. React. 1997, 50, 1-652. (d) Espinet, P.; Echavarren,
A. M. Angew. Chem., Int. Ed. 2004, 43, 4704-4734.
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A. H. J. Am. Chem. Soc. 2003, 125, 9032-9034.
(3) Nicolaou, K. C.; Li, Y.; Sugita, K.; Monenschein, H.; Guntupalli, P.;
Mitchell, H. J.; Fylaktakidou, K. C.; Vourloumis, D.; Giannakakou, P.;
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(4) Yu, H.-h.; Xu, B.; Swager, T. M. J. Am. Chem. Soc. 2003, 125, 1142-1143.
(5) “The most toxic organotin chemicals belong to the class of the triorganotin
compounds”: Bulten, E. J.; Meinema, H. A. In Metals and Their
Compounds in the EnVironment; Merian, E., Ed.; VCH: New York, 1991;
Chapter II.30, p 1243.
a Isolated yield (average of two experiments). b Only the 3S isomer is
observed.
other families of alkyl electrophiles (secondary iodides, primary
bromides, and primary iodides; Table 3).
(6) For examples and leading references, see: (a) (Polymer-supported tin
reagents) Kuhn, H.; Neumann, W. P. Synlett 1994, 123-124. Nicolaou,
K. C.; Winssinger, N.; Pastor, J.; Murphy, F. Angew. Chem., Int. Ed. Engl.
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P.; Curran, D. P. J. Org. Chem. 1997, 62, 8341-8349. (c) (Catalytic
hydrostannation/Stille reaction) Gallagher, W. P.; Terstiege, I.; Maleczka,
R. E., Jr. J. Am. Chem. Soc. 2001, 123, 3194-3204.
Because a large number of aryl- and alkenyltributylstannanes
are commercially available, we decided to determine if we could
make use of these families of compounds in cross-couplings with
alkyl electrophiles. These stannanes are not themselves suitable
partners for NiCl2/2,2′-bipyridine-catalyzed Stille couplings, but
through a redistribution reaction with SnCl4, they can be converted
into aryl- and alkenyltrichlorotin reagents.17 Upon the addition of
the other components of the cross-coupling reaction, the desired
carbon-carbon bond formation occurs (eqs 2 and 3).
(7) (a) For Stille couplings that employ trichloroorganotin reagents, see:
Roshchin, A. I.; Bumagin, N. A.; Beletskaya, I. P. Tetrahedron Lett. 1995,
36, 125-128. Rai, R.; Aubrecht, K. B.; Collum, D. B. Tetrahedron Lett.
1995, 36, 3111-3114. (b) For Stille couplings that employ other
monoorganotin reagents, see: Fouquet, E.; Pereyre, M.; Rodriguez, A.
L. J. Org. Chem. 1997, 62, 5242-5243.
(8) “Inorganic tin salts are generally acknowledged to be of a low order of
toxicity”: see ref 5.
(9) For leading references, see: (a) Ca´rdenas, D. J. Angew. Chem., Int. Ed.
2003, 42, 384-387. (b) Netherton, M. R.; Fu, G. C. AdV. Synth. Catal.
In press (nickel-catalyzed processes). (c) Powell, D. A.; Fu, G. C. J. Am.
Chem. Soc. 2004, 126, 7788-7789.
(10) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 14726-14727.
(11) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340-1341.
(12) Copper-, cobalt-, and iron-based methods have been developed for
couplings of more reactive Grignard reagents: (a) Donkervoort, J. G.;
Vicario, J. L.; Jastrzebski, J. T. B. H.; Gossage, R. A.; Cahiez, G.; van
Koten, G. J. Organomet. Chem. 1998, 558, 61-69 (copper). (b) Tsuji,
T.; Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed. 2002, 41, 4137-
4139 (cobalt). (c) Brinker, U. H.; Ko¨nig, L. Chem. Ber. 1983, 116, 882-
893 (iron). (d) Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am.
Chem. Soc. 2004, 126, 3686-3687 (iron). (e) Nagano, T.; Hayashi, T.
Org. Lett. 2004, 6, 1297-1299 (iron). (f) Martin, R.; Fu¨rstner, A. Angew.
Chem., Int. Ed. 2004, 43, 3955-3957 (iron).
(13) For related three-component couplings of secondary alkyl halides with
olefins and Grignard reagents, see: (a) Mizutani, K.; Shinokubo, H.;
Oshima, K. Org. Lett. 2003, 5, 3959-3961. (b) Terao, J.; Nii, S.;
Chowdhury, F. A.; Nakamura, A.; Kambe, N. AdV. Synth. Catal. 2004,
346, 905-908.
In earlier studies, we suggested that nickel-catalyzed couplings of
secondary alkyl halides may proceed through the initial generation of
an alkyl radical, which then combines with nickel to afford an alkyl-
nickel complex.10,11,18 We subjected secondary bromides 1 and 2
to our Stille conditions and determined that both substrates undergo
cyclization/cross-coupling to yield cis-fused 5,5 ring systems (eq
4); product 3 is formed with a low endo/exo ratio (2:1), whereas 4
is generated with high stereoselection (>20:1). Interestingly, these
diastereoselectivities are independent of ligand structure (e.g., 2,2′-
bipyridine, bathophenanthroline, or 4,4′-dimethoxy-2,2′-bipyridine),
and they correlate with those observed in radical cyclizations of
these compounds,19,20 consistent with the possibility that an initially
formed secondary alkyl radical cyclizes before reacting with nickel.
In summary, we have developed the first catalyst that achieves
Stille cross-couplings of secondary (as well as primary) alkyl
halides. The method employs easily handled and inexpensive
catalyst components (NiCl2 and 2,2′-bipyridine) and, through the
use of monoorganotin reagents, avoids the formation of toxic and
difficult-to-remove triorganotin side products. Efforts to expand the
scope of Stille cross-couplings of alkyl electrophiles, as well as to
achieve catalytic asymmetric reactions, are underway.
(14) Prices from Strem Chemicals (2004-2006 catalog): NiCl2, $47/mol;
NiBr2, $260/mol; Ni(cod)2, $5900/mol.
(15) The role of KOt-Bu may be to generate a hypervalent tin species that
undergoes efficient transmetalation. For early studies of the use of
hypervalent tin compounds in Stille reactions, see: (a) Vedejs, E.; Haight,
A. R.; Moss, W. O. J. Am. Chem. Soc. 1992, 114, 6556-6558. (b) Brown,
J. M.; Pearson, M.; Jastrzebski, J. T. B. H.; van Koten, G. J. Chem. Soc.,
Chem. Commun. 1992, 1440-1441. (c) Martinez, A. G.; Barcina, J. O.;
Cerezo, A. de F.; Subramanian, L. R. Synlett 1994, 1047-1048.
(16) (a) The yields reported in Table 2 are for reactions conducted with 1.0
mmol of the electrophile. An increase in the scale of the process (without
additional optimization) leads to a slightly lower yield (e.g., for entry 1,
1.28 g (63%) of the desired product was obtained when the cross-coupling
was run with 10 mmol of the alkyl bromide). (b) Under these conditions,
Cl3Sn-Bu, secondary alkyl tosylates, and secondary alkyl chlorides are
not suitable cross-coupling partners. (c) The presence of functional groups
on the alkyl halide can lead to significantly diminished reaction efficiency.
For example, certain substrates that contain ketones, secondary amines,
imides, and nitriles cross-couple in <20% yield. (d) The reaction is
moisture-sensitive. (e) According to ICP-MS analysis, the tin contamina-
tion in the product (after chromatography) is less than 5 ppm.
(17) Wood, M. E. In Science of Synthesis; Moloney, M. G., Ed.; Georg Thieme
Verlag: Stuttgart, 2003; Vol. 5, Section 5.2.8.5.2.
(18) For an interesting recent mechanistic study, see: Anderson, T. J.; Jones,
G. D.; Vicic, D. A. J. Am. Chem. Soc. 2004, 126, 8100-8101.
(19) (a) Pandey, G.; Rao, K. S. S. P.; Palit, D. K.; Mittal, J. P. J. Org. Chem.
1998, 63, 3968-3978. (b) Hackmann, C.; Scha¨fer, H. J. Tetrahedron 1993,
49, 4559-4574. (c) Mayer, S.; Prandi, J.; Bamhaoud, T.; Bakkas, S.;
Guillou, O. Tetrahedron 1998, 54, 8753-8770.
(20) For a similar Co-catalyzed reaction of Grignard reagents, see: Wakabayashi,
K.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2001, 123, 5374-5375.
Acknowledgment. Support has been provided by the NIH
(NIGMS, R01-GM62871), NSERC of Canada (postdoctoral fel-
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