Ligands for Palladium-Catalyzed Cross-Couplings of Alkyl Halides: Use of an Alkyldiaminophosphane Expands the Scope of the Stille Reaction

Article abstract of DOI:10.1002/anie.200352668

Alkyldiaminophosphanes (PR(NR′₂)₂) are a new class of ligands for palladium-catalyzed cross-couplings of alkyl halides (see scheme). In comparison with trialkylphosphanes, alkyldiaminophosphanes furnish more versatile catalysts for Stille reactions of alkyl bromides and achieve efficient couplings with both vinyl and aryl stannanes, Furthermore, Pd/PR(NR′₂)₂ provides the first method for accomplishing Stille cross-couplings of simple alkyl iodides that bear β-hydrogen atoms.

Full text of DOI:10.1002/anie.200352668

Angewandte
Chemie
Expanding the Stille Coupling
Ligands for Palladium-Catalyzed Cross-Couplings
of Alkyl Halides: Use of an
Alkyldiaminophosphane Expands the Scope of
the Stille Reaction**
Haifeng Tang, Karsten Menzel, and Gregory C. Fu*
Dedicated to Professor Manfred T. Reetz
on the occasion of his 60th birthday
Whereas nickel- and palladium-catalyzed methods for cross-
coupling aryl and vinyl halides and sulfonates with a range of
organometallic reagents have reached a fairly high level of
sophistication,[1] comparable progress has not yet been
achieved for reactions of alkyl halides and sulfonates.[2]
Recently, we and others have begun to address this short-
coming by describing catalysts for certain Suzuki,[3]
Negishi,[4,5] Kumada,[6,7] Stille,[8] and Hiyama[9] couplings of
primary alkyl electrophiles. With the exception of Suzuki's
observation that [Pd(PPh3)4] effects cross-couplings of alkyl
iodides with R-(9-BBN),[3a] the palladium-based catalysts that
were reported for coupling alkyl electrophiles have all
employed
a
hindered trialkylphosphane (PCy3 or
P(tBu)2Me) as the ligand.
To increase the likelihood of expanding the still-limited
scope of cross-couplings of alkyl electrophiles, we have been
exploring the use of new classes of ligands for these processes.
Herein, we establish that, in the presence of alkyldiamino-
phosphanes (PR(NR’2)2), we can accomplish palladium-
catalyzed Stille cross-couplings of alkyl bromides and iodides
not only with vinyl stannanes, but also with aryl stannanes
[Eq. (1)], a class of reaction partners that are not efficiently
coupled by Pd/PR3 (PR3 = trialkylphosphane).
As a consequence of the electron-richness and the ready
accessibility of alkyldiaminophosphanes (PR(NR’2)2),[10] we
[*] Prof. Dr. G. C. Fu, Dr. H. Tang, Dr. K. Menzel
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Fax: (+1)617-258-7500
E-mail: gcf@mit.edu
[**] We thank Johnson Matthey for supplying palladium compounds.
Support has been provided by the National Institutes of Health
(National Institute of General Medical Sciences, R01-GM62871),
Merck, and Novartis. Funding for the MIT Department of Chemistry
Instrumentation Facility has been furnished in part by NSF CHE-
9808061 and NSF DBI-9729592.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200352668
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Table 2: Room-temperature Stille cross-couplings of functionalized alkyl
bromides with aryl stannanes catalyzed by Pd/PCy(pyrrolidinyl)2.
decided to examine the utility of this family of ligands in
palladium-catalyzed couplings of alkyl electrophiles. In ear-
lier work, we determined that P(tBu)2Me is useful for Stille
cross-couplings of alkyl bromides with vinyl-, but not with
aryl-, stannanes.[11] Thus, as illustrated in Table 1, neither
P(tBu)2Me nor PCy3 is effective for the palladium-catalyzed
Stille reaction of 1-bromodecane with PhSnBu3 under our
previously reported conditions (entries 1 and 2, respec-
tively).[12]
ꢀ
Entry
1
R Br
Aryl stannane
Yield [%][a]
72
ꢀ
n-Dec Br
Table 1: Effect of ligand structure on the cross-coupling of 1-bromode-
cane with PhSnBu3.
2
3
4
63
71
57
Entry
Ligand
Yield [%][a]
5
6
61
62
1
2
3
4
5
6
7
8
9
10
P(tBu)2Me
PCy3
12
22
9
32
45
4
PMe(pyrrolidinyl)2
PEt(pyrrolidinyl)2
PCy(pyrrolidinyl)2
P(tBu)(pyrrolidinyl)2
PPh(pyrrolidinyl)2
P(iBuNCH2CH2)3N
PPh3
7
68
64
53
7
<2
<2
<2
8[b]
9
no ligand
[a] Determined by GC versus a calibrated internal standard (average of
two runs).
[a] Yield of isolated product (except for entry 1, which is a yield by GC
versus a calibrated internal standard), average of two runs. [b] THP=
tetrahydropyran.
We therefore synthesized a sterically diverse set of
alkyldiaminophosphanes, and we explored their use in this
Stille cross-coupling process. Although Pd/PMe(pyrroli-
dinyl)2 (pyrrolidinyl = 1-pyrrolidinyl) furnishes very little of
the desired product (9%; Table 1, entry 3), an increase in the
steric demand of the alkyl group can provide an improvement
in yield (Me!Et!Cy: 9%!32%!45%; entries 3–5). As
we have observed for couplings catalyzed by Pd/
PR3,[3b–d,5,8,9] there is a window of maximum reactivity
for alkyldiaminophosphane ligands—thus, if the alkyl
group, R, of PR(NR’2)2 becomes too large (e.g., tBu),
the yield decreases (4%; entry 5 versus entry 6). In the
presence of an aryldiaminophosphane (entry 7), a
bicyclic triaminophosphane (entry 8),[13] and PPh3
(entry 9), almost no cross-coupling occurs.
be applied without modification to couplings of alkyl iodides
[Eq. (2)]. To the best of our knowledge, this is the first
example of a Stille cross-coupling of a simple alkyl iodide that
bears b hydrogen atoms.[17,18]
Additional optimization of the most effective
catalyst system, Pd/PCy(pyrrolidinyl)2 (45%; Table 1,
entry 5), produced an enhancement in yield (72%; Table 2,
entry 1; MTBE = tBuOMe).[14] As illustrated in Table 2,
under a standard set of conditions, an array of functionalized
alkyl bromides can be coupled at room temperature with a
variety of aryl stannanes.[15,16] Thus, the catalyst tolerates
esters (entries 2–6), nitriles (entry 7), ethers (entry 8), and
olefins (entry 9). In addition, both electron-rich and electron-
poor aryl stannanes (entries 2–8), as well as a heteroaryl
stannane (entry 9), are suitable cross-coupling partners.
We have determined that the conditions that we have
developed for Stille reactions of alkyl bromides (Table 2) can
In addition to aryl stannanes, Pd/PCy(pyrrolidinyl)2 can
be employed for cross-couplings of vinyl stannanes. Thus,
under the conditions that we previously reported for Pd/
P(tBu)2Me-catalyzed processes,[8,19] Pd/PCy(pyrrolidinyl)2
catalyzes room-temperature couplings of functionalized
alkyl bromides with a range of vinyl stannanes (Table 3).[20]
Groups such as ethers, acetals, nitriles, esters, amides, and
olefins may be present, and a variety of substitution patterns
for the vinyl stannane are tolerated.
Finally, we can apply the same Pd/PCy(pyrrolidinyl)2
catalyst system to room-temperature Stille cross-couplings
of alkyl iodides with vinyl stannanes (90% yield; [Eq. (3)]).[21]
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Coupling Reactions: A Practical Guide”: Top. Curr. Chem.
Table 3: Room-temperature Stille cross-couplings of functionalized alkyl
bromides with vinyl stannanes catalyzed by Pd/PCy(pyrrolidinyl)2.
2002, 219; c) Handbook of Organopalladium Chemistry for
Organic Synthesis (Ed.: E.-I. Negishi), Wiley Interscience, New
York, 2002.
[2] For an overview of the difficulty of achieving coupling reactions
of alkyl electrophiles, see: D. J. Cµrdenas, Angew. Chem. 1999,
111, 3201 – 3203; Angew. Chem. Int. Ed. 1999, 38, 3018 – 3020;
D. J. Cµrdenas, Angew. Chem. Int. Ed. 2003, 42, 384 – 387. See
also: T.-Y. Luh, M.-k. Leung, K.-T. Wong, Chem. Rev. 2000, 100,
3187 – 3204.
Entry
1
Vinyl stannane
Yield [%][a]
74
ꢀ
R Br
[3] a) Iodides: T. Ishiyama, S. Abe, N. Miyaura, A. Suzuki, Chem.
Lett. 1992, 691 – 694; b) bromides: M. R. Netherton, C. Dai, K.
Neuschütz, G. C. Fu, J. Am. Chem. Soc. 2001, 123, 10099 –
10100; J. H. Kirchhoff, M. R. Netherton, I. D. Hills, G. C. Fu, J.
Am. Chem. Soc. 2002, 124, 13662 – 13663; c) chlorides: J. H.
Kirchhoff, C. Dai, G. C. Fu, Angew. Chem. 2002, 114, 2025 –
2027; Angew. Chem. Int. Ed. 2002, 41, 1945 – 1947; d) tosylates:
M. R. Netherton, G. C. Fu, Angew. Chem. 2002, 114, 4066 – 4068;
Angew. Chem. Int. Ed. 2002, 41, 3910 – 3912.
2
3
4
60
68
89
5
79
[4] For nickel-based catalysts, see: a) A. Devasagayaraj, T. Stüde-
mann, P. Knochel, Angew. Chem. 1995, 107, 2952 – 2954; Angew.
Chem. Int. Ed. Engl. 1995, 34, 2723 – 2725; b) R. Giovannini, T.
Stüdemann, G. Dussin, P. Knochel, Angew. Chem. 1998, 110,
2512 – 2515; Angew. Chem. Int. Ed. 1998, 37, 2387 – 2390; c) R.
Giovannini, P. Knochel, J. Am. Chem. Soc. 1998, 120, 11186 –
11187; d) R. Giovannini, T. Stüdemann, A. Devasagayaraj, G.
Dussin, P. Knochel, J. Org. Chem. 1999, 64, 3544 – 3553; e) M.
Piber, A. E. Jensen, M. Rottländer, P. Knochel, Org. Lett. 1999,
1, 1323 – 1326; f) A. E. Jensen, P. Knochel, J. Org. Chem. 2002,
67, 79 – 85.
6
7
8
78
54
73
[a] Yield of the isolated product, average of two runs.
[5] For a palladium-based catalyst, see: J. Zhou, G. C. Fu, J. Am.
Chem. Soc., in press.
[6] For nickel-based catalysts, see: a) J. Terao, H. Watanabe, A.
Ikumi, H. Kuniyasu, N. Kambe, J. Am. Chem. Soc. 2002, 124,
4222 – 4223; b) J. Terao, A. Ikumi, H. Kuniyasu, N. Kambe, J.
Am. Chem. Soc. 2003, 125, 5646 – 5647.
[7] For a palladium-based catalyst, see: A. C. Frisch, N. Shaikh, A.
Zapf, M. Beller, Angew. Chem. 2002, 114, 4218 – 4221; Angew.
Chem. Int. Ed. 2002, 41, 4056 – 4059.
[8] K. Menzel, G. C. Fu, J. Am. Chem. Soc. 2003, 125, 3718 – 3719.
[9] J.-Y. Lee, G. C. Fu, J. Am. Chem. Soc. 2003, 125, 5616 – 5617.
[10] For pioneering studies by Woollins, see: a) M. L. Clarke, D. J.
Cole-Hamilton, A. M. Z. Slawin, J. D. Woollins, Chem.
Commun. 2000, 2065 – 2066; b) M. L. Clarke, G. L. Holliday,
A. M. Z. Slawin, J. D. Woollins, J. Chem. Soc. Dalton Trans. 2002,
1093 – 1103.
In conclusion, we have identified a new class of ligands
(alkyldiaminophosphanes, PR(NR’2)2) that are effective in
palladium-catalyzed cross-couplings of alkyl electrophiles. In
comparison with trialkylphosphanes, alkyldiaminophos-
phanes furnish more versatile catalysts for Stille reactions of
alkyl halides, thus achieving, for example, efficient couplings
with aryl stannanes. In view of the ready accessibility of a
range of alkyldiaminophosphanes, as well as the potential for
chiral variants, we anticipate that our observations will add a
significant new dimension to the development of broadly
applicable catalysts for cross-couplings of alkyl electrophiles.
[11] See reference [8], including footnote [15].
[12] Among the large array of trialkylphosphanes that we have
examined, P(tBu)2Me and PCy3 are the most effective.
[13] a) Verkade has established that certain triaminophosphanes
provide reactive catalysts for palladium-catalyzed Suzuki and
Buchwald–Hartwig cross-couplings of aryl halides. See: S.
Urgaonkar, M. Nagarajan, J. G. Verkade, Tetrahedron Lett.
2002, 43, 8921 – 8924; S. Urgaonkar, M. Nagarajan, J. G. Ver-
kade, Org. Lett. 2003, 5, 815 – 818; S. Urgaonkar, M. Nagarajan,
J. G. Verkade, J. Org. Chem. 2003, 68, 452 – 459; b) With acyclic
triaminophosphanes, we have obtained small amounts of Stille
cross-coupling products.
Received: August 18, 2003 [Z52668]
Published Online: October 14, 2003
[14] Notes: 1) The increased yield is primarily due to the change of
solvent (to MTBE). CH3CN, tert-amyl alcohol, and CH2Cl2 are
not suitable solvents for this process. 2) For the cross-coupling
illustrated in entry 1 of Table 2, use of P(tBu)2Me, rather than
PCy(pyrrolidinyl)2, under the conditions of Table 2 leads to a
poor yield (< 40%) of the desired product. 3) In the absence of
Me4NF, no coupling is observed. 4) PdBr2 and PdCl2(PhCN)2
provide yields that are comparable with [{(p-allyl)PdCl}2],
whereas Pd(OAc)2 is ineffective.
Keywords: cross-coupling · homogeneous catalysis · palladium ·
phosphane ligands · Stille reaction
.
[1] For reviews of metal-catalyzed cross-coupling reactions, see:
a) Metal-Catalyzed Cross-coupling Reactions (Eds.: F. Dieder-
ich, P. J. Stang), Wiley-VCH, New York, 1998; b) “Cross-
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[15] Notes: 1) Reactions of (o-tolyl)SnBu3 and (p-nitrophenyl)SnBu3
tion of 0.2m, versus 0.1m for Pd/P(tBu)2Me (for Pd/P(tBu)2Me,
reactions run at higher concentration lead to the precipitation of
a black solid, presumably Pd).
proceed in more modest yield. 2) Allylstannanes, alkynylstan-
nanes, alkyl chlorides, alkyl tosylates, and certain (tertiary,
secondary, and b-branched primary) alkyl bromides are not
useful coupling partners, furnishing at best a poor yield of the
desired product.
[20] Notes: 1) The stereochemistry of the vinyl stannane is retained
in the cross-coupling product. 2) For entries 1, 4, and 5 of
Table 3, the isolated yields for Pd/PCy(pyrrolidinyl)2 are 14–
24% higher than for Pd/P(tBu)2Me (see Reference [8]); for
entry 7, the yields are essentially identical, and for entry 2 the
yield is 11% lower for Pd/PCy(pyrrolidinyl)2.
[16] After the completion of
a
cross-coupling reaction, if
Cy2PCH2CH2PCy2 is added, then a substantial amount of
PCy(pyrrolidinyl)2 is observed by 31P NMR.
[17] For a discussion and leading references, see Reference [8].
[18] The use of P(tBu)2Me, rather than PCy(pyrrolidinyl)2, leads to a
significant loss in yield (< 50%).
[21] Under these conditions, we have also efficiently coupled 1-
iododecane with tributyl(vinyl)tin (93% yield by GC versus a
calibrated internal standard).
[19] The only modification: the cross-couplings catalyzed by Pd/
PCy(pyrrolidinyl)2 are conducted at an alkyl-halide concentra-
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