Palladium-catalyzed oxidative intermolecular difunctionalization of terminal alkenes with organostannanes and molecular oxygen

Full text of DOI:10.1002/anie.200900218

Communications
DOI: 10.1002/anie.200900218
Cross-Coupling
Palladium-Catalyzed Oxidative Intermolecular Difunctionalization of
Terminal Alkenes with Organostannanes and Molecular Oxygen**
Kaveri Balan Urkalan and Matthew S. Sigman*
The Heck reaction is a widely used transformation in organic
synthesis in which a terminal alkene and an organic halide are
coupled in the presence of a palladium(0) catalyst.[1] Palla-
dium(II)-catalyzed oxidative Heck reactions, in which a
terminal oxidant (dioxygen or benzoquinone)[2] and an
organometallic reagent are used, have also been developed
to expand the scope of this transformation. In both types of
Heck reaction, alkene insertion leads to a s-alkyl palladi-
um(II) intermediate D, which undergoes b-hydride elimina-
tion to form the product (Scheme 1).[3] Recently, significant
effort has been invested in attempts to intercept related
s-alkyl palladium(II) intermediates derived from alkenes in
various processes to access diverse difunctionalized prod-
ucts.[4] However, there have been few successful intermolec-
ular difunctionalization reactions initiated through a Heck
insertion. A noteworthy example was recently reported by
Sanford and Kalyani, who developed a 1,1-arylhalogenation
of alkenes with an aryl stannane and a chloride source.[5]
Other examples are mainly restricted to substrates that can
not undergo b-hydride elimination.[6] Herein we report a new
palladium(II)-catalyzed alkene difunctionalization reaction,
which we presume is initiated by an oxidative Heck insertion.
Two carbon–carbon single bonds are formed in a 1,2-
difunctionalization of conjugated alkenes and a 1,1-difunc-
tionalization of nonconjugated terminal alkenes with O2 as
the terminal oxidant.
Recently, our research group has been focused on the
development of palladium-catalyzed alkene hydrofunctional-
ization[7] and difunctionalization[8] reactions that avoid prod-
ucts derived from b-hydride elimination. In successful hydro-
functionalization reactions,[7] the proposed s-alkyl palladiu-
m(II) intermediates, which are accessed by the insertion of a
styrene derivative into a palladium hydride, are thought to be
stabilized by a p-benzyl interaction prior to functionaliza-
tion.[9] On the basis of this concept, it was proposed that a
p-benzyl intermediate of type E, accessed through a Heck
insertion, could slow b-hydride elimination and thus enable
subsequent transmetalation to form F and reductive elimi-
nation to yield the product of diarylation (Scheme 1). Thus,
the key issue to be addressed is the control of the relative
rates of b-hydride elimination and transmetalation of the
second equivalent of the organostannane. We believed that
these rates could be controlled by tuning the ligand environ-
ment in the palladium complex.
Initially, the diarylation product 5a was observed as a side
product under conditions originally used in the hydroaryla-
tion of 4-methylstyrene (Table 1, entry 1).[7b] Palladium(II)–
N-heterocyclic carbene (NHC) complexes were selected early
on in the optimization process, because they have been found
to be robust catalysts for various aerobic oxidation[7d,10] and
cross-coupling reactions.[11] The use of [Pd(IiPr)(OAc)2] led to
a greater preference for diarylation over hydroarylation,
although the oxidative Heck product was formed in higher
yield (Table 1, entry 2). Enhancement of the cationic nature
of the complex improved the selectivity for diarylation over
the oxidative Heck reaction (Table 1, entry 3). This result
suggests that the p-benzyl interaction is stronger with a more
electrophilic catalyst (and b-hydride elimination is slower as a
consequence), which is consistent with the reported isolation
of p-benzyl complexes with cationic palladium species.[9]
A dramatic change in selectivity for the diarylation
product over the oxidative Heck product was observed
when the counterion was changed from trifluoroacetate to
tosylate. Unfortunately, the more cationic complex [PdII-
(IiPr)(OTs)2] was unstable under these conditions (Table 1,
Scheme 1. Proposed mechanism for the oxidative Heck reaction (a)
and interception of the s-alkyl palladium(II) intermediate by trans-
metalation (b).
[*] K. B. Urkalan, Prof. M. S. Sigman
Department of Chemistry, University of Utah
315 South 1400 East, Salt Lake City, UT 84112 (USA)
Fax: (+1)801-581-8433
E-mail: sigman@chem.utah.edu
Homepage: http://www.chem.utah.edu/faculty/sigman/index.htm
[**] This research was supported by the National Institutes of Health
(NIGMS RO1 GM3540). M.S.S. thanks the Dreyfus Foundation
(Teacher-Scholar Award) and Pfizer for their support. We are grateful
to Johnson Matthey for the gift of various palladium salts. We thank
Keith Gligorich for initial experiments.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200900218.
3146
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 3146 –3149

Angewandte
Chemie
Table 1: Optimization for the diarylation of 4-methyl styrene.
tions led to excellent conversion into 5a (92% yield, as
determined by GC). A greater than 10:1 ratio of the 1,2- to
the 1,1-diarylation product was mainly observed for reactions
carried out under these conditions (see below).
The generality of the PdII-catalyzed difunctionalization of
styrenes was explored under the optimized conditions,
initially by the evaluation of different organostannanes
(Table 2, entries 1–5). The electronic nature of the aryl
stannane had little effect on the cross-coupling reaction,
with the exception of a decrease in selectivity for the 1,2-
Table 2: Scope of the palladium-catalyzed 1,2-diarylation of styrene
derivatives and 1,3-dienes with organostannanes.
Entry
Pd complex
Solvent
Conv.
[%][a]
Yield of 5a
[%][b]
(5a/4/3a)
Entry R1
R2
Product Yield [%][a]
1[c]
2[d]
[Pd(sp)Cl2]
IPA
90
99
32
1
2
3
4
5
6
7
8
p-MeC6H4
Ph (2a)
p-FC6H4 (2b)
p-MeOC6H4 (2c)
m,m-(MeO)2C6H3 (2d) 5d
p-CF3C6H4 (2e)
Ph
Ph
Ph
5a
5b
5c
78
64
65[b]
65
68
85
73
73
(1.6:0.8:1)
41
(8.2:8.6:1)
55
(4.2:0.9:1)
26
(26:2.0:1)
55
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeOC6H4
o-MeC6H4
o-MeOC6H4
[Pd(IiPr)(OAc)2]
[Pd(IiPr)(OCOCF3)2]
[Pd(IiPr)(OTs)2]
[Pd(IiPr)(OTs)2]
[Pd(IiPr)(OTs)2]
[Pd(IiPr)(OTs)2]
[Pd(IiPr)(OTs)2]
[Pd(IiPr)(OTs)2]
[Pd(IiPr)(OTs)2]
[Pd(IiPr)(OTs)2]
[Pd(IiPr)(OTs)2]
IPA
3[d]
IPA
99
5e
5 f
5g
5h
4[d]
IPA
30
5[d]
DCE
dioxane
DMA
DMA
DMA
DMA
DMA
DMA
99
(3.0:0.3:1)
58
9
p-MeC6H4
5i
57
6[d]
99
(4.1:0.6:1)
60
(7.0:2.4:1)
36
7[d]
99
10[c]
11[c]
m,m-(MeO)2C6H3
p-FC6H4
5j
5k
55
59
8
46
(20:4.5:1)
50
(17:5.3:1)
63
12[d]
13[d]
p-FC6H4
5l
62
37
9[e]
78
5m
10[e,f]
11[e–g]
12[e–h]
91
(16:0.3:1)
90
(22:2.3:1)
92
[a] Average yield of the isolated product in at least two experiments. [b] A
3:1 mixture of 1,2- and 1,1-diarylation products was formed. [c] The
reaction was performed at 458C. [d] The reaction was performed at 408C.
>99
>99
(42:1.5:1)
[a] The conversion was measured by GC with an internal standard.
[b] The yield was determined by GC. [c] CuCl2 (7.5 mol%) was used.
[d] The reaction was performed at 458C. [e] Pd complex: 6 mol%.
[f] Activated molecular sieves (3 ꢀ, 100 mg) were added. [g] Cu(OTf)2
(25 mol%) was used. [h] Concentration of the reaction mixture (with
respect to 1): 0.1m. Tf=trifluoromethanesulfonyl, Ts=p-toluenesul-
fonyl.
diarylation product with the electron-rich stannane 2c
(Table 2, entry 3). Electron-rich styrenes, including those
with ortho substitution, were found to undergo the diarylation
reaction successfully with PhSnBu3 in good yields (Table 2,
entries 6–8). The good reactivity of an organostannane
derived from a cyclic enol ether indicates that a wide range
of alternative organostannanes can be anticipated as sub-
strates (Table 2, entry 9). Terminal 1,3-dienes were also
evaluated. With these substrates, a p-allyl species[15] can be
entry 4). However, a change of solvent from isopropyl alcohol
(IPA) to dichloroethane (DCE), dioxane, or N,N-dimethyl-
acetamide (DMA) resulted in improved catalyst stability
(Table 1, entries 5–7), whereby the use of DMA led to the
most promising result.[12] Further optimization led to a
decrease in temperature (Table 1, entry 8) and an increase
in catalyst loading (Table 1, entry 9). Three final changes were
needed: 1) the addition of molecular sieves[13] (Table 1,
entry 10), 2) the addition of Cu(OTf)2 (Table 1, entry 11),
which has been shown to facilitate transmetalation,[14] and 3) a
decrease in concentration (Table 1, entry 12). These condi-
formed rather than
a p-benzyl-stabilized intermediate
(Table 2, entries 10–12). To our delight, the 1,2-diarylation
of 1,3-dienes yielded the desired product as a single isomer.
Finally, the difunctionalization of a 1,3-diene with a non-aryl
organostannane was successful, albeit relatively low yielding
(Table 2, entry 13).
Conspicuously absent from our discussion of the reaction
scope so far are electron-poor styrene derivatives. The
Angew. Chem. Int. Ed. 2009, 48, 3146 –3149
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3147

Communications
treatment of various electron-poor styrene derivatives with
reductive elimination to yield the 1,1-diarylation product.[16]
Indeed, the treatment of 1-nonene with several aryl stannanes
yielded the 1,1-diarylation products exclusively (Scheme 2).
We carried out several mechanistic experiments to explore
this process further. When the isotopically labeled alkene
[D2]6 was used as a substrate in the reaction with 2b, both
PhSnBu3 under the optimized conditions described above
resulted in a mixture of 1,2- and 1,1-diarylation products
(Figure 1). Of significance is a clear relationship between the
electronic nature of the styrene substrate and the resulting
ratio of 1,2- to 1,1-diarylation products, whereby the most
Scheme 2. 1,1-Diarylation of terminal alkenes (a) and related mecha-
nistic experiments (b).
deuterium atoms were conserved in the product. This result is
consistent with the mechanistic proposal outlined above.
Furthermore, no crossover was observed when [D2]6 and
1-undecene were used as substrate, which suggests that the
coordinated alkene does not dissociate prior to formation of
the 1,1-diarylation product.
In summary, we have disclosed a unique difunctionaliza-
tion reaction of terminal alkenes, whereby conjugated alkenes
undergo the 1,2-addition of organostannanes, and simple
terminal alkenes undergo 1,1-addition. Two carbon–carbon
bonds are formed in this transformation, which provides facile
access to diaryl methine compounds, a common pharmaco-
phore.[17] The outcome of the reaction is controlled both by
the stability of the p-benzyl or p-allyl intermediate formed
and by the unique cationic catalyst employed. Mechanistic
experiments suggest that the regioselectivity of the reaction is
determined by the relative rates of the second transmetala-
tion versus b-hydride elimination. These concepts will guide
the development of enantioselective variants of this trans-
formation and new reactions in which two different groups
can be added to a terminal alkene.
Figure 1. 1,2-Diarylation versus 1,1-diarylation of styrenes and resulting
Hammett analysis.
electron poor substrate, with an NO2 substituent in the meta
position, led to the lowest ratio of the 1,2- to the 1,1-
diarylation product (1,2/1,1). When the Hammett s values
were plotted against log(1,2/1,1), a linear free-energy rela-
tionship was observed with a 1 value of À0.88. This observa-
tion is consistent with the destabilization of the cationic
p-benzyl palladium complex E by an electron-withdrawing
group to enable b-hydride elimination and reinsertion of the
coordinated alkene with formation of the more stable
p-benzyl palladium complex H. In other words, the ratio is
dependent on the relative rates of b-hydride elimination and
transmetalation of the second equivalent of PhSnBu3.
On the basis of these findings, we turned our attention
towards terminal alkene substrates, as we believed that with
these substrates b-hydride elimination and reinsertion would
lead to a stable p-benzyl palladium complex. This complex
could then undergo a second transmetalation and subsequent
Received: January 14, 2009
Published online: March 23, 2009
Keywords: cross-coupling · homogeneous catalysis ·
.
molecular oxygen · palladium · reaction mechanisms
3148
www.angewandte.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 3146 –3149

Angewandte
Chemie
[7] a) K. M. Gligorich, M. J. Schultz, M. S. Sigman, J. Am. Chem.
[1] For reviews of the Heck reaction, see: a) R. F. Heck, Org. React.
1982, 27, 345 – 390; b) I. P. Beletskaya, A. V. Cheprakov, Chem.
Rev. 2000, 100, 3009 – 3066; c) N. J. Whitcombe, K. K. Hii, S. E.
Gibson, Tetrahedron 2001, 57, 7449 – 7476; d) I. Kondolff, H.
Doucet, M. Santelli, Tetrahedron Lett. 2003, 44, 8487 – 8491.
[2] For examples of oxidative Heck reactions, see: a) X. Du, M.
Suguro, K. Hirabayashi, A. Mori, T. Nishikata, N. Hagiwara, K.
Kawata, T. Okeda, H. F. Wang, K. Fugami, M. Kosugi, Org. Lett.
2001, 3, 3313 – 3316; b) J. P. Parrish, Y. C. Jung, S. I. Shin, K. W.
Jung, J. Org. Chem. 2002, 67, 7127 – 7130; c) Y. C. Jung, R. K.
Mishra, C. H. Yoon, K. W. Jung, Org. Lett. 2003, 5, 2231 – 2234;
d) M. M. S. Andappan, P. Nilsson, H. von Schenck, M. Larhed, J.
Org. Chem. 2004, 69, 5212 – 5218; e) K. S. Yoo, C. H. Yoon,
K. W. Jung, J. Am. Chem. Soc. 2006, 128, 16384 – 16393; f) J. H.
Delcamp, A. P. Brucks, M. C. White, J. Am. Chem. Soc. 2008,
130, 11270 – 11271; g) for an example in which oxygen and base-
free conditions are used, see: J. Ruan, X. Li, O. Saidi, J. Xiao, J.
Am. Chem. Soc. 2008, 130, 2424 – 2425.
Soc. 2006, 128, 2794 – 2795; b) K. M. Gligorich, S. A. Cummings,
M. S. Sigman, J. Am. Chem. Soc. 2007, 129, 14193 – 14195;
c) S. M. Podhajsky, M. S. Sigman, Organometallics 2007, 26,
5680 – 5686; d) Y. Iwai, K. M. Gligorich, M. S. Sigman, Angew.
Chem. 2008, 120, 3263 – 3266; Angew. Chem. Int. Ed. 2008, 47,
3219 – 3222.
[8] a) M. J. Schultz, M. S. Sigman, J. Am. Chem. Soc. 2006, 128,
1460 – 1461; b) Y. Zhang, M. S. Sigman, J. Am. Chem. Soc. 2007,
129, 3076 – 3077.
[9] a) Y. Becker, J. K. Stille, J. Am. Chem. Soc. 1978, 100, 845 – 850;
b) Y. S. Lin, A. Yamamoto, Organometallics 1998, 17, 3466 –
3478; c) Y. S. Lin, A. Yamamoto, Bull. Chem. Soc. Jpn. 1998,
71, 723 – 734; d) A. M. Johns, M. Utsunomiya, C. D. Incarvito,
J. F. Hartwig, J. Am. Chem. Soc. 2006, 128, 1828 – 1839; e) A. M.
Johns, J. W. Tye, J. F. Hartwig, J. Am. Chem. Soc. 2006, 128,
16010 – 16011.
[10] a) D. R. Jensen, M. J. Schultz, J. A. Mueller, M. S. Sigman,
Angew. Chem. 2003, 115, 3940 – 3943; Angew. Chem. Int. Ed.
2003, 42, 3810 – 3813; b) M. S. Sigman, D. R. Jensen, Acc. Chem.
Res. 2006, 39, 221 – 229.
[3] M. G. Organ, G. A. Chass, D. C. Fang, A. C. Hopkinson, C.
Valentea, Synthesis 2008, 2776 – 2797.
[4] For an overview of alkene difunctionalization reactions under
palladium catalysis, see: a) K. H. Jensen, M. S. Sigman, Org.
Biomol. Chem. 2008, 6, 4083 – 4088; for examples of alkene
diamination, see: b) K. Muniz, C. H. Hovelmann, J. Streuff, J.
Am. Chem. Soc. 2008, 130, 763 – 773; c) K. Muniz, J. Streuff,
C. H. Hovelmann, A. Nunez, Angew. Chem. 2007, 119, 7255 –
7258; Angew. Chem. Int. Ed. 2007, 46, 7125 – 7127; for an
example of aminooxygenation, see: d) L. V. Desai, S. S. Melanie,
Angew. Chem. 2007, 119, 5839 – 5842; Angew. Chem. Int. Ed.
2007, 46, 5737 – 5740; for an example of aminoacetoxylation, see:
e) G. Liu, S. S. Stahl, J. Am. Chem. Soc. 2006, 128, 7179 – 7181.
[5] D. Kalyani, M. S. Sanford, J. Am. Chem. Soc. 2008, 130, 2150 –
2151.
[11] a) E. A. B. Kantchev, C. J. OꢀBrien, M. G. Organ, Angew. Chem.
2007, 119, 2824 – 2870; Angew. Chem. Int. Ed. 2007, 46, 2768 –
2813; b) N. M. Scott, S. P. Nolan, N-Heterocyclic Carbenes in
Synthesis (Ed.: S. P. Nolan), Wiley-VCH, Weinheim, 2006,
pp. 55 – 72; c) M. S. Viciu, S. P. Nolan, Topics in Organometallic
Chemistry, Vol. 14, Springer, Berlin, 2005, pp. 241 – 278.
[12] The hydroarylation product is thought to be formed from a
palladium hydride generated from the Heck reaction. However,
in some cases in Table 1, the yield of the hydroarylation product
is greater than that of the Heck product. The additional
palladium hydride may be formed by transmetalation of an
n-butyl group from PhSnBu3, followed by b-hydride elimination.
[13] B. A. Steinhoff, A. E. King, S. S. Stahl, J. Org. Chem. 2006, 71,
1861 – 1868.
[6] For examples of alkene difunctionalization reactions with
norbornene-type compounds, see: a) K. M. Shaulis, B. L.
Hoskin, J. R. Townsend, F. E. Goodson, C. D. Incarvito, A. L.
Rheingold, J. Org. Chem. 2002, 67, 5860 – 5863; b) K. Fugami, S.
Hagiwara, H. Oda, M. Kosugi, Synlett 1998, 477 – 478; c) H. Oda,
K. Ito, M. Kosugi, T. Migita, Chem. Lett. 1994, 1443 – 1444; for
examples of alkene difunctionalization reactions in which the
alkyl palladium intermediate can not undergo b-hydride elim-
ination, see: d) P. Fretwell, R. Grigg, J. M. Sansano, V. Sridharan,
S. Sukirthalingam, D. Wilson, J. Redpath, Tetrahedron 2000, 56,
7525 – 7539; e) G. Poli, G. Giambastiani, A. Heumann, Tetrahe-
dron 2000, 56, 5959 – 5989; f) R. Grigg, V. Sridharan, J. Organo-
met. Chem. 1999, 576, 65 – 87; for examples of alkene difunc-
tionalization reactions with allenes, see: g) M. Jeganmohan,
C. H. Cheng, Chem. Commun. 2008, 3101 – 3117; h) M. Jegan-
mohan, M. Shanmugasundaram, C. H. Cheng, Chem. Commun.
2003, 1746 – 1747; for an example of alkyne difunctionalization,
see: i) C. Zhou, R. C. Larock, J. Org. Chem. 2005, 70, 3765 –
3777.
[14] For reviews of the Stille reaction and the effect of copper salts,
see: a) P. Espinet, A. M. Echavarren, Angew. Chem. 2004, 116,
4808 – 4839; Angew. Chem. Int. Ed. 2004, 43, 4704 – 4734; b) V.
Farina, V. Krishnamurthy, W. J. Scott, Org. React. 1997, 50, 1 –
652.
[15] O. Lꢁber, M. Kawatsura, J. F. Hartwig, J. Am. Chem. Soc. 2001,
123, 4366 – 4367.
[16] For an example of 1,1-diarylation, see: E. Thiery, D. Harakat, J.
Le Bras, J. Muzart, Organometallics 2008, 27, 3996 – 4004.
[17] For recent examples of biologically active diaryl methine
derivatives, see: a) A. Moriconi, M. C. Cesta, M. N. Cervellera,
A. Aramini, S. Coniglio, S. Colagioia, A. R. Beccari, C. Bizzarri,
M. R. Cavicchia, M. Locati, E. Galliera, P. Di Benedetto, P.
Vigilante, R. Bertini, M. Allegretti, J. Med. Chem. 2007, 50,
3984 – 4002; b) J.-J. Chen, P.-H. Chen, C.-H. Liao, S.-Y. Huang,
I.-S. Chen, J. Nat. Prod. 2007, 70, 1444 – 1448; c) H. Liang, X.
Wu, J. C. Yalowich, B. B. Hasinoff, Mol. Pharmacol. 2008, 73,
686 – 696.
Angew. Chem. Int. Ed. 2009, 48, 3146 –3149
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3149