Negishi alkyl-aryl cross-coupling catalyzed by Rh: Efficiency of novel tripodal 3-diphenylphosphino-2-(diphenylphosphino)methyl-2-methylpropyl acetate ligand

Article abstract of DOI:10.1021/ol100210u

3-Diphenylphosphino-2-(diphenylphoshino)methyl-2-methylpropyl acetate acted as an efficient ligand for a Rh catalyst, achieving cross-coupling between arylzinc compounds bearing electron-withdrawing groups and alkyl electrophiles. The beneficial effect of the tripodal ligand and such aryl nucleophiles was discussed with regard to the specificity of the Rh catalysis.

Full text of DOI:10.1021/ol100210u

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1692-1695
Negishi Alkyl-Aryl Cross-Coupling
Catalyzed by Rh: Efficiency of Novel
Tripodal 3-Diphenylphosphino-2-
(diphenylphosphino)methyl-2-methylpropyl
Acetate Ligand
Syogo Ejiri, Shunsuke Odo, Hideki Takahashi, Yugo Nishimura, Kazuma Gotoh,
Yasushi Nishihara, and Kentaro Takagi*
Department of Chemistry, Faculty of Science, Okayama UniVersity, Tsushima-Naka,
Okayama 700-8530, Japan
takagi@cc.okayama-u.ac.jp
Received January 27, 2010
ABSTRACT
3-Diphenylphosphino-2-(diphenylphoshino)methyl-2-methylpropyl acetate acted as an efficient ligand for a Rh catalyst, achieving cross-coupling
between arylzinc compounds bearing electron-withdrawing groups and alkyl electrophiles. The beneficial effect of the tripodal ligand and such
aryl nucleophiles was discussed with regard to the specificity of the Rh catalysis.
Pd- or Ni-catalyzed cross-coupling between carbon electro-
philes, R-X (R ) alkenyl, aryl, or alkynyl; X ) halides,
sulfonates, etc.), and organometallic nucleophiles, R′-m (R′
) alkyl, alkenyl, aryl, or alkynyl; m ) Mg, Zn, B, Sn, Si,
etc.), provides one of the most valuable methods for
constructing carbon-carbon bonds in organic synthesis.1
However, alkyl electrophiles, especially when R is an alkyl
group possessing ꢀ-hydrogens, are not readily available for
the reaction, since these electrophiles react far more reluc-
tantly with the catalyst than other commonly employed ones.
Additionally, the resulting intermediates, oxidative adducts,
are apt to suffer from ꢀ-hydride elimination. Subsequently,
the yields of the desired cross-coupling products are dimin-
ished.2 To solve these problems of alkyl cross-coupling, a
number of investigations have been undertaken in recent
years to develop efficient catalyst systems, with the aid
of novel ligands such as trif1uoromethylstyrenes,3a 1,3-
butadiene,3b P(c-C6H11)3,3c N-heterocyclic carbenes,3d
bathophenanthroline,3e P(t-Bu)2Me,3f and pincers3g of a Pd
or Ni catalyst2 or with the aid of novel metallic species such
(2) For reviews, see: (a) Frisch, A. C.; Beller, M. Angew. Chem., Int.
Ed. 2005, 44, 674–688. (b) Luh, T.-Y.; Leung, M.-K.; Wong, K.-T. Chem.
ReV. 2000, 100, 3187–3204.
(3) Ni-Mg: (a) Giovannini, R.; Knochel, P. J. Am. Chem. Soc. 1998,
120, 11186–11187. (b) Terao, J.; Watanabe, H.; Ikumi, A.; Kuniyasu, H.;
Kambe, N. J. Am. Chem. Soc. 2002, 124, 4222–4223. Pd-Mg: (c) Frisch,
A. C.; Shaikh, N.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed. 2002, 41,
4056–4059. (d) Frisch, A. C.; Rataboul, F.; Zapf, A.; Beller, M. J.
Organomet. Chem. 2003, 687, 403–409. Ni-Sn: (e) Zhou, J.; Fu, G. C.
J. Am. Chem. Soc. 2004, 126, 1340–1341. Pd-Sn: (f) Netherton, M. R.;
Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 3910–3912. Pincer Ni-Mg:
(g) Vechorkin, O.; Hu, X. Angew. Chem., Int. Ed. 2009, 48, 2937–2940.
(1) For reviews, see: (a) Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998. (b)
Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
E., Ed.; John Wiley & Sons: New York, 2002. (c) Tsuji, J. Palladium
Reagents and Catalysis: InnoVation in Organic Synthesis; John Wiley &
Sons: New York, 1995.
10.1021/ol100210u  2010 American Chemical Society
Published on Web 03/12/2010

as Fe2a,4 or Co.2a,5 In our continuing studies on the synthesis
and synthetic applications of arylzinc compounds,6 the utility
of Rh catalysts in the Negishi alkyl-aryl cross-coupling was
examined for the first time. These studies revealed that
catalytic cross-coupling takes place smoothly in the presence
of Rh-1,1′-bis(diphenylphosphino)ferrocene (dppf), pro-
vided either of the coupling components, ArZnX or R-X,
contains functional groups like carbonyl or phosphoryl near
the reaction centers (Scheme 1).7 In these instances, the
Table 1. Effect of Ligand on the Rh-Catalyzed Reaction
between 1a and 2aa
entry
ligand
yieldb (%)
1
2
3
4
5
6
L1
dppp
L2
>5
13
>5
>5
>5
9
L3
Scheme 1. Effect of Coordinating Functional Groups on the
EtO2CCH2PPh2 (L4)
o-MeO2CC6H4PPh2 (L5)
Rh-Catalyzed Negishi Alkyl-Aryl Cross-Coupling
7
8
9
10
11
12
13c
14d
15e
L6
L7
L8
L9
L6
L7
L6
L6
L6
66
64
36
14
99
83
82
>5
99
a 1a (0.20 mmol), 2a (0.60 mmol), [RhCl(cod)]2 (0.01 mmol), Ligand (0.02
mmol), and TMU (0.1 mL) were employed for all entries, except for entries
11-15, where 2a of 0.30 mmol was used, and entries 5 and 6, where Ligand
of 0.06 mmol was used. In entries 11-15, cod was removed from the reaction
solution. b GLC yield. c DMF was used in place of TMU. d THF was used in
place of TMU. e C7H5Br was used in place of 2a. NaI (0.60 mmol) was added.
vacant sites of the oxidative adducts are favorably occupied
by the coupling components to prevent ꢀ-hydride elimination
(A and B, Scheme 1). Here, we describe the design and
development of new efficient ligands such that the role
preveously exerted by the substituents is now performed by
the ligands themselves (C, Scheme 1).
worked successfully in the bidentate phosphorus ligands L6
and L7, affording the desired product 3aa predominantly
(entries 7 and 8). L8 and L9 were less effective (entries 9
and 10). ꢀ-Hydride elimination is suppressed completely after
the removal of cod in the catalyst precursor [RhCl(cod)]2
from the reaction solution (entries 11 and 12), and this
procedure was applied in every subsequent run. For the
solvent, N,N-dimethylformamide (DMF) was also compatible
with the reaction but THF was not (entries 13 and 14). In
the presence of NaI, 1-bromoheptane reacted favorably with
1a to afford the desired cross-coupling product in good yield
(entry 15). Thus, with typical alkyl electrophiles, i.e., ones
possessing ꢀ-hydrogens and no special coordinating groups
near the reaction cnter, Rh-catalyzed Negishi alkyl-aryl cross-
coupling was achieved for the first time by means of the
utility of L6.
The effect of adjunctive groups in the ligand molecules
was examined in the reaction of p- ethoxycarbonylphenylzinc
iodide 1a and 1-iodoheptane 2a (1.5-3 equiv) in the presence
of 5 mol % of [RhCl(cod)]2 (cod ) 1,5-cyclooctadiene) in
N,N,N′,N′-tetramethylurea (TMU) at room temperature for
24 h, and the results are summarized in Table 1. At first, L1,
containing the phosphorus adjunctive group, quenched every
catalytic reaction (entry 1), though the parent molecule, 1,3-
bis(diphenylphosphino)propane (dppp), was a slightly better
ligand than dppf (entry 2 and Scheme 1). Similarly, tripodal
ligand L2 and L3 were ineffective (entries 3 and 4), which
implies that simple occupation of the vacant site is insuf-
ficient to promote the alkyl-aryl cross-coupling by Rh
catalysis. The adjunctive ester group did not work well in
the monodentate phosphorus ligands L4 and L5 (entries 5
and 6), but the adjunctive ester and phosphoryl groups
(8) To our knowledge, six catalytic alkyl-aryl cross-couplings have been
accomplished using arylmetallic nucleophiles, containing such reactive
functional groups as ester, nitrile, and nitro,3a,e,8a-d which utilized an
unstable catalyst,3a a high reaction temperature (60-80 °C),3e,8a,b manipu-
lated nucleophiles (ArZnCH2TMS),8c or special procedures:8a,d (a) Duncton,
M. A. J.; Estiarte, M. A.; Tan, D.; Kaub, C.; O’Mahony, D. J. R.; Johnson,
R. J.; Cox, M.; Edwards, W. T.; Wan, M.; Kincaid, J.; Kelly, M. G Org.
Lett. 2008, 10, 3259–3262. (b) Lu, F.; Chi, S.-W.; Kim, D.-H.; Han, K.-
H.; Kuntz, I. D.; Guy, R. K. J. Comb. Chem. 2006, 8, 315–325. (c)
Nakamura, M.; Ito, S.; Matsuo, K.; Nakamura, E. Synlett 2005, 1794–1798.
(d) Vechorkin, O.; Proust, V.; Hu, X. J. Am. Chem. Soc. 2009, 131, 12078–
12079.
(4) Sherry, B. D.; Fuerstner, A. Acc. Chem. Res. 2008, 41, 1500–1511
.
(5) (a) Gosmini, C.; Begouin, J.-M.; Moncomble, A. Chem. Commun.
2008, 3221–3233. (b) Yorimitsu, H.; Oshima, K. Pure Appl. Chem. 2006,
78, 441–449
.
(6) (a) Takagi, K. Chem. Lett. 1993, 469–472. (b) Ogawa, Y.; Saiga,
A.; Mori, M.; Shibata, T.; Takagi, K. J. Org. Chem. 2000, 65, 1031–1036.
(c) Ikegami, R.; Koresawa, A.; Shibata, T.; Takagi, K. J. Org. Chem. 2003,
68, 2195–2199.
(7) (a) Takahashi, H.; Inagaki, S.; Nishihara, Y.; Shibata, T.; Takagi,
K. Org. Lett. 2006, 8, 3037–3040. (b) Takahashi, H.; Inagaki, S.; Yoshii,
N.; Gao, F.; Nishihara, Y.; Takagi, K. J. Org. Chem. 2009, 74, 2794–2797.
Org. Lett., Vol. 12, No. 8, 2010
1693

Arylzinc compounds containing electron-withdrawing
groups such as CN, COPh, CO2Me, or Cl at the para, meta,
or ortho positions 1b-f readily underwent catalysis by
Rh-L6 in the reaction with 2a to afford the coupling products
in moderate to good yields (entries 1-5, Table 2). Under
Table 3. Rh-L6-Catalyzed Synthesis of Functionalized
Alkylbenzenesa
Table 2. Rh-L6-Catalyzed Cross-Coupling between Various
Arylzinc Compounds and 2aa
entry RC6H4ZnI X(CH2)nCH2I RC6H4CH2(CH2)nX yieldb (%)
1
2
3
4
5
6
7
8
9
1a
1a
1b
1b
1b
1b
1c
1c
1j
2b
2c
2d
2e
2f
2g
2b
2g
2g
3ab
3ac
3bd
3be
3bf
3bg
3cb
3cg
3jg
85
96
83
96
95
79
95
90
54
entry
RC6H4ZnI
RC6H4C7H15
yieldb (%)
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
1g
1h
1i
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
99
80
51
(90)
(90)
23
a RC6H4ZnI (0.40 mmol), 2a (0.60 mmol), [RhCl(cod)]2 (0.02 mmol),
L6 (0.04 mmol), and TMU (0.2 mL) were employed for all entries. b Isolated
yield.
27
21
a RC6H4ZnI (0.20 mmol), 2a (0.30 mmol), [RhCl(cod)]2 (0.01 mmol),
L6 (0.02 mmol), and TMU (0.1 mL) were employed for all entries, except
for entries 4 and 5, where every component was doubled. b GLC yield.
Values in parentheses are isolated yields.
conditions and the facility of the reaction procedure,8
provides efficient and novel access to polyfunctionalized
alkylbenzenes.
Although a detailed mechanism remains to be clarified,
the observed unique specificity of the reaction might provide
some insight into the catalytic properties of Rh in the cross-
coupling.7,9 In Rh-catalyzed cross-coupling, two catalytic
cycles are possible, one commencing with transmetalation
and the other with oxidative addition (catalytic cycle A and
B, respectively, Scheme 2). In both cases, Rh3+ species
similar conditions, arylzinc compounds containing electron-
donating groups such as alkyl or OCH3 (1h,i) as well as
unsubstituted compound 1g gave the cross-coupling products
in minor amounts, instead affording Ar-H derived from
ꢀ-hydride elimination as the main products (entries 6-8).
As for the alkyl electrophile, various substituents such as
CO2Et, Ph, OBz, Cl, or CN on the chain at the C2-C4
positions (2b,c,e-g) were tolerated under catalysis
by Rh-L6, giving the desired cross-coupling products
3ab,ac,bd-bg,cb,cg,jg in good yields (entries 1-8, Table
3). The o-tolylzinc compound afforded the desired product
3jg in 54% yield (entry 9). Although quite a number of
catalytic alkyl-aryl cross-couplings have been developed
recently,2,3 there exist few examples using functionalized
arylmetallic nucleophiles as coupling components.8 There-
fore, the present reaction, featuring the availability of such
nucleophiles,6 along with the mildness of the reaction
Scheme 2. Two Possible Catalytic Cycles for Rh-Catalyzed
Cross-Coupling between R-X and Ar-ZnX
(9) In comparison with the vast numbers of Pd- or Ni-catalyzed cross-
couplings of R-X and R′-m, Rh-catalyzed ones are few: Larock, R. C.;
Hershberger, S. S J. Organomet. Chem. 1982, 225, 31–41. (b) Larock, R. C.;
Narayanan, K.; Hershberger, S. S. J. Org. Chem. 1983, 48, 4377–4380. (c)
Evans, P. A.; Uraguchi, D. J. Am. Chem. Soc. 2003, 125, 7158–7159. (d)
Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2003, 125, 8974–8975. (e)
Uemura, K.; Satoh, T.; Miura, M. Org. Lett. 2005, 7, 2229–2231. (f) Yasui,
H.; Mizutani, K.; Yorimitsu, H.; Oshima, K. Tetrahedron 2006, 62, 1410–
1415. (g) Wu, J.; Zhang, L.; Luo, Y. Tetrahedron Lett. 2006, 47, 6747–
6750. (h) Wu, J.; Zhang, L.; Gao, K. Eur. J. Org. Chem. 2006, 5260–5263.
(i) Kantam, M. L.; Roy, S.; Roy, M.; Sreedhar, B.; Choudary, B. M.; De,
R. L. J. Mol. Catal. A: Chem. 2007, 273, 26–31. (j) Zhang, L.; Wu, J. AdV.
Synth. Catal. 2008, 350, 2409–2413. (k) Yu, J.-Y.; Kuwano, R. Angew.
Chem., Int. Ed. 2009, 48, 7217–7219.
(intermediates III and IV) are formed by the oxidative
addition of the alkyl electrophile. Binding of either the third
functional group of the tripod ligand L6 or the ꢀ-C-H bond
in the alkyl electrophile to the empty orbital is then possible,
since the coordination number (CN) is increased via the
1694
Org. Lett., Vol. 12, No. 8, 2010

change in the oxidation state of Rh from +1 to +3. Notably,
the reaction using a 1:1 molar mixture of 1a and 1g with 2a
afforded 3aa (89%) and 3ga (16%) (Scheme 3), which
carbon bond-forming reductive elimination of intermediate
III is speculated to be accelerated by the electron transfer
from an alkyl ligand11 to an aryl ligand12 and by the
concomitant acceptance of the electrons on the metallic center
by the carbonyl group of L6 (Scheme 5).13,14
Scheme 3. Reaction between 1a, 1g, and 2a
Scheme 5. Supeculative View of Reductive Elimination
coincides well with the reactions using 1a and 1g individually
(entry 12, Table 1, and entry 6, Table 2). These results
suggest that there is no free HX derived from ꢀ-hydride
elimination in the reaction solution: HX would decompose
ArZnX, resulting in a reduced yield of 3aa. Thus, Ar-H was
likely derived from the oxidative adduct III through the
intermediate V (bold arrow, Scheme 4). Therefore, the
In conclusion, the novel Rh catalysis enables the cross-
coupling of alkyl halides with arylzinc compounds bearing
electron-withdrawing groups by means of the efficient
assistance of tripodal ligand, L6, which provides a facile and
useful synthetic method of polyfunctionalized alkylbenzenes.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research (No. 20550043) from the Japan
Society for the Promotion of Science.
Scheme 4. ꢀ-Hydride Elimination from Intermediate III or IV
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and DFT calcula-
tion. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL100210U
(11) In the Rh-catalyzed alkyl-aryl cross-coupling between ArZnX and
YCH2I (Y ) H, OMe, or CN), the higher the electronic density of the YCH2
fragment is, the larger the reactivity becomes: Hossain, K. M.; Takagi, K.
Chem. Lett. 1999, 1241–1242.
catalytic cycle A most likely operates in the present reac-
tion,10 where III is a common intermediate before the
reaction diverges between cross-coupling and ꢀ-hydride
elimination (Schemes 2 and 4). Accordingly, from the fact
that electron-deficient arylzinc nucleophiles and/or tripodal
ligand L6 exert a beneficial effect on the cross-coupling, while
relatively restraining the ꢀ-hydride elimination, the carbon-
(12) The electronic deficiency of the aryl fragment is known to promote
the reductive elimination of certain aryl transition-metal complexes, which
generally retards the process. See: (a) Driver, M. S.; Hartwig, J. F. J. Am.
Chem. Soc. 1997, 119, 8232–8245. (b) Mann, G.; Baranano, D.; Hartwig,
J. F.; Reingold, A. L.; Guzei, I. A. J. Am. Chem. Soc. 1998, 120, 9205–
9219. (c) Shekhar, S.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 13016–
13027.
(13) Electron-accepting ligands are known to promote the reductive
elimination, yielding a carbon-carbon bond between aryl and alkyl
fragments See ref 3a.
(14) The DFT calculation established that little interaction exists between
Rh and either the third arm of L6 or the alkyl group in the analogue of
intermediate III itself. See the Supporting Information.
(10) Catalytic cycle A was believed to operate in the Rh-catalyzed
Negishi alkyl-aryl cross-coupling utilizing TMSCH2I as an alkyl electro-
phile: Takahashi, H.; Hossain, K. M.; Nishihara, Y.; Shibata, T.; Takagi,
K. J. Org. Chem. 2006, 71, 671–675.
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