Novel Rh catalysis in cross-coupling between alkyl halides and arylzinc compounds possessing ortho-COX (X = OR, NMe2, or Ph) groups

Article abstract of DOI:10.1021/ol060969d

Rh-dppf was found to be an efficient catalyst for the cross-coupling between primary alkyl halides bearings-hydrogens and arylzinc compounds possessing carbonyl groups such as ester, amide, or ketone at the ortho position. Various functional groups such as ester, nitrite, or acyloxylate moieties on the halides were tolerated under the catalysis conditions. Arylzinc compounds free of ortho-carbonyl groups reacted well with ethyl 3-iodopropanoate, suggesting that the essential intramolecular interaction between carbonyl groups and Rh promotes the reductive elimination.

Full text of DOI:10.1021/ol060969d

ORGANIC
LETTERS
2006
Vol. 8, No. 14
3037-3040
Novel Rh Catalysis in Cross-Coupling
between Alkyl Halides and Arylzinc
Compounds Possessing ortho-COX
(X
) OR, NMe2, or Ph) Groups
Hideki Takahashi, Shinya Inagaki, Yasushi Nishihara, Takanori Shibata, and
Kentaro Takagi*
Department of Chemistry, Faculty of Science, Okayama UniVersity,
Tsushima, Okayama 700-8530, Japan
takagi@cc.okayama-u.ac.jp
Received April 23, 2006
ABSTRACT
Rh−dppf was found to be an efficient catalyst for the cross-coupling between primary alkyl halides bearing
â-hydrogens and arylzinc compounds
possessing carbonyl groups such as ester, amide, or ketone at the ortho position. Various functional groups such as ester, nitrile, or acyloxylate
moieties on the halides were tolerated under the catalysis conditions. Arylzinc compounds free of ortho-carbonyl groups reacted well with
ethyl 3-iodopropanoate, suggesting that the essential intramolecular interaction between carbonyl groups and Rh promotes the reductive
elimination.
Transition-metal-catalyzed cross-coupling of organometallic
compounds (R-m) with organic halides (R′-X) has become
one of the most useful methods for constructing carbon-
carbon bonds in organic synthesis.1 The present utility and
efficiency of catalysis have been mainly achieved by refining
auxiliary components of the catalyst system such as ligands,
additives, and/or solvents with fixed metallic centers of Pd
or Ni, which at the same time eliminate the incidental
drawbacks stemming from the reluctant catalytic reaction.1
This was exemplified by the recently reported successful
application of novel Ni-4-(trifluoromethyl)styrene,2a Pd-P(c-
C6H11)3,2b or Pd-P(c-C5H9)3 catalytic systems2c to the
difficult cross-coupling between R-m (R ) aryl; m ) ZnX)
and R′-X (R′ ) alkyl; X ) I, Br, or Cl).3,4 Hereupon, we
envisaged the necessity for reinvestigating the catalytic
activity of other transition metals, particularly Rh, in the
cross-coupling reaction. Although only a few papers exist
on Rh-catalyzed cross-coupling between R-m and R′-X,5
Rh catalysis is intriguing in view of the following: (1) Rh
may commence the catalytic cycle with transmetalation (path
A, Scheme 1) instead of with more conventional oxidative
addition (path B) and (2) the number of d-electrons, d6 or
d8, and the coordination numbers, CN ) 4 or 6, of the
metallic species involved differ from those of Pd or Ni
(1) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: Weinheim, 1998. (b) Handbook of Organopal-
ladium 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.
(2) (a) Giovannini, R.; Knochel, P. J. Am. Chem. Soc. 1998, 120, 11186-
11187. (b) Frisch, A. C.; Shaikh, N.; Zapf, A.; Beller, M. Angew. Chem.,
Int. Ed. 2002, 41, 4056-4059. (c) Zhou, J.; Fu, G. C. J. Am. Chem. Soc.
2003, 125, 12527-12530.
(3) (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.
(4) Among various combinations of reaction components, the catalytic
cross-couplings of R ) aryl and R′ ) alkyl are the most problematic because
alkyl electrophiles, aryl nucleophiles, or the resulting oxidative adducts are
less susceptible to oxidative addition, transmetalation, or reductive elimina-
tion caused by overwhelmingly facile side reactions such as â-elimination,
respectively.3a
10.1021/ol060969d CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/17/2006

Scheme 1. Two Possible Catalytic Cycles for Rh-Catalyzed
Cross-Coupling between R-m and R′-X
Scheme 2. Rh-dppf-Catalyzed Cross-Coupling of Arylzinc
Compounds with Alkyl Halides
2.5 mol % of [RhCl(cod)]2 and 5 mol % of dppf, in
N,N,N′,N′-tetramethylurea (TMU) was stirred at 40 °C for
24 h under nitrogen. As shown in Scheme 3, arylzinc
Scheme 3. Reaction between 1 and 2a
catalysis (d8 or d10 and CN ) 4), which perhaps is the cause
for complication with conventional catalysts.5b,6,7b Further-
more, along with the long-standing Cu catalysis,8 recently
disclosed Fe or Co catalysis9 suggests the latent catalytic
activity of transition metals other than Pd or Ni toward the
cross-coupling with R′ ) alkyl. On the basis of these
phenomena, we previously initiated an investigation of the
catalytic activity of Rh toward the cross-coupling reaction
of our arylzinc compounds 1 (Scheme 2)10 with alkyl halides
and found that the catalyst system composed of Rh and 1,1′-
bis(diphenylphosphino)ferrocene (dppf) exhibits excellent
catalytic activity toward the reaction between 1 and alkyl
halides such as iodomethane, (iodomethyl)trimethylsilane,
or (iodomethyl)tributyltin.7 In this study, we applied the Rh-
dppf catalyst system to the reaction of 1 with alkyl halides
containing â-hydrogens (Scheme 2).
compounds 1a-c were converted into the protodezincation
products 3a-c quantitatively, indicating that the â-elimina-
tion of alkyl-Rh intermediates III and/or IV took place
rapidly under these conditions. The coexistence of 5 mol %
of PPh3 in the reaction solution inhibited all reactions
including the â-elimination where 92% of 1a was recovered
after the reaction. Even without any additives, 1d was
quantitatively recovered after exposure to the catalytic system
and 1e afforded the desired cross-coupled product 3e in 13%
yield (17% conversion) from the reaction at 80 °C for 12 h
with 10 mol % of Rh-dppf. 1f afforded the protodezincation
product 3f, quantitatively.11 To our delight, the cross-coupled
product 3g was quantitatively formed in the reaction of 1g
and 2a at 40 °C for 1 h under Rh-dppf catalysis. As shown
in Table 1, the reaction proceeded smoothly at room
temperature (entry 2) or with 2 mol % of Rh-dppf at 80 °C
(entry 3) to provide 3g in good yield.
The reaction solution composed of 1, 1-iodoheptane 2a
(1.1 equiv), and 5 mol % of Rh-dppf, generated in situ from
(5) (a) 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) Andrianome, M.; Delmond, B. J. Org.
Chem. 1988, 53, 542-545. (d) Andrianome, M.; Haberle, K.; Delmond, B.
Tetrahedron 1989, 45, 1079-1088. (e) Uemura, K.; Satoh, T.; Miura, M.
Org. Lett. 2005, 7, 2229-2231. (f) Evans, P. A.; Uraguchi, D. J. Am. Chem.
Soc. 2003, 125, 7158-7159. (g) Evans, P. A.; Leahy, D. K. J. Am. Chem.
Soc. 2003, 125, 8974-8975.
(6) (a) Schwartz, J.; Hart, D. W.; Holden, J. L. J. Am. Chem. Soc. 1972,
94, 9269-9271. (b) Semmelhack, M. F.; Ryono, L. Tetrahedron Lett. 1973,
2967-2970. (c) Hegedus, L. S.; Kendall, P. M.; Lo, S. M.; Sheats, J. R. J.
Am. Chem. Soc. 1975, 97, 5448-5452. (d) Fanizzi, F. P.; Sunley, G. J.;
Maitlis, P. M. J. Organomet. Chem. 1987, 330, C31-C32.
(7) (a) Hossain, K. M.; Takagi, K. Chem. Lett. 1999, 1241-1242. (b)
Takahashi, H.; Hossain, K. M.; Nishihara, Y.; Shibata, T.; Takagi, K. J.
Org. Chem. 2006, 71, 671-675.
(8) Kochi, J. K. J. Organomet. Chem. 2002, 653, 11-19.
(9) (a) Shinokubo, H.; Oshima, K. Eur. J. Org. Chem. 2004, 2081-
2091. (b) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004,
248, 2337-2364. (c) Furstner, A.; Martin, R. Chem. Lett. 2005, 34, 626-
629.
(10) For our synthesis of arylzinc compounds, see: (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. Except
for Zn, other arylmetal compounds such as those of B, Si, Sn, Bi, or Ti are
not available via synthesis from aryl halides and simple substances as
metallic sources.
(11) None of the 1’s including 2-isopropoxy-, 2-acetoxy-, 2-(methoxy)-
methyl-, or 2-(trifluoromethyl)phenylzinc iodide afforded the desired cross-
coupling products. However, the rates of protodezincation of 1 depended
on the substituents and decreased in the order of 2-acetoxy, 2-(methoxy)-
methyl > 2-trifluoromethyl > 2-isopropoxy. The coexistence of 1 equiv of
benzophenone in the reaction solution of 1b did not change the course of
the reaction.
3038
Org. Lett., Vol. 8, No. 14, 2006

Table 1. Reaction between 1 with an ortho-Carbonyl Group
and 1-Haloheptane 2a-ca
Table 2. Reaction between 1g and Various Iodoalkanes 4-12a
yieldb
temp/°C
entry
1
2
catalyst/mol %
time/h
3
1/%
1
2
3
4
5
6c
7
8
1g
1g
1g
1g
1g
1g
1h
1i
2a
2a
2a
2b
2b
2c
2a
2a
5
5
2
10
10
10
10
10
40/1
rt/1
3g
3g
3g
3g
3g
3g
3h
3i
98 (74)
92
72
78
71
98
(75)
(63)
80/3
80/1
rt/72
40/24
40/2
40/12
a 1 (0.44 mmol), 2 (0.40 mmol), Rh-dppf (0.008-0.04 mmol), and TMU
(0.22 mL) were employed for all entries. b GLC yield. Values in parentheses
are isolated yields. c NaI (1.2 mmol) was added.
a 1 (0.44 mmmol), 4-12 (0.40 mmol), Rh-dppf (0.02-0.04 mmol), and
TMU (0.22 mL) were employed for all entries. b Isolated yield. Yields in
parentheses determined by GLC. c 5-Bromo-1-pentene 22 was used in place
of 7. The reaction temperature was 80 °C.
1-Bromoheptane 2b was also successful in the reaction,
though stirring at 80 °C (entry 4) or for a long time (entry
5) was required. In the presence of 3 equiv of NaI,
1-chloroheptane 2c favorably reacted with 1g under catalysis
by Rh-dppf to afford the desired cross-coupled product 3g
in good yield (entry 6). Besides 1g, 1h and 1i also reacted
with 2a to afford the desired cross-coupled products 3h and
3i in good yield under similar conditions (entries 7 and 8).
As shown in Table 2, various substituents such as chloro 5,
ethoxycarbonyl 6, alkenyl 7, benzoyloxy 8, cyano 9, alkoxy
10, or phenyl 11 on the alkyl chains at the C2-C5 positions
were tolerated under catalysis by Rh-dppf giving the desired
cross-coupled products 13-20, all isolated in good yields
(entries 2-9). Under similar conditions, sec-alkyl iodide 12
did not afford the cross-coupling product at all (entry 10).
To our knowledge, this is the first example of Rh-catalyzed
cross-coupling of alkyl halides containing â-hydrogens with
any organometallic compounds. Furthermore, it provides a
facile synthetic method for alkylbenzenes possessing ortho-
carbonyl groups, with the beneficial features of simplicity,
a great degree of functional group tolerance, and utility of
readily available starting materials.12
â-elimination, resulting in protodezincation of 1 (Scheme
4).13 Hence, it might be reasonable to speculate that the
Scheme 4
carbonyl group occupies the sixth site preventing elimination.
However, a simple occupation of the site by some groups
was inadequate for the promotion of cross-coupling, as could
be seen in the reactions between 2a and 1a with PPh3 or 1d
or 1f (vide supra).14 Consequently, the activating effect
Although the detailed mechanism still remains to be
clarified, the critical effect exerted by the ortho-carbonyl
groups in 1 was made apparent for the Rh-dppf-catalyzed
reaction of 1 with alkyl halides. As a d6 complex, our alkyl-
Rh intermediates, III and/or IV, have a vacant coordination
site, which must be responsible for the occurrence of the
(13) Depending on the kinds of 1, the reaction course was selected from
both protodezincation of 1 and cross-coupling of 1 with R. This result
possibly means that the cross-coupling products were formed through path
A.
(14) The o-MeO group is known to interact with the rhodium center in
o-anisylrhodium complexes; see, for example: (a) Jones, R. A.; Wilkinson,
G. J. Chem. Soc., Dalton Trans. 1979, 472-477. (b) Fagnou, K.; Lautens,
M. Chem. ReV. 2003, 103, 169-196.
(12) Arylzinc compounds containing ortho-carbonyl groups are readily
prepared from the corresponding iodoarenes and zinc powder.10 Directed
ortho metalation of arenes containing carbonyl groups provides another route
to the compounds; see, for example: (a) Kondo, Y.; Shilai, M.; Uchiyama,
M.; Sakamoto, T. J. Am. Chem. Soc. 1999, 121, 3539-3540. (b) Mills, R.
J.; Taylor, N. J.; Snieckus, V. J. Org. Chem. 1989, 54, 4372-4385.
Org. Lett., Vol. 8, No. 14, 2006
3039

exerted by the coordination of carbonyl groups to the metallic
center is conceivable to control the following course of
reactions (Scheme 4). To clarify this, the reactions of 1, free
of ortho-carbonyl groups, with alkyl halides possessing an
ester group at the R-, â-, or γ-position of 23a, 23b, or 6
were examined. As shown in Table 3, methyl 3-iodopro-
panoate 23b readily reacted with 1a, 1j, or 1k to afford the
cross-coupled products 25-27 in moderate to good yield and
with 1c to afford 28 in a low yield (entries 2-6) under the
conditions15 where the reaction between 1a and 2a afforded
the protodezincation product 3a quantitatively (vide supra).
On the other hand, ethyl iodoacetate 23a or ethyl 4-iodobu-
tanoate 6 afforded a trace and low yield of the cross-coupled
products 24 and 29, respectively (entries 1 and 7), probably
suggesting that an intramolecular interaction between the
carbonyl group and Rh is essential to induce the reductive
elimination.16
Table 3. Reaction between 1 and Iodoalkane Bearing an Ester
Group 6, 23a,ba
In conclusion, the novel and efficient Rh catalysis of the
cross-coupling of primary alkyl halides with arylzinc com-
pounds possessing carbonyl groups at the ortho position was
disclosed, which provides a facile synthetic method for
polyfunctionalized alkylbenzenes.
Acknowledgment. We are grateful to Prof. Hiroshi
Nakazawa and Dr. Masami Itazaki at Osaka City University
for measurements of HRMS.
yieldb
entry
1
23
24-29
1/%
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
2
3c
4
5
6
7
1a
1a
1a
1j
1k
1c
1a
23a
23b
23b
23b
23b
23b
6
24
25
25
26
27
28
29
0
55 (89)
(92)
57
47
21
OL060969D
(15) As a ligand, BINAP was equally effective, but others such as PPh3
or 1,3-bis(diphenylphosphino)propane were less effective than dppf.
(16) The desired effect not only was limited to â- or γ-carbonyl
substituents in alkyl halides but also included ketone additives in the Ni-
catalyzed cross-coupling between two C sp3 centers: Giovannini, R.;
Studemann, T.; Devasagayaraj, A.; Dussin, G.; Knochel, P. J. Org. Chem.
1999, 64, 3544-3553.
6
a 1 (0.44 mmmol), 23 (0.40 mmol), Rh-dppf (0.04 mmol), and TMU
(0.22 mL) were employed for all entries. b Isolated yield. Yields in
parenthesese determined by GLC. c BINAP was used in place of dppf.
3040
Org. Lett., Vol. 8, No. 14, 2006