Direct synthesis of ferrocenylmethylphosphines from ferrocenylmethyl alcohols and their application as ligands for room temperature Pd(0)-catalyzed Suzuki cross-couplings of aryl bromides

Article abstract of DOI:10.1021/ol0272601

(Matrix presented) The direct, high-yield conversion of readily available ferrocenylmethyl alcohols to ferrocenylmethylphosphines and the application of ferrocenylmethylphosphines as efficient ligands for room temperature Suzuki cross-coupling reaction of aryl bromides with phenylboronic acid are reported. The procedure of directly converting ferrocenylmethyl alcohols to ferrocenylmethylphosphines described here should find applications in the synthesis of many metallocenylmethylphosphines including optically active ones.

Full text of DOI:10.1021/ol0272601

ORGANIC
LETTERS
2003
Vol. 5, No. 3
297-300
Direct Synthesis of
Ferrocenylmethylphosphines from
Ferrocenylmethyl Alcohols and Their
Application as Ligands for Room
Temperature Pd(0)-Catalyzed Suzuki
Cross-Couplings of Aryl Bromides
Zhen-Yu Tang, Yong Lu, and Qiao-Sheng Hu*
Department of Chemistry, College of Staten Island and the Graduate Center of the
City UniVersity of New York, Staten Island, New York 10314
qiaohu@postbox.csi.cuny.edu
Received November 10, 2002
ABSTRACT
The direct, high-yield conversion of readily available ferrocenylmethyl alcohols to ferrocenylmethylphosphines and the application of
ferrocenylmethylphosphines as efficient ligands for room temperature Suzuki cross-coupling reaction of aryl bromides with phenylboronic
acid are reported. The procedure of directly converting ferrocenylmethyl alcohols to ferrocenylmethylphosphines described here should find
applications in the synthesis of many metallocenylmethylphosphines including optically active ones.
The study of using bulky, electron-rich monophosphines as
ligands for transition metal-catalyzed reactions has attracted
much attention in recent years since they have been
demonstrated as unique, highly efficient ligands for a number
of transition metal-catalyzed transformations.1-6 For example,
Fu and others showed that tri-tert-butylphosphine (1) is a
highly efficient ligand for palladium(0)-catalyzed cross-
coupling reactions of Suzuki coupling, Heck coupling, Stille
coupling, and aminations.1,2 Miyaura demonstrated the
uniqueness of 1 for Rh-catalyzed arylation of aldehydes.3
Buchwald and co-workers developed a series of dialkyl-
arylphopshines as represented by 2 for the room temperature
Suzuki cross-coupling reactions and aminations.4 Hartwig
and co-workers showed that ferrocenylphosphines such as
(2) (a) Stambuli, J. P.; Buhl, M.; Hartwig, J. F. J. Am. Chem. Soc. 2002,
124, 9346. (b) Nishiyama M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett.
1998, 39, 617. (c) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy,
K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575. (d)
Shaughnessy, K. H.; Kim, P.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121,
2123. (e) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473.
(f) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am. Chem.
Soc. 1999, 121, 3224.
(1) (a) Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am. Chem. Soc. 2002,
124, 6343. (b) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989.
(c) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020. (d)
Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C. Org. Lett. 2000,
2, 1729. (e) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1999, 38, 2411.
(f) Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10. (g) Littke, A. F.;
Fu, G. C. Angew. Chem., Int. Ed. 1998, 38, 3387.
(3) (a) Ueda, M.; Miyaura, N. J. Org. Chem. 2000, 65, 4450. (b) Sakai,
M.; Ueda, M.; Miyaura, N. Angew. Chem., Int. Ed. 1998, 37, 3279.
10.1021/ol0272601 CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/04/2003

3 are also very effective ligands for arylation and amination
reactions.5 However, only a few examples of electron-rich
monophosphines have been developed to date.1-6 It is thus
of continuing interest to develop new electron-rich mono-
phosphines including optically active ones for transition metal
catalysis.
ferrocenylmethyl alcohols to ferrocenylmethylphosphines in
synthetically useful yields. Achieving this would provide a
highly efficient method to access a large family of potentially
useful ferrocenylmethylphosphines. Herein the direct conver-
sion of ferrocenylmethyl alcohols to ferrocenylmethylphos-
phines and the application of ferrocenylmethylphosphines
as efficient ligands for the room temperature Suzuki cross-
coupling of phenylboronic acid with aryl bromides are
reported.
We began our study by preparing ferrocenylmethyl alco-
hols. Three methods have been used for this purpose: the
procedure developed by Kagan,11 the reaction of ferrocene-
carboxaldehyde or ferrocenyl ketones with aryllithium
reagents,9a and reduction of ferrocenyl ketones.12,13 By
following Kagan’s method, reaction of ferrocene with t-BuLi
in THF at 0 °C followed by treatment with aldehydes or
benzophenone generated alcohols 4 in 33-78% yields, along
with the disubstituted products which are separable from 4
by flash chromatography. Since ferrocenecarboxaldehyde and
ferrocenyl ketones are readily available, we have also
explored their reaction with lithium reagents. This route gave
higher yields than Kagan’s procedure. For example, reaction
of ferrocenecarboxaldehyde or benzoylferrocene with phe-
nyllithium generated 4a and 4b in 91% and 92% yield,
respectively (Scheme 1).
In our efforts to develop highly efficient ligands for
transition metal-catalyzed reactions, we are interested in
developing a system that will allow us to access a family of
monophosphines including optically active ones. We have
elected to synthesize ferrocenylmethylphosphines from fer-
rocenylmethyl alcohols based on the following consider-
ations: (a) ferrocenylmethyl alcohols including optically
active forms are readily available, (b) the unique retentive
SN1 reaction at the R-position would allow the easy access
of a family of ferrocenylmethylphosphines including optically
active ones,7 and (c) the steric and electronic properties of
ferrocenylmethylphosphines can be systematically tuned.
Although directly converting ferrocenylmethyl alcohols to
ferrocenylmethylphosphines is the most efficient way to
synthesize ferrocenylmethylphosphines, this process was only
realized in low yields and has not been established as a
synthetically useful method.8 Instead, indirect methods
involving two or more steps, i.e., converting ferrocenylmethyl
alcohols to ferrocenylmethyl acetates or ferrocenylmethyl-
amines followed by conversion to ferrocenylmethylphos-
phines, have been developed and used.9,10 We reasoned that
if ferrocenylmethyl carbocations, which are involved as the
intermediates in the indirect methods, can be efficiently
formed directly from ferrocenylmethyl alcohols in the
presence of phosphines, it is possible to directly convert
Scheme 1. Synthesis of Ferrocenylmethylphopshines 5
(4) (a) Hamada, T.; Chieffi, A.; Ahman, J.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 1261. (b) Moradi, W. A.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7996. (c) Parrish, C. A.; Buchwald, S. L. J. Org. Chem.
2001, 66, 3820. (d) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.;
Buchwald, S. L. J. Org. Chem. 2000, 65, 1158. (e) Wolfe, J. P.; Singer, R.
A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9550. (f)
Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120,
9722. (g) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1998, 37,
2413. (h) Okazawa, T.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem.
Soc. 2002, 124, 5286.
(5) (a) Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org.
Chem. 2002, 67, 5553. (b) Kawatsura, M.; Hartwig, J. F. J. Am. Chem.
Soc. 1999, 121, 1473. (c) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37,
2046. (d) Hartwig, J. F.; Paul, F. J. Am. Chem. Soc. 1995, 117, 5373. (e)
Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116, 5969.
(6) (a) Schnyder, A.; Indolese, A.; Studer, M.; Blaser, H.-U. Angew.
Chem., Int. Ed. 2002, 41, 3668. (b) Zapf, A.; Ehrentraut, A.; Beller, M.
Angew. Chem., Int. Ed. 2000, 39, 4153.
(7) Togni, A.; Hayashi, T. Ferrocene. Homogeneous Catalysis. Organic
Synthesis. Materials Sciences; VCH: Weinheim, Germany, 1995.
(8) Marr, G.; White, T. M. J. Chem. Soc., Perkin Trans. 1 1973, 1955.
(9) (a) Fukuzawa, S.; Tsuchiya, D.; Sasamoto, K.; Hirano, K.; Ohtaguchi,
M. Eur. J. Org. Chem. 2000, 16, 2877. (b). Watanabe, M. Tetrahedron
Lett. 1995, 36, 8991. (c) Hayashi, T.; Mise, T.; Fukushima, M.; Kagotani;
Nagashima, M.; Hamada, Y.; Matsumoto, A.; Kawakami, S.; Konishi, M.;
Yamamomoto, K.; Kumada, M. Bull. Chem. Soc. Jpn. 1980, 53, 1138.
(10) Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.; Lander, H.; Tijani,
A. J. Am. Chem. Soc. 1994, 116, 4062.
Acetic acid has been demonstrated as a suitable reaction
media (proton source and solvent) for reactions involving
ferrocenylmethyl carbocation intermediates and has been
demonstrated to be compatible with phosphines.9,10,14 For
example, Richards reported the conversion of ferrocenyl-
methyl alcohols to ferrocenylmethyl methyl ethers using
acetic acid as the proton source.14 Togni reported the
synthesis of ferrocenylmethylphosphines from ferrocenyl-
(11) (a) Guillaneux, D.; Kagan, H. B. J. Org. Chem. 1995, 60, 2502. (b)
Rebiere, F.; Samuel, O.; Kagan, H. B Tetrahedron Lett. 1990, 31, 3121.
(12) (a) Schwink, L.; Knochel, P. Chem. Eur. J. 1998, 4, 950. (b) Perea,
J. J. A.; Lotz, M.; Knochel, P. Tetrahedron: Asymmetry 1999, 10, 375. (c)
Sato, H.; Watanabe, H.; Ohtsuka, Y.; Ikeno, T.; Fukuzawa, S.; Yamada, T.
Org. Lett. 2002, 4, 3313.
(13) Wright, J.; Frambes, L.; Reeves, P. J. Organomet. Chem. 1994, 476,
215.
(14) (a) Locke, A. J.; Gouti, N.; Richards, C. J.; Hibbs, D. E.; Hursthouse,
M. B. Tetrahedron 1996, 52, 1461. (b) Locind, A. H.; Richards, C. J.
Tetrahedron Lett. 1996, 37, 7861.
298
Org. Lett., Vol. 5, No. 3, 2003

methylamines in acetic acid.10 Acetic acid was thus selected
as solvent and proton source for the conversion of ferroce-
nylmethyl alcohols 4 to ferrocenylmethylphosphines 5. We
found that 4 smoothly reacted with diphenylphosphine in
acetic acid to afford 5 in 70-85% yields (Scheme 1).
Although the reaction was initially carried out at 60 °C, we
later found the conversion occurred smoothly at room
temperature. As an example, the synthesis of 5a is given
here: under nitrogen, to a solution of 4a (1 mmol) in acetic
acid (8 mL) was added diphenylphosphine (4 mL, 10% in
hexanes) at room temperature. The solution turned from
reddish yellow to yellow immediately and a precipitation,
readily accessible from optically active ferrocenylmethyl
alcohols which are readily available by asymmetric reduction
of ferrocenyl ketones.13 We have carried out the direct
conversion of optically active ferrocenylmethyl alcohol (R)-
4a to optically active bis(ferrocenylmethyl)phosphine (R,R)-6
(Scheme 3). (R)-4a was prepared in 98% ee by the asym-
Scheme 3. Synthesis of Optically Active
Ferrocenylmethylphosphine (R,R)-6
1
which was confirmed as the product by H and 31P NMR,
was observed within 5 min. After the mixture was stirred
for 4 h, the solvent was evaporated and the solid was
collected by filtration and washing with hexanes and
methanol. After the solid was dried under vacuum, 5a was
obtained as a yellow solid in 83% yield. The 31P NMR
spectrum of 5a shows a singlet at 4.8 ppm (H3PO4 as
standard). Other ferrocenylmethylphosphines 5b-d were
prepared in a similar manner. 5a-d are air-stable solids, but
can be gradually oxidized in solution under air.
When 4a reacted with di-tert-butylphosphine, trialkylphos-
phine 5e was obtained (Scheme 1). Like other trialkylphos-
phines, 5e is air-sensitive. For easy handling, 5e was
protected as the 5e‚BH3 complex.15,16
The successful realization of diphenylphosphine with
ferrocenylmethyl alcohols to form ferrocenylmethylphos-
phines in high yields encouraged us to synthesize bis-
(ferrocenylmethyl)phosphines such as 6 directly from fer-
rocenylmethyl alcohols.8 Thus, reaction of 4a with phenyl-
phosphine in acetic acid at room temperature smoothly
yielded 6 as a yellow solid in 83% (Scheme 2). The 31P NMR
metric reduction with (S)-methyl oxazaborolidine (CBS) as
the chiral catalyst.13 When (R)-4a was treated with phe-
nylphosphine in acetic acid at room temperature, (R,R)-6 was
obtained in 80%. The 31P NMR spectrum of (R,R)-6 shows
a predominant singlet at 17.4 ppm and a minor peak at 19.2
ppm in a 53:1 ratio. The ratio corresponds to a 99% portion
of (R)-ferrocenylmethyl and a 1% portion of (S)-ferrocenyl-
methyl based on the assumption that the initially formed
chiral (ferrocenylphenylmethyl)phenylphosphines further re-
Table 1. Room Temperature Pd(0)-Catalyzed Suzuki
Cross-Coupling Reaction of Aryl Bromides with Phenylboronic
Acida
Scheme 2. Synthesis of Bis(ferrocenylmethyl)phosphine 6
spectrum of 6 showed two singlets at 17.4 and 19.2 ppm,
corresponding to the two isomers (R,R/S,S and R,S). The
almost 1:1 ratio of the two singlets suggests that the initially
formed chiral (ferrocenylphenylmethyl)phenylphosphines
further react with (R)- or (S)-ferrocenylmethyl alcohol 4a at
similar rates.
It has been established that the nucleophilic substitution
at the R-position of the ferrocenyl group is configurationally
retentive.17 This unique retentive SN1 reaction pattern implies
that optically active ferrocenyl monophosphines could be
a Reaction conditions: aryl bromide (1.0 equiv), phenylboronic acid (1.5
equiv), KF (3 equiv), ligand (1-2%), THF (2 mL), room temperature.
Reaction times have not been minimized.
(15) Mckinstry, L.; Livinghouse, T. Tetrahedron 1995, 51, 7655.
(16) Recently, Fu reported the use of HBF4 as a protection reagent:
Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
(17) Reference 8, Chapter 4, p 173. See also: refs 10 and 12a,b.
Org. Lett., Vol. 5, No. 3, 2003
299

act with (R)- or (S)-4a at the same rates. Therefore, the
conversion of (R)-4a to (R,R)-6 is not accompanied by
racemization.
aryl bromides including electron-rich ones and phenylboronic
acid. The cross-coupling reaction of less active p-chloroani-
sole with phenylboronic acid catalyzed by 2% 5a/Pd(OAc)2
(1:1 or 2:1) was also carried out and no reaction was
observed.
Pd(0)-catalyzed Suzuki cross-coupling reactions of aryl
halides with arylboronic acids represent one of the most
powerful transformations in organic synthesis.18 Among
numerous protocols developed, relatively few examples of
Suzuki cross-coupling reactions of aryl bromides occur at
room temperature and most of them involve the use of dialkyl
or trialkyl monophosphines as ligands.19 We have employed
monoalkylphosphines 5a-c, which are less electron-rich than
dialkyl or trialkyl monophosphines, as ligands for the room
temperature Suzuki cross-coupling reactions of aryl bro-
mides. Our results showed that these ferrcenylmethylphos-
phines are highly efficient ligands for this transformation.
As shown in Table 1, (1-2%) 5a-c/Pd(0) complexes (1:1
or 2:1) can smoothly catalyze the coupling reaction between
In summary, we have demonstrated that ferrocenylmeth-
ylphosphines including monoalkyl, dialkyl, and trialkyl ones
can be directly synthesized in high yields from readily
available ferrocenylmethyl alcohols. Monoalkyl ferrocenyl-
methylphosphines have been used as efficient ligands for
room temperature Suzuki cross-coupling reaction of aryl
bromides with phenylboronic acid. The method of directly
converting ferrocenylmethyl alcohols to ferrocenylmeth-
ylphosphines should find applications in the synthesis of
many ferrocenylmethylphosphines and metallocenylmeth-
ylphosphines, including optically active ones. The synthesis
and application of these monophosphines are under active
investigation and the results will be reported in due course.
(18) For recent reviews: (a) Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz,
E.; Lemaire, M. Chem. ReV. 2002, 102, 1359. (b) Suzuki, A. J. Organomet.
Chem. 1999, 576, 147. (c) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95,
2457.
Acknowledgment. This work was supported by the
Department of Chemistry, College of Staten Island-City
University of New York (CUNY). Partial support from the
Petroleum Research Fund administered by the American
Chemical Society and Professional Staff Congress-CUNY
Research Award Programs is gratefully acknowledged.
(19) (a) Colacot, T. J.; Gore, E. S.; Kuber, A. Organomettallics 2002,
21, 3301. (b) Rocaboy, C.; Gladysz, J. A. Tetrahedron 2002, 58, 4007. (c)
Zim, D.; Gruber, A. S.; Ebeling, G.; Dupont, J.; Monteiro, A. L. Org. Lett.
2000, 2, 2881-2884. (d) Bussolari, J. C.; Rehborn, D. C. Org. Lett. 1999,
1, 965. (e) Uozumi, Y.; Danjo, H.; Hayashi, T. J. Org. Chem. 1999, 64,
3384. (f) Kamatani, A.; Overman, L. E. J. Org. Chem. 1999, 64, 8743. (g)
Bussolari, J. C.; Rehborn, D. C. Org. Lett. 1999, 1, 965. (h) Albisson, D.
A.; Bedford, R. B.; Lawrence, S. E.; Scully, P. N. Chem. Commun. 1998,
2095. (i) Anderson, J. C.; Namli, H.; Roberts, C. A. Tetrahedron 1997, 53,
15123. (j) Johnson, C. R.; Johns, B. A. Synlett 1997, 1406. (k) Bumagin,
N. A.; Bykov, V. V. Tetrahedron 1997, 53, 14437. (l) Campi, E. M.;
Jackson, W. R.; Marcuccio, S. M.; Naeslund, C. G. M. J. Chem. Soc., Chem.
Commun. 1994, 2395. Also see refs 1, 2, 4, and 5.
Supporting Information Available: Synthesis of 4, 5,
and 6, and procedure for the Suzuki cross-couplings. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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