An Improved Synthesis of Functionalized Biphenyl-Based Phosphine Ligands

Article abstract of DOI:10.1021/jo000691h

Functionalized dicyclohexyl- and di-tert-butylphosphinobiphenyl ligands are prepared by the reaction of arylmagnesium halides with benzyne, followed by the addition of a chlorodialkylphosphine. This one-pot procedure is considerably less expensive and time-consuming than the method used previously to prepare such ligands. The cost of introducing the dicyclohexylphosphine group can be decreased by preparing chlorodicyclohexylphosphine from PCl₃ and cyclohexylmagnesium chloride, and using the reagent without further purification. The new method is significant, as a variety of ligands can be produced in useful amounts by a procedure that is simple, with starting materials that are relatively inexpensive, and, in most cases, without chromatographic purification.

Full text of DOI:10.1021/jo000691h

5334
J . Org. Chem. 2000, 65, 5334-5341
An Im p r oved Syn th esis of F u n ction a lized Bip h en yl-Ba sed
P h osp h in e Liga n d s
Hiroshi Tomori, J oseph M. Fox, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received May 5, 2000
Functionalized dicyclohexyl- and di-tert-butylphosphinobiphenyl ligands are prepared by the reaction
of arylmagnesium halides with benzyne, followed by the addition of a chlorodialkylphosphine. This
one-pot procedure is considerably less expensive and time-consuming than the method used
previously to prepare such ligands. The cost of introducing the dicyclohexylphosphine group can
be decreased by preparing chlorodicyclohexylphosphine from PCl3 and cyclohexylmagnesium
chloride, and using the reagent without further purification. The new method is significant, as a
variety of ligands can be produced in useful amounts by a procedure that is simple, with starting
materials that are relatively inexpensive, and, in most cases, without chromatographic purification.
We recently reported that aminophosphine 1, when
be more readily available. Thus, the discovery that Pd-
catalysts based on ligands 3 and 4 are also highly active
in Suzuki8,9 and amination8,10 reactions was of consider-
able importance, since these can be prepared in one step
from 2-bromobiphenyl and are now commercially avail-
able.11 The scope of substrates that can be coupled by
Pd-catalysts that employ 3 and 4 is large, and in many
instances, the utility of these ligands equals or is superior
to that of 1.8-10 For example, in amination and Suzuki
coupling reactions that are conducted at room tempera-
ture, catalysts from ligand 4 are more active than those
based on 1.8-10 However, 1 cannot be substituted by 3 or
4 for every substrate combination. Thus, for Suzuki
combined with a source of Pd, gives an exceptional
catalyst for the amination1 and Suzuki coupling2 reac-
tions of aryl chlorides and bromides.3,4 The catalyst based
on 1 could transform aryl bromides or an activated aryl
chloride to arylamines at room temperature, and it was
the first catalyst that was useful for the amination
reactions of electron-rich aryl chlorides. The activity of
the catalyst for Suzuki coupling reactions was also
unprecedented: even electron-rich aryl chlorides and aryl
bromides could be coupled with arylboronic acid deriva-
tives at room temperature.3,5 Preliminary experiments
further indicated that 1 would be a useful ligand for Pd-
catalyzed formation of R-aryl ketones.3,6,7 For the first
time, an aryl chloride was used in a ketone arylation
reaction, and an aryl bromide could be coupled with a
ketone at room temperature.3
(5) For other reports on the Suzuki reactions of aryl chlorides, see
(a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37, 3387. (b)
Beller, M.; Fischer, H.; Herrmann, W. A.; O¨ fele, K.; Brossmer, C.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1848. (c) Herrmann, W. A.;
Reisinger, C.-P.; Spiegler, M. J . J . Organomet. Chem. 1998, 557, 93.
(d) Weskamp, T.; Bo¨hm, V. P. W.; Herrmann, W. A. J . Organomet.
Chem. 1999, 585, 348. (e) Zhang, C.; Huang, J .; Trudell, M. L.; Nolan,
S. P. J . Org. Chem. 1999, 64, 3804. (f) Zhang, C.; Trudell, M. L.
Tetrahedron Lett. 2000, 41, 595. (g) Shen, W. Tetrahedron Lett. 1997,
38, 5575. (h) Firooznia, F.; Gude, C.; Chan, K.; Satoh, Y. Tetrahedron
Lett. 1998, 39, 3985. (i) Bei, X.; Turner, H. W.; Weinberg, H.; Guram,
A. S.; Peterson, J . L. J . Org. Chem. 1999, 64, 6797. (j) Bei, X.; Crevier,
T.; Guram, A. S.; J andeleit, B.; Powers, T. S.; Turner, H. W.; Uno, T.;
Weinberg, W. H. Tetrahedron Lett. 1999, 40, 3855. (k) Littke, A. F.;
Dai, C.; Fu, G. C. J . Am. Chem. Soc. 2000, 122, 4020.
(6) For earlier reports on the Pd-catalyzed intermolecular R-aryla-
tion of ketones, see (a) Palucki, M.; Buchwald, S. L. J . Am. Chem. Soc.
1997, 119, 11108. (b) Hamann, B. C.; Hartwig, J . F. J . Am. Chem.
Soc. 1997, 119, 12382. (c) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura,
M. Angew. Chem., Int. Ed. Engl. 1997, 36, 1740. (d) Hou, D.; Mas, J .
L. U.S. Patent, 4992591, 1991. Chem. Abstr. 1991, 115, 28927z. For
more recent reports, see ref 12, and (e) Satoh, T.; Inoh, J .-i.; Kawamura,
Y.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. J pn. 1998,
71, 2239. (f) Kawatsura, M.; Hartwig, J . F. J . Am. Chem. Soc. 1999,
121, 1473.
(7) For the asymmetric Pd-catalyzed R-arylation of ketones, see (a)
Åhman, J .; Wolfe, J . P.; Troutman, M. V.; Palucki, M.; Buchwald, S.
L. J . Am. Chem. Soc. 1998, 120, 1918. For the Pd-catalyzed asymmetric
R-vinylation of ketones, see (b) Chieffi, A.; Kamikawa, K.; Åhman, J .;
Buchwald, S. L., submitted.
(8) Wolfe, J . P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38,
2413.
(9) Wolfe, J . P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J . Am.
Chem. Soc. 1999, 121, 9550.
(10) Wolfe, J . P.; Tomori, H.; Sadighi, J . P.; Yin, J .; Buchwald, S. L.
J . Org. Chem. 2000, 65, 1158.
Although the Pd-catalyst derived from 1 was, at the
time of publication, the most active catalyst for amination
and Suzuki reactions, its usefulness was limited because
four steps were required to prepare it (Scheme 1).3
Accordingly, efforts were focused on the synthesis of
ligands that would function as efficiently as 1, but would
(1) For reviews on Pd-catalyzed amination, see (a) Yang, B. H.;
Buchwald, S. L. J . Organomet. Chem. 1999, 576, 125. (b) Hartwig, J .
F. Angew. Chem., Int. Ed. 1998, 37, 2046. (c) Wolfe, J . P.; Wagaw, S.;
Marcoux, J .-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805.
(2) Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F.; Stang, P. J ., Eds.; Wiley-VCH: Weinheim, Germany,
1998; Ch. 2.
(3) Old, D. W.; Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc. 1998,
120, 9722.
(4) For other reports on the amination reactions of aryl chlorides,
see (a) Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998,
39, 617. (b) Yamamoto, M.; Nishiyama, M.; Koie, Y. Tetrahedron Lett.
1998, 39, 2367. (c) Reddy, N. P.; Tanaka, M. Tetrahedron Lett. 1997,
38, 4807. (d) Hamann, B. C.; Hartwig, J . F. J . Am. Chem. Soc. 1998,
120, 7369. (e) Bei, X.; Guram, A. S.; Turner, H. W.; Weinberg, W. H.
Tetrahedron Lett. 1999, 40, 1237. (f) Bei, X.; Uno, T.; Norris, J .; Turner,
H. W.; Weinberg, W. H.; Guram, A. S.; Peterson, J . L. Organometallics
1999, 18, 1840. (g) Riermeier, T. H.; Zapf, A.; Beller, M. Top. Catal.
1997, 4, 301, and references therein. (h) Huang, J .; Grasa, G.; Nolan,
S. P. Org. Lett. 1999, 1, 1307. For a recent report of room-temperature
Pd-catalyzed amination reactions of aryl bromides and aryl chlorides
using P(t-Bu)3, see (i) Hartwig, J . F.; Kawatsura, M.; Hauck, S. I.;
Shaughnessy, K. H.; Alcazar-Roman, L. M. J . Org. Chem. 1999, 64,
5575.
(11) Ligands 1, 3, and 4 are commercially available from Strem
Chemical Co.
10.1021/jo000691h CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/02/2000

Biphenyl-Based Phosphine Ligands
J . Org. Chem., Vol. 65, No. 17, 2000 5335
Sch em e 1
reactions of some sterically hindered substrates, and for
the catalytic N-arylation of acyclic dialkylamines, cata-
lysts derived from 3 or 4 are less useful than those from
1.8-10 In these cases, catalysts based on 5 and 7 function
similarly to the catalysts from 1.8-10 For the R-arylation
of ketones, the most active catalysts that have been
reported to date are obtained when 1, 5, or 7 is combined
with Pd(OAc)2.12 While these catalysts are selective for
a broad range of substrates, in most cases, catalysts
based on either 3 or 4 were less useful.12 Our group has
also shown that the N-arylation of indoles can be ac-
complished with the Pd-catalysts derived from 1, 3, 4, 8,
9 and from a related ligand with a binaphthyl core.13,14
It is necessary to have access to all of these phosphines
in order to effectively couple a large number of function-
alized aryl halides and indoles, as the selection of the
optimal ligand is dependent on the substrates that are
reacted. Similarly, for the Pd-catalyzed formation of
diaryl ethers, several biphenyl-derived ligands, including
2 and 4, must be employed in order to effectively couple
a range of aryl halides and phenols.15,16
benzyne in the presence of an arylmagnesium halide
or an aryllithum;17 cine-addition of the organometallic
species to benzyne produces an ortho-metalated biphenyl
derivative, which can subsequently react with an
electrophile (eq 1).18 We hypothesized that, if a dialkyl-
chlorophosphine were used the electrophile, the reaction
depicted in eq 1 would be well suited for the preparation
of biphenyl-based phosphine ligands, as the precursors
for benzyne and the required aryl Grignard or aryllithium
reagents are inexpensive. We report here the realization
of this possibility: a one-pot process that utilizes aryl-
magnesium reagents and benzyne that is prepared in situ
from 1-bromo-2-chlorobenzene and magnesium. The
method is applied to the synthesis of phosphine ligands
1, 2, and 5-9, and to the preparation of a number of new,
structurally related ligands. Although the yields for these
reactions are modest (18-59%), 11 of the 13 phosphines
that are synthesized can be purified without chromatog-
raphy, and therefore substantial quantities of these
ligands can be obtained with little time, cost, or effort.
Furthermore, it is shown that chlorodicyclohexylphos-
phine can be made from PCl3 and cyclohexylmagnesium
chloride and used without purification to prepare 1 and
5 in a yield similar to that obtained with pure (and more
costly) chlorodicyclohexylphosphine.
Phosphines 2 and 5-9 were originally synthesized by
methods analogous to that used to prepare 1 (Scheme
1),8-10,12,13,15 and although the syntheses of 5-9 were
shorter than those of 1 or 2, their utility was still
compromised by the requirement of two- to three-step
preparations. Thus, a concise route to ligands 1, 2, and
5-9 was necessary. Ideally, the syntheses would require
only one reaction vessel, use precursors that are inex-
pensive, and be amenable to application on a large scale.
Furthermore, it would be advantageous if the method
could be applied to the synthesis of new biphenyl-based
phosphine ligands, since, as is noted above, subtle
changes of the structure of the ligands can dramatically
alter their reactivity.
Resu lts a n d Discu ssion
Three strategies for the synthesis of biaryls via a
benzyne intermediate were considered (Scheme 2). A
well-precedented method is to generate benzyne by
dehydrohalogenation of an aryl halide, followed by ad-
dition of an aryllithium (Scheme 2, route A).17b,18,19
Alternatively, benzyne can be prepared by metal-
halogen exchange of an o-dihalobenzene with an aryl-
lithium or arylmagnesium halide, followed by the addi-
(17) The formation of biphenyls from arylmetals and benzyne dates
back to experiments that were conducted in a retort by Fittig: (a)
Fittig, R. Ann. 1864, 132, 202. For a discussion of the history of benzyne
chemistry, see pp 1-8 of (b) Hoffmann, R. W. Dehydrobenzene and
Cycloalkynes; Academic Press: New York, 1967.
(18) For reviews, see Ch 2 of ref 17b and (a) Sharp, J . T. In
Comprehensive Organic Chemistry; Barton, D., Ollis, W. D., Stoddart,
J . F., Eds., Pergamon Press: Oxford, 1979; Vol. 1, p 455. (b) Gilchrist,
T. L. In The Chemistry of Functional Groups; Patai, S., Rappoport, Z.,
Eds., Wiley: Chichester, 1983, Suppl. C, part 1, Chapter 11. (c)
Grundmann, C. In Methoden der Organischen. Chemie (Houben-Weyl);
Mu¨ller, E., Bayer, O., Ed., Thieme: Stuttgart, New York, 1981, Board
5/2b, pp 613-515. (d) Kessar, S. V. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Semmelhack, M. F., Eds., Perga-
mon Press: Oxford, 1991; Vol. 4, Chapter 2.3. (e) Huisgen, R.; Sauer,
J . Angew. Chem. 1960, 72, 91.
The need to improve the syntheses of these ligands
prompted us to survey the known procedures for biphenyl
synthesis. One of the oldest methods is to generate
(12) Fox, J . M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J . Am. Chem.
Soc. 2000, 122, 1360.
(13) Old, D. W.; Harris, M. C.; Buchwald, S. L. Org. Lett., in press.
(14) For other reports on the Pd-catalyzed formation of N-aryl
indoles, see ref 4i, and Mann, G.; Hartwig, J . F.; Driver, M. S.;
Ferna´ndez-Rivas, C. J . Am. Chem. Soc. 1998, 120, 827.
(15) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J . P.; Sadighi, J .
P.; Buchwald, S. L. J . Am. Chem. Soc. 1999, 121, 4369.
(16) For an additional report on the Pd-catalyzed formation of diaryl
ethers, see: Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J . F.
J . Am. Chem. Soc. 1999, 121, 3224.
(19) (a) Wittig, G.; Pieper, G.; Fuhrmann, G. Chem. Ber. 1940, 73,
1193. (b) Wittig, G.; Merkle, W. Chem. Ber. 1942, 75, 1491. (c) Huisgen,
R.; Rist, H. Liebigs Ann. Chem. 1955, 594, 137. (d) Wittig, G.; Pohmer,
L. Chem. Ber. 1956, 89, 1334.

5336 J . Org. Chem., Vol. 65, No. 17, 2000
Tomori et al.
Sch em e 2
tion of a second equivalent of the organometal (Scheme
Initially, experiments were conducted so that the
synthesis of ligand 1 could be optimized (eq 2). Thus,
20
2, route B).17b,18
Both of these approaches require at
least 2 equiv of an organometallic reagent,21 and in order
for the latter method to work efficiently with aryl
Grignard reagents, it is necessary to use an expensive
o-iodohalobenzene derivative.20e A more economical way
to prepare biphenyls would be to combine equal amounts
of magnesium, an aryl Grignard reagent, and an o-dihalo-
benzene (Scheme 2, route C). Unexpectedly, we could
find only one example of such a reactionsthat of 2-fluoro-
phenylmagnesium bromide with benzyne generated from
the same reagentsand it occurred in low yield.24 Also
surprising is that the combination of magnesium and
2-bromochlorobenzene is almost never used to generate
benzyne, despite the frequent use of more expensive
2-bromofluorobenzene for this purpose.25 The probable
reason is that, in an early study on the reactivity of
benzyne with furan, Wittig and Pohmer suggested that
2-chlorophenylmagnesium bromide decomposes only slowly
to benzyne in refluxing THF.26 However, more recent
studies by Hart showed that derivatives of 2-chloro-
phenylmagnesium bromide (formed by metal-halogen
exchange) do form benzyne derivatives in refluxing
THF, and that products from subsequent addition of a
Grignard reagent to the benzyne can be prepared.27 In
the present work, we show that the combination of an
arylmagnesium halide, 2-bromochlorobenzene, and mag-
nesium does indeed provide an inexpensive route to
derivatives of o-biphenylmagnesium halides and that
these can be converted into a series of phosphine ligands
in useful yields.
magnesium (2 equiv), 2-bromo-N,N-dimethylaniline
(1 equiv), and an internal standard were heated in
THF at 60 °C until formation of the Grignard reagent
was complete. 2-Bromochlorobenzene was then added,
and heating at 60 °C was continued. After 1, 2, 3, and
4 h, aliquots were taken from the reaction mixture,
quenched with methanol, and analyzed by GC/MS and
GC. The major product of the reaction was 10, and it was
formed in highest yield (66%) after 2 h. At this time, the
yield of chlorobenzene was determined to be <2%,
indicating that consumption of 2-chlorophenylmagnesium
bromide was almost complete. After 3 and 4 h, the yield
of 10 was measured to be 55% and 56%, respectively. The
major byproduct of this reaction was determined by
GC/MS to be a terphenyl derivative, presumably 11,
which could arise from the addition of 2-(2-dimethyl-
aminophenyl)phenylmagnesium bromide to benzyne.28
After 2 h, the ratio of 10:11 was determined to be 11:1.
In a similar experiment, in which 1.2 equiv of 2-di-
methylaminophenylmagnesium bromide were used, 10
was produced in 76% yield, and only a relatively small
amount of 11 was formed (the ratio of 10: 11 was 25:1).
Again, the yield of 10 was lower if the reaction time was
increased. Thus, in subsequent experiments, the aryl-
magnesium halide and 2-chlorobromobenzene were used
in a 1.2:1 ratio, and reactions were allowed to proceed
for 2 h.
At this time, we found that 2-chloro-N,N-dimethyl-
aniline is commercially available, and it was therefore
used instead of 2-bromo-N,N-dimethylaniline in subse-
quent experiments. The Grignard reagent of 2-chloro-
N,N-dimethylaniline was formed using 1,2-dibromo-
ethane to activate the magnesium.29 Phosphine ligand 1
was obtained in 50% yield when 2-bromochlorobenzene
was added to magnesium and the Grignard reagent and
subsequently allowed to react with CuCl30 and ClPCy2
(Table 1, entry 1). It is notable that, in a single 250 mL
round-bottom flask and without the need for chromatog-
(20) (a) Wittig, G.; Fuhrmann, G. Chem. Ber. 1940, 73, 1197. (b)
Hellwinkel, D. Chem. Ber. 1966, 99, 3642. (c) Hellwinkel, D.; Knabe,
B. Chem. Ber. 1971, 104, 1761. (d) Hellwinkel, D.; Reiff, G.; Nykodym,
V. Liebigs Ann. Chem. 1977, 1013. (e) Hart, H.; Harada, K.; Du, C.-J .
F. J . Org. Chem. 1985, 50, 3104.
(21) For routes A and B of Scheme 2, the organometallic reagent
that is the nucleophile is also used for the dehydrohalogenation or for
the metal halogen exchange.17b,18 However, it is also possible to use
inexpensive organometallic reagents such as n-BuLi22 or vinylmagne-
sium bromide23 for the metal-halogen exchange reaction, with sub-
sequent capture of benzyne by an aryllithium or arylmagnesium halide,
respectively. The use of vinylmagnesium bromide is of significant value
when the arylmagnesium halides are expensive.23
(22) Gilman, H.; Gorsich, R. D. J . Am. Chem. Soc. 1956, 78, 2217.
(23) (a) Vinod, T.; Hart, H. J . Org. Chem. 1990, 55, 881. (b) Grewal,
R. S.; Hart, H.; Vinod, T. J . Org. Chem. 1992, 57, 2721. (c) Hart, H.;
Rajakumar, P. Tetrahedron 1995, 51, 1313.
(24) Bartle, K. D.; Heaney, H.; J ones, D. W.; Lees, P. Tetrahedron
1965, 21, 3289.
(25) See Ch 1 of ref 17b. For a specific example, see Wittig, G.
Organic Syntheses; Wiley: New York, 1963; Collect. Vol. IV, p 964.
(26) Wittig and Pohmer compared the reactions of o-fluorophenyl-
magnesium bromide and o-chlorophenylmagnesium bromide with
furan in refluxing THF. After 1 h and treatment with 5 N HCl, the
former reaction produced R-naphthol in 54% yield and gave no
fluorobenzene; the latter reaction gave R-naphthol in 11% yield and
chlorobenzene in 55% yield. After 5 weeks, 1,4-dihydronaphthalene-
1,4-endoxide was isolated in 40% yield from the latter reaction. See
ref 19d.
(28) The formation of terphenyls from the reaction of 2 equiv of
benzyne with 1 equiv of an arylmetal is well-known. For examples,
see refs 22, 24, and Wittig, G.; Hellwinkel, D. Chem. Ber. 1964, 97,
769.
(27) (a) Du, C.-J . F.; Hart, H.; Ng, K.-K. D. J . Org. Chem. 1986, 51,
3162. (b) Ghosh, T.; Hart, H. J . Org. Chem. 1988, 53, 3555. (c) Saednya,
A.; Hart, H. Synthesis 1996, 1455.
(29) Lai, Y.-H. Synthesis 1981, 585.

Biphenyl-Based Phosphine Ligands
J . Org. Chem., Vol. 65, No. 17, 2000 5337
Ta ble 1. Syn th esis of Electr on -r ich P h osp h in e Liga n d s w ith Bip h en yl Ba ck bon esa
a
Yields are based on the use of 2-bromochlorobenzene as the limiting reagent. Reactions with ClPCy2 were conducted at room
temperature. Those with ClP(t-Bu)2 were conducted at 60 °C. 50 mmol scale using 1.2 equiv of ClPCy2. c 1.3 equiv of arylmagnesium
chloride were used. ClPCy2 was prepared from PCl3 and cyclohexylmagnesium chloride and used without further purification.
b
d
raphy, 9.8 g of ligand 1 was prepared. Since the develop-
ment of this protocol, ligand 1 has become commercially
available.11 To make the synthesis of 1 even less costly,
we prepared chlorodicyclohexylphosphine from cyclo-
hexylmagnesium chloride and PCl3, both of which are
inexpensive. Without further purification, the crude
ClPCy2 was employed, and the yield of the reaction was
similar (52%) to that obtained when pure ClPCy2 is used
(Table 1, entry 2).
butylphosphinobiphenyl derivatives can also be prepared
by the method introduced here (Table 1, entries 3, 5, 7,
8, and 11). A temperature of 60 °C is needed for the
reaction with di-tert-butylchlorophosphine to be efficient,
whereas the reactions with chlorodicyclohexylphosphine
proceeded smoothly at room temperature. In the prepa-
rations of the di-tert-butylphosphino derivatives, quater-
phenyl byproducts were detected by GC/MS. Although
full characterization was not pursued, it is likely that
these byproducts have structure 18, and are formed by
The conditions that were used to make 1 could be
applied to the synthesis of a variety of phosphine ligands
(Table 1). As for synthesis of 1, unpurified chlorodicyclo-
hexylphosphine was used to prepare 5, and the material
was obtained in 58% yield (Table 1, entry 4). 2-Di-tert-
(30) Ligand 4 is obtained in highyield when Cu(I)Cl is added to the
reaction of biphenyl-2-ylmagnesium bromide and di-tert-butylchloro-
phosphine. Much lower yields are obtained when CuCl is omitted.15

5338 J . Org. Chem., Vol. 65, No. 17, 2000
Tomori et al.
temperature for 9 h. The resulting suspension was poured
into a flask containing hexane:EtOAc (1:1, 700 mL), 30%
aqueous NH4OH (500 mL), and brine (500 mL). The mixture
was stirred at room temperature for 10 min and transferred
to a separatory funnel. The layers were separated, and the
organic phase was sequentially washed with 30% aqueous
NH4OH (100 mL × 3) and brine (100 mL), dried over
anhydrous MgSO4, filtered, and concentrated. To the residual
solid was added EtOAc:MeOH (1:6, 175 mL), and the resulting
suspension was stirred and cooled in an ice bath for 0.5 h. The
solid was collected by filtration, and the damp solid was
slurried with 1:6 EtOAc:MeOH (70 mL) in an ice bath for 1 h.
Filtration, washing with cold MeOH (20 mL), and drying in
vacuo gave 9.77 g (50% yield) of the title compound as a white
solid. A similar experiment that was carried out on a 5.00
mmol scale gave 1.08 g (55%) of the title compound. Mp: 116-
118 °C (lit.3 110 °C): 1H NMR (300 MHz, CDCl3) δ 7.54 (d,
1H, J ) 6.9 Hz), 7.42-7.24 (m, 4H), 7.08-6.93 (m, 3H), 2.44
(s, 6H), 2.10-1.93 (m, 1H), 1.97-0.68 (m, 21H); 13C NMR (75
MHz, CDCl3) δ 151.4 (d, J CP ) 1.9 Hz), 149.6 (d, J CP ) 30.7
Hz), 135.9 (d, J CP ) 5.4 Hz), 135.3 (d, J CP ) 20.1 Hz), 132.8
(d, J CP ) 3.8 Hz), 132.4, 130.5 (d, J CP ) 6.3 Hz), 128.6, 128.2,
125.9, 120.8, 117.3, 43.4, 36.8 (d, J CP ) 15.7 Hz), 33.5 (d, J CP
) 14.2 Hz), 31.0 (d, J CP ) 15.8 Hz), 30.7 (d, J CP ) 19.8 Hz),
the homocoupling reaction of the biphenyl-2-ylmagne-
sium halides. Consequently, when ClP(t-Bu)2 was used,
the yields were lower than those obtained with ClPCy2.
Nonetheless, the scope of the method is quite broad, and
even phosphines that are very sterically encumbered can
be obtained in useful yields (Table 1, entries 10, 11, and
14). Of importance is that only one reaction vessel is
required for each of the preparations described in Table
1 and that chromatography is required only for the
purification of 9 and 14; the other 11 ligands can be
obtained in pure form by crystallization. Because the
synthesis of the ligands is so straightforward, any of the
protocols that utilize them is considerably more practical
than before. Furthermore, since the scope of the method
introduced here is broad, it should be valuable for
the design and rapid synthesis of new ligands, and
consequently, for the development and optimization of
Pd-catalyzed processes.
Con clu sion s
Functionalized dialkylphosphinobiphenyl ligands were
prepared by the addition of arylmagnesium halides to
benzyne, followed by reaction with dialkylchlorophos-
phines. This one-pot method is significantly less expen-
sive and time-consuming than the route used previously
to access such ligands. For the synthesis of phosphines
1 and 5, it is shown that the cost of synthesis can be
reduced further by preparing ClPCy2 from PCl3 and
cyclohexylmagnesium chloride and by using the reagent
without further purification.
29.9 (d, J CP ) 13.0 Hz), 28.6 (d, J CP ) 4.5 Hz), 27.8 (d, J CP
)
15.2 Hz), 27.8, 27.7, 27.5 (d, J CP ) 11.5 Hz), 26.9, 26.6; 31P
NMR (121 MHz, CDCl3) δ -8.7; IR (neat, cm-1) 2923, 2850,
2821, 2771, 1495, 1443, 1426, 947.
Syn th esis of 1 Usin g Un p u r ified Ch lor od icycloh exyl-
p h osp h in e (Table 1, Entry 2). An oven-dried 50 mL Schlenk
tube was capped with a rubber septum, evacuated, backfilled
with argon, and then charged with PCl3 (0.65 mL, 7.5 mmol)
and diethyl ether (15 mL). The solution was cooled to -40 °C
and cyclohexylmagnesium chloride in diethyl ether [prepared
from cyclohexyl chloride (2.0 mL, 17 mmol) and magnesium
turnings (0.39 g, 16 mmol) in diethyl ether (8 mL)] was added
dropwise over 15 min. During the addition, a white solid
(MgCl2) precipitated. The mixture was warmed to 0 °C over 2
h, and the solid material was removed with a Schlenk filter
and washed with diethyl ether (5 mL) under an argon
atmosphere. The filtrate and washing were combined and
concentrated in vacuo to give a colorless oil that was diluted
with THF (5 mL) and used directly in the reaction described
below.
A 25 mL Schlenk tube was charged with magnesium
turnings (304 mg, 12.5 mmol) and capped with a rubber
septum. 2-Chloro-N,N-dimethylaniline (1.06 g, 6.50 mmol), and
THF (10 mL) were then added via syringe, and the mixture
was heated to reflux. At this point, 1,2-dibromoethane (86 µL,
1.0 mmol) was added dropwise via syringe over 1 h,31 and
the mixture was refluxed for 40 h, and subsequently cooled
to 60 °C. 2-Bromochlorobenzene (584 µL, 5.00 mmol) was
added dropwise, and the resulting mixture was heated for
2 h in an oil bath at 60 °C. The mixture was then cooled to
room temperature, the septum was removed, and anhydrous
copper(I) chloride (0.50 g, 5.0 mmol) was added. The septum
was then replaced and the tube purged with argon for 1 min.
The solution of unpurified ClPCy2 in THF was added dropwise
with a syringe, and the mixture was stirred overnight at
ambient temperature. The resulting suspension was poured
into a flask containing hexane:EtOAc (1:1, 50 mL), 30%
aqueous NH4OH (50 mL), and brine (25 mL). The mixture was
stirred at room temperature for 5 min and transferred to a
separatory funnel. The layers were separated and organic
phase was sequentially washed with 30% aqueous NH4OH (25
Exp er im en ta l Section
Gen er a l Con sid er a tion s. All of reactions were carried out
under an argon atmosphere in glassware that had been dried
in an oven and cooled under argon. Elemental analyses were
performed by Atlantic Microlabs Inc, Norcross, GA. Toluene
was distilled under nitrogen from molten sodium. THF was
distilled under argon from sodium benzophenone ketyl. Aryl
halides were purchased from commercial sources and were
used without further purification. 2-Chloro-N,N-dimethyl-
aniline (95.5% chemical purity; the impurity was characterized
by GC/MS as 2-chloro-N-methylaniline) was purchased from
Karl Industries Inc (Aurora, OH) and was used without further
purification. Magnesium turnings were purchased from
Mallinckrodt. Di-tert-butylchlorophosphine was purchased
from either Aldrich Chemical Co. or Strem Chemicals, Inc.
Copper(I) chloride and chlorodicyclohexylphosphine were pur-
chased from Strem Chemicals, Inc. Phosphorus trichloride was
purchased from EM Science and was distilled before use.
Yields of Table 1 refer to isolated yields (based on 1-bromo-
2-chlorobenzene) of compounds estimated to be g97% pure as
determined by 1H NMR, 31P NMR, GC, and elemental analysis.
2-Dicycloh exylp h osp h in o-2′-d im eth yla m in obip h en yl
(1)3 (Table 1, entry 1). An oven-dried 250 mL round-bottomed
flask equipped with a magnetic stirbar, a rubber septum, and
a reflux condenser was charged with magnesium turnings
(2.92 g, 120 mmol), 2-chloro-N,N-dimethylaniline (9.3 g, 58
mmol), and THF (100 mL). The mixture was heated to reflux,
and 1,2-dibromoethane (0.62 mL, 10 mmol) was added drop-
wise via syringe over 1.5 h.31 The mixture was refluxed for an
additional 28 h and then cooled to 60 °C. 2-Bromochloro-
benzene (5.84 mL, 50.0 mmol) was added dropwise over 10
min, and the resulting mixture was heated for 2 h in an oil
bath at 60 °C and subsequently cooled to room temperature.
The septum was removed and anhydrous copper(I) chloride
(6.43 g, 65.0 mmol) was added. The septum was then replaced,
and the flask was purged with argon for 5 min. A solution of
ClPCy2 (14.0 g, 60.0 mmol) in THF (20 mL) was added
dropwise via syringe, and the mixture was stirred at ambient
(31) The formation of 2-dimethylaminophenylmagnesium chloride
was monitored by taking aliquots from the reaction mixture, quenching
them with methanol, and analyzing them by GC. The preparation of
2-dimethylaminophenylmagnesium chloride was most efficient when
dibromoethane was added to the 2-chloro-N,N-dimethylaniline and
magnesium dropwise over the course of 1-1.5 h. The formation of the
Grignard reagent was more sluggish when the dibromoethane was
added in one portion to the 2-chloro-N,N-dimethylaniline and magne-
sium, or when the dibromoethane was added to the magnesium prior
to the addition of 2-chloro-N,N-dimethylaniline.

Biphenyl-Based Phosphine Ligands
J . Org. Chem., Vol. 65, No. 17, 2000 5339
mL × 3) and brine (25 mL), dried over anhydrous MgSO4,
filtered, and concentrated. To the residual oil was added
EtOAc:MeOH (1:6, 17.5 mL) and the resulting suspension was
stirred in an ice/water bath for 1 h. Filtration, washing with
cold EtOAc:MeOH (1:6, 3 mL), and drying in vacuo gave 1.03
g (52% yield) of the title compound. An identical experiment
gave 1.02 g (52%).
and the organic phase was sequentially washed with 30%
aqueous NH4OH (25 mL × 2) and brine (25 mL), dried over
anhydrous MgSO4, filtered, and concentrated. To the residual
oil was added EtOAc:MeOH (1:4, 10 mL), and the resulting
suspension was stirred and cooled in an ice bath for 1 h.
Filtration, washing with cold EtOAc:MeOH (1:4, 3 mL), and
drying in vacuo gave 1.07 g (59%) of the title compound, a
white solid. An identical experiment gave 1.04 g (57%). Mp:
109-111 °C (lit.9 107-109 °C): 1H NMR (300 MHz, acetone-
d6) δ 7.70-7.62 (m, 1H), 7.46-7.34 (m, 2H), 7.28-7.10 (m, 4H),
7.0 (d, 1H, J ) 7.2 Hz), 2.04 (s, 3H), 2.00 (m, 1H), 1.82-1.52
(m, 11H), 1.40-0.90 (m, 10H); 13C NMR (75 MHz, acetone-d6)
δ 150.5 (d, J CP ) 31.2 Hz), 143.4 (d, J CP ) 6.3 Hz), 136.2 (d,
J CP ) 1.6 Hz), 135.4 (d, J CP ) 20.9 Hz), 133.5 (d, J CP ) 3.0
Hz), 131.6 (d, J CP ) 2.6 Hz), 130.7 (d, J CP ) 5.7 Hz), 130.0,
129.2, 127.7, 127.3, 125.3, 36.5 (d, J CP ) 16.7 Hz), 33.9 (d, J CP
) 14.0 Hz), 31.7 (d, J CP ) 15.5 Hz), 31.1 (d, J CP ) 17.3 Hz),
2-Di-ter t-bu tylph osph in o-2′-dim eth ylam in obiph en yl (2)
(Table 1, Entry 3).15 A 25 mL Schlenk tube was charged with
magnesium turnings (304 mg, 12.5 mmol) and capped with a
rubber septum. 2-Chloro-N,N-dimethylaniline (gross 0.93 g,
ca. 6.0 mmol), and THF (10 mL) were sequentially added via
syringe, and the reaction mixture was heated to reflux. At this
point,1,2-dibromoethane (86 µL, 1.0 mmol) was added dropwise
over 10 min.31 The mixture was allowed to reflux for an
additional 48 h, and was then cooled to 60 °C. 2-Bromochloro-
benzene (584 µL, 5.00 mmol) was added dropwise, and the
resulting mixture was stirred for 2 h in an oil bath at 60 °C
and subsequently cooled to room temperature. The septum was
removed and anhydrous copper(I) chloride (0.64 g, 6.5 mmol)
was added. The septum was then replaced and the tube purged
with argon for 1 min. Di-tert-butylchlorophosphine (1.1 mL,
6.0 mmol) was added via syringe, and the mixture was stirred
at 60 °C for 15 h. After cooling to room temperature, the
resulting suspension was poured into a flask that contained
hexane:EtOAc (1:1, 80 mL), 30% aqueous NH4OH (50 mL), and
brine (50 mL). The mixture was stirred at room temperature
for 5 min and transferred to a separatory funnel. The layers
were separated and the organic phase was sequentially washed
with 30% aqueous NH4OH (20 mL × 3) and brine (20 mL),
dried over anhydrous MgSO4, filtered, and concentrated. The
residual oil was crystallized from cold MeOH (5 mL). White
crystals of 2 were collected by filtration, washed with a small
amount of cold MeOH (3 mL), and dried in vacuo to give 0.356
g (21%) of the title compound. A similar experiment on a 25.0
mmol scale gave 2.07 g (24%). Mp: 111-113 °C (lit.15 116-
117 °C): 1H NMR (300 MHz, CDCl3) δ 7.80-7.75 (m, 1H),
7.40-7.20 (m, 4H), 7.00-6.90 (m, 3H), 2.44 (s, 6H), 1.26 (d,
9H, J HP ) 11.3 Hz), 0.90 (d, 9H, J HP ) 33.0 Hz); 13C NMR (75
MHz, CDCl3) δ 151.6 (d, J CP ) 2.4 Hz), 150.1 (d, J CP ) 33.7
Hz), 137.2 (d, J CP ) 7.6 Hz), 136.9 (d, J CP ) 15.2 Hz), 135.6
(d, J CP ) 3.2 Hz), 132.9, 131.1 (d, J CP ) 7.1 Hz), 128.8 (d, J CP
) 1.2 Hz), 128.0, 125.3, 121.0, 117.6, 43.5, 33.5 (d, J CP ) 24.3
Hz), 31.7 (d, J CP ) 16.1 Hz), 31.6 (d, J CP ) 27.8 Hz), 30.2 (d,
J CP ) 15.2 Hz); 31P NMR (121 MHz, CDCl3) δ 25.6; IR (neat,
cm-1) 2954, 2861, 1495, 1472, 1457, 1360, 1054, 947.
30.9 (d, J CP ) 11.3 Hz), 30.0 (d, J CP ) 6.3 Hz), 28.2 (d, J CP
)
3.9 Hz), 28.1 (d, J CP ) 1.3 Hz), 27.7, 27.6 (d, J CP ) 3.1 Hz),
27.3, 27.2 (d, J CP ) 1.0 Hz), 21.1 (d, J CP ) 5.6 Hz); 31P NMR
(121 MHz, CDCl3) δ -11.1; IR (neat, cm-1) 2927, 2910, 2844,
1463, 1443, 849.
Gen er a l P r oced u r e: Syn th esis of Liga n d s Sta r tin g
fr om Ar yl Br om id es. A Schlenk tube was charged with
magnesium turnings (11.5 mmol) and capped with a rubber
septum. THF (10 mL) and the aryl bromide (6.00 mmol) were
sequentially added via syringe, and the mixture was heated
in an oil bath at 60 °C for 2 h. At this point, 2-bromochloro-
benzene (5.00 mmol) was added dropwise, and the resulting
mixture was heated at 60 °C for 2 h and subsequently cooled
to room temperature. The septum was removed and anhydrous
copper(I) chloride (6.5 mmol) was added. The septum was then
replaced, and the tube was purged with argon for 1 min. A
solution of ClPCy2 (6.5 mmol) in THF or neat ClP(t-Bu)2 (6.5
mmol) was added dropwise via syringe. Reactions with ClPCy2
were conducted at ambient temperature, and those with ClP-
(t-Bu)2 were heated at 60 °C. The reactions were stopped after
1-17 h, when judged complete by GC analysis. The reaction
was worked up by one of the two methods below:
Wor k u p Meth od A. The resulting suspension was poured
into a flask containing hexane:EtOAc (1:1, 50 mL) and 30%
aqueous NH4OH (50 mL). The mixture was stirred at room
temperature for 5 min and transferred to a separatory funnel.
The layers were separated, and the organic phase was washed
with 30% aqueous NH4OH (25 mL × 2) and brine (25 mL),
dried over anhydrous MgSO4, filtered, and concentrated. The
resulting residue was further purified as specified.
2-Dicycloh exylp h osp h in o-2′-m eth ylbip h en yl (5) (Table
1, entry 4).9 A 50 mL Schlenk tube was capped with a rubber
septum and sequentially charged with PCl3 (0.65 mL, 7.5
mmol) and diethyl ether (15 mL). The solution was cooled to
-40 °C, and a 2.0 M solution of cyclohexylmagnesium chloride
in diethyl ether (7.5 mL, 15 mmol, purchased from Aldrich
Chemical Co.) was added dropwise over 15 min. The mixture
was warmed to 0 °C over 2 h, and then the MgCl2 that had
precipitated was removed with a Schlenk filter and washed
with diethyl ether (5 mL) under an atmosphere of argon. The
filtrate was used directly in the reaction described below.
A 25 mL Schlenk tube was charged with magnesium
turnings (280 mg, 11.5 mmol) and capped with a rubber
septum. 2-Chlorotoluene (0.70 g, 6.0 mmol) and THF (10 mL)
were sequentially added, and the mixture was heated to reflux.
At this point, 1,2-dibromoethane (43 µL, 0.5 mmol) was added
dropwise, and the mixture was refluxed for 15 h, and cooled
to 60 °C. 2-Bromochlorobenzene (584 µL, 5.00 mmol) was then
added dropwise, and the resulting mixture was heated in an
oil bath at 60 °C for 2 h and subsequently cooled to room
temperature. The septum was removed, anhydrous copper(I)
chloride (0.64 g, 6.5 mmol) was added, and the tube was purged
with argon for 1 min. The solution of crude ClPCy2 in diethyl
ether was then added dropwise via syringe, and the mixture
was stirred for 2 h at ambient temperature. The resulting
suspension was poured into a flask containing hexane:EtOAc
(1:1, 50 mL), 30% aqueous NH4OH (50 mL), and brine (25 mL).
The mixture was stirred at room temperature for 5 min and
transferred to a separatory funnel. The layers were separated,
Wor ku p Meth od B. Solvent A (hexane or 10:1 hexane:THF)
was added to the reaction mixture, and the resulting suspen-
sion was cooled in an ice/water bath for 0.5 h, filtered, and
washed with solvent B (hexane or 4:1 hexane:THF). The
filtered solid was then subjected to workup A.
2-Di-ter t-bu tylp h osp h in o-2′-m eth ylbip h en yl (6) (Table
1, entry 5).12 This reaction was conducted on a 3.00 mmol scale
according to the general procedure using workup method A.
The reaction of the biphenylylmagnesium halide, CuCl, and
chlorophosphine was stopped after 12 h. Crystallization from
MeOH (5 mL) in an ice/water bath gave 0.429 g (46% yield) of
the title compound as a white solid. A similar experiment on
a 25 mmol scale gave 3.90 g (50%). Mp: 91-92 °C (lit.12
86-87 °C): 1H NMR (300 MHz, CDCl3) δ 7.90-7.84 (m, 1H),
7.36-7.07 (m, 7H), 2.11 (s, 3H), 1.16 (d, 9H, J HP ) 11.5 Hz),
1.15 (d, 9H, J HP ) 11.3 Hz); 13C NMR (75 MHz, CDCl3) δ 150.3
(d, J CP ) 33.0 Hz), 142.8 (d, J CP ) 6.8 Hz), 136.2 (d, J CP
)
27.6 Hz), 135.6 (d, J CP ) 2.9 Hz), 135.4 (d, J CP ) 1.4 Hz), 131.7
(d, J CP ) 3.2 Hz), 130.9 (d, J CP ) 6.6 Hz), 129.6, 128.4, 127.1,
125.8, 124.3, 33.4 (d, J CP ) 24.2 Hz), 32.6 (d, J CP ) 25.2 Hz),
31.4 (d, J CP ) 15.4 Hz), 31.1 (d, J CP ) 14.8 Hz), 21.1 (d, J CP
)
)
2.9 Hz); 31P NMR (121 MHz, CDCl3) δ 20.7; IR (neat, cm-1
2981, 2960, 2890, 2861, 1468, 1459, 1360, 1171.
2-Dicycloh exylp h osp h in o-2′-isop r op ylb ip h en yl
(7)
(Table 1, entry 6).9 The general procedure on a 25.0 mmol scale
using workup method B (solvent A ) hexane; solvent B ) 4:1
hexane:THF) was followed. The reaction of the biphenylyl-
magnesium halide, CuCl, and chlorophosphine was stopped

5340 J . Org. Chem., Vol. 65, No. 17, 2000
Tomori et al.
after 22 h. Crystallization from 1:4 EtOAc:MeOH (25 mL) in
an ice/bath gave 4.65 g (47%) of the title compound, a white
crystalline solid. An identical experiment gave 4.99 g (51%)
of the title compound. Mp: 111-113 °C (lit.9 104 °C): 1H NMR
(300 MHz, acetone-d6) δ 7.67-7.63 (m, 1H), 7.42-7.25 (m, 4H),
7.20-7.10 (m, 2H), 7.00-6.96 (m, 1H); 2.70 (septet, 1H, J )
6.6 Hz); 1.86-1.50 (m, 12H), 1.40-0.82 (m, 10H), 1.24 (d, 3H,
J ) 6.9 Hz), 0.98 (d, 3H, J ) 6.9 Hz); 13C NMR (75 MHz,
CDCl3) δ 149.8 (d, J CP ) 31.1 Hz), 146.3, 141.2 (d, J CP ) 6.7
Hz), 134.9 (d, J CP ) 18.9 Hz), 132.4 (d, J CP ) 3.2 Hz), 131.0
(d, J CP ) 2.2 Hz), 130.5 (d, J CP ) 6.0 Hz), 128.0, 127.8, 126.4,
124.9, 124.4, 35,9 (d, J CP ) 15.3 Hz), 34.0 (d, J CP ) 13.7 Hz),
mmol scale gave 0.746 g (37% yield) of the title compound.
Mp: 111-113 °C: 1H NMR (300 MHz, acetone-d6) δ 7.92 (d,
1H, J ) 9.3 Hz), 7.89 (d, 1H, J ) 9.3 Hz), 7.78-7.74 (m, 1H),
7.54-7.43 (m, 4H), 7.40-7.24 (m, 4H), 2.04-1.90 (m, 1H),
1.74-1.52 (m, 10H), 1.30-0.82 (m, 11H); 13C NMR (75 MHz,
acetone-d6) δ 149.2 (d, J CP ) 31.4 Hz), 141.6 (d, J CP ) 6.7 Hz),
136.9 (d, J CP ) 21.5 Hz), 134.2, 133.6 (2 resonances), 131.5 (d,
J CP ) 5.6 Hz), 129.1 (d, J CP ) 1.1 Hz), 128.9 (d, J CP ) 2.9 Hz),
128.7, 128.0, 127.8, 127.6 (d, J CP ) 1.2 Hz), 126.3, 126.1, 125.4,
36.2 (d, J CP ) 16.4 Hz), 34.3 (d, J CP ) 14.4 Hz), 31.8 (d, J CP
)
16.8 Hz), 31.1 (d, J CP ) 18.5 Hz), 30.7 (d, J CP ) 12.2 Hz), 30.0
(d, J CP ) 6.7 Hz), 28.1 (d, J CP ) 3.5 Hz), 28.0 (d, J CP ) 2.1
Hz), 27.8, 27.7, 27.5, 27.3 (d, J CP ) 0.9 Hz), 27.2 (d, J CP ) 1.1
Hz); 31P NMR (121 MHz, CDCl3) δ -11.1; IR (neat, cm-1) 2921,
2846, 1507, 1443, 1393, 849, 799, 778. Anal. Calcd for
C28H33P: C, 83.96; H, 8.30. Found: C, 83.75; H, 8.26.
31.1 (d, J CP ) 15.3 Hz), 30.4 (d, J CP ) 17.6 Hz), 30.2 (d, J CP
)
1.9 Hz), 29.9 (d, J CP ) 12.5 Hz), 29.1 (d, J CP ) 5.4 Hz), 27.8 (d,
J CP ) 7.5 Hz), 27.7, 27.5, 27.4 (d, J CP ) 18.6 Hz), 26.7 (d, J CP
) 7.4 Hz), 25.6, 22.9 (d, J CP ) 1.7 Hz); 31P NMR (121 MHz,
CDCl3) δ -12.7; IR (neat, cm-1) 2960, 2923, 2844, 1463, 1447,
1003, 849, 756.
2-Dicycloh exylp h osp h in o-2′,6′-d im eth ylbip h en yl (13)
(Table 1, entry 10). The general procedure on a 5.00 mmol scale
using workup method A was followed. The reaction of the
biphenylylmagnesium halide, CuCl, and chlorophosphine was
stopped after 15 h. The residue was dissolved in 1 mL of ethyl
acetate, and the solution was cooled in an ice bath and stirred
vigorously. Methanol was then added dropwise until the
solution became cloudy. Stirring was continued as additional
methanol was added dropwise over the course of several hours.
After a substantial number of white crystals had formed,
additional methanol (the total volume was 20 mL) was added,
and stirring was continued for 1 h. The solid was filtered and
then slurried with methanol:ethyl acetate (4:1, 5 mL). The
suspension was cooled in an ice bath and stirred for 1 h. The
white solid was then filtered and dried in vacuo. The yield of
the title compound was 0.982 g (52% yield). A similar experi-
ment on a 25.0 mmol scale gave 4.98 g (53%) of the title
compound. Mp: 90-92 °C: 1H NMR (300 MHz, acetone-d6) δ
7.67-7.60 (m, 1H), 7.45-7.34 (m, 2H), 7.15-7.02 (m, 4H), 1.99
(s, 6H), 1.85-1.55 (m, 12H). 1.30-1.00 (m, 10H); 13C NMR (75
2-Di-ter t-bu tylph osph in o-2′-isopr opylbiph en yl (8) (Table
1, entry 7).13 This reaction was conducted on a 2.00 mmol scale
according to the general procedure and workup method B
(solvent A ) 10:1 hexane: THF; solvent B ) hexane). The
reaction of the biphenylylmagnesium halide, CuCl, and chloro-
phosphine was stopped after 17 h. Crystallization from cold
MeOH (4 mL) gave 0.200 g (29%) of the title compound as a
white solid. Mp: 92-94 °C (lit.13 98.5-99.5 °C): 1H NMR (300
MHz, CDCl3) δ 7.88-7.84 (m, 1H), 7.38-7.28 (m, 4H), 7.21-
7.00 (m, 3H), 2.73 (septet, 1H, J ) 6.8 Hz), 1.23 (d, 3H, J )
6.8 Hz), 1.18 (d, 9H, J HP ) 11.7 Hz), 1.12 (d, 9H, J HP ) 11.4
Hz), 1.04 (d, 3H, J ) 6.8 Hz); 13C NMR (75 MHz, CDCl3) δ
150.3 (d, J CP ) 34.6 Hz), 146.2 (d, J CP ) 1.2 Hz), 141.7 (d, J CP
) 6.6 Hz), 136.3 (d, J CP ) 27.6 Hz), 135.5 (d, J CP ) 2.9 Hz),
131.6 (d, J CP ) 2.4 Hz), 131.2 (d, J CP ) 6.4 Hz), 128.2 (d, J CP
) 1.2 Hz), 127.5, 125.8, 125.0, 124.2, 33.5 (d, J CP ) 24.2 Hz),
32.7 (d, J CP ) 25.4 Hz), 31.5 (d, J CP ) 15.4 Hz), 30.9 (d, J CP
)
14.5 Hz), 30.2, 26.0, 23.1; 31P NMR (121 MHz, CDCl3) δ 20.1;
IR (neat, cm-1) 2973, 2956, 2889, 2860, 1472, 1459, 1441, 1362.
1-(2-Di-ter t-b u t ylp h osp h in op h en yl)n a p h t h a len e (9)
(Table 1, entry 8).13 This reaction was carried out on a 2.00
mmol scale according to the general procedure and workup
method B (solvent A ) 10:1 hexane:THF; solvent B ) hexane).
The reaction of the biphenylylmagnesium halide, CuCl, and
chlorophosphine was stopped after 15 h. Purification by
chromatography on silica gel (eluent: 20:1 hexane:EtOAc)
followed by crystallization from cold MeOH (3 mL) and
recrystallization from MeOH (4 mL) in an ice/water bath gave
0.219 mg (31% yield) of the title compound, a white solid. Mp:
110-111 °C (lit.13 107-108 °C): 1H NMR (300 MHz, CDCl3) δ
8.00-7.94 (m, 1H), 7.87-7.81 (m, 2H), 7.49-7.24 (m, 8H), 1.16
(d, 9H, J HP ) 11.5 Hz), 1.05 (d, 9H, J HP ) 10.3 Hz); 13C NMR
MHz, acetone-d6)) δ 149.3 (d, J CP ) 30.7 Hz), 143.2 (d, J CP
)
5.9 Hz), 137.2 (d, J CP ) 7.7 Hz), 137.1 (d, J CP ) 10.8 Hz), 134.2
(d, J CP ) 2.7 Hz). 131.8 (d, J CP ) 6.0 Hz), 130.2, 128.6, 128.5,
128.1, 35.6 (d, J CP ) 15.8 Hz), 32.4 (d, J CP ) 13.9 Hz), 31.3 (d,
J CP ) 13.9 Hz), 29.0 (d, J CP ) 8.9 Hz), 28.9 (d, J CP ) 8.6 Hz),
28.1 (d, J CP ) 4.4 Hz); 31P NMR (121 MHz, acetone-d6) δ -7.3;
IR (neat, cm-1) 2937, 2917, 2850, 1459, 1443, 996, 851, 764,
741. Anal. Calcd for C26H35P: C, 82.50; H, 9.32. Found: C,
82.68; H, 9.25.
2-Di-ter t-b u t ylp h osp h in o-2′,6′-d im et h ylb ip h en yl (14)
(Table 1, entry 11). The general procedure on a 5.00 mmol scale
using workup method A was followed. The reaction of the
biphenylylmagnesium halide, CuCl, and chlorophosphine was
stopped after 15 h. Purification by chromatography on silica
gel (eluting first with hexane and then 20:1 hexane:EtOAc),
followed by crystallization from cold methanol (5 mL) gave
0.293 g (18% yield) of the title compound, a white solid. Mp:
86-88 °C: 1H NMR (300 MHz, CDCl3) δ 7.86-7.82 (m, 1H),
7.38-7.27 (m, 2H), 7.17-7.02 (m, 4H), 2.06 (s, 6H), 1.15 (d,
18H, J HP ) 11.5 Hz); 13C NMR (75 MHz, CDCl3) δ 148.9 (d,
J CP ) 33.0 Hz), 142.0 (d, J CP ) 5.4 Hz), 136.6 (d, J CP ) 30.0
Hz), 136.2 (d, J CP ) 1.8 Hz), 136.1 (d, J CP ) 1.4 Hz), 131.3 (d,
J CP ) 6.9 Hz), 128.6 (d, J CP ) 1.2 Hz), 127.1, 127.0, 125.7, 32.9
(d, J CP ) 24.7 Hz), 31.2 (d, J CP ) 14.9 Hz), 22.4 (d, J CP ) 4.5
Hz); 31P NMR (121 MHz, CDCl3) δ 25.0; IR (neat, cm-1) 2993,
2983, 2956, 2890, 2861, 1474, 1457, 1362. Anal. Calcd for
(75 MHz, CDCl3) δ 149.1 (d, J CP ) 34.6 Hz), 141.3 (d, J CP
)
7.1 Hz), 137.4 (d, J CP ) 27.6 Hz), 135.6 (d, J CP ) 2.9 Hz), 133.4,
132.8, 132.7, 131.6 (d, J CP ) 6.3 Hz), 128.5 (d, J CP ) 3.3 Hz),
128.3 (d, J CP ) 1.2 Hz), 128.2, 127.4 (d, J CP ) 2.9 Hz), 126.2,
125.4, 125.2, 124.6, 33.2 (d, J CP ) 24.5 Hz), 32.3 (d, J CP ) 25.1
Hz), 31.4 (d, J CP ) 15.5 Hz), 30.1 (d, J CP ) 14.9 Hz); 31P NMR
(121 MHz, CDCl3) δ 20.3; IR (neat, cm-1) 2962, 2943, 2892,
2861, 1470, 1391, 1362, 1173.
1-(2-Dicycloh exylp h osp h in op h en yl)n a p h th a len e (12)
(Table 1, entry 9). The reaction was conducted on a 25.0 mmol
scale according to the general procedure and workup method
A. The reaction of the biphenylylmagnesium halide, CuCl, and
chlorophosphine was stopped after 15 h. The residue was
dissolved in 15 mL of ethyl acetate, and the solution was cooled
in an ice bath and stirred vigorously. Methanol was then added
dropwise until the solution became cloudy. Stirring was
continued as several milliliters of methanol were added
dropwise over the course of several hours. After a substantial
number of white crystals had formed, additional methanol (the
total volume was 150 mL) was added, and stirring was
continued for 1 h. The solid was filtered and then slurried with
methanol:ethyl acetate (12:1, 32 mL). The suspension was
cooled in an ice bath and stirred for 1 h. The white solid was
then filtered and dried in vacuo. The yield of the title
compound was 3.42 g (34%). A similar experiment on a 5.00
C
22H31P: C, 80.94; H, 9.57. Found: C, 80.76; H, 9.56.
2-Dicycloh exylp h osp h in o-2′,5′-d im eth ylbip h en yl (15)
(Table 1, entry 12). This reaction was conducted on a 2.00
mmol scale according to the general procedure and workup
method A. The reaction of the biphenylylmagnesium halide,
CuCl, and chlorophosphine was stopped after 1.5 h. Two
crystallizations from 8 mL portions of cold EtOAc:MeOH (1:3,
8 mL) gave 0.373 g (49% yield) of the title compound, a white
solid. Mp: 93-95 °C: 1H NMR (300 MHz, acetone-d6) δ 7.66-
7.58 (m, 1H), 7.42-7.34 (m, 2H), 7.16-6.98 (m, 3H), 6.86 (s,
1H), 2.29 (s, 3H), 1.98 (s, 3H), 1.80-0.90 (m, 22H); 13C NMR
(75 MHz, CDCl3) δ 150.0 (d, J CP ) 31.5 Hz), 142.4 (d, J CP
)
6.7 Hz), 134.5 (d, J CP ) 18.5 Hz), 133.7, 132.6, 132.5, 131.6,

Biphenyl-Based Phosphine Ligands
J . Org. Chem., Vol. 65, No. 17, 2000 5341
130.0 (d, J CP ) 5.8 Hz), 129.3, 128.3, 128.0, 126.3, 35.6 (d, J CP
) 15.2 Hz), 33.4 (d, J CP ) 13.5 Hz), 31.0 (d, J CP ) 15.1 Hz),
mmol scale according to the general procedure and workup
method A. Crystallization from EtOAc (3 mL), filtration, and
drying in vacuo gave 436 mg (53%) of 17, a white crystalline
solid that contained ca. 6% EtOAc by weight. Heating at 80
°C under vacuum for 24 h failed to remove the solvent. Mp:
124-126 °C: 1H NMR (300 MHz, CDCl3) δ 7.60-7.50 (br m,
1H), 7.40-7.28 (br m, 2H), 7.10-7.04 (br m, 1H), 6.90 (s, 2H).
2.31 (s, 3H), 1.97 (s, 6H), 1.84-1.53 (m, 12H), 1.32-1.00 (m,
10H); 13C NMR (75 MHz, CDCl3) δ 148.2 (d, J CP ) 30.6 Hz),
138.7, 136.5, 135.7 (d, J CP ) 1.7 Hz), 135.4 (d, J CP ) 18.3 Hz),
132.6, 130.7(d, J CP ) 4.4 Hz), 128.5, 128.0, 126.2, 34.2 (d, J CP
) 14.9 Hz), 30.5 (d, J CP ) 12.1 Hz), 29.8 (d, J CP ) 13.7 Hz),
27.8 (d, J CP ) 4.8 Hz), 27.7 (d, J CP ) 6.0 Hz), 26.7, 21.6 (d, J CP
) 4.0 Hz), 21.5; 31P NMR (121 MHz, CDCl3) δ -8.9; IR (neat,
cm-1) 2916, 2846, 1445, 1001, 847, 766, 748, 739. Anal. Calcd
for C27H37P‚0.28EtOAc: C, 80.95; H, 9.48. Found: C, 81.07;
H, 9.44.
30.2 (d, J CP ) 17.4 Hz), 30.1 (d, J CP ) 11.5 Hz), 29.1 (d, J CP
)
5.1 Hz), 27.8 (d, J CP ) 11.6 Hz), 27.7 (d, J CP ) 5.8 Hz), 27.4,
27.3, 26.6 (2 resonances), 21.2, 20.4 (d, J CP ) 4.8 Hz); 31P NMR
(121 MHz, CDCl3) δ -10.6; IR (neat, cm-1) 2931, 2921, 2846,
1465, 1445, 1119, 886, 807. Anal. Calcd for C26H35P: C, 82.50;
H, 9.32. Found: C, 82.40; H, 9.19.
2-Dicycloh exylp h osp h in o-2′,4′-d im eth ylbip h en yl (16)
(Table 1, entry 13). This reaction was carried out on a 1.00
mmol scale according to the general procedure and workup
method A. Crystallization from cold EtOAc:MeOH (1:4, 5 mL)
and recrystallization from cold EtOAc:MeOH (1:8, 4.5 mL) in
a freezer gave 0.145 g (38% yield) of the title compound, a
white solid. Mp: 112-114 °C: 1H NMR (300 MHz, acetone-
d6) δ 7.65-7.60 (m, 1H), 7.41-7.34 (m, 2H), 7.14-7.07 (m, 1H),
7.02-6.90 (m, 3H), 2.32 (s, 3H), 2.00 (s, 3H), 1.80-0.90 (m,
22H); 13C NMR (75 MHz, CDCl3) δ 149.9 (d, J CP ) 30.1 Hz),
139.6, 136.6, 135.3, 134.5 (d, J CP ) 19.6 Hz), 132.6, 130.7, 130.3
(2 resonances), 128.3, 126.3, 125.4, 35.5 (d, J CP ) 15.1 Hz),
33.4 (d, J CP ) 13.6 Hz), 31.0 (d, J CP ) 14.6 Hz), 30.2, 30.0,
29.8, 28.9 (d, J CP ) 4.3 Hz), 27.9, 27.7, 27.4 (d, J CP ) 9.8 Hz),
26.7, 26.6, 21.5, 20.9 (d, J CP ) 8.4 Hz); 31P NMR (121 MHz,
CDCl3) δ -11.3; IR (neat, cm-1) 2916, 2844, 1461, 1445, 1003,
849, 816, 764. Anal. Calcd for C26H35P: C, 82.50; H, 9.32.
Found: C, 82.46; H, 9.25.
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM 58160 and 34917). We also ac-
knowledge Pfizer and Merck for additional unrestricted
support. H.T. thanks Sankyo Chemical Co. for support.
J .M.F. thanks the National Institutes of Health for
fellowship support. We thank Mr. Steven Kaye for
experimental assistance.
2-Dicycloh exylph osph in o-2′,4′,6′-tr im eth ylbiph en yl (17)
(Table 1, entry 14). This reaction was conducted on a 2.00
J O000691H