A novel P,O-type phosphorinane ligand for the Suzuki-Miyaura cross-coupling of aryl chlorides

Article abstract of DOI:10.1016/j.tetlet.2009.07.088

The Pd-mediated Suzuki-Miyaura cross-coupling of substituted and unsubstituted aryl chlorides with phosphorinane ligands was investigated uncovering an interesting ligand effect. The scope of the most effective 4-hydroxyl-substituted phosphorinane ligand in Suzuki cross-coupling with challenging aryl chlorides is described.

Full text of DOI:10.1016/j.tetlet.2009.07.088

Tetrahedron Letters 50 (2009) 5599–5601
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel P,O-type phosphorinane ligand for the Suzuki–Miyaura
cross-coupling of aryl chlorides
Ehsan Ullah , James McNulty a,*, Al Robertson b
a
a
Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4M1
Cytec Canada Inc., PO Box 240, Niagara Falls, Ontario, Canada L2E 6T4
b
a r t i c l e i n f o
a b s t r a c t
Article history:
The Pd-mediated Suzuki–Miyaura cross-coupling of substituted and unsubstituted aryl chlorides with
phosphorinane ligands was investigated uncovering an interesting ligand effect. The scope of the most
effective 4-hydroxyl-substituted phosphorinane ligand in Suzuki cross-coupling with challenging aryl
chlorides is described.
Received 2 July 2009
Revised 14 July 2009
Accepted 16 July 2009
Available online 21 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1
. Introduction
Palladium-catalyzed C–X (X = C, N, O, S) bond forming reactions
the design of all these ligands is the presence of a bulky, elec-
tron-rich phosphine donor in addition to a weaker, tunable n- or
p
- Lewis basic hemilabile donor. Monodentate complexes of type
0
1p
have been extensively investigated over the last few decades.
Many of these processes have become standard reactions in effect-
ing these important bond connections.1 A wide range of applica-
tions on both laboratory and industrial scales have been
developed. New and emerging ligands have expanded the scope
of substrates that enter such catalytic cycles to include less reac-
tive aryl chlorides and chemoselectivity to include substrates sus-
ceptible to b-hydride elimination. The dialkylbiarylphosphines
1
L -Pd are implicated as the key species involved in the initiating
oxidative addition step in these catalytic cycles. The additional
weak Pd-ligand interaction provides a stabilizing and tunable
appendage to the unsaturated catalyst.
2
,3
2
. Results and discussion
We recently reported on the use of a series of a P-substituted
(Fig. 1, A) introduced by Buchwald and co-workers have allowed
phorone-derived tertiary phosphines, analogs of ligand 3c
(
Fig. 2), as part of our ongoing research with new ligand scaffolds.9
The phosphorinane ligands incorporate a variably substituted
for some remarkable advances in catalyst stability and general
reactivity. The ligand structural features required have been exten-
sively investigated in this series.1b In general, incorporation of an
electron-rich phosphine increases the rate of oxidative addition
while steric bulk at phosphorus increases the rate of reductive
elimination. In addition, the lower aryl ring of these ligands is gen-
phosphine within a rigid, bulky di-tertbutyl-like framework. Many
structurally interesting P,O-type ligands have now been reported
1
d
in the Suzuki and other cross-coupling reactions. It occurred to
us that the monodentate ligand scaffold 3c could possibly be further
erally electron rich which provides additional p-type Pd-arene sta-
bilizing interactions in the active L -Pd catalyst.
1
0
4
Other interesting examples of such hemilabile ligands include
O
Cy
the P,O-type indolylphosphines B introduced by Kwong and
PCy2
R
co-workers for Suzuki–Miyaura and other coupling,1
d,5
the BIPI
PCy2
N
N
R
Ph
Ph
N
P,N-type ligands C introduced by Busacca et al. for Pd-mediated
Heck coupling and asymmetric hydrogenation,6 the pyrrole- and
imidazole- based systems D introduced by Beller,7 and the ketal-
containing P,O-type ligands E introduced by Guram and co-work-
Cy P
2
O
R N
2
C
A
B
N
8c
ers for the Suzuki cross-coupling of aryl chlorides. The desire to
activate inexpensive, readily available aryl chlorides has been a
driving force behind the development and application of many of
O
N
PCy2
R
O
R
8
these ligands. The general structural feature incorporated into
PCy2
D
E
*
Corresponding author. Tel.: +1 905 525 9140x27393; fax: +1 905 522 2509.
E-mail address: jmcnult@mcmaster.ca (J. McNulty).
Figure 1. Selected examples of hemilabile phosphine ligands.
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.088

5
600
E. Ullah et al. / Tetrahedron Letters 50 (2009) 5599–5601
O
P
OH
P
O
O
HO
A
P
3
a
Cy
O
P
P
O
B
C
O
+
CyPH2
1
P
2
Cy
O
P
Cy
2
3a
3b
3c
3b
Figure 2. P-Cyclohexylphosphorinone 2 and 4-substituted analogs 3a, 3b, and 3c.
P
Cy
3c
tuned to function as a hemilabile-bidentate ligand 3a of the type de-
scribed above through the incorporation of a novel design feature
involving a chair–boat conformational change. This design feature
is outlined in Figure 3 in which it is postulated that a remote 4-hy-
Scheme 1. Reagents: (A) LiAlH , THF; (B) ethylene glycol, PTSA; (C) hydrazine, KOH.
4
P-substituted phosphorinanes previously investigated,7b and re-
quired up to 48 h to achieve full conversion.
droxyl substituent could function to stabilize the catalyst in a boat
0
conformer, but generate the reactive monodentate L
1
-Pd species
The scope of the Suzuki–Miyaura cross-couplings employing li-
gand 3a with a range of activated and non activated aryl chlorides
was investigated and results are collected in Table 1. All reactions
through a ring flip to the chair conformer of 3a as shown.
In order to probe this possibility, the series of phosphorinane
derivatives shown in Figure 2 were prepared. In this Letter we re-
port on the synthesis of these phosphorinane ligands (Fig. 2) and
their application in the Suzuki–Miyaura cross-coupling reaction,
including the successful activation of challenging aryl chlorides.
The required parent P-cyclohexylphosphorinone 2 (Scheme 1)
was readily obtained through the double Michael addition of
mono-cyclohexylphosphine 1 to phorone.10 Attempts to prepare
Table 1
Suzuki cross-coupling reaction of various aryl chlorides and phenylboronic acids with
Pd-complex of 3a12
3
a, Pd(OAc) , 1.0 mol%
2
Ar-Cl
+
PhB(OH)2
Ar-Ph
6
Cs CO , 3.0 eq
toluene, 110 ºC, 16h
2
3
4
the 4-hydroxylphosphorinone 3a using NaBH -mediated reduction
4
5
of the ketone 2 yielded the phosphine-borane adduct of 3a which
proved difficult to deprotect.9a The desired product 3a was readily
Entry R-Cl
Boronic acid
Product 6
Isolated yield
of 6 (%)
4
made via LiAlH -mediated reduction of 2 however. The 4-substi-
tuted ketal 3b, analogous to the Guram ligand E (Fig. 1) and the
unsubstituted derivative 3c were prepared via standard ketalization
and Wolf-Kishner reduction, respectively, of the parent ketone.
Many catalyst systems are now known for Suzuki–Miyaura
cross-couplings of aryl bromides and iodides. We opted to focus
on the activation of challenging aryl chlorides, in particular elec-
tron-rich and ortho-substituted derivatives, in order to realize the
true potential of these new ligands. The Suzuki cross-coupling of
Cl
Ph
B(OH)2
1
93
85
78
60
80
70
62
82
74
85
1
1
O
O
Cl
Ph
B(OH)2
2
3
H
H
O
O
Cl
B(OH)2
Ph
4
(
-chloroacetophenone (1.0 equiv) with phenyl boronic acid
2.0 equiv) was first investigated. A catalyst system comprising
palladium (II) acetate (1.0 mol %), ligand 2, 3a, 3b, or 3c
3.0 mol %) and cesium carbonate was investigated in toluene.
(
Cl
Ph
B(OH)2
4
The cross-coupling was followed through monitoring the disap-
pearance of the aryl chloride and appearance of the biaryl using
GC. While all the ligands proved partly successful, ligands 3a
and 3c gave a complete conversion of the aryl chloride in 1.5 and
MeO
MeO
OMe
MeO
MeO
OMe
Cl
Ph
B(OH)2
5
2
h, respectively. The ketal-containing ligand 3b was least success-
ful, requiring 24 h to give 80% conversion of the aryl chloride. The
activation of electron-rich aryl chlorides is among the more chal-
lenging issues in Pd-mediated cross-coupling. Ligands 3a and 3c
also proved effective in the activation of 4-chloroanisole under
the same conditions, although as expected the reactions were
slower. Nonetheless, full conversion of 4-chloroanisole was
realized within 16 hours using ligand 3a. Under these conditions,
ligand 3c gave around 69% conversion, comparable to other
Cl
B(OH)2
Ph
6
B(OH)2
Ph
Cl
7
MeO
MeO
NH2
Cl
Ph
B(OH)2
8
NH2
Pd
H
Pd
O
P
Cl
Cl
B(OH)2
Ph
9
P
Cy
Cy
HO
B(OH)2
Ph
3a Bidentate boat
3a Monodentate chair
10
O
O
Figure 3. Bi- and monodentate complexes of ligand 3a.

E. Ullah et al. / Tetrahedron Letters 50 (2009) 5599–5601
5601
were performed under the conditions described above and, in
References and notes
order to allow direct comparison, the reactions in the Table were
terminated after 16 h and isolated yields of the biaryl adducts
are shown. The Pd-complex of ligand 3a proved to be highly effec-
tive in activating a wide range of substrates including most notably
chloroanisole (entry 5) and the more difficult 2,4-dimethoxychlo-
robenzene (entry 4), which gave a respective 60% isolated yield.
By direct comparison, the use of a Pd-DABCO-based catalyst in
1
.
(a) Handbook of Organopalladium Chemistry for Organic Synthesis; Tsuji, J., Ed.;
Wiley: New York, 2000; (b) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41,
1461–1471; (c) Fu, G. C. Acc. Chem. Res. 2008, 41, 1555–1564; (d) Kwong, F. K.;
Chan, A. S. C. Synlett 2008, 1440–1448.
2
.
.
(a) Handbook of Organopalladium Chemistry for Organic Synthesis; Tamaru, Y.,
Ed.; Wiley: New York, 2000; (b) Rouhi, A. M. Chem. Eng. News 2004, 82, 49–58.
Nakamura, H.; Iwama, H.; Yamamoto, Y. Chem. Commun. 1996, 1459–1460.
3
4. (a) Buchwald, S. L.; Surrey, D. L. Angew. Chem., Int. Ed. 2008, 47, 2–26; (b)
Barder, T. M.; Walker, S. D.; Martenille, J. R.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 4685–4695; (c) (a) Strieter, E. R.; Buchwald, S. L. Angew. Chem., Int.
Ed. 2006, 45, 925–928. (d) Barder, T. M.; Buchwald, S. L. Angew. Chem., Int. Ed.
DMF, at 110 °C for 19 h provided 63% yield of the same product
from 2,4-dimethoxychlorobenzene,1
3a
while
a
solvent-free
Pd-Cy
product.
3
P catalyst system was reported to give 78% yield of this
2004, 43, 1871–1876.
1
3b
The present results therefore place the 4-hydroxyl-
5. So, C. M.; Chiu, C. C.; Lau, C. P.; Kwong, F. K. J. Org. Chem. 2008, 73, 7803–7806.
6
.
(a) Busacca, C. A.; Grossbach, D.; So, R. C.; O’Brien, E. M.; Spinelli, E. M. Org. Lett.
003, 5, 595–598; (b) Busacca, C. A.; Lorenz, J. C.; Grinberg, N.; Haddad, N.; Lee,
substituted phorone 3a among only a handful of systems that
allow activation of these most challenging electron-rich and
ortho-substituted aryl chlorides.
That the 4-hydroxyl substituted phosphorinane 3a proved to be
the ligand of choice in this reaction is interesting given the remote
nature of this hydroxyl group from the strongly co-ordinating
phosphorus donor. It is difficult to consider an explanation other
than the hypothesis that this ligand functions as a hemilabile
P,O-bidentate ligand in accord with the models shown in Figure
2
H.; Li, Z.; Liang, M.; Reeves, D.; Saha, A.; Varsolona, R.; Senanayake, C. H. Org.
Lett. 2008, 10, 341–344.
Schulz, T.; Torborg, C.; Schaffner, B.; Huang, J.; Zapf, A.; Kadrov, R.; Borner, A.;
Beller, M. Angew. Chem., Int. Ed. 2009, 48, 918–921.
For a summary of earlier developments in the Pd-mediated Suzuki coupling of
aryl chlorides see: (a) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
7
.
.
8
1998, 120, 9722–9723; (b) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37,
3387–3388; (c) Bei, X.; Crevier, T.; Guram, A. S.; Jandeleit, B.; Powers, T. S.;
Turner, H. W.; Uno, T.; Weinberg, W. H. Tetrahedron Lett. 1999, 40, 3855–3858;
(d) Bei, X.; Turner, H. W.; Weinberg, W. H.; Guram, A. S.; Petersen, J. L. J. Org.
Chem. 1999, 64, 6797–6803; (e) Wolfe, J. P.; Buchwald, S. L. Angew Chem., Int.
Ed. 1999, 38, 2413–2416; (f) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000,
3. Ligand 3a may thus be considered a member of the expanding
class of useful hemilabile-bidentate ligands collected in Figure 1.
The incorporation of a strongly co-ordinating, sterically hindered
soft phosphine donor and a second, weaker co-ordinating atom
into a bidentate ligand core may thus be a useful general feature
allowing participation of 14- and 16-electron palladium species
at various points in the catalytic cycle.
1
22, 4020–4028; (g) Schnyder, A.; Aemmer, T.; Indolese, A. F.; Pittelkow, U.;
Studer, M. Adv. Synth. Catal. 2002, 344, 495–498; (h) Yin, J.; Rainka, M. P.;
Zhang, X. X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1162–1163; (i)
Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67,
5553–5566; (j) Jensen, J. F.; Johannsen, M. Org. Lett. 2003, 5, 3025–3028; (k)
Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11818–
11819; (l) Zapf, A.; Jackstell, R.; Rataboul, F.; Riermeier, T.; Monsees, A.;
Fuhrmann, C.; Shaikh, N.; Dingerdissen, U.; Beller, M. Chem. Commun. 2004, 38–
39; (m) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2004, 43, 1871–1876; (n) Kwong, F. Y.; Lam, W. H.; Yeung, C. H.;
Chan, K. S.; Chan, A. S. C. Chem. Commun. 2004, 1922–1923; (o) Bei, X.;
Hagemeyer, A.; Volpe, A.; Saxton, R.; Turner, H.; Guram, A. S. J. Org. Chem. 2004,
3
. Conclusion
6
4
9, 8626–8633; (p) Anderson, K. W.; Buchwald, S. L. Angew. Chem., Int. Ed. 2005,
4, 6173–6177; (q) Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. Org.
In conclusion, a series of 4-substituted phosphorinane ligands
were prepared. The ligand P-cyclohexyl-4-hydroxy-2,2,6,6-tetram-
ethylphosphorinane 3a proved most effective in the Suzuki–Miya-
ura cross-coupling of challenging aryl chlorides disclosing an
interesting ligand substituent effect. This ligand is among a handful
that are currently available that allow activation of these sub-
strates. The use of such hemilabile ligands in cross-coupling pro-
Lett. 2005, 7, 1991–1994.
9
.
(a) McNulty, J.; Zhou, Y. Tetrahedron Lett. 2004, 45, 407–410; (b) Brenstrum, T.;
Clattenburg, J.; Britten, J.; Zavorine, S.; Dyck, A. J.; McNulty, J.; Capretta, A. Org.
Lett. 2006, 8, 103–105.
10. Welcher, R. P.; Castellion, M. E.; Wystrach, V. P. J. Am. Chem. Soc. 1959, 81,
2541–2547; Welcher, R. P.; Day, N. E. J. Org. Chem. 1962, 27, 1824–1827.
1. Pastor, S. D.; Odorisio, P. A.; Spivack, J. D. J. Org. Chem. 1984, 49, 2906–2909.
2. General procedure for reactions reported in Table 1. Into an oven dried Schlenk
flask equipped with a magnetic stirring stir bar were added under argon the
1
1
cesses appears to be
a general structural feature, we are
currently exploring other structural types that incorporate this fea-
ture. Ligand 3a is easily prepared in two steps from commercial
aryl halide (0.20 g, 1.30 mmol), boronic acid (0.31 g, 2.58 mmol), Pd(OAc)
2
(
0.003 g, 0.013 mmol), ligand (0.009 g, 0.039 mmol), and Cs
2
CO (1.27 g,
3
3.9 mmol, Aldrich, ReagentPlus, 99%). The flask was capped, evacuated, and
materials. Further modification of ligand 3a, including immobiliza-
flushed with argon three times. Toluene (10.0 ml) was introduced and the
reaction mixture was immersed in a pre-heated oil bath at the indicated
temperature until the reaction was complete (Table 1, 16 h at 110 °C). The
reaction mixture was then diluted with ethyl acetate, filtered through silica
and the solvent was removed at reduced pressure. The crude product was then
purified by column chromatography on silica gel. The physical and spectral
data of all biphenyl compounds were identical to those previously described.
3. (a) Li, J. H.; Zhu, Q. M.; Xie, Y. X. Tetrahedron 2006, 62, 10888–10895; (b) Li, J.
H.; Deng, C. L.; Xie, Y. X. Synth. Commun. 2007, 37, 2433–2448.
tion onto a solid support1
4,15
and its application to other cross-cou-
pling processes is under investigation.
Acknowledgments
1
1
We thank NSERC, Cytec Canada Inc. and McMaster University
for financial support of this work.
4. Leadbeater, N. E.; Marco, M. Chem. Rev. 2002, 102, 3217–3274.
15. Benaglia, M.; Puglisi, A.; Cozzi, F. Chem. Rev. 2003, 103, 3401–3430.