A mixed naphthyl-phenyl phosphine ligand motif for Suzuki, Heck, and hydrodehalogenation reactions

Article abstract of DOI:10.1055/s-2006-951538

Nap-Phos, representing a new naphthyl-phenyl biaryl-type phosphine ligand class and available by a short synthesis (4 steps, 71% overall yield), effectively catalyzes the Suzuki-Miyaura (including highly hindered cases), hydrodehalogenation, and Heck reactions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-951538

2908
LETTER
A Mixed Naphthyl-Phenyl Phosphine Ligand Motif for Suzuki, Heck, and
Hydrodehalogenation Reactions
M
ixe
d
N
aphthyl-P
l
henyl
P
e
hosphine
L
g
igandMotif for
H
e
M
ck
R
eactions . Demchuk,* Bilge Yoruk, Tom Blackburn, Victor Snieckus*
Department of Chemistry, Queen’s University, 90 Bader Lane, Kingston, ON, K7L 3N6, Canada
Fax +1(613)5336089; E-mail: snieckus@chem.queensu.ca
Received 25 September 2006
Dedicated to Richard Heck who let fly the first arrow of transition-metal-catalyzed reactions for organic synthesis
catalytic activity is emerging7 concurrently with wide-
Abstract: Nap-Phos, representing a new naphthyl-phenyl biaryl-
type phosphine ligand class and available by a short synthesis (4
steps, 71% overall yield), effectively catalyzes the Suzuki–Miyaura
(including highly hindered cases), hydrodehalogenation, and Heck
reactions.
ranging application, especially with respect to the Suzuki–
Miyaura methodology.8 Thus, at the forefront of current
work, ligands such as S-Phos,6 X-Phos,6 and Cy-MAP9
(Figure 1) display high catalytic activity in Suzuki–
Miyaura reactions of hindered biaryls even at room tem-
perature and extremely low (ppm) catalyst loading.
Key words: cross-coupling, Suzuki–Miyaura, homogenous cataly-
sis, Heck reaction, phosphorus ligand, hindered biaryls, dehydroha-
logenation
We report on the design and synthesis of a new monoden-
tate P-ligand (Nap-Phos, 7) and its application to the
Suzuki–Miyaura, hydrodehalogenation, and Heck reac-
tions. Of the approximately 60 known biaryl phosphines
frameworks,4b Nap-Phos is, to the best of our knowledge,
the first mixed naphthyl-phenyl P-ligand and is prepared
by non-metalation/metal–halogen exchange routes. Our
results, by implication, support concurring evidence of the
importance of bulk and electronic criteria in the P-ligand
structure and provide a new basis for future ligand devel-
opment for transition metal catalysis.
In the last decade, the inspiration gained from the discov-
eries of the now-eminent transition-metal-catalyzed name
reactions1 has been translated into extensive application to
synthetic problems, especially in pharmaceutical industry
practice2 and has witnessed increased mechanistic under-
standing,1c to further drive the development of highly
active and selective catalysts.
Recognition that ligand variation constitutes the most
powerful tool in deriving the new catalytic advantage3 has
resulted in a continuous superfluity of reports aimed to ex-
plore and exploit the subtle crosstalk between steric and
electronic parameters which determine the properties of
the catalyst.4 In the growing catalogue of available
ligands, the phosphine-based systems are dominant,4
arguably followed by the N-heterocyclic carbenes;5 how-
ever, a variety of others are being developed, including
ligandless protocols.6
Cognizant of the difficulties associated with the construc-
tion of unsymmetrical, hindered ortho-substituted biaryl
P-ligand cores by direct coupling reactions,4,6a,10 we
sought, in our approach to Nap-Phos (7), an effective
short synthesis whose accent was on the introduction of
ortho-P-functionality by a non-coupling route10b subse-
quent to aryl–aryl bond formation. In addition, a process,
which was based on commercial starting materials and
amenable to scale-up, was aspired.
Although ‘no universal guidelines’4b as yet exist for phos-
phine ligands, insight into the critical contributions of
steric bulk and electron-donating ability of the ligand on
Thus (Scheme 1), treatment (1 mmol scale) of naphtho-
quinone (1a) and 2-bromonaphthoquinone (1b) under
oxidative Heck11 and Suzuki6 conditions with the boronic
N
N
PCy2
OMe
PCy2
PCy2
NMe2
MeO
i-Pr
i-Pr
i-Pr
S-Phos6
X-Phos6
Cy-MAP9
IPr5
Figure 1 Some effective ligands for the Suzuki–Miyaura reaction.
SYNLETT 2006, No. 18, pp 2908–2913
0
3
.1
1
.2
0
0
6
Advanced online publication: 25.10.2006
DOI: 10.1055/s-2006-951538; Art ID: S40006ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Mixed Naphthyl-Phenyl Phosphine Ligand Motif for Heck Reactions
2909
conditions a: X = H
Pd(OAc)2, K2S2O8
HOAc, 80 °C
(30%)
were obtained at somewhat above ambient temperatures,
even for unactivated aryl chlorides17,22 (entries 1 and 2).
As expected from previous results6 more hindered cou-
pling partners require higher temperatures, aprotic sol-
vents, and higher ligand loading (entries 3–8). These
reaction conditions were optimized for the coupling of
2,6-dimethylbromobenzene with 2,4,6-trimethylphenyl
boronic acid (entry 3) using 5:1 ratio of ligand:[Pd] at
150 °C. These conditions proved also effective for an
unactivated heterocyclic bromide (entry 9). Of significant
note, due to the connection to directed ortho-metalation
(DoM) chemistry,18 the high-yield coupling of a highly
hindered benzamide was achieved (entry 8).19
O
MeO
(HO)2B
X
conditions b: X = Br
(t-Bu3P)2Pd, K3PO4·H2O
DMF, 50 °C
O
1a: X = H
1b: X = Br
1
2
(77–98%)
Me
Me
O
O
O
HO
O
Cy PH
2
, DBU
PhH, 120 h
82%
PCy2
O
O
O
H
3
Me
O
4
Me
O
In a second application of Nap-Phos, aryl bromide
hydrodebromination, a fundamental synthetic reaction of
considerable environmental relevance,20b,c has been de-
monstrated. The above Suzuki coupling results indicating
the ready activation of the carbon–halogen bond by the
Nap-Phos-Pd catalyst are reflected in facile hydrode-
bromination (Table 2): quantitative yields of products
were observed in 40–100 °C temperature ranges using 2
mol% of [Pd]–ligand (1:1) catalyst precursor. Interesting-
ly (entry 4), deuteriodehalogenation using excess CD3OD
and H2O is inefficient at 40 °C but suggests hydride trans-
fer with concomitant formation of formaldehyde.
MeO
MeI, Cs2CO3
Bu4N(HSO4)
MeO
HSiCl3, Et3N
xylenes
DMF, 36 h, r.t.
quant.
PCy2
O
100 °C
(80%)
PCy2
OMe
O
O
H
5
6
Me
O
MeO
1. HSi(OEt)3
Ti(Oi-Pr)4
THF, 70 °C
PCy2
Nap-Phos
2. HSiCl3, Et3N
PhMe, 80 °C
7
(89%)
conditions a: 22% overall yield
conditions b: 71% overall yield
In another preliminary study, the application of Nap-Phos
in the venerable Heck reaction21,22 has also been realized
(Table 3). Thus, using typical Heck reaction conditions,21
products are obtained even for sterically hindered and
deactivated aryl bromides (entries 1 and 2) and ortho-sub-
stituted aromatics and heteroaromatics (entries 3–5)
derived by DoM tactics.18
Scheme 1 The synthesis of Nap-Phos (7) in 4 steps and 71% overall
yield.
acid 2 gave the aryl naphthoquinone 3 in 30% and 98%
yields, respectively, from commercially available materi-
als. The Suzuki conditions furnished 3 in 77% yield on a
preparative (15 mmol) scale. Treatment with dicyclohex-
ylphosphine oxide in the presence of DBU12 afforded the
phosphine oxide (4, 82% yield),13 which was precipitated
from the reaction mixture with pentane and used without
In conclusion, the efficacy of the first mixed naphthyl-
phenyl ligand, Nap-Phos (7) in Suzuki–Miyaura, hy-
drodebromination, and Heck reactions has been demon-
strated. In the Suzuki protocol, Nap-Phos appears to be of
similar high activity to the current benchmark, S-Phos and
additional purification. Methylation under mild condi- gives comparable results23 for difficult cases (entries 2–7,
tions afforded the dimethyl ether phosphinoxide 5 in Table 1). Moreover, highly substituted sterically hindered
quantitative yield. Attempts to reduce 5 to the correspond- bromo benzamides19 (entry 8) and deactivated hetero-
ing phosphine, with the intent to investigate its ligand aromatic bromides (entries 9) afford excellent yields of
properties, failed but provided a remarkable result.
coupled products. The new catalytic reductive hydro-
debromination methodology provides an effective and
simple alternative to traditional, generally more harsh,
procedures.20a,b The biaryl amide Suzuki (entry 8,
Table 1) and Heck (entries 3–5, Table 3) products are
retrosynthetically related to DoM chemistry,18 a fact
which invites further synthetic exploration. Further
studies of Nap-Phos (7) and related new ligands is in
progress.24
Under conventional HSiCl3/Et3N conditions,10b the de-
methylated product 6 was obtained, likely the result of
phosphinoxide–HSiCl3 coordination followed by hydride
reductive cleavage.14 Compound 6 resisted reduction to
the corresponding phosphine by several established pro-
cedures.15 To circumvent this difficulty, the 1-OMe group
was cleaved by taking advantage of the presumed coordi-
nation effect. Thus, treatment of 5 with Ti(i-PrO)4 and
(EtO)3SiH to derive titanium hydride in situ16 afforded the
corresponding 1-desmethoxy compound (81% yield)
which, upon standard reduction with HSiCl3/Et3N, gave 7
in 71% overall yield from the phosphinoxide 5.
Dicyclohexyl[4-methoxy-3-(2-methoxyphenyl)naphth-2-
yl]phosphinoxide
A dried Schlenk tube containing a magnetic stirring bar was
charged with 5 (3.92 g, 7.7 mmol) and anhyd THF (50 mL). The
flask was capped with a rubber septum and evacuated and back-
filled with argon. This sequence was repeated three times. Then
Results of Suzuki–Miyaura cross-coupling reactions us-
ing Nap-Phos (7) are summarized in Table 1. For unhin-
dered cross-couplings, excellent yields of biaryl products
Synlett 2006, No. 18, 2908–2913 © Thieme Stuttgart · New York

2910
O. M. Demchuk et al.
LETTER
Table 1 Suzuki–Miyaura Cross-Coupling Reaction Using Nap-Phos (7)
R
[Pd2dba3] (1 mol%)
R
(HO)2B
R1
7 (10 mol%)
+
K3PO4 (4 equiv), PhMe
150 °C, 18 h
R1
Hal
Entry
1
Ar–Hal
Ar–B(OH)2
Product
Yield (%)a
NC
NC
OMe
98b, 98b,c
(98)b
OMe
OMe
B(OH)2
OMe
Br (Cl)
Me
Me
Me
98b
2
3
4
(98)b
Me
Me
Br (Cl)
Me
Me
Me
B(OH)2
Me
Me
76
70
Me
Me
Me
Me
Me
B(OH)2
Br
Br
Me
Me
Me
OMe
OMe
MeO
OMe
Me
Me
Me
MeO
B(OH)2
Me
5
6
7
71
OMe
B(OH)2
Me
Me
Br
58d
62d
OMe
OMe
B(OH)2
OMe
OMe
Br
2
OMe
MeO
OMe
B(OH)2
Br
MeO
MeO
MeO
OMe
OMe
OMe
MeO
OMe
Br
8
9
98d
OMe
B(OH)2
Et2N(O)C
MeO
Et2N(O)C
HeptO
OMe
N
HeptO
N
80d
OMe
B(OH)2
Br
a Isolated yields obtained after silica gel chromatography or micro distillation. Products of the reactions of entries 2–4 contain about 4 mol%
of boronic acid homocoupling by-products according to GC-MS.
b Conditions: Pd(OAc)2 (2 mol%), Nap-Phos (7, 2 mol%), K3PO4·H2O, anhyd MeOH, 40 °C.
c DMF as solvent, 40 °C.
d Mesitylene as solvent, 150 °C.
Synlett 2006, No. 18, 2908–2913 © Thieme Stuttgart · New York

LETTER
Mixed Naphthyl-Phenyl Phosphine Ligand Motif for Heck Reactions
2911
Table 2 Catalytic Hydrodehalogenation Using Nap-Phos (7)
Table 3 Heck Reaction Using Nap-Phos (7)
Pd(OAc)2 (2 mol%)
Pd2(dba)3 (2 mol%)
7 (2–5 mol%)
R
R
7 (2 mol%)
O
Ar
O
Ar-Hal
+
Cs2CO3 (2 equiv)
dioxane, 110 °C, 16 h
K3PO4·H2O, MeOH
OMe
Br
OMe
16 h, 40 °C
Entry Ar–Hal
Product
Yield
(%)
Entry Ar–Hal
Product
Yield (%)
quanta
O
1
Me
Me
Me
Me
1
85
OMe
Br
Me
Me
Br
2
3
quant
OMe
OMe
O
Br
OMe
2
3
80a
84
OMe
OMe
OMe
MeO
OMe
Br
MeO
OMe
Br
N
quantb
OMe
O
Et2N(O)C
Et2N(O)C
Br
OMe
N
O
4
5
quanta
NEt2
NEt2
O
O
Br
OMe
I
OMe
OMe
O
4
5
40
42
MeO
OMe
Br
MeO
OMe
D
N
40c
O
O
NEt2
N
O
NEt2
OMe
Et2N(O)C
Et2N(O)C
O
a Yield based on GC-MS analysis.
b Reaction at 100 °C.
I
O
S
O
c When CD3OD or CD3OH was used as solvent at 40 °C, the corre-
sponding deuterated product was obtained in 40% yield with above
95% d1-incorporation (NMR analysis).
O
S
O
NEt2
O
O
NEt2
a E:Z = 4.3:1 as determined by GC-MS and 1H NMR analysis.
HSi(OEt3)16 (18.0 g, 20 mL, 108 mmol) and Ti(i-PrO)4 (4.4 g, 4.6
mL, 16 mmol) were sequentially added through the septum, and the
reaction mixture was slowly heated to 100 °C with vigorous stirring
during which time pyrophoric SiH4 was liberated. Caution: SiH4 is
a pyrophoric gas and should be diluted at the outlet with argon. The
septum was replaced with a glass cap, the tube was sealed, and the
reaction mixture was vigorously stirred and heated at 100–110 °C
until 5 was almost completely consumed (31P NMR analysis). After
cooling to r.t., the mixture was evaporated under high vacuum, the
resulting solid residue was impregnated with silica gel (6 g) and the
material was subjected to column chromatography (40:1 hexane–
EtOAc to 5:3:0.2 hexane–EtOAc–MeOH as eluents) to give 5
(0.08 g, 2%), 6 (0.04 g, 1%), dicyclohexyl[4-methoxy-3-(2-meth-
oxyphenyl)naphth-2-yl]phosphinoxide (3.0 g, 81%), and 7 (0.18 g,
5%). Pure dicyclohexyl[4-methoxy-3-(2-methoxyphenyl)naphth-2-
yl]phosphinoxide was obtained by recrystallization from hexane–
EtOAc, colourless crystals, mp 197–198 °C. 31P NMR (162 MHz,
126.7, 126.0 (d, 1 C, JC–P = 2.2 Hz), 122.5, 120.0, 110.4, 61.7, 55.3,
37.9 (d, 1 C, JC–P = 66.5 Hz), 37.8 (d, 1 C, JC–P = 65.1 Hz), 27.02,
26.99, 26.92, 26.89, 26.82, 26.69, 26.59, 26.57, 26.51, 26.46, 26.38,
26.28, 26.25, 25.77, 25.63, 25.59. IR (film): 1172, 1105 (P=O)
cm–1. HRMS (EI): m/z calcd for C30H37O3P: 476.2480; found:
476.2475.
Dicyclohexyl[4-methoxy-3-(2-methoxyphenyl)naphth-2-
yl]phosphine (7)
To a stirred solution of dicyclohexyl[4-methoxy-3-(2-methoxyphe-
nyl)naphth-2-yl]phosphinoxide (3.5 g, 6.9 mmol) in degassed tolu-
ene (100 mL) under argon was sequentially added Et3N (50 mL) and
HSiCl3 (6.7 g, 5 mL, 50 mmol). The flask was sealed and the mix-
ture was stirred and heated at 80 °C for 16–18 h (the completion of
the reaction was ascertained by 31P NMR analysis). After cooling to
r.t., toluene (100 mL) and then 30% aq NaOH (50 mL) were added
under vigorous stirring. After 20 min, the organic layer was separat-
ed, dried (Na2SO4), and concentrated in vacuo to give a residue
which was purified by column chromatography (40:1 hexane–
EtOAc as eluent) to give 7 (2.6 g, 77% yield) as a pale yellow solid
which undergoes slow oxidation in air. 31P NMR (162 MHz, C6D6):
d = –10.2. 1H NMR (400 MHz, C6D6): d = 8.35 (d, 1 H, J = 8.1 Hz),
8.10, 7.85 (d, 1 H, J = 8.1 Hz), 7.52 (d, 1 H, J = 7.1 Hz), 7.44–7.36
(m, 3 H), 7.14 (~t, 1 H, J = ca. 7.5 Hz), 6.82 (d, 1 H, J = 8.1 Hz),
1
CDCl3): d = 48.3. H NMR (400 MHz, CDCl3): d = 8.55 (d, 1 H,
J = 12.1 Hz), 8.07 (d, 1 H, J = 8.1 Hz), 8.02 (d, 1 H, J = 8.1 Hz),
7.61 (~t, 1 H, J = ca. 7.9 Hz), 7.57 (~t, 1 H, J = ca. 7.6 Hz), 7.48 (~t,
1 H, J = ca. 7.6 Hz), 7.18 (d, 1 H, J = 7.1 Hz), 7.08 (t, 1 H, J = 7.1
Hz), 7.02 (d, 1 H, J = 8.0 Hz), 3.75 (s, 3 H), 3.63 (s, 3 H), 1.94–0.97
(m, 22 H). 13C NMR (100 MHz, CDCl3): d = 157.6, 154.4 (d, 1 C,
JC–P = 12.4 Hz), 133.5 (d, 1 C, JC–P = 12.4 Hz), 132.0 (d, 1 C,
JC–P = 5.1 Hz), 131.2, 130.2 (d, 1 C, JC–P = 79.8 Hz), 129.9, 129.3,
129.0 (d, 1 C, JC–P = 2.2 Hz), 127.7, 127.3 (d, 1 C, JC–P = 10.3 Hz),
Synlett 2006, No. 18, 2908–2913 © Thieme Stuttgart · New York

2912
O. M. Demchuk et al.
LETTER
3.56 (s, 3 H), 3.50 (s, 3 H), 2.35–0.93 (m, 22 H). 13C NMR (100
References and Notes
MHz, C6D6): d = 157.5, 154.1 (d, 1 C, JC–P = 8.8 Hz), 136.3 (d, 1 C,
(1) (a) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.;
Meijere, A.; Diederich, F., Eds.; Wiley-VCH: Weinheim,
2004. (b) Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E., Ed.; Wiley-Interscience:
Weinheim, 2002. (c) For mechanistic aspects, see: Kozuch,
S.; Amatore, C.; Jutand, A.; Shaik, S. Organometallics 2005,
24, 2319.
JC–P = 22.0 Hz), 135.2 (d, 1 C, JC–P = 32.2 Hz), 134.1, 133.2 (d, 1 C,
JC–P = 2.1 Hz), 128.9, 128.8, 128.3, 128.2 (d, 1 C, JC–P = 2.9 Hz),
128.1, 126.2 (d, 1 C, JC–P = 14.6 Hz), 122.8, 119.8, 110.1, 60.6,
54.5, 35.2 (d, 1 C, JC–P = 144.9 Hz), 35.0 (d, 1 C, JC–P = 144.2 Hz),
30.9, 30.7, 30.32, 30.27, 30.18, 30.09, 29.23, 29.15, 27.57, 27.50,
27.44, 27.43, 27.39, 27.35, 27.28, 26.86, 26.85, 26.49. HRMS
(ESI): m/z calcd for C30H37O2P + [H+]: 461.2609; found: 461.2588.
(2) See, for example: (a) King, A. O.; Yasuda, N. Top.
Organomet. Chem. 2004, 6, 205. (b) Rouhi, A. M. Chem.
Eng. News 2004, 82 (Sept. 6), 49. (c) Carey, J. S.; Laffan,
D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2006,
4, 2337; especially p. 2345.
(3) Review: Wilkinson, M. J.; van Leeuwen, P. W. N. M.; Reek,
J. N. H. Org. Biomol. Chem. 2005, 3, 2371.
(4) Reviews: (a) Clarke, M. L.; Heydt, M. Organometallics
2005, 24, 6475. (b) Shimizu, H.; Nagasaki, I.; Saito, T.
Tetrahedron 2005, 61, 5405. (c) Valentine, D. H. Jr.;
Hillhouse, J. H. Synthesis 2003, 2437.
(5) Hillier, A. C.; Grasa, G. A.; Viciu, M. S.; Lee, H. M.; Yang,
C.; Nolan, S. P. J. Organomet. Chem. 2002, 653, 69.
(6) (a) For an excellent overview and comprehensive list of
references, see: Barder, T. E.; Walker, S. D.; Martinelli, J.
R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685.
For additional impact of SPhos on Suzuki–Miyaura
chemistry, see: (b) Walker, S. D.; Martinelli, J. R.;
Buchwald, S. L. Angew. Chem. Int. Ed. 2004, 43, 1871.
(c) Barder, T. E.; Buchwald, S. L. Org. Lett. 2004, 6, 2649.
(d) Billingsley, K. L.; Anderson, K. W.; Buchwald, S. L.
Angew. Chem. Int. Ed. 2006, 45, 3484.
In a simple procedure, the mixture obtained in the preparation of
dicyclohexyl[4-methoxy-3-(2-methoxyphenyl)naphth-2-yl]phos-
phinoxide as described above, after fast filtration through a plug of
silica gel, was subjected to directly to the HSiCl3/Et3N/PhMe/
80 °C/18 h conditions to give, after normal work-up, 7 in 90% yield.
Suzuki–Miyaura Cross-Coupling Reaction – General
Procedure
A Schlenk tube containing a magnetic stirring bar, powdered
K3PO4·H2O (3 mmol, 3 equiv), aryl boronic acid (2 mmol, 2 equiv)
and MeOH (4 mL) was capped with a glass stopper and then evac-
uated and backfilled with argon. This sequence was repeated three
times. The aryl halide (1.0 mmol, 1.0 equiv; aryl halides which were
solids at r.t. were added as sat. solutions in MeOH or C6H6) and a
solution of ligand 7 (0.02 mmol, 0.02 equiv) in C6H6 (0.2 mL) were
then added followed by a solution of Pd(OAc)2 (0.02 mmol, 0.02
equiv) in MeOH (1 mL). After 10 min, the reaction mixture was
heated at 40 °C with stirring until the aryl halide was completely
consumed as judged by GC analysis but not longer then 18 h. The
reaction mixture was cooled to r.t., diluted with H2O (20 mL), and
extracted with CH2Cl2 (2 × 15 mL). The organic extract was dried
(Na2SO4) and concentrated in vacuo, and the crude material ob-
tained was purified by flash chromatography on silica gel.
(7) The significance of an h1-Pd-C(ipso) interaction to the
lifetime of the catalyst is being investigated, see ref. 6 and:
Kočovský, P.; Vyskočil, S.; Cisařová, I.; Sejbal, J.; Tilerová,
I.; Smrčina, M.; Lloyd-Jones, G. C.; Stephen, S. C.; Butts, C.
P.; Murray, M.; Langer, V. J. Am. Chem. Soc. 1999, 121,
7714.
(8) (a) For an outstanding critical review on the Heck and
Suzuki reactions focusing on the active species, which
presents a detailed analysis of P-ligands, see: Phan, N. T. S.;
Van Der Sluys, M.; Jones, C. W. Adv. Synth. Catal. 2006,
348, 609. (b) For a review on hydrophilic P-based ligands,
see: Shaughnessy, K. H. Eur. J. Chem. 2006, 1827.
(9) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122,
12051.
(10) For a practical synthesis of biphenyl phosphine ligands using
a Grignard–benzyne reaction, see: (a) Tomori, H.; Fox, J.
M.; Buchwald, S. L. J. Org. Chem. 2000, 65, 5334. (b) For
recent work, see: Baillie, C.; Chen, W.; Xiao, J. Tetrahedron
Lett. 2001, 42, 9085; and references cited therein.
(11) Schenck, H. V.; Nilsson, P.; Andappan, M. S.; Larhed, M. J.
Org. Chem. 2004, 69, 5212.
Suzuki–Miyaura Cross-Coupling Reaction – Hindered
Aromatics
The above cross coupling procedure was used with the following
changes: anhyd K3PO4 (3 equiv) was used in lieu of K3PO4·H2O,
Pd2(dba)3 (2 mol%) was employed instead of a solution of
Pd(OAc)2, a 5:1 ligand–[Pd] ratio was applied, and reaction was
carried out in 1,3,5-Me3C6H3 or 1,4-Me2C6H4 or PhMe at 150 °C for
18 h.
Hydrodehalogenation Reaction
The general procedure for the cross coupling reaction described
above was used with the exclusion of the aryl boronic acid as fol-
lows: K3PO4·H2O (3 mmol, 3 equiv), and MeOH (4 mL) aryl halide
(1.0 mmol, 1.0 equiv), ligand 7 (0.02 mmol, 0.02 equiv) in C6H6
(0.2 mL), Pd(OAc)2 (0.02 mmol, 0.02 equiv) in MeOH (1 mL),
40 °C, 18 h.
Heck Reaction
The general procedure for the cross-coupling reaction was used
with the following changes in reagents: anhyd Cs2CO3 (3 equiv)
was used in lieu of K3PO4·H2O, methyl acrylate (2 equiv) was used
instead of the boronic acid, Pd2(dba)3 (1 mol%) was used instead of
a solution of Pd(OAc)2, a 2:1 ligand–[Pd] ratio was employed, and
reaction was carried out in dry dioxane at 150 °C for 18 h or at
200 °C under MW irradiation for 1 h.
(12) Villemin, D.; Racha, F. Tetrahedron Lett. 1986, 27, 1789.
(13) As established by X-ray single crystal (Figure 2) and NMR
analysis, compound 4 shows strong intra- and intermolecular
hydrogen bonds in the solid state and in solution. The
(C1)O–H–O=P intramolecular bond distances are 1.079 Å
and 1.533 Å, respectively, while intermolecular (C4¢)O–H–
O=P bond distances are 1.046 Å and 1.794 Å, respectively.
The 31P NMR spectrum reveals a low field shifted
phosphorus signal at d = 67.9 ppm and the 1H NMR
spectrum (anhyd DMSO-d6) exhibits two widely separated
signals for the hydroxyl hydrogens at d = 13.66 ppm and d =
7.95 ppm confirming the presence of only one
Acknowledgment
We are grateful to NSERC Canada for continuing support and to
Merck Frosst Canada for an unrestricted grant. O.M.D. acknowled-
ges with gratitude the NATO organization for a NATO Science Fel-
lowship (2004-06). T.B. is an NSERC Undergraduate Summer
Research Awardee, 2006.
intramolecular (C1)OH–O=P hydrogen bond. A similar
phenomenon was observed in benzene-d6 solution.
Crystallographic data (excluding structure factors) for the
structure of 4 have been deposited with the Cambridge
Synlett 2006, No. 18, 2908–2913 © Thieme Stuttgart · New York

LETTER
Mixed Naphthyl-Phenyl Phosphine Ligand Motif for Heck Reactions
2913
Crystallographic Data Centre as supplementary publication
no. CCDC-609270. Copies of the data can be obtained free
of charge on application to CCDC, 12 Union Road,
Cambridge CB21EZ, UK [fax: +44(1223)336033; e-mail:
deposit@ccdc.cam.ac.uk).
(16) (a) Coumhe, T.; Lawrence, N. J.; Muhammad, F.
Tetrahedron Lett. 1994, 35, 625; and references cited
therein. (b) Replacement of (EtO)3SiH with the more
economical and non-toxic polyhydromethylsiloxane
(PMHS), as suggested in the above reference, was similarly
effective (110 °C, 56 h) but caused problems of incomplete
separation of polymeric siloxanes in column
chromatography.
(17) Use of an equimolar ligand 7:Pd(OAc)2 ratio produced a
very active catalyst, leading to 50% product formation in 15
min in DMF or MeOH at 40 °C (Table 1, entry 1).
(18) (a) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P.
Angew. Chem. Int. Ed. 2004, 43, 2206. (b) Macklin, T.;
Snieckus, V. In Handbook of C–H Transformations; Dyker,
G., Ed.; Wiley-VCH: Weinheim, 2005, 106.
(19) For previous cross-coupling of hindered benzamides which
required special conditions and led to poorer yields, see: Fu,
J.-m.; Sharp, M. J.; Snieckus, V. Tetrahedron Lett. 1988, 29,
5459.
(20) (a) Monguchi, M.; Kume, A.; Hattori, K.; Maegawa, T.;
Sajiki, H. Tetrahedron 2006, 62, 7926. (b) Review: Alonso,
F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2002, 102, 4009.
(c) Morra, M. J.; Borek, V.; Koolpe, J. J. Environ. Qual.
2000, 29, 706; and refs cited therein.
Figure 2 X-ray crystal structure of 4. For clarity, hydrogen
atoms are excluded except those involved in hydrogen bon-
ding.
(21) Reviews: (a) Qadir, M.; Möchel, T.; Hii, K. K. Tetrahedron
2000, 56, 7975. (b) Beletskaya, I. P.; Cheprakov, A. V.
Chem. Rev. 2000, 100, 3009. (c) Oestreich, M. Eur. J. Org.
Chem. 2005, 783.
(14) For similar nucleophilic aromatic substitutions driven by
coordination effects, see: (a) Meyers, A. I.; Hummelsbach,
R. J. J. Am. Chem. Soc. 1985, 107, 682. (b) Review:
Meyers, A. I.; Nelson, T. D.; Moorlag, H.; Rawson, D. J.;
Merier, A. Tetrahedron 2004, 60, 4459. (c) For recent
work, see: Qiu, L.; Kwong, F. Y.; Wu, J.; Lam, W. H.; Chan,
S.; Yu, W.-Y.; Li, Y. M.; Guo, R.; Zhou, Z.; Chan, A. S. C.
J. Am. Chem. Soc. 2006, 128, 5955.
(22) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989.
(23) For hindered examples, Table 1, entry 2: S-phos (93%),6a
Nap-Phos: (98%); entry 3: S-phos (82%),6a Nap-Phos:
(76%); entry 4: S-phos (86%),6a Nap-Phos (70%).
(24) A preliminary PM3 modeling study shows a low
racemization barrier (20 kcal/mol) for Nap-Phos which
precludes its use as a chiral ligand in cross coupling
reactions under conditions described herein. Few chiral non-
racemic atropisomeric ligand motifs are known. For
discussion, see ref. 14c.
(15) Reduction attempts on 5 using MeI/LiAlH4 and PhSiH3
were also unsuccessful. See: Imamoto, T.; Kikuchi, S.;
Miura, T.; Wada, Y. Org. Lett. 2001, 3, 87.
Synlett 2006, No. 18, 2908–2913 © Thieme Stuttgart · New York