Suzuki-miyaura cross-couplings mediated by trans-PdBr(N-Succ)(PPh 3)2: A convenient synthetic method for diarylmethanes and aryl(heteroaryl)- methanes

Article abstract of DOI:10.1055/s-0028-1083293

Diarylmethanes can be accessed efficiently by Suzuki-Miyaura cross-couplings of arylboronic acids with benzyl halides mediated by trans-PdBr(N-Succ) (PPh₃)₂. The methodology can be applied to the synthesis of aryl(heteroaryl)methanes. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0028-1083293

5
08
PRACTICAL SYNTHETIC PROCEDURES
Suzuki–Miyaura Cross-Couplings Mediated by trans-PdBr(N-Succ)(PPh ) :
3
2
A Convenient Synthetic Method for Diarylmethanes and Aryl(heteroaryl)-
methanes
S
I
ynthesi
a
s
of
D
iarylm
n
e
thanes andAryl(
J
heteroaryl
.
)methane
s
S. Fairlamb,* Petr Sehnal, Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK
Fax +44(1904)432516; E-mail: ijsf1@york.ac.uk; E-mail: rjkt1@york.ac.uk
Received 4 September 2008; revised 8 September 2008
PSP
No146
Abstract: Diarylmethanes can be accessed efficiently by Suzuki–Miyaura cross-couplings of arylboronic acids with benzyl halides medi-
ated by trans-PdBr(N-Succ)(PPh ) . The methodology can be applied to the synthesis of aryl(heteroaryl)methanes.
3
2
Key words: catalysis, palladium, pseudohalide, phosphine
Procedure 1
Procedure 1
trans-PdBr(N-Succ)(PPh ) , (1, 0.1 mol%)
trans-PdBr(N-Succ)(PPh3)2, (1, 0.1 mol%)
3
2
2
M Na2CO3–THF (1:2, v/v),
0 °C, 40 h
2 M Na2CO3–THF (1:2, v/v),
0 °C
6
6
Br
Br
B(OH)2
B(OH)2
F
2
b
NO2
5 g, 23 mmol)
NO2
4b
2a
4a
3
a
(12.5 g, 73 mmol)
F
3b
(12.02 g, 88%)
(
(4.71 g, 96%)
(
2.82 g, 23 mmol)
(10.23 g, 73 mmol)
Procedure 2
1
. as for Procedure 1,
using 0.01 mol% Pd
2
a
4a
(
25 g, 0.116 mol)
(17.19 g, 70%)
3
a
(
14.11 g, 0.116 mol)
. 35% aq NH3–2-PrOH (1:1, v/v),
0 °C, 15 h
2
4
Scheme 1
Palladium(0)-catalysed carbon–carbon bond-forming could be used on small-scale (0.8 mmol with respect to 2).
1,2
processes are used widely in synthetic chemistry. The The central aim of this paper is to report convenient pro-
portfolio of catalyst systems available for the coupling of cedures for the gram-scale synthesis of diarylmethanes
aryl and heteroaromatic components has increased com- using exemplar cross-coupling substrates (Scheme 1).
mensurately with growing applications for such process- The broader scope of the methodology is also highlighted.
es. Organ’s recently developed PEPPSITM catalysts are
3
–5
6
The reaction of 3-nitrobenzyl bromide (2a; 23 mmol) with
phenylboronic acid (3a; 23 mmol) to give 1-benzyl-3-ni-
trobenzene (4a) was run initially using 0.1 mol% 1 at
of particular note. In the last few years we have exploited
the reactivity of palladium(II) complexes possessing suc-
7
cinimide and related ligands in cross-coupling processes,
for example, Sonogashira, Suzuki–Miyaura, and Stille.
6
0 °C (Procedure 1). A longer reaction time (40 h) was re-
quired than for the smaller-scale reaction (at 0.8 mmol),
but pleasingly 4a was produced in 96% yield. Running the
reaction under similar conditions, but using 1 at 0.01
mol% loading (Procedure 2), with increasing substrate
quantities (0.116 mol), a 78% conversion into 4a was de-
8
The synthesis of diarylmethanes is difficult using a vari-
9
ety of palladium catalyst systems, which led us to inves-
tigate the precatalyst, trans-PdBr(N-Succ)(PPh ) (1), for
3
2
the cross-coupling of arylboronic acids with benzyl bro-
1
0
mides 2. These reactions can be run at low palladium
loadings (typically 1 mol%). For a few examples we were
able to demonstrate that loadings as low as 0.01 mol%
1
termined by H NMR spectroscopy after 40 hours. Whilst
unreacted 2a is inseparable from 4a by silica gel chroma-
tography, heating the crude product mixture to 40 °C in
aqueous ammonia in propan-2-ol for 15 hours allows 2a
to be removed as the benzylammonium salt. The product
4a is then isolated by filtration through a short silica gel
column in 70% yield.
SYNTHESIS 2009, No. 3, pp 0508–0510
x
x
.
x
x
.2
0
0
8
Advanced online publication: 19.12.2008
DOI: 10.1055/s-0028-1083293; Art ID: Z20708SS
Georg Thieme Verlag Stuttgart · New York
©

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of Diarylmethanes and Aryl(heteroaryl)methanes
509
Table 1 Cross-Couplings Using Precatalyst 1a
1
(1 mol%)
2
M Na2CO3–THF (1:2, v/v),
60–80 °C (see Table)
Br
R
ArB(OH)2
Entry
1
ArB(OH)2
Cross-coupled product
Yield
(
HO)2B
7
7% (3 h); 97% (3 h at 80 °C)
[
from BnCl (80 °C): 90% (3 h)]
OMe
OMe
F
(
HO)2B
F
6
9% (5 h)
2
[
from BnCl (80 °C): 97% (5 h)]
F
S
F
S
(
HO)2B
HO)2B
91% (4 h)
3
4
b
9
8% (3 h)
(
S
S
S
79% (4 h)
Cl
Cl
O
[from BnCl (80 °C): 83% (4 h)]
79% (4 h)
O
(
HO)2B
S
S
5
6
[
from BnCl (80 °C): 82% (4 h)]
(
HO)2B
HO)2B
S
60% (4 h)
[from BnCl (80 °C): 54% (4 h) ]
CHO
c
CHO
(
O
O
7
94% (2 h)b
a
Reactions were run at 60 °C, unless otherwise stated.
Amount of organoboronic acid used = 1.5 equiv.
A small amount of protodeborylation was observed (~10%).
b
c
Scale-up was also carried out for the reaction of benzyl alyst 1 is that both lower palladium loadings and lower re-
bromide (2b) with 4-fluorophenylboronic acid (3b) using action temperatures can be used.
0
.1 mol% of 1 at 60 °C for 40 hours, which afforded 1-
benzyl-4-fluorobenzene (4b) in 88% yield (Procedure 1).
The broader scope of the methodology is exemplified by stored under N
All solvents were dried using standard procedures prior to use and
. TLC analyses were performed using Merck 5554
aluminum-backed silica plates. Compounds were visualised using
UV light (254 nm) and a solution of cerium sulfate tetrahydrate and
2
the cross-couplings of benzyl bromides or chlorides with
a series of arylboronic acids or heteroarylboronic acids
phosphomolybdic acid in 10% aq H SO . Column chromatography
1
0
2
4
(
Table 1).
was performed with silica gel 60 (35–70 mm) purchased from Ald-
Both activated and deactivated arylboronic acids react rich. NMR spectra were recorded on a Jeol ECX400 or Jeol EX270
1
13
spectrometer, H and C NMR spectra were referenced using resid-
ual solvent peak. Electron ionisation (EI) measurements were per-
formed by Dr. T. A. Dransfield on a Fisons analytical VG Autospec
instrument.
with either benzyl bromide or benzyl chloride in good
yields (entries 1 and 2, respectively). Several thiophene-2-
boronic acids are also effectively coupled (entries 3–6).
Finally, cross-coupling of the hydrolytically sensitive fu-
ran-2-boronic acid with benzyl bromide is possible, pro-
vided that an excess of the boronic acid is used (entry 7).
The benzyl halides and organoboronic acids are commercially
available and were used as received: 3-nitrobenzyl bromide (98+%,
Cat. No. A 14310), phenylboronic acid (98+%, Cat. No. A 14257),
In conclusion, we have developed a convenient method and benzyl bromide (99%, Cat. No. A 13535) were from Alfa
Aesar; Pd[(N-succ)Br(PPh ) ] (97%, Cat. No. 643742) was from
for the gram-scale synthesis of diarylmethanes. The
broader scope of the method to give aryl(heteroaryl)meth-
anes has been highlighted. Our methodology comple-
ments other recently reported conditions for the cross-
coupling of benzyl chloride with various organoboronic
3 2
Aldrich; and 4-fluorophenylboronic acid (97%, Cat. No. 006182)
was from Fluorochem. Petroleum ether (PE) used refers to the frac-
tion boiling in the range 40–60 °C.
Furan-2-boronic acid and thiophene-2-boronic acid were found to
degrade rapidly at r.t. and repeatable results could only be achieved
when these were stored at –20 °C and used within several weeks.
1
1
acids [using Pd(PPh ) ]. The advantage of using precat-
3
4
Synthesis 2009, No. 3, 508–510 © Thieme Stuttgart · New York

5
10
I. J. S. Fairlamb et al.
PRACTICAL SYNTHETIC PROCEDURES
1
Procedure 1
sion (by H NMR spectroscopic analysis). The mixture was cooled
Gram-Scale Synthesis of 1-Benzyl-3-nitrobenzene (4a) Using
to r.t. and extracted with Et O (2 × 100 mL). The combined organic
2
0
.1 mol% trans-Pd[(N-succ)Br(PPh ) ] (1)
phases were dried (Na SO ), filtered, and evaporated with silica gel
3
2
2
4
A 250 mL three-necked flask was charged with 3-nitrobenzyl bro-
mide (2a; 5.0 g, 23.1 mmol, 1.0 equiv), phenylboronic acid (3a;
(100 g). The crude product adsorbed on silica gel was transferred
onto a short silica gel column. Elution with PE gave the desired 1-
benzyl-4-fluorobenzene (4b) as a colourless oil; yield: 12.02 g
1
3
2
.82 g, 23.1 mmol, 1.0 equiv), and trans-Pd(N-succ)Br(PPh ) (18.7
3
2
mg, 23.1 mmol, 0.1 mol%) under N . Degassed THF (58 mL) was
(88%).
1
2
added via cannula and the mixture was stirred at r.t. (ca. 23 °C) for
H NMR (400 MHz, CDCl ): d = 7.30 (t, J = 7.3 Hz, 2 H), 7.23–
3
1
0 min until the starting materials were fully dissolved. A solution
7
1
.12 (m, 5 H), 6.97 (t, J = 8.7 Hz, 2 H), 3.96 (s, 2 H).
of anhyd Na CO (2 M in degassed H O, 29 mL) was added via sy-
ringe. The reaction flask was fitted with a reflux condenser under a
stream of N . The mixture was then stirred vigorously and heated to
6
2
3
2
3
C NMR (100 MHz, CDCl ): d = 161.4 (d, J = 243.9 Hz), 140.9
3
C,F
(
d, JC,F = 1.0 Hz), 136.7 (d, J = 3.2 Hz), 130.3 (d, JC,F = 7.8 Hz),
C,F
2
1
28.8, 128.5, 126.2, 115.2 (d, JC,F = 21.2 Hz), 41.0.
0 °C for 40 h. The mixture was cooled to r.t. and extracted with
Et O (2 × 50 mL). The combined organic phases were dried
+
2
MS (EI): m/z (%) = 186 ([M ], 100), 171 (9), 165 (28), 109 (18), 91
(Na SO ), filtered, and evaporated with silica gel (50 g). The crude
2 4
(14).
product adsorbed on silica gel was transferred onto a short silica gel
column. Elution with PE–Et O (100:0 → 90:10, v/v) gave the de-
sired 1-benzyl-3-nitrobenzene (4a) as a light yellow oil; yield: 4.71
The characterisation data for the compounds listed in Table 1 can be
found in reference 10.
2
g (96%).
1
H NMR (400 MHz, CDCl ): d = 8.09–8.05 (m, 2 H), 7.52 (d, Acknowledgment
3
J = 7.6 Hz, 1 H), 7.47–7.43 (m, 1 H), 7.33 (t, J = 7.3 Hz, 2 H), 7.25
We are grateful to the EPSRC for funding (EP/D078776/1) and the
Royal Society and Astra-Zeneca (Dr. D. M. Hollinshead) for an un-
restricted research award (to I.J.S.F).
(
1
t, J = 7.3 Hz, 1 H), 7.19 (d, J = 7.2 Hz, 2 H), 4.08 (s, 2 H).
3
C NMR (100 MHz, CDCl ): d = 148.4, 143.2, 139.3, 135.1, 129.3,
3
1
28.9, 128.8, 126.7, 123.7, 121.3, 41.5.
+
MS (EI): m/z (%) = 213 ([M ], 100), 196 (21), 165 (83), 152 (32).
References
Procedure 2
(
1) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.;
de Meijere, A.; Diederich, F., Eds.; Wiley-VCH: New York,
2004.
Gram-Scale Synthesis of 1-Benzyl-3-nitrobenzene (4a) Using
0
.01 mol% trans-Pd[(N-succ)Br(PPh ) ] (1)
3 2
A 1000 mL three-necked flask was charged with 3-nitrobenzyl bro-
mide (2a; 25.0 g, 115.7 mmol, 1.0 equiv), phenylboronic acid (3a;
(
2) Transition Metals for Organic Synthesis, 2nd ed., Vol. 1;
Beller, M.; Bolm, C., Eds.; Wiley-VCH: Weinheim, 2004.
1
4.11 g, 115.7 mmol, 1.0 equiv), and trans-Pd(N-succ)Br(PPh3)
2
(3) Nguyen, H.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 11818; and references cited therein.
(
(
(6) O’Brien, C. J.; Kantchev, E. A. B.; Hadei, N.; Valente, C.;
Chass, G. A.; Nasielski, J. C.; Lough, A.; Hopkinson, A. C.;
Organ, M. G. Chem. Eur. J. 2006, 12, 4743; and references
cited therein.
(
9.4 mg, 11.6 mmol, 0.01 mol%) under N . Degassed THF (289 mL)
2
was added via cannula and the mixture was stirred at r.t. (ca. 23 °C)
for 10 min until the starting materials were fully dissolved. A solu-
tion of anhyd Na CO (2 M in degassed H O, 145 mL) was added
4) Zapf, A.; Beller, M. Chem. Commun. 2005, 431.
5) Bedford, R. B. Chem. Commun. 2003, 1787.
2
3
2
via syringe. The reaction flask was fitted with a reflux condenser
under a stream of N . The mixture was then stirred vigorously and
2
heated to 60 °C for 40 h after which time the reaction reached 78%
1
conversion ( H NMR spectroscopic analysis). The mixture was
(
7) (a) Fairlamb, I. J. S.; Kapdi, A. R.; Lynam, J. M.; Taylor, R.
J. K.; Whitwood, A. C. Tetrahedron 2004, 60, 5711.
cooled to r.t. and extracted with Et O (2 × 200 mL). The combined
organic phases were dried (Na SO ), filtered, and concentrated in
vacuo. The residue was suspended in a mixture of 35% aq ammonia
and propan-2-ol (1:1, v/v) and heated to 40 °C for 15 h after which
time the remaining 3-nitrobenzyl bromide (2a) was completely con-
2
2
4
(b) Chaignon, N. M.; Fairlamb, I. J. S.; Kapdi, A. R.; Taylor,
R. J. K.; Whitwood, A. C. J. Mol. Catal. A: Chem. 2004,
219, 191. (c) Serrano, J. L.; Fairlamb, I. J. S.; Sánchez, G.;
García, L.; Pérez, J.; Vives, J.; López, G.; Crawforth, C. M.;
Taylor, R. J. K. Eur. J. Inorg. Chem. 2004, 2706.
sumed (TLC). The mixture was extracted with Et O (3 × 200 mL),
the combined organic phases were then washed with 6 M aq HCl
2
(
d) Crawforth, C. M.; Fairlamb, I. J. S.; Kapdi, A. R.;
(
3 × 100 mL), dried (Na SO ), filtered, and evaporated with silica
2
4
Serrano, J. L.; Taylor, R. J. K.; Sanchez, G. Adv. Synth.
Catal. 2006, 348, 405. (e) Young, G. L.; Smith, S. A.;
Taylor, R. J. K. Tetrahedron Lett. 2004, 45, 3797.
gel (100 g). The crude product adsorbed on silica gel was trans-
ferred onto a short silica gel column. Elution with PE–Et O (100:0
2
1
2
→
90:10, v/v) gave the desired 1-benzyl-3-nitrobenzene (4a) as a
light yellow oil; yield: 17.19 g (70%). The characterisation data
NMR, MS) were identical to those reported above.
(
f) Fairlamb, I. J. S.; Taylor, R. J. K.; Serrano, J. L.; Sanchez,
G. New J. Chem. 2006, 30, 1685.
(
(
(
8) (a) McPhail, K. L.; Rivett, D. E. A.; Lack, D. E.; Davies-
Coleman, M. T. Tetrahedron 2000, 56, 9391. (b) Long, Y.-
Q.; Jiang, X.-H.; Dayam, R.; Sachez, T.; Shoemaker, R.; Sei,
S.; Neamati, N. J. Med. Chem. 2004, 47, 2561..
Gram-Scale Synthesis of 1-Benzyl-4-fluorobenzene (4b) Using
.1 mol% trans-Pd[(N-succ)Br(PPh ) ] (1) (Procedure 1)
0
3
2
A 1000 mL three-necked flask was charged with benzyl bromide
2b; 12.5 g, 73.1 mmol, 1.0 equiv), 4-fluorophenylboronic acid (3b;
0.23 g, 73.1 mmol, 1.0 equiv), and trans-Pd(N-succ)Br(PPh3)2
59.1 mg, 73.1 mmol, 0.1 mol%) under N . Degassed THF (183 mL)
9) (a) Botella, L.; Nájera, C. J. Organomet. Chem. 2002, 663,
(
1
(
46. (b) Alonso, D. A.; Nájera, C.; Pacheco, M. C. J. Org.
Chem. 2002, 67, 5588.
2
(10) Burns, M. J.; Fairlamb, I. J. S.; Kapdi, A. R.; Sehnal, P.;
was added via cannula and the mixture was stirred at r.t. (ca. 23 °C)
for 10 min until the starting materials were fully dissolved. A solu-
tion of anhyd Na CO (2 M in degassed H O, 91 mL) was added via
syringe. The reaction flask was fitted with a reflux condenser under
a stream of N . The mixture was then stirred vigorously and heated
Taylor, R. J. K. Org. Lett. 2007, 9, 5397.
(
(
11) Henry, N.; Enguehard-Gueiffier, C.; Thery, I.; Gueiffier, A.
Eur. J. Org. Chem. 2008, 4824.
12) McLaughlin, M. Org. Lett. 2005, 7, 4875.
2
3
2
2
(13) Yi, W.-B.; Cai, C. J. Fluorine Chem. 2005, 126, 831.
to 60 °C for 40 h after which time the reaction reached 96% conver-
Synthesis 2009, No. 3, 508–510 © Thieme Stuttgart · New York