Solid-phase Suzuki coupling for C-C bond formation

Full text of DOI:10.1021/jo9604301

J . Org. Chem. 1996, 61, 5169-5171
5169
Solid -P h a se Su zu k i Cou p lin g for C-C Bon d
Sch em e 1
F or m a tion
J oseph W. Guiles,* Sigmond G. J ohnson, and
William V. Murray
The R. W. J ohnson Pharmaceutical Research Institute, 1000
Route 202, P.O. Box 300, Raritan, New J ersey 08869
Received March 1, 1996
In tr od u ction
Methods describing the use of polymer supports for
performing chemical reactions in a heterogeneous me-
1
,2
dium are enjoying a pronounced resurgence.
This
renewed interest has been sparked by the combinatorial
synthesis of pharmaceutically interesting compounds.3
Newly emerging solid phase synthesis techniques for the
formation of nonpeptidic C-C bonds include 1,3-cycload-
4
5
ditions, palladium-catalyzed couplings, Mitsonubu cou-
pling,6 enolate alkylation,7 and reductive amination.8
Optimization of these reactions is central for performing
multiple simultaneous syntheses in the generation of
compound libraries. Additionally, performing chemistry
in an automated fashion may place restrictions on
temperature and pressure. Palladium-catalyzed coupling
Ta ble 1. P olym er Bou n d Bip h en yl Cou p lin g a t Room
Tem p er a tu r e
b
conversion
(% yield )
c
time
(h)
entry
ArI
catalysta
of biphenyl
via Stille or Suzuki reactions are powerful methods for
1
2
3
4
5
6
7
8
3-I
3-I
3-I
4-I
3-I
2-I
3-I
3-I
PdCl2(dppf)
18
18
20
18
18
18
2
0
0
C-C bond formation.9 These reactions generally result
NiCl (dppp)
2
Pd2(dba)3
100 (84)
100 (72)
100 (56)
57 (N.A.)
20 (N.A.)
72 (N.A.)
in excellent yields when performed at temperatures of
Pd2(dba)3
Pd(PPh3)4
Pd(PPh3)4
Pd2(dba)3
Pd2(dba)3
5
0-80 °C. Adapting these powerful C-C coupling reac-
d
5
a,c,7,10
tions to a resin mounted procedure is of interest.
Reported herein are the results from our study on the
generality of the solid-phase Suzuki reaction.
6
a
-10 mol %, 2 equiv of K2CO3 in DMF. b Conversion estimated
5
from 1H NMR and HPLC. c Isolated yield based on loading of
Discu ssion
d
iodobenzoic acid (mmol/g resin). 2% H2O-DMF.
The central objective for performing our chemistry on
a solid support was to identify a general set of conditions
that allows for complete conversion to product, over a
wide range of substrates. Commercially available resins
(SASRIN11 or Wang12 ) 1 were coupled with an iodo-
benzoic acid such as 2 via standard protocol with
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide, EDCI,
and 1-hydroxybenzotriazole, HOBT, to provide resin 3
(Scheme 1).
Numerous catalysts were investigated to effect the
coupling of 3 with phenylboronic acid 4, at room tem-
perature (Table 1). Commercial Pd(0) sources, tris-
(
1) (a) Merrifield, R. B. J . Am. Chem. Soc. 1963, 85, 2149. (b) Leznoff,
C. C. Acc. Chem. Res. 1978, 11, 327.
2) (a) DeWitt, S. H.; Kiely, J . S; Stankovic, C. J .; Schroeder, M. C.;
Cody, D. M. R.; Pavia, M. R. Proc. Natl. Acad. Sci. U.S.A. 1993, 90,
(
6
1
5
3
909. (b) Bunin, B. A.; Ellman, J . A. J . Am. Chem. Soc. 1992, 114,
0997. (c) Moon, H.; Schore, N. E.; Kurth, M. J . J . Org. Chem. 1992,
7, 6088. (d) Hutchins, S. M.; Chapman, K. T. Tetrahedron Lett. 1994,
5, 4055. (e) Ahlberg R. L. A.; Miller, R. B.; J ones, A. D.; Kurth, M. J .
(dibenzylideneacetone)dipalladium {Pd
2
3
(dba) } or tetrakis-
(
triphenylphosphine)palladium {Pd(PPh )
3 4
} were found
J . Am. Chem. Soc. 1994, 116, 2661.
3) (a) Houghten, R. A.; Pinilla, C.; Blondelle, S. E.; Appel, J . R.;
Dooley, C. T.; Cuervo, J . H. Nature 1991, 354, 84. (b) Gallop, M. A.;
Barret, R. W.; Dower, W. J .; Fodor, S. P. A.; Gordon, E. M. J . Med.
Chem. 1994, 37, 1233. (c) Gordon, E. M.; Barret, R. W.; Dower, W. J .;
Fodor, S. P. A.; Gallop, M. A. J . Med. Chem. 1994, 37, 1385.
to be very effective catalysts. Whereas, Pd(II) or Ni(II)
catatlysts such as [1,1′-bis(diphenylphosphino)ferrocene]-
(
palladium chloride, {PdCl
nylphosphino)propane]nickel chloride {NiCl
2
(dppf)} and [1,1′-bis(diphe-
(dppp)} were
2
ineffective. At room temperature the couplings were
found to proceed at a modest rate, requiring approxi-
mately 18 h for completion (entry 3 vs 7, 8). The coupling
of o-iodobenzoate was noticeably slower than its meta or
para congeners, perhaps as a response to steric crowding
(
4) (a) Beebe, X.; Schore, N. E.; Kurth, M. J . J . Am. Chem. Soc. 1992,
14, 10061. (b) Pei, Y.; Moos, W. H. Tetrahedron Lett. 1994, 35, 5825.
c) Murphy, M. M.; Schullek, J . R.; Gordon, E. M.; Gallop, M. A. J .
Am. Chem. Soc. 1995, 117, 7029.
5) (a) Deshpande, M. S. Tetrahedron Lett. 1994, 35, 5613. (b) Yu,
K.-L., Deshpande, M. S.; Vyas, D. M. Tetrahedron Lett. 1994, 35, 8919.
c) Sucholeiki, I.; Forman, F. W. J . Org. Chem. 1995, 60, 523. (d)
1
(
(
(
(entry 6). The bromo-substituted benzoate analogs were
Plunkett M. J .; Ellman, J . A. J . Am. Chem. Soc. 1995, 117, 3306. (e)
Hiroshige, M.; Hauske, J . R.; Zhou, P. Tetrahedron Lett. 1995, 36, 4567.
found to be completely unreactive under similar reaction
conditions. The benzoate is cleaved from the polymer
support with dilute trifluoroacetic acid in 30 min provid-
ing the biaryl acid product 5. The purity of the cleaved
(
f) Goff, D. A.; Zuckermann, R. N. J . Org. Chem. 1995, 60, 5748.
6) Krchnak, V.; Flegelova, Z.; Weichsel, S. A.; Lebl, M. Tetrahedron
Lett. 1995, 36, 6193.
(
(
(
7) Ellman, J . A.; Backes, B. J . J . Am. Chem. Soc. 1994, 116, 11171.
8) Steele, J .; Gordon, D. W.; Bioorg. Med. Chem. Lett. 1995, 5, 47.
1
biaryl products was verified by HPLC and H NMR and
Bray, A. M.; Chiefari, D. S.; Valerio, R. M.; Maeji, N. J . Bioorg. Med.
Chem. Lett. 1995, 5, 5081.
routinely found to be >95%. The isolated yields were
(
9) (a) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b)
Suzuki, A. Pure Appl. Chem. 1985, 57, 1749.
10) (a) Reference 7. (b) Friesen, R. W.; Frenette, R. W. Tetrahedron
Lett. 1994, 35, 9177.
(11) Mergler, M.; Tanner, R.; Gosteli, J .; Grogg, P. Tetrahedron Lett.
1988, 29, 4005.
(12) Wang, S.-S. J . Am. Chem. Soc. 1973, 95, 1328.
(
S0022-3263(96)00430-6 CCC: $12.00 © 1996 American Chemical Society

5
170 J . Org. Chem., Vol. 61, No. 15, 1996
Ta ble 2. Cou p lin g of P olym er Bou n d Ar yl Iod id e w ith Bor on Rea gen ts
Notes
a
-10 mol % catalyst, 2 equiv of K2CO3 in DMF at rt. b Conversion estimated from 1H NMR and HPLC. c Reaction required heating
5
d
at 70 °C. TMS removal with TBAF/THF, followed by cleavage with MeOH/MeONa (3.0 equiv)/THF, 1 h.
Sch em e 2
Ta ble 3. Cou p lin g of P olym er Bou n d Ar yl Bor on a te 7
reaction
time, h
%conversion
entrya
ArXb
R, R′
H, H
to 9
c
1
2
3
4
5
I
I
I
Br
Br
24
48
24
48
24
43
60
59
H, H
NO2, H
H, OMe
CN, H
d
62
77 (100)e
d
a
5
mol % Pd(PPh3)4, 6 equiv of K2CO3, 10% H2O added to all
b
c
reactions. 6 equiv of ArX added to all reactions. GC/MS analy-
sis. d Reaction heated to 55 °C. e Resin submitted to two couplings.
best for reactions involving the alkenylborane, in sharp
contrast to its complete lack of activity in the biphenyl
coupling.
The irreversible immobilization of an aryl boronic acid
and subsequent Suzuki coupling has been described
previously.13 The resin bound aryl boronic acid reagent
7, prepared by standard coupling procedures, has been
found to couple with a variety of substituted bromo- or
iodobenzenes 8 (Scheme 2). Initial studies have shown
that the resin-bound boronate couplings proceed at a
slower rate than the resin-bound aryl iodides, (Table 3).
In general, the couplings proceed to within 40-77% of
completion after 24 or 48 h, with the balance as unreacted
boronate. The reactions may be driven to completion
somewhat variable, but routinely >56% based upon
loading of the iodobenzene (mequiv/g resin).
This method was next investigated for the formation
of a variety of other C-C bonds onto an aromatic ring. A
diverse scope of boronic coupling agents (heteroaryl,
alkyl, alkenyl, and alkynyl) were chosen. This wide array
of coupling partners was optimized under conditions
similar to those used for the phenylboronic acid coupling
(
Table 2). The optimal Pd catalyst was found to vary
depending upon the boronic coupling partner. The aryl
or heterobiarylboronic acids exhibited excellent conver-
(13) Wulff, G.; Schmidt, H.; Witt, H.; Zentel, R. Angew. Chem., Int.
2 3 2
sion with Pd (dba) . The PdCl (dppf) catalyst worked
Ed. Engl. 1994, 33, 188.

Notes
J . Org. Chem., Vol. 61, No. 15, 1996 5171
upon resubmission to the reaction conditions (entry 5).
Where aryl bromides were employed the reaction pro-
ceeded only upon heating.
theoretical load) was swelled in DMF (10 mL) for 10 min. To
this slurry was added, 1-hexynyldiisopropoxyborane (99 mg, 0.47
mmol, prepared by literature procedure from 1-hexyne and
1
5
triisopropoxyborane ), PdCl
2 2
(dppf) (17 mg, 0.021 mmol), and K -
In conclusion, procedures for resin bound Suzuki
coupling at both ambient and elevated temperatures to
form a wide array of substituted benzoates has been
described. The mild reaction conditions are viewed as
being well suited for robotic synthesis and the generation
of combinatorial or traditional libraries. A more thor-
ough examination of the resin-bound boronate coupling
and its application are under investigation.
CO (118 mg, 0.85 mmol). The mixture was stirred or swirled
for 20 h under a nitrogen atmosphere. The resin was filtered
3
and washed alternately with DMF/H O (4:1), followed by MeOH
2
and CH
CH Cl
with CH
in vacuo. Alternatively, the Wang-bound product was treated
with TFA/CH Cl (1:1, 4 mL) for 30 min. The filtrate was
concentrated in vacuo and the product, 4-(1-hexynyl)benzoic acid
2
Cl
(2%, 2 mL) for 30 min, the resin was filtered and washed
Cl /MeOH (2 mL), and the filtrate was concentrated
2
. The SASRIN-bound product was treated with TFA/
2
2
2
2
2
2
(65 mg), isolated in 91% overall yield.
Gen er a l Meth od for Resin -Bou n d Ar ylbor on a te Cou -
Exp er im en ta l Section
p lin g. The phenyldioxaborinane 6, prepared via the procedure
of Takahashi,16 was coupled to Wang resin (vida infra) to
generate 7. Resin-bound phenyldioxaborinane 7 (0.100 g, 0.628
mmol/g theoretical load) was swelled in DMF (2 mL) for 10 min.
High and low resolution mass spectra were recorded using
desorption chemical ionization and electrospray ionization.
Analytical reversed-phase HPLC was carried out on a YMC
ODS-A C-18 column with gradient elution (CH
3
CN/H
2
O/
To this slurry were added iodobenzene (51 µL, 0.45 mmol), K
2
-
1
0
.1%TFA) and UV detection at 254 and 280 nM. H NMR
CO (62 mg, 0.45 mmol), Pd(PPh (4 mg, 0.003 mmol), and H O
3
3
)
4
2
spectra were recorded at 300 MHz. All compounds exhibited
H NMR and mass spectral data in agreement with those
previously reported.
(200 µL). The mixture was swirled for 24 h under a nitrogen
atmosphere and then the resin collected on a medium porosity
fritted glass funnel. The resin was washed alternately with 50%
1
Ma ter ia ls. All solvents were Fisher HPLC grade and used
as received. Reagents were obtained from Aldrich with the
following exceptions: SASRIN resin obtained from Bachem,
Wang resin from Advanced Chemtech, and thiophene-2-boronic
acid through Lancaster. The 1-alkenyl and alkynyl boronates
MeOH(aq) and DMF followed by MeOH and CH
bound product 9 was treated with TFA/CH Cl
30 min, the resin was filtered and washed with CH
2
Cl
(1:1, 2 mL) for
Cl /MeOH
(2 mL), and the filtrate was concentrated in vacuo. The solid
residue was suspended in CHCl /MeOH (3:1, 3 mL) and chilled
2
. The resin-
2
2
2
2
3
1
4,15
were prepared according to literature procedure.
agents were used without further purification.
All re-
in an ice bath, and (trimethylsilyl)diazomethane (2 M in hex-
anes) was added until a yellow color persisted. After 10 min
the ice bath was removed and the sample swirled for ap-
proximately 3 h. The sample was concentrated in vacuo and
analyzed by GC/MS.
Gen er a l Meth od for Atta ch m en t of Su bstitu ted P h en y-
la cetic Acid s. SASRIN resin (9.93 g, 0.89 mmol/g) was first
swelled in CH
2 2
Cl (200 mL) for approximately 10 min. In
sequential order 4-iodobenzoic acid (2.63 g, 10.6 mmol), Et
3
N
(
1.48 mL, 10.6 mmol), EDCI‚HCl (2.03 g, 10.6 mmol), and HOBT
Ack n ow led gm en t. The authors wish to thank Scott
Easlick and William J ones for mass spectrometry data,
and Ken Allison for literature searches.
(0.143 g, 1.60 mmol) are added to the reaction vessel at ambient
temperature. The reaction was stirred for 20 h and then filtered
and washed with DMF (3×) and CH Cl (3×) and dried in vacuo.
Mass recovery was used to determine resin loading after
cleavage of an aliquot with 2% TFA/CH Cl . Typically, coupling
2
2
Su p p or tin g In for m a tion Ava ila ble: Copies of sample
HPLC, GC/MS, and NMR spectra (3 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
2
2
was achieved with greater than 95% efficiency (the above
sequence was repeated for optimal coupling).
Gen er a l Meth od for Resin -Bou n d Ar yl Iod id e Cou p lin g.
SASRIN-bound 4-iodobenzoic acid 3 (0.480 g, 0.738 mmol/g
J O9604301
(
14) (a) Vaultier, M.; J ehanno, E. Tetrahedron Lett. 1995, 36, 4439.
b) Hoffmann, R. W.; Dresely, S. Synthesis 1988, February, 103.
15) Brown, H. C.; Bhat, N. G.; Srebnik, M. Tetrahedron Lett. 1988,
9, 2631.
(
(
(16) Matsubara, H.; Seto, K.; Tahara, T.; Takahashi, S. Bull. Chem.
Soc. J pn. 1989, 62, 3896.
2