Rapid microwave promoted Sonogashira coupling reactions on solid phase

Article abstract of DOI:10.1021/jo034284s

A microwave-enhanced, rapid, and efficient solid-phase version of the Sonogashira reaction is presented. It has been applied to the coupling of aryl iodides and bromides with various acetylene derivatives giving excellent yields in 15-25 min. The scopes of homogeneous, solventless, and solid-phase conditions for Sonogashira coupling of aryl halides are compared.

Full text of DOI:10.1021/jo034284s

Ra p id Micr ow a ve P r om oted Son oga sh ir a
Cou p lin g Rea ction s on Solid P h a se
possibly because of the difficulty of controlling the
reaction rate and the requirement of special heavy-walled
vials for microwave irradiation that makes resin handling
rather complicated.
M a´ t e´ Erd e´ lyi†,‡ and Adolf Gogoll*,†
In the present paper, we describe a microwave-
promoted version of the Sonogashira reaction of aryl
iodides and bromides on Rink amide linker attached to
polystyrene resin. Single mode microwave irradiation
with an automatic power control keeping the reaction
temperature constant was used throughout. Pressure,
temperature, and irradiation power vs time were moni-
tored. A unique, modified Smith Process vial was used
that provided the possibility of both simplified resin
handling and microwave heating. The vial was equipped
with a polypropylene frit and screw cap at one end and
Department of Organic Chemistry, Uppsala University,
Box 599, 751 24 Uppsala, Sweden, and Department of
Organic Pharmaceutical Chemistry, Uppsala University,
Box 574, 751 23 Uppsala, Sweden
adolf@kemi.uu.se
Received March 4, 2003
Abstr a ct: A microwave-enhanced, rapid, and efficient solid-
phase version of the Sonogashira reaction is presented. It
has been applied to the coupling of aryl iodides and bromides
with various acetylene derivatives giving excellent yields in
5-25 min. The scopes of homogeneous, solventless, and
solid-phase conditions for Sonogashira coupling of aryl
halides are compared.
was sealed with an aluminum crimp cap fitted with a
silicon septum at the other end.7
1
Our optimization studies have been performed for the
coupling of moderately reactive trimethylsilylacetylene
with 3-haloaryl-substituted resins. The conditions pro-
ducing full conversion of these compounds were then
applied to further substrates. In reactions involving the
The Sonogashira cross-coupling is an important ex-
ample of metal-catalyzed carbon-carbon bond-forming
reactions.1 It has been applied to the preparation of
various target compounds, many of them being of phar-
3 2 2
more reactive aryl iodides, the use of 5% Pd(PPh ) Cl
catalyst and 10% CuI cocatalyst at 120 °C, in a 3:1
mixture of diethylamine and DMF, gave full conversion
within 15 min. To achieve cross-coupling of aryl bromides
with full conversion within 25 min, the presence of 10%
2
maceutical interest. Some weaknesses of the original
procedure are long reaction times (hours to days), limited
choice of aryl halides, and complicated workup proce-
palladium catalyst, 20% of CuI, and 20% PPh
3
was
3
dures. Recently, we have developed an improved meth-
required when using the same temperature and solvent
mixture. During the trifluoroacetic acid mediated cleav-
odology that allows the use of aryl iodides, as well as less
reactive aryl bromides, triflates, and chlorides under
3
age of products from the resin, the SiMe group of 1 was
homogeneous conditions using microwave heating.2
A
lost, as has been reported for similar conditions.
5c,f
8
microwave-assisted solventless procedure for the Sono-
gashira coupling of aryl iodides has also been reported
Likewise, the Boc or Fmoc protecting groups of 4 and 5
were removed, and an acid-catalyzed rearrangement of
3 to the thermodynamically most stable conjugated R,â-
unsaturated ketone was observed. The Sonogashira
coupling of polymer-bound 3-chlorophenol was attempted
using similar conditions as for the coupling of aryl bro-
mides, but was without success. The use of an o-tolyl-
phospine complex of palladium in the presence of
4
by others. In this paper, we describe an efficient solid-
phase version of the Sonogashira reaction of aryl iodides
and bromides using controlled microwave heating.
Solid-phase organic synthesis (SPOS) is an efficient
methodology for the production of combinatorial libraries
and is extensively used by the pharmaceutical and the
agricultural industries. The application of a polymer
support offers the advantage of automatization and ease
of purification. However, this approach often is limited
by the narrower choice of reactants and reaction medium
and by longer reaction times. Examples for a Sonogashira
2 3
Cs CO base was recently described to be advantageous
9
for coupling of aryl chlorides. Therefore, reactions were
performed using 10% of palladium o-tolylphosphine
catalyst and 1 equiv of ZnCl
2
cocatalyst in the presence
of Cs CO , but without giving any improvement. In the
2
3
5
3+
coupling on solid phase were reported recently, but these
Heck reaction of aryl bromides, the presence of Tl
additive was proposed to promote halide abstraction.
1
0
procedures suffer from the demand of long reaction times
(
5-120 h) and the large amount of catalysts required
(10-40%). Enhancements of SPOS by the use of micro-
(5) (a) Izumi, M.; Fukase, K.; Kusumoto, S. Synlett 2002, 9, 1409.
(b) Liao, Y.; Fathi, M.; Zhang, Y.; Yang, Z. Tetrahedron Lett. 2001, 42,
6
wave heating have so far received limited attention,
1
815. (c) Zhang, H.-C.; Brumfield, K. K.; Maryanoff, B. E.Tetrahedron
Lett. 1997, 38, 2439. (d) Wu, T. Y. H.; Ding, S.; Gray, N. S.; Schults, P.
G. Org. Lett. 2001, 3, 3827. (e) Sammelson, R. E.; Kurth, M. J . Chem.
Rev. 2001, 101, 137. (f) Dai, W.-M.; Guo, D.-S.; Sun, L.-P. Tetrahedron
Lett. 2001, 41, 5275.
†
Department of Organic Chemistry.
Department of Organic Pharmaceutical Chemistry.
‡
(
1) Metal-catalyzed Cross-coupling Reactions; Diederich, F., Stang,
P. J ., Eds.; J ohn &Wiley & Sons Ltd.: New York, 1998.
2) Erd e´ lyi, M.; Gogoll, A. J . Org. Chem. 2001, 66, 4165 and
references therein.
3) (a) Thorand, S.; Krause, N. J . Org. Chem. 1998, 63, 8551. (b)
Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C. Org. Lett.
(6) (a) Stadler, A.; Kappe, C. O. Eur. J . Org. Chem. 2001, 919. (b)
Kuster, G.; Scheren, H. W. Tetrahedron Lett. 2000, 41, 515. (c) Hoel,
A. M. L.; Nielsen, J . Tetrahedron Lett. 1999, 40, 3941. (d) Larhed, M.;
Lindeberg, G.; Hallberg, A. Tetrahedron Lett. 1996, 37, 8219. (e) Lew,
A.; Krutzik, P. O.; Hart, M. E.; Chamberlin, A. R. J . Comb. Chem.
2002, 4, 95. (f) Erd e´ lyi, M.; Gogoll, A. Synthesis 2002, 11, 1592.
(7) Details available as Supporting Information.
(
(
2
1
000, 2, 1729. (c) Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett.
989, 30, 2581.
(
4) (a) Kabalka, G. W.; Wang, L.; Namboodiri, V.; Pagni, R. M.
(8) Fmoc ) 9-fluorenylmethoxycarbonyl.
(9) Eberhard, M. R.; Wang, Z.; J ensen, C. M. Chem. Commun. 2002,
818.
Tetrahedron Lett. 2000, 41, 5151. (b) Kabalka, G. W.; Wang, L.; Pagni,
R. M. Tetrahedron 2001, 57, 8017.
1
0.1021/jo034284s CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/04/2003
J . Org. Chem. 2003, 68, 6431-6434
6431

TABLE 1. Son oga sh ir a Cou p lin g of Ar yla cetylen es on Iod op h en yl a n d Br om op h en yl Resin s
a
Method A, 120 °C, 15 min, 5% Pd, 10% Cu. b Method B, 120 °C, 25 min, 10% Pd, 20% Cu, 20% PPh3. c Yield determined by H NMR.
1
However, in our hands the use of Tl(OAc)
no beneficial effect.
The results of selected cross-coupling experiments,
containing highest yields and reaction conditions, are
included in Table 1.
3
additive had
of aryl halides at elevated temperature under homoge-
neous (5 min) and solventless (2.5 min) conditions occurs
faster than catalyst decomposition. On solid phase with
longer reaction times (15-25 min), due to the slower
diffusion of the reactants, the cross-couplingsinside of
the resinscannot compete with the amine-mediated
decomposition of the catalyst taking place in solution.
Amines can be used when they are protected by Fmoc or
Boc groups (4 and 5). Because of the lower affinity of
palladium to oxygen, free alcohols were tolerated under
all conditions.
Whereas aryl iodides react readily in all media, the
Sonogashira coupling of aryl bromides is limited to
2
homogeneous-phase as well as solid-phase conditions.
Cross-coupling of the least reactive aryl chlorides could
2
,8
only be performed using homogeneous catalysis. The
presence of a primary amine during Sonogashira coupling
was tolerated under homogeneous2 and solventless4
conditions, whereas no conversion was observed on solid
phase. This observation might be explained by the
relative rates of the competing processes: Rapid coupling
The amount of catalysts and additives required for the
coupling of aryl iodides on solid phase (5% Pd, 10% Cu,
15 min) was slightly higher than under homogeneous
conditions (2% Pd, 4% Cu, 5 min),2 but nevertheless
considerably lower than that needed for a solventless
4
(
10) (a) Cabri, W.; Candiani, I.; Bedeschi, A.; Penco, S.; Santi, R. J .
reaction (37% Pd, 37% Cu and 70% PPh
3
, 2.5 min). The
Org. Chem. 1992, 57, 1481-1486. (b) Grigg, R.; Loganathan, V.;
Santhakumar, V.; Sridharan, V.; Teasdale, A. Tetrahedron Lett. 1991,
2, 687-690. (c) Karabelas, K.; Westerlund, C.; Hallberg, A. J . Org.
Chem. 1985, 50, 3896.
presence of triphenylphosphine additive can complicate
the workup procedure when solventless or homogeneous
conditions are applied. Therefore, to improve the stability
3
6
432 J . Org. Chem., Vol. 68, No. 16, 2003

of the Pd catalyst in homogeneous-phase reactions, the
use of polymer-bound triphenylphosphine was investi-
gated, but remained without effect. Using aryl bromides
on solid phase in a heavy-walled Smith vial equipped
with a polypropylene frit, the Sonogashira couplings
could be rapidly performed, and the resin-bound sub-
on a rotatory evaporator, followed by removal of remaining
solvent under reduced pressure overnight.
Meth od B. Loa d in g of 3-Br om oben zoic Acid on to th e
Rin k Am id e Resin (B1). Procedure A1 was followed with the
exception of using a resin with a loading of 0.69 mmol/g and
using 3-bromobenzoic acid (0.78 mmol, 156.8 mg) instead of the
iodo-derivative, yielding 3-bromophenyl-derivatized Rink amide
resin. The substitution level was determined to be 0.39 mmol/g
by cleavage of 3-bromophenylamide following procedure A3.
Son oga sh ir a Cou p lin g on Br om op h en yl Resin (B2) a n d
Clea va ge a n d P u r ifica tion of th e Ar yla cetylen es (B3). The
3
strates could easily be separated from PPh .
In conclusion, we have developed a general procedure
for rapid Sonogashira coupling of aryl iodides and
bromides on solid phase. Furthermore, a modified heavy-
walled glass vial equipped with a polypropylene frit is
introduced, allowing both microwave heating and simpli-
fied resin handling. The described procedure should prove
valuable for the fast automatized generation of chemical
libraries.
3
-bromophenyl resin obtained in procedure B1 (500 mg, 0.39
mmol/g), Pd(PPh Cl (13.7 mg, 0.020 mmol), CuI (7.4 mg, 0.039
3
)
2
2
mmol), triphenylphosphine (20.5 mg, 0.078 mmol), the acetylene
derivative 1-6 (0.43 mmol), diethylamine (1.5 mL, 13.60 mmol),
and DMF (0.5 mL) were stirred in a modified heavy-walled
Smith Process Vial at 120 °C for 25 min in the microwave cavity.
Subsequent workup followed the procedure described for meth-
ods A2 and A3.
3
-Iod oben za m id e.13 Method A: 59.0 mg, 0.239 mmol, 62%,
white solid, corresponding to a loading rate of 0.48 mmol/g. Mp:
Exp er im en ta l Section
1
Gen er a l Com m en ts. For a general description of methods
and microwave irradiation procedures, see ref 2.
Ma ter ia ls. The starting materials were purchased from
commercial suppliers and were used without purification with
the exception of (3-ethynylphenyl)carbamic acid tert-butyl ester
183-184 °C. H NMR (400 MHz, CD OD): δ 8.22 (dd, J ) 1.1,
3
1.1 Hz, 1H, H-2), 7.89 (ddd, J ) 1.1, 1.6, 7.9 Hz, 1H, H-6), 7.86
(
ddd, J ) 1.1, 1.6, 7.9 Hz, H-4), 7.23 (dd, J ) 7.9, 7.9 Hz, H-5).
1
3
C NMR (100 MHz, CD
3
OD): δ 169.2, 140.5, 136.5, 135.7, 130.0,
+
1
(
26.6, 93.4. EI-MS m/z (relative intensity): 247 (M , 100), 231
-
1
84), 203 (40), 127 (16), 76 (82). IR ν (cm ): 3404, 3202, 1665.
-Br om oben za m id e.14 Method B: 39.2 mg, 0.195 mmol,
7%, white solid, giving a loading rate of 0.39 mmol/g. Mp: 153-
(
9
3-ethynyl-Boc-aniline) and (3-ethynylphenyl)carbamic acid
H-fluoren-9-ylmethyl ester (3-ethynyl-Fmoc-aniline), which
were prepared from 3-ethynylaniline using standard protection
3
5
1
1
1
154 °C. H NMR (400 MHz, CDCl
3
): δ 7.91 (dd, J ) 1.8, 1.8 Hz,
H, H-2), 7.68 (ddd, J ) 1.1, 1.8, 7.8 Hz, 1H, H-6), 7.56 (J ) 1.1,
.8, 7.8 Hz, H-4), 7.23 (dd, J ) 7.8, 7.8 Hz, H-5). 13C NMR (100
): δ 168.9, 135.3, 134.9, 130.7, 130.1, 126.1, 122.6.
procedures.
1
1
Meth od A. Loa d in g of 3-Iod oben zoic Acid on to th e Rin k
Am id e Resin (A1). To 500 mg of Rink amide linker attached
MHz, CDCl
EI-MS m/z (relative intensity) 201 (M , 73), 200 (M , 59), 185
3
to polystyrene resin (loading 0.78 mmol/g) were added DMF (3
+
+
mL), 3-iodobenzoic acid (0.78 mmol, 193.5 mg), PyBOP12 (0.78
-
1
(
96), 183 (100), 76 (18). IR ν (cm ): 3560, 3180, 1640.
-Eth yn ylben za m id e. (1A) Method A: 91.5 mg, white solid
containing 32.8 mg, 0.226 mmol, 94% product. (1B) Method B:
7.9 mg, yellowish solid containing 27.9 mg, 0.191 mmol, 97%
product. H NMR (400 MHz, CD
.3 Hz, 1H, H-2), 7.86 (ddd, J ) 1.3, 1.8, 7.9 Hz, 1H, H-6), 7.62
ddd, J ) 1.3, 1.8, 7.7 Hz, 1H, H-4), 7.45 (ddd, J ) 0.6, 7.7, 7.9
Hz, 1H, H-5). C NMR (100 MHz, CD
34.1, 130.8, 128.5, 127.6, 122.9, 82.2, 78.4. EI-MS m/z (relative
mmol, 405.8 mg), and diisopropylethylamine (1.34 mmol, 0.4
mL). The mixture was stirred in a modified heavy-walled Smith
Process Vial under microwave irradiation at 110 °C for 20 min,
then washed with DMF, ethanol, and dichloromethane to yield
3
5
1
3
OD): δ 7.96 (ddd, J ) 0.6, 1.3,
3
-iodophenyl-derivatized Rink amide resin. The substitution
level of the iodophenyl-derivatized resin was determined to be
.48 mmol/g by cleavage and quantification of 3-iodophenylamide
1
(
0
1
3
3
OD): δ 170.0, 134.8,
following procedure A3.
Son oga sh ir a Cou p lin g on Iod op h en yl Resin (A2). The
1
+
intensity): 145 (M , 63), 129 (79), 101 (100), 75 (71), 51 (39). IR
ν (cm ): 3682, 3622, 2398, 1518. Anal. (C
3
-iodophenyl-resin obtained in procedure A1 (500 mg, 0.48 mmol/
g), Pd(PPh Cl (8.2 mg, 0.012 mmol), CuI (4.5 mg, 0.024 mmol),
the acetylene derivative 1-6 (0.43 mmol), diethylamine (1.5 mL,
3.60 mmol), and DMF (0.5 mL) were stirred in a modified
-
1
9 7
H NO) C, H, N.
3
)
2
2
3
-P h en yleth yn ylben za m id e. (2A) Method A: 47.0 mg,
white solid (0.212 mmol, 89%). (2B) Method B: 39.7 mg 27.9
1
1
mg, white solid (0.179 mmol, 92%). Mp: 164-165 °C. H NMR
heavy-walled Smith Process Vial at 120 °C for 15 min in the
microwave cavity. The mixture was then washed with DMF,
ethanol, and dichloromethane.
(
(
3
400 MHz, CDCl ): δ 7.94 (dd, J ) 1.5, 1.7 Hz, 1H, H-2), 7.75
ddd, J ) 1.3, 1.7, 7.9 Hz, 1H, H-6), 7.63 (ddd, J ) 1.3, 1.5, 7.9
Hz, 1H, H-4), 7.46-7.51 (m, 2H, AA′ part of AA′BB′C), 7.40 (dd,
Clea va ge a n d P u r ifica t ion of t h e Ar yla cet ylen e (A3).
Four milliliters of 95% trifluoroacetic acid was added to the resin,
and the mixture was stirred in a modified heavy-walled Smith
Process Vial at 70 °C for 20 min in the microwave cavity. The
mixture was then filtered, and the resulting solution was
concentrated on a rotatory evaporator. The residue was extracted
with aqueous sodium hydroxide solution (pH ) 12), reextracting
the aqueous phase with dichloromethane twice. After filtration
J ) 7.9, 7.9 Hz, 1H, H-5), 7.29-7.35 (m, 3H, BB′C part of
13
3
AA′BB′C). C NMR (100 MHz, CDCl ): δ 169.9, 134.7, 133.6,
1
31.5, 130.6, 128.6, 128.5, 128.4, 127.2, 123.8, 122.7, 90.2, 88.2.
+
EI-MS m/z (relative intensity): 221 (M , 100), 205 (61), 176 (79),
1
(C H
15
-1
51 (32), 88 (18). IR ν (cm ): 3522, 3413, 2392, 1674. Anal.
11NO) C, H, N.
E)-3-(3′-Oxo-3-p h en ylp r op -1-en yl)b en za m id e.
1
3
(
(3A)
Method A: 55.9 mg, white solid (0.222 mmol, 92%). (3B) Method
4
of the combined organic layers through MgSO , they were
B: 48.4 mg, white solid (0.193 mmol, 98%). Mp: 153-154 °C.
concentrated under reduced pressure. The further purification
of 3-ethynylbenzamide and 3-(3-aminophenylethynyl)benzamide
was omitted because of their tendency to adsorb on silica, and
1
H NMR (400 MHz, CDCl ): δ 8.15 (dd, J ) 1.8, 1.8 Hz, 1H,
3
H-2), 8.06 (m, 2H, AA′ part of AA′BB′C), 7.83 (d, J ) 15.8 Hz,
H, CdC-H), 7.81 (ddd, J ) 1.1, 1.8, 7.7 Hz, 1H, H-6), 7.79
ddd, J ) 1.1, 1.8, 7.7 Hz, 1H, H-4), 7.62 (d, J ) 15.8 Hz, 1H,
CdC-H), 7.61 (ddd, J ) 1.1, 1.1, 7.7 Hz, 1H, H-5), 7.52 (m, 3H,
BB′ and C part of AA′BB′C). 13C NMR (100 MHz, CDCl
): δ
91.0, 170.3, 143.1, 137.8, 135.2, 134.4, 133.1, 131.9, 129.5, 129.1,
1
(
1
these compounds were therefore quantified by H NMR using
hydroquinone diacetate as an internal standard. In the case of
all other arylacetylene derivatives, the obtained residue was
purified by column chromatography (silica gel 60, particle size
3
1
0
1
.040-0.063 mm, hexane/ethyl acetate stepwise gradient from
2:1 to 1:1). The combined product fractions were concentrated
(13) Reich, S. H.; J ohnson, T.; Wallace, M. B.; Kephart, S. E.;
Fuhrman, S. A.; Worland, S. T.; Matthews, D. A.; Hendrickson, T. F.;
Chan, F.; Meador, M.; Ferre, R. A.; Brown, E. L.; DeLisle, D. M.; Patick,
A. K.; Binford, S. L.; Ford C. E. J . Med. Chem. 2000, 43, 1670.
(14) Pearson, D. E.; Stanper, W. E.; Suthers, B. R. J . Org. Chem.
1963, 3147.
(
11) Protecting groups in Organic Chemistry; Greene, T. W., Wuts,
P. G. M., Eds.; J ohn Wiley & Sons Inc.: New York, 1999.
12) PyBOP ) benzotriazol-1-yloxytrispyrrolidinophosphoniumhexa-
fluorophosphate.
(
J . Org. Chem, Vol. 68, No. 16, 2003 6433

236 (M ,100), 220 (21), 191 (19), 165 (41), 139 (7). IR ν (cm-1):
+
1
28.6, 128.5, 127.2, 122.9. EI-MS m/z (relative intensity): 251
+
(M , 81), 207 (100), 178 (25), 157 (48), 129 (19), 105 (65), 77 (91).
3683, 3615, 3544, 3404, 2391, 1674, 1210. Anal. (C15
H, N.
12 2
H N O) C,
-
1
IR ν (cm ): 3413, 3353, 1665, 1607.
-(3′-Am in op h en yleth yn yl)ben za m id e. (4B) Method B:
1.1 mg, yellowish solid containing 44.3 mg, 0. 188 mmol, 95%
3
Ack n ow led gm en t. We thank the Swedish Research
Council for financial support and Personal Chemistry
AB for access to the Smith Synthesizer and modified
Smith process vials. We are also grateful to Ida Niklason
for her excellent assistance during the early stage of this
project.
9
product. (5A) Method A:, 129.5 mg, white solid containing 57.8
mg, 0.245 mmol, 98% product. (5B) Method B: 130.3 mg,
yellowish solid containing 43.9 mg, 0.186 mmol, 94% product.
1
H NMR (400 MHz, CD OD): δ 9.06 (dd, J ) 1.7, 1.8 Hz, 1H,
3
H-2), 8.88 (ddd, J ) 0.8, 1.7, 7.8 Hz, 1H, H-6), 8.67 (ddd, J )
0
.8, 1.8, 7.8 Hz, 1H, H-4), 8.49 (dd, J ) 7.8, 7.8 Hz, 1H, H-5),
.13 (dd, J ) 7.7, 7.7 Hz, 1H, H-5′), 7.93 (dd, J ) 2.1, 2.1 Hz,
H, H-2′), 7.89 (ddd, J ) 0.8, 2.1, 7.7 Hz, 1H, H-6′), 7.77 (ddd, J
8
1
)
1
1
Su p p or tin g In for m a tion Ava ila ble: A description of the
modified heavy-walled glass microwave vial. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
3
3
0.8, 2.1, 7.7 Hz, 1H, H-4′). C NMR (100 MHz, CD OD): δ
70.2, 147.8, 134.3, 134.1, 130.4, 129.0, 128.5, 127.0, 124.0, 123.2,
21.0, 117.6, 115.7, 90.5, 87.0. EI-MS m/z (relative intensity):
J O034284S
6
434 J . Org. Chem., Vol. 68, No. 16, 2003