Practical thiol surrogates and protective groups for arylthiols for Suzuki-Miyaura conditions

Article abstract of DOI:10.1021/jo052624z

We have developed practical thiol surrogates and arylthiol protective groups for the Suzuki-Miyaura reaction. 2-Ethylhexyl-3-mercaptopropionate and 4-(2′-mercaptoethyl)pyridine were shown to be not only good thiol surrogates but also good protective groups for thiol. We have demonstrated toleration of these protective groups under aqueous Suzuki-Miyaura conditions.

Full text of DOI:10.1021/jo052624z

SCHEME 1. Problems Associated with Thiol Groups in the
Suzuki-Miyaura Reaction
Practical Thiol Surrogates and Protective Groups
for Arylthiols for Suzuki-Miyaura Conditions
Takahiro Itoh* and Toshiaki Mase
Process Research, Process R&D, Banyu Pharmaceutical Co.
Ltd., 9-1, Kamimutsuna 3-chome, Okazaki, Aichi 444-0858,
Japan
SCHEME 2. Issues with Using Carbonyl Groups for Thiol
Protection
takahiro_itoh@merck.com
ReceiVed December 21, 2005
in particular, S-acetyl is considered to be a favorable choice
for arylthiols,5 since arylthiol acetates undergo cleavage under
mild basic conditions. Thioethers and thioheterocycles are good
protective groups for thiols in the Suzuki-Miyaura reaction
under aqueous or anhydrous basic conditions. However, the
deprotection of thioethers to thiols is problematic due to the
requirement of the harsh conditions. Acetyl groups are suitable
for the Heck reaction,6 but acyl groups are potentially not
suitable as protective groups for aqueous basic Suzuki-Miyaura
conditions. Terfort et al. reported that a suitable protective group
for anhydrous Suzuki-Miyaura conditions is not an acetyl group
but a 2-methoxyisobutyryl group, which is easily cleaved by
aqueous bases; however, the carbonyl group may cause problems
in the Suzuki-Miyaura reaction. They suggest that a ketone is
formed by insertion of palladium between the sulfur atom and
the carbonyl group, leading to a palladium-acyl complex with
one thiolate ligand (Scheme 2).7
Recently, we have developed a method of efficient arylsulfur
bond formation using aryl bromide/triflate and aryl/alkanethiols
with Pd2(dba)3 and Xantphos.8 2-Ethylhexyl-3-mercaptopro-
pionate 1 and 4-(2′-mercaptoethyl)pyridine hydrochloride 2,
which are odorless and inexpensive reagents, are good thiol
surrogates for coupling under these conditions, and should be
easily cleaved to the corresponding thiols under mild basic
conditions via a â-elimination mechanism (Scheme 3).9
We expected that these thiol surrogates would be suitable
for the Suzuki-Miyaura reaction even under aqueous basic
conditions. This proved to be the case, and we report herein
We have developed practical thiol surrogates and arylthiol
protective groups for the Suzuki-Miyaura reaction. 2-Eth-
ylhexyl-3-mercaptopropionate and 4-(2′-mercaptoethyl)py-
ridine were shown to be not only good thiol surrogates but
also good protective groups for thiol. We have demonstrated
toleration of these protective groups under aqueous Suzuki-
Miyaura conditions.
The biaryl scaffold has received much attention in the
pharmaceutical industry as a privileged structure. This motif
has shown activity across a wide range of therapeutic classes,
and compounds that contain it have been shown to exhibit
antifungal, antiinflammatory, antirheumatic, antitumor, and
antihypertensive properties.1 For the preparation of biaryl
compounds, the Suzuki-Miyaura coupling reaction2 is the most
useful method, as it has been proven to offer distinct practical
advantages over other approaches. Cross-coupling reactions have
been developed for a tremendous variety of substrates containing
various functional groups. However, thiols are one of the few
compound types not suitable for the Suzuki-Miyaura reaction,
as they tend to poison catalysts. For example, the coupling of
4-bromobenzenethiol with arylboronic acid did not proceed in
high yield under typical conditions and resulted in the production
of disulfide side products (Scheme 1).3
(3) Disulfide compounds were identified by LCMS. (a) Khodaei, M. M.;
Salehi, P.; Goodarzi, M.; Yazdanipour, A. Synth. Commun. 2004, 34, 3661-
3666. (b) Hori, M.; Kataoka, T.; Shimizu, H.; Ban, M.; Matsushita, H. J.
Chem. Soc., Perkin Trans. 1 1987, 1, 187-194.
(4) (a) Greene, T. W.; Wuts, P. G. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999. (b) Coulon, E.;
Pinson, J. J. Org. Chem. 2002, 67, 8513-8518.
There are few studies in the literature that address this
problem. The protective groups for thiols are well established;4
(5) (a) Hsung, R. P.; Chidsey, C. E. D.; Sita, L. R. Organometallics
1995, 14, 4808-4815. (b) Yao, Y. X.; Tour, J. M. J. Org. Chem. 1999, 64,
1968-1971. (c) Gryko, D. T.; Clausen, C.; Lindsey, J. S. J. Org. Chem.
1999, 64, 8635-8647.
(1) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103,
893-930.
(2) (a) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11,
513-519. (b) Suzuki, A. Acc. Chem. Res. 1982, 15, 178-184. (c) Miyaura,
N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483. (d) Suzuki, A. J.
Organomet. Chem. 1999, 576, 147-168. (e) Kotha, S.; Lahiri, K.; Kashinath,
D. Tetrahedron 2002, 58, 9633-9695. (f) Hassan, J.; Se´vignon, M.; Gozzi,
C.; Schulz, E.; Lemaire, M. Chem. ReV. 2002, 102, 1359-1470. (g) Suzuki,
A. Proc. Jpn. Acad., Ser. B 2004, 80, 359. (h) Bellina, F.; Carpita, A.;
Rossi, R. Synthesis 2004, 2419-2440.
(6) Hsung, R. P.; Babcook, J. R.; Chidsey, C. E. D.; Sita, L. R.
Tetrahedron Lett. 1995, 36, 4525-4528.
(7) Zeysing, B.; Gosch, C.; Terfort, A. Org. Lett. 2000, 2, 1843-1845.
(8) Itoh, T.; Mase, T. Org. Lett. 2004, 6, 4587-4590.
(9) (a) Katritzky, A. R.; Takahashi, I.; Marson, C. M. J. Org. Chem.
1986, 51, 4914-4920. (b) Katritzky, A. R.; Khan, G. R.; Schwarz, O. A.
Tetrahedron Lett. 1984, 25, 1223-1226.
10.1021/jo052624z CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/09/2006
J. Org. Chem. 2006, 71, 2203-2206
2203

TABLE 1. Suzuki-Miyaura Reactions of Protected
Bromobenzenethiol 4
SCHEME 3. Preparation of Thiophenol Using Thiol
Surrogates
entry
arylboronic acid
yield of thiola (%)
1
2
3
PhB(OH)2
4-F-C6H4B(OH)2
4-MeO-C6H4B(OH)2
85
82
81
the development of suitable thiol protective groups and thiol
surrogates for the Suzuki-Miyaura reaction.
a Yields refer to the average isolated yield over two runs.
p-Bromobenzene thioether 4 was easily prepared by two
routes. 1-Bromo-4-iodobenzene was reacted with 2-ethylhexyl-
3-mercaptopropionate 1 under previously reported conditions,8
affording 4 in 90% yield. An alternative preparation of 4 was
achieved via 1,4-conjugate addition of 4-bromobenzenethiol and
isooctyl acrylate 3.10 The resulting thioether 4 was stable in
aqueous Na2CO3, which is a typical base in Suzuki-Miyaura
conditions (Scheme 4, eq 1). The stability of 4 was also
investigated under various other basic conditions. For bases
(pKa) such as Na2CO3 (6.35-10.32), K2CO3, Cs2CO3, Li2CO3
(6.2, 9.7), KOH, LiOH (11.6), K3PO4 (12.4), NaHCO3, NaF
(3.18), CsF, Et3N (10.8), pyridine (5.2), N-methylmorpholine
(8.4), Na2B4O7 (9.2), and DBU (12) in toluene/water (1:1) or
dried toluene at reflux temperature for 12 h, cleavage of the
thiol protective group did not proceed, and the recovery yield
of 4 was over 95% by HPLC analysis. In addition, it was found
that 4-[2-(4-bromophenylthio)ethyl]pyridine 5, which was pre-
pared in high yield by Pd-catalyzed cross-coupling of 1-bromo-
4-iodobenzene with 2 under previously reported conditions,8 was
stable not only under aqueous Suzuki-Miyaura conditions but
also to stronger bases such as NaO-t-Bu (Scheme 4, eq 2).
Although the 2-(4-pyridinyl)ethyl protective group has been used
for the Sonogashira reaction,11 there have been no previous
reports of this group being used for the introduction of a thiol
moiety to aryl halides via a Pd-catalyzed coupling reaction.
coupling,12 the Heck reaction,13 the Suzuki-Miyaura reaction,
and Buchwald-Hartwig amination14 (Scheme 5). The Sono-
gashira reaction with 4 and phenylacetylene in the presence of
0.1 mol % of Pd2(dba)3, 0.5 mol % of PPh3, and 0.1 mol % of
CuI, in combination with DMF/i-Pr2NH, was successfully
carried out at 70 °C, forming the desired thioether 6 in 91%
yield (eq 1). For the Heck reaction, the coupling of 4 and styrene
with 0.1 mol % of Pd(PPh3)4 in NMP proceeded well at 110
°C to afford the corresponding thioether 7 in 80% yield (eq 2).
Thioether 5 was also tolerated in the Suzuki-Miyaura
reaction. The coupling of 5 with phenylboronic acid in the
presence of Pd(PPh3)4 (1 mol %) and aqueous Na2CO3 in toluene
at reflux temperature proceeded in high yield without cleavage
of the protective group to give the biaryl product 8 in 87% yield
(eq 4). The thiol protective group in 4 was not suitable for
treatment with a strong base such as NaO-t-Bu under typical
Buchwald-Hartwig amination conditions, but cleavage of the
protective group in 5 did not occur in the presence of the same
base. The amination of 5 with morpholine proceeded well using
0.1 mol % of Pd(OAc)2 and 0.1 mol % of 1,1′-bis(di-tert-
butylphosphino)ferrocene (D-t-BPF)15 in the presence of NaO-
t-Bu in toluene at reflux temperature to afford the desired
product 9 in 84% yield (eq 5). Using 1,1′-bis(diphenylphos-
phino)ferrocene (DPPF) instead of D-t-BPF was not effective.
Cleavage of the protective groups did not occur in these
reactions. The resulting thioethers 6, 7, 8, and 9 underwent
â-elimination to generate the corresponding thiols in quantitative
yields.
The Suzuki-Miyaura coupling of 4 with phenylboronic acid
in the presence of Pd(PPh3)4 (1 mol %) and aqueous Na2CO3
in toluene at reflux temperature proceeded in high yield without
formation of the corresponding disulfide byproduct. After
coupling, NaOEt in EtOH was added to the reaction mixture
for deprotection of propionate group via a â-elimination
mechanism. Finally, the reaction mixture was acidified with
aqueous citric acid to afford biphenyl-4-thiol in 85% yield (Table
1, entry 1). In the same manner, electron-deficient and electron-
rich substituted arylboronic acids were coupled with 4 under
aqueous conditions with high yields; the corresponding thiols
were obtained in 82% and 81% yields, respectively (entries 2
and 3).
There are few suitable protective groups for thiol against a
strong base such as n-BuLi.4a The protective group of 4 was
stable to treatment with n-BuLi at -78 °C. Cleavage of the
propionate group with n-BuLi was slow even at -15 °C (about
a 30% yield in 2 h). Halogen-metal exchange with 4 proceeded
smoothly at -78 °C, and the resulting lithiated product was
quenched with D2O to obtain the deuterated product in 90%
yield. For formylation, the resulting lithiated product was
quenched by DMF instead of H2O to afford 10 in 72% isolated
yield (Scheme 6).
Next, we investigated the stability of these protective groups
under strong basic conditions and the harsher conditions required
for palladium-catalyzed coupling reactions. The stability of the
thiol protective group in 4 was investigated in Sonogashira
To summarize, we have developed practical thiol surrogates
and arylthiol protective groups for the Suzuki-Miyaura reaction,
(12) Sonogashira, K.; Tohda, Y,; Hagihara, N. Tetrahedron Lett. 1975,
50, 4467-4470.
(13) Patel, P. A.; Ziegler, C. B.; Cortese, N. A.; Plevyak, J. E.; Zebovitz,
T. C.; Terpko, M.; Heck, R. F. J. Org. Chem. 1977, 42, 3903-3907
(14) (a) Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116,
5969-5970. (b) Guram, A. S.; Buchwald. S. L. J. Am. Chem. Soc. 1994,
116, 7901-7902.
(10) Various other alkyl propionates and acrylates beside 1 and 3 were
commercially available at inexpensive prices.
(11) (a) Yu, C. J.; Chong, Y.; Kayyem, J. F.; Gozin, M. J. Org. Chem.
1999, 64, 2070-2079. (b) Collman, J. P.; Zhong, M.; Costanzo, S.;
Sunderland, C. J.; Aukauloo, A.; Berg, K,; Zeng, L. Synthesis 2001, 3, 367-
369.
(15) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 7369-
7370.
2204 J. Org. Chem., Vol. 71, No. 5, 2006

SCHEME 4. Synthesis and Stability of Substrates
SCHEME 5. Pd-Catalyzed Reactions of Protected Thiols 4
and 5
SCHEME 6. Formylation of Protected Thiol 4
and back-filled with nitrogen (three cycles). Pd2(dba)3 (69 mg,
0.075 mmol), Xantphos (87 mg, 0.15 mmol), and 2-ethylhexyl-
3-mercaptopropionate (0.69 mL, 3 mmol) were added, and then
the mixture was degassed twice more. The mixture was heated
to reflux for 4 h, and HPLC confirmed the completion of the
reaction. The reaction mixture was then allowed to reach
ambient temperature. The reaction mixture was then filtered and
concentrated. The crude product was purified by flash column
chromatography on silica gel to afford 3-(4-bromophenylsul-
fanyl)propionic acid 2-ethylhexyl ester (4) (813 mg, 90% yield)
as slightly yellowish oil.
Method B: To a round-bottom-flask were added p-bro-
mobenzylthiol (5.7 g, 30 mmol), 2-Ethylhexyl-3-mercaptopro-
pionate (5.5 g, 30 mmol), THF (57 mL), and tetrabutylammo-
nium fluoride (30 mL, 30 mmol, 1 M in THF), and then the
mixture was aged at ambient temperature for 15 h. The mixture
was poured into EtOAc (50 mL) and water (30 mL). After
separation, the aqueous layer was extracted with EtOAc (50
mL), and then the organic layers were combined and concen-
trated to dryness. The crude product was purified by flash
column chromatography on silica gel to afford 3-(4-bromophen-
ylsulfanyl)propionic acid 2-ethylhexyl ester (4) (10.5 g, 93%
yield) as a slightly yellowish oil: column chromatography
solvent (n-heptane/ethyl acetate ) 100:1); Rf ) 0.33 (n-heptane/
which are suitable even under basic aqueous conditions. These
protective groups were also successfully used in other Pd-
catalyzed reactions such as the Sonogashira, Heck, and Buch-
wald-Hartwig reactions and were tolerated in a formylation
reaction using n-BuLi.
1
ethyl acetate ) 100:1); H NMR (DMSO, 500 MHz) δ 7.29
Experimental Section
(d, 2H, J ) 8.5 Hz), 7.29 (d, 2H, J ) 8.5 Hz), 3.94 (d, 2H, J
) 5.7 Hz), 3.18 (t, 2H, J ) 6.8 Hz), 2.62 (t, 2H, J ) 6.8 Hz),
1.50-1.51 (m, 1H), 1.24-1.31 (m, 8H), 0.82-0.87 (m, 6H);
13C NMR (DMSO, 125 MHz) δ 171.0, 135.1, 131.9, 130.4,
118.9, 66.2, 38.1, 33.6, 29.8, 28.3, 27.8, 23.2, 22.4, 13.9, 10.8;
3-(4-Bromophenylsulfanyl)propionic Acid 2-Ethylhexyl
Ester (4). Method A: To a round-bottom-flask were added
p-bromoiodobenzene (850 mg, 3 mmol), i-Pr2NEt (1.04 mL, 6
mmol), and dry toluene (17 mL). The mixture was evacuated
J. Org. Chem, Vol. 71, No. 5, 2006 2205

1
IR (neat, cm-1) 2958, 2929, 2859, 1735, 1473, 1387, 1349,
1243, 1175, 1092, 1069, 1008, 810, 480; HRMS m/z calcd for
C17H25BrO2S 372.0759, found 372.0741.
ethyl acetate ) 2:1); mp 38-40 °C; H NMR (DMSO, 500
MHz) δ 8.47-8.48 (m, 2H), 7.50-7.51 (m, 2H), 7.28-7.32
(m, 4H), 3.30 (t, 2H, J ) 7.5 Hz), 2.89 (t, 2H, J ) 7.5 Hz); 13
C
4-[2-(4-Bromophenylsulfanyl)ethyl]pyridine (5). To a round-
bottom-flask were added p-bromoiodobenzene (850 mg, 3
mmol), i-Pr2NEt (1.04 mL, 6 mmol), and dry toluene (17 mL).
The mixture was evacuated and backfilled with nitrogen (three
cycles). Pd2(dba)3 (69 mg, 0.075 mmol), Xantphos (87 mg, 0.15
mmol), and 4-(2′-mercaptoethyl)pyridine hydrochloride salt (527
mg, 3 mmol) were added, and then the mixture was degassed
twice more. The mixture was heated to reflux for 15 h, and
HPLC confirmed the completion of the reaction. The reaction
mixture was then allowed to reach ambient temperature. The
reaction mixture was then filtered and concentrated. The crude
product was purified by flash column chromatography on silica
gel to afford 4-[2-(4-bromophenylsulfanyl)ethyl]pyridine (5)
(794 mg, 90% yield) as a white solid: column chromatography
solvent (n-heptane/ethyl acetate ) 10:1); Rf ) 0.21 (n-heptane/
NMR (DMSO, 125 MHz) δ 1149.5, 148.5, 135.5, 131.8, 130.0,
124.1, 118.6, 33.5, 32.0; IR (KBr, cm-1) 1937, 1600, 1474,
1318, 1240, 1088, 1007, 849, 815, 725, 703, 572, 494; HRMS
m/z calcd for C13H12BrNS 292.9874, found 292.9886.
Acknowledgment. We acknowledge Dr. M. Palucki and Dr.
N. Yasuda, Merck & Co., Inc., for their critical reading of this
manuscript. We thank Mr. M. Ishikawa for HRMS analysis.
Supporting Information Available: Detailed experimental
procedures and characterization data for each compound. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JO052624Z
2206 J. Org. Chem., Vol. 71, No. 5, 2006