A facile one-pot preparation of alkyl aminoaryl sulfides for the synthesis of GW7647 as an agonist of peroxisome proliferator-activated receptor α

Article abstract of DOI:10.1021/jo060361i

We have developed two simple and high yielding one-pot syntheses of alkyl aminoaryl sulfides containing a series of four-steps: in situ protection of the free amine by reaction with a Grignard reagent, halogen-lithium exchange, sulfur insertion, and a substitution reaction with various electrophiles. Through this protocol, we have successfully synthesized tert-butyl-2-[4-(2-aminoethyl) phenylsulfanyl]-2-methylpropanoate, a key intermediate for the synthesis of GW7647 and GW9578 (ureido-TiBAs), in 92% yield. Furthermore, we were able to improve the overall yield of, GW7647 to 66%, 3 times the yield previously reported.

Full text of DOI:10.1021/jo060361i

A Facile One-Pot Preparation of Alkyl Aminoaryl
Sulfides for the Synthesis of GW7647 as an
Agonist of Peroxisome Proliferator-Activated
Receptor r
Jungyeob Ham, Sung Jin Cho, Jaeyoung Ko,
Jungwook Chin, and Heonjoong Kang*,†
Center for Marine Natural Products and Drug DiscoVery,
School of Earth and EnVironmental Sciences, Seoul National
UniVersity, NS-80, Seoul 151-747, Korea
hjkang@snu.ac.kr
ReceiVed February 21, 2006
FIGURE 1. Chemical structures of GW7647 and GW9578 (ureido-
TiBAs) as PPARR synthetic agonists.
nol in the presence of strong alkaline bases.2 Although these
classical methods result in good yields, there is limited avail-
ability of aminothiophenol derivatives from commercial sources.
In 1989, McKinnie and Ranken reported the synthesis of alkyl
aminoaryl sulfides from aromatic amines and aliphatic disulfides
in the presence of Lewis acid catalysts, such as AlCl3 and CuI,
at 130-170 °C.3 Taniguchi et al. have shown that alkyl
aminoaryl sulfides can be synthesized by nickel-catalyzed
(NiBr2-bpy/Zn) alkyl- or arylthiolation of aryl iodide with a
disulfide in moderate yields.4 However, the above methods are
limited by their long reaction times and high reaction temper-
atures.
Recently, the research group of GlaxoSmithKline discovered
a series of urea-substituted thioisobutyric acids (ureido-TiBAs),
such as GW7647 and GW9578, containing an alkyl aminoaryl
sulfide bond (Figure 1), which are known to be highly selective
agonists of peroxisome proliferator-activated receptor R (PPARR)
and a potential therapeutic remedy for dyslipidemia.5
However, the synthesis of alkyl aminoaryl sulfide as the key
intermediate in the preparation of GW7647 was complicated,
and its yield was only 53%, so the target compound (GW7647)
was obtained in only 20% overall yield. This demonstrates the
need for a new method of synthesis of alkyl aminoaryl sulfides
that can be easily used for the construction of new medicinal
agents.
We have developed two simple and high yielding one-pot
syntheses of alkyl aminoaryl sulfides containing a series of
four-steps: in situ protection of the free amine by reaction
with a Grignard reagent, halogen-lithium exchange, sulfur
insertion, and a substitution reaction with various electro-
philes. Through this protocol, we have successfully synthe-
sized tert-butyl-2-[4-(2-aminoethyl)phenylsulfanyl]-2-meth-
ylpropanoate, a key intermediate for the synthesis of
GW7647 and GW9578 (ureido-TiBAs), in 92% yield.
Furthermore, we were able to improve the overall yield of
GW7647 to 66%, 3 times the yield previously reported.
Alkyl aminoaryl sulfides are very useful moieties in many
pharmaceutical compounds and are common building blocks
to synthesize bioactive natural products in organic chemistry.1
However, despite the importance of alkyl aminoaryl sulfides,
streamlined methods for synthesizing these sulfides have not
been fully investigated. Generally, most alkyl aminoaryl sulfides
are prepared by a substitution reaction of electrophiles, such as
organic halides and/or epoxides, etc., with alkali metal aminoaryl
thiolate which is generated from 2-, 3-, and/or 4-aminothiophe-
In our previous report, we showed that various alkyl aryl
sulfides could be easily obtained through the substitution
reaction of various electrophiles and lithium aryl thiolates that
(2) (a) Paquette, L. A.; Liu, Z.; Efremov, I. J. Org. Chem. 2005, 70,
514-518. (b) Kirkovsky, L.; Mukherjee, A.; Yin, D.; Dalton, J. T.; Miller,
D. D. J. Med. Chem. 2000, 43, 581-590. (c) Bernstein, P. R.; Vacek, E.
P.; Adams, E. J.; Snyder, D. W.; Krell, R. D. J. Med. Chem. 1988, 31,
692-696. (d) Daines, R. A.; Chambers, P. A.; Foley, J. J.; Griswold, D.
E.; Kingsbury, W. D.; Martin, L. D.; Schmidt, D. B.; Sham, K. K. C.; Sarau,
H. M. J. Med. Chem. 1996, 39, 3837-3841. (e) Gourdie, T. A.; Prakash,
A. S.; Wakelin, L. P. G.; Woodgate, P. D.; Denny, W. A. J. Med. Chem.
1991, 34, 240-248. (f) Larsen, S. D.; DiPaolo, B. A. Org. Lett. 2001, 3,
3341-3344.
* To whom correspondence should be addressed. Tel. 82-2-880-5730; Fax
82-2-883-9289; E-mail: hjkang@snu.ac.kr.
† Also affiliated with the Research Institute of Oceanography, SNU.
(1) (a) Vangala, V. R.; Bhogala, B. R.; Dey, A.; Desiraju, G. R.; Broder,
C. K.; Smith, P. S.; Mondal, R.; Howard, J. A. K.; Wilson, C. C. J. Am.
Chem. Soc. 2003, 125, 14495-14509. (b) Vlahakis, J. Z.; Kinobe, R. T.;
Bowers, R. J.; Brien, J. F.; Nakatsu, K.; Szarek, W. A. Bioorg. Med. Chem.
Lett. 2005, 15, 1457-1461. (c) Xing, B.; Khanamiryan, A.; Rao, J. J. Am.
Chem. Soc. 2005, 127, 4158-4159. (d) So¨derholm, A. A.; Lehtovuori, P.
T.; Nyro¨nen, T. H. J. Med. Chem. 2005, 48, 917-925. (e) Molteni, V.; He,
X.; Nabakka, J.; Yang, K.; Kreusch, A.; Gordon, P.; Bursulaya, B.; Warner,
I.; Shin, T.; Biorac, T.; Ryder, N. S.; Goldberg, R.; Doughty, J.; He, Y.
Bioorg. Med. Chem. Lett. 2004, 14, 1477-1481. (f) Makedonski, P.;
Brandes, M.; Grahn, W.; Kowalsky, W.; Wichern, J.; Wiese, S.; Johannes,
H.-H. Dyes Pigments 2004, 61, 109-119. (g) Harrop, T. C.; Rodriguez,
K.; Mascharak, P. K. Synth. Commun. 2003, 33, 1943-1949.
(3) Ranken, P. F.; McKinnie, B. G. J. Org. Chem. 1989, 54, 2985-
2988.
(4) Taniguchi, N. J. Org. Chem. 2004, 69, 6904-6906.
(5) Brown, P. J.; Winegar, D. A.; Plunket, K. D.; Moore, L. B.; Lewis,
M. C.; Wilson, J. G.; Sundseth, S. S.; Koble, C. S.; Wu, Z.; Champman, J.
M.; Lehmann, J. M.; Kliewer, S. A.; Willson, T. M. J. Med. Chem. 1999,
42, 3785-3788.
10.1021/jo060361i CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/28/2006
J. Org. Chem. 2006, 71, 5781-5784
5781

TABLE 1. Optimization of Reaction Conditions for the One-Pot
Synthesis of Alkyl Aminoaryl Sulfidea
Concerning the reactivity of halides on 1 (Table 1, entries 5-7),
4-iodo- and 4-bromoaniline provided excellent yields of the
respective sulfide compound (2). However, 4-chloroaniline did
not undergo lithium-halogen exchange and resulted in recov-
ered starting material. As might be expected, the in situ
protection of the free amine by reaction with iso-propylmag-
nesium chloride was shown to be extremely stable under our
reaction conditions and was easily removed by aqueous NH4Cl
solution at the end of reaction.
On the basis of the preliminary study, we performed the one-
pot synthesis of alkyl aminoaryl sulfides (4) with various
haloanilines (3) and electrophiles. The results are summarized
in Table 2.
entry
X
A (equiv)
none
B (equiv)
% yieldb
1
2
3
4c
5
6
7
I
n-BuLi (3.0)
t-BuLi (4.0)
none
no reaction
no reaction
no reaction
53
I
I
I
I
Br
Cl
none
iPrMgCl (3.0)
iPrMgCl (2.0)
iPrMgCl (2.0)
iPrMgCl (2.0)
iPrMgCl (2.0)
n-BuLi (1.0)
t-BuLi (2.0)
t-BuLi (2.0)
t-BuLi (2.0)
94
88
no reaction
In the reactivity test of ortho-, meta-, and para-haloanilines,
yields of the target sulfides were shown to increase according
to the order of para > meta > ortho under the same conditions
(Table 2, entries 1-3). Although, ortho-substituted sulfides were
obtained in a low yield (66%) when using 2-bromoaniline as
the starting material, both para- and meta-substituted sulfides
could be obtained in 81-94% yields from bromo- and/or
iodoaniline(s).
In the synthesis of dialkyl-substituted aminoaryl sulfide using
2,4-dibromoaniline (Table 2, entry 4), despite all the reagents
for 2,4-dibromoaniline being used at twice the amounts of those
used in the previous cases, we were not able to obtain any of
the desired product except for a monoalkyl-substituted aminoaryl
sulfide, 4-benzylsulfanyl-2-bromophenylamine in 74% yield.
Also, the presence of an electron-donating or -withdrawing
group on the haloaniline or electrophile (Table 2, entries 5 and
6) did not affect yields of products (86 and 89%, respectively).
In the reactivity study of various electrophiles, activated alkyl
halides, such as benzylic, allylic, carbonyl, or carboxyl (Table
2, entries 3, 7, 8, and 9), gave good yields (92-95%). By
contrast, saturated alkyl bromides, such as 5-bromopentyl
benzene (Table 2, entry 10) or bromomethyl cyclohexane (Table
2, entry 11), took longer (about 2 h) to complete the substitutions
and gave lower yields under the same conditions (84 and 81%,
respectively). Also, 1,2-epoxy-5-hexene (Table 2, entry 12) gave
the desired sulfide in 87% yield.
Although we did not directly detect the generated intermedi-
ates during the one-pot synthesis of alkyl aminoaryl sulfide (4),
we assumed the presence of those compounds at each step from
the yields of the target compounds at the end of the reaction.
From the results of the alkyl aminoaryl sulfide reaction, we
anticipated that our protocol could be expanded to the synthesis
of alkyl (aminoalkyl)aryl sulfides (6), such as tert-butyl-2-[4-
(2-aminoethyl)phenylsulfanyl]-2-methylpropanoate, which is a
key intermediate of GW7647 (Figure 1). Although GW7647 is
known to be a very effective and selective agonist of PPARR,
the synthesis of the key intermediate sulfide consists of four
steps and suffers from long reaction times, expensive reagents,
such as Wilkinson’s catalyst, and lower 53% overall yield.5 The
other method used sulfenylation of dimethyl ketene acetal with
benzene sulfenyl chloride. Yet it required disulfide formation
in the beginning and amination of the phenethyl chloride at the
end.8 We attempted a formal synthesis of GW7647 by applying
the alkyl aminoaryl sulfide method. First, we performed the
reaction using 4-bromobenzylamine hydrochloride and 4-bro-
mophenethylamine (5) as starting materials (Table 3). Carrying
a Reaction conditions: 0.5 mmol of 4-haloaniline (1), 0.5 mmol of
powdered sulfur, 0.5 mmol of benzyl bromide, dried THF (5 mL), 0 °C
(added A), -78 °C (added B), -78 °C to room temperature (after addition
of sulfur), 0 °C (added benzyl bromide), under N2. b Yields were given for
isolated products and average values of triplicate reactions. c 4-Butylsul-
fanylphenylamine as a side product was isolated in 32% yield.
were prepared in situ from the corresponding aryl bromides,
n-BuLi, and sulfur powder.6 On the basis of the previous work,
we expected to find a new method for the formation of alkyl
aminoaryl sulfides using aminoaryl halides as starting materials.
In this paper, we wish to report a one-pot synthesis of alkyl
aminoaryl sulfides from various aminoaryl halides and electro-
philes. We also utilized this method in a formal synthesis of
GW7647.
As a starting point, we needed to choose an appropriate amine
protecting group in the various haloanilines used as starting
materials. The protection group should be stable during the
lithium-halogen exchange conditions and easily removed under
neutral conditions at the end of the reaction. In this regard, a
good way to protect the amine group of a haloaniline in situ
would be by using a Grignard reagent. Indeed, Bumagin and
Luzikova reported a protection method for free amine groups
using Grignard reagent in 1997.7 However, the strategic point
of their report was not the preparation of sulfide derivatives
but an alkyl aryl cross-coupling under palladium catalysis.
Therefore, as a model reaction, we attempted to synthesize
4-benzylsulfanylphenylamine (2) through a one-pot reaction,
including in situ protection of the amine group by reaction with
a Grignard reagent. The results of the initial test are summarized
in Table 1.
Initially, n-butyllithium (3.0 equiv), tert-butyllithium (4.0
equiv), or iso-propylmagnesium chloride was chosen for the in
situ protection of the free amine and for the metal-halogen
exchange. However, these reactions resulted in no reaction
(Table 1, entries 1-3). On the other hand, when Grignard
reagent (2.0 equiv) was used to pretreat the haloaniline before
the metal-halogen exchange, we were able to obtain compound
2 in various yields depending on the lithium reagent used and
the halide in the haloaniline (Table 1, entries 4-6). The best
result was achieved with a combination of iso-propylmagnesium
chloride (2.0 equiv) at 0 °C in the amine protection step and
tert-butyllithium (2.0 equiv) at -78 °C in the halogen-lithium
exchange step (Table 1, entry 5). From the reaction conditions,
we were able to obtain the desired compound 2 in 94% yield.
(6) Ham, J.; Yang, I.; Kang, H. J. Org. Chem. 2004, 69, 3236-3239.
(7) Bumagin, N. A.; Luzikova, E. V. J. Organomet. Chem. 1997, 532,
271-273.
(8) Boros, E. E.; Kaldor, I.; Brown, P. J.; Styles, V. L. Synth. Commun.
2001, 31, 505-510.
5782 J. Org. Chem., Vol. 71, No. 15, 2006

TABLE 2. Simple One-Pot Synthesis of Alkyl Aminoaryl Sulfides from Haloanilines
a Yields were given for isolated products. b Epoxide used as an electrophile was a racemic mixture.
out the reaction with benzyl bromide (Table 3, entries 1 and
2), tert-butyl bromoacetate (Table 3, entry 3), and tert-butyl-
R-bromoisobutyrate (Table 3, entry 4) as electrophiles gave the
respective product in good yields (92-98%). When 4-bro-
mobenzylamine hydrochloride was used (Table 3, entry 1), we
added 1.0 equiv excess of iso-propylmagnesium chloride (3.0
equiv in total) to the reaction without an additional step for
removing HCl from the starting material.
Although the tert-butyl-2-[4-(2-aminoethyl)phenylsulfanyl]-
2-methylpropanoate was not obtained under the general condi-
tions, we could successfully prepare the desired compound in
92% yield by changing the solvent from THF to methanol after
formation of lithium thiolate, using KOH as a strong base, and
refluxing for 1 h. After solving a problem of the key step, we
completed the synthesis of GW7647 according to a modified
procedure of GlaxoSmithKline’s5 and obtained the GW7647 in
66% overall yield (data not shown). Compared to the previous
procedure, our one-pot synthesis is very quick, convenient, and
economical.
In summary, we have developed a simple one-pot synthesis
of alkyl aminoaryl sulfide through in situ protection of the free
amine by reaction with a Grignard reagent. Using this method,
we have successfully obtained tert-butyl-2-[4-(2-aminoethyl)-
phenylsulfanyl]-2-methylpropanoate, which is a key intermediate
J. Org. Chem, Vol. 71, No. 15, 2006 5783

TABLE 3. One-Pot Synthesis of Alkyl (Aminoalkyl)aryl Sulfides
i
a Yields were given for isolated products. b Reaction was performed in the presence of 3.0 equiv of PrMgCl. c See Experimental Section for detailed
reaction conditions.
(3 × 30 mL). The combined extract was washed with water, dried
of GW7647 and GW9578 (ureido-TiBAs), in 92% yield. Finally,
(MgSO4), filtered, and evaporated under reduced pressure to give
the crude product. The crude compound was purified by chroma-
tography on silica gel to obtain the desired compound.
we were able to obtain the desired compound (GW7647) in 66%
overall yield. Therefore, our method could be a useful protocol
for the preparation of pharmaceutical drugs and their intermedi-
ates containing various alkyl aminoaryl sulfides.
Preparation of tert-Butyl-2-[4-(2-aminoethyl)phenylsulfanyl]-
2-methylpropanoate (Table 3, entry 4). To a solution of 4-bro-
mophenethylamine (400.2 mg, 2.0 mmol) in anhydrous THF (30
Experimental Section
i
mL) was slowly added PrMgCl (2.0 M solution in diethyl ether,
2.0 mL, 4.0 mmol) at 0 °C for 10 min under N2. After 30 min,
t-BuLi (1.7 M solution in pentane, 2.4 mL, 4.0 mmol) was slowly
added at -78 °C for 20 min, and the reaction mixture was stirred
for an additional 30 min. Sulfur powder (64 mg, 2.0 mmol) was
added at once, and the reaction mixture was slowly warmed to room
temperature for 30 min. After the reaction was complete, the solvent
was completely removed by an evaporator under the atmosphere.
To a solution of the residual product in MeOH (30 mL) was added
KOH (117.8 mg, 2.1 mmol). The reaction mixture was heated at
60 °C for an additional 1 h. After that time, the reaction mixture
was poured into a NH4Cl solution (35 mL) and extracted with
EtOAc (3 × 30 mL). The combined organic layer was washed with
H2O, dried (MgSO4), filtered off, and then concentrated on a rotary
evaporator. The crude compound was purified by chromatography
(eluent: 5% MeOH in CH2Cl2) on silica gel to obtain the desired
compound (544 mg, 92%).
General Procedure for the Formation of Alkyl Aminoaryl
Sulfides (Table 2). To a solution of haloanilines (2.0 mmol) in
anhydrous THF (30 mL) was added a solution of iPrMgCl (2.0 M
solution in diethyl ether, 4.0 mmol) at 0 °C under N2 atmosphere,
and a solution of t-BuLi (1.7 M solution in pentane, 4.0 mmol)
was slowly added for 15 min at -78 °C. After 30 min, sulfur
powder (2.0 mmol) was then added, and the reaction mixture was
slowly warmed to room temperature for 30 min. Finally, alkyl halide
(2.0 mmol) was added at 0 °C. The reaction was monitored by
thin-layer chromatography. After the reaction was complete, it was
quenched with aqueous NH4Cl (35 mL). The organic layer was
separated, and then the aqueous layer was extracted with EtOAc
(3 × 30 mL). The combined organic layer was washed with water,
dried (MgSO4), filtered, and evaporated under reduced pressure to
give the crude product. The crude compound was purified by
chromatography on silica gel to obtain the desired product.
General Procedure for the Formation of Alkyl (Aminoalkyl)-
aryl Sulfides (Table 3). To a solution of 4-bromobenzylamine
hydrochloride or 4-bromophenethylamine (2.0 mmol) in anhydrous
THF (30 mL) was added a solution of iPrMgCl (2.0 M solution in
diethyl ether, 4.0 mmol) at 0 °C under N2 atmosphere, and then a
solution of t-BuLi (1.7 M solution in pentane, 4.0 mmol) was slowly
added for 15 min at -78 °C. After 30 min, sulfur powder (2.0
mmol) was added, and the reaction mixture was slowly warmed to
room temperature for 30 min. Finally, alkyl halide (2.0 mmol) was
slowly added. The reaction was monitored by thin-layer chroma-
tography. After the reaction was completed, the reaction mixture
was quenched with aqueous NH4Cl (35 mL). The organic layer
was separated, and then the aqueous layer was extracted with EtOAc
Acknowledgment. J.H., S.-J.C., J.K., and J.C. were sup-
ported by the BK21 Program, Ministry of Education and Human
Resources, and the Molecular and Cellular BioDiscovery
Research Program (M1-0311-00-0145), Ministry of Science and
Technology. This work was supported by the MarineBio 21
Program, Ministry of Maritime Affairs and Fisheries, Korea.
Supporting Information Available: Experimental procedures,
1
spectral characterization, and copies of H and 13C NMR spectra
for all compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO060361I
5784 J. Org. Chem., Vol. 71, No. 15, 2006