Efficient synthesis of 1,3,5-trisubstituted benzenes via three Pd-mediated carbon-sulfur, carbon-nitrogen and carbon-carbon bond formation reactions

Article abstract of DOI:10.1016/j.tetlet.2011.01.140

An efficient synthesis of 1,3,5-trisubstituted benzenes via a sequential Pd-mediated carbon-sulfur, carbon-nitrogen, and carbon-carbon bond formation reactions is reported. Selective amidation and sulfonamidation reactions are accomplished via Pd-catalyze

Full text of DOI:10.1016/j.tetlet.2011.01.140

Tetrahedron Letters 52 (2011) 1680–1684
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Tetrahedron Letters
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Efficient synthesis of 1,3,5-trisubstituted benzenes via three Pd-mediated
carbon–sulfur, carbon–nitrogen and carbon–carbon bond formation reactions
⇑
Bin Liu , Rupa S. Shetty, Kristofer K. Moffett, Martha J. Kelly
Ansaris, Four Valley Square, 512 Township Line Road, Blue Bell, PA 19422, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of 1,3,5-trisubstituted benzenes via a sequential Pd-mediated carbon–sulfur, car-
bon–nitrogen, and carbon–carbon bond formation reactions is reported. Selective amidation and sulfo-
namidation reactions are accomplished via Pd-catalyzed reactions between aryl chlorides and an
acetamide or a methanesulfonamide.
Received 15 December 2010
Revised 25 January 2011
Accepted 28 January 2011
Available online 4 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
During our effort to develop novel anti-mitotic drugs, we dis-
covered compound 1 as a potent anti-cancer agent.1 Compound 1
inhibits cell proliferation in Jurkats/T-cell leukemic and HeLa/cer-
vical with an IC50 of 21 nM and 130 nM, respectively. In addition,
Compound 1 appeared to be a noteworthy lead molecule based
on its favorable pharmacokinetics in mice and on its physical prop-
erties. Further medicinal chemistry efforts were focused on
addressing high protein binding and possible undesirable metabo-
lism issues. Toward this end, we decided to replace the phenol hy-
droxyl group with its common bioisosteres, such as an acetamide
or a methanesulfonamide,2 in order to improve metabolic stability
and reduce the glucuronidation of the phenol functional group. In
addition, the amine linker could be substituted with a sulfonyl lin-
ker in order to reduce the electron density of the central aromatic
ring (Scheme 1).
literature suggested that there is no straightforward method to a
generic structure as shown in Figure 1.3 The lack of a general method
is partly due to the synthetic difficulty to selectively make 1,3,5-
trisubstituted benzenes via aromatic substitution. The most com-
mon synthetic route would include amidation or sulfonamidation
of functionalized anilines. However, access to these anilines is
fairly complicated. In this communication, we report our efforts
to develop a highly efficient synthetic approach to diversified
1,3,5-trisubstituted benzene analogs utilizing sequentially three
Pd-mediated carbon–sulfur, carbon–nitrogen, and carbon–carbon
bond formation reactions.
H
N
H
N
R
R
Aryl
Aryl
S
O
O
O
The synthesis of this series of compounds calls for a synthetic
approach to benzenes having the following 1,3,5-trisubstitutions:
an aryl sulfide, the precursor for the sulfonyl group; an acetamide
or a methanesulfonamide; and an aryl group. A survey of the
S
S
Heteroaryl/Aryl
Heteroaryl/Aryl
Figure 1.
NH
O
NH
O
HO
N
NH
S
O
HN
HN
and
O
O
NH
S
S
O
O
N
N
1
Scheme 1.
⇑
Corresponding author. Tel.: +1 215 358 2063; fax: +1 215 358 2030.
E-mail address: bliu@ansarisbio.com (B. Liu).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.140

B. Liu et al. / Tetrahedron Letters 52 (2011) 1680–1684
1681
With the current development of Pd-catalyzed reactions, aryl
halides have become feasible precursors for aniline derivatives.
In our initial synthetic plan, we envisioned that the amide or sul-
fonamide, as well as the indole group attached to the phenyl ring,
could be accessed by Pd-mediated Buchwald type4 and Suzuki type
coupling reactions,5 respectively. Meanwhile, the sulfur ether bond
could be approached via a traditional nucleophilic aromatic substi-
tution reaction (Scheme 2). Alternatively, Pd-mediated coupling
between an aryl halide and an aryl thiol could be used to form
the thioether bond. Following this strategy, we decided to start
with 3,5-dichlorobenzenethiol, which is commercially available.
Not surprisingly, the nucleophilic aromatic substitution of 3-
bromopyridine with 3,5-dichlorobenzenethiol did not yield desired
product. To increase the reactivity of 3-bromopyridine, it was then
converted to the N-oxide by treatment with mCPBA.6 Although the
nucleophilic substitution of the N-oxide generated the desired
product 3-(3,5-dichlorophenylthio)pyridine 1-oxide, the yield
was only about 40%. In addition, an extra reductive step would
be required to regenerate pyridine.
Hal
NH
Hal
Hal
R
N
HN
+
S
O
S
Hal
Hal
O
N
N
SH
Hal=I, Br or Cl
R=Ac or Ms
Scheme 2.
Cl
Cl
Pd2dba3, t-BuOK
Cl
I
Cl
DPEphos toluene
+
N
S
72%
SH
To overcome the shortcomings of the thermal substitution reac-
tion, we turned our attention to Pd-mediated sulfur–carbon bond
formation reactions. Many Pd-catalyzed carbon–sulfur bond for-
mation reactions of aryl bromides, triflates, and occasionally highly
activated aryl chlorides have been reported.7 A procedure for syn-
thesis of aromatic and heteroaromatic thioethers using Pd catalyst
was brought to our attention.8 This system uses Pd2dba3 as cata-
lyst, DPEphos as ligand, t-BuOK as base and toluene as solvent. In
our hands, the coupling between 3-iodopyridine and 3,5-dichloro-
benzenethiol afforded a 72% yield of the desired product without
further optimization of the literature conditions (Scheme 3). Com-
pared with the substitution reaction, this approach allows us to
introduce more diversified aryl thiol groups at this position. Next,
N
2
3
Cl
H2O2, Na2WO4
92%
Cl
O
S
O
N
4
Scheme 3.
Table 1
Pd-mediated coupling between aryl bromides and acetamide or methanesulfonamide
NH
S
Aryl
O
S
NH
O
O
Aryl
O
or
or
Aryl Br
+
O
NH2
O
NH2
Entry
Substrate
Br
Condition
Product
Yielda
56%
O
O
S
O O
S
NH
Pd2(dba)3ꢀCHCl3
Xantphos, Cs2CO3
1,4-dioxane, 110°C
H2N
1
Br
NO2
Br
NO2
5a
Br
Br
O
O
S
NH
O O
O
Pd(PPh3)4
Xantphos, Cs2CO3
1,4-dioxane, 110°C
S
N
Br
H2N
2
60%
Br
OMe
O
N
OMe
5b
O
O
NH
H2N
Pd2(dba)3ꢀCHCl3
Xantphos, Cs2CO3
1,4-dioxane, 110°C
3
54%
Br
NO2
Br
NO2
5c
a
Isolated yield.

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B. Liu et al. / Tetrahedron Letters 52 (2011) 1680–1684
Table 2
Pd-catalyzed reaction between aryl chlorides and acetamide or methanesulfonamide
Pd2(dba)3
Xantphos
Aryl NH
O
O
Aryl NH
O
O
S
S
or
or
Aryl Cl
+
O
NH2
O
Cs2CO3
NH2
1,4-dioxane
Entry
1
Substrate
Product
Yielda
44%
Cl
Cl
O
S
O
S
O
O
O
6a
NH2
O
N
NH
N
Cl
O
Cl
Cl
Cl
O
O
O
O
S
S
6b
2
3
47%
42%
NH2
O N
O
O N
O
NH
O
Cl
Cl
O
S
O
S
O
S NH2
O
6c
N
N
Cl
Cl
NH
N
N
S
O
O
Cl
O
S
S
4
5
6
NH2
31%
78%
0%
6d
NH
Cl
O
Cl
Cl
O
N
S
S
N
NH2
6e
Cl
Cl
NH
Cl
O
O
O
O S
NH
O
O S
NH
6f
NH2
N
N
Cl
NH
Cl
O
N
NH
S
O
O
O
6g
Cl
O
O
7
30%b
NH2
O
N
S
N
NH
O
O
Cl
a
Isolated yield.
Yield after removal of Boc group.
b
the sulfonyl compound was obtained by oxidation using Na2WO4
(cat.) and H2O2.9
we wanted to find feasible coupling conditions for chloride
substrates.
With compound 4 in hand, we turned our attention to the key
amidation step. In the past few years, mild and versatile Pd- and
Cu-mediated amidation reactions have been developed.4 Most of
the examples that are reported in the literature used aryl iodides
or aryl bromides. There are only limited examples in which aryl
chlorides were used, especially when coupling with an acetamide
or a methanesulfonamide.4a,c However, as in our case, aryl chlo-
rides are still the most abundant starting materials. For this reason,
In a related synthetic effort, we previously identified effective
reaction conditions for coupling an aryl bromide to an acetamide
or a methanesulfonamide (Table 1). The coupling reaction was car-
ried out either using Pd2(dba)3 (entries 1 and 3) or Pd(PPh3)4 (entry
2) as catalyst, Xantphos as ligand, 1,4-dioxane as solvent, and
Cs2CO3 as base. Amidation and sulfonamidation were carried out
at 110 °C with 10 mol % of Pd catalyst loading. Desired products
5a, 5b, and 5c were obtained in good yields (54–60%). With this

B. Liu et al. / Tetrahedron Letters 52 (2011) 1680–1684
1683
TIPS
N
H
N
Cl
Pd catalyst 7
R
O
O
B
O
S
2M K3PO4
+
O
N
1,4-dioxane
O
S
O
NH
N
N
TIPS
R
6a R= acetyl
6c R= methanesulfonyl
8a R=acetyl, 68%
8b R=methanesulfonyl, 45%
H
N
R
N
HN
TBAF
THF
Cl
Pd
N
P
O
S
O
H
Pd catalyst 7
9a
R=acetyl
9b
R=methanesulfonyl
Scheme 4.
in mind, we decide to test these conditions with aryl chloride sub-
strates. To our delight, with slight modification, the reaction pro-
vided moderate yields with various substrates (Table 2).
ino)(20-dimethylamino-1,10-biphenyl-2-yl) palladium(II) (Scheme
4, catalyst 7), is an efficient catalyst for aryl chloride substrates.12
Indeed, the same catalytic system worked well on current sub-
strates, such as 6a and 6c from Table 2, to provide the desired
products in 68% and 45% yield, respectively (Scheme 4).13 Finally,
compounds 8a and 8b were converted into final target molecules
9a and 9b, after removal of the TIPS protection group.14
In summary, we have reported an efficient and diversified ap-
proach to synthesize 1,3,5-trisubstituted benzenes in conjunction
with the development of our drug candidate. This protocol utilizes
recently developed Pd-catalyzed cross-coupling reactions to form
sulfur–carbon, nitrogen–carbon, and carbon–carbon bonds
sequentially and selectively. Thus, this method allows one to intro-
duce diversified functional groups on the central phenyl ring. Aryl/
heteroaryl sulfide, sulfonamide, and amide, as well as aryl groups
could be introduced into the 1,3,5 position of the benzene by a
three-step sequence. The chemistry reported here is suitable for
building focused libraries.
To accelerate the reaction, microwave conditions were imple-
mented. The reaction mixture was heated at 120 °C using a micro-
wave reactor for 1 h. As demonstrated in Table 2, the coupling
between dichlorobenzene substrates and acetamide or methane-
sulfonamide afforded moderate to good yields (31–78%) of desired
products.10 Increasing the reaction temperature or the reaction
time did not significantly change the reaction outcome. As men-
tioned earlier, there are very few reports of Pd-catalyzed coupling
between aryl chlorides and sulfonamides, especially for alkyl sul-
fonamides like methanesulfonamide, which is an important func-
tional group in medicinal chemistry. As shown in entry 3, Table
2, the dichloride substrate successfully coupled with methanesul-
fonamide to afford the desired product in a 42% yield. The linker
could be thioether (entries 4 and 5) or sulfone. Interestingly, when
the substrate bearing a sulfonamide group was treated with an
acetamide under these coupling conditions, the desired product
was not obtained at all (entry 6). Instead, the bond was formed
on the sulfonamide site, presumably because of the higher reactiv-
ity of the sulfonamide than the acetamide.11 This side reaction
could be prevented by protection of the sulfonamide with a Boc
group. It was observed that the Boc group partially fell off during
the subsequent coupling reaction. In this case, the desired product
was obtained in 30% yield over two steps after the removal of the
Boc group with HCl (entry 7). As demonstrated in these examples,
aryl chlorides are convenient precursors to access aryl sulfona-
mides and amides. Due to the lower reactivity of the second chlo-
ride after the first amidation reaction, the bis-coupling product was
not observed under current conditions. Although the examples
listed in Table 2 are for dichlorobenzene substrates, we expect
the current conditions will also work with monochlorobenzene
having proper electronic properties.
References and notes
1. Shetty, R. S.; Lee, Y.; Liu, B.; Husain, A.; Joseph, R. W.; Lu, Y.; Nelson, D.;
Mihelcic, J.; Chao, W.; Moffett, K. K.; Schumacher, A.; Flubacher, D.; Stojanovic,
A.; Bukhtiyarova, M.; Williams, K.; Lee, K.-J.; Ochman, A. R.; Saporito, M. S.;
Moore, W. R.; Flynn, G. A.; Dorsey, B. D.; Springman, E. B.; Fujimoto, T.; Kelly, M.
J. J. Med. Chem. 2011, 54, 179.
2. Clark, R. D.; Caroon, J. M.; Isaac, N. E.; McClelland, D. L.; Michel, A. D.; Petty, T.
A.; Rosenkranz, R. P.; Waterbury, L. D. J. Pharm. Sci. 1987, 76, 411.
3. (a) Satyanarayana, J.; Reddy, K. R.; Ila, H.; Junjappa, H. Tetrahedron Lett. 1992,
33, 6173; (b) Shi, F.; Smith, M. R., III; Maleczka, R. E., Jr. Org. Lett. 2006, 8, 1411.
4. (a) Burton, G.; Cao, P.; Li, G.; Rivero, R. Org. Lett. 2003, 5, 4373; (b) Yin, J.;
Buchwald, S. L. Org. Lett. 2000, 2, 1101; (c) Forsa, B. P.; Dooleweerdta, K.; Zenga,
Q.; Buchwald, S. L. Tetrahedron 2009, 65, 6576.
5. Fu, G. C.; Littke, A. F. Angew. Chem., Int. Ed. 2002, 41, 4176.
6. Batmanghelich, S.; Turner, J. R. J. Chem. Res., Synop. 1987, 11, 378.
7. Itoh, T.; Mase, T. Org. Lett. 2004, 6, 4587.
8. Schopfer, U.; Schlapbach, A. Tetrahedron 2001, 57, 3069.
9. Sato, K.; Hyodo, M.; Aoki, M.; Zheng, X.-Q.; Noyori, R. Tetrahedron 2001, 57, 2469.
10. General procedure for Pd-mediated carbon–nitrogen bond formation:
a
The last step is the introduction of the indole group via a Suzuki
reaction to form the carbon–carbon bond. Previously, we have
reported that the preformed catalyst, chloro(di-2-norbornylphosph-
microwave vial was charged with Pd2(dba)3 or Pd2(dba)3.CHCl3 (0.1 equiv)
and Xantphos (0.11 equiv) followed by 1,4-dioxane. The mixture was stirred at
room temperature for 15 min. To this vial was then added acetamide or

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B. Liu et al. / Tetrahedron Letters 52 (2011) 1680–1684
sulfonamide (1.5 equiv), and Cs2CO3 (1.5 equiv) followed by dichloro benzenes
(1.0 equiv) in 1,4-dioxane. The vial was flushed with N2 gas and heated in a
12. Liu, B.; Moffett, K. K.; Joseph, R. W.; Dorsey, B. D. Tetrahedron Lett. 2005, 46,
1779.
microwave reactor at 120 °C for 1 h. The mixture was diluted with EtOAc. The
organic phase was washed with water and brine, then dried, and concentrated.
The product was purifed by flash chromatography to provide the desired
product.
13. General procedure for Pd-mediated carbon–carbon bond formation reaction:
to the aryl halide (1 equiv) and boronate (1 equiv) in a microwave vial was
added 2 M aq solution of K3PO4 (2 equiv), preformed catalyst 7 (5–10 mol %),
and 1,4-dioxane. The vial then was flushed with N2, sealed and heated using
microwave at 120 °C for 1 h. After completion, the reaction mixture was
filtered through a celite pad and the solvents were removed under reduced
pressure. The product was purified by flash chromatography.
11. The structure of the product from this reaction:
N
14. (a) Analytical data for compounds 9a: 1H NMR (400 MHz, CD3OD): d 9.17 (br s,
1H), 8.82 (br s, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.30 (s, 1H), 8.12 (s, 1H), 7.96 (d,
J = 1.4 Hz, 1H), 7.63 (s, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 3.3 Hz, 1H), 7.19
(t, J = 7.7 Hz, 1H), 7.10 (d, J = 7.4 Hz, 1H), 6.53 (d, J = 3.2 Hz, 1H), 2.15 (s, 3H).
(b) Analytical data for compound 9b: 1H NMR (400 MHz, CD3OD): d 9.11 (d,
J = 1.6 Hz, 1H), 8.77 (d, J = 4.0 Hz, 1H), 8.38–8.35 (m, 1H), 7.79–7.78 (m, 1H),
7.74–7.72 (m, 2H), 7.63–7.60 (m, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.29 (d, J = 3.3 Hz,
1H), 7.19 (t, J = 7.7 Hz, 1H), 7.10 (d, J = 6.8 Hz, 1H), 6.53 (d, J = 3.2 Hz, 1H), 2.85
(s, 3H).
O
NH
S
O
O
O
S
Cl
N
Cl
Cl
N