A general approach to indole-7-yl derivatives of isoxazole, oxadiazole, thiadiazole and pyrazole

Article abstract of DOI:10.1016/j.tetlet.2009.11.073

Isosteric replacement of the α,β-unsaturated amide at the C-7 position of indoles with a diverse set of five-membered amino-heterocycles including isoxazole, oxadiazole, thiadiazole and pyrazole followed by subsequent derivatization of the heterocyclic amino group to yield amides, sulfonamides and phosphoramides is described. Distinctive features of these procedures include the versatility and robust nature of the synthetic steps along with the high yields of the targeted molecules.

Full text of DOI:10.1016/j.tetlet.2009.11.073

Tetrahedron Letters 51 (2010) 575–578
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A general approach to indole-7-yl derivatives of isoxazole, oxadiazole,
thiadiazole and pyrazole
*
Alexandre M. Polozov, Georgeta Hategan, Hua Cao, Alex S. Kiselyov, Wayne Zeller, Jasbir Singh
deCODE Chemistry, Inc, 2501 Davey Road, Woodridge, IL, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Isosteric replacement of the
a
,b-unsaturated amide at the C-7 position of indoles with a diverse set of
Received 19 September 2009
Revised 9 November 2009
Accepted 16 November 2009
Available online 20 November 2009
five-membered amino-heterocycles including isoxazole, oxadiazole, thiadiazole and pyrazole followed
by subsequent derivatization of the heterocyclic amino group to yield amides, sulfonamides and phos-
phoramides is described. Distinctive features of these procedures include the versatility and robust nat-
ure of the synthetic steps along with the high yields of the targeted molecules.
Ó 2009 Elsevier Ltd. All rights reserved.
Recently, we have reported antagonists of the human EP3 recep-
tor as novel platelet aggregation inhibitors that do not extend the
bleeding time1 and thus are of great interest as potential anti-
thrombotic agents. These potent, isoform selective hEP3 antago-
nists, based on the 1,7-indole disubstituted series 1 (Scheme 1),
showed an excellent activity in platelet aggregation assays.1,2
These analogues contain the acylsulfonamide functionality as a
key pharmacophoric feature. Based on both extensive SAR3 data
and our modelling studies4 we sought to explore heterocyclic isos-
teres for the –C@CH–CO– fragment in 1. This modification was ex-
pected to affect the topology, steric and electronic features of the
sulfonamide bearing appendage, as shown by the general structure
2.5 In particular, we were interested in preparing 1-alkylaryl 7-het-
erocyclic indole derivatives 2 as a diverse set of EP3 receptor antag-
onist chemotypes. However, examination of the literature revealed
lack of a general approach to indoles featuring five-membered
amino-heterocycles at C-7 position.6 In this report, we describe a
versatile and flexible approach to a diverse set of five-membered
amino-heterocycles 3 from the 1,7-disubstituted indole derivatives
4 (Scheme 2). A subsequent derivatization of the amino group in 3
is expected to furnish the targeted substituted indoles 2.
Formation of 7-carbomethoxy indole from 7-bromoindole by
metalation with n-BuLi, followed by reaction with methyl chloro-
formate has been reported earlier.7 N-Alkylation of indole 68 pro-
vided 7-bromo indole 7 (Scheme 3). Treatment of 7 with n-BuLi
(1.5 equiv) followed by the addition of ethyl chloroformate
(2.0 equiv) afforded the desired ester derivatives 4 (Table 1) in
good to excellent isolated yields (76–90%) and purity.9 These key
intermediates were subsequently converted into a diverse set of
heterocycles as described below (Scheme 4).
Reaction of 4 with hydrazine provided the corresponding
hydrazides 8 in 70–90% yield. Subsequent exposure of 8 to cyano-
gen bromide in aqueous p-dioxane in the presence of sodium or
potassium bicarbonate furnished 2-amino-1,3,4-oxadiazoles
9
F
F
F
N
N
N
Ar1
Ar1
Ar1
(2)
X
Y
z
X
Y
z
NH2
(3)
NH
O2S
O
NH
(1)
Ar2
W
X,Y,Z heteroatoms (N, O or S) or X = CH
W = H, CO, SO2, PO(R)
Ar2
Scheme 1. Heterocycles as isosteres for a,b-unsaturated amides.
* Corresponding author. Tel.: +1 630 904 2218.
E-mail address: jsingh@decode.com (J. Singh).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.073

576
A. M. Polozov et al. / Tetrahedron Letters 51 (2010) 575–578
Table 1
F
F
F
Yields of 7-substituted indoles from (6)
7a
64%
7b
95%
7c
90%
7d
93%
7e
80%
N
N
H
N
Ar1
Ar1
COOR
Br
(6)
4a
90%
4b
85%
4c
90%
4d
83%
4e
76%
X
Y
z
(3)
(4) R = Et
(5) R =H
NH2
Scheme 2. Retrosynthetic analysis.
thiosemicarbazide in the presence of POCl3, provided 2-amino-
1,3,4-thiadiazoles 10.
The carboxylic acid 5a was converted to the acid chloride which
was immediately converted to the 7-carboxylic acid iminomethy-
leneamide, 11a (Scheme 4).11,12 This key intermediate was subse-
(53–90% overall yields). Similar to a reported procedure,10 the
hydrolysis of 4 followed by the reaction of resultant acid 5 with
F
F
F
(i)
(ii)
N
N
H
N
Ar1
Ar1
Br
(6)
Br
O
O
Et
(7)
(4)
OMe
*
O
Cl
F
O
*
Ar1 =
Cl
F
*
*
*
(e)
(d)
(a)
(b)
(c)
Scheme 3. Synthesis of C7-indole esters (4). Reagents and conditions: (i) (a) NaH, DMF, À10 °C, (b) Ar1-CH2-Br; (ii) (a) n-BuLi, Et2O, (b) EtOCOCl, À78 °C–rt, 1 h.
F
F
N
N
Ar1
(9)
Ar1
(8)
(a)
(c)
(b)
(d)
O
NH
NH2
O
F
N
N
NH2
N
Ar1
F
F
O
OEt
(4)
N
N
Ar1
Ar1
S
O
OH
N
(5)
N
NH2
(10)
(e)
(g)
F
F
N
N
F
(f)
(h), (j)
Ar1
Ar1
Ar1
(11)
(14)
N
O
F
N
N
O
N
(12)
NH2
O
NH
(h)
(13)
N
F
F
(i )
N
N
N
+
Ar1
Ar1
F
Ar1
N
O
O
N
OH
O
N
N
NH2
NH2
(16a)
NH2
(14)
Ar1
(17)
(15)
N
N
NH2
(j)
Scheme 4. Reagents and conditions: (a) NH2NH2, MTBE, 120 °C, 12 h; (b) BrCN/NaHCO3, p-dioxane-water, rt, 2 h; (c) 2 N NaOH, MeOH/THF (1:1), 75 °C, 1 h; (d)
NH2C(S)NH2NH2, POCl3, 120 °C, 30 min; (e) (i) (COCl)2/DMF cat, THF, rt, 5 min; (ii) cyanoamide, 2 N NaOH, THF–H2O, rt, 5 min; (f) NH2OH, pyridine, 60 °C, 4 h; (g) nBuLi,
CH3CN, THF, À78 °C?rt, 1 h; (h) NH2OHÁHCl or (NH2OH)2SO4, NaOH, H2O–EtOH, (2:3, v/v), reflux, 17 h; (j) 36% aq HCl, 90 °C, 2 h; (k) (l) NH2NHCH3, HOAc, iPrOH, heat.

A. M. Polozov et al. / Tetrahedron Letters 51 (2010) 575–578
577
Table 2
Yields for individual intermediates corresponding to the steps described in Scheme 4
F
F
Amine heterocycle
For Ar1 substituents, see legend in Scheme 3
N
N
Ar1
a
b
c
d
e
Ar1
X
Y
A : W = CO
B : W = SO2
C : W = PO
X
5
8
9
10
11
12
13
14
15
17
95
75
79
47
68
44
93
39
11
94
86
53
94
79
62
Y
z
z
NH
(3)
NH2
W
52
Ar2
Scheme 5. Derivatization of the amino-heterocycle.
75
80
37
29* 49**
17
isoxazoles 14a–c.16 Reaction of b-ketonitrile 13a with hydroxyl-
amine under basic conditions (EtOH/H2O, 1:1, v/v, 80 °C, 10 h), pro-
vided 14a and 15a as major products along with a small amount
(ꢀ10%) of the amidoxime intermediate 16a. Upon treatment with
aqueous HCl in EtOH/H2O, 16a cyclized to result in 14a in ꢀ75%
isolated yield. Similarly, 13b and 13c were converted to 14b and
14c, respectively, except the initial products following reaction
with hydroxyl amine were treated with aq HCl before isolation of
the final products, 14b and 14c in yields reported in Table 2. The
structure of 3-amino-isoxazole 14a was unequivocally confirmed
by a single crystal X-ray analysis.5 Alternatively, the reaction of
b-ketonitrile 13b with methyl hydrazine afforded 3-amino pyra-
zole 17b in 30% yield. Yields for the representative heterocyclic
intermediates featured on Scheme 4 are summarized in Table 2.
A diverse set of amino heterocyclic intermediates (9, 10, 12, 14,
15 and 17) were subsequently reacted with a variety of aryl and
heteroaryl acyl chlorides, sulfonyl chlorides and phosphoryl chlo-
rides to provide the corresponding amide, sulfonamide and phos-
phoramide derivatives, respectively, (Scheme 5). Generally, the
amides and phosphoramides were obtained in good to excellent
30
*
From chromatographic separation.
Following acid hydrolysis step prior to purification.
**
quently reacted with two equivalents of hydroxylamine in pyridine
to yield the 1,2,4-oxadiazole 12a.
A number of methods for the preparation of amino-5-aryl isox-
azoles starting from alkyl propiolates, b-ketonitriles or amidoxime
have been reported.13,14 Due to the accessibility and versatility of
b-ketonitriles 13 we used these in our synthetic sequence. Cycliza-
tion of b-ketonitriles with hydroxylamine is known to be non-reg-
ioselective, leading to the formation of a mixture of 3-amino- and
5-amino-isoxazoles.15 b-Ketonitriles 13 were readily accessible in
75–80% yields by reacting the respective carbanion of acetonitrile
with esters 4. Subsequent reaction of 13 with hydroxylamine led
to the regioisomeric isoxazole derivatives 14 and 15. Alternatively,
reaction of b-ketonitrile 13 with hydroxylamine under basic condi-
tions followed by hydrolytic ring opening of the acid labile 5-ami-
no-isoxazole isomer with concentrated HCl provided 3-amino-
Table 3
Heterocyclic amides (A), sulfonamides (B) and phosphoramides (C)
Compound
X
Y
Z
W
Ar1
Ar2
Yield (%)
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
O
N
N
CO
CO
CO
CO
CO
CO
CO
CO
2,4-Dichloro phenyl
2,4-Dichloro phenyl
2,4-Dichloro phenyl
2,4-Dichloro phenyl
2,4-Dichloro phenyl
2,4-Dichloro phenyl
2,4-Dichloro phenyl
2,4-Dichloro phenyl
2,4-Dichloro phenyl
2,4-Dichloro phenyl
2,4-Dichloro phenyl
2,4-Dichloro phenyl
2,4-Dichloro phenyl
2,4-Dichloro phenyl
2,4-Dichloro phenyl
2,4-Dichloro phenyl
2,4-Dichloro phenyl
3,4-Difluoro phenyl
3-Methoxy phenyl
2,3-Dihydro-benzo[1,4]dioxan-6-yl
2,4-Dichloro phenyl
2,4-Dichloro phenyl
2,4-Dichloro phenyl
2,4-Dichloro phenyl
3,4-Difluoro phenyl
3,4-Difluoro phenyl
3,4-Difluoro phenyl
2-Naphthyl
CF3
90
55
34
37
57
41
74
35
55
26
17
27
17
18
49
25
10
18
22
10
27
35
43
46
16
16
44
19
33
33
24
36
89
33
4-Fluoro phenyl
Isoxazol-5yl
3,5-Dichloro phenyl
3,4-Difluoro phenyl
2,4-Difluoro phenyl
2,4-Dichloro phenyl
5-[2,2-Difluoro-benzo[1,3]dioxole]
2-Furanyl
CO
SO2
SO2
SO2
SO2
SO2
PO
CH3
2,4,5-Trifluoro phenyl
4,5-Dichloro thiophenyl
3,4-Dichloro phenyl
3,4-Difluoro phenyl
Phenyl
PO
2,4-Dichloro phenoxy
4,5-Dichloro thiophenyl
4,5-Dichloro thiophenyl
3,4-Difluoro phenyl
3,4-Difluoro phenyl
2,4.5-Trifluoro phenyl
4,5-Dichloro thiophenyl
3,4-Dichloro phenyl
3,4-Difluoro phenyl
2,4.5-Trifluoro phenyl
2,4,5-Trifluoro phenyl
3,4-Difluoro phenyl
2,4,5-Trifluoro phenyl
4,5-Dichloro thiophenyl
3,4-Dchloro phenyl
3,4-Difluoro phenyl
CH3
N
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
2-Naphthyl
2-Naphthyl
2-Naphthyl
3,4-Difluoro phenyl
3,4-Difluoro phenyl
3,4-Difluoro phenyl
N-Me
N-Me
CH3
4,5-Dichloro thienyl
The unoptimized yields shown are from the corresponding amine.

578
A. M. Polozov et al. / Tetrahedron Letters 51 (2010) 575–578
16.
A reaction sequence for the regioselective synthesis of 5-amino-isoxazole
yields (50–90%), while reactions with substituted phenyl and het-
erocyclic sulfonyl chlorides provided poor to modest yield of the
targeted acyl sulfonamides (typically 10–50%).
derivative of 3-(cyanoacetyl indole) using buffered media has been reported:
Slatt, J.; Janosik, T.; Wahlsrom, K.; Bergman, J. J. Heterocycl. Chem. 2005, 42,
141–143.
17. The synthesis of 14a and its transformation to 39 is provided below as a
representative example.
The flexibility and general versatility of the synthetic proce-
dures described above are further demonstrated by the prepara-
tion of a diversity of 7-substituted indoles (Table 3).
In summary, versatile, robust and generally high-yielding reac-
tion sequences have been described for the elaboration of 7-car-
boxylate /carboxylic acid substituents of indoles to provide a
diverse set of five-membered amino-heterocycles.17 The resulting
amines were further derivatized to furnish the respective amide,
sulfonamide and phosphoramide derivatives 18–51. Several deriv-
7-Bromo-1-(2,4-dichlorobenzyl)-5-fluoro-3-methyl-1H-indole (7a). NaH (60% in
oil, 526 mg, 13.15 mmol) was added to a solution of 6 (2 g, 8.77 mmol) in DMF
(30 mL) at À10 °C. Reaction mixture was warmed to rt and then stirred for
30 min. A solution of 2,4-dichlorobenzyl chloride (2.06 g, 10.52 mmol) in DMF
(10 mL) was added at À10 °C. The reaction mixture was allowed to warm to rt,
stirred for 30 min and then the reaction was quenched with 10% HCl/water/
ether (1:1:2, 40 mL). The aqueous layer was extracted with ether (2 Â 10 mL)
and the combined organic layers were washed with water (3 Â 75 mL), brine
(75 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to
afford crude product as a brown solid. Ether (4 mL) was added and the solution
was cooled, and the off-white solid was filtered to afford indole 7a (2.49 g,
73%). Rf = 0.70 (EtOAc/hexanes, 1:5). MS (ESI+) m/z: 388 (M+). 1H NMR
(400 MHz, CDCl3) d 2.27 (s, 3H), 5.69 (s, 2H), 6.22 (dd, J = 8.4, 1.0 Hz, 1H),
6.89 (d, J = 0.5 Hz, 1H), 7.04 (dd, J = 8.4, 2.0 Hz, 1H), 7.13 (ddd, J = 8.4, 2.0,
0.4 Hz, 1H), 7.19 (dd, J = 8.8, 2.0 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H).
atives showed 1–5 lM activity in the functional rat platelet aggre-
gation assay prompting further evaluation of these lead candidates.
Details of their biological evaluation will be reported elsewhere.5
5-[1-(2,4-Dichloro-benzyl)-5-fluoro-3-methyl-1H-indol-7-yl]-isoxazol-3-ylamine
(14a). n-BuLi (1.6 M in hexanes, 0.97 mL, 1.55 mmol) was added under an
Argon atmosphere to a solution of 7a (400 mg, 1.03 mmol) in ether (7 mL) at
À78 °C over 7 min. The reaction mixture was stirred at À78 °C for 30 min. Ethyl
chloroformate (0.2 mL, 2.07 mmol) was added slowly and the reaction mixture
was warmed up to rt, stirred at rt for 30 min and then the reaction was
quenched with 10% aqueous HCl (5 mL). The organic layer was washed with
water (2 Â 10 mL), brine (10 mL), dried over anhydrous MgSO4, filtered and
concentrated in vacuo to afford ester 4a (386 mg, 98%) as a brown oil. Rf = 0.45
(EtOAc/hexanes, 1:19). MS (APCI+): m/z 379 (M+). This material was used
without further purification.
Acetonitrile (1.01 mL, 19.25 mmol) was slowly added over 3 min to a solution
of n-BuLi (2.5 M, 8.7 mL, 21.66 mmol) in THF (90 mL) at À78 °C. The reaction
mixture was stirred for additional 15 min at À78 °C and a solution of the ester
4a (3.66 g, 9.63 mmol) in THF (20 mL) was added slowly and the reaction
mixture was allowed to warm to rt over 30 min. The reaction mixture was
cooled to À78 °C and 10% aqueous HCl (40 mL) was added followed by ether
(40 mL). The aqueous phase was extracted with ether (2 Â 40 mL). The
combined organic extracts were washed with water (3 Â 100 mL), brine
(100 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to
References and notes
1. Singh, J.; Zeller, W.; Zhou, N.; Hategen, G.; Mishra, R.; Polozov, A.; Yu, P.; Onua,
E.; Zhang, J.; Zembower, D.; Kiselyov, A.; Ramírez, J.; Sigthorsson, G.; Bjornsson,
J.; Thorsteinsdottir, M.; Andrésson, Þ.; Bjarnadottir, M.; Magnusson, O.; Fabre,
J.; Stefansson, K.; Gurney, M. A. C. S. Chem. Biol. 2009, 4, 115–126.
2. Singh, J.; Zhou, N.; Hategan, G.; Zeller, W.; Polozov, A.; Goldsmith, M.; Krohn,
M.; Anderson, H.; Mishra, R.; Zhang, J.; Onua, E.; Ramirez, J.; Palsdottir, G.;
Halldorsdottir, G.; Andresson, T.; Gurney, M. 230th ACS National Meeting,
Washington, DC, Aug 28–Sept 1, 2005. MEDI (Abstract #250).
3. Singh, J.; Zeller, W.; Zhou, N.; Hategen, G.; Mishra, R.; Polozov, A.; Yu, P.; Onua,
E.; Zhang, J.; Ramírez, J.; Sigthorsson, G.; Thorsteinnsdottir, M.; Kiselyov, A.;
Zembower, D.; Andrésson, Þ.; Gurney, M., J. Med. Chem. 2009, Accepted.
4. We have generated a six-point pharmacophore for the EP3 receptor. Strategies
utilized in the development of this pharmacophore will be reported in a
forthcoming disclosure, being submitted to J. Chem. Int. Model.
5. Hategan, G.; Polozov, A. M.; Zeller, W.; Cao, H.; Mishra, R. M.; Kiselyov, A. K.;
Ramirez, J.; Halldorsdottir, G.; Andrésson, Þ.; Gurney, M. E.; Singh, J. Bioorg.
Med. Chem. Lett. 2009, 19, 6797–6800.
6. (a) Black, D.; Bowyer, M.; Kumar, N. Tetrahedron 1977, 53, 8573–8584. This
report utilizes highly electron rich indole and Vilsmeier reaction methodology
using the pyrrolidin-2-one approach for synthesis indol-7-yl-pyrrole; (b) A
yield crude product (3.61 g, 100%) as
a brown oil. The crude oil, upon
trituration with hexane (3 Â 4 mL) afforded the b-ketonitrile 13a 2.70 g (75%)
as a light brown solid. Rf = 0.11 (hexanes/acetone, 9:1). This material was used
without any further purification. 1H NMR (400 MHz, CDCl3), 2.32 (s, 3H), 3.66
(s, 2H), 5.42 (s, 2H), 6.08 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 1.6 Hz, 1H), 7.09–7.12
(dd, J = 8.8, 2.4 Hz, 1H), 7.26 (s, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.51–7.54 (dd,
J = 8.8, 2.8 Hz, 1H). To a mixture of b-ketonitrile 13a (2.33 g, 6.2 mmol, 1 equiv)
in water–ethanol (2:3, 22 mL) was added sodium hydroxide (295 mg,
7.15 mmol) and hydroxylamine sulfate (0.506 g, 3.42 mmol) and the reaction
mixture was heated to reflux for 20 h. A solution of 36% aqueous HCl (0.8 mL)
was added and the reaction mixture was heated to reflux for additional 2 h.
The reaction mixture was cooled to 0 °C and the reaction was quenched
through the addition of saturated aqueous NaHCO3 (25 mL), followed by solid
Na2CO3 (2.5 g). Mixture was extracted with EtOAc (2 Â 25 mL). The combined
organic extracts were washed with water (2 Â 50 mL), brine (50 mL), dried
over anhydrous MgSO4, filtered and concentrated in vacuo to yield crude
product as brown oil. Purification by flash silica gel chromatography, using
CH2Cl2 as eluent, afforded 1.04 g (43%) of the compound 14a as brown crystals.
Rf = 0.25 (CH2Cl2). 1H NMR (400 MHz, CDCl3) d 2.31 (s, 3H), 3.89 (br s, 2H), 5.14
(s, 2H), 5.61 (s, 1H), 6.21 (d, J = 8 Hz, 1H), 6.88 (s, 1H), 6.92–6.95 (dd, J = 9.2,
2.4 Hz, 1H), 7–7.02 (dd, J = 8, 2 Hz, 1H), 7.33 (s, 1H), 7.35–7.37 (dd, J = 9.2,
2.4 Hz, 1H). MS (ESIÀ) m/z: 392 (M+1). LCMS 97%.
relevant paper describes synthesis of
a trisubstituted indole-7-triazolyl
derivatives: Contour-Galcera, M.; Alban, S.; Pascale, P.; Pierre, R. Bioorg. Med.
2009, 19, 6797–6800. Chem. Lett. 2005, 15 3555–3559.; For recent patent
examples see: (c) US20030069245, describes preparartion of several
aminosubstituted 5-membered heteroaromatics.; (d) WO2009071577,
aminooxadiazole derivatives.
7. Li, L.; Martins, A. Tetrahedron Lett. 2003, 44, 689–692.
8. Zegar, S.; Tokar, C.; Enache, L.; Rajagopol, V.; Zeller, W.; O’Connell, M.; Singh, J.;
Muellner, F.; Zembower, D. E. Org. Process Res. Dev. 2007, 11, 747–753.
9. Smaller excesses (1.1–1.2 equiv) of n-BuLi in Et2O or THF followed by addition
of 1.2 equiv of methyl chloroformate afforded both poor yield and low purity of
the desired acylation products; LCMS analysis of crude reaction mixtures
indicated a considerable amount of unreacted bromo derivative 6 was present.
10. (a) Pomslb, K. T.; Huseby, R. M. J. Org. Chem. 1966, 31, 3528–3531; (b) Turner, S.
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1023–1028; (f) Carvalho, S. A.; daSilva, E. F.; Santa-Rita, R. M.; de Castro, S. L.;
Fraga, C. A. M. Bioorg. Med. Chem. Lett. 2004, 14, 5967–5970.
4,5-Dichloro-thiophene-2-sulfonic acid {5-[1-(2,4-dichloro-benzyl)-5-fluoro-3-
methyl-1H-indol-7-yl]-isoxazol-3-yl}-amide (39). To
a suspension of 14a
11. Howard, J. C.; Youngblood, F. E. J. Org. Chem. 1966, 31, 959–961.
12. Acid 5 was reacted with oxalyl chloride to yield the respective acyl chloride.
Sodium hydrogen cyanamide (prepared from cyanamide and 2 N NaOH) was
reacted with 5 in THF for 2 h at rt, the reaction mixture was partitioned
between EtOAc and 10% aq HCl (4:1), the organic layer was dried over
anhydrous MgSO4 and concentrated in vacuo to furnish the cyanamide 11a in a
68% overall yield.
13. (a) Iwai, I.; Nakamura, N. Chem. Pharm. Bull. 1966, 14, 1277–1286; (b) Kloetzer,
W.; Bretschneider, H.; Fitz, E.; Reiner, R.; Bader, G. Monatsh. Chem. 1970, 101,
1109–1122; (c) Stachel, H. D. Chem. Ber. 1963, 96, 1088–1097; (d) Uno, H.;
Kurokawa, M.; Nishimura, H. Chem. Pharm. Bull. 1976, 24, 644–647.
14. (a) Rouchaud, J.; Gustin, F.; Moulard, C. Bull. Soc. Chim. Belg. 1991, 102, 545–
555; (b) Takasa, A.; Murabayashi, A.; Sumimoto, S.; Ueda, S.; Makisumi, Y.
Heterocycles 1991, 32, 1153–1158.
(180 mg, 0.447 mmol) in 0.5 ml pyridine was added DMAP (81 mg,
0.67 mmol, 1.5 equiv). This mixture was briefly heated in a 70 °C bath until a
clear solution was obtained. Then, 2,3-dichlorothiophene-5-sulfonyl chloride
(140 mg, 0.536 mmol, 1.2 equiv) was added to the solution at rt and stirred for
3 h. The mixture was concentrated in vacuo to give an oil and then dissolved in
EtOAc (15 mL). The organic layer was washed with 10% aqueous HCl
(2 Â 3 mL), water (2 Â 3 mL), brine (2 Â 3 mL), dried over anhydrous MgSO4,
filtered and concentrated in vacuo to provide 280 mg of a residue. Purification
of this residue by column chromatography using 20–50% EtOAc/ hexanes gave
100 mg (35%) of the pure desired product as white solid. 1H NMR (400 MHz,
CDCl3) d 2.32 (s, 3H), 5.05 (s, 2H), 6.24 (d, J = 8.0 Hz, 1H), 6.34 (s, 1H), 6.90 (s,
1H), 6.97 (dd, J = 8.8, 2.8 Hz, 1H), 7.03 (dd, J = 8.8, 2.0 Hz, 1H), 7.3 (d, J = 2.0 Hz,
1H), 7.41 (dd, J = 8.8, 2.8 Hz, 1H), 7.45 (s,1H), 7.55 (br s, 1H). MS(ESIÀ) m/z: 604
(MÀ1). HPLC (Phenomenex Prodigy C18 column, 4.6 Â 150 mm, 5
lm, 254 nm)
15. Claisse, J. A.; Foxton, M. W.; Gregory, G. I.; Sheppard, A. H.; Tiley, E. P.;
Warburton, W. K.; Wilson, M. J. J. Chem. Soc., Perkin Trans. 1 1973, 2241–2249.
eluted using a gradient elution 95/5 to 5/95 A/B over 20 min at a flow rate of
1.0 mL/min methanol) = 99.4%.