Efficient regioselective synthesis of 3-iodoindole N-carboximidamides and N-carboximidoates by a sequential aza-wittig/iodine induced cyclization

Article abstract of DOI:10.1002/cjoc.201200281

3-Iodoindole N-carboximidamides and N-carboximidoates 4 were prepared regioselectively via a sequential aza-Wittig/iodine induced cyclization, starting from easily accessible 2-alkynylphenyl iminophosphorane, isocyanates, various nucleophiles and iodine.

Full text of DOI:10.1002/cjoc.201200281

FULL PAPER
DOI: 10.1002/cjoc.201200281
Efficient Regioselective Synthesis of 3-Iodoindole
N-Carboximidamides and N-Carboximidoates by a
Sequential Aza-Wittig/Iodine Induced Cyclization
Nie, Yibo(聂熠博)
Duan, Zhuan(段专)
Ding, Mingwu*(丁明武)
Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Central China Normal University,
Wuhan, Hubei 430079, China
3-Iodoindole N-carboximidamides and N-carboximidoates 4 were prepared regioselectively via a sequential
aza-Wittig/iodine induced cyclization, starting from easily accessible 2-alkynylphenyl iminophosphorane, iso-
cyanates, various nucleophiles and iodine.
Keywords indole, aza-Wittig reaction, iodine, cyclization, iminophosphorane
Introduction
the synthesis of nitrogen-containing heterocyclic com-
pounds.[10] We have recently been interested in the syn-
thesis of various heterocycles through aza-Wittig reac-
tions, with the aim of evaluating their biological activi-
ties.[11] Herein we wish to report a mild and efficient
synthesis of 3-iodoindole N-carboximidamides and
N-carboximidoates by iodine induced cyclization of
(2-alkynylphenyl)guanidines (or isoureas), which were
obtained by aza-Wittig reaction and further reaction of
the carbodiimides with amines or alcohols.
Among the electrophilic cyclization leading to het-
erocycles, iodine induced cyclization is a widely used
process and has become an effective protocol in the
preparation of a variety of heterocyclic and carbocyclic
compounds.[1] For example, iodine induced cyclization
of some alkynes has been proved to be an effective
method for the synthesis of furans,[2] pyrroles,[3] thio-
phenes[4] and indoles[5,6] in recent years. Iodine induced
cyclization has received considerable attention because
the iodine is inexpensive, non-toxic and readily avail-
able.
Experimental
Indole is one of the most ubiquitous heterocycle
found in a large number of natural products and phar-
macologically active compounds.[7] Due to the great
structural diversity of biologically active indoles, the
synthesis and functionalization of indoles has been a
major focus in research. Several efficient methodologies
have been developed for preparation of indoles. One of
the synthetic method for polysubstituted indole deriva-
tives is the intramolecular cyclization of 2-alkynyl-
aniline derivatives, catalyzed by some expensive palla-
dium, gold or silver complexes.[8] The reaction can also
be carried out by iodine induced cyclization to give
N-tosyl or N-Boc-protected 3-iodo-indoles.[6,9] However,
3-iodoindole N-carboximidamides and N-carboximido-
ates are not prepared by this method previously proba-
bly due to the fact that the starting material (2-alkynyl-
phenyl)guanidines (or isoureas) are not easily accessible
by routine synthetic methods.
General procedure
Melting points were determined using a Beijing
Taike X-4 model apparatus and uncorrected. MS data
were measured on a Finnigan Trace MS instrument.
NMR spectra were recorded in CDCl3 or DMSO-d6 on a
Varian Mercury 600 or 400 spectrometer using TMS as
interal standard. Elemental analyses were taken on a
Vario EL III elemental analysis instrument.
General procedure for the preparation of 4a—4k
To a solution of iminophosphorane 1[12] (3.0 mmol)
in dry methylene dichloride (15 mL) was added aro-
matic isocyanate (3.0 mmol) under nitrogen at room
temperature. After the reaction mixture was left un-
stirred for 8—12 h at 0—5 ℃, enyne-carbodiimides 2
were obtained in high yield, which were used directly
without further purification. To the solution of enyne-
carbodiimides 2 prepared above was added secondary
The aza-Wittig reactions of iminophosphoranes have
received increased attention in view of their utility in
amines (HNR2 , 3.0 mmol). After the reaction mixture
2
was stirred for 0.5—6 h, the guanidine-enyne interme-
*
E-mail: mwding@mail.ccnu.edu.cn; Tel.: 0086-027-67867958; Fax: 0086-027-67862041
Received March 23, 2012; accepted June 26, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200281 or from the author.
Chin. J. Chem. 2012, 30, 1807—1812
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1807

Nie, Duan & Ding
FULL PAPER
diate 3 was generated. The solvent was removed off
under reduced pressure. To the solution of 3 prepared
above in anhydrous acetonitrile (10 mL) was added I2
(6.0 mmol, 1.5 g) and K2CO3 (9.0 mmol, 1.3 g). After
the reaction mixture was stirred for 3 h, saturated aque-
ous Na2S2O3 solution was added to remove the unre-
acted I2. The mixture was extracted by methylene di-
chloride and the organic layer was evaporated under
reduced pressure. The crude product was purified by
flash chromatography (petroleum ether/diethyl ether,
V∶V＝4∶1) to yield indole derivatives 4a—4k.
197 (1), 191 (4). Anal. calcd for C26H24IN3O: C 59.89,
H 4.64, N 8.06; found C 59.56, H 4.79, N 8.30.
N-[(3-Iodo-2-phenyl-1H-indol-1-yl)(morpholino)-
methylene]-3-methylaniline (4e): White solid (yield
1
81%), m.p. 170—172 ℃; H NMR (CDCl3, 600 MHz)
δ: 7.52—7.48 (m, 2H), 7.36—7.24 (m, 5H), 7.06—7.04
(m, 2H), 6.70—6.59 (m, 2H), 5.75—5.73 (m, 2H), 3.88
—3.80 (m, 3H), 3.62—3.56 (m, 3H), 3.20—3.15 (m,
2H), 1.98 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ: 146.2,
143.6, 139.2, 137.7, 136.5, 130.8, 130.5, 129.8, 128.5,
128.0, 127.7, 124.5, 123.5, 123.2, 122.3, 122.1, 122.0,
117.8, 111.4, 66.5, 63.9, 46.6, 46.5, 21.1; MS (EI, 70 eV)
m/z (%): 521 (M＋, 3), 203 (100), 197 (1), 191 (4), 175
(1). Anal. calcd for C26H24IN3O: C 59.89, H 4.64, N
8.06; found C 60.12, H 4.66, N 8.19.
4-Chloro-N-[(3-iodo-2-phenyl-1H-indol-1-yl)(mor-
pholino)methylene]aniline (4a): White solid (yield
1
77%), m.p. 223—225 ℃; H NMR (CDCl3, 600 MHz)
δ: 7.51—7.47 (m, 2H), 7.38—7.29 (m, 5H), 7.10—7.09
(m, 2H), 6.81—6.80 (m, 2H), 5.89 (d, J＝8.4 Hz, 2H),
3.87—3.80 (m, 3H), 3.62—3.54 (m, 3H), 3.18—3.14
(m, 2H); 13C NMR (CDCl3, 150 MHz) δ: 145.0, 143.9,
138.9, 136.1, 130.8, 130.3, 129.8, 128.7, 128.3, 127.9,
127.8,124.8, 123.0, 122.5, 122.3, 111.2, 66.5, 64.3, 46.5,
46.0; MS (EI, 70 eV) m/z (%): 541 (M＋, 4), 223 (100),
190 (6), 179 (12), 165 (3), 151 (6), 138 (4), 111 (10).
Anal. calcd for C25H21ClIN3O: C 55.42, H 3.91, N 7.76;
found C 55.71, H 4.12, N 7.90.
N,N-Dibutyl-3-iodo-N',2-diphenyl-1H-indole-1-car-
boximidamide (4f): White solid (yield 84%), m.p. 95—
1
97 ℃; H NMR (CDCl3, 600 MHz) δ: 7.46—7.45 (m,
1H), 7.37—7.30 (m, 4H), 7.27—7.22 (m, 4H), 6.86—
6.83 (m, 2H), 6.75—6.74 (m, 1H), 6.13 (d, J＝7.2 Hz,
2H), 3.63—3.62 (m, 1H), 3.48—3.46 (m, 1H), 2.87—
2.84 (m, 2H), 1.59—1.56 (m, 2H), 1.44—1.41 (m, 2H),
1.27—1.26 (m, 2H), 1.04—1.00 (m, 2H), 0.92 (t, J＝7.2
Hz, 3H ), 0.68 (t, J＝7.2 Hz, 3H); 13C NMR (CDCl3,
150 MHz) δ: 147.2, 143.2, 139.0, 136.4, 130.7, 130.5,
130.0, 128.5, 128.2, 127.8, 124.1, 122.1, 121,8, 121.7,
111.8, 63.3, 47.5, 47.1, 30.6, 28.6, 20.4, 20.0, 14.0, 13.6;
MS (EI, 70 eV) m/z (%): 549 (M＋, 2), 319 (2), 293 (3),
231 (100). Anal. calcd for C29H32IN3: C 63.39, H 5.87,
N 7.65; found C 63.56, H 6.08, N 7.83.
4-Fluoro-N-[(3-iodo-2-phenyl-1H-indol-1-yl)(mor-
pholino)methylene]aniline (4b): White solid (yield
1
80%), m.p. 196—198 ℃; H NMR (CDCl3, 600 MHz)
δ: 7.51—7.47 (m, 2H), 7.38—7.29 (m, 5H), 7.10—7.09
(m, 2H), 6.56—6.53 (m, 2H), 5.91—5.89 (m, 2H),
3.85—3.79 (m, 3H), 3.62—3.54 (m, 3H), 3.18—3.13
(m, 2H); 13C NMR (CDCl3, 150 MHz) δ: 159.7, 158.1,
143.8, 142.5, 138.9, 136.2, 130.8, 130.4, 129.7, 128.7,
127.9, 124.7,122.8, 122.4, 122.2, 114.9, 114.8, 111.3,
66.3, 64.2, 46.5, 46.0; MS (EI, 70 eV) m/z (%): 525 (M＋,
3), 311 (1), 207 (100). Anal. calcd for C25H21FIN3O: C
57.15, H 4.03, N 8.00; found C 57.12, H 4.21, N 8.26.
N-[(3-Iodo-2-phenyl-1H-indol-1-yl)(morpholino)-
methylene]aniline (4c): White solid (yield 85%), m.p.
3-Iodo-N,N-diisopropyl-N',2-diphenyl-1H-indole-1-
carboximidamide (4g): White solid (yield 79%), m.p.
1
128—130 ℃; H NMR (CDCl3, 600 MHz) δ: 7.47—
7.45 (m, 1H), 7.37—7.34 (m, 6H), 7.25—7.22 (m, 2H),
6.87—6.85 (m, 2H), 6.74—6.72 (m, 1H), 6.20 (d, J＝
7.8 Hz, 2H), 3.59—3.58 (m, 1H), 3.32—3.30 (m, 1H),
1.67 (d, J＝6.0 Hz, 3H), 1.49 (d, J＝6.0 Hz, 3H), 1.00
(d, J＝6.0 Hz, 3H), 0.88 (d, J＝6.0 Hz, 3H); 13C NMR
(CDCl3, 150 MHz) δ: 147.1, 139.9, 138.7, 136.6, 130.5,
130.4, 130.2, 128.7, 128.2, 127.7, 123.9, 122.0, 121.8,
111.6, 62.3, 49.1, 49.0, 46.6, 21.6, 21.2, 20.4, 19.7; MS
(EI, 70 eV) m/z (%): 521 (M＋, 2), 293 (2), 203 (100).
Anal. calcd for C27H28IN3: C 62.19, H 5.41, N 8.06;
found C 62.34, H 5.53, N 8.28.
1
191—193 ℃; H NMR (CDCl3, 600 MHz) δ: 7.49—
7.47 (m, 2H), 7.37—7.23 (m, 5H), 7.09—7.07 (m, 2H),
6.85—6.76 (m, 3H), 6.00 (d, J＝7.8 Hz, 2H), 3.84—
3.74 (m, 3H), 3.58—3.48 (m, 3H), 3.14—3.09 (m, 2H);
13C NMR (CDCl3, 150 MHz) δ: 146.3, 143.5, 139.0,
136.2, 130.8, 130.4, 129.8, 128.6, 128.2, 127.8, 124.5,
122.8, 122.3, 122.0, 121.6, 111.4, 66.3, 64.1, 46.4, 46.0;
MS (EI, 70 eV) m/z (%): 507 (M＋, 3), 293 (1), 191 (5),
189 (100). Anal. calcd for C25H22IN3O: C 59.18, H 4.37,
N 8.28; found C 59.36, H 4.51, N 8.22.
3-Iodo-N',2-diphenyl-N,N-dipropyl-1H-indole-1-car-
boximidamide (4h): White solid (yield 84%), m.p. 111
1
—113 ℃; H NMR (CDCl3, 600 MHz) δ: 7.47—7.46
(m, 1H), 7.37—7.31 (m, 4H), 7.28—7.20 (m, 4H), 6.85
—6.83 (m, 2H), 6.75—6.73 (m, 1H), 6.09 (d, J＝7.8 Hz,
2H), 3.57—3.45 (m, 2H), 2.88 (t, J＝7.8 Hz, 2H), 1.66
—1.63 (m, 2H), 1.52—1.49 (m, 2H), 0.88 (t, J＝7.2 Hz,
3H), 0.68 (t, J＝7.2 Hz, 3H); 13C NMR (CDCl3, 150
MHz) δ: 147.2, 143.2, 139.0, 136.5, 130.8, 130.5, 130.0,
128.6, 128.2, 127.7, 124.1, 122.1, 121.8, 121.7, 121.6,
111.7, 63.4, 49.6, 21.8, 19.7, 11.7, 11.4; MS (EI, 70 eV)
m/z (%): 521 (M＋, 2), 293 (2), 203 (100). Anal. calcd
for C27H28IN3: C 62.19, H 5.41, N 8.06; found C 62.28,
H 5.57, N 8.24.
N-[(3-Iodo-2-phenyl-1H-indol-1-yl)(morpholino)-
methylene]-4-methylaniline (4d): White solid (yield
1
84%), m.p. 214—216 ℃; H NMR (CDCl3, 600 MHz)
δ: 7.50—7.44 (m, 2H), 7.36—7.24 (m, 5H), 7.14—7.12
(m, 2H), 6.69—6.66 (m, 2H), 5.97 (d, J＝7.8 Hz, 2H),
3.79—3.42 (m, 6H), 3.08—3.02 (m, 2H), 2.14 (s, 3H);
13C NMR (CDCl3, 150 MHz) δ: 146.7, 143.2, 139.0,
136.1, 132.2, 130.7, 130.5, 129.8, 128.9, 128.6, 127.8,
124.5, 122.2, 122.0, 121.5, 111.5, 66.4, 63.9, 46.3, 46.1,
20.7; MS (EI, 70 eV) m/z (%): 521 (M＋, 2), 203 (100),
1808
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Chin. J. Chem. 2012, 30, 1807—1812

Efficient Regioselective Synthesis of 3-Iodoindole N-Carboximidamides and N-Carboximidoates
N-[(3-Iodo-5-methyl-2-phenyl-1H-indol-1-yl)(piper-
idin-1-yl)methylene]aniline (4i): White solid (yield
75%), m.p. 154—156 ℃; H NMR (CDCl3, 600 MHz)
600 MHz) δ: 7.77—7.16 (m, 9H), 6.92—6.88 (m, 2H),
6.38—6.34 (m, 2H), 4.59—4.54 (m, 2H), 4.49—4.22
(m, 2H), 3.89—3.79 (m, 3H), 3.58—3.38 (m, 3H),
2.76—2.63 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ:
145.7, 145.4, 137.3, 136.6, 136.4, 135.9, 133.4, 130.9,
128.8, 128.7, 128.5, 128.4, 128.2, 124.9, 122.8, 122.7,
122.1, 112.8, 110.9, 85.7, 73.1, 66.0, 65.6, 64.4, 64.3,
46.4, 46.2; MS (EI, 70 eV) m/z (%): 585 (M＋, 3), 494
(4), 479 (5), 223 (100), 179 (10), 138 (4), 111 (4), 91 (7).
Anal. calcd for C27H25ClIN3O2: C 55.35, H 4.30, N 7.17;
found C 55.42, H 4.34, N 7.32.
N-((2-((Benzyloxy)methyl)-3-iodo-1H-indol-1-yl)-
(pyrrolidin-1-yl)methylene)-4-chloroaniline (4n): White
solid (yield 72%), m.p. 108—110 ℃; 1H NMR (CDCl3,
400 MHz) δ: 7.77—6.86 (m, 11H), 6.38—6.34 (m, 2H),
4.58—4.22 (m, 4H), 3.69—3.66 (m, 2H), 2.95—2.78
(m, 2H), 1.89—1.66 (m, 2H), 1.46—0.84 (m, 2H); 13C
NMR (CDCl3, 100 MHz) δ: 146.5, 146.2, 142.5, 135.8,
135.6, 133.3, 130.9, 129.5, 128.7, 128.4, 128.1, 128.0,
127.5, 124.9, 123.1, 123.0, 122.0, 121.7, 112.6, 110.7,
85.2, 73.2, 64.6, 48.1, 46.8, 25.0; MS (EI, 70 eV) m/z
(%): 569 (M＋, 1), 463 (3), 272 (1), 207 (100), 165 (14).
Anal. calcd for C27H25ClIN3O: C 56.91, H 4.42, N 7.37;
found C 57.02, H 4.49, N 7.13.
1
δ: 7.39—7.25 (m, 5H), 7.15—7.13 (m, 1H), 7.05—7.04
(m, 2H), 6.82—6.80 (m, 2H), 6.76—6.73 (m, 1H), 5.93
(d, J＝7.8 Hz, 2H), 3.97—3.95 (m, 1H), 3.45—3.39 (m,
1H), 3.25—3.24 (m, 1H), 3.00—2.99 (m, 1H), 2.50 (s,
3H), 1.75—1.69 (m, 3H), 1.55—1.44 (m, 3H); 13C
NMR (CDCl3, 150 MHz) δ: 147.0, 144.0, 139.2, 134.9,
131.6, 130.8, 130.7, 129.8, 128.3, 128.1, 127.6, 125.8,
122.2, 121.7, 121.6, 121.5, 111.5, 111.4, 63.1, 47.2,
46.6, 25.9, 25.3, 24.4, 21.4, 21.3; MS (EI, 70 eV) m/z
(%): 519 (M＋, 2), 205 (3), 196 (2), 187(100). Anal.
calcd for C27H26IN3: C 62.43, H 5.05, N 8.09; found C
62.38, H 5.25, N 8.26.
N-[(3-Iodo-5-methyl-2-phenyl-1H-indol-1-yl)(pyr-
rolidin-1-yl)methylene]aniline (4j): White solid (yield
1
79%), m.p. 175—177 ℃; H NMR (CDCl3, 600 MHz)
δ: 7.34—7.28 (m, 4H), 7.26—7.24 (m, 1H), 7.16—7.15
(m, 1H), 7.05—7.04 (m, 2H), 6.81—6.79 (m, 2H),
6.75—6.74 (m, 1H), 5.94 (d, J＝7.8 Hz, 2H), 3.72—
3.69 (m, 2H), 3.28—3.24 (m, 2H), 2.51 (s, 3H), 2.02—
2.00 (m, 2H), 1.92—1.86 (m, 2H); 13C NMR (CDCl3,
150 MHz) δ: 147.1, 142.3, 138.4, 134.5, 131.4, 130.9,
130.8, 129.6, 128.3, 128.1, 127.7, 126.0, 122.0, 121.9,
121.8, 121.7, 111.0, 62.4, 47.9, 25.7, 25.0, 21.4; MS (EI,
70 eV) m/z (%): 505 (M＋ , 3), 204 (3), 189 (11),
173(100). Anal. calcd for C26H24IN3: C 61.79, H 4.79, N
8.31; found C 61.92, H 4.87, N 8.09.
N-((2-((Benzyloxy)methyl)-3-iodo-1H-indol-1-yl)-
(piperidin-1-yl)methylene)-4-chloroaniline (4o): Light
1
yellow oil (yield 74%); H NMR (CDCl3, 400 MHz) δ:
7.75—6.85 (m, 11H), 6.40—6.36 (m, 2H), 4.57—4.26
(m, 4H), 3.94—3.44 (m, 2H), 2.70—2.64 (m, 2H),
1.73—0.83 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ:
146.4, 137.6, 136.0, 135.6, 133.0, 130.7, 129.5, 128.7,
128.5, 128.4, 128.3, 128.2, 128.1, 124.7, 122.9, 122.8,
121.9, 113.2, 111.3, 85.5, 73.0, 64.5, 63.6, 47.2, 25.8,
25.0, 24.3; MS (EI, 70 eV) m/z (%): 583 (M＋, 1), 492
(1), 221 (100), 165 (8), 91 (5), 69 (4). Anal. calcd for
C28H27ClIN3O: C 57.60, H 4.66, N 7.20; found C 57.87,
H 4.73, N 7.26.
N-[(3-Iodo-5-methyl-2-phenyl-1H-indol-1-yl)(mor-
pholino)methylene]aniline (4k): White solid (yield
1
80%), m.p. 187—189 ℃; H NMR (CDCl3, 600 MHz)
δ: 7.39—7.31 (m, 4H), 7.26—7.25 (m, 1H), 7.15—7.14
(m, 1H), 7.07—7.06 (m, 2H), 6.86—6.84 (m, 2H),
6.80—6.79 (m, 1H), 6.01 (d, J＝6.6 Hz, 2H), 3.84—
3.76 (m, 3H), 3.60—3.51 (m, 3H), 3.16—3.10 (m, 2H),
2.50 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ: 146.3,
143.7, 139.0, 134.5, 131.8, 130.9, 130.5, 129.7, 128.4,
128.2, 127.7, 126.1, 122.7, 121.7, 111.1, 66.5, 63.7,
46.4, 46.0, 21.3; MS (EI, 70 eV) m/z (%): 521 (M＋, 3),
205 (4), 189 (100). Anal. calcd for C26H24IN3O: C 59.89,
H 4.64, N 8.06; found C 59.67, H 4.72, N 8.25.
General procedure for the preparation of 4p—4w
To the solution of enyne-carbodiimides 2 prepared
above was added anhydrous alcohol (ROH, 10 mL) with
several drops of sodium alkyloxide (RONa) in corre-
sponding ROH. After the reaction mixture was stirred
for 0.5—6 h, the solvent was removed off under re-
duced pressure. Then anhydrous acetonitrile (10 mL), I2
(6.0 mmol, 1.5 g) and K2CO3 (9.0 mmol, 1.3 g) were
added. After the reaction mixture was stirred for 3 h,
saturated aqueous Na2S2O3 solution was added to re-
move the unreacted I2. The mixture was extracted by
methylene dichloride and the organic layer was evapo-
rated under reduced pressure. The crude product was
purified by flash chromatography (petroleum ether/di-
ethyl ether, V∶V＝4∶1) to yield indole derivatives 4p
—4w.
N-((2-((Benzyloxy)methyl)-3-iodo-1H-indol-1-yl)-
(morpholino)methylene)aniline (4l): White solid (yield
1
82%), m.p. 116—118 ℃; H NMR (CDCl3, 600 MHz)
δ: 7.76—7.24 (m, 9H), 6.96—6.79 (m, 3H), 6.47—6.43
(m, 2H), 4.58—4.56 (m, 2H), 4.46—4.26 (m, 2H),
3.92—3.40 (m, 6H), 2.78—2.68 (m, 2H); 13C NMR
(CDCl3, 150 MHz) δ: 146.7, 144.3, 137.4, 136.9, 135.7,
129.6, 128.9, 128.8, 128.7, 128.6, 128.4, 128.3, 128.2,
128.0, 124.9, 122.0, 121.9, 121.7, 121.4, 111.2, 111.1,
85.6, 73.3, 73.1, 66.5, 65.4, 64.5, 64.4, 46.5, 46.4; MS
(EI, 70 eV) m/z (%): 551 (M＋, 1), 189 (100), 145 (9),
119 (7), 91 (14), 77 (21). Anal. calcd for C27H26IN3O2:
C 58.81, H 4.75, N 7.62; found C 58.97, H 4.88, N 7.83.
N-((2-((Benzyloxy)methyl)-3-iodo-1H-indol-1-yl)-
(morpholino)methylene)-4-chloroaniline (4m): White
solid (yield 78%), m.p. 121—123 ℃; 1H NMR (CDCl3,
Ethyl N-(4-chlorophenyl)-3-iodo-2-phenyl-1H-
indole-1-carbimidate (4p): White solid (yield 68%), m.p.
1
187—189 ℃; H NMR (CDCl3, 600 MHz) δ: 7.49—
7.48 (m, 1H), 7.42—7.41 (m, 1H), 7.33—7.22 (m, 5H),
Chin. J. Chem. 2012, 30, 1807—1812
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1809

Nie, Duan & Ding
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7.12—7.11 (m, 2H), 6.85—6.84 (m, 2H), 6.80—6.79
(m, 2H), 5.91 (d, J＝7.2 Hz, 2H), 4.81—4.75 (m, 2H),
1.45—1.39 (m, 3H); 13C NMR (CDCl3, 150 MHz) δ:
145.6, 142.8, 138.3, 136.0, 130.9, 130.6, 129.4, 128.9,
128.4, 127.9, 124.7, 122.8, 122.5, 122.0, 111.6, 64.9,
14.0; MS (EI, 70 eV) m/z (%): 500 (M＋, 21), 347 (39),
205 (25), 191 (56), 165 (35), 154 (100). Anal. calcd for
C23H18ClIN2O: C 55.17, H 3.62, N 5.59; found C 55.35,
H 3.57, N 5.32.
Ethyl 3-iodo-5-methyl-N,2-diphenyl-1H-indole-1-
carbimidate (4q): White solid (yield 85%), m.p. 116—
118 ℃; 1H NMR (CDCl3, 600 MHz) δ: 7.31—7.28 (m,
5H), 7.13—7.10 (m, 3H), 6.89—6.86 (m, 3H), 6.03—
6.02 (m, 2H), 4.48—4.45 (m, 2H), 2.50 (s, 3H), 1.42—
1.38 (m, 3H); 13C NMR (CDCl3, 150 MHz) δ: 145.3,
144.2, 138.6, 134.5, 131.9, 130.9, 129.4, 128.4, 128.2,
127.8, 126.0, 123.6, 121.5, 111.5, 64.6, 21.4, 14.0; MS
(EI, 70 eV) m/z (%): 480 (M＋, 29), 333 (17), 219 (17),
205 (32), 190 (17), 178 (11), 148 (11), 120 (100). Anal.
calcd for C24H21IN2O: C 60.01, H 4.41, N 5.83; found C
60.26, H 4.68, N 6.04.
Methyl N-(4-chlorophenyl)-3-iodo-5-methyl-2-
phenyl-1H-indole-1-carbimidate (4u): White solid
(yield 74%), m.p. 189—191 ℃; H NMR (CDCl3, 600
1
MHz) δ: 7.32—7.27 (m, 5H), 7.17—7.16 (m, 1H), 7.08
—7.06 (m, 2H), 6.85—6.84 (m, 2H), 5.86 (d, J＝6.6 Hz,
2H), 4.07 (s, 3H), 2.51 (s, 3H); 13C NMR (CDCl3, 150
MHz) δ: 146.5, 142.7, 138.1, 134.4, 132.1, 131.0, 130.5,
129.2, 128.9, 128.3, 127.9, 126.2, 122.7, 121.7, 121.6,
111.4, 64.8, 55.8, 21.4; MS (EI, 70 eV) m/z (%): 500
(M＋, 21), 347 (70), 205 (35), 190 (19), 178 (10), 168
(84), 153 (100). Anal. calcd for C23H18ClIN2O: C 55.17,
H 3.62, N 5.59; found C 55.35, H 3.86, N 5.38.
Methyl 3-iodo-5-methyl-2-phenyl-N-(p-tolyl)-1H-
indole-1-carbimidate (4v): White solid (yield 79%), m.p.
1
152—154 ℃; H NMR (CDCl3, 600 MHz) δ: 7.29—
7.20 (m, 5H), 7.12—7.07 (m, 3H), 6.69—6.68 (m, 2H),
5.90 (d, J＝7.2 Hz, 2H), 4.00 (s, 3H), 2.48 (s, 3H), 2.17
(s, 3H); 13C NMR (CDCl3, 150 MHz) δ: 145.8, 141.4,
138.5, 134.5, 133.1, 131.8, 130.9, 130.8, 129.3, 129.0,
128.2, 127.8, 126.0, 121.5, 121.3, 111.5, 64.2, 55.5,
21.4, 20.8; MS (EI, 70 eV) m/z (%): 480 (M＋, 14), 347
(35), 205 (18), 190 (10), 178 (5), 148 (74), 133 (100).
Anal. calcd for C24H21IN2O: C 60.01, H 4.41, N 5.83;
found C 60.34, H 4.37, N 6.04.
Ethyl N-(4-chlorophenyl)-3-iodo-5-methyl-2-phenyl-
1H-indole-1-carbimidate (4r): White solid (yield 76%),
1
m.p. 159—161 ℃; H NMR (CDCl3, 600 MHz) δ:
7.32—7.29 (m, 4H), 7.25—7.10 (m, 4H), 6.86—6.84
(m, 2H), 5.91 (d, J＝7.2 Hz, 2H), 4.49—4.45 (m, 2H),
2.50 (s, 3H), 1.42 (t, J＝6.3 Hz, 3H); 13C NMR (CDCl3,
150 MHz) δ: 145.8, 142.9, 138.3, 134.4, 132.1, 131.0,
130.8, 129.3, 128.8, 128.4, 128.3, 127.9, 126.2, 122.8,
121.7, 111.4, 64.8, 21.4, 14.0; MS (EI, 70 eV) m/z (%):
514 (M＋, 17), 361 (42), 333 (30), 234 (13), 219 (24),
205 (56), 190 (28), 178 (17), 154 (100). Anal. calcd for
C24H20ClIN2O: C 56.00, H 3.92, N 5.44; found C 55.73,
H 4.09, N 5.48.
Methyl
N-(4-chlorophenyl)-3-iodo-2-phenyl-1H-
indole-1-carbimidate (4w): White solid (yield 74%),
m.p. 159—161 ℃; H NMR (CDCl3, 600 MHz) δ:
1
7.52—7.49 (m, 1H), 7.45—7.42 (m, 1H), 7.38—7.30
(m, 5H), 7.10—7.09 (m, 2H), 6.86—6.85 (m, 2H), 5.90
—5.84 (m, 2H), 4.09 (s, 3H); 13C NMR (CDCl3, 150
MHz) δ: 146.4, 142.6, 138.2, 136.1, 130.9, 130.4, 129.2,
129.0, 128.4, 128.0, 124.8, 122.7, 122.6, 122.0, 111.7,
64.2, 55.5, 21.4, 20.8; MS (EI, 70 eV) m/z (%): 486 (M＋,
18), 333 (58), 204 (10), 190 (35), 170 (28), 168 (84),
153 (100). Anal. calcd for C22H16ClIN2O: C 54.29, H
3.31, N 5.76; found C 54.46, H 3.09, N 5.82.
Ethyl 3-iodo-5-methyl-2-phenyl-N-(p-tolyl)-1H-
indole-1-carbimidate (4s): White solid (yield 81%), m.p.
1
100—102 ℃; H NMR (CDCl3, 600 MHz) δ: 7.33—
7.24 (m, 5H), 7.13—7.10 (m, 3H), 6.71—6.70 (m, 2H),
5.98 (d, J＝7.2 Hz, 2H), 4.43—4.42 (m, 2H), 2.50 (s,
3H), 2.18 (s, 3H), 1.36—1.34 (t, J＝6.6 Hz, 3H); 13C
NMR (CDCl3, 150 MHz) δ: 145.0, 141.7, 138.7, 134.4,
133.0, 131.8, 131.0, 130.9, 129.4, 129.0, 128.2, 127.8,
126.0, 121.5, 121.3, 111.5, 64.5, 21.4, 20.8, 14.0; MS
(EI, 70 eV) m/z (%): 494 (M＋, 9), 361 (17), 205 (20),
190 (10), 178 (6), 162 (11), 134 (100). Anal. calcd for
C25H23IN2O: C 60.74, H 4.69, N 5.67; found C 60.98, H
4.52, N 5.83.
Methyl 3-iodo-5-methyl-N,2-diphenyl-1H-indole-1-
carbimidate (4t): White solid (yield 84%), m.p. 147—
150 ℃; 1H NMR (CDCl3, 600 MHz) δ: 7.32—7.25 (m,
5H), 7.15—7.14 (m, 1H), 7.06—6.87 (m, 5H), 5.99—
5.93 (m, 2H), 4.06 (s, 3H), 2.50 (s, 3H); 13C NMR
(CDCl3, 150 MHz) δ: 146.1, 144.0, 138.4, 134.6, 131.9,
130.9, 130.7, 129.2, 128.4, 128.2, 127.8, 126.1, 123.6,
121.6, 121.4, 111.5, 64.4, 55.6, 21.4; MS (EI, 70 eV)
m/z (%): 466 (M＋, 17), 347 (37), 205 (21), 190 (11),
178 (6), 134 (100). Anal. calcd for C23H19IN2O: C 59.24,
H 4.11, N 6.01; found C 59.15, H 4.06, N 6.24.
Results and Discussion
The easily accessible iminophosphoranes 1 were
treated with aromatic isocyanate in dry CH2Cl2 to give
carbodiimides 2. Further reaction of 2 with various nu-
cleophiles (HY, such as secondary amines or alcohols)
provided the (2-alkynylphenyl)guanidine (or isourea)
intermediates 3. In the presence of 3 equiv. of anhy-
drous potassium carbonate and 2 equiv. of molecular
iodine, the (2-alkynylphenyl)guanidines (or isoureas) 3
were converted easily to 3-iodoindole N-carboximid-
amides and N-carboximidoates 4 in satisfactory yields at
room temperature (Scheme 1). The results are listed in
Table 1. The structure of indoles 4 was confirmed by
their spectrum data. For example, the 1H NMR spectrum
of 4a shows multiplets at δ 3.87—3.54 and 3.18—3.14
due to the OCH2 and NCH2 respectively. The signals
attributable to the ArH are found at δ 7.51—5.88 as mu-
tiplet (the relative high field absorption at δ 5.89 can be
due to the aryl-2-H of the ArN＝ group, showing its
existence as N-carboximidamide). The 13C NMR spec-
1810
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1807—1812

Efficient Regioselective Synthesis of 3-Iodoindole N-Carboximidamides and N-Carboximidoates
trum data in 4a showed the signals of the two OCH2 at δ
66.5 and 64.3, and the two NCH2 at δ 46.5 and 46.0.
The MS spectrum of 4a shows molecular ion peak at
m/z 541 with 4% abundance.
scribed above was suggested in Scheme 2. It presuma-
bly involves (i) the formation of complex A through the
coordination of the alkynyl moiety of 3 with the elec-
trophile iodide, (ii) regioselective nucleophilic anti-at-
tack of the nitrogen of the guanidine or isourea on the
activated triple bond to produce the salt B, and (iii) de-
hydroiodination of the presumed intermediate B by the
base K2CO3 and formation of indole product 4.
Scheme 1 Preparation of 3-iodoindoles 4 by a sequential
aza-Wittig/iodine induced cyclization
R2
R2
R1
R1
HY
ArNCO
Scheme 2 Proposed mechanism for the synthesis of 4
N=C=NAr
N
PPh3
R2
I
R2
R1
R1
1
2
I2
NHAr
Y
I
R2
NHAr
R1
N C
N
R1
R2
I2
K2CO3
Y
NHAr
3
N
A
N
C
Y
Ar
N
Y
4
3
I
I
R1
R1 = H, Me; R2 = Ph, CH2OCH2Ph
R1
R2
R2
-HI
Ar = Ph, 4-Cl-C6H4, 4-F-C6H4, 4-Me-C6H4, 3-Me-C6H4
Y = NR3R4, OR5
N
N
Y
Base
Y
N+HAr
Ar
N
Table 1 Preparation of compounds 4a—4s
4
B
R1
R2
Ar
Y
Yielda/%
77
It is noteworthy that this reaction shows very high
regioselectivity. Presumably the cyclization of (2-alky-
nylphenyl)guanidine (or isourea) intermediate 3 could
produce two products (Scheme 3). The indole deriva-
tives 4 should be obtained from the complex A, while
the complex C could cyclize into quinazoline deriva-
tives 5. However, only one exclusive product 4 was ob-
served and isolated in satisfactory yields.
H
H
Ph
4-Cl-C6H4 Morpholin-4-yl
4-F-C6H4 Morpholin-4-yl
4a
4b
4c
4d
4e
4f
Ph
80
H
Ph
Ph
Morpholin-4-yl
85
H
Ph
4-Me-C6H4 Morpholin-4-yl
3-Me-C6H4 Morpholin-4-yl
84
H
Ph
81
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
N(n-Bu)2
N(i-Pr)2
84
H
Ph
79
4g
4h
4i
Scheme 3 Regioselective formation of 3-iodoindoles 4
H
Ph
N(n-Pr)2
84
I
Me
Me
Me
H
Ph
Piperidin-1-yl
Pyrrolidin-1-yl
Morpholin-4-yl
Morpholin-4-yl
75
R1
I
R2
R1
R2
Ar
Ph
Ph
79
4j
N
NHAr
80
4k
4l
N
C
N
Y
CH2OCH2Ph
82
Y
4
A
H
CH2OCH2Ph 4-Cl-C6H4 Morpholin-4-yl
CH2OCH2Ph 4-Cl-C6H4 Pyrrolidin-1-yl
CH2OCH2Ph 4-Cl-C6H4 Piperidin-1-yl
78
4m
4n
4o
4p
4q
4r
4s
H
72
I
R2
R2
N
H
74
I
R1
R1
Ar
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-Cl-C6H4
Ph
OEt
OEt
68
NAr
Y
Me
Me
Me
Me
Me
Me
H
85
N
H
N
Y
4-Cl-C6H4
4-Me-C6H4
Ph
OEt
76
C
5
OEt
81
OMe
OMe
OMe
OMe
84
4t
Conclusions
4-Cl-C6H4
4-Me-C6H4
4-Cl-C6H4
74
4u
4v
4w
We have developed an efficient regioselective syn-
thesis of 3-iodoindole N-carboximidamides and N-car-
boximidoates via aza-Wittig/iodine induced cyclizations.
The mild reaction conditions and the easy commercial
availability of starting material make this method a
valuable tool for generating 3-iodoindole N-carboximid-
79
74
a Isolated yield.
A plausible mechanism for the transformations de-
Chin. J. Chem. 2012, 30, 1807—1812
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1811

Nie, Duan & Ding
FULL PAPER
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versatile intermediates for further transformation in
combinatory or medicinal chemistry.
Acknowledgement
We gratefully acknowledge financial support of this
work by the National Natural Science Foundation of
China (No. 21172085) and and the self-determined re-
search funds of CCNU from the colleges’ basic research
and operation of MOE (No. 10020176).
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