Hypervalent iodine mediated One-Pot C-H functionalization at 2α- Or 3α -position of indole derivatives

Article abstract of DOI:10.3987/COM-14-13065

The one-pot 2α- and 3α-functionalization of 2,3-disubstituted indoles using a hypervalent iodine reagent has been developed. The substitution at the 2α-position of indoles took place using phenyliodinebis(trifluoroacetate) with oxygen and carbon nucleophi

Full text of DOI:10.3987/COM-14-13065

HETEROCYCLES, Vol. 89, No. 9, 2014
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HETEROCYCLES, Vol. 89, No. 9, 2014, pp. 2105 - 2121. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 30th July, 2014, Accepted, 26th August, 2014, Published online, 28th August, 2014
DOI: 10.3987/COM-14-13065
HYPERVALENT IODINE MEDIATED ONE-POT C-H
FUNCTIONALIZATION AT 2- OR 3-POSITION OF INDOLE
DERIVATIVES
Kazuhiro Higuchi,* Masato Inaba, Asuka Naganuma, Takako Ishizaki,
Masanori Tayu, and Tomomi Kawasaki*
Meiji Pharmaceutical University, 2-522-1 Noshio Kiyose, Tokyo 204-8588, Japan:
kawasaki@my-pharm.ac.jp; khiguchi@my-pharm.ac.jp
Abstract – The one-pot 2- and 3-functionalization of 2,3-disubstituted indoles
using a hypervalent iodine reagent has been developed. The substitution at the
2-position of indoles took place using phenyliodinebis(trifluoroacetate) with
oxygen and carbon nucleophiles in moderate yields. The combination of
iodosobenzene and trimethylsilyl azide afforded 3-azide derivatives preferentially.
The latter reaction was applied to other 2,3-disubstituted indoles.
INTRODUCTION
Hypervalent iodine reagents1 having a strong leaving-group ability and electrophilicity allow a wide range
of reactions, such as oxidations and C-C coupling reactions under mild conditions with a tolerance for a
wide range of other functional groups. The reaction between arenes and hypervalent iodine is attractive for
one of the interesting research area.2 Especially the application of the electron-rich arenes such as indoles
give rise to the substitution via cation radical intermediate,3 indolyliodonium fragmentation,4 and so on.5
Recently, Ishibashi’s group revealed the combination of phenyliodine diacetate (PIDA) and
tetrabutylammonium iodide (TBAI) reacted with tetrahydrocarbazoles to give 2-acetoxy derivatives.6
Alternatively, Du Bois and co-workers developed that the reaction of tetrahydrocarbazoles using imino
3-iodanes with a rhodium catalyst affords 2- and 3-amino derivatives.7
Recently, we developed the concise 2-functionalization of indole derivatives using a thionium species
generated from DMSO-TFAA (Scheme 1).8

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Scheme 1. Thionium mediated 2-functionalization of indole derivatives
This method is useful for the introduction of various substituents to the 2-position9 in one-pot procedure
under mild reaction conditions. However, we require a more practical method to access to
2-functionalized indoles for the synthesis of biologically active compounds.10 We report herein the 2-
and 3-functionalization of indole derivatives using a hypervalent iodine reagent.
RESULTS AND DISCUSSION
Optimization of Reaction Conditions
To obtain the desired 2-methoxy indole derivatives more conveniently, we investigated the reactivity of
hypervalent iodine reagents toward N-p-methoxybenzyl (PMB)-tetrahydrocarbazole 1a (Table 1). To a
solution of 1a in CH2Cl2 added one equivalent of hypervalent iodine reagent at 0 °C. After consumption of
1a, ten equivalents of MeOH as a nucleophile was added to the reaction mixture. When Dess-Martin
periodinane (DMP, entry 1) and phenyliodine diacetate (PIDA, entry 2) were used, carbazole 4 and dimer 3
was obtained respectively instead of the desired 2-methoxy product 2a. PhI(OH)OTs (Koser’s reagent)11
afforded a trace amount of 2a along with dimer 3 (22%) and carbazole 4 (5%), respectively (entry 3). The
use of iodopentafluorobenzene bis(trifluoroacetate) (FPIFA) as a more electrophilic iodan produced 2a
and 3 in 8% and 29% yields, respectively (entry 4). In the case of phenyliodine bis(trifluoroacetate) (PIFA)
gave 2a in 35% yield (entry 5). The substituent effect at the indole nitrogen was examined for PIFA.
N-Unsubstituted tetrahydrocarbazole gave a complex-mixture (entry 6) and Boc and acetyl derivatives
produced a trace amount of 2-methoxy compounds 2c and 2d (entries 7, 8).
Subsequently, we examined the effect of reaction temperature using PIFA (Table 2). At room temperature,
the reaction afforded no desired product 2a and gave dimer 3 in 43% yield (entry 1). When the reaction was
performed at –20 °C, 2a was given in 30% yield (entry 3). At –30 °C, the 2-methoxy compound 2a was
obtained in 24% yield without the formation of dimer 3 (entry 4). At –40 °C, carbazole 4 was the sole
product (entry 5). We concluded that the condition proceeded with PIFA at 0 °C is an optimized condition
(entry 2).

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Table 1. Optimization of reaction conditions
Table 2. Effect of reaction temperature using PIFA
The plausible reaction mechanism is as follows (Scheme 2). First, the 3-position of 1a attacks an iodine
atom of PIFA to generate iminium intermediate 5. Transformation of iminium 5 to enamine 6, followed by

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the nucleophilic attack of MeOH afforded 2-methoxy compound 2a. At room temperature (Table 2, entry
1), the immediate attack of unreacted 1a to intermediate 6 produced dimer 3 before addition of MeOH.
Since 1a was consumed at 0 °C and –20 °C (checked by TLC), the regeneration of 1a would be caused by
the attack of MeOH on the iodine atom in iminium 5. The addition of MeOH to 6 is faster than 1a, therefore,
both yield of 2a and ratio of 2a/3 were increased (entries 2 and 3). At –30 °C and –40 °C, starting material
1a was not consumed completely and nucleophiles (1a and/or MeOH) react more slowly with 6.
Consequently, the elimination of iodobenzene from intermediates and the subsequent oxidation occurs to
give carbazole 4 (entries 4 and 5). The structures of 2a-d and 3 were determined by differential nOe and
H-H cosy spectra (Figure 1).
Scheme 2. Plausible reaction mechanism
Figure 1. Structure determination of 2a-d and 3
Study of Nucleophiles
With the optimized conditions in hand, we investigated the scope and limitation of nucleophiles for this
reaction (Table 3). As is the case in MeOH, an isopropoxy group was introduced to give 2e in 41% yield
(entry 1). The carbon nucleophiles MeMgBr and Me2Zn gave 2-methyl derivative 2f in 26% and 21%
yields, respectively (entries 2, 3). Vinyl and allyl groups were also introduced at the 2-position to give
products 2g (39%) and 2h (31%) (entries 4, 5). Additionally, the use of N-methylindole as an aryl
nucleophile provided compound 2i in 9% yield (entry 6). Also, the nitrogen nucleophiles, aniline and
benzylamine afforded the products 2j and 2k in 5% and 8% yields, respectively (entries 7, 8).

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Table 3. Study of nucleophiles
3-Azide Substituent
When TMSN3 was used as a nucleophile at 0 °C for substrate 1a, 2-azide product 2l was obtained in 20%
yield (Table 4, entry 1, Method A). At –20 °C, 3-azide product 7a was produced in 45% yield along with
2-product 2l in 26% yield (entry 2). For N-Boc derivative 1c under this reaction condition, both 2- and
3-substituted products 2m and 7c were obtained in 22% and 25% yields, respectively (entry 3).
Table 4. Azidation of 1 with the combination of hypervalent iodine and TMSN3

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Since the treatment of 1c with MeOH produced trace of 2-derivative 2c (3% yield, Table 1, entry 7), we
hypothesized that the mechanism of azidation is different from that of other nucleophiles as shown in Table
3. It is known that combinations of iodosobenzene (PhIO) and TMSN3 generate phenyliodine bisazide
(PhI(N3)2),12 which is an extremely labile intermediate for producing radical species.13 Thus, we
investigated the use of preformed PhI(N3)2 for the azidation14 of 1 (Table 4, entries 4-8, Method B). To a
solution of PIFA in MeCN was added TMSN3 at –40 °C and the mixture was stirred for 5 min. After the
addition of 1a, 2-azide 2l and 3-azide 7a were formed in 9% and 33% yields, respectively (entry 4). The
combination of PhIO and TMSN3 increased the yield of 7a to 43% (entry 5). The other substrates 1c-e gave
3-azide compounds 7c-e in 16-30 % yields (entries 6-8). The position of the substituted azide group in 2
and 7 was determined by differential nOe and H-H cosy spectra (Figure 2).
Figure 2. Structure determination of 2l,m and 7a,c
Based on these results, we suggest the following plausible mechanism included both ionic and radical
pathways (Scheme 3). In the ionic pathway, 1a and PIFA generate iminium 5 followed by formation of
enamine 6 and then SN2’-type reaction between the azide ion and 6 gives 2-compound 2l. In the radical
Scheme 3. Plausible reaction mechanism

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pathway, the iodine atom of iminium 5 or PIFA reacts with TMSN3 to produce PhI(N3)2 8. Then, the azide
radical from 8 reacts with tetrahydrocarbazole 1a at 2 and/or 3 position and then the generated benzylic
radical coupled with the iodo radical to form intermediates 9 and 10. Finally, reductive elimination of
iodobenzene gave the corresponding products 2l and 7a.
Using the combination of iodosobenzene and TMSN3 (Table 4, entry 5), we studied the scope and
limitations of the substrates for a variety of 2,3-disubstituted indoles (Table 5). N-Boc cyclopenta[b]indole
1g and cyclohepta[b]indoles 1i produced the corresponding 2- and 3-azide products 2 and 7 in higher
yield than N-PMB derivatives 1f and 1h (entries 1 vs 2, 3 vs 4). The reaction of cyclohepta[b]indole 1h was
accompanied by formation of olefin 11 in 23% yield (entry 3). In the case of 2,3-dialkyl substituted indoles,
N-PMB derivatives gave better yields and selectivity than the N-Boc indoles (entries 5 vs 6, 7 vs 8). In
particular, N-PMB-2-propyl-3-ethylindole 1n gave only 3-product 7n in 75% yield (entry 9).
Table 5. Study of various 2,3-disubstituted indole derivatives
CONCLUSION
We studied the one-pot functionalization of 2,3-substituted indoles with hypervalent iodine reagents. We
developed the substitution at 2-position of indoles using PIFA with oxygen and carbon nucleophiles,
which afforded 2-derivatives in moderate yields. In the case of the combination of PhIO and TMSN3, the

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radical mechanism was also included to afford 3-azide derivatives preferentially. These results provide an
interesting complementary approach to our previous method using thionium species, which afforded
2-azide derivatives.
EXPERIMENTAL
All melting points were measured on a Yanagimoto micro melting point apparatus, and are uncorrected. IR
1
13
spectra were recorded on a Shimadzu IR Prestige-21 spectrophotometer. H and C NMR spectra were
measured on a JEOL JNM-AL300 (300 MHz), a JEOL JNM-AL400 (400 MHz), a JEOL JNM-ECS400
(400 MHz), or a JEOL JNM-LA500 (500 MHz) spectrometer with tetramethylsilane as an internal standard.
J-Values are given in Hertz. Mass spectra were recorded on a JEOL JMS 700 instrument with a direct inlet
system. Thin layer chromatography (TLC) was carried out on a Merck silica gel plate 60F254. Column
chromatography was carried out on a silica gel [Fuji Silysia Co. Inc. (silica gel PSQ 60B)]. All solvents
were purified by standard procedures prior to use. The following compounds were characterized by the
previous reports: 1a-d, 1f-m, 2a, 2d-m, 3, 4.6,8,15
Repesentative procedure for C-H functionalization of indole derivatives with hypervalent iodine
reagent (Table 1-3, Table 4 entries 1-3)
Under argon atmosphere, to a solution of 1a (92 mg, 0.31 mmol) in CH2Cl2 (0.1 M) was added PIFA (0.13
g, 0.31 mmol) at 0 °C. After 10 min stirring, MeOH (0.13 mL, 3.1 mmol) was added to the reaction mixture.
The mixture was stirred for 10 min and quenched by aqueous sodium sulfite (3 mL) and then extracted with
CH2Cl2 (10 mL, 3 times). The organic layer was washed by brine and dried over MgSO4. The concentrated
residue was purified by silica gel chromatography (AcOEt/n-hexane = 1/20) to give 2a8 (34 mg, 35%); 38
(24 mg, 27%); 415 (3.5 mg, 4%).
9-(tert-Butoxycarbonyl)-1-methoxy-1,2,3,4-tetrahydro-9H-carbazole (2c)
Colorless oil. IR (CHCl3): 2982, 2934, 1722, 1454, 1371, 1314 cm-1. 1H NMR (300 MHz, CDCl3): δ 1.69
(9H, s, tBu), 1.78-2.04 (3H, m, CH2CH2CHOMe, CH2CH2CHOMe), 2.28 (1H, ddt, J = 3.0, 6.6, 13.8 Hz,
CH2CHOMe), 2.53 (1H, ddd, J = 6.3, 11.4, 16.8 Hz, CCH2CH2), 2.80 (1H, ddd, J = 2.1, 5.4, 16.2 Hz,
CCH2CH2), 3.50 (3H, s, OCH3), 5.04 (1H, t, J = 3.0 Hz, CHOMe), 7.19 (1H, dt, J = 0.9, 7.2 Hz, Ar-H), 7.27
(1H, dt, J = 1.5, 7.2 Hz, Ar-H), 7.43 (1H, dd, J = 0.6, 8.1 Hz, Ar-H), 8.02 (1H, d, J = 8.1 Hz, Ar-H). 13C
NMR (75 MHz, CDCl3): δ 17.2, 21.1, 27.1, 28.3, 56.3, 70.6, 83.2, 115.7, 118.5, 119.8, 122.2, 128.9, 124.5,
134.2, 136.2, 150.3. MS (EI): m/z (%) 301 (M＋, 34), 214 (11), 201 (54), 170 (63), 169 (100), 168 (44), 167
(13), 57 (29). HRMS (EI): m/z Calcd for C18H23NO3: 301.1678; Found: 301.1680.

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9-(4-Methoxybenzyl)-1-phenylamino-1,2,3,4-tetrahydro-9H-carbazole (2j)
Yellow oil. IR (CHCl3): 2928, 2839, 1601, 1512, 1501, 1464, 1246 cm-1. 1H NMR (300 MHz, CDCl3): δ
1.77-1.91 (3H, m, CH2CH2CHN, CH2CH2CHNHAr), 2.17-2.27 (1H, m, CH2CHNHAr), 2.67 (1H, dt, J =
5.4, 8.7 Hz, CCH2CH2), 2.90 (1H, dt, J = 4.2, 16.2 Hz, CCH2CH2), 3.75 (3H, s, OCH3), 3.83 (1H, brs,
NHPh), 4.65 (1H, brs, CHNHAr), 5.20 (1H, d, J = 16.8 Hz, NCH2Ar), 5.31 (1H, d, J = 16.8 Hz, NCH2Ar),
6.53 (2H, d, J = 7.8 Hz, Ar-H), 6.67-6.71 (1H, m, Ar-H), 6.77-6.73 (2H, m, Ar-H), 6.84-6.86 (2H, m, Ar-H),
7.11 (1H, ddd, J = 0.9, 6.6, 7.5 Hz, Ar-H), 7.17 (2H, dd, J = 7.5, 8.4 Hz, Ar-H), 7.18 (1H, dt, J = 1.2, 6.6 Hz,
13
Ar-H), 7.26 (1H, dt, J = 0.9, 7.2 Hz, Ar-H), 7.57 (1H, dt, J = 0.8, 7.5 Hz, Ar-H). C NMR (100 MHz,
CDCl3): δ 18.4, 21.0, 28.5, 44.9, 45.8, 55.2, 109.5, 112.6, 113.0, 114.0, 117.4, 118.6, 119.0, 122.1, 126.6,
127.3, 129.3, 130.4, 134.2, 137.1, 146.3, 158.7. MS (EI) m/z (%): 382 (M+, 1), 290 (23), 289 (56), 121 (100),
93 (13). HRMS (EI): m/z Calcd for C26H26N2O: 382.2045; Found: 382.2040.
Representative procedure for C-H functionalization of indole derivatives with hypervalent iodine
reagent (Table 4 entries 4-8, Table 5)
Under argon atmosphere, a solution of iodosobenzene (PhIO, 57 mg, 0.26 mmol) in CH2Cl2 (2.2 mL) was
added trimethylsilyl azide (TMSN3, 72 μL, 0.52 mmol) and stirred for 5 min. Subsequently, 1a (63 mg, 0.22
mmol) was added to the reaction mixture and stirred for 60 min at –40 °C. The mixture was quenched by
aqueous sodium sulfite (2 mL) and then extracted with CH2Cl2 (10 mL, 3 times). The organic layer was
washed by brine and dried by MgSO4. The concentrated residue was purified by silica gel chromatography
(AcOEt/n-hexane = 1/20) or preparative silica gel chromatography to give 2l (6.4 mg, 9%); 7a (32 mg,
43%).
4-Azido-9-(4-methoxybenzyl)-1,2,3,4-tetrahydro-9H-carbazole (7a)
1
Brown oil. IR (CHCl3): 2947, 2837, 2097, 1730, 1612, 1512, 1464 cm-1. H NMR (300 MHz, CDCl3): δ
1.88-2.15 (4H, m, CHN3CH2CH2, CHN3CH2CH2), 2.53-2.63 (1H, m, CCH2), 2.73 (1H, dt, J = 4.8, 16.2 Hz,
CCH2), 3.73 (3H, s, OCH3), 4.88 (1H, t, J = 4.2 Hz, CHN3), 5.19 (2H, d, J = 1.8 Hz, NCH2Ar), 6.78-6.83
(2H, m, Ar-H), 6.90-6.95 (2H, m, Ar-H), 7.12-7.20 (2H, m, Ar-H), 7.23-7.29 (1H, m, Ar-H), 7.68-7.73 (1H,
m, Ar-H). 13C NMR (75 MHz, CDCl3): δ 19.0, 21.9, 29.9, 45.8, 54.9, 55.2, 107.5, 109.4, 114.1, 118.2, 119.9,
121.6, 126.6, 127.3, 129.4, 136.6, 138.2, 158.8. HRMS (FAB): m/z Calcd for C20H20N4O: 332.1637; Found:
332.1635.
4-Azido-9-(tert-butoxycarbonyl)-1,2,3,4-tetrahydro-9H-carbazole (7c)
Yellow oil. IR (CHCl3): 3009, 2980, 2945, 2934, 2100, 1724, 1454, 1369, 1314 cm-1. 1H NMR (300 MHz,
CDCl3): δ 1.71 (9H, s, tBu), 1.93-2.12 (4H, m, CHN3CH2CH2, CHN3CH2CH2), 2.84-3.04 (1H, m, CCH2),

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3.18 (1H, dt, J = 4.8, 18.0 Hz, CCH2), 4.72 (1H, t, J = 3.9 Hz, CHN3), 7.22-7.32 (2H, m, Ar-H), 7.57-7.67
(1H, m, Ar-H), 8.08-8.18 (1H, m, Ar-H).
13C NMR (75 MHz, CDCl3): δ 19.5, 25.6, 28.2, 28.9, 54.2, 84.0, 114.1, 115.6, 118.0, 123.0, 124.0, 128.2,
135.8, 138.7, 150.4. MS (EI): m/z (%) 312 (19), 270 (16), 215 (14), 214 (100), 213 (19), 170 (66), 169 (20),
168 (30), 167 (12), 57 (41). HRMS (EI): m/z Calcd for C17H20N4O2: 312.1586; Found: 312.1585.
1-Azido-9-(methoxycarbonyl)-1,2,3,4-tetrahydro-9H-carbazole (2n)
White solid. mp 93-95 ºC. IR (CHCl3): 2953, 2100, 1734, 1456, 1443, 1369 cm-1 1H NMR (300 MHz,
.
CDCl3): δ 1.89-2.05 (3H, m, CH2CH2CHN3), 2.15-2.29 (1H, m, CH2CH2CHN3), 2.50-2.65 (1H, m, CCH2),
2.85 (1H, dt, J = 3.6, 16.8 Hz, CCH2), 4.10 (3H, s, OCH3), 5.29 (1H, t, J = 3.0 Hz, CHN3), 7.27 (1H, dt, J =
0.9, 7.5 Hz, Ar-H), 7.36 (1H, dt, J = 1.2, 7.2 Hz, Ar-H), 7.47 (1H, dt, J = 0.6, 7.8 Hz, Ar-H), 8.15 (1H, d, J
= 8.1 Hz, Ar-H). 13C NMR (100 MHz, CDCl3): δ 17.4, 20.8, 30.7, 53.8, 55.1, 116.0, 118.8, 121.3, 123.1,
125.5, 128.8, 131.4, 136.1, 152.0. MS (EI): m/z (%) 270 (M+, 15), 229 (15), 228 (100), 168 (16), 167 (11).
HRMS (EI): m/z Calcd for C14H14N4O2: 270.1117; Found: 270.1115.
4-Azido-9-(methoxycarbonyl)-1,2,3,4-tetrahydro-9H-carbazole (7e)
Yellowish white solid. mp 77-79 ºC. IR (CHCl3): 2955, 2359, 2340, 2099, 1734, 1458, 1443, 1368 cm-1. 1H
NMR (300 MHz, CDCl3): δ 1.90-2.17 (4H, m, CHN3CH2CH2), 2.80-3.04 (1H, m), 3.20 (1H, dt, J = 4.5,
18.3 Hz, CCH2), 4.05 (3H, s, OCH3), 4.72 (1H, t, J = 4.2 Hz, CHN3), 7.30 (1H, t, J = 3.3 Hz, Ar-H), 7.30
(1H, ddd, J = 1.8, 7.2, 17.1 Hz, Ar-H), 7.56-7.67 (1H, m, Ar-H), 8.07-8.20 (1H, m, Ar-H). 13C NMR (100
MHz, CDCl3): 19.4, 25.2, 28.9, 53.5, 54.1, 114.8, 115.6, 118.2, 123.3, 124.3, 128.3, 135.7, 138.6, 152.4.
MS (EI): m/z (%) 270 (M+, 12), 229 (15), 228 (100), 168 (16), 167 (12). HRMS (EI): m/z Calcd for
C14H14N4O2: 270.1117; Found: 270.1118.
9-Acetyl-1-azido-1,2,3,4-tetrahydro-9H-carbazole (2o)
1
Brown oil. IR (CHCl3): 2947, 2930, 2100, 1697, 1460, 1373, 1308 cm-1. H NMR (300 MHz, CDCl3): δ
1.91-2.05 (3H, m, CH2CH2CHN3), 2,12- 2.25 (1H, m, CH2CH2CHN3), 2.504-2.70 (1H, m, CCH2), 2.84
(3H, s, COCH3), 2.81-2.91 (1H, m, CCH2), 5.39 (1H, t, J = 3.0 Hz, CHN3), 7.29 (1H, dt, J = 0.9, 7.5 Hz,
Ar-H), 7.37 (1H, dt, J = 1.2, 7.2 Hz, Ar-H), 7.51 (1H, dt, J = 0.6, 7.8 Hz, Ar-H), 7.76 (1H, dt, J = 0.6, 8.1 Hz,
Ar-H). 13C NMR (75 MHz, CDCl3): δ 17.4, 20.8, 27.4, 30.7, 55.3, 114.7, 119.5, 121.8, 123.1, 125.3, 129.5,
132.7, 135.7, 169.6. MS (EI): m/z (%) 254 (M+, 25), 213 (11), 212 (74), 211 (17), 184 (18), 183 (17), 171
(13), 170 (100), 169 (38), 168 (56), 167 (23), 156 (12). HRMS (EI): m/z Calcd for C14H14N4O: 254.1168;
Found: 254.1167.

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9-Acetyl-4-azido-1,2,3,4-tetrahydro-9H-carbazole (7d)
Colorless solid. mp 76-79 ºC. IR (CHCl3): 3009, 2949, 2099, 1701, 1371, 1304 cm-1. 1H NMR (300 MHz,
CDCl3): δ 1.90-2.30 (4H, m, CHN3CH2CH2), 2.74 (3H, s, COCH3), 2.91-3.04 (1H, m, CCH2), 3.17 (1H, dt,
J = 4.5, 17.7 Hz, CCH2), 4.73 (1H, t, J = 3.9 Hz, CHN3), 7.31 (1H, t, J = 3.6 Hz, Ar-H), 7.31 (1H, ddd, J =
2.1, 7.2, 15.6 Hz, Ar-H), 7.60-7.70 (1H, m, Ar-H), 7.92-8.02 (1H, m, Ar-H). 13C NMR (100 MHz, CDCl3):
δ 19.8, 26.3, 27.4, 28.7, 54.2, 115.2, 115.5, 118.6, 123.5, 124.5, 128.8, 135.7, 138.7, 170.0. MS (EI): m/z
(%) 254 (M+, 13), 212 (43), 211 (15), 184 (11), 171 (12), 170 (100), 169 (33), 168 (46), 167 (20), 156 (13).
HRMS (EI): m/z Calcd for C14H14N4O: 254.1168; Found: 254.1161.
3-Azido-4-(4-methoxybenzyl)-1,2,3,4-tetrahydrocyclopenta[b]indole (2p)
1
Brown oil. IR (CHCl3): 3007, 2936, 2864, 2094, 1512, 1464, 1246 cm-1. H NMR (400 MHz, CDCl3) δ:
2.62 (1H, ddt, J = 2.8, 7.6, 16.4 Hz, CH2CH2CHN3), 2.82 (1H, ddd, J = 3.6, 8.8, 14.0 Hz, CH2CH2CHN3),
2.95 (1H, ddt, J = 6.0, 8.0, 13.8 Hz, CH2CH2CHN3), 3.02-3.15 (1H, m, CH2CH2CHN3), 3.77 (3H, s, OCH3),
4.64 (1H, dt, J = 2.8, 9.2 Hz, CHN3), 5.19 (1H, d, J = 16.1 Hz, NCH2Ar), 5.34 (1H, d, J = 15.6 Hz, NCH2Ar),
6.77-6.89 (2H, m, Ar-H), 7.03-7.08 (2H, m, Ar-H), 7.10 (1H, td, J = 1.0, 8.0 Hz, Ar-H), 7.17 (1H, td, J = 1.6,
8.4 Hz, Ar-H), 7.25 (1H, td, J = 1.2, 8.4 Hz, Ar-H), 7.52 (1H, dt, J = 0.8, 7.6 Hz, Ar-H).13C NMR (100 MHz,
CDCl3): 23.2, 36.7, 47.6, 55.2, 60.0, 110.5, 114.1, 119.6, 119.8, 121.9, 122.2, 123.5, 127.9, 129.6, 141.2,
142.0, 159.0. MS (EI): m/z (%) 318 (M+, 12), 290 (13), 276 (29), 275 (23), 121 (100). HRMS (EI): m/z
Calcd for C19H18N4O: 318.1481; Found: 318.1479.
3-Azido-4-(tert-butoxycarbonyl)-1,2,3,4-tetrahydrocyclopenta[b]indole (2q)
Yellowish green oil. IR (CHCl3): 2980, 2936, 2099, 1730, 1368, 1319 cm-1. 1H NMR (300 MHz, CDCl3): δ
1.69 (9H, s, tBu), 2.56 (1H, ddd, J = 0.8, 6.0, 9.9 Hz, CH2CH2CHN3), 2.70-2.92 (2H, m, CH2CH2CHN3),
2.98 (1H, ddt, J = 1.5, 2.1, 12.3 Hz, CH2CH2CHN3), 5.10 (1H, d, J = 6.6 Hz, CHN3), 7.25 (1H, dt, J = 1.2,
7.5 Hz, Ar-H), 7.33 (1H, dt, J = 1.2, 7.2 Hz, Ar-H), 7.46 (1H, dd, J = 0.6, 5.7 Hz, Ar-H), 8.20 (1H, d, J = 8.1
Hz, Ar-H). 13C NMR (100 MHz, CDCl3): δ 22.8, 28.2, 36.6, 62.0, 84.1, 116.2, 119.8, 123.0, 124.9, 125.5,
129.1, 139.8, 140.8, 149.3. MS (EI): m/z (%) 298 (M+, 26), 256 (20), 242 (11), 201 (13), 200 (97), 169 (21),
157 (12), 156 (100), 155 (47), 57 (43). HRMS (EI): m/z Calcd for C16H18N4O2: 298.1430; Found: 298.1424.
1-Azido-4-(tert-butoxycarbonyl)-1,2,3,4-tetrahydrocyclopenta[b]indole (7g)
1
Brown oil. IR (CHCl3): 3007, 2980, 2936, 2093, 1730, 1369, 1321 cm-1. H NMR (300 MHz, CDCl3): δ
1.66 (9H, s, tBu), 2.49 (1H, ddt, J = 3.0, 8.4, 14.4 Hz, CHN3CH2CH2), 2.81-2.98 (1H, m, CHN3CH2CH2),
3.06 (1H, ddd, J = 3.6, 8.7, 17.1 Hz, CHN3CH2CH2), 3.27 (1H, dddd, J = 1.8, 5,1, 7.8, 16.8 Hz,
CHN3CH2CH2), 4.96 (1H, dt, J = 2.1, 7.8 Hz, CHN3), 7.27 (1H, ddd, J = 1.8, 7.2, 19.2 Hz, Ar-H), 7.27 (1H,

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t, J = 2.1 Hz, Ar-H), 7.52 (1H, dd, J = 2.7, 6.9 Hz, Ar-H), 8.18 (1H, dd, J = 1.8, 6.6 Hz, Ar-H). 13C NMR
(100 MHz, CDCl3): δ 27.9, 28.2, 35.6, 60.7, 83.9, 115.9, 118.7, 122.5, 123.2, 123.8, 125.1, 140.3, 146.3,
149.6. MS (EI): m/z (%) 298 (M+, 14), 256 (22), 201 (13), 200 (100), 199 (16), 169 (11), 156 (56), 155 (22),
154 (12), 57 (41). HRMS (EI): m/z C16H18N4O2: 298.1430; Found: 298.1424.
6-Azido-5-(4-methoxybenzyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (2r)
1
Brown oil. IR (CHCl3): 2930, 2100, 1512, 1464 cm-1. H NMR (300 MHz, CDCl3): δ 1.50-1.75 (1H, m,
CCH2CH2), 1.83 (1H, ddt, J = 3.0, 12.0, 16.8 Hz, CH2CHN3), 1.90-2.12 (3H, m, CCH2CH2CH2), 2.20 (1H,
ddt, J = 2.4, 5.1, 13.2 Hz, CH2CHN3), 2.86 (1H, ddd, J = 2.7, 11.7, 14.7 Hz, CCH2), 3.10 (1H, ddd, J = 2.4,
6.0, 15.9 Hz, CCH2), 3.76 (3H, s, OCH3), 4.76 (1H, dd, J = 2.7, 5.4 Hz, CHN3), 5.32 (1H, d, J = 17.1 Hz,
NCH2Ar), 5.41 (1H, d, J = 17.1 Hz, NCH2Ar), 6.76-6.85 (2H, m, Ar-H), 6.85-6.95 (2H, m, Ar-H), 7.14 (1H,
ddd, J = 1.5, 6.9, 8.1 Hz, Ar-H), 7.21 (1H, dt, J = 1.2, 6.6 Hz, Ar-H), 7.27 (1H, d, J = 7.2 Hz, Ar-H), 7.61
13
(1H, d, J = 6.9 Hz, Ar-H). C NMR (75 MHz, CDCl3): δ 23.7, 24.8, 27.9, 32.3, 46.0, 55.2, 57.1, 109.6,
114.2, 117.5, 119.0, 119.4, 122.6, 126.9, 127.3, 129.8, 132.9, 136.4, 158.9. MS (EI): m/z (%) 346 (M+, 3),
304 (21), 303 (57), 121 (100). HRMS (EI): m/z Calcd for C21H22N4O: 346.1794; Found: 346.1791.
5-(4-Methoxybenzyl)-5,6,7,8-tetrahydrocyclohepta[b]indole (11)
Green oil. IR (CHCl3): 2932, 1612, 1512, 1468, 1248 cm-1. 1H NMR (300 MHz, CDCl3): δ 2.02 (2H, quint,
J = 5.7 Hz, CH2CH2CH2), 2.46 (2H, dd, J = 5.1, 10.8 Hz, CHCH2CH2), 2.95 (2H, t, J = 5.7 Hz, CCH2CH2),
3.74 (3H, s, OCH3), 5.24 (2H, s, NCH2Ar), 5.74 (1H, dt, J = 5.7, 11.4 Hz, CHCHCH2), 6.68 (1H, dt, J = 1.5,
11.4 Hz, CHCHCH2), 6.73-6.84 (2H, m, Ar-H), 6.85-7.00 (2H, m, Ar-H), 7.08-7.18 (2H, m, Ar-H),
7.18-7.22 (1H, m, Ar-H), 7.60-7.70 (1H, m, Ar-H). 13C NMR (100 MHz, CDCl3): δ 23.3, 28.3, 30.6, 45.9,
55.2, 109.0, 110.8, 114.2, 117.6, 119.6, 120.0, 121.3, 125.3, 127.2, 127.5, 129.7, 136.3, 138.6, 158.8. MS
(EI): m/z (%) 303 (M+, 44), 121 (100). HRMS (EI): m/z Calcd for C21H21NO: 303.1623; Found: 303.1622.
6-Azido-5-(tert-butoxycarbonyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (2s)
1
Dark green oil. IR (CHCl3): 2932, 2104, 1722, 1454, 1371, 1360, 1315, 1308 cm-1. H NMR (300 MHz,
t
CDCl3): δ 1.71 (9H, s, Bu), 1.45-1.81 (1H, m, CHN3CH2CH2CH2), 1.81-1.98 (2H, m, CHN3CH2CH2),
1.98-2.13 (2H, m, CHN3CH2CH2CH2), 2.13-2.23 (1H, m, CHN3CH2), 2.75-2.97 (2H, m, CCH2), 5.92 (1H,
dd, J = 2.1, 6.3 Hz, CHN3), 7.24 (1H, dt, J = 1.2, 7.5 Hz, Ar-H), 7.31 (1H, dt, J = 1.5, 7.2 Hz, Ar-H), 7.50
(1H, dt, J = 0.6, 7.5 Hz, Ar-H), 8.04 (1H, dt, J = 1.2-7.5 Hz, Ar-H). 13C NMR (100 MHz, CDCl3): δ 23.1,
24.4, 26.6, 28.3, 31.5, 57.4, 84.5, 115.8, 118.7, 122.6, 124.8, 124.9, 129.3, 134.4, 135.5, 150.6. MS (EI):
m/z (%) 326 (M+, 20), 228 (34), 227 (30), 226 (16), 185 (15), 184 (100), 183 (30), 182 (32), 180 (30), 169
(15), 168 (14), 57 (42). HRMS (EI): m/z Calcd for C18H22N4O2: 326.1743; Found: 326.1746.

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10-Azido-5-(tert-butoxycarbonyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (7i)
1
Dark green oil. IR (CHCl3): 2981, 2932, 2102, 1726, 1456, 1371, 1354, 1312 cm-1. H NMR (300 MHz,
t
CDCl3): δ 1.69 (9H, s, Bu), 1.60-1.80 (1H, m, CHN3CH2CH2CH2), 1.82-1.98 (2H, m, CHN3CH2CH2),
1.98-2.16 (2H, m, CHN3CH2CH2CH2), 2.16-2.36 (1H, m, CHN3CH2), 3.15 (1H, ddd, J = 2.4, 9.9, 17.1 Hz,
CCH2), 3.45 (1H, ddd, J = 2.4, 8.1, 17.1 Hz, CCH2), 5.10 (1H, dd, J = 1.8, 5.7 Hz, CHN3), 7.20-7.30 (2H, m,
Ar-H), 7.44-7.60 (1H, m, Ar-H), 7.94-8.07 (1H, m, Ar-H). 13C NMR (100 MHz, CDCl3): δ 24.4, 26.5, 27.3,
28.3, 31.5, 56.5, 84.2, 115.2, 117.2, 117.5, 122.8, 123.8, 129.3, 135.2, 142.3, 150.6. MS (EI): m/z (%) 326
(M+, 19), 284 (17), 283 (25), 229 (15), 228 (100), 227 (89), 185 (10), 184 (76), 183 (57), 182 (51), 180 (12),
169 (11), 168 (31), 167 (18), 57 (66). HRMS (EI): m/z Calcd for C18H22N4O2: 326.1743; Found: 326.1742.
2-(Azidomethyl)-1-(4-methoxybenzyl)-3-methyl-1H-indole (2t)
1
Brown oil. IR (CHCl3): 3007, 2936, 2108, 1512, 1248 cm-1. H NMR (300 MHz, CDCl3): δ 2.40 (3H, s,
CCH3), 3.75 (3H, s, OCH3), 4.40 (2H, s, CH2N3), 5.33 (2H, s, NCH2Ar), 6.74-6.83 (2H, m, Ar-H),
6.86-6.95 (2H, m, Ar-H), 7.14 (1H, ddd, J = 1.5, 6.3, 7.5 Hz, Ar-H), 7.22 (1H, dt, J = 1.5, 8.1 Hz, Ar-H),
7.24-7.29 (1H, m, Ar-H), 7.61 (1H, dt, J = 1.2, 7.8 Hz, Ar-H). 13C NMR (75 MHz, CDCl3): δ 8.9, 44.2, 46.3,
55.2, 109.6, 111.9, 114.2, 119.3, 119.4, 122.8, 127.1, 127.8, 128.9, 129.8, 137.1, 158.9. MS (EI): m/z (%)
306 (M+, 23), 278 (28), 264, (21), 157 (15), 121 (100). HRMS (EI): m/z Calcd for C18H18N4O: 306.1480;
Found: 306.1478.
3-(Azidomethyl)-1-(4-methoxybenzyl)-2-methyl-1H-indole (7j)
1
Brown oil. IR (CHCl3): 3007, 2936, 2106, 1512, 1248 cm-1. H NMR (300 MHz, CDCl3): δ 2.39 (3H, s,
CCH3), 3.75 (3H, s, OCH3), 4.55 (2H, s, CH2N3), 5.28 (2H, s, NCH2Ar), 6.76-6.82 (2H, m, Ar-H),
6.86-6.93 (2H, m, Ar-H), 7.11-7.20 (2H, m, Ar-H), 7.22-7.28 (1H, m, Ar-H), 7.59-7.68 (1H, m, Ar-H). 13C
NMR (100 MHz, CDCl3): δ 10.4, 45.4, 46.2, 55.3, 105.8, 109.4, 114.2, 117.9, 120.0, 121.7, 127.1, 127.5,
129.4, 136.0, 136.5, 158.9. MS (EI): m/z (%) 306 (M+, 12), 278 (16), 264 (27), 121 (100). HRMS (EI): m/z
Calcd for C18H18N4O: 306.1481; Found: 306.1478.
2-(Azidomethyl)-1-(tert-butoxycarbonyl)-3-methyl-1H-indole (2u)
1
Yellowish green oil. IR (CHCl3): 2982, 2928, 2102, 1724, 1454, 1357, 1339, 1329 cm-1. H NMR (300
MHz, CDCl3): δ 1.71 (9H, s, tBu), 2.32 (3H, s, CH3), 4.78 (2H, s, CH2N3), 7.27 (1H, dt, J = 1.2, 9.6 Hz,
Ar-H), 7.35 (1H, dt, J = 1.5, 7.2 Hz, Ar-H), 7.52 (1H, dd, J = 0.9, 7.5 Hz, Ar-H), 8.12 (1H, d, J = 9.6 Hz,
13
Ar-H). C NMR (100 MHz, CDCl3): δ 8.8, 28.2, 45.6, 84.4, 115.9, 119.06, 119.11, 122.7, 125.3, 129.4,
129.7, 136.1, 150.2. MS (EI): m/z (%) 286 (M+, 34), 230 (13), 188 (28), 186 (26), 159 (16), 158 (32), 157
(29), 145 (13), 144 (100), 143 (24), 130 (25), 57 (80), 41 (11). HRMS (EI): m/z Calcd for C15H18N4O2:

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286.1430; Found: 286.1428.
3-(Azidomethyl)-1-(tert-butoxycarbonyl)-2-methyl-1H-indole (7k)
Yellowish green oil. IR (CHCl3): 2982, 2934, 2108, 1730, 1458, 1358 cm-1. 1H NMR (300 MHz, CDCl3): δ
1.70 (9H, s, tBu), 2.63 (3H, s, CH3), 4.46 (2H, s, CH2N3), 7.21-7.35 (2H, m, Ar-H), 7.53 (1H, ddd, J = 3.9,
5.2, 10.1 Hz, Ar-H), 8.12 (1H, ddd, J = 4.5, 5.4, 11.4 Hz, Ar-H). 13C NMR (75 MHz, CDCl3): δ 14.0, 28.2,
44.5, 84.1, 112.3, 115.5, 117.7, 122.9, 124.0, 128.8, 135.6, 136.6, 150.5. MS (EI): m/z (%) 286 (M+, 47),
230 (39), 213 (11), 188 (76), 158 (25), 157 (23), 145 (12), 144 (100), 143 (17), 130 (14), 57 (89), 41 (12).
HRMS (EI): m/z Calcd for C15H18N4O2: 286.1430; Found: 286.1427.
2-(1-Azidoethyl)-1-(4-methoxybenzyl)-3-methyl-1H-indole (2v)
Yellow oil. IR (CHCl3) 3007, 2932, 2106, 1512, 1466, 1246 cm-1. 1H NMR (300 MHz, CDCl3): δ 1.47 (3H,
d, J = 7.2 Hz, CHN3CH3), 2.43 (3H, s, CCH3), 3.75 (3H, s, OCH3), 5.05 (1H, q, J = 7.2 Hz, CHN3), 5.37 (1H,
d, J = 17.4 Hz, NCH2Ar), 5.46 (1H, d, J = 17.4 Hz, NCH2Ar), 6.75-6.83 (2H, m, Ar-H), 6.84-6.93 (2H, m,
Ar-H), 7.10-7.18 (3H, m, Ar-H), 7.59-7.63 (1H, m, Ar-H). 13C NMR (75 MHz, CDCl3): δ 9.0, 20.5, 46.8,
53.8, 55.2, 109.7, 114.1, 119.0, 119.3, 122.5, 126.9, 128.2, 130.0, 133.2, 137.0, 144.7, 158.9. MS (EI): m/z
(%) 320 (M+, 24), 278 (33), 277 (29), 122 (12), 121 (100). HRMS (EI): m/z Calcd for C19H20N4O:
320.1637; Found: 320.1635.
3-(Azidomethyl)-2-ethyl-1-(4-methoxybenzyl)-1H-indole (7l)
1
Brown oil. IR (CHCl3): 3007, 2970, 2936, 2108, 1512, 1466, 1248 cm-1. H NMR (300 MHz, CDCl3): δ
1.17 (3H, t, J = 7.5 Hz, CH2CH3), 2.79 (2H, q, J = 7.5 Hz, CH2CH3), 3.73 (3H, s, OCH3), 4.54 (2H, s,
CH2N3), 5.29 (2H, s, NCH2Ar), 6.74-6.81 (2H, m, Ar-H), 6.83-6.90 (2H, m, Ar-H), 7.10-7.22 (3H, m,
Ar-H), 7.60-7.68 (1H, m, Ar-H). 13C NMR (100 MHz, CDCl3): δ 15.4, 17.9, 45.5, 46.1, 55.2, 105.1, 109.8,
114.2, 118.1, 120.1, 121.8, 127.0, 127.7, 129.6, 136.5, 141.9, 158.9. MS (EI): m/z (%) 320 (M+, 14), 278
(31), 121 (100). HRMS (EI): m/z Calcd for C19H20N4O: 320.1637; Found: 320.1638.
3-(1-Azidomethyl)-1-(tert-butoxycarbonyl)-2-ethyl-1H-indole (7m)
Yellow oil. IR (CHCl3): 2982, 2108, 1730, 1458, 1371, 1360, 1329 cm-1. 1H NMR (300 MHz, CDCl3): δ
1.27 (3H, t, J = 7.2 Hz, CH2CH3), 1.70 (9H, s, tBu), 3.09 (2H, q, J = 7.2 Hz, CH2CH3), 4.45 (2H, s, CH2N3),
7.25 (1H, dt, J = 2.4, 7.8 Hz, Ar-H), 7.29 (1H, dt, J = 2.4, 7.2 Hz, Ar-H), 7.50-7.58 (1H, m, Ar-H), 8.12 (1H,
dd, J = 1.8, 6.6 Hz, Ar-H). 13C NMR (100 MHz, CDCl3): δ 15.4, 20.1, 28.2, 44.7, 84.2, 111.9, 115.7, 118.0,
123.0, 124.1, 128.8, 135.9, 142.5, 150.2. MS (EI) m/z (%): 300 (M+, 44), 244 (36), 216 (13), 203 (12), 202
(89), 172 (32), 171 (35), 159 (12), 158 (100), 157 (21), 156 (24), 155 (12), 144 (13), 143 (12), 57 (86), 41

HETEROCYCLES, Vol. 89, No. 9, 2014
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(12). HRMS (EI): m/z Calcd for C16H20N4O2: 300.1586; Found: 300.1583.
3-Ethyl-1-(4-methoxybenzyl)-2-propyl-1H-indole (1n)
To a suspension of NaH (128 mg, 60% in mineral oil, 3.21 mmol) in dry DMF (5.0 mL) was added
3-ethyl-2-propylindole16 (400 mg, 214 mmol) at 0 °C. After stirring at room temperature for 10 min, the
reaction mixture was added tetrabutylammonium iodide (79 mg, 0.214 mmol) and p-methoxybenzyl
chroride (260 L, 2.57 mmol) and stirred for 30 min. The reaction was quenched by the addition of
saturated aqueous NH4Cl (10 mL) and extracted with Et2O (30 mL, 3 times). The organic layer was dried
over MgSO4 and filtrate was concentrated. The residue was purified by silica gel chromatography
(AcOEt/n-hexane = 1/5) to afford 1n (504 mg, 77%).
1
Yellow oil. IR (CHCl3): 3005, 2963, 2932, 2870, 1612, 1512, 1468, 1246 cm-1. H NMR (400 MHz,
CDCl3): δ 0.93 (3H, t, J = 7.2 Hz, CH2CH2CH3), 1.23 (3H, t, J = 7.2 Hz, CCH2CH3), 1.50 (2H, ddd, J = 7.2,
15.2, 15.2 Hz, CH2CH2CH3), 2.66 (2H, t, J = 8.0 Hz, CH2CH2CH3), 2.76 (2H, q, J = 7.2 Hz, CCH2CH3),
3.71 (3H, s, OCH3), 5.22 (2H, s, NCH2Ar), 6.70-6.82 (2H, m, Ar-H), 6.82-6.92 (2H, m, Ar-H), 7.02-7.10
(2H, m, Ar-H), 7.11-7.22 (1H, m, Ar-H), 7.54-7.61 (1H, m, Ar-H). 13C NMR (100 MHz, CDCl3): δ 15.6,
17.5, 19.4, 25.3, 28.1, 47.5, 56.7, 110.9, 115.5 (2C), 119.8, 120.3, 122.2, 128.5, 129.3, 132.0, 137.8, 138.0,
160.2. MS (EI): m/z (%) 308 ([M++1], 12), 307 (M+, 52), 121 (100). HRMS (EI): m/z Calcd for C21H25NO:
307.1936; Found: 307.1936.
3-(1-Azidoethyl)-1-(4-methoxybenzyl)-2-propyl-1H-indole (7n)
1
Yellowish green oil. IR (CHCl3): 3007, 2961, 2934, 2872, 2104, 1612, 1512, 1466, 1248, 1223 cm-1. H
NMR (300 MHz, CDCl3): δ 0.95 (3H, t, J = 7.2 Hz, CH2CH2CH3), 1.42-1.62 (2H, m, CH2CH2CH3), 1.69
(3H, d, J = 6.9 Hz, CHN3CH3), 2.71 (2H, t, J = 7.8 Hz, CCH2), 3.73 (3H, s, OCH3), 5.04 (1H, q, J = 6.9 Hz,
CCHN3), 5.25 (2H, s, NCH2Ar), 6.74-6.82 (2H, m, Ar-H), 6.82-6.90 (2H, m, Ar-H), 7.06-7.21 (3H, m,
Ar-H), 7.75-7.83 (1H, m, Ar-H). 13C NMR (100 MHz, CDCl3): δ 14.0, 21.5, 24.0, 26.6, 46.0, 55.2, 55.5,
109.8, 110.9, 114.1, 119.56, 119.64, 121.4, 125.7, 126.9, 129.6, 136.8, 138.2, 158.8. MS (EI): m/z (%) 348
(M+, 1), 306 (14), 305 (44), 122 (10), 121 (100). HRMS (EI): m/z Calcd for C21H24N4O: 348.1950; Found:
348.1946.
ACKNOWLEDGEMENTS
We thank N. Eguchi, T. Koseki, and S. Yamada at the Analytical Center of our university for performing
microanalysis, NMR and mass spectrometry measurements.

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