AlMe3-mediated regio- and chemoselective reactions of indole with carbamoyl electrophiles

Article abstract of DOI:10.1002/ejoc.201300085

Herein, we report the regio- and chemoselective reactions of indole with carbamoyl electrophiles in presence of AlMe₃. Indole-3-carboxamide was prepared in one-step from a reaction of indole with tertiary carbamoylimidazole in the presence AlMe

Full text of DOI:10.1002/ejoc.201300085

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FULL PAPER
DOI: 10.1002/ejoc.201300085
AlMe3-Mediated Regio- and Chemoselective Reactions of Indole with
Carbamoyl Electrophiles
A. Velavan,[a] S. Sumathi,*[a] and K. K. Balasubramanian*[a]
Keywords: Synthetic methods / Acylation / Regioselectivity / Chemoselectivity / Nitrogen heterocycles / Lewis acids /
Aluminum
Herein, we report the regio- and chemoselective reactions of
indole with carbamoyl electrophiles in presence of AlMe3.
Indole-3-carboxamide was prepared in one-step from a reac-
tion of indole with tertiary carbamoylimidazole in the pres-
ence AlMe3. Under conditions for the formation of an alumin-
ium ate complex, the reaction was diverted to the indole ni-
trogen. Secondary carbamoyl electrophiles in the presence
of AlMe3 regiospecifically yielded trisubstituted ureas. The
regiospecificity and chemoselectivity of the indole nitrogen
towards ester and tertiary carbamoylimidazole functionalities
were also studied.
Introduction
Indoles are very important and attractive structural moi-
eties to both medicinal and synthetic organic chemists. The
Friedel–Crafts acylation/alkylation at the C-3 position of
indole has been extensively investigated by many research-
ers.[1a,1b] In continuation of our research,[2a] we attempted
to synthesize tetrasubstituted ureas that contain an indole
motif by using a tertiary carbamoylimidazole in the pres-
ence of AlMe3. As a result, we were pleasantly surprised
by the formation of indole-3-carboxamides instead of the
expected urea. The use of a carbamoylimidazole as a com-
ponent in an electrophilic reaction has previously been lim-
ited to the synthesis of ureas. The chemical transformation
that uses a carbamoylimidazole in a Friedel–Crafts-type
carboxamidation has not been reported until now.
Indole-3-carboxamides and ureas that contain an indole
motif have received wide attention as potent and selective
antagonists of the serotonin 5-HT3 receptor (i.e., 1),[3a] as
platelet activating factor antagonists (i.e., 2),[3b] as canna-
binoid receptor modulators (i.e., 3),[3c,3d] as p38α MAP kin-
ase inhibitors (i.e., 4),[4a] as BACE-1 inhibitors,[4b] as Met
kinase inhibitors,[4c] and also as useful ligands in organic
transformations (see Figure 1).[4d]
The most frequent methods employed for the prepara-
tion of indole-3-carboxamide include (see Scheme 1): (i) the
conversion of indole-3-carbaldehyde to its carboxylic acid/
ester followed by a coupling reaction with an amine;[5]
(ii) the reaction of indole with a Grignard reagent followed
Figure 1. Some bioactive indole-3-carboxamides and an indole
urea.
by treatment with ethyl chloroformate to give a mixture of
C-3- and N-ethoxycarbonyl products;[6] (iii) the reaction of
indole with Viehe’s reagent,[7a] chlorosulfonyl isocyan-
ate,[7b–7d] or isocyanatophosphoryl dichloride[7e] followed
by basic hydrolysis; (iv) the treatment of indole with chloro-
formates[6b] or toxic triphosgene followed by coupling with
amines;[8](v) a Pd-catalyzed carboxamidation of indole by
using isocyanide, which was recently reported by Zhu et
al.;[9] and (vi) a Friedel–Crafts acylation of indole that was
explored in detail by Katritzky et al. by using carbonyl-
benzotriazole.[10a] However, a Friedel–Crafts carbamo-
ylation with carbamoylazole has not been studied so far.
Recently, Sarpong et al.[10b] reported a chemoselective acyl-
ation of the indole nitrogen by using 1,8-diazabicyclo[5.4.0]
undec-7-ene (DBU) and imidazole carbamates.
[a] Department of Chemistry, Hindustan University, Rajiv Gandhi
Salai, Padur,
(Via) Kelambakkam, Chennai 603103, India
E-mail: sumathi@hindustanuniv.ac.in
kkbalu@hotmail.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300085.
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A. Velavan, S. Sumathi, K. K. Balasubramanian
Table 1. Optimization of reaction conditions.[a]
FULL PAPER
Scheme 1. Some reported methods for C-3 carboxamidation.
Entry Lewis acid
Equiv. Solvent
Time Temp. Yield
[h]
[°C][b] [%][c]
1
2
3
4
5
6
7
8
Amberlyst 15
Amberlyst 15
Amberlyst 15
AlCl3
AlCl3
AlCl3
AlCl3
BF3·AcOH
FeCl3
AlMe3
BF3·Et2O
CuCl2
FeCl3
TFA
ZnBr2
CeCl3/NaI/silica
ZnCl2
ZnCl2/iPrMgCl
AlMe3
TFA
AlMe3
AlMe3
wt/wt
wt/wt
wt/wt
1.1
1.1
2.1
2.1
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
ACN
DCE
toluene
DCM[e]
DCE
24
24
24
6
24
24
24
6
86
86
86
n.r.[d]
n.r.
n.r.
n.r.
5
Results and Discussion
52
reflux
reflux
110
52
52
52
86
86
86
86
90
90
90
90
90
86
110
110
110
110
90
90
90
110
We began our study by screening a number of acid cata-
lysts that are commonly employed in a Friedel–Crafts reac-
tion such as Amberlyst 15, BF3·Et2O, trifluoroacetic acid
(TFA), FeCl3, CeCl3, CuCl2, ZnBr2, and ZnCl2. Treating
indole with a tertiary carbamoylimidazole and any of these
catalysts did not lead to the desired carbamoylation. The
regioselective C-3 acylation of indole by N-chlorozinc com-
plex, which was reported earlier,[10c] did not work with a
tertiary carbamoylimidazole. After extensive screening, we
determined that AlMe3 was the best catalyst for the C-3
carbamoylation (see Table 1).
DCE
9
14
toluene
DCM
DCM
DCM
ACN
ACN
ACN
ACN
ACN
ACN
DCE
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
35
9
6
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
24
24
24
24
24
24
48
48
24
48
24
48
48
48
48
48
48
48
2.0/1.0 DCE
1.5
1.5
2.5
3.0
2.5
2.5
3.0
3.0
3.0
3.0
ACN
ACN
Among the several solvents tried (see Table 1) 1,2-di-
chloroethane (DCE) and toluene were better than the
others. Toluene was chosen as the solvent for rest of the
study. At a higher reaction temperature with AlCl3, indole-
3-carboxamide 1a was obtained in very low yield (5–15%),
and extensive decomposition of carbamoylimidazole 5 oc-
curred. The reaction with AlMe3 was clean, but slow to
furnish indole-3-carboxamide 1a. The yield decreased in
solvents such as acetonitrile (ACN) and 1,4-dioxane. The
optimal conditions were achieved by using 3 equiv. of
AlMe3 in toluene at 110 °C. The preparation and structural
characterization by single crystal XRD and NMR spec-
toluene
toluene
toluene
toluene
DCE
ACN
toluene
1,4-dioxane
70
BF3·AcOH
FeCl3
AlMe3
AlMe3
AlMe3
n.r.
n.r.
79
12
68
AlMe3
45
[a] Reagents and conditions: Indole (1.0 mmol), 5 (1.1 mmol; Im =
imidazole). [b] Oil bath temperature. [c] Yield of isolated product.
[d] n.r. = no reaction. [e] DCM = dichloromethane.
troscopy of the indole-aluminium amide complex was pre- mation). 2-Methylindole also underwent C-3 carbamoyl-
viously reported.[11] However, the synthetic utility of the re- ation to give product 1j in 80% yield (see Table 2).
action remained unexplored until now. Using the optimal
Generally, indole ureas are synthesized from triphosgene
conditions, a host of indole-3-carboxamides were synthe- derivatives.[12] This method suffers from a disadvantage in
sized (see Table 2). The yields were moderate to good (45– that the reaction is always accompanied by the formation
90%), as the solubility of these indole-3-carboxamides was of a self-coupled symmetrical urea. Furthermore, electron-
a concern during the workup and column purification.
deficient indole systems gave low yields, which limited the
All of these compounds were highly soluble in tetra- scope of this methodology. With the purpose of under-
hydrofuran (THF) and were purified by silica gel column standing the factors that determine the regiochemical
chromatography. The carboxamidation reaction was highly course of the carboxamidation, several secondary carbamo-
sensitive to the nature of the substituent on the benzene ylimidazoles were treated with indole under similar reaction
ring and indole nitrogen. N-substituted indoles such as N- conditions. Interestingly, in the case of secondary carbam-
methylindole and N-benzylindole did not undergo reaction, oyl electrophiles, the reaction was diverted to the indole ni-
whereas a smooth reaction occurred using indole with a trogen to give trisubstituted indole ureas 2a–2e (see
free N–H. Also, electron-deficient substrates such as 5- Scheme 2). Under these conditions, secondary carbamates
cyanoindole and 5-nitroindole failed to react under the were reactive unlike tertiary carbamates and furnished the
above conditions. No reaction was observed when tertiary indole ureas. So far, only one example of the formation of
phenyl carbamates were treated with indole in the presence an indole urea from a secondary carbamate has been re-
of AlMe3. This may be attributed to the poor leaving group ported under similar conditions.[2b]
ability of phenoxide in comparison to a tertiary carbamoyl-
As ate complexes are used as switches to tune the regiose-
imidazole[2a] (see Scheme 1a in the Supporting Infor- lectivity of many organometallic reactions,[13] we envisioned
2
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Selective Reactions of Indole with Carbamoyl Electrophiles
Table 2. C-3 carbamoylation of indole under optimized reaction
condition.[a,b]
Scheme 2. Trisubstituted indole ureas from secondary carbamates
and carbamoylimidazoles.[a]
ferent regiochemical preference. The aluminium ate com-
plex that is derived from tetramethylpiperidine has basic
properties and is well-known.[14a] The aluminium ate com-
plex of indole, which is nucleophilic in nature, has not been
reported until now, although the synthesis of an indole-alu-
minium amide complex has been described in the litera-
ture.[15] Using the conditions for aluminium ate complex
formation, which involves the treatment of indole with lith-
ium hexamethyldisilazide (LiHMDS) followed by the ad-
[a] Reagents and conditions: Indole (1.0 mmol), carbamoylimid-
azole (1.1 mmol), toluene, 110 °C, 48 h. [b] Yield of isolated prod-
uct.
that the aluminium ate complex of indole might exhibit not dition of AlMe3, and finally treating with carbamoylimid-
only a higher reactivity towards electrophiles but also a dif- azole in THF, tertiary carbamoylimidazoles were converted
Table 3. N-Carbamoylindole synthesis using conditions for aluminium ate complex formation.[a]
[a] Reagents and conditions: Indole (1.0 mmol), THF, –30 °C, LiHMDS (1.0 mmol), then AlMe3 (1.1 mmol), –30 °C, 30 min, carb-
amoylimidazole (1.025 mmol), 80 °C. [b] Isolated yield. [c] Imidazolide is the leaving group. [d] Ultra performance liquid chromatography
(UPLC) conversion. [e] Phenoxide is the leaving group.
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A. Velavan, S. Sumathi, K. K. Balasubramanian
FULL PAPER
exclusively into N-carbamoylindoles 3a–3m in good yields
(see Table 3). Thus, we achieved the synthesis of a variety
of unsymmetrical tetrasubstituted indole ureas under the
conditions for aluminium ate complex formation. Tetra-
hydrocarbazole, which failed to undergo any reaction with
tertiary carbamoylimidazole in presence of AlMe3, readily
underwent reaction by using the aluminium ate complex
conditions to give 3m. The indole ate complex generated
from bases such as nBuLi, KHMDS, NaHMDS, and the
Grignard reagent iPrMgCl also exclusively underwent this
N-carboxamidation reaction (see Table 4).
Table 4. Combination of different metal bases with AlMe3 for N-
carbamoylindole synthesis.
Entry
Base
% Yield[a]
1
2
3
4
5
LiHMDS
iPrMgCl
NaHMDS
KHMDS
nBuLi
90
89
89
90
91
Scheme 3. Regio- and chemoselective competitive reactions of in-
dole with ester and carbamoylimidazole functional groups.
Table 5. One-pot direct bis(carbamoylation) of indole 5a.
[a] Yield of isolated product.
Halogenated indoles, which gave 3b and 3k, and 2-substi-
tuted indoles, which gave 3d, 3e, 3g, 3h, 3j, and 3l, also
underwent the reaction very well to form indole ureas. The
N-(tert-butoxycarbonyl) and N-benzyloxycarbonyl (Boc
and Cbz, respectively) groups were stable under the reaction
conditions. An interesting chemoselectivity was observed
when indole was treated with a carbamoylimidazole that
contained an ester moiety under the conditions for ate com-
plex formation. N-carbamoylindole 3l was prepared with-
out affecting the ester functional group, even with an excess
amount of AlMe3 (2.0 equiv.). An equimolar mixture of di-
ethyl terephthalate (4a), ethyl (4-chlorophenyl)acetate (4b),
ethyl 1-(imidazole-1-carbonyl)piperidine-4-carboxylate (4c),
and indole was subjected to the standard conditions (see
Scheme 3). Only the formation of urea was observed as re-
vealed by TLC and LC–MS analysis of the crude product.
Workup and purification of this reaction furnished ureas 4d
and 4e. We also observed the formation of the trans esterifi-
cation product 4e. The high chemoselectivity in favor of car-
bamoylimidazole functionality under these conditions is
noteworthy.
Entry
5b [equiv.]
% 5c[a]
% 5d[a]
1
2
3
1.1
1.6
2.3
80
43 (30)[b]
15
12
57 (45)[b]
79
[a] Percent determined by UPLC analysis. [b] Purified by prepara-
tive HPLC (isolated yield).
We also attempted a direct one-pot C-3 and N-bis(carb-
amoylation) of indole 5a by using AlMe3 (see Table 5) in
the absence of base and ate complex formation. Although
the reaction did not go to completion, the transformation
was successful. Products 5c and 5d were separated by pre-
parative HPLC. Compound 5c was also converted into the
bis(carbamoylated) product 5d when treated with AlMe3
and 5b (see Scheme 4).
The contrasting regiochemical preference that is exhib-
ited by secondary and tertiary carbamoylimidazoles, the Scheme 4. N-acylation of indole-3-carboxamide.
4
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Selective Reactions of Indole with Carbamoyl Electrophiles
former for nitrogen and the latter for C-3, in this AlMe3-
mediated reaction suggests that the two reactions follow dif-
ferent mechanistic pathways. Because secondary carbamo-
ylimidazoles are known to form isocyanates in situ,[12c] it is
likely that their reactions proceed through isocyanate inter-
mediates.
A control experiment with indole and phenyl or benzyl
isocyanate in presence of AlMe3 (see Scheme 5) yielded ex-
clusively the respective indole ureas, which provided sup-
port to this mechanistic proposition. Because the migration
of groups from nitrogen to C-3 is known to occur with in-
doles, we wanted to determine if the C-3 carboxamidation
of indole by using a tertiary carbamoylimidazole proceeded
through an initial N-carbamoylation followed by a mi-
gration of the carbamoyl group from the nitrogen to C-3.
When urea 3a was heated in presence of 3 equiv. of AlMe3
at 110 °C for 48 h, the major starting material was reco-
vered (87%) along with minor cleavage products such as N-
acetyl piperidine and indole. There was no evidence of the
formation of 1e, which ruled out the possibility of this path-
way (see Scheme 6). Both electronic and steric factors ap-
pear responsible for the preferential C-3 acylation in the
case of the tertiary carbamoylimidazoles. Indole dimethyl-
aluminium amide[15] is a covalent compound that is steri-
cally bulky. When it undergoes a reaction with the trimeth-
ylaluminium complex of a carbamoylimidazole (i.e., B, see
Scheme 7), there is considerable steric crowding at the carb-
onyl reaction centre and also an unfavorable peri interac-
tion. As a result, the reaction is diverted to C-3 of the in-
dole, which is a softer centre. Under the conditions for the
formation of the aluminium ate complex, we believe that
the lithium indole, and not the sterically encumbered ate
complex, acts as the nucleophile and attacks the trimeth-
ylaluminium complex B of the tertiary carbamoylimidazole.
Scheme 7. Possible mechanism.
centre). This line of reasoning is supported by the observa-
tion that indolyllithium does react with tertiary carbamo-
ylimidazoles, albeit slowly, to form N-indolyl ureas in low
yield. In the absence of trimethylaluminium, the tertiary
carbamoylimidazole is not activated, and, hence, the slow
reaction in this case (see Scheme 8).
Scheme 8. Tetrasubstituted ureas from simple lithiation.
Conclusions
Scheme 5. Reaction of indole with isocyanates in presence of
AlMe3.
We have developed an efficient one-step method for the
synthesis of indole-3-carboxamide by the reaction of a free
N–H indole with tertiary carbamoylimidazoles in the pres-
ence of trimethylaluminium. Under these conditions, sec-
ondary carbamoyl electrophiles were converted to trisubsti-
tuted indole ureas. The combination of base and AlMe3
diverted the reaction from C-3 to N-carbamoylation to pro-
vide an efficient method for the synthesis of tetrasubstituted
indole ureas in excellent yields. This reaction displays high
chemoselectivity towards carbamoylimidazoles and is com-
Scheme 6. Possible rearrangement from nitrogen to C-3.
The reaction of the sterically less demanding indolyl- patible with variety of functional groups. It is interesting
lithium with complex B does not suffer from any peri inter- that highly reactive isocyanates in presence of AlMe3 gave
action, unlike the indole dimethylaluminium amide. The re- indole ureas exclusively in good yields, whereas according
action takes place at the negatively charged nitrogen of in- to earlier literature methods, chloroformates, chlorosulfon-
dole (hard centre) rather than at the C-3 of indole (soft ylisocyanates, and isocyanatophosphoryl dichloride gave a
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A. Velavan, S. Sumathi, K. K. Balasubramanian
FULL PAPER
N-Diallylimidazole-1-carboxamide: Yellow liquid. IR (KBr): ν =
˜
mixture of products resulting from N- and C-3 acylation.
We have also demonstrated a one-pot C-3- and N-dicarbox-
amidation by using AlMe3. The detailed mechanism of
these reactions has been investigated.
3386, 3122, 3085, 2985, 2934, 1694, 1644, 1456, 1413, 1355, 1283,
1241, 1198, 1102, 1068, 970, 931, 832, 755, 655 cm–1. 1H NMR
(300 MHz, [D6]DMSO): δ = 8.02 (s, 1 H), 7.46 (s, 1 H), 7.03 (s, 1
H), 5.95–5.83 (m, 2 H), 5.27–5.23 (m, 4 H), 3.93 (d, J = 4.8 Hz, 4
H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 151.7, 137.3, 133.0,
129.4, 118.7, 118.5, 50.5 ppm. HRMS calcd. for C10H13N3ONa [M
+ Na] 214.0951; found 214.0961.
Experimental Section
Phenyl Piperidine-1-carboxylate:[16] Yellow solid; m.p. 75–77 °C. IR
General Methods: Purifications were performed with a Combiflash
Companion flash column chromatography instrument. Analytical
thin layer chromatography was carried out with silica gel (60 F254)
plates, which were viewed by exposing them to ultraviolet light. IR
spectra were recorded using KBr pellets with a PE-983 infrared
spectrometer. The absorption data are reported in cm–1. The NMR
spectrocopic data were recorded in CDCl3 or [D6]DMSO with a
Bruker 300 MHz spectrometer. The resonances are reported rela-
tive to TMS.
(KBr): ν = 3394, 2945, 2667, 2402, 1947, 1705, 1429, 1332, 1026,
˜
907, 804, 689 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.42–7.26
(m, 2 H), 7.25–7.08 (m, 3 H), 3.60 (br. s, 2 H), 3.51 (br. s, 2 H),
1.71–1.56 (m, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 153.8,
151.6, 129.6, 125.0, 121.8, 45.5, 45.1, 25.9, 25.5, 24.3 ppm.
Phenyl 2-(4-Fluorobenzyl)morpholine-4-carboxylate: Yellow sticky
mass; R = 0.4 (EtOAc/hexane, 3:7). IR (KBr): ν = 3127, 3008,
˜
f
2864, 1892, 1718, 1599, 1425, 1204, 1109, 1017, 906, 836, 748, 690,
659 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 7.51–7.22 (m, 6
H), 7.19–7.08 (m, 3 H), 3.97–3.49 (m, 5 H), 2.97–2.75 (m, 4
H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 163.0, 159.8, 153.4,
151.5, 134.3, 131.6, 131.5, 130.1, 129.7, 125.7, 122.3, 121.7, 115.4,
115.2, 76.0, 75.9, 48.8, 48.0, 44.4, 43.7, 38.3, 38.2 ppm.
N,N-Diphenylindole-3-carboxamide (1b): AlMe3 (2 m solution in
toluene, 3 mL, 6.0 mmol) was added dropwise to indole (234 mg,
2.0 mmol) and (diphenylcarbamoyl)imidazole (577 mg, 2.2 mmol)
in dry toluene (6 mL) at 0 °C in a flame-dried two-neck flask under
nitrogen. The resulting mixture was stirred at r.t. for 30 min and
then heated to 110 °C (oil bath temperature) for 48 h. The reaction
mixture was cooled to 0 °C and then quenched with a saturated
NaHCO3 solution (8 mL). The resulting solution was extracted
with THF (3ϫ25 mL). Purification of the crude mass by flash col-
umn chromatography (hexane/ethyl acetate, 1:9 and then THF/eth-
anol, 9:1) furnished indole-3-carboxamide 1b (562 mg, 90%) as an
off-white solid.
[(2,3-Dihydroindol-1-yl)imidazol-1-yl]methanone:[17] Off-white solid;
m.p. 101–103 °C. IR (KBr): ν = 3128, 3041, 2965, 2854, 2867, 1928,
˜
1681, 1482, 1400, 1260, 1163, 1101, 1022, 997, 951, 902 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 8.02 (s, 1 H), 7.41–7.35 (m, 1 H),
7.24–7.06 (m, 5 H), 4.19 (t, J = 16.5 Hz, 2 H), 3.19 (t, J = 16.5 Hz,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 148.2, 141.3, 136.6,
132.0, 129.8, 127.6, 125.1, 125.0, 117.5, 116.5, 51.0, 28.3 ppm.
C12H11N3O (213.24): calcd. C 67.59, H 5.20, N 19.71; found C
67.99, H 4.98, N 19.66. Direct mass (LC): m/z = 214.0 [M + 1].
(1H-Indol-1-yl)(piperidin-1-yl)methanone (3a): LiHMDS (1.0 m in
hexane, 2.0 mL, 2.0 mmol) was added dropwise to indole (234 mg,
2.0 mmol) in dry THF (2 mL) at –30 °C in a flame-dried two-neck
flask under nitrogen. The resulting mixture was stirred for 20 min
at –30 °C. Then, AlMe3 (2 m in toluene, 1.1 mL, 2.2 mmol) was
added dropwise at –30 °C, and the mixture stirred for 40 min. (Pi-
peridinecarbamoyl)imidazole (367 mg, 2.05 mmol) in THF (5 mL)
was added slowly, and the reaction mixture was slowly warmed to
r.t. and then heated to 80 °C (oil bath temperature) for 14 h. The
reaction mixture was cooled to 0 °C and then quenched with a
saturated NaHCO3 solution (4 mL). The resulting solution was ex-
tracted with ethyl acetate (2ϫ30 mL). Purification by flash column
chromatography (hexane/ethyl acetate, 3:97) furnished indole urea
3a (410 mg, 90%) as a colourless sticky substance.
Phenyl (Pyridin-3-yl)carbamate:[18] White solid; m.p. 136–138 °C.
IR (KBr): ν = 3180, 2820, 1940, 1738, 1589, 1551, 1492, 1427, 1343,
˜
1
1226, 1015, 894, 805, 783 cm–1. H NMR (300 MHz, [D6]DMSO):
δ = 10.47 (s, 1 H), 8.71 (s, 1 H), 8.26 (d, J = 4.2 Hz, 1 H), 7.94 (d,
J = 7.5 Hz, 1 H), 7.46–7.34 (m, 3 H), 7.29–7.24 (m, 3 H) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 152.3, 150.8, 144.5, 140.7, 135.9,
129.9, 126.1, 125.8, 124.2, 122.4 ppm. Direct mass (LC): m/z = 215
[M + 1].
Phenyl (4-Fluorophenyl)carbamate:[19] White solid; m.p. 139–
140 °C. R = 0.5 (EtOAc/hexane. 1:4). IR (KBr): ν = 3315, 3081,
˜
f
2748, 2564, 2343, 2226, 2025, 1886, 1715, 1555, 1505, 1411, 1311,
1221, 1102, 1013, 834, 732 cm–1. 1H NMR (300 MHz, [D6]DMSO):
δ = 10.29 (s, 1 H), 7.54–7.50 (m, 2 H), 7.27–7.14 (m, 7 H) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 152.3, 147.1, 135.4, 124.3,
124.2, 120.6, 116.6, 116.3, 116.1, 115.8, 105.0 ppm.
N-(4-Bromobenzyl)imidazole-1-carboxamide
: White solid; m.p.
108–110 °C. R = 0.3 (EtOAc/hexane, 1:1). IR (KBr): ν = 3747,
˜
f
3130, 2911, 2400, 1920, 1683, 1438, 1288, 1110, 748, 659 cm–1. H
1
NMR (300 MHz, [D6]DMSO): δ = 9.11 (br. s, 1 H), 8.28 (s, 1 H),
7.70 (s, 1 H), 7.54 (d, J = 8.1 Hz, 2 H), 7.31 (d, J = 8.1 Hz, 2 H),
7.05 (s, 1 H), 4.44 (d, J = 5.7 Hz, 2 H) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 149.5, 138.4, 136.5, 131.7, 130.1, 130.0, 120.6,
117.0, 43.3 ppm. HRMS (ESI): calcd. for C11H11BrN3O [M + H]
281.0080; found 281.0085.
N-Methyl-N-phenyl-1H-indole-3-carboxamide (1a): Yellow solid;
m.p. 230 °C. R = 0.3 (EtOAc/hexane, 1:1). IR (KBr): ν = 3157,
˜
f
1897, 1703, 1570, 1478, 1446, 1386, 1317, 1230, 1149, 1110, 1072,
1010, 979, 883, 849, 753, 702, 667 cm–1. 1H NMR (300 MHz, [D6]-
DMSO): δ = 11.28 (br. s, 1 H), 8.05–8.03 (m, 1 H), 7.41–7.27 (m,
6 H), 7.13–7.07 (m, 2 H), 6.35 (m, 1 H) 3.3 (s, 3 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 165.6, 146.0, 135.5, 129.9, 129.3, 128.0,
127.6, 127.3, 122.4, 121.7, 120.8, 112.0, 110.0, 38.3 ppm. HRMS
(ESI): calcd. for C16H15N2O [M + H] 251.1179; found 251.1165.
LC–MS: m/z = 251.07 [M + 1]. UPLC purity: 97.9%.
{[2-(4-Fluorobenzyl)morpholin-4-yl]imidazol-1-yl}methanone (5b):
Off white waxy solid; m.p. 68–70 °C. IR (KBr): ν = 3748, 3130,
˜
3128, 2910, 2369, 1682, 1602, 1440, 1289, 1262, 1113, 1041, 1012,
822, 659 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.84 (s, 1 H),
7.22–7.11 (m, 3 H), 7.08 (s, 1 H), 7.01–6.96 (m, 2 H), 3.99–3.86 (m,
3.2 H), 3.72–3.53 (m, 2.4 H), 3.31–3.22 (m, 1.3 H), 2.99–2.7 (m,
N,N-Diphenyl-1H-indole-3-carboxamide (1b): Off-white solid; m.p.
3.6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 163.4, 160.1, 150.8, 200–202 °C. IR (KBr): ν = 3238, 2926, 1901, 1737, 1610, 1595,
˜
136.8, 132.3, 131.0, 130.9, 130.7, 130.6, 129.9, 117.7, 115.5, 115.2,
76.2, 66.3, 50.3, 46.4, 38.6 ppm. C15H16FN3O2 (289.31): calcd. C
62.27, H 5.57, N 14.52; found C 62.44, H 6.04, N 14.99.
1490, 1431, 1371, 1318, 1278, 1236, 1139, 1075, 1042, 956,
749 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 11.45 (s, 1 H),
8.06 (d, J = 7.5 Hz, 1 H), 7.41–7.36 (m, 5 H), 7.3–7.20 (m, 6 H),
6
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Job/Unit: O30085
/KAP1
Date: 28-03-13 15:51:34
Pages: 11
Selective Reactions of Indole with Carbamoyl Electrophiles
7.17–7.08 (m, 2 H), 6.53 (s, 1 H) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 165.8, 144.9, 135.6, 130.6, 129.6, 128.4, 127.7, 126.7,
122.6, 121.7, 121.1, 112.2, 110.2 ppm. C21H16N2O (312.37): calcd.
C 80.75, H 5.16, N 8.97; found C 80.13, H 5.07, N 8.63. LC–MS:
m/z = 313.17 [M + 1]. UPLC purity: 99.19%.
(2,3-Dihydroindol-1-yl)(1H-indol-3-yl)methanone (1i): Brown solid;
m.p. 246–248 °C. IR (KBr): ν = 3380, 3161, 3050, 2570, 1947, 1702,
˜
1693, 1592, 1491, 1389, 1334, 1321, 1312, 1226 cm–1. 1H NMR
(300 MHz, [D6]DMSO): δ = 11.78 (br. s, 1 H), 8.05–7.98 (m, 3 H),
7.47 (d, 1 H), 7.24–7.11 (m, 4 H), 6.99–6.94 (m, 1 H), 4.36 (t, J =
16.8 Hz, 2 H), 3.13 (t, J = 16.8 Hz, 2 H) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 164.9, 144.6, 136.5, 132.9, 129.5, 127.9, 127.5,
125.5, 123.7, 123.0, 122.1, 121.3, 117.5, 112.6, 112.3, 50.8,
28.9 ppm. HRMS (ESI): calcd. for C17H15N2O [M + H] 263.1179;
found 263.1192.
N,N-Dibenzyl-1H-indole-3-carboxamide (1c):[20] White solid. M.p
186–187 °C; ref. m.p. 187–188 °C. IR (KBr): ν = 3382, 3056, 2932,
˜
2342, 1637, 1537, 1339, 1265, 1206, 1131, 1072, 973, 937, 821,
744 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 11.52 (br. s., 1 H),
7.88–7.84 (m, 1 H), 7.51 (s, 1 H), 7.46–7.33 (m, 5 H), 7.32–7.24 (m,
6 H), 7.22–7.10 (m, 2 H), 4.68 (s, 4 H) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 166.5, 137.2, 135.1, 128.2, 127.9, 126.7, 126.2,
121.6, 120.0, 119.9, 111.4, 108.7, 49.3 ppm.
Compound 1j: Brown solid; m.p. 61–63 °C. 1H NMR (300 MHz,
[D6]DMSO): δ = 11.40 (s, 1 H), 7.38–7.32 (m, 6.7 H), 7.06–7.04
(m, 2 H), 4.66 (s, 2 H), 2.86 (s, 3 H), 2.43 (s, 3 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 167.5, 137.8, 137.0, 134.62, 128.5,
127.3, 127.0, 126.0, 120.8, 119.7, 118.4, 111.0, 107.7, 51.5, 34.6,
12.3 ppm. HRMS (ESI): calcd. for C18H19N2O [M + H] 279.1492;
found 279.1499.
N,N-Diallyl-1H-indole-3-carboxamide (1d):[21] White solid; m.p. 163
–165 °C. IR (KBr): ν = 3168, 2690, 2581, 2358, 1932, 1897, 1860,
˜
1778, 1591, 1578, 1508, 1458, 1362, 1341, 1313, 1206, 1136, 1073,
996, 970, 925, 751 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ =
11.54 (br. s., 1 H), 7.80 (dd, J = 7.0, 0.9 Hz, 1 H), 7.63 (s, 1 H),
7.52–7.39 (m, 1 H), 7.20–7.06 (m, 2 H), 5.98–5.84 (m, 2 H), 5.30–
5.16 (m, 4 H), 4.07 (d, J = 5.3 Hz, 4 H) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 165.8, 135.2, 133.8, 126.3, 126.0, 121.5, 120.1,
119.7, 116.3, 111.3, 108.8, 48.4 ppm. HRMS (ESI): calcd. for
C15H17N2O [M + H] 241.1335; found 241.1340.
N-Phenylindole-1-carboxamide (2a):[25] White solid. M.p 120–
121 °C; ref. m.p. 124–125 °C. Rf = 0.35 (EtOAc/hexane, 1:9). IR
(KBr): ν = 3244, 3046, 2869, 2785, 1678, 1597, 1529, 1448, 1342,
˜
1258, 1207, 1119, 1011, 884, 811, 744 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 8.21–7.92 (m, 1 H), 7.65 (d, J = 7.2 Hz, 1 H), 7.59–
7.46 (m, 3 H), 7.44–7.34 (m, 4 H), 7.32–7.07 (m, 2 H), 6.81–6.55
(m, 1 H) ppm.
[(1H-Indol-3-yl)piperidin-1-yl]methanone (1e):[22] Brown solid. IR
(KBr): ν = 3190, 2857, 1937, 1896, 1817, 1783, 1725, 1588, 1566,
˜
N-Benzylindole-1-carboxamide (2b):[26] Pink solid. M.p 85–87 °C;
1523, 1447, 1336, 1139, 1025, 854, 811, 745, 694, 629 cm–1. 1H
NMR (300 MHz, [D6]DMSO): δ = 11.53 (br. s., 1 H), 7.65–7.61
(m, 2 H), 7.45–7.42 (m, 1 H), 7.17–7.03 (m, 2 H), 3.77–3.42 (br. s,
4 H), 1.65–1.55 (m, 2 H), 1.55–1.47 (m, 4 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 165.0, 135.1, 127.0, 125.4, 121.3, 119.6,
119.5, 111.4, 109.9, 45.0, 25.5, 23.8 ppm. LC–MS: m/z = 229.19 [M
+ 1]. UPLC purity: 99.78%.
ref. m.p. 85–86 °C. R = 0.35 (EtOAc/hexane, 1:4). IR (KBr): ν =
˜
f
3371, 3144, 3053, 2935, 2784, 2536, 2342, 1674, 1541, 1338, 1208,
1033, 880, 729, 617 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.10
(dd, J = 8.1, 0.9 Hz, 1 H), 7.78–7.53 (m, 1 H), 7.47–7.21 (m, 9 H),
6.63 (dd, J = 3.8, 0.8 Hz, 1 H), 5.88 (br. s., 1 H), 4.67 (d, J =
5.7 Hz, 2 H) ppm.
N-(4-Bromobenzyl)indole-1-carboxyamide (2c): White solid; m.p.
[2-(4-Fluorobenzyl)morpholin-4-yl](1H-indol-3-yl)methanone
(1f):
138–140 °C. R = 0.4 (EtOAc/hexane, 3:7). IR (KBr): ν = 3382,
˜
f
White solid; m.p. 181–183 °C. IR (KBr): ν = 3177, 2867, 1890,
˜
3057, 2934, 2780, 1673, 1537, 1337, 1207, 1031, 1012, 939, 744,
603 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 8.76 (t, J =
5.9 Hz, 1 H), 8.32–8.18 (m, 1 H), 7.88 (d, J = 3.4 Hz, 1 H), 7.68–
7.49 (m, 3 H), 7.38–7.31 (m, 2 H), 7.30–7.13 (m, 2 H), 6.70 (dd, J
= 3.8, 0.8 Hz, 1 H), 4.46 (d, J = 5.7 Hz, 2 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 152.0, 138.9, 135.4, 131.3, 129.5, 129.4,
124.7, 123.7, 122.0, 120.7, 120.0, 115.0, 106.4, 42.9 ppm. HRMS
(ESI): calcd. for C16H14BrN2O [M + H] 330.0284; found 330.0354.
N-(Pyridin-3-yl)indole-1-carboxamide (2d): 1H NMR (300 MHz,
[D6]DMSO): δ = 10.25 (s, 1 H), 8.86 (s, 1 H), 8.36–8.25 (m, 2 H),
8.11–8.05 (m, 2 H), 7.64 (d, J = 7.5 Hz, 1 H), 7.45–7.41 (m, 1 H),
7.34–7.14 (m, 2 H), 6.79 (d, 1 H) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 150.4, 145.2, 142.8, 135.8, 130.2, 129.8, 128.3, 125.9,
124.4, 124.0, 122.8, 121.3, 115.5, 107.3 ppm. HRMS (ESI): calcd.
for C14H12N3O [M + H] 238.0975; found 238.0969.
1825, 1721, 1589, 1548, 1530, 1445, 1391, 1339, 1309, 1214, 1154,
1
1104, 1027, 975, 838, 759 cm–1. H NMR (300 MHz, [D6]DMSO):
δ = 11.58 (br. s, 1 H), 7.64–7.62 (m, 2 H), 7.43–7.40 (m, 1 H), 7.27–
7.22 (m, 2 H), 7.16–7.02 (m, 4 H), 4.18–4.14 (m, 1 H), 4.07–4.03
(m, 1 H), 3.84–3.80 (m, 1 H), 3.63–3.57 (m, 1 H), 3.51–3.37 (m, 1
H), 3.15–3.1 (m, 1 H), 2.85–2.71 (m, 3 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 165.7, 162.5, 159.3, 135.7, 134.0, 133.9,
131.1, 131.0, 128.1, 125.9, 121.9, 120.3, 120.2, 115.0, 114.7, 112.0,
109.4, 76.1, 66.2, 48.7, 44.9, 15.2 ppm. C20H19FN2O2 (338.38):
calcd. C 70.99, H 5.66, N 8.28; found C 70.74, H 5.75, N 8.13.
LC–MS: m/z = 339.25 [M + 1]. UPLC purity: 99.78%.
(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)(1H-indol-3-yl)methanone
(1g):[23] Brown solid; m.p. 195–197 °C. IR (KBr): ν = 3142, 2962,
˜
1922, 1589, 1567, 1524, 1450, 1366, 1337, 1204, 1105, 1063, 960,
946, 911, 801, 772, 743 cm–1. 1H NMR (300 MHz, CDCl3): δ =
10.16 (s, 1 H), 7.68 (d, J = 4.5 Hz, 1 H), 7.28–7.17 (m, 3 H), 7.08
(s, 1 H), 4.0 (s, 4 H), 3.82 (m, 4 H), 1.76 (m, 4 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 167.4, 135.8, 127.4, 125.4, 122.4, 120.8,
119.9, 112.0, 110.6, 107.1, 64.5, 43.4, 35.4 ppm.
N-(4-Fluorophenyl)indole-1-carboxamide (2e):[26] White fluffy solid.
(KBr): ν = 3240, 3040, 1903, 1674, 1610, 1529, 1537, 1411, 1342,
˜
1298, 1209, 1122, 1012, 827, 745 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 8.17–7.98 (m, 1 H), 7.73–7.56 (m, 1 H), 7.53–7.40 (m,
4 H), 7.39–7.22 (m, 2 H), 7.11–6.95 (m, 2 H), 6.65 (dd, J = 3.4,
0.8 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 161.4, 158.2,
149.8, 135.1, 132.9, 130.3, 124.5, 123.9, 122.7, 122.6, 122.5, 122.4,
116.1, 115.7, 114.0, 107.9 ppm.
(4-Benzylpiperazin-1-yl)(1H-indol-3-yl)methanone (1h):[24] Yellow
solid; m.p. 182–185 °C. IR (KBr): ν = 3130, 2810, 1897, 1731, 1589,
˜
1565, 1524, 1446, 1310, 1148, 1008, 935, 864, 745, 702 cm–1. 1H
NMR (300 MHz, [D6]DMSO): δ = 11.59 (br. s., 1 H), 7.75–7.58
(m, 2 H), 7.53–7.39 (m, 1 H), 7.37–7.22 (m, 5 H), 7.20–7.04 (m, 2
[(Indol-1-yl)piperidin-1-yl]methanone (3a): Colourless sticky mass;
H), 3.88–3.59 (m, 4 H), 3.56–3.43 (br. s, 2 H), 2.40 (t, J = 4.7 Hz, 4 Rf = 0.5 (EtOAc/hexane, 1:9). Purified by flash column chromatog-
H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 165.6, 137.9, 135.7, raphy (ethyl acetate/hexane, 3:97). 1H NMR (300 MHz, CDCl3): δ
129.0, 128.3, 128.0, 127.1, 126.0, 122.0, 120.3, 120.2, 112.0, 109.8,
62.0, 52.9, 44.6 ppm.
= 7.68–7.65 (m, 1 H), 7.60–7.57 (m, 1 H), 7.37–7.25 (m, 1 H), 7.21–
7.15 (m, 2 H), 6.59–6.55 (m, 1 H), 3.67–3.45 (m, 4 H), 1.74–1.56
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O30085
/KAP1
Date: 28-03-13 15:51:34
Pages: 11
A. Velavan, S. Sumathi, K. K. Balasubramanian
(br. s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 154.2, 135.4, 3354, 2976, 2928, 2863, 1694, 1618, 1588, 1478, 1454, 1416, 1286,
FULL PAPER
129.4, 126.3, 123.4, 121.6, 120.9, 113.2, 105.5, 47.6, 25.8, 22.6 ppm.
HRMS (ESI): calcd. for C14H16N2ONa [M + Na] 251.1155; found
251.1147. UPLC purity: 99.16%.
1247, 1206, 1170, 1147, 1104, 1034, 1002, 925, 859, 840, 788,
1
769 cm–1. H NMR (300 MHz, CDCl3): δ = 7.17 (d, J = 9.1 Hz, 1
H), 6.96 (d, J = 2.6 Hz, 1 H), 6.80 (dd, J = 8.9, 2.5 Hz, 1 H), 6.27–
6.25 (m, 1 H), 3.83 (s, 3 H), 3.64–3.35 (m, 8 H), 2.44 (s, 3 H), 1.46
(s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 155.2, 154.4, 143.4,
137.1, 130.4, 129.4, 111.5, 111.5, 104.6, 102.6, 80.5, 55.7, 46.0, 43.6,
28.3, 13.5 ppm. HRMS (ESI): calcd. for C20H27N3O4Na [M + Na]
396.1894; found 396.1883. LC–MS: m/z = 374.17 [M + 1]. UPLC
purity: 97.48%.
[(5-Chloroindol-1-yl)piperidin-1-yl]methanone
(3b):
Colourless
sticky substance; R = 0.4 (EtOAc/hexane, 1:9). IR (KBr): ν = 3331,
˜
f
3110, 2940, 2857, 1682, 1606, 1569, 1520, 1423, 1316, 1269, 1200,
1
1066, 987, 870, 789, 761, 718 cm–1. H NMR (300 MHz, CDCl3):
δ = 7.72–7.52 (m, 2 H), 7.33–7.18 (m, 2 H), 6.60–6.43 (m, 1 H), 3.52
(d, J = 6.0 Hz, 4 H), 1.55–1.75 (m, 6 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 153.8, 133.8, 130.5, 125.5, 123.7, 120.4, 120.0, 114.3,
105.0, 47.7, 25.9, 24.3 ppm. HRMS (ESI): calcd. for
C14H15ClN2ONa [M + Na] 285.0765; found 285.0768.
Benzyl 4-(2-Methyl-5-methoxyindole-1-carbonyl)piperazine-1-carb-
oxylate (3h): Brown solid; m.p. 98–100 °C. IR (KBr): ν = 3507,
˜
3066, 3033, 2996, 2934, 2863, 1701, 1617, 1587, 1477, 1452, 1420,
1286, 1220, 1206, 1122, 1102, 1035, 1004, 840, 786, 697, 604 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.38–7.25 (m, 5 H), 7.14 (s, 1
H), 6.96 (d, J = 2.3 Hz, 1 H), 6.80 (dd, J = 9.1, 2.6 Hz, 1 H), 6.27–
6.25 (m, 1 H), 5.15 (s, 2 H), 3.82 (s, 3 H), 3.71–3.58 (m, 2 H), 3.58–
3.41 (m, 6 H), 2.44 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 155.2, 153.4, 137.1, 136.2, 130.3, 129.4, 129.1, 128.6, 128.5, 128.2,
128.0, 127.8, 111.5, 104.8, 102.6, 67.5, 55.7, 45.9, 43.9, 13.6 ppm.
HRMS (ESI): calcd. for C23H25N3O4Na [M + Na] 430.1737; found
430.1743. LC–MS: m/z = 408.25 [M + 1]. UPLC purity: 99.33%.
{[2-(4-Fluorobenzyl)morpholin-4-yl]indol-1-yl}methanone
(3c):
Colourless sticky substance; Rf = 0.3 (EtOAc/hexane, 1:9). Purified
by flash column chromatography (3–4% EtOAc/hexane). IR (KBr):
ν = 3394, 2945, 2891, 1717, 1600, 1430, 1205, 907, 804, 748 cm–1.
˜
1H NMR (300 MHz, CDCl3): δ = 7.80–7.55 (m, 1 H), 7.55–7.42
(m, 1 H), 7.34–7.19 (m, 1 H), 7.19–7.05 (m, 4 H), 6.99–6.82 (m, 2
H), 6.52 (d, J = 3.4 Hz, 1 H), 3.90–3.52 (m, 5 H), 3.38–3.29 (m, 1
H), 2.90–2.82 (m, 1 H), 2.76–2.62 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 163.3, 160.1, 154.2, 135.2, 132.9, 132.6,
130.7, 130.6, 129.6, 126.0, 123.7, 122.1, 121.9, 121.1, 115.4, 115.1,
113.2, 110.9, 106.3, 76.4, 66.6, 66.5, 50.7, 46.8, 38.8, 38.6 ppm.
HRMS (ESI): calcd. for C20H19FN2O2Na [M + Na] 361.1323;
found 361.1313.
[(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)indol-1-yl]methanone (3i): White
solid; m.p. 80–82 °C. Purified by flash column chromatography
(10–20% EtOAc/hexane). IR (KBr): ν = 3331, 3134, 2967, 2879,
˜
2674, 1900, 1675, 1577, 1520, 1424, 1311, 1210, 1129, 1104, 915,
1
775, 757 cm–1. H NMR (300 MHz, CDCl3): δ = 7.71–7.63 (m, 1
[(2-Methylindol-1-yl)piperidin-1-yl]methanone (3d): Colourless
H), 7.63–7.55 (m, 1 H), 7.35–7.25 (m, 2 H), 7.24–7.15 (m, 1 H),
6.60 (dd, J = 3.4, 0.8 Hz, 1 H), 3.99 (s, 4 H), 3.76–3.59 (m, 4 H),
1.86–1.72 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 154.1,
135.3, 129.5, 126.3, 123.6, 121.8, 121.0, 113.2, 106.6, 105.9, 64.5,
44.7, 35.1 ppm. HRMS (ESI): calcd. for C16H19N2O3[M + H]
287.1390; found 287.1387. LC–MS: m/z = 287.17 [M + 1]. UPLC
purity: 100%
sticky mass; R = 0.35 (EtOAc/hexane, 1:9). IR (KBr): ν = 3345,
˜
f
3054, 2996, 2938, 1682, 1561, 1455, 1427, 1328, 1302, 1256, 1217,
999, 742, 784 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.57–7.42
(m, 1 H), 7.34–7.23 (m, 1 H), 7.21–7.06 (m, 2 H), 6.33 (s,1 H),
3.60–3.26 (m, 4 H), 2.49 (s, 3 H), 1.56–1.71 (m, 6 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 152.9, 136.2, 135.6, 128.5, 121.9,
120.9, 119.8, 110.7, 103.8, 46.9, 26.1, 24.3, 13.6 ppm. HRMS (ESI):
calcd. for C15H19N2O [M + H] 243.1492; found 243.1503. UPLC
purity: 94.28%.
[(2-Phenylindol-1-yl)piperidin-1-yl]methanone (3j): Yellow solid;
m.p. 124–125 °C. Rf = 0.4 (EtOAc/hexane, 1:4). Purified by flash
column chromatography (8–10% EtOAc/hexane). IR (KBr): ν =
˜
(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)(2-phenylindol-1-yl)methanone
(3e): White solid; m.p. 136–138 °C. Rf = 0.3 (EtOAc/hexane, 2:3).
3380, 3064, 2936, 2853, 1677, 1443, 1266, 1162, 1021, 994, 803,
757 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.64–7.50 (m, 4 H),
7.45–7.27 (m, 3 H), 7.26–7.16 (m, 2 H), 6.71 (s, 1 H), 3.8–2.5 (br.
s, 4 H), 1.56–0.55 (m, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
152.8, 139.3, 137.0, 132.1, 128.6, 128.4, 128.1, 127.6, 123.3, 121.5,
120.6, 111.5, 104.1, 45.2, 44.8, 25.4, 24.0 ppm. HRMS (ESI): calcd.
for C20H21N2O [M + H] 305.16484; found 305.16433. LC–MS: m/z
= 305.25 [M + 1]. UPLC purity: 100%.
IR (KBr): ν = 3320, 2961, 2879, 2678, 1956, 1896, 1669, 1602, 1427,
˜
1341, 1305, 1146, 1108, 1056, 946, 917, 803, 764, 742 cm–1 1H
.
NMR (300 MHz, CDCl3): δ = 7.69–7.60 (m, 1 H), 7.58–7.36 (m, 6
H), 7.32–7.18 (m, 2 H), 6.74 (s, 1 H), 3.89 (s, 4 H), 3.83–2.74 (br.
s, 4 H), 1.76–0.82 (br. s, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 152.8, 139.2, 137.0, 131.9, 128.6, 128.4, 128.2, 127.5,123.4, 121.6,
120.6, 111.4, 106.3, 104.5, 64.4, 44.1, 34.4 ppm. HRMS (ESI):
calcd. for C22H23N2O3 [M + H] 363.1703; found 363.1683.
(4-Benzylpiperazin-1-yl)(5-bromoindol-1-yl)methanone (3k): Colour-
less sticky mass; Rf = 0.35 (EtOAc/hexane, 3:7). Purified by flash
[2-(4-Fluorobenzyl)morpholin-4-yl](5-methoxyindol-1-yl)methanone
(3f): Colourless sticky mass; Rf = 0.3 (EtOAc/hexane, 1:4). Purified
by flash column chromatography (15% EtOAc/hexane). IR (KBr):
column chromatography (20–30% EtOAc/hexane). IR (CHCl ): ν
˜
3
= –2814, 2771, 1681, 1319, 1270, 1000, 898 cm–1 1H NMR
.
(300 MHz, CDCl3): δ = 7.71 (d, J = 1.9 Hz, 1 H), 7.57 (d, J =
9.1 Hz, 1 H), 7.23–7.39 (m, 8 H), 6.52 (dd, J = 3.4, 0.8 Hz, 1 H),
3.54–3.62 (m, 6 H), 2.61–2.51 (m, 4 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 153.6, 137.4, 134.1, 131.2, 129.1, 128.4, 128.3, 127.3,
127.3, 127.2, 126.5, 123.6, 115.1, 114.7, 105.2, 63.0, 52.5, 46.7 ppm.
HRMS (ESI): calcd. for C20H21BrN3O [M + H] 398.0863; found
398.0862. UPLC purity: 97.26%.
ν = 3394, 2945, 2825, 1717, 1590, 1430, 1205, 907, 804, 747,
˜
1
690 cm–1. H NMR (300 MHz, CDCl3): δ = 7.56 (d, J = 8.7 Hz, 1
H), 7.22 (d, J = 3.4 Hz, 1 H), 7.19–7.10 (m, 2 H), 7.04 (d, J =
2.6 Hz, 1 H), 7.01–6.87 (m, 3 H), 6.51 (dd, J = 3.8, 0.8 Hz, 1 H),
3.97–3.89 (m, 2 H), 3.86 (s, 3 H), 3.84–3.60 (m, 3 H), 3.26–3.18 (m,
1 H), 2.87–2.77 (m, 1 H), 2.76–2.62 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 163.3, 160.1, 155.5, 154.3, 132.6, 132.6,
130.7, 130.6, 130.3, 130.1, 126.6, 115.4, 115.1, 114.0, 111.6, 106.2,
103.2, 66.6, 55.7, 50.7, 46.8, 38.6 ppm. HRMS (ESI): calcd. for
C21H21FN2O3Na [M + Na] 391.1416; found 391.1428.
Ethyl 1-(5-Methoxy-2-methylindole-1-carbonyl)piperidine-4-carb-
oxylate (3l): Green sticky mass. IR (KBr): ν = 2954, 2863, 2834,
˜
2062, 1731, 1682, 1616, 1586, 1478, 1427, 1316, 1206, 1142, 1038,
1002, 945, 924, 839, 800 cm–1. 1H NMR (300 MHz, CDCl3): δ =
tert-Butyl 4-(5-Methoxy-2-methylindole-1-carbonyl)piperazine-1- 7.23 (d, J = 8.7 Hz, 0.7 H), 7.10 (d, J = 9.1 Hz, 0.6 H), 6.96 (d, J
carboxylate (3g): Brown solid; m.p. 132–134 °C. IR (KBr): ν = = 2.6 Hz, 1 H), 6.81 (ddd, J = 8.8, 7.6, 2.5 Hz, 1 H), 6.30–6.23 (m,
˜
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30085
/KAP1
Date: 28-03-13 15:51:34
Pages: 11
Selective Reactions of Indole with Carbamoyl Electrophiles
1 H), 4.15 (q, J = 7.1 Hz, 2 H), 3.96–3.75 (m, 2 H), 3.83 (s, 3 H),
132.9, 132.5, 132.3, 130.8, 130.7, 129.1, 128.7, 126.6, 115.4, 115.3,
3.24–3.02 (m, 2 H), 2.66–2.49 (m, 1 H), 2.44 (s, 1.5 H), 2.43 (s, 1.5 115.1, 112.7, 111.9, 111.8, 111.5, 111.4, 101.9, 101.5, 76.4, 67.2,
H), 1.94–1.64 (m, 4 H), 1.26 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR 66.9, 66.4, 55.8, 50.3, 46.4, 38.8, 38.6, 12.3, 12.1 ppm. HRMS
(75 MHz, CDCl3): δ = 173.9, 155.1, 155.0, 153.6, 153.0, 137.3, (ESI): calcd. for C34H36F2N3O5 [M + H] 604.2618; found 604.2634.
136.9, 130.7, 130.5, 129.4, 129.3, 111.5, 111.4, 104.3, 104.2, 60.7,
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra for all key intermedi-
ates and final products
55.7, 45.5, 45.1, 40.9, 40.4, 28.4, 28.0, 14.1, 13.5, 13.4 ppm. HRMS
(ESI): calcd. for C19H24N2O4Na [M + Na] 367.1628; found
367.1627. UPLC purity: 99.72%.
N-Benzyl-N-methyl-1,2,3,4-tetrahydrocarbazole-9-carboxamide
(3m): Colourless sticky mass. 1H NMR (300 MHz, CDCl3): δ =
7.43 (d, J = 7.2 Hz, 1 H), 7.36–7.30 (m, 3 H), 7.28–7.18 (m, 3 H),
7.15–7.10 (m, 2 H), 4.70–4.60 (m, 1 H), 4.55–4.50 (m, 1 H), 2.89
(s, 3 H), 2.82–2.78 (m, 2 H), 2.69–2.66 (m, 2 H), 1.88–1.86 (m, 4
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 154.6, 136.3, 135.3,
135.0, 128.8, 128.7, 128.0, 127.8, 122.3, 120.8, 118.1, 113.9, 111.2,
53.9, 35.7, 23.1, 23.0, 22.7, 20.8 ppm. HRMS (ESI): calcd. for
C21H23N2O [M + H] 319.1805; found 341.1814.
[1] For selected recent reviews on Friedel–Crafts-type reactions
with indoles, see: a) C. C. J. Loh, D. Enders, Angew. Chem.
2011, 123, 46; Angew. Chem. Int. Ed. 2011, 51, 46–48; b) G.
Bartoli, G. Bencivenni, R. Dalpozzo, Chem. Soc. Rev. 2010, 39,
4449–4465.
[2] a) A. Velavan, S. Sumathi, K. K. Balasubramanian, Org. Bio-
mol. Chem. 2012, 10, 6420–6431; b) S.-H. Lee, H. Matsushita,
G. Koch, J. Zimmermann, B. Clapham, K. D. Janda, J. Comb.
Chem. 2004, 6, 822–827.
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G. M. Thomforde, D. D. Burton, J. Rubin, H. C. Pitot, A. R.
Zinsmeister, Gut 1998, 42, 628–634; b) S. K. Davidsen, J. B.
Summers, D. H. Albert, J. H. Holms, H. R. Heyman, T. J. Ma-
goc, R. G. Conway, D. A. Rhein, G. W. Carter, J. Med. Chem.
1994, 37, 4423–4429; c) J. Hynes Jr., K. Leftheris, H. Wu, C.
Pandit, P. Chen, D. J. Norris, B.-C. Chen, R. Zhao, P. A. Ki-
ener, X. Chen, L. A. Turk, V. Patil-Koota, K. W. McIntyre,
D. J. Shuster, K. M. Gillooly, Bioorg. Med. Chem. Lett. 2002,
12, 2399–2402; d) S. T. Wrobleski, P. Chen, H. Hynes Jr., S.
Lin, D. J. Norris, C. R. Pandit, S. Spergel, H. Wu, J. S. Tokar-
ski, X. Chen, K. M. Gillooly, P. A. Kiener, K. W. McIntyre, V.
Patilkoota, D. J. Shuster, L. A. Turk, G. Yang, L. Leftheris, J.
Med. Chem. 2003, 46, 2110–2116.
Ethyl 1-(Indole-1-carbonyl)piperidine-4-carboxylate (4d): Green
sticky mass. IR (KBr): ν = 3441, 2956, 2105, 1901, 1731, 1688,
˜
1608, 1524, 1424, 1320, 1125, 1041, 944, 885, 861, 751, 685,
621 cm–1 1H NMR (300 MHz, CDCl3): δ = 7.68 (dd, J = 8.3,
.
0.8 Hz, 1 H), 7.64–7.52 (m, 1 H), 7.39–7.28 (m, 2 H), 7.25–7.18 (m,
1 H), 6.61 (dd, J = 3.4, 0.8 Hz, 1 H), 4.20 (q, J = 7.2 Hz, 2 H),
4.08–3.96 (m, 2 H), 3.25–3.11 (m, 2 H), 2.42–2.66 (m, 1 H), 2.16–
1.95 (m, 2 H), 1.95–1.77 (m, 2 H), 1.26 (t, J = 7.2 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 174.0, 154.3, 135.3, 129.5, 126.2,
123.6, 121.9, 121.0, 131.2, 106.0, 60.7, 46.0, 40.8, 28.0, 14.2 ppm.
HRMS (ESI): calcd. for C17H20N2O3Na [M + Na] 323.1366; found
323.1355.
Methyl 1-(Indole-1-carbonyl)piperidine-4-carboxylate (4e): Green
[4] a) B. J. Mavunkel, J. J. Perumattam, X. Tan, G. R. Luedtke, Q.
Lu, D. Lim, D. Kizer, S. Dugar, S. Chakravarty, Y.-J. Xu, J.
Jung, A. Liclican, D. E. Levy, J. Tabora, Bioorg. Med. Chem.
Lett. 2010, 20, 1059–1062; b) L. R. Marcin, M. A. Higgins,
F. C. Zusi, Y. Zhang, M. F. Dee, M. F. Parker, J. K. Muckel-
bauer, D. M. Camac, P. E. Morin, V. Ramamurthy, A. J.
Tebben, K. A. Lentz, J. E. Grace, J. A. Marcinkeviciene, L. M.
Kopcho, C. R. Burton, D. M. Barten, J. H. Toyn, J. E. Mered-
ith, C. F. Albright, J. J. Bronson, J. E. Macor, L. A. Thompson,
Bioorg. Med. Chem. Lett. 2011, 21, 537–541; c) Z.-W. Cai, D.
Wei, G. M. Schroeder, L. A. M. Cornelius, K. Kim, X.-T.
Chen, R. J. Schmidt, D. K. Williams, J. S. Tokarski, Y. An, J. S.
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L. J. Lombardo, J. Fargnoli, R. M. Borzilleri, Bioorg. Med.
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7621–7623; d) R. Todd, M. M. Hossain, Synthesis 2009, 1846–
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[6] a) E. Reimann, T. Haßler, H. Lotter, Arch. Pharm. (Weinheim)
1990, 323, 255–258; b) G. Malesani, G. Chiarelotto, M. G. Fer-
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1942; b) G. Mehta, Synthesis 1978, 374–376; c) M. Seefelder,
Chem. Ber. 1963, 96, 3243–3253; d) K. Esses-Reiter, J. Rite, J.
Heterocycl. Chem. 2000, 37, 927–933; e) R. V. Smaliy, A. A.
Chaikovskaya, A. M. Pinchuk, A. A. Tolmachev, Synthesis
2003, 2525–2529.
sticky mass. IR (KBr): ν = 3448, 2953, 2104, 1902, 1731, 1683,
˜
1524, 1452, 1421, 1320, 1267, 1125, 1040, 943, 884, 831, 751, 685,
621 cm–1 1H NMR (300 MHz, CDCl3): δ = 7.68 (dd, J = 8.3,
.
0.8 Hz, 1 H), 7.64–7.52 (m, 1 H), 7.39–7.28 (m, 2 H), 7.25–7.18 (m,
1 H), 6.61 (dd, J = 3.4, 0.8 Hz, 1 H), 4.08–3.96 (m, 2 H), 3.70 (s,
3 H), 3.25–3.11 (m, 2 H), 2.66–2.42 (m, 1 H), 2.16–1.95 (m, 2 H),
1.95–1.75 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 174.4,
154.3, 135.3, 129.5, 126.2, 123.6, 121.9, 121.0, 131.1, 106.0, 51.9,
46.0, 40.8, 40.7, 28.0, 27.8 ppm. HRMS (ESI): calcd. for
C16H19N2O3 [M + H] 287.1390; found 287.1384.
[2-(4-Fluorobenzyl)morpholin-4-yl](5-methoxy-2-methyl-1H-indol-3-
yl)methanone (5c): White solid; m.p. 60–62 °C. IR (KBr): ν = 3244,
˜
2857, 2370, 1896, 1747, 1603, 1449, 1354, 1270, 1219, 1173, 1105,
1033, 972, 836, 764 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.82
(s, 1 H), 7.13 (dd, J = 8.3, 5.7 Hz, 2 H), 7.05 (d, J = 8.7 Hz, 1 H),
7.00–6.85 (m, 3 H), 6.74 (dd, J = 8.7, 2.6 Hz, 1 H), 4.21–3.84 (m,
3 H), 3.80 (s, 3 H), 3.74–3.56 (m, 2 H), 3.25–3.05 (br. s,1 H), 2.96–
2.67 (m, 3 H), 2.24 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 163.3, 160.0, 154.9, 138.3, 133.1, 130.7, 130.6, 129.7, 126.7, 115.3,
115.0, 111.6, 111.4, 107.6, 101.1, 76.6, 67.2, 55.8, 49.2, 46.4, 38.8,
12.6 ppm. HRMS (ESI): calcd. for C22H24FN2O3 [M + H]
383.1765; found 383.1751. LC–MS: m/z = 381.33 [M – 1]. UPLC
purity: 100%.
{1-[2-(4-Fluorobenzyl)morpholine-4-carbonyl]-5-methoxy-2-methyl-
1H-indol-3-yl}[2-(4-fluorobenzyl)morpholin-4-yl]methanone (5d):
White solid; m.p. 92–95 °C. IR (KBr): ν = 2924, 2856, 1689, 1625,
˜
1530, 1424, 1330, 1219, 1105, 1034, 835, 761 cm–1 1H NMR
.
[8] a) G. A. M. Giardina, M. Artico, S. Cavagnera, A. Cerri, E.
Consolandi, S. Gagliardi, D. Graziani, M. Grugni, D. W. P.
Hay, M. A. Luttmann, R. Mena, L. F. Raveglia, R. Rigolio,
H. M. Sarau, D. B. Schmidt, G. Zanoni, C. Farina, Farmaco
1999, 54, 364–374; b) J. Bergman, R. Carlsson, B. Sjöberg, J.
Heterocycl. Chem. 1977, 14, 1123–1134; c) R. Zhao, B. Wang,
(300 MHz, CDCl3): δ = 7.36–7.19 (m, 2 H), 7.19–7.11 (m, 3 H),
7.11–6.91 (m, 4 H), 6.91–6.53 (m, 2 H), 4.55–4.05 (br. s, 1 H), 4.1–
3.74 (m, 5 H), 3.73–3.30 (m, 6 H), 3.29–3.06 (m, 3 H), 3.05–2.61
(m, 6 H), 2.55–2.43 (br. m, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 166.4, 166.1, 163.4, 163.3, 160.1, 155.8, 152.6, 151.8,137.1,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O30085
/KAP1
Date: 28-03-13 15:51:35
Pages: 11
A. Velavan, S. Sumathi, K. K. Balasubramanian
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Received: January 17, 2013
Published Online: ᭿
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Job/Unit: O30085
/KAP1
Date: 28-03-13 15:51:35
Pages: 11
Selective Reactions of Indole with Carbamoyl Electrophiles
Synthetic Methods
A. Velavan, S. Sumathi,*
K. K. Balasubramanian* .................. 1–11
AlMe3-Mediated Regio- and Chemoselec-
tive Reactions of Indole with Carbamoyl
Electrophiles
Keywords: Synthetic methods / Acylation /
Regioselectivity / Chemoselectivity / Nitro-
gen heterocycles / Lewis acids / Aluminum
The regioselective one-step synthesis of
indole-3-carboxamide was achieved from
the reaction between indole and a tertiary
carbamoylimidazole in the presence of
AlMe3. Alternatively the reaction was di-
verted to the indole nitrogen when an alu-
minium ate complex was employed. Sec-
ondary carbamoyl electrophiles in the pres-
ence of AlMe3 exclusively yielded trisubsti-
tuted ureas.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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