A Cascade C–H-Functionalization/Cyclization Reaction of Indoles with α-Halo or α-Sulfonyloxy Ketones for the Synthesis of Dihydropyrimidoindolone Derivatives

Article abstract of DOI:10.1002/ejoc.201600885

A new cascade C–H-functionalization/cyclization reaction of N-carbamoylindoles 1 with α-halo, α-mesyloxy, or α-tosyloxy ketones 2 has been developed under rhodium(III) catalysis, leading to dihydropyrimido[1,6-a]indolone derivatives 3 in moderate to excellent yields.

Full text of DOI:10.1002/ejoc.201600885

DOI: 10.1002/ejoc.201600885
Full Paper
Cascade Reactions
A Cascade C–H-Functionalization/Cyclization Reaction of Indoles
with α-Halo or α-Sulfonyloxy Ketones for the Synthesis of
Dihydropyrimidoindolone Derivatives
Zi-Jun Wu,[a] Ya-Qiong Li,[a] and Zhi-Zhen Huang*[a,b]
Abstract: A new cascade C–H-functionalization/cyclization re- talysis, leading to dihydropyrimido[1,6-a]indolone derivatives 3
action of N-carbamoylindoles 1 with α-halo, α-mesyloxy, or α-
tosyloxy ketones 2 has been developed under rhodium(III) ca-
in moderate to excellent yields.
Introduction
cent results on the cascade α-C–H-functionalization/cyclization
reaction of N-carbamoylindoles 1 with α-halo or α-sulfonyloxy
ketones 2 for the synthesis of dihydropyrimido[1,6-a]indolone
derivatives 3.
Recently, much attention has been given to the C–H functionali-
zation of indoles.[1] Very recently, some work has been done
on the α-C–H functionalization of indoles directed by an N-
carbamoyl group under rhodium(III) catalysis.[2] In 2014, the Cui
group developed cascade α-C–H-functionalization/cyclization
reactions of N-carbamoylindoles 1 with arylboronic acids, alk-
ynes, alkenes, or diazo carboxylate derivatives using rhodium
catalysis (Scheme 1).[3] In 2015, Zeng and co-workers reported
an α-C–H-functionalization reaction of N-carbamoylindoles with
alkynes to give alkenylated indoles using rhodium catalysis.[4]
However, to the best of our knowledge, the α-C–H functionali-
zation of indoles with α-halo ketones still remains unknown.
Chi et al. reported that free indoles underwent a coupling reac-
tion with α-halo ketones to give ꢀ-C–H-functionalized indoles.[5]
Considering that an N-carbamoyl group can direct and assist
in the activation of an α-C–H bond,[3,4] we embarked on an
investigation of the α-C–H functionalization of N-carbamoyl-
indoles 1 with α-halo ketones 2. In 2014, Glorius and co-work-
ers reported a cascade C–H-functionalization/cyclization reac-
tion of benzamides with α-mesyloxy, α-tosyloxy, or α-chloro
ketones by α-C–H activation to give isoquinolones under
rhodium catalysis.[6] Thus, we further envisioned that the α-C–
H-functionalization products of N-carbamoylindoles with α-halo
ketones, i.e., α-indolyl ketones, might subsequently undergo
cyclization through intramolecular nucleophilic attack of the
nitrogen atom in the N-carbamoyl group onto the carbonyl
group in the ketone moiety. This would produce dihydropyr-
imido[1,6-a]indolone derivatives 3 (Scheme 1), which have im-
portant biological activities.[7] In this paper, we present our re-
Scheme 1. Cascade C–H-functionalization/cyclization reactions of N-carb-
amoylindoles.
Results and Discussion
[a] Department of Chemistry, Zhejiang University,
Hangzhou 310058, China
Initially, N-carbamoylindole 1a and α-chloro ketone 2aC (C rep-
resents chloro) were chosen as model substrates to explore and
optimize the cascade C–H-functionalization/cyclization reac-
tion. When [Cp*RhCl2]2 (Cp* = 1,2,3,4,5-pentamethylcyclopenta-
dienyl) and CsOAc were used as a transition-metal catalyst and
an additive, respectively, the expected cascade reaction took
E-mail: huangzhizhen@zju.edu.cn
http://mypage.zju.edu.cn/huangzhizhen
[b] Jiangsu Coben Pharmaceutical Co. Ltd,
Qidong, Jiangsu, P. R. China
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600885.
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place in MeOH at 60 °C, and the desired dihydropyrimido[1,6- ketones also underwent the cascade reaction with N-
a]indolone derivative (i.e., 3aa) was obtained, albeit in a low carbamoylindole 1a expediently, producing dihydropyrimido-
yield (Table 1, Entry 1). When [Rh(COD)2Cl]2 (COD = cyclooctadi- [1,6-a]indolone derivatives 3ag and 3ah in excellent yields. α-
enyl) or Pd(OAc)2 was used as catalyst, product 3aa was not Mesyloxy and α-tosyloxy aromatic ketones 2aM and 2aT also
obtained (Table 1, Entries 2 and 3). When NaOAc was used as readily underwent the cascade reaction with 1a to give the
an additive instead of CsOAc, the yield of 3aa increased from desired dihydropyrimido[1,6-a]indolone derivative (i.e., 3aa).
35 to 95 % (Table 1, Entry 5).[3b] Optimization experiments with α-Mesyloxy aromatic ketones 2hM and 2iM, bearing electron-
different solvents revealed that a solvent with a higher polarity withdrawing groups on the benzene rings, seem more liable to
is beneficial to the cascade reaction (Table 1, compare Entries 5 undergo the cascade reaction than those (2eM and 2jM) bear-
and 6 with Entries 7 and 8). The effect of temperature on the ing electron-donating groups. Switching the directing group
reaction was also studied, and lower yields of 3aa were ob- from an N-methoxycarbamoyl group to an N-ethoxycarbamoyl
tained when the temperature was either higher or lower than group also led to dihydropyrimido[1,6-a]indolone derivative
60 °C (Table 1, Entries 9 and 10). When the cascade reaction 3ha in a satisfactory yield.
was carried out under air instead of nitrogen, the yield of 3aa
decreased remarkably (Table 1, compare Entry 5 with Entry 11).
In the absence of either [RhCp*Cl2]2 or NaOAc, none of the
dihydropyrimido[1,6-a]indolone derivative (i.e., 3aa) was ob-
tained (Table 1, Entries 12 and 13).
Table 1. Optimization of the cascade C–H-functionalization/cyclization reac-
tion of N-carbamoylindole 1a with α-chloro ketone 2aC.[a]
Figure 1. X-ray structure of dihydropyrimido[1,6-a]indolone derivative 3da.
Further experiments indicated that in the presence of AlCl3,
Entry
[M]
Additive (equiv.)
Solvent
Yield [%][b]
dihydropyrimido[1,6-a]indolone derivative 3aa was dehydrated
in MeOH at room temperature to give pyrimido[1,6-a]indolone
4aa in good yield (Scheme 2). However, pyrimido[1,6-a]indol-
one 4aa is unstable at room temperature.
1
2
3
4
5
6
7
8
9
10
11
12
13
[Cp*RhCl2]2
Pd(OAc)2
CsOAc (1.2)
CsOAc (1.2)
CsOAc (1.2)
Cu(OAc)2 (1.2)
NaOAc (1.2)
NaOAc (1.2)
NaOAc (1.2)
NaOAc (1.2)
NaOAc (1.2)
NaOAc (1.2)
NaOAc(1.2)
NaOAc(1.2)
–
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
35
0
0
trace
95
90
[Rh(COD)2Cl]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
–
MeCN
DCE
9
trace
73[c]
trace[d]
45[e]
0
MeOH
MeOH
MeOH
MeOH
MeOH
Scheme 2. Dehydration reaction of dihydropyrimido[1,6-a]indolone derivative
3aa for the formation of pyrimido[1,6-a]indolone 4aa.
[Cp*RhCl2]2
0
[a] Reaction conditions: 1a (0.10 mmol), 2aC (0.12 mmol), [M] (2 mmol-%),
solvent (1 mL), N2, 60 °C, 18 h. DCE = 1,2-dichloroethane. [b] Isolated yields.
[c] At 90 °C. [d] At 25 °C. [e] Under air.
A plausible mechanism for the cascade C–H-functionaliza-
tion/cyclization reaction is proposed. [Cp*RhCl2]2 is not a typical
Lewis acid catalyst for Friedel–Crafts alkylation reactions. If it
After screening the reaction conditions, we concluded that had functioned as a Lewis acid catalyst in the cascade reaction,
the optimized reaction should be carried out using [Cp*RhCl2]2 ꢀ-alkylated products would have been observed instead of α-
as a catalyst and NaOAc as an additive at 60 °C in methanol alkylated products 3; ꢀ-alkylated indoles are formed more usu-
under nitrogen. We investigated the substrate scope of the re- ally than α-alkylated indoles in Friedel–Crafts reactions of ind-
action under the optimized conditions, and found that various oles with alkyl halides.[5,8] When N-methylindole was used in-
N-carbamoylindoles 1 were able to undergo the cascade C– stead of N-carbamoylindole 1a, none of the α-C–H-coupling
H-functionalization/cyclization reaction smoothly with α-chloro product was observed (Scheme 3). The result of this control
phenyl ketone 2aC, leading to dihydropyrimido[1,6-a]indolone experiment supports the idea that the N-carbamoyl group may
derivatives 3aa–3ga in moderate to excellent yields (Table 2). direct and assist the α-C–H activation by rhodium catalysis in
The structure of dihydropyrimido[1,6-a]indolone derivative 3da the cascade C–H-functionalization/cyclization reaction.[3] Thus,
was further determined by X-ray crystallography (Figure 1). we tend towards a mechanism that proceeds through α-C–H
α-Chloro aromatic ketones 2bC–2eC bearing different substitu- activation by rhodium catalysis rather than via a carbocationic
ents on the benzene rings led to dihydropyrimido[1,6-a]- intermediate by Lewis acid catalysis. The plausible mechanism
indolone derivatives 3ad–3ef in good yields. α-Chloro aliphatic is as follows (Scheme 4). First, NaOAc reacts with [Cp*RhCl2]2 to
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Table 2. Cascade C–H-functionalization/cyclization reactions of N-carbamoylindoles 1a–1h with α-chloro, α-mesyloxy, or α-tosyloxy ketones 2a–2m.[a,b]
[a] Reaction conditions: 1 (0.10 mmol), 2 (0.12 mmol), [Cp*RhCl2]2 (2 mmol-%), NaOAc (0.12 mmol), MeOH (1 mL), N2, 60 °C, 18 h. [b] Isolated yields.
generate Cp*Rh(OAc)2.[3b] The carbamoyl group in N-carbamo- α-chloro ketone 2aC nucleophilically to produce α-indolyl ket-
ylindole 1a directs and assists the α-C–H-bond activation to one intermediate B.[6] Finally, the nitrogen atom in the N-car-
form rhodacycle A. The α-carbon atom in rhodacycle A attacks bamoyl group carries out an intramolecular nucleophilic addi-
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(0.10 mmol), α-chloro or α-sulfonyloxy ketone 2 (0.12 mmol),
[Cp*RhCl2]2 (1.2 mg, 2 mol-%), and NaOAc (9.8 mg, 1.2 equiv) was
stirred under nitrogen at 60 °C for 18 h. After this time, the mixture
was cooled to room temperature, and then concentrated under vac-
uum. The residue was purified by column chromatography (silica
gel; petroleum ether/ethyl acetate) to give dihydropyrimidoindol-
one derivative 3aa–3hj.
tion to the carbonyl group in intermediate B to give the desired
dihydropyrimidoindolone derivative (i.e., 3aa).
3-Hydroxy-2-methoxy-3-phenyl-3,4-dihydropyrimido[1,6-a]-
indol-1(2H)-one (3aa): Yellow solid (95 %); m.p. 165–167 °C. H
Scheme 3. Control experiment.
1
NMR (400 MHz, CDCl3): δ = 8.37 (d, J = 8.0 Hz, 1 H), 7.64 (d, J =
7.2 Hz, 2 H), 7.47–7.37 (m, 4 H), 7.30–7.21 (m, 2 H), 6.30 (s, 1 H),
4.13 (br., 1 H), 3.69 (s, 3 H), 3.60 (d, J = 16.4 Hz, 1 H), 3.45 (d, J =
16.4 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.9, 140.9,
135.6, 131.2, 130.2, 128.8, 128.6, 125.9, 124.2, 123.5, 120.3, 115.6,
105.4, 91.9, 64.7, 38.0 ppm. HRMS (ESI): calcd. for [C18H15N2O3]–
307.1088; found 307.1095.
3-Hydroxy-2-methoxy-5-methyl-3-phenyl-3,4-dihydropyr-
imido[1,6-a]indol-1(2H)-one (3ba): Pale yellow solid (86 %); m.p.
1
200–202 °C. H NMR (400 MHz, [D6]DMSO): δ = 8.27 (d, J = 7.6 Hz,
1 H), 7.66 (d, J = 7.2 Hz, 2 H), 7.50 (d, J = 7.2 Hz, 1 H), 7.43 (t, J =
7.6 Hz, 2 H), 7.38–7.35 (m, 2 H), 7.32–7.24 (m, 2 H), 3.62 (s, 3 H),
3.61 (d, J = 16.0 Hz, 1 H), 3.33 (d, J = 16.4 Hz, 1 H), 2.09 (s, 3 H)
ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 152.7, 141.5, 134.3, 130.9,
128.2, 128.0, 126.2, 123.8, 122.9, 118.5, 114.5, 111.5, 91.0, 63.6, 36.7,
7.9 ppm. HRMS (ESI): calcd. for [C19H18N2O3 + Na]+ 345.1210; found
345.1194.
3-Hydroxy-2-methoxy-6-methyl-3-phenyl-3,4-dihydropyr-
imido[1,6-a]indol-1(2H)-one (3ca): White solid (83 %); m.p. 192–
1
193 °C. H NMR (400 MHz, [D6]DMSO): δ = 8.10 (d, J = 8.0 Hz, 1 H),
7.62 (d, J = 7.2 Hz, 2 H), 7.43–7.33 (m, 4 H), 7.17 (t, J = 7.8 Hz, 1 H),
7.03 (d, J = 7.2 Hz, 1 H), 6.46 (s, 1 H), 3.74 (d, J = 16.0 Hz, 1 H), 3.64
(s, 3 H), 3.38 (d, J = 16.0 Hz, 1 H), 2.42 (s, 3 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 152.4, 141.2, 134.5, 131.8, 129.4, 129.1,
128.1, 128.0, 126.1, 123.6, 123.4, 112.2, 102.9, 91.1, 63.6, 38.3,
18.1 ppm. HRMS (ESI): calcd. for [C19H18N2O3 + Na]+ 345.1210; found
345.1193.
Scheme 4. Plausible mechanism for the cascade C–H-functionalization/
cyclization reaction.
7-Chloro-3-hydroxy-2-methoxy-3-phenyl-3,4-dihydropyr-
imido[1,6-a]indol-1(2H)-one (3da): White solid (89 %); m.p. 205–
1
208 °C. H NMR (400 MHz, [D6]DMSO): δ = 8.25 (d, J = 8.8 Hz, 1 H),
Conclusions
7.64–7.62 (m, 3 H), 7.44–7.34 (m, 4 H), 7.31 (dd, J = 8.8, J = 2.0 Hz,
1 H), 6.44 (s, 1 H), 3.78 (d, J = 16.4 Hz, 1 H), 3.62 (s, 3 H), 3.39 (d,
J = 16.4 Hz, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 152.1,
We have developed a new cascade C–H-functionalization/cycli-
zation reaction of N-carbamoyl indoles 1 with α-halo or α-sulf-
onyloxy ketones 2. We found that under rhodium(III) catalysis, 140.9, 134.3, 133.2, 131.4, 128.2, 128.0, 127.4, 126.1, 123.3, 119.7,
115.8, 103.8, 91.1, 63.6, 38.1 ppm. HRMS (ESI): calcd. for
various N-carbamoylindoles 1a–1h were able to undergo the
cascade C–H-functionalization/cyclization reaction smoothly
with α-chloro, α-mesyloxy, or α-tosyloxy ketones 2 to give the
desired dihydropyrimido[1,6-a]indolone derivatives (i.e., 3aa–
3hj) in moderate to excellent yields. A plausible mechanism
proceeding through α-C–H functionalization directed by the N-
carbamoyl group in substrate 1 is postulated for the cascade
reaction. The cascade C–H-functionalization/cyclization reaction
may have applications in the synthesis of related pharmaceuti-
cals in the future.
[C18H15ClN2O3 + Na]+ 365.0663; found 365.0652.
8-Chloro-3-hydroxy-2-methoxy-3-phenyl-3,4-dihydropyr-
imido[1,6-a]indol-1(2H)-one (3ea): Yellow solid (90 %); m.p. 203–
1
205 °C. H NMR (400 MHz, [D6]DMSO): δ = 8.28 (d, J = 2.0 Hz, 1 H),
7.63 (d, J = 7.6 Hz, 2 H), 7.57 (d, J = 8.4 Hz, 1 H), 7.44–7.35 (m, 4 H),
7.28 (dd, J = 8.4, J = 2.0 Hz, 1 H), 6.48 (s, 1 H), 3.73 (d, J = 16.4 Hz,
1 H), 3.63 (s, 3 H), 3.38 (d, J = 15.6 Hz, 1 H) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 152.1, 140.9, 135.0, 133.6, 128.7, 128.2, 128.0, 127.9,
126.1, 123.3, 121.6, 114.2, 104.2, 91.1, 63.7, 38.2 ppm. HRMS (ESI):
calcd. for [C18H15ClN2O3 + Na]+ 365.0663; found 365.0646.
7-Fluoro-3-hydroxy-2-methoxy-3-phenyl-3,4-dihydropyr-
imido[1,6-a]indol-1(2H)-one (3fa): Pale yellow solid (76 %); m.p.
198–200 °C. 1H NMR (400 MHz, [D6]DMSO): δ = 8.27 (dd, J = 8.8, J =
4.8 Hz, 1 H), 7.65 (d, J = 7.2 Hz, 2 H), 7.45–7.35 (m, 5 H), 7.16–7.11
(m, 1 H), 6.45 (s, 1 H), 3.77 (d, J = 16.4 Hz, 1 H), 3.64 (s, 3 H), 3.39
(d, J = 16.0 Hz, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 158.8
(d, J = 235.2 Hz), 152.2, 141.0, 134.5, 131.3, 131.1 (d, J = 10.3 Hz),
Experimental Section
General Procedure for the Cascade C–H-Functionalization/Cycli-
zation Reaction of N-Carbamoyl Indoles 1 with α-Chloro or α-
Sulfonyloxy Ketones 2 for the Synthesis of Dihydropyrimido-
indolone Derivatives 3: A mixture of N-carbamoylindole 1a–1h
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128.2, 128.0, 126.2, 115.6 (d, J = 9.3 Hz), 110.9 (d, J = 24.9 Hz), 105.9
Methyl 2-(3-Hydroxy-2-methoxy-1-oxo-1,2,3,4-tetrahydro-
(d, J = 23.9 Hz), 104.2 (d, J = 3.8 Hz), 91.2, 63.6, 38.2 ppm. 19F pyrimido[1,6-a]indol-3-yl)acetate (3ag): White solid (90 %); m.p.
1
NMR (376 MHz, [D6]DMSO): δ = –119.99 ppm. HRMS (ESI): calcd. for
168–170 °C. H NMR (400 MHz, [D6]DMSO): δ = 8.21 (d, J = 7.6 Hz,
1 H), 7.53 (d, J = 7.2 Hz, 1 H), 7.27–7.20 (m, 2 H), 7.00 (s, 1 H), 6.50
(s, 1 H), 3.83 (s, 3 H), 3.66 (d, J = 16.8 Hz, 1 H), 3.62 (s, 3 H), 3.47 (d,
J = 16.4 Hz, 1 H), 3.06 (s, 2 H) ppm. 13C NMR (100 MHz, [D6]DMSO):
δ = 169.3, 151.3, 134.6, 132.1, 129.8, 123.4, 123.0, 120.1, 114.5, 104.5,
87.9, 64.1, 51.6, 41.1, 34.0 ppm. HRMS (ESI): calcd. for [C15H16N2O5
+ Na]+ 327.0951; found 327.0935.
[C18H15FN2O3 + Na]+ 349.0959; found 349.0939.
3-Hydroxy-2,7-dimethoxy-3-phenyl-3,4-dihydropyrimido-
[1,6-a]indol-1(2H)-one (3ga): White solid (66 %); m.p. 206–209 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 8.13 (d, J = 8.8 Hz, 1 H), 7.62 (d,
J = 7.6 Hz, 2 H), 7.43–7.31 (m, 4 H), 7.06 (d, J = 2.4 Hz, 1 H), 6.88
(dd, J = 9.0, J = 2.6 Hz, 1 H), 6.35 (s, 1 H), 3.78 (s, 3 H), 3.72 (d, J =
16.4 Hz, 1 H), 3.61 (s, 3 H), 3.34 (d, J = 16.0 Hz, 1 H) ppm. 13C NMR
3-Hydroxy-2-methoxy-3-(4-nitrophenyl)-3,4-dihydropyr-
(100 MHz, [D6]DMSO): δ = 155.8, 152.3, 141.2, 133.1, 130.9, 129.3, imido[1,6-a]indol-1(2H)-one (3ah): Yellow solid (88 %); m.p. 201–
1
128.1, 127.9, 126.1, 115.1, 111.8, 104.2, 103.2, 91.1, 63.6, 55.3,
38.2 ppm. HRMS (ESI): calcd. for [C19H18N2O4 + Na]+ 361.1159; found
361.1142.
203 °C. H NMR (400 MHz, [D6]DMSO): δ = 8.31–8.26 (m, 3 H), 7.95
(d, J = 8.8 Hz, 2 H), 7.68 (s, 1 H), 7.56 (d, J = 7.2 Hz, 1 H), 7.32–7.22
(m, 2 H), 6.48 (s, 1 H), 3.82 (d, J = 16.0 Hz, 1 H), 3.36 (s, 3 H), 3.40
(d, J = 16.4 Hz, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 152.1,
148.3, 147.3, 134.8, 132.1, 129.9, 127.8, 123.7, 123.23, 123.17, 120.3,
114.6, 104.7, 90.6, 63.7, 37.7 ppm. HRMS (ESI): calcd. for [C18H15N3O5
+ Na]+ 376.0904; found 376.0892.
3-(4-Fluorophenyl)-3-hydroxy-2-methoxy-3,4-dihydropyr-
imido[1,6-a]indol-1(2H)-one (3ab): Yellow solid (76 %); m.p. 184–
1
186 °C. H NMR (400 MHz, [D6]DMSO): δ = 8.31 (d, J = 8.0 Hz, 1 H),
7.72 (dd, J = 8.2, J = 5.4 Hz, 2 H), 7.58 (d, J = 7.2 Hz, 1 H), 7.44 (s, 1
H), 7.34–7.25 (m, 4 H), 6.49 (s, 1 H), 3.81 (d, J = 16.0 Hz, 1 H), 3.66
3-(4-Bromophenyl)-3-hydroxy-2-methoxy-3,4-dihydropyr-
(s, 3 H), 3.41 (d, J = 15.6 Hz, 1 H) ppm. 13C NMR (100 MHz, imido[1,6-a]indol-1(2H)-one (3ai): White solid (86 %); m.p. 206–
1
[D6]DMSO): δ = 161.8 (d, J = 242.9 Hz), 152.3, 137.4 (d, J = 2.9 Hz),
134.8, 132.4, 129.9, 128.5 (d, J = 8.3 Hz), 123.5, 123.1, 120.3, 114.8,
114.6 (d, J = 4.8 Hz), 104.4, 90.6, 63.6, 38.1 ppm. 19F NMR (376 MHz,
207 °C. H NMR (400 MHz, [D6]DMSO): δ = 8.26 (d, J = 8.0 Hz, 1 H),
7.64–7.58 (m, 4 H), 7.54 (d, J = 7.6 Hz, 1 H), 7.43 (s, 1 H), 7.30–7.21
(m, 2 H), 6.45 (s, 1 H), 3.75 (d, J = 16.4 Hz, 1 H), 3.63 (s, 3 H), 3.36
[D6]DMSO): δ = –114.50 ppm. HRMS (ESI): calcd. for [C18H15FN2O3 + (d, J = 16.4 Hz, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 152.2,
Na]+ 349.0959; found 349.0944.
140.6, 134.7, 132.3, 130.9, 129.9, 128.5, 123.5, 123.1, 121.5, 120.3,
114.6, 104.4, 90.7, 63.6, 37.9 ppm. HRMS (ESI): calcd. for
[C18H14BrN2O3]– 385.0193; found 385.0200.
3-(4-Chlorophenyl)-3-hydroxy-2-methoxy-3,4-dihydropyr-
imido[1,6-a]indol-1(2H)-one (3ac): White solid (91 %); m.p. 197–
1
200 °C. H NMR (400 MHz, [D6]DMSO): δ = 8.28 (d, J = 8.0 Hz, 1 H),
3-Hydroxy-2-methoxy-3-(4-methoxyphenyl)-3,4-dihydropyr-
7.67 (d, J = 7.6 Hz, 2 H), 7.56–7.44 (m, 4 H), 7.31–7.24 (m, 2 H), 6.46
(s, 1 H), 3.77 (d, J = 16.0 Hz, 1 H), 3.63 (s, 3 H), 3.37 (d, J = 16.4 Hz,
imido[1,6-a]indol-1(2H)-one (3aj): White solid (66 %); m.p. 188–
1
189 °C. H NMR (400 MHz, [D6]DMSO): δ = 8.26 (d, J = 8.0 Hz, 1 H),
1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 152.2, 140.2, 134.7, 7.53 (d, J = 7.6 Hz, 3 H), 7.28–7.20 (m, 3 H), 6.95 (d, J = 8.8 Hz, 2 H),
132.8, 132.3, 129.9, 128.2, 128.0, 123.5, 123.1, 120.3, 114.6, 104.4, 6.42 (s, 1 H), 3.76 (s, 3 H), 3.74 (d, J = 14.4 Hz, 1 H), 3.62 (s, 3 H),
90.6, 63.6, 37.9 ppm. HRMS (ESI): calcd. for [C18H15ClN2O3 + Na]+
365.0663; found 365.0646.
3.35 (d, J = 16.8 Hz, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
158.9, 152.3, 134.7, 133.1, 132.6, 129.9, 127.5, 123.4, 123.0, 120.2,
114.5, 113.2, 104.2, 90.8, 63.6, 55.1, 38.2 ppm. HRMS (ESI): calcd. for
[C19H18N2O4 + Na]+ 361.1159; found 361.1142.
3-Hydroxy-2-methoxy-6-methyl-3-phenyl-3,4-dihydropyr-
imido[1,6-a]indol-1(2H)-one (3ad): White solid (88 %); m.p. 204–
1
205 °C. H NMR (400 MHz, [D6]DMSO): δ = 8.26 (d, J = 8.0 Hz, 1 H),
2-Ethoxy-3-hydroxy-3-phenyl-3,4-dihydropyrimido[1,6-a]indol-
1(2H)-one (3ha): White solid (66 %); m.p. 200–203 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.41 (d, J = 8.4 Hz, 1 H), 7.65 (d, J = 7.6 Hz,
2 H), 7.47–7.35 (m, 4 H), 7.32–7.28 (m, 1 H), 7.25–7.21 (m, 1 H), 6.32
7.91 (d, J = 1.6 Hz, 1 H), 7.72–7.64 (m, 2 H), 7.55–7.54 (m, 2 H), 7.31–
7.22 (m, 2 H), 6.47 (s, 1 H), 3.83 (d, J = 16.4 Hz, 1 H), 3.63 (s, 3 H),
3.37 (d, J = 16.4 Hz, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
152.1, 142.3, 134.7, 132.2, 130.9, 130.8, 130.3, 129.9, 128.6, 126.7, (s, 1 H), 4.25–4.17 (m, 2 H), 3.75 (br., 1 H), 3.65 (d, J = 16.4 Hz, 1 H),
123.6, 123.1, 120.3, 114.6, 104.6, 90.2, 63.7, 37.6 ppm. HRMS (ESI):
3.47 (d, J = 16.4 Hz, 1 H), 0.83 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 152.4, 141.1, 134.8, 132.6, 129.9, 128.1,
127.9, 126.2, 123.4, 123.0, 120.2, 114.5, 104.2, 90.8, 71.7, 37.9,
13.3 ppm. HRMS (ESI): calcd. for [C19H18N2O3 + Na]+ 345.1210; found
345.1192.
calcd. for [C18H14Cl2N2O3 + Na]+ 399.0274; found 399.0258.
3-Hydroxy-2-methoxy-3-(p-tolyl)-3,4-dihydropyrimido[1,6-a]-
indol-1(2H)-one (3ae): White solid (87 %); m.p. 198–201 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 8.27 (d, J = 8.0 Hz, 1 H), 7.53–7.49 (m, 3
H), 7.29–7.19 (m, 5 H), 6.42 (s, 1 H), 3.72 (d, J = 16.0 Hz, 1 H), 3.63
Dehydration Reaction of Dihydropyrimido[1,6-a]indolone De-
(s, 3 H), 3.34 (d, J = 16.0 Hz, 1 H), 2.31 (s, 3 H) ppm. 13C NMR rivatives 3aa for the Synthesis of Pyrimido[1,6-a]indolone 4aa:
(100 MHz, [D6]DMSO): δ = 152.4, 138.3, 137.3, 134.8, 132.5, 129.9, A mixture of N-carbamoylindole 3aa (0.10 mmol) and anhydrous
128.5, 126.1, 123.4, 123.0, 120.2, 114.5, 104.2, 91.0, 63.6, 38.2,
20.6 ppm. HRMS (ESI): calcd. for [C19H18N2O3 + Na]+ 345.1210; found
345.1215.
AlCl3 (0.20 mmol) in MeOH (1 mL) was stirred at room temperature
for 2 h. Then, the mixture was concentrated. The residue was sub-
jected to flash column chromatography [silica gel; ethyl acetate/
petroleum ether (1:10, v/v)] to give pyrimido[1,6-a]indolone 4aa.
3-(tert-Butyl)-3-hydroxy-2-methoxy-3,4-dihydropyrimido-
[1,6-a]indol-1(2H)-one (3af): White solid (63 %); m.p. 151–153 °C.
1H NMR (400 MHz,[D6]DMSO): δ = 8.20 (d, J = 7.6 Hz, 1 H), 7.51 (d,
J = 6.8 Hz, 1 H), 7.22–7.18 (m, 2 H), 6.43 (s, 1 H), 6.39 (s, 1 H), 3.86
(s, 3 H), 3.63 (d, J = 16.4 Hz, 1 H), 3.28 (d, J = 17.2 Hz, 1 H), 0.92 (s,
2-Methoxy-3-phenylpyrimido[1,6-a]indol-1(2H)-one (4aa): Yel-
low solid (77 %); a melting point could not be obtained due to the
thermal instability of the compound. 1H NMR (400 MHz, CDCl3): δ =
8.69–8.65 (m, 1 H), 7.66–7.62 (m, 3 H), 7.48–7.46 (m, 3 H), 7.40–7.36
9 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 149.5, 134.6, 132.6, (m, 2 H), 6.57 (s, 1 H), 6.38 (s, 1 H), 3.70 (s, 3 H) ppm. 13C NMR
129.6, 123.2, 122.7, 120.1, 114.2, 102.7, 93.6, 64.3, 40.6, 33.2,
26.0 ppm. HRMS (ESI): calcd. for [C16H20N2O3 + Na]+ 311.1366; found
311.1344.
(100 MHz, CDCl3): δ = 146.5, 139.0, 133.8, 133.7, 132.0, 130.9, 129.5,
129.1, 128.5, 124.2, 123.1, 120.1, 116.1, 99.2, 99.1, 63.9 ppm. HRMS
(EI-TOF): calcd. for C18H14N2O2 [M]+ 290.1055; found 290.1057.
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Financial support from the National Natural Science Foundation
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Keywords: Cascade reactions · C-H functionalization ·
Cyclization · Nitrogen heterocycles · Rhodium ·
Homogeneous catalysis
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Received: July 18, 2016
Published Online: ■
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Cascade Reactions
Z.-J. Wu, Y.-Q. Li, Z.-Z. Huang* ....... 1–7
A
Cascade C–H-Functionalization/
Cyclization Reaction of Indoles with
α-Halo or α-Sulfonyloxy Ketones for
the Synthesis of Dihydropyrimido-
indolone Derivatives
A rhodium(III)-catalyzed cascade C–H has been developed, affording a novel
functionalization/cyclization reaction synthesis of dihydropyrimido[1,6-a]-
of N-carbamoylindoles 1 with α-halo, indolone derivatives 3.
α-mesyloxy or α-tosyloxy ketones 2
DOI: 10.1002/ejoc.201600885
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