Cationic Ir(I)-catalyzed sp3 C-H bond alkenylation of ureas with alkynes for the synthesis of 2,3-disubstituted indoles

Article abstract of DOI:10.1055/s-0030-1261205

Secondary sp³ C-H bond activation of ureas was achieved by a cationic Ir(I)-JOSIPHOS catalyst. Regioselective C-H bond cleavage adjacent to the nitrogen atom in N-benzylureas and an N-allyl urea possessing a 2-alkynylphenyl group, and subsequen

Full text of DOI:10.1055/s-0030-1261205

LETTER
2171
Cationic Ir(I)-Catalyzed sp3 C–H Bond Alkenylation of Ureas with Alkynes for
the Synthesis of 2,3-Disubstituted Indoles
S
ynthesis of 2,3
a
-Disubstitu
k
ted Indoles anori Shibata,*a Hiroyuki Hirashima,a Mitsugu Kasagawa,a Kyoji Tsuchikama,a Kohei Endob
a
Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University,
Okubo, Shinjuku, Tokyo 169-8555, Japan
Fax +81(3)52868098; E-mail: tshibata@waseda.jp
Waseda Institute for Advanced Study, Shinjuku, Tokyo 169-8050, Japan
b
Received 27 June 2011
dole 2 was obtained via acetyl rearrangement, which was
already reported using Pt catalysts,7 and C–H bond cleav-
age at the methyl group did not proceed at all (Scheme 1).
Abstract: Secondary sp3 C–H bond activation of ureas was
achieved by a cationic Ir(I)–JOSIPHOS catalyst. Regioselective C–
H bond cleavage adjacent to the nitrogen atom in N-benzylureas and
an N-allyl urea possessing a 2-alkynylphenyl group, and subsequent
intramolecular reaction with an alkyne along with double-bond
isomerization provided 2,3-disubstituted indoles.
n-Bu
O
Me
[Ir(cod)2]OTf (10 mol%)
Key words: C–H bond activation, directing group, indoles, iridi-
um, ureas
rac-BINAP (10 mol%)
n-Bu
NMe
PhCl, 135 °C, 30 min
N
Me
Me
O
1
2 58%
The direct functionalization of C–H bonds is an ideal
transformation in organic synthesis, because C–H bonds
are ubiquitous in organic molecules, and the introduction
of activating groups, such as halogens and metals, is un-
necessary. However, C–H bonds are generally more sta-
ble than carbon–heteroatom bonds, therefore, some
ingenious tricks are required for the regioselective cleav-
age of C–H bonds. The directed C–H bond activation by
transition-metal catalysts has led to the drastic develop-
ment of this area, where the Murai’s carbonyl-directed C–
H activation by a Ru catalyst is a monumental work.1 In
last decade, various directing groups have been reported
for the initiation of C–H bond cleavage, and many syn-
thetically useful transformations have been disclosed.2
Among them, sp2 C–H bond activation such as aromatic
and vinylic C–H bonds has been a main research topic,
and the examples of sp3 C–H bond activation are relative-
ly few,3 in particular, those of secondary sp3 C–H bond ac-
tivation are scarce and limited to benzylic and allylic
positions.4 We herein disclose that a cationic Ir–diphos-
phine complex promotes benzylic and allylic secondary
sp3 C–H bond cleavage using urea as a directing group,
and that the following intramolecular reaction with
alkynes results in the formation of substituted indoles.5
Scheme 1 Ir(I)-catalyzed indole synthesis from amide 1 via acetyl
rearrangement
We changed the directing group from amide to urea and
subjected 1-[2-(hex-1-ynyl)phenyl]-1,3,3-trimethylurea
(3a) to the same reaction conditions (Scheme 2). To our
delight, 3-pentylindole 4a was obtained in good yield ini-
tiated by primary sp3 C–H bond activation of the methyl
group. Phenyl and trimethylsilyl groups were also avail-
able as substituents at the alkyne terminus, and the corre-
sponding 3-substituted indoles 4b and 4c were obtained.
R
R
[Ir(cod)2]OTf (10 mol%)
rac-BINAP (10 mol%)
N
PhCl, 135 °C
NMe
O
O
Me2N
Me2N
3a R = n-Bu
3b R = Ph
3c R = TMS
4a 79%, 1.5 h
4b 49%, 24 h
4c 40%, 24 h
Scheme 2 Ir(I)-catalyzed indole synthesis from urea 3 initiated by
primary sp3 C–H bond cleavage
We further tried secondary sp3 C–H bond activation of a
benzylic position under the same reaction conditions and
obtained 2-phenyl-3-pentylindole 6a, albeit in low yield
due to the low conversion of urea 5a (Table 1, entry 1). To
improve the yield, we screened various diphosphine
ligands for cationic Ir(I) complex. When DPPF was used,
the yield significantly increased (Table 1, entry 4). After
screening several ferrocenyl ligands, we determined
JOSIPHOS to be the best ligand, but urea 5a was not com-
pletely consumed even after 48 hours (Table 1, entry 5).
We have focused on the development of cationic iridi-
um(I)-catalyzed C–H bond activation and reported on the
carbonyl-directed sp2 C–H bond cleavage for the reaction
with alkynes, alkenes, and ketones.6 We recently achieved
an amide-directed sp3 C–H bond alkenylation by the inter-
molecular reaction with alkynes.3h We next examined an
intramolecular reaction of (2-alkynylphenyl)amide 1 un-
der the previously reported conditions, but N-methyl in-
SYNLETT 2011, No. 15, pp 2171–2176
x
x
.x
x
.2
0
1
1
Advanced online publication: 30.08.2011
DOI: 10.1055/s-0030-1261205; Art ID: U05011ST
© Georg Thieme Verlag Stuttgart · New York

2172
T. Shibata et al.
LETTER
Table 1 Screening of Various Diphosphine Ligands in the Ir(I)-Cat-
served, and indole 6d was obtained in the highest yield of
75% (Table 2, entry 3).
alyzed Secondary sp3 C–H Bond Activation
n-Bu
n-Bu
Ph
With the optimal conditions in hand, we next examined
the substrate scope (Table 3). We first introduced elec-
tron-withdrawing groups on the benzene ring (Table 3,
entries 1–3). As a result, the corresponding 2-arylindoles
6e–g were obtained, and especially in the case of trifluo-
romethyl group, urea 5g was completely consumed within
3 hours, and the highest yield of 80% was achieved
(Table 3, entry 3). An electron-donating group could be
installed at the meta position (Table 3, entry 4).8 In addi-
tion to the benzylic position, a secondary sp3 C–H bond of
the allylic position of urea 5i was also activated, and 2-vi-
nylindole 6i was obtained, part of which was hydrogenat-
ed at the vinyl group to afford 2-ethylindole (Table 3,
entry 5).9 As for the substituent on the alkyne terminus,
phenyl group was also used, and 2-phenyl-3-benzylindole
6j was afforded in moderate yield (Table 3, entry 6). This
reaction provides a synthetic protocol of 2,3-disubstituted
indoles.10
[Ir(cod)2]OTf (10 mol%)
ligand (10 mol%)
N
N
Ph
PhCl, 135 °C, 48 h
O
Me2N
O
Me2N
6a
5a
Entry
Liganda
Yield of 6a (%)
1
2
3
4
5
6
7
rac-BINAP
(S)-SEGPHOS
(R,R)-MeDUPHOS
DPPF
26
32
24
40
JOSIPHOS
SL-JOO1-1
SL-JOO2-1
53
trace
trace
As a mechanistic study, we first subjected deuterated sub-
strate 5d-d2 to the same reaction conditions (Scheme 3).
As a result, high rate of deuterium incorporation was as-
certained in the obtained indole.
a SEGPHOS: 5,5¢-bis(diphenylphosphino)-4,4¢-bi-1,3-benzodioxole,
MeDUPHOS: 1,2-bis(2,5-dimethylphospholano)benzene, DPPF:
1,1¢-bis(diphenylphosphino)ferrocene.
PR2
82%D
n-Bu
JOSIPHOS R = 3,5-xylyl
SL-J001-1 R = Cy
SL-J002-1 R = t-Bu
Ph2P
n-Bu
Fe
Me
[Ir(cod)2]OTf (10 mol%)
JOSIPHOS (10 mol%)
D
D
Ph
N
Ph
N
PhCl, 135 °C, 6 h
We next examined substituents on the nitrogen atom,
which can electronically and/or sterically affect the direct-
ing ability of the urea group (Table 2). When a pyrrolidi-
nyl group was used as the NR2 moiety, desired indole 6b
was not obtained at all, and a rearranged product was
mainly produced (58% yield, Table 2, entry 1). In con-
trast, a piperidinyl group was installed, desired indole 6c
was obtained, but urea 5c partly remained unconsumed
(Table 2, entry 2). Finally, when a diethylamino group
was used, complete consumption of the substrate was ob-
O
Et2N
O
Et2N
72%
5d–d2
Scheme 3 Reaction using deuterated substrate 5d-d2
We next examined the reaction of urea 5d in the presence
of excess amounts of D2O, quenched it after 2 hours and
recovered unreacted urea 5d (Scheme 4). Deuterium in-
corporation (25%) was observed at the expected benzylic
position along with slight deuterium incorporation at the
methylene moiety.
Table 2 Screening of Various Ureas in the Ir(I)-Catalyzed Second-
ary sp3 C–H Bond Activation
n-Bu
[Ir(cod)2]OTf (10 mol%)
JOSIPHOS (10 mol%)
n-Bu
n-Bu
Ph
25% D
5d
[Ir(cod)2]OTf (10 mol%)
JOSIPHOS (10 mol%)
PhCl, 135 °C, 2 h
D2O (6 equiv)
N
Ph
N
N
Ph
PhCl, 135 °C
N
O
O
R2N
O
R2N
6b–d
5% D
5b–d
Scheme 4 Reaction in the presence of D2O
Entry
NR2
Urea
Time (h) Yield of 6 (%)
Based on the above results, we now assume the present re-
action is likely initiated by secondary sp3 C–H bond
cleavage. Subsequent intramolecular carboiridation to
alkynes, reductive elimination, and isomerization of an
exo double bond would provide 2-substituted indoles
(Scheme 5).
1
5b
3
n.d.
N
2
3
5c
24
6
6c 45
6d 75
N
NEt2
5d
Synlett 2011, No. 15, 2171–2176 © Thieme Stuttgart · New York

LETTER
Synthesis of 2,3-Disubstituted Indoles
2173
Table 3 Substrate Scope of the Ir(I)-Catalyzed Secondary sp3 C–H Bond Activation for the Synthesis of Indolesa
Entry
Substrate
Product
Time (h)
Yield of 6 (%)
n-Bu
n-Bu
p-BrC6H4
1
24
54
64
80
75
61
48
N
N
p-BrC6H4
O
Et2N
O
O
O
O
Et2N
5e
6e
6f
6g
6h
6i
n-Bu
n-Bu
p-NCC6H4
2
48
N
N
N
N
p-NCC6H4
O
Et2N
Et2N
Et2N
Et2N
5f
5g
5h
5i
n-Bu
n-Bu
p-F3CC6H4
3
3
N
p-F3CC6H4
O
Et2N
n-Bu
n-Bu
m-MeOC6H4
O
4
24
24
24
N
m-MeOC6H4
Et2N
n-Bu
n-Bu
5b
N
N
O
Et2N
O
Et2N
Ph
Ph
Ph
Ph
O
6
N
N
Et2N
O
Et2N
5j
6j
a [Ir(cod)2]OTf (10 mol%) and JOSIPHOS (10 mol%) in chlorobenzene at 135 °C.
b Hydrogenated product of the vinyl group was included (ca. 1/3).
In conclusion, we achieved a cationic Ir(I)-catalyzed in- be involved in a catalytic cycle. The application of our iri-
dole synthesis initiated by secondary sp3 C–H bond acti- dium-catalyzed sp3 C–H bond activation for other types of
vation. Selective C–H bond cleavage at benzylic and transformations are under way in our laboratory.
allylic positions proceeded with the aid of an urea moiety
as a directing group, and 2-aryl- and 2-vinyl-3-substituted
indoles were obtained. The use of urea as a directing
group and the choice of substituent on the urea were a key
to success. Preliminary mechanistic studies by labeling
experiments elucidated that secondary sp3 C–H bond
cleavage and intramolecular alkyne insertion seemed to
Synthesis of Compounds 6d–j
[Ir(cod)2]OTf (5.6 mg, 10 mmol), JOSIPHOS (6.4 mg, 10 mmol),
and ureas 5d–j (0.10 mmol) were placed in a Schlenk tube, which
was then evacuated and backfilled with argon (3×). Chlorobenzene
(0.2 mL) was added into the reaction vessel. The reaction mixture
Synlett 2011, No. 15, 2171–2176 © Thieme Stuttgart · New York

2174
T. Shibata et al.
LETTER
3,3-Diethyl-1-[4-(trifluoromethyl)benzyl]-1-[2-(hex-1-ynyl)phe-
nyl]urea (5g)
R1
R1
R2
Pale yellow oil. 1H NMR (400 MHz, CDCl3): d= 0.83 (t, J = 7.1 Hz,
6 H), 0.91 (t, J = 7.1 Hz, 3 H), 1.36–1.54 (m, 4 H), 2.34 (t, J = 7.1
Hz, 2 H), 3.14 (q, J = 7.1 Hz, 4 H), 4.78 (s, 2 H), 6.87 (dd, J = 7.6,
1.8 Hz, 1 H), 7.11 (ddd, J = 7.3, 7.3, 1.8 Hz, 1 H), 7.15 (ddd, J = 7.6,
7.6, 1.8 Hz, 1 H), 7.44 (dd, J = 7.3, 1.8 Hz, 1 H), 7.45–7.50 (br, 4
H). 13C NMR (125 MHz, CDCl3): d = 12.6, 13.6, 19.4, 22.1, 30.7,
41.9, 54.2, 77.7, 97.1, 121.9, 124.8, 124.9, 125.9, 127.6, 128.5,
128.8, 129.1, 133.8, 143.2, 146.8, 161.6. IR (neat): 2962, 2935,
2873, 1660, 1644, 1488, 1427, 1322, 1160, 1068, 761, 754 cm–1.
HRMS (FAB+): m/z calcd for C25H30F3N2O: 431.2310; found:
431.2299 [M + H].
H
[Ir]
H
H
N
R2
N
[Ir]H
Et2N
O
Et2N
O
H
N
R1
R1
R2
[Ir]H
H
H
R2
O
– [Ir]
N
O
3,3-Diethyl-1-(3-methoxybenzyl)-1-[2-(hex-1-ynyl)phenyl]urea
(5h)
Et2N
Et2N
Pale yellow oil. 1H NMR (400 MHz, CDCl3): d = 0.83 (t, J = 7.1 Hz,
6 H), 0.91 (t, J = 7.1 Hz, 3 H), 1.38–1.57 (m, 4 H), 2.37 (t, J = 7.1
Hz, 2 H), 3.13 (q, J = 7.1 Hz, 4 H), 3.73 (s, 3 H), 4.74 (s, 2 H), 6.72
(dd, J = 8.0, 1.7 Hz, 1 H), 6.84 (d, J = 8.0 Hz, 1 H), 6.90 (s, 1 H),
6.92 (d, J = 8.0 Hz, 1 H), 7.06–7.15 (m, 3 H), 7.42 (dd, J = 7.1, 2.0
Hz, 1 H). 13C NMR (100 MHz, CDCl3): d = 12.6, 13.6, 19.4, 22.0,
30.6, 41.8, 54.2, 55.1, 77.7, 96.8, 112.4,113.9, 120.9, 121.9, 125.6,
127.8, 128.2, 128.8, 133.5, 140.7, 146.9, 159.3, 161.7. IR (neat):
3060, 2932, 2872, 1645, 1595, 1487, 1378, 762, 698 cm–1. HRMS
(ESI+): m/z calcd for C25H32N2NaO2: 415.2361; found: 415.2366
[M + Na].
Scheme 5 A possible mechanism of Ir(I)-catalyzed indole synthesis
initiated by secondary sp3 C–H bond cleavage
was then stirred at 135 °C for appropriate hours listed in Tables 2
and 3, then the solvent was evaporated under reduced pressure. The
resultant crude products were purified by TLC to give indoles 6d–j.
1-Benzyl-3,3-diethyl-1-[2-(hex-1-ynyl)phenyl]urea (5d)
Pale yellow oil. 1H NMR (400 MHz, CDCl3): d = 0.82 (t, J = 7.4 Hz,
6 H), 0.92 (t, J = 7.4 Hz, 3 H), 1.39–1.55 (m, 4 H), 2.37 (t, J = 7.4
Hz, 2 H), 3.12 (q, J = 7.4 Hz, 4 H), 4.76 (s, 2 H), 6.82 (dd, J = 7.4,
1.7 Hz, 1 H), 7.07 (ddd, J = 7.4, 7.4, 1.7 Hz, 1 H), 7.09 (ddd, J = 7.4,
7.4, 1.7 Hz, 1 H), 7.14–7.22 (m, 3 H), 7.32 (d, J = 7.4 Hz, 2 H), 7.41
(dd, J = 7.4, 1.7 Hz, 1 H). 13C NMR (125 MHz, CDCl3): d = 12.7,
13.7, 19.5, 22.1, 30.7, 41.9, 54.3, 77.8, 96.8, 122.0, 125.7, 126.8,
127.9, 128.0, 128.2, 128.8, 133.6, 139.0, 146.9, 161.8. IR (neat):
3062, 2960, 2933, 2871, 1650, 1486, 1413, 1270, 1072, 759, 700
cm–1. HRMS (FAB+): m/z calcd for C24H31N2O: 363.2436; found:
363.2430 [M + H].
1-Allyl-3,3-diethyl-1-[2-(hex-1-ynyl)phenyl]urea (5i)
Pale yellow oil. 1H NMR (400 MHz, CDCl3): d = 0.82 (t, J = 6.8 Hz,
6 H), 0.93 (t, J = 7.4 Hz, 3 H), 1.46–1.59 (m, 4 H), 2.43 (t, J = 7.3
Hz, 2 H), 3.08 (q, J = 6.8 Hz, 4 H), 4.14 (d, J = 5.7 Hz, 2 H), 4.99–
5.04 (m, 2 H), 6.05 (ddt, Jd = 17.0, 10.2 Hz, Jt = 5.7 Hz, 1 H), 6.97
(dd, J = 7.7, 1.4 Hz, 1 H), 7.09 (ddd, J = 7.4, 7.4, 1.4 Hz, 1 H), 7.19
(ddd, J = 7.7, 7.7, 1.4 Hz, 1 H), 7.41 (dd, J = 7.4, 1.4 Hz, 1 H). 13
C
NMR (125 MHz, CDCl3): d = 12.7, 13.7, 19.4, 22.1, 30.8, 41.9,
53.8, 77.7, 96.6, 116.8, 122.1, 125.7, 127.9, 128.3, 133.5, 135.4,
146.9, 161.7. IR (neat): 2960, 2933, 2871, 1650, 1646, 1486, 1407,
1378, 1270, 1000, 921, 796, 761 cm–1. HRMS (FAB+): m/z calcd for
C20H29N2O: 313.2280; found: 313.2270 [M + H].
1-(4-Bromobenzyl)-3,3-diethyl-1-[2-(hex-1-ynyl)phenyl]urea
(5e)
Pale yellow oil. 1H NMR (400 MHz, CDCl3): d = 0.82 (t, J = 7.1 Hz,
6 H), 0.93 (t, J = 7.3 Hz, 3 H), 1.39–1.57 (m, 4 H), 2.38 (t, J = 7.1
Hz, 2 H), 3.12 (q, J = 7.1 Hz, 4 H), 4.69 (s, 2 H), 6.81 (dd, J = 7.4,
1.7 Hz, 1 H), 7.13 (ddd, J = 7.2, 7.2, 2.1 Hz, 1 H), 7.09 (ddd, J = 7.4,
7.4, 1.7 Hz, 1 H), 7.22 (d, J = 8.3 Hz, 2 H), 7.33 (d, J = 8.3 Hz, 2
H), 7.43 (dd, J = 7.2, 2.1 Hz, 1 H). 13C NMR (100 MHz, CDCl3):
d = 12.5, 13.6, 19.4, 22.0, 30.6, 41.8, 53.7, 77.7, 96.8, 120.6, 121.8,
125.8, 127.8, 128.3, 130.6, 130.9, 133.7, 137.9, 146.5, 161.6. IR
(neat): 2960, 2933, 2871, 1646, 1486, 1417, 1274, 1178, 796, 759
cm–1. HRMS (FAB+): m/z calcd for C24H30BrN2O: 441.1541; found:
441.1560 [M + H].
1-Benzyl-3,3-diethyl-1-[2-(2-phenylethynyl)phenyl]urea (5j)
White solid; mp 65–70 °C. 1H NMR (400 MHz, CDCl3): d = 0.83
(t, J = 7.1 Hz, 6 H), 3.15 (q, J = 7.1 Hz, 4 H), 4.86 (s, 2 H), 6.94 (dd,
J = 7.6, 1.0 Hz, 1 H), 7.13–7.23 (m, 5 H), 7.29–7.38 (m, 5 H), 7.48–
7.49 (m, 2 H), 7.55 (dd, J = 7.3, 1.7 Hz, 1 H). 13C NMR (125 MHz,
CDCl3): d = 12.7, 42.0, 54.8, 86.7, 95.1, 121.4, 123.2, 125.8, 126.9,
128.0, 128.4, 128.5, 128.9, 129.1, 131.7, 133.6, 138.8, 147.0, 161.8
(a pair of aromatic peaks is overlapped). IR (KBr disk): 3060, 2975,
2933, 2873, 1646, 1494, 1477, 1442, 1413, 1268, 1070, 757, 694
cm–1. HRMS (ESI+): m/z calcd for C26H26N2NaO: 405.1943; found:
405.1946 [M + Na].
1-(4-Cyanobenzyl)-3,3-diethyl-1-[2-(hex-1-ynyl)phenyl]urea
(5f)
Pale yellow oil. 1H NMR (400 MHz, CDCl3): d = 0.83 (t, J = 7.1 Hz,
6 H), 0.92 (t, J = 7.3 Hz, 3 H), 1.37–1.54 (m, 4 H), 2.34 (t, J = 7.1
Hz, 2 H), 3.13 (q, J = 7.1 Hz, 4 H), 4.77 (s, 2 H), 6.85 (dd, J = 7.6,
1.7 Hz, 1 H), 7.11 (ddd, J = 7.3, 7.3, 2.2 Hz, 1 H), 7.15 (ddd, J = 7.6,
7.6, 1.7 Hz, 1 H), 7.44 (dd, J = 7.3, 2.2 Hz, 1 H), 7.47 (d, J = 8.3 Hz,
2 H), 7.52 (d, J = 8.3 Hz, 2 H). 13C NMR (100 MHz, CDCl3):
d = 12.5, 13.6, 19.3, 22.0, 30.5, 41.8, 54.2, 77.5, 97.0, 110.5, 119.1,
121.7, 125.9, 127.4, 128.5, 129.2, 131.7, 133.8, 144.6, 146.5, 161.3.
IR (neat): 2962, 2933, 2873, 2227, 1610, 1654, 1486, 1378, 1272,
761, 752 cm–1. HRMS (FAB+): m/z calcd for C25H30N3O: 388.2389;
found: 388.2379 [M + H].
N,N-Diethyl-3-pentyl-2-phenyl-1H-indole-1-carboxamide (6d)
Pale yellow oil. 1H NMR (400 MHz, CDCl3): d = 0.84 (t, J = 6.8 Hz,
3 H), 0.86–0.99 (br, 6 H), 1.22–1.33 (m, 4 H), 1.66 (tt, J = 7.7, 7.7
Hz, 2 H), 2.76 (m, 2 H), 2.87–3.78 (br, 4 H), 7.18 (dd, J = 8.0, 8.0
Hz, 1 H), 7.26 (dd, J = 8.0, 8.0 Hz, 1 H), 7.35–7.48 (m, 6 H), 7.62
(d, J = 8.0 Hz, 1 H). 13C NMR (100 MHz, CDCl3): d = 13.1, 13.9,
22.4, 24.3, 30.5, 31.8, 41.5, 111.1, 116.9, 119.4, 120.7, 123.2,
127.9, 128.3, 128.6, 129.5, 131.9, 134.8, 135.9, 153.7. IR (neat):
2928, 1682, 1455, 1422, 1321, 1277, 741 cm–1. HRMS (ESI+): m/z
calcd for C24H30N2NaO: 385.2256; found: 385.2251 [M + Na].
Synlett 2011, No. 15, 2171–2176 © Thieme Stuttgart · New York

LETTER
Synthesis of 2,3-Disubstituted Indoles
2175
2-(4-Bromophenyl)-N,N-diethyl-3-pentyl-1H-indole-1-carbox-
3-Benzyl-N,N-diethyl-2-phenyl-1H-indole-1-carboxamide (6j)
Pale red solid; mp 107–109 °C. H NMR (400 MHz, CDCl3): d =
1
amide (6e)
1
White oil. H NMR (400 MHz, CDCl3): d = 0.84 (t, J = 6.7 Hz, 3
0.79–1.02 (m, 6 H), 2.58–3.75 (br, 4 H), 4.09–4.21 (br, 2 H), 7.08–
7.47 (m, 14 H). 13C NMR (100 MHz, CDCl3): d = 12.7, 30.4, 41.8,
111.1, 114.1, 119.8, 119.8, 120.9, 123.4, 125.8, 128.1, 128.3, 128.4,
128.6, 129.4, 131.4, 136.0, 136.1, 141.0, 153.5. IR (KBr disk):
2933, 1681, 1216, 744, 700 cm–1. HRMS (ESI+): m/z calcd for
C26H26N2NaO: 405.1943; found: 405.1926 [M + Na].
H), 0.89–1.05 (br, 6 H), 1.25–1.30 (m, 4 H), 1.64 (tt, J = 7.5, 7.5 Hz,
2 H), 2.71–2.75 (m, 2 H), 2.81–3.69 (br, 4 H), 7.19 (dd, J = 7.4, 7.4
Hz, 1 H), 7.26 (dd, J = 8.0 Hz, 7.4 Hz, 1 H), 7.34 (d, J = 8.3 Hz, 2
H), 7.39 (d, J = 8.0 Hz, 1 H), 7.56 (d, J = 8.3 Hz, 2 H), 7.62 (d,
J = 7.3 Hz, 1 H). 13C NMR (125 MHz, CDCl3): d = 13.1, 13.9, 22.4,
24.3, 30.4, 31.8, 41.6, 111.1, 117.6, 119.5, 120.9, 122.1, 123.5,
128.5, 130.9, 131.0, 131.5, 133.6, 136.0, 153.5. IR (neat): 2928,
1681, 1216, 825, 743 cm–1. HRMS (ESI+): m/z calcd for
C24H29BrN2NaO: 463.1361; found: 463.1354 [M + Na].
Acknowledgment
This research was supported by Grant-in-Aid for Scientific Re-
search on Innovative Areas, ‘Molecular Activation Directed toward
Straightforward Synthesis’, MEXT, Japan, and Global COE pro-
gram ‘Practical Chemical Wisdom’, Waseda University, Japan.
2-(4-Cyanophenyl)-N,N-diethyl-3-pentyl-1H-indole-1-carbox-
amide (6f)
White solid; mp 99–101 °C. 1H NMR (400 MHz, CDCl3): d = 0.85
(t, J = 6.8 Hz, 3 H), 0.94–1.05 (br, 6 H), 1.25–1.30 (m, 4 H), 1.66
(tt, J = 7.6, 7.6 Hz, 2 H), 2.73–2.77 (m, 2 H), 2.87–3.55 (br, 4 H),
7.22 (dd, J = 7.8, 7.8 Hz, 1 H) 7.31 (dd, J = 7.8, 7.8 Hz, 1 H), 7.40
(d, J = 7.8 Hz, 1 H), 7.58 (d, J = 8.3 Hz, 2 H), 7.64 (d, J = 7.8 Hz, 1
H), 7.73 (d, J = 8.3 Hz, 2 H). 13C NMR (125 MHz, CDCl3): d = 13.3,
13.9, 22.3, 24.3, 30.4, 31.8, 41.8, 111.2, 111.3, 118.7, 119.2, 119.9,
121.2, 124.2, 128.5, 129.9, 132.1, 132.8, 136.3, 136.8, 153.3. IR
(KBr disk): 1716, 1683, 1068, 750 cm–1. HRMS (ESI+): m/z calcd
for C25H29N3NaO: 410.2208; found: 410.2189 [M + Na].
References and Notes
(1) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani,
A.; Sonoda, M.; Chatani, N. Nature (London) 1993, 366,
529.
(2) For recent reviews, see: (a) Handbook of C-H
Transformations; Dyker, G., Ed.; Wiley-VCH: Weinheim,
2005. (b) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev.
2007, 107, 174. (c) Davies, H. M. L.; Manning, J. R. Nature
(London) 2008, 451, 417. (d) Kakiuchi, F.; Kochi, T.
Synthesis 2008, 3013. (e) Kitamura, T. Eur. J. Org. Chem.
2009, 1111. (f) Giri, R.; Shi, B.-F.; Engle, K. M.; Maugel,
N.; Yu, J.-Q. Chem. Soc. Rev. 2009, 38, 3242. (g) Colby, D.
A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110,
624. (h) Lyons, T. M.; Sanford, M. S. Chem. Rev. 2010, 110,
1147. (i) C–H Activation; Yu, J.-Q.; Shi, Z., Eds.; Springer:
Berlin, 2010.
(3) For selected examples, see: (a) Tokunaga, Y.; Sakakura, T.;
Tanaka, M. J. Mol. Catal. 1989, 56, 305. (b) Sakaguchi, S.;
Kubo, T.; Ishii, Y. Angew. Chem. Int. Ed. 2001, 40, 2534.
(c) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810.
(d) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am.
Chem. Soc. 2005, 127, 13154. (e) Giri, R.; Maugel, N.; Li,
J.-J.; Wang, D.-H.; Breazzano, S. P.; Saunders, L. B.; Yu,
J.-Q. J. Am. Chem. Soc. 2007, 129, 3510. (f) Lafrance, M.;
Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2007, 129,
14570. (g) Chaumontet, M.; Piccardi, R.; Audic, N.; Hitce,
J.; Peglion, J.-L.; Baudoin, O. J. Am. Chem. Soc. 2008, 130,
15157. (h) Tsuchikama, K.; Kasagawa, M.; Endo, K.;
Shibata, T. Org. Lett. 2009, 11, 1821.
N,N-Diethyl-3-pentyl-2-[4-(trifluoromethyl)phenyl]-1H-indole-
1-carboxamide (6g)
White solid; mp 57–59 °C. 1H NMR (400 MHz, CDCl3): d = 0.84
(t, J = 6.9 Hz, 3 H), 0.88–1.02 (br, 6 H), 1.23–1.33 (m, 4 H), 1.66
(tt, J = 7.6, 7.6 Hz, 2 H), 2.73–2.77 (m, 2 H), 2.92–3.46 (br, 4 H),
7.29 (dd, J = 7.7, 7.7 Hz, 1 H), 7.29 (dd, J = 7.7, 7.7 Hz, 1 H), 7.41
(d, J = 7.7 Hz, 1 H), 7.59 (d, J = 8.0 Hz, 2 H), 7.64 (d, J = 7.7 Hz, 1
H), 7.67 (d, J = 8.0 Hz, 2 H). 13C NMR (100 MHz, CDCl3): d = 13.1,
13.9, 22.4, 24.3, 30.5, 31.8, 41.8, 111.1, 118.5, 119.7, 121.0, 123.8,
125.2, 125.3, 128.5, 129.7, 133.3, 135.7, 136.2, 153.4. IR (KBr
disk): 2931, 1682, 1324, 1216, 1018, 843, 744 cm–1. HRMS (ESI+):
m/z calcd for C25H29F3N2NaO: 453.2130; found: 453.2124 [M +
Na].
N,N-Diethyl-2-(3-methoxyphenyl)-3-pentyl-1H-indole-1-car-
boxamide (6h)
Pale yellow oil. 1H NMR (400 MHz, CDCl3): d = 0.84 (t, J = 7.0 Hz,
3 H), 0.87–0.98 (br, 6 H), 1.24–1.34 (m, 4 H), 1.67 (tt, J = 7.9, 7.9
Hz, 2 H), 2.76–2.79 (m, 2 H), 2.96–3.52 (br, 4 H), 3.83 (s, 3 H), 6.91
(d, J = 8.0 Hz, 1 H), 7.02 (s, 1 H), 7.06 (d, J = 8.0 Hz, 1 H), 7.18
(dd, J = 7.8, 7.8 Hz, 1 H), 7.25 (dd, J = 7.8, 7.8 Hz, 1 H), 7.33 (dd,
J = 8.0, 8.0 Hz, 1 H), 7.42 (d, J = 7.8 Hz, 1 H), 7.61 (d, J = 7.6 Hz,
1 H). 13C NMR (125 MHz, CDCl3): d = 12.9, 14.1, 22.5, 24.5, 30.6,
31.9, 41.9, 55.4, 111.1, 113.9, 114.9, 117.1, 119.5, 120.8, 122.1,
123.3, 128.7, 129.4, 133.2, 134.8, 136.1, 153.8, 159.5. IR (neat):
2930, 1680, 1456, 1321, 1221, 743 cm–1. HRMS (ESI+): m/z calcd
for C25H29N2NaO2: 415.2361; found: 415.2343 [M + Na].
(4) (a) Ishii, Y.; Chatani, N.; Kakiuchi, F.; Murai, S.
Organometallics 1997, 16, 3615. (b) Jun, C.-H.; Hwang,
D.-C.; Na, S.-J. Chem. Commun. 1998, 1405. (c) Chatani,
N.; Asaumi, T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi, F.;
Murai, S. J. Am. Chem. Soc. 2001, 123, 10935. (d) DoBoef,
B.; Pastine, S. J.; Sames, D. J. Am. Chem. Soc. 2004, 126,
6556. (e) Pastine, S.; Gribkov, D. V.; Sames, D. J. Am.
Chem. Soc. 2006, 128, 14220.
N,N-Diethyl-3-pentyl-2-vinyl-1H-indole-1-carboxamide (6i)
Yellow oil. 1H NMR (400 MHz, CDCl3): d = 0.99 (t, J = 7.6 Hz, 3
H), 1.19–1.27 (m, 8 H), 1.49–1.59 (m, 4 H), 2.23–2.29 (m, 2 H),
2.77–2.98 (br, 2 H), 3.30–3.48 (br, 2 H), 6.17–6.25 (m, 1 H), 6.50
(5) Indole synthesis initiated by transition-metal-catalyzed sp2
C–H bond activation: (a) Stuart, D. R.; Bertrand-Laperle,
M.; Burgess, K. M. N.; Fagnou, K. J. Am. Chem. Soc. 2008,
130, 16474. (b) Wurtz, S.; Rakshit, S.; Neumann, J. J.;
Droge, T.; Glorius, F. Angew. Chem. Int. Ed. 2008, 47,
7230. (c) Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.; Cui,
Y.; Jiao, N. Angew. Chem. Int. Ed. 2009, 48, 4572.
(d) Stuart, D. R.; Alsabeh, P.; Kuhn, M.; Fagnou, K. J. Am.
Chem. Soc. 2010, 132, 18326. (e) Huestis, M. P.; Chan, L.;
Stuart, D. R.; Fagnou, K. Angew. Chem. Int. Ed. 2011, 50,
1338. (f) Chen, J.; Pang, Q.; Sun, Y.; Li, X. J. Org. Chem.
2011, 76, 3523.
(d, J = 15.6 Hz, 1 H), 7.05–7.24 (m, 4 H), 7.79–7.81 (m, 1 H). 13
C
NMR (100 MHz, CDCl3): d = 12.7, 13.9, 22.4, 24.3, 30.5, 31.8,
41.3, 111.1, 116.9, 119.4, 120.4, 120.6, 123.2, 127.9, 128.3, 128.6,
129.5, 131.9, 135.9, 153.7. IR (neat): 2931, 1682, 1423, 1278, 743
cm–1. HRMS (ESI+): m/z calcd for C20H28N2NaO: 335.2099; found:
335.2093 [M + Na].
Synlett 2011, No. 15, 2171–2176 © Thieme Stuttgart · New York

2176
T. Shibata et al.
LETTER
(6) (a) Tsuchikama, K.; Kasagawa, M.; Hashimoto, Y.; Endo,
K.; Shibata, T. J. Organomet. Chem. 2008, 693, 3939.
(b) Tsuchikama, K.; Hashimoto, Y.; Endo, K.; Shibata, T.
Adv. Synth. Catal. 2009, 351, 2850. (c) Tsuchikama, K.;
Kasagawa, M.; Endo, K.; Shibata, T. Synlett 2010, 97.
(7) (a) Shimada, T.; Nakamura, I.; Yamamoto, Y. J. Am. Chem.
Soc. 2004, 126, 10546. (b) Nakamura, I.; Sato, Y.; Konta,
S.; Terada, M. Tetrahedron Lett. 2009, 50, 2075.
(8) When a methoxy group was installed at the para position,
the reaction gave a complex mixture.
(9) Dehydrogenation from diethylurea group is a possible
hydrogen source.
(10) Removal of the N,N-diethylcarboxyamide group from the
N-protected indoles: (a) Comins, D. L.; Stroud, E. D.
Tetrahedron Lett. 1986, 27, 1869. (b) Castells, J.; Tram, Y.;
Diez, A.; Rublralta, M. Tetrahedron 1991, 47, 7911.
Synlett 2011, No. 15, 2171–2176 © Thieme Stuttgart · New York

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