Copper-Catalyzed Oxidative Dehydrogenative C(sp3)?H Bond Amination of (Cyclo)Alkanes using NH-Heterocycles as Amine Sources

Article abstract of DOI:10.1002/cssc.201700783

A copper-catalyzed oxidative C(sp³)?H/N?H coupling of NH-heterocycles with affordable (cyclo)alkanes has been developed. This procedure involves C(sp³)?N bond formation through a radical pathway generated by homolytic cleavage of di-tert-butyl peroxide and trapping of the radical(s) by copper catalysts. The reaction tolerates a series of functional groups, such as bromo, fluoro, ester, ketone, nitrile, methyl, and methoxy. free-NH-containing indoles, pyrroles, pyrazoles, indazoles, and benzotriazoles are successfully N-alkylated.

Full text of DOI:10.1002/cssc.201700783

Accepted Article
Title: Copper-Catalyzed Oxidative Dehydrogenative C(sp3)-H Bond
Amination of (Cyclo)Alkanes using NH-Free Heterocycles as
Amine Sources
Authors: Chang-Sheng Wang, Xiao-Feng Wu, Pierre H Dixneuf, and
Jean-Francois Soule
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the VoR from the journal website shown below when it is published
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To be cited as: ChemSusChem 10.1002/cssc.201700783
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10.1002/cssc.201700783
ChemSusChem
FULL PAPER
Copper-Catalyzed Oxidative Dehydrogenative C(sp3)–H Bond
Amination of (Cyclo)Alkanes using NH-Free Heterocycles as
Amine Sources
Chang-Sheng Wang,[a] Xiao-Feng Wu,[b] Pierre H. Dixneuf[a] and Jean-François Soulé*[a]
Abstract: A copper-catalyzed oxidative C(sp3)–H/N–H coupling of
NH-heterocycles with affordable (cyclo)alkanes was developed. This
protocol involved C(sp3)–N bond formation via a radical pathway
generated by a homolytic cleavage of di-tert-butyl peroxide and
trapping of the radical(s) by copper catalysts. The reaction tolerated
a series of functional groups, such as bromo, fluoro, ester, ketone,
nitrile, methyl and methoxy. NH-free indoles, pyroles, pyrazoles,
indazoles and benzotriazoles have been successfully N-alkylated.
Despite this wide applicability, ecofriendly routes for the synthesis
of N-alkyl heterocycles are limited. One of the most common
synthetic pathway involves SN2 reaction using a stoichiometric
amount of a strong base and an appropriate alkylating agent (e.g.,
alkyl halide, alkyl triflate, etc.) generation a lot of waste (Figure
2a).[6] Since the discovery of transition-metal catalyzed C–H bond
functionalizations,[7] catalytic C–H amination provides an
appealing method for the straightforward construction of C–N
bonds.[8] General protocols for the transition-metal catalyzed C–
H amination required electrophilic amines, via an internal oxidant
strategy (e.g., azides,[9] N-haloamines[10] or oximes[11]). However,
such protocols could not be employed for the N-functionalization
of NH-heterocycles. Amines can be directly used, although an
external oxidant is required.[12] However, only rare examples of
C–H amination with NH-heterocycles have been reported.[13] This
lack of exploitation is probably due to the presence of competitive
C(sp2)–H bonds on NH-heterocycles, which are generally more
reactive.[14] Although synthetic tools enabling C(sp2)–N bond
formation have been well established,[15] facile intermolecular
amination of C(sp3)–H bonds under mild conditions still remains a
challenge in synthetic chemistry.[4, 11d, 16]
Recently, cross-dehydrogenative coupling reactions have
attracted increasing attention owing to the use of abundant
hydrocarbons (i.e., arenes, olefins, or cycloalkanes) as unreactive
coupling partners for the C–C, C–O, and C–N bond formation.[17]
Warren and co-workers reported the oxidative dehydrogenative
amination of alkanes with unactivated amines using copper(II) as
catalyst associated to di-tert-butyl peroxide (DTBP) (Figure 2b).[18]
Outstanding achievements are emerging in this area[19] although
only amines with low nucleophilicity were successfully alkylated.
For example, Hartwig and co-workers reported C(sp3)–H
amination of cyclohexane with phthalimide and sulfonamides.[19c]
Cai and co-workers have reported that with NH-indole, using
nickel catalyst, regiospecific C2- or C3-products were obtained
without the formation of N–alkylated indole (Figure 2c).[20] In
addition, Yi and co-workers have reported that under metal-free
conditions in the presence of DTBP, the cross-dehydrogenative
coupling between NH-indoles and (cyclo)alkanes took place at
the C7 position of the indole unit, and in some cases C2 or C4
regioselectivity was overserved (Figure 2d).[21] To the best of our
Introduction
N-alkyl heterocycle derivatives constitute an important class of
organic compounds, which have been widely used in biology,
synthetic and polymer chemistry.[1] As example, The N-alkyl
indole
I displays biological activity for the treatment of
neurodegenerative diseases.[2] The N-cycloalkyl pyrrole II is an
analogue of BN1212 exhibiting antitubercular properties.[3] The
N-cyclopentylindazole III was used as a selective inhibitor of
EZH2.[4] The N-(tert-butoxymethyl)indole IV has shown inhibition
properties on vascular endothelial growth factors, which are
important signaling proteins involved in both vasculogenesis and
angiogenesis (Figure 1).[5]
OMe
MeO
H
OMe
HN
Cl
N
O
N
O
F
II
I
F
HN
N
N
O
O
IV
OtBu
N
N
NH
N
O
Cl
O
EPZ005687 (III)
Figure 1. Examples of N-Alkyl heterocycles Displaying Biological Activities.
[a]
[b]
Mr. C.-S. Wang, Prof. Dr. P.H. Dixneuf and Dr. J.-F. Soulé
Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS-
Université de Rennes "Organométalliques: Matériaux et Catalyse",
Campus de Beaulieu, 35042 Rennes, France
E-mail: jean-francois.soule@univ-rennes1.fr
knowledge,
oxidative
dehydrogenative
amination
of
(cyclo)alkanes using electron-rich NH-heteroarenes as amine
sources has not been reported yet owing to the chemoselectivity
issue between C–H or N–H reactivity.[22] Inspired by previous
works on the generation of alkyl radical in the presence of
coordinated amines,[18, 19c] we herein report a general method for
the C−N bond formation via C−H/N−H cross-coupling of NH-free
Prof. Dr. X.-F. Wu
Leibniz-Institut für Katalyse e.V. an der Universität Rostock,
Albert-Einstein-Straße 29a, 18059 Rostock, Germany.
Supporting information for this article is given via a link at the end of
the document
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10.1002/cssc.201700783
ChemSusChem
FULL PAPER
indoles, pyrroles, benzotriazoles, indazoles, and pyrazoles with
(cyclo)alkanes to afford the corresponding N-alkylated
heterocycles in good yields with a high chemoselectivity (Figure
2e).
activity for this reaction and N-cyclohexylindole (1) was isolated
in 67% yield (Table 1, entry 10). Next, we evaluated without
success the influence of other N,N-bidentate ligands, such as 4,7-
diphenyl-1,10-phenanthroline (L2), 2,2'-bipyridine (L3), 4,4'-di-
tert-butyl-2,2'-bipyridine (L4) and 2,2':6',2''-terpyridine (L5) (Table
1, entries 11-14). When the reaction is performed in absence of
phenanthroline (L1), the yield in 1 dropped to 10% concurrent with
the formation of other C2, C3 and C7–alkylated products (Table
1, entry 15). Other oxidants such as TBHP, BPO were inefficient
for the coupling of cyclohexane bonds with NH-indole; whereas,
DCP give a lower yield of 32% in the desired product 1 (Table 1,
entries 16−18). It is important to note that using a lower amount
of cyclohexane the yield of 1 decreased (Table 1, entry 19). The
reaction is less efficient in other solvents such as benzene,
trifluorotoluene, or 1,2-dichloroethane (Table 1, entries 20-22).
a. Synthesis of N-Alkylheterocycles via SN2 reaction.[6]
Z
Z
Y
Y
Alk
N
NH
BM
+
X
Alk
-(BH + MX)
Z, Y = CH or N
X = Cl, Br, I, OTf
b. Copper-Catalyzed Oxidative Dehydrogenative Amination of Electron-Deficient
Amine Derivatives (Warren).[18]
Cl
R2
N
R1
R2
NH
R1
Cl
[Cu] (1mol%)
N
N
+
H
Alk
Alk
Cu
DTBP (1.2 equiv.)
benzene
Cl
Cl
c. Ni-Catalyzed CDC C2 or C3 Alkylations of Indole Derivatives (Cai).[19]
NiF2 (10 mol%)
PPh3 (10 mol%)
O
Table 1 Optimization of Oxidative Dehydrogenative Amination of Cyclohexane
with NH-free Indole.
DTBP (2 equiv.)
N
O
O
O
H
120 ºC
+
Cat. (5 mol%)
L (10 mol%
N
Ni(acac)2 (10 mol%)
Zn(OTf)2 (10 mol%)
NH
N
H
O
+
oxidant (4 equiv.)
solvent (1 mL)
135 ºC, 15 h
DTBP (2 equiv.)
HN
c = 0.167
mol/L
120 ºC
O
1
(0.5 mmol)
Entry
d. Metal-Free C7 Alkylation of Indole Derivatives with Cyclohexanes via CDC
(Yi).[21]
Cat.
L
oxidant
solvent Yield in 1 (%)[a]
0[b]
5[b]
8[b]
41
50
77
62
65
52
87 (67)
55
–
–
–
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19[c]
20
21
22
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
TBHP
BPO
no-catalyst
+
FeCl3
FeCl2
CuO (II)
Cu2O (I)
CuBr
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
–
L1
L1
L1
L1
L1
L1
L1
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
C6H6
DTBP (1.5 equiv.)
N
HN
H
140 ºC
e. Copper-Catalyzed Oxidative Dehydrogenative Amination with NH-Heterocycles
(this work)
CuI
Cat. (5 mol%)
L (10 mol%)
Z
Z
.
Y
Y
Cu(OAc)2 n-H2O
Alk
N
NH
Cu(CH3CN)4PF6
CuBr(Me2S)
CuBr(Me2S)
CuBr(Me2S)
CuBr(Me2S)
CuBr(Me2S)
CuBr(Me2S)
CuBr(Me2S)
CuBr(Me2S)
CuBr(Me2S)
CuBr(Me2S)
CuBr(Me2S)
CuBr(Me2S)
CuBr(Me2S)
H
Alk
DTBP (4 equiv.)
tBuOH, 135 ºC, 15 h
Z, Y = CH or N
exclusively C–N bond formation
22
39
13
10[b]
NR
NR
32
Figure 2. N-Alkylation of amines and NH–Heterocycles
DCP
46
28
35
45
DTBP
DTBP
DTBP
DTBP
Results and Discussion
CF3C6H5
DCE
We started our investigation using NH-free indole and
cyclohexane as model substrates. The reaction was initially
studied with DTBP as an oxidant, in tBuOH without catalyst. As
reported by Yi,[21] we have not observed the formation of the
amination product 1 after heating at 135 °C over 15 h, but we did
observe the formation of C-alkylated products (Table 1, entry 1).
When FeCl3 (5 mol%) in the presence of phenanthroline (L1) (10
mol%) was used as the catalytic system, the amination product 1
was obtained in low yield with predominant formation of other C2,
C3 and C7–alkylated products (Table 1, entry 2). FeCl2, in
concert with L1, gave a similar result (Table 1, entry 3). In
contrast, when copper (II or I) oxides, combined with L1, were
used as catalysts, 1 was selectively obtained in 41% and 50%
yield, respectively without the formation of other C2, C3 and C7–
alkylated products (Table 1, entries 4 and 5). Encouraged by
these results, a number of other copper sources, including CuBr,
CuI, [MeCN]4Cu(I)PF6, Cu(I)Br(Me2S), and Cu(OAc)2.n-H2O were
evaluated in the presence of L1 (Table 1, entries 6−10). The
results showed that Cu(I)Br(Me2S) displayed the highest catalytic
R
R
R
R
N
N
N
N
N
N
N
L1 R = H
L2 R = Ph
L3 R = H
L4 R = tBu
L5
[a] Determined by GC-analysis using n-dodecane as internal standard,
isolated yield is shown in parentheses. [b] Formation of of other C2, C3
and C7-alkylated products. [c] Reaction performed at 0.5 mol/L of
cyclohexane.
With the optimized reaction conditions in hands, we then explored
the substrate scope. Firstly, we investigated the reactivity of NH-
heterocycles with cyclohexane using Cu/L1/DTBP system
(Scheme 1). NH-6-Fluoroindole and NH-5-bromoindole were
successfully N-alkylated to deliver the corresponding N-
cyclohexylindoles 2 and 3 in 64% and 94% yield, respectively. It
should be mentioned that for these reactions, no cleavage of the
C–halogen
bonds
were
observed,
allowing
further
transformations. An electron-donating group on the indole moiety,
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X
Y
CuBr(Me2S) (5 mol%)
such as 5-methoxyl, slightly affected the yield in the coupling
product 4; while an electron-withdrawing group such as nitrile or
methyl ester allowed the formation of the desired N-alkylindoles 5
and 6 in 54% and 62% yields, respectively. The reaction
conditions tolerate a C3 substituent on the indole moiety such as
ester. Indeed, from methyl NH-indole-3-carboxylate the optimized
reaction conditions gave exclusively the N-alkylation product 7 in
81%. Whereas, indole bearing a C2-substituent such as methyl or
phenyl did not allow the formation of the corresponding N-
alkylation product. Under these reaction conditions, NH-pyrrole
was also alkylated affording N-cyclohexylpyrrole 8 in 65% yield,
without the formation of C2 or C3 alkylation products.
Cu/L1/DTBP-catalyzed oxidative dehydrogenative amination
tolerated functional groups such as ketone and nitrile. Indeed, 2-
acetyl, 2-propionyl, and 2-nitrile pyrroles successfully reacted with
cyclohexane to afford the N-cyclohexylpyrroles 9–11 in 84–97%
yields. A trisubstituted pyrrole including ethyl ester group was
also N-alkylated to afford 12 in 55% yield. Poly-nitrogen
heterocyclic compounds are ubiquitous structural elements
important to a wide range of fine and bulk chemical fields.[23]
Therefore, we investigated their reactivity in oxidative
dehydrogenative amination. NH-3,5-Dimethylpyrazole and NH-
indazole smoothly reacted in the presence of cyclohexane to give
the corresponding N-alkylated products 13 and 14 in moderate
yields, but without the formation of C-alkylation products. NH-
Benzotriazole displayed poor reactivity, as the N-alkylated
products 15–17 were isolated in moderate to low yields. In the
case of 5-methylbenzo[1,2,3]triazole, the product was isolated as
mixture of two regioisomers 17a and 17b in 55:45 ratio. Finally,
our catalytic system displayed similar performance than other
protocols[19a] for the N-alkylation of sulfonamides, as 18 and 19
were obtained in 96% and 86% yields. It is important to note that
some functional groups on the heterocycle moiety such as nitro,
amino, or hydroxyl are not compatible with the reaction conditions.
X
Y
NH
L1 (10 mol%)
N
+
H
DTPB (4 equiv.)
tBuOH (1 mL)
135 ºC, 15 h
c = 0.167
mol/L
(0.5 mmol)
N
N
N
Br
MeO
F
2 64%
3 94%
4 41%
MeO2C
N
N
N
MeO2C
N
NC
5 54%
6 62%
7 81%
N
N
N
Et
O
CN
O
8 65%
9 84%
10 78%
11 97%
N
N
N
N
N
N
N
N
CO2Et
12 55%
13 44%
14 56%
15 35%
N
N
N
N
N
N
N
N
+
N
17a
17b
16 30%
17 41% (17a:17b = 45:55)
HN
HN
SO2
Cl
SO2
18 R = H 96%
19 R = Cl 86%
Scheme 1. Scope of NH-Heterocycle in Cu-catalyzed C(sp3)–H Amination of
Cyclohexane.
Substrate scope studies were also carried out on other
hydrocarbons using NH-pyrrole or NH-indole as amine sources
(Scheme 2). As expected, the reaction between NH-indole with
linear alkanes (e.g., pentane or hexane) leads to a variety of N-
alkylated product at C1, C2, C3 carbons. The direct amination of
other cycloalkanes (e.g., cyclopentane and cyclooctane) with NH-
indole allowed the formation of 20 and 21 in 58% and 55% yields,
respectively. Tetrahydrofuran can be also used as suitable
alkylating agent through the regioselective C(sp3)–H bond
activation.[24] The amination occurred at the α-position of the
oxygen atom to afford 22 and 23 in 69% and 61% yields from NH-
2-cyanopyrrole and NH-indole.
Similarly, 1,4-dioxane was
successfully coupled with 2-cyanopyrrole and indole giving the N-
alkylated products 24 and 25 in 68% and 43% yield, respectively.
Interestingly, the reaction of 2-cyanopyrrole with 2,2-
dimethoxypropane led selectively to the formation of N-(2-
methoxypropan-2-yl)-2-cyanopyrrole (26) in 57% yield. This
product results from the substitution of one methoxy group. Methyl
tert-butyl ether reacted at the methoxy position to afford
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10.1002/cssc.201700783
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FULL PAPER
regioselectively the N-alkylated heterocycle 27 in 46% yield. In
contrast, cyclopentyl methyl ether provided a mixture of two
regioisomers 28a and 28b in 1:1 ratio. These regioselectivities are
in line with a radical pathway, in which the radical is stabilized by
the oxygen atom. Finally, from toluene, pyrrole was N-benzylated
in moderate yield.
cleavage of the DTBP peroxide under heating allowed the
formation of tert-butoxyl radical (tBuO•) which is trapped by the
copper(I) A to generate the copper(II) alkoxide B. σ-Bond
metathesis of B with an NH-heterocycle regenerates intermediate
C. The coordination of the N-heterocycle to the copper centre
renders the N atom particularly reactive toward reaction with C-
based radicals (R•), which are generated by abstracting a
hydrogen atom from (cyclo)alkane by tert-butoxyl radical (tBuO•).
Reaction of the alkyl radical (R•) with Cu(II) C should allow the
formation of the Cu(III) intermediate D, which undergoes a
reductive elimination to release the desired N-alkylated
heterocycle and reduce the Cu center to regenerate active
copper(I) A.
CuBr(Me2S) (5 mol%)
NH
N
Alk
L1 (10 mol%)
+
H
Alkyl
DTPB (4 equiv)
tBuOH (1 mL)
135 ºC, 15 h
c = 0.167
mol/L
(0.5 mmol)
N
N
N
N
O
O
CN
23 61%
20 58%
21 55%
22 69%
N
N
Cu
Br
A
N
O
N
tBuO OtBu
"heat"
O
O
N
N
O
N
O
O
CN
tBuO
CN
26 57%[a]
27 46%[b]
24 68%
25 43%
OMe
N
O
N
Br
N
N
N
+
Ph
Cu
tBuOH
N
N
N
CN
Cu
a
CN
b
CN
D
Br
OtBu
B
28 48% (a/b = 1:1[c]
29 24%
HN
Scheme 2. Scope of (Cyclo)Alkanes in Cu-catalyzed C(sp3)–H Amination with
NH-Heterocycle. [a] Using 2,2-dimethoxypropane as alkane source; [b] Using
methyl tert-butyl ether as alkane source; [c] Using methyl cyclopentyl ether as
alkane source
N
N
tBuOH
Cu
Br
N
C
Scheme 4. Proposed Mechanism.
To obtain a better understanding of the mechanism, a radical
control experiment was carried out in the presence of a radical
scavenger (Scheme 3).
When 2 equivalents of 2,2,6,6-
Conclusions
tetramethylpiperidine1-oxyl (TEMPO) was added to the reaction
under the standard conditions, no desired product 1 was detected.
However, we have observed the formation of the adduct
cyclohexane–TEMPO 30 (determined by GC−MS), which implied
that a radical process is involved in the oxidative dehydrogenative
amination of (cyclo)alkanes with NH-heterocycles.
In summary, we have described a copper-catalyzed oxidative
dehydrogenative amination of unactivated alkanes with NH-
heterocycles to produce exclusively the corresponding N-
alkylated products without formation of a C–C bond. Choice of
copper source as well as the phenanthroline ligand were found to
be critical to suppress the formation of C-alkylated heterocycles.
N
A
wide variety of NH-heterocycles including poly-nitrogen
CuBr(Me2S) (5 mol%)
NH
L1 (10 mol%)
heterocyclic compounds were successfully N-alkylated.
Moreover, the reaction conditions tolerate a broad variety of
substituents of the heterocycles such as methyl, methoxy, fluoro,
bromo, ketone, ester, and nitrile. This method employs abundant
and cheap feedstock under oxidative conditions, without any pre-
functionalization or the production of stoichiometric metal salt
waste, making it very attractive for practical use in the preparation
of useful N–alkylated heterocyclic derivatives.
1 trace
+
DTPB (4 equiv.)
tBuOH (1 mL)
TEMPO (2 equiv.)
135 ºC, 15 h
O
N
c = 0.167
mol/L
(0.5 mmol)
30 Major product
observed in GC-MS
Scheme 3. Radical Trapping Experiment with TEMPO.
Based on our experimental results and previous reports,[19]
possible mechanism is described in Scheme 4. First, homolytic
a
Experimental Section
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General Remarks: All reactions were run in Schlenk tubes without
the use of an inert atmosphere. Commercial NH-free heterocycles
and (cyclo)alkanes were used without purification. The reactions
pentane : ethyl acetate = 40 : 1. 1H NMR (300 MHz, CDCl3) δ (ppm)
7.29 (d, J = 8.9 Hz, 1H), 7.21 (d, J = 3.2 Hz, 1H), 7.12 (d, J = 2.4 Hz,
1H), 6.91 – 6.85 (m, 1H), 6.44 (d, J = 3.1 Hz, 1H), 4.17 (tt, J = 11.7,
3.6 Hz, 1H), 3.87 (s, 3H), 2.23 – 2.10 (m, 2H), 2.01 – 1.87 (m, 2H),
1.85 – 1.75 (m, 1H), 1.75 – 1.65 (m, 2H), 1.54 – 1.43 (m, 2H), 1.38 –
1.23 (m, 1H). 13C NMR (101 MHz, CDCl3) δ (ppm) 153.9, 130.9,
128.7, 124.6, 111.5, 110.1, 102.6, 100.5, 55.9, 55.3, 33.6, 26.0, 25.7.
MS(EI) m/z(%) = 229 ([M]+,100), 214 (8), 186 (26), 147 (57), 132
(63), 104 (14), 55( 18).
1
were followed by GC and NMR. H and 13C spectra were recorded
with a Bruker 400 MHz spectrometer in CDCl3 solutions. Chemical
shifts are reported in ppm relative to CDCl3 (7.26 for 1H NMR and
77.0 for 13C NMR). Flash chromatography was performed on silica
gel (230–400 mesh).
General Procedure for Copper-Catalyzed Oxidative Dehydrogenative
C(sp3)–H Bond Amination of (Cyclo)Alkanes with NH-free
Heterocycles: In a dried 25 mL Schlenk tube equipped with a magnetic
N-Cyclohexylindole-5-carbonitrile (5): Following the general
procedure
A. using NH-indole-5-carbonitrile (71 mg, 0.5 mmol) and
stirrer, CuBr(Me2S) (5.0 mg, 0.025 mmol,
5
mol%) and 1,10-
cyclohexane 3 mL, 5
was isolated in 54 % yield (60 mg) as a light
phenanthroline (9.0 mg, 0.05 mmol, 10 mol%) were dissolved in t-BuOH
(1 mL) and (cyclo)alkane (1 mL). Then, NH-free heterocycles (0.5 mmol)
and additional (cyclo)alkane (2 mL) were successfully added before
addition of DTBP (292 mg, 2.0 mmol, 4 equiv.). The resulting solution
mixture was stirred at 135 ºC over 15 h. After evaporation of solvent, the
product was purified using flash column chromatography on silica gel.
yellow oil, after purification using flash column chromatography with
pentane : ethyl acetate = 40 : 1. 1H NMR (300 MHz, CDCl3) δ (ppm)
7.96 (s, 1H), 7.43 – 7.39 (m, 2H), 7.34 (d, J = 3.3 Hz, 1H), 6.58 (d, J
= 3.3 Hz, 1H), 4.23 (tt, J = 3.7, 11.9 Hz, 1H), 2.16 – 2.08 (m, 2H),
2.01 – 1.92 (m, 2H), 1.86 – 1.78 (m, 1H), 1.72 (ddd, J = 3.2, 12.5,
24.7 Hz, 2H), 1.57 – 1.44 (m, 2H), 1.36 – 1.23 (m, 1H). 13C NMR (75
MHz, CDCl3) δ (ppm) 137.0, 128.2, 126.6, 126.5, 124.1, 120.9,
110.3, 102.3, 102.2, 55.6, 33.5, 25.8, 25.5. MS(EI) m/z(%) = 224
([M]+,41), 181 (18), 142 (100),115 (9), 83 (10), 55 (26).
N-Cyclohexylindole (1): Following the general procedure using NH-
indole (58 mg, 0.5 mmol) and cyclohexane (3 mL),
1 was isolated in
67% yield (66 mg) as a colorless oil after purification using flash
column chromatography with pentane : ethyl acetate = 40 : 1. 1H
NMR (300 MHz, CDCl3) δ (ppm) 7.70 (d, J = 7.8 Hz, 1H), 7.45 (d, J
= 8.2 Hz, 1H), 7.30 – 7.22 (m, 2H), 7.16 (d, J = 7.2 Hz, 1H), 4.28 (tt,
J = 3.7, 11.8 Hz, 1H), 2.28 – 2.12 (m, 2H), 2.08 – 1.92 (m, 3H), 1.74
(td, J = 3.1, 12.3 Hz, 2H), 1.56 (tdd, J = 3.3, 8.1, 12.9 Hz, 3H), 1.44
– 1.25 (m, 2H). 13C NMR (75 MHz, CDCl3) δ (ppm) 135.6, 128.5,
124.1, 121.1, 121.0, 119.3, 109.5, 101.0, 55.1, 33.6, 26.1, 25.8.
MS(EI) m/z(%) = 199 ([M]+,49), 156 (30), 130 (10),117 (100), 90 (14),
55 (13).
Methyl N-cyclohexylindole-5-carboxylate (6): Following the
general procedure
A. using methyl NH-indole-5-carboxylate (88 mg,
0.5 mmol) and cyclohexane 3 mL,
6
was isolated in 62 % yield (80
mg) as a light yellow oil, after purification using flash column
chromatography with pentane : ethyl acetate = 30 : 1. 1H NMR (300
MHz, CDCl3) δ (ppm) 8.40 (d, J = 1.3 Hz, 1H), 7.91 (dd, J = 1.6, 8.7
Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 3.3 Hz, 1H), 6.60 (d, J
= 3.2 Hz, 1H), 4.24 (tt, J = 3.7, 11.9 Hz, 1H), 3.93 (s, 3H), 2.13 (d, J
= 11.3 Hz, 2H), 1.95 (d, J = 13.5 Hz, 2H), 1.81 (d, J = 13.1 Hz, 1H),
1.71 (qd, J = 3.2, 12.5 Hz, 2H), 1.58 – 1.44 (m, 2H), 1.36 – 1.22 (m,
1H). 13C NMR (75 MHz, CDCl3) δ (ppm) 168.3, 138.0, 128.0, 125.5,
124.0, 122.5, 121.3, 109.0, 102.8, 55.4, 51.8, 33.5, 25.9, 25.6.
MS(EI) m/z(%) = 257 ([M]+,100), 226 (14), 214 (19),175 (45), 144
(97), 116 (31), 89 (11), 55 (31).
N-Cyclohexyl-6-fluoroindole (2): Following the general procedure
using 6-Fluoro-NH-indole (68 mg, 0.5 mmol) and cyclohexane (3
mL),
2 was isolated in 64% yield (69 mg) as a light yellow oil after
purification using flash column chromatography with pentane : ethyl
acetate = 40 : 1. 1H NMR (300 MHz, CDCl3) δ (ppm) 7.55 (dd, J =
8.6, 5.5 Hz, 1H), 7.22 (d, J = 3.2 Hz, 1H), 7.08 (dd, J = 10.2, 1.7 Hz,
1H), 6.89 (dd, J = 9.4, 2.2 Hz, 1H), 6.51 (d, J = 3.1 Hz, 1H), 4.12 (tt,
J = 11.8, 3.6 Hz, 1H), 2.23 – 2.06 (m, 2H), 2.04 – 1.90 (m, 2H), 1.76
– 1.64 (m, 2H), 1.60 – 1.44 (m, 2H), 1.40 – 1.24 (m, 2H). 19F NMR
(376 MHz, CDCl3) δ(ppm) -121.6. 13C NMR (75 MHz, CDCl3) δ (ppm)
159.6 (d, J = 236.6 Hz), 135.5 (d, J = 12.0 Hz), 124.9, 124.5 (d, J =
3.6 Hz), 121.5 (d, J = 10.2 Hz), 108.0 (d, J = 24.6 Hz), 101.2, 95.9
(d, J = 26.3 Hz), 55.4, 33.4, 25.9, 25.6. MS(EI) m/z(%) = 217
([M]+,36), 174 (11), 135 (100), 108 (14), 55 (19).
Methyl 1-cyclohexyl-1H-indole-3-carboxylate (7): Following the
general procedure
A. using methyl 1H-indole-3-carboxylate (88 mg,
0.5 mmol) and cyclohexane 3 mL,
7
was isolated in 81% yield (104
mg) as a light yellow oil, after purification using flash column
chromatography with pentane : ethyl acetate = 30 : 1. 1H NMR (300
MHz, CDCl3) δ (ppm) 8.24 – 8.19 (m, 1H), 7.97 (s, 1H), 7.45 – 7.38
(m, 1H), 7.31 – 7.25 (m, 2H), 4.23 (tt, J = 3.6, 11.8 Hz, 1H), 3.93 (s,
3H), 2.16 (d, J = 11.5 Hz, 2H), 2.00 – 1.91 (m, 2H), 1.81 (d, J = 13.1
Hz, 1H), 1.76 – 1.64 (m, 2H), 1.58 – 1.43 (m, 2H), 1.36 – 1.23 (m,
1H). 13C NMR (75 MHz, CDCl3) δ (ppm) 165.6, 136.2, 131.0, 126.7,
122.4 121.8, 121.8, 110.0, 106.9, 55.6, 50.9, 33.4, 25.8, 25.5. MS(EI)
m/z(%) = 257 ([M]+,88), 226 (14), 175 (43),144 (100), 116 (12), 55
(23).
5-Bromo-N-cyclohexylindole (3): Following the general procedure
using 5-bromo-NH-indole (97 mg, 0.5 mmol) and cyclohexane (3
mL),
3 was isolated in 94% yield (130 mg) as a light yellow oil after
purification using flash column chromatography with pentane : ethyl
acetate = 40 : 1. 1H NMR (300 MHz, CDCl3) δ (ppm) 7.75 (dd, J =
1.4, 1.0 Hz, 1H), 7.28 – 7.24 (m, 2H), 7.22 (d, J = 3.2 Hz, 1H), 6.45
(d, J = 3.2 Hz, 1H), 4.17 (tt, J = 11.8, 3.7 Hz, 1H), 2.19 – 2.03 (m,
2H), 2.01 – 1.86 (m, 2H), 1.87 – 1.75 (m, 1H), 1.75 – 1.62 (m, 2H),
1.61 – 1.40 (m, 2H), 1.40 – 1.21 (m, 1H). 13C NMR (101 MHz, CDCl3)
δ (ppm) 134.2, 130.1, 125.2, 123.9, 123.4, 112.4, 110.9, 100.6, 55.4,
33.5, 25.9, 25.6. MS(EI) m/z (%) = 277 ([M]+,100), 236 (20), 197
(82), 168 (8), 155 (37), 116 (62), 89 (35), 55(73).
N-Cyclohexylpyrrole (8). Following the general procedure using
NH-pyrrole (34 mg, 0.5 mmol) and cyclohexane (3 mL),
8 was
isolated in 65% yield (48 mg) as a light yellow oil after purification
using flash column chromatography with pentane : ethyl acetate = 40
: 1. 1H NMR (300 MHz, CDCl3) δ (ppm) 6.79 – 6.74 (m, 2H), 6.20 –
6.15 (m, 2H), 3.83 (tt, J = 11.6, 3.6 Hz, 1H), 2.20 – 2.06 (m, 2H), 1.97
– 1.87 (m, 2H), 1.81 – 1.70 (m, 1H), 1.70 – 1.57 (m, 2H), 1.52 – 1.37
(m, 2H), 1.33 – 1.19 (m, 1H). 13C NMR (101 MHz, CDCl3) δ (ppm)
118.4, 107.4, 58.7, 34.7, 25.8, 25.5.
([M]+,67), 106 (19), 94 (23), 67 (100), 55 (23).
MS(EI) m/z(%) = 149
N-Cyclohexyl-5-methoxyindole (4)
procedure using 5-methoxy-NH-indole (74 mg, 0.5 mmol) and
cyclohexane (3 mL), was isolated in 41% yield (46 mg) as a light
yellow oil after purification using flash column chromatography with
.
Following the general
4
2-Acetyl-N-Cyclohexylpyrrole (9). Following the general procedure
using 2-acetyl-NH-pyrrole (55 mg, 0.5 mmol) and cyclohexane (3
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10.1002/cssc.201700783
ChemSusChem
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mL),
9
was isolated in 84% yield (80 mg) as a light yellow oil after
Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.13 (t, J =
7.5 Hz, 1H), 4.60 – 4.26 (m, 1H), 2.11 – 1.99 (m, 2H), 1.99 – 1.92 (m,
2H), 1.84 – 1.74 (m, 1H), 1.63 – 1.59 (m, 1H), 1.54 – 1.41 (m, 2H),
1.41 – 1.30 (m, 2H). 13C NMR (101 MHz, CDCl3) δ (ppm) 138.6,
132.5, 125.8, 124.0, 121.2, 120.4, 109.2, 58.2, 32.5, 25.9, 25.5.
MS(EI) m/z(%) = 200 ([M]+,37), 171 (13), 157 (37), 131(59), 118
(100), 91 (23), 77 (13).
purification using flash column chromatography with pentane : ethyl
acetate = 40 : 1. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.11 – 7.07 (m,
1H), 6.96 (dd, J = 4.0, 1.6 Hz, 1H), 6.14 (dd, J = 4.0, 2.7 Hz, 1H),
5.17 – 5.06 (m, 1H), 2.43 (s, 3H), 2.17 – 1.95 (m, 2H), 1.92 – 1.81
(m, 2H), 1.77 – 1.68 (m, 1H), 1.54 – 1.42 (m, 4H), 1.27 – 1.12 (m,
1H). 13C NMR (101 MHz, CDCl3) δ (ppm) 188.4, 130.0, 125.5, 120.4,
108.1, 56.6, 34.6, 27.8, 25.9, 25.7.
MS(EI) m/z(%) = 191
([M]+,38), 176 (62), 148 (10), 120 (7), 109 (46), 94 (100) 55 (25).
N-Cyclohexylbenzo[d][1,2,3]triazole (15). Following the general
procedure using NH-benzo[d][1,2,3]triazole (60 mg, 0.5 mmol) and
cyclohexane (3 mL), 15 was isolated in 35% yield (35 mg) as a light
yellow oil after purification using flash column chromatography with
pentane : ethyl acetate = 40 : 1. 1H NMR (300 MHz, CDCl3) δ (ppm)
8.06 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.45 (t, J = 6.6 Hz,
1H), 7.34 (d, J = 6.9 Hz, 1H), 4.72 – 4.59 (m, 1H), 2.23 – 2.15 (m,
2H), 2.06 – 1.94 (m, 2H), 1.87 – 1.77 (m, 1H), 1.62 – 1.34 (m, 5H).
13C NMR (101 MHz, CDCl3) δ (ppm) 146.1, 132.2, 126.7, 123.7,
120.1, 109.8, 59.1, 32.6, 25.6, 25.3. MS(EI) m/z(%) = 201
([M]+,26), 147 (12), 133 (27), 120 (100), 91 (57), 64(29), 55(25). mp
102-104 oC.
N-Cyclohexyl-2-propionylpyrrole (10)
. Following the general
procedure using 2-propionyl-NH-pyrrole (62 mg, 0.5 mmol) and
cyclohexane (3 mL), 10 was isolated in 78% yield (80 mg) as a light
yellow oil after purification using flash column chromatography with
pentane : ethyl acetate = 40 : 1. 1H NMR (300 MHz, CDCl3) δ (ppm)
7.10 – 7.07 (m, 1H), 6.98 (dd, J = 1.6, 4.0 Hz, 1H), 6.14 (dd, J = 2.7,
4.0 Hz, 1H), 5.22 – 5.05 (m, 1H), 2.82 (q, J = 7.4 Hz, 2H), 2.14 – 2.00
(m, 2H), 1.92 – 1.78 (m, 2H), 1.79 – 1.67 (m, 1H), 1.54 – 1.44 (m,
4H), 1.20- – 1.17 (m, 1H), 1.17 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz,
CDCl3) δ (ppm) 191.9, 129.7, 125.2, 119.3, 108.0, 56.7, 34.6, 32.7,
25.9, 25.7, 9.0. MS(EI) m/z(%) = 205 ([M]+,24), 176 (42), 162
(3), 148 (8), 123 (14), 94(100), 81 (5),55(16).
N-Cyclohexyl-5,6-dimethylbenzo[d][1,2,3]triazole (16). Following
the general procedure using 5,6-dimethyl-NH-benzo[d][1,2,3]triazole
(74 mg, 0.5 mmol) and cyclohexane (3 mL), 16 was isolated in 30%
yield (35 mg) as a light yellow solid after purification using flash
column chromatography with pentane : ethyl acetate = 40 : 1. 1H
NMR (300 MHz, CDCl3) δ (ppm) 7.79 (s, 1H), 7.33 (s, 1H), 4.68 –
4.52 (m, 1H), 2.44 (s, 3H), 2.41 (s, 3H), 2.21 – 2.14 (m, 4H), 2.07 –
1.96 (m, 2H), 1.86 – 1.77 (m, 1H), 1.61 – 1.34 (m, 3H). 13C NMR (75
MHz, CDCl3) δ (ppm) 145.4, 136.9, 133.4, 131.2, 119.1, 109.3, 58.9,
32.5, 25.6, 25.3, 20.9, 20.4. MS (EI) m/z(%) = 229 ([M]+,26), 158 (9),
119(100), 91 (13), 55 (36). mp 122-124 oC.
N-Cyclohexylpyrrole-2-carbonitrile (11). Following the general
procedure using NH-pyrrole-2-carbonitrile (46 mg, 0.5 mmol) and
cyclohexane (3 mL), 11 was isolated in 97% yield (84 mg) as a light
yellow oil after purification using flash column chromatography with
pentane : ethyl acetate = 40 : 1. 1H NMR (300 MHz, CDCl3) δ (ppm)
6.91 (dd, J = 2.6, 1.6 Hz, 1H), 6.74 (dd, J = 3.9, 1.6 Hz, 1H), 6.15 (dd,
J = 3.9, 2.8 Hz, 1H), 4.08 (tt, J = 11.9, 3.8 Hz, 1H), 2.14 – 2.03 (m,
2H), 1.96 – 1.84 (m, 2H), 1.80 – 1.69 (m, 1H), 1.69 – 1.57 (m, 2H),
1.52 – 1.35 (m, 2H), 1.30 – 1.18 (m, 1H). 13C NMR (75 MHz, CDCl3)
δ (ppm) 123.1, 119.6, 114.1, 109.2, 102.8, 58.4, 34.2, 25.6, 25.2.
MS(EI) m/z(%) = 174 ([M]+,59), 93 (84), 83 (38), 67 (52), 55 (100).
N-Cyclohexyl-5-methylbenzo[d][1,2,3]triazole (17a) and N-
cyclohexyl-6-methylbenzo[d][1,2,3]triazole (17b). Following the
general procedure using 5-methyl-NH-benzo[d][1,2,3]triazole (74
mg, 0.5 mmol) and cyclohexane (3 mL), 17a and 17b was isolated in
41% yield (44 mg) in 45:55 ratio as a light yellow oil after purification
using flash column chromatography with pentane : ethyl acetate = 40
: 1. 1H NMR (300 MHz, CDCl3) δ (ppm) 7.92 (d, J = 8.5 Hz, 1H, 17b),
7.81 (s, 1H, 17a), 7.46 (d, J = 8.5 Hz, 1H, 17a), 7.34 (s, 1H, 17b),
7.31 – 7.26 (m, 1H, 17a), 7.17 (dd, J = 1.4, 8.5 Hz, 1H, 17b), 4.76 –
Ethyl-N-cyclohexyl-3,5-dimethylpyrrole-2-carboxylate
(12).
Following the general procedure using ethyl 3,5-dimethyl-NH-
pyrrole-2-carboxylate (84 mg, 0.5 mmol) and cyclohexane (3 mL), 12
was isolated in 55% yield (68 mg) as a light yellow oil after purification
using flash column chromatography with pentane : ethyl acetate = 40
: 1. 1H NMR (300 MHz, CDCl3) δ (ppm) 5.73 (s, 1H), 5.08 – 4.77 (m,
1H), 4.28 (q, J = 7.1 Hz, 2H), 2.33 (s, 3H), 2.25 (s, 3H), 2.14 – 1.96
(m, 2H), 1.91 – 1.80 (m, 4H), 1.76 – 1.62 (m, 2H), 1.36 (t, J = 7.1 Hz,
3H), 1.30 – 1.16 (m, 2H). 13C NMR (75 MHz, CDCl3) δ (ppm) 162.3,
135.4, 129.6, 119.5, 112.5, 59.4, 57.1, 31.9, 26.6, 25.5, 15.2, 14.7,
14.5. MS(EI) m/z(%) = 249 ([M]+,96), 204 (23), 176 (68), 167
(72), 138 (82), 121 (100), 95 (76), 55 (36).
4.47 (m, 1H, 17a
2.09 (m, 4H, 17a
(m, 1H, 17a 17b), 1.61 – 1.46 (m, 2H, 17a
17a
17b). 13C NMR (75 MHz, CDCl3) δ (ppm) 146.7 (17a), 144.7
17b), 137.2 (17b), 133.7 (17a), 132.7 (17a), 130.7 (17b), 129.1
+
+
17b), 2.54 (s, 3H, 17b), 2.51 (s, 3H, 17a), 2.23 –
17b), 2.08 – 1.92 (m, 2H, 17a 17b), 1.87 – 1.75
17b), 1.45 – 1.33 (m, 1H,
+
+
+
+
(
(
(
17a), 126.0 (17b), 119.4 (17b), 118.9 (17a), 109.3 (17b), 109.0
17a), 59.0 (17a), 58.8 (17b), 32.5 (17a), 32.5 (17b), 25.6 (17a and
N-Cyclohexyl-3,5-dimethylpyrazole (13). Following the general
procedure using 3,5-dimethyl-1H-pyrazole (48 m, 0.5 mmol) and
cyclohexane (3 mL), 13 was isolated in 44% yield (39 mg) as a light
yellow oil after purification using flash column chromatography with
pentane : ethyl acetate = 40 : 1. 1H NMR (300 MHz, CDCl3) δ (ppm)
5.75 (s, 1H), 3.96 – 3.74 (m, 1H), 2.23 (s, 3H), 2.22 (s, 3H), 1.93 –
1.81 (m, 6H), 1.74 – 1.64 (m, 1H), 1.43 – 1.27 (m, 3H). 13C NMR (75
MHz, CDCl3) δ (ppm) 146.8, 137.6, 104.5 (d, J = 11.9 Hz), 57.2 (d, J
= 10.7 Hz), 32.9, 25.9, 25.2, 13.6 (d, J = 8.9 Hz), 11.0 (d, J = 9.1 Hz).
MS(EI) m/z(%) = 178 ([M]+,30), 163 (9), 135 (9), 123 (14), 109 (63),
97 (100), 81 (9).
17b), 25.3 (17a and 17b), 22.0 (17a or 17b), 21.4 (17a or 17b). MS
(EI) m/z(%) = 215 ([M]+,74), 186 (15), 172(28), 158 (75), 144 (53),
105 (100), 91 (38), 55 (76).
N-Cyclohexylbenzenesulfonamide (18). Following the general
procedure using benzenesulfonamide (79 mg, 0.5 mmol) and
cyclohexane (3 mL), 18 was isolated in 96 % yield (114 mg) as a light
yellow oil after purification using flash column chromatography with
pentane : ethyl acetate = 10 : 1. 1H NMR (400 MHz, CDCl3) δ (ppm)
7.93 – 7.86 (m, 2H), 7.57 – 7.51 (m, 1H), 7.51 – 7.43 (m, 2H), 5.14
(d, J = 7.5 Hz, 1H), 3.18 – 3.03 (m, 1H), 1.74 – 1.66 (m, 2H), 1.64 –
1.56 (m, 2H), 1.51 – 1.41 (m, 1H), 1.27 – 1.19 (m, 1H), 1.19 – 1.12
(m, 3H), 1.12 – 1.00 (m, 1H). 13C NMR (101 MHz, CDCl3) δ (ppm)
141.5, 132.4, 129.0, 126.9, 52.7, 33.8, 25.1, 24.6. MS (EI)
m/z(%) = 239 ([M]+,32), 210 (7), 196 (87), 158 (9), 141(72), 98 (46),
77 (100), 51 (23).
N-Cyclohexylindazole (14). Following the general procedure using
NH-indazole (59 mg, 0.5 mmol) and cyclohexane (3 mL), 14 was
isolated in 56% yield (56 mg) as a light yellow oil after purification
using flash column chromatography with pentane : ethyl acetate = 40
: 1. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.02 (s, 1H), 7.73 (d, J = 8.1
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10.1002/cssc.201700783
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4-Chloro-N-Cyclohexylbenzenesulfonamide (19). Following the
general procedure using 4-chlorobenzenesulfonamide (95 mg, 0.5
mmol) and cyclohexane (3 mL), 19 was isolated in 86% yield (117
mg) as a light yellow solid after purification using flash column
chromatography with pentane : ethyl acetate = 10 : 1. 1H NMR (400
MHz, CDCl3) δ (ppm) 7.83 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz,
1H), 5.15 (d, J = 7.6 Hz, 1H), 3.12 (tt, J = 6.8, 13.5 Hz, 1H), 1.76 –
1.67 (m, 2H), 1.64 – 1.56 (m, 2H), 1.53 – 1.42 (m, 1H), 1.26 – 1.05
(m, 5H). 13C NMR (75 MHz, CDCl3) δ (ppm) 140.1, 138.8, 129.3,
128.4, 52.8, 33.8, 25.1, 24.6. MS (EI) m/z(%) = 273 ([M]+,34), 244
(7), 230 (100), 175 (70), 153 (8), 111(84), 75 (33), 55(21).
light yellow oil after purification using flash column chromatography
with pentane : ethyl acetate = 40 : 1. 1H NMR (400 MHz, CDCl3) δ
(ppm) 7.20 (dd, J = 2.7, 1.5 Hz, 1H), 6.85 (dd, J = 3.9, 1.4 Hz, 1H),
6.23 (t, J = 3.6 Hz, 1H), 5.55 (dd, J = 6.7, 3.0 Hz, 1H), 4.01 (dd, J =
11.8, 3.0 Hz, 1H), 3.93 – 3.71 (m, 5H). 13C NMR (101 MHz, CDCl3)
δ (ppm) 125.1, 121.2, 113.2, 110.1, 103.6, 80.6, 68.7, 66.0, 64.9.
MS(EI) m/z(%) = 178 ([M]+,20), 118 (7), 86 (100), 59 (12).
N-(1,4-Dioxan-2-yl)indole (25). Following the general procedure
A.
using NH-indole (58 mg, 0.5 mmol) and 1,4-dioxane (3 mL), 25 was
isolated in 43% yield (44 mg) as a white solid after purification using
flash column chromatography with pentane : ethyl acetate = 40 : 1.
1H NMR (400 MHz, CDCl3) δ (ppm) 7.68 (d, J = 7.8 Hz, 1H), 7.52 (d,
J = 8.2 Hz, 1H), 7.47 (d, J = 3.4 Hz, 1H), 7.32 – 7.26 (m, 1H), 7.23 –
7.16 (m, 1H), 6.61 (d, J = 3.2 Hz, 1H), 5.80 – 5.74 (m, 1H), 4.14 –
4.10 (m, 2H), 3.97 – 3.81 (m, 4H). 13C NMR (101 MHz, CDCl3) δ
(ppm) 136.1, 128.8, 125.5, 122.2, 121.1, 120.4, 110.1, 103.0, 79.2,
68.7, 66.4, 64.6. MS (EI) m/z (%) = 203([M]+,18), 117(100), 90 (12).
mp 76-78 oC.
N-Cyclopentylindole (20). Following the general procedure using
NH-indole (58 mg, 0.5 mmol) and cyclopentane (3 mL), 20 was
isolated in 58 % yield (54 mg) as a light orange oil after purification
using flash column chromatography with pentane : ethyl acetate = 40
: 1. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.69 (d, J = 7.8 Hz, 1H), 7.46
(d, J = 8.2 Hz, 1H), 7.30–7.23 (m, 2H), 7.20–7.12 (m, 1H), 6.56 (d, J
= 3.2 Hz, 1H), 4.91–4.79 (m, 1H), 2.32 – 2.21 (m, 2H), 2.06–1.90 (m,
4H), 1.86–1.77 (m, 2H). 13C NMR (75 MHz, CDCl3) δ (ppm) 136.2,
128.6, 124.5 (d, J = 6.9 Hz), 121.2 (d, J = 1.8 Hz), 120.9 (d, J = 4.2
Hz), 119.3, 109.9, 101.0, 57.0, 32.6, 24.1. MS (EI) m/z(%) = 185
([M]+,40), 156 (24), 117 (100), 90 (16).
N-(2-Methoxypropan-2-yl)pyrrole-2-carbonitrile (26)
. Following
the general procedure using NH-pyrrole-2-carbonitrile (46 mg, 0.5
mmol) and 2,2-dimethoxypropane (3 mL), 26 was isolated in 57%
yield (47 mg) as a light yellow oil after purification using flash column
chromatography with pentane : ethyl acetate = 40 : 1. 1H NMR (400
MHz, CDCl3) δ (ppm) 6.93 (dd, J = 2.8, 1.7 Hz, 1H), 6.91 (dd, J = 3.8,
1.6 Hz, 1H), 6.15 (dd, J = 3.7, 3.0 Hz, 1H), 3.12 (s, 3H), 1.81 (s, 6H).
13C NMR (101 MHz, CDCl3) δ (ppm) 124.3, 123.4, 114.7, 108.7,
101.4, 89.8, 50.1, 27.0. MS(EI) m/z(%) = 164 ([M]+,4), 133 (11),
92(11), 73 (100).
N-Cyclooctylindole (21). Following the general procedure using
NH-indole (58 mg, 0.5 mmol) and cyclooctane (3 mL), 21 was
isolated in 55% yield (62 mg) as a light yellow oil after purification
using flash column chromatography with pentane : ethyl acetate = 40
: 1. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.69 (d, J = 7.9 Hz, 1H),
7.43 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 3.3 Hz, 1H), 7.24 (d, J = 7.5 Hz,
1H), 7.15 (t, J = 7.5 Hz, 1H), 6.55 (d, J = 3.1 Hz, 1H), 4.63 – 4.53 (m,
1H), 2.21 – 1.99 (m, 2H), 1.94 – 1.83 (m, 2H), 1.82 – 1.65 (m, 10H).
13C NMR (75 MHz, CDCl3) δ (ppm) 135.3, 128.5, 124.7, 121.1, 121.0,
119.2, 109.6, 101.0, 56.0, 33.4, 26.9, 26.1, 24.9. MS (EI) m/z(%) =
227 ([M]+,67), 156 (54), 143 (37), 130 (23), 117 (100), 90 (14), 69
(15), 14 (55).
N-(Tert-butoxymethyl)indole (27). Following the general procedure
using NH-indole (58 mg, 0.5 mmol) and 2-methoxy-2-methylpropane
(3 mL), 27 was isolated in 46% yield (47 mg) as a light yellow oil after
purification using flash column chromatography with pentane : ethyl
acetate = 40 : 1. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.66 (d, J = 7.9
Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.31 – 7.25 (m, 1H), 7.22 (d, J =
3.2 Hz, 1H), 7.20 – 7.14 (m, 1H), 6.56 (d, J = 3.2 Hz, 1H), 5.56 (s,
2H), 1.29 (s, 9H). 13C NMR (101 MHz, CDCl3) δ (ppm) 136.1, 129.1,
127.5, 121.9, 120.9, 119.9, 110.1, 102.4, 74.2, 70.3, 28.0. MS(EI)
m/z(%) = 203 ([M]+,20), 130 (35), 117(100), 57 (22).
N-(Tetrahydrofuran-2-yl)pyrrole-2-carbonitrile (22). Following the
general procedure using NH-pyrrole-2-carbonitrile (46 mg, 0.5 mmol)
and tetrahydrofuran (3 mL), 22 was isolated in 69% yield (56 mg) as
a light yellow oil after purification using flash column chromatography
with pentane : ethyl acetate = 40 : 1. 1H NMR (400 MHz, CDCl3) δ
(ppm) 6.97 (dd, J = 1.7, 2.5 Hz, 1H), 6.83 (dd, J = 1.5, 3.8 Hz, 1H),
6.17 (t, J = 3.4 Hz, 1H), 6.00 (dd, J = 3.7, 6.5 Hz, 1H), 4.21 (dd, J =
7.4, 14.1 Hz, 1H), 3.99 (dd, J = 7.2, 15.3 Hz, 1H), 2.54 – 2.35 (m,
1H), 2.28 – 2.17 (m, 1H), 2.16 – 2.00 (m, 2H). 13C NMR (101 MHz,
CDCl3) δ (ppm) 123.6, 121.4, 113.7, 109.6, 101.6, 88.3, 69.5, 33.6,
24.5. MS(EI) m/z(%) = 162 ([M]+,12), 131 (5), 92 (10), 71 (100).
N-((Cyclopentyloxy)methyl)pyrrole-2-carbonitrile (28a) and 1-(1-
methoxycyclopentyl)pyrrole-2-carbonitrile (28b). Following the
general procedure using NH-pyrrole-2-carbonitrile (46 mg, 0.5 mmol)
and methoxycyclopentane (3 mL), 28a was isolated in 24% yield (23
mg) as pure form as a light yellow oil, and 28b was isolated in 24%
yield (23 mg) as pure form as a light yellow oil after purified using
flash column chromatography with pentane : ethyl acetate = 40 : 1.
28a 1H NMR (400 MHz, CDCl3) δ (ppm) 7.00 (dd, J = 2.6, 1.6 Hz,
1H), 6.83 (dd, J = 3.9, 1.5 Hz, 1H), 6.24 (dd, J = 3.8, 2.9 Hz, 1H),
5.35 (s, 2H), 4.01 – 3.91 (m, 1H), 1.68 (ddd, J = 6.9, 4.2, 1.7 Hz, 4H),
1.63 – 1.44 (m, 4H). 13C NMR (101 MHz, CDCl3) δ (ppm) 126.7,
N-(Tetrahydrofuran-2-yl)indole (23)
.
Following the general
procedure using NH-indole (58 mg, 0.5 mmol) and tetrahydrofuran (3
mL), 23 was isolated in 61% yield (57 mg) as a colorless yellow oil
after purification using flash column chromatography with pentane :
ethyl acetate = 40 : 1. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.69 (d, J
= 7.8 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.31 – 7.26 (m, 2H), 7.20 (t,
J = 7.5 Hz, 1H), 6.60 (d, J = 3.1 Hz, 1H), 6.60 (d, J = 3.1 Hz, 1H),
6.29 (dd, J = 6.1, 4.3 Hz, 1H), 4.18 (td, J = 7.9, 6.0 Hz, 1H), 4.05 (dd,
J = 15.3, 7.3 Hz, 1H), 2.47 – 2.39 (m, 2H), 2.26 – 2.11 (m, 2H). 13C
NMR (101 MHz, CDCl3) δ (ppm) 135.7, 129.2, 124.0, 121.8, 121.0,
120.0, 110.0, 102.3, 85.8, 68.4, 31.6, 24.8. MS(EI) m/z (%) = 187
([M]+,21), 117 (100), 89 (10), 71 (22).
120.9, 113.4, 110.4, 104.0, 80.2, 76.1, 32.3, 23.5.
MS(EI)
m/z(%) = 190 ([M]+,51), 159 (43), 145 (15), 132 (25), 106 (100), 97
(25), 71 (48), 67 (52).
28 b 1H NMR (400 MHz, CDCl3) δ (ppm) 6.97 (dd, J = 2.8, 1.7 Hz,
1H), 6.90 (dd, J = 3.8, 1.6 Hz, 1H), 6.13 (dd, J = 3.8, 2.9 Hz, 1H),
2.96 (s, 3H), 2.59 – 2.47 (m, 2H), 2.20 – 2.06 (m, 2H), 1.92 – 1.73
(m, 4H). 13C NMR (101 MHz, CDCl3) δ (ppm) 125.3, 123.2, 114.7,
108.4, 102.5, 99.1, 50.0, 35.9, 22.2.
MS(EI) m/z(%) = 190
N-(1,4-Dioxan-2-yl)pyrrole-2-carbonitrile (24)
.
Following the
([M]+,4), 119 (3), 106 (4), 92 (100), 78 (77), 69(44), 51(12).
general procedure using NH-pyrrole-2-carbonitrile (46 mg, 0.5 mmol)
and 1,4-dioxane (3 mL), 24 was isolated in 68% yield (60 mg) as a
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10.1002/cssc.201700783
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X. Hu, Z. Wang, T. Yang, H. Sun, G. Li, H. Lu, Chem. Eur. J. 2016, 22,
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N-Benzylpyrrole-2-carbonitrile (29)
.
Following the general
procedure using NH-pyrrole-2-carbonitrile (46 mg, 0.5 mmol,) and
toluene (3 mL), 29 was isolated in 24% yield (22 mg) as a light yellow
oil after purification using flash column chromatography with pentane
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Acknowledgements
We acknowledge the China Scholarship Council (CSC) for a grant
to C.-S.W. and the Centre National de la Recherche Scientifique
(CNRS) and “Rennes Metropole” for providing financial support
Keywords: Alkanes• Amination • Copper • C(sp3)–H Activation •
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C.-S. Wang, X.-F. Wu, P. H. Dixneuf and
J.-F. Soulé*
Page No. – Page No.
Copper-Catalyzed Oxidative
Dehydrogenative C(sp3)–H Bond
Amination of (Cyclo)Alkanes using
NH-Free Heterocycles as Amine
Sources
A variety of N-alkylated heterocycles is facilely synthesized by direct C−H bond
amination of low cost (cyclo)alkanes catalyzed by inexpensive copper salts. A
broad NH-free heterocycles scope has been used as amine sources and the
reaction displayed a good functional group compatibility.
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