Synthesis of 1,2-Disubstituted Indoles from α-Aminonitriles and 2-Halobenzyl Halides

Article abstract of DOI:10.1021/acs.joc.5b02659

The α-alkylation of deprotonated Strecker products derived from primary amines and aromatic aldehydes with 2-halobenzyl halides furnishes intermediates that can be cyclized to 1,2-disubstituted indoles in moderate to high yields (up to 94% over two steps) by microwave-assisted copper- or palladium-catalyzed intramolecular cross-coupling.

Full text of DOI:10.1021/acs.joc.5b02659

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Article
Synthesis of 1,2-Disubstituted Indoles from
alpha-Aminonitriles and 2-Halobenzyl Halides
Anne-Katrin Bachon, and Till Opatz
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02659 • Publication Date (Web): 02 Feb 2016
Downloaded from http://pubs.acs.org on February 3, 2016
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Synthesis of 1,2-Disubstituted Indoles from α-Aminonitriles and 2-
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Halobenzyl Halides
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AnneꢀKatrin Bachon and Till Opatz*
Institute of Organic Chemistry, Johannes GutenbergꢀUniversity, Duesbergweg 10–14, Dꢀ
55128 Mainz, Germany
Eꢀmail: opatz@uniꢀmainz.de
Abstract. The αꢀalkylation of deprotonated Strecker products derived from primary
amines and aromatic aldehydes with 2ꢀhalobenzyl halides furnishes intermediates which
can be cyclized to 1,2ꢀdisubstituted indoles in moderate to high yields (up to 94% over
two steps) by microwaveꢀassisted copperꢀ or palladiumꢀcatalyzed intramolecular cross
coupling.
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Introduction
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The indole nucleus is one of the most ubiquitous moieties found in bioactive heterocyclic
compounds. Various drugs and an overwhelming number of natural products bearing an
indole moiety are known, e.g. serotonin, lysergic acid and the triptans.1ꢀ3 Due to its
paramount role in the chemistry of life, numerous synthetic approaches towards indoles
have been developed over the last century, including wellꢀestablished procedures like
the Fischer indole synthesis, the Larock indole synthesis and the BatchoꢀLeimgruber
synthesis.4ꢀ7 In view of the large structural diversity of indole derivatives and their
importance for biomedical applications, the development and improvement of new and
efficient protocols for the assembly and decoration of indoles still represent a rewarding
task for academic and industrial research. In the past decades transition metalꢀcatalyzed
cross coupling reactions and cyclizations have emerged as powerful tools for the
synthesis of heterocycles. Today numerous transitionmetalꢀcatalyzed syntheses of
indoles exist, including catalysis by copper, palladium, ruthenium and other metals.8,9
The Hegedus indole synthesis and the Larock indole synthesis are only two out of many
examples for transition metalꢀcatalyzed indole syntheses.4,10
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One possible retrosynthetic strategy for the synthesis of substituted indoles (9) focuses
on the transition metalꢀcatalyzed cyclization of imines 3 or the corresponding enamines.
The employed imines or enamines are mostly formed in situ from ketones 1a and
amines, as reported by May et al. and by Karchava et. al.11,12 A Pdꢀcatalyzed double
arylation of preformed imines was used by the Barluenga group to access intermediates
3 in situ which cyclize to indoles 9 under the same reaction conditions.13 The Buchwald
group obtained indoles 9 by oxidation of indolines 5 prepared by Pdꢀcatalyzed aryl
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9
amination reaction from dibromides 4a.14 Following the same strategy, Monguchi et al.
obtained indoles 9 from phenethylamines 4b.15 The Willis group synthesized
benzofurans and benzothiphenes from benzyl ketones.16 The same authors also
employed 2ꢀ(2ꢀhaloalkenyl)halides 1b and amines as substrates for the synthesis of
indoles 9.17 Following this retrosynthetic approach, we assumed that it should also be
possible to prepare 1,2ꢀsubstituted indoles 9 by transition metalꢀcatalyzed cyclization
from αꢀaminonitriles 8 which in turn can be prepared by Cꢀbenzylation of αꢀaminonitriles
7. Substrates 7 can be easily obtained from cheap and commercially available starting
materials using a Strecker reaction. Thus, the C2–Nꢀfragment of the indole ring would be
preassembled in a modular fashion prior to attachment of the other ring atoms
(Scheme 1).
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Scheme 1: Exemplary synthetic approaches towards indoles.
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The outlined route should also permit the synthesis of isoquinolineꢀ1ꢀones by a
carbonylative process. Isoquinolineꢀ1ꢀones (isocarbostyrils) are also found in nature,
although they are not as wellꢀknown and widespread as indoles. Nevertheless, their
skeleton is represented in a number of alkaloids and drugs with interesting
pharmaceutical and biological properties, e.g. narciclasine, palonosetron and tilisolol.
Since isoquinolineꢀ1ꢀones are found in antidepressant, antiꢀinflammatory and anticancer
drugs, , diverse methods for their preparation exist.18ꢀ21 Two of these strategies also
feature the construction of the C1–C8a and the C1–N bond. Lete et al. prepared
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isoquinolineꢀ1ꢀones by oꢀlithiiation, formylation and cyclization of phenethylamines, while
a transition metalꢀcatalyzed carbonylation/cyclization from oꢀbromophenethylamines was
employed by Beak et al.22,23
Results and Discussion
In a first attempt to synthesize 1,2ꢀdisubstituted indoles 9, 1,2ꢀdiphenylꢀ1Hꢀindole (9a)
was chosen as a model compound. 2ꢀPhenylꢀ2ꢀphenylaminoacetonitrile (7a) was
Cꢀalkylated with 1ꢀ(bromomethyl)ꢀ2ꢀiodobenzene (6a) to obtain a starting material for
transition metalꢀcatalyzed cyclization reactions. An alkylation procedure developed
earlier by us for the synthesis of 4ꢀquinolones was used as the starting point for an
optimization of the reaction conditions.24 It turned out that the deprotonation should be
carried out at –78 °C while the temperature should be gradually raised to –20 °C after
addition of the electrophile to ensure a complete conversion and to prevent the
undesired retroꢀStrecker reaction (Scheme 2).
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CN
Br
6a
Ph
Ph
N
N
CN
CN
H
KHMDS
I
Ph
Ph
Ph
Ph
N
N
Ph
N
Ph
THF
–78 °C –20 °C
THF
–78 °C
I
H
H
H
8a
7a
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Scheme 2: Deprotonation and alkylation of α-aminonitriles 7 affording α-aminonitriles 8.
The anionꢀstabilizing effect of at least one C=C double bond or an aromatic or
heteroaromatic ring in conjugation to the αꢀcenter of the αꢀaminonitrile is required to
ensure the correct regiochemistry in the deprotonation step if no Nꢀprotecting groups are
used.25 The results of the alkylation of αꢀaminonitriles 7a–n with 1ꢀ(bromomethyl)ꢀ2ꢀ
iodobenzene (6a) or 1ꢀ(bromomethyl)ꢀ2ꢀbromobenzene (6b) are summarized below
(Table 1). In particular the alkylation of αꢀaminonitriles 7 carrying bulky Nꢀsubstituents R2
with the sterically more demanding electrophile 6a afforded lower yields while higher
yields were observed for αꢀaminonitriles with electron withdrawing Nꢀsubstituents (e.g.
the 4ꢀbenzoylphenylꢀsubstituent in 8f and 8i). Since the alkylation products 8 were prone
to spontaneous dehydrocyanation, isolation and purification by silica gel column
chromatography was impracticable and the crude alkylation products were subjected to
the metalꢀcatalyzed ring closure (vide infra). Only compounds 8a, 8b, and 8f could be
purified by flash chromatography without significant losses of yield or complete
decomposition.
Table 1: Synthesis of alkylated α-aminonitriles 8a–o.a
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Entry
1
Aminonitrile
R1
R2
Ph
X
Product
8a
Yield/%
43b
70b
85c
77c
39c
66b
70c
32c
95c
62c
38c
96c
71c
31c
68c
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7a
7a
7b
7c
7d
7e
7f
Ph
I
Br
I
2
Ph
Ph
8b
8c
3
Ph
Cy
4
Ph
iPr
Br
Br
I
8d
8e
5
4ꢀCl–C6H4
4ꢀMeO–C6H4
4ꢀCl–C6H4
naphthalenꢀ2ꢀyl
naphthalenꢀ2ꢀyl
naphthalenꢀ2ꢀyl
4ꢀMeO–C6H4
4ꢀCl–C6H4
4ꢀCl–C6H4
4ꢀMeO–C6H4
4ꢀF–C6H4
mesityl
6
4ꢀbenzoylphenyl
4ꢀMeO–C6H4
4ꢀMeO–C6H4
4ꢀbenzoylphenyl
Me
8f
7
I
8g
8h
8i
8
7g
7h
7i
I
9
I
10
11
12
13
14
15
I
8j
7j
mesityl
I
8k
7k
7l
4ꢀCl–C6H4
pꢀtolyl
I
8l
I
8m
8n
8o
7m
7n
pꢀtolyl
I
CH2CH2Ph
I
a: Reaction conditions: 7 (1.0 equiv.), KHMDS (1.3 equiv.), 6a or 6b (1.3 equiv.) in THF (12 mL per mmol
7) at –78 °C to –20 °C; b: Isolated yield.; c: Determined using dimethyl sulfone as internal NMRꢀ
standard.26
The cyclization of alkylation product 8a to indole 9a was attempted in a copperꢀcatalyzed
Ullmannꢀtype reaction and with a palladiumꢀcatalyzed BuchwaldꢀHartwigꢀtype
reaction.27ꢀ30 Both methods were optimized with respect to catalyst loadings and yields
before αꢀaminonitriles 7b–n were synthesized and subjected to the reaction sequence to
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investigate the scope of the reaction. As the bromides proved to be unsuitable for the
copperꢀcatalyzed cross coupling reaction, only the iodides could be employed.
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Initial experiments on the Ullmannꢀtype cyclization of 8a to 9a were performed according
to a modified protocol of Ma and Cai employing CuI (50 mol%), dimethylglycine
(50 mol%) and K3PO4 (2.0 equiv.) in 1,4ꢀdioxane with microwave irradiation at 150 °C.31
Since 9a could not be obtained under these conditions, other solvents (DMF, DMSO,
NMP) were tested, proving NMP to be the most suitable reaction medium (Table 2).
Table 2: Screening of different solvents for the Ullmann-type reaction.a
Entry
solvent
1,4ꢀdioxane
DMF
Reaction Conditions
150 °C, 10 min
220 °C, 10 min
290 °C, 10 min
180 °C, 10 min
Yield/ %
1
2
3
4
ꢀ
40b
ꢀ
DMSO
NMP
62b
a: Reaction conditions: CuI (0.5 equiv.), dimethylglycine (0.5 equiv.), K3PO4 (2.0 equiv.) under microwave
irradiation.; b: Determined using dimethyl sulfone as internal NMRꢀstandard.26
Under the aboveꢀmentioned conditions with NMP as the solvent, 9a could be obtained in
a yield of 62%. In the course of the optimization process the catalytic system was
changed to CuBr·SMe2 (50 mol%) and Cs2CO3 (2.0 equiv.) in NMP with microwave
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irradiation at 180 °C and afforded 9a in quantitative yield within 1 h. Attempts to reduce
the catalyst loading to 20 mol% resulted in lower yields but these could be increased by
addition of neocuproine hemihydrate as a ligand for copper. Prior to the optimization
process, dimethyl glycine, 1,10ꢀphenanthroline and 1,2ꢀdiaminocyclohexane were
screened as alternative ligands. While the utilization of 1,2ꢀdiaminocyclohexane resulted
in slightly lower yields compared to neocuproine, utilization of dimethyl glycine was
impractible due to low conversion. Application of 1,10ꢀphenanthroline surprisingly did not
lead to any conversion of 8a to 9a, since the catalyst precipitated under identical
conditions. The optimization process also revealed that a longer reaction time resulted in
decreased yields (Table 3).
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Table 3: Optimization of the Ullmann-type reaction.a
Catalyst
Reaction
Entry
Ligand
Solvent
Yield/ %
loading/ mol%
conditions
1
2
3
50
20
20
ꢀ
NMP
NMP
NMP
180 °C, 60 min
180 °C, 60 min
180 °C, 60 min
quant,b
43b
ꢀ
Neocup,
1,2ꢀDiaminoꢀ
cyclohexane
Neocup,
64b
4
20
NMP
180 °C, 60 min
58c
5
6
7
20
20
20
NMP
NMP
NMP
180 °C, 20 min
150 °C, 60 min
180 °C, 120 min
32c
ꢀd
Neocup,
Neocup
54b
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20c
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7
8
a: Reaction conditions: CuBr⋅SMe2, ligand (ligandꢀcopperꢀratio 1:1), Cs2CO3 (2.0 equiv.) in NMP with
microwave irradiation.; b: Isolated yield.; c: Determined using dimethyl sulfone as internal NMRꢀ
standard.26; d: Due to low purity, the yield could not be determined.
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Decreasing the temperature led to a drastically increased amount of byproducts and
incomplete convcersion. Subsequently, other alkylated αꢀaminonitriles were subjected
without prior purification to the modified reaction conditions to obtain indoles 9a–g in 28–
76% yield over two steps from aminonitriles 7 (Table 4).
Table 4: Synthesis of indoles 9 from α-aminonitriles 7 by copper-catalyzed cyclization.
Yield (from
Entry
Aminonitrile
R1
R2
Product
7)/%a
28
1
2
3
4
5
6
7
7a
7b
7f
Ph
Ph
Cy
9a
9b
9c
9d
9e
9f
Ph
76
4ꢀCl–C6H4
naphthalenꢀ2ꢀyl
naphthalenꢀ2ꢀyl
4ꢀCl–C6H4
4ꢀF–C6H4
4ꢀMeO–C6H4
4ꢀbenzoylphenyl
Me
56
7h
7i
76
46
7k
7n
4ꢀCl–C6H4
CH2CH2Ph
64
9g
58
a: Isolated yield.
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The cyclization of alkylated αꢀaminonitriles 8 was also performed in a palladiumꢀ
catalyzed BuchwaldꢀHartwigꢀtype reaction. The method was optimized for the
conversion of 8b to indole 9a (for key steps of the optimization process, see Table 5).
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Table 5: Optimization of the Buchwald-Hartwig-type reaction.
Entry
Pd—source
Pd(OAc)2,
50 mol%
Pd(OAc)2,
50 mol%
Pd(OAc)2,
20 mol%
Pd(OAc)2,
20 mol%
Pd(OAc)2,
10 mol%
PdCl2,
ligand
DPEphos,
50 mol%
DPEphos,
50 mol%
DPEphos,
30 mol%
DPEphos,
30 mol%
DPEphos,
15 mol%
dppf,
base
solvent reaction conditions
yield
Cs2CO3,
110 °C (conventional
toluene
ꢀc
1
3.0 equiv., MS 4 Å
Cs2CO3,
heating), 30 min
2
3
4
5
toluene 150 °C (MW), 30 min
32a
47a
3.0 equiv., MS 4 Å
Cs2CO3,
DMF
EtOH
EtOH
180 °C (MW), 30 min
150 °C (MW), 30 min
150 °C (MW), 30 min
3.0 equiv., MS 4 Å
Cs2CO3,
76b
3.0 equiv., MS 4 Å
Cs2CO3,
ꢀc
3.0 equiv., MS 4 Å
6
7
NaOtBu 3.0 equiv., toluene 180 °C (MW), 90 min
85b
84a
10 mol%
10 mol%
PdCl2, 5 mol% dppf, 5 mol% NaOtBu 3.0 equiv. toluene 180 °C (MW), 90 min
a: Isolated yield.; b: Determined using dimethyl sulfone as internal NMRꢀstandard.26; c: Due to low purity,
the yield could not be determined.
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Initially, a procedure of Wennemers et al. using Pd(OAc)2 (50 mol%), DPEphos
(50 mol%) and Cs2CO3 (3.0 equiv.) in toluene at 110 °C (conventional heating) was
applied.32 Since 9a was only formed in traces under these conditions, all subsequent
reactions were carried out under microwave irradiation. An initial attempt to synthesize
9a using the abovementioned catalytic system in toluene under microwave irradiation
(150 °C) afforded 9a with a yield of 32% after a reaction time of 30 minutes. Screening
of other solvents proved EtOH to be more effective but lowering of the catalyst loading to
10 mol% led to a drastically increased formation of byproducts. Therefore, the catalytic
system was switched to PdCl2 (10 mol%), dppf (10 mol%) and NaOtBu (3.0 equiv.) in
toluene at 150 °C under microwave irradiation.33 The reaction time was extended to
90 minutes to ensure the complete conversion of the starting materials. This method
afforded indole 9a with a yield of 85%. Lowering of the catalyst loading to 5 mol% still
provided 9a in 84% yield.
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The reaction was applied to other substrates but for practical reasons the cyclization
was again performed without purification of the alkylated aminonitriles 8 (Table 6).
Table 6: Synthesis of 1,2-substituted indoles 9 from alkylated α-aminonitriles 8 by palladium-
catalyzed cyclization.
Yield over
Entry
Aminonitrile
R1
R2
X
Product
2 steps/%a
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Ph
Ph
Cy
Br
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9b
9c
9d
9e
9f
59
4
Ph
I
I
3
4ꢀCl–C6H4
naphthalenꢀ2ꢀyl
naphthalenꢀ2ꢀyl
4ꢀCl–C6H4
4ꢀF–C6H4
4ꢀMeO–C6H4
4ꢀbenzoylphenyl
Me
34
94
26
64
49
34
32
49
28
31
55
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4
7h
7i
I
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5
I
6
7k
7n
7c
7d
7e
7j
4ꢀCl–C6H4
CH2CH2Ph
iPr
I
7
I
9g
9h
9i
8
Ph
Br
Br
I
9
4ꢀCl–C6H4
4ꢀMeO–C6H4
4ꢀMeO–C6H4
naphthalenꢀ2ꢀyl
4ꢀCl–C6H4
4ꢀMeO–C6H4
mesityl
10
11
12
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14
4ꢀbenzoylphenyl
mesityl
9j
I
9k
9l
7g
7l
4ꢀMeO–C6H4
pꢀtolyl
I
I
9m
9n
7m
pꢀtolyl
I
a: Isolated yield.
Generally, the cyclization proceeded more efficiently on aryl iodides but since the yields
for the alkylation of αꢀaminonitriles 7 with 6a were low in some cases, alkylation with
bromide 6b was applied instead. Both Nꢀaryl and Nꢀalkyl substituents were tolerated
although the Ullmann procedure was more efficient than palladium catalysis for Nꢀalkyl
substrates. Electron withdrawing substituents R1 and R2 increased the efficiency of the
indole synthesis while steric hindrance and/or electron donating substituents led to lower
overall yields.
To access isoquinolineꢀ1ꢀones from intermediates 8 in a palladiumꢀcatalyzed
carbonylative crossꢀcoupling reaction, 8a was again chosen as a model substrate and a
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modified protocol of Buchwald et al. was used.34 Different palladium sources (Pd(OAc)2,
Pd(dba)2, Pd(dppf)Cl2), ligands (dppf, Xantphos, PCy3) and bases (NaOtBu, Cs2CO3)
were screened in combination with gaseous CO in toluene. The system Pd(dba)2
(5 mol%)/ Xantphos (5.5 mol%)/ Cs2CO3 (3.0 equiv.) proved to be most effective. Using
Pd(dppf)Cl2 as the catalytic system as well as NaOtBu as the base afforded large
amounts of indole 9a instead. Since application of Cs2CO3 as the base did not yield 9a
as a byproduct but also did not promote complete dehydrocyanation of the previously
formed carbonitrile 10, NaOtBu was added after complete consumption of the starting
material (TLC and HPLCꢀESIꢀMS) to promote the dehydrocyanation of intermediate 10
to isoquinolineꢀ1ꢀone 11 (Scheme 3).
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Scheme 3: Synthesis of 2,3-diphenylisoquinoline-1-one (11) from 8a.
We also found that the reaction temperature had to be increased to 120 °C compared to
the temperature used by Buchwald et al. (80 °C) since only incomplete conversion of the
starting materials was otherwise observed. With the optimized protocol
2,3ꢀdiphenylisoquinolineꢀ1ꢀone (11) was obtained from 8a in 53% yield. Although higher
conversions were likely achievable in this way, the use of pressurized CO in the
cyclocarbonylation was refrained from for safety reasons.
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Conclusion
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In summary two simple procedures for the synthesis of 1,2ꢀdisubstituted indoles from
αꢀaminonitriles based on an Ullmannꢀ and a BuchwaldꢀHartwigꢀtype ring closure were
developed and yields of up to 94% over two steps could be achieved. A modification of
the latter procedure also permits the synthesis of isoquinolineꢀ1ꢀones. While the
Nꢀsubstituent can either be an alkyl or an aryl group in both cases, the Ullmann
procedure proved more suitable for the former. The introduction of aliphatic 2ꢀ
substituents into indoles (and of 3ꢀsubstituents into isoquinolineꢀ1ꢀones) would require
an additional protection/deprotection at nitrogen and was not undertaken for the sake of
operational simplicity. Advantages of the presented synthetic strategy are the modular
assembly of stable precursors, i. e. the αꢀaminonitriles, in a facile three component
reaction which does not require strongly dehydrating conditions as e.g. necessary for the
formation of imines. There is no risk for the formation of regioisomeric products and the
use of substituted 2ꢀhalobenzyl halides should allow the selective synthesis of more
complex indoles. The employed elements of diversity (aldehyde, amine) are inexpensive
and are available in large structural diversity. High yields can be achieved and the use of
a carbonylative coupling permits the synthesis of isoquinolineꢀ1ones from the same
precursors.
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Experimental Section
Materials and Methods
Unless otherwise noted all reagents were reagent grade and used without further
purification. NMP was purchased in “extra dry” quality (99.5%, over molecular sieves).
All reactions involving air or moisture sensitive reagents or intermediates were
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performed in oven dried glassware under an inert atmosphere of argon. Compounds 7d
and 7n were previously synthesized by Jens Emsermann (Mainz; for analytical data see
Supporting Information).35 Reaction temperatures are referred to the particular
cooling/heating bath. Microwave reactions were carried out in a monomode laboratory
microwave reactor with pressure monitoring and IR temperature control. Melting points
were determined in open capillary tubes using an electrothermal apparatus with a
resolution of 0.1 °C. NMR spectra were recorded on a 300 MHz, 400 MHz or 600 MHz
spectrometer equipped with a 5 mm BBFO probe with zꢀgradient and ATM capability.
Chemical shifts were referenced to the deuterated solvent (e.g. for CDCl3: δ = 7.26 ppm
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1
and 77.16 ppm, for DMSOꢀd6: δ = 2.50 ppm and 39.52 ppm for H and 13C NMR,
respectively) and reported in parts per million (ppm, δ) relative to tetramethylsilane
(TMS, δ = 0.00 ppm).36 Coupling constants (J) were reported in Hz and the splitting
abbreviations used were: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br,
broad. Standard pulse sequences were used for the 2D experiments. To evaluate the
yields of compounds that could not be isolated a defined amount dimethyl sulfone was
added to the NMR samples as internal standard.26 To calculate the yield the NMRꢀ
signals of dimethyl sulfone were integrated and compared to characteristic signals of the
sample, respectively. Infrared spectra were recorded as FTꢀIR spectra using a diamond
ATR unit and are reported in terms of frequency of absorption (ν, cm–1). Highꢀresolution
masses were recorded on a QToFꢀInstrument with a dual electrospray source and a
suitable external calibrant. Thinꢀlayer chromatography (TLC) was carried out on 0.25
mm silica gel plates (60F254) using UV light as visualizing agent and an ethanolic
solution of hydrochloric acid and 4ꢀ(N,Nꢀdimethylamino)ꢀbenzaldehyde (Ehrlich’s
reagent), Seebach’s reagent (ethanolic solution of ammonium pentamolybdate, diluted
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aqueous sulfuric acid and cerium(IV) sulfate) and Ninhydrin reagent (ethanolic solution
of ninhydrin and acetic acid). Flash column chromatography was performed with silica
gel with 35–70 ꢁm particle size. Solvent ratios are referred to the volume fractions
before mixing.
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General procedure for the synthesis of α-aminonitriles 7: (Warning: KCN and
αꢀaminonitriles may release highly toxic HCN. Caution should be exercised.) Unless
otherwise stated, αꢀaminonitriles 7 were prepared according to a procedure of
n
Emsermann et.al.35 The crude products were purified by washing with hexane and/or
diethyl ether.
2-Phenyl-2-(phenylamino)acetonitrile (7a). The title compound was prepared
according to a protocol of Opatz et al. using benzaldehyde (59.2 g, 86.5 mmol), aniline
(8.05 g, 86.4 mmol) and KCN (6.19 g, 95.2 mmol).25 Purification of the crude product by
recrystallization from diethyl ether/nhexane (3:1) yielded 7a (12.7 g, 61.0 mmol, 70%,
Lit.:25 83%) as colorless needles. mp 84.9–86.0 °C (Lit.:37 85–86 °C); Rf = 0.41 (silica
gel, cyclohexane/ethyl acetate 5:1); IR (ATR) ꢀ̅
(cm–1) = 3362, 3056, 1603, 1503, 1453,
1314, 1267, 1101, 752, 694; 1HꢀNMR, COSY (400 MHz, CDCl3) δ (ppm) = 7.63–7.60 (m,
2H, Hꢀ2’, 6’), 7.49–7.44 (m, 3H, Hꢀ3’, 4‘, 5‘), 7.33–7.276 (m, 2H, Hꢀ3’’, 4’’), 6.94–6.89 (m,
3
3
1H, Hꢀ5’’), 6.81–6.78 (m, 2H, Hꢀ2’’, 6’’), 5.44 (d, J = 8.3 Hz, 1H, Hꢀ2), 4.06 (dbr, J =
13
8.3 Hz, 1H, NH); CꢀNMR, HSQC, HMBC (75.5 MHz, CDCl3) δ (ppm) = 144.8 (Cꢀ1’’),
134.0 (Cꢀ1’), 129.7 (2C, Cꢀ3’’, 5’’), 129.6 (Cꢀ4’), 129.4 (2C, Cꢀ3’, 5’), 127.4 (2C, Cꢀ2’, 6’),
120.4 (Cꢀ4’’), 118.3 (Cꢀ1), 114.2 (2C, Cꢀ2’’, 6’’), 50.3 (Cꢀ2). The data are in accordance
with the literature.37
2-(Cyclohexylamino)-2-phenylacetonitrile (7b). The title compound was prepared
from benzaldehyde (5.30 g, 49.9 mmol), cyclohexylamine (4.99 g, 50.3 mmol) and KCN
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(6.50 g, 99.8 mmol). Purification of the crude product by washing with hexane yielded
5
6
7b (4.71 g, 21.0 mmol, 44%) as light yellow solid. mp 52.7–54.9 °C (Lit.:38 56–58 °C);
7
8
9
Rf = 0.19 (silica gel, cyclohexane/ethyl acetate 20:1); IR (ATR) ꢀ̅
(cm–1) = 3317, 3065,
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1
2928, 1451, 1375, 1192, 1117, 1029, 758, 697; HꢀNMR, COSY (300 MHz, CDCl3)
δ (ppm) = 7.53–7.49 (m, 2H, Hꢀ2’, 6’), 7.44–7.37 (m, 3H, Hꢀ3’, 4’, 5’), 4.83 (s, 1H, Hꢀ2),
2.90–2.83 (m, 1H, Hꢀ1’’), 2.02–1.99 (m, 1H, CH2Cy), 1.82–1.72 (m, 3H, CH2Cy), 1.67–
1.62 (m, 1H, CH2Cy), 1.41–1.10 (m, 5H, CH2Cy); 13CꢀNMR, HSQC, HMBC (75.5 MHz,
CDCl3) δ (ppm) = 135.5 (Cꢀ1’), 129.3 (Cꢀ4’), 129.2 (2C, Cꢀ3’, 5’), 127.4 (2C, Cꢀ2’, 6’),
119.4 (Cꢀ1), 55.1 (Cꢀ1’’), 51.8 (Cꢀ2), 33.9 (CH2Cy), 32.0 (CH2Cy), 26.0 (CH2Cy), 24.8
(CH2Cy), 24.4 (CH2Cy). The data are in accordance with the literature.38
2-(Isopropylamino)-2-phenylacetonitrile (7c). The title compound was prepared from
benzaldehyde (5.41 g, 51.0 mmol), isopropyl amine (2.95 g, 49.9 mmol) and KCN
n
(6.56 g, 101 mmol). Purification of the crude product by washing with cold hexane
yielded 7c (3.06 g, 17.6 mmol, 35%) as light yellow solid. mp 32.7–34.3 °C (Lit.:39
colorless oil); Rf = 0.08 (silica gel, cyclohexane/ethyl acetate 15:1); IR (ATR) ꢀ̅
(cm–1) =
1
3321, 3035, 2934, 1454, 1373, 1176, 1029, 929, 755, 697; HꢀNMR, COSY (400 MHz,
CDCl3) δ (ppm) = 7.54–7.50 (m, 2H, Hꢀ2’, 6’), 7.44–7.35 (m, 3H, Hꢀ3‘, 4‘, 5‘), 4.78 (s, 1H,
Hꢀ2), 3.23 (sept, 3J = 6.2 Hz, 1H, Hꢀ1’), 1.16 (d, 3J = 6.2 Hz, 6H, CH3); 13CꢀNMR, HSQC,
HMBC (100.6 MHz, CDCl3) δ (ppm) = 135.5 (Cꢀ1’), 129.1 (2C, Cꢀ3’, 5’), 129.1 (Cꢀ4’),
127.4 (2C, Cꢀ2’, 6’), 119.3 (Cꢀ1), 52.4 (Cꢀ2), 47.3 (Cꢀ1’’), 23.7 (CH3), 21.6 (CH3) ppm.
The data are in accordance with the literature.39
((4-Benzoylphenyl)amino)-2-(4-methoxyphenyl)acetonitrile (7e). The title compound
was
prepared
from
4ꢀmethoxybenzaldehyde
(3.42 g,
25.1 mmol),
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4ꢀaminobenzophenone (4.57 g, 25.5 mmol) and KCN (3.29 g, 50.5 mmol). Purification of
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the crude product by washing with hexane and diethyl ether yielded 7e (5.12 g,
5
6
15.0 mmol, 60%) as light yellow solid. mp 136.2–137.3 °C; Rf = 0.10 (silica gel,
7
8
9
cyclohexane/ethyl acetate/triethylamine 30:10:1); IR (ATR) ꢀ̅
(cm–1) = 3334, 1598, 1513,
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1318, 1279, 1178, 1150, 1030, 839, 701; HꢀNMR, COSY (400 MHz, CDCl3) δ (ppm) =
7.83–7.80 (AA’ꢀpart of AA’XX’ꢀsystem, 2H, Hꢀ3‘’, 5‘’), 7.76–7.73 (m, 2H, Hꢀ2’’’, 6’’’),
7.58–7.54 (m, 1H, Hꢀ4’’’), 7.53–7.50 (XX’ꢀpart of AA’XX’ꢀsystem, 2H, Hꢀ2’, 6’), 7.49–7.45
(m, 2H, Hꢀ3’’’, 5’’’), 7.00–6.96 (AA’ꢀpart of AA’XX’ꢀsystem, 2H, Hꢀ3’, 5’), 6.81–6.77 (XX’ꢀ
part of AA’XX’ꢀsystem, 2H, Hꢀ2’’, 6’’), 5.45 (s, 1H, Hꢀ2), 4.51 (sbr, 1H, NH), 3.85 (s, 3H,
OCH3); 13CꢀNMR, HSQC, HMBC (100.6 MHz, CDCl3) δ (ppm) = 195.4 (CO), 160.8
(Cꢀ4’), 148.5 (Cꢀ1’’), 138.6 (Cꢀ1’’’), 132.9 (2C, Cꢀ3’’, 5’’), 131.9 (Cꢀ4’’’), 129.8 (2C,
Cꢀ2’’, 6’’’), 129.1 (Cꢀ4’’), 128.8 (2C, Cꢀ2’, 6’), 128.3 (2C, Cꢀ3’’’, 5’’’), 125.1 (Cꢀ1’), 117.8
(Cꢀ1), 115.0 (2C, Cꢀ3’, 5’), 112.9 (Cꢀ2’’), 55.6 (OCH3), 49.1 (Cꢀ2); ESIꢀHRMS (m/z) calcd
for [C22H18N2O2 + Na]+ 365.1266, found 365.1262.
2-(4-Chlorophenyl)-2-((4-methoxyphenyl)amino)acetonitrile (7f). The title compound
was prepared from 4ꢀchlorobenzaldehyde (3.51 g, 25.0 mmol), pꢀanisidine (3.13 g,
25.4 mmol) and KCN (3.29 g, 50.5 mmol). Purification of the crude product by washing
n
with pentane and diethyl ether yielded 7f (4.42 g, 16.2 mmol, 65%) as light grey solid.
mp 86.1–87.4 °C (Lit.:40 78–80 °C); Rf = 0.10 (silica gel, cyclohexane/ethyl acetate 7:1);
IR (ATR) ꢀ̅
(cm–1) = 3342, 2935, 1598, 1512, 1465, 1244, 1093, 1034, 820, 699;
1HꢀNMR, COSY (300 MHz, CDCl3) δ (ppm) = 7.55–7.52 (AA‘ꢀpart of AA’XX’ꢀsystem, 2H,
Hꢀ2‘, 6‘), 7.44–7.39 (XX‘ꢀpart of AA’XX’ꢀsystem, 2H, Hꢀ3‘, 5‘), 6.87–6.82 (XX‘ꢀpart of
AA’XX’ꢀsystem, 2H, Hꢀ3‘‘, 5‘‘), 6.77–6.72 (AA‘ꢀpart of AA’XX’ꢀsystem, 2H, Hꢀ2‘‘, 6‘‘), 5.33
(s, 1H, Hꢀ2), 3.77 (s, 3H, OCH3); 13CꢀNMR, HMBC, HSQC (75.5 MHz, CDCl3) δ (ppm) =
154.4 (Cꢀ4‘‘), 138.3 (Cꢀ1‘‘), 135.5 (Cꢀ4‘), 132.7 (Cꢀ1‘), 129.5 (2C, Cꢀ3‘, 5‘), 128.7 (2C,
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Cꢀ2‘, 6‘), 118.2 (Cꢀ1), 116.7 (2C, Cꢀ2‘‘, 6‘‘), 115.1 (2C, Cꢀ3‘‘, 5‘‘), 55.7 (OCH3), 51.1
(Cꢀ2). The data are in accordance with the literature.41
7
8
9
2-((4-Methoxyphenyl)amino)-2-(naphthalen-2-yl)acetonitrile (7g). The title compound
was prepared from 2ꢀnaphthaldehyde (2.51 g, 16.1 mmol), pꢀanisidine (2.27 g,
18.4 mmol) and KCN (2.16 g, 33.2 mmol). Purification of the crude product by washing
with diethyl ether yielded 7g (3.10 g, 10.8 mmol, 67%) as light grey solid. mp 105.0–
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107.5 °C; Rf = 0.13 (silica gel, cyclohexane/diethyl ether 7:1); IR (ATR) ꢀ̅
(cm–1) = 3346,
1
3057, 1618, 1512, 1465, 1243, 1127, 1034, 819, 751; HꢀNMR, COSY (300 MHz,
3
CDCl3) δ (ppm) = 8.13 (sbr, 1H, Hꢀ1’), 7.94–7.86 (m, 3H, Hꢀ6, 3’, 7’), 7.64 (dd, J =
4
8.5 Hz, J = 1.9 Hz, 1H, Hꢀ8’), 7.59–7.54 (m, 2H, Hꢀ4’, 5’), 6.88–6.84 (XX‘ꢀpart of
AA’XX’ꢀsystem, 2H, Hꢀ3’’, 5’’), 6.82–6.78 (AA‘ꢀpart of AA’XX’ꢀsystem, 2H, Hꢀ2’’, 6’’), 5.52
(s, 1H, Hꢀ2), 3.78 (s, 3H, OCH3); 13CꢀNMR, HSQC, HMBC (75.7 MHz, CDCl3) δ (ppm) =
154.3 (Cꢀ4’’), 138.7 (Cꢀ1’’), 133.6 (Cꢀ4a’), 133.2 (Cꢀ2’), 131.5 (Cꢀ8a’), 129.5 (Cꢀ7’), 128.4
(Cꢀ3’), 127.9 (Cꢀ1’), 127.2 (Cꢀ4’), 127.1 (Cꢀ5’), 126.7 (Cꢀ1’), 124.6 (Cꢀ8’), 118.6 (Cꢀ1),
116.5 (2C, Cꢀ2’’, 6’’), 115.2 (2C, Cꢀ3’’, 5’’), 55.8 (OCH3), 51.9 (Cꢀ2). The data are in
accordance with the literature.42
2-((4-Benzoylphenyl)amino)-2-(naphthalen-2-yl)acetonitrile (7h). The title compound
was prepared from 2ꢀnaphthaldehyde (2.54 g, 16.2 mmol), 4ꢀaminobenzophenone
(3.17 g, 16.1 mmol) and KCN (2.25 g, 34.6 mmol). Purification of the crude product by
washing with diethyl ether yielded 7h (3.39 g, 9.40 mmol, 58%) as light yellow solid.
mp 137.6–138.4 °C; Rf = 0.12 (silica gel, cyclohexane/ethyl acetate 3:1); IR (ATR) ꢀ
̅
1
(cm–1) = 3328, 3058, 1640, 1596, 1522, 1318, 1281, 1150, 740, 700; HꢀNMR, COSY
(300 MHz, CDCl3) δ (ppm) = 8.11 (sbr, 1H, Hꢀ1’), 7.94–7.87 (m, 3H, Hꢀ4’, 5’, 7’), 7.80–
7.78 (AA‘ꢀpart of AA’XX’ꢀsystem, 2H, Hꢀ3’’, 5’’), 7.74–7.71 (m, 2H, Hꢀ2’’’, 6’’’), 7.60–7.53
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(m, 4H, Hꢀ3’, 6’, 8’, 4’’’), 7.48–7.43 (m, 2H, Hꢀ3’’’, 5’’’), 6.82–6.80 (XX‘ꢀpart of AA’XX’ꢀ
5
6
7
8
3
3
system, 2H, Hꢀ2’’, 6’’), 5.67 (d, J = 5.6 Hz, 1H, Hꢀ2), 4.88 (dbr, J = 5.6 Hz, 1H, NH);
13CꢀNMR, HMBC, HSQC (75.5 MHz, CDCl3) δ (ppm) = 195.5 (CO), 148.5 (Cꢀ1’’), 138.5
(Cꢀ1’’’), 133.7 (Cꢀ4a’), 133.2 (Cꢀ2’), 132.9 (2C, Cꢀ3’’, 5’’), 131.9 (Cꢀ8’), 130.4 (Cꢀ8a’),
129.8 (Cꢀ4’), 129.7 (2C, Cꢀ2’’’, 6’’’), 129.1 (Cꢀ4’’), 128.3 (Cꢀ7’), 128.3 (2C, Cꢀ3’’’, 5’’’),
127.9 (Cꢀ5’), 127.5 (Cꢀ6’), 127.3 (Cꢀ4’’’), 126.9 (Cꢀ1’), 124.2 (Cꢀ3’), 117.7 (Cꢀ1), 113.0
(2C, Cꢀ2’’, 6’’), 49.6 (Cꢀ2); ESIꢀHRMS (m/z) calcd for [C25H18N2O – CN]+: 336.1388,
found 336.1390.
9
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2-(Methylamino)-2-(naphthalen-2-yl)acetonitrile (7i). The title compound was
prepared from 2ꢀnaphthaldehyde (3.46 g, 22.2 mmol), methylamine (33 wt% in EtOH,
2.80 mL, 2.12 g, 22.5 mmol) and KCN (2.89 g, 44.4 mmol). Purification of the crude
product by recrystallization from diethyl ether/nhexane yielded 7i (3.42 g, 17.4 mmol,
79%) as light yellow solid. mp 69.4–71.7 °C (Lit.:25 72.0–73.5 °C); Rf = 0.30 (silica gel,
cyclohexane/ethyl acetate 1:1); IR (ATR) ꢀ̅
(cm–1) = 3331, 3057, 2947, 1691, 1509,
1
1451, 1273, 1143, 819, 750; HꢀNMR (300 MHz, CDCl3) δ (ppm) = 8.02 (s, 1H, Hꢀ1’),
7.90–7.83 (m, 3H, Hꢀ4’, 5’, 8’), 7.60–7.51 (m, 3H, Hꢀ3’, 6’, 7’), 4.94 (s, 1H, Hꢀ2), 2.61 (s,
3H, NCH3). The data are in accordance with the literature.25
2-(Mesitylamino)-2-(4-methoxyphenyl)acetonitrile (7j). The title compound was
prepared from 4ꢀmethoxybenzaldehyde (3.40 g, 25.0 mmol), 2,4,6ꢀtrimethylaniline
(3.44 g, 25.4 mmol) and KCN (3.29 g, 50.5 mmol). Purification of the crude product by
n
washing with pentane and diethyl ether yielded 7j (4.06 g, 14.5 mmol, 58%) as light
brown solid. mp 92.7–95.6 °C (Lit.:43 102 °C); Rf = 0.56 (silica gel, cyclohexane/ethyl
acetate 7:1); IR (ATR) ꢀ̅
(cm–1) = 3356, 2936, 1612, 1512, 1484, 1306, 1252, 1157,
1032, 854; 1HꢀNMR (300 MHz, CDCl3) δ (ppm) = 7.60–7.55 (AA‘ꢀpart of AA’XX’ꢀsystem,
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2H, Hꢀ2‘, 6‘), 7.01–6.96 (XX‘ꢀpart of AA’XX’ꢀsystem, 2H, Hꢀ3‘, 5‘), 6.90 (s, 2H, Hꢀ3‘‘, 5‘‘),
5.04 (s, 1H, Hꢀ2), 3.85 (s, 3H, OCH3), 2.33 (s, 6H, oꢀCH3), 2.27 (s, 3H, pꢀCH3). The data
are in accordance with the literature.43
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2-(4-Chlorophenyl)-2-((4-chlorophenyl)amino)acetonitrile (7k). The title compound
was prepared from 4ꢀchlorobenzaldehyde (3.54 g, 25.2 mmol), 4ꢀchloroaniline (3.26 g,
25.5 mmol) and KCN (3.28 g, 50.4 mmol). Purification of the crude product by washing
n
with pentane and diethyl ether yielded 7k (5.25 g, 18.9 mmol, 75%) as colorless solid.
mp 116.3–117.4 °C (Lit.:40 121–123 °C); Rf = 0.37 (silica gel, cyclohexane/ethyl
acetate/triethylamine 50:10:1); IR (ATR) ꢀ̅
(cm–1) = 3354, 3028, 1617, 1518, 1492, 1262,
1094, 1015, 928, 803; 1HꢀNMR, COSY (300 MHz, CDCl3) δ (ppm) = 7.53–7.50 (AA‘ꢀpart
of AA’BB’ꢀsystem, 2H, Hꢀ2’, 6’), 7.45–7.40 (BB‘ꢀpart of AA’BB’ꢀsystem, 2H, Hꢀ3’, 5’),
7.24–7.19 (XX‘ꢀpart of AA’XX’ꢀsystem, 2H, Hꢀ3’’, 5’’), 6.70–6.65 (AA‘ꢀpart of AA’XX’ꢀ
13
system, 2H, Hꢀ2’’, 6’’), 5.37 (s, 1H, Hꢀ2), 4.14 (sbr, 1H, NH); CꢀNMR, HSQC, HMBC
(75.5 MHz, CDCl3) δ (ppm) = 143.0 (Cꢀ1’’), 135.8 (Cꢀ4’), 132.0 (Cꢀ1’), 129.7 (2C,
Cꢀ3’, 5’), 129.6 (2C, Cꢀ3’’, 5’’), 128.6 (2C, Cꢀ2’, 6’), 125.5 (Cꢀ4’’), 117.7 (Cꢀ1), 115.6 (2C,
Cꢀ2’’, 6’’), 49.8 (Cꢀ2). The data are in accordance with the literature.44
2-(4-Chlorophenyl)-2-(p-tolylamino)acetonitrile (7l). The title compound was
prepared from 4ꢀchlorobenzaldehyde (3.56 g, 25.3 mmol), pꢀtoluidine (2.70 g,
25.2 mmol) and KCN (3.26 g, 50.1 mmol). Purification of the crude product by washing
with npentane and diethyl ether yielded 7l (4.76 g, 18.6 mmol, 73%) as light yellow solid.
mp 89.0–91.5 °C (Lit.:40 92–94 °C); Rf = 0.38 (silica gel, cyclohexane/ethyl
acetate/triethyl amine 50:10:1); IR (ATR) ꢀ̅
(cm–1) = 3305, 1597, 1490, 1237, 1085,
1014, 907, 818, 730, 651; 1HꢀNMR, COSY (300 MHz, CDCl3) δ = 7.55–7.52 (AA‘ꢀpart of
AA’BB’ꢀsystem, 2H, Hꢀ2’, 6’), 7.44–7.41 (BB‘ꢀpart of AA’BB’ꢀsystem, 2H, Hꢀ3’, 5’), 7.10–
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7.07 (XX‘ꢀpart of AA’XX’ꢀsystem, 2H, Hꢀ3’’, 5’’), 6.70–6.67 (AA‘ꢀpart of AA’XX’ꢀsystem,
2H, Hꢀ2’’, 6’’), 5.38 (s, 1H, Hꢀ2), 3.97 (sbr, 1H, NH), 2.29 (s, 3H, CH3); 13CꢀNMR, HSQC,
HMBC (75.5 MHz, CDCl3) δ (ppm) = 142.2 (Cꢀ1’’), 135.5 (Cꢀ4’), 132.7 (Cꢀ1’), 130.2 (2C,
Cꢀ3’’, 5’’), 130.1 (Cꢀ4’’), 129.5 (2C, Cꢀ3’, 5’), 128.7 (2C, Cꢀ2’, 6’), 118.1 (Cꢀ1), 114.7 (2C,
Cꢀ2’’, 6’’), 50.2 (Cꢀ2), 20.6 (CH3). The data are in accordance with the literature.45
2-(4-Methoxyphenyl)-2-(p-tolylamino)acetonitrile (7m). The title compound was
prepared from 4ꢀmethoxybenzaldehyde (3.48 g, 25.6 mmol), pꢀtoluidine (2.76 g,
25.8 mmol) and KCN (3.36 g, 51.6 mmol). Purification of the crude product by washing
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with pentane and diethyl ether yielded 7m (3.73 g, 14.8 mmol, 58%) as colorless solid.
mp 102.2–104.5 °C (Lit.:45 101–103 °C); Rf = 0.26 (silica gel, cyclohexane/ethyl
acetate/triethylamine 50:10:1); IR (ATR) ꢀ̅
(cm–1) = 3359, 2936, 1613, 1512, 1463, 1250,
1178, 1031, 926, 809; 1HꢀNMR, COSY (400 MHz, CDCl3) δ (ppm) = 7.53–7.49 (AA‘ꢀpart
of AA’XX’ꢀsystem, 2H, Hꢀ2’, 6’), 7.10–7.08 (XX‘ꢀpart of AA’XX’ꢀsystem, 2H, Hꢀ3’’, 5’’),
6.98–6.95 (XX‘ꢀpart of AA’XX’ꢀsystem, 2H, Hꢀ3’, 5’), 6.72–6.69 (AA‘ꢀpart of AA’XX’ꢀ
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system, 2H, Hꢀ2’’, 6’’), 5.33 (d, J = 6.7 Hz, 1H, Hꢀ2), 3.84 (s, 3H, OCH3), 2.30 (s, 3H,
CH3); 13CꢀNMR, HSQC, HMBC (100.6 MHz, CDCl3) δ (ppm) = 160.4 (Cꢀ4’), 142.6
(Cꢀ1’’), 130.1 (2C, Cꢀ3’’, 5’’), 129.7 (Cꢀ4’’), 128.7 (2C, Cꢀ2’, 6’), 126.2 (Cꢀ1’), 118.7 (Cꢀ1),
114.7 (2C, Cꢀ3’, 5’), 114.5 (2C, Cꢀ2’’, 6’’), 55.5 (OCH3), 50.2 (Cꢀ2), 20.6 (CH3).
General procedure for the alkylation of α-aminonitriles 7: (Warning: αꢀAminonitriles
may release highly toxic HCN. Caution should be exercised.) The alkylation of
αꢀaminonitriles 7 was performed according to a modified procedure from Opatz et al.24
Unless otherwise stated, αꢀaminonitrile 7 (1.0 equiv.) was dissolved in dry THF (4.0 mL
per mmol αꢀaminonitrile) under argon atmosphere and the solution was cooled to –
78 °C. A solution of KHMDS (1.3 equiv.) in dry THF (4.0 mL per mmol αꢀaminonitrile)
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was quickly added at –78 °C. The mixture was stirred at –78 °C for 5 minutes before a
solution of 1ꢀ(bromomethyl)ꢀ2ꢀiodobenzene (1.3 equiv.) in dry THF (4.0 mL per mmol
αꢀaminonitrile) was added over a period of 60 minutes. After stirring for a further
60 minutes at –78 °C, the solution was allowed to warm to –20 °C before a saturated
solution of sodium bicarbonate (12.0 mL per mmol αꢀaminonitrile) and ethyl acetate
(5.0 mL per mmol αꢀaminonitrile) were added. The organic layer was separated and the
aqueous layer was extracted with ethyl acetate (2 × 5.0 mL per mmol αꢀaminonitrile).
The combined organic layers were washed with brine (5.0 mL per mmol αꢀaminonitrile),
dried over MgSO4 and evaporated under reduced pressure. Unless otherwise stated,
alkylated aminonitriles 8 were subjected to the next reaction step without further
purification due to their instability during chromatography on silica gel.
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3-(2-Iodophenyl)-2-phenyl-2-(phenylamino)propanenitrile
(8a).
The
general
procedure was applied using 7a (705 mg, 3.39 mmol), KHMDS (870 mg, 4.40 mmol)
and 1ꢀ(bromomethyl)ꢀ2ꢀiodobenzene (1.30 g, 4.37 mmol). Purification of the crude
product by flash column chromatography (cyclohexane/ethyl acetate, 30:1) on silica gel
yielded 8a (619 mg, 1.46 mmol, 43%) as a colorless solid. mp 170.8–171.8 °C; Rf = 0.18
(silica gel, cyclohexane/ethyl acetate 30:1); IR (ATR) ꢀ̅
(cm–1) = 3379, 3030, 1602, 1499,
1
1436, 1315, 1256, 1012, 751, 698; HꢀNMR, COSY (400 MHz, CDCl3) δ (ppm) = 7.94–
7.92 (m, 1H, Hꢀ3‘‘‘), 7.64–7.60 (m, 2H, Hꢀ2‘, 6‘), 7.43–7.38 (m, 3H, Hꢀ3‘, 4‘, 5‘), 7.35–
7.30 (m, 2H, Hꢀ5‘‘‘, 6‘‘‘), 7.10–7.01 (m, 2H, Hꢀ3‘‘, 5‘‘), 7.04–7.00 (m, 1H, Hꢀ4‘‘‘), 6.78–
6.74 (m, 1H, Hꢀ4‘‘), 6.50–6.47 (m, 2H, Hꢀ2‘‘, 6‘‘), 4.68 (sbr, 1H, NH), 3.63–3.54 (m, 2H,
CH2); 13CꢀNMR, HSQC, HMBC (100.6 MHz, CDCl3) δ (ppm) = 143.3 (Cꢀ1‘‘), 140.4
(Cꢀ3‘‘‘), 138.4 (Cꢀ1‘), 136.6 (Cꢀ1‘‘‘), 132.0 (Cꢀ5‘‘‘) , 130.2 (Cꢀ4‘‘‘), 129.3 (Cꢀ4‘), 129.0 (2C,
Cꢀ3‘, 5‘), 128.9 (2C, Cꢀ3‘‘, 5‘‘), 126.1 (2C, Cꢀ2‘, 6‘), 120i.0 (Cꢀ4‘‘), 119.7 (Cꢀ1), 116.0 (2C,
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Cꢀ2‘‘, 6‘‘), 102.9 (Cꢀ2‘‘‘), 62.3 (Cꢀ2), 53.4 (CH2); ESIꢀHRMS (m/z) calcd for [C21H17IN2 +
Na]+ 447.0334, found 447.0336.
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3-(2-Bromophenyl)-2-phenyl-2-(phenylamino)propanenitrile (8b). The general
procedure was applied using 7a (250 mg, 1.20 mmol), KHMDS (335 mg, 1.68 mmol)
and 1ꢀ(bromomethyl)ꢀ2ꢀbromobenzene (390 mg, 1.56 mmol). Purification of the crude
product by flash column chromatography (cyclohexane/ethyl acetate, 30:1) on silica gel
yielded 8b (315 mg, 0.840 mmol, 70%) as a colorless solid. mp 171.7–172.3 °C; Rf =
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0.16 (silica gel, cyclohexane/ethyl acetate 30:1); IR (ATR) ꢀ̅
(cm–1) = 3384, 3056, 3030,
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1601, 1499, 1438, 1318, 1027, 744, 692; HꢀNMR, COSY (300 MHz, CDCl3) δ (ppm) =
7.64–7.56 (m, 3H, Hꢀ2‘, 6‘, 3‘‘‘), 7.43–7.36 (m, 3H, Hꢀ3‘, 4‘, 5‘), 7.30–7.17 (m, 3H,
Hꢀ4’’’, 5‘‘‘, 6‘‘‘), 7.11–7.04 (m, 2H, Hꢀ3‘‘, 5‘‘), 6.78–6.72 (m, 1H, Hꢀ4‘‘), 6.50–6.46 (m, 2H,
Hꢀ2‘‘, 6‘‘), 4.86 (sbr, 1H, NH), 3.66–3.51 (m, 2H, CH2); 13CꢀNMR, HSQC, HMBC
(75.5 MHz, CDCl3) δ (ppm) = 143.3 (Cꢀ1‘‘), 138.3 (Cꢀ1‘), 133.4 (Cꢀ3‘‘‘), 133.1 (Cꢀ1‘‘‘),
133.0 (Cꢀ6‘‘‘), 130.0 (Cꢀ4‘‘‘), 129.2 (2C, Cꢀ3‘, 5‘), 129.0 (3C, Cꢀ3‘‘, 5‘‘, 2’’’), 127.9
(Cꢀ5‘‘‘),126.0 (3C, Cꢀ2‘, 4’, 6‘), 119.9 (Cꢀ4‘‘), 119.7 (Cꢀ1), 115.9 (2C, Cꢀ2‘‘, 6‘‘), 62.3
(Cꢀ2), 49.2 (CH2); ESIꢀHRMS (m/z) calcd for [C21H1779BrN2 + Na]+ 399.0473, found
399.0473.
2-((4-Benzoylphenyl)amino)-3-(2-iodophenyl)-2-(4-methoxyphenyl)
propanenitrile (8f). The general procedure was applied using 7e (406 mg, 1.19 mmol),
KHMDS (315 mg, 1.58 mmol) and 1ꢀ(bromomethyl)ꢀ2ꢀiodobenzene (451 mg,
1.52 mmol). The crude product (693 mg, 0.863 mmol (int. NMRꢀstandard), 73%) was
obtained as yellow solid. Purification of an aliquot (201 mg) by flash column
chromatography (cyclohexane/ethyl acetate/triethylamine 40:10:1) on silica gel yielded
8f (133 mg, 0.237 mmol, 66%) as a colorless solid. mp 189.8–190.7 °C; Rf = 0.13 (silica
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gel, cyclohexane/ethyl acetate/ triethylamine 40:10:1); IR (ATR) ꢀ̅
(cm–1) = 3351, 1645,
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1597, 1510, 1254, 1173, 1151, 1014, 837, 740; HꢀNMR, COSY (300 MHz, DMSOꢀd6)
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δ (ppm) = 7.94 (Sbr, 1H, NH), 7.83 (dd, J = 8.0 Hz, J = 1.2 Hz, 1H, Hꢀ6’’’’), 7.61–7.46
(m, 7H, Hꢀ3’’’, 4’’’, 5’’’, 2’’’, 6’’’, 3’’, 5’’), 7.33–7.27 (m, 1H, Hꢀ3’’’’), 7.18–7.13 (AA‘ꢀpart of
AA’BB’ꢀsystem, 2H, Hꢀ2’, 6’), 7.07–6.99 (m, 2H, Hꢀ4’’’’, 5’’’’), 6.95–6.90 (BB‘ꢀpart of
AA’BB’ꢀsystem, 2H, Hꢀ3’, 5’), 6.67–6.63 (AA‘ꢀpart of a AA’XX’ꢀsystem, 2H, Hꢀ2’’, 6’’),
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3.88 (d, J = 13.7 Hz, 1H, Hꢀ3a), 3.74 (s, 3H, OCH3), 3.48 (d, J = 13.7 Hz, 1H, Hꢀ3b);
13CꢀNMR, HSQC, HMBC (75.5 MHz, DMSOꢀd6) δ (ppm) = 193.9 (CO), 159.5 (Cꢀ4’),
148.6 (Cꢀ1’’), 139.5 (Cꢀ6’’’’), 138.2 (Cꢀ1’’’), 136.2 (Cꢀ1’’’’), 131.6 (3C, Cꢀ3’’, 5’’, 4’’’’),
129.6 (Cꢀ5’’’’), 129.0 (2C, Cꢀ2’’’, 6’’’), 128.3 (2C, Cꢀ3’’’, 5’’’), 128.3 (Cꢀ1’), 127.8 (Cꢀ3’’’’),
127.4 (2C, Cꢀ2’, 6’), 126.5 (Cꢀ4’’), 118.9 (Cꢀ1), 114.3 (2C, Cꢀ3’, 5’), 114.2 (2C, Cꢀ2’’, 6’’),
104.1 (Cꢀ2’’’’), 60.5 (Cꢀ2), 55.2 (OCH3), 51.3 (Cꢀ3); ESIꢀHRMS (m/z) calcd for
[C29H23IN2O2 – CN]+ 532.0774, found 532.0787.
2-((4-Benzoylphenyl)amino)-3-((2-iodophenyl)-2-naphthalen-2-yl)propanenitrile
(8i). The general procedure was applied using 7h (300 mg, 0.828 mmol), KHMDS
(215 mg, 1.08 mmol) and 1ꢀ(bromomethyl)ꢀ2ꢀiodobenzene (320 mg, 1.08 mmol). The
crude product (535 mg, 0.782 mmol (int. NMRꢀstandard), 95%) was obtained as yellow
solid. Purification of an aliquot (205 mg) of the crude product by flash column
chromatography (cyclohexane/ethyl acetate/triethylamine 50:10:1) on silica gel yielded
8i (65.1 mg, 0.112 mmol, 35%) as a colorless solid. mp 205.0–205.9 °C; Rf = 0.17 (silica
gel, cyclohexane/ethyl acetate/triethylamine 50:10:1); IR (ATR) ꢀ̅
(cm–1) = 3347, 3059,
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1644, 1596, 1518, 1282, 1151, 906, 729, 648; HꢀNMR, COSY (400 MHz, DMSOꢀd6)
δ (ppm) = 8.10 (sbr, 1H, NH), 7.94–7.91 (m, 2H, Hꢀ6‘, 7‘), 7.87–7.85 (m, 1H, Hꢀ1‘), 7.78–
7.77 (m, 2H, Hꢀ3‘, 6‘‘‘‘), 7.58–7.51 (m, 7H, Hꢀ8‘, 3‘‘, 5‘‘, 2‘‘‘, 6‘‘‘, 3‘‘‘, 5‘‘‘), 7.48–7.41 (m,
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3H, Hꢀ4‘, 5‘, 4‘‘‘), 7.24–7.20 (m, 1H, Hꢀ3‘‘‘‘), 7.02–6.97 (m, 2H, Hꢀ4‘‘‘‘, 5‘‘‘‘), 6.71–6.67
(AA‘ꢀpart of AA’XX’ꢀsystem, 2H, Hꢀ2‘‘, 6‘‘), 4.00 (d, 2J = 13.7 Hz, 1H, Hꢀ3a), 3.63 (d, 2J =
13.7 Hz, 1H, Hꢀ3b); 13CꢀNMR, HSQC, HMBC (100.6 MHz, DMSOꢀd6) δ (ppm) = 193.9
(CO), 148.6 (Cꢀ1‘‘), 139.5 (Cꢀ6’’’’), 138.1 (Cꢀ1‘‘‘), 136.1 (Cꢀ1‘‘‘‘), 134.2 (Cꢀ4a’), 132.8
(Cꢀ8a’), 131.6 (3C, Cꢀ3‘‘, 5‘‘, 4‘’‘‘), 131.5 (Cꢀ4‘‘‘), 129.7 (Cꢀ5‘‘‘‘), 129.0 (4C,
Cꢀ1‘, 6‘, 2’’’, 6’’’), 128.3 (2C, Cꢀ3‘‘‘, 5’’’), 128.2 (2C, Cꢀ5‘, 2’), 127.8 (Cꢀ7‘), 127.6 (Cꢀ3’’’’),
126.8 (Cꢀ8’), 126.6 (Cꢀ4’’), 125.8 (Cꢀ3’), 123.1 (Cꢀ4’), 118.8 (Cꢀ1), 114.1 (2C, Cꢀ2’’, 6’’),
104.0 (Cꢀ2’’’’), 61.2 (Cꢀ2), 51.0 (Cꢀ3); ESIꢀHRMS (m/z) calcd for [C32H23IN2O – CN]+
552.0824, found 552.0803.
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Synthesis of 1,2-disubstituted indoles 9. (Warning: αꢀAminonitriles may release
highly toxic HCN. Caution should be exercised.) Unless otherwise stated, catalyst
loadings for the conversion of crude intermediates 8 were calculated based on an
assumed quantitative yield of the preceding alkylation reactions. General procedure A:
A modification of a procedure by Lange et al. was applied.46 Unless otherwise stated,
Cs2CO3 (2.0 equiv.) and molecular sieves 4 Å (115 mg per mmol αꢀaminonitrile) were
flameꢀdried in a 15 mLꢀmicrowaveꢀvessel equipped with a magnetic stirring bar. The
vessel was charged with CuBrꢂSMe2 (20 molꢀ%), neocuproine hemihydrate (20 molꢀ%)
and the alkylated αꢀaminonitrile 8 (1.0 equiv.). The vessel was evacuated and backfilled
with argon three times before dry NMP (0.4 mL per 0.1 mmol alkylated αꢀaminonitrile)
was added. The resulting suspension was irradiated in a monomode microwave reactor
(200 W, 180 °C) for 1 h. Subsequently, the mixture was diluted with ethyl acetate
(1.5 mL per mmol alkylated αꢀaminonitrile), filtered over a plug of silica and eluted with
ethyl acetate (7.0 mL per 0.1 mmol alkylated αꢀaminonitrile). The filtrate was washed
with water (3 × 1.5 mL per 0.1 mmol αꢀalkylated aminonitrile), the combined aqueous
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layers were extracted with ethyl acetate (3 × 1.5 mL per 0.1 mmol alkylated
αꢀaminonitrile respectively) and the combined organic layers were washed with brine,
dried over MgSO4 and evaporated under reduced pressure. The resulting crude
products were purified by flash column chromatography on silica gel. General
procedure B: The palladiumꢀcatalyzed synthesis of indoles 9 was performed according
to a protocol of Wennemers et al.32 A flameꢀdried 15 mLꢀmicrowave reaction vessel
equipped with a magnetic stirring bar was charged with the alkylated αꢀaminonitrile 8
(1.0 equiv.), Pd(dppf)Cl2 (5.0 mol%) and NaOtBu (3.0 equiv.). The vessel was evacuated
and backfilled with nitrogen three times before dry, degassed toluene was added
(0.5 mL per 0.1 mmol alkylated αꢀaminonitrile). The resulting suspension was irradiated
in a monomode microwave reactor (300 W, 150 °C) for 1.5 h. Subsequently the reaction
mixture was evaporated in vacuo, the crude products were purified by flash column
chromatography on silica gel.
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1,2-Diphenyl-1H-indole (9a). General procedure A was applied using 8a (30.2 mg,
71.2 ꢁmol), CuBrꢂSMe2 (3.87 mg, 18.8 ꢃmol), neocuproine hemihydrate (4.44 mg,
20.5 ꢃmol), Cs2CO3 (82.4 mg, 253 ꢃmol) and molecular sieves 4 Å (94.5 mg).
Purification of the crude product by flash column chromatography (cyclohexane/ethyl
acetate 200:1) on silica gel yielded 9a (12.3 mg, 45.6 ꢁmol, 64%, 28% over 2 steps) as
colorless solid. Alternatively, general procedure B was applied using 8b (99.4 mg,
0.263 mmol), Pd(dppf)Cl2 (10.2 mg, 0.0139 mmol) and NaOtBu (75.7 mg, 0.788 mmol).
Purification of the crude product by flash column chromatography (cyclohexane/ethyl
acetate 100:1) on silica gel yielded 9a (59.3 mg, 0.220 mmol, 84%, 59% over 2 steps)
as a colorless solid. mp 79.2–85.0 °C (Lit.:13 78–80 °C); Rf = 0.34 (silica gel,
cyclohexane/ethyl acetate 60:1); IR (ATR) ꢀ̅
(cm–1) = 3058, 1596, 1500, 1456, 1381,
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1323, 1208, 794, 761, 697; HꢀNMR, COSY (300 MHz, DMSOꢀd6) δ (ppm) = 7.69–7.64
(m, 1H, Hꢀ5), 7.52–7.46 (m, 2H, Hꢀ3’’, 5’’), 7.44–7.39 (m, 1H, Hꢀ4’’), 7.29–7.26 (m, 7H,
Hꢀ2’, 3‘, 4‘, 5‘, 6’, 2’’, 6’’), 7.17–7.12 (m, 3H, Hꢀ4, 6, 7), 6.88 (s, 1H, Hꢀ3); 13CꢀNMR,
HSQC, HMBC (75.5 MHz, DMSOꢀd6) δ (ppm) = 140.2 (Cꢀ7a), 138.7 (Cꢀ2), 137.9 (Cꢀ1’’),
131.9 (Cꢀ1’), 129.6 (Cꢀ3’’, 5’’), 128.5 (2C, Cꢀ3’, 5’), 128.3 (2C, Cꢀ2’, 6’), 127.9 (2C,
Cꢀ2’’, 6’’), 127.8 (Cꢀ3a), 127.6 (Cꢀ4’’), 127.5 (Cꢀ4’), 122.4, 120.6, 120.5 (3C, Cꢀ4, 5, 7),
110.3 (Cꢀ6), 103.5 (Cꢀ3). The data are in accordance with the literature.13
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1-Cyclohexyl-2-phenyl-1H-indole (9b). The general procedure for alkylation was
applied using 7b (254 mg, 1.19 mmol), KHMDS (323 mg, 1.62 mmol) and
1ꢀ(bromomethyl)ꢀ2ꢀiodobenzene (451 mg, 1.51 mmol). The crude alkylation product (8c,
581 mg, 1.01 mmol (int. NMRꢀstandard), 85%) was obtained as a yellow oil and was
directly subjected to the next reaction step. Rf = 0.11 (silica gel, cyclohexane/ethyl
acetate 30:1); IR (ATR) ꢀ̅
(cm–1) = 3059, 2929, 1689, 1579, 1448, 1331, 1218, 1013,
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752, 699; HꢀNMR, COSY (400 MHz, CDCl3) δ (ppm) = 7.86 (dd, J = 7.9 Hz, J =
1.3 Hz, 1H, Hꢀ3‘‘‘), 7.67–7.64 (m, 2H, Hꢀ1‘, 6‘), 7.39–7.35 (m, 3H, Hꢀ3‘, 4‘, 5‘), 7.24 (dd,
3J = 7.9 Hz, 4J = 1.3 Hz, 1H, Hꢀ5‘‘‘), 7.15 (dd, 3J = 7.9 Hz, 4J = 1.5 Hz, 1H, Hꢀ6‘‘‘), 6.97–
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6.93 (dt, J = 7.9 Hz, J = 1.5 Hz, 1H, Hꢀ4‘‘‘), 3.47 (d, 1H, J = 13.7 Hz, Hꢀ3a), 3.28 (d,
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1H, J = 13.7 Hz, Hꢀ3b), 2.62–2.55 (m, 1H, Hꢀ1‘‘), 1.98–1.96 (m, 1H, CH2Cy), 1.65–1.60
(m, 2H, CH2Cy), 1.53–1.46 (m, 2H, CH2Cy), 1.23–1.07 (m, 4H, CH2Cy) 0.99–0.90 (m, 1H,
CH2Cy); 13CꢀNMR, HSQC, HMBC (100.6 MHz, CDCl3) δ (ppm) = 140.2 (Cꢀ3‘‘‘), 139.7
(Cꢀ1‘), 137.4 (Cꢀ1‘‘‘), 131.4 (Cꢀ6‘‘‘), 129.5 (Cꢀ4‘‘‘), 128.8 (Cꢀ4‘), 128.6 (2C, Cꢀ3‘, 5‘),
128.3 (Cꢀ5‘‘‘), 127.0 (2C, Cꢀ2‘, 6‘), 121.3 (Cꢀ1), 103.4 (Cꢀ2‘‘‘), 64.9 (Cꢀ2), 54.1 (Cꢀ1‘‘),
53.3 (Cꢀ3), 35.1 (CH2Cy), 34.5 (CH2Cy), 25.8 (CH2Cy), 25.2 (CH2Cy), 25.1 (CH2Cy); ESIꢀ
HRMS (m/z) calcd for [C21H23IN2 – CN]+ 404.0875, found 404.0878. The indole
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synthesis was performed according to general procedure A using 8c (crude, 36.6 mg),
CuBrꢂSMe2 (4.64 mg, 22.5 ꢃmol), neocuproine hemihydrate (4.70 mg, 21.6 ꢃmol),
Cs2CO3 (69.1 mg, 212 ꢃmol), and molecular sieves 4 Å (81.7 mg). Purification of the
crude product by flash column chromatography (cyclohexane/ethyl acetate 200:1) on
silica gel yielded 9b (15.7 mg, 57.0 ꢁmol, 76% over 2 steps) as colorless solid.
Alternatively, general procedure B was applied using 8c (crude, 210 mg), Pd(dppf)Cl2
(18.6 mg, 0.0254 mmol) and NaOtBu (137 mg, 1.42 mmol). Purification of the crude
product by flash column chromatography (cyclohexane/ethyl acetate 500:1) on silica gel
yielded 9b (4.70 mg, 17.1 ꢁmol, 4% over 2 steps) as a colorless solid. mp 102.6–
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104.3 °C (Lit.:13 103.7–104.5 °C); Rf = 0.34 (silica gel, cyclohexane/ethyl acetate 60:1);
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̅
(cmꢀ1) = 3059, 1602, 1489, 1455, 1345, 1315, 1011, 750, 734, 700; HꢀNMR
(400 MHz, CDCl3) δ (ppm) = 7.70–7.63 (m, 2H), 7.52–7.40 (m, 5H), 7.22–7.17 (m, 1H),
7.15–7.09 (m, 1H), 6.49 (sbr, 1H), 4.29–4.18 (m, 1H), 2.47–2.33 (m, 2H, CH2Cy), 1.96–
1.88 (m, 4H, CH2Cy), 1.77–1.72 (m, 1H, CH2Cy), 1.35–1.26 (m, 3H, CH2Cy). The data are
in accordance with the literature.13
2-(4-Chlorophenyl)-1-(4-methoxyphenyl)-1H-indole (9c). The general procedure for
alkylation was applied using 7f (254 mg, 0.931 mmol), KHMDS (241 mg, 1.21 mmol)
and 1ꢀ(bromomethyl)ꢀ2ꢀiodobenzene (376 mg, 1.27 mmol). The crude alkylation product
(8g, 501 mg, 0.651 mmol (int. NMRꢀstandard), 70%) was obtained as green solid which
was directly subjected to the next reaction step. mp 135.2–136.4 °C; Rf = 0.15 (silica gel,
cyclohexane/ethyl acetate 10:1); IR (ATR) ꢀ̅
(cm–1) = 3017, 1511, 1291, 1242, 1134,
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1093, 1013, 936, 761, 821; HꢀNMR, COSY (300 MHz, CDCl3) δ (ppm) = 7.92–7.90 (m,
1H, Hꢀ3‘‘‘), 7.57–7.52 (AA‘ꢀpart of AA’BB’ꢀsystem, 2H, Hꢀ2‘, 6‘), 7.39–7.35 (BB‘ꢀpart of
AA’BB’ꢀsystem, 2H, Hꢀ3‘, 5‘), 7.34–7.32 (m, 2H, Hꢀ4‘‘‘, 6‘‘‘), 7.06–7.00 (m, 1H, Hꢀ5‘‘‘),
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