Metal-Free Cyclocarboamination of ortho-Formyl Phenylacetylenes with Secondary Amines: Access to 1,3-Diamino-1H-Indenes and 3-Amino-1-Indanones

Article abstract of DOI:10.1002/adsc.201801318

This work first discloses a new strategy for amine activation to give reactive amine anion by in situ generated iminium cation-amine anion pair through decomposition of sterically hindered aminals. Utilizing this strategy, a highly regio- and chemoselective cyclocarboamination of ortho-formyl phenylacetylenes with secondary amines has been realized under metal-free mild reaction conditions. The cyclocarboamination with notably tunable product profiles depends on the separation and purification procedure, a diverse range of 1, 3-diamino-1H-indenes (essentially reactive enamines) and 3-amino-1-indanones were obtained, respectively. Moreover, using iodine as an electrophile to couple with various ortho-formyl phenylacetylenes and secondary amines, a series of 3-amino-2-iodo-1-indanones were efficiently achieved with four bonds (C=O, C?C, C?N and C?I) formation in an one-pot three-component reaction. These results demonstrated an unprecedented methodology for the construction of highly functionalized 1H-indene and 1-indanone compounds. (Figure presented.).

Full text of DOI:10.1002/adsc.201801318

Title: Metal-Free Cyclocarboamination of ortho-Formyl
Phenylacetylenes with Secondary Amines: Facile Access to 1, 3-
Diamino-1H-Indenes and 3-Amino-1-Indanones
Authors: Man Kin Wong, Jian-Fang Cui, Rishi Tang, Bin Yang,
Nathanael Chun-Him Lai, Jia-Jun Jiang, and Jie-Ren Deng
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801318
Link to VoR: http://dx.doi.org/10.1002/adsc.201801318

10.1002/adsc.201801318
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Metal-Free Cyclocarboamination of ortho-Formyl
Phenylacetylenes with Secondary Amines: Access to 1, 3-
Diamino-1H-Indenes and 3-Amino-1-Indanones
Jian-Fang Cui,a, b Rishi Tang,a Bin Yang,a Nathanael Chun-Him Lai,a Jia-Jun Jiang,a
Jie-Ren Deng,a and Man-Kin Wonga*
a
State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical
Technology, The Hong Kong Polytechnic University, Hong Kong, People’s Republic of China. E-mail:
mankin.wong@polyu.edu.hk
Department of Chemistry, Southern University of Science and Technology, Shenzhen, People’s Republic of China.
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. This work first discloses a new strategy for amine Moreover, using iodine as an electrophile to couple with
activation to give reactive amine anion by in situ generated various ortho-formyl phenylacetylenes and secondary
amine anion-iminium cation pair through decomposition of amines, a series of 3-amino-2-iodo-1-indanones were
sterically hindered aminals. Utilizing this strategy, a highly efficiently achieved with four bonds (C=O, C-C, C-N and
regio- and chemoselective cyclocarbo-amination of ortho- C-I) formation in an one-pot three-component reaction.
formyl phenylacetylenes with secondary amines has been These results demonstrated an unprecedented methodology
realized under metal-free mild reaction conditions. The for the construction of highly functionalized 1H-indene and
cyclocarboamination with notably tunable product profiles 1-indanone compounds.
depends on the separation and purification procedure, a
diverse range of 1, 3-diamino-1H-indenes (essentially
reactive enamines) and 3-amino-1-indanones were obtained,
respectively.
Keywords: Carboamination; Amine activation; Indene;
Indanone; Aminal
enamine and imine intermediates can be
considered as an advantage because it offers high
synthetic flexibility for access to various
important classes of products. In contrast to
Introduction
Amines are abundant in biologically active
natural products, medicines and functional hydroamination of alkynes, carboamination of
materials.[1] Selective synthesis of amines from alkynes has attracted more attention in organic
readily available precursors is a significant
synthesis due to simultaneous incorporation of
research direction in chemical research. Efficient both C−C and C−N bonds across an alkyne in
methods including transition-metal-catalyzed C- one-step to build complex molecules which
N bond cross-coupling, nucleophilic addition to
possess significant synthetic utility in chemical
imines, carbene insertion into N-H bond and synthesis.[6]
enzymatic synthesis for access to various amines
have been well developed.[2] Hydroamination and
Generally, catalysts are mandatory for the
[3], [4]
carboamination of alkenes,
or alkynes with hydroamination/carboamination of electronically
sequential reduction of enamine or imine
unactivated alkynes through activation of amines
[5], [6]
intermediates,
are potentially the most atom by alkali metals or transition-metals with anti-
economic process and efficient approaches for the
formation of highly functional amines. Over the
decades, great progress has been achieved in the
hydroamination and carboamination of alkenes
Markovnikov selectivity, and through activation
of carbon-carbon triple bond by transition-metals
(or Brønsted acids) with Markovnikov
selectivity.[8] Alternatively, metal-free or catalyst-
due to the direct access to stable desirable free hydroamination of alkynes with amines is
amines. However, hydroamination and generally limited to the activated electron-
carboamination of alkynes remains a challenging deficient alkynes through direct nucleophilic
issue because of the reactive enamines[7] and addition (conjugate addition) and afforded the
imines generated are difficult to be isolated and
purified. Yet, the formation of the reactive
products with Markovnikov selectivity (Scheme
1A).[9]
However,
metal-free/catalyst-free
1
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10.1002/adsc.201801318
Advanced Synthesis & Catalysis
(cyclo)carboamination of alkynes remains rare.[6a, nucleophilic nitrogen atom intramolecularly
6b]
Herein we report an unprecedented metal-free reacts with ortho-alkynyl (hydroamination) to
cyclocarboamination
phenylacetylenes
of
with secondary amines
ortho-formyl yield diverse amines.[13c] Nevertheless, studies on
1
2
reactions of ortho-formyl phenylacetylenes with
involving a transient iminium cation/amine anion secondary amines remain sparse.[13a,
pair 6[10] which generated in situ via reversible Recently, we found that 5-methyl ortho-formyl
equilibrium of aminal 5[11] to give 3-amino-1H- phenylacetylene (1a) reacted smoothly with
13d, 13e]
indenes
3
and 3-amino-1-indanones
4
(Scheme piperidine (2a) in CH3CN at room temperature
and produced an off-white precipitate. The
precipitate was isolated and purified by direct
filtration and subsequent washing by cold CH3CN
to afford a white solid 3aa (50% isolated yield)
1B).[12]
1
confirmed by H NMR, 13C NMR and HRMS
spectroscopy analysis (Scheme 2A, Path 1).
Additionally, the residual 3aa in the filtrate was
determined by 1H NMR in 34% yield. As a result,
the total yield of 3aa is actually 84%. When the
reaction mixture was purified by column
chromatography on silica gel, instead of 3aa
another product 3-amino-6-methyl-1-indanone
4aa) was afforded in 76% yield (Scheme 2A,
,
(
Path 2). These results indicated that this
transformation with interestingly tunable product
profiles depends on the separation and
purification procedure.[15] The initially formed
reactive enamine 3aa was readily converted to
stable ketone 4aa upon column chromatography
on silica gel owing to its inherent sensitivity to
hydrolysis. It was also demonstrated by treatment
of pure 3aa with silica gel upon column
chromatography to give 4aa in 93% yield
(Scheme 2A, Path 3). It is noteworthy that the
regioselectivity
in
this
Markovnikov
cyclocarboamination is not in accord with the
results that of the previously reported metal-free
hydroamination/carboamination of activated
electron-deficient alkynes.[9a-c] We rationalize
herein the Markovnikov regioselectivity towards
2-formyl phenylacetylene arised from the
Scheme 1. A) General methods for hydroamination and
carboamination of alkynes; B) New amine activation
strategy for metal-free cyclocarboamination by in situ
generated iminium cation/amine anion pair.
LUMO-lowering
activation
by
iminium
formation leading to enhanced electrophilicity
versus that of the original aldehyde, so that the
iminium generated was more readily to accept
nucleophilic attack from the in situ generated
alkenyl anion (intermediate 6’
Furthermore, synergetic
，
see Figure 1).[16]
thermodynamically
Results and Discussion
favorable five-membered ring formation would
also be the driving force leading to Markovnikov
cyclocarboamination.
Ortho-Formyl phenylacetylenes are versatile
building blocks for many organic transformations
through
transition
metal
catalysis
and
organocatalysis.[13] The carbon-carbon triple
bonds of ortho-formyl phenylacetylenes are
generally activated by transition metals leading to
highly reactive ylide intermediates, which are
amendable to subsequent nucleophilic addition,
[3+2]-annulation, and [4+2]-cycloaddition, to
Substrates 1b and 1c bearing one more
alkynyl group at the para- or meta-position of the
aldehyde group, respectively, were employed to
react with piperidine in CH3CN at room
temperature for 24 h. The reactions also
proceeded smoothly and the expected products
3ab and 3ac also precipitated out in CH3CN and
were isolated by filtration in 38% and 42% yield,
respectively (Scheme 2B). Notably, the
cyclocarboamination exclusively occurs at the
alkynyl group which is adjacent to aldehyde
group, whereas the alkynyl group at the para-
afford
structurally
diverse
For example, we have
heterocyclic
compounds.[13b,
13c]
reported a chemoselectively gold(III)-catalyzed
cyclization of ortho-formyl phenylacetylenes
with trialkyl orthoformate.[14] Notably, ortho-
formyl phenylacetylenes readily react with
primary amines to give imines in which the
2
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10.1002/adsc.201801318
Advanced Synthesis & Catalysis
position or meta-position of the aldehyde group
this reaction was examined by using ortho-formyl
kept inert during the reaction. The inertness of the phenylacetylene (1d) to react with various
alkynyl groups that are not adjacent to the secondary amines to give 3i
-
3l in 35-48% yield.
Using 3-methylpiperidine, 3i was isolated as a
high white solid in 41% yield. Piperidine derivatives
including 4-phenyl piperidine and 1,4-dioxa-8-
aldehyde
group
showed
was
that
of
this
cyclocarboamination
chemoselectivity. Furthermore, we noted that the
enamine products 3aa, 3ab and 3ac were bench azaspiro[4.5]decane also afforded the separable
stable for months although they are inherently pure products 3j and 3k in 48% and 40% yield,
sensitive to acid medium and moisture for respectively. Finally 1-Boc-piperazine reacted
hydrolysis.
with 1d provided product 3j in 35% isolated yield.
Table
1.
Scope
of
substituted
ortho-formyl
phenylacetylenes 1 and secondary amines 2 for separable
1,3-diamino-1H-indenes 3.[a][b]
Reaction conditions: 1 (0.5 mmol), 2 (1.5 mmol, 3.0 equiv.),
o
CH3CN (1.5 mL), 25 C, 24 h. [a] Isolated yield by filtration, the
yield in parentheses is the total yield calculated by combining the
isolated yield and the yield of residual product in filtrate which
1
was determined by H NMR using 1,3,5-trimethoxybenzene as
the internal reference. [b] Isolated yield by column
chromatography on silica gel.
Scheme 2. A) Initial findings of the metal-free cyclocarbo-
amination of 1a and 2a; B) Experiments for evaluating the
chemoselectivity of the cyclocarboamination between
ortho-formyl phenylacetylenes and secondary amines.
[a] Reaction conditions:
1 (0.5 mmol), 2 (1.5 mmol, 3.0
equiv.), CH3CN (1.5 mL), room temperature, reaction time:
24 h. [b] Yield of isolated product by filtration. [c] Yield
1
determined by H NMR using 1,3,5-trimethoxybenzene as
It is well known that enamines are reactive
and usually difficult to isolate and purify.[7] With
the newly developed isolation procedure for an
easy access to pure enamines, we attempted to
extend the scope of using ortho-formyl
phenylacetylenes and secondary amines to
prepare more separable 1,3-diamino-1H-indenes.
First, the scope of substituted ortho-formyl
phenylacetylenes was explored by using
commercially available piperidine (2a) as amine
partner. As shown in Table 1, ortho-formyl
phenylacetylene (1d) reacted with 2a to provide
1,3-dipiperidyl-1H-indene (3a) in 81% NMR
yield. Various ortho-formyl phenylacetylenes
with electron-neutral group (methyl), electron-
donating groups (methoxyl, methylenedioxyl,
ortho-dimethoxyl), electron-withdrawing groups
(Cl, F), as well as two substituents (both
methoxyl and F) on the benzene ring were well-
the internal reference. [d] Reaction time: 48 h. [e] CH3CN
(3.0 mL), reaction time: 72 h.
The access to pure 1,3-diamino-1H-indenes
depends on whether they could precipitate out
3
in CH3CN for filtration. Some of the other
secondary amines reacted with 1d to afford the
corresponding 1,3-diamino-1H-indenes but they
could not precipitate out in CH3CN and hence
could not be isolated. As a result, the scope of
secondary amines for access to separable
products
indenes
3
is limited. Note that 1,3-diamino-1H-
3
are readily converted to 3-amino-1-
indanones
4 by hydrolysis (see Scheme 1A). 1-
Indanone derivatives have been widely used in
medicine and agriculture research, such as
applications in antiviral and antibacterial agents,
anticancer
drugs,
cardiovascular
drugs,
insecticides and fungicides, owing to their
prominent biological activity.[17] Next, we paid
attention to the formation of 3-amino-1-
tolerated. Separable pure 3b-3h were afforded in
36-52% yield by filtration of the resulted
precipitate and subsequent washing by cold
CH3CN. Then, the scope of secondary amines for
indanones
4 and sought to extend the scope for
this cyclocarboamination. First, ortho-formyl
3
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10.1002/adsc.201801318
Advanced Synthesis & Catalysis
phenylacetylene (1d) and piperidine (2a) were 4f and 4g in 86% and 80% yield, respectively. 5-,
employed to investigate the effect of different 7- or 8-Membered ring amines (including
solvent, temperature and amount of piperidine pyrrolidine, azepane, azacyclooctane) also
towards the reaction (Table 2). Solvent screening successfully gave 4h-4i in 58-77% yield.
experiments suggested that CH3CN provided the Moreover, heteroatom piperidine derivatives such
best yield (84%) of 4a for the reaction (Table 2, as 1-Boc-piperazine and morpholine afforded the
entries 1–10). Raising the reaction temperature expected 41 and 4m in 79% and 82% yield,
led to the decreased yield of 4a (Table 2, entries respectively. The structure of 4m was further
11–13). Attempt to improve yield by increase or
decrease the amount of piperidine was
unsuccessful (Table 2, entries 14–16). Therefore,
1d (0.5 mmol) reacted with 3.0 equivalent of 2a
in CH3CN (1.5 mL) at room temperature for 24 h
was used as the optimized reaction conditions for
confirmed by X-ray crystallographic analysis.[18]
Table 3. Scope of secondary amines and substituted ortho-
formyl phenylacetylenes for 3-amino-1-indanones 4. [a][b]
the synthesis of 3-amino-1-indanones 4a
.
Table 2. Condition Screening Experiments for Synthesis
of 3-Amino-1-indanone 4a. [a]
Temp. Usage of Yield of 4a[b]
Entry
Solvent
(oC)
2a
(%)
1
CH3CN 25
3.0 equiv. 84 (80)[c]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
THF 25
Dioxane 25
3.0 equiv.
3.0 equiv.
3.0 equiv.
3.0 equiv.
3.0 equiv.
3.0 equiv.
3.0 equiv.
3.0 equiv.
3.0 equiv.
3.0 equiv.
3.0 equiv.
3.0 equiv.
4.0 equiv.
2.5 equiv.
2.0 equiv.
68
59
46
60
46
51
48
75
70
77 (72)[c]
71
63
74
69
56
DCM
DCE
CHCl3
25
25
25
Toluene 25
Acetone 25
MeOH
EtOH
25
25
CH3CN 40
CH3CN 60
CH3CN 80
CH3CN 25
CH3CN 25
CH3CN 25
[a] Reactions were performed with 1d (0.5 mmol) and 2a in
1
solvent (1.5 mL) for 24 h. [b] Yield determined by H NMR
using 1,3,5-trimethoxybenzene as the internal reference. [c]
Isolated yield by column chromatography on silica gel.
[a] Reaction conditions:
1 (0.5 mmol), 2 (1.5 mmol, 3
With the optimized reaction conditions in
hand, a diverse range of substituted ortho-formyl
phenylacetylenes and various secondary amines
equiv.), CH3CN (1.5 mL), room temperature, reaction time:
24 h. [b] Yield of isolated product. [c] Reaction time: 48 h,
CH3CN (1.5 mL) and CHCl3 (1.5 mL). [d] Structure of 4m
validated by X-ray crystallographic analysis, for details of
the crystallographic data, see SI.
was evaluated for the reaction (Table
coupling reactions of ortho-formyl
phenylacetylene (1d) with a variety of cyclic
secondary amines proceeded smoothly to give 4a
3). The
-
However, the use of acyclic secondary
amines (including diethylamine, dibenzylamine
and diphenylamine) failed to give the desired
products. Then, transformations of 3- and 4-
substituted as well as 3,4-disubstituted ortho-
formyl phenylacetylene derivatives reacted with
4m in good to excellent yields. The reaction was
well tolerated of piperidine and its derivatives
that bearing 3-methyl, 4-methyl, 4-phenyl and 4-
benzyl group, generating 4a
Piperidine derivatives including 1,4-dioxa-8-
azaspiro[4.5]decane and 1,2,3,4-tetrahydro-
isoquinoline afforded the corresponding products
-4e in 80–86% yields.
piperidine (2a) were also successful to give 4n
-
4w in 43%-79% yields. A naphthalene-derived
4
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10.1002/adsc.201801318
Advanced Synthesis & Catalysis
substrate reacted with 2a in CH3CN/CHCl3 for 48
h afforded 4x in 70% yield. Substrates 1b and 1c
gave 4y and 4z in 77% and 81% yield,
respectively, with the alkynyl group not at the
Scheme 3. A) Experiments by using internal alkynes
reacted with piperidine (2a); B) Experiments by using
primary amines reacted with ortho-formyl phenylacetylene
(1d); C) Experiments by using sterically hindered
ortho-position of the CHO group remaining intact. secondary amines reacted with 1d; D) Access to
Furthermore, a 3-substituted substrate, 3-chloro-
2-ethynylbenzaldehyde, reacted with piperidine
to give the corresponding product 4ab in 82%
yield. However, when a 6-substituted substrate
(6-chloro-2-ethynylbenzaldehyde) was used to
react with piperidine under the same reaction
conditions, the reaction failed to give the
corresponding 3-amino-1-indanone product. The
reason would be that the sterically hindered
aldehyde group is unfavorable for the formation
of aminal.
To further investigate the substrate scope of
this transformation, the following control
experiments have been carried out (Scheme 3).
Internal alkynes (R = trimethylsilyl, phenyl, 4-
methoxyphenyl and 4-fluorophenyl) were
unreactive with 2a in CH3CN at room
temperature after stirring for 24 h (Scheme 3A).
No expected 3-amino-1-indanones were found
when primary amines (such as cyclohexylamine,
benzylamine and aniline) reacted with ortho-
formyl phenylacetyle (1d) in CH3CN for 24 h
(Scheme 3B). Notably, sterically hindered
secondary amines such as 2,6-dimethylpiperidine,
2-methylpiperidine and (S)-α,α-diphenylprolinol
tert-butyldimethylsilyl ether remained inert
towards 1d under the same reaction conditions
(Scheme 3C). Interestingly, using (S)-α,α-
diphenylprolinol that bearing a free hydroxyl
group under the same reaction conditions, an
oxazolidine product 8a was isolated in 90%
yield.[19] We propose that the transformation
might go through the formation of iminium 8b
which is preferred to be attacked by the adjacent
hydroxyl group to form a 5-membered-ring
compound 8a prior to the cyclocarboamination
process (Scheme 3D).
oxazolidine 8a by using 1d reacted with (S)-α,α-
diphenylprolinol.
Enamines are versatile intermediates which
generally act as nucleophiles to attack various
electrophiles by contributing its lone pair electrons on
nitrogen, and subsequent hydrolysis to give α-
substituted carbonyl compounds.[7] Initially, we found
that adding iodine to the reaction of 1d and
morpholine in CH3CN at room temperature for 1 h
gave a highly functionalized indane derivatives 7a in
41% isolated yield with excellent trans selectivity
(trans/cis >20:1, Table 4, entry 1). Solvent screening
experiments suggested that CHCl3 provided the best
yield (82%) of 7a for the reaction (Table 4, entries 2–
7). Furthermore, the yield of 7a was improved to 91%
by prolonging the reaction time to 3 h when using
CHCl3 as solvent (Table 4, entry 8).
Table 4. Condition screening experiments for synthesis of
3-amino-2-iodo-1-indanone 7a. [a]
Entry Solvent Time (h)
Yield of 7a trans/cis[d]
(%)[b]
1
2
3
4
5
6
7
8[c]
CH3CN
Dioxane
THF
Et2O
DCE
CH2Cl2
CHCl3
CHCl3
1
1
1
1
1
1
1
3
41
50
60
30
72
77
82
91
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
[a] Reactions were performed with 1d (0.5 mmol) and
morpholine (1.5 mmol, 3.0 equiv.) in solvent (1.5 mL) for 1
h. [b] Isolated yield by column chromatography on silica
gel. [c] Reaction time: 3 h. [d] Detected by 1H NMR
analysis.
Encouraged by this result, we used iodine as
an electrophile to couple with various secondary
amines and ortho-formyl phenylacetylenes in
CHCl3, and a variety of 3-amino-2-iodo-1-
indanones
7 were obtained with moderate to
excellent yields and excellent stereoselectivity
(Table 5). Apart from morpholine, 1,4-dioxa-8-
azaspiro[4.5]decane
and
1-Boc-piperazine
smoothly afforded 7b and 7c in good isolated
yields (76% and 56%, respectively). A diversity
of 3-amino-2-iodo-1-indanones 7d–7j with good
isolated yields (55-88%) were also obtained from
various electron-donating groups (methoxyl,
Reactions were performed with ortho-formyl phenylacetylenes
(0.5 mmol) and amines (1.5 mmol, 3.0 equiv.) in CH3CN (1.5
mL) at room temperature for 24 h.
methylenedioxyl,
ortho-dimethoxyl)
and
electron-withdrawing groups (F, trifluoromethyl)
5
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10.1002/adsc.201801318
Advanced Synthesis & Catalysis
reaction was performed with 5a (0.3 mmol) in CH3CN (3.0 mL)
at room temperature for 96 h.
substituted ortho-formyl phenylacetylenes. An
ethynyl-substituted (meta-position towards -CHO
group) substrate (1c) proceeded smoothly and the
Scheme 4. A) Control experiments by using dimethyl
acetals of 1 as substrates reacted with piperidine; B)
Control experiment by using ortho-acetyl phenylacetylene
reacted with piperidine; C) Synthesis of separable aminal
intermediates 5 by using 1d reacted with various secondary
amines; D) Synthesis of 1,3-diamino-1H-indene 3j from
separable aminal 5a.
meta-ethynyl
kept
inert
during
this
transformation, thus giving the corresponding 3-
amino-5-ethynyl-2-iodo-1-indanone 7k in 80%
yield. Furthermore, the naphthalene-derived
substrate also afforded the corresponding product
7l in moderate yield (52%) under the same
reaction conditions.
Table
5.
Scope
of
substituted
ortho-formyl
phenylacetylenes 1 and secondary amines 2 for synthesis
of 3-amino-2-iodo-1-indanones 7. [a][b][c]
We have conducted mechanistic studies to
provide support for
a
proposed reaction
mechanism (Scheme 4). Using dimethyl acetals
that come from the corresponding ortho-formyl
phenylacetylenes to react with piperidine (2a) in
CH3CN for 24 h, the expected 3-piperidyl-1-
indanones were not obtained (Scheme 4A).
Moreover,
the
use
of
ortho-acetyl
phenylacetylene[20] reacted with 2a in CH3CN for
24 h failed to afford the proposed product 9a
(Scheme 4B). To demonstrate the aminal
5 act as
the key intermediate for this transformation, the
following control experiments have been carried
out. Using 1d reacted with 4-phenylpiperidine,
1,4-dioxa-8-azaspiro[4.5]decane and 1-Boc-
piperazine in CH3CN at room temperature for 4
h, the corresponding aminals 5a, 5b and 5c (well-
characterized by 1H NMR and 13C NMR
spectroscopy, high-resolution ESI-MS) were
isolated in 75%, 82% and 87% yield, respectively
(Scheme 4C). We also checked the possibility of
the formation of aminals by using acyclic amines,
such as diethylamine and dibenzylamine, with 2-
ethynylbenzaldedhyde, respectively. However,
the corresponding aminals were not isolated or
[a] Reactions were performed with
secondary amine (1.5 mmol) in CHCl3 (1.5 mL) for 3 h. [b]
Isolated yield by column chromatography on silica gel. [c]
The ratio of trans/cis was detected by H NMR analysis. [d]
Reaction time: 24 h.
1 (0.5 mmol) and
1
1
detected by H NMR analysis from the reaction
mixture. Furthermore, we observed that 5a was
readily converted to the 1,3-diamino-1H-indene
3j in 43% yield upon prolong reaction time (96 h)
in CH3CN (Scheme 4D). Cross over experiment
between aminal 5d and 4-phenylpiperidine was
performed, products 4ac and 4ad were isolated in
37% and 29% yield, respectively. The results
indicated that the carboamination step would be
an intermolecular process (see details of the
reaction procedures and conditions in the
Supporting Information on pages S5-S6).
Based on the observed results, a proposed
reaction pathway accounting for this metal-free
cyclocarboamination is outlined in Figure 1.
Initially,
phenylacetylene
an aminal intermediate
reversible equilibrium to give an iminium
cation/amine anion pair Subsequent
nucleophilic attack by the transient reactive
amine anion towards carbon-carbon triple bond
(at this step, transient intermediate 6’ presumably
generated in situ) and simultaneous nucleophilic
attack to the proximal iminium to complete the
the
reaction
and secondary amine
, which then undergoes
of
ortho-formyl
1
2
leads to
5
6.
For A and B, reactions were performed with phenylacetylene
substrates (0.5 mmol) and piperidine (1.5 mmol, 3.0 equiv.) in
CH3CN (1.5 mL) at room temperature for 24 h; For C, reactions
were performed with 1d (0.5 mmol) and amines (1.5 mmol, 3.0
equiv.) in CH3CN (3.0 mL) at room temperature for 4 h; For D,
6
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10.1002/adsc.201801318
Advanced Synthesis & Catalysis
cyclocarboamination process and give versatile
enamine products
to electrophiles. So 3-amino-indanones
obtained by column chromatography on silica
gel, and 3-amino-2-iodo-1-indanones were
3
. The enamines
3
are reactive
4
were
7
obtained when I2 was used as an electrophile for
the reaction. Therefore, we consider that the
driving
cyclocarboamination process are both the
LUMO-lowering activation (iminium
formation) and HOMO-rising activation (enamine
force
for
the
metal-free
6
3
formation), as well as the enhanced
nucleophilicity of the transient amine anion,
which comes from the in situ generated iminium
cation/amine anion pair 6, versus the free amine.
To demonstrate the practical synthetic utility
of our new protocol for synthesis of 3-amino-
indanones, a gram-scale cyclocarboamination
reaction of 1d (1.30 g, 10.0 mmol) with 1,2,3,4-
tetrahydro-isoquinoline (4.0 g, 30.0 mmol) was
conducted at room temperature in CH3CN for 48
h. The reaction proceeded smoothly and afforded
2.16 g of product 4g in 82% yield (Scheme 5A).
Visible-light-mediated alkynylation of 4g with
trimethylsilylacetylene was carried out under
irradiation of 5W LED at room temperature by
using Rose Bengal and CuI as co-catalysts and
subsequent desilylation to furnish 10a with 34%
yield.[21] The photo-reaction of 4g with
phenylacetylene gave 10b in 63% yield (Scheme
5B). The resulting alkynyl-containing carbonyl
compounds 10a and 10b are versatile synthetic
blocks for our on-going research work.
Scheme 5. A) Gram-scale synthesis of 4g; and B)
Synthetic utility of 4g.
Conclusion
In conclusion, we have developed an efficient
metal-free cyclocarboamination of ortho-formyl
phenylacetylenes with secondary amines. This new
protocol is distinguished by easy operation, readily
available starting materials, good functional-group
compatibility, excellent atom economy and high
chemo- and regioselectivity, which provide a new
attractive access to the construction of highly
functionalized indenes and indanones complementary
to the existing methods. Experimental results
suggested that the in situ generated transient iminium
cation/amine anion pair 6 plays an important role in
the reaction.
Experimental Section
General Procedure for Synthesis of 1,3-Diamino-1H-
Indenes 3
To a solution of ortho-formyl phenylacetylene 1 (0.5 mmol)
in CH3CN was added secondary amine 2 (1.5 mmol, 3.0
o
equiv.) at room temperature (25 C). The mixture was
o
stirred at 25 C for 24 h (or indicated time, monitored by
TLC). The resulting precipitate was collected by suction
filtration and quickly washed by cold CH3CN to give the
corresponding pure 1,3-diamino-1H-indene 3.
General Procedure for Synthesis of 3-Amino-1-
Indaones 4
To a solution of ortho-formyl phenylacetylene 1 (0.5 mmol)
in CH3CN was added secondary amine 2 (1.5 mmol, 3.0
Figure 1. Proposed reaction pathway for this metal-free
cyclocarboamination.
o
equiv.) at room temperature (25 C). The mixture was
o
stirred at 25 C for 24 h (or indicated time, monitored by
TLC). The solvent was removed under vacuum and the
residue was purified by column chromatography
(EA/Hexane as eluent) to give the corresponding 3-amino-
1-indaones 4.
7
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10.1002/adsc.201801318
Advanced Synthesis & Catalysis
W. Davis-Gilbert, L. J. Yao, I. A. Tonks, J. Am. Chem.
Soc. 2016, 138, 14570-14573; g) L. B. Wolf, K. C. M.
F. Tjen, H. T. ten Brink, R. H. Blaauw, H. Hiemstra, H.
E. Schoemaker, F. P. J. T. Rutjes, Adv. Synth. Catal.
2002, 344, 70-83; h) A. Fürstner, P. W. Davies, J. Am.
Chem. Soc. 2005, 127, 15024-15025.
a) D. A. Bock, C. W. Lehmann, B. List, P. Natl. Acad.
Sci. 2010, 107, 20636-20641; b) S. Mukherjee, J. W.
Yang, S. Hoffmann, B. List, Chem. Rev. 2007, 107,
5471-5569; c) B. List, Acc. Chem. Res. 2004, 37, 548-
557; d) B. Kempf, N. Hampel, A. R. Ofial, H. Mayr,
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General Procedure for Synthesis of 3-Amino-2-Iodo-1-
Indaones 7
To a solution of ortho-formyl phenylacetylene 1 (0.5 mmol)
and secondary amine 2 (1.5 mmol, 3.0 equiv.) in CH3CN
was added iodine (0.525 mmol, 1.05 equiv.) at room
temperature (25 oC). The mixture was stirred at 25 oC for 3
h (or indicated time, monitored by TLC). The solvent was
removed under vacuum and the residue was purified by
flash column chromatography (EA/Hexane as eluent) to
give the corresponding 3-amino-2-iodo-1-indaones 7.
[7]
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R. Bergeron, K. P. Ellsworth, W. M. Geissler, R. W.
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We are grateful for the financial support from Hong Kong
Research Grants Council (PolyU 153031/14P and X-ray
diffractometer-PolyU11/CRF/13E), the State Key Laboratory of
Chemical Biology and Drug Discovery, and The Hong Kong
Polytechnic University (G-YBM8). We thank Prof. Zhou
Zhongyuan for X-ray crystallographic analysis.
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Advanced Synthesis & Catalysis
FULL PAPER
Metal-Free Cyclocarboamination of ortho-Formyl
Phenylacetylenes with Secondary Amines: Access
to 1, 3-Diamino-1H-Indenes and 3-Amino-1-
Indanones
Adv. Synth. Catal. Year, Volume, Page – Page
Jian-Fang Cui,a, b Rishi Tang,a Bin Yang,a
Nathanael Chun-Him Lai,a Jia-Jun Jiang,a Jie-Ren
Deng,a and Man-Kin Wonga*
10
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