Cs2CO3 Catalyzed Intramolecular Aminocarbonylation of Alkynes: Synthesis of 3-Amino-1H-inden-1-ones from N-tert-Butyl-2-(1-alkynyl)benzaldimines

Article abstract of DOI:10.1002/adsc.201901349

Synthesis of a wide variety of 3-amino-1H-inden-1-ones from N-tert-butyl-2-(1-alkynyl)benzaldimines via intramolecular aminocarbonylation of alkynes using Cs₂CO₃ as catalyst and air as oxidant has been developed. This highly atom-efficient, transition-metal-free reaction proceeds under thermal conditions. We propose that the reaction proceeds through an unprecedented 5-exo-dig cyclization of N-tert-butyl-2-(1-alkynyl)benzaldimines and thermal rearrangement of 3-methylene-2λ²-isoindolin-1-ols. (Figure presented.).

Full text of DOI:10.1002/adsc.201901349

Title: Cs2CO3 Catalyzed Intramolecular Aminocarbonylation of
Alkynes: Synthesis of 3-Amino-1H-inden-1-ones from N-tert-
Butyl-2-(1-alkynyl)benzaldimines
Authors: Zhen Guo, Tao Liu, Xiujuan Liang, Yuting Wu, and Tuanli Yao
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901349
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10.1002/adsc.201901349
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Cs2CO3 Catalyzed Intramolecular Aminocarbonylation of
Alkynes: Synthesis of 3-Amino-1H-inden-1-ones from N-tert-
Butyl-2-(1-alkynyl)benzaldimines
Zhen Guo,‡ Tao Liu,‡ Xiujuan Liang, Yuting Wu and Tuanli Yao*
Shaanxi Key Laboratory of Chemical Additives for Industry, College of Chemistry and Chemical Engineering, Shaanxi
University of Science and Technology, Xi’an, 710021, P. R. of China. e-mail: yaotuanli@sust.edu.cn
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. Synthesis of a wide variety of 3-amino-1H-
inden-1-ones from N-tert-butyl-2-(1-alkynyl)benzaldimines
via intramolecular aminocarbonylation of alkynes using
Cs2CO3 as catalyst and air as oxidant has been developed.
This highly atom-efficient, transition-metal-free reaction
proceeds under thermal conditions. We propose that the
reaction proceeds through an unprecedented 5-exo-dig
cyclization of N-tert-butyl-2-(1-alkynyl)benzaldimines and
thermal rearrangement of 3-methylene-2λ2-isoindolin-1-ols.
Keywords: aminocarbonylation; 3-amino-indenone; N-
tert-butyl-2-(1-alkynyl)benzaldimines; catalysis; cesium
carbonate
Scheme 1. Palladium-catalyzed domino Heck/inter-
molecular cross-coupling of 2-(1-alkynyl)benzaldimines.
The cyclization of alkynes bearing a proximate
nucleophilic center is one of the most useful
strategies to construct heterocycles.[1] The feasibility
of cyclization can be guided by the Baldwin’s rules of
kinetically
favored
5-exo-dig
cyclization
ring closure,[2] in which both 5-exo-dig and 6-endo-
dig cyclization are allowed. Indeed, both 5-exo-dig
and 6-endo-dig cyclization products were observed in
the cyclization of 2-alkynylbenzoic acids, 2-
alkynylbenzamides, and 2-alkynylbenzimidates etc.[3]
In contrast, cyclization of 2-alkynylarylimine
derivatives such as N-alkyl benzaldimines,
benzaldehyde oximes and benzaldehyde hydrazones,
afforded only 6-endo-dig cyclization products
(isoquinoline derivatives).[4] Considering the broad
interest in cyclization reactions, it is remarkable that,
to the best of our knowledge, the counterpart 5-exo-
dig cyclization of imine derivatives remains unknown.
intermediates can be trapped and undergo
thermodynamically favorable fragmentation into a
stable product, the overall selectivity of cyclization
will certainly be changed.
During the study on the palladium-catalyzed
domino Heck/intermolecular cross-coupling of 2-
alkynylbenzaldimines,[6] a minor product was isolated,
which was identified as 3-(tert-butylamino)-2-
phenyl-1H-inden-1-one (Scheme 1).[7] The formation
of inden-1-one product is intriguing since an
unprecedented 5-exo-dig cyclization of imine group
and a novel rearrangement might be involved. In
addition, inden-1-ones are important synthons in
organic synthesis and privileged scaffolds in
medicinal chemistry.[8] Driven by the potential
mechanistic implications and the possibility to
develop a novel method for the synthesis of 3-amino-
1H-inden-1-ones, we therefore set out to investigate
this unusual intramolecular aminocarbonylation of
alkyne reaction in more detail.
5-Exo-dig is kinetically preferred over 6-endo-dig
in the stereoelectronic rules for cyclization.[5] In the
previous reported cyclization of 2-alkynylarylimine
derivatives, the 5-exo-dig cyclization has to be
readily reversible. Thus, under thermodynamic
conditions, the exclusive 6-endo-dig selectivity is
driven by the aromatic stabilization gained in
isoquinoline-type products. However, if the
1
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10.1002/adsc.201901349
Advanced Synthesis & Catalysis
Table 1. Optimization of Reaction Conditions[a]
Table 2. Scope of the Substituents on the Acetylenes[a]
Base
Yields of 2a
Solvent (mL)
DMF (5.0)
Pd catalyst (equiv)
Entry
(equiv) and 2a’ (%)[b]
1
2
3
4
5
6
7
Pd(PPh3)4 (0.05) K2CO3 (3.0) 8 + 38
DMF (4.85) + H2O (0.15) Pd(PPh3)4 (0.05) K2CO3 (3.0) 40 + 26
DMF (4.75) + H2O (0.25) Pd(PPh3)4 (0.05) K2CO3 (3.0) 41 + 11
DMF (4.0) + H2O (1.0) Pd(PPh3)4 (0.05) K2CO3 (3.0) 31 + 17
DMF (4.75) + H2O (0.25) Pd(PPh3)4 (0.05) Cs2CO3 (3.0) 45 + 11
DMF (4.75) + H2O (0.25) Pd(PPh3)4 (0.05) NaOH (3.0) trace
Pd(dba)2 (0.05)
+ BINAP (0.1)
-
DMF (4.75) + H2O (0.25)
Cs2CO3 (3.0) 65 + 12
8
9
DMF (4.75) + H2O (0.25)
DMF (4.75) + H2O (0.25)
10[c] DMF (4.75) + H2O (0.25)
Cs2CO3 (3.0) 55 + 9
Cs2CO3 (0.1) 54 + 10
-
-
-
0 + 6
[a] Conditions: 1a (0.3 mmol), base, Pd catalyst (0.05 equiv
if used) and H2O in DMF at 135 °C under an air balloon
[b]
[c]
for 4h.
Isolated yield.
55% of 2-
(phenylethynyl)benzaldehyde recovered.
We began by investigating the intramolecular
aminocarbonylation of N-tert-butyl-2-(1-
alkynyl)benzaldimine 1a (For detailed optimization,
see SI, Table S1). Exposure of 1a to 5 mol % of
Pd(PPh3)4 and 3.0 equivalent of K2CO3 in DMF at
135 °C under air for 4h afforded 2a in an 8% isolated
yield along with isoquinoline 2a' which is the 6-
endo-dig cyclization product (Table 1, entry 1).
Addition of water to the reaction (H2O:DMF = 3:97
v/v) dramatically increased the yield of 2a to 40%
(entry 2). Increasing the amount of water (H2O:DMF
= 5:95 v/v) afforded a similar yield of 2a, but much
less undesired isoquinoline 2a' (entry 3). Further
increasing the amount of water was detrimental to the
reaction (entry 4). Switching base to Cs2CO3
improved the yield of 2a to 45% (entry 5) and strong
base such as NaOH only provided a trace of desired
2a (entry 6). Applying 5 mol% of Pd(dba)2 and 10
mol % of BINAP further improved the yield of 2a to
65% (entry 7). The control experiment showed that
palladium catalyst was advantageous, but not
essential to the reaction (entry 8). The reaction
proceeded smoothly when using a catalytic amount of
Cs2CO3 (entry 9). Finally, no conversion of 1a to 2a
was observed when the reaction was performed in the
absence of Cs2CO3 (entry 10).
[a]
Conditions: 1 (0.3 mmol), Cs2CO3 (0.03 mmol), H2O
(0.25 mL), DMF(4.75mL), air balloon, 4h, 135°C. isolated
The substrate scope of this reaction was explored
next. As shown in Table 2, the reaction worked well
when phenyl on the remoted end of alkyne was
substituted with an electron-withdrawing group or a
halide (2b-e and 2h-j). An electron-donating m-OMe
or o-OMe also afforded desired products 2k and 2l in
good yields, but a p-OMe led to an incomplete
reaction because the carbon-carbon triple bond is not
sufficiently polarized (2g). when R was 2-pyridinyl
or disubstituted phenyl groups, 3-amino-1H-inden-1-
yield. [b]Pd(dba)2 (0.015 mmol), BINAP (0.03mmol) and
[d]
[e]
[f]
[g]
Cs2CO3 (0.9 mmol). [c] 100 °C. 8h. 2h. 1h. 47%
of 2-[(4-methoxyphenyl)ethynyl]-benzaldehyde recovered.
[h] 80% of 2-(hex-1-yn-1-yl)benzaldehyde recovered.
ones 2n-q were obtained in moderate to excellent
yields. Unfortunately, when R was an alkyl group, no
product was obtained and the starting material was
2
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10.1002/adsc.201901349
Advanced Synthesis & Catalysis
Scheme 2. Mechanistic studies.
recovered. The effect of substitution on the aromatic
ring bearing imine group has also been examined.
The presence of CF3, halide and alkyl group on 3-
and 4-position were all well tolerated (2s-u and 2w-y).
Although alkoxy group on 3- and 4-position led to the
lower yields of desired products (2v, 2z and 2aa),
alkoxy group on 2-position afforded 2ab in a good
75% yield. Gratifyingly, cyclopenta[b]pyridin-5-one
2ac and cyclopenta[b]quinolin-1-one 2ad could also
be efficiently prepared by this method.
Scheme 3. Proposed mechanism.
We ruled out the possibility of a mechanism
involving formation a ketone intermediate by
addition of water to the alkyne, as no reaction
happened when performing the reaction using 2-
(phenylethynyl)benzaldehyde under our standard
conditions (Scheme 2). Alkynylbenzaldimine 1y only
produced inden-1-one 2y and no other isomer was
observed. The structure of 2y was confirmed by
single crystal X-ray diffraction.[9] So the reaction
should involve migration of t-butylamino group.
To support the proposed mechanism, imine 1b
was exposed to 3.0 equivalent of Cs2CO3 in
DMF/H2O at 60 °C under argon for 0.5 h (Scheme 4).
An unstable product which was assumed to be
intermediate E was formed. It could be converted into
3-amino-1H-inden-1-one 2b in a 66% isolated yield
under our standard conditions. Since this unstable
intermediate could not be isolated, it was hydrolyzed
and 3-hydroxy-2,3-dihydro-1H-inden-1-one 4 was
obtained in a 45% yield, which strongly supports the
formation of intermediate E.
A possible mechanism for this transformation was
illustrated in Scheme 3. The reaction begins with the
intramolecular nucleophilic attack of the nitrogen
atom of the imine on the carbon-carbon triple bond.
The 5-exo-dig cyclization generates zwitterionic
intermediate A whose addition with H2O lead to
isoindolin-1-ol B. The
B
undergoes thermal
fragmentation driven by base to form alkenyl amine
anion C. The cyclization of C following by
protonation and isomerization would produce inden-
1-ol E'[10]. Cs2CO3 is regenerated by the reaction of
hydroxide with cesium bicarbonate. The oxidation by
air or Pd(II) (if used) or the thermal dehydrogenation
when performed under Ar (SI, Table S1, entry 39)
would convert E to product 2a. On the other hand, 6-
endo-dig cyclization and cleavage of the tert-butyl
group leads to formation of isoquinoline 2a'.
Scheme 4. Formation of intermediate E
3
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10.1002/adsc.201901349
Advanced Synthesis & Catalysis
This work was financially supported by Shaanxi University of
Science and Technology (BJ15-33) and the Natural Science
Foundation of Shaanxi Province of China (2017JM2004). Dr.
Yifan Kang (SUST) is acknowledged for assistance with X-ray
diff raction studies on compounds 2a and 2y.
Other benzaldimines such as N-n-butyl imines, N-
i-propyl imines, or N-phenyl imines did not afford 3-
amino-1H-inden-1-one products under our standard
conditions because they are not stable enough or
nucleophilic enough under our conditions.
References
Table 3. Transformation of 2a[a]
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[a]
Conditions: 2a (0.2 mmol), amine (1.0 mL), EtOH (1.0
mL), reflux for 36 h. Isolated yield.
The synthetic utility of this method was
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primary and secondary amines, which afforded
various 3-amino-1H-inden-1-ones in good to
excellent yields (Table 3).
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In conclusion, we have developed a transition-
metal free synthesis of 3-amino-1H-inden-1-ones
from N-tert-butyl-2-(1-alkynyl)benzaldimines via
intramolecular aminocarbonylation of alkynes using
Cs2CO3 as catalyst and air as oxidant. This highly
atom-efficient, environmentally benign reaction is
proposed to proceed through an unprecedented 5-exo-
[5] I. V. Alabugin, K. Gilmore, M. Manoharan, J. Am.
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2386-2389.
[7] CCDC 1949095 contains the supplementary
crystallographic data for this compound 2a. The data
can be obtained free of charge from the Cambridge
dig
cyclization
of
N-tert-butyl-2-(1-
alkynyl)benzaldimines and thermal rearrangement of
3-methylene-2λ2-isoindolin-1-ols.
Crystallographic
Data
Centre
via
http://www.ccdc.cam.ac.uk/ data_request/cif.
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Experimental Section
3-Amino-1H-inden-1-ones
2
by
Intramolecular
Aminocarbonylation of Alkynes 1; General Procedure
To a solution of imine 1 (0.3 mmol, 1.0 equiv) in DMF
(4.75 mL) and H2O (0.25 mL) was added Cs2CO3 (0.03
mmol, 0.1 equiv.). The resulting mixture was stirred at
135 °C or 100 °C under air by using an air balloon. The
progress of the reaction was monitored by TLC analysis to
establish its completion. After cooling to room temperature,
the reaction mixture was diluted with ethyl acetate (20 mL),
washed with water (20 mL) and brine (20 mL), dried
(MgSO4) and concentrated. The residue was purified by
column chromatography (silica gel, petroleum ether/ethyl
acetate).
[9] CCDC 1949112 contains the supplementary
crystallographic data for 2y. The data can be obtained
free of charge from the Cambridge Crystallographic
Data
Centre
via
http://www.ccdc.cam.ac.uk/
Acknowledgements
data_request/cif.
4
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10.1002/adsc.201901349
Advanced Synthesis & Catalysis
[10] For selected aza-Petasis-Ferrier rearrangement, see: a)
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6002−6006; b) Z. Cao, H. Zhu, X. Meng, J. Guan, Q.
Zhang, L. Tian, X. Sun, G. Chen, J. You, Chem. Eur. J.
2016, 22, 16979-16985; c) M. Terada, T. Komuro, Y.
Toda, T. Korenaga, J. Am. Chem. Soc. 2014, 136, 7044
-7057. d) M. Terada, Y. Toda, J. Am. Chem. Soc. 2009,
131, 6354-6355.
5
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10.1002/adsc.201901349
Advanced Synthesis & Catalysis
COMMUNICATION
Cs2CO3 Catalyzed Intramolecular
Aminocarbonylation of Alkynes: Synthesis of 3-
Amino-1H-inden-1-ones from N-tert-Butyl-2-(1-
alkynyl)benzaldimines
Adv. Synth. Catal. Year, Volume, Page – Page
Zhen Guo,a,‡ Tao Liu,a,‡ Xiujuan Liang,a Yuting
Wua and Tuanli Yao*,a,§
6
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