Visible light mediated intermolecular [3 + 2] annulation of cyclopropylanilines with alkynes

Article abstract of DOI:10.3762/bjoc.10.96

Intermolecular [3 + 2] annulation of cyclopropylanilines with alkynes is realized using visible light photoredox catalysis, yielding a variety of cyclic allylic amines in fair to good yields. This method exhibits significant group tolerance particularly w

Full text of DOI:10.3762/bjoc.10.96

Visible light mediated intermolecular [3 + 2]
annulation of cyclopropylanilines with alkynes
Theresa H. Nguyen, Soumitra Maity and Nan Zheng*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 975–980.
Department of Chemistry and Biochemistry, University of Arkansas,
Fayetteville, Arkansas, 72701, USA
doi:10.3762/bjoc.10.96
Received: 04 February 2014
Accepted: 04 April 2014
Published: 29 April 2014
Email:
Nan Zheng* - nzheng@uark.edu
* Corresponding author
This article is part of the Thematic Series "Organic synthesis using
photoredox catalysis".
Keywords:
[3 + 2]; alkyne; annulation; cyclopropylaniline; photoredox catalysis;
visible light
Guest Editor: A. G. Griesbeck
© 2014 Nguyen et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Intermolecular [3 + 2] annulation of cyclopropylanilines with alkynes is realized using visible light photoredox catalysis, yielding a
variety of cyclic allylic amines in fair to good yields. This method exhibits significant group tolerance particularly with hetero-
cycles. It can also be used to prepare complex heterocycles such as fused indolines.
Introduction
Cyclopropanes have been used as a three-carbon synthon to manipulate the redox chemistry of organic compounds [21-26].
prepare a diverse array of organic compounds [1-4]. The Amines have been used as an electron donor to reduce the
unusual reactivity, exhibited by cyclopropanes, is largely due to excited state of photocatalysts, while they are oxidized to amine
their inherent ring strain that makes cleavage of the C–C bonds radical cations. Our group and others have taken advantage of
facile [5]. A number of methods have been developed to regio- this facile redox process and developed a number of synthetic
selectively cleave cyclopropanes, generating synthetically methods that harness the synthetic potential of amine radical
useful intermediates that can be further manipulated [1-5]. For cations [21,27,28]. One of the reported methods from our group
one subclass of cyclopropanes, cyclopropylamines, the requi- involves [3 + 2] annulation of cyclopropylanilines with alkenes
site ring opening is often accomplished by one-electron oxi- [29]. We were intrigued by the possibility of extending this
dation of the parent amine. This oxidation step can be realized annulation method to include alkynes. The immediate benefits
enzymatically [6-8], chemically [9-14], electrochemically of using alkynes include eliminating the diastereoselectivity
[15,16], and photochemically [17-20]. Recently, visible light issue observed in the annulation of monocyclic cyclopropyl-
photoredox catalysis has emerged as a powerful method to anilines with alkenes and introducing an alkene functional
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Beilstein J. Org. Chem. 2014, 10, 975–980.
group into the annulation product. Furthermore, the synthesis of [29]. White 18 W LEDs were found to be more effective for the
cyclic allylic amines is non-trivial in general [30]. Herein, we annulation with alkynes, resulting in a higher yield (Table 1,
report intermolecular [3 + 2] annulation of monocyclic cyclo- entry 6). Control studies showed that both the photocatalyst and
propylanilines with alkynes under visible light photoredox light were required, though some background reaction was
conditions.
observed (Table 1, entries 7 and 8).
Results and Discussion
To determine the scope of this annulation process, a range of
Biphenylcyclopropylamine 1 and phenylacetylene (2) were cyclopropylanilines with various electronic and steric character-
chosen as the standard substrates to optimize the catalyst system istics were prepared and then subjected to the optimized cata-
for the [3 + 2] annulation with alkynes (Table 1). Similar to the lyst system. The results of the scope studies are summarized in
annulation with alkenes [29], several reactivity patterns were Figure 1. Both electron-donating (OMe, 7, and OTBS, 8) and
observed. CH3NO2 was far superior to DMF and CH3CN as the electron-withdrawing (CF3, 9, 14, 18, and CN, 10, 13)
solvent (Table 1; entries 1–3). Ru(bpz)3(PF6)2 was a more substituents were well tolerated, and the annulation products
effective photocatalyst than Ru(bpy)3(PF6)2 (Table 1, entry 4). were generally obtained in modest to good yields. The annula-
Air was detrimental to the annulation reaction (Table 1, entry tion process also tolerated steric hindrance. Hindered cyclo-
5). However, we noticed the annulation with alkynes was propylanilines, such as those possessing an ortho-isopropyl
slower than with alkenes, previously reported by our group group, were satisfactorily converted to the annulation products
[29]. To compensate for lower reactivity of alkynes, we investi- (6 and 12). With respect to the other annulation partner,
gated commercially available light resources that were stronger terminal alkynes substituted with an electron-withdrawing
than 13 W compact fluorescent lamps (CFLs). 13 W CFLs were group were typically required for the annulation process. Alkyl-
used as the light source to mediate the annulation with alkenes substituted terminal alkynes and internal alkynes were not reac-
Table 1: Catalyst screening.
Entrya
Catalyst
Light
Solvent
GC yield of 3 [%]b
1
2
4a
4a
18 W LED
18 W LED
18 W LED
18 W LED
18 W LED
13 W CFL
18 W LED
none
CH3NO2
DMF
82 (80)c
20
36
55
41
68
6
3
4a
CH3CN
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
4
4b
5d
6
4a
4a
7
none
4a
8
3
aConditions: 1 (0.2 mmol), 2 (1 mmol), solvent (2 mL), degassed, irradiation at rt for 8 h. bDodecane was used as an internal standard. cIsolated yield
by silica gel chromatography. dThe reaction was conducted in the presence of air.
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Beilstein J. Org. Chem. 2014, 10, 975–980.
Figure 1: Substrate scope.
tive under the optimized conditions. This reactivity trend cyclopropylanilines uneventfully (15–18). The alkyne moiety at
towards alkynes is consistent with that exhibited in intermolec- the C2 or C3 position of thiophene or pyridine showed similar
ular addition of nucleophilic carbon-based radicals to alkynes reactivity towards the annulation.
[31-33]. In addition to phenylacetylene, acetylenic methyl ester
is a viable annulation partner, leading to annulation products Fused indolines are common structural motifs that appear in a
11–14 in good yields. Heterocycles are frequently used in number of biologically active alkaloids and pharmaceuticals
organic electronic materials [34] and pharmaceuticals [35,36]. [37,38]. The [3 + 2] annulation of monocyclic cyclopropyl-
Therefore, the ability to incorporate them is usually considered anilines with alkynes provides a fast entry to this motif
a benchmark for developing new synthetic methods. This (Scheme 1). Starting from commercially available 1-bromo-2-
method has certainly passed this test as two pairs of hetero- iodobenzene (19) and cycloproylamine, 2-bromo-N-cyclo-
cycle-containing alkynes underwent the [3 + 2] annulation with propylaniline (20) was prepared in 75% yield via the Buch-
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Beilstein J. Org. Chem. 2014, 10, 975–980.
Scheme 1: Synthesis of a fused indoline.
wald–Hartwig amination [39,40]. The [3 + 2] annulation of the vinyl radical to the iminium ion of distonic radical cation 28
2-bromo-N-cyclopropylaniline (20) and phenylacetylene (2) closes the five membered ring and furnishes amine radical
was performed using the optimized catalyst system to provide cation 29. Finally, Ru(bpz)31+ reduces amine radical cation 29
cyclic allylic amine 21 in 52% yield. The fused indoline motif to the annulation product 30 while regenerating Ru(bpz)32+.
was formed via an intramolecular Heck reaction under Fu’s The proposed mechanism accounts for lower reactivity of
conditions [41] to provide a mixture of two olefinic regioiso- alkynes towards intermolecular addition of nucleophilic carbon-
mers 22, which were converted to saturated fused indoline 23 centered radicals as well as their regiochemistry in the annula-
under standard catalytic hydrogenation conditions in a tion [31-33]. Addition of radicals to alkynes generally occurs at
combined yield of 40% from 21.
the less hindered carbon, i.e., the terminal carbon.
Mechanistically, the annulation with alkynes probably proceeds Conclusion
through a pathway similar to the one we proposed for the annu- In summary, we have successfully expanded the [3 + 2] annula-
lation with alkenes (Scheme 2) [29]. The photoexcited tion of cyclopropylanilines to include alkynes. This annulation
Ru(bpz)32+ oxidizes cyclopropylaniline 24 to the corres- process with alkynes has addressed some limitations existing in
ponding amine radical cation 25, which triggers the cyclo- the annulation with alkenes. Moreover, the annulation products
propyl ring opening to generate distonic radical cation 26. The from alkynes are highly useful synthetic intermediates. Their
primary carbon radical of 26 adds to the terminal carbon of utility is demonstrated by a four-step synthesis of fused indo-
alkyne 27 to afford vinyl radical 28. Intramolecular addition of lines in which the [3 + 2] annulation with alkynes is used to set
Scheme 2: Proposed catalytic cycle.
978

Beilstein J. Org. Chem. 2014, 10, 975–980.
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Experimental
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This publication was supported by the University of Arkansas,
Arkansas Bioscience Institute, Grant Number P30 GM103450
from the National Institute of General Medical Sciences of the
National Institutes of Health (NIH), NSF Career Award under
Award Number CHE-1255539. We thank Jiang Wang and
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