Copper(i)/Lewis acid triggered ring-opening coupling reaction of cyclopropenes with nitriles

Article abstract of DOI:10.1039/c5ra01541c

A ring-opening coupling reaction of D-A cyclopropenes and nitriles is described for the facile synthesis of γ-amino ketones. The co-catalytic system combining copper(i) and boron trifluoride would be inspiring because it disfavors the [3 + 2] cycloadditio

Full text of DOI:10.1039/c5ra01541c

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DOI: 10.1039/C5RA01541C
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Copper(I)/Lewis Acid Triggered Ring-Opening
Coupling Reaction of Cyclopropenes with Nitriles
Cite this: DOI: 10.1039/x0xx00000x
Huawen Huang*, Xiaochen Ji, Fuhong Xiao and Guo-Jun Deng*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
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A ring-opening coupling reaction of D–A cyclopropenes and
nitriles is described for the facile synthesis of γ-amino ketones.
The copper(I)/Lewis acid co-catalytic system would be
inspiring since it disfavors [3+2] cycloaddition to turn the
selectivity over Ritter process.
In last decade, two popular ways of crucial transformations of
donor–acceptor (D–A) cyclopropanes en route to more sophisticated
molecules were cycloaddition with unsaturated compounds such as
alkynes, alkenes, aldehydes, and imines, and ring-opening coupling
process with other active partners (Scheme 1).[1] Lewis acid-
catalyzed [3+2][2] and [3+3][3] cycloaddition of cyclopropanes
Scheme 2 Cycloadditon and ring-opening coupling of cyclopropyl
ketone with nitrile.
bearing
a malonyl diester acceptor group with unsaturated
compounds has been intensively studied for use in the preparation of
useful five- and six-membered-ring compounds, although some
cycloaddition reactions of other type of cyclopropanes, such as
cyclopropyl ketones,[4] amides,[5] amines,[6] and vinylcyclopropanes[7]
etc., were known. However, of them ring-opening reactions of
cyclopropyl ketones generally proceeded under strong acidic
conditions probably because of the relative low-energy HOMO of
this species.
Cyclopropyl ketone (1a) and benzonitrile (2a) were chosen as the
model substrates (Scheme 2). On the assumption that intermediate A
is generated by intermolecular nucleophilic attack of 2a to the Lewis
acid-activated 1a, the subsequent intramolecular 1–5 nucleophilic
cyclization gives [3+2] cycloaddition product 3aa,[10] otherwise the
intermediate A reacts with water to give the ring-opened Ritter
product 4aa.[10c] Further investigation, however, indicates that water
is not the crucial fact for the selectivity and interestingly the reaction
is enhanced with copper(I) catalyst exclusively giving the ring-
opened Ritter reaction product. Mechanistically, we envisioned that
the coordination interaction that may arise between the transition
metal and intermediate A has disfavored intramolecular 1–5
nucleophilic cyclization of A to turn the selectivity over Ritter
process.
Scheme 1 Cycloaddition and ring-opening coupling reaction of D–
A cyclopropanes.
To optimize the reaction conditions, several Lewis acids, such as
AlClMe2, Sn(OTf)2, and SnCl4, were firstly subjected to this ring-
opening reaction, and it was found that neither 3aa nor 4aa was
detected when the reaction was performed at room temperature
(Table 1, entries 1–2). Higher reaction temperature gave low yield of
3aa, with over 50% of 1a recovered (Table 1, entries 3–4),
suggesting that this reaction requires increased Lewis acidity to
Ring-opening coupling reaction of cyclopropane plays important
role in synthetic chemistry to provide chain products which are
hardly obtained by traditional route.[8] Herein, we report Lewis acid
and copper(I)-promoted ring-opening coupling reaction of
cyclopropyl ketones with nitriles for the facile Ritter synthesis of γ-
amino ketones,which usually used to be linker groups in preparation
of active pharmaceuticals and agrochemicals.[9]
.
active the cyclopropane. BF3 Et2O-mediated reaction gave
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significant yield enhancement for cycloaddition product (Table 1, Scheme 3 The scope of the substrates for the synthesis of γ-amino
entry 5). Medium testing showed that nitromethane was greater than ketones. Reaction conditions: the mixture of cyclopropyl ketone (0.2
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others although a little yield of chain product was obtained, and this mmol, 1.0 equiv) and nitrile (aryl-carbonitrile: 3 equiv; alkyl-
.
reaction was found to be optimal at 85 oC (Table 1, entries 6-8).
Table 1 Optimization of reaction conditions.a
carbonitrile: 1.5 equiv), CuBr (5 mol%), PBu3 (10 mol%), BF3 Et2O
(1.0 equiv), H2O (1.0 equiv), and MeNO2 (1.5 mL) was stirred under
85 oC for 18 h, isolated yields were given.
DOI: 10.1039/C5RA01541C
Entry Lewis acid Cat.
H2O
Solvent
Temp
(oC)
Yield (%)b
Having identified selective reaction conditions set, the novel
copper-catalyzed Ritter-type process triggered us to screen the
generality and scale of the substrates for the ring-opening coupling
reaction. Various aryl-substituted carbonitriles reacted smoothly to
access the respective product (4aa–4ai). Generally, electron-
donating groups on the aryl ring enhanced the reaction (4ab and
4ad), consistent with the nucleophilic attack in the first step of Lewis
acid-activated ring-opening process. Halogens including F, Cl, Br,
and I were all tolerated, furnishing the corresponding γ-amino
ketones (4af–4ai) in 70-85% yield. In case of alkyl nitriles,
pentanenitrile (2j), dodecanenitrile (2k), cyclopropanecarbonitrile
(2l), adamantane-1-carbonitrile (2m), 4-phenyl-butyronitrile (2n),
and phenyl-acetonitrile (2o) gave the final products in good to
excellent yield. Moreover, alkyl nitriles with terminal vinyl, ether,
halogen, or terminal alkynyl were successfully converted to final γ-
amino ketone products in the ring-opening coupling reactions (4ap–
4at). This result was particularly satisfying given that these
functional groups are considered primary in synthetic chemistry. An
interesting case was found with hexanedinitrile which only delivered
the product with one nitrile group transformed (4au).
(equiv)
3aa
4aa
n.d.
n.d.
n.d.
n.d.
n.d.
<5
1
AlClMe2
Sn(OTf)2
Sn(OTf)2
SnCl4
-
-
THF
rt
n.d.
n.d.
22
19
68
80
82
82
80
79
15
8
2
-
-
CH2Cl2
(CH2)2Cl2
(CH2)2Cl2
(CH2)2Cl2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
rt
3
-
-
80
80
80
80
85
90
85
85
85
85
85
85
85
85
85
4
-
-
.
5
BF3 Et2O
-
-
.
6
BF3 Et2O
-
-
.
7
BF3 Et2O
-
-
<5
.
8
BF3 Et2O
-
-
<5
.
9
BF3 Et2O
-
1
4
1
1
1
1
1
1
1
<5
.
10
11
12
13
14
15c
16d
17e
BF3 Et2O
-
8
.
BF3 Et2O
CuI
CuBr
CuCl
CuCl2
CuBr
CuBr
CuBr
42
.
BF3 Et2O
56
.
BF3 Et2O
6
50
.
BF3 Et2O
54
9
n.d.
61
.
BF3 Et2O
.
BF3 Et2O
8
85
.
BF3 Et2O
5
92
a
Reaction conditions: 1a (0.2 mmol), 2a (3.0 equiv), Lewis acid (1 equiv),
1a
standard
catalyst (5 mol%), water in solvent (1.5 mL) for 18 h. b GC yield based on 1a was
O
H
CN
c
d
N
conditions
given. n.d. means no product was detected. With addition of PPh3 (10 mol%).
(1)
Ph
With addition of P(p-Me-C6H4)3 (10 mol%). e With addition of PBu3 (10 mol%).
O
92%
O
O
2v
4av
.
After establishing the capability of BF3 Et2O for ring-opening of
cyclopropyl ketones, we presumed that addition of water was
competent for the Ritter reaction product, but that was not the case
even with four equivalents of water (Table 1, entries 9 and 10). Our
first success in reversing the selectivity was found with copper(I)
catalysts that favored the ring-opened Ritter reaction product (Table
1, entries 11–13). By way of contrast copper(II) did not work for 4aa
(Table 1, entry 14), indeed indicating that the reaction forming
amide was not conventional Ritter process. Finally, we tried
different ligands and found electron-rich tributylphosphine was
optimal for the reaction affording 4aa in 92% yield (Table 1, entries
15–17), which may be complained by the increased stability of
copper complex intermediate.
Ph
1a
O
O
O
O
CN standard conditions
N
(2)
66%
O
4aw
2w
1a
standard
Ph
Ph
[Ref. 12]
80%
S
conditions
S
N
N
(3)
72%
CN
O
Ph
O
2x
4ax
5
A surprising result was observed when methoxyl-substituted
phenyl-acetonitriles 2v and 2w were subjected to the reaction
conditions. While the reaction of 2v and 1a under the standard
conditions even for 24 hours smoothly gave the γ-amino ketone 4av
in 92% yield [Eq. (1)], the only product observed was the indolizine
derivative 4aw (66% yield) when 2w was transformed [Eq. (2)],
which was postulated to be generated via Pictet–Spengler type
reaction[11] from the corresponding γ-amino ketone prepared in situ.
Interestingly 4aw contains the key structure of the natural product
Crispine A. According this reaction patern, 3-benzo[b]thiophen
acetonitrile 2x readily generated expected polycyclic product 4ax in
72% yield, which could smoothly undergo desulfurization[12] to give
corresponding hexahydro-indolizin-5-one (5) in 80% yield [Eq. (3)].
Conclusions
In summary, we have developed a novel copper(I)-catalyzed
Ritter reaction for synthesis of γ-amino ketones by Lewis acid-
assisted ring-opening reaction of cyclopropyl ketones. This
method is efficient, highly applicable, and allows the facile
formation of functionalized ketones. Thus it shows potential
capabilities to construct complex molecules in synthetic and
pharmaceutical chemistry. More importantly copper-mediated
2 | J. Name., 2012, 00, 1‐3
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selectivity over Ritter-type process will be inspired to other
case with the fact that almost all conventional Ritter reactions
proceed under acidic condition rather than with transition metal.
Efforts to understand the actual role of copper in this
transformation are currently underway.
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Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (no. 21372187), and the Xiantan
University Scientific Research Foundation for Introducing
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Notes and references
a Key Laboratory of Environmentally Friendly Chemistry and Application
of Ministry of Education, College of Chemistry, Xiangtan University,
Xiangtan 411105, China.
E-mail: hwhuang@xtu.edu.cn; gjdeng@xtu.edu.cn.
Electronic Supplementary Information (ESI) available: experimental
details and spectral data for all synthesized compounds. See
DOI: 10.1039/c000000x/
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