Copper-Catalyzed Cyclization/aza-Claisen Rearrangement Cascade Initiated by Ketenimine Formation: An Efficient Stereocontrolled Synthesis of α-Allyl Cyclic Amidines

Article abstract of DOI:10.1002/anie.201405331

An efficient and convenient synthesis of α-allyl cyclic amidines has been achieved by applying a novel cascade reaction. Copper(I)-mediated insitu N-sulfonyl ketenimine formation from the reaction of a terminal alkyne with sulfonyl azide is followed by an intramolecular nucleophilic attack on the central carbon atom by an allylic tertiary amine, and then an aza-Claisen rearrangement takes place through a chair transition state to furnish the titled amidines with complete stereocontrol. After a pattern: A convenient copper-catalyzed method for cyclic amidine synthesis with high yield under mild reaction conditions has been established. By using this method, tertiary allyl enynes, with broad substitution patterns, can be converted stereoselectively into α-allyl cyclic amidines bearing multiple functionalities for potential elaboration. DIPEA=diisopropylethylamine.

Full text of DOI:10.1002/anie.201405331

Angewandte
Chemie
DOI: 10.1002/anie.201405331
Heterocycle Synthesis
Copper-Catalyzed Cyclization/aza-Claisen Rearrangement Cascade
Initiated by Ketenimine Formation: An Efficient Stereocontrolled
Synthesis of a-Allyl Cyclic Amidines**
Hua-Dong Xu,* Zhi-Hong Jia, Ke Xu, Mei Han, Sai-Nan Jiang, Jing Cao, Jia-Cheng Wang, and
Mei-Hua Shen*
Abstract: An efficient and convenient synthesis of a-allyl
cyclic amidines has been achieved by applying a novel cascade
reaction. Copper(I)-mediated in situ N-sulfonyl ketenimine
formation from the reaction of a terminal alkyne with sulfonyl
azide is followed by an intramolecular nucleophilic attack on
the central carbon atom by an allylic tertiary amine, and then
an aza-Claisen rearrangement takes place through a chair
transition state to furnish the titled amidines with complete
stereocontrol.
strong C3 nucleophilicity,[5] the reactivity of the N-sulfonyl
ketenimine B is mainly characterized by initial nucleophilic
attack on C2 of the ketenimines,[6] and the ketenimines C
bearing N-alkyl/aryl groups are frequently observed in
concerted processes.[7] Although great advances have been
made in ketenimine chemistry recently, we anticipated there
was new reactivity to explore.
The amidine moiety exhibits a unique structure which is
present in numerous bioactive natural products and medicinal
compounds.[8] This functional group also finds broad applica-
tions in catalysis,[9] metal ligation,[10] and chemical biology.[11]
Herein we report an unprecedented reaction model of
a ketenimine featuring an intramolecular ketenimine cap-
ture[12]/aza-Claisen cascade[13] to provide an efficient method
for preparing functionalized cyclic amidines.
Studies of reactive species comprise a large part of research
in organic chemistry and contribute continually to the
development of new chemistry because transformations of
such energetic entities are typically exothermic and have
a significant thermodynamic driving force.[1] Very often,
interception of these reactive species by other functionalities
has proved to be an efficient strategy for reaction discovery.[2]
By comparison with their oxygen congeners, ketenes,[3] the
ketenimine class of reactive intermediates (Figure 1; A, B,
The tertiary amino enyne 1a was reacted with tosyl azide
in the presence of a catalytic amount of copper(I) thiophene-
2-carboxylate (CuTc) in anhydrous toluene at room temper-
ature, and the substrate was consumed in 30 minutes (TLC)
and two compounds, the triazole 3a and amidine 2a, were
isolated in 40 and 44% yield, respectively (Figure 2).
Figure 1. Three types of ketenimines.
and C) has an additional N1 substitution site, and therefore
has demonstrated more diverse and tunable reactivity.[4] The
nature of the N substitution plays a pivotal role in ketenimine
reactivity. While the silyl ketenimine A is well known for its
[*] Dr. H. Xu, Z. Jia,[+] K. Xu,[+] M. Han, S. Jiang, J. Cao, J. Wang,
Dr. M. Shen
Figure 2. Proposed divergent pathways for the formation of triazole
and amidine. Ts=4-toluenesulfonyl.
School of Pharmaceutical Engineering and Life Science
Changzhou University, First Middle Gehu Road
Changzhou, Jiangsu Province, 213164 (China)
E-mail: huadongxu@gmail.com
According to the elegant protocol from Chang and co-
workers on N-tosyl ketenimine formation from the terminal
alkyne/sulfonyl azide combination,[14] we reasoned that these
interesting outcomes derived from two competing pathways,
as shown in Figure 2. The initial [3+2] adduct I is protonated
to give 3a (path b). In contrast, I can further decompose to
the sulfonyl ketenimine III, and then cyclize by virtue of
a tethered nitrogen nucleophile to acquire the cyclic zwitter-
ion IV. Finally, sequential aza-Claisen rearrangement gives
rise to 2a (path a). The conversion of I into the N-tosyl
ketenime II must be facilitated by the basicity of the tertiary
meihuashen@gmail.com
[+] These authors contributed equally to this work.
[**] This work was supported by the Natural Science Foundation of
China (21002032 and 21272077), Shanghai Pujiang Program
(11J1403100), Priority Academic Program Development of Jiangsu
High Education Institutions (PAPD), and the Natural Science
Foundation of Jiangsu Province (SBK201321632). We are grateful to
Prof. Yang Yang at the Instrument Analysis Center of CCZU for his
generous help with the NOSEY analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201405331.
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Table 2: The reaction of 1a or 4a with various sulfonyl azides under
optimal reaction conditions.
amine in the substrate since previous mechanistic studies have
proved the necessity of a tertiary amine for N-sulfonyl
ketenime formation.[15] The novelty of both the reaction
itself and the structure of 2a motivated us to carry out further
investigations on path a.
Efforts to improve the selectivity by changing the reaction
medium and the copper(I) source were not fruitful (entries 1–
4, Table 1). Reactions carried out in tetrahydrofuran (THF),
Table 1: Optimization of reaction conditions for the metal-catalyzed
reaction of 1a with TsN3.[a]
Entry
Cat.
Base
Solvent
Yield [%][b]
3a/2a
1
2
3
4
5
CuTc
CuTc
CuTc
CuI
none
none
none
none
DIPEA
(1 equiv)
DIPEA
(3 equiv)
DIPEA
(5 equiv)
Et3N
toluene
CH2Cl2
THF
THF
THF
84
1.0:1.1
1.0:1.1
1.0:1.2
1.0:1.5
1.0:3.0
85
Mbs=p-methoxybenzenesulfonyl, Mts=mesitylenesulfonyl, Nos=4-
nitrobenzenesulfonyl, PMB=para-methoxybenzyl, SES=2-[(trimethyl)-
ethyl]sulfonyl.
86[c]
87
CuI
65
6
7
CuI
CuI
THF
THF
82
88
1.0:12
0:1.0
temperature using CuI (5 mol%) as the catalyst and anhy-
drous THF as the solvent.
The impact of the sulfonyl azide on this reaction was
inspected under the optimal reaction conditions (Table 2).
Sulfonyl azides with different electronic and steric properties
reacted with the benzylamino enyne 1a or p-methoxybenzyl-
amino enyne 4a to form the corresponding six- or five-
membered cyclic amidines reliably in excellent yields.
Replacement of the benzyl group in 1a or the p-
methoxybenzyl moiety in 4a with other substituents resulted
in an array of substrates (1b–f and 4b–i, Table 3), which were
subjected to the optimal reaction conditions. The electronic
nature of the para substituent on the benzyl group has
a negligible effect, if any, on the reaction yield. Substrates
with either electron-donating or electron-withdrawing groups
gave more than 90% yields (2b–e; 10a–e). Other N-alkyl
groups such as the carboethoxymethyl and hexyl groups
provided almost equally high yields (2 f, 10 f–g), thus demon-
strating the scope of compatible N-alkyl substituents. Inter-
estingly, the benzyl amine 4i, bearing an ortho-hydroxy group,
unlike the prototype 1a, does not react at room temperature
without an external base, however, it proceeds smoothly at
608C to produce the non-aza-Claisen product 10i in 86%
yield. We assumed that intramolecular hydrogen bonding
masks the basic nitrogen center at low temperature and 10i is
formed by 1,4-elimination of o-quinone methide[16] (13) from
the cyclized zwitterion IV4i (Figure 3a). Removal of this
interaction by acylation of the phenolic group brought 4h
back into the desired reaction manifold.
8
9
CuI
CuI
CuI
CuTc
Cu(OTf)2
AgOTf
CuI
CuI
CuI
THF
THF
THF
THF
THF
THF
CHCl3
toluene
DMSO
MeCN
tBuOH
CH2Cl2
76
78
78
75
0:1.0
0:1.0
0:1.0
0:1.0
0:1.0
0:1.0
0:1.0
0:1.0
0:1.0
0:1.0
0:1.0
0:1.0
Py
10
11
12
13
14
15
16
17
18
19
2,6-lutidine
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
69[d]
38[e]
73
72
70
74
68
CuI
CuI
CuI
83
[a] Reaction conditions: 1a (1.0 equiv, 0.1m), TsN3 (1.1 equiv), DIPEA,
and metal catalyst (5 mol%) were stirred in solvent at RT for half an hour.
[b] Yield of isolated product. [c] Reaction performed at 608C. [d] Recov-
ered 25% starting material. [e] Complex reaction mixture. DMSO=di-
methyl sulfoxide, THF=tetrahydrofuran, Tf=trifluoromethanesulfonyl.
CH2Cl2, and toluene all gave 2a and 3a, largely in equal
amounts, and catalysis by CuI instead of CuTc slightly favored
path a (entry 4). The use of higher temperature did not afford
a significant change (entry 3). As expected, the introduction
of an external organic base shifts the reaction course to path a
substantially (entries 5–10), and the use of 5 equivalents of
base completely excluded the formation of 3a. While other
organic bases function well, diisopropylethyl amine (DIPEA)
proved to be the best in terms of the yield. Several other
catalysts were tested under these reaction conditions but were
found to be inferior to CuI. For example, 5 mol% Cu(OTf)2 is
not sufficient for full conversion of the starting material and
AgOTf delivered a complex reaction mixture (entries 11–13).
Although THF is the optimum solvent among those tested,
the reaction tolerates various types of solvent, even with
nucleophilic DMSO and tert-butyl alcohol offering 70 and
68% yield, respectively. The current optimal reaction con-
ditions involve reacting the enyne 1 with the sulfonyl azide
(1.1 equiv) in the presence of DIPEA (5.0 equiv) at room
Next, variations on the allyl segment were examined, thus
leading to the discovery that substitution on each of the three
positions is well tolerated with respect to yields (1g–m!2g–
m; 4j–l!10j–l, Table 3) as clean reactions and high yields
were obtained without exception (85–95%). Normally diffi-
cult quaternary carbon centers are constructed with ease by
this method (10j–k, 2g). Substrates of bis(allyl) amino enynes
such as 1l and 1m raise the issue of chemoselectivity. The fact
that almost equal amounts of the cyclic amidines 2l and 2l’
were obtained indicates that conjugation to the ester carbonyl
2
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Table 3: Reactions of various tertiary amino enyne with TsN3.[a,b]
[a] All reactions were carried out on 25–100 mg scale under optimal reaction conditions unless otherwise mentioned. [b] Yield of isolated product.
[c] Heating to 608C without DIPEA. [d] Inseparable mixture of 4o/4p. [e] Combined yield. [f] The d.r. value was determined by NMR spectroscopy.
[g] Reaction carried out at 08C in the presence of 1.5 equivalents of DIPEA. PMP=para-methoxyphenyl.
hands, 2m was isolated as the sole product. Although the
reason for these intriguing phenomena is not clear at this
stage, we rationalized that the aza-Claisen rearrangement of
intermediate IV (Figure 3c, top) proceeds through the
transition-state TS-IV1m, characterized by a benzylic carbon
atom bearing significant positive charge. This transition state,
therefore, is stabilized by the conjugation to the aromatic ring.
Single-crystal X-ray structure analysis established the anti
configuration of 2m, and the same relative stereochemistry
was assigned to other congeners by analogy. The exclusive
observation of the single epimers 2j–m and 10l demonstrates
Figure 3. a) Explanation of the formation of 10i. b) X-ray crystal
the outstanding diastereoselectivity of this reaction.
structure of 2m.[18] c) Proposed transition states TS-IV1m and TS-IV.
Further efforts have been devoted to exploring the
substrate scope with regard to diversity of the alkyne.
in 1l does not interfere with the reaction profile, whereas the
resonance effect of a phenyl ring on the double bond has
pronounced influence on the reaction outcome as, in our
Substitution with an alkyl or a carboxy group on each
methylene group provides excellent substrates for this
reaction as five- or six-membered cyclic amidines were
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obtained in exceptionally high yields (1n–o!2n–o, 4m–o!
10m–o, Table 3). The two-dimensional 1H-1H NOESYexperi-
ments have been performed on 10n and 2o to reveal their
relative configuration to be trans, thus illustrating the high
stereoselectivity of this reaction. It is worth noting that under
standard reaction conditions, an inseparable mixture of
diastereomers 2o (d.r.: 4:1) was obtained from the substrate
1o. However, by reducing the amount of external base to
1.5 equivalents and the reaction temperature to 08C, the same
reaction provides 100% diasteroselectivity. The compound
1p, with one-carbon elongation of the alkyne linkage, gave
rise to the linear amidine 2p, a product of intermolecular
attack on the nascent ketenimine III1p by DIPEA instead of
attack by the intramolecular competitor. However, 1q
afforded the seven-membered cyclic amidine 2q, thus
smoothly reflecting the prominent template effect of a ring.
In contrast, the reaction of the propargyl amine 11 with tosyl
azide under identical reaction conditions delivered a 90%
yield of 12, the product of a cyclization/b-elimination cascade,
a process which has been observed very recently by the group
of Talukdar.[17]
Overall, we consider that the aza-Claisen reaction pro-
ceeds through the chairlike transition-state TS-IV (Figure 3c,
bottom), which explains both the anti selectivity attained
ꢀ
during the C3 C4 bond formation and the trans-stereoselec-
tivity controlled by the R group on the nascent ring.
Finally, we draw attention to the divergent results
presented by the close homologues 4p,q and 1r. The p-
methoxyphenyl amino enyne 4p underwent the cyclization/
aza-Claisen rearrangement smoothly to furnish the cyclic
amidine 10p in 94% yield. In contrast, its comparatively less-
electron-rich tolyl counterpart 4q gave the noncylization
products 10q/10q’ in a combined yield of 93%. The obser-
vation that such a subtle change in nucleophilicity can confer
so remarkable a divergence in the reaction courses is amazing.
Furthermore, with the p-methoxyphenyl amine 1r as a sub-
strate, only the intermolecular product 2r was obtained with
55% yield, thus testifying to the sensitivity of the reaction to
the tether length.
In summary, a new ketenimine reaction mode has been
established and thus provides a convenient copper-catalyzed
protocol for cyclic amidine synthesis with high yield under
mild reaction conditions. By using this method, tertiary allyl
enynes, with broad substitution patterns, can be converted
stereoselectively into a-allyl cyclic amidines bearing multiple
functionalities for potential elaboration.
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Received: May 16, 2014
Published online: && &&, &&&&
Keywords: allylic compounds · copper · cyclization ·
.
heterocycles · rearrangements
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4
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[15] E. J. Yoo, M. Ahlquist, I. Bae, K. B. Sharpless, V. V. Fokin, S.
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[18] CCDC 1000762 (2m) contains the supplementary crystallo-
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Communications
Heterocycle Synthesis
H. Xu,* Z. Jia, K. Xu, M. Han, S. Jiang,
J. Cao, J. Wang, M. Shen*
&&&& — &&&&
Copper-Catalyzed Cyclization/aza-Claisen
Rearrangement Cascade Initiated by
Ketenimine Formation: An Efficient
Stereocontrolled Synthesis of a-Allyl
Cyclic Amidines
After a pattern: A convenient copper-
catalyzed protocol for cyclic amidine
synthesis with high yield under mild
reaction conditions has been established.
By using this method, tertiary allyl
enynes, with broad substitution patterns,
can be converted stereoselectively into a-
allyl cyclic amidines bearing multiple
functionalities for potential elaboration.
DIPEA=diisopropylethylamine.
6
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
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