Copper-Catalyzed Cascade Aminoalkynylation-Oxidation of Propargylic Alcohols: Stereospecific Synthesis of (Z)-2-Amino Conjugated Enynals/Enynones

Article abstract of DOI:10.1021/acs.orglett.8b02272

Copper-catalyzed cascade aminoalkynylation-oxidation of propargylic alcohols has been realized, sterospecifically providing an array of (Z)-2-amino conjugated enynals/enynones in good yields under mild conditions. This transformation involves a rare 1,3-a

Full text of DOI:10.1021/acs.orglett.8b02272

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Catalyzed Cascade Aminoalkynylation−Oxidation of
Propargylic Alcohols: Stereospecific Synthesis of (Z)‑2-Amino
Conjugated Enynals/Enynones
Jiaqiong Sun, Guangfan Zheng, Yongmei Fu, Lihong Wang, Yan Li,* and Qian Zhang
Key Laboratory of Functional Organic Molecule Design & Synthesis of Jilin Province, Department of Chemistry, Northeast Normal
University, Changchun, 130024, China
S
* Supporting Information
ABSTRACT: Copper-catalyzed cascade aminoalkynylation−oxidation of propargylic alcohols has been realized, sterospecifi-
cally providing an array of (Z)-2-amino conjugated enynals/enynones in good yields under mild conditions. This
transformation involves a rare 1,3-alkynyl migration of propargylic alcohols and simultaneously forms C−C, C−N, and CO
bonds. Furthermore, (Z)-2-amino conjugated enynals were applied to efficiently synthesize 3,5-disubstituted-1H-pyrrole-2-
carbaldehyde and conjugated enynol derivatives.
Initially, 1,5-diphenylpenta-1,4-diyn-3-ol (1a) was chosen as
the model substrate. Treatment of 1a and N-fluorobenzene-
sulfonimide (NFSI, 2a 1.2 equiv) with CuCl (10 mol %) and
pyridine in CHCl3 at 50 °C led to formation of the desired
aminoalkynylation/oxidation product (Z)-2-amino conjugated
enynal 3a in 19% isolated yield as the sole stereoisomer (Table
1, entry 1). Upon increasing the amount of NFSI to 2.0 equiv,
the yield of 3a increased to 34% (Table 1, entry 2). Evaluation
of the solvent effect was subsequently carried out. Switching to
DCE and CH3CN solvent only diminished the efficiency
(Table 1, entries 3−4), while THF, 1,4-dioxane, and toluene
were unsuitable for this transformation (Table 1, entries 5−7).
Among the various copper catalysts (CuI, CuCN, CuCl2,
CuBr2, Cu(OAc)2, and Cu(OTf)2) examined, CuCN gave the
best result (Table 1, entries 8−13). Both increasing and
decreasing the temperature failed to improve the yield (Table
1, entries 14 and 15). With the screening of other additives
such as 4-methylpyridine, 3-bromopyridine, 4-acetylpyridine,
3-nitropyridine, and 2-acetylpyridine, a satisfactory yield of
69% was achieved when 4-acetylpyridine was employed (Table
1, entries 16−20).8a Finally, the yield of 3a was increased to
76% when 4 Å molecular sieves (0.2 g) were introduced
(Table 1, entry 21).8b It should be noted that this novel
reaction involved a rare 1,3-alkynyl migration of propargylic
alcohols9 and simultaneously formed C−C, C−N, and CO
bonds.
onjugated enynals/enynones are important structural
Cunits that are widely encountered in synthetic chemistry,
medicinal chemistry, and materials science.1 Consequently,
efficient synthesis of these compounds has been increasingly
explored.2−5 The condensation reaction of ynals with ketones
with α-H2 (Scheme 1ia) and the reaction of ynals with Wittig
reagents3 (Scheme 1ib) could efficiently provide access to E-
conjugated enynals/enynones. Sonogashira coupling reaction
of terminal alkynes with β-substituted α,β-unsaturated ketone
derivatives could form the conjugated enynones with retention
of the unsaturated ketone configuration4 (Scheme 1ic), but
easily coordinating groups were usually incompatible in the
presence of Pd-catalyst. Despite these achievements, it is
necessary to develop novel methods that allow rapid access to
diversely functionalized conjugated enynals/enynones starting
from readily available starting materials.
Recently, our group6 realized aminoarylation and amino-
vinylation of alkynes via 1,4-aryl or 1,3-vinyl migration
triggered by nitrogen-centered radical addition to alkynes.
Lately, Zhu7a and Studer7b described a perfluoroalkylative
alkynylation of alkenes via 1,4- or 1,5-alkynyl migration
initiated by perfluoroalkyl radical addition to alkenes. As part
of our continued interest in functional group migration, we
considered the possibility of extending this strategy to
functionalization of gem-diyne via 1,3-alkynyl migration, thus
realizing the alkynylation of unactivated alkynes. Herein, we
report a copper-catalyzed cascade radical amination−alkynyl
migration−oxidation of 1,4-diyn-3-ols with high stereoselec-
tivity under mild conditions, leading to facile synthesis of (Z)-
2-amino conjugated enynals/enynones (Scheme 1ii), which are
important building blocks for the synthesis of other complex
organic structures.
With the optimized conditions in hand, we next investigated
the scope and the limitation of this aminoalkynylation−
oxidation reaction (Scheme 2). First, variation of 1,4-diyn-3-ols
Received: July 20, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02272
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Synthetic Methods of Conjugated Enynals/
Enynones
Table 1. Copper-Catalyzed Aminoalkynylation of 1a and
NFSI
a b
,
b
entry
catalyst
CuCl
CuCl
CuCl
CuCl
additive
pyridine
pyridine
pyridine
pyridine
solvent
CHCl3
CHCl3
DCE
CH3CN
1,4-dioxane
THF
3a (%)
c
1
19
34
30
25
0
2
3
4
5
CuCl
CuCl
pyridine
pyridine
6
0
7
8
9
10
11
12
13
14
15
16
17
18
19
20
CuCl
CuI
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
toluene
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
trace
12
42
30
28
20
24
36
34
33
41
69
31
19
76
CuCN
CuCl2
CuBr2
Cu(OAc)2
Cu(OTf)2
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
d
e
pyridine
4-methylpyridine
3-bromopyridine
4-acetylpyridine
3-nitropyridine
2-acetylpyridine
4-acetylpyridine
f
21
a
Reaction conditions: 1a (0.2 mmol), NFSI (2a, 2.0 equiv), catalyst
(10 mol %), additive (1.5 equiv), solvent (2 mL), 50 °C for 8 h under
1 was performed, with the data being summarized in Scheme 2.
Gratifyingly, a range of 1,5-diarylpenta-1,4-diyn-3-ols 1a−1o
bearing electron-withdrawing and -donating substituents, such
as alkyl, alkoxyl, halide, and trifluoromethyl, led to desired (Z)-
2-amino conjugated enynals 3a−3o in moderate to high yields.
The configuration of 3a was further confirmed by X-ray
analysis (CCDC 1562685). Halogen atoms were tolerant (3g,
3h, 3j, 3k, 3n, 3o), which offers an opportunity for further
transformation. Substrate 1p with different substituents on the
benzene ring of 1,4-diyn-3-ol reacted with NFSI smoothly and
formed the desired product 3p and 3p′ in a total yield of 51%
with a 5:1 ratio. Furthermore, unsymmetrical 1,4-diyn-3-ols
with an aryl substituted alkynyl and alkyl substituted alkynyl
group could react smoothly affording product 3q (51%) and 3r
(43%) with excellent selectivity. Dialkynyl substituted
substrate 2,2,8,8-tetramethylnona-3,6-diyn-5-ol (1s) were also
found to be compatible and afforded product 3s in 59% yield.
In addition, tertiary propargyl alcohols 1t−1y were also tested.
To our delight, expected (Z)-2-amino conjugated enynones
3t−3y were obtained in moderate yields (61−76%). Notably,
during the reactions of tertiary alcohols, 1,3-alkynyl migration
was exclusive. Moreover, the novel aminoalkynylation of
alkynes showed good stereoselectivity, only giving a cis-isomer.
The generality of this aminoalkynylation−oxidation of
propargylic alchohols was then examined by screening
amination sources. Different NFSI derivatives 2 were
investigated under the standard reaction conditions (Scheme
3). NFSI derivatives bearing both electron-donating and
-withdrawing substituents at the para position (2b−2g) all
reacted smoothly with 1,5-diphenylpenta-1,4-diyn-3-ol (1a),
and the corresponding Z-2-amino conjugated enynals 4b−4g
were isolated in 77%−85% yields.
b
a nitrogen atmosphere. The yield was determined after isolation of
c
d
products by column chromatography. 1.2 equiv NFSI was used. The
e
reaction was conducted at 40 °C. The reaction was conducted at 70
°C. 4 Å Molecular sieves (0.2 g) were used.
f
The synthetic utility of the reaction was investigated by
performing gram-scale preparation of the conjugated enynals.
Under identified conditions, the reaction of 1a (3 mmol) and
2a provided 1.10 g of 3a (Scheme 4). To further demonstrate
synthetic applications of this method, we next investigated the
follow-up chemistry using 3a as the starting material (Scheme
5). Desulfonylation was conducted by treatment of 3a with n-
Bu4NF in THF 70 °C. Pleasingly, desulfonylation and
cyclization product 3,5-diphenyl-1H-pyrrole-2-carbaldehyde 5
was smoothly isolated in 42% yield.10 Chemoselective
reduction of the carbonyl group in 3a was achieved using
NaBH4 at room temperature to provide conjugated enynol 6 in
75% yield.
To gain insight into the reaction mechanism, radical
inhibition experiments were performed (see Supporting
Information). When 2,6-di-tert-butyl-4-methylphenol (BHT,
1.5 equiv) or 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO,
1.5 equiv) was added under the standard conditions, the
reaction of 1a and NFSI was completely suppressed and no
desired 3a was observed. These results suggested that the
transformation might involve radical intermediates. On the
basis of the experimental results and our previous studies,6,11
a
possible mechanism is proposed in Scheme 6. Initially,
nitrogen-centered radical A′ was generated through the
interaction of CuCN and NFSI. Oxygen coordination of the
propargylic alcohol 1a with HF removal gives intermediate B.
B
DOI: 10.1021/acs.orglett.8b02272
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 2. Scope of Aminoalkynylation of Alkynes
Scheme 3. Reaction of NFSI Derivatives
a
Reaction conditions: 1a (0.2 mmol), 2 (2.0 equiv), CuCN (10 mol
%), 4-acetylpyridine (1.5 equiv), 0.2 g of 4 Å molecular sieves, CHCl3
(2 mL), 50 °C, N2, 8 h. The yield was determined after isolation of
products by column chromatography.
Scheme 4. Gram-Scale Preparation of 3a
Scheme 5. Follow-up Chemistry
Scheme 6. Plausible Mechanism
comitant regeneration of the Cu(I) species, thus completing
the catalytic cycle.
a
Reaction conditions: 1 (0.2 mmol), 2a (NFSI, 2.0 equiv), CuCN
(10 mol %), 4-acetylpyridine (1.5 equiv), 0.2 g of 4 Å molecular
sieves, CHCl3 (2 mL), 50 °C, N2, 8 h. The yield was determined after
isolation of products by column chromatography.
In conclusion, an unprecedented aminoalkynylation−
oxidation of propargylic alcohols has been realized with copper
as catalyst, stererospecifically providing access to various Z-2-
amino enynals/enynones. This novel transformation involves a
rare 1,3-alkynyl migration of propargylic alcohols and
simultaneously forms C−C, C−N, and CO bonds. The
reactions proceed under mild conditions and show good
functional group compatibility. The strategy for alkyne
aminoalkynylation via 1,3-alkynyl migration might provide a
new avenue toward alkynylative functionalization of unsatu-
rated substrates. Furthermore, (Z)-2-amino conjugated enynals
were applied to efficiently synthesize 3,5-disubstituted-1H-
pyrrole-2-carbaldehyde and conjugated enynol derivatives.
Next, highly selective intermolecular addition of the nitrogen-
centered radical to the CC bond takes place to generate a
linear vinyl radical C. For the unsymmetrical 1,4-diyn-3-ols
1p−1r, the radical addition preferentially occurs at the
(electron-rich) aryl alkynyl unit. Then, C rapidly undergoes
1,3-alkynyl migration to form a radical D, which is further
transformed into a more stable radical F through resonance
structure E.12 Finally, homolysis of Cu−O bond of F affords
stable Z-2-amino conjuated enynal 3a together with con-
C
DOI: 10.1021/acs.orglett.8b02272
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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(8) (a) Inorganic bases such as K2CO3 and NaOAc did not work,
and 1a was recovered completely. (b) 4 Å Molecular sieves might
remove a very small amount of water in the reaction to improve the
yield of 3a.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02272.
■
S
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Experimental procedures, spectral data for new com-
pounds, and crystallographic data for 3a (PDF)
Accession Codes
CCDC 1562685 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: liy078@nenu.edu.cn.
ORCID
Yan Li: 0000-0003-2083-6991
Notes
(12) For the substrate 1w, the ring-opening reaction of cyclopropyl
group was not observed, which might be attributed to the better
stability of radical intermediate D generated from 1w than that of the
resultant radical via ring openging of D. For some radical clocks, ring-
opening reactions are reversible, and the cyclic forms are
thermodynamically favored; see:Newcomb, M. In Radicals in Organic
Synthesis, Vol. 2; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH, Weinheim,
2001; pp 317−336.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the financial support from the Jilin Province
Natural Science Foundation (20160519003JH) and the
Changbai Mountain Scholarship Program.
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DOI: 10.1021/acs.orglett.8b02272
Org. Lett. XXXX, XXX, XXX−XXX