Catalytic one-pot synthesis of trisubstituted allenes from terminal alkynes and ketones

Article abstract of DOI:10.1021/acs.orglett.7b02443

An efficient one-pot synthesis of trisubstituted allenes from readily available terminal alkynes and ketones is realized. A wide range of trisubstituted allenes may be synthesized efficiently via this method. Preliminary mechanistic studies revealed that CuI and Ti(OEt)₄ are in charge of the formation of propargylic amine, while ZnBr₂ is responsible for the transformation from propargylic amine to allene.

Full text of DOI:10.1021/acs.orglett.7b02443

Letter
pubs.acs.org/OrgLett
Catalytic One-Pot Synthesis of Trisubstituted Allenes from Terminal
Alkynes and Ketones
Qi Liu,†,‡ Xinjun Tang,† Yujuan Cai,†,‡ and Shengming Ma*,†,§
†State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Lu, Shanghai 200032, P. R. China
‡University of Chinese Academy of Sciences, Beijing 100049, P. R. China
§Department of Chemistry, Fudan University, 220 Handan Lu, Shanghai 200433, P. R. China
S
* Supporting Information
ABSTRACT: An efficient one-pot synthesis of trisubstituted
allenes from readily available terminal alkynes and ketones is
realized. A wide range of trisubstituted allenes may be
synthesized efficiently via this method. Preliminary mecha-
nistic studies revealed that CuI and Ti(OEt)4 are in charge of the formation of propargylic amine, while ZnBr2 is responsible for
the transformation from propargylic amine to allene.
study in this group revealed that the substrate scope of ketones
is quite narrow: only cyclic ketones and methyl alkyl ketones
work well. Moreover, CdI2 is not environmentally friendly.
Herein, we report an efficient and practical one-pot synthesis of
trisubstituted allenes from the ATA reaction with ketones
under the catalysis of CuI with the help of ZnBr2 and Ti(OEt)4.
We initiated our study with the reaction of TBS-protected
propargyl alcohol 1a (1 mmol), propiophenone 2a (1.4 equiv),
pyrrolidine (1.1 equiv), ZnBr2 (0.8 equiv), and Ti(OEt)4 (2
equiv) in toluene. After screening different copper catalysts, we
discovered that when 10 mol % of CuI was used, the desired
allene product 3aa was formed in 56% yield (entry 4, Table 1).
Increasing the loading of ketone 2a improved the yield of 3aa
to 60% (entry 5, Table 1). When the reaction time was
prolonged from 12 to 18 h, the yield of propargylic amine 4aa
llenes are not only important structural motifs in natural
1
Aproducts, drugs, and molecular materials but also useful
intermediates in organic synthesis.2 Differences in steric and
electronic effects between the two cumulated double bonds are
helpful for solving selectivity problems in organic trans-
formation. Therefore, great efforts have been directed toward
the synthesis of this type of compounds,3−7 such as transition-
metal-catalyzed coupling reaction of propargylic derivatives,4
[3,3]-sigmatropic rearrangement,3e,5 coupling of terminal
alkynes with diazo compounds,6 and conjugate addition to
enynes.7 However, convenient and straightforward methods for
synthesizing trisubstituted allenes from readily available starting
materials are very rare. In 2013, our group reported that the
CdI2-mediated allenylation of terminal alkynes (ATA) reaction
realized the one-pot synthesis of trisubstituted allenes from
terminal alkynes and ketones (Scheme 1).8 However, further
a
Table 1. Optimization of the Reaction Conditions
Scheme 1. Allenylation of Terminal Alkynes Using Ketones
b
b
entry
x/y (equiv)
[Cu]
yield of 3aa (%)
yield of 4aa (%)
c
1
1.4/1.1
1.4/1.1
1.4/1.1
1.4/1.1
1.6/1.1
1.6/1.1
0
8
7
2
3
4
5
CuBr2
CuCl
CuI
45
45
56
2
14
14
7
d
CuI
60 (55 )
e
6
CuI
42
a
The reaction was carried out on a 1 mmol scale in 5 mL of toluene.
b
1
Determined by H NMR analysis with mesitylene or CH2Br2 as the
c
d
e
internal standard. The reaction time was 10 h. Isolated yield. The
reaction time was 18 h.
Received: August 8, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02443
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
dropped from 14% to 7%, whereas the yield of 3aa also
dropped from 60% to 42% (entry 6, Table 1).9 Thus, 1a (1
mmol), 2a (1.6 equiv), pyrrolidine (1.1 equiv), CuI (10 mol
%), ZnBr2 (0.8 equiv), and Ti(OEt)4 (2 equiv) in toluene at
120 °C for 12 h (entry 5, Table 1) were defined as the
optimized reaction conditions for further study.
Scheme 2. ATA Reaction with Ketone 2p and 2q
With the optimized conditions in hand, we began to
investigate the scope of the method. At first, different kinds
of ketones were tested. Cyclic ketones from 5-membered ring
2b to 12-membered ring 2f all could afford trisubstituted
allenes 3ab−af in 45−77% yields (entries 1−6, Table 2). The
reaction could also be extended to acyclic aliphatic ketones,
such as nonmethyl hexan-3-one 2h and methyl 2-phenylethyl
ketone 2i (entries 7 and 8, Table 2). Even the sterically
hindered α-substituted ketones 2g and 2j yielded the
corresponding products in 69% (dr = 2.5:1) and 60% yield,
respectively (entries 6 and 9, Table 2). As for the aromatic
ketones, long-chain alkyl aromatic ketone 2k was also suitable
for this reaction, with a yield of 44% (entry 10, Table 2).
Propiophenone analogues with m-Br, p-Cl, p-F, and m-MeO
substituents all afforded 48−51% yields of the corresponding
products (entries 11−14, Table 2).
3). The terminal alkyl-substituted alkyne, 1-octyne 1g, could
also react smoothly, forming products 3gs and 3gc (entries 8
and 9, Table 3).
a
Table 3. Scope of Terminal Alkynes and Ketones
a
Table 2. Scope of Ketones
isolated yield of 3
entry
R1
R2, R3
(%)
b
c
1
CH(Ph)OTBS (1b) Me, Me (2r)
CH(Me)OTBS (1c) −(CH2)5− (2c)
CH(Ph)OTBS (1b) −(CH2)5− (2c)
CH2CH2OTBS (1d) −(CH2)5− (2c)
55 (3br)
84 (3cc)
2
3
4
5
6
7
8
9
entry
R2, R3
isolated yield of 3 (%)
85 (3bc)
56 (3dc)
51 (3ec)
49 (3ea)
43 (3fc)
1
−(CH2)4− (2b)
−(CH2)5− (2c)
−(CH2)6− (2d)
−(CH2)7− (2e)
−(CH2)11− (2f)
−CH(CH3)(CH2)4− (2g)
n-Pr, Et (2h)
54 (3ab)
77 (3ac)
67 (3ad)
45 (3ae)
60 (3af)
CH2NPhth (1e)
CH2NPhth (1e)
p-MeOC6H4 (1f)
n-C6H13 (1g)
−(CH2)5− (2c)
Ph, Et (2a)
2
3
−(CH2)5− (2c)
Me, CH(Me)OBn (2s)
−(CH2)5− (2c)
4
d
46 (3gs)
40 (3gc)
5
b
n-C6H13 (1g)
6
69 (3ag)
a
The reaction was carried out on a 1 mmol scale in 5 mL of toluene.
7
65 (3ah)
66 (3ai)
60 (3aj)
44 (3ak)
48 (3al)
50 (3am)
48 (3an)
51 (3ao)
b
c
d
3 equiv of acetone was used. 23 mol % of 1b was recovered. dr =
1:1.
8
PhCH2CH2, Me (2i)
i-Pr, Me (2j)
9
10
11
12
13
14
Ph, n-Bu (2k)
The reaction may be easily conducted on a 1-g scale,
affording the trisubstituted allene 3ac in 70% yield (eq 3).
m-BrC6H4, Et (2l)
p-ClC6H4, Et (2m)
p-FC6H4, Et (2n)
m-MeOC6H4, Et (2o)
a
The reaction was carried out on a 1 mmol scale in 5 mL of toluene.
dr = 2.5:1.
b
This method can also be utilized in a relatively complex
For the TBS-protected chiral alkynol (S)-1b, optically active
TBS-protected α-allenol (S)-3bc was afforded in 85% yield with
≥97% ee (eq 4).
substrate, such as tropinone 2p (Scheme 2, eq 1). The acid-
sensitive functional group ketal 2q can be tolerated under the
reaction conditions (Scheme 2, eq 2).
Even with acetone 2r with a low boiling point, the yield of
3br was 55% with 23% of 1b recovered (entry 1, Table 3). A
wide range of different alkynes were examined. Secondary
propargyl alcohol derivatives (1b and 1c) afforded 3bc and 3cc
in 85% and 84% yields, respectively (entries 2 and 3, Table 3),
and TBS-protected homopropargyl alcohol 1d could also
produce 3dc in 56% yield (entry 4, Table 3). The phthalimide
1e could also be applied in this reaction to afford the
trisubstituted allenes 3ec and 3ea in 49% and 51% yields,
respectively (entries 5 and 6, Table 3). In addition, 4-
ethynylanisole 1f afforded 43% of product 3fc (entry 7, Table
To investigate the role of CuI, ZnBr2, and Ti(OEt)4 in the
reaction, control experiments were conducted (Scheme 3).
When the reaction was carried out with 0.8 equiv of ZnBr2 and
2 equiv of Ti(OEt)4 in the absence of CuI at 120 °C for 12 h,
B
DOI: 10.1021/acs.orglett.7b02443
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Letter
no allene product 3aa was detected, and only propargylic amine
4aa was formed in 9% NMR yield. But when the reaction was
carried out with 10 mol % of CuI and 2 equiv of Ti(OEt)4, 3aa
and 4aa were produced in 16% and 39% NMR yield,
respectively. However, when the reaction was carried out
with both 0.8 equiv of ZnBr2 and 10 mol % of CuI in the
absence of Ti(OEt)4, no 3aa or 4aa was formed. These results
suggested that Ti(OEt)4 is necessary, and CuI was more
efficient than ZnBr2 in promoting the formation of propargylic
amine 4aa as the first step.
Scheme 4. Plausible Mechanism
When the isolated propargylic amine 4aa was reacted with 10
mol % of CuI for 8 h, allene 3aa was obtained in 23% yield,
with 77% of 4aa being recovered. On the contrary, with 0.8
equiv of ZnBr2, 76% of the 3aa was obtained and 5% of 4aa was
recovered, and when 4aa was treated with 10 mol % of CuI and
0.8 equiv of ZnBr2, the yield of 3aa is the same as that when
only ZnBr2 was used with a complete conversion of 4aa
(Scheme 3). These data indicate ZnBr2 is more effective in
converting propargylic amine 4aa to allene 3aa than CuI in the
second step. In addition, no allene 4aa was detected when only
Ti(OEt)4 was used. Thus, Ti(OEt)4 did not participate in the
second step.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02443.
Scheme 3. Control Experiments
Experimental procedure, spectroscopic data, and 1H, 13C,
and 19F NMR spectra for all the products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: masm@sioc.ac.cn.
ORCID
Shengming Ma: 0000-0002-2866-2431
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from National Natural Science Foundation of
China (21690063) is greatly appreciated. We thank Xingguo
Jiang in this group for reproducing the results of entry 3 and
entry 10 in Table 2 and entry 6 in Table 3 presented in the text.
Based on the above data and related reports on this field,10,11
we proposed a plausible mechanism for the current protocol of
ATA reaction: The alkynylmetal species 5, generated from
terminal alkyne in the presence of CuI, ZnBr2, pyrrolidine,
reacted with ketoniminum 6 formed in situ from ketone,
pyrrolidine, and Ti(OEt)4 to form the corresponding
propargylic amine 4 (Scheme 4). Zn(II) and/or Cu(I)
coordinated to the carbon−carbon triple bond in the
propargylic amine 4 to form complex 7, which then underwent
an intramolecular 1,5-hydride transfer and β-elimination to
afford the corresponding trisubsituted allene 3.
In summary, we have developed an efficient one-pot ATA
reaction to synthesize trisubstituted allenes from readily
available alkynes and ketones using environmentally friendly
metallic catalyst and reagents. This method has a much broader
substrate scope. Control experiments suggested that each of
them, CuI, ZnBr2, and Ti(OEt)4, played a crucial and different
role in this transformation. Further studies, including the
asymmetric version of this reaction, are being conducted in our
laboratory.
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