Triflic Acid-Catalyzed Enynes Cyclization: A New Strategy beyond Electrophilic π-Activation

Article abstract of DOI:10.1002/chem.201601599

The cyclization of enynes, catalyzed by a transition metal, represents a powerful tool to construct an array of cyclic compounds through electrophilic π-activation. In this paper, we disclose a new and efficient strategy for enynes cyclization catalyzed b

Full text of DOI:10.1002/chem.201601599

DOI: 10.1002/chem.201601599
Communication
&
Cyclization
Triflic Acid-Catalyzed Enynes Cyclization:
A New Strategy beyond Electrophilic p-Activation
Zhunzhun Yu,[a] Lu Liu,*[a] and Junliang Zhang*[a, b]
carbocation, all of which can be attacked by nucleophiles.
Over the past decades, Brønsted acids exhibited their unique
privilege and became more and more commonly used for the
carbon-carbon bond-forming reaction.[2] Inspired by biomimet-
ic cationic cyclizations of polyenyne derivatives developed
some decades ago and the recent work developed by Yama-
moto,[3] we reasoned that the concept of using Brønsted acids
could be applied to the cyclization of enynes to synthesize im-
portant cyclic compounds, which are beyond traditional elec-
trophilic p-activation catalyzed by metals. We assumed that
the carbonyl of alkyne enone derivatives can be activated se-
lectively by Brønsted acids to give allylic carbocation I-A. Next,
the alkyne group would attack this carbocation to generate al-
kenyl cation intermediate I-B,[4] which subsequently could be
intercepted by nucleophiles to furnish the desired cyclic com-
pounds (Scheme 1b). Herein, we report an unprecedented and
attractive triflic acid-catalyzed method, which is beyond the
traditional electrophilic p-activation protocol, to synthesize
cyclic compounds.
Due to the importance of cyclic 1,5-diketones,[5] which are
synthesized from enynes using a ruthenium catalyst, as syn-
thetic synthons,[6] we selected this skeleton as our target. Ac-
cordingly, we synthesized enyne 1a as the model substrate to
test our idea. Because of the efficiency of triflic acid in numer-
ous transformations,[7] we employed it primarily as the catalyst
in the reaction of 1a with water. To our delight, the reaction
was carried out smoothly and afforded the desired product 2a
in 93% NMR yield with 3:1 d.r. (Table 1, entry 1). Although
other Brønsted acids, such as H2SO4, CF3CO2H, TsOH·H2O, were
also tested, no better results were obtained (entries 2–4),
which indicate that the acidity of the Brønsted acid is vital to
this transformation. Besides, the screening of solvents shows
that dichloroethane is the best one. It was a little surprising
that the reaction did not work in THF and toluene (entry 5
versus 7), which may be attributed to the coordination be-
tween oxygen and H+ in THF and low solubility of triflic acid
in toluene. Further optimization revealed that the loading of
triflic acid could be reduced to 2.5 mol% (entry 8), resulting in
a comparable result. Pleasingly, wet DCE can dramatically ac-
celerate the transformation, and the reaction could be done in
one minute, affording the desired 2a in 99% yield (entry 9).
Then, we wanted to convert the diastereoisomers to only one
by treating with bases. Gratifyingly, single trans isomer was ob-
tained in 88% yield after the reaction mixture in dichloro-
ethane was treated with DBU (4.0 equiv) at r.t. (entry 10).
With the optimized conditions in hand, a variety of enynes
1 were prepared and subjected to the aforementioned condi-
Abstract: The cyclization of enynes, catalyzed by a transi-
tion metal, represents a powerful tool to construct an
array of cyclic compounds through electrophilic p-activa-
tion. In this paper, we disclose a new and efficient strategy
for enynes cyclization catalyzed by triflic acid. The salient
features of this transformation includes a broad substrate
scope, metal free synthesis, open flask and mild condi-
tions, good yields, ease of operation, low catalyst loading,
and easy scale-up to gram scale. A preliminary mechanism
study demonstrated that the activation model of the reac-
tion was s-activation, which is different from the transi-
tion-metal-catalyzed enynes cyclization. Our strategy af-
fords a complementary method to the traditional strat-
egies, which use transition-metal catalysts.
Carbo- and heterocycles are essential and fundamental skele-
tons found in numerous natural products, biologically active
compounds, and drugs. Among reported strategies, a transi-
tion-metal-catalyzed cyclization of enynes through electrophilic
p-activation has emerged as a general and efficient method to
construct various functionalized cyclic compounds from rela-
tively simple linear unsaturated substrates in a single step
(Scheme 1a).[1] However, these transformations usually rely on
expensive and even toxic noble metals, such as rhodium, gold,
palladium, and so forth. Thus, the development of a metal-free
strategy to deliver functionalized cyclic compounds is highly
desirable.
Compared to Lewis acids and transition-metal catalysts,
Brønsted acids are easy to handle, low price, environment
friendly, generally stable toward oxygen and water, and can be
stored for a long period of time. Brønsted acids are usually ap-
plied to activate carbonyl, imine, alkene, alkyne, and hydroxyl
groups, forming oxonium, iminium, carbocation, and vinylic
[a] Z. Yu, Prof. Dr. L. Liu, Prof. Dr. J. Zhang
Shanghai Key Laboratory of Green Chemistry and Chemical Processes,
School of Chemistry and Molecular Engineering
East China Normal University
3663 North Zhongshan Road, Shanghai 200062 (P. R. China)
E-mail: lliu@chem.ecnu.edu.cn
jlzhang@chem.ecnu.edu.cn
[b] Prof. Dr. J. Zhang
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Or-
ganic Chemistry, Chinese Academy of Sciences
354 Fenglin Road, Shanghai 200032 (P. R. China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201601599.
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lowered the nucleophilicity of alkyne moiety and the
stability of the forming alkenyl carbocation inter-
mediate. Meanwhile, the position of the substituent
had no effect on the yield (e.g., 2 f, 2g). When the
methyl group was introduced to the terminal of the
alkyne, substrate 1h needed higher temperature
(708C), delivering 2h in 35% yield, and 2h’ by a fur-
ther aldol annulation in 38% yield. Compared to the
corresponding ketone, the aldehyde substrates (1i–
1n) showed lower reactivity, and the desired prod-
ucts 2i–2n could still be obtained in 51–71% yields
at 708C that may be attributed to the weaker coordi-
nation ability of the aldehyde to the proton and side
reactions of the aldehyde under basic conditions
with DBU. Besides pyrrole derivatives, both 3,4-disub-
stituted tetrahydrofurans 2o–2q and all-carbon ring
cyclopentanes 2r–2t could be stereoselectively syn-
thesized in moderate to good yields.
To gain mechanistic insights of the reaction, sever-
al control experiments were conducted. Because the
Brønsted acid-catalyzed hydration of alkynes[8] is well
known and an alternative pathway through tandem
hydration/Michael addition might be also reasonable for this
transformation, intermediate 1a’ was synthesized and subject-
Scheme 1. Previous strategies and our design for the enyne cyclization.
tions. The results are summarized in Scheme 2. When the link-
age moiety was TsN, the reaction of substrates 1b–1d with
electron-donating groups or weak electron-withdrawing
groups at the para-position of the phenyl ring attached the al-
kynyl part could afford the corresponding adducts 2b–2d in
good yields. The structure of compound 2c was further con-
firmed as the trans isomer by single-crystal X-ray crystallogra-
phy. The reaction of 1e with a strong electron-withdrawing
group (NO2) at the para-position of the phenyl ring afforded
2e in 60% yield, probably because the conjugated nitro group
Table 1. Optimization of reaction conditions.[a]
Entry
HB
Solvent
Time
Yield [%][f]
d.r.
1
2
3
4
TfOH
Cl(CH2)2Cl
Cl(CH2)2Cl
Cl(CH2)2Cl
Cl(CH2)2Cl
Toluene
12 h
36 h
36 h
36 h
93
3:1
–
–
3:1
–
CF3CO2H
H2SO4
TsOH·H2O
TfOH
trace
trace
67
5
36 h
NR
6
7
TfOH
TfOH
CH3CN
THF
36 h
36 h
70
NR
5:1
–
8[b]
9[b,c]
10[b,c,d]
TfOH
TfOH
TfOH
Cl(CH2)2Cl
Cl(CH2)2Cl
Cl(CH2)2Cl
36 h
1 min
31 min[e]
91
>99
(88)
2:1
1:1
[a] 1a (0.15 mmol) was dissolved in solvent (3 mL). [b] TfOH (2.5 mol%)
was used. [c] Wet dichloroethane (3 mL) was used and no extra water
was added. [d] DBU (4.0 equiv) was added after the reaction was com-
plete. [e] The solution of 1a in DCE was treated with TfOH (2.5 mol%) for
1 min, then DBU was added and stirred at r.t. for 30 min. [f] Yields were
1
determined by H NMR using CH2Br2 as internal standard. Numbers in pa-
renthesis are isolated yields. TfOH=triflic acid. DBU=1,5-diazabicyclo-
[4.3.0] non-5-ene.
Scheme 2. Synthesis of carbo- and heterocycles.
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Scheme 3. Preliminary mechanism study.
ed to the standard conditions but no desired product was de-
tected (Scheme 3a), which indicated that the hydration/Mi-
chael addition pathway through 1a’ might be ruled out. Be-
sides, other nucleophiles, such as anisole and bromide, were
also used to trap the alkenyl cation intermediate I-B. For the
reaction of 1a and anisole, the desired product 2aa was ob-
tained in 25% yield along with 2a (67% yield) due to H2O in
DCE. 1a was consumed completely and only 2ab was isolated
in 25% yield when 1a was treated with Bu4NBr3 under the
standard conditions.
Because the intermolecular trapping of alkenyl cation I-B
was successful, we next wanted to extend this strategy to in-
tramolecular version. Inspired by the transition-metal-catalyzed
propargyl ester rearrangement,[9–12] we envisioned that a pivo-
late group adjacent to the alkyne moiety that can act as an
inner nucleophile, could trap the alkenyl carbocation sponta-
neously and the resulting intermediate I-C could undergo fur-
ther rearrangement and hydrolysis to offer unsaturated carbo-
cycles (Scheme 4). The formed scaffold (4), which is a key syn-
thon in natural products synthesis,[13] is normally synthesized
by the Rauhut–Currier reaction,[14] albeit with limited regiose-
lectivity.
Scheme 5. Preparation of unsaturated carbocycles.
action, such as 4a, 4d, 4h, 4i, and so forth.[16] The scope of
the reaction is surveyed in Scheme 5. In general, the desired
cycloadducts could be obtained in high to excellent yields. It
was found that alkyl substituents and electron-rich and -poor
aryl substituents at both R2 and R3 positions were tolerated.
For butyl-substituted substrate 3n, 10 mol% loading of the
catalyst was required, offering the corresponding product 4n
in 63% yield.
To demonstrate the synthetic value of our methodology,
two gram-scale reactions were performed (Scheme 6). Addi-
tionally, several further transformations of the products were
also conducted (Scheme 7). The Wittig olefin reaction of 2a
and 2j afforded the desired products 5a and 5j, respectively,
in moderate yields. Besides, further annulation products 5d
and 6 could be obtained in 50 and 71% yields, respectively, in
the presence of K2CO3 in methanol. The treatment of aldehyde
2k with PPh3 and CBr4 led to the corresponding homologated
dibromoolefin product 5k in 54% yield. The olefin epoxidation
of 4a with m-CPBA delivered 7 in good yield.
Scheme 4. Our proposal for the intramolecular trapping.
To prove our hypothesis, we chose 3a as the model sub-
strate.[15] To our delight, the desired product 4a was obtained
(99% yield) in an open flask catalyzed by triflic acid (2.5 mol%)
with wet nitromethane as the solvent. Fortunately, our method
is applicable to synthesize a series of symmetrical and unsym-
metrical unsaturated carbocycles. Of particular note is that our
protocol allows to synthesize cycloadducts that would be re-
gioselectively disfavored by the traditional Rauhut–Currier re-
Scheme 6. Gram-scale synthesis.
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In summary, we have developed a novel and efficient triflic
acid-catalyzed cyclization of enynes. This method provides
a facile access to structurally diverse carbo- and heterocycles in
moderate to excellent yields. The salient features of this trans-
formation includes a broad scope of substrates, metal free syn-
thesis, open flask and mild conditions, high yields, ease of op-
eration, low catalyst loading, and easy scale-up to gram scale.
A preliminary mechanism study indicated that the activation
model was indeed s-activation rather than the normal p-acti-
vation, which is catalyzed by a metal. We believe that our strat-
egy will shine some light on the design of novel pathways for
enynes and Brønsted acid-catalyzed reactions.
Acknowledgements
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We are grateful to the Shanghai Pujiang Program
(14J1403100), 973 Program (2015CB856600), the National Natu-
ral Science Foundation of China (21372084, 21425205,
21572065), STCSM (13ZR1412900) and Changjiang Scholars
and Innovative Research Team in University (PCSIRT) for finan-
cial supports.
Keywords: s-activation
· enynes · organic chemistry ·
synthetic methods · triflic acid
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Published online on May 3, 2016
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