Metal-Free Oxidative Radical Alkynylation/Ring Expansion Rearrangement of Alkenyl Cyclobutanols with Ethynylbenziodoxolones

Article abstract of DOI:10.1021/acs.orglett.6b01856

The first metal-free alkynylation/ring expansion cascade process of alkenyl cyclobutanols with ethynylbenziodoxolones has been developed. A variety of synthetically valuable β-alkynylated cyclopentanones were prepared in moderate to good yields. Alkynyl c

Full text of DOI:10.1021/acs.orglett.6b01856

Letter
pubs.acs.org/OrgLett
Metal-Free Oxidative Radical Alkynylation/Ring Expansion
Rearrangement of Alkenyl Cyclobutanols with
Ethynylbenziodoxolones
Ruo-Yi Zhang, Long-Yi Xi, Lei Shi, Xiao-Zhuan Zhang, Shan-Yong Chen,* and Xiao-Qi Yu*
Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu
610064, China
S
* Supporting Information
ABSTRACT: The first metal-free alkynylation/ring expansion cascade
process of alkenyl cyclobutanols with ethynylbenziodoxolones has been
developed. A variety of synthetically valuable β-alkynylated cyclo-
pentanones were prepared in moderate to good yields. Alkynyl
cyclobutanols could also undergo this transformation, providing a new
approach to substituted ene-yne-carbonyl compounds.
Scheme 1. Recent Developments on Ring Expansion
Rearrangement of Vinylcyclobutanol and Ring-Opening
Alkynylation of Cycloalkanols
ubstituted cyclopentanones are valuable scaffolds, as they
S
widely exist in medicinal molecules1 and are utilized as
intermediates for natural product syntheses.2 Much more
attention has been focused on the development of synthetic
methodologies in this area. Among this research, ring expansion
rearrangement reactions of vinylcyclobutanol derivatives have
been recognized as one of the most powerful methods for
synthetically useful substituted five-membered ring systems.3
Alexakis’s group realized enantioselective fluorination and
iodination/ring expansion reaction of strained allylic alcohols
to synthesize a series of β-halofunctionalization spiroketones
(Scheme 1a).4 Later, You et al. reported the synthesis of 2-alkyl-
2-aryl cycloalkanones by a highly enantioselective chlorination/
ring expansion cascade (Scheme 1a).5 Recently, Glorius et al.
expanded the reaction to trifluoromethylation under visible-
light-mediated photo-redox-catalyzed conditions (Scheme 1b).6
Additionally, arylation and alkylation could also be successfully
applied to the cascade process reported by the groups of Toste7
and Tu8 (Scheme 1c). On the other hand, good work on the ring
opening/alkynylation of cycloalkanols was realized previously
(Scheme 1d).9 In spite of the notable advances, there is still no
efficient approach for the one-step alkynylation and ring
expansion rearrangement of vinylcyclobutanol. Alkynes are not
only important structural motifs in a broad range of natural
products, bioactive compounds, and materials but also valuable
building blocks in organic synthesis due to their versatile
transformations.10 Thus, the investigation toward tandem
alkynylation/ring expansion rearrangement is highly desirable.
Ethynylbenziodoxolone (EBX) as one of the most powerful
and useful alkynylating reagents has been increasingly inves-
tigated over the past few years because of its stability toward air
and moisture. Since 2009, EBX has been applied for the direct
C−H alkynylation of a range of (hetero)aromatic rings with the
use of transition metal catalysts.11,12 Furthermore, EBX reagents
are also ideally suited for the alkynylation of carbon
nucleophiles13 and radicals14 under metal-free conditions,
making alkynylation much more convenient and environ-
mentally friendly. Encouraged by our previous work14c,d and
recent progress in ring rearrangement radical reactions,6 we
envisioned that EBX might be applied to ring rearrangement to
afford useful alkynylated five-membered ring derivatives. Herein,
Received: June 26, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01856
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
b
entry
1a/2a (equiv)
catalyst (20%)
oxidant (equiv)
solvent (1 mL/1 mL)
yield (%) (dr)
1
2
3:1
3:1
3:1
3:1
2:1
1:2
3:1
3:1
3:1
2:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
AgBF4
Bu4NI
KI
K2S2O8 (2.0)
K2S2O8 (2.0)
K2S2O8 (2.0)
K2S2O8 (2.0)
K2S2O8 (2.0)
K2S2O8 (2.0)
K2S2O8 (3.0)
K2S2O8 (4.0)
K2S2O8 (5.0)
K2S2O8 (4.0)
Na2S2O8 (4.0)
(NH4)2S2O8 (4.0)
TBHP (4.0)
m-CPBA (4.0)
K2S2O8 (4.0)
K2S2O8 (4.0)
K2S2O8 (4.0)
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
acetone/H2O
toluene/H2O
DCE/H2O
68 (2.2:1)
49 (2.8:1)
41 (2.4:1)
69 (1.9:1)
65 (1.7:1)
trace
3
4
5
6
7
68 (1.6:1)
76 (1.6:1)
67 (1.9:1)
57 (1.6:1)
71 (1.7:1)
6
8
9
10
11
12
13
14
15
16
17
15
nd
67 (1.6:1)
trace
trace
a
b
All reactions were carried out on a 0.2 mmol scale at 60 °C in 2 mL of solvent under an argon atmosphere for 12 h. Yield of isolated product.
Number in parentheses is dr values (determined by the yields of isolated isomers).
a
we describe the first metal-free oxidative radical alkynylation/
ring expansion rearrangement of vinylcyclobutanol with the use
of EBX.
Scheme 2. Scope of Alkenyl Cyclobutanol 1
Initially, we selected phenyl-1,2-benziodoxol-3(1H)-one (Ph-
EBX) and (E)-1-styrylcyclobutanol as the standard substrates to
optimize the reaction conditions (Table 1). With potassium
persulfate (K2S2O8) as the oxidant and silver tetrafluoroborate
(AgBF4) as the catalyst in aqueous media, CH3CN/H2O (1 mL/
1 mL), at 60 °C, desired product 3a was isolated in 68% yield
(Table 1, entry 1). Then, to our delight, we found that the
reaction proceeded smoothly in the absence of a catalyst (entry 4
vs entries 1−3), affording the desired product in a good yield of
69%. We further studied the effect of the amount of K2S2O8 and
2a on the reaction (entries 4−10), and the yield of the product
further increased to 76% yield (entry 8). Subsequently, a few of
other oxidants and solvents were also screened, but no further
increase in the yield was observed (entry 8 vs entries 11−17).
The substrate scope was subsequently investigated under the
optimized conditions. First, various substituted (E)-1-styrylcy-
clobutanols were applied to react with Ph-EBX. As shown in
Scheme 2, several electron-withdrawing (3e−3g) and electron-
donating (3b−3d) substituents on the benzene ring of (E)-1-
styrylcyclobutanols were well-tolerated and furnished the
corresponding products in moderate to good yields. The
reaction was sensitive to steric hindrance. A significantly
decreased yield was observed for the ortho-substituted alkenyl
cycloalkanol in comparison with para- and meta-substituted
substrates (3i vs 3b and 3h). Other aromatic substituted
substrates were suitable for this transformation, as well, such as
(E)-1-(2-(naphthalen-1-yl)vinyl)cyclobutanol (3j) and (E)-1-
(2-(thiophen-3-yl)vinyl)cyclobutanol (3k).
a
Reaction conditions: 2a (0.2 mmol), 1 (3.0 equiv), K2S2O8 (4.0
equiv), CH3CN (1 mL)/H2O (1 mL) under an argon atmosphere at
60 °C for 12 h. Yield of isolated product. Number in parentheses is dr
values (determined by the yields of isolated isomers).
We further evaluated the scope of the reaction by preparing
several other EBX reagents with different substituents to react
with (E)-1-styrylcyclobutanols under the developed conditions.
As shown in Scheme 3, most of the corresponding products were
obtained in moderate to good yields. o-MePh-EBX provided a
lower yield than m-MePh-EBX and p-MePh-EBX probably
B
DOI: 10.1021/acs.orglett.6b01856
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 3. Scope of Ethynylbenziodoxolones 2
Scheme 4. Scope of Ethynylcyclobutanols 5
a
Reaction conditions: 2 (0.2 mmol), 1a (3.0 equiv), K2S2O8 (4.0
equiv), CH3CN (1 mL)/H2O (1 mL) under an argon atmosphere at
60 °C for 12 h. Yield of isolated product. Number in parentheses is dr
values (determined by the yields of isolated isomers).
a
Reaction conditions: 5 (0.2 mmol), 2 (3.0 equiv), K2S2O8 (4.0
equiv), CH3CN (1 mL)/H2O (1 mL) under an argon atmosphere at
60 °C for 12 h. Yield of isolated product. Number in parentheses is the
ratio of Z/E configuration of products (determined by NMR analysis).
Reaction conditions: 2 (0.2 mmol), 5 (3.0 equiv), K2S2O8 (4.0
equiv), acetone (1 mL)/H2O (1 mL) under an argon atmosphere at
because of the steric hindrance (4d (E) vs 4b (E) and 4c (E)). In
addition, we studied reactions between the substrates of Z/E
configuration with various EBX. We found that substrates with
either Z or E configuration could give the products in moderate
to good yields, and the reaction was not sensitive to the
substituents of EBX when the substrates with Z configuration
participated in the reaction.
b
60 °C for 12 h.
Scheme 5. Derivatization of 3a
As far as we know, the metal-free ring expansion reaction of
alkynyl cyclobutanols has not been reported yet.15 Encouraged
by the above results obtained for the vinylcyclobutanol, we
further explored the reaction between the cyclobutanols bearing
various ethynyl groups and ethynylbenziodoxolones. We were
pleased to find that the cascade alkynylation/ring expansion
reaction could proceed smoothly under slightly modified
conditions,16 which provided a straightforward route to
synthesize ene-yne-carbonyl compounds (Scheme 4). Remark-
ably, 1-(thiophen-2-ylethynyl)cyclobutanol (6e) was success-
fully applied to this transformation, giving the heterocycle-
substituted ene-yne-carbonyl compound in synthetically useful
yields. The reactions between Ph-EBX or t-Bu-EBX and 1-
(phenylethynyl)cyclobutanol gave the corresponding products
in lower yields (6f and 6g).
Scheme 6. Radical Inhibition Experiment
The products obtained here are highly functionalized with
carbonyl and alkynyl groups, which could be readily converted
into complex organic structures. We further performed
subsequent transformations to explore the versatility of this
method. As shown in Scheme 5, product 3a could be converted
to the corresponding hydrazine 7 and oxime 10 in good yields,
and oxime derivatives are well-known potential precursors for the
Beckmann rearrangement. It is worth mentioning that the
corresponding hydrazine 7 realized a cyclization to afford
pyridazine 8, which could be further isomerized to pyridazine
9. Compound 9 is the analogue of important monoamine
oxidase-A (MAO-A) and MAO-B inhibitors, which are valuable
antidepressant agents and useful as co-adjuvants in the treatment
of Parkinson’s disease, respectively.17 These results show the
transformation diversity of the β-alkynylated cyclopentanones
and their potential in organic synthesis as useful intermediates.
To gain mechanistic insight into the reaction, a controlled
experiment was performed. The addition of the radical scavenger
TEMPO significantly decreased the yield of the model reaction,
and the trapped product 11 was detected by HR-MS (Scheme 6).
This result indicates that the reaction most likely proceeds via a
radical pathway. Subsequently, a possible mechanism is proposed
in Scheme 7. First, an oxygen-centered radical species A is
generated from 1-styrylcyclobutanol in the presence of K2S2O8.
Then, radical migration/ring expansion occur to form the radical
intermediate B, which adds to EBX to form an intermediate C. β-
Elimination of radical C affords the desired product accompanied
by the formation of a benziodoxolonyl radical, which is further
transformed to 2-iodobenzoic acid via a reduction−protonation
sequence.
C
DOI: 10.1021/acs.orglett.6b01856
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Scheme 7. Proposed Reaction Mechanism
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In summary, we have developed the first alkynylation/ring
expansion rearrangement of vinylcyclobutanol by using
ethynylbenziodoxolones. The reaction proceeds under mild
conditions without metal catalyst via a radical mechanism to
afford a variety of β-alkynylated cyclopentanone derivatives in
moderate to good yields. Analogously, alkynyl cyclobutanols
could also undergo this transformation, providing a new
approach to substituted ene-yne-carbonyl compounds. The
highly functionalized cyclopentanones obtained here would be
very useful in biochemistry and synthetic chemistry to construct
valuable scaffolds.
ASSOCIATED CONTENT
* Supporting Information
■
(12) (a) Finkbeiner, P.; Kloeckner, U.; Nachtsheim, B. J. Angew. Chem.,
Int. Ed. 2015, 54, 4949. (b) Ai, W.; Wu, Y.; Tang, H.; Yang, X.; Yang, Y.;
Li, Y.; Zhou, B. Chem. Commun. 2015, 51, 7871. (c) Feng, C.; Loh, T.-P.
Angew. Chem., Int. Ed. 2014, 53, 2722. (d) Collins, K. D.; Lied, F.;
Glorius, F. Chem. Commun. 2014, 50, 4459. (e) Xie, F.; Qi, Z.; Yu, S.; Li,
X. J. Am. Chem. Soc. 2014, 136, 4780.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01856.
Experimental details and spectral data for new compounds
(PDF)
(13) Selected examples of the metal-free alkynylation of carbon
nucleophiles: (a) Utaka, A.; Cavalcanti, L. N.; Silva, L. F. Chem.
AUTHOR INFORMATION
Corresponding Authors
́
Commun. 2014, 50, 3810. (b) Fernandez Gonzalez, D.; Brand, J. P.;
■
Mondiere, R.; Waser, J. Adv. Synth. Catal. 2013, 355, 1631.
(c) Fernandez Gonzalez, D.; Brand, J. P.; Waser, J. Chem. - Eur. J.
2010, 16, 9457.
*E-mail: chensy@scu.edu.cn.
*E-mail: xqyu@scu.edu.cn.
Notes
(14) Selected examples of the metal-free alkynylation of radicals with
EBX: (a) Wang, H.; Guo, L. N.; Wang, S.; Duan, X.-H. Org. Lett. 2015,
17, 3054. (b) Liu, X.; Yu, L.; Luo, M.; Zhu, J.; Wei, W. Chem. - Eur. J.
2015, 21, 8745. (c) Zhang, R.-Y.; Xi, L.-Y.; Zhang, L.; Chen, S.-Y.; Yu,
X.-Q. Tetrahedron 2015, 71, 6176. (d) Zhang, R.-Y.; Xi, L.-Y.; Zhang, L.;
Liang, S.; Chen, S.-Y.; Yu, X.-Q. RSC Adv. 2014, 4, 54349.
(15) Selected examples of transition-metal-catalyzed ring expansion
reactions of alkynyl cyclobutanols: (a) Jones, C.; Nguyen, Q.; Driver, T.
G. Angew. Chem., Int. Ed. 2014, 53, 785. (b) Hashmi, A. S. K.; Wang, T.;
Shi, S.; Rudolph, M. J. Org. Chem. 2012, 77, 7761. (c) Larock, R. C.;
Reddy, C. K. J. Org. Chem. 2002, 67, 2027. (d) Larock, R. C.; Reddy, C.
K. Org. Lett. 2000, 2, 3325.
(16) Here, the excess of TIPS-EBX was used to promote the reaction
yield. An unknown byproduct was generated when TIPS-EBX was
employed as the limiting reagent, making the isolation of products very
difficult.
(17) Altomare, C.; Cellamare, S.; Summo, L.; Catto, M.; Carotti, A.;
Thull, U.; Carrupt, P.-A.; Testa, B.; Stoeckli-Evans, H. J. Med. Chem.
1998, 41, 3812.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported financially by the National Program on
Key Basic Research Project of China (973 Program,
2013CB328905) and the National Science Foundation of
China (Grant Nos. 21202107, 21321061, and J1103315).
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DOI: 10.1021/acs.orglett.6b01856
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