K2S2O8-promoted [2+2]-cycloaddition of benzyl-2-(3-hydroxypropynyl)-benzoates: A new route to polysubstituted cyclobutanes

Article abstract of DOI:10.1016/j.tetlet.2016.10.098

An efficient and convenient metal-free [2+2]-cycloaddition of benzyl-2-(3-hydroxypropynyl)-benzoates via allene processes has been developed, which provides impressive access to fused cyclobutanes from easily accessed π-components. This transformation involved the cleavage of two C–O bonds, the formations of two C–O bonds and two C–C bonds and showed some advantages, including mild conditions and wide substrate scope.

Full text of DOI:10.1016/j.tetlet.2016.10.098

Tetrahedron Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
K2S2O8-promoted [2+2]-cycloaddition of benzyl-2-(3-
hydroxypropynyl)-benzoates: A new route to
polysubstituted cyclobutanes
⇑
Hai-Tao Zhu , Xiao-Juan Tong, Ni-Ni Zhou, De-Suo Yang, Ming-Jin Fan
Shaanxi Key Laboratory of Phytochemistry, College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences, Baoji 721013, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and convenient metal-free [2+2]-cycloaddition of benzyl-2-(3-hydroxypropynyl)-benzoates
via allene processes has been developed, which provides impressive access to fused cyclobutanes from
easily accessed p-components. This transformation involved the cleavage of two C–O bonds, the forma-
tions of two C–O bonds and two C–C bonds and showed some advantages, including mild conditions and
wide substrate scope.
Received 22 September 2016
Revised 22 October 2016
Accepted 25 October 2016
Available online xxxx
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Allenylic esters
[2+2]-Cycloaddition
K2S2O8
Cyclobutanes
Propargyl alcohols
Introduction
cyclobutane products (Scheme 1c) [12]. Although these methods
have made important contribution to the synthesis of cyclobu-
The cyclobutane skeleton as a key structural element is found in
biologically active natural product and pharmaceutical chemistry
such as pipercyclobutanamide A (1), piperarborenine D (2), or Pro-
coralan 3 (Fig. 1) [1]. Therefore, much attention has been paid to
developing simple and effective methods for the synthesis of
cyclobutane compounds.
As one of the most straightforward approaches, the [2+2]-
cycloaddition have been extensive studied for the construction of
diverse cyclobutanes. To date, many protocols was reported
tanes, they still suffer from limited substrate scopes, harsh reaction
conditions, low regioselectivity and the use of transition metal
catalysts, the toxic and high cost of the reagent. Thus, further
developments for more practical and efficient, high regioselectivity
four-membered ring cyclization methodologies are quite desired.
Herein, we have reported an efficient and convenient K2S2O8-pro-
moted [2+2] cycloaddition of benzyl-2-(3-hydroxypropynyl)-ben-
zoates for the synthesis of polysubstituted cyclobutanes.
involving the p-electronic systems of olefins [2], allenes [3], alkadi-
enes [4] or alkynes [5] in the presence of transition metal [6], chiral
ligands [7], auxiliaries [8], Brønsted or Lewis acid [9]. In 2006, Kita-
gaki developed an elegant method for the synthesis of cyclobu-
tanes from benzene-bridged bis(propargyl alcohols) via allene
intermediates (Scheme 1a) [10]. In 2009, Tejedor synthesized
cyclobutanes by a tertiary amine-catalyzed reaction involving
1,2-diketones and terminal conjugated acetylides, which appears
to be an environmentally friendly method (Scheme 1b) [11]. In
2011, Chan reported the 1,3-migration/[2+2] cycloaddition of 1,7-
enyne benzoates using Au(I) catalysis to provide the corresponding
Results and discussion
At the outset of our investigation, we selected benzyl-2-(3-
hydroxypropynyl)-benzoates (1a) as model substrate in the pres-
ence of 2.0 equiv K2S2O8 in MeCN at 60 °C for 10 h. Then, the
desired cyclobutane 2a was isolated in 88% yield (Table 1, entry
1). The structure of the representative product 2a was determined
by X-ray crystallographic analysis (see the Supporting information)
[13]. Further investigation showed that Na2S2O8 and (NH4)2S2O8
were also effective for this cycloaddition and the desire product
2a were obtained in 78% and 65% yields, respectively (entries 2
and 3). Next, several solvents such as THF, dioxane and DMF were
screened and no significant improvements were observed (entries
3–9). Changing the amount of K2S2O8 was less effective to the
yields (entries 10 and 11). In addition, we also tested the effect
⇑
Corresponding author.
E-mail address: zhuht@bjwlxy.edu.cn (H.-T. Zhu).
http://dx.doi.org/10.1016/j.tetlet.2016.10.098
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Zhu H.-T., et al.. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.10.098

2
H.-T. Zhu et al. / Tetrahedron Letters xxx (2016) xxx–xxx
O
O
O
MeO
MeO
N
N
N
Me
N
N
O
O
O
O
O
O
O
N
MeO
O
OMe
procoralan
3
piperarborenine D (2)
pipercyclobutanamide A (1)
Figure 1. Examples of cyclobutanes in natural products and pharmaceutical chemistry.
a) Kitagaki's work(2006)
OH
R1
P(O)
Ph2P(O)
R1
Ph2
R1
R2
R2
R3
R2
[2+2]
Ph2PCl, Et3N, THF
-78 oC, 2h
rt, 2h
R3
R3
R4
R4
R4
P(O)
Ph2
Ph2P(O)
OH
b) Tejedor's work (2009)
O
CO2Me
BzO
Ph
Et3N(10mol%)
Ph
Ph
+
Z
O
w
o
+
l
s
BzO
Ph
BzO
Ph
Ph
Z
Z
Ph
OBz
+
Z
Ph
Z
Ph
Z
Z
BzO
BzO
c) Chan's work(2011)
OBz
Ph
BzO
Ph
Ph
Et
Au
Et
BzO
Et
+
4A MS, 80 oC
15h
H
iBu
N
iBu
N
iBu
N
Ts
Ts
Ts
d) This work
O
O
O
O O
O
Ar
K2S2O8
R
2
MeCN, 60 o
C
R
Ar
R
Ar
Ar
Ar
OH
Ar
Ar
Scheme 1. The [2+2]-cycloaddition of allene intermediates for the synthesis of cyclotubanes.
of temperature. The obtained results revealed that lower or higher
temperatures were not beneficial to the transformation.
substrate 1j with a nitro substituent (2c vs 2j). Remarkably, the
cyclobutane product 2e having a bromo group was obtained in
78% yield, which could be further elaborated by palladium-cat-
alyzed processes. Furthermore, we examined the electronic effects
of the substituents on the aromatic ring adjacent to the hydroxyl
group. An electron-withdrawing (F) substituent on the aryl group
afforded the corresponding product 2s in 80% yield, but an elec-
tron-donating (OMe) substituent only resulted in a 46% yield of
the product 2p. We hypothesized that the electrophilicity of the
allenolic cation intermediate was decreased in the latter case.
The substrate 1t with a methoxy and fluoro substituents was sub-
jected to the optimum conditions, and the desired product 2t was
produced in low yield along with several unknown by-products.
With the optimal conditions in hand, the scope of the reaction
was examined, as depicted in Table 2. We first investigated the
reaction of substrate 1b with isopropyl group instead of benzyl
group under the optimized conditions, but the yield of the desired
product 2a greatly decreased. This might be because of the weaker
nucleophilicity of the oxygen of the carbonyl group on isopropyl
ester. Subsequently, we examined the electronic and steric effects
of the substituents on R2 of benzyl benzoate. It was found that sub-
strates bearing either electron-withdrawing or electron-donating
substituents reacted well. However, substrate 1c with a methoxyl
on the C-4 position of the aryl group showed better efficiency than
Please cite this article in press as: Zhu H.-T., et al.. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.10.098

H.-T. Zhu et al. / Tetrahedron Letters xxx (2016) xxx–xxx
3
Table 1
Table 2
Optimization study for the [2+2]-cycloaddition.a
[2+2]-cycloaddition of propargyl alcohols 1a–1v catalyzed by K2S2O8.a
O
O
O
O
O
O
R1
O O
O O
O
O
Ph
K2S2O8 (2 equiv)
MeCN, 60 oC
R2
2
2
K2S2O8 (2.0 equiv)
R2
R2
Ar
OH
solvent, temperature, 10 h
Ar
OH
Ar
Ar
Ar
Ar
1
2
1a
2a
O
2
O
O
O
Entry
Promotor
Solvent
Temperature (°C)
Yield (%)b
1
6
O O
O O
1
2
3
4
5
6
7
8
K2S2O8
Na2S2O8
(NH4)2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
MeCN
MeCN
MeCN
THF
Toluene
CHCl3
60
60
60
60
60
60
60
60
60
60
60
rt
88
78
65
Trace
Trace
Trace
25
21
<5
80
87
nr
79
5
R2
R2
3
4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a (86%, based on the reaction of 1a
2c: R2 = 5-OMe (79%)
bearing a benzyl group on R1)
: R2 = 5-Me (64%)
: R2 = 5-Br (78%)
: R2 = 5-Cl (74%)
1,4-Dioxane
DMF
2d
2e
2f
2a
1b
(30%, based on the reaction of
bearing a isopropyl group on R1)
9
DMSO
MeCN
MeCN
MeCN
MeCN
10c
11d
12
13
2g: R2 = 5-F (80%)
2h: R2 = 4-Cl (76%) b
2i: R2 = 4-F (77%)
O
2
O
1
6
O O
2j: R2 = 4-NO2 (55%) b
5
80
: R2 = 6-Cl (67%)
: R2 = 6-F (81%)
2k
2l
3
4
a
Ar
Ar
Unless noted, all reactions were performed with
(2.0 equiv), and solvent (2.0 mL) under air for 10 h.
1 (0.2 mmol), K2S2O8
Ar
Ar
: R2 = 6-Me (68%)
2m
:
2o:
R2 = 4,5-OMe (73%)
b
2n
Isolated yield.
K2S2O8 (1.0 equiv).
K2S2O8 (3.0 equiv).
2p: Ar = 4-OMe-C6H4 (46%)
R
2 = 4,5-F (82%)
c
2q
: Ar = 4-Me-C6H4 (62%)
d
2r: Ar = 4-Cl-C6H4 (71%)
2s: Ar = 4-F-C6H4 (80%)
O
O
O
2
O
O
O
6
1
O O
5
Specially, the reaction of benzyl-2-(9-hydroxy-9H-fluorenethynyl)
benzoate 1v could also give the polycyclic product 2v in good
yield.
R2
R2
3
4
Ar
Ar
Ar
Ar
2t: R2 = 5-OMe, Ar = 4-F-C6H4 (29%)
2u
To gain insights into the mechanism of this reaction, we
used KHSO4 instead of K2S2O8 to promote this reaction of 1a,
and the cyclobutane 2a was obtained in 64% yield (Scheme 2,
Eq. 1). In addition, 2,2,4,4-tetramethyl-1-piperidinyloxy (TEMPO,
2 equiv), and 2,6-di-tert-butyl-p-cresol (BHT, 2 equiv) as radical
scavengers was employed to the [2+2]-cycloaddition of 1a
under standard reaction conditions (Scheme 2, Eqs. 2 and 3).
Experimental results demonstrated that the [2+2]-cycloaddition
of 1a was only suppressed by TEMPO. We speculated that the
interaction of K2S2O8 with BHT may generate the acidic KHSO4,
which could active the hydroxy of 1a to produce the allene
intermediate.
On the basis of the results obtained above, a tentative mecha-
nism was proposed in Scheme 3. Initially, sulfate radical anion
(.OSOÀ3 ), generated in situ from the process thermolysis of
K2S2O8, activated the hydroxy of 1a to afford HSO-4 which could
ionized a hydrion. Subsequently, the proton of HSO-4 induced the
losing of the hydroxy of 1a was followed by nucleophilic attack
by the oxygen of the carbonyl group on the alkynyl to obtain the
allenylic ester A along with benzyl alcohol. Ultimately, the inter-
molecular dimerization of the allenylic ester A afforded the highly
substituted cyclobutane 2a probably through the concerted
: R2 = 4-NO2, Ar = 4-Cl-C6H4 (63%) b
2v (79%)
a
All reactions were performed on 0.2 mmol 1 with 2.0 equiv K2S2O8 in MeCN
(2 mL) at 60 °C under air for 7–15 h.
b
2.0 equiv Na2S2O8 were used.
O
O
O O
KHSO4 (2 equiv)
(1)
(2)
MeCN, 60 o
C
Ph
Ph
Ph
Ph
2a, 64%
O
O
O
TEMPO (2 equiv)
K2S2O8 (2 equiv)
O
Ph
O O
2
Ph
Ph
MeCN, 60 o
C
Ph
Ph
OH
Ph
Ph
O
1a
2a, 0%
[
p2s
+
p
2a] or radical process [14].
O
In conclusion, we have developed a metal-free and effective
BHT (2 equiv)
K2S2O8 (2 equiv)
method for the synthesis of polysubstituted cyclobutanes from
readily available benzyl-2-(3-hydroxypropynyl)-benzoates involv-
ing allenylic ester intermediates. The advantages of this cycloaddi-
tion include environmentally friendly conditions, the wide range of
substrate scope and high regioselectivity. Application of symmetric
cyclobutane derivatives to complex polycyclic compounds and axis
chiral ligands is on the way.
O O
(3)
MeCN, 60 o
C
Ph
Ph
Ph
Ph
2a, 74%
Scheme 2. Preliminary Mechanism Study.
Please cite this article in press as: Zhu H.-T., et al.. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.10.098

4
H.-T. Zhu et al. / Tetrahedron Letters xxx (2016) xxx–xxx
Tetrahedron Lett.. 2001;42:2497–2499;
2-
-
S2O8
2
SO4
(d) Tsai LL, Lee FP, Wu CC, Duh CY, Ishikawa T, Chen YC, Seki H, Chen JJ. Planta
Med.. 2005;71:535–542;
SO4- + 1a
(e) Vilaine JP, Thollon C, Villenueve N, Peglion JL. Eur. Heart J. Suppl..
2003;5:26–35.
Ph
O
O
[2] (a) Coote SC, Pothig A, Bach T. Chem. Eur. J.. 2015;21:6906–6912;
¯
O
Ph
(b) Rasik CM, Brown MK. Angew. Chem., Int. Ed.. 2014;53:14522–14526;
(c) Xu Y, Conner ML, Brown MK. Angew. Chem., Int. Ed.. 2015;54:11918–11928;
(d) Du J, Skubi KL, Schultz DM, Yoon TP. Science. 2014;344:392–396;
(e) Du J, Yoon TP. J. Am. Chem. Soc.. 2009;131:14604–14605;
(f) Duan G-J, Ling J-B, Wang W-P, Luo Y-C, Xu P-F. Chem. Commun..
2013;49:4625–4627;
HSO4
O
Ph
Ph
Ph
Ph
OH
OH
1a
H+
(g) Wu B-Q, Wu G-S. Chin. J. Org. Chem.. 1990;10:106–116.
[3] (a) Siebert MR, Osbourn JM, Brummond KM, Tantillo DJ. J. Am. Chem. Soc..
2010;132:11952–11966;
(b) Lu P, Ma SM. Chin. J. Chem.. 2010;28:1600–1606;
(c) Gulías M, Collado A, Trillo B, López F, Oñate E, Esteruelas MA, Mascareñas JL.
J. Am. Chem. Soc.. 2011;133:7660–7663;
PhCH2OH, H+
(d) Burke EG, Schomaker JM. Angew. Chem., Int. Ed.. 2015;54:12097–12101;
(e) Mei L-Y, Wei Y, Tang X-Y, Shi M. J. Am. Chem. Soc.. 2015;137:8131–8137;
(f) Hu H, Wang Y, Qian D, Zhang Z-M, Liu L, Zhang J. Org. Chem. Front..
2016;3:759–763;
O
O
O
O O
π
π
[
+
2a] or radical
2s
O
[2+2]-cycloaddition
(g) Jiang X, Cheng X, Ma S. Angew. Chem., Int. Ed.. 2006;45:8009–8013.
[4] (a) Ishihara K, Fushimi M. J. Am. Chem. Soc.. 2008;130:7532–7533;
(b) Schmidt VA, Hoyt JM, Margulieux GW, Chirik PJ. J. Am. Chem. Soc..
2015;137:7903–7914;
(c) Russell SK, Lobkovsky E, Chirik PJ. J. Am. Chem. Soc.. 2011;133:8858–8861.
[5] (a) Takenaka Y, Ito H, Iguchi K. Tetrahedron. 2007;63:510–513;
(b) Enomoto K, Oyama H, Nakada M. Chem. Eur. J.. 2015;21:2798–2802;
(c) Schotes C, Bigler R, Mezzetti A. Synthesis. 2012;44:513–526.
[6] (a) Fan B-M, Li X-J, Peng F-Z, Zhang H-B, Chan ASC, Shao Z-H. Org. Lett..
2010;12:304–306;
Ph
Ph
Ph
Ph
Ph
Ph
2a
A
Scheme 3. Proposed Mechanism.
(b) López-Carrillo V, Echavarren AM. J. Am. Chem. Soc.. 2010;132:9292–9294;
(c) Nishimura A, Ohashi M, Ogoshi S. J. Am. Chem. Soc.. 2012;134:15692–15695;
(d) Noucti NN, Alexanian EJ. Angew. Chem., Int. Ed.. 2015;54:5447–5450.
[7] (a) Vallavoju N, Selvakumar S, Jockusch S, Sibi MP, Sivaguru J. Angew. Chem., Int.
Ed.. 2014;53:5604–5608;
Acknowledgments
We gratefully acknowledge the financial support of this work
by the Education Department of Shaanxi Province Key Laboratory
Project (15JS006), Ph.D. scientific research projects of Baoji Univer-
sity of Arts And Sciences (ZK15045 and ZK16060), and a China
Postdoctoral Science Foundation funded project (2016M592826).
(b) Brimioulle R, Guo H, Bach T. Chem. Eur. J.. 2012;18:7552–7560;
(c) Aikawa K, Hioki Y, Shimizu N, Mikami K. J. Am. Chem. Soc..
2011;133:20092–20095.
[8] (a) Muratore ME, Homs A, Obradors C, Echavarren AM. Chem. Asian J..
2014;9:3066–3082;
(b) Gonzlez AZ, Benitez D, Tkatchouk E, Goddard WA, Toste FD. J. Am. Chem. Soc..
2011;133:5500–5507.
[9] (a) Lewis FD, Barancyk SV. J. Am. Chem. Soc.. 1989;111:8653–8661;
(b) Conner ML, Xu Y, Brown MK. J. Am. Chem. Soc.. 2015;137:3482–3485;
A. Supplementary data
(c) Barluenga J, Alvarez-Pérez M, Wuerth K, Rodríguez F, Faaanás FJ. Org. Lett..
2003;5:905–908.
[10] Kitagaki SJ, Okumura YK, Mukai C. Tetrahedron. 2006;62:10311–10320.
[11] Tejedor D, Méndez-Abt G, González-Platas J, Ramírez MA, García-Tellado F.
Chem. Commun. 2009;2368–2370.
¯
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.10.
098.
[12] Rao WD, Susanti D, Chan PWH. J. Am. Chem. Soc.. 2011;133. 15248-15241.
[13] CCDC 1422313 (2a) contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[14] Murakami M, Matsuda T, Krause N. In: Hashmi ASK, editor. Modern Allene
Chemistry, vol. 2. Wiley-VCH; 2004:727–781.
References and notes
[1] (a) Dembitsky VM. J. Nat. Med.. 2008;62:1–33;
(b) Jiménez-Osés G, Corzana F, Busto JH, Pérez-Fernández M, Peregrina JM,
Avenoza A. J. Org. Chem.. 2006;71. 1869-187;
(c) Fujiwara Y, Naithou K, Miyazaki T, Hashimoto K, Mori K, Yamamoto Y.
Please cite this article in press as: Zhu H.-T., et al.. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.10.098