C–C Bond Formation by Oxidative Ring-Opening Homocoupling of Cyclobutanols

Article abstract of DOI:10.1002/ejoc.201601505

The formation of a C(sp³)–C(sp³) bond by oxidative ring-opening homocoupling of cyclobutanols was explored. A broad scope of 1-substituted cyclobutanols were transformed into C(sp³)–C(sp³) bond-formation products by oxidative ring opening in good to high yields under exceptionally mild conditions in an open flask in just 30 s.

Full text of DOI:10.1002/ejoc.201601505

A Journal of
Accepted Article
Title: C-C Bond Formation via Oxidative Ring-opening Homo-coupling
of Cyclobutanol
Authors: Huiying Zeng, Pan Pan, Jinping Chen, Hang Gong, and
Chao-Jun Li
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601505
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601505
Supported by

10.1002/ejoc.201601505
European Journal of Organic Chemistry
COMMUNICATION
CC Bond Formation via Oxidative Ring-opening Homo-coupling
of Cyclobutanol
Huiying Zeng,*[a] Pan Pan,[a] Jinping Chen,[b] Hang Gong*[b] and Chao-Jun Li*[a],[c]
Abstract: A C(sp3)C(sp3) bond formation via oxidative ring-opening
homo-coupling of cyclobutanol is reported. A broad scope of 1-
substituted-cyclobutanols are transformed into C(sp3)C(sp3) bond
formation products via oxidative ring-opening in good to high yields
under exceptionally mild conditions with open flask in just 30 seconds.
Introduction
Selective CC bond activation is one of the most fundamental
processes in chemistry owing to its potential utility in organic
synthesis.[1] Furthermore, CC bond cleavage is one of the most
important reactions for reforming long chain alkanes and
degrading polymers and biomass.[2] Due to the strained cyclic
CC bonds, tertiary cycloalkanols as good precursors for
regiospecific synthesis of chain ketones via CC bond cleavage
were achieved.[3] Cyclopropanols are the most small ring
compounds, have been broadly used as useful synthons in
various coupling reactions.[4] Owing to a lower ring strain energy,
cyclobutanol is relatively more difficult than cyclopropanol.[5]
Some important achievments for oxidizing ring-opening of
cyclobutanol include: a) C(sp3)heteroatom bond formation
(Scheme 1a) (for example, Chalogen (F, Cl, Br, I) bond[6], CN
bond,[7] CS bond[8], CO bond[9]), b) C(sp3)C(sp) bond
formation[10] (Scheme 1b), c) C(sp3)C(sp2) bond formation[11]
(Scheme 1c). Despite all these important progresses, the efficient
formation of CC bond via CC bond activation of cyclobutanols,
especially more challenger C(sp3)C(sp3) formation, continues to
attract the interest of chemists. Herein we would like to report a
oxidative ring-opening C(sp3)C(sp3) homo-coupling for forming a
new σ-C(sp3)C(sp3) bond product under exceptionally mild
conditions with open flask in just 30 seconds (Scheme 1d).
Scheme 1. Ring-opening -C(sp3)Hetero, -C(sp3)C(sp) and -C(sp3)C(sp2)
bond formation VS ring-opening -C(sp3)C(sp3) bond formation
[a]
Prof. Dr. H.Y. Zeng, P. Pan and Prof.Dr. C.-J. Li
The State Key Laboratory of Applied Organic Chemistry, Lanzhou
University.
To begin our study, 1-phenylcyclobutanol was reacted with 2.5
equiv of MnO2 in acetonitrile and water at room temperature under
open flask (Table 1). Gratifyingly, a trace amount of the desired
homo-coupling product 1,8-diphenyloctane-1,8-dione was
obtained (Table 1, entry 1). Encouraged by this preliminary result,
we then examined different oxidants, and found that Mn(OAc)3
was beneficial to this reaction (Table 1, entry 2)[12], with the
desired product being obtained in 15% yield. However, strong
oxidizing reagents such as KMnO4, as well as organic oxidizing
reagent DDQ, did not produce any desired product at all (Table 1,
entries 3 and 4). Further investigation of the oxidants showed that
high valent cerium (IV) gave better results (Table 1, entries 5-7).
222 Tianshui Road, Lanzhou, Gansu, 730000 (China)
E-mail: zenghy@lzu.edu.cn; cj.li@mcgill.ca: http://www.cjlimcgill.ca/
J.P. Chen and Prof. Dr. H. Gong
College of Chemistry, Xiangtan University.
E-mail: hgong@xtu.edu.cn
[b]
[c]
Prof. Dr. C.-J. Li
Department of Chemistry and FQRNT Centre for Green Chemistry
and Catalysis, McGill University.
801 Sherbrooke St. W., Montreal, Quebec H3A 0B8 (Canada)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601505
European Journal of Organic Chemistry
COMMUNICATION
With CAN as oxidant, the desired product was obtained in 45%
yield (Table 1, entry 7). Increasing the reaction temperature to 40
˚C resulted in a slightly lower yield (Table 1, entry 8). When the
temperature was downed to 0˚C, an improved yield (73%) was
obtained (Table 1, entry 9). Then, we investigated different
solvents which revealed that it is less effective ether in acetonitrile
or water[13] alone as solvent (Table 1, entries10-11). In the use of
other co-solvent was also less effective (Table 1, entries12-14).
Both increasing or reducing the equiv of CAN, led to lower yields
of this reaction (Table 1, entries15-17). Prolonging the reaction
time, it also decreased the product yield (Table 1, entry18).
little effect on the outcome of the reactions, and the
corresponding1,8-diaryloctane-1,8-diones were obtained in good
to high yields in all cases (Table 2, 2a – 2j). While 1-
phenylcyclobutanol gave a high yield of the desired product
(Table 2, 2a), the presence of an electron-donating group (Table
2, 2b–2d) on different positions (para-, meta-, ortho-) of the phenyl
group had little effect for this reaction, and the corresponding
homo-coupling products were obtained in good to high yields. The
chloro-substituted phenyl group gave a same result under the
standard conditions (Table 2, 2e). The presence of a weak
electron-donating group on different positions of the phenyl group
had the similar results (Table 2, 2f-2g). With a more sterically
hindered substituent on the phenyl ring, 1-mesitylcyclobutanol
also gave the coupled product in high yield (Table 2, 2h). On the
other hand, the presence of a strong electron-withdrawing group
(Table 2, 2i) on the phenyl moiety
With the optimized conditions in hand, we then evaluated the
substrate scope at 0 ˚C using 2.5 equiv of CAN as the oxidant in
acetonitrile/H2O under open flask in only 30 seconds. As shown
in Table 2, the reaction proceeded efficiently with various aryl and
alkyl groups. Diverse substituents on the aryl groups had
was found to be less favorable to this transformation. It is
interesting to note that the use of a heteroarylcyclobutanol, 1-
(thiophen-2-yl)cyclobutanol, also led to the corresponding product
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601505
European Journal of Organic Chemistry
COMMUNICATION
in good yield (Table 2, 2j). Besides aryl substituted derivatives,
the 1-alkylcyclobutanols were found to be even more effective for
this transformation, giving the desired products in better yields
than with the 1-arylcyclobutanols (Table 2, 2k-2o). The different
ring sizes of the 1-cycloalkylcyclobutanols had the same results
for this reaction, high yields were obtained in all cases (Table 2,
2k-2l). The 1-linearalkylcyclobutanols with different chain length
also reacted very well (Table 2, 2m-2n), including the one with a
phenyl substituent at the terminal position of the chain (Table 2,
2o).
disubstituted-1,8-diketone from the oxidation of 1-substituted-
cyclobutanol. A tentative mechanism is proposed for this novel
process. The scope, mechanism and application of this
transformation is undergoing in our lab.
Experimental Section
A typical experimental procedure is as follows: cyclobutanol 1a (30 mg,
0.2mmol, 1.0 equiv) was loaded in a flask. A mixed solvent CH3CN/H2O
(0.8 mL : 0.8 mL) was then added, which was followed the addition of
cerium ammonium nitrate (274 mg, 0.5mmol, 2.5 equiv). The mixture was
stirred in an ice bath for 30 seconds, and then the reaction was quenched
by adding 10% sodium thiosulfate aqueous solution. The mixture was
extracted with ethyl acetate 3x20mL, and the combined organic extracts
were washed by brine, dried over Na2SO4, filtered, and concentrated. The
crude mixture was purified by flash chromatography on silica gel
(PE/EA=8:1) to give product 2a.
To explore the reaction mechanism, 1.5 equiv of TEMPO was
added with an attempt to trap the intermediate under the standard
conditions. Compound 3 was isolated in 55% yield, with no homo-
coupling product being detected (Scheme 2).
Based on this experimental result, a tentative mechanism is
proposed in Scheme 4: Initially, 1-phenylcyclobutanol reacts with
CAN via a single electron transfer process to form the oxygen free
radical intermediate A. Subsequently, with the ring strain as the
driving force, homolytic CC cleavage forms free radical B[14]
,
which homo-coupled rapidly to form the desired product (Scheme
3).
Acknowledgements
We thank the National Science Foundation of China (Nos.
21302073 and 21402168), the Fundamental Research Funds for
the Central Universities (lzujbky-2016-53) and Lanzhou University,
the Recruitment Program of Global Experts (to C.J.L.) for their
support of our research.
Keywords: cyclobutanol • homo-coupling • CC bond formation
[1]
For selected reviews, see: a) R. H. Crabtree, Chem. Rev. 1985, 85, 245;
b) P. Steenwinkel, R. A. Gossage, G. van Koten, Chem. Eur. J. 1998, 4,
759; c) B. Rybtchinski, D. Milstein, Angew. Chem. Int. Ed. 1999, 38, 870;
d) V. Ritleng, C. Sirlin, M. Pfeffer, Chem. Rev. 2002, 102, 173; e) M. E.
van der Boom, D. Milstein, Chem. Rev. 2003, 103, 1759; f) C. H. Jun,
Chem. Soc. Rev. 2004, 33, 610; g) A. Corma, S. Iborra, A. Velty, Chem.
Rev. 2007, 107, 2411; h) A. S. Goldman, Nature 2010, 463, 435; i) A.
Sattler, G. Parkin, Nature 2010, 463, 523; j) T. Seiser, T. Saget, D. N.
Tran, N. Cramer, Angew. Chem. Int. Ed. 2011, 50, 7740; k) G. Dong,
Topics in Current Chemistry 2014, Vol. 346 (Ed.: G. Dong); l) A.
Dermenci, J. W. Coe, G. Dong, Org. Chem. Front. 2014, 1, 567; m) I.
Marek, A. Masarwa, P.-O. Delaye, M. Leibeling, Angew. Chem. Int. Ed.
2015, 54, 414; n) M. Murakami, N. Ishida, J. Am. Chem. Soc. 2016,
ASAP, DOI: 10.1021/jacs.6b01656.
Scheme 2. Experiments for mechanistic elucidation with radical scavenger
[2]
[3]
[4]
A. Göpferich, Mechanisms of polymer degradation and elimination (Eds:
A. J. Domb, J. Kost, D. M. Wiseman, Handbook of Biodegradable
Polymers, Harwood Academic, Amsterdam, 1997, 451-471.
For selected reviews, see: a) L. Souillart, E. Parker, N. Cramer, Top.
Curr. Chem. 2014, 346, 163; b) I. Marek, A. Masarwa, P. Delaye, M.
Leibeling, Angew. Chem. Int. Ed. 2015, 54, 414; and ref 1m.
For selected reviews, see: a) D. H. Gibson, C. H. DePuy, Chem. Rev.
1974, 74, 605; b) I. Ryu, S. Murai, Houben−Weyl Methods of Organic
Chemistry; Thieme: Stuttgart, 1997; Vol. E17c, 1985; c) O. G.
Kulinkovich, Chem. Rev. 2003, 103, 2597; d) D. Rosa, N. Nithiy, A.
Orellana, Synthesis 2013, 45, 3199. For selected examples, see: e) I.
Ryu, M. Ando, A. Ogawa, S. Murai, N. Sonoda, J. Am. Chem. Soc. 1983,
105, 7192; f) S. Aoki, T. Fujimura, E. Nakamura, I. Kuwajima, J. Am.
Chem. Soc. 1988, 110, 3296; g) S. Aoki, E. Nakamura, Synlett 1990, 741;
h) T. Fujimura, S. Aoki, E. Nakamura, J. Org. Chem. 1991, 56, 2809; i) I.
Ryu, K. Matsumoto, Y. Kameyama, M. Ando, N. Kusumoto, A. Ogawa,
N. Kambe, S. Murai, N. Sonoda, J. Am. Chem. Soc. 1993, 115, 12330; j)
S.-K. Kang, T. Yamaguchi, P.- S. Ho, W.-Y. Kim, S.-K. Yoon,
Tetrahedron Lett. 1997, 38, 1947; k) S. Chiba, Z. Cao, S. A. A. E. Bialy,
Scheme 3. Tentative mechanism for the homo-coupling of 1-substituted-
cyclobutanol
In conclusion, we have discovered a CC bond formation via a
ring-opening homocoupling of cyclobutanols under mild reaction
conditions. The method allowed the direct formation of 1,8-
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601505
European Journal of Organic Chemistry
COMMUNICATION
K. Narasaka, Chem. Lett. 2006, 35, 18; l) Y.-F. Wang, S. Chiba, J. Am.
Chem. Soc. 2009, 131, 12570; m) D. Rosa, A. Orellana, Org. Lett. 2011,
13, 110; n) Y.-F. Wang, K. K. Toh, E. P. J. Ng, S. Chiba, J. Am. Chem.
Soc. 2011, 133, 6411; o) D. Rosa, A. Orellana, Chem. Commun. 2012,
48, 1922; p) B. B. Parida, P. P. Das, M. Niocel, J. K. Cha, Org. Lett. 2013,
15, 1780; q) K. Cheng, P. J. Walsh, Org. Lett. 2013, 15, 2298; r) D. Rosa,
A. Orellana, Chem. Commun. 2013, 49, 5420; s) N. Nithiy, A. Orellana,
Org. Lett. 2014, 16, 5854; t) Y. Li, Z. Ye, T. M. Bellman, T. Chi, M. Dai,
Org. Lett. 2015, 17, 2186; u) Z. Ye, M. Dai, Org. Lett. 2015, 17, 2190.
d) R. Ren, Z. Wu, Y. Xu, C. Zhu, Angew. Chem. Int. Ed. 2016, 55, 2866;
e) J. Yu, H. Yan, C. Zhu, Angew. Chem. Int. Ed. 2016, 55, 1143.
[11] a) N. I. Kapustina, L. L. Sikova, A. V. Ignatenko, G. I. Nikishin, Izvestiya
Akademii Nauk, Seriya Khimicheskaya 1993, 11, 1923; b) S. Tsunoi, I.
Ryu, Y. Tamura, S. Yamasaki, N. Sonoda, Synlett 1994, 1009; c) T.
Nishimura, S. Uemura, J. Am. Chem. Soc. 1999, 121, 11010; d) T.
Nishimura, S. Matsumura, Y. Maeda, S. Uemura, Chem. Comm. 2002,
50; e) T. Nishimura, S. Matsumura, Y. Maeda, S. Uemura, Tetrahedron
Lett. 2002, 43, 3037; f) S. Matsumura, Y. Maeda, T. Nishimura, S.
Uemura, J. Am. Chem. Soc. 2003, 125, 8862; g) A. Schweinitz, A.
Chtchemelinine, A. Orellana, Org. Lett. 2011, 13, 232; h) D. Rosa, A.
Chtchemelinine, A. Orellana, Synthesis 2012, 44, 1885; i) A. Ziadi, R.
Martin, Org. Lett. 2012, 14, 1266; j) N. Ishida, Y. Nakanishi, M. Murakami,
Angew. Chem. Ed. Int. 2013, 52, 11875.
[5]
[6]
DFT calculations have shown that the total C-C bond strain of
cyclopropanes is about 10.1 kcal/mol higher than that of cyclobutanes,
see: R. D. Bach, O. Dmitrenko, J. Am. Chem. Soc. 2004, 126, 4444.
a) P. Galatsis, S. D. Millan, T. Faber, J. Org. Chem. 1993, 58, 1215; b)
T. Hirao, T. Fujii, T. Tanaka, Y. Ohshiro, Synlett 1994, 845; c) M. G.
Vinogradov, L. S. Gorshkova, V. A. Ferapontov, A. V. Zinenkov, Izvestiya
Akademii Nauk, Seriya Khimicheskaya 1995, 4, 774; d) N. I. Kapustina,
L. L. Sokova, V. D. Makhaev, L. A. Petrova, G. I. Nikishin, Rus. Chem.
Bull. 1999, 48, 2080; e) C. S. A. Antunes, M. Bietti, O. Lanzalunga, M.
Salamone, J. Org. Chem. 2004, 69, 5281; f) B. M. Casey, C. A. Eakin, R.
A. Flowers, Tetrahedron Lett. 2009, 50, 1264; g) S. Ren, C. Feng, T.-P.
Loh, Org. Biomol. Chem. 2015, 13, 5105; h) H. Zhao, X. Fan, J. Yu, C.
Zhu, J. Am. Chem. Soc. 2015, 137, 3490; i) N. Ishida, S. Okumura, Y.
Nakanishi, M. Murakami, Chem. Lett. 2015, 44, 821; j) F.-Q. Huang, J.
Xie, J.-G. Sun, Y.-W. Wang, X. Dong, L.-W. Qi, B. Zhang, Org. Lett. 2016,
18, 684.
[12] Nikishin reported a single example that 1-methylcyclobutanol reacted
with Mn(OAc)3 in HOAc giving low yield (4%) of dimerization product,
see: a) N. L Kapustina, L. L. Sokova, G. L Nikishin, Izvestiya Akademii
Nauk. Seriya Khimicheskaya, 1996, 1306; b) N. I. Kapustina, G. I.
Nikishin, Izvestiya Akademii Nauk, Seriya Khimicheskaya, 1992, 2760.
[13] Rocek reported only one example that 1-methylcyclobutanol reacted with
CAN in H2O giving a low yield of dimerization product, see: K. Meyer, J.
Rocek, J. Am. Chem. Soc. 1972, 94, 1209.
[14] For selected examples of similar oxidation ring-opening of cycloalkanols
via single electron transfer, please see: a) J. Jiao, L. X. Nguyen, D. R.
Patterson, R. A. Flowers II, Org. Lett. 2007, 9, 1323; b) A. Ilangovan, S.
Saravanakumar, S. Malayappasamy, Org. Lett. 2013, 15, 4968; c) S.
Bloom, D. D. Bume, C. R. Pitts, T. Lectka, Chem. Eur. J. 2015, 21, 8060;
d) D. G. Kananovich, Y. A. Konik, D. M. Zubrytski, I. Järving, M. Lopp,
Chem. Commun. 2015, 51, 8349; e) J. Yu, H. Zhao, S. Liang, X. Bao, C.
Zhu, Org. Biomol. Chem. 2015, 13, 7924.
[7]
a) R. Ren, H. Zhao, L. Huan, C. Zhu, Angew. Chem. Int. Ed. 2015, 54,
12692; b) D. Wang, R. Ren, C. Zhu, J. Org. Chem. 2016, 81, 8043.
R. Ren, Z. Wu, C. Zhu, Chem. Comm. 2016, 8160.
[8]
[9]
H. Fujioka, H. Komatsu, A. Miyoshi, K. Murai, Y. Kita, Tetrahedron Lett.
2011, 52, 973.
[10] a) A. Ziadi, A. Correa, R. Martin, Chem. Comm. 2013, 49, 4286; b) S.
Wang, L.-N. Guo, H. Wang, X.-H. Duan, Org. Lett. 2015, 17, 4798; c) K.
Jia, F. Zhang, H. Huang, Y. Chen, J. Am. Chem. Soc. 2016, 138, 1514;
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601505
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Radical Homo-coupling
COMMUNICATION
Huiying Zeng*, Pan Pan, Jinping Chen,
Hang Gong* and Chao-Jun Li*
Page No. – Page No.
CC Bond Formation via Oxidative Ring-
opening Homo-coupling of Cyclobutanol
A C(sp3)C(sp3) bond was formed via oxidative ring-opening homo-coupling of
cyclobutanol. 1,8-disubstituentoctane-1,8-diones were obtained efficiently with
homo-coupling of 1-substituted-cyclobutanol.
This article is protected by copyright. All rights reserved.