Cu-based carbene involved in a radical process: A new crossover reaction to construct γ-peroxy esters and 1,4-dicarbonyl compounds

Article abstract of DOI:10.1039/c5cc05183e

Through merging Cu-based carbenes in a radical process, a novel crossover reaction has been successfully established, leading to the facile and efficient syntheses of various γ-peroxy esters and 1,4-dicarbonyl compounds. Considering that both Cu-based carbene complexes and radicals are extremely reactive, and therefore exist only in extraordinarily low concentrations, the high selectivity of this coupling reaction is unusual.

Full text of DOI:10.1039/c5cc05183e

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: J. Jiang, J. Liu, L.
Yang, Y. Shao, J. Cheng, X. Bao and X. wan, Chem. Commun., 2015, DOI: 10.1039/C5CC05183E.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/chemcomm

Please do not adjust margins
ChemComm
Page 1 of 4
View Article Online
DOI: 10.1039/C5CC05183E
Journal Name
COMMUNICATION
Cu-Based Carbene Involved in a Radical Process: A New Crossover
Reaction to Construct γ-Peroxy Ester and 1,4-Dicarbonyl
Compounds
Received 00th January 20xx,
Accepted 00th January 20xx
Jiewen Jiang,a,§ Jiajun Liu,a,§ Ling Yang,a Ying Shao,b Jiang Cheng,b Xiaoguang Bao*,a and Xiaobing
DOI: 10.1039/x0xx00000x
Wan*,a
www.rsc.org/
undoubtedly broaden the utility of Cu carbene transfer reactions.
From a synthetic perspective, it also provides a simple method for
the concurrent installation of peroxy9 and ester functionalities, both
of which are common structural motifs in a wide range of valuable
organic molecules.
Through merging Cu-based carbene in a radical process, a novel
crossover reaction has been successfully established, leading to
the facile and efficient syntheses of various γ-peroxy esters
compounds and 1,4-dicarbonyl compounds. Considering both Cu-
based carbene complexes and radicals are extremely reactive, and
therefore exist only in extraordinarily low concentrations, the high
selectivity of this coupling reaction is unusual.
Scheme 1. Copper Carbene Complexes Involved Reaction.
Transition-metal-based carbene complexes have proven in the past
few decades to be highly efficient intermediates in various organic
synthesis.1 Among them, the copper carbene complexes,2 which are
mainly generated from copper-induced decomposition of diazo
compounds, have been extensively employed in transformations
such as X-H insertion,3a-c cross-coupling,3d-f cyclization and ylide
reactions.3g-I, 4 Copper carbene complexes have also been found to
play a key role in the cyclopropanation of styrenes with diazo
compounds.4 In this transformation, the Cu(I) complexes are often
proposed to be the catalytically active species (Scheme 1a).5
The pilot reaction set-up comprised styrene (1a) and ethyl
diazoacetate (2a) in the presence of Cu(acac)2 (10 mol%), TBHP
Despite the versatile reactivity of Cu-carbene complexes, little
attention has been paid to their potential in crossover reactions
with radicals.6 This is primarily due to the formidable
chemoselectivity challenge posed by the fact that both Cu-based
carbene complexes and radicals are extremely reactive, and
therefore exist only in extraordinarily low concentrations. Recently,
we developed a novel tandem reaction to construct various β-ester-
γ-amino ketones involving the cross-coupling between Co-based
carbene radical7 and α-aminoalkyl radicals.8 Herein, we envision an
unprecedented crossover reaction between a Cu carbene generated
in situ from copper complex and ethyl diazoacetate and the t-
BuOO• radical to afford γ-peroxy esters (Scheme 1b). This would
(tert-butyl
hydroperoxide,
2.9
equiv.)
and
1,4-
diazabicyclo[2.2.2]octane (DABCO, 2.0 equiv.) in iPrOH. Stirring this
o
mixture at 70 C for 1 h afforded the desired product ethyl 4-(tert-
butylperoxy)-4-phenylbutanoate (3a) in 61% yield, which could be
further improved to 76% if Cu(acac)2 was replaced with
.
Cu(NO3)2 3H2O, while the side product ethyl 4-oxo-4-
phenylbutanoate was isolated in the yield of 18% generated from
the unavoidable Komblum-DeLaMare rearrangement (For more
details, see Table S1, Supporting Information). The reaction could
be performed under atmospheric conditions, indicating its
insusceptibility to both oxygen and moisture, and could be easily
scaled up to 15 mmol with no significant loss in product formation
efficiency (entry 10, Table S1).
a.Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, Suzhou 215123,
P. R. China.Fax: (+86) 512-65880334; Tell: (+86) 512-65880334; E-mail:
xgbao@suda.edu.cn; wanxb@suda.edu.cn
A variety of substituted styrenes were then tested under the
optimal reaction conditions identified above. As shown in Scheme 2,
the electronic properties of the functional groups on the phenyl ring
in most cases did not produce a significant impact on the reaction
efficiency. For example, ether, ester, sulfonate and halogens were
all shown to be well tolerated. The noteworthy exception was
b.Jiangsu Key Laboratory of Advanced Catalytic Materials and
Technology,Changzhou University, Changzhou, 213164, China
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 4
COMMUNICATION
Journal Name
nitrile, whose strong electron-withdrawing ability might have three radical adducts 6a-8a (Scheme 5), which conseqVuieewntAlryticimle Opnlileinde
DOI: 10.1039/C5CC05183E
facilitated the subsequent DABCO-promoted Kornblum–DeLaMare the role of 6b-8b as the key mechanistic intermediates in this
rearrangement10 of the desired peroxy product into a γ-ketoester, transformation.
resulting in the lower yield of 3f. Ortho-substitution of styrenes did
not negatively affect the formation of product 3n. Unfortunately,
Scheme 4. Investigation on Reaction Mechanism.
aliphatic alkene was not suitable reaction partner for this
transformation and no desired product 3o was detected in the
reaction mixture.
Scheme 2. Scope of Olefins a
Scheme 5. Trapping of Radical Intermediates by TEMPO.
a
Since the existence of a redox cycle between the Cu(II) and Cu(I)
species in the presence of TBHP,4e computational studies were
carried out to address the question: which Cu species is more ready
to activate 2a to afford a Cu-carbene complex, Cu(I) or Cu(II)? The
energy profile for the Cu(I) species, CuNO3-DABCO, promoted
activation of 2a to afford a Cu-carbene intermediate was shown in
Figure 1. The predicted energy barrier for breaking the C-N bond of
2ato release a dinitrogen is only 6.0 kcal/mol relative to the
separated 2a + CuNO3-DABCO. After the leaving of a dinitrogen, the
Cu-carbene intermediate (INT2) is formed, which is exothermic by
21.1 kcal/molrelative to 2a + CuNO3-DABCO. For the Cu(II) species,
Cu(NO3)2-DABCO, catalyzed activation of 2ato form a Cu-carbene
intermediate, however, a much higher energy barrier (26.5 kcal/mol)
was obtained. Moreover, the resulted intermediate is
thermodynamically unstable (see SI, Figure S1). Thus, one can
conclude that the activation of 2a is readily promoted by Cu(I),
instead of Cu(II) species.
.
1 (0.5 mmol), 2a (1.0 mmol), Cu(NO3)2 3H2O (0.05 mmol), TBHP (1.45 mmol),
DABCO (1.0 mmol) in 3.0 mL i-PrOH was stirred at 70 °C for 1 h.
Several diazo compounds were also chosen to expand the
applicability of the strategy as shown in Scheme 3. Isopropyl 2-
diazoacetate, allyl 2-diazoacetate and dimethyl 2-diazomalonate
could all furnish the corresponding products with moderate yields.
Scheme 3. Scope of Diazo Compounds a
.
a1a (0.5 mmol), 2 (1.0 mmol), Cu(NO3)2 3H2O (0.05 mmol), TBHP (1.45 mmol),
DABCO (1.0 mmol) in 3.0 mL i-PrOH was stirred at 70 °C for 1 h.
To probe whether the peroxyester products resulted from the
cyclopropanation of styrene, ethyl 2-phenylcyclopropane-1-
carboxylate (5) was used as a model substrate. However, the
predicted 3a was not detected (Scheme 4), suggesting that the
involvement of a cyclopropane intermediate was unlikely. On the
other hand, the addition of TEMPO (2,2,6,6-tetramethyl-1-
piperidinyloxy) to the reaction depicted in Table S1 was observed to
suppress the product 3a formation and lead to the identification of
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 3 of 4
Journal Name
COMMUNICATION
t
Figure 1. Energy profile for the activation of 2a by Cu(I) species to barrier than the OA of BuOOH onto INT7, and hence, to form 6b.
View Article Online
DOI: 10.1039/C5CC05183E
form a Cu-carbene intermediate. H atoms on DABCO are omitted Subsequently, the yielded 6b would add to the styrene double bond
for clarity. Bond lengths are shown in Å.
to afford the benzylic radical 7b (Figure S8). Eventually, the target
product 3a could be furnished via the radical cross-couplingof 7b
The yielded Cu-carbene intermediate (INT2) may undergo
hydrogen abstraction reaction to afford an organocopper
intermediate. To determine the most energetically favourable
mechanistic pathway, three potential donor bonds, including the
O‒H of i-PrOH, that of TBHP, and the secondary C‒H of i-PrOH,
were subjected to computational studies. The results suggested
that abstracting the secondary hydrogen of i-PrOH (Figure S2)
enjoyed a much lower energy barrier (only 6 kcal/mol) than cleaving
the O‒H bond of i-PrOH or TBHP (Figure S3 and S4). The calculation
was consistent with the experimental finding that 3-pentanol,
which also contained a secondary hydrogen, could be used as a
substitute solvent (Scheme 6a), while the tertiary t-BuOH could not
(Scheme 6b). As further evidence, conducting the coupling reaction
in perdeuterated i-PrOH furnished α-deuterated 3a (Scheme 6c);
however, the use of TBHP-d1 and undeuterated i-PrOH mainly led
to the formation of undeuterated 3a (Scheme 6d).
t
and BuOO• generated in situ from a catalytic redox cycle of Cu(II)
and TBHP.12
Scheme 7. Proposed Mechanism for γ-peroxy-esters Formation
Reaction.
Scheme 6.Hydrogen Source Experiments.
Scheme 8. Construction of 1,4-Dicarbonyl Compoundsa
a1 (0.5 mmol), 2a (1.0 mmol), Cu(acac)2 (0.05 mmol), TBHP (1.45 mmol), DABCO
(1.5 mmol) in 3.0 mL i-PrOH was stirred at 70 °C for 1 h.
One may envision that the afforded Cu-carbene intermediate
might undergo cyclopropanation in the presence of styrene.4
Computational studies on the cyclopropanation reaction (Figure S5)
indicate that the energy barrier (7.4 kcal/mol) is 1.4 kcal/mol higher
than the most favourable H-abstraction from i-PrOH. Thus, the
intermediate INT7 is more feasible to be formed from the Cu-
carbene intermediate via H-abstraction reaction.
1,4-Dicarbonyl compounds are important building blocks for the
synthesis of heterocyclic compounds.13 We recently demonstrated
that the tert-butyl peroxy group could be readily converted to a
14
carbonyl via Komblum-DeLaMare rearrangement.8,
Combined
with the Cu-catalyzed coupling of styrene, TBHP and ethyl
diazoacetate we developed herein, this will allow facile preparation
of 1,4-dicarbonyl compounds. We theorized that the two reactions
could be performed in one pot by allowing DABCO used in the
radical coupling step to also serve as the base for the subsequent
rearrangement. To test this idea, the coupling reaction was
prolonged and the target product ethyl 4-oxo-4-phenylbutanoate
9a was isolated in 53% yield. It was then discovered that the yield
could be further increased to 72% by using Cu(acac)2 as the catalyst
t
In the presence of BuOOH, INT7 might beoxidized to INT15 via
an oxidative addition (OA) step (Figure S6). Subsequently, INT15
could undergo the homolytic cleavage of the Cu-C bond to generate
radical 6b (INT16) and a Cu(II) species. On the other hand, INT7
might participate in an intermolecular organocuprationreaction11
with styrene to generate INT19 (Figure S7). Computational studies
suggested that the formation of INT19 has a higher free-energy
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 4
COMMUNICATION
Journal Name
6
7
F. Li, L. Xiao, Y. Li, C. Chen and L. Liu, Chem. Commun., 2015,
(For more details, see Table S2, Supporting Information). The
synthetic application of this tandem reaction system could be
extended to a variety of 1,4-dicarbonyl compounds as shown in
Scheme 8.
View Article Online
51, DOI: 10.1039/c5cc03716f.
DOI: 10.1039/C5CC05183E
(a) T. Ikeno, I. Iwakura and T. Yamada, J. Am. Chem. Soc.,
2002, 124, 15152; (b) T. Ikeno, I. Iwakura, S. Yabushita and T.
Yamada, Org. Lett., 2002, 4, 517; (c) W. I. Dzik, X. Xu, X. P.
Zhang, J. N. H. Reek and B. de Bruin, J. Am. Chem. Soc., 2010,
132, 10891; (d) W. I. Dzik, X. P. Zhang and B. de Bruin, Inorg.
Chem., 2011, 50, 9896.
In summary, we have developed an unprecedented crossover
reaction that combined Cu carbene and radical intermediates in a
single catalytic cycle, allowing simple and efficient synthesis of
various γ-peroxy ester derivatives and 1,4-dicarbonyl compounds.
The result represents a significant technological advancement in the
fields of both copper carbene and radical chemistry. Further
investigations that aim to expand the repertoire of crossover
reactions between these two fields are currently underway in our
laboratory.
8
9
J. Zhang, J. Jiang, D. Xu, Q. Luo, H. Wang, J. Chen, H. Li, Y.
Wang and X. Wan, Angew. Chem. Int. Ed., 2015, 54, 1231.
(a) W. Adam, Peroxide Chemistry, Wiley-VCH, Weinheim,
2000; (b) G. H. Posner and P. M. O'Neill, Acc. Chem. Res.,
2004, 37, 397; (c) Y. Tang, Y. Dong and J. L. Vennerstrom,
Med. Res. Rev., 2004, 24, 425; (d) Z. Rappoport, The
Chemistry of Peroxides, Wiley, Chichester, 2006; (e) H. Yin, L.
Xu and N. A. Porter, Chem. Rev., 2011, 111, 5944; (f) W. Liu, Y.
Li, K. Liu and Z. Li, J. Am. Chem. Soc., 2011, 133, 10756; (g) B.
Schweitzer-Chaput, J. Demaerel, H. Engler and M. Klussmann,
Angew. Chem. Int. Ed., 2014, 53, 8737.
We gratefully acknowledge the Priority Academic Program
Development of Jiangsu Higher Education Institutions (PAPD) and
the Natural Science Foundation of China (No. 21272165). YS and XB
are supported by the Natural Science Foundation of China (NSFC
21302015 and 21302133).
10 (a) N. Kornblum and H. E. DeLaMare, J. Am. Chem. Soc., 1951,
73, 880; (b) K. C. Nicolaou, S. Totokotsopoulos, D. Giguère,
Y.-P. Sun and D. Sarlah, J. Am. Chem. Soc., 2011, 133, 8150;
(c) M. Zhang, N. Liu and W. Tang, J. Am. Chem. Soc., 2013,
135, 12434.
11 (a) K. K. Toh, Y.-F. Wang, E. P. J. Ng and S. Chiba, J. Am. Chem.
Soc., 2011, 133, 13942; (b) H. Saijo, M. Ohashi and S. Ogoshi,
J. Am. Chem. Soc., 2014, 136, 15158; (c) A. Bunescu, Q. Wang
and J. Zhu, Angew. Chem. Int. Ed., 2015, 54, 3132.
Notes and references
12 For reviews on the persistent radical effect, please see: (a) A.
§
Studer, Chem. Eur. J., 2001, 7, 1159; (b) H. Fischer, Chem.
These authors contribute equally.
Rev., 2001, 101, 3581; (c) A. Studer, Chem. Soc. Rev., 2004,
33, 267; for selected examples on radical cross-coupling,
please see: (e) W. Liu, Y. Li, K. Liu and Z. Li, J. Am. Chem. Soc.,
2011, 133, 10756, (f) J.-K. Cheng and T.-P. Loh, J. Am. Chem.
Soc., 2015, 137, 42; (g) J. Xuan, T.-T. Zeng, Z.-J. Feng, Q.-H.
Deng, J.-R. Chen, L.-Q. Lu, W.-J. Xiao and H. Alper, Angew.
Chem. Int. Ed., 2015, 54, 1625; (h) J. Xie, S. Shi, T. Zhang, N.
Mehrkens, M. Rudolph and A. S. K. Hashmi, Angew. Chem.
Int. Ed., 2015, 54, 6046; (i) J. L. Jeffrey, F. Petroni evid and
D. W. C. MacMillan, J. Am. Chem. Soc., 2015, DOI:
10.1021/jacs.5b05376; and ref 10, 14b-c.
1
(a) G. Bertrand, Carbene Chemistry: From Fleeting
Intermediates to Powerful Reagents, Taylor & Francis, 2002;
(b) H. G. Raubenheimer and S. Cronje, Chem. Soc. Rev., 2008,
37, 1998; (c) H. M. L. Davies and J. R. Manning, Nature, 2008,
451, 417; (d) M. P. Doyle, R. Duffy, M. Ratnikov and L. Zhou,
Chem. Rev., 2010, 110, 704; (e) H. M. L. Davies and D.
Morton, Chem. Soc. Rev., 2011, 40, 1857; (f) S.-F. Zhu and Q.-
L. Zhou, Acc. Chem. Res., 2012, 45, 1365; (g) D. Gillingham
and N. Fei, Chem. Soc. Rev., 2013, 42, 4918; (h) Q. Xiao, Y.
Zhang and J. Wang, Acc. Chem. Res., 2013, 46, 236; (i) R. A.
Moss and M. P. Doyle, Contemporary Carbene Chemistry,
Wiley, Hoboken, 2013.
13 (a) T. Eicher, S. Hauptmann and A. Speicher, The Chemistry of
Heterocycles, Wiley-VCH, 2003; (b) S. F. Kirsch, Org. Biomol.
Chem., 2006, 4, 2076; (c) F. Bellina and R.Rossi, Tetrahedron,
2006, 62, 7213.
14 (a) F. Zhang, P. Du, J. Chen, H. Wang, Q. Luo and X. Wan, Org.
Lett., 2014, 16, 1932; (b) P. Du, H. Li, Y. Wang, J. Cheng and X.
Wan, Org. Lett., 2014, 16, 6350; (c) C. Liu, E. Shi, F. Xu, Q. Luo,
2
3
X. Zhao, Y. Zhang and J. Wang, Chem. Commun., 2012, 48
10162.
(a) T. C. Maier and G. C. Fu, J. Am. Chem. Soc., 2006, 128
,
,
4594; (b) B. Liu, S.-F. Zhu, W. Zhang, C. Chen and Q.-L. Zhou, J.
Am. Chem. Soc., 2007, 129, 5834; (c) A. Suárez and G. C. Fu,
Angew. Chem. Int. Ed., 2004, 43, 3580; (d) Q. Xiao, Y. Xia, Y.
H. Wang, J. Chen and X. Wan, Chem. Commun., 2015, 51
,
Li, Y. Zhang and J. Wang, Angew. Chem. Int. Ed., 2011, 50
,
1214.
1114; (e) F. Ye, X. Ma, Q. Xiao, H. Li, Y. Zhang, J. Wang, J. Am.
Chem. Soc., 2012, 134, 5742; (f) C. V. Galliford, M. A. Beenen,
S. T. Nguyen and K. A. Scheidt, Org. Lett., 2003, 5, 3487; (g) S.
Son and G. C. Fu, J. Am. Chem. Soc., 2007, 129, 1046; (h) J.
Barluenga, G. Lonzi, L. Riesgo, L. A. López and M. Tomás, J.
Am. Chem. Soc., 2010, 132, 13200; (i) E. Lourdusamy, L. Yao
and C.-M. Park, Angew. Chem. Int. Ed., 2010, 49, 7963.
4
5
(a) M. P. A. Lyle and P. D. Wilson, Org. Lett., 2004, 6, 855; (b)
Z.-H. Xu, S.-N. Zhu, X.-L. Sun, Y. Tang and L.-X. Dai, Chem.
Commun., 2007, 1960; (c) C. Aranda, A. Cornejo, J. M. Fraile,
E. García-Verdugo, M. J. Gil, S. V. Luis, J. A. Mayoral, V.
Martinez-Merino and Z. Ochoa, Green Chem., 2011, 13, 983;
(d) T. Godau, S. M. Bleifuß, A. L. Müller, T. Roth, S. Hoffmann,
F. W. Heinemann and N. Burzlaff, Dalton Trans., 2011, 40
,
6547; (e) R. G. Salomon, J. K. Kochi, J. Am. Chem. Soc., 1973
,
95, 3300.
(a) W. R. Moser, J. Am. Chem. Soc., 1969, 91, 1135; (b) J. M.
Fraile, J. I. García, V. Martínez-Merino, J. A. Mayoral and L.
Salvatella, J. Am. Chem. Soc., 2001, 123, 7616.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins