Metal-free oxidative C(sp3)-H bond functionalization of alkanes and alkylation-initiated radical 1,2-aryl migration in α,α-diaryl allylic alcohols

Article abstract of DOI:10.1039/c4cc07654k

An oxidative C(sp³)-H bond functionalization of alkanes and alkylation-initiated radical 1,2-aryl migration in α,α-diaryl allylic alcohols using di-tert-butyl peroxide (DTBP) as the oxidant was established, which tolerates a wide range of simpl

Full text of DOI:10.1039/c4cc07654k

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Metal-free oxidative C(sp3)–H bond functionalization
of alkanes and alkylation-initiated radical 1,2-aryl
migration in a,a-diaryl allylic alcohols†
Cite this: Chem. Commun., 2015,
51, 599
Received 28th September 2014,
Accepted 13th November 2014
Jincan Zhao,a Hong Fang,a Ruichun Song,a Jie Zhou,a Jianlin Han*ab and Yi Pana
DOI: 10.1039/c4cc07654k
www.rsc.org/chemcomm
An oxidative C(sp3)–H bond functionalization of alkanes and alkylation- but scarcely studied. Several groups have reported C(sp3)–H
initiated radical 1,2-aryl migration in a,a-diaryl allylic alcohols using bond functionalization reactions for the C(sp2)–C(sp3) bond
di-tert-butyl peroxide (DTBP) as the oxidant was established, which formation by cross-dehydrogenative coupling (CDC) of simple
tolerates a wide range of simple alkane substrates and a,a-diaryl allylic alkanes with heteroaromatic compounds.10 And, our group also
alcohols for direct preparation of a-aryl-b-alkylated carbonyl ketones.
described an efficient pathway leading to cycloalkyl aryl sulfides
via DTBP-promoted oxidative C(sp3)–H bond thiolation of
The direct and selective functionalization of the sp3 C–H bonds, cycloalkanes under metal free conditions.11
which is a great challenge due to their high bond-dissociation
Intermolecular neophyl rearrangements, which could construct
energy (BDE) and low polarity, has attracted much attention in multiple chemical structures and reorganize molecular skeletons, have
recent years.1 Over the past few decades, significant advances have attracted broad attention in the synthetic chemistry community.12
been made in C(sp3)–H bond activation adjacent to heteroatoms,2 Recently, Tu,13 Sodeoka14 and Wu15 groups independently reported
double bonds,3 phenyl4 or electron-withdrawing groups.5 However, the preparation of b-trifluoromethyl ketones from allylic alcohols via
selective activation of the inactive C–H bonds of simple alkanes to 1,2-aryl migration (Scheme 1a). The Ji group has developed a silver-
generate C–C bonds is a more challenging target. In the past several catalyzed radical phosphonation of a,a-diaryl allylic alcohols via 1,2-aryl
years, cross-dehydrogenative-coupling (CDC) reactions forming migration of an aryl group involving new C(Ar)–C(sp3) and C(sp3)–P
C–C bonds by using transition metals as catalysts with simple bond formation in one step (Scheme 1b).16 Based on our long term
alkanes have been developed by Li and other groups.6 In addition, interest in the C–C bond formation via direct selective sp3 C–H bond
our group and others have explored transition metal-catalyzed functionalization of alkanes,9,11,17 we hypothesized that a neophyl-type
decarboxylative cross-coupling for C(sp2)–C(sp3) bond formation
with sp3 C–H bonds via radical addition–elimination processes.7
Recently, the Liu group explored free-radical addition/cyclization of
N-arylacrylamides with simple alkanes and free-radical addition/
cyclization of isocyanides with simple alkanes.8 Very recently, our
group described an example of Cu-catalyzed dehydrogenation–
olefination and esterification of the C(sp3)–H bond of cycloalkanes
with aromatic aldehydes in the presence of TBHP as the oxidant.9
Although considerable advances in this field have been made, the
development of more efficient and versatile strategies for C(sp3)–H
bond functionalization of simple alkanes under metal free
conditions is a more challenging task and highly appreciated
a School of Chemistry and Chemical Engineering, Nanjing University, Nanjing,
210093, China. E-mail: hanjl@nju.edu.cn; Fax: +86-25-83686133;
Tel: +86-25-83686133
b Institute for Chemistry & BioMedical Sciences, Nanjing University, Nanjing,
210093, China
† Electronic supplementary information (ESI) available: Experimental proce-
dures, full spectroscopic data for compounds 3 and copies of 1H NMR and 13C
Scheme 1 Radical-initiated neophyl rearrangement reactions.
Chem. Commun., 2015, 51, 599--602 | 599
NMR spectra. See DOI: 10.1039/c4cc07654k
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rearrangement would be applicable to this area. To the best of
With the optimized reaction conditions in hand, we proceeded
our knowledge, a neophyl-type rearrangement, driven by alkyl to explore the scope of the rearrangement reactions. Cyclohexane
radical addition to a,a-diaryl allylic alcohols, leading to a variety (2b) was used as the simple alkane reactant in the scope study of
of a-aryl-b-alkylated carbonyl ketones has never been reported. various a,a-diaryl allylic alcohols. As shown in Scheme 2, a series
The previous method of preparing a-aryl-b-alkylated carbonyl of symmetrical a,a-diaryl allylic alcohols with para and meta
ketones generally involves toxic chemicals, such as mercuric substituents on the aryl ring were examined (3ab–3ib). The
alkyl chloride (Scheme 1c).18 Herein, we report an unprece- process has a broad scope, tolerating a variety of groups such as
dented radical-initiated 1,2-aryl migration in a,a-diaryl allylic methyl, methoxy, phenoxy, halo and trifluoromethyl, giving good
alcohols with simple alkanes under metal free conditions to excellent yields of 70–90%. Compared with the a,a-diaryl allylic
(Scheme 1d).
alcohols associated with electron-donating groups, the reaction of
Our previous study showed that the alkyl radicals could be easily a,a-diaryl allylic alcohols substituted with electron-withdrawing
generated from simple alkanes using DTBP as an oxidant.9,11,17 groups gave better results, except 3db. A substrate containing a
Based on this achievement, the model reaction of a,a-diphenyl strong electron-withdrawing group (CF3) on the para position of
allylic alcohol 1a (0.3 mmol) and cyclohexane 2a (1 mL) was carried aryl groups also underwent the reaction smoothly, giving the
out in the presence of 2.0 equiv. of DTBP without any additive at corresponding product in 72% yield (3hb). In order to investigate
120 1C for 24 h. The reaction did happen, and afforded the expected the selectivity of aryl group migration, we turned our attention to
product of 3-cyclohexyl-1,2-diphenylpropan-1-one 3ab in moderate unsymmetrical a,a-diaryl allylic alcohols. For substrates 3j with
yield (72%, Table 1, entry 1). When the amount of DTBP was meta and para substituents, the more electron-deficient aryl group
increased to 3.0 equiv., a substantial improvement in the yield of migrated preferentially to give the major product 3jb and the
product 3ab to 90% was observed (entry 2). A further increase in the minor product 3jb0 in total 82% yield with a ratio of 2 : 1. This
loading of the oxidant did not result in any improvement (Table 1, selectivity suggested that the reaction might involve a radical
entry 3). The reaction could not take place at all if K2S2O8, BQ or O2 (‘‘neophyl’’) rearrangement process.12 The result of the reaction
(1 atm) was employed as the oxidant (entries 4–6). And the use of of 1k was similar to that of 1j, and the electron-deficient aryl
other oxidants such as H2O2 (30% aqueous solution), TBHP (5.5 M group migrates preferentially to give the major product 3kb.
in decane), TBPB, PhI(OAc)2, and BPO did not provide any better However, the reaction of 1l gave a different regioselectivity.
results (entries 7–11). When the reaction was performed at 100 1C,
almost no product was obtained (entry 12). No significant effect on
the yield of 3ab was found at 140 1C (entry 13). When the reaction
was performed under a N2 atmosphere, it did not result in any
improvement of the yield (87%, entry 14). Further optimization of
the conditions showed that the reaction could not proceed without
the use of DTBP as an oxidant (Table 1, entry 15).
Table 1 Optimization of reaction conditionsa
Entry
Oxidant (equiv.)b
t (1C)
Yieldc (%)
1
2
3
4
5
6
7
8
DTBP (2.0)
DTBP (3.0)
DTBP (4.0)
K2S2O8 (3.0)
BQ (3.0)
120
120
120
120
120
120
120
120
120
120
120
100
140
120
120
72
90
90
N.D.
N.D.
N.D.
Trace
Trace
85
O2 (1 atm)
d
H2O2 (3.0)
TBHP (3.0)
TBPB (3.0)
PhI(OAc)2 (3.0)
BPO (3.0)
DTBP (3.0)
DTBP (3.0)
DTBP (3.0)
—
9
10
11
12
13
14
16
60
68
Trace
89
87d
N.D.
Scheme 2 Reaction of 1 with cyclohexane. a Reaction conditions: 1
(0.3 mmol), cyclohexane (1 mL), DTBP (3.0 equiv.), 120 1C, 24 h. Isolated
yield based on 1. b The total yields of two isomers, and only major products
are shown. c The ratio was determined by 1H NMR analysis.
a
Reaction conditions: 1 (0.3 mmol), cyclohexane (1 mL), oxidant, 24 h.
b DTBP: di-tert-butyl peroxide, H2O2: 30% aqueous solution, TBHP: tert-butyl
hydroperoxide 5.5 M in decane, TBPB: tert-butyl peroxybenzoate, BPO:
benzoyl peroxide. Isolated yield based on 1a. d Under a N2 atmosphere.
c
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The aryl group with a methoxyl substituent migrated preferentially
to give the major product 3lb. The ortho-fluoro substituted
aryl rings migrated less effectively, which indicated that steric
hindrance had a detrimental effect on the migration. Also, the
fluorine atom in substrate 1l could partially stabilize the radical
during migration, which may be another reason for the formation
of the major methoxyl migrated product. A large scale reaction
was also carried out with 1.0 g of alcohol 1a, giving product 3ab in
a slightly low chemical yield of 85%.
As a continuation of this study on the radical-initiated
neophyl rearrangement reaction, the variation in the cycloalkane
part of the reaction was studied (Scheme 3). The reaction was found
to work well with a range of cycloalkanes, including cyclopentane,
cycloheptane and cyclooctane. Fortunately, they work well in the
system under the optimized conditions, and can react with various
a,a-diaryl allylic alcohols 1, giving the desired products 3aa–3fd in
Scheme 4 Radical-trapping experiment.
70–93% chemical yields. It is noteworthy that the reaction with
cyclooctane showed a higher efficiency than with smaller cyclo-
alkanes. Interestingly, cycloalkanes with high boiling points also
resulted in moderate yields of the products in benzene. For
example, when cyclododecane was used, the corresponding pro-
ducts were isolated in moderate yields (3ae and 3be). Then, the
open chain compound, 2,3-dimethylbutane, was also investigated,
and the corresponding products were obtained in a yield of 64%
with a ratio of 7 : 3 (3af :3af0). It is interesting that the reactions
showed evident regioselectivity, in which tertiary C–H of alkane
had a higher reactivity than primary C–H (3af and 3af0), which
is consistent with the stability order of the radicals. Finally, four
more branched alkanes, norbornane, adamantine, methylcyclo-
pentane and methylcyclohexane, were examined in the current
reaction. They also gave the corresponding product in good yields
(3ag–3aj). It was noted that the reaction of adamantine showed
good regioselectivity (3ah, 6 :1).
To investigate the mechanism of this reaction, a control experiment
of 1a and 2b in the presence of the radical-trapping reagent 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) was carried out (Scheme 4).
As expected, the formation of desired product 3ab was suppressed,
and only the TEMPO–cyclohexane adduct was observed (deter-
mined by LC-MS analysis). The results indicates that the
transformation may proceed via a radical course.
Based on the above results and literature reports,10,14,15,19 a plausible
catalytic cycle for the rearrangement is proposed (Scheme 5). At the
beginning, homolysis of DTBP gives tert-butoxy radical intermediate A
Scheme 3 Reaction of 1 with other simple alkanes. a Reaction conditions:
1 (0.3 mmol), 2 (1 mL), DTBP (3.0 equiv.), 120 1C, 24 h. Isolated yield based
on 1. b 2e (5.0 equiv.) in benzene (2.0 mL). c The ratio was determined by
1H NMR analysis. d The total yields of isomers.
Scheme 5 A plausible reaction mechanism.
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S. Y. Wang, Z. Y. Gu, X. Wang and S. J. Ji, Chem. Commun., 2014,
50, 6439; (k) D. Liu, C. Liu, H. Li and A. Lei, Chem. Commun., 2014,
50, 3623.
under the conditions of heating. Then, cyclohexane radical
intermediate B is generated via reaction of intermediate A and
cyclohexane 2b through a C–H bond cleavage. Subsequently, a
cyclohexane radical intermediate B reacts with allylic alcohol 1a
to generate radical C. Subsequent migration of the aryl group via
spiro[2,5]octadienyl radical D produces intermediate E. Finally,
the radical intermediate E reacted with tert-butoxy radical inter-
mediate A affording the desired product 3ab and t-BuOH.
In conclusion, we have developed an unprecedented DTBP-
promoted radical alkylation reaction of a,a-diaryl allylic alcohols
with simple alkanes under metal free conditions. It involves new
C(Ar)–C(sp3) and C(sp3)–C(sp3) bond formation in one step via a
C(sp3)–H bond functionalization and 1,2-aryl migration cascade
process. It tolerates a wide range of simple alkane substrates to
react with symmetrical and unsymmetrical a,a-diaryl allylic
alcohols for direct preparation of a-aryl-b-alkylated carbonyl
ketones in moderate to excellent yields. Notably, chemoselective
migration of the two different aryl groups was observed in this
reaction. This method not only enriched the content of neophyl
rearrangement, but also represented a new strategy for selective
functionalization of simple alkanes. Further investigation of this
strategy focusing on the selective activation of unactivated sp3
C–H bonds and concomitant 1,2-aryl migration in one single
step, to provide a novel strategy for increasing the efficiency of
C–H bond functionalization, is underway in our laboratory.
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (No. 21102071
and 21472082).
3 For selected recent examples of C(sp3)–H bond activation adjacent
to double bonds, see: (a) Z. Li and C. J. Li, J. Am. Chem. Soc., 2006,
128, 56; (b) E. Shi, Y. Shao, S. Chen, H. Hu, Z. Liu, J. Zhang and
X. Wan, Org. Lett., 2012, 14, 3384; (c) M. Sekine, L. Ilies and
E. Nakamura, Org. Lett., 2013, 15, 714; (d) X. Zhang, M. Wang,
P. Li and L. Wang, Chem. Commun., 2014, 50, 8006.
4 For selected recent examples of C(sp3)–H bond activation adjacent to
phenyls, see: (a) Z. Li, L. Cao and C.-J. Li, Angew. Chem., Int. Ed., 2007,
46, 6505; (b) S. Guin, S. K. Rout, A. Banerjee, S. Nandi and B. K. Patel,
Org. Lett., 2012, 14, 5294; (c) L. Niu, H. Yang, D. Yang and H. Fu, Adv.
Synth. Catal., 2012, 354, 2211; (d) S. K. Rout, S. Guin, K. K. Ghara,
A. Banerjee and B. K. Patel, Org. Lett., 2012, 14, 3982; (e) Z. Yin and
P. Sun, J. Org. Chem., 2012, 77, 11339; ( f ) S. K. Rout, S. Guin, A. Banerjee,
N. Khatun, A. Gogoi and B. K. Patel, Org. Lett., 2013, 15, 4106;
(g) H. Yang, H. Yan, P. Sun, Y. Zhu, L. Lu, D. Liu, G. Rong and
J. Mao, Green Chem., 2013, 15, 976; (h) Q. Xue, J. Xie, H. Li, Y. Cheng
and C. Zhu, Chem. Commun., 2013, 49, 3700; (i) H. Liu, G. Laurenczy,
N. Yan and P. J. Dyson, Chem. Commun., 2014, 50, 341; ( j) S.-L. Zhou,
L.-N. Guo, S. Wang and X.-H. Duan, Chem. Commun., 2014, 50, 3589.
5 For selected recent examples of C(sp3)–H bond activation adjacent
to electron-withdrawing groups, see: (a) Z. Li and C. J. Li, J. Am.
Chem. Soc., 2005, 127, 3672; (b) N. Borduas and D. A. Powell, J. Org.
Chem., 2008, 73, 7822; (c) H. Wang, L. N. Guo and X. H. Duan, Chem.
Commun., 2013, 49, 10370.
6 For selected recent examples of C(sp3)–H bond activation via CDC
reactions, see: (a) Y. Zhang and C. J. Li, Eur. J. Org. Chem., 2007,
4654; (b) G. Deng, L. Zhao and C. J. Li, Angew. Chem., Int. Ed., 2008,
47, 6278; (c) C. J. Li, Acc. Chem. Res., 2008, 42, 335; (d) G. Deng and
C. J. Li, Org. Lett., 2009, 11, 1171; (e) X. Guo and C. J. Li, Org. Lett.,
2011, 13, 4977; ( f ) Y. Zhu and Y. Wei, Chem. Sci., 2014, 5, 2379.
7 (a) J. C. Zhao, H. Fang, J. L. Han and Y. Pan, Beilstein J. Org. Chem.,
2013, 9, 1718; (b) Z. Cui, X. Shang, X. F. Shao and Z. Q. Liu, Chem.
Sci., 2012, 3, 2853.
8 (a) Z. Li, Y. Zhang, L. Zhang and Z. Q. Liu, Org. Lett., 2014, 16, 382;
(b) Z. Li, F. Fan, J. Yang and Z. Q. Liu, Org. Lett., 2014, 16, 3396.
9 J. Zhao, H. Fang, J. Han and Y. Pan, Org. Lett., 2014, 16, 2530.
10 (a) G. Deng, K. Ueda, S. Yanagisawa, K. Itami and C. J. Li,
Chem. – Eur. J., 2009, 15, 333; (b) R. Xia, H. Y. Niu, G. R. Qu and
H. M. Guo, Org. Lett., 2012, 14, 5546; (c) A. P. Antonchick and
L. Burgmann, Angew. Chem., Int. Ed., 2013, 52, 3267; (d) R. Narayan
and A. P. Antonchick, Chem. – Eur. J., 2014, 20, 4568.
Notes and references
1 For selected reviews on C(sp3)–H bond functionalization, see:
(a) K. Godula and D. Sames, Science, 2006, 312, 67; (b) R. G. Bergman,
Nature, 2007, 446, 391; (c) H. M. L. Davies and D. Morton, Chem. Soc. Rev.,
2011, 40, 1857; (d) K. M. Engle, T. S. Mei, M. Wasa and J. Q. Yu, Acc. Chem.
Res., 2011, 45, 788; (e) C. Liu, H. Zhang, W. Shi and A. Lei, Chem. Rev.,
2011, 111, 1780; ( f ) T. Newhouse and P. S. Baran, Angew. Chem., Int. Ed.,
2011, 50, 3362; (g) S. Y. Zhang, F.-M. Zhang and Y. Q. Tu, Chem. Soc.
Rev., 2011, 40, 1937; (h) J. L. Roizen, M. E. Harvey and B. J. Du, Acc. Chem.
Res., 2012, 45, 911; (i) M. C. White, Science, 2012, 335, 807; ( j) G. Rouquet
and N. Chatani, Angew. Chem., Int. Ed., 2013, 52, 11726.
11 J. C. Zhao, H. Fang, J. L. Han, Y. Pan and G. G. Li, Adv. Synth. Catal.,
2014, 356, 2719.
12 (a) C. Ru¨chardt and R. Hecht, Chem. Ber., 1965, 98, 2471; (b) M. Tada,
K. Inoue and M. Okabe, Bull. Chem. Soc. Jpn., 1983, 56, 1420;
(c) C. S. A. Antunes, M. Bietti, G. Ercolani, O. Lanzalunga and
M. Salamone, J. Org. Chem., 2005, 70, 3884; (d) H. Egami, R. Shimizu,
Y. Usui and M. Sodeoka, Chem. Commun., 2013, 49, 7346.
13 Z. M. Chen, W. Bai, S. H. Wang, B. M. Yang, Y. Q. Tu and
F. M. Zhang, Angew. Chem., Int. Ed., 2013, 52, 9781.
14 H. Egami, R. Shimizu, Y. Usui and M. Sodeoka, Chem. Commun.,
2013, 49, 7346.
15 X. Liu, F. Xiong, X. Huang, L. Xu, P. Li and X. Wu, Angew. Chem., Int.
Ed., 2013, 52, 6962.
2 For selected recent examples of C(sp3)–H bond activation adjacent
to heteroatoms, see: (a) S. Pan, J. Liu, H. Li, Z. Wang, X. Guo and
Z. Li, Org. Lett., 2010, 12, 1932; (b) L. Chen, E. Shi, Z. Liu, S. Chen,
W. Wei, H. Li, K. Xu and X. Wan, Chem. – Eur. J., 2011, 17, 4085;
(c) R. Y. Tang, Y. X. Xie, Y. L. Xie, J. N. Xiang and J. H. Li, Chem.
Commun., 2011, 47, 12867; (d) J. C. Zhao, W. Zhou, J. L. Han, G. Li
and Y. Pan, Tetrahedron Lett., 2013, 54, 6507; (e) Z. Xie, Y. Cai, H. Hu,
C. Lin, J. Jiang, Z. Chen, L. Wang and Y. Pan, Org. Lett., 2013,
15, 4600; ( f ) D. Liu, C. Liu, H. Li and A. Lei, Angew. Chem., Int. Ed.,
2013, 52, 4453; (g) S. R. Guo, Y. Q. Yuan and J. N. Xiang, Org. Lett.,
2013, 15, 4654; (h) W. T. Wei, M. B. Zhou, J. H. Fan, W. Liu,
16 X. Q. Chu, Y. Zi, H. Meng, X. P. Xu and S. J. Ji, Chem. Commun., 2014,
50, 7642.
17 J. C. Zhao, H. Fang, P. Qian, J. L. Han and Y. Pan, Org. Lett., 2014,
16, 5342.
R. J. Song, Y. Liu, M. Hu, P. Xie and J. H. Li, Angew. Chem., Int. 18 B. Giese, J. He and W. Mehl, Chem. Ber., 1988, 121, 2063.
Ed., 2013, 52, 3638; (i) J. C. Zhao, H. Fang, W. Zhou, J. L. Han and 19 X. Q. Chu, H. Meng, Y. Zi, X. P. Xu and S. J. Ji, Chem. Commun., 2014,
Y. Pan, J. Org. Chem., 2014, 79, 3847; ( j) J. J. Cao, T. H. Zhu,
50, 9718.
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