Visible light-mediated arylalkylation of allylic alcohols through concomitant 1,2-aryl migration

Article abstract of DOI:10.1039/c4cc10321a

A photocatalytic process for selective arylalkylation of allylic alcohols with α-bromo diethyl malonate has been developed. The reaction provided a straightforward approach to synthesize α-aryl-β-alkylated ketones via unique 1,2-aryl migration. The procedure is highlighted by its operational simplicity and mild reaction conditions.

Full text of DOI:10.1039/c4cc10321a

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Visible Light-Mediated Arylalkylation of Allylic
Alcohols through Concomitant 1,2-Aryl Migration
Cite this: DOI: 10.1039/x0xx00000x
Hong-Li Huang, Hang Yan, Chao Yang* and Wujiong Xia*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
A photocatalytic process for selective arylalkylation of allylic aryl migration to achieve the difunctionalization of alkenes
alcohols with -bromo diethyl malonate has been developed. (Scheme 1, b).
The reaction provided straightforward approach to
synthesize -aryl- -alkylated ketones via unique 1,2-aryl
α
a
α
β
migration. The procedure is highlighted by its operational
simplicity and mild reaction conditions.
The alkene functional group is ubiquitous, and alkene
difunctionalization, that can introduce two functional groups
across a double bond, exemplifies a class of reactions with
significant synthetic potential.1 As a result, several valuable
strategies for difunctionalization of alkenes by transition-metal2
and photoredox3 catalysis have been successfully developed to
prepare versatile and fascinating compounds. Recently, aryl
allylic alcohols were found to be viable substrates for
difunctionalization of alkenes by transition-metal catalysis
(Scheme 1, a) or oxidative radical addition under heating,
which afforded α-aryl-β-alkylated ketones via 1,2-aryl
migration.4 However, these transformations suffer from the
drawbacks of harsh reaction conditions, such as high
temperature, high catalyst loading or limitation to the substrates.
Scheme 1 Reported difunctionalization of allylic alcohols and our
strategy.
Our initial investigation was carried out on the reaction of
aryl allylic alcohol 1a with α-bromo diethyl malonate 2, using
2,6-lutidine as base in the presence of fac-Ir(ppy)3 (5 mol%)
under visible light irradiation (blue LEDs). The reaction was
performed in CH3CN for 143 h at room temperature (Table 1,
entry 1). To our delight, a mixture of arylalkylation products
3a1 and 3a2 were isolated in 45% and 15% yields, respectively.
Such a result presented the first example of visible-light
Therefore,
a
mild and effective methodology for
difunctionalization of aryl allylic alcohol is still desirable.
Nowadays, the application of visible light photoredox
catalysis has emerged as a novel and powerful tool for chemical
transformations in organic chemistry, owing to its attractive
features of environmentally friendly, excellent functional group
tolerance, and high reactivity.5 The pioneering work from
Stephenson,6 MacMillan,7a and others7b,c, that utilized α-bromo
esters in various visible light-induced synthetic transformations,
have attracted our attention. We envisioned that if the reaction
was conducted by using aryl allylic alcohols as substrates, α-
bromo diethyl malonate as oxidative quenching reagent in the
presence of photoredox catalyst, the carbon-centered alkyl
radical generated from oxidative quenching process could be
captured by aryl allylic alcohols to initiate a subsequential 1,2-
photocatalytic arylalkylation of alkenes via
a
radical
addition/1,2-aryl migration process that inspired us to explore
in details. Therefore, optimization of the reaction conditions
was conducted by the screening of solvents, additives, and
photocatalysts using 1a and
2 as the representative substrates.
Other solvents, such as CH2Cl2, THF, DMF and DMSO, also
gave the desired products in 21%, 51%, 86%, and 89% yields,
respectively (Table 1, entries 2-5). Thus, DMSO was chosen as
the ideal solvent for the reaction. While 2,6-lutidine was
replaced by K2HPO4, Et3N, or K2CO3, the reaction was less
effective (Table 1, entries 6-8). The presence of 2.0 equivalents
of 2,6-lutidine proved to be more beneficial than 1.5, or 1.7
equivalents (Table 1, entries 9-10). Using 1 mol% of fac-
Ir(ppy)3 reduced the yield to 13% (Table 1, entry 11). Notably,
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no reaction was observed if Ru(bpy)3Cl2 or Eosin Y was served with related results shown in Table 2. The substituents R on
as photocatalysts (Table 1, entries 12-13). In this case, the aromatic rings, bearing both electron-donating and electron-
optimal reaction conditions were established on the treatment of withdrawing groups, were all smoothly transformed to the
1a (0.1 mmol, 0.1 M in DMSO) with
2 (0.2 mmol) in the corresponding α-aryl-β-alkylated ketones (3b-3i) in good to
presence of fac-Ir(ppy)3 (0.005 mmol) as catalyst and 2,6- excellent yields. Remarkably, when the alkene was substituted
lutidine as additive (0.2 mmol) under irradiation with a 1 W with a methyl group, the substrate was still tolerant with the
blue LEDs. Moreover, in the absence of fac-Ir(ppy)3 or light, no reaction conditions to afford the desired product containing
product was observed.
Table 1 Screening of reaction conditionsa
full-carbon quaternary center in good yield (3i).
Table 3 Photocatalytic arylalkylation reaction of unsymmetrical aryl
allylic alcoholsa
Entry
1
2
3
4
Photocatalyst
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
Ru(bpy)3Cl2
Eosin Y
Additive
Solvent
CH3CN
CH2Cl2
THF
Yieldb (%)
60
21
51
86
89
49
Trace
Trace
50
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine DMSO
K2HPO4
DMF
5
6
7
8
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Et3N
K2CO3
9c
10d
11e
12
13
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
85
13
N.R.
N.R.
a Reaction conditions: 1a (0.1 mmol, 0.1 M in solvent), 2 (0.2 mmol),
additive (0.2 mmol), fac-Ir(ppy)3 (0.005 mmol), under N2 atmosphere
b
irradiation with a 1 W blue LEDs at room temperature for 143 h.
c
d
Isolated total yield of 3a1 and 3a2. Additive (0.15 mmol), additive
(0.17 mmol), and e fac-Ir(ppy)3 (0.001 mmol) were used in the reaction,
respectively.
a All reactions are carried out under the standard conditions. b Isolated yield
only of major products, and the ratio of 3 to its isomer was > 25:1. c Isolated
total yield of 3 and its isomer, only major products are shown. d The ratio of
3 to its isomer was determined by 1H NMR analysis of the crude product. e
Isolated yield.
Table 2 Photocatalytic arylalkylation reaction of symmetrical diaryl
allylic alcoholsa
To further investigate the selectivity of the aryl migration
in this reaction, allylic alcohols bearing two different groups
were examined, which results are listed in Table 3. Substituents
at para, meta, or ortho position of the aryl groups were well
tolerated, e.g. 1j
transformed to the desired ketones 3j
,
1n
,
1o, and 1p, which were efficiently
3n 3o, and 3p with high
,
,
regioselectivity (>25:1), in which the electron-deficient groups
preferentially migrated. The reactions of methoxyphenyl
substrates (1j
with good yields than electron-deficient ones (1k
,
1m
,
1o, and 1s) were completed in a shorter time
1n 1q, and
-
l,
,
1r). On the other hand, ortho-substituted aryl rings migrated
less effectively than the phenyl group, regardless of an electron-
donating or electron-withdrawing (1o-1q) substituent, which
a Standard conditions: 1b-i (0.1 mmol, 0.1 M in DMSO), 2 (0.2 mmol), 2,6-
lutidine (0.2 mmol), fac-Ir(ppy)3 (0.005 mmol), irradiation with a 1 W blue
LEDs under N2 atmosphere at room temperature; isolated yield in
parentheses.
might be owing to the steric hindrance on the aryl ring.
Specially, when one of the two aryl groups was replaced by an
alkyl group, e.g. substrate 1s, the reaction still underwent
smoothly to give the sole product 3s in 54% yield with the 4-
Next we turned to test the scope of this arylalkylation
reaction. Therefore, symmetrical diaryl allylic alcohols (1b-1i)
were prepared and subjected to the optimal reaction conditions
2 | J. Name., 2012, 00, 1-3
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methoxyphenyl group migrated, which suggested a radical The visible light induced excited state, fac-*Ir(ppy)3, was
(“neophyl”) rearrangement pathway.4a,4c,8
oxidatively quenched by α-bromo diethyl malonate to afford
To demonstrate the potential applications of this protocol the electron-deficient radical and bromine ion along with fac-
in organic synthesis, a formal synthesis of (±)-sequirin D was IrIV(ppy)3.7 The radical
underwent intermolecular radical
performed (Scheme 2).9 Diaryl allylic alcohol 1t bearing 4- addition to aryl allylic alcohol
, leading to alkyl radical
methoxyphenyl groups was prepared through straightforward Then an intramolecular cyclization occured on the aromatic
pathways in three steps with very good yields, which was then ring to generate spiro[2,5]octadienyl radical . Subsequently,
reacted with α-bromo diethyl malonate to afford the key the radical 7 recovered its stable aryl structure and furnished the
2
5
5
1
6.
7
2
intermediate compound 3t in 76% yield under the standard benzyl radical
reaction conditions. According to the literature, 3t could be IrIV(ppy)3 was reduced by the radical
converted to (±)-sequirin D, which was an unusual carbon (ppy)3 and yield the desired product
skeleton norlignan with antigonatropic activity.9
8
through 1,2-aryl migration.4a,c, At last, fac-
Ⅲ
8
3
to regenerate fac-Ir
along with loss of a
proton.
Conclusions
In summary, we have developed a visible light-mediated
arylalkylation reaction for the synthesis of α-aryl-β-alkylated
ketones via 1,2-aryl migration from aryl allylic alcohols. This
novel photocatalytic approach is characterized by its
operational simplicity, excellent functional group tolerance, and
high yields under mild conditions. Selective migration of the
two different groups was observed in this reaction, in general,
electron-deficient groups migrated preferentially over electron-
rich groups, ortho-substituted aryl rings were reluctant to
migrate.
We are grateful for the financial supports from China
NSFC (Nos. 21272047, 21372055 and 21472030), SKLUWRE
(No. 2014DX01) and the Fundamental Research Funds for the
Central Universities (Grant No. HIT. BRETIV. 201310) and
HLJNSF (B201406).
Scheme 2 Formal Synthesis of (±)-Sequirin D.
Notes and references
State Key Lab of Urban Water Resource and Environment, the Academy
of Fundamental and Interdisciplinary Sciences, Harbin Institute of
Technology, Harbin 150080; Fax: (+86)-451-86403760; Email:
xyyang@hit.edu.cn (C. Y.); xiawj@hit.edu.cn (W. X.)
†Electronic Supplementary Information (ESI) available: Experimental
procedures and 1H and 13C NMR spectra for all new compounds. See
DOI: 10.1039/b000000x/
1. For recent review on alkene difunctionalization, see: (a) E. Merino, C.
Nevado, Chem. Soc. Rev., 2014, 43, 6598; (b) R. I. McDonald, G. S.
Liu, S. S. Stahl, Chem. Rev., 2011, 111, 2981; (c) H. Egami, M.
Sodeoka, Angew. Chem. Int. Ed., 2014, 53, 8294; (d) E. M. Beccalli,
G. Broggini, S. Gazzola, A. Mazza, Org. Biomol. Chem., 2014, 12
,
6767; (e) K. H. Jensen, M. S. Sigman, Org. Biomol. Chem., 2008,
6
,
4083.
Scheme 3 Proposed mechanism.
2. For recent alkene difunctionalization examples with metal-mediated,
see: (a) W. Kong, E. Merino, C. Nevado, Angew. Chem., Int. Ed.,
2014, 53, 5078; (b) B. W. Turnpenny, S. R. Chemler, Chem. Sci.,
In addition, a control experiment of 1b (Scheme 1, Ar1, R1=
Ph, R2 =H) and
2 in the presence of 2.2 equiv. of TEMPO was
2014,
Chem. Soc., 2013, 135, 18327; (d) R. M. Romero, T. H. Wöste, K.
Muñiz, Chem. - Asian J., 2014, , 972; (e) L. Xu, X. Q. Mou, Z. M.
5, 1786; (c) Y. Xie, J. Hu, P. Xie, B. Qian, H. Huang, J. Am.
carried out under the standard conditions for 50 h, and only
trace amount of desired product 3b was detected based upon
GC-MS analysis. Such a result suggests that the reaction
involves a diethyl malonate radical pathway. Accordingly, a
plausible mechanism of this reaction was depicted in Scheme 3.
9
Chen, S. H. Wang, Chem. Commun., 2014, 50, 10676; (f) X. X. Peng,
Y. J. Deng, X. L. Yang, L. Zhang, W. Yu, B. Han, Org. Lett., 2014,
16, 4650; (g) X. Xu, Y. Tang, X. Li, G. Hong, M. Fang, X. Du, J.
This journal is © The Royal Society of Chemistry 2012
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Org. Chem., 2014, 79, 446; (h) A. K. Singh, R. Chawla, T. Keshari,
V. K. Yadav, L. D. S. Yadav, Org. Biomol. Chem., 2014, 12, 8550.
3. For recent alkene difunctionalization examples with photoredox
catalysis, see: (a) S. H. Oh, Y. R. Malpani, N. Ha, Y. S. Jung, S. B.
Han, Org. Lett., 2014, 16, 1310; (b) K. Miyazawa, Y. Yasu, T. Koike,
Kong, M. Casimiro, E. Merino, C. Nevado, J. Am. Chem. Soc., 2013,
135, 14480; (e) W. Kong, M. Casimiro, N. Fuentes, E. Merino, C.
Nevado, Angew. Chem., Int. Ed., 2013, 52, 13086; (f) C. S. A.
Antunes, M. Bietti, G. Ercolani, O. Lanzalunga, M. Salamone, J. Org.
Chem., 2005, 70, 3884.
M. Akita, Chem. Commun., 2013, 49, 7249; (c) G. Dagousset, A. 9. (a) M. J. Begley, R. V. Davies, P. Henley-Smith, D. A. Whiting, J.
Carboni, E. Magnier, G. Masson, Org. Lett., 2014, 16, 4340; (d) B.
Sahoo, M. N. Hopkinson, F. Glorius, J. Am. Chem. Soc., 2013, 135
Chem. Soc., Perkin Trans., 1, 1978, 750; (b) M. P. Reddy, G. S. K.
Rao, J. Chem. Soc., Perkin Trans., 1, 1981, 2662; (c) D. M. Lynch,
W. Cole, J . Medicin. Chem., 1968, 11, 291.
,
5505; (e) R. Tomita, Y. Yasu, T. Koike, M. Akita, Angew. Chem., Int.
Ed., 2014, 126, 7272; (f) Y. Yasu, T. Koike, M. Akita, Angew. Chem.,
Int. Ed., 2012, 51, 9567; (g) T. Keshari, V. K. Yadav, V. P.
Srivastava, L. D. S. Yadav, Green Chem., 2014, 16, 3986.
4. (a) X. Liu, F. Xiong, X. Huang, L. Xu, P. Li, X. Wu, Angew. Chem.,
Int. Ed., 2013, 52, 6962; (b) H. Egami, R. Shimizu, Y. Usuiac, M.
Sodeoka, Chem. Commun., 2013, 49, 7346; (c) X. Q. Chu, Y. Zi, H.
Meng, X. P. Xu, S. J. Ji, Chem. Commun., 2014, 50, 7642; (d) R. J.
Song, Y. Q. Tu, D. Y. Zhu, F. M. Zhang, S. H. Wang, Chem.
Commun., 2015, 51, 749; (e) X. Mi, C. Wang, M. Huang, Y. Wu, Y.
Wu, Org. Biomol. Chem., 2014, 12, 8394; (f) Y. Li, B. Liu, H. B. Li,
Q. Wang, J. H. Li, Chem. Commun., 2015, 51, 1024; (g) J. Zhao, H.
Fang, R. Song, J. Han, Y. Pan, Chem. Commun., 2015, 51, 599; (h) X.
Chu, H. Meng, Y. Zi, X. P. Xu, S. J. Ji, Chem. Commun., 2014, 50
,
9718.
5. For recent reviews on visible light photoredox catalysis, see: (a) C. K.
Prier, D. A. Rankic, D. W. C. MacMillan, Chem. Rev., 2013, 113
,
5322; (b) L. Shi, W. Xia, Chem. Soc. Rev., 2012, 41, 7687; (c) J.
Xuan, W. J. Xiao, Angew. Chem., Int. Ed., 2012, 51, 6828; (d) J. M.
R. Narayanam, C. R. J. Stephenson, Chem. Soc. Rev., 2011,40, 102;
(e) A. E. Allen, D. W. C. MacMillan, Chem. Sci., 2012, 3, 633; (f) J.
W. Tucker, C. R. J. Stephenson, J. Org. Chem., 2012, 77, 1617; (g) D.
P. Hari, B. Kӧnig, Chem. Commun., 2014, 50, 6688; (h) T. P. Yoon,
ACS Catal., 2013,
Catal., 2014, , 355; (j) T. P. Yoon, M. A. Ischay, J. Du, Nat. Chem.,
2010, , 527.
3, 895; (i) D. A. Nicewicz, T. M. Nguyen, ACS
4
2
6. (a) C. J. Wallentin, J. D. Nguyen, P. Finkbeiner, C. R. J. Stephenson, J.
Am. Chem. Soc., 2012, 134, 8875; (b) J. D. Nguyen, J. W. Tucker, M.
D. Konieczynska, C. R. J. Stephenson, J. Am. Chem. Soc., 2011, 133
,
4160; (c) L. Furst, B. S. Matsuura, J. M. R. Narayanam, J. W. Tucker,
C. R. J. Stephenson, Org. Lett., 2010, 12, 3104; (d) J. W. Tucker, J. D.
Nguyen, J. M. R. Narayanam, S. W. Krabbe, C. R. J. Stephenson,
Chem. Commun., 2010, 46, 4985; (e) J. W. Tucker, J. M. R.
Narayanam, S. W. Krabbe, C. R. J. Stephenson, Org. Lett., 2010, 12
,
368.
7. (a) D. A. Nicewicz, D. W. C. MacMillan, Science 2008, 322, 77; (b) X.
J. Wei, D. T. Yang, L. Wang, T. Song, L. Z. Wu, Q. Liu, Org. Lett.,
2013, 15, 6054; (c) M. Neumann, S. Füldner, B. König, K. Zeitler,
Angew. Chem., Int. Ed., 2011, 50, 951; (d) T. Courant, G. Masson,
Chem. Eur. J., 2012, 18, 423.
8. For reviews and selected examples of aryl migration reactions, see: (a)
S. M. Bonesi, M. Fagnoni, Chem. Eur. J., 2010, 16, 13572; (b) P.
Gao, Y. W. Shen, R. Fang, X. H. Hao, Z. H. Qiu, F. Yang, X. B. Yan,
Q. Wang, X. J. Gong, X. Y. Liu, Y. M. Liang, Angew. Chem., Int. Ed.,
2014, 53, 7629; (c) Z. M. Chen, W. Bai, S. H. Wang, B. M. Yang, Y.
Q. Tu, F. M. Zhang, Angew. Chem., Int. Ed., 2013, 52, 9781; (d) W.
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