Reductive Aromatization of Quinols with B2pin2 as Deoxidizing Agent

Article abstract of DOI:10.1002/asia.202000064

We have demonstrated B₂pin₂ as superior deoxidizing agent for the reductive deoxygenation of quinol derivatives under basic conditions. A wide range of highly functionalized phenols were obtained in good yields including a complex drug molecule, which revealed the high functional group tolerance of this protocol.

Full text of DOI:10.1002/asia.202000064

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Accepted Article
Title: Reductive Aromatization of Quinols with B2pin2 as Deoxidizing
Agent
Authors: Bin Liu, Yin Xu, Zhibin Luo, and Jimin Xie
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Reductive Aromatization of Quinols with B2pin2 as Deoxidizing
Agent
Bin Liu,*[a][b] Yin Xu,[a] Zhibin Luo,[a] Jimin Xie*[a]
[a]
[b]
Dr. B. Liu, Y. Xu, Dr. Z. Luo, Prof. Dr. J. Xie
School of Chemistry and Chemical Engineering
Jiangsu University
Xuefu Road 301, Zhenjiang, 212013 (China)
E-mail: liub@ujs.edu.cn; xiejm@ujs.edu.cn
Dr. B. Liu
Jurong Ningwu New Material Development Co.,Ltd.
Zhenjiang, 212405 (China)
Supporting information for this article is given via a link at the end of the document.
Abstract: We have demonstrated B2pin2 as superior deoxidizing
agent for the reductive deoxygenation of quinol derivatives under
basic conditions. A wide range of highly functionalized phenols were
obtained in good yields including complex drug molecule which
revealed the high functional group tolerance of this protocol.
C-O bond, achieving nucleophilic substitution towards borate
ester. Alternatively, deoxygenation process with diboron
compounds is also available, requiring anchimeric assistance of
alkene to undergo Fernádez-type diborylation/B-O elimation[5] or
via six-membered ring[6] (followed by protodeboronation
sometimes[7]) to complete deoxygenation process (Scheme 2b)
wherein the olefin migration during this transformation is
inevitable. Parallelly, Song-type cascade borylation/B-O
elimation from propynols could also afford deoxygenated
structures (Scheme 2c).[8] Inspired by these works, we
envisaged that reductive aromatization of quinols could be
realized with B2pin2 as deoxidizing agent under basic conditions.
Quinols usually emerge as key units in various natural
products and drug molecules as exemplified by estrone or
eatradiol in steroids. Meanwhile, quinols represent highly
versatile intermediates in organic transformations like
cycloaddition,[1] Michael addition[2] and reductive aromatization[3].
The nucleophilic addition to quinone followed by reductive
aromatization provide an efficient protocol to introduce
functionalized phenols wherein classical coupling methods might
be hardly accessible. Indeed, such strategy had been employed
in the synthesis of C-aryl glycosides as successively reported by
Parker et. al.[3c, 3f, 3k] as shown in Scheme 1b. The successful
reductive aromatization relied on the use of Na2S2O4 as
reductant while NaBH4, Zn/AcOH, Al(Hg) would lead to
undesired side product.[3c] In this consider, it is always of
demand to develop straightforward and mild methods for the
selective reductive aromatization of quinols.
Scheme 2. Deoxygenation with organoboron compounds
The reaction was initially conducted with 1a and B2pin2
following conditions from our previous work of borylation on
propargylic alcohols,[5c] however, reductive deoxygenation of
quinol led to the product 2a in 65% yield in this case. Switching
alkali metal hydroxides to NaH slightly increased the yield to
70% (Entry 4, Table 1). Solvent effect was thereafter examined
and polar solvents like DMF and MeCN were verified to be
Scheme 1. Reductive aromatization of quinols in natural product synthesis
Boron compounds are mostly known as reducing agent
towards unsaturated C-C or C-heteroatom bonds. In case of
deoxygenation,[4] borohydride is crucial to drive the cleavage of
1
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10.1002/asia.202000064
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COMMUNICATION
inferior to DMSO, affording the product in 55% and 58% yield,
respectively. When conducted in THF, complex mixture was
observed. Improvements was achieved in DCE providing 2a in
80% yield. Further exploration of other typically employed alkali
salts or organic bases failed to deliver better outcomes (entries
10-14) wherein 1a were recovered.
observed with dihalogeno substrate 1s, treating with 1.5 equiv.
of B2pin2 resulted in mono-dehalogenation while fully reduction
to phenol 2i required 4.5 equiv. of reductant. Comparatively, if
switching halogen atom to C-3 position (1t), only reductive
aromatization observed under the standard condition while
bromine represents inert.
Table 1. Optimization of conditions[a]
Entry
1
Base
LiOHH2O
NaOH
KOH
Solvent
DMSO
DMSO
DMSO
DMSO
DMF
Yield(%)[b]
65
60
2
3
62
4
NaH
70
5
NaH
55
6
NaH
MeCN
THF
58
7
NaH
complex
65
8
NaH
Toluene
DCE
9
NaH
80
Scheme 3. Substrate scope (conditions: 1 (0.2 mmol) and B2pin2 (0.3 mmol)
was carried out in solvent (1 mL) at 70 °C in the presence of base (0.26 mmol)
for 12 h. Isolated yield.)
10
11
12
13
14
t-BuOK
t-BuOLi
Cs2CO3
DABCO
DBU
DCE
20
DCE
31
DCE
59
DCE
60
DCE
35
[a] The reaction of 1a (0.2 mmol) and B2pin2 (0.3 mmol) was carried out in
solvent (1 mL) at 70 °C in the presence of base (0.26 mmol) for 12 h. [b]
Isolated yield.
Thereafter we assessed the substrate scope with the optimal
conditions in hand (Scheme 3). Various arylethynyl substituted
quinols bearing electron-donating (2e-2f) and electron-
withdrawing (2b-2d) groups well participated in the reductive
deoxygenation providing functionalized phenols in good yields
ranging from 66% to 92%. Meanwhile, alkylethynyl substituted
quinols reacted efficiently to give desired products (2g-2h) with
intact triple bonds. The unsaturated bonds on substrates were
found not necessary from the outcomes of 2i-2m. It is notable
that substitutions on quinol moiety do not obstruct this
transformation although slightly lower yield was obtained (2k).
The naphthoquinol substrate displayed lower reactivity,
delivering the product 2n in 41% yield with starting material
recovered. We then investigated the reaction of complex
molecules estrone quinol 2o. To our delight, site-selective
reduction on quinol generated estrogen in 43% wherein the
carbonyl group remained silent during this process.
Scheme 4. Reaction with halogen-substituted compounds
Based on the aforementioned observations and previous
reports,[5-9] we propose a mechanism shown in Scheme 3. Non-
halogen-substituted
1 would undergo borylation on ɑ,β-
Some interesting results were observed as we screening
halogen-substituted compounds (Scheme 4). When subjecting
1p-1r to the standard conditions, dehalogenate quinols were
produced in high yields instead of reductive aromatization.
Moreover, if we doubled the amount of reductant and base,
unsaturated carbonyl moiety[10] assisted by neighboring hydroxyl
group. Following B-O elimination and aromatization give product
2. In case of halogen-substituted 1, the initial borylation
happened on the bromo-substituted double bond which is more
electron-deficient. B-Br elimination which is triggered by the
borate moeity[9] dominated the following step instead of B-O
elimination, resulting dehalogenation product 1’. In the presence
phenols
eventually
formed
after
the
cascade
dehalogenation/deoxygenation process. Similar trend was
2
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Org. Chem. 1983, 48, 1811. (c) K. C. Nicolaou, A. F. Stepan, T. Lister,
A. Li, A. Montero, G. S. Tria, C. I. Turner, Y. Tang, J. Wang, R. M.
Denton, D. J. Edmonds, J. Am. Chem. Soc. 2008, 130, 13110. (d) D.
Liotta, M. Saindane, C. Barnum, J. Am. Chem. Soc. 1981, 103, 3224.
For selected examples of Michael addition reactions of quinols, see: (a)
T. J. Brocksom, F. Coelho, J. P. Deprés, A. E. Greene, M. E. Freire de
Lima, O. Hamelin, B. Hartmann, A. M. Kanazawa, Y. Wang, J. Am.
Chem. Soc. 2002, 124, 15313. (b) D. Giomi, M. Piacenti, A. Brandi, Eur.
J. Org. Chem. 2005, 4649. (c) R. Imbos, M. H. G. Brilman, M. Pineschi,
B. L. Feringa, Org. Lett. 1999, 1, 623. (d) A. C. Meister, P. F. Sauter, S.
Bräse, Eur. J. Org. Chem. 2013, 7110.
of extra B2pin2 and base, secondary borylation generated
intermediate A and eventually continued to phenol 2.
[2]
[3]
For selected examples of reductive aromatization of quinols, see: (a) L.
Zhang, W. Wang, R. Fan, Org. Lett. 2013, 15, 2018. (b) M. P.
Capparelli, R. E. DeSchepper, J. S. Swenton, J. Org. Chem. 1987, 52,
4953. (c) K. A. Parker, C. A. Coburn, J. Org. Chem. 1992, 57, 5547. (d)
H. de Nijs, W. N. Speckamp, Tetrahedron Lett. 1973, 3631. (e) G. W.
Morrow, B. Schwind, Synth. Commun. 1995, 25, 265. (f) K. A. Parker, C.
A. Coburn, J. Am. Chem. Soc. 1991, 113, 8516. (g) D. Crich, X. Mo, J.
Am. Chem. Soc. 1998, 120, 8298. (h) K. Miki, M. Fujita, Y. Inoue, Y.
Senda, T. Kowada, K. J. Ohe, Org. Chem. 2010, 75, 3537. (i) F.
Glöcklhofer, M. Lunzer, J. Fröhlich, Synlett 2015, 26, 950. (j) L. A. Miller,
M. A. Marsini, T. R. R. Pettus, Org. Lett. 2009, 11, 1955. (k) K. A.
Parker, A. T. Georges, Org. Lett. 2000, 2, 497. (l) L. Wang, Z. Yan,
Synlett 2016, 27, 1602.
Scheme 5. Proposed mechanism
Several sets of know conditions for reductive aromatization of
quinols were examined with 1a to evaluate our apporach.
Exposing 1a to borane or borohydride resulted in the formation
of 2a in very low yields (<15%) along with hydroquinone 2a’
obtained as decomposited product (Figure 3). Under the
conditions developed by Parker,[3c] phenol 2a was generated in
50% yield while decomposition is still unavoidable. Better results
were given when treated with Zn/AcOH affording the desired
product in 66% yield without observation of hydroquinone but
still inferior comparing to our conditions.
[4]
For example of deoxygenation with diboron on N-oxides, carbon
dioxide and nitro group, see (a) D. S. Laitar, P. Müller, J. P. Sadighi, J.
Am. Chem. Soc. 2005, 127, 17196. (b) S. Bae, M. K. Lakshman, J. Org.
Chem. 2008, 73, 1311. (c) H. P. Kokatla, P. F. Thomson, S. Bae, V. R.
Doddi, M. K. Lakshman, J. Org. Chem. 2011, 76, 7842. (d) V. Gurram,
H. K. Akula, R. Garlapati, N. Pottabathini, M. K. Lakshman, Adv. Synth.
Catal. 2015, 357, 451. (e) J. Kim, C. R. Bertozzi, Angew. Chem., Int. Ed.
2015, 54, 15777. (f) K. Yang, F. Zhou, Z. Kuang, G. Gao, T. G. Driver,
and Q. Song. Org. Lett. 2016, 18, 4088.
2a 80%
standard
condition
Zn (2 eq.)
EtOH/AcOH 80% aq.
(1:1)
[5]
[6]
[7]
[8]
(a) N. Miralles, R. Alman, K. Szabó and E. Fernández, Angew. Chem.,
Int. Ed., 2016, 55, 4303.
NaBH4(1.5 eq.)
EtOH (0.2 M)
2a/2a'
13%/76%
2a
66%
K. Harada, M. Nogami, K. Hirano, D. Kurauchi, H. Kato, K. Miyamoto, T.
Saito and M. Uchiyama, Org. Chem. Front., 2016, 3, 565.
r.t, 12h
reflux, 8h
Ph
O
M. J. Hesse, C. P. Butts, C. L. Willis, and V. K. Aggarwal. Angew.
Chem. Int. Ed. 2012, 51, 12444.
HO
1a
Na2S2O4 (3 eq.)
THF/H2O (5:2)
BH3 Me2S(1.5 eq.)
DCE, r.t, 12h
2a/2a'
11%/83%
2a/2a'
(a) H. Chen, T. Zhang, C. Shan, S. Liu, Q. Song, R. Bai, Y. Lan, Org.
Lett., 2019, 21, 4924. (b) Z. Kuang, H. Chen, J. Yan, K. Yang, Y. Lan,
Q. Song, Org. Lett., 2018, 20, 5153. (c) S. Bhavanarushi, Y. Xu, I. Khan,
Z. Luo, B. Liu, J. Xie, Org Chem Front 2019, 6, 1895.
50%/30%
r.t, 12h
(2a' = hydroquinone)
Scheme 6. Comparison experiments
[9]
(a) D. J. Pasto, and Sr. R. Snyder, J. Org. Chem. 1966, 31, 2773. (b) D.
S. Matteson, J. D. Liedtke, J. Am. Chem. Soc. 1965, 87, 1526.
[10] H. Wu, J. M. Garcia, F. Haeffn, S. Radomkit, A. R. Zhugralin and A. H.
Generally, we have developed a mild approach for the
selective reductive aromatization of quinols using B2pin2 as
deoxidizing reagents. Cascade borylation/B-O elimination
process was suggested to furnish the formal deoxygenation
process. Moreover, this protocol had been demonstrated highly
efficient by comparison experiments.
Hoveyda, J. Am. Chem. Soc., 2015, 137, 10585
Acknowledgements
The authors acknowledge the financial support from the Natural
Science Foundation of China (21801099) and the Senior Talent
Foundation of Jiangsu University (18JDG016, 13JDG062).
Keywords: reductive aromatization • boron • deoxygenation •
quinols
[1]
For selected examples of cycloaddition reactions of quinols, see: (a) M.
Dipakranjan, R. Sutapa, Eur. J. Org. Chem. 2008, 3014. (b) F.
Fringuelli, L. Minuti, F. Pizzo, A. Taticchi, T. D. J. Halls, E. J. Wenkert,
3
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Entry for the Table of Contents
Reductive deoxygenation of quinols was achieved under B2pin2/NaH conditions affording functionalized phenols in good yields. This
approach featured in high functional group tolerance and chemoselectivity comparing to well-established methods.
4
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