Iron-catalyzed regioselective alkylation of 1,4-quinones and coumarins with functionalized alkyl bromides

Article abstract of DOI:10.1039/c9ob02289a

A simple and efficient Fe-catalyzed regioselective alkylation of 1,4-quinones and coumarins, using functionalized alkyl bromides as alkylating reagents, has been developed. The reaction proceeds under mild conditions with the addition of alkyl bromides to a wide range of 1,4-quinone and coumarin derivatives with a broad substrate scope and wide functional group tolerance to provide the products in good yields. Further application of these strategies could be extended to important biologically active antimalarial lead drugs, such as plasmodione on a gram scale in a single step for medicinal purposes.

Full text of DOI:10.1039/c9ob02289a

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DOI: 10.1039/C9OB02289A
ARTICLE
Iron-catalyzed regioselective alkylation of 1,4-quinones and
coumarins with functionalized alkyl bromides
Dengke Li,a, * and Xianfu Shen b, *
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A
simple and efficient Fe-catalyzed regioselective alkylation of and co-workers with tertiary alkyl bromides for heteroaromatic or
1,4-quinones and coumarins, using functionalized alkyl vinylic C–H alkylations to construct all carbon quaternary centers11b
bromides as alkylating reagents, has been developed. The (b, Scheme 1). Although impressive achievements have been
reaction proceeds under mild conditions with addition of alkyl made,11 other types of substrate scope upon alkyl halides with iron
bromides to
a
wide range of 1,4-quinone and coumarin catalyst in synthetic chemistry were still highly desirable.
The 1,4-quinone12a-b and coumarin12c-e scaffolds are frequently
derivatives with broad substrate scope and densely functional
group tolerance in good yields. Further application of these studied in natural products, biological systems and pharmaceutical
strategies could be accessed to important biologically active chemistry.12 Therefore, particular attention has been paid in the
antimalarial lead drugs, such as Plasmodione in gram scale in development of new methods for the construction of alkyl-
single step for medicinal purposes.
containing compounds in this area.13, 14 Inspired by these seminal
13, 14
works11,
and our continuous interest in radical chemistry,15
herein, we wish to report a general iron-catalyzed protocol for the
synthesis of alkylated 1,4-quinones and coumarins with
functionalized alkyl bromides with high regioselectivity (c, Scheme
1).
Introduction
The introduction of alkyl groups into molecules of medicinal interest
has been recognized as a significant strategy in drug discovery, due
to their unique chemical properties and biological activities.1 Among
the numerous methods, using commercially available and bench
stable coupling partners should be a desirable project to pursue.
Functionalized alkyl halides, especially the readily available α-
bromocarbonyl compounds, are among the most ubiquitous chemical
blocks, have been studied extensively as one of the most
straightforward strategies for the preparation of alkylating
compounds.2 In this context, great efforts have been devoted in
cross-coupling reactions3 between alkenes, alkynes and heteroarenes
by Ru-, Ir-based photoredox strategies4 or transition metals with
Ni-,5 Pd-,6 or Cu-7 catalytic systems (a, Scheme 1).
As the most abundant transition metal on earth with low cost,
nontoxic and environmentally benign nature, the utilization of iron
catalysts in synthetic chemistry should have powerful advantages.8
Although iron-catalyzed cross-coupling of Grignard reagents9 as
well as the atom transfer radical polymerization (ATRP) reaction10
with alkyl halides has been well established. However, Fe-catalyzed
reactions to construct alkyl groups are remain to be addressed. In
2017, Thomas and Shaver developed an elegant iron-catalyzed atom
transfer radical elimination (ATRE) reaction to facilitate a formal
Heck cross-coupling with styrenes and functionalized alkyl
bromides.11a Later on, similar strategies were disclosed by Nishikata
R2
FG
R1
(a) ref. 4, 5, 6, 7
well developed
(1) Previous work:
R
Het
hv or [TM]
R
Het
R2
[TM] = [Ni], [Pd], [Cu]
FG
R1
Br
+
R2
FG
R1
(b) ref. 11, rare
[TM] = [Fe]
(FG = ester, phenyl, nitrile)
R
R
O
O
R1
R
O
O
(2) This work:
FG
R2
R2
FG
R1
R
[Fe] cat.
Br
+
(c) This work
O
O
O
O
(FG = ester, phenyl)
(1o, 2o, 3o Br)
R
R2
FG
R
R1
Scheme 1. Selected strategies for the alkylation with functionalized
alkyl bromides
Results and discussion
To test this possibility, we began our initial study with 2-
methylnaphthalene-1,4-dione (1a) in the reaction with ethyl 2-
bromopropanoate (2a) as the model substrates to optimize the
reaction conditions.13 To our delight, the desired product 3a was
isolated in 48% yield when the reaction was performed in the
presence of FeCl2 (10 mol%) and DIPEA (2.0 equiv) in 1,4-dioxane
a. College of Chemistry and Environmental Science; b Center for Yunnan-Guizhou
Plateau Chemical Functional Materials and Pollution Control, Qujing Normal
University, Qujing 655011, Yunnan, China. E-mail: dengkeli2011@163.com;
xianfu_shen@163.com.
† Electronic Supplementary Information (ESI) available: See
DOI: 10.1039/x0xx00000x
o
at 100 C for 24 h (entry 1, Table 1). Control experiments revealed
that iron catalyst and DIPEA were all indispensable, and no desired
product was detected in the absence of neither of them (entries 2-3).
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Other solvents (see ESI for details), such as, DCE (27%), toluene Triethylenediamine; PMDTA = Pentamethyldiethylenetriamine; n.d.
View Article Online
DOI: 10.1039/C9OB02289A
(36%), CH3CN (28%), or DMSO (n.d.) was proven less effective. = not detected.
Screening of other Fe(II) and Fe(III) species, suggested that FeCl2
With the optimized conditions in hand, the scope of 1,4-quinones
and alkyl bromides was investigated first (Scheme 2). Alkyl
bromides with ester groups derivate from various substituents, such
as, Et, Me, Bn were examined, all could undergo the alkylation
reaction smoothly, and generate the corresponding products 3a-3i in
moderate yields in 21-69%. It should be noted that, an obvious
substituent effect was observed in electronic and steric properties
with alkyl bromides7i during the formation of 3e-3f and 3h-3i. Then
the substitution effect of the aromatic rings of 1,4-quinones was
examined. Anthracene-1,4-dione (1e) also reacted smoothly to give
the desired products 3j-3l in moderate yields. 1,4-Quinone (1f)
bearing a BnO-group was also tolerated, albeit with low yield (3m,
26% yield and 1/0.4 regioselectivity). Unfortunately, 1,4-quinones
1g-1j; alkyl bromides 2h-2j, such as ethyl 2-bromoacetate or
bromocyclohexane, could not be used as substrates to give the
desired products, and complete decomposition of the starting
materials were observed.
(48%, entry 1, Table 1) was superior to other iron catalysts (entries
5-9, Table 1). Gratifyingly, increasing the temperature (115 oC)
could improve the yield of 3a to 57% (entry 10). Finally, decreasing
the amount of FeCl2 and base, a significant higher of the yield was
obtained (69%, entry 16). Thus, we wonder whether a catalytic
amount of iron-catalyst could cooperate with substrate 1a under the
reaction conditions. From these experiments, we determined the
optimized catalytic reaction conditions: FeCl2 (5.0 mol%), DIPEA
(1.5 equiv) in 1,4-dioxane at 115 oC for 28 h.
Table 1. Optimization of the reaction conditionsa
O
O
O
CO2Et
[Fe] cat.
+
OEt
1,4-dioxane, N2
Br
O
O
Conditions (?)
1a
2a
3a
Catalyst
(mol%)
Base
(equiv)
T (oC )
/ t (h)
Yield
O
R1
O
Entry
1
FG
R2
(%)b
FeCl2 (5.0 mol%)
DIPEA (1.5 equiv)
R2
FG
R1
+
Br
FeCl2 (10)
FeCl2 (10)
--
DIPEA (2.0)
--
100 / 24
48
R
R
1,4-dioxane, N2
115 oC, 26-48 h
O
O
2
100 / 18
100 / 30
85 / 30
n.d.
n.d.
< 5
46
1
2
3
(13 examples)
3
DIPEA (2.0)
DIPEA (2.0)
DIPEA (2.0)
DIPEA (2.0)
DIPEA (2.0)
DIPEA (2.0)
DIPEA (2.0)
DIPEA (2.0)
O
O
O
O
CO2R
4
FeCl2 (10)
FeCl3 (10)
CO2Et
CO2Et
5
100 / 24
100 / 22
100 / 22
100 / 24
100 / 24
115 / 24
115 / 22
115 / 22
115 / 22
115 / 22
115 / 24
115 / 28
115 / 28
115 / 28
3a
3b
3c
, R = Et, 28 h, 69%
, R = Me, 36 h, 62%
, R = Bn, 45 h, 35%
O
O
6
Fe(acac)3 (10)
Fe(acac)2 (10)
Fe(OTf)2 (10)
Fe(OAc)2 (10)
FeCl2 (10)
20
3e
, 36 h, 38%
3d
, 36 h, 54%
O
R
O
O
7
24
CO2Et
CO2Et
OMe
CO2Et
8
36
O
, R = H, 26 h, 46%
3h,
O
O
9
25
3g
3i
3f
, 32 h, 28%
, 36 h, 21%
R = Me, 26 h, 29%
10
11
12
13
14
15
16
17
18
57 c
n.d.
19
O
O
CO2Et
FeCl2 (10)
DABCO (2.0)
NEt3 (2.0)
CO2R
FeCl2 (10)
O
O
3j
, R = Et, 48 h, 44%
3k
3l
, 48 h, 21%
, R = Me, 46 h, 46%
FeCl2 (10)
PMDTA (2.0)
Na2CO3 (2.0)
DIPEA (2.0)
DIPEA (1.5)
DIPEA (1.5)
DIPEA (1.5)
n.d.
22
OBn O
O
O
O
O
OH
O
FeCl2 (10)
CO2Et
R
R
FeCl2 (7.5)
FeCl2 (5.0)
FeCl2 (5.0)
FeCl2 (3.0)
68 c
69 c
60 c, d
59 c
OH
O
O
3m,
1i
1j
48 h, 26%
(regiosel. = 1/0.4)
, R = H, n.d.
, R = Me, n.d.
1g
, n.d.
1h, n.d.
Scheme 2. Substrate scope of 1,4-quinones with alkyl bromidesa
a Reaction conditions: In N2 atmosphere, 1 (1.0 equiv, 0.20 mmol), 2
(2.0 equiv, 0.40 mmol), FeCl2 (5.0 mol%), DIPEA (1.5 equiv, 0.30
o
mmol) in 1,4-dioxane (1.5 mL) at 115 C for 26-48 h; n.d. = not
a Reaction conditions: In N2 atmosphere, 1a (1.0 equiv, 0.20 mmol),
2a (2.0 equiv, 0.40 mmol), [Fe], base (2.0 equiv, 0.40 mmol) in 1,4-
dioxane (1.5 mL) at 100 oC for 18-28 h; b Isolated yield; c 0.40 mmol
scale of 1a was used; d 2a (1.5 equiv) was used. Unless otherwise
detected.
We then turned our interest to benzyl bromides, which could
lead to important biologically active molecules, such as
benzylmenadione analogs, identified as potent and fast-acting
antimalarial lead drug in pharmaceutical industry16 (Scheme 3).
noted, DIPEA
=
N,N-Diisopropylethylamine; DABCO
=
2 | J. Name., 2012, 00, 1-3
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O
O
It was showed that, benzyl bromides bearing different
substituents, either electron-donating (e.g., Me, OMe) or
electron-withdrawing groups (F, Cl, Br, CF3), even the strong
electron-withdrawing group (4-NO2), at different positions of
the benzene ring, could be functionalized as the competent
coupling partners to generate the desired product 4a-4o in
moderate to good yields in 31-80% successfully. Notably,
ortho-substituted effect was not found during the formation of
4g and 4k (68% and 77%). However, product 4l was formed in
lower yield (31%), likely due to the steric effects. When 2,6-
dimethylcyclohexa-2,5-diene-1,4-dione was tested under
standard conditions, a complicated mixture containing bis-
benzylated products including 4p and 4q were obtained in 33%
and 21% yield, respectively.
FeCl2 (7.5 mol%)
DIPEA (2.0 equiv)
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R2
FG
R1
O
O
R
2
DOI: 10.1039/C9OB02289A
R
R
Br
+
toluene, N2
130 oC, 45 h
FG
R1
1
2
5
(16 examples)
O
O
O
O
R
5a,
5b,
5c,
R = H, 50%
R = 6-Me, 40%
R = 6-NO2, 27%
CO2Et
41%
CO2Et
5d,
O
O
O
O
R = H, 57% (48%)c (n.d.)d
R = 4-Me, 53%
5g,
5h,
5i,
R
R = 4-F, 31%
CO2Et
b
5j,
R = 4-Cl, 55%
5e,
5f,
R = H, 32%
R
b
5k,
5l,
R = 3-MeO, 56%
R = 4-CF3, 71%
R = Me, 30%
O
O
O
O
FeCl2 (5.0 mol%)
DIPEA (1.5 equiv)
O
O
R1
Br
+
R1
R
R
R
1,4-dioxane, N2
115 oC, 26-48 h
O
O
Cl
2
4
1
(16 examples)
5n,
5o,
5p,
R = 6-Me, 57%
R = 6-Cl, 49%
R = 7-MeO, 32%
4a
, R = H, 48 h, 69%
, R = 4-Me, 48 h, 80%
, R = 4-F, 48 h, 67%
, R = 4-Cl, 48 h, 72%
, R = 3-Cl, 48 h, 57%
, R = 4-Br, 48 h, 70%
4b
4c
4d
4e
F
5m,
71%
O
O
Cl
Scheme 4. Substrate scope of coumarins with alkyl bromidesa
a Reaction conditions: In N2 atmosphere, 1 (1.0 equiv, 0.20 mmol), 2
(2.0 equiv, 0.40 mmol), FeCl2 (7.5 mol%), DIPEA (2.0 equiv, 0.40
R
4f
F
4g
4h
4i
4j
, R = 2-Br, 46 h, 68%
, R = 3-MeO, 28 h, 74%
, R = 4-CF3, 48 h, 66%
, R = 4-NO2, 48 h, 53%
O
O
o
b
mmol) in toluene (2.0 mL) at 130 C for 45 h; in 1,4-dioxane/
4k
c
d
o
, 48 h, 77%
toluene (2.0 mL, v/v = 1/1); in 1,4-dioxane; 115 C; n.d. = not
detected.
O
O
OMe
It is noteworthy that, the reaction could be performed at large
scale without significant loss of the yield (Scheme 5). A simple 10-
fold scale reaction in the formation of 4a (2.0 mmol scale, 67%
yield) or a gram-scale reaction for the preparation of antimalarial
lead drug Plasmodione analogs16 4i (1.21g scale, 61% yield) was
performed successfully with these commercially available and bench
stable coupling partners in good results.
R
O
O
4m
4n
, R = Cl, 26 h, 68%
, R = MeO, 46 h, 46%
4l
, 46 h, 31%
O
O
O
+
O
O
O
O
O
b
b
4o
4p
4q
, 36 h, 21%
, 46 h, 49%
, 36 h, 33%
FeCl2 (5.0 mol%)
DIPEA (1.5 equiv)
Scheme 3. Substrate scope of 1,4-quinones with benzyl bromidesa
a Reaction conditions: In N2 atmosphere, 1 (1.0 equiv, 0.20 mmol), 2
(2.0 equiv, 0.40 mmol), FeCl2 (5.0 mol%), DIPEA (1.5 equiv, 0.30
mmol) in 1,4-dioxane (1.5 mL) at 115 oC for 26-48 h; b 100 oC.
Br
+
1,4-dioxane (8.0 mL)
115 oC, N2, 48 h
O
O
1a
2k
4a,
67%
(2.0 mmol)
(2.0 equiv)
O
O
FeCl2 (5.0 mol%)
DIPEA (1.5 equiv)
Encouraged by these results, we then studied the feasibility of the
Br
+
current reaction with a range of coumarins for further expansion of
CF3
CF3
1,4-dioxane (20 mL)
115 oC, N2, 48 h
(gram scale)
O
15e
O
the substrate scope14,
(Scheme 4). Numerous coumarins with
1a
2s
4i,
61% (1.21 g)
different electronic properties and substitution patterns (1k-1o) were
successful in providing the desired products 5a-5p in moderate to
good yields in 27-71%.
(6.0 mmol)
(2.0 equiv)
Plasmodione (antimalarial)
Scheme 5. Large-scale synthesis
Several control experiments were conducted to probe the reaction
mechanism. For example, some radical scavengers, such as, 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) was performed to gain
insights into the mechanism of the reaction.11 The reactions were
completely inhibited by TEMPO, and almost no desired product 3a
was generated (a, Scheme 6). Importantly, the alkyl radical was
trapped by 1,1-diphenylethylene or (1-cyclopropylvinyl)benzene,15d-
e, 17
albeit in low yield (b-d, Scheme 6, and ESI for details),
indicating that radical intermediates were involved in the reaction.11,
17
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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O
yields. Further application of these strategies could be utilized for
DOI: 10.1039/C9OB02289A
the preparation of important biologically active antimalarial lead
drugs, such as Plasmodione in gram scale in single step for
medicinal purposes.
View Article Online
FeCl2 (5.0 mol%)
DIPEA (1.5 equiv)
O
CO2Et
+
OEt
1,4-dioxane, N2
115 oC, 32 h
Radical scavenger (2.0 equiv)
Br
O
O
1a
2a
3a
Radical inhibiting experiments:
Conflicts of interest
There are no conflicts to declare.
(a)
(b)
TEMPO (2.0 equiv)
3a,
n.d.
and trace of
1a
was recovered
3a,
trace
and 49% of
Ph
Ph
Acknowledgements
1a
was recovered
We are grateful to the National Natural Science Foundation of China
(21861032) and Natural Science Foundation of Yunnan Province
(2018FD078), Yunnan Local Colleges Research Projects
(2017FH001-020, 2018FH001-021) for financial support.
(2.0 equiv)
Ph
Ph
CO2Et
55%
3a,
and trace of
48%
(c)
1a
was recovered
Ph
(2.0 equiv)
Notes and references
CO2Et
trace
1. For selected reviews, see: (a) Lipophilicity in Drug Action and
Toxicology (Eds.: V. Pliska, B. Testa, H. Waterbeemd), Wiley-
VCH, Weinheim, 2008; (b) L. Ackermann, Chem. Commun. 2010,
46, 4866; (c) C. S. Leung, S. S. F. Leung, J. Tirado-Rives, W. L.
Jorgensen, J. Med. Chem. 2012, 55, 4489; (d) M. Yan, J. C. Lo, J.
T. Edwards, P. S. Baran, J. Am. Chem. Soc. 2016, 138, 12692.
2. (a) G. W. Gribble, Acc. Chem. Res. 1998, 31, 141; (b) N. Kambe,
T. Iwasaki, J. Terao, Chem. Soc. Rev. 2011, 40, 4937.
(d)
Ph
(0.20 mmol)
CO2Et
2a
standard conditions
+
only
(2.0 equiv)
17%
(endo/exo = 1/0.4, detected by 1H NMR)
Scheme 6. Mechanistic study
3. For selected reviews, see: (a) T. Pintauer, K. Matyjaszewski,
Chem. Soc. Rev. 2008, 37, 1087; (b) K. W. Shimkin, D. A.
Watson, Beilstein J. Org. Chem. 2015, 11, 2278; (c) S. Tang, K.
Liu, C. Liu, A. Lei, Chem. Soc. Rev. 2015, 44, 1070; (d) X.-H.
Ouyang, R.-J. Song, J.-H. Li, Chem. Asian J. 2018, 13, 2316.
4. For selected examples of photoredox strategies, see: (a) J. D.
Nguyen, J. W. Tucker, M. D. Konieczynska, C. R. J. Stephenson,
J. Am. Chem. Soc. 2011, 133, 4160; (b) C. J. Wallentin, J. D.
Nguyen, P. Finkbeiner, C. R. J. Stephenson, J. Am. Chem. Soc.
2012, 134, 8875; (c) T. Courant, G. Masson, Chem. Eur. J. 2012,
18, 423; (d) X.-J. Wei, D.-T. Yang, L. Wang, T. Song, L.-Z. Wu,
Q. Liu, Org. Lett. 2013, 15, 6054; (e) Q. Liu, H. Yi, J. Liu, Y.
Yang, X. Zhang, Z. Zeng, A. Lei, Chem. Eur. J. 2013, 19, 5120;
(f) Y. Li, B. Liu, X.-H. Ouyang, R.-J. Song, J.-H. Li, Org. Chem.
Front. 2015, 2, 1457.
Based on these results and previous established reports,11
a
plausible reaction pathway was proposed in Scheme 7. Initially,
functionalized alkyl bromide 2a is reduced by the Fe(II)-catalyst to
afford Fe(III)-species A and alkyl radical B. Then, radical addition
of B to the C-3 position of 1,4-quinone 1a generates radical
intermediate C.13j Ultimately, C undergoes single electron transfer
(SET) oxidation11b by A and proton elimination in the presence of
the amine,11b leads to the desired product 3a, with concurrent
regeneration of the Fe(II)-catalyst.
amine-HBr
O
O
OEt
- e-, - H+
CO2Et
Br
2a
Fe(II)
O
5. For selected examples of Ni-catalysts, see: (a) C. Liu, S. Tang, D.
Liu, J. Yuan, L. Zheng, L. Meng, A. Lei, Angew. Chem., Int. Ed.
2012, 51, 3638; (b) S. Tang, C. Liu, A. Lei, Chem. Commun.
2013, 49, 2442; (c) A. Nakatani, K. Hirano, T. Satoh, M. Miura,
Chem. Eur. J. 2013, 19, 7691; (d) Z. Li, A. Garccía-Domínguez,
C. Nevado, Angew. Chem., Int. Ed. 2016, 55, 6938.
3a
O
amine
BrFe(III)
(A)
OEt
O
O
(B)
H
CO2Et
O
(C)
6. For selected examples of Pd-catalysts, see: (a) J.-H. Fan, W.-T.
Wei, M.-B. Zhou, R.-J. Song, J.-H. Li, Angew. Chem., Int. Ed.
2014, 53, 6650; (b) J.-H. Fan, J. Yang, R.-J. Song, J.-H. Li, Org.
Lett. 2015, 17, 836.
Radical addition
O
1a
Scheme 7. Plausible mechanism
7. For selected examples of Cu-catalysts, see: (a) T. Nishikata, Y.
Noda, R. Fujimoto, T. Sakashita, J. Am. Chem. Soc. 2013, 135,
16372; (b) X. Zhang, H. Yi, Z. Liao, G. Zhang, C. Fan, C. Qin, J.
Liu, A. Lei, Org. Biomol. Chem. 2014, 12, 6790; (c) C. Che, H.
Zheng, G. Zhu, Org. Lett. 2015, 17, 1617; (d) X. Chen, X. Liu, J.
T. Mohr, J. Am. Chem. Soc. 2016, 138, 6364; (e) M. Hu, R.-J.
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Conclusions
In summary, we have developed a highly efficient Fe-catalyzed
regioselective alkylation of 1,4-quinones and coumarins with
functionalized alkyl bromides as alkylating reagents. The reaction
proceeds under mild conditions with addition of alkyl bromides to a
wide range of 1,4-quinone and coumarin derivatives with broad
substrate scope and densely functional group tolerance in good
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