Construction of vicinal quaternary carbons via Cu-catalyzed dearomative radical addition

Article abstract of DOI:10.1246/cl.190247

In this paper, we confirmed the dearomative addition of tertiary alkyl radicals onto BHT derivatives to form highly congested vicinal quaternary carbons to produce tert-alkylated styrenes in the presence of copper catalyst. Although there are three candid

Full text of DOI:10.1246/cl.190247

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Construction of vicinal quaternary carbons via Cu-catalyzed dearomative radical addition
Naoki Tsuchiya and Takashi Nishikata*
Advance Publication on the web May 28, 2019
doi:10.1246/cl.190247
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1
Construction of vicinal quaternary carbons via Cu-catalyzed dearomative radical addition
Naoki Tsuchiya and Takashi Nishikata*
Graduate School of Science and Engineering, Yamaguchi University 2-16-1 Tokiwadai, Ube, Yamaguchi, 755-8611, Japan
E-mail: nisikata@yamaguchi-u.ac.jp
the ipso position of BHT6, whereas BHT generates
In this paper, we confirmed the dearomative addition of
tertiary alkyl radicals onto BHT derivatives to form highly
congested vicinal quaternary carbons to produce tert-
alkylated styrenes in the presence of copper catalyst.
Although there are three-candidate in the reaction of BHT
with a radical species, we found that α-radical selectively
reacted at ipso position of BHT to produce the
corresponding dienone structure. Moreover, heteroatom
substituted BHT underwent C-C cleavage coupling
reactions with α-radicals.
benzyl radical from a phenoxy radical, and the
resulting benzyl radical couples with a carbon radical
species7. Therefore, there are three candidates
including (A) dearomative addition, (B) coupling
with OH moiety, and (C) the reaction with benzylic
position in a radical reaction or ionic reaction
(Scheme 1).
We and other groups have studied tertiary alkyl
Keywords: vicinal quaternary carbon, dearomatize,
radical, copper
radical
chemistry
using
α-bromocarbonyl
compounds: 1) substitution reaction with terminal
alkenes8, 2) coupling type reaction with nucleophiles9,
3) addition reaction with alkynes10, and 4) aromatic
C-H bond substitutions11. Those tert-alkylations
resulted in various quaternary carbon structures via
new alkylation methodologies. Our next goal is to
synthesize highly congested vicinal quaternary
carbon compounds via dearomative addition to
produce cyclic dienone derivatives. Herein, we
disclose our findings on the reaction of BHT
derivatives and α-bromocarbonyl compounds in the
presence of a Cu catalyst at room temperature.
Dearomatization reactions are one of the most
difficult reactions in organic synthesis due to the
breaking aromaticity1, can efficiently convert
aromatic compounds into aliphatic compounds.
Although there are many reports on this topic 2-5, an
intermolecular dearomative tert-alkylation reaction to
produce vicinal quaternary carbons has not yet been
accomplished. One of the problems in this topic is the
stability of the dearomative product. The most of the
resulting products have
a
1,4-cyclohexadiene
structure that is easily oxidized to produce the starting
aromatic ring. Therefore, the resulting product must
be stabilized by bulky substituents in the examination
of dearomative addition to aromatic ring. In this
context, BHT is very nice reaction partner with a
radical species. Because the resulting dearomative
adduct has sterically bulky tert-butyl groups to
stabilize the structure (Scheme 1 A).
BHT (butylhydroxytoluene) has been used for a
radical scavenger reagent6. But the resulting products
in the reaction of BHT are ambiguous and not fully
investigated so far. An oxyl radical species react with
Scheme 2 This work.
Optimization studies employed the combination of 1a (0.5
mmol), 2a (0.5 mmol), and a base (2 equiv) in the
presence of CuI (10 mol%) and ligand (10 mol%) in a
solvent at room temperature. The ligand is very important
to obtain the product 3a in good yield. L1 and L2 were
not effective to obtain the product 3a, but L3 resulted in
76% NMR yield of 3a (entries 1-3). The structures
between L2 and L3 are not big difference but the results
were quite different. In the case of L1 and L2, 1a was
recovered completely. The reason of this result is not
clear. In previous our study8a,9a,9b,10c,11c and ATRP (atom-
transfer radical polymerization) chemistry12, multi-dentate
aliphatic amine ligands are effective but L4 and L5 did
not gave high yield of the product 3a (entries 4 and 5).
The reaction using L3 for longer reaction time (15 h) gave
Scheme 1. The reaction modes of BHT with a radical
species.

2
93% NMR yield of 3a (entry 6). We have tested solvents,
such as 1,4-dioxane, MeCN, and dichloromethane (DCM)
but toluene was the best (entries 7-9). We also tried BHT
methyl ether, but no reaction occurred.
Under optimal conditions, the dearomative additions
proceeded smoothly by using various substrates
(Table 2). The reaction of various BHT derivatives
1
Table 2. Substrate scopea
Table 1. Optimizationa
R2 R3
R1
CuI (10 mol%)
L3
R1
CO2R4
R3
CO2R4
R2
Br
(10 mol%)
DBU (2 equiv)
toluene
tBu
tBu
tBu
tBu
r.t. , 1 h
OH
1
O
3
2
3
Yield of
CO2Et
tBu
CO2Et
CO2Et
tBu
tBu
tBu
tBu
tBu
O
O
O
b
b
3b
: 90%
3c
3d
: 12% (98% )
: (98% )
OH
O
Ph
O
O
tBu
tBu
3e
: >99%
O
3f
: 91%
tBu
O
tBu
O
CO2Et
Br
Et Et
O
O
O
O
tBu
tBu
tBu
tBu
b
O
3g
: 81%
3h
: 88%
O
NHPh
CO2Et
CO2Bn
tBu
O
tBu
tBu
3k
tBu
tBu
tBu
O
O
O
b
b
3j
: >99%
3i
: trace (64% )
: trace (61% )
H
N
H
N
a
OMe
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), CuI (0.05
mmol), Ligand (0.05 mmol), base (1.0 mmol) in solvent (1.0 mL). b
Determined by 1H NMR using 1,1,2,2-tetrachloroethane as an
internal standard. c Isolated yield.
O
tBu
O
tBu
Ac
tBu
tBu
b
b
O
3l
: 69%
3m
: 53%
O
aAll reactions were carried out in toluene at rt for 1 h with CuI (10
mol%), L3 (10 mol%), DBU (2 equiv), (1.0 equiv.) and (1.0
equiv.). Yields were isolated. bReaction time was 20 h.
A base is also important factor to carry out the
reaction efficiently (entries 10-12). When DBU (1,8-
Diazabicyclo[5.4.0]-7-undecene) was employed for
the reaction, >99% NMR yield of 3a was obtained
(entry 12). Ultimately, the reaction at room
temperature for 1 h in the presence of CuI and L3 was
identified as the most effective at mediating the
dearomative addition in excellent yield (entries 13-
15).
1
2
and α-bromocarbonyl compounds
stabilized dienone products (3b-3m) achieved the
yields of up to 99%. Methyl (3b 3i-3m), Ethyl (3f),
2-butyl (3c and 3e), and tertiary butyl (3d 3g, and
3h) groups were able to be used as the substituents
(R1) of BHT derivatives . The reactions were partly
slow but longer reaction time was effective to obtain
2 to give tert-butyl
,
,
1

3
good yields. α-Bromoesters
2 possessing highly
congested structure (3h), cyclic structure (3i and 3j),
propargyl alcohol (3f), and conjugated olefin (3g
were tested. Sterically bulky products (3e 3f 3g, and
)
,
,
3h) were obtained within an hour. On the other hand,
longer reaction time (20 hrs) was required to obtain
the products (3c, 3d and 3h) in good yields. It was
curious that the structures of substrates are very
closed but the reactivities were different compared
Scheme 3 Reaction with 4.
with other combinations. When substrate
2
R1
CuI (10 mol%)
L3
possessing alkyl−Br bonds was used, elimination of
H−Br occurred to produce the corresponding
eliminated product 3n because of the strong basicity
of DBU (Scheme 3). Compared with α-bromoesters,
R3
R2
(10 mol%)
Complex mixture
CO2R4
DBU (2 equiv)
toluene
Br
tBu
R
R
R
r.t. , 3 h
OH
1
2
the reactivities of α-bromocarboxamides
probably due to the bonding energy of C−Br. But α-
bromocarboxamides also gave good yields (3k 3m).
2 were low
Scheme 4 Reaction with
1
(R≠tBu).
2
-
Ph
CuI (10 mol%)
L3
The substituent on BHT is very important. For
example, p-cresol possessing two ortho-alkyl groups
(other than t-Bu) did not give the corresponding
Ph
O
(10 mol%)
2a
O
DBU (2 equiv)
toluene
tBu
tBu
tBu
tBu
dearomative adduct
mixture (Scheme 4). We also tried the reaction of
para-phenyl substituted phenol . The reaction only
to give in good yield.
possessing carboxylic
3 and the reactions were complex
r.t. , 5 h
OH
5
O
6
: 95%
5
Scheme 5 Reaction with
5
.
occurred at para-position of
Interestingly, substrates
5
7
6
Table 3 C-C cleavage reactiona.
acid (7a), dimethylaminomethyl group (7b), and
hydroxymethyl group (7c) at para-position underwent
C−C cleavage couplings to give the corresponding
tert-alkyl substituted product
8 (Table 3). Although
the mechanistic details are unknown, these reactions
could occur through a radical reaction. The reaction
of 8d gave neither dearomative adduct
3 nor C−C
cleavage coupling product . We have tried to trap
8
fragmentated substituents but the corresponding
products were not obtained. We also tried the reaction
with substrates (7a-7c) without tert-butyl groups but
no reaction occurred.
The proposed reaction mechanism is shown in Figure 1.
The reaction starts with the generation of tertiary-alkyl
radical species A from the reaction between CuI and 2.
We also detected the homo-coupling products of 2, but the
yields were very low. Next, the reaction of CuII and the
anion of 1 generated from the reaction of 1 and DBU
might give the corresponding cyclohexadienyl radical B.
An evidence of this step is the reaction in the presence of
stoichiometric amounts of CuII and 1a (Scheme 6). In this
case, the corresponding dearomative and C−C cleavage
coupling product 9 was obtained. We also tried the
reaction of BHT and tempo (2,2,6,6-tetramethylpiperidine
1-oxyl) but the existence of tempo adduct was not clear
because the reaction was a complex mixture. This could
be through the generation of B. Finally, the radical
coupling of A and B could occur to produce 3.
aAll reactions were carried out in toluene at rt for 1 h with CuI (10
mol%), L3 (10 mol%), DBU (2 equiv),
7 (1.0 equiv.) and 2a (1.0
equiv.). Yields were isolated.
In conclusion, we discovered Cu catalyzed
dearomative addition reactions of BHT derivatives
and α-bromocarbonyl compounds as a tertiary alkyl
source to form vicinal quaternary carbons at room
temperature. The reaction could occur with the
corresponding radical species. Substrates possessing
carboxylic acid, dimethylaminomethyl group, and
hydroxymethyl group at para-position underwent

4
Nakayama, S. Harada, M. Kono, T. Nemoto, J. Am. Chem. Soc.
,
C−C cleavage couplings to give the corresponding
tert-alkyl substituted product 8. These results will
show new aspects of the reactivities of BHT
derivatives. Further investigations including synthetic
applications using our methodology are currently
underway.
2017
,
139, 10188; e) H. Wang, K. Wang, Y. Xiang, H. Jiang, X.
Wan, N. Li, B. Tang, Adv. Synth. Catal.
Intermolecular dearomative arylations: a) A. Ozanne‐Beaudenon,
S. Quideau, Angew. Chem. Int. Ed. 2005 44, 7065; b) R.-Q. Xu,
P. Yang, H.-F. Tu, S.-G. Wang, S.-L. You, Angew. Chem. Int.
Ed. 2016 55, 15137.
, 2018, 360, 2352.
4
5
,
,
,
,
Miscellaneous reactions for dearomative C-C bond formations:
a) J. Garcia-Fortanet, F. Kessler, S.-L. Buchwald, J. Am. Chem.
Soc.
Commun.
Li, T.-F. Xu, J.-R. Gao, Y.-X. Jia, J. Am. Chem. Soc.
4936; d) J.-T.-R. Liddon, J.-A. Rossi-Ashton, R.-J.-K. Taylor,
W.-P. Unsworth, Org. Lett., 2018 20, 3349; e) M. Zhu, K. Zhou,
X. Zhang, S.-L. You, Org. Lett. 2018 20, 4379; f) N. Hu, H.
Jung, Y. Zheng, J. Lee, L. Zhang, Z. Ullah, X. Xie, K. Harms,
M.-H. Baik, E. Meggers, Angew. Chem. Int. Ed. 2018 57, 6242;
g) M.-W. Gribble, Jr., S. Guo, S.-L. Buchwald, J. Am. Chem.
Soc. 2018 140, 5057. The reaction with benzyl halides: h) M.
,
2009
,
131, 6676; b) K.-J. Wu, L.-X. Dai, S.-L. You, Chem.
2013 49, 8620; c) C. Shen, R.-R. Liu, R.-J. Fan, Y.-L.
2015 137
,
,
,
,
,
,
,
,
,
,
,
,
Bao, H. Nakamura, Y. Yamamoto, J. Am. Chem. Soc. 2001, 123,
759. i) S. Lu, M. Bao, Y. Yamamoto, Angew. Chem. Int. Ed.,
2008
Lett., 2018
,
47, 4366. j) M. Komatsuda, K. Muto, J. Yamaguchi, Org.
20, 4354.
,
Figure 1 Proposed mechanism.
6
7
S. Fujisawa, Y. Kadomab, I. Yokoe, Chem. Phys. Lipids
130, 189.
, 2004,
a) H. Egami, T. Ide, Y. Kawato, Y. Hamashima, Chem.
Commun. 2015 51, 16675; b) Y. Gao, G. Lu, P. Zhang, L.
Zhang, G. Tang, Y.-A. Zhao, Org. Lett. 2016 18, 1242.
a) T. Nishikata, Y. Noda, R. Fujimoto, T. Sakashita, J. Am.
Chem. Soc. 2013 135, 16372. See other related reports: b) C.
Liu, S. Tang, D. Liu, J. Yuan, L. Zheng, L. Meng, A. Lei, Angew.
Chem. Int. Ed. 2012 51, 3638; c) X. Chen, X. Liu, J.-T. Mohr, J.
Am. Chem. Soc. 2016 138, 6364; d) Z. Kailong, D. Joanne, P.-S.
Michael, P.-T. Stephen, ACS Catal. 2017 , 2353; e) C. Tang,
R. Zhang, B. Zhu, J. Fu, Y. Deng, L. Tian, W. Guan, X. Bi, J.
Am. Chem. Soc. 2018 140, 16929. See cyclization reactions: f)
M. Iwasaki, N. Miki, Y. Ikemoto, Y. Ura, Y. Nishihara, Org.
Lett. 2018 20, 3848. g) D. Liu, S. Tang, H. Yi, C. Liu, X. Qi, Y.
Lan, A. Lei, Chem. Eur. J., 2014 20, 15605.
Fluorination: a) T. Nishikata, S. Ishida, R. Fujimoto, Angew.
Chem. Int. Ed. 2016 55, 10008. Amination: b) S. Ishida, K.
Takeuchi, N. Taniyama, Y. Sunada, T. Nishikata, Angew. Chem.
Int. Ed. 2017 56, 11610. Alkoxylation: c) Z. Zhou, N.-E.
Behnke, L. Kürti, Org. Lett. 2018 20, 5452.
10 a) C. Che, H. Zheng, G. Zhu, Org. Lett 2015
A. García-Domínguez, C. Nevado, Angew. Chem. Int. Ed., 2016
,
,
,
,
8
,
,
,
,
Scheme 6 Reaction with 1a with Cu
,
,
,
, 7
We warmly thank YU Project for Formation of the Core
Research Centre and JSPS KAKENHI Grant Number JP
18H04262(TN) in Precisely Designed Catalysts with
Customized Scaffolding.
,
,
,
,
,
9
References and Notes
,
,
1
See recent reviews: a) A.-R. Pape, K.-P. Kaliappan, E.-P.
Kgndig, Chem. Rev., 2000 100, 2917; b) S. Quideau, L.
Pouységu, D. Deffieux, Synlett 2008 , 467; c) L. Pouysügu, D.
Deffieux, S. Quideau, Tetrahedron 2010 66, 2235; d) S.-P.
Roche, J.-A. Porco, Jr., Angew. Chem. Int. Ed. 2011 50, 4068;
e) C.-X. Zhuo, W. Zhang, S.-L. You, Angew. Chem. Int. Ed.,
,
,
,
,
,
,
, 4
,
.
, 17, 1617; b) Z. Li,
,
,
,
,
,
55, 6938; c) K. Nakamura, T. Nishikata, ACS Catal., 2017, 7
1049.
2012
1; g) W. Sun, G. Li, L. Hong, R. Wang, Org. Biomol. Chem.
2016
Rev.
Warudikar, R. Ranjan, B.-B. Rao, Org. Biomol. Chem.
,
51, 12662; f) Q. Ding, Y. Ye, R. Fan, Synthesis
,
2013
,
45
,
,
11 a) L. Furst, B. S. Matsuura, J. M. R. Narayanam, J. W. Tucker, C. R
J. Stephenson Org. Lett., 2010, 12, 3104; b) C. Theunissen, J. Wang
G. Evano, Chem. Sci., 2017, 8, 3465; c) Y. Yamane, K. Yoshinaga,
N. Sumimoto, T. Nishikata, ACS Catal., 2019, 9, 1757.
12 a) T. Pintauer, K. Matyjaszewski, Chem. Soc. Rev. 2008, 37, 1087.
b) K. Matyjaszewski, J. Xia, Chem. Rev. 2001, 101, 2921. c) M.
Kamigaito, T. Ando, M. Sawamoto, Chem. Rev. 2001, 101, 3689.
,
14, 2164; h) W.-T. Wu, L. Zhang, S.-L. You, Chem. Soc.
2016 45, 1570; i) C.-R. Reddy, S.-K. Prajapti, K.
,
,
,
2017
2017,
,
15
56
,
,
3130; j) S. Park, S. Chang, Angew. Chem. Int. Ed.
7720.
,
2
3
For selected examples for alkylations, see: intermolecular: a) M.-
F. Bartlett, W.-I. Taylor, J. Am. Chem. Soc. 1960 82, 5941; b) L.
Luo, H. Zheng, J. Liu, H. Wang, Y. Wang, X. Luan, Org. Lett.
2016 18, 2082; c) L. Shao, X.-P. Hu, Chem. Commun. 2017 53
8192; d) M. Okumura, A.-S. Shved, D. Sarlah, J. Am. Chem.
Soc. 2017 139, 17787.
Intramolecular: a) C. Zheng, L. Wang, J. Li, L. Wang, D.-Z.
Wang, Org. Lett. 2013 15, 4046; b) G. Han, Y. Liu, Q. Wang,
Org. Lett. 2014 16, 3188; c) B. Hu, Y. Li, W. Dong, K. Ren, X.
Xie, J. Wan, Z. Zhang, Chem. Commun. 2016 52, 3709; d) H.
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,