Remote C(sp3)?H Arylation and Vinylation of N-Alkoxypyridinium Salts to δ-Aryl and δ-Vinyl Alcohols

Article abstract of DOI:10.1002/chem.201902918

The reaction of readily available and bench-stable N-alkoxypyridinium salts with arylboronic and vinylboronic acids afforded δ-aryl and δ-vinyl alcohols, respectively, in the presence of fac-Ir(ppy)₃ and Cu(OTf)₂ dual catalysts. The reaction takes place through a domino process involving the reductive generation of alkoxyl radicals, 1,5-hydrogen atom transfer (1,5-HAT) and the copper-catalyzed cross-coupling reaction of the resulting translocated carbon radicals with boronic acids. Complementary to the Minisci reaction, this method allows for the arylation of nucleophilic alkyl radicals with both electron-rich and electron-poor arenes under mild reaction conditions.

Full text of DOI:10.1002/chem.201902918

A Journal of
Accepted Article
Title: Remote-C(sp3)-H Arylation and Vinylation of N-Alkoxypyridinium
Salts to δ-Aryl and δ-Vinyl Alcohols
Authors: Xu Bao, Qian Wang, and Jieping Zhu
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To be cited as: Chem. Eur. J. 10.1002/chem.201902918
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Remote-C(sp3)-H Arylation and Vinylation of N-Alkoxypyridinium
d
d
Salts to -Aryl and -Vinyl Alcohols
Xu Bao, Qian Wang, Jieping Zhu*
developed independently by the groups of Zhu,[7] Chen,[8] Baik
and Hong.[17a]
Abstract: Reaction of readily available and bench-stable N-
alkoxypyridinium salts with arylboronic and vinylboronic acids
afforded the d-aryl and d-vinyl alcohols, respectively, in the
presence of fac-Ir(ppy)3 and Cu(OTf)2 dual catalysts. The
reaction went through a domino process involving reductive
generation of alkoxyl radicals, 1,5-hydrogen atom transfer (1,5-
HAT) and copper-catalyzed cross-coupling of the resulting
Inherent to the Minisci type arylation of nucleophilic alkyl
radicals,[20] only electron-deficient heteroarenes are effective
reaction partners of the aforementioned d-C(sp3)-H arylation
protocols. To overcome this intrinsic reactivity issue, an
umpolung approach would have to be developed and transition-
metal catalyzed cross coupling of carbon radical with
organometallics deemed to be interest.[21-22] We report herein
the synthesis of d-aryl alcohols by a dual photoredox/Cu-
cataylzed arylation of d-C(sp3)-H of N-alkoxypyridinium salts 1
by aryl boronic acids 2 (Scheme 1c). Complementary to the
Minisci reaction, the present method allowed for the arylation of
nucleophilic alkyl radicals with both electron-rich and electron-
poor arenes under mild conditions. As the stating materials 1
are easily accessible from the corresponding alcohols, the
present method represented the first general synthesis of d-aryl
alcohols. Vinyl boronic acids are also suitable reaction partners
leading to unprecedented synthesis of d-C vinylated alcohols 4
under mild conditions (Scheme 1c).
translocated
carbon
radicals
with
boronic
acids.
Complementary to the Minisci reaction, the present method
allowed for the arylation of nucleophilic alkyl radicals with both
electron-rich and electron-poor arenes under mild conditions.
The generation of high energy heteroatom-centered
radicals followed by 1,5-hydrogen atom transfer (1,5-HAT) and
functionalization of the translocated carbon radical is a proven
strategy for the regioselective functionalization of the remote
unactivated C(sp3)-H bond.[1] The Hofmann-Löffler-Freytag
(HLF) reaction[2] and the Barton reaction[3] involving the N- and
O-centered radicals, respectively, are two prominent examples
that have been applied in complex natural product synthesis
and in late stage functionalization of bioactive molecules.[4]
a) Zhu and Chen’s intermolecular δ-heteroarylation of alcohols with electron-poor
heteroarenes
OH
OH
N
To further expand the synthetic utility of the alkoxyl radical-
based remote C(sp3)-H functionalization reactions,[5] recent
efforts have been focused mainly on the following two aspects:
a) the development of mild conditions for the generation of
alkoxyl radicals. Hypervalent iodine reagent alone[6] or in
combination with photoredox catalysts[7-9] and other oxidative
conditions[10-11] have been developed for the generation of the
alkoxyl radicals directly from alcohols.[12] However, in most of
the cases, over stoichiometric amount of oxidants were
generally required to derivatize in situ the hydroxyl group to a
weaker O-X bond with Zou’s conditions being a notable
exception.[11] On the other hand, N-alkoxyphthalimides[13-15] and
N-alkoxypyridinium[16-18] have recently been shown to be
excellent precursors of the alkoxyl radicals under reductive
conditions; b) the functionalization of the translocated C-
centered radicals. Besides classic atom/group transfer
reactions,[19] other interesting transformations have been
Ar
R2
Conditions
R2
R1
+
Het
R
R
R1
H
Zhu’s conditions: PIFA, TFA, 100W Blue LEDs, DCM, RT
Chen’s conditions: PFBI-OH, Ru(bpy)3Cl2, 23W CFL, HFIP, 30 °C
b) Baik and Hong’s heteroaryl transfer reaction
R1
R2
N
Ar
Photocatalyst
O
N
HO
R2
Ar
R1
TsO–
Blue LEDs
c) This work: Intermolecular δ-arylation/vinylation of alcohols with aryl/vinyl boronic acids
Me
fac-Ir(ppy)3 (0.01 equiv)
Cu(OTf)2 (0.05 equiv)
OH
BF4
1,10-Phen (0.075 equiv)
R3
R2
R3B(OH)2
Me
N
O
Me
R
+
R2
R1
Na3PO4 (1.5 equiv)
R1
3 R3 = Ar
4 R3 = vinyl
MeCN (c 0.1 M), Blue LEDs, RT
H
R
1
2
Scheme 1. Strategies for the d-arylation and d-vinylation of alcohols: Only
electron-poor heteroarenes can be introduced to the d position of alcohols by
existing methodologies.
[5]
developed for the synthesis of d-functionalized alcohols.
Among them, powerful intramolecular heteroaryl transfer and
intermolecular C-heteroarylation (Scheme 1a, 1) have been
The arylation of easily available and bench-stable N-
alkoxypyridinium salt 1a (Ar = Ph) by 4-(tert-butyl)phenylboronic
acid 2a was chosen as a test reaction (Scheme 2). Under
conditions developed previously for the azidation of 1a [fac-
Ir(ppy)3 (0.02 equiv), CuOAc (0.2 equiv), 1,10-Phen (0.3 equiv),
Blue LEDs, RT],[18] reaction of 1a with 2a failed to produce the
coupled product 3aa. Adding different base into the reaction
mixture has no positive effect. In most of these cases, 2-
phenyltetrahydrofuran was formed as a main product. While this
cycloetherification process involving the remote C(sp3)-H
functionalization is of interest,[23] we focused our efforts on the
planned C-C bond-forming process. Conditions were therefore
[*]
Dr. X. Bao, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fédérale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
Homepage: http://lspn.epfl.ch
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/chem.201902918
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surveyed varying systematically the copper source [Cu(I) and
Cu(II) salts], the ligands, the bases, the solvents, the
photoredox catalysts, the structure of pyridinium salts and their
counterions to encourage the cross-coupling reaction (See SI).
Interestingly, only Cu(II) salts were suitable pre-catalysts
capable of catalyzing the domino arylation process with
Cu(OTf)2 being the best copper source. The optimum conditions
consisted of performing the reaction of 1a (0.1 mmol) and 2a
(0.2 mmol) in MeCN at room temperature in the presence of fac-
Ir(ppy)3 (0.01 equiv), Cu(OTf)2 (0.05 equiv), 1,10-phen (0.075
equiv), and Na3PO4 (1.5 equiv). Under these conditions, the
desired product 3aa was obtained in 65% isolated yield. The
transfer of pyridine was completely suppressed under these
conditions. We note also that the aryl-alkyl ether resulting from
the Chan-Lam coupling of resulting alcohol with arylboronic acid
was not observed.[24] Only the unfunctionalized 4-phenylbutan-
1-ol was isolated as a side product.
successfully incorporated in the reaction to give 3au in 57%
yield. The heteroarylboronic acids, derived from benzofuran,
thiophene, and indole, were tolerated to deliver the
heteroarylation products (3av-3ax). The reaction was also not
very sensitive to the electronic and steric effects of the Ar group
as evidenced by the successful synthesis of compounds 3bn-
3ei. No diastereselectivity was observed when secondary
alcohol derived N-alkoxypyridinium salt was used as a starting
material (3ka). It is important to note that bromide and chloride
in both coupling partners were well tolerated providing therefore
an handle for further functionalization.
R
R1
Conditions[a]
Ar
O
N
+
OH
ArB(OH)2
H
Me
Me
R1
R
BF4
1
Me
2
3
tBu
tBu
tBu
tBu
R
Ar1
Ar
Conditions[a]
O
N
Ar1B(OH)2
+
OH
H
Me
Me
Ar
OH
OH
Ph
OH
R
Ph
OH
R
BF4
n
3oa/3oa’(5:1), 54%
3pa R = Ph, 63%
3qa R = N3, 48%
3ma n = 4, 61%
3na n = 5, 55%
1
2
3
Me
Me
3aa R1 = tBu, 65%
3ab R1 = H, 57%
3ac R1 = Me, 68%
3ag R1 = OCF3, 56%
3ah R1 = OAc, 67%
3ai R1 = F, 67%
F
R1
tBu
tBu
tBu
3ad R1 = cC6H11, 61% 3aj R1 = Cl, 60%
F
3ae R1 = OMe, 59%
3af R1 = OPh, 67%
3ak R1 = Br, 71%
3al R1 = CF3, 45%
OH
OH
OH
OH
OH
OH
OH
OH
O
Ph
Ph
Ph
Ph
H
4
BnO
3as 62%
3ra 37%
3sa 53%
3ta 38%
3mc 46%
Cl
Cl
R1
3an R1 = Me, 73%
3ao R1 = Ph, 58%
F
Br
Ph
Me
3ap R1 = CO2Me, 58%
3aq R1 = Br, 71%
OH
Ph
3au 57%
F
OH
3ar R1 = CH=CH2, 56%
3at 69%
OH
OH
OH
Me
4
5
5
4
NBoc
S
3mk 42%
3mn 45%
3nm 43%
3ns 36%
O
OH
OH
Scheme 3. Arylation of non-benzylic C(sp3)-H bond. [a] 1 (0.1 mmol), 2 (2.0
equiv), Cu(OTf) (0.10 equiv), 1,10-Phen (0.15 equiv), Na PO (1.5 equiv),
fac-Ir(ppy)3 (0.01 equiv) in CH3CN (1.0 mL), Blue LEDs irradiation, RT, 48 h.
OH
Ph
3aw 48%
Ph
3av 56%
OH
Ph
R
,
2
3
4
3bn R = Me, 72%
3cn R =OMe, 53%
3ax 37%
Br
tBu
Me
Me
Cl
The reaction was not restricted to the benzylic position as
non-benzylic aliphatic C(sp3)-H underwent arylation without
event as shown in Scheme 3. Both electron-rich and electron-
poor arylboronic acids were viable coupling partners. The azide
group (3qa) was compatible with the reaction conditions and the
C(sp3)-H a to the benzyl ether was similarly arylated (3sa, 3ta).
Importantly, the most challenging CH3 arylation can also be
accomplished, albeit with a reduced yield (3ra, 37%). When N-
alkoxypyridinium salt derived from 5-phenylpentanol was used,
compounds 3oa and 3oa’ resulting from 1,5-HAT and 1,6-HAT,
respectively, were formed in a ratio of 5:1.
OH
F
OH
OH
R
OH
Ph
3fa R = Br, 74%
3ga R = CF3, 56%
3jc 61%
3dk 65%
R1
3ec 56%
Br
tBu
F
OH
OH
OH
F
OH
R
Me
3kc R = R1 = Me, 63%
3lc R = Et, R1 = Me, 59%
3ka R = Me, R1 = tBu, 53%
d.r. 1:1
Cl
Br
3hk 43%
3ia 67%
3ei 52%
Gratifyingly, the arylation conditions were applicable to the
d-vinylation of N-alkoxypyridinium salts using vinyl boronic acids
as reaction partners (Scheme 4). As shown in Scheme 4,
diverse aryl, alkyl and unsubstituted vinyl boronic acids
underwent reaction with a range of N-alkoxypyridinium salts to
afford the corresponding vinylation products in good yields.
Recently, the groups of Yu[25a] and Duan,[25b] respectively,
reported elegant g-vinylation of oxime esters by addition of the
translocated carbon radicals to styrene or styrene derived
boronic acids for the synthesis of the g-vinyl ketones. However,
Scheme 2. Arylation of benzylic C(sp3)-H bond. 1 (0.1 mmol), 2 (2.0 equiv),
Cu(OTf)2 (0.05 equiv), 1,10-Phen (0.075 equiv), Na3PO4 (1.5 equiv), fac-
Ir(ppy)3 (0.01 equiv) in CH3CN (1.0 mL), Blue LEDs irradiation, RT, 48 h.
The scope of this dual photoredox/copper-catalyzed d-
C(sp3)-H bond arylation of N-alkoxypyridinium salts was first
examined varying the nature of the aryl boronic acids 2. As
shown in Scheme 2, arylboronic acids bearing electron-
donating (alkyl, OMe, OPh) and electron-withdrawing groups
(OAc, F, Cl, Br, CF3, CO2Me) at different positions participated
in the reaction to afford 4,4’-diaryl substituted butanols (3aa-
3at) in good yields. 2-Naphthylboronic acid could be
only styrene and its derivatives were active as vinylating agents
[25a,b]
under their conditions.
To the best of knowledge, the
present method represented the first general methods for the
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incorporation of a diversely substituted vinyl group into the d
position of alcohols.
standard conditions furnished 8a/8a’ (Z/E mixture) in 86% yield
indicating that the alkoxyl radical intermediate underwent 1,5-
HAT much faster than the 6-exo-trig cyclization. [17b, 27]
R1
R2
O
N
Conditions[a]
R2
+
O
H
Me
Me
B(OH)2
tBu
tBu
Me
Standard Conditions
HO
H
Me
N
OH
BF4
R1
+
BF4
B(OH)2
Me
1
2
4
Me
8a/8a'(Z/E = 1:2), 86%
1u
2a
Ph
R2
4ay R2 = Ph, 53%
4az R2 = 4-F-C6H4, 62%
OH
OH
4by R1 = Me, 52%
4ey R1 = F, 56%
4fy R1 = Br, 47%
Scheme 6. Competition experiments: 1,5-HAT vs 6-exo-trig cyclization.
4aa' R2 = 4-CF3-C6H4, 55%
4ab' R2 = 4-Ph-C6H4, 46%
4ac' R2 = 4-Me-C6H4, 63%
R1
R2
Ph
R2
On the basis of the aforementioned experimental results, a
photoredox/copper dual catalytic reaction pathway[28-29] is
proposed to account for the formation of d-aryl/vinyl alcohols
from N-alkoxypyridinium salts and boronic acids (Scheme 7).
Reduction of 1a by excited Ir(III)* complex would generate the
radical A and Ir(IV). Reduction of the latter by Cu(I)X would
regenerate the Ir(III) and Cu(II) species which, upon
transmetallation with aryl or vinyl boronic acid, would afford
RCu(II)X B. On the other hand, fragmentation of the radical A
would generate the alkoxyl radical C which was subsequently
converted to the carbon radical D by a facile 1,5-HAT process.
Radical rebound of D with B would afford the Cu(III) species E.
Reductive elimination would then deliver the d-C(sp3)-H
arylated or vinylated product 3 or 4 with the concurrent
regeneration of Cu(I) salt. In spite of the presence of alkoxyl
radicals and copper salts in the reaction mixture, the acetonitrile
(BDE of H-CH2CN: 96 Kcal/mol)[30] is compatible with the
present mild conditions as a result of a kinetically competent
1,5-HAT of the alkoxyl radical intermediates.
OH
Cl
OH
OH
Cl
MeO
4hy 54%
4ja' R2 = 4-CF3-C6H4, 49%
4ca' R2 = 4-CF3-C6H4, 43%
R2
R2
Ph
OH
OH
OH
n
n
R1
4ad' R1 = H, R2 = nC6H13, 58%
4cd' R1 = OMe, R2 = nC6H13, 51%
4ae' R1 = R2 = H, 58%
4my n = 4, 46%b
4ny n = 5, 41%b
4mc' n = 4, R2 = 4-Me-C6H4, 52%b
4nc' n = 5, Ar = 4-Me-C6H4, 43%b
Scheme 4. Vinylation of unactivated C(sp3)-H bond. [a] 1 (0.1 mmol), 2 (2.0
equiv), Cu(OTf)2 (0.05 equiv), 1,10-Phen (0.075 equiv), Na3PO4 (1.5 equiv),
fac-Ir(ppy)3 (0.01 equiv) in CH3CN (1.0 mL), Blue LEDs irradiation, RT, 48 h;
[b] Cu(OTf) (0.10 equiv), 1,10-Phen (0.15 equiv).
,
2
To illustrate the synthetic potential of this remote
functionalization methodology, synthesis of pimozide (5),[26] an
antipsychotic drug, was undertaken (Scheme 5). Reaction of 1e
with 2i under standard conditions afforded 4,4’-di(4-
fluorophenyl) butanol (3ei) in 52% yield. Conversion of hydroxy
group to iodide under Apple conditions followed by its SN2
reaction with piperidine derivative 7 afforded pimozide (5) in
excellent overall yield.
R
Ir(III)
hν
OH
Ph
3 R = Ar
4 R = vinyl
Cu(I)X
Ir(III)*
R
Me
Me
Cu(III)X
OH
Ir(IV)
Ph
N
Ph
Cu(II)
O
BF4
E
F
F
1a
Me
Me
Me
F
RB(OH)2
O
N
2
[a]
RCu(II)X
B
OH
[b]
Ph
Me
N
O
H
Me
Me
H
+
Me
A
OH
O
O
Ph
Ph
BF4
B(OH)2
N
Me
D
C
F
Me
1e
2i
3ei
Me
F
O
NH
F
H
N
N
Scheme 7. Possible reaction pathway. Ligands were omitted for the sake of
clarity.
[c]
I
N
N
HN
7
F
6
5 Pimozide
F
In summary, a dual photoredox/copper catalytic system has
been developed for the conversion of N-alkoxypyridinium salts
to the d-aryl or d-vinyl alcohols. The reaction went through a
domino sequence involving the reductive generation of alkoxyl
radicals, 1,5-HAT followed by Cu-mediated cross coupling of
the resulting translocated carbon radicals with the aryl/vinyl
boronic acids. Complementary to the Minisci type reaction, the
present methodology allowed us to introduce both electron-rich
and electron-poor arenes to the d position of alcohols.
Scheme 5. Synthesis of pimozide. [a] Cu(OTf)2 (0.05 equiv), 1,10-Phen
(0.075 equiv), Na3PO4 (1.5 equiv), fac-Ir(ppy)3 (0.01 equiv) in CH3CN (1.0 mL),
Blue LEDs irradiation, RT, 52%; [b] I2, PPh3, imidazole, RT, 92%; [c] Na2CO3,
CH3CN/(ClCH2)2, 80 °C, 71%.
To gain insight on the reaction mechanism, several control
experiments were conducted. Reaction of 1a with 2a failed to
produce 3aa in the absence of either one of the following
ingredients, fac-Ir(ppy)3 (RT and 80 °C), Cu(OTf)2 or irradiation.
Acknowledgements
Addition of radical scavengers
such as 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO) or 2,6-di-tert-butyl-4-
methylphenol (BHT) to the reaction mixture inhibited completely
the process. Interestingly, the reaction of 1u with 2a under
We thank EPFL (Switzerland) and Swiss National Science
Foundation (SNSF, N° 200021-178846/1) for financial supports.
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10.1002/chem.201902918
Chemistry - A European Journal
COMMUNICATION
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10.1002/chem.201902918
Chemistry - A European Journal
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
Synthetic Method
fac-Ir(ppy)3 (0.01 equi)
Cu(OTf)2 (0.05 equiv)
1,10-Phen (0.075 equiv)
OH
Me
BF4
R1
R2
R2
Xu Bao, Qian Wang, and Jieping
Zhu*__________ Page – Page
O
R3
+
RB(OH)2
R1
R3
R
N
H
Na3PO4 (1.5 equiv)
MeCN (c 0.1 M), Blue LEDs, RT
Me
Me
2 R = Ar
3 R = vinyl
1
Remote-C(sp3)-H Arylation and Vinylation
of N-Alkoxypyridinium Salts to
-Vinyl Alcohols
d
-Aryl and
d
Through space walking: Under mild dual photoredox/copper catalysis, the N-alkoxypyridinium salts
were transformed to d-aryl and d-vinyl alcohols via a sequence of reductive generation of alkoxyl radicals
followed by 1,5-HAT and copper-catalyzed cross-coupling of the resulting translocated carbon radicals
with boronic acids.
This article is protected by copyright. All rights reserved.