Dual Photoredox/Copper Catalysis for the Remote C(sp3)?H Functionalization of Alcohols and Alkyl Halides by N-Alkoxypyridinium Salts

Article abstract of DOI:10.1002/anie.201813356

Under mild dual photoredox/copper catalysis, the reaction of N-alkoxypyridinium salts with readily available silyl reagents (TMSN₃, TMSCN, TMSNCS) afforded δ-azido, δ-cyano, and δ-thiocyanato alcohols in high yields. The reaction went through a domino process involving alkoxy radical generation, 1,5-hydrogen atom transfer (1,5-HAT) and copper-catalyzed functionalization of the resulting C-centered radical. Conditions for catalytic enantioselective δ-C(sp³)?H cyanation were also documented.

Full text of DOI:10.1002/anie.201813356

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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International Edition
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Accepted Article
Title: Dual Photoredox/Copper Catalysis for the Remote C(sp3)-
H Functionalization of Alcohols and Alkyl Halides Via N-
Alkoxypyridinium Salts
Authors: Xu Bao, Qian Wang, and Jieping Zhu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201813356
Angew. Chem. 10.1002/ange.201813356
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10.1002/anie.201813356
Angewandte Chemie International Edition
COMMUNICATION
Dual Photoredox/Copper Catalysis for the Remote C(sp3)-H
Functionalization of Alcohols and Alkyl Halides Via N-
Alkoxypyridinium Salts
Xu Bao, Qian Wang, Jieping Zhu*
Abstract: Under mild dual photoredox/copper catalysis, the
a) Alkoxy radicals: generation and application in organic synthesis
R1
X
H
reaction of N-alkoxypyridinium salts with readily available silyl
reagents (TMSN3, TMSCN, TMSNCS) afforded d-azido, d-
cyano, d-thiocyanato alcohols in high yields. The reaction went
through a domino process involving alkoxy radical generation,
1,5-hydrogen atom transfer (1,5-HAT) and copper-catalyzed
functionalization of the resulting C-centered radical. Conditions
for catalytic enantioselective d-C(sp3)-H cyanation were also
documented.
O
R1
R1
H
R1
X
R1
●O
X
H
●
hν
OH
OH
O
or ꢀ
A
B
Common alkoxy radical precursors:
O
RO–NO
RO–SPh
RO–OH
RO–Cl
R1
1a R = Et, R1 = 2-Me
1b R = CF3, R1 = 4-CN
RO N
S
RO N
N
OR
X–
1
O
b) N-Alkoxypyridinium salts as precursors of alkoxy radicals
2
Ar
HO
Photocatalyst
N
R1
Ar
R1
OTs
Since Arigoni’s seminal paper on the remote
●
N
O
R2
Blue LEDs
HO
3
R1 R2
functionalization of unactivated C(sp )-H bond involving in situ
R2
3
B
2
generated alkoxy radicals,[1] several synthetically useful
protocols have been developed with the classic Barton reaction
of alkyl nitrites (RONO) being the most influential.[2]
Mechanistically, homolytic cleavage of the O-X or O-metal
bonds under photolysis or thermal conditions would generate
the alkoxy radical A. Regioselective 1,5-hydrogen atom transfer
(1,5-HAT) would afford the carbon radical B which, upon
abstraction of the X• from the starting material, would furnish the
d-C(sp3)-H functionalized product with concurrent regeneration
of the alkoxy radical A to propagate the radical chain process
(Scheme 1a).[3] One major competitive reaction of the 1,5-HAT
process is the b-scission of the alkoxy radical A. Indeed, the
alkoxy radical generated from alcohol under oxidative,[4] or
c) This work: Photoredox/Cu dual-catalyzed remote C(sp3)-H bond functionalization
Me
R1
R2
X
R2
R3
Me
Ir(III, IV)
Cu(I, II, III)
+
TMSX
HO
N
O
BF4
R3
Blue LEDs
Me
R1
5 X = N3, 6 X = CN, 7 X = SCN
4
Scheme 1. Remote C(sp3)-H functionalization of N-alkoxypyridinium salts.
interested in merging the radical 1,5-HAT[17] with the metal-
catalyzed cross-coupling reactions.[18,19] While generation of
alkoxy radical directly from alcohols are well developed, the
oxidative conditions [Pb(OAc)4, PIDA/I2, Ce4+/photoredox
catalysis] associated with such processes may impose certain
limitation to the subsequent functionalization of the translocated
carbon radical B. To complement this oxidative approach, we
have been searching for alkoxy radical precursors that can be
homolytically cleaved under reductive conditions in order to
photoredox
catalytic
conditions,[5,6]
and
from
alkyl
benzenesulfenates[7] and N-alkoxypyridine-2-thiones[8] were
initially developed for the functionalization via b-scission
pathway.[9]
While many different transformations could in principle be
envisaged for the functionalization of the translocated C-
centered radical B, most of the literature examples dealt with its
oxidation to alcohols[10] and to olefins[11] and the formation of the
C-halide bond.[12] Recently, the intramolecular addition of
intermediate B to the tethered carbon-carbon multiple bonds,[13]
to heteroaromatics[14] and intermolecular addition to polarized
double bonds have been developed for the creation of C-C[12a,15]
as well as C-N bonds.[12a, 16]
streamline
the
subsequent
metal-catalyzed
cross
coupling/ligand transfer reactions. Towards this end, the easily
available N-alkoxypyridinium salts 1 attracted our attention.
Lakhdar and coworkers were the first to demonstrate that the
ethoxy radicals can be generated from 1a (R = Et, R1 = 2-Me)
under mild photocatalytic conditions.[20] Independently, Togni’s
group invented N-trifluoromethoxypyridinium salt 1b (R = CF3)
as a novel trifluoromethoxylation reagent for arenes,[21] while
Dagousset and co-workers developed an alkoxylative
difunctionalization of alkenes using 1 as precursors of alkoxy
radicals.[22] Baik, Hong et al reported the conversion of the N-
alkoxypyridinium salts 2 to the d-pyridylated alcohols 3 under
organocatalytic photoredox conditions.[14c] The reaction was
proposed to proceed by radical chain mechanism involving the
1,5-HAT of alkoxy radical and reaction of the resulting carbon
radical B with 2 as the chain carrying step (Scheme 1b).
Prompted by this report, we disclose herein unprecedented
transformations converting N-alkoxypyridinium salts 4 to d-
azido (5 X = N3), d-cyano (6 X = CN) and d-thiocyanato (7 X =
SCN) alcohols using readily accessible silyl reagents TMSX (X
= N3, CN, NCS) as reaction partners (Scheme 1c). While dual
photoredox/copper catalysis has been developed for the
To expand the repertoire of the aforementioned remote
C(sp3)-H functionalization processes, we recently became
[*]
Dr. Xu. 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/anie.201813356
Angewandte Chemie International Edition
COMMUNICATION
formation of C-C and C-X bonds, they have not been, to the best
of our knowledge, exploited for the remote C(sp3)-H bond
functionalization.[23]
compatible with the reaction conditions. Azidation of N-
alkoxypyridinium salts 4 derived from secondary alcohols
proceeded smoothly to afford 5t and 5u in yields of 73% and
71%, respectively. Importantly, the methyl group which is the
most difficult to be functionalized by the 1,5-HAT chemistry
underwent azidation smoothly to afford, after benzoylation of
the primary alcohol, the 4-azidobutyl benzoate (5v) in 42% yield.
The N-alkoxypyridinium salts 4 were prepared in one step
by reaction of pyridine-N-oxide with the alkyl tosylates or alkyl
halides. Gratefully, irradiation of an acetonitrile solution of 4a
and TMSN3 in the presence of CuCl and fac-Ir(ppy)3 at room
temperature provided indeed 4-azido-4-phenylbutan-1-ol (5a) in
28% yield together with 2-phenyltetrahydrofurane (8a) and 4-
phenylbutan-1-ol (9) (Scheme 2a).[24] Importantly, resubmitting
8a to the reaction conditions did not afford 5a indicating that 5a
did not result from the ring opening of 8a by TMSN3.[25]
Submitting
1-(4-(benzyloxy)butoxy)-2,4,6-trimethylpyridin-1-
ium (R1 = R2 = H, R3 = BnO) to the reaction conditions afforded
2-(benzyloxy)tetrahydrofuran (8y) in 64% yield resulting from
the rapid oxidation of the translocated carbon radical to the
oxonium intermediate followed by cyclization.
Me
Me
N3
R1
Conditions[a]
a) Initial results
R2
R3
OH
R3
N
+
TMSN3
fac-Ir(ppy)3 (2 mol%)
CuCl (0.2 equiv)
Me
Me
O
H
R1
Me
+
TMSN3
R2
Ph
N
BF4
5
4
O
Blue LEDs, CH3CN, RT
Me
BF4
4a
N3
N3
N3
OH
N3
R
OH
OH
OH
5a 28%
O
Ph
Ph
OH
+
Ph
+
R
X
8a 29%
9 26%
5a R = H, 72%
5b R = Me, 64%
5c R = OMe, 41%
5d R = Ph, 69%
5e R = F, 75%
5f R = Cl, 69%
5g R = Br, 76%
5h R = CF3, 63%
N3
5i R = Cl, 71%
5j R = Br, 78%
N3
5k 73%
b) Effects of counterions and pyridinium structures on the reaction efficiency
N3
fac-Ir(ppy)3 (2 mol%)
CuOAc (0.2 equiv)
N3
R
R
OH
OH
OH
+
TMSN3
Ph
N
R
O
X
1,10-Phen (0.3 equiv)
CH3CN (c 0.05 M)
Blue LEDs, RT
5m R = Me, 53%
5n R = Et, 62%
4a
5a
5l 61%
N3
R
R = Me, X = BF4
R = Me, X = ClO4
R = Me, X = PF6
R = Me, X = TsO
R = Ph, X = BF4
72%
54%
66%
63%
12%
N3
OH
OH
OH
OH
Ph
5p 59%
5q 46%
N3
5o 56%
N3
N3
OH
OH
BnO
N3
R
Scheme 2. Proof of concept: Initial results and optimum conditions.
5t R = Me, 73%
5u R = Et, 71%
5r 63%
5s 58%
Me N3
N3
OH
OCOPh
5v 42%
H
5w R = Me, 66%
5x R = F, 66%
O
BnO
Encouraged by these initial results, reaction conditions were
systematically surveyed varying the photoredox catalysts (Ir
and Ru complex), the metal salts (Cu and Fe salts), the ligands
and the solvents. The best conditions found consisted of
irradiating (blue LEDs) an acetonitrile solution (c 0.05 M) of 4a
and TMSN3 in the presence of fac-Ir(ppy)3 (0.02 equiv), CuOAc
(0.2 equiv),1,10-Phen (0.3 equiv) at room temperature. Under
these conditions, the desired 4-azido-4-phenybutan-1-ol (5a)
was isolated in 72% yield. It’s important to note that a) for the
reason that was unclear to us, the counterion of the pyridinium
salt influenced the reaction efficiency with tetrafluoroborate
being the best (Scheme 2b); b) the substituents on the pyridine
ring impacted significantly the reaction outcome; Under
optimized conditions, the reaction of 2,4,6-triphenyl substituted
N-alkoxypyridinium salt with TMSN3 afforded 5a in only 12%
yield. We note that partial decomposition of this salt occurred
upon irradiation with Blue LEDs as it absorbs in the visible range.
8y
R
Scheme 3. Remote d-C(sp3)-H azidation of alcohols. [a] 4 (0.1 mmol), TMSN3
(4.0 equiv), CuOAc (0.2 equiv), 1,10-Phen (0.3 equiv), and fac-Ir(ppy)3 (0.02
equiv) in CH3CN (2.0 mL), blue LEDs irradiation, RT, 48 h.
Me
Me
CN
R1
Conditions[a]
R2
R3
OH
R1
R3
+
TMSCN
N
O
H
R2
Me
BF4
4
6
CN
CN
CN
OH
R
OH
OH
OH
R
6a R = H, 73%
6b R = Me, 65%
6i R = Cl, 78%
6j R = Br, 82%
6k 56%
CN
6c R = OMe, 48%
6d R = Ph, 82%
6e R = F, 71%
6f R = Cl, 76%
6g R = Br, 83%
6h R = CF3, 81%
CN
OH
R
6m R = Me, 59%
6n R = Et, 65%
6l 53%
The scope of this dual photoredox/copper-catalyzed d-
C(sp3)-H azidation is depicted in Scheme 3. The 4-aryl-4-
azidobutan-1-ols were synthesized in moderate to high yields
from the corresponding N-alkoxypyridinium salts 4. The
presence of electron-withdrawing group in the aromatic ring (F,
Cl, Br, CF3) was well tolerated. However, electron-rich aromatic
substituent (R = OMe) afforded the azidation product 5c in
moderate yield due to the competitive formation of the 2-aryl
substituted tetrahydrofuran. Tertiary d-C(sp3)-H including the
benzylic ones can be similarly functionalized to furnish the
quaternary azides (5k-5n, 5t, 5u, 5w, 5x) The reaction was not
restricted to the benzylic position as aliphatic alkanols
underwent the d-C(sp3)-H azidation without event. Functional
groups such as benzyl ether (5r) and azide (5s) were
CN
CN
CN
OH
OH
OH
OH
OH
CN
Ph
6p 83%
6q 75%
6o 87%
CN
CN
CN
OH
OH
N3
BnO
H
R
6t R = Me, 56%
6u R = Et, 61%
6r 81%
6s 71%
6v 53%
Scheme 4. Remote d-C(sp3)-H cyanation of alcohols. [a] 4 (0.1 mmol),
TMSCN (3.0 equiv), CuOAc (0.2 equiv), 1,10-Phen (0.3 equiv), and fac-
Ir(ppy)3 (0.02 equiv) in CH3CN (1.0 mL), blue LEDs irradiation, RT, 48 h.
To extend the application scope of this dual catalytic
approach, cyanation of N-alkoxypyridinium salts 4 was next
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10.1002/anie.201813356
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COMMUNICATION
investigated. Replacing TMSN3 by TMSCN under otherwise
identical conditions converted 4a to 4-cyano-4-phenylbutan-1-
ol (6a) in 73% yield (Scheme 4).[26] Screening the copper salts
and the ligand structures (See SI) did not improve the reaction
outcome and the azidation conditions were directly exploited for
the scope of this novel cyanation reaction. As it is shown in
Scheme 4, the cyanation took place not only on the benzylic,[27]
but also on the simple aliphatic carbons including the methyl
group (6v). In line with the radical mechanism, cyanation of
tertiary d-C(sp3)-H proceeded smoothly to afford the
corresponding quaternary nitriles in good yields (6l-6n, 6t, 6u).
To gain insight on the reaction mechanism, several control
experiments were conducted. Reaction of 4a with TMSN3 failed
to produce 5a in the absence of either one of the following
ingredients, fac-Ir(ppy)3, CuOAc or irradiation. Addition of
radical scavenger such as TEMPO or BHT to the reaction
mixture of 4p and TMSX (X = N3, CN) inhibited completely the
process. Finally, reaction of 4a and 4-(p-tolyl)butan-1-ol (12,
one to one mole ratio) under standard azidation conditions
afforded 5a in 68% yield without producing even a trace amount
of 5b (Scheme 7). The results of this crossover experiment
suggested that the activation of the remote C(sp3)-H process
occurred exclusively in an intramolecular 1,5-HAT fashion.
To our delight, thiocyanation of N-alkoxypyridinium salts 4
with trimethylsilylisothiocyanate (TMSNCS) took place under
standard azidation conditions to afford the 4-thiocyanato
substituted alcohols, albeit with moderate yields. Three
representative examples involving the functionalization of
benzylic, aliphatic and tertiary C(sp3)-H are shown in Scheme
5. Although thiocyanation of (hetero)arenes and alkenes have
been well developed,[28] the thiocyanation of unactivated
alkanes was, to the best of our knowledge, unknown.[29]
BF4 Me
O
N
N3
N3
Conditions[a]
Me
4a
Me
OH
+
OH
+
OH
5a 68%
5b 0%
12
Me
Scheme 7. Crossover experiment. [a] 4a (0.1 mmol), 12 (0.1 mmol), TMSN3
(4.0 equiv), CuOAc (0.2 equiv), 1,10-Phen (0.3 equiv), and fac-Ir(ppy)3 (0.02
equiv) in CH3CN (2.0 mL), blue LEDs irradiation, RT, 48 h.
Me
Me
SCN
Conditions[a]
R1
R2
R3
OH
R1
+
R3
TMSNCS
N
O
H
R2
Me
On the basis of the aforementioned experimental results, a
possible reaction pathway is depicted in Scheme 8. Reduction
of 4a by excited Ir(III)* species would produce the radical C and
Ir(IV). The latter could oxidize the Cu(I) salt in the presence of
TMSX to afford Cu(II)X(OAc) salt with concurrent regeneration
of the Ir(III) species. On the other hand, the fragmentation of
radical C would generate the alkoxy radical A which, upon 1,5-
HAT, would give the carbon radical B. Radical rebound of B with
Cu(II)X(OAc) would afford the Cu(III) species D. Reductive
elimination would then deliver the d-C(sp3)-H functionalized
products (5a, 6a, 7a) with the concurrent release of Cu(I) salt
(route a). Alternatively, radical B could also be converted to the
product via a Cu-centered redox ligand transfer process,
especially in the case of azidation reaction (route b).[31] The fact
that high enantioselective cyanation could be realized
suggested that the Cu might be involved in the functionalization
of C-centered radical B. The oxidation of radical B to cation
followed by nucleophilc trapping, although mechanistically
viable, should not be occurring. The involvement of benzylic
cation intermediate would inevitably lead to the formation of
tetrahydrofuran 8a as it was observed in our initial conditions
screening (cf Scheme 2a).
BF4
4
7
SCN
SCN
SCN
OH
OH
Me
OH
7o 48%
7a 52%
7u 56%
Scheme 5. Remote d-C(sp3)-H thiocyanation of alcohols. [a] 4 (0.1 mmol),
TMSNCS (4.0 equiv), CuOAc (0.2 equiv), 1,10-Phen (0.3 equiv), and fac-
Ir(ppy)3 (0.02 equiv) in CH3CN (2.0 mL), blue LEDs irradiation, RT, 48 h.
Inspired by the recent work of Liu on the Cu-catalyzed
enantioselective benzylic cyanation, we examined the catalytic
enantioselective cyanation of 4a.[27] As the reaction liberates
one equivalent of pyridine which is an excellent ligand for
copper, the difficulty associated with the development of
catalytic enantioselective process is obvious. To minimize the
interference of the pyridine, tridentate (pybox) and bidentate
(bisoxazoline) ligands were selected for this purpose (See SI for
ligand screening). The best results were obtained using 10 as
ligand in the presence of fac-Ir(ppy)3 (4 mol%) and CuOAc (20
mol%) as catalysts. Under these conditions, 6a was isolated in
74% yield with 86% ee. The (S) absolute configuration of 6a was
determined by its conversion to the known (S)-2-
phenylpentane-1,5-diol (11) and by comparing the sign of the
optical rotations.[30]
X
TMSX
Ir(III)
Ir(IV)
O
hv
OH
Ph
Cu(I)OAc
route a
5a X = N3
6a X = CN
7a X = SCN
Ir(III)*
Me
Me
[a]
Ph
Cu(III)X(OAc)
OH
Me
Me
+
OH
TMSCN
Ph
N
O
CN
Ph
Ph
Ph
N
N
O
BF4
D
Me
6a 74%, 86% ee
BF4
4a
1a
X
O
O
Me
Me
OH
[b]
Ph
Cu(II)X(OAc)
N
N
route b
Ph
O
OH
11
Cu(I)OAc
H
Me
C
OH
10
OH
Ph
Ph
N
B
A
Scheme 6. Catalytic enantioselective cyanation. [a] 4a (0.1 mmol), TMSCN
(3.0 equiv), CuOAc (0.2 equiv), 10 (0.3 equiv), and fac-Ir(ppy)3 (0.04 equiv)
in CH3CN (1.0 mL), blue LEDs irradiation, RT, 48 h; [b] i) DIBAL-H, DCM, -
78 °C, ii) NaBH4, MeOH, 0 °C, 57%.
Scheme 8. Possible reaction pathway. Ligands were omitted for the sake of
clarity.
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10.1002/anie.201813356
Angewandte Chemie International Edition
COMMUNICATION
Campbell, J. C. T. Leung, K. M. Johnson, G. M. Sammis, Org. Lett.
2009, 11, 2019; c) H. Zhu, J. C. T. Leung, G. M. Sammis, J. Org.
Chem. 2015, 80, 965.
In summary, we developed three unprecedented remote
C(sp3)-H functionalization protocols by means of dual
photoredox/copper catalysis. Azido, cyano and thiocyanato
groups were successfully introduced to the d position of alcohols
under the same reaction conditions. Since N-alkoxypyridinium
salts 4 were prepared in one step from alkyl halides, the present
transformation represented a two-step conversion of alkyl
halides to d-functionalized alcohols, an unchartered
retrosynthetic logic. A catalytic enantioselective cyanation
protocol has also been developed which, to the best of our
knowledge, represented the first example of asymmetric
transformation involving a 1,5-HAT process.
[14] X. Wu, M. Wang, L. Huan, D. Wang, J. Wang, C. Zhu, Angew. Chem.
Int. Ed. 2018, 57, 1640; Angew. Chem. 2018, 130, 1656; b) X. Wu, H.
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[15] a) J. Zhang, Y. Li, F. Zhang, C. Hu, Y. Chen, Angew. Chem. Int. Ed.
2016, 55, 1872; Angew. Chem. 2016, 128, 1904; b) C. Wang, K.
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Acknowledgements
[16] A. Hu, J.-J. Guo, H. Pan, H. Tang, Z. Gao, Z. Zuo, J. Am. Chem. Soc.
2018, 140, 1612.
We thank EPFL (Switzerland) and Swiss National Science
Foundation (SNSF, N° 200021-178846/1) for financial supports.
[17] D. P. Curran, D. Kim, H. T. Liu, W. Shen, J. Am. Chem. Soc. 1988,
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[18] Z. Li, Q. Wang, J. Zhu, Angew. Chem. Int. Ed. 2018, 57, 13288; Angew.
Chem. 2018, 130, 13472.
Keywords: alkoxy radical, C-H activation, 1,5-HAT,
photoredox catalyst, dual catalysis
[19] Similar reaction has been developed independently by the group of
Nagib, see: Z. Zhang, L. M. Stateman, D. A. Nagib, Chem. Sci. 2018,
DOI: 10.1039/c8sc04366c.
[20] a) V. Quint, F. Morlet-Savary, J.-F. Lohier, J. Lalevée, A.-C. Gaumont,
S. Lakhdar, J. Am. Chem. Soc. 2016, 138, 7436; b) I. Kim, M. Min, D.
Kang, K. Kim, S. Hong, Org. Lett. 2017, 19, 1394.
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10.1002/anie.201813356
Angewandte Chemie International Edition
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
Synthetic Method
Me
fac-Ir(ppy)3 (2 mol%)
Cu(OAc) (0.2 equiv)
R1
R2
R3
O
O
H
X
R2
Xu Bao, Qian Wang, and Jieping
Zhu*__________ Page – Page
Me
+
TMSX
HO
N
N
N
O
BF4
1,10-Phen (0.3 equiv)
CH3CN
Blue LEDs, RT
R3
Me
R1
X = N3, CN, SCN
Dual Photoredox/Copper Catalysis for the
3
Remote C(sp)-H Functionalization of Alcohols
and Alkyl Halides via N-Alkoxypyridinium
Salts
Be selective: d-Azido, d-cyano, d-thiocyanato alcohols were obtained in high yields from N-
alkoxypyridinium salts under mild dual photoredox/copper catalysis. A catalytic enantioselective d-
cyanation protocol in the presence of a chiral bisoxazoline ligand was also developed.
This article is protected by copyright. All rights reserved.