Amidyl Radical Directed Remote Allylation of Unactivated sp3 C?H Bonds by Organic Photoredox Catalysis

Article abstract of DOI:10.1002/anie.201811004

The development of visible-light-mediated allylation of unactivated sp³ C?H bonds is reported. The remote allylation was directed by the amidyl radical, which was generated by photocatalytic fragmentation of a pre-functionalized amide precursor. Both aromatic and aliphatic amide derivatives could successfully deliver the remote C?H allylation products in good yields. A variety of electron deficient allyl sulfone systems could be used as δ-carbon radical acceptor.

Full text of DOI:10.1002/anie.201811004

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
International Edition Chemie
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Accepted Article
Title: Amidyl Radical Directed Remote Allylation of Unactivated sp3 C-
H Bonds via Organic Photoredox Catalysis
Authors: Kui Wu, Lushun Wang, Sonivette Colon-Rodriguez, Gerd-
Uwe Flechsig, and Ting Wang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201811004
Angew. Chem. 10.1002/ange.201811004
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Angewandte Chemie International Edition
10.1002/anie.201811004
COMMUNICATION
3
Amidyl Radical Directed Remote Allylation of Unactivated sp C-H
Bonds via Organic Photoredox Catalysis
+
+
Kui Wu , Lushun Wang , Sonivette Colón-Rodríguez, Gerd-Uwe Flechsig*, and Ting Wang*
Abstract: The development of visible-light-mediated allylation of
transformation. Applying such radical acceptors into the HAT
reaction system, we herein report an amidyl radical directed
3
unactivated sp C-H bonds is reported. The remote allylation was
3
directed by the amidyl radical, which was generated by
photocatalytic fragmentation of a pre-functionalized amide precursor.
Both aromatic and aliphatic amide derivatives could successfully
deliver the remote C-H allylation products in good yields. A variety of
electron deficient allyl sulfone systems could be used as δ-carbon
radical acceptor.
remote allylation of unactivated sp C-H bonds via an amidyl
radical promoted radical cascade reaction.
(A) Hofmann-Löffler-Freytag reaction and modifications
1
. H , Δ
. Base
R1
R2
R2
HLF reaction
N
X
N
R
2
1
3
The selective functionalization of unactivated sp carbon-
hydrogen (C-H) bond is a long-standing challenge in modern
[
1],[2]
[3]
PhI(OAc) , I
FG
R
2
2
Suárez modification
organic synthesis.
Hydrogen atom transfer (HAT) catalysis
N
R
N
H
has shown its advances in regioselective activation of an inert C-
H bond for direct formation of new carbon-carbon (C-C) bonds
hν
FG
2 2
FG = P(O)(OR) , CN, NO
[
4]
and carbon-heteroatom (C-O, C-N, C-X) bonds. Particularly,
the 1,5-hydrogen atom abstraction of nitrogen radicals, the key
R
N
t-BuO
2
C
N
R
N
[
5]
step of the Hofmann-Loffler-Freytag (HLF) reaction , has been
widely used in the synthesis of heterocyclic compounds and
Ts
Ts
/I
Ts
PhI(OAc)
2
2
NaI/PhI(OAc)
visible-light
I2 (catalytic)
PhI(mCBA)
2
[
6]
portionwise
addition
visible-light
natural products (Scheme 1A). A major milestone in the
[
7]
development of HLF reaction is Suárez modification , which
precludes the requirement of the pre-formed haloamine
Muñiz (2015)
Herrera (2015)
Nagib (2016)
[
4f]
[4m]
[4e]
(
Scheme 1A). In addition, Muñiz , Herrera , and Nagib
have also reported their discoveries toward the HLF reaction
Scheme 1A). Recently, visible-light photoredox catalysis has
been leading efficient accesses to N-radicals under mild
(
B) Remote C-H functionalization
(
Amidyl radical generated
by SET oxidation
3
R
O
Published works
[
8]
conditions. Abstraction of the δ C-H followed by coupling with
R
1
N
H
R2
radical acceptors realized the remote functionalization of
[
9]-[12]
a
unactivated C-H bonds (Scheme 1B).
Particularly,
O
[
9]
[10]
O
H
Knowles and Rovis reported their works on direct homolysis
of N-H bonds of amides via a single-electron-transfer (SET)
R3
1. HAT
R1
R
4
N
R1
N
H
R2
2. Radical
Acceptor
2
R3
R
[
13]
process . The challenging SET oxidation was realized by Ir(III)
[
14]
Amidyl Radical (I)
photocatalyst, generating the electrophilic amidyl radical (I)
O
smoothly. However, due to the difficulty of direct homolysis of N-
R3
R1
N
1
H bonds, the amide substrates were relatively limited (R =aryl or
R2
OAr
This work
[
15]
Amidyl radical generated
by SET reduction
CF
3
) in order to keep the high efficiency of the transformation
.
[
16]
a'
Taking advantage of the pre-functionalized amide (a’),
the
amidyl radical (I) could be readily accessible through a SET
reduction. Subsequent 1,5-HAT and intermolecular radical
addition would realize the remote functionalization of unactivated
Scheme 1. Remote C-H functionalization.
3
sp C-H bonds. This synthetic strategy would potentially broaden
Inspired by Leonori’s pioneer studies on the aryloxy
the amide substrate scope for such transformation. In our
[16],[20]
amides
, we began our reaction condition optimization with
amide substrate 1, allyl sulfone 2 as radical coupling partner,
organic photocatalyst eosin Y, and green light-emitting diode
[
17]
previous studies , we have found that electron-deficient allyl
[
18],[19]
sulfones
could be a suitable radical acceptor in such
(
LED) irradiation (Table 1). A careful survey of various bases
demonstrated that DIPEA serves best in this reaction (Table 1,
entries 1-4). In addition, CH Cl was found to be the optimal
solvent after careful screening of various solvents (CH Cl
MeOH, CF CH OH, CH CN, DMF, DMSO, and 1,4-dioxane)
Table 1, entries 5-10). It is worth mentioning that, since the
+
+
[*]
Dr. K. Wu, Dr. L. Wang, S. Colon-Rodriguez, Prof. Flechsig, and
Prof. T. Wang
2
2
2
2
,
Department of Chemistry
3
2
3
University at Albany, State University of New York
(
1400 Washington Avenue, Albany, NY 12222 (USA)
E-mail: twang3@albany.edu
Homepage: www.albany.edu/twanglab
These authors contributed equally to this work.
reaction was very sensitive to oxygen, degas procedure (freeze-
pump-thaw) was necessary for the success of such
transformation. With the optimized condition, 3 was generated in
+
[
]
7
5% yield after 12 hours at room temperature (Table 1, entry 2).
Control experiments (Table 1, entries 11-13) verified that the
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Angewandte Chemie International Edition
10.1002/anie.201811004
COMMUNICATION
additive, photocatalyst, and light irradiation are necessary for the
success of this transformation. Light on-off experiments
2
i-Pr NEt
EY
5
30 nm LEDs
(
Supporting Information) showed continuous light irradiation is
necessary for the reaction to reach completion.
i-Pr2NEt
EY
EY*
[
a]
Table 1. Reaction Condition Optimizations
eosin Y (2 mol %)
additive
O
O
O
α
SO2Ph
COOEt
O
solvent
Me
δ
Me
COOEt
Ph
N
O
Ph
N
+
Ph
N
H
Green LEDs
Ph
N
O
OAr
Me Me
3
ArO
Ar = 2,4-dinitrophenyl
O2N
NO2
1
2
O N
NO2
2
1
a
1
O
H
[
b]
[c]
entry
additive
Et
solvent
yield (%)
Ph
N
I
1
2
3
4
5
6
7
8
9
3
N
CH
CH
CH
CH
2
2
2
2
Cl
2
61
75
55
0
HAT
O
DIPEA
DMAP
DABCO
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
--
Cl
2
COOEt
2
PhO2S
O
Cl
Cl
2
2
COOEt
Ph
N
H
Ph
N
H
PhO2S
II
3
MeOH
CF CH
CH CN
70
15
56
23
25
34
0
Scheme 2. Proposed mechanism.
3
2
OH
3
We next focused our attention on exploring the scope of
the photocatalytic cascade reaction. Scheme 3 summarizes
experiments probing a range of amides substrates. We were
pleased to find that a variety of tertiary C-H bonds could be
selectively functionalized by the optimized conditions, furnishing
DMF
DMSO
1
1
1
1
0
1
2
3
1,4-dioxane
3
-8 in good yields (56%-78%). Substituted benzoyl amides and
other aromatic amides could also deliver the corresponding
products 9-12 in good yields (62%-77%). Since an aryloxy group
is pre-installed for the generation of the amidyl radical, the scope
of amide was not limited to aryl amides or strong electron-
CH
CH
CH
2
2
2
Cl
Cl
Cl
2
2
2
[
[
d]
e]
DIPEA
DIPEA
0
0
withdrawing substituted alkyl amides. In fact, N-acetyl substrate
red
1
3s (E1/2, = -0.885 V vs SCE) tends to be easier reducible than
[
a] Reactions conducted by irradiating 1 (1 equiv), 2 (2 equiv), additive (2
red
N-Benzoyl substrate 1 (E1/2, = -0.925 V vs SCE). Excitingly, N-
acetyl, N-isobutyryl, N-pivaloyl, and N-cyclopentylcarbonyl
substrates (13s, 14s, 15s, and 16s) reacted smoothly under
these conditions, providing the corresponding products 13-16 in
the yields of 63%, 73%, 58%, and 64% respectively. Moreover,
this radical process is compatible with a variety of functional
groups, such as ester (17), silyl ether (18), alkene (19), and
oxalate (20). Carbamate derivative 21s could also be used as
starting material, furnishing corresponding allylation product 21
in excellent yield (84%). More excitingly, a variety of secondary
C-H bonds could also be selectively functionalized, affording
corresponding products 22-26 in moderate to good yields (42%-
equiv), and photocatalyst (2 mol %) in solvent (0.05 M) with two 6 W, 530 nm
light-emitting diode (LED) flood lamps for 12 h. [b] All solvents was degassed
via Freeze-Pump-Thaw procedure for 3 times. [c] Isolated yields. [d] Reaction
conducted in the dark. [e] Reaction conducted without photocatalyst.
Mechanistically, although DIPEA was known to be able to
reductively quench excited eosin Y (EY*), our Stern-Volmer
emission quenching studies suggested that reactant aryloxy-
amide 1 quenches EY* at a significantly higher rate (Supporting
Information). The evidence validated that the catalyst eosin Y
red
(
E
1/2,
= -1.06 V vs SCE), upon photo excitation, would reduce
red
the aryl unit of 1 (E1/2, = -0.925 vs SCE) to generate 1a, which
would deliver the amidyl radical I through a fragmentation. The
electrophilic amidyl radical I promoted a 1,5-hydrogen atom
transfer, affording nucleophilic carbon radical II. The subsequent
intermolecular radical addition to allyl sulfone (2) would afford
7
4%). The excellent scope of the reaction would potentially
broaden the synthetic application of such remote C-H
functionalization strategy.
2
the remote allylation product 3 by extruding the PhSO Ÿ. The
photoactive catalyst (EY) is likely to be regenerated by oxidizing
a molecule of DIPEA (Scheme 2).
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Angewandte Chemie International Edition
10.1002/anie.201811004
COMMUNICATION
O
eosin Y (2 mol %)
DIPEA
O
PhO2S
R3
COOEt
R1
N
R1
N
H
+
R2 R3
OAr
R2
COOEt
Green LEDs
CH2Cl2
Ar = 2,4-dinitrophenyl
Tertiary C-H Bonds
R1= aromatics
Substrates
Products
Substrates
Products
Substrates
Products
COOEt
O
O
O
O
O
O
COOEt
COOEt
Ph
N
Ph
N
H
Ph
N
Ph
N
H
Ph
N
Ph
N
H
Ph Me
OAr
OAr
OAr
Ph
1
3
75%
4s
4
75%
5s
5
56%
E1/2,red = -0.925 V vs SCE
E1/2,red = -0.900 V vs SCE
COOEt
COOEt
O
OAr
O
O
O
Ph
N
H
N
Ph
N
Ph
COOEt
Ph
N
H
Ph
N
Ph
N
H
OAr
O
O
OAr
6
s
6
65%
7s
7
73%
8s
8
78%
O
O
O
O
O
O
O
COOEt
O
N
H
COOEt
N
COOEt
N
Ar
N
Ar
N
H
N
H
OAr
OAr
OAr
F
F
1
2s
12 77%
9
s. Ar = 4-methylphenyl
9. Ar = 4-methylphenyl, 72%
11s
11. 67%
1
0s. Ar = 4-methoxyphenyl
10. Ar = 4-methoxyphenyl, 62%
E1/2,red = -0.880 V vs SCE
E1/2,red = -0.890 V vs SCE
R1= aliphatics
Substrates
Products
Substrates
Products
Substrates
Products
O
O
O
O
O
O
COOEt
COOEt
N
N
H
N
N
H
COOEt
N
N
H
OAr
OAr
OAr
1
3s
13 63%
15 58%
1
4s
14 73%
15s
O
E1/2,red = -0.885 V vs SCE
O
O
O
O
O
TBSO
HO
COOEt
COOEt
N
N
H
AcO
AcO
COOEt
N
N
H
N
N
H
OAr
OAr
OAr
1
8
60%[a]
1
6s
16 64%
17s
18s
17 65%
E1/2,red = -0.905 V vs SCE
E1/2,red = -0.930 V vs SCE
O
O
O
O
COOEt
MeO
COOEt
Boc
N
BocHN
COOEt
N
H
N
H
MeO
N
N
O
OAr
OAr
O
OAr
1
9s
19 55%
20 50%
21s
21 84%
2
0s
E1/2,red = -0.890 V vs SCE
E1/2,red = -0.895 V vs SCE
E1/2,red = -0.938 V vs SCE
Secondary C-H Bonds
Substrates
Products
Substrates
Products
Substrates
Products
O
O
O
O
O
O
COOEt
Ph
N
Ph
N
H
Ph
COOEt
Ph
N
Ph
N
H
Ph
N
Ph
N
H
COOEt
OAr
OAr
Ph
OAr
Me
2
2s
22 74%
23s
23 66%
E1/2,red = -0.905 V vs SCE
24s
24 67%
O
O
O
O
Ph
N
H
OBz
Ph
N
Ph
N
H
Ph
N
OBz
4
4
OH
OAr
OAr OBz
COOEt
COOEt
26 42%
[b], d.r. = 1:1
2
5s
26s
2
5
51%
E1/2,red = -0.900 V vs SCE
Scheme 3. Reaction Scope. [a] Yield was obtained after removal of TBS
group. [b] Yield was obtained after removal of Bz group.
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Angewandte Chemie International Edition
10.1002/anie.201811004
COMMUNICATION
allyl sulfone system could be used as δ-carbon radical acceptor.
Moreover, the strategy could be also applied on functionalization
of γ-carbon of amides, and oxidation of C(δ)-H bond of amines.
Applications of this synthetic strategy in more complicated
molecular settings are ongoing in our laboratory.
a
O
eosin Y (2 mol %)
DIPEA
O
2
PhO S
R
Ph
N
+
Ph
N
H
Green LEDs
OAr
R
2 2
CH Cl
Ar = 2,4-dinitrophenyl
O
O
O
O
Acknowledgements
COOMe
COOt-Bu
Ph
Ph
N
H
Ph
N
H
N
H
Ph
We are grateful to the University at Albany, State University of
New York, for financial support. We thank Prof. Alexander
Shekhtman (SUNY-Albany) and Prof. Zhang Wang (SUNY-
Albany) for NMR assistance.
2
7
69%
29 65%
2
8
66%
O
O
O
2
SO Ph
CN
SO
2
Ph
Me
N
H
Ph
N
H
Ph
N
H
3
2 55%
3
1
76%
Keywords: photoredox catalysis • metal free • amidyl radical •
3
0 71%
Unactivated C-H Bonds • eosin Y
H
[
1] M. C. White, Science 2012, 335, 807-809.
O
O
O
O
O
H
H
O
OMe
OBn
[
2] For selected reviews, see: a) J. He, M. Wasa, K. S. Chan, Q. Shao, J.-Q.
Yu, Chem. Rev. 2016, 117, 8754-8786. b) W. R. Gutekunst, P. S. Baran,
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Ph
N
H
O
Ph
N
H
BnO
OBn
3
3
69%
34 61%
2
015, 44, 7764-7786.
eosin Y (2 mol %)
, DIPEA
O
O
2
Me
COOEt
[3] For selected reviews, see: a) S. Chiba, H. Chen, Org. Biomol. Chem.
2014, 12, 4051-4060. b) J. Robertson, J. Pillai, R. K. Lush, Chem. Soc.
Rev. 2001, 30, 94-103. c) J. M. Mayer, Acc. Chem. Res. 2010, 44, 36-
b
Me
N
H
N
Green LEDs
CH Cl
OAr
2
2
3
5
36 42%
4
1
6. d) S. Protti, M. Fagnoni, D. Ravelli, ChemCatChem 2015, 7, 1516-
523.
O
1. eosin Y (2 mol %),
, DIPEA
Green LEDs, CH
O
O
2
[4] For selected examples on C-H activation by Hydrogen-Atom Transfer,
see: a) W. Liu, X. Huang, M.-J. Cheng, R. J. Nielsen, W. A. Goddard, J.
T. Groves, Science 2012, 337, 1322-1325. b) J. L. Jeffrey, J. A. Terrett,
D. W. MacMillan, Science 2015, 349, 1532-1536. c) M. S. Chen, M. C.
White, Science 2010, 327, 566-571. d) P. Becker, T. Duhamel, C. J.
Stein, M. Reiher, K. Muñiz, Angew. Chem. Int. Ed. 2017, 56, 8004-8008.
e) E. A. Wappes, S. C. Fosu, T. C. Chopko, D. A. Nagib, Angew. Chem.
Int. Ed. 2016, 55, 9974-9978. f) C. Martínez, K. Muñiz, Angew. Chem.
Int. Ed. 2015, 54, 8287-8291. g) Q. Qin, S. Yu, Org. Lett. 2015, 17,
c
OH
Ph
N
2
Cl
2
Ph
N
H
OAr
2
3
. Ph P
1
3
7 75%
O
eosin Y (2 mol %)
TEMPO, DIPEA
O
d
O
Ph
N
Ph
N
H
N
Green LEDs
OAr
2 2
CH Cl
1
3
8 45%
1
894-1897. h) J. Zhang, Y. Li, F. Zhang, C. Hu, Y. Chen, Angew. Chem.
Scheme 4. Reaction Scope: a) radical acceptor scope; b) remote allylation of
C-H bond at Cγ position; c) Oxygen as radical acceptor; d) TEMPO (2 equiv)
as radical acceptor.
Int. Ed. 2016, 55, 1872-1875. i) M. A. Short, J. M. Blackburn, J. L.
Roizen, Angew. Chem. Int. Ed. 2018, 57, 296-299. j) K. A. Hollister, E.
S. Conner, M. L. Spell, K. Deveaux, L. Maneval, M. W. Beal, J. R.
Ragains, Angew. Chem. Int. Ed. 2015, 54, 7837-7841. k) L. M.
Stateman, K. M. Nakafuku, D. A. Nagib, Synthesis 2018, 50, 1569-1586.
l) E. A. Wappes, K. M. Nakafuku, D. A. Nagib, J. Am. Chem. Soc. 2017,
Next, we evaluated the scope of radical acceptor that can
[
16],[17]
participate in this process. A variety of allyl sulfone
bearing
1
39, 10204-10207. m) N. R. Paz, D. Rodríguez-Sosa, H. Valdés, R.
different electron-withdrawing-group (i.e. ester, ketone, nitrile,
sulfone) could be used as radical acceptor, reacting smoothly
under the optimized reaction conditions to afford 27-32 in good
yields (55%-76%). In addition, the strategy could be successfully
utilized in more complex molecular settings, such as steroid (33,
Marticorena, D. Melián, M. B. Copano, C. C. Gonázlez, A. J. Herrera,
Org. Lett. 2015, 17, 2370. n) C. Q. O’Broin, P. Fernández, C. Martínez,
K. Muñiz, Org. Lett. 2016, 18, 436. o) H. Zhang, K. Muñiz ACS Catal.
2017, 7, 4122.
[
[
5] M. E. Wolff, Chem. Rev. 1963, 63, 55-64.
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Song, G.-X. Cai, W.-H. Wang, Z.-J. Shi, J.. Am. Chem. Soc. 2008, 30,
6
9%) and carbohydrate (34, 61%). Moreover, the carboxylic acid
derived aryloxy amide 35 could also undergo the corresponding
remote functionalization of C-H bond at γ position, furnishing 36
in 42% yield (Scheme 4, eq b). Beside electron-deficient alkene
1
2901-12903. d) C. Wang, K. Harms, E. Meggers, Angew. Chem. Int.
system, O
2
and TEMPO could also be used as radical acceptor,
Ed. 2016, 55, 13495-13498. e) W. Shu, C. Nevado, Angew. Chem. Int.
Ed. 2017, 56, 1881-1884. f) W. Shu, A. Lorente, E. Gomez-Bengoa, C.
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offering the opportunity to functionalize the tertiary C-H as an
alcohol (Scheme 4, eq c) or marked C-O bond (Scheme 4, eq d).
2
011, 13, 1622-1625. i) H. Chen, S. Sanjaya, Y. F. Wang, S. Chiba, Org.
In summary, we have developed an organic photocatalytic
3
Lett. 2013, 15, 212-215. j) H. Chen, S. Chiba, Org Biomol Chem 2014,
method for the radical allylation of unactivated sp C-H bonds via
1
2, 42-46. k) Y. F. Wang, H. Chen, X. Zhu, S. Chiba, J. Am. Chem. Soc.
012, 134, 11980-11983.
an
amidyl
radical
promoted
1,5-hydrogen
atom
2
transfer/intermolecular radical addition cascade. A range of
amide substrates, both aromatic amides and aliphatic amides,
are suitable for this transformation. A variety of electron deficient
[
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