Palladium-Catalyzed Atom-Transfer Radical Cyclization at Remote Unactivated C(sp3)?H Sites: Hydrogen-Atom Transfer of Hybrid Vinyl Palladium Radical Intermediates

Article abstract of DOI:10.1002/anie.201712775

A novel mild, visible-light-induced palladium-catalyzed hydrogen atom translocation/atom-transfer radical cyclization (HAT/ATRC) cascade has been developed. This protocol involves a 1,5-HAT process of previously unknown hybrid vinyl palladium radical intermediates, thus leading to iodomethyl carbo- and heterocyclic structures.

Full text of DOI:10.1002/anie.201712775

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Pd-Catalyzed Atom Transfer Radical Cyclization at Remote
Unactivated C(sp3)-H Sites Enabled by Hydrogen Atom Transfer
of Hybrid Vinyl Pd-Radical Intermediates
Authors: Vladimir Gevorgyan, Maxim Ratushnyy, Marvin Parasram,
and Yang Wang
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201712775
Angew. Chem. 10.1002/ange.201712775
Link to VoR: http://dx.doi.org/10.1002/anie.201712775
http://dx.doi.org/10.1002/ange.201712775

10.1002/anie.201712775
Angewandte Chemie International Edition
COMMUNICATION
Pd-Catalyzed Atom Transfer Radical Cyclization at Remote
Unactivated C(sp3)−H Sites Enabled by Hydrogen Atom Transfer
of Hybrid Vinyl Pd-Radical Intermediates
Maxim Ratushnyy, Marvin Parasram, Yang Wang, and Vladimir Gevorgyan*
Abstract: A novel mild, visible light-induced Pd-catalyzed hydrogen
atom translocation/atom transfer radical cyclization (HAT/ATRC)
a) Aryl hybrid Pd-radicals enable proximal desaturation, ref. 2
cascade has been developed. This protocol involves a 1,5-HAT
β-H
elimination
Pd(I)I
1,5-HAT
Pd-cat.
process of previously unknown hybrid vinyl Pd-radical intermediates
leading to iodomethyl carbo- and heterocyclic structures.
I
H
H
visible light
H
H
T
T
T
T
Pd(I)I
T
= OSiR2
b) Alkyl hybrid Pd-radicals enable distal desaturation, ref. 4
Transformations involving translocation of radical
intermediates via hydrogen atom transfer have received much
attention over the past few years as a highly regioselective
Pd(I)I
1,n-HAT
β-H
elimination
H
I
T
T
T
T
H
Pd-cat.
visible light
m = 1-3
H
H
n = 5-7
Pd(I)I
m
m
m
m
and
mild
approach
toward
remote
C(sp3)
−
H
functionalization.[1] Recently, our group reported an HAT
process triggered by a hybrid aryl Pd-radical intermediate
(Scheme 1, a).[2] Induced by visible light, these aryl Pd-radical
species underwent a 1,5-HAT step followed by the ꢀ -H
elimination to generate silyl enol ethers in an efficient manner.
Expanding this strategy by utilizing hybrid alkyl Pd-radical
species,[3] led to the development of a method for remote
desaturation of alcohols at unactivated C(sp3) − H sites
(Scheme 1, b).[4] Based on the ability of these hybrid Pd-
radical species to activate C–H bonds via HAT process, we
were eager to investigate the possibility of achieving a HAT
process with vinyl hybrid Pd-radical intermediates, as a
platform for development of new transformations. To the best
of our knowledge, there have been no reports on generation
and reactivity of vinyl hybrid Pd-radical intermediates.[5]
Herein, we report a mild, visible light-induced exogenous
photosensitizer free[6,7] formation of novel hybrid vinyl Pd-
radical species, which triggers an HAT process at unactivated
C(sp3)−H site[8]/non-chain atom transfer radical cyclization
cascade to produce valuable iodoalkyl carbo- and
heterocycles (Scheme 1, c).
c) This work: vinyl hybrid Pd-radicals enable unprecedented HAT/ATRC cascade
formation of novel vinyl hybrid
non-chain ATRC at remote 3o C-H site
Pd-radical intermediates
Pd(I)I
Pd(I)I
I
H
I
H
Rn
Rn
Rn
R'
R"
R'
R"
Pd-cat.
Rn
Rn
1
visible light
2
R'
R"
R'
R"
1,5-HAT process
R'
H
H
Pd(I)I
valuable syntons
R"
exogeneous
photosensitizer free
Scheme 1. Hydrogen atom translocation of hybrid Pd-radical intermediates.
cyclopentane derivatives,[12] we commenced investigation of this
interesting transformation. First, optimization of the reaction
conditions, employing benchmark substrate 1a, was conducted
(Table 1). It was found that this reaction proceeded more
efficiently
at
higher
dilution,
producing
iodomethyl
dihydrobenzofuran derivative 2a in 51% yield (entry 3).
Employment of sterically demanding
Curran disclosed translocation of vinyl radicals, which,
under standard tin hydride conditions, enabled reductive
formation of methylcyclopentane cores via a sequential 1,5-
HAT/5-exo trig cyclization cascade.[9] Inspired by this work,
we aimed at developing an oxidative version of this
transformation toward methylenecyclopentane fragments (eq
1). The proposed sequence presumed formation of hybrid
vinyl Pd intermediate (1a→i), followed by its transposition
(i→ii), cyclization (ii→iii), and a ꢀ-H elimination step (iii→3).
However, reaction of the benchmark substrate 1a under our
Pd(I)I
Pd(I)I
I
H
Me
Me
Me
Me
X
O
O
O
i
O
1a
H
ii
O
3, 0%
iii
Me
Me
Me
Me
Me
Me
H
(1)
Pd(I)I
I
atom
transfer
Me
Me
O
2a, 35%
2
previously employed conditions[ ] did not result in formation of
the expected Heck type-product 3, instead, iodomethyl
dihydrobenzofuran 2a was produced selectively. Apparently,
the latter is a product of an unprecedented HAT/ATRC-type
cascade reaction involving activation of the C(sp3)−H bond
(eq 1).[10,11]
tertiary amines (Cy2NMe) was equally efficient compared to
Cs2CO3 (entry 5). Switching to more bulky amines or other
inorganic bases, however, played a detrimental role (Table
S2). Different palladium sources exhibited minor effects on
the outcome of this reaction producing the products in nearly
equal amounts (Table S3). Extensive ligand screening proved
DPEphos as the ligand of choice (entry 6). Surprisingly,
except for dtbdppf, neither parent dppf (entry 7), nor any of its
other derivatives tested (Table S4), produced appreciable
amounts of the product.[13] Commonly for radical chemistry,[1]
benzene proved to be the best among variety of solvents
tested (Table S5). Employment of degassed benzene (entry
8), as well as lowering amount of the base (entry 9), led to
further improvement of the yield. Performing the reaction
under standard free radical conditions[9] delivered no target
product (Table S6). Finally, control experiments
Inspired by the discovery of a new HAT/ATRC reaction (eq
1), and motivated by the importance of iodomethyl
[*]
M. Ratushnyy, M. Parasram, Y. Wang, Prof. Dr. V. Gevorgyan
Department of Chemistry
University of Illinois at Chicago
845 W. Taylor Street, Chicago, Illinois, 60607-7061 (USA)
E-mail: vlad@uic.edu
Supporting information for this article is given via a link at the end of
the document
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10.1002/anie.201712775
Angewandte Chemie International Edition
COMMUNICATION
spiroheterocycles 2l,m in good yields. Reaction of substrates,
possessing 4-susbtituted tetrahydropyran and piperidine led to
efficient formation of spiroheterocyclic molecules 2n,o. Finally, a
cascade reaction of γ-butyrolactone-containing substrate led to a
valuable spirolactone core[14] 2p in 47% yield.
Table 1. Optimization of reaction conditions.[a]
PPh2
Pd(OAc)2 (10 mol %)
ligand (20 mol %)
base (2 equiv)
I
Fe
I
Me
Me
O
Table 2. Scope of HAT/ATRC cascade reaction.[a]
benzene, [M]
blue LED, rt, 15 h
PPh2
PPh2
O
Oi-Pr
P(t-Bu)2
dtbdppf
DPEphos
1a
2a
I
I
Rn
R'
R"
Pd-cat.
Rn
[a]
base[b]
ligand[c]
dtbdppf
dtbdppf
dtbdppf
dtbdppf
dtbdppf
DPEphos
dppf
yield, %[b]
blue LED 450 nm
#
1
2
3
4
5
6
7
8
9
[M]
R'
1
H
R"
2
0.02
0.05
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
Cs2CO3
Cs2CO3
Cs2CO3
i-Pr2NEt
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
35
I
R
I
2a, 69% (54%[b]
2b, 59%
)
R
1a, R = H
Me
Me
5
1b, R = OMe
1c, R = Cl
O
O
2c, 61%
51
Me
Me
I
I
42
1d
2d, 63%
O
53
O
55
I
1e, R = CO2Et
1f, R = CO2Bn
1g, R = CO2Me
1h, R = CO2tBu
2e, 60%
nr
I
I
Me
Me
Me
2f, 59%
2g, 51%
2h[c], 50%
R
R
R
64[c]
Me
DPEphos
DPEphos
DPEphos
DPEphos
DPEphos
R
I
71[c,d], (69[e]
0[f]
)
Cl
Me
2i[d], 57%
1i
EtO2C
EtO2C
EtO2C
10
11
12
Me
EtO2C
Cl
I
7[g]
I
1j
2j, 64%
2k, 41%
EtO2C
EtO2C
EtO2C
decomp[h]
EtO2C
I
I
I
[a] All reactions were performed on 0.05 mmol scale. [b] GC/MS yields. [c]
Degassed benzene was used. [d] 1 equivalent of Cy2NMe was used. [e]
Isolated yield. [f] In dark. [g] No Pd(OAc)2 was used. [h] 90 °C, no light.
1k
EtO2C
EtO2C
EtO2C
EtO2C
I
2l[e], 64%
1l
EtO2C
EtO2C
EtO2C
EtO2C
O
O
O
indicated that both light and the catalyst are vital for this
transformation (entries 10-12).
I
I
2m[f], 62%
1m
EtO2C
EtO2C
EtO2C
EtO2C
With the optimized conditions in hand, the scope of this
transformation was explored (Table 2). Reaction of electronically
diverse iodovinylbenzyl derivatives (1a-c) provided the
corresponding iodomethyl dehydrobenzofurans (2a-c) in good
yield. Scaling up this reaction to 1 mmol provided comparable
yield of 2a. Replacing the isopropyl group with a cyclohexyl
group led to spirocyclic derivative 2d in reasonable yield. Next,
we were eager to probe this methodology on linear aliphatic
systems toward assembly of an important cyclopentyl core.
Gratifyingly, acyclic precursors proved to be competent
reactants leading to formation of a variety of iodomethyl
cyclopentyl derivatives! Substrates, possessing various ester
substituents at the carbon tether were nearly equally efficient
(2e-2h). Notably, substrate 1i, bearing a pendant chlorine atom,
smoothly underwent reaction to produce bis-halogenated 2i in
57% yield, albeit as the mixture of diastereomers. Markedly,
substrates possessing cycloalkyl groups reacted smoothly
producing 5/5- (2j) and 5/6- (2k) spirocyclic molecules in 64%
and 41% yield, respectively. Importantly, employment of
O
I
I
X
1n, X = O
1o, X = NBoc
O
2n, 61%
2o, 54%
EtO2C
EtO2C
EtO2C
EtO2C
I
I
2p[g], 47%
1p
O
EtO2C
EtO2C
EtO2C
EtO2C
O
O
O
[a] Reaction conditions: 1 0.1 mmol, Pd(OAc)2 0.01 mmol, DPEphos 0.02 mmol,
Cy2NMe 0.1 mmol, benzene 0.01 M, 34 W blue LED. [b] 1 mmol scale reaction.
[c] NMR yield. [d] 1.1:1 d.r. [e] 5.3 (trans):1 d.r. [f] Single diastereomer (trans). [g]
1.2:1 d.r.
Apparently, the presence of an iodomethyl moiety in the
products of the HAT/ATRC cascade provides a convenient
handle for further modification. Indeed, nucleophilic substitution
of the iodide in 2o with cyanide- and azide groups resulted in 4
and 5, respectively, in good yields. Alternatively, base-mediated
elimination of HI provided the exo-methylene-containing
spiroheterocycle 6 in 71% yield.
substrates,
(tetrahydrofuryl-, 1l, or tetrahydropyranyl-, 1m) with heteroatom
adjacent to the C–H abstraction site reacted
diastereoselectively, producing iodomethyl-containing
possessing
a
heterocyclic
substituent
We propose the following mechanism for this novel
HAT/ATRC cascade transformation (Scheme 3). The active
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10.1002/anie.201712775
Angewandte Chemie International Edition
COMMUNICATION
iodomethyl functionality in the formed reaction products can
easily be further functionalized. It is believed that the discovery
of novel reactivity of vinyl halides under visible light/Pd-
catalyzed conditions would trigger elaboration of new methods,
and that the developed methods would find applications in
synthesis.
CN
NaCN (5 equiv)
EtO2C
NBoc
NBoc
NBoc
DMF, 50 o
C
EtO2C
4
5
6
63%
N3
I
NaN3 (5 equiv)
DMF, 50 o
NBoc
C
EtO2C
EtO2C
EtO2C
EtO2C
2o
84%
Acknowledgements
DBU (1.05 equiv)
DMF, 70 o
C
EtO2C
EtO2C
This research was supported by the National Institutes of Health
(GM120281) and the National Science Foundation (CHE-
1663779).
71%
Scheme 2. Further transformations of HAT/ATRC cascade products.
Keywords: vinyl radicals • HAT • ATRC • palladium • cascade
LnPd(0)
I
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hv = 452 nm
I
R'
R"
Rn
Rn
1
LnPd(0)*
2
R'
H
R"
1
SET
AT-Pd
AT-I
2
Pd(I)I
Pd(I)I
R'
R"
Rn
Rn
7
9
R'
H
R"
5-exo-trig
1,5-HAT
H
Rn
Pd(I)I
R'
8
R"
Scheme 3. Proposed mechanism for HAT/ATRC cascade.
photoexcited[15] Pd(0) complex undergoes an SET with vinyl
iodide 1 to produce, upon homolysis of the C–I bond, the hybrid
vinyl Pd-radical intermediate 7. The latter, upon 1,5-HAT step
generates the tertiary alkyl hybrid Pd-radical 8, which upon 5-
exo trig cyclization forms primary alkyl radical species 9. A
subsequent iodine atom transfer from the putative Pd(I)I species
to 9 furnishes the product 2 and regenerates the Pd(0)
catalyst.[16] The radical nature of this transformation was
confirmed by radical trap- and deuterium labeling
experiments.[17] The UV-vis analysis indicated that the Pd(0)
complex is the photoabsorbing species. Alternatively, a radical
chain mechanism could be operative,[18] where the Pd catalyst
and light would only be needed for the initiation step of the
reaction (1 → 9). Then, an atom transfer chain reaction (AT-I)
between 9 and 1 (9 + 1 → 2 + 7) would propagate the process.
However, due to unfavorable BDEs of the C–I bonds in vinyl- vs
alkyl iodides,[19] this scenario is unlikely.
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Pd catalyst and visible light in the absence of exogenous
photosensitizers at room temperature leads to formation of a
novel vinyl hybrid Pd-radical species. This intermediate triggers
a novel 1,5-HAT/non-chain ATRC cascade reaction to form
valuable iodomethyl-containing cyclopentanes, as well as
spiroannulated cyclopentanes with carbo- and heterocycles. The
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10.1002/anie.201712775
Angewandte Chemie International Edition
COMMUNICATION
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You, J. Nat. Prod. 2015, 78, 272-278; b) C. A. Leverett, V. C. Purohit, A.
G. Johnson, R. L. Davis, D. L. Tantillo, D. Romo, J. Am. Chem. Soc.
2012, 134, 13348-13356.
H
AIBN
HSnBu3
H
Br(I)
R'
R"
E
R'
R"
E
E
E
R'
R"
E
R'
R"
E
R'
R"
E = CO2Me
E
[15] T. L. Andersen, S. Kramer, J. Overgaard, T. Skrydstrup,
Organometallics 2017, 36, 2058-2066.
E
E
E
H
H
[16] Although the exact role of base in this transformation is not completely
understood, it may prevent formation of catalytically inactive PdI2
species (see ref. 10g).
[10] Most established Pd-catalyzed ATRC protocols employing alkyl halide
precursors operate via a radical chain mechanism. Moreover, the active
Pd species were found to serve as initiators rather than a catalyst. For
selected references, see: a) D. P. Curran, C.-T. Chang, Tetrahedron
Lett. 1990, 31, 933-936; b) M. Mori, Y. Kubo, Y. Ban, Tetrahedron 1988,
44, 4321-4330; c) M. Mori, N. Kanda, Y. Ban, K. Aoe, J. Chem. Soc.,
Chem. Commun. 1988, 12-14; d) M. Mori, Y. Kubo, Y. Ban,
Tetrahedron Letters 1985, 26, 1519-1522; e) M. Mori, I. Oda, Y. Ban,
Tetrahedron Letters 1982, 23, 5315-5318; f) H. Liu, Z. Qiao, X. Jiang,
Org. Biomol. Chem. 2012, 10, 7274-7277; g) B. M. Monks, S. P. Cook,
Angew. Chem. 2013, 125, 14464-14468; Angew. Chem. Int. Ed. 2013,
52, 14214-14218.
[17] See Supporting Information for details.
[18] A. Studer, D. P. Curran, Angew. Chem. 2016, 128, 58-106; Angew.
Chem. Int. Ed. 2016, 55, 58-102.
[19] a) Y. R. Luo in Comprehensive Handbook of Chemical Bond Energies,
CRC Press, Boca Raton, FL, 2007; b) S. J. Blanksby, G. B. Ellison, Acc.
Chem. Res. 2003, 36, 255-263.
[11] Although Pd-catalyzed ATRC radical cyclizations of alkyl halides are
much more developed, a few reports on employment of aryl or vinyl
halides have been reported. However, these methods typically employ
high reaction temperatures and substrates that lack β-hydrogens (post-
cyclization). For a review, see: a) D. A. Petrone, J. Ye, M. Lautens,
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10.1002/anie.201712775
Angewandte Chemie International Edition
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Maxim Ratushnyy, Marvin Parasram,
Yang Wang, Vladimir Gevorgyan*
cascade HAT/non-chain ATRC
involving remote C(sp3)-H sites
H
I
R'
R''
Pd-cat.
Page No. – Page No.
I
Rn
Rn
blue LED
room temperature
no exogenous
photosensitizers!
Pd-Catalyzed Atom Transfer Radical
Cyclization at Remote Unactivated
C(sp3)−H Site Enabled by Hydrogen
Atom Transfer of Hybrid Vinyl Pd-
Radical Intermediate
valuable synthons
R'
R"
H
first generation of
hybrid vinyl Pd-radicals
AT
SET
Pd(I)I
Pd(I)I
H
H
R'
R''
Rn
Rn
1,5-HAT~
5-exo-trig~
Rn
R'
R"
R'
R"
H
Pd(I)I
This article is protected by copyright. All rights reserved.