General, Auxiliary-Enabled Photoinduced Pd-Catalyzed Remote Desaturation of Aliphatic Alcohols

Article abstract of DOI:10.1021/jacs.7b08459

A general, efficient, and site-selective visible light-induced Pd-catalyzed remote desaturation of aliphatic alcohols into valuable allylic, homoallylic, and bis-homoallylic alcohols has been developed. This transformation operates via a hybrid Pd-radical mechanism, which synergistically combines the favorable features of radical approaches, such as a facile remote C-H HAT step, with that of transition-metal-catalyzed chemistry (selective β-hydrogen elimination step). This allows achieving superior degrees of regioselectivity and yields in the desaturation of alcohols compared to those obtained by the state-of-the-art desaturation methods. The HAT at unactivated C(sp³)-H sites is enabled by the easily installable/removable Si-auxiliaries. Formation of the key hybrid alkyl Pd-radical intermediates is efficiently induced by visible light from alkyl iodides and Pd(0) complexes. Notably, this method requires no exogenous photosensitizers or external oxidants.

Full text of DOI:10.1021/jacs.7b08459

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Communication
General, Auxiliary-Enabled Photoinduced Pd-
Catalyzed Remote Desaturation of Aliphatic Alcohols
Marvin Parasram, Padon Chuentragool, Yang Wang, Yi Shi, and Vladimir Gevorgyan
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Journal of the American Chemical Society
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General, Auxiliary-Enabled Photoinduced Pd-Catalyzed
Remote Desaturation of Aliphatic Alcohols
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Marvin Parasram, Padon Chuentragool, Yang Wang, Yi Shi, and Vladimir Gevorgyan*
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Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061, United States
Supporting Information Placeholder
Scheme 1. Desaturations Methods in Aliphatic Systems
ABSTRACT: A general, efficient, and site-selective visible
light-induced Pd-catalyzed remote desaturation of aliphatic
alcohols into valuable allylic-, homoallylic-, and bis-
homoallylic alcohols has been developed. This transformation
operates via a hybrid Pd-radical mechanism, which synergisti-
cally combines the favorable features of radical approaches,
such as a facile remote C–H HAT step, with that of transition
metal-catalyzed chemistry (selective β-hydrogen elimination
step). This allows achieving superior degrees of regioselectivi-
ty and yields in desaturation of alcohols compared to those
obtained by the state-of-the-art desaturation methods. The
HAT at unactivated C(sp3)–H sites is enabled by the easily
installable/removable Si-auxiliaries. Formation of the key
hybrid alkyl Pd-radical intermediates is efficiently induced by
visible light from alkyl iodides and Pd(0) complexes. Notably,
this method requires no exogenous photosensitizers or exter-
nal oxidants.
a) TM-catalyzed approach: Yu,4a Boudoin,4b Catellani4c
B
TM
H
1o, 2o
H
DG
n
TM-cat.
120-150 o
DG
n
DG
n
C
limited scope
CMD mechanism
b) Radical/cationic approach for γ-/δ- desaturation, Baran5b
Hβ
Hδ
R
O
O
H+
Ts
O2S
Hγ
O
Et2N3
R
[O]
homoallylic alcohols
Hβ
Hδ
Hβ
Hδ
R
Me
3o
O
O2S
O2S
[O]
-Hβ or Hδ
R
Hγ
Hγ
difficult to control
H+-elimination
selective HAT
at unactivated
γ-tertiary C–H site
Me
cationic intermediates
Me
c) Our prior work: desaturation involving hybrid Pd-radical 1,5-HAT at proximal activated C(sp3)–H site7
Hβ
O
Pd-cat.
O
PhEt2Si
Et2Si
R
visible light
rt
R
I
Hα
silyl enol ethers
Hβ
R
Hβ
3o
O
O
Et2Si
Et2Si
-Hβ
Alkenes are one of the most widely used functional groups
in organic synthesis, broadly found in a wide range of bioac-
tive molecules and natural products. Methods toward synthe-
I-Pd(I)
R
Hα
Hα
I-Pd(I)
1
selective HAT
at activated
α-tertiary C–H site
hybrid Pd-radical
intermediates
sis of these privileged motifs often involve non-universal
strategies that require pre-functionalization of starting materi-
als at the desired reaction site. Unfortunately, methods for
synthesis of alkenes via direct desaturation of aliphatic chains
are less explored. This is mainly attributed to the inherent
difficulty of activating the kinetically inert C(sp3)–H bonds.
Although, considerable progress has been made in converting
unactivated C–H bonds into valuable C–C and C–
d) This work: desaturation involving hybrid Pd-radical 1,n-HAT at remote unactivated C(sp3)–H sites
H
Hβ
Hδ
I
Pd-cat.
O
HO
Si
R2
visible light
rt
n
n=0-2
Hα
Hγ
H
ε
allylic-, homoallylic-,
and bis-homoallylic alcohols
generally good yields
R = i-Pr, Me
and high regioselectivity
H
Hβ
Hδ
H
-H
(I)
I-Pd
3o, 2o
O
O
H
Si
R2
Si
R2
n
controlled
I-Pd(I)
Hα
Hγ
H
ε
β-H elimination
mild conditions
no exogenous
oxidants and
photosensitizers
A
B
hybrid Pd-radical
intermediates
2
selective HAT
at unactivated
heteroatom fragments via transition metal (TM) catalysis, a
β-,γ-,δ- C–H sites
synthetically appealing selective site-controlled desaturation
of aliphatic systems into privileged olefins still remains un-
derdeveloped. Modern TM-catalyzed approaches typically
and is limited to activation of 1° and 2° γ-/δ -C–H bonds
(Scheme 1a). To the best of our knowledge, there have been
no reports on TM-catalyzed functionalization of unactivated
3° C–H bonds. Emerging radical strategies, however, have
3
operate via a direct transfer-hydrogenation process or a di-
4
rected concerted metalation-deprotonation (CMD) pathway.
Between the two pathways, the latter approach is an attractive
option owning to its site-controlled capability (Scheme 1a).
Nevertheless, this method suffers from low selectivity and
efficiency, limited substrate scope, and harsh reaction condi-
tions. Moreover, the site of functionalization is often restrict-
ed based on formation of a favorable TM-cyclic intermediate
5,6
provided solutions for 3° C–H bond functionalization.
Thus, in Baran’s pioneering work,5b he showcased a guided C–
H desaturation of aliphatic systems involving a tether-
possessing an aryl radical hydrogen abstracting group, which
due to geometrical constraints, favors γ-C–H HAT at 3° site
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(Scheme 1b). Owing to the nature of this transformation, the Scheme 2. Comparison Study
Page 2 of 5
a) Radical/cationic approach: Baran's results5b
1
2
3
4
5
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7
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translocated radical undergoes oxidation with an external
oxidant, followed by elimination into the alkene moiety.
While groundbreaking, in some cases, this approach suffers
from regioselectivity issues due to a non-selective proton loss
step from the formed cationic intermediate. Overall, both
TM-catalyzed and radical approaches are complementary but
still have certain limitations. We have recently reported visible
light-induced formation of hybrid aryl Pd-radical intermediate
O
O
N3Et2
TFA (3 equiv), 60 o
- or-
TfOH (2 equiv), rt
C
O
Ts
Ts
2a-1
S
+
=
T0
O
Me
TEMPO (1 equiv), CH3NO2
2a-1’
55%, 2a-1 : 2a-1’ = 1.15 : 1
H
O
T
b) Hybrid Pd-radical approach: This work
10 mol % Pd(OAc)2
20 mol % L
1a
OH
2a
9
2 equiv Cs2CO3
i-Pr
i-Pr
I
+
OH
Si
10
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12
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PhH, Blue LED, rt, 24 h
then, TBAF, 2 h
capable of HAT process, and a subsequent β-hydrogen elimi-
nation step to furnish an alkene moiety. Due to the favorable
1,5-HAT process of the aryl hydrogen atom-abstracting group
of the silicon tether, the H atom abstraction occurred exclu-
sively at the proximal α-C–H site, thus resulting in the α-/β-
=
T1
2a’
77%, 2a : 2a’ = 100 : 0
Table 1. γ-/δ- Desaturation of Alcoholsa
i-Pr
i-Pr
PPh2
7
10 mol % Pd(OAc)2
20 mol % L
2 equiv Cs2CO3
desaturation of silyl ethers into silyl enols (Scheme 1c).
Si
I
T1/2
T1/2
R2
Fe
O
R2
O
T1
H
Herein, we report a general, efficient, selective, and mild
δ
R1
P(t-Bu)2
δ
γ
Me Me
Si
R1
0.1 M, PhH, Blue LED,
rt , 12-48 h
then, 4-10 equiv TBAF
γ
8
visible light-induced Pd-catalyzed remote desaturation of
I
H
H
2
L
1
T2
aliphatic alcohols. This method involves unprecedented, for
9
alkyl hybrid Pd-radical species, HAT process at unactivated
OH
OH
HO
HO
OH
2c, 47%b
3
10
OH
C(sp )–H sites (Scheme 1d). The abstraction at β-, γ-, or δ-
sites is enabled by employment of easily installa-
2d, 71%,b
4.7 : 1 r.r.
2a, 77%b
2b, 48%b
H
11
i-Pr
Si
i-Pr
i-Pr
ble/removable Si-auxiliaries (A). The formed transposed
i-Pr
Si
O
Me
O
Me
Boc
hybrid species B furnishes a remote alkene moiety upon a
controlled β-hydrogen elimination step, thus resulting in
desaturated alcohols with degrees of regioselectivity, unseen,
for radical methods.
OH
OH
N
H
OH
2e, 67%b,d
2i, 76%b,e
9.5 : 1 r.r.
2f, 79%c
2g, 70%c,d
2h, 77%b,e
i-Pr
OH
H
OH
HO
Based on our recent work on the formation of silyl methyl
hybrid-Pd radicals from iodomethylsilanes, we hypothesized
2j, 80%c
2k, 73%c
2m, 53%b
2l, 68%c
3.3 : 1 r.r.
OH
12
O
that if this moiety (T1, Scheme 2) could be engaged in a 1,6-
13,14
HAT event,
it would subsequently enable γ-/δ-
HO
15
desaturation toward important homoallylic alcohols. Fur-
thermore, based on the usually selective β-hydride elimina-
tion step in the hybrid Pd-radical mechanism,9b,12 it was antic-
ipated that the alkenol product would be formed with high
degrees of regiocontrol. Accordingly, we were eager to vali-
date this premise on desaturation of challenging alcohol de-
rivative 1a, which under conditions of reported radi-
cal/cationic protocol5b resulted in nearly equal mixture of
regioisomeric alkenols (2a-1, 2a-1’, Scheme 2a). We were
pleased to find that exposure of T1-tethered alcohol 1a-T1 to
2n, 43%b
10 : 1 r.r.
H
HO
2o, 65%b
aIsolated yields, r.r. = regioisomeric ratio. bT1 was used. T2 was
used. dContains minor amount of hydrodehalogenation by-
product. eThe desilylation step (TBAF) was omitted.
c
the cases with volatile low-molecular weight alkenols, the
silyl-based tethers were in one-pot routinely removed by
treatment with TBAF. It was found that various primary
alcohols, possessing functional groups such as alcohols (1b,
c) and amides (1e), underwent smooth γ-/δ-desaturation to
generate their respective homoallylic derivatives (2b, c, e) in
good yields. Then, desaturation of bulkier secondary alcohols
was tested (1f–1j). For these cases, due to the relative ease of
installation, we opted to employ sterically less hindered dime-
thyl(iodomethyl)silane tether T2 instead of bulkier T1. De-
saturation of naturally occurring (-)-menthol (1f), possessing
two equally distant sites of functionalization, selectively fur-
nished chiral building block (-)-isopulegol (2f) in 79% yield
16
our optimized photocatalytic conditions resulted in γ-/δ-
desaturation product 2a in 77% yield as a single regioisomer,
thus fully supporting the above hypothesis! Notably, this out-
come represents the first remote Pd-catalyzed 3° C–H func-
tionalization event under mild and neutral conditions. Finally,
it deserves mentioning that this photochemical transfor-
mation does not require the employment of exogenous pho-
17
tosensitizers or external oxidants.
due to a favorable transition state for an HAT event at the
Next, the generality of the γ-/δ-desaturation of aliphatic al-
cohols toward homoallylic alcohols was investigated (Table
1). After completion of the desaturation reaction, except for
18,19
isopropyl group.
Endogenous alkene moiety 1g did not
compromise the reaction, as diene 2g was formed efficiently.
2
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Table 2. β-/γ- and δ-/ε- Desaturation of Alcoholsa
Desaturation of 1h proceeded uneventfully, producing alkene
1
2
3
4
5
6
7
8
2h in good yield. Notably, substrates 1i and 1j, which along
with Hγ, possess competitive Hβ and Hδ sites of abstraction,
reacted selectively at the γ-C–H sites, thus producing 2i and
2j in good yields and high regioselectivity. Based on these, as
well as on the results of a direct competition between Hβ and
Hδ sites (vide infra, 2z using T1) and the kinetic studies,16 the
following reactivity preference order for silyl tethers T1 and
T2 for HAT in substrates possessing 3° C–H sites with similar
BDEs20 was revealed: 1,6 HAT of Hγ >1,5 HAT of Hβ > 1,7
HAT of H. Tertiary alcohols were also compatible with our
desaturation protocol (2k, l). Importantly, HAT at challenging
2° C–H bonds of tertiary alcohol 1l was also achieved, producing
2l in good yield. Furthermore, this method proved competent
for desaturation of complex natural products and derivatives.
Thus, remote desaturation of abietol (1m) generated its
dehydrogenated analog 2m in moderate yield. Moreover, γ-
/δ-desaturation of secondary cis-androsterone (1n) and
tertiary cholestanol derivative (1o) worked well, furnishing
2n and 2o in reasonable yields.
T1/2
O
i-Pr
β
i-Pr
γ
R1
10 mol % Pd(OAc)2
20 mol % L
2 equiv Cs2CO3
T1/2
Si
I
O
H
H
R2
T1
β
δ
R1
γ
ε
T1/2
or
0.1 M, PhH, Blue LED,
rt , 12-48 h
then, 4-10 equiv TBAF
Me Me
Si
H
R2
O
H
I
δ
1
R1
ε
T2
R2
2
Me
O
i-Pr
i-Pr
TMS
OH
Si
O
OH
9
Fe
10
11
12
13
14
15
16
17
18
19
20
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2s, 48%c
2p, 80%b
2q, 71% (NMR)b,d 2r, 87% (NMR)c,d
3.1 : 1 r.r.
OH
OH
O
i-Pr
i-Pr
O
i-Pr
Si i-Pr
Si
Me
t-Bu
Me
Me
2we, 50%b,d
2ve, 49%b,d
2t, 82%c
2u, 66%c
i-Pr i-Pr
i-Pr
OH
OH
Si
O
O
Me
Si i-Pr
Me
2z, 73%b
8 : 1 r.r.
2aa, 57%b,d,f
i-Pr
2xe, 42%b,d
2ye, 70%c
OH
OH
2ab, 77%c
2ac, 89%c
2ad, 40%b
7.3 : 1 r.r.
OH
b
c
aIsolated yields, r.r. = regioisomeric ratio. T1 was used. T2 was
used. dThe desilylation step (TBAF) was omitted. eFor 1v-1y, the
trans precursor was used. fContains minor amount of hy-
drodehalogenation by-product.
After developing efficient method for γ-/δ-desaturation of
aliphatic alcohols into homoallylic alcohols, we aimed at
extending this protocol toward formation of valuable allylic
alcohols21 via β-/γ-desaturation process involving 1,5 HAT
(Table 2). Delightfully, it was found that secondary and ter-
tiary alcohols bearing an isopropyl unit underwent selective
desaturation to generate the corresponding alcohols in a
highly efficient manner (2p–2u). Subjecting 5-membered
cycloalkane 1v to the reaction conditions unexpectedly re-
sulted in the formation of the thermodynamically more stable
endo-isomer 2v. In contrast, 6-membered β-methyl cycloal-
kanes produced the kinetic exo-methylene products 2w–x in
reasonable yields. Complex limonene derivative 1y under-
went β-/γ-desaturation producing exo-alkene 2y in 70% yield.
Expectedly, based on the Si-tether reactivity preference for
HAT (vide supra), desaturation of ambident substrate 1z,
possessing competing β-/γ- and δ-/ε- desaturation sites,
preferably occurred at the former site, producing allylic alco-
hol 2z in good yield. Finally, we examined the boundaries of
this methodology toward δ-/ε- desaturation of alcohols.
Gratifyingly, primary (1aa), secondary (1ab),and tertiary alco-
hols (1ac) all produced the δ-C–H functionalized products in
moderate to excellent yields! Likewise, desaturation of complex
the Pd(0) catalyst by alkyl iodide 1f.16 Based on the aforemen-
tioned studies, the following mechanism is proposed (Scheme
3). Visible light induction of the in-situ generated Pd(0) com-
plex produces the active photoexcited Pd(0) complex, which
engages in an SET process with alkyl iodide 1 to form alkyl
hybrid intermediate 3. Next, the formed radical species un-
dergoes a rate-limiting 1,n-HAT event (for n=5, kH/kD=3.516)
to generate translocated alkyl hybrid Pd-radical species 4. The
latter, either via a recombination of 4 with the putative Pd(I)
intermediate followed by a β-hydride elimination from 5
22
(path A) or via a direct abstraction of β-hydrogen atom by
23
24
Pd(I) species (4→2, path B), produces the alkene 2 and
regenerates the Pd catalyst.
Scheme 3. Proposed Mechanism
B
HbI
LnPd(0)*
Hb
I
B
O
T
n
Ha
Ha
hν 450 nm
HbPd(II)I
SET
1
O
-
via
T
LnPd(0)
n
1
2
Hb
Pd(I)I
derivative dehydroabietol 1ad resulted in δ-/ε- desaturation
product 2ad in moderate yield.
Hb
O
Ha
T
O
n
T
n
Ha
3
Pd(II)I
5
direct
The results of performed radical trap-, radical clock-, and
isotope labeling studies,16 supported the radical nature of this
transformation. The UV-Vis analysis revealed that the Pd(0)
complex is the photoabsorbing species. Moreover, the Stern-
Volmer studies supported quenching of the excited state of
H-abstraction
B
β-H-elimination
1,n-HAT
A
Hb
Ha
O
T
n
Pd(I)I
4
3
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In summary, we have developed a room temperature, auxil-
Page 4 of 5
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3
4
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iary-enabled visible light-induced Pd-catalyzed remote β-/γ-
, γ-/δ-, and δ-/ε- desaturation of alcohols. The hybrid Pd-
radical nature of this protocol enabled efficient functionaliza-
tion of unactivated C–H sites. Moreover, the desaturation
products were formed with superior degrees of regioselectivi-
ty compared to the state-of-the-art radical/cationic methods
due to a better-controlled Pd-involved β-hydrogen elimina-
tion step. Overall, this transformation represents the first
practical catalytic desaturation of aliphatic alcohols. We be-
lieve that this approach addresses the shortcomings of prior
art and provides a new avenue for targeted aliphatic C–H
functionalization under photoinduced transition metal-
catalysis.
(5) (a) Breslow, R.; Baldwin, S.; Flechner, T.; Kalicky, P.; Liu, S.; Wash-
burn, W. J. Am. Chem. Soc. 1973, 95, 3251. (b) Voica, A.-F.; Mendoza, A.;
Gutekunst, W. R.; Fraga, J. O.; Baran, P. S. Nat. Chem. 2012, 4, 629. (c)
Hollister, K. A.; Conner, E. S.; Spell, M. L.; Deveaux, K.; Maneval, L.;
Beal, M. W.; Ragains, J. R. Angew. Chem., Int. Ed. 2015, 54, 7837.
(6) For moderately selective desaturation of alkyl peroxides via HAT at
9
δ-C–H site employing stoichiometric amounts of transition metals, see:
Cekovic, Z.; Dimitrijevic, L.; Djokic, G.; Srnic, T. Tetrahedron 1979, 35,
2021.
(7) Parasram, M.; Chuentragool, P.; Sarkar, D.; Gevorgyan, V. J. Am.
Chem. Soc. 2016, 138, 6340.
(8) For a review on exogenous photosensitizer-free, visible light-induced
TM-catalyzed transformations, see: Parasram, M.; Gevorgyan, V. Chem.
Soc. Rev. 2017, DOI: 10.1039/c7cs00226b.
10
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(9) For a review, see: (a) Liu, Q.; Dong, X.; Li, J.; Xiao, J.; Dong, Y.; Liu,
H. ACS Catal. 2015, 5, 6111. See also: (b) Bloome, K. S.; McMahen, R.
L.; Alexanian, E. J. J. Am. Chem. Soc. 2011, 133, 20146. (c) Bonney, K. J.;
Proutiere, F.; Schoenebeck, F. Chem. Sci. 2013, 4, 4434. (d) Venning, A.
R.O.; Kwiatkowski, M. R.; Peña, J. E. R.; Lainhart, B. C.; Guruparan, A. A.;
Alexanian, E. J. J. Am. Chem. Soc. 2017, 139, 11595. For a review on UV-
induced Pd-catalyzed transformations involving alkyl iodides, see: (e)
Sumino, S.; Fusano, A.; Fukuyama, T.; Ryu, I. Acc. Chem. Res. 2014, 47,
1563.
ASSOCIATED CONTENT
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
(10) For alkyl hybrid Pd-radical intermediates capable of HAT of acti-
vated C–H bonds, see: Peacock, D. M.; Roos, C. B.; Hartwig, J. F. ACS
Cent. Sci. 2016, 2, 647.
(11) For a review, see: Parasram, M.; Gevorgyan, V. Acc. Chem. Res.
2017, 50, 2038.
vlad@uic.edu
Notes
The authors declare no competing financial interest.
(12) (a) Parasram, M.; Iaroshenko, V. O.; Gevorgyan, V. J. Am. Chem.
Soc. 2014, 136, 17926. (b) Kurandina, D.; Parasram, M.; Gevorgyan, V.;
Angew. Chem., Int. Ed. DOI: 10.1002/anie.201706554.
ACKNOWLEDGMENT
This research was supported by the National Science Foun-
dation (CHE-1663779) and the National Institutes of Health
(GM120281).
(13)For a review featuring examples beyond 1,5-HAT, see: Nechab, M.;
Mondal, S.; Bertrand, M. P.; Chem. Eur. J. 2014, 20, 16034.
(14) Generally, 1,5-HAT is conformationally favored (6-membered
transition state) for carbon-based radicals, see ref 13. However, owning to
the longer bond length of C–Si bonds, silyl methyl radicals are predis-
posed to adopt transition states beyond that of analogous carbon-based
radicals. Thus, for T1 and T2 presented in this work, 1,6-HAT (7-
membered transition state) is the most preferred process, see also: (a)
Koreeda, M.; Hamann, L. G. J. Am. Chem. Soc. 1990, 112, 8175 (b) Wilt, J.
W.; Lusztyk, J.; Peeran, M.; Ingold, K. U. J. Am. Chem. Soc. 1988, 110,
281.
REFERENCES
(1) Comprehensive Organic Transformations; Larock, R. C.; 2nd Ed.;
Wiley: New York, 1999.
(15) Classics in stereoselective synthesis; Carreira, E. M.; Kvaerno, L.;
Wiley-VCH: Weinheim, Germany, 2009, 153.
(16 ) See Supporting Information for details.
(2) (a) He, J.; Wasa, M.; Chan, K. S. L.; Shao, Q.; Yu, J.-Q. Chem. Rev.
2017, 117, 8754. (b) Daugulis, O.; Roane, J.; Tran, L. D. Acc. Chem. Res.
2015, 48, 1053. (c) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.;
Baudoin, O. Chem. Eur. J. 2010, 16, 2654. (d) Topczewski, J. J.; Cabrera,
P. J.; Saper, N. I.; Sanford, M. S. Nature 2016, 531, 220. (e) McNally, A.;
Haffemayer, B.; Collins, B. S. L.; Gaunt, M. J. Nature 2014, 510, 129. (f)
Davis, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861. (g) White,
M. C. Science 2012, 335, 807. (h) Howell, J. M.; Feng, K.; Clark, J. R.;
Trzepkowski, L. J.; White, M. C. J. Am. Chem. Soc. 2015, 137, 14590. (i)
Gensch, T.; Hopkinson, M. N.; Glorius, F.; Wencel-Delord, J. Chem. Soc.
Rev. 2016, 45, 2900.
(3) Choi, J.; MacArthur, A. H. R.; Brookhart, M.; Goldman, A. S. Chem.
Rev. 2011, 111, 1761.
(4) (a) Giri, R.; Maugel, N.; Foxman, B. M.; Yu, J-Q. Organometallics
2008, 27, 1667. (b) Baudoin, O.; Herrbach, A.; Gueritte, F. Angew. Chem.,
Int. Ed. 2003, 42, 5736. (c) Motti, E.; Catellani, M. Adv. Synth. Catal.
2008, 350, 565.
(17) For reviews, see: (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W.
C. Chem. Rev. 2013, 113, 5322. (b) Skubi, K. L.; Blum, T. R.; Yoon, T. P.
Chem. Rev. 2016, 116, 10035. (c) Romero, N. A.; Nicewicz, D. A. Chem.
Rev. 2016, 116, 10075. (d) Staveness, D.; Bosque, I.; Stephenson, C. R. J.
Acc. Chem. Res. 2016, 49, 2295. (e) Tellis, J. C.; Kelly, C. B.; Primer, D.
N.; Jouffroy, M.; Patel, N. R.; Molander, G. A. Acc. Chem. Res. 2016, 49,
1429 (f) Meggers, E. Chem. Commun. 2015, 51, 3290. (g) Xie, J.; Jin, H.;
Hashmi, A. S. K. Chem. Soc. Rev. 2017, 46, 5193. For selected examples,
see: (h) Shu, W.; Nevado, C. Angew. Chem., Int. Ed. 2017, 56, 1881 (i)
Shu, W.; Genoux, A.; Li, Z.; Nevado, C. Angew. Chem., Int. Ed. 2017, 56,
10521. (j) Hu, X.-Q.; Chen, J.-R.; Xiao, W.-J. Angew. Chem., Int. Ed. 2017,
56, 1960. (k) Zhang, J.; Li, Y.; Zhang, F.; Hu, C.; Chen, Y. Angew. Chem.,
Int. Ed .2016, 55, 1872. (l) Wang, C.; Harms, K.; Meggers, E. Angew.
Chem. Int. Ed. 2016, 55, 13495. (m) Chu, J. C. K.; Rovis, T. Nature 2016,
539, 272. (n) Choi, G. J.; Zhu, Q.; Miller, D. C.; Gu, C. J.; Knowles, R. R.
Nature 2016, 539, 268.
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(18) Analogous stereochemical outcome was observed upon desatura-
tion of (-) menthol under Baran’s protocol, see ref 5b.
(19) The stereoselectivity of the HAT process was investigated using cis-
and trans-stereoisomers of 1w-T2. For the cis-isomer, for which a quasi-
liner TS required for an HAT event is unlikely, the reaction produced the
hydrodehalogenation by-product only. Conversely, the trans-isomer un-
derwent HAT to produce 43% of the desaturation product. See SI for
details.
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(20) Blanksby, S. J.; Ellison, G. B. Acc. Chem. Res. 2003, 36, 255.
(21) Lumbroso, A.; Cooke, M. L.; Breit, B. Angew. Chem., Int. Ed. 2013,
52, 1890.
(22) For BDEs of C–H bonds adjacent to radical centers, see: Zhang, X.-
M. J. Org. Chem. 1998, 63, 1872.
(23) (a) Kuo, J. L.; Hartung, J.; Han, A.; Norton, J. R. J. Am. Chem. Soc.
2015, 137, 1036. (b) Hu, Y.; Shaw, A. P.; Estes, D. P.; Norton, J. R. Chem.
Rev. 2016, 116, 8427.
(24) The endgame, Pd-assisted H-atom elimination, occurs predomi-
nantly at the sterically less hindered site. For discussion via path A, see ref.
12a.
TOC GRAPHIC
Hβ Hδ
I
General, mild, and selective remote
desaturation of alcohols at unactivated C(sp3)-H sites
H
O
Si
R2
HO
Hα Hγ Hε
n
30 examples
up to 89% yield
up to perfect
regioselectivity
R = i-Pr, Me
The first alkyl hybrid Pd-radical
HAT process at inert C(sp3)–H sites
Hβ Hδ
3o, 2o
H
Pd-cat.
H
controlled
(I)
I-Pd
selective
O
O
visible light
room temp
H
β-H elimination
Si
R2
Si
R2
1,n-HAT
n
I-Pd(I)
Hα Hγ Hε
no exogenous
oxidants or
photosensitizers
5
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