General, Mild, and Selective Method for Desaturation of Aliphatic Amines

Article abstract of DOI:10.1021/jacs.8b00488

A novel method for desaturation of aliphatic amines into enamines as well as allylic and homoallylic amines has been developed. This general protocol operates via putative aryl hybrid Pd-radical intermediates, which combine the signature features of radic

Full text of DOI:10.1021/jacs.8b00488

Subscriber access provided by UNIVERSITY OF TOLEDO LIBRARIES
Communication
General, Mild, and Selective Method for Desaturation of Aliphatic Amines
Padon Chuentragool, Marvin Parasram, Yi Shi, and Vladimir Gevorgyan
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b00488 • Publication Date (Web): 05 Feb 2018
Downloaded from http://pubs.acs.org on February 5, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
General, Mild, and Selective Method for Desaturation of
Aliphatic Amines
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Padon Chuentragool, Marvin Parasram, Yi Shi, and Vladimir Gevorgyan*
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061, United States
Supporting Information Placeholder
ABSTRACT: A novel method for desaturation of aliphatic
Scheme 1. Methods for Directed Desaturation of Amines
amines into enamines, allylic-, and homoallylic amines has
been developed. This general protocol operates via putative
aryl hybrid Pd-radical intermediates, which combine the
signature features of radical chemistry, a hydrogen atom
transfer (HAT) process, and transition metal chemistry, a
selective β-hydride elimination step, to achieve efficient and
selective desaturation of amines. These hybrid Pd-radical
intermediates are efficiently generated under mild photoin-
duced conditions, and are capable of 1,n-HAT (n=5-7) event
at C(sp3)–H sites. The selectivity of HAT is tunable by vary-
ing different auxiliaries, which highlight the generality of this
method. Remarkably, this desaturation method, which oper-
ates under mild conditions and does not require employ-
ment of exogenous photosensitizers or oxidants, can be per-
formed in a practical scalable fashion from simple amines.
a) State-of-the-art methods for desaturation of amines
Hβ Hδ
R
R
N
Refs. 7-8, 10a
N
T
n
T
Hα Hγ
N3Et2
O
S
O
S
=
T
O
O
Me Me
Si
Br
Me
Baran, 201210a
Doucet, 20148a
[Pd]
Brookhart, 20077b
[M] = Co, Rh
H+, [O]
150 o
C
80-140 o
C
α-/β desaturation
via C–H activation
β-/γ-, γ-/δ desaturation
via radical/cationic
α-/β desaturation
via transfer hydrogenation
low regiocontrol
of deprotonation
moderate yields
limited practicability
harsh conditions
moderated yields
harsh conditions
b) This work: α-/β-, β-/γ- and γ-/δ- desaturation involving hybrid Pd-radical 1,n-HAT
1) T-Cl, base
R
N
Hβ Hδ
2) Pd-cat.
R
N
T
n
visible light, rt
H
n=0-2
• no isolated intermediates
• good to high yields
Hα Hγ
H
enamines, allylic-,
and homoallylic amines
high regioselectivity of
β-H elimination
• from alipahtic
amines
O
I
O
S
O
T
I
T1
I
T2
Unsaturated amines are common functional groups found
in natural products, bioactive molecules, and are versatile
synthetic building blocks. Thus, not surprisingly, an array of
hybrid Pd-radical
intermediates
H
R
Hβ Hδ
I-Pd(I)
R
N
N
1
H
T
n
Pd-X
T
Hα Hγ
methods toward these important motifs has been developed.
Conventional approaches to enamines2 involve condensa-
tions of carbonyl group,2 cross-coupling reactions,3 or hy-
droaminations of alkynes.4 Main methods toward allylic- and
homoallylic amines usually rely on alkylation of amines5 and
imines6 with alkenyl halides. While most of the aforemen-
tioned methods are efficient, they all require pre-
functionalized starting materials. It is apparent that straight-
forward conversion of cheap and abundant aliphatic amines
into valuable alkenyl amines could serve as a more practical
approach. However, methods for direct dehydrogenation of
amines into unsaturated amines have not been broadly de-
veloped. One elegant strategy for converting amines into
enamines employs non-directed7a or directed7b transfer-
hydrogenation process (Scheme 1a). Nonetheless, these
methods have limited practicability, as they work on
H
B
A
selective HAT
at α-,β-,γ- C–H sites
non-functionalizable tertiary alkyl amines7a or employ mois-
ture-sensitive N-vinylsilane substrates.7b Another notewor-
thy, yet moderately efficient approach towards enamine by
Doucet8a relies on conventional Pd-catalyzed C–H activation
methodology. Both approaches suffer from harsh reaction
conditions, and are limited to secondary α-/β-desaturation
of amines due to restricted size and steric hindrance of tran-
sition metal (TM)-cyclic intermediates.9 Conversely, radical
strategies have shown exceptional capability for functionali-
zation of unactivated tertiary and secondary C(sp3)–H sites
due to a facile HAT event.10,11 The current state-of-the-art
method for a remote desaturation of amines was developed
by Baran,10a which follows a radical-polar crossover path
(Scheme 1a). However, due to generation of cationic inter-
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
a
mediates, the end game of this protocol, the proton elimina-
Table 1. α-β Desaturation of Amines with T1
1
2
3
4
5
6
7
8
O
tion step, in some cases, results in low regioselectivity of de-
saturation. Based on these limitations, the development of a
practical and universal method for site-selective desaturation
of aliphatic amines is highly desirable. Herein, we report a
mild, practical, and general protocol for selective desatura-
tion of aliphatic amines (Scheme 1b). This method employs
simple aliphatic amines, which, under practical conditions,
are selectively and efficiently transformed into enamines,
allylic amines, and homoallylic amines. The high selectivity
of desaturation is achieved via auxiliaries-controlled 1,5-, 1,6-
and 1,7-HAT process of the photo-generated aryl hybrid Pd-
radical intermediates12 (Scheme 1b, A→B), and a subse-
quent Pd-involved β-H-elimination step.13
2) 10 mol %
Pd(OAc)2
20 mol % L
I
Hβ
1) T1-Cl
Et3N, CH2Cl2
Hβ
R
N
R
R
T1
N
N
Bz
H
T1
2 equiv Cs2CO3
PhH, Blue LED
rt, 5-16 h
rt, 3-12h
PPh2
Hα
Hα
2
1
Fe
L
no isolated intermediates
P(t-Bu)2
9
Bz
N
Bz
N
Bz
Bz
Bz
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
N
O
OH
OMOM
2c
2d
(89%)
2a
85% (98%)
2b
90% (95%)
2e
(94%)
87% (97%)
Bz
Bz
Bz
N
N
N
N
Bz
N
Bz
2h
99%
1.2 : 1 r.r
2i
72%
Recently, we developed Si-based auxiliaries for proximal
and remote desaturation of aliphatic alcohols via photoin-
duced generation of hybrid aryl- and alkyl Pd-radical spe-
cies.14 Expectedly, due to the much lower hydrolytic stability
of the N–Si bond compared to that of the O–Si bond,15 em-
ployment of these Si-based tethers for desaturation of ali-
phatic amines was not feasible. Thus, we examined more
practical amide-based tethers. Delightfully, it was found that
piperidine 1a, protected with commercially available o-
iodobenzoyl chloride (tether T1), under our previously re-
ported conditions14 underwent efficient α-/β- desaturation
via a facile 1,5-HAT11 producing cyclic enamine 2a in nearly
quantitative yield (Table 1). This represents the first room
temperature dehydrogenation of an amine into an enamine,
which operates under visible light-induced16 Pd-catalyzed
conditions without employment of exogenous photosensi-
tizers17 or oxidants. Moreover, this method can efficiently be
performed in a practical fashion without isolation of the
tethered amine intermediate to produce enamine 2a directly
from amine 1a in excellent yield over the two steps.
Next, the generality of the α-/β-desaturation of aliphatic
amines was examined. Morpholine derivative 1b found to be
a competent substrate, producing dihydrooxazine 2b in 95%
yield. Piperidines, possessing an unprotected secondary al-
cohol moiety (1c) or a labile acetal group (1d), also reacted
well, producing enamines 2c and 2d in high yields. These
results represent the efficient synthesis of endocyclic
enamines, which are difficult to access via traditional meth-
ods mentioned above.2-4 Linear amines were also amenable,
yielding almost quantitative yields of enamine products (2e,
2f-α/β). It is worth mentioning that amine 1f failed to react
under reported C–H activation conditions.8a Gratifyingly,
desaturation of pyrrolidine derivative and a bicyclic substrate
produced the corresponding enamines in good yields (2g,
2h). Interestingly, double-fold desaturation of piperazine,
decorated with two reacting tethers, produced dehydropyra-
zine 2i in good yield. Notably, caprolactam derivative was
selectively desaturated at an unusual reaction site (2j).18 De-
hydrogenation of proline- and pipecolic esters (1k-m)
2g
2f-α/β
99%
80% (88%)
Bz
N
Bz
N
O
Bz
Bz
O
O
N
N
OR
OMe
N
2l; R = Me
2k
88%
86%, 2.8 : 1 r.r
2m; R = t-Bu
81%, 2.2 : 1 r.r
2j
67%
2n
4 : 1 r.r
64% (NMR)
aIsolated yields for two steps (1→2) are shown. Yields for one-
step desaturation (from amine protected with reactive tether) are
shown in parenthesis. r.r, regiomeric ratio. Bz, benzoyl.
furnished separable mixtures (except for 2k) of regioisomers,
with the less substituted alkenes being the major products.
Finally, desaturation of substrate 1n, containing two amine
moieties underwent selective directed reaction at the proxi-
mal site producing enamine 2n in 64% NMR yield.
After establishing the scope of α-/β-desaturation, we
turned our attention to remote desaturation of amines (Ta-
ble 2). Apparently, for achieving this goal, the development
of the tether capable of HAT at a more distant C–H site was
necessary. Based on the efficient and selective remote HAT
of Baran’s tosyl triazene auxiliary (Scheme 1a),10a we as-
sumed that the aryl iodide derivative of it could be an appro-
priate choice of tether (T2, Scheme 2). Indeed, this tether
can easily be installed at the amine group using a commer-
cially available o-iodobenzenesulfonyl chloride. Upon gener-
ation of the hybrid Pd-radical species, it expected to undergo
1,n-HAT (n=6,7) at an unactivated C(sp3)–H site,10a fol-
lowed by Pd-involved elimination to selectively furnish a
remote alkene moiety. Remarkably, it was found that amine
1f, now protected by T2 tether underwent efficient 1,6-HAT
to produce β-/γ-desaturation product in 47% yield together
with 31% of the cyclic sulfonamide, a product of cyclization
of the formed alkyl radical at the aromatic ring of the aryl-
sulfonyl group19 (Table 2). On the other hand, the same
amine (1f), while decorated with T1 tether (vide supra), un-
derwent efficient α-/β-desaturation to produce enamine 2f-
α/β (Table 1). These results, where two auxiliaries com-
pletely switched the regioselectivity of desaturation of
2
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
a
smoothly, furnishing the corresponding products (2y, 2z) in
good to excellent yields. Markedly, functionalization of inert
secondary C−H bonds occurred efficiently (1aa, 1ab), resulting
in homoallylic amines 2aa, 2ab in respectable yields, where
substrate possessing bulkier substituent at N-atom (1ab)
resulted in better selectivity of the HAT event. A heterocy-
clic substrate, azepane derivative 1ac, reacted efficiently to
produce 2ac in 77% yield. Importantly, under the reported
conditions,15 benzenesulfonyl group in homoallylic amine 2y
can easily be removed.19 Finally, the practicality of this
method was illustrated by a gram-scale desaturation of amine
1p into homoallylic amine 2p in nearly quantitative yield
over the three steps (eq 1).
Table 2. β-γ- and γ-δ Desaturation of Amines with T2
1
2
3
4
5
6
7
8
3) 10 mol %
Pd(OAc)2
1) T2-Cl
Hβ Hδ DMAP, CH2Cl2
rt, 3-12h
SO2Ph
O
O
R
N
20 mol % L
N
n
S
I
R/Boc
H
2)b (Boc)2O
2 equiv Cs2CO3
PhH, Blue LED
rt, 12-36 h
n= 1,2
Hα Hγ
DMAP, CH2Cl2
rt, 12h
2
1
T2
no isolated intermediates
PhO2S
BocN SO2Ph
N
BocN SO2Ph
BocN SO2Ph
2p
95%
2o
2q
79%d
87% (98%)
9
2f-β/γ
47%c
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
SO2Ph
NBoc
BocN SO2Ph
SO2Ph
NBoc
OR
2s; R = TBS
56% (70%)
2t; R = MOM
61% (71%)
SO2Ph
N
Boc
2u CO2t-Bu
2r
40% d
68% (78%)
5:1 r.r
2v
(75%)d
BocN SO2Ph
NH2
3 steps
(1)
SO2Ph
4.4 mmol
scale
SO2Ph
BocN
1p
2p
N
MeN SO2Ph
BocN SO2Ph
98% isolated yield
1.46 g
no isolated intermediates
2w
80%
2z
2y
84%
2x
77%d
48% (57%)
Based on the literature reports13,14 and our initial mecha-
nistic studies,19 including the radical scavenger experiments,
deuterium labeling studies, and Stern-Volmer quenching
studies, the following mechanism for this remote desatura-
tion reaction of amines is proposed (Scheme 2). The formed
in situ Pd(0) complex undergoes excitation by the visible
light to form the active Pd(0)* catalyst. The latter engages in
an SET event with aryl iodide 1-T to generate aryl hybrid
Pd-radical species 3, which via 1,n-HAT (n=5-7) produces
alkyl hybrid Pd-radical species 4. A subsequent β-hydrogen
elimination (path A)13 or a direct hydrogen abstraction
(path B)21 generates the desaturated product 2 and regener-
ates the catalyst.
SO2Ph
N
BuN SO2Ph
BocN
SO2Ph
2aa
46%
7:4 r.r.
2ab
56%
2ac
77%
8:1:1 r.r
aIsolated yields for two steps (1→2) are shown. Yields for one-step
desaturation (from amine protected with reactive tether) are
shown in parenthesis. r.r, regiomeric ratio. bThe Boc installation
was not applicable for secondary amines (1f, 1y-1aa, 1ac). c31% of
HAT/cyclization at aromatic ring product was also isolated. Con-
tains minor amount of hydrodehalogenation by-product.
d
the same substrate,20 clearly indicate the potential of this
strategy toward development of auxiliaries-controlled site
selective C–H functionalizations. Due to the observed com-
peting cyclization of the formed β-alkyl radical at the aryl-
sulfonyl group, at the moment, the attempts on further ex-
ploration of the β-/γ-desaturation of amines were halted;
and we turned our attention to the γ-/δ-desaturation reac-
tion. Delightfully, it was found that γ-/δ-desaturation of the
amine 1o via a three-step procedure (without isolation of the
intermediates) produced 2o as a sole product in excellent
yield, which is superior, in both yield and regioselectivity, to
those reported via the radical/cationic approach.10a Evident-
ly, the observed highly regioselective outcome reflects the
nature of the “controlled” β-Pd-H elimination step of the
operative hybrid Pd-radical mechanism (vide infra). Desatu-
ration of various aliphatic amines (1p-1r) proceeded une-
ventfully, resulting in the formation of homoallylic amines
(2p-2r) in good yields. Particularly, acid-sensitive groups,
such as primary TBS-ether (1s) or acetal groups (1t) which
do not withstand the reported acidic conditions,10a,19 were
well-preserved in this reaction. Leucine ester (1u) and
menthyl-amine (1v) were found to be competent substrates
yielding the corresponding desaturation products 2u-2v in
reasonable yields. Amines bearing primary (1w) and tertiary
(1x) alkyl carbon chains also provided high yields of the cor-
responding desaturation products. Notably, unprecedented
remote desaturation of secondary amines 1y, 1z proceeded
Scheme 2. Proposed Mechanism
LnPd(0)
I
hν 450 nm
Ha
B
B
HbI
X
LnPd(0)*
NR
1-T
Ha
Hb
n
X = CO, SO2
HbPd(II)I
SET
X
-
via
1
NR
n
2
Pd(I)I
Ha
Ha
X
Pd(II)I
X
NR
Hb
NR
n
3
Hb
n
5
direct
H-abstraction
B
β-H-elimination
1,n-HAT
A
Ha
Pd(I)I
X
NR
Hb
n
4
In summary, a general, mild, efficient, and selective
method for desaturation of aliphatic amines has been devel-
oped. This method employs easily installable/removable15,19
aryl iodide-containing tethers, which upon visible light irra-
diation/Pd-catalysis generate an aryl radical at the tether,
which triggers an auxiliary-controlled 1,n-HAT event at the
aliphatic amine moiety, followed by the Pd-assisted β-H
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
elimination step. It is expected that this operationally simple
Page 4 of 5
1
2
3
4
5
6
7
8
and easily scalable method, which does not require employ-
ment of exogenous photosensitizers or external oxidants, will
find broad applications in synthesis.
Chem., Int. Ed. 2003, 42, 5736. (e) Motti, E.; Catellani, M. Adv. Synth.
Catal. 2008, 350, 565.
(9) (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.
ASSOCIATED CONTENT
Supporting Information
This Supporting Information is available free of charge via the
Internet at http://pubs.acs.org.
9
(10) (a) Voica, A.-F.; Mendoza, A.; Gutekunst, W. R.; Fraga, J. O.; Baran,
P. S. Nat. Chem. 2012, 4, 629. (b) Liu, T.; Mei, T.-S.; Yu, J.-Q. J. Am. Chem.
Soc. 2015, 137, 5871. (c) Liu, T.; Myers, M. C.; Yu, J.-Q. Angew. Chem. Int.
Ed. 2017, 56, 306. (d) Wappes, E. A.; Fosu, S. C.; Chopko, T. C.; Nagib, D.
A. Angew. Chem. Int. Ed. 2016, 55, 9974. (e) Wappes, E. A.; Nakafuku, K.
M.; Nagib, D. A. J. Am. Chem. Soc. 2017, 139, 10204. (f) Chen, K.; Richter,
J. M.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7247. (g) Wang, Y.-F.;
Chen, H.; Zhu, X.; Chiba, S. J. Am. Chem. Soc. 2012, 134, 11980. (h)
Zhang, X. et al., Angew. Chem. Int. Ed. 2010, 49, 10192. (i) Chu, J. C. K.;
Rovis, T. Nature 2016, 539, 272. (j) Choi, G. J.; Zhu, Q.; Miller, D. C.; Gu,
C. J.; Knowles, R.R. Nature 2016, 539, 272. (k) Chen, D.-F.; Chu, J. C. K.;
Rovis, T. J. Am. Chem. Soc. 2017, 139, 14897. (l) Shu, W.; Nevado, C.
Angew. Chem., Int. Ed. 2017, 56, 1881. (m) Shu, W.; Genoux, A.; Li, Z.;
Nevado, C. Angew. Chem., Int. Ed. 2017, 56, 10521. (n) Du, S.; Kimball, E.
A.; Ragains, J. R. Org. Lett. 2017, 19, 5553. (o) 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. (p) Breslow, R.; Baldwin, S.; Flechner, T.;
Kalicky, P.; Liu, S.; Washburn, W. J. Am. Chem. Soc. 1973, 95, 3251.
(11) For a review, see: Nechab, M.; Mondal, S.; Bertrand, M. P. Chem.
Eur. J. 2014, 20, 16034.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental procedures and compound characteriza-
tion data (PDF).
AUTHOR INFORMATION
Corresponding Author
*vlad@uic.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank National Institutes of Health (GM120281) for
financial support of this work. We also thank Dr. Yang Wang
(Northwestern University) for helpful discussions.
(12) 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) Bonney, K. J.; Proutiere, F.;
Schoenebeck, F. Chem. Sci. 2013, 4, 4434. (c) Venning, A. R.O.; Kwiat-
kowski, 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: (d) Sumino, S.;
Fusano, A.; Fukuyama, T.; Ryu, I. Acc. Chem. Res. 2014, 47, 1563.
(13) (a) Bloome, K. S.; McMahen, R. L.; Alexanian, E. J. J. Am. Chem. Soc.
2011, 133, 20146. (b) Parasram, M.; Iaroshenko, V. O.; Gevorgyan, V. J.
Am. Chem. Soc. 2014, 136, 17926. (c) Kurandina, D.; Parasram, M.; Ge-
vorgyan, V. Angew. Chem., Int. Ed. 2017, 56, 14212. (d) Kurandina, D.;
Rivas, M.; Radzhabov, M.; Gevorgyan, V. Org. Lett. 2018, 20, 357. (e)
Wang, G.-Z.; Shang, R.; Cheng, W.-M.; Fu, Y. J. Am. Chem. Soc. 2017, 139,
18307. (f) Zhou, W.-J.; Cao, G.-M.; Shen, G.; Zhu, X.-Y.; Gui, Y.-Y.; Ye, J.-
H.; Sun, L.; Liao, L.-L.; Li, J.; Yu, D.-G. Angew. Chem., Int. Ed. 2017, 56,
15683.
(14) (a) Parasram, M.; Chuentragool, P.; Sarkar, D.; Gevorgyan, V. J. Am.
Chem. Soc. 2016, 138, 6340. (b) Parasram, M.; Chuentragool, P.; Wang, Y.;
Shi, Y.; Gevorgyan, V. J. Am. Chem. Soc. 2017, 139, 14857. (c) For a review
on employment of Si-tethers in C–H functionalizations, see: Parasram, M.;
Gevorgyan, V. Acc. Chem. Res. 2017, 50, 2038.
(15) (a) Greene’s protective groups in organic synthesis; Wuts, P. G. M.;
Greene, T. W., 4th Ed.; Wiley: New York, 2007. (b) Sabitha, G.; Reddy,
B.V. S.; Abraham, S.; Yadav, J.S. Tetrahedron Lett. 1999, 40, 1569.
(16) For selected reviews of photocatalytic transformations, see: (a) Pri-
er, 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.
REFERENCES
(1) (a) Besada, P.; Mamedova, L.; Thomas, C. J.; Costanzi, S.; Jacobson,
K. A. Org. Biomol. Chem. 2005, 3, 2016. (b) Rai, U. S.; Isloor, A. M.; Shetty,
P. et al. Med. Chem. Res. 2012, 21, 1090. (c) Steele, A. D.; Keohane, C. E.;
Knouse, K. W.; Rossiter, S. E.; Williams, S. J.; Wuest, W. M. J. Am. Chem.
Soc. 2016, 138, 5833. (d) Tabor, M. G.; Shenvi, R. A. Org. Lett. 2015, 17,
5776.
(2) (a) Enamines: Synthesis: Structure, and Reactions; Cook, G.; 2nd Ed.;
Marcel Dekker: NY, 1988. (b) The Chemistry of Enamines, Parts 1 & 2;
Rappoport, Z., Ed.; Wiley: New York, 1994. (c) Hickmott, P. W. Tetrahe-
dron 1982, 38, 3363. (d) Tada, N.; Jansen, D. J.; Mower, M. P.; Blewett, M.
M.; Umotoy, J. C.; Cravatt, B. F.; Wolan, D. W.; Shenvi, R. A. ACS Cent.
Sci. 2016, 2, 401.
(3) For a review, see: Dehli, J. R.; Legros, J.; Bolm, C. Chem. Commun.
2005, 973.ꢀ
(4) (a) Pohlki, F.; Doye, S. Chem. Soc. Rev. 2003, 32, 104. (b) Severin, R.;
Doye, S. Chem. Soc. Rev. 2007, 36, 1407.
(5) For reviews, see: (a) Johannsen, M.; Jørgensen, K. A. Chem. Rev.
1998, 98, 1689. (b) Ramirez, T. A.; Zhao, B.; Shi, Y. Chem. Soc. Rev. 2012,
41, 931.
(6) For a review, see: Campos, K. R. Chem. Soc. Rev. 2007, 36, 1069.
(7) (a) Zhang, X.; Fried, A.; Knapp, S.; Goldman, A. S. Chem. Commun.
2003, 2060. (b) Bolig, A. D.; Brookhart, M. J. Am. Chem. Soc. 2007, 129,
14544. For reviews on iridium pincer complexes catalyzed transfer-
hydrogenation, see: (c) Choi, J.; MacArthur, A. H. R.; Brookhart, M.;
Goldman, A. S. Chem. Rev. 2011, 111, 1761. (d) Daugulis, O.; MacArthur,
A. H. R.; Rix, F. C.; Templeton, J. L. ACS Catal. 2016, 6, 1518.
(8) (a) Bheeter, C. B.; Jin, R.; Bera, J. K.; Dixneuf, P. H.; Doucet, H. Adv.
Synth. Catal. 2014, 356, 119. (b) Benjamin, G.; Chung, K. W.; Fagnou, K. J.
Am. Chem. Soc. 2010, 132, 10692. For desaturation of non-amine tethered
substrates, see, (c) Giri, R.; Maugel, N.; Foxman, B. M.; Yu, J-Q. Organome-
tallics 2008, 27, 1667. (d) Baudoin, O.; Herrbach, A.; Gueritte, F. Angew.
(17) For a review on exogenous photosensitizer-free, visible light-induced
TM-catalyzed transformations, see: Parasram, M.; Gevorgyan, V. Chem.
Soc. Rev. 2017, 46, 6227.
4
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
(18) For examples of desaturation of lactam systems, generally producing
alkene proximal to the carbonyl group, see: (a) Yifeng Chen, Y.; Turlik, A.;
Newhouse, T. R. J. Am. Chem. Soc. 2016, 138, 1166. (b) Pineschi, M.; Del
Moro, F.; Di Bussolo, V.; Macchia, F. Adv. Synth. Catal. 2006, 348, 301. (c)
Chen, M.; Dong, G. J. Am. Chem. Soc. 2017, 139, 7757. (d) Garnier, E. C.;
Liebeskind, L. S. J. Am. Chem. Soc. 2008, 130, 7449. (e) Wang, Z.; He, Z.;
Zhang, L.; Huang, Y. J. Am. Chem. Soc. 2018, 140, 735. For α/β-
desaturation of esters, see: (f) Chen, Y.; Romaire, J. P.; Newhouse, T. R. J.
Am. Chem. Soc. 2015, 137, 5875.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(19) See Supporting Information for details.
(20) Generally, 1,5-HAT process is the most favorable for carbon-
tethered radicals due to conformationally favored 6-membered transition
state. See ref 11, see also Yoshikai, N.; Mieczkowski, A.; Matsumoto, A.;
Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2010, 132, 5568. However, for the
sulfonyl tether, owing to longer C–S bonds, larger rings to adopt a quasi-
linear transition state for an HAT process are required, which results in
preferred 1,6- or 1,7-HAT events. See refs 10a, 11.
(21) (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.
TOC GRAPHICS
R
Practical, mild, and selective
desaturation of aliphatic amines
Hβ Hδ
N
R
N
T
n
H
H
30 examples
Hα Hγ
enamines, allylic-,
and homoallylic amines
• from alipahtic
amines
Auxiliaries-controlled selective HAT
at α-,β-,γ- C(sp3)–H sites
up to quantitative yield
& perfect regioselectivity
T
I
H
R
Hβ Hδ
controlled
N
tunable
auxiliaries
I-Pd(I)
R
N
Pd-cat.
H
T
n
β-H elimination
I-Pd(I)
visible light
room temp
T
Hα Hγ
H
no exogenous
oxidants or
photosensitizers
5
ACS Paragon Plus Environment