Catalytic Olefin Hydroamidation Enabled by Proton-Coupled Electron Transfer

Article abstract of DOI:10.1021/jacs.5b09671

Here we report a ternary catalyst system for the intramolecular hydroamidation of unactivated olefins using simple N-aryl amide derivatives. Amide activation in these reactions occurs via concerted proton-coupled electron transfer (PCET) mediated by an excited state iridium complex and weak phosphate base to furnish a reactive amidyl radical that readily adds to pendant alkenes. A series of H-atom, electron, and proton transfer events with a thiophenol cocatalyst furnish the product and regenerate the active forms of the photocatalyst and base. Mechanistic studies indicate that the amide substrate can be selectively homolyzed via PCET in the presence of the thiophenol, despite a large difference in bond dissociation free energies between these functional groups.

Full text of DOI:10.1021/jacs.5b09671

Subscriber access provided by UNIV OF LETHBRIDGE
Communication
Catalytic Olefin Hydroamidation Enabled by Proton-Coupled Electron Transfer
David C Miller, Gilbert J Choi, Hudson S Orbe, and Robert R Knowles
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b09671 • Publication Date (Web): 05 Oct 2015
Downloaded from http://pubs.acs.org on October 6, 2015
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 free 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 accessible to all
readers and 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
Catalytic Olefin Hydroamidation Enabled by Proton-Coupled Elec-
tron Transfer
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
David C. Miller, Gilbert J. Choi, Hudson S. Orbe, and Robert R. Knowles*
Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
Supporting Information Placeholder
Current methods for amidyl-based hydroamidation
ABSTRACT: Here we report a ternary catalyst system for the
R1
intramolecular hydroamidation of unactivated olefins using sim-
O
O
R2
O
H
N
AIBN,Bu3SnH
R1
ple N-aryl amide derivatives. Amide activation in these reactions
occurs via concerted proton-coupled electron transfer (PCET)
mediated by an excited state iridium complex and weak phosphate
base to furnish a reactive amidyl radical that readily adds to pen-
dant alkenes. A series of H-atom, electron, and proton transfer
events with a thiophenol co-catalyst furnish the product and re-
generate the active forms of the photocatalyst and base. Mecha-
nistic studies indicate that the amide substrate can be selectively
homolyzed via PCET in the presence of the thiophenol, despite a
large difference in bond dissociation free energies between these
functional groups.
N
X
R3
R3
N-prefunctionalization,
stoichiometric reductant
R2
4 equiv.IBX
THF/DMSO, 90°C
Ar
R1
O
H
N
Ar
N
H
R2
stoichiometric oxidant
R2
R1
This work: catalytic olefin hydroamidation enabled by PCET
IrIII redox cat.
Ar
O
R1
O
phosphate base cat.
H
N
Ar
N
R2
H-atom donor cat.
R2
R1
H
visible hν
O
R1
PCET
Ar
N
R2
Olefin hydroamidation is a powerful approach to C-N bond
construction, and one that continues to motivate the develop-
ment of new synthetic methods.1-3 Among the most versatile
hydroamidation technologies reported to date are those that
make use of amidyl radicals. Pioneering contributions from
Newcomb, Zard, Studer, Nicolaou and others have demon-
strated that amidyl-based methods benefit from broad scope,
predictable anti-Markovnikov regioselectivity and low kinetic
barriers to C-N bond formation.4 While enabling, these meth-
ods typically require either prefunctionalization of the amide
nitrogen or the use of strong stoichiometric oxidants to facili-
tate efficient amidyl generation (Figure 1). As such, catalytic
schemes for radical hydroamidation that utilize native amide
substrates and occur under redox-neutral conditions have the
potential to significantly increase the value and atom-economy
of these methods.
Figure 1. Catalytic olefin hydroamidation enabled by PCET activa-
tion of amide N-H bonds.
base combination found to be most effective for amidyl gener-
ation. Subsequent olefin addition would result in C-N bond
formation and creation of a nascent carbon-centered radical
that would be reduced by an appropriate H-atom donor cata-
lyst (Scheme 1). Next, the oxidized form of the HAT catalyst
could accept an electron from the reduced form of the photo-
catalyst to form an anion. In turn this anion would be proto-
nated by the phosphoric acid produced in the PCET event to
regenerate the active forms of all three catalytic components.
The feasibility of this proposal finds support in similar
schemes reported recently for photocatalytic olefin hydrofunc-
tionalization, most notably in the work of Nicewicz.3a,8
To this end, we recently disclosed a catalytic protocol for
olefin carboamination enabled by proton-coupled electron
transfer (PCET) activation of N-aryl amides.5,6 In this process,
a weak phosphate base and an excited state iridium photocata-
lyst jointly mediate the homolysis of a strong anilide N-H
bond, furnishing a reactive amidyl radical that can undergo
addition to a pendant olefin.7 Here we demonstrate that this
manner of PCET activation can be further leveraged to enable
efficient intramolecular hydroamidation reactions of unacti-
vated olefin partners when carried out in the presence of a
thiol hydrogen atom donor co-catalyst (Figure 1). The devel-
opment, scope and mechanistic evaluation of this process are
described herein.
A principal concern in the development of such a process
was identifying conditions wherein the amide N-H bond can
be selectively homolyzed in the presence of the H-atom donor.
In homolytic bond activations, selectivities are often correlated
with bond strength differential, with weaker bonds being acti-
vated preferentially.9 As the substrate anilide N-H bonds are
significantly stronger (BDFEs ~ 100 kcal/mol) than those of
any commonly used H-atom donors, it was not clear at the
outset that chemoselective amide homolysis would be feasible.
With these considerations in mind, we evaluated a number of
potential HAT catalysts in the hydroamidation of amide 1
(Table 1). First, we observed that when amide 1 was subject-
ed to irradiation with blue LEDs in the presence of 2 mol%
Ir(dF(CF3)ppy)2(bpy)PF6 and 20 mol% dibutyl phosphate a
small amount of lactam 2 was produced together with addi-
tional non-productive substrate conversion (Table 1, entry 1).
Reaction design and optimization Building on our carbo-
amination
protocol,
we
elected
to
retain
the
Ir(dF(CF3)ppy)2(bpy)PF6 photocatalyst and dibutyl phosphate
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
20 kcal/mol weaker (S-H BDFE ~ 79 kcal/mol)12 than the N-H
Scheme 1. Proposed catalytic cycle
bond of the amide substrate (N-H BDFE ~ 99 kcal/mol).13 The
observation of efficient amide activation in the presence of
such large thermodynamic bias raises intriguing questions
about the origins of selectivity in radical generation (vide in-
fra).
1
2
3
4
IrIII
O
hν
Ph
(BuO)2PO2
N
H
concerted
PCET
ET/PT
5
6
7
8
9
Substrate scope With these optimized reaction conditions,
we set out to examine the scope of this new hydroamidation
process. On preparative scale, model amide 1 underwent hy-
droamidation to provide lactam 2 in 85% isolated yield (Table
2). With respect to the olefin component, a variety of di-, tri-,
and tetrasubstituted olefins with differing substitution patterns
were successfully accommodated (3 – 6). Styrenyl acceptors
could also be utilized, though an increased loading of the thio-
phenol (30 mol%) was required to achieve optimal yields (7).
Steric hindrance adjacent to the site of C-N bond formation
was also tolerated (8). In addition to amide substrates, the hy-
droamidations of carbamates and ureas proceed smoothly un-
der the standard conditions (6, 7, 9, 10). As such the reported
method provides a simple means of converting common allylic
alcohol and allylic amine starting materials to vicinal amino
alcohols and 1,2-diamines, respectively. Thiolcarbamates
could also be cyclized to furnish thiazolidinone products (11).
Acyclic carbamates derived from stereogenic allylic alcohols
could also be amidated with synthetically useful levels of dia-
stereoselectivity (12, 13). Moreover, these reactions are large-
ly insensitive to the olefin geometry of the substrate as carba-
mates derived from the isomeric polyolefins nerol and geraniol
both cyclized to afford 14 in high yield. Interestingly, when
hydroamidation reactions of either of these isomeric starting
materials were run to partial conversion, no olefin isomeriza-
tion was observed in the recovered starting material, suggest-
ing C-N bond formation in these reactions is irreversible.
O
H-atom
donor
catalyst
IrII
Ph
IrII
(BuO)2PO2H
R
R–H
N
(BuO)2PO2H
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
H-atom
transfer
C-N bond
formation
O
O
Ph
N
Ph
N
H
(BuO)2PO2H
IrII
This finding was attributed to the ability of the carbon-
centered radical formed in the amidyl cyclization to abstract a
hydrogen atom from the weak allylic C-H bonds present in the
starting material.10 Consistent with this hypothesis, when these
allylic protons are replaced with methyl groups, no product
was observed (entry 2). Addition of catalytic quantities of
many common H-atom donor classes, including phenols, tri-
phenylsilane, arylamines, and diphenyl acetonitrile, did not
provide a meaningful improvement over background (entries
3–7). However, we were pleased to find that inclusion of 10
mol% of thiophenol produced the desired hydroamidation
product 2 in 95% yield (entry 8). Further evaluation of elec-
tronically and structurally varied thiophenols demonstrated
that none were better than the parent catalyst (entries 9–11).
Control experiments run in the absence of light, photocatalyst,
or phosphate base furnished none of the desired product (en-
tries 12–14). The success of thiophenol was somewhat surpris-
ing in that thiols are known to be substrates for multisite
PCET activation11 and the thiophenol S-H bond is more than
In addition to these acyclic examples, a number of bicyclic
products (15 – 19) could be synthesized in excellent yield and
high diastereoselectivity, including oxazolidinones derived
from both diastereomers of carveol. Notably, these substrates
demonstrate distal olefin functionality and unprotected hy-
droxyl groups are well tolerated. In addition, spirocyclic prod-
ucts bearing tertiary carbinamine centers were also accessible
under standard conditions (20). Moreover, hydroamidation of
canonical Diels-Alder products could also be accomplished to
afford more complex polycyclic structures (21, 22). The reac-
tion is also successful with differentially protected glucal sub-
strates (23, 24) to furnish deoxygenated amino sugars. A num-
ber of natural product derivatives were also investigated as
substrates. An amide derived from cis-chrysanthemic acid was
successfully cyclized to deliver a fused 3,5-ring system in
good yield and excellent diastereoselectivity (25). Similarly, a
progesterone-derived carbamate was hydroamidated to furnish
a vicinal amino alcohol on a steroid framework as a single
detectable diastereomer (26). Lastly, a carbamate derived from
the bridgehead alcohol of gibberellic acid provided complex
polycyclic oxazolidinone 27 in 68% isolated yield.
Table 1. Optimization studies
O
2 mol% Ir(dF(CF3)ppy)2(bpy)PF6
20 mol% NBu4OP(O)(OBu)2
Ph
O
R
R
N
Ph
H
N
H
10 mol% H-atom donor
0.3 M CH2Cl2
blue LEDs, rt, 20 hr
R
R
1
2
R
Entry
H-atom donor
Yield (%)
1
2
3
4
5
6
7
8
9
H
None
None
Phenol
24
0
Me
H
H
H
H
H
H
H
H
H
18
19
21
28
16
95
45
86
83
2,4,6-tBu-phenol
4-Aminopyridine
Diphenyl acetonitrile
Ph3SiH
Thiophenol
2-Naphthalenethiol
4-Trifluoromethyl thiophenol
2,4,6-iPr-thiophenol
10
11
R
Entry
Change from best conditions (Entry 8)
Yield (%)
With respect to the arene component, a variety of substitut-
ed phenyl derivatives were investigated (28 – 38). Of note,
both electron-deficient and electron-rich anilides cyclized
smoothly, including an oxidatively cleavable PMP derivative
(28).4d Aryl bromide partners could be tolerated without any
observable dehalogenation (32). Moreover, the reaction also
proved insensitive to ortho-substitution (35) and even a steri-
12
13
14
15
H
H
H
No Light
No Photocatalyst
No NBu4OP(O)(OBu)2
None
0
0
0
Me
89
Optimization reactions run on 0.1 mmol scale. Yields determined by
1H-NMR analysis of the crude reaction mixture relative to an internal
standard. Irradiation supplied by 4W blue LED strips.
2
ACS Paragon Plus Environment

Page 3 of 5
Table 2. Substrate scope
Journal of the American Chemical Society
O
2 mol% Ir(dF(CF3)ppy)2(bpy)PF6
R1
Ar
1
2
3
4
5
6
7
8
O
20 mol% NBu4OP(O)(OBu)2
X
N
Ar
N
H
X
R2
H
10 mol% thiophenol
0.3 M CH2Cl2, blue LEDs, rt
R1 R2
O
O
O
O
O
O
Ph
Ph
Ph
Ph
Ph
O
Ph
Ph
N
N
N
N
N
N
Me
N
O
H
O
H
H
H
H
H
H
H
Me
Me Me
Me Me
Me Me
Me
Ph
2 85%
3 88%a
4 90%
5 87%
6 89%
7 81%b
8 91%
9
Me
Ph
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
O
O
O
O
O
O
O
O
S
Ph
N
Ph
N
Ph
Ph
N
Ph
Ph
N
H
O
N
N
N
H
O
N
Me
H
H
H
H
O
O
Me Me
Me Me
Me Me
Me Me
Me Me
iPr
iPr
Me
Me
14 85% (90%)c
1:1 dr (1:1 dr)c
9 89%
10 90%
11 73%
12 82%
10:1 dr
13 72%
4:1 dr
15 88%
>20:1 dr
Ph
Ph
O
Ph
O
Me
N
Me
H
H
O
O
H
Ph
N
Ph
N
N
O
Me
O
N
H
O
H
N
O
O
O
Me
Ph
H
Me
OH
N
H
Ph
O
Me
Me
Me
Me
20 86%
21 91%
16 89%
>20:1 dr
17 88%
>20:1 dr
18 94%
>20:1 dr
19 92%
>20:1 dr
22 87%
5:1 dr
O
Me
Me
O
N
O
O
O
O
N
O
Ph
O
O
N
Me
Me
N
Me
H
H
Ph
Ph
CO
O
BnO
H
Ph
Me
TBSO
H
H
O
TBSO
Me Me
H
CO2Me
Me
H
H
Me
O
O
O
N
23 78%
>20:1 dr
24 94%
>20:1 dr
25 68%
>20:1 dr
26 94%
>20:1 dr
27 68%
>20:1 dr
Ph
O
OMe
CN
F
OCF3
Me
Ar
O
X
Br
N
H
28 X = CH2
29 X = CH2
30 X = CH2
88%
31 X = CH2
33 X = CH2
32 X = O
92%
Me Me
87%
80%
91%
93%
Me
O
Me
Me
Me
SMe
OH
N
S
N
N
Me
Me
Me
34 X = CH2
35 X = CH2
36 X = CH2
37 X = CH2
90%
38 X = CH2
39 X = CH2
40 X = O
41 X = O
86%
88%
87%
82%
90%
90%
88%
Reactions run on 1.0 mmol scale. Reported yields are for isolated and purified material and are the average of two experiments. Irradi-
1
a
ation supplied by a 34W Kessil LED lamp. Diastereomeric ratios determined by H-NMR analysis of the crude reaction mixtures. Start-
ing material was a trans olefin b30 mol% thiophenol. cYield and dr in parentheses are for a geraniol-derived substrate.
cally hindered mesityl-derived lactam 36 could be produced
with high efficiency. In addition, functional groups that are
typically incompatible with the current state-of-the-art hy-
droamidation methods employing strong iodonium oxidants,
such as thioethers and unprotected primary alcohols, are readi-
ly accommodated by this catalytic protocol (37, 38).14 Nu-
merous N-heteroaryl amides proved competent starting mate-
rials as well, undergoing hydroamidation in good to excellent
yields (39 – 41). With respect to limitations, this method cur-
rently does not accommodate intermolecular couplings or the
formation of larger rings with high efficiency. In both cases
we believe that favorable back electron transfer between the
amidyl and the reduced form of the photocatalyst is kinetically
favored over productive C-N bond formation. Efforts to ad-
dress these limitations and expand the scope of this process to
include N-alkyl amides are ongoing.
Mechanistic studies The synthetic results reported above
suggest that amidyl generation is possible in the presence of
the thiophenol, despite the fact that both functionalities are
known substrates for multisite PCET and a significant thermo-
dynamic driving force (ΔΔG° ~ 20 kcal/mol) for thiol activa-
tion.5,11 To shed light on these issues, we designed a series of
competitive luminescence quenching experiments. First, we
observed that neither acetanilide nor thiophenol affect the
emission intensity of the Ir photocatalyst in CH2Cl2. However,
solutions containing either amide or thiol as well as phosphate
base lead to efficient and concentration-dependent lumines-
cence quenching (acetanilide Ksv = 2860 M-1 and thiophenol
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
Ksv = 470 M-1), consistent with PCET activation. Tellingly,
solutions containing fixed concentrations of thiol and phos-
phate and varying concentrations of amide exhibited quench-
ing that retained a first order dependence on the amide concen-
tration, albeit with slightly reduced efficiency (Ksv = 1250 M-
1). However, analogous experiments wherein solutions con-
taining fixed concentrations of both amide and phosphate and
varying concentrations of thiol exhibited no additional
quenching above background. Taken together, these results
indicate that amide PCET in the presence of thiophenol is not
only feasible but is likely the kinetically dominant reaction
pathway for radical generation.
23, 1649. (c) LaLonde, R. L.; William, E.; Brenzovich Jr., W. E.. Benitez,
D.; Tkatchouk, E.; Kelley, K.; Goddard III, W. A.; Toste, F. D. Chem. Sci.
2010, 1, 226. (d) Komeyama, K.; Morimoto, T.; Takaki, K. Angew.
Chem., Int. Ed. 2006, 45, 2938.
1
2
3
4
5
6
7
8
(2) For selected advances in catalytic hydroamination, see: (a) Utsuno-
miya, M.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 2702. (b) Hong, S.;
Marks, T. J. Acc. Chem. Res. 2004, 37, 673. (c) Waser, J.; Gaspar, B.;
Nambu, H.; Carreira, E. M. J. Am. Chem. Soc. 2006, 128, 11693. (d)
Cochran, B. M.; Michael, F. E. J. Am. Chem. Soc. 2008, 130, 2786. (e)
Shen, X.; Buchwald, S. L. Angew. Chem. Int. Ed. 2010, 49, 564 (f)
Brown, A. R.; Uyeda, C.; Brotherton, C. A.; Jacobsen, E. N. J. Am. Chem.
Soc. 2013, 135, 6747. (g) Sevov, C. S.; Zhou, J. S.; Hartwig, J. F. J. Am.
Chem. Soc. 2014, 136, 3200. (h) Yang. Y.; Shi, S. –L.; Liu, P.; Buchwald,
S. L. Science 2015, 349, 62.
9
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
(3) For examples of photoredox-mediated olefin amination, see: (a)
Nguyen, T. M.; Nicewicz, D. A. J. Am. Chem. Soc. 2013, 135, 9588. (b)
Nguyen, T. M.; Manohar, N.; Nicewicz, D.A. Angew. Chem. Int. Ed.,
2014, 53, 6198. (c) Gesmundo, N. J.; Grandjean, J. M.; Nicewicz, D.A.
Org. Lett. 2015, 17, 1316. (d) Musacchio, A. J.; Nguyen, L. Q.; Beard, G.
H.; Knowles, R. R. J. Am. Chem. Soc. 2014, 136, 12217. (e) Hu, Q.-X.;
Chen, J.-R.; Wei, Q.; Liu, F.-L.; Deng, Q.-H.; Beauchemin, A. M.; Xiao,
W.-J. Angew. Chem. Int. Ed., 2014, 53, 12163. (f) Maity, S.; Zheng, N.
Angew. Chem. Int. Ed., 2012, 51, 9562.
(4) (a) Newcomb, M.; Esker, J. L. Tet. Lett. 1990, 32, 1035. (b) Boivin,
J.; Callier-Dublanchet, A.-C.; Quiclet-Sire; B.; Schiano, A.-M.; Zard, S. Z.
Tetrahedron 1995, 51, 6517. (c) Kemper, J.; Studer, A. Angew. Chem.,
Int. Ed. 2005, 44, 4914. (d) Guin, J.; Frohlich, R.; Studer, A. Angew.
Chem. Int. Ed. 2008, 47, 779. (e) Chou, C. M.; Guin, J.; Muck-
Lichtenfeld, C.; Grimme, A.; Studer, A. Chem. Asian. J. 2011, 6, 1197. (f)
Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Barluenga, S.; Hunt, K. W.;
Kranich, R.; Vega, J. A. J. Am. Chem. Soc. 2002, 124, 2233. (g) Tang, Y.;
Li, C. Org. Lett. 2004, 6, 3229.
(5) Choi, G. C.; Knowles, R. R. J. Am. Chem. Soc. 2015, 137, 9226.
(6) (a) Reece, S. Y.; Nocera, D. G. Annu. Rev. Biochem. 2009, 78, 673.
(b) Mayer, J. M. Annu. Rev. Phys. Chem. 2004, 55, 363. (c) Hammes-
Schiffer, S.; Stucherbrukhov, A. A. Chem. Rev., 2010, 110, 6939. (d)
Weinberg, D. R.; Gagliardi, C. J.; Hull, J. F.; Murphy, C. F.; Kent, C. A.;
Westlake, B. C., Paul, A.; Ess, D. H.; McCafferty, D. G., Meyer, T. J.
Chem. Rev. 2012, 112, 4016.
(7) (a) Wenger, O. S. Acc. Chem. Res. 2013, 46, 1517. (b) Gagliardi, C.
J.; Westlake, B. C.; Kent, C. A.; Paul, J. J.; Papanikolas, J. M.; Meyer, T.
J. Coord. Chem. Rev. 2010, 254, 2459. (c) Tarantino, K. T.; Liu, P.;
Knowles, R. R. J. Am. Chem. Soc. 2013, 135, 10022.
(8) (a) Hamilton, D. S.; Nicewicz, D. A. J. Am. Chem. Soc. 2012, 134,
18577. (b) Wilger, D. J.; Grandjean, J.-M.; Lammert, T. R.; Nicewicz, D.
A. Nature Chem., 2014, 6, 720.
(9) Warren, J. J., Mayer, J. M. Proc. Natl. Acad. Sci. U.S.A. 2010, 107,
5282.
(10) (a) Roberts, B. P.; Steel, A. J. J. Chem. Soc., Perkin Trans 2 1994,
2155. (b) Pais, A. A. C. C.; Arnaut, L. G.; Formosinho, S. J. J. Chem Soc.
Perkin Trans. 2, 1998, 2577.
(11) (a) Gagliardi, C. J.; Murphy, C. F.; Binstead, R.A.; Thorp, H. H.;
Meyer, T. J. J. Phys. Chem. C, 2015, 119, 7028. (b) Medina-Ramos, J.;
Oyesanya, O.; Alvarez, J. C. J. Phys. Chem. C, 2013, 117, 902. (c) Kuss-
Petermann, M.; Wenger, O. S. J. Phys. Chem. Lett. 2013, 4, 2535.
(12) Bordwell, F. G.; Cheng, J.-P., Ji, G.-Z.; Satish, A. V.; Zhang, X. J.
Am. Chem. Soc. 1991, 113, 9790.
While the physical origins of this surprising selectivity are
not certain, one potential explanation relates to the differential
hydrogen bond donor abilities of the amide and thiol function-
alities. Multisite PCET oxidations require the formation of a
hydrogen bond between the transferring proton and the
Brønsted base prior to the electron transfer event.15 Density
functional
calculations
(ωB97XD
6-31G++(2d,2p)
CPCM=CH2Cl2) indicate that formation of the amide-
phosphate H-bond complex is more favorable than the thio-
phenol-phosphate H-bond complex by 5.2 kcal/mol.16,17 As
such, there is a significantly higher concentration of amide-
phosphate complex relative to the thiol-phosphate complex in
solution which may contribute to this unusual but synthetically
advantageous selectivity.
In conclusion, we have developed a novel method for olefin
hydroamidation jointly mediated by three distinct catalysts –
an iridium photocatalyst, a phosphate base and a thiol H-atom
donor. This protocol enables catalytic amidyl generation di-
rectly from simple amide starting materials and accommodates
a wide variety of olefinic reaction partners. More fundamen-
tally, this work demonstrate that multisite PCET enables the
selective homolysis of strong anilide N-H bonds in the pres-
ence of a thiol with a much weaker S-H bond. Efforts to un-
derstand and generalize the basis of this surprising selectivity
are currently ongoing.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
rknowles@princeton.edu
(13) Cheng, J. P.; Zhao, Y.Y. Tetrahedron, 1993, 49, 5267.
(14) (a) Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J.
Org. Chem. 1995, 60, 7272. (b) Shukla, V. G.; Salgaonkar, P. D.; Aka-
manchi, K. G. J. Org. Chem., 2003, 68, 5422.
(15) (a) Turro, C.; Chang, C. K.; Leroi, G. E.; Cukier, R. I.; Nocera, D.
G. J. Am. Chem. Soc. 1992, 114, 4013. (b) Kirby, J.; Roberts, J.; Nocera,
D. G. J. Am. Chem. Soc. 1997, 119, 9230. (c) Young, E. R.; Rosenthal, J.;
Hodgkiss, J. M.; Nocera, D. G. J. Am. Chem. Soc. 2009, 131, 7678. (d)
Sjodin, M.; Irebo, T.; Utas, J. E.; Lind, J.; Merenyi, G.; Akermark, B.;
Hammarstrom, L. J. Am. Chem. Soc. 2006, 128, 13076. (e) Markle, T. F.;
Mayer, J. M. Angew. Chem., Int. Ed. 2008, 47, 738.
(16) Chai, J. D.; Head-Gordon, M. Phys. Chem. Chem. Phys. 2008, 10,
6615.
(17) For the performance of this functional to describe hydrogen bond-
ing: DiLabio, G. A.; Johnson, E. R.; Otero-de-la-Rosa, A. Phys. Chem.
Chem. Phys. 2013, 15, 12821.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support was provided by the NIH (R01 GM113105).
R.R.K is a fellow of the A. P. Sloan Foundation. We thank Istvan
Pelczer and Ken Conover for assistance with NMR experiments
and Phillip Jeffrey for X-ray crystallographic analysis.
REFERENCES
(1) (a) Gooßen, L. J.; Rauhaus, J. E.; Deng, G. Angew. Chem., Int. Ed.
2005, 44, 4042. (b) Wang, X.; Widenhoefer, R. A. Organometallics, 2004,
4
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
O
O
O
O
Ir(III) redox cat.
phosphate base cat.
Ph
O
O
N
H
N
CO
Me
Ph
CO
Me
thiophenol cat.
visible hν
(40 examples)
TBSO
TBSO
H
CO2Me
CO2Me
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
Olefin Hydroamidation Enabled By PCET Activation of Amide N-H Bonds
5
ACS Paragon Plus Environment