PCET-Enabled Olefin Hydroamidation Reactions with N-Alkyl Amides

Article abstract of DOI:10.1021/acscatal.9b00966

Olefin aminations are important synthetic technologies for the construction of aliphatic C-N bonds. Here we report a catalytic protocol for olefin hydroamidation that proceeds through transient amidyl radical intermediates that are formed via proton-coupl

Full text of DOI:10.1021/acscatal.9b00966

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Letter
PCET-Enabled Olefin Hydroamidation Reactions with N-Alkyl Amides
Suong T Nguyen, Qilei Zhu, and Robert R Knowles
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b00966 • Publication Date (Web): 17 Apr 2019
Downloaded from http://pubs.acs.org on April 17, 2019
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PCET-Enabled Olefin Hydroamidation Reactions with N-Alkyl
Amides
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Suong T. Nguyen, Qilei Zhu, and Robert R. Knowles*
Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
ABSTRACT: Olefin aminations are important synthetic technologies for the construction of aliphatic C–N bonds. Here we
report a catalytic protocol for olefin hydroamidation that proceeds through transient amidyl radical intermediates that are
formed via proton-coupled electron transfer (PCET) activation of the strong N–H bonds in N-alkyl amides by an excited-state
iridium photocatalyst and a dialkyl phosphate base. This method exhibits a broad substrate scope, high functional group tol-
erance, and amenability to use in cascade polycyclization reactions. The feasibility of this PCET protocol in enabling the in-
termolecular anti-Markovnikov hydroamidation reactions of unactivated olefins is also demonstrated.
KEYWORDS: hydroamidation, proton-coupled electron
transfer, hydrogen atom transfer, amidyl radicals, photore-
dox catalysis
Oxidative proton-coupled electron transfer (PCET) has
emerged as a promising technology for catalytic radical gen-
eration, enabling formal H• abstraction from strong E–H
bonds found in many common protic functional groups.1 In
this context, numerous light-driven PCET methods for ole-
fin amination have been reported in recent years that utilize
N-radical intermediates derived from the homolytic activa-
tion of the N–H bonds in anilides and sulfonamides.2 How-
ever, analogous PCET-based olefin aminations with N-alkyl
amides have proven more challenging to develop. This
stems in part from the unusually strong N–H bonds in these
amide derivatives (N–H bond dissociation free energies
(BDFEs) ~ 110 kcal/mol)3, which makes them difficult sub-
strates for PCET activation (Figure 1a). Moreover, as sug-
gested by their high BDFEs, this class of amidyls is highly
reactive and capable of engaging in numerous non-produc-
tive pathways that can compete kinetically with olefin addi-
tion.2f, 2g, 4 We recently addressed the thermodynamic con-
straints associated with N-alkyl amide activation in the de-
Figure 1. (a) BDFEs of N–H bonds in amine derivatives. (b)
velopment of a catalytic PCET method for amidyl-directed
PCET-enabled generation of amidyl radicals for C–C and C–N
C–H alkylation (Figure 1b).5 Building on this work, we re-
bonds formation reactions.
port here a PCET-based protocol for catalytic olefin hy-
droamidation reactions of N-alkyl amides for the prepara-
temperature in fluorobenzene furnished the desired lactam
product 2 in 44% yield (entry 1). Using less oxidizing pho-
tion of γ-lactams and cyclic N-acyl amine derivatives (Figure
1b).4b, 6 The optimization, substrate scope studies, and pre-
tocatalysts [Ir(dF(CF3)ppy)2(4,4’-d(CF3)bpy)]PF6 (B) and
liminary mechanistic evaluation of this process are pre-
sented herein.
[Ir(dF(CF3)ppy)2(bpy)]PF6 (C)8 diminished the reaction
yields significantly (entries 2, 3), consistent with a less fa-
To begin, we focused on the conversion of amide 1 to lac-
tam 2 by adapting the PCET conditions previously reported
for amide-directed C–H alkylation (Table 1).5a Specifically,
blue light irradiation of a solution containing 1 with 3 mol%
of photocatalyst [Ir(dF(CF3)ppy)2(5,5’-d(CF3)bpy)]PF67 (A),
25 mol% of tetrabutylphosphonium dibutylphosphate base,
and 40 mol% of hydrogen atom transfer (HAT) catalyst
2,4,6-triisopropyl thiophenol (TRIP thiol) at room
vorable driving force for the PCET event. Investigation of
numerous thiols revealed that TRIP thiol was the optimal
co-catalyst for this transformation (entries 4–6). However,
we observed that the use of 10 mol% of 2,4,6-triisopropyl
diphenyldisulfide (TRIP disulfide)9 in addition to 40 mol%
of the corresponding thiol dramatically improved the yield
to 95% (entry 7). Alternative conditions employing either
60 mol% of TRIP thiol or 30 mol% of TRIP disulfide proved
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less effective (entries 12, 13). Evaluation of the reaction ef-
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disubstituted olefins, both cis and trans isomers were pro-
cessed with high efficiency (4, 5). Cyclization onto a 1,1-di-
substituted olefin to form a tertiary carbinamine center was
also realized to form 6 in 92% yield. Moreover, the reaction
can accommodate steric bulk adjacent to the site of C–N
bond formation as evidenced by the formation of gem-dime-
thyl product 7 in 89% yield. With respect to the N-alkyl
group, we found that branched N-cyclohexyl and N-tetrahy-
dropyranyl substrates provided lactams 8 and 9, respec-
tively, in good yields. We also observed that silyl ethers and
acetals were tolerated under these reaction conditions,
providing lactams 10 and 11. More complex polycyclic lac-
tams were also accessible using this protocol (12–14). In
addition to amides, urea and S-thiocarbamate substrates
could be cyclized efficiently to furnish imidazolidinone (15)
and thiazolidinone (16) products. This method could fur-
ther be employed for the functionalization of the muscle re-
laxant Baclofen to afford 17 in 73% yield. Similarly, a leela-
mine-derived substrate was successfully hydroamidated to
furnish lactam 18 in 67% yield as a ~ 1.3:1 mixture of dia-
stereoisomers.
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2
3
4
5
6
7
8
ficiency in numerous solvents revealed that fluorobenzene
was optimal (entries 8–11). Lowering phosphate base load-
ing while doubling reaction concentration maintained the
reactivity, enhancing the practicality for preparative-scale
reactions (entries 14–16). Control experiments confirmed
that visible light, photocatalyst A, phosphate base, and HAT
co-catalyst are all required to achieve the observed reactiv-
ity (entries 17–20).
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Table 1. Reaction Optimizationa
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Yield
(%)b
Entry Solvent PC H-Atom Donor
Additive
1
2
3
4
PhF
PhF
PhF
PhF
A
B
C
TRIP thiol
TRIP thiol
TRIP thiol
thiophenol
-
-
-
-
44
With respect to the formation of cyclic N-acyl amines, the hy-
droamidation reaction proceeded smoothly with various olefin
substitution patterns (19–21). Notably, a substrate bearing a
1,1-disubstituted olefin acceptor underwent 6-endo cyclization
at a faster rate than 5-exo to form a 2:1 mixture of piperidine-
and pyrrolidine-derived amides (20).10 The amidation also tol-
erated alkyl fluoride and Boc-protected amine substrates to af-
ford products 22 and 23 in good yields. Spirocycle 24 and
bridged bicyclic amide 25 were also obtained in excellent
yields using this protocol. A urea substrate cyclized smoothly
to furnish 26 in 71% yield. Lastly, hydroamidation of a
peracetylated cholic acid derivative was accomplished to pro-
vide 27 in 91% yield.
26
10
32
A
tri(tBu)
thiophenol
5
PhF
A
-
33
6
7
8
9
PhF
PhF
A
A
A
A
A
A
tDodecanethiol
TRIP thiol
TRIP thiol
TRIP thiol
TRIP thiol
TRIP thiol
-
8
TRIP disulfide
TRIP disulfide
TRIP disulfide
TRIP disulfide
TRIP disulfide
95
46
73
51
62
PhMe
PhCF3
This hydroamidation method also proved efficient in the
synthesis of cyclic carbamates, though optimization was more
challenging due to the unfavorable conformational preferences
of these substrates.11 More specifically, carbamates derived
from allylic alcohols are known to favor (Z)-configurations, ori-
enting the reactive amidyl distal to the olefin and rendering it
unable to engage in C–N bond formation. Together, these fac-
tors suggest that both non-productive HAT4b from the thiol and
back electron transfer (BET)12 between N-radical and the re-
duced Ir(II) state of the photocatalyst may compete favorably
with the desired isomerization and cyclization pathway. Ac-
cordingly, we found that decreasing reaction concentration and
utilizing 30 mol% of TRIP disulfide to minimize the concentra-
tion of free thiol in solution gave markedly improved results,
delivering cyclic carbamate 28 in 89% yield, as compared to
33% under the standard conditions from Table 1. Other olefin
substitution patterns were also accommodated (29–32). It is
worth noting that substrates bearing stereogenic centers adja-
cent to the olefin acceptors were amidated with high levels of
diastereoselectivity (33, 34). Distal olefin functionality is also
well tolerated in this protocol, as illustrated by the isolation of
the spirocycle 35.
10 CH2Cl2
11
CHCl3
Change from entry 7
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18
19
20
60 mol% TRIP thiol, no TRIP disulfide
no TRIP thiol, 30 mol% TRIP disulfide
5 mol% phosphate base
0.1 M PhF
58
81
80
85
97
0
5 mol% phosphate base and 0.1 M PhF
no light
no photocatalyst
0
no phosphate base
0
no TRIP thiol and/or TRIP disulfide
0
aOptimization reactions were performed on 0.05 mmol scale.
bYields were determined by 1H-NMR analysis of crude reaction
mixtures relative to an internal standard.
We next questioned whether this method could be extended
to cascade processes, wherein the alkyl radical formed upon N-
radical cyclization can engage in a second C–C bond forming
event with a pendant alkene prior to HAT from the thiol to form
a polycyclic product (Scheme 1a–c).13 Upon subjecting amide
36 to the standard hydroamidation conditions described
above, monocyclized product 38 and a mixture of diastereo-
meric bicycles 39 and 40 were observed in 20% and 54% yield,
respectively (Table S.1). Gratifyingly, this observation implies
With these optimized conditions established, we next
evaluated the scope of the method with respect to the for-
mation of both lactams and cyclic N-acyl amines (Table 2).
In the lactam series, hydroamidation of a substrate bearing
a terminal olefin provided 3 in 97% isolated yield. For 1,2-
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that the rate of the second cyclization step from intermediate
Lastly, preliminary results suggest that this methodology
can be extended to intermolecular hydroamidation reac-
tions of primary amides (Scheme 1d).2c, 9a, 14 We initially
questioned whether the bimolecular addition of these
amidyl radicals to olefins would be fast enough to outcom-
pete BET and non-productive HAT from the thiol co-cata-
lyst. In addition, PCET activation of the secondary amide
product might lead to product inhibition or undesired side-
reactions. Using standard conditions from Table 1, the in-
termolecular hydroamidation of 4-methoxybenzamide 47
and diisobutylene afforded the desired product 48 in 17%
yield. Gratifyingly, further optimization of the reaction pro-
vided 48 in 67% isolated yield as a single regioisomer. No-
tably, to the best of our knowledge, this reaction represents
1
2
3
4
5
6
7
8
37 is kinetically competitive with bimolecular HAT from thio-
phenol (~ 108 M-1s-1).4a In order to further suppress the for-
mation of undersired 38, TRIP thiol was replaced with 30
mol% of TRIP disulfide, providing a ~ 4:1 mixture of 39 and 40
in 83% isolated yield (Scheme 1a). Similarly, structurally com-
plex tricyclic lactams (42, 43) could be successfully synthe-
sized in 69% yield from simple amide 41 using the modified
conditions (Scheme 1b). Polycyclization of cyclohexene-de-
rived amide 44 was also accomplished, affording a 1.4:1 iso-
meric mixture of lactams 45 and 46 in 76% combined yield
(Scheme 1c). These results demonstrate that this PCET method
is amenable to the direct construction of valuable indolizidine
and pyrrolizidine cores from simple linear precursors.
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Table 2. Substrate Scopea
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the first reported example of a catalytic intermolecular anti-
efficiencies. This work inspired us to consider whether the
beneficial role of disulfides in these reactions of N-alkyl am-
ides could be attributed to a similar cause. DFT calculations
(UωB97XD/6-311G++(2d,3p)//UB3LYP/6-31+G(d,p)) in-
dicated that the reaction of an N-alkyl amidyl radical with
TRIP disulfide to form a N-thioamide adduct and thiyl radi-
cal is energetically favorable (∆G°calc. = –4.3 kcal/mol) (See
SI). Moreover, trace amounts of N-thioamide adduct 49
could be detected via MS analysis of the crude reaction mix-
ture from an incomplete hydroamidation of model amide 1.
Lastly, irradiation of independently synthesized 49 under
standard conditions in the presence of Ir(III) photocatalyst
A, phosphate base, and TRIP thiol provided lactam 2 in 86%
yield (Scheme 2). As such, the viability of 49 as an interme-
diate in these reactions is plausible and likely plays a role in
suppressing non-productive charge recombination, in line
with Nocera’s findings.
Markovnikov hydroamidation reaction2c,9a,15 between pri-
mary amides and unactivated alkyl olefins.
1
2
3
4
5
6
7
8
As previously noted, the addition of TRIP disulfide was found
to dramatically improve the reaction efficiency compared with
the use of TRIP thiol alone. Initially, we attributed this observa-
tion to disulfide-mediated oxidation of any photocatalyst that
is captured in the reduced Ir(II) state following an undesired
side reaction of the amidyl. From cyclic voltammetry measure-
ments, reduction potentials of TRIP disulfide and Ir(III)/(II)
couple of A were found to be –2.16 V and –1.07 V5a (vs. Fc+/Fc
in MeCN), respectively, suggesting that direct electron transfer
between the two compounds is unlikely to occur. However, it is
known that aryl disulfides can be homolyzed under blue-light
irradiation to afford aryl thiyl radicals (Ep/2 = –0.22 V vs. Fc+/Fc
in MeCN),2c which are capable of oxidizing the Ir(II) complex to
form thiolate and regenerate the ground-state Ir(III) photo-
catalyst.
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Scheme 2. Olefin hydroamidation with N-thioamide
In conclusion, we have developed a catalytic protocol for di-
rect homolysis of the strong N–H bonds in unactivated N-alkyl
amide derivatives using excited-state PCET. The resulting
amidyl radicals can engage successfully in a wide range of ole-
fin hydroamidation reactions to provide valuable lactams and
cyclic N-acyl amines from simple linear starting materials.
Moreover, this methodology can be adapted to enable both the
cascade polycyclization reactions of polyunsaturated amides,
as well as the first example of an anti-Markovnikov intermolec-
ular hydroamidation with primary amides. We are optimistic
that these results can be further adapted to enable challenging
aliphatic C–N bond constructions in a wide variety of synthetic
contexts.
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental details, characterization data, and spectral
data (PDF)
AUTHOR INFORMATION
Scheme 1. Polycyclization cascade and intermolecular
anti-Markovnikov hydroamidation reaction.
Corresponding Author
* Email: rknowles@princeton.edu
Nocera and coworkers recently put forward an alterna-
tive explanation for the beneficial role of disulfides in their
detailed kinetic study of PCET-based olefin hydroamidation
reactions of N-aryl amides.16 These authors found that,
while excited-state PCET is relatively efficient, BET between
the amidyl radical and the reduced Ir(II) state of the photo-
catalyst is faster than cyclization, which in turn greatly di-
minishes the quantum yield. They observed that reversible
trapping of the amidyl radical occurs through reaction with
an aryl disulfide (which forms in equilibrium with free thiol
under the reaction conditions), forming a stable N-thioam-
ide intermediate. This adduct serves as an off-cycle resting
state for the amidyl radical and can eventually be converted
back to the reactive N-radical, leading to productive C–N
bond formation and significantly improved quantum
Funding Sources
Financial support was provided by the NIH (R01 GM113105).
Notes
The authors declare no competing financial interests.
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