Enantioselective Hydroamination of Alkenes with Sulfonamides Enabled by Proton-Coupled Electron Transfer

Article abstract of DOI:10.1021/jacs.0c01332

An enantioselective, radical-based method for the intramolecular hydroamination of alkenes with sulfonamides is reported. These reactions are proposed to proceed via N-centered radicals formed by proton-coupled electron transfer (PCET) activation of sulfonamide N-H bonds. Noncovalent interactions between the neutral sulfonamidyl radical and a chiral phosphoric acid generated in the PCET event are hypothesized to serve as the basis for asymmetric induction in a subsequent C-N bond forming step, achieving selectivities of up to 98:2 er. These results offer further support for the ability of noncovalent interactions to enforce stereoselectivity in reactions of transient and highly reactive open-shell intermediates.

Full text of DOI:10.1021/jacs.0c01332

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Communication
Enantioselective Hydroamination of Alkenes with
Sulfonamides Enabled by Proton-Coupled Electron Transfer
Casey B Roos, Joachim Demaerel, David E. Graff, and Robert R Knowles
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c01332 • Publication Date (Web): 17 Mar 2020
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Page 1 of 7
Journal of the American Chemical Society
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Enantioselective Hydroamination of Alkenes with Sulfonamides Ena-
bled by Proton-Coupled Electron Transfer
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Casey B. Roos, Joachim Demaerel, David E. Graff, and Robert R. Knowles*
Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
Supporting Information Placeholder
ABSTRACT: An enantioselective, radical-based
(a) Previous Work: Electrostatic contributions to hydrogen bonding interactions
method for the intramolecular hydroamination of al-
H-bonded ketyl radical
H-bonded indole radical cation
kenes with sulfonamides is reported. These reactions are
proposed to proceed via N-centered radicals formed by
proton-coupled electron transfer (PCET) activation of
sulfonamide N–H bonds. Non-covalent interactions be-
tween the neutral sulfonamidyl radical and a chiral
phosphoric acid generated in the PCET event are hy-
pothesized to serve as the basis for asymmetric induc-
tion in a subsequent C–N bond forming step, achieving
selectivities of up to 98:2 er. These results offer further
support for the ability of non-covalent interactions to en-
force stereoselectivity in reactions of transient and
highly reactive open-shell intermediates.
R
Ar
R
R
R
Ar
R
N
O
O
H
O
O
O
O
O
O
P
H
P
O
H
N
H
Ph
R
R
Ar
N
R
Ar
R
radical cation-phosphate ion pair
(b) Hypothesis: Hydrogen bonding in PCET successor complex
neutral ketyl-phosphate anion
*Mn
Mn-1
O
O
O
photocatalyst
chiral base
O
P
R
O
ET
P
R
O
N
H
O
O
O
O
N
H
O
O
PCET
S
S
R1
PT
R1
Can we extend this principle to neutral radical interfaces?
Non-covalent interactions provide a powerful means to
control selectivity in asymmetric transformations, both in
nature and in the laboratory.1 However, a lack of clear un-
derstanding about how these weak interactions can serve
to bind and activate open-shell intermediates has largely
precluded their use a control element in the enantioselec-
tive reactions of free radical species.2-4 Seeking address
this deficit, our group has become interested in the use of
proton-coupled electron transfer (PCET) as a platform for
developing catalytic asymmetric free radical chemistry.
Oxidative PCET—which effects formal bond homolysis
through the joint movement of a proton and electron to a
Brønsted base and one-electron oxidant, respectively5—
generally requires pre-equilibrium hydrogen bonding be-
tween the reactive E–H bond of the substrate and the
Brønsted base prior to the electron transfer step. In addition
to controlling site-selectivity,6 this H–bond interface can
remain intact following the PCET event, furnishing a tran-
sient hydrogen-bonded complex between the nascent free
radical and the conjugate acid of the Brønsted base.7 In
principle, this association can then serve as a basis for
achieving asymmetric induction in subsequent bond form-
ing steps when chiral bases are employed.
(c) This Work: Enantioselective C–N bond formation enabled by PCET
Ir photocatalyst
H3C
CH3
CH3
O
O
O
O
chiral phosphate base
S
S
R1
N
H
CH3
R1
N
thiol catalyst
blue LEDs
up to 98:2 er
Figure 1. (a) Examples of PCET-enabled enantioselective
reactions; (b) Hypothesis for PCET-enabled asymmetric
olefin hydroamination. (c) Enantioselective hydroamina-
tion with sulfonamides
This manner of asymmetric PCET activation has
been demonstrated previously in a reductive aza-pinacol
cyclization and in the oxidative activation of indoles en
route to the formation of pyrolloindolines (Figure 1a).8
In these examples, the neutral ketyl radical and indole
radical cation remain associated with a chiral anionic
phosphate, wherein the negatively charged acceptor was
proposed to increase the strength of the post-PCET hy-
drogen bonding interaction. We questioned whether this
blueprint could be extended further to enable high enan-
tioselectivity in the reactions of neutral free radical in-
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Journal of the American Chemical Society
termediates associated with neutral hydrogen bond do-
Page 2 of 7
Table 1. Optimization Studiesa
1
nors. To evaluate this hypothesis, we chose to investi-
gate enantioselective variants of a recently reported hy-
droamination of alkenes with sulfonamides.9,10 This
transformation proceeds through a key sulfonamidyl
radical intermediate generated via PCET activation of
the substrate N–H bond by an excited-state Ir(III) oxi-
dant and a dialkyl phosphate base. This electrophilic ni-
trogen-centered radical then undergoes addition to a
pendant olefin to furnish a new C–N bond.11 We hypoth-
esized that if chiral phosphate bases were employed,
then a successor H-bonding complex between the chiral
phosphoric acid and the neutral sulfonamidyl radical
could nucleate a network of non-covalent interactions
that would in turn differentiate competing diastereo-
meric transition states for C–N bond formation (Figure
1b).7 Here, we report the successful realization of this
goal, and preliminary mechanistic observations con-
sistent with the design hypothesis presented above (Fig-
ure 1c). To put this effort in context, we note that rela-
tively few methods for catalytic asymmetric C–N bond
formation with N-radical intermediates have been re-
ported to date, and all involve strong bonding interac-
tions between the substrates and the chiral catalysts.
Meggers and MacMillan13 have reported methods
where a free N-radical undergoes addition to an alkene
acceptor bound to either a chiral Rh-complex or a chiral
enamine, respectively, while Zhang and Chemler have
developed approaches using metalloradical com-
plexes.14
2
3
4
5
6
7
8
9
Me
2 mol% [Ir(dF(CF3)ppy)2(5,5’-dCF3bpy)]PF6
Me
Me
O
O
O
O
2.5 mol% chiral phosphate
S
S
PMP
N
PMP
N
H
Me
30 mol% TRIP thiol
0.1 M PhCF3
blue LEDs, −20 ˚C, 24 hr
1
2
Phosphate
Entry
er
Yield (%)
1
2
3
4
5
6
7
P1
P2
P3
P4
P5
P6
P7
54
30
96
62
97
98
85
55:45
52:48
35:65
86:14
93:7
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
87:13
95:5
N
Chiral phosphate bases:
N
R
N
Ar
C8H17
R
Ar
O
O
O
O
P
O
O
NBu4
P
O
NBu4
O
C8H17
R
Ar
N
Ar
R
N
N
Ar = 9-phenanthryl
Ar = C6H5
Ar = (2,6-iPr)C6H3
Ar = (3,5-Ph)C6H3
P4
P5
P6
P7
P1 Ar = C6H5
P2 Ar = (2,4,6-iPr)C6H2
P3 Ar = 9-phenanthryl
Change from Entry 7
Entry
er
Yield (%)
8
9
93
81
89
<1
<5
<1
<1
89:11
94:6
95:5
room temperature
thiophenol H-atom donor
10 mol% P7
10
11
12
13
14
-
-
-
-
no base
no thiol
no photocatalyst
no light
a Reactions were conducted on a 0.05 mmol scale,
and yields determined by NMR analysis relative to an
internal standard. Enantioselectivity was determined
by HPLC analysis on a chiral stationary phase.
We began by evaluating the cyclization of acy-
clic 4-methoxyphenyl (PMP) sulfonamide 1 to form
pyrrolidine 2 under the previously reported PCET con-
ditions for hydroamination in the presence of a variety
of chiral phosphate bases. Phenyl-substituted BINOL
phosphate P1 and commercially available TRIP-
phosphate P2 provided pyrrolidine product 2 in reason-
able yield and low, but measurable levels of enantiose-
lectivity (Table 1, Entries 1 and 2). A modest increase in
selectivity and reactivity was observed with 9-phenan-
threne substituted P3, affording 2 in 96% yield and
35:65 er (Table 1, Entry 3). Further evaluation of chiral
phosphate scaffolds led to an improvement in selectivity
with the analogous 1,2,3- triazole containing P4, which
provided 2 in 62% yield and 86:14 er (Table 1, Entry
4).15 As this 1,2,3-triazole containing chiral phosphate
scaffold provided higher enantioselectivity, we evalu-
ated the effect of substitution pattern on the aryl triazole
moiety. The parent phenyl substituted catalyst P5 af-
forded 2 in 93:7 er. Substituents at the ortho positions
(P6) were detrimental to selectivity compared to P5
yielding the product in 87:13 er (Table 1, Entry 5). Of
the catalysts examined, the highest selectivities were
observed with meta substituents on the arene (See SI,
Tables S1 and S2). Of these, phosphate P7 proved opti-
mal, affording the product 2 in 85% yield and 95:5 er
(Table 1, Entry 7).
With phosphate P7, we next evaluated the sensi-
tivity of the transformation to variations in other reac-
tion parameters. At room temperature, 2 was formed in
93% yield, but with a lower selectively of 89:11 er (Ta-
ble 1, entry 8). Further changes to the conditions, such
as substituting commercially available thiophenol for
TRIP-thiophenol resulted in a similar enantioselectivity
of 94:6 er (Table 1, Entry 9). Increasing the catalyst
loading of P7 to 10 mol% improved the yield margin-
ally, but afforded no enhancement in selectivity (Table
1, Entry 10). Control reactions excluding base, light, and
photocatalyst resulted in no detectable product for-
mation, and only trace product was observed in the ab-
sence of the thiol HAT catalyst (Table 1, Entries 11–14).
We then sought to evaluate the reaction scope
with respect to both the sulfonamide (products 2–22)
and alkene (products 23–27) moieties of the substrate.
Uniformly high selectivities were observed upon varia-
tion of the para substituent of the sulfonamide arene
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Journal of the American Chemical Society
Table 2. Scope of Enantioselective Amination Reactiona
1
2
3
4
5
2 mol% [Ir(dF(CF3)ppy)2(5,5’-dCF3bpy)]PF6
R2
R3
R2
2.5 mol% chiral phosphate P7
O
O
O
O
S
S
R1
N
R1
N
H
R3
30 mol% TRIP thiol
0.1 M PhCF3
6
blue LEDs, –20 ˚C, 72 hr
7
Sulfonamide Variation (R2 = R3 = Me):
8
9
R1
=
2 X = OMe 86%, 96:4 er
Me
OMe
3 X = Me
4 X = H
5 X = Br
6 X = Cl
7 X = CN
8 X = CF3
83%, 95:5 er
91%, 95:5 er
76%, 95:5 er
61%, 96:4 er
63%, 96:4 er
74%, 98:2 er
OMe
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
Me
Me
9 91%, 92:8 er
X
10 78%, 90:10 er
11 79 %, 95:5 er
12 92%, 96:4 er
S
S
N
Me
N
O
n
Me
13 53%, 93:7 er
14 79%, 97:3 er
15 n = 1 98%, 91:9 er
16 n = 2 98%, 96:4 er
17 87%, 92:8 er
18 80%, 94:6 er
(R)-12
Me
O
N
CF3
Me
Me
Me
Me
Me
O
S
O
O
O
Me
N
O
NH
O
S
Me
O
O
Me
O
N
N
N
O
N
S
O
O
O
Me
S
O
S
N
S
S
N
N
N
N
Me
N
N
N
Me
CF3
22 50%, 96:4 erc
19 84%, 87:13 erb
Alkene Variation:
20 89%, 96:4 er
21 83%, 95:5 er
X
Me
Me
Me
Me
Me
O
O
O
O
O
O
N
O
O
Me
Me
O
O
S
S
S
N
S
S
H
N
N
N
Me
MeO
Me
Me
Me
23 98%, 94:6 er
24 91%, 90: 10 er
X = CH2
X = NBoc
72%, 93:7 erd
83%, 95:5 erd
93%, 98:2 erd
48%, 96:4 erd
from cis: 26
from trans: 26
from cis: 27
from trans: 27
from cis: 28 85%
96:4 er; 1.5:1 dr
25 96%, 95:5 er
a
Yields and enantioselectivities are for isolated material following chromatography on silica gel and are the
average of two experiments. Reactions were conducted on 0.5 mmol scale. b Reaction was run at room temperature.
c Reaction was run in dichloromethane. d Reactions were run at 0 ˚C with substitution of TRIP-disulfide for thiol.
(2– 8). Substituents at the ortho positions (9, 91% yield,
92:8 er & 10, 78% yield, 90:10 er) modestly reduced the
observed enantioselectivity, whereas selectivity was re-
tained upon meta substitution (11, 79% yield, 95:5 er).
The reaction accommodated benzofuran (12, 92% yield,
96:4 er), thiophene (13, 53% yield, 93:7 er), and thiazole
(14, 79% yield, 97:3 er) heterocycles. Benzyl substitu-
tion on the sulfonamide led to a modest decrease in se-
lectivity (15, 98% yield, 91:9 er), whereas a longer
phenethyl chain was well tolerated (16, 98% yield, 96:4
er). The reaction was also successful for sulfamate ester
(17, 87% yield, 92:8 er) and sulfamide (18, 80% yield,
94:6 er) substrates. We further applied this methodology
to more complex sulfonamide substrates. Product 19,
containing a thioether linked 1,2,4-triazole moiety, was
afforded in 84% yield and 87:13 er at room temperature
under otherwise standard conditions. Sultiame-derived
product 20 was isolated in 89% yield and 96:4 er, and
the reaction of a celecoxib-derived sulfonamide pro-
vided cyclized product 21 in 83% and 95:5 er. The reac-
tion also tolerated the presence of other hydrogen bond-
ing donor and acceptor functionalities to afford sildena-
fil derivative 22 in 50% yield and 96:4 er.
The enantioselectivity of the reaction was then
probed for a variety of alkene substitution patterns
(products 23–27). Cyclohexyl-substituted product 23
was delivered in 98% yield and 94:6 er and protected
piperidine-substituted alkene provided the cyclized chi-
ral product 24 in 91% yield and 90:10 er. Cyclobutyl-
substituted 25 was afforded in 96% yield and 95:5 er.
ACS Paragon Plus Environment

Journal of the American Chemical Society
The conditions also afforded high levels of enantiose-
Page 4 of 7
in the absence of the phosphate base (Table 1, Entry 11)
no cyclized product is detected, and increased loadings
of phosphate (Table 1, Entry 10) do not result in higher
observed enantioselectivities. These results suggest the
absence of a racemic background reaction proceeding
through alkene oxidation.21 Furthermore, high reactivity
and enantioselectivity were observed in reactions of di-
substituted alkenes (products 26–27), for which single
electron oxidation is prohibitively endergonic (Ep/2(cy-
clopentene) = +1.99 V vs. Fc+/Fc) for the Ir complex
employed.17
1
2
3
4
5
6
7
8
lectivity for cis and trans disubstituted alkenes. While
initial reactivity of these substrates was low at –20 ˚C,
the yields were significantly improved with an increase
in reaction temperature to 0 ˚C and substitution of 15
mol% of TRIP-disulfide for the thiol (See SI, Table S2).
Product 26 was afforded in 72% yield and 93:7 er from
the cis-disubstituted alkene, while the trans isomer af-
forded 26 in 93% yield and 95:5 er. A bulkier tert-butyl
substituted alkene provided product 27 in 93% yield and
98:2 er from the cis isomer. 27 was also generated in
48% yield and 96:4 er from the corresponding trans iso-
mer of the starting acyclic alkene. Unsymmetrical tri-
substituted alkene substrates were also effective with a
nerol-derived sulfonamide furnishing 28 in 85% yield
as a 1.5:1 mixture of diastereomers, wherein each dia-
stereomer was generated in 96:4 er.16
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
Lastly, an inverse relationship between solvent
polarity and enantioselectivity is often been taken as
support for an ion pairing mechanism. 22 In contrast, we
observed that the enantioselectivity of this hydroamina-
tion reaction was notably insensitive to solvent dielec-
tric. Nearly identical selectivities are observed for reac-
tions run in either toluene (ꢀ = 2.4, er = 93:7) or acetoni-
trile (ꢀ = 36.6, er = 94:6), and only a moderate decrease
was found for reactions run in highly polar propylene
carbonate (ꢀ = 66.2, er = 85:15) (Table 4, Entries 1,5,
and 6), though the reactivity was significantly diminsi-
hed.23 This insensitivity to solvent polarity argues
strongly against a key role for ionic intermediates in C–
N bond forming step.
Seeking to shed light on the enantiodetermining
step of this transformation, we conducted an amination
experiment where the thiol co-catalyst was removed
from solution and several equivalents of methyl vinyl
ketone were added (Figure 2). From this reaction carbo-
amination product 29 was isolated in 65% yield and
95:5 er - a nearly identical enantioselectivity to the hy-
droamination reaction of the same sulfonamide sub-
strate. These results suggest that the common C–N bond
forming step is stereoselectivity-determining in both
transformations.
Table 3. Enantioselectivity as a Function of Solvent Die-
lectric
Me
2 mol% [Ir(dF(CF3)ppy)2(5,5’-dCF3bpy)]PF6
Me
Me
O
O
O
O
O
2.5 mol% chiral phosphate P7
S
S
2 mol% [Ir(dF(CF3)ppy)2(5,5’-dCF3bpy)]PF6
PMP
N
Me
PMP
N
H
Me
30 mol% TRIP thiol
0.1 M solvent
blue LEDs, −20 ˚C, 24 hr
2.5 mol% chiral phosphate P7
methyl vinyl ketone (4.0 equiv)
Me
Me
O
O
O
O
Me
1
2
S
S
0.1 M PhCF3
blue LEDs, −20 ˚C, 72 hr
N
H
Me
N
O
O
Entry
er
!
Solvent
toluene
fluorobenzene
tetrahydrofuran
Yield (%)
85
77
45
54
15
29 65% yield, 95:5 er
1
2
3
4
5
6
7
93:7
94:6
94:6
94:6
94:6
2.4
5.5
7.5
Figure 2. Carboamination Reaction
dichloromethane
acetonitrile
N,N-dimethylformamide
propylene carbonate
8.9
36.6
38.3
66.2
With this information in hand, we sought to better
understand the nature of the interaction between the sub-
strate and the chiral catalyst. While our initial design
conjectured a neutral hydrogen bonding interaction re-
sulting from a PCET-generated sulfonamidyl radical,
we also considered that an alternative ion-pairing path-
way may be responsible for asymmetric induction as
previously proposed by Luo and Nicewicz.17 This inter-
action could arise by an alternative mechanism where
the pendant olefin (Ep/2(2-methyl-2-butene) = +1.60 V
vs. Fc+/Fc) undergoes an endergonic single electron ox-
idation by the excited state of the Ir photocatalyst (E1/2
[*Ir(III)/(II)] = +1.30 V vs. Fc+/Fc).18,19 The resulting
ion pairing interaction between the alkene radical cation
and chiral phosphate anion would then provide a basis
for enantioinduction.
trace
trace
83:17
85:15
a
Reactions were conducted on a 0.05 mmol
scale, and yields determined by NMR analysis rela-
tive to an internal standard. Enantioselectivity deter-
mined by HPLC analysis on a chiral stationary
phase.
In conclusion, we have developed a PCET-based
protocol for the asymmetric hydroamination of alkenes
with sulfonamides to prepare enantioenriched pyrroli-
dine products. This method shows high enantioselectiv-
ity for a variety of alkene substitution patterns and sul-
fonamide substrates, including complex drug-derived
examples. A variety of observations are consistent with
a neutral catalyst-substrate interaction governing selec-
tivity in an enantiodetermining C–N bond forming step.
Further work will aim to elucidate the precise interac-
tions underlying the observed selectivity, including the
potential role of a post-PCET hydrogen bonding inter-
In seeking to distinguish between these pathways,
we note that previously reported cyclic voltammetry and
Stern-Volmer quenching studies were consistent with
PCET-activation of sulfonamides under nearly identical
conditions using achiral phosphate bases.20 Moreover,
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Journal of the American Chemical Society
of enantioselective organocatalysis with light. Nature, 2018, 554,
41−49.
(4) For examples of a role for hydrogen bonding in radical reac-
action to the nitrogen radical that served as the key de-
1
2
3
4
5
6
7
8
sign hypothesis in the development of this work. We are
optimistic that the results presented here can be ex-
tended more broadly to enable the development of other
enantioselective reactions of free radical intermediates
mediated solely by non-covalent associations.
tions: (a) Waldner, A.; De Mesmaeker, A.; Hoffmann, P.; Mindt, T.;
Winkler, T. ꢁ-Sulfinyl Substituted Radicals; 1. Stereoselective Radi-
cal Addition Reactions of Cyclic ꢁ-Sulfinyl Radicals. Synlett, 1991,
2, 101−104. (b) De Mesmaeker, A.; Waldner, A.; Hoffmann, P.;
Mindt, T. ꢁ-Sulfinyl Substituted Radicals; II. Stereoselective Inter-
and Intramolecular Addition Reactions of Acyclic ꢁ-Sulfinyl Radi-
cals. Synlett, 1993, 11, 871−874. (c) Curran, D. P.; Kuo, L. H. Alter-
ing the stereochemistry of Allylation Reactions of Cyclic ꢁ-Sulfinyl
Radicals with Diarylureas. J. Org. Chem. 1994, 59, 3259−3261. (d)
Böhm, A.; Bach, T. Synthesis of Supramolecular Iridium Catalysts
and Their Use in Enantioselective Visible-Light-Induced Reactions.
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ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on
the ACS Publications website.
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Experimental procedures, spectral data, and optical purity
determinations (PDF).
Crystal structure of 12 (CIF)
Crystal structure of 14 (CIF)
AUTHOR INFORMATION
Corresponding Author
rknowles@princeton.edu
ACKNOWLEDGMENT
Financial support was provided by the NIH (R35
GM134893). Qilei Zhu is thanked for generously provid-
ing substrates. J.D. kindly acknowledges the MolDesignS
lab for financial support, and also the Research Foundation
- Flanders (FWO) for generous funding through Funda-
mental Research fellowship 11ZY118N and travel grant
V416618N.
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