Tuning Triplet Energy Transfer of Hydroxamates as the Nitrene Precursor for Intramolecular C(sp3)-H Amidation

Article abstract of DOI:10.1021/jacs.0c00868

Reported herein is the design of a photosensitization strategy to generate triplet nitrenes and its applicability for the intramolecular C-H amidation reactions. Substrate optimization by tuning physical organic parameters according to the proposed energy transfer pathway led us to identify hydroxamates as a convenient nitrene precursor. While more classical nitrene sources, representatively organic azides, were ineffective under the current photosensitization conditions, hydroxamates, which are readily available from alcohols or carboxylic acids, are highly efficient in accessing synthetically valuable 2-oxazolidinones and γ-lactams by visible light. Mechanism studies supported our working hypothesis that the energy transfer path is mainly operative.

Full text of DOI:10.1021/jacs.0c00868

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Article
Tuning Triplet Energy Transfer of Hydroxamates as the
3
Nitrene Precursor for Intramolecular C(sp)–H Amidation
Hoimin Jung, Hyeyun Keum, Jeonguk Kweon, and Sukbok Chang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c00868 • Publication Date (Web): 04 Mar 2020
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Tuning Triplet Energy Transfer of Hydroxamates as the Nitrene
Precursor for Intramolecular C(sp3)–H Amidation
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Hoimin Jung,†,‡ Hyeyun Keum,†,‡ Jeonguk Kweon,†,‡ and Sukbok Chang‡,†,*
†Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South
Korea
‡Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, South Korea
ABSTRACT: Reported herein is the design of a photosensitization strategy to generate triplet nitrenes and its applicability
for the intramolecular C–H amidation reactions. Substrate optimization by tuning physical organic parameters according
to the proposed energy transfer pathway led us to identify hydroxamates as a convenient nitrene precursor. While more
classical nitrene sources, representatively organic azides, were ineffective under the current photosensitization conditions,
hydroxamates which are readily available from alcohols or carboxylic acids are highly efficient in accessing synthetically
valuable 2-oxazolidinones and -lactams by visible light. Mechanism studies supported our working hypothesis that the
energy transfer path is mainly operative.
Scheme 1. Photocatalytic approaches accessing amidyl
radicals and nitrenes
Introduction
(a) Photoredox catalytic approach generating amidyl radicals
Nitrogen-centered reactive intermediates such as amidyl
single electron
photoreduction
R
N–LG cleavage
R
LG
R
LG
N
radicals and nitrenes have attracted an increasing interest
mainly due to their potential applicability in the
construction of C–N bonds.1-4 In this context, the
development of new synthetic approaches to generate
these reactive N-centered intermediates more selectively
by identifying effective precursors has been highly desired.
Recent advances in visible-light photoredox catalysis
allowed for the selective generation of amidyl radicals, and
their subsequent amination reactivity toward various
substrates has been widely explored.5-7 For example, single-
N
N
– LG–
R'
R'
R'
amidyl radicals
amidyl radical precursors: widely explored
O
O
NO2
O
R
N
N
X
R
N
N
R'
Ts
NO2
O
phthalimides
pyridinium salts
N-hydroxylamides
(b) Photosensitization of azides to generate triplet nitrenes
R = OCH2CCl3
O
Energy transfer
(EnT)
3
NTroc
O
R
N3
electron
photoreduction
of
N-
R
N
– N2
acyloxy(halo)phthalimides,8,9 N-aminopyridinium salts10-13
and hydroxylamides14-18 gives rise to the corresponding
amidyl radicals upon heterolytic cleavage of the leaving
groups (Scheme 1a).
R = Ar or
Me
OCH2CCl3
triplet nitrenes
H
R = Ar
N
N
Challenges
High triplet energy (ET) &
O
NMe
H
Ar
High reorganization energy ()
(c) This work
Identification of nitrene precursors enabling photosensitized C(sp3)–H amidation
Photosensitization or energy transfer is an efficient
strategy to activate ground state substrates into their
triplet states.19,20 Pioneered by Bach21-23, Yoon24-27 and
Xiao,28 this energy transfer approach was utilized to excite
alkenes to enable elegant [2+2] cycloaddition reactions.
More recently, Glorius and coworkers reported the
photosensitization of disulfides to lead to sulfur radical
species.29 Oxime esters were known to be activated by the
energy transfer to furnish iminyl radicals along with alkyl
radicals.30-32 On the other hand, nitrenes can also be
produced via energy transfer catalysis by employing
azides33-36 or triazoles37 upon release of molecular nitrogen
(Scheme 1b). Given that azides are known to absorb UV
light to undergo photodecomposition process leading to
free organic nitrenes,38,39 Yoon and coworkers successfully
demonstrated the viability of azide photosensitization.
Indeed, by utilizing azidoformates as a triplet nitrene
3
3
O
O
O
O
N–LG
cleavage
LG
LG
elusive
EnT
N
N
N
NH
H
H
H
R
R
R
R
Lowering ET and  by introducing
a leaving group with a -abundant unit
Tunable intramolecular cyclization
of nitrenes via energy transfer
CF3
(X = O, CH2)
O
O
O
Ru-photocatalyst
O
Brønsted base catalyst
and
NH
NH
R
O
X
N
CF3
blue light
H
H
O
R
R
readily accessible from
feedstock chemicals
2-oxazolidinones -lactams
precursor, aziridination reactivity toward alkenes was
explored.33 They also highlighted the energy transfer of
vinyl azides for the formation of pyrrole rings.34 In
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addition,
König
and
Brachet
showcased
the
Scheme 2. Identification of effective triplet nitrene
precursors by combined experimental and
computational studies
photosensitization of benzoyl azides to achieve C(sp2)–H
amidation of heteroarenes36 and olefin cycloaddition
affording oxazolines.35
1
2
3
4
5
6
7
8
Attempts of photosensitization using azidoformate
(a)
O
O
O
Despite this recent promise, since the azide
photosensitization was found to be capricious to the
nature of existing substituents, the reactivity of thus
generated free organic nitrenes has been rather
underexplored especially when compared to that of amidyl
radicals. Low efficiency in the energy transfer is another
issue often observed in certain azides, and this difficulty
can be ascribed to the intrinsically high triplet energy (ET)
and/or reorganization energy (λ) of those azide substrates.
In this regard, we were encouraged to identify
photosensitizable organic precursors for generating triplet
nitrenes that can efficiently undergo C(sp3)–H amidation,
eventually affording azacyclic products (Scheme 1c). Given
that we and others recently revealed notable reactivity of
metal-acylnitrenoids,40-47 it was highly interesting to
examine the viability of the current energy transfer
approach for the targeted intramolecular photosensitized
C–H amidation reaction. In 1965, Lwowski and coworkers
explored the reactivity of azides under UV irradiation,
where free nitrenes were shown to undergo C–H amination
albeit with low selectivity.38,39 Lu and coworkers recently
reported the construction of 2-oxazolidinones from N-
benzoyloxycarbamates using photoredox catalysis, and
they proposed the intermediacy of amidyl radicals.18 To our
best knowledge, an energy transfer pathway endowing the
reactivity of organic nitrenes for the selective C(sp3)–H
amidation has not been explored. Considering the fact that
the previous reports were limited mainly to the
photoactivation of azidoformates or benzoyl azides, we
envisioned to newly explore triplet nitrene precursors to
overcome the intrinsic challenges of azides for the
photosensitization process. Guided by the combined
computational and experimental studies, we identified
hydroxamates as highly efficient and convenient sources to
effectuate an intramolecular C(sp3)–H amination via
energy transfer.
photocatalyst (5 mol%)
Ph
O
O
O
N3
NH
Ph
NH2
Ph
+
Ar, CH2Cl2 (0.1 M)
Kessil lamp (456 nm)
12 h
H
1
ET = 50.57
2
3
ET
G (EnT)
9
2
3
yield of
yield of
entry
photocatalyst
(kcal/mol) (kcal/mol)
10
11
12
13
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15
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<5
<5
5
18
13
16
<5
51.0
61.0
55.4
47.7
-0.43
-10.43
-4.83
Ir1
)
1
2
3
4
Ir(ppy)2(dtbbpy)(PF6) (
Ir2
[Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (
Ir3
)
Ir(ppy)3
(
)
<5
+2.87
Ru1
Ru(bpy)3(PF6)2
(
)
(Yields were determined by crude 1H NMR)
Identification of competent triplet nitrene sources
(b)
our approach
O
O
N
Ph
OR
N
Ph
O
N
O
N
computation-guided
Challenges
ET, , = ?
ET = 50.57,  = 64.55
Inefficient energy transfer?
How to modulate ET & ?
Hydroxamate derivatives
CF3
O
O
O
O
Me
O
CF3
A
B
C
D
O
ET = 40.05
 = 35.67
most promising!
ET = 73.46
 = 29.54
ET = 75.34
 = 17.87
ET = 50.91
 = 47.41
Decreasing ET and  by introducing
aryl group & EWG
triplet energy was totally ineffective in converting the
starting material (entry 4).
The observed inefficiency of azidoformate toward
photoactivation was reasoned to originate from the
incompatible triplet sensitization. To check this rationale,
we subsequently computed the Marcus energy transfer
parameters, triplet energy (ET) and structural
reorganization energy (λ), of the nitrene precursors, as
they are critical to the overall energy transfer efficiency
(Scheme 2b).24,27 The fact that 11 has a high singlet
reorganization energy of 64.6 kcal/mol can be ascribed to
the significant structural distortion of the azido moiety
from linear to bent upon reaching its triplet state (see the
Results and Discussion
1
supporting information for details). Moreover, since 1
Identification of nitrene sources. Inspired by the
previous work of Yoon,33 we initially examined
azidoformate 1 as a model substrate for the proposed
photosensitization to obtain a cyclic carbamate 2 (Scheme
2a). When visible light was shined in the presence of
iridium photocatalysts Ir1 or Ir2, no desired oxazolidinone
2 was detected while carbamate byproduct 3 was observed
to form in low yields (entries 1 and 2). In fact, Brown and
coworkers previously observed the formation of amide
when hexanoyl azide was photosensitized.48 Interestingly,
the use of homoleptic photocatalyst Ir3 resulted in a small
amount of oxazolidinone 2 (5%), but carbamate 3 was still
major. Triplet energies of the above employed iridium
photocatalysts are higher than that of 1, thereby leading
the photosensitization event to be exergonic. On the other
hand, a ruthenium photocatalyst Ru1 bearing smaller
possesses a relatively high triplet energy of 50.6 kcal/mol,
the energy transfer to azidoformate is inefficient as
experimentally observed (Scheme 2a). This result led us to
envision to develop alternative types of triplet acceptors to
enable the desired cyclization. In fact, there are several
precedents showing the activation of hydroxamates via
photoredox catalysis to generate amidyl radicals.14-18 In
addition, hydroxamates were used as a metal nitrenoid
precursor by the action of transition metal catalysts.44,49-52
As summarized in Scheme 2b, it was calculated that the
simplest hydroxamate A bearing a N-methoxy group
exhibits higher triplet energy (ET, 73.5 kcal/mol) compared
to 1 but with lower reorganization energy (λ, 29.5
kcal/mol). N-Phenyloxy derivative B shows even smaller λ
of 17.9 kcal/mol, yet, ET is in a similar range. We further
scrutinized the impact of a carboxylate leaving group (-
2
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3
3
(a)
supported the formation of triplet nitrene E (see the
supporting information for detailed computations). On the
other hand, an interconversion between the triplet nitrene
3E and its singlet state 1E could also be considered, while 1E
is higher than 3E by 8.3 kcal/mol. And subsequent
concerted C–H insertion from the presumed singlet
H
O
1
2
3
4
5
6
7
O
N
Ph
O
ArF
O
3
3D-TS
G
N
O
H
(kcal/mol)
(8.12)
O
3D
Ph
3E-TS
(0.00)
(–16.37)
1
nitrene E was calculated to proceed with a low barrier of
3.0 kcal/mol (see the supporting information for details).
3E
(–27.02)
3F
(–39.16)
8
9
3
H
ISC
Scheme 3. Photocatalytic access to -amino alcohols
O
N
Ph
1D
3
HN
O
access to 1,2-amino alcohols
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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41
42
43
44
45
46
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48
49
50
51
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53
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55
56
57
58
59
60
H
O
(–40.05)
O
H
O
=
O
N
CF3
H
O
NH2
H
R
O
NH
Ph
O
N
O
2 steps
O
Ph
ArF
O
OH
OH
Ph
R
R
12
(–105.1)
O
 bench-stable, scalable CF3
(b)
0.124
ring
opening
1.029
O
O
0.109
HN
photocatalytic CH amidation
4a
(R = 9-fluorenyl,
)
R
0.136
3D-TS
0.289
0.585
3D
Reaction development. The above computational
studies suggest that our designed photocatalytic
cyclization of hydroxamates would be highly plausible to
access synthetically versatile 2-oxazolidinones. We,
therefore, envisioned that the current approach can serve
as a competent photocatalytic procedure eventually
installing an amino group at the -position of alcohols
(Scheme 3).53 Hydroxamate derivatives bearing the 3,5-
bis(trifluoromethyl)benzoyl group are easy to prepare
from the corresponding alcohols in 2 steps and they are
bench-stable crystalline solid in most cases. The structure
Figure 1. (a) Computed reaction pathway of the
photosensitized triplet nitrene formation of 3D. (b)
Structures and spin-densities of D and D-TS. ArF = 3,5-
3
3
bis(trifluoromethyl)phenyl; ISC = intersystem crossing.
OR) and found that the introduction of a benzoyl
substituent (C) decreases the triplet energy to 50.9
kcal/mol. Finally, it was found that the introduction of N-
[3,5-bis(trifluoromethyl)benzoyl] group (D) decreases ET
to 40.1 kcal/mol with λ of 35.7 kcal/mol.
To check the viability of utilizing hydroxamates as an
effective nitrene precursor toward the envisaged
photosensitization, a plausible pathway was first evaluated
with DFT calculations (Figure 1a). Once anionic
Table 1. Optimization of reaction parametersa
O
H
O
K2CO3 (20 mol%)
Ru(bpy)3(PF6)2 (5 mol%)
H
O
O
N
CF3
NH
Ph
1
3
Ph
O
hydroxamate D is activated to its triplet state D, it can
O
Ar, TCE (0.1 M)
Kessil lamp (456 nm)
12 h
undergo an N–O bond cleavage by traversing the transition
CF3
3
2
4
state D-TS located at 8.1 kcal/mol to form triplet nitrene
3E which will then induce a hydrogen atom transfer (HAT)
with low barrier of 10.7 kcal/mol. A radical recombination
is assumed to proceed finally to access the desired
oxazolidinone product 2.
Change
from
standard
Entry
2 (%)
RSM (%)
conditions
none
1
2
75 (70)b
<5
<5
>95
>95
>95
<5
without K2CO3
The nature of N–O bond cleavage was further
3
interrogated by analyzing the Mulliken spin density of D
3
without Ru(bpy)3(PF6)2
in dark condition
<5
and D-TS. Previous studies by the groups of Glorius30,31
3
4
5
<5
and Cho32 suggested that N–O bond breaks homolytically
when an oxime ester is sensitized into its triplet state.30-32
As illustrated in Figure 1b, our calculations revealed that
the spin density of the nitrogen core is almost doubled
from 0.59 to 1.03 during the bond cleavage event. On the
contrary, the nitrogen-bonded oxygen atom of the
benzoate decreases its spin density from 0.29 to 0.14,
suggesting that the radical character shifts significantly to
the nitrogen center. Hence, we concluded that the N–O
cleavage of photosensitized hydroxamate (3D) is a
heterolytic -bond cleavage. In contrast to the
photosensitization of oxime esters affording iminyl
radical,30-32 the activated hydroxamate would give a triplet
nitrene releasing anionic benzoate. Indeed, an intrinsic
reaction coordinate (IRC) analysis on 3D-TS further
using 1 equiv of K2CO3 (6 h)
0.05 M instead of 0.1 M
under air
70
6
7
75
<5
70
<5
8
9
10
CH2Cl2 instead of TCE
CH3CN instead of TCE
DMF instead of TCE
using Penn reactor instead of
Kessil lamp (450 nm, 3 h)
70
<5
9
25
<5
47
11
70
<5
aReaction conditions: 0.1 mmol scale in a 4 mL glass vial
1
and yields were based on H NMR analysis of the reaction
mixture using an internal standard (1,1,2-trichloroethane).
bIsolated yield. TCE: 1,1,2,2-tetrachloroethane, RSM:
Remaining starting material.
3
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presumably for the deprotonation of carbamate, the use of
Scheme 4. Expansion to -lactam construction
1
2
3
4
5
6
7
8
How about -lactam formation?
catalytic amounts was sufficient (20 mol% of powdered
K2CO3, entry 2), implying that the energy transfer occurs to
anionic carbamate. Indeed, the triplet energy of neutral
substrate 4 was calculated to be 71.4 kcal/mol, which is out
of the regime that Ru1 can sensitize. Starting material was
remained intact either in the absence of photocatalyst or
in dark (entries 3–4). When a stoichiometric amount of
base was employed, the reaction proceeded slightly faster
(entry 5). Concentration of the reaction solution was
observed to be flexible (entry 6). On the other hand, the
reaction turned out to be more sensitive to the choice of
solvents: while 1,1,2,2-tetrachloroethane (TCE) or
dichloromethane were optimal (entries 1 and 7), the use of
polar media was less effective (entries 9–10). The
cyclization took place with slightly lower efficiency by
using a Penn photoreactor (entry 11).54
O
H
O
H
Cp*Ir-catalyst
NH
OH
N
Ph
Ph
O
ArF
(Ref 42)
O
O
Ph
6
easy to
prepare
5
O
NCO
K2CO3 (20 mol%)
Ru(bpy)3(PF6)2 (5 mol%)
NH
+
Ar, TCE (0.1 M)
Kessil lamp (456 nm)
12 h
Ph
, 75%
Ph
, <5%
6
7
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
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
of one substrate 4a was confirmed by an X-ray
crystallographic analysis.
To validate our working hypothesis, we tested a model
reaction of 4 using Ru(bpy)3(PF6)2 photosensitizer (Ru1, 5
mol%), which carries sufficient triplet energy of 47.7
kcal/mol (Table 1). N-Benzoyloxycarbamate 4 was found to
cyclize smoothly to form the desired oxazolidinone
product 2 in 75% yield upon irradiation of blue light (entry
1). While base was required to induce the reaction
With a promise accessing 2-oxazolidinone starting from
N-benzoyloxycarbamate 4 under the photosensitization
Table 2. Substrate scope of photosensitized construction of azacyclesa
H
O
O
H
H
K2CO3 (20 mol%)
H
X
N
CF3
Ru(bpy)3(PF6)2 (5 mol%)
OH
OH
X
or
O
NH
O
O
Ar, TCE (0.1 M)
Kessil lamp (456 nm)
12 h
X = O or CH2
CF3
O
O
(a) 2-oxazolidinone synthesis
O
O
O
O
O
O
NH
NH
O
NH
NH
O
NH
O
O
O
NH
NH
O
O
NH
O
CF3
Me
OMe
, 69%
Br
Cl
b,c
b,c
2
8
9
10
11
12
13
14
, 70%
, 53%
, 56%
, 44%
, 75%
NH
, 42%
NH
, 50%
O
O
H
O
O
O
O
O
O
N
NH
Ph
O
NH
Et
NH
O
O
O
O
O
N
H
Et
Et
O
15
, 70%
(>20:1 d.r.)
c
b
16
18
19
21
, 64%
, 86%
O
, 63%
, 32%
17
20
, 31%
, 70%
O
O
O
O
O
O
O
H
O
H
ArF
O
HN
N
O
NH
H
NH
HN
O
O
O
HN
H
ArF
H
O
O
O
ArF
c
23
, 36%
(>20:1 d.r.)
from
(+)-myrtanol
from
from
(+)-cedrol
22
24
, 41%
, 52%
(>20:1 d.r.)
(+)-isopinocampheol
(>20:1 d.r.)
O
(b) -lactam synthesis
O
O
O
O
O
O
NH
O
NH
NH
NH
NH
NH
NH
S
NH
Ph
Me
OMe
Cl
F
30
, 81%
b
b
6
25
26
27
28
, 84%
, 70%
, 67%
, 45%
, 67%
29
31
, 65%
, 84%
O
(>20:1 d.r.)
O
O
O
O
ArF
O
O
O
O
N
NH
NH
NH
NH
NH
H
H
NH
O
NH
Ph
Ph
H
d
H
38
, 39%
from
sclareolide
32
33
34
35
36
37
, 61%
, 58%
, 50%
, 48%
, 50%
, 43%
(>20:1 d.r.)
aIsolated yields. bPerformed with a Penn reactor (450 nm, 3 h). c1.0 Equiv of K2CO3 was used. d-Trifluorotoluene
was used as the solvent instead of TCE.
4
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conditions, we were next wondered whether the present
approach can also be applied toward -lactam formation
Scheme 5. Synthetic applicability of the present
protocol
1
2
3
4
5
6
7
8
from N-benzoyloxyamide which is easy to prepare from
carboxylic acid (Scheme 4). Pleasingly, the standard
reaction conditions also worked well for the
intramolecular C−H lactamization and -lactam 6 was
obtained in 75% yield with effective suppression of a
byproduct, isocyanate (7) which can be formed by a Lossen
rearrangement. While we recently reported a highly
efficient Ir-catalyzed nitrene transfer protocol to provide 6
from the same starting material (5),44 the current approach
represents the first example of photocatalytic -lactam
formation to our best knowledge.
(a) Synthetic route to 1,2-aminoalcohol and recovery of released carboxylic acid
H
O
O
H
K2CO3 (20 mol%)
Ru(bpy)3(PF6)2 (5 mol%)
O
O
N
Ph
O
ArF
NH
Ph
O
+
HO
ArF
O
Ar, CH2Cl2 (0.1 M)
Kessil lamp (456 nm)
20 h
4
69%
(recovered)
2
, 63%
(2.5 mmol scale)
9
NH2
H
NH2
Ph
HN
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
HO
Ph
NH2
HO
140 °C, 12 h
90%
alcohol -amination
39
Substrate scope and synthetic utility. With the
optimized photosensitization conditions in hand, we
subsequently explored the substrate scope to access
(b) Stereoretentive -lactam formation
O
O
H
Me
standard conditions
H
NH
N
O
ArF
Penn reactor (450 nm)
3 h
oxazolidinones
and
-lactams
(Table
2).
N-
O
Benzoyloxycarbamate derivatives with electronic variation
on the phenyl moiety all smoothly underwent the
cyclization to furnish the corresponding oxazolidinones in
moderate to good yields (8–12). A substrate possessing the
9-fluorenyl group was also viable for the photosensitized
reaction to give a spirocyclic product 13. Oxazolidinone
product (14) bearing a quaternary carbon–nitrogen bond
could also be obtained. N-Benzoyloxycarbamate substrates
derived from not only primary alcohols but also secondary
(15 and 16) and tertiary alcohols (17) were fully amenable
for the current cyclization protocol. An excellent level of
diastereoselectivity was observed in the production of 15.
Interestingly, the cyclization of a substrate bearing two
potentially reactive C–H bonds (secondary vs benzylic
tertiary) occurred highly selectively at the later position
(16). It should be emphasized that while the scope of
alcohol precursors are broad (1o, 2o, and 3o) in the present
approach, the previously reported photoredox-catalyzed
intramolecular C–H amination via the amidyl radical
intermediacy operates mainly for substrates of tertiary
alcohols while those of primary and secondary alcohols
were reported to be sluggish.18 N-Benzoyloxycarbamates
having  C–H bonds being at the allylic (18–20) and
propargylic (21) position also underwent the desired
cyclization. Notably, the stereochemistry of double bonds
(E/Z) in substrates was not deteriorated during the course
of the reaction as exemplified by 18 and 19.
The applicability of the present photoamination reaction
was briefly examined by using substrates prepared from
terpene-derived alcohols. Substrate prepared from
myrtanol underwent the desired cyclization exclusively at
the tertiary C–H bond (22), and the product structure was
confirmed by an X-ray crystallographic analysis. The same
reactivity pattern towards the quaternary C–N bond
formation in the presence of potentially reactive secondary
C–H bonds was also observed with substrates derived from
isopinocampheol (23) and cedrol (24) albeit in moderate
yields along with free carbamate as a side product.
40
41
, 51% (99% ee)
(S)-
carboxylic acids (Table 2b). This research direction was
motivated from our previous reports, where the same
lactam products could be obtained by using tailored
transition metal catalysts including Ir and Ru species.40-44
We were pleased to find that the current
photosensitization procedure can also be viable in
delivering a broad range of -lactams. This reaction was
observed to be compatible with methoxy and halide
substituents at the phenyl moiety (26–28). -Lactam
product having the thienyl group was obtained in good
yield (29). Our present system also worked efficiently for
the construction of benzofused -lactams (31–32). Products
bearing a quaternary C–N bond were readily obtained (33–
34). In addition, -lactams having allylic (36) and
propargylic (37) chains could be prepared albeit in
moderate yield in the former case. Finally, a substrate
derived from sclarelolide was cyclized selectively leading
to the corresponding -lactam (38) in moderate yield along
with isocyanate as a side product.43 On the other hand, the
current amidation was not effective for obtaining 6-
membered azacyclic compounds via 1,6-HAT process (see
the supporting information for details).
As highlighted in Scheme 5a, the present
photosensitization procedure can readily be utilized as a
convenient route to 1,2-amino alcohols starting from
alcohols.55 Importantly, 3,5-bis(trifluoromethyl)benzoic
acid was recovered in high efficiency from the cyclization
process. In addition, the reaction was observed to proceed
in a stereoretentive manner as shown in Scheme 5b (41,
99% ee), thus allowing an access to enantioenriched -
lactams. This result led us to suggest a rapid radical
recombination of the postulated 1,4-diradical intermediate
before racemization, while an alternative pathway of the
singlet nitrene intermediacy cannot be completely ruled
out at the present stage.
Mechanistic investigations. To validate our working
mode that deprotonated carbamates are a triple acceptor,
we carried out a Stern-Volmer quenching experiment. As
shown in Scheme 6a, the emission intensity of excited Ru1
was not changed by the addition of neutral substrate 4. In
stark contrast, in the presence of carbonate base,
After establishing the photosensitization approach
accessing cyclic carbamates, we turned our attention to the
-lactam synthesis starting from N-benzoyloxyamides
which can be readily prepared from the corresponding
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Page 6 of 10
Scheme 6. Mechanistic experiments on the triplet energy transfer pathway
1
2
3
4
5
6
7
(a) Stern-Volmer quenching study
(b) Electrochemical potentials of substrates
[Ru(bpy)32+]*
4
5
4
X
Cs2CO3
4
–1.87
+ Cs2CO3
red
–1.47
E1/2
red
E1/2
E*ox
–0.81
0
8
9
+0.70
+0.78
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
+0.77
E*red
ox
ox
E1/2
4–
E1/2
5–
[Quencher] (M)
(c) Radical trapping study
O
O
O
H
H
N
O
Ru(bpy)3(PF6)2 (5 mol%)
K2CO3 (20 mol%)
CF3
O
N
O
CF3
+
NH
O
O
Ar, Penn reactor (450 nm)
TCE, 3 h
O
CO2Me
CF3
70%
(<5% RSM)
CF3
(5 equiv)
<5% (olefin-trapped)
(d) Use of Ru(dmb)32+ photocatalyst with lower oxidizing ability
O
2+
5–
Ru(dmb)3
O
X
N
N
H
Ru(dmb)3(PF6)2 (5 mol%)
CF3
K2CO3 (20 mol%)
N
N
Ph
O
Ru2+
NH
Ph
N
N
O
0.22
Penn reactor (450 nm)
TCE, 3 h
N
E*red
5
45%
CF3
<5% RSM
0.78
2+
Ru(dmb)3
ox
E1/2
ET = 45.97
(e) Radical clock experiment
O
H
Ru(bpy)3(PF6)2 (5 mol%)
K2CO3 (20 mol%)
H
N
Ph
Ph
O
O
N
CF3
Ph
O
NH2
Ph
Ph
O
+
O
Ar, Penn reactor (450 nm)
TCE, 3 h
O
Ph
O
CF3
43
44
, 8%
, 38%
42
luminescence quenching was significantly increased, thus
suggesting that the anionic carbamate is active to interact
with the excited Ru1. Moreover, electrochemical potentials
of substrates further supported this rationale. The cyclic
voltammograms of representative substrates 4 and 5
displayed irreversible reduction features and their half
potentials (E1/2) were estimated to be –1.47 and –1.87 V vs.
SCE, respectively. Since the oxidation potential of the
excited Ru1 was known to be –0.81 V vs. SCE,56 the single
electron reduction of neutral substrates will not be
operative as we proposed.
Half potentials of substrates 4 and 5 were measured to
be +0.70 and +0.77 V vs. SCE, respectively, in the presence
of KOtBu base.57 Since the reduction potential of excited
state of Ru(bpy)32+ is 0.77 V vs. SCE,56 the obtained
electrochemical values indicate that an electron transfer
pathway is still a viable alternative working mode in our
current photocatalytic reactions. As a result, we next
carried out an olefin-trapping experiment which has been
generally used as a compelling probe to support the radical
intermediacy induced by electron transfer pathways.58
When the cyclization was attempted in the presence of an
efficient trapping reagent, methyl methacrylate (5.0
equiv), no olefin-coupled compound was observed
(Scheme 6c). This result suggests that an electron transfer
pathway cannot be completely ruled out at the present
stage, it will be a non-productive process according to our
mechanistic studies.
Ruthenium photocatalyst with less oxidizing power was
also examined in the current cyclization reaction to gain
more mechanistic insights. Ru(dmb)3(PF6)2 possesses
much lower excited state redox potential (0.22 V vs. SCE)56
compared to that of Ru1 (0.77 V vs. SCE) while both
ruthenium complexes have similar triplet energy (46 ~ 48
kcal/mol). When the reaction was performed in the
presence of Ru(dmb)3(PF6)2, the desired lactam product
was obtained in 45% yield (Scheme 6d). Considering that
fact that this ruthenium photocatalyst Ru(dmb)3(PF6)2 is
insufficient for the oxidation of the deprotonated
substrate, the product formation strongly supports that
our current amidation operates via an energy transfer
pathway.
Unfortunately, our attempts to directly capture triplet
nitrene intermediate using an intermolecular reaction of
hydroxamate with pyrrole36 or alkene33 were unsuccessful
(see the supporting information for details). On the other
hand, when a radical clock experiment was performed, not
only cyclization product (43) but ring-opened olefinic
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Journal of the American Chemical Society
experiments with synchrotron radiation performed at the MX-
11C in Pohang Accelerator Laboratory.
compound (44) was also formed (Scheme 6e). This result
1
2
3
4
5
6
7
8
supports our mechanistic proposal that the current
cyclization reaction proceeds via stepwise HAT with a fast
radical recombination from triplet nitrene although a
concerted C–H insertion at the singlet state is not
completely ruled out.
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Herein,
we
successfully
demonstrated
that
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bis(trifluoromethyl)benzoyl] moiety for the photocatalytic
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ASSOCIATED CONTENT
Supporting Information. The Supporting Information is
available free of charge on the ACS Publications website.
Experimental procedures; characterization data;
spectra for all new compounds; crystallographic
data; Cartesian coordinates of all computed
structures (PDF)
Crystallographic data for 4a
Crystallographic data for 17
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AUTHOR INFORMATION
Corresponding Authors
*S.C. Email: sbchang@kaist.ac.kr
Notes
ORCID:
Hoimin Jung: 0000-0002-3026-6577
Hyeyun Keum: 0000-0001-8508-9259
Jeonguk Kweon: 0000-0002-6892-001X
Sukbok Chang: 0000-0001-9069-0946
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ACKNOWLEDGMENT
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(IBS-R10-D1) in Korea. H.J. is grateful to the National Research
Foundation of Korea (NRF) for the global Ph.D. fellowship
(NRF-2019H1A2A1076213). We sincerely appreciate Professor
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Photosensitized intramolecular C(sp3)H amidation
CF3
O
Ru photocatalyst
O
X
NH
O
R
energy transfer
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CF3
X
N
R
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O
(X = O/CH2)
H
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O
O
3
3
O
O
LG
LG
R
N
R
N
OAr
Tuning triplet energy (ET) & reorganization energy ()
+
N2
via computer-aided approach
LG
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