Photochemical C?H Amination of Ethers and Geminal Difunctionalization Reactions in One Pot

Article abstract of DOI:10.1002/anie.201905209

A mild, atom-economic, and metal-free α-C?H amination of ethers using relatively stable nonafluorobutanesulfonyl (nonaflyl, Nf) azide as the aminating reagent to give N-sulfonyl hemiaminals is reported. This enables unprecedented C(sp³) difunctionalization reactions, leading to diverse functionalized amino group containing compounds starting from simple ethers in one pot.

Full text of DOI:10.1002/anie.201905209

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Photochemical C-H Amination of Ethers and Geminal
Difunctionalization Reactions in One Pot
Authors: Daniel Hernandez-Guerra, Anna Hlavackova, Chiranan
Pramthaisong, Ilaria Vespoli, Radek Pohl, Tomas Slanina,
and Ullrich Jahn
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201905209
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10.1002/anie.201905209
Angewandte Chemie International Edition
RESEARCH ARTICLE
Photochemical C–H Amination of Ethers and Geminal
Difunctionalization Reactions in One Pot
Daniel Hernández-Guerra, Anna Hlavačková, Chiranan Pramthaisong, Ilaria Vespoli, Radek Pohl,
Tomáš Slanina and Ullrich Jahn*
Dedication ((optional))
Abstract: A mild, atom-economic and metal-free a-C–H amination of
ethers using relatively stable nonafluorobutanesulfonyl (nonaflyl, Nf)
azide as the aminating reagent resulting in N-sulfonyl hemiaminals is
reported. This enables unprecedented C(sp3) difunctionalization
reactions leading to diverse functionalized amino group-containing
compounds starting from simple ethers in one-pot.
based oxidative methods were explored for the amination of
ethers.[10] Following up on intramolecular oxidative radical C(sp3)–
H amination of alkyl sulfonamides mediated by iodobenzene
diacetate/I2,[11] the Crabtree/Gunnoe[10] and Guo/Qu[12a] or Lin[12b]
groups developed similar methodologies for the intermolecular
amination of ethers with trichloroethyl sulfamate C or purine bases
D. More recently, Buslov and Hu reported oxidative aminations of
ethers with sulfonamides or carboxylic amides E as well as
nitrogen heterocycles using diphenyliodonium salts as the
stoichiometric oxidant in the presence of NaH as a base.[13] All
these methods are not atom-economic with respect to the
amination precursors and are limited to the amination step.
Direct amination of unactivated C(sp3)–H bonds is a very
attractive transformation in organic synthesis, since nitrogen-
containing compounds are ubiquitous bioactive entities.[1] Amine
functions are to date predominately introduced into organic
molecules by substitution reactions of prefunctionalized
precursors, such as alkyl halides, alcohols or carbonyl
compounds. This often requires multiple steps and sometimes
harsh conditions.[2]
TfN–
Previous metal-free
amination methods
This approach:
Br+
H
X
H
OH
+
N
Nu
A more attractive strategy would be direct amination reactions
at unfunctionalized positions using nitrene chemistry, but their
reactivity is hard to control and therefore selectivity often cannot
be accomplished.[3] Only aryl azides are known to form indoles in
photoinduced intramolecular aminations.[4] To tame nitrenes,
transition metal catalysis has been recently extensively
developed using predominately Cu, Ag, Au, Pd, Co, Rh, Fe, Ru,
or Mn catalysts and nitrenoid precursors, such as N-
sulfonylimino-l3-iodanes or chloramine-T.[5] A single example of a
main group-initiated intramolecular C-H amination of 1-aza-2-
azoniaallene salts to form pyrazolines was recently described.[6]
Nf
X = O, CH2
H
CH2
CF3
TfN3
B
+
A
Nu
r.t., hν
r.t.
H
H
O
O
O
H
O
S
O
O
H2N
PhI(OAc)2
60 °C
O
N
X
+
S
R
F9C4
N3
hν
C
CCl3
1a
PhI(OAc)2/
hν,
70 °C
NaH, then
Ph2IPF6, r.t.
I2
R
N
H
O
N
+
H
O
H
+
N
H
R
N
N
Examples of metal-free intermolecular C-H aminations are
scarce and limited to cross-dehydrogenative couplings, oxidative
amidations, requiring the use of stoichiometric external oxidants,
and C(sp2)–H aryl aminations.[7] A pioneering direct nitrenoid-
based hydrocarbon and ether amination approach was developed
by Ochiai et al., applying hypervalent sulfonylimino-l3-bromane A
as the reagent (Scheme 1).[8] Before that, explosive and hard to
R
EWG
D
E EWG = SO2R, COR
Scheme 1. Reported metal-free C-H aminations of ethers and new atom-
economic approach. Tf = Trifluoromethanesulfonyl, Nu = Nucleophile, EWG =
Electron-withdrawing group.
handle triflyl azide
B and some not easily accessible
In the course of exploring nonaflyl azide (NfN3) (1a)[14] as a
unique diazo transfer reagent in tandem addition/cycloaddition
reactions,[15] we discovered that it reacted to a certain extent with
tetrahydrofuran (THF), if the desired reaction was not that efficient.
Reasoning that this might be a photochemically induced process,
we hypothesized that the direct amination of cheap and easily
available ethers by 1a may be a valuable and atom-economic
strategy to achieve molecular complexity, since the resulting N-
sulfonyl hemiaminals are expected to be an excellent platform for
subsequent C-C bond formation,[16,17] resulting in overall geminal
difunctionalization of saturated compounds, which is to the best
of our knowledge without precedence.
fluoroalkanesulfonyl azides were tested as a nitrene sources in
hydrocarbon amination under photochemical conditions, but
these methods were not further developed.[9] Recently, radical-
[*]
Dr. D. Hernández-Guerra,[+] Ing. A. Hlavačková,[+] MSc. C.
Pramthaisong, MSc. I. Vespoli, Dr. R. Pohl, Dr. T. Slanina, Dr. U.
Jahn
Institute of Organic Chemistry and Biochemistry of the Czech
Academy of Sciences
Flemingovo námĕstí 2, 16610 Prague 6, Czech Republic
E-mail: jahn@uochb.cas.cz
[+]
These authors contributed equally to this work.
We report here nonaflyl azide (1a) as a relatively stable, yet
reactive photoactivable reagent for the amination of structurally
Supporting information for this article is given via a link at the end of
the document.
1
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10.1002/anie.201905209
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RESEARCH ARTICLE
diverse ethers with high chemoselectivity under very mild
conditions. Importantly, through direct amination typically
unreactive ethers become subject to one-pot C-H amination/polar
C-C bond forming C(sp3) difunctionalization reactions, in which
both heteroatom groups can be retained in the products.
failed and led to production of intractable polymeric materials.
However, the compound can be further reacted in situ (vide infra).
Tetrahydropyran (THP) (2e) underwent the amination reaction in
60% yield but required significantly higher reaction temperatures
and longer times compared to five-membered ring systems 2a-c
and the formation of 5e was accompanied by 33% of 4a (entry 6).
In order to confirm the initial finding, excess of THF (2a) was
irradiated with 400 or 450 W high-pressure mercury lamps in the
presence of nonaflyl azide (1a) at 0 °C for an hour furnishing the
C–H insertion product in virtually quantitative yield (Table 1, entry
1). Repetition with new glassware and stirring bar to exclude a
potential contamination with transition metal contaminants gave
essentially the same results. The amination took place exclusively
at the a-position to the ethereal oxygen. Other commonly
employed sulfonyl azides 1b-e are not applicable in the C–H
amination reaction under the same conditions. Whereas
electronically variable arylsulfonyl azides 1b,c exclusively formed
the reduced arylsulfonamides 4b,c (entries 2,3), ethanesulfonyl
azide (1d) and diphenylphosphoryl azide (1e) were unreactive
under the irradiation conditions (entries 4,5).
Table 2. Scope of the C-H amination of ethers 2 with nonaflyl azide (1a).[a]
H
O
H
O
S
O
N
R1
hν, temp., time
R1
Nf
F9C4
N3
+
R2
Ar
R2
5a-i
O
1a
2a-i
Light source,[b]
T (°C)
Entry
1
2
t (h)
1
5
Yield
(%)[c]
UV (A), 0
UV (A), 0
UV (B), 0
quant.
NHNf
O
a
a
2
3
2
2
46[d]
NHNf
O
5b-s
b
Table 1. Optimization of the C-H amination of THF by various azides.[a]
b
93[e]
NHNf
O
S
O
S
O
O
R
O
5b-s
NfHN
5b-t
UV light, 0 °C, 1 h
Ar
S
R
N3
R
+
NH2
+
+
N
H
O
O
O
1a-e
O
4a-e
2a
3a-e
O
3 [%][b]
quant.
<5
4 [%][b]
5b-s:5b-t 1:1.3
Entry
1
R
4[f]
UV (B), 0
6
75
O
1
2
3
4
5
a
b
c
d
e
F9C4
<1
NHNf
c
c
4-O2NC6H4
4-AcNHC6H4
Et
>95
>95
<5
5
6
7
8
9
UV (B), 50
6
90[g]
60
<5
d
e
d
e
<5
UV (A),
r.t.→ 40
6
(PhO)2PO
<5
<5
[a] General conditions: 1a-e (0.25 mmol) in THF (0.5 mL, 10 equiv.), irradiation
at 0 °C for the given time. [b] Conversion determined by NMR spectroscopy.
UV (B), 0
UV (B), 40
UV (B), 0
1
70
f
f
Based on these results the scope of the photoamination of
ethers with nonaflyl azide (1a) was explored (Table 2). Besides
THF (2a), which reacted quantitatively (entry 1), other five-
membered ring derivatives 2b,c underwent the amination reaction
under mild conditions in moderate to excellent yields (entries 2-4).
The reaction of 2-methyltetrahydrofuran (2b) gave 5-methyl
derivative 5b-s in 46% yield after concentration of the reaction
mixture in vacuum, accompanied by 50% of nonaflylamide (4a)
(entry 3). Puzzled by the large amount of co-formed 4a, the
reaction mixture was not concentrated after stopping UV
irradiation and analyzed by NMR spectroscopy (entry 3). This
showed the formation of a 1:1.3 regioisomeric mixture of
amination products 5b-s and 5b-t at the secondary and tertiary
position, respectively, with almost complete conversion without
formation of detectable byproducts. Tertiary amination product
5b-t hydrolyzed apparently very easily on contact to moisture in
air with formation of 4a and volatile products, whereas the
secondary hemiaminal 5b-s is more stable under ordinary
conditions. Phthalan (2c) reacted smoothly furnishing 5c in 75%
yield (entry 4). Dioxolane was much less reactive but provided
orthoamide 5d after six hours of irradiation at 50 °C (entry 5),
however its access required much experimentation, since it is only
stable in the diluted reaction solution. Multiple isolation attempts
Bu
NHNf
O
13
2
50
Bu
O
g
g
NHNf
86[h]
h
O
+
NHNf
O
5h-Et:5h-Bu 1.1:1
Bn
NHNf
99[i]
O
10
UV (B), 0
1.5
Bn
O
i
5i
+
Ph
NfN
6i
5i:6i 2:1
[a] Conditions: Azide 1a (1 equiv.) was mixed with ethers 2a-i (10 equiv.) and
the reaction mixture was irradiated using the indicated light source at the
indicated temperature and time under an argon atmosphere. [b] (A) 450 W or
(B) 400 W high-pressure mercury lamps used. [c] Crude material after
evaporation unless otherwise noted. [d] Nonaflylamide (4a) co-formed in 50%
yield. [e] Conversion of 1a according to 19F NMR. On exposure of the reaction
solution to ambient conditions, 5b-t hydrolyzed, 5b-s was isolated on
concentration in 46% yield, d.r. 1.4:1. [f] 1.25 Equiv. 2c. [g] Conversion of 1a
according to 19F NMR spectroscopy. On exposure of the reaction solution to
ambient conditions, 5d hydrolyzed to polymeric materials. [h] Slow exchange,
2
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RESEARCH ARTICLE
the symmetrical amination products were also detected, ratio 5h-Et:5h-
Bu:5f:5g 10:9:3:1. [i] Complete conversion of 1a according to 19F NMR
spectroscopy. The material is sensitive to hydrolysis, benzaldehyde and 4a
detected in equal ratio to 20% of the mass balance.
nucleophile-substituted ethers by exchange of the sulfonylamino
unit were observed.
Table 3. Sequential C–N/C–C bond formation reactions of ethers 2 with nonaflyl
azide (1a) and nucleophiles (TMS = trimethylsilyl).
Acyclic ethers undergo the C–H insertion as well. The
amination of diethyl ether (2f) took place smoothly even at 0 °C,
yielding 70% of product 5f (entry 7). Hemiaminal 5f is however
somewhat sensitive to hydrolytic decomposition on concentration,
therefore it should be immediately further reacted in solution (vide
infra). Longer chain ethers, such as dibutyl ether (2g), reacted in
moderate yield (entry 8). Unsymmetrical ether 2h displayed only
a slight preference for reaction at the shorter ethyl unit of 2h (entry
9). Moreover, the formed hemiaminals are sensitive to exchange
since besides major 5h-Et and 5h-Bu the symmetric N-nonaflyl
hemiaminals 5f and 5g were also detected to a noticeable extent
in the photoamination mixture, showing that the hemiaminal must
be in equilibrium with its imine. This was clearly manifested in the
reaction of dibenzyl ether (2i), which provided in contrast to all
other ethers a mixture of hemiaminal 5i and the corresponding
imine 6i together with the hydrolysis products benzaldehyde and
nonaflyl amide (4a) (entry 10). Methyl ethers react very slowly,
thus their amination reactions are synthetically not useful. It
proved to be very important that ethers 2a-i were free of peroxide
impurities for all reactions, because their presence seriously
retarded or even stalled the amination reactions.
H
H
O
H
O
N
Nu
N
R1
hν, NfN3
HO
R1
R1
Nu
Nf
Nf
R2
2a-i
R2
R2
7a-o
cf. Table 2
5a-i
Substrate
T
(°C)
t
Yield
(%)[a]
Entry
Nu
Product 7
2
(h)
NfHN
O
HO
1
2
r.t.
r.t.
2
72[b]
65
Ph
a
a
a
a
18
a
a
TMSCN
PhMgBr
3
4
65
40
4
74
64
b
c
72
TMSCN
PhMgCl
5
6
40
40
22
36
50
57
c
c
d
N,O-Acetals are a versatile compound class, since they are
N-acylimine surrogates and can be subjected to reactions with
nucleophiles in the presence of Lewis acids.[16,17] Thus, when 2-
(nonaflylamino)tetrahydrofuran (5a) was mixed with 1-phenyl-1-
(trimethylsiloxy)ethylene in the presence of 20 mol% trimethylsilyl
triflate (TMSOTf)[18] the ring-opened Mukaiyama-Mannich product
7a was obtained in 72% yield (Table 3, entry 1). Surprisingly, the
reaction can be also performed with a similar yield under Lewis
acid-free conditions (entry 2). This result is important when
considering substrates with Lewis acid-sensitive functionality in
such sequences. Other nucleophiles, such as trimethylsilyl
cyanide or phenylmagnesium halides as representatives of
organometallic reagents were also used, giving a-amino nitrile 7b,
which may serve as precursor for the corresponding amino acid,
or a-methylbenzyl amide 7c (entries 3,4). Phthalan (2c) can be
used similarly, providing functionalized benzylic nonaflylamide
derivatives 7d and 7e in good yields over the two steps (entries
5,6). The yields of tetrahydropyran-derived nonaflylamides 7f-h
were in contrast rather low, which is attributed to the reluctance of
the intermediate N,O-acetal to undergo efficient ring opening, but
the selectivity remained the same (entries 7-10). Diethyl ether (2f)
provided the a-amination/C–C coupling products 7i-k in good
yields over the two steps (entries 11-13). These results are
significant given the difficulty to work with acetaldehyde imines in
Mannich and related reactions. Thus, cheap and easy to handle
diethyl ether becomes an efficient acetaldehyde surrogate by
application of the presented methodology. The reaction of longer-
chain dibutyl ether (2g) also proceeded cleanly, but the yield of
amide derivative 7l remained lower as a result of the moderate
yield of amination step (entry 14, cf. Table 2, entry 8). The
amination/C–C coupling reactions of dibenzyl ether (2i)
proceeded in contrast smoothly furnishing products 7m-o in good
to very good yields over the two-step sequence (entries 15-17). It
is worth pointing out the high chemoselectivity of the reaction of
the intermediate N,O-acetals with all nucleophiles, since the
formation of N-nonaflylamines 7 is exclusively observed and no
e
NfHN
O
7
8
9
88
40
88
18
20
18
HO
16[c]
28
Ph
f
f
e
e
e
e
TMSCN
PhMgCl
33
g
h
10
11
40
35
72
16
25
70
NfHN
O
Ph
f
f
i
j
12
13
14
TMSCN
PhMgCl
PhMgCl
35
35
40
23
40
69
80
63
22
f
k
l
Bu
O
g
15
50
18
70
i
i
m
n
TMSCN
PhMgCl
16
17
40
r.t.
67
67
55
56[d]
i
o
[a] Isolated over two steps from ethers 2. [b] Conditions: From 1a (1 equiv.) and
2a (10 equiv.), then TMSOTf (0.2 equiv.), 1-phenyl-1-(trimethylsiloxy)ethylene
(1.1 equiv.) in dichloromethane (0.1 M) at 0 ºC. [c] Conditions: From 1a (1 equiv.)
and
2e
(10
equiv.),
then
TMSOTf
(0.2
equiv.),
1-phenyl-1-
3
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10.1002/anie.201905209
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RESEARCH ARTICLE
(trimethylsiloxy)ethylene (2.0 equiv.) at 0 ºC, no removal of excess THP after
one molecule of 1a (Scheme 4). To exclude potential direct
reactions of TEMPO (10) with THF (1a) or photoinduced
exchange of amination product 5a by 10 under the reaction
conditions appropriate experiments were conducted. They
revealed that TEMPO (10) neither reacts with THF (2a) nor
exchanges the nonaflyl unit in 5a by UV irradiation (see the SI).
amination step. [d] Benzhydrol 8 formed in 8% yield.
Since reactive 2-amino-1,3-dioxolane 5d could be only
generated and stored in 1,3-dioxolane (2d) solution, it was
important to demonstrate the applicability of this compound in
subsequent steps. Indeed, when the solution of 5d resulting from
photoamination of 2d was treated with an excess of
phenylmagnesium chloride
a
mixture of N-benzhydryl
hν, NfN3
N
+
+
NfNH2
+
nonaflylamide (7o) and benzhydrol (8) was isolated in 30% and
25% yields, respectively (Scheme 2). Sulfonamide 7o proved to
be identical to the compound obtained by amination/substitution
of dibenzyl ether (2i) (cf. Table 3, entry 17). If phenyllithium was
used, benzhydrol (8) was the sole product isolated in good yield
over the two reaction steps accompanied by nonaflylamide (4a)
(26%). Alcohol 8 likely results from solvolysis of the initially formed
N-benzhydryl nonaflylamide (7o) during workup and
chromatographic isolation.
NHNf
O
N
O
O
O
5a
O
11
25 °C
4a
2a
10
10 equiv. 0.5 equiv.
10 equiv. 2 equiv.
1 equiv.
1 equiv.
5a:4a:11 1:2:1
5a:4a:11 0:1:2
Scheme 4. Photoamination of THF (2a) in the presence of TEMPO (10).
The kinetics of the amination reaction of THF (2a) with UV
irradiation were determined by monitoring by 19F NMR
spectroscopy (Figure 1). Under the typical UV irradiation
conditions, a clear pseudo-first order kinetic behavior of the
amination was found and the rate constant was determined in
duplicate to 5.3´10–2 s–1 (Figure 1) at 0 °C.
O
O
NHNf
OH
hν, NfN3
PhMgCl
+
NHNf
50 °C, 24 h
Ph
Ph
O
Ph
Ph
O
cf. Table 2
2d
7o 30%
5d
8 25%
OH
PhLi, –20 °C, 2 h
The deuterium kinetic isotope effect (KIE) was determined
from parallel reactions of THF and THF-d8 with 1a under identical
conditions resulting in a KIE kTHF/kDTHF of 1.3 for the C-H insertion
reaction (see the SI). This KIE is in line with the value of 1.48,
which was obtained from the photolytic reaction of tosyl azide with
THF.[23] This low value is not in agreement with a concerted
amination mechanism by nitrene 12 (Scheme 5), since typically
KIEs of larger than 2.5 have been observed for concerted C-H
insertions.[23] The observed KIE is rather in line with a radical
process, in which hydrogen transfer is not the rate determining
step, or a single electron transfer process.
Ph
Ph
8 66% (2 steps)
Scheme 2. C–H Amination of dioxolane and subsequent reaction with
organometallic reagents.
Normally perfluoroalkylsulfonyl groups cannot be easily
deprotected.[19] However, we found that treatment of N-
nonaflylamines 7k or 7o with sodium naphthalenide allows mild
deprotection of the nonaflyl group to give free amines 9a,b
(Scheme 3).
NHNf
NH2
Na, C10H8, DME, r.t., 2 h
Ph
R
Ph
R
7k R = Me
7o R = Ph
9a 44% (75% brsm)
9b 55% (82% brsm)
Scheme 3. Liberation of the amine function from N-nonaflylamines (brsm =
based on recovered starting material).
The photoamination is remarkable since azidation is normally
observed when sulfonyl azides react with radical precursors
under photochemical or thermal conditions.[20] Therefore, control
experiments were performed in order to shed light on the
mechanism of the C–H insertion reaction. The reaction requires
continuous irradiation. An experiment, in which irradiation is
interrupted for defined times, showed no conversion during the
dark periods (see the Supporting information (SI)). To distinguish
a concerted C–H insertion of triplet N-nonaflyl nitrene from a
radical process,[21] THF (2a) and nonaflyl azide (1a) were mixed
in the presence of half or two equivalents of 2,2,6,6-
Figure 1. Kinetics of the amination reaction of THF (2a) at 0 °C at UV irradiation
and ambient light.
tetramethylpiperidin-1-oxyl (TEMPO) (10) in
rigorously
deoxygenated solution and irradiated by UV light at 25 °C for 7.5
and 3.5 h, respectively, until complete consumption of 1a. With
half an equivalent of 10 a 1:2:1 mixture of 5a:4a:11 was observed
in the crude reaction mixture, whereas with two equivalents of
TEMPO (10) a 1:2 mixture of 4a:11 was formed with 52% mass
balance.[22] This reveals that two THF radicals are generated from
Finally, the quantum yield of the amination reaction was
determined. The value of 468±50 is in clear agreement with an
fairly efficient radical chain mechanism (See the SI for details).
The following mechanism is best in line with all observations
(Scheme 5). Triplet nitrene 12[21] is initially formed by photolysis.
Both, the reaction with TEMPO (10) and the KIE speak against a
4
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10.1002/anie.201905209
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RESEARCH ARTICLE
concerted C-H insertion reaction via transition state 13, but rather
point to facile hydrogen atom abstraction from ethers 2 by nitrene
12 generating a-alkoxy radicals 15. These radicals react in the
rate determining step with NfN3 (1a). The radical addition may
either proceed at the internal position of the azide unit of 1a via
transition state 16 because of the unhindered, but electron-
deficient nature of the nonaflyl group, or in line with radical
azidation reactions[20] at the terminal end via 17. However, in
contrast to radical azidations, which proceed by scission of a
sulfonyl radical, this process may be slow for the nonaflyl group,
which instead rearranges to the internal position forming
intermediate 18, from which nitrogen extrusion takes place. Thus,
both addition pathways lead to sulfonamidyl radicals 19. These
electrophilic radicals undergo facile reduction by ethers 2 re-
forming radicals 15, which continue the chain process. This
reaction course is supported by the formation of two equivalents
of TEMPO adducts 11 and one of nonaflylamide (4a) from one
equivalent of azide 1a (cf. Scheme 4), because addition of
radicals 15 to 1a cannot compete with coupling to TEMPO (10).
Acknowledgements
Generous financial support by the Institute of Organic Chemistry
and Biochemistry of the Czech Academy of Sciences (RVO:
613889633), the Grant Agency of the Czech Republic (17-
14510S), the Gilead Sciences & IOCB Research Center and the
COST action CM1201 “Biomimetic Radical Chemistry” is
gratefully acknowledged. Lanxess Deutschland is acknowledged
for a gift of nonafluorobutanesulfonyl fluoride.
Keywords: amination • C-H activation • photoreactions •
radicals • sulfonyl azides
[1]
[2]
[3]
H. M. L. Davies, Angew. Chem. Int. Ed. 2006, 45, 6422-6425.
F. Collet, R. H. Dodd, P. Dauban, Chem. Commun. 2009, 5061-5074.
(a) D. S. Breslow, M. F. Sloan, N. R. Newburg, W. B. Renfrow, J. Am.
Chem. Soc. 1969, 91, 2273-2279; (b) D. S. Breslow, E. I. Edwards, R.
Leone, P. v. R. Schleyer, J. Am. Chem. Soc. 1968, 90, 7097-7102.
L. Junk, U. Kazmaier, Org. Biomol. Chem. 2016, 14, 2916-2923 and cited
ref.
[4]
[5]
Reviews: a) K. Shin, H. Kim, S. Chang, Acc. Chem. Res. 2015, 48, 1040-
1052; b) T. A. Ramirez, B. Zhao, Y. Shi, Chem. Soc. Rev. 2012, 41, 931-
942; c) R. T. Gephart, T. H. Warren, Organometallics 2012, 31, 7728-
7752; d) J. L. Roizen, M. E. Harvey, J. Du Bois, Acc. Chem. Res. 2012,
45, 911-922; e) J. Du Bois, Org. Process Res. Dev. 2011, 15, 758-762;
f) C. M. Che, V. K. Lo, C. Y. Zhou, J. S. Huang, Chem. Soc. Rev. 2011,
40, 1950-1975; g) F. Collet, C. Lescot, P. Dauban, Chem. Soc. Rev. 2011,
40, 1926-1936; h) D. Zalatan, J. Du Bois, Top. Curr. Chem. 2010, 292,
347-378; i) F. Collet, R. H. Dodd, P. Dauban, Chem. Commun. 2009,
5061-5074; j) H. M. L. Davies, J. R. Manning, Nature 2008, 451, 417-
424; k) M. Díaz-Requejo, P. Pérez, Chem. Rev. 2008, 108, 3379-3394;
l) H. M. L. Davies, M. S. Long, Angew. Chem. Int. Ed. 2005, 44, 3518-
3520; m) P. Muller, C. Fruit, Chem. Rev. 2003, 103, 2905-2920.
X. Hong, D. A. Bercovici, Z. Y. Yang, N. Al-Bataineh, R. Srinivasan, R.
C. Dhakal, K. N. Houk, M. Brewer, J. Am. Chem. Soc. 2015, 137, 9100-
9107.
O
O
11
1a
Nf
S
Fast
trapping
N
N–
O
F9C4
N3
10
N
N
1a
Nf
N–
N
O
R1
hν
–N2
O
R1
R2
Initiation
2
R2
O
O
R2
R1
S
15
17
F9C4
N
16
–NfNH
12
Chain
Nf
14
O
H
N
R1
Nf
N
N
R2
N
2
–N2
O
R1
O
R2
C4F9
R2
18
R1
[6]
[7]
O2S
NHNf
R2
N
H
19
O
O
R1
R1
2
Cross-dehydrogenative coupling: Review a) R. Samanta, K. Matcha, A.
P. Antonchick, Eur. J. Org. Chem. 2013, 5769-5804; Intramolecular
oxidative aminations: b) V. P. Mehta, B. Punji, RCS Adv. 2013, 3, 11957-
11986; Aryl aminations: Review: c) R. Samanta, A. P. Antonchick, Synlett
2012, 23, 809-813.
R2
5
13
Scheme 5. Mechanistic proposal for the C-H amination.
[8]
[9]
a) M. Ochiai, K. Miyamoto, T. Kaneaki, S. Hayashi, W. Nakanishi,
Science 2011, 332, 448-451. b) M. Ochiai, S. Yamane, M. M. Hoque, M.
Saito, K. Miyamoto, Chem. Commun. 2012, 48, 5280-5282.
S.-Z. Zhu, J. Chem. Soc., Perkin Trans. 1 1994, 2077–2081. b) For a
review on TfN3, see: B. A. Shainyan, L. L. Tolstikova, Chem. Rev. 2013,
113, 699-733; For selected other uses of TfN3 see: c) L. Benati, D. Nanni,
P. Spagnolo, J. Org. Chem. 1999, 64, 5132-5138; d) N. Kamigata, K.
Yamamoto, O. Kawakita, K. Hikita, H. Matsuyama, M. Yoshida, M.
Kobayashi, Bull. Chem. Soc. Jpn. 1984, 57, 3601-3602.
In summary, we have developed a direct and versatile
photochemical C(sp3)–H amination in the a-position of readily
available and commercial feedstock ethers using stable
nonafluorobutanesulfonyl azide as a unique amination reagent
instead of the classically observed azidation reactions of sulfonyl
azides. UV irradiation is optimal for activation of nonaflyl azide to
the corresponding nitrene releasing molecular nitrogen as the
only byproduct. The amination reactions proceed under mild and
atom-economic conditions and are regioselective. Mechanistic
studies suggest a radical chain process for the amination. The
resulting N-nonaflyl hemiaminal intermediates were applied for
the synthesis of functionalized amino group-containing
compounds in one-pot, two step C–N/C–C geminal
difunctionalization reactions without the necessity of activating
mediators. A significant advantage is that for example diethyl
ether serves as a stable and efficient equivalent for acetaldehyde
imines, which are difficult to generate and to handle. The
described reactions have many implications for the design of
further direct C–H amination reactions, which are under
investigations in these laboratories.
[10] For excellent overviews about radical-based amination methods, see: a)
L. Y. Dian, Q. Y. Xing, D. Zhang-Negrerie, Y. F. Du, Org. Biomol. Chem.
2018, 16, 4384-4398; b) Campos, S. K. Goforth, R. H. Crabtree, T. B.
Gunnoe, RSC Adv. 2014, 4, 47951-47957; c) Y. T. Zhao, W. J. Xia, Chem.
Soc. Rev. 2018, 47, 2591-2608.
[11] R. Fan, D. Pu, F. Wen, J. Wu, J. Org. Chem. 2007, 72, 8994-8997.
[12] a) H.-M. Guo, C. Xia, H.-Y. Niu, X.-T. Zhang, S.-N. Kong, D.-C. Wang,
G.-R. Qu, Adv. Synth. Catal. 2011, 353, 53-56; b) Z. Luo, Z. Y. Jiang, W.
Jiang, D. G. Lin, J. Org. Chem. 2018, 83, 3710-3718.
[13] I. Buslov, X. Hu, Adv. Synth. Catal. 2014, 356, 3325-3330.
[14] a) M. J. Mitcheltree, Z. A. Konst, S. B. Herzon, Tetrahedron 2013, 69,
5634-5639; b) J. L. Chiara, J. R. Suárez, Chem. Commun. 2013, 49,
9194-9196; c) J. L. Chiara, J. R. Suárez, Adv. Synth. Catal. 2011, 353,
575-579 and cited ref.
[15] V. Kapras, R. Pohl, I. Císařová, U. Jahn, Org. Lett. 2014, 16, 1088-1091.
5
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10.1002/anie.201905209
Angewandte Chemie International Edition
RESEARCH ARTICLE
[16] Reviews on the reactivity of similar N-acyliminium ions: a) A. Yazici,; S.
G. Pyne, Synthesis 2009, 339-368; b) A. Yazici,; S. G. Pyne, Synthesis
2009, 513-541; c) W. J. N. Meester, J. H. van Maarseveen, H. E.
Schoemaker, H. Hiemstra, F. P. J. T. Rutjes, Eur. J. Org. Chem. 2003,
2519-2529.
[17] Review on N-sulfonyliminium ions: a) S. M. Weinreb, Top. Curr. Chem.
1997, 190, 131-184; Leading recent references: b) C. A. Leverett, M. P.
Cassidy, A. Padwa, J. Org. Chem. 2006, 71, 8591-8601 and cited ref.; c)
S. S. Kinderman, M. M. T. Wekking, J. H. van Maarseveen, H. E.
Schoemaker, H. Hiemstra, F. P. J. T. Rutjes, J. Org. Chem. 2005, 70,
5519-5527 and cited ref.
[18] TMSOTf was necessary to promote reactions of N-Cbz hemiaminals with
nucleophiles: M. Sugiura, H. Hagio, R. Hirabayashi, S. Kobayashi, J. Am.
Chem. Soc. 2001, 123, 12510-12517.
[19] Leading references for nonaflyl: ref. 14a; triflyl: a) K. S. L. Chan, H.-Y.
Fu, J.-Q. Yu, J. Am. Chem. Soc. 2013, 135, 16344-16347. b) L. Chu, X.-
C. Wang, C. E. Moore, A. L. Rheingold, J.-Q. Yu, J. Am. Chem. Soc.
2015, 137, 2042-2046. c) Y. Wang, Y. Wu, Y. Lia, Y. Tang, Chem. Sci.
2017, 8, 3852-3857.
[20] Leading review: P. Panchaud, L. Chabaud, Y. Landais, C. Ollivier, P.
Renaud, S. Zigmantas, Chem. Eur. J. 2004, 10, 3606-3614.
[21] Triflyl nitrene was recently determined to have a triplet ground state and
1a is assumed to be so by analogy: X. Q. Zeng, H. Beckers, H. Willner,
P. Neuhaus, D. Grote, W. Sander, J. Phys. Chem. A 2015, 119, 2281-
2288.
[22] The radical coupling of THF radicals with TEMPO under photolytic radical
conditions is facile: R. Braslau, L. C. Burrill II, M. Siano, N. Naik, R. K.
Howden, L. K. Mahal, Macromolecules 1997, 30, 6445-6450.
[23] A. Das, A. G. Maher, J. Telser, D. C. Powers, J. Am. Chem. Soc. 2018,
140, 10412-10415. Hydrogen abstraction by tosylaminyl radicals
generated from chloramine-T proceeds with a KIE of 4.4. Concerted
nitrenoid insertions have a KIE of 2.6. The photolytic reaction of TsN3
with THF proceeded only in 7% yield, what is in line with results obtained
for the related arenesulfonyl azides 1b,c (cf. Table1, entries 2,3).
6
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10.1002/anie.201905209
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RESEARCH ARTICLE
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Lazy ethers made active: Direct and
versatile metal-free a-amination of
typically unreactive ethers proceed
with nonaflyl azide. One-pot
Daniel Hernández-Guerra, Anna
Hlavačková, Chiranan Pramthaisong,
Ilaria Vespoli, Radek Pohl, Tomáš
Slanina and Ullrich Jahn*
amination/C–C bond forming geminal
difunctionalization reactions enable
the use of ethers as aldehyde imine
equivalents.
Page No. – Page No.
Photochemical C-H Amination of
Ethers and Geminal
Difunctionalization Reactions in One
Pot
Layout 2:
COMMUNICATION
Author(s), Corresponding Author(s)*
((Insert TOC raphic here))
Page No. – Page No.
Title
7
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