Iron-Catalysed Remote C(sp3)?H Azidation of O-Acyl Oximes and N-Acyloxy Imidates Enabled by 1,5-Hydrogen Atom Transfer of Iminyl and Imidate Radicals: Synthesis of γ-Azido Ketones and β-Azido Alcohols

Article abstract of DOI:10.1002/chem.201901079

In the presence of a catalytic amount of iron(III) acetylacetonate [Fe(acac)₃], the reaction of structurally diverse ketoxime esters with trimethylsilyl azide (TMSN₃) afforded γ-azido ketones in good to excellent yields. This unprecedented distal γ-C(sp³)?H bond azidation reaction went through a sequence of reductive generation of an iminyl radical, 1,5-hydrogen atom transfer (1,5-HAT) and iron-mediated redox azido transfer to the translocated carbon radical. TMSN₃ served not only as a nitrogen source to functionalise the unactivated C(sp³)?H bond, but also as a reductant to generate the catalytically active Fe^II species in situ. Based on the same principle, a novel β-C(sp³)?H functionalisation of alcohols via N-acyloxy imidates was subsequently realised, leading, after hydrolysis of the resulting ester, to β-azido alcohols, which are important building blocks in organic and medicinal chemistry.

Full text of DOI:10.1002/chem.201901079

A Journal of
Accepted Article
Title: Iron-Catalyzed Remote C(sp3)-H Azidation of O-Acyl Oximes and
N-Acyloxy Imidates Enabled by 1,5-Hydrogen Atom Transfer of
Iminyl and Imidate Radicals: Synthesis of γ-Azido Ketones and β-
Azido Alcohols
Authors: Rubén Torres-Ochoa, Alexandre Leclair, Qian Wang, and
Jieping Zhu
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To be cited as: Chem. Eur. J. 10.1002/chem.201901079
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10.1002/chem.201901079
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Iron-Catalyzed Remote C(sp3)-H Azidation of O-Acyl Oximes and
N-Acyloxy Imidates Enabled by 1,5-Hydrogen Atom Transfer of
g
b
Iminyl and Imidate Radicals: Synthesis of -Azido Ketones and -
Azido Alcohols
Rubén O. Torres-Ochoa, Alexandre Leclair, Qian Wang and Jieping Zhu*
Abstract: In the presence of a catalytic amount of iron(III) acetylacetonate [Fe(acac)3], the reaction of structurally diverse ketoxime
esters with trimethylsilyl azide (TMSN3) afforded g-azido ketones in good to excellent yields. This unprecedented distal g-C(sp3)-H bond
azidation reaction went through a sequence of reductive generation of iminyl radical, 1,5-hydrogen atom transfer (1,5-HAT) and iron-
mediated redox azido transfer to the translocated carbon radical. TMSN3 served not only as a nitrogen source to functionalize the
unactivated C(sp3)-H bond, but also as a reductant to generate in situ the catalytically active Fe(II) species. Based on the same principle,
a novel b-C(sp3)-H functionalization of alcohols via N-acyloxy imidates was subsequently realized leading, after hydrolysis of the
resulting ester, to b-azido alcohols, important building blocks in organic and medicinal chemistry.
dormant for many years probably due to the harsh oxidative
conditions associated with this reaction. However, recent
advances in the field of photoredox catalysis have provided the
Introduction
impetus for the exploitation of this cascade reaction in the remote
By virtue of its weak N-O bond, the easily accessible O-acyl
functionalization of unactivated C(sp3)-H bond.[13] Indeed, mild
oximes have been widely exploited in organic synthesis. In
photocatalytic conditions have been developed by Nevado,[14]
addition to the classic Beckmann[1] and Neber rearrangements,[2]
,
Wu,[15] Leonori,[16] Studer,[17] Yu,[18] Duan,[19] and Guo,[20]
the O-acyl oximes can also be converted to the organometallic
species via oxidative addition,[3] to the iminyl radicals by single
electron transfer reduction[4] and to the iminato-metal species
through two consecutive SET processes.[5-6] Among those known
transformations, the 5-exo-trig cyclizations of g,d-unsaturated
oxime esters via either iminopalladium[3,7] or iminyl radical
intermediates[4,8-10] have been developed into powerful synthetic
tools and have been extensively exploited for the synthesis of
pyrrolidines and related N-heterocycles of biological importance.
respectively, for the conversion of oxime derivatives to g-
functionalized ketones (Scheme 1b). Synthetic transformations
involving translocated carbon radicals were nevertheless limited
to the radical addition (C-C bond formation), homolytic
substitution (SH2) and Minisci-type reactions. Parallel to these
works,
Nagib
developed
a
PIDA/NaI-mediated
g-
amination/halogenation of imidates under photolysis or thermal
conditions to access, after acidic hydrolysis of the resulting
oxazolines, the b-functionalized alcohols (Scheme 1c).[21]
A
similar reaction was reported independently from the group of
Chen and He using NIS as an oxidant.[22] Only photoredox
catalysis has been exploited for this purpose at the outset of this
work. However, Guo and coworkers have very recently
communicated an Fe(OAc)2-catalyzed g-heteroarylation of
ketones featuring a key 1,5-HAT of the iminyl radicals followed by
Minisci arylation of the resulting carbon radical.[20]
Several elegant methods for the generation of iminyl radical
from oxime esters have been established. However, in spite of the
recent resurgence on the chemistry of N-centered radicals and
the rapid development of the remote C(sp3)-H functionalization of
amides involving the key 1,5-hydrogen atom transfer (1,5-HAT) of
the in situ generated amidyl radicals,[11] the 1,5-HAT of iminyl
radical is far less developed. Indeed, the bond dissociation energy
(BDE) of iminyl NH (93 kcal/mol) is lower than most of the aliphatic
C(sp3)-H (96-105 kcal/mol), rendering the 1,5-HAT of iminyl
radical to carbon radical thermodynamically unfavorable.
Notwithstanding the endergonic nature of this process, Forrester
demonstrated in 1979 the feasibility of this type of domino process
by transforming the phenylalkylideneamino-oxyacetic acids to
tetralones 1 under strong oxidative conditions (Scheme 1a) and
pointed out the importance of performing the reaction under acidic
conditions to favour the 1,5-HAT.[12] This discovery remained
We have been interested in exploiting the metal-catalyzed
remote C(sp3)-H functionalization of ketones via oxime esters.
The underlying principle is to exploit the dual role of metal as
reductant to generate the iminyl radicals and as a redox center to
transfer an organic functional group to the translocated C(sp3)
radical.[23,24] The realization and generalization of this
conceptually simple domino process would significantly enlarge
the accessibility of the g-functionalized ketones and influence the
development of other radical-based remote functionalization
processes. In view of the importance of the alkyl azides in organic
synthesis and in biology,[25] azidation of unactivated C(sp3)-H
bond deemed interest. We report herein the first example of
Fe(acac)3-catalyzed, HOAc-promoted g-C(sp3)-H azidation of O-
acyl oximes 2. The reaction afforded the g-azido ketones 3,[26]
difficultly accessible otherwise, in good to excellent yields. In
addition, N-acyloxy imidates 4 were similarly g-azidated to afford,
after hydrolysis, the corresponding b-azido alcohols 5 (Scheme
1d).
[a]
Dr. R. O. Torres-Ochoa, A. Leclair, Dr. Q. Wang, Dr. Jieping Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
École Polytechnique Fédérale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
Homepage: http://lspn.epfl.ch
Supporting information for this article is given via a link at the end of
the document.
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a) Forrester’s seminal work on the synthesis of tetralone involving 1,5-HAT of
iminyl radical
together with 1,4-diphenylbutan-1-one (6a) as a major product.
The formation of ketone 6a suggested the presence of the iminyl
copper species A and/or B, generated most probably by way of
the oxidative addition of oxime ester to Cu(I)X[30] and/or a second
SET between the iminyl radical C and the Cu(I) salt,[5] respectively.
The formation of 3a, albeit in low yield, proved nevertheless the
feasibility of the planned domino transformation.
O
O
NH
O
N
OH
persulfate
R2
·
R2
R1 R2
1
R1
R1
b) Substrates for remote C(sp3)-H functionalization of oxime derivatives under
photoredox catalysis
NOCOR
O
O
Cu salts, conditions
O
Ph
Ph
Ph
(a)
O
Ph
Ph
+
Ph
O
Ar
O
N
O
H
N
OH
N3
Ph
N
OH
O
2 R = p-CF3C6H4, tBu, C6F5
Me
R2
3a
6a
Me
R2
R
Me
R
R
R2
Cu(II)X
Ph
Cu(III)X(OCOR)
Ph
N
·
N
N
Ph
R1
R1
R1
Leonori (2018)
Ph
Ph
Nevado (2017), Wu (2017)
Duan (2018), Yu (2018)
Guo (2019)
A
B
C
Studer (2018)
O
c) Nagib’s C-H amination of alcohols via trichloromethylimidates or benzimidates
N3
NH
N3
N
Ph
Ar
(b)
R2
Ph
Ph
Ph
NH
PhI(OAc)2, NaI
R1
NH2
R2
R1
HCl
N3
R2
Ph
Ph
N
HO
Ar
R
O
7
8
9
MeCN, hν
R1
O
R
R = CCl3 or Ph
Scheme 2. Initial survey of the reaction conditions: Mechanistic divergence,
intermediates and side products.
d) This work: Iron-catalyzed remote C(sp3)-H azidation
Fe(acac)3 (0.2 equiv)
O
N3
NOCOR
TMSN3 (3.0 equiv)
R2
H
R2
R1
R1
We next turned our attention to the iron catalysts.[28,31]
Gratefully, reaction of 2a (R = p-CF3C6H4) with TMSN3 in the
presence of Fe(acac)3 (0.2 equiv) in DCE afforded 3a in 51% yield.
Further optimization of the reaction parameters (see SI for details)
led to the following key observations: a) Fe(acac)3 was the
catalyst of choice and the reaction was best performed under
ligandless conditions; Low yield of g-azidoketone 3a was obtained
when Fe(acac)2 was used as catalyst. b) TMSN3 was a better
azide donor than alkali azides MN3 (M = Li, Na, K); c) The
presence of a small amount of water was essential to ensure the
high yield of the desired product. Performing the reaction in
anhydrous solvent afforded a significant amount of the aza-diene
7 (Scheme 2b), resulting most probably from the dimerization of
R3
AcOH (1.0 equiv)
tBuOH (c 0.05 M), 50 °C
R3
2
3
5
1) Fe(acac)3 (0.05 equiv)
TMSN3 (1.5 equiv)
EtOAc (c 0.05 M), 70 °C
NOCOR
N3
H
R2
R2
R1
HO
O
R3
R3
2) NaOH (2.0 M), MeOH
0 °C to RT
4
Dual role of Fe catalyst:
a) as a reductant to generate the iminyl radical.
b) as a redox center to transfer the azide to the translocated carbon radical.
Scheme 1. Remote C(sp3)-H functionalization involving 1,5-HAT of iminyl and
imidate radicals.
1
the g-azido imine 8,[32] which was also observed in the H NMR
Results and Discussion
spectrum of the crude product. In practice, the commercially
available tBuOH was the best reaction media; d) Adding one
equivalent of acetic acid (HOAc) to the reaction mixture increased
Iron-catalyzed -azidation of O-acyl oximes: synthesis of -
g g
azido ketones. Nickel,[27] copper[8,9] and iron salts[28] are known
to reduce the O-acyl oximes to the iminyl radicals. Our major
concern at the outset of this research was that the translocation
of the iminyl to the carbon radicals is in general endergonic and
reversible[16] and that the iminyl radicals can undergo the second
SET with these metals or metal salts to afford the iminato-metal
species, diverting therefore the reaction sequence. Note that this
second SET process was not an issue with cyclobutanones
derived iminyl radicals due to the very rapid strain-releasing C-C
bond cleavage process.[29] Therefore, to accomplish the planned
domino transformations, following kinetic requirements of the
cascade process have to be satisfied: a) the azidation of the C-
centered radical must be kinetically faster than the reverse 1,5-
HAT; b) the 1,5-HAT of the iminyl radical has to be kinetically
competent relative to its reduction to the iminato-metal species.
Using 1,4-diphenylbutan-1-one oxime esters (2, Scheme 2a) as
test substrates and simple alkali azides or TMSN3 as reactants,
reaction conditions were initially screened varying the copper
salts, the ligands, the additives and the solvents. In the best cases,
a trace amount of the desired azido compound 3a was isolated
the yield of 3a and accelerated the reaction by speeding up most
[12a,14]
probably the 1,5-HAT process.
Overall, performing the
reaction of 2a with TMSN3 (3.0 equiv) in tBuOH (c 0.05 M) in the
presence of AcOH (1.0 equiv) and Fe(acac)3 (0.2 equiv) at 50 °C
afforded the azido ketone 3a in 89% isolated yield. The reaction
was also carried out on gram scale to afford 3a in a slightly
decreased yield (82%).
The scope of this azidation protocol was next examined
(Scheme 3). Aryl alkyl oxime esters were converted to the
corresponding g-azido ketones (3a-3f) in good to high yields
regardless of the electronic nature of the substituents on the
arenes. Notably, the azide 3f was isolated as the only regioisomer
although its starting material contained two g-benzylic positions.
The reaction was also insensitive to the electronic nature of the g-
aryl substituents (3g-3i). Heteroarenes including furan, thiophene
and indole, were well tolerated (3j, 3k and 3m). Importantly, the
tetralone 9 (Scheme 2b) resulting from the cyclization of the
translocated carbon radical to the tethered arene was not formed
suggesting the rapid azidation of the translocated carbon radical.
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However, when oxime ester of the naphthyl ketone was submitted
to the standard azidation conditions, the 4-azido ketone 3l was
isolated in only 30% yield together with the dihydrophenanthren-
1-one 9l (48%).[33] The reduced aromaticity of the naphthalene
might be responsible for the formation of 9l. The presence of alkyl
substituents on the aliphatic chain did not exert significant impact
on the reaction (3n-3p). Remarkably, 3p was isolated in 73% yield
although its iminyl radical intermediate was prone to undergo b-
scission reaction. The dialkyl oxime esters were similarly
converted to the corresponding azides 3q-3v in very good yields,
except for 3q due to its relatively low boiling point. Benzylic
C(sp3)-H was selectively functionalized in the presence of the
tertiary g-C(sp3)-H (3w vs 3w’), in accordance with the bond
dissociation energy (BDE) of these two types of C-H bond.[34]
Functional groups such as alkynyl, cyano, phthalimidoyl, ether
and ester were well tolerated (3x-3ab). In line with the polar effect,
the electrophilic iminyl radical abstracted preferentially the
electron-rich benzylic CH2 at the expense of the electron-deficient
a-CH2 of the ester leading to 3ab (88%) with excellent
regioselectivity.[35] Importantly, the d-azido ketone 10 involving
1,6-translocation of the iminyl radical was isolated in 30% yield
together with the unfunctionalized ketone (52% yield). To the best
of our knowledge, this represented the first example of d-
functionalization of an iminyl radical involving a 1,6-HAT process.
was the unfunctionalized ketone arising most probably from the
competitive reduction of the iminyl radical to imine followed by
hydrolysis. Treatment of 2ai [R1 = Ph(CH2)4, R2 = R3 = Me] under
standard conditions afforded 3ai in 51% yield together with 3ai’
resulting from 1,6-HAT in 9% yield. Azidation of (E)-1,6-
diphenylhex-5-en-1-one (2aj) afforded 3aj exclusively in 83%
yield. On the other hand, (E)-1-phenylhex-5-en-1-one (2ak) was
converted initially to the terminal azide 3ak’ which underwent
[3,3]-sigmatropic rearrangement[36] to afford a mixture of terminal
and internal allyl azides 3ak/E-3ak’/Z-3ak’ (ratio: 0.5:1:0.13) in
76% combined yields. While azido thioether 3al was prepared in
81% yield, 2am was converted to pyrroline 11 resulting
presumably from the rapid oxidation of the translocated carbon
radical to N-Boc iminium followed by cyclization.
NOCOR
O
R2
R3
H
conditions[a]
R2
N3
R3
R1
R1
2 R = p-CF3C6H4
3
O
O
O
O
NBoc
Ph
Me
Me
Me
N3
nBu
Ph
Ph
Ph
Ph
O
N3
N3
N3
3ac 40%
3ad 42%[b]
R1
3ae 79%
3af 41%
O
O
Me
Me
Me
Me
Ph
R
Ph
R2
N3
N3
NOCOR
O
conditions[a]
3ai R1 = H, R2 = N3, 51%
3ai’ R1 = N3, R2 = H, 9%
R2
3ag R = nBu, 58%
3ah R = nC6H13, 63%
R2
3aj 83%
R1
R1
Ph
H
N3
O
O
2 R = p-CF3C6H4
O
3
SPh
Ph
Ph
3al 81%[c]
N3
O
NBoc
O
Ph
O
N3
N3
Ph
3ak
3ak’
X
3ak/E-3ak’/Z-3ak’ 76%
Ph
3m 88%
R
N3
N3
N3
Ph
conditions[a]
OCOC6H4-pCF3
N
3j X = S, 73%[b]
3k X = O, 77%
O
3a R = H, 89%
Ph
NHBoc
11 93%
N
3b R = pMe, 78%
3c R = pOMe, 71%
3d R = pCF3, 81%
3e R = mCl, 69%
3f R = oMe, 55%
NHBoc
Ph
2am
H
Ph
O
N3
Scheme 4. g-Azidation at non-benzylic positions. [a] 2 (0.1 mmol), TMSN3 (0.3
mmol), Fe(acac)3 (0.02 mmol), AcOH (0.1 mmol), tBuOH (2 mL, c 0.05 M), 50 °C.
Isolated yields; [b] At 60 °C; [c] tBuOH/DCE = 4:1 (2.0 mL, c 0.05 M).
3l 30%[b]
9l 48%
O
R
O
O
Me
Ph
Ph
Ph
Ph
N3
Ph
N3
3g R = pMe, 84%[b]
3h R = pOMe, 88%
3i R = oBr, 76%
Me N3
3o 82%
3n 67%
O
Ph
Me
O
O
Me
Ph
conditions[a]
O
Ph
Ph
ROCON
(a)
(b)
R1
R2
Ph
Ph
N
3w R1 = H, R2 = N3, 73%
3w' R1 = N3, R2 = H, 18%
N3
Me Me
N3
3p 73%[c]
N
N
O
3x 65%
2an R = p-CF3C6H4
12 84%
O
Ph
O
Cl
Cl
Cl
Cl
conditions[a]
Me
Ph
Ph
N
N
R
N3
O
NOCOR
R
N3
CO2Me
N3
3y R = CN, 89%[b]
3z R = Phth, 77%
Me
3ab 88%
3q R = Me, 61%
3r R = iPr, 91%
3s R = nBu, 81%
3t R = tBu, 69%
3u R = Cy, 85%
3v R = Bn, 71%
N3
2ao R = p-CF3C6H4
3ao 61%
O
O
N3
Ph
Scheme 5. [a] 2 (0.1 mmol), TMSN3 (0.3 mmol), Fe(acac)3 (0.02 mmol), AcOH
(0.1 mmol), tBuOH (2 mL, c 0.05 M), 50 °C. Isolated yields.
Ph
Ph
OPh
3aa 94%
N3
10 30%
Scheme 3. g-Azidation at benzylic positions. [a] 2 (0.1 mmol), TMSN3 (0.3
mmol), Fe(acac)3 (0.02 mmol), AcOH (0.1 mmol), tBuOH (2.0 mL, c 0.05 M),
50 °C. Isolated yields; [b] tBuOH/DCE = 4:1 (2.0 mL, c 0.05 M); [c] At 80 °C.
To further illustrate the synthetic potential of this protocol, a
domino process integrating this g-azidation reaction was
developed. Simply heating a tBuOH solution of 2an and TMSN3
in the presence of Fe(acac)3 afforded the triazole fused
isoindoline 12 in 84% yield (Scheme 5a). Fused triazoles are
known to exhibit a broad range of important biological activities.[37]
Finally, the method was applied to the chlorambucil derived oxime
2ao to afford the azido derivative 3ao in good yield in spite of the
presence of sensitive chloroamine function (Scheme 5b).
Azidation of non-benzylic C(sp3)-H was next investigated.
As shown in Scheme 4, the tertiary C(sp3)-H bond underwent
azidation smoothly to afford the g-azido ketones in moderate to
good yields (3ac-3ah). The major side product in these reactions
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Control experiments were carried out to gain insights on the
reaction mechanism. Reaction of 2a with TMSN3 in the presence
of TEMPO (3.0 equiv) afforded the adduct 13 in 64% yield at the
expense of the azide 3a (Scheme 6a). The radical clock
experiment with 2ap yielded the homoallylic azide 3ap in 69%
yield (Scheme 6b). Both experimental results supported the
involvement of a C-centered radical in our azidation reaction.
Finally, heating a tBuOH solution of 2a in the presence of
Fe(acac)3 (0.2 equiv) and AcOH (1.0 equiv) at 50 °C for 3 days
led only to the recovered starting material. Therefore, we inferred
that the azide played a dual role in this transformation. It served
not only as a nitrogen source but also as a reductant to generate
in situ the catalytically active Fe(II) species. In our initial conditions
screening, we noted that Fe(acac)2 was a much less efficient
catalyst. We assumed that the slow generation of Fe(acac)2 was
important since this could keep the concentration of the iminyl
radical low enough to avoid the dimerization as well as to render
the second SET process between iminyl radical and Fe(II) non-
competitive.
azido transfer, would afford the azido iminium 14 with the
concurrent regeneration of the Fe(II) catalyst. Hydrolysis of 14
furnished then the g-azido ketone 3 and ammonium acetate. The
in situ occurrence of this last seemingly trivial step was important
in ensuring the high yield of 3 as 14 dimerized readily. (cf Scheme
2). We assumed therefore that the acetic acid had also a dual role.
It accelerated not only the 1,5-HAT process, but also the
hydrolysis of imines to ketones.
Iron-catalyzed
g
-azidation of N-acyloxy imidates followed by
-azido alcohols. The hydroxyl group
hydrolysis: synthesis of
b
is one of the most prominent functional groups in organic
chemistry and is frequently found in bioactive natural products
and pharmaceuticals. Many simple aliphatic alcohols are also
available in bulk. Consequently, the catalytic site-selective C(sp3)-
H functionalization of alcohols is a highly valued tool for the
synthesis of building blocks and for streamlining the late stage
functionalization of complex molecules.[38] The d C(sp3)-H
functionalization of alcohols involving the 1,5-HAT of alkoxy
radicals, as represented by the Barton reaction,[39] is of historical
importance in steroid field and there is a recent resurgence on this
topic.[23c, 40]. To a lesser extent, the development of transition
metal catalyzed g-[41] and b-[21,42] functionalization methodologies
has also attracted attention of synthetic chemists. The general
approach consisted of transforming the hydroxyl group to an
elongated reactive group and functionalization occurred then
intramolecularly to afford the cyclic intermediates that could be
hydrolyzed/oxidized to 1,3- or 1,2-amino alcohols/diols. In this
sense, the Pd(II)-catalyzed acetoxylation and sulfonyloxylation of
O-alkyl oximes developed by Dong[42b,c] is unique as the in situ
formed C(sp3)-Pd species reacted intermolecularly with an
external nucleophile to afford, after removal of the directing group,
selectively protected 1,2-diols.
O
conditions[a]
Ph
N
NOCOR
(a)
(b)
Ph
O
Ph
O
TEMPO (3.0 equiv)
Ph
2a R = p-CF3C6H4
13 64%
NOCOR
N3
conditions[a]
Ph
Ph
Ph
Ph
2ap R = p-CF3C6H4
3ap 69%
Scheme 6. Control experiments. [a] 2 (0.1 mmol), TMSN3 (0.3 mmol), Fe(acac)3
(0.02 mmol), AcOH (0.1 mmol), tBuOH (2 mL, c 0.05 M), 50 °C. Isolated yields
TEMPO = 2,2,6,6-tetramethyl-1-piperidinyloxy.
O
NH
Ph
Ph
O
R1
R1
O
O
Fe(III)
R2
R3
NH4OAc
H2O
Fe(acac)3, (0.05 equiv)
TMSN3 (1.5 equiv)
N3
Ph
NOCOR
O
N3
R1
15
16
TMSN3
+
3
Ph
R1
N3
AcO
LG
N3
EtOAc (c 0.05 M), 70 °C
N
OH
OTMS
Ph
NH2
R2
Fe(II)
4a R1 = Ph, R = 4-CF3C6H4
4a' R1 = Me, R = 4-CF3C6H4
Ph
Ph
R2
R3
N
R1
R1
R3
O
2
R1
N3
5a
N3
17
14
N3
18
Fe(III)N3
N
OH
Fe(III)
NaOH (2.0 M), MeOH
0 °C to RT
R2
AcO NH2
R1
Ph
N
R1
+
R2
R3
O
C
N3
5a
R1
TMSN3
E
R3
18
AcOH
From 4a
From 4a’
77%
84%
5%
0%
AcO
H
N
R2
R1
Scheme 8. Optimized reaction conditions for the conversion of N-acyloxy
imidates to b-azido alcohols.
R3
D
Scheme 7. Possible reaction pathway. Ligand was omitted for the sake of clarity.
On the basis of the aforementioned g-azidation of O-acyl
oximes, we thought to develop an iron-catalyzed g-azidation of N-
acyloxy imidates 4. Should the reaction follow the same
mechanistic pathway postulated in Scheme 7, the reaction would
then furnish the imidate 15 or ester 16 which, upon hydrolysis,
would afford the b-azido alcohol 5 (Scheme 8). Since imidates 4
are derived from alcohols, the overall sequence represented a b-
azidation of alcohols. This would complement the method
On the basis of aforementioned results,
a plausible
mechanism is postulated (Scheme 7). Reduction of Fe(acac)3 by
TMSN3 would afford the active Fe(II) catalyst which underwent
single electron transfer (SET) with the oxime ester 2 to afford the
iminyl radical C. Protonation of the latter by acetic acid led to more
electrophilic radical cation D. 1,5-HAT would provide the
translocated carbon radical E which, upon iron-mediated redox
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developed by Nagib[21] and Chen[22] as our transformation will be
realized under reductive rather than oxidative conditions.
5g’). Tertiary C(sp3)-H could also be azidated, albeit with reduced
yields (5h-5j).
Applying the conditions developed for the azidation of O-
acyloximes 3 to N-acyloxy imidate 4a (R1 = Ph) afforded a
complex reaction mixture. However, performing the reaction in the
absence of AcOH under otherwise identical conditions provided a
reaction mixture comprising of the azido imidate 15, azido ester
16, azido alcohol 5a and its TMS-protected derivative 17 as well
as oxazoline 18. After saponification of the crude reaction mixture
(MeOH, aq NaOH, RT), compound 5a was isolated in moderate
yield. The reaction was therefore further optimized varying the
catalysts, the solvents, the azide sources and the temperature
(see Supporting Information). The optimized conditions consisted
of performing the azidation of 4a in EtOAc in the presence of
Fe(acac)3 (0.05 equiv), TMSN3 (1.5 equiv) at 70 °C to afford a
mixture of 5a, 15, 16, 17 and a small amount of 18. Stirring a
solution of the above crude reaction mixture in MeOH and aq
NaOH solution (2.0 N) at room temperature afforded then 5a in
77% isolated yield. It is interesting to note that the yield of 5a
decreased when the reaction was performed with higher loading
of Fe(acac)3 under otherwise identical conditions.
A possible reaction pathway leading to the formation of 5f
and 5f’ is depicted in Scheme 10. A SET reduction of the N-O
bond in 4f would afford imidate radical F which, upon 1,5-HAT,
would produce the C-centered radical G. Redox azido transfer
from the in situ generated Fe(III)N3 to the translocated carbon
radical would afford 15f with concurrent regeneration of the active
Fe(II) catalyst. Hydrolysis of 15f afforded then the b-azido alcohol
5f. On the other hand, intramolecular nucleophilic displacement
of imidate function by the electron-rich aromatic ring would lead
to phenonium intermediate H which, upon ring opening of the
cyclopropane unit by azide, would furnish the vicinal diazide 5f’.
OMe
OMe
1,5-HAT
NOCOR
N
Me
Me
O
Fe(II) Me
Fe(III)N3
O
4f
F
OMe
OMe
NH
NH
Me
O
O
N3
15f
G
We also examined the impact of the R1 group on the overall
efficiency of the transformation. It was found that N-acyloxy
acetimidate 4a’ (R1 = Me) gave the azido alcohol 5a (84%) in a
slightly higher yield than that from the benzimidate 4a (R1 = Ph).
Since both 4a and 4a’ are perfectly stable, these results, opposite
to the trend observed by Nagib, might reflect the different
reactivity of the two imidate radicals.
OMe
OMe
TMSN3
OMe
HO
N3
N3
N3
N3
5f’
5f
H
Scheme 10. Postulated mechanism for the formation of b-azido alcohol 5f and
vicinal diazide 5f’.
1) Fe(acac)3 (0.05 equiv)
TMSN3 (1.5 equiv)
EtOAc (c 0.05 M), 70 °C
NOCOR
N3
R3
H
R2
R2
Conclusion
HO
Me
O
R3
2) NaOH (2.0 M), MeOH
0 °C to RT
4
5
In summary, we developed two novel protocols for the
synthesis of g-azido ketones and b-azido alcohols via O-acyl
oximes and N-acyloxy imidates, respectively. The reaction
proceeded via reductive cleavage of the N-O bond of the
substrates followed by 1,5-HAT of the resulting iminyl or imidate
radical and finally, iron-mediated redox azido transfer to the
translocated carbon radicals. We demonstrated that the 1,5-HAT
process, as the 5-exo-trig cyclization,[43] can compete with the
second SET between iminyl radical and metal salts, rendering the
remote C(sp3)-H functionalization possible under reductive
conditions.
F
HO
HO
Me
HO
HO
N3
N3
5c 64%
N3
5a 84%
5b 69%
OMe
N3
HO
X
N3 Cl
N3
5f X = OH, 34%
5f’ X = N3, 30%
5d 58%
5e 50%[a]
OMe
N3
Experimental Section
HO
N3
HO
X
X
N3
For details of the synthetic procedures, physical and
spectroscopic data, copies of 1H, 13C NMR spectra of compounds,
see the Supporting Information.
5g X = OH, 30%
5g’ X = N3, 24%
5i X = CH2, 45%
5j X = O, 37%
5h 46%
General procedure for the synthesis of -azido ketones 3.
g
Scheme 9. The scope of b-azidation of alcohols via N-acyloxy imidates.
A solution of the oxime ester (2, 0.1 mmol, 1 equiv) and
Fe(acac)3 (0.02 mmol) in tBuOH (0.05 M) was deoxygenated by
freeze-pump-thaw cycle. AcOH (0.1 mmol) and TMSN3 (0.3
mmol) were added consecutively via syringe. The reaction
mixture was stirred at 50 °C until the complete consumption of
starting materials (monitored by TLC). The reaction mixture was
filtered through a short pad of silica gel and rinsed with EtOAc.
The combined filtrate was washed with a saturated aqueous
The scope of this transformation was next examined
(Scheme 9). The presence of halo substituents (F, Cl) and a weak
electron donor group (Me) was tolerated in the phenyl ring of
phenylethanol derivatives. However, the presence of strong
electron donating group diverted the reaction pathway leading to
the formation of b-azido alcohols (5f, 5g) and 1,2-diazides (5f’,
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10.1002/chem.201901079
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[7]
[8]
[9]
Evidence for the concurrent occurrence of radical pathway under certain
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NaHCO3 solution, dried over Na2SO4 and evaporated to dryness
under reduced pressure. The residue was purified by flash column
chromatography on silica gel (eluent: petroleum ether/EtOAc) to
provide the corresponding g-azido ketones 3.
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To a solution of N-acyloxy imidate (4, 0.15 mmol) and
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with EtOAc/H2O and the methanol was removed under reduced
pressure. The aqueous layer was extracted with EtOAc. The
combined organic layers were washed with brine, dried over
Na2SO4, filtered and concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica gel
(eluent: petroleum ether/EtOAc) to provide the corresponding β-
azido alcohol 5.
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Acknowledgements
We thank Ms Léa Philippe for having participated in this project
during her intern. Financial supports from EPFL (Switzerland) and
Swiss National Science Foundation (SNSF, N° 200021-178846/1)
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
Synthetic Methods
1) Fe(acac)3 (0.05 equiv)
OCOR
Fe(acac)3 (0.2 equiv)
TMSN3 (3.0 equiv)
TMSN3 (1.5 equiv)
EtOAc (c 0.05 M), 70 °C
O
N3
N
N3
Rubén O. Torres-Ochoa, Alexandre
Leclair, Qian Wang and Jieping
Zhu*__________ Page – Page
R2
H
R2
R2
R1
HO
R1
X
R3
HOAc (1.0 equiv)
tBuOH (c 0.05 M), 50 °C
R3
2) NaOH (2.0 M), MeOH
0 °C to RT
R3
X = O
X = CH2
Iron-Catalyzed Remote C(sp3)-H
Azidation of O-Acyl Oximes and N-
Acyloxy Imidates Enabled by 1,5-
Hydrogen Atom Transfer of Iminyl and
Dual roles of two reagents Fe acted as reductant and redox azido transfer reagent, while
azide served not only as a nitrogen source to functionalize the unactivated C(sp3)-H bond, but
also as a reductant to generate the catalytically active Fe(II) species.
Imidate Radicals: Synthesis of
Ketones and -Azido Alcohols
g
-Azido
b
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