A New Dioxazolone for the Synthesis of 1,2-Aminoalcohols via Iridium(III)-Catalyzed C(sp3)?H Amidation

Article abstract of DOI:10.1002/anie.202110019

Vicinal aminoalcohols are widespread structural motifs in bioactive molecules. We report the development of a new dioxazolone reagent containing a p-nitrophenyldifluoromethyl group, which 1. displays a good safety profile; 2. shows a remarkably high react

Full text of DOI:10.1002/anie.202110019

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Accepted Article
Title: A New Dioxazolone for the Synthesis of 1,2-Aminoalcohols via
Iridium(III)-Catalyzed C(sp3)–H Amidation
Authors: Kevin Antien, Andrea Geraci, Michael Parmentier, and Olivier
Baudoin
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10.1002/anie.202110019
Angewandte Chemie International Edition
RESEARCH ARTICLE
A New Dioxazolone for the Synthesis of 1,2-Aminoalcohols via
Iridium(III)-Catalyzed C(sp3)–H Amidation
Kevin Antien, Andrea Geraci, Michael Parmentier, and Olivier Baudoin*
[*]
Dr. K. Antien, A. Geraci, Prof. Dr. O. Baudoin
University of Basel, Department of Chemistry
St. Johanns-Ring 19, 4056 Basel (Switzerland)
E-mail: olivier.baudoin@unibas.ch
Dr. M. Parmentier
Novartis Pharma AG, Chemical & Analytical Development
4056 Basel (Switzerland)
Supporting information for this article is given via a link at the end of the document.
Abstract: Vicinal aminoalcohols are widespread structural motifs in
bioactive molecules. We report the development of a new dioxazolone
reagent containing a p-nitrophenyldifluoromethyl group, which 1.
displays a good safety profile; 2. shows a remarkably high reactivity
in the oxime-directed iridium(III)-catalyzed amidation of unactivated
C(sp3)–H bonds; 3. leads to amide products which can be hydrolyzed
under mild conditions. The amidation reaction is mild, general and
compatible with both primary C–H bonds of tertiary and secondary
alcohols, as well as secondary C–H bonds of cyclic secondary
alcohols. This method provides an easy access to free 1,2-
aminoalcohols after efficient and mild cleavage of the oxime directing
group and activated amide.
Over the past decade, the construction of the C–N bond
through metal-catalyzed C–H functionalization has emerged as a
powerful new synthetic tool, allowing chemists to devise shorter
retrosynthetic routes.[2] In this respect, the directed β-C(sp3)–H
amidation of alcohols can be regarded as a highly attractive and
straightforward approach towards vicinal aminoalcohol
derivatives. This can be achieved with the assistance of a suitable
directing group appended to the alcohol, with oximes having
proven to be optimal via the so-called “exo” directing mode
(Scheme 1a).[3-5] Mechanistically, the coordination of the oxime
nitrogen atom to the metal center is followed by a concerted
metallation-deprotonation (CMD) process, affording
a five-
membered metallacycle.[2f,g,6] The subsequent amido-transfer
step is believed to proceed via an inner-sphere mechanism
involving a high-valent metal-nitrenoid intermediate. Several
classes of reagents are known to affect such a transformation,
including azides, iminoiodanes (RN=IAr), and 1,4,2-dioxazol-5-
ones.[4,5]
Introduction
The 1,2-aminoalcohol motif is a recurrent feature found
across a large panel of natural products, agrochemicals and
active pharmaceutical ingredients (Figure 1). The traditional
elaboration of this motif calls upon aminohydroxylation of olefins,
epoxide/aziridine ring-opening with a suitable nucleophile, or
multistep synthetic sequences often involving carbonyl/imine
reduction steps.[1]
Figure 1. Examples of active pharmaceutical ingredients displaying the 1,2-
Scheme 1. Literature precedents on oxime-directed C(sp3)–H (sulfon)amidation
aminoalcohol motif.
and current work.
1
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RESEARCH ARTICLE
In particular, iridium(III)-based catalytic systems have been
optimization, it was found that the desired transformation could
easily be achieved using a Cp*-rhodium(III) catalyst (see the
supporting information, Table S1). Tertiary alcohol-derived
substrate 1a, bearing an adamantanone-based oxime directing
group, could be transformed into the corresponding amide 3 with
up to 80% yield. However, the unstable iminoiodane species
undergoes rapid degradation at higher temperatures (>50 °C),
rendering this approach inapplicable to less reactive secondary
alcohol-derived substrates such as 2a.
Our attention was then naturally drawn to the highly robust
and stable dioxazolone reagent class.[2g] Their facile preparation
from carboxylic acids and their uniquely high reactivity towards
the amido-transfer process in metal-catalyzed transformations
made them immensely appealing. However, the stability and
applicability of these reagents is intrinsically linked to the nature
of the only possible substituent in the 1,4,2-dioxazol-5-one
scaffold. 3-Alkyl and 3-aryl groups give rise to highly stable
dioxazolones, widely employed in the literature, but for which
cleavage of the resulting amide tends to be severely problematic.
On the other hand, highly electron-deficient substituents (e. g.,
CF3) result in notoriously unstable and explosive compounds,[7a]
although milder cleavage of the N-acyl bond in the product can
then be foreseen. On that account, we decided to explore
potential alternatives to trifluoromethyldioxazolone 5, with the aim
of retaining the benefits of its electron-withdrawing character,
combined
with
sulfonylazides,[4a]
acylazides,[5b]
and
azidoformates,[5d,e] to affect primary C–H bonds and furnish the
corresponding (sulfon)amide or carbamate products. These
reagents allow for a facile generation of the iridium-nitrenoid
intermediate complex, with nitrogen gas being the sole byproduct
of the reaction. However, they are prone to explosive
decomposition, and their hydrolysis leads to the release of
toxic/volatile/explosive hydrazoic acid, making them highly
hazardous for large-scale operations. Additionally, rhodium(III)
complexes have successfully been employed in combination with
sulfonyl-iminoiodanes[4b,e] and aryl-or alkyldioxazolones,[4d,5c] also
affecting primary C–H bonds, and giving rise to the corresponding
sulfonamides and aryl- or alkylamides. However, in these cases,
the cleavage of the (sulfon)amide to generate the free amine is
problematic, and requires reaction conditions that are either harsh
or inapplicable on larger scale. Ideally, this issue might be
circumvented by relying on reagents capable of transferring highly
labile perfluoroalkylamide groups. Unfortunately, known reagents
of this type are extremely sensitive to hydrolysis and undergo
explosive decomposition.[7] In recent years, dioxazolones have
emerged as versatile, highly robust and easily accessible nitrogen
sources in combination with transition-metal catalysts.[2g]
Methodologies for the functionalization of unactivated C(sp3)–H
bonds using these reagents have so far quasi-solely relied on
cobalt(III)[8] and rhodium(III)[4d,5c,9] catalytic systems. Very recently, while improving the stability of the reagent (Scheme 3a). Our
Baik, Chang and co-workers reported two low-yielding examples
under nickel(II)-catalysis.[10] To the best of our knowledge, only a
single example (from 8-methylquinoline) employing an iridium(III)-
catalyst has been reported thus far.[11]
investigations led us to design the new dioxazolone reagent 6,
incorporating a p-nitrophenyldifluoromethyl group, which we
named K-diox.
Herein, we report an efficient and scalable iridium(III)-
catalyzed directed amidation method affecting both unactivated
primary and secondary C(sp3)–H bonds for the synthesis of 1,2-
aminoalcohol derivatives (Scheme 1b). Our approach relies on
the use of a novel and bench-stable 3-fluoroalkyl-1,4,2-dioxazol-
5-one, which provides a high reactivity and furnishes amide
products that are cleavable under very mild hydrolytic conditions.
Results and Discussion
Scheme 3. Development and synthesis of a new dioxazolone reagent: K-diox.
The synthesized compound is an off-white crystalline solid,
remarkably stable to moisture and air, which can be stored for
more than 1 year in the freezer (–18 °C) without any degradation.
Differential Scanning Calorimetry (DSC) displays a strong
exothermic event with an initiation temperature of 164°C and an
enthalpy of decomposition of – 726 J.g–1 (– 187 kJ.mol–1) (see the
supporting information for details). Comparatively, the simpler
and widely used 3-phenyl-1,4,2-dioxazol-5-one exhibits a lower
Scheme 2. Preliminary results.
During our preliminary investigations, we first considered the
possibility
to
employ
known
trifluoroacetyliminoiodane
(F3CCON=IAr) reagents to obtain easily-cleavable amide
products. Given the reported explosiveness of such reagents,[7b]
by its very nature incompatible with our safety requirements, in
situ generation appeared mandatory. This was done by simply
combining stoichiometric amounts of (diacetoxyiodo)benzene and
trifluoroacetamide in the reaction mixture (Scheme 2). After
onset
at
142 °C
while
a
similar
decomposition
energy of – 171 kJ.mol–1 is recorded. By contrast, 2,2,2-
trichloroethoxycarbonyl azide (TrocN3) displays a much stronger
exothermal process (– 248 kJ.mol–1) initiating at a far lower
temperature of 95 °C. The straightforward preparation of K-diox
2
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10.1002/anie.202110019
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starts with the copper-mediated difluoroacetylation of 4-
iodonitrobenzene 7, followed by conversion of the resulting ethyl
ester into the corresponding hydroxamic acid, which is finally
reacted with CDI (CDI = carbonyldiimidazole) to construct the
dioxazolone ring (Scheme 3b). It was found that adding one
equivalent of PPTS (PPTS = pyridinium p-toluenesulfonate) to the
reaction mixture was of crucial importance to the reproducibility
and scalability of the process. Indeed, in the absence of PPTS,
the highly electron-deficient hydroxamic acid tends to precipitate
as the corresponding imidazolium salt, preventing any further
reaction. Overall, K-diox 6 could easily be obtained on decagram
scale with a highly-reproducible 63% yield over a 3-step sequence
requiring no purification by column chromatography.
adjusted by using potassium or cesium acetate, hence effectively
reducing the amount of diamidated product 9a while retaining a
full conversion of 1a (entries 3, 4). Satisfyingly, employing cesium
pivalate almost completely suppressed the formation of 9a, while
the desired product was isolated in an excellent 95% yield (entry
5). From that point on, halving the catalyst loading proved
detrimental to the conversion, as 70% of the starting material was
then recovered (entry 6). To our delight, a high reactivity was
regained when switching the additive to acetic acid, with full
conversion of the starting material at 2.5 mol% of iridium dimer
(entry 7). 1,2-Aminoalcohol derivative 8a could then be isolated in
83% yield using only 1.1 equiv of K-diox, while the reaction also
furnished 13% of the over-amidated product. Our optimization
study revealed that pivalic acid, when used in place of acetic acid,
was enhancing even further the reactivity of the system, resulting
in a large propensity towards diamidation (Table S2).
Table 1. Optimization of the Ir(III)-catalyzed C(sp3)-H amidation on tertiary
alcohols.
Table 2. Optimization of the IrIII-catalyzed C(sp3)-H amidation on tertiary
alcohols: alternative nitrogen sources and directing groups.
Entry
n (mol%) Additive
K-diox
equiv.
%Yield[a]
1a
8a
9a
1[b]
2
5
AgOAc
NaOAc
KOAc
1.2
1.2
1.2
1.2
1.2
1.1
1.1
13 (10)
n.d.
71 (66) 16 (15)
5
84
82
79
14
8
3
5
n.d.
4
5
CsOAc
CsOPiv
CsOPiv
AcOH
n.d.
10
5
5
n.d. (1.6) 92 (95) 4 (3)
6
2.5
2.5
70
30
n.d.
Entry 1 (R1)
10 (R2)
%Yield[a]
7
n.d.
85 (83) 15 (13)
1
8
9
[a] 1H NMR yields using CH2Br2 as the internal standard, yield of the isolated
product in parentheses. [b] Reaction time: 72 h. n.d. = not determined.
Reactions were run on 0.2 mmol scale with a catalyst loading of 5 mol%, or on
0.4 mmol scale with a catalyst loading of 2.5 mol% (a constant concentration of
0.25 M was employed).
1
2
3
4
5
6
7
8
9
1a (Ad)
1a (Ad)
1a (Ad)
1a (Ad)
1a (Ad)
1b (Cyo)
1c (Cy)
1d (Cyp)
1e (Cyb)
K-diox
10a
0 (1a)
26 (1a)
76 (1a)
4 (1a)
10 (1a)
– (1b)
– (1c)
– (1d)
– (1e)
83 (8a)
13 (9a)
0 (9aa)
0 (9ab)
0 (9ac)
0 (9ad)
7 (9b)
59[b] (8aa)
14 (8ab)
95 (8ac)
58 (8ad)
87 (8b)
92 (8c)
10b
With this new reagent in hand, we went back to exploring the
catalytic C(sp3)–H amidation of compound 1a. We hypothesized
that an IrIII-based catalytic system could potentially outperform its
RhIII equivalent under the appropriate reaction conditions. Indeed,
recently published DFT calculations highlighted the fact that IrIII
might accelerate the often rate-determining CMD step through a
metal-assisted proton transfer.[6b] Additionally, a drastically lower
kinetic barrier for the metal-nitrenoid formation step was shown
by DFT calculations to originate from the stronger relativistic
contraction of iridium.[6a] Delightfully, when K-diox was used in
combination with [IrCp*Cl2]2, AgSbF6 and AgOAc at 35 °C in
dichloromethane, not only could the desired product 8a be
isolated in 66% yield, but the reaction also furnished diamide 9a
in 15% yield (Table 1, entry 1). Replacing the silver carboxylate
additive with sodium acetate led to the full conversion of the
starting material within 24 h (entry 2). The reactivity could be
10c
TrocN3
K-diox
K-diox
K-diox
K-diox
6 (9c)
79 (8d)
74 (8e)
10 (9d)
12 (9e)
[a] Yields of the isolated products. [b] Combined yield of C(sp3)–H
monoamidation and C(sp2)–H polyamidation products. Reactions were run on
0.4 mmol scale at a concentration of 0.25 M. Troc = C(O)OCH2CCl3.
At this stage, we wished to compare the reactivity of
dioxazolone 6 with other amidation reagents under our reaction
conditions (Table 2). 3-Phenyldioxazolone 10a, undoubtedly the
3
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RESEARCH ARTICLE
most commonly employed dioxazolone in the literature, only
furnished a 59% mono-C(sp3)–H amidation yield (entry 2).
Moreover, amide 8aa was isolated as a mixture of products
originating from ortho-C(sp2)–H amidation on the phenyl ring. This
issue was however predictable, as dioxazolone 10a exhibited a
similar behavior under rhodium(III)-catalyzed conditions in the
recent work of Xu and co-workers.[4d] The authors showed that its
2-furyl analogue 10b displayed superior reactivity while
suppressing the formation of the undesired byproducts. However,
under our reaction conditions 10b only furnished a low 14% yield
of product 8ab (entry 3). The pivaloyl dioxazolone 10c performed
noticeably better, as the monoamidation product 8ac could be
isolated with an excellent 95% yield while no diamidation was
observed (entry 4). Azidoformate TrocN3, which has proven highly
competent in several metal-catalyzed C–H amidation
processes,[5e,12] only furnished a moderate 58% yield of the
corresponding product 8ad (entry 5). Overall, K-diox displayed a
remarkably superior reactivity in comparison to the other tested
nitrene sources (entry 1). Nonetheless, we deemed necessary to
tame this reactivity and minimize the formation of the diamidated
product 9a. We surmised that changing the nature of the oxime
directing group, and in particular providing the substrate with a
higher conformational flexibility, could potentially allow us to
achieve this goal. Satisfyingly, the cyclooctanone-derived oxime
1b performed as intended, and diamide 9b was isolated in only
7% yield (entry 6). The yield of monoamidation product (8c) could
C(sp2)–H activation on benzylic alcohol scaffolds. Indeed, in the
case of compounds 19, the undesired γ-(Csp2)–H product 19γ
was formed in 8% yield while the reaction only furnished 28% of
the expected product 19β. Additionally, 49% the starting material
could be recovered. To circumvent this problem, we surmised that,
in analogy to what was observed for rhodium,[4d] reverting to an
adamantanone-based oxime directing group might suppress the
formation of the 6-membered iridacycle leading to the undesired
product. Gratifyingly, the intended transformation could be
achieved with excellent regioselectivity when opting for this
bulkier oxime, and 20a was isolated in 76% yield. Similarly,
employing an adamantanone-derived oxime proved mandatory
for the α-terpineol scaffold to avoid the competing allylic
amidation.[13] In this way, the required transformation took place
nearly quantitatively (21).
be further increased to 92% when exchanging for
a
cyclohexanone-derived oxime (entry 7). On the other hand,
smaller cyclopentanone and cyclobutanone-derived oximes
displayed product ratios shifting towards the formation of 9, while
overall yields dropped below 90% (entries 8, 9). In light of these
results, the cyclohexanone-based oxime appeared as the
optimum directing group for this transformation.
We then set out to investigate the scope of the reaction on
tertiary alcohol-derived substrates under these mild optimized
conditions (Scheme 4). Unsurprisingly, aliphatic alcohol-based
substrates performed very well, with a slightly larger propensity
towards diamidation (11a-b, 12a-b). Nevertheless, the
corresponding diamidated products could be separated off. When
a single methyl position was available for functionalization and
steric bulk was minimal such as in 1-methylcyclohexan-1-ol, the
reaction proceeded quantitively in a matter of minutes to deliver
compound 13. Pleasingly, in the presence of a competing benzylic
site such as in the case of 14a-b, the reaction occurred
exclusively at the primary position(s).The reaction tolerated the
presence of an α-trifluoromethyl group, although harsher
conditions (pivalic acid, DCE, 60 °C) were required to reach a
good yield (72%) of amide 15. Presumably, the coordination
strength of the oxime directing group is weakened by the
presence of this strongly electron-withdrawing group, although
the acidity of the β protons is simultaneously enhanced. Similarly,
the presence of an ethyl ester at the a-position to the oxime-
decorated alcohol proved to be slightly detrimental to the reaction
kinetics. Longer reactions times (72 h) were required to reach full
conversion of the starting material (16a-b). Steric congestion was
sometimes observed to be challenging, as per the example of (+)-
sclareolide derivative 17, for which enhanced conditions furnished
a moderate 53% yield of the amide product. Comparatively, the
less hindered (+)-cedrol aminoalcohol derivative 18 could be
obtained in a very satisfying 82% yield under standard reaction
conditions. The system exhibited a tendency towards competing
Scheme 4. Reaction scope for tertiary alcohols. [a] Reaction time: 5 min. [b]
PivOH (15 mol%), DCE, 60 °C, 14 h. [c] Reaction time: 72 h. [d] d.r. 1:1.
Reactions were run on a 0.4 mmol scale at a concentration of 0.25 M.
We then turned our attention to the functionalization of
secondary alcohols, for which our original methodology had
shown to be completely ineffective (see Scheme 2). After a quick
reoptimization
(Table
S4),
the
adamantanone-
and
cyclohexanone-derived oximes 22a-b were obtained in excellent
yields (96-97%) using K-diox (1.4 equiv) and a catalytic system
composed of [IrCp*Cl2]2 (2.5 mol%), AgSbF6 (10 mol%) and
pivalic acid (15 mol%) in DCE at 60 °C (Scheme 5). With these
4
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optimal conditions in hand, we started to explore the scope of the
reaction. As previously observed, the reaction went smoothly for
purely aliphatic compounds such as in the case of 23, which was
isolated in 94% yield. At this temperature of 60 °C, we expected
to observe appreciable competition between the desired terminal
C(sp3)–H bonds and more activated benzylic positions. Pleasingly,
no such effect was observed, and homobenzylic alcohol-derived
substrates all exhibited perfect regiocontrol for primary C–H
bonds, with the electronics of the aryl ring having no influence in
the process (o-Br, o-Cl, p-OMe, m-CF3, p-F). Compounds 24a-f
were all obtained in nearly quantitative yields. When the aryl
group was replaced with a furan ring, the reaction furnished
product 25 in a more moderate yield (47%). By contrast, when a
thiophene ring was instead introduced, no side-reaction was
observed, and amide 26 was produced in excellent yield (93%).
Interestingly, the presence of an ester group at the b-position to
the alcohol was inconsequential to the reaction, which proceeded
with 88% yield and full regioselectivity at the primary C–H bond
(27). However, when the ester moiety was installed directly a- to
the directing group, the transformation occurred at a slower pace
and full conversion was only observed after 72 h (28). The same
observation had previously been made for the tertiary alcohol-
based analogue 16 (Scheme 4). The presence of a sensitive a-
cyclopropane moiety was tolerated, although milder conditions
and longer reaction times (40 °C, 96 h) were required to afford
aminoalcohol derivative 29 in a moderate 43% yield. Surprisingly,
the catalytic system was also compatible with the presence of a
carboxylic acid and a potentially coordinative valine-derived
amide, although a stronger activation via microwave-assisted
heating was required to generate the corresponding products in
30% (30) and 50% (31) yields. The iridium-catalyzed
transformation proved compatible with benzyl- and acetyl-
protected alcohols, affording the corresponding terminal amides
32 and 33 with very good yields. Additionally, trifluoroacetyl-
protected amines also proved suitable, as diamide 34 was formed
in very good yield (92%). The stronger reaction conditions were
also accompanied by a higher degree of competition with the
undesired γ-(Csp2)–H amidation in benzylic alcohol-derived
substrates. Indeed, in the case of compounds 35, the amide
moiety was largely introduced at the ortho position of the p-
trifluoromethyl-phenyl ring (35γ, 30%). Functionalization at the
expected aliphatic position accounted for a moderate 48% yield
(35β), while 15% of the starting material could be recovered. With
a more electron rich p-tolyl ring, the transformation proceeded
with a lower global yield (36, 46%), a significant third of the
material being amidated at the g-position, while the substrate
could be recovered in 24% yield. Gratifyingly, trading the directing
group for an adamantanone-derived oxime in 37 resulted in a
significantly higher yield of the desired product 37β (64%), while
the side-reaction was completely shut down. The same directing-
group-swapping strategy also proved valuable in the presence of
an olefin moiety, thus limiting the competing allylic amidation
process, as per the example of 38 which was isolated in a
moderate 41% yield. At last, our methodology was successfully
applied to the functionalization of the pregnenolone scaffold,
providing an excellent yield (91%) of aminoalcohol derivative 39.
Scheme 5. Reaction scope for secondary alcohols. [a] Reaction time: 72 h. [b]
Temperature: 40 °C, reaction time: 96 h. [c] [IrCp*(MeCN)3](SbF6)2 (10 mol%),
PivOH (30 mol%), microwave, 100 °C, 1 h. [d] The starting material was
engaged as a mixture of anti/syn diastereoisomers (d.r. 75:25). Reactions were
run on a 0.4 mmol scale at a concentration of 0.25 M.
Bearing in mind that our K-diox reagent had been able to
withstand prolonged reaction times at temperatures as high as
80 °C, we contemplated the possibility to amidate less reactive
secondary C(sp3)–H bonds (Table 3). Encouragingly, under the
optimized conditions for secondary alcohols, cyclopentanol-
based substrate 40 was successfully converted to cis-
aminoalcohol derivative 41 with 12% yield (93% based on the
recovery of 40, Table S5). However, the [IrCp*Cl2]2 precatalyst
appeared too reactive and was leading to substantial degradation
of the substrate. Switching to the dicationic [IrCp*(MeCN)3](SbF6)2
complex proved largely beneficial in tempering the uncontrolled
5
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side-reactions. After 24 h in the presence of 10 mol% of the
dicationic complex at a temperature of 70 °C, the desired
compound 41 could be isolated in 32% yield (entry 1), and
inspection of the crude NMR spectra revealed that no degradation
had occurred.
derivative 43 was indeed isolated in moderate yield (50%). This
trend was confirmed with its 7-membered analogue, for which the
expected product was obtained in a lower yield of 25% as a single
diastereomer.
Table 3. Optimization of the amidation of secondary C(sp3)–H bonds
Entry
n (mol%) T (°C) Heating mode
t (h)
%Yields[a]
40
41
1
2
3
4
5
6
7
8
10
10
5
70
convection
convection
convection
convection
microwave
microwave
microwave
microwave
24
40
24
24
0.5
1
65 (56)
51
34 (32)
44
70
70
87
11
5
100
100
100
100
120
34
18
Scheme 6. Reaction scope for methylene bonds. Reactions were run on a 0.4
mmol scale at a concentration of 0.25 M.
10
10
10
10
62
38
34 (33)
20
61 (61)
64
Interestingly, 5-membered oxygen- and nitrogen-heterocycles
could also be amidated, albeit in lower yields of 31% (45) and 10%
(46), with very good cis-diastereoselectivity. These reactions
were accompanied by significant degradation, possibly originating
from functionalization of the more activated C–H bonds in α-
position to the endocyclic heteroatom, leading to unstable
(hemi)aminal products. Furthermore, their 6-membered
counterparts 47 and 48 were isolated in 44% and 29% yield,
respectively. Unexpectedly, those systems exhibited a noticeable
reversal in diasteroselectivity, as the trans products were
predominantly formed.
We then wished to gain some insight into the mechanism of
this transformation. A significant primary kinetic isotope effect
(kH/kD = 5.0) was observed by measuring the initial reaction rate
in the transformation of protiated and deuterated oximes 49/49-d3
(Figure 1). Given the high reactivity observed with these
substrates, the catalyst loading and temperature had to be
reduced to 1 mol% and 25 °C, respectively. This result clearly
implicates that the breaking of the C–H bond occurs in the rate-
determining step of the reaction. A mechanistic proposal based
on literature precedents is shown in the Supporting Information
(Scheme S1).[2g]
1.5
1
10
64
[a] 1H NMR yields using CH2Br2 as the internal standard, yield of the isolated
product in parentheses. [b] Isolated yields after column chromatography. [c]
Reaction time: 72 h. n.d. = not determined. Reactions were run on a 0.2 mmol
scale at a concentration of 0.25 M.
Prolonging the reaction time to 40 h allowed the conversion to
reach 44%, although up to 5% degradation was then observed
(entry 2). A lower catalyst loading of 5 mol% was subsequently
employed, but only 11% of amide 41 was formed under these
conditions (entry 3). As the precatalyst was leading to a fully
homogenous mixture at room temperature, we surmised that this
system would be suitable for microwave-assisted heating.
Gratifyingly, using 10 mol% of the precatalyst, the desired product
was then formed in 38% yield after only 30 min in the microwave
reactor at 100 °C (entry 5), which proved superior to conventional
heating (entry 4). Doubling the reaction time to 1 h led to the
isolation of 41 in 61% yield while the starting oxime was recovered
in 33% yield (entry 6). However, prolonging the reaction time or
increasing the temperature to 120 °C only led to degradation of
the starting material with no significant further conversion into the
product (entries 7, 8).
The scope of the methylene functionalization on cyclic
systems under our best amidation conditions was then explored
(Scheme 6). As expected, the more strained cyclobutanol scaffold
behaved better than the 5-membered model substrate, affording
compound 42 in 76% yield as a single cis diastereomer. On the
other hand, larger rings, which are less prone to angular strain
and for which the s-character and hence the acidity of the C–H
bonds are decreased, displayed lower reactivity towards the
desired transformation. The six-membered 1,2-aminoalcohol
6
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10.1002/anie.202110019
Angewandte Chemie International Edition
RESEARCH ARTICLE
available or quickly accessed substrates bearing a variety of
different directing groups, and possessing C(sp3)–H or C(sp2)–H
bonds, were tested under our established set of conditions for
secondary alcohols without any further optimization (Scheme 8).
Activation of the C–H bond endo to the oxime coordinating group
proceeded smoothly as demonstrated with 55, which was β-
amidated in 85% yield. By contrast, the benzylic C–H amidation
of 8-methylquinoline occurred less efficiently (56). Surprisingly,
not only was 1-acetylindoline readily functionalized on the
benzene ring (57a), but a significant third of the isolated material
accounted for overamidation at the meta position (57b). This
seemed to indicate that even though the resulting amide is highly
electron-deficient, it is still able to direct the functionalization of
the adjacent C(sp2)–H bonds.[15]
Figure 1. Initial reaction rate comparison for the protiated (49) and deuterated
(49-d3) substrates. Reactions were performed in parallel.
To assess the scalability of the transformation, a 10-fold
scale-up of the reaction was performed starting from (+)-cedrol-
and pregnenolone-derived substrates 51 and 53 (Scheme 7). In
both cases, the catalyst loadings could be decreased while
retaining excellent yields of the corresponding amides 18 (85%)
and 39 (93%). The hydrolysis of the amide groups proceeded
effortlessly in the presence of aqueous sodium hydroxide at room
temperature in ethanol, to furnish the corresponding free amines
in excellent yields (96-100%).[14] The oximes could then be swiftly
deprotected by simple treatment with sodium borohydride and
molecular iodine in refluxing THF, yielding after recrystallization
the pure 1,2-aminoalcohols 52 and 54 in overall yields exceeding
80% over 3 steps.
Scheme 8. Applicability of K-diox to the directed amidation of other systems.
A similar observation was made from N-(tert-butyl)benzamide,
which was transformed into the desired amide 58a with 79% yield,
while an inseparable mixture of ortho-ortho and ortho-meta
diamidated products 58b was isolated in 12% yield. Interestingly,
the same trend was not observed for 2,2-dimethylpropiophenone,
as only the monofunctionalized product 59 was formed in 70%
yield. In line with what was previously observed for compounds
19, 35 and 36, γ-oxime-directed amidation occurred smoothly on
the aromatic ring, delivering product 60 in 67% yield. Moreover,
using a more classical pyridine directing group was also effective,
as the targeted C(sp2)–H bond was affected in 65% yield (61).
Conclusion
We have established a robust, mild, efficient and scalable
methodology for the synthesis of 1,2-aminoalcohol derivatives
through an iridium(III)-catalyzed C(sp3)–H amidation process. Our
approach relies on the use of a new bench-stable and yet
Scheme 7. Tenfold scale-up of the reaction and subsequent deprotection.
electron-deficient
fluoroalkyldioxazolone,
which
proved
significantly superior to traditional alkyl/aryl-dioxazolones in both
reactivity and amide cleavability aspects. The synthetic utility and
applicability of this method was demonstrated over a broad range
Finally, the applicability of our new amidation reagent to other
systems was investigated. To this end, a number of commercially
7
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10.1002/anie.202110019
Angewandte Chemie International Edition
RESEARCH ARTICLE
[10] Y. B. Kim, J. Won, J. Lee, J. Kim, B. Zhou, J.-W. Park, M.-H. Baik, S.
Chang, ACS Catal. 2021, 11, 3067–3072.
of substrates, including terpene and steroid derivatives. We
anticipate that this reaction will be broadly applicable to introduce
the amino group in a medicinal chemistry context.
[11] Y. Hwang, Y. Park, S. Chang, Chem. Eur. J. 2017, 23, 11147–11152.
[12] (a) M. Lee, H. Jung, D. Kim, J.-W. Park, S. Chang, J. Am. Chem. Soc.
2020, 142, 11999–12004. (b) X. Dong, P. Ma, T. Zhang, H. B. Jalani, G.
Li, H. Lu, J. Org. Chem. 2020, 85, 13096–13107. (c) J. Lee, S. Jin, D.
Kim, S. H. Hong, S. Chang, J. Am. Chem. Soc. 2021, 143, 5191–5200.
[13] (a) T. Knecht, S. Mondal, J.-H. Ye, M. Das, F. Glorius, Angew. Chem. Int.
Ed. 2019, 58, 7117–7121. (b) J. S. Burman, R. J. Harris, C. M. B. Farr,
J. Basca, S. B. Blakey, ACS Catal. 2019, 9, 5474–5479. (c) P. Sihag, M.
Jeganmohan, J. Org. Chem. 2019, 84, 13053–13064. (d) H. Lee, T.
Rovis, Nat. Chem. 2020, 12, 725–731.
Acknowledgements
This work was financially supported by Novartis AG and the
University of Basel. We thank Prof. Dr. D. Häussinger (University
of Basel) for NMR experiments, S. Mittelheisser and Dr. M. Pfeffer
(University of Basel) for MS analyses, and Dr. P. Hoehn (Novartis
Pharma AG) for DSC experiments.
[14] The deprotection of the p-nitrophenyldifluoroacetamide group was
benchmarked against those of the more common trifluoroacetamide and
pivalamide groups. See the supporting information for details (Table S6).
[15] J. Park, J. Lee, S. Chang, Angew. Chem. Int. Ed. 2017, 56, 4256–4260.
Keywords: amidation • 1,2-amino alcohol • C–H activation •
dioxazolone • iridium
[1]
(a) D. J. Ager, I. Prakash, D. R. Schaad, Chem. Rev. 1996, 96, 835–876.
(b) P. O’Brien, Angew. Chem. Int. Ed. 1999, 38, 326–329. (c) S. C.
Bergmeier, Tetrahedron 2000, 56, 2561–2576. (d) J. B. Sweeney, Chem.
Soc. Rev. 2002, 31, 247–258. (e) S. Kobayashi, Y. Mori, J. S. Fossey, M.
M. Salter, Chem. Rev. 2011, 111, 2626–2704. (f) O. K. Karjalainen, A. M.
P. Koskinen, Org. Biomol. Chem. 2012, 10, 4311–4326. (g) T. Sehl, Z.
Maugeri, D. Rother, J. Mol. Catal. B-Enzym. 2015, 114, 65–71.
(a) A. R. Dick, M. S. Sanford, Tetrahedron 2006, 62, 2439–2463. (b) F.
Collet, R. H. Dodd, P. Dauban, Chem. Commun. 2009, 5061–5074. (c)
F. Collet, C. Lescot, P. Dauban, Chem. Soc. Rev. 2011, 40, 1926–1936.
(d) J. L. Roizen, M. E. Harvey, J. Du Bois, Acc. Chem. Res. 2012, 45,
911–922. (e) J. L. Jeffrey, R. Sarpong, Chem. Sci. 2013, 4, 4092. (f) Y.
Park, Y. Kim, S. Chang, Chem. Rev. 2017, 117, 9247–9301. (g) S. Y.
Hong, Y. Hwang, M. Lee, S. Chang, Acc. Chem. Res. 2021, 54, 2683–
2700.
[2]
[3]
[4]
Seminal work: Z. Ren, F. Mo, G. Dong, J. Am. Chem. Soc. 2012, 134,
16991–16994.
Metal-catalyzed exo-directed (sulfon)amidation with oximes: (a) T. Kang,
H. Kim, J. G. Kim, S. Chang, Chem. Commun. 2014, 50, 12073–12075.
(b) X. Huang, Y. Wang, J. Lan, J. You, Angew. Chem. Int. Ed. 2015, 54,
9404–9408. (c) Y. Dong, G. Liu, J. Org. Chem. 2017, 82, 3864–3872. (d)
Y. Dong, J. Chen, H. Xu, Chem. Commun. 2018, 54, 11096–11099. (e)
Liu, P. Xie, J. Zhao, J. Wang, M. Wang, Y. Jiang, J. Chang, X. Li, Angew.
Chem. Int. Ed. 2021, 60, 8396–8400.
[5]
Metal-catalyzed endo-directed (sulfon)amidation with oximes: (a) H.-Y.
Thu, W.-Y. Yu, C.-M. Che, J. Am. Chem. Soc. 2006, 128, 9048–9049.
(b) T. Kang, Y. Kim, D. Lee, Z. Wang, S. Chang, J. Am. Chem. Soc. 2014,
136, 4141–4144. (c) H. Wang, G. Tang, X. Li, Angew. Chem. Int. Ed.
2015, 54, 13049–13052. (d) H. Kim, G. Park, J. Park, S. Chang, ACS
Catal. 2016, 6, 5922–5929. (e) T. Zhang, X. Hu, X. Dong, G. Li, H. Lu,
Org. Lett. 2018, 20, 6260–6264.
[6]
[7]
(a) Y. Park, J. Heo, M.-H. Baik, S. Chang, J. Am. Chem. Soc. 2016, 138,
14020–14029. (b) N. Ma, Z. Liu, J. Huang, Y. Dang, Org. Biomol. Chem.
2021, 19, 3850–3858.
(a) 3-Perfluoroalkyl-1,4,2-dioxazol-5-ones: W. J. Middleton, J. Org.
Chem. 1983, 48, 3845–3847. (b) Trifluoroacetyliminoiodane: D. Mansuy,
J.-P. Mahy, A. Dureault, G. Bedi, P. Battioni, J. Chem. Soc., Chem.
Commun. 1984, 1161–1163.
[8]
[9]
(a) N. Barsu, A. Rahman, M. Sen, B. Sundararaju, Chem. Eur. J. 2016,
22, 9135–9138. (b) P. W. Tan, A. M. Mak, M. B. Sullivan, D. J. Dixon, J.
Seayad, Angew. Chem. Int. Ed. 2017, 56, 16550–16554. (c) S.
Fukagawa, Y. Kato, R. Tanaka, M. Kojima, T. Yoshino, S. Matsunaga,
Angew. Chem. Int. Ed. 2019, 58, 1153–1157. (d) D. Sekine, K. Ikeda, S.
Fukagawa, M. Kojima, T. Yoshino, S. Matsunaga, Organometallics 2019,
38, 3921–3926.
(a) Q. Ma, X. Yu, R. Lai, S. Lv, W. Dai, C. Zhang, X. Wang, Q. Wang, Y.
Wu, ChemSusChem 2018, 11, 3672–3678. (b) H. Shi, D. J. Dixon, Chem.
Sci. 2019, 10, 3733–3737. (c) S. Fukagawa, M. Kojima, T. Yoshino, S.
Matsunaga, Angew. Chem. Int. Ed. 2019, 58, 18154–18158.
8
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10.1002/anie.202110019
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RESEARCH ARTICLE
Entry for the Table of Contents
A new safe and bench-stable dioxazolone reagent was developed for the oxime-directed iridium(III)-catalyzed amidation of unactivated
C(sp3)–H bonds in tertiary and secondary alcohol-based substrates. The amidation reaction is mild, general and compatible with both
primary and secondary C–H bonds. The free 1,2-aminoalcohols are easily accessed after efficient and mild cleavage of the appendages.
9
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