Traceless Directing Group Assisted Cobalt-Catalyzed C?H Carbonylation of Benzylamines

Article abstract of DOI:10.1002/adsc.201700780

The first example of cobalt-catalyzed C(sp²)?H carbonylation of benzylamines using a traceless directing group is reported, which was successfully applied to the synthesis of N?unprotected iso-indolinones through direct C?H/N?H bonds activation. This protocol tolerates a variety of functional groups and provides a facile and efficient method for the formal synthesis of (+)-garenoxacin. (Figure presented.).

Full text of DOI:10.1002/adsc.201700780

Title: Traceless Directing Group Assisted Cobalt-Catalyzed C-H
Carbonylation of Benzylamines
Authors: Fei Ling, Chongren Ai, Yaping Lv, and Weihui Zhong
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10.1002/adsc.201700780
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Traceless Directing Group Assisted Cobalt-Catalyzed C-H
Carbonylation of Benzylamines
Fei Ling, Chongren Ai, Yaping Lv and Weihui Zhong*
Key Laboratory of Pharmaceutical Engineering of Ministry of Education, College of Pharmaceutical Science, Zhejiang
University of Technology, Hangzhou 310014, P.R. China.
Tel.&Fax:+86(571)88320117 E-mail: weihuizhong@zjut.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. The first example of cobalt-catalyzed C(sp2)−H
carbonylation of benzylamines using a traceless directing
group is reported, which was successfully applied to the
synthesis of N-unprotected iso-indolinones through direct
C−H/N−H bonds activation. This protocol tolerates a
variety of functional groups and provides a facile and
efficient method for the formal synthesis of (+)-
garenoxacin.
Keywords: traceless directing group; C−H carbonylation;
cobalt; benzylamine; (+)-garenoxacin
Figure 1. Biologically active isoindolinone derivatives.
Isoindolinones are widely existed in pharmaceuticals
and complex natural products,[1] for example,
indoprofen (an anti-inflammatory),[2] lennoxamine (an
anticancer),[3] 9b-phenyl-2,3-dihydrothiazolo[2,3-a]-
isoindol-5(9bH)-one (a HIV-1 reverse transcriptase
of these motifs remains a barely exploited topic. The
cobalt-catalyzed carbonylation of Schiff bases and
carbon monoxide reported by Murahashi is perhaps the
earliest example of directed C–H bond
functionalization for the synthesis of N-protected
isoindolinones (Scheme 1b-1).[12] Following this
report, several groups have disclosed aminoquinoline
directed cobalt-, nickel- or copper-catalyzed C(sp2)−H
bond carbonylation of benzamides for the synthesis of
substituted phthalic acids (Scheme 1b-2).[13] Although
phthalic acids could be converted to N-substituted
isoindolinones, additional steps must be employed,
including removal of DG and mono-reduction of
carbonyl group. Thus, the strategy using a traceless
directing group, the removal of which does not require
extra steps, is much more preferred.[14] To the best of
our knowledge, traceless directing group assisted C−H
bond carbonylation under first-row transition metal
catalysis has not been reported yet. Herein, we
described a versatile and efficient cobalt-catalyzed
regioselective ortho-C(sp2)−H carbonylation of
benzylamines with DEAD (diethyl azodicarboxylate)
through C−H/N−H bonds activation. This procedure
employs cost-effective Co(OAc)2•4H2O as the catalyst
and picolinamide[15] as a traceless directing group,
inhibitor),[4] pestalachloride
A
(an antifungal
metabolite),[5] chlortalidoneis (a diuretic drug),[6]
garenoxacin (an antibiotic).[7] Thus devising novel and
efficient methods to access these structural motifs is of
great interest. In this regard, a plenty of approaches
have been developed for the synthesis of N-substituted
isoindolinones,
both
non-asymmetric[8]
and
asymmetric.[9] Conversely, the strategies for the
preparation of N-unprotected isoindolinones have
rarely been reported, especially on the asymmetric
matter.[10] Moreover, most of these methods require
complicated starting materials, expensive regents,
noble metals or multi steps, which are not from the
atom-economic concern.
In the past decades, transition-metal-catalyzed
direct C−H carbonylation by employing a directing
group to control chemo- and regio-selectivities
provides a more straightforward and atom-economic
route to N-unprotected isoindolinones. In this context,
the Pd-catalyzed directly cabonylation of arylalkyl
amines has been well established by using various
directing groups, such as oxalyl amide, [11e,11f] N-(2-
pyridyl)sulfonyl amine[11g] and etc. (Scheme 1a).[11]
However, the use of first-row metals for construction
which accesses
a
variety of N-unprotected
isoindolinones with good functional-group tolerance
1
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10.1002/adsc.201700780
Advanced Synthesis & Catalysis
Table 1. Optimization of Reaction Conditions[a]
Yield
(%)
Entry
Cat.
Oxidant
Additive
1
2
Co(acac)2 Ag2CO3
-
-
trace
25
CoCl2
Co(OAc)2
•4H2O
Ag2CO3
Ag2CO3
3
4
5
6
-
31
53
Co(OAc)2
•4H2O
Co(OAc)2
•4H2O
Co(OAc)2
•4H2O
Ag2CO3
Ag2CO3
AgOAc
PivOH
NaOPiv 37
PivOH
PivOH
49
11
Mn(OAc)2•
Co(OAc)2
7
2H2O
•4H2O
Co(OAc)2
•4H2O
Co(OAc)2
•4H2O
Co(OAc)2
•4H2O
Co(OAc)2
•4H2O
Co(OAc)2
•4H2O
Co(OAc)2
•4H2O
Co(OAc)2
•4H2O
-
Cu(OAc)2
8
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
trace
93
Scheme 1. Synthesis of isoindolinones via C-H
carbonalation.
9[b]
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
10[b,c]
11[b,d]
12[b,e]
13[b,f]
87
and excellent regioselectivity. Furthermore, chiral
precursors could also undergo this process smoothly to
give chiral isoindolinones without racemization,
which enables further synthesis of chiral isoindoline-
containing natural products and drugs.
65
85
The initial assays were carried out with N-
benzylpicolinamide (1a) and DEAD (2a) in 1,4-
dioxane at 120 oC under air (Table 1). After exploring
a set of cobalt salts, Co(OAc)2•4H2O was identified as
the optimal catalyst to enables a C-H carbonylation
reaction between 1a and 2a, producing isoindolin-1-
one 3a in 31% yield, albeit in low yield (entries 1-3).
Among the examined additives, acidic additives
exhibited higher efficiency than basic additives,
especially PivOH, leading to the corresponding
product 3a in 53% yield (entries 4 and 5). Additionally,
switching Ag2CO3 to other oxidants did not improve
the yield (entries 6-8). It was of note that a
79
14[b,g]
15[b]
16[b]
Ag2CO3
Ag2CO3
-
PivOH
PivOH
PivOH
65
-
Co(OAc)2
•4H2O
trace
[a] Reactions conditions: 1a (0.4 mmol), 2a (0.8 mmol), Co
catalyst (0.08 mmol), oxidant (0.8 mmol), and additive (0.8
mmol) in Dioxane (4 mL) at 120 °C under air for 24 h.
Isolated yield. [b] TFE as solvent. [c] 130 °C. [d] 110 °C. [e] 2b
was used. [f] 2c was used. [g] 1atm CO gas was used instead
of DEAD.
breakthrough
was
made
by
using
TFE
With the optimal conditions in hand (Table 1), we
set out to probe its versatility in the ortho-C(sp2)−H
carbonylation of various substituted benzylamines.
The developed synthetic methodology is general and
has a broad substrate scope as well as functional group
tolerance, leading to the expected products in 53-94%
yields (Table 2). Generally, benzylamines containing
an electron-withdrawing group (1d and 1g) proceeded
in better yield than those with electron-donating
counterparts (1b and 1c). In addition, the substitution
patterns of aryl moieties had a slight effect on this
reaction, forming 3h−k from ortho- and meta-
substituted benzylamines in relatively lower yields,
compared with 3b and 3f. It is note of that this process
exhibited excellent selectivity for meta-substituted
substrates at 6-position, giving the corresponding
product 3j or 3k as a single isomer, presumably due to
(trifluoroethanol) as the solvent, giving the desired
product 3a in 93% isolated yield (entry 9). Moreover,
a decrease in yield was observed, when raising or
lowing the reaction temperature (entries 10 and 11).
Furthermore, other azodicarboxylates, such as
diisopropyl azodiformate (2b) or dibenzyl
azodicarboxylate (2c), were compatible with this
process, resulting in relatively lower yield (entries 12
and 13). Delightfully, this process also underwent
smoothly to afford 3a in 65% yield by using CO gas as
the carbonyl source (entry 14). In contrast, no desired
product was detected in the absence of Co catalyst, and
only a trace of 3a was observed without the addition
of oxidant (entries 15 and 16). These blank tests
clearly indicated that both Co catalyst and oxidant
were required for this reaction.
2
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10.1002/adsc.201700780
Advanced Synthesis & Catalysis
[a]
the steric issue encountered in the C-H activation step.
In addition, di-substituted benzylamines (1l and lm)
also underwent smoothly under our optimized
conditions and afforded the targeted product in 75%
and 53% yield, respectively. Moreover, this
transformation is compatible with α-mono- or di-
substituted benzylamines, giving the expected
products in 64-85% isolated yields. Notably, the
developed cobalt-catalyzed C−H carbonylation
strategy is applicable for practical synthesis of
Reaction conditions: 1 (0.4 mmol), DEAD (0.8 mmol),
Co(OAc)2•4H2O (0.08 mmol), Ag2CO3 (0.8 mmol), PivOH
(0.8 mmol), TFE (4 mL), 24 h at 120 oC. Isolated yield.
To demonstrate the scalability and utility of this
method, we applied it in the formal synthesis of (+)-
garenoxacin on a gram scale (Scheme 2). Firstly, using
EDCI and HOBt as condensing agents, the N-acylation
of (R)-1-(4-bromophenyl)ethan-1-amine and picolinic
acid underwent smoothly, forming 1s in 91% yield and
98.9% ee. Next, under the modified conditions for the
developed cobalt-catalyzed C−H carbonylation
reaction, the carbonyl product (R)-3a was obtained on
a gram scale in 1.56 grams with a slight increase of ee
(99.7%). After the sequential amide reduction with
NaBH4 and BF3•Et2O, and N-protection with
triphenylmethyl chloride, the key intermediate 4s was
obtained in 61% yield and 99.4% ee. In an additional
two steps, 4s was converted into (+)-garenoxacin.[16]
enantiomerically
pure
ortho-carbonylated
benzylamines, and no racemization was observed
under the standard reaction conditions (products 3n, 3r,
and 3s).
Table 2. Optimization of Reaction Conditions.[a]
Scheme 2. Formal Synthesis of (+)-Garenoxacin.
[a]
Reaction conditions: 1 (0.4 mmol), DEAD (0.8 mmol),
Co(OAc)2•4H2O (0.08 mmol), Ag2CO3 (0.8 mmol), PivOH
o
[b]
(0.8 mmol), TFE (4 mL), 24 h at 120 C. Isolated yield.
Parallel experiments with racemic 1.
Intriguingly, this carbonylation strategy is also
compatible with varieties of aromatic or hetero-
aromatic substituted amines, giving the corresponding
products in 64-90% yields (Table 3). The naphthyl
group was tolerated, forming 3t and 3u in excellent
yields. Nevertheless, 3u was obtained with 3:1
regioselectivity
in
64%
yield.
Notably,
tetrahydronaphthalene amine 1v proceeded smoothly
to afford the desired product in 71% yield. Moreover,
a heteroaromatic ring (2-thienyl) could also be used in
this reaction to give the targeted product 3w in good
yield. Delightfully, ethylamine (1x) was also
compatible with this reaction, delivering 3x in
moderate yield.
Scheme 3. Mechanistic Hypothesis.
Table 3. Reaction Scope of Other Amines.[a]
Based on the mechanism studies (see the Supporting
Information) and the literature reports on Co
catalysis,[13d,17] a plausible reaction mechanism for the
cobalt-catalyzed C−H carbonylation is depicted in
Scheme 3 with 1a as the model substrates. The
reaction is believed to be initiated by the oxidiation of
Co(II) salt to Co(III) species,[13d,17b-e] which then
3
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10.1002/adsc.201700780
Advanced Synthesis & Catalysis
Acknowledgements
coordinates with benzylpicolinamide (1a), followed
by the C(sp2)−H bond cobaltation to form intermediate
B. The esteric radical, generated from thermal
decomposition of DEAD,[19] could attack the
intermediate B to form the intermediate E (path a).
Subsequent reductive elimination of the Co(IV)
species E generates the esterification product F and
release the Co(II) species, which could be reoxidized
to Co(III) species by silver salts. The ester F then
undergoes intramolecular N-nucleophilic cyclization
and hydrolysis of picolinamide to afford isoindolinone
3a, along with elimination of ethanol and picolinate.
However, Alternatively, the CO gas might be
generated from the esteric radical, which then inserts
into the C−Co bond of the intermediate B to afford the
species C (path b).[13a,18a] The reductive elimination of
species C results in the formation of intermediate D
and generates Co(I) species. Subsequently hydrolysis
of intermediate D leads to the expected product 3a,
might due to the activation of the amide group by the
coordination of Co(I) species with intermediate D via
N,O-coordination. The released Co(I) species are
reoxidized by silver to active Co(III) species to
complete the catalytic cycle. Mechanism study shows
that only 10% yield of 3a is obtained, when subjecting
the intermediate F under standard conditions, which
suggests that path a is not the major reaction pathway.
In conclusion, we have established an expedient and
convenient strategy for the C(sp2)−H bond
carbonylation of benzylamines to synthesize various
N-unprotected isoindolinones by using earth-abundant
and inexpensive Co(OAc)2•4H2O as the catalyst and
the commercially available azodicarboxylates as the
environmentally benign carbonyl source. This
protocol features a wide substrate scope including
sterically hindered and enantiopure benzylamines and
various functional group tolerances. The utility of this
methodology is undoubtedly demonstrated by the
formal synthesis of (+)-garenoxacin. To the best of our
knowledge, the current approach represents the first
example of traceless directing group assisted cobalt-
catalyzed C−H bond carbonylation. Further researches
based on this novel approach are currently going on in
our laboratory.
We thank the National Natural Science Foundation of China
(No. 21676253 and 21276238) for financial support.
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Experimental Section
Typical procedure for the current cobalt-catalyzed C−H
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reaction mixture was cooled to room temperature, and then
the solvent was removed under vacuum. The crude product
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white solid.
Procedures and analytical data for all compounds are given
in the Supporting Information.
4
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10.1002/adsc.201700780
Advanced Synthesis & Catalysis
COMMUNICATION
Traceless Directing Group Assisted Cobalt-
Catalyzed C-H Carbonylation of Benzylamines
Adv. Synth. Catal. 2017, Volume, Page – Page
Fei Ling, Chongren Ai, Yaping Lv and Weihui
Zhong*
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