A chiral Br?nsted acid-catalyzed highly enantioselective Mannich-type reaction of α-diazo esters with in situ generated N -acyl ketimines

Article abstract of DOI:10.1039/c8cc01436a

A chiral phosphoric acid-catalyzed asymmetric Mannich-type reaction of α-diazo esters with in situ generated N-acyl ketimines, derived from 3-hydroxyisoindolinones has been demonstrated in this communication. A variety of isoindolinone-based α-amino diazo esters bearing a quaternary stereogenic center were afforded in high yields (up to 99%) with excellent enantioselectivities (up to 99% ee). Furthermore, the synthetic utility of the products has been depicted by the hydrogenation of the diazo moiety of adducts.

Full text of DOI:10.1039/c8cc01436a

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Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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Chiral Brønsted Acid Catalyzed Highly Enantioselective Mannich-
type Reaction of α-Diazo Esters with in Situ Generated N-Acyl
Ketimines
Received 00th January 20xx,
Accepted 00th January 20xx
Rajshekhar A. Unhale,a,ǂ Milon M. Sadhu,a,ǂ Sumit K. Ray,a Rayhan G. Biswasa and Vinod K. Singh*a,b
DOI: 10.1039/x0xx00000x
Dedicated to Professor Goverdhan Mehta on the occasion of his 75th birthday
www.rsc.org/
A chiral phosphoric acid catalyzed asymmetric Mannich-type nitrogen atom (Scheme 1b). Diazo esters have been used as
reaction of α-diazo esters with in situ generated N-acyl ketimines, potential nucleophiles in asymmetric allylic substitution
derived from 3- hydroxyisoindolinones, has been demonstrated in reaction of Morita−Baylis−Hillman carbonates under the
this communication. A variety of isoindolinone based α-amino influence of chiral Lewis base (Scheme 1c).16 Recently, α-diazo
diazo esters bearing
a quaternary stereogenic center were phosphonates have been successfully employed in asymmetric
afforded in high yields (up to 99%) with excellent Mannich reaction of isatin-based ketimines.17 There are few
enantioselectivities (up to 99% ee). Furthermore, the synthetic elegant strategies in the literature for the enantioselective
utility of the products has been depicted by hydrogenation of the decarboxylative Mannich reaction18 as well as direct Mannich
diazo moiety of adducts.
reaction19 of ketimines with enolate equivalents. However, to
the best of our knowledge, there is no report in the literature
for the enantioselective nucleophilic addition of diazo esters to
functionalized cyclic ketimines.
α
-Diazocarbonyl compounds are quite valuable precursors in
synthetic organic chemistry due to their versatile reactivity and
remarkable synthetic value.1,2 Consequently, they have been
widely used in various organic transformations. For instance,
transition-metal-catalyzed decomposition of diazo compounds
generates highly reactive metal carbene intermediates which
undergo a large variety of reactions including X-H insertions
(X= C, N, O, Si, S, etc.),3 cyclopropanations,4 1,2-shift,5 ylide
formations6 and cycloadditions.7 Among various diazo
---------------------------------------------------------------------------------------------------------------------------
Previous work:
(a)
et al.9
et al.10
Cozzi
et al.11 et al.12
and Trost
Wang
O
Feng
[Zr], [Mg], [Sc] or [Zn]
+
chiral Lewis acids
O
OH
R3
*
R1
O
R1
H
O
R2
O
+
R2 R3
N2
N2
---------------------------------------------------------------------------------------------------------------------------
(b)
Terada
et al.13
Maruoka
et al.14
and Peng
et al.15
R2
R3
O
HN
*
O
R2
N
R1
chiral Bronsted acids
R1
H
O
O
+
R3
H
N2
N2
----------------------------------------------------------------------------------------------------------------------------------
(c)
et al.16
Zhu
O
compounds,
α-diazo esters can serve as important
OBoc
O
R2
*
COR3
chiral Lewis base
nucleophiles for the construction of enantioselective C-C bond
under various conditions with the retention of diazo
functionality.8 Elegant studies have been reported by Wang,9
Feng,10 Cozzi,11 and Trost12 for the chiral Lewis acid catalyzed
enantioselective aldol reaction of carbonyl compound with
R1
O
COR3
R1
H
R2
O
+
N2
N2
----------------------------------------------------------------------------------------------------------------------------------
(d)
This work:
O
O
H
R1
O
O
O
BA*
H
N2
X
NH
N
NH
OH
O
*
BA*
Ar
R1
O
Ar
Ar
N2
in situ generated
ketimine
quaternary stereocenter
diazo ester to afford enantioenriched
β-hydroxy-α-
Scheme 1 Asymmetric reactions using diazo esters as nucleophiles.
diazocarbonyl compounds (Scheme 1a). Furthermore, diazo
esters as nucleophiles were extensively investigated by the
groups of Terada,13 Maruoka14 and Peng15 for the catalytic
enantioselective Mannich-type reaction with activated
aldimine bearing strong electron withdrawing group at the
Figure 1 Selected drugs containing isoindolinones
aDepartment of Chemistry, Indian Institute of Science Education and Research
Bhopal, Bhopal, MP-462 066, India
On the other hand, isoindolinone scaffolds are omnipresent in
many complex natural products and drug molecules (Figure 1).
Their diverse array of pharmaceutical properties are evident
from observed antihypertensive,20 antifungal,21 antitumor,22
antileukemic,23 and antiviral24 activities. Therefore,
development of new synthetic routes for the enantioselective
bDepartment of Chemistry, Indian Institute of Technology Kanpur, Kanpur, UP-
208016, India
Email: vinodks@iitk.ac.in; Fax: (+) 91-755-4092392
ǂBoth authors contributed equally.
†Electronic supplementary information (ESI) available: Experimental
procedures and analytical data. CCDC 1822336 (4).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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synthesis of this fascinating N-heterocyclic scaffold is highly 1, entry 1). Encouraged by this preliminary outcome, an array
appealing. 3-Aryl-3-hydroxyisoindolinones have been used as of chiral phosphoric acids BA1 BA7 were screened for the
-
excellent substrates for the synthesis of enantioenriched reaction (Table 1, entries 3-10). Among them, BA5 was found
isoindolinone derivatives through various asymmetric to be the best Brønsted acid catalyst to afford 3aa in 96% yield
strategies, such as Friedel-Craft,25 arylation,26 hydrogenolysis,27 and 90% enantioselectivity (Table 1, entry 6). It is noteworthy
hydrophosponylation,28 and asymmetric addition of thiols29 to mention that the use of 4Å molecular sieves as a water
involving organometallic catalysis as well as organocatalysis. scavenger was essential to promote the reaction (Table 1,
Very recently, these substrates have been used for entry 7). Interestingly, (R)-BINOL-derived phosphoric acid (R)-
enantioselective three-component reaction via trapping of BA5 afforded the opposite enantiomer of 3aa (R) in the same
oxonium ylides in presence of Rh(II)/chiral phosphoric acid.30
Inspired by aforementioned studies, we hypothesized that
level of yield and enantioselectivity (Table 1, entry 8).
Subsequently, the influence of solvent on enantioselectivity
α-
diazo esters can serve as nucleophile to the in situ generated was examined. Among various solvents screened, CHCl3 and
N-acyl ketimines derived from 3-aryl-3-hydroxyisoindolinones 1,2-dichloroethane afforded the product 3aa in comparable
in a Mannich-type fashion. In this communication, we report a yields and enantioselectivities (Table 1, entries 11-12). Toluene
enantioselective
enantioselective synthesis of isoindolinone based α-amino of the product 3aa was improved to 95% albeit with lower
diazo esters via Mannich-type reaction of -diazo esters with yield (Table 1, entry 13). Importantly, the use of two equiv of
in situ generated ketimines of 3-aryl-3-hydroxyisoindolinone EDA 2a was found to be the best way to achieve higher yield
chiral
Brønsted
acid
catalyzed was found to be the choice of solvent as the enantioselectivity
α
(Scheme 1d).
Table 1 Optimization of reaction conditions a
(98%) (Table 1, entry 16). To further improve the
enantioselectivity of the product, the reaction was conducted
at 0 °C. Although the product 3aa was afforded with similar
level of enantioselectivity (95% ee), the chemical yield
dropped to 38% (Table 1, entry 18)
Having established optimal reaction condition, the substrate
scope was explored.
Entry
catalyst
solvent
Time (h) yield (%)b
ee (%)c
1
2
rac-BA1
(S)-BA1
(S)-BA2
(S)-BA3
(S)-BA4
(S)-BA5
(S)-BA5
(R)-BA5
(S)-BA6
(S)-BA7
(S)-BA5
(S)-BA5
(S)-BA5
(S)-BA5
(S)-BA5
(S)-BA5
(S)-BA5
(S)-BA5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
1
81
99
60
86
97
96
trace
94
53
78
98
99
83
32
31
98
98
38
racemic
0
2
3
20
20
5
90
63
19
90
ND
90
86
5
4
5
Scheme 2 Scope of various α-diazo esters in Mannich-type reaction.
6
5
7d
8e
72
5
First, differently substituted
α-diazo esters (2a-2h) were
subjected to the optimized reaction conditions. To our delight,
a variety of chiral diazo compounds (3aa-3ah) with delicate
functionalities were afforded in synthetically viable yields (up
to 98%) and excellent enantioselectivities (up to 96% ee)
(Scheme 2). Interestingly, t-butyl diazoacetate 2b having a
bulky ester group was equally efficient to this reaction,
furnished the product 3ab with excellent yield (98%) and
enantioselectivity (94% ee). In contrast, 2,2,2-trifluroethyl
diazoacetate 2c having a comparable lower pKa value took
longer time to complete the reaction, affording the product
3ac with similar level of enantioselectivity (93% ee) but with
lower yield (52%). This probably indicates that electronic
factors in the diazo esters play a pivotal role in the reactivity of
Mannich-type process. Afterward, differently substituted
benzyl diazo acetates (2e-2h) were examined affording the
chiral diazo compounds (3ae-3ah) in synthetically viable yields
(up to 98%) and excellent enantioselectivities (up to 96% ee).
Noticeable, benzyl diazoacetate having electron donating
group took comparable longer time to complete the reaction
than benzyl diazoacetate having electron withdrawing group
9
20
20
20
12
20
24
36
22
22
96
10
11
12
13
14
15
16f
17g
18f,h
84
90
95
92
93
96
96
95
DCE
Toluene
Et2O
EtOAc
Toluene
Toluene
Toluene
aReactions conditions: 0.2 mmol of 1a and 0.24 mmol of 2a in 1 mL of solvent
with 0.02 mmol of Brønsted acid at rt with 4Å MS (50 mg), unless noted
otherwise. bIsolated yield of 3aa. cDetermined by HPLC using chiralpak ID column.
f
dWithout MS, eProduct having (R) configuration, 0.4 mmol of 2a was used. g0.6
mmol of 2a was used. hReaction was conducted at 0 °C. ND = Not determined
At the outset, the model reaction was conducted using 3-
hydroxy-3-phenylisoindolinone 1a and ethyl diazoacetate
(EDA) 2a in presence of 10 mol % rac-BINOL-derived
phosphoric acid (rac-BA1) in dichloromethane at room
temperature. To our delight, the reaction worked efficiently,
(
3af vs 3ag-ah).
affording the desired racemic product 3aa in 81% yield (Table
2 | J. Name., 2012, 00, 1-3
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Next, the scope of the reaction was further investigated by the
reaction of EDA 2a with variety of 3-aryl-3-
a
hydroxyisoindolinones (3a-3u) under optimized conditions.
Scheme 4 Higher mmol scale reaction and synthetic transformation of 3aa
To demonstrate the potential utility of this protocol in organic
synthesis, we converted the isoindolinones 3aa into
corresponding benzylated analogue
bromide and sodium hydride with the retention of optical
purity. Compound was crystallized from the mixture of
CH2Cl2/hexane solvent. The absolute configuration of
compound was unambiguously determined by single crystal
X-ray structure analysis. The absolute configuration of the
chiral diazo compounds were assigned by analogy. We have
4 in the presence of benzyl
4
Scheme 3 Scope of various 3-hydroxy-3-arylisoindolinones in Mannich-type reaction
Gratifyingly, the corresponding chiral diazo compounds 3aa-
3ua were afforded in good to excellent yields (up to 99%) and
enantioselectivities (up to 99% ee) (Scheme 3). Notable, the
electronic nature of substituent on the aromatic ring at the C-3
4
3
position of 3-aryl-3-hydroxyisoindolinones had a very little also proposed a transition state to rationalize the observed
effect on the enantioselectivities of the product formation.
However, the rate of the reaction was considerably faster with
electron donating substituents at the 3-aryl ring than bearing
electron withdrawing groups (3ba-ca vs 3ga-ha). Moreover,
the position on the substituent on the aromatic ring at the C-3
position of 3-aryl-3-hydroxyisoindolinones had no significant
effect in enantioinduction. However, substrate with ortho
substituent at 3-aryl ring took longer reaction time for
completion and afforded albeit lower yield than with the meta
stereochemical outcome of the products (Fig. 3, ESI). The diazo
functionality of the adduct 3aa was subjected to
hydrogenation by PtO2 under hydrogen atmosphere. The
hydrogenated product
5 was obtained in 40% yield without
compromising the enantiopurity. To our surprise, the
treatment of compound 3aa with LiOH.H2O, afforded the 2-
quinolinone derivative
6 in 52% yield via a decarboxylative
rearrangement reaction. Although during this transformation
chiral center was lost, the newly formed 2-quinolinone
derivative is a very important skeleton present in many
bioactive natural products.31
and para substituents at 3-aryl ring
(3da vs 3ea-fa).
Rewardingly, heteroaromatic substrates 1n-o having a furan
and thiophene moiety furnished corresponding products 3na-
oa with excellent yields and enantioselectivities ( up to 95%
ee). Additionally, 3,5-dimethyl, 3,4-dimethoxy and 3,4,5-
trimethoxy groups on the 3-aryl substituent were well
tolerated, affording products 3ak-am in excellent yields and
enantioselectivities (up to 96% ee). Surprisingly, the substrates
containing naphthyl ring took six days to complete the
In summary, we have established
a process for asymmetric
Mannich-type reaction of α-diazo esters with in situ generated N-
acyl ketimines in the presence of chiral Brønsted acid under
ambient conditions for the first time, to the best of our knowledge.
A
variety of diazo esters were utilized to access biologically
interesting chiral isoindolinone based α-amino diazo esters with
reaction, affording the corresponding product 3pa in 75% yield remarkably high enantioselectivities (up to 99% ee).
and 92% ee. Moreover, isoindolinone motifs having different
substituent on the phthalimide aromatic ring were tested. A
5,6-dimethyl or 5,6-dichloro substituent on the phthalimide
aromatic ring responded well to this protocol, furnished
products 3ra-sa in good yields (up to 98%) and
enantioselectivities (up to 98% ee). Unfortunately, the
substrate 1v bearing alkyl side chain at C-3 position and acyclic
ketimines such as 1-Phenylethan-1-imine and 4-Methoxy-N-
(2,2,2-trifluro-1-phenylethylidene)benzamine failed to react
with EDA under our optimized reaction conditions.
Enantioselective construction of chiral diazo compounds comprising
a quaternary stereogenic center is one of the salient features of this
exciting chemistry. The utility of this protocol has also been
demonstrated by hydrogenation of diazo moiety of the product.
V. K. S. thanks the Department of Science and Technology,
India, for J. C. Bose fellowship and SERB, DST
(EMR/2014/001165), for a research grant. S. K. R. thanks DST
for INSPIRE Faculty award (DST/INSPIRE/04/2016001704). R. A.
U. and R. G. B thank to the IISER Bhopal for fellowship. M. M. S
thanks to DST-Inspire for fellowship.
To illustrate the practical efficacy of our methodology, a higher
mmol scale reaction of 3-hydroxy-3-phenylisoindolinone 1a (2
mmol, 0.45 g) and ethyl diazoacetate (EDA) 2a (4 mmol) was
carried out under optimized reaction conditions, furnishing
3aa in 99% yield and 96% ee (Scheme 4).
Conflicts of interest
There are no conflicts to declare.
Notes and references
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DOI: 10.1039/C8CC01436A
Journal Name
COMMUNICATION
TOC
Chiral Brønsted Acid Catalyzed Highly
Enantioselctive Mannich-type Reaction
of -Diazo esters with in Situ Generated
α
N-Acyl Ketimines
Rajshekhar A. Unhale,a,ǂ Milon M. Sadhu,a,ǂ Sumit K. Ray,a
Rayhan G. Biswasa and Vinod K. Singh*a,b
The chiral phosphoric acid catalyzed asymmetric Mannich-type
reaction of
derived
α
-diazo esters with in situ generated N-acyl ketimines,
from 3-aryl-3-hydroxyisoindolinones, has been
demonstrated. The reaction proceeds smoothly under mild reaction
conditions affording a variety of enantioenriched isoindolinone
based α-amino diazo esters with a quaternary stereogenic center in
high yields (up to 99%) with excellent enantioselectivities (up to
99% ee).
This journal is © The Royal Society of Chemistry 20xx
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