Chiral Aryliodine-Catalyzed Asymmetric Oxidative C-N Bond Formation via Desymmetrization Strategy

Article abstract of DOI:10.1021/acs.orglett.8b01849

An asymmetric oxidative C-N bond-forming reaction is developed using a chiral diiodospirobiindane derivative as the catalyst and mCPBA as a terminal oxidant. The protocol is based on an asymmetric desymmetrization strategy and affords lactams or spirolact

Full text of DOI:10.1021/acs.orglett.8b01849

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Chiral Aryliodine-Catalyzed Asymmetric Oxidative C−N Bond
Formation via Desymmetrization Strategy
Qiang Ding,†,‡ Huan He,†,‡,§ and Qian Cai*,†,‡
†College of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou 510632, China
§
‡Guangzhou City Key Laboratory of Precision Chemical Drug Development and College of Chemical and Pharmaceutical
Engineering, Hebei University of Science and Technology, Shijiazhuang 050018, China
S
* Supporting Information
ABSTRACT: An asymmetric oxidative C−N bond-forming
reaction is developed using a chiral diiodospirobiindane
derivative as the catalyst and mCPBA as a terminal oxidant.
The protocol is based on an asymmetric desymmetrization
strategy and affords lactams or spirolactams according to the
different substituents on the substrates. The products are
obtained in good yields and moderate to high enantiose-
lectivities.
ransition-metal-catalyzed coupling reactions of aryl
formation of central chirality. The substrate scope has been
Thalides or pseudohalides with nucleophiles, such as a constrained in some cases due to the limited availability of
prefunctionalized aryl substrates. This prompted us to seek the
possibility of using unprefunctionalized substrates, and our
attention was turned to chiral hypervalent iodine mediated
oxidative coupling reactions.
Aryl-substituted amides have been reported to undergo
intramolecular lactamization8,9 or spirolactamization10 in the
presence of hypervalent iodine species. We envisioned that an
asymmetric oxidative C−N bond-forming reaction may be
achieved through a catalytic desymmetrization process by
chiral hypervalent iodine(III) generated in situ from chiral ArI
and mCPBA (Scheme 1). Herein, we would like to disclose the
details of this research.
Our research was initiated with the asymmetric desymmet-
rization of 2-benzyl-N-isopropoxy-2-methyl-3-phenyl propana-
mide (1a) as a model case. The reaction was first explored in
different solvents under the catalysis of 10 mol % of
diiodospirobiindane (C1) with mCPBA as a terminal oxidant.
Pd-catalyzed Buchwald−Hartwig reaction or copper-catalyzed
Ullmann-type coupling reactions, have become the most
important methods for the construction of aryl carbon−carbon
and carbon−heteroatom bonds.1 However, despite its
enormous utility, the requirement of using prefunctionalized
substrates such as aryl halides or aryl pseudohalides may cause
synthetic inconvenience as it often takes multiple steps for
prefunctionalization. Important alternatives to avoid the
prefunctionalization of the aryl ring have been developed for
the formation of aryl carbon−heteroatom bonds, such as
transition-metal-catalyzed C−H activation/functionalization2
and hypervalent iodine(III) reagent (or the hypervalent
iodine(III) species generated in situ from ArI and oxidants)
mediated oxidative coupling reactions.3
Hypervalent iodine(III)-promoted transformations have
gained much attention from synthetic chemists due to its
avoidance of transition metals, low toxicity, and mild reaction
conditions.4 The use of chiral hypervalent iodine(III) species
in enantioselective transformations has also emerged in recent
years, and many advances have been achieved,5 such as
asymmetric oxidation of sulfides to sulfoxides, dearomatization
reactions, arylation reactions, α-functionalization of ketones,
and functionalization of alkenes. However, chiral hypervalent
iodine-promoted asymmetric reactions still remain one of the
most challenging areas in asymmetric chemistry due to the
limitation of reaction types, the poor availability of the chiral
skeleton, and the unsatisfactory enantioselectivity in many
reactions. Thus, it is highly desirable to develop chiral
hypervalent iodine(III)-promoted novel asymmetric trans-
formations.
Scheme 1. Lactamization or Spirolactamization via
Asymmetric Oxidative C−N Bond Formation
We have developed a variety of transition-metal-catalyzed
enantioselective aryl carbon−heteroatom coupling reactions6
via the asymmetric desymmetrization strategy7 for the
Received: June 14, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01849
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
It was found that HFIP is the best solvent, which afforded the
coupling product 2a in 60% yield and 28% ee at room
temperature (Table 1, entries 1−5). It has been reported by
Scheme 2. Asymmetric Oxidative Lactamization
a
Table 1. Screening Reaction Conditions for Cyclization
b
c
entry
ArI
solvent
additive
yield (%)
ee (%)
1
2
3
4
5
6
7
8
C1
C1
C1
C1
C1
C1
C1
C1
C1
C2
C3
C4
C5
C6
C7
C8
C8
HFIP
i-PrOH
MeCN
DCM
toluene
HFIP
HFIP
HFIP
TFA
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
60
50
62
55
60
68
70
72
87
67
65
70
80
78
79
84
81
28
0
<10
<5
<10
46
50
51
44
40
30
61
60
54
60
69
85
TFA (1.5 equiv)
TFA (5.0 equiv)
TFA (10.0 equiv)
9
10
11
12
13
14
15
16
TFA (10.0 equiv)
TFA (10.0 equiv)
TFA (10.0 equiv)
TFA (10.0 equiv)
TFA (10.0 equiv)
TFA (10.0 equiv)
TFA (10.0 equiv)
TFA (10.0 equiv)
amide was first examined. It revealed that substrate 1c, with a
cyclopentyloxy substituent, delivered the corresponding
product 2c with an enantioselectivity better than that of 2a.
Then we explored different substituents, such as −Et, −CN,
and hydrogen on the prochiral carbon center. The correspond-
ing lactam products 2e−g were obtained in good yields and
moderate enantioselectivity. The substrates with different
substituents, such as Me-, i-Pr-, Ph-, or CF3- on the para-
positions of the aryl rings and a hydrogen atom at the prochiral
carbon center (1h−k), were then explored and also afforded
the desired coupling products with high yields and moderate
enantioselectivity (2h−k). For substrate 1l with methyl groups
on the meta-positions of two aryl rings, two regioisomers 2l-1
and 2l-2 were formed in a 1:1 ratio and were found with 62
and 58% ee, respectively. However, for substrate 1n with o-
methyl groups on the two aryl rings, one rearrangement
product was also isolated in addition to the normal coupling
product 2n.15 Finally, the absolute configurations of products
2a and 2g were assigned as R by reducing these compounds to
their corresponding tetrahydroquinolines and comparing them
with our previously reported literature data.16
d
17
a
Reagents and conditions: 1a (0.1 mmol), ArI* (0.01 mmol),
b
mCPBA (0.12 mmol), HFIP (0.5 mL), rt, 4 h. Isolated yield.
c
d
Enantiomeric ratio was determined through HPLC. −10 °C.
Barton11 that hypervalent iodine could be activated by acid
additives, and the effect of acid promoters has also been
investigated in other asymmetric transformations.12 Thus, we
investigated the effect of acid promoters in our reactions. It
revealed the enantioselectivity could be improved to about
50% ee by adding 5 or 10 equiv of TFA (Table 1, entries 6−
8).13 Further additions of TFA led to a slight reduction of
enantioselectivity, and 44% ee was obtained with TFA as the
solvent (Table 1, entry 9). Further modifications on the
catalyst were then conducted. The introduction of substituents
on the ortho-position of iodides seemed detrimental to the
enantioselectivity, as observed in the case of C2 and C314
(Table 1, entries 10 and 11). However, better enantioselectiv-
ities were observed when suitable substituted groups were
installed on the para-positions of the two iodine atoms (Table
1, entries 12−15). Finally, chiral catalyst C8 was found to
afford the desired product with 84% yield and 69% ee at room
temperature (Table 1, entry 16). Similar yield and better
enantioselectivity (81% yield and 85% ee) were obtained by
reducing the reaction temperature to −10 °C (Table 1, entry
17).
It was reported by Kikugawa8f,g and Kita10 that 3-aryl-
propanamides with halide or −OR groups on the para-
positions of aryl rings will undergo oxidative spirocyclization to
afford interesting dearomatizing17−19 N-fused spirolactam
products. Such patterns were also observed in desymmetriza-
tion reactions. As shown in Scheme 3, the reaction of 3a
afforded spirolactam 4a in high yield and good enantiose-
lectivity. Similar results were obtained in the cases of 3b−d
with F, Br, and −OMe on the aryl rings. Corresponding
products 4b−d were delivered in high yields and low to
moderate enantioselectivity. Similarly, substrates 3e−f, with
variant substituents (H or Et) on the prochiral carbon, have
With the optimized conditions in hand, we then explored
the substrate scope, and the results are shown in Scheme 2.
The effect of different alkoxy substituents on the nitrogen of
B
DOI: 10.1021/acs.orglett.8b01849
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
structure was confirmed to be the C-migration product.15
Thus, we cannot exclude the C-migration mechanism to form
B′ and lead to the formation of 2′ in other cases. A similar
rearrangement mechanism was also reported in recent
literature.20 Our observations further confirmed the possibility
of such a rearrangement and showed the mechanistic
complications in hypervalent iodine(III)-promoted reactions.
In summary, we have developed a chiral aryliodine-catalyzed
oxidative C−N bond-forming reaction. Intramolecular desym-
metrization reactions transformed amide into lactams or
spirolactams in moderate to good enantioselectivities.
Although the mechanisms for reaction selectivity and
enantiocontrol are unclear, some interesting results have
been observed, which may provide important hints in further
development of hypervalent iodine-promoted asymmetric
reactions.
Scheme 3. Asymmetric Oxidative Spirolactamization
ASSOCIATED CONTENT
* Supporting Information
■
S
also been explored and furnished the corresponding
spirolactam products 4e−f in high yields and moderate
enantioselectivities.
Although hypervalent iodine(III)-promoted reactions have
been studied for a long time, the mechanism is far from being
fully understood. Based on the literature reports,4,8−10 the C−
N bond-forming mechanism may be through the reactions of
key intermediate nitrenium ion A, which was formed by
reacting the amide substrates with a hypervalent iodine(III)
species (Scheme 4). Intramolecular attack of nitrenium ion by
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01849.
Full experimental and characterization data, including
1H and 13C NMR for all the new compounds, chiral
HPLC spectra for the products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: caiqian@jnu.edu.cn.
ORCID
Scheme 4. Proposed Mechanism
Qian Cai: 0000-0002-5700-3275
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to the National Natural Science
Foundation (Grants 21772066 and 21572229) and the
Fundamental Research Funds for the Central Universities for
their financial support.
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