Copper(I)-Catalyzed Enantioselective Intramolecular Aminotrifluoromethylation of O-Homoallyl Benzimidates

Article abstract of DOI:10.1021/acs.orglett.9b01552

In the present paper, the Cu(I)-catalyzed intramolecular aminotrifluoromethylation of O-homoallyl benzimidates with Togni reagent I was reported. O-Homoallyl benzimidates equipped with terminal alkenes produced chiral 1,3-oxazines with high enantioselectivity in the presence of a chiral BOX ligand, and racemic tetrahydro-1,3-oxazepines were obtained in high yields from internal alkene derivatives with a monoprotected amino acid additive under similar conditions.

Full text of DOI:10.1021/acs.orglett.9b01552

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper(I)-Catalyzed Enantioselective Intramolecular
Aminotrifluoromethylation of O‑Homoallyl Benzimidates
Xue-Qing Mou, Feng-Ming Rong, Heng Zhang, Gong Chen,* and Gang He*
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071,
China
S
* Supporting Information
ABSTRACT: In the present paper, the Cu(I)-catalyzed intramolecular
aminotrifluoromethylation of O-homoallyl benzimidates with Togni reagent
I was reported. O-Homoallyl benzimidates equipped with terminal alkenes
produced chiral 1,3-oxazines with high enantioselectivity in the presence of a
chiral BOX ligand, and racemic tetrahydro-1,3-oxazepines were obtained in
high yields from internal alkene derivatives with a monoprotected amino acid
additive under similar conditions.
he direct functionalization of alkenes is an efficient route
terminal alkene derivatives in a 6-exo-trig fashion, and CF3-
Tto synthesize complex organic architectures with valuable carrying racemic tetrahydro-1,3-oxazepines were derived from
functional groups.1 In this regard, trifluoromethylation of
1-aryl O-homoallyl-benzimidates with the N-Ac-Trp-OH
additive followed by the 7-endo-trig pathway under similar
reaction conditions (Scheme 1C).
alkenes has attracted considerable attention due to the unique
physical and biological properties of molecules carrying a
trifluoromethyl group (CF3).2−7 In particular, the trifluor-
omethylative intramolecular difunctionalization of alkenes
provides a streamlined synthesis of CF3-carrying heterocycles,
which are widely used in pharmaceutical, agrichemical, and
materials science research.8 Since the pioneer works of
Buchwald,9a,10a Sodeoka,11a and Liu,11b a broad range of
unactivated alkenes equipped with pendant nucleophilic
groups, such as carboxylic acid, amine, urea, amide, and
oxime, have been transformed into CF3-containing hetero-
cycles in racemic or enantioselective fashion (Scheme 1A).9−12
However, despite these achievements, the enantioselective
trifluoromethylation of alkenol substrates remains challenging
due to the weak affinity of hydroxyl group to transition metals.
In 2017, Liu et al.13 first reported the enantioselective
intramolecular oxytrifluoromethylation of geminal-substituted
alkenol derivatives using a chiral phosphoric acid ligand
(Scheme 1B). We have been interested in functionalization of
aliphatic alcohols via a radical relay strategy14 and found that
the imidate group can serve as directing group as well as amine
source to yield oxazolines with high yield and regioselectivi-
ty.14a Therefore, it can be speculated that this strategy is also
amenable for the functionalization of alkenol substrates. In the
present work, the Cu(I)-catalyzed intramolecular amino-
trifluoromethylation of O-homoallyl benzimidate derivatives15
with Togni reagent I (serving as the CF3 source) is reported.16
In the presence of a chiral BOX ligand,17 CF3-containing chiral
1,3-oxazines were obtained with high enantioselectivity from
We commenced our study with functionalization of O-
homoallyl benzimidate 1 using Togni reagent I as CF3 source
and Cu(CH3CN)4PF6 as catalyst in DCE (dichloroethane) at
45 °C (initial conditions, Table 1). The reaction without any
ligand or additive gave trace amounts of 1,3-oxazine 2, and
most of the starting material was recovered (Table 1, entry 1).
The addition of chiral phosphoric acid ligands (L1, L2) or
monoprotected amino acid (L4) accelerated the reaction, but
all gave racemic product. It was observed that addition of chiral
BOX ligand L5 produced 2 with moderate yield and
enantiometric excess (ee). Moreover, an increase in the steric
hindrance of the C4 substituent caused a diminishing trend in
enantioselectivity (L5−L8). The diphenyl-substituted BOX
ligand L10 generated 2 with improved yield and ee. An
increase in the steric hindrance of the substituent at the bridge
carbon of BOX manifested improvements in both yield and ee,
and 4-tBu-benzyl-substituted L12 was optimal, giving 2 in 64%
yield and 73% ee (see the SI for more screening conditions and
synthesis of chiral BOX ligands). The following inferences
were made from examination of other reaction parameters: (1)
Replacement of DCE with DCM and a decrease in reaction
temperature to 40 °C gave better results (entries 5 and 6). (2)
Addition of o-(3′,5′-di-tert-butylphenyl)benzoic acid (3′,5′-
tBu-oPBA) was beneficial for both conversion and enantiose-
Received: May 2, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01552
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Letter
Scheme 1. Copper-Catalyzed Trifluoromethylative
Intramolecular Difunctionalization of Alkene
Table 1. Enantioselective Intramolecular
Aminotrifluoromethylation of 1 with Togni Reagent I
a
yield of 2
(%) (ee, %)
entry
change from initial conditions
1
2
3
4
5
6
7
8
9
no ligand
L12
L12, DCE → AcOEt
L12, DCE → CHCl3
L12, DCE → DCM
L12, DCE → DCM, 45 → 40 °C
L12, DCE → DCM, 45 → 35 °C
<5
64 (73)
45 (57)
31 (80)
75 (77)
70 (82)
54 (81)
L12, DCE → DCM, 45 → 40 °C, oPBA (20 mol %) 50 (69)
L12, DCE → DCM, 45 → 40 °C, 3′,5′-tBu-oPBA
84 (92)
(20 mol %)
10
11
L12, DCE → DCM, 45 → 40 °C, 3′,5′-tBu-oPBA
(20 mol %), 24 → 48 h (conditions A)
Togni reagent I → Togni reagent II
90 (92)/
81 (92)
30 (84)
b
c
lectivity and produced 2 with 92% ee (entries 9 and 10),
whereas with 3′,5′-tBu-oPBA alone formed racemic 2 in 46%
yield. (3) Togni reagent II generated moderate ee with low
conversion under optimal conditions (entry 11).
With the optimized conditions in hand, we explored the
substrate scope of the Cu-catalyzed enantioselective intra-
molecular aminotrifluoromethylation reaction. As shown in
Scheme 2, O-homoallyl benzimidates with electron-donating
or electron-withdrawing groups on the phenyl ring proceeded
well under conditions A, giving CF3-containing 2-aryl-1,3-
oxazines in good yields and ee (3−11). Halogen atoms were
well tolerated and provided a versatile path for further
transformation. Substrate with a gem-dimethyl substituent
generated the desired product with high ee and low conversion
(12). 2-Aryl-substituted alkene substrate failed to produce
satisfying results, and a trace amount 13 was obtained with
27% ee. However, racemic 13 was obtained in 63% yield under
conditions B with 20 mol % of of N-Ac-Trp-OH as additive.18
The trichloroacetimidate analogue of 1 was not compatible
with this enantioselective intramolecular aminotrifluoromethy-
lation reaction, leaving most of starting material unconsumed.
The reaction of benzimidate substrates equipped with 1,2-
disubstituted alkene were investigated under conditions A.
Interestingly, with 1-aryl-substituted O-homoallyl benzimi-
dates, 7-membered tetrahydro-1,3-oxazepines were obtained
in low yield without any enantioselectivity (Scheme 3, 15 and
16). Tetrahydro-1,3-oxazepines are widely used in medicinal
chemistry and material science; however, very few methods
have been developed for their synthesis.19 It was disappointing
a
1
Yields are based on H NMR analysis of reaction mixture with
1,1,2,2-tetrachloroethane as internal standard on a 0.1 mmol scale.
The enantioselectivity was determined by chiral HPLC analysis of the
b
c
crude reaction mixture. Isolated yield on a 0.1 mmol scale. Change
from conditions A.
that no improvement in enantioselectivity was observed under
the conditions evaluated (see the SI for detailed information).
However, racemic 2-aryltetrahydro-1,3-oxazepines were ob-
tained with improved yields and moderate to excellent
diastereoselectivity under conditions B (15−17). It is worth
noting that both substrates equipped with E and Z alkenes gave
the cyclized product 16 with identical stereochemistry.20 1,1-
Diaryl-substituted substrates resulted in relatively higher yields
(18, 19), whereas 1,1-dialkyl-substituted substrate only
furnished 35% yield (20).
Some control reactions were carried out to probe the
mechanism. As shown in Scheme 4A, when a radical scavenger
(TEMPO or BHT) was added into the reaction of 1 under
conditions A or B, the reaction was dramatically inhibited, and
B
DOI: 10.1021/acs.orglett.9b01552
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Scheme 2. Substrate Scope of the Cu-Catalyzed
Scheme 4. Mechainsm Study
Enantioselective Intramolecular Aminotrifluoromethylation
a
Reaction
a
Yields are based on 1H NMR analysis of reaction mixture with
1,1,2,2-tetrachloroethane as internal standard on a 0.1 mmol scale.
b
Most of 1 was unconsumed. TEMPO, 2,2,6,6-tetramethyl-1-
piperidinyloxy; BHT, 2,6-di-tert-butyl-4-methylphenol.
a
All yields are based on isolated product on a 0.1 mmol scale. The
b
enantioselectivity was determined by chiral HPLC analysis. Most
starting material was unconsumed; only a small amount of hydrolyzed
byproduct was detected. Conditions B: Cu(CH3CN)4PF6 (10 mol
%), Togni reagent I (1.5 equiv), N-Ac-Trp-OH (20 mol %), in DCE
at 45 °C, 24 h.
the corresponding trifluoromethyl-captured product 21 was
detected as the major product (based on the 19F NMR
analysis; see the SI for detailed information). Therefore, these
results indicated the radical nature of the intramolecular amino
trifluoromethylation reaction.
c
Scheme 3. Synthesis of CF3 Carrying Tetrahydro-1,3-
Based on the results of the present study and previous
reports,9a,c,10a,11c a possible mechanism for the Cu-catalyzed
enantioselective intramolecular aminotrifluoromethylation re-
action is proposed in Scheme 4B. Togni reagent I first reacts
with Cu(I) through single-electron transfer (SET) followed by
a
oxazepine.
•
the homolytic cleavage of the I-CF3 bond, generating CF3
radical species and Cu(II) along with an anion species 22,
which serves as base in the following transformation. There
might be two possible pathways for the addition of
trifluoromethyl radical with alkene: with terminal alkene (R
= H), CF3· added at the terminal position and generated a
secondary carbon centered radical A. Radical A was then
captured by L12-ligated Cu(II) in a enantioselective fashion to
form a Cu(III) intermediate. Reductive elimination of the
Cu(III) intermediate produced chiral 1,3-oxazines with high ee
and regenerated the Cu(I) catalyst. With 1-aryl-substituted O-
homoallyl benzimidates, CF3· preferentially attacks the C2
position and generated a stabilized benzylic radical B. Radical
B was oxidized by Cu(II) to a secondary carbocation
intermediate and regenerated Cu(I) catalyst. Finally, the
carbocation intermediate was intramolecularly attacked by
the benzimidate motif to produce racemic tetrahydro-1,3-
oxazepines.
a
b
All yields are based on isolated product on a 0.1 mmol scale. About
60% of starting material was unconsumed; only a trace amount of
hydrolyzed byproduct was detected.
C
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01552.
Additional experimental procedures and spectroscopic
data for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: gongchen@nankai.edu.cn.
*E-mail: hegang@nankai.edu.cn.
ORCID
Gong Chen: 0000-0002-5067-9889
Gang He: 0000-0002-9064-3418
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully thank the Natural Science Foundation of China
(21672105, 21702109, 91753124), NSF of Tianjin
(17JCYBJC19700, 18JCZDJC32800), and the Fundamental
Research Funds for the Central Universities (Nankai
University (No. 63191746)) for financial support of this work.
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E
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