Stereospecific copper-catalyzed domino ring opening and sp3 C-H functionalization of activated aziridines with N-alkylanilines

Article abstract of DOI:10.1021/acs.orglett.6b03458

Copper efficiently catalyzed nucleophilic ring opening, sp³ C-H functionalization, and C-N bond formation in the presence of tert-butyl hydroperoxide to afford functionalized imidazolidines starting from N-sulfonylaziridines and Nalkylanilines. The products were obtained in high optical purities (95 → 99% ee) with excellent functional group tolerance.

Full text of DOI:10.1021/acs.orglett.6b03458

Letter
pubs.acs.org/OrgLett
Stereospecific Copper-Catalyzed Domino Ring Opening and sp3 C−H
Functionalization of Activated Aziridines with N‑Alkylanilines
Mani Sengoden, Abhisikta Bhowmick, and Tharmalingam Punniyamurthy*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India
S
* Supporting Information
ABSTRACT: Copper efficiently catalyzed nucleophilic ring opening, sp3 C−H functionalization, and C−N bond formation in
the presence of tert-butyl hydroperoxide to afford functionalized imidazolidines starting from N-sulfonylaziridines and N-
alkylanilines. The products were obtained in high optical purities (95 → 99% ee) with excellent functional group tolerance.
ecent advances in transition-metal catalysis have led to the
development of effective methods for regioselective
(TBHP)8 to produce imidazolidines that are important in
synthetic and medicinal sciences (Scheme 1b).9−12 This protocol
provides a potential route for the selective construction of the
target five-membered heterocycles with excellent substrate scope
and optical purities.
R
carbon−carbon and carbon−heteroatom bond formation.1,2
Among these, the construction of C−N bonds has attracted
considerable attention since nitrogen-containing heterocycles
have broad applications in the biological and medicinal
sciences.1a,b,3 Aziridines are versatile building blocks in organic
synthesis, and several excellent examples have been reported
involving nucleophilic ring opening.4,5 Recently, Wang and co-
workers described a copper(II)-catalyzed domino ring opening
and sp2-C−H functionalization of racemic aziridines to produce
tetrahydrotriazines (Scheme 1a).6 This tandem strategy provides
First, the reaction conditions were optimized using N-
methylaniline 1a and 2-phenyl-1-tosylaziridine 2a as the model
substrates and varying copper sources, oxidants, and solvents
(Table 1). The reaction produced imidazolidine 3a in 53%
conversion when substrates 1a and 2a were stirred at 60 °C for 6
h using 5 mol % of Cu(OTf)2 and 3.0 equiv of TBHP in toluene.
Between the four Cu sources screened, Cu(OTf)2 Cu(OAc)2,
CuCl2, and Cu(NO3)2·3H2O, the Cu(OTf)2 afforded the highest
conversion (entries 2−4). Subsequent screening of the solvents
revealed that the reaction went to completion in 1 h with 100%
conversion using 1,2-dichloroethane, whereas THF, DMSO, and
CHCl3 furnished 3a in 66−85% conversion (entries 5−8). When
the quantity of TBHP was decreased to 2.5 equiv, a slightly
longer reaction time (5 h) was required to produce 3a in 89%
conversion (entry 9). When the reaction was conducted using O2
and urea·H2O2 as the oxidants, 3a was formed in 8−9%
conversions (entries 11 and 12). A control experiment confirmed
that the formation of 3a was not observed in the absence of
Cu(OTf)2.
Scheme 1. Domino Reaction of Aziridines with Aniline
Derivatives
Using the optimized conditions, the substrate scope was
studied for the reaction of substituted anilines 1b−s with
aziridine 2a as a standard substrate (Scheme 2). N-Methylani-
lines 1b−e and 1g−m with 2-chloro, 3-cyano, 3-methoxy, 3-
methyl, 4-cyano, 4-isopropyl, 4-methyl, 4-nitro, 4-methylthio, 4-
(trimethylsilyl)ethynyl, and 4-trifluoromethoxy substituents in
the aryl ring underwent reaction to furnish imidazolidines 3b−e
an effective synthetic tool for the construction of two C−N
bonds in one-pot without isolating the intermediates, which
greatly enhances the synthetic efficiency.7 As a continuation of
our studies on domino reaction of aziridines,5e we report an
efficient stereospecific copper(II)-catalyzed nucleophilic ring
opening (SN2) and sp3 C−H functionalization of N-sulfonylazir-
idines with N-alkylanilines using tert-butyl hydroperoxide
Received: November 19, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03458
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a b
,
Table 1. Optimization of the Reaction Conditions
Scheme 2. Reaction of N-Methylanilines with Aziridine 2a
b
time
(h)
conv of 3a
entry
catalyst
oxidant
TBHP
solvent
(%)
1
2
3
4
Cu(OTf)2
Cu(OAc)2
CuCl2
toluene
toluene
toluene
toluene
6
6
6
6
53
18
23
39
TBHP
TBHP
TBHP
Cu(NO3)2·
3H2O
5
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
-
TBHP
TBHP
TBHP
TBHP
TBHP
O2
(CH2Cl)2
THF
1
1
1
1
5
1
1
1
100
66
6
7
DMSO
72
8
CHCl3
85
c
9
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
89
9
10
11
12
urea•H2O2
TBHP
8
nr
a
Reaction conditions: 1a (0.55 mmol), 2a (0.5 mmol), catalyst (5 mol
%), solvent (1 mL), 60 °C for 1 h; TBHP (1.5 mmol), 60 °C.
b
c
Determined by 400 MHz 1H NMR spectroscopy. TBHP (1.25
mmol) used. n.d. = not detected. n.r. = no reaction.
and 3g−m in 45−79% yields. The reaction of N-methylanilines
1n−q bearing 2,4-dimethyl, 2,5-dimethyl, 3,4-dimethyl, and 3,5-
dimethyl substituents afforded imidazolidines 3n−q in 71−76%
yields. Further, N-(methylamino)fluorene 1r underwent reaction
to give imidazolidine 3r in good yield. In contrast, N-
methylaniline 1f bearing a 4-amido group in the aryl ring led
to the nucleophilic ring opening of 2a; however, the subsequent
cyclization had not occurred to yield 3f. In addition, N-
methylpyridin-3-amine 1s showed no reaction with 2a to yield
3s. These results may be due to the chelation of the 4-amido 1f
and pyridine nitrogen 1s functionalities to Cu(OTf)2.
a
Reaction condition: 1b−s (0.55 mmol), 2a (0.5 mmol), Cu(OTf)2 (5
b
mol %), (CH2Cl)2 (1 mL), 60 °C, 1 h; TBHP (1.5 mmol). Isolated
yield.
Next, the reaction of anilines with different N-alkyl
substituents was studied (Scheme 3). N-Ethylaniline underwent
reaction to give imidazolidine 3t in moderate yield. In contrast,
N-benzyl- and N-isopropylanilines failed to produce the desired
products 3u−v, which may be due to the steric hindrance of the
alkyl substituents. However, tetrahydroisoquinoline 1w under-
went reaction to provide the tricyclic imidazolidine 3w in 90%
yield. The relative configuration of 3t and 3w was determined
using 2D NOESY (see the Supporting Information).
a b
,
Scheme 3. Reaction of N-Alkylanilines with Aziridine 2a
The protocol was further extended to the reaction of a series of
substituted N-tosylaziridines 2b−r with N-methylaniline 1a as a
representative example (Scheme 4). Aziridines 2b−k containing
2-chloro, 2-methyl, 3-bromo, 3-chloro, 4-acetoxy, 4-CH2Cl, 4-
bromo, 4-chloro, 4-fluoro, and 4-methyl substituents in the aryl
ring reacted to furnish the corresponding functionalized
imidazolidines 3x−ag in 69−89% yields. The reaction of 2-
arylaziridines bearing 2,4-dimethyl (2l) and 2,4,6-trimethyl (2m)
substituents produced imidazolidines 3ah and 3ai in 63% and
80% yield, respectively. Similar results were observed for 2-
naphthyl- (2n), 2-n-hexyl- (2o), 2-n-octyl- (2p), and 2-n-decyl-
substituted (2q) aziridines, affording 3aj−am in 61−81% yields.
In addition, N-(phenylsulfonyl)-2-arylaziridine (2p) underwent
reaction to give the desired imidazolidine 3an in 82% yield.
Finally, the enantiospecific synthesis of imidazolidines was
investigated with a series of N-methylanilines using optically
a
Reaction conditions: 1t−w (0.55 mmol), 2a (0.5 mmol), Cu(OTf)2
(5 mol %), (CH2Cl)2 (1 mL), 60 °C, 1 h; TBHP (1.5 mmol).
b
Isolated yield.
active aziridine 2a′ as a standard substrate (Scheme 5). This
reaction took place to afford the corresponding functionalized
imidazolidines with excellent optical purities (>95% ee). For
example, N-methylaniline underwent reaction to give imidazo-
lidine 3a′ in 97% ee, whereas N-methylanilines containing 3-
methyl, 4-methyl, 4-isopropyl, 2,4-dimethyl, 2,5-dimethyl, 3,4-
B
DOI: 10.1021/acs.orglett.6b03458
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Scheme 4. Reaction of 1a with Substituted Aziridines
Scheme 5. Reaction of N-Alkylanilines with Chiral Aziridine
2a′ −
a c
a
a
Reaction condition: 1a (0.55 mmol), 2b−r (0.5 mmol), Cu(OTf)2 (5
Reaction condition: 1 (0.55 mmol), 2a− (0.5 mmol), Cu(OTf)2 (5
b
b
mol %), (CH2Cl)2 (1 mL), 60 °C, 1 h; TBHP (1.5 mmol). Isolated
yield.
mol %), (CH2Cl)2 (1 mL), 60 °C, 1 h; TBHP (1.5 mmol). Isolated
c
yield. Determined by HPLC using Chiralcel OD with 2-propanol and
hexane as eluent (1:9).
dimethyl and 3,5-dimethyl substituents in the aryl ring produced
the corresponding imidazolidine derivatives 3e′, 3h′,i′, and 3n′−
q′ in 95−99% ee. A similar result was observed with
tetrahydroisoquinoline, affording 3w′ in 99% ee, whose structure
and absolute configuration were determined using single-crystal
X-ray analysis (see the Supporting Information). These results
suggest that the protocol can be utilized for the enantiospecific
synthesis of imidazolidines with excellent optical purity.
Scheme 6. Control Experiments
To gain insight into the catalytic cycle, the reaction of 1a was
performed with 2a in the presence of 1 equiv of 2,6-di-tert-butyl-
4-methylphenol (BHT) as a radical scavenger (Scheme 6, eq 1).
1H NMR and ESI-MS analyses of the reaction mixture revealed
the formation of BHT adduct 5 along with the acyclic 1,2-
diamine derivative 4 and imidazolidine 3a (see the Supporting
Information).13 Next, the cyclization of 4 was investigated using
Cu(OTf)2 and TBHP (Scheme 6, eq 2). The reaction occurred
to produce 3a in 91% yield. However, in the absence of
Cu(OTf)2, 4 showed no reaction (Scheme 6, eq 2). These results
suggest that the N-methyl C−H bond selectively undergoes
homolysis compared to the benzylic C−H bond. This effect may
be due to the steric hindrance of the benzylic C−H bond toward
the bulky BHT radical. Thus, coordination of Cu(OTf)2 with the
nitrogen lone pair of aziridine and its subsequent SN2 reaction
with N-methylaniline can give a (Scheme 7).5e Single-electron
transfer (SET) reduction of Cu(OTf)2 using the nitrogen lone
pair of a may lead to the formation of an intermediate b.2e
Homolysis of the N-methyl C−H bond using tert-butoxy radical
can generate imine derivative c, which may lead to cyclization to
Scheme 7. Proposed Catalytic Cycle
−
furnish the target heterocycles. Oxidation of Cu(OTf)2 using
TBHP may regenerate Cu(OTf)2 to complete the catalytic cycle.
C
DOI: 10.1021/acs.orglett.6b03458
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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The proposed catalytic cycle also explains the requirement of
excess TBHP to achieve high yields of the products.
In summary, a copper-catalyzed domino reaction of N-
alkylanilines with aziridines is presented for the construction of
1,3-imidazolidines in the presence of TBHP via a sequence of
selective nucleophilic ring opening (SN2), C(sp3)−H function-
alization, and C−N bond formation. The regio- and stereo-
specificities, shorter reaction time, high yields, and functional
group tolerance are important practical advantages of this
strategy.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03458.
Experimental procedures, characterization data, HPLC
1
chromatograms, H NMR and HRMS of the reaction
mixture of 3a, 4, and 5, and NMR spectra of the products
(PDF)
(6) Hong, D.; Lin, X.; Zhu, Y.; Lei, M.; Wang, Y. Org. Lett. 2009, 11,
5678.
X-ray data for compound 3w′ (CIF)
(7) Tietze, L. F. Chem. Rev. 1996, 96, 115.
(8) Caution: the concentration of peroxide-containing mixtures is an
explosive hazard. Take appropriate safety measures including, but not
limited to, the use of a blast shield and other personal protective
equipment. Decomposition of any remaining peroxides prior to
concentration is a best practice.
(9) For imidazolidines ligands and catalysts, see: (a) Citadelle, C. A.;
Nouy, E. L.; Bisaro, F.; Slawin, A. M. Z.; Cazin, C. S. J. Dalton Trans.
2010, 39, 4489. (b) Allen, A. E.; MacMillan, D. W. C. J. Am. Chem. Soc.
2011, 133, 4260. (c) Hopkinson, M. N.; Richter, C.; Schedler, M.;
Glorius, F. Nature 2014, 510, 485.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tpunni@iitg.ernet.in.
ORCID
Tharmalingam Punniyamurthy: 0000-0003-4696-8896
Notes
The authors declare no competing financial interest.
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D.; Nauen, R.; Sertchook, R.; Stevenson, B. J.; Paine, M. J. I.; Morin, S.;
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ACKNOWLEDGMENTS
■
We thank the Science and Engineering Research Board (EMR-
2015-43) and the Council of Scientific and Industrial Research
(02(0255)/16/EMR-II) for financial support. M.S. thanks the
University Grants Commission. A.B. thanks the Council of
Scientific and Industrial Research for Research Fellowships. We
are grateful to the Central Instrumentation Facility, Indian
Institute of Technology Guwahati, for NMR, single-crystal X-ray,
and mass facilities.
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DOI: 10.1021/acs.orglett.6b03458
Org. Lett. XXXX, XXX, XXX−XXX