A Cu(I)-catalyzed C-H α-amination of esters. Direct synthesis of hydantoins

Article abstract of DOI:10.1021/ja802242h

This paper describes a novel intermolecular α-amination process of esters using CuCl as catalyst and di-tert-butyldiaziridinone as nitrogen source. A variety of hydantoins can be formed effectively under mild reaction conditions. Copyright

Full text of DOI:10.1021/ja802242h

Published on Web 05/13/2008
A Cu(I)-Catalyzed C-H r-Amination of Esters. Direct Synthesis of Hydantoins
Baoguo Zhao, Haifeng Du, and Yian Shi*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
Received March 26, 2008; E-mail: yian@lamar.colostate.edu
Table 1. Cu(I)-Catalyzed R-Amination of Estersa
Amines and their derivatives are very important functional
moieties present in a wide variety of biologically and chemically
significant molecules. The C-N bond formation represents one of
very important synthetic transformations. Various effective methods
have been developed for the construction of C-N bonds.1 Convert-
ing C-H bonds to C-N bonds by direct amination is also an
attractive strategy to introduce nitrogens to molecules. Significant
progress has been made in this area.2,3 During our studies on
amination with diaziridinones,4,5 we found that ester 1 can be
aminated at the R position using di-tert-butyldiaziridinone (2)6,7
as a nitrogen source and CuCl as a catalyst, leading to a direct
formation of hydantoin (3) (Scheme 1). Herein we wish to report
our preliminary results on this subject.
Treating methyl phenylacetate (1a) with di-tert-butyldiaziridinone
(2) and 10 mol % of CuCl-P(n-Bu)3 (1:1) in CDCl3 at 65 °C in an
NMR tube for 12 h gave hydantoin 3a with 54% conversion
(Scheme 1). Lower conversions were obtained with the correspond-
ing ethyl ester (44%) and tert-butyl ester (25%) under the same
reaction conditions, suggesting that the bulkier esters are less
effective toward the amination. Further studies show that the
reaction can be improved by slow addition of di-tert-butyldiaziri-
dinone over 8 h. Under this protocol, hydantoin 3a was obtained
in 79% yield using 5 mol % of CuCl-P(n-Bu)3 (1:1) as catalyst
(Table 1, entry 1) (the X-ray structure of 3a is shown in Figure 1).
As shown in Table 1, various methyl arylacetates were efficiently
R-aminated to give the corresponding hydantoin derivatives in good
yields (Table 1, entries 1-6). Heteroaryl and ꢀ,γ-unsaturated methyl
esters were also R-aminated to give the corresponding hydantoins
with somewhat lower yields (Table 1, entries 7-9). However,
aliphatic methyl esters such as methyl octanoate are not effective
substrates under the current reaction conditions.
The deprotection of the resulting hydantoin derivatives was
investigated with compound 3a. Both tert-butyl groups were
smoothly removed with CH3SO3H in hexane (1:10, v/v) at 65 °C
for 3.5 h to give compound 4 in 92% yield. However, when the
deprotection was carried out at room temperature, one tert-butyl
group was selectively removed to give compound 5 in 96% yield
(Scheme 2). The structure of compound 5 was determined by the
X-ray structure of its acetyl derivative 5a (Scheme 2) (Figure 1).
The ability of selective removal of the protection groups provides
opportunities to introduce different groups on the two nitrogen
atoms of hydantoins if it is desired.
While an exact reaction mechanism awaits further study, a
plausible catalytic cycle is shown in Scheme 3. The CuCl
probably first reduces the N-N bond to form species 64c,8–11 or
Scheme 1
a All reactions were carried out with ester (1) (0.4 mmol),
di-tert-butyldiaziridinone (2) (0.8 mmol), CuCl-P(n-Bu)3 (1:1) (0.02
mmol) in CHCl3 (0.05 mL) at 65 °C under argon for 12 h unless
otherwise stated. For entry 7, the reaction scale was doubled. For entries
1 and 3, the reaction scale was doubled except CHCl3 (0.05 mL).
b Isolated yield based on ester.
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7220 J. AM. CHEM. SOC. 2008, 130, 7220–7221
10.1021/ja802242h CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Supporting Information Available: Complete ref 14c, the ami-
nation and deprotection procedures, the characterization of amination
products, and the X-ray data of compounds 3a and 5a along with
the 1H and 13C NMR spectra of amination products. This material
is available free of charge via the Internet at http://pubs.acs.org.
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Figure 1. The X-ray structure of hydantoins 3a and 5a.
Scheme 2
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Scheme 3. A Proposed Catalytic Cycle for the R-Amination
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Acknowledgment. This paper is dedicated to the memory of
Professor Albert I. Meyers. We are grateful for the generous
financial support from the Camille and Henry Dreyfus Foundation.
JA802242H
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