Direct aza-darzens aziridination of N-tosylimines with 2-bromomalonates for the synthesis of highly functionalized donor-acceptor aziridines

Article abstract of DOI:10.1002/adsc.201200628

An approach to highly functionalized donor-acceptor aziridines by the aziridination of N-tosylimines and 2-bromomalonates in the presence of sodium hydride under mild conditions has been developed. The high-yielding reaction has a relatively broad scope and can be easily scaled up to the gram level.

Full text of DOI:10.1002/adsc.201200628

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DOI: 10.1002/adsc.201200628
Direct Aza-Darzens Aziridination of N-Tosylimines with
2-Bromomalonates for the Synthesis of Highly Functionalized
Donor-Acceptor Aziridines
Xingxing Wu,a Lei Li,a and Junliang Zhanga,b,*
a
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal
University, 3663 N. Zhongshan Road, Shanghai 200062, Peopleꢀs Republic of China
Fax : (+86)-021-6223-5039; e-mail: jlzhang@chem.ecnu.edu.cn
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
b
Sciences, Shanghai 200032, Peopleꢀs Republic of China
Received: July 18, 2012; Revised: September 22, 2012; Published online: December 4, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200628.
Abstract: An approach to highly functionalized
donor-acceptor aziridines by the aziridination of N-
tosylimines and 2-bromomalonates in the presence
of sodium hydride under mild conditions has been
developed. The high-yielding reaction has a relative-
ly broad scope and can be easily scaled up to the
gram level.
dines has been synthesized by these protocols, among
which, aziridine-2,2-diesters are special members as
one kind of donor-acceptor aziridine. These highly
functionalized three-membered nitrogen heterocyclic
molecules are of particular significance, not only be-
cause of the pronounced biological activities as inhibi-
tors,[3] but also for their wide applications in organic
synthesis. Since Huisgenꢀs[4j] pioneering work, aziri-
dine-2,2-diesters have been largely utilized as precur-
sors of azomethine ylide (AMYs) intermediates by
thermal or photolytic aziridine ring-opening.[4] Re-
cently, Carrie,[5a] Johnson,[5b] Engle[5c] and our
Keywords: aziridination; 2-bromomalonates; donor-
acceptor aziridines; sodium hydride; N-tosylimines
group[5d–g] achieved the Lewis acid-catalyzed C C
À
bond heterolysis, leading to AMYs, and providing
Aziridines are highly useful synthetic intermediates in general and direct access to five-membered heterocy-
organic synthesis and structural units of many biologi- cles, such as 1,3-oxazolidines,[5e] 1,3-imidazolidines,[5g]
cally natural products and drugs.[1] Various synthetic pyrroles[5a,d] and pyrrolines[5f]. However, in contrast
methods, including Wenker synthesis,[2a,b] aza-Darzens with the extensive studies on the synthesis of aziridine
reaction,[2c–g] Corey–Chaykovsky aziridination,[2h,i] re- 2-monocarboxylate,[6] the preparation of aziridine 2,2-
actions of a-halo ketimines with nucleophiles,[2j–l] or dicarboxylates is not always straightforward.[3d,7–9] Typ-
the direct aziridination of olefins[2m,n] have been large- ical synthetic methods are illustrated in Scheme 1, in-
ly reported. So far, a vast and diverse family of aziri- cluding: (a) Michael-type addition of diphenylsulfi-
Scheme 1. Approaches to aziridine-2,2-dicarboxylates.
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Xingxing Wu et al.
Table 1. Screening of the reaction conditions.[a]
COMMUNICATIONS
Entry
Base
Solvent
Time [h]
Yield [%][c]
1
2
t-BuOK
Cs2CO3
K2CO3
K2CO3
NaOH
KOH
KOH
DBU
NaH
NaH
CH3CN
CH3CN
CH3CN
acetone
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
0.5
2.5
3.5
4
4
4
4
8
0.16
0.16
83
74
69
73
81
86
85
70
92
91
Scheme 2. Proposed mechanism for the formation of aziri-
dine-2,2-dicarboxylates.
3[b]
4[b]
5
mide,[3d] hydroxylamino derivatives,[3a–c] or nosyloxy
carbamates[7] to the electron-deficient alkenes to pro-
duce the desired aziridines (Type I); (b) aziridination
of N-tosylimines with activated methylene compounds
6
7[b]
8
9
10
induced by PhIACHTUNGTRENNUNG
(OAc)2/TBAB[8a] or PhI=O[8b] under
[a]
Reaction conditions: 1a (0.5 mmol), 2a (1.1 equiv.), and
base (1.1 equiv.) in 5 mL of solvent at room temperature.
2 equiv of base was used.
mild conditions (Type II); (c) Cu(II)-catalyzed formal
aziridination of 2-alkyl-substituted 1,3-dicarbonyl
compounds with PhI=NTs.[9] (Type III). Type I reac-
tions (a, b, c) suffer from several drawbacks, such as
the not commercial availability of starting material
for reactions (b) and (c), the limited reaction scope
for reactions of type (a), or the use of transition
metals in reactions (b). The second and third classes
[b]
[c]
Isolated yield.
We began our investigation with N-tosylimine 1a,
of transformations are generally more efficient in which was readily prepared from the condensation of
terms of the high yield of the products and broad re- p-toluenesulfonamide with benzaldehyde,[10] and the
action scope. However„ an excess of the high-cost hy- inexpensive diethyl 2-bromomalonate 2a as model
pervalent iodine reagents (2–3 equiv,) is required and substrates. As illustrated in Table 1, treatment of 1a
an equivalent amount of by-product iodobenzene is and 2a (1.1 equiv.) with t-BuOK (1.1 equiv.) in aceto-
generated, which makes the work-up step quite hard nitrile provided aziridine 3aa in 83% yield (Table 1,
on a large scale.[8,9] Considering the significance of the entry 1). Other selected representative bases including
aziridine-2,2-diesters in organic synthesis and pharma- Cs2CO3, K2CO3, NaOH, or DBU were tested to opti-
ceuticals, the facile and practical preparation of 2,2-di- mize the reaction conditions. Notably, relatively lower
functionalized aziridines from readily available mate- product yields (69–81%) were afforded with relatively
rials without the use of transition metals and high- longer reaction times (2.5–8 h), probably due to the
cost reagents is still highly desirable. Herein, in this weak alkalinity of the bases. (Table 1, entries 2-5 and
context we describe an efficient direct aza-Darzens 8) A slight increase in yield was observed when KOH
aziridination of N-tosylimines with 2-functionalized was employed as the base, and a higher KOH loading
malonates under mild conditions, providing a facile (2 equiv.) only gave a 1% decrease in product yield
and practical route to synthetic useful aziridinyl die- (Table 1, entries 6 and 7). To our delight, the reaction
sters.
worked very well in CH3CN at room temperature by
During the course of our studies on the cycloaddi- using NaH (1.1 equiv.) as the base, which provided
À
ton reactions of donor-acceptor aziridines via C C the aziridine 3aa in 92% isolated yield (Table 1,
bond cleavage,[5d–g] we became interested in develop- entry 9). Replacement of CH3CN by THF as the sol-
ing a novel and easy access to this class of aziridines, vent failed to improve the yield (Table 1, entry 10).
if applicable, which would in turn enhance the syn-
The reaction scope of this direct aziridination of N-
thetic value of the aziridine-2,2-diesters, especially in tosylimines with 2-bromomalonate derivatives was
the synthesis of N-heterocycles. Scheme 2 shows further explored under the optimal conditions
a mechanism for our proposed annulation reaction. (Table 2). For reactions of aromatic imines 1 with di-
Nucleophilic addition of enolate, generated from the ethyl 2-bromomalonate 2a, both electron-deficient
activated methylene compound under basic condi- and electron-rich arylaldimines reacted well to afford
tions, to the N-tosylimine gives the intermediate IA, the corresponding aziridines in good to high yields
which undergoes subsequent intramolecular nucleo- within 10–20 min (Table 2, entries 1–11). Some obser-
philic substitution to afford the donor-acceptor aziri- vations were particularly noteworthy: (i) generally,
dines.
the aromatic N-tosylimines bearing electron-with-
drawing groups worked better than those electron-
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Adv. Synth. Catal. 2012, 354, 3485 – 3489

Direct Aza-Darzens Aziridination of N-Tosylimines with 2-Bromomalonates
Table 2. Reaction scope of the aziridination of N-tosylimines
We next sought to evaluate the scope of this practi-
cal methodology with respect to the N-tosyl-
with 2-bromomalonates.[a]
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
dard conditions. It was pleasing to find that the ex-
pected alkyl-substituted aziridinyl-2,2-diesters could
be prepared in good to excellent yields (Table 2, en-
tries 12–15). It was noteworthy that only moderate
yields can be obtained by Fanꢀs approach.[9a]. Finally,
a series of 2-bromomalonates were examined, which
showed the similar reactivity as diethyl 2-bromomalo-
nate (2a) (Table 2, entries 16–23). Gratifyingly, the re-
actions of sterically hindered tert-butyl and neopentyl
2-bromomalonates with imine 1a also gave the corre-
sponding aziridines in excellent yields within 20 min
(Table 2, entries 18–23). Notably, those aziridines
bearing a neopentyl ester group are much more stable
than those substituted by ethyl, or methyl ester
groups (Table 2, entries 19–23). To demonstrate the
synthetic utility of this protocol, the reaction – scaled
up to 20 mmol – was performed under the optimal
conditions, which also proceeded smoothly to give
7.18 g of aziridine 3aa in 86% yield (Table 2,
entry 24). It was noteworthy that aziridine 3qa bear-
ing the easy removable N-Boc protecting group can
also be prepared from the corresponding N-Boc-
imine 1q and 2a by the use of this protocol [Eq. (1)].
Entry
R1
R2
Yield [%][d]
1
2
3
4
5
6
7
8
Ph (1a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Me (2b)
i-Pr (2c)
t-Bu (2d)
t-BuCH2 (2e)
t-BuCH2 (2e)
t-BuCH2 (2e)
t-BuCH2 (2e)
t-BuCH2 (2e)
Et (2a)
3aa (92)
3ba (92)
3ca (95)
3da (96)
3ea (99)
3fa (99)
3ga (95)
3ha (51)[b]
3ia (81)
3ja (83)
3ka (91)
3la (82)
3ma (97)
3na (99)
3oa (91)
3ab (92)
3ac (95)
3ad (89)
3ae (99)
3ce (97)
3de (98)
3ie (95)
3pe (96)
3aa (86)
p-FC6H4 (1b)
p-ClC6H4 (1c)
p-BrC6H4 (1d)
p-O2NC6H4 (1e)
p-NCC6H4 (1f)
o-BrC6H4 (1g)
p-MeOC6H4 (1h)
p-MeC6H4 (1i)
m-MeC6H4 (1j)
1-naphthyl (1k)
H (1l)
Me (1m)
Et (1n)
i-Bu (1o)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24[c]
p-ClC6H4 (1c)
p-BrC6H4 (1d)
p-MeC6H4 (1i)
p-i-PrC6H4 (1p)
Ph (1a)
[a]
Standard conditions: 1 (0.5 mmol), 2 (1.1 equiv.), and
NaH (1.1 equiv.) in 5 mL of CH3CN at room tempera-
ture.
82% NMR yield was detected for the crude product
(CH2Br2 as a standard).
Reaction on the gram-level scale: 1a (20 mmol),
1.05 equiv. of 2a, and 1.05 equiv. of NaH were used.
Isolated yield.
[b]
[c]
[d]
In summary, we have developed an efficient, con-
venient and practical method for the synthesis of
donor-acceptor aziridines from N-tosyl- or N-Boc-
imines and 2-bromomalonates in the presence of
rich ones. For instance, the 4-nitrophenyl-N-tosyl- NaH. The wide substrate scope, excellent yield (up to
ACHTUNGTRENNUNGimine (1e) and 4-cyanophenylimine (1f) both gave the 99%), simple operating and purification procedures,
desired products in nearly quantitative yield (Table 2, as well as the readily available and low-cost starting
entries 5 and 6); (ii) aziridines bearing the electron- materials, provide a practical method for the prepara-
donating aromatic group were not stable and decom- tion of highly synthetic important donor-acceptor azir-
posed during the purification by column chromatogra- idines. Further investigations including synthetic ap-
phy, which resulted in a relatively low isolated yield plications of the aziridines are underway and will be
(Table 2, entries 8–10). For example, for the imine reported in due course.
(1h) derived from 4-methoxybenzaldehyde, the reac-
tion was clean as determined by the TLC analysis to
give an 82% NMR yield, while only a 51% isolated
Experimental Section
yield of 3ha can be obtained due to the easy decom-
position[8a] upon work-up to give
a by-product
[5b,d]
Typical Procedure for Aziridination of N-Tosylimines
1 with 2-Bromomalonates 2
TsNHCH
(CO2Et)2
(Table 2, entry 8); (iii) when 1-
naphthyl-derived imine (1k) was employed as the sub-
strate, the reaction also worked very well to give the
product in 91% yield (Table 2, entry 11).
In an inert atmosphere, a solution of imine 1 (0.5 mmol,
1 equiv.), 2-bromomalonate 2 (0.55 mmol, 1.1 equiv.) in
Adv. Synth. Catal. 2012, 354, 3485 – 3489
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Xingxing Wu et al.
COMMUNICATIONS
5 mL of dry CH3CN was cooled to 08C, and treated with
NaH (22 mg, 60% dispersion in mineral oil, 1.1 equiv.). The
resultant mixture was warmed up and stirred at room tem-
perature. After 10–20 min when the reaction was completed
(determined by TLC analysis), the reaction mixture was
then passed over a small plug of silica gel eluted with
CH2Cl2 to remove the excess NaH and resulting NaBr. After
evaporation under reduced pressure, usually, the crude prod-
uct was of sufficient purity; it can be quickly purified by
flash chromatography on 10 cm-long silica gel column
(eluent, 10–30% ethyl acetate in petroleum ether) to afford
the desired product 3. The resulting compounds were con-
firmed by 1H NMR and 13C NMR.
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1
Experimental details and copies of H/13C NMR spectra of
all new compounds are available in the Supporting Informa-
tion.
Acknowledgements
We are grateful to National Natural Science Foundation of
China (20972054), 973 program (2009CB825300), Fok Ying
Tung Education Foundation (121014) and the Program of
Eastern Scholar at Shanghai Institutions of Higher Learning
for financial support.
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