Synthesis of aziridines by visible-light induced decarboxylative cyclization of N-aryl glycines and diazo compounds

Article abstract of DOI:10.1007/s11426-015-5513-8

A visible-light induced decarboxylative aza-Darzens reaction between N-aryl glycines and diazo compounds was developed, which affords various mono-substituted aziridines in good yields.

Full text of DOI:10.1007/s11426-015-5513-8

SCIENCE CHINA
Chemistry
February 2016 Vol.59 No.2: 1–4
doi: 10.1007/s11426-015-5513-8
• COMMUNICATIONS •
· SPECIAL TOPIC · Organic Photochemistry
doi: 10.1007/s11426-015-5513-8
Synthesis of aziridines by visible-light induced decarboxylative
cyclization of N-aryl glycines and diazo compounds
Yong Liu1,2, Xichang Dong1, Guojun Deng2* & Lei Zhou1*
1School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China
2Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of Education; College of Chemistry, Xiangtan University,
Xiangtan 411105, China
Received August 21, 2015; accepted September 10, 2015
A visible-light induced decarboxylative aza-Darzens reaction between N-aryl glycines and diazo compounds was developed,
which affords various mono-substituted aziridines in good yields.
visible light, diazo compound, decarboxylation, aza-Darzens reaction
Citation:
Liu Y, Dong XC, Deng GJ, Zhou L. Synthesis of aziridines by visible-light induced decarboxylative cyclization of N-aryl glycines and diazo com-
pounds. Sci China Chem, doi: 10.1007/s11426-015-5513-8
Aziridines are versatile and powerful intermediates in or-
ganic synthesis, acting as precursors of many complex
molecules due to the strain incorporated in their skeletons
[1–5]. They are also key structural motifs which are widely
found in natural products and biologically important mole-
cules [6–9]. To date, a number of catalytic protocols have
been developed for the synthesis of aziridines [10–16]. One
of the oldest and most flexible methods is the Lewis or
Bronsted acid-promoted aziridination of imines with diazo
compounds [15,17–21]. These reactions proceed through
the nucleophilic addition of diazo carbon to imines followed
by 3-exo-tet cyclization of the amide anions, which are of-
ten described as “aza-Darzens reactions”.
tinuation of this work, we envisioned that the visible-light
photoredox-mediated decarboxylation of N-aryl glycine
would afford an -amino alkyl radical [26,27], which could
be further oxidized in the presence of oxygen to generate
active imine [28]. The attack of imine by diazo compound
would lead to intermediate B. In contrast to the intermediate
A, intermediate B containing a negative amide anion might
undergo a 3-exo-tet cyclization instead of the deprotonation,
which ultimately forms aziridine as the product. In this
study, we endeavored to develop a decarboxylative aza-
Darzens reaction between N-aryl glycines and diazo com-
pounds for the synthesis of mono-substituted aziridines us-
ing visible-light photoredox catalysis [29–32].
Our group [22] have recently reported a visible-light in-
duced oxidative coupling of tertiary amines and diazo
compounds (Scheme 1). This process involves the nucleo-
philic addition of diazo compound to the in situ generated
iminium ion [23–25], followed by the deprotonation of in-
termediate A to give -amino--diazo compound. As a con-
Initially, when the mixture of N-phenyl glycine 1a, ethyl
diazoacetate 2a and 1 mol% of Rose Bengal (RB) in MeCN
was irradiated by a 5 W blue LED at room temperature for
6 h, we obtained the desired N-phenyl aziridine 3a in 40%
yield (Table 1, Entry 1). Several solvent such as 1,4-diox-
ane, DCE, MeOH, EtOH, and CF3
CH OH, were screened
2
for this transformation, and MeOH was found to be the best
one (Table 1, Entries 2–6). Further optimizations indicated
eosin Y, eosin B, Ru(bpy)3Cl2 were also effective photo-
*Corresponding authors (email: gjdeng@xtu.edu.cn; zhoul39@mail.sysu.edu.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2015
chem.scichina.com link.springer.com

2
Liu et al. Sci China Chem February (2016) Vol.59 No.2
Scheme 1 Visible-light induced oxidative cross coupling and decarboxylative aza-Darzen reaction between amines and diazo compounds.
catalysts for the reaction, but they were not better than rose
bengal (Table 1, Entries 7, 8 and 10). None of aziridine 3a
was detected when methylene blue was employed (Table 1,
Entry 9). Although the Lewis acid has been reported to
promote the aza-Darzens reaction between imines and diazo
compounds, the addition of 0.2 equiv. of Zn(OTf)2 has a
negative effect on this photocatalytic reaction (Table 1, En-
try 11). When the reaction was carried out in the open air
condition, only 16% yield of 3a was observed (Table 1,
Entry 12). The diminished yield might be attributed to the
low concentration of oxygen and the moisture in the air,
which accelerate the decomposition of the active intermedi-
ate. The control experiments indicated the reaction could
not proceed in the absence of either light or the photocata-
lyst (Table 1, Entries 13 and 14). A kinetic study demon-
strated that the best reaction time is 6 h. The side products
might be generated from the further oxidation of aziridine
3a through iminium ions as reactive intermediates (for the
details see the Supporting Information online) [33].
Table 1 Optimization of reaction conditions a)
Having established the optimized reaction conditions, an
investigation into the versatility and functional group toler-
ance of this reaction process was performed. First, the pho-
tocatalytic decarboxylative cyclization of various N-aryl
glycines with ethyl diazoacetate was examined. As shown
in Table 2, para-, meta-, and ortho-substituted N-phenyl
glycines all worked well in the present system to afford the
corresponding aziridines 3b–3d in good to excellent yields
(Table 2, Entries 2–4). Both electron-donating groups such
as methoxy, and electron-withdrawing groups such as fluo-
ro, chloro, and bromo could be well-tolerated (Table 2, En-
tries 5–8). Unfortunately, none of the desired product was
detected when a strong electron-withdrawing NO2 group
was introduced to the para-position of N-aryl gylcine (Table
2, Entry 9). The reaction was found to be significantly af-
fected by the N-protection groups, glycines protected by
electron-withdrawing groups, such as Boc, Ts, and Ac, were
not compatible for this transformation. Switching the ethyl
group in diazoacetate to isopropyl, n-butyl or tert-butyl
group led to desired aziridines 3j–3l in slightly diminished
yields (Table 2, Entries 10–12). We were pleased to find
that diazoacetates with functional groups such as chloro-
ethyl (3m), allyl (3n), cinnamyl (3o), and propargyl (3p)
were also suitable substrates for the reaction (Table 2, En-
tries 13–16). Finally, diazo ketone was tested, and its cy-
clization with N-phenyl glycine gave the aziridine 3p in the
yield of 34% (Table 2, Entry 15). The low yield might be
attributed to the weaker nucleophilicity of diazoketone.
Entry
1
Photocatalyst
rose bengal
rose bengal
rose bengal
rose bengal
rose bengal
rose bengal
eosin Y
Solvent
MeCN
Yield (%) b)
40
15
<5
79
57
33
50
61
0
2
1,4-dioxane
DCE
3
4
MeOH
EtOH
5
6
CF3CH2OH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
7
8
eosin B
9
methylene blue
Ru(bpy)3Cl2
rose bengal
rose bengal
rose bengal
none
10
11 c)
12 d)
13 e)
14 f)
53
35
16
NT
NT
a) Reaction conditions: N-phenyl glycine 1a (0.26 mmol), ethyl diazo-
acetate 2a (0.2 mmol), photocatalyst (1 mol%), 5 W blue LED at r.t. under
1 atm of oxygen for 6 h; b) yields were determined by H NMR spectros-
copy using mesitylene as internal standard; c) 0.2 equiv. of Zn(OTf)2 was
added; d) in the open air; e) without light; f) in the absence of photocata-
lyst.
1

Liu et al. Sci China Chem February (2016) Vol.58 No.2
3
Table 2 Visible-light induced decarboxylative cyclization of N-aryl
glycines 1 and diazo compounds 2 a)
the cation radical A. Decarboxylation of A leads to -amino
alkyl radical B. Further oxidation of B by superoxide radical
gives iminium ion C, which then deprotonates to generate
active imine D. Finally, aziridines 3 were formed by the
nucleophilic addition of diazo compounds on the C=N
bond, followed by an intramolecular nucleophilic attack of
the nitrogen atom on another carbon atom with N2 as the
leaving group.
In conclusion, we have developed a metal-free, visible-
light induced decarboxylative cyclization of N-aryl glycines
and diazo compounds. The reaction provides a useful alter-
native route to mono-substituted aziridines by using easily
available amino acid derivatives as the starting materials.
Further investigation on the scope as well as the synthetic
applications is ongoing in our group.
Entry
1
R1
H
R2
OEt
Product
3a
Yield (%) b)
75
70
62
92
60
52
71
70
0
2
p-Me
m-Me
o-Me
p-OMe
p-F
p-Cl
p-Br
p-NO2
H
OEt
3b
3
OEt
3c
4
OEt
3d
5
OEt
3e
6
OEt
3f
Acknowledgments This work was supported by the National Natural
Science Foundation of China (21472249, 21202207), the Pearl River S&T
Nova Program of Guangzhou (2013J2200017), and the Fundamental Re-
search Funds for the Central Universities (14lgzd05).
7
OEt
3g
8
OEt
3h
9
OEt
3i
Conflict of interest The authors declare that they have no conflict of
interest.
10
11
12
13
14
15
16
17
OiPr
3j
49
67
51
52
48
54
55
34
H
OnBu
3k
Supporting information The supporting information is available online
at http://chem.scichina.com and http://link.springer.com/journal/11426.
The supporting materials are published as submitted, without typesetting or
editing. The responsibility for scientific accuracy and content remains
entirely with the authors.
H
OtBu
3l
H
OCH2CH2Cl
OCH2CH=CH2
OCH2CH=CHPh
OCH2C≡CH
p-ClC6H4
3m
3n
H
H
3o
1
Stanković S, D’hooghe M, Catak S, Eum H, Waroquier M, Van
Speybroeck V, De Kimpe N, Ha HJ. Chem Soc Rev, 2012, 41: 643–
655
H
3p
H
3q
2
3
4
Lu P. Tetrahedron, 2010, 66: 2549–2560
a) Reaction conditions: N-aryl glycine 1 (0.26 mmol), diazo compound
2 (0.2 mmol), rose bengal (RB, 1 mol%), MeOH (0.8 mL), O2 balloon, 5 W
blue LED at room temperature for 6 h; b) isolated yields.
Florio S，Luisi R. Chem Rev, 2010, 110: 5128–5157
Olsen CA, Franzyk H, Jaroszewski JW. Eur J Org Chem, 2007:
1717–1724
5
6
Shipman M. Synlett, 2006: 3205–3217
Komano K, Shimamura S, Inoue M, Hirama M. J Am Chem Soc,
2007, 129: 14184–14186
The nucleophilicity of ethyl diazoacetate is 4.91, while the
N parameter of diazoketone is around 3.96 [34].
A plausible mechanism for the present visible-light in-
duced decarboxylative cyclization of N-aryl glycines and
diazo compounds was proposed in Scheme 2. Initially,
photoexcitation of RB by visible light generates excited
RB*, which is readily quenched by N-aryl glycine to give
7
8
9
Na Y, Wang S, Kohn H. J Am Chem Soc, 2002, 124: 4666–4677
Frmeier S, Metzger JO. Eur J Org Chem, 2003: 649–659
Regueiro-Ren A, Borzilleri RM, Zheng X, Kim SH, Johnson JA,
Fairchild CR, Lee FYF, Long BH, Vite GD. Org Lett, 2001, 3: 2693–
2696
10 Adams CS, Weatherly CD, Burke EG, Schomaker JM. Chem Soc
Rev, 2014, 43: 3136–3163
11 Degennaro L, Trinchera P, Luisi R. Chem Rev, 2014, 114: 7881–
7929
12 Callebaut G, Meiresonne T, De Kimpe N, Mangelinckx S. Chem Rev,
2014, 114: 7954–8015
13 Jenkins DM. Synlett, 2012: 1267–1270
14 Pellissier H. Tetrahedron, 2010, 66: 1509–1555
15 Sweeney J. Eur J Org Chem, 2009: 4911–4919
16 Singh GS, D’hooghe M, De Kimpe N. Chem Rev, 2007, 107: 2080–
2135
17 Zhao Y, Wang G, Zhou S, Li Z, Meng X. Org Biomol Chem, 2014,
12: 3362–3365
18 Bew SP, Carrington R, Hughes DL, Liddle J, Pesce P. Adv Synth
Catal, 2009, 351: 2579–2588
19 Kubo T, Sakaguchi S, Ishii Y. Chem Commun, 2000: 625–626
20 Rasmussen KG, Jørgensen KA. J Chem Soc Perkin Trans 1, 1997:
1287–1292
21 Rasmussen KG, Jørrgensen KA. J Chem Soc Chem Commun, 1995:
Scheme 2 Plausible mechanism.

4
Liu et al. Sci China Chem February (2016) Vol.59 No.2
1401–1402
28 Chen L, Chao CS, Pan Y, Dong S, Teo YC, Wang J, Tan CH. Org
Biomol Chem, 2013, 11: 5922–5925
29 Shang R, Liu L. Sci China Chem, 2011, 54: 1670–1687
30 Weaver JD, RecioIII A, Grenning AJ, Tunge JA. Chem Rev, 2011,
111: 1846–1913
22 Xiao T, Li L, Lin G, Mao ZW, Zhou L. Org Lett, 2014, 16:
4232–4235
23 Prier CK, Rankic DA, MacMillan DWC. Chem Rev, 2013, 113:
5322–5363
24 Xie J, Jin H, Xu P, Zhu C. Tetrahedron Lett, 2014, 55: 36–48
25 Shi L, Xia WJ. Chem Soc Rev, 2012, 41: 7687–7697
26 Noble A, McCarver SJ, MacMillan DWC. J Am Chem Soc, 2015,
137: 624–627
31 Rodríguez N, Gooßen LJ. Chem Soc Rev, 2011, 40: 5030–5048
32 Dzik WI, Lange PP, Gooßen LJ. Chem Sci, 2012, 3: 2671–2678
33 Kim E, Choi S, Kim H, Cho EJ. Chem Eur J, 2013, 19: 6209–6212
34 Bug T, Hartnagel M, Schlierf C, Mayr H. Chem Eur J, 2003, 9:
4068–4076
27 Zuo Z, MacMillan DWC. J Am Chem Soc, 2014, 136: 5257–5260