Guanidinium Ylide mediated aziridination from arylaldehydes: Scope and limitations in the formation of unactivated 3-arylaziridine-2-carboxylates

PAPER

▌2201

^pG^apu^eranidinium Ylide Mediated Aziridination from Arylaldehydes: Scope and

Limitations in the Formation of Unactivated 3-Arylaziridine-2-carboxylates

Formation of Unactivated 3-Arylaziridine-2-carboxylates

Yukiko Oda, Kihito Hada, Marie Miyata, Chisato Takahata, Yukiko Hayashi, Masato Takahashi, Naoki Yajima,

Makiko Fujinami, Tsutomu Ishikawa*

Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8675, Japan

Fax +81(43)2262944; E-mail: benti@faculty.chiba-u.jp

Received: 28.02.2014; Accepted after revision: 23.03.2014

isomer when arylaldehydes bearing an electron-with-

Abstract: The scope and limitations of guanidinium ylide mediated

drawing group, such as 4-chlorobenzaldehyde (3g), are

aziridinations from arylaldehydes yielding unactivated 3-arylaziri-

used. Based on these stereochemical results, we tentative-

dine-2-carboxylates, applicable to asymmetric synthesis, are dis-

ly postulated a mechanism for the asymmetric induction

through spiro intermediates 4 formed by formal 1,3-dipo-

lar cycloaddition between the guanidinium ylide 2 and an

arylaldehyde 3. Precise examination of this asymmetric

aziridination using a variety of 4-substituted benzalde-

hydes allowed us to propose more reasonable mechanisms

to cover the overall aziridine preparation from guanidini-

um ylides by application of the Hammett relation.⁴

Furthermore, we succeeded in expanding this aryl azirid-

ination to an alkenyl (or alkynyl) version by the use of un-

saturated aldehydes⁵in place of arylaldehydes as the

electrophile, and fully characterized a spiro intermediate

like 4 in the reaction with α-bromocinnamaldehyde as a

crystalline product.^5bThus, although we have fragmental-

ly reported the application of this guanidinium ylide par-

ticipated asymmetric aziridination to natural product

synthesis^5a,6in addition to approaches to the reaction po-

tentials of the aziridine systems formed,^3–5,7we discuss

here the scope and limitations of aryl aziridinations, partly

including the previous data reported as a preliminary com-

munication³as the backbone to this new methodology for

the preparation of nitrogen-containing three-membered

heterocycles.

cussed.

Key words: aldehydes, asymmetric synthesis, chiral auxiliaries,

esters, ylides

Aziridine is the smallest nitrogen-containing heterocycle

with a highly strained three-membered system.¹Owing to

its high reactivity, the aziridine unit not only plays an im-

portant role in biological actions, such as being responsi-

ble for the mode of action in the antitumor activity of

mitomycin, but also is used as a versatile synthetic precur-

sor for biologically important nitrogen-containing com-

pounds, especially 3-substituted aziridine-2-carboxylates

for amino acid derivatives through a ring-opening reac-

tion.²Thus, although a variety of aziridine preparation

methods involving asymmetric synthesis have been de-

veloped, they are basically classified into three approach-

es:¹(1) cyclization of β-amino alcohol derivatives under

nucleophilic substitution, (2) cycloaddition of carbenes to

imines, and (3) cycloaddition of nitrenes to olefins.

In 2001¹, we³made a preliminarily report of a new syn-

thetic method for the preparation of 3-aryl-1-benzylaziri-

dine-2-carboxylates 5 from guanidinium salts 1, which

incorporated an N-benzylglycine unit in the 2-position of

an imidazolidine skeleton, and aryl- and heteroarylalde-

hydes 3, possibly through the corresponding guanidinium

ylides 2 by treatment with a base (Scheme 1). This azirid-

ination can be extended to an asymmetric version by in-

troduction of chiral center(s) in the guanidinium templates

(e.g., L = Ph). In this unique cycle, unactivated 3-aryla-

ziridine-2-carboxylates 5 are generated with excellent to

moderate stereoselectivity depending upon the choice of

arylaldehydes 3, and urea 6 is also co-produced as a recy-

clable synthetic precursor for the guanidinium salt 1. In

general, trans-aziridines are efficiently obtained with sat-

isfactory enantioselectivity when arylaldehydes bearing

an electron-donating group such as piperonal [3,4-(meth-

ylenendioxy)benzaldehyde, 3a] are used as the electro-

phile, whereas cis-aziridines are obtained as the major

–

+

N

Bn

+

N

Bn

CO₂R

ArCHO

CO₂R

NMe

base

3

NMe

MeN

L

MeN

L

Br^–

base

HBr

L

2

1

RO₂C

Ar

O

BnN

MeN

NMe

O

MeN

NMe

L

6

CO₂R

Ar

L

Bn

N

4

L = H or Ph

5

Scheme 1 Cycle aziridination from guanidinium salt 1 and arylalde-

hyde 3 through a spiro adduct 4

SYNTHESIS 2014, 46, 2201–2219

Advanced online publication: 12.05.2014

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DOI: 10.1055/s-0033-1341233; Art ID: ss-2014-f0141-op

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Y. Oda et al.

PAPER

We⁸studied guanidine chemistry focusing on their poten- benzylglycinate, 7a·Br, was treated with sodium hydride

tial utility in synthesis, such as their use as organocata- in N,N-dimethylformamide with ice cooling, the reaction

lysts. Thus, general preparative methods for modified mixture turned yellow from colorless, strongly suggesting

guanidines⁹have been established by applying the multi- the formation of a ylide-type compound in situ; however,

functionality of 2-chloro-1,3-dimethyl-4,5-dihydroimid- more positive evidence could not be obtained despite the

azolium chloride (DMC),¹⁰and the guanidine-participated use of spectroscopic approaches. The yellow reaction

asymmetric synthesis¹¹examined have been reported. mixture formed was then stirred with benzyl bromide as

Guanidinium salts can also be prepared by either quater- an electrophile under ice cooling with monitoring by thin

nization of guanidines with alkyl halides or direct amina- layer chromatography, but this showed TLC patterns with

tion of 2-chloro-1,3-dimethyl-4,5-dihydroimidazolium multiple spots and not the expected formation of ethyl

chloride type compounds with secondary amines.^10aIt was α,N-dibenzylglycinate (ethyl N-benzylphenylalaninate,

reasonable to expect that guanidinium ylides, derived 10a).

from the corresponding guanidinium salts by treatment

with base, are resonance-stabilized equivalents of azo-

methine ylides, which could show unique reactivity, for

example as dipoles in 1,3-dipolar cycloaddition reactions

Therefore, we turned our attention to an aldol-type reac-

tion using 4-chlorobenzaldehyde (3g) as the electrophile

in place of alkylation (route b in Scheme 3). Treatment of

7a·Br with 3g for 24 hours under the same conditions led

to the generation of new products, TLC of which showed

three spots: two less polar and one more polar spot than

that of the starting aldehyde 3g. Purification of the prod-

ucts using preparative TLC (PTLC) resulted in the isola-

with unsaturated compounds. To the best of our knowl-

edge, there has been only one literature report¹²on guani-

dinium ylides at the start of our research work; the

synthetic utility of guanidinium ylides was unknown be-

cause the literature had only reported their physicochemi-

tion of two products only; these corresponded to the less

cal properties. Thus, we decided to uncover the reactivity

polar spots on TLC because the more polar spot disap-

of guanidinium ylides focusing on a new type of prepara-

peared during purification. These two products showed

tion of α-substituted α-amino acid derivatives through C–

the same molecular ion peaks [m/z = 316 (M⁺) and 318

C bond formation reactions with carbon electrophiles; this

concept is shown in Scheme 2. Guanidinium salt 7 con-

taining an N-benzylglycinate ester unit was selected as a

(M⁺+ 2)] in FAB-MS and the presence of common func-

tionalities such as a 1,4-disubstituted benzene ring sys-

tem, ethyl ester, N-benzyl, and two methine units in the ¹H

representative source of ylide 8 not only because of the

and ¹³C NMR spectra, indicating that these are cis and

easy generation of the carbanion under mild conditions

trans isomers of ethyl 1-benzyl-3-(4-chlorophenyl)aziri-

dine-2-carboxylate (5ag). 1,3-Dimethylimidazolidin-2-

due to substitution of an electron-attractive ester function,

but also because of the expected formation of versatile α-

substituted N-benzyl-α-amino ester 10 after hydrolysis of

the electrophile-incorporated intermediate 9. The co-pro-

duced urea, 1,3-dimethylimidazolidin-2-one (11), could

be recycled as a synthetic precursor for the guanidinium

salt 7 through 2-chloro-1,3-dimethyl-4,5-dihydroimidaz-

olium chloride.

one (11) was also isolated as the expected co-product. In

the ¹H NMR spectrum of the less polar aziridine isomer,

methine protons were observed as singlets at δ = 2.74 and

3.29, whereas those of the more polar one as doublets

(J = 6.7 Hz) at δ = 2.64 and 3.01. In the literature¹³the ste-

reochemistry of 2,3-disubstituted aziridines is assigned by

the coupling constant between the C2 and C3 methine

–

+

Bn

+

N

Bn

electrophile

(E-Y)

CO₂R

NMe

base

N

+

N

CO₂R

NMe

–

Bn

CO₂Et

+

N

Bn

CO₂Et

NMe

BnBr

CO₂Et

NMe

NaH

DMF

MeN

BnHN

X^–

MeN

Br^–

10a

7

(route a)

8

7a⋅Br

8a

amination

E

Cl

O

+

N

Cl

+

Bn

Cl^–

CO₂R

Y^–

(route b)

H₂O

NMe

MeN

CHO

NMe

MeN

3g

chlorination

E

DMI (11)

BnHN

DMC

9

CO₂R

O

CO₂Et

10

Bn

N

NMe

MeN

Scheme 2 Concept for the preparation of α-substituted α-amino ester

10 from guanidinium salt 7

DMI (11)

Cl

5ag

(cis + trans)

At first we attempted alkylation of the guanidinium ylide

8a containing an ethyl ester function (route a in Scheme Scheme 3 Trials for alkylation and aldol-type reaction of guanidini-

um salt 7a·Br

3). When the guanidinium bromide containing ethyl N-

Synthesis 2014, 46, 2201–2219

PAPER

Formation of Unactivated 3-Arylaziridine-2-carboxylates

2203

protons: in general, the trans isomer shows J = ~4 Hz, In NOE experiments of the major invertomer at –90 °C

whereas cis isomer J = ~7 Hz. Thus, a larger coupling the C2 methine proton showed correlations with not only

constant is observed in the cis isomer compared to the N-benzylmethylene protons but also the 1′-olefinic pro-

trans. According to this general rule we concluded that the

less polar isomer was trans-aziridine-2-carboxylate trans-

5ag and that the more polar one the corresponding cis de-

rivative cis-5ag.

Table 1 Reaction of the Guanidinium Salt 7a·Br with Various Ary-

laldehydes 3 (NaH, DMF)

Br

Bn

CO₂Et

The unexpected formation of aziridine products in the re-

action of guanidinium salt 7a·Br and 4-chlorobenzalde-

hyde (3g) using sodium hydride in N,N-dimethyl-

formamide made us examine the generality of guanidini-

um ylide participated aziridination by application to other

arylaldehydes (Table 1). Benzaldehyde (3f) (entry 3) and

arylaldehydes 3 substituted with electron-donating groups

(entries 1 and 2) or electron-withdrawing group (entries 4

and 5) served as electrophiles to give the corresponding

ethyl 3-arylaziridine-2-carboxylates 5aa,ad,af,ag,ak,al in

which trans isomer predominated.

N

CO₂Et

NaH, DMF

ArCHO

Bn

N

+

MeN

NMe

–20 °C, 24 h

Ar

3

5a

7a·Br

Entry Aldehyde

Product Yield (%)

3

Ar

cis

trans Total

1

3a

3d

3f

3,4-(OCH₂O)C₆H₃5aa

4

0

66

54

32

45

29

28

70

54

39

54

29

50

2^a

3

2-MeOC₆H₄

Ph

5ad

5af

5ag

5ak

5al

7

3-Cinnamylaziridine isomers 5al were produced in total

yield of 50% albeit with low diastereoselectivity (entry 6),

in which the trans isomer showed a complex signal pat-

4

3g

3k

3l

4-ClC₆H₄

4-O₂NC₆H₄

CH=CHPh

9

1

tern that was assigned to invertomers¹⁴in the H NMR

5

0

6^b

22

spectrum. The ratio of invertomers was slightly changed

dependent upon temperature measured such as 1:1 at

20 °C, 1:1.1 at 0 °C, 1:1.4 at –30 °C, and 1:1.8 at –90 °C.

^aTreated for 8 h.

^bTreated for 4 h.

Table 2 Effect of Base on the Aziridinations Using Piperonal (3a)

CO₂Et

CHO

Br

base (1.2 equiv)

solvent

Bn

N

Bn

N

CO₂Et

+

temp, time

MeN

NMe

O

7a·Br

3a

5aa

Entry

Base, solvent

Temp, time

Yield (%)

cis

trans

Total

1^a

2

NaH, DMF

–20 °C, 23 h

4

3

66

47

19

70

50

19

Cs₂CO₃, DMF

Ag₂CO₃, DMF

K₂CO₃, DMF

CsF, DMF

0 °C → r.t., 24 h

–20 °C → r.t., 48 h

–20 °C → r.t., 5 h

–78 °C, 8h

b

3

–

b

4

0

10

1

–

b

5

–

6

n-BuLi, THF, HMPA

NaOEt, EtOH

TMG, CH₂Cl₂

TMG^d

18

–

19

–

7

r.t., 1 h

–

8

r.t., 24 h

–

17

54

–

17

57

–

9^c

10

11

r.t., 24 h

3

DBU

r.t., 21 h

–

Et₃N

r.t., 22 h

–

^aAs in Table 1, entry 1.

^bDetectable on TLC but not isolated.

^cWithout solvent.

^dFreshly distilled before use.

Synthesis 2014, 46, 2201–2219

2204

Y. Oda et al.

PAPER

ton, whereas only correlation between the C2 methine and anol (entries 5 and 6), a methoxy-inserted ring-opened

the 1′-olefinic protons occurred in the minor invertomer. product was additionally produced in the latter case. Fur-

These findings indicated that configuration of the N-ben- thermore, it was found that the quality of the silica gel was

zyl group was cis to the cinnamyl function in the former, basically unimportant, because silica gel was used from

whereas it was trans in the latter (Figure 1).

several different sources (Fujisilysia, Micro Bead, and

Mallinckrodt) and they were equally effective, but basic

alumina (Woelm, basic super I) was ineffective (no data

shown). Thus, we selected nonaqueous workup B for the

conversion of the intermediate polar component into aziri-

dine products.

EtO₂C

2

Ph

H

3

N

H

1'

Ph

H

Ph

H

Ph

H

Table 3 Comparison of Workup Procedures for the Aziridination

Using Piperonal (3a)

minor invertomer

major invertomer

Figure 1 NOE experiments of the trans-3-cinnamylaziridine-2-car-

boxylate trans-5al at –90 °C

CO₂Et

CHO

Br

Bn

N

Bn

N

CO₂Et

step 1

(conditions)

Next, we examined the use of various bases in the azirid-

ination using piperonal (3a) as a typical electrophile (Ta-

ble 2), because it gave the most satisfactory result in Table

1 (entry 1). Treatment with cesium carbonate in N,N-di-

methylformamide afforded the aziridine 5aa in an even

lower yield (entry 2) compared to that with the sodium hy-

dride in N,N-dimethylformamide system (entry 1), but the

results were observed with other carbonates even worse

(entries 3 and 4). Tetramethylguanidine (TMG), a typical

guanidine-type organobase, could act as an alternative ac-

tive base, especially when a freshly distilled tetramethyl-

guanidine was used without solvent (entry 9), while no

reaction was observed with the use of other amidine-type

and amine-type organobases (entries 10 and 11). Thus, we

selected sodium hydride in N,N-dimethylformamide (re-

action conditions A) and tetramethylguanidine without

solvent (reaction conditions B) as two standard reaction

conditions for later aziridination trials.

+

MeN

NMe

step 2

(workup)

O

7a·Br

3a

5aa

Entry Step 1

Step 2

Yield (%)

cis trans Total

Reaction conditions,^aWorkup,^b

temp, time

solvent, time

1^c

2

A, –20 °C, 23 h

A, –20 °C, 24 h

B, r.t., 22 h

A

4

8

3

4

3

8

66

69

54

64

65

49

70

77

57

68

57^e

B, CHCl₃, 20 h

A

3^d

4

B, r.t., 24 h

B, CHCl₃, 13 h

B, MeCN, 20 h

B, MeOH, 26 h

5

B, r.t., 24 h

6

B, r.t., 24 h

^aReaction conditions: A: NaH, DMF; B: TMG without solvent.

^bWorkup A: aqueous; B: nonaqueous (SiO₂).

^cAs Table 1, entry 1.

As discussed above, we detected a polar spot on the TLC

of the reaction mixture, which disappeared during purifi-

cation by PTLC after quenching the reaction by the addi-

tion of water. The same phenomenon was also observed

during purification by silica gel column chromatography

and, in addition, nonreproducible results were often en-

countered. These findings suggested that the polar compo-

nent was an intermediate precursor for aziridine products

and we, thus, changed the aqueous workup (workup A) to

a nonaqueous workup (workup B) as follows: The reac-

tion mixture obtained after stirring for an appropriate time

under either the standard reaction conditions A (NaH,

DMF) or B (TMG) was concentrated under reduced pres-

sure, dissolved in chloroform, and stirred with silica gel at

room temperature until disappearance of the polar spot on

TLC. After removal of the silica gel by filtration the fil-

trate was evaporated under reduced pressure to afford the

crude aziridine mixture, which was directly subjected to

purification by either PTLC or column chromatography.

Comparison results between workups A and B in the aziri-

dination using piperonal (3a) are summarized in Table 3

and higher isolation of aziridine products was observed in

nonaqueous workup B (entries 1 and 3 vs 2 and 4) regard-

less of the reaction conditions. Although the chloroform

in workup B could be replaced with acetonitrile or meth-

^dAs Table 2, entry 9.

^eA methoxy-inserted ring-opened amino ester was additionally pro-

duced in 8% yield.

Using the established workup B, we examined the azirid-

ination between two different guanidinium bromides with

ethyl, 7a·Br, or tert-butyl, 7b·Br, ester units as the ylide

(nucleophile) source and a variety of arylaldehydes 3 un-

der either reaction conditions A or B (Table 4). Both elec-

tron-donating groups (entries 1–12) and electron-

withdrawing groups substituted on the benzaldehyde (en-

tries 17–27), and benzaldehyde (3f) (entries 13–16) and

cinnamaldehyde (3l) (entry 28), acted as electrophiles to

generally provide aziridines in good yields, except in the

case of 4-nitrobenzaldehyde (3k) (entries 26 and 27). 3-

(Heteroaryl)aziridine-2-carboxylates were also produced

in reasonable yields when heteroaryl-substituted alde-

hydes incorporating indole, pyridine, furan, and ben-

zothiophene skeletons were subjected to the reaction

(entries 29–41); however, lower yields of aziridines were

obtained in the cases of quinoline and coumarin deriva-

tives (entries 42–45).

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Formation of Unactivated 3-Arylaziridine-2-carboxylates

2205

Table 4 Aziridinations under Reaction Conditions A or B Followed by Nonaqueous Workup B

Br

step 1

(conditions, time)

Bn

CO₂R

Ar

N

CO₂R

Bn

N

+

ArCHO

step 2

(SiO₂; CHCl₃or MeCN)

MeN

NMe

7a·Br R = Et

3

5

7b·Br R = t-Bu

Entry Aldehyde

7

Step 1

Reaction

Step 2

Product Yield^c(%)

3

Ar

Workup,^b

cis

trans Total

conditions,^atime solvent, time

1^3,d3a

2^3,e3a

3,4-(OCH₂O)C₆H₃

3,4-(MeO)₂C₆H₃

4-MeOC₆H₄

2-MeOC₆H₄

4-AcHNC₆H₄

Ph

7a·Br

7b·Br

7a·Br

7b·Br

7a·Br

7b·Br

7a·Br

7b·Br

7a·Br

7b·Br

7a·Br

7b·Br

7a·Br

A, 2 h

CHCl₃, 20 h

CHCl₃, 3 h

5aa

5ba

5bb

5ac

5bc

5ad

5bd

5be

5af

8

4

69

64

69

61

56

58

78

66

93^g

85

77

43

61

41

29

20

48

45

23

38

44

20

47

45

43

53^g

75^g

57

72^g

77

68

77^f

67^f

63

61

85

71

95

89

77

43

84

69

85

77

65

61

76

70^f

68

60

64

73

57

47

46

70

79

62^h

76

B, 24 h

A, 24 h

B, 24 h

A, 24 h

B, 24 h

A, 9 h

3³

4³

5

3a

3b

3c

3d

3e

3f

8

CHCl₃, 3 h

6

MeCN, 4 h

MeCN, 24 h

CHCl₃, 20 h

MeCN, 24 h

CHCl₃, 20 h

CHCl₃, 14 h

MeCN, 17 h

MeCN, 19 h

CHCl₃, 20 h

MeCN, 6 h

CHCl₃, 20 h

MeCN, 16 h

MeCN, 20 h

MeCN, 22 h

MeCN, 23 h

MeCN, 12 h

MeCN, 22 h

CHCl₃, 20 h

7

6

3

7³

8

7

A, 24 h

A, 8 h

6

9³

2

10

A, 8 h

4

11

A, 7 h

–

12

B, 24 h

A, 24 h

B, 24 h

A, 24 h

B, 19 h

A, 24 h

B, 24 h

A, 2 h

–

13³

14³

15

23

28

56

57

17

16

53

47

30

16

44

26

12

2

3f

Ph

5af

3f

Ph

5bf

5ag

5bg

5bh

5bi

16³

17³

18³

19

3f

Ph

3g

3h

3i

4-ClC₆H₄

20³

21

4-ClC₆H₄

B, 24 h

A, 24 h

B, 24 h

A, 18 h

A, 6 h

2-ClC₆H₄

22

2-ClC₆H₄

23

4-BrC₆H₄

24

3j

2-BrC₆H₄

5bj

5ak

5al

25

3j

2-BrC₆H₄

B, 24 h

A, 24 h

B, 2 h

26³

27³

28³

29³

30³

31³

3k

3l

4-O₂NC₆H₄

CH=CHPh^c

N-Boc-indol-2-yl

N-Boc-indol-3-yl

3

A, 24 h

A, 7 h

17

4

3m

3n

5am

5bm

5an

B, 6 h

5

A, 24 h

4

Synthesis 2014, 46, 2201–2219

2206

Y. Oda et al.

PAPER

Table 4 Aziridinations under Reaction Conditions A or B Followed by Nonaqueous Workup B (continued)

Br

step 1

(conditions, time)

Bn

CO₂R

Ar

N

CO₂R

Bn

N

+

ArCHO

step 2

(SiO₂; CHCl₃or MeCN)

MeN

NMe

7a·Br R = Et

3

5

7b·Br R = t-Bu

Entry Aldehyde

7

Step 1

Reaction

Step 2

Product Yield^c(%)

3

Ar

Workup,^b

cis

trans Total

conditions,^atime solvent, time

32³

33^j

34^j

35^j

36³

37³

38

3n

3o

3p

3q

3r

3s

3t

N-Boc-indol-3-yl

N-Boc-indol-4-yl

pyridin-3-yl

7b·Br

7a·Br

7b·Br

7a·Br

7b·Br

B, 24 h

A, 24 h

B, 22 h

B, 27 h

A, 7 h

CHCl₃, 20 h

MeCN, 24 h

MeCN, 72 h

MeCN, 48 h

CHCl₃, 20 h

MeCN, 15 h

MeCN, 19 h

MeCN, 7 h

MeCN, 19 h

MeCN, 24 h

MeCN, 18 h

MeCN, 24 h

CHCl₃, 2 h

5bn

5ao

5bo

5ap

5bp

5bq

5br

5bs

5bt

2

–

21

43

62

53

58

31

28

39

59

32

35

37

12

23ⁱ

43^k

75

61^l

66

70^f

51

55

65

67

35

37

12

13

8

pyridin-3-yl

A, 4 h

39

23

6

furan-2-yl

A, 3 h

39

furan-2-yl

B, 24 h

A, 24 h

B, 24 h

A, 26 h

B, 23 h

A, 6 h

40

benzothiophen-3-yl

quinolin-4-yl

6

41

8

42

3

43

quinolin-4-yl

–

44

6,7-dimethoxy-2-oxo-2H-1-benzopyran-5-yl 7b·Br

–

45

3t

B, 24 h

CHCl₃, 4 h

–

^aConditions A: NaH, DMF, –20 °C; B: TMG without solvent, r.t, time.

^bWorkup B: nonaqueous (SiO₂).

^cNot optimized, isolated yield.

^dAs in Table 3, entry 2.

^eAs in Table 3, entry 4.

^fThe yield reported in the previous paper³was improved.

^gExisted as a mixture of invertomers.

^hDeprotected indolecarbaldehyde was recovered in 22% yield and a hydroxy-inserted ring-opened α-amino ester was obtained in 3% yield.

ⁱDeprotected indolecarbaldehyde was recovered in 73% yield.

^jA limited amount of THF was used as solvent.

^kDeprotected indolecarbaldehyde was recovered in 21% together with 3o (24%).

^lStarting 3o (20%) was recovered.

Electron-donating group substituted arylaldehydes (en- benzaldehydes, in which the electronic character of the

tries 1–12) including N-[tert-butoxycarbonyl (Boc)]-pro- benzylic position in a sterically favored the trans-oxazoli-

tected indolecarbaldehydes (entries 29–35) always dine system of a spiro intermediate 4 controlled the for-

afforded the trans-aziridine as the major isomer indepen- mation of the aziridine isomer 5 (Scheme 4). Thus,

dent of the ester function. On the other hand, interestingly, electron-donating group substituted arylaldehydes mainly

the ratio of cis- and trans-aziridines was dependent upon afforded trans-aziridine trans-5, with retention of the con-

the ester function in the reactions of benzaldehyde (3f) figuration, by S_Ni mode [route (a)] in the fragmentation of

(entries 13 and 14 vs 15 and 16), 4-chlorobenzaldehyde 4, while cis-aziridine cis-5 are formed by S_N2 mode with

(3g) (entries 17 and 18 vs 19 and 20), and pyridine-3-car- inversion, after cleavage of the oxazolidine C–N bond in

baldehyde (3p) (entries 36 vs 37), in which the cis isomer 4 [route (b)], in the case of electron-withdrawing-group-

was predominantly obtained in the case of the tert-butyl substituted arylaldehydes. The bulkier tert-butyl ester

ester. These findings could be rationalized by a mecha- would prefer a spiro intermediate 4 with the trans-oxazo-

nism⁴proposed in the systematically approached asym- lidine system, compared to the corresponding methyl es-

metric aziridination using a range of 4-substituted

Synthesis 2014, 46, 2201–2219

PAPER

Formation of Unactivated 3-Arylaziridine-2-carboxylates

2207

RO₂C

C₆H₄-4-Y

+

N

Bn

4-YC₆H₄CHO

Y = EDG in 3

CO₂R

NMe

route (a)

CO₂R

3

(a)

BnN

(b)

MeN

O

DMI

+

Bn

N

MeN

(11)

Br^–

base

S_Ni

C₆H₄-4-Y

NMe

(retention)

trans-5

7a·Br R = Et

7b·Br R = t-Bu

(step 1)

4

Y = EWG in 3

route (b)

(step 2)

RO₂C

C₆H₄-4-Y

CO₂R

DMI

(11)

Bn

N

cis-5

+

BnN^-

MeN

O

S_N2

(inversion)

C₆H₄-4-Y

+

NMe

Scheme 4 Proposed mechanism based on the reported asymmetric aryl aziridination⁴

ter, which results in the predominant formation of the cis- and the trans isomer was mainly formed, albeit with lower

aziridine in the reactions of arylaldehydes 3f,g,p.

diastereoselectivity. Thus, the guanidinium ylide mediat-

ed aziridination is potentially applicable to the preparation

of a variety of N-modified 3-arylaziridine-2-carboxylates

when the glycinate nitrogen is substituted with less-

hindered primary alkyl groups.

The guanidinium ylide mediated aziridinations obtained

in Table 4 can be summarized as follows; (1) substituents

on the arylaldehydes are tolerated in the aziridination, (2)

the yields are dependent upon the arylaldehyde used, (3)

in general, reaction conditions A gave better yields of Aziridination between the guanidinium salt 7a·Br and pi-

aziridines than conditions B, and (4) heteroaryl-substitut- peronal (3a) under reaction conditions B was attempted

ed aldehydes can also served as electrophiles. However, it using a catalytic amount of tetramethylguanidine (Table

should be noted here (no data shown), that (1) no reaction 5). The expected reaction occurred when potassium car-

occurred with unprotected 4-hydroxybenzaldehyde and bonate was used as an additive in dichloromethane to give

indolecarbaldehydes, (2) reactions were unsuccessful trans-aziridine trans-5aa in the same 61% yield as ob-

with aliphatic aldehydes such as isovaleryl and pivaloyl tained by the stoichiometric version (see, entry 1), albeit a

aldehydes, ethyl polyglyoxalate, trioxane, and parafor- longer reaction time was required (entry 4).

maldehyde, and (3) ketone substrates, such as acetophe-

As previously discussed, we have independently recog-

none derivatives, were also unsuccessful. Unsuccessful

nized that modified chiral guanidines could serve as effec-

aziridinations using aliphatic aldehydes and ketone sub-

tive organocatalysts in asymmetric syntheses,¹¹such as

strates could also be explained by taking the mechanism

kinetic silylation of secondary alcohols^11band in the

shown in Scheme 4 into consideration (no benzylic posi-

Michael addition,^11cand, as will be discussed later, this

tion and steric repulsion in the oxazolidine system of a

guanidinium ylide-mediated aziridination can be extend-

spiro intermediate 4, respectively).

ed to an asymmetric version. Thus, we examined the cat-

Finally, the aziridination under reaction conditions A was alytic aziridination in the presence of a chiral guanidine in

applied to the reaction of N-tosylindole-4-carbaldehydes place of potassium carbonate; however, almost no asym-

13 with guanidinium hexafluorophosphates 12 bearing an metric induction was observed in the aziridine products

allyl substituent on the glycinate nitrogen (Scheme 5). formed (12–33% yields) (no data shown).

The expected 3-(indol-4-yl)aziridine isomers 14 were

smoothly afforded in acceptable total yields (84–92%)

In order to evaluate the variation of guanidinium nucleo-

philes, structure-modified salts were prepared (Scheme

CO₂R

CHO

+

N

Y

N

Y

1. NaH, DMF

CO₂R

NMe

2. SiO₂, CHCl₃

+

MeN

–

N

PF₆

N

Ts

12b R = t-Bu

12c R = Me

13a Y = H

13b Y = I

14ca R = Me, Y = H : trans (70%); cis (17%)

14ba R = t-Bu, Y = H : trans (55%); cis (37%)

14cb R = Me, Y = I : trans (60%); cis (24%)

14bb R = t-Bu, Y = I : trans (65%); cis (25%)

Scheme 5 Aziridination of N-tosylindole-4-carbaldehydes 13 with N-allylguanidinium hexafluorophosphates 12

Synthesis 2014, 46, 2201–2219

2208

Y. Oda et al.

PAPER

nitrile 16, and trifluoromethyl functions 17, substituted

esters 18 and 19, and the 1,3-diethylimidazolidine skele-

ton 20 were targeted as the substrates.

Table 5 Catalytic Aziridination To Give 5aa

CO₂Et

CHO

Br

Bn

N

Bn

1. TMG, solvent

additive, r.t.

N

CO₂Et

Reactions using modified guanidinium salts 15–17 with

non-ester functions did not result in the formation of aziri-

dine products. In ¹H NMR spectra, functionalized methy-

lene protons (N⁺CH₂R) of the guanidinium salts appeared

at δ = 3.91 (16: R = CN), 3.99 (17: R = CF₃), and 4.20 (15:

R = COMe), respectively, while the corresponding pro-

tons in the ethyl ester derivative 7a·Br were observed at

δ = 3.74. The order of the chemical shift should reflect the

acidity of these guanidinium derivatives; the lower the

chemical shift, the stronger the acidity. Thus, we conclud-

ed that the reactivity of ylide functionality derived from

the modified guanidinium salts 15–17 may be decreased

by more effective resonance stabilization compared to the

ethyl ester derivative 7a.

+

MeN

NMe

2. SiO₂; CHCl₃

r.t., 24 h

O

7a·Br

3a

5aa

Entry TMG Solvent

(equiv)

Additive Time Yield

(2 equiv) (h) (%)

cis trans Total

1

1.2

0.2

–

none

24

30

44

45

6

–

61

–

67

–

2^a

3

–

Et₃N

b

–

K₂CO₃

–

4

CH₂Cl₂

61

Results on reactions using guanidinium salts 18 and 19

with α-substituted ester functions or 1,3-diethylimidazo-

line skeleton 20 are given in Table 6.

^aGuanidinium salt decomposed to give a ring-opened urea derivative.

^bDetectable on TLC but not isolated.

Although modification of the 1,3-dimethylimidazolidine

skeleton 7b to the corresponding diethyl analogue 20 was

tolerated in the aziridination (entries 7 and 8), introduc-

tion of a bulky benzyl group (R³= Bn) to the α-position of

6), in which the preparation of the standard N-benzylgly-

cinate-incorporated guanidinium bromides 7a and 7b is

included for reference. Guanidinium salts with acetyl 15,

Bn

+

N

Bn

1. BrCH₂R

MeCN

1. BnBr

N

R

MeCN

NMe

MeN

NMe

MeN

2. NH₄PF₆

H₂O

2. NH₄PF₆

H₂O

X^–

7b·Br: R = CO₂t-Bu, X = Br (100%)

7a·Br: R = CO₂Et, X = Br (100%)

15: R = COMe, X = PF₆(44%)

16: R = CN, X = PF₆(10%)

NH₂CH₂R

MeCN

BnNH₂

MeCN

17: R = CF₃, X = PF₆(26%)

Bn = CH₂Ph

Y

Bn

+

N

Bn

+

N

Me

Cl^–

Cl

CO₂R

Cl^–

CO₂Et

(53%)

Bn

Cl^–

+

NMe

MeN

NMe

MeN

Y

Bn

Me

DMC

N

H

19

CO₂R

N

H

CO₂Et

18a R = Y = Me (64%)

18b R = Et, Y = Bn (56%)

(85%)

Bn

(92%)

on 18b

Bn

N

CO₂Et

Pd(OH)₂/C, H₂

AcO₂H

Me

HCHO

HCO₂H

+

N

O

Bn

1. BnBr

MeCN

N

CO₂t-Bu

NEt

1. (COCl)₂

EtN

NEt

EtN

–

PF₆

2. NH₂CH₂CO₂t-Bu

2. NH₄PF₆

H₂O

20

(87%)

(49%)

Scheme 6 Preparation of modified guanidinium salts

Synthesis 2014, 46, 2201–2219

PAPER

Formation of Unactivated 3-Arylaziridine-2-carboxylates

2209

Table 6 Aziridination Using Modified Guanidinium Salts and Piperonal (3a)

R³

CHO

X^–

R³

CO₂R⁴

R²

+

N

CO₂R⁴

R²

N

1. conditions

O

NR¹

+

2. SiO₂; MeCN

r.t., 24 h

R¹N

O

7b·Br, 18–20

5ba, 21, 22

3a

Entry

Guanidinium R¹

salt

R²

R³

R⁴

X

Reaction

Product

Yield^b

(%)

conditions^a

1

18a

18b

19

Me

Bn

Me

Bn

Me

Bn

H

Me

Et

Cl

PF₆

Br

A

B

A

B

A

B

trans-21

8^c

43^c

–

2

Me

Et

trans-21

3

–

4

Et

–

5

Et

22

3^d

5^d

48

61

6

19

Et

22

7^e

8^f

20

t-Bu

trans-5ba

7b·Br

Me

H

^aConditions A: NaH, DMF, –20 °C; B: TMG without solvent, r.t.

^bIsolated, not optimized yield.

^cThe stereochemical relation between the ester and aryl functions is trans.

^dThe stereochemistry was not determined.

^eThe counteranion of guanidinium salt is PF₆^–and CHCl₃was used as the solvent in step 2.

^fAs in Table 4, entry 4; CHCl₃was used as a solvent in the workup.

the ester function remarkably suppressed the reaction (en-

CO₂t-Bu

BnBr

tries 3–6); however, the aziridine was obtained under re-

action conditions B in the case of the methyl substituent

(R³= Me) (entry 2). Thus, it was found that reaction was

sensitive to the steric bulkiness of the ylide carbon. The

stereochemistry of the aziridine product 21 was deduced

to be trans between the aryl and ester functions because an

NOE enhancement (8.6%) between the C2 methyl protons

and the C2 proton of the 3,4-(methylenedioxy)phenyl

group was observed.

Bn

+

Br^–

N

MeCN

N

r.t., 6 h

(74%)

N

Ph

23

BrCH₂CO₂t-Bu

+

Ph

N

CO₂t-Bu

MeCN

MeN

NMe

MeN

NMe

Br^–

r.t., 24 h

(75%)

Theoretically, the use of chiral guanidinium templates

could expand this new aziridination reaction to an asym-

metric version, as previously briefly reported.³We pre-

pared three types of chiral guanidinium bromides with a

tert-butyl N-substituted glycinate function at the 2 posi-

tion of imidazolidine ring {tert-butyl N-benzylglycinate

incorporated 1,3-bis[(S)-1-phenylethyl]imidazolidinium

bromide (23), tert-butyl N-[(R)-1-phenylethyl]glycinate

incorporated 1,3-dimethylimidazolidinium bromide 24,

and an enantiomeric pair of tert-butyl N-benzylglycinate-

incorporated 1,3-dimethyl-5,6-diphenylimidazolidinium

bromides^6b25b·Br} from the corresponding chiral guani-

dine precursors by conventional quaternization with an

appropriate alkyl halide (Scheme 7) and screened them for

aziridinations with piperonal (3a) (Table 7).

24

Bn

+

N

CO₂t-Bu

NMe

BnBr

N

CO₂t-Bu

NMe

Ph

MeCN

MeN

Ph

Br^–

MeN

Ph

r.t.

Ph

25b·Br

(R,R)-deriv: 100% (3 h)

(S,S)-deriv: 99% (4 h)

Scheme 7 Preparation of three types of guanidinium bromides from

chiral guanidines by alkylation

Although disappointing results were encountered with the

two guanidinium bromides 23 and 24 (entries 1–3), asym-

metric inductions were observed when the third guanidin-

ium bromide 25b·Br with a 4,5-diphenyl-substitued

Synthesis 2014, 46, 2201–2219

2210

Y. Oda et al.

PAPER

Table 7 Screening of Chiral Guanidinium Templates on Asymmetric Aziridination

CHO

*

CO₂t-Bu

Bn

N

1. conditions

2. workup

O

23, 24, or 25b·Br

+

O

3a

5ba*

Entry

Guanidinium bromide

Reaction conditions^a

Workup^b

Yield (%)

cis

trans

1

23

A: –20 °C, 5.5 h

A: –15 °C, 6 h

B: r.t., 9 h

A

B

–

42 (9% ee)

c

2

24

–

c

3

24

–

4

(R,R)-25b·Br

(S,S)-25b·Br

A: –20 °C, 65 h

B: r.t., 3.5 h

2^d

1^d

7^d

4^d

6^d

45 (61% ee)

37 (71% ee)

75 (72% ee)

49 (45% ee)

82 (97% ee)

5

6³

7

A: –20 °C, 39 h

B: –15 °C, 52 h

B^e: r.t., 4 h

8³

^aConditions: A: NaH, DMF; B: TMG without solvent.

^bWorkup A: aqueous; B: nonaqueous (SiO₂).

^cHydrolyzed urea derivative was formed.

^dThe ee was not determined.

^eTMG was freshly distilled before use.

imidazolidine skeleton was used as the chiral template The general application of the 4,5-diphenylguanidinium

even under non-optimized aqueous workup A (entries 4 salt induced asymmetric aziridinations was examined by

and 5). No improvement was observed under the modified treatment with arylaldehydes in freshly distilled te-

nonaqueous workup B (entries 6 and 7). Satisfactory re- tramethylguanidine (reaction conditions B) followed by

sults were achieved when freshly distilled tetramethyl- the optimized nonaqueous workup B (Table 8). Excellent

guanidine was used under reaction conditions B (entry 8), to moderate asymmetric inductions were obtained in the

in which a chiral tert-butyl trans-3-[3,4-(methylenedi- screening and, especially, trans-3-(N-Boc-indol-3-yl)-

oxy)phenyl]aziridine-2-carboxylate (trans-5ba*) was ob- trans-5bn* and trans-3-(N-Boc-indol-4-yl)aziridine-2-

tained in 82% yield and with 97% ee. This encouraged us carboxylate trans-5bo* were afforded in 70% and 73%

to further examine asymmetric aziridination with the 4,5- yields with 95% and 93% ee, respectively, when N-Boc-

diphenylguanidinium bromide 25b·Br.

indole-3-carbaldehyde 3n and N-Boc-indole-4-carbalde-

hyde 3o were subjected to the reaction (entries 7 and 8).

Bn

PhCHO

+

N

CO₂t-Bu

NMe

3f

CO₂t-Bu

Ph

+

N

MeN

Ph

Br^–

see Table 8, entry 4

Ph

cis-5bf* (t-Bu)

trans-5bf* (t-Bu)

(79% ee)

(77% ee)

(S,S)-25b·Br

Pd(OH)₂/C, H₂

(Boc)₂O

(91%)

(79%)

MeOH, r.t.

NaHCO₃

BocHN

CO₂t-Bu

BocHN

CO₂t-Bu

H₂N

CO₂t-Bu

(Boc)₂O

CHCl₃–H₂O, r.t.

(91%)

Ph

(–)-26

[α]_D²⁵–20.3

(+)-26

[α]_D²⁵+38.0

(S)-phenylalaninate

Scheme 8 Absolute configuration of 1-benzyl-3-phenylaziridine-2-carboxylates 5bf* produced in asymmetric aziridination

Synthesis 2014, 46, 2201–2219

PAPER

Formation of Unactivated 3-Arylaziridine-2-carboxylates

2211

Thus, it was found that the 4,5-diphenylguanidinium bro- tert-butyl ester and bromide 25b·Br^6b(see, Scheme 7),

mide 25b·Br effectively served as a chiral auxiliary in the three possible guanidinium variants [methyl ester/bro-

guanidinium ylide mediated asymmetric aziridination.

mide 25c·Br, methyl ester/hexafluorophosphate 25c·PF₆,

and tert-butyl ester/hexafluorophosphate 25b·PF₆] were

prepared from the corresponding chiral 2-chloro-1,3-di-

methylimidazolinium chloride type compound 27. Prepa-

ration of the S,S enantiomers is shown in Scheme 9 as an

example.

As previously reported in a preliminary communication,³

the absolute configuration of chiral centers in tert-butyl

cis- and trans-1-benzyl-3-phenylaziridine-2-carboxylates

cis- and trans-5bf* was determined by their conversion

into phenylalaninates under hydrogenolysis because the

cis and trans isomers were produced with low diastereo-

selectivities, but reasonable enantioselectivities (see, Ta-

ble 8, entries 3 and 4). Thus, each aziridine isomer derived

from (S,S)-25b·Br (entry 4) was independently subjected

to hydrogenolysis in methanol with palladium hydroxide

on carbon in the presence of di-tert-butyl dicarbonate to

give the same (–)-tert-butyl N-Boc-phenylalaninate (–)-

26 in 91% and 79% yields, respectively (Scheme 8);

during the reaction no racemization occurred. These facts

indicated that the diastereomeric aziridines cis- and trans-

5bf* should have the opposite stereochemistry at C3 but

the same stereochemistry at C2. On the other hand, enan-

tiomeric (+)-tert-butyl N-Boc-phenylalaninate (+)-26 was

derived from commercially available tert-butyl (S)-phe-

nylalaninate. Therefore, it was concluded that tert-butyl

cis- and trans-1-benzyl-3-phenylaziridine-2-carboxylates

cis- and trans-5bf* synthesized from the (S,S)-4,5-di-

phenylguanidinium bromide (S,S)-25b·Br should have

the 2R,3R and 2R,3S configurations, respectively.

Table 9 Effects of an Ester Residue and Counteranion of (S,S)-

Guanidinium Variants (S,S)-25 on Asymmetric Aziridination

X^–

CHO

Bn

+

N

CO₂R

1. TMG, THF

r.t., ca 1 d

CO₂R

Bn

N

O

+

NMe

MeN

Ph

2. Ac₂O, CHCl₃

r.t., ~20 min

O

Ph

O

(S,S)-25

3a

trans-5*

Entry (S,S)-25

R

X

Product

Yield ee

(%)

1

2

3

4

(S,S)-25b·Br

(S,S)-25b·PF₆

(S,S)-25c·Br

(S,S)-25c·PF₆

t-Bu Br

trans-5ba*

77

50

69

50

91

19

81^a

37

t-Bu PF₆trans-5ba*

Me

Br

trans-5ca*

PF₆trans-5ca*

^atrans-5ca* was also obtained in 60% yield with 89% ee when the

aziridination was conducted under reaction conditions A (NaH in

DMF).

For evaluation of the ester function and counteranion in an

N-benzylglycinate-incorporated

1,3-dimethyl-4,5-di-

phenylimidazolidinium salt, except for the combination of

Table 8 Asymmetric Aziridination in Tetramethylguanidine

Br

Bn

N

CO₂t-Bu

1. TMG

r.t., time

*

CO₂t-Bu

Ar

MeN

Ph

NMe

Bn

N

+

ArCHO

2. SiO₂, r.t., 24 h

Ph

25b·Br

3

5b*

Entry

Aldehyde

25b·Br

Time (h)

Product

Yield (%)

3

Ar

cis

trans

1^3,a

2

3a

3b

3f

3,4-(OCH₂O)C₆H₃

3,4-(MeO)₂C₆H₃

Ph

(S,S)

(R,R)

(S,S)

(R,R)

4

5ba

5bb

5bf

6^b

82 (97% ee)

73 (84% ee)

32 (73% ee)

31 (77% ee)

35 (59% ee)

87 (76% ee)

70 (95% ee)

73 (93% ee)

9^b

3³

4³

5³

6³

7³

8^d

5

61 (75% ee)

3f

Ph

3

5bf

60 (79% ee)

3g

3m

3n

3o

4-ClC₆H₄

4

5bg

5bm

5bn

5bo

51^c

9^b

N-Boc-indol-2-yl

N-Boc-indol-3-yl

N-Boc-indol-4-yl

5.5

7

6^b

24

19^b

^aAs in Table 7, entry 8.

^bThe ee was not determined.

^cRetention time (>120 min) was too long under the conditions used.

^dA limited amount of THF was used as a solvent.^6b

Synthesis 2014, 46, 2201–2219

2212

Y. Oda et al.

PAPER

Bn

form (workup C) at room temperature for ca. 20 minutes.

Workup C was identified as an alternative nonaqueous de-

composition of the intermediate adduct to the aziridine

product during examination for substituent effects on

aziridination.⁴tert-Butyl trans-3-[3,4-(methylenedi-

oxy)phenyl]aziridine-2-carboxylate (trans-5ba*) was

produced in 77% yield and with 91% ee when piperonal

(3a) was treated with the tert-butyl glycinate incorporated

guanidinium bromide (S,S)-25b·Br (entry 1). The enan-

tiomeric excess greatly decreased when the hexafluoro-

phosphate salt was used instead of the bromide (entry 2).

A similar tendency was observed in the reactions of the

methyl glycinate incorporated variants (entries 3 and 4).

Thus, methyl trans-3-[3,4-(methylenedioxy)phenyl]aziri-

dine-2-carboxylate (trans-5ca*) was obtained in 69%

yield and with 81% ee when (S,S)-25c·Br was used (entry

3), indicating that the bulkiness of the ester function in the

4,5-diphenylguanidinium salts is relatively tolerated in

the aziridination (entries 1 and 3).

Bn

+

N

BnNH₂

MeCN

N

CO₂Me

NMe

BrCH₂COMe

MeCN

MeN

Ph

NMe

Ph

MeN

Ph

Br^–

94%

Cl^–

70%

Cl

Ph

(S,S)-25c·Br

MeN

Ph

NMe

+

Ph

Bn

+

N

Bn

+

N

NH₄PF₆

CO₂R

(S,S)-27

CO₂R

H₂O

MeN

Ph

NMe

Ph

MeN

Ph

NMe

Cl^–

–

Bn

PF₆

N

H

CO₂R

Ph

(S,S)-25c·PF₆: 63%

(S,S)-25b·PF₆: 88%

R = Me (79%)

R = t-Bu (72%)

BnNH₂

Br

CO₂R

Scheme 9 Preparation of (S,S)-guanidinium variants with 4,5-diphe-

nyl pendants

Finally we applied asymmetric aziridination to either N-

modified 4,5-diphenylguanidinium salts with a different

substituent at the nitrogen atom from benzyl group or a

functionalized aldehyde (Scheme 10, Table 10). (R,R)-2-

(tert-Butyldimethylsiloxy)ethyl-substituted guanidinium

salt (R,R)-28 was subjected to aziridination under modi-

fied reaction conditions B (TMG, THF) with piperonal

(3a) followed by treatment with nonaqueous workup B to

afford the corresponding trans-aziridine-2-carboxylate 29

The results on aziridination with these 4,5-diphenylguan-

idinium salts are summarized in Table 9. A mixture of pi-

peronal (3a) and (S,S)-25 was stirred with

tetramethylguanidine in a limited amount of tetrahydrofu-

ran (modified reaction conditions B)^6bat room tempera-

ture for one day and then the reaction mixture was stirred

with acetic anhydride after the addition of excess chloro-

CHO

TBSO

+

N

CO₂t-Bu

TBSO

CO₂t-Bu

NMe

1. conditions

N

O

(1)

+

MeN

Ph

–

2. SiO₂, MeCN

r.t., 1 d

PF₆

O

Ph

O

29

(R,R)-28

3a

conditions

TMG, THF, r.t., 8 h: 58%, 92% ee

NaH, DMF, –20 °C, 5 h: 74%, 82% ee

CO₂R

N

+

N

CHO

I

CO₂R

NMe

1. TMG, THF

2. work-up

MeN

Ph

(2)

+

X^–

N

I

Ph

N

Boc

31

Boc

(R,R)-30

32

CO₂t-Bu

Ph

OHC

CO₂t-Bu

N

Bn

+

N

1. TMG, THF

(3)

O

+

O

MeN

Ph

NMe

Br^–

2. SiO₂, CHCl₃

r.t., 1 d

OMOM

Ph

OMOM

34

(R,R)-25b·Br

33

82%, >95% de

Scheme 10 Asymmetric aziridination using N-modified guanidinium salts and a functionalized aldehyde

Synthesis 2014, 46, 2201–2219

PAPER

Formation of Unactivated 3-Arylaziridine-2-carboxylates

2213

Table 10 Aziridinations Using Workup Conditions B or C To Give 32 [Scheme 10 (2)]

Entry

Guanidinium salt

R

X

Workup^a

Product

Yield (%)

trans

cis

1

2

3

4

5

6

(R,R)-30c·Br

(R,R)-30c·PF₆

(R,R)-30a·Br

(R,R)-30b·Br

Me

Et

Br

B

C

B

C

B

32c

32a

32b

58 (66% ee)

54 (68% ee)

56 (11% ee)

55 (15% ee)

47 (56% ee)

47 (61% ee)

22 (87% ee)

22 (39% ee)

14 (78% ee)

18 (66% ee)

17 (94% ee)

16 (60% ee)

Br

PF₆

Br

t-Bu

Br

^aWorkup B: nonaqueous (SiO₂); workup C: nonaqueous (Ac₂O).⁴

netic sector mass spectrometer and ToF mass spectrometer, respec-

tively. For column and flash chromatography silica gel 60 (63–210

mm) and NH-coated silica gel (100–200 mesh) and silica gel 60

(40–100 mm), respectively, were used. All reactions were carried

out using dry solvents under an argon atmosphere and organic ex-

tracts were evaporated under reduced pressure after drying (Mg-

SO₄), unless otherwise noted.

in 58% yield and with 92% ee, while slightly lower enan-

tiomeric excess was observed using reaction conditions A

(NaH, DMF) but with a higher chemical yield (78%)

[(Scheme 10 (1)]. Reaction of the N-Boc-3-iodoindole-4-

carbaldehyde 31 with N-allylglycinate-incorporated

guanidinium salts (R,R)-30 under modified reaction con-

ditions B also provided the expected aziridine derivatives

32 in reasonable chemical yields (Table 10); however, not

only the diastereoselectivity of cis and trans isomers, but

also the enantiomeric excess of the major trans isomer

were not necessarily good compared to the reactions of

N-Boc-indolecarbaldehydes without an iodo-substituent

with the corresponding N-benzyl guanidinium salt 25b·Br

(see, Table 8, entries 6–8), even when different combina-

tions of the ester (R) and the counteranion (X) functions

were used. Interestingly, quite high diastereoselectivity

(de) was observed in the reaction using a chiral aldehyde

[Scheme 10 (3)]. Treatment of (S)-dihydrobenzofurancar-

baldehyde 33¹⁵with a standard chiral guanidinium bro-

mide (R,R)-25b·Br under modified reaction conditions B

gave (2S,3R)-trans-aziridine 34 as the sole isolated prod-

uct in 82% yield.

Stepwise Preparation of Guanidinium Salts from Primary

Amines through Alkylation of Guanidine; General Procedure 1

To a solution of a 2-chloro-4,5-dihydroimidazolium chloride in

CH₂Cl₂was added Et₃N followed by a primary amine at r.t. and the

mixture was stirred at r.t. After the addition of ice-water and then

20% aq NaOH solution, the mixture was extracted with toluene.

The combined organic solution extracts were washed with H₂O and

brine to give a guanidine that was purified by column chromatogra-

phy (silica gel or NH-silica gel) if necessary. An alkyl bromide was

added to a solution of the guanidine in MeCN at r.t. and then the

mixture was stirred at r.t. After evaporation of the solvent the resi-

due was isolated either as the bromide by successively washing with

hexane and Et₂O or after purified by column chromatography (silica

gel) if necessary as the hexafluorophosphate by treatment with aq

NH₄PF₆solution at r.t. Following this procedure gave:

N-Benzyl-N-[(ethoxycarbonyl)methyl]-N′,N′′-ethylene-N′,N′′-

dimethylguanidinium Bromide [7a·Br]; Typical Procedure for

GP1

2-(Benzylimino)-1,3-dimethylimidazolidine

In conclusion, we have established a new efficient prepa-

ration method of unactivated 3-arylaziridine-2-carboxyl-

ates from guanidinium ylides carrying a glycinate unit and

arylaldehydes, applicable to asymmetric synthesis. How-

ever, it is noteworthy that the use of well-purified compo-

nents, especially the guanidinium salt, is important for

successful aziridination because unsatisfactory results

were often encountered in the reactions using incomplete-

ly purified guanidinium salts even if solidified. It is well

known that nitrogen ylides such as ammonium, azometh-

ine, and nitrile ylides are useful in organic synthesis.¹²The

results described here indicate that guanidinium ylides are

also synthetically versatile nitrogen ylides, and we have

developed a promising method for asymmetric amino acid

synthesis.

A mixture of 2-chloro-1,3-dimethyl-4,5-dihydroimidazolium chlo-

ride (4.03 g, 23.8 mmol), Et₃N (7.0 mL, 50.3 mmol), and BnNH₂

(1.45 mL, 13.3 mmol) in CH₂Cl₂(51 mL) was reacted for 5 h and

worked up to give guanidine (2.78 g, quant) as a yellow oil.

IR (neat): 1639 cm^–1.

¹H NMR (400 MHz): δ = 2.84 (s, 6 H), 3.17 (s, 4 H), 4.66 (s, 2 H),

7.17 (t, J = 7.9 Hz, 1 H), 7.29 (t, J = 7.9 Hz, 2 H), 7.39 (dd, J = 7.9,

0.8 Hz, 2 H).

N-Benzyl-N-[(ethoxycarbonyl)methyl]-N′,N′′-ethylene-N′,N′′-

dimethylguanidinium Bromide [7a·Br]

Treatment of the benzylguanidine (2.90 g, 14.2 mmol) in MeCN

(100 mL) with ethyl bromoacetate (1.74 mL, 15.7 mmol) for 5 h fol-

lowed by washing gave 7a·Br (5.31 g, quant) as colorless prisms;

mp 68–71 °C.

IR (ATR): 1736, 1597 cm^–1.

¹H NMR (600 MHz): δ = 1.29 (t, J = 7.2 Hz, 3 H), 3.22 (s, 6 H),

3.81 (s, 2 H), 4.03 (s, 4 H), 4.23 (q, J = 7.2 Hz, 2 H), 4.64 (s, 2 H),

7.32–7.53 (m, 5 H).

¹³C NMR (150 MHz): δ = 14.0, 36.2, 49.2, 49.7, 54.4, 62.1, 128.8,

129.2, 129.3, 133.7, 164.0, 168.4.

Melting points were determined with a melting point hot-stage in-

1

strument and are uncorrected. H and ¹³C NMR spectra were re-

corded with Jeol 400 and 600 MHz spectrometers in CDCl₃. FAB

and ESI mass spectra were obtained using a double-focusing mag-

Synthesis 2014, 46, 2201–2219

2214

Y. Oda et al.

PAPER

HRMS (ESI): m/z [M] calcd for C₁₆H₂₄N₃O₂: 290.1869; found:

290.1876.

mmol) and BnBr (0.02 mL, 0.17 mmol)] gave 23 (0.063 g, 74%) as

a colorless amorphous mass.

N-Benzyl-N-[(tert-butoxycarbonyl)methyl]-N′,N′′-ethylene-

N′,N′′-dimethylguanidinium Bromide (7b·Br)

Following GP1: from benzylguanidine (2.89 g, 14.2 mmol) and

tert-butyl bromoacetate (2.6 mL, 17.6 mmol)] as colorless prisms

(washed with Et₂O); yield: 5.73 g (quant); mp 75–77 °C.

N-[(tert-Butoxycarbonyl)methyl]-N′,N′′-ethylene-N′,N′′-di-

methyl-N-[(R)-1-phenylethyl]guanidinium Bromide (24)

Following GP1: from 1,3-dimethyl-2-[(R)-1-phenethylimino]-4,5-

dihydroimidazolidine^9a(0.052 g, 0.241 mmol) and tert-butyl bro-

moacetate (0.04 mL, 0.271 mmol) gave 24 (0.074 g, 75%) as a

brownish oil.

N-(Acetylmethyl)-N-benzyl-N′,N′′-ethylene-N′,N′′-dimethyl-

guanidinium Hexafluorophosphate (15)

Following GP1.

(S,S)-N-Benzyl-N′,N′′-(1,2-diphenylethylene)-N-[(methoxycar-

bonyl)methyl]-N′,N′′-dimethylguanidinium Bromide [(S,S)-

25c·Br)

Following GP1.

Step 1: Benzylguanidine (0.65 g, 3.2 mmol) and bromoacetone

(97%, 0.33 mL, 3.8 mmol) gave the guanidinium bromide (0.863 g,

80%).

Step 1: (S,S)-27 (2.45 g, 7.12 mmol) and BnNH₂(0.65 mL, 5.95

mmol) gave the guanidine (1.98 g, 94%).

Step 2: The guanidinium bromide (0.750 g, 2.2 mmol) and NH₄PF₆

(0.481 g, 2.95 mmol) gave 15 (0.77 g, 84%) as colorless prisms

(EtOAc–hexane); mp 127–131 °C.

Step 2: The guanidine (1.99 g, 5.57 mmol) and methyl bromoacetate

(0.57 mL, 6.02 mmol) gave (S,S)-25c·Br (1.97 g, 70%) as a pale yel-

low solid (washed with Et₂O–hexane); mp 122–124 °C.

N-Benzyl-N-(cyanomethyl)-N′,N′′-ethylene-N′,N′′-dimethyl-

guanidinium Hexafluorophosphate (16)

Following GP1.

(R,R)-N-[2-(tert-Butyldimethylsiloxy)ethyl]-N-[(tert-butoxycar-

bonyl)methyl]-N′,N′′-(1,2-diphenylethylene)-N′,N′′-dimethyl-

guanidinium Hexafluorophosphate [(R,R)-28]

Step 1: 2-Chloro-1,3-dimethyl-4,5-dihydroimidazolium chloride

(0.52 g, 3.1 mmol) and aminoacetonitrile (97%, 0.274 g, 1.7 mmol)

gave the guanidine (0.132 g, 50%).

(R,R)-(Siloxyethyl)guanidine

To an ice-cooled solution of (R,R)-27 (5.55 g, 17.3 mmol) in CH₂-

Cl₂(40 mL) was successively added Et₃N (7 mL, 50.2 mmol) and a

solution of 2-(tert-butyldimethylsiloxy)ethylamine¹⁶(1.83 g, 10.4

mmol) in CH₂Cl₂(10 mL) and the mixture was stirred at r.t. for 5 h.

After the addition of THF (50 mL) the separated solids were re-

moved by filtration. After evaporation of the filtrate, the residue

was purified by column chromatography (NH-silica gel, hexane–

toluene, 3:1 to toluene–MeOH, 30:1) to give the product (3.45 g,

78%) as a pale yellow oil that solidified on standing; mp 68–70 °C.

Step 2: The guanidine (0.394 g, 2.6 mmol) and BnBr (0.31 mL, 2.6

mmol) gave the guanidinium bromide (0.462 g, 55%).

Step 3: The guanidinium bromide (0.115 g, 0.36 mmol) and NH₄PF₆

(0.065 g, 0.40 mmol) gave 16 (0.05 g, 37%) as colorless prisms

(EtOAc–hexane); mp 150–152 °C.

N-Benzyl-N′,N′′-ethylene-N′,N′′-dimethyl-N-(2,2,2-trifluoro-

ethyl)guanidinium Hexafluorophosphate (17)

Following GP1.

[α]_D¹⁸–47.9 (c 1.0, CHCl₃).

IR (ATR): 1669 cm^–1.

Step 1: 2-Chloro-1,3-dimethyl-4,5-dihydroimidazolium chloride

(1.203 g, 7.12 mmol) and 2,2,2-trifluoromethylamine hydrochlo-

ride (0.537 g, 3.96 mmol) gave the guanidine (0.696 g, 90%).

¹H NMR (400 MHz): δ = 0.12 (s, 3 H), 0.13 (s, 3 H), 0.94 (s, 9 H),

2.57 (br s, 3 H), 2.84 (br s, 3 H), 3.57–3.63 (m, 1 H), 3.69–3.80 (m,

2 H), 3.82–3.90 (m, 3 H), 7.13–7.15 (m, 4 H), 7.27–7.34 (m, 6 H).

¹³C NMR (100 MHz): δ = –5.1, 18.5, 26.0, 29.9, 49.9, 65.8, 70.2,

127.4, 128.0, 128.5, 138.4, 157.5.

Step 2: The guanidine (0.679 g, 3.48 mmol) and BnBr (0.46 mL,

3.87 mmol) gave the guanidinium chloride (0.908 g, 71%).

Step 3: The guanidinium chloride (0.128 g, 0.35 mmol) and NH₄PF₆

(0.064 g, 0.39 mmol) gave 17 (0.06 g, 40%) as colorless prisms

(EtOAc–hexane); mp 112–113 °C.

HRMS (FAB): m/z [M + H] calcd for C₂₅H₃₈N₃OSi: 424.2784;

found: 424.2764.

N-Benzyl-N-[(tert-butoxycarbonyl)methyl]-N′,N′′-diethyl-

N′,N′′-ethyleneguanidinium Hexafluorophosphate (20)

Following GP1.

(R,R)-N-[2-(tert-Butyldimethylsiloxy)ethyl]-N-[(tert-butoxycar-

bonyl)methyl]-N′,N′′-(1,2-diphenylethylene)-N′,N′′-dimethyl-

guanidinium Hexafluorophosphate [(R,R)-28]

Step 1: 1,3-Dimethylimidazolin-2-one (5.00 g, 58.2 mmol) and EtI

(0.2 mL, 128 mmol) gave 1,3-diethylimidazolin-2-one (6.61 g,

80%).

The (R,R)-(siloxyethyl)guanidine (2.70 g, 6.37 mmol) was treated

with tert-butyl bromoacetate (1.0 mL, 6.77 mmol) in MeCN (20

mL) (12 h). After evaporation CH₂Cl₂(5 mL), H₂O (20 mL) and

NH₄PF₆(1.11 g, 6.82 mmol) were added. The mixture was stirred

(15 min) and extracted with CH₂Cl₂(4 × 40 mL). The combined or-

ganic solutions were washed with H₂O (5 mL) and brine (5 mL),

dried (K₂CO₃), and evaporated. Trituration of the residue (hexane–

Et₂O, 1:4) afforded (R,R)-28 (4.36 g, quant) as a colorless solid; mp

107–115 °C.

Step 2: The imidazolidinone (0.503 g, 3.54 mmol) and oxalyl chlo-

ride (1.6 mL, 18.3 mmol) gave 2-chloro-1,3-diethyl-4,5-dihydroim-

idazolium chloride (0.606 g, 88%, 94% purity by ¹H NMR).

Step 3: The chloroamidinium chloride (0.589 g, 2.81 mmol, 94%

purity) and tert-butyl glycinate hydrochloride (0.378 g, 2.25 mmol)

gave the guanidine (0.574 g, quant).

[α]_D²⁵–36.4 (c 1.0, CHCl₃).

IR (ATR): 1742 cm^–1.

Step 4: The guanidine (0.573 g, 2.25 mmol) and BnBr (0.33 mL,

2.77 mmol) gave the guanidinium bromide (0.786 g, 82%).

¹H NMR (400 MHz): δ = 0.12 (s, 3 H), 0.14 (s, 3 H), 0.93 (s, 9 H),

1.54 (s, 9 H), 3.05 (s, 6 H), 3.66 (t, J = 4.5 Hz, 2 H), 3.95 (dt,

J = 12.2, 4.5 Hz, 1 H), 4.03 (dt, J = 12.2, 4.5 Hz, 1 H), 4.19 (d,

J = 18.7 Hz, 1 H), 4.52 (dd, J = 18.7, 2.2 Hz, 1 H), 4.59 (s, 2 H),

7.24–7.26 (m, 4 H), 7.42–7.44 (m, 6 H).

¹³C NMR (100 MHz): δ = –5.6, 17.8, 25.5, 27.7, 35.8, 51.3, 54.7,

61.8, 74.2, 83.2, 126.9, 129.1, 129.2, 135.4, 165.0, 167.4.

Step 5: The guanidinium bromide (0.355 g, 0.832 mmol) and

NH₄PF₆(0.149 g, 0.923 mmol) gave 20 (0.243 g, 59%) as colorless

prisms; mp 148–150 °C.

N-Benzyl-N-[(tert-butoxycarbonyl)methyl]-N′,N′′-ethylene-

N′,N′′-bis[(S)-1-phenylethyl]guanidinium Bromide (23)

Following GP1: from 2-[(tert-butoxycarbonyl)methylimino]-1,3-

bis[(S)-1-phenylethyl]-4,5-dihydroimidazolidine^9a(0.06 g, 0.147

Synthesis 2014, 46, 2201–2219

PAPER

Formation of Unactivated 3-Arylaziridine-2-carboxylates

2215

HRMS (FAB): m/z [M] calcd for C₃₁H₄₈N₃O₃Si: 538.3465; found:

538.3449.

(0.302 g, 1.76 mmol), and NH₄PF₆(0.416 g, 2.55 mmol) gave 12b

(0.450 g, 62%) colorless prisms (EtOAc); mp 93–94 °C.

(R,R)-N-Allyl-N′,N′′-(1,2-diphenylethylene)-N-[(methoxycar-

N-Benzyl-N′,N′′-ethylene-N-[1-(methoxycarbonyl)ethyl]-

N′,N′′-dimethylguanidinium Chloride (18a)

Following GP2: from 2-chloro-1,3-dimethyl-4,5-dihydroimidazoli-

um chloride (1.15 g, 6.81 mmol) and methyl N-benzylalaninate

(1.013 g, 5.24 mmol)] gave 18a (1.092 g, 64%) colorless prisms

(EtOAc–hexane); mp 97–99 °C.

bonyl)methyl]-N′,N′′-dimethylguanidinium Bromide [(R,R)-

30c·Br]

Following GP1.

Step 1: (R,R)-27 (0.548 g, 1.71 mmol) and allylamine (0.09 mL, 1.2

mmol) gave allylguanidine (0.346 g, 94%).

Step 2: Allylguanidine (0.500 g, 1.64 mmol) and methyl bromoace-

tate (0.18 mL, 1.90 mmol) gave (R,R)-30c·Br (0.703 g, 94%) as

colorless prisms (washed with Et₂O–hexane); mp 143–145 °C;

[α]_D²⁵–70.2 (c 1.0, CHCl₃).

N-Benzyl-N-[1-(ethoxycarbonyl)-2-phenylethyl]-N′,N′′-eth-

ylene-N′,N′′-dimethylguanidinium Chloride (18b)

Following GP2: from 2-chloro-1,3-dimethyl-4,5-dihydroimidazoli-

um chloride (0.208 g, 1.23 mmol) and ethyl N-benzylphenylala-

ninate (0.220 g, 0.776 mmol) gave 18b (0.182 g, 56%) as pale

yellow prisms (EtOAc–MeOH); mp 195–196 °C.

(R,R)-N-Allyl-N′,N′′-(1,2-diphenylethylene)-N-[(methoxycar-

bonyl)methyl]-N′,N′′-dimethylguanidinium Hexafluorophos-

phate [(R,R)-30c·PF₆]

Following GP1: from the allylguanidine (0.501 g, 1.64 mmol) and

methyl bromoacetate (0.18 mL, 1.90 mmol), and NH₄PF₆(0.390 g,

2.40 mmol) gave (R,R)-30c·PF₆(0.594 g, 69%) as colorless needles

(EtOAc); mp 146–148 °C; [α]_D²¹–46.3 (c 1.0, CHCl₃).

N-[1-(Ethoxycarbonyl)-2-phenylethyl]-N′,N′′-ethylene-

N,N′,N′′-trimethylguanidinium Chloride (19)

Following GP2: from 2-chloro-1,3-dimethyl-4,5-dihydroimidazoli-

um chloride (0.117 g, 0.691 mmol) and ethyl N-methylphenylala-

ninate (0.091 g, 0.437 mmol)] gave 19 (0.079 g, 53%) as pale

yellow prisms (EtOAc); mp 71–73 °C.

(R,R)-N-Allyl-N′,N′′-(1,2-diphenylethylene)-N-[(ethoxycarbon-

yl)methyl]-N′,N′-dimethylguanidinium Bromide [(R,R)-

30a·Br]

Following GP1: from allylguanidine (0.364 g, 1.19 mmol) and ethyl

bromoacetate (0.15 mL, 1.36 mmol) gave (R,R)-30a·Br (0.531 g,

94%) as a colorless oil; [α]_D²⁵–75.1 (c 1.0, CHCl₃).

(S,S)-N-Benzyl-N′,N′′-(1,2-diphenylethylene)-N-[(methoxycar-

bonyl)methyl]-N′,N′′-dimethylguanidinium Hexafluorophos-

phate [(S,S)-25c·PF₆]

Following GP2: from (S,S)-27 (2.41 g, 7.00 mmol, 93% purity by

¹H NMR), methyl N-benzylalaninate (0.834 g, 4.66 mmol), and

NH₄PF₆(0.992 g, 1.31 mmol) gave (S,S)-25c·PF₆(1.734 g, 65%) as

colorless prisms (EtOAc); mp 168–169 °C.

(R,R)-N-Allyl-N-[(tert-butoxycarbonyl)methyl]-N′,N′′-(1,2-di-

phenylethylene)-N′,N′′-dimethylguanidinium Bromide [(R,R)-

30b·Br]

Following GP1: from the allylguanidine (0.371 g, 1.22 mmol) and

ethyl bromoacetate (0.20 mL, 1.36 mmol) gave (R,R)-30b·Br

(0.523 g, 86%) as a colorless oil, [α]_D²⁵–84.6 (c 0.97, CHCl₃).

(S,S)-N-Benzyl-N-[(tert-butoxycarbonyl)methyl]-N′,N′′-(1,2-di-

phenylethylene)-N′,N′′-dimethylguanidinium Hexafluorophos-

phate [(S,S)-25b·PF₆]

Reaction of tert-butyl bromoacetate and BnNH₂in THF in the pres-

ence of Et₃N at r.t. for 20 h gave tert-butyl 2-(benzylamino)acetate

(72% yield). Et₃N (1.6 mL, 11.5 mmol) and a solution of the above

2-(benzylamino)acetate (0.834 g, 3.8 mmol) in MeCN (6 mL) were

successively added to a solution of (S,S)-27 (75% purity, 2.386 g,

5.6 mmol) in MeCN (45 mL) at 0 °C and the mixture was stirred at

95 °C (3 h). Workup followed by flash column chromatography

(CHCl₃–MeOH, 15: 1 to 5:1) gave a pale brown oil, which was

treated with NH₄PF₆(0.803 g, 4.9 mmol) in H₂O (75 mL) (25 min)

and triturated (hexane–Et₂O) to afford (S,S)-25b·PF₆(2.046 g,

88%) as a yellow solid; mp 66–69 °C; [α]_D²³+65.0 (c 0.50, CHCl₃).

Direct Preparation of Guanidinium Salts from Secondary

Amines; General Procedure 2

A solution of a 2-chloroimidazolinium chloride in MeCN was add-

ed to an ice-cooled solution of a secondary amine in MeCN contain-

ing Et₃N and then the mixture was stirred either at r.t. or under

reflux. After removal of insoluble precipitates by filtration, evapo-

ration of the filtrate followed by column chromatography (NH-

silica gel) gave a guanidinium chloride. In the case of a hexafluoro-

phosphate salt the residue was treated according to the stepwise pro-

cedure given in GP1.

IR (ATR): 1747 cm^–1.

N-Allyl-N′,N′′-ethylene-N-[(methoxycarbonyl)methyl]-N′,N′′-

dimethylguanidinium Hexafluorophosphate (12c); Typical Pro-

cedure for GP2

Treatment of 2-chloro-1,3-dimethyl-4,5-dihydroimidazolium chlo-

ride (2.90 g, 17.1 mmol) in MeCN (25 mL) with a solution of meth-

yl N-allylglycinate (1.42 g, 11.0 mmol) and Et₃N (4.60 mL, 33.0

mmol) in MeCN (110 mL) at r.t. for 3 h followed by a solution of

NH₄PF₆(2.58 g, 15.8 mmol) in H₂O (60 mL) gave 12c (3.28 g,

80%) as colorless prisms (EtOAc); mp 133–134 °C.

¹H NMR (400 MHz): δ = 1.53 (s, 9 H), 3.07 (s, 6 H), 4.05 (d,

J = 19.0 Hz, 1 H), 4.21 (d, J = 19.0 Hz, 1 H), 4.58 (s, 2 H), 4.62 (d,

J = 14.6 Hz, 1 H), 4.82 (d, J = 14.6 Hz, 1 H), 7.05–7.08 (m, 4 H),

7.34–7.38 (m, 6 H), 7.45–7.54 (m, 5 H).

¹³C NMR (100 MHz): δ = 27.9, 35.5, 52.1, 55.7, 74.7, 84.0, 127.1,

128.6, 128.8, 129.5, 129.6, 129.7, 133.9, 135.4, 164.3, 167.9.

HRMS (ESI): m/z [M] calcd for C₃₀H₃₆F₆N₃O₂P: 470.2808; found:

470.2822.

IR (ATR): 1758 cm^–1.

Aziridination under Optimized Conditions (Table 4); Reaction

Conditions A

¹H NMR (400 MHz, acetone-d₆): δ = 3.20 (s, 6 H), 3.73 (s, 3 H),

3.89 (s, 4 H), 4.07 (d, J = 6.4 Hz, 2 H), 4.20 (s, 2 H), 5.32 (dd,

J = 10.1, 0.9 Hz, 1 H), 5.39 (dd, J = 17.0, 1.1 Hz, 1 H), 5.88 (ddt,

J = 17.0, 10.1, 6.9 Hz, 1 H).

¹³C NMR (100 MHz, acetone-d₆): δ = 36.0, 50.0, 52.8, 54.4, 121.5,

133.1, 164.6, 169.9.

A solution of arylaldehyde 3 (1 mmol) in DMF (1–4 mL) was added

to a stirred mixture of a guanidinium bromide 7·Br (1.1–1.3 equiv)

and 60% NaH (1.2–1.4 equiv) in DMF (1–2 mL) at –20 °C, and the

mixture was stirred at this temperature and worked up. In workup

A, the reaction mixture was poured into ice-water and extracted

with EtOAc. The combined organic solution extracts were washed

with H₂O and brine, and evaporated to give a crude product. In

workup B, after evaporation of the reaction mixture, the residue was

dissolved in either CHCl₃or MeCN (ca 30 mL) and then stirred with

silica gel (ca 20 g) at r.t. for an appropriate time. The silica gel was

filtered off and repeatedly washed with either CHCl₃or MeCN. The

filtrate and washings were combined and evaporated to give a crude

HRMS (ESI): m/z [M] calcd for C₁₁H₂₀N₃O₂: 226.1556; found:

226.1518.

N-Allyl-N-[(tert-butoxycarbonyl)methyl]-N′,N′′-ethylene-

N′,N′′-dimethylguanidinium Hexafluorophosphate (12b)

Following GP2: from 2-chloro-1,3-dimethyl-4,5-dihydroimidazoli-

um chloride (0.628 g, 3.71 mmol), tert-butyl N-allylglycinate

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Y. Oda et al.

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product. Purification of the latter by column chromatography (silica

gel, hexane–EtOAc) afforded an aziridine product 5.

7.4 Hz, 1 H), 7.32 (dd, J = 7.4, 7.4 Hz, 2 H), 7.43 (d, J = 7.4 Hz, 2

H), 7.46 (d, J = 7.4 Hz, 1 H).

¹³C NMR (100 MHz): δ = 13.9, 44.2, 45.2, 55.3, 60.5, 63.8, 109.6,

120.0, 123.4, 127.2, 128.1, 128.3, 128.4, 129.6, 137.9, 157.9, 168.5.

Aziridination under Optimized Conditions (Table 4); Reaction

Conditions B

A mixture of an arylaldehyde 3 (1 mmol) and a guanidinium bro-

mide 7·Br (1.1 equiv) in freshly distilled TMG (1.1–1.8 equiv) was

stirred at r.t. for an appropriate time and evaporated. Treatment of

the residue under similar conditions A gave an aziridine product 5.

Data is given for selected racemic aziridine products:

HRMS (ESI): m/z [M + Na] calcd for C₁₉H₂₁NO₃Na: 334.1419;

found: 334.1420.

Ethyl 1-Benzyl-3-phenylaziridine-2-carboxylate (5af)

trans-5af¹⁷

Colorless oil.

IR (neat): 1725 cm^–1.

Ethyl 1-Benzyl-3-[3,4-(methylenedioxy)phenyl]aziridine-2-car-

boxylate (5aa)

trans-5aa

¹H NMR (400 MHz): δ = 1.21 (t, J = 7.0 Hz, 3 H), 2.78 (br s, 1 H),

3.32 (br s, 1 H), 4.09 (d, J = 14.0 Hz, 1 H), 4.16 (q, J = 7.0 Hz, 2 H),

4.26 (d, J = 14.0 Hz, 1 H), 7.20–7.38 (m, 10 H).

Yellow oil.

IR (neat): 1725 cm^–1.

¹H NMR (400 MHz): δ = 1.22 (t, J = 7.0 Hz, 3 H), 2.71 (d, J = 2.1

Hz, 1 H), 3.26 (br s, 1 H), 4.01 (d, J = 13.7 Hz, 1 H), 4.15 (q, J = 7.0

Hz, 2 H), 4.23 (d, J = 13.7 Hz, 1 H), 5.93 (s, 2 H), 6.72–6.81 (m, 3

H), 7.21–7.42 (m, 5 H).

¹³C NMR (100 MHz): δ = 14.1, 44.4, 48.3, 54.8, 61.1, 101.0, 106.3,

108.1, 120.0, 126.9, 128.0, 128.2, 132.2, 139.1, 147.1, 147.8, 168.6.

MS (EI): m/z (%) = 281 (0.4) [M].

cis-5af¹⁸

Colorless oil.

IR (neat): 1745 cm^–1.

¹H NMR (400 MHz): δ = 0.96 (t, J = 7.2 Hz, 3 H), 2.63 (d, J = 6.7

Hz, 1 H), 3.07 (d, J = 6.7 Hz, 1 H), 3.65 (d, J = 13.7 H, 1 H), 3.87–

4.02 (m, 3 H), 7.20–7.44 (m, 10 H).

HRMS (FAB): m/z [M + H] calcd for C₁₉H₂₀NO₄: 326.1392; found:

326.1402.

MS (EI): m/z (%) = 281 (3) [M].

cis-5aa

Ethyl 1-Benzyl-3-(4-chlorophenyl)aziridine-2-carboxylate

(5ag)

Yellow oil.

IR (neat): 1745 cm^–1.

¹H NMR (400 MHz): δ = 1.06 (t, J = 7.0 Hz, 3 H), 2.58 (d, J = 6.7

Hz, 1 H), 2.99 (d, J = 6.7 Hz, 1 H), 3.60 (d, J = 13.7 Hz, 1 H), 3.93

(d, J = 13.7 Hz, 1 H), 3.94–4.06 (m, 2 H), 5.91 (s, 2 H), 6.70–6.97

(m, 3 H), 7.22–7.46 (m, 5 H).

¹³C NMR (100 MHz): δ = 14.0, 45.9, 47.6, 60.7, 63.5, 100.9, 107.7,

108.4, 121.2, 127.2, 127.9, 128.4, 128.9, 137.6, 146.9, 147.2, 168.0.

trans-5ag

Yellow oil.

IR (neat): 1726 cm^–1.

¹H NMR (500 MHz): δ = 1.22 (t, J = 7.0 Hz, 3 H), 2.74 (br s, 1 H),

3.29 (br s, 1 H), 4.08 (d, J = 13.7 Hz, 1 H), 4.17 (q, J = 7.0 Hz, 2 H),

4.23 (d, J = 13.7 Hz, 1 H), 7.21–7.36 (m, 9 H).

HRMS (ESI): m/z [M + H] calcd for C₁₉H₂₀NO₄: 326.1392; found:

326.1363.

¹³C NMR (125 MHz): δ = 14.1, 44.8, 47.7, 54.8, 61.3, 127.0, 127.6,

128.0, 128.3, 128.5, 133.3, 136.8, 139.0, 168.4.

HRMS (FAB): m/z [M + H] calcd for C₁₈H₁₉ClNO₂: 316.1104;

found: 316.1112.

Ethyl 1-Benzyl-3-(2-methoxyphenyl)aziridine-2-carboxylate

(5ad)

cis-5ag

Yellow oil.

trans-5ad

Pale yellow oil.

IR (neat): 1744 cm^–1.

IR (neat): 1726 cm^–1.

¹H NMR (500 MHz): δ = 1.01 (t, J = 7.2 Hz, 3 H), 2.64 (d, J = 6.7

Hz, 1 H), 3.01 (d, J = 6.7 Hz, 1 H), 3.61 (d, J = 13.7 Hz, 1 H), 3.90–

4.03 (m, 3 H), 7.23–7.41 (m, 9 H).

¹³C NMR (125 MHz): δ = 14.0, 46.0, 46.9, 60.8, 63.4, 127.3, 127.9,

128.0, 128.4, 129.2, 133.2, 133.5, 137.5, 167.8.

¹H NMR (600 MHz): δ = 1.21 (t, J = 7.2 Hz, 3 H × 5/7), 1.29 (t,

J = 7.2 Hz, 3 H × 2/7), 2.70 (d, J = 2.4 Hz, 1 H × 5/7), 2.72 (br s, 1

H × 2/7), 3.63 (br s, 1 H × 2/7), 3.65 (d, J = 2.4 Hz, 1 H × 5/7), 3.74

(s_,3 H × 2/7), 3.82 (s, 3 H × 5/7), 4.10 (d, J = 13.7 Hz, 1 H), 4.17 (q,

J = 7.2 Hz, 2 H), 4.25 (d, J = 13.7 Hz, 1 H), 6.82–6.94 (m, 2 H),

7.20–7.40 (m, 7 H).

¹³C NMR (150 MHz): δ (major invertomer) = 14.16, 43.6, 44.0,

55.3, 61.0, 110.0, 125.0, 126.4, 126.9, 128.1, 128.2, 128.3, 129.8,

138.7, 158.0, 169.0; δ (minor invertomer) = 14.21, 41.7, 44.7, 55.1,

55.5, 61.1, 110.3, 119.8, 126.4, 126.7, 128.1, 128.2, 130.8, 139.4,

159.7, 170.8.

HRMS (ESI): m/z [M + H] calcd for C₁₈H₁₉ClNO₂: 316.1104;

found: 316.1117.

Ethyl 1-Benzyl-3-(4-nitrophenyl)aziridine-2-carboxylate [(5ak)

trans-5ak

Yellow oil.

IR (neat): 1727 cm^–1.

¹H NMR (400 MHz): δ = 1.23 (t, J = 7.2 Hz, 3 H), 2.80 (d, J = 2.1

Hz, 1 H), 3.41 (br s, 1 H), 4.11 (d, J = 13.4 Hz, 1 H), 4.19 (q, J = 7.2

Hz, 2 H), 4.25 (d, J = 13.4 Hz, 1 H), 7.21–7.36 (m, 5 H), 7.46 (d,

J = 8.5 Hz, 2 H), 8.16 (d, J = 8.5 Hz, 2 H).

HRMS (FAB): m/z [M + H] calcd for C₁₉H₂₂NO₃: 312.1599; found:

312.1578.

cis-5ad

Colorless oil.

IR (ATR): 1746 cm^–1.

¹³C NMR (100 MHz): δ = 14.1, 45.4, 47.2, 54.7, 61.5, 123.6, 127.1,

127.2, 128.0, 128.4, 138.6, 145.8, 147.4, 175.5.

¹H NMR (400 MHz): δ = 0.95 (t, J = 7.2 Hz, 3 H), 2.67 (d, J = 7.0

Hz, 1 H), 3.21 (d, J = 7.0 Hz, 1 H), 3.62 (d, J = 14.0 Hz, 1 H), 3.80

(s, 3 H), 3.83–4.01 (m, 2 H), 3.96 (d, J = 14.0 Hz, 1 H), 6.78 (d,

J = 8.4 Hz, 1 H), 6.89 (dd, J = 7.4, 7.4 Hz, 1 H), 7.19 (dd, J = 8.4,

HRMS (FAB): m/z [M + H] calcd for C₁₈H₁₉N₂O₄: 327.1345; found:

327.1341.

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Formation of Unactivated 3-Arylaziridine-2-carboxylates

2217

cis-5ak

Yellow oil.

120.0, 123.5, 124.5, 126.6, 127.7, 128.1, 128.9, 131.7, 135.2, 138.5,

149.6, 170.7.

IR (neat): 1743 cm^–1.

HRMS (FAB): m/z [M + H] calcd for C₂₅H₂₉N₂O₄: 421.2127; found:

¹H NMR (400 MHz): δ = 1.02 (t, J = 7.0 Hz, 3 H), 2.74 (d, J = 6.8

Hz, 1 H), 3.11 (d, J = 6.8 Hz, 1 H), 3.63 (d, J = 13.6 Hz, 1 H), 3.89–

4.03 (m, 2 H), 4.02 (d, J = 13.6 Hz, 1 H), 7.21–7.42 (m, 5 H), 7.58

(d, J = 8.5 Hz, 2 H), 8.13 (d, J = 8.5 Hz, 2 H).

¹³C NMR (100 MHz): δ = 14.0, 45.3, 46.7, 61.0, 63.3, 122.8, 123.1,

127.6, 127.9, 128.5, 128.8, 137.1, 142.6, 167.3.

421.2097.

cis-5ao

Colorless oil.

IR (ATR): 1736 cm^–1.

¹H NMR (500 MHz): δ = 0.85 (t, J = 7.2 Hz, 3 H), 1.66 (s, 9 H),

2.74 (d, J = 6.6 Hz, 1 H), 3.34 (d, J = 6.6 Hz, 1 H), 3.73 (d, J = 13.8

Hz, 1 H), 3.77–3.92 (m, 2 H), 4.00 (d, J = 13.8 Hz, 1 H), 6.70 (d,

J = 3.6 Hz, 1 H), 7.22–7.36 (m, 5 H), 7.46 (d, J = 7.6 Hz, 2 H), 7.57

(d, J = 3.6 Hz, 1 H), 8.01 (d, J = 8.0 Hz, 1 H).

¹³C NMR (125 MHz): δ = 13.8, 28.2, 45.3, 46.0, 60.6, 63.8, 83.7,

105.1, 114.3, 122.3, 123.9, 125.8, 127.1, 127.4, 128.1, 128.5, 129.3,

134.8, 137.6, 149.8, 168.2.

HRMS (ESI): m/z [M + Na] calcd for C₁₈H₁₈N₂O₄Na: 349.1164;

found: 349.1172.

Ethyl 1-Benzyl-3-cinnamylaziridine-2-carboxylate (5al)

trans-5al

Yellow oil.

IR (neat): 1725 cm^–1.

HRMS (FAB): m/z [M + H] calcd for C₂₅H₂₉N₂O₄: 421.2127; found:

¹H NMR (500 MHz, CD₂Cl₂, –90 °C): δ (major invertomer) = 1.20

(t, J = 7.0 Hz, 3 H), 2.54 (d, J = 1.8 Hz, 1 H), 3.09 (dd, J = 10.1, 1.8

Hz, 1 H), 3.73 (d, J = 14.3 Hz, 1 H), 3.88 (d, J = 14.3 Hz, 1 H),

4.05–4.09 (m, 2 H), 6.21 (dd, J = 15.5, 10.1 Hz, 1 H), 6.78 (d,

J = 15.6 Hz, 1 H), 7.20–7.38 (m, 10 H); δ (minor invertomer) = 1.15

(t, J = 7.0 Hz, 3 H), 2.71 (d, J = 1.8 Hz, 1 H), 2.97 (dd, J = 8.9, 1.8

Hz, 1 H), 3.89 (d, J = 13.7 Hz, 1 H), 4.05–4.09 (m, 2 H), 4.14 (d,

J = 13.7 Hz, 1 H), 5.88 (dd, J = 16.2, 8.9 Hz, 1 H), 6.67 (d, J = 16.2

Hz, 1 H), 7.20–7.38 (m, 10 H).

¹³C NMR (150 MHz, CD₂Cl₂, 21 °C): δ (1:1) = 14.1, 14.2, 42.4,

45.3, 46.4, 48.5, 54.7, 56.1, 61.2, 121.7, 126.3, 126.4, 127.0, 127.1,

127.66, 127.73, 128.0, 128.1, 128.3, 128.4, 128.6, 128.7, 132.9,

136.1, 136.4, 137.1, 138.4, 140.0, 168.9, 170.3.

421.2097.

Methyl 1-Allyl-3-(1-tosylindol-4-yl)aziridine-2-carboxylate

(14ca)

trans-14ca

Yellow oil.

IR (ATR): 1730 cm^–1.

¹H NMR (400 MHz): δ (major invertomer) = 2.28 (s, 3 H), 2.84 (d,

J = 1.8 Hz, 1 H), 3.43 (d, J = 1.8 Hz, 1 H), 3.55 (dd, J = 14.2, 5.5

Hz, 1 H), 3.69–3.83 (m, 4 H), 5.08 (d, J = 10.5 Hz, 1 H), 5.23 (d,

J = 17.4 Hz, 1 H), 5.90–6.00 (m, 1 H), 6.88 (d, J = 3.2 Hz, 1 H),

7.08–7.27 (m, 4 H), 7.58 (d, J = 3.7 Hz, 1 H), 7.74 (d, J = 7.3 Hz, 2

H), 7.91 (d, J = 7.8 Hz, 1 H); δ (minor invertomer) = 2.28 (s, 3 H),

2.43 (d, J = 8.2 Hz, 1 H), 2.78 (s, 1 H), 2.96 (d, J = 10.5 Hz, 1 H),

3.69–3.83 (m, 4 H), 4.84 (d, 16.9 Hz, 1 H), 4.90 (d, J = 10.1 Hz, 1

H), 5.76–5.78 (m, 1 H), 6.92 (s, 1 H), 7.08–7.27 (m, 4 H), 7.65 (s, 1

H), 7.74 (d, J = 7.3 Hz, 2 H), 8.00 (d, J = 7.8 Hz, 1 H).

¹³C NMR (100 MHz): δ (major invertomer) = 21.3, 43.0, 46.3, 52.0,

53.7, 106.7, 112.5, 116.3, 120.3, 124.4, 124.7, 126.2, 126.6, 129.0,

129.7, 130.6, 134.9, 135.0, 144.8, 168.8; δ (minor invertomer) 21.3,

40.9, 45.3, 52.3, 54.4, 107.1, 113.6, 116.5, 123.8, 123.9, 124.7,

126.6, 126.8, 129.0, 129.7, 131.7, 134.2, 134.6, 145.0, 170.9.

HRMS (FAB): m/z [M + H] calcd for C₂₀H₂₂NO₂: 308.1651; found:

308.1644.

cis-5al

Yellow oil.

IR (neat): 1741 cm^–1.

¹H NMR (500 MHz): δ = 1.26 (t, J = 7.0 Hz, 3 H), 2.53 (d, J = 6.7

Hz, 1 H), 2.65 (dd, J = 8.2, 6.7 Hz, 1 H), 3.69 (d, J = 13.7 Hz, 1 H),

3.76 (d, J = 13.7 Hz, 1 H), 4.12–4.28 (m, 2 H), 6.26 (dd, J = 16.2,

8.2 Hz, 1 H), 6.71 (d, J = 16.2 Hz, 1 H), 7.20–7.37 (m, 10 H).

¹³C NMR (125 MHz): δ = 14.3, 44.7, 48.0, 61.1, 63.3, 124.7, 126.4,

127.2, 127.8, 128.4, 128.5, 134.3, 136.5, 137.5, 169.0.

HRMS (ESI): m/z [M + H] calcd for C₂₂H₂₃N₂O₄S: 411.1379;

found: 411.1331.

cis-14ca

HRMS (FAB): m/z [M + H] calcd for C₂₀H₂₂NO₂: 308.1651; found:

308.1648.

Yellow prisms; mp 103–105 °C.

IR (ATR): 1747 cm^–1.

Ethyl 1-Benzyl-3-[1-(tert-butoxycarbonyl)indol-4-yl]aziridine-

2-carboxylate (5ao)

¹H NMR (400 MHz): δ = 2.33 (s, 3 H), 2.65 (d, J = 6.4 Hz, 1 H),

3.10–3.16 (m, 2 H), 3.26 (s, 3 H), 3.35 (dd, J = 13.7, 5.5 Hz, 1 H),

5.17 (d, J = 10.5 Hz, 1 H), 5.28 (d, J = 17.4 Hz, 1 H), 6.03 (ddt,

J = 16.5, 11.0, 5.5 Hz, 1 H), 6.82 (d, J = 3.7 Hz, 1 H), 7.21 (d,

J = 8.2 Hz, 2 H), 7.25 (t, J = 7.8 Hz, 1 H), 7.33 (d, J = 6.9 Hz, 1 H),

7.57 (d, J = 3.2 Hz, 1 H), 7.75 (d, J = 8.2 Hz, 2 H), 7.88 (d, J = 8.2

Hz, 1 H).

¹³C NMR (100 MHz): δ = 21.5, 44.9, 45.5, 51.7, 62.7, 106.7, 112.7,

117.9, 122.5, 124.3, 126.3, 126.8, 127.6, 129.5, 129.8, 133.7, 134.5,

135.2, 144.9, 168.6.

trans-5ao

Colorless oil.

IR (ATR): 1726 cm^–1.

¹H NMR (500 MHz): δ (major invertomer) = 1.22 (t, J = 7.1 Hz, 3

H), 1.67 (s, 9 H), 2.92 (d, J = 2.0 Hz, 1 H), 3.62 (d, J = 2.0 Hz, 1 H),

4.13–4.21 (m, 3 H), 4.32 (d, J = 13.9 Hz, 1 H), 6.76 (d, J = 3.3 Hz,

1 H), 7.15–7.32 (m, 5 H), 7.40 (d, J = 7.3 Hz, 2 H), 7.59 (d, J = 3.3

Hz, 1 H), 8.05 (d, J = 7.5 Hz, 1 H); δ (minor invertomer) = 1.32 (t,

J = 7.1 Hz, 3 H), 1.67 (s, 9 H), 2.95 (d, J = 2.0 Hz, 1 H), 3.68 (d,

J = 2.0 Hz, 1 H), 4.13–4.21 (m, 3 H), 4.23 (d, J = 13.9 Hz, 1 H),

6.84 (d, J = 3.3 Hz, 1 H), 7.15–7.32 (m, 5 H), 7.33 (d, J = 7.3 Hz, 2

H), 7.64 (d, J = 3.3 Hz, 1 H), 8.21 (d, J = 7.5 Hz, 1 H).

¹³C NMR (125 MHz): δ (major invertomer) = 14.1, 28.2, 43.7, 47.3,

55.1, 61.2, 83.8, 105.2, 114.4, 120.0, 124.3, 126.0, 126.9, 128.1,

128.3, 128.9, 130.2, 135.2, 139.2, 149.7, 168.9; δ (minor

invertomer) = 14.3, 28.2, 41.8, 46.0, 55.7, 61.3, 84.0, 105.5, 115.5,

HRMS (ESI): m/z [M + Na] calcd for C₂₂H₂₂N₂O₄SNa: 433.1198;

found: 433.1153.

tert-Butyl 1-Allyl-3-[3-iodo-1-tosylindol-4-yl]aziridine-2-car-

boxylate (14bb)

trans-14bb

Pale yellow prisms; mp 100–101 °C.

IR (ATR): 1721 cm^–1.

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¹H NMR (400 MHz): δ = 1.48 (s, 9 H), 2.36 (s, 3 H), 2.57 (d, J = 2.4

Hz, 1 H), 3.65 (dd, J = 14.4, 5.4 Hz, 1 H), 3.75 (dd, J = 14.7, 5.6 Hz,

1 H), 4.21 (d, J = 2.6 Hz, 1 H), 5.12 (d, J = 10.4 Hz, 1 H), 5.26 (d,

J = 17.2 Hz, 1 H), 5.99 (dddd, J = 17.2, 10.4, 5.6, 5.4 Hz, 1 H),

7.24–7.31 (m, 3 H), 7.37 (d, J = 7.5 Hz, 1 H), 7.74 (s, 1 H), 7.77 (d,

J = 8.2 Hz, 2 H), 7.90 (d, J = 8.2 Hz, 1 H).

¹³C NMR (100 MHz): δ = 21.6, 28.2, 43.5, 45.5, 53.3, 60.2, 81.7,

112.4, 116.6, 121.6, 125.4, 127.0, 130.0, 131.4 (2 C), 131.9, 134.7

(2 C), 135.5, 145.4, 167.2.

¹H NMR (400 MHz): δ = –0.01 (s, 3 H), 0.03 (s, 3 H), 0.83 (s, 9 H),

1.23 (s, 9 H), 2.43 (d, J = 7.0 Hz, 1 H), 2.46 (dd, J = 11.9, 5.6 Hz, 1

H), 2.85 (dd, J = 11.9, 5.6 Hz, 1 H), 2.87 (d, J = 7.0 Hz, 1 H), 3.89

(t, J = 5.6 Hz, 2 H), 5.91 (s, 2 H), 6.71 (d, J = 8.0 Hz, 1 H), 6.85 (dd,

J = 8.0, 1.4 Hz, 1 H), 6.91 (d, J = 1.4 Hz, 1 H).

¹³C NMR (100 MHz): δ = –5.6, 18.1, 25.8, 27.8, 45.9, 47.0, 62.0,

62.5, 80.9, 100.7, 107.5, 108.6, 121.2, 129.6, 146.5, 146.9, 167.5.

HRMS (EI): m/z [M] calcd for C₂₂H₃₅NO₅Si: 421.2284; found:

421.2295.

MS (FAB): m/z = 579 [M + H], 578 [M].

Determination of the Absolute Configurations of 3-Phenylaziri-

dine-2-carboxylate 5bf*

Anal. Calcd for C₂₅H₂₇IN₂O₄S: C, 51.91; H, 4.70; N, 4.84. Found:

C, 51.81; H, 4.63; N, 4.82.

tert-Butyl N-[(tert-Butoxycarbonyl)methyl]phenylalaninate

(26)

cis-14bb

Colorless prisms, mp 165–166 °C.

A mixture of (±)-cis-5bf (52 mg, 0.168 mmol), (Boc)₂O (40 mg,

0.182 mmol), and Pd(OH)₂on C (16 mg) in MeOH (2 mL) was vig-

orously stirred at r.t. for 10 h under a H₂atmosphere; the catalyst

was filtered off through Celite. After evaporation of the filtrate the

residue was purified by column chromatography (silica gel, hex-

ane–benzene, 15:1 to hexane–Et₂O, 5:1) to give 26 as colorless

prisms (50 mg, 92%); mp 91–93 °C; chiral HPLC (Daicel Chiralcel

OD-H, hexane–i-PrOH, 100:1; detection: 254 nm; flow rate: 1.0

mL/min): t_R= 6.1, 7.5 min.

IR (ATR): 1740 cm^–1.

¹H NMR (400 MHz): δ = 0.83 (s, 9 H), 2.34 (s, 3 H), 2.60 (d, J = 6.8

Hz, 1 H), 3.01 (dd, J = 13.7, 6.2 Hz, 1 H), 3.52 (dd, J = 13.7, 5.5 Hz,

1 H), 3.64 (d, J = 6.8 Hz, 1 H), 5.16 (dd, J = 10.5, 1.6 Hz, 1 H), 5.29

(dd, J = 17.3, 1.7 Hz, 1 H), 6.03 (ddt, J = 16.6, 10.4, 5.9 Hz, 1 H),

7.21 (d, J = 8.6 Hz, 2 H), 7.29 (t, J = 9.1 Hz, 1 H), 7.55 (d, J = 7.5

Hz, 1 H), 7.72 (s, 1 H), 7.74 (d, J = 8.4 Hz, 2 H), 7.89 (d, J = 8.2 Hz,

1 H).

¹³C NMR (100 MHz): δ = 21.5, 27.3, 44.2, 48.4, 61.0, 62.5, 80.6,

112.4, 117.5, 124.7, 125.1, 126.9, 128.4, 129.0, 129.9, 131.1, 134.2,

134.5, 134.6, 145.2, 166.9.

IR (Nujol): 3352, 1719, 1702, 1648 cm^–1.

¹H NMR (400 MHz): δ = 1.40 (s, 9 H), 1.42 (s, 9 H), 3.05 (d, J = 6.1

Hz, 2 H), 4.45 (dd, J = 6.7, 6.1 Hz, 1 H), 4.99 (d, J = 6.7 Hz, 1 H),

7.16–7.31 (m, 5 H).

MS (FAB): m/z = 579 [M + H].

Anal. Calcd for C₁₈H₂₇NO₄: C, 67.26; H, 8.47; N, 4.36. Found: C,

67.11; H, 8.45; N, 4.27.

Anal. Calcd for C₂₅H₂₇IN₂O₄S: C, 51.91; H, 4.70; N, 4.84. Found:

C, 51.85; H, 4.60; N, 4.77.

(–)-(R)-26

tert-Butyl 1-[2-(tert-Butyldimethylsiloxy)ethyl]-3-[3,4-(methy-

lenedioxy)phenyl]aziridine-2-carboxylate (29); Typical Proce-

dure for Asymmetric Aziridination

Following the procedure, (–)-cis-5bf* (104 mg, 0.337 mmol, 79%

ee), obtained in the asymmetric aziridination using (S,S)-25b·Br,

was hydrogenated with Pd(OH)₂on C (32 mg) in MeOH (2 mL)

containing (Boc)₂O (80 mg, 0.368 mmol) for 7 h to give (–)-(R)-26

(99 mg, 91%); 77% ee; mp 91–93 °C; [α]_D²⁵–20.3 (c 0.67, CH₂Cl₂).

Freshly distilled TMG (0.54 mL, 4.3 mmol) was added to a mixture

of (R,R)-28 (1.881g, 2.75 mmol) and 3a (0.379 g, 2.52 mmol) in

THF (0.5 mL) and the mixture was stirred at r.t. for 22 h. After ad-

dition to a suspension of silica gel (50 g) in MeCN (80 mL), the

mixture was stirred at r.t. for 11 h, filtered, and washed with CHCl₃

(400 mL). The filtrate was evaporated and the residue was subjected

to column chromatography (silica gel, hexane–EtOAc, 30:1 to 20:1)

to afford trans-29 (0.617 g, 58%) and cis-29 (0.051 g, 5%).

(+)-(S)-26

A solution of (Boc)₂O (44 mg, 0.202 mmol) in CHCl₃(0.5 mL) was

added to a mixture of (S)-phenylalanine (52 mg, 0.200 mmol), NaH-

CO₃(18 mg, 0.208 mmol), and NaCl (43 mg) in CHCl₃(1 mL) and

H₂O (0.7 mL) and the mixture was stirred at r.t. for 3 h. After re-

moved the separated organic layer, the aqueous layer was extracted

with CHCl₃. The combined organic layers were washed with H₂O

and brine and evaporated. Purification of the residue by column

chromatography (silica gel, hexane–benzene, 10:1 to hexane–Et₂O,

5:1) gave (+)-(S)-26 (58 mg, 91%) as colorless prisms; mp 92–

93 °C; 100% ee; [α]_D²⁵+38.0 (c 1.00, CH₂Cl₂).

trans-29

Colorless oil; chiral HPLC [Daicel Chiralcel OD-H, hexane; flow

rate: 1.0 mL/min, detection: 254 nm): t_R= 11.7 (minor), 14.3 min

(major).

[α]_D¹⁷–5.40 (c 0.5, CHCl₃).

IR (ATR): 1721 cm^–1.

Chiral HPLC for Enantiomeric Excess Determination of Select-

ed Aziridine Products

trans-5ba*: Column: Daicel Chiralcel OD; solvent: hexane–i-PrOH

(99:1); detection: 254 nm; flow rate: 1.0 mL/min: t_R= 7.9, 9.1 min.

¹H NMR (400 MHz): δ (major invertomer) = –0.01 (s, 3 H), 0.02 (s,

3 H), 0.85 (s, 9 H), 1.49 (s, 9 H), 2.53 (br s, 1 H), 3.00–3.04 (m, 3

H), 3.80 (br s, 2 H), 5.93 (s, 2 H), 6.74–6.80 (m, 3 H).

¹³C NMR (100 MHz): δ = –5.42, –5.37, 18.3, 25.9, 28.1, 44.9, 47.7,

53.4, 63.1, 81.6, 100.9, 106.4, 107.9, 120.0, 132.9, 146.8, 147.7,

167.7.

trans-5bb*: Column: Daicel Chiralcel OD-H; solvent: hexane–i-PrOH

(250:1); detection: 254 nm; flow rate: 1.0 mL/min: t_R= 10.0, 13.2

min.

cis-5bb*: Column: Daicel Chiralcel OD-H; solvent: hexane–i-PrOH

(100:1); detection: 254 nm; flow rate: 1.0 mL/min: t_R= 7.7, 8.5 min.

HRMS (EI): m/z [M] calcd for C₂₂H₃₅NO₅Si: 421.2284; found:

421.2285.

trans-5bf*: Column: Daicel Chiralcel OD-H; solvent: hexane–i-PrOH

(250:1); detection: 254 nm; flow rate: 0.5 mL/min: t_R= 12.1 min,

13.0 min.

cis-29

Colorless oil; chiral HPLC (Daicel Chiralcel OD-H, hexane–i-

PrOH, 50: 1; flow rate: 1.0 mL/min; detection: 254 nm): t_R= 4.7

(minor), 5.3 min (major).

cis-5bf*: Column: Daicel Chiralcel OD-H; solvent: hexane–i-PrOH

(100:1); detection: 254 nm; flow rate: 1.0 mL/min: t_R= 7.7, 8.5 min.

[α]_D¹⁸+15.1 (c 0.3, CHCl₃).

trans-5bg*: Column: Daicel Chiralcel OD-H; solvent: hexane–i-PrOH

(300:1); detection: 254 nm; flow rate: 0.3 mL/min: t_R= 22.9, 24.2

min.

IR (ATR): 1723 cm^–1.

Synthesis 2014, 46, 2201–2219

PAPER

Formation of Unactivated 3-Arylaziridine-2-carboxylates

2219

trans-5bn*: Column: Daicel Chiralcel OD-H; solvent: hexane–i-PrOH

(100:1); detection: 254 nm; flow rate: 1.0 mL/min: t_R= 4.9, 5.4 min.

(7) (a) Manaka, T.; Nagayama, S.-I.; Desadee, W.; Yajima, N.;

Kumamoto, T.; Watanabe, T.; Ishikawa, T.; Kawahata, M.;

Yamaguchi, K. Helv. Chim. Acta 2007, 90, 128. (b) Hayashi,

Y.; Kumamoto, T.; Nakanishi, W.; Kawahata, M.;

Yamaguchi, K.; Ishikawa, T. Tetrahedron 2010, 66, 3836.

(c) Kumamoto, T.; Suzuki, K.; Kim, S.-K.; Hoshino, K.;

Takahashi, M.; Sato, H.; Iwata, H.; Ueno, K.; Fukuzumi, M.;

Ishikawa, T. Helv. Chim. Acta 2010, 93, 2109.

trans-5bm*: Column: Daicel Chiralcel OD-H; solvent: hexane–i-PrOH

(100:1); detection: 254 nm; flow rate: 0.9 mL/min: t_R= 6.4, 7.3 min.

trans-5bo*: Column: Daicel Chiralpak AD-H; solvent: EtOH; de-

tection: 254 nm; flow rate: 0.9 mL/min: t_R= 5.7, 8.4 min.

trans-32c: Column: Daicel Chiralcel AD-H; solvent: EtOH; detec-

tion: 254 nm; flow rate: 0.3 mL/min; t_R= 14.9 (major), 16.2 min

(minor).

(8) Ishikawa, T. Chem. Pharm. Bull. 2010, 58, 1555.

(9) (a) Isobe, T.; Fukuda, K.; Ishikawa, T. J. Org. Chem. 2000,

65, 7770. (b) Isobe, T.; Fukuda, K.; Tokunaga, T.; Seki, H.;

Yamaguchi, K.; Ishikawa, T. J. Org. Chem. 2000, 65, 7774.

(c) Isobe, T.; Fukuda, K.; Yamaguchi, K.; Seki, H.;

Tokunaga, T.; Ishikawa, T. J. Org. Chem. 2000, 65, 7779.

(10) (a) Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 5832.

(b) Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 6984.

(c) Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 6989.

(11) (a) Isobe, T.; Fukuda, K.; Ishikawa, T. Tetrahedron:

Asymmetry 1998, 9, 1729. (b) Isobe, T.; Fukuda, K.; Araki,

Y.; Ishikawa, T. Chem. Commun. 2001, 243. (c) Ishikawa,

T.; Araki, Y.; Kumamoto, T.; Seki, H.; Fukuda, K.; Isobe, T.

Chem. Commun. 2001, 245. (d) Ishikawa, T.; Isobe, T.

Chem. Eur. J. 2002, 8, 552. (e) Ishikawa, T.; Isobe, T. Synth.

Org. Chem. Jpn. 2003, 61, 60. (f) Kumamoto, T.; Ebine, K.;

Endo, M.; Araki, Y.; Fushimi, Y.; Miyamoto, I.; Ishikawa,

T.; Isobe, T.; Fukuda, K. Heterocycles 2005, 66, 347.

(g) Kitani, Y.; Kumamoto, T.; Isobe, T.; Fukuda, K.;

Ishikawa, T. Adv. Synth. Catal. 2005, 347, 1653.

cis-32c: Column: Daicel Chiralcel AD-H; solvent: EtOH; detection:

254 nm; flow rate: 0.3 mL/min; t_R= 12.9 (major), 14.8 min (minor).

trans-32b: Column: Daicel Chiralcel AD-H; solvent: EtOH; detec-

tion: 254 nm; flow rate: 0.3 mL/min; t_R= 13.7 (major), 15.3 min

(minor).

cis-32b: Column: Daicel Chiralcel AD-H; solvent: EtOH; detec-

tion: 254 nm; flow rate: 0.3 mL/min; t_R= 11.7 (major), 12.5 min

(minor).

Supporting Information for this article is available online

at

http://www.thieme-connect.com/products/ejournals/journal/

10.1055/s-00000084.SunpfgIpi

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References

(1) (a) Aube, J. In Comprehensive Organic Synthesis; Vol. 1;

Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991,

835. (b) Rosen, T. In Comprehensive Organic Synthesis;

Vol. 2; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford,

1991, 428. (c) Kemp, J. E. G. In Comprehensive Organic

Synthesis; Vol. 7; Trost, B. M.; Fleming, I., Eds.; Pergamon:

Oxford, 1991, 469. (d) Tanner, D. Angew. Chem., Int. Ed.

Engl. 1994, 33, 599. (e) Osborn, H. M. I.; Sweeney, J.

Tetrahedron: Asymmetry 1997, 18, 1693. (f) Atkinson, R. S.

Tetrahedron 1999, 55, 1519. (g) Mitchinson, A.; Nadin, A.

J. Chem. Soc., Perkin Trans. 1 2000, 2862.

(2) (a) Tsuge, O.; Kanemasa, S. Adv. Heterocycl. Chem. 1989,

45, 231. (b) Padwa, A. In Comprehensive Organic

Synthesis; Vol. 4; Trost, B. M.; Fleming, I., Eds.; Pergamon:

Oxford, 1991, 1085. (c) Gothelf, K. V.; Jorgensen, K. A.

Chem. Rev. 1998, 98, 863. (d) Ishikawa, T. Heterocycles

2012, 85, 2837.

(h) Wannaporn, D.; Ishikawa, T. Mol. Diversity 2005, 9,

321. (i) Ishikawa, T.; Kumamoto, T. Synthesis 2006, 737.

(j) Ryoda, A.; Yajima, N.; Haga, T.; Kumamoto, T.;

Nakanishi, W.; Kawahata, M.; Yamaguchi, K.; Ishikawa, T.

J. Org. Chem. 2008, 73, 133. (k) Saito, N.; Ryoda, A.;

Nakanishi, W.; Kumamoto, T.; Ishikawa, T. Eur. J. Org.

Chem. 2008, 2759. (l) Zhang, G.; Kumamoto, T.; Heima, T.;

Ishikawa, T. Tetrahedron Lett. 2010, 51, 3927.

(m) Tokunou, S.; Nakanishi, W.; Kagawa, N.; Kumamoto,

T.; Ishikawa, T. Heterocycles 2012, 84, 1045. (n) Ishikawa,

T.; Heima, T.; Yoshida, M.; Kumamoto, T. Helv. Chim. Acta

2014, 97, 307.

(12) Lloyd, D.; Millar, R. W. J. Chem. Soc., Chem. Commun.

1976, 266.

(13) For example, see: Davoli, P.; Moretti, I.; Prati, F.; Alper, H.

J. Org. Chem. 1999, 64, 518.

(14) Davoli, P.; Forni, A.; Moretti, I.; Prati, F.; Torre, G.

Tetrahedron 2001, 57, 1801; and references therein.

(15) Takahashi, M.; Suzuki, N.; Ishikawa, T.; Huang, H.-Y.;

Chang, H.-S.; Chen, I.-S. unpublished results.

(16) (a) Larsen, S. B.; Bang-Andersen, B.; Johansen, T. N.;

Jorgensen, M. Tetrahedron 2008, 64, 2938. (b) Palomo, C.;

Aizpurua, J. M.; Balentova, E.; Jimenez, A.; Oyarbide, J.;

Fratila, R. M.; Miranda, J. I. Org. Lett. 2007, 9, 101.

(17) Wattanasin, S.; Kathawala, F. G. Synth. Commun. 1992, 22,

1487.

(3) Hada, K.; Watanabe, T.; Isobe, T.; Ishikawa, T. J. Am.

Chem. Soc. 2001, 123, 7705.

(4) Haga, T.; Ishikawa, T. Tetrahedron 2005, 61, 2857.

(5) (a) Wannaporn, D.; Ishikawa, T. J. Org. Chem. 2005, 70,

9399. (b) Wannaporn, D.; Ishikawa, T.; Kawahata, M.;

Yamaguchi, K. J. Org. Chem. 2006, 71, 6600.

(6) (a) Khantikaew, I.; Takahashi, M.; Kumamoto, T.; Suzuki,

N.; Ishikawa, T. Tetrahedron 2012, 68, 878. (b) Kondo, Y.;

Suzuki, N.; Takahashi, M.; Kumamoto, T.; Masu, H.;

Ishikawa, T. J. Org. Chem. 2012, 77, 7988. (c) Kojima, H.;

Takahata, C.; Lemin, D.; Takahashi, M.; Kumamoto, T.;

Nakanishi, W.; Suzuki, N.; Ishikawa, T. Helv. Chim. Acta

2013, 96, 379. (d) Takahashi, M.; Suzuki, N.; Ishikawa, T.

J. Org. Chem. 2013, 78, 3250.

(18) (a) Casarrubios, L.; Perez, J. A.; Brookhart, M.; Templeton,

J. L. J. Org. Chem. 1996, 61, 8358. (b) Irgolic, K. J. In

Houben–Weyl, 4th ed., Vol. E12b; Klamann, D., Ed.;

Thieme: Stuttgart, 1990, 150.

Synthesis 2014, 46, 2201–2219

Article Doi

Guanidinium Ylide mediated aziridination from arylaldehydes: Scope and limitations in the formation of unactivated 3-arylaziridine-2-carboxylates

DOI: 10.1055/s-0033-1341233

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Article abstract of DOI:10.1055/s-0033-1341233

Full text of DOI:10.1055/s-0033-1341233

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