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Chapter 2: Three-Membered Heterocycles. Structure and Reactivity

Chapter 2: Three-Membered Heterocycles. Structure and Reactivity

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j 2 Three-Membered Heterocycles. Structure and Reactivity



12



Figure 2.1 Geometry of aziridine.



biological activity springs from an ability to form interstrand purine base crosslinks

in duplex DNA [20–23]. Central to this behavior is the aziridine ring bound up in the

1-aza-bicyclo[3.1.0]hexane system, a structural feature also found in ficellomycin (4),

an antibacterial isolated from Streptomyces ficellus [24]. A similar 3,6-diaza-bicyclo

[3.1.0]hexane system is at the functional heart of mitomycin C (5), a notable

representative of the mitosanes extracted from Streptomyces verticillatus [25] and the

target of many synthetic studies [26]. For decades, mitomycin C has found place in the

arsenal of clinically relevant antibiotic and anti-tumor drugs, and the mitomycins

have inspired studies into many promising non-natural analogs [27].

Also equipped with a 2,3-dialkylaziridine residue is the protease inhibitor miraziridine A (6), which is isolated from the marine sponge Theonella aff. mirabilis [28]

and which exhibits a linear peptide structure vaguely similar to madurastatin A1 (7), a

compound demonstrated in a culture of a pathogenic Actinomadura madurae IFM

0745 strain, which shows activity against Micrococcus luteus [29]. An even more

exposed aziridine ring is seen in the azicemicins A (8) and B (9), antibacterials

isolated from Amycolatopsis sp. Mj126-NF4 [30, 31]. These naturally occurring

aziridine alkaloids have also inspired a genre of semi-synthetic and synthetic analogs

of medicinal interest [32].

2.1.2

Synthesis of Aziridines



Generally speaking, there are three major synthetic routes to the aziridines

(Scheme 2.1): (a) the addition of monovalent nitrogen species to alkenes; (b) the

addition of divalent carbon centers to imines; and (c) the N-alkylative ring closure of

amines equipped with b-leaving groups . A fourth route (pathway d) is less frequently

encountered, but is nevertheless included here because of its potential synthetic

utility. Enantioselective protocols in the first two categories have been the subject of a

review [33], and aziridine synthesis as a whole has been more generally summarized

by Sweeney [34].

2.1.2.1 Aziridination of Alkenes

Analogous to epoxidation, in which olefins react with electrophilic oxygen reagents,

the aziridination of alkenes involves the addition of nitrenes (or nitrenoids) to a

b-bond. Common nitrene precursors include [N-(p-toluenesulfonyl)imino]phenyliodinane (PhI¼NTs), N-chloro-p-toluenesulfonamide sodium salt (Chloramine-T), and



2.1 Aziridines

OH



O



O



O



O

MeO



O



O



O



NH



O H

N



O

MeO



N



NH



O H

N



O



O



AcO



N

AcO



OH



OH



3, Azinomycin B



2, Azinomycin A



H

N



H 2N

O



O



O

OH



NH 2



O



O

OMe



H2 N



N



HN



N



Me



NH



NH



O



H2 N



5, Mitomycin C



4, Ficellomycin



O



O



HO



N

H



N

H



OH



H

N



O

N

H



O



O



H

N



OH



O



NH

H2 N



NH



6, Miraziridine A

O

N

OH



O



H

N

O



Me



O

N

H



O

N

OH



NHMe



7, Madurastatin A1



MeO



NR



O

OH



HO

OH

MeO

OH



j13



OH



O



8, Aicemicin A, R=H

9, Aicemicin B, R=Me

Figure 2.2 Some naturally occurring aziridines.



H



N

H



N

O



OH



j 2 Three-Membered Heterocycles. Structure and Reactivity



14



N



+



C



:



b



:



N



:



a



:



+



N



N



X



Y



NH

d

- X=Y



c

- "HLG"



LG



Scheme 2.1 General synthetic routes to aziridines.



its N-bromo analogue (Bromamine-T), although use of the more esoteric N-iodo-Npotassio-p-toluenesulfonamide (TsNÁKI) has also been reported [35]. These precursors can be activated using various transition-metal catalysts (Figure 2.3).

Also mirroring epoxidation methodology, a common model reaction is the

aziridination of styrene (Scheme 2.2). Some illustrative examples are summarized

in Table 2.1. For example, the copper(I) complex of a fluorinated tris(pyrazolyl)borate

(or homoscorpionate) ligand forms an adduct with ethylene (12a), which catalyzes the

aziridination of styrene with great efficiency using PhI¼NTs as a nitrene precursor [36]. The more readily available Chloramine-T can be used effectively in the

presence of methyl homoscorpionate complex 12b, even with equimolar charges of

olefin and nitrene precursor [37]. This catalyst motif has been incorporated into a

heterogeneous system [38]. Other interesting copper(I) catalysts include those

derived from pyridyl-1,5-diazacyclooctanes (e.g., 13) [39] and bispidones (e.g.,

14) [40]. A particularly intriguing protocol using copper(I)iodide under aqueous

phase-transfer conditions (entry 5) has also been reported [41].

Examples of copper(II) catalysts include the 1,4,7-triazacyclononane complex 15,

which requires a rather large excess of olefin [42], copper(II) acetylacetonate immobilized in ionic liquids (entry 7), which can be recycled many times without loss of

activity [43], and Cu2 þ exchanged zeolite Y (CuHY) in acetonitrile (entry 8), which

allows for respectable conversion using almost equimolar alkene : nitrene ratios [44].

Other transition metals can be used to advantage, as well. For example, the

fluorinated iron(III) porphyrin catalyst 16a [45], although certainly dearer to synthesize, exhibits marked advantages over its older manganese-based cousin 16b [46];

and even iron(II) triflate is effective in promoting high-yielding aziridination reactions [47] (Table 2.1, entry 11).

In the realm of precious metals, a novel and structurally interesting disilver(I)

complex (17) has been shown to function as a competent catalyst in aziridination, a

process that may involve high-valent silver intermediates [48]. Some polymersupported ruthenium porphyrin catalysts have been employed for this transformation; however, conversions tend to be low [51, 52].

The use of a metal catalyst can be circumvented in some cases. In one particularly

convenient example, a nitrene precursor is generated in situ from p-toluenesulfo-



2.1 Aziridines

NTs



conditions



Ph



(seeTable2.1)



Ph



10



11



Scheme 2.2 Aziridination of styrene.



namide using iodobenzene diacetate. The aziridination is facilitated by substoichiometric quantities of iodine [49] (Table 2.1, entry 13). A conceptually related protocol is

carried out using t-butylhypoiodite, prepared in situ from t-butylhypochlorite and

sodium iodide [50] (Table 2.1, entry 14).

R

N



H R

B

N N



R

Ar



N N

Cu

R

H2C CH2



N

R



R



N Cl N

Ar



M



12a, R = CF3

12b, R = Me



N



Ar

N



Ar

N

N



N

Cu

O2CCF3



Me



PF6



16a, Ar = C 6F5; M = FeIII

16b, Ar = C 6H5; M = MnIII



13



MeO2C



HO



N

Me



OH

Me

N

NMe

Cu



t-Bu

CO2Me

t-Bu

N



14



i-Pr



N



Ag

N



N

O O



N



N



i-Pr



Cu

N



Ag



t-Bu



N



i-Pr



N



N

Me



Cl



t-Bu



N



O



t-Bu

O2CCF3

O2CCF3



15



Figure 2.3 Representative catalysts for racemic aziridination.



17



t-Bu



j15



j 2 Three-Membered Heterocycles. Structure and Reactivity



16



Table 2.1 Reaction conditions for styrene aziridination.



Entry



Catalyst

(mol.%)a)



Nitrene

source



Styrene :

nitrene



Solvent



Time

(h)



Yield

(%)a)



Reference



Copper(I) catalysts

1

12a (5)

2

12b (5)

3

13 (5)

4

14 (3.5)

5

CuI(10)



PhI¼NTs

Chloramine-T

PhI¼NTs

PhI¼NTs

Chloramine-T



1 : 1.5

1:1

3.8 : 1

2:1

2:1



CH3CN

CH3CN

CH3CN

CH3CN

H2Ob)



16

n.r.

1.5

7

3



99

84

99

80

91



[32]

[33]

[34]

[35]

[36]



Copper(II) catalysts

6

15 (5)

7

Cu(acac)2 (8)c)

8

CuHY



PhI¼NTs

PhI¼NTs

PhI¼NTs



20 : 1

5:1

1 : 1.5



CH3CN

CH3CN

CH3CN



16

1

3



96

95

86



[37]

[38]

[39]



Other metal catalysts

9

16a (5)

10

16b (5)

11

Fe(OTf)2 (5)

12

17 (2)



Bromamine-T

PhI¼NTs

PhI¼NTs

PhI¼NTs



5:1

100 : 1

7:1

5:1



CH3CN

CH2Cl2

CH3CN

CH3CN



12

n.r.

3

6



80

80

82

91



[40]

[41]

[47]

[42]



TsNH2/PhI(OAc)2/

I2/t-BuOK

TsNH2/t-BuOCl/

NaI



1:3



DCE



2



88



[49]



2:1



CH3CN



5



95



[50]



No metal catalyst

13

none

14



none



a) Based on nitrene source.

b) Bu4NBr used as PTC.

c) Immobilized in bmimBF4.



Progress continues to be made in the asymmetric aziridination of olefins using the

same general approach (Scheme 2.3), but with chiral catalyst systems (Table 2.2). For

example, impressive enantioselectivity has been reported for copper-exchanged

zeolite Y (CuHY) modified with the chiral bis(oxazoline) 18a (Figure 2.4) using

[N-(p-nitrosulfonyl)imino]phenyliodinane (PhI¼NNs) as the nitrene precursor [53].

Inferior results are obtained when [N-(p-toluenesulfonyl)imino]phenyliodinane

(PhI¼NTs) is used [54]. A one-pot homogeneous variant using bis(oxazoline) 18b

and commercially available iodobenzene diacetate has also been reported [55].

Evidence suggests that the ultimate stereochemical outcome may be affected by a

secondary reaction between the aziridines formed and other components in the

reaction mixture [56].



conditions



Ph



(see Table 2.2)



10



Ph



*



NR



11



Scheme 2.3 Asymmetric aziridination of styrene.



2.1 Aziridines

Table 2.2 Reaction conditions for asymmetric styrene aziridination.



Entry



Catalyst

(mol.%)a)



Nitrene

source



Styrene :

nitrene



Solvent



Time

(h)



Yield

(%)a)



ee

(%)



Reference



1

2

3



CuHY ỵ 18 (7%)

19 (5)

20(0.1)



PhI¼NNs

PhI¼NTs

TsN3



1 : 1.3

1:5

1:1



CH3CN

CH2Cl2

CH2Cl2



16

n.r.

24



82

76

78



91

94

85



[45]

[49]

[51]



based on nitrene source.



a)



Another major avenue for enantioselective aziridination is offered through the

use of (salen)manganese(III) complexes, such as the Katsuki catalyst (19) [57].

Evidence from the Jacobsen group suggests that the high enantiofacial selectivity

observed for aryl alkenes may derive from well-defined bidentate aromatic interactions between substrate and catalyst [58]. Analogous ruthenium-based catalysts

(e.g., 20) allow for the use of tosyl azide as a nitrene precursor and are effective

even at extremely low catalyst loadings [59]. Metalloporphyrin catalysts continue to

show some promise for asymmetric aziridination, although enantioselectivities

remain modest [60].

Some very convenient methodology has developed around bromine-catalyzed

aziridination reactions using Chloramine-T as the source of electrophilic nitrogen



Me



O



Mn

O



N



R



X N



N



O

N



Me



O



Ph Ph



R



18a, R = Ph

18b, R = t-Bu

19, X = OAc



N



X



N



Ru

O



O

Ar Ar



F



20, X = CO; Ar =



Me

F



Figure 2.4 Chiral catalysts for asymmetric alkene aziridination.



j17



j 2 Three-Membered Heterocycles. Structure and Reactivity



18



Chloramine-T



( )n



CH3 CN, rt

bromine catalyst

(see Table 2.3)



21



( )n



NTs



22



Scheme 2.4 Bromine-catalyzed aziridination.



(Scheme 2.4). For example, when cyclohexene is treated with Chloramine-T trihydrate in the presence of substoichiometric quantities of hydrogen peroxide and

hydrobromic acid, the corresponding bicyclic aziridine is produced in good yield

(Table 2.3, entry 1). The process involves the in situ generation of hypobromous acid,

which in turn gives rise to bromonium intermediates [61]. N-Bromosuccinimide is

also a competent catalyst in this regard (entry 2) [62]. Both of these protocols might be

seen as modifications to an earlier report by Sharpless [63], which describes the use of

phenyltrimethylammonium bromide (PTAB) as both bromine source and phasetransfer catalyst (entry 3).

The Sharpless protocol is in some ways complementary to prior art. For example,

methylcyclohexadiene oxide (23) can be aziridinated in good yield using ChloramineT trihydrate and catalytic amounts of PTAB (Scheme 2.5), a conversion that failed

using PhI¼NTs and Cu(acac)2. Interestingly, only the trans aziridino epoxide (i.e., 24)

is observed, presumably due to preferential formation of the cis-epoxy bromonium

intermediate 25, which has been calculated to lie about 2.4 kcal molÀ1 lower in

energy than the corresponding trans isomer [64].



1.1 TsNClNa·3H 2 O



O



PTAB (10 mol%)

CH3 CN, 12 h, rt

67%



23



O



NTs



O



Br



via



24



25



Scheme 2.5 Aziridination of epoxyalkenes.



Some progress has been made in using sulfonamides as starting materials for

aziridination. Thus, the pyridinesulfonamide 26 is converted into a nitrene precursor

(i.e., 28) in situ using commercially available iodosobenzene diacetate as an oxidant,

providing aziridine 27 in very good yield (Scheme 2.6). Another notable aspect of this

Table 2.3 Reaction conditions for bromine-catalyzed aziridination.



Entry



n



Catalyst

(loading mol.%)



Chloramine-T

type



Olefin :

nitrene



Time

(h)



Product



Yield

(%)



Reference



1

2

3



2

2

1



H2O2/HBr (20)

NBS (20)

PTAB (30)



trihydrate

anhydrous

anhydrous



1 : 1.3

1 : 1.0

1 : 1.1



5

3

12



22b

22b

22a



75

82

86



[53]

[54]

[55]



2.1 Aziridines

10 (1.2 eq.)

1.0 PhI (OAc)2

N



S

O2



NH 2



0.03 Cu(tfac)2

CH3 CN, rt

12 h

84%



26



N



S

O2



N



Ph



via



N



SO2



[Cu] N



28



27



Scheme 2.6 Chelating sulfonamides.



system is that it obviates the need for external ligands and bases, since the pyridyl

nitrogen provides intermolecular chelation. The free aziridine can be accessed by

deprotection using magnesium in methanol [65]. A copper-catalyzed aziridination of

tosylamides using iodine has also been reported [66].

DuBois and Guthikonda [67] have developed a similar rhodium-based strategy for

the aziridination of sulfonamides, which they have applied to various unfunctionalized alkenes. With v-butenyl sulfonamide 29a, an intramolecular process can ensue

to provide the bicyclic aziridine in good yield (Scheme 2.7). These and other

investigations have shown the process to be stereospecific (Table 2.4, entry 2),

whereby alkene geometry is preserved in the product [68]. Moreover, existing chiral

centers can impose diastereoselectivity, as shown by the intramolecular aziridination

of alkenyl sulfonamide 29c, which proceeds with a 10 : 1 syn : anti ratio [69].



O



O2

S



NH 2



O



conditions

(see Table 2.4)



R1

R2



29a, R1 = R 2 = H

29b, R1 = H; R2 = Et

29c, R1 = Me; R2 = octyl



R1



O2

S



N



R2



H



30



Scheme 2.7 Intramolecular aziridinations.



The Padwa group has reported that the analogous intramolecular aziridination of

cycloalkenyl carbamates proceeds without the need of a metal catalyst (Scheme 2.8).

Thus, cyclohexenyl carbamate 31a underwent clean conversion into the tricyclic

heterocycle 32a upon treatment with 2 equivalents of iodosobenzene [70] (Table 2.5,



Table 2.4 Reaction conditions for intramolecular aziridinations.



Entry



Substrate



Catalyst (loading mol.%)



Oxidant



Solvent



Yield (%)



Reference



1

2

3



29a

29b

29c



Rh2(tfacam)4 (1)

Cu(CH3CN)4PF6 (10)

Rh2(Ooct)4 (2)



PhI(OAc)2

PhI¼O

PhI(OAc)2



Benzene

CH3CN

CH2Cl2



84

80

84



[59]

[60]

[61]



j19



j 2 Three-Membered Heterocycles. Structure and Reactivity



20



O

O



O



O

N



conditions



NHR



(see Table 2.5)



31a, R = H

31b, R = Ts



32



Scheme 2.8 Intramolecular aziridination of carbamates.



Table 2.5 Reaction conditions for the intramolecular aziridination of carbamates.



Entry



Substrate



Conditions



Yield

(%)



Reference



1

2



31a

31b



PhIO (2.0 eq), CH2Cl2, 40 C

K2CO3 (7 eq), Rh2(OAc)4

(5 mol %), acetone, 25 C



75

79



[71]

[72]



entry 1). A similar rhodium-catalyzed variant has been reported for N-tosyloxycarbamates [71] (Table 2.5, entry 2).

Electron-deficient olefins often require different conditions for efficient aziridination than their unactivated counterparts. Along these lines, while certainly not

limited to electron-poor alkenes, N-aminophthalimide (34) acts as a versatile nitrogen

donor for aziridinations under various oxidizing conditions. The classical protocol

involves the mild but environmentally questionable reagent lead tetraacetate [72],

under which conditions the active aziridinating agent is believed to be an N-acetoxy

species rather than a nitrene [73]. Meanwhile, other innovative methodologies have

evolved. For example, using the conventional oxidant of iodosylbenzene diacetate

(Table 2.6, entry 1), chalcone (33) is aziridinated in excellent yield (Scheme 2.9) [74].



Table 2.6 Reaction conditions for phthalimide aziridinations.



Entry



Eq 34



Oxidant

(loading where

appropriate)



Additive



Solvent



Time

(h)



Yield

(%)



Reference



1

2



1.4

1.4



K2CO3

K2CO3



CH2Cl2

CH2Cl2



12

12



93

94



[65]

[66]



3



1.3



PhI(OAc)2 (1.5 eq)

p-MeOPhI/mCPBA

(1.4 eq)

ỵ 1.80 V (vs. Ag wire)



Et3NHOAc



CH3CN



4



83



[67]



2.1 Aziridines



O

O

N



+

Ph



Ph



Pth

O

N



conditions

(see Table 2.6)



NH2



Ph



Ph

O



33



34



35



Scheme 2.9 N-Aminophthalimide as nitrogen donor.



These conditions have also been used to advantage for the aziridination of allylic

alcohols [75].

The hypervalent iodine reagent can also be generated in situ by combining

equimolar amounts of p-iodoanisole and m-chloroperbenzoic acid (entry 2) with no

negative impact on yield [76]. An even more atom-economical approach can be

realized using electrochemical conditions (entry 3), a stereospecific process that has

been described as a click preparation of aziridines [77], and which may proceed via a

nitrene intermediate [78–80]. A similarly efficient oxidation has been reported using

superoxide ion [81].

Addition of the chiral camphor-derived ligand 36 (Scheme 2.10) can result in an

enantioselective process. Thus, the unsaturated oxazolidinone imide 37 is converted

into the corresponding aziridine (38) in good yield and impressive enantiomeric

excess. By comparison, ( þ )-tartaric acid gave only 42% ee. The choice of solvent is

important, as migration to THF results in no loss of yield but an almost total

disappearance of enantioselectivity [82].

Chiral bis(oxazoline) (BOX) ligands allow for a tunable aziridination of chalcones

(Scheme 2.11) merely by changing the connecting backbone moiety (Figure 2.5).

Thus, use of the cyclohexyl catalyst 41 provides the 2R,3S product (Table 2.7, entry 1)

with very good enantioselectivity [83], while the anthracene derivative 42 yields the

Me



HO 2 C



Me



N



36



O

O



Ph



37



Me



CO 2H



Me



1.5 eq 34

1.6 eq 36

1.6 eq Pb(OAc) 4



O

N



N



CH2 Cl2, 0°C

5 min

83% yield

95% ee



O

O



O



H



N

H



N



Ph



Pth



38



Scheme 2.10 Asymmetric N-aminophthalimide-mediated aziridination.



j21



j 2 Three-Membered Heterocycles. Structure and Reactivity



22



Ts



PhI=NTs

CuOTf

chiral ligand



O

Ph



N

*



CH2Cl2

(see Table 2.7)



Me



O

Ph



*



Me

39



40



Scheme 2.11 Tunable BOX-mediated asymmetric aziridination.



O



O

N



Ph



O



N



Ph



N



N



O



i-Pr i-Pr



41, S-cHBOX



42, AnBOX



Figure 2.5 cHBOX and AnBOX ligands.



other antipode with even better yield and enantioselectivity (entry 2). The origin of

this interesting crossover has been rationalized on the basis of a more crowded steric

environment in the latter case [84]. The scope of the organocatalytic asymmetric

aziridination of enones has been expanded to substrates other than chalcones by

using a hydroquinine-derived catalyst and N-protected hydroxylamine tosylates as

nitrogen donors [85].

Cinnamate esters can be aziridinated using axially dissymmetric binaphthyldiimine copper(I) catalysts, such as those derived from salen-type ligand 43

(Scheme 2.12). Thus, trans-t-butyl cinnamate (44) was aziridinated stereospecifically

and enantioselectively to provide the product in excellent yield [86]. A later report

from another set of investigators using essentially identical conditions gave the same

high enantioselectivity but significantly lower yield [87].



Table 2.7 Reaction conditions for tunable BOX-mediated asymmetric aziridination.



Entry



PhI¼NTs

(eq)a)



CuOTf

(eq)a)



Ligand

(loading

mol.%)a)



Time

(h)



Yield

(%)b)



Configuration



ee (%)



Reference



1

2



0.67

0.67



0.03

0.03



41 (4)

42 (4)



5

5



62

86



2R,3S

2S,3R



94

98



[71]

[72]



a) Based on olefin.

b) Based on PhI¼NTs.



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