The "Non-Oxidative" Chloro-Pummerer Reaction: Novel stereospecific entry to vicinal chloroamines and aziridines

Article abstract of DOI:10.1002/1099-0690(200210)2002:19<3336::AID-EJOC3336>3.0.CO;2-T

This article describes a new, useful synthetic tool, the "Non-Oxidative" Chloro-Pummerer Reaction (NOCPR), which allows for the use of enantiomerically pure α-Li alkylsulfoxides as chiral α-chloroalkyl carbanions with N-protected imines. In this reaction the sulfinyl group of N-alkoxycarbonyl-β-sulfinylamines derived from aryl-, fluoroalkyl- and alkylimines is displaced by a chlorine atom in a one-pot reaction with clean stereoinversion at carbon. Several 1,2-chloroamines produced via NOCPR were transformed into the corresponding aziridines. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200210)2002:19<3336::AID-EJOC3336>3.0.CO;2-T

FULL PAPER
The ‘‘Non-Oxidative’’ Chloro-Pummerer Reaction: Novel Stereospecific Entry
to Vicinal Chloroamines and Aziridines
Alessandro Volonterio,*[a] Pierfrancesco Bravo,[a,b] Walter Panzeri,[a] Cristina Pesenti,[b] and
Matteo Zanda*[a]
Keywords: Sulfoxides / Rearrangements / Diastereoselectivity / Amines / Nitrogen heterocycles
This article describes a new, useful synthetic tool, the ‘‘Non-
Oxidative’’ Chloro-Pummerer Reaction (NOCPR), which al-
lows for the use of enantiomerically pure α-Li alkylsulfoxides
is displaced by a chlorine atom in a one-pot reaction with
clean stereoinversion at carbon. Several 1,2-chloroamines
produced via NOCPR were transformed into the correspond-
as chiral α-chloroalkyl carbanions with N-protected imines. ing aziridines.
In this reaction the sulfinyl group of N-alkoxycarbonyl-β-sul-
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
finylamines derived from aryl-, fluoroalkyl- and alkylimines 2002)
Introduction
fluoroalkyl).[10] Now we disclose, in full detail, the ‘‘Non-
Oxidative’’ Chloro-Pummerer Reaction (NOCPR),[11] a new
The sulfinyl group is one of the most extensively used methodology which extends the spectrum of application of
auxiliaries in asymmetric synthesis,[1] yet its synthetic po- α-lithium sulfoxides to synthetic equivalents of chiral α-
tential is underutilised owing to the lack of direct methods chloro-carbanions B (Scheme 1). The NOCPR allows for a
for removing this group from a stereogenic centre while pre- one-pot SN2 displacement of an arylsulfinyl group by chlor-
serving the stereochemical information. This represents a ine under Swern-type conditions[12] from N-alkoxycarbonyl
serious drawback, because the ability of the sulfinyl auxili- α-alkyl-, α-fluoroalkyl-, and α-aryl-β-sulfinylamines. The
ary to give rise to excellent 1,2-induction in C-C bond-for- NOCPR provides a general and efficient entry to a wide
ming reactions[2,3] cannot easily be exploited for the cre- range of enantiomerically pure vicinal chloroamine derivat-
ation of new stereodefined sulfur-free stereogenic centres. ives, which are important building blocks in modern or-
Recently, we reported a stereospecific intramolecular vari- ganic and medicinal chemistry.[13]
ant of an ‘‘interrupted’’ Pummerer reaction,[4] which was
dubbed by us as the ‘‘Non-Oxidative’’ Pummerer Reaction
(NOPR).[5] This reaction allows for a one-pot replacement
of a sulfinyl group with hydroxyl in a stereospecific SN2
fashion (Scheme 1 and 2).[6] This protocol enabled us and
others to transform a number of β-sulfinylamines N-mono-
protected as amides or carbamates, which are nowadays
easily accessible intermediates,[7] into the corresponding β-
amino alcohols with high yields and total stereocontrol.
Taking advantage of the NOPR, α-lithiated sulfoxides
could be successfully used as synthetic equivalents of chiral
Scheme 1. (a) (NOPR): (CF3CO)2O, sym-collidine, then H2O/
α-hydroxy carbanions A[8] (Scheme 1) with enolisable (R3 ϭ
K2CO3, NaBH4; (b) (NOCPR): (COCl)2, sym-collidine, then
alkyl)[9] as well as with non-enolizable imines (R3 ϭ aryl,
MeOH, NaBH4
[a]
C.N.R. Ϫ Istituto di Chimica del Riconoscimento Molecolare,
sezione ‘‘A. Quilico’’,
Results and Discussion
Via Mancinelli 7, 20131 Milano, Italy
Fax: (internat) ϩ039-02/2399-3080
E-mail: alessandro.volonterio@dept.chem.polimi.it
A representative set of N-alkoxycarbonyl-β-sulfinylam-
zanda@dept.chem.polimi.it
[b]
ines 1aϪk (Scheme 2 and Table 1), with known stereochem-
istry,[9,10] was prepared by a C-C bond-forming reaction of
enantiomerically pure α-lithium sulfoxides with suitably N-
protected imines. Substrates 1 were treated with oxalyl
Dipartimento di Chimica, Materiali e Ingegneria Chimica ‘‘G.
Natta’’, Politecnico di Milano,
Via Mancinelli 7, 20131 Milano, Italy
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
3336
 WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/1019Ϫ3336 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2002, 3336Ϫ3340

The “Non-Oxidative” Chloro-Pummerer Reaction
FULL PAPER
α-methoxy-α-trifluoromethylglycine ethyl ester, presumably
arising from retro-Mannich fragmentation of 1g and nucle-
ophilic attack of methanol on the intermediate N-Cbz imine
of ethyl trifluoropyruvate, was isolated in 25% yield. It is
worth noting that epimerization by double displacement
(ClϪ displaces ClϪ), which is a potential side-reaction, was
never observed. The addition of (COCl)2 in the presence of
sym-collidine is crucial to achieve high yields of 3, because
in the absence of a base, oxalyl chloride is able to deoxy-
genate competitively the sulfoxides 1 to the corresponding
sulfides.
The mechanism of the NOCPR is very likely to be as
shown in Scheme 3, consistent with the proposed outcome
of the Swern reaction,[12] and in analogy with the mechan-
ism of the NOPR, which has recently been investigated in
detail.[14] One equivalent of oxalyl chloride acylates the sulf-
inyl oxygen of 1 providing salt 4, which decomposes into 5
by loss of CO and CO2. Then, a molecule of HCl is re-
moved by sym-collidine and the sulfur cation is intercepted
by the adjacent carbamic nitrogen atom, producing the in-
termediate cyclic four-membered σ-sulfurane 6.
Scheme 2
Table 1. Synthesis of β-chloroamines by NOCPR[a]
Entry
Prod.
R
R1
R2
R3
Yield (%)
1
2
3
4
5
6
7
8
2a
3b
3c
3d
3e
3f
H
H
H
H
CH3
H
Ph
Allyl
CH3
H
H
H
H
H
H
Ph
H
H
H
H
H
H
H
CF3
H
CF3
H
H
iBu
CHF2
CClF2
3-F-C6H4
PMP[b]
CO2Me
CF3
CO2Et
CF3
C2H5
82
85
Ͼ98
Ͼ98
60
65
72
3g
3h
3j
87
9
75
10[c]
3k
Allyl
H
68[d]
[a]
Ar ϭ p-Tol except for entry 1, where Ar ϭ 1-Naphthyl; R4
ϭ
Bn except for entry 5, where R4 ϭ Et.
PMP ϭ 4-MeO-C6H4.
[b]
[c]A p-tolylsulfinyl group having (S)-configuration was used. [d] The
intermediate sulfenamide 2k could be isolated in nearly quantitat-
ive yield by FC.
Scheme 3
chloride (1.5 equiv.) in the presence of sym-collidine (3
equiv., CH2Cl2, Ϫ50 °C), which resulted in a fast and ster-
Dissociation of the latter into an ion-pair 7 triggers its
eoselective rearrangement to the β-chlorosulfenamides 2. In recombination via SN2-type attack of the generated chloride
this process, the sulfinyl group undergoes deoxygenation anion to the sulfur-substituted stereogenic carbon, which
and migration to the β-nitrogen, while a new CϪCl bond produces the final β-chlorosulfenamide 2. Release of the
is formed with stereoinversion at carbon. This key issue is four-membered ring strain in 6 is likely to play a significant
demonstrated for the transformations of 1eϪk into 2eϪk role, favouring a fast, stereocontrolled displacement. It is
(entries 5Ϫ10), which took place with a degree of stereose- more than likely that deoxygenation of 1 to the correspond-
lection greater than 98:2, as shown by the fact that no mi- ing sulfides, a side-reaction observed when oxalyl chloride
1
nor diastereomers of 3 could be detected either by H and is used without sym-collidine (see above), involves forma-
19F NMR analysis of the crude reaction mixtures, or isol- tion of Cl2 from 5 when it cannot be rapidly transformed
ated by flash chromatography (FC). Crude intermediates 2, into 6 by action of the base.[12b]
which can be isolated by FC (see entries 1 and 10), were
Besides the combination (COCl)2/sym-collidine, we ex-
diluted with methanol, then treated in situ with an excess amined other reagents as possible NOCPR promoters, but
of NaBH4 (about 5 equiv.), providing the final β-chloroam- the results were disappointing. In fact, treatment of sulfox-
ines 3 as single diastereomers (entries 5Ϫ10), isolated in ide 1h with thionyl chloride/sym-collidine produces deoxy-
good to excellent overall yields by FC. The NOCPR is gen- genation to the sulfide, while SO2Cl2/sym-collidine affords
erally applicable to β-sulfinylamines 1 N-monoprotected as a complex mixture of unidentified products. Also, in the
carbamates, including fluoroalkyl, aryl (1c,d), alkyl (1j,k), case of an attempted ‘‘ Non-oxidative’’ Bromo-Pummerer
and sterically congested structures such as 1e,g. In the case reaction, the deoxygenation of sulfoxides 1 to the corres-
of highly hindered 1g, a side-product identified as N-Cbz ponding sulfides took place quantitatively upon treatment
Eur. J. Org. Chem. 2002, 3336Ϫ3340
3337

A. Volonterio, P. Bravo, W. Panzeri, C. Pesenti, M. Zanda
FULL PAPER
benzophenone. Diisopropylamine and dichloromethane were
freshly distilled from over CaH2. In all other cases, commercially
available reagent-grade solvents were employed without purifica-
tion. All reactions where anhydrous organic solvents were em-
ployed were performed under nitrogen, after flame-drying the glass
apparatus. The synthesis of β-sulfinylamines 1 is described in refer-
ences 9 and 10.
of 1 with oxalyl bromide under the optimized NOCPR con-
ditions.
Among the possible derivatives of vicinal chloroamines,
aziridines constitute a valuable class of compounds both
for their pharmaceutical properties and for their synthetic
versatility.[15] Treatment of 3c,f,h,j,k with NaH (1.5 equiv.)
in DMF (Scheme 4) gives the enantiomerically pure N-Cbz
aziridines 8c,f,h,j,k in moderate to good yields, except for
8j which forms at a very slow rate. In contrast, under the
same conditions, the sterically congested β-chloroamine 3g
does not produce the corresponding aziridine.
The ‘‘Non-oxidative’’ Chloro-Pummerer reaction. General Proced-
ure: Neat oxalyl chloride (1.5 equiv.) was added dropwise to a solu-
tion of N-alkoxycarbonyl β-sulfinylamine 1 (1 equiv.) and sym-col-
lidine (3 equiv.) in dry CH2Cl2 at Ϫ50 °C. After complete consump-
tion of the starting material (TLC) the reaction was allowed to
reach room temperature. Sulfenamides 2a and 2k could be isolated
in pure form by FC, otherwise (in the one-pot reaction protocol)
the crude mixture was diluted with MeOH, then excess NaBH4
(ca. 5 equiv.) was added portionwise. After consumption of the
intermediate sulfenamide 2 (TLC), the reaction was quenched with
a saturated aqueous NH4Cl solution and extracted with CH2Cl2.
The collected organic layers were dried over anhydrous Na2SO4,
filtered and the solvent removed in vacuo. Purification of the crude
mixture by FC produced the corresponding β-chloroamine 3.
[a]
Scheme 4.
Unchanged 3j recovered in nearly quantitative yield
[b]
after 48 hours.
hours.
Unchanged 3k recovered in 35% yield after 2
Benzyl (S)-N-(1-Chloromethyl)-2,2-difluoroethyl[(1-naphthyl)thio]-
carbamate (2a): Formula mass 421.89. Yield 82%. Rf ϭ 0.69 (hex-
ane/Et2O, 80:20). [α]2D3 ϭ ϩ23.4 (c ϭ 0.6, CHCl3). FTIR (film): ν˜ ϭ
1718, 1383, 1278 cmϪ1. 1H NMR (250 MHz, CDCl3): δ ϭ 8.08 (d,
J ϭ 9.5 Hz, 1 H), 7.86 (d, J ϭ 9.5 Hz, 1 H), 7.75 (d, J ϭ 7.7 Hz,
1 H), 7.40 (m, 9 H), 5.80 (dt, J ϭ 55.9 and 5.2 Hz, 1 H), 5.34 (d,
J ϭ 12.9 Hz, 1 H), 5.27 (d, J ϭ 12.9 Hz, 1 H), 4.89 (m, 1 H), 3.94
(dd, J ϭ 11.2 and 10.3 Hz, 1 H), 3.76 (dd, J ϭ 11.2 and 4.3 Hz, 1
H) ppm. 13C NMR (62.3 MHz, CDCl3): δ ϭ 157.7, 135.2, 133.6,
129.7, 128.7, 128.6, 128.5, 128.1, 128.0, 126.6, 126.4, 125.7, 124.7,
123.0, 113.6 (t, J ϭ 246.0 Hz), 69.6, 64.5 (t, J ϭ 25.9 Hz), 39.6
ppm. 19F NMR (235.4 MHz, CDCl3): δ ϭ Ϫ122.4 (dd, J ϭ 291.9
and 55.9 Hz, 1F), Ϫ128.1 (ddd, J ϭ 291.9, 55.9 and 9.5 Hz, 1 F)
ppm. MS (DIS EI, 70 eV): m/z (%) ϭ 423 (25) [M ϩ 2]ϩ, 421
(12) [Mϩ].
The relative configurations of aziridines 8f,h,k were un-
ambiguously determined by NOE experiments. For ex-
ample, irradiation of the CF3 group of 8h produced 1.5%
and 2.0% heteronuclear NOE enhancements of the diastere-
otopic CH2 allylic protons in cis position (R ϭ allyl), and
only 0.5% of the aziridine ring proton (R1 ϭ H) trans to
the trifluoromethyl. In the case of 8f, irradiation of CHCF3
produced a 3.0% NOE on the ortho-phenyl protons in cis,
but no NOE was observed with the CHPh proton in trans.
Finally, irradiation of the allylic methylene of 8k produced
a relevant 2.8% NOE on the cis isobutyl methylene. The
1
stereochemistry of 8j was assigned by comparison of its H
NMR spectrum and polarimetric analyses with those de-
[7a]
´
scribed by Garcıa Ruano et al.
Benzyl (R)-(2-Chloro-1-chloromethyl-2,2-difluoroethyl)carbamate
(3b): Formula mass 298.11. Yield 85%. Rf ϭ 0.55 (hexane/EtOAc,
80:20). [α]2D3 ϭ ϩ1.3 (c ϭ 0.8, CHCl3). M.p. 50Ϫ51 °C. FTIR
In summary, we have disclosed in full detail the ‘‘Non-
Oxidative’’ Chloro-Pummerer reaction (NOCPR), a ste-
reospecific process for replacing a sulfinyl group of N-al-
koxycarbonyl β-sulfinylamines with chlorine. This reaction
(KBr) : ν˜ ϭ 3310, 1703, 1546, 1279 cmϪ1 1H NMR (250 MHz,
.
CDCl3): δ ϭ 7.39 (m, 5 H), 5.31 (br. d, J ϭ 9.7 Hz, 1 H), 5.28 (s,
opens up a straightforward route to enantiomerically pure, 2 H), 4.72 (m, 1 H), 3.85 (dd, J ϭ 12.0 and 3.9 Hz, 1 H), 3.70 (dd,
J ϭ 12.0 and 6.9 Hz, 1 H) ppm. 13C NMR (62.3 MHz, CDCl3):
stereodefined β-chloroamines and some important derivat-
ives like aziridines, and extends the scope of sulfoxides in
asymmetric synthesis.
δ ϭ 155.6, 135.6, 128.6, 128.5, 128.2, 127.6 (t, J ϭ 297.8 Hz), 67.9,
58.6 (t, J ϭ 25.9 Hz), 41.5 ppm. 19F NMR (235.4 MHz, CDCl3):
δ ϭ Ϫ60.8 (dd, J ϭ 166.8 and 9.2 Hz, 1F), Ϫ61.6 (dd, J ϭ 166.8
and 8.1 Hz, 1F) ppm. MS (DIS EI, 70 eV): m/z (%) ϭ 300 (2)
[M ϩ 3]ϩ, 299 (16) [M ϩ 2]ϩ, 298 (4) [M ϩ 1]ϩ, 297 (22) [Mϩ].
Experimental Section
Benzyl (S)-[2-Chloro-1-(3-fluorophenyl)ethyl]carbamate (3c): For-
mula mass 307.75. Yield Ͼ 98%. Rf ϭ 0.44 (hexane/EtOAc, 80:20).
General Details: Melting points (m.p.): uncorrected; capillary ap-
paratus. Polarimetric analyses: PROPOL polarimeter. Analytical
[α]2D3 ϭ ϩ13.6 (c ϭ 1.2, CHCl3). M.p. 49Ϫ50 °C. FTIR (KBr): ν˜ ϭ
3333, 1691, 1535, 1267 cmϪ1 1H NMR (250 MHz, CDCl3): δ ϭ
.
TLC: routinely used to monitor reactions, plates precoated with E.
Merck silica gel 60 F254 of 0.25 mm thickness were used. Flash
chromatography (FC): silica gel 60 (230Ϫ400 ASTM mesh). 1H,
13C and 19F NMR: Bruker 250 MHz and 500 MHz spectrometers,
chemical shifts in ppm (δ), tetramethylsilane (TMS) as internal
standard for 1H and 13C nuclei (δH/C ϭ 0.00), C6F6 external stand-
ard (δF ϭ Ϫ162.90) for 19F. MS: TSQ Finnigan Mat three-stage
quadrupole instrument, DIS (Direct Inlet System) used for pure
compounds. IR: PerkinϪElmer System 2000 FT-IR (scan range:
15600 cmϪ1; combined scan direction), with a PerkinϪElmer
Multiscope FTIR Microscope. THF was freshly distilled from Na/
7.34 (m, 5 H), 7.02 (m, 4 H), 5.57 (br. d, J ϭ 7.2 Hz, 1 H), 5.14
(d, J ϭ 12.1 Hz, 1 H), 5.09 (m, 1 H), 5.07 (d, J ϭ 12.1 Hz, 1 H),
3.79 (m, 2 H) ppm. 13C NMR (62.3 MHz, CDCl3): δ ϭ 162.9 (d,
J ϭ 246.0 Hz), 155.6, 141.3 (d, J ϭ 7.4 Hz), 136.0, 130.3 (d, J ϭ
9.2 Hz), 128.6, 128.2 (d, J ϭ 7.4 Hz), 122.2, 115.0 (d, J ϭ 20.3
Hz), 113.6 (d, J ϭ 22.2 Hz), 67.2, 55.1, 47.7 ppm. 19F NMR
(235.4 MHz, CDCl3): δ ϭ Ϫ113.3 (dt, J ϭ 9.8 and 6.5 Hz) ppm.
MS (DIS EI, 70 eV): m/z (%) ϭ 309 [[M ϩ 2]ϩ, 4], 307 [(M)ϩ, 13]
Benzyl (S)-[2-Chloro-1-(4-methoxyphenyl)ethyl]carbamate (3d): For-
mula mass 319.78. Yield Ͼ 98%. Rf ϭ 0.50 (hexane/EtOAc, 70:30).
3338
Eur. J. Org. Chem. 2002, 3336Ϫ3340

The “Non-Oxidative” Chloro-Pummerer Reaction
FULL PAPER
[α]2D3 ϭ Ϫ33.7 (c ϭ 0.8, CHCl3). M.p. 103Ϫ104 °C. FTIR (KBr):
Benzyl (1R,2R)-N-(2-Chloro-1-isobutylpent-4-enyl)-N-[(4-methyl-
phenyl)thio]carbamate (2k): Formula mass 432.02. Yield Ͼ 98%.
Rf ϭ 0.60 (hexane/Et2O, 80:20). 1H NMR (500 MHz, CDCl3): δ ϭ
ν˜ ϭ 3449, 1719, 1509, 1385, 1248 cmϪ1 1H NMR (500 MHz,
.
CDCl3): δ ϭ 7.32 (m, 5 H), 7.21 (d, J ϭ 8.5 Hz, 2 H), 6.87 (d, J ϭ
8.5 Hz, 2 H), 5.39 (br. d, J ϭ 8.1 Hz, 1 H), 5.12 (d, J ϭ 12.4 Hz, 7.35 (m, 7 H), 7.05 (d, J ϭ 7.7 Hz, 2 H), 5.88 (m, 1 H), 5.30 (d,
1 H), 5.08 (d, J ϭ 12.4 Hz, 1 H), 5.00 (m, 1 H), 3.80 (m, 2 H), 3.78 J ϭ 12.9 Hz, 1 H), 5.27 (d, J ϭ 12.9 Hz, 1 H), 5.10 (m, 2 H), 4.59
(s, 3 H) ppm. 13C NMR (125.7 MHz, CDCl3): δ ϭ 159.4, 155.6, (br. m, 1 H), 4.15 (br. m, 1 H), 2.64 (br. m, 1 H), 2.40 (m, 1 H),
136.2, 128.5, 128.2, 127.7, 125.5, 114.2, 67.1, 55.3, 47.8 ppm. MS
2.31 (s, 3 H), 1.68 (br. t, J ϭ 11.9 Hz, 1 H), 1.20 (m, 2 H), 0.90
(m, 1 H), 0.79 (d, J ϭ 5.6 Hz, 3 H), 0.53 (br. d, J ϭ 4.7 Hz, 3 H)
ppm. MS (EI, 70 eV): m/z (%) ϭ 431 (30) [Mϩ], 123 (15), 91 (100).
(DIS EI, 70 eV): m/z (%) ϭ 322 (9) [M ϩ 3]ϩ, 320 (9) [M ϩ 1]ϩ.
Methyl
(2S,3S)-2-Benzyloxycarbonylamino-3-chloro-2-trifluoro-
methylbutyrate (3e): Formula mass 291.65. Yield 60%. Rf ϭ 0.49 Benzyl (1R,2R)-(2-Chloro-1-isobutylpent-4-enyl)carbamate (3k):
(hexane/Et2O, 80:20). [α]D23 ϭ Ϫ2.0 (c ϭ 0.9, CHCl3). FTIR (film):
Formula mass 309.83. Yield 68%. Rf ϭ 0.30 (hexane/EtOAc, 95:5).
ν˜ ϭ 3408, 1741, 1508, 1250, 1199 cmϪ1
.
1H NMR (250 MHz, [α]D23 ϭ ϩ40.3 (c ϭ 0.52, CHCl3). FTIR (film): ν˜ ϭ 3328, 1705,
CDCl3): δ ϭ 5.75 (br. s, 1 H), 5.20 (q, J ϭ 6.9 Hz, 1 H), 4.16 (q,
J ϭ 6.9 Hz, 2 H), 3.92 (s, 3 H), 1.71 (d, J ϭ 6.9 Hz, 3 H), 1.28 (t,
1511, 1248, 1219 cmϪ1. 1H NMR (500 MHz, CDCl3): δ ϭ 7.33 (m,
5 H), 5.85 (m, 1 H), 5.13 (m, 2 H), 5.10 (m, 2 H), 4.90 (d, J ϭ 6.4
J ϭ 6.9 Hz, 3 H) ppm. 13C NMR (62.3 MHz, CDCl3): δ ϭ 164.5, Hz, 1 H), 4.06 (q, J ϭ 6.4 Hz, 1 H), 3.93 (t, J ϭ 6.4 Hz, 1 H), 2.54
154.1, 123.0 (q, J ϭ 289.4 Hz), 69.1 (q, J ϭ 28.7 Hz), 61.8, 54.2,
(m, 1 H), 2.56 (m, 1 H) 1.63 (m, 1 H), 1.54 (m, 1 H), 1.34 (m, 1
54.0, 20.8, 14.3 ppm. 19F NMR (235.4 MHz, CDCl3): δ ϭ Ϫ69.2 H), 0.93 (d, J ϭ 6.7 Hz, 3 H), 0.91 (d, J ϭ 6.7 Hz, 3 H) ppm. 13C
(s) ppm. MS (DIS EI, 70 eV): m/z (%) ϭ 292 (2) [M ϩ 1]ϩ.
NMR (125.7 MHz, CDCl3): δ ϭ 156.2, 136.5, 133.9, 128.5, 128.2,
128.0, 118.4, 66.9, 66.4, 52.1, 43.1, 40.1, 24.7, 22.9, 22.3 ppm. MS
(EI, 70 eV): m/z (%) ϭ 310 (1) [M ϩ 1]ϩ, 309 (0.6) [Mϩ·], 274 (0.5)
[M Ϫ Cl]ϩ, 220 (10), 176 (10), 91 (100).
Benzyl (1S,1ЈR)-[1-(Chlorophenylmethyl)-2,2,2-trifluoroethyl]carba-
mate (3f): Formula mass 357.75. Yield 65%. Rf ϭ 0.32 (hexane/
Et2O, 80:20). [α]2D3 ϭ Ϫ81.3 (c ϭ 0.8, CHCl3). M.p. 112Ϫ113 °C.
1
FTIR (KBr): ν˜ ϭ 3330, 17802, 1543, 1290, 1254 cmϪ1. H NMR
Synthesis of Aziridines 8. General procedure: A dispersion (60% by
(250 MHz, CDCl3): δ ϭ 7.35 (m, 11 H), 5.26 (d, J ϭ 2.3 Hz, 1 H), weight) of NaH (1.5 equiv.) was added portionwise to a cooled
5.14 (s, 2 H), 5.03 (m, 1 H) ppm. 13C NMR (62.3 MHz, CDCl3): solution of the β-chloroamine 3 (1 equiv.) in dry DMF at 0 °C.
δ ϭ 155.6, 135.6, 135.2, 129.4, 128.8, 128.6, 128.5, 128.2, 127.9,
123.6 (q, J ϭ 283.0 Hz), 67.9, 58.5 (q, J ϭ 29.6 Hz), 58.0 ppm. 19
After complete consumption of the starting material (1Ϫ2 hours,
except for 3j and 3k whose incomplete reactions were quenched
F
NMR (235.4 MHz, CDCl3): δ ϭ Ϫ72.8 (d, J ϭ 6.8 Hz) ppm. MS after 48 and 2 hours respectively) the reaction was quenched with
(DIS EI, 70 eV): m/z (%) ϭ 359 (3) [M ϩ 2]ϩ, 357 (8) [Mϩ].
a saturated solution of NH4Cl and extracted with EtOAc. The col-
lected organic layers were dried over anhydrous Na2SO4, filtered
and the solvent removed in vacuo. Purification of the crude reac-
tion mixture by FC afforded pure aziridine 8.
Ethyl (2R,3S)-2-Benzyloxycarbonylamino-2-(chlorophenylmethyl)-
3,3,3-trifluoropropionate (3g): Formula mass 429.82. Yield 72%.
Rf ϭ 0.33 (hexane/EtOAc, 80:20). [α]2D3 ϭ Ϫ23.7 (c ϭ 0.7, CHCl3).
FTIR (film): ν˜ ϭ 3414, 1748, 1496, 1220 cmϪ1
(250 MHz, CDCl3): δ ϭ 7.37 (m, 10 H), 5.80 (br. s, 1 H), 5.76 (s,
.
1H NMR Benzyl (S)-2-(3-Fluorophenyl)aziridine-1-carboxylate (8c): Formula
mass 271.29. Yield 60%. Rf ϭ 0.62 (hexane/EtOAc, 80:20). [α]D23
1 H), 5.16 (d, J ϭ 12.4 Hz, 1 H), 5.10 (d, J ϭ 12.4 Hz, 1 H), 4.02 ϩ76.9 (c ϭ 0.4, CHCl3). FTIR (film): ν˜ ϭ 1725, 1299, 1196 cmϪ1
(m, 2 H), 1.04 (t, J ϭ 7.0 Hz, 3 H) ppm. 13C NMR (62.3 MHz, 1H NMR (500 MHz, CDCl3): δ ϭ 7.32 (m, 5 H), 6.99 (m, 4 H),
CDCl3): δ ϭ 163.3, 154.0, 135.6, 134.6, 129.8, 128.8, 128.6, 128.4, 5.18 (d, J ϭ 11.9 Hz, 1 H), 5.14 (d, J ϭ 11.9 Hz, 1 H), 3.48 (dd,
ϭ
.
128.3, 123.2 (q, J ϭ 290.4 Hz), 69.4 (q, J ϭ 27.7 Hz), 67.6, 60.7, J ϭ 6.4 and 4.7 Hz, 1 H), 2.71 (d, J ϭ 6.4 Hz, 1 H), 2.26 (d, J ϭ
13.4 ppm. 19F NMR (235.4 MHz, CDCl3): δ ϭ Ϫ67.7 (s) ppm. MS 4.7 Hz, 1 H) ppm. 13C NMR (125.7 MHz, CDCl3): δ ϭ 163.5 (d,
(DIS EI, 70 eV): m/z (%) ϭ 432 (1) [M ϩ 3]ϩ, 430 (3) [M ϩ1]ϩ.
J ϭ 153.1 Hz), 162.1, 139.7 (d, J ϭ 7.6 Hz), 135.6, 131.3, 130.1 (d,
J ϭ 8.4 Hz), 130.0, 128.6, 128.4, 128.3, 122.0, 114.9 (d, J ϭ 21.1
Hz), 113.1 (d, J ϭ 22.6 Hz), 68.5, 38.9, 35.3 ppm. 19F NMR
(470.6 MHz, CDCl3): δ ϭ Ϫ113.3 (dt, J ϭ 8.9 and 5.8 Hz) ppm.
MS (EI, 70 eV): m/z (%) ϭ 271 (5) [M]ϩ.
Benzyl (1S,2S)-(2-Chloro-1-trifluoromethylpent-4-enyl)carbamate
(3h): Formula mass 321.72. Yield 87%. Rf ϭ 0.38 (hexane/EtOAc,
80:20). [α]2D3 ϭ ϩ4.6 (c ϭ 0.4, CHCl3). FTIR (film): ν˜ ϭ 1741,
1271, 1500, 1159 cmϪ1. 1H NMR (500 MHz, CDCl3): δ ϭ 7.36 (m,
5 H), 5.86 (m, 2 H), 5.24 (dq, J ϭ 17.0 and 1.5 Hz, 1 H), 5.16 (s, (2S,3R)-2-Phenyl-3-trifluoromethyl-aziridine-1-carboxylic
2 H), 5.15 (dq, J ϭ 10.0 and 1.5 Hz, 1 H), 3.04 (quintet, J ϭ 5.8 benzyl ester (8f). Formula mass 321.29. Yield 79%. Rf ϭ 0.54 (hex-
Hz, 1 H), 2.72 (qq, J ϭ 6.2 and 1.5 Hz, 1 H), 2.50 (m, 1 H), 2.39
ane/EtOAc, 80:20). [α]2D3 ϭ ϩ22.6 (c ϭ 0.8, CHCl3). FTIR (film):
(m, 1 H) ppm. 13C NMR (125.7 MHz, CDCl3): δ ϭ 161.3, 135.2, ν˜ ϭ 1734, 1282, 1155 cmϪ1. 1H NMR (500 MHz, CDCl3): δ ϭ 7.20
132.9, 128.7, 128.6, 128.1, 123.3 (q, J ϭ 275.6 Hz), 117.9, 68.9, (m, 10 H), 5.05 (d, J ϭ 11.9 Hz, 1 H), 4.94 (d, J ϭ 11.9 Hz, 1 H),
41.0, 39.0 (q, J ϭ 40.7 Hz), 31.7 ppm. 19F NMR (470.6 MHz, 3.80 (d, J ϭ 2.7 Hz, 1 H), 3.50 (m, 1 H) ppm. 13C NMR
acid
CDCl3): δ ϭ Ϫ67.1 (dd, J ϭ 100.1 and 6.6 Hz) ppm. MS (DIS EI,
(125.7 MHz, CDCl3): δ ϭ 158.8, 134.9, 131.5, 129.3, 128.9, 128.5,
128.42, 128.40, 127.2, 122.7 (q, J ϭ 275.0 Hz), 68.9, 42.2 (q, J ϭ
2.8 Hz), 41.3 (q, J ϭ 40.0 Hz) ppm. 19F NMR (470.6 MHz,
CDCl3): δ ϭ Ϫ71.4 (d, J ϭ 5.0 Hz) ppm. MS (EI, 70 eV): m/z
(%) ϭ 322 (2) [M ϩ 1]ϩ.
70 eV): m/z (%) ϭ 323 (1) [M ϩ 2]ϩ, 321 (3) [(M)ϩ].
Benzyl (1S,2S)-(2-Chloro-1-ethylpropyl)carbamate (3j): Formula
mass 255.74. Yield 75%. Rf ϭ 0.35 (hexane/EtOAc, 90:10). [α]D23
ϭ
Ϫ26.3 (c ϭ 1.02, CHCl3). FTIR (film): ν˜ ϭ 3326, 1704, 1513, 1233
cmϪ1. 1H NMR (500 MHz, CDCl3): δ ϭ 7.33 (m, 5 H), 5.11 (m, 2 Benzyl
(2R,3R)-2-Allyl-3-trifluoromethylaziridine-1-carboxylate
H), 4.89 (br. d, J ϭ 6.9 Hz, 1 H), 4.17 (q, J ϭ 6.9 Hz, 1 H), 3.74
(q, J ϭ 6.9 Hz, 1 H), 1.59 (quintet, J ϭ 6.9 Hz, 2 H), 1.49 (d, J ϭ
(8h): Formula mass 285.26. Yield 70%. Rf ϭ 0.38 (hexane/EtOAc,
80:20). [α]2D3 ϭ ϩ4.6 (c ϭ 0.4, CHCl3). FTIR (film): ν˜ ϭ 1741,
6.9 Hz, 3 H), 0.94 (t, J ϭ 6.9 Hz, 3 H) ppm. 13C NMR (125.7 MHz, 1271, 1500, 1159 cmϪ1. 1H NMR (500 MHz, CDCl3): δ ϭ 7.36 (m,
CDCl3): δ ϭ 156.5, 136.5, 128.5, 128.1, 128.0, 66.9, 61.0, 57.3, 29.4, 5 H), 5.86 (m, 1 H), 5.24 (dq, J ϭ 17.0 and 1.5 Hz, 1 H), 5.16 (s,
22.4, 10.4 ppm. MS (DIS EI, 70 eV): m/z (%) ϭ256 (5) [M ϩ 1]ϩ, 2 H), 5.15 (dq, J ϭ 10.0 and 1.5 Hz, 1 H), 3.04 (quintet, J ϭ 5.8
148 (12), 91 (100).
Hz, 1 H), 2.72 (qq, J ϭ 6.2 and 1.5 Hz, 1 H), 2.50 (m, 1 H), 2.39
Eur. J. Org. Chem. 2002, 3336Ϫ3340
3339

A. Volonterio, P. Bravo, W. Panzeri, C. Pesenti, M. Zanda
FULL PAPER
[7] [7a]
(m, 1 H) ppm. 13C NMR (125.7 MHz, CDCl3): δ ϭ 161.3, 135.2,
132.9, 128.7, 128.6, 128.1, 123.3 (q, J ϭ 275.6 Hz), 117.9, 68.9,
41.0, 39.0 (q, J ϭ 40.7 Hz), 31.7 ppm. 19F NMR (470.6 MHz,
CDCl3): δ ϭ Ϫ66.5 (d, J ϭ 6.6 Hz) ppm. MS (EI, 70 eV): m/z
(%) ϭ 285 (17) [Mϩ].
´
´
J. L. Garcıa Ruano, A. Lorente, J. H. Rodrıguez Ramos,
[7b]
Tetrahedron Lett. 1998, 39, 9765Ϫ9768.
Guidetti, F. Viani, M. Zanda, A. L. Markovsky, A. E. Soroch-
P. Bravo, M.
insky, I. V. Soloshonok, V. A. Soloshonok, Tetrahedron 1998,
[7c]
54, 12789Ϫ12806.
A. Arnone, P. Bravo, S. Capelli, G.
Fronza, S. V. Meille, M. Zanda, M. Crucianelli, G. Cavicchio,
J. Org. Chem. 1996, 61, 3375Ϫ3387. [7d] P. Bravo, G. Cavicchio,
Benzyl (2S,3R)-2-Ethyl-3-methylaziridine-1-carboxylate (8j): For-
mula mass 219.28. Yield 16%. Rf ϭ 0.35 (hexane/EtOAc, 90:10).
[α]2D3 ϭ Ϫ14.3 (c ϭ 0.35, CH2Cl2). FTIR (film): ν˜ ϭ 1723, 1288,
M. Crucianelli, A. L. Markovsky, A. Volonterio, M. Zanda,
[7e]
Synlett 1996, 887Ϫ889.
S. Fustero, A. Navarro, B. Pina, J.
´
´
´
Garcıa Soler, A. Bartolome, A. Asensio, A. Simon, P. Bravo,
G. Fronza, A. Volonterio, M. Zanda, Org. Lett. 2001, 3,
2621Ϫ2624 and references cited therein.
1
1223 cmϪ1. H NMR (500 MHz, CDCl3): δ ϭ 7.32 (m, 5 H), 5.11
(m, 2 H), 2.55 (quintet, J ϭ 6.1 Hz, 1 H), 2.37 (q, J ϭ 6.1 Hz, 1
H), 1.55 (m, 1 H), 1.46 (m, 1 H), 1.23 (d, J ϭ 6.1 Hz, 3 H), 1.05
(t, J ϭ 7.5 Hz, 3 H) ppm. 13C NMR (125.7 MHz, CDCl3): δ ϭ
163.9, 136.2, 128.5, 128.2, 128.0, 67.8, 44.0, 37.8, 20.8, 12.8, 11.4
ppm. MS (CI, 70 eV): m/z (%) ϭ 220 (100) [M ϩ 1]ϩ, 176 (8),
91 (40).
[8]
[8a]
For other examples of α-hydroxyalkyl carbanions:
D. R.
Cheshire, in Comprehensive Organic Synthesis (Ed.: B. A.
Trost), Pergamon: New York, 1991; Vol. 3, p 193Ϫ205. See
also: [8b]E. Fernandez-Megıa, S. V. Ley, Synlett 2000, 455Ϫ458
´
´
[8c]
and the list of references cited therein.
R. J. Linderman, A.
Ghannam, J. Am. Chem. Soc. 1990, 112, 2392Ϫ2398.
C. Pesenti, P. Bravo, E. Corradi, M. Frigerio, S. V. Meille, W.
Panzeri, F. Viani, M. Zanda, J. Org. Chem. 2001, 66,
5637Ϫ5640.
[9]
Benzyl (2S,3R)-2-Allyl-3-isobutylaziridine-1-carboxylate (8k): For-
mula mass 273.37. Yield 43%. Rf ϭ 0.37 (hexane/EtOAc, 95:5).
[α]2D3 ϭ ϩ11.2 (c ϭ 0.4, CHCl3). FTIR (film): ν˜ ϭ 1723, 1291, 1219
cmϪ1. 1H NMR (500 MHz, CDCl3): δ ϭ 7.32 (m, 5 H), 5.89 (m, 1
H), 5.19 (d, J ϭ 17.2 Hz, 1 H), 5.11 (m, 2 H), 5.08 (d, J ϭ 10.4
Hz, 1 H), 2.52 (m, 2 H), 2.32 (m, 1 H), 2.19 (m, 1 H), 1.82 (sept,
J ϭ 6.7 Hz, 1 H), 1.38 (m, 2 H), 0.99 (d, J ϭ 6.7 Hz, 3 H), 0.98
(d, J ϭ 6.7 Hz, 3 H) ppm. 13C NMR (125.7 MHz, CDCl3): δ ϭ
163.8, 136.2, 134.6, 128.5, 128.1, 128.0, 116.7, 67.9, 41.4, 41.3, 36.5,
32.2, 29.7, 27.1, 22.7, 22.4 ppm. MS (CI, 70 eV): m/z (%) ϭ 274
(100) [M ϩ 1]ϩ, 138 (6), 91 (38).
[10] [10a]
P. Bravo, A. Farina, V. P. Kukhar, A. L. Markovsky, S. V.
Meille, A. V. Soloshonok, A. E. Sorochinsky, F. Viani, M.
[10b]
`
Zanda, C. Zappala, J. Org. Chem. 1997, 62, 3424Ϫ3425.
P. Bravo, M. Guidetti, F. Viani, M. Zanda, A. L. Markovsky,
A. E. Sorochinsky, I. V. Soloshonok, V. A. Soloshonok, Tetra-
[10c]
hedron 1998, 54, 12789Ϫ12806.
P. Bravo, M. Zanda, C.
Zappala, Tetrahedron Lett. 1996, 37, 6005Ϫ6006. [10d] P. B ravo,
E. Corradi, C. Pesenti, B. Vergani, F. Viani, A. Volonterio, M.
Zanda, Tetrahedron: Asymmetry 1998, 9, 3731Ϫ3735.
Bravo, F. Viani, M. Zanda, V. P. Kukhar, V. A. Soloshonok, N.
`
[10e]
P.
Fokina, O. V. Shishkin, Yu. T. Struchkov, Gazz. Chim. Ital.
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We thank C.N.R. for financial support.
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J. L. Garcıa Ruano, A. Alcudia, M.
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G. Solladie, in
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Received May 6, 2002
[O02245]
3340
Eur. J. Org. Chem. 2002, 3336Ϫ3340