The 'non-oxidative' chloro-Pummerer reaction: A highly stereoselective entry to β-chloro amines and aziridines

Article abstract of DOI:10.1016/S0040-4039(01)00651-7

Enantiomerically pure α-Li alkyl-sulfoxides can be used as chiral α-chloroalkyl carbanions with N-protected imines by means of the 'non-oxidative' chloro-Pummerer reaction (NOCPR). This novel methodology allows for a one-pot displacement of a sulfinyl group by chlorine from N-alkoxycarbonyl β-sulfinylamines derived from aryl, fluoroalkyl and alkyl imines, with clean stereoinversion at carbon. Several 1,2-chloroamines produced via NOCPR were transformed into the corresponding aziridines.

Full text of DOI:10.1016/S0040-4039(01)00651-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3985–3988
The ‘non-oxidative’ chloro-Pummerer reaction: a highly
stereoselective entry to b-chloro amines and aziridines
Alessandro Volonterio,a,* Pierfrancesco Bravo,a,b Cristina Pesentib and Matteo Zandab,*
aC.N.R.-Centro di Studio sulle Sostanze Organiche Naturali, via Mancinelli 7, I-20131 Milan, Italy
bDipartimento di Chimica del Politecnico di Milano, via Mancinelli 7, I-20131 Milan, Italy
Received 29 March 2001; accepted 18 April 2001
Abstract—Enantiomerically pure a-Li alkyl-sulfoxides can be used as chiral a-chloroalkyl carbanions with N-protected imines by
means of the ‘non-oxidative’ chloro-Pummerer reaction (NOCPR). This novel methodology allows for a one-pot displacement of
a sulfinyl group by chlorine from N-alkoxycarbonyl b-sulfinylamines derived from aryl, fluoroalkyl and alkyl imines, with clean
stereoinversion at carbon. Several 1,2-chloroamines produced via NOCPR were transformed into the corresponding aziridines.
© 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
the corresponding b-amino alcohols with high yields
and total stereocontrol.2c,6 Thus, a-lithiated sulfoxides
could be successfully used as synthetic equivalents of
chiral a-hydroxy-carbanions A (Scheme 1) with non-
enolizable imines (R3=aryl, fluoroalkyl).7,8 In this com-
In spite of its extensive use in asymmetric synthesis, the
potential of the sulfinyl group as a chiral auxiliary is
hitherto partially unexploited.1 In fact, the lack of
methods for removing a sulfinyl group from a stereo-
genic centre while preserving the stereochemical infor-
mation is detrimental to its ability to give rise to
excellent 1,2-induction in CꢀC bond-forming reac-
tions.2,3 Recently, we reported on a stereospecific
intramolecular variant of an ‘interrupted’ Pummerer
reaction,4 the ‘non-oxidative’ Pummerer reaction
(NOPR), which allows for a one-pot replacement of a
sulfinyl group with hydroxyl in a stereospecific SN2-
fashion (Schemes 1 and 2).5 This protocol enabled us
and others to transform a wide range of b-sulfinyl
amines N-monoprotected as amides or carbamates,
which are nowadays easily accessible intermediates, into
munication
we
report
the
‘non-oxidative’
chloro-Pummerer reaction (NOCPR), a new methodol-
ogy which extends the spectrum of applicability of
a-lithium sulfoxides to synthetic equivalents of chiral
a-chloro-carbanions B (Scheme 1). A further progress
presented in this paper is the extension of the ‘non-oxi-
dative’ Pummerer chemistry to enolizable imines (R2 or
R3=alkyl). In fact, the NOCPR allows for a clean SN2
displacement of an arylsulfinyl group by chlorine under
Swern-type conditions from N-alkoxycarbonyl a-alkyl,
a-fluoroalkyl, and a-aryl b-sulfinyl amines.9 This pro-
vides a general and efficient entry to a wide range of
enantiomerically pure vicinal chloroamine derivatives,
N
R3
a or b
(− ArSO)
PG
O
O
H
E
R2
E
X
S
Li
S
Ar
Ar
H
NOPR: X = OH
NOCPR: X = Cl
R
R
R
E = C(NHCOR4)R2R3
X
NOPR: "Non-Oxidative"
Pummerer Reaction
NOCPR: "Non-Oxidative"
H
A X = OH (NOPR)
B X = Cl (NOCPR)
R
Chloro-Pummerer Reaction
Scheme 1. (a) (NOPR): (CF3CO)2O, sym-collidine, then H2O/K2CO3, NaBH4; (b) (NOCPR): (COCl)2, then MeOH, NaBH4.
* Corresponding authors. Fax: +039 02 2399-3080; e-mail: alessandro.volonterio@dept.chem.polimi.it; zanda@dept.chem.polimi.it
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00651-7

3986
A. Volonterio et al. / Tetrahedron Letters 42 (2001) 3985–3988
were diluted with methanol and then treated in situ
with an excess of NaBH4 (about 5 equiv.), providing
the final b-chloro amines 3 as single diastereomers
(entries 5–10), isolated in good to excellent overall
yields by FC. The NOCPR is generally applicable to
b-sulfinyl amines 1 N-monoprotected as carbamates,
including fluoroalkyl, aryl (1c,d), alkyl (1j,k),12 and
sterically congested/densely functionalized structures
such as 1e,g. It is worth noting that epimerization by
double displacement (Cl− displaces Cl−), which is a
potential side-reaction, was never observed. Addition of
(COCl)2 in the presence of sym-collidine is crucial for
achieving high yields of 3, because, in the absence of a
base, oxalyl chloride was able to deoxygenate competi-
tively the sulfoxides 1 to the corresponding sulfides.14
The mechanism of the NOCPR is very likely to be as
shown in Scheme 3, consistently with the proposed
outcome of the Swern reaction, and in analogy with the
mechanism of the NOPR, which has been recently
investigated in detail.15 One equiv. of oxalyl chloride
acylates the sulfinyl oxygen of 1 providing the salt 4,
which decomposes into 5 by loss of CO and CO2. Then,
a molecule of HCl is removed by sym-collidine and the
Scheme 2.
COCOCl
NHCOOR4
NHCOOR4
O
which are important building blocks in modern organic
and medicinal chemistry.10
O
(ClCO)2
S
R2
S
R2
R3
Ar
R3
Ar
Cl
R R1
4
R R1
1
2. Results and discussion
COOR4
Cl
NHCOOR4
R2
R3
Ar
S N
Treatment of a set of representative N-alkoxycarbonyl
b-sulfinyl amines 1, having known stereochemistry
(Scheme 1 and Table 1),11,12 with oxalyl chloride (1.5
equiv.) in the presence of sym-collidine (3 equiv.,
CH2Cl2, −50°C) resulted in a fast and stereoselective
rearrangement to the b-chloro sulfenamides 2. In this
process, the sulfinyl group undergoes deoxygenation
and migration to the b-nitrogen, while a new CꢀCl
bond is formed with inversion of configuration. This
point is demonstrated for the transformations of 1e–k
into 2e–k (entries 5–10), which took place with a degree
of stereoselection >98:2.13 Intermediates 2, which can
be isolated by flash chromatography (FC) (see entry 1),
sym-Coll.
− HCl
Cl
Cl
S
Ar
R2
R1
R R1
6
5
R
R3
+ CO + CO2
COOR4
Ar-S
Ar
N-COOR4
R2
R3
S
N
R1
SN2
R
R2
R1
7
R
R3
2
Cl
Cl
Scheme 3.
Table 1. Synthesis of b-chloro-amines via NOCPRa
Entry
Prod.
R
R1
R2
R3
Yield (%)
1
2
3
4
5
6
7
8
2a
3b
3c
3d
3e
3f
3g
3h
3j
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
CHF2
CClF2
3-F-C6H4
PMPb
CO2Me
CF3
CO2Et
CF3
C2H5
H
82
85
\98
\98
60
65
72
87
75
9
10c
3k
Allyl
i-Bu
68
a Ar=p-Tol except for entry 1, where Ar=1-naphthyl; R4=Bn except for entry 5, where R4=Et.
b PMP=4-MeO-C6H4.
c A p-tolylsulfinyl group having (S)-configuration was used.

A. Volonterio et al. / Tetrahedron Letters 42 (2001) 3985–3988
3987
sulfur cation is intercepted by the adjacent carbamic
nitrogen atom, producing the intermediate cyclic four
membered s-sulfurane 6.
Thieme Verlag: Stuttgart, 1995; Vol. E21b, pp. 1793–
1815.
3. Walker, A. J. Tetrahedron: Asymmetry 1992, 3, 961–998.
4. (a) Pummerer, R. Ber. 1909, 42, 2282; (b) Padwa, A.;
Gunn, Jr., D. E.; Osterhout, M. H. Synthesis 1997,
1353–1377 and references cited therein; (c) Kita, Y.;
Shibata, N. Synlett 1986, 289–296; (d) For the ‘inter-
rupted’ Pummerer reaction, see: Xia, M.; Chen, S.; Bates,
D. K. J. Org. Chem. 1996, 61, 9289–9292 and references
cited therein.
5. Zanda, M.; Bravo, P.; Volonterio, A. In Asymmetric
Fluoro-Organic Chemistry: Synthesis, Applications, and
Future Directions; Ramachandran, P. V., Ed.; American
Chemical Society Symposium Series 746, American
Chemical Society: Washington DC, 1999; pp. 127–141.
For further applications of the NOPR, see: Ref. 2c.
6. (a) Garc´ıa Ruano, J. L.; Lorente, A.; Rodr´ıguez Ramos,
J. H. Tetrahedron Lett. 1998, 39, 9765–9768; (b) Bravo,
P.; Guidetti, M.; Viani, F.; Zanda, M.; Markovsky, A.
L.; Sorochinsky, A. E.; Soloshonok, I. V.; Soloshonok,
V. A. Tetrahedron 1998, 54, 12789–12806.
7. For other examples of a-hydroxyalkyl carbanions: (a)
Ferna´ndez-Meg´ıa, E.; Ley, S. V. Synlett 2000, 455–458
and references cited therein. (b) Linderman, R. J.; Ghan-
nam, A. J. Am. Chem. Soc. 1990, 112, 2392–2398.
8. As sulfoxides can thereby convert the adjacent carbon
into both a nucleophilic and electrophilic centre, we
dubbed them ‘chiral chemical chameleons’. A well estab-
lished class of ‘chemical chameleons’ are sulfones, accord-
ing to the definition of Trost: Trost, B. A.; Organ, M. G.;
O’Doherty, G. A. J. Am. Chem. Soc. 1995, 117, 9662–
9670.
9. (a) Mancuso, A. J.; Swern, D. Synthesis 1981, 165–185;
(b) For non-asymmetric replacements of sulfinyl groups
by chlorine under Pummerer reactions, see: Uchida, Y.;
Oae, S. Gazz. Chim. Ital. 1987, 117, 649–654; (c) Chupp,
J. P.; Balthazor, T. M.; Miller, M. J.; Pozzo, M. J. J.
Org. Chem. 1984, 49, 4711–4716; (d) Schwan, A. L.;
Dufault, R. Tetrahedron Lett. 1992, 33, 3973–3974; (e)
Lane, S.; Quick, S. J.; Taylor, R. J. K. Tetrahedron Lett.
1984, 25, 1039–1042.
Dissociation of the latter into an ion-pair 7 triggers its
recombination via SN2-type attack of the generated
chloride anion to the sulfur-substituted stereogenic car-
bon, which produces the final b-chloro sulfenamide 2.
Release of the four-membered ring strain in 6 is likely
to play a significant role, favoring a fast, stereocon-
trolled displacement. It is more than likely that deoxy-
genation of
1 to the corresponding sulfides, a
side-reaction observed when oxalyl chloride is used
without sym-collidine (see above), involves formation
of Cl2 from 5 when it cannot be rapidly transformed
into 6 by action of the base.9b
Among the possible derivatives of vicinal chloroamines,
aziridines constitute a valuable class of compounds
both for their pharmaceutical properties and synthetic
versatility.16 Treatment of 3c,f,h,j,k with NaH (1.5
equiv.) (Scheme 4) afforded the enantiomerically pure
N-Cbz aziridines 8c,f,h,j,k in good yields.17
In summary, the disclosure of the NOCPR opens up a
straightforward route to enantiomerically pure,
stereodefined b-chloro amines and some important
derivatives like aziridines, and extends the applicability
of sulfoxides in asymmetric synthesis. We are currently
working toward the development of NOCPR and
NOPR-based sulfoxide reagents for solution and solid-
phase synthesis to be used as chiral a-chloro and a-
hydroxy-alkyl anion equivalents.18
10. (a) Kemp, J. E. G. In Comprehensive Organic Synthesis;
Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, UK,
1991; Vol. 7, pp. 469–513; (b) Li, G.; Wei, H.-X.; Kim, S.
H. Org. Lett. 2000, 2, 2249–2252 and references cited
therein.
Scheme 4. (a) Unreacted 3j recovered in nearly quantitative
yield after 48 hours. (b) Unreacted 3k recovered in 35% yield
after 2 hours.
Acknowledgements
11. b-Sulfinyl amines 1 can be conveniently prepared through
CꢀC bond-forming reaction of enantiomerically pure a-
lithium sulfoxides with suitably N-protected imines
(Scheme 1): (a) Bravo, P.; Farina, A.; Kukhar, V. P.;
Markovsky, A. L.; Meille, S. V.; Soloshonok, A. V.;
Sorochinsky, A. E.; Viani, F.; Zanda, M.; Zappala`, C. J.
Org. Chem. 1997, 62, 3424–3425. (b) Bravo, P.; Guidetti,
M.; Viani, F.; Zanda, M.; Markovsky, A. L.; Sorochin-
sky, A. E.; Soloshonok, I. V.; Soloshonok, V. A. Tetra-
hedron 1998, 54, 12789–12806. (c) Bravo, P.; Zanda, M.;
Zappala`, C. Tetrahedron Lett. 1996, 37, 6005–6006. (d)
Bravo, P.; Corradi, E.; Pesenti, C.; Vergani, B.; Viani, F.;
Volonterio, A.; Zanda, M. Tetrahedron: Asymmetry 1998,
9, 3731–3735. (e) Bravo, P.; Viani, F.; Zanda, M.;
Kukhar, V. P.; Soloshonok, V. A.; Fokina, N.; Shishkin,
O. V.; Struchkov, Yu. T. Gazz. Chim. Ital. 1996, 126,
645–652.
This work was supported by MURST COFIN-2000
and CNR-CSSON.
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3988
A. Volonterio et al. / Tetrahedron Letters 42 (2001) 3985–3988
12. Compounds 1j,k were obtained by condensation (THF,
−70°C) of lithiated (R)-ethyl and (S)-3-butenyl p-tolylsul-
8f,h,k were unambiguously determined by NOE experi-
ments. For example, irradiation of the CF3 group of 8h
produced 1.5 and 2.0% heteronuclear NOE enhancements
on the diastereotopic CH2 allylic protons in cis position
(R=allyl), and only 0.5% on the aziridine ring proton
(R1=H) trans to the trifluoromethyl; (c) The stereochem-
istry of 8j was assigned by comparison of its 1H NMR
and polarimetric analyses with those described by Garc´ıa
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foxides
with
Cbz-NꢁCHCH2CH3
and
Cbz-
NꢁCHCH2CH(CH3)2, respectively, prepared according to
the method of Mecozzi and Petrini: Mecozzi, T.; Petrini,
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this topic, including configuration assignment to 1j,k, will
be reported in a forthcoming full paper.
13. No minor diastereomers of 3 could be either detected by
500 MHz 1H NMR analysis of the crude reaction mix-
tures, or isolated by FC.
14. Deoxygenation of sulfoxides 1 to the corresponding
sulfides took place quantitatively also in the case of
attempted ‘non-oxidative’ bromo-Pummerer reaction,
namely upon treatment of 1 with oxalyl bromide under
the optimized NOCPR conditions.
15. Crucianelli, M.; Bravo, P.; Arnone, A.; Corradi, E.;
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18. Experimental. The non-oxidative ‘chloro-Pummerer reac-
tion’. General procedure. To a solution of N-alkoxycar-
bonyl b-sulfinylamine 1 (1 equiv.) and sym-collidine (3
equiv.) in dry CH2Cl2 at −50°C, under a nitrogen atmo-
sphere, neat oxalyl chloride (1.5 equiv.) was added drop-
wise. After complete consumption of the starting material
(TLC) the reaction was allowed to reach room tempera-
ture, diluted with MeOH and then an excess of NaBH4
(ca. 5 equiv.) was added portion-wise. After consumption
of the intermediate sulfenamide 2 (TLC), the reaction was
quenched with saturated solution of NH4Cl and extracted
with AcOEt. The collected organic layers were dried on
anhydrous Na2SO4, filtered and the solvent removed in
vacuo. Purification of the crude by FC afforded the
corresponding b-chloro amine 3.
17. (a) In contrast, the sterically congested b-chloro-amine 3g
did not afford the corresponding aziridine under the same
conditions; (b) The relative configurations of aziridines
.