Enantiomerically pure 2-aryl(alkyl)-2-trifluoromethylaziridines: Synthesis and ring opening with selected O- and N-nucleophiles

Article abstract of DOI:10.1039/c0ob00690d

We report herein the synthesis of enantiomerically pure 2-phenyl- and 2-ethyl-2-trifluoromethylaziridines by Mitsunobu-type cyclisation of the corresponding N-protected amino alcohols, and our results regarding their ring opening with selected nucleophiles. Under basic conditions, N-tosyl aziridines have been regioselectively opened at the less hindered carbon. Under acidic conditions, the regioselectivity of the attack depends on the nature of the substituent at C-2 and on the nitrogen protecting group.

Full text of DOI:10.1039/c0ob00690d

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PAPER
Enantiomerically pure 2-aryl(alkyl)-2-trifluoromethylaziridines: synthesis and
ring opening with selected O- and N-nucleophiles†‡
Fabienne Grellepois,* Jean Nonnenmacher, Fabien Lachaud and Charles Portella
Received 7th September 2010, Accepted 28th October 2010
DOI: 10.1039/c0ob00690d
We report herein the synthesis of enantiomerically pure 2-phenyl- and
2-ethyl-2-trifluoromethylaziridines by Mitsunobu-type cyclisation of the corresponding N-protected
amino alcohols, and our results regarding their ring opening with selected nucleophiles. Under basic
conditions, N-tosyl aziridines have been regioselectively opened at the less hindered carbon. Under
acidic conditions, the regioselectivity of the attack depends on the nature of the substituent at C-2 and
on the nitrogen protecting group.
In this context, we planned the synthesis of the enantiopure N-
tosyl 2-phenyl- and 2-ethyl-2-trifluoromethylaziridines from the
corresponding enantiopure a-trifluoromethyl-a-alkoxyaldehydes.
Introduction
Trifluoromethylated compounds have found a wide range of
applications as pharmaceuticals, agrochemicals or materials due to
These aziridines, one containing an aryl group and the other one
the specific properties introduced by the fluorine atoms.1 Nitrogen-
an alkyl group, allowed us to study the influence of the substituent
containing derivatives in particular are of great interest,1,2 however
geminal to the trifluoromethyl group on the regioselectivity of the
the synthesis of enantiopure molecules with a quaternary trifluo-
ring opening with selected nucleophiles. The observed results led
romethyl group adjacent to the nitrogen atom is still challenging.1
us to assess the influence of the substituent at nitrogen, thus to
Aziridines,3 and chiral ones in particular, are recognized as im-
portant intermediates for the synthesis of a wide array of nitrogen-
containing compounds by way of ring-opening reactions,4 the
regioselectivity of these reactions being strongly dependent on
the nature of the substituents and the reaction conditions.4b,e
synthesize also the N-benzyl-2-phenyl-2-trifluoromethylaziridine.
Results and discussion
We recently reported the diastereoselective synthesis of the starting
However, despite their great synthetic interest, only a few
optically active aziridines bearing a trifluoromethyl moiety have
been reported.5 Amongst them, only one derivative belonging
to the class of 2-aryl(alkyl)-2-trifluoromethylaziridines has been
described. Its synthesis involved the stereospecific alkylation of a
trifluoromethylated aziridinyl anion with benzylbromide, albeit in
low yield which prevent further studies.5e–g
alkoxyaldehydes (R)-1 from (L)-tartaric acid derived ketoamide
(Scheme 1).7,8
Studies on the ring opening of variously N-substituted tri-
fluoromethyl aziridines5e–g,6 have shown that: (i) the activating
electron withdrawing sulfonyl group facilitates their reaction with
nucleophiles; (ii) the reaction is always totally regioselective,
with the nucleophile attacking on the carbon not bearing the
trifluoromethyl group, due to the electrostatic repulsion of this
substituent towards nucleophiles.
Scheme 1 Preparation of alkoxyaldehydes (R)-1.7
Universite´ de Reims-Champagne-Ardenne, Institut de Chimie Mole´culaire
de Reims, UMR CNRS 6229, UFR des Sciences Exactes et Naturelles,
BP 1039, 51687 Reims cedex 2, France. E-mail: fabienne.grellepois@univ-
reims.fr; Fax: +33 3 26 91 31 66; Tel: +33 3 26 91 31 64
The reaction of the alkoxyaldehyde (R)-1a with p-toluene-
sulfonamide in the presence of TiCl4 and triethylamine9 afforded
the corresponding imine (R)-2a in 75% yield (Scheme 2). The N-
tosylimine function then needed to be reduced into sulfonamide.
The treatment of (R)-2a with sodium borohydride in methanol
afforded only the stable hemiaminal derivative 3a in 63% yield.
To overcome this drawback, the imine was reduced using either
† This publication is part of the web themed issue on fluorine chemistry.
‡ Electronic supplementary information (ESI) available: Preparation of
racemic samples, copies of NMR spectra (19F, 1H and 13C) for all new
compounds and chromatograms. CCDC reference number 779933. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c0ob00690d
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Table 1 Acidic hydrolysis of the N-tosylaziridines (S)-6a,b
entry aziridine R time ratioa (R)-5 : (S)-7 isolated product
yield
1
2
(S)-6a
(S)-6b
Ph 1 h 30 100 : 0
Et 20 h 7 : 93
(R)-5a (ee = 88%)b 83%
(S)-7b 69%
a determined by 19F NMR on the crude mixture. b determined by chiral
HPLC, see ESI.‡
Scheme 2 First attempts for the preparation of the alkoxysulfonamide
(R)-4a.
LiAlH4 in diethylether or NaBH(OAc)3 in dichloromethane to give
the alkoxysulfonamide (R)-4a in respectively 74 and 60% yield.
After optimisation of the reaction conditions, we were able to
perform a “sequential one-pot” reductive amination of (R)-1a,b
which afforded directly the b-alkoxysulfonamides (R)-4a,b in quite
good yields (respectively 58% and 60%) (Scheme 3). Subsequent
cleavage of the O-benzyl protecting group of (R)-4a,b led to
the b-hydroxysulfonamides (R)-5a,b in excellent yields (93 and
89%). (R)-5a,b which contain a tertiary-alcohol function bearing
a trifluoromethyl group were then subjected to the Mitsunobu
conditions.10,11 Their treatment with diethyl azodicarboxylate and
triphenylphosphine in the presence of triethylamine in THF
afforded cleanly the aziridines (S)-6a,b which were isolated in
excellent yields after chromatography on silica gel (respectively
93 and 81% yields) (Scheme 3).
88%). This high ee suggests that the acid hydrolysis of the N-
tosyl-2-phenyl-2-trifluoromethylaziridine (S)-6a proceeds mainly
via an SN2 pathway at the more electrophilic position, whereas
the slight racemisation might result from the formation of an
incipient a-trifluoromethylated carbenium ion stabilized by the
phenyl group.13,14
As the presence of the phenyl group4e,15 should explain this
unusual reactivity of a trifluoromethylated aziridine, we performed
the same reaction on the 2-ethyl analogue (S)-6b. The treatment of
N-tosyl-2-ethyl-2-trifluoromethylaziridine (S)-6b under the same
conditions led indeed predominantly to the b-hydroxysulfonamide
(S)-7b which was isolated in 69% yield, but surprisingly, a small
amount of the regioisomer (R)-5b was also detected by 19F NMR
in the crude mixture (Table 1, entry 2). Owing to this unusual
nucleophilic attack on the CF3-bearing carbon, we were keen
to investigate the influence of the activating tosyl group on the
regioselectivity of the acid hydrolysis.
As N-benzyl-2-trifluoromethylaziridine is known to react with
various nucleophiles under acidic conditions,6b we prepared the N-
benzyl-2-phenyl-2-trifluoromethylaziridine (S)-6c, a non activated
analogue of aziridine (S)-6a. The palladium catalysed deallylation
of the known N-benzyl amino ether (R)-4c16 afforded the N-
benzyl amino alcohol (R)-5c in 74% yield (Scheme 4). We first
attempted to cyclize the N-benzyl b-amino alcohol (R)-5c (ee =
97%)17 under Mitsunobu conditions (DEAD, PPh3, Et3N, THF)
but not surprisingly10b the aziridine (S)-6c was isolated in low yield
(39%) due to the formation of many byproducts. (R)-5c was thus
cyclised into the aziridine (S)-6c using an alternative method.18,19
Scheme 3 Preparation of the activated aziridines (S)-6a,b.
The enantiomeric purity of the aziridine (S)-6a (ee = 100%)
was confirmed by chiral HPLC, and the clean inversion of
configuration at the tertiary-alcohol stereocenter11 was confirmed
by X-ray diffraction (vide infra).
Having found a convenient access to disubstituted aziridines
(S)-6a,b, we evaluated their reactivity toward the synthesis of the
b-hydroxysulfonamides 7,12 regioisomers of 5.
The aziridine (S)-6a proved to be inert under neutral conditions.
◦
Under acidic conditions (HClO4, H2O, 90 C)4b the N-tosyl-2-
phenyl-2-trifluoromethylaziridine (S)-6a was opened with com-
plete regioselectivity, leading to the b-hydroxysulfonamide (R)-5a
(83% yield) (Table 1, entry 1). The protected b-amino alcohol (R)-
5a, which is unfortunately the precursor of (S)-6a, results from
water attacking at the benzylic position, on the carbon bearing
the trifluoromethyl group. (R)-5a was isolated in good yield albeit
with partial racemization of the quaternary stereocenter (ee =
Scheme 4 Preparation of the non-activated aziridine (S)-6c.
Under the previous acidic hydrolysis conditions, the nucleophile
attacked preferentially the non-activated aziridine (S)-6c at C-3
leading to the b-amino alcohol (S)-7c as the major product (78%
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Table 2 Basic hydrolysis of N-tosylaziridines (S)-6a,b
Table 3 Reactions of N-tosylaziridines (S)-6a,b with N-nucleophiles
entry aziridine
R
time ratioa(R)-5 : (S)-7 isolated product yield
entry aziridine R1R2NH
time isolated product yield
1
2
(S)-6a
(S)-6b
Ph 26 h 3 : 97
Et 21 h 0 : 100
(S)-7a
(S)-7b
84%
93%
1
2
(S)-6a
(S)-6b
(S)-6a
(S)-6b
(S)-6a
(S)-6b
(S)-6a
(S)-6b
(S)-6a
(S)-6b
BnNH2
BnNH2
(R)-a-Me-BnNH2
20 h (S)-8a
22 h (S)-8b
24 h (S)-9a
90%
96%
95%
98%
93%
97%
99%
98%
85%
76%
a determined by 19F NMR on the crude mixture.
3
4
5
6
7
8
9
10
(R)- a-Me-BnNH2 24 h (S)-9b
morpholine
morpholine
anilinea
22 h (S)-10a
15 h (S)-10b
48 h (S)-11a
40 h (S)-11b
22 h (S)-12a
22 h (S)-12b
anilinea
b
TsNH2
TsNH2
b
a 2 equiv of aniline were used. b K2CO3 (1.2 equiv) was added.
Scheme 5 Acidic hydrolysis of N-benzylaziridine (S)-6c.
yield), along with a small amount of (R)-5c (3% yield, ee = 92%)
(Scheme 5).
The above results highlighted that the nucleophilic ring opening
of the 2-phenyl substituted aziridine (S)-6a at the CF3-bearing
carbon C-2, under acidic conditions, is due to the presence of
both the aryl group geminal to CF3 and the sulfonyl group of
the nitrogen which enhances the electrophilicity of the adjacent
carbons.
Despite scarce reports on the ring opening of aziridines with
hydroxide ion,4b we finally attempted reactions under basic
conditions with the aim of favouring the ring opening at C-3 for
both aziridines (S)-6a and (S)-6b (Table 2).20 Aziridine (S)-6a was
treated with sodium hydroxide in a mixture of tert-butanol and
water at reflux. The hydroxide attack was highly regioselective
at C-3, giving the b-hydroxysulfonamide (S)-7a in excellent yield
(84%) (entry 1). Only traces of its regioisomer (R)-5a could be
observed by 19F NMR of the crude product. The ring opening
of the aziridine (S)-6b under these conditions afforded only the
b-hydroxysulfonamide (S)-7b which was isolated in 93% yield
(entry 2).
The ring opening of aziridines (S)-6a and (S)-6b was also
examined with various amines in refluxing acetonitrile (Table 3).20
In all cases, the ring opening proceeded solely at C-3, the less
hindered carbon (Table 3). Treatment with primary and secondary
amines afforded the corresponding b-aminosulfonamides12 (S)-
8a,b, (S)-9a,b and (S)-10a,b in excellent yields (from 90 to
97%) (entries 1–6). Not surprisingly, the reaction with the less
nucleophilic aniline was more sluggish (entries 7–8).21 Aziridines
(S)-6a,b also reacted with paratoluenesulfonamide in the presence
of potassium carbonate (entries 9,10).
Fig. 1 Structure of compound (S)-9a from single crystal X-ray data.
Conclusion
In conclusion we have reported the synthesis of enantiomerically
pure or enriched N-tosyl and N-benzyl 2-phenyl- and N-tosyl-
2-ethyl-2-trifluoromethylaziridines by cyclisation of the corre-
sponding N-protected amino alcohols, and their reaction with
selected nucleophiles. Under acidic conditions the attack depends
on the nature of the substituent at C-2 and on the nitrogen
protecting group. Remarkably, attack on the carbon bearing
the trifluoromethyl group has been observed for the first time.
The ring opening of N-tosyl 2,2-disubstituted trifluoromethylated
aziridines with hydroxide or amines is highly regioselective, at the
less hindered carbon.
Experimental section
General experimental
THF and ether were distilled from sodium–benzophenone.
CH2Cl2 was distilledfrom CaH2. Others reagents andsolvents were
obtained from common commercial sources and used as received.
Thin-layer chromatography using precoated aluminium backed
plates (Merck Kieselgel 60F254) were visualized by UV light
and an aqueous solution of potassium permanganate. Silicagel
(Macherey–Nagel GmbH & Co KG – (40–63 mm, ASTM for
column chromatography) was used for flash chromatography.
Melting points (mp) were determined on a Stuart apparatus SMP3
Recrystallization of b-diamine (S)-9a from ether–petroleum
ether gave colorless needles, which were subjected to X-ray
diffraction analysis.‡ The absolute configuration of the quaternary
carbon bearing the trifluoromethyl group was found to be S, thus
confirming the inversion of its configuration during the cyclisation
reaction (Mitsunobu reaction)11 of the b-hydroxysulfonamide (R)-
5a leading to the aziridine (S)-6a (Fig. 1).
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and were uncorrected. Optical rotations were measured on a
Perkin Elmer precisely model 341 polarimeter at room temperature
(c.a. 20 ◦C). NMR spectra were recorded on a Bruker advance 250.
Coupling constants (J) are reported in Hz. In the 13C NMR data,
reported signal multiplicities are related to C–F coupling. HRMS
were recorded on a Micromass ESI-Q–TOF mass spectrometer
using an electrospray source in positive mode (ESI+). Analytical
HPLC were performed either on an Agilent 1100 series LC
or a Shimadzu LC10AS system equipped with a tunable UV
detector. Crystallographic data were recorded on a Bru¨ker Kappa
Apex II equipped with an Oxford Cryosystem 700 cryostat. The
structures were solved by direct methods with additional light
atoms found by Fourier methods. Hydrogen atoms were added at
calculated positions and refined using a riding model. Anisotropic
displacement parameters were used for all non H-atoms; H-atoms
were given isotropic displacement parameters equal to 1.2 or 1.5
times the equivalent isotropic displacement parameter of the atom
to which the H-atom is attached. Aldehydes (R)-1a,b7 and N-
benzylamino alcohol (R)-4c16 were prepared according to reported
procedures.
d, J 10.0, 1 H), 5.26 (m, 1 H), 6.85–7.70 (m, 14 H); dC (62.9 MHz;
CDCl3; Me4Si) 21.4 and 21.5, 56.9 and 57.7, 67.7 and 68.0, 84.2
(q, J 25.5) and 85.3 (q, J 24.0), 86.5 and 88.8, 126.4, 126.8, 126.9,
127.2, 127.5, 127.8, 127.9, 128.1, 128.3, 128.4, 128.5, 128.7, 129.1,
129.4, 129.5 (q, J 314.0) and 129.8 (q, J 312.0), 137.8 and 138.3,
142.9 and 143.4.
General procedure for the synthesis of b-benzyloxysulfonamides
(R)-4a,b by reductive amination of (R)-1a,b
To a solution of aldehyde (R)-1a,b, p-toluenesulfonamide (1 equiv)
and triethylamine (distilled over KOH, 3 equiv) in CH2Cl2 was
◦
added, at 0 C and under Ar, a solution of TiCl4 (0.75 equiv) in
CH2Cl2. The reaction mixture was stirred 5 min at 0 ◦C and at rt
until the completion of the conversion of the aldehyde (R)-1a,b
into tosylimine (R)-2a,b (reaction monitored by 19F NMR). The
reaction mixture was then filtered through celite and NaBH(OAc)3
(2.5 equiv) was added to the filtrate. The reaction mixture was
stirred for 15 supplementary hours. The reaction mixture was then
washed with a sat. aq. sol. of Na2CO3 and brine. The organic layer
was extracted, dried (MgSO4), filtered and concentrated under
reduced pressure. Chromatography of the residue on silica gel
afforded the b-benzyloxysulfonamide (R)-4a,b.
(R)-2-Benzyloxy-3,3,3-trifluoro-2-phenyl-N-tosylpropylamine
(R)-2a
(+)-(R)-2-Benzyloxy-3,3,3-trifluoro-2-phenyl-N-tosypropylamine
(R)-4a
To a solution of aldehyde (R)-1a (428 mg, 1.46 mmol), p-
toluenesulfonamide (249 mg, 1.46 mmol, 1 equiv) and triethy-
lamine distilled over KOH (608 mL, 4.37 mmol, 3 equiv) in CH2Cl2
(10 mL) was added, at 0 ◦C and under Ar, a solution of TiCl4
(120 mL, 1.09 mmol, 0.75 equiv) in CH2Cl2 (3 mL). The reaction
mixture was stirred for 5 min at 0 ◦C and at rt for 3 h. The reaction
mixture was then filtered through celite and the filtrate was
concentrated under reduced pressure. The residue was triturated
with Et2O (dried over MgSO4), the suspension was heated at reflux
for 10 min, filtered and the filtrate was concentrated under reduced
pressure to give the aldimine (R)-2a (491 mg, 75%) as a yellow–
brownish oil which was used in the next step without further
purification. dF (235.3 MHz; CDCl3; CFCl3) -73.0 (s, 3 F); dH
(250 MHz; CDCl3; Me4Si) 2.46 (s, 3 H), 4.56 (d, J 11.5, 1 H), 4.70
(d, J 11.5, 1 H), 7.30–7.45 (m, 12 H), 7.80 (d, J 8.0, 2 H), 8.76 (d,
J 1.5, 1 H); dC (62.9 MHz; CDCl3; Me4Si) 21.7, 68.7, 82.8 (q, J
28.5), 123.2 (q, J 288.0), 127.3, 128.0, 128.3, 128.6, 128.8, 130.0,
133.5, 136.9, 145.8, 169.7.
Following the general procedure, a solution of TiCl4 (292 mL,
2.66 mmol, 0.75 equiv) in CH2Cl2 (5 mL) was added to a solution
of aldehyde (R)-1a (1.04 g, 3.55 mmol), p-toluenesulfonamide
(608 mg, 3.55 mmol, 1 equiv) and Et3N (1.48 mL, 10.65 mmol,
3 equiv) in CH2Cl2 (30 mL). After 4 h of reaction the reaction
was filtered on celite and NaBH(OAc)3 (1.88 g, 8.88 mmol,
2.5 equiv) was added. Chromatography (PE : EtOAc 6 : 1) afforded
the b-benzyloxysulfonamide (R)-4a (955 mg, 60%) as a white
solid (Found: [M+Na]+, 472.1168. C23H22F3NNaO3S requires
◦
472.1170); mp 86 C (from EtOAc–PE); [a]2D0 +21 (c 1.05 in
CHCl3); dF (235.3 MHz; CDCl3; CFCl3) -72.1 (s, 3 F); dH (250
MHz; CDCl3; Me4Si) 2.41 (s, 3 H), 3.54 (dd, J 5.0 and 13.0, 1 H),
3.77 (dd, J 6.5 and 13.0, 1 H), 4.50 (s, 2 H), 4.72 (br s, 1 H), 7.26
(d, J 8.0, 2 H), 7.33–7.40 (m, 10 H), 7.65 (d, J 8.0, 2 H); dC (62.9
MHz; CDCl3; Me4Si) 21.3, 45.6, 66.6, 80.8 (q, J 27.0), 124.6 (q,
J 295.5), 126.99, 127.04, 127.4, 128.4, 128.7, 129.3, 129.7, 132.8,
136.0, 136.7, 143.6.
(2R)-2-Benzyloxy-3,3,3-trifluoro-1-methoxy-2-phenyl-N-
tosylpropylamine 3a
(-)-(R)-2-Benzyloxy-N-tosyl-2-trifluoromethylbutylamine (R)-4b
A solution of imine (R)-2a (134 mg, 0,30 mmol) and NaBH4
(11 mg, 0,30 mmol, 1 equiv) in MeOH (2 mL) was stirred
at rt and under Ar for 18 h. The reaction mixture was then
concentrated under reduced pressure. The residue was dissolved
in CH2Cl2 and was washed with HCl 20%. The organic layer
was extracted, dried (MgSO4), filtered and concentrated under
reduced pressure. Chromatography of the residue (mixture of 2
diastereomers 51 : 49 according to the 19F NMR) on silica gel
(PE : EtOAc 6 : 1) afforded the hemiaminal 3a (91 mg, 63%) as
a colorless oil (Found: [M+Na]+, 502.1166. C24H24F3NNaO4S
requires 502.1276); dF (235.3 MHz; CDCl3; CFCl3) -65.2 and
-68.4 (s, 3 F); dH NMR (250 MHz; CDCl3; Me4Si) 2.26 and 2.29
(2 s, 3 H), 3.09 and 3.32 (2 s, 3 H), 4.55 (m, 2 H), 4.87 and 5.11 (2
Following the general procedure for the reductive amination, a
solution of TiCl4 (69 mL, 0.62 mmol, 0.75 equiv) in CH2Cl2 (1 mL)
was added to a solution of aldehyde (R)-1b (204 mg, 0.83 mmol),
p-toluene sulfonamide (142 mg, 0.835 mmol, 1 equiv) and Et3N
(347 mL, 2.49 mmol, 3 equiv) in CH2Cl2 (4 mL). After 5 h of
reaction the reaction was filtered on celite and NaBH(OAc)3
(439 mg, 2.07 mmol, 2.5 equiv) was added. Chromatography
(PE : CH2Cl2 1 : 6) afforded the b-benzyloxysulfonamide (R)-4b
(193 mg, 58%) as a white solid (Found: [M+Na]+, 424.1182.
C19H22F3NNaO3S requires 424.1170); mp 59 ◦C (from CH2Cl2–
PE); [a]2D0 -32 (c 0.99 in CHCl3); dF (235.3 MHz; CDCl3; CFCl3)
-73.3 (s, 3 F); dH (250 MHz; CDCl3; Me4Si) 1.01 (t, J 7.5, 3 H),
1.98 (q, J 7.5, 2 H), 2.39 (s, 3 H), 3.16 (dd, J 6.0 and 13.0, 1 H),
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3.28 (dd, J 7.0 and 13.0, 1 H), 4.51 (d, J 11.5, 1 H), 4.55 (d, J 11.0,
1 H), 4.91 (t, J 6.5, 1 H), 7.24–7.34 (m, 7 H), 7.70 (d, J 8.0, 2 H);
dC (62.9 MHz; CDCl3; Me4Si) 7.0, 21.3, 21.7, 43.8, 66.1, 79.1 (q,
J 25.5), 125.5 (q, J 291.0), 127.0, 127.6, 127.9, 128.4, 129.7, 136.2,
137.0, 143.6.
through celite (Et2O). The filtrate was washed with brine, dried
(MgSO4) and concentrated under reduced pressure. Purification
of the residue by chromatography on silica gel (PE : Et2O 3 : 1)
afforded the b-amino alcohol (R)-5c (284 mg, 74%) as a colorless
oil (Found: [M+H]+, 296.1267. C16H17F3NO requires 296.1262);
[a]2D0 -14 (c 0.96 in CHCl3), (R)-5c·HCl [a]2D0 -16 (c 0.66 in MeOH)
[lit.8d enantiomer S·HCl [a]D23 +1.5 (c 0.92 in MeOH)]; dF (235.3
MHz; CDCl3; CFCl3) -78.6 (s, 3 F); dH (250 MHz; CDCl3; Me4Si)
2.98 (dd, J 1.0 and 13.0, 1 H), 3.43 (d, J 13.0, 1 H), 3.72 (s, 2 H),
7.15–7.40 (m, 7 H), 7.56 (dd, J 1.0 and 7.5 Hz, 2 H), OH and NH
not detected; dC NMR (62.9 MHz; CDCl3; Me4Si) 52.4, 53.8, 73.7
(q, J 28.0), 125.5 (q, J 285.5), 126.1, 127.4, 128.0, 128.3, 128.5,
128.6, 137.6, 138.9. 97% ee determined by chiral HPLC (chiralpak
IC column, hexane : isopropanol 90 : 10, flow rate 0.5 mL min-1):
tminor = 9.5 min, tmajor = 10.3 min.
General procedure for the synthesis of b-hydroxysulfonamides
(R)-5a,b
A suspension of benzyloxysulfonamide (R)-4a,b, ammonium
formate (3.0 equiv) and Pd/C (10%, 0.05 equiv) in methanol
was heated at reflux. After the complete disappearance of the
amino-ether (R)-4a,b, the reaction mixture was cooled to rt,
filtered through celite and the filtrate was concentrated under
reduced pressure. Purification by chromatography on silica gel
or recrystallisation afforded the b-hydroxysulfonamide (R)-5a,b.
General procedure for the synthesis of aziridines (S)-6a,b
(+)-(R)-1,1,1-Trifluoro-2-phenyl-3-tosylaminopropan-2-ol (R)-5a
A solution of b-hydroxysulfonamide (R)-5a,b, diethylazodicar-
boxylate (1.5 equiv), triphenylphosphine (1.5 equiv) and triethy-
lamine (2.5 equiv) in THF was stirred at rt and under Ar. After the
complete disappearance of the b-hydroxysulfonamide (R)-5a,b,
the reaction was concentrated under reduced pressure and was
purified by chromatography on silica gel to give the aziridine (S)-
6a,b.
According to the general procedure, the benzyloxysulfonamide
(R)-4a (900 mg, 2.0 mmol) was reacted with ammonium formate
(378 mg, 6.0 mmol, 3.0 equiv) and Pd/C (10%, 107 mg, 0.1 mmol,
0.05 equiv) in methanol (10 mL) for 2 h. Recrystallization (PE–
Et2O) yielded the b-hydroxysulfonamide (R)-5a (660 mg, 93%)
as a white solid (Found: [M+Na]+, 382.0712. C16H16F3NNaO3S
requires 382.0701); mp 139 ◦C (from Et2O–PE); [a]D20 +42 (c 0.97
in CHCl3); dF (235.3 MHz; CDCl3; CFCl3) -78.4 (s, 3 F); dH (250
MHz; CDCl3; Me4Si) d 2.43 (s, 3 H), 3.51 (dd, J 6.0 and 14.0,
1 H), 3.59 (dd, J 7.5 and 14.0, 1 H), 3.98 (br s, 1 H), 4.96 (t, J
7.0, 1 H), 7.25–7.38 (m, 5 H), 7.49 (m, 2 H), 7.66 (d, J 8.0, 2 H);
dC (62.9 MHz; CDCl3; Me4Si): 21.4, 47.3, 75.7 (q, J 28.5), 124.7
(q, J 286.5), 126.4, 127.0, 128.6, 129.0, 129.9, 134.8, 135.7, 144.2.
100% ee determined by chiral HPLC (chiralcel OD-H column,
hexane : isopropanol 95 : 5, flow rate 1 mL min-1): t = 17.4 min
(rac. t = 17.4 and 23.8 min).
(-)-(S)-2-Phenyl-N-tosyl-2-trifluoromethylaziridine (S)-6a
According to the general procedure,
a solution of b-
hydroxysulfonamide (R)-5a (1.10 g, 3.07 mmol) was reacted with
DEAD (724 mL, 4.60 mmol, 1.5 equiv), PPh3 (1.21 g, 4.60 mmol,
1.5 equiv) and triethylamine (1.07 mL, 7.68 mmol, 2.5 equiv) in
THF (30 mL) for 5 h. Purification by chromatography on silica
gel (PE : EtOAc 4 : 1) afforded the aziridine (S)-6a (978 mg, 93%)
as a white solid (Found: [M+Na]+, 364.0609. C16H14F3NNaO2S
◦
requires 364.0595); mp 135–136 C (from EtOAc–PE); [a]2D0 -96
(+)-(R)-1-Tosylamino-2-trifluoromethylbutan-2-ol (R)-5b
(c 1.11 in CHCl3); dF (235.3 MHz; CDCl3; CFCl3) -74.0 (s, 3 F);
dH (250 MHz; CDCl3; Me4Si) 2.41 (s, 3 H), 2.84 (s, 1 H), 3.20 (d,
J 1.0, 1 H), 7.28 (d, J 8.0, 2 H), 7.41 (m, 3 H), 7.60 (d, J 7.0, 2 H),
7.71 (d, J 8.0, 2 H); dC (62.9 MHz; CDCl3; Me4Si) 21.5, 34.2 (d, J
2.5), 51.9 (q, J 36.5), 122.6 (q, J 278.0), 126.7, 128.0, 128.3, 129.6,
130.4, 131.2, 135.4, 144.9. 100% ee determined by chiral HPLC
(chiralcel OD-H column, hexane : isopropanol 90 : 10, flow rate 1
mL min-1): t = 11.2 min (rac. t = 11.2 and 17.0 min).
According to the general procedure, the benzyloxysulfonamide
(R)-4b (250 mg, 0.62 mmol) was reacted with ammonium formate
(117 mg, 1.86 mmol, 3.0 equiv) and Pd/C (10%, 33 mg, 0.03 mmol,
0.05 equiv) in methanol (4 mL) for 2 h. Chromatography on
silica gel (PE : Et2O 2 : 1) yielded the b-hydroxysulfonamide (R)-
5b (169 mg, 89%) as a white solid (Found: [M+◦Na]+, 334.0702.
C12H16F3NNaO3S requires 334.0701); mp 62–63 C (from Et2O–
PE); [a]2D0 +31 (c 0.99 in CHCl3); dF NMR (235.3 MHz; CDCl3;
CFCl3) -79.1 (s, 3 F); dH (250 MHz; CDCl3; Me4Si) 0.95 (t, J 7.5,
3 H), 1.77 (m, 2 H), 2.43 (s, 3 H), 3.09 (dd, J 6.0 and 14.0, 1 H),
3.17 (dd, J 9.0 and 14.0, 1 H), 3.38 (br s, 1 H), 5.38 (dd, J 6.0 and
7.5, 1 H), 7.32 (d, J 8.0, 2 H), 7.75 (d, J 8.0, 2 H); dC (62.9 MHz;
CDCl3; Me4Si) 6.9, 21.4, 25.4, 44.6, 74.3 (q, J 27.0), 125.7 (q, J
287.0), 127.0, 129.9, 135.9, 144.1.
(-)-(S)-2-Ethyl-N-tosyl-2-trifluoromethylaziridine (S)-6b
According to the general procedure,
a solution of b-
hydroxysulfonamide (R)-5b (146 mg, 0.47 mmol) was reacted with
DEAD (112 mL, 0.71 mmol, 1.5 equiv), PPh3 (185 mg, 0.71 mmol,
1.5 equiv) and triethylamine (164 mL, 1.18 mmol, 2.5 equiv) in
THF (3 mL) for 3 h 30. Purification by chromatography on silica
gel (PE : Et2O 3 : 1) afforded the aziridine (S)-6b (110 mg, 81%)
as a white solid (Found: [M+Na]+, 316.0597. C12H14F3NNaO2S
(-)-(R)-3-Benzylamino-1,1,1-trifluoro-2-phenylpropan-2-ol (R)-5c
◦
A suspension of amino ether (R)-4c (436 mg, 1.30 mmol),
tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.065 mmol,
0.05 equiv) and potassium carbonate (539 mg, 3.90 mmol, 3 equiv)
in absolute ethanol (10 mL) was heated at reflux, under Ar,
for 40 min. The reaction mixture was cooled to rt and filtered
requires 316.0595). mp 44–45 C (from Et2O–PE); [a]2D0 -19 (c
0.99 in CHCl3); dF NMR (235.3 MHz; CDCl3; CFCl3) -73.7 (s,
3 F); dH (250 MHz; CDCl3; Me4Si) 1.25 (td, J 1.5 and 7.5, 3 H),
2.35 (q, J 7.5, 2 H), 2.45 (s, 3 H), 2.55 (s, 1 H), 2.73 (d, J 1.5, 1 H),
7.35 (d, J 8.0, 2 H), 7.85 (d, J 8.0, 2 H); dC (62.9 MHz; CDCl3;
1164 | Org. Biomol. Chem., 2011, 9, 1160–1168
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Me4Si) 11.2, 20.2, 21.6, 35.1 (d, J 2.0), 50.4 (q, J 35.0), 123.2 (q, J
279.0), 127.6, 129.7, 136.5, 144.8.
(S)-7b (80 mg, 93%) as a white solid (Found: [M+Na]+, 334.0694.
C12H16F3NNaO3S requires 334.0701); mp 140 C (from EtOAc–
◦
PE); [a]2D0 -1 (c 0.91 in CHCl3); dF NMR (235.3 MHz; CDCl3;
CFCl3) d -74.0 (s, 3 F); dH (250 MHz; CDCl3; Me4Si) 0.88 (t, J
7.5, 3 H), 1.82 (m, 2 H), 2.36 (s, 3 H), 2.80 (m, 1 H), 3.67 (dd, J
6.0 and 12.5, 1 H), 3.95 (d, J 12.5, 1 H), 5.44 (s, 3 H), 7.23 (d, J
8.0, 2 H), 7.71 (d, J 8.0, 2 H); dC (62.9 MHz; CDCl3; Me4Si) 7.4,
21.5, 24.4, 61.4, 65.2 (q, J 25.0), 125.3 (q, J 288.0), 126.9, 129.6,
138.3, 143.8.
(-)-(S)-N-Benzyl-2-phenyl-2-trifluoromethylaziridine (S)-6c
A solution of triphenylphosphine (759 mg, 2.89 mmol, 4 equiv)
and carbon tetrachloride (698 mL, 7.23 mmol, 10 equiv) in
acetonitrile (2 mL) was stirred at rt and under Ar for 1 h. A solution
of b-amino alcohol (R)-5c (213 mg, 0.72 mmol) in acetonitrile
(3 mL) was then added to the reaction mixture followed by the
addition of triethylamine (504 mL, 3.62 mmol, 5 equiv). The
reaction mixture was stirred for additional 4 h and was then
concentrated under reduced pressure. Purification of the residue
by chromatography on silica gel (PE : Et2O 7 : 1, solid deposit)
afforded the aziridine (S)-6c (171 mg, 80%) as a colorless oil
(Found: [M+Na]+, 300.0982. C16H14F3NNa requires 300.0976);
[a]2D0 -19 (c 0.92 in CHCl3); dF (235.3 MHz; CDCl3; CFCl3) -72.9
(s, 3 F); dH (250 MHz; CDCl3; Me4Si) 2.00 (s, 1 H), 2.62 (s, 1 H),
3.00 (d, J 14.0, 1 H), 3.57 (d, J 14.0, 1 H), 7.28 (m, 5 H), 7.38 (m,
5 H); dC (62.9 MHz; CDCl3; Me4Si) 35.2, 48.1 (q, J 35.0), 57.8,
124.5 (q, J 276.0), 127.1, 127.6, 128.3, 128.4, 129.1, 129.5, 131.7,
138.4.
(-)-(S)-2-Benzylamino-3,3,3-trifluoro-2-phenylpropan-1-ol (S)-7c
A suspension of aziridine (S)-6c (123 mg, 0.44 mmol) in a
mixture of HClO4–H2O (0.75 mL/2 mL) was heated at 90 ◦C
for 1 h 30. The reaction mixture was then cooled to rt, diluted
with Et2O and hydrolyzed with a sat. aq. sol. of Na2CO3. The
organic layer was extracted, washed with brine, dried (MgSO4)
and concentrated under reduced pressure to give the b-amino
alcohols (R)-5c and (S)-7c as a 10 : 90 mixture (determined by
19F NMR). Chromatography (PE : EtOAc 15 : 1) afforded first the
minor b-amino alcohol (R)-5c (4 mg, 3%, 92% ee determined by
chiral HPLC, chiralpak IC column, hexane : isopropanol 90 : 10,
flow rate 0.5 mL min-1: tminor = 9.5 min, tmajor = 10.3 min) as a
colorless oil, and then the major b-amino alcohol (S)-7c (102 mg,
78%) as a white solid (Found: [M+Na]+, 318.1079. C16H16F3NNaO
General procedure for the preparation of b-amino alcohol (S)-7a,b
by ring opening of N-tosylaziridines (S)-6a,b with hydroxyl anion
◦
requires 318.1082); mp 73 C (from EtOAc–PE); [a]2D0 -8 (c 0.77
A solution of aziridine (S)-6a,b and NaOH (5.5 equiv) in a
mixture of t-BuOH–H2O (1 : 5) was heated at reflux. After the
complete disappearance of aziridine, the reaction mixture was
cooled to rt, acidified with HCl 10% and extracted with CH2Cl2.
The organic layer was washed with brine, dried (MgSO4) and
concentrated under reduced pressure. Purification of the residue
by recrystallisation or by chromatography on silica gel afforded
the b-amino alcohol (S)-7a,b.
in CHCl3); dF (235.3 MHz; CDCl3; CFCl3) -68.7 (s, 3 F); dH (250
MHz; CDCl3; Me4Si) 2.38 (br s, 2 H), 3.71 (s, 2 H), 3.80 (dd, J 1.5
and 12.0, 1 H), 4.16 (d, J 12.0, 1 H), 7.26–7.44 (m, 8 H), 7.63 (d,
J 7.0, 2 H); dC (62.9 MHz; CDCl3; Me4Si) 46.7, 65.6, 67.2 (q, J
23.5), 126.8 (q, J 291.0), 127.2, 127.5, 127.9, 128.5, 128.7, 134.5,
139.8. 97% ee determined by chiral HPLC (chiralpak IC column,
hexane : isopropanol 90 : 10, flow rate 0.5 mL min-1): tminor = 11.9
min, tmajor = 13.5 min.
(+)-(S)-3,3,3-Trifluoro-2-phenyl-2-tosylaminopropan-1-ol (S)-7a
General procedure for the ring opening of N-tosylaziridines
S)-6a,b with amines
According to the general procedure, aziridine (S)-6a (125 mg,
0.37 mmol) was reacted with NaOH (80 mg, 2.03 mmol, 5.5 equiv)
in a mixture of t-BuOH (3 mL) and H2O (15 mL) for 26 h to give the
b-amino alcohols (R)-5a : (S)-7a as a 3 : 97 mixture (determined
by 19F NMR). Recrystallisation from CH2Cl2–PE afforded the
b-amino alcohol (S)-7a (110 mg, 84%) as a white solid (Found:
[M+Na]+, 382.0694. C16H16F3NNaO3S requires 382.0701); mp 155
◦C (from CH2Cl2–PE); [a]2D0 +28 (c 0.94 in CHCl3); dF (235.3 MHz;
CDCl3; CFCl3) -73.6 (s, 3 F); dH (250 MHz; CDCl3; Me4Si) 2.43
(s, 3 H), 2.97 (m, 1 H), 4.26 (br d, J 13.0, 1 H), 4.47 (br d, J 13.0,
1 H), 5.46 (br s, 1 H), 7.22–7.41 (m, 7 H), 7.66 (d, J 8.0, 2 H); dC
NMR (62.9 MHz; CD2Cl2; Me4Si) 21.6, 63.1 (d, J 8.0), 68.4 (q, J
25.5), 125.1 (q, J 287.0), 127.5, 127.9, 128.7, 129.4, 129.9, 133.0,
138.2, 144.7. 100% ee determined by chiral HPLC (chiralpak IC
column, hexane : isopropanol 90 : 10, flow rate 1 mL min-1): t =
24.3 min (rac. t = 24.3 and 26.0 min)
A solution of aziridine (S)-6a,b and amine (1.2 or 2.0 equiv) in
acetonitrile was heated at reflux. After the complete disappearance
of aziridine (S)-6a,b, the reaction mixture was cooled to rt and con-
centrated under reduced pressure. Purification by chromatography
on silica gel or recrystallisation afforded the b-diamines (S)-8a,b,
(S)-9a,b, (S)-10a,b or (S)-11a,b.
(+)-(S)-N-Benzyl-3,3,3-trifluoro-2-phenyl-2-
tosylaminopropylamine (S)-8a
According to the general procedure, aziridine (S)-6a (102 mg,
0.30 mmol) was reacted with benzylamine (39 mL, 0.36 mmol,
1.2 equiv) in MeCN (3 mL) for 20 h. Chromatography (PE : EtOAc
5 : 1) afforded the b-diamine (S)-8a (120 mg, 90%) as a white solid
(Found [M+H]+, 449.1511. C23H24F3N2O2S requires 449.1511); mp
122 ◦C (from EtOAc–PE); [a]D20 +61 (c 1.02 in CHCl3); dF (235.3
MHz; CDCl3; CFCl3) -69.3 (s, 3 F); dH (250 MHz; CDCl3; Me4Si)
2.39 (s, 3 H), 3.03 (d, J 13.0, 1 H), 3.34 (d, J 13.0, 1 H), 3.78 (s, 2
H), 7.16–7.41 (m, 12 H), 7.54 (d, J 8.0, 2 H), 2 NH not detected;
dC (62.9 MHz; CDCl3; Me4Si) 21.5, 53.8, 54.1, 66.3 (q, J 26.5),
125.2 (q, J 288.0), 127.0, 127.4, 128.1, 128.2, 128.5, 128.6, 129.1,
134.1, 139.0, 139.2, 143.1. 100% ee determined by chiral HPLC
(-)-(S)-2-Tosylamino-2-trifluoromethylbutan-1-ol (S)-7b
According to the general procedure, aziridine (S)-6b (81 mg,
0.28 mmol) was reacted with NaOH (61 mg, 1.54 mmol, 5.5 equiv.)
in a mixture of t-BuOH (2 mL) and H2O (10 mL) for 21 h.
Chromatography (PE : EtOAc 2 : 1) afforded the b-amino alcohol
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(chiralpak IC column, hexane : isopropanol 90 : 10, flow rate 1 mL
min-1): t = 18.6 min (rac. t = 16.4 and 18.6 min)
5 H), 7.62 (d, J 8.0, 2 H); dC (62.9 MHz; CDCl3; Me4Si) 7.2, 21.4,
23.0, 24.2, 48.4, 58.3, 62.4 (q, J 25.5), 125.6 (q, J 288.5), 126.7,
126.9, 127.5, 128.7, 129.2, 139.5, 142.9, 143.8.
(+)-(S)-N-Benzyl-2-tosylamino-2-trifluoromethylbutylamine
(S)-8b
(+)-(S)-1,1,1-Trifluoro-3-morpholin-4-yl-2-phenyl-N-tosylpropan-
2-amine (S)-10a
According to the general procedure, aziridine (S)-6b (77 mg,
0.26 mmol) was reacted with benzylamine (34 mL, 0.31 mmol,
1.2 equiv) in MeCN (3 mL) for 22 h. Chromatography (PE : EtOAc
5 : 1) afforded the b-diamine (S)-8b (101 mg, 96%) as a colorless
oil (Found: [M+H]+, 401.1502. C19H24F3N2O2S requires 401.1511);
[a]2D0 +12 (c 1.02 in CHCl3); dF (235.3 MHz; CDCl3; CFCl3) -73.4
(s, 3 F); dH (250 MHz; CDCl3; Me4Si) 0.90 (t, J 7.5, 3 H), 1.74
(sext, J 7.5, 1 H), 2.12 (sext, J 7.5, 1 H), 2.39 (s, 3 H), 2.58 (br
d, J 13.5, 1 H), 3.03 (d, J 13.5, 1 H), 3.75 (d, J 13.5, 1 H), 3.81
(d, J 13.5, 1 H), 7.20–7.35 (m, 7 H), 7.68 (d, J 8.0, 2 H), 2 NH
not detected; dC (62.9 MHz; CDCl3; Me4Si) 7.3, 21.4, 23.1, 50.0,
53.9, 62.7 (q, J 25.5), 125.9 (q, J 288.5), 126.7, 127.4, 128.2, 128.6,
129.2, 139.1, 139.3, 143.0.
According to the general procedure, aziridine (S)-6a (102 mg,
0.30 mmol) was reacted with morpholine (32 mL, 0.36 mmol,
1.2 equiv.) in MeCN (3 mL) for 22 h. Chromatography (PE : EtOAc
4 : 1) afforded the b-diamine (S)-10a (119 mg, 93%) as a white solid
(Found: ◦[M+H]+, 429.1465. C20H24F3N2O3S requires 429.1460);
mp 114 C (from EtOAc–PE); [a]2D0 +38 (c 1.04 in CHCl3); dF
(235.3 MHz; CDCl3; CFCl3) d -69.9 (s, 3 F); dH (250 MHz; CDCl3;
Me4Si) 2.32 (s, 3 H), 2.48 (m, 4 H), 2.95 (d, J 14.5, 1 H), 3.07 (d,
J 14.5, 1 H), 3.58 (m, 4 H), 6.40 (br s, 1 H), 7.13–7.21 (m, 5 H),
7.32 (d, J 7.0, 2 H), 7.51 (d, J 8.0, 2 H); dC (62.9 MHz; CDCl3;
Me4Si) 21.4, 55.0, 64.3, 65.8 (q, J 26.0), 67.0, 125.0 (q, J 287.5),
127.0, 127.5, 128.0, 128.5, 129.1, 134.2, 139.1, 143.2.
(+)-(1S,1¢R)-N-[(1¢-Phenyl)ethyl]-3,3,3-trifluoro-2-phenyl-2-
tosylaminopropylamine (S)-9a
(+)-(S)-1-Morpholin-4-yl-N-tosyl-2-trifluoromethylbutan-2-amine
(S)-10b
According to the general procedure, aziridine (S)-6a (59 mg,
0.173 mmol) was reacted with (R)-(+)-a-methylbenzylamine
(27 mL, 0.207 mmol, 1.2 equiv) in MeCN (3 mL) for 24 h. Re-
crystallisation (PE : AcOEt) afforded the b-diamine (S)-9a (76 mg,
95%) as a white solid (Found: [M+H]+, 463.1650. C24H26F3N2O2S
According to the general procedure, aziridine (S)-6b (78 mg,
0.27 mmol) was reacted with morpholine (28 mL, 0.32 mmol,
1.2 equiv) in MeCN (3 mL) for 15 h. Chromatography (PE : EtOAc
2 : 1) afforded the b-diamine (S)-10b (99 mg, 97%) as a white solid
(Found: ◦[M+H]+, 381.1464. C16H24F3N2O3S requires 381.1460);
mp 112 C (from EtOAc–PE); [a]2D0 +34 (c 1.04 in CHCl3); dF
(235.3 MHz; CDCl3; CFCl3) -73.4 (s, 3 F); dH (250 MHz; CDCl3;
Me4Si) 0.94 (t, J 7.5, 3 H), 1.77 (sext, J 7.5, 1 H), 2.12 (sext, J 7.5,
1 H), 2.42 (s, 3 H), 2.54 (br d, J 15.0, 1 H), 2.64 (m, 4 H), 2.82 (d,
J 15.0, 1 H), 3.71 (m, 4 H), 6.29 (br s, 1 H), 7.29 (d, J 8.0, 2 H),
7.75 (d, J 8.0, 2 H); dC (62.9 MHz; CDCl3; Me4Si) 7.4, 21.4, 23.4,
54.8, 59.9, 62.1 (q, J 25.5), 67.2, 125.6 (q, J 288.0), 126.8, 129.3,
139.1, 143.2.
◦
requires 463.1667); mp 150 C (from Et2O–PE); [a]2D0 +40 (c 1.0
in CHCl3); dF (235.3 MHz; CDCl3; CFCl3) -68.9 (s, 3 F); dH (250
MHz; CDCl3; Me4Si) 1.38 (d, J 6.5, 3 H), 2.40 (s, 3 H), 2.79 (d, J
13.5, 1 H), 3.24 (d, J 13.5, 1 H), 3.74 (q, J 6.5, 1 H), 7.12–7.39 (m, 12
H), 7.48 (d, J 8.0, 2 H), 2 NH not detected; dC (62.9 MHz; CDCl3;
Me4Si) 21.5, 24.0, 53.0, 58.2, 65.9 (q, J 26.5), 125.3 (q, J 288.5),
126.7, 127.0, 127.3, 127.4, 128.1, 128.4, 128.7, 129.0, 139.1, 143.0,
143.9. An analytical sample of (S)-9a was crystallized in Et2O–PE.
Selected crystallographic data: C24H25F3N2O2S, FW = 462.52, T =
˚
100(2) K, l = 0.71073 A, Orthorhombic, P21 21 21, a = 9.6263(13)
(-)-(S)-3,3,3-Trifluoro-N,2-diphenyl-2-tosylaminopropylamine
(S)-11a
3
˚
˚
˚
˚
A, b = 14.1765(14) A, c = 16.473(2) A, V = 2248.1(5) A , Z =
4, crystal size = 0.4 ¥ 0.1 ¥ 0.1 mm3, reflections collected = 6529,
independent reflections = 5364, R (int) = 0.0452, parameters = 291,
R1 [I > 2s(I)] = 0.0420, wR2 [I > 2s(I)] = 0.0978, R1 (all data) =
0.0566, wR2 (all data) = 0.1031. Full crystallographic data for this
compound have been deposited with the CCDC, reference number
779933.‡
According to the general procedure, aziridine (S)-6a (127 mg,
0.37 mmol) was reacted with aniline (68 mL, 0.75 mmol, 2.0 equiv)
in MeCN (2 mL) for 48 h. Chromatography (PE : Et2O 3 : 1)
afforded the b-diamine (S)-11a (156 mg, 99%) as a colorless oil
(Found: [M+H]+, 435.1336. C22H22F3N2O2S requires 435.1354);
[a]2D0 -20 (c 0.3 in CHCl3); dF (235.3 MHz; CDCl3; CFCl3) -72.4
(s, 3 F); dH (250 MHz; CDCl3; Me4Si) 2.38 (s, 3 H), 3.68 (br s, 1
H), 3.90 (d, J 14.0, 1 H), 4.03 (d, J 14.0, 1 H), 5.79 (s, 1 H), 6.49 (d,
J 8.0, 2 H), 6.74 (t, J 7.5, 1 H), 7.09–7.18 (m, 4 H), 7.23–7.35 (m, 3
H), 7.49 (d, J 7.0, 2 H), 7.59 (d, J 8.5, 2 H); dC (62.9 MHz; CDCl3;
Me4Si) 21.5, 47.6, 67.3 (q, J 26.5), 113.5, 118.7, 124.9 (q, J 287.5),
127.0, 127.5, 128.5, 129.2, 129.3, 133.2, 138.5, 143.5, 146.8.
(+)-(1S,1¢R)-N-[(1¢-Phenyl)ethyl]-2-tosylamino-2-
trifluoromethylbutylamine (S)-9b
According to the general procedure, aziridine (S)-6b (62 mg,
0.213 mmol) was reacted with (R)-(+)-a-methylbenzylamine
(33 mL, 0.256 mmol, 1.2 equiv) in MeCN (3 mL) for 24 h.
Chromatography (PE : Et2O 3 : 1) afforded the b-diamine (S)-
9b (87 mg, 98%) as a white solid (Found: [M+H]+, 415.1680.
C20H26F3N2O2S requires 415.1667); mp 91 ◦C (from Et2O–PE);
[a]2D0 +18 (c 0.84 in CHCl3); dF (235.3 MHz; CDCl3; CFCl3) -73.4
(s, 3 F); dH (250 MHz; CDCl3; Me4Si) 0.70 (t, J 7.5, 3 H), 1.39 (d,
J 6.5, 3 H), 1.50 (br s, 1 H), 1.73 (sext, J 7.5, 1 H), 1.92 (sext, J 7.5,
1 H), 2.37 (d, J 13.0, 1 H), 2.40 (s, 3 H), 2.97 (d, J 13.0, 1 H), 3.75
(q, J 6.5, 1 H), 6.38 (br s, 1 H), 7.21 (d, J 8.0, 2 H), 7.22–7.36 (m,
(-)-(S)-1-Phenyl-2-tosylamino-2-trifluoromethylbutylamine
(S)-11b
According to the general procedure, aziridine (S)-6b (99 mg,
0.34 mmol) was reacted with aniline (61 mL, 0.67 mmol, 2.0 equiv)
in MeCN (2 mL) for 40 h. Chromatography (PE : Et2O 3 : 1)
afforded the b-diamine (S)-11b (128 mg, 98%) as a colorless oil
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(Found: [M+H]+, 387.1339. C18H22F3N2O2S requires 387.1354);
[a]2D0 -47 (c 0.1 in CHCl3); dF (235.3 MHz; CDCl3; CFCl3) -73.9
(s, 3 F); dH (250 MHz; CDCl3; Me4Si) 1.00 (t, J 7.5, 3 H), 1.89
(sext, J 7.5, 1 H), 2.14 (sext, J 7.5, 1 H), 2.41 (s, 3 H), 3.45 (d, J
14.0, 1 H), 3.54 (d, J 14.0, 1 H), 3.80 (br s, 1 H), 5.56 (s, 1 H), 6.63
(d, J 7.5, 2 H), 6.79 (t, J 7.5, 1 H), 7.19 (dd, J 7.5 and 8.5, 2 H),
7.27 (d, J 8.0, 2 H), 7.75 (d, J 8.5, 2 H); dC (62.9 MHz; CDCl3;
Me4Si) 7.6, 21.5, 23.7, 46.0, 64.2 (q, J 25.5), 113.8, 118.8, 125.7 (q,
J 288.5), 126.9, 129.3, 129.5, 138.7, 143.6, 147.3.
Acknowledgements
We thank CNRS and Re´gion Champagne-Ardenne for a fel-
lowship to one of us (J.N.). This project has been supported
(programme GLYCOVAL) by the “Contrat de Plan Etat-Re´gion”
(Ministe`re de la Recherche, Re´gion Champagne-Ardenne, Ville de
Reims). We express our thanks to Aure´lien Lebrun for NMR anal-
yses, Sylvie Lanthony for the chiral HPLC analyses, Dominique
Harakat for HRMS analyses and Re´gis Guillot (ICMMO, Orsay,
universite´ Parix XI) for X-ray data collection.
General procedure for the ring opening of N-tosylaziridines
(S)-6a,b with sulfonamide
Notes and references
1 (a) K. Uneyama, in Organofluorine Chemistry, Blackwell publishing
Ltd, Oxford, 2006; (b) J. P. Be´gue´ and D. Bonnet-Delpon, in Bioor-
ganic and Medicinal Chemistry of Fluorine, Wiley-VCH, Weinheim,
2008.
2 For reviews on fluorinated N-containing compounds, see: (a) X. L.
Qiu, W. D. Meng and F. L. Qing, Tetrahedron, 2004, 60, 6711; (b) J. P.
Be´gue´, D. Bonnet-Delpon, B. Crousse and J. Legros, Chem. Soc. Rev.,
2005, 34, 562; (c) R. Smits, C. D. Cadimaco, K. Burger and B. Koksch,
Chem. Soc. Rev., 2008, 37, 1727; (d) S. Fustero, J. F. Sanz-Cervera, J. L.
Acena and M. Sanchez-Rosello, Synlett, 2009, (04), 525.
A
suspension of aziridine (S)-6a,b, p-toluenesulfonamide
(1.2 equiv) and potassium carbonate (1.2 equiv) in acetonitrile was
heated at reflux. After the complete disappearance of aziridine (S)-
6a,b, the reaction mixture was cooled to rt, diluted with CH2Cl2
and washed with water. The organic layer was extracted, dried
(MgSO4) and concentrated under reduced pressure. Purification by
chromatography on silica gel (PE : EtOAc) afforded the b-diamine
(S)-12a,b.
3 For an overview of aziridine chemistry, see: (a) D. Tanner, Angew.
Chem., Int. Ed. Engl., 1994, 33, 599; (b) H. M. I. Osborn and J. Sweeney,
Tetrahedron: Asymmetry, 1997, 8, 1693; (c) J. B. Sweeney, Chem. Soc.
Rev., 2002, 31, 247; (d) A. K. Yudin, in Aziridines and Epoxides in
Organic Synthesis, Wiley-VCH, Weinheim, 2006; (e) G. SH. Singh, M.
D’Hooghe and N. De Kimpe, Chem. Rev., 2007, 107, 2080; (f) H.
Pellissier, Tetrahedron, 2010, 66, 1509.
4 For reviews on aziridine ring opening, see: (a) W. McCoull and F. A.
Davis, Synthesis, 2000, (10), 1347; (b) X. E. Hu, Tetrahedron, 2004,
60, 2701; (c) M. Pineschi, Eur. J. Org. Chem., 2006, 19, 4979; (d) T. X.
Me´tro, B. Duthion, D. Gomez Pardo and J. Cossy, Chem. Soc. Rev.,
2010, 39, 89; (e) P. Lu, Tetrahedron, 2010, 66, 2549.
5 For the preparation of optically active aziridines bearing a triflu-
oromethyl group, see: (a) T. Katagiri, H. Ihara, M. Takahashi, S.
Kashino, K. Furuhashi and K. Uneyama, Tetrahedron: Asymmetry,
1997, 8, 2933; (b) P. Davoli, A. Forni, C. Franciosi, I. Moretti and F.
Prati, Tetrahedron: Asymmetry, 1999, 10, 2361; (c) A. Volonterio, P.
Bravo, W. Panzeri, C. Pesenti and M. Zanda, Eur. J. Org. Chem., 2002,
15, 3336; (d) T. Akiyama, S. Ogi and K. Fuchibe, Tetrahedron Lett.,
2003, 44, 4011; (e) Y. Yamauchi, T. Kawate, H. Itahashi, T. Katagiri
and K. Uneyama, Tetrahedron Lett., 2003, 44, 6319; (f) Y. Yamauchi,
T. Kawate, T. Katagiri and K. Uneyama, Tetrahedron, 2003, 59, 9839;
(g) T. Katagiri and K. Uneyama, Chirality, 2003, 15, 4; (h) R. Maeda,
K. Ooyama, R. Anno, M. Shiosaki, T. Azema and T. Hanamoto, Org.
Lett., 2010, 12, 2548.
6 (a) K. Quinze, A. Laurent and P. Mison, J. Fluorine Chem., 1989,
44, 233; (b) T. Katagiri, M. Takahashi, Y. Fujiwara, H. Ihara and K.
Uneyama, J. Org. Chem., 1999, 64, 7323; (c) B. Crousse, S. Narizuka,
D. Bonnet-Delpon and J. P. Be´gue´, Synlett, 2001, (05), 679; (d) F.
Palacios, A. M. Ochoa de Retana and J. M. Alonso, J. Org. Chem.,
2006, 71, 6141; (e) G. Rinaudo, S. Narizuka, N. Askari, B. Crousse and
D. Bonnet-Delpon, Tetrahedron Lett., 2006, 47, 2065.
(-)-(S)-3,3,3-Trifluoro-2-phenyl-2-tosylamino-N-tosylpropylamine
(S)-12a
According to the general procedure, aziridine (S)-6a (102 mg,
0.30 mmol) was reacted with p-toluenesulfonamide (61 mg,
0.36 mmol, 1.2 equiv) and potassium carbonate (49 mg,
0.36 mmol, 1.2 equiv) in MeCN (3 mL) for 22 h. Chromatography
(PE : EtOAc 3 : 2) afforded the b-diamine (S)-12a (130 mg, 85%)
as a white solid (Found: [M+◦Na]+, 535.0952. C23H23F3N2NaO4S2
requires 535.0949); mp 149 C (from EtOAc–PE); [a]2D0 -25 (c
0.95 in CHCl3); dF (235.3 MHz; CDCl3; CFCl3) -72.6 (s, 3 F);
dH (250 MHz; CDCl3; Me4Si) 2.42 (s, 3 H), 2.45 (s, 3 H), 3.77
(d, J 7.5, 2 H), 5.28 (t, J 7.5, 1 H), 5.58 (s, 1 H), 7.19–7.39 (m,
9 H), 7.56 (d, J 8.5, 2 H), 7.71 (d, J 8.5, 2 H); dC (62.9 MHz;
CDCl3; Me4Si) 21.4, 45.3, 66.7 (q, J 27.0), 124.2 (q, J 288.0),
127.0, 127.3, 128.4, 129.1, 129.4, 129.8, 132.2, 136.3, 137.8, 143.7,
143.8. 100% ee determined by chiral HPLC (chiralpak IC column,
hexane : isopropanol 75 : 25, flow rate 1 mL min-1): t = 28.7 min
(rac. t = 28.7 and 36.0 min)
(-)-(S)-2-Tosylamino-N-tosyl-2-trifluoromethylbutylamine
(S)-12b
According to the general procedure, aziridine (S)-6b (92 mg,
0.31 mmol) was reacted with p-toluenesulfonamide (64 mg,
0.38 mmol, 1.2 equiv) and potassium carbonate (52 mg,
0.38 mmol, 1.2 equiv) in MeCN (3 mL) for 22 h. Chromatography
(PE : EtOAc 2 : 1) afforded the b-diamine (S)-12b (110 mg, 76%)
as a white solid (Found: [M+Na]+, 487.0957. C19H23F3N2NaO4S2
requires 487.0949); mp 169 ◦C (from EtOAc–PE); [a]2D0 -71 (c 0.94
in CHCl3); dF (235.3 MHz; CDCl3; CFCl3) -73.5 (s, 3 F); dH (250
MHz; CDCl3; Me4Si) 1.00 (t, J 7.0, 3 H), 1.99 (m, 2 H), 2.42 (s, 3
H), 2.45 (s, 3 H), 3.25 (dd, J 10.0 and 14.0, 1 H), 3.40 (dd, J 5.5
and 14.0, 1 H), 5.36 (s, 1 H), 5.53 (dd, J 5.5 and 10.0, 1 H), 7.26
(d, J 8.0, 2 H), 7.35 (d, J 8.0, 2 H), 7.67 (d, J 8.0, 2 H), 7.78 (d,
J 8.0, 2 H); dC NMR (62.9 MHz; CDCl3; Me4Si) 7.2, 21.5, 26.1,
43.0, 64.2 (q, J 26.0), 124.9 (q, J 288.5), 126.7, 126.9, 129.3, 129.9,
136.6, 138.4, 143.4, 143.7.
7 J. Nonnenmacher, F. Massicot, F. Grellepois and C. Portella, J. Org.
Chem., 2008, 73, 7990.
8 For other preparations of enantio-enriched or enantiopure quater-
nary a-trifluoromethyl a-hydroxy(alkoxy)aldehydes, see: (a) F. J. A.
Hundscheid, V. K. Tandon, P. H. F. M. Rouwette and A. M. Van
Leusen, Tetrahedron, 1987, 43, 5073; (b) C. Pareja, E. Martin-Zamora,
R. Fernandez and J. M. Lassaletta, J. Org. Chem., 1999, 64, 8846;
(c) R. Fernandez, E. Martin-Zamora, C. Pareja, J. Vazquez, E. Diez,
A. Monge and J. M. Lassaletta, Angew. Chem., Int. Ed., 1999, 37,
3428; (d) R. Pedrosa, S. Sayalero, M. Vicente and A. Maestro, J. Org.
Chem., 2006, 71, 2177; (e) F. Massicot, N. Monnier-Benoit, N. Deka,
R. Plantier-Royon and C. Portella, J. Org. Chem., 2007, 72, 1174.
9 W. B. Jennings and C. J. Lovely, Tetrahedron, 1991, 47, 5561.
10 (a) O. Mitsunobu, Synthesis, 1981, 1; (b) T. Y. S. But and P. H. Toy,
Chem.–Asian J., 2007, 2, 1340; (c) C. Kumara Swany, N. N. Bhuvan
Kumar, E. Balaraman and K. V. P. Pavan Kumar, Chem. Rev., 2009,
109, 2551.
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11 Only two publications described the intramolecular Mitsunobu re-
action of b-amino-alcohols derivatives containing a tertiary alcohol
function: (a) P. Li, C. D. Evans and M. M. Joullie´, Org. Lett., 2005, 7,
5325; (b) J. J. Caldwell and D. Craig, Angew. Chem., Int. Ed., 2007, 46,
2631.
12 For another strategy for the synthesis of b-amino alcohols and
b-diamines containing a quaternary trifluoromethyl group, see: F.
Huguenot and T. Brigaud, J. Org. Chem., 2006, 71, 7075.
13 See for example: G. Hughes, P. O’Shea, J. Goll, D. Gauvreau and J.
Steele, Tetrahedron, 2009, 65, 3189.
16 J. Nonnenmacher, F. Grellepois and C. Portella, Eur. J. Org. Chem.,
2009, 22, 3726.
17 ee = 97% for the aminoalcohol (R)-5c refects the enantiopurity of the
starting ether (R)-4c, no racemization occurred during the deprotection
step.
18 T. Kametani, Y. Kigawa and M. Ihara, Tetrahedron, 1979, 35,
313.
19 The synthesis of racemic N-alkyl-2-aryl-2-trifluoromethyl aziridines by
cyclisation of the corresponding b-amino alcohol using Ph3PCl2 has
been reported during the reviewing process of this manuscript, see: E.
Obijalska, G. Mloston, A. Linden and H. Heimgartner, Helv. Chim.
Acta, 2010, 93, 1725.
14 The partial racemization of the aziridinium salt through its intercon-
version with the carbenium ion was ruled out, since a small amount
of enantiomerically pure aziridine (S)-6a (16%, ee = 100%) was also
recovered.
20 As expected, the ring opening of the Bn-aziridine (S)-6c with hydroxide
ion or amine was unsuccessful.
15 For a similar example of acid hydrolysis of N-tosyl-2-phenylaziridine-
2-carboxylate at C-2, see: P. Dauban and R. H. Dodd, Tetrahedron
Lett., 1998, 39, 5739.
21 Heating of aziridines (S)-6a,b with aniline (1.2 equiv) under micro-wave
irradiation (150 ◦C) significantly reduced the reaction time (20–40 min)
without altering the yield.
1168 | Org. Biomol. Chem., 2011, 9, 1160–1168
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