Synthesis of (trifluoromethyl)aziridines in 1,1,1,3,3,3-hexafluoropropan-2-ol: First example of coupling reactions of fluoral, an amine and a diazo compound

Article abstract of DOI:10.1135/cccc20021359

The influence of solvent on the Yb(OTf)₃ or BF₃·Et₂O-catalyzed reaction of (trifluoromethyl)aldimines with ethyl diazoacetate has been investigated. The reaction of fluoral ethyl hemiacetal, an aromatic amine, and ethyl diazoacetate could be performed in 1,1,1,3,3,3-hexafluoropropan-2-ol to provide the corresponding (trifluoromethyl)aziridines.

Full text of DOI:10.1135/cccc20021359

Synthesis of (Trifluoromethyl)aziridines
1359
SYNTHESIS OF (TRIFLUOROMETHYL)AZIRIDINES IN
1
,1,1,3,3,3-HEXAFLUOROPROPAN-2-OL: FIRST EXAMPLE
OF COUPLING REACTIONS OF FLUORAL, AN AMINE AND
A DIAZO COMPOUND
1
2,
3
Maria Vittoria SPANEDDA , Benoit CROUSSE *, Satoru NARIZUKA
4
,
5
Dan ièle BONNET-DELPON * and Jean-Pierre BÉGUÉ
BioCIS, Centre d’Etudes Pharmaceutiques, rue J. B. Clément, Châtenay-Malabry, F-92296 Cedex,
1
2
France; e-mail: m-vittoria.spanedda@cep.u-psud.fr, benoit.crousse@cep.u-psud.fr,
3
satoru.narizuka@cgco.co.jp, 4 daniele.bonnet-delpon@cep.u-psud.fr,
jean-pierre.begue@cep.u-psud.fr
5
Received May 27, 2002
Accepted August 18, 2002
This paper is dedicated to the memory of Professor Miloš Hudlický.
Th e in fluen ce of solven t on th e Yb(OTf)3 or BF ·Et O-catalyzed reaction of (trifluoro-
3
2
m eth yl)aldim in es with eth yl diazoacetate h as been in vestigated. Th e reaction of fluoral
eth yl h em iacetal, an arom atic am in e, an d eth yl diazoacetate could be perform ed in
1
,1,1,3,3,3-h exafluoropropan -2-ol to provide th e correspon din g (trifluorom eth yl)aziridin es.
Keywords: Aziridines; Aziridination; Fluorine; Hexafluoropropan-2-ol; Im ines; Diazo com pounds.
Aziridin es are versatile buildin g blocks for th e syn th esis of a variety of bio-
logically im portan t com poun ds, such as am in o alcoh ols, un n atural am in o
1
acids an d n itrogen -con tain in g h eterocyclic com poun ds . A n um ber of
m eth ods are available for th e syn th esis of aziridin es. Th e sim plest approach
is eith er th e addition of a n itren e to an alken e, or th e addition of a carben e
2
to an im in e . In both cases tran sition m etals (copper, rh en ium ) h ave been
foun d to act as effective catalysts by favorin g th e form ation of th e n itren e
or carben e species. In th e case of reaction between eth yl diazoacetate (EDA)
an d im in es, Lewis acids such as BF ·Et O or AlCl are also excellen t catalysts
3
2
3
3
by in creasin g th e electroph ilicity of th e im in e .
Utilisation of th ese m eth ods for th e preparation of (triflu oro-
m eth yl)aziridin es h ad received n o atten tion before our recen tly reported
4
prelim in ary results . BF ·Et O, an d, to a lesser exten t, Yb(OTf) , appeared to
3
2
3
be good catalysts for th e n ucleoph ilic addition of eth yl diazoacetate to
Collect. Czech. Chem. Commun. (Vol. 67) (2002)
doi:10.1135/cccc20021359

1
360
Spanedda et al.:
(
trifluorom eth yl)im in es leadin g to 3-(trifluorom eth yl)aziridin e-2-carboxylic
4
a
acids . We n ow describe our effort to perform th e catalyzed couplin g reac-
tion s of a fluoral h em iacetal, am in es an d eth yl diazoacetate.
First, takin g in to accoun t th at Yb(OTf) -catalysed aziridin ation reaction s
3
can be perform ed in various solven ts, in cludin g aqueous an d protic, we
in vestigated th e in fluen ce of solven t on th e Yb(OTf) -catalysed aziridin -
3
ation of aldim in e 1a with EDA. Th e results are sum m arised in Sch em e 1
an d Table I.
Com pared to h exan e, n o solven t allowed an im provem en t of th e reaction
5
an d even wh en th e reaction was perform ed in alcoh ols , n o trace of
aziridin e could be detected. Due to its great electroph ilicity, th e fluorin ated
aldim in e 1a readily added EtOH an d MeOH to afford th e correspon din g
h em iam in al 3 isolated in quan titative yield. In order to avoid th is parasitic
reaction , EtOH was replaced by 1,1,1,3,3,3-h exafluoropropan -2-ol (HFIP),
wh ich is kn own to be a n on -n ucleoph ilic alcoh ol. Th e value of n ucleo-
ph ilicity of HFIP is –4.23 wh ereas th at of EtOH is con sidered th e zero refer-
6
en ce .
Th e reaction was perform ed with im in e 1a an d eth yl diazoacetate in th e
presen ce of Yb(OTf) as catalyst (10 m ole %) in HFIP, an d un der th ese con -
3
dition s a cis/trans m ixture of aziridin e 2a was obtain ed in h igh yield after
F3C
F3C
2
CO Et
10% Yb(OTf)3
+
N2CHCOOEt
N
N
PMP
PMP
PMP = 4-methoxyphenyl
1a
2a
SCHEME 1
TABLE I
Aziridin ation reaction s of fluoral im in e
En try
Solven t
Tim e, h
cis/trans
Recovered, %
Yield, %
1
2
3
4
h exan e
20
20
20
20
70/30
75/25
54/46
–
0
5
83
68
55
Et O
2
CH CN
14
0
3
MeOH or
EtOH
0a
a
1
00% yield of CF (OR)NH-PMP, R = Me, Et (3).
3
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Synthesis of (Trifluoromethyl)aziridines
1361
on ly 3 h . Th e reaction was also efficien t with oth er (trifluorom eth yl)ald-
im in es: from 1b an d 1c, aziridin es 2b an d 2c could be obtain ed in 85%
(
cis/trans = 64/36) an d 82% (cis/trans = 70/30) yields, respectively (Table II).
As expected, HFIP did n ot react with aldim in es an d, furth erm ore, its use as
solven t sign ifican tly im proved th e aziridin ation reaction (yield an d reac-
4
tion tim e) com pared to h exan e . Th is efficien cy prom pted us to also
in vestigate th is reaction in HFIP with BF ·Et O as catalyst (Sch em e 2 an d Ta-
3
2
ble II).
With BF ·Et O, th e aziridin ation was less effective in HFIP th an in eth er:
3
2
th e yields of aziridin es were sligh tly lower an d th e stereoselectivity was
lower (ca 65/35 in stead of 85/15 in eth er). Th e great im provem en t of th e re-
action with Yb(OTf) could be due to th e en h an cem en t of its Lewis acid
3
power th rough h ydrogen bon din g between th e sulfon ate fun ction an d
HFIP.
Th e th ree-com pon en t reaction s were th en in vestigated of fluoral eth yl
h em iacetal (4) usin g 4-m eth oxyan ilin e as am in e (0.95 equivalen t) un der
four system con dition s: 10% Yb(OTf) in h exan e an d in HFIP, 10% BF ·Et O
3
3
2
in eth er an d in HFIP (Sch em e 3 an d Table III). Th e reaction was perform ed
as a two-step on e-pot reaction . Th e first step of th ese reaction s was per-
form ed at room tem perature with or with out a dryin g agen t an d th e reac-
F3C
F3C
2
CO Et
10% catalyst
+
N2CHCOOEt
N
R
N
R
1
2
SCHEME 2
TABLE II
Aziridin ation reaction s of fluoral im in e in 1,1,1,3,3,3-h exafluoropropan -2-ol
Im in e
R
Catalyst
Tim e, h
Yield, %
cis/trans
1
1
1
1
1
1
a
b
c
a
b
c
PMP
Bn
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
BF ·Et O
3
90
85
82
88
73
64
57/43
64/36
70/30
60/40
64/36
66/33
1.5
18
1
Ph CH
2
PMP
Bn
3
2
BF ·Et O
1.5
24
3
2
Ph CH
BF ·Et O
3 2
2
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

1
362
Spanedda et al.:
tion was followed by 19F NMR. After disappearan ce of fluoral h em iacetal 4,
th e eth yl diazoacetate (1.5 equivalen ts) was added.
Th e two system s Yb(OTf) in h exan e an d BF ·Et O in eth er, provided on ly
3
3
2
traces of aziridin es 2a. Con versely, in HFIP, with both Yb(OTf)3 an d
BF ·Et O, aziridin es 2a were obtain ed in 65% (cis/trans = 55/45) an d 72%
3
2
(
cis/trans = 60/40) yields, respectively (Table III).
Th is essen tial in fluen ce of HFIP in th e form ation of aziridin es in th e
th ree-com pon en t reaction , com pared to its weak in fluen ce on th e reaction
of th e im in e 1a with EDA prom pted us to follow th e course of th ese se-
1
9
quen tial reaction s by F NMR. In eth er an d in h exan e, fluoral h em iacetal 4
reacted with th e am in e providin g a m ixture of several tetrah edral in term e-
1
9
diates ( F NMR, δ from –79 to –89 ppm ) with on ly a sm all am oun t of im in e
a (δ –71 ppm ). Th e form ation of 1a could n ot be en h an ced wh en th e reac-
1
tion was con ducted in th e presen ce of a dryin g agen t. In HFIP, with both
catalysts, th e im in e 1a was th e m ajor com poun d (ca 60%) in a m ixture of
tetrah edral adducts. Th is predom in an t form ation of im in e 1a in HFIP is n ot
th e on ly reason for successful preparation of aziridin es in th e th ree-
com pon en t reaction sin ce, after addition of eth yl diazoacetate, th e tetrah e-
dral adducts also disappeared, an d at th e en d of th e reaction on ly aziridin es
were obtain ed. Un like in th e reaction s perform ed with n on -fluorin ated al-
7
deh ydes , th e rate-determ in in g step in th ese sequen tial reaction s is n ot th e
aziridin ation itself, but th e slow form ation of aldim in es due to th e stabilisa-
F3C
F3C
2
CO Et
F3C OEt
OH
PMP
NH2
+
2
N CHCOOEt
10% catalyst
+
N
N
PMP
PMP
4
1
2
SCHEME 3
TABLE III
Th ree-com pon en t aziridin ation of fluoral im in e
En try
Solven t
Catalyst
Yield, %
cis/trans
1
2
3
4
h exan e
HFIP
Yb(OTf)3
Yb(OTf)3
BF ·Et O
traces
65
–
55/45
–
eth er
HFIP
traces
72
3
2
BF ·Et O
60/40
3
2
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Synthesis of (Trifluoromethyl)aziridines
1363
tion of tetrah edral in term ediates by th e CF substituen t. Alth ough n ot well
3
un derstood, HFIP appeared to be essen tial to solve th is difficulty.
In con clusion , we h ave sh own th at th e Yb(OTf) - or BF ·Et O-catalyzed
3
3
2
th ree-com pon en t reaction of fluoral eth yl h em iacetal, an arom atic am in e,
an d eth yl diazoacetate is efficien t in 1,1,1,3,3,3-h exafluoropropan -2-ol as
solven t. (Trifluorom eth yl)aziridin es 2 could be prepared in good yields but
with m oderate diastereoselectivity. Th e role of HFIP is crucial in th e prod-
uct lim itin g step of th ese sequen tial reaction s wh ich is th e form ation of an
aldim in e an d th e reactivity of tetrah edral adducts. More in vestigation s are
required to determ in e param eters govern in g th e ch em ical an d stereo-
ch em ical course of differen t steps of th ese th ree-com pon en t reaction s.
EXPERIMENTAL
Gen eral Procedure for th e Aziridin ation of Im in es
To a solution of im in e 1 (1 m m ol) in HFIP (3 m l) were added th e Lewis acid (0.01 m m ol)
an d EDA (1.5 m m ol, 0.16 m l) at room tem perature. Th e reaction was followed by GC. Wh en
startin g m aterial was n o m ore detected, th e reaction m ixture was quen ch ed by addition of
saturated NaHCO3 solution (10 m l). Th e aqueous layer was extracted with dieth yl eth er (3 ×
5
m l), th en th e organ ic layers were wash ed with saturated NaCl solution , dried (Na SO ), fil-
2 4
tered an d evaporated un der reduced pressure. Th e products were purified by flash ch rom a-
tograph y on silica gel (petroleum eth er–eth yl acetate, 4 : 1).
trans-1-(4-Methoxyphenyl)-3-trifluoromethyl-2-ethoxycarbonylaziridine (2a): pale yellow liquid.
1
H NMR (CDCl , 200 MHz): 6.82 (4 H, m ); 4.08 (2 H, q, J = 7.0); 3.75 (3 H, s); 3.42 (2 H, m );
3
1
3
1
4
.14 (3 H, t, J = 7.0). C NMR (CDCl ): 166.1, 157.2, 140.4, 124.1, 121.4, 115.4, 62.9, 56.4,
3
1
9
3.4, 40.4, 14.8.
F NMR (CDCl , CFCl ): –71.4 (d, J = 4.0). IR: 1 736 (CO). For
3 3
C13H14F3NO3 calculated: 53.98% C, 4.88% H, 4.84% N; foun d: 53.88% C, 5.02% H, 4.83% N.
cis-1-(4-Methoxyphenyl)-3-trifluoromethyl-2-ethoxycarbonylaziridine (2a): pale yellow liquid.
1
H NMR (CDCl , 200 MHz): 6.96 (2 H, d, J = 9.0); 6.81 (2 H, d, J = 9.0); 4.32 (2 H, q, J =
3
7
7
.0); 3.77 (3 H, s); 3.07 (1 H, d, J = 6.5); 2.89 (1 H, q, J
= 4.5, JH-H = 6.5); 1.33 (3 H, t, J =
H-F
1
3
.0). C NMR (CDCl ): 166.7, 157.5, 144.1, 121.4, 123.2, 115.5, 62.9, 56.3, 43.9, 42.3, 14.8.
3
1
9
F NMR (CDCl , CFCl ): –68.3 (d, J = 4.5). IR (n eat): 1 753 (CO).
trans-1-Benzyl-3-trifluoromethyl-2-ethoxycarbonylaziridine (2b): pale yellow liquid. 1H NMR
3
3
(
(
3
CDCl , 200 MHz): 7.31 (4 H, m ); 4.14 (2 H, q, J = 7.0); 3.93 (2 H, q); 2.95 (2 H, m ); 1.21
3
1
3
3 H, t, J = 7.0). C NMR (CDCl ): 167.5, 138.6, 129.3, 129.1, 128.3, 124.2, 62.7, 55.2, 44.5,
3
8.5, 14.6. 19F NMR (CDCl , CFCl ): –68.3 (d, J = 5.0). IR: 1 732 (CO). For C13H14F3NO2 cal-
3 3
culated: 57.14% C, 5.16% H, 5.13% N; foun d: 56.95% C, 5.25% H, 5.10% N.
1
cis-1-Benzyl-3-trifluoromethyl-2-ethoxycarbonylaziridine (2b ): H NMR (CDCl , 200 MHz):
3
7
.35 (2 H, m ); 4.26 (2 H, m ); 3.77 (3 H, s); 2.56 (1 H, d, J = 6.5); 2.43 (1 H, q, J
= 5.5,
H-F
1
3
JH-H = 6.5); 1.26 (3 H, t, J = 7.0). C NMR (CDCl ): 166.9, 136.6, 129.5, 129.2, 128.8, 124.2,
6
3
3.1, 62.6, 43.9, 42.2, 14.8. 1 F NMR (CDCl , CFCl ): –67.3 (d, J = 5.5). IR: 1 751 (CO).
9
3
3
trans-1-Diphenylmethyl-3-trifluoromethyl-2-ethoxycarbonylaziridine (2c): wh ite powder, m .p.
1
1
36 °C. H NMR (CDCl , 200 MHz): 7.56 (2 H, d, J = 8.0); 7.44 (2 H, d, J = 8.0); 7.39–7.20
3
(
6 H, m ); 4.91 (1 H, s); 4.23 (2 H, q, J = 7.0); 3.13 (1 H, d, J = 2.0); 3.08 (1 H, q, JH-F = 3.5,
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

1
364
Spanedda et al.:
JH-H = 2.0); 1.25 (3 H, t, J = 7.0). 13C NMR (CDCl ): 166.5, 141.8, 128.5, 127.7, 127.4, 127.0,
3
1
9
1
1
22.8, 67.4, 61.5, 43.3, 38.3, 13.6. F NMR (CDCl , CFCl ): –71.2 (d, J = 3.5).
3 3
cis-1-Diphenylmethyl-3-trifluoromethyl-2-ethoxycarbonylaziridine (2c): wh ite powder, m .p.
1
31 °C. H NMR (CDCl , 200 MHz): 7.56 (2 H, d, J = 8.0); 7.44 (2 H, d, J = 8.0); 7.39–7.20
3
(
6 H, m ); 4.23 (2 H, q, J = 7.0); 3.85 (1 H, s); 2.66 (1 H, d, J = 7.0); 2.54 (1 H, q, J
= 5.0,
H-F
1
3
JH-H = 7.0); 1.25 (3 H, t, J = 7.0). C NMR (CDCl ): 165.7, 141.0, 128.5, 127.8, 127.5, 125.8,
7
3
6.9, 61.5, 43.3, 42.0, 13.8. 1 F NMR (CDCl , CFCl ): –67.3 (3 F, d, J = 5.0). IR: 1 741. For
9
3
3
C19H18F3NO2 calculated: 65.32% C, 5.19% H, 4.01% N; foun d: 64.77% C, 4.99% H, 3.87% N.
Gen eral Procedure for Th ree-Com pon en ts Couplin g Reaction s of Fluoral,
4
-Meth oxyan ilin e an d Eth yl Diazoacetate
A m ixture of trifluoroacetaldeh yde eth yl h em iacetal (TFAE) (1.2 m m ol, 0.12 m l), 4-m eth oxy-
an ilin e (1 m m ol, 123 m g) an d catalyst (0.01 m m ol) in 3 m l of HFIP was stirred at room
1
9
tem perature for 1 h ( F NMR was used to ch eck th e com position of th e m ixture), th en EDA
(
1.5 m m ol, 0.16 m l) was added, an d th e reaction was treated as previously described.
With Yb(OTf) : th e startin g m ixture was com posed by im in e (63%), (1-eth oxy-2,2,2-tri-
3
fluoroeth yl)-(4-m eth oxyph en yl)am in e (20%) an d oth er tetrah edral in term ediates (7%). After
reaction with EDA, aziridin es 2a were recovered in an overall 65% yield (188 m g) an d
a 55/45 cis/trans ratio.
With BF ·Et O: th e startin g m ixture was com posed by im in e (44%), (1-eth oxy-2,2,2-tri-
3
2
fluoroeth yl)-(4-m eth oxyph en yl)am in e (53%) an d traces of oth er tetrah edral in term ediates.
After reaction with EDA, aziridin es 2a were recovered in an overall 72% yield (208 m g) an d
a 60/40 cis/trans ratio.
We thank Central Glass Co., Ltd for kindly providing HFIP and fluoral. We also thank the Euro-
pean Contract of Research Training Network (“Fluorous Phase” HPRN CT 2000-00002) and the
COST-Action (“Fluorous Medium” D12/98/0012).
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Synthesis of (Trifluoromethyl)aziridines
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