Facile synthesis of bicyclo orthoesters and bicyclo amide acetals using α,α-difluoroalkylamines

Article abstract of DOI:10.1055/s-0028-1083145

Bicyclo orthoesters and amide acetals were prepared from the corresponding triols or diethanolamines using α,α-difluoroalkylamines. The reaction proceeded under milder conditions than conventional methods. 4-tert-Butyl-1-(4-ethynylphenyl)trioxabicyclo[2.2.2]octane, a new class of insecticide, was prepared from a triol in three steps using a difluoroalkylamine.

Full text of DOI:10.1055/s-0028-1083145

PAPER
3219
Facile Synthesis of Bicyclo Orthoesters and Bicyclo Amide Acetals
Using a,a-Difluoroalkylamines
B
icycloOrtho
e
B
i
icyclo
k
A
mide
A
cet
o
als from
a
,
a
-Difluo
T
r
oalkylaminesange, Tsuyoshi Fukuhara, Shoji Hara*
Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
Fax +81(11)7066556; E-mail: shara@eng.hokudai.ac.jp
Received 23 May 2008; revised 1 July 2008
the same conditions, the tert-butyl-substituted bicyclo
orthoester 6 was obtained from 1 in 70% yield with
N-(1,1-difluoro-2,2-dimethylpropyl)pyrrolidine instead
of DFBA. On the other hand, the benzoyloxy-substituted
Abstract: Bicyclo orthoesters and amide acetals were prepared
from the corresponding triols or diethanolamines using a,a-difluo-
roalkylamines. The reaction proceeded under milder conditions
than conventional methods. 4-tert-Butyl-1-(4-ethynylphenyl)tri-
oxabicyclo[2.2.2]octane, a new class of insecticide, was prepared triol 2, which is less soluble in DMF, did not react to com-
from a triol in three steps using a difluoroalkylamine.
pletion with DFBA under the same conditions. When the
reaction was performed in deuterated chloroform and fol-
lowed by NMR, the reaction was found to be complete in
one hour at 50 °C; the corresponding bicyclo orthoester 7
was obtained in 62% yield. The bis-bicyclo orthoester of
dipentaerythritol 3 was previously prepared by transether-
ification using triethyl orthopropionate. The reaction was
performed at high temperature (180–200 °C) for six
hours, and the desired bifunctional bicyclo orthoester was
obtained in only 1.4% yield.4c On the other hand, the reac-
tion of 3 with DFBA was complete in one hour at 60 °C,
and the bis-bicyclo orthoester of benzoate 8 was obtained
in 96% yield. Difluoroalkylamines can be used for the
synthesis of cyclic amide acetals through reaction with di-
ethanolamine 4.7 The reaction of N,N-diethyl-a,a-difluo-
ro-3-methylbenzylamine (DFMBA) with 4 was complete
in 30 minutes at room temperature, and the resulting cy-
clic amide acetal 9 was isolated in 79% yield by distilla-
tion.
Key words: bicyclo orthoesters, bicyclo amide acetals, a,a-difluo-
roalkylamines, protecting groups, polymers
Bicyclo orthoesters have been used by organic chemists as
a protecting group for carboxylic acids,1 however, they
have recently attracted the attention of a wide range of
chemists because bicyclo orthoesters, such as 1,4-disub-
stituted 2,4,6-trioxabicyclo[2.2.2]octanes, have been
found to be a highly potent insecticide.2 Moreover, it was
found that bicyclo orthoesters polymerize reversibly to of-
fer an environmentally-friendly recycling system for
polymeric materials.3 The bicyclo orthoesters were pre-
pared by transetherification from the corresponding tri-
alkyl orthocarboxylates and triols, however, the reaction
is reversible and requires high temperature over a long pe-
riod to obtain the products.4 The bicyclo orthoesters were
also prepared by acid-catalyzed isomerization of the car-
boxylate esters of hydroxymethyloxetanes,1,5 however, in
this case, harsh reaction conditions are required for the
preparation of the starting hydroxymethyloxetanes.5
Therefore, more facile and convenient methods are re-
quired for the synthesis of bicyclo orthoesters.
HO
HO
HO
O
F
F
R2
R1
R2
+
O
O
R1
NR3
2
Equation 1
Recently, we found that the reaction of a,a-difluoroalkyl-
amines with 2-aminoalcohols, 2-aminothiols, and 1,3-di-
amines proceeds rapidly to give five-membered
heterocyclic compounds under mild conditions.6 During
the course of the study, we found that the reaction of the
difluoroalkylamines with triols proceeds quickly to give
bicyclo orthoesters under mild conditions (Equation 1).
4-tert-Butyl-1-(4-ethynylphenyl)trioxabicyclo[2.2.2]oc-
tane (13) is a highly potent insecticide among the bicyclo
orthobenzoate derivatives and was previously prepared
from a hydroxymethyloxetane in four steps.2b It can be
prepared more readily from 2-tert-butyl-2-hydroxymeth-
ylpropane-1,3-diol (11)8 in three steps. Thus, preparation
of a key intermediate, 1-(4-bromophenyl)-4-tert-butyl-
2,6,7-trioxabicyclo[2.2.2]octane (12), was achieved in
79% yield from 11 by reaction with N,N-diethtyl-a,a-di-
fluoro-4-bromobenzylamine at room temperature in two
hours. Target 13 was prepared from 12 in 71% yield by a
Sonogashira coupling reaction with trimethylsilylacety-
lene, followed by desilylation (Scheme 1).
Various difluoroalkylamines can be prepared from the
corresponding carboxylic amides in two steps.6 When
1,1,1-tris(hydroxymethyl)ethane (1) was allowed to react
with N,N-diethyl-a,a-difluorobenzylamine (DFBA) in
DMF, the reaction went to completion at room tempera-
ture in two hours to give 4-methyl-1-phenyl-2,6,7-trioxa-
bicyclo[2.2.2]octane (5) in 66% yield (Table 1). Under
Although difluoroalkylamines have been used for deoxy-
fluorination of alcohols, fluorination products were not
formed under the conditions used (reaction temperature
<70 °C).9 The reaction must be proceeding through a cy-
SYNTHESIS 2008, No. 20, pp 3219–3222
Advanced online publication: 25.09.2008
DOI: 10.1055/s-0028-1083145; Art ID: F11608SS
x
x.
x
x
.
2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

3220
S. Tange et al.
PAPER
Table 1 Reaction of a,a-Difluoroalkylamines with Di- and Triols
Substrate
RCF2NR¢2
Solvent
DMF
Time (h)
2
Temp (°C) Product
Yield (%)a
66
O
F
F
MeC(CH2OH)3
1
O
Ph
Me
r.t.
Ph
NEt2
O
DFBA
5
O
F
F
O
t-Bu
6
Me
1
DMF
2
1
r.t.
50
70
62
t-Bu
N
O
O
O
BzOCH2C(CH2OH)3
2
O
Ph
7
CH2OBz
Ph
DFBA
CDCl3
O
O
C(CH2OH)3
O
O
O
DFBA
DMF
1
60
96
O
C(CH2OH)3
O
Ph
3
O
8
CH2CH2OH
HN
O
O
F
F
79b
64b
m-Tol
N
CH2Cl2
CDCl3
0.5
0.5
r.t.
40
m-Tol
NEt2
CH2CH2OH
DFMBA
DFBA
4
4
9
O
Ph
N
O
10
a Isolated yield based on substrate used.
b Isolated yield based on difluoroalkylamine used.
clic intermediate 14, as in the reaction with 1,2- or 1,3-di- yields. Compared with the conventional methods, the re-
ols.10 If a fluoride attacked the oxygen-attached carbon of action conditions are very mild and therefore, the present
14, a deoxyfluorination reaction would take place to give reaction is useful for the synthesis of various bicyclo
the fluorination product. However, due to the low nucleo- orthoesters or amide acetals.
philicity of the fluoride ion, attack of the free hydroxy
group in 14 preceded the fluoride attack, to give the bicy-
IR spectra were recorded using a JASCO FT/IR-410 spectropho-
tometer. H NMR (400 MHz) and 13C NMR (100 MHz) spectra
were recorded in CDCl3 on a JEOL JNM-A400II FT NMR spec-
trometer and chemical shifts (d) are referred to TMS. The low and
high-resolution mass spectra (EI) were measured on a JEOL JMS-
700TZ, JMS-FABmate or JMS-HX110 spectrometer. Small-scale
distillations were carried out using a SIBATA glass tube oven
1
clo orthoester (Scheme 2). Since all steps other than the
fluoride attack are fast, the bicyclo orthoesters were
formed under mild conditions.
In conclusion, a facile synthesis of bicyclo orthoesters and
amide acetals from the corresponding triols or diethanol-
amine using a,a-difluoroalkylamines has been shown.
The reaction was complete within two hours at room tem-
perature to 60 °C and the products were obtained in good
R2
R2
OH
F
F
HO OH
– 2 HF
– NR3
2
HO
O
O
R1
NR3
2
Br
CF2NEt2
O
NR3
R1
2
Br
t-Bu
t-BuC(CH2OH)3
O
O
DMF
11
R2
R2
R2
79%
12
– H
1) TMS-C CH
O
OH
O
Et2NH, Cul, Pd cat.
O
HC
C
t-Bu
O
O
O
O
O
O
O
O
2) TBAF, THF
H
R1
14
R1
R1
71%
13
Scheme 1
Scheme 2
Synthesis 2008, No. 20, 3219–3222 © Thieme Stuttgart · New York

PAPER
Bicyclo Orthoesters and Bicyclo Amide Acetals from a,a-Difluoroalkylamines
3221
GTO-350RD. Polyols 1, 3 and diethanolamine 4 were purchased
from Tokyo Chemical Industry Co., Ltd. Triol 2 was prepared by
mono-benzoylation of pentaerythritol obtained from Tokyo Chem-
ical Industry Co., Ltd. 2-tert-Butyl-2-hydroxymethylpropane-1,3-
diol (11) was prepared according to the literature.8 Activated alumi-
num oxide (200 mesh) was obtained from Wako Pure Chemicals In-
dustries, LTD. Difluoroalkylamines were prepared from the
corresponding carboxylic amides according to the literature.6
under reduced pressure. The product was isolated by column chro-
matography (activated alumina; hexane–CH2Cl2, 1:1).
Yield: 202 mg (62%); white solid; mp 117–118 °C.
IR (KBr): 2950, 2889, 1735, 1338, 1101 cm–1.
1H NMR (CDCl3): d = 8.03 (d, J = 7.0 Hz, 2 H), 7.65–7.60 (m, 3 H),
7.50–7.46 (m, 2 H), 7.37–7.36 (m, 3 H), 4.31 (s, 6 H), 4.21 (s, 2 H).
13C NMR (CDCl3): d = 165.9, 137.0, 133.6, 129.6 (2 × C), 129.3,
129.1, 128.6 (2 × C), 128.0 (2 × C), 125.6 (2 × C), 108.0, 69.7 (3 ×
C), 62.4, 34.9.
N,N-Diethyl-a,a-difluorobenzylamine (DFBA)
Bp 42–45 °C (0.1 mmHg).
HRMS (FAB): m/z [M + 1] calcd for C19H19O5: 327.1232; found:
327.1231.
1H NMR (CDCl3): d = 7.62–7.59 (m, 2 H), 7.43–7.40 (m, 3 H), 2.90
(q, J = 10.5 Hz, 4 H), 1.06 (t, J = 10.5 Hz, 6 H).
1-Phenyl-4-{[(1-phenyl-2,6,7-trioxabicyclo[2.2.2]octane-4-
yl)methoxy]methyl}-2,6,7-trioxabicyclo[2.2.2]octane (8)
A mixture of 3 (254 mg, 1 mmol) and DFBA (796 mg, 4 mmol) in
anhydrous DMF (1 mL) was stirred at 60 °C for 1 h. The mixture
was poured into sat. aq NaHCO3 (20 mL) and extracted with CH2Cl2
(3 × 20 mL). The combined organic layer was dried (MgSO4) and
concentrated under reduced pressure. Recrystallization from
CH2Cl2–hexane gave the pure product.
N,N-Diethyl-a,a-difluoro-3-methylbenzylamine (DFMBA)
Bp 84–88 °C (5 mmHg).
1H NMR (CDCl3): d = 7.41–7.17 (m, 4 H), 2.92 (q, J = 7.0 Hz, 4 H),
2.39 (s, 3 H), 1.07 (t, J = 7.1 Hz, 6 H).
N-(1,1-Difluoro-2,2-dimethylpropyl)pyrrolidine
Bp 51 °C (7 mmHg).
1H NMR (CDCl3): d = 3.07–3.03 (m, 4 H), 1.80–1.76 (m, 4 H), 1.13
(s, 9 H).
Yield: 409 mg (96%); white solid; mp 210 °C.
IR (KBr): 2883, 1339, 1088 cm–1.
1H NMR (CDCl3): d = 7.63–7.61 (m, 4 H), 7.37–7.35 (m, 6 H), 4.19
(s, 12 H), 3.27 (s, 4 H).
N,N-Diethyl-a,a-difluoro-4-bromobenzylamine
Bp 62–64 °C (0.1 mmHg).
13C NMR (CDCl3): d = 137.1 (2 × C), 129.3 (2 × C), 128.0 (4 × C),
125.6 (4 × C), 107.9 (2 × C), 70.2 (2 × C), 69.8 (6 × C), 35.4 (2 × C).
1H NMR (CDCl3): d = 7.55 (d, J = 8.5 Hz, 2 H), 7.47 (d, J = 8.5 Hz,
2 H), 2.85 (q, J = 7.1 Hz, 4 H), 1.04 (t, J = 7.2 Hz, 6 H).
HRMS (FAB): m/z [M + 1] calcd for C24H27O7: 427.1757; found:
427.1758.
4-Methyl-1-phenyl-2,6,7-trioxabicyclo[2.2.2]octane (5); Typical
Procedure
A mixture of 1 (180 mg, 1.5 mmol) and powdered MS (4 Å; 300
mg) in anhyd DMF (3 mL) was stirred at r.t. for 1 h. The mixture
was cooled to 0 °C and DFBA (199 mg, 1 mmol) was added. After
stirring at r.t. for 2 h, the mixture was poured into sat. aq NaHCO3
(20 mL), and extracted with CH2Cl2 (3 × 20 mL). The combined or-
ganic layer was dried (MgSO4) and concentrated under reduced
pressure. Purification by column chromatography (activated alumi-
na; hexane–Et2O, 1:1) gave 5.
5-(3-Methylphenyl)-1-aza-4,6-dioxabicyclo[3.3.0]octane (9)
To a solution of 4 (788 mg, 7.5 mmol) in CH2Cl2 (3 mL), was added
DFMBA (1.07 g, 5 mmol) at 0 °C, and the mixture was stirred at r.t.
for 30 min. The mixture was poured into sat. aq NaHCO3 (20 mL)
and extracted with CH2Cl2 (3 × 20 mL). The combined organic lay-
er was dried (MgSO4), concentrated under reduced pressure and pu-
rified by Kugelrohr distillation to give 9.
Yield: 810 mg (79%); bp 120 °C (bath temperature) / 0.1 mmHg.
IR (neat): 2882, 1631, 1471, 1300, 1080 cm–1.
Yield: 136 mg (66%); white solid; mp 125–126 °C (Lit.11 128–
129 °C).
1H NMR (CDCl3): d = 7.43–7.41 (m, 1 H), 7.27–7.21 (m, 2 H),
7.14–7.12 (m, 1 H), 4.17–4.09 (m, 2 H), 4.05–3.94 (m, 2 H), 3.43–
3.33 (m, 2 H), 3.15–3.07 (m, 2 H), 2.63 (s, 3 H).
13C NMR (CDCl3): d = 14.00, 137.7, 129.2, 127.9, 126.5, 123.2,
122.9, 65.6 (2 × C), 53.0 (2 × C), 21.4.
IR (KBr): 2881, 1337, 996 cm–1.
1H NMR (CDCl3): d = 7.63–7.61 (m, 2 H), 7.35–7.34 (m, 3 H), 4.10
(s, 6 H), 0.89 (s, 3 H).
13C NMR (CDCl3): d = 137.4, 129.1, 128.0 (2 × C), 125.6 (2 × C),
107.4, 73.2 (3 × C), 30.5, 14.5.
HRMS (EI): m/z calcd for C12H15NO2: 205.1103; found: 205.1104.
1-tert-Butyl-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane (6)
Product was isolated by column chromatography (activated alumi-
na; hexane–Et2O, 1:1).
White sold; mp 94–95 °C (Lit.12 102 °C).
IR (KBr): 2881, 1337, 996 cm–1.
1H NMR (CDCl3): d = 3.86 (s, 6 H), 0.96 (s, 9 H), 0.78 (s, 3 H).
5-Phenyl-1-aza-4,6-dioxabicyclo[3.3.0]octane (10)
Bp 95 °C (bath temperature)/0.1 mmHg (Lit.7a 79–80 °C/0.03
mmHg).
IR (neat): 2883, 1626, 1448, 1281, 1067 cm–1.
1H NMR (CDCl3): d = 7.62–7.60 (m, 2 H), 7.34–7.28 (m, 3 H),
4.13–4.08 (m, 2 H), 4.01–3.96 (m, 2 H), 3.38–3.33 (m, 2 H), 3.11–
3.05 (m, 2 H).
13C NMR (CDCl3): d = 140.2, 128.3, 128.0, 125.9 (2 × C), 123.2
(2 × C), 65.6 (2 × C), 53.0 (2 × C).
13C NMR (CDCl3): d = 111.9, 72.6 (3 × C), 37.3, 30.1, 24.8 (3 × C),
14.5.
4-Benzoyloxymethyl-1-phenyl-2,6,7-trioxabicyclo[2.2.2]octane
(7)
A mixture of 2 (240 mg, 1 mmol) and DFBA (199 mg, 1.5 mmol)
1-(4-Bromophenyl)-4-tert-butyl-2,6,7-trioxabicyclo[2.2.2]oc-
tane (12)
The reaction was carried out as described for 5, to give 12, which
was isolated by column chromatography (activated alumina; hex-
ane–CH2Cl2, 1:1).
in CDCl3 (5 mL) was stirred at 50 °C for 1 h (consumption of 2 was
1
confirmed from H NMR analysis). The mixture was poured into
sat. aq NaHCO3 (20 mL) and extracted with CH2Cl2 (3 × 20 mL).
The combined organic layer was dried (MgSO4) and concentrated
Synthesis 2008, No. 20, 3219–3222 © Thieme Stuttgart · New York

3222
S. Tange et al.
PAPER
Yield: 258 mg (79%); white solid; mp 177 °C.
IR (KBr): 2962, 1340, 1008, 820 cm–1.
1H NMR (CDCl3): d = 7.47 (s, 4 H), 4.17 (s, 6 H), 0.91 (s, 9 H).
13C NMR (CDCl3): d = 136.6, 131.1 (2 × C), 127.5 (2 × C), 123.4,
107.2, 68.4 (3 × C), 38.4, 31.4, 25.2 (3 × C).
References
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HRMS (FAB): m/z [M + 1] calcd for C15H20BrO3: 327.0596; found:
327.0606.
4-tert-Butyl-1-(4-ethynylphenyl)-2,6,7-trioxabicyclo[2.2.2]oc-
tane (13)
A mixture of 12 (262 mg, 0.8 mmol), trimethylsilylacetylene (393
mg, 4 mmol), Pd(PPh3)2Cl2 (40 mg, 0.057 mmol), and CuI (3 mg,
0.015 mmol) in Et3N (8 mL) was stirred under an N2 atmosphere at
80 °C overnight (consumption of 12 was confirmed by GC). Vola-
tile material was removed under reduced pressure and the residue
was extracted with Et2O (3 × 20 mL). The combined organic layer
was concentrated under reduced pressure. and the residue was dis-
solved in THF (8 mL). A THF solution of TBAF (1 M, 1.2 mL, 1.2
mmol) was added and the mixture was stirred at r.t. for 1 h. The
product was extracted with CH2Cl2 (3 × 20 mL) and the combined
organic layer was dried (MgSO4) and concentrated under reduced
pressure. Purification by column chromatography (activated alumi-
na; hexane–CH2Cl2, 1:1) gave 13.
Yield: 154 mg (71% yield from 12); white solid; mp 148–150 °C
(Lit.2b 167–168 °C).
IR (KBr): 3265, 2962, 2892, 1344, 1130, 1009, 834 cm–1.
1H NMR (CDCl3): d = 7.65 (d, J = 8.3 Hz, 2 H), 7.47 (d, J = 8.3 Hz,
2 H), 4.18 (s, 6 H), 3.07 (s, 1 H), 0.92 (s, 9 H).
13C NMR (CDCl3): d = 137.9, 131.8 (2 × C), 125.7 (2 × C), 122.8,
107.2, 83.4, 77.6, 68.4 (3 × C), 38.4, 31.4, 25.2 (3 × C).
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Synthesis 2008, No. 20, 3219–3222 © Thieme Stuttgart · New York