Synthesis of 6,6-difluorohomopiperazines via microwave-assisted detosylation

Article abstract of DOI:10.1055/s-2003-36834

[1,4]-Diazepan-6-ols are easily oxidized to ketones using Swern or Dess-Martin oxidation conditions. The fluorination of these [1,4]-diazepanones with diethylaminosulfur trifluoride (DAST) affords gem-difluorohomopiperazines. Detosylation under microwave conditions represents a rapid method to access the corresponding amines in high yields.

Full text of DOI:10.1055/s-2003-36834

PAPER
223
Synthesis of 6,6-Difluorohomopiperazines via Microwave-Assisted
Detosylation
S
ynthesis of 6,6
r
-Difluor
i
ohomo
c
piperazines Wellner,* Helena Sandin, Leila Pääkkönen
Department of Drug Discovery, Active Biotech Research AB, Box 724, 22007 Lund, Sweden
Fax +46(46)191246; E-mail: eric.wellner@activebiotech.com
Received 22 July 2002; revised 6 November 2002
R
R
Abstract: [1,4]-Diazepan-6-ols are easily oxidized to ketones using
DAST
CH2Cl2
Swern or Dess–Martin oxidation conditions. The fluorination of
these [1,4]-diazepanones with diethylaminosulfur trifluoride
(DAST) affords gem-difluorohomopiperazines. Detosylation under
microwave conditions represents a rapid method to access the cor-
responding amines in high yields.
oxidation
TosN
NTos
TosN
NTos
1a: R = H
3: R = H, 50%
4: R = (R)- Me, 85%
OH
O
2b: R = (R)- Me
Key words: heterocycles, sulfonamides, protecting groups, di-
ethylaminosulfur trifluoride (DAST), microwaves
R
HBr/HOAc/phenolc
microwave, 100 oC
R
TosN
NTos
H2N
NH2
2 Br
HBr/HOAc/phenold
110 oC
As part of our research program we were interested in new
functionalized homopiperazines bearing a difluoro-
methylene unit. The high electronegativity of fluorine in a
gem-difluoromethylene group can have a pronounced ef-
fect on the basicity1 of the neighboring nitrogen. Its high
metabolic stability, as well as the rather small steric dis-
turbance makes the gem-difluoromethylene group an in-
teresting replacement for the methylene or CHOH group2
in drugs. Furthermore, the difluoromethylene group pos-
sesses hydrogen-bonding potential,3 which provides an
additional point of interaction with solvents and biomole-
cules. Ziegler et al.4 demonstrated the use of the 6-fluoro-
homopiperazine moiety in biologically active
compounds. However, the prochirality of this compound
makes it a less versatile building block in drug synthesis.
F
F
F
F
7: R = H, 95%c, 90%d
5: R = H, 80%
6: R = (R)- Me, 37%
8: R = (R)- Me, 82%c,
70%d
b
Scheme 1 a Substrate 1 was oxidized via Swern oxidation. Sub-
strate 2 was oxidized via Dess–Martin oxidation.
were performed in a sealed pressure tube.
c,d
The reactions
2
7 at = 54.8 ppm with a JC,F coupling constant of 36.1
Hz.
Surprisingly, the N-detosylation of compound 5 proved to
be the critical step of our synthetic approach. Reflux in
30% anhydrous hydrogen bromide–acetic acid and
phenol5,7 afforded only traces of the difluorohomopipera-
zine 7. Red-Al (70% in toluene)8 and sodium
naphthalenide9 led to complete decomposition of the sul-
fonamide 5, while LiAlH4 in toluene (reflux) yielded only
recovered starting material. By evaluating other condi-
tions for the removal of the N-tosyl protecting group, it
was found that heating 5 with 30% hydrogen bromide and
phenol in acetic acid for 200 seconds at 100 °C under mi-
crowave radiation lead to complete cleavage of the tosyl-
group (quantitative yield of 7). The reason for this clean
deprotection was thought to be due to the high HBr and
solvent pressure (up to 15 bar) in the sealed tube during
the reaction. To prove this, 5 was heated in a pressure tube
for 30 minutes at 110 °C. After washing with Et2O and
EtOH, the dihydrobromide 7 was obtained in very high
yield.
The starting point for our synthetic approach was the 6-
hydroxy-diazepane 1,5 which yielded the corresponding
ketone 3 after Swern oxidation (Scheme 1). The most
common strategy for gem-difluorination is the conversion
of a keto-group with diethylaminosulfur trifluoride
(DAST).6 In the presence of DAST as a fluorinating agent,
the difluorinated compound 5 was readily accessible at
ambient temperature in 90% yield. The presence of a dif-
1
luoromethylene group was confirmed by H NMR spec-
troscopy, which shows one triplet at = 3.69 ppm with a
value of 3JF,H = 12.3 Hz for the two neighboring methyl-
ene groups. In the 13C NMR spectrum, the C-6 atom has
significantly shifted ( = 83 ppm) to higher field
( = 122.2 ppm), with a typical 1JC,F coupling of 249.0 Hz,
compared to the carbonyl atom in the precursor 3. The
symmetry and flexibility of the molecule is reflected by
the two isochronous neighboring carbon atoms C-5 and C-
The first attempt to liberate the free base 9 from the salt 7,
using Dowex1-X4 (OH form) ion-exchange resin failed.
After evaporation of the water from the filtrate, only ring-
opened fragments were obtained. To avoid decomposition
and co-evaporation of the amine 9, a suspension of 7 in
CH2Cl2 was treated with (polystyrylmethyl)trimethylam-
monium bicarbonate10 to afford the homopiperazine 9 af-
Synthesis 2002, No. 2, Print: 31 01 03.
Art Id.1437-210X,E;2002,0,02,0223,0226,ftx,en;T08402SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

224
E. Wellner et al.
PAPER
ter filtration of the resin and evaporation of the solvent
(Scheme 2).
All reactions were carried out in an inert gas atmosphere with dried
solvents under anhydrous conditions, unless otherwise stated. Etha-
nol was dried over 3 Å molecular sieves. Thin-layer chromatogra-
phy (TLC) was performed on Silica Gel 60 F254 (Merck) with
detection by UV light. Flash column chromatography was per-
formed on silica gel (60 Å, 35–70 m). Organic solutions were dried
over Na2SO4 before being concentrated. Precipitates were dried in a
desiccator over phosphorus pentoxide. DAST was purchased from
Acros Organics.
1H and 13C NMR spectra were recorded at 400 and 100 MHz, re-
spectively, in CDCl3 (residual CHCl3
( H = 7.27) or CDCl3
(
C = 77.0) as internal standards) at 300 K, unless otherwise speci-
Scheme 2
fied. For compounds, first-order chemical shifts and coupling con-
stants were obtained from one-dimensional spectra: carbon and
proton signals were assigned from COSY and DEPT experiments.
Signals for aromatic protons and signals that could not be assigned
are not reported. 19F NMR spectra were recorded at 470.95 MHz us-
ing TFA ( F = –78.50) as external standard. Optical rotations were
measured at 20 °C in CHCl3. The microwave-assisted reactions
were performed in capped vials using the SimthSynthesizer™ from
Personal Chemistry.
To demonstrate the feasibility of this approach as a race-
mization-free procedure, (R)-2-methyl-6,6-difluoro-
homopiperazine 8 was prepared. The construction of the
precursor 2 follows the protocol described by Saari et al.5
Firstly, the sulfonamide 11 was conveniently generated by
the reaction of the amine 10 with tosyl chloride. In the sec-
ond step, the disodium salt of 1111 was cyclized in the
presence of 1,3-dibromo-2-propanol to form 2 as a dia-
stereoisomeric mixture. Finally, without separation, 2 was
oxidized to the corresponding ketone 4. This Dess–Martin
Periodinane (DMP, 1,1,1-triacetoxy-1,1-dihydro-1,2-
benziodoxol-3-(1H)-one) oxidation was worked-up using
Dowex1-X4 in its thiosulfate form12 to yield ketone 413
(85%) with no need for further purification (Scheme 3).
(R)-N-(2-Toluenesulfonylamino-1-methyl-ethyl)-toluenesul-
fonamide (11)
A solution of (R)-(+)-1,2-diaminopropane dihydrochloride 10 (1.00
g, 6.8 mmol) and NaOH (1.21 g, 30.0 mmol) in water (20 mL) was
added to a solution of tosyl chloride (2.72 g, 14.3 mmol) in Et2O–
H2O (1:1, 50 mL) at 0 °C. The mixture was stirred rapidly overnight
at r.t. The precipitate was collected, washed with H2O and Et2O and
dried to give 11 as a white solid.
Yield: 724 mg (28%); [ ]D +37.0 (c 1).
1H NMR (CDCl3): = 1.02 (d, 3 H, J = 6.7 Hz, CH3), 2.44 (s, 6 H,
2Cl
NH3
Tos-Cl, NaOH
2
CH3), 2.85–2.88 (m, 1 H, H-2), 2.98–3.01 (m, 1 H, H-2), 3.31–
H3N
TosHN
NHTos
11 28%
Br
Et2O–H2O (1:1.5)
3.34 (m, 1 H, H-1), 4.71 (d, 1 H, J = 6.7 Hz, NH), 4.97 (br s, 1 H,
NH).
13C NMR (CDCl3): = 18.9, 21.5, 21.5, 48.3, 49.4, 127.0, 127.1,
129.7, 129.8, 136.7, 137.0 143.6 143.8.
10
Br
1. NaOMe 2.
HOMe
ESI-MS: m/z (%) = 383 (100) [M + H+], 405 [M + Na+], 446 [M +
OH
CH3CN + Na+].
Anal. Calcd for C17H22N2O4S2: C, 53.38; H, 5.80; N, 7.32; S, 16.77.
Found: C, 53.6; H, 5.80; N, 7.28; S, 16.8.
DMP
TosN
NTos
TosN
NTos
CH2Cl2
1,4-Bis-(toluene-4-sulfonyl)-[1,4]diazepan-6-one (3)
2
4 85%
To a solution of oxalyl chloride (1.71 g, 4.0 mmol) in CH2Cl2 was
added DMSO (685 mg, 8.8 mmol) at –78 °C and the mixture was
stirred for 10 min. 1,4-Bis-(toluene-4-sulfonyl)-[1,4]-diazepan-6-ol
(1) was added and the Swern oxidation was finished after 1 h by ad-
dition of triethylamine (1.22 g, 12.0 mmol). After 30 min the reac-
tion mixture was allowed to attain r.t. and 0.25 M HCl (45 mL) was
added. The organic phase was separated and the aqueous layer ex-
tracted with CH2Cl2 (2 15 mL). The combined organic phases
were dried and concentrated. The residue was submitted to flash
column chromatography (EtOAc–n-heptane, 2:1) to give 3 as a
white solid.
OH
O
Scheme 3
Fluorination and detosylation were performed according
to the protocol outlined in Scheme 1. The gem-difluoride
6 showed a much more complex line pattern in the H
NMR spectrum compared with compound 5 due to the in-
troduction of the methyl group. The final step of our ap-
proach provided the detosylated homopiperazine 8 in
excellent yields, via microwave radiation or heating in a
sealed tube respectively.14
1
Yield: 832 mg (50%).
1H NMR (CDCl3): = 2.39 (s, 6 H, CH3), 3.56 (s, 4 H, H-2,-3), 3.91
(s, 4 H, H-5,-7).
13C NMR (CDCl3): = 21.4, 52.4, 57.6, 127.2, 130.5, 136.1, 144.3,
205.1.
In summary, we have discovered a facile synthetic route
to new functionalized homopiperazines. These com-
pounds are useful as building blocks for the synthesis of
potential drugs. We also demonstrated that microwave ra-
diation can be a fast and powerful tool in detosylation re-
actions, superior to other conventional methods.
ESI-MS: m/z (%) = 423 [M + H+], 445 (100) [M + Na+], 486 [M +
CH3CN + Na+].
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Synthesis of 6,6-Difluorohomopiperazines
225
Anal. Calcd for C19H22N2O5S2: C, 54.01; H, 5.25; N, 6.63; S, 15.18.
Found: C, 54.0; H, 5.28; N, 6.63; S, 14.8.
extracted with CH2Cl2. The combined organic layers were dried and
concentrated. The residue was washed several times with EtOAc–
n-heptane (1:2) and Et2O. The residue was dried in vacuum to give
6 as a white solid.
(R)-2-Methyl-1,4-bis-(toluene-4-sulfonyl)-[1,4]diazepan-6-one
(4)
Yield: 32 mg (37%); [ ]D +28.2 (c 1).
Sodium (105 mg, 4.54 mmol) was dissolved in MeOH (5 mL). The
mixture was added to a solution of 11 (720 mg, 1.89 mmol) in
MeOH (2 mL). The reaction mixture was heated to reflux for 0.5 h.
After cooling to r. t., the solvent was removed to give the crude so-
dium salt of 11 as a white solid.
1H NMR (CDCl3): = 1.06 (d, 3 H, J = 6.8 Hz, CH3), 2.44 (s, 3 H,
CH3), 2.46 (s, 3 H, CH3), 2.97 (dd, 1 H, J = 13.8, 3.8 Hz, H-3), 3.11
(ddd, 1 H, J = 23.2, 15.0, 8.1 Hz, H-5), 3.45 (ddd, 1 H, J = 24.6,
16.0, 8.2 Hz, H-7), 3.58 (br d, 1 H, J = 13.8 Hz, H-3), 4.04 (ddd, 1
H, J = 15.0, 15.0, 4.2 Hz, H-5), 4.15 (br dd, 1 H, J = 16.0, 15.0 Hz,
H-7), 4.21–4.26 (m, 1 H, H-2).
13C NMR (CDCl3): = 14.6, 21.5, 21.5, 47.0, 52.4, 55.4, 57.5,
122.5, 127.0, 127.1, 129.9, 130.1, 135.2, 136.8, 144.0, 144.3.
19F NMR (CDCl3) = –101.03 (d, 1 F, J = 244.7 Hz), –102.48 (d, 1
F, J = 244.7 Hz).
1,3-Dibromo-2-propanol (223 L, 2.1 mmol, 2.1 g/mL) was added
to a solution of the salt of 11 in EtOH (15 mL). The mixture was re-
fluxed overnight and then allowed to attain r.t. H2O (20 mL) was
added and the pH was adjusted to 10. The precipitate was filtered
off, washed with H2O and dried to give the crude 2 (683 mg, 83%)
as a diastereoisomeric mixture. The crude 2 was used in the next re-
action without further purification.
ESI-MS: m/z (%) = 459 [M + H+], 481 (100) [M + Na+].
To a solution of 2 (93 mg, 0.21 mmol) in CH2Cl2 (2 mL) was added
Dess–Martin periodinane (135 mg, 0.32 mmol) and the reaction
mixture was stirred for 1 h at r.t. Dowex-1-chloride (1 4-50, 1 g)
was washed with H2O, activated with Na2S2O3 (1 M, 4 20 mL),
washed with H2O and MeOH and dried in vacuum. The resin (1 g)
was added to the reaction mixture. After agitation overnight, the
resin was filtered off, TBD-methyl polystyrene 2% DVB (2.39
mmol/g, 2.1 mmol) was added and the resulting suspension was ag-
itated for an additional 1.5 h. The resin was removed, washed with
CH2Cl2 and the combined filtrates were concentrated to give 4 as a
white solid.
6,6-Difluoro-[1,4]diazepane dihydrobromide (7)
Method A
A suspension of 5 (80 mg, 0.2 mmol) and phenol (72 mg, 0.8 mmol)
in HOAc–HBr (3 mL, 30 wt%) was heated to 100 °C for 200 s in a
pressure tube using microwave irradiation. The solvent was re-
moved in vacuum and the residue triturated with Et2O, washed with
EtOH and Et2O to give 7 as a white solid.
Yield: 57 mg (95%).
Method B
Yield: 78.9 mg (85%); [ ]D +14.8 (c 1).
A suspension of 5 (1.46 g, 3.3 mmol) and phenol (1.23 g, 13.1
mmol) in HOAc–HBr (20 mL, 30 wt%) was heated to 110 °C in a
sealed tube. After 30 min, the mixture was allowed to attain r.t., the
solvent was removed in vacuum and the residue triturated with
Et2O, washed with EtOH and Et2O to give 7 as a white solid.
1H NMR (CDCl3): = 1.26 (d, 3 H, J = 7.0 Hz, CH3), 2.42 (s, 3 H,
CH3), 2.44 (s, 3 H, CH3), 3.20 (dd, 1 H, J = 13.9, 3.3 Hz, H-3), 3.56
(d, 1 H, J = 16.9 Hz, H-5,-7), 3.89 (mAB, 1 H, J = 17.9 Hz, H-7,-5),
3.93 (d, 1 H, J = 13.9 Hz, H-3), 3.97 (mAB, 1 H, H-7,-5), 4.11 (dd, 1
H, J = 16.9, 1.2 Hz, H-5,-7), 4.44–4.48 (m, 1 H, H-2).
Yield: 884 mg (90%).
13C NMR (CDCl3): = 15.3, 21.5, 50.5, 52.6, 57.5, 57.8, 126.9,
127.0, 129.9, 130.0, 135.2, 136.6, 144.1, 144.2, 203.8.
1H NMR (DMSO-d6): = 3.45 (s, 4 H, H-2,-3), 3.86 (t, 4 H,
J = 13.0 Hz, H-5,-7).
13C NMR (DMSO-d6): = 44.4, 49.6, 119.6.
19F (DMSO-d6): = –93.79 (s, 2 F).
Anal. Calcd for C20H24N2O5S2: C, 55.03; H, 5.54; N, 6.42; S, 14.69.
Found: C, 55.40; H, 5.59; N, 6.43; S, 14.8.
ESI-MS: m/z (%) = 137 [M + H+], 178 (100) [M + CH3CN + Na+].
6,6-Difluoro-1,4-bis(toluene-4-sulfonyl)-[1,4]diazepane (5)
To a solution of 3 (351 mg, 0.83 mmol) in CH2Cl2 (10 mL) was add-
ed DAST (671 mg, 4.15 mmol) in two portions over 30 min. The re-
action mixture was stirred overnight at r.t. and carefully quenched
with sat. aq NaHCO3. The aqueous layer was extracted with CH2Cl2
and the combined organic phases were dried and concentrated. The
crude yellow solid was recrystallized from EtOAc to yield 5 as a
white solid.
Anal. Calcd for C5H12Br2F2N2: C, 20.16; H, 4.06; N, 9.40. Found:
C, 20.1; H, 4.22; N, 9.25.
(R)-6,6-Difluoro-2-methyl-[1,4]diazepane dihydrobromide (8)
Following method A 8 was obtained as a white solid.
Yield: 51 mg (82%); [ ]D +27.2 (c 0.5).
Following method B 8 was obtained as a white solid.
Yield: 720 mg (70%).
Yield: 297 mg (80%).
1H NMR (CDCl3): = 2.45 (s, 6 H, CH3), 3.42 (s, 4 H, H-2,-3), 3.69
1H NMR (DMSO-d6): = 1.27 (d, 1 H, J = 6.7 Hz, CH3), 3.12 (dd,
1 H, J = 14.3, 10.3 Hz, H-3), 3.45 (dd, 1 H, J = 14.3, 2.0 Hz, H-3),
3.64–3.76 (m, 3 H, H-7,-5,-2), 3.80–3.93 (m, 2 H, H-5,-7).
13C NMR (DMSO-d6): = 17.4, 45.9, 49.4, 50.7, 53.7, 120.3.
19F NMR (DMSO-d6): = –90.79 (d, 1 F, J = 247.7 Hz), –92.34 (d,
1 F, J = 247.7 Hz).
(t, 4 H, J = 12.3 Hz, H-5,-7).
13C NMR (CDCl3): = 21.5, 52.4, 54.8, 122.2, 127.1, 130.1, 135.4,
144.3.
19F NMR (CDCl3): = –103.00 (s, 2 F).
ESI-MS: m/z (%) = 445 [M + H+], 467 (100) [M + Na+], 508 [M +
CH3CN + Na+].
ESI-MS: m/z (%) = 151(100) [M + H+], 192 [M + CH3CN + Na+],
Anal. Calcd for C20H24F2N2O4S2: C, 51.34; H, 4.99; N, 6.30; S,
14.42. Found: C, 51.4; H, 5.03; N, 6.16; S, 14.2.
383 [M + M + HBr + H+].
Anal. Calcd for C6H14Br2F2N2: C, 23.10; H, 4.52; N, 8.98. Found:
C, 23.1; H, 4.72; N, 8.83.
(R)-6,6-Difluoro-2-methyl-1,4-bis-(toluene-4-sulfonyl)-[1,4]di-
azepane (6)
DAST (116mg, 0.72mmol) was added to a solution of 4 (79 mg,
0.18 mmol) in CH2Cl2 (2 mL). The mixture was stirred at r.t. over-
night. The reaction was carefully quenched with sat. NaHCO3 and
6,6-Difluoro-[1,4]diazepane (9)
A suspension of 5 (60 mg, 0.2 mmol) and (polystyrylmethyl)trime-
thylammonium bicarbonate (240 mg, 1.2 mmol, loading: 5 mmol/g)
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E. Wellner et al.
PAPER
in CH2Cl2 (3 mL) was agitated overnight. The resin was separated
from the clear solution by filtration and the filtrate was carefully
concentrated to give 9 (27 mg, quant.) as a white solid.
1H NMR (DMSO-d6): = 2.75 (s, 4 H, H-2,-3), 3.08 (t, 4 H,
J = 14.6 Hz, H-5,-7).
13C NMR (DMSO-d6): = 53.0, 55.8, 127.1.
19F NMR (DMSO-d6): = –95.02 (s, 2 F).
(4) Ziegler, C. B.; Bitha, P.; Kuck, N. A.; Fenton, T. J.; Petersen,
P. J.; Lin, Y.-I. J. Med. Chem. 1990, 33, 142.
(5) Saari, W. S.; Raab, A. W.; King, S. W. J. Org. Chem. 1971,
36, 1711.
(6) Wilkinson, J. A. Chem. Rev. 1992, 92, 505.
(7) Opalka, C. J.; D’Ambra, T. E.; Faccone, J. J.; Bodson, G.;
Cossement, E. Synthesis 1995, 766.
(8) Gold, E. H.; Babad, E. J. Org. Chem. 1972, 37, 2208.
(9) Henry, J. R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.;
G, D.; Weinreb, S. M. Tetrahedron Lett. 1989, 30, 5709.
(10) Stauffer, S. R.; Katzenellenbogen, J. A. J. Comb. Chem.
2000, 2, 318.
ESI-MS: m/z (%) = 137 (100) [M + H+], 178 [M + CH3CN+].
Anal. Calcd for C5H10F2N2: C, 44.11; H, 7.4; N, 20.58. Found: C,
44.3; H, 7.54; N, 19.4.
(11) Stetter, H.; Roos, E. E. Chem. Ber. 1954, 87, 566.
(12) Parlow, J. J.; Case, B. L.; South, M. S. Tetrahedron 1999,
55, 6785.
References
(13) Subramanyam, C.; Chang, S.-P. Tetrahedron Lett. 2000, 41,
7145.
(14) To prove the enantiomeric purity of 8, a tight ion-pair of 8
with (S)-(+)-ketoprofen was compared with its racemate
using 1H NMR.
(1) Welch, J. T. Tetrahedron 1987, 43, 3123.
(2) Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619.
(3) Baker, A. W.; Shuglin, A. T. Nature (London) 1965, 206,
712.
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