First synthesis of 4-chloro-2,2-difluoro[1,3]dioxole[4,5-c]pyridine

Article abstract of DOI:10.1016/j.tetlet.2010.10.119

The 2,2-difluorobenzodioxole moiety has been introduced in medicinal chemistry research as a potential metabolically more stable derivative of the benzodioxole fragment. Herein we present, to the best of our knowledge, the first synthesis of 4-chloro-2,2-

Full text of DOI:10.1016/j.tetlet.2010.10.119

Tetrahedron Letters 51 (2010) 6783–6785
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Tetrahedron Letters
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First synthesis of 4-chloro-2,2-difluoro[1,3]dioxole[4,5-c]pyridine
⇑
,
Maria Pia Catalani , Alfredo Paio , Lorenzo Perugini à
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Medicines Research Centre, Via Fleming 4, 37135 Verona, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The 2,2-difluorobenzodioxole moiety has been introduced in medicinal chemistry research as a potential
metabolically more stable derivative of the benzodioxole fragment. Herein we present, to the best of our
knowledge, the first synthesis of 4-chloro-2,2-difluoro[1,3]dioxole[4,5-c]pyridine, a 5-aza-derivative of
the 2,2-difluorobenzodioxole, from simple and cheap starting materials. The chlorine atom in position
4 could be useful for further functionalisation by cross coupling reactions.
Received 1 September 2010
Revised 20 October 2010
Accepted 22 October 2010
Available online 30 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Benzodioxole
2,2-Difluorobenzodioxole
2,2-Difluoro-5-azabenzodioxole
This Letter describes the synthesis of a novel building block
which could be considered very important and useful for medicinal
chemistry purposes.
In the literature there are several examples of biologically active
drugs and potential drugs, containing a benzodioxole moiety,1–5
for the treatment of a wide variety of conditions and disorders,
including those associated with the dysfunction of the central ner-
vous system (for example unipolar depression, Alzheimer’s and
Parkinson’s diseases).
However it has been hypothesized that the benzodioxole moi-
ety metabolism could be responsible of some Idiosyncratic Adverse
Drug Effects (IADE).6 Therefore, the 2,2-difluorobenzodioxole
group has been proposed as a potentially more stable analogue,7
in order to prevent the metabolism of the oxo-methylene-oxo
(OCH2O) portion, without differing much in terms of steric
requirements.
To the best of our knowledge a 5-aza-derivative (Fig. 1) of such
moiety has not been described in the literature so far; recently only
a 4-aza analogue of the 2,2-difluorobenzodioxole structure has
been described.8
recovery. Particular care had to be taken in processing unstable,
reactive or volatile intermediates.
The 3-pyridinol 1 was first protected as MOM ether 2, in order
to direct the following lithiation in position 4 and generate the
halo-intermediate 39,10 by reaction with either hexachloroethane
(X = Cl)5 or 1,2-dibromotetrachloroethane (X = Br).
As reported in the literature,9,10 while relatively stable in
solution, both those intermediates were unstable once isolated
and had to be quickly reacted with MeONa in dry MeOH to give
the 3-methoxymethyl-4-methoxypyridine 4.
Another chlorine atom was selectively introduced in position 2
by further lithiation with BuLi and reaction with hexachloroethane.
After that, the protecting groups of the chloropyridine 511 were
cleaved with boron tribromide in dry DCM to give the 2-chloro-
3,4-dihydroxypyridine 6.
After careful quenching with MeOH, the recovery in excellent
yield of this water-soluble diol, from the extremely acidic reaction
crude, was performed by removal of the solvent, trituration in
AcOEt, filtration and final purification of the isolated solid on an
ion exchange cartridge (SCX).
Therefore we would like to report herein the first synthesis of
4-chloro-2,2-difluoro[1,3]dioxole[4,5-c]pyridine.
In a first attempt, the synthesis of the target material 8 was
investigated following the route shown in Scheme 1, starting from
the easily accessible 3-pyridinol (1).
N
Although the reactions occurred with excellent regioselectivity
(confirmed by NMR studies) and fair yields, a lot of work was done
in the optimization of the reaction parameters and intermediate
O
O
O
O
O
O
F
F
F
F
⇑
Corresponding author.
E-mail address: mariapia.catalani@inwind.it (M.P. Catalani).
Present address: Aptuit (Verona) srl, Via Fleming 4, I-37135 Verona, Italy.
Present address: Rottapharm, Via Valosa di Sopra, 9, I-20053 Monza (Mi), Italy.
2,2-difluoro-5-azabenzodioxole
Figure 1. Structural modifications on benzodioxole moiety.
benzodioxole
2,2-difluorobenzodioxole
à
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.119

6784
M. P. Catalani et al. / Tetrahedron Letters 51 (2010) 6783–6785
N
N
N
ation in Scheme 1, necessary to reach intermediates 3, both
a
observed to be unstable once isolated.9,10
b
The starting material 9 was methylated with TMS-diazometh-
ane to give 3,4-dimethoxypyridine 10. ortho-Directed lithiation
with BuLi again occurred in position 2, allowing the formation of
the 2-chloro-3,4-dimethoxypyridine 11 by reaction with hexachlo-
roethane. This was then cleaved as previously reported with boron
tribromide in DCM, to give the known dihydroxy intermediate 6.
The synthesis then proceeded as described above.
The chlorine atom in position 4 could be useful for further func-
tionalisation by cross coupling reactions, for example the reactivity
of the chlorine atom could be tested with the N-Boc-piperazine
under Buchwald conditions (Pd2dba, BINAP, t-BuOK, toluene)15 or
O
O
OH
O
O
X
1
2
3
c
X=Cl, Br
N
O
Cl
N
N
Cl
e
d
O
O
O
O
OH
O
OH
6
5
4
1,1-dimethylethyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
f
yl)-3,6-dihydro-1(2H)-pyridinecarboxylate under Suzuki condi-
tions (Pd tetrakis, K2CO3, DMF, microwave irradiation).16
N
Cl
N
Cl
In conclusion, the chemistry for the preparation of functional-
ised 5-aza-benzodioxoles, which could be used as new scaffolds
in medicinal chemistry, has been developed, leading also to the
first synthesis of 4-chloro-2,2-difluoro[1,3]dioxole[4,5-c]pyridine.
g
O
O
O
O
F
S
F
7
8
Acknowledgements
Scheme 1. Reagents and conditions: (a) NaH 60 wt %, DMF, MOMCl, 0 °C, 2 h,
Y = 81%; (b) t-BuLi, C2Cl6 or C2Cl4Br2, Et2O, À70 °C, Y = 87% or 91%; (c) MeONa,
MeOH, 80 °C, overnight, Y = 31%; (d) BuLi, C2Cl6, THF, À70 °C, 2 h, rt, 1 h, Y = 61%; (e)
BBr3 1 M solution in DCM, DCM, 50 min, Y = 91%; (f) Cl2CS, DMAP, DCM, 1 h, rt,
Y = 79%; (g) HF/pyridine, 1,3-dibromo-5,5-dimethylhydantoin, DCM, À78 °C, 1 h,
Y = 87%.
The authors wish to thank Emiliano Castiglioni and Paola Zaran-
tonello for the contribution to the scientific discussions and to Elisa
Moro and Silvia Davalli for the analytical support.
References and notes
Thiocarbamate 7, obtained12 by reaction of 6 with thiophosgene
and DMAP in dry DCM, proved to be extremely reactive towards
weak nucleophiles such as MeOH or even water. Therefore it had
to be isolated loading the untreated reaction crude on a silica car-
tridge and eluting with 100% DCM.
The white solid was then reacted at low temperature with HF/
pyridine and 1,3-dibromo-5,5-dimethylhydantoin in dry DCM to
give the desired compound 8.13,14 In addition to required precau-
tions, when manipulating HF containing mixtures, special care
had to be taken in recovering the product, since it proved to be
rather volatile. Fortunately all the work up and chromatography
could be performed in DCM and it allowed to control solvent evap-
oration using mild conditions.
1. Fuller, R. W. Prog. Drug Res. 1995, 45, 167–204.
2. Zhou, Y.; Bourque, E.; Zhu, Y.; langille, J.; Metz, M.; Yang, W.; Mceachern, E. J.;
Harwig, G.; Baird, I.; Li, T. S.; Sherlj, R.T. PCT Int. Appl. WO 2006/138350, 2006.
3. Lynch, J. K.; Freeman, J. C.; Judd, A. S.; Iyengar, R.; Mulhern, M.; Zhao, G.; Napier,
J. J.; Wodka, D.; Brodjian, S.; Dayton, B.; Falls, D.; Ogiela, C.; Reilly, R. M.;
Campbell, T. J.; Polakowski, J. S.; Hernandez, L.; Marsh, K. C.; Shapiro, R.;
Knourek-Segel, V.; Droz, B.; Bush, E.; Brune, M.; Preusser, L. C.; Fryer, R. M.;
Reinhart, G. A.; Houseman, K.; Diaz, G.; Mikhail, A.; Limberis, J. T.; Sham, H. L.;
Collins, C. A.; Kym, P. R. J. Med. Chem. 2006, 49, 6569–6584.
4. Schmidt, W. J.; Moyerhofer, A.; Meyer, A.; Koudr, K. A. Neurosci. Lett. 2002, 330,
251–254.
5. Runyin, S. P.; Burgess, J. P.; Abraham, P.; Keverline-Frantz, K. I.; Flippen-
Anderson, J.; Deachamos, J.; Lewin, A. H.; Navarro, H. A.; Boja, J. W.; Kuhar, M. J.;
Carroll, F. I. Bioorg. Med. Chem. 2005, 13, 2439–2449.
6. Kalgutkar, A. S.; Didiuk, M. T. Chem. Biodivers. 2009, 6, 2115–2135.
7. Trachsel, D.; Hadorn, M.; Baumberger, F. Chem. Biodivers. 2006, 3, 326–336.
8. Mazurov, A.; Miao, L.; Xiao, Y.; Yohannes, D.; Akireddy, S. R.; Breining, S. R.;
Kombo, D.; Murthy, V. S. PCT Patent Application International Publication
number WO 2010/002971, 2010.
9. Rommel, M.; Ernst, A.; Koert, U. Eur. J. Org. Chem. 2007, 26, 4408–4430.
10. Shimano, M.; Noriyuki, K.; Tetsuo, S.; Kiyoshi, I. Nobuko, l I.; Takashi, I.; Hisato, S.
Tetrahedron 1998, 54, 12745–12774.
In order to devise an alternative synthetic route to access 8, a
shorter and easy strategy was planned, taking advantage of the
commercial availability of 3,4-dihydroxypyridine 9 (Scheme 2).
The new process avoids the tricky step (b) of chlorination/bromin-
11. BuLi (1.6 M in hexane, 8866
ll, 14.19 mmol) was added, under nitrogen, to dry
THF (60 ml) at À70 °C, followed by
a
solution of 4-methoxy-3-
methoxymethoxy-pyridine (Intermediate 4, 1000 mg, 5.91 mmol) in dry THF
(7 ml). After being stirred for 1 h, a solution of hexachloroethane (3079 mg,
13.00 mmol) in dry THF (7 ml) was added to the orange reaction mixture. The
temperature of the reaction mixture was kept at À70 °C for 1 h, then at rt for 1
more hour. The reaction mixture was quenched by addition of saturated NH4Cl
and the aqueous phase was extracted with Et2O twice. The combined organics
were washed with brine, dried over Na2SO4 and evaporated to dryness. The
residue was purified by flash-chromatography with Biotage SP4 (silica
N
N
O
N
O
Cl
O
a
b
OH
O
OH
9
10
11
cartridge), eluting with cyclohexane/EtOAc (from 0% to 60%), to afford
(730 mg, 61% yield) as a yellow oil.
5
c
1H NMR (400 MHz, CDCl3)
d
ppm 8.07 (1H, d, J = 5.56 Hz,) 6.83 (1H, d,
J = 5.56 Hz,) 5.20 (2H, s) 3.93 (3H, s) 3.66 (3H, s). UPLC (IPQC): tR 0.70 min, m/z
N
Cl
N
Cl
N
Cl
204 [M+H]+1
.
e
d
The 1H spectra reported in the paper were obtained in CDCl3 at 25 °C using a
Bruker instrument 400 MHz. Chemical shifts are reported in ppm (d) using the
residual solvent line as the internal standard.
OH
O
O
S
O
O
OH
Total ion current (TIC) and DAD UV chromatographic traces together with MS
and UV spectra associated with the peaks were taken on a UPLC/MS AcquityTM
system equipped with 2996 PDA detector and coupled to a Waters Micromass
ZQTM mass spectrometer operating in positive or negative electrospray
ionisation mode [LC/MS—ES (+ or À): analyses performed using an
F
F
8
7
6
Scheme 2. Reagents and conditions: (a) TMSN2 (2 M hexane solution), DCM/MeOH,
5 h, rt, Y = 49%; (b) BuLi, C2Cl6, THF, À70 °C, 2 h, rt 1 h, Y = 70%; (c) BBr3 1 M solution,
DCM, rt, 3 h, Y = 84%; (d) Cl2CS, DMAP, DCM,1 h, rt, Y = 79%; (e) HF/pyridine, 1,3-
dibromo-5,5-dimethylhydantoin, DCM, À78 °C 1 h, Y = 87%.
AcquityTM UPLC BEH C18 column (50 Â 2.1 mm, 1.7
lm particle size). Acidic
conditions: Mobile phase: A—water + 0.1% HCO2H/B—CH3CN + 0.06% HCO2H.
Gradient: t = 0 min 3% B, t = 0.05 min 6% B, t = 0.57 min 70% B, t = 1.06 min 99%

M. P. Catalani et al. / Tetrahedron Letters 51 (2010) 6783–6785
6785
B lasting for 0.389 min, t = 1.45 min 3% B, stop time 1.5 min. Column T = 40 °C.
Flow rate = 1.0 mL/min. Mass range: ES (+): 100–1000 amu. ES (À): 100–
800 amu. UV detection range: 210–350 nm.
mixture was then stirred for 40 min, turning to dark red. After further 20 min,
the cold reaction mixture was quenched by careful addition of 130 ml of
aqueous ꢀ5 M NaOH. A small amount of solid sodium thiosulphate was added
to the mixture. The mixture was diluted with water, a white thick residue was
removed by filtration and washed with DCM. The organic layer was separated
with a phase separator tube and the aqueous one was extracted with further
DCM. The collected organics were carefully evaporated under reduced
pressure, keeping the heating bath at 30 °C and working above 300 mbar.
The residual liquid was purified by flash chromatography on silica gel, using a
100 g SNAP prepacked Biotage cartridge and eluting with DCM. The product
was partially coeluted with a byproduct, so the mixed fractions were carefully
concentrated under reduced pressure and again purified by flash
chromatography on silica gel, this time using a 50 g SNAP Biotage prepacked
column and eluting with DCM. The pure fractions from both purifications were
carefully evaporated, to give 1.17 g of compound 8 as a colourless oil.
12. 2-Chloro-3,4-pyridinediol (Intermediate 6, 2.2 g, 13.60 mmol) and DMAP
(6.65 g, 54.4 mmol) were suspended in 60 ml of dry DCM under argon
atmosphere. The mixture was cooled at 0 °C and thiophosgene (2.6 ml,
33.9 mmol) was dropwise added. During the addition the formation of a
light red precipitate was immediately observed. After 10 min the cooling bath
was removed and the mixture was stirred at room temperature for 1 h. The
reaction was diluted with DCM and silica was added to the reaction mixture.
The solvent was removed under vacuum and the resulting red powder was
loaded on
a 100 g SNAP silica gel Biotage prepacked column for
chromatographic purification. The intermediate
yielding, after evaporation, 2.02 g of a white solid.
7 was eluted with DCM
1H NMR (400 MHz, CDCl3)
d ppm 8.42 (1H, d, J = 5.43 Hz), 7.31 (1H, d,
J = 5.43 Hz); UPLC (IPQC): tR 0.91 min, m/z 188 [M+H]+, 1Cl isotopic pattern.
13. Koruboshi, M.; Hyama, T. Synlett 1994, 251–252.
1H NMR (400 MHz, CDCl3)
d ppm 8.25 (1H, d, J = 5.31 Hz), 7.10 (1H, d,
J = 5.31 Hz); UPLC (IPQC): tR 0.94 min, m/z 194 [M+H]+, 1Cl isotopic pattern.
15. Betzemeier, B.; Krist, B.; McConnell, D.; Steurer, S.; Impagnatiello, M.; Weyer-
Czernilofsky, U.; Hilberg, F.; Brueckner, R.; Daiimann, G.; Hecker, A.; Kley, J.;
Lehmann-Lintz, T.; Roth, G. Eur. Pat. Appl. EP 1,645,556, 2006.
14. 4-Chloro[1,3]dioxolo[4,5-c]pyridine-2-thione
7
(1.3 g, 6.93 mmol) was
dissolved in 40 ml of dry DCM. The solution was cooled with an acetone and
dry ice bath and HF/pyridine (Aldrich, HF/pyridine 7/3 wt, 9/1 mole ratio)
(13 ml)
was
carefully
added
dropwise.
Solid
1,3-dibromo-5,5-
16. Lu, P. P.; Qian, X.; Finer, J. T.; Chuang, C.; Morgan, B. P.; Morgans, D. J. J. PCT Int.
Appl. WO 2008/016643, 2008.
dimethylhydantoin (6 g, 20.98 mmol) was immediately added portionwise.
After 20 min the cooling bath was replaced by one made of ice and NaCl. The