Tetrakis(dimethylamino)ethylene (TDAE) mediated addition of heterocyclic difluoromethyl anions to heteroaryl aldehydes. A facile synthetic method for new gem-difluorinated alcohols derived from 4-bromo-1-naphthylamine and 8-quinolylamine

Article abstract of DOI:10.1055/s-2001-14594

New heterocyclic-CF₂CHOH-Ar derivatives, derived from N,N-dimethyl-4-bromo-2-difluoracetyl-1-naphthylamine and N,N-dimethyl-5-difluoroacetyl-8-quinolylamine, are easily obtained in moderate to good yields from the tetrakis(dimethylamino) ethylene (TDAE) mediated reduction of the corresponding - COCF₂Cl starting materials in the presence of heteroaryl aldehydes.

Full text of DOI:10.1055/s-2001-14594

LETTER
821
Tetrakis(dimethylamino)ethylene (TDAE) Mediated Addition of Heterocyclic
Difluoromethyl Anions to Heteroaryl Aldehydes. A Facile Synthetic Method
for New gem-Difluorinated Alcohols Derived from 4-Bromo-1-naphthylamine
and 8-Quinolylamine
Maurice Médebielle,*a Robert Keirouz,a Etsuji Okada,b Takuro Ashidab
aUniversité Claude Bernard-Lyon 1, Laboratoire de Synthèse, Electrosynthèse et Réactivité des Composés Organiques Fluorés (SERCOF),
UMR CNRS 5622, Bâtiment E. Chevreul, 43 Bd du 11 Novembre 1918, F-69622 Villeurbanne Cedex, France
bDepartment of Chemical Science and Engineering, Faculty of Engineering, Kobe University, Rokkodai-cho, Nada-ku, Kobe 657-8501,
Japan
Fax +33 (4) 72 43 13 23; E-mail: medebiel@univ-lyon1.fr
Received 15 March 2001
rivatives that incorporate quinoline as well as naphthalene
Abstract: New heterocyclic-CF2CHOH-Ar derivatives, derived
units. These new difluoromethylene aromatics and hetero-
cycles were designed for further chemical elaboration as
part of a project devoted to the synthesis of new therapeu-
from N,N-dimethyl-4-bromo-2-difluoracetyl-1-naphthylamine and
N,N-dimethyl-5-difluoroacetyl-8-quinolylamine, are easily ob-
tained in moderate to good yields from the tetrakis(dimethylami-
no)ethylene (TDAE) mediated reduction of the corresponding - tic agents.
COCF2Cl starting materials in the presence of heteroaryl aldehydes.
Careful examination, by cyclic voltammetry, of the re-
Key words: electron transfer, fluorine, naphthylamines, quinoly-
duction potential of starting materials N,N-dimethyl-4-
bromo-2-chlorodifluoracetyl-1-naphthylamine 1 (Epc1 =
–1.20 V vs SCE, first peak potential measured in DMF/
0.1 M NBu4PF6) and N,N-dimethyl-5-chlorodifluoro-
acetyl-8-quinolylamine 2 (Epc1 = –1.14V vs SCE, first
peak potential measured in DMF/0.1 M NBu4PF6), clearly
shown that these -COCF2Cl substrates were good elec-
tron-acceptors and therefore prompted us to use the tet-
rakis(dimethylamino)ethylene (TDAE) as a mild and
efficient organic reductant11 for the in situ generation and
trapping of the corresponding , -difluoroacetyl anions,
with a series of aromatic and heterocyclic aldehydes
(Scheme 1).
lamines, heterocycles
There continues to be an interest in the synthesis of new
gem-difluorinated compounds because of the potential bi-
ological properties of such molecules.1 For example elec-
trophilic carbonyl derivatives, such as
, -
difluoroketones, are compounds of great interest because
they have the capability to form stable adducts (such as
hydrates and hemiketals) with nucleophiles;1 it is believed
that this property allows some fluorinated ketones to mim-
ic the transition states involved in the hydrolytic action of
many enzymes.1 Fluorinated substituted aromatics and
heterocycles, may found broad applications such as agro-
chemicals, anticancer and antiviral agents.2 Quinolines are
important heterocyclic systems, constituting the structure
of many naturally occurring products and having interest-
ing pharmacological properties.3 In particular quinoly-
lamine derivatives have been used as the basis in the
molecular design for synthetic antimalarial compounds,4
anti-HIV agents,5 and for the treatment of the Alzheimer
disease.6
TDAE/Ar'CHO
Ar-COCF2CHOH-Ar'
Ar-COCF2Cl
anhyd DMF
-20 °C to r.t
TDAE: (Me2N)2C=C(NMe2)2
Scheme 1
Starting materials 1 and 2 were prepared in good yields in
two steps, N,N-dimethylation (MeI/KOH in DMSO for 1;
trimethyl phosphate/NaOH for 2) and subsequent 2-chlo-
rodifluoroacetylation [chlorodifluoroacetic anhydride
(CDFAA)/Pyridine in CHCl3] from commercially avail-
able 4-bromo-1-naphthylamine and 8-quinolylamine
(Scheme 2).
Recently we have been interested in the aromatic nucleo-
philic substitution reactions of N, N-dimethyl-2,4-bis(trif-
luoroacetyl)-1-naphthylamine,7 N, N-dimethyl-2-trifluo-
roacetyl-4-halo-1-naphthylamine,8 and N, N-dimethyl-
5,7-bis-trifluoroacetyl-8-quinolylamine,9 with amines,
thiols and alcohols and we have shown that the corre-
sponding exchanged products could be easily converted in
various fluorinated fused-heterocycles of potential bio-
logical importance. As part of our ongoing efforts in the
search of new methodologies to the synthesis of fluorinat-
ed compounds with potential biological and synthetic ap-
plications,10 we wish to present a synthetic method to
prepare, under very mild conditions, new -CF2CHOH- de-
In a typical experiment, 1 equivalent of ketone 1 was con-
densed, in anhydrous DMF at 20 °C, with 5 equivalent of
benzaldehyde in the presence of TDAE; a 1.2 equivalent
of TDAE was necessary for complete reduction of the
starting ketone 1, with the reaction being almost complete
after two hours (TLC monitoring). After usual work-up,
Synlett 2001 No. 6, 821–823 ISSN 0936-5214 © Thieme Stuttgart · New York

822
M. Médebielle et al.
LETTER
NMe2
NH2
NMe2
NMe2
COCF2Cl
MeI (6 eq)
KOH (2.5 eq)
TDAE (1.2 eq)
ArCHO (5 eq)
COCF2CHOHAr
DMSO/r.t/18 h
anhyd DMF
-20 °C to r.t
95%
Br
Br
Br
Br
1
Ar= phenyl; 3 (45%)
p- fluorophenyl; 4 (62%)
3-pyridinyl; 5 (49%)
NMe2
(ClCF2CO)2O (1.2 eq)
Pyridine (1.2 eq)
COCF2Cl
3,4-dimethoxyphenyl; 6 (21%)
CHCl3/r.t/18 h
84%
NMe2
NMe2
N
Br
TDAE (1.2 eq)
ArCHO (5 eq)
N
1
NH2
NMe2
anhyd DMF
-20 °C to r.t
N
N
1. (MeO)3PO/reflux/1 h
COCF2Cl
COCF2CHOHAr
2. NaOH/100 °C/1 h
2
Ar= phenyl; 7 (65%)
p- fluorophenyl; 8 (74%)
2-pyridinyl; 9 (75%)
3-pyridinyl; 10 (70%)
4-pyridinyl; 11 (61%)
69%
NMe2
(ClCF2CO)2O (1eq)
Pyridine (1eq)
N
3,4-dimethoxyphenyl; 12 (19%)
CHCl3/r.t/18 h
75%
Scheme 3
COCF2Cl
2
Scheme 2
rived from quinoline and naphthalene, could be obtained
in reasonable yields with the tetrakis(dimethylamino)eth-
ylene (TDAE) as an efficient electron transfer reagent.
fluorine NMR of the crude product revealed the presence The compounds synthesized in this work are potentially
of the desired alcohol 3 characterized by two doublets of useful for biological applications. Work is under progress
doublet ( F –109.1 and –118.7 ppm/CFCl3 with JF-F = 269 to extend this methodology to other halogenodifluorome-
Hz and 3JH-F = 17.42 and 6.42 Hz) and the hydrogenolysis thylated heterocycles of biological interest. Further chem-
product, the difluoroacetylated ketone (
125.7 ppm/ ical elaboration with these derivatives will be done in a
F
2
CFCl3; doublet with JH-F = 54.2 Hz) in the ratio 2 to 1. due course.
The alcohol adduct was isolated as a yellowish solid in
45% yield after purification by silica gel chromatography
Acknowledgement
and recrystallization.12 Similarly, in the presence of ben-
zaldehyde (5 equiv) and TDAE (1 equiv), ketone 2 gave M. M. would like to thank the CNRS for support of this work
the desired alcohol 7 in 65% yield. Formation of the prod- through a research grant (Aide aux Jeunes Equipes-Appel d’Offres
ucts was monitored by TLC and the yields were moderate 2000).
to good (Scheme 3). At the end of the reaction, the corre-
sponding insoluble TDAE2+, 2Cl- salt is recovered, dem-
References and Notes
onstrating that the TDAE has been clearly oxidized. The
(1) Tozer, M. J.; Herpin, T. Tetrahedron 1996, 52, 8619-8683.
(2) Burger, K.; Wucherpfennig, U.; Brunner, E. Adv. Heterocycl.
Chem. 1994, 60, 1. Bergstrom, D. E.; Swartling, D. J. Fluorine
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Dolbier, Jr, W. R., Eds.; VCH : New York 1988, pp 259-308.
(3) Larsen, R. D.; Marcoux, J.-F. In Progress in Heterocyclic
Chemistry; Gribble, G. W.; Gilchrist, T. L., Eds.; Pergamon:
Oxford, UK, 2000, Vol. 12, p 237.
only side-products which represent the remaining balance
material were the hydrogenolysis compounds RCF2H re-
sulting from protonation of the difluoromethyl anions. All
of the compounds were isolated as colored solids, in mod-
erate to good yields, after purification by silica gel chro-
matography.
With
3,4-dimethoxybenzaldehyde,
formation of significant amount of fluorinated by-prod-
ucts was observed by fluorine NMR of the crude products;
as a consequence, yields of the corresponding alcohols
were quite low. These polar compounds were removed
during the silica gel chromatography purification.
(4) Raynes, K. J.; Stocks, P. A.; O’Neill, P. M.; Park, B. K.; Ward,
S. A. J. Med. Chem. 2000, 42, 2747.
(5) Wilson, W. D.; Zhao, M.; Patterson, S. E.; Wydra, R. L.;
Janda, L.; Strekowski, L. Med. Chem. Res. 1992, 2, 102.
Strekowski, L.; Mokrosz, J. L.; Honkan, V. A.; Czarny, A.;
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None of the yields have been optimized and room for im-
provement certainly exists.
In conclusion, we have demonstrated, that under very
mild conditions, new gem-difluorinated heterocycles de-
(6) Proctor, G. R.; Harvey, A. L. Curr. Med. Chem. 2000, 7, 295.
Synlett 2001, No. 6, 821–823 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Facile Synthetic Method for New gem-Difluorinated Alcohols
823
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solution was vigorously stirred at –20 °C for 1 hour and then
warmed up to room temperature for two hours (orange-red
color). After this time TLC analysis [EtOAc/petroleum ether
(85:15)] clearly showed that 1 was totally consumed. The
orange-red turbid solution was filtered (to remove the
octamethyloxamidinium dichloride) and hydrolyzed with 30
mL of an aqueous NaCl solution. The aqueous solution was
extracted with CH2Cl2 (3 30 mL), the combined organic
solutions washed with brine (3 30 mL), H2O (3 30 mL)
and dried over MgSO4. Evaporation of the solvent left a red
viscous liquid as crude product. Fluorine NMR shown that the
desired alcohol adduct was obtained with some reduction
product in a ratio 2 to 1. Purification by silica gel
chromatography [EtOAc/petroleum ether (95:5)] gave 0.27 g
(0.62 mmol, 45%) of 3 as a yellowish crystalline solid after
recrystallization from EtOAc/petroleum ether (1/4): 1-(4-
Bromo-1-dimethylamino-2-naphthyl)-2,2-difluoro-3-
hydroxy-3-phenyl-propan-1-one: Mp = 139-140 °C. 1H
NMR (CDCl3): H 2.93 (6H, s, -NMe2), 5.38-5.48 (1H, dd,
J = 17.3, 6.40 Hz, -CHOH), 7.44-7.65 (8H, m), 8.15-8.22 (2H,
dd, J = 7.39, 6.42 Hz), 19F NMR (CDCl3/ CFCl3): F –106.96
(1F, dd, J = 269, 6.40 Hz), –117.62 (1F, dd, J = 269, 17.32
Hz). HRMS: Calcd for C21H18BrF2NO2 433.0489, Found
433.0495.
(9) Okada, E.; Tsukushi, N.; Shimomura, N. Synthesis 2000, 237.
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(12) A typical procedure for the reaction between 1, 3 and TDAE
is as follows: Into a three-necked flask equipped with a
calcium chloride drying tube, and a nitrogen inlet was added,
under nitrogen, 5 mL of anhydrous DMF and then 1 (0.50 g,
1.38 mmol) followed by 3 (0.73 g, 6.9 mmol). The solution
was cooled down to –20 °C, stirred and maintained at this
temperature for 30 min and then was added dropwise (via a
syringe) TDAE (0.34 g, 1.66 mmol). A red color immediately
developed with the formation of a white fine precipitate. The
Article Identifier:
1437-2096,E;2001,0,06,0821,0823,ftx,en;D06801ST.pdf
Synlett 2001, No. 6, 821–823 ISSN 0936-5214 © Thieme Stuttgart · New York