Modular, Concise, and Efficient Synthesis of Highly Functionalized 5-Fluoropyridazines by a [2 + 1]/[3 + 2]-Cycloaddition Sequence

Article abstract of DOI:10.1021/acs.orglett.5b01370

An easy access to 5-fluoropyridazines by a [2 + 1]/[3 + 2]-cycloaddition sequence between terminal alkynes, a difluorocarbene, and a diazo compound is reported. This approach does not necessitate the isolation of any intermediates, and a wide range of novel 5-fluoropyridazines was synthesized from readily available starting materials. Additionally, these compounds were used as a platform to access novel and highly diversified pyridazines.

Full text of DOI:10.1021/acs.orglett.5b01370

Letter
pubs.acs.org/OrgLett
Modular, Concise, and Efficient Synthesis of Highly Functionalized
5‑Fluoropyridazines by a [2 + 1]/[3 + 2]-Cycloaddition Sequence
Gael Tran, Domingo Gomez Pardo, Tomoki Tsuchiya,† Stefan Hillebrand,‡ Jean-Pierre Vors,†
̈
and Janine Cossy*
Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI), ESPCI ParisTech, UMR 8231,
PSL Research University. 10 rue Vauquelin, Paris 75231 Cedex 05, France
S
* Supporting Information
ABSTRACT: An easy access to 5-fluoropyridazines by a [2 + 1]/[3 + 2]-cycloaddition sequence between terminal alkynes, a
difluorocarbene, and a diazo compound is reported. This approach does not necessitate the isolation of any intermediates, and a
wide range of novel 5-fluoropyridazines was synthesized from readily available starting materials. Additionally, these compounds
were used as a platform to access novel and highly diversified pyridazines.
mediated C−H fluorination, which only allows fluorination at the
C3/C6 position (Scheme 1, eq 2).5 In this paper, we report a
concise, efficient, and mild method to access a wide range of
fluoropyridazines.
Based on the known instability of cyclopropano[c]pyrazolines
such as I,7 we envisioned that a [2 + 1]/[3 + 2]-cycloaddition
sequence between an acetylenic derivative, a difluorocarbene
(:CF2) source, and a diazo compound would constitute a
powerful and straightforward access to 5-fluoropyridazines K
(Scheme 2). Indeed, dihydropyridazine J should aromatize
spontaneously to produce K upon elimination of HF, whereas
cyclopropano[c]pyrazoline I should undergo a facile ring
expansion to J due to the weakening effect of the distal fluorine
atoms onto the fused [c] bond.8 In this method, the major
yridazines are prevalent heterocycles that have recently
Pfound a broad range of applications in the pharmaceutical,
agrochemical, and material industries.1 Although they are behind
more popular heterocycles in terms of medicinal and agro-
chemical applications, a surge of interest for pyridazines has
recently appeared among medicinal chemists.1a Most notably, the
pyridazine ring has been ranked as the “most developable heterocycle
ring” by GSK scientists, based on its performance in terms of
solubility, HSA binding, and P450 inhibition tests.2
Corollary to the ancient contempt of medicinal chemists for
the pyridazine ring, synthesis and functionalization methods of
this heterocycle are rare compared to the number of procedures
reported for other nitrogen-containing rings.3 Due to the
considerable benefits that can be brought by a fluorine atom on
the pharmacodynamic and pharmacokinetic properties of a
compound, and in light of the recent recognition received by
pyridazines, it appears that there is a need for the development of
methods to access a diversity of substituted fluoropyridazines.
Indeed, until now, only two methods have been reported to
selectively access fluoropyridazines (Scheme 1): (1) the
displacement of a chlorine atom by a metal fluoride, which
requires harsh conditions and the previous synthesis of the
chlorinated pyridazine (Scheme 1, eq 1),4 and (2) the AgF2-
Scheme 2. Retrosynthesis of 5-Fluoropyridazines from
Readily Available Alkynes
challenge is the [3 + 2]-cycloaddition involving gem-difluoro-
cyclopropenes H, as these compounds have never been used as
partners in a [3 + 2]-cycloaddition. Even though the reactivity of
cyclopropenes H remains somewhat underexplored, these
cyclopropenes can be efficiently prepared by a [2 + 1]-
cycloaddition of difluorocarbene onto alkynes G (Scheme 2).8,9
To test our hypothesis, the unstable 1-aryl-2,2-difluorocyclo-
propenes10 were prepared and immediately treated with
Scheme 1. Methods for the Introduction of a Fluorine Atom
onto a Pyridazine Ring
Received: May 11, 2015
© XXXX American Chemical Society
A
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diazoesters (Scheme 3). Thus, 1-phenyl-2,2-difluorocyclopro-
pene 2a was prepared from phenylacetylene 1a [TMS-CF3, NaI,
THF, 110 °C, 2 h],10 and after removal of the solvent, compound
2a was treated with ethyl diazoacetate 3a in the presence of Et3N
in DMF at rt. Under these conditions, fluoropyridazine 4aa was
isolated in 77% overall yield as a single regioisomer. When 3a was
replaced by benzyl diazoacetate 3b or tert-butyl diazoacetate 3c,
good yields in the corresponding pyridazines 4ab and 4ac were
obtained. The scope of the reaction was then evaluated by
involving various acetylenic derivatives in the reaction sequence
using 3a. Overall, the expected 5-fluoropyridazines were obtained
in modest to excellent yields (30−86%). Acetylenic derivatives
possessing an aryl group substituted by an electron-donating
group (4b−d) as well as electron-withdrawing groups (EWG)
(4f,g) were converted to the corresponding 5‑fluoropyridazines
in good yields over two steps. The only exception were 1h,
possessing a m-CF3 group, as 4h was obtained in a modest 33%
yield, and 1e, possessing a p-NMe2 group, as only degradation of
this latter was observed. Alkynes bearing a cycloalkyl substituent,
such as cyclopropylacetylene 1i and cyclohexylacetylene 1j, also
appeared to be suitable substrates, although in the case of 1i, only
a modest yield of 30% in the corresponding pyridazine 4i was
obtained. This was most likely due to the high volatility of
intermediate 2i (R1 = cyclopropyl) (Scheme 3).
(120 °C, 3 h), and then with diazoacetate 3a in the presence of
Et3N, pyridazine 4h was isolated in good yields (60%). Similarly,
when various alkynes bearing electron-poor aryl substituents
were involved in the reaction sequence, the corresponding
5‑fluoropyridazines 4k−m were isolated in good yields (Scheme
4). However, in the case of propargyl acetate 1n and 3-phenyl-1-
propyne 1o, modest yields of 4n (27%) and 4o (14%) were
obtained. These results could be rationalized by the known
tendency of intermediates 2n and 2o to undergo a double-bond
migration.12,13
Scheme 4. Alternative Sequential Procedure for Electron-
Poor Alkynes
Scheme 3. Scope of the Reaction
Having demonstrated the scope of the [2 + 1]/[3 + 1]-
cycloaddition sequence with 1-arylalkynes and 1-alkylalkynes, we
turned our attention to heteroaromatic acetylenic starting
materials. These compounds were expected to be significantly
more challenging in the difluorocyclopronenation step, due to
the fact that heteroaromatic compounds are Lewis bases that can
coordinate :CF2, thus resulting in difluoromethylation or
degradation of the starting material.14 Up to now, and to the
best of our knowledge, no successful [2 + 1]-cycloaddition has
ever been reported between difluorocarbene and alkynes bearing
heterocyclic substituents (with the exception of 3-ethynylth-
iophene).
This incompatibility between :CF2 and Lewis bases was
confirmed by the low yield in pyridazine 6a obtained when
2‑ethynylpyridine 5a was engaged in the [2 + 1]/[3 + 2]-
cycloaddition sequence (Table 1, entry 1). In the case of
3‑ethynylpyridine 5b, for which the basicity of the nitrogen is not
lowered by a proximal triple bond, only degradation of 5b was
observed during the difluorocyclopropenation step (Table 1,
entry 2). This small but significant difference of reactivity
between 5a and 5b encouraged us to investigate the use of
heterocycles for which the Lewis basicity is modulated by
electronegative atoms. Accordingly, when2-chloro-5-ethynylpyr-
idine 5c was involved in the reaction sequence, the desired
pyridazine 6c was obtained in good yields (54% over two steps)
using TMS-CF3 as the :CF2 source (Table 1, entry 3). When
2‑chloro-6-ethynylpyridine 5d was reacted under the same
conditions, a low yield of 20% of the desired product 6d was
obtained (Table 1, entry 4). However, when TMS-CF3 was
replaced by TFDA as the :CF2 source, 6d was isolated in 60%
yield (Table 1, entry 5).15 Considering that embedded sulfur and
oxygen atoms can also act as Lewis basicity modulators,
4‑ethynylthiazole 5e, 5-ethynylbenzoxazole 5f, and 4-ethynyl-
thiophene 5g were involved in the reaction sequence, and the
As a significant decrease in yield was observed with electron-
poor alkynes, the use of trimethylsilyl 2-(fluorosulfonyl)-2,2-
difluoroacetate (TFDA) as an alternative source of :CF2 was
investigated. This reagent developed by Dolbier et al.11a,b was
reported to be an efficient agent for the difluorocyclopronenation
of electron-poor α,β-acetylenic ketones11c,d and propargyl
esters,11e although it has never been applied to terminal,
electron-poor 1-arylalkynes. Thus, when 1h was treated with
TFDA in the presence of a catalytic amount of NaF in diglyme
B
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cyclic alkynes, provided that the Lewis basic character of the
heterocycles is appropriately modulated.
Table 1. Scope of the [2 + 1]/[3 + 2]-Cycloaddition Sequence
with Heterocycle-Substituted Alkynes
This [2 + 1]/[3 + 2]-cycloaddition sequence allows the
introduction of a wide functional diversity at the C6 position to
produce substituted pyridazines 4 and 6, but the scope remains
limited to an ester at the C3 position, a hydrogen at the C4
position, and a fluorine at the C5 position. Moreover, all of the
obtained structures remain of moderate utility if they cannot be
further functionalized. For this reason, we also demonstrated that
5-fluoropyridazine 4aa canbe selectively diversified at the C3, C4,
and C5 position by carefully selecting the reagents (Scheme 5).
a
Scheme 5. Structural Diversification of 5-Fluoropyridazines
a
a
Combined yield. Obtained as a 95:5 mixture of regioisomers in favor
Conditions to obtain 7a: N-methylaniline (2.0 equiv), MeCN,
b
of 6k. Combined yield. Obtained as a 92:8 mixture of regioisomers in
100 °C, 14 h; 7b: morpholine (2.0 equiv), MeCN, rt, 4 h; 7c: TFA
(1.0 equiv), cyclopropylcarbinol (1.1 equiv), rt, 80 h; 7d: EtSNa (1.3
equiv), MeCN, 100 °C, 3 h; 7e: dimethylmalonate (3.0 equiv), DBU
(3.0 equiv), DMSO, 80 °C, 3 h; 7f: MeNO2 (3.0 equiv), DBU (3.0
equiv), DMSO, 80 °C, 2 h; 8a: DIBAL-H (2.0 equiv), CH2Cl2,
−78 °C, 1 h; 8b: DIBAL-H (2.0 equiv), CH2Cl2, −78 °C to rt, 18 h;
8c: n‑BuLi (1.1 equiv), pyrrolidine (1.2 equiv), THF, −78 °C, 10 min;
8d: cyclopropylmagnesium bromide (1.35 equiv), THF, −78 °C, 1 h;
9a: (1) TMP-MgCl.LiCl (1.1 equiv), THF, −78 °C, 3−4 h, (2) I2 (1.2
equiv), −78 °C to rt, 2 h; 9b: (1) deprotonation, (2) PhSO2SPh (1.3
equiv), THF, −78 °C to rt, 0.5 h; 9c: (1) deprotonation, (2)
cyclopropanecarboxaldehyde (1.3 equiv), THF, −78 °C to rt, 3 h; 9d:
(1) deprotonation, (2) CuCN·2LiCl, THF, −78 to −40 °C, 1.5 h,
then allyl bromide (1.3 equiv), −40 °C to rt, 2 h; 9e: (1)
deprotonation, (2) CuCN.2LiCl, THF, −78 to −40 °C, 1.5 h, then
benzoyl chloride (1.3 equiv), −40 °C to rt, 1.5 h; 9f: (1)
deprotonation, (2) ZnCl2, THF, −78 to −40 °C, 2.5 h, then
Pd(dba)2, (5 mol %), P(furyl)3 (10 mol %), ethyl 3-iodobenzoate (1.5
equiv), THF, −40 °C to rt, 18 h.
favor of 6m.
desired pyridazines 6e−g were isolated in good yields (Table 1,
entries 6−8). However, the presence of an sp3-nitrogen in the
heterocycle was detrimental, as 5-ethynylimidazole 5h and
4‑ethynylpyrazole 5i decomposed upon treatment with TMS-
CF3 (Table 1, entries 9 and 10). By contrast, when 4-ethynyl-N-
tosylpiperidine 5j was involved in the reaction sequence, the
desired product 6j was isolated in 66% yield (Table 1, entries 11).
Even primary aliphatic amines adequately protected as a
phthalimide or a N,N-bis-Boc derivative appeared to be suitable
substrates as 6k, 6l, and 6m were isolated in 63%, 66%, and 73%
yield, respectively (Table 1, entries 12−14).
Thus, we have demonstrated that the [2 + 1]/[3 + 2]-
cycloaddition sequence tolerates 1-aryl-, 1-alkyl-, and 1‑hetero-
C
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The fluorine at the C5 position was displaced by soft
nucleophiles, such as amines, alcohols, thiolates, or stabilized
carbanions, to give products 7a−f in good to quantitative yields.
By contrast, hard nucleophiles, such as DIBAL-H, lithium amides
or Grignard reagents, were reactive toward the carbonyl group at
C3, and the corresponding aldehyde 8a, alcohol 8b, amide 8c, and
ketone 8d were obtained in modest to excellent yields. The
remaining C4 position could be deprotonated by the Knochel−
Hauser base TMP-MgCl·LiCl,16a and the corresponding
magnesiated species reacted with electrophiles, such as I2,
PhSO2SPh, or cyclopropanecarboxaldehyde, yielding products
9a−c. Alternatively, transmetalation of the magnesiated species
by CuCN·2LiCl followed by the addition of allyl bromide or acyl
chloride led to 9d,e in excellent yields. In addition, a
transmetalation by ZnCl2 followed by a Negishi cross-coupling
afforded 9f in 41% yield (Scheme 5).16b
5-Fluoropyridazines such as 4aa are therefore not only
molecules of interest by themselves, as they can also be extremely
versatile platforms to access a variety of substituted pyridazines in
a very limited number of steps. Combined with the [2 + 1]/[3 +
2]-cycloaddition sequence, this platform ability of 5-fluoro-
pyridazines arguably makes this method one of the most versatile
and efficient routes to highly functionalized pyridazines, allowing
an increase of the chemical space coverage.
In summary, a versatile, concise, and efficient route to
5‑fluoropyridazines was developed, and it has been shown that
these products could be efficiently and easily diversified at the C3,
C4, and C5 positions. A considerable increase in the chemical
space coverage is brought by this simple route to highly
functionalized pyridazines, which should be of interest for
pharmaceutical and agrochemical companies. From a more
general point of view, we demonstrated that gem-difluorocyclo-
propenes can be used as partners in [3 + 2]-dipolar cycloaddition
and that these transformations can occur with high regioselec-
tivity and in high yields. This novel reactivity of gem-
difluorocyclopropenes and its application to various [3 + 2]-
dipolar species can potentially lead to countless new methods to
access fluorinated heterocycles.
ACKNOWLEDGMENTS
Financial support and a Ph.D. grant (G.T.) from Bayer S.A.S. is
gratefully acknowledged.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, spectroscopic data, and experimental
spectra. The Supporting Information is available free of charge on
the ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01370.
(14) For a recent review on the difluoromethylation of heteroatoms by
difluorocarbene, see: Ni, C.; Hu, J. Synthesis 2014, 46, 842−863.
(15) This difference in yield was due to a competitive deprotonation
−
(by CF3 )/trimethylsilylation (by TMS-I) of the acidic acetylenic
AUTHOR INFORMATION
proton. As no base or trimethysilylating agent were present in the TFDA
protocol, this pathway was efficiently circumvented.
(16) (a) Lin, W.; Baron, O.; Knochel, P. Org. Lett. 2006, 8, 5673−5676.
(b) Wunderlich, S. H.; Knochel, P. Chem. Commun. 2008, 6387−6389.
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Corresponding Author
*E-mail: janine.cossy@espci.fr.
Present Addresses
†(T.T., J.-P.V.) Bayer S.A.S., Small Molecule Research - Disease
Control Chemistry, 14 Impasse Pierre Baizet, 69263 Lyon Cedex
09, France.
‡(S.H.) Bayer S.A.S., Research - Disease Control Chemistry,
BCS-R&D-SMR-DC-DCM, Building 6240, 50 Alfred Nobel Str,
D-40789 Monheim, Germany.
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.5b01370
Org. Lett. XXXX, XXX, XXX−XXX