Nucleophilic Difluoroalkylation of Isocyanates with Difluoromethyl 2-Pyridyl Sulfone

Article abstract of DOI:10.1002/adsc.201500150

The nucleophilic difluoroalkylation of isocyanates with difluoromethyl 2-pyridyl sulfone furnished 2,2-difluoro-2-pyridinylsulfonylacetamides with good to excellent yield. These products can be converted to 2,2-difluoroacetamide sulfinate, iododifluoroacetamide and 2-aminopyridine derivatives easily.

Full text of DOI:10.1002/adsc.201500150

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DOI: 10.1002/adsc.201500150
Nucleophilic Difluoroalkylation of Isocyanates with
Difluoromethyl 2-Pyridyl Sulfone
Shan Li,+a Peng Peng,+a Jun Wei,a Yongzhou Hu,a Jinbo Hu,b and Rong Shenga,*
a
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang
University, Hangzhou 310058, Peopleꢀs Republic of China
E-mail: shengrong1973@163.com
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
b
Shanghai 200032, Peopleꢀs Republic of China
+
These authors contribute equally to this work.
Received: February 13, 2015; Revised: August 18, 2015; Published online: November 12, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500150.
Abstract: The nucleophilic difluoroalkylation of iso-
cyanates with difluoromethyl 2-pyridyl sulfone fur-
yielded a wide range of iodo- and bromodifluoro-
methyl derivatives.[6] In addition, it also can react with
alkyl halides to yield alkyl 2,2-difluorinated 2-pyridyl
sulfones, which undergo dearylation with EtSNa to
produce alkyl 2,2-difluorosulfinates, such as sodium
difluoroethylsulfinate (DFES-Na), which acts as an
efficient difluoroethylation agents for a variety of het-
erocycles, including quinoxaline, indole, pyridine and
pyrimidine derivatives.[7,8] Besides that, 2-PySO2CF2H
also can realize a highly stereoselective nucleophilic
difluoro-(sulfinato) methylation of N-tert-butanesulfi-
nylimine to yield optically active a,a-difluoro-b-
amino sulfonic acids as well as fluorinated peptidosul-
fonamides.[9]
nished
2,2-difluoro-2-pyridinylsulfonylacetamides
with good to excellent yield. These products can be
converted to 2,2-difluoroacetamide sulfinate, iodo-
difluoroacetamide and 2-aminopyridine derivatives
easily.
Keywords: difluoromethyl 2-pyridyl sulfone; 2,2-di-
fluoro-2-pyridylsulfonylacetamide;
Julia–Kocienski reaction
isocyanates;
Up to date, the substrate scope of 2-PySO2CF2H is
Incorporation of fluorine atoms into organic mole- still limited to the above reported carbonyl, alkyl
cules has become a powerful strategy to modulate halide and imine derivatives. Isocyanates are highly
their biological properties due to the high electrone- potent electrophilic substrates for a variety of nucleo-
gativity and small size of fluorine as well as its very philic agents, including Grignard reagents, amines and
different chemical reactivity with respect to hydro- alcohols, resulting in the production of numerous bio-
gen.[1] Fluorinated drugs have constituted approxi- logically active compounds, including ureas, carba-
mately 5–12% of the total number of launched drugs mates and amides.[10] Therefore, the reactions between
all over the world and with a noticeable increase in 2-PySO2CF2H and isocyanates were carried out to ex-
the past few years.[2] As the bioisostere of methylene plore the novel usage of this difluromethylation
(CH2), the difluoromethyl moiety (CF2) has attracted agent.
much attention in the field of medicinal chemistry
We first attempted the reaction of 2-PySO2CF2H
and it was incorporated into the structure of the (1) with phenyl isocyanate 2a by applying lithium
PDE-4 inhibitor Roflumilast.[3] Among all the di- hexamethyldisilazide (LiHMDS) as the base with
fluoromethylation reagents,[4] difluoromethyl 2-pyridyl THF as the solvent at À788C. After simple work-up,
sulfone (2-PySO2CF2H, Scheme 1) has aroused much we isolated the desired 2,2-difluoro-2-pyridylsulfonyl-
interest due to its wide use in the construction of vari- acetamide 3a in 29% yield. The addition of hexame-
ous difluoromethyl derivatives.[5] For example, 2-Py- thylphosphoramide (HMPA) to the system had no
SO2CF2H could act as a novel and efficient gem-di- beneficial effect to improve the yield (Table 1, en-
fluoroolefination reagent for both aldehydes and ke- tries 1 and 2). With the use of sodium hydride as the
tones through the Julia–Kocienski reaction,[5] the in base, no sulfonylacetamide was found and the diphe-
situ halogenation of Julia–Kocienski intermediates nylurea was the main product. (Table 1, entry 3) We
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Shan Li et al.
Scheme 1. The reactions of difluoromethyl 2-pyridyl sulfone.
Table 1. Optimization of the reaction conditions.[a]
Entry
1 (equiv.)
2 (equiv.)
Base (equiv.)
Solvent
Temperature [8C]
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.2
1.2
1.2
1.2
1.2
1.0
1.2
1.5
1.2
1.2
LiHMDS (1.8)
LiHMDS (1.8)
NaH (1.8)
t-BuOK (1.8)
t-BuONa (1.8)
t-BuONa (1.8)
t-BuONa (2.5)
t-BuONa (1.8)
t-BuONa (1.8)
t-BuONa (1.8)
THF
THF:HMPA=10:1
DMF
DMF
DMF
DMF
DMF
DMF
DMF
À78
À78
À45
À45
À45
À45
À45
À45
À55
À35
29
31
0
41
52
32
67
61
58
55
DMF
[a]
This reaction was run on a 1.0 mmol scale.
Yields of isolated products.
[b]
surmised that it was produced via the condensation of reaction, and we were pleased to find that the yield
phenyl isocyanate with in situ formed aniline (reduc- increased to 41% and 52%, respectively.
tion of phenyl isocyanate with H2 in the system). To
The obvious difference between the two tert-butox-
avoid this severe side reaction, potassium tert-butox- ide bases indicated that the counterion (M+ =Na+,
ide and sodium tert-butoxide were employed in the K+) would significantly influence the stability of the
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Nucleophilic Difluoroalkylation of Isocyanates
À
imine intermediate as a result of the different M O cyano and acetyl moieties in this reaction. In addition,
bond strengths. With exhaustive optimization of the the reaction is also amenable to phenyl thioisocya-
proportions of the substrates, the best reaction condi- nates with good yields (3r, 81%; 3s, 84%). Especially
tions were established as 1.0 equivalent of 2-Py- for aliphatic isocyanates, good to excellent yields
SO2CF2H reacting with 1.2 equivalents of phenyl iso- were achieved, indicating the extensive application of
cyanate and 2.5 equivalents of t-BuONa in DMF at this reaction. However, when 4-nitrophenyl isocya-
À458C for 2 h (Table 1, entry 7). An additional inves- nate was used as the substrate, no desired product 3t
tigation on the influence of the reaction temperature was detected even using LC-MS analysis of the reac-
also confirmed that À458C was the optimal one tion mixture, probably due to the weak electrophilic
(Table 1, entries 8 and 9).
activity of 2t and its poor solubility in DMF.
With the optimized reaction conditions in hand, we
To explore the potential synthetic application of
examined the substrate scope of this novel nucleophil- these novel 2,2-difluoro-2-pyridylsulfonylacetamides,
ic difluoromethylation reaction. As shown in Table 2, compound 3p was used as a model compound to be
the reaction tolerates various substituents on the treated with EtSH/EtSNa and KI/I2, as expected, io-
phenyl isocyanate as well as in different positions, in- dodifluoroacetamide 4p was obtained in moderate
cluding alkyl (3f, 3g), methoxy (3j, 3k, 3l), halides yield (Scheme 2), which has been revealed as an im-
(3b, 3c, 3d, 3i). Interestingly, condensation of 2-Py- portant intermediate for a variety of Cu-mediated flu-
SO2CF2H with 4-cyano- and 4-acetylphenyl isocyanate oroalkylation reaction reported by our lab.[11]
also produced the anticipated products with moderate
In an attempt to treat compound 3a with NaH and
yield (3n, 41%; 3o, 68%), which revealed that the iso- i-PrBr to get tertiary amide 5a, to our surprise, 3a was
cynate moiety is a more favorable substrate than the easily transformed to N-phenylpyridin-2-amine 6a in
Table 2. Preparation of substituted 2,2-difluoro-2-pyridylsulfonylacetamides from isocyanates.[a]
[a]
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), t-BuONa (1.25 mmol), DMF, À458C, 1–3 h.
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these difluoro-2-sulfonylacetamides experienced an
intramolecular Julia–Kocienski reaction.[5,6,12]
We speculate that the driving force of this new
Julia–Kocienski reaction is based on the weak acidity
of the amide moiety of 3p. The reaction mechanism
was proposed as shown in Scheme 4. First, 3p is de-
protonated under basic conditions to obtain amide
anion 8p, which was cyclized to a five-membered ring
Scheme 2. Preparation of iododifluoroacetamide from 2,2-
difluoro-2-sulfonylacetamide.
À
to obtain intermediate 9p, then the C S bond was
excellent yield. This transformation was also suitable broken to form sulfinate salt 10p, which can be easily
for other 2,2-difluoro-2-sulfonylacetamide compounds protonated in the presence of H+, followed by remov-
including 3g, 3m and 3p, which result in the produc- al of 2,2-difluoroethenone and sulfur dioxide to get
tion of corresponding 6g, 6m and 6p with good yields N-cyclohexylpyridin-2-amine 6p.
(Scheme 3). Based on these results, we deduce that
To get some solid support for the proposed mecha-
nism, we attempted to separate the intermediate 9p
but failed, probabaly due to its high reactivity and in-
stability. Therefore, we performed an LC-MS analysis
on the the reaction mixture to trap the intermediate
9p.[13] To a solution of 3p (0.15 mmol) in DMF was
added NaH (0.23 mmol) in one portion and the mix-
ture was stirred at room temperature for 10 min, then
10 mL of the solution were taken out for LC-MS anal-
ysis (Figure 1 and Supporting Information). The
HPLC chromatogram shows that there are three
peaks (A, B and C) with retention times of 4.75 min,
7.00 min and 10.63 min, respectively. The positive
ESI-MS of the peak A (m/z=177.25) indicates the
production of target compound 6p (calcd. for
+
C11H17N2 : m/z=177.14 [M+H]+). The positive ESI-
MS of peak B (m/z=319.20) is consistent with the
compound 3p (calcd. for C13H17F2N2O3S+: m/z=
319.35 [M+H]+). The negative ESI-MS of peak C
(m/z=317.10) proved the presence of intermediate 9p
(calcd. for C13H15F2N2O3SÀ: m/z=317.08 [MÀH]À).
Therefore, these LC-MS analysis results provide the
solid proof for our proposed mechanism.
In conclusion, the first nucleophilic difluoroalkyla-
tion of isocyanates with difluoromethyl 2-pyridyl sul-
fone has been reported. The produced 2,2-difluoro-2-
pyridinylsulfonylacetamides can be converted to di-
fluoroacetamide sulfinate and iododifluoroacetamide
easily. More interestingly, the unusual Julia–Kocienski
Scheme 3. Unexpected Julia–Kocienski reaction.
Scheme 4. Proposed mechanism for the Julia-Kocienski reaction.
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Nucleophilic Difluoroalkylation of Isocyanates
Figure 1. The HPLC chromatograms from the HPLC-MS analysis of the Julia–Kocienski reaction.
cap and the mixture was stirred at 08C for about 2 h, then at
reaction results in the production of pyridine-2-
amines under basic conditions.
room temperature overnight. After removal of the solvent
in vacuum, the residue was equilibrated with 10 mL water
and 15 mL Et2O. The ether layer was discarded, and KI
(249 mg, 1.5 mmol) and I2 (477 mg, 1.75 mmol) were added
to the aqueous solution in one portion. The mixture was
stirred at 808C for 3 h. After cooling to room temperature,
the mixture was extracted with EtOAc (15 mL”3) and the
combined organic phase was washed with brine, dried over
anhydrous Na2SO4. After removal of the solvent under
vacuum, the residue was purified with silica gel column
chromatography to give product 5p as a white solid; yield:
Experimental Section
N-Phenyl-2,2-difluoro-2-(pyridin-2-ylsulfonyl)-
acetamide (3a)
To a mixture of isocyanatobenzene (2a) (65 mL, 0.6 mmol),
2-(difluoromethylsulfonyl)pyridine 1 (96 mg, 0.5 mmol) in
5 mL DMF, t-BuONa (120 mg, 1.25 mmol) was added at
À458C under an N2 atmosphere. The mixture was continu-
ously stirred until the TLC indicated the disappearence of
2a. Then, aqueous saturated ammonium chloride (1 mL)
was added to the mixture and the resulting mixture was
warmed up to room temperature. After extraction with
EtOAc (15 mL”3), the combined organic layer was washed
with brine, dried over anhydrous Na2SO4. After removal of
solvent under vacuum, the residue was purified with silica
gel column chromatography to give 3a as a white solid;
1
175 mg (58%). H NMR (500 MHz, DMSO-d6): d=8.77 (d,
J=9.0 Hz, 1H), 3.61–3.46 (m, 1H), 1.79–1.63 (m, 4H), 1.60–
1.52 (m, 1H), 1.33–1.20 (m, 4H), 1.12–1.06 (m, 1H);
19F NMR: d=À59.88 (s, 2F); 13C NMR: d=161.72 (t, J=
24.3 Hz), 95.90 (t, J=318.4 Hz), 49.27, 31.90, 25.43, 25.12;
MS (ESI): m/z=304.3 (M+H+).
N-Phenylpyridin-2-amine (6a)
1
yield: 105 mg (67%). H NMR (400 MHz, CDCl3): d=8.85
(d, J=4.0 Hz, 1H), 8.54 (s, 1H), 8.24 (d, J=8.0 Hz, 1H),
8.10 (dt, J=8.0 Hz, J=1.6 Hz, 1H), 7.73–7.71 (m, 1H), 7.58
(d, J=8.0 Hz, 2H), 7.40 (t, J=8.0 Hz, 2H), 7.24 (m, 1H);
19F NMR: d=À108.48 (s, 2F); 13C NMR: d=155.06 (t, J=
24.7 Hz), 151.84, 150.99, 138.75, 135.65, 129.37, 129.32,
126.53, 126.25, 120.54, 117.48 (t, J=298.5 Hz); HR-MS (CI):
m/z=313.0459, calcd. for C13H10F2N2O3S [M]+: 313.0453.
To a solution of 2,2-difluoro-N-phenyl-2-(pyridin-2-ylsulfo-
nyl)acetamide (3a) (78 mg, 0.25 mmol) in DMF (10 mL) was
added NaH (15 mg, 0.37 mmol) in one portion at 08C, the
reaction mixture was stirred at 608C for 3 h. After being
quenched with water at room temperature, the mixture was
extracted with EtOAc (30 mL”3) and the combined organic
phase was washed with brine, dried over anhydrous Na2SO4.
After removal of the solvent under vacuum, the residue was
subjected to silica gel column chromatography to provide 6a
N-Cyclohexyl-2,2-difluoro-2-iodoacetamide (5p)
1
as a white solid; yield: 40 mg (92%). H NMR (500 MHz,
EtSH (6 mL) was slowly added into a sealed tube containing
NaH ( 80 mg, 2.0 mmol) and THF (8 mL) at 08C under an
N2 atmosphere. After stirring for 5 min, a solution of 3p
(318 mg, 1.0 mmol) in THF was added to this EtSNa suspen-
sion. Then, the tube was closed with a PTFE-lined screw
CDCl3): d=8.22 (d, J=5.0 Hz, 1H), 7.51 (dt, J=8.0 Hz, J=
2.0 Hz, 1H), 7.34–7.32 (m, 4H), 7.07–7.04 (m, 1H), 6.90 (d,
J=8.5 Hz, 1H), 6.87 (s, 1H), 6.74–6.72 (m, 1H); 13C NMR:
d=156.10, 148.31, 140.51, 137.76, 129.32, 122.86, 120.44,
114.98, 108.24; MS (ESI): m/z=171.2 (M+H+).
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Acknowledgements
This work was financially supported by the Science and Tech-
nology Department of Zhejiang Province (2014C33181). We
thank Mrs. Jianyang Pan (Pharmaceutical Informatics Insti-
tute, Zhejiang University) for performing the NMR and mass
spectrometry.
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