Reactions of sulfur- and phosphorus-substituted fluoroalkylating silicon reagents with imines and enamines under acidic conditions

Article abstract of DOI:10.1021/jo202669w

Nucleophilic fluoroalkylation reactions of imines and enamines with α-phenylthio, α-phenylsulfonyl, and α-diethylphosphoryl substituted fluorinated silanes have been investigated. The reactions are promoted by hydrofluoric acid generated in situ from pota

Full text of DOI:10.1021/jo202669w

Note
pubs.acs.org/joc
Reactions of Sulfur- and Phosphorus-Substituted Fluoroalkylating
Silicon Reagents with Imines and Enamines under Acidic Conditions
Mikhail D. Kosobokov,† Alexander D. Dilman,*,† Marina I. Struchkova,† Pavel A. Belyakov,†
and Jinbo Hu‡
†N. D. Zelinsky Institute of Organic Chemistry, Leninsky prosp. 47, 119991 Moscow, Russian Federation
‡Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Ling-Ling Road, Shanghai 200032, P. R. China
S
* Supporting Information
ABSTRACT: Nucleophilic fluoroalkylation reactions of imines and
enamines with α-phenylthio, α-phenylsulfonyl, and α-diethylphos-
phoryl substituted fluorinated silanes have been investigated. The
reactions are promoted by hydrofluoric acid generated in situ from
potassium hydrodifluoride and trifluoroacetic acid. Sulfur reagents
worked well with both imines and enamines, whereas phosphorus
reagent efficiently coupled only with enamines.
rganofluorine compounds have attracted significant
O
attention in recent years due to their increasing role in
pharmaceutical and agrochemical industries.1 Among different
methodologies for the synthesis of fluorinated molecules that
have been investigated,2 nucleophilic fluoroalkylation reactions
have emerged as a general and reliable approach for the direct
introduction of fluorinated groups.3,4
Figure 1. Silicon reagents.
The general mechanism for HF-mediated fluoroalkylation is
shown in Scheme 1. Hydrofluoric acid is generated from
potassium hydrodifluoride and trifluoroacetic acid in acetoni-
trile. The interaction of the substrate A (imine 4 or enamine 5)
with HF leads to the equilibrium formation of iminium ions
along with the hydrodifluoride anion. Then, the hydrodifluoride
activates the silicon reagent to generate five-coordinate
intermediate 6, which subsequently interacts with iminium
ions. It is believed that the transfer of fluorinated carbanion
from silicon to the iminium electrophile proceeds in a
concerted fashion. Otherwise, if the free carbanion were
formed, it would likely be rapidly quenched with acid present
in the mixture.11 However, five-coordinate silicon complex 6
can undergo protonation, and this side reaction leads to
irreversible consumption of the silicon reagent.
We studied those compounds that cannot be fluoroalkylated
using conventional naked-fluoride mediated methodology,3a−c
that is, imines bearing at nitrogen alkyl or benzyl group (4) and
enamines (5), as substrates in nucleophilic fluoroalkylation
reactions. First, their reactions with phenylthio and phenyl-
sulfonyl substituted fluorinated silanes (reagents 1 and 2) were
investigated, and results are summarized in Table 1.
Fluoroalkyl organosilicon reagents have become particularly
widespread as equivalents of fluorinated carbanions, which is
associated with their availability, stability, convenience of
handling, and favorable reactivity. Most studies were carried
out using trimethyl(trifluoromethyl)silane and higher alkyl
analogues.3a−c However, within the past few years the
chemistry of silanes substituted with sulfur and phosphorus
groups began its development.5−7 Indeed, the major feature of
these substituents is that a carbon−heteroatom bond (e.g., C−S
bond) can be further functionalized or reduced to a C−H bond,
thereby providing compounds inaccessible by other means.8
Typically, trimethylsilyl-capped fluoroalkylating reagents
exhibit nucleophilic properties only in the presence of Lewis
basic activators capable of generating reactive five-coordinate
intermediate.3a−c,9 These reactions are performed under aprotic
conditions since the fluorinated carbanion can readily abstract a
proton from the medium. Recently we found that N-alkyl
substituted imines and enamines, which are unreactive under
conventional Lewis basic conditions, can undergo nucleophilic
trifluoromethylation in the presence of hydrofluoric acid.10
While anhydrous HF is highly dangerous, in our protocol it is
generated in situ by mixing easily available and convenient
chemicals. Furthermore, reactions can be performed in
conventional glassware with no noticeable deterioration of
glass surface. Herein we demonstrate that acidic conditions can
be applied for α-phenylthio, α-phenylsulfonyl, and α-
diethylphosphoryl substituted silicon reagents 1−3 (Figure 1).
The reactions were performed under standard conditions:
overnight at room temperature using 1.5 equiv of the silicon
reagent and 1.5 equiv of generated HF. The reaction mixtures
Received: December 30, 2011
Published: January 24, 2012
© 2012 American Chemical Society
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Scheme 1. Reaction Mechanism
were typically homogeneous except for a few cases where final
product precipitated out of solution. As follows from the
results, the sulfonyl reagent 2 provides higher yields compared
to sulfide reagent 1 (see entries 3−6). This can be explained by
the greater susceptibility of silane 2 to basic activation owing to
stronger electron-withdrawing effect of the phenylsulfonyl
group compared to that of the phenylsulfide counterpart.
Enamines 5a−f gave high yields of products in all cases
examined. Indeed, enamines are expected to be intrinsically
more reactive than imines, since under acidic conditions the
former more readily generate iminium cations.
The fluoroalkylation with phosphorus reagent 3 was
evaluated in reaction with imine 4c under standard conditions,
and the desired product 9 was formed in only 30% yield
(Scheme 2). The low yield may be associated with competitive
protodesilylation of the silane. Attempts to improve the yield
were unsuccessful. On the contrary, enamines reacted well and
afforded products 10 in good yields (Table 2).
concerted interaction of the five-coordinate intermediate with
iminium electrophile.
To demonstrate the utility of products obtained after
fluoroalkylation of imines and enamines, we performed the
desulfurization of sulfide and sulfonyl groups (Scheme 4).
Thus, the sulfone fragment was removed from product 7g by
treatment with magnesium in methanol,12 furnishing α-
difluoromethyl substituted secondary amine 11. The phenylthio
group was abstracted under radical conditions using tributhyltin
hydride,13 affording after acidic treatment the crystalline amine
hydrochloride 12.
In summary, we demostrated that fluoroalkylating reagents
bearing phenylthio, phenylsulphonyl, and diethylphosphoryl
groups can be effectively applied in HF-mediated nucleophilic
fluoroalkylations. In contrast to phosphoryldifluoromethylsi-
lane, which works only with the most reactive substrates such
enamines, the sulfur reagents are effective for fluoroalkylation
of imines and enamines. The products can be readily
desulfurized thereby providing access to amines containing
the difluoromethyl group.
It was interesting to evaluate the stability of reagents 1−3 in
the presence of generated hydrofluoric acid (Scheme 3). In a
typical experiment, silane was added to a homogeneous
solution of KHF2 and CF3CO2H in d3-acetonitrile at room
EXPERIMENTAL SECTION
■
1
temperature, and the mixture was monitored by H and 19F
[Difluoro(phenylthio)methyl](trimethyl)silane (1). Obtained
NMR spectroscopy. The protodesilylation of sulfonyl silane 2
to give CHF2SO2Ph proceeded quite rapidly, and 90%
conversion was achieved within 5 h. Silanes 1 and 3 reacted
much slower, and only 30% decomposition was noted after 24
h. While protodesilylation of phosphonate 3 leading to
CHF2P(O)(OEt)2 was the sole decomposition pathway, the
reaction of phenylthio substituted silane 1 was more complex,
and only 6% of protodesilylated compound (CHF2SPh) was
produced along with some unidentified nonfluorinated species.
The slow decomposition of phosphonate 3 was surprising in
view of poor yield in its reaction with imine 4c (Scheme 2).
The latter result may be explained by supposing that the
protodesilylation of a five-coordinate intermediate originating
from silane 3 prevails over the interaction with iminium
electrophile (see side reaction in Scheme 1). Furthermore, the
difference in reactivities of silanes 1 and 3 toward imines may
be due to greater steric hindrance of the P(O)(OEt)2 group
compared to that of SPh group, which is manifested upon
according to literature procedure.14
[Difluoro(phenylsulfonyl)methyl](trimethyl)silane (2). Ob-
tained from PhSO2CF2Br15 according to modified literature
procedure.16 n-Butyl lithium (13.2 mL of 2.5 M solution in hexane,
33.1 mmol) was added dropwise to a solution of PhSO2CF2Br (5.0 g,
18.2 mmol) and Me3SiCl (4.7 mL, 35 mmol) in tetrahydrofuran (60
mL) at −100 °C, and the mixture was stirred for 1 h at −70 °C. The
mixture was allowed to warm to room temperature, and the volatile
materials were evaporated using conventional rotary evaporator. The
residue was diluted with hexane (20 mL), filtered followed by washing
with hexane, and concentrated under vacuum. The crude product was
distilled under vacuum to give 3.8 g of the silicon reagent (78% yield).
Bp 114−115 °C/2 Torr. NMR spectra were identical to reported
data.16
Diethyl (Difluoro(trimethylsilyl)methyl)phosphonate (3).
Magnesium turnings (486 mg, 20 mmol), tetrahydrofuran (30 mL),
and Me3SiCl (5.37 mL, 40 mmol) were added to a Schlenk flask, and
the mixture was cooled to −100 °C. Diethyl (bromodifluoromethyl)-
phosphonate17 (2.52 g,10 mmol) was added, and the mixture was
stirred for 1 h at −78 °C. The temperature was allowed to rise to −25
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Table 1. Reactions of Imines and Enamines with Sulfur Reagents 1 and 2
a
Isolated yield.
solvent was evaporated, and the residue was distilled under vacuum to
give 2.0 g of the title compound (yield 77%). Bp 56−57 °C/1 Torr.
NMR spectra were identical to the reported data.7a
Scheme 2. Reaction of Imine 4c with Reagent 3
N-(Furan-2-ylmethylene)cyclohexanamine (4a). Obtained ac-
cording to literature procedure.18 1H NMR (300 MHz, CDCl3): δ
1.04−1.36 (m, 3H), 1.40−1.82 (m, 7H), 2.92−3.14 (m, 1H), 6.30−
6.40 (m, 1H), 6.53−6.67 (m, 1H), 7.35−7.46 (m, 1H), 7.98−8.07 (m,
1H). 13C NMR (75 MHz, CDCl3): δ 24.6, 25.3, 34.1, 69.8, 111.2,
113.3, 144.1, 147.0, 151.5.
Propyl-(3,4,5-trimethoxybenzylidene)amine (4b). Obtained
°C during 3 h, and mixture was kept overnight at −25 °C. The volatile
materials were evaporated using a conventional rotary evaporator. The
residue was treated with ether/hexane (1:1, 10 mL) and water (20
mL), the aqueous phase was extracted with ether/hexane (1:1, 3 × 5
mL), and the combined organic phase was dried over MgSO4. The
according to literature procedure.10a
N-Benzylidenemethanamine (4c). Obtained according to
literature procedure.19 1H NMR spectra were identical to the reported
data.20
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4-(1-Phenylvinyl)morpholine (5c). Obtained according to
literature procedure.28 1H NMR spectra were identical to the reported
data.29
Table 2. Reactions of Enamines with Phosphorus Reagent 3
1-Cyclohex-1-en-1-ylpyrrolidine (5d). Obtained according to
literature procedure.25 1H NMR spectra were identical to the reported
data.30
Methyl 3-(Pyrrolidin-1-yl)but-2-enoate (5e). Obtained accord-
ing to literature procedure.31 NMR spectra were identical to the
reported data.32
Enamine 5f. Mixture of 4-(1-Isopropylvinyl)morpholine (5f-
A) and 4-(1,2-Dimethylprop-1-enyl)morpholine (5f-B); Ratio
A:B = 2:1. A solution of TiCl4 (8.55 g, 45 mmol) in hexane (10 mL)
was added dropwise to a solution of morpholine (24.8 g, 285 mmol) in
hexane (100 mL) at 0 °C. Then, a solution of isopropyl methyl ketone
(4.3 g, 50 mmol) in hexane (20 mL) was added, and the mixture was
refluxed for 1 h and cooled to room temperature. The mixture was
filtered washing with small amount of hexane, the filtrate was
concentrated, and the mixture was distilled under vacuum to give 5.4 g
(70% yield) of a mixture of enamines (5f-A and 5f-B, 2:1). Bp 90−92
°C/35 Torr. The product contains ca. 10% of unidentified impurity.
1H NMR (300 MHz, CDCl3): δ isomer 5f-A, 1.07 (d, 6H, J = 6.6),
2.38 (sept, 1H, J = 6.6), 3.87 (s, 1H), 4.00 (s, 1H), 2.73−2.93 (m,
4H); isomer 5f-B, 1.6 (s, 6H), 1.73 (s, 3H), 2.48−2.61 (m, 4H); both
isomers, 3.60−3.78 (m). 13C NMR (75 MHz, CDCl3): δ 9.6, 18.7,
a
Isolated yield.
1
19.4, 22.4, 29.3, 48.9, 50.2, 66.9, 67.4, 84.9, 122.0, 137.5, 162.5. H
NMR spectrum was identical to the reported data for a mixture of
regioisomers.33
Scheme 3. Stability of Silanes in the Presence of HF
Fluoroalkylation of Imines and Enamines (General Proce-
dure). Trifluoroacetic acid (48 μL, 0.625 mmol) was added to a
mixture of the substrate (0.5 mmol) and KHF2 (29 mg, 0.375 mmol)
in acetonitrile (1.5 mL) at 0 °C, and the suspension was stirred for 5
min. Silicon reagent (0.75 mmol) was added, the cooling bath was
removed, and the mixture was stirred for 18 h at room temperature.
For the workup, saturated aqueous Na2CO3 (1 mL) was added
dropwise, and the mixture was stirred for an additional 2 min, diluted
with water (7 mL), and extracted with ether/hexane (1:1, 3 × 4 mL).
The combined organic phase was filtered through Na2SO4 and
concentrated under vacuum to give the crude material, which was
purified by one of the following methods.
Method A. Column chromatography on silica gel.
Method B. A solution of HCl in dioxane (150 μL, 4 M, 0.6 mmol)
was added dropwise to a solution of crude material in diethyl ether (2
mL), which caused the precipitation of the hydrochlorided salt. The
solvent was decanted, and the salt was washed with ether (2 × 1 mL).
The residue was treated with saturated aqueous Na2CO3 (2 mL), the
aqueous phase was extracted with ether/hexane (1:1, 3 × 3 mL), the
combined organic phase was filtered through Na2SO4, concentrated
under vacuum. The residue was dissolved in ether containing 0.5 vol %
of triethylamine, passed through a short silica gel pad, and
concentrated to give analytically pure product.
Scheme 4. Desulfurization Reactions
Method C. Concentrated aqueous HCl (1 mL) was added to a
solution of crude product in diethyl ether (2 mL). The mixture was
diluted with water (3 mL) and vigorously shaken. The aqueous phase
was washed with ether/hexane (1:1, 10 × 1.5 mL) and then treated
dropwise with saturated aqueous Na2CO3 until basic reaction. The
aqueous phase was extracted with ether/hexane (1:1, 3 × 6 mL), and
the combined organic phase was filtered through Na2SO4,
concentrated under vacuum. The residue was dissolved in ether
containing 0.5 vol % of triethylamine, passed through a short silica gel
pad, and concentrated to give analytically pure product.
N-(2,2-Dimethylpropylidene)-1-phenylmethanamine (4d).
Obtained according to literature procedure.21 NMR spectra were
identical to the reported data.22
N-[1-Naphthylmethylene]methanamine (4e). Obtained ac-
cording to literature procedure.23 1H NMR spectra were identical to
the reported data.24
N-[2,2-Difluoro-1-(2-furyl)-2-(phenylsulfonyl)ethyl]-
cyclohexanamine (7a). Purified by method A; 157 mg, 85% yield.
Mp 106−108 °C. Chromatography hexanes/EtOAc 10:1. Rf 0.25
Cyclopropyl-naphthalen-1-ylmethylene-amine (4f). Obtained
according to literature procedure.10a
1
(hexanes/EtOAc 10:1). H NMR (300 MHz, CDCl3): δ 1.00−1.30
4-Cyclohex-1-en-1-ylmorpholine (5a). Obtained according to
literature procedure.25 1H NMR spectra were identical to the reported
data.26
1-(2-Methylprop-1-en-1-yl)pyrrolidine (5b). Obtained accord-
ing to literature procedure.27 NMR spectra were identical to the
reported data.26b
(m, 5H), 1.45−1.82 (m, 5H), 1.82−2.05 (m, 1H), 2.30−2,52 (m, 1H),
4.85 (dd, 1H, J = 20.9, 6.6), 6.28−6.50 (m, 2H), 7.42 (br, 1H), 7.57 (t,
2H, J = 7.7) 7.71 (t, 1H, J = 7.7), 7.99 (d, 2H, J = 7.7). 13C NMR (50
MHz, CDCl3): δ 24.4, 24.7, 25.8, 32.2, 33.9, 53.9 (dd, J = 23.4, 19.2),
54.4, 110.2, 110.5, 121.4 (dd, J = 296.0, 290.3), 128.9, 130.5, 134.3,
134.8, 143.1, 148.3. 19F NMR (282 MHz, CDCl3): δ −112.5 (dd, 1F, J
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Note
= 234.2, 20.9), −101.7 (dd, 1F, J = 234.2, 6.6). Anal. Anal. Calcd for
C18H21F2NO3S (369.43): C, 58.52; H, 5.73; N, 3.79. Found: C, 58.69;
H, 5.79; N, 3.76.
for C19H17F2NO2S (361.41): C, 63.14; H, 4.74; N, 3.88. Found: C,
63.00; H, 4.66; N, 3.72.
N-[2,2-Difluoro-1-(1-naphthyl)-2-(phenylsulfonyl)ethyl]-
cyclopropanamine (7h). Purified by method A; 141 mg, 73% yield.
Chromatography hexanes/EtOAc 5:1. Rf 0.22 (hexanes/EtOAc 5:1).
Mp 113−115 °C. 1H NMR (300 MHz, CDCl3): δ 0.30−0.55 (m, 3H),
0.62−0.75 (m, 1H), 1.95−2.10 (m, 1H), 2.56 (d, 1H, J = 8.7), 5.65−
5.95 (m, 1H), 7.43−7.78 (m, 7H), 7.89 (t, 2H, J = 8.0), 7.95−8.03 (m,
2H), 8.19−8.27 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 6.0, 7.2,
28.8, 56.5 (br), 122.4 (dd, J = 294.2, 291,4) 122.9, 125.2, 125.8, 126.8,
128.8, 129.0, 129.3, 130.5, 131.0, 132.7, 133.8, 134.4, 134.8. 19F NMR
(282 MHz, CDCl3): δ −115.1 (br d, 1F, J = 239.5), −99.5 (d, 1F, J =
239.5). Anal. Calcd for C21H19F2NO2S (387.44): C, 65.10; H, 4.94; N,
3.62. Found: C, 65.28; H, 4.99; N, 3.57.
N-[2,2-Difluoro-2-(phenylthio)-1-(3,4,5-trimethoxyphenyl)-
ethyl]-N-propylamine (7b). Purified by method A; 141 mg, 71%
yield. Chromatography hexanes/EtOAc 5:1. Rf 0.27 (hexanes/EtOAc
5:1). Oil. 1H NMR (300 MHz, CDCl3): δ 0.92 (t, 3H, J = 7.3), 1.39−
1.61 (m, 2H), 1.77 (br, 1H), 2.52 (t, 2H, J = 6.9), 3.85 (s, 9H), 4.08
(dd, 1H, J = 12.3, 7.5), 6.67 (s, 2H), 7.20−7.43 (m, 3H), 7.56 (d, 2H, J
= 6.4). 13C NMR (75 MHz, CDCl3): δ 11.5, 22.9, 49.4, 56.0, 60.6, 68.5
(dd, J = 24.3, 23.3), 105.9, 126.6, 128.7, 129.4, 129.8 (t, J = 284.2),
131.2 (d, J = 1.4), 136.0, 138.0, 152.9. 19F NMR (282 MHz, CDCl3): δ
−80.9 (dd, 1F, J = 206.6, 12.3), −76.8 (dd, 1F, J = 206.6, 7.5). Anal.
Calcd for C20H25F2NO3S (397.48): C, 60.43; H, 6.34; N, 3.52. Found:
C, 60.55; H, 6.40; N, 3.40.
4-{1-[Difluoro(phenylthio)methyl]cyclohexyl}morpholine
(8a). Purified by method A; 139 mg, 85% yield. Mp 68−70 °C.
Chromatography hexanes/EtOAc/NEt3 20:1:0.005. Rf 0.2 (hexanes/
N-[2,2-Difluoro-1-phenyl-2-(phenylthio)ethyl]-N-methyl-
amine (7c). Purified by method A; 101 mg, 72% yield.
Chromatography hexanes/EtOAc 15:1. Rf 0.30 (hexanes/EtOAc
1
EtOAc 20:1). H NMR (300 MHz, CDCl3): δ 1.18−1.41 (m, 1H),
1
1.43−1.85 (m, 7H), 2.00−2.20 (m, 2H), 2.94 (br, 4H), 3.67 (br, 4H),
7.30−7.50 (m, 3H), 7.56−7.68 (m, 2H). 13C NMR (75 MHz, CDCl3):
δ 20.6, 25.9, 28.8, 46.9, 64.6 (t, J = 18.5), 68.5, 126.7 (t, J = 1.1), 128.8,
129.5, 134.8 (t, J = 294.4), 136.6. 19F NMR (282 MHz, CDCl3): δ
−76.6 (s, 2F). Anal. Calcd for C17H23F2NOS (327.43): C, 62.36; H,
7.08; N, 4.28. Found: C, 62.55; H,7.09; N, 4.08.
15:1). Oil. H NMR (300 MHz, CDCl3): δ 1.94 (br, 1H), 2.43 (s,
3H), 4.11 (dd, 1H, J = 12.3, 8.3), 7.30−7.52 (m, 8H), 7.56−7.68 (m,
2H). 13C NMR (75 MHz, CDCl3): δ 34.5, 70.3 (dd, J = 24.8, 23.2),
126.9 (t, J = 1.9), 128.3, 128.5, 128.8, 128.9, 129.5, 129.8 (t, J = 283.9),
135.2, 136.2. 19F NMR (282 MHz, CDCl3): δ −81.3 (dd, 1F, J =
207.7, 12.3), −77.1 (dd, 1F, J = 207.7, 8.3). Anal. Calcd for
C15H15F2NS (279.35): C, 64.49; H, 5.41; N, 5.01. Found: C, 64.48; H,
5.46; N, 4.90.
4-{1-[Difluoro(phenylsulfonyl)methyl]cyclohexyl}-
morpholine (8b). Purified by method B; 153 mg, 85% yield. Mp
1
167−169 °C. H NMR (300 MHz, CDCl3): δ 1.20−1.84 (m, 6H),
N-[2,2-Difluoro-1-phenyl-2-(phenylsulfonyl)ethyl]-N-methyl-
amine (7d). Purified by method A; 120 mg, 77% yield.
Chromatography hexanes/EtOAc 5:1. Rf 0.44 (hexanes/EtOAc 5:1).
1.95−2.35 (m, 4H), 2.60−3.11 (br, 4H), 3.34−3.91 (br, 4H), 7.60 (t,
2H, J = 7.7), 7.74 (t, 1H, J = 7.7), 7.95 (d, 2H, J = 7.7). 13C NMR (75
MHz, CDCl3): δ 20.2, 25.5, 28.5 (t, J = 3.0), 46.8 (t, J = 2.8), 64.9 (t, J
= 16.9) 68.3, 126.8 (t, J = 300.5), 129.0, 130.6, 134.5, 134.8. 19F NMR
(282 MHz, CDCl3): δ −101.7 (s, 2F). Anal. Calcd for C17H23F2NO3S
(359.43): C, 56.81; H, 6.45; N, 3.90. Found: C, 56.97; H, 6.35; N,
3.75.
1
Oil. H NMR (300 MHz, CDCl3): δ 2.00 (s, 1H), 2.36 (s, 3H), 4.54
(dd, 1H, J = 20.2, 5.9), 7.26−7.46 (m, 5H), 7.55 (t, 2H, J = 7.7) 7.68
(t, 1H, J = 7.7), 7.98 (d, 2H, J = 7.7). 13C NMR (75 MHz, CDCl3): δ
34.0, 64.1 (dd, J = 23.0, 17.9), 121.7 (dd, J = 295.0, 287.9), 128.4,
128.87, 128.91, 128.94, 130.5, 133.7, 134.9. 19F NMR (282 MHz,
CDCl3): δ −114.7 (dd, 1F, J = 237.4, 20.2), −100.4 (dd, 1F, J = 237.4,
5.9). Anal. Calcd for C15H15F2NO2S (311.35): C, 57.86; H, 4.86; N,
4.50. Found: C, 57.81; H, 5.02; N, 4.32.
N-Benzyl-N-{1-[difluoro(phenylthio)methyl]-2,2-
dimethylpropyl}amine (7e). Purified by method A; 101 mg, 60%
yield. Chromatography hexanes/EtOAc 30:1. Rf 0.26 (hexanes/EtOAc
30:1) Oil. 1H NMR (300 MHz, CDCl3): δ 1.18 (s, 9H), 1.55 (s, 1H),
2.97 (dd, 1H, J = 16.9, 6.9), 4.00 (d, 1H, J = 12.4), 4.30 (d, 1H, J =
12.4), 7.30−7.60 (m, 8H), 7.65−7.78 (m, 2H). 13C NMR (75 MHz,
CDCl3): δ 27.9 (t, J = 2.6), 36.1, 56.0, 71.5 (t, J = 22.3), 127.2, 127.9
(d, J = 2.6), 128.36, 128.38, 128.8, 129.3, 133.8 (dd, J = 292.5, 289.6),
136.4, 140.3. 19F NMR (282 MHz, CDCl3): δ −75.8 (dd, 1F, J =
201.3, 16.9), −65.6 (dd, 1F, J = 201.3, 6.9). HRMS (ESI): calcd for
C19H24F2NS (M + H) 336.1592, found 336.1590.
1-{1-[Difluoro(phenylthio)methyl]-2-methylpropyl}-
1
pyrrolidine (8c). Purified by method C; 113 mg, 79% yield. Oil. H
NMR (300 MHz, CDCl3): δ 1.04 (d, 3H, J = 6.9), 1.11 (dd, 3H, J =
6.4, 4.1), 1.79−1.94 (m, 4H), 2.20−2.40 (m, 1H), 2.94−3.20 (m, 5H),
7.33−7.50 (m, 3H), 7.62−7.73 (m, 2H). 13C NMR (75 MHz, CDCl3):
δ 20.1 (dd, J = 5.8, 1.2), 21.1, 25.0, 27.5, 49.0, 69.7 (t, J = 23.6), 128.6,
128.9, 129.6, 134.7 (t, J = 293.7), 135.9. 19F NMR (282 MHz, CDCl3):
δ −75.7 (dd, 1F, J = 197.1, 17.0), −66.6 (br d, 1F, J = 197.1). Anal.
Calcd for C15H21F2NS (285.40): C, 63.13; H, 7.42; N, 4.91. Found: C,
63.03; H, 7.37; N, 4.82.
4-[2,2-Difluoro-1-methyl-1-phenyl-2-(phenylsulfonyl)ethyl]-
morpholine (8d). Purified by method A; 155 mg, 81% yield.
Chromatography hexanes/EtOAc/NEt3 5:1:0.005. Rf 0.29 (hexanes/
1
EtOAc 5:1). Mp 93−95 °C. H NMR (300 MHz, CDCl3): δ 1.91 (s,
3H), 2.45−2.83 (m, 4H), 3.56−3.85 (m, 4H), 7.29−7.44 (m, 3H),
7.45−7,59 (t, 2H, J = 7.8), 7.60−7.77 (m, 3H), 7.77−7.92 (d, 2H, J =
7.8). 13C NMR (75 MHz, CDCl3): δ 14.7, 47.7 (d, J = 2.9), 67.3, 68.5
(dd, J = 18.4, 15.6), 124.4 (dd, J = 308.6, 302.3), 127.9, 128.4, 128.9,
129.0, 130.2, 134.4, 134.8, 137.4 (d, J = 4.6). 19F NMR (282 MHz,
CDCl3): δ −101.4 (d, 1F, J = 231.0), −92.3 (d, 1F, J = 231.0). HRMS
(ESI): calcd for C19H21F2NNaO3S (M + Na) 404.1102, found
404.1106.
N-Benzyl-N-{1-[difluoro(phenylsulfonyl)methyl]-2,2-
dimethylpropyl}amine (7f). Purified by method A; 129 mg, 70%
yield. Chromatography hexanes/EtOAc 10:1. Rf 0.33 (hexanes/EtOAc
1
10:1). Mp 62−63 °C. H NMR (300 MHz, CDCl3): δ 1.11 (s, 9H),
1.49 (br, 1H), 3.47 (dd, 1H, J = 27.5, 3.2), 3.92 (d, 1H, J = 11.5), 4.39
(d, 1H, J = 11.5), 7.18−7.42 (m, 3H) 7.49 (d, 2H, J = 6.8), 7.60 (t, 2H,
J = 7.7) 7.74 (t, 1H, J = 7.7), 7.95 (d, 2H, J = 7.7). 13C NMR (50
MHz, CDCl3): δ 27.6 (dd, J = 3.6, 1.4), 37.6 (d, J = 2.1), 55.2, 64.4
(dd, J = 19.9, 17.7), 125.3 (dd, J = 300.2, 298.1), 127.1, 128.3, 128.5,
129.1, 130.5 (d, J = 1.4), 134.3, 134.7, 140.0. 19F NMR (282 MHz,
CDCl3): δ −110.8 (dd, 1F, J = 229.9, 27.5), −91.9 (d, 1F, J = 229.9).
Anal. Calcd for C19H23F2NO2S (367.45): C, 62.10; H, 6.31; N, 3.81.
Found: C, 62.02; H, 6.44; N, 3.72.
1-{1-[Difluoro(phenylthio)methyl]cyclohexyl}pyrrolidine
1
(8e). Purified by method C; 140 mg, 90% yield. Mp 46−48 °C. H
NMR (300 MHz, CDCl3): δ 1.10−1.30 (m, 1H), 1.35−1.81 (m,
11H), 1.96−2.12 (m, 2H), 2.90−3.10 (m, 4H), 7.30−7.46 (m, 3H),
7.50−7.68 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 21.5, 24.9, 25.6,
29.9 (t, J = 1.6), 45.1 (t, J = 1.9), 63.4 (t, J = 16.9), 127.4, 128.7, 129.3,
136.0 (t, J = 296.3), 136.6. 19F NMR (282 MHz, CDCl3): δ −76.1 (s,
2F). Anal. Calcd for C17H23F2NS (311.43): C, 65.56; H, 7.44; N, 4.50.
Found: C, 65.67; H, 7.50; N, 4.64.
2 , 2 -D i f l u o r o - N- m e t h y l - 1 - ( n a ph th al e n - 1 - y l ) - 2 -
(phenylsulfonyl)ethanamine(7g). Purified by method B; 136 mg,
75% yield. Mp 116−118 °C. 1H NMR (300 MHz, CDCl3): δ 2.24 (br,
1H), 2.39 (s, 3H), 5.60 (d, 1H, J = 22.9), 7.48−7.66 (m, 5H), 7.67−
7.81 (m, 2H), 7.84−7.95 (m, 2H), 8.02 (d, 2H, J = 7.3), 8.15−8.26
(m, 1H). 13C NMR (75 MHz, CDCl3): δ 34.2, 58.2 (br), 122.0 (dd, J
= 297.1, 287.9), 122.8, 125.2, 125.7, 126.2, 126.6, 128.9, 129.0, 129.4,
129.7, 130.6, 132.9, 133.7, 133.8, 135.0. 19F NMR (282 MHz, CDCl3):
δ −116.1 (br d, 1F, J = 224.7), −99.3 (d, 1F, J = 224.7). Anal. Calcd
Methyl 4,4-Difluoro-3-methyl-4-(phenylsulfonyl)-3-pyrroli-
din-1-ylbutanoate (8f). Purified by method C; 157 mg, 87% yield.
Oil. 1H NMR (300 MHz, CDCl3): δ 1.52−1.68 (m, 4H), 1.82 (s, 3H),
2.72 (d, 1H, J = 13.7), 2.78−2.88 (m, 2H), 2.93−3.08 (m, 3H), 3.64
(s, 3H), 7.55 (t, 2H, J = 7.6), 7.68 (t, 1H, J = 7.6), 7.94 (d, 2H, J =
7.6). 13C NMR (75 MHz, CDCl3): δ 20.1 (dd, J = 3.9, 2.2), 24.1, 37.6
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Note
(d, J = 5.0), 46.4 (t, J = 2.2), 51.5, 63.4 (dd, J = 19.3, 17.7), 125.0 (dd,
J = 305.7, 303.0), 128.9, 130.2, 134.6, 135.0, 170.2. 19F NMR (282
MHz, CDCl3): δ −103.8 (d, 1F, J = 237.4), −97.8 (d, 1F, J = 237.4).
Anal. Calcd for C16H21F2NO4S (361.40): C, 53.17; H, 5.86; N, 3.88.
Found: C, 53.20; H, 5.83; N, 3.84.
and the mixture was stirred for 1 h. The solvent was evaporated, and
the residue was treated with saturated aqueous NH4Cl (5 mL),
extracted with ether (3 × 3 mL), and dried over MgSO4. The solvent
was evaporated, and the residue was distilled under vacuum in a short-
path apparatus to give 96 mg (87% yield) of amine 11 as colorless
liquid. Bp 106−115 °C (bath temperature)/0.35 Torr. 1H NMR (300
MHz, CDCl3): δ 1.81 (br, 1H), 2.44 (s, 3H), 4.75 (dt, 1H, J = 10.9,
5.7), 6.03 (dt, 1H, J = 56.8, 5.7), 7.48−7.63 (m, 3H), 7.69 (d, 1H, J =
7.3), 7.83−7.95 (m, 2H), 8.26 (d, 1H). 13C NMR (75 MHz, CDCl3):
δ 34.5, 62.4 (t, J = 21.6), 117.3 (dd, J = 245.1, 246.2), 122.9, 125.4,
125.65, 125.69, 126.4, 128.9, 129.0, 131.7 (dd, J = 4.6, 3.0), 132.3,
134.0. 19F NMR (282 MHz, CDCl3): δ −124.5 (ddd, 1F, J = 280.8,
56.8, 10.9), −122.6 (ddd, 1F, J = 280.8, 56.8, 5.7). Anal. Calcd for
C13H13F2N (221.25): C, 70.57; H, 5.92; N, 6.33. Found: C, 70.71; H,
6.01; N, 6.24.
4-{1-[Difluoro(phenylsulfonyl)methyl]-1,2-dimethylpropyl}-
morpholine (8g). Purified by method B; 136 mg, 78% yield. Mp
1
105−107 °C. H NMR (300 MHz, CDCl3): δ 0.84 (dd, 3H, J = 6.4,
4.1), 0.94 (d, 3H, J = 6.9), 1.77 (d, 3H, J = 3.7), 2.52−2.69 (m, 1H),
2.90−3.13 (m, 4H), 3.67−3.8 (m, 2H), 3.86−3.98 (m, 2H), 7.53−7.62
(m, 2H), 7.64−7.73 (m, 1H), 7.93 (d, 2H, J = 7.78). 13C NMR (75
MHz, CDCl3): δ 12.2 (dd, J = 3.8, 5.5), 17.8, 17.9 (d, J = 1.1), 30.0
(dd, J = 1.7, 3.9), 47.6, 67.3, 68.0 (t, J = 18.5), 126.4 (t, J = 311.5),
128.8, 129.9 (d, J = 2.2), 134.0, 136.4. 19F NMR (282 MHz, CDCl3): δ
−102.2 (d, 1F, J = 228.9), −79.6 (d, 1F, J = 228.9). Anal. Calcd for
C16H23F2NO3S (347.42): C, 55.31; H, 6.67; N, 4.03. Found: C, 55.10;
H, 6.74; N, 3.98.
1-[1-(Difluoromethyl)cyclohexyl]pyrrolidine Hydrochloride
(12). A solution of amine 5d (156 mg, 0.5 mmol), Bu3SnH (202
μL, 0.75 mmol), and azobisisobutyronitrile (5 mg) in toluene (3 mL)
was heated for 2 h at 90 °C. Then an additional portion of
azobisisobutyronitrile (5 mg) was added, and the mixture was heated
for 3 h at 90 °C. The mixture was cooled to room temperature, treated
with concentrated aqueous hydrochloric acid (1 mL), and vigorously
stirred for 5 min. The organic phase was separated, and the aqueous
phase was washed with ether/pentane (1:1, 1 mL). The aqueous phase
was treated with saturated aqueous Na2CO3 until basic reaction and
extracted with ether/pentane (1:1, 3 × 2 mL). The combined organic
phase was filtered through Na2SO4, the solvent was evaporated under
ambient pressure until the volume of 2 mL, and HCl in dioxane (150
μL, 4 M solution) was added. The precipitate was filtered, washed with
ether/pentane (1:1), and dried to give 96 mg (80% yield) of amine
Diethyl [1,1-Difluoro-2-(methylamino)-2-phenylethyl]-
phosphonate (9). Purified by method B. For final purification, the
product was fractionally flash chromatographed using small silica gel
column eluting with ether containing 0.5 vol % of triethylamine; 46
mg, 30% yield. Mp 42−44 °C. 1H NMR (300 MHz, CDCl3): δ 1.22−
1.37 (m, 6H), 1.84 (s, 1H), 2.34 (s, 3H), 4.01−4.33 (m, 5H), 7.30−
7.45 (m, 5H). 13C NMR (75 MHz, CDCl3): δ 16.2 (d, J = 3.5),
16.3(d, J = 3.5), 34.2, 64.1 (d, J = 6.9), 64.5 (d, J = 6.9), 66.4 (ddd, J =
15.6, 19.0, 23.3), 119.5 (td, J = 267.2, 210.2), 128.3, 128.4, 129.2,
134.6 (m). 19F NMR (282 MHz, CDCl3): δ −122.0 (ddd, 1F, J =
302.3, 104.8, 19.1), −112.2 (ddd, 1F, J = 302.3, 101.9, 10.6). 31P NMR
(121 MHz, CDCl3): δ 7.18 (dd, J = 101.9, 104.8). Anal. Calcd for
C13H20F2NO3P (307.27): C, 50.81; H, 6.56; N, 4.56. Found: C, 50.60;
H, 6.32; N, 4.30.
1
hydrochloride 12. Mp 168−171 °C. H NMR (300 MHz, CDCl3): δ
1.24−2.36 (m, 14H), 3.35 (br m), 3.61 (br m,), 6.24 (t, 1H, J = 51.9),
12.25 (br, 1H). 13C NMR (75 MHz, CDCl3): δ 21.5, 23.45, 23.48,
28.6 (t, J = 3.2), 49.0 (t, J = 3.7), 64.5 (t, J = 16.7), 115.6 (t, J = 249.9).
19F NMR (121 MHz, CDCl3): δ −128.4 (d, J = 51.9). Anal. Calcd for
C11H20F2NCl (239.73): C, 55.11; H, 8.41; N, 5.84. Found: C, 55.17;
H, 8.50; N, 5.86.
Diethyl (Difluoro(1-morpholinocyclohexyl)methyl)-
phosphonate (10a). Purified by method B; 126 mg, 71% yield.
Mp 57−60 °C. 1H NMR (300 MHz, CDCl 3): δ 1.19−1.80 (m, 14H),
1.92−2.08 (m, 2H), 2.93 (br, 4H), 3.62 (br, 4H), 4.16−4.31 (m, 4H).
13C NMR (150 MHz, CDCl3): δ 16.4 (d, J = 5.4), 20.3, 25.7, 28.0 (t, J
= 3.3), 47.1 (t, J = 3.0), 62.7 (q, J = 16.7), 64.4 (d, J = 7.5), 68.6, 126.9
(td, J = 271.2, 191.9). 19F NMR (282 MHz, CDCl3): δ −112.4 (d, J =
108.2). 31P NMR (121 MHz, CDCl3): δ 6.05 (t, J = 108.2). Anal.
Calcd for C15H28F2NO4P (355.36): C, 50.70; H, 7.94; N, 3.94. Found:
C, 50.76; H, 8.03; N, 3.77.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
Diethyl (1,1-Difluoro-3-methyl-2-pyrrolidin-1-ylbutyl)-
phosphonate (10b). Purified by method C; 122 mg, 78% yield.
1
Oil. H NMR (300 MHz, CDCl3): δ 0.95 (d, 3H, J = 6.9), 1.03 (dd,
3H, J = 6.4, 4.6), 1.26−1,37 (m, 6H), 1.63−1.76 (m, 4H), 2.14−2.30
(m, 1H), 2.75−3.00 (m, 4H), 3.10 (dt, 1H, J = 29.3, 7.6), 4.06−4.28
(m, 4H). 13C NMR (75 MHz, CDCl3): δ 16.3 (t, J = 6.1), 20.1 (dd, J =
7.5, 1.2), 21.6, 24.5, 26.0 (dt, J = 6.9, 2.3), 48.8, 63.6 (m), 64.9 (ddd, J
= 11.5, 20.7, 23.6), 124.0 (ddd, J = 277.5, 274.7, 218.8). 19F NMR
(282 MHz, CDCl3): δ −121.0 (ddd, 1F, J = 297.8, 108.3, 29.3), −97.4
(dd, 1F, J = 297.8, 108.3). 31P NMR (121 MHz, CDCl3): δ 7.71 (dd, J
= 110.4, 106.3). Anal. Calcd for C13H26F2NO3P (313.32): C, 49.83; H,
8.36; N, 4.47. Found: C, 49.71; H, 8.23; N, 4.44.
Diethyl Difluoro(1-(pyrrolidin-1-yl)cyclohexyl)-
methylphosphonate (10c). Purified by method C. 143 mg, 84%
yield. Oil. 1H NMR (300 MHz, CDCl3): δ 1.08−1.74 (m, 18H), 1.91−
2.07 (m, 2H), 2.87−3.04 (m, 4H), 4.13−4.28 (m, 4H). 13C NMR (75
MHz, CDCl3): δ 16.2 (d, J = 6.1), 21.1, 24.8, 25.4, 28.9 (t, J = 3.6),
44.9 (t, J = 2.8, 61.5 (dt, J = 17.7, 15.5), 64.0 (d, J = 7.2), 126.4 (dt, J =
273.7, 191.8). 19F NMR (282 MHz, CDCl3): δ −112.2 (d, 2F, J =
110.3). 31P NMR (121 MHz, CDCl3): δ 7.13 (t, J = 110.3). Anal.
Calcd for C15H28F2NO3P (339.36): C, 53.09; H, 8.32; N, 4.13. Found:
C, 52.99; H, 8.34; N, 4.13.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: adil25@mail.ru.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Ministry of Science (project
MD-1151.2011.3), the Russian Foundation for Basic Research
(project 10-03-91159), and the Russian Academy of Sciences
(program no. 7). We also thank Dr. V. Levin for helpful
discussions.
DEDICATION
■
This paper is dedicated to Professor Herbert Mayr on the
occasion of his 65th birthday.
N-[2,2-Difluoro-1-(1-naphthyl)ethyl]-N-methylamine (11). A
suspension of magnesium turnings (243 mg, 10 mmol) in methanol
(15 mL) was treated with dibromoethane (2 μL), and the mixture was
stirred for a few minutes until slow evolution of hydrogen started.
Then, a solution of amine 7g (98 mg, 0.5 mmol) in methanol (3 mL)
was added, and the mixture was stirred for 1 h at room temperature.
An additional portion of magnesium (243 mg, 10 mmol) was added,
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