Synthesis of Small 3-Fluoro- and 3,3-Difluoropyrrolidines Using Azomethine Ylide Chemistry

Article abstract of DOI:10.1021/acs.joc.5b00853

Here, we report accessing small 3-fluoropyrrolidines and 3,3-difluoropyrrolidines through a 1,3-dipolar cycloaddition with a simple azomethine ylide and a variety of vinyl fluorides and vinyl difluorides. We demonstrate that vinyl fluorides within α,β-unsaturated, styrenyl and even enol ether systems can participate in the cycloaddition reaction. The vinyl fluorides are relatively easy to synthesize through a variety of methods, making the 3-fluoropyrrolidines very accessible.

Full text of DOI:10.1021/acs.joc.5b00853

Note
pubs.acs.org/joc
Synthesis of Small 3‑Fluoro- and 3,3-Difluoropyrrolidines Using
Azomethine Ylide Chemistry
Indrawan McAlpine,*,† Michelle Tran-Dube,† Fen Wang,† Stephanie Scales,† Jean Matthews,†
́
Michael R. Collins,† Sajiv K. Nair,† Mary Nguyen,† Jianwei Bian,‡ Luis Martinez Alsina,‡ Jianmin Sun,‡
Jiaying Zhong,‡ Joseph S. Warmus,‡ and Brian T. O’Neill‡
†Pfizer Worldwide Medicinal Chemistry, Pfizer Research & Development, 10770 Science Center Drive, San Diego, California 92121,
United States
‡Pfizer Worldwide Medicinal Chemistry, Pfizer Research & Development, 445 Eastern Point Road, Groton, Connecticut 06340,
United States
S
* Supporting Information
ABSTRACT: Here, we report accessing small 3-fluoropyrro-
lidines and 3,3-difluoropyrrolidines through a 1,3-dipolar
cycloaddition with a simple azomethine ylide and a variety
of vinyl fluorides and vinyl difluorides. We demonstrate that
vinyl fluorides within α,β-unsaturated, styrenyl and even enol
ether systems can participate in the cycloaddition reaction. The vinyl fluorides are relatively easy to synthesize through a variety
of methods, making the 3-fluoropyrrolidines very accessible.
eplacing a hydrogen atom for a fluorine atom is very
advantageous in medicinal chemistry and can have
within α,β-unsaturated, styrenyl and even enol ether systems
can undergo the cycloaddition reaction to give pharmaceutically
relevant fluoropyrrolidines and further the scope of dipolar-
ophiles used in the cycloaddition reaction.
To our knowledge, there are only two reported examples
(Scheme 1, lines 1 and 2) of reacting a fluoroacrylate with the
simple azomethine ylide precursor, N-benzyl-1-methoxy-N-
((trimethylsilyl)methyl) methanamine (1).7 These results
suggest that any fluoroacrylate should be amenable to the
R
dramatic effects on enzyme binding, absorption, distribution,
and metabolic profile of a compound while having minimal
changes in size.1 Because of pKa changes, placement of a
fluorine atom beta or gamma to a basic nitrogen has major
effects on the lipophilicity and thereby the permeability,
solubility, efflux, and safety profile of a compound.2 For these
reasons, efficient and scalable syntheses of small fluorinated
aliphatic amines benefit drug discovery programs.
The most common way to synthesize fluoropyrrolidines and
gem-difluoropyrrolidines is through deoxofluorination of the
respective precursor pyrrolidinol or pyrrolidinone.3 This
approach often forms the corresponding vinyl fluoride as a
side product, which can make purification difficult.3b,c
Furthermore, there are limited cases reporting the synthesis
of 4-substituted 3,3-difluoropyrrolidines in this manner, most
likely due to steric hindrance.4 The synthesis of 4-substituted
3,3-difluoropyrrolidnes usually proceeds through a carbonyl
reduction of the lactam or imide precursor.5 This approach
requires building the difluorolactam or difluoroimide in a
multistep sequence. There are numerous examples of
generating 3,4-substituted pyrrolidines by reacting an elec-
tron-deficient alkene with azomethine ylides.6 The ability to
control the relative stereochemistry provided by the dipolar-
ophile geometry through a concerted cycloaddition reaction is
an attractive aspect to forming substituted pyrrolidines in this
manner. However, there are only a few examples in the
literature of using this reaction to generate simple fluoropyrro-
lidines7 and almost none to generate gem-difluoropyrrolidines8
despite the fact that vinyl fluorides should be reasonable
substrates for the dipolar cycloaddition. We demonstrate,
herein, that easily accessible vinyl fluorides and vinyl difluorides
Scheme 1. Fluoroacrylates
Received: April 16, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b00853
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Note
Scheme 2. Difluoroacrylate
Scheme 3. 3α-Fluoro-octahydropyrrolo[3,4-c]pyrrole
cycloaddition reaction. In our hands, we’ve used similar
dipolarophiles such as diethylfluoro fumarate9 (Scheme 1, line
3) and ethyl (Z)-2-fluoro-3-phenyl acrylate10 (Scheme 1, line
4) to generate the corresponding fluoropyrrolidines 211 and 3,
respectively. The challenge arises in synthesizing the desired
fluoroacrylate.
difluoropyrrolidine-3-carboxylate ethyl ester 7b in 32% yield
over the two steps.13 The pyrrolidines 7a and 7b are fairly
sensitive to base and can readily eliminate to unwanted pyrrole
compounds. However, benzyl deprotection and pyrrolidine
reprotection with a Boc group can be done in excellent yield
using standard hydrogenolysis in the presence of Boc
anhydride. For compound 7a, this leads to the difluoropyrro-
lidine acid 8a, which is reduced to the desired Boc-protected
3,3-difluoro-4-(hydroxymethyl)pyrrolidine 9 in 99% yield using
borane−THF complex. For compound 7b, hydrogenolysis
leaves the ethyl ester intact (8b), which can be reduced to
pyrrolidine 9 using lithium aluminum hydride in 84% yield.
One of the more elaborate systems we desired is 3α-fluoro-
octahydropyrrolo[3,4-c]pyrrole (10) with orthogonal protect-
ing groups (Scheme 3, line 1). We envisioned we could utilize
3-fluoromaleimide (11) in the 1,3-dipolar cycloaddition
reaction. A very scalable synthesis of 3,3-difluoropyrrolidine
published by Xu et al. proceeds through 3,3-difluoroimide
(14).5c We speculated that a controlled HF elimination of 3,3-
difluoroimide would generate the desired 3-fluoromaleimide.
Following this route, 3,3-difluoroimide is made from 2,2-
difluorosuccinic acid (15) in two steps (Scheme 3, line 2).
Initial attempts to perform the selective HF elimination using
potassium t-butoxide generated 3-t-butoxymaleimide (15) in
65% yield. Presumably, the desired elimination occurs;
To the best of our knowledge, there are no reports describing
the use of simple difluoroacrylate esters in the 3 + 2
cycloaddition shown in Scheme 2 (line 1). We envisioned
that the resulting 3,3-difluoropyrrolidine would allow access to
an N-protected 4-hydroxymethyl-3,3-difluoropyrrolidine 4.
Starting with 3,3,3-trifluoropropionic acid (Scheme 2, line 2),
the benzyl ester 5a is made in 70% yield via the acid chloride.
We found the method published by Shimada et al. to be a
reliable process to generate the difluoroacrylate benzyl ester.12
Treatment of benzyl ester 5a with trimethylsilyl triflate
generates the trimethylsilyl enol ether, which is then exposed
to titanium tetrachloride effecting the elimination and creating
the difluoroacrylate benzyl ester 6a in 49% yield. Subjecting
difluoroacrylate 6a to the azomethine precursor, 1, in
dichloromethane with a catalytic amount of trifluoroacetic
acid reveals the desired benzyl protected 4,4-difluoropyrroli-
dine-3-carboxylate benzyl ester 7a in a modest 61% yield. A
similar sequence can be applied to the commercially available
3,3,3-trifluoropropionic ethyl ester 5b to generate 4,4-
B
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however, t-butoxide performs a subsequent Michael addition
and eliminates fluoride ion. If this is true, we reasoned that we
could trap the intermediate 3-fluoromaleimide with azomethine
ylide if we can concomitantly promote the elimination and
generation of the azomethine ylide using lithium fluoride.
Treatment of a mixture containing 3,3-difluoroimide (14) and
azomethine ylide precursor (1) in acetonitrile with lithium
fluoride reveals the desired 3α-fluoro-tetraydropyrrolo imide
system (16) in good yield. The benzyl group on the pyrrolidine
can be selectively exchanged for a Boc group via hydrogenolysis
conditions. The cyclic imide is reduced to the pyrrolidine using
borane-dimethylsulfide to give our desired orthogonally
protected 3α-fluoro-octahydropyrrolo[3,4-c]pyrrole (18) in
excellent yield. Starting from 2,2-difluorosuccinic acid, a five-
step sequence generates the complex [3.3.0] system in 11%
overall yield.
compound 23 with magnesium metal in methanol or refluxing
with Super-Hydride in THF.
While doing this work, we could only find one report of a
difluorostyrenyl compound used in a 1,3-dipolar cycloaddition
with an azomethine ylide.8 The patent reports reacting p-
bromo-(2,2-difluorovinyl)benzene (24) with lithium fluoride
and the azomethine ylide precursor 1, but gave no yield for the
reaction. Under modified reaction conditions using 3 equiv of
LiF and 4 equiv of azomethine precursor (1) in acetonitrile at
60 °C generates the desired difluoropyrrolidne (25) in 80%
yield (Scheme 6). Running the reaction at 120 °C using 10%
TFA instead of LiF generates the desired product in 82% yield.
Scheme 6. p-Bromodifluorostyrene
In another instance, synthesis of 4,4-difluoropyrrolidin-3-ol
(19), a close variant of the pyrrolidine (9), was desired. To
utilize the 3 + 2 cycloaddition would require reacting the
azomethine ylide with a difluoroenol ether (Scheme 4, line 1).
We tested a number of 2,2-difluorostyrenes synthesized using
the difluoromethylsulfonyl-2-pyridine reagent developed by Hu
and co-workers15 and reacting with various benzaldehydes, as
shown in Scheme 7. As shown in Table 1, having electron-
Scheme 4. Benzyl Difluoroenol Ether
Scheme 7. Difluorostyrenes
Table 1. Difluorostyrenes and 3,3-Difluoro-4-phenyl
Pyrroldines
Simple difluoroenol ethers are commonly made by eliminating
HF from protected trifluoroethanol.14 Synthesis of benzyl
difluoroenol ether (20) is done by treating trifluoroethylbenzyl
ether with butyl lithium in THF (Scheme 4, line 2). Subjecting
benzyl difluoroenol ether (20) to the azomethine ylide
precursor (1) under TFA conditions yielded the desired
difluoropyrrolidine (21) in 26%. Using lithium fluoride
conditions to generate the azomethine ylide gave a modest
improvement in yield.
We hypothesized that a more electron-deficient difluoroenol
ether would improve the yield of the 3 + 2 reaction. To that
end, we synthesized the tosyl difluoroenol ether (22) using the
same HF elimination route (Scheme 5). Treatment of tosyl-
protected trifluoroethanol with butyl lithium in THF generates
the desired difluoroenol ether (22) in excellent yield. Reacting
this material with the azomethine ylide precursor under TFA
condition reveals the desired difluoropyrrolidine (23) in greater
than 90% yield. This reaction works extremely well and can be
carried out on 10 g scale. By comparison, using lithium fluoride
conditions to generate the azomethine ylide only gave a 60%
yield of the difluoropyrrolidine (23). The tosyl group is
removed to reveal the difluoropyrroldinol (19) by treating
a
Low yield is due to the volatility of 26d.
Scheme 5. Tosyl Difluoroenol Ether
C
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Scheme 8. Heterocyclic Difluorostyrenes
Diethyl (3R,4S)-1-Benzyl-3-fluoropyrrolidine-3,4-dicarbox-
ylate (2). To a colorless solution of diethyl but-2-ynedioate (5.0 g,
29.4 mmol) in DMF (450 mL) was added the solution of CsF (13.5 g,
88.1 mmol) and KHF2 (3.24 g, 41.1 mmol) in H2O (240 mL) slowly.
The mixture was stirred at 80 °C for 3 h. The dark mixture was
quenched with H2O and extracted with Et2O (200 mL × 3). The
organic layers were washed with H2O (100 mL) and brine (100 mL).
The organic layers were dried over MgSO4 and filtered. The organic
layers were concentrated by flushing with N2 through the organic
layers overnight. The organic layers were concentrated in vacuum to
give diethyl 2-fluorofumarate (2.36 g, 60.1%) as a yellow oil. 1H NMR
deficient groups on the benzene ring gives higher yields in the 3
+ 2 cycloaddition reaction. The low yield in the p-tolyl system
(entry d) is due to the difficulty in isolating the volatile p-
methyl-(2,2-difluorovinyl)benzene. In general, all the difluor-
ostyrenes participate in the cycloaddition reaction to give their
respective gem-difluoropyrrolidines in moderate to good yields.
Another approach to making difluorostyrene compounds was
shown by Gøgsig et. al.16 utilizing the difluoroenol ether (22)
previously described in a Suzuki coupling. We explored using
this method to make heterocyclic difluorostyrenes and
subjecting them to the 3 + 2 cycloaddition reaction (Scheme
8, line 1). Using the same coupling conditions, 2.5 mol %
Pd2(dba)3 catalyst with 5 mol % HBF4PCy3 ligand and
potassium phosphate base in a dioxane/water mixture gives
moderate yields of the heterocyclic difluorostyrenes (Scheme 8,
lines 2−4). Subjecting these to the LiF activating conditions to
generate the azomethine ylide gives moderate to good yields of
the desired gem-difluoropyrrolidines. In the case of the
methoxypyrimidine (line 3), higher equivalents of LiF and
azomethine ylide are needed to push the reaction. This route
demonstrates the ease of accessing 4,4-difluoro-3-heteroaryl
pyrrolidines starting from heteroaryl boronates and boronic
acids.
1
show roughly a 9:1 ratio of Z:E isomers. H NMR (Z-isomer) (400
MHz, CDCl3) δ ppm 6.30−6.38 (m, 1H), 4.24−4.37(m, 4H), 1.57−
1.25 (m, 6H). This mixture of diethyl 2-fluorofumarate (2.34 g, 12.3
mmol) was diluted with dichloromethane (30 mL). To this was added
N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (2.92 g,
12.3 mmol), and the mixture was cooled to 0 °C. To this mixture was
added TFA (0.095 mL, 1.23 mmol), and the reaction was stirred at 0
°C for 30 min. The reaction mixture was then stirred at 25 °C for 48 h.
The mixture was concentrated to give the crude product (6.35 g) as an
orange residue. Silica gel chromatography (5:95 EtOAc:Heptanes)
gave the desired product 2 as a clear oil (3.25 g, 81%). 1H NMR (400
MHz, CDCl3) δ ppm 7.45−7.17 (m, 5H), 4.32 (q, J = 7.1 Hz, 2H),
4.26−4.09 (m, 2H), 3.84−3.63 (m, 3H), 3.39−3.25 (m, 1H), 3.16 (dd,
J = 2.2, 8.8 Hz, 2H), 3.04−2.88 (m, 1H), 1.38−1.31 (m, 3H), 1.25 (t, J
= 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ ppm 169.3 (d, J = 27.1
Hz, 1C), 167.7 (d, J = 5.1 Hz, 1C), 138.0, 128.7 (s, 2C), 128.4 (s, 2C),
127.3, 99.1 (d, J = 198.8 Hz, 1C), 63.4 (d, J = 24.2 Hz, 1C), 62.3, 61.2,
59.8, 53.1, 52.2 (d, J = 22.0 Hz, 1C), 14.1, 14.1; 19F NMR (376 MHz,
CDCl3) δ ppm −164.74 (s, 1 F); HRMS calculated for C17H22FNO4
323.1533, found 323.1537.
Ethyl (3R,4R)-1-Benzyl-3-fluoro-4-phenylpyrrolidine-3-
carboxylate (3). To a mixture of acid-washed Zn (5.61 g, 85.7
mmol), CuCl (849 mg, 8.57 mmol), and 15 g of 4 Å molecular sieves
in 125 mL of THF were added benzaldehyde (3.64 g, 34.3 mmol) and
acetic anhydride (3.5 g, 34.3 mmol). The reaction was heated at 50 °C
for 5 min under N2. To this reaction mixture was added ethyl 2,2-
dichloro-2-fluoroacetate (5 g, 28.57 mmol). The mixture was stirred at
80 °C for 16 h under N2. The mixture was filtered through Celite and
concentrated to give the crude product (23.4 g) as a yellow oil, which
was purified by silica gel column chromatography (EtOAc in
petroleum ether from 0% to 5%) to give ethyl (Z)-2-fluoro-3-phenyl
acrylate (8.05 g, 145%) as a colorless oil. 1H NMR (400 MHz, CDCl3)
In summary, we have shown that a variety of vinyl fluorides
and vinyl difluorides can participate in a 1,3-dipolar cyclo-
addition with a simple azomethine ylide to generate novel 3-
fluoropyrrolidines and 3,3-difluoropyrrolidines. The vinyl
fluorides and vinyl difluorides can exist as α,β-unsaturated,
styrenyl and even enol ether moieties. These can be readily
prepared through a variety of methods, which gives easy and
efficient access to structurally diverse fluoropyrrolidines.
EXPERIMENTAL SECTION
■
Silica gel chromatography purification was usually performed on
Biotage or ISCO systems using prepacked cartridges. All 13C NMR
data reported are 1H decoupled. All 19F NMR data are 13C decoupled.
HRMS data were collected using a TOF method with an Atmospheric
Pressure Chemical Ionization source.
D
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δ ppm 7.70−7.59 (m, 2H), 7.47−7.33 (m, 3H), 7.01−6.84 (m, 1H),
4.36 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H). To a solution of
ethyl (Z)-2-fluoro-3-phenyl acrylate (6.85 g, 35.27 mmol) and N-
benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (31.4 g,
106 mmol) in dichloromethane (150 mL) was added TFA (18 mL)
at 0 °C. The mixture was stirred at 55 °C for 16 h. The mixture was
concentrated to give the crude product (27 g), which was purified by
prep-HPLC to give compound 3 (2.21 g, 19.1%). 1H NMR (400
MHz, CDCl3) δ ppm 7.25−7.47 (m, 10 H), 4.26 (q, J = 7.09 Hz, 2 H),
3.84−3.99 (m, 1 H), 3.77−3.92 (m, 2 H), 3.49−3.63 (m, 1 H), 3.24−
3.33 (m, 1 H), 3.14 (t, J = 9.40 Hz, 1 H), 3.08 (q, J = 12.30 Hz, 1 H),
1.28 (t, J = 7.09 Hz, 3 H); 13C NMR (101 MHz, CDCl3) δ ppm 170.1
(d, J = 27.9 Hz, 1C), 138.5, 134.7 (d, J = 3.1 Hz, 1C), 129.2 (d, J = 1.5
Hz, 2C), 128.7 (s, 2C), 128.4 (s, 2C), 128.3 (s, 2C), 127.5, 127.3, 99.9
(d, J = 199.5 Hz, 1C), 63.9 (d, J = 24.6 Hz, 1C), 62.0, 60.3, 57.8, 52.5
(d, J = 20.2 Hz, 1C), 14.2; 19F NMR (376 MHz, CDCl3) δ ppm
−161.11 (br. s., 1F); HRMS calculated for C20H22FNO2 327.1635,
found 327.1638.
127.2 (dd, J = 252.4, 256.8 Hz, 1C), 67.1, 61.3 (t, J = 27.9 Hz, 1C),
59.4, 54.1 (d, J = 3.7 Hz, 1C), 51.7 (dd, J = 22.7, 24.9 Hz, 1C); 19F
NMR (376 MHz, CDCl3) δ ppm −91.12 (d, J = 231.2 Hz, 1F),
−100.43 (d, J = 231.2 Hz, 1F); HRMS calculated for C19H19F2NO2
331.1384, found 332.1389.
Ethyl 1-Benzyl-4,4-difluoropyrrolidine-3-carboxylate (7b).
To a microwave vial containing a solution of commercially available
ethyl 3,3,3-trifluoropropanoate (1.0 g, 6.41 mmol) in CDCl3 (10 mL)
was added triethylamine (0.78 mg, 7.69 mmol), followed by dropwise
addition of trimethylsilyl triflate (1.74 g, 7.69 mmol). Upon addition,
the clear solution changes to an orange color. After 1.5 h, the reaction
was cooled in an ice bath, and then titanium(IV) chloride (0.961 mL,
1.0 M in DCM) was added. The orange solution changes to a deep
black-red color. The ice bath was removed, and the reaction was
stirred at rt for 1 h and then recooled in an ice bath. The reaction was
quenched with water (10 mL), the layers separated, and then the
organic phase was dried (MgSO4) and filtered. The resulting solution
was cooled in an ice bath and N-(methoxymethyl)-N-(trimethylsilyl-
methyl)-benzylamine (2.32 g, 9.4 mmol, 2.50 mL) was added,
followed by trifluoroacetic acid (100 mg, 1 mmol, 0.1 mL). The
reaction was stirred in the ice bath for 1 h, warmed to rt, and stirred for
2 h and then quenched with saturated NaHCO3 solution. The layers
were separated, and the organic phase was dried (MgSO4), filtered,
and concentrated. The crude residue was purified by column
chromatography using a 0−40% EtOAc/heptane gradient to provide
543.0 mg (32%, 2 steps) as a clear oil. 1H NMR (400 MHz, CDCl3) δ
ppm 7.36−7.31 (m, 4H), 7.30−7.25 (m, 1H), 4.37−4.13 (m, 2H),
3.77−3.57 (m, 2H), 3.46−3.31 (m, 1H), 3.21 (dt, J = 8.6, 11.8 Hz,
1H), 3.12 (t, J = 8.8 Hz, 1H), 3.02−2.93 (m, 1H), 2.77 (ddd, J = 11.0,
14.4, 17.0 Hz, 1H), 1.30 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ ppm 167.5 (dd, J = 2.6, 4.0 Hz, 1C), 137.3, 128.6 (s, 2C),
128.4 (s, 2C), 127.4, 127.7 (dd, J = 252.0, 256.4 Hz, 1C), 61.4, 61.8−
60.9 (m, 1C), 59.4, 54.1 (d, J = 3.7 Hz, 1C), 51.7 (dd, J = 22.0, 24.9
Hz, 1C), 14.1; 19F NMR (376 MHz, CDCl3) δ ppm −91.15 (d, J =
231.2 Hz, 1F), −101.02 (d, J = 233.5 Hz, 1F); HRMS calculated for
C14H17F2NO2 269.1227, found 269.123.
1-(tert-Butoxycarbonyl)-4,4-difluoropyrrolidine-3-carboxylic
Acid (8a). To a nitrogen-purged solution of 1-benzyl-4,4-difluor-
opyrrolidine-3-carboxylic acid (93 mg, 0.28 mmol) in EtOH (3 mL)
was added 20% palladium hydroxide on carbon (7.2 mg, 0.05 mmol),
followed by di-tert-butyl-dicarbonate (88 mg, 0.40 mmol). The
reaction was evacuated and backfilled with H2 three times and then
run under a hydrogen atmosphere (balloon) for 66 h. The crude
reaction was filtered through a bed of Celite and then rinsed with
dichloromethane (15 mL) and methanol (15 mL). The filtrate was
concentrated to give 71 mg (99%) as a clear oil. 1H NMR (400 MHz,
DMSO-d6) δ ppm 1.44 (s, 9 H) 3.55−3.77 (m, 5 H); 13C NMR (101
MHz, at 80 °C in DMSO-d6) δ ppm 167.3 (br. s., 1C), 152.8, 129.2−
120.1 (m, 1C), 79.3, 52.1 (t, J = 30.8 Hz, 1C), 48.4 (t, J = 22.0 Hz,
1C), 45.6 (br. s., 1C), 27.7 (s, 3C); 19F NMR (376 MHz, at 80 °C in
DMSO-d6) δ ppm −106.34 (s, 1F), −106.96 (s, 1F); HRMS
calculated for C10H15F2NO4 251.0969, found 251.0958.
Benzyl 3,3,3-Trifluoropropanoate (5a). To a solution of 3,3,3-
trifluoropropionic acid (1.76 g, 13.7 mmol) in dichloromethane (12.00
mL) was added oxalyl chloride (20 mmol, 1.80 mL), followed by DMF
(0.10 mL). Gas evolution was observed while stirring was continued at
rt for 2 h. Benzyl alcohol (1.78 g, 16.5 mmol, 1.70 mL) was added, and
the reaction was heated to 60 °C for 3 h. The reaction was cooled to rt
and then quenched with saturated NaHCO3 solution (20 mL) and
extracted with DCM (2 × 15 mL). The combined extracts were
washed with brine (20 mL) and then dried (MgSO4), filtered, and
concentrated. The crude residue was purified by column chromatog-
raphy using a 0−50% DCM/heptane gradient to give 2.11 g (70%) as
1
a clear oil. H NMR (400 MHz, CDCl3) δ ppm 7.46−7.31 (m, 5H),
5.23 (s, 2H), 3.23 (q, J = 10.0 Hz, 2H); 13C NMR (101 MHz, CDCl3)
δ ppm 163.9 (q, J = 4.2 Hz, 1C), 134.8, 128.6 (s, 2C), 128.6 (s, 1C),
128.3 (s, 2C), 122.0(q, J = 276.6 Hz, 1C), 67.4 (s, 1C), 39.6 (q, J =
30.8 Hz, 1C); 19F NMR (376 MHz, CDCl3) δ ppm −63.42 (s, 3F).
Benzyl 3,3-Difluoroacrylate (6a). To a solution of benzyl 3,3,3-
trifluoropropanoate (490 mg, 2.25 mmol) in DCM (10 mL) was
added triethylamine (0.273 g, 2.70 mmol, 0.38 mL), followed by
dropwise addition of trimethylsilyl triflate (0.611 g, 2.70 mmol, 0.499
mL). The pale yellow solution was stirred at rt for 18 h and then
cooled in an ice bath. Titanium(IV) chloride (0.225 mmol, 0.225 mL,
1.0 M) was added, and the reaction turned deep red and then brown.
The reaction was taken out of the ice bath, stirred at rt for 12 h,
recooled in the ice bath, and then quenched with water. The layers
were separated, and the organic phase was washed with brine (5 mL)
and then dried (MgSO4), filtered, and concentrated. The crude
concentrate was purified by column chromatography using a 0−50%
DCM/heptane gradient. 286 mg (49% by NMR) was isolated as a
1
clear oil. H NMR (400 MHz, CDCl3) δ ppm 7.37−7.41 (m, 5H),
5.21 (s, 2H), 4.99−5.09 (m, 1H); 13C NMR (101 MHz, CDCl3) δ
ppm 162.8 (dd, J = 7.7, 17.2 Hz, 1C), 162.1 (dd, J = 298.9, 312.1 Hz,
1C), 135.5 (s, 1C), 128.6 (s, 2C), 128.4 (s, 1C), 128.3 (s, 2C), 77.1
(dd, J = 8.1, 30.1 Hz, 1C), 66.6 (s,1C); 19F NMR (376 MHz, CDCl3)
δ ppm −63.28 (d, J = 18.3 Hz, 1F), −68.83 (d, J = 18.3 Hz, 1F).
Benzyl 1-Benzyl-4,4-difluoropyrrolidine-3-carboxylate (7a).
To a solution of benzyl 3,3-difluoroacrylate (195 mg, 0.98 mmol) and
N-(methoxymethyl)-N-(trimethylsilylmethyl)-benzylamine (2.2 mmol,
0.550 mL) in DCM (1.2 mL) was added slowly trifluoroacetic acid
(22.5 mg, 0.197 mmol, 0.02 mL) at rt. Upon addition, an exotherm
was observed with vigorous bubbling. The reaction was stirred at rt for
1 h and then quenched with saturated NaHCO3 solution (15 mL) and
extracted with DCM (2 × 10 mL). The combined organic extracts
were washed with brine (15 mL) and then dried (MgSO4), filtered,
and concentrated. The crude oil was purified by column chromatog-
raphy using a 0−40% EtOAc/heptane gradient. 200 mg (61%) was
isolated as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.34−7.40
(m, 5H), 7.28−7.33 (m, 5H), 5.22 (s, 2H), 3.61−3.75 (m, 2H), 3.37−
3.53 (m, 1H), 3.17−3.27 (m, 1H), 3.13 (t, J = 8.80 Hz, 1H), 2.94−
3.04 (m, 1H), 2.80 (ddd, J = 10.94, 14.15, 16.96 Hz, 1H); 13C NMR
(101 MHz, CDCl3) δ ppm 167.4 (br. s., 1C), 137.2 (br. s., 1C), 135.4,
128.7 (s, 2C), 128.5 (s, 2C), 128.5 (s, 2C), 128.3, 128.2 (s, 2C), 127.5,
1-(tert-Butyl) 3-Ethyl 4,4-Difluoropyrrolidine-1,3-dicarbox-
ylate (8b). To a nitrogen-purged solution of ethyl 1-benzyl-4,4-
difluoropyrrolidine-3-carboxylate (543.0 mg, 2.02 mmol) in ethyl
alcohol (13.4 mL) was added 20% palladium hydroxide on carbon
(55.0 mg, 0.39 mmol), followed by di-tert-butyl-dicarbonate (528 mg,
2.42 mmol). The reaction was evacuated and backfilled with H2 three
times and then stirred under a hydrogen atmosphere (balloon) for 18
h. The crude reaction was filtered through a bed of Celite and then
rinsed with DCM (15 mL) and MeOH (15 mL). The filtrated was
concentrated and purified by column chromatography using a 0−60%
EtOAc/heptane gradient to give 415 mg (74%) as a clear oil. 1H NMR
(400 MHz, CDCl3) δ ppm 4.35−4.18 (m, 2H), 3.93−3.69 (m, 4H),
3.38 (br. s., 1H), 1.48 (s, 9H), 1.31 (t, J = 7.2 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ = 166.8 (br. s., 1C), 153.7, 80.6, 61.8, 53.4−51.9 (m,
1C), 50.6−48.9 (m, 1C), 46.5−45.5 (m, 1C), 28.3 (s, 3C), 14.0; 19F
NMR (376 MHz, CDCl3) δ ppm −100.55 (dd, J = 235.8, 604.3 Hz,
1F), −108.15 (dd, J = 162.5, 235.8 Hz, 1F); HRMS calculated for
C12H19F2NO4 279.1282, found 279.1292.
E
DOI: 10.1021/acs.joc.5b00853
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
tert-Butyl 3,3-Difluoro-4-(hydroxymethyl)pyrrolidine-1-
carboxylate (9). From 8a: To a capped microwave vial containing
1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-3-carboxylic acid (714
mg, 2.84 mmol) was added BH3−THF (5.68 mL, 5.68 mmol, 1 M) at
rt. The reaction was heated to 75 °C for 15 min, cooled to rt, carefully
quenched with saturated NH4Cl solution, and then diluted with
EtOAc. The layers were separated, and the organic phase was dried
(MgSO4), filtered, and concentrated to give 674 mg (99%) as a clear
oil. From 8b: To a cooled (ice bath) solution of 1-(tert-butyl) 3-ethyl
4,4-difluoropyrrolidine-1,3-dicarboxylate (358 mg, 1.28 mmol) in
tetrahydrofuran (4.27 mL) was added lithium aluminum hydride
(1.41 mL, 1.0 M in THF). After 5 min, the reaction was carefully
quenched with Rochelle’s salt (satd, 10 mL) and then extracted with
EtOAc (2 × 15 mL). The combined organic extracts were washed with
brine (20 mL) and then dried (MgSO4), filtered, and concentrated.
The crude residue was purified by column chromatography using 0−
50% EtOAc/heptane gradient to provide 255 mg (84%) as a clear oil.
1H NMR (400 MHz, at 80 °C in DMSO-d6) δ ppm 4.65 (br. s., 1H),
3.74−3.57 (m, 4H), 3.52 (t, J = 7.5 Hz, 1H), 3.30 (dd, J = 7.0, 11.0 Hz,
1H), 2.66 (tq, J = 7.0, 13.7 Hz, 1H), 1.43 (s, 9H); 13C NMR (101
MHz, at 80 °C in DMSO-d6) δ ppm 153.0 (s, 1 C), 126.8 (t, J = 249.8
Hz, 1 C), 78.9 (s, 1 C), 56.9 (dd, J = 7.0, 3.3 Hz, 1 C), 52.3 (t, J = 31.5
Hz, 1 C), 46.6 (br. s., 1 C), 45.5 (t, J = 20.2 Hz, 1 C), 27.7 (s, 3 C);
19F NMR (376 MHz, at 100 °C in DMSO-d6) δ ppm −113.07 (d, J =
233.46 Hz, 1 F), −99.95 (d, J = 233.46 Hz, 1 F); HRMS calculated for
C10H17F2NO3 237.1176, found 237.1182.
under H2. The Pd(OH)2/C was removed by filtration. The filtrate was
concentrated under reduced pressure and purified by column
chromatography eluting with 2−20% EtOAc/heptane to obtain the
desired compound 17 as a white solid (244 mg, 88% yield). 1H NMR
(400 MHz, CDCl3) δ ppm 7.29−7.37 (m, 5 H) 4.70 (s, 2 H) 3.97−
4.19 (m, 2 H) 3.62−3.80 (m, 2 H) 3.34−3.47 (m, 1 H) 1.43 (s, 9 H);
13C NMR (101 MHz, CDCl3) δ ppm 172.8 (d, J = 8.8 Hz, 1 C)
171.0−171.9 (m, 1 C) 153.3 (s, 1 C) 134.6 (s, 1 C) 128.8 (s, 2 C)
128.5 (s, 2 C) 128.3 (s, 1 C) 96.6−99.9 (m, 1 C) 81.1 (s, 1 C) 52.8−
54.0 (m, 1 C) 50.4 (br. s., 1 C) 46.5 (s, 1 C) 43.1 (s, 1 C) 28.2 (s, 3
C); 19F NMR (377 MHz, CDCl3) δ ppm −104.15 (s, 1 F); HRMS
calculated for C18H21FN2O4 348.1485, found 348.1475.
tert-Butyl 5-Benzyl-3a-fluorohexahydropyrrolo[3,4-c]-
pyrrole-2(1H)-carboxylate (18). Compound 17 (212 mg, 0.609
mmol) was dissolved in THF (6 mL), and borane dimethyl sulfide
complex (0.231 mL, 2.43 mmol) was added. The reaction mixture was
heated to 55 °C for 2.5 h. The reaction was then cooled to 0−5 °C
(ice water bath), quenched with MeOH (6 mL), concentrated under
reduced pressure, and then dried under high vacuum. The borane-
amine crude adduct was diluted with MeOH (6 mL), and under N2,
20% Pd(OH)2/C (60 mg) was added. The reaction mixture was
stirred for 18 h. The Pd(OH)2/C was removed by filtration, and the
filtrate was concentrated. The crude product was purified by column
chromatography, eluting with a 2−20% EtOAc/heptane gradient to
1
obtain the desired product 18 as a clear oil (106 mg, 55% yield). H
NMR (400 MHz, CDCl3) δ ppm 7.28−7.32 (m, 4 H) 7.18−7.25 (m, 1
H) 3.65−3.89 (m, 2 H) 3.49−3.64 (m, 3 H) 3.18 (dd, J = 11.19, 4.46
Hz, 1 H) 2.63−2.95 (m, 4 H) 2.37 (br. s., 1 H) 1.44 (s, 9 H); 13C
NMR (101 MHz, CDCl3) δ ppm 154.1 (s, 1 C) 138.1 (s, 1 C) 128.5
(s, 2 C) 128.3 (s, 3 C) 127.1 (s, 1 C) 79.7 (s, 1 C) 62.3−63.6 (m, 1 C)
59.2 (s, 1 C) 58.6 (d, J = 3.7 Hz, 1 C) 55.9 (br. s., 1 C) 50.5 (br. s., 1
C) 47.5 (br. s., 1 C) 28.4 (s, 3 C); 19F NMR (377 MHz, CDCl3) δ
ppm −147.75 (br. s., 1 F); HRMS calculated for C18H25FN2O2
320.1900, found 320.1903.
1-Benzyl-4-(benzyloxy)-3,3-difluoropyrrolidine (21). Method
A (TFA). The a solution of the (((2,2-difluorovinyl)oxy)methyl)-
benzene 20 (1.0 g, 5.877 mmol) and N-benzyl-1-methoxy-N-
((trimethylsilyl)methyl)methanamine (5.58 g, 23.5 mmol) was stirred
in the preheated heating block at 130 °C for 5 min. TFA (58.3 uL,
0.588 mmol) was added dropwise (white smoke evolved upon
addition). The mixture was heated at 130 °C for 30 min. The reaction
was concentrated to an orange oil and purified by column
chromatography using a 0−15% EtOAc/heptane gradient, leading to
the desired product as a colorless oil (469 mg, 26%).
Method B (LiF). To a solution of the (((2,2-difluorovinyl)oxy)-
methyl)benzene 20 (100 mg, 0.59 mmol) in ACN (1.18 mL, 0.5 M)
were added LiF (61 mg, 2.35 mmol) and N-benzyl-1-methoxy-N-
((trimethylsilyl)methyl)methanamine (601 uL, 2.35 mmol). The
mixture was stirred in a preheating heating block at 130 °C for 4 h.
The reaction was concentrated to an orange oil and purified by column
chromatography (EtOAc/heptane, 0−15%), leading to the desired
product as a colorless oil (65 mg, 37%). 1H NMR (400 MHz, CDCl3)
δ ppm 7.32−7.08 (m, 10H), 4.71 (d, J = 11.7 Hz, 1H), 4.44 (d, J =
11.6 Hz, 1H), 4.02−3.88 (m, 1H), 3.58−3.42 (m, 2H), 3.14−2.98 (m,
2H), 2.67 (dt, J = 11.2, 16.4 Hz, 1H), 2.45−2.36 (m, 1H); 13C NMR
(101 MHz, CDCl3) δ ppm 137.3 (s, 1 C), 137.2 (s, 1 C), 128.8 (s, 2
C), 128.5 (s, 2 C), 128.4 (s, 2 C), 128.0 (s, 2 C), 128.0 (s, 1 C), 127.5
(s, 1 C), 126.4 (dd, J = 245.8, 242.1 Hz, 1 C), 79.0 (dd, J = 30.1, 16.9
Hz, 1C), 72.8 (d, J = 2.9 Hz, 1 C), 60.3 (t, J = 28.2 Hz, 1 C), 59.8 (s, 1
C), 57.7 (d, J = 5.9 Hz, 1 C); 19F NMR (376 MHz, CDCl3) δ ppm
−95.29 (d, J = 254.8 Hz, 1F), −112.33 (d, J = 253.4 Hz, 1F); HRMS
calculated for C18H19F2NO 303.1435, found 303.1446.
1-Benzyl-4,4-difluoropyrrolidin-3-yl 4-Methylbenzene-
sulfonate (23). Method A (TFA). The mixture of 2,2-difluorovinyl
4-methylbenzenesulfonate 22 (5.528 g, 23.6 mmol) and N-benzyl-1-
methoxy-N-((trimethylsilyl)methyl)methanamine (22.4 g, 94.4 mmol)
was heated in an oil bath (preheated to 130 °C) for 5 min; then, TFA
(182 uL, 2.36 mmol) was added dropwise slowly. A couple of minutes
after the TFA was added, the reaction mixture reacted vigorously.
Smoke and volatile material were generated, and the reaction turned
1-Benzyl-3-tert-butoxy-1H-pyrrole-2,5-dione (15). To a sol-
ution of 1-benzyl-3,3-difluoropyrrolidine-2,5-dione (14) (80 mg, 0.36
mmol) in THF (1.2 mL) was added KOtBu (0.71 mL, 0.71 mmol, 1
M in THF). The solution turned immediately dark brown. After
stirring for 1 h, the reaction mixture was quenched with AcOH to pH
4, diluted with H2O (15 mL), extracted with EtOAc (2 × 15 mL),
washed with brine (10 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude residue was purified
by column chromatography and eluted with 2−25% EtOAc/heptane
1
gradient to obtain compound 15 as an oil (66 mg, 72%). H NMR
(400 MHz, CDCl3) δ ppm 7.12−7.32 (m, 5 H) 5.27 (s, 1 H) 4.56 (s, 2
H) 1.42 (s, 9 H); 13C NMR (101 MHz, CDCl3) δ ppm 170.8 (s, 1 C)
166.6 (s, 1 C) 155.9 (s, 1 C) 136.4 (s, 1 C) 128.5 (s, 2 C) 128.4 (s, 2
C) 127.6 (s, 1 C) 97.3 (s, 1 C) 84.1 (s, 1 C) 41.1 (s, 1 C) 27.1 (s, 3
C); HRMS calculated for C15H17NO3 259.1205, found 259.1213.
2,5-Dibenzyl-3a-fluorotetrahydropyrrolo[3,4-c]pyrrole-1,3-
(2H,3aH)-dione (16). To a solution of compound 15 (200 mg, 2.66
mmol) in MeTHF (2.22 mL) was added LiF (57.7 mg, 2.22 mmol),
and the mixture was sonicated for 2 h. N-(Methoxymethyl)-N-
(trimethylsilylmethyl)-benzylamine (0.400 mL, 1.39 mmol) and
additional LiF (37 mg, 1.43 mmol) were added, and sonication
continued for 18 h. The reaction mixture was diluted with H2O (30
mL) and extracted with EtOAc (2 × 30 mL), and the combined
organic layers were washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude residue was purified
by column chromatography eluting with 2−10% EtOAc/heptane
gradient to obtain the desired compound 16 as a clear oil (152 mg,
50% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.32−7.42 (m, 5 H)
7.23−7.31 (m, 3 H) 7.06−7.15 (m, 2 H) 4.70−4.84 (m, 2 H) 3.56−
3.68 (m, 2 H) 3.53 (dd, J = 10.21, 2.75 Hz, 1 H) 3.34 (d, J = 9.54 Hz,
1 H) 3.21 (dd, J = 18.89, 6.91 Hz, 1 H) 2.75 (dd, J = 9.54, 7.09 Hz, 1
H) 2.60−2.70 (m, 1 H); 13C NMR (101 MHz, CDCl3) δ ppm 174.6
(d, J = 7.3 Hz, 1 C) 172.4−173.4 (m, 1 C) 136.9 (s, 1 C) 134.9 (s, 1
C) 128.7 (s, 2 C) 128.4 (s, 2 C) 128.2 (s, 2 C) 128.1 (s, 2 C) 128.0 (s,
1 C) 127.4 (s, 1 C) 96.4−100.9 (m, 1 C) 59.7−60.5 (m, 1 C) 58.1 (s,
1 C) 54.8 (d, J = 1.5 Hz, 1 C) 49.7 (d, J = 18.3 Hz, 1 C) 42.7 (s, 1 C);
19F NMR (377 MHz, CDCl3) δ ppm −104.15 (s, 1 F); HRMS
calculated for C20H19FN2O2 338.1431, found 338.1431.
tert-Butyl 5-Benzyl-3a-fluoro-4,6-dioxohexahydropyrrolo-
[3,4-c]pyrrole-2(1H)-carboxylate (17). To a nitrogen-purged
solution of compound 16 (270 mg, 0.798 mmol) in EtOH (8 mL)
were added 20% Pd(OH)2/C (60 mg) and Boc anhydride (209 mg,
0.957 mmol, 1.20 equiv). The reaction was evacuated and backfilled
with H2 (balloon) three times. The reaction mixture was stirred for 3 h
F
DOI: 10.1021/acs.joc.5b00853
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The Journal of Organic Chemistry
Note
dark. After 20 min, LCMS indicated that the reaction was complete.
The volatiles were evaporated, and the residue was purified by column
chromatography with 15−20% EtOAc/heptane gradient to obtain an
oil (8.0 g, 92%).
General Procedure Using LiF and Difluoro Styrenes Using 1-
Bromo-4-(2,2-dfluorovinyl)benzene as an Example: 1-Benzyl-
4-(4-bromophenyl)-3,3-difluoropyrrolidine (25). In a 2 dram vial
with a Teflon cap charged with a stir bar were added 1-bromo-4-(2,2-
difluorovinyl)benzene (24) (150 mg, 0.685 mmol), N-benzyl-1-
methoxy-N-((trimethylsilyl)methyl)methanamine (488 mg, 2.05
mmol, 0.526 mL), and acetonitrile (1.37 mL, 0.5 M). To this solution
was added LiF (71.1 mg, 2.74 mmol), and the mixture was stirred at
60 °C for 6 h on an aluminum block. LCMS shows complete
conversion. The resulting mixture was concentrated in vacuo and
purified by silica gel chromatography (0−10% EtOAc/Heptane) to
afford 25 as a clear oil (192 mg, 80% y). 1H NMR (400 MHz, CDCl3)
δ ppm 7.38−7.47 (m, 2H), 7.25−7.35 (m, 5H), 7.15 (d, J = 8.44 Hz,
2H), 3.63−3.73 (m, 2H), 3.48−3.62 (m, 1H), 3.14−3.31 (m, 2H),
2.86−2.97 (m, 1H), 2.75−2.86 (m, 1H); 13C NMR (101 MHz,
CDCl3) δ ppm 137.6 (s, 1 C), 133.7 (d, J = 3.7 Hz, 1C), 131.5 (s, 2
C), 130.6 (s, 2 C), 128.7 (s, 2 C), 128.5 (s, 2 C), 127.5 (s, 1 C), 127.9
(dd, J = 252.4, 253.8 Hz, 1C), 121.6 (s, 1 C), 62.0 (dd, J = 24.9, 27.9
Hz, 1C), 59.9 (s, 1 C), 58.0 (d, J = 5.9 Hz, 1C), 51.6 (dd, J = 22.0,
24.9 Hz, 1C); 19F NMR (376 MHz, CDCl3) δ ppm −93.36 (d, J =
228.9 Hz, 1F), −98.90 (d, J = 231.6 Hz, 1F); HRMS calculated for
C17H16BrF2N 351.0434, found 351.0431.
Method B (LiF). To a solution of 2,2-difluorovinyl 4-methylbenze-
nesulfonate 22 (45.0 mg, 0.192 mmol) and N-benzyl-1-methoxy-N-
((trimethylsilyl)methyl)methanamine (197 uL, 0.769 mmol) was
added LiF (15.0 mg, 0.576 mmol), and the mixture was stirred at
160 °C for 4 h. The reaction was dissolved in EtOAc and washed with
10 mL of water. The aqueous layer was extracted with EtOAc (2 × 50
mL), dried over Na2SO4, filtered, and concentrated. The crude
material was purified by column chromatography using a 0−40%
1
EtOAc/heptane gradient to obtain an oil (42.6 mg, 60%). H NMR
(400 MHz, CDCl3) δ ppm 7.83 (d, J = 8.3 Hz, 2H), 7.41−7.22 (m,
7H), 4.91−4.76 (m, 1H), 3.70−3.52 (m, 2H), 3.23 (dd, J = 6.7, 10.4
Hz, 1H), 3.08 (ddd, J = 7.5, 11.2, 14.4 Hz, 1H), 2.79 (dt, J = 11.2, 15.7
Hz, 1H), 2.72−2.63 (m, 1H), 2.47 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ ppm 145.3 (s, 1 C), 136.5 (s, 1 C), 132.9 (s, 1 C), 129.9 (s,
2 C), 128.6 (s, 2 C), 128.5 (s, 2 C), 128.0 (s, 2 C), 127.6 (s, 1 C),
123.8 (dd, J = 260.2, 252.8 Hz, 1 C), 77.9 (dd, J = 34.5, 16.9 Hz, 1 C),
59.2 (s, 1 C), 59.5 (dd, J = 28.6, 28.0 Hz, 1 C), 56.7 (d, J = 5.1 Hz, 1
C), 21.7 (s, 1 C); 19F NMR (376 MHz, CDCl3) δ ppm −98.45 (d, J =
239.8 Hz, 1F), −109.41 (d, J = 239.8 Hz, 1F); HRMS calculated for
C18H19F2NO3S 367.1054, found 367.1051.
1-Benzyl-4-(2,4-dichlorophenyl)-3,3-difluoropyrrolidine
(27a). Similar reaction conditions to make compound 25 were used to
1
make 27a in 89% yield. H NMR (400 MHz, CDCl3) δ 7.48 (dd, J =
1-Benzyl-4,4-difluoropyrrolidin-3-ol (19). Method A. Magne-
sium (small turnings, 5.29 g, 218 mmol) was added to the solution of
1-benzyl-4,4-difluoropyrrolidin-3-yl 4-methylbenzenesulfonate 23 (8.0
g, 21.77 mmol) in MeOH (78 mL, 0.28 M), and the mixture was
stirred at room temperature for 1 h. (The reaction became exothermic
and a solid foam formed.) The reaction mixture was cooled in a water
bath, and cold water was added. Concentrated HCl was added to
dissolve the solids, and the mixture was extracted with EtOAc three
times. The aqueous layer still contained product and, therefore, was
adjusted to pH 6−7 by adding solid KOH. The mixture was then
extracted with EtOAc three times again. The organic layers were
combined, dried over Na2SO4, concentrated, and purified by column
chromatography with a 20% EtOAc/heptane through 10% MeOH/
EtOAc gradient to obtain 3.83 g of a brown oil (3.83 g, 82%)
Method B. To a solution of 1-benzyl-4,4-difluoropyrrolidin-3-yl 4-
methylbenzenesulfonate 23 (811 mg, 2.21 mmol) in THF (11 mL, 0.1
M) was added Super Hydride (8.83 mL, 8.83 mmol, 1 M) at room
temperature. The mixture turned to light yellow and was then heated
at reflux overnight. The reaction was then cooled to room
temperature. To the reaction mixture was added 8 mL of sat. aq.
NH4Cl, and it was extracted with EtOAc twice. The combined organic
layer was carefully washed with 1 N HCl. The aqueous layer was
adjusted to ph 7−8 with solid NaHCO3 and then extracted by EtOAc
three times, dried over Na2SO4, and concentrated. The crude material
was purified by column chromatography using a 0−40% EtOAc/
1.1, 8.4 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.35−7.21 (m, 6H), 4.28−
4.13 (m, 1H), 3.78−3.64 (m, 2H), 3.16−3.01 (m, 3H), 2.89 (dd, J =
6.7, 9.5 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ ppm 137.5 (s, 1 C),
135.8 (s, 1 C), 133.8 (s, 1 C), 132.2 (t, J = 2.7 Hz, 1 C), 130.8 (d, J =
2.0 Hz, 1 C), 129.2 (s, 1 C), 128.7 (s, 2 C), 128.6 (s, 2 C), 127.6 (s, 1
C), 127.1 (s, 1 C), 128.1 (t, J = 253.8 Hz, 1 C), 62.0 (t, J = 29.0 Hz, 1
C), 59.9 (s, 1 C), 58.5 (d, J = 5.1 Hz, 1 C), 47.4 (dd, J = 26.0, 20.7 Hz,
1 C); 19F NMR (376 MHz, CDCl3) δ −92.25 (d, J = 228.9 Hz, 1F),
−98.42 (d, J = 230.2 Hz, 1F); HRMS calculated for C17H15Cl2F2N
341.055, found 341.0558.
1-Benzyl-4-(2,5-dichlorophenyl)-3,3-difluoropyrrolidine
(27b). Similar reaction conditions to make compound 25 were used to
1
make 27b in 84% yield. H NMR (400 MHz, CDCl3) δ 7.59 (d, J =
1.34 Hz, 1H), 7.36−7.41 (m, 4H), 7.28−7.35 (m, 2H), 7.20 (dd, J =
2.57, 8.56 Hz, 1H), 4.14−4.30 (m, 1H), 3.63−3.84 (m, 2H), 3.05−
3.20 (m, 3H), 2.93 (dd, J = 6.24, 9.54 Hz, 1H); 13C NMR (101 MHz,
CDCl3) δ ppm 138.6 (s, 1 C), 136.4−136.8 (m, 1 C), 134.6 (s, 1 C),
133.8 (s, 1 C), 131.6 (s, 1 C), 131.1 (d, J = 2.2 Hz, 1 C), 129.9 (s, 2
C), 129.8 (s, 1 C), 129.8 (s, 2 C), 128.7 (s, 1 C), 129.3 (t, J = 253.8
Hz, 1 C), 62.5−63.9 (m, 1 C), 60.9 (s, 1 C), 59.5 (d, J = 5.1 Hz, 1 C),
48.5−49.5 (m, 1 C); 19F NMR (376 MHz, CDCl3) δ −94.91 to
−88.61 (m, 1F), −102.24 to −96.34 (m, 1F); HRMS calculated for
C17H15Cl2F2N 342.0622, found 342.0631.
1-Benzyl-3,3-difluoro-4-(3-nitrophenyl)pyrrolidine (27c).
Similar reaction conditions to make compound 25 were used to
make 27c in 76% yield using LiF (Method B), and it also was made
using TFA (Method A): In a scintillation vial, a mixture of 1-(2,2-
difluorovinyl)-3-nitrobenzene 26c (40 mg, 0.22 mmol) and N-benzyl-
1-methoxy-N-((trimethylsilyl)methyl)methanamine (0.221 mL, 0.864
mmol) was heated at 120 °C in an oil bath for 5 min. TFA (3 uL,
0.043 mmol) was added, and the mixture was heated for 30 min.
LCMS showed the product formed and the starting material mostly
consumed. The reaction was cooled to room temperature and purified
by column chromatography using a 20% EtOAc/heptane gradient to
1
Heptane gradient to give a yellow oil (417 mg, 89%). H NMR (400
MHz, CDCl3) δ ppm 7.39−7.22 (m, 5H), 4.29−4.17 (m, 1H), 3.73−
3.60 (m, 2H), 3.13−3.04 (m, 1H), 3.04−2.88 (m, 2H), 2.63 (ddd, J =
2.4, 4.9, 10.2 Hz, 1H), 2.37 (br. s., 1H); 13C NMR (151 MHz, CDCl3)
δ ppm 137.0 (s, 1 C), 128.8 (s, 2 C), 128.5 (s, 2 C), 127.6 (s, 1 C),
125.9 (t, J = 253.5 Hz, 1 C), 73.3 (dd, J = 31.9, 19.8 Hz, 1 C), 59.7 (s,
1 C), 59.6 (t, J = 28.1 Hz, 1 C), 59.3 (d, J = 4.4 Hz, 1 C); 19F NMR
(376 MHz, CDCl3) δ ppm −100.56 (d, J = 223.4 Hz, 1F), −113.56 (d,
J = 237.1 Hz, 1F); HRMS calculated for C11H13F2NO 213.0965, found
231.0975.
1
afford a colorless oil (55 mg, 80%). H NMR (400 MHz, CDCl3) δ
Compounds 26a−f. Compounds 26a−f were prepared according
to literature methods.15 Analytical data for compounds 26a and 26c−f
match those in the literature. 1,4-Dichloro-2-(2,2-difluorovinyl)-
ppm 8.26 (s, 1 H) 8.17 (dd, J = 8.19, 1.35 Hz, 1 H) 7.66 (d, J = 7.70
Hz, 1 H) 7.52 (t, J = 7.95 Hz, 1 H) 7.34−7.42 (m, 4 H) 7.28−7.33 (m,
1 H) 3.69−3.82 (m, 3 H) 3.22−3.34 (m, 2 H) 3.05 (dt, J = 18.43,
11.02 Hz, 1 H) 2.95 (t, J = 8.74 Hz, 1 H); 13C NMR (101 MHz,
CDCl3) δ ppm 148.3 (s, 1 C), 137.3 (s, 1 C), 137.1 (s, 1 C), 135.3 (s,
1 C), 129.2 (s, 1 C), 128.7 (s, 2 C), 128.6 (s, 2 C), 127.8 (t, J = 253.1
Hz, 1 C), 127.6 (s, 1 C), 123.8 (s, 1 C), 122.6 (s, 1 C), 61.8 (t, J = 29.3
Hz, 1 C), 59.8 (s, 1 C), 57.8 (d, J = 5.1 Hz, 1 C), 51.7 (td, J = 22.0, 2.9
Hz, 1 C); 19F NMR (376 MHz, CDCl3) δ ppm −92.84 (d, J = 231.61
1
benzene (26b). H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 2.32
Hz, 1H), 7.33 (d, J = 8.56 Hz, 1H), 7.18 (dd, J = 2.45, 8.56 Hz, 1H),
5.58−5.73 (m, 1H); 13C NMR (101 MHz, CDCl3) δ = 156.9 (dd, J =
264.8, 300.0 Hz, 1C), 132.9, 131.3−131.0 (m, 1C), 130.6, 130.2 (dd, J
= 6.2, 7.7 Hz, 1C), 128.7 (dd, J = 1.5, 10.3 Hz, 1C), 128.4, 78.6 (ddd, J
= 11.0, 13.2, 21.3 Hz, 1C); 19F NMR (376 MHz, CDCl3) δ −80.01−
79.55 (m, 1F), −80.81−80.25 (m, 1F).
G
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The Journal of Organic Chemistry
Note
Hz, 1 F) −98.16 (d, J = 230.25 Hz, 1 F); HRMS calculated for
C17H16F2N2O2 318.1180, found 318.1182.
1-Benzyl-3,3-difluoro-4-(p-tolyl)pyrrolidine (27d). Similar re-
−97.99 (d, J = 230.25 Hz, 1F); HRMS calculated for C16H17F2N3O
305.1340, found 305.1343.
3-(1-Benzyl-4,4-difluoropyrrolidin-3-yl)quinolone (33). Sim-
ilar reaction conditions to make compound 25 were used to make 33
in 34% yield. H NMR (600 MHz, CDCl3) δ ppm 2.90−2.96 (m, 1
action conditions to make compound 25 were used to make 27d in
13% yield. H NMR (400 MHz, CDCl3) δ ppm 6.97−7.26 (m, 9 H)
1
1
H), 2.97−3.03 (m, 1 H), 3.17−3.23 (m, 1 H), 3.23−3.28 (m, 1 H),
3.63−3.72 (m, 2 H), 3.72−3.80 (m, 1 H) 7.19−7.23 (m, 1 H), 7.26−
7.30 (m, 2 H), 7.29−7.33 (m, 2 H), 7.47 (t, J = 7.43 Hz, 1 H), 7.62 (t,
J = 7.24 Hz, 1 H), 7.72 (d, J = 7.89 Hz, 1 H), 8.00 (s, 1 H), 8.02 (d, J =
8.44 Hz, 1 H), 8.81 (br. s., 1 H); 13C NMR (151 MHz, CDCl3) δ ppm
151.3 (s, 1 C), 147.5 (s, 1 C), 137.5 (s, 1 C), 135.7 (s, 1 C), 129.5 (s, 1
C), 129.2 (s, 1 C), 128.7 (s, 2 C), 128.5 (s, 2 C), 127.95−127.99 (m, 1
C), 127.71−127.76 (m, 1 C), 127.67 (s, 1 C), 127.5 (s, 1 C), 126.8 (s,
1 C), 127.2 (dd, J = 252.0, 249.8 Hz, 1 C), 62.0 (t, J = 28.61 Hz, 1 C),
59.9 (s, 1 C), 58.0 (d, J = 5.5 Hz, 1 C), 50.1 (dd, J = 25.3, 22.0 Hz, 1
C); 19F NMR (376 MHz, CDCl3) δ −92.90 (d, J = 228.9 Hz, 1F),
−98.02 (d, J = 228.9 Hz, 1F); HRMS calculated for C20H18F2N2
324.1438, found 324.1441.
5-(2,2-Difluorovinyl)-2-methoxypyridine (28). In a microwave
vial were added 2,2-difluorovinyl 4-methylbenzenesulfonate (400 mg,
1.71 mmol), 2-methoxypyridine-5-boronic acid pinacol ester (703 mg,
2.99 mmol), and dioxane (8.54 mL, 0.2 M). The system was purged
with N2. Pd2(dba)3 (39 mg, 0.043 mmol) was added, followed by a
solution of tricyclohexylphosphine tetrafluoroborate (31 mg, 0.85
mmol) in water (2 mL). The system was purged again with N2, and
the vial was sealed and stirred for 100 °C for 18 h. The reaction was
cooled to room temperature. Water and EtOAc (20 mL each) were
added, and the aqueous layer was extracted with EtOAc (3 × 20 mL).
The organics were combined and dried over Na2SO4, filtered, and
concentrated in vacuo. The crude material was purified by silica gel
chromatography (0−20% EtOAc/Heptanes) to afford 5-(2,2-difluoro-
vinyl)-2-methoxypyridine (122 mg, 42% yield). Analytical data match
those in the literature.16
3.54−3.65 (m, 2 H) 3.42−3.54 (m, 1 H) 3.08−3.27 (m, 2 H) 2.69−
2.84 (m, 2 H) 2.21 (s, 3 H); 13C NMR (101 MHz, CDCl3) δ ppm
139.3 (s, 1 C) 138.8 (s, 1 C) 133.0 (d, J = 2.9 Hz, 1 C) 130.6 (s, 1 C)
130.5 (s, 1 C) 130.3 (s, 1 C) 130.1 (s, 1 C) 129.7 (t, J = 251.6 Hz, 1
C) 129.0 (s, 1 C) 63.6 (t, J = 29.3 Hz, 1 C) 61.7 (s, 1 C) 59.8 (d, J =
5.9 Hz, 1 C) 53.3 (dd, J = 21.3, 2.2 Hz, 1 C) 22.7 (s, 1 C); 19F NMR
(376 MHz, CDCl3) δ ppm −93.37 (d, J = 228.88 Hz, 1 F) −99.25 (d,
J = 228.88 Hz, 1 F); HRMS calculated for C18H19F2N 287.1486, found
287.1496.
1-Benzyl-3,3-difluoro-4-(4-methoxyphenyl)pyrrolidine
(27e). Similar reaction conditions to make compound 25 were used to
make 27e in 41% yield. 1H NMR (400 MHz, CDCl3) δ 7.32−7.06 (m,
7H), 6.80 (d, J = 8.7 Hz, 2H), 3.72 (s, 3H), 3.69−3.58 (m, 2H), 3.58−
3.45 (m, 1H), 3.32−3.09 (m, 2H), 2.88−2.65 (m, 2H); 19F NMR (376
MHz, CDCl3) δ −93.74 (d, J = 233.0 Hz, 1F), −99.33 (d, J = 228.9
Hz, 1F); 13C NMR (101 MHz, CDCl3) δ ppm 160.3 (s, 1 C), 139.1 (s,
1 C), 131.3 (s, 2 C), 130.0 (s, 2 C), 129.8 (s, 2 C), 128.7 (s, 1 C),
127.9 (d, J = 3.5 Hz, 1 C), 129.4 (t, J = 245.6 Hz, 1 C), 115.1 (s, 2 C),
63.4 (t, J = 29.2 Hz, 1 C), 61.4 (s, 1 C), 59.7 (d, J = 6.2 Hz, 1 C), 56.6
(s, 1 C), 52.7 (dd, J = 24.4, 21.5 Hz, 1 C); HRMS calculated for
C18H19F2NO 303.1435, found 303.1421.
1-Benzyl-4-(4-(tert-butyl)phenyl)-3,3-difluoropyrrolidine
(27f). Similar reaction conditions to make compound 25 were used to
make 27f in 67% yield. 1H NMR (400 MHz, CDCl3) δ 7.28−7.43 (m,
7H), 7.24 (d, J = 8.19 Hz, 2H), 3.66−3.82 (m, 2H), 3.54−3.66 (m,
1H), 3.20−3.39 (m, 2H), 2.81−2.99 (m, 2H), 1.32 (s, 9H); 13C NMR
(101 MHz, CDCl3) δ ppm 151.5 (s, 1 C), 139.0 (s, 1 C), 132.6 (d, J =
3.7 Hz, 1 C), 129.9 (s, 4 C), 129.6 (s, 2 C), 128.5 (s, 1 C), 129.6 (t, J =
252.4 Hz, 1 C), 126.4 (s, 2 C), 62.8−63.9 (m, 1 C), 61.3 (s, 1 C), 59.5
(d, J = 5.9 Hz, 1 C), 52.4−53.3 (m, 1 C), 35.6 (s, 1 C), 32.5 (s, 3 C);
HRMS calculated for C21H25F2N 330.2028, found 330.2036.
5-(1-Benzyl-4,4-difluoropyrrolidin-3-yl)-2-methoxypyridine
(29). Similar reaction conditions to make compound 25 were used to
make 29 in 70% yield. 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 2.20
Hz, 1H), 7.56 (d, J = 8.68 Hz, 1H), 7.28−7.39 (m, 5H), 6.72 (d, J =
8.56 Hz, 1H), 3.92 (s, 3H), 3.65−3.78 (m, 2H), 3.49−3.62 (m, 1H),
3.18−3.34 (m, 2H), 2.93 (td, J = 11.32, 18.80 Hz, 1H), 2.79 (t, J =
9.11 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 163.7 (s, 1C), 146.9 (s,
1C), 139.1 (s, 1C), 137.6 (s, 1C), 128.6 (s, 2C), 128.5 (s, 2C), 127.5
(s, 1C), 127.9 (dd, J = 249.4, 252.4 Hz, 1C), 123.2 (d, J = 3.7 Hz, 1C),
110.6 (s, 1C), 61.9 (dd, J = 27.1, 29.3 Hz, 1C), 59.9 (s, 1C), 58.2 (d, J
= 5.9 Hz, 1C), 53.4 (s, 1C), 49.2 (dd, J = 22.7, 30.8 Hz, 1C); 19F NMR
(376 MHz, CDCl3) δ −93.95 (d, J = 227.5 Hz, 1F), −98.90 (d, J =
228.9 Hz, 1F); HRMS calculated for C17H18F2N2O 304.1387, found
304.1395.
5-(2,2-Difluorovinyl)-2-methoxypyrimidine (30). Followed
similar procedures to make compound 28 using 2-methoxypyrimi-
dine-5-boronic acid pinacol ester, compound 30 was obtained in 38%
1
yield. H NMR (400 MHz, CDCl3) δ 8.49 (s, 2H), 5.41−5.01 (m,
1H), 4.03 (s, 3H); 13C NMR (101 MHz, CDCl3) δ ppm 164.4 (t, J =
2.2 Hz, 1 C), 157.6 (dd, J = 6.6, 3.5 Hz, 2 C), 156.5 (dd, J = 297.3,
290.6 Hz, 1 C), 118.5 (dd, J = 6.6, 6.5 Hz, 1 C), 76.0 (dd, J = 32.1,
16.2 Hz, 1 C), 55.0 (s, 1 C); 19F NMR (376 MHz, CDCl3) δ −80.47
(d, J = 28.6 Hz, 1F), −82.11 (d, J = 28.6 Hz, 1F); HRMS calculated for
C7H6F2N2O 172.0448, found 172.0445.
3-(2,2-Difluorovinyl)quinolone (32). Followed similar proce-
dures to make compound 28 using quinoline-3-boronic acid pinacol
1
ester, compound 32 was obtained in 72% yield. H NMR (400 MHz,
CDCl3) δ 8.85 (d, J = 1.8 Hz, 1H), 8.21−8.00 (m, 2H), 7.80 (d, J = 8.2
Hz, 1H), 7.71 (ddd, J = 1.3, 7.0, 8.4 Hz, 1H), 7.63−7.49 (m, 1H),
5.56−5.39 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 160.5−159.2 (m,
1C), 158.0−156.6 (m, 1C), 154.5−153.5 (m, 1C), 149.9 (dd, J = 2.9,
5.1 Hz, 1C), 146.9 (s, 1C), 133.4 (dd, J = 3.7, 8.1 Hz, 1C), 129.4 (d, J
= 1.0 Hz, 1C), 128.0−127.6 (m, 1C), 127.2 (s, 1C), 124.0−123.5 (m,
1C), 80.0−79.2 (m, 1C); 19F NMR (376 MHz, CDCl3) δ −79.70 (d, J
= 27.2 Hz, 1F), −81.03 (d, J = 25.9 Hz, 1F); HRMS calculated for
C11H7F2N 191.0547, found 191.0539.
5-(1-Benzyl-4,4-difluoropyrrolidin-3-yl)-2-methoxypyrimi-
dine (31). To a reaction vial was added 5-(2,2-difluorovinyl)-2-
methoxypyrimidine 30 (50.0 mg, 0.29 mmol), followed by N-benzyl-1-
methoxy-N-((trimethylsilyl)methyl)methanamine (0.446 mL, 1.74
mmol). Then, LiF (60 mg, 2.32 mmol) was added and the reaction
was stirred at 120 °C for 5 h. LCMS and TLC showed that the starting
material was consumed. The reaction was diluted with water and
EtOAc. The aqueous layer was extracted with EtOAc (3 × 60 mL).
The combined organics were washed with brine, dried over MgSO4,
and then filtered and concentrated. The resultant was purified by
column chromatography using a 0−100% EtOAc/heptane gradient to
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental methods of HRMS and NMR spectra for
compounds listed in the Experimental Section. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.joc.5b00853.
1
obtain a clear oil (60 mg, 68%). H NMR (400 MHz, CDCl3) δ 8.47
(s, 2H), 7.39−7.33 (m, 4H), 7.33−7.28 (m, 1H), 4.02 (s, 3H), 3.79−
3.66 (m, 2H), 3.62−3.45 (m, 1H), 3.31−3.15 (m, 2H), 3.02 (td, J =
11.1, 18.4 Hz, 1H), 2.83 (t, J = 8.7 Hz, 1H); 13C NMR (101 MHz,
CDCl3) δ ppm 165.3 (s, 1 C), 159.4 (s, 2 C), 137.3 (s, 1 C), 128.6 (s,
2 C), 128.6 (s, 2 C), 127.6 (s, 1 C), 127.7 (dd, J = 258.2, 250.2 Hz, 1
C), 122.0 (d, J = 2.2 Hz, 1 C), 61.7 (t, J = 29.0 Hz, 1 C), 59.7 (s, 1 C),
57.8 (d, J = 5.1 Hz, 1 C), 55.0 (s, 1 C), 47.4 (dd, J = 25.7, 22.0 Hz, 1
C); 19F NMR (376 MHz, CDCl3) δ −93.76 (d, J = 230.25 Hz, 1F),
AUTHOR INFORMATION
Corresponding Author
*E-mail: indrawan.mcalpine@pfizer.com.
■
Notes
The authors declare no competing financial interest.
H
DOI: 10.1021/acs.joc.5b00853
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The Journal of Organic Chemistry
Note
ACKNOWLEDGMENTS
■
We are grateful to Jason Ewanicki for his help with NMR
spectroscopy and Muhammad Alimuddin for his help with
HRMS.
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J. Org. Chem. XXXX, XXX, XXX−XXX