Nucleophilic Iododifluoromethylation of Aldehydes Using Bromine/Iodine Exchange

Article abstract of DOI:10.1021/acs.joc.5b01590

A method for the iododifluoromethylation of aromatic aldehydes using (bromodifluoromethyl)trimethylsilane (Me₃SiCF₂Br) is described. The selective formation of the CF₂I group is based on using sodium iodide, with the sodium serving as a scavenger of bromide and iodide serving as a nucleophile with respect to difluorocarbene. The primary CF₂I-addition products can undergo HI-elimination or iodine/zinc exchange followed by allylation in a one-pot manner.

Full text of DOI:10.1021/acs.joc.5b01590

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Note
Nucleophilic Iododifluoromethylation of
Aldehydes Using Bromine/Iodine Exchange
Vitalij V. Levin, Vladimir O. Smirnov, Marina I. Struchkova, and Alexander D. Dilman
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01590 • Publication Date (Web): 24 Aug 2015
Downloaded from http://pubs.acs.org on August 27, 2015
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Nucleophilic Iododifluoromethylation of Aldehydes Using Bromine/Iodine Exchange
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Vitalij V. Levin, Vladimir O. Smirnov, Marina I. Struchkova, Alexander D. Dilman*
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N. D. Zelinsky Institute of Organic Chemistry, 119991 Moscow, Leninsky prosp. 47, Russian
Federation
adil25@mail.ru
OH
I
Ar
desilylation
F
F
OSiMe3
O
Me3Si
Br
O
HI-elimination
I
F
Ar
F
F
Ar
Ar
Ar
F
F
F
Na
I
OH
I/Zn-exchange,
allylation
F
F
Abstract.
A
method for the iododifluoromethylation of aromatic aldehydes using
(bromodifluoromethyl)trimethylsilane (Me3SiCF2Br) is described. The selective formation of CF2I
group is based on using sodium iodide, with the sodium serving as a scavenger of bromide, and
iodide serving as a nucleophile with respect to difluorocarbene. The primary CF2Iꢀaddition products
can undergo HIꢀelimination or iodine/zinc exchange followed by allylation in a oneꢀpot manner.
Despite significant advances in the methodology for the synthesis of organofluorine
compounds,1 some structural fragments are still difficult to access. For example, in contrast to
trifluoromethylation reactions, which have enjoyed great attention,2 approaches for the direct
introduction of valuable mixed fluorinated groups CF2X are limited. In a series of interhalogen
substituents CF2X (X = Cl, Br, I), iododifluoromethyl group occupies a special position due to
opportunities for its functionalization. Indeed, relatively facile activation of carbonꢀiodine bond in a
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freeꢀradical or electronꢀtransfer processes can be exploited for the synthesis of various
difluoromethylenated products.3 Furthermore, ability of the CF2I group to engage in halogen
bonding can be used in crystal engineering and medicinal chemistry.4
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Methods for the synthesis of compounds with the CF2I group involve radical atomꢀtransfer
processes starting from CF2I2,5 or Br/I exchange in the CF2Br group which is typically performed
by organozinc formation followed by iodination,3b,6 or, in rare cases, using direct nucleophilic
substitution.7 Iododifluoromethylation of aldehydes was also achieved by a halogenative Juliaꢀ
Kocienski reaction with subsequent deprotection.8 Recently we reported on a nucleophilic
iododifluoromethylation of aldehydes and iminium ions using corresponding silicon reagent
Me3SiCF2I,9 which has to be prepared from Me3SiCF2Br (1) using zincation/iodination sequence
(Scheme 1). At the same time, it has been noted that in the presence of halide ion, silicon reagents
can undergo reversible halogen exchange.9a,10 To synthesize chloroꢀsubstituted silane, Hu and coꢀ
workers applied stoichiometric amount of silver salt to shift the equilibrium from bromine (X1) to
chlorine (X2) (Scheme 1). Herein we demonstrate that nucleophilic iododifluoromethylation
reaction can efficiently be carried out with readily available bromoꢀsubstituted silane 111,12 by using
iodide ion in combination with sodium counterꢀion.
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Scheme 1.
O
Previous work
Ar
I
Bu4NI, LiI
(a) i-PrZnI
Br (b) I2
OH
F
Me3Si
Me3Si
I
Ar
F
F
F
F
F
F
1
X2
X1
X2
X1
Me3Si
X1
Me3Si
X2
C
F
F
F
F F
This work
Me3Si
F
Br
+ NaI
CF2I
F
1
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First, the reaction of pꢀchlorobenzaldehyde 2a with silane 1 was evaluated under previously
described conditions (heating in propionitrile, ca. 100 °C),9a but involving tetrabutylammonium and
lithium iodides (Table 1, entry 1). Virtually equimolar mixture of 3a and 4a was formed reflecting
rapid halogen exchange. When sodium iodide was used instead of lithium iodide, the portion of
iodinated product 3a increased (entry 2), while the use of 1.5 equiv of sodium salt gave 3a
contaminated with only 2% of 4a (entry 3). Application of sodium iodide taken in excess amount
(2.5 equiv) provided iodinated product exclusively, though at incomplete conversion. Switching to
1,2ꢀdymethoxyethane (glyme, DME), which serves as a better solvent for sodium salts, caused
some rate acceleration that allowed to decrease the temperature to 80 °C and reduce the amount of
silane 1 from 3 to 1.5 equiv (entry 5). Finally, addition of a lithium salt, which is believed to effect a
Lewis acidic activation of the aldehyde, would be helpful. Despite the fact that lithium iodide would
be a good candidate, it is usually supplied in the hydrate form, and its drying in the reaction flask is
inconvenient on small scale. Rewardingly, addition of only 0.3 equiv of lithium bromide gave good
yield of iodinated product 3a (entry 6). Notably, the bromide ion from lithium salt does not lead to
brominated product 4a, likely because it is counterbalanced by sodium cation (vide infra). pꢀ
Anysaldehyde proved to be less reactive under the same conditions (entry 7), and increased loading
of the reagents was required (entry 8).
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Table 1. Optimization studies.
3
4
5
OSiMe3
OSiMe3
Br
6
7
8
9
Me3Si
Br
O
iodide
4 h
I
+
+
F
F
Ar
Ar
Ar
2a, Ar = 4-ClC6H4
2b, Ar = 4-MeOC6H4
1
F
F
F F
3a,b
4a,b
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no.
2
1
iodide (equiv)
conditionsa 3 : 4a Yield
of 3,%b
1:1.2 45
(equiv)
3
1
2
3
4
5
6
7
8
2a
2a
2a
Bu4NI (1.1), LiI (0.5) EtCN, ꢁ
Bu4NI (1.1), NaI (0.5) EtCN, ꢁ
Bu4NI (1.1), NaI (1.5) EtCN, ꢁ
3
3
1.7:1 58
50:1 72
> 99:1 44
DME, 80 °C > 99:1 61
2a 1.5
2a 1.5
2a 1.5
2b 1.5
2b 2.4
NaI (2.5)
NaI (2.5)
EtCN, ꢁ
NaI (2.5), LiBr (0.3) DME, 80 °C > 99:1 95
NaI (2.5), LiBr (0.3) DME, 80 °C > 99:1 59
NaI (3.6), LiBr (1.0) DME, 80 °C > 99:1 87
a Reaction time 4 h.
b Determined by 19F NMR of reaction mixtures.
Under the optimized conditions, a series of aldehydes were iododifluoromethylated with silane 1
using methods A or B differing in excess of the reagents (Table 2). As a rule, 1.5 equiv of silane 1
was sufficient for aldehydes bearing electron withdrawing groups (method A), whereas for electron
reach substrates a bit more forcing conditions were required (method B). In reaction of
cinnamaldehyde, a small amount of a difluorocyclopropane (ca. 15%) arising from
cyclopropanation of iododifluoromethylation product was formed that led to a decreased 69% yield
of expected product 5m (entry 13). Hydrocinnamaldehyde provided complex mixture containing
less than 30% of the target product, presumably, due to propensity of the aldehyde to enolization. In
this case, generation of enol ether fragment from enolizable aldehydes and ketones would lead to
fast difluorocarbene addition to the electron reach double bond12c,d thereby consuming the carbonyl
substrate irreversibly.13
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Table 2. Iododifluoromethylation of aldehydes.
3
4
5
OH
F
6
7
8
9
O
Me3Si
Br
NaI/LiBr
I
+
R
R
F
F
DME, 80 °C
F
2
5
1
then desilylation
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Method A: 1 (1.5 equiv), NaI (2.5 equiv), LiBr (0.3 equiv)
Method B: 1 (2.4 equiv), NaI (3.6 equiv), LiBr (1.0 equiv)
no.
1
aldehyde
method time, h
yield of 5, %a
5
O
A
A
A
A
A
4
2
2
2
5
94
5a
5c
5d
5e
5f
Cl
O
O
2
3
4
5
87
74
90
93
MeO
O
NC
O
O2N
MeO
O
O
6
7
8
A
A
B
1
3
4
97
86
78
5g
NO2
O
5h
5i
O
O
N
Ts
O
9
B
B
4
4
88
87
5j
Ph
O
10
5b
MeO
O
11
12
B
B
4
4
92
74
5k
5l
Br
O
O
13
14
B
B
4
4
69
22
5m
5n
Ph
BzO
O
a Isolated yield.
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Concerning the reaction mechanism, first of all, the opportunity of formation of iodoꢀsubstituted
product 3a by Br/I exchange after carbonyl addition event was discarded, since in a blank
experiment no conversion of preformed compound 4a into 3a under the reaction conditions was
observed (Scheme 2). At the same time, the equilibrium formation of iodoꢀsubstituted silane 6 from
silane 1 upon reaction with NaI/LiBr combination does take place, and proceeds even at room
temperature (see table on Scheme 2). However, attempts to shift the equilibrium between silanes 1
and 6 towards 6 using excess of NaI (without LiBr) were unsuccessful. We believe that the ability
of sodium ion to bind bromide better than iodide is the key factor responsible for the bromine/iodine
selectivity for the product formation.14 After initial attack of halogen on the silicon atom of reagent
1 or 6, carbaniononic species 7 and 8 are formed. Sodium ion can decrease the concentration of
carbanion 7 by abstracting the bromide. Furthermore, bromide present in reaction mixture is
associated with sodium tighter compared to that of iodide, and, as a result, iodide outperforms
bromide in nucleophilic reactivity towards difluorocarbene. The role of lithium ion is likely to
activate the carbonyl group towards nucleophilic attack by shortꢀlived intermediate 8 (Scheme 2,
bottom equation).
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Scheme 2. Mechanistic studies.
OSiMe3
Br
OSiMe3
I
NaI (2.5), LiBr (0.3)
DME, 80 °C, 4 h
Ar
Ar
F
F
F F
3a, not observed
4a, Ar = 4-ClC6H4
time
1 : 6
NaI (1.5)
LiBr (0.3)
Me3Si
Br
Me3Si
I
2 h
1 d
2 d
4 d
1 : 0.4
1 : 2.1
1 : 3.2
1 : 3.3
F
F
F F
DME, rt
1
6
Na
NaBr
F
Br
I
F
X
7
Me3Si
X
C
F
F
F
F
Me3SiX
1 or 6
I
F
F
8
Li
O
OSiMe3
I
OLi
F
Me3SiX
I
Ar
Ar
Ar
F
F
F
F
I
F
8
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Compounds 5 can be employed in the synthesis of organofluorine compounds. Thus, addition of
isopropylzinciodide to initially formed addition product 3a led to organozinc species 9 (Scheme 3).
This organozinc intermediate is reasonably stable, and upon storage at room temperature for 24
hours its decomposition did not exceed 5%. Organozinc 9 was allylated with allylbromide in the
presence of copper cyanide furnishing alcohol 10 in 80% yield based on aldehyde 2a. Iodide in
compound 3a can suffer elimination when the reaction mixture was treated with trimethylamine in
ethanol affording difluoroketone 11.15 The latter transformation constitutes a convenient oneꢀpot
protocol for a formal insertion of CF2 fragment into CꢀH bond of the aldehyde.16
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Scheme 3. Synthesis of fluorinated compounds.
OSiMe3
O
1, NaI, LiBr
i-PrZnI (1.6 equiv)
I
Ar
3a
Ar
0 °C, 1 h
F
F
2a, Ar = 4-ClC6H4
Br
OSiMe3
ZnI
OH
10% CuCN
rt, 18 h
Ar
Ar
F
F
F
F
9
10, 80%
O
O
NMe3, EtOH
4 h, 70 °C
1, NaI, LiBr
F
3a
Ar
Ar
11, 72%
F
2a
In summary, a method for nucleophilic iododifluoromethylation using a readily available silicon
reagent is described. The use of sodium iodide is crucial for selective formation of iodoꢀsubstituted
addition product, with the sodium cation playing a role of a binder for the bromide counterꢀion.
Experimental section
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General Methods. All reactions were performed under an argon atmosphere. Column
chromatography was carried out employing silica gel (230ꢀ400 mesh). Precoated silica gel plates Fꢀ
254 were used for thinꢀlayer analytical chromatography visualizing with UV and/or aq. KMnO4
solution. Me3SiCF2Br (1)12a and 2,2ꢀdimethylꢀ3ꢀoxopropyl benzoate (2n)12e were obtained
according to literature procedures.
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Iododifluoromethylation of aldehydes.
Method A (General Procedure). A mixture of NaI (3.75 mmol, 563 mg) and LiBr (0.5 mmol, 44
mg) was dried under vacuum (0.5 mm Hg) using heat gun for three minutes. After cooling to room
temperature, glyme (1.5 mL), Me3SiCF2Br (2.25 mmol, 457 mL), and aldehyde (1.5 mmol) were
added, and the mixture was stirred at 80 °C for the time given in Table 2, and then cooled to room
temperature. For the workꢀup, ethanol (0.75 mL) and CF3CO2H (3 mmol, 231 µL) were added, and
the mixture was stirred for 1 hour at room temperature. Then, water (7 mL) was added, and the
product was extracted with hexane/EtOAc (2/1, 3×5 mL). The combined organic layers were
filtered through Na2SO4, concentrated under vacuum, and the residue was purified by column
chromatography.
Method B (General Procedure). Lithium bromide (87 mg, 1.0 mmol) and sodium iodide (540
mg, 3.6 mmol) were dried under vacuum (0.5 mm Hg) using heat gun for three minutes. After
cooling to room temperature, glyme (1.0 mL), aldehyde (1.0 mmol) and TMSCF2Br (490 mg, 2.4
mmol), and the mixture was stirred at 80 °C for 4 hours, cooled to room temperature.
Work-up for compounds 5b,i,j,k,m: Trifluoroacetic acid (0.27 mL, 3.6 mmol) and KHF2 (140
mg, 1.8 mmol) were added to the reaction mixture and stirring was continued for 1 hour. Then,
EtOAc (5.0 mL) and saturated aqueous Na2CO3 (2.0 mL) and sodium thiosulphate pentahydrate
(250 mg, 1.0 mmol) were added and stirring was continued for 5 min. Organic layer was separated,
and the aqueous layer was washed with EtOAc (2×3 mL). The combined organic layers were,
concentrated, and the residue was purified by column chromatography.
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Work-up for compounds 5l,n: The reaction mixture was diluted with hexane (6 mL) with stirring,
then the stirring was discontinued and inorganic solids were allowed to settle down. Liquid phase
was separated with a Pasteur pipette and solid residue were washed with hexane (2×6 mL). The
combined organic layers were concentrated, and the residue was subjected to column
chromatography on silica gel (CH2Cl2/hexane, 1/1) collecting nonꢀpolar fractions (Rf >0.8 for 5l; Rf
>0.4 for 5n). Solvents were evaporated, the residue was dissolved in glyme (1.0 mL) and methanol
(0.5 mL), and treated with trifluoroacetic acid (0.075 mL, 1.0 mmol). After completion of
desilylation (TLC control; 15 hours for 5l; 3 days for 5n,), solvents were removed under vacuum,
and the residue was purified by column chromatography.
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1-(4-Chlorophenyl)-2,2-difluoro-2-iodoethanol (5a).9a Method A. Yield 448 mg (94%). Pale
1
yellow oil. Chromatography hexanes/EtOAc 10 : 1 → 5 : 1. Rf 0.32 (hexanes/EtOAc 5 : 1). H
NMR (300 MHz, CDCl3), δ: 2.88 (br s, 1H), 4.66 (dd, 1H, J = 10.1, 7.8 Hz), 7.33–7.47 (m, 4H). 19F
NMR (282 MHz, CDCl3), δ: –54.2 (dd, 1F, J = 182.3, 10.1), –49.2 (dd, 1F, J = 182.3, 7.8).
2,2-Difluoro-2-iodo-1-(4-methoxyphenyl)ethanol (5b).9a Method B. Yield 274 mg (87%) Offꢀ
1
white crystals. Mp 63–65 °C (hexanes). H NMR (300 MHz, CDCl3), δ: 2.83 (br s), 3.83 (s, 3H),
19
4.64 (dd, 1H, J = 10.5, 7.8 Hz), 6.93 (d, 2H, J = 8.5 Hz), 7.41 (d, 2H, J = 8.5 Hz). F NMR (282
MHz, CDCl3), δ: –53.7 (dd, 1F, J = 180.2, 10.5 Hz), –49.1 (dd, 1F, J = 180.2, 7.8 Hz).
Methyl 4-(2,2-difluoro-1-hydroxy-2-iodoethyl)benzoate (5c). Method A. Yield 446 mg (87%).
1
Colorless crystals. Mp 82–83 Rf 0.25 (hexane/EtOAc, 4/1). H NMR (300 MHz, CDCl3) δ: 3.85 (d
1H, J =4.6 Hz), 3.91 (s, 3H), 4.73 (ddd. 1H, 10.2, 8.0, 5.0 Hz), 7.56 (d, 2H, J = 8.2 Hz), 8.01 (d,
13
2H, J = 8.2 Hz). C{1H} NMR (75 MHz, CDCl3) δ: 52.5, 79.5 (t, J = 23.5 Hz), 107.2 (dd, J =
19
317.8, 319.5 Hz), 128.2 (t, J = 1.5 Hz), 129.6, 130.8, 140.0 (d, J = 3.4 Hz), 167.2. F NMR (282
MHz, CDCl3) δ: –53.7 (dd, 1F, J = 182.3, 10.2 Hz), –48.7 (dd, 1F, J = 182.3, 8.0 Hz). Calcd for
C10H9F2IO3 (342.08): C, 35.11; H, 2.65; Found C, 35.21; H, 2.69.
4-(2,2-Difluoro-1-hydroxy-2-iodoethyl)benzonitrile (5d). Method A. Yield 342 mg (74%).
1
Colorless crystals. Mp 106–107 °C. Rf 0.26 (hexane/EtOAc, 3/1). H NMR (300 MHz, CDCl3) δ:
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3.71 (d, 1H, J = 4.6 Hz), 4.73 (ddd, 1H, J = 9.8, 7.4, 4.8 Hz), 7.60–7.71 (m, 4H). 13C{1H} NMR (75
MHz, CDCl3) δ: 79.0 (t, J = 24.1 Hz), 106.7 (dd, J = 317.8, 319.5 Hz), 113.0, 118.4, 128.9 (t, J =
1.4), 132.1, 140.0 (d, J = 3.4 Hz). 19F NMR (282 MHz, CDCl3) δ: –54.1 (dd, 1F, J = 184.4, 9.8 Hz),
–48.8 (dd, 1F, J = 184.4, 7.4 Hz). Calcd for C9H6F2INO (309.05): C, 34.98; H, 1.96; N, 4.53 Found
C, 35.06; H, 2.08; N, 4.36.
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2,2-Difluoro-2-iodo-1-(4-nitrophenyl)ethanol (5e).9a Method A. Yield 444 mg (90%). White
crystals. Mp 104–106 °C (hexanes). Chromatography hexanes/EtOAc 5 : 1 → 3 : 1. Rf 0.31
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(hexanes/EtOAc 3 : 1). H NMR (300 MHz, CDCl3), δ: 3.12 (d, 1H, J = 4.4), 4.81 (ddd, 1H, J =
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10.1, 7.4, 4.4), 7.71 (d, 2H, J = 8.5), 8.26 (d, 2H, J = 8.5). F NMR (282 MHz, CDCl3), δ: –54.4
(dd, 1F, J = 185.5, 10.1), –49.1 (dd, 1F, J = 185.5, 7.4).
2,2-Difluoro-2-iodo-1-(3-methoxyphenyl)ethanol (5f). Method A. Yield 438 mg (93%). Colorless
crystals. Mp 57–58 °С. Rf 0.18 (hexane/EtOAc, 6/1). 1H NMR (300 MHz, CDCl3) δ: 3.10 (d, 1H, J
= 4.6 Hz), 4.57 (s, 3H), 4.64 (ddd, 1H, J = 10.6, 7.7, 5.0 Hz), 6.93–7.00 (m, 1H), 7.02–7.09 (m,
2H), 7.31 (t, 1H, J = 7.9 Hz). 13C{1H} NMR (75 MHz, CDCl3) δ: 55.5, 79.9 (t, J = 23.0 Hz), 107.6
(dd, J = 319.5, 317.2 Hz), 113.7 (t, J = 1.1 Hz), 115.1, 120.5 (t, J = 1.7 Hz), 129.5, 136.2 (d, J = 2.9
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Hz), 159.5. F NMR (282 MHz, CDCl3) δ: –53.4 (dd, 1F, J = 181.1, 10.6 Hz), –48.7 (dd, 1F, J =
181.1, 7.7 Hz). Calcd for C9H9F2IO2 (314.07): C, 34.42; H, 2.89; Found C, 34.29; H, 2.87.
2,2-Difluoro-2-iodo-1-(2-nitrophenyl)ethanol (5g). Method A. Yield 479 mg (97%). Yellow oil.
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Rf 0.28 (hexane/EtOAc, 4/1). H NMR (300 MHz, CDCl3) δ: 3.67 (d, 1H, J = 5.0 Hz), 5.87–6.01
(m, 1H), 7.52–7.61 (m, 1H), 7.67–7.75 (m, 1H), 7.92–8.02 (m, 2H). 13C{1H} NMR (75 MHz,
CDCl3) δ: 73.9 (dd, J = 25.8, 23.0 Hz). 105.9 (dd, J = 320.1, 318.4 Hz), 125.0, 129.1 (d, J = 2.9
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Hz), 130.1 (t, J = 1.1 Hz), 130.3, 133.5, 148.7. F NMR (282 MHz, CDCl3) δ: –54.3 (dd, 1F, J =
184.4, 10.6 Hz), –48.7 (dd, J = 184.4, 6.4 Hz). Calcd for C8H6F2INO3 (329.04): C, 29.20; H, 1.84;
N, 4.26 Found C, 29.14; H, 1.72; N, 4.21.
2,2-Difluoro-1-(2-furyl)-2-iodoethanol (5h). Method A. Yield 353 mg (86%). Yellow oil. Rf 0.23
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(hexane/EtOAc, 8/1). H NMR (300 MHz, CDCl3) δ: 3.07 (d, 1H, J = 7.3 Hz), 4.79 (ddd, 1H, J =
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8.7, 8.7, 7.3 Hz), 6.44 (d, 1H, J = 3.4, 1.8 Hz), 6.55 (d, 1H, J = 3.4 Hz), 7.48 (d, 1H, J = 1.8 Hz).
13C{1H} NMR (75 MHz, CDCl3) δ: 75.3 (t, J = 25.2 Hz), 104.8 (t, J = 318.9 Hz), 110.7 (t, J = 1.2
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Hz), 110.9, 143.6, 147.8 (dd, J = 3.6, 1.4 Hz). F NMR (282 MHz, CDCl3) δ: –53.1 (dd, 1F, J =
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182.3, 8.7 Hz), –51.4 (dd, 1F, J = 182.3, 8.7 Hz). Calcd for C6H5F2IO2 (274.01): C, 26.30; H, 1.84;
Found C, 26.19; H, 1.77.
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2,2-Difluoro-2-iodo-1-{1-[(4-methylphenyl)sulfonyl]-1H-indol-2-yl}ethanol (5i). Method B.
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Yield 370 mg (78%). Amber viscous oil. Rf 0.26 (CH2Cl2). H NMR (300MHz, CDCl3) δ: 2.21 (br
s, 1H), 2.35 (s, 3H), 4.93 (t, 1H, J = 8.7 Hz), 7.20–7.30 (m, 3H), 7.35 (t, 1H, J = 7.7 Hz), 7.62 (d,
1H, J = 7.7 Hz), 7.78 (d, 2H, J = 8.2 Hz), 7.81 (s, 1H), 7.98 (d, 1H, J = 8.2 Hz). 13C NMR (75 MHz,
CDCl3) δ: 21.7, 75.2 (t, J = 25.0 Hz), 108.4 (t, J = 318.9 Hz), 113.7, 117.2 (d, J = 3.4 Hz), 120.7
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(dd, J = 2.9, 1.1 Hz), 123.7, 125.3, 126.5, 127.1, 128.7, 130.1, 135.0 (d, J = 1.7 Hz), 145.5. F
NMR (282 MHz, CDCl3) δ: −52.6 (dd, 1F, J = 181.6, 8.7 Hz), −49.1 (dd, 1F, J = 181.6, 8.7 Hz).
Calcd for C17H14F2INO3S (477.27): C, 42.78; H, 2.96; N, 2.93. Found, %: C, 42.54; H, 2.81; N,
2.87.
2,2-Difluoro-2-iodo-1-phenylethanol (5j).9a Method B. Yield 249 mg (88%). Colorless oil.
Chromatography hexanes/EtOAc 10 : 1 → 5 : 1. Rf 0.4 (hexanes/EtOAc 5 : 1). 1H NMR (300 MHz,
CDCl3), δ: 2.84 (br s, 1H), 4.70 (t, 1H, J = 9.9 Hz), 7.37–7.54 (m, 5H). 19F NMR (282 MHz,
CDCl3), δ: –53.7 (dd, 1F, J = 180.1, 9.9 Hz), –48.8 (dd, 1F, J = 180.1, 9.9 Hz).
1-(2-Bromophenyl)-2,2-difluoro-2-iodoethanol (5k).9a Method B. Yield 335 mg (92%). Pale
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yellow oil. Chromatography hexanes/EtOAc 10 : 1 → 5 : 1. Rf 0.35 (hexanes/EtOAc 5 : 1). H
NMR (300 MHz, CDCl3), δ: 2.97 (d, 1H, J = 4.4 Hz), 5.42 (ddd, 1H, J = 12.2, 6.9, 4.4 Hz), 7.23–
7.33 (m, 1H), 7.35–7.45 (m, 1H), 7.60 (dd, 1H, J = 8.1, 1.1 Hz), 7.71 (d, 1H, J = 8.1 Hz). 19F NMR
(282 MHz, CDCl3), δ: –52.7 (dd, 1F, J = 180.1, 12.2 Hz), –49.0 (dd, 1F, J = 180.1, 6.9 Hz).
2,2-Difluoro-2-iodo-1-mesitylethanol (5l). Method B. Yield 242 mg (74%). Offꢀwhite crystals.
Mp 73–76 °C. Rf 0.24 (CH2Cl2/hexane, 1/1). 1H NMR (300MHz, CDCl3) δ: 2.29 (s, 3H), 2.44 (br s,
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6H), 2.86 (br s, 1H), 5.58 (dd, 1H, J = 23.3, 2.7 Hz), 6.90 (s, 2H). C NMR (75 MHz, CDCl3) δ:
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316.7 Hz), 130.0, 130.7 (br), 138.3 (br), 138.8. F NMR (282 MHz, CDCl3) δ: −48.9 (dd, 1F, J =
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174.3, 23.3 Hz), −47.4 (dd, 1F, J = 174.3, 2.7 Hz). Calcd for C11H13F2IO (326.12): C, 40.51; H,
4.02. Found, %: C, 40.57; H, 3.94.
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(3E)-1,1-difluoro-1-iodo-4-phenylbut-3-en-2-ol (5m). Method B. Rf 0.38 (CH2Cl2). After column
chromatography, the product was purified by crystallization from hexane (ca. 5 mL) affording 215
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mg (69%). White crystals. Mp 66–67 °C. H NMR (300MHz, CDCl3) δ: 2.65 (d, 1H, J = 6.0 Hz),
4.19 (qn, 1H, J = 6.5 Hz), 6.18 (dd, 1H, J = 16.0, 6.5 Hz), 6.91 (d, 1H, J = 16.0 Hz), 7.30–7.52 (m,
5H). 13C NMR (75 MHz, CDCl3) δ: 78.7 (dd, J = 24.7, 22.9 Hz), 108.2 (t, J = 318.7 Hz), 122.7 (dd,
J = 4.0, 1.2 Hz), 127.0, 128.8, 128.9, 135.7, 136.2. 19F NMR (282 MHz, CDCl3) δ: −53.8 (dd, 1F, J
= 180.1, 6.5 Hz), −49.6 (dd, 1F, J = 180.1, 6.5 Hz). Calcd for C10H9F2IO (310.08): C, 38.73; H,
2.93. Found, %: C, 38.85; H, 2.84.
4,4-Difluoro-3-hydroxy-4-iodo-2,2-dimethylbutyl benzoate (5n). Method B. Yield 86 mg (22%).
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White crystals. Mp 63–65 °C. Rf 0.27 (CH2Cl2). H NMR (300MHz, CDCl3) δ: 1.19 (s, 3H), 1.26
(d, 3H, J = 3.3 Hz), 3.09 (br d, 1H, J = 5.5 Hz), 3.95 (br d, 1H, J = 23.1 Hz), 4.01 (d, 1H, J = 11.0
Hz), 4.50 (d, 1H, J = 11.0 Hz), 7.49 (d, 2H, J = 7.5 Hz), 7.61 (t, 1H, J = 7.5 Hz), 8.05 (d, 2H, J =
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7.5 Hz). C NMR (75 MHz, CDCl3) δ: 20.7 (dd, J = 4.0, 1.1 Hz), 22.2 (dd, J = 5.2, 1.7 Hz), 39.1,
71.8, 81.6 (dd, J = 23.5, 20.1 Hz), 108.9 (dd, J = 328.7, 320.1 Hz), 128.7, 129.7, 129.9, 133.4,
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166.8. F NMR (282 MHz, CDCl3) δ: −49.2 (dd, 1F, J = 171.9, 23.4 Hz), −40.4 (d, 1F, J = 171.8
Hz). Calcd for C13H15F2IO3 (384.16): C, 40.64; H, 3.94. Found, %: C, 40.54; H, 3.99.
Synthesis of 1-(4-chlorophenyl)-2,2-difluoropent-4-en-1-ol (10).
Preparation of organozinc 9. Reaction mixture obtained from reaction of 4ꢀchlorobenzaldehyde
2a with Me3CF2Br according Method A was cooled to –30 °C. A solution of iꢀPrZnI (2.0M in THF,
2.5 mmol, 1.25 mL) was added at –30 °C, and the reaction flask was immersed into ice/water bath
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and stirred for one hour to give a solution of reagent 9. F NMR (282 MHz, THF/DME, 1/1) δ: –
110.1 (br d, J = 303 Hz), –112.4 (br d, J = 303 Hz).
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Reaction of organozinc 9. To a freshly prepared solution of reagent 9, CuCN (0.15 mmol, 13
mg) was added at 0 °C and stirring was continued for 3 hours at 0 °C. The cooling bath was
removed, and the mixture was stirred for 18 h at room temperature. For the workꢀup, water (5 mL)
and hexane (10 mL) of hexane were added, and the mixture was shaken. The organic phase was
separated, and concentrated under vacuum. To the residue, MeOH (1.5 mL) and NH4F (4.5 mmol,
166 mg) were added and the mixture was stirred for 30 minutes. Then, water (7 mL) was added, the
mixture was extracted with hexane (3×5 mL). The combined organic layers were filtered through
Na2SO4, concentrated under vacuum, and the residue was purified by column chromatography.
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Yield 279 mg (80%). Yellow oil. Rf 0.20 (hexane/EtOAc, 8/1). H NMR (300 MHz, CDCl3) δ:
2.37–2.58 (m, 1H), 2.61–2.83 (m,1H), 2.96 (br s, 1H), 4.82 (t, 1H, J = 10.4 Hz), 5.19 (dd, 1H, J =
17.5, 1.4 Hz) 5.25 (dd, 1H, J = 10.9, 1.4 Hz), 5.82 (ddt, 1H, J = 17.1, 10.2, 7.1 Hz), 7.37 (s, 4H).
13C NMR (75 MHz, CDCl3) δ: 37.2 (t, J = 24.4 Hz), 74.3 (t, J = 28.4 Hz), 120.8, 122.3 (t, J = 247.2
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Hz), 128.6 (t, J = 5.2 Hz), 128.7, 129.0 (t, J = 1.3 Hz), 134.8, 135.0 (t, J = 2.4 Hz). F NMR (282
MHz, CDCl3) δ: –109.9 (dddd. 1F, J = 248.0, 19.6, 12.6, 10.6 Hz), –109.1 (dddd, 1F, J = 248.0,
19.1, 14.8, 8.5 Hz). Calcd for C11H11ClF2O (232.65): C, 56.79; H, 4.77; Found C, 56.74; H, 4.97.
1-(4-Chlorophenyl)-2,2-difluoroethanone (11).17 To a reaction mixture obtained from the
reaction of 4ꢀchlorobenzaldehyde 2a with Me3CF2Br according Method A, at room temperature
were successively added ethanol (0.75 ml) and 50% aqueous solution of Me3N (7.5 mmol, 1.03
mL). The reaction vessel was tightly closed and the mixture was heated at 70 °C for 4 hours with
stirring. Then, the mixture was cooled to room temperature, water (7 mL) was added, and the
product was extracted with pentane (3×5 mL). The combined organic layers were filtered through
Na2SO4, and pentane was evaporated at atmospheric pressure. The residue was distilled under
vacuum in a shortꢀpath apparatus, bp 70ꢀ80 °C (bath temperature)/4.5 Torr. Yield 205 mg (72%).
1H NMR (300 MHz, CDCl3) δ: 6.25 (d, 1H, J = 53.6 Hz), 7.49 (d, 2H, J = 7.8 Hz), 8.01 (d, 2H, J =
7.8 Hz). 19F NMR (282 MHz, CDCl3) δ: –122.5 (d, J = 53.6 Hz).
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Acknowledgement
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This work was supported by the Russian Science Foundation (project 14ꢀ13ꢀ00034).
Supporting Information
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Copies of NMR spectra for all compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
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(13) In the experiment with cinnamaldehyde, F NMR and GCMS data suggest the formation of
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(14) Ghosh, S. K.; Hazra, D. K.; Lahiri, S. C. Z. Phys. Chem. 1996, 194, 213–222.
(15) Other bases (NEt3, DBU, K2CO3) gave inferior results.
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128, 755–761.
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