Copper-Catalyzed O-Difluoromethylation of Functionalized Aliphatic Alcohols: Access to Complex Organic Molecules with an OCF2H Group

Article abstract of DOI:10.1021/acs.joc.6b00628

A two-step synthetic strategy toward difluoromethyl ethers via a CuI-catalyzed reaction of the alcohols, bearing additional protected functionalities, with FSO₂CF₂CO₂H has been developed. The high potential of the developed protocol has been shown by preparing novel OCF₂H-analogues of GABA and l-proline. The described transformation has good functional group compatibility and can serve as a powerful synthetic tool for late-stage preparation of complex OCF₂H-containing organic compounds as well as building blocks for drug discovery.

Full text of DOI:10.1021/acs.joc.6b00628

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Featured Article
Cu-catalyzed O-Difluoromethylation of Functionalized Aliphatic
Alcohols: An Access to Complex Organic Molecules with OCF2H group.
Kostiantyn Levchenko, Olexandr P. Datsenko, Oleh Serhiichuk,
Andrei Tolmachev, Viktor O. Iaroshenko, and Pavel K. Mykhailiuk
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00628 • Publication Date (Web): 06 May 2016
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Cu-catalyzed O-Difluoromethylation of Functionalized Aliphatic Al-
cohols: An Access to Complex Organic Molecules with OCF2H group.
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Kostiantyn Levchenko,† Olexandr P. Datsenko,† Oleh Serhiichuk,§ Andrei Tolmachev,† Viktor O. Iaro-
shenko,⊥* Pavel K. Mykhailiuk†‡*
†Enamine Ltd., 78 Chervonotkatska str., 02094, Kyiv, Ukraine, www.enamine.net
‡Department of Chemistry, Taras Shevchenko National University of Kyiv, Volodymyrska Street, 64, Kyiv 01601, Ukraine.
§Department of Organic Chemistry, Kiev Polytechnic Institute, Pr. Pobedy 37, 03056 Kiev, Ukraine.
⊥ Homogeneous Catalysis and Molecular Design Research Group at Center of Molecular and Macromolecular Studies, Polish
Academy of Sciences, Sienkiewicza 112, PL-90-363 Łódź, Poland.
ABSTRACT: Two-step synthetic strategy towards the difluoromethyl ethers via a CuI-catalyzed reaction of the alcohols, bearing
additional protected functionalities, with FSO2CF2CO2H has been developed. The high potential of the developed protocol has been
shown by preparing novel OCF2H-analogues of GABA and L-Proline. The described transformation has good functional group
compatibility and can serve as a powerful synthetic tool for late-stage preparation of complex OCF2H-containing organic com-
pounds as well as building blocks for drug discovery.
INTRODUCTION
The isosteric substitution of hydrogen atoms with fluorine or introduction of fluorine-bearing functionalities into complex organic
molecules are well-established strategies in medicine and life science for the design and optimization of biologically active mole-
cules, as well as in material science for devising new functional materials.1,2 The fluorine atom is similar in size to hydrogen. This
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feature is accepted to be the main reason why the biological objects, like microorganisms and enzymes, under particular circum-
stances, do not recognize the difference between a natural substrate and its fluorine-modified analogue, obtained via the replace-
ment of the particular C-H bond by C-F bond. This phenomenon is often considered as the “mimic effect” of fluorine for hydro-
gen.1b However, the C-F bond comparing with C-H has much stronger bonding energy which results in the increased stability of the
C-F bond. These structural alterations are the main reasons for the changes in the metabolic pathways of fluorinated compounds
and in particular augmentation of the in vivo stability towards various enzymes. For instance, introduction of a fluorine into aro-
matic core is a well-known strategy to improve the stability of the lead compounds, for instance towards the Cytochrome C en-
zymes of liver cells, which dramatically changes the clearance and longevity of the drug candidate in vivo.3 Nonetheless, twenty
seven among worldwide 150-best-selling drugs in the year 2013 are fluorinated compounds.1b,d
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Figure 1. Pharmacologically relevant aromatic OCF2H compounds.
The effects associated with stereo-electronic interplays of fluorine atom with other fluorines or fluorine-containing groups, as well
as with various polar or charged functional groups including, oxygen and nitrogen, are commonly used in the medicinal chemis-
try1c,d,4 and in the catalytic science for the development of pharmacologically significant substances, catalysts5,6 and/or catalytic
moieties with enhanced properties, edited efficacy and performance. In medicinal chemistry, however, these particular tools deliver
a practical handle for “fine-tune” of biological and physicochemical profiles of lead structures.1c,d In this context, several fluorine
modifications of naturally occurring and pharmacologically relevant structures were undertaken.1b
In a continuation of our ongoing medicinal chemistry program dedicated to engineering of fluorinated pharmacologically relevant
scaffolds,7 we have undertaken the current study aiming the synthesis of OCF2H-containing complex organic molecules. Our choice
of this group is rather not at random, but was stipulated by a pivotal role this functionality plays as a pharmacophore in the market-
ed drugs;3 for instance, such well-known medicines as Roflumilast I1b,c,3 and Pentaprazole II1b,c,3 contain this group (Figure 1).
Besides, the OCF2H group is a commonly occurring structural motif found in numerous pharmaceuticals and biologically active
compounds8 including enzyme inhibitors, anti-HIV agents and antimicrobial agents. In the life science this group is presented by
several OCF2H containing nucleosides,1c,d having visible impact on the conformational preferences of the nucleosides themselves
and the DNA double strand in particular. In addition to that, the OCF2R functionalities are commonly used for the stereocontrol of
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rotational profile9 in organic molecules of different types. The elevated interest to the difluoromethyl group can be also explained
by the fact that it acts as bioisostere of alcohols and thiols.1b,4 This makes the OCF2R groups and OCF2H in particular as desirable
pharmacophores and valuable tool to tune the properties of organic molecules and their conformational bias.
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HO
HO
OBn
Alcohols
OBn
1a
1b
8
9
NHCbz
HO
HO
NHCbz
HO
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Primary
amines
HO
NHCbz
NHCbz
1c, 1d
1e
trans-1f
NHCbz
HO
HO
NHCbz
HO
NHCbz
HO
NHCbz
OH
O
1g
trans-1h
1i
1j
HO
HO
(R)
HO
(S)
Secondary
amines
N
Cbz
N
N
N
Cbz
1n
Cbz
1m
Cbz
1k
1l
HO
CO2Bn
HO
CO2Bn
Acids
CO2Bn
HO
1o
1p
1q
HO
(R)
OH
CO2Me
(S)
Amino
acids
BocHN
CO2Me
(S)
N
1s
1r
Boc
Table 1. List of used starting materials.
Analyzing the OCF2H drugs presently available on the market as well as the drug candidates in clinical and preclinical studies, we
witnessed the lack of aliphatic OCF2H molecules. In a view of recent trends in the field of medicinal chemistry related to the design
of architecturally more complex molecules with greater three-dimensionality (3D-shape), via the formal saturation of aromatic
precursors,10 the functionalized OCF2H aliphatic building blocks with high degree of saturation are highly desirable scaffolds for
drug discovery. The deficit of OCF2H aliphatic structural motives is a result of underdeveloped synthetic methodologies enabling
the preparation of such scaffolds.
Concerning the synthetic routes known to date for the furnishing of organic compounds with the OCF2H group, there are four main
strategies. Namely, (i) the O-difluoromethylation11 of phenols and alcohols using various sources of difluorocarbene; (ii) the C-O
coupling reaction using the chemical equivalents12 of the [OCF2H]- synthon; (iii) the transformation of CO and CS groups;13 (iv) the
nucleophilic exchange14 of other halogens to fluorine in the OCHal2H groups. Concerning the strategy (i), there are a number of
sources amenable for generation of difluorocarbene; for instance, such chemical synthons as HalCF2CO2Na; FSO2CF2CO2TMS;
FSO2CF2CO2H; TMSCF2R (R = F, Cl, Br); (Et2O)2POCF2Br; CF3SO3CF2H etc. are commonly used for this purpose.11a However,
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the FSO2CF2CO2H due to its high reaction efficiency, low price and synthetic availability, is often considered to be the optimal
reagent of choice for O-difluoromethylation, in particular for large-scale synthesis. Despite the diversity of the strategies known to
date, the most commonly used synthetic route towards difluoromethyl ethers from alcohols requires the use of ozone-depleting
HCF2Cl, the so-called Freon 22.15 The environment friendly preparative methods, however, often require elevated temperatures, are
not compatible with many functional groups and are only efficient on the structurally simple substrates.11 Due to the aforemen-
tioned limitations of presently used methodologies, the development of new, simple, straightforward and concise methods, to con-
vert functional alcohols to difluoromethyl ethers, are of considerable interests.
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Herein, we report a practical entry towards structurally diverse difluoromethyl ethers, using the set of readily available alcohols,
bearing an additional functional group, and FSO2CF2CO2H11 as a source CF2 structural motif. Our methodology commenced with
the preparation of the protected substrates 1a-s. For the current study we selected O-protected aliphatic diols 1a,b; N-protected
amino alcohols 1c-n; carboxyl-protected hydroxyl acids 1m-q, as well as N- and carboxyl- protected amino acids bearing free
hydroxyl group 1r,s (Table 1). The method we are communicating here is an extension of the methodology for non-functionalized
alcohols developed by Chen at al.16 that in our case covers the functionalized aliphatic alcohols and results in improved reaction
efficiency and overall yields. Within the current research program we have developed the diverse libraries of complex OCF2H-
containing organic compounds, however here as a quintessential we are communicating only 18 examples (Table 3).
RESULTS AND DISCUSSION
With the set of the starting compounds 1a-s in hand (Table 1), we focused on the setting up the standard reaction condition applica-
ble for the title transformation (Scheme 1, Table 2). We pointed out the reaction conditions that were used in the early works of
Chen17 as a starting point of our research. Noteworthy, these conditions require from 2- to 3-fold excess of alcohol along with ele-
vated temperatures, and in our opinion cannot be used for the multi gram preparation of structurally diverse OCF2H compounds. At
the same time, many synthetic methods known to date utilise strong bases for the difluorocarbene generation; these methods usually
demonstrate low functional group tolerance and cannot be employed for the late-stage functionalization of complex organic mole-
cules.
F
F
H
O
X
O
X
FSO2CF2CO2H, CuI (0.2 eq)
FG
FG
MeCN, 50oC
X = O, N
2a-s (7-90%)
X = O, N
1a-s
18 examples
F
FG = Bn, CO2Bn; i: Pd/C,
30 atm H2, MeOH, r.t.
FG = Me; ii: LiOH,
THF/H2O, 0oC
F
X
O
H
i or ii
X = O, N
3a-s (10-74%)
18 examples
i: for 2a-2q
ii: for 2r, 2s
Scheme 1. Synthesic scenario for the preparation of OCF2H substituted intermediates and final PG-free products.
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Recent studies showcased that the transition metals enable the transfer of the carbene moieties by formation of corresponding car-
bene complexes. Additionally, the existence of such adducts and their stability were supported by spectroscopic means along with
the chemical transformations of the aforementioned metallic species.18 The difluorocarbene complexes of transition metals are
studied, however their existence as intermediates was proven in several catalytic processes.19 This in particular turned our attention
towards transition-metal-mediated protocols and prompted us to start the reaction trials applying Cu(I) salts, which are known to be
capable to trap carbenes forming suitable carbene complexes.18a,d On the other hand, the recent progress on the application of
CuCF3 as an intermediate of choice for the catalytic trifluoromethylation as well as difluoromethylation20 brought us on the idea
that the O-difluoromethylation can also follow the second possible mechanistic route, namely via the formation of a CF3 metal
species. Since we were not sure about the mechanism the reaction undergoes within the designed and tested reaction conditions, we
decided to consider both possible routes mentioned above. Accordingly, we have selected a set of transition metals capable for
formation of metal carbene complexes and CF3 metal species.
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Table 2. Optimization of reaction conditions for the synthesis of 2a.a
yield
entry catalyst/solvent
T
time
(%)b
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2
3
4
5
6
CuBr (0.2 eq)/C6H6
CuBr (0.2 eq)/C6H6
CuBr (0.2 eq)/C6H6
CuBr (0.2 eq)/MeCN
CuI (0.2 eq)/C6H6
CuI (0.2 eq)/C6H6
60oC
60oC
45min traces
3h
traces
traces
5c
100oC 3h
60oC
50oC
90oC
2h
1h
2h
17c
12c
67
7
8
CuI (0.2 eq)/MeCN
CuI (0.2 eq)/MeCN
50oC
80oC
2h
2h
(75c)
60
(69c)
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73
45min
50oC
1
2
3
9
CuI (0.2 eq)/MeCN
(82c)
4
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7
8
9
10
11
12
13
14
15
16
CuI (0.1 eq)/MeCN
50oC
50oC
60oC
60oC
60oC
60oC
60oC
45min 58c
45min 81c
CuI (0.3 eq)/MeCN
NiBr2 (0.2 eq)/MeCN
NiI2 (0.2 eq)/MeCN
1h
1h
1h
1h
3h
15 c
19c
-
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Cu(OAc)2 (0.2 eq)/MeCN
Cu(OTf)2 (0.2 eq)/MeCN
Rh2(OAc)4 (0.1 eq)/C6H6
25c
45c
Rh2(O2CCF3)4
eq)/C6H6
(0.1
17
60oC
3h
38c
a Optimization of the reaction condition was performed on the 10 mmol scale taking 1.5 equivalents of FSO2CF2CO2H.
b Yields.
c GC/MS detected yields.
The substance 1a was chosen as a model compound. After reaction condition optimization, consisted in variation of solvents,
amount and type of transition metals, temperature and time of reaction, the optimal reaction condition was developed (Table 2 entry
9). We mainly focused on the exploration of CuBr and CuI as catalysts enabling introduction of CF2H group. First, the CuBr was
checked (Table 2, entries 1-4); accordingly, to our great disappointment we did observe the formation of desired product but in
trace amounts. The best result showcased by utilizing the combination of CuBr with MeCN as a solvent. Under these conditions the
product 2a was detected by GC/MS in 5% yield. Furthermore, the CuI/C6H6 system improved the situation dramatically, delivering
the desired product in 17% GC/MS-yield (Table 2, entry 5). Nonetheless, these results were not sufficient enough to deploy a chem-
istry using these reaction conditions. The crucial improvement in terms of yields appeared to be the usage of MeCN as a solvent,
which increased the GC/MS-yield up to 75% (Table 2, entry 7). The following crucial parameters during the reaction condition
optimization were the screening of time and the temperature. We encountered with the problem of the thermal instability of the
product 2a under the Cu-catalysis (Table 2, entry 8). This observation prompted us to decrease the reaction time up to 45 minutes
o
and the reaction temperature to 50 C. Finally, we reached the synthesis of the corresponding difluoromethyl ether 2a in 82%
GC/MS-yield and 73% isolated yield (Scheme 1, Table 2). The best yield was obtained using 1.5 equivalents of difluoromethyla-
tion agent (FSO2CF2CO2H) and 0.2 equivalents of CuI, in MeCN as reaction media at 50 oC (Table 2, entry 9). Further, increasing
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the amount of CuI to 0.3 equivalents did not improve visibly the efficiency of the title reaction. However, when we took 0.1 equiva-
lent of CuI, the GC/MS-yield dropped significantly (entry 10). At the same time, other transition metals, such as Ni(II) (Table 2,
entries 12, 13) and Cu(II) (Table 2, entries 14, 15) salts, were not prone to catalyze the title reaction in a sufficient manner. In con-
trary, the Rh(II) salts, known previously to promote the formation of carbene metalocomplexes,18c demonstrated promising results
when applied to the title reaction (Table 2, entries 16, 17). However, owing the availability and overall costs of Rh-based catalysts,
we excluded this option for the further optimization of reaction condition basing on the goal of the gram scale production of desired
OCF2H substituted substances.
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F
O
F
O
O
F
OFG
OFG
NHFG
F
F
F
2a: FG = Bn (73%)
3a: FG = H (74%, 54%*)
2b: FG = Bn (73%)
3b: FG = H (65%, 47%*)
2c: FG = Cbz (86%)
3c: FG = H (10%, 9%*)
NHFG
F
O
NHFG
F
O
NHFG
O
F
F
F
F
2d: FG = Cbz (86%)
3d: FG = H (73%, 63%*)
2e: FG = Cbz (7%)
3e: FG = H (25%, 2%*)
trans-2f: FG = Cbz (67%)
trans-3f: FG = H (71%, 47%*)
NHFG
NHFG
NHFG
O
O
F
F
F
O
F
F
F
2g: FG = Cbz (83%)
3g: FG = H (67%, 55%*)
trans-2h: FG = Cbz (79%)
trans-3h: FG = H (72%, 57%*)
2i: FG = Cbz (90%)
3i: FG = H (74%, 67%*)
F
O
F
O
(S)
F
O
NHFG
F
F
F
N
N
O
FG
FG
2j: FG = Cbz (13%)
3j: FG = H (43%, 6%*)
2k: FG = Cbz (80%)
3k: FG = H (69%, 55%*)
2l: FG = Cbz (85%)
3l: FG = H (55%, 47%*)
F
F
O
(R)
F
O
F
O
CO2FG
F
F
N
N
FG
FG
2m: FG = Cbz (82%)
3m: FG = H (63%, 52%*)
2n: FG = Cbz (87%)
3n: FG = H (53%, 46%*)
2o: FG = Bn (81%)
3o: FG = H (64%, 52%*)
F
CO2FG
O
F
O
F
CO2FG
F
O (S)
CO2FG
F
F
BocHN
2p: FG = Bn (73%)
cis-3p: FG = H (60%, 44%*)
2q: FG = Bn (74%)
3q: FG = H (57%, 42%*)
2r: FG = Me (80%)
3r: FG = H (58%, 46%*)
F
O
(R)
(S)
F
CO2FG
* overall yields via two steps
N
Boc
2s: FG = Me (84%)
3s: FG = H (61%, 51%*)
Table 3. The scope of the OCF2H intermediates as well as finial protecting-group-free products.
Prompted by these results and having optimized reaction conditions, we turned our attention towards evaluation of the generality of
the developed synthetic protocol. We found that the O-protected diol 1b under the aforementioned reaction conditions can be swift-
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ly converted to the corresponding protected intermediate compound 2b (Table 3). The same results were observed for a variety of
N-protected amino alcohols 1c-n and carboxyl-protected hydroxyl acids 1o-q (Table 1 and 3). To our delight, the developed reac-
tion conditions appeared to be general and allowed the synthesis of corresponding difluoromethyl ethers 2a-q bearing various func-
tionalities. From the results summarized in Table 3, it is evident that the described CuI-catalyzed difluoromethylation reaction
turned out to be rather general. The obtained compounds were either high viscous oils or liquids; thus the purification was accom-
plished by distillation in vacuum or preparative column chromatography on the silica gel. In the case of compounds 2e, 2j and 3c
we observed the drop in the yields. For 2e and 2j most probably this can be addressed to the sterical bulkiness of the corresponding
substrates 1e, 1j. The rather low yield of the amine 3c can be explaned by its high volatility. Upon scale-up production of com-
pounds 2d, 2l, 2m, 2r and 2s the amount of FSO2CF2CO2H could be decreased up to 1.2-1.3 equivalents without visible lose in
yields.
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The removal of the concrete protecting group was achieved following the standard reaction condition commonly used for the given
case (Scheme 1). For instance, the Bn and CO2Bn moieties, present in the compounds 2a-2q, were easily removed from corre-
sponding ethers and amides by the high pressure catalytic hydrogenation. The reaction was conducted in methanol, using 5%-Pd/C
as catalyst under 30 atm of H2 at room temperature. The title reaction can be easily scaled-up on gram- and decagram-scales with-
out further optimization. Of note, the mildness of the developed methodology enabled the synthesis of enantiomerically pure com-
pounds 3l and 3m from the corresponding (S) and (R) precursors without any notable racemization.
Scheme 2. Follow-up chemistry: Synthesis of (S)-3-(difluoromethoxy)pyrrolidin-2-one 5 by base-promoted cyclization of (S)-
methyl 4-amino-2-(difluoromethoxy)butanoate 4.
In the light of these results, we anticipated that the title reaction could be also applicable for the late-stage diversification of phar-
macologically relevant compounds, for instance, hydroxy amino acids. In a view of our current interests in the fluorine modified
natural and semi-natural products7 like amino acids and nucleosides, for this study two model amino acids were selected; namely,
the (4R)-4-hydroxy-L-proline and (2S)-2-hydroxy GABA ((2S)-4-amino-2-hydroxybutanoic acid). Following the known synthetic
methods,21 these compounds were converted into the protected derivatives 1r and 1s, which were suitable for the subsequent CF2-
functionalization (Table 1). Using the optimal conditions, the corresponding compounds were successfully converted into interme-
diate structures 2r and 2s in good yields (80% and 84% respectively). The further saponification of these amino acid esters by solu-
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tion of LiOH in THF afforded N-Boc-protected (4R)-4-(difluoromethoxy)-L-proline 3r and N-t-Boc-protected (2S)-4-amino-2-
(difluoromethoxy)butanoic acid 3s in 61% and 58% yield respectively. The Boc and t-Boc protecting groups on the amino function
were not removed, since according to our actual research plans those building blocks will be used further for the peptide synthesis.
The attempts to incorporate the synthesized OCF2H-analogue of L-Proline into the oligo- and polypeptide strings7a-c, 22 are currently
underway in our laboratories.
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In order to illustrate the follow-up chemistry, the synthetic transformation of the 2r was undertaken. The cyclization of the protect-
ed (2S)-2-hydroxy GABA was achieved by the treatment of the title compound with TFA followed by the basic neutralization with
K2CO3, which afforded to the pharmacologically relevant (3S)-3-(difluoromethoxy)pyrrolidin-2-one 5 in 52% yield as a pure (S)-
enantiomer (Scheme 2). The racemization in the course of the reaction was not detected. At the same time, in order to cut off two
extra steps related with protection and deprotection, we had a notion to set under investigation the unprotected hydroxy amino
substrates including hydroxy amino acids. Unfortunately, these attempts experienced a failure, the corresponding reactions leaded
to the formation of a mixture of unidentified products accompanied by the tar formation.
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To confirm the constitution of the obtained structural scaffolds 2, 3 and 5 we mainly used the NMR means. The characteristic fea-
tures of the OCF2H products in 1H and 13C NMR spectra are accompanied by the equal volume of corresponding JC-F, JF-H coupling
constants in proton and 19F NMR spectra. For the structures with the chiral carbon in the close proximity to the OCF2H group we
observed the diastereotopism of two geminal fluorine atoms with the characteristic spin pictures and coupling patterns.23 The chem-
ical shifts of OCF2H function is in accordance to the previously communicated data.23
SUMMARY
In summary, we developed operationally simple protocol for O-difluoromethylation of various functional alcohols with 1.2-1.5
excess amount of FSO2CF2CO2H which is so far an optimal difluoromethylation reagent. The CuI-catalyzed reaction of the poly-
functional alcohols provides corresponding difluoromethyl ethers from moderate to high yields. Furthermore, this protocol is dis-
tinguished by a wide substrate scope, including aliphatic alcohols bearing additional protected OH, NH2, or CO2H groups, without
compromising its efficiency and scalability. As the following task to be solved in the frames of this research program, we see the
extension of the developed protocol on the synthesis of other OCF2H-modified amino acids and natural products as well as subse-
quent assembly of OCF2H-analogues of several pharmacologically relevant peptides. At the same time, we are intended to disclose
the mechanism of the title CuI-catalyzed reaction by spectroscopic (1D, 2D NMR, IR) and rational means. These attempts are cur-
rently underway in our laboratories.
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EXPERIMENTAL SECTION
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Solvents were purified according to standard procedures. Column chromatography was performed using Kieselgel Merck 60 (230-
400 mesh) as the stationary phase. 1H-, 19F-, 13C NMR spectra were recorded on at 499.9, 470.3 and 124.9 MHz. Chemical shifts are
reported in ppm downfield from TMS (1H, 13C) or CFCl3 (19F) as internal standards. The information associated with preparation of
the compounds 1a-s one can find in the SI.
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((4-(Difluoromethoxy)butoxy)methyl)benzene (2a).
Compound 1a (15 g, 0.083 mol, 1 eq) was dissolved in 200 mL of acetonitrile and copper iodide (3.16 g, 0.017 mol, 0.2 eq) was
o
added thereto. The mixture was heated to 50 C and the solution of 2-fluorosulfonyl-2,2-difluoroacetic acid (22.3 g, 0.125 mol, 1.5
eq) in 100 mL acetonitrile was added dropwise over a period of 45 minutes. The reaction mixture was heated for additional 30
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minutes at 50 C. Then acetonitrile was evaporated, the rest was dissolved in EtOAc and the solid phase was filtered out. The
EtOAc solution was concentrated under vacuum to give the product 2a. Yield = 73 % (14 g).
1
The product is a transparent colorless liquid. H NMR (500 MHz, CDCl3): δ = 1.71-1.74 (m, 4H), 3.20, 3.49 (s, 2H), 3.85, 4.18 (t,
2H, 3J = 5.4 Hz), 4.49 (s, 2H), 6.16 (t, 1H, 2JH-F= 75.3 Hz, CF2H), 7.27-7.32 (m, 5H).
19F NMR (376 MHz, CDCl3): δ = -842 (d, 2F, 2J = 76.0 Hz).
13C{1H} NMR (125.7 MHz, CDCl3): δ = 25.9, 26.0, 63.4 (t, J = 5.9 Hz), 69.5, 72.8, 116.1 (t, 1JC-F= 259.0 Hz, CF2H), 127.4, 127.5,
128.3, 138.5.
Anal. calcd for C12H16F2O2: C, 62.60; H, 7.00. Found: C, 62.74; H, 7.07.
4-(Difluoromethoxy)butan-1-ol (3a).
Compound 2a (14 g, 0.061 mol, 1 eq) was dissolved in 100 mL of methanol and 1.5g of 5%-Pd/C was added thereto. The mixture
was stirred under 30 atm of H2 for 96 h at room temperature. Then Pd/C was filtered out and the resulting mixture was concentrated
under vacuum to give compound 3a. Yield = 74% (6.3 g).
The product is a pale liquid. 1H NMR (500 MHz, CDCl3): δ = 1.60-1.73 (m, 4H), 2.78 (br. s, 1H), 3.63 (t, 2H, 3J = 6.8 Hz), 3.85 (t,
2H, 3J = 6.7 Hz), 6.17 (t, 1H, 2JH-F = 73.3 Hz, CF2H).
19F NMR (376 MHz, CDCl3): δ = -84.5 (d, 2F, 2JH-F = 75.1 Hz).
13C{1H} NMR (125 MHz, CDCl3): δ = 25.1, 29.3, 62.1, 63.0 (t, J = 5.5 Hz), 115.7 (t, 1JC-F = 256.3 Hz, CF2H).
Anal. calcd for C5H10F2O2: C, 42.86; H, 7.19. Found: C, 42.72; H, 7.22.
(((4-(Difluoromethoxy)cyclohexyl)oxy)methyl)benzene (2b) (Mixture of diastereomers).
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The Journal of Organic Chemistry
Compound 1b (28.8 g, 0.14 mol, 1 eq) was dissolved in 300 mL of acetonitrile and copper iodide (5.3 g, 0.028 mol, 0.2 eq) was
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added thereto. The mixture was heated to 50 C and the solution of 2-fluorosulfonyl-2,2-difluoroacetic acid (37.3 g, 0.21 mol, 1.5
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eq) in 100 mL acetonitrile was added dropwise over a period of 45 minutes. The reaction mixture was heated for additional 30
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minutes at 50 C. Then acetonitrile was evaporated, the rest was dissolved in EtOAc and the insoluble solid was filtered out. The
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resulting solution of EtOAc was evaporated and the crude of 2b was purified by column chromatography (EtOAc : Hexane - 1 : 6,
Rf = 0.65). Yield = 73 % (27.6g). We encountered with the problems related to the prefabrication of the compound 2b, however the
impurities of the batch did not effected the purity of the final product 3b.
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The product is a transparent colorless oil. 1H NMR (400 MHz, CDCl3) (mixture of diastereomers): δ = 1.15-1.19 (m, 2H), 1.69-1.72
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(m, 2H), 1.95-1.99 (m, 2H), 2.07-2.14 (m, 2H), 3.50-3.53 (m, 1H), 4.20-4.25 (m, 1H), 4.58 (s, 2H), 6.27 (dt, 1H, JH-F = 75.6 Hz, J
= 9.0 Hz, CF2H), 7.33-7.34 (m, 1H), 7.39-7.40 (m, 4H).
19F NMR (376 MHz, CDCl3): δ = -81.1 (t, 2F, 2JH-F = 77.0 Hz).
13C{1H} NMR (100 MHz, DMSO-d6) (mixture of diastereomers): δ = 27.4, 28.2, 28.4, 29.4, 69.3, 69.7, 74.3, 75.0, 117.7 (dt, 1JC-F
=
258.5 Hz, J = 12.2 Hz, CF2H), 127.6, 127.7, 128.6, 139.6, 139.6 (d, J = 14.0 Hz).
Anal. calcd for C14H18F2O2: C, 65.61; H, 7.08. Found: C, 65.43; H, 7.11.
4-(Difluoromethoxy)cyclohexanol (3b) (Mixture of diastereomers).
Compound 2b (25.5 g, 0.1 mol) was dissolved in 200 mL of methanol and 3.5 g of 5%-Pd/C was added thereto. The mixture was
stirred under 30 atm of H2 for 96 h at room temperature. Then Pd/C was filtered out and the resulting mixture was concentrated
o
under vacuum. The crude product was distilled under vacuum (1 Torr, 54 C) to give compound 3b. Yield = 64.7% (10.7 g).
The product is a pale liquid. 1H NMR (500 MHz, CDCl3) (mixture of diastereomers): δ = 1.25-1.71 (m, 4H), 1.75 (s, 1H), 1.90-2.02
(m, 4H), 3.73-3.75 (m, 1H), 4.18 (m, 1H), 6.22 (dt, 1H, 2JH-F = 75.9 Hz, J = 7.8 Hz, CF2H).
13C{1H} NMR (125 MHz, CDCl3) (mixture of diastereomers): δ = 28.2, 29.3, 29.8, 31.5, 35.1, 68.2, 72.6, 115.9 (t, 1JC-F = 259.6 Hz,
CF2H).
Anal. calcd for C7H12F2O2: C, 50.60; H, 7.28. Found: C, 50.39; H, 7.25.
Benzyl (2-(difluoromethoxy)ethyl)carbamate (2c).
Compound 1c (6 g, 0.0307 mol, 1 eq) was dissolved in 60 mL of acetonitrile and copper iodide (1.15 g, 0.006 mol, 0.2 eq ) was
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added thereto. The reaction mixture was heated to 50 C and the solution of 2-fluorosulfonyl-2,2-difluoroacetic acid (8.2 g, 0.046
mol, 1.5 eq) in 10 mL of acetonitrile was added dropwise over a period of 30 minutes. The reaction mixture was heated for addi-
tional 30 minutes at 50 oC. Then acetonitrile was evaporated, the rest was dissolved in EtOAc and the insoluble solids were filtered
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out. The resulting solution of EtOAc was evaporated and the crude of 2c was purified by column chromatography (Hexane : EtOAc
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- 4 : 1, Rf = 0.65). Yield = 86% (6.35 g).
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The product is a transparent colorless thick oil. H NMR (400 MHz, CDCl3): δ = 3.40 (br. s, 2H), 3.86 (m, 2H), 5.07 (s, 2H), 5.32
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(br. s, 1H), 6.15 (t, 1H, 2JH-F = 71.4 Hz, CF2H), 7.31 (s, 5H).
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19F NMR (376 MHz, CDCl3): δ = -84.6 (d, 2F, 2JH-F = 79.6 Hz, CF2H).
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13C{1H} NMR (125.7 MHz, CDCl3): δ = 40.2, 62.5, 66.9, 115.8 (t, 1JC-F = 260.0 Hz, CF2H), 127.9, 128.0, 128.4, 136.3, 156.3.
Anal. calcd for C11H13F2NO3: C, 53.88; H, 5.34; N, 5.71. Found: C, 54.00; H, 5.40; N, 5.65.
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2-(Difluoromethoxy)ethanamine (3c).
Compound 2c (6.35g, 0.026 mol, 1 eq) was dissolved in 65 mL of methanol and 0.6 g of 5%-Pd/C was added thereto. The mixture
was stirred under 30 atm of H2 for 12 h at room temperature. Then Pd/C was filtered out and the reaction mixture was concentrated
o
under atmospheric pressure. Product 3c was purified by distilled under vacuum (18 Torr, 35 C). Yield = 10% (0.29 g); the main
reason of low yield is the high volatility of the product.
The product is a transparent colorless liquid. 1H NMR (500 MHz, CDCl3): δ = 1.22 (s, 2H), 2.85 (t, 2H, 3J = 5.0 Hz), 3.78 (t, 2H, 3J
= 5.0 Hz), 6.17 (t, 1H, 2JH-F= 76.3 Hz, CF2H).
19F NMR (376 MHz, CDCl3): δ = -74.1 (d, 2F, 2JH-F= 74.7 Hz).
13C{1H} NMR (125 MHz, CDCl3): δ = 40.8, 65.5, 115.7 (t, 1JC-F = 258.8 Hz, CF2H).
Anal. calcd for C3H7F2NO: C, 32.43; H, 6.35; N, 12.61. Found: C, 32.22; H, 6.28; N, 12.50.
Benzyl (3-(difluoromethoxy)propyl)carbamate (2d).
Compound 1d (60 g, 0.287 mol, 1 eq) was dissolved in 600 mL of acetonitrile and copper iodide (10.95 g, 0.058 mol, 0.2 eq) was
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added thereto. The mixture was heated to 50 C and the solution of 2-fluorosulfonyl-2,2-difluoroacetic acid (61.3 g, 0.344 mol, 1.2
eq) in 100 mL acetonitrile was added dropwise over a period of 45 minutes. The reaction mixture was heated for additional 30
minutes at 50 oC. Then acetonitrile was evaporated, the rest was dissolved in EtOAc and the insoluble solids were filtered out. The
resulting solution of EtOAc was evaporated and the crude of 2d was purified by column chromatography (Hexane : EtOAc - 4 : 1,
Rf=0.65). Yield = 86% (63 g).
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The product is a transparent colorless thick oil. H NMR (400 MHz, CDCl3): δ = 1.85-1.87 (m, 2H), 3.31 (br. s, 2H), 3.91 (m, 2H),
4.99 (br. s, 1H), 5.10 (s, 2H), 6.20 (t, 1H, 2JH-F = 72.4 Hz, CF2H), 7.36 (s, 5H, Ph).
19F NMR (376 MHz, CDCl3): δ = -81.8 (dd, F, 2JH-F = 76.8 Hz), -81.0 (dd, F, 2JH-F = 76.8 Hz).
13C{1H} NMR (125.7 MHz, CDCl3): δ = 29.4, 38.00, 61.4, 66.8, 116.2 (t, 1JC-F = 261.3 Hz, CF2H), 128.2, 128.6, 136.7, 156.7.
Anal. calcd for C12H15F2NO3: C, 55.59; H, 5.83; N, 5.40. Found: C, 55.75; H, 5.87; N, 5.31.
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3-(Difluoromethoxy)propan-1-amine (3d).
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Compound 2d (63 g, 0.243 mol, 1 eq) was dissolved in 300 mL of methanol and 5 g of 5%-Pd/C was added thereto. The mixture
was stirred under 30 atm of H2 for 36 h at room temperature. Then Pd/C was filtered out and the reaction mixture was concentrated
under atmospheric pressure. Product 3d was purified by distilled under vacuum (18 Torr, 43 oC). Yield = 72.6% (22.1 g).
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The product is a transparent colorless liquid. H NMR (400 MHz, CDCl3): δ = 1.42 (s, 2H), 1.77 (quint, 2H, J = 6.5 Hz), 2.81 (t,
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2H, 3J = 7.0 Hz), 3.92 (t, 2H, 3J = 6.0 Hz), 6.18 (t, 1H, 2JH-F = 75.2 Hz, CF2H).
19F NMR (376 MHz, CDCl3): δ = -84.6 (d, 2F, 2JH-F = 76.1 Hz).
13C{1H} NMR (100 MHz, CDCl3): δ = 32.6, 38.6, 61.4, 116.0 (t, 1JC-F = 272.0 Hz, CF2H).
Anal. calcd for C4H9F2NO: C, 38.40; H, 7.25; N, 11.19. Found: C, 38.55; H, 7.19; N, 11.13.
Benzyl (2-hydroxy-2-methylpropyl)carbamate (1e).
Benzyl chloroformate (CbzCl) (94.95 g, 0.557 mol, 1 eq) was added dropwise to the stirred solution of aminoalcohol (49.6 g, 0.557
mol, 1 eq) and potassium carbonate (153.8 g, 1.115 mol, 2 eq) in mixture of THF: water (800:400) at 0oC. Then the reaction mix-
ture was stirred 18 hours at room temperature. After completion of the reaction, THF was rotary evaporated and the rest was ex-
tracted 3 times with DCM. DCM was dried with sodium sulfate and after filtration evaporated. Crude product was purified by flash-
chromatography (EtOAc – petroleum ether 1:3). Yield = 71.9% (89.3 g).
The product is a transparent yellowish oil. 1H NMR (500 MHz, CDCl3): δ = 1.19 (s, 6H), 2.66 (s, 1H), 3.17 (s, 2H), 5.09 (br. s, 2H),
5.45 (s, 1H), 7.33 (br. s, 5H).
13C{1H} NMR (125 MHz, CDCl3): δ = 27.1, 51.8, 67.0, 71.0, 128.2, 128.3, 128.6, 136.6, 157.5.
Anal. calcd for C12H17NO3: C, 64.55; H, 7.67; N, 6.27; O, 21.50. Found: C, 64.34; H, 7.79; N, 6.18.
Benzyl (2-(difluoromethoxy)-2-methylpropyl)carbamate (2e).
Compound 1e (89.3 g, 0.4 mol, 1 eq) was dissolved in 750 mL of acetonitrile and copper iodide (15.25 g, 0.08 mol, 0.2 eq) was
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added thereto. The mixture was heated to 50 C and the solution of 2-fluorosulfonyl-2,2-difluoroacetic acid (106.85g, 0.6 mol, 1.5
eq) in 200 mL acetonitrile was added dropwise over a period of 45 minutes. The reaction mixture was heated for additional 30
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minutes at 50 C. Then acetonitrile was evaporated, the rest was dissolved in EtOAc and the insoluble solid was filtered out. The
resulting solution of EtOAc was evaporated and the crude product 2e was purified by column chromatography (Hexane : EtOAc - 3
: 1, Rf = 0.6). Yield = 6.8% (7.4 g).
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The product is a transparent colorless oil. H NMR (400 MHz, CDCl3): δ = 1.34 (s, 6H), 3.32 (d, 2H, 3J = 6.7 Hz), 5.10 (br. s, 3H),
6.25 (t, 1H, 2JH-F = 76.4 Hz, CF2H), 7.34 (br. s, 5H).
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19F NMR (376 MHz, CDCl3): δ = -79.3 (d, 2F, 2JH-F = 76.5 Hz).
Page 14 of 29
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13C{1H} NMR (125 MHz, CDCl3): δ = 24.0, 50.3, 67.0, 80.3, 115.6 (t, 1JC-F = 250.8 Hz, CF2H), 128.2, 128.3, 128.7, 136.6, 157.0.
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Anal. calcd for C13H17F2NO3: C, 57.14; H, 6.27; N, 5.13. Found: C, 56.98; H, 6.30; N, 5.20.
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2-(Difluoromethoxy)-2-methylpropan-1-amine (3e).
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Compound 2e (7.4 g, 0.027 mol, 1 eq) was dissolved in 100 mL of methanol and 1 g of 5%-Pd/C was added thereto. The mixture
was stirred under 30 atm of H2 for 48 h at room temperature. Then Pd/C was filtered out and the reaction mixture was concentrated
under atmospheric pressure. The product 3e was purified by distillation under vacuum (18 Torr, 32 oC). Yield = 25.2% (0.95 g).
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The product is a transparent colorless liquid. H NMR (500 MHz, CDCl3): δ = 1.33 (s, 6H), 1.37 (s, 2H), 2.73 (s, 2H), 6.35 (t, 1H,
2JH-F = 75.9 Hz, CF2H).
19F NMR (376 MHz, CDCl3): δ = -76.9 (d, 2F, 2JH-F = 77.1 Hz).
13C{1H} NMR (125 MHz, CDCl3): δ = 23.6, 51.6, 80.3, 115.1 (t, 1JC-F = 250.0 Hz, CF2H).
Anal. calcd for C5H11F2NO: C, 43.16; H, 7.97; N, 10.07. Found: C, 43.08; H, 8.02; N, 10.01.
Benzyl trans-2-(Difluoromethoxy)cyclopentyl)carbamate (2f).
Compound 1f (41.6 g, 0.177 mol, 1 eq) was dissolved in 400 mL of acetonitrile and copper iodide (6.7 g, 0.035 mol, 0.2 eq) was
o
added thereto. The mixture was heated to 50 C and the solution of 2-fluorosulfonyl-2,2-difluoroacetic acid (47.2 g, 0.265 mol, 1.5
eq) in 100 mL acetonitrile was added dropwise over a period of 45 minutes. The reaction mixture was heated for additional 30
o
minutes at 50 C. Then acetonitrile was evaporated, the rest was dissolved in EtOAc and the insoluble solid was filtered out. The
resulting solution of EtOAc was evaporated and the crude of 2f was purified by column chromatography (Hexane : EtOAc - 2 : 1,
Rf = 0.6). Yield = 67% (33.6g).
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The product is a transparent colorless thick oil. H NMR (500 MHz, CDCl3): δ = 1.49-2.03 (m, 6H), 3.97 (br. s, 1H), 4.39 (br. s,
1H), 5.10 (br. s, 3H), 6.32 (t, 1H, 2JH-F = 75.2 Hz, CF2H), 7.34 (br. s, 5H).
19F NMR (376 MHz, CDCl3): δ = -81.7 (m, 2F).
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13C{1H} NMR (125 MHz, CDCl3): δ = 29.3, 30.1, 53.1, 57.3, 66.3, 80.1, 116.0 (t, JC-F = 255.9 Hz, CF2H), 127.7, 127.8, 128.1,
136.0, 155.6.
Anal. calcd for C14H17F2NO3: C, 58.94; H, 6.01; N, 4.91. Found: C, 58.81; H, 6.05; N, 4.82.
trans-2-(Difluoromethoxy)cyclopentanamine (3f).
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Compound 2f (33.6 g, 0.1177 mol, 1 eq) was dissolved in 300 mL of methanol and 4 g of 5%-Pd/C was added thereto. The mixture
was stirred under 30 atm of H2 for 36 h at room temperature. Then Pd/C was filtered out and the reaction mixture was concentrated
under vacuum. The product 3f was purified by distillation under vacuum (18 Torr, 67 oC). Yield = 71% (12.6 g).
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The product is a transparent colorless liquid. H NMR (500 MHz, CDCl3): δ = 1.21-1.27 (m, 3H), 1.60-1.66 (m, 3H), 1.88-1.98 (m,
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2H), 3.16-3.20 (m, 1H), 4.01-4.03 (m, 1H), 6.16 (t, 1H, 2JH-F = 76.3 Hz, CF2H).
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19F NMR (376 MHz, CDCl3): δ = -81.5 (dd, F, 2JF-F = 164.6 Hz, 2JH-F = 75.4 Hz), -80.9 (dd, F, 2JF-F = 160.4 Hz, 2JH-F = 76.0 Hz).
13C{1H}NMR (125 MHz, CDCl3): δ = 19.8, 30.0, 31.3, 57.5, 83.5, 115.8 (t, 1JC-F = 257.7 Hz, CF2H).
Anal. calcd for C6H11F2NO: C, 47.68; H, 7.34; N, 9.27. Found: C, 47.80; H, 7.38; N, 9.30.
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Benzyl (3-(difluoromethoxy)cyclopentyl)carbamate (2g) (Mixture of diastereomers).
Compound 1g (35.7 g, 0.152 mol, 1 eq) was dissolved in 350 mL of acetonitrile and copper iodide (5.8 g, 0.03 mol, 0.2 eq) was
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added thereto. The mixture was heated to 50 C and the solution of 2-fluorosulfonyl-2,2-difluoroacetic acid (40.5 g, 0.227 mol, 1.5
eq) in 100 mL of acetonitrile was added dropwise over a period of 45 minutes. The reaction mixture was heated for additional 30
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minutes at 50 C. Next, acetonitrile was evaporated, the rest was dissolved in EtOAc and the insoluble solid was filtered out. The
resulting solution of EtOAc was evaporated and the crude of 2g was purified by column chromatography (Hexane : EtOAc - 2 : 1,
Rf = 0.6). Yield = 83% (36 g).
The product is a transparent colorless oil. 1H NMR (400 MHz, CDCl3) (mixture of diastereomers): δ = 1.66-1.93 (m, 2H), 1.96-2.21
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(m, 4H), 4.20 (br. s, 1H), 4.68 (m, 1H), 5.05 (br. s, 1H), 5.10 (s, 2H), 6.18 (dt, 1H, JH-F = 74.6 Hz, J = 6.7 Hz, CF2H), 7.33-7.36 (m,
5H).
19F NMR (376 MHz, CDCl3): δ = -82.4 - -81.9 (m, 2F).
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13C{1H} NMR (125 MHz, CDCl3) (mixture of diastereomers): δ = 31.1, 31.5, 40.1, 50.5, 53.0, 60.0, 66.3, 115.6 (t, JC-F = 259.6 Hz,
CF2H), 127.8, 128.2, 136.1, 144.5, 155.3.
Anal. calcd for C14H17F2NO3: C, 58.94; H, 6.01; N, 4.91. Found: C, 58.81; H, 6.06; N, 4.87.
3-(Difluoromethoxy)cyclopentanamine (3g) (Mixture of diastereomers).
Compound 2g (36 g, 0.1261 mol, 1 eq) was dissolved in 300 mL of methanol and 4 g of 5%-Pd/C was added thereto. The mixture
was stirred under 30 atm of H2 for 36 h at room temperature. Then Pd/C was filtered out and the reaction mixture was concentrated
under vacuum. Finally, the product 3g was purified by distillation under vacuum (18 Torr, 65 oC). Yield = 66.6% (12.7 g).
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The product is a transparent colorless oil. H NMR (400 MHz, CDCl3) (mixture of diastereomers): δ = 1.24 (s, 2H), 1.42-1.69 (m,
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2H), 1.75-1.87 (m, 2H), 1.91-2.15 (m, 2H), 3.24, 3.48 (quintet, 1H, 3J = 6.0 Hz), 4.50-64 (m, 1H), 6.10 (dt, 1H, JH-F= 75.7 Hz, J =
13.7 Hz, CF2H).
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19F NMR (376 MHz, CDCl3): δ = -82.2- -81.7 (m, 2F).
Page 16 of 29
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13C{1H} NMR (125 MHz, CDCl3) (mixture of diastereomers): δ = 31.2, 31.5, 33.2, 33.8, 42.7, 42.8, 50.5, 51.1, 76.1, 76.2, 115.8 (t,
1JC-F = 258.1 Hz, J = 12.8 Hz).
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Anal. calcd for C6H11F2NO: C, 47.68; H, 7.34; N, 9.27. Found: C, 47.81; H, 7.40; N, 9.23.
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Benzyl (trans-2-(difluoromethoxy)cyclohexyl)carbamate (2h).
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Compound 1h (39 g, 0.156 mol, 1 eq) was dissolved in 350 mL of acetonitrile and copper iodide (6 g, 0.032 mol, 0.2 eq) was added
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thereto. The mixture was heated to 50 C and the solution of 2-fluorosulfonyl-2,2-difluoroacetic acid (41.8 g, 0.235 mol, 1.5 eq) in
100 mL acetonitrile was added dropwise over a period of 45 minutes. The reaction mixture was heated for additional 30 minutes at
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50 C. Then acetonitrile was evaporated, the rest was dissolved in EtOAc and the insoluble solid was filtered out. The resulting
solution of EtOAc was evaporated and the crude 2h was purified by column chromatography (Hexane : EtOAc - 2 : 1, Rf = 0.6).
Yield = 78.6% (36.8 g).
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The product is a transparent colorless thick oil. H NMR (500 MHz, CDCl3): δ = 1.28-1.75 (m, 6H), 2.04-2.08 (m, 2H), 3.56 (br. s,
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1H), 3.92 (m, 1H), 4.97 (br. s, 1H), 5.11 (s, 2H), 6.22 (t, 1H, JH-F = 74.6 Hz, CF2H), 7.30-7.34 (m, 5H).
19F NMR (376 MHz, CDCl3): δ = -81.0 (m, 2F).
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13C{1H} NMR (125 MHz, CDCl3): δ = 23.5, 31.2, 31.9, 53.3, 60.0, 66.2, 75.6, 115.6 (t, JC-F = 257.3 Hz, CF2H), 127.6, 128.1,
136.3, 155.7.
Anal. calcd for C15H19F2NO3: C, 60.19; H, 6.40; N, 4.68. Found: C, 60.23; H, 6.35; N, 4.60.
trans-2-(Difluoromethoxy)cyclohexanamine (3h).
Compound 2h (30 g, 0.1 mol, 1 eq) was dissolved in 300 mL of methanol and 4 g of 5%-Pd/C was added thereto. The mixture was
stirred under 30 atm of H2 for 36 h at room temperature. Then Pd/C was filtered out and the reaction mixture was concentrated
under vacuum. The product 3h was purified by destination under vacuum (18 Torr, 75 oC). Yield = 72.5% (12 g).
The product is a transparent colorless liquid. 1H NMR (500 MHz, CDCl3): δ = 0.96-1.14 (m, 4H), 1.19-1.25 (m, 4H), 1.49-1.57 (m,
2H), 1.73-1.87 (m, 2H), 2.47-2.53 (m, 1H), 3.43-3.48 (m, 1H), 6.14 (t, 1H, 2JH-F = 75.0 Hz, CF2H).
19F NMR (376 MHz, CDCl3): δ = -80.7 (dd, F, 2JF-F = 161.0 Hz, 2JH-F = 70.0 Hz), -79.0 (dd, 2F, 2JF-F = 155.0 Hz, 2JH-F= 75.0 Hz).
13C{1H} NMR (125 MHz, CDCl3): δ = 23.7, 23.8, 31.3, 33.0, 53.6, 81.5, 116.1 (t, 1JC-F = 258.9 Hz, CF2H).
Anal. calcd for C7H13F2NO: C, 50.90; H, 7.93; N, 8.48. Found: C, 50.79; H, 7.96; N, 8.53.
Benzyl (3-(difluoromethoxy)cyclohexyl)carbamate (2i) (Mixture of diastereomers).
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Compound 1i (49.8 g, 0.2 mol, 1 eq) was dissolved in 450 mL of acetonitrile and copper iodide (7.6 g, 0.04 mol, 0.2 eq) was added
thereto. The mixture was heated to 50 oC and the solution of 2-fluorosulfonyl-2,2-difluoroacetic acid (53.4g, 0.3 mol, 1.5 eq) in 100
mL acetonitrile was added dropwise over a period of 45 minutes. The reaction mixture was heated for additional 30 minutes at 50
oC. Then acetonitrile was evaporated, the rest was dissolved in EtOAc and the insoluble solids were filtered out. The resulting solu-
tion of EtOAc was evaporated and the crude of 2i was purified by column chromatography (Hexane : EtOAc - 2 : 1, Rf = 0.6).
Yield = 90.3% (54 g).
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The product is a transparent colorless oil. H NMR (500 MHz, CDCl3) (mixture of diastereomers): δ = 1.16-2.26 (m, 6H), 3.62,
3.90 (br. s, 1H), 4.11, 4.48 (m, 1H), 5.01-5.18 (m, 3H), 5.26 (s, 2H), 6.20 (dt, 1H, 2JH-F = 75.3 Hz, J = 5.4 Hz, CF2H), 7.31-7.34 (m,
5H).
19F NMR (376 MHz, CDCl3): δ = -81.8 (d, F, 2J = 74.0 Hz), -81.0 (d, F, 2J = 74.0 Hz).
13C{1H} NMR (125 MHz, CDCl3) (mixture of diastereomers): δ = 18.9, 20.2, 30.3, 31.5, 37.3, 38.7, 45.5. 47.8, 53.1, 66.1, 70.5,
72.3, 115.9 (dt, 1JC-F = 258.1 Hz, J = 10.6 Hz, CF2H), 127.7, 128.1, 136.3, 155.2.
Anal. calcd for C15H19F2NO3: C, 60.09; H, 6.40; N, 4.68. Found: C, 60.22; H, 6.42; N, 4.76.
3-(Difluoromethoxy)cyclohexanamine (3i) (Mixture of diastereomers).
Compound 2i (30 g, 0.1 mol, 1 eq) was dissolved in 300 mL of methanol and 4 g of 5%-Pd/C was added thereto. The mixture was
stirred under 30 atm of H2 for 36 h at room temperature. Then Pd/C was filtered out and the reaction mixture was concentrated
under vacuum. The product 3i was purified by destination under vacuum (18 Torr, 77 oC). Yield = 74.3% (12.3 g).
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The product is a transparent colorless liquid. H NMR (400 MHz, CDCl3) (mixture of diastereomers): δ = 0.97-1.46 (m, 4H), 1.52
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(s, 2H), 1.49-1.57 (m, 2H), 1.62-2.18 (m, 2H), 2.68-3.11 (m, 1H), 4.02-4.49 (m, 1H), 6.19 (dt, 1H, JH-F = 76.0 Hz, J = 4.6 Hz,
CF2H).
19F NMR (376 MHz, CDCl3): δ = -81.4 - -81.0 (m, 2F).
13C{1H} NMR (100 MHz, CDCl3) (mixture of diastereomers): δ = 19.2, 21.7, 30.8, 32.2, 35.1, 35.3, 40.8, 43.2, 45.4, 49.0, 71.6,
73.0, 116.1, 116.4 (t, 1JH-F = 253.4 Hz, CF2H).
Anal. calcd for C15H19F2NO3: C, 60.19; H, 6.40; F, 12.69; N, 4.68. Found: C, 60.15; H, 6.42; F, 12.65; N, 4.65.
Benzyl ((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)carbamate (1j).
Benzyl chloroformate (CbzCl) (43 g, 0.252 mol, 1 eq) was added dropwise to the stirring solution of aminoalcohol (31.5 g, 0.516
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mol, 2 eq) and potassium carbonate (66.4 g, 0.481 mol, 1.9 eq) in the mixture THF/water (400/200 mL) at 0 C. Afterwards, the
reaction mixture was stirred for additional 18 h at room temperature. Upon completion the THF was evaporated and the rest was
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extracted 3 times with DCM. The organic layer was dried with sodium sulphate, filtered and evaporated to dryness. The crude
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product 1j was purified by flash-chromatography (EtOAc : Petroleum ether - 1 : 3). Yield = 75.1% (47.85 g).
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The product is a white solid, mp = 143-146 oC. H NMR (500 MHz, CDCl3): δ = 1.48-1.51 (m, 2H), 1.59-1.64 (m, 2H), 2.72 (s,
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1H), 3.21 (br. s, 2H), 3.72 (br. s, 4H), 5.09 (s, 2H), 5.41 (br. s, 1H), 7.34 (s, 5H).
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13C{1H} NMR (125 MHz, CDCl3): δ = 35.5, 51.3, 63.7, 67.2, 69.2, 128.2, 128.4, 128.7, 136.4, 157.7.
Anal. calcd for C14H19NO4: C, 63.38; H, 7.22; N, 5.28. Found: C, 63.22; H, 7.27; N, 5.25.
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Benzyl ((4-(difluoromethoxy)tetrahydro-2H-pyran-4-yl)methyl)carbamate (2j).
Compound 1j (47.85 g, 0.18 mol, 1 eq) was dissolved in 450 mL of acetonitrile and copper iodide (6.9 g, 0.036 mol, 0.2 eq) was
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added thereto. The mixture was heated to 50 C and the solution of 2-fluorosulfonyl-2,2-difluoroacetic acid (48.3 g, 0.271 mol, 1.5
eq) in 100 mL acetonitrile was added dropwise over a period of 45 minutes. The reaction mixture was heated for additional 30
minutes at 50 oC. Afterwards, acetonitrile was evaporated, the rest was dissolved in EtOAc and the solid phase was filtered out. The
resulting solution of EtOAc was evaporated and the crude of 2j was purified by column chromatography (EtOAc : Hexane - 3 : 1,
Rf = 0.65). Yield = 12.8% (7.3 g).
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The product is a transparent colorless thick oil. H NMR (500 MHz, CDCl3): δ = 1.70-1.83 (m, 4H), 3.44-3.46 (m, 2H), 3.74 (br. s,
4H), 5.11 (s, 2H), 5.23 (br. s, 1H), 6.36 (t, 1H, 2JH-F = 76.0 Hz, CF2H), 7.35 (s, 5H).
19F NMR (376 MHz, CDCl3): δ = -77.6 (d, 2F, 2JH-F = 77.7 Hz).
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13C{1H} NMR (125 MHz, CDCl3): δ = 33.3, 47.6, 63.3, 67.3, 78.8, 114.7 (t, JC-F= 264.6 Hz, CF2H), 127.7, 127.8, 128.2, 135.8,
156.4.
Anal. calcd for C15H19F2NO4: C, 57.14; H, 6.07; N, 4.44. Found: C, 57.01; H, 6.13; N, 4.41.
(4-(Difluoromethoxy)tetrahydro-2H-pyran-4-yl)methanamine (3j).
Compound 2j (7.3 g, 0.232 mol, 1 eq) was dissolved in 100 mL of methanol and 1 g of 5%-Pd/C was added thereto. The mixture
was stirred under 30 atm of H2 for 48 h at room temperature. Then Pd/C was filtered out and the reaction mixture was concentrated
under vacuum. The product 3j was purified by distillation under vacuum (1 Torr, 44 oC). Yield = 42.9% (1.8 g).
The product is a transparent colorless liquid. 1H NMR (400 MHz, CDCl3): δ = 1.24 (m, 2H), 1.64-1.86 (m, 4H), 2.87 (s, 2H), 3.74-
3.76(m, 4H), 6.54 (t, 1H, 2J = 77.8 Hz, CF2H).
19F NMR (376 MHz, CDCl3): δ = -77.2 (d, 2F, 2JH-F = 84.7 Hz).
13C{1H}NMR (100 MHz, CDCl3): δ = 33.2, 49.3, 63.1, 79.4, 115.2 (t, 1JC-F = 231.2 Hz, CF2H).
Anal. calcd for C7H13F2NO2: C, 46.40; H, 7.23; N, 7.73. Found: C, 46.53; H, 7.27; N, 7.68.
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Benzyl 3-((difluoromethoxy)methyl)pyrrolidine-1-carboxylate (2k).
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Compound 1k (40g, 0.17 mol, 1 eq) was dissolved in 400 mL of acetonitrile and copper iodide (6.5 g, 0.034 mol, 0.2 eq) was added
thereto. The mixture was heated to 50 oC and the solution of 2-fluorosulfonyl-2,2-difluoroacetic acid (45.4g, 0.2549 mol, 1.5 eq) in
100 mL acetonitrile was added dropwise over a period of 45 minutes. The reaction mixture was heated for additional 30 minutes at
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Yield = 80% (39 g).
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The product is a transparent thick oil. H NMR (400 MHz, CDCl3): δ = 1.67 (m, 1H), 1.99 (br. s, 1H), 2.48 (m, 1H, CHpyrrolidine),
3.14-3.37 (m, 2H), 3.49-3.81 (m, 4H), 5.08 (s, 2H), 6.16 (t, 1H, 2JH-F = 74.7 Hz, CF2H), 7.28-7.33 (m, 5H).
19F NMR (376 MHz, CDCl3): δ = -85.0 (d, F, 2JH-F = 74.2 Hz), -84.9 (d, F, 2JH-F = 74.2 Hz).
13C{1H} NMR (125.7 MHz, CDCl3): δ = 27.5, 28.3, 37.6, 38.5, 45.2, 45.6, 48.5, 48.9, 63.3, 66.9, 115.9 (t, JC-F = 262.3 Hz, CF2H),
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128.0, 128.1, 128.6, 137.1, 154.9.
Anal. calcd for C14H17F2NO3: C, 58.99; H, 6.01; N, 4.91. Found: C, 58.93; H, 6.07; N, 4.83.
3-((Difluoromethoxy)methyl)pyrrolidine (3k).
Compound 2k (30 g, 0.105 mol, 1 eq) was dissolved in 150 mL of methanol and 3 g of 5%-Pd/C was added thereto. The mixture
was stirred under 30 atm of H2 for 36 h at room temperature. After completion of the reaction Pd/C was filtered out and the reaction
mixture was concentrated under vacuum. The product 3k was purified by distillation under vacuum (18 Torr, 57 oC). Yield = 68.6%
(10.9 g).
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The product is a transparent colorless liquid. H NMR (400 MHz, CDCl3): δ = 1.15-1.20 (m, 1H), 1.61-1.70 (m, 1H), 1.75 (s, 1H),
2.11-2.18 (m, 1H), 2.41-2.45 (m, 1H), 2.59-2.80 (m, 3H), 3.46-3.56 (m, 2H), 5.95 (t, 1H, 2JH-F = 75.1 Hz, CF2H).
19F NMR (376 MHz, CDCl3): δ = -84.5 (d, 2F, 2JH-F = 77.0 Hz).
13C{1H} NMR (125 MHz, CDCl3): δ = 28.4, 37.8, 46.2, 49.5, 65.5 (t, J = 4.7 Hz), 115.4 (t, 1JC-F = 258.8 Hz, CF2H).
Anal. calcd for C6H11F2NO: C, 47.68; H, 7.34; N, 9.27. Found: C, 47.81; H, 7.29; N, 9.21.
(S)-Benzyl 3-(difluoromethoxy)pyrrolidine-1-carboxylate (2l).
Compound 1l (50g, 0.226 mol, 1 eq) was dissolved in 400 mL of acetonitrile and copper iodide (8.6 g, 0.045 mol, 0.2 eq) was add-
ed thereto. The mixture was heated to 50 oC and the solution of 2-fluorosulfonyl-2,2-difluoroacetic acid (52.3 g, 0.294 mol, 1.3 eq)
in 100 mL acetonitrile was added dropwise over a period of 45 minutes. The reaction mixture was heated for additional 30 minutes
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at 50 C. As next, acetonitrile was evaporated, the rest was dissolved in EtOAc and the insoluble solids were filtered out. The re-
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sulting solution of EtOAc was evaporated and the crude of 2l was purified by column chromatography (Hexane : EtOAc - 7 : 1, Rf
= 0.6). Yield = 84.8% (52 g).
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The product is a transparent colorless oil. 1H NMR (400 MHz, CDCl3, Ethyl acetate inside): δ = 2.06 (br. s, 2H), 3.50-3.58 (m, 4H),
4.79 (m, 1H), 5.11 (s, 2H), 6.20 (t, 1H, 2JH-F = 74.8 Hz, CF2H), 7.28-7.34 (m, 5H).
19F NMR (376 MHz, CDCl3): δ = -83.1 (d, 2F, 2JH-F = 72.5 Hz).
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13C{1H} NMR (125.7 MHz, CDCl3): δ = 31.6, 32.4, 43.6, 44.0, 52.0, 52.3, 66.9, 72.5, 73.1, 115.8 (t, JC-F = 273.0 Hz, CF2H),
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127.9, 128.0, 128.5, 136.8, 154.8.
Anal. calcd for C13H15F2NO3: C, 57.56; H, 5.57; N, 5.16. Found: C, 57.70; H, 5.61; N, 5.11.
(S)-3-(Bifluoromethoxy)pyrrolidine (3l).
Compound 2l (52 g, 0.192 mol, 1 eq) was dissolved in 300 mL of methanol and 5 g of 5%-Pd/C was added thereto. The mixture
was stirred under 30 atm of H2 for 36 h at room temperature. Then Pd/C was filtered out and the reaction mixture was concentrated
under vacuum. The product 3l was purified by distillation under vacuum (18 Torr, 51 oC). Yield = 55.2% (14.5 g).
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The product is a transparent colorless liquid, [α]D = -9.03 (EtOH, c= 72.925 mmol/L). H NMR (400 MHz, CDCl3): δ = 1.87-2.00
(m, 3H), 2.81-3.11 (m, 4H), 4.71 (br. s, 1H), 6.17 (t, 1H, 2JH-F = 74.6 Hz, CF2H).
19F NMR (376 MHz, CDCl3): δ = -82.1 (d, 2F, 2JH-F = 74.1 Hz).
13C{1H} NMR (100 MHz, CDCl3): δ = 33.6, 45.5, 54.0, 75.8, 116.0 (t, 1JC-F = 258.4 Hz, CF2H).
Anal. calcd for C5H9F2NO: C, 43.79; H, 6.62; N, 10.21. Found: C, 43.65; H, 6.65; N, 10.15.
(R)-Benzyl 3-(difluoromethoxy)pyrrolidine-1-carboxylate (2m).
Compound 1m (40 g, 0.181 mol, 1 eq) was dissolved in 400 mL of acetonitrile and copper iodide (6.9 g, 0.036 mol, 0.2 eq) was
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added thereto. The mixture was heated to 50 C and the solution of 2-fluorosulfonyl-2,2-difluoroacetic acid (41.9 g, 0.235 mol, 1.3
eq) in 100 mL acetonitrile was added dropwise over a period of 45 minutes. The reaction mixture was heated for additional 30
minutes at 50 oC. Then acetonitrile was evaporated, the rest was dissolved in EtOAc and the insoluble solids were filtered out. The
resulting solution of EtOAc was evaporated and the crude of 2m was purified by column chromatography (Hexane : EtOAc - 7 : 1,
Rf = 0.6). Yield = 82.6% (40.5 g).
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The product is a transparent colorless oil. H NMR (500 MHz, DMSO-d6): δ = 2.08 (br. s, 2H), 3.55-3.57 (m, 4H), 4.79 (m, 1H),
5.12 (s, 2H), 6.21 (t, 1H, 2JH-F = 74.4 Hz, CF2H), 7.29-7.35 (m, 5H).
19F NMR (376 MHz, CDCl3): δ = -83.0 (d, 2F, 2JH-F = 74.5 Hz).
13C{1H} NMR (125 MHz, CDCl3): δ = 31.2, 31.9, 43.2, 43.5, 51.5, 51.9, 66.5, 72.2, 72.9, 115.5 (t, JC-F = 261.9 Hz, CF2H), 127.5,
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Anal. calcd for C13H15F2NO3: C, 57.56; H, 5.57; N, 5.16. Found: C, 57.41; H, 5.52; N, 5.13.
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(R)-3-(Difluoromethoxy)pyrrolidine (3m).
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Compound 2m (40.5 g, 0.149 mol, 1 eq) was dissolved in 300 mL of methanol and 5 g of 5%-Pd/C was added thereto. The mixture
was stirred under 30 atm of H2 for 36 h at room temperature. Then Pd/C was filtered out and the mixture was concentrated under
vacuum. The product 3m was purified by distillation under vacuum (18 Torr, 51 oC). Yield = 63.5% (13 g).
The product is a transparent colorless liquid, [α]D = +6.31 (EtOH, c= 72.925 mmol/L). 1H NMR (500 MHz, CDCl3): δ = 1.95-2.05
(m, 2H), 2.92-3.14 (m, 3H), 3.43 (s, 2H), 4.75 (s, 1H), 6.20 (t, 1H, 2JH-F = 74.4 Hz).
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19F NMR (376 MHz, CDCl3): δ = -82.3 (d, 2F, 2JH-F = 74.5 Hz).
13C{1H} NMR (125 MHz, CDCl3): δ = 33.3, 45.1, 53.5, 75.4, 116.0 (t, 1JC-F = 295.8 Hz, CF2H).
Anal. calcd for C5H9F2NO: C, 43.79; H, 6.62; N, 10.21. Found: C, 43.72; H, 6.70; N, 10.15.
Benzyl 3-(difluoromethoxy)azetidine-1-carboxylate (2n).
Compound 1n (44.7g, 0.218 mol, 1 eq) was dissolved in 400 mL of acetonitrile and copper iodide (8.2g, 0.043 mol, 0.2 eq) was
added thereto. The mixture was heated to 50 oC and the solution of 2-fluorosulfonyl-2,2-difluoroacetic acid (57.65 g, 0.324 mol, 1.5
eq) in 100 mL acetonitrile was added dropwise over a period of 45 minutes. The reaction mixture was heated for additional 30
minutes at 50 oC. Then acetonitrile was evaporated, the rest was dissolved in EtOAc and the insoluble solid was filtered out. After-
wards, the resulting solution of EtOAc was evaporated and the crude of 2n was purified by column chromatography (Hexane :
EtOAc - 7 : 1, Rf = 0.6). Yield = 86.5% (48 g).
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The product is a transparent yellowish oil. H NMR (400 MHz, CDCl3): δ = 4.06-4.09 (m, 2H), 4.26-4.31 (m, 2H), 4.93-4.94 (m,
1H), 5.11 (s, 2H), 6.24 (t, 1H, 2JH-F = 73.0 Hz, CF2H), 7.36 (br. s, 5H).
19F NMR (376 MHz, CDCl3): δ = -84.9 (d, 2F, 2JH-F = 74.9 Hz).
13C{1H} NMR (125 MHz, CDCl3): δ = 56.8, 62.1 (t, 66.3 J = 6.5 Hz), 66.8, 115.3 (t, 1JC-F = 260.6 Hz, CF2H), 127.9, 128.0, 128.4,
136.3, 156.1.
Anal. calcd for C12H13F2NO3: C, 56.03; H, 5.09; N, 5.45. Found: C, 55.89; H, 5.16; N, 5.39.
3-(Difluoromethoxy)azetidine (3n).
Compound 2n (48 g, 0.187 mol, 1 eq) was dissolved in 300 mL of methanol and 5 g of 5%-Pd/C was added thereto. The mixture
was stirred under 30 atm of H2 for 36 h at room temperature. Then Pd/C was filtered out and the reaction mixture was concentrated
under vacuum. The product 3n was purified by distillation under vacuum (18 Torr, 47 oC). Yield = 53.5% (12.3 g).
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The product is a transparent colorless liquid. 1H NMR (500 MHz, CDCl3): δ = 2.08 (s, 1H), 3.70-3.71 (m, 4H), 4.91 (quintet, 1H, 3J
= 7.0 Hz), 6.21 (t, 1H, 2JH-F = 73.9 Hz, CF2H).
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19F NMR (376 MHz, CDCl3): δ = -84.1 (d, 2F, 2JH-F = 74.4 Hz).
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13C{1H} NMR (125 MHz, CDCl3): δ = 54.3, 66.3, 115.4 (t, 1JC-F = 261.1 Hz, CF2H).
Anal. calcd for C4H7F2NO: C, 39.03; H, 5.73; N, 11.38. Found: C, 39.11; H, 5.79; N, 11.34.
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Benzyl 2-(difluoromethoxy)acetate (2o).
Compound 1o (50.15 g, 0.302 mol, 1 eq) was dissolved in 500 mL of acetonitrile and copper iodide (11.5 g, 0.06 mol, 0.2 eq) was
added thereto. The mixture was heated to 50 oC and the solution of 2-fluorosulfonyl-2,2-difluoroacetic acid (80.65 g, 0.453 mol, 1.5
eq) in 100 mL acetonitrile was added dropwise over a period of 45 minutes. The reaction mixture was heated for additional 30
minutes at 50 oC. Then acetonitrile was evaporated, the rest was dissolved in EtOAc and the solid phase was filtered out. The result-
ing solution of EtOAc was evaporated and the crude of 2o was purified by column chromatography (Hexane : EtOAc - 1 : 7, Rf =
0.7). Yield = 81.2% (53g).
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The product is a transparent colorless liquid. H NMR (400 MHz, CDCl3): δ = 4.44 (s, 2H), 5.21 (s, 2H), 6.34 (t, 1H, JH-F = 73.9
Hz, CF2H), 7.36 (br. s, 5H).
19F NMR (376 MHz, CDCl3): δ = -86:6 (d, 2F, 2JH-F = 73.6 Hz).
13C{1H} NMR (100 MHz, CDCl3): δ = 59.9, 67.3, 115.3 (t, 1JC-F = 272.0 Hz, CF2H), 128.5, 128.8, 134.9, 167.6.
Anal. calcd for C10H10F2O3: C, 55.56; H, 4.66; F, 17.58. Found: C, 55.67; H, 4.71; F, 17.52.
2-(Difluoromethoxy)acetic acid (3o).
Compound 2o (53 g, 0.245 mol, 1 eq) was dissolved in 300 mL of methanol and 7 g of 5%-Pd/C was added thereto. The mixture
was stirred under 30 atm of H2 for 72 h at room temperature. After completion of the reaction Pd/C was filtered out and the reaction
mixture was concentrated under vacuum. The product 3o was dissolved in conc. solution of sodium bicarbonate and the obtained
solution was washed three times with EtOAc. Then the solution was carefully acidified with conc. solution of citric acid and ex-
tracted three times with EtOAc. Combined organic layer was washed twice with brine, dried over magnesium sulphate and concen-
trated under vacuum to give the product 3o. Yield = 64.1% (19.8 g).
o
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The product is a white solid, mp = 46-48 C. H NMR (400 MHz, CDCl3): δ = 4.51 (s, 2H), 6.36 (t, 1H, JH-F = 75.9 Hz, CF2H),
10.62 (br. s, 1H).
19F NMR (376 MHz, CDCl3): δ = -86.8 (d, 2F, 2JH-F = 87.9 Hz).
13C{1H} NMR (100 MHz, CDCl3): δ = 59.1, 115.2 (t, 1JC-F = 285.6 Hz, CF2H), 173.7.
Anal. calcd for C3H4F2O3: C, 28.58; H, 3.20. Found: C, 28.52; H, 3.10.
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1,4-Benzyl 4-(difluoromethoxy)cyclohexanecarboxylate (2p) (Mixture of diastereomers).
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Compound 1p (as a mixture of cis- and trans- isomers 7:3) (42 g, 0.179 mol, 1 eq) was dissolved in 500 mL of acetonitrile and
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copper iodide (6.85 g, 0.36 mol, 0.2 eq) was added thereto. The mixture was heated to 50 C and the solution of 2-fluorosulfonyl-
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2,2-difluoroacetic acid (47.9 g, 0.269 mol, 1.5 eq) in 100 mL acetonitrile was added dropwise over a period of 45 minutes. The
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reaction mixture was heated for additional 30 minutes at 50 C. Then acetonitrile was evaporated, the rest was dissolved in EtOAc
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and the insoluble solids were filtered out. The resulting solution of EtOAc was evaporated and the crude of 2p was purified by
column chromatography (Hexane : EtOAc - 1 : 7, Rf = 0.6). Yield = 73.4% (37.4 g).
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The product is a transparent colorless thick oil. H NMR (400 MHz, CDCl3): δ = 1.47-2.42 (m, 8H), 4.06, 4.33 (s, 1H), 5.10 (br. s,
1H), 5.26 (s, 2H), 6.21 (t, 1H, 2JH-F = 73.9 Hz, CF2H), 7.34 (br. s, 5H).
19F NMR (376 MHz, CDCl3): δ = -83.6 (d, 2F, 2J H-F = 73.7 Hz), -83.1 (d, 2F, 2J H-F = 73.7 Hz).
13C NMR{1H} (100 MHz, DMSO-d6) (mixture of diastereomers): δ = 14.0, 22.1, 23.2, 26.3, 29.3, 31.3, 40.8, 65.5, 74.3, 117.2 (t,
1JC-F = 253.0 Hz, CF2H), 117.4 (t, 1JC-F = 253.0 Hz, CF2H), 127.8, 128.0, 128.5, 136.3, 136.4, 174.2, 174.2.
Anal. calcd for C15H18F2O3: C, 63.37; H, 6.38. Found: C, 63.22; H, 6.43.
1,4-cis-(difluoromethoxy)cyclohexanecarboxylic acid (3p).
Compound 2p (30 g, 0.106 mol, 1 eq) was dissolved in 300 mL of methanol and 6.5 g of 5%-Pd/C was added thereto. The mixture
was stirred under 30 atm of H2 for 72 h at room temperature. Then Pd/C was filtered out and the reaction mixture was concentrated
under vacuum. The crude was dissolved in conc. solution of sodium bicarbonate and the obtained solution was washed three times
with EtOAc. Then the solution was carefully acidified with conc. solution of citric acid and extracted three times with EtOAc.
Combined organic layer was washed twice with brine, dried over magnesium sulphate and concentrated under vacuum and recrys-
tallized from petroleum ether – ethyl acetate (10:1) to give the product 3p. Yield = 60% (12.3 g). Compaund 3p was obtained as a
pure cis-isomer.
The product is a white solid, mp = 117-119 oC. 1H NMR (400 MHz, CDCl3): δ = 1.45-1.61 (m, 4H), 2.07-2.10 (m, 4H), 2.32-2.37
(m, 1H), 4.09 (br. s, 1H), 6.23 (t, 1H, 2JH-F = 74.6 Hz, CF2H), 11.0 (br. s, 1H).
19F NMR (376 MHz, CDCl3): δ = -81.2 (d, 2F, 2JH-F = 76.4 Hz).
13C{1H} NMR (100 MHz, CDCl3): δ = 28.3, 31.6, 41.4, 73.0, 116.2 (t, 1JC-F = 258.4 Hz, CF2H), 181.6.
Anal. calcd for C8H12F2O3: C, 49.48; H, 6.23; F, 19.57. Found: C, 49.33; H, 6.19.
Benzyl 3-(difluoromethoxy)cyclobutanecarboxylate (2q) (Mixture of diastereomers).
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Compound 1q (12.2 g, 0.059 mol, 1 eq) was dissolved in 200 mL of acetonitrile and copper iodide (2.25 g, 0.012 mol, 0.2 eq) was
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added thereto. The mixture was heated to 50 C and the solution of 2-fluorosulfonyl-2,2-difluoroacetic acid (15.8 g, 0.089 mol, 1.5
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eq) in 100 mL acetonitrile was added dropwise over a period of 45 minutes. The reaction mixture was heated for additional 30
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minutes at 50 C. Then acetonitrile was evaporated, the rest was dissolved in EtOAc and the insoluble solid was filtered out. The
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resulting solution of EtOAc was evaporated and the crude of 2q was purified by column chromatography (Hexane : EtOAc - 1 : 7,
Rf = 0.6). Yield = 73.9% (11.2g).
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The product is a transparent colorless oil. 1H NMR (400 MHz, CDCl3) (mixture of diastereomers): δ = 2.40-2.47 (m, 2H), 2.57-2.59
(m, 2H), 2.71-2.75 (m, 1H), 4.51-4.57 (m, 1H), 5.11 (s, 2H), 6.13 (t, 1H, 2JH-F = 74.0 Hz, CF2H), 7.34 (br. s, 5H).
19F NMR (376 MHz, CDCl3): δ = -83.6 (d, 2F, 2JH-F = 72.0 Hz).
13C{1H}NMR (125.7 MHz, CDCl3): δ = 29.9, 34.4, 63.9, 66.7, 115.7 (t, 1JC-F = 259.8 Hz, CF2H), 128.3, 128.4, 128.7, 136.0, 173.7.
Anal. calcd for C13H14F2O3: C, 60.93; H, 5.51. Found: C, 61.03; H, 5.45.
3-(Difluoromethoxy)cyclobutanecarboxylic acid (3q) (Mixture of diastereomers).
Compound 2q (3.5 g, 0.014 mol, 1 eq) was dissolved in 100 mL of methanol and 0.9 g of 5%-Pd/C was added thereto. The mixture
was stirred under 30 atm of H2 for 36 h at room temperature. Then Pd/C was filtered out and the reaction mixture was concentrated
under vacuum. The product 3q was dissolved in conc. solution of sodium bicarbonate and the obtained solution was washed three
times with EtOAc. Then the solution was carefully acidified with conc. solution of citric acid and extracted three times with EtOAc.
Combined organic layer was washed twice with brine, dried over magnesium sulphate and concentrated under vacuum to give the
product 3q. Yield = 57.3% (1.3 g).
The product is a transparent colorless oil. 1H NMR (400 MHz, CDCl3) (mixture of diastereomers): δ = 2.43-2.48 (m, 2H), 2.61-2.63
(m, 2Hbutyl), 2.71-2.76 (m, 1H), 4.55-4.59 (m, 1H), 6.15 (t, 1H, 2JH-F = 74.0 Hz, CF2H), 12.0 (s, 1H).
19F NMR (376 MHz, CDCl3): δ = -83.9 (d, 2F, 2JH-F = 71.6 Hz).
13C{1H} NMR (125 MHz, CDCl3): δ = 29.3, 31.6, 33.7, 63.1 (t, J = 5.6 Hz), 115.1 (t, 1JC-F = 261.2 Hz, CF2H), 181.1.
Anal. calcd for C6H8F2O3: C, 43.38; H, 4.85. Found: C, 43.49; H, 4.91.
Tert-butyl (S)-3-(methoxycarbonyl)-3-(difluoromethoxy)propylcarbamate (2r).
Compound 1r (3.2 g, 0.014 mol, 1 eq) was dissolved in 50 mL of acetonitrile and copper iodide (0.5 g, 0.0026 mol, 0.2 eq) was
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added thereto. The mixture was heated to 50 C and the solution of 2-fluorosulfonyl-2,2-difluoroacetic acid (2.95 g, 0.017 mol, 1.2
eq) in 20 mL acetonitrile was added dropwise over a period of 30 minutes. The reaction mixture was heated for additional 30
minutes at 50 oC. Then acetonitrile was evaporated, the rest was dissolved in EtOAc and the insoluble solids were filtered out. The
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The Journal of Organic Chemistry
resulting solution of EtOAc was evaporated and the crude of 2r was purified by column chromatography (Hexane : EtOAc - 3 : 1,
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Rf = 0.65). Yield = 79.8% (3.1 g).
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The product is a transparent colorless oil, [α]D = -20.2 (MeOH, c= 35.3 mmol/L). H NMR (400 MHz, CDCl3): δ = 1.45 (s, 9H),
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19F NMR (376 MHz, CDCl3): δ = -85.0 (dd, F, 2JF-F = 160.2 Hz, 2JH-F = 73.4 Hz), -83.9 (dd, F, 2JF-F = 158.5 Hz, 2JH-F = 71.8 Hz).
13C{1H} NMR (100 MHz, CDCl3): δ = 27.7, 28.4, 32.4, 52.6, 69.8, 80.0, 115.5 (t, 1JC-F = 272.0 Hz, CF2H), 155.8, 170.7.
Anal. calcd for C11H19F2NO5: C, 46.64; H, 6.76; N, 4.94. Found: C, 46.78; H, 6.70; N, 5.02.
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(2S)-2-(difluoromethoxy)-4-[[(1,1-dimethylethoxy)carbonyl]amino]-butanoic acid (3r).
Compound 2r (1 g, 0.0035 mol, 1 eq) was dissolved in 20 mL of THF and the solution of LiOHxH2O (0.178 g, 0.0042 mol, 1.2 eq)
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in 5 mL of water was added all at once at 0 C. The reaction mixture was heated to room temperature and was stirred for 4 h. Af-
terwards, the reaction mixture was diluted with 25 mL of EtOAc and 20 mL of water. The organic layer was separated, washed
twice with 20 mL of water. Combined water solution was washed once with 25 mL of EtOAc, carefully acidified with 20 mL of
conc. solution of citric acid and extracted three times with 30 mL of EtOAc. Combined organic layer was washed with brine, dried
with magnesium sulphate and concentrated under vacuum to give compound 3r. Yield = 57.9% (0.55 g).
The product is a white solid, mp = 96-99 oC, [α]D = -21.3 (MeOH, c= 37.14 mmol/L). 1H NMR (500 MHz, DMSO-d6): δ = 1.37 (s,
9H), 1.76-1.91 (m, 2H), 3.01 (br. s, 2H), 4.50-4.52 (m, 1H), 6.70 (t, 1H, 2JH-F = 76.0 Hz, CF2H), 6.87 (br. s, 1H), 13.20 (br. s, 1H).
19F NMR (376 MHz, DMSO-d6): δ = -82.3 (d, 2F, 2JH-F = 75.5 Hz).
13C{1H} NMR (125 MHz, DMSO-d6): δ = 28.2, 32.0, 36.0, 71.5, 77.7, 116.9 (t, 1JC-F = 280.5 Hz, CF2H), 155.6, 171.3.
Anal. calcd for C10H17F2NO5: C, 44.61; H, 6.36; N, 5.20. Found: C, 44.72; H, 6.30; N, 5.17.
(2S,4R)-1-tert-butyl 2-methyl 4-(difluoromethoxy)pyrrolidine-1,2-dicarboxylate (2s).
Compound 1s (7.5 g, 0.031 mol, 1 eq) was dissolved in 100 mL of acetonitrile and copper iodide (1.18 g, 0.0062 mol, 0.2 eq) was
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added thereto. The mixture was heated to 50 C and the solution of 2-fluorosulfonyl-2,2-difluoroacetic acid (6.6 g, 0.037 mol, 1.2
eq) in 30 mL acetonitrile was added dropwise over a period of 30 minutes. The reaction mixture was kept for additional 30 minutes
at 50 oC. Then acetonitrile was evaporated, the rest was dissolved in EtOAc and the insoluble solids were filtered out. The resulting
solution of EtOAc was evaporated and the crude of 2s was purified by column chromatography (Hexane : EtOAc - 1 : 4, Rf = 0.7).
Yield = 84.2% (7.4 g).
The product is a transparent colorless oil, [α]D = +20.2 (MeOH, c= 33.87 mmol/L). 1H NMR (500 MHz, CDCl3): δ = 1.46 (s, 3H),
1.51 (s, 6H), 2.21-2.26 (m, 1H), 2.45-2.50 (m, 1H), 3.59-3.78 (m, 2H), 3.79 (s, 3H), 4.39-4.50 (m, 1H), 4.90 (s, 1H), 6.28 (t, 1H,
2JH-F = 74.8 Hz, CF2H).
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19F NMR (376 MHz, CDCl3): δ = -84.0- -82.8 (m, 2F).
Page 26 of 29
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13C{1H} NMR (125 MHz, CDCl3): δ = 28.2, 28.3, 36.2, 37.2, 52.1, 52.3, 71.2, 71.9, 80.5, 115.6 (t, JC-F = 262.8 Hz, CF2H), 153.4,
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154.1, 172.6.
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Anal. calcd for C12H19F2NO5: C, 48.83; H, 6.49; N, 4.74. Found: C, 48.68; H, 6.45; N, 4.69.
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(2S,4R)-1-(tert-butoxycarbonyl)-4-(difluoromethoxy)pyrrolidine-2-carboxylic acid (3s).
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Compound 2s (2.75 g, 0.0093 mol, 1 eq) was dissolved in 40 mL of THF and the solution of LiOHxH2O (0.47 g, 0.0112 mol, 1.2
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eq) in 10 mL of water was added all at once at 0 C. The reaction mixture was heated to room temperature and was stirred for 4 h.
Afterwards, the reaction mixture was diluted with 75 mL of EtOAc and 40 mL of water. The organic layer was separated, washed
twice with 20 mL of water. Combined water solution was washed once with 50 mL of EtOAc, carefully acidified with 35 mL of
conc. solution of citric acid and extracted three times with 40 mL of EtOAc. Combined organic layer was washed with brine, dried
over magnesium sulphate and concentrated under vacuum to give compound 3s. Yield = 61.1% (1.6 g).
The product is a white solid, mp = 70-75 oC, [α]D = -36.6 (EtOH, c= 35.55 mmol/L). 1H NMR (400 MHz, CDCl3): δ = 1.14 (s, 3H),
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1.45 (s, 6H), 2.23-2.47 (m, 2H), 3.56-3.68 (m, 2H), 4.35-4.42 (m, 1H), 4.83 (s, 1Hidine), 6.21 (t, 1H, JH-F = 73.5 Hz, CF2H), 8.70
(br. s, 1H).
19F NMR (376 MHz, CDCl3): δ = -84.0 - -82.9 (m, 2F).
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13C{1H} NMR (125 MHz, CDCl3): δ = 28.2, 28.3, 35.5, 37.2, 52.1, 52.5, 71.2, 71.5, 81.0, 81.8, 115.6 (t, JC-F = 262.6 Hz, CF2H),
153.6, 155.7, 177.8.
Anal. calcd for C11H17F2NO5: C, 46.97; H, 6.09; N, 4.98. Found: C, 47.09; H, 6.15; N, 4.91.
(S)-3-(difluoromethoxy)pyrrolidin-2-one (5).
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Compound 2r (1.5 g, 0.0053 mol, 1 eq) was dissolved in 5 mL of DCM and cooled to 0 C using ice bath. Afterwards trifluoroace-
o
tic acid (5 mL, 0.0653 mol, 12.3 eq) was added all at once. The reaction mixture was stirred for 30 minutes at 0 C and then basified
with conc. solution of potassium carbonate. Obtained suspension was extracted three times with 30 mL of EtOAc. Combined organ-
ic layer was washed with brine, dried with magnesium sulphate and concentrated under vacuum. The crude product was purified by
flash-chromatography (Hexane : EtOAc - 5 : 1) to give compound 5. Yield = 52.5% (0.42 g).
The product is a white solid, mp = 57-61 oC, [α]D = -72.9 (MeOH, c= 66.18 mmol/L ). 1H NMR (400 MHz, CDCl3): δ = 2.16-2.53
(m, 2H), 3.28-3.45 (m, 2H), 4.67 (t, 1H, 3J = 8.1 Hz), 6.48 (t, 1H, 2JH-F = 75.8 Hz), 7.50 (br. s, 1H).
19F NMR (376 MHz, CDCl3): δ = -84.3 (dd, F, 2JH-F = 158.5 Hz, 2JH-F = 75.7 Hz), -83.4 (dd, F, 2JF-F = 158.5 Hz, 2JH-F = 73.5 Hz).
13C{1H} NMR (100 MHz, CDCl3): δ = 28.7, 38.8, 70.8, 115.8 (t, 1JC-F = 258.4 Hz, CF2H), 173.7.
Anal. calcd for C5H7F2NO2: C, 39.74; H, 4.67; N, 9.27. Found: C, 39.80; H, 4.71; N, 9.33.
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Supporting Information
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AUTHOR INFORMATION
Corresponding Authors
* E-mail:
iva108@gmail.com (VI),
viktori@cbmm.lodz.pl (VI),
Pavel.Mykhailiuk@gmail.com (PM),
Pavel.Mykhailiuk@mail.enamine.net (PM).
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