Utilization of fluoroform for difluoromethylation in continuous flow: A concise synthesis of α-difluoromethyl-amino acids

Article abstract of DOI:10.1039/c7gc02913f

Fluoroform (CHF₃) can be considered as an ideal reagent for difluoromethylation reactions. However, due to the low reactivity of fluoroform, only very few applications have been reported so far. Herein we report a continuous flow difluoromethyl

Full text of DOI:10.1039/c7gc02913f

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Utilization of fluoroform for difluoromethylation in continuous
flow: a concise synthesis of α-difluoromethyl-amino acids†
Manuel Köckinger,a Tanja Ciaglia,a Michael Bersier,b Paul Hanselmann,b Bernhard Gutmann,*ac and
C. Oliver Kappe*ac
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Production of CHF2Cl:
CHF2Cl:
Fluoroform (CHF3) can be considered as an ideal reagent for
difluoromethylation reactions. However, due to the low reactivity
of fluoroform, only very few applications have been reported so
far. Herein we report a continuous flow difluoromethylation
protocol on sp3 carbons employing fluoroform as reagent. The
protocol is applicable for the direct Cα-difluoromethylation of
protected α-amino acids, and enables a highly atom efficient
synthesis of the active pharmaceutical ingredient eflornithine.
- potent greenhouse gas
(~1800 times higher than CO2)
- ozone depleter
CHCl3 + HF
CHF2Cl + CHF3
side-product
20,000-25,000 t/a (ref 4e)
applications are phased out
-
(Montreal Protocol)
Difluoromethylation with CHF2Cl:
B-
[CF2Cl-]
CHF2Cl
CHF3:
- potent greenhouse gas
(~15 000 times higher than CO2)
- needs capturing from emissions
1. :CF2; 2. H+
B-
little to no practical use ->
incineration
-
The difluoromethyl group is found in an increasing array of
pharmaceutical and agrochemical products.1 Not surprisingly,
therefore, significant efforts have been devoted towards the
development of novel protocols for the introduction of the
CHF2-moiety into organic molecules.2 In addition to well-
established methods based on deoxyfluorination of aldehydes,
various methods for direct difluoromethylation have recently
become available.2 Among the cheapest and most versatile
reagents for direct CHF2-transfer is chlorodifluoromethane
(CHF2Cl, Freon 22). Chlorodifluoromethane is produced on a
massive scale, particularly for the production of
fluoropolymers, and it is available at relatively little cost (Fig.
1). With sufficiently strong bases, CHF2Cl can be deprotonated.
The so-formed carbanion, chlorodifluoromethanide (CF2Cl-),
immediately loses chloride to generate an electrophilic singlet
X-H
X-
CHF2
X
Fig. 1 CHF3 is a large-volume by-product in CHF2Cl synthesis.
limited and expensive.
A
plethora of alternative
difluoromethane-sources have been developed in recent
years, including TMSCF2Br, (EtO)2POCF2Br, PhCOCF2Cl and
CHF2OTf.2 Although these reagents cover the needs of
chemists for difluoromethlyation on laboratory scale, their
high cost, low atom economy and limited commercial
availability prohibits their usage in an industrial setting.
The most attractive CF3- and CHF2- source is fluoroform
(CHF3, Freon 23). Fluoroform is generated as a large-volume
waste-product during chlorodifluoromethane synthesis (Fig. 1).
It is a nontoxic and ozone-friendly gas with a boiling point of -
82 °C. Since fluoroform has an extraordinary global warming
potential (14,800 times higher than carbon dioxide over a 100-
year period),3 discharge into the environment is restricted by
the Kyoto Protocol. As a consequence, fluoroform needs to be
destroyed or, alternatively, captured and used as a feedstock
for manufacturing. The latter option, though vastly preferable,
is difficult to realize due to the extraordinarily low reactivity of
fluoroform. Only very recently have the first synthetically
relevant transformations involving fluoroform started to
emerge.4 Most relevant for the present work is a series of
seminal publications from the laboratories of Mikami.5-7
Mikami and co-workers have shown that fluoroform can be
utilized for the direct difluoromethylation of a variety of
substrates utilizing strong lithium bases (lithium
diisopropylamide (LDA) or lithium hexamethyldisilazide
difluorocarbene (CF2Cl-
→ CF2 +
Cl-). The short-lived
difluorocarbene can then be trapped with a suitably reactive
nucleophilic species to produce the difluoromethylated
product (Fig. 1).2 This reaction has been shown to proceed
successfully with
a range of NH-, OH- and CH-acidic
compounds.2 However, CHF2Cl is a strong ozone depleting gas
and it is controlled under the Montreal Protocol. As a
consequence, production and usage has become increasingly
(LiHMDS)).5-7
In
addition
to
Mikami’s
work,
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difluoromethylation reactions of alkynes with CHF3 and 1a as substrate, no product was formed with nBuLi, LDA or
tBuOK,8 as well as difluoromethylation of phenols and tBuOK as base (entries 1 to 5 in Table 1). Furthermore,
malonates with aqueous KOH,9 have been described by attempts to reproduce the results reported by Dolbier and co-
Shibata and Dolbier, respectively. The mechanism of the workers failed in our hands.9 According to Dolbier’s procedure,
difluoromethylation reaction is believed to resemble that of the phenylmalonate 1a is stirred in aqueous KOH for 30 min at
the corresponding reaction with CHF2Cl.8-10 An electrophilic room temperature. MeCN or dioxane is then added and
singlet difluorocarbene is formed by deprotonation of CHF3 fluoroform is bubbled through the solution.9 Our experiments
and subsequent rapid α-elimination of fluoride. The under these reaction conditions did not yield any
difluorocarbene then reacts with the anion of the substrate difluoromethylated product (entry
7 in Table 1). Small
(Fig. 1). amounts of the desired product were formed using LiHMDS as
The main objective of the present work was to establish a base (entry 6 in Table 1). Mikami and co-workers have already
scalable, continuous flow synthesis route to Cα-difluoromethyl shown that fluoroform in combination with LiHMDS can be
amino acids using fluoroform as the reagent (Scheme 1). Cα- utilized for the direct difluoromethylation of cyclic amides,
Difluoromethyl amino acids are potent and selective cyclic and open esters, and certain simple malonates.5
irreversible inhibitors of their respective α-amino acid According to the authors, the reaction proceeds best with 2
decarboxylases.11 Representatives of this class of compounds equiv of base and 5 equiv of CHF3. Reaction times of 6 to 48 h
exhibit a broad spectrum of biological activities, such as at reaction temperatures of 0 to 25 °C were needed to provide
antibacterial, antihypertensive, cancerostatic, and cytotoxic the desired products in good yields.5
activity.11 Currently only D,L-α-difluoromethylornithine
a
Table 1 Difluoromethylation of diethyl phenylmalonate 1a with CHF3
(eflornithine), an inhibitor of the ornithine decarboxylase, is in
medical use (Scheme 1). Eflornithine is explored as anticancer
agent, and it is in clinical use for the treatment of African
sleeping disease as well as of Pneumocystis carinii pneumonia,
the most frequent opportunistic infection associated with the
acquired immune deficiency syndrome (AIDS).11 It is on the
World Health Organization's Model List of Essential Medicines.
Two different strategies can be employed for the generation of
Cα-difluoromethyl amino acids: (i) construction of the amino
acid from fluorine-containing building blocks (e.g. α-
difluoromethyl malonates),12,13 or (ii) direct substitution of the
α-hydrogen of amino acids with a CHF2 moiety (Scheme 1).14
The direct Cα-difluoromethylation of Schiff base-protected α-
amino acid methyl esters with CHF2Cl as the reagent has been
demonstrated by Bey and others.14 α-Difluoromethylation of
protected amino acids with CHF3 is currently not reported.
Indeed, the protocol described herein is, to the best of our
knowledge, the first example where fluoroform is utilized for
the preparation of a pharmaceutical end-product.
1. base, THF
T1,t1
2. CHF3 (balloon)
T2,t2
Ph
CO2Et
Ph
CO2Et
F2HC
CO2Et
1a
CO2Et
2a
base
t1
T1
t2
T2
conv
(%)b
sel
(equiv)
(min)
(°C)
(min)
(°C)
(%)b
1
2
tBuOK (3)
5
5
25
25
25
25
-80
25
25
60
60
5
25
25
25
25
-80
25
25
28
4
0
0
tBuOLi (3)
LDA (2)
3
5
0
0
4
nBuLi (2)
nBuLi (2)
LiHMDS (2)
KOH (15)
5
5
0
0
5
5
5
0
0
6
5
60
120
2
100
0
7c
30
32d
a Conditions: 0.5 mmol diethyl phenylmalonate 1a in 0.5 mL THF, base, CHF3
(balloon). b analyzed by HPLC-UV/VIS at 215 nm. c method B in ref 9a. d 20%
ethyl phenylacetate (by hydrolysis and decarboxylation).
Encouraged by this result, we were keen to develop a
continuous flow protocol for this reaction. Continuous
processing techniques have had a significant impact in the
development of more sustainable manufacturing routes for
several pharmaceuticals.15-18 For gas-liquid reactions several
specific advantages exist: high pressures operation and fast
gas-liquid mass transfer enhances availability of the gaseous
reagent in the liquid phase.16,17 In addition, the gaseous
reagent can be dosed into the liquid phase with precise
stoichiometry using mass flow controllers.16,17 Our initial flow
setup consisted of two continuous syringe pumps to introduce
(i) a 0.5 M solution of substrate in THF (Feed A, Table 2), and
(ii) a commercial solution of LiHMDS (Feed B, Table 2). The two
feeds were mixed in a Y-shaped connector in a cooling bath.
The substrate is deprotonated in a 2 mL residence loop
(reactor 1), before the mixture is combined with fluoroform in
Scheme 1 Synthesis of D,L-Cα-difluoromethyl amino acids.
First preliminary batch experiments were performed with
diethyl phenylmalonate (1a) as model substrate (Table 1). For
these reactions the malonate was dissolved in the desired
solvent and the base was added. After stirring the mixture for
a few minutes at the indicated temperatures (t1,T1 in Table 1),
fluoroform was slowly passed through the reaction mixture
under vigorous stirring (t2,T2 in Table 1). Using phenylmalonate
2 | J. Name., 2012, 00, 1-3
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a second Y-shaped connector in a second cooling bath. The water. The analytically pure compounds were isolated by
flow rate of the fluoroform stream was controlled using a preparative thin-layer chromatography (TLC). The yield for the
calibrated mass flow controller (MFC). The combined mixture diethyl methylmalonate 2e was the same as previously
then went through a second cooled residence loop (reactor 2) reported for the batch protocol, even though the reaction time
and left the flow system through a third residence loop at for the present procedure was significantly shorter (20 min vs
room temperature (reactor 3) and an adjustable back pressure 20 h for the batch procedure).5 The yield for product 2c was
regulator. With pressures of ~5 bar and temperatures below ~ lower than that reported for the batch procedure (39% vs 78%
25 °C for reactor 2, the fluoroform dissolved completely in the according 19F-NMR).5 The other difluoromethylated
liquid feed. At higher temperatures at this pressure, distinct compounds prepared in this work have not been previously
gas-liquid segments were formed. The processed reaction reported.
mixture was finally collected in a quench solution of aqueous
As mentioned in the introduction, the synthesized α-
HCl/Et2O and the organic phase was analyzed by GC-FID and difluoromethyl malonates can be converted to the respective
19F-NMR. Methyl diphenylacetate 1b was used as the model α-difluoromethyl amino acids in a multi-step transformation
substrate for the initial optimization. With flow rates of 300 (Scheme 1).12,13 However, since a direct difluoromethylation of
µL/min for Feed A, 200 µL/min for Feed B and 8.3 mL/min for natural α-amino acids has clear advantages, reactions with
fluoroform,
a
stoichiometry
of
1:1.3:2.5
for Schiff base-protected α-amino acid methyl esters were
substrate/LiHMDS/CHF3 and a total residence time of ~20 min investigated.14 The N-benzylidene-protected α-amino acid
was obtained. The flow reactions clearly revealed that the methyl esters were readily available from the parent amino
conversion increased with decreasing temperature and esters using literature procedures (for experimental details,
increasing pressure (Table 2). Also the selectivity increased see ESI†).14 Gratifyingly, subjecting the N-benzylidene-
slightly with decreasing temperatures (Table 2). As already protected α-amino acid methyl esters 1g to 1k to the general
observed by Mikami and co-workers, the best results are reaction conditions resulted in >95% conversion to the desired
obtained with 2 equiv of base (see Table S1 in the ESI†). Also, product. Indeed, the reaction was remarkably clean with only
for fluoroform, 2 to 3 equiv were identified as the ideal one CHF2-moiety (two doublets of doublets) detectable in the
amount.
19F-NMR spectra of the crude reaction mixtures.
Difluoromethylation on the imine carbon, a side reaction
typically encountered in reactions with CHF2Cl as reagent, was
not observed.14b Due to the instability of the Schiff base to
hydrolysis, isolation of the intermediate products was not
attempted. Instead, the N-benzylidene- and the O-methyl-
protecting group were directly removed by heating the crude
Table 2 Difluoromethylation of methyl diphenylacetate 1b under flow conditionsa
T
p
conv
(%)b
sel
(%)b
(°C)
(bar)
1
2
3
4
5
40
25
5
5
63
65
82
86
92
81
80
88
91
91
-10
-15
-15
5
10
12
a
Conditions: Feed A: 0.5 M diethyl phenylmalonate 1b in THF; Feed B: 1 M
LiHMDS in THF; with flow rates for Feed A/Feed B/CHF3 = 0.30 : 0.20 : 8.3
mL/min, respectively, the following conditions were obtained: LiHMDS (1.33
b
equiv); CHF3 (2.5 equiv). analyzed by GC-FID. For a detailed description of the
esperiments see the ESI†.
The general reaction conditions were suitable for a variety of
substrates (Fig. 2). Malonates with sterically benign alkyl
groups in the α-position performed particularly well (1d to 1f
in Fig. 2), while the phenyl derivative 1a resulted in low
conversion. The reaction was remarkably clean, with
unreacted substrate and tris(trimethylsilyl)amine being the
only contamination in the crude mixture after washing with
a
Fig.
2
Continuous flow Cα-difluoromethylation with fluoroform.
19F-NMR yields
b
(trifluorotoluene as internal standard); isolated yields (TLC) in parentheses. isolation
c
was not attempted. isolated yields after
2
steps (Cα-difluoromethylation and
hydrolysis of the N-benzylidene- and the O-methyl- protecting groups). See
experimental details see the ESI†.
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2
3
For recent reviews, see: (a) C. Ni and J. Hu, Synthesis 2014,
46, 842-863; (b) D. E. Yerien, S. Barata-Vallejo and A. Postigo,
Chem. Eur. J. 2017, 23, 14676 –14701.
product in 6N HCl in a microwave batch autoclave (150 °C for
45 min). The released benzaldehyde was removed by
extracting with ether and the aqueous phase was
concentrated. After recrystallization from MeOH/EtOH, the Cα-
difluoromethyl amino acids were obtained as their
monohydrochloride salts (dihydrochloride salt for product 2k).
As expected, [α]D20 measurements on product 2h revealed that
the chirality of the substrate was lost. The yields were above
70% for all tested amino acids over the two reaction steps, i.e.
difluoromethylation and deprotection (Fig. 2). Importantly,
eflornithine (2g) was isolated in 76% yield after the two
reaction steps. The yield of eflornithine for the present
chromatography-free method is significantly higher than that
previously reported for the less desirable process based on
chlorodifluoromethan (37% to 40%).14d,e
P. Forster, V. Ramaswamy, P. Artaxo, T. Berntsen, R. Betts,
D.W. Fahey, J. Haywood, J. Lean, D. C. Lowe, G. Myhre, J.
Nganga, R. Prinn, G. Raga, M. Schulz and R. Van Dorland,
Changes in atmospheric constituents and in radiative forcing.
In Climate change 2007: The Physical Science Base, Fourth
Assessment Report of the Intergovernmental Panel on
Climate Change, (Eds.: S. Soloman, D. Qin, M. Manning, Z.
Chen, M. Marquis, K. B. Averyt, M. Tignor, H. L. Miller),
Cambridge University Press: Cambridge, 2007.
For selected publications see: (a) T. Shono, M. Ishifune, T.
Okada and S. Kashimura, J. Org. Chem. 1991, 56, 2-4; (b) B.
Folléas, I. Marek, J.-F. Normant and L. Saint-Jalmes,
Tetrahedron, 2000, 56, 275-283; (c) J. Russell and N. Roques,
Tetrahedron, 1998, 54, 13771-13782; (d) A. Zanardi, M. A.
Novikov, E. Martin, J. Benet-Buchholz and V. V. Grushin, J.
Am. Chem. Soc., 2011, 133, 20901-20913; (e) P. Novák, A.
4
It should be noted that the process described herein
consumes only two of the three introduced equivalents of
fluoroform. For large scale applications, separation of
fluoroform from the processed solution and recycling needs to
Lishchynskyi, and V. V. Grushin, J. Am. Chem. Soc. 2012, 134
,
16167−16170; (f) G. K. S. Prakash, P. V. Jog, P. T. D. Batamack
and G. A. Olah, Science, 2012, 338, 1324-1327.
T. Iida, R. Hashimoto, K. Aikawa, S. Ito and K. Mikami, Angew.
Chem. Int. Ed. 2012, 51, 9535-9538.
K. Aikawa, K. Maruyama, K. Honda and K. Mikami, Org. Lett.
2015, 17, 4882−4885.
5
6
7
8
9
be
considered.19
Further
optimization
of
the
difluoromethylation process, in particular with regard to
stoichiometry and reaction time, is ongoing in our laboratories
and will be reported in due course.
K. Aikawa, K. Maruyama, J. Nitta, R. Hashimoto and K.
Mikami, Org. Lett. 2016, 18, 3354-3357.
S. Okusu, E. Tokunaga and N. Shibata, Org. Lett. 2015, 17
3802-3805.
(a) C. S. Thomoson and W. R. Dolbier, J. Org. Chem. 2013, 78
,
Conclusions
,
8904-8908; (b) C. S. Thomoson, L. Wang and W. R. Dolbier, J.
Fluorine Chem. 2014, 168, 34-39.
A gas-liquid continuous flow difluoromethylation protocol
employing fluoroform as reagent was reported. Fluoroform, a
byproduct of Teflon manufacture with little current synthetic
value, is the most attractive reagent for difluoromethylation
reactions. The continuous flow process allows this reaction to
be performed within reaction times of 20 min with 2 equiv of
base and 3 equiv of fluoroform. Importantly, the protocol
allows the direct Cα-difluoromethylation of protected α-amino
acids. These compounds are highly selective and potent
inhibitors of pyridoxal phosphate-dependent decarboxylases.
The starting materials are conveniently derived from the
commercially available α-amino acid methyl esters, and the
final products are obtained in excellent purity and yield after
simple hydrolysis and precipitation. The developed process
appears to be especially appealing for industrial applications,
where atom economy, sustainability, reagent cost and reagent
availability are important factors.
10 For an alternative mechanistic hypothesis suggested by
Mikami and co-workers, see ref. 5.
11 For a review on the synthesis of Cα-difluoromethyl amino
acids, see: (a) X.-L. Qiu, W.-D. Meng and F.-L. Qing,
Tetrahedron, 2004, 60, 6711-6745; (b) R. Smits, C. D.
Cadicamo, K. Burger and B. Koksch, Chem. Soc. Rev., 2008,
37, 1727-1739.
12 B. Gutmann, P. Hanselmann, M. Bersier, D. Roberge and C.
O. Kappe, J. Flow Chem. 2017, 7, 46-51.
13 (a) P. Bey, F. Gerhart, V. V. Dorsselaer and C. Danzin, J. Med.
Chem. 1983, 26, 1551-1556; (b) T. Tsushima, K. Kawada, S.
Iahihara, N. Uchida, O. Shiratori, J. Higaki and M. Hirata,
Tetrahedron, 1988, 44, 5375-5387; (c) D. Schirlin, F. Gerhart,
J. M. Hornsperger, M. Hamon, J. Wagner and M. J. Jungs, J.
Med. Chem. 1988, 31, 30-36; (d) S. N. Osipov, A. S. Golubev,
N. Sewald and K. Burger, Tetrahedron Lett. 1979, 38, 5965-
5966; (e) T. Tsushima and K. Kawada, Tetrahedron Lett. 1985,
26, 2445-2448; (f) P. Bey and D. Schirlin, Tetrahedron Lett.
1978, 52, 5225-5228; (g) S. N. Osipov, A. S. Golubev, N.
Sewald, T. Michel, A. F. Kolomiets, A. V. Fokin and K. Burger,
J. Org. Chem. 1996, 61, 7521-7528; (h) I. I. Gerus, A. A.
Kolomeitsev, M. I. Kolycheva and V. P. Kukhar, J. Fluorine
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Conflicts of interest
14 (a) P. Bey and J. P. Vevert, Tetrahedron Lett. 1978, 14, 1215-
1218; (b) P. Bey, J. B. Ducep and D. Schirlin, Tetrahedron
Lett., 1984, 25, 5657-5660; (c) P. Bey, J.-P. Vevert, V. V.
Dorsselaer and M. Kolb, J. Org. Chem., 1979, 44, 2732-2742;
(d) M. Seki, M. Suzuki and K. Matsumoto, Biosci. Biotech.
Biochem., 1993, 57, 1024-1025; (e) P. Bey and M. Jung
(Merrell Toraude et Compagnie), Method of treating benign
prostatic hypertrophy, US4330559, 1982; e) P. Bey and M.
Jung (Merrell Toraude et Compagnie), 2-(Difluoromethyl)-
2,5-diaminopentanoic acid, US 4413141, 1983.
There are no conflicts to declare.
Notes and references
1
(a) Fluorine-containing Amino Acids, Synthesis and
Properties, ed. V. P. Kukhar and V. A. Soloshonok, Wiley &
Sons, Chichester, 1995; (b) Organofluorine Compounds in
Medicinal Chemistry & Biomedical Applications (Eds.: R.
Filler, Y. Kobayashi, L. M. Yagupolskii), Elsevier, Amsterdam,
1993.
15 D. Dallinger and C. O. Kappe, Curr. Opin. Green Sust. Chem.
2017,
7
, 6-12 and references cited therein.
4 | J. Name., 2012, 00, 1-3
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16 (a) B. Gutmann, D. Cantillo and C. O. Kappe, Angew. Chem.
Int. Ed., 2015, 54, 6688-6728; (b) M. Movsisyan, E. I. P.;
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18 For a recent protocol for introducing CF2 using
photochemistry in continuous flow, see: X.-J. Wei, W. Boon,
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19 Methods for continuous flow gas-liquid separation are well
developed. For previous reports on continuous inline gas
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Green Chemistry
Page 6 of 6
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DOI: 10.1039/C7GC02913F
TOC Entry
Difluromethylated esters, malonates and amino acids (including the drug Elfornithine) are
obtained by a gas-liquid continuous flow protocol employing the abundant waste product
fluoroform as atom-efficient reagent.