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Green Chemistry
Page 4 of 6
DOI: 10.1039/C7GC02913F
COMMUNICATION
Green Chemistry
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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,
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Kolomeitsev, M. I. Kolycheva and V. P. Kukhar, J. Fluorine
Chem. 2000, 105, 31-33.
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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