10.1002/chem.201704972
Chemistry - A European Journal
FULL PAPER
501 minutes afforded and excellent 13.8 grams (88% yield) of 8
after silica plug filtration. Repeating this setup for 13 resulted in
a similar 11.7 grams (85% yield) isolated material (Scheme 3,
results in brackets).
tested under continuous flow. Finally, the enantioselective
trichloromethylation was investigated under the novel conditions
leading to ee´s as high as 87% favoring a S-configuration.
Finally, we turned our focus towards the enantioselective
installment of the trichloromethyl group onto the Morita-Baylis-
Hillman substrates. In the manuscript published by the group of
Shibata they found that the chiral pool derived catalysts
(DHQ)2PHAL and its pseudo-enantiomer (DHQD)2PHAL
performed with the highest selectivity.[4] As test substrate the L-
menthyl-ester 15 was prepared, allowing direct determination of
diastereomeric excess of the formed products by 1H-NMR
analysis (Scheme 4).
Experimental Section
A detailed description of all general methods, the continuous flow setup,
experimental details including 1H-NMR, 19F-NMR and 13C-NMR for all
reported compounds.
The
following
files
are
available
spectroscopic
free
of
data
charge.
(PDF)
Experimental
details
and
X-ray structure of R - 16 (CIF)
O
CCl3
O
Cl3C
O
O
*
Chiral Cat. (20 mol %)
NaTCA (20 mol %)
O
Acknowledgements
O
16
CHCl3, r.t.
Cl
(DHQ)2PHAL
15
Cl
:
79% (89% de) - R
The authors are deeply appreciative of generous financial
support from the Danish Counsel of Independent Research –
Technology and Production (Grant No. 4148-00031), Danish
National Research Foundation (Grants No. DNRF118 and
DNRF-93), and Aarhus University.
(DHQD) PHAL
2
: 71% (84% de) - S
O
CCl3
O
*
Cl3C
O
O
OMe
Chiral Cat. (20 mol %)
NaTCA (20 mol %)
2
OMe
Cl
(DHQ)2PHAL
CHCl3, r.t.
:
63% (60% ee) - R
14
Cl
(DHQD) PHAL
2
: 71% (87% ee) - S
Keywords: Trichloromethylation • decarboxylation • Continuous
Scheme 4. Enatioselective Decarboxylative Trichloromethylation of
Trichloroacetylated-MBH Derivatives. See Supporting Information for reaction
details.
flow • organocatalysis • Morita-Baylis-Hillman
[1]
[2]
(a) G. W. Gribble, Mar. Drugs. 2015, 13, 4044. (b) M. T. Cabrita, C.
Vale, A. P. Rauter, Mar. Drugs, 2010, 8, 2301. (c) G. W. Gribble, J.
Chem. Educ. 2004, 10, 1441. (d) G. W. Gribble, Acc. Chem. Res. 1998,
31, 141. (e) G. W. Gribble, Prog. Chem. Org. Nat. 1996, 68, 1.
For selected examples on biologically relevant structures carrying the
trichloromethyl group, see: (a) W. Schmidt, T. M. Schulze, G. Brasse, E.
Nagrodzka, M. Maczka, J. Zettel, P. G. Jones, J. Grunenberg, M. Hilker,
U. Trauer-Kizilelma, U. Braun, S. Schulz, Angew. Chem. Int. Ed. 2015,
54, 7698. (b) Q. Xioa, K. Young, A. Zakarian, J. Am. Chem. Soc. 2015,
137, 5907. (c) S. E. Brantley,T. F. Molinski, Org. Lett. 1999, 1, 2165.
(d) G. Helmchen, G. Wegner, Tetrahedron Lett. 1985, 26, 6047. (e) W.
A. Cook, K. H. Cook, W. H. Rueggeberg, Ind. Eng. Chem. 1947, 39,
868.
Subjecting 15 to the in Scheme 2 developed conditions, using
(DHQ)2PHAL and (DHQD)2PHAL as the organocatalysts,
afforded 16 in 78% and 71% isolated yield, respectively.[18]
Recrystallization of the product obtained from the (DHQ)2PHAL
allowed determination of the R-configuration at the installed
stereocenter by X-ray crystallography, which is in accordance
with the findings made by the group of Shibata (see Supporting
Information).[4] Stereo-inversion was obtained in S-16 using
(DHQD)2PHAL with a good 84% de. Next, the same series of
experiments were repeated for methyl ester derivative 14. This
afforded 2 in isolated yields of 63% and 71% for the two
catalysts. Application of (DHQ)2PHAL only revealed a 60% ee of
the R-enantiomer upon UPC analysis.[19] However, selectivity
was restored when the reaction was performed using
(DHQD)2PHAL as the chiral catalyst with a high 87% ee favoring
the S-configuration as determined by UPCC.
[3]
(a) A. A. Dudinov, D. V. Kozhinov, M. M. Krayushkin, Russ. Chem. Bull.
2001, 50, 1259. (b) H. Yu, Y. Xia, J. Wu, Synth. Commun. 2006, 36,
2421. (c) F. G. Menezes, H. Gallardo, C. Zucco, Quim. Nova 2010, 33,
2233. (d) T. S. Snowden, ARKIVOC 2012, 2, 24.
[4]
[5]
T. Nishimine, H. Taira, E. Tokunaga, M. Shiro, N.Shibata, Angew.
Chem. Int. Ed. 2016, 55, 359.
For a few selected articles on enantioselective transformations starting
with achiral MBH-analogues, see: (a) R. Rios, Catal. Sci. Technol. 2012,
2, 267. b) T. Furukawa, T. Nishimine, E. Tokunaga, K. Hasegawa, M.
Shiro, N. Shibata, N. Org. Lett. 2011, 13, 3972. (c) Y. Wei, M. Shi,
Chem. Rev. 2013, 113, 6659.
Conclusions
[6]
[7]
(a) S. Nag, S. Bhowmik, H. M. Gauniyal, S. Batra, Eur. J. Org. Chem.
2010, 4705. (b) D. Majee, S. Biswas, S. M. Mobin, S. Samanta, Org.
Biomol. Chem. 2017, 15, 3286. (c) J. Peng, X. Huang, P.-F. Zheng, Y.-
C. Chen, Org. Lett. 2013, 15, 5534. (d) M. Baidya, G. Y. Remennikov, P.
Mayer, H. Mayr, Chem. Eur. J. 2010, 16, 1365.
In conclusion, a simple protocol for the organocatalyzed
decarboxylative trichloromethylation of Morita-Baylis-Hillman
derivatives has been developed. The reaction was, initially,
studied in batch applying sodium trichloroacetate as the
trichloromehyl anion equivalent leading to moderate yields of the
tested substrates. To ensure efficient formation of a key
intermediate, the reaction was further developed into a two-step
continuous flow protocol starting directly from the Morita-Baylis-
Hillman alcohols. Trichloroacetylation of the alcohol functionality
and subsequent telescoped decarboxylative trichloromethylation
was achieved using simple tributylamine both as base and
organocatalyst. Improved yield were obtained for all entries
For
a few examples on decarboxylative transformations using
trichloroacetates, see: (a) E. P. Ávila, I. F. Souza, A. V. B. Oliveira, V.
Kartnaller, J. Cajaiba, R. O. M. A. Souza, C. C. Corrêa, G. W.
Amarante, RSC Adv. 2016, 6, 108530. (b) A. B. Jensen, A. T. Lindhardt,
J. Org. Chem. 2014, 79, 1174. (c) N. R. Ram, V. K. Soni, J. Org. Chem.
2015, 80, 8922. (d) E. J. Corey, J. O. Link, Y. Shao. Tetrahedron Lett.
1992, 33, 3435.
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