Oxidative Chlorination of Activated Methylene Compounds with Sodium Chloride

Article abstract of DOI:10.1055/s-0033-1340793

An operationally simple protocol for the direct chlorination of 1,3-dicarbonyls (and related compounds such as α-cyano A?ketones) is described. The procedure relies on mild conditions using IBX-SO₃K as the stoichiometric oxidizing agent and the

Full text of DOI:10.1055/s-0033-1340793

LETTER
▌813
letter
Oxidative Chlorination of Activated Methylene Compounds with Sodium
Chloride
1,3-Dicarbonyl Chlorination
Klaus-Daniel Umland,a,b Camilla Mayer,b Stefan F. Kirsch*a
a
Organic Chemistry, Bergische Universität Wuppertal, Gaußstr. 20, 42119 Wuppertal, Germany
Fax +49(202)4392648; E-mail: sfkirsch@uni-wuppertal.de
b
Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany
Received: 19.12.2013; Accepted after revision: 17.01.2014
umpolung of halide reactivity in conjunction with, for ex-
ample, TiCl4 as chloride source, we now report a protocol
for the chlorination of 1,3-dicarbonyls that relies on the
mild oxidation power of IBX–SO3K and the ubiquitous
Abstract: An operationally simple protocol for the direct chlorina-
tion of 1,3-dicarbonyls (and related compounds such as α-cyano
ketones) is described. The procedure relies on mild conditions using
IBX–SO3K as the stoichiometric oxidizing agent and the ubiquitous
sodium chloride. The presence of a phase-transfer catalyst is sup- sodium chloride. The reaction conditions show great func-
portive to obtain good yields in a THF–water mixture.
tional group tolerance, in particular in comparison with
the previously described methods5,6,7b that make use of
Key words: hypervalent iodine, oxidations, chlorides, carbonyls,
nitriles
significantly harsher oxidants. Of primary importance,
our combination of reagents is also capable of chlorinat-
ing α-cyano and α-nitro carbonyl substrates.
Enolizable 1,3-dicarbonyl compounds are ideal substrates
for the electrophilic functionalization.1 For example, the
introduction of a halogen substituent at the activated
α-position is easily achieved when using an electrophilic
halogenating agent. In particular, the use of N-halosuccin-
imides (NXS), alone or in combination with additives, has
developed as a standard strategy for the halogenation of
1,3-dicarbonyls.2–4 Only recently, several methods were
reported that produce the electrophilic halogens through
in situ oxidation of halide equivalents by strong oxi-
dants.5,6 The arguably most effective method of this type
appears to be the one reported by Maulide and co-workers
in 2012 that employs a combination of commercially
available sulfoxides and trimethylsilyl triflate to accom-
plish the formal oxidation of alkali halides and subsequent
dicarbonyl halogenation.7a Also of relevance, Zhou and
co-workers recently reported a convenient method that al-
lows the direct chlorination of ketones by use of ammoni-
um chloride and oxone.7b
When testing the pH dependence of the IBX-mediated
oxygen transfer on 1,3-dicarbonyls,9 we set up an experi-
ment in which β-keto ester 2a was treated with IBX at pH
1 in a 2:1 mixture of aqueous HCl and EtOAc (Scheme 1).
It was found that, in the presence of benzyltriphenylphos-
phonium chloride at 50 °C, the expected tertiary alcohol
3a was formed alongside with the chlorinated product 4a.
Our following optimization studies towards the formation
of tertiary chloride 4a then revealed that IBX–SO3K is
likewise suited for the oxidation. Since IBX–SO3K exhib-
its, in comparison to the IBX parent, enhanced functional
group orthogonality,9,12 it became the chosen oxidant for
the further investigations summarized in Table 1. Good
results with regard to the formation of chloride 4a were
obtained at 50 °C; higher and lower temperatures led to
significantly reduced yield. The solvent screening indicat-
ed that EtOAc and THF are the best choices. Although
both solvents showed a similar performance, we preferred
the use of THF due to the fact that a homogeneous solu-
tion was formed with the chloride-containing aqueous
phase. While the chloride source had little influence, the
addition of a phase-transfer catalyst13 such as benzyltri-
phenylammonium or methyltrioctylammonium chloride
(20 mol%) was of great importance to obtain substantial
conversion of the starting 1,3-dicarbonyl. Further screen-
ing experiments with respect to chloride concentrations,
solvent ratios, and stoichiometry of reagents finally led to
Our recent works focused on the oxidative functionaliza-
tion of enolizable carbonyls with hypervalent iodine com-
pounds, specifically with iodoxybenzoic acid (IBX).8,9 In
the course of these studies, we found that, when using
IBX–SO3K (1) as a mild oxidant and sodium azide in
aqueous DMSO, the pretty chemoselective azidation of
1,3-dicarbonyls is possible.10,11 Given that this azidation
apparently involves nothing more than combining a wa-
ter-soluble IBX derivative and a sodium salt with a nu-
cleophilic anion, we challenged whether this oxidant and
simple alkali halides could actually be used to install hal-
ogens onto the 1,3-dicarbonyl skeleton. While hyperva-
lent iodine compounds such as Koser’s reagent6b or
(diacetoxyiodo)benzene6a,d,f were previously used for the
IBX
BnPh3P+Cl–
O
O
(20 mol%)
pH 1
O
OH
Cl
CO2Et
CO2Et
CO2Et
+
50 °C
0.1 M HCl–EtOAc
(2:1)
SYNLETT 2014, 25, 0813–0816
Advanced online publication: 05.03.2014
2a
3a (38%)
4a (53%)
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340793; Art ID: ST-2013-B1151-L
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Initial experiment setup

814
K.-D. Umland et al.
LETTER
Table 1 Optimization Studies for the Conversion 2a → 4aa
the identification of the following, easy-to-handle, reac-
tion conditions for the oxidative chlorination of 1,3-dicar-
bonyl compounds with sodium chloride: substrate 2,
IBX–SO3K (3 equiv), MeOct3NCl (0.2 equiv), 50 °C, 24
h, NaCl (1 M in H2O)–THF (2:1). Again we would like to
point out that in all our experiments IBX could be used in-
stead of IBX–SO3K to give nearly identical yields.
O
O
O
KO3S
CO2Et
IBX–SO3K (3 equiv)
R4N+Cl– (20 mol%)
Cl
CO2Et
O
I
24 h
MClx (1 M in H2O)–
solvent
HO
IBX–SO3K
(1)
O
2a
4a
(2:1)
Several observations merit note: 1) In contrast to our pre-
vious disclosure on the azidation of 1,3-dicarbonyls,10 the Entry R4N+Cl–
addition of catalytic amounts of sodium iodide was not re-
(°C)
Solvent
MClx
Yield (%)c
b
1
BnPh3NCl
BnPh3NCl
BnPh3NCl
BnPh3NCl
BnPh3NCl
BnPh3NCl
BnPh3NCl
BnPh3NCl
BnPh3NCl
BnPh3NCl
BnPh3NCl
MeOct3NCl
–
23
50
80
50
50
50
50
50
50
50
50
50
50
THF
NaCl
NaCl
NaCl
KCl
no conv.
48
quired. 2) Under our optimized reaction conditions, the
competing formation of the hydroxylated product 3a is
fully suppressed.
2
THF
3
THF
7
With the conditions from entry 12 (Table 1) in hand, we
began to investigate the scope. As shown in Scheme 2, a
great variety of 1,3-diketones and β-keto esters were
smoothly chlorinated in yields ranging from moderate to
high. Both cyclic and acyclic 1,3-dicarbonyl systems un-
derwent clean chlorination with tertiary hydroxyl, acetal,
amide, and alkyne functionalities being tolerated.
When 1,3-dicarbonyls with no additional substituent at
the 2-position were subjected to the reaction conditions,
the dichlorinated product was formed.
4
EtOAc
Et2O
CH2Cl2
DMF
THF
44
5
KCl
19
6
KCl
27
7
KCl
21
8
NH4Cl
CuCl
SrCl2
KCl
46
9
THF
43
10
11
12
13d
THF
32
O
O
O
O
1 (3 equiv)
MeOct3N+Cl– (20 mol%)
Cl
THF
45
R1
R3
R1
R3
THF
THF
NaCl
NaCl
57
R2
R2
NaCl (1 M in H2O)–
THF (2:1)
27
(yields)a
2
4
a Conditions: 2a, 1 (3 equiv), R4NCl (0.2 equiv), 24 h, MClx (1 M in
H2O)–solvent (2:1).
O
O
O
O
O
O
Cl
Cl
Cl
b MClx was added as a 0.1 M solution in H2O.
c Isolated yield after column chromatography.
d No phase-transfer catalyst was added.
OEt
OMe
Ph
4c (86%)
4d (65%)
4b (66%)
O
O
tion pathway while circumventing the dehydrogenation
pathway. To our great delight, the chlorination of α-cyano
carbonyls was indeed possible when employing IBX–SO3K
and 20 mol% of MeOct3NCl in a mixture of aqueous NaCl
and THF. Various acyclic nitriles 5 were successfully
chlorinated to result in the formation of the corresponding
chlorides 6 in acceptable yields (Scheme 3).
O
O
O
O
O
O
Cl
Cl
Cl
O
Ph
OEt
OEt
OEt
Ph
4e (82%)
4f (28%)
4g (62%)
Ph
O
O
OH
O
O
O
O
Cl
Cl
Cl
OEt
OEt
OEt
OMe
Ph
Ph
OBn
4j (44%)b
4h (80%)
4i (46%)b
1 (3 equiv)
O
O
MeOct3N+Cl– (20 mol%)
Cl
O
O
CN
O
O
CN
R1
R1
Cl
R2
NaCl (1 M in H2O)–
THF (2:1)
R2
N
OEt
H
(yields)a
Cl Cl
4l (72%)
5
6
4k (80%)
O
Scheme 2 Scope of the chlorination of 1,3-dicarbonyls. Reactions
6a: R2 = Et (59%)
6b: R2 = Bn (73%)
Cl
a
CN
O
O
were run at 50 °C. Isolated yield after column chromatography.
b Configuration of the stereogenic center was not assigned; product
was obtained as a single diastereomer (dr >95:5).
R2
O
Cl
Cl
CN
CN
We next questioned whether our chlorination protocol
might be mild enough to transfer chlorine onto α-cyano
carbonyl substrates. Since we had previously observed
that this class of substrates undergoes rapid dehydrogena-
tion when treated with IBX in aqueous DMSO,9b our hope
was that the use of IBX–SO3K (1) as the oxidation agent
under phase-transfer conditions might open the chlorina-
Synlett 2014, 25, 813–816
Ph
Ph
6c (78%)
6d (52%)
Scheme 3 Chlorination of α-cyano carbonyls. Reactions were run at
50 °C. a Isolated yield after column chromatography.
© Georg Thieme Verlag Stuttgart · New York

LETTER
1,3-Dicarbonyl Chlorination
815
(e) Tona, M.; Guardiola, M.; Fajari, L.; Messeguer, A.
Tetrahedron 1995, 51, 10041.
Finally, it was briefly studied how α-nitro carbonyls be-
have under the chlorination conditions. The mild chlorina-
tion of those substrates might attract some interest, since
they can be considered as α-amino acid precursors.14 As
exemplary shown for the conversion of 7 into 8, chlorine
can be transferred onto the α-nitro carbonyl skeleton un-
der the reaction conditions in good yields (Scheme 4).
However, further studies on this particular substrate class
are recommended.
(3) (a) Yang, D.; Yan, Y.-L.; Lui, B.; Zhang, C. J. Org. Chem.
2002, 67, 7429. (b) Shibatomi, K.; Soga, Y.; Narayama, A.;
Fujisawa, I.; Iwasa, S. J. Am. Chem. Soc. 2012, 134, 9836.
(c) Tucker, J. W.; Narayanam, J. M. R.; Jagan, M. R.;
Krabbe, S. W.; Stephenson, C. R. J. Org. Lett. 2010, 12, 368.
(d) Curran, D. P.; Chen, M.-H.; Spletzer, E.; Seong, C. M.;
Chang, C.-T. J. Am. Chem. Soc. 1989, 111, 8872.
(4) (a) Atkins, E. F.; Dabbs, S.; Guy, R. G.; Mahomed, A. A.;
Mountford, P. Tetrahedron 1994, 50, 7253. (b) Shi, X.-X.;
Dai, L.-X. J. Org. Chem. 1993, 58, 4596. (c) Nobrega, J. A.;
Goncalves, S. M. C.; Peppe, C. Synth. Commun. 2002, 32,
3711. (d) Meketa, M. L.; Mahajan, Y. R.; Weinreb, S. M.
Tetrahedron Lett. 2005, 46, 4799. (e) Shimakoshi, H.;
Abiru, M.; Izumi, S.-I.; Hisaeda, Y. Chem. Commun. 2009,
6427. (f) Reddy, D. S.; Shibata, N.; Nagai, J.; Nakamura, S.;
Toru, T.; Kanemasa, S. Angew. Chem. Int. Ed. 2008, 47, 164.
(g) De Kimpe, N.; De Cock, W.; Schamp, N. Synthesis 1987,
188. (h) Akula, R.; Galligan, M. J.; Ibrahim, H. Synthesis
2011, 347. (i) Barluenga, J.; Martinez-Gallo, J. M.; Najera,
C.; Yus, M. Synthesis 1986, 678. (j) Bekaert, A.; Barberan,
O.; Gervais, M.; Brion, J.-D. Tetrahedron Lett. 2000, 41,
2903. (k) Jereb, M.; Zupan, M.; Stavber, S. Chem. Commun.
2004, 2614.
(5) (a) Kim, J.-J.; Kweon, D.-H.; Cho, S.-D.; Kim, H.-K.; Lee,
S.-G.; Yoon, Y.-J. Synlett 2006, 194. (b) Khan, A. T.;
Goswami, P.; Choudhury, L. H. Tetrahedron Lett. 2006, 47,
2751. (c) Ranu, B. C.; Adak, L.; Banerjee, S. Aust. J. Chem.
2007, 60, 358. (d) Dieter, R. K.; Nice, L. E.; Velu, S. E.
Tetrahedron Lett. 1996, 37, 2377. (e) For oxidative
chlorination in nature, see: Neumann, C. S.; Fujimori, D. G.;
Walsh, C. T. Chem. Biol. 2008, 15, 99.
(6) For the use of hypervalent iodine reagents as oxidants, see:
(a) Akula, R.; Galligan, M.; Ibrahim, H. Chem. Commun.
2009, 6991. (b) Lee, J. C.; Park, J. Y.; Yoon, S. Y.; Bae, Y.
H.; Lee, S. J. Tetrahedron Lett. 2004, 45, 191. (c) Coats, S.
J.; Wassermann, H. H. Tetrahedron Lett. 1995, 36, 7735.
(d) Braddock, D. C.; Cansell, G.; Hermitage, S. A. Synlett
2004, 461. (e) Ibrahim, H.; Kleinbeck, F.; Togni, A. Helv.
Chim. Acta 2004, 87, 605. (f) Galligan, M. J.; Akula, R.;
Ibrahim, H. Org. Lett. 2014, 16, 600.
(7) (a) Klimczyk, S.; Huang, X.; Farès, C.; Maulide, N. Org.
Biomol. Chem. 2012, 10, 4327. (b) Zhou, Z. S.; Li, L.; He,
X. H. Chin. Chem. Lett. 2012, 23, 1213.
(8) For reviews, see: (a) Duschek, A.; Kirsch, S. F. Angew.
Chem. Int. Ed. 2011, 50, 1524. (b) Satam, V.; Harad, A.;
Rajule, R.; Pati, H. Tetrahedron 2010, 66, 7659.
(9) (a) Kirsch, S. F. J. Org. Chem. 2005, 70, 10210. (b) Crone,
B.; Kirsch, S. F. Chem. Commun. 2006, 764. (c) Duschek,
A.; Kirsch, S. F. Chem. Eur. J. 2009, 15, 10713.
(10) Harschneck, T.; Hummel, S.; Kirsch, S. F.; Klahn, P. Chem.
Eur. J. 2012, 18, 1187.
(11) For related azidation protocols, see inter alia: (a) Magnus,
P.; Hulme, C.; Weber, W. J. Am. Chem. Soc. 1994, 116,
4501. (b) Tohma, H.; Egi, M.; Ohtsubo, M.; Wantanabe, H.;
Takizawa, S.; Kita, Y. Chem. Commun. 1998, 173. (c) Chen,
D.-J.; Chen, Z.-C. Tetrahedron Lett. 2000, 41, 7361.
(d) Magnus, P.; Lacour, J.; Weber, W. Synthesis 1998, 547.
(e) Vita, M. V.; Waser, J. Org. Lett. 2013, 15, 3246.
(12) IBX–SO3K does not react with primary and secondary
alcohols at r.t. Even at 60 °C, alkyl-substituted alcohols
remain untouched while secondary benzylic and propargylic
alcohols are prone to oxidation.
1 (3 equiv)
O
O
Cl
MeOct3N+Cl– (20 mol%)
NO2
Ph
NO2
Ph
EtO
EtO
NaCl (1 M in H2O)
THF (2:1)
7
8
(72%)
Scheme 4 Chlorination of α-nitro carbonyl compound 7. Reaction
was run at 50 °C.
In summary, a novel and operationally simple method for the
direct chlorination of several types of activated methylene
compounds (e.g., 1,3-dicarbonyls, β-keto esters, α-cyano
carbonyls and α-nitro carbonyls) has been reported.15 The
method uses, under metal-free conditions, sodium chloride
as universally available chlorine source and relies on the ox-
idation power of IBX–SO3K that was found to be mild
enough to tolerate a plethora of functional groups.10 Further
oxidative functionalization procedures making use of IBX–
SO3K will be reported in due course.
Acknowledgment
We gratefully acknowledge the opening works of Wolfgang
Heydenreuther at Technische Universität München. Research on
this project was performed at Technische Universität München and
Bergische Universität Wuppertal. This research was supported by
Deutsche Forschungsgemeinschaft (DFG).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Inclu-
ded are copies of the 1H NMR and 13C NMR spectra of compounds
4a–i, 6a–d, and 8.SuInopigfmot
rniSupratpInfigor
m
o
ti
References and Notes
(1) For selected examples, see: (a) Bi, H.-P.; Guo, L.-N.; Duan,
X.-H.; Gou, F.-R.; Huang, S.-H.; Liu, X.-Y.; Liang, Y.-M.
Org. Lett. 2007, 9, 397. (b) Loy, R. N.; Jacobsen, E. N.
J. Am. Chem. Soc. 2009, 131, 2786. (c) Yoo, W.-J.;
Miyamura, H.; Kobayashi, S. J. Am. Chem. Soc. 2011, 133,
3095. (d) Mekonnen, A.; Carlson, R. J. Org. Chem. 2006,
2005. (e) Tereda, M.; Sorimachi, K.; Uraguchi, D. Synlett
2006, 133. (f) Reddy, D. S.; Shibata, N.; Nagai, J.;
Nakamura, S.; Toru, T.; Kanemasa, S. Angew. Chem. Int.
Ed. 2008, 47, 164.
(2) (a) Meshram, H. M.; Reddy, P. N.; Vishnu, P.; Sadashiv, K.;
Yadav, J. S. Tetrahedron Lett. 2006, 47, 991. (b) Mei, Y.;
Bentley, P. A.; Du, J. Tetrahedron Lett. 2008, 49, 3802.
(c) Fletcher, D.; Ablenas, F. J.; Hopkinson, A. C.; Lee-Ruff,
E. Tetrahedron Lett. 1986, 27, 4853. (d) Dechoux, L.; Ebel,
M.; Jung, L.; Stambach, J. F. J. Org. Chem. 1993, 34, 7405.
(13) For leading reviews on phase-transfer catalysis, see:
(a) Novacek, J.; Waser, M. Eur. J. Org. Chem. 2013, 637.
(b) Hashimoto, T.; Maruoka, K. Chem. Rev. 2007, 107,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 813–816

816
K.-D. Umland et al.
LETTER
aqueous phase were separated. The aqueous phase was
extracted with Et2O (3 ×). The combined organic phase was
washed with aq sat. NaHCO3 solution and dried over
Na2SO4. After concentration, the residue was purified by
flash chromatography. Ethyl 1-Chloro-2-
5656. (c) Takashi, O.; Maruoka, K. Angew. Chem. Int. Ed.
2007, 46, 4222.
(14) (a) Ohmatsu, K.; Ito, M.; Kunieda, T.; Ooi, T. Nat. Chem.
2012, 4, 473. (b) Harel, T.; Rozen, S. J. Org. Chem. 2007,
72, 6500. (c) Alvarez-Ibarra, C.; Csakye, A. G.; de la Oliva,
C. G. J. Org. Chem. 2000, 65, 3544. (d) Shirakawa, S.; Ota,
K.; Shogo, S. J.; Maruoka, K. Org. Biomol. Chem. 2012, 10,
5753. (e) Shirakawa, S.; Terao, S. J.; He, R.; Maruoka, K.
Chem. Commun. 2011, 47, 10557. (f) Ji, C.-B.; Liu, Y.-L.;
Cao, Z.-Y.; Zhou, J.; Zhang, Y.-Y. Tetrahedron Lett. 2011,
52, 6118.
(15) General Procedure: The carbonyl substrate (1 equiv) was
dissolved in a mixture of THF and aq 1 M NaCl solution
(1:2, 0.3 M regarding substrate). Then, MeOc3NCl (20
mol%) and IBX–SO3K (3 equiv) were added and the
suspension was heated to 50 °C for 24 h. After the
suspension was cooled to r.t., the organic phase and the
oxocyclohexanecarboxylate (ref. 6a): Following the
general procedure, 4a was obtained from 2a (25.0 mg, 147
μmol) in 57% yield (17.2 mg, 84.0 μmol) as a colorless oil
(flash chromatography with cyclohexane–Et2O, 95:5); Rf
0.35 (cyclohexane–Et2O, 9:1). 1H NMR (400 MHz, CDCl3):
δ = 4.29 (qd, J = 7.1, 0.6 Hz, 2 H), 2.74–2.89 (m, 2 H), 2.39–
2.46 (m, 1 H), 2.09–2.14 (m, 1 H), 1.81–2.00 (m, 3 H), 1.68–
1.80 (m, 1 H), 1.31 (t, J = 7.1 Hz, 3 H). 13C NMR (101 MHz,
CDCl3): δ = 199.8, 167.4, 73.6, 63.0, 39.8, 39.0, 26.8, 22.3,
14.0. HRMS (ESI): m/z [M + Na+] calcd for C9H13ClNaO3 :
+
227.0445; found: 227.0451.
Synlett 2014, 25, 813–816
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