A direct copper-promoted three-component entry to trifluoromethylketoximes

Article abstract of DOI:10.1021/ol500203m

A new copper-promoted three-component method for constructing ketoximes has been developed. This transformation can be achieved using indoles/pyrroles with the in situ generated 2,2,2-trifluorodiazoethane and nitrite species under mild conditions, thus offering a direct pathway to (E)-3-indolyl/2-pyrrolyl trifluoromethylketoximes.

Full text of DOI:10.1021/ol500203m

Letter
pubs.acs.org/OrgLett
A Direct Copper-Promoted Three-Component Entry to
Trifluoromethylketoximes
Shuai Wang, Jing Nie, Yan Zheng, and Jun-An Ma*
Department of Chemistry, Key Laboratory of Systems Bioengineering (the Ministry of Education), Tianjin University, and
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, P. R. of China
S
* Supporting Information
ABSTRACT: A new copper-promoted three-component method
for constructing ketoximes has been developed. This transformation
can be achieved using indoles/pyrroles with the in situ generated
2,2,2-trifluorodiazoethane and nitrite species under mild conditions,
thus offering a direct pathway to (E)-3-indolyl/2-pyrrolyl trifluoro-
methylketoximes.
etoximes are common structural motifs in both chemical
and biological contexts.1 Among them are Cyclo-
three-component reaction in one pot for ketoxime construction
has not been reported to date. Through our attempts to use
2,2,2-trifluorodiazoethane as a C2-synthon for the preparation
of organofluorines,10 we have discovered a new three-
component route to trifluoromethylketoximes involving a
copper-promoted reaction of indoles/pyrroles with the in situ
generated 2,2,2-trifluorodiazoethane11 and nitrite species (eq
3). Herein, we report our preliminary results on this subject.
In an initial study, we explored the reaction of N-
methylindole 1a with the in situ generated 2,2,2-trifluorodiazo-
ethane and nitrite species. In the presence of CuI at room
temperature, no product was observed (Table 1, entry 1).
Subsequently, the reaction was conducted at higher temper-
atures (60 and 80 °C), and (E)-3-indolyl trifluoromethyl-
ketoxime 2a was obtained in 18−33% yield (entries 2 and 3).
The structure of 2a was further confirmed by means of X-ray
crystallographic analysis (see the Supporting Information).
Then, a series of copper salts were screened for this model
reaction (entries 4−7), and CuCl was found to deliver the
desired product in 37% yield. When the amount of CuCl was
increased, the reaction proceeded to afford the product 2a in
moderated to good yields (entries 8−10). The solvent was
found to have an important effect on the reactivity (entries 11−
16). Among the solvents tested, dichloroethane (DCE) was
found to be the choice of solvent for this three-component
reaction (entry 16). The use of an excess of the CF3CH2NH2·
HCl reagent was essential for this transformation, but 4.0 equiv
of CF3CH2NH2·HCl did not improve the yield when compared
to that obtained with 3.0 equiv of CF3CH2NH2·HCl (entries 17
and 18). It was noteworthy that in all cases cyclopropanation or
cross-coupling of indole with 2,2,2-trifluorodiazoethane was not
a detectable side reaction for these copper-promoted processes.
Having established an optimal protocol for this three-
component reaction, we examined the scope of the indole
substrates, and the results are summarized in Scheme 1. A series
K
hexanone-oxime (precursor to Nylon 6),2 Thiofluoximate
(insecticide),3 Alloxydim (herbicide),4 Cymoxanil (fungicide),5
Risperidone (antipsychotic),6 and Fluvoxamine (antidepres-
sant)7 (Figure 1). Traditional methods for the synthesis of
Figure 1. Ketoxime-based chemical and biological compounds.
ketoximes have usually focused on two-component condensa-
tions, including the oximation of ketones with hydroxylamine
(eq 1)8 and the reaction of nitrites with compounds containing
the active methylene group (eq 2).9 Moreover, the correspond-
ing ketones or reactants containing the active methylene group
have to be prepared beforehand. It is striking, however, that the
Received: January 20, 2014
Published: March 5, 2014
© 2014 American Chemical Society
1606
dx.doi.org/10.1021/ol500203m | Org. Lett. 2014, 16, 1606−1609

Organic Letters
Letter
a
Table 1. Screening Optimal Conditions
Scheme 1. Substrate Scope of CuCl-Promoted Three-
a
Component Reaction
b
entry
copper salt (x equiv)
solvent/temp (°C)
yield (%)
1
CuI (0.2)
benzene/25
benzene/60
benzene/80
benzene/80
benzene/80
benzene/80
benzene/80
benzene/80
benzene/80
benzene/80
toluene/80
0
18
33
28
37
22
17
44
59
60
67
59
23
0
2
CuI (0.2)
3
CuI (0.2)
4
CuBr (0.2)
CuCl (0.2)
Cu(OAc)2 (0.2)
Cu(acac)2 (0.2)
CuCl (0.5)
CuCl (1.0)
CuCl (1.5)
CuCl (1.0)
CuCl (1.0)
CuCl (1.0)
CuCl (1.0)
CuCl (1.0)
CuCl (1.0)
CuCl (1.0)
CuCl (1.0)
5
6
7
8
9
10
11
12
13
14
15
16
toluene/110
1,4-dioxane/80
CH3CN/80
DMF/80
0
ClCH2CH2Cl/80
ClCH2CH2Cl/80
ClCH2CH2Cl/80
71
82
83
c
17
d
18
a
General reaction conditions: 1a (0.3 mmol), Cu salt (0.2−1.5 equiv),
CF3CH2NH2·HCl (2.0 equiv), NaNO2 (5.0 equiv), and 36% HCl (3.0
equiv) in solvent (4 mL) were conducted in one pot for 6 h. Isolated
yield. CF3CH2NH2·HCl (3.0 equiv) and NaNO2 (6.0 equiv) was
used. CF3CH2NH2·HCl (4.0 equiv) and NaNO2 (7.0 equiv) was
used.
b
c
d
of N-substituted indoles were employed in this one-pot
transformation, and the corresponding trifluoromethyl-
ketoximes 2a−2f were obtained in 58−82% yields. For
example, the reaction worked well with the indoles bearing
N-alkyl protecting groups to afford (E)-3-indolylketoximes 2a−
2e in good yields. When N-alkyl protecting groups were
replaced with a phenyl substituent, the yield was reduced to
58%. In addition, when indole without an N-protecting group
was subjected to this three-component transformation under
the same conditions, the desired product 2g was obtained in
63% yield without any detectable quantities of the N−H
insertion product. Four N-methylindoles bearing electron-
donating groups on the aromatic ring could also participate in
this transformation, affording the trifluoromethylketoximation
products 2h−2k in good yields. The substrates bearing
electron-withdrawing groups on the aromatic ring delivered
the desired products 2l−2o in 54−63% yields. Unfortunately,
ester- and cyano-substituted indoles were poor substrates,
providing the corresponding products 2p and 2q in lower
yields. Accordingly, the reaction worked well with N-benzyl-
pyrrole under our current reaction conditions to afford the
regioselective product 2r in 84% yield, whereas 2-acetyl-N-
benzylpyrrole furnished the product 2s in 35% yield. In
addition, it was found that the use of other electron-enriched
arenes, such as anisole, N,N-dimethylaniline, and 3-dimethyl-
aminoanisole, did not deliver any desired products, even when
the reaction time is prolonged to 48 h.
a
General reaction conditions: 1 (0.3 mmol), CuCl (1.0 equiv),
CF3CH2NH2·HCl (3.0 equiv), NaNO2 (6.0 equiv), and 36% HCl (3.0
b
equiv) were conducted in 4 mL of DCE at 80 °C for 6 h. Isolated
yield.
Scheme 2. Further Synthetic Transformation of
Trifluoromethylketoxime 2a
C catalyst and H2 at atmospheric pressure gave rise to 2,2,2-
trifluoro-1-(1-methyl-1H-indol-3-yl)ethanamine 3 in 78% yield.
Treatment of 2a with Selectfluor and K2CO3 at room
temperature afforded the corresponding ketone 4 in 83%
yield. Also, the reaction of 2a with benzenesulfonyl chloride
and acetyl chloride in the presence of triethylamine delivered
The products obtained here can be readily transformed into
other trifluoromethylated compounds, and some examples are
illustrated in Scheme 2. Direct hydrogenation of 2a using a Pd/
1607
dx.doi.org/10.1021/ol500203m | Org. Lett. 2014, 16, 1606−1609

Organic Letters
Letter
O-phenylsulfonylated and acetylated oximes 5 and 6 in 93%
and 84% yield, respectively.
Scheme 4. Proposed Mechanism for This Copper-Promoted
Three-Component Reaction
With the aim of providing preliminary mechanistic insight
into this transformation, we conducted the following isotopic
labeling experiments. Reaction of 1a with the in situ generated
2,2,2-trifluorodiazoethane and nitrite species in the presence of
D2O gave the corresponding trifluoromethylketoxime 2a in
63% yield upon isolation (Scheme 3a), and 3-deuterated indole
Scheme 3. Isotopic Labeling Experiments
analysis will be necessary to elucidate the nature of this three-
component reaction more accurately.
In summary, we have developed a new Cu-promoted three-
component reaction of indoles/pyrroles with the in situ
generated 2,2,2-trifluorodiazoethane and nitrite species. This
strategy enables rapid access to a series of (E)-3-indolyl and 2-
pyrrolyl trifluoromethylketoximes. In addition, we proposed a
mechanistically novel C−N bond-forming reaction of nitro-
sonium species utilizing NaNO2 as the sole nitrogen source. A
more detailed mechanistic investigation and extension of the
present chemistry to the synthesis of other ketoximes are
currently ongoing in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, spectral data of all the new compounds,
and the CIF information of 2a. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
1a-D delivered the product 2a in 80% yield under the standard
■
reaction conditions (Scheme 3b). In these two cases, however,
1
the deuterated product 2a-D was not detected by H NMR
*E-mail: majun_an68@tju.edu.cn.
spectroscopy. Furthermore, in the control experiment (Scheme
3c), we did not observe any proton exchange when the OD-
labeled ketoxime was refluxed under our current conditions.
Therefore, the reaction could not proceed by an Owater−H or
Cindole−H insertion process. Subsequently, by using 18O-labeled
H2O and 15N-labeled NaNO2, we were delighted to find
compelling evidence that both oxygen and nitrogen atoms are
derived from water and/or the nitrite salt, as the 18O and 15N
labels were effectively incorporated into the products 2a-O and
2a-N, respectively (Scheme 3d and 3e).
With these results taken into consideration, a plausible
mechanism for this three-component reaction is shown in
Scheme 4. Initially, the copper carbenoid is formed by the
reaction of the in situ generated 2,2,2-trifluorodiazoethane with
copper(I). Then, the indole 1 attacks the copper carbenoid to
give the intermediate A, which is trapped by a nitrosonium
cation (in situ generated from NaNO2 and HCl) to form the
intermediate B. The subsequent step is the intramolecular 1,3-
hydrogen shift of B, thus giving rise to the ketoxime 2. In
addition, a zwitterionic species formed from the indole and the
copper carbenoid is not excluded as the intermediate involved
in this process (see the Supporting Information).12 Further
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Nos. 21172170 and 21225208) and the
National Basic Research Program of China (973 Program,
2014CB745100).
REFERENCES
■
(1) For reviews, see: (a) Blatt, A. H. Chem. Rev. 1933, 12, 215.
(b) Freeman, J. P. Chem. Rev. 1973, 73, 283. (c) Kassa, J. J. Toxicol.
Clin. Toxicol. 2002, 40, 803. (d) Carey, F. A.; Sundberg, R. J. Advanced
Organic Chemistry, Vol. A, 5th ed.; Springer: New York, 2008; pp 650−
653. (e) Subiros-Funosas, R.; Khattab, S. N.; Nieto-Rodríguez, L.; El-
́
Faham, A.; Albericio, F. Aldrichimica Acta 2013, 46, 21.
(2) (a) Luedeke, V. D. In Encyclopedia of Chemical Processing and
Design: Chemical Processing Handbook; McKetta, J. J., Ed.; Marcel
Dekker: New York, 1978; p 72. (b) Rademacher, H. In Ullmann’s
Encyclopedia of Industrial Chemistry, 5th ed.; Gerhartz, W., Ed.; Wiley:
New York, 1987; Vol. A8, p 201. (c) Wessermel, K.; Arpe, H.-J.
Industrial Organic Chemistry, 4th ed.; Wiley-VCH: Weinheim, 2003; p
1608
dx.doi.org/10.1021/ol500203m | Org. Lett. 2014, 16, 1606−1609

Organic Letters
Letter
239. (d) Hashimoto, M.; Obora, Y.; Ishii, Y. Org. Process Res. Dev.
2009, 13, 411.
(3) Liu, A.; Wang, X.; Ou, X.; Liu, X.; Huang, M.; Wang, Y.; Pei, H.;
Chen, C. PCT Int. Appl. WO 2005056518 (2005).
(4) Iwataki, I.; Shibuya, M.; Ishikawa, H.; Kawana, T. (Nippon Soda
Co., Ltd.) U.S. Patent 4249937 (1981).
(5) Klopping, H. L.; Delp, C. J. J. Agric. Food Chem. 1980, 28, 467.
(6) (a) Strupczewski, J. T.; Allen, R. C.; Gardner, B. A.; Schmid, B.
L.; Stache, U.; Glamkowski, E. J.; Jones, M. C.; Ellis, D. B.; Huger, F.
P.; Dunn, R. W. J. Med. Chem. 1985, 28, 761. (b) Colpaert, F. C. Nat.
Rev. Drug Discovery 2003, 2, 315.
(7) (a) Shopsin, B.; Cassano, G. B.; Conti, L. In Antidepressants:
Neurochemical, Behavioral and Clinical Perspectives; Enna, S. J., Malick,
J. B., Richelson, E., Eds.; Raven Press: New York, 1981; pp 219−251.
(b) Benfield, P.; Ward, A. Drugs 1986, 32, 313.
(8) For selected examples: (a) Sommer, F.; Schulz, O. F.; Nassau, M.
Anorg. Allgem. Chem. 1926, 147, 142. (b) Sanford, J. K.; Blair, F. T.;
Arroya, J.; Sherk, K. W. J. Am. Chem. Soc. 1945, 67, 1941. (c) Smith, P.
A. S. J. Am. Chem. Soc. 1948, 70, 323. (d) Baczynskyj, L.; Mizsak, S.;
Szmuszkovicz, J. J. Org. Chem. 1972, 37, 4104. (e) Armor, J. N. J. Am.
Chem. Soc. 1980, 102, 1453.
(9) For selected examples: (a) Fischer H. Org. Synth. 1943, Coll. Vol.
2, 202. (b) Semon, W. L.; Damerell, V. R. Org. Synth. 1943, Coll. Vol.
2, 204. (c) Levin, N.; Hartung, W. H. Org. Synth. 1955, Coll. Vol. 3,
191. (d) Fischer H. Org. Synth. 1955, Coll. Vol. 3, 513. (e) Ferris, J. P.;
Sanchez, R. A.; Mancuso, R. W. Org. Synth.1973, Coll. Vol. 5, 32.
(10) (a) Liu, C.-B.; Meng, W.; Li, F.; Wang, S.; Nie, J.; Ma, J.-A.
Angew. Chem., Int. Ed. 2012, 51, 6227. (b) Li, F.; Nie, J.; Sun, L.;
Zheng, Y.; Ma, J.-A. Angew. Chem., Int. Ed. 2013, 52, 6375.
(11) (a) Morandi, B.; Carreira, E. M. Angew. Chem., Int. Ed. 2010, 49,
938. (b) Morandi, B.; Carreira, E. M. Angew. Chem., Int. Ed. 2010, 49,
4294. (c) Morandi, B.; Mariampillai, B.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2011, 50, 1101. (d) Morandi, B.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2011, 50, 9085. (e) Morandi, B.; Cheang, J.; Carreira, E. M.
Org. Lett. 2011, 13, 3080. (f) Kunzi, S. K.; Morandi, B.; Carreira, E. M.
̈
Org. Lett. 2012, 14, 1900.
(12) The zwitterionic intermediates generated from rhodium(II)
complexes and diazo carbonyl compounds, see: (a) Doyle, M. P.;
Shanklin, M. S.; Pho, H. Q.; Mahapatro, S. N. J. Org. Chem. 1988, 53,
1017. (b) Zhang, D.; Qiu, H.; Jiang, L. Q.; Lv, F. P.; Ma, C. Q.; Hu, W.
H. Angew. Chem., Int. Ed. 2013, 52, 13356. (c) Qiu, H.; Li, M.; Jiang, L.
Q.; Lv, F. P.; Zan, L.; Zhai, C. W.; Doyle, M. P.; Hu, W. H. Nat. Chem.
2012, 4, 733. (d) Qiu, H.; Zhang, D.; Liu, S. Y.; Qiu, L.; Zhou, J.;
Qian, Y.; Zhai, C. W.; Hu, W. H. Acta Chim. Sinica 2012, 70, 2484.
1609
dx.doi.org/10.1021/ol500203m | Org. Lett. 2014, 16, 1606−1609