Copper-catalyzed one-pot denitrogenative-dehydrogenative-decarboxylative coupling of β-ketoacids with trifluorodiazoethane: Facile access to trifluoromethylated aldol products

Article abstract of DOI:10.1002/chem.201403073

A novel copper-catalyzed one-pot cross-coupling of β-ketoacids with in situ generated trifluorodiazoethane has been developed. This reaction provides a direct and efficient method, in which one C-C bond and one C-O bond were formed in a carbenoid center with concomitant denitrogenation-dehydrogenation- decarboxylation, to afford trifluoromethylated aldol products. In several preliminary experiments, good to high enantioselectivities were also obtained.

Full text of DOI:10.1002/chem.201403073

DOI: 10.1002/chem.201403073
Communication
&
Synthetic Methods
Copper-Catalyzed One-Pot Denitrogenative–Dehydrogenative–
Decarboxylative Coupling of b-Ketoacids with
Trifluorodiazoethane: Facile Access to Trifluoromethylated Aldol
Products
Heng-Ying Xiong, Zhen-Yan Yang, Zhen Chen, Jun-Liang Zeng, Jing Nie, and Jun-An Ma*[a]
Abstract: A novel copper-catalyzed one-pot cross-cou-
pling of b-ketoacids with in situ generated trifluorodiazo-
ethane has been developed. This reaction provides
a direct and efficient method, in which one CÀC bond and
one CÀO bond were formed in a carbenoid center with
concomitant denitrogenation–dehydrogenation–decarbox-
ylation, to afford trifluoromethylated aldol products. In
several preliminary experiments, good to high enantiose-
lectivities were also obtained.
Scheme 1. Observations from the reaction of b-ketoacid 1a with 2,2,2-tri-
fluorodiazoethane.
The incorporation of fluorinated moieties into organic mole-
cules has become an important requirement for pharmaceuti-
cal, agrochemical, and material synthesis.[1] One of the most
common and attractive approaches is to exploit readily acces-
sible fluorinated building blocks in a multi-step process to-
wards more complex small molecules. A particularly useful ex-
ample is 2,2,2-trifluorodiazoethane, CF3CHN2, a valuable re-
agent available to the organic chemists.[2] The development of
new synthetic methods that use this fluorinated C2-synthon
has been the subject of recent research.[3] As a continuation of
our interest in this area,[4] we hoped to explore the Japp–Klin-
gemann reaction[5,6] between b-ketoacids and trifluorodiazo-
ethane. It was expected that an alkylhydrazone product would
be obtained from the initial decarboxylative condensation of
b-ketoacid 1a with trifluorodiazoethane. To our surprise, the
unexpected aldol product 2a was obtained from the reaction
of b-ketoacid 1a with trifluorodiazoethane and no related
Japp–Klingemann products were observed (Scheme 1). Herein
we report this new one-pot transformation involving denitro-
genative–dehydrogenative–decarboxylative coupling of b-ke-
toacids and trifluorodiazoethane. The notable features of this
reaction are its operational simplicity, inexpensive catalyst,
easily accessible starting materials, and mild reaction condi-
tions. Additionally, a highly enantioselective catalytic cross cou-
pling that constructs one CÀC and one CÀO bond in a carbe-
noid center with exceptional enantioselectivities was accom-
plished.
We began our studies by evaluating the reaction of 3-oxo-3-
phenylpropanoic acid 1a with the stock solution of CF3CHN2 in
dichloromethane using triethylamine as the base at room tem-
perature. No product was obtained after 24 h and a significant
amount of acetophenone, generated through decarboxylative
protonation of 1a, was recovered. The lack of reactivity may
be explained by the weak electrophilic ability of CF3CHN2.
Therefore, we turned our attention to the use of various Lewis
acid catalysts. With CuI as the catalyst, the unexpected aldol
product 2a was obtained in 10% yield. The structure of 2a
was further confirmed by means of X-ray crystallographic anal-
ysis (see the Supporting Information).[7] To improve the reac-
tion yield, it was envisioned that water might be favorable
toward bringing about carbenoid center hydroxylation. On the
basis of previous elegant reports by the Carreira group,[3d–i] we
evaluated the in situ generation of CF3CHN2 from the corre-
sponding amine with NaNO2 in aqueous media. The results are
summarized in Table 1. To our delight, the yield of 2a could be
increased to 35% (entry 1). The use of other copper complexes
resulted in a slight lower yield (entries 2–5). The solvent was
found to have an important effect on the reactivity (entries 6–
11). Among the solvents tested, the mixed solvent system was
found to be the best choice for this cross-coupling reaction
(entry 10). Evaluation of other organic bases led to finding that
8-diazabicyclo[5.4.0]undec-7-ene (DBU) was the most promis-
ing additive for the model reaction (entries 12–14). A lower
[a] Dr. H.-Y. Xiong, Z.-Y. Yang, Z. Chen, J.-L. Zeng, Dr. J. Nie, Prof. J.-A. 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 University
Tianjin 300072 (P. R. of China)
Fax: (+86)22-2740-3475
E-mail: majun_an68@tju.edu.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403073.
Chem. Eur. J. 2014, 20, 1 – 6
1
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
Reducing the loading of CF3CH2NH2·HCl to two equivalents re-
sulted in much lower yield of 2a (entry 16).
Table 1. Screening optimal reaction condition.[a]
With these interesting results in hand, we next investigated
the scope of this catalytic cross coupling under the optimal re-
action conditions (Table 1, entry 14) with a series of b-ketoa-
cids. As shown in Scheme 2, the cross-coupling of the in situ
generated CF3CHN2 with b-aryl-substituted b-ketoacids bearing
electron-neutral and -donating groups at the aromatic ring fur-
nished the corresponding products 2a–j in good yields. When
b-aryl-b-ketoacids containing electron-withdrawing substitu-
ents were used, the desired products 2k–o were obtained in
moderate yields. 1-Naphthyl-, 2-naphthyl-, 3-thiophenyl-, and
2-furanyl-substituted b-ketoacids were also found to be good
substrates, delivering the aldol products 2p–s in 65–81%
yields. In addition, b-ionone based b-ketoacid was subjected to
this cross-coupling reaction under the same conditions, and
the corresponding product 2t was obtained in 52% yield with-
out any detectable quantities of the cyclopropanation byprod-
ucts despite the presence of olefin moieties in the reactant.
Unfortunately, b-alkyl-substituted b-ketoacids were poor sub-
strates under the current conditions, providing the cross-cou-
pling products 2u–w in lower yields. We also attempted to op-
timize the reactions with b-alkylketoacids by decreasing the
temperature and increasing the amount of trifluoroethanamine
hydrochloride, but still could not improve the product yields.
To use this copper-catalyzed, one-pot cross coupling for the
modification of biologically interesting compound, we tested
the reaction of progesterone-derived b-ketoacid 3 with the in
situ generated CF3CHN2 under our standard conditions
(Scheme 3). The reaction provided a 4:1 mixture of diastereo-
CuXn/base
[mol%]
Solvent
Yield
[%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16[c]
CuI/Et3N (10)
CuBr/Et3N (10)
CuCl/Et3N (10)
CuOTf/Et3N (10)
Cu(OTf)2/Et3N (10)
CuI/Et3N (10)
CuI/Et3N (10)
CuI/Et3N (10)
CuI/Et3N (10)
CuI/Et3N (10)
CuI/Et3N (10)
CuI/DMAP (10)
CuI/DABCO (10)
CuI/DBU (10)
CuI/DBU (5)
CH2Cl2/H2O (20:1)
CH2Cl2/H2O (20:1)
CH2Cl2/H2O (20:1)
CH2Cl2/H2O (20:1)
CH2Cl2/H2O (20:1)
THF, Et2O, CH3CN, or DMF/H2O (20:1)
toluene/H2O (20:1)
toluene/THF/H2O (20:1:1)
toluene/CH3CN/H2O (10:1:1)
toluene/CH3CN/H2O (20:1:1)
toluene/CH3CN/H2O (30:1:1)
toluene/CH3CN/H2O (20:1:1)
toluene/CH3CN/H2O (20:1:1)
toluene/CH3CN/H2O (20:1:1)
toluene/CH3CN/H2O (20:1:1)
toluene/CH3CN/H2O (20:1:1)
35
23
26
30
26
0
56
55
71
76
70
69
70
80
67
65
CuI/DBU (10)
[a] Reactions conducted on 0.2 mmol scale of 1a: CuXn (5–10 mol%), or-
ganic base (5–10 mol%), CF3CH2NH2·HCl (4.0 equiv), NaNO2 (4.0 equiv),
and H2O (0.2 mL) in solvent (4 mL) at 08C for 24 h. [b] Isolated yields.
[c] CF3CH2NH2·HCl (2.0 equiv). DMAP: 4-(N,N- dimethylamino)pyridine;
DABCO: 1,4-diazabicyclo[2.2.2] octane.
catalyst loading reduced the reaction yield (entry 15). In addi-
tion, the use of an excess of the CF3CH2NH2·HCl reagent was
essential for the high efficiency of this cross-coupling reaction.
Scheme 2. The substrate scope of copper-catalyzed cross-coupling of b-ketoacids 1a with the in situ generated CF3CHN2.
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
2
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
As
a
successive study, the
enantioselective version of the
described cross-coupling reac-
tion using chiral bis(oxazoline) li-
gands was also disclosed
(Scheme 5). The model reaction
occurred in low yield (18%)
when performed with 12 mol%
of (R,R)-tBu-bis(oxazoline) L1,
possibly due to its secondary
role as a base to promote a com-
peting decarboxylation of b-ke-
toacid. Accordingly, a 1:1 ratio of
CuI/L1 (3 mol%) was used, and
as expected, the yield was in-
creased to 70%. Preliminary op-
Scheme 3. Copper-catalyzed cross-coupling of progesterone-derived b-ketoacid 3 with the in situ generated
CF3CHN2.
mers 4a and b in 51% overall yield, and both diastereomers
were readily separated by flash chromatography. Furthermore,
the single stereoisomer of 4a proved to be crystalline, allowing
the determination of the absolute configuration of the newly
formed stereogenic center by means of X-ray crystallographic
analysis (see the Supporting Information).[7]
The cross-coupling products 2 are also versatile synthetic in-
termediates and can be readily transformed into other highly
functionalized organofluorine compounds. For example, direct
treatment of 4,4,4-trifluoro-3-hydroxy-1-phenylbutan-1-one 2a
with (CF3CO)2O and Et3N at room temperature gave rise to the
corresponding trifluoromethylated enone 5 in excellent yield
(Scheme 4a). Oximation of 2a with NH2OH·HCl in EtOH, and
subsequent ring-closing afforded 5-(trifluoromethyl)-4,5-dihy-
droisoxazole 6 in 50% yield (Scheme 4b). The Baeyer–Villiger
Scheme 5. Catalytic enantioselective cross-coupling reaction.
oxidation of 2g using m-chloroperoxybenzoic acid (m-CPBA)
and Na2HPO4 gave 4,4,4-trifluoro-3-hydroxybutanoate 7 in 86%
yield (Scheme 4c). Also, direct reduction of 2w with NaBH4 in
MeOH delivered the trifluoromethylated diol 8 in quantitative
yield (Scheme 4d). These interesting results indicate that the
present protocol provides a reliable and rapid approach for
the construction of diverse CF3-containing molecules.
timization of the other reaction conditions (including chiral li-
gands L1–4, solvent, temperature, and time; see the Support-
ing Information) led to the discovery that the best results were
obtained when the reaction was performed in toluene and
water at À208C in the presence of (R,R)-Ph-bis(oxazoline) L4
(81% yield, 93% ee). Furthermore, several other cross-coupling
products were also obtained in respectable yields (66–85%)
with high enantioselectivities (86–93% ee).[8]
To gain some preliminary understanding of the mechanism,
we performed the following isotopic labeling experiments
under the standard reaction conditions. Reaction 1a with the
in situ generated 2,2,2-trifluorodiazoethane in the presence of
D2O delivered the cross-coupling product in 29% yield upon
isolation (Scheme 6a). The deuterated products were detected
by 1H NMR spectroscopy as anticipated. Meanwhile, in the
presence of 18O-labeled water, it was found that the 18O-label
was also effectively incorporated into the corresponding prod-
uct (Scheme 6b). Accordingly, we conducted one control ex-
periment, and did not observe any incorporation of the 18O
label in the product when 18O2 were used as an oxidant at at-
mospheric pressure (Scheme 6c). These experimental results
showed that water can indeed transfer an oxygen atom into
the cross-coupling product under copper catalysis.
Scheme 4. Further transformation of the cross-coupling products.
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
3
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
cross-coupling reactions will open up a novel way to access
the diversity of trifluorodiazoethane chemistry. Further investi-
gation of the reaction mechanism, as well as full development
of the enantioselective copper-catalyzed cross-coupling are on-
going in our laboratory and will be reported in due course.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (No. 21172170 and 21225208) and the Na-
tional Basic Research Program of China (973 Program,
2014CB745100). The authors also thank Dr. Dominique Cahard
(CNRS & Universitꢁ et INSA de Rouen) and Ning Jiao (Peking
University) for their helpful suggestions.
Scheme 6. Isotopic labeling and control experiments.
Keywords: 2,2,2-trifluorodiazoethane
·
decarboxylation
·
dehydrogenation cross-coupling reaction · enantioselectivity ·
b-ketoacids
[1] For selected reviews, see: a) P. Kirsch, Modern Fluoroorganic Chemistry:
Synthesis Reactivity, Applications, Wiley-VCH, Weinheim, 2004; b) M. Shi-
mizu, T. Hiyama, Angew. Chem. 2005, 117, 218; Angew. Chem. Int. Ed.
2005, 44, 214; c) K. Uneyama, T. Katagiri, H. Amii, Acc. Chem. Res. 2008,
41, 817; d) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc.
Rev. 2008, 37, 320; e) J.-A. Ma, D. Cahard, Chem. Rev. 2008, 108, PR1;
f) N. Shibata, S. Mizuta, H. Kawai, Tetrahedron: Asymmetry 2008, 19,
2633; g) I. Ojima, Fluorine in Medicinal Chemistry and Chemical Biology,
Wiley-Blackwell, Chichester, 2009; h) J. Hu, W. Zhang, F. Wang, Chem.
Commun. 2009, 7465; i) S. Lectard, Y. Hamashima, M. Sodeoka, Adv.
Synth. Catal. 2010, 352, 2708; j) J. Nie, H.-C. Guo, D. Cahard, J.-A. Ma,
Chem. Rev. 2011, 111, 455; k) O. A. Tomashenko, V. V. Grushin, Chem. Rev.
2011, 111, 4475; l) T. Liang, C. N. Neumann, T. Ritter, Angew. Chem. 2013,
125, 8372; Angew. Chem. Int. Ed. 2013, 52, 8214.
Scheme 7. Proposed mechanism.
On the basis of the preliminary results described above and
previous studies,[9] we proposed the reaction mechanism as
outlined in Scheme 7. Initially, the copper complex A is formed
by the reaction of the in situ generated trifluorodiazoethane
with copper salt. Meanwhile, the amine bonds to the b-ketoa-
cid 1 (in its enol form) through a salt bridge to give intermedi-
ate B. Subsequently, the intermediate B attacks the complex A
and terminates with water to form the addition intermediate
C, with the regeneration of the catalyst and the release of dia-
zene. Diazene rapidly undergoes a disproportionation reaction
to form nitrogen gas and hydrazine (or H2).[10] The subsequent
step is decarboxylation and release of the amine additive of C,
thus giving rise to the final cross-coupling product 2. However,
the detailed mechanism of this cross-coupling reaction remains
to be elucidated.
[2] a) H. Gilman, R. G. Jones, J. Am. Chem. Soc. 1943, 65, 1458; b) W. L.
Mock, M. E. Hartman, J. Org. Chem. 1977, 42, 459; c) R. Fields, R. N. Has-
zeldine, J. Chem. Soc. 1964, 1881; d) J. H. Atherton, R. Fields, J. Chem.
Soc. 1968, 1507.
[3] a) P. Maux, S. Juillard, G. Simmoneaux, Synthesis 2006, 1701; b) P. K. My-
khailiuk, S. Afonin, G. V. Palamarchuk, O. V. Shishkin, A. S. Ulrich, I. V. Ko-
marov, Synthesis 2008, 1757; c) P. K. Mykhailiuk, S. Afonin, G. V. Pala-
marchuk, O. V. Shishkin, A. S. Ulrich, I. V. Komarov, Angew. Chem. 2008,
120, 5849; Angew. Chem. Int. Ed. 2008, 47, 5765; d) B. Morandi, E. M. Car-
reira, Angew. Chem. 2010, 122, 950; Angew. Chem. Int. Ed. 2010, 49, 938;
e) B. Morandi, E. M. Carreira, Angew. Chem. 2010, 122, 4390; Angew.
Chem. Int. Ed. 2010, 49, 4294; f) B. Morandi, B. Mariampillai, E. M. Car-
reira, Angew. Chem. 2011, 123, 1133; Angew. Chem. Int. Ed. 2011, 50,
1101; g) B. Morandi, E. M. Carreira, Angew. Chem. 2011, 123, 9251;
Angew. Chem. Int. Ed. 2011, 50, 9085; h) B. Morandi, J. Cheang, E. M. Car-
reira, Org. Lett. 2011, 13, 3080; i) S. K. Kꢂnzi, B. Morandi, E. M. Carreira,
Org. Lett. 2012, 14, 1900; j) Z. Chai, J.-P. Bouillon, D. Cahard, Chem.
Commun. 2012, 48, 9471; k) G. A. Molander, L. N. Cavalcanti, Org. Lett.
2013, 15, 3166; l) O. A. Argintaru, D. Ryu, I. Aron, G. A. Molander, Angew.
Chem. 2013, 125, 13901; Angew. Chem. Int. Ed. 2013, 52, 13656; m) H.
Mao, A. Lin, Z. Tang, H. Hu, C. Zhu, Y. Cheng, Chem. Eur. J. 2014, 20,
2454; n) T.-R. Li, S.-W. Duan, W. Ding, Y.-Y. Liu, J.-R. Chen, L.-Q. Lu, W.-J.
Xiao, J. Org. Chem. 2014, 79, 2296.
[4] a) C.-B. Liu, W. Meng, F. Li, S. Wang, J. Nie, J.-A. Ma, Angew. Chem. 2012,
124, 6331; Angew. Chem. Int. Ed. 2012, 51, 6227; b) F. Li, J. Nie, L. Sun, Y.
Zheng, J.-A. Ma, Angew. Chem. 2013, 125, 6375; Angew. Chem. Int. Ed.
2013, 52, 6255.
[5] Seminal reports on the Japp–Klingemann reaction, see: a) R. Japp, F.
Klingemann, Ber. Dtsch. Chem. Ges. 1887, 20, 2942; b) R. Japp, F. Klinge-
mann, Ber. Dtsch. Chem. Ges. 1887, 20, 3284; c) R. Japp, F. Klingemann,
Ber. Dtsch. Chem. Ges. 1887, 20, 3398; d) R. Japp, F. Klingemann, Ann.
In conclusion, we have developed a novel copper-catalyzed
cross coupling of b-ketoacids with in situ generated 2,2,2-tri-
fluorodiazoethane under mild reaction conditions. During this
transformation, one CÀC and one CÀO bond are constructed
in a carbenoid center with concomitant denitrogenation, dehy-
drogenation, and decarboxylation. This one-pot synthetic pro-
tocol enables the efficient preparation of a variety of trifluoro-
methylated aldol adducts, which are versatile synthetic inter-
mediates toward other useful building blocks. In several pre-
liminary experiments, good to high enantioselectivities were
also obtained. Application of 2,2,2-trifluorodiazoethane in
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
4
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
Chim. 1888, 247, 190. For a review on the Japp- Klingemann reaction,
see: e) R. R. Phillips, Org. React. 1959, 10, 143.
Matsui, J. Org. Chem. 2011, 76, 3545. The assignment of all other cross-
coupling products was made by analogy.
[6] For two recent examples about the electrophilic addition to a-diazoest-
ers for the synthesis of hydrazone compounds, see: a) E. Yasui, M.
Wada, N. Takamura, Tetrahedron 2009, 65, 461; b) W. Li, X. Liu, X. Hao, X.
Hu, Y. Chu, W. Cao, S. Qin, C. Hu, L. Lin, X. Feng, J. Am. Chem. Soc. 2011,
133, 15268.
[7] CCDC 983606 and 983512 contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif
[8] The absolute stereochemistry of the cross-coupling product 2a was as-
signed by comparison of the optical rotation to literature reported
data; a) K. Funabiki, W. Hashimoto, M. Matsui, Chem. Commun. 2004,
2056; b) K. Funabiki, K. Hasegawa, Y. Murase, H. Nagaya, M. Matsui, J.
Fluorine Chem. 2006, 127, 545; c) K. Funabiki, Y. Itoh, Y. Kubota, M.
[9] For the relative mechanism of b-ketoacid decarboxylation, see: a) Y.
Zheng, H.-Y. Xiong, J. Nie, M.-Q. Hua, J.-A. Ma, Chem. Commun. 2012,
48, 4308; b) C.-F. Yang, C. Shen, J.-R. Wang, S.-K. Tian, Org. Lett. 2012, 14,
3092; c) C. Jiang, F. Zhong, Y. Lu, Beilstein J. Org. Chem. 2012, 8, 1279;
d) F. Zhong, W. Yao, X. Dou, Y. Lu, Org. Lett. 2012, 14, 4018; e) H.-N.
Yuan, S. Wang, J. Nie, W. Meng, Q. Yao, J.-A. Ma, Angew. Chem. 2013,
125, 3961; Angew. Chem. Int. Ed. 2013, 52, 3869.
[10] Although all attempts to use phthalaldehyde for the trapping of hydra-
zine failed, hydrazine was not excluded as the byproduct involved in
this process.
Received: April 14, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Synthetic Methods
H.-Y. Xiong, Z.-Y. Yang, Z. Chen, J.-L. Zeng,
J. Nie, J.-A. Ma*
&& – &&
Copper-Catalyzed One-Pot
Denitrogenative–Dehydrogenative–
Decarboxylative Coupling of b-
Ketoacids with Trifluorodiazoethane:
Facile Access to Trifluoromethylated
Aldol Products
Unexpected aldol: A novel copper-cata-
lyzed one-pot cross-coupling of b-ketoa-
cids with in situ generated trifluorodia-
zoethane has been developed. This re-
action provides a direct and efficient
method, in which one CÀC and one CÀ
O bond were formed in a carbenoid
center with concomitant denitrogena-
tion–dehydrogenation–decarboxylation,
to afford trifluoromethylated aldol prod-
ucts (see scheme; DBU=1,8-diazabicy-
cloundec-7-ene).
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!