Lewis- and Bronsted-acid cooperative catalytic radical coupling of aldehydes and azodicarboxylate

Article abstract of DOI:10.1039/c4ra05028b

An efficient radical coupling reaction of aldehydes and azodicarboxylate was developed by using the strategy of merging Lewis- and Bronsted- acid catalysis. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra05028b

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
Lewis- and Brønsted-acid cooperative catalytic
radical coupling of aldehydes and
azodicarboxylate†
Cite this: RSC Adv., 2014, 4, 27796
Received 28th May 2014
Accepted 13th June 2014
*
Hong-Bo Zhang, Yao Wang, Yun Gu and Peng-Fei Xu
DOI: 10.1039/c4ra05028b
www.rsc.org/advances
An efficient radical coupling reaction of aldehydes and azodicarboxy- Cobalt, as one of the “life” elements existing in many metal-
late was developed by using the strategy of merging Lewis- and loenzymes, has received considerable attention from synthetic
Brønsted- acid catalysis.
community. The development of cobalt-mediated radical reac-
tions such as cyclization and polymerization etc. has attracted
great interests.13–21
The formation of the C–N bond is one of the most important
transformations in organic synthesis that has wide applications
for the synthesis of numerous natural and unnatural biologi-
cally active molecules.1 As a result, tremendous efforts have
been made to develop various C–N bond forming methods over
the last few decades. One subclass of these efficient reactions
using azodicarboxylates as electrophiles has generated a
considerable amount of interest.2–6 Although many types of
reactions using azodicarboxylates have been extensively
studied, the hydroacylation reaction with aldehydes has far less
been investigated.7–10 Some limitations still exist and need to be
further addressed despite a few elegant reports of this kind of
hydroacylation. Especially, the reactivity and scope of substrates
need to be signicantly improved. For examples, the reactions
with aromatic aldehydes are very slow and generally complete in
several days with low yields. Therefore, it is highly desired to
develop an efficient and straightforward method with broad
scope of the substrates and high yields for such reactions.7–11
Cooperative catalysis has emerged as one of the most stimu-
lating, dynamic and synthetically powerful areas in contempo-
rary organic synthesis,12 while Lewis acid catalysis and Brønsted
acid catalysis represent two fundamental activation modes in
organic synthesis. We envisaged that the merging of these two
modes could provide new insights into designing and devel-
oping new reactions.
Inspired by these elegant cobalt-mediated radical works, we
further reasoned that with the use of both an appropriate cobalt
catalyst and Brønsted acid catalyst, an efficient radical coupling
of aldehydes and azodicarboxylate with broad substrates scope
might be realized. Here, we report that the merging of
cobalt Lewis acid catalysis and Brønsted acid catalysis can
efficiently promote the radical coupling of aldehydes and
azodicarboxylates.
However, due to its low reactivity, 4-methoxybenzaldehyde
has a limited application on this kind of reaction.7–10 Therefore,
we reasoned that this relative inert substrate could serve as a
good starting point to test the feasibility of our hypothesis. To
our delight, very simple and cheap catalysts can promote the
reaction efficiently. The desired product can be obtained with
91% yield in the presence of 20 mol% of CoCO3 and 5 mol%
TFA (triuoroacetic acid) (Table 1, entry 1). In sharp contrast, in
the absence of either CoCO3 or TFA, only very low conversion
was observed. These results indicated that CoCO3 and TFA
worked cooperatively to generate the product (Table 1, entries 2
and 3). In the presence of TFA, two different cobalt catalysts
were tested, as shown in Table 1, the desired hydroacylation
product 2a was obtained in 74% and 56% yield, respectively
(Table 1, entries 2 and 3). However, poor yield was obtained
when Co(acac)2 was used as catalyst (Table 1, entry 4).
Next, we investigated the solvent effect. As shown in Table 1,
when toluene or CH3CN was used as the solvent, the desired
product was obtained with 85% and 88% yield, respectively
(Table 1, entries 5 and 6). However, complex mixture was
observed when Et2O or THF was used as the solvent (Table 1,
entries 7 and 8). Poor yield was also obtained when methanol
was used as the solvent (Table 1, entry 9).
Modern transition-metal-catalysed reactions have been
shown to be of indispensable value for organic synthesis.8,9
State Key Laboratory of Applied Organic Chemistry and College of Chemistry
&Chemical Engineering, Lanzhou University, Lanzhou 730000, P.R. China. E-mail:
xupf@lzu.edu.cn; Fax: +86-931-8915557
† Electronic supplementary information (ESI) available: Experimental procedures
and spectra of all new compounds. For EPR spectroscopy data See DOI:
10.1039/c4ra05028b
We further optimized the catalyst loading. When we reduced
the loading of CoCO3 from 20 mol% to 10 mol%, there is no
27796 | RSC Adv., 2014, 4, 27796–27799
This journal is © The Royal Society of Chemistry 2014

View Article Online
Communication
RSC Advances
Table 1 Screening the reaction conditionsa
Table 2 Substrates scopea
Yieldb (%)
Entry
Solvent
Lewis acid
Yieldb (%)
Entry
Aldehyde
R
Product
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
CH3CN
Et2O
CoCO3
Co(OAc)2
CoCl2
91
74
56
26
85
88
Complex
Complex
<5
93
64
<10
<10
<10
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
4-MeOC6H4
4-FC6H4
3-CH3C6H4
3-BrC6H4
2-CH3C6H4
2-ClC6H4
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
92
94
92
93
80
77
94
96
95
96
94
94
96
95
51
52
77
Co(acac)2
CoCO3
CoCO3
CoCO3
CoCO3
CoCO3
CoCO3
CoCO3
CoCO3
CoCO3
CoCO3
C6H5
THF
2-Methyl propyl
Isopropyl
Propyl
tert-Butyl
Cyclohexyl
C6H5(CH2)2
Propenyl
C6H5CH(CH3)
C6H5(CH)2
2-thienyl
9
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
9
10c
11d
12e
13f
14g
10
11
12
13
14
15
16
17
a
Unless otherwise noted, the reactions were carried out with 1a (0.24
mmol, 32.6 mg), diethyl azodicarboxylate (34.8 mg, 0.2 mmol), Lewis
acid (0.04 mmol, 20 mol%) and TFA (0.01 mmol, 5 mol%) in the
b
c
indicated solvent (0.2 mL) for 12 h. Isolated yield. 10 mol% CoCO3
was used. 5 mol% CoCO3 was used. In the absence of CoCO3.
mol% TFA was used. g Without TFA.
a
Unless otherwise noted, the reactions were carried out with 1 (0.24
mmol), diethyl azodicarboxylate (34.8 mg, 0.2 mmol), CoCO3 (2.4 mg,
0.02 mmol, 10 mol%) and TFA (0.01 mmol, 5 mol%) in CH2Cl2
d
e
f
1
b
(0.2 mL) for 12 h. Isolated yield.
effect on the reaction (Table 1, entries 1 and 10). However, when
the catalyst loading was further reduced, the yield of 2a
decreased dramatically. (Table 1, entry 11). Further optimiza-
tion of the reaction conditions showed that DCM was the
solvent of choice and CoCO3 and TFA were the optimal cata-
lysts. This new cooperative catalysis system showed powerful
reactivity since the desired product was obtained with excellent
yield only in 12 h while this compound was obtained only in low
substrate in the title reaction was also successful albeit with
lower yield (Table 2, entry 16).
Notably, this coupling reaction is also amenable to scale-up.
When the reaction was carried out on a 24 mmol scale, the
desired product was obtained in 93% yield. Therefore, this
method is fast, easy to handle, and adaptable to large scale
synthesis (Scheme 1).
Finally, the mechanism of this transformation was studied
preliminarily. Under the optimal conditions, no desired
product was obtained with using either catalytic amount (0.02
mmol, 10 mol%) but also stoichiometric amount (0.30 mmol,
1.5 equiv.) of TEMPO, which indicated that this transformation
was likely to involve a radical intermediate (Scheme 2).22 As
shown in Fig. 1, electron paramagnetic resonance (EPR) exper-
iments were then performed in the presence of a mixture of
CoCO3, 1h, DEAD and TFA. A strong signal was clearly detected
which revealed a free radical of nitrogen was formed. However,
In the absence of either CoCO3 or TFA, no signal was
detected.23–26
yield even aer 96
procedures.7–10
h with all the previously reported
Encouraged by these results, we next probed the scope of this
hydroacylation reaction with a variety of aldehydes (Table 2). All
reactions were carried out simply by mixing the reactants in a
single operation at room temperature to afford the corre-
sponding products 2a–q. To our delight, various aliphatic and
aromatic aldehydes could be well tolerated in our optimised
reaction system. Different type of aliphatic aldehydes, regard-
less of steric effect, either linear or branched, gave the desired
products in excellent yields (Table 2, entries 8 and 15). Cyclo-
hexanecarbaldehyde is also an excellent partner for this reac-
tion and the desired product was obtained in 94% yield (Table
2, entry 12). The aromatic aldehydes, bearing either electron
withdrawing or donating groups in para-, meta-, and ortho-
positions, were tolerated as well. Heteroaromatic aldehydes
such as thienyl aldehyde could also be successfully employed to
afford amide with excellent yield (Table 2, entries 1–7 and 17).
The steric effect was observed when aldehydes 1e and 1f were
used as substrates which resulted in lower yields (Table 2,
entries 5 and 6). The application of cinnamaldehyde as a
Scheme 1 Example of scalable synthesis.
RSC Adv., 2014, 4, 27796–27799 | 27797
This journal is © The Royal Society of Chemistry 2014

View Article Online
RSC Advances
Communication
Conclusions
In conclusion, we have developed a new and efficient radical
coupling reaction of aldehydes and azodicarboxylates employ-
ing the strategy of merging Lewis- and Brønsted- acid catalysis.
This powerful reaction system afforded the desired products
with broader substrates scope, in shorter reaction time, more
efficiently.
Scheme 2 Mechanism study.
Acknowledgements
We are grateful for the NSFC (21032005, 21172097, 21372105),
the National Basic Research Program of China (no.
2010CB833203), the International S&T Cooperation Program of
China (2013DFR70580), the National Natural Science Founda-
tion from Gansu Province of China (no. 1204WCGA015), and
the “111” program from MOE of P. R. China.
Notes and references
Fig. 1 EPR experiment in the presence of 1h, diethyl azodicarboxylate,
CoCO3 and TFA in CH2Cl2 at room temperature.
1 (a) J. Bariwal and E. Van der Eycken, Chem. Soc. Rev., 2013,
42, 9283–9303; (b) G. Song, F. Wang and X. Li, Chem. Soc.
Rev., 2012, 41, 3651–3678; (c) R. J. Lundgren and G. C. Fu,
Angew. Chem., Int. Ed., 2013, 52, 2525–2528.
2 M. C. Willis, Chem. Rev., 2010, 110, 725–748.
3 D. A. Colby, R. G. Bergman and J. A. Ellman, Chem. Rev.,
2010, 110, 624–655.
4 (a) V. Nair, A. T. Biju, S. C. Mathew and B. P. Babu, Chem.–
Asian J., 2008, 3, 810–820; (b) A. Vallribera, R. M. Sebastian
and A. Shar, Curr. Org. Chem., 2011, 15, 1539–1577.
5 T. Kanzian and H. Mayr, Chem.–Eur. J, 2010, 16, 11670–
11677.
6 R. Huisgen and F. Jakob, Liebigs Ann. Chem., 1954, 590, 37–
47.
7 C. H. Jun, E. A. Jo and J. W. Park, Eur. J. Org. Chem., 2007,
1869–1881.
8 V. Chudasama, J. M. Ahern, D. V. Dhokia, R. J. Fitzmaurice
and S. Caddick, Chem. Commun., 2011, 47, 3269–3271.
9 Q. Zhang, E. Parker, A. D. Headley and B. Ni, Synlett, 2010,
16, 2453–2456.
10 B. Ni, Q. Zhang, S. Garre and A. D. Headley, Adv. Synth.
Catal., 2009, 351, 875–880.
11 (a) D. Lee and R. D. Otte, J. Org. Chem., 2004, 69, 3569–3571;
(b) Y. Qin, Q. Peng, J. Song and D. Zhou, Tetrahedron Lett.,
2011, 52, 5880–5883; (c) S. M. Inamdar, V. K. More and
S. K. Mandal, Chem. Lett., 2012, 41, 1484–1486; (d)
V. Chudasama, A. R. Akhbar, K. A. Bahou, R. J. Fitzmaurice
and S. Caddick, Org. Biomol. Chem., 2013, 11, 7301–7317.
12 (a) J. Parka and S. Hong, Chem. Soc. Rev., 2012, 41, 6931–
6943; (b) F. Lv, S. Liu and W. Hu, Asian J. Org. Chem., 2013,
2, 824–836; (c) W. Hu, X. Xu, J. Zhou, W. Liu, H. Huang,
J. Hu, L. Yang and L. Gong, J. Am. Chem. Soc., 2008, 130,
7782–7783; (d) N. Yamagiwa, H. Qin, S. Matsunaga and
M. Shibasaki, J. Am. Chem. Soc., 2005, 127, 13419–13427;
(e) T. Yang, A. Ferrali, F. Sladojevich, L. Campbell and
D. J. Dixon, J. Am. Chem. Soc., 2009, 131, 9140–9141.
Scheme 3 Proposed mechanism.
Based on these experimental results, we proposed a possible
mechanism for the reaction. Initially, an acyl radical I is
generated by cobalt catalyst, which then reacts with the
Brønsted acid activated intermediate II to form radical III.
Finally, intermediate III is trapped by aldehyde to give product 2
and regenerates acyl radical. In this transformation, radical III
can be identied by EPR (Scheme 3).27–29
27798 | RSC Adv., 2014, 4, 27796–27799
This journal is © The Royal Society of Chemistry 2014

View Article Online
Communication
RSC Advances
13 Metal-Catalyzed Cross-Coupling Reactions, ed. A. de Meijere 24 (a) S. Esposti, D. Dondi, M. Fagnoni and A. Albini, Angew.
and F. Diederich, Wiley-VCH, Weinheim, 2004.
14 Transition Metals for Organic Synthesis, 2nd Ed., ed. M. Beller
and C. Bolm, Wiley-VCH, Weinheim, 2004.
15 J. E. Backvall, A. K. Awasthi and Z. D. Renko, J. Am. Chem.
Soc., 1987, 109, 4750–4752.
Chem., Int. Ed., 2007, 46, 2531–2534; (b) M. D. Tzirakis and
M. Orfanopoulos, J. Am. Chem. Soc., 2009, 131, 4063–4069;
(c) D. Ravelli, M. Zema, M. Mella, M. Fagnoni and
A. Albini, Org. Biomol. Chem., 2010, 8, 4158–4164.
25 S. Angioni, D. Ravelli, D. Emma, D. Dondi, M. Fagnoni and
A. Albini, Adv. Synth. Catal., 2008, 350, 2209–2214.
16 Y. Katayama, K. Hashimoto, H. Nakayama, H. Mino,
M. Nojiri, T. Ono, H. Nyunoya, M. Yohda, K. Takio and 26 (a) D. Dondi, M. Fagnoni and A. Albini, Chem.–Eur. J., 2006,
M. Odaka, J. Am. Chem. Soc., 2006, 128, 728–729.
17 J. A. Kovacs, Chem. Rev., 2004, 104, 825–848.
18 M. Kobayashi and S. Shimizu, Eur. J. Biochem., 1999, 261, 1–
9.
19 I. Ryu, A. Tani, T. Fukuyama, D. Ravelli, S. Montanaro and
M. Fagnoni, Org. Lett., 2013, 15, 2554–2557.
20 J. Kim, J. A. Ashenhurst and M. Movassaghi, Science, 2009,
324, 238–241.
12, 4153–4163; (b) M. D. Tzirakis and M. Orfanopoulos,
Angew. Chem., Int. Ed., 2010, 49, 5891–5893; (c)
M. D. Tzirakis, M. N. Alberti and M. Orfanopoulos, Chem.
Commun., 2010, 46, 8228–8230; (d) D. Ravelli, A. Albini and
M. Fagnoni, Chem.–Eur. J, 2011, 17, 572–579; (e) D. Ravelli,
S. Montanaro, C. Tomasi, P. Galinetto, E. Quartarone,
D. Merli, P. Mustarelli and M. Fagnoni, ChemPlusChem,
2012, 77, 210–216.
21 W. Affo, H. Ohmiya, T. Fujioka, Y. Ikeda, T. Nakamura, 27 J. Wang, C. Liu, J. Yuan and A. Lei, Angew. Chem., Int. Ed.,
H. Yorimitsu, K. Oshima, Y. Imamura, T. Mizuta and
K. Miyoshi, J. Am. Chem. Soc., 2006, 128, 8068–8077.
22 Z. Huang, L. Jin, Y. Feng, P. Peng, H. Yi and A. Lei, Angew.
Chem., Int. Ed., 2013, 52, 7151–7155.
23 (a) B. S. Jaynes and C. L. Hill, J. Am. Chem. Soc., 1993, 115,
12212–12213; (b) D. Dondi, A. M. Cardarelli, M. Fagnoni
and A. Albini, Tetrahedron, 2006, 62, 5527–5535; (c)
M. D. Tzirakis and M. Orfanopoulos, Org. Lett., 2008, 10,
873–876; (d) S. Protti, D. Ravelli, M. Fagnoni and A. Albini,
Chem. Commun., 2009, 7351–7353; (e) D. Dondi, D. Ravelli,
M. Fagnoni, M. Mella, A. Molinari, A. Maldotti and
A. Albini, Chem.–Eur. J., 2009, 15, 7949–7957.
2013, 52, 2256–2259.
28 (a) R. R. Ferguson and R. H. Crabtree, J. Org. Chem., 1991, 56,
5503–5510; (b) W. T. Boese and A. S. Goldman, Tetrahedron
Lett., 1992, 33, 2119–2122; (c) S. Tsunoi, I. Ryu, T. Okuda,
M. Tanaka, M. Komatsu and N. Sonoda, J. Am. Chem. Soc.,
1998, 120, 8692–8701; (d) S. Kato, T. Iwahama,
S. Sakaguchi and Y. Ishii, J. Org. Chem., 1998, 63, 222–223;
(e) Y. Uenoyama, T. Fukuyama, K. Morimoto, O. Nobuta,
H. Nagai and I. Ryu, Helv. Chim. Acta, 2006, 89, 2483–2494.
Also see reviews; (f) I. Ryu and N. Sonoda, Angew. Chem.,
Int. Ed., 1996, 35, 1050–1066.
29 V. Chudasama, R. J. Fitzmaurice and S. Caddick, Nat. Chem.,
2010, 2, 592–596.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 27796–27799 | 27799