nBu4NI-catalyzed C–C bond formation to construct 2-carbonyl-1,4-diketones under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2018.03.011

An nBu₄NI-catalyzed oxidative cross-dehydrogenative-coupling of β-dicarbonyl compounds with acetone under mild reaction conditions is described. This methodology provides a straightforward pathway to synthesize 2-carbonyl-1,4-diketones and feat

Full text of DOI:10.1016/j.tetlet.2018.03.011

Accepted Manuscript
nBu NI-catalyzed C-C bond formation to construct 2-carbonyl-1,4-diketones
4
under mild conditions
Yunhe Lv, Weiya Pu, Jiejie Niu, Qingqing Wang, Qian Chen
PII:
S0040-4039(18)30308-3
https://doi.org/10.1016/j.tetlet.2018.03.011
TETL 49780
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
13 December 2017
3 March 2018
5 March 2018
Please cite this article as: Lv, Y., Pu, W., Niu, J., Wang, Q., Chen, Q., nBu NI-catalyzed C-C bond formation to
4
construct 2-carbonyl-1,4-diketones under mild conditions, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/
j.tetlet.2018.03.011
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
nBu NI-catalyzed C-C bond formation to
Leave this area blank for abstract info.
4
construct 2-carbonyl-1,4-diketones under
mild conditions
Yunhe Lv*, Weiya Pu, Jiejie Niu, Qingqing Wang, and Qian Chen

1
Tetrahedron Letters
nBu NI-catalyzed C-C bond formation to construct 2-carbonyl-1,4-diketones
4
under mild conditions
a, b
a
a
a
a
Yunhe Lv , Weiya Pu , Jiejie Niu , Qingqing Wang , and Qian Chen
a
College of Chemistry and Chemical Engineering, Anyang Normal University, Anyang 455000, P. R. China
Henan Province Key Laboratory of New Opto-Electronic Functional Materials, Anyang 455000, P. R. China.
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
4
An nBu NI-catalyzed oxidative cross-dehydrogenative-coupling of β-dicarbonyl compounds
with acetone under mild reaction conditions is described. This methodology provides a
straightforward pathway to synthesize 2-carbonyl-1,4-diketones and features a simple system,
low reaction temperature, and environmental friendliness.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
C–C bond formation
C–H functionalization
Cross-dehydrogenative-coupling
Environmental friendliness
Metal-free
Baran and co-workers reported intermolecular oxidative enolate
heterocoupling using stoichiometric amounts of iron(III)-
Introduction
C–C bond formation is one of the most important reactions in
organic synthesis because they provide key steps in building
more complex molecules from simple substrates. In this context,
cross-dehydrogenative-coupling (CDC) reaction directly from
two simple C–H bonds represents the most efficient and
straightforward route for the synthesis of the target molecules
due to their operational simplicity and atom economy. Although
great progress has been made in this area, CDC reaction is
dominated by transition-metal catalysis and the application of
acetylacetonate (2.0 equiv) or copper(II)-2-ethylhexanoate (2.75
9
1
equiv) as the oxidant in the presence of LDA at -78 °C. As part
of our continuing interest in metal-free catalyzed oxidative C–N,
1
0
C–O cross-coupling reaction directly from a C–H bond, we
present herein a simple and straightforward method to obtain 2-
2
carbonyl-1,4-diketones by nBu
4
NI-catalyzed oxidative CDC of
1
,3-diketones and β-keto esters with acetone under mild reaction
conditions (Scheme 1, eqn c). To the best of our knowledge, this
3
3
is the first report on C–C cross coupling reaction of C(sp )–H
organocatalysis is largely lagging behind. Therefore, new
synthetic methods for the construction of C–C bonds starting
from C–H bonds under metal-free conditions are still required.
bonds of two different ketones to generate a C–C bond with high
selectivity under metal-free conditions.
1
,4-Dicarbonyl compounds are often used as the common
substructures of natural products. Additionally, these compounds
are useful precursors for the synthesis of cyclopentenone and
4
heterocyclic compounds. 1,4-Dicarbonyl compounds are
traditionally prepared by the substitution reaction of α-halo
5
6
ketones with nucleophilic enolates, Stetter reaction, oxidative
7
8
coupling of enolates or silyl enol ethers, and other approaches
Scheme 1). For the synthesis of 1,4-dicarbonyl compounds via a
(
nucleophilic substitution reaction, prefunctionalization of the α-
position of ketones is needed (for example, Scheme 1, eqn a). For
an oxidative coupling reaction, pre-preparation of enolates or
silyl enol ethers is required (for example, Scheme 1, eqn b).
Obviously, the most simple and efficient route for the synthesis
of 1,4-dicarbonyl compounds might be the oxidative C–C bond
3
Scheme 1. Different pathways for the synthesis of 1,4-dicarbonyl
compounds.
coupling reaction of C(sp )–H bonds of two different ketones.
—
——

Corresponding author. e-mail: luyh086@nenu.edu.cn; lvyunhe0217@163.com

2
Tetrahedron
c
Results and Discussion
Yield of the isolated product.
d
We initiated our investigation with 1,3-diphenylpropane-1,3-
2 2
H O 30% in water.
dione 1a and acetone 2 as model substrates to identify suitable
reaction conditions (Table 1). To our delight, the direct C–C
cross coupling reaction took place in the presence of n-
Table 2
a,b
CDC reaction of 1,3-diarylpropane-1,3-dione with acetone.
butylammonium iodide (nBu NI, 0.2 equiv.) and tert-
4
o
butylhydroperoxide (TBHP, 2.0 equiv.) at 100 C under air,
affording product 3a in 45% yield along with some unidentified
by-products (Table 1, entry 1). Because the high temperature
may lead to decomposition of the product, the reaction
temperature was decreased from 100 to 50 °C, and 3a was
isolated in 61-75% yield (Table 1, entries 2–4). However, the use
of temperatures below 50 °C reduced the reactivity and
conversion (Table 1, entries 5 and 6). Other iodine catalysts such
as KI, NH I, NIS, and nBu NBr were not effective (Table 1,
4
4
entries 7–10). TBHP played a paramount role in this
transformation. As shown in Table 1, TBHP was the most
effective peroxide in the process. A trace amount of 3a was
observed when K S O , di-tert-butylperoxide (TBP), 30% H O ,
2
2
8
2
2
or m-CPBA was used as the oxidant (Table 1, entries 11–14). In
addition, no desired coupling product was observed in the
absence of nBu NI or TBHP (Table 1, entries 15 and 16).
4
Notably, this coupling reaction was performed under
environmentally benign condition (with tert-butyl alcohol and
water as by-products) without utilizing any metal.
Table 1
a
Optimization of the reaction conditions.
Yield
b
o
Entry
Oxidant
Catalyst
T ( C)
c
(%)
1
2
3
4
5
6
7
8
9
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
nBu
nBu
nBu
4
4
4
NI
NI
NI
100
45
a
Standard reaction conditions: 1 (0.3 mmol), 2 (3.0 mL), TBHP (0.6 mmol,
80
60
50
40
30
50
50
50
50
50
50
50
50
61
o
7
4
0% in water), nBu NI (0.06 mmol), 50 C, 2 h.
b
73
Yield of the isolated products.
nBu
4
NI
NI
NI
75
The generality of the C–C cross coupling reaction was next
examined. As described in Table 2, a broad range of 1,3-
diarylpropane-1,3-dione derivatives were investigated. All tested
1,3-diarylpropane-1,3-dione derivatives could be successfully
converted to the desired products in moderate to good yields (3a-
y). Generally, 1,3-diarylpropane-1,3-dione substrates bearing
electron-donating substituents provided higher yields than those
containing electron-withdrawing substituents on the aromatic
ring (3b-g). Halo-substituted 1,3-diarylpropane-1,3-dione
substrates (1c, 1d) were tolerated in the coupling reaction,
allowing for further functionalization through a cross-coupling
manifold. In these reactions, the para-, meta-, and ortho-methoxy
nBu
nBu
KI
4
62
4
5
trace
trace
0
4
NH I
NIS
nBu
nBu
nBu
1
1
1
1
1
0
1
2
3
4
4
4
4
NBr
NI
0
K S
2 2
O
8
trace
trace
trace
trace
1
(
,3-diarylpropane-1,3-dione afforded the corresponding 3g
72%), 3h (65%), and 3i (53%), respectively. The steric
TBP
NI
d
H2O2
4
nBu NI
hindrance on the aryl ring played little role in the reaction. For
further investigation, other unsymmetrical 1,3-diketones such as
1
methoxyphenyl)propane-1,3-diones (3p-v) were also employed
to explore the scope of this transformation, and the corresponding
products were obtained in moderate to good yields. In addition,
m-CPBA
nBu
4
4
NI
NI
-aryl-3-(p-tolyl)propane-1,3-diones (3j-o) and 1-aryl-3-(4-
1
1
5
6
-
nBu
50
50
0
0
TBHP
-
a
Reaction conditions: 1a (0.3 mmol), 2 (3.0 mL), oxidant (0.6 mmol),
catalysts (0.06 mmol), 2 h.
1
-(naphthalen-2-yl)-3-phenylpropane-1,3-dione 1w was also
effective to provide 3w in 71% yield. Heterocycle 1,3-
diarylpropane-1,3-dione were subsequently examined. Starting
b
TBHP 70% in water.

3
from 1-phenyl-3-(thiophen-2-yl)propane-1,3-dione 1x and 1-
furan-2-yl)-3-phenylpropane-1,3-dione 1y, 3x and 3y were
(
obtained in 77 and 76% yields, respectively. Remarkably, the
reaction was also highly selective, affording only mono-α-
substituted products 3, and no disubstituted products were
detected.
Encouraged by the abovementioned results, a variety of ethyl
3
-oxo-3-arylpropanoates 4 were examined as substrates to react
with acetone under the optimized reaction conditions (Table 3).
This reaction of acetone with various ethyl 3-oxo-3-
arylpropanoates afforded the desired coupling products 5a-g in
yields within the range of 46-71%. In addition, this reaction trend
is also consistent with the steric and electronic effect of 1,3-
diarylpropane-1,3-diones.
Table 3
a,b
CDC reaction of ethyl 3-oxo-3-arylpropanoates with acetone.
Scheme 3. Preliminary mechanism studies.
Some control experiments were performed to gain insight into
the reaction. ESI-MS analysis of the reaction system of 1a
(reacted for 30 min) and 50 mL of the mixture was used for the
negative ion ESI-MS analysis in CH CN. The ESI/MS analyses
3
showed the presence of the in situ generated I (see ESI). In
2
addition to this, we performed the reactions using α-iodo-β-
ketoester 7 and acetone as the substrates. No reaction occurred
under the same experiment conditions and substrate 7 was
recovered in 87% yield (Scheme 3a). When the radical scavenger
2
,6-di-tert-butyl-4-methylphenol (BHT, 2.0 equiv.) was added to
the reaction of 1a under the optimal conditions, a trace amount of
a was detected after 2 h of reaction (Scheme 3b). In the
3
presence of another radical inhibitor, 2,2,6,6-
tetramethylpiperidine N-oxide (TEMPO, 2.0 equiv.), 3a was
isolated in lower yields of 40% (Scheme 3c). These results
indicate that a radical mechanism was involved.
a
Standard reaction conditions: 4 (0.3 mmol), 2 (3.0 mL), TBHP (0.6 mmol,
o
7
0% in water), nBu
4
NI (0.06 mmol), 50 C, 2 h.
b
Yield of the isolated products.
The utility of 1,4-dicarbonyl compounds as synthons in
organic chemistry has expanded significantly in recent years.
4
,11
For example, 3a can be readily transformed into the trisubstituted
furan 6a in the presence of TsOH (Scheme 2). In addition,
starting from 4a and 4b, the corresponding compounds could be
obtained in 71% and 74% yields, respectively.
Scheme 4. Proposed mechanism.
Although an in-depth discussion should await further
investigations, based on the above results and literature precedent,
a tentative mechanism was proposed in Scheme 4. Initially, the
tert-butoxyl, tert-butylperoxyl radicals, and hydroxide form
Scheme 2. Synthetic applications of 1,4-dicarbonyl compounds.

4
Tetrahedron
1
2
t
•
t
•
(
e) Fujisawa, T.; Igeta, K.; Odake, S.; Morita, Y.; Yasuda, J.;
catalytically (Scheme 4a). The BuO or BuOO radicals
Morikawa, T. Bioorg. Med. Chem. 2002, 10, 2569-2581.
6. (a) Stetter, H. Angew. Chem., Int. Ed. 1976, 15, 639. (b) Rafiński,
Z.; Kozakiewicz, A.; Rafińska, K. ACS Catal. 2014, 4, 1404-1408.
subsequently abstract hydrogen atoms from 1,3-diphenylpropane-
1
3
1
,3-dione 1a to provide radical A (Scheme 4b). Then, in the
presence of hydroxide, the enol form of acetone will perform an
(c) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc.
addition reaction with carbon-centered radical A to give a tertiary
carbon radical B, which was oxidized to product 3a (Scheme 4c,
d).
2002, 124, 10298-10299.
1
4
7. (a) Jang, H. Y.; Hong, J.-B.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2007, 129, 7004-7005. (b) Clift, M. D.; Taylor, C. N.;
Thomson, R. J. Org. Lett. 2007, 9, 4667-4669. (c) Ryter, K.;
Livinghouse, T. J. Am. Chem. Soc. 1998, 120, 2658-2659.
8. (a) Parida, B. B.; Das, P. P.; Niocel, M.; Cha, J. K. Org. Lett.
Conclusions
2
013, 15, 1780-1783. (b) Shen, Z.-L.; Goh, K. K. K.; Cheong, H.-
In conclusion, we have reported a simple and straightforward
L.; Wong, C. H. A.; Lia, Y.-C.; Yang, Y.-S.; Loh, T.-P. J. Am.
Chem. Soc. 2010, 132, 15852-15855. (c) Custar, D. W.; Le, H.;
Morken, J. P. Org. Lett. 2010, 12, 3760-3763. (d) Xue, S.; Li, L.-
Z.; Liu, Y.-K.; Guo, Q.-X. J. Org. Chem. 2006, 71, 215-218. (e)
Setzer, P.; Beauseigneur, A.; Pearson-Long, M. S. M.; Bertus, P.
Angew. Chem., Int. Ed. 2010, 49, 8691-8694. (f) Li, N.-S.; Yu, S.;
Kabalka, G. W. Organometallics 1998, 17, 3815-3818.
nBu NI-catalyzed CDC reaction of β-dicarbonyl compounds with
4
inactivated acetone to construct 2-carbonyl-1,4-diketones under
metal-free conditions. Various 1,3-diketones and β-keto esters
were well tolerated in this methodology to give the
corresponding desired products in moderate to good yields. The
mild reaction conditions, inexpensive starting materials, synthetic
simplicity, and using TBHP (70% in water) as an
9
.
(a) Baran, P. S.; DeMartino, M. P. Angew. Chem., Int. Ed. 2006,
4
5, 7083-7086. (b) DeMartino, M. P.; Chen, K.; Baran, P. S. J.
environmentally friendly oxidant make this method attractive.
Importantly, this strategy can greatly simplify the operation and
workup procedures for the efficient and practical synthesizing
various 2-carbonyl-1,4-diketones from two different ketones,
which may be a good alternative for the established routes.
Further studies on the reaction mechanism and its application in
other coupling reactions are ongoing in our group.
Am. Chem. Soc. 2008, 130, 11546-11560.
10. (a) Lv, Y.-H.; Li, Y.; Xiong, T.; Lu, Y.; Liu, Q.; Zhang, Q. Chem.
Commun. 2014, 50, 2367-2379. (b) Lv, Y.-H.; Sun, K.; Wang, T.-
T.; Li, G.; Pu, W.-Y.; Chai, N.-N.; Shen, H.-H.; Wu, Y.-T. RSC
Adv. 2015, 5, 72142-72145. (c) Lv, Y.-H.; Sun, K.; Wang, T.-T.;
Wu, Y.-T.; Li, G.; Pu, W.-Y.; Mao, S.-K. Asian J. Org. Chem.
2016, 5, 325-329. (d) Lv, Y.-H.; Sun, K.; Pu, W.-Y.; Mao, S.-K.;
Li, G.; Niu, J.-J.; Chen, Q.; Wang, T.-T. RSC Adv. 2016, 6, 93486-
9
3490.
1
1
1. Liu, G.; Shirley, M. E.; Van, K. N.; McFarlin, R. L.; Romo, D.
Nature Chem. 2013, 5, 1049-1057.
2. (a) Liu, Z.-J.; Zhang, J.; Chen, S.-L.; Shi, E.-B.; Xu, Y.; Wan, X.-
B. Angew. Chem., Int. Ed. 2012, 51, 3231-3235. (b) Gan, L.-B.;
Huang, S.-H.; Zhang, X.; Zhang, A.-X.; Cheng, B.-C.; Cheng, H.;
Li, X.-L.; Shang, G. J. Am. Chem. Soc. 2002, 124, 13384-13385.
Acknowledgments
We gratefully acknowledge the Foundation of Henan
Educational Committee (18A150001), the Henan Province Key
Laboratory of New Opto-electronic Functional Materials, the
Science & Technology Foundation of Henan Province (China),
and AYNU-KP-A04 for financial support.
(c) Jones, C. M.; Burkitt, M. J. J. Am. Chem. Soc. 2003, 125,
6
946-6954. (d) McLaughlin, E. C.; Choi, H.; Wang, K.; Chiou, G.;
Doyle, M. P. J. Org. Chem. 2009, 74, 730-738.
1
1
3. (a) Wang, H.; Guo, L.-N.; Duan, X.-H. Org. Lett. 2013, 15, 5254-
5257. (b) Satish, G.; Ilangovan, A. RSC Adv. 2015, 5, 46163-
A. Supplementary data
4
6172. (c) Wang, C. Y.; Li, Y. B.; Gong, M.; Wu, Q.; Zhang, J.
Y.; Kim, J. K.; Huang, M. M.; Wu, Y. J. Org. Lett. 2016, 18,
151-4153.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2017.xx.
xxx.
4
4. (a) Tan, B.; Toda, N.; Barbas III, C. F. Angew. Chem. Int. Ed.
2012, 51, 12538-12541. (b) Casey, B. M.; Flowers II, R. A. J. Am.
Chem. Soc. 2011, 133, 11492-11495.
References and notes
1
.
(a) Van de Vyver, S.; Roman-Leshkov, Y. Angew. Chem., Int. Ed.
015, 54, 12554-12561. (b) Liu, Q.; Jackstell, R.; Beller, M.
2
Angew. Chem., Int. Ed. 2013, 52, 13871-13873. (c) Tsubogo, T.;
Ishiwata, T.; Kobayashi, S. Angew. Chem., Int. Ed. 2013, 52,
Highlights
6
2
590-6604. (d) Schonherr, H.; Cernak, T. Angew. Chem., Int. Ed.
013, 52, 12256-12267. (e) Cho, S. H.; Kim, J. Y.; Kwak, J.;
3

The C–C coupling reaction of C(sp )–H
bonds of two different ketones was
achieved.
The reaction proceeds under metal-free
conditions.
Chang, S. Chem. Soc. Rev. 2011, 40, 5068-5083.
2
3
4
.
.
.
(a) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215-1292.
(
b) Li, C.-J. Acc. Chem. Res. 2009, 42, 335-344. (c) Li, Z.; Bohle,
D. S.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 8928-8933.
d) Li, C.-J.; Li, Z. Pure Appl. Chem. 2006, 78, 935-945. (e) Yoo,



(
W.-J.; Li, C.-J. Top. Curr. Chem. 2010, 292, 281-302.
(a) Qin, Y.; Zhu, L.; Luo, S. Chem. Rev. 2017, 117, 9433-9520.
This methodology features mild conditions
(b) Sun, C.-L.; Shi, Z.-J. Chem. Rev. 2014, 114, 9219-9280. (c)
Bhunia, A.; Yetra, S. R.; Biju, A. T. Chem. Soc. Rev. 2012, 41,
and environmental friendliness.
2-carbonyl-1,4-diketones can be readily
transformed into the trisubstituted furan.
3
4
140-3152. (d) Roscales, S.; Csákÿ, A. G. Chem. Soc. Rev. 2014,
3, 8215-8225.
(a) Csákÿ, A. G.; Plumet, J. Chem. Soc. Rev. 2001, 30, 313-320. (b)
Zabicky, J. The Chemistry of Metal Enolates, Wiley, Chichester,
2
1
009. (c) Piancatelli, G.; D’Auria, M.; D’Onofrio, F. Synthesis.
994, 867-889. (d) Lipshutz, B. H. Chem. Rev. 1986, 86, 795-819.
(
e) Ferreira, V. F.; de Souza, M. C. B. V.; Cunha, A. C.; Pereira, L.
O. R.; Ferreira, M. L. G. Org. Prep. Proced. Int. 2001, 33, 411-
54.
4
5
.
(a) Liu, C.; Deng, Y.; Wang, J.; Yang, Y.; Tang, S.; Lei, A. Angew.
Chem., Int. Ed. 2011, 50, 7337-7341. (b) Yasuda, M.; Tsuji, S.;
Shigeyoshi, Y.; Baba, A. J. Am. Chem. Soc. 2002, 124, 7440-7447.
(c) Yasuda, M.; Katoh, Y.; Shibata, I.; Baba, A.; Matsuda, H.;
Sonoda, N. J. Org. Chem. 1994, 59, 4386-4392. (d) Yasuda, M.;
Tsuji, S.; Shibata, I.; Baba, A. J. Org. Chem. 1997, 62, 8282-8283.