Palladium-Catalyzed Nitration of Meyer-Schuster Intermediates with tBuONO as Nitrogen Source at Ambient Temperature

Article abstract of DOI:10.1021/acs.orglett.6b01740

A novel domino palladium-catalyzed nitration of Meyer-Schuster intermediates which were generated in situ from propargylic alcohols was developed, by the use of t-BuONO, leading to α-nitro enones in good to excellent yields at room temperature with a broa

Full text of DOI:10.1021/acs.orglett.6b01740

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Nitration of Meyer−Schuster Intermediates with
tBuONO as Nitrogen Source at Ambient Temperature
Yuanguang Lin,† Weiguang Kong,† and Qiuling Song*,†,‡
†Institute of Next Generation Matter Transformation, College of Chemical Engineering and College of Material Sciences Engineering
at Huaqiao University, 668 Jimei Boulevard, Xiamen, Fujian 361021, P. R. China
‡National Laboratory for Molecular Sciences, Institute of Chemistry, CAS, Beijing, 100190, P. R. China
S
* Supporting Information
ABSTRACT: A novel domino palladium-catalyzed nitration
of Meyer−Schuster intermediates which were generated in situ
from propargylic alcohols was developed, by the use of t-
BuONO, leading to α-nitro enones in good to excellent yields
at room temperature with a broad functional group tolerance.
itro compounds are widely used as building blocks1 and
Nkey intermediates in synthetic chemistry, the pharma-
ceutical industry, and material sciences.2 The conventional
nitration, which proceeds via an electrophilic substitution
pathway, usually requires nitric acid as the nitrating reagent
with another strong acid as the catalyst at high temperature,
causing poor selectivities and severe strong acid waste.2
Therefore, the development of new nitrating reagents and
new approaches to synthesize nitro compounds under mild
conditions with high selectivities is highly desirable. Radical
chemistry has boomed in the past decade. Synthesis of nitro
compounds through the radical process attracted great
attention, and great effort has been devoted to this topic. In
2011, Beller and his co-workers reported a metal-free nitration
of arylboronic acids under mild conditions, by the use of tert-
butyl nitrite as a nitro reagent.3 Recently, Maiti discovered that
AgNO2 along with TEMPO can serve a nitrating reagent to
lead to nitro olefins with good regio- and stereoselectivities.4a,b
And later on, the same group reported a pretty similar reaction
with Fe(NO3)2 as the NO2 source.4c In 2014, Li reported a
cascade nitration/cyclization reaction to synthesize pyrrolo-
[4,3,2-de]quinolinones.5 In 2015, Liang developed a metal-free
nitro-carbocyclization of 1,6-enynes.6 However, all of the
above-mentioned nitration reactions were limited to alkynes
and alkenes, and the addition of nitro radicals to allenes has not
yet been reported.
It is well documented that the propargylic alcohols or
propargyl esters could generate allenols via Meyer−Schuster
rearrangement.7 As part of our continuous interest in radical
chemistry, we envisioned that nitro radicals, which could be
generated from a NO source under oxidative conditions, might
attack the allene intermediate A which comes from the
rearrangement of propargylic alcohols, rendering α-NO2
enones via a cascade reaction (Figure 1). To the best of our
knowledge, the efficient methods for preparation of complex
polysubstituted α-NO2 enones have not yet been explored
despite the fact that enones are valuable building blocks in
many reactions.8 Herein, we reported a radical involved Pd-
Figure 1. Proposed nitration of propargylic alcohols.
catalyzed nitration of allene intermediates which were
generated via Meyer−Schuster rearrangement, leading to α-
nitro enones in good to excellent yields at ambient temperature.
To verify our hypothesis, we chose 2-methyl-4-phenylbut-3-
yn-2-ol (1a) as model substrates (Table 1). To our delight,
when 10 mol % of Pd(OAc)2 was employed, the nitration
a
Table 1. Optimization of Reaction Conditions
b
entry
cat. (10 mol %)
solvent (1 mL)
temp (°C)
yield (%)
1
2
Pd(OAc)2
−
PdCl2
THF
60
60
60
60
60
60
60
50
40
30
73
0
THF
3
THF
49
0
4
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
THF
5
THF
15
74
84
89
84
6
1,4-dioxane
CH3CN
CH3CN
CH3CN
CH3CN
7
8
9
c
10
92(86)
a
Reaction conditions (unless otherwise mentioned): 1a (0.25 mmol),
t-BuONO (2 equiv), catalyst (10 mol %), solvent (1 mL), 18 h, under
b
c
air. Determined by GC yield. Isolated yield (THF = tetrahydrofuran,
CH3CN = acetonitrile).
Received: June 15, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01740
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product 2a was obtained in 73% yield by GC (entry 1);
however, the desired product could not be obtained without a
metal catalyst (entry 2). We next investigated other palladium
catalysts, such as PdCl2, Pd(PPh3)2Cl2, and Pd(PPh3)4, and no
better results were obtained (entries 3−5). Subsequent solvent
optimization suggested that CH3CN was the best choice
(entries 6−7). In addition, we found that decreasing the
reaction temperature to 30 °C could increase the yield from
84% to 92% (entries 8−10). Thus, based on the above
experiments, we determined the optimized conditions to be t-
BuONO (2 equiv), Pd(OAc)2 (10 mol %), and CH3CN (1
mL) at 30 °C under air for 18 h.
such as thiophene, were also good substrates for this
transformation, and corresponding desired products were
formed in 90% and 71% yields respectively (2n−2o).
To further investigate the scope and limitations of this
reaction, we next turned our attention toward the propargylic
alcohols prepared from phenylacetylene and various ketones
(Scheme 2). The desired products were obtained in good to
Scheme 2. Propargylic Alcohols Scope with Various γ-
a
Substituents
Under the optimal reaction conditions, the nitration of
propargylic alcohols via Meyer−Schuster rearrangement to
generate α-nitro enones was performed. We first applied the
reaction to a range of propargylic alcohols which were prepared
from corresponding aryl bromides and 2-methylbut-3-yn-2-ol
(Scheme 1). Electron-donating substituents such as 2-methyl,
a
Scheme 1. Nitration of γ,γ-Dimethyl Propargylic Alcohols
a
Reaction conditions: 1 (0.25 mmol), t-BuONO (0.5 mmol),
Pd(OAc)2 (10 mol %), CH3CN (1 mL), strried at 30 °C under air
for 18 h. Isolated yield.
excellent yields from the substrates started from different cyclic
ketones (2p−2r). Other propargylic alcohols prepared from
aryl aliphatic ketones or aliphatic aliphatic ketones also gave
excellent outcomes (2s−2t). It should be pointed out that the
desired product was obtained in low yields when we employed
the present reaction conditions with propargylic alcohols with
only one substituent on the γ-position.
Gratifyingly, the reaction could be readily scaled up without
loss of its efficiency: 1.1 g (66%) of α-nitro enone 2a was
obtained in 8 mmol scale (Scheme 3), implying its potential
synthetic utility in industry.
Scheme 3. Scaled-up Reaction
In order to understand the reaction mechanism, various
control experiments were carried out as described in Scheme 4.
In the presence of radical quencher 2,6-di-tert-butyl-4-
methylphenol (BHT) or 1,1-diphenylethylene, the reaction
were completely suppressed (eq 1). It also showed that, in the
absence of oxygen, the reaction did not perform at all (eq 2).
Moreover, when enones 3 and 4 were subjected to the standard
conditions, no corresponding desired α-nitro enones were ever
detected by GC, which implied that the reaction should not
proceed through direct nitration of enones.
On the basis of the above-mentioned control experiments, a
tentative reaction mechanism was proposed in Scheme 5:
Initially, the combination of t-BuONO and H2O leads to the
formation of HNO2, which promotes the M-S rearrangement to
a
Reaction conditions: 1 (0.25 mmol), t-BuONO (0.5 mmol), 10 mol
% of Pd(OAc)2, CH3CN (1 mL), strried at 30 °C under air for 18 h.
Isolated yield.
4-tert-butyl, 4-methoxy gave the expected products in 89%,
73%, 87% yields respectively (2b, 2c, 2d). Halo substituents
were also well tolerable under the standard conditions, giving
corresponding desired products which could be employed for
further structural manipulations in good yields (2e−2g).
Moreover, various electron-deficient groups, including trifluor-
omethyl, aldehyde, esters, ketone, nitro and cyano were
compatible in the method as well (2h−2m). Polyphenylene
compound 2-ethynylnaphthalene and a heteroaromatic one,
B
DOI: 10.1021/acs.orglett.6b01740
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Scheme 4. Experiments for Mechanistic Studies
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01740.
Information regarding materials and methods, and all
characterization data of compounds from this study
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: qsong@hqu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (21202049), the Recruitment Program
of Global Experts (1000 Talents Plan), the Natural Science
Foundation of Fujian Province (2016J01064), Fujian Hundred
Talents Plan and Program of Innovative Research Team of
Huaqiao University (Z14X0047), and Graduate Innovation
Fund (for Y.L.) of Huaqiao University is gratefully acknowl-
edged. We also thank Instrumental Analysis Center of Huaqiao
University for analysis support.
Scheme 5. Plausible Mechanism
REFERENCES
■
(1) (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH:
New York, 2001. (b) Prakash, G. K. S.; Mathew, T. Angew. Chem., Int.
Ed. 2010, 49, 1726. (c) Byun, E.; Hong, B.; De Castro, K. A.; Lim, M.;
Rhee, H. J. Org. Chem. 2007, 72, 9815. (d) Ragaini, F.; Rapetti, A.;
Visentin, E.; Monzani, M.; Caselli, A.; Cenini, S. J. Org. Chem. 2006,
71, 3748. (e) Zhu, H.; Ke, X.; Yang, X.; Sarina, S.; Liu, H. Angew.
Chem., Int. Ed. 2010, 49, 9657. (f) Lee, C.; Liu, S. Chem. Commun.
2011, 47, 6981. (g) Peng, Q.; Zhang, Y.; Shi, F.; Deng, Y. Chem.
Commun. 2011, 47, 6476.
(2) (a) Burland, D. M.; Miller, R. D.; Walsh, C. A. Chem. Rev. 1994,
94, 31. (b) Ishow, E.; Bellaiche, C.; Bouteiller, L.; Nakatani, K.;
Delaire, J. A. J. Am. Chem. Soc. 2003, 125, 15744. (c) Papagiannouli, I.;
Iliopoulos, K.; Gindre, D.; Sahraoui, B.; Krupka, O.; Smokal, V.;
Kolendo, A.; Couris, S. Chem. Phys. Lett. 2012, 554, 107. (d) Bafana,
A.; Devi, S. S.; Chakrabarti, T. Environ. Rev. 2011, 19, 350. (e) Barrett,
A. G. M.; Graboski, G. G. Chem. Rev. 1986, 86, 751. (f) Bui, T.; Syed,
S.; Barbas, C. F. J. Am. Chem. Soc. 2009, 131, 8758. (g) Fan, F.-R. F.;
Yao, Y.; Cai, L.; Cheng, L.; Tour, J. M.; Bard, A. J. J. Am. Chem. Soc.
2004, 126, 4035. (h) Belciug, M.; Ananthanarayanan, V. S. J. Med.
Chem. 1994, 37, 4392.
generate intermediate A. Subsequently, the NO2 radical is
formed from the NO radical which is directly generated from t-
BuONO under aerobic conditions.9 In the presence of a Pd
catalyst and NO2 radical, intermediate A is converted into
intermediate B, which is further oxidized into intermediate C.10
The desired product 2a is formed with reductive elimination
along with the recovery of the Pd catalyst, thus completing the
catalytic cycle.
In conclusion, we have developed an efficient protocol for
Meyer−Schuster/nitration of propargylic alcohols into α-nitro
enones with a Pd-catalyzed aerobic oxidative system. The α-
nitro enones have been widely used as synthetic building blocks
in organic chemistry and material sciences. The significant
features of this method are (1) mild reaction conditions
avoiding use of any ligand; (2) very good functional group
tolerance; (3) high efficiency with good to excellent isolated
yields. We think this method will merit the synthetic organic
field, and further studies on its scope, mechanism, and
application will be reported in due course in our laboratory.
(3) Wu, X.; Schranck, J.; Neumann, H.; Beller, M. Chem. Commun.
2011, 47, 12462.
(4) (a) Maity, S.; Manna, S.; Rana, S.; Naveen, T.; Mallick, A.; Maiti,
D. J. Am. Chem. Soc. 2013, 135, 3355. (b) Maity, S.; Togati, N.;
Upendra, S.; Maiti, D. Synlett 2014, 25, 603. (c) Naveen, T.; Maity, S.;
Sharma, U.; Maiti, D. J. Org. Chem. 2013, 78, 5949.
(5) Liu, Y.; Zhang, J.; Song, R.; Qian, P.; Li, J. Angew. Chem., Int. Ed.
2014, 53, 9017.
(6) Hao, X.; Gao, P.; Song, X.; Qiu, Y.; Jin, D.; Liu, X.; Liang, Y.
Chem. Commun. 2015, 51, 6839.
(7) (a) Zhang, G.; Peng, Y.; Cui, L.; Zhang, L. Angew. Chem., Int. Ed.
2009, 48, 3112. (b) Onishi, Y.; Nishimoto, Y.; Yasuda, M.; Baba, A.
Org. Lett. 2014, 16, 1176. (c) Zhu, Y.; Sun, L.; Lu, P.; Wang, Y. ACS
Catal. 2014, 4, 1911. (d) Collins, B. S. L.; Suero, M. G.; Gaunt, M. J.
Angew. Chem., Int. Ed. 2013, 52, 5799. (e) Xiong, Y.-P.; Wu, M.-Y.;
Zhang, X.-Y.; Ma, C.-L.; Huang, L.; Zhao, L.-T.; Tan, B.; Liu, X.-Y.
Org. Lett. 2014, 16, 1000. (f) Um, J.; Yun, H.; Shin, S. Org. Lett. 2016,
C
DOI: 10.1021/acs.orglett.6b01740
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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18, 484. (g) Zhang, X.; Teo, W. T.; Chan, P. W. H. Org. Lett. 2009, 11,
4990. (h) Chatterjee, P. N.; Roy, S. J. Org. Chem. 2010, 75, 4413.
(8) (a) Erkkila, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107,
5416. (b) Melchiorre, P. Angew. Chem., Int. Ed. 2012, 51, 9748.
(9) For selected papers on the use of t-BuONO in synthesis:
(a) Manna, S.; Jana, S.; Saboo, T.; Maji, A.; Maiti, D. Chem. Commun.
2013, 49, 5286. (b) Maity, S.; Naveen, T.; Sharma, U.; Maiti, D. Org.
Lett. 2013, 15, 3384. (c) Shen, T.; Yuan, Y.; Jiao, N. Chem. Commun.
2014, 50, 554. (d) Liu, Y.; Zhang, J. L.; Song, R. J.; Qian, P. C.; Li, J.
H. Angew. Chem., Int. Ed. 2014, 53, 9017. (e) Chen, F.; Huang, X.; Li,
X.; Shen, T.; Zou, M.; Jiao, N. Angew. Chem., Int. Ed. 2014, 53, 10495.
(f) Dutta, U.; Maity, S.; Kancherla, R.; Maiti, D. Org. Lett. 2014, 16,
6302.
(10) Majhi, B.; Kundu, D.; Ahammed, S.; Ranu, B. C. Chem. - Eur. J.
2014, 20, 9862.
D
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