Nucleophilic Nitration of Arynes by Sodium Nitrite and its Multicomponent Reaction Leading to Double-Functionalized Arenes

Article abstract of DOI:10.1021/acs.orglett.6b01384

An unusual nucleophilic nitration of arynes by NaNO₂ in the presence of water has been developed, and the concept was further demonstrated to accomplish a double functionalization of arynes using a multicomponent reaction protocol to synthesize pharmaceutically important (2-nitrophenyl)methanol derivatives. Such substitution ortho to -NO₂ is difficult by other means. The reaction conditions are mild and avoid the use of strong acids, expensive transition metal catalysts, and additives.

Full text of DOI:10.1021/acs.orglett.6b01384

Letter
pubs.acs.org/OrgLett
Nucleophilic Nitration of Arynes by Sodium Nitrite and its
Multicomponent Reaction Leading to Double-Functionalized Arenes
Ranjeet A. Dhokale and Santosh B. Mhaske*
Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pune 411 008, India
*
S Supporting Information
ABSTRACT: An unusual nucleophilic nitration of arynes by
NaNO in the presence of water has been developed, and the
2
concept was further demonstrated to accomplish a double
functionalization of arynes using a multicomponent reaction
protocol to synthesize pharmaceutically important (2-
nitrophenyl)methanol derivatives. Such substitution ortho to −NO is difficult by other means. The reaction conditions are
2
mild and avoid the use of strong acids, expensive transition metal catalysts, and additives.
itroaromatics constitute an important class of compounds
that are commonly found in pigments, dyes, advanced
unknown nucleophilic nitration of arynes. Herein we present
our results on the outcome of our envisioned transformation
and its application in a multicomponent reaction.
N
materials, polymers, agrochemicals, rubber, specialty chemicals,
1
−5
intermediates, colorants, explosives, and pharmaceuticals.
The protocol for the nitration of arynes (generated by
11
They are important building blocks in organic synthesis fo5r
accessing complex molecules of pharmaceutical interest.
Nitration is at least one of the steps in the whole synthetic
Kobayashi’s method) was optimized on o-silylaryl triflate 1
using several permutations and combinations (Table 1). Our
initial attempts (Table 1, entries 1 and 2) using NaNO and
2
3
process of almost 65% of active pharmaceutical ingredients. In
CsF as a fluoride source were met with failure. Addition of a
small amount of tetrabutylammonium fluoride (TBAF) in the
same reaction mixture was found to initiate the reaction (Table
view of the above-mentioned applications, nitration of
aromatics is one of the most utilized transformations of
6
industrial interest. Generally it is achieved by strong-acid-
1
, entry 3). However, the use of only TBAF as a fluoride source
catalyzed electrophilic substitution using HNO3 or by
furnished merely a trace amount of nitrobenzene (2) (Table 1,
entry 4). The yield of nitrobenzene could be improved to 40%
by using TBAF as an additive (Table 1, entry 9). At this stage
we speculated that the water present in TBAF might facilitate
the reaction and that probably TBAF as such has no role as an
additive.
Our hypothesis was found to be correct when we performed
the reaction using water as an additive. Finally, by the addition
of a controlled amount of water as an additive, we obtained
nitrobenzene in a maximum 54% yield (Table 1, entry 18). The
use of other metal nitrites did not result in any improvement.
The scalability of the aryne nitration protocol was tested by
performing the reaction of aryne precursor 1 on a 0.5 g scale.
The reaction worked very well, furnishing 2 in 60% yield
7
dinitrogen pentoxide, but examples of nucleophilic aromatic
nitrations are also known, although not very common
5
,8
initially.
Poor regioselectivity, poor functional group
tolerance under harsh reaction conditions, and overnitration
are some of the major issues in nitration processes. Over the
past century, several important advances in the area of aromatic
1
−9
nitration have been reported (Figure 1).
In continuation of
our research interest in the development of novel and original
10
methodologies using arynes as reactive intermediates, we
were curious to see whether an alternative protocol using
simple reagents and mild reaction conditions could be
developed for the synthesis of nitroaromatics by hitherto
(
Table 1, entry 18).
The generality of the optimized protocol was studied on
varyingly substituted aryne precursors (Scheme 1). Aryne
nitration worked equally well with alkyl-substituted aryne
precursors similar to the unsubstituted aryne precursor 1 to
furnish the corresponding nitroaromatics in good yields
(
Scheme 1, 3−5). In the case of halo-substituted aryne
precursors, the expected products formed in the complex
reaction mixture could not be purified to a purity sufficient for
analytical purposes (Scheme 1, 6 and 7).
1
Figure 1. Developments in aromatic nitration. −9
Received: May 12, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01384
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Organic Letters
Table 1. Optimization of the Protocol for Nitration of Arynes ,
Letter
ab
c
entry
solvent
equiv of NaNO2
source of F− (equiv)
additive (equiv)
time (h)
yield (%)
trace
1
2
3
4
5
6
7
8
9
CH CN
1.2
1.2
1.2
1.2
3.0
3.0
2.0
1.5
1.5
4.0
4.0
1.5
2.5
2.5
2.5
2.0
2.0
CsF (3.0)
CsF (3.0)
CsF (3.0)
TBAF (2.0)
KF (2.0)
−
−
24
24
5
3
d
THF
−
15
CH CN
TBAF (0.1)
3
CH CN
−
24
1
trace
29
3
CH CN
18-crown-6 (2.0) + TBAF (0.1)
18-crown-6 (2.0) + TBAF (0.1)
18-crown-6 (3.0)
TBAF (0.1)
3
toluene
THF
KF (2.0)
24
5
27
KF (3.0)
38
CH CN
CsF (2.0)
CsF (4.0)
CsF (4.0)
CsF (4.0)
CsF (4.0)
CsF (4.0)
CsF (4.0)
CsF (4.0)
CsF (4.0)
CsF (4.0)
12
7
30
3
CH CN
TBAF (0.1)
40
3
10
11
12
13
14
15
16
17
18
CH CN
TBAF (0.2)
7
35
3
CH CN
TBAF (0.2)
24
24
24
24
24
24
24
4
27
3
d
CH CN
H O (0.2)
trace
3
2
e
e
e
CH CN
−
−
−
40
3
d
CH CN + H O (1:1)
−
−
3
2
d
CH CN + H O (2:1)
3
2
CH CN
H O (1.0)
27
3
2
CH CN
H O (1.0) premixed in CH CN
40
3
2
3
f
CH CN
2.0
CsF (4.0)
H O (0.25) in CH CN
54/60
3
2
3
a
b
c
d
e
Reactions were performed on a 50 mg scale of 1. 0.8 mL of solvent. Isolated yields. Aryne precursor remained unconsumed. Bottle-grade
f
acetonitrile. The reaction was performed on a 0.5 g scale of 1.
12
Scheme 1. Nitration of Variously Substituted Arynes
functionalized aromatics from arynes. Initially, we screened
several electrophiles such as ketones, alkynes, alkenes, arynes,
alkyl halides, etc. However, the expected product was observed
only in the case of aldehydes. Aldehyde 13 and aryne precursor
1
were used as the substrates for the optimization of the
multicomponent reaction (MCR) protocol. Our first attempt at
the MCR used the reaction condition developed for the
nitration of arynes (Table 1, entry 18). As expected, this did not
furnish the MCR product, since it was obvious that acetonitrile
and water can quench the carbanion intermediate quickly.
Hence, we turned our attention to other reaction conditions
(
Table 1, entry 7). Optimization of the protocol by varying the
ratio of reactants/reagents or by changing the additives (Table
, entries 2−6) provided the best possible conditions for the
MCR, which furnished the desired carbinol 14 in 60% yield
Table 2, entry 3). The suitability of the MCR protocol on a
2
(
larger scale was demonstrated on representative compound 14
by performing the reaction on 0.5 g of aryne precursor 1. We
observed that on the larger scale, the MCR worked better at
room temperature and with less NaNO (3 equiv), providing a
2
6
2% yield of 14 (Table 2, entry 3). Since the aryne precursor
was in excess, it is obvious that the formation of only nitrated
product was also observed in all the cases. 2-Substituted
nitroaromatic compounds such as carbinol 14 and its congeners
obtained from the MCR reaction are of immense pharmaceut-
ical interest and also are precursors to bioactive com-
a
b
The reaction was performed on a 0.5 g scale of 1. ND: yield not
determined.
13−15
pounds.
Hartmann and co-workers reported that these
Electron-donating substituents furnished the corresponding
small-molecule inhibitors can repress the formation of biofilms
nitro compounds in moderate to good yields (Scheme 1, 8−
and hence are important in the development of anti-
14
1
1). The nitration protocol furnished β-nitronaphthalene (12)
infectives. They have also reported their synthesis using a
Grignard reaction, but few other approaches to such carbinols
as the major product in moderate yield and regioselectivity (α:β
1:5) with an unsymmetrically substituted naphthalene-based
1
6
=
are also known. In view of their importance and to
demonstrate the generality of the developed MCR protocol,
we studied the substrate scope.
aryne precursor.
The above results prompted us to take up the challenge of
developing a three-component reaction utilizing aryne, NaNO2,
and an electrophile that would provide access to double-
A good yield of the MCR product 14 was obtained for p-
chlorobenzaldehyde during optimization; however, when the
B
DOI: 10.1021/acs.orglett.6b01384
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Organic Letters
Letter
Table 2. Optimization of the MCRa,b
source of F− (equiv)
additive (equiv)
time (h)
yield (%)
c
entry
solvent
NaNO (equiv)
2
1
2
3
4
5
6
CH CN
2.0
CsF (4.0)
KF (5.0)
KF (5.0)
KF (5.0)
KF (5.0)
H O (0.25)
12
24
2/24
2
−
44
3
2
THF
THF
THF
THF
THF
3.0
18-crown-6 (5.0)
d
4.0/3.0
2.0
18-crown-6 (5.0)
18-crown-6 (5.0)
60/62
36
−
−
t
3.0
18-crown-6 (6.0) + Mg(O Bu) (0.2)
24
24
2
3.0
KF (5.0)
18-crown-6 (6.0) + Cu(OTf) (0.2)
d
2
a
b
c
reaction was performed on 50 mg scale of 1. 0.5 mL solvent. isolated yields. reaction was performed on 0.5 g scale of 1 at rt.
para substituent was changed to methyl to obtain carbinol 15,
Scheme 3. MCR with Selected Aryne Precursors
the yield decreased drastically (Scheme 2). Using aldehydes
Scheme 2. Aldehyde Substrate Scope of the MCR
Scheme 4. Deuterium Incorporation Experiments
substituted with an electron-withdrawing group resulted in
improved yields, furnishing carbinols 16−18. In the case of p-
methoxybenzaldehyde, the corresponding carbinol 19 was not
observed. These results clearly show that electronic factors play
an important role in this MCR. β-Naphthaldehyde and
furfuraldehyde also reacted smoothly to provide the corre-
sponding carbinols 20 and 21 in 35% and 31% yield,
respectively. However, butyraldehyde did not react at all
under the developed reaction conditions, and carbinol 22 was
not observed. In all of these MCRs, a varying amount of
aldehyde remained unreacted.
The MCR worked well with the unsubstituted aryne
precursor 1. We also performed the reaction on varyingly
substituted aryne precursors (Scheme 3) and found that it
worked well with alkyl-substituted and electron-rich aryne
precursors to furnish carbinols 23−25 in moderate to good
yields. However, product 26 was not observed when a difluoro-
substituted aryne precursor was used as the substrate.
when the reaction conditions of Table 1, entry 7 were applied
on this substrate using THF-d as the solvent (Scheme 4a),
8
suggesting that the moisture present in 18-crown-6 or in the
reaction mixture might be the probable source of protons in 10.
This experiment also provides an explanation for the formation
of only nitrated products in the MCR. Our standard protocol
(Table 1, entry 18) was applied in the presence of CD CN and
3
H O, which provided 10 with 24% deuterium incorporation
2
(Scheme 4b), suggesting that the solvent CH CN also acts as a
3
source of protons. When D O was used in combination with
2
CD CN, we observed 49% deuterium incorporation (Scheme
3
4c), indicating that water and the solvent are sources of protons
in this reaction.
In summary, we have developed a novel transformation of
arynes to obtain nitroaromatics under mild reaction conditions
in the presence of water and have also demonstrated an
application of the concept in a multicomponent reaction
involving aryne, NaNO , and aromatic aldehyde to synthesize
2
A tentative mechanistic aspect study was performed by
means of deuterium incorporation experiments (Scheme 4).
Incorporation of deuterium in product 10 was studied by using
deuterated solvents. Deuterium incorporation was not observed
carbinol derivatives of pharmaceutical interest. We believe that
both of the protocols developed herein will be useful in late-
stage functional group transformations. Currently, we are
working on developing MCRs involving other electrophiles and
C
DOI: 10.1021/acs.orglett.6b01384
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
exploring the possibility of applying the developed protocol in
total syntheses of natural products.
H.; Ohshita, J.; Kunai, A. Org. Lett. 2007, 9, 3367. (d) Yoshida, H.;
Fukushima, H.; Ohshita, J.; Kunai, A. Angew. Chem., Int. Ed. 2004, 43,
3
935.
(
(
13) Chauhan, J.; Fletcher, S. Tetrahedron Lett. 2012, 53, 4951.
14) Storz, M. P.; Maurer, C. K.; Zimmer, C.; Wagner, N.; Brengel,
ASSOCIATED CONTENT
Supporting Information
■
*
S
̈
̈
C.; de Jong, J. C.; Lucas, S.; Musken, M.; Haussler, S.; Steinbach, A.;
Hartmann, R. W. J. Am. Chem. Soc. 2012, 134, 16143.
(15) Storz, M. P.; Allegretta, G.; Kirsch, B.; Empting, M.; Hartmann,
R. W. Org. Biomol. Chem. 2014, 12, 6094.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01384.
(16) (a) Nagaki, A.; Kim, H.; Yoshida, J-i. Angew. Chem., Int. Ed.
Experimental procedures, spectral and analytical data,
and copies of NMR spectra of all compounds (PDF)
2
009, 48, 8063. (b) Yu, A.; Cheng, B.; Wu, Y.; Li, J.; Wei, K.
Tetrahedron Lett. 2008, 49, 5405. (c) Sapountzis, I.; Knochel, P. Angew.
Chem., Int. Ed. 2002, 41, 1610.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: sb.mhaske@ncl.res.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
R.A.D. thanks UGC-New Delhi for a research fellowship.
S.B.M. gratefully acknowledges generous financial support from
DST, CSIR-ORIGIN, CSIR-OSDD New Delhi, and CSIR-
NCL (startup grant).
REFERENCES
■
(
1) (a) Surya Prakash, G. K.; Gurung, L.; Glinton, K. E.; Belligund,
K.; Mathew, T.; Olah, G. A. Green Chem. 2015, 17, 3446. (b) Fors, B.
P.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 12898.
(
2) Yang, H.; Li, Y.; Jiang, M.; Wang, J.; Fu, H. Chem. - Eur. J. 2011,
17, 5652.
(
3) Kulkarni, A. A. Beilstein J. Org. Chem. 2014, 10, 405.
(
4) Nowrouzi, N.; Mehranpour, A. M.; Bashiri, E.; Shayan, Z.
Tetrahedron Lett. 2012, 53, 4841.
(
5) Firth, D. Innovations Pharm. Technol. 2001, 132.
(
6) Surya Prakash, G. K.; Panja, C.; Mathew, T.; Surampudi, V.;
Petasis, N. A.; Olah, G. A. Org. Lett. 2004, 6, 2205.
7) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New
York, 2001.
8) Baik, W.; Yun, S.; Rhee, J. U.; Russell, G. A. J. Chem. Soc., Perkin
Trans. 1 1996, 1, 1777.
9) Selected references: (a) Pawar, G. G.; Brahmanandan, A.; Kapur,
(
(
(
M. Org. Lett. 2016, 18, 448. (b) Natarajan, P.; Chaudhary, R.;
Venugopalan, P. J. Org. Chem. 2015, 80, 10498. (c) Liang, Y.-F.; Li, X.;
Wang, X.; Yan, Y.; Feng, P.; Jiao, N. ACS Catal. 2015, 5, 1956. (d) Ji,
Y-f.; Yan, H.; Jiang, Q-b. Eur. J. Org. Chem. 2015, 2015, 2051.
(
(
e) Zhao, J.; Li, P.; Xia, C.; Li, F. RSC Adv. 2015, 5, 32835.
f) Chatterjee, N.; Bhatt, D.; Goswami, A. Org. Biomol. Chem. 2015,
́
13, 4828. (g) Hernando, E.; Castillo, R. R.; Rodríguez, N.; Arrayas, R.
G.; Carretero, J. C. Chem. - Eur. J. 2014, 20, 13854. (h) Zhu, C.; Falck,
J. R. Adv. Synth. Catal. 2014, 356, 2395. (i) Majhi, B.; Kundu, D.;
Ahammed, S.; Ranu, B. C. Chem. - Eur. J. 2014, 20, 9862. (j) Li, Y.-X.;
Li, L.-H.; Yang, Y.-F.; Hua, H.-L.; Yan, X.-B.; Zhao, L.-B.; Zhang, J.-B.;
Ji, F.-J.; Liang, Y. M. Chem. Commun. 2014, 50, 9936. (k) Lu, Y.; Li, Y.;
Zhang, R.; Jin, K.; Duan, C. Tetrahedron 2013, 69, 9422. (l) Olah, G.
A.; Malhotra, R.; Narang, S. C. Nitration: Methods and Mechanisms;
Wiley-VCH: New York, 1989. (m) Schofield, K. Aromatic Nitration;
Cambridge University Press: Cambridge, U.K., 1980.
(
10) (a) Pandya, V. G.; Mhaske, S. B. Org. Lett. 2014, 16, 3836.
(
(
b) Dhokale, R. A.; Mhaske, S. B. Org. Lett. 2013, 15, 2218.
c) Dhokale, R. A.; Thakare, P. R.; Mhaske, S. B. Org. Lett. 2012, 14,
3
(
1
(
994.
11) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
211.
12) (a) Bhojgude, S. S.; Baviskar, D. B.; Gonnade, R. G.; Biju, A. T.
Org. Lett. 2015, 17, 6270. (b) Bhunia, A.; Yetra, S. R.; Biju, A. T. Chem.
Soc. Rev. 2012, 41, 3140. (c) Yoshida, H.; Morishita, T.; Fukushima,
D
DOI: 10.1021/acs.orglett.6b01384
Org. Lett. XXXX, XXX, XXX−XXX