The Baylis-Hillman acetates in organic synthesis: Unprecedented sodium nitrite induced intramolecular Friedel-Crafts cyclization of secondary nitro compounds

Article abstract of DOI:10.1039/c4ra03573a

Unprecedented sodium nitrite mediated intramolecular Friedel-Crafts cyclization of alkyl (E)-2-arylidene-4-nitroalkanoates and (E)-3-arylidene-5- nitroalkan-2-ones derived from Baylis-Hillman acetates, providing a facile protocol for synthesis of naphthal

Full text of DOI:10.1039/c4ra03573a

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
The Baylis–Hillman acetates in organic synthesis:
Unprecedented sodium nitrite induced
intramolecular Friedel–Crafts cyclization of
secondary nitro compounds†
Cite this: RSC Adv., 2014, 4, 23966
Received 19th April 2014
Accepted 19th May 2014
*
Deevi Basavaiah and Daggula Mallikarjuna Reddy
DOI: 10.1039/c4ra03573a
www.rsc.org/advances
Unprecedented sodium nitrite mediated intramolecular Friedel–Crafts
Although the in situ generated transient (Kornblum–Mios-
cyclization of alkyl (E)-2-arylidene-4-nitroalkanoates and (E)-3-aryli- kowski) species A, B and C in Scheme 1, look potential elec-
dene-5-nitroalkan-2-ones derived from Baylis–Hillman acetates, trophiles for F–C reaction, to the best of our knowledge, there
providing a facile protocol for synthesis of naphthalenes, phenan- have been, so far, no such reports in the literature. Therefore we
threnes, and carbazoles has been described.
envisioned that secondary nitro-alkanes (3) obtained from the
BH acetates (1) would be excellent synthons for intramolecular
F–C cyclization using NaNO2 as reagent to provide a simple
protocol for obtaining naphthalenes (4a–p), phenanthrenes
(4q–s) and carbazoles (4t, 4u) as shown in the retro synthetic
strategy (Scheme 2). Accordingly, in continuation of ongoing
research program7 on the BH reaction8,9 we examined these
reactions and were pleased to see NaNO2 mediated intra-
molecular F–C cyclization of secondary nitroalkanes (3) work
reasonably well. These results are reported in this
communication.
We began our investigations with methyl (E)-2-(3-methoxy-
benzylidene)-4-nitropentanoate (3a, R1 ¼ OMe, R2 ¼ Me, Ar ¼ 3-
MeOC6H4) which was easily obtained via alkylation of nitro-
ethane 2a with the BH-acetate, methyl 3-acetoxy-3-(3-methox-
yphenyl)-2-methylenepropanoate (1a, R1 ¼ OMe, Ar ¼ 3-
MeOC6H4).
The nitro group is one of the key functional groups that plays a
vital role in synthetic chemistry.1 The high electron withdrawing
ability of the nitro group has resulted in numerous applications
of nitroalkanes as carbon nucleophiles in various carbon–
carbon bond forming reactions.2 The Nef reaction is yet another
useful reaction which transforms the nitro group into the
carbonyl group.3 It is very interesting to note the work of
Kornblum who, as early as in 1956, reported an elegant
conversion of aliphatic nitro compounds into ketones via the
reaction with alkyl nitrite and sodium nitrite. The reaction is
believed to proceed via nitrosation of aci-nitronate.4 Four
decades later in 1997 Mioskowski has reported an interesting
sodium nitrite mediated nitrosation of primary nitroalkanes
leading to the formation of carboxylic acids.5a In 2004 the
research group of Mioskowski also described facile conversion
of secondary nitroalkanes into ketones using sodium nitrite
under neutral conditions (Scheme 1).5b
(1)
It needs to be mentioned here that there are a few reports in
the literature on the application of aliphatic nitro compounds
as electrophiles in the Friedel–Cras (F–C) reaction in the
presence of various acids.6 Kim and co-workers reported sul-
phuric acid mediated intramolecular F–C reaction of the
aliphatic nitro compounds obtained from the Baylis–Hillman
(BH) adducts producing naphthalene derivatives.6d
We performed the reaction between methyl (E)-2-(3-
methoxybenzylidene)-4-nitropentanoate (3a) (1 mmol) with
sodium nitrite in the presence of various solvents and at
different reaction conditions (entries 1–14, Table 1). In this
direction, best results were obtained when a solution of 3a
(1 mmol) and NaNO2 (1 mmol) in DMF (4 mL) was heated at
100 ꢀC for 8 h, thus providing methyl 5-methoxy-4-methyl-
naphthalene-2-carboxylate (ortho-4a) (ortho cyclized product)
and methyl 7-methoxy-4-methylnaphthalene-2-carboxylate
(para-4a) (para cyclized product) in 13% and 71% isolated yields
respectively (Table 1, entry 11) aer usual work up, followed by
purication through silica gel column chromatography.10
School of Chemistry, University of Hyderabad, Hyderabad-500 046, India. E-mail:
dbsc@uohyd.ernet.in; Fax: +91-40-23012460
† Electronic supplementary information (ESI) available: Representative
experimental procedure with spectral data of 3a–v, 4a–u, 5a, 6 and 1H and 13C
NMR spectra of 4a–u and 6, crystal data (CCDC 982203, 982204, 982657 and
982658) and ORTEP diagrams of ortho-4c, 4r–t. See DOI: 10.1039/c4ra03573a
23966 | RSC Adv., 2014, 4, 23966–23970
This journal is © The Royal Society of Chemistry 2014

View Article Online
Communication
RSC Advances
Scheme 1 Formation of ketone from secondary nitroalkane
With a view to further understand this strategy we have
subjected the nitro compounds (3b and 3c) [prepared from the
BH acetate (1a) and nitroalkanes (2b and 2c) (R2 ¼ Ph, Bn)] to
the reaction with NaNO2 which provided the required
substituted naphthalenes 4b and 4c in overall 86 and 84%
yields respectively [see Table 2 for composition of para (major)
and ortho (minor) cyclized products]. We have also
examined the F–C cyclization of the nitro compound (3d,
Scheme 2 Retro synthetic strategy.
Table 1 Optimization of reaction conditionsa
Entry
NaNO2 (eq.)
Solvent
Temp/ꢀC
Time/h
Yieldb (%) o-4a/p-4a
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
2.0
DMSO–H2Oc
DMSO
DMF
DMF
DMF
DMF
EtOH
1,4-dioxane
Water
DMSO
DMF
60
60
RT
40
60
20
20
24
24
20
15
24
24
24
8
16/65
14/68
N.R
N.R
11/67
12/71
N.R
N.R
N.R
12/69
13/71
8/40
8/48
10/70
80
78
100
100
100
100
120
100
100
9
10
11
12
13
14
8
8
8
8
DMF
DMF
DMF
a
c
All reactions were carried out on 1 mmol scale of 3a in 4 mL of solvent. b Isolated yields based on 3a. DMSO–H2O (3.5 : 0.5 mL).
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 23966–23970 | 23967

View Article Online
RSC Advances
Communication
Table 2 Understanding the scope of reactiona
Table 3 Scope of the reactiona
a
All reactions were carried out on 1 mmol scale of 3 with 1 equiv. of
NaNO2 in DMF (4 mL). The yields in parentheses are isolated yields
b
based on 3. The structure of this molecule was also conrmed by
single crystal X-ray data analysis [see ESI†].
R1 ¼ Me, R2 ¼ Ph, Ar ¼ 3-MeOC6H4) with NaNO2 which gave the
desired naphthalene, para-4d in 70% yield along with ortho-4d
in 14% yield (Table 2).
With a view to understand the generality of this reaction we
have prepared representative arylidene secondary nitroalkane
compounds (3e–u) (eqn (1)) and subjected them to Friedel–
Cras cyclization reaction under the inuence of NaNO2. The
resulting naphthalene (4e–p), phenanthrene (4q–s) and carba-
zole (4t and 4u) derivatives were obtained in good to excellent
yields as shown in Table 3.
a
All reactions were carried out on 1 mmol scale of 3 with 1 equiv. of
NaNO2 in DMF (4 mL). The yields in parentheses are isolated yields
based on nitro compounds 3. The structures of these molecules
were conrmed by single crystal X-ray data analysis (see ESI†).
b
With a view to understand the role of electron withdrawing
group on aryl system in the F–C cyclization we have selected
methyl
3-acetoxy-3-(2-nitrophenyl)-2-methylenepropanoate
(1m) as a substrate for reaction with nitroethane (2a) in the
presence of K2CO3 in DMF. In this case we did not observe
formation of any arylidene secondary nitroalkane compound,
but we have directly obtained methyl 4-methylnaphthalene-2-
carboxylate (6) in 57% yield (Scheme 3). It should be mentioned
here that a similar reaction is already reported by Horn and
Perez.11 We have examined alkylation of methyl 3-acetoxy-3-(3-
nitrophenyl)-2-methylenepropanoate (1n) with nitroethane (2a)
in the presence of K2CO3 and found that this reaction was not
clean (Scheme 3). However alkylation of methyl 3-acetoxy-3-(4-
nitrophenyl)-2-methylenepropanoate (1o) with nitroethane (2a)
in the presence of K2CO3 provided the desired nitroarylidene
secondary nitroalkane derivative (3v) in 45% yield. But, our
attempts for intramolecular F–C reaction of 3v with NaNO2
under similar conditions were not successful (Scheme 3).
Next we have studied the role of acids12 (both Lewis and
Brønsted) as additives on the NaNO2 mediated F–C reaction of
3a. Since similar F–C reactions of arylidene secondary nitro
compounds using conc. H2SO4 is already known in the litera-
ture6d we did not use strong acids in our studies.12 We have
Scheme 3 Towards understanding role of nitro group on aryl system.
examined the applications of AlCl3 and AcOH as additives in our
studies (Table 4). From these studies it is clear that AcOH–DMF
at 100 ꢀC accelerates the rate of reaction to a reasonable extent
(entry 8: Table 4) providing slightly inferior yields in compar-
ison to our earlier result (entry 11: Table 1). The rate accelera-
tion might be attributed to the possible stabilization of aci-
nitronate with acid as mentioned in Scheme 1.
A plausible mechanism for NaNO2 mediated intramolecular
F–C reaction is illustrated in Scheme 4 taking the nitro
compound 3a as a model case and assuming that transient
species oxaziridine (B) as the reactive electrophile. However we
cannot rule out the involvement of any other similar reactive
electrophiles. In fact, we have also considered the possibility of
23968 | RSC Adv., 2014, 4, 23966–23970
This journal is © The Royal Society of Chemistry 2014

View Article Online
Communication
RSC Advances
Table 4 Role of acid additive on NaNO2 mediated F–C reactiona
Entry
Additive
Solvent
Temp/ꢀC
Time/h
Yieldb (%) o-4a/p-4a
1
2
3
4
5
6
7
8
AlCl3
AlCl3
AlCl3
AlCl3
AcOH
AcOH (excess)
AcOH
DCE
DCE
DMF
DMF
DCE
RT
80
24
12
24
12
24
24
24
4
N.R
N.R
N.R
Trace
N.R
N.R
5/21
14/66
RT
100
RT
RT
RT
100
DMF
DMF
AcOH
a
All reactions were carried out on 1 mmol scale of 3a in 4 mL of solvent. b Isolated yields based on 3a.
In summary, we have, for the rst time, described novel
sodium nitrite mediated intramolecular Friedel–Cras alkyl-
ation of secondary nitroalkanes derived from Baylis–Hillman
adducts under neutral conditions. This reaction provides a
facile methodology for the synthesis of naphthalene, phenan-
threne and carbazole derivatives that are of tremendous
importance in medicinal and material chemistry. Since this
methodology describes the Friedel–Cras reaction under
neutral conditions we believe this protocol will nd extensive
applications in synthetic chemistry.
Scheme 4 Plausible mechanism.
generation of in situ ketone (D as in Scheme 1) which might
cyclize in the presence of NaNO2. Even though we are not sure of
such possibility, with a view to conrm our understanding we
made the ketone13 [methyl (E)-2-(3-methoxybenzylidene)-4-oxo-
pentanoate (5a)] via Nef reaction of 3a which then was treated
with NaNO2 in DMF at 100 ꢀC for longer times (upto 20 h). We
did not notice formation of any Friedel–Cras product. This
result unequivocally conrms that the ketone (5a) is not the key
intermediate and further conrms that the electrophile is the
Kornblum–Mioskowski transient oxaziridine species (B) or
related transient such as A or C as shown in Scheme 1. It is
believed that the formation of heterocyclic compound (4t) from
3t follows a similar mechanism as in the formation of 4a from
3a as described in Scheme 4.
It should be mentioned here the importance of polycyclic
aromatic compounds, especially substituted naphthalenes,
phenanthrenes and carbazoles as these structural frameworks
are present in several biologically active molecules14 and
natural products.14d,15 Also these compounds are extensively
used as building blocks for the synthesis of biologically active
molecules14 and polycyclic aromatic materials.16 Therefore,
development of facile strategies for obtaining these molecules
has been and continues to be a challenging endeavor in
synthetic chemistry.17,9j,18 The present methodology indeed
constitutes another important strategy for obtaining these
structurally important frameworks using NaNO2 as a mild
reagent.
Acknowledgements
We thank the DST (New Delhi) for funding this project. DMR
thanks CSIR and DST (New Delhi) for his research fellowships.
We thank the UGC (New Delhi) for support and providing some
instrumental facilities. We are grateful to the National Single-
Crystal X-ray and HRMS facilities funded by the DST. We also
thank Professor S. Pal, School of Chemistry, and University of
Hyderabad for helpful discussions regarding X-ray data
analysis.
Notes and references
1 (a) J. P. Adams and J. R. Paterson, Perkin 1 (2000), 2000, 3695;
(b) J. P. Adams, J. Chem. Soc., Perkin Trans. 1, 2002, 2586.
2 (a) F. A. Luzzio, Tetrahedron, 2001, 57, 915; (b) R. Ballini,
A. Palmieri and L. Barboni, Chem. Commun., 2008, 2975; (c)
R. Ballini and M. Petrini, ARKIVOC, 2009, 195.
3 R. Ballini and M. Petrini, Tetrahedron, 2004, 60, 1017.
4 N. Kornblum, R. K. Blackwood and D. D. Mooberry, J. Am.
Chem. Soc., 1956, 78, 1501.
5 (a) C. Matt, A. Wagner and C. Mioskowski, J. Org. Chem.,
1997, 62, 234; (b) A. Gissot, S. N’Gouela, C. Matt,
A. Wagner and C. Mioskowski, J. Org. Chem., 2004, 69, 8997.
6 (a) V. Bonvino, G. Casini, M. Ferappi, G. M. Cingolani and
B. R. Pietroni, Tetrahedron, 1981, 37, 615; (b) G. Casini,
M. Ferappi, G. M. Cingolani and B. R. Pietroni, La Chimica
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 23966–23970 | 23969

View Article Online
RSC Advances
Communication
e l'Industria, 1974, 56, 463; (c) N. Ono, T. Yanai, A. Kamimura
and A. Kaji, J. Chem. Soc., Chem. Commun., 1986, 1285; (d)
product and compound 3a was intact. We thank this
referee for the suggestion.
K. Y. Lee, S. Gowrisankar, Y. J. Lee and J. N. Kim, 11 C. R. Horn and M. Perez, Synlett, 2005, 1480.
Tetrahedron, 2006, 62, 8798.
7 (a) D. Basavaiah, B. S. Reddy and H. Lingam, Tetrahedron,
2013, 69, 1994; (b) D. Basavaiah, S. S. Badsara and
12 As suggested by one of the referee, we have examined the
role of acid additives in the F–C reactions. We thank this
referee for the suggestion.
B. C. Sahu, Chem. – Eur. J., 2013, 19, 2961; (c) D. Basavaiah, 13 We prepared methyl (E)-2-(3-methoxybenzylidene)-4-
K. S. Kumar, K. Aravindu and B. Lingaiah, RSC Adv., 2013,
3, 9629; (d) D. Basavaiah and D. M. Reddy, Org. Biomol.
Chem., 2012, 10, 8774; (e) D. Basavaiah and D. V. Lenin,
Eur. J. Org. Chem., 2010, 5650; (f) D. Basavaiah and
R. J. Reddy, Org. Biomol. Chem., 2008, 6, 1034; (g)
oxopentanoate (5a) from 3a via the Nef reaction following
the literature procedure(a) A. Chamakh, M. M'hirsi,
J. Villieras, J. Lebreton and H. Amri, Synthesis, 2000, 295;
(b) J. M. Kim, Y. J. Im, T. H. Kim and J. N. Kim, Bull.
Korean Chem. Soc., 2002, 23, 657.
D. Basavaiah and T. Satyanarayana, Chem. Commun., 2004, 14 (a) T. Ukita, Y. Nakamura, A. Kubo, Y. Yamamoto,
32; (h) D. Basavaiah, D. S. Sharada and A. Veerendhar,
Tetrahedron Lett., 2004, 45, 3081; (i) D. Basavaiah and
R. M. Reddy, Tetrahedron Lett., 2001, 42, 3025; (j)
D. Basavaiah, M. Bakthadoss and S. Pandiaraju, Chem.
Commun., 1998, 1639.
8 For recent reviews on BH reaction see:(a) Y. Wei and M. Shi,
Chem. Rev., 2013, 113, 6659; (b) D. Basavaiah and B. C. Sahu,
Chimia, 2013, 67, 8; (c) T.-Y. Liu, M. Xie and Y.-C. Chen,
M. Takahashi, J. Kotera and T. Ikeo, J. Med. Chem., 1999,
42, 1293; (b) D. V. K. Murty, M. Kruseman-Aretz,
S. Rouhafza-Fard, C. J. Bedord, J. M. Young, G. Jones and
M. Venuti, Neuropharmacology, 1985, 44, 886; (c)
W. T. Colwell, V. Brown, P. Christie, J. Lange, C. Reece,
K. Yamamoto and D. W. Henry, J. Med. Chem., 1972, 15,
771; (d) H.-J. Knolker and K. R. Reddy, Chem. Rev., 2002,
102, 4303.
Chem. Soc. Rev., 2012, 41, 4101; (d) D. Basavaiah and 15 (a) J. Ren, F. Zhang, X. Liu, L. Li, G. Liu, X. Liu and Y. Che,
G. Veeraraghavaiah, Chem. Soc. Rev., 2012, 41, 68; (e)
D. Basavaiah, B. S. Reddy and S. S. Badsara, Chem. Rev.,
2010, 110, 5447; (f) V. Declerck, J. Martinez and F. Lamaty,
Chem. Rev., 2009, 109, 1; (g) V. Singh and S. Batra,
Tetrahedron, 2008, 64, 4511; (h) G. Masson, C. Housseman
and J. Zhu, Angew. Chem., Int. Ed., 2007, 46, 4614; (i)
Org. Lett., 2012, 14, 6226; (b) K. Krohn, S. F. Kouam,
S. Cludius-Brandt, S. Draeger and B. Schulz, Eur. J. Org.
Chem., 2008, 3615; (c) M. Gondo, N. Tanaka, T. Tanaka,
K. Shimomura, F. Nakanishi and K. Ishimaru,
Phytochemistry, 1999, 51, 879; (d) T.-S. Wu, L.-F. Ou and
C.-M. Teng, Phytochemistry, 1994, 36, 1063.
D. Basavaiah, A. J. Rao and T. Satyanarayana, Chem. Rev., 16 (a) K. M. Omer, S.-Y. Ku, Y.-C. Chen, K.-T. Wong and
2003, 103, 811.
A. J. Bard, J. Am. Chem. Soc., 2010, 132, 10944; (b)
A. M. Machado, M. Munaro, T. D. Martins, L. Y. A. Davila,
R. Giro, M. J. Caldas, T. D. Z. Atvars and L. C. Akcelrud,
Macromolecules, 2006, 39, 3398; (c) J. E. Anthony, Angew.
Chem., Int. Ed., 2008, 47, 452.
9 For recent papers on BH reactions see:(a) F.-L. Hu, Y. Wei,
M. Shi, S. Pindi and G. Li, Org. Biomol. Chem., 2013, 11,
1921; (b) D. Basavaiah, B. S. Reddy and H. Lingam,
Tetrahedron, 2013, 69, 10060; (c) J. T. M. Correia,
M. T. Rodrigues, Jr, H. Santos, C. F. Tormena and 17 For recent synthesis of naphthalenes, see:(a) R. S. Reddy,
F. Coelho, Tetrahedron, 2013, 69, 826; (d) T. Kumar,
S. M. Mobin and I. N. N. Namboothiri, Tetrahedron, 2013,
69, 4964; (e) Y. Yao, J.-L. Li, Q.-Q. Zhou, L. Dong and
Y.-C. Chen, Chem. – Eur. J., 2013, 19, 9447; (f) H. Zhu,
N. Shao, T. Chen and H. Zou, Chem. Commun., 2013, 49,
7738; (g) Y.-L. Yang, Y. Wei and M. Shi, Org. Biomol. Chem.,
P. K. Prasad, B. B. Ahuja and A. Sudalai, J. Org. Chem.,
2013, 78, 5045; (b) C. C. Malakar, K. Sudheendran,
H.-G. Imrich, S. Mika and U. Beifuss, Org. Biomol. Chem.,
2012, 10, 3899; (c) C. Feng and T.-P. Loh, J. Am. Chem. Soc.,
2010, 132, 17710; (d) R. Balamurugan and V. Gudla, Org.
Lett., 2009, 11, 3116.
2012, 10, 7429; (h) M. E. Kra, M. J. Campbell, S. Kerrigan 18 For recent synthesis of phenanthrenes and carbazoles see:(a)
and J. W. Cran, Tetrahedron Lett., 2011, 52, 1090; (i)
H.-H. Kuan, R. J. Reddy and K. Chen, Tetrahedron, 2010,
66, 9875; (j) S. H. Kim, S. Lee, H. S. Lee and J. N. Kim,
Tetrahedron Lett., 2010, 51, 6305.
L. Nassar-Hardy, C. Deraedt, E. Fouquet and F.-X. Felpin,
Eur. J. Org. Chem., 2011, 4616; (b) K. Wang, M. Lu, A. Yu,
X. Zhu and Q. Wang, J. Org. Chem., 2009, 74, 935; (c)
A. W. Freeman, M. Urvoy and M. E. Criswell, J. Org. Chem.,
2005, 70, 5014; (d) J. Zhao and R. C. Larock, Org. Lett.,
2005, 7, 701.
10 As suggested by one of the referees, we have also performed
the reaction with NaNO3 instead of NaNO2. In this case
(using NaNO3) we did not notice formation of any F–C
23970 | RSC Adv., 2014, 4, 23966–23970
This journal is © The Royal Society of Chemistry 2014