A new synthesis of 'push-pull' naphthalenes by condensation of nitro-2-methylbenzoate esters with dimethylacetamide dimethyl acetal

Article abstract of DOI:10.1016/S0040-4039(02)00228-9

Whereas condensation of 2-methyl-3-nitrobenzoate esters with dimethylformamide dimethyl acetal gives 5-nitroisocoumarin, analogous condensation with dimethylacetamide dimethyl acetal proceeds via a different route, affording 1-methoxy-3-dimethylamino-5-ni

Full text of DOI:10.1016/S0040-4039(02)00228-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2299–2302
A new synthesis of ‘push–pull’ naphthalenes by condensation of
nitro-2-methylbenzoate esters with dimethylacetamide
dimethyl acetal
See-Mun Wong, Bhavini Shah, Priyal Shah, Ian C. Butt, Esther C. Y. Woon, James A. Wright,
Andrew S. Thompson, Christopher Upton and Michael D. Threadgill*
Department of Pharmacy & Pharmacology, University of Bath, Bath BA2 7AY, UK
Received 2 January 2002; revised 21 January 2002; accepted 30 January 2002
Abstract—Whereas condensation of 2-methyl-3-nitrobenzoate esters with dimethylformamide dimethyl acetal gives 5-nitroisocou-
marin, analogous condensation with dimethylacetamide dimethyl acetal proceeds via a different route, affording 1-methoxy-3-
dimethylamino-5-nitronaphthalene in good yield. Extension of the reaction to other naphthalenes with this novel ‘push–pull’
substitution motif has been explored. A deuterium labelling study revealed that equilibration of the alkoxy groups in the reaction
mixture took place before the final carbocyclisation. © 2002 Elsevier Science Ltd. All rights reserved.
followed a similar path but the cyclisation with silica
gel was much slower and gave lower yields of 3
(Scheme 1). This observation is consistent with steric
obstruction by the bulky isopropyl group during
cyclisation.
Most syntheses of polysubstituted naphthalenes involve
modification and substitution of a preformed bicyclic
naphthalene core, with a few employing construction of
the rings with the substituents already attached to the
acyclic or monocyclic precursors. Examples of the latter
ring-closure routes include Diels–Alder cyclisations of
dienes with benzoquinones,1,2 acid-catalysed cyclisa-
tions of phenylethylidenemalononitriles to 2-cyanon-
aphthyl-1-amines3 and base-catalysed cyclisation of
2-allyl-N,N-dialkylbenzamides to naphth-1-ols.4 How-
ever, these routes are not generally amenable to synthe-
sis of substituted alkoxy- and amino-naphthalenes. We
report here a new synthesis of novel polysubstituted
naphthalenes, which bear the ‘push–pull’ motif of elec-
tron-withdrawing substituents on one ring and electron-
donating substituents on the other.
We5,6 and others7 have previously reported that con-
densation of methyl 2-methyl-3-nitrobenzoate 1a with
dimethylformamide dimethyl acetal (dimethoxymethyl
dimethylamine, DMFDMA) gives the enamine
2
(Scheme 1). Treatment of this crude enamine with silica
gel provides sufficient acid catalysis to hydrolyse the
enamine and cyclise the intermediate enol to the isocou-
marin 3. In an initial attempt to explore the scope and
mechanism of this reaction, the isopropyl ester 1b8 was
treated similarly with DMFDMA; the condensation
Scheme 1. Reactions of 2-methyl-3-nitrobenzoate esters with
orthoamides. Reagents and conditions: (i) HC(OMe)2NMe2,
DMF, 150°C, 16 h, 53%; (ii) SiO2, EtOAc; (iii)
MeC(OMe)2NMe2, MeCONMe2, 150°C, 16 h, 77%.
* Corresponding author. Tel.: +44-1225-826840; fax: +44-1225-
826114; e-mail: m.d.threadgill@bath.ac.uk
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00228-9

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S.-M. Wong et al. / Tetrahedron Letters 43 (2002) 2299–2302
In contrast, when the ester 1a was treated with
dimethylacetamide dimethyl acetal (1,1-dimethoxyethyl
dimethylamine, DMADMA),9 none of the expected
3-methyl-5-nitroisocoumarin was formed. The sole
isolable product was a deep red solid, formed in high
yield. The strong colour suggested that it was not an
isocoumarin (most 5-nitroisocoumarins are pale yel-
low); this was borne out by the lack of a carbonyl
absorption in the IR spectrum.9 The 1H NMR
spectrum9 showed five aromatic protons, together with
signals for NMe2 and OMe. One of the aromatic pro-
ton signals was shifted markedly upfield at l 6.48,
corresponding to a location between the electron-
donating NMe2 and OMe groups. These data, together
with the mass spectrum, allowed the assignment of the
naphthalene structure 6 to the condensation product.
The locations of the NMe2 and OMe substituents were
confirmed by a NOESY spectrum, which showed NOE
connectivity between OMe and the 2-H (l 6.48, d,
J=2.3 Hz) and between NMe2 and the 2-H and 4-H (l
7.37, d, J=2.3 Hz). The deep red colour is a conse-
quence of the ‘push–pull’ substitution pattern of the
naphthalene chromophore. Compounds with a nitro
group at one end of a conjugated system and an amine
at the other are often deeply coloured, ranging from
simple 2-nitroethenamines10 to laser dyes and dark red
1-nitro-7-aminonaphthalenes.11–14 For this unprece-
dented synthesis of the naphthalene ring system, we
propose the course of reaction shown in Scheme 1.
Initial condensation with the DMADMA gives the
enamine 4, by analogy with the identified intermediate
enamine 2 for the sequence employing DMFDMA.
Whereas the C–H enamine 2 has no opportunity for
further reaction under the conditions, the C–Me enam-
ine 4 can tautomerise to the alternative enamine 5,
presumably via an iminium species. This second enam-
ine 5 then provides a nucleophilic carbon correctly
located to attack the ester carbonyl. It is noteworthy
that water is the sole leaving group in the condensation
of the enamine with the ester (giving 6); no 3-dimethyl-
amino-5-nitronaphth-1-ol was obtained (through loss of
methanol).
transfer and ester exchange), an isotopic competition
experiment was performed (Scheme 2). 2-Methyl-3-
nitrobenzoic acid
7
was converted to its
trideuteromethyl (CD3) ester 815 in 88% yield. This
isotopomer was then treated with DMADMA in which
the methoxy groups were all OCH3, under the standard
reaction conditions. Mass spectroscopic and NMR
analysis of the product 9 showed that the ratio of
OCD3 to OCH3 corresponded to the ratio of OCD3 (in
8) to OCH3 (in DMADMA) in the reaction mixture.
Thus, as there is virtually no difference between the
steric requirements of CD3 and CH3, the mechanism
must involve full equilibration of the alkoxy groups
between the ester and the orthoamide before final ring-
closure. Hence, introduction of alternative alkoxy
groups at position-1 of the naphthalene in this new
condensation
orthoamides.
will
require
other
appropriate
Scheme 3 shows three further studies on the generality
of the reaction. Treatment of methyl 2-methyl-5-
nitrobenzoate 1016 with DMADMA under the standard
reaction conditions gave the corresponding 1-methoxy-
3-dimethylamino-7-nitronaphthalene 11.17 In contrast,
similar treatment of the 3,5-dinitro analogue 12,18 in
which the arylmethyl group is further activated, gave
only degradation products. To explore an alternative
approach to activating the arylmethyl further and,
simultaneously, to introduce a 4-substituent into the
naphthalene, methyl 2-benzyl-3-nitrobenzoate 16 was
synthesised. 3-Nitrophthalic acid 14 was decarboxyl-
ated/mercurated with Hg(OAc)2 and the intermediate
aryl-Hg compound was treated with iodine to give
2-iodo-3-nitrobenzoic acid, by the method of Seno et
al.;19 this was converted to its methyl ester 15. Negishi
coupling with benzyl zinc bromide/DIBAL-H/
Pd(PPh3)2Cl2 then afforded the novel 2-benzylbenzoate
ester 16 in moderate yield.20 However, this failed to
afford the target 4-phenylnaphthalene 17 on treatment
with DMADMA.
In this letter, we report a novel method for the synthe-
sis of substituted naphthalenes by treatment of nitro-2-
methylbenzoate esters with dimethylacetamide dimethyl
acetal (DMADMA), together with early studies on its
A short study revealed aspects of the mechanism, gen-
erality and limitations of this new synthesis of substi-
tuted naphthalenes. Firstly, condensation of the
isopropyl ester 1b8 with DMADMA gave the methoxy-
naphthalene 6 as the sole naphthalene product (Scheme
1); no isopropoxynaphthalene was evident in the crude
product mixture. This observation suggests either that
the mechanism of the reaction is complex and involves
intramolecular transfer of a methoxy group in an inter-
mediate or that there is an equilibrium exchange of
alkoxy groups (PriOlMeO) between the ester and the
orthoamide before the final ring-closure. The complete
absence of isopropoxynaphthalenes is consistent with
the latter, since it is likely that ring-closure with the
isopropyl ester 5b will be much slower than that with
the methyl ester 5a, owing to the greater steric bulk of
the PriO; this steric retardation of ring-closure is
analogous to that observed in the formation of the
isocoumarin 3 from 1b. Secondly, to select between
these two alternative mechanisms (intramolecular MeO
Scheme 2. Studies on the source of the naphthalene 1-sub-
stituent. Reagents and conditions: (i) CD3OD, H2SO4, reflux,
72 h; (iii) MeC(OCH3)2NMe2 (3 equiv.), MeCONMe2, 150°C,
16 h.

S.-M. Wong et al. / Tetrahedron Letters 43 (2002) 2299–2302
2301
Scheme 3. Synthesis of 1-methoxy-3-dimethylamino-7-nitronaphthalene 11 and preliminary exploration of the limitations of the
naphthalene-forming condensation reaction. Reagents and conditions: (i) MeC(OMe)2NMe2, MeCONMe2, 150°C, 16 h, 5.3%; (ii)
Hg(OAc)2, aq. NaOH (10%), reflux, 3 days; (iii) I2, aq. NaOH (3.4%), reflux, 16 h; (iv) MeOH, H2SO4, 62% from 14; (v)
PhCH2ZnBr, Bui2AlH, Pd(PPh3)2Cl2, THF, 45°C, 72 h, 32%.
mechanism and generality. This condensation has con-
siderable potential for construction of ‘push-pull’-sub-
stituted polycyclic arenes. The results of a more
comprehensive study on this reaction will be published
later.
as dark red needles; mp 123–124°C; IR wmax 1522, 1343
cm−1; NMR (CDCl3) lH 3.13 (6H, s, NMe2), 4.00 (3H, s,
OMe), 6.48 (1H, d, J=2.3 Hz, 2-H), 7.11 (1H, dd,
J=8.2, 7.8 Hz, 7-H), 7.37 (1H, d, J=2.3 Hz, 4-H), 8.24
(1H, dd, J=7.8, 1.2 Hz, 8-H), 8.37 (1H, dd, J=8.2, 1.2
Hz, 6-H); MS (EI) m/z 246 (M). Found: C, 63.4; H, 5.72;
N, 11.4. C13H14N2O3 requires C, 63.41; H, 5.69; N,
11.38%.
Acknowledgements
10. Gate, E. N.; Meek, M. A.; Schwalbe, C. H.; Stevens, M.
F. G.; Threadgill, M. D. J. Chem. Soc., Perkin Trans. 2
1985, 251.
11. Schurman, J. V.; Becker, E. I. J. Org. Chem. 1953, 18,
211.
12. Friedla¨nder, P.; Szymanski, S. Chem. Ber. 1892, 25, 2076.
13. Machida, M.; Bando, M.; Migata, Y.; Machida, M. I.;
Kanaoka, Y. Chem. Pharm. Bull. 1976, 24, 3045.
14. Gould, R. G.; Jacobs, W. A. J. Biol. Chem. 1939, 130,
407.
We thank Mr. R. R. Hartell and Mr. D. J. Wood for
the NMR spectra and Mr. C. Cryer for the mass
spectra. J.A.W. held a Research Studentship from the
Department of Pharmacy & Pharmacology, University
of Bath. Part of this work was carried out by S.-M.W.,
B.S., P.S. and I.C.B. as an Undergraduate Research
Project for the MPharm degree.
15. Data for 8: Mp 62–65°C; IR (KBr) wmax 2186, 1724, 1524,
1363 cm−1; NMR ((CD3)2SO) lH 2.40 (3H, s, Me), 7.56
(1H, dd, J=8.2, 7.8 Hz, 5-H), 8.00 (1H, d, J=7.8 Hz,
6-H), 8.04 (1H, d, J=8.2 Hz, 4-H). Found: C, 54.4; H,
4.59; N, 7.05. C9H6D3NO4 requires C, 54.5; H, 4.54; N,
7.07%.
References
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17. Data for 11: Dark red needles; mp 172–174°C; NMR
(CDCl3) lH 3.15 (6H, s, NMe2), 4.03 (3H, s, OMe), 6.52
(1H, brs, 2-H), 6.56 (1H, brs, 4-H), 7.54 (1H, d, J=9.5
Hz, 5-H), 8.08 (1H, dd, J=9.5, 2.6 Hz, 6-H), 9.00 (1H, d,
J=2.6 Hz, 8-H); lC 40.5, 55.5, 95.1, 98.3, 117.0, 120.4,
120.6, 126.0, 138.7, 141.0, 151.8, 158.0; MS (EI) m/z
246.0998 (M) (C13H14N2O3 requires 246.1004). Found: C,
63.2; H, 5.80; N, 11.2. C13H14N2O3 requires C, 63.41; H,
5.69; N, 11.38%.
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20. Synthesis of 16. Compound 15 (2.5 g, 8.1 mmol) and
benzyl zinc bromide (0.5 M in THF, 24.5 mL, 12.2 mmol)
in dry THF (30 mL) were added to Pd(PPh3)2Cl2 (330
4. Sibi, M. P.; Dankwart, J. W.; Snieckus, V. J. Org. Chem.
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9. Synthesis of 6. Ester 1a (1.01 g, 5.2 mmol) was heated at
150°C with MeC(OMe)2NMe2 (2.5 g, 18.8 mmol) in
MeCONMe2 (6 mL) for 16 h. Evaporation and chro-
matography (hexane/EtOAc, 10:1) gave 6 (990 mg, 77%)

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S.-M. Wong et al. / Tetrahedron Letters 43 (2002) 2299–2302
mg, 500 mmol) and Bui2AlH (1.0 M in hexane, 1.0 mL,
1.0 mmol) in dry THF (15 mL) under Ar and the
mixture was stirred for 72 at 45°C. Extraction
(CHCl3), evaporation and chromatography (hexane/
EtOAc, 9:1) gave 16 (700 mg, 32%) as a yellow oil: IR
(film) wmax 1731, 1532, 1362 cm−1; NMR (CDCl3) lH
3.77 (3H, s, Me), 4.52 (2H, s, CH2), 7.02 (2H, d, J=7.4
Hz, Ph 2,6-H2), 7.14 (1H, t, J=7.4 Hz, Ph 4-H), 7.21
(2H, t, J=7.4 Hz, Ph 3,5-H2), 7.42 (1H, t, J=7.8 Hz,
5-H), 7.81 (1H, dd, J=7.8, 1.6 Hz, 6-H), 7.95 (1H, dd,
J=7.8, 1.6 Hz, 4-H); MS (FAB) m/z 272.0921 (M+H)
(C15H14NO4 requires 272.0923).
h