H-bond-assisted intramolecular nucleophilic displacement of the 1-NMe 2 group in 1,8-bis(dimethylamino)naphthalenes as a route to multinuclear heterocyclic compounds and strained naphthalene derivatives

Article abstract of DOI:10.1021/jo201171z

It has been shown that azomethines, hydrazones, and oximes derived from 2(7)-carbonyl derivatives of 1,8-bis(dimethylamino)naphthalene can undergo acid-catalyzed heterocyclization leading to a nucleophilic displacement of the 1-NMe₂ group. The

Full text of DOI:10.1021/jo201171z

ARTICLE
pubs.acs.org/joc
H-Bond-Assisted Intramolecular Nucleophilic Displacement of the
1-NMe2 Group in 1,8-Bis(dimethylamino)naphthalenes as a Route to
Multinuclear Heterocyclic Compounds and Strained Naphthalene
Derivatives
Maria A. Povalyakhina, Alexander S. Antonov, Olga V. Dyablo, Valery A. Ozeryanskii, and
Alexander F. Pozharskii*
Department of Organic Chemistry, Southern Federal University, Zorge 7, 344090 Rostov-on-Don, Russian Federation
S Supporting Information
b
ABSTRACT: It has been shown that azomethines, hydrazones,
and oximes derived from 2(7)-carbonyl derivatives of 1,8-bis-
(dimethylamino)naphthalene can undergo acid-catalyzed hetero-
cyclization leading to a nucleophilic displacement of the
1-NMe2 group. The process is believed to be directly connected
with the proton sponge nature of the substrates, in which
1-NMe2, being a poor leaving group, is preliminary activated
via the formation of a chelated protonated form. A number of
difficult to access derivatives of benzo[g]indazole, benzo[g]quinazoline, naphtho[2,1-d]isoxazole, and 8-dimethylamino-1-naphthol
have been prepared in moderate to high yields.
’ INTRODUCTION
with mild nucleophiles (PhSꢀ, PhSeꢀ, SCNꢀ, Iꢀ), protonated
proton sponges lose one of the N-methyl groups, producing N,N,
N0-trimethyl-1,8-diaminonaphthalene 3 or its derivatives in high
yield.22ꢀ24 The reaction is thought to occur via a classical SN2
mechanism and is assisted by IHB, making compound 3 a good
leaving group (Scheme 1). Interestingly, that N-ethyl group, e.g.,
in cation 5, is almost inert to elimination, and the ease of removing
the methyl attached to the same nitrogen atom as the ethyl is
somewhat higher than that of methyls in the NMe2 group. This
circumstance was used for exhaustive realkylation of proton
sponge 1 into its tetraethyl and tetrapropyl counterparts 4 that
has no analogy in the arylamine series.24
Discovery of the abnormally high basicity of 1,8-bis-
(dimethylamino)naphthalene (1),1 widely known as ‘proton
sponge’, has raised a great interest in the nature of intramolecular
hydrogen bonding (IHB) of its cation 2. In dozens of papers such
properties of the IHB such as symmetry and geometry,2ꢀ5
energy,6ꢀ8 the barrier and mechanism for proton transfer,9ꢀ12
unusually strong deshielding of the chelated NH proton (δ 18ꢀ
20 ppm),13 etc., have been investigated (see reviews14ꢀ19 for a
general survey of the topic). As a result, it was concluded that the
IHB strength in 2 after electrostatic and steric destabilization of
the free base 1 is, by importance, a second factor contributing to
the proton sponge basicity.1,6,14ꢀ17 Due to the unique shortness
of the IHB (rN
= 2.52ꢀ2.57 Å),8,15ꢀ18 the proton sponge
N
3 3 3
’ RESULTS AND DISCUSSION
cations have also attracted considerable attention for proton
transfer modeling in enzymatic reactions.20
In the present work, we report for the first time that the IHB in
proton sponge cations can promote not only nucleophilic
replacement of the N-methyl group but the whole NMe2 group
as well. The process normally operates for proton sponge
derivatives containing a nucleophilic center in the ortho-func-
tionality and is accompanied by heterocyclization. Thus, after
heating aldehyde 625 with hydrazine monohydrobromide (1.2
equiv) in ethanol for 1 h, we have obtained hydrazone 7 and
9-dimethylaminobenzo[g]indazole 8 in 41% and 22% yields,
respectively; a trace amount of azine 9 has also been isolated
(Scheme 2).
For a long time, one question concerning the IHB in cations of
type 2, namely its influence on proton sponge reactivity, re-
mained largely unexplored. However, even scarce information on
this account reveals that such an influence is rather significant and
can be displayed in specific forms.21 For example, upon heating
Received: June 7, 2011
Published: August 11, 2011
r
2011 American Chemical Society
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Scheme 1
Scheme 2
Owing to the enhanced basicity of proton sponges, the process
most likely proceeds via cationic intermediate 7H+ equilibrating
with σ-complex 7S, thus furnishing the elimination of dimethyl-
amine in the form of dimethylammonium cation as a good
leaving group in an SN2Ar reaction. After the reaction time was
increased to 3 h, the products 8 and 9 were obtained in 63% and
6% yields, respectively, while hydrazone 7 was not detected in
the reaction mixture at all. Replacing ethanol by acetic acid
(reflux, 1 h) dropped the yield of 8 to 6% due to acetylation of the
hydrazone NH2 group with the formation of compound 11a
(54%); azine 9 was not formed in this case. In contrast, 9 became
the only isolable product in 45% or 99% yield when 1.2 equiv of
hydrazine hydrate (24 h) or 0.5 equiv of hydrazine monohydro-
bromide (12 h) was used in EtOH at room temperature. Similar
to that for hydrazine hydrobromide, heating aldehyde 6 with
methylhydrazine hydrosulfate (1.2 equiv, EtOH, 5 h) gave 1-
methylbenzo[g]indazole 10 in 67% yield. Use of AcOH as a
solvent led in this case to the formation of commeasurable
amounts of 10 (30%) and 11b (33%).
resides on pyrazole fragment [N(1) H(2N) = 2.38 Å]. Thus,
there is no substantial IHB in 8 between the N(1) and N(2) atoms.
Instead, intermolecular hydrogen pairing is realized between mole-
3 3 3
cules of 8via the heterocyclic N(3) atom [N(3) H(2N) = 2.20 Å]
3 3 3
(Figure 1b, cf., ref 27). Apparently, in solution the NH proton in
8 is also located almost entirely at the N(2) nitrogen, because it
resonates at δ = 12 ppm (CDCl3), which is close to that of
indazole (13.1 ppm in DMSO-d6) and strongly differs from that
of proton sponge cations (18ꢀ20 ppm).
Another kind of heterocyclization with the replacement of the
1-NMe2 group was observed at interaction of aldehyde 6 with
3-aminoindazole in acetic acid or a ethanolꢀhydrochloric acid
mixture (Scheme 3). This gave benzo[h]quinazoline derivative
13 as a single product in good yield in both cases. Obviously, the
N(2) atom of the indazole system acts here as a nucleophile, and
the cyclization is promoted by IHB in the protonated azomethine
intermediate 12. Having changed 3-aminoindazole for 2-amino-
benzimidazole, we observed no reaction upon heating in acidic
media (AcOH or EtOHꢀHCl). However, to our satisfaction,
aldehyde 6 reacted with 2-aminobenzimidazole without any
solvents upon melting at 135 °C for 10 min to give highly
strained and likely helical isomeric derivative 15 in a moderate
yield (Scheme 3).28
X-ray analysis of perchlorate 13 HClO4 has shown that the
3
N(2) N(4) distance (2.550 Å) in the seven-membered che-
3 3 3
late is practically the same as in most proton sponge cations
(Figure 2). It is therefore not surprising that the NH proton in
1
the H NMR spectrum of the salt resonates at δ 18.15 ppm
We had also prepared phenyl- and 2,4-dinitrophenylhydra-
zones 11c,d, which failed to cyclize upon heating in acidic media
(AcOH, HCl) probably due to their lowered nucleophilicity and
sterics.
(CD3CN). At the same time, the IHB thus formed is highly
asymmetric with the NH proton predominantly located on the
NMe2 group: the N(4)ꢀH(4N) and N(2) H(4N) distances
3 3 3
are equal to 0.96 Å and 1.61 Å, respectively. As a consequence of
this asymmetry, which is coupled with rather poor basicity of 13,
cation 13 H+ undergoes easy deprotonation not only in rather
3
basic DMSO-d6 but even in wet CD3CN.
1
In the H NMR spectrum (CDCl3, 20 °C), benzoindazolo
quinazoline 13 displays strong dynamics, showing a very diffuse
signal from the NMe2 group at δ 0.9ꢀ4.0 ppm; upon cooling to
ꢀ50 °C, molecular movement is frozen and peaks from two
magnetically unequal NꢀMe groups are distinctly separated (δH
1.48 and 3.46 ppm), indicating their asymmetrical disposition
relative to the aromatic ring plane. In contrast to 13, its benzi-
midazole counterpart 15 already reveals two magnetically unequal
NꢀMe groups at room temperature (δH 1.45 and 2.61 ppm),
reflecting more hindered dynamics of the NMe2 group in this case
that are apparently due to the nonflat, helical-like structure of 15
(see Supporting Information for peak assignments).
In accordance with X-ray measurements, benzoindazole 8
exists in the solid state as the 1H-tautomer (Figure 1a,b). Though
the N(1) N(2) distance in molecule 8 (2.800 Å) is exactly the
3 3 3
same as in the base 1,26 it is considerably larger than in proton
sponge cations (see above). Besides, the NꢀH proton practically
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Figure 1. Molecular structure of compound 8 showing (a) weak H-bonding between the NMe2 and pyrazole units and (b) pairing of 8 in crystals at 120 K.
Scheme 3
ꢀ
Figure 2. Molecular structure of salt 13 HClO4 at 120 K (anion ClO4
is omitted) showing intramolecular NHN bonding.
3
Interaction of aldehyde 6 with 5-aminotetrazole in boiling
AcOH proceeds in a more complex manner than that with 3-
aminoindazole and 2-aminobenzimidazole and gives 1-amino-
10-dimethylaminobenzo[h]quinazolin-2-one 18 in 35% yield
(Scheme 4). We suggest, that initially formed cyclization product
16 undergoes acid-catalyzed covalent hydration with subsequent
elimination of a N2 molecule from the intermediate 17. The
structure of 18, apart from the high-resolution mass spectrum, is
proved by the presence in its 1H NMR spectrum of an exchange-
able two-proton peak of the NH2 group at δ 5.26 ppm (CDCl3)
or 6.72 ppm (DMSO-d6). In the IR spectrum of 18, absorption
bands of the NH2 and CdO groups are exhibited at νmax 3324,
3183 cmꢀ1 and 1653 cmꢀ1, respectively.30
Whereas the formation of 22 can be treated as ordinary oxime
dehydration, naphthol 21 may arise from the base-catalyzed31
and well-known32 isoxazole izomerization 20 f 21. In special
experiments (refluxing bases 19 and 22 or their hydrochlorides in
water for 6 h or treatment of 19 and 22 with KOH in DMSO at
120 °C for 15 min), we have proved that the alternative for-
mation of naphthol 21 via direct substitution of the dimethylamino
group by an external hydroxylic nucleophile33 does not occur.
Remarkably, the transformation of 19 in DMSO at 140ꢀ
150 °C goes much faster (2 h against 12 h than that for the melt),
giving naphthol 21 with almost perfect selectivity in more than
1
95% yield. In the H NMR spectrum of the crude reaction
We then reasoned that by analogy with hydrazone 7 the
intramolecular replacement of the 1-NMe2 group could be
also possible for aldoxime 19. In this case, naphtho[2,1-d]-
isoxazole derivative 20 would be the expected reaction product.
However, after melting the solid 19 at 120ꢀ130 °C for 12 h, we only
isolated naphthonitriles 21 and 22, in ∼30% yield each (Scheme 5).
mixture, only signals of 21 and dimethylamine (δ = 2.3 ppm)
were seen. This observation in combination with several other
facts may shed some light on the mechanism of the conversion
19 f 21. We suggest that three main events should occur in
the coversion of 19 to 21 (Scheme 6). The first one is the
cleavage of aldoxime dimer 23, to produce free 19 (see the
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Scheme 4
For more evidence in favor of the involvement of zwitterion
24a, we have measured by a NMR competitive method42 the
pKa values of aldoxime 19 as a nitrogen base and a OH-acid. In
Scheme 5
1
the first case, the H NMR spectrum of the equilibrating 1:1
mixture of 19 and 1 HClO4 has revealed that 19 (pKa = 7.3,
3
DMSO-d6, 25 °C) is ca. 0.2 pKa units less basic than the parent
sponge 1 (see Supporting Information).43 In the case of OH-
acidity, no visible proton transfer occurred in DMSO-d6 between
19 and 1. At the same time, a strongly shifted equilibrium is
established between 19 and its anion 26 in the presence of much
more basic 1,8-bis(dimethylamino)-2,7-dimethoxynaphthalene
(pKa = 11.5, DMSO-d6, 25 °C) (see Supporting Information).44
The observed concentration of anion 26 (∼1.5%) allowed us to
estimate that the OH-acidity of 19 lies near pKa = 15.1. Such a
large difference between the pK0as of the peri-nitrogen center and
the OH group corresponds to a concentration of 24a on the level
of 10ꢀ7ꢀ10ꢀ6 M. At first glance, this value is negligible, but one
cannot exclude that the cyclization may still proceed via equi-
librium quantities of the zwitterion species due to their high activity.45
It is also known46 that zwitterions are commonly strongly stabi-
lized by the close proximity of the opposite charges as in the case
of 24a.
Supporting Information for X-ray structure of 19); such dimers
are typical for most oximes36 and are usually rather stable.37
Presumably, polarity (μ = 3.9 D) and basicity (pKa = 0) of DMSO
are high enough to disrupt the dimer structure, at least partially.
Because the E-form 19a, arising from the dimer disruption, is
stereochemically unready for cyclization, the second event
should be the E f Z isomerization (19a f 19b). This process
also demands polar media and elevated temperature,38 which are
likely provided by using DMSO. The third event, namely the
nucleophilic substitution of the 1-NMe2 group, appears to be the
most complex and unclear stage. We have come to a conclusion
that both the nucleophilic group (OH) and the electrophilic
center (C1-atom) should be activated for the transformation
19 f 20 f 21. Indeed, acidic ionization of the oxime group
upon heating 19 in the KOHꢀDMSO system, where 19 exists
exclusively as O-anion 26 (see Experimental Section for 1H NMR
data), is itself insufficient for heterocyclization and yields nitrile
22 as a sole product. Obviously, the capability of the CHd
NꢀOꢀ group in 26 to act as a nucleophile in the heterocycliza-
tion reaction is considerably lowered owing to conjugation
between the negatively charged oxygen atom and the ring
π-system (Scheme 7).
In light of the recent report that about 20% of hydroxylamine
exists in water as ammonia oxide, NH3 ꢀOꢀ,47 we wonder if the
+
related zwitterionic form 27 can contribute in the heterocycliza-
tion reaction (Scheme 8). In this case, the process could develop
as a more complex version of the proton translation mechanism
19 f 27a f 27b f 24b with the final E f Z isomerization into
24a. Although the reliable choice between both pathways is
difficult, Scheme 6 seems more preferable because the nitrogen
basicity of hydroxylamine (pKa = 5.7, in H2O)47 is much smaller
than that of the proton sponges 1 and 19 (pKa ∼12).
Next, we have found that thermolysis of 2,7-dioxime 28 results
in intramolecular substitution of only one NMe2 group, furnish-
ing compounds 30 and 31 in 32% and 20% yield, respectively
(Scheme 9). This experiment can be considered as additional
support in favor of the bifunctional catalysis, because the forma-
On the other hand, prolonged reflux of the oxime hydro-
chloride 19 HCl in EtOH or THF produces only traces of the
3
tion of OH N hydrogen bonding in the primarily formed
naphthol 21 while melting of 19 HCl leads to complete tarring.
3 3 3
3
naphthol 29 should hamper the subsequent proton transfer from
the remaining oxime group thus preventing its activation.
As expected, thermolysis of ketoximes 33a and 33b produces
exclusively isoxazoles 34a and 34b in 64% yield each. Interest-
ingly, unlike aldoximes 19 and 28, we could not obtain ketoximes
33a and 33b directly by oximation of the corresponding 2-aroyl-
1,8-bis(dimethylamino)naphthalenes25 with hydroxylamine. Fortu-
nately, this could be easily done from ketone imines 32a and 32b
by their treatment with hydroxylamine hydrochloride (Scheme 10).
The success of the latter protocol seems to consist of acid cat-
alysis, allowing easier protonation of the imino function and
therefore higher activity of an iminium group in nucleophilic
addition as compared with the CdO group. Previously unknown
At the same time, naphthol 21 was obtained in 18% yield upon
reflux of 19 in AcOH for 4 h, demonstrating once again that an
enhanced temperature is an essential factor for the hetero-
cyclization.39 Thus, we have hypothesized that the Z-form self-
stabilizes via the formation of hydrogen out-chelate 19b,25,40
which then rearranges41 into zwitterionic chelate 24a. A great
advantage of the latter mechamsim is the simultaneous activation
of the nucleophilic center (OH f Oꢀ) and the enhancement of
the leaving ability of the 1-NMe2 group (bifunctional catalysis).
Dimethyl sulfoxide is thought to play a key role as a polar media
and proton-transfer carrier in the whole process; it may also more
strongly accelerate the heterocyclization reaction (19 f 20) if
compared with the dehydration of 19 into nitrile 22.
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Scheme 6
(1H, dd, J = 7.3, 1.4 Hz), 7.18 (1H, d, J = 8.4 Hz), 7.26ꢀ7.53 (3H, m),
7.94 (1H, s). Anal. Calcd for C15H20N4: C, 70.28; H, 7.86; N, 21.86.
Found: C, 70.29; H, 7.98; N, 21.91.
Scheme 7
9-Dimethylamino-1H-benzo[g]indazole (8). A solution of 6
(100 mg, 0.41 mmol) and hydrazine hydrobromide (56 mg, 0.49 mmol)
in ethanol (10 mL) was refluxed for 3 h. After evaporation of volatiles to
dryness, the residue was treated with a 5% solution of NH4OH (5 mL)
and then extracted with CHCl3 (3 ꢁ 3 mL). The solvent was evaporated
to dryness, and the residue was chromatographed on Al2O3, first with
CHCl3 elution and then with Et2Oꢀn-hexane (1:1) to yield 8 (55 mg,
63%) and 9 (6 mg, 6%). Colorless crystals, mp 131ꢀ133 °C (n-hexane).
1H NMR (250 MHz, CDCl3): δ 2.87 (6H, s), 7.38ꢀ7.57 (3H, m), 7.70
(2H, m), 8.11 (1H, s), 12.15 (1H, br s). 13C NMR (62.5 MHz, CDCl3):
δ 46.3, 117.6, 117.7, 119.8, 120.2, 122.7, 125.3, 126.9, 134.4, 134.9,
137.0, 151.3. EI MS: m/z (I, %) 211 [M]+ (100), 196 (54), 181 (23),
168 (45), 140 (31), 115 (16), 44 (16). Anal. Calcd for C13H13N3: C,
73.91; H, 6.20; N, 19.89. Found: C, 73.85; H, 6.30; N, 19.92.
and unexpectedly stable imines 32 were prepared upon treatment
of 2-lithio-1,8-bis(dimethylamino)naphthalene25 with the corres-
ponding benzonitriles (see Experimental Section for details).
Note that 2-dimethylaminobenzophenone oxime, as we have
found, does not undergo reaction similar to that for 35 f 36, and
it remains unchanged upon heating at 120ꢀ130 °C (Scheme 11).
This experiment gives further support to the main idea of the
present work that the disclosed heterocyclizations of the above
proton sponge substrates are promoted by acidic catalysis via
chelation of the peri-NMe2 groups.
1,8-Bis(dimethylamino)naphthalene-2-carbaldehyde Azine
(9). A solution of 6 (100 mg, 0.41 mmol) and hydrazine hydrobromide
(24 mg, 0.21 mmol) in ethanol (10 mL) was kept at room temperature
for 12 h. After evaporation of the volatiles to dryness, the residue was
treated with a 5% solution of NH4OH (5 mL) and then extracted with
CHCl3 (3 ꢁ 3 mL). The solvent was evaporated to dryness, and the
residue was chromatographed on Al2O3 with CHCl3 to yield 9 (97 mg,
’ CONCLUSIONS
In summary, in the present work we have demonstrated for the
first time that naphthalene proton sponges with an appropriate
nucleophilic ortho-functionality, such as the hydrazone, azo-
methine, or oxime group, can undergo intramolecular displace-
ment of the nearest NMe2 group, resulting in heterocyclization.
The method is useful for the preparation of a number of
naphthalene-based heterocycles and peri-substituted naphtha-
lene derivatives, including strained molecules, which are obtain-
able with difficulty by other ways. The success of these transfor-
mations seems to originate from the proton sponge nature of the
above substrates, which are strongly activated under conditions
of acid or bifunctional acidꢀbase catalysis or autocatalysis due to
intramolecular H-bonding.
1
99%) as orange crystals with mp 165ꢀ166 °C (n-hexane). H NMR
(250 MHz, CDCl3): δ 2.77 (12H, s), 3.16 (12H, s), 7.05 (2H, dd, J = 7.1,
1.3 Hz), 7.27ꢀ7.43 (4H, m), 7.46 (2H, d, J = 8.5 Hz), 8.06 (2H, d, J =
8.5 Hz), 9.02 (2H, s). 13C NMR (62.5 MHz, CDCl3): δ 46.0, 46.4, 115.2,
123.2, 124.5, 124.7, 125.7, 127.3, 128.2, 139.5, 152.1, 152.9, 162.6. EI MS: m/z
(I, %) 240 [M/2]+ (49), 225 (91), 210 (82), 196 (92), 181 (82), 168 (100),
154 (50), 141 (18), 127 (37), 115 (20), 58 (98), 44 (72). Anal. Calcd for
C30H36N6: C, 74.97; H, 7.55; N, 17.48. Found: C, 74.82; H, 7.39; N, 17.61.
9-Dimethylamino-1-methylbenzo[g]indazole (10). A solu-
tion of 625 (100 mg, 0.41 mmol) and methylhydrazine hydrosulfate
(71 mg, 0.49 mmol) in ethanol (10 mL) was refluxed for 5 h. After
evaporation of volatiles to dryness, the residue was treated with a 5%
solution of NH4OH (5 mL) and then extracted with CHCl3 (3 ꢁ 3 mL).
The solvent was evaporated to dryness, and the residue was chromato-
graphed on Al2O3, first with CHCl3 elution and then with n-hexane to
yield 10 (62 mg, 67%) as a pale-yellow oil. 1H NMR (250 MHz, CDCl3):
δ 2.98 (6H, s), 4.26 (3H, s), 7.23 (1H, dd, J = 6.5, 2.5 Hz), 7.34 (1H, d,
J = 8.9 Hz), 8.11 (1H, s), 7.40ꢀ7.49 (2H, m), 7.52 (1H, d, J = 8.9 Hz),
7.85 (1H, s). 13C NMR (62.5 MHz, CDCl3): δ 40.7, 45.8, 115.7, 118.8,
120.4, 120.7, 123.2, 123.7, 124.8, 126.6, 135.2, 144.9, 151.0. EI MS: m/z
(I, %) 225 [M]+ (91), 211 (20), 210 [M ꢀ Me]+ (100), 196 (43), 195
(25), 181 (25), 140 (18), 57 (26), 55 (19), 43 (34), 42 (42), 41 (29).
Anal. Calcd for C14H15N3: C, 74.64; H, 6.71; N, 18.65. Found: C, 74.72;
H, 6.80; N, 18.61.
’ EXPERIMENTAL SECTION
1,8-Bis(dimethylamino)-2-(hydrazonomethyl)naphthalene
(7). A solution of 625 (100 mg, 0.41 mmol) and hydrazine hydrobromide
(56 mg, 0.49 mmol) in ethanol (10 mL) was refluxed for 1 h. After
evaporation of volatiles to dryness, the residue was treated with a 5%
solution of NH4OH (5 mL) and then extracted with CHCl3 (3 ꢁ 3 mL).
The solvent was evaporated to dryness, and the residue was chromato-
graphed on Al2O3, first with CHCl3 elution and then with Et2Oꢀ
n-hexane (1:1) to yield 7 (43 mg, 41%), 8 (19 mg, 22%), and a trace
amount of 9. Light-beige crystals, mp 171ꢀ173 °C (n-hexane). 1H NMR
(250 MHz, CDCl3): δ 2.90 (9H, s), 3.12 (3H, s), 4.57 (2H, br s), 7.03
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Scheme 8
mp 114ꢀ116 °C (n-hexane). 1H NMR (250 MHz, CDCl3): δ 2.50 (3H,
s), 2.75 (6H, s), 3.08 (6H, s), 3.40 (3H, s), 7.09 (1H, dd, J = 7.0, 1.2 Hz),
7.31 (1H, t, J = 7.7 Hz), 7.39 (1H, dd, J = 7.9, 1.2 Hz), 7.46 (1H, d, J =
8.6 Hz), 7.86 (1H, d, J = 8.6 Hz), 7.96 (1H, s). 13C NMR (62.5 MHz,
CDCl3): δ 22.2, 27.9, 45.8, 46.3, 115.7, 123.6, 124.6, 125.0, 125.3, 126.9,
129.2, 138.7, 140.2, 150.0, 152.7, 173.3. Anal. Calcd for C18H24N4O: C,
69.20; H, 7.74; N, 17.93. Found: C, 69.38; H, 7.67; N, 18.00.
Scheme 9
General Procedure for Preparation of 11c and 11d. A solu-
tion of 6 (100 mg, 0.41 mmol), corresponding arylhydrazine (0.41 mmol),
and 38% HCl (0.033 mL, 0.41 mmol) in EtOH (10 mL) was refluxed for
1 h. After evaporation of volatiles to dryness, the residue was treated
with a 5% solution of NH4OH (5 mL) and then extracted with CHCl3
(3 ꢁ 4 mL). The solvent was evaporated to dryness, and the residue was
chromatographed on Al2O3 with CHCl3 elution to yield 11c or 11d.
1,8-Bis(dimethylamino)-2-((2-phenylhydrazo-
no)methyl)naphthalene (11c). Yield 25%. Light-beige crystals, mp
136ꢀ139 °C (decomp, n-hexane). 1H NMR (250 MHz, CDCl3): δ 2.75
(6H, s), 3.07 (6H, s), 6.85 (1H, t, J = 7.3 Hz), 7.05ꢀ7.19 (3H, m),
7.23ꢀ7.33 (3H, m), 7.40 (1H, d, J = 7.9 Hz), 7.48 (1H, d, J = 8.7 Hz),
7.68 (1H, br s), 8.20 (2H, m). Anal. Calcd for C21H24N4: C, 75.87; H,
7.28; N, 16.85. Found: C, 75.79; H, 7.30; N, 16.74.
Scheme 10
1,8-Bis(dimethylamino)-2-((2-phenylhydrazono)methyl)naphthalene
hydrochloride (11c HCl) was prepared in MeOH upon addition of
3
1 equiv of 38% aqueous HCl; yellow crystals, mp 280ꢀ283 °C (decomp,
MeOH), yield 96%. 1H NMR (250 MHz, DMSO-d6): δ 3.24 (6H, s),
3.30 (6H, d, J = 3.2 Hz), 6.85 (1H, t, J = 7.1 Hz), 7.16 (2H, m), 7.29 (2H,
m), 7.70 (1H, t, J = 7.9 Hz), 7.99ꢀ8.16 (3H, m), 8.35 (1H, d, J = 8.8 Hz),
Scheme 11
8.58 (1H, s), 11.02 (1H, s), 18.56 (1H, br s). Anal. Calcd for C21H24N4
3
HCl: C, 68.37; H, 6.83; Cl, 9.61; N, 15.19. Found: C, 68.47; H, 6.95; Cl,
9.54; N, 15.24.
1,8-Bis(dimethylamino)-2-(2-(2,4-dinitrophenyl)hydrazono)-
methylnaphthalene (11d). Yield 52%. Wine-red crystals, mp 201ꢀ
1
203 °C (EtOH). H NMR (250 MHz, CDCl3): δ 2.72 (6H, s), 3.11
(6H, s), 7.10 (1H, dd, J = 7.0, 1.3 Hz), 7.27ꢀ7.54 (3H, m), 7.91 (1H, d,
J = 8.5 Hz) 8.11 (1H, d, J = 9.8 Hz), 8.35 (2H, m), 9.14 (1H, d, J =
2.5 Hz), 11.34 (1H, br s). Anal. Calcd for C21H22N6O4: C, 59.71; H,
5.25; N, 19.89. Found: C, 59.79; H, 5.30; N, 19.83.
N0-[(1,8-Bis(dimethylamino)naphthalen-2-yl)methylene]-
acetohydrazide (11a). A solution of 6 (100 mg, 0.41 mmol) and
hydrazine hydrobromide (56 mg, 0.49 mmol) in AcOH (10 mL) was
refluxed for 1 h. After evaporation of volatiles to dryness, the residue was
treated with a 10% solution of NH4OH (5 mL) and then extracted with
CHCl3 (3 ꢁ 4 mL). The solvent was evaporated to dryness, and the
residue was chromatographed on Al2O3 with CHCl3 elution to yield 11a
as yellow crystals (66 mg, 54%) with mp 198ꢀ200 °C (n-hexaneꢀ
CHCl3, 1:1). 1H NMR (250 MHz, CDCl3): δ 2.39 (3H, s), 2.74 (6H, s),
3.06 (6H, s), 7.07 (1H, d, J = 7.0 Hz), 7.25ꢀ7.47 (3H, m), 7.81 (1H, d,
J = 8.5 Hz), 8.02 (1H, s), 9.00 (1H, br s). Anal. Calcd for C17H22N4O: C,
68.43; H, 7.43; N, 18.78. Found: C, 68.52; H, 7.56; N, 18.83.
N,N-Dimethylbenzo[h]indazolo[2,3-a]quinazolin-1-amine
(13). A solution of 6 (100 mg, 0.41 mmol) and 3-aminoindazole (55 mg,
0.41 mmol) was refluxed in AcOH (10 mL) for 4 h or in EtOH (10 mL)
for 12 h with addition of aqueous 38% HCl (0.033 mL, 0.41 mmol).
After evaporation of volatiles to dryness, the residue was treated with a
10% solution of NH4OH (5 mL) and then extracted with CHCl3 (3 ꢁ
5 mL). The solvent was evaporated to dryness, and the residue was
chromatographed on Al2O3 with CHCl3 elution to yield 13 as orange
crystals (90 mg, 70%) with mp 129ꢀ132 °C(n-hexane). 1HNMR(250MHz,
1
N0-[(1,8-Bis(dimethylamino)naphthalen-2-yl)methylene]-
N-methylacetohydrazide (11b). A solution of 6 (100 mg, 0.41
mmol) and methylhydrazine hydrosulfate (71 mg, 0.49 mmol) in AcOH
(10 mL) was refluxed for 2 h. After evaporation of volatiles to dryness,
the residue was treated with a 10% solution of NH4OH (5 mL) and then
extracted with CHCl3 (3 ꢁ 4 mL). The solvent was evaporated to
dryness, and the residue was chromatographed on Al2O3 with CHCl3
elution to yield 11b (42 mg, 33%) and 10 (28 mg, 30%). Yellow crystals,
CDCl3, 1Hꢀ H COSY): δ 0.9ꢀ4.0 (6H, br s), 7.29ꢀ7.43 (3H, m), 7.65
(2H, m), 7.80 (2H, m), 7.95 (1H, d, J = 8.53 Hz), 8.47 (1H, d, J =
8.21 Hz), 9.80 (1H, s). 1H NMR (250 MHz, CDCl3, ꢀ50 °C): δ 1.48
(3H, br s), 3.46 (3H, br s), 7.30ꢀ8.09 (8H, m), 8.46 (1H, br d, J =
7.9 Hz), 9.09 (1H, s). 1H NMR (250 MHz, CD3OD): δ 1.00ꢀ3.90 (6H,
very br s), 7.38ꢀ7.58 (3H, m), 7.73 (2H, m), 7.95 (1H, d, J = 8.5 Hz),
8.02 (2H, m), 8.46 (1H, d, J = 8.4 Hz), 9.24 (1H, s). 1H NMR (250 MHz,
DMSO-d6): δ 1.40ꢀ3.20 (6H, very br s), 7.33ꢀ7.51 (3H, m), 7.69
7162
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ARTICLE
(2H, m), 7.93 (1H, d, J = 8.7 Hz), 8.02 (1H, d, J = 8.5 Hz), 8.09 (1H, d, J =
8.7 Hz), 8.38 (1H, d, J = 8.2 Hz), 9.32 (1H, s). 13C NMR (62.5 MHz,
CDCl3): δ 41.0, 110.0, 114.3, 115.1, 116.2, 117.5, 118.5, 121.2, 121.6,
123.2, 128.4, 129.1, 130.1, 134.8, 138.6, 142.1, 144.7, 150.6, 151.7. EI
MS: m/z (I, %) 312 [M]+ (51), 297 (100), 269 (16), 193 (22), 148 (11),
44 (11). Anal. Calcd for C20H16N4: C, 76.90; H, 5.16; N, 17.94. Found: C,
76.87; H, 5.11; N, 18.00.
equiv KOH, O-anion 26): δ 2.69 (6H, s), 2.89 (6H, s), 7.00 (1H, br d, J =
7.0 Hz), 7.12 (1H, t, J = 7.5 Hz), 7.25ꢀ7.34 (m, 2H), 8.08 (1H, d, J =
8.8 Hz), 8.13 (1H, s). 13C NMR (62.5 MHz, CDCl3): δ 46.2, 46.4,
116.2, 124.2, 125.7, 125.8, 125.9, 127.1, 127.8, 139.8, 151.0, 152.2, 153.7.
EI MS, m/z (I, %): 257 [M]+ (67), 241 (20), 240 [M ꢀ OH]+ (100),
225 (24), 224 (29), 212 (22), 211 (26), 209 (32), 197 (49), 196 (52),
195 (35), 193 (24), 182 (33), 181 (22), 168 (33), 167 (23). UVꢀvis
(MeCN): λmax (log ε) 224 (4.49), 266 (4.60), 338 (3.95). Anal. Calcd
for C15H19N3O: C, 70.01; H, 7.44; N, 16.33. Found: C, 70.29; H, 7.47;
N, 16.39.
1,8-Bis(dimethylamino)naphthalene-2,7-dicarbaldehyde
Dioxime (28). Yield 78%. Yellow crystals, mp 160ꢀ162 °C (from n-
octane). IR (ν/cmꢀ1) (KBr): 3430ꢀ3105 (br, OH). 1H NMR (250 MHz,
DMSO-d6): δ 2.95 (12H, s), 7.59 (2H, d, J = 8.5 Hz), 7.73 (2H, d, J =
8.5 Hz), 8.27 (2H, s), 11.33 (2H, s). 13C NMR (62.5 MHz, DMSO-d6):
δ 46.6, 126.3, 127.7, 131.9, 132.6, 139.4, 149.1, 150.7. EI MS, m/z (I, %):
300 [M]+ (61), 283 (74), 265 (35), 251 (31), 238 (87), 236 (48), 223
(43), 222 (68), 221 (46), 220 (39), 210 (29), 209 (29), 208 (31), 207
(42), 206 (28), 194 (27), 193 (38), 167 (28), 58 (64), 44 (100), 42 (50),
40 (36), 36 (77). UVꢀvis (MeCN): λmax (log ε) 273 (5.04), 341 (4.15).
Anal. Calcd for C16H20N4O2: C, 63.98; H, 6.71; N, 18.65. Found: C,
63.72; H, 6.74; N, 18.72.
General Procedure for Preparation of 32a and 32b. A solu-
tion of the corresponding nitrile (benzonitrile for 32a (0.49 mL, 0.5 mmol)
or p-methoxybenzonitrile for 32b (67 mg, 0.5 mmol)) in absolute Et2O
(10 mL) was added to a cold (ꢀ20 °C) solution of 2-lithio-1,8-bis-
(dimethylamino)naphthalene25 (100 mg, 0.45 mmol) in absolute Et2O
(10 mL) under argon atmosphere. The resulting mixture was kept
at ꢀ20 °C for 30 h and quenched with water (10 mL). The organic layer
was separated, and the water layer was extracted with Et2O (3 ꢁ 10 mL).
The combined organic extracts were evaporated to dryness, and the
residue was chromatographed on Al2O3 with Et2Oꢀhexanes (2:1) elution
to yield 32a or 32b.
1,8-Bis(dimethylamino)-2-(imino(phenyl)methyl)naphthalene
(32a). Yield 65%. Yellow crystals, mp 113ꢀ114 °C (n-hexane). IR
(ν/cmꢀ1) (paraffin oil): 3250 (NH). 1H NMR (250 MHz, DMSO-d6):
δ 2.54 (6H, s), 2.70 (6H, s), 7.03 (1H, dd, J = 7.6, 1.0 Hz), 7.07ꢀ7.19
(1H, very br d), 7.30ꢀ7.55 (8H, m), 10.25 (1H, s). 13C NMR (62.5
MHz, CDCl3): δ 45.0, 45.6, 115.2, 123.3, 124.0, 124.3, 127.6, 128.4,
129.3, 129.4, 131.8, 133.8, 139.8, 141.0, 148.7, 153.5, 181.9. EI MS, m/z
(I, %): 317 [M]+ (100), 302 (41), 301 (70), 286 (68), 273 (41), 240
(28), 168 (36), 127 (28), 104 (38), 77 (60), 44 (35), 42 (37). Anal.
Calcd for C21H23N3: C, 79.46; H, 7.30; N, 13.24. Found: C, 79.14; H,
7.33; N, 13.29.
N,N-Dimethylbenzo[h]indazolo[2,3-a]quinazolin-1-amine perchlo-
rate (13 HClO4) was prepared in MeOH upon addition of 1 equiv of
3
40% aqueous HClO4; beige crystals, mp 264ꢀ267 °C (decomp, dry
MeCN). 1H NMR (250 MHz, CD3CN): δ 3.29 (6H, s), 7.64 (1H, t, J =
7.4 Hz), 7.96 (1H, m), 8.15 (1H, d, J = 8.8 Hz), 8.25 (1H, t, J = 8.1 Hz),
8.40ꢀ8.60 (5H, m), 9.63 (1H, s), 18.15 (1H, br s). Anal. Calcd for
C20H16N4 HClO4: C, 58.19; H, 4.15; Cl, 8.59; N, 13.57. Found: C,
3
58.21; H, 4.23; Cl, 8.52; N, 13.64.
N,N-Dimethylbenzo[h]benzimidazolo[2,3-a]quinazolin-1-
amine (15). A mixture of 6 (100 mg, 0.41 mmol) and 2-aminobenzi-
midazole (55 mg, 0.41 mmol) was heated in an argon atmosphere at
135 °C for 10 min. The fused mixture was cooled to 20 °C and chro-
matographed on Al2O3 with CHCl3 elution to yield 15 as orange crystals
(68 mg, 53%) with mp 109ꢀ111 °C (n-hexane). 1H NMR (250 MHz,
1
CDCl3, 1Hꢀ H COSY): δ 1.45 (3H, s), 2.61 (3H, s), 7.15ꢀ7.31 (3H,
m), 7.46ꢀ7.58 (2H, m), 7.73 (1H, t, J = 7.8 Hz), 7.84 (2H, m), 8.03 (1H,
d, J = 8.4 Hz), 9.22 (1H, s). 1H NMR (250 MHz, CDCl3 + 3CF3COOH,
crimson-colored solution): δ 1.59 (3H, s), 2.69 (3H, s), 7.45 (3H, m),
7.71 (1H, d, J = 7.5 Hz), 7.82 (1H, m), 7.93ꢀ8.07 (3H, m), 8.15 (1H, d,
J = 8.8 Hz), 9.57 (1H, s), 9.75 (1H, br s). EI MS: m/z (I, %) 312 [M]+
(100), 311 (64), 297 (15), 268 (33), 267 (17), 44 (16), 42 (30). Anal.
Calcd for C20H16N4: C, 76.90; H, 5.16; N, 17.94. Found: C, 76.98; H,
5.23; N, 17.89.
1-Amino-10-dimethylaminobenzo[h]quinazolin-2(1H)-one
(18). A solution of 6 (100 mg, 0.41 mmol) and 5-aminotetrazole (35 mg,
0.41 mmol) was refluxed in AcOH (10 mL) for 4 h. After evaporation of
volatiles to dryness, the residue was treated with a 10% solution of
NH4OH (5 mL) and then extracted with CHCl3 (3 ꢁ 10 mL). The
solvent was evaporated to dryness, and the residue was chromato-
graphed on Al2O3 with CHCl3 elution to yield 18 as yellow crystals
(37 mg, 35%) with mp 159ꢀ160 °C (n-octane). IR (ν/cmꢀ1) (KBr):
3324, 3183 (NH2), 1653 (CdO). 1H NMR (250 MHz, CDCl3): δ 2.95
(6H, br s), 5.26 (2H, br s), 7.19 (1H, d, J = 6.5 Hz), 7.32ꢀ7.61 (4H, m),
8.88 (1H, s). 1H NMR (250 MHz, DMSO-d6): δ 2.86 (6H, s), 6.72 (2H,
br s), 7.12 (1H, dd, J = 7.9, 1.1 Hz), 7.35 (1H, dd, J = 7.9, 1.1 Hz), 7.43
(1H, d, J = 8.9 Hz), 7.52 (2H, m), 8.92 (1H, s). 13C NMR (62.5 MHz,
DMSO-d6): δ 45.6, 115.2, 117.5, 120.5, 120.9, 124.4, 125.2, 130.2, 139.9,
153.1, 153.3, 160.6, 161.4. CI MS: m/z (I, %) 478 [2M + 2H]2+ (2.8),
255 [M + H]+ (0.7), 239 [M ꢀ NH2 + H]+ (100). EI MS: m/z (I, %) 238
[M ꢀ NH2]+ (20), 223 (43), 296 (55), 195 (21), 168 (38), 152 (19),
140 (61), 126 (37), 119 (25), 113 (18), 75 (17), 63 (22), 42 (100). Anal.
Calcd for C14H14N4O: C, 66.13; H, 5.55; N, 22.03. Found: C, 66.21; H,
5.48; N, 22.07.
1,8-Bis(dimethylamino)-2-(imino(p-methoxyphenyl)methyl)-
naphthalene (32b). Yield 60%. Yellow crystals, mp 108ꢀ109 °C
(n-hexane). 1H NMR (250 MHz, DMSO-d6): δ 2.58 (6H, s), 2.71 (6H,
s), 3.77 (3H, s), 6.93 (2H, d, J = 8.9 Hz), 7.02 (1H, dd, J = 7.4, 1.3 Hz),
7.08 (1H, d, J = 8.4 Hz), 7.33 (1H, t, J = 7.9 Hz), 7.38ꢀ7.58 (4H, m),
9.96 (1H, s). 13C NMR (62.5 MHz, CDCl3): δ 45.1, 45.5, 56.1, 114.5,
115.1, 123.2, 123.8, 124.1, 127.5, 128.3, 131.3, 133.4, 133.8, 139.7, 148.5,
153.5, 163.0, 180.9. EI MS, m/z (I, %): 347 [M]+ (100), 332 (48), 331
(98), 316 (54), 303 (28), 168 (34). Anal. Calcd for C22H25N3O: C,
76.05; H, 7.25; N, 12.09. Found: C, 76.35; H, 7.22; N, 12.14.
General Procedure for Preparation of 33a and 33b. Solid
imines (32a (230 mg, 0.73 mmol) or 32b (250 mg, 0.72 mmol)) were
General Procedure for Preparation of 19 and 28. A mixture
of NH2OH HCl (100 mg, 1.5 mmol) and K2CO3 (220 mg, 1.6 mmol)
3
in EtOH (10 mL) was stirred for 15 min at 20 °C. Then a solution of
6(150 mg, 0.65 mmol) or 1,8-bis(dimethylamino)-2,7-diformylnaphthalene25
(90 mg, 0.33 mmol) in EtOH (2 mL) was added, and the stirring was
continued for 2 h. The resulting mixture was filtered, the solvent was
evaporated to dryness, and the residue was recrystallized from n-hexane
to give 19 or from n-octane to give 28.
added to a solution of NH2OH HCl (100 mg, 1.5 mmol) in EtOH
3
(10 mL). The resulting dark red mixture was refluxed for 4 h. The sol-
vent was evaporated, and the residue was neutralized with a 5% NH4OH
solution (10 mL) and extracted with CH2Cl2 (3 ꢁ 5 mL). The solvent
was evaporated to dryness, and the residue was recrystallized from
benzeneꢀn-hexane (for 33a) or methanolꢀwater (for 33b) to give an
inseparable mixture of syn- and anti-forms of the corresponding oximes
(2:1 for 33a and 3:1 for 33b).
(E)-1,8-Bis(dimethylamino)naphthalene-2-carbaldehyde
Oxime (19). Yield 80%. Golden-yellow crystals, mp 109ꢀ110 °C
1
(n-hexane). IR (ν/cmꢀ1) (KBr): 3150ꢀ3450 (OH). H NMR (250
MHz, DMSO-d6): δ 2.69 (6H, s), 2.97 (6H, s), 7.09 (1H, br d, J =
7.3 Hz), 7.32 (1H, t, J = 7.9 Hz), 7.40ꢀ7.50 (m, 2H), 7.66 (1H, d, J =
8.5 Hz), 8.29 (1H, s), 11.15 (1H, s). 1H NMR (250 MHz, DMSO-d6 + 1
7163
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ARTICLE
(1,8-Bis(dimethylamino)naphthalen-2-yl)(phenyl)methanone
Oxime (33a). Yield 71%. Yellow crystals, mp 120ꢀ122 °C (C6H6ꢀ
n-hexane). IR (ν/cmꢀ1) (paraffin oil): 3430ꢀ3105 (br, OH). 1H NMR
(250 MHz, DMSO-d6): δ 2.49ꢀ2.80 (12H, m), 6.96ꢀ7.07 (2H, m),
7.20ꢀ7.53 (8H, m), 11.27 (0.65H, s), 11.38 (0.35H, s). 13C NMR
(62.5 MHz, CDCl3): δ 43.8, 44.4, 44.7, 45.9, 46.1, 47.3, 114.8, 115.2,
123.3, 123.6, 123.9, 124.3, 125.2, 126.0, 127.4, 127.5, 128.3, 128.7, 129.0,
129.4, 129.6, 130.4, 130.7, 131.3, 131.9, 135.5, 138.5, 139.8, 149.6, 150.0,
153.3, 153.5, 159.6, 161.4. EI MS, m/z (I, %): 333 [M]+ (44), 316
[M ꢀ OH]+ (58), 289 (40), 288 (100), 273 (87), 258 (27), 193 (27),
182 (33), 168 (95), 167 (47), 154 (35), 128 (29), 127 (51), 115 (35),
91 (38), 77 (92), 51 (41), 44 (62), 42 (56). Anal. Calcd for C21H23-
N3O: C, 75.65; H, 6.95; N, 12.60. Found: C, 75.55; H, 6.98; N,
12.55.
2,7-Dicyano-8-dimethylamino-1-naphthol (30). Yield 32%.
Yellow crystals, decomp above 180 °C (n-hexane). IR (ν/cmꢀ1
)
1
(paraffin oil): 2263 (CtN). H NMR (250 MHz CDCl3): δ 3.15
(6H, d, J = 0.6 Hz), 7.24 (1H, d, J = 8.7 Hz), 7.56 (1H, d, J = 8.5 Hz), 7.62
(1H, d, J = 8.5 Hz), 7.76 (1H, d, J = 8.5 Hz), 16.60 (1H, s). 13C NMR
(62.5 MHz, CDCl3): δ 44.1, 96.6, 106.8, 117.8, 118.2, 119.2, 119.7,
129.8, 132.4, 132.8, 140.4, 154.7, 166.2. EI MS, m/z (I, %): 237 [M]+
(23), 222 (19), 139 (21), 44 (72), 42 (100). UVꢀvis (MeCN):
λmax (log ε) 360 (3.90), 343 (3.82), 262 (4.52), 226 (4.49). Fluores-
cence (MeCN): 338 nm (excitation), 421 nm (fluor.). Anal. Calcd for
C14H11N3O: C, 70.87; H, 4.67; N, 17.71. Found: C, 70.59; H, 4.65;
N, 17.66.
2,7-Dicyano-1,8-bis(dimethylamino)naphthalene(31).Yield
20%. Yellow crystals, mp 194ꢀ196 °C (n-octane). IR (ν/cmꢀ1) (paraffin
oil): 2196 (CtN). 1H NMR (250 MHz, CDCl3): δ 3.15 (12H, s), 7.21
(2H, d, J = 8.9 Hz), 7.39 (2H, d, J = 8.9 Hz). 13C NMR (62.5 MHz,
CDCl3): δ 45.5, 101.8, 121.7, 122.7, 133.4, 143.3, 157.0. EI MS, m/z
(I, %): 264 [M]+ (58), 249 (17), 233 (81), 232 (83), 220 (47), 219 (39),
218 (100), 44 (78), 41 (29). UVꢀvis (MeCN): λmax (log ε) 405 (4.09),
378 (4.18), 271 (4.73), 228 (4.68). Anal. Calcd for C16H16N4: C, 72.70;
H, 6.10; N, 21.20. Found: C, 72.99; H, 6.12; N, 21.13.
9-Dimethylamino-3-phenylnaphtho[2,1-d]isoxazole (34a).
Yield 64%. Beige crystals, mp 111ꢀ112 °C(n-hexane). 1H NMR(250 MHz,
CDCl3): δ 3.01 (6H, s), 7.23 (1H, dd, J = 8.2, 1.1 Hz), 7.49ꢀ7.58 (5H,
m), 7.67 (1H, d, J = 8.7 Hz), 7.79 (1H, d, J = 8.7 Hz), 7.99 (2H, dd, J =
7.7, 1.9 Hz). 13C NMR (62.5 MHz, CDCl3): δ 40.0, 116.7, 117.3, 117.7,
119.6, 123.3, 127.3, 129.5, 129.5, 130.4, 130.6, 131.2, 137.5, 151.8, 158.6,
163.1. EI MS, m/z (I, %): 288 [M]+ (100), 287 (15), 273 (64), 140 (25),
115 (33), 77 (59), 51 (35). Anal. Calcd for C19H16N2O: C, 79.14; H,
5.59; N, 9.72. Found: C, 78.82; H, 5.57; N, 9.70.
9-Dimethylamino-3-(p-methoxyphenyl)naphtho[2,1-d]iso-
xazole (34b). Yield 64%. Beige crystals, mp 126ꢀ127 °C (n-heptane).
1H NMR (250 MHz, CDCl3): δ 2.99 (6H, s), 3.84 (3H, s), 7.06 (2H, d,
J = 8.9 Hz), 7.20ꢀ7.24 (1H, m), 7.48ꢀ7.58 (2H, m), 7.66 (d, 1H,
J = 8.5 Hz), 7.78 (1H, d, J = 8.5 Hz), 7.92 (2H, d, J = 8.9 Hz). 13C NMR
(62.5 MHz, CDCl3): δ 46.0, 56.1, 115.7, 116.6, 117.3, 117.7, 119.7,
122.9, 123.3, 127.1, 129.4, 130.8, 137.4, 151.8, 158.2, 162.5, 163.0. EI
MS, m/z (I, %): 318 [M]+ (100), 304 (21), 303 (97), 211 (16),
140 (15), 115 (20), 92 (22), 77 (19), 64 (13). Anal. Calcd for
C20H18N2O2: C, 75.45; H, 5.70; N, 8.80. Found: C, 75.15; H, 5.72;
N, 8.76.
Attempted Preparation of Compound 36. (2-Dimethylamino-
phenyl)(phenyl)methanone oxime48 (35) (100 mg, 0.42 mmol) was
kept for 2 h at 120ꢀ130 °C with stirring under argon atmosphere. The
fused mixture was cooled to 20 °C, and the starting oxime 35 was
recovered almost quantitatively.
(1,8-Bis(dimethylamino)naphthalen-2-yl)(p-methoxyphenyl)-
methanone Oxime (33b). Yield 70%. Yellow crystals, mp 126ꢀ
129 °C (MeOHꢀH2O). IR (ν/cmꢀ1) (paraffin oil): 3430ꢀ3134
1
(br, OH). H NMR (DMSO-d6): δ 2.55ꢀ2.90 (12H, m), 3.76 (3H,
s), 6.88ꢀ6.94 (∼2H, m), 6.98ꢀ7.70 (∼2H, m), 7.22 (2H, d, J = 9.0 Hz),
7.25ꢀ7.55 (∼3H, m), 11.08 (0.75H, s), 11.30 (0.25H, s). EI MS,
m/z (I, %): 363 [M]+ (40), 346 [M ꢀ OH]+ (53), 319 (32), 318 (73),
303 (100), 168 (49), 127 (27), 121 (58), 115 (26), 92 (35), 77 (56),
64 (32), 63 (28), 44 (55), 42 (47). Anal. Calcd for C22H25N3O2: C,
72.70; H, 6.93; N, 11.56. Found: C, 72.99; H, 6.96; N, 11.61.
General Procedure for Preparation of 21 and 22, 30 and
31, 34a and 34b. A solid compound [19 (100 mg, 0.39 mmol) or 28
(100 mg, 0.33 mmol) or 33a (100 mg, 0.30 mmol) or 33b (100 mg, 0.28
mmol)] was kept for 12 h at 120ꢀ130 °C (for 19), 2 h at 160ꢀ165 °C
(for 28), 2 h at 120ꢀ130 °C (for 33a), or 3 h at 130ꢀ140 °C (for 33b)
with stirring under argon atmosphere. The fused mixture was cooled to
20 °C and chromatographed on Al2O3/Et2Oꢀn-hexane (1:1) (for 21
and 22), Al2O3/CHCl3ꢀn-hexane (1:1) (for 30 and 31), or Al2O3/
CHCl3 (for 34a and 34b), correspondingly. The solvents were evapo-
rated to yield the products.
2-Cyano-8-dimethylamino-1-naphthol (21). Yield 32%. Beige
crystals, mp 105ꢀ106 °C (n-hexane). IR (ν/cmꢀ1) (paraffin oil): 2220
(CtN). 1H NMR (250 MHz, CDCl3): δ 2.84 (6H, s), 7.18 (1H, d, J =
8.6 Hz), 7.37 (1H, d, J = 8.6 Hz), 7.43 (1H, d, J = 7.4, 1.1 Hz), 7.52 (1H, t,
J = 7.7 Hz), 7.65 (1H, d, J = 8.0 Hz), 16.53 (1H, s). 13C NMR (62.5 MHz,
CDCl3): δ 46.9, 94.0, 118.9, 119.1, 119.2, 128.3, 129.2, 130.1, 138.7, 151.4,
164.8. EI MS: m/z (I, %) 212 [M]+ (55), 197 (33), 140 (72), 115 (61),
114 (54), 113 (51), 98 (37), 89 (28), 88 (40), 87 (33), 77 (31), 76 (32),
75 (45), 74 (27), 71 (38), 64 (34), 63 (88), 62 (45), 52 (33), 51 (49), 50
(36), 44 (97), 43 (34), 42 (100). UVꢀvis (MeCN): λmax (log ε) 348
(3.94), 333 (3.86), 316 (3.74), 228 (4.50). Fluorescence (MeCN): λmax
347 (excitation), 446 (fluor.). Anal. Calcd for C13H12N2O: C, 73.56; H,
5.70; N, 13.20. Found: C, 73.27; H, 5.72; N, 13.16.
X-ray Crystallography. Atomic coordinates, bond lengths, bond
angles, and thermal parameters for 8, 13 HClO4, and 19 have been
2-Cyano-1,8-bis(dimethylamino)naphthalene (22). Yield
3
1
32%. Yellow oil. IR (ν/cmꢀ1) (liquid film): 2209 (CtN). H NMR
deposited at the Cambridge Crystallographic Data Centre (CCDC).
These data can be obtained free of charge via www.ccdc.cam.uk/conts/
retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2
1EZ; fax: +44 1223 335 033; or deposit@ccdc.cam.ac.uk). Any request
to the CCDC for data should quote the full literature citation and CCDC
reference numbers.
(250 MHz, CDCl3): δ 2.80 (6H, s), 3.19 (6H, s), 7.00 (1H, br d, J =
7.4 Hz), 7.28ꢀ7.44 (4H, m). 13C NMR (62.5 MHz, CDCl3): δ 45.0,
45.3, 101.1, 115.3, 121.9, 112.4, 123.4, 129.7, 129.9, 141.1, 153.5, 156.5.
EI MS: m/z (I, %) 239 [M]+ (70), 224 (22), 209 (31), 208 (75), 207
(67), 195 (72), 194 (34), 193 (100), 179 (26), 152 (29), 44 (60).
UVꢀvis (MeCN): λmax (log ε) 388 (3.62), 342 (3.65), 259 (4.36), 216
(4.25). Anal. Calcd for C15H17N3: C, 75.28; H, 7.16; N, 17.56. Found: C,
75.28; H, 7.13; N, 17.49.
Alternatively, this compound may be prepared as follows. A
mixture of 19 (100 mg, 0.39 mmol) and KOH (22 mg, 0.39 mmol)
in DMSO (5 mL) was kept for 20 min at 150 °C. The solvent was
evaporated, and the residue was chromatographed on Al2O3 with
CHCl3 elution. The solvent was evaporated to yield 84 mg (90%) of
22 with properties identical to those for the sample described
above.
Crystal Data for 8. Obtained from MeCN: C13H13N3, M = 211.26,
space group Pbca (orthorhombic), a = 7.4737(14), b = 12.984(2), c =
23.026(4) Å, V = 2234.4(7) Å3, Z = 8, Dc = 1.256 g cmꢀ3, μ(Mo KR) =
0.077 mmꢀ1, 120 K, 19782 reflections collected, 2420 unique (Rint
=
0.0730), 1850 reflections with I > 2σ(I), 145 parameters, R1 = 0.0676,
wR2 (all data) = 0.1087. CCDC reference number 828288.
Crystal Data for 13 HClO4. Obtained from dry MeCN: C20H17Cl-
3
N4O4, M= 412.83, space group P1 (triclinic), a= 8.9925(16), b= 9.4538(17),
c = 11.710(2) Å, R = 109.472(4)o, β = 105.396(4)o, γ = 90.581(4)o, V =
899.5(3) Å3, Z = 2, Dc = 1.524 g cmꢀ3, μ(Mo KR) = 0.251 mmꢀ1, 120 K,
7164
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The Journal of Organic Chemistry
ARTICLE
8606 reflections collected, 3874 unique (Rint = 0.0305), 2621 reflections with
I > 2σ(I), 285 parameters, R1 = 0.0771, wR2 (all data) = 0.1092. CCDC
reference number 828289.
(19) Sobzyk, L.; Grabowskii, S. J.; Krygowskii, T. M. Chem. Rev.
2005, 105, 3513.
(20) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic
Chemistry; University Science Book: Sausalito, CA, 2006; p 179.
(21) Kurasov, L. A.; Pozharskii, A. F.; Kuz’menko, V. V.; Klyuev,
N. A.; Chernyshev, A. I.; Goryaev, S. S.; Chikina, N. L. Zh. Org. Khim.
1983, 19, 590. Chem. Abstr. 1983, 99, 22064v.
(22) Alder, R. W.; Anderson, J. E. J. Chem. Soc., Perkin Trans. 2
1973, 2086.
(23) Reich, H. J.; Cohen, M. L. J. Org. Chem. 1979, 44, 3148.
(24) Ozeryanskii, V. A.; Pozharskii, A. F.; Koroleva, M. G.; Shevchuk,
D. A.; Kazheva, O. N.; Chekhlov, A. N.; Shilov, G. V.; Dyachenko, O. A.
Tetrahedron 2005, 61, 4221.
(25) Pozharskii, A. F.; Degtyarev, A. V.; Ryabtsova, O. V.; Ozeryanskii,
V. A.; Kletskii, M. E.; Starikova, Z. A.; Sobczyk, L.; Filarowski, A. J. Org.
Chem. 2007, 72, 3006.
(26) Mallinson, P. R.; Smith, G. T.; Wilson, C. C.; Grech, E.;
Wozniak, K. J. Am. Chem. Soc. 2003, 125, 4259.
(27) Elguero, J.; Cano, F. H.; Foces-Foces, C.; Llamas-Saiz, A. L.;
Limbach, H.-H.; Aguilar-Parrilla, F.; Claramunt, R. M.; Lꢀopez, C.
J. Heterocycl. Chem. 1994, 31, 695.
(28) Apparently, the inertness of 2-aminobenzimidazole toward
aldehyde 6 in acidic media results from its considerably higher
basicity (pKa = 7.54, H2O, 25 °C) in comparison with 3-aminoinda-
zole (pKa = 3.15).29 Consequently, under acidic conditions, the
imidazole ring can be protonated with complete loss of nucleophi-
licity. Upon melting, the cyclization may proceed via zwitterionic
form 14 in which the anionic imidazole ring should be strongly
nucleophilic. Apparently, in the absence of external protons, the
zwitterionic motif may be a widespread phenomenon in such trans-
formations: see data below on similar reactions of proton sponge-
based aldoximes.
(29) Albert, A. In Physical Methods in Heterocyclic Chemistry;
Katritzky, A. R., Ed.; Academic Press: New York, 1963; Chapter 1.
(30) 5-Aminotetrazole and 2-aminobenzimidazole can be consid-
ered as cyclic guanidine derivatives. However, we were unsuccessful in
conducting the same reaction with the parent guanidine, probably owing
to its much higher basicity and existing under employed acidic condi-
tions solely as a non-nucleophilic protonated form. The same may be
applied for benzamidine, while urea did not react with 6 in either acidic
or neutral media.
Crystal Data for 19. Obtained from n-hexane: C15H19N3O, M =
257.33, space group P 1 (triclinic), a = 8.3498(11), b = 10.0042(13),
c = 17.756(2) Å, V = 1390.2(3) Å3, Z = 4, Dc = 1.229 g cmꢀ3, μ(Mo KR) =
0.079 mmꢀ1, 120 K, 14373 reflections collected, 6637 unique (Rint
=
0.0368), 3325 reflections with I > 2σ(I), 351 parameters, R1 = 0.1132,
wR2 (all data) = 0.1210. CCDC reference number 828290.
’ ASSOCIATED CONTENT
S
Supporting Information. ORTEP structures of com-
b
pounds 8, 13 HClO4, and 19; selected structural parameters
3
of oxime 19; 1H and 13C NMR spectra of all new compounds;
1
COSY data for 13 and 15; H NMR spectra of competitive
transprotonation mixtures for oxime 19. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Tel: +7 863 297 5146. E-mail: apozharskii@sfedu.ru.
’ ACKNOWLEDGMENT
The authors thank Dr. Zoya A. Starikova (A. N. Nesmeyanov
Institute of Organoelement Compounds of Russian Academy of
Sciences, Moscow) for X-ray diffraction studies and Drs. Anna V.
Tkachuk, Alexandra A. Kolodina, and Oleg N. Burov for NMR
measurements. This work was supported by the Russian Foun-
dation for Basic Research (project 11-03-00073).
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