Naphthalene proton sponges as hydride donors: Diverse appearances of the tert-amino-effect

Article abstract of DOI:10.1039/c0ob00899k

It has been shown that the 1-NMe₂ group in the 2-substituted 1,8-bis(dimethylamino)naphthalenes (proton sponges) can intramolecularly donate a hydride ion to an appropriate electron-accepting ortho-substituent such as diarylcarbenium ion, β,β′-

Full text of DOI:10.1039/c0ob00899k

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PAPER
Naphthalene proton sponges as hydride donors: diverse appearances of the
tert-amino-effect†
Alexander F. Pozharskii,*a Maria A. Povalyakhina,a Alexander V. Degtyarev,a Oxana V. Ryabtsova,a
Valery A. Ozeryanskii,a Olga V. Dyablo,a Anna V. Tkachuk,a Olga N. Kazheva,b Anatolii N. Chekhlovb and
Oleg A. Dyachenkob
Received 18th October 2010, Accepted 13th December 2010
DOI: 10.1039/c0ob00899k
It has been shown that the 1-NMe2 group in the 2-substituted 1,8-bis(dimethylamino)naphthalenes
(proton sponges) can intramolecularly donate a hydride ion to an appropriate electron-accepting
ortho-substituent such as diarylcarbenium ion, b,b¢-dicyanovinyl or methyleneiminium group. This
produces the 1-N+(Me) CH2 functionality and triggers a number of further transformations
(tert-amino effect) including peri-cyclization, ortho-cyclization or hydrolytic demethylation. In each
particular case, the course of the reaction is determined by the nature of the ortho-substituent and the
most potent nucleophile presenting in the reaction mixture. For 2,7-disubstituted
1,8-bis(dimethylamino)naphthalenes, two types of tandem tert-amino effect with the involvement of
both peri-NMe2 groups have been registered. The conclusion was made that proton sponges are
generally more active in the tert-amino reactions than the corresponding monodimethylaminoarenes.
This is ascribed both to higher electron donor ability of proton sponges and markedly shortened
distance between electrophilic Ca-atom in the ortho-substituent and hydrogen atoms of the nearest
NMe2 group. Most conversions observed proceed in good to high yields and are useful for the
preparation of derivatives of benzo[h]quinoline, quino[7,8:7¢,8¢]quinoline, 2,3-dihydroperimidine,
N,N,N¢-trimethyl-1,8-diaminonaphthalene and proton sponge itself.
dride donor from one of its methyl groups.4 The methyleneiminium
Introduction
cation 5 thus formed rapidly cyclizes into 1a (Scheme 2). Thus,
Some time ago one of us and co-workers had demonstrated that
2,3-dihydroperimidinium salts and naphthalene proton sponges
lithium aluminium hydride (LAH) reduction of 1,1,3-trimethyl-
form a redox-system interconverting through the same iminium
2,3-dihydroperimidinium salt 1a quantitatively produces 1,8-
intermediate.
bis(dimethylamino)naphthalene (proton sponge, 2, Scheme 1).1a,2
In the present article a number of novel and synthetically useful
cases of the hydride-donor activity of naphthalene proton sponges
Though for the parent 2 this is not the method of choice, it
together with a general survey of the topic are reported.5 The
central point of this study is to demonstrate that the proton
sponge N-methyl groups are able to donate a hydride ion not
only to external acceptors as in the above examples but also
intramolecularly to various ortho-substituents with appropriate
electron deficiency that initiates a set of interesting cyclizations
and transformations. This type of reactivity of tertiary aromatic
amines is commonly referred to as a tert-amino effect.6
can be indispensable for some proton sponge derivatives, e.g.
those with unequal N-alkyl substituents1a or peri-halogen atoms.1b
It is interesting, that unlike 1a, the 1,1,2,2,3-pentamethyl-2,3-
dihydroperimidinium salt 1b preferably exists in the ring-opened
form 3 (apparently due to a steric crowding) and even on
treatment with NaBH4 smoothly converts into monoisopropyl
proton sponge 4.3
Independently, other authors had shown that this reaction can
be reversed. It was found that in the presence of transition metal
(Ir3+, Rh3+, Ru3+) complexes, the proton sponge 2 behaves as a hy-
Results and discussion
aDepartment of Organic Chemistry, Southern Federal University, Zorge 7,
344090 Rostov-on-Don, Russian Federation. E-mail: apozharskii@sfedu.ru
Proton sponge-based 2-naphthylmethyl carbocations
bInstitute of Problems of Chemical Physics, Russian Academy of Sciences,
Semenov 1, 142432 Chernogolovka, Moscow Region, Russian Federation
First, we have found that the tert-amino effect is readily displayed
by proton sponge-based 2-naphthylmethyl carbocations.5a For
example, on treatment of tertiary alcohol 6a with conc. HCl
an orange-red colour, characteristic for triarylmethyl cations,
immediately develops followed by a fast discolouration and
† Electronic supplementary information (ESI) available. CCDC reference
numbers 804543 (29f), 720578 (33), 801823 (35a) and 801824 (56). For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c0ob00899k
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Scheme 1
Scheme 2
Scheme 3
precipitation of 4-benzhydryl-2,3-dihydroperimidinium salt 12a
The structures of the salts 12 and 16 were proved by common
in quantitative yield. Similarly, secondary alcohols 6b,c and 15
give chlorides 12b,c and 16 in a good yield (Schemes 3 and 4).
Reductive cleavage of salts 12 and 16 with LAH gives the proton
sponge derivatives 13a,b and 17, respectively.
spectral methods; for 12b X-ray studies were also conducted.5a
A
plausible mechanism for the transformation is shown in Scheme 3.
The process is thought to start with the formation of chelated
cation 7 equilibrating with hydroxonium salt 8, which is supposed
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Scheme 4
to be direct precursor of carbocation 9.7 The latter immediately ac-
cepts a hydride ion from the nearest N–Me group and the iminium
intermediate 10 is then cyclized into 2,3-dihydroperimidinium
salt 12. Obviously, rotation of the N+(Me) CH2 group
around the Carom–N bond (10 → 11) should precede the ring
closure.
Unlike alcohols 6 and 15, their analogue 23a with the a-
hydroxyisopropyl ortho-substituent being treated with conc. HCl
forms carbocation 24, which undergoes E1 elimination to produce
on basification 1,8-bis(dimethylamino)-2-isopropenylnaphthalene
25 in 96% yield (Scheme 6).5a The primary alcohol 23b on heating
with acids, e.g. conc. HBr, exchanges the hydroxylic group with the
formation of a 2-bromomethyl derivative isolated as hydrobromide
27.5a Obviously, both these reactions reflect the relatively low
stability of the corresponding 2-naphthylmethyl carbenium ions.
The ease, directionality and even possibility of the above tert-
amino reactions strongly depend on stability of the intermediate
carbenium ion. Thus, if in the case of tertiary alcohol 6a the
reaction ends in seconds, for the secondary alcohols, producing
less stable diarylmethyl carbocations, it requires minutes (6b)
or even hours (6c and 15). The behaviour of the alcohol 6c
is of special interest since in this case a hydride ion can be
donated either by the proton sponge or the N,N-dimethylaniline
(DMA) residue (structure 14). The exclusive formation of salt
12c shows that the proton sponge is a stronger hydride donor
than DMA, this is in accord with its much higher basicity and
slightly lower first ionization potential (IP1 = 7.05 eV8 against
7.10 eV9 for DMA). In this context, it seemed to us reasonable
to test the principle ability of dimethylaniline-based carbocations
to undergo the tert-amino reaction. With this aim, we treated
2-dimethylaminotriphenylmethanol 1910 with conc. HCl under
reflux (Scheme 5). 2-Benzhydryl-N-methylaniline 22 was isolated
from the reaction mixture as a single product in 93% yield.
Thus, the tert-amino effect is also valid for the triphenylmethyl
cation 20, though its final stage is a hydrolytic cleavage of
the iminium intermediate 21 with the loss of one N-methyl
group. It is worth noting that dihydroperimidinium salts are
also cleaved on alkali treatment.1a For example, salt 16 can be
alternatively converted into the compound 17 on treatment with
aqueous NaOH and a subsequent methylation of the transient
tetraamine 18.
Proton sponges with electron-deficient ortho-vinyl groups
Next, we have found that another and more common type
of the tert-amino effect takes place for 2-vinyl- 29 and 2,7-
divinyl-1,8-bis(dimethylamino)naphthalenes 34 which have strong
electron-withdrawing groups in the b-positions of the side chains.
These alkenes were prepared by the Knoevenagel condensation
of aldehydes 28 and 33 with malonodinitrile, dimedone, tosy-
lacetonitrile, ethyl cyanoacetate and 2-cyanomethylbenzimidazole
(Schemes 7 and 8).5b Monoaldehyde 28 easily reacts with these
methylene-active compounds in alcohol or toluene solution;
reaction in toluene demands an addition of piperidine, while
in EtOH the condensation occurs without external catalyst.11
We were able to isolate in a pure state only alkenes 29c,d,f;14
alkenes 29a,b spontaneously transform into benzo[h]quinolines
31a,b, though their formation as intermediates can be monitored
spectrophotometrically.15 Evidently, in this case hydride transfer
produces zwitter-ions 30 which undergo subsequent cyclization
(Scheme 7).
Isomerisation of alkenes 29c,d into benzo[h]quinolines 31c,d
occurs rapidly and almost quantitatively on heating the solid
samples or (more slowly) on incubation of their solutions in
Scheme 5
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Scheme 6
Scheme 7
Scheme 8
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Table 1 tert-Amino-effect
in
2-vinyl-
and
2,7-divinyl-1,8-
DMSO or ethanol at ambient temperature. On interaction of the
aldehyde 2816 with ethyl cyanoacetate in MeOH (25 ◦C, 72 h)
along with the condensation and subsequent tert-amino reaction,
the complete re-esterification occurs allowing isolation of only
benzo[h]quinoline 31e.
bis(dimethylamino)naphthalenes
Reaction conditions
Alkene
Solvent T/◦C
Time, h
Product Isolated yield (%)
The situation with benzimidazolyl-2-alkene 29f is somewhat
different: it remains intact at room temperature even in polar
solvents (DMSO, DMF, EtOH) but on heating as solid or in
DMSO under reflux it converts with considerable tarring into 31f
in 25% yield. Such behaviour can be attributed to enlarged NH-
acidity of the benzimidazole moiety in 29f17 causing its conversion
to anion 32 which should be more inert to a hydride reduction (see
below X-ray data for 29f).
29aa
29ba
29c
29c
29d
29f
34a
34a
34ba
34c
34d
PhMe
PhMe
neat
DMSO
DMSO
DMSO
neat
DMSO
PhMe
DMSO
DMSO
r.t.
r.t.
96
24
31a
31b
31c
31c
31d
31f
35a
35a
35b
35c
35d
80
96
90
100
100
25
96
100
98
100
100
140–180 < 0.15
r.t.
r.t.
189
48
72
1
145–155 < 0.15
r.t.
r.t.
r.t.
r.t.
48
24
48
72
a The alkene was not isolated in the Knovenagel condensation due to its
high reactivity.
assignment has been done for compound 31e by using correlation
1H–13C spectroscopy and the results obtained were applied to the
other compounds of type 31.16 For tetrahydroquinolines 31a5b and
35a X-ray studies have been also performed (Fig. 1).
The divinylic compound 34b is especially active, self-cyclizing
into 35b even under ambient conditions. In contrast, the dialkenes
34a,c,d14 can be isolated; on heating in the solid state or on incu-
bation in DMSO at room temperature they undergo double tert-
amino cyclization giving the quino[7,8:7¢,8¢]quinoline derivatives
35a,c,d in high yields (Scheme 8). The data obtained for cyclization
of the mono- and dialkenes are summarized in Table 1.
Structures of 31 and 35 are confirmed by the absence in their
NMR spectra of signals from one or two N–Me groups and an
appearance of the two-proton peaks for the ring methylene groups.
For example, in the 13C and 1H NMR spectra of benzoquinoline
31a the 2- and 4-CH2 groups resonate at dC 57.0 and 37.6 and
dH 3.98 and 3.63 ppm, respectively (the assignment is based on
the HETCOR experiments).18 In the 1H NMR spectra registered
at 600 MHz one can see that unlike the 4-CH2 group the 2-CH2
hydrogens are magnetically non-equivalent due to pyramidality of
the 1-NMe group (Fig. 1) and give two broadened signals at dH
4.07 and 3.89 ppm. In quinolines 31c–f and 35c,d the substituents
at C-3 are different, which results in nonequivalence of the
geminal hydrogens of both 2-CH2 and 4-CH2 groups. Their exact
In principle, the readiness of the tert-amino cyclization of
alkenes 29 and 34 might be caused not only by the intrinsically
high hydride donacity of the proton sponge NMe2 groups but
also by the stereochemical peculiarities of these compounds
such as spatial proximity of the N–Me groups and the Ca-
atom of the ortho-substituent or their favourable orientation.
Since peri-disubstituted naphthalenes are known to be classical
objects for the testing proximity effects,6c,f,19 we had chosen 1-
dimethylamino-8-(2,2-dicyanovinyl)naphthalene 366c,f for addi-
tional study. Surprisingly, this alkene was rather inert in regard
to the tert-amino cyclization and remained unchanged on short
melting (~160 ◦C, <0.3 h), after prolonged heating in EtOH
or incubation of its solution in DMSO at room temperature.
Nevertheless, nearly quantitative cyclization of 36 into 1-methyl-
3,3-dicyanonaphtho[1,8-b,c]azepine 37 occurs when a solution of
36 in DMSO was refluxed for 30 min (Scheme 9).20
To shed some light on factors determining higher reactivity of
alkenes 29 and 34 in comparison with 36 we have performed X-
ray study of compound 29f (geometry of 36 has been reported
Fig. 1 Molecular structure of quino[7,8:7¢,8¢]quinoline 35a (left) and view along the naphthalene plane with the N–Me groups directed to the viewer
(right). Thermal ellipsoids are drawn at the 50% probability level with hydrogens being omitted for clarity.
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Scheme 9
Fig. 2 Molecular structure of alkene 29f: two independent molecules are shown. Thermal ellipsoids are drawn at the 40% probability level.
previously19a). The data obtained (Fig. 2) have disclosed that the
nearest CH3 hydrogen atoms in molecule 29f are much closer
˚
(2.56–2.60 A) to the electrophilic Ca atom of vinyl group than
21
˚
in alkene 36 (3.04 A). Most likely, the same should be true for
proton sponge alkenes 29a–e and 34a–d. Since an intramolecular
1,5-hydrogen transfer (1,6 transfer for 36) is the rate-determining
step for the tert-amino reactions,22 the HMe ◊ ◊ ◊ CCH distances can
be considered as one of the most important factors influencing
such processes.
The geometrical specificity of ortho-substituted proton sponges
originates from two contradictory effects: 1) the steric and electron
repulsion of the peri-dimethylamino groups and 2) the pressure
exerted by the ortho-substituents and causing considerable pla-
narization of the amine nitrogen atoms.24 Indeed, both NMe2
groups in molecule 33 and 1-NMe2 group in 29f are almost flat
with the sums of the valence angles at nitrogen atoms being near
358–359◦. Besides, peri-NMe2 groups are turned relatively to the
naphthalene ring plane on ca. 55◦. Both these factors bring the
methyl hydrogens and electrophilic centre in close proximity thus
facilitating the hydride shift. Since the electrophilicity of the CHO
group is rather low (sp = 0.22),25 aldehydes 28 and 33 do not
displayatert-aminoeffectneitheronheatingofmeltedcompounds
nor on refluxing their solutions with Et2O·BF3 as a catalyst.
However, a transition to more electrophilic substituents such as
Obviously, the large HMe ◊ ◊ ◊ CCH separation in molecule 36
results from a strong attractive interaction between the nucle-
ophilic and electrophilic groups in the peri-position.6c This leads
to a dramatic decrease of the N ◊ ◊ ◊ CCH distance accompanied
by strong pyramidalization and rotation of the NMe2 group to
provide better directionality of its unshared electron pair towards
the electrophilic centre. Consequently, the N-methyl hydrogens
move away from the vinyl Ca atom. Another example of such a
kind is the pair 8-dimethylamino-1-naphthalenecarbaldehyde 3823
and 2,7-dialdehyde 33, for which in the present work we have also
performed X-ray measurements (Fig. 3). While the HMe ◊ ◊ ◊ CCHO
˚
distance in the former molecule is equal 3.07 A, for 33 it is much
˚
shorter (2.54 A).
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Fig. 3 Molecular structure of dialdehyde 33 (left) and view along the naphthalene plane with the NMe2 groups directed to the viewer (right). Thermal
ellipsoids are drawn at the 20% probability level with hydrogens being omitted for clarity.
Scheme 10
2,2-dicyanovinyl makes the hydride shift possible. There is little
doubt that the intrinsic hydride donor ability of the peri-NMe2
groups should be also at play, favouring higher activity of the
proton sponge derivatives. This follows from a comparison of the
first ionization potentials of 1,8-bis(dimethylamino)naphthalene 2
(IP1 = 7.05 eV) and 1-dimethylaminonaphthalene (IP1 = 7.50 eV).8
The reasons why iminium intermediates like 30 undergo ortho-
and not peri-cyclization are understandable. Firstly, the nucle-
ophilicity of the carbanion centre in 30 should be higher than
that of the 8-NMe2 group. Secondly, the peri-cyclization requires
rotation of the N(Me) CH2 group around the Carom–N bond (see
10 → 11, Scheme 3), which costs some extra energy.
either reduce the heterocyclic ring with subsequent peri-cyclization
into 2,3-dihydroperimidinium salt 40 or migrate into the alkene
chain ultimately producing benzo[h]quinoline derivative 41. As
we found, neither of these possibilities is realized. Compounds
39a,b14 obtained by a condensation of aldehyde 28 with 1,2-
dimethylpyridinium iodide and 1,2-dimethylquinolinium perchlo-
rate, respectively, remained unchanged on heating as solids (150–
180 ◦C, 20 min) or in polar solvents (DMSO, 90 ◦C, 1 h; DMF or
EtOH, reflux, 5 h).
Analogously, 2-(2-nitrovinyl)- 42a and 2-(2-nitropropen-1-yl)-
1,8-bis(dimethylamino)naphthalenes 42b have been prepared by
a condensation of aldehyde 28 with nitromethane or nitroethane
in the presence of piperidine as a catalyst (Scheme 11). Inter-
estingly, in both cases, in addition to the target compounds
42, 1-dimethylamino-8-methylamino-7-piperidinomethyl naph-
thalene 43a was isolated as a by-product in a 10% yield.
Further we decided to examine whether the tert-amino-effect
can be also observed for proton sponges 39 with electron-
deficient heterocyclic groups in the vinyl chain (Scheme 10). In
principle, as it is shown for the salt 39a, the hydride ion can
Scheme 11
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Scheme 12
The nitroalkenes 42a,b14 are rather stable compounds and
do not enter the tert-amino reaction on heating as solid or
under reflux in polar solvents such as DMSO (1 h), DMF or
EtOH (5 h). At the same time, the formation of demethylated
Mannich base 43a clearly indicated that some kind of a tert-amino
reaction, possibly involving 2-methyleneiminium intermediate, yet
occurs. Therefore, we examined the last transformation in more
detail.
group producing another iminium intermediate 45. The latter is
transformed into final product 43 either by the direct hydrolytic
loss of the N-methyl group or via the preliminary formation of 2,3-
dihydroperimidinium 46 or benzo[h]quinazolinium 47 salts, which
both can undergo similar basic hydrolysis. Indeed, in a special
experiment we found that salt 1a on treatment with piperidine
(3 eq) in methanol (20 ◦C, 96 h) furnished N,N,N¢-trimethyl-1,8-
diaminonaphthalene in 59% yield.
Especially interesting results were obtained when 2,7-dialdehyde
33 reacted with secondary amines in the presence of 2-
nitropropane (Scheme 13). In this case, the main reaction
product was the corresponding 4,9-bis(dialkylaminomethyl)-1,3-
dimethyl-2,3-dihydroperimidine 53. Unlike the uniform tan-
dem tert-amino effect, which has been described above for
quino[7,8:7¢,8¢]quinolines 35 (Scheme 8), the formation of bis-
Mannich bases 53 can be qualified as a mixed tandem tert-amino
process (Scheme 13). As one can see, two subsequent hydride ion
transfers occur from the two different N-methyl groups of the
same molecule. On the first stage, the reaction develops similarly
to monoaldehyde 28 (Scheme 12) yielding the demethylated
Mannich base 48 and then the iminium intermediates 49 and
50. However, the next stage is not the demethylation of 50 but
instead the peri-cyclization in which the 8-N+(Me) CH2 and 1-
NHMe functionalities participate. At the first glance, it seems
strange since the nucleophilicity of the 1-NHMe group should be
Proton sponges with methyleneiminium functionalities in
ortho-positions
We proposed that the 2-methyleneiminium salt of type 44
(Scheme 12), which results from the nucleophilic addition of
piperidine to the carbonyl group of aldehyde 28, is the initial
intermediate in the formation of Mannich base 43a. Since 43a is
not formed in the absence of nitromethane or nitroethane, the
latter appears to act as a mild acidic catalyst. To exclude the
formation of nitroalkenes 42 and thus to increase the yield of
43a, we replaced MeNO2 and EtNO2 by 2-nitropropane. Indeed,
in this case compound 43a became a single isolable product
with a 74% yield. When some other secondary alkylamines have
been used instead of piperidine, the Mannich bases 43b–e were
obtained in 30–43% non-optimized yields. Evidently, the primarily
formed iminium salt 44 accepts a hydride ion from the 1-NMe2
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Scheme 13
Scheme 14
substantially lower than that of OH-. A possible rationale might
be the participation of OH- or dialkylamine in the basic catalysis
that sharply increases nucleophilicity of the 1-NHMe group as it
is depicted in structure 51. Apart from this, such cyclization can
be promoted by the pressure of the two ortho-CH2NR2 groups
(“buttressing effect”)24 which forces the peri-substituents to be
closer to each other. Alternatively, the reaction may indeed involve
hydrolytic demethylation with the loss of CH2O molecule to give
the N,N¢-dimethylated diaminonaphthalene 52, which afterwards
transforms into 53.
producing benzo[h]quinazolinium salts of type 47. Apparently,
such cyclization is less favourable because of two reasons: 1)
the close proximity of peri-substituents and 2) the unfavourable
conformation of the ortho-CH2NR2 groups relative to the peri-
substituents. To some extent both these points were resolved
by an X-ray diffraction experiment for the proton sponge bis-
Mannich base 56, which was obtained in high yield from dialcohol
5416 as shown in Scheme 14. In all three independent molecules
constituting the room-temperature solid state structure of 56
the nitrogen atoms of peri- and ortho-substituents are splayed
outwards with an average separation N1(8) ◊ ◊ ◊ NAlk equal to 4.17
As we have already pointed out, in principle, the methylenei-
minium cations 45 and 50 could undergo alternative cyclization
˚
˚
A against 2.79 A for N1 ◊ ◊ ◊ N8 (Fig. 4).
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Fig. 4 Molecular structure of one of three independent molecules of bis-Mannich base 56 (left) and view along the naphthalene plane with the aromatic
NMe2 groups directed to the viewer (right). Thermal ellipsoids are drawn at the 30% probability level with hydrogens being omitted for clarity.
Aldrich). The progress of reactions and the purity of products
were monitored by TLC on Al2O3 and Silufol plates; development
with iodine vapour. The melting points were measured in sealed
capillaries and are uncorrected. The solvents were purified and
Conclusions
The analysis of the tert-amino reactions in the series of naph-
thalene proton sponges allows us to conclude that their course
is largely determined by the nature of the ortho-substituent and
the strongest nucleophile present in the reaction mixture. In the
dried by standard methods.
case of proton sponge-based 2-naphthylmethyl carbenium ions,
[1,8-Bis(dimethylamino)naphth-2-yl](2¢-dimethylamino-
no nucleophilic centre appears in the ortho-substituent after a
hydride ion transfer, and the only possibility for the methylenei-
minium intermediate is the peri-cyclization on the adjacent 8-
NMe2 group. When the hydride ion moves to a neutral ortho-
substituent such as the electron-deficient vinyl group, the side-
chain carbanion is formed, whose higher nucleophilicity deter-
mines the following ortho-cyclization. If the strongest nucleophile
in the reaction mixture is an external base, e.g. OH-, the 1-
N+(Me) CH2 group typically undergoes hydrolytic fission into
the demethylated NHMe function. For the proton sponges with
electron-accepting groups in both ortho-positions, two types of
tandem tert-amino effect, uniform and mixed, are possible. It
has also been shown that the hydride donor ability of the proton
sponge NMe2 groups exceeds that of monodimethylaminoarenes.
This can be ascribed to the lower ionization potential of proton
sponges and especially to the close proximity of the peri-NMe2
groups and the electrophilic centres of ortho-substituents. The
data obtained have disclosed not only new features of the
proton sponge reactivity, but also provided a convenient approach
to the syntheses of such compounds as benzo[h]quinolines,
quino[7,8:7¢,8¢]quinolines, 2,3-dihydroperimidinium salts, 2,3-
dihydroperimidines, N,N,N¢-trimethyl-1,8-diaminonaphthalenes,
and naphthalene proton sponges bearing substituents which are
otherwise difficult to introduce.
phenyl)methanol (6c)
n-Butyllithium (1.6
0.68 mmol) was added to
M
solution in hexane, 0.43 ml,
solution of 2-bromo-1,8-
a
bis(dimethylamino)naphthalene26 (0.2 g, 0.68 mmol) in dry
Et2O (5 ml) at -15 ◦C. After 0.5 h at -15 ◦C, a solution of
2-dimethylaminobenzaldehyde (0.1 g, 0.68 mmol) in dry Et2O (2
ml) was added and the mixture was left overnight at -15 ◦C. The
resulting solution was poured into water, the organic layer was
separated and the aqueous layer was extracted with Et2O (3 ¥
2 ml). The solvents were evaporated to dryness and the residue
was chromatographed on Al2O3 with CHCl3-elution to yield
6c (0.114 g, 46%) as brown oil. dH(CDCl3) 2.68–2.88 (m, 12H,
1,8-NMe2), 2.98 (s, 6H, 2¢-NMe2), 6.67 (br s, 1H, CH(OH)),
3
3
6.74 (d, 1H, H-3¢, J 7.61), 6.95 (t, 1H, H-4¢, J 7.62), 7.11–7.57
(m, 7H, H-3,4,5,6,7,5¢,6¢); dH(DMSO-d6) 2.40–3.08 (m, 18H,
1,8,2¢-NMe2), 5.63 (br s, 1H, CH(OH)), 6.57 (s, 1H, CH(OH)),
6.90–7.53 (m, 9H, H-3,4,5,6,7,3¢,4¢,5¢,6¢).
General procedure for preparation of 12c, 16 and 22
A solution of 6c (0.1 g, 0.28 mmol) or 15 (0.13 g, 0.28 mmol), or
199 (0.085 g, 0.28 mmol) in conc. HCl (3 ml) was refluxed for 3 h.
After evaporation of volatiles to dryness, the residue was treated
with a cold solution of NH4OH (5 ml) and then the residue was
dissolved in CHCl3 and filtrated. The solvent was evaporated to
dryness to yield 12c or 16, or 22.
Experimental
4-((2-Dimethylaminophenyl)methyl)-1,1,3-trimethyl-2,3-dihy-
droperimidinium chloride (12c). Yield 76%. Pale beige crystals
with mp 169–170 ◦C (from CHCl3); dH(DMSO-d6) 2.66 (s, 6H,
2¢-NMe2), 3.34 (s, 3H, 3-NMe), 3.60 (s, 6H, 1-N+Me2), 4.26 (s,
2H, CH2Ar), 5.25 (br s, 2H, NCH2N), 6.93 (m, 2H, H-3¢,5¢), 7.21
General information
1H and 13C NMR spectra for 31a,e were recorded on a Bruker
Avance 600 (600 MHz) device, while for the rest a Bruker DPX-250
(250 MHz) spectrometer was used with the solvent as the internal
standard (d (ppm), nJ/Hz). IR spectra were measured in paraffin
oil on a Specord IR-71 spectrometer. Mass spectra were obtained
from Finnigan MAT INCOS 50 instrument (electron impact, 70
eV). UV spectra were measured in MeOH on a Varian Cary-
50 spectrometer. Thin layer chromatography was carried out on
Al2O3 with Brockmann activity III and on silica gel (70–230 mesh,
3
3
(m, 2H, H-4¢,6¢), 7.37 (d, 1H, H-5, J 8.53), 7.68 (t, 1H, H-8, J
7.90), 7.78 (d, 1H, H-6, 3J 8.53), 8.10 (m, 2H, H-7,9).
4-((1,8-Bis(dimethylamino)naphth-2-yl)methyl)-1,1,3-trimethyl-
2,3-dihydroperimidinium chloride (16). Yield 82%. Colourless
crystals with mp 170–172 C (from MeOH); dH(DMSO-d6) 2.65
(s, 6H, 3¢-NMe2), 2.76 (s, 6H, 2¢-NMe2) 3.39 (s, 3H, 3-NMe), 3.59
◦
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(s, 6H, 1-N+Me2), 4.30 (s, 2H, CH2Ar), 5.27 (br s, 2H, NCH2N),
7.04–8.01 (m, 10H, H-5,6,7,8,9,4¢,5¢,6¢,7¢,8¢).
(d, 2H, H-3,6, J 8.53), 7.42 (d, 2H, H-3¢,5¢, J 8.53), 7.82 (d,
3
3
3
3
2H, H-4,5, J 8.53), 7.91 (d, 2H, H-2¢,6¢, J 8.53), 8.33 (s, 2H,
CH ); dC(CDCl3) 22.2, 47.2, 112.9, 113.9, 123.6, 123.7, 123.9,
128.8, 128.9, 130.8, 135.8, 143.1, 146.2, 152.2, 155.8.
2-Benzhydryl-N-methyla◦niline (22). Yield 93%. Colourless
crystals with mp 214–216 C (from MeOH); dH(CDCl3) 2.69 (s,
3H, 1-NMe), 5.43 (s, 1H, CHPh2), 6.58–7.72 (m, 3H, H-2,4,5),
7.05–7.35 (m, 11H, H-3, CHPh2).
3,10-Dicyano-1,12-dimethyl-3,10-ditosyl-1,2,3,4,9,10,11,12-
octahydroquino[7,8:7¢,8¢]quinoline (35c)
Bis[1,8-bis(dimethylamino)naphth-2-yl]methane (17)
A solution of 34c (0.1 g, 0.16 mmol) in DMSO (5 ml) was kept at
room temperature for 48 h until its discolouration, providing after
evaporation of the solvent pure 35c. Pale beige crystals (0.98 g,
98%) with mp 252–253 ◦C (from EtOH); dH(CDCl3) 2.52 (m, 6H,
A mixture of 16 (0.2 g, 0.42 mmol) and LiAlH4 (0.02 g, 0.53
mmol) in dry THF (5 ml) was stirred at room temperature for 2 h,
then hydrolyzed with H2O (20 ml) and extracted with Et2O (30 ml).
The solvent was evaporated and the residue was chromatographed
(Al2O3, CHCl3) to give 17 (0.172 g, 93%) as colourless crystals
with mp 107–108 ◦C (from n-hexane); dH(CDCl3) 2.75 (s, 12H,
8,8¢-NMe2), 2.93 (s, 12H, 1,1¢-NMe2), 4.26 (s, 2H, CH2Ar), 6.97
(d, 2H, H-7,7¢, 3J 8.42), 7.06 (d, 2H, H-5,5¢, 3J 7.37), 7.24 (t, 2H,
a
4¢-CH3), 2.76–3.02 (m, 12H, 1,12-NMe2), 3.16 (m, 2H, 4,9-CH2 ),
b
3.59–4.07 (m, 6H, 4,9-CH2 , 2,11-CH2a,b), 6.98 (m, 2H, H-5,8),
7.28 (m, 2H, H-6,7), 7.48 (m, 2H, H-3¢,5¢), 7.96 (m, 2H, H-2¢,6¢);
dC(CDCl3) 22.3, 33.6, 45.8, 46.3, 52.8, 55.2, 117.5, 117.6, 118.1,
118.4, 123.1, 127.3, 127.6, 130.7, 130.9, 131.0, 131.2, 136.2, 136.8,
141.4, 147.4, 147.5.
3
H-6,6¢, J 7.54), 7.36 (m, 4H, H-3,3¢,4,4¢); dH(DMSO-d6) 2.7 (s,
12H, 8,8¢-NMe2), 2.87 (s, 12H, 1,1¢-NMe2), 4.24 (s, 2H, CH2Ar),
6.91 (d, 2H, H-7,7¢, 3J 8.33), 7.18 (d, 2H, H-5,5¢, 3J 7.28), 7.26 (t,
2H, H-6,6¢, 3J 7.68), 7.36 (m, 4H, H-3,3¢,4,4¢).
3,3-Dicyano-1-methyl-1,2,3,4-tetrahydronaphth[1,8-b,c]azepine
(37)
A solution of 3619 (0.05 g, 0.2 mmol) in DMSO (2 ml) was refluxed
for 0.5 h until its discolouration, providing after evaporation of the
solvent pure 37. White crystals (0.04 g, 85%) with mp 114–115 ◦C
General procedure for preparation of benzo[h]quinolines 31a,e
A mixture of aldehyde 2816 (0.1 g, 0.41 mmol) and the correspond-
ing CH-acid (0.41 mmol) in 5 ml of EtOH (for 31a) or MeOH (for
31e) was kept at room temperature for 48 h (for 31a) or 72 h (for
31e). The crystals formed in the reaction mixture were filtered off
and washed with cold EtOH to give pure 31a or 31e.
◦
(from MeOH); lit.6f 126.0–126.5 C (solvent was not indicated);
dH(CDCl3) 3.17 (s, 3H, 1-NMe), 3.73–3.94 (m, 4H, 2,4-CH2), 6.86
(dd, 1H, H-10, 3J 7.42, 4J 1.26), 7.23 (dd, 1H, H-5, 3J 6.95,
3
4
4J 1.26), 7.29–7.45 (m, H-6,8,9), 7.73 (dd, 1H, H-7, J 8.21, J
1.26); dC(CDCl3) 36.9, 41.5, 42.4, 64.3, 110.6, 115.9, 122.3, 126.3,
126.4, 126.9, 128.6, 129.4, 129.7, 136.3, 150.3. Other analytic and
spectroscopic properties are consistent with those published in
ref. 6f.
3,3-Dicyano-10-dimethylamino-1-methyl-1,2,3,4-tetrahydro-
benzo[h]quinoline (31a). Yield 65%. Shiny colourless crystals
with mp 157–158 ◦C (from n-hexane); dH(CDCl3) 2.62 (br s, 3H,
10-NMe), 2.90 (br s, 3H, 10¢-NMe), 3.08 (s, 3H, 1-NMe), 3.63 (m,
a
b
2H, 4-CH2), 3.89 (m, 1H, 2-CH2 ), 4.07 (m, 1H, 2-CH2 ), 6.99 (t,
1H, H-9, 3J 4.32), 7.01 (d, 1H, H-5, 3J 8.22), 7.35 (m, 2H, H-7,8),
7.40 (d, 1H, H-6, 3J 8.28); dC(CDCl3) 25.8, 37.6, 41.5, 45.6, 46.5,
57.0, 113.8, 114.2, 115.4, 119.0, 121.4, 122.9, 126.1, 136.8, 141.1,
150.0.
General procedure for preparation of alkenes 29f and 39a,b
A mixture of aldehyde 2816 (0.1 g, 0.41 mmol), the corresponding
CH-acid (0.41 mmol) and piperidine (0.035 g, 0.41 mmol) in EtOH
(5 ml) was kept at room temperature for 24 h. The crystals formed
in the reaction mixture was filtered off and washed with cold EtOH
to give pure 29f, and 39a,b.
3-Cyano-10-dimethylamino-3-methoxycarbonyl-1-methyl-1,2,3,
4-tetrahydrobenzo[h]quinoline (31e). Yield 99%. Pale orange
crystals with mp 120–122 ◦C (from n-hexane); dH(CDCl3) 2.69
(br s, 3H, 10-NMe), 2.84 (br s, 3H, 10¢-NMe), 3.05 (s, 3H, 1-
2-(2-(1¢,8¢-Bis(dimethylamino)naphth-2¢-yl)-1-cyanoethenyl)-
benzimidazole (29f). Yield 90%. Wine-coloured crystals, mp 181–
183 ◦C (from EtOH); dH(CDCl3) 2.73 (s, 6H, 8¢-NMe2), 3.20 (s, 6H,
1¢-NMe2), 7.03 (m, 1H, H-7¢), 7.24–7.53 (m, 6H, H-4,6,7,3¢,5¢,6¢),
7.77 (m, 1H, H-5), 7.93 (d, 1H, H-4¢, 3J 8.53), 8.66 (s, 1H, CH ),
9.48 (br s, 1H, 1-NH); dH(DMSO-d6) 2.72 (s, 6H, 8¢-NMe2), 3.13
(s, 6H, 1¢-NMe2), 7.09 (m, 1H, H-7¢), 7.17–7.33 (m, 2H, H-4,7),
7.42 (m, 2H, H-5¢,6¢), 7.53 (m, 2H, H-3¢,6), 7.70 (br d, 1H, H-5, 3J
7.65), 7.85 (d, 1H, H-4¢, 3J 8.65), 8.35 (s, 1H, CH ), 13.08 (br s,
1H, 1-NH); dC(DMSO-d6) 45.6, 46.4, 101.4, 112.3, 115.5, 117.6,
119.9, 122.8, 123.0, 123.6, 124.2, 126.1, 126.4, 128.7, 135.7, 139.6,
144.4, 147.6, 149.1, 152.4, 153.2.
NMe), 3.42 (br d, 1H, 4-CH2 , 2J 16.14), 3.64 (d, 1H, 4-CH2 , 2J
a
b
a
16.50), 3.70 (d, 1H, 2-CH2 , 2J 13.02), 3.88 (s, 3H, OCH3) 3.93 (d,
1H, 2-CH2 , 2J 13.02), 6.95 (d, 1H, H-9, 3J 7.26), 7.07 (d, 1H, H-5,
b
3J 8.22), 7.30 (m, 3H, H-6,7,8); dC(CDCl3) 35.8, 38.3, 41.5, 45.5,
46.0, 53.7, 56.63, 113.2, 116.9, 118.9, 119.3, 121.4, 122.0, 125.5,
126.7, 136.8, 141.6, 150.1, 168.3.
1,8-Bis(dimethylamino)-2,7-di(2-cyano-2-tosylvinyl)naphthalene
(34c)
A mixture of dialdehyde 3316 (0.1 g, 0.37 mmol), tosylacetonitrile
(0.144 g, 0.74 mmol) and piperidine (0.063 g, 0.74 mmol) in EtOH
(10 ml) was kept at room temperature for 24 h. The red crystals
formed in the reaction mixture were filtered off and washed with
cold EtOH to give pure 34c (0.173 g, 75%); mp 157–160 ◦C
(from n-hexane); lmax/nm (log e) 490 (4.31), 312 (4.40), 228 (4.72);
dH(CDCl3) 2.49 (s, 6H, 4¢-CH3), 3.23 (s, 12H, 1,8-NMe2), 7.32
1-Methyl-2-(2-(1¢,8¢-bis(dimethylamino)naphth-2¢-yl)ethenyl)py-
ridinium iodide (39a). Yield 70%. Wine-coloured crystals with
gold shine, mp 137–138 ◦C (from EtOH); lmax/nm (log e), 490
(4.17), 324 (4.57), 218 (4.73); nmax/cm-1 1521, 1628; dH(DMSO-d6)
3.13 (s, 6H, 8¢-NMe2), 3.33 (s, 6H, 1¢-NMe2), 4.40 (s, 3H, 1-CH3),
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7.09 (dd, 1H, H-7¢, 3J 7.26, 4J 1.26), 7.32–7.57 (m, 4H, H-3¢,5¢,6¢,
1,8-Bis(dimethylamino)-2-(2-nitro-2-methylvinyl)naphthalene
(42b)
3
CHa–), 7.85 (m, 2H, H-5,4¢), 8.03 (d, 1H, –CHb , J 15.79),
8.45 (t, 1H, H-4, 3J 8.21), 8.60 (d, 1H, H-3, 3J 8.21), 8.88 (d, 1H,
H-6, 3J 6.63); dH(CD3OD) 2.80 (s, 6H, 8¢-NMe2), 3.24 (s, 6H, 1¢-
NMe2), 4.44 (s, 3H, 1-CH3), 7.18 (dd, 1H, H-7¢, 3J 6.49, 4J 2.26),
7.36–7.57 (m, 4H, H-3¢,5¢,6¢, –CHb ), 7.82 (m, 2H, H-5,4¢), 8.14
(d, 1H, –CHa , 3J 15.96), 8.47 (m, 2H, H-3,4), 8.78 (d, 1H, H-6,
3J 6.31); dC(DMSO-d6) 45.0, 45.5, 46.0, 114.8, 115.6, 122.0, 122.9,
123.4, 124.4, 124.5, 125.4, 127.4, 127.9, 138.3, 142.7, 144.1, 145.8,
150.5, 152.3, 152.8; m/z 317 (M+, 44), 302 (17), 271 (10), 223 (13),
195 (16), 181 (23), 168 (15), 151 (15), 142 (100), 136 (14), 127 (32),
106 (38), 93 (13).
Method A. A mixture of 2816 (0.21 g, 0.87 mmol), piperidine
(0.075 g, 0.87 mmol) and C2H5NO2 (0.196 g, 2.61 mmol) in MeOH
(10 ml) was kept at room temperature for 48 h. The solvent was
evaporated and the residue was purified on Al2O3 (Et2O–n-hexane,
1 : 1) to give 42b (0.172 g, 66%) as red oil.
Method B. A mixture of 28 (0.21 g, 0.87 mmol) and piperidine
(0.075 g, 0.87 mmol) in C2H5NO2 (7 ml) was kept at room
temperature for 48 h. The solvent was evaporated and the rest
was purified as in method A to give 42b (0.228 g, 88%); lmax/nm
(log e) 446 (3.41), 296 (3.96); nmax/cm-1 1648 (C C); dH(CDCl3)
2.44 (s, 3H, CH3), 2.72 (s, 6H, 8-NMe2), 3.08 (s, 6H, 1-NMe2),
1-Methyl-2-(2-(1¢,8¢-bis(dimethylamino)naphth-2¢-yl)ethenyl)-
quinolinium perchlorate (39b). Yield 99%. Dark blue crystals, mp
152–153 ◦C (from EtOH); lmax/nm (log e), 554 (3.82), 344 (4.02);
dH(DMSO-d6) 2.75 (s, 6H, 8¢-NMe2), 3.20 (s, 6H, 1¢-NMe2), 4.56
(s, 3H, 1-CH3), 7.09 (m, 1H, H-7¢), 7.41 (m, 2H, H-5¢,6¢), 7.52
3
4
3
7.02 (dd, 1H, H-7, J 5.37, J 3.47), 7.19 (d, 1H, H-3, J 8.53),
7.31–7.40 (m, 3H, H-4,5,6), 8.20 (s, 1H, –CH ); dC(CDCl3) 14.6,
45.5, 45.9, 115.0, 122.8, 123.3, 123.6, 125.2, 127.0, 127.6, 136.3,
139.0, 145.3, 151.9, 152.7; m/z 299 (M+, 73), 282 (47), 265 (23), 248
(13), 237 (40), 225 (57), 210 (50), 194 (20), 181 (23), 168 (33), 139
(10), 127 (20), 119 (10), 111 (23), 104 (23), 97 (27), 91 (10), 83 (27),
77 (17), 71 (37), 65 (13), 57 (100), 41 (87). Perchlorate 42b·HClO4
(prepared in MeOH on addition of 1 equiv of aqueous HClO4):
3
3
(d, 1H, H-3¢, J 8.53), 7.64 (d, 1H, CHa–, J 15.48), 7.93 (m,
2H, H-7,4¢), 7.38–8.09 (m, 3H, H-5,6, –CHb ), 8.53 (d, 1H, H-3,
3J 8.84), 8.63 (d, 1H, H-8, J 9.16), 8.95 (d, 1H, H-4, J 8.84);
dC(DMSO-d6) 45.6, 46.7, 115.6, 117.5, 119.9, 121.7, 122.6, 123.1,
124.0, 126.4, 127.9, 128.3, 129.0, 129.4, 130.9, 135.5, 139.7, 140.1,
144.3, 147.7, 153.2, 153.4, 157.2.
3
3
◦
light blue crystals with mp 121–123 C (decomp., from MeCN);
dH(DMSO-d6) 2.20 (s, 3H, CH3), 3.09 (s, 6H, 1-NMe2), 3.30 (d,
6H, 8-NMe2, 3J 3.51), 7.57 (d, 1H, H-3, 3J 8.42), 7.83 (t, 1H, H-6,
3J 8.07), 8.10–8.27 (m, 3H, H-4,5,7), 8.43 (s, 1H, –CH ), 18.32
(br s, 1H, H+).
3-(Benzimidazol-2¢yl)-3-cyano-10-dimethylamino-1-methyl-
1,2,3,4-tetrahydrobenzo[h]quinoline (31f)
A solution of 29f (0.1 g, 0.26 mmol) in DMSO (5 ml) was
refluxed for 1 h. The solvent was evaporated and the residue was
purified on Al2O3 with CHCl3 elution. Pale purple crystals of 31f
(0.025 g, 25%) with mp 82–83 ◦C (from n-hexane) were obtained.
dH(DMSO-d6) 2.78 (br s, 6H, 10-NMe2), 3.08 (br s, 3H, 1-NMe),
General procedure for preparation of 43a–e
A mixture of 28 (0.21 g, 0.87 mmol), 2-nitropropane (0.232 g,
2.61 mmol) and the corresponding secondary amine (2.61 mmol)
in MeOH (10 ml) was kept at room temperature for 120 h (for
43a,c,d,e) or 168 h (for 43b). After evaporation of the volatiles the
residue was purified on Al2O3 (Et2O–n-hexane, 1 : 1; then CHCl3)
to yield 43a–e as pale yellow crystals.
a
2
b
3.71 (d, 1H, 4-CH2 , J 15.32), 3.88 (m, 4H, 2,4-CH2 ), 4.20 (d,
a
2
3
2H, 2-CH2 , J 13.13), 6.93 (d, 1H, H-9, J 6.91), 7.17–7.41 (m,
4H, H-4¢,5¢,6¢,7¢), 7.57 (d, 1H, H-7, 3J 7.07), 7.68 (d, 1H, H-6, 3J
7.24), 13.05 (s, 1H, NH).
1-Dimethylamino-8-methylamino-7-piperidinomethylnaphtha-
lene (43a). Yield 74%. Mp 114–115 ◦C (from n-hexane);
1,8-Bis(dimethylamino)-2-(2-nitrovinyl)naphthalene (42a)
n
max/cm-1 3181; dH(CDCl3) 1.49 (m, 2H, 4¢-CH2), 1.61 (m, 4H,
A mixture of 2816 (0.21 g, 0.87 mmol), CH3NO2 (0.159 g, 2.61
mmol) and piperidine (0.075 g, 0.87 mmol) in MeOH (10 ml)
was kept at -20 ◦C for 48 h. The solvent was evaporated and
the crude solid material was purified on Al2O3 (Et2O–n-hexane,
1 : 1). Wine-coloured crystals of 42a (0.102 g, 41%) with mp 112–
3¢,5¢-CH2), 2.45 (m, 4H, 2¢,6¢-CH2), 2.80 (s, 6H, 1-NMe2), 2.89 (s,
3H, 8-NMe), 3.65 (s, 2H, CH2), 7.23 (d, 1H, H-2, 3J 7.19), 7.33 (m,
2H, H-3,6), 7.56 (d, 1H, H-4, 3J 7.89), 7.67 (d, 1H, H-5, 3J 8.42);
dC(CDCl3) 25.0, 26.5, 37.9, 46.3, 55.1, 60.3, 116.6, 120.3, 122.2,
124.5, 125.2, 125.9, 129.3, 136.0, 149.6, 151.5; m/z 297 (M+, 34),
212 (96), 197 (84), 182 (100), 168 (70), 154 (35), 141 (23), 127 (21),
115 (28), 98 (29), 84 (54), 55 (39), 42 (59).
◦
113 C (from EtOH) were obtained; lmax/nm (log e), 478 (3.79),
308 (4.31), 224 (4.60); nmax/cm-1 1613 (C C); dH(CDCl3) 2.74 (s,
6H, 8-NMe2), 3.15 (s, 6H, 1-NMe2), 7.05 (br dd, 1H, H-7, 3J 6.32,
4J 2.11), 7.28–7.43 (m, 4H, H-3,4,5,6), 7.55 (d, 1H, CH(NO2),
1-Dimethylamino-8-methylamino-7-diethylaminomethylnaph-
thalene (43b). Yield 43%. Mp 117–119 ◦C (from n-hexane);
3
3J 13.68), 8.40 (d, 1H, –CH , J 13.68); dC(CDCl3) 45.8, 46.5,
n
max/cm-1 3255; dH(CDCl3) 1.04 (t, 6H, NCH2CH3, 3J 7.36), 2.54
115.6, 122.9, 123.4, 124.2, 124.6, 125.0, 128.5, 135.5, 139.9, 140.2,
153.3, 153.5; m/z 285 (M+, 100), 268 (14), 239 (26), 223 (88), 210
(41), 198 (15), 192 (32), 180 (23), 168 (22), 152 (17), 127 (10),
58 (17), 44(20). Perchlorate 42a·HClO4 (prepared in MeOH on
addition of 1 equiv of aqueous HClO4): light beige crystals with
mp 114–115 ◦C (decomp., from MeCN); dH(DMSO-d6) 3.22 (s,
6H, 1-NMe2), 3.37 (d, 6H, 8-NMe2, 3J 3.86), 7.87 (t, 1H, H-6, 3J,
8.07), 8.07 (d, 1H, H-3, 3J 8.77), 8.14-8.29 (m, 3H, H-4,5,7), 8.34
(d, 1H, CHa–, 3J 13.33), 8.44 (d, 1H, –CHb , 3J 13.33), 17.60
(br s, 1H, H+).
(q, 4H, NCH2CH3, 3J 7.36), 1.72–2.84 (m, 9H, 1-NMe2, 8-NMe),
3
4
3.69 (s, 2H, CH2), 7.19 (dd, 1H, H-2, J 7.36, J 1.41), 7.30 (m,
2H, H-3,6), 7.52 (dd, 1H, H-4, 3J 7.42, 4J 1.41), 7.70 (d, 1H, H-5,
3J 8.42); m/z 285 (M+, 20), 212 (66), 197 (67), 182 (73), 168 (49),
154 (25), 141 (16), 127 (17), 115 (22), 86 (26), 72 (34), 58 (100), 42
(80).
1-Dimethylamino-8-methylamino-7-morpholinomethylnaphtha-
lene (43c). Yield 36%. Mp 119–120 ◦C (from n-hexane);
n
max/cm-1 3249; dH(CDCl3) 2.48 (m, 4H, 2¢,6¢-CH2), 2.77 (s, 6H,
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1-NMe2), 2.86 (s, 3H, 8-NMe), 3.67 (s, 2H, CH2), 3.72 (t, 4H,
3¢,5¢-CH2, 3J 4.56), 7.21 (dd, 1H, H-2, 3J 7.36, 4J 1.41), 7.29 (m,
2H, H-3,6), 7.52 (dd, 1H, H-4, 3J 7.72, 4J 1.41), 7.60 (d, 1H, H-5,
3J 8.41); m/z 299 (M+, 33), 212 (91), 197 (97), 182 (100), 168 (65),
154 (36), 141 (23), 127 (22), 115 (31), 100 (19), 88 (17), 56 (46), 44
(54).
2¢,6¢-CH2), 3.18 (s, 6H, 1,3-NMe), 3.61 (s, 4H, CH2), 4.31 (s, 2H,
2-CH2), 7.43 (d, 2H, H-5,8, 3J 8.53), 7.60 (d, 2H, H-6,7, 3J 8.53);
m/z 420 (M+, 11), 112 (55), 98 (65), 84 (10), 69 (21), 55 (61), 42
(100).
4,9-Bis(4¢-methylpiperazinomethyl)-1,3-dimethyl-2,3-dihydro-
perimidine (53e). Yield 54%. Mp 95–98 ◦C (from n-octane);
dH(CDCl3) 2.28 (s, 6H, 4¢-CH3), 2.32–2.65 (m, 16H, 2¢,3¢,5¢,6¢-
CH2), 3.17 (s, 6H, 1,3-NMe), 3.60 (s, 4H, CH2), 4.29 (s, 2H, 2-
1-Dimethylamino-8-methylamino-7-(4-methylpiperidino)methy-
lnaphthalene (43d). Yield 32%. Mp 123–124 ◦C (from n-hexane);
max/cm-1 3255; dH(CDCl3) 0.90 (m, 4H, 4¢-CH, CH3), 1.30 (m,
3
3
n
CH2), 7.41 (d, 2H, H-5,8, J 8.53), 7.54 (d, 2H, H-6,7, J 8.53);
dC(CDCl3) 45.6, 46.4, 53.5, 55.7, 58.3, 72.7, 121.5, 121.9, 124.1,
128.8, 133.7, 144.0; m/z 422 (M+, 17), 113 (30), 99 (55), 70 (61),
56 (100), 42 (89).
4H, 3¢,5¢-CH2), 1.58 (m, 2H, 2¢,6¢-CH2), 1.98 (m, 2H, 2¢,6¢-CH2),
2.74 (s, 6H, 1-NMe2), 2.84 (s, 3H, 8-NMe), 3.64 (s, 2H, CH2), 7.18
(dd, 1H, H-2, 3J 7.68, 4J 1.28), 7.26 (m, 2H, H-3,6), 7.50 (dd, 1H,
H-4, 3J 7.90, 4J 1.28), 7.61 (d, 1H, H-5, 3J 8.32); m/z 311 (M+, 6),
98 (21), 69 (16), 55 (63), 42 (100).
2,7-Bis(bromomethyl)-1,8-bis(dimethylamino)naphthalene
hydrobromide (55)
1-Dimethylamino-8-methylamino-7-(4-methylpiperazino)methy-
lnaphthalene (43e). Yield 30%. Mp 150–152 ◦C (from n-hexane);
A solution of alcohol 5416 (0.097 g, 0.35 mmol) in 46% aqueous
HBr (5 ml) was kept at 100 ◦C for 0.5 h. The reaction mixture was
then evaporated to dryness in vacuum to give hydrobromide 55
quantitatively as colourless plates with mp 315–317 ◦C (decomp.,
darkens above 250 ◦C, from MeCN). Anal. Calcd for C16H21Br3N2:
C, 39.95; H, 4.40; Br, 49.83. Found: C, 39.57; H, 4.22; Br, 49.51%;
dH(CD3CN) 3.40 (d, 12H, NMe2, 4J 2.9), 4.96 (s, 4H, CH2Br), 7.74
(d, 2H, H-3,6, 3J 8.8), 8.05 (d, 2H, H-4,5, 3J 8.8), 20.37 (br m, 1H,
NH).
n
max/cm-1 3252; dH(CDCl3) 2.36 (s, 1H, NCH3) 2.31–2.60 (m, 8H,
2¢,3¢,5¢,6¢-CH2), 2.74 (s, 6H, 1-NMe2), 2.84 (s, 3H, 8-NMe), 3.64
3
4
(s, 2H, CH2), 7.12 (dd, 1H, H-2, J 7.36, J 1.28), 7.27 (m, 2H,
3
4
3
H-3,6), 7.49 (dd, 1H, H-4, J 8.00, J 1.28), 7.57 (d, 1H, H-5, J
8.32); m/z 312 (M+, 10), 213 (22), 197 (33), 182 (28), 168 (18), 154
(11), 115 (10), 99 (58), 70 (27), 56 (74), 42 (100).
General procedure for preparation of 53a–e
A mixture of 33 (0.21 g, 0.78 mmol), 2-nitropropane (0.208 g,
2.34 mmol) and the corresponding secondary amine (2.34 mmol)
in MeOH (10 ml) was kept at room temperature for 120 h (for
53a,c,d,e) or 168 h (for 53b). After evaporation of volatiles the
residue was purified on Al2O3 (Et2O–n-hexane, 1 : 1; then CHCl3)
to yield 53a–e as pale yellow crystals.
1,8-Bis(dimethylamino)-2,7-bis(dimethylaminomethyl)naphthalene
(56)
The above hydrobromide 55 was dissolved in EtOH (2 ml) and
combined with 33% aqueous dimethylamine (4 ml). The resulting
mixture was kept at room temperature for 24 h, then MeCN (2
ml) was added and the mixture was made strongly basic with solid
KOH. The reaction product was extracted with hexane (3 ¥ 3
ml), dried over KOH and evaporated to dryness. This gave pure
bis-Mannich compound 56 (0.085 g, 73%) as light-yellow plates
with mp 79–81 ◦C (from n-hexane). Anal. Calcd for C20H32N4: C,
73.13; H, 9.82; N, 17.05. Found: C, 73.29; H, 10.01; N, 17.34%;
dH(300 MHz, CDCl3) 2.23 (s, 12H, aliph. NMe2), 2.94 (s, 12H,
4,9-Bis(piperidinomethyl)-1,3-dimethyl-2,3-dihydroperimidine
(53a). Yield 45%. Mp 68–71 ◦C (from n-octane); dH(CDCl3) 1.46
(m, 4H, 4¢-CH2), 1.59 (m, 8H, 3¢,5¢-CH2), 2.45 (m, 8H, NCH2,
2¢,6¢-CH2), 3.18 (s, 6H, 1,3-NMe), 3.61 (s, 4H, CH2), 4.32 (s, 2H,
2-CH2), 7.44 (d, 2H, H-5,8, 3J 8.53), 7.60 (d, 2H, H-6,7, 3J 8.53);
dC(CDCl3) 25.0, 26.5, 45.7, 55.1, 59.1, 72.8, 121.7, 121.9, 124.7,
128.7, 133.6, 143.8; m/z 392 (M+, 28), 98 (100), 84 (90), 70 (13),
55 (57), 42 (91).
3
arom. NMe2), 3.50 (s, 4H, CH2N), 7.51 (d, 2H, H-3,6, J 8.46),
3
7.55 (d, 2H, H-4,5, J 8.46). Perchlorate 56·HClO4 (prepared in
4,9-Bis(diethylaminomethyl)-1,3-dimethyl-2,3-dihydroperimi-
dine (53b). Yield 52%. Mp 43–46 ◦C (from n-hexane); dH(CDCl3)
1.05 (t, 12H, CH3, 3J 7.27), 2.56 (q, 8H, NCH2, 3J 7.27), 3.14 (s,
6H, 1,3-NMe), 3.68 (s, 4H, CH2), 4.34 (s, 2H, 2-CH2), 7.47 (d, 2H,
H-5,8, 3J 8.53), 7.69 (d, 2H, H-6,7, 3J 8.53); dC(CDCl3) 12.3, 45.9,
47.6, 53.0, 72.8, 121.7, 122.0, 126.3, 128.3, 133.4, 143.2; m/z 368
(M+, 7), 223 (18), 86 (100), 72 (59), 58 (48), 42 (33).
MeCN on addition of 1 equiv of aqueous HClO4): light beige
crystals with mp 256–260 ◦C (decomp., from MeCN); dH(CD3CN)
2.40 (s, 12H, aliph. NMe2), 3.33 (d, 12H, arom. NMe2, 4J 2.6), 3.87
(s, 4H, CH2N), 7.90 (d, 2H, H-3,6, 3J 8.8), 8.00 (d, 2H, H-4,5, 3J
8.8), 20.36 (br m, 1H, NH).
X-Ray crystallography
4,9-Bis(morpholinomethyl)-1,3-dimethyl-2,3-dihydroperimidine
(53c). Yield 47%. Mp 112–115 C (from n-octane); dH(CDCl3)
2.52 (m, 8H, 3¢,5¢-CH2), 3.20 (s, 6H, 1,3-NMe), 3.64 (s, 4H, CH2),
3.73 (m, 8H, 2¢,6¢-CH2) 4.32 (s, 2H, 2-CH2), 7.43 (d, 2H, H-5,8, 3J
8.53), 7.58 (d, 2H, H-6,7, 3J 8.53); m/z 396 (M+, 7), 100 (69), 86
(27), 70 (17), 56 (100), 42 (78), 35 (20).
X-Ray measurements were carried out with an Enraf Nonius
CAD-4 (for compound 33) and with a Bruker APEX II CCD
area detector (for 29f, 35a and 56), using graphite monochromated
◦
˚
Mo-Ka radiation (g = 0.71073 A, w/2q-scanning for 33 and w-
scanning for 29f, 35a and 56). The structures were solved by direct
methods and subsequent Fourier syntheses using SHELXS-97 and
were refined by the full-matrix least-squares technique against F2
in anisotropic approximation for all non-hydrogen atoms with
SHELXL-97. For 33, the H atoms were determined experimentally
and refined in isotropic approximation. The hydrogen atom
4,9-Bis(4¢-methylpiperidinomethyl)-1,3-dimethyl-2,3-dihydro-
perimidine (53d). Yield 43%. Mp 95–98 ◦C (from n-octane);
dH(CDCl3) 0.92 (m, 6H, 4¢-CH3), 1.30 (m, 6H, 4¢-CH, 3¢,5¢-CH2),
1.60 (m, 4H, 3¢,5¢-CH2), 2.02 (m, 4H, 2¢,6¢-CH2), 2.90 (m, 4H,
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positions for 29f, 35a and 56 were calculated and were refined
in isotropic approximation in riding model with the Uiso(H)
parameters equal to 1.2 Ueq(Ci) (for Me groups the Uiso(H)
parameters equal to 1.5 Ueq(Ci)), where Ueq(Ci) are the equivalent
thermal parameters of the atoms to which corresponding H atoms
are bonded.
V. A. Ozeryanskii, in The Chemistry of Anilines, ed. by Z. Rappoport,
J. Wiley & Sons, Chichester, 2007, Part 2, Ch. 17, p. 931.
3 V. A. Ozeryanskii, E. A. Filatova, V. I. Sorokin and A. F. Pozharskii,
Russ. Chem. Bull., 2001, 50, 846.
4 (a) S. N. Gamage, R. H. Morris, S. J. Rettig, D. C. Thackray, I. S.
Thornburn and B. R. James, Chem. Commun., 1987, 894; (b) R. P.
Hughes, I. Kovacik, D. Lindner, J. M. Smith, S. Willemsen, D. Zhang,
I. A. Guzei and A. L. Rheingold, Organometallics, 2001, 20, 3190.
5 Preliminary reports on this topic: (a) O. V. Ryabtsova, A. F. Pozharskii,
A. V. Degtyarev and V. A. Ozeryanskii, Mendeleev Commun., 2006,
16, 313; (b) M. A. Povalyakhina, A. F. Pozharskii, O. V. Dyablo, V. A.
Ozeryanskii and O. V. Ryabtsova, Mendeleev Commun., 2010, 20, 36.
6 Selected articles on tert-amino effect: (a) O. Meth-Cohn and D. L.
Taylor, Chem. Commun., 1995, 1463 and references cited therein;
(b) O. N. Semenova, Yu. A. Kudryavtseva, I. G. Ermolenko and L. D.
Patsenker, Russ. J. Org. Chem., 2005, 41, 1100; (c) J. O’Leary, X.
Formosa, W. Skranc and J. D. Wallis, Org. Biomol. Chem., 2005, 3,
3273; (d) C. Zhang, S. Murarka and D. Seidel, J. Org. Chem., 2009,
74, 419; (e) S. Murarka, C. Zhang and D. Seidel, Org. Lett., 2009, 11,
129; (f) A. A. Fo¨ldi, K. Luda´nyi, A. C. Be´nyei and P. Ma´tyus, Synlett.,
2010, 2109.
7 Remarkably, that this t-amino reaction is completely inhibited by
dimethyl sulfoxide. Thus, on treatment of alcohol 6a in DMSO-d6
solution in an NMR tube with 70% HClO4 only the chelated cation 7a
can be registered even after prolonged standing at room temperature.
Apparently, DMSO as a rather basic solvent (pKa 0) does not allow
oxonium salts 8 to be formed.
8 J. P. Maier, Helv. Chim. Acta, 1974, 57, 994.
9 J. P. Maier and D. W. Turner, J. Chem. Soc., Faraday Trans. 2, 1973,
69, 521.
Crystal data for 29f. (Obtained from EtOAc): C24H22N5, M
= 380.47, space group: P21/c (monoclinic), a = 10.247(4), b =
◦
3
˚
˚
11.520(4), c = 34.634(13) A, b = 102.208(7) , V = 3996(2) A , Z
= 8, Dc = 1.265 g cm-3, m(Mo-Ka) = 0.078 mm-1, T = 100 K,
29279 reflections collected, 5974 unique (Rint = 0.2366), 2961
reflections with I > 2s(I), 509 parameters, R1 = 0.1712, wR2
(all data) = 0.1612. CCDC reference number 804543. There are
two independent molecules packing through the benzimidazolyl
nitrogens short contacts along the a axis.
Crystal data for 33. (Obtained from CHCl3): C16H18N2O2, M
= 270.32, space group: P21/c (monoclinic), a = 13.333(2), b =
◦
3
˚
˚
10.094(2), c = 11.308(4) A, b = 109.94(2) , V = 1430.6(6) A , Z =
4, Dc = 1.255 g cm-3, m(Mo-Ka) = 0.084 mm-1, T = 293 K, 2635
reflections collected, 2508 unique (Rint = 0.0182), 1678 reflections
with I > 2s(I), 241 parameters, R1 = 0.0692, wR2 (all data) =
0.1347. CCDC reference number 720578.
Crystal
data
for
35a. (Obtained
from
MeCN):
10 H. T. Al-Masri, J. Seiler, P. Lo¨nnecke, S. Blaurock, K. Domasevitch
and E. Hey-Hawkins, Tetrahedron, 2004, 60, 333.
C22H18N6·0.25Me2NH·0.75MeCN, M = 408.49, space group:
11 As it was earlier reported, both the parent proton sponge12 and
its derivatives13 can effectively function as basic catalysts in the
Knoevenagel reaction.
¯
˚
P1 (triclinic), a = 6.6455(7), b = 12.9280(13), c = 12.9430(13) A,
a = 101.997(2), b = 92.8910(10), g = 94.532(2)◦, V = 1083.94(19)
3
-3
-1
˚
12 I. Rodriguez, G. Sastre, A. Corma and S. Iborra, J. Catal., 1999, 183,
A , Z = 2, Dc = 1.252 g cm , m(Mo-Ka) = 0.079 mm , T =
100 K, 10008 reflections collected, 4202 unique (Rint = 0.0259),
3262 reflections with I > 2s(I), 317 parameters, R1 = 0.0501,
wR2 (all data) = 0.1327. CCDC reference number 801823. The
crystal structure of 35a contains channels along the a axis that are
occupied by highly disordered solvent molecules including some
amount of dimethylamine absorbed on crystallisation.
14.
13 N. V. Vistorobskii and A. F. Pozharskii, Zh. Org. Khim., 1991, 27, 1543;
Chem. Abstr., 1992, 116, 193866g.
14 For a discussion on stereochemistry of the proton sponge alkenes and
products of their isomerisation see Fig. 2 and the special section and
Table S1 in the Supporting information.
15 See Fig. S1 in the Supporting information.
16 A. F. Pozharskii, A. V. Degtyarev, O. V. Ryabtsova, V. A. Ozeryanskii,
M. E. Kletskii, Z. A. Starikova, L. Sobczyk and A. Filarowski, J. Org.
Chem., 2007, 72, 3006.
17 Though we did not measure NH-acidity of 29f, one can estimate it as
being between pKa 10–11. This originates from pKa = 11.48 (in H2O)
for 2-cyanomethylbenzimidazole (V. A. Anisimova, O. I. Askalepova,
K. N. Bagdasarov and M. S. Chernov’yants, Chem. Heterocycl. Compd.,
1988, 24, 281. Clearly, the NH-acidity of 29f should be higher, especially
Crystal data for 56. (Obtained from MeOH): C20H32N4, M =
328.50, space group: Pc (monoclinic), a = 34.582(2), b = 10.1577(6),
◦
3
˚
˚
c = 8.3390(5) A, b = 92.8910(10) , V = 2925.5(3) A , Z = 6, Dc =
1.119 g cm-3, m(Mo-Ka) = 0.067 mm-1, T = 295 K, 29486 reflections
collected, 12592 unique (Rint = 0.0344), 7117 reflections with I >
2s(I), 673 parameters, R1 = 0.1034, wR2 (all data) = 0.1043. CCDC
reference number 801824. There are three independent molecules
in the unit cell.
in more polar than water DMSO, due to the presence of extra C
bond at the Ca-atom of cyanomethyl group.
C
18 See Table S2 and Figs. S2 and S3 in the Supporting information.
19 (a) P. C. Bell and J. D. Wallis, Chem. Commun., 1999, 257; (b) H.-B.
Bu¨rgi, J. D. Dunitz and E. Schefter, J. Am. Chem. Soc., 1973, 95, 5062.
20 Independently, cyclization of 36 into 37 has been recently reported by
other authors.6f.
Acknowledgements
21 Due to rather low quality of crystals for X-ray study of 29f we could
not directly determine the position of the NH-proton. Nevertheless,
its location in the imidazole ring is unambiguous due to a specific
intermolecular aggregation (see Fig. S4 and further details in the
Supporting information).
22 L. C. Groenen, W. Verboom, W. H. N. Nijhuis, D. H. Reinhoudt, G. J.
van Hummel and D. Feil, Tetrahedron, 1988, 44, 4637.
23 D. R. W. Hodgson, A. J. Kirby and N. Feeder, J. Chem. Soc., Perkin
Trans. 1, 1999, 949.
We are grateful to Dr Zoya A. Starikova for X-ray experiments
on compounds 29f, 35a and 56 and Dr Vladimir I. Sorokin for IR
and UV measurements. The authors are also indebted to RFBR
for financial support (grant No 08-03-00028).
References
24 A. F. Pozharskii, O. V. Ryabtsova, V. A. Ozeryanskii, A. V. Degtyarev,
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2003, 68, 10109.
25 A. J. Gordon, R. A. Ford, The Chemist’s Companion, the Handbook
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1 (a) A. F. Pozharskii, L. A. Kurasov, V. V. Kuz’menko and L. L. Popova,
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Saupe, Angew. Chem., Int. Ed. Engl., 1988, 27, 865; (b) R. W. Alder,
Chem. Rev., 1989, 89, 1215; (c) A. L. Llamas-Saiz, C. Foces-Foces and
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1900 | Org. Biomol. Chem., 2011, 9, 1887–1900
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The Royal Society of Chemistry 2011
©