Steric hindrance to the syntheses and stabilities of 1,5- and 2,6-naphthalene N-permethylated diammonium salts

Article abstract of DOI:10.1016/j.tet.2016.02.002

A series of naphthalene-1,5- and 2,6-diamines and their N-methyl derivatives were synthesized and characterized. ¹H NMR spectroscopy showed that an aqueous solution of naphthalene-2,6-di(NMe₃I) (2) underwent considerable demethylation over a 24 h period after its initial preparation. Exchange of the iodide nucleophilic anion by the triflate non-nucleophilic counter-ion afforded a stable quaternary aminium salt. H/D α-position exchange in D₂O solutions of naphthalene-2,6-di(NH₂MeCl) (3·HCl) and naphthalene-2,6-di(NHMe₂Cl) (4·HCl) with acidic ⁺NH protons was observed, but not in those of naphthalene-2,6-di(NMe₃I) or triflate (2 or 5). Exhaustive per-N-methylation of naphthalene-1,5-di(NMe₂) (7) afforded only the mixed naphthalene-1-NMe₃I-5-NHMe₂I quaternary aminium-tertiary ammonium salt due to severe 1,8-type peri-strain.

Full text of DOI:10.1016/j.tet.2016.02.002

Tetrahedron xxx (2016) 1e6
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Steric hindrance to the syntheses and stabilities of 1,5- and 2,6-
naphthalene N-permethylated diammonium salts
a
b
b
,
c
,
a,
*
ꢀ
*
*
ꢁ
Ðani Skalamera , Liping Cao , Lyle Isaacs , Robert Glaser , Kata Mlinaric-Majerski
a
ꢀ
ꢁ
ꢀ
Department of Organic Chemistry and Biochemistry, RuCer Boskovic Institute, Bijenicka cesta 54, 10000 Zagreb, Croatia
b Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA
c Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of naphthalene-1,5- and 2,6-diamines and their N-methyl derivatives were synthesized and
characterized. 1H NMR spectroscopy showed that an aqueous solution of naphthalene-2,6-di(NMe3I) (2)
underwent considerable demethylation over a 24 h period after its initial preparation. Exchange of the
iodide nucleophilic anion by the triflate non-nucleophilic counter-ion afforded a stable quaternary
Received 5 November 2015
Received in revised form 20 January 2016
Accepted 1 February 2016
Available online xxx
aminium salt. H/D a-position exchange in D2O solutions of naphthalene-2,6-di(NH2MeCl) (3$HCl) and
naphthalene-2,6-di(NHMe2Cl) (4$HCl) with acidic þNH protons was observed, but not in those of
naphthalene-2,6-di(NMe3I) or triflate (2 or 5). Exhaustive per-N-methylation of naphthalene-1,5-
di(NMe2) (7) afforded only the mixed naphthalene-1-NMe3I-5-NHMe2I quaternary aminium-tertiary
ammonium salt due to severe 1,8-type peri-strain.
Keywords:
Naphthalene diamines
Quaternary aminium salts
H/D-exchange
Ó 2016 Elsevier Ltd. All rights reserved.
Stereochemistry
1,8-Type peri-strain
1. Introduction
The ultra high binding of diamantane-4,9-di(NMe3I) 1 to a cu-
curbit[7]uril host (with a Ka¼7.2ꢀ1017
M
ꢁ1 association constant in
The naphthalene compounds are of on-going interest in our
group.3 It is well known that naphthalene amines have many ap-
plications and they are useful in many fields, such as in assisted
laser desorption/ionization mass spectrometry for imaging of small
molecules in tissues,4 as a part of conducting polymers as a matrix
for biomolecule immobilization,5 in the preparation of functional-
ized Pt nanoparticles for study of electrochemical activity and re-
dox chemistry occurring on one surface,6 in naphthylamine-based
organic photovoltaic cells,7 as well as for reductive electron trans-
fer to DNA.8 For these reasons we believe that it is important to
improve known, or develop new, synthetic methods to make these
compounds easily accessible.
pure D2O, and Ka¼2.1ꢀ1015
M
ꢁ1 in 50 mM NaO2CCD3 buffered D2O
at pD 4.74)1 was the impetus to prepare other rigid-skeleton bis-
quaternary aminium guests with similar Nþ/Nþ distances, but
different space filling capabilities within the binding cavity.
Naphthalene-2,6-di(NMe3I) 2 was deemed to be aþparticularly
auspicious candidate for synthesis since its 7.87(9) A N /Nþ mean
ꢂ
distance calculated from eight crystal structures in the Cambridge
Structural Database (CSD) compared quite favorably with the
ꢂ
7.82(3) A mean distance for 1 and its derivatives, while its planar
skeleton differs greatly from that of cylindrical 1. Ka binding con-
stants and BLYP-D3/def2TZVPP quantum mechanical calculations
of cucurbit[7]uril complexes of naphthalene, 4,40-bipiperidine, and
diamantane quaternary diaminium salts have recently been re-
ported by us.2
Although
the
synthesis
of
1,5-
and
2,6-
dimethylaminonaphthalenes was previously described,9,10 their
N-permethylated derivatives are unknown in the literature, which
is not surprising because the synthesis of naphthalene quaternary
ammonium salts was not an easy task. The facile demethylation of
initially formed naphthalene-2,6-di(NMe3I) prompted us to also
study steric factors in the more spatially challenged 1,5-
naphthalene analogue.
* Corresponding authors. Tel.: þ385 (0)1 4680196; fax: þ385 (0)1 4680 195
(K.M.-M.); tel.: þ972 (0)8 646 9812; fax: þ972 (0)8 690 0084 (R.G.); tel.: þ1 301
405 1884; fax: þ1 301 314 9121 (L.I.); e-mail addresses: LIsaacs@umd.edu (L. Isaacs),
In this paper we report simple methods for the synthesis of
secondary to quaternary ammonium salts of 1,5- and 2,6-
ꢁ
glaser.robert@gmail.com (R. Glaser), majerski.@irb.hr (K. Mlinaric-Majerski).
http://dx.doi.org/10.1016/j.tet.2016.02.002
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
ꢀ
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2
Ð. Skalamera et al. / Tetrahedron xxx (2016) 1e6
diaminonaphthalenes. These procedures are based upon the stan-
dard reductive amination using formaldehyde/H2/PtO2, which can
be easily scaled-up if necessary. Permethylation using methyl io-
dide and methyl triflate as methylating agents is described as well.
derivative 2 (42% yield) was synthesized by methylation of 3 with
an excess of MeI under basic conditions (CaCO3), see Scheme 1. 1H
NMR spectra (D2O) recorded immediately after isolation of salt 2,
compared to those recorded after 24 h in solution, showed that
demethylation of compound 2 had occurred in the aqueous me-
dium over a period of time (see Supplementary data, Fig. S12 and
S13).
2. Results and discussion
A search of the CSD afforded 27 Ph-NþMe2H tertiary ammonium
substructures where the þNeH bond eclipses a CAr(non-proto-
nated)dCAr(methine) bond. Six of these structures exhibited
ꢂ3(2)ꢃ synperiplanar HeNeCAr(non-protonated)eCAr(methine)
torsion angles. In these six structures, the two more sterically de-
manding þNeC(methyl) bonds are staggered to the second CAr(non-
protonated)dCAr(methine) bond [e.g., ꢂ63(4)ꢃ synclinal C(meth-
yl)eNeCAr(non-protonated)eCAr(methine) torsion angles]. An-
other characteristic feature of these aromatic amines is their
106.8(3)ꢃ HeNeCAr(non-protonated) and 112.3(6)ꢃ C(methyl)e
NeCAr(non-protonated) bond angles. The N,N,N-trimethyl-aniline
10 (Ref. code ICOVIG12) Cs-symmetry quaternary aminium cation
occupies a special position of crystallographic mirror symmetry
within the P21/m lattice. This crystal structure is an appropriate
model to discuss the situation when a more sterically demanding
þNeMe bond ideally eclipses a CAr(non-protonated)dCAr(methine)
2.1. Synthesis of compounds
The synthesis of 2,6- and 1,5-substituted naphthalene de-
rivatives 2e5, 6e9, and 15e16, was based upon the corresponding
dibromo or diamino derivatives as shown in Schemes 1e3,
respectively.
þ
bond, and the two other NeMe bonds each exhibit ꢂ59.6ꢃ syn-
clinal C(methyl)eNeCAr(non-protonated)eCAr(methine) torsion
angles. The result of this steric challenge is a more opened 113.3ꢃ
CMe(eclipsed)eNeCAr(non-protonated) bond angle and two corre-
spondingly compressed 109.8ꢃ CMe(staggered)eNeCAr(non-pro-
tonated) bond angles (Fig. 1). Furthermore, 10’s angular
Scheme 1. (a) CH3NH2(aq), 10 mol % Cu,
CH2O(aq), H2/PtO2, EtOH, rt, 16 h,
¼55%; (d) MeI, CaCO3, MeOH/H2O,
(e) MeOTf, K2CO3, CH3CN, , 16 h,
¼75%.
D,
h
¼78%; (b) HCl/Et2O,
h
¼quant.; (c)
h
D
, 16 h,
h
¼42%;
D
h
compression
is
further
exacerbated
by
its
shorter
ꢂ
1.495
A
C(sp2þ)dþNMe3 bond length12 versus the longer
3
1.596 A C(sp )d NMe3 bonds13 in the diamantane-4,9-di(NMe3I),1
crystal structure (Refcode TOCMEF), see Fig. 1. Now, C(sp3)-hy-
bridization at the bridgehead-C(4 or 9) of crystalline 1 enabled all
three NeCH3 bonds to be staggered relative to the three vicinal
ꢂ
C
Diam(sp3-quat)dC(methylene) bonds, and thereby produced more
stable 111.4(5)ꢃ CMe(staggered)eNeCDiam(quat.) bond angles.13 The
putative strain in the CMe(eclipsed)eNeCAr(non-protonated) and
CMe(staggered)eNeCAr(non-protonated) bond angles in naphtha-
lene-2,6-di(NMe3I) (2) is likely to be a dominant factor behind its
aqueous solution decomposition in the presence of the iodide nu-
cleophilic anion over a period of time. This instability was over-
come by permethylation with methyl triflate which afforded
a stable bis-quaternary aminium salt 5 (75% yield) having triflate
non-nucleophilic anions.
Scheme 2. (a) HCl/Et2O,
Et2O,
¼93%; (d) MeI, CaCO3, MeOH/H2O,
(f) MeOTf, K2CO3, CH3CN, , 16 h; (g) HI(aq)/MeOH,
h
¼90%; (b) CH2O(aq), H2/PtO2, EtOH, rt, 16 h,
, 16 h; (e) Me2SO4, Na2CO3, MeOH,
¼39%.
h
¼95%; (c) HCl/
h
D
D
, 16 h;
D
h
Fig. 1. Left: Strained 113.3 ꢃC(sp2)eNeCMe(eclipsed) and one of the two 109.8 ꢃC(sp2)e
NeCMe(staggered) unequal bond angles within a fragment of crystalline N,N,N-tri-
methyl-aniline 10. Right: Two of the three equal 111.4 ꢃC(sp3)eNeC(methyl) less-
strained bond angles in an N,N,N-trimethylammonium-segment of crystalline dia-
mantane-4,9-di(NMe3I), 1.
Scheme 3. (a) Mg/THF,
16 h; (e) MeI, Na2CO3/MeOH,
D
,
h
¼15%; (b) DMF; (c) H3Oþ; (d) Me2NH, H2/PtO2, MeOH, rt,
D, 16 h,
h
¼62% (2 steps).
The methylamino derivative 3 was obtained by an Ullmann re-
action11 between 2,6-dibromonaphthalene and methylamine (78%
yield). It was then converted to the corresponding 3 HCl salt upon
addition of HCl/Et2O solution. To avoid permethylation, the re-
ductive amination of naphthalene derivative 3 was utilized to
prepare bis(dimethylamino)naphthalene derivative 4, which was
then converted to the hydrochloride salt 4$HCl. The permethylated
Since we noticed steric problems in the stability of the 2,6-
diaminonaphthalene permethylated quaternary ammonium salts,
we were stimulated to investigate the preparation of the corre-
sponding 1,5-diaminonaphthalene permethylated quaternary am-
monium salts where we expected even greater steric interactions to
be present.
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Ð. Skalamera et al. / Tetrahedron xxx (2016) 1e6
3
The permethylation of readily available 1,5-di(NH2)-naphtha-
lene (6) with MeI resulted in formation of dimethylamino de-
rivative 7, which was further reacted to give mono salt 8a (Scheme
2). Salt 9 was obtained by addition of hydroiodic acid to the
methanolic solution of salt 8a. Our attempts to achieve per-
methylation using dimethyl sulfate as the methylating agent only
provided a mixture of bis-tertiaryammonium tetra-N-methyl 7 and
penta-N-methyl 8b, with no observed permethylated product.
Isolation of product 8b turned out to be very difficult due to con-
tamination with inorganic byproducts (probably NaMeSO4). We
decided next to perform the permethylation reaction with methyl
triflate as the methylating agent because methyl triflate generates
triflate non-nucleophilic anions. All hexa-N-permethylation at-
tempts of naphthalene-1,5-diamine with methyl triflate were un-
successful since only the penta-N-methyl compound 8c was
produced.
readily observed by a change of the þNH-synperiplanar relationship
to H(4 or 8) tertiary ammonium conformation in 11, 12, 13 to one in
which H(4) or H(8) now become staggered (i.e., a synclinal re-
lationship) to their two immediate N-methyl neighbors in the
quaternary substituent of 13, 14 due to the well-known 1,8-peri-
interaction in naphthalene. This concurrently also produces an in-
crease in angles involving the ordinarily parallel C(1)dX and C(8)d
X bonds [corresponding C(4)dX and C(5)dX] for X]H peri-sub-
stituents. In the tertiary ammonium peri-interaction, the N(1)e
C(1)/C(8) and opposite H(8)eC(8)/C(1) angles are 91.2(9)ꢃ and
92.6(3)ꢃ, respectively. These open up due to lateral strain so that the
N(1)eC(1)/C(8) and opposite H(8)eC(8)/C(1) angles now be-
come 93.8(3)ꢃ and 94.1(7)ꢃ for quaternary aminium peri-sub-
stituents. The above measurements appear to afford a rationale for
the observation of only one quaternary trimethylammonium peri-
substituent on the 1,5-disubstituted naphthalene skeleton.
A search of the CSD produced no crystal structures with either
a 1-mono- or 1,5-di(N,N,N-trimethyl)aminium substituted naph-
thalene skeleton. Therefore, 1,8-type peri-strain was studied with
BLYP-D3/def2SVP geometry optimized models for tetra-N-methyl
(11 and 12), penta-N-methyl (13), and hexa-N-methyl (14)
substituted naphthalene 1,5-diamine cations. These correspond to
6$HCl, 8, and its permethylated derivative, respectively (Fig. 2). The
same sterically favored þNH-synperiplanar-to-H(4 or 8) conforma-
tion (found twice in model-11 and once in model-13), is also ap-
parent in the naphthalene-1,5-di(iPr) carbon analogue Ref. code
PAZLUZ crystal structure,14 see 12. Since the constitutions of the
calculated DFT models all differed, one should not compare their
calculated energies. However, a structural comparison of their op-
timized geometries is certainly possible. The transition from ter-
tiary ammonium þNHMe2 to quaternary aminium þNMe3 in the
naphthalene-1,5-diamine models seem to engender considerable
bond-angle strain which results in conformational change. This is
Permethylated 2,6-bis(aminomethyl)naphthalene derivative 16
was prepared starting from 2,6-dibromonaphthalene as shown in
Scheme 3. The Grignard reagent prepared from 2,6-
dibromonaphthalene was reacted with DMF to afford dialdehyde
15 which was subsequently converted to 16 in 9% overall yield via
a reductive amination and permethylation reaction sequence.
2.2. H/D exchange NMR studies
In the initial 1H NMR spectrum of the bis-secondary ammonium
salt 3$HCl measured in D2O, the integral of the aromatic-H signal at
8.05 ppm did not correspond to the 2 protons that are commonly
assigned to the H(1) and H(5) peri-protons on naphthalene-2,6-
disubstituted rings. Therefore, we decided to investigate possible
H/D exchange (Scheme 4).
Scheme 4. Deuterium incorporation at positions 1- and 8- in 2,6-substituted naph-
thalene salts 3$HCl and 4$HCl.
The low-intensity or missing signal was now visible when the
solvent was changed from D2O to DMSO-d6 or H2O with benzene as
a spin lock (see Supplementary data, Fig. S4, S6 and S7). This ob-
servation was consistent with deuterium-exchange of the peri-
protons. A second finding of deuterium exchange arises from the 1H
NMR (CDCl3) spectrum of naphthalene-2,6-di(NHMe) 3 free base
measured before and after addition of a drop of D2O (see
Supplementary data, Fig. S1 and S2). Twenty-four hours after D2O
addition, the H(1)/H(5) fine structure at 6.84ꢂ0.02 ppm was still
present, but the integral intensity decreased. A similar H/D ex-
change at naphthalene-1,5-positions was also found to take place
for the 4$HCl bistertiary ammonium salt, but did not take place in
the bisquaternary aminium salts (2 and 5). However, it is known
from the literature that C-protonation, rather than N-protonation in
1,8-diaminonaphthalenes occurs in solvents which can act as
hydrogen-bond acceptors, resulting in incorporation of deuterium
into the naphthalene moiety.15 H/D exchange also takes place in
pure naphthalene by acid-catalyzed reaction.16 Exchange at the
position of naphthalene is faster than that at the -position by
a factor of ca. 10, and our results [the exchange observed in naph-
thalene 2,6-substituted derivatives (at the naphthalene -posi-
tion)] are in good agreement with those previously reported.
a-
b
Fig. 2. Non-bonding angles [N(1)eC(1)/C(8)], [N(2)eC(5)/C(4)], [H(4)eC(4)/C(5)],
and [H(8)eC(8)/C(1)] open up due to lateral (1,8)-peri-strain in BLYP-D3/def2SVP
models of N,N,N-trimethyl quaternary nitrogen disubstituted naphthalene-1,5-
diamine.
a
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Furthermore, exchange in 1,5-substituted derivatives was not ob-
served due to its slower kinetic rate (at naphthalene -position).
We can conclude that þNH protonated 2,6-naphthalenes (such as
4.3. 2,6-Bis(methylamino)naphthalene dihydrochloride 3$HCl
b
HCl/Et2O was added dropwise to an ethereal solution of 3
(342 mg, 1.84 mmol) until complete precipitation was achieved.
The solvent was removed by rotary evaporation to obtain pure
3$HCl (477 mg, 100%) as a white solid; Mp¼225e228 ꢃC; nmax (KBr/
cmꢁ1) 3431 (w), 2062 (s), 2762 (s), 2664 (s), 2428 (s), 1616 (w), 1525
(m), 1458 (m); dH (300 MHz, DMSO-d6) 7.78 (d, J¼8.8 Hz, 2H), 7.43
(br s, 2H, exchangeable), 7.34 (d, J¼8.8 Hz, 2H), 2.88 (s, 6H); dC
3$HCl and 4$HCl)$catalyze H/D exchange at the
a-positions of
naphthalene in D2O solution. Lack of an exchangeable þNH proton
in the bisquaternary aminium salts 2 and 5 is in complete accord
with the absence of H/D exchange observed for these compounds.
3. Conclusions
(150 MHz, DMSO-d6) d: 128.3 (d), 128.1 (s), 123.1 (d), 121.7 (s), 120.4
(d), 33.5 (q).
Simple procedures for the synthesis of secondary to quaternary
ammonium salts of 1,5- and 2,6-diaminonaphthalene 2e9 and 16
were reported. Analyses of DFT calculated models (BLYP-D3/
def2SVP) were in accordance with experimental observations that
bisquaternization of 1,5-diaminonaphthalene is unfavorable due to
strong (1,8)-peri steric hindrance. Bis-quaternary iodide salt 2 was
unstable in solution due to reaction with its iodide nucleophilic
counterion. However, bis-quaternary salt 5, which has a triflate
non-nucleophilic counterion, is stable in solution.
4.4. 2,6-Bis(dimethylamino)naphthalene 4
2,6-Bis(methylamino)naphthalene 3 (62 mg, 0.33 mmol) and
36% aqueous formaldehyde (1 mL) were dissolved in absolute
ethanol (15 mL) in a round-bottomed flask and stirred vigorously
overnight. The in situ formed Schiff base underwent reductive
amination under a hydrogen atmosphere (balloon, 1 atm) and PtO2
catalyst (10 mg, 0.04 mmol). The mixture was then filtered, and
solvent removed on a rotary evaporator to afford a brown oil. The
product was purified on a short column of silica gel using hexane/
ethyl acetate (9:1) as the eluent to afford pure 4 (39 mg, 55%) as
a light yellow solid, mp¼150e151 ꢃC [lit. 148e150 ꢃC];10 dH
(300 MHz, CDCl3) 7.56 (d, J¼8.9 Hz, 2H), 7.13 (dd, J¼8.9, 2.5 Hz, 2H),
6.90 (br s, 2H), 2.98 (br s, 12H); dC (75 MHz, CDCl3) 146.7 (s), 128.3
(s), 127.1 (d), 117.6 (d), 107.5 (d), 41.4 (q).
H/D exchange was observed in 3$HCl and 4$HCl in D2O solution.
It was found that H/D exchange at the a-positions of naphthalene in
D2O solution was catalyzed by þNH.
4. Experimental section
4.1. General information
1H and 13C spectra were recorded on a Bruker AV-300 or
600 MHz NMR spectrometer in solvents: D2O (using dioxane as
a reference in 13C spectra), DMSO-d6 or CDCl3 and are reported in
4.5. 2,6-Bis(dimethylamino)naphthalene dihydrochloride
4$HCl
€
ppm. Melting points were determined using an original Kofler
Amine 4 (39 mg, 0.21 mmol) was converted to the corre-
sponding 4$HCl salt by adding a saturated solution of ethereal HCl
to a Et2O solution of 4 until complete precipitation was achieved.
The crude product was recrystallized three times from ethanol/
acetone (7:3) to obtain pure 4$HCl (45 mg, 47%) as a white solid;
Mp¼210e213 ꢃC dec; nmax (KBr/cmꢁ1) 3437 (w), 3020 (w), 2847
(w), 2536 (m), 2359 (s), 1618 (w), 1527 (m), 1475 (w); dH (300 MHz,
D2O) 8.28e8.22 (m, 4H), 7.83 (d, J¼8.8 Hz, 2H), 3.41 (s, 12H); dC
(150 MHz, D2O) 141.7 (s), 133.2 (s), 132.1 (d), 120.0 (d, 2C), 46.8 (q).
Mikroheiztisch apparatus (Reichter, Wien) and are uncorrected. IR
spectra were recorded on an FT-IR-ABB Bomem MB 102 spectro-
photometer in KBr plates. HRMS were recorded only for new
compounds. MALDI-TOF HRMS were obtained on an Applied Bio-
systems 4800 Plus MALDI TOF/TOF instrument (AB, Foster City, CA).
Compounds 1,5-diaminonaphthalene, 2,6-dibromonaphthalene
and 40% aqueous methylamine were purchased from commercial
sources and were used as received. Solvents for chromatographic
separations and recrystallizations (hexane, ethyl acetate, methanol,
ethanol, diethyl-ether, and acetone) were used as received (p.a.
grade purity) or purified by distillation (CH2Cl2).
4.6. N,N,N,N0,N0,N0-hexamethylnaphthalene-2,6-diaminium
diiodide 2
No negative vibrational frequencies were found for the BLYP-D3/
def2SVP calculated molecular models 11, 13, and 14.
2,6-Bis(methylamino)naphthalene 3 (62 mg, 0.33 mmol), CaCO3
(62 mg, 0.67 mmol) and MeI (180
mL, 2.8 mmol) were mixed in
4.2. 2,6-Bis(methylamino)naphthalene 3
MeOH/H2O (4:1, 400 L) and the resulting suspension was refluxed
m
overnight. Most of the CaCO3 dissolved as the reaction proceeded.
The resulting solution was filtered while hot, and the solvent was
removed on a rotary evaporator. The solid residue was washed with
hot acetone (5ꢀ10 mL) to afford a white powder, which was
recrystallized three times from ethanol/acetone (3:7) to obtain pure
2 (70 mg, 42%) in the form of white crystals; Mp¼252e254 ꢃC dec;
nmax (KBr/cmꢁ1) 3446 (s), 3030 (m), 3011 (m), 2918 (w), 1630 (s),
1606 (s), 1514 (s), 1472 (m), 1389 (m), 945 (s); dH (300 MHz, D2O)
8.54 (d, J¼2.8 Hz, 2H), 8.36 (d, J¼9.2 Hz, 2H), 8.12 (dd, J¼9.2, 2.8 Hz,
2H), 3.81 (s, 18H); dC (75 MHz, D2O) 146.2 (s), 132.9 (s), 132.8 (d),
124.3 (s), 119.8 (d), 119.6 (d), 57.6 (q); HRMS (MALDI): calcd for
[C16H24N2I] requires 371.0984; found 371.1010.
A mixture of 2,6-dibromonaphthalene (500 mg,1.75 mmol), 30%
aqueous methylamine solution (10 mL, 87 mmol), and copper
powder (32 mg, 0.5 mmol) were placed in a screw-cap pressure
tube (50 mL) with a stirring bar, and stirred overnight on an oil bath
at 100 ꢃC. The color changed from light blue to dark blue during the
reaction, and finally to black. After completion of the reaction, the
reaction mixture was cooled to RT and the product was extracted
with CH2Cl2 (3ꢀ20 mL). The combined extracts were dried over
anhydrous MgSO4 and the solvent was removed under reduced
pressure. The crude product was purified on a column of silica gel
using ethyl acetate/hexane (3:7) as the eluent to afford pure
product
3 (342 mg, 78%) as a yellow crystalline solid;
Mp¼126e128 ꢃC; nmax (KBr/cmꢁ1) 3402 (m), 3051 (w), 2922 (w),
1608 (s), 1522 (s), 1254 (s); dH (300 MHz, CDCl3) 7.47 (d, J¼8.7 Hz,
2H), 6.83 (dd, J¼8.7, 2.0 Hz, 2H), 6.75 (d, J¼2.0 Hz, 2H); dC (150 MHz,
CDCl3) 144.4 (s), 128.9 (s), 126.9 (d), 118.1 (d), 104.9 (d), 31.0 (q);
HRMS (MALDI): calcd for [C12H14N2]þ requires 186.1150; found
186.1153.
4.7. N,N,N,N0,N0,N0-hexamethylnaphthalene-2,6-diaminium
ditriflate 5
In a round-bottomed two-necked flask equipped with reflux
condenser (all under N2-atmosphere), diamine
4 (40 mg,
0.19 mmol) was dissolved in anhydrous CH3CN (8 mL) and K2CO3
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Ð. Skalamera et al. / Tetrahedron xxx (2016) 1e6
5
was added. Methyl triflate (212
m
L, 1.87 mmol) was slowly added
Mp¼173e174 ꢃC; nmax (KBr/cmꢁ1) 3448 (w), 3105 (w), 2939 (m),
2842 (w), 1595 (s), 1454 (s), 793 (vs); dH (600 MHz, D2O) 8.50 (d,
J¼8.6 Hz, 1H), 8.16 (d, J¼9.2 Hz, 1H), 8.10 (d, J¼8.6 Hz, 1H), 7.78 (t,
J¼9.2 Hz, 1H), 7.70 (t, J¼8.2 Hz, 1H), 7.47 (d, J¼8.2 Hz, 1H), 4.00 (s,
9H), 2.89 (s, 6H); dC (150 MHz, D2O) 152.4 (s), 142.2 (s), 131.3 (s),
128.8 (d), 128.4 (d), 125.8 (s), 124.8 (d), 120.1 (d), 118.5 (d), 116.4 (d),
58.4 (q), 45.6 (q); HRMS (MALDI): calcd for [C15H21N2]þ requires
229.1705; found 229.1709.
with a microliter syringe. The resulting solution was refluxed
overnight under N2, then cooled to RT, and diethyl-ether was added
dropwise until complete precipitation occurred. The resulting
white solid was washed with diethyl ether (5ꢀ5 mL) and then
recrystallized three times from methanol/ether (9:1) to afford pure
5 (76 mg, 75%) as a white crystals; Mp>320 ꢃC; nmax (KBr/cmꢁ1
)
3454 (w), 3088 (w), 3055 (w), 1608 (m), 1490 (s), 1255 (s), 1157 (s),
1030 (s), 638 (s); dH (300 MHz, D2O) 8.57 (d, J¼2.8 Hz, 2H), 8.41 (d,
J¼9.2 Hz, 2H), 8.16 (dd, J¼9.2, 2.8 Hz, 2H), 3.85 (s, 18H); dC (75 MHz,
D2O) 146.3 (s), 132.9 (d), 132.8 (s), 120.3 (q, 1JCF¼318 Hz), 119.7 (d),
119.6 (d), 57.6 (q); HRMS (MALDI): calcd for [C15H21N2CF3SO3]þ
requires 393.1454; found 393.1458.
4.12. N,N,N-Trimethylnaphthalen-1-aminium iodide-5-
dimethylamine hydroiodide salt 9
Compound 8a (500 mg, 1.4 mmol) was dissolved in methanol
and few drops of HI (concn) was added. After evaporation of solvent
and recrystallization from ethanol/acetone (3:7), pure 9 (270 mg,
39%) was obtained in the form of grayish-white crystals;
Mp¼180e182 ꢃC dec; nmax (KBr/cmꢁ1) 3418 (w), 3005 (m), 1616
(m), 1520 (m), 1472 (s); dH (300 MHz, D2O) 8.70 (d, J¼9.1 Hz, 1H),
8.43 (d, J¼8.8 Hz, 1H), 8.29 (d, J¼7.9 Hz, 1H), 8.15 (d, J¼7.9 Hz, 1H),
8.05e7.89 (m, 2H), 4.03 (s, 9H), 3.52 (s, 6H); dC (150 MHz, D2O)
142.9 (s), 140.8 (s), 128.4 (d), 128.3 (s), 127.7 (d), 126.0 (s), 125.6 (d),
124.5 (d), 121.6 (d), 119.8 (d), 58.8 (q), 47.4 (q); HRMS (MALDI):
calcd for [C15H21N2]þ requires 229.1705; found 229.1710.
4.8. Naphthalene-1,5-diammonium dichloride 6$HCl
1,5-Diaminonaphthalene 6 (164 mg, 1 mmol) was dissolved in
Et2O (20 mL) and a saturated solution of ethereal HCl was added
until complete precipitation was achieved. The resulting gray pre-
cipitate was recrystallized from methanol/ether to afford pure
6$HCl (208 mg, 90%) in the form of a greyish-white powder;
Mp¼266e269 ꢃC dec; nmax (KBr/cmꢁ1) 3440 (w), 3022 (m), 2818
(s), 2590 (m), 1620 (m), 1577 (m), 1533 (s), 1414 (m); dH (300 MHz,
D2O) 8.08 (dd, J¼6.8, 2.5 Hz, 2H), 7.84e7.75 (m, 4H); dC (75 MHz,
D2O) 128.1 (s), 128.0 (d), 127.92 (d), 127.90 (d), 127.7 (s).
4.13. Naphthalene-2,6-dicarbaldehyde 15
4.9. 1,5-Bis(dimethylamino)naphthalene 7
The bis-Grignard reagent was prepared by adding the solution of
2,6-dibromonaphthalene (290 mg, 1 mmol) in dry THF (3 mL) to
magnesium (97 mg, 4 mmol) in refluxing THF (dry, 7 mL). The re-
action mixture was then cooled to RT and dry DMF (1 mL, 13 mmol)
was added dropwise. After the resulting mixture was stirred 2 h at
rt and 1 h at reflux, 1M HCl (15 mL) was slowly added, and stirring
was continued overnight to completely convert the bis-Schiff base
into the dialdehyde. The solvent was removed on a rotary evapo-
rator, and the crude product was subjected to column chromatog-
raphy on silica gel using CH2Cl2/hexane (1:1) as eluent to afford the
dialdehyde product 15 (27 mg, 15%) in the form of an off-white
1,5-Diaminonaphthalene (164 mg, 1 mmol) and 36% aqueous
formaldehyde (1 mL) were dissolved in absolute ethanol (20 mL) in
a round-bottomed flask and stirred vigorously overnight. The in
situ formed Schiff base underwent reductive amination under
a hydrogen atmosphere (balloon, 1 atm) and PtO2 catalyst (15 mg,
0.07 mmol). The mixture was filtered and solvent was then re-
moved on rotary evaporator to afford crude product (378 mg) in the
form of brown-yellowish oil. The product was purified on a short
column of silica gel using hexane/ethyl acetate (9:1) as eluent to
afford pure
7 (204 mg, 95%) in the form of white solid;
solid; Mp¼170e172 ꢃC [lit. 173.4e174.0 ꢃC];17 nmax (KBr/cmꢁ1
)
Mp¼88e89 ꢃC [lit. 87e88 ꢃC];10 dH (300 MHz, CDCl3) 7.93 (d,
J¼8.8 Hz, 2H), 7.42e7.34 (m, 2H), 7.05 (dd, J¼7.4, 0.6 Hz, 2H), 2.88 (s,
12H); dC (75 MHz, CDCl3) 151.1 (s), 130.2 (s), 124.8 (d), 118.9 (d),
113.7 (d), 45.2 (q).
3448 (w), 2840 (m), 1687 (vs), 1333 (m), 1227 (m), 1111 (m); dH
(300 MHz, CDCl3) 10.22 (s, 2H), 8.40 (s, 2H), 8.15e8.03 (m, 4H); dC
(75 MHz, CDCl3) 191.6 (d), 136.1 (s), 135.6 (s), 133.5 (d), 130.5 (d),
124.0 (d).
4.10. 1,5-Bis(dimethylamino)naphthalene dihydrochloride
7$HCl
4.14. 1,10-(Naphthalene-2,6-diyl)-bis-(N,N,N-trimethylmetha-
naminium) diiodide 16
Compound 7 (204 mg, 0.95 mmol) was dissolved in Et2O (20 mL)
and saturated solution of ethereal HCl was added until complete
precipitation was achieved The salt was recrystallized three times
from ethanol/acetone (7:3) to obtain pure product 7$HCl (268 mg,
93%) in the form of white crystals; Mp¼214e216 ꢃC dec; nmax (KBr/
cmꢁ1) 3431 (s), 3022 (w), 2850 (w), 2615 (s), 2434 (m), 1618 (w),
1520 (m), 1473 (s); dH (300 MHz, D2O): 8.34 (d, J¼8.7 Hz, 2H), 8.13
(d, J¼7.7 Hz, 2H), 8.01e7.93 (m, 2H), 3.52 (s, 12H); dC (150 MHz,
D2O) 139.7 (s), 128.7 (d), 126.5 (s), 122.8 (d), 120.3 (d), 47.3 (q).
Dialdehyde 15 (27 mg, 0.15 mmol) and 40% aqueous dimethyl
amine (1 mL) were dissolved in absolute methanol (5 mL) in
a round-bottomed flask. The in situ formed Schiff base underwent
reductive amination under a hydrogen atmosphere (baloon, 1 atm)
and PtO2 catalyst (5 mg, 0.02 mmol) with vigorous stirring over-
night. The mixture was filtered and the solvent was removed on
rotary evaporator to afford the dimethylamino intermediate prod-
uct (31 mg, 0.13 mmol) in the form of a white film on the walls of
the flask. MeOH (10 mL) was added to dissolve the intermediate
amine, followed by addition of Na2CO3 (20 mg, 0.2 mmol) and MeI
(1 mL, 16 mmol). The resulting suspension was then refluxed
overnight under N2 atmosphere. The solvent was removed on
a rotary evaporator and resulting yellow solid was washed with hot
acetone (5ꢀ15 mL) until the yellow color was washed out. After
drying, pure product 16 (49 mg, 62% over two steps) was obtained
in the form of a white powder; Mp>320 ꢃC; nmax (KBr/cmꢁ1) 3427
(w), 2995 (m), 2966 (w), 1479 (s), 1402 (m), 877 (s); dH (300 MHz,
DMSO-d6) 8.23 (s, 2H), 8.16 (d, J¼8.5 Hz, 2H), 7.74 (dd, J¼8.5, 1.0 Hz,
2H), 4.76 (s, 4H), 3.12 (s, 18H); dC (75 MHz, DMSO-d6) 132.6 (d),
4.11. N,N,N-Trimethylnaphthalen-1-aminium iodide-5-
dimethylamine 8a
MeI (2.6 mL, 41.8 mmol) was added to a suspension of 1,5-
diaminonaphthalene (816 mg,
5 mmol) and CaCO3 (1.12 g,
11.2 mmol) in MeOH/H2O (4:1,10 mL). Following reflux (48 h) of the
reaction mixture, the solvent was then removed by rotary evapo-
ration to obtain black thick oil. After three recrystallizations from
ethanol/acetone (3:7) the free amine-quaternary salt 8a (712 mg,
40%) was obtained in the form of
a grayish-white solid;
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6
Ð. Skalamera et al. / Tetrahedron xxx (2016) 1e6
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2. Cao, L.; Skalamera, Ð.; Zavalij, P. Y.; Hostas, J.; Hobza, P.; Mlinaric-Majerski, K.;
129.8 (d), 128.8 (d), 127.2 (s, 2C), 67.8 (t), 52.0 (q); HRMS (MALDI):
calcd for [C17H25N2]þ requires 257.2012; found 257.2016.
Glaser, R.; Isaacs, L. Org. Biomol. Chem. 2015, 13, 6249e6254.
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P.; Basaric, N. J. Org. Chem. 2012, 77, 4596e4610; (b) Skalamera, Ð.; Mlinaric-
Majerski, K.; Uzelac, L.; Kralj, M.; Wan, P.; Basaric, N. Photochem. Photobiol. Sci.
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We thank the Croatian Ministry of Science, Education and Sports
(grant 098-0982933-2911 to K.M.-M.), the US NSF (CHE-1404911 to
L.I.) and the Ben-Gurion University Research Fund for Scientific
Relations (to R.G.) for financial support of this study. Gratitude is
€
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expressed to Prof. Dr. Pavel Hobza and Jirí Hostas (Institute of Or-
ganic Chemistry and Biochemistry, Academy of Sciences of the
Czech Republic, Praha, Czech Republic) for the BLYP-D3/SVP cal-
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Supplementary data
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NMR spectra of compounds 2e9, 15, 16 and their corresponding
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SVP calculated cationic models of 11, 13, and 14.
828e836.
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References and notes
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