Novel formaldehyde-mediated dimerization reaction of n-alkyl-1-naphthylamine derivatives under mild/neutral conditions; application to synthesis of naphthylamine-derived macrocycles

Article abstract of DOI:10.3987/com-01-9339

The dimerization reaction of N-methyl-1-naphthylamine (1) with formaldehyde is described. Reaction of 1 with formaldehyde under mild/neutral conditions gave bis-4-(1-N-methylaminonaphthyl)methane (2) in high yield as a single dimerization product. This formaldehyde-mediated aromatic condensation reaction is chemo- and regio-selective, and it takes place particularly with N-monoalkyl-1-naphthylamines as substrates. The novel naphthylamine-derived macrocyclic compounds 1,6,28,33-tetraaza-[6.1.6.1]paranaphthalenophane (13a) and 1,13-diaza[13,1]paranaphthalenophane (12c) were synthesized by application of this formaldehyde-mediated mild/neutral condensation reaction as the key step.

Full text of DOI:10.3987/com-01-9339

HETEROCYCLES, Vol. 55, No. 12, 2001, pp. 2305 - 2313, Received, 6th September, 2001
NOVEL
FORMALDEHYDE-MEDIATED
DIMERIZATION
REACTION OF N-ALKYL-1-NAPHTHYLAMINE DERIVATIVES
UNDER MILD/NEUTRAL CONDITIONS; APPLICATION TO
SYNTHESIS OF NAPHTHYLAMINE-DERIVED MACROCYCLES
Hiroyasu Takahashi, Yuichi Hashimoto, and Kazuo Nagasawa*
Institute of Molecular and Cellular Biosciences,
The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
Abstract - The dimerization reaction of N-methyl-1-naphthylamine (1) with
formaldehyde is described. Reaction of 1 with formaldehyde under
mild/neutral conditions gave bis-4-(1-N-methylaminonaphthyl)methane (2) in
high yield as a single dimerization product. This formaldehyde-mediated
aromatic condensation reaction is chemo- and regio-selective, and it takes
place particularly with N-monoalkyl-1-naphthylamines as substrates. The
novel naphthylamine-derived macrocyclic compounds 1,6,28,33-tetraaza-
[6.1.6.1]paranaphthalenophane (13a) and 1,13-diaza[13,1]paranaphthaleno-
phane (12c) were synthesized by application of this formaldehyde-mediated
mild/neutral condensation reaction as the key step.
Many studies on formaldehyde (FA)-related reactions have been reported over the past few decades.1-5
FA reacts with nucleophiles as a C1 unit to give a variety of useful functional groups in organic synthesis,
e.g., in alkylation at carbonyl α-positions,1 hydroxymethylation of aromatic rings,2 addition to alkenes

(ene reaction),3 condensation with alkenes in the presence of Brφnsted acids (known as the Prins
reaction),4 and the Mannich reaction.5
On the other hand, FA is also well known as an embalming agent and as a genotoxic substance that causes
DNA-protein or DNA-DNA cross-link formation.6 In the course of our recent work on FA-mediated
modification of nucleic acids with aromatic amines,7 we found that the reaction of N-methyl-1-
naphthylamine (1) with FA under neutral and very mild conditions gave bis-4-(1-N-
methylaminonaphthyl)methane (2) in good yield as a single product. In general, in the presence of FA,
N-methylaniline is known to be converted into iminal derivatives (R1R2N-CH2-NR1R2: R1=Ph, R2=Me)
via an imine intermediate,8 or Friedel-Crafts type alkylation or condensation of aromatic compounds with
aldehyde usually takes place under acidic or basic conditions.2,9 Thus, FA-mediated reaction of N-
methyl-1-naphthylamine (1) appears to be a novel chemo- and regio-selective alkylation under neutral
conditions.
We were interested in this novel and facile FA-mediated C-C bond-forming reaction of naphthylamine
derivatives.10 In this paper, we describe the FA-mediated dimerization of naphthylamine derivatives
and its application to macrocyclic compound syntheses.
Table 1. Formaldehyde-Mediated Dimerization of N-Methyl-1-naphthylaminea
NHMe
NHMe
HCHO
1
NHMe
2
b
Entry
Solvent
MeOH
Temp
Time
5 h
Yield (%)
i
rt
rt
rt
rt
rt
84
85
20
90
95
ii
MeCN
5 h
iii
iv
v
THF
48 h
1 h
MeOH-5% AcOH
5% HCl aq
1 min
a
b
0.3 mol/L of 1 and 10 equiv. of 35% HCHO were used. Isolated yield.

Reaction of 1 with FA in MeCN or MeOH under neutral conditions gave bis-4-(1-N-
methylaminonaphthyl)methane (2) in high yield (Table 1. Entries i, ii). The structure of the adduct (2)
was determined by NMR and MS spectroscopic analysis after acetylation of the amino group.11 The
dimerization reaction was suppressed in THF (Entry iii), but remarkably accelerated in acidic media. In
aqueous hydrogen chloride solution, this reaction was completed within 1 min and gave 2 almost
quantitatively (Entries iv, v) without forming Mannich-type reaction products of 1 via an iminium ion
intermediate, which is usually observed under acidic reaction conditions. Thus, this FA-mediated
dimerization of N-methyl-1-naphthylamine (1) appears to be chemo- and regio-specific under both neutral
and acidic conditions.
To investigate the generality of this FA-mediated dimerization reaction with naphthalene derivatives
having an electron-donating group at the C1-position, reactions of 1-substituted naphthalenes with FA
were examined (Table 2). Treatment of 1-naphthylamine (3a) with an excess amount of FA gave a
complex mixture of polymeric products (Entry i). N,N’-Dimethyl- and N-acetyl-1-naphthylamines (3b,
3c), did not react with FA under neutral conditions even at higher temperature (Entries ii, v). On the
other hand, when the reaction was performed in AcOH as a solvent, N,N’-dimethyl-1-naphthylamine
(3b) gave the 4-hydroxymethylated product (4b) together with the dimer (5b) (Entries iii, iv).12
Dimerization of N-acetyl-1-naphthylamine (3c) did not take place in AcOH solution (Entry. vi).
Condensation of the 4-hydroxymethylated product (4b) with an equal amount of 3b gave the
corresponding dimer (5b) quantitatively, just upon heating in AcOH at 80°C.
Though this 4-hydroxylmethylnaphthylamine (4) is a possible intermediate in the FA-mediated
condensation reaction, 4 could not be observed in the reaction of N-methyl-1-naphthylamine (1). These
dimerization reactions of the 1-naphthylamine derivatives (1) and (3b) with FA may proceed via the
putative reactive intermediate dienoiminium ion (6).

Table 2. Formaldehyde-Mediated Dimerization of 1-Naphthylamine Derivativesa
Proposed active
R
1
R
2
intermediate
N
R
1
R
2
R
1
R
2
R
1
R
2
N
N
N
HCHO
+
3a R =R =H
1
2
6
R
2
OH
R =R =H
3b
3c
N
R
R =R =Me
1
2
R =R =H
R =R =Me
1 2
R =Ac, R =H
1 2
4a
4b
4c
5a
5b
5c
1
2
1
2
R =Ac, R =H
1
2
1
R =R =Me
1
2
R =Ac, R =H
1
2
b
Entry
R1
R2
Solvent
Temp
Time (h)
Yield (%)
4
5
i
H
H
Me
Me
Me
H
MeOH
MeOH
AcOH
AcOH
MeOH
AcOH
rt
70°C
rt
5
48
48
2
polymerized
ii
Me
Me
Me
Ac
Ac
-
-
19
50
-
iii
iv
v
17
15
-
70°C
rt
48
3
vi
H
70°C
-
-
a
b
0.3 mol/L of 3 and 10 equiv. of 35% HCHO were used. Isolated yield.
FA-mediated dimerization reactions of other aromatic amines were examined (Figure 1). Alkylation of
both N-methylaniline (7a) and N-methyl-2-naphthylamine (8a) with FA under neutral conditions
selectively proceeded onto nitrogen and gave iminal derivatives.13 Under acidic conditions (in AcOH),
7a and 8a were polymerized with FA. On the other hand, N,N-dimethylaniline (7b) and N,N’-dimethyl-
2-naphthylamine (8b) gave the corresponding dimers (9b) and (10b) in AcOH as a solvent in 82 and 45%
yields, respectively,12,14 while this dimerization reaction of 7b and 8b did not proceed under neutral
conditions.
Figure 1. Dimerized Aromatic Amines by Formaldehyde-Mediated Condensation
Me
R
N
Me
R
Me
N
Me
N
N
N
R
R
R
Me
R
N
7a: R = H
8a: R = H
7b: R = Me
8b: R = Me
9a: R = H
9b: R = Me
10a: R = H
10b: R = Me
Me

We applied this specific condensation reaction of naphthylamine for construction of macrocyclic
compounds. The FA-mediated direct alkylation and subsequent condensation of aromatic
compounds are a useful synthetic method to create macrocyclic compounds such as calix[n]arene or
porphyrin derivatives,9 and the biarylaminomethane skeleton is a basic component of cyclophanes,15
which are widely utilized as artificial organic hosts. Thus, we examined naphthylamine-type
cyclophane (naphthalenophane)16 synthesis by applying this condensation reaction to the N-alkyl-1-
naphthylamine derivatives (11a-c),15a and the results are summarized in Table 3.
Table 3. Synthesis of Naphthalenophanes via the FA-mediated Condensation
H
N
(CH )
2 n
NH
HN
HN (CH ) NH
2 n
(CH )
2 n
HCHO
11a n=4
+
n=6
11b
11c
NH
n=11
(CH )
2 n
N
H
NH
n=4
n=6
n=11
13a n=4
12a
12b
12c
n=6
n=11
13b
13c
a
Entry
n
Solvent Concentration
(mmol/L)
HCHO (eq)
Temp
Time (h)
Yield (%)
12
13
i
4
6
MeOH
1
3
1
25
80
80
rt
17
30
48
-
-
27
c
b
ii
MeCN
MeOH
60°C
3
iii
11
60°C
c
45
-
a
b
Isolated yield. Compound (11b) was hardly desolved in MeOH.
Linear dimer of 11b was obtained in 8% yield.
Reaction of 11a with FA took place to give the cyclodimerized cyclophane (13a) in 27% yield (Entry i).
Elongation of the methylene spacer from butyl to hexyl essentially blocked this cyclodimerization. Even
at a higher concentration (3 mmol/L) and with an excess of FA, 11b gave only a trace amount of the
cyclophane (13b), while the linear dimer of 11b was formed predominantly (Entry ii). This remarkable
difference of reactivity in the cyclization step is presumably due to the different conformation and/or
solubility of the linear precursor. Solubility of 11b and the cyclodimerized product (13b) in MeOH or
MeCN is very poor compared to that of 11a and 13a. In contrast to the cyclization of 11a and 11b, the

intramolecularly cyclized cyclophane (12c) was obtained in a good yield from 11c, which has a further
elongated spacer (Entry iii). This novel naphthylamine oligomer is a new variety of cyclophane, and
this new cyclophane synthetic method has potential applications in the field of supramolecular chemistry.
In summary, we found selective C-C bond formation in the reaction of N-methyl-1-naphthylamine (1)
with FA under very mild neutral conditions. This novel condensation reaction is classified as a
substrate-specific aromatic substitution reaction for N-alkyl-1-naphthylamines, such as 1 or 11.
Moreover, we succeeded in applying this novel FA-mediated dimerization reaction to naphthylamine-
derived cyclophane synthesis.
ACKNOWLEDGEMENT
The work described in this paper was partially supported by Grants-in-Aid from the Ministry of
Education, Culture, Sports, Science and Technology of Japan, and funds for the Promotion of
Fundamental Studies in Health Science from the Organization for Pharmaceutical Safety Research.
EXPERIMENTAL
The general procedure of the reaction. To 1-naphthylamine derivatives (1 or 3) in appropriate solvents
was added 35% formaldehyde solution (10 eq), and then the mixture was stirred with monitoring of the
reaction. After the usual work up, the adduct (2, 4, 5) was purified by silica gel column chromatography.
1
N,N’-Dimethyl-4-hydroxymethyl-1-naphthylamine (4b): Colorless oil; H NMR (CDCl3, 500 MHz)δ
2.89 (6H, s), 5.06 (2H, s), 7.01 (1H, d, J = 7.5 Hz), 7.40 (1H, d, J = 7.5 Hz), 7.51 (1H, t, J = 7.5 Hz), 7.54
13
(1H, t, J = 7.5 Hz), 8.13 (1H, d, J = 7.5 Hz), 8.28 (1H, d, J = 7.5 Hz); C NMR (CDCl3, 125 MHz)δ
45.23, 63.80, 113.28, 124.25, 124.79, 125.19, 125.98, 126.26, 129.06, 130.91, 132.60, 151.26;
HRFABMS. Calcd for C25H26N2 (M+): 354.2096. Found: 354.2115.

Bis-4-(1-N,N’-dimethylaminonaphthyl)methane (5b): Colorless solid, mp 103-105°C (hexanes-ethyl
acetate); 1H NMR (CDCl3, 500 MHz)δ2.87 (12H, s), 4.75 (2H, s), 6.95 (2H, d, J = 7.6 Hz), 6.98 (2H, d,
J = 7.6 Hz), 7.46 (2H, t, J = 7.5 Hz), 7.51 (2H, t, J = 7.5 Hz), 8.02 (2H, d, J = 8.0 Hz), 8.33(2H, d, J = 8.0
Hz); 13C NMR (CDCl3, 125 MHz)δ35.23, 45.41, 113.93, 124.49, 124.68, 124.99, 125.90, 126.94, 129.00,
133.34; FABMS. 354 (M)+. HRFABMS. Calcd for C27H27N2O2 (MH+): 411.2073. Found: 411.2054.
1
Bis-4-(1-N,N’-dimethylaminoanilino)methane (9b): H NMR (CDCl3, 500 MHz)δ2.89 (12H, s), 3.80
13
(2H, s), 6.88 (4H, d, J = 8.8 Hz), 7.05 (4H, d, J = 8.8 Hz); C NMR (CDCl3, 125 MHz)δ39.85, 40.93,
113.06, 129.38, 130.37, 149.02; HRFABMS. Calcd for C17H22N2 (M+): 254.1783. Found: 254.1883.
Bis-1-(2-N,N’-dimethylaminonaphthyl)methane (10b): Colorless solid, mp 100-103°C (hexanes-ethyl
acetate); 1H NMR (CDCl3, 500 MHz)δ2.18 (12H, s), 5.14 (2H, s), 7.10 (2H, t, J = 7.5 Hz), 7.14 (2H, t, J
= 7.2 Hz), 7.46 (2H, d, J = 8.9 Hz), 7.58 (2H, d, J = 8.0 Hz), 7.62 (2H, d, J = 8.9 Hz), 8.28 (2H, d, J = 8.2
Hz); 13C NMR (CDCl3, 125 MHz)δ24.88, 45.63, 119.21, 123.84, 124.85, 126.22, 127.43, 127.74, 131.21,
132.24, 134.03, 148.77; HRFABMS. Calcd for C25H26N2 (MH+): 354.2096. Found: 354.2145.
1,6,28,33-Tetraaza[6.1.6.1]paranaphthalenophane (13a): Colorless amorphous solid (gradually colored
1
green); mp 160°C< decomp (hexanes-ethyl acetate); H NMR (CDCl3, 500 MHz)δ1.83-1.95 (8H, m),
3.27~3.33 (8H, m), 4.62 (4H, s), 6.45 (4H, d, J = 8.0 Hz), 6.86 (3H, d, J = 8.0 Hz), 6.89 (1H, d, J = 8.0
Hz), 7.30-7.43 (8H, m), 7.80 (4H, d, J = 8.1 Hz), 7.98 (4H, d, J = 8.1 Hz); 13C NMR (CDCl3, 125 MHz)
δ26.40, 43.57, 49.50, 104.57, 120.30, 123.91, 124.30, 124.72, 125.63, 127.72, 132.81, 142.00;
HRFABMS. Calcd for C50H48N4 (M+): 704.3879. Found: 704.3896.
1,8,30,37-Tetraaza[8.1.8.1]paranaphthalenophane (13b): Colorless amorphous solid (gradually colored
1
green); mp 160°C< decomp (hexanes-ethyl acetate); H NMR (CDCl3, 500 MHz)δ1.55 (8H, br), 1.78
(8H, br), 3.25 (8H, t, J = 7.0 Hz), 4.63 (4H, s), 6.45 (4H, d, J = 7.8 Hz), 6.88 (4H, d, J = 7.8 Hz), 7.43

(8H, m), 7.84 (4H, m), 8.00 (4H, m); HRFABMS. Calcd for C54H56N4 (M+): 760.4505. Found: 750.4563.
1,13-Diaza[13.1]paranaphthalenophane (12c): Colorless amorphous solid (gradually colored green);
1
mp 101-103°C (hexanes-ethyl acetate); H NMR (CDCl3, 500 MHz)δ1.02-1.27 (14H, m), 1.56 (4H,
quintet, J = 7.0 Hz), 3.38 (4H, t, J = 7.0 Hz), 4.67 (2H, s), 6.55 (2H, d, J = 8.0 Hz), 6.69 (2H, d, J =
8.0 Hz), 7.40-7.48 (4H, m), 7.84 (2H, d, J = 7.8 Hz), 8.08 (2H, d, J = 8.0 Hz); 13C NMR (CDCl3, 125
MHz)δ26.23, 27.54, 28.72, 29.54, 30.19, 33.56, 43.93, 106.31, 120.55, 124.25, 124.65, 125.63,
125.97, 127.56, 133.16, 141.99; HRFABMS. Calcd for C32H38N2 (M+): 450.3035. Found: 450.3083.
REFERENCES AND NOTES
1. (a) J. Tsuji, M. Nisar, and I. Minami, Tetrahedron Lett., 1986, 27, 2483. (b) P. T. Ho, Tetrahedron
Lett., 1978, 1623.
2. (a) X. C. Wu and R. G. Anthony, J. Catal., 1999, 184, 294. (b) A. A. Moshfegf, B. Mazardarani, A.
Nahid, G. H. and Hakimelah, Helv. Chim. Acta, 1982, 65, 1229.
3. (a) D. A. Singleton and C. Hang, J. Org. Chem., 2000, 65, 895. (b) K. Maruoka, A. B. Concepcion, N.
Murase, M. Oishi, N. Hirayama, and H. Yamamoto, J. Am. Chem. Soc., 1993, 115, 3943.
4. (a) K. Ishihara, H. Nakamura, and H. Yamamoto, Synlett, 2000, 9, 1245. (b) D. R. Adams and S. P.
Bhatnagar, Synthesis, 1977, 661.
5. For reviews see, (a) M. Arend, B. Westermann, and N. Risch, Angew. Chem., Int. Ed. Engl., 1998, 37,
1044. (b) M. Tramontini and L. Angiolini, Tetrahedron, 1990, 46, 1791. (c) M. Tramontini, Synthesis,
1973, 703.
6. (a) N. Schwencke and B. Ekert, Mutat. Res., 1978, 51, 11. (b) R. J. Wilkins and H. D. MacLeod,
Mutat. Res., 1976, 36, 11. (c) Y. F. M. Chaw, L. E. Crane, P. Lange, and R. Shapiro, Biochemistry,
1980, 19, 5525. (d) H. Huang and P. B. Hopkins, J. Am. Chem. Soc., 1993, 115, 9402.
7. H. Takahashi and Y. Hashimoto, Bioorg. Med. Chem. Lett., 2001, 11, 729.
8. M. Miocque and J. M. Vierfond, Bull. Soc. Chim. Fr., 1970, 5, 1901.

9. Acid or base-catalyzed condensation of phenol or aniline derivatives is well known and widely used
for calixarene syntheses; see (a) J. L. Sessler, A. Mozaffari, and M. R. Johnson, Organic Synthesis,
John Wiley and Sons, New York 1992, Vol. 70, 68. (b) D. R. Stewart and C. D. Gutsche, J. Am. Chem.
Soc., 1999, 121, 4136. (c) V. Bohmer, Angew. Chem., Int. Ed. Engl., 1995, 34, 713.
10. For FA-mediated condensation between 2-naphthol and N-methyl-2-naphthylamine under neutral
conditions, see H. Mohrler and D. Schake, Arch. Pharm., 1992, 325, 695.
11. P. Magnus, J. Lacour, and W. Weber, Synthesis, 1998, 547.
12. G. T. Morgan, J. Chem. Soc., 1900, 814.
1
13. Identification of iminal derivatives formed from 7a and 8a was performed by H NMR (ref. 8).
These compounds are unstable on silica gel.
14. R. J. Carney, J. Am. Chem. Soc., 1912, 34, 32.
15. (a) K. Odashima, A. Itai, I. Yoichi, and K. Koga, J. Am. Chem. Soc., 1980, 102, 2504. (b) H. J.
Schneider and R. Busch, Chem. Ber., 1986, 119, 747. (c) H. J. Schneider, Angew. Chem., Int. Ed.
Engl., 1991, 30, 1417.
16. F. Vogtle and P. Neumann, Angew. Chem., Int. Ed. Engl., 1972, 11, 73.