Direct synthesis of imines from gem-dibromomethylaryl derivatives: Application to unsymmetrically substituted bipyridine frameworks

Article abstract of DOI:10.1021/jo020260u

An efficient methodology for the one-pot synthesis of imines is described starting from gem-dibromomethylaryl compounds and primary amines. The synthesis was applied to various aliphatic mono- and polyamines as well as to electron-rich anilines. The proto

Full text of DOI:10.1021/jo020260u

compounds.6 Nevertheless, this route often requires
multistep synthetic schemes for generating the aldehydes
or ketones, which may conflict with the presence of
sensitive functionalities on the molecules. In some cases,
the instability of the formyl derivatives is a major
drawback.
Dir ect Syn th esis of Im in es fr om
gem -Dibr om om eth yla r yl Der iva tives:
Ap p lica tion to Un sym m etr ica lly
Su bstitu ted Bip yr id in e F r a m ew or k s
Nicolas Weibel, Lo¨ıc J . Charbonnie`re,* and
Raymond F. Ziessel*
Examples for the preparation of an imino compound
from molecules where the aldehyde function is masked
in the form of a gem-dibromomethyl derivative appeared
to be rare and not specifically designed for preparative
purposes.7 However, in some cases, the intermediate
imino derivative is postulated to undergo an intramo-
lecular rearrangement, leading to substituted hetero-
cycles such as pyrazines,8 benzopyrazines,9 triazines,10
benzimidazoles,11 and elaborated poly-heteroaromatic
derivatives.12 As a result of our recent interest in the
design of ligands for complexation of lanthanide(III)
cations, we have been interested in the reactivity of gem-
dibromomethyl-functionalized aromatic compounds.13-15
The scope of application was investigated with dibro-
momethylbenzene and 6-bromo-5′-dibromomethyl-2,2′-
bipyridine with various primary aliphatic amines, poly-
amines, and aniline derivatives. Two of the bipyridine
derivatives (compounds 6 and 7) were subjected to a
sequence of reactions that led to the selective formation
of the secondary amine on one side and the n-butylcar-
boxylate moiety on the other side of the molecule (com-
pounds 12 and 13). Cleavage of the esters provided the
acids, which in their anionic or zwitterionic forms are
promising candidates for the complexation of lanthanide-
(III) cations and for their applications as luminescent
devices. They afford both a chromophoric bipyridine unit
for sensitization of lanthanides and an anionic carboxy-
late function able to bind tightly to the triply charged
cation.15
Laboratoire de Chimie Mole´culaire, UMR 7008 au CNRS,
Ecole de Chimie, Polyme`res et Mate´riaux (ECPM),
25 rue Becquerel, 67087 Strasbourg Cedex 02, France
ziessel@chimie.u-strasbg.fr
Received April 12, 2002
Abstr a ct: An efficient methodology for the one-pot synthe-
sis of imines is described starting from gem-dibromomethyl-
aryl compounds and primary amines. The synthesis was
applied to various aliphatic mono- and polyamines as well
as to electron-rich anilines. The protocol was extended to
6-bromo-5′-dibromomethyl-2,2′-bipyridine to afford the cor-
responding imines. With n-propyl- and n-decylamine, further
conversion, in three steps, to the corresponding 6-carboxy-
5′-alkylaminomethyl-2,2′-bipyridine derivatives was selec-
tively achieved, providing new tridentate ligands that may
find interesting applications for the complexation of lan-
thanide(III) cations in their anionic or zwitterionic form.
The synthesis of so-called Schiff bases has attracted
much attention in the field of coordination chemistry. The
presence of the lone pair on the nitrogen atom of the
imine group enables the coordination of numerous metal
cations, especially when the imine function is located at
the ortho position of the heteroaromatic cycles such as
pyridines. These molecules have recently found very
interesting applications as ligands in various homoge-
neous catalytic reactions such as hydrosilation, Mu-
kaiyama aldolization, cyclopropanation,1 homologation of
aromatic aldehydes,2 and ethylene polymerization.3 Fur-
thermore, imines are also of particular interest because
the hydrogenation of the CdN bond affords an alternative
to the synthesis of secondary amines. Although method-
ologies exist for the synthesis of imines, the easiest access
is probably the acid-catalyzed condensation of primary
amines with aldehydes or ketones.4 In particular, this
protocol has been extensively used to produce sophisti-
cated ligands such as polyazamacrocycles5 or polycatenar
The strategy depicted in Scheme 1 required the use of
a readily available gem-dibromomethyl derivative dis-
playing good stability. Dibromomethylbenzene fulfilled
these requirements and was used in a first step to adjust
the experimental conditions. This commercially available
compound was reacted with propylamine, decylamine,
triethylenetetramine, and p-anisidine under anhydrous
(6) Ziessel, R. Coord. Chem. Rev. 2001, 216-217, 195.
(7) (a) Prosyanik, A. V.; Moskalenko, A. S.; Moretti, I.; Forni, A.;
Torre, G.; Kostyanovkii, R. G. Khim. Geterosikl. Soedin. 1984, 4, 525.
(b) Moormann, A. E.; Yen, C. H.; Yu, S. Synth. Commun. 1987, 14,
1695.
(8) Sejbal, J .; Klinot, J .; Protiva, J .; Vystrcil, A. Collect. Czech. Chem.
Commun. 1986, 51, 118.
(9) Gushmann, M.; Patel, H. J . Org. Chem. 1988, 53, 5088. Pillai,
P. P.; Sanjeev, B. V. Indian J . Chem., Sect. B 1993, 32B, 1024.
(10) Haenel, F.; J ohn, R.; Seitz, G. Arch. Pharm. (Weinheim) 1992,
325, 349. Seitz, G.; J ohn, R. Chem.-Ztg. 1988, 112, 243.
(11) Pashkevich, K. I.; Skryabina, Z. E.; Saloutin, V. I. Izv. Akad.
Nauk. SSSR, Ser. Khim. 1987, 11, 2527.
(12) Mellor, J . M.; Pathirana, R. N. J . Chem. Soc., Perkin Trans. 1
1984, 753. Breining, T.; Hermecz, I.; Podanyi, B.; Sessi, J . J . Heterocycl.
Chem. 1985, 22, 1253. Zav’yalov, S. I.; Zavozin, A. G. Izv. Akad. Nauk.
SSSR, Ser. Khim. I 1986, 2, 452; Randles, D.; Taguchi, H.; Armarego,
W. L. F. Heterocycles 1993, 35, 807.
(1) Dias, E. L.; Brookhart, M.; White, P. S. Chem. Commun. 2001,
423.
(2) Dias, E. L.; Brookhart, M.; White, P. S. J . Am. Chem. Soc. 2001,
123, 2442.
(3) Small, B. L.; Brookhart, M.; Bennett, A. M. A. J . Am. Chem.
Soc. 1998, 120, 4049. Small, B. L.; Brookhart, M. J . Am. Chem. Soc.
1998, 120, 7143. Britovsek, G. J . P.; Gibson, V. C.; Kimberley, B. S.;
Maddox, P. J .; McTavish, S. J .; Solan, G. A.; White, A. J . P.; Williams,
D. J .; Bruce, M.; Mastroianni, S.; Redshaw, C.; Stro¨mberg, S. J . Am.
Chem. Soc. 1999, 121, 8728.
(4) Layer, R. W. Chem. Rev. 1963, 63, 489.
(13) Hauser, F. M.; Prasanna, S. J . Org. Soc. 1982, 47, 383.
(14) Yu, X. Y.; Hill, J . M.; Yu, G.; Yang, Y.; Kluge, A. F.; Keith, D.;
Finn, J .; Gallant, P.; Silverman, J .; Lim, A. Bioorg. Med. Chem. Lett
2001, 11, 541.
(15) Charbonnie`re, L. J .; Guardigli, M.; Cesario, M.; Roda, A.;
Sabbatini, N.; Ziessel, R. J . Am. Chem. Soc. 2001, 123, 2436.
(5) (a) Avecilla, F.; Bastida, R.; de Blas, A.; Fenton, D. E.; Macias,
A.; Rodriguez, A.; Rodriguez-Blas, T.; Garcia-Granda, S.; Corzo-Suarez,
R. J . Chem. Soc., Dalton Trans. 1997, 409. (b) Bastida, R.; de Blas, A.;
Castro, P.; Fenton, D. E.; Macias, A.; Rial, R.; Rodriguez, A.; Rodriguez-
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10.1021/jo020260u CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/02/2002
7876
J . Org. Chem. 2002, 67, 7876-7879

SCHEME 1. Gen er a l Syn th etic Meth od ology for
SCHEME 2. Gen er a l Syn th etic Meth od ology for
th e P r ep a r a tion of Im in es 1-4a
th e P r ep a r a tion of Im in es 6-9a
a
Key: (i) RNH2, CH3CN, K2CO3, 80 °C.
TABLE 1. Exp er im en ta l Con d ition s a n d Best Yield s for
th e Syn th esis of Im in es 1-4 fr om
Dibr om om eth ylben zen ea
equiv of equiv of reaction
yield
(%)
a
Key: (i) RNH2, CH3CN, K2CO3, 80 °C.
RNH2
imine
amine
K2CO3
time (h)
nC3H7NH2
1
2
3
4
5.0
3.3
1.2
0.33
1.0
0
1.0
2.4
17
30
22
65
98
69
76
87
TABLE 2. Exp er im en ta l Con d ition s a n d Best Yield s for
th e Syn th esis of Im in es 6-9 fr om
nC10H21NH2
p-MeOC6H4NH2
N(C2H4NH2)3
6-Br om o-5′-d ibr om om eth yl-2,2′-bip yr id in ea
equiv of equiv of reaction yield
a
RNH2
imine
amine
K2CO3
time (h)
(%)
In hot anhydrous acetonitrile with dry potassium carbonate.
All isolated yields are given versus dibromomethylbenzene.
nC3H7NH2
6
7
8
9
5.8
3.0
3.0
0.33
2.5
2.0
1.0
3.0
17
26
52
91
92
81
85
83
nC10H21NH2
p-MeOC6H4NH2
N(C2H4NH2)3
conditions with K2CO3 as base to quench the nascent
hydrobromic acid (Scheme 1).
a
In hot anhydrous acetonitrile with dry potassium carbonate.
All isolated yields are given versus 6-bromo-5′-dibromomethyl-2,2′-
bipyridine.
Although the use of an excess amine ensured a basic
medium, it was noticed that the absence of K2CO3
decreased the reaction rate as well as the yield, due to
the fact that an incomplete condensation took place.
Furthermore, the omission of the inorganic base lead to
subsequent purification problems involving the am-
monium salts and the excess of free base. Selected
reaction conditions and best yields are gathered in Table
1.
Compounds 1-4 were isolated in good yields, and their
spectroscopic data are identical to those obtained by
conventional condensation of aldehydes with the amines.
However, in the case of 2, the yield was much lower due
to purification difficulties inherent to the in situ forma-
tion of decylammonium salts. In the case of the tris-imino
derivative 4, an X-ray molecular structure unambigu-
ously confirmed that all three primary amine functions
had indeed reacted with dibromomethylbenzene.16 An
ORTEP view is given in the Supporting Information.
Crystalline compound 4 adopts a pseudo-C3 symmetrical
conformation in which the three strands are wrapped
around a noncrystallographic C3 axis. Interestingly, the
lone pair of the apical nitrogen atom amines points
toward the center of the cavity formed by the pendant
arms. An average CdN bond distance of 1.26 Å was
observed with a mean value of 117° for the CdN-CH2
angle. Neither hydrogen bonds nor (intra- or intermo-
lecular) stacking interactions could be evidenced from the
structure, and it remains unclear why, in the solid state,
such a conformation is preferred when compared to a
planar one.
To gain flexibility for the synthesis of the imine
compounds and to allow the use of the resulting ligands
in complexation studies with lanthanides, the same set
of primary amines was reacted under similar conditions
with 6-bromo-5′-dibromomethyl-2,2′-bipyridine 5, itself
prepared by a double radical bromination reaction of
6-bromo-5′-methyl-2,2′-bipyridine.17 The imines 6-8 and
9 were prepared with good yields (>80%) and results
from single to multiple condensations (Scheme 2). Se-
lected reaction conditions and best yields are collected
in Table 2.
To obtain tridentate chelating ligands with a 6-car-
boxylic-2,2′-bipyridine frame and an amino aliphatic
chain at the 5′ position, compounds 6 and 7 were
subjected to the following synthetic sequence of reactions
(Scheme 3). In a first step, the imine function was
reduced to the corresponding secondary amines (10 and
11) by treatment with NaBH4 in hot ethanol. A quite
selective carboalkoxylation protocol18 was then applied
in which the amines were reacted with bubbling CO in a
Et3N/nBuOH mixture, using 5% [Pd(PPh3)2Cl2] as a
(16) Crystallographic data (0.10 × 0.10 × 0.08 mm): C27H30N4, M
) 410.57, T ) 173 K, monoclinic, space group 2/c, a ) 29.3303(2) Å, b
) 9.5854(5) Å, c ) 17.1277(5) Å, â ) 99.116(5)°, V ) 4754.5(3) Å3, Dcalc
) 1.15 g‚cm-3, Z ) 8, F(000) ) 1760, µ(Mo KR)) 0.069 mm-1, 15 347
data collected, 1698 with I > 3σ(I), R1 ) 0.038, Rw ) 0.041. GOF )
1.035.
(17) Charbonnie`re, L. J .; Weibel, N.; Ziessel, R. F. Synthesis 2002,
1101.
(18) El Ghayoury, A.; Ziessel, R. J . Org. Chem. 2000, 65, 7557.
J . Org. Chem, Vol. 67, No. 22, 2002 7877

SCHEME 3a
standardized. Thin Layer Chromatography (TLC) were per-
formed on silica gel or aluminum oxide plates coated with
fluorescent indicator. Deactivated plates are previously treated
with 90:10 CH2Cl2-Et3N. All mixtures of solvents are given in
v/v ratio. Details for the X-ray crystal structure determination
for compound 4 are given in ref 16.
Ma ter ia ls. CH2Cl2 was distilled from CaH2. THF was dried
over Na/benzophenone prior to distillation. CH3CN was filtered
over aluminum oxide and distilled over P2O5. [Pd(PPh3)2Cl2] was
recrystallized from hot DMSO. Et3N and EtOH were used as
purchased. Analytical and spectroscopic data for compounds 1,20
2,21 3,22 and 423 are in agreement with literature data.
[(6-Br om o-2,2′-bipyr idin -5′-yl)m eth ylen e]pr opylam in e (6).
A Schlenk tube under argon was successively charged with 5
(230 mg, 0.6 mmol), n-propylamine (272 µL, 3.3 mmol), and
anhydrous K2CO3 (195 mg, 1.4 mmol) in 10 mL of dry acetoni-
trile. The suspension was heated at 80 °C during 17 h. The
mixture was evaporated to dryness, 50 mL of CH2Cl2 and 15
mL of water were added, and the organic phase was separated.
The aqueous phase was extracted twice with 50 mL of CH2Cl2,
and the combined organic layers were dried over Na2SO4,
filtered, and evaporated to dryness. The residue was recrystal-
lized with CH2Cl2/hexane to afford 6 (158 mg, 92%) as a yellow
powder: mp 99-100 °C; Rf ) 0.43 (Al2O3, CH2Cl2); 1H NMR
(CDCl3) δ 0.97 (t, 3H, 3J ) 7.5 Hz), 1.75 (sx, 2H, 3J ) 7.5 Hz),
3.63 (td, 2H, 3J ) 7.0 Hz, 4J ) 1.0 Hz), 7.49 (dd, 1H, 3J ) 8.0
Hz, 4J ) 1.0 Hz), 7.67 (t, 1H, 3J ) 7.5 Hz), 8.20 (dd, 1H, 3J )
8.0 Hz, J ) 2.0 Hz), 8.35 (s, 1H), 8.41 (dd, 1H, J ) 7.5 Hz, J
) 0.5 Hz), 8.45 (d, 1H, 3J ) 8.0 Hz), 8.88 (d, 1H, 4J ) 1.5 Hz);
13C NMR (CDCl3) δ 11.9, 24.0, 63.9, 120.1, 121.3, 128.3, 132.2,
135.5, 137.1, 139.2, 141.7, 149.6, 155.8, 157.7; IR (KBr, cm-1) ν
2959, 2919, 1642, 1583, 1545, 1431, 1123; FAB+-MS m/ z 306.1
(99), 304.1 (100). Anal. Calcd for C14H14N3Br: C, 55.28; H, 4.64;
N, 13.81. Found: C, 55.02; H, 4.49; N, 13.78.
a
Key: (i) NaBH4, EtOH, 80 °C, 70% for 10, 84% for 11; (ii)
nBuOH, Et3N, CO (1 atm), [Pd(PPh3)2Cl2] 5 mol %, 100 °C, 40 %
for 12, 30% for 13; (iii) 10% aq HCl, 63% for 14, 59% for 15.
catalyst. Esters 12 and 13 were obtained in modest yields
when compared to more conventional bromoaromatic
substrates and the yields were even lower if ethanol was
used. The boiling point of n-butanol allowed one to heat
the reaction mixture higher, thus pointing to a thermo-
dynamic barrier for formation of the esters. Interestingly,
a carboamidation reaction19 in which the secondary
amine function would play the role of the nucleophile in
place of the alcohol was not observed, because the alcohol
is in large excess. Finally, the esters were hydrolyzed to
the corresponding acids 14 and 15 by treatment with
diluted HCl.
In summary, we have developed a methodology for the
direct synthesis of imines from gem-dibromomethylaryl
or heteroaryl compounds and primary amines. The di-
bromomethylbenzene was chosen as a test compound,
and the isolated yields are good to excellent and ap-
plicable to a few primary amines. This methodology was
extended to the synthesis of 6-carboxy-2,2′-bipyridine acid
substituted at the 5′ position by alkylaminomethylene
groups. This synthetic protocol appears as a suitable
alternative for the synthesis of imines, as well as for the
easy conversion of primary amines into secondary ben-
zylamines after reduction of the imine. Because of these
notable characteristics of the reaction, one can also
envisage to use these gem-dibromo-substituted deriva-
tives in Wittig-type reactions. Further efforts are cur-
rently directed toward the enlargement of the scope of
the reaction toward phosphorus ylides and related di-
bromomethyl compounds on one hand and the use of the
6-carboxy-2,2′-bipyridine acid derivatives for complex-
ation of lanthanide(III) cations on the other hand.
4
3
4
[(6-Br om o-2,2′-bipyr idin -5′-yl)m eth ylen e]decylam in e (7).
The same procedure as for the synthesis of 6 was used starting
from 5 (200 mg, 0.5 mmol), decylamine (300 µL, 1.5 mmol), and
anhydrous K2CO3 (135 mg, 1.0 mmol) in 5 mL of dry acetonitrile.
The suspension was heated to 80 °C during 26 h. The residue
was recrystallized with Et2O to afford 7 (160 mg, 81%) as a white
powder: mp 84-85 °C; Rf ) 0.71 (deactivated SiO2, 98:2 CH2-
1
3
Cl2-MeOH); H NMR (CDCl3) δ 0.87 (t, 3H, J ) 6.5 Hz), 1.26
(m, 14H), 1.60-1.81 (m, 2H), 3.65 (t, 2H, 3J ) 6.5 Hz), 7.49 (dd,
1H, 3J ) 7.5 Hz, 4J ) 0.5 Hz), 7.67 (t, 1H, 3J ) 7.5 Hz), 8.20
3
4
3
(dd, 1H, J ) 8.5 Hz, J ) 2.0 Hz), 8.35 (s, 1H), 8.41 (dd, 1H, J
) 7.5 Hz, 4J ) 0.5 Hz), 8.45 (d, 1H, 3J ) 7.5 Hz), 8.88 (d, 1H, 4J
) 1.5 Hz); 13C NMR (CDCl3) δ 14.1, 22.7, 27.4, 29.3, 29.4, 29.6,
30.8, 31.9, 62.2, 120.1, 121.4, 128.3, 132.2, 135.5, 139.2, 141.7,
149.6, 155.8, 156.8, 157.6; IR (KBr, cm-1) ν 2921, 2852, 1640,
1584, 1541, 1432, 1122; FAB+-MS m/z (%) 404.2 (100), 402.2 (80),
199.2 (25). Anal. Calcd for C21H28N3Br: C, 62.69; H, 7.01; N,
10.44. Found: C, 62.53; H, 6.98; N, 10.38.
[(6-Br om o-2,2′-b ip yr id in -5′-yl)m et h ylen e]-4-m et h oxy-
a n ilin e (8). The same procedure as for the synthesis of 6 was
used starting from 5 (200 mg, 0.5 mmol), p-anisidine (190 mg,
1.5 mmol), and K2CO3 (70 mg, 0.5 mmol) in 5 mL of dry
acetonitrile. The solution was heated to 80 °C for 52 h. Recrys-
tallization with CH2Cl2/hexane afforded 8 (154 mg, 85%) as pale
green crystals: mp 195-198 °C; Rf ) 0.56 (SiO2, 97:3 CH2Cl2-
MeOH); 1H NMR (CDCl3) δ 3.85 (s, 3H), 6.96 (d, 2H, 3J ) 9.0
3
3
Hz), 7.30 (d, 2H, J ) 9.0 Hz), 7.52 (d, 1H, J ) 7.5 Hz), 7.70 (t,
1H, 3J ) 7.5 Hz), 8.38 (dd, 1H, 3J ) 8.5 Hz, 4J ) 2.0 Hz), 8.45
(d, 1H, 3J ) 7.5 Hz), 8.50 (s, 1H), 8.56 (d, 1H, 3J ) 8.0 Hz), 9.03
(d, 1H, 4J ) 2.0 Hz); 13C NMR (CDCl3) δ 55.5, 114.5, 120.3, 121.5,
122.5, 128.4, 132.5, 135.7, 139.3, 141.8, 144.2, 150.2, 154.5, 156.1,
Exp er im en ta l Section
Gen er a l Meth od s. The 200.1 (1H) and 50.3 MHz (13C) NMR
spectra were recorded at room temperature using perdeuterated
solvents as internal standard: δ (H) in ppm relative to residual
protiated solvent; δ (C) in ppm relative to the solvent. FT-IR
spectra were recorded as KBr pellets. Melting points were
obtained on a capillary melting point apparatus in open-ended
capillaries and are uncorrected. Chromatographic purification
was conducted using 40-63 µm silica gel or aluminum oxide 90
(20) (a) Wuerthwein, E. U.; Halim, H.; Schwarz, H.; Nibbering, N.
M. M. Chem. Ber. 1982, 7, 2626. (b) Hayes, J . F.; Hayler, J . D.;
Walsgrove, T. C.; Wicks, C. J . Heterocycl. Chem. 1996, 1, 209. (c) Texier-
Boullet, F. Synthesis 1985, 679-681.
(21) Vercruysse, K.; Dejugnat, C.; Munoz, A.; Etemad-Moghadam,
G. Eur. J . Org. Chem. 2000, 2, 281.
(22) (a) Tanaka, M.; Kobayashi, T. Synthesis 1985, 967-969. (b)
Olah, G. A.; Donovan, D. J . J . Org. Chem. 1978, 5, 860-865.
(23) Baeg, J .-O.; Holm, R. H. Chem. Commun. 1998, 571.
(19) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J . Org. Chem. 1974,
39, 3318; Schoenberg, A.; Heck, R. F. J . Org. Chem. 1974, 39, 3327.
7878 J . Org. Chem., Vol. 67, No. 22, 2002

4
156.7, 158.9; IR (KBr, cm-1) ν 2956, 2833, 1619, 1505, 1432,
1123; FAB+-MS m/ z 370.2 (100), 368.2 (100), 249.2 (20), 247.2
(20). Anal. Calcd for C18H14N3OBr: C, 58.71; H, 3.83; N, 11.41.
Found: C, 58.45; H, 3.63; N, 11.30.
) 8.0 Hz, J ) 2.0 Hz), 8.25-8.45 (m, 2H), 8.87 (s, br, 1H); 13C
NMR (CDCl3) δ 11.3, 13.7, 19.1, 20.4, 30.6, 49.0, 49.8, 65.9, 121.6,
124.5, 125.1, 129.3, 138.1, 139.2, 147.6, 150.8, 155.0, 155.5, 165.3;
IR (KBr, cm-1) ν 3438, 2926, 1738, 1640, 1589, 1457, 1141,
1077; FAB+-MS m/z 328.2 (100), 254.2 (30). Anal. Calcd for
19H25N3O2: C, 69.70; H, 7.70; N, 12.83. Found: C, 69.51; H,
7.39; N, 12.69.
N-[(6-Br om o-2,2′-bip yr id in -5′-yl)m eth ylen e]-N′,N′-bis-[2-
[(6-b r om o-2,2′-b ip yr id in -5′-yl)m e t h yle n e a m in o]e t h yl]-
eth a n e-1,2-d ia m in e (9). The same procedure as for the syn-
thesis of 6 was used starting from 5 (325 mg, 0.80 mmol),
triethylenetetramine (40 µL, 0.27 mmol), and K2CO3 (331 mg,
2.4 mmol) in 10 mL of dry acetonitrile. The solution was heated
to 80 °C for 91 h. Recrystallization from hexane afforded 9 (195
mg, 83%) as a yellow powder: mp 170-171 °C; Rf ) 0.55 (Al2O3,
CH2Cl2); 1H NMR (CDCl3) δ 2.99 (t, 6H, 3J ) 6.0 Hz), 3.77 (t,
6H, 3J ) 6.0 Hz), 7.48 (dd, 3H, 3J ) 7.5 Hz, 4J ) 0.5 Hz), 7.65
(t, 3H, 3J ) 8.0 Hz), 8.00 (dd, 3H, 3J ) 8.0 Hz, 4J ) 2.0 Hz),
8.25 (s, 3H), 8.32 (s, 3H), 8.36 (s, 3H), 8.75 (d, 3H, 4J ) 1.5 Hz);
13C NMR (CDCl3) δ 55.2, 60.3, 120.2, 121.3, 128.3, 131.9, 135.5,
138.6, 139.2, 141.7, 149.4, 156.7, 158.8; IR (KBr, cm-1) ν 2919,
2831, 1644, 1543, 1431, 1126; FAB+-MS m/z 883.3 (100), 881.3
(92), 662.5 (35). Anal. Calcd for C39H33N10Br3: C, 53.10; H, 3.77;
N, 15.90. Found: C, 52.64; H, 3.42; N, 15.62.
[(6-Br om o-2,2′-bip yr id in -5′-yl)m eth yl]p r op yla m in e (10).
In a Schlenk tube under argon were dissolved 6 (117 mg, 0.4
mmol) and NaBH4 (73 mg, 1.9 mmol) in 10 mL of ethanol. The
solution was heated to 65 °C for 18 h. A few drops of water were
carefully added, and the mixture was evaporated to dryness. The
compound was extracted with CH2Cl2 and the resulting solution
dried with MgSO4, filtered, and evaporated to dryness. Com-
pound 10 (82 mg, 70%) was isolated as a greenish solid: mp
31-32 °C; Rf ) 0.44 (deactivated SiO2, 97:3 CH2Cl2-MeOH);
C
[(6-Car bu toxy-2,2′-bipyr idin -5′-yl)m eth yl]decylam in e (13).
A solution of 11 (156 mg, 0.4 mmol) and [Pd(PPh3)2Cl2] (16 mg,
23 µmol) in a mixture of 12 mL of nBuOH and 8 mL of Et3N was
heated at 100 °C for 15 h under a CO atmosphere. The solution
was cooled to rt and filtered over Celite. The solvents were
distilled under reduced pressure, and the resulting solid was
purified by flash column chromatography (SiO2, 100:0-97:3 CH2-
Cl2-MeOH) to give 13 (50 mg, 30%) as a beige solid: mp 40-41
°C; Rf ) 0.60 (deactivated SiO2, 97:3 CH2Cl2-MeOH); 1H NMR
(CDCl3) δ 0.84 (t, 3H, 3J ) 6.5 Hz), 0.98 (t, 3H, 3J ) 7.5 Hz),
1.21 (m, 14H), 1.39-1.70 (m, 4H), 1.72-1.89 (m, 2H), 2.73 (t,
2H, J ) 7.5 Hz), 3.97 (s, 2H), 4.41 (t, 2H, J ) 6.5 Hz), 7.91 (t,
1H, 3J ) 8.0 Hz), 7.95 (dd, 1H, 3J ) 8.0 Hz, 4J ) 2.5 Hz), 8.07
(dd, 1H, 3J ) 8.0 Hz, 4J ) 1.0 Hz), 8.44 (d, 1H, 3J ) 7.5 Hz),
8.51 (dd, 1H, 3J ) 7.5 Hz, 4J ) 1.0 Hz), 8.69 (d, 1H, 4J ) 2.0
Hz); 13C NMR (CDCl3) δ 13.7, 14.1, 19.2, 22.6, 27.1, 28.8, 29.2,
29.3, 29.5, 30.7, 31.8, 48.8, 50.2, 121.4, 124.1, 124.8, 133.6, 137.7,
137.8, 147.7, 149.7, 154.5, 156.0, 165.3; IR (KBr, cm-1) ν 3439,
2927, 1739, 1641, 1588, 1466, 1157, 1087; FAB+-MS m/z 426.2
(100), 368.2 (20). Anal. Calcd for C26H39N3O2: C, 73.37; H, 9.24;
N, 9.87. Found: C, 73.00; H, 8.99; N, 9.64.
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3
[(6-Ca r boxy-2,2′-bip yr id in -5′-yl)m eth yl]p r op yla m m on i-
u m Ch lor id e (14). A solution of 12 (69 mg, 0.2 mmol) in 1 mL
of concentrated HCl (37%) and 9 mL of water was heated to 70
°C for 2 h. The mixture was evaporated to dryness, and
recrystallization of the residue with a mixture of MeOH/Et2O
afforded 14 (43 mg, 63%) as a white powder: mp >230 °C dec;
3
3
1H NMR (CDCl3) δ 0.90 (t, 3H, J ) 7.5 Hz), 1.51 (sx, 2H, J )
3
3
7.5 Hz), 2.58 (t, 2H, J ) 7.0 Hz), 3.82 (s, 2H), 7.43 (dd, 1H, J
) 8.0 Hz, 4J ) 1.0 Hz), 7.62 (t, 1H, 3J ) 8.0 Hz), 7.76 (dd, 1H,
3J ) 8.0 Hz, J ) 2.0 Hz), 8.30 (s, 1H), 8.34 (s, 1H), 8.57 (d, 1H,
4
4J ) 2.0 Hz); 13C NMR (CDCl3) δ 11.6, 23.0, 50.9, 51.2, 119.4,
121.0, 127.6, 135.3, 136.6, 139.0, 141.4, 149.0, 153.1, 157.2; IR
(KBr, cm-1) ν 3433, 2946, 1647, 1569, 1544, 1430, 1123; FAB+-
MS m/ z 308.2 (100), 306.2 (100), 249.5 (26), 247.5 (30). Anal.
Calcd for C14H16N3Br: C, 54.92; H, 5.27; N, 13.72. Found: C,
54.76; H, 4.96; N, 13.53.
1H NMR (CD3OD) δ 1.07 (t, 3H, J ) 7.5 Hz), 1.83 (sx, 2H, J )
7.5 Hz), 3.17 (t, 2H, 3J ) 7.5 Hz), 4.58 (s, 2H), 8.28-8.47 (m,
2H), 8.72 (dd, 1H, 3J ) 7.5 Hz, 4J ) 1.5 Hz), 8.84-9.02 (m, 2H),
9.28 (s, br, 1H); 13C NMR (CDCl3) δ 11.3, 20.8, 48.3, 51.0, 125.7,
127.2, 129.1, 133.1, 141.8, 146.1, 148.7, 149.2, 149.6, 150.4, 167.4;
IR (KBr, cm-1) ν 3448, 2969, 2768, 1749, 1635, 1465, 1263, 1188;
FAB+-MS m/ z 272.5 (80). Anal. Calcd for C15H18N3O2Cl‚H2O:
C, 55.30; H, 6.19; N, 12.90. Found: C, 55.25; H, 6.01; N, 12.75.
[(6-Ca r b oxy-2,2′-b ip yr id in -5′-yl)m et h yl]d ecyla m m on i-
u m Ch lor id e (15). A solution of 13 (24 mg, 56 µmol) in 1 mL of
concentrated HCl (37%) and 4 mL of water was heated to 70 °C
for 3 h. The mixture was evaporated to dryness, and recrystal-
lization of the residue with a mixture of MeOH/Et2O afforded
15 (14 mg, 59%) as a white powder: mp >185 °C dec;1H NMR
(CD3OD) δ 0.89 (t, 3H, 3J ) 6.5 Hz), 1.29 (m, 14H), 1.71-1.91
(m, br, 2H), 3.21 (t, 2H, 3J ) 8.0 Hz), 4.59 (s, 2H), 8.26-8.46
3
3
[(6-Br om o-2,2′-bip yr id in -5′-yl)m et h yl]d ecyla m in e (11).
The same procedure as for synthesis of 10 was used starting
from 7 (130 mg, 0.3 mmol) and NaBH4 (61 mg, 1.6 mmol) in 10
mL of ethanol. Compound 11 (110 mg, 84%) was isolated as a
pale yellow powder: mp 59-60 °C; Rf ) 0.54 (deactivated SiO2,
1
98:2 CH2Cl2-MeOH); H NMR (CDCl3) δ 0.84 (t, 3H, 3J ) 6.5
Hz), 1.22 (m, 14H), 1.47 (t, 2H, 3J ) 6.5 Hz), 2.59 (t, 2H, 3J )
7.0 Hz), 3.81 (s, 2H), 7.42 (dd, 1H, 3J ) 8.0 Hz, 4J ) 1.0 Hz),
7.61 (t, 1H, 3J ) 7.5 Hz), 7.75 (dd, 1H, 3J ) 8.0 Hz, 4J ) 2.0
Hz), 8.30 (d, 1H, 4J ) 0.5 Hz), 8.34 (d, 1H, 4J ) 0.5 Hz), 8.56 (d,
1H, 4J ) 1.5 Hz); 13C NMR (CDCl3) δ 14.1, 22.6, 27.3, 29.2, 29.5,
30.0, 31.8, 49.4, 51.1, 119.5, 121.1, 127.7, 136.6, 136.7, 139.1,
141.5, 149.0, 153.2, 157.3; IR (KBr, cm-1) ν 3440, 2923, 1620,
1568, 1543, 1431, 1384, 1122; FAB+-MS m/z 406.2 (100), 404.3
(100), 264.2 (30), 262.3 (30). Anal. Calcd for C21H30N3Br: C,
62.37; H, 7.48; N, 10.39. Found: C, 62.09; H, 7.26; N, 10.15.
[(6-Ca r bu toxy-2,2′-bip yr id in -5′-yl)m eth yl]p r op yla m in e
(12). A solution of 10 (191 mg, 0.6 mmol) and [Pd(PPh3)2Cl2]
(26 mg, 37 µmol) in a mixture of 15 mL of nBuOH and 10 mL of
Et3N was heated at 100 °C for 19 h, under a continuous flow of
CO at atmospheric pressure. After the solution was cooled to
rt, the solvents were distillated under reduced pressure, and the
resulting solid was purified by flash column chromatography
(SiO2, 100:0-95:5 CH2Cl2-MeOH) to give compound 12 (82 mg,
40%) as a yellowish gum: Rf ) 0.63 (deactivated SiO2, 95:5 CH2-
Cl2-MeOH);1H NMR (CDCl3) δ 0.93 (t, 3H, 3J ) 7.5 Hz), 0.92
(t, 3H, 3J ) 7.5 Hz), 1.33-1.58 (m, 2H), 1.66-1.91 (m, 4H), 2.95
3
4
(m, 2H), 8.72 (dd, 1H, J ) 7.0 Hz, J ) 1.5 Hz), 8.86-9.03 (m,
2H), 9.31 (s, 1H); 13C NMR (CD3OD) δ 14.4, 23.7, 27.4, 27.6, 30.2,
30.4, 30.5, 30.6, 33.0, 48.2, 49.6, 125.7, 127.1, 129.0, 133.1, 141.8,
146.1, 148.7, 149.2, 149.6, 150.4, 167.4; IR (KBr, cm-1) ν 3441,
2923, 2775, 1700, 1636, 1466, 1257; FAB+-MS m/z 370.4 (70).
Anal. Calcd for C22H32N3O2Cl‚H2O: C 62.32, H 8.08, N 9.91.
Found: C 62.19, H 7.88, N 9.72.
Ack n ow led gm en t. This work was supported by the
Centre National de la Recherche Scientifique and
Engineer School of Chemistry of Strasbourg, ECPM,
France.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for compounds 1-4, crystallographic data for compound
4, and an ORTEP view. This material is available free of
charge via the Internet at http://pubs.acs.org.
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(t, 2H, J ) 7.5 Hz), 4.20 (s, 2H), 4.39 (t, 2H, J ) 6.5 Hz), 7.90
3
3
3
(t, 1H, J ) 7.5 Hz), 8.05 (d, 1H, J ) 7.5 Hz), 8.15 (dd, 1H, J
J O020260U
J . Org. Chem, Vol. 67, No. 22, 2002 7879