Nucleophilic addition of organolithium reagents to cyanine dyes. A new access to functionalized hexatrienes

Article abstract of DOI:10.1016/S0040-4039(01)01672-0

The possibility for extending a pentamethine carbon chain by the use of an appropriate pair of electrophilic substrates, a cyanine dye- and nucleophilic-organolithium reagent is explored. A new synthetic approach to differently functionalized hexatrienes

Full text of DOI:10.1016/S0040-4039(01)01672-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7945–7948
Nucleophilic addition of organolithium reagents to cyanine dyes.
A new access to functionalized hexatrienes
Lilia Viteva,a Tzveta Gospodova,a Yuri Stefanovski,a Marie-Rose Mazie`resb and Jean Ge´rard Wolfb,*
aInstitute of Organic Chemistry, Bulgarian Academy of Sciences, Sofia 1113, Bulgaria
bUniversite´ Paul Sabatier, Synthe`se et Physicochimie de Mole´cules d’Inte´reˆt Biologique, UMR 5068,
F-31062 Toulouse cedex 4, France
Received 27 July 2001; accepted 6 September 2001
Abstract—The possibility for extending a pentamethine carbon chain by the use of an appropriate pair of electrophilic substrates,
a cyanine dye- and nucleophilic-organolithium reagent is explored. A new synthetic approach to differently functionalized
hexatrienes was achieved as a result of spontaneous or accelerated on silica gel surface Hofmann type elimination of the initially
formed adducts. A series of trifunctional ligands were obtained by means of a two-step reduction with Pd/C and LAH. © 2001
Elsevier Science Ltd. All rights reserved.
While the reactivity of polymethine dyes towards nucleo-
philes has been a subject of numerous studies,1 the data
concerning organometallic reagents as specific nucleo-
philes are isolated. The synthesis2 and the reactivity of
the cyanine dyes is of our current interest due to the
versatility of their design for specific purposes in non
linear optics3 or biological applications.4 In general, the
reactivity is determined by a relative thermodynamic
stability of the polymethine system and hence, tendency
towards regeneration after the reaction.1 The second
important factor is the charge alternation, thus even-num-
bered carbon atoms of the cyanine chain being negatively
charged and odd-numbered ones positively charged.
Recently we investigated the reaction of pentamethine-
cyanine dyes and hemicarboxonium salts substituted by
terminal aromatic groups with ‘soft’ metal reagents, i.e.
lithiated phenylacetic acid derivatives.5 The nucleophilic
attack was found to occur regioselectively on the central
C3 carbon atom due either to steric control imposed by
the aromatic substituents or better acid–base fit according
to the Pearson’s theory. A deeper understanding of the
factors controlling the regioselectivity of the addition of
organometallic reagents to cyanine dyes is of major
importance since it implies the possibility of deliberately
ramify or lengthen the cyanine chain by an appropriate
choice of the electrophile/nucleophile partners.
To rationalize this regioselectivity, herein we present a
study of the behavior of model pentamethinecyanines in
which the steric hindrance for C1/C5 attack is avoided,
towards ‘hard’ (acetic acid derivatives) and ‘soft’ (benzyl
cyanide) metal reagents.6
The model pentamethine cyanines II were obtained from
the corresponding all-trans-5-amino-2,4-pentadienals I7
following the Scheme 1.
Scheme 1.
Keywords: cyanine dyes; carbanions; iminium salts; Hofmann’s elimination; hexatrienes.
* Corresponding author. Fax: +(33) 05 61 55 82 45; e-mail: wolf@chimie.ups-tlse
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01672-0

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L. Vite6a et al. / Tetrahedron Letters 42 (2001) 7945–7948
to the terminal C1/C5 carbon atoms, followed by a
spontaneous Hofmann type elimination of the morpho-
line moiety.
The reaction was investigated in the temperature range
−40° to +25°C (Scheme 2). The introduction of the
pentamethinium salt to the clear solution of the corre-
sponding lithium reagent resulted in the immediate
disappearance of the deep red-brownish color of the
pentamethinium dye. Simultaneous TLC analysis of the
reaction mixture on silica gel (CH2Cl2/MeOH=9/1)
showed a quantitative consumption of the cyanine dye
and the appearance of a new yellow spot. After warm-
ing to room temperature, the reaction mixture turned
back to deeply colored. The rapidity of this process
depended on the particular nucleophile used. For exam-
ple with the lithium reagent of benzyl cyanide, the
process of coloration started immediately after removal
of the refrigerating bath, while in the other cases the
solution remained clear for several hours at room
temperature.
This finding drew our attention to the yellow spots
always observed in the course of TLC monitoring of
the reaction. It seemed now, that these yellow products
resulted from analogous Hofmann’s elimination reac-
tion. Since IIIa–c are stable enough in solution (as
1
proved by conversion to V or repeated recording of H
NMR spectra during several days) obviously in these
cases the process is accelerated on the silica gel surface.
The retarded elimination in comparison with IIId is
probably due to the less acidic character of the C2
hydrogen. Having in mind the above considerations, we
turned our efforts to the isolation of the yellow prod-
ucts by means of a short-way column chromatography.
Actually, flash chromatography of the crude reaction
mixtures III afforded new differently functionalized
hexatrienes IVa, IVc and IVd in fair yields. Only in the
case of IVb, although the elimination occurs (following
the MS-data), no pure product was isolated.
A detailed analysis of the crude reaction mixtures by a
series of 1H, 13C, DEPT, 1H/13C correlation, and COSY
experiments proved unambiguously that the ‘hard’
lithium reagents (acetic acid derivatives) added quanti-
tatively and with a complete regioselectivity to the
terminal C1/C5 carbon atoms, thus furnishing adducts
III with lengthened and functionalized carbon chain.
Additional evidence was provided by the conversion of
III to V in high yields by means of catalytic reduction
with Pd/C (Scheme 3).
The stereochemistry of the newly formed double bond
seems to depend on the steric bulk of the nucleophile
used. Thus, in the case of more sterically demanding
benzyl cyanide and tert-butyl acetate the elimination
occurs stereospecifically, while in the case of acetonitrile
cis/trans isomers in 1:1 ratios were formed. The
observed C1/C5 regioselectivity of the addition of the
‘hard’ lithium reagents (acetic acid derivatives) could be
explained with the combined effect of both electronic
(acid-base fit) and steric factors. In the case of the ‘soft’
lithium reagent (benzyl cyanide) the steric effect seems
In the case of the lithium reagent of benzyl cyanide the
spectra of the crude III were too complicated. It was
identified only by the result of the reduction step. The
product thus obtained was found to have structure VII,
obviously resulting from addition of the ‘soft’ metallate
Scheme 2.
Scheme 3.

L. Vite6a et al. / Tetrahedron Letters 42 (2001) 7945–7948
7947
to be of crucial importance, as far as in this case the
partial charge difference between C3 and C1/C5 car-
bon atoms is weaker (0.120 versus 0.135 in the case
of morpholine-dye and 0.118 versus 0.144 in the case
of diethylamino-dye) than in the case of substituted
chains (0.125/0.250). (Hyperchem 5.01 (1997) charge
distribution calculated after semi-empirical geometry
optimization of either diethylamino or di-morpholino
derivatives by AM1 Hamiltonian.)
reflux for 2 h. The evaporation of the solvent in vac-
uum gave a dark red-brownish oil. TLC and 1H
NMR analysis of the crude products showed some
impurities, the main of which was the quaternary salt
between the starting amine and the trifluoromethane-
sulfonic acid. Analytically pure cyanine dyes were
obtained after two-fold washing with small portions
of water of the methylene chloride solution of II or
by column chromatography on silica, CH2Cl2/MeOH
(80/20), in the case of II%.
As mentioned before, catalytic reduction of III with
5% Pd/C in dry ethanol resulted with high yields in
stable trifunctional ligand V with lengthened carbon
chain. Additional derivatization was achieved by
means of a second reduction step of V with LAH
(Scheme 3).
1.2. Metallation
The lithium reagents were prepared by the use of
LDA at −40°C. In the case of N,N-dimethylacetamide
the metallation was performed at 0°C. Thus, to 1.1
mmol of LDA, prepared in 2 ml of dry ether (with-
out elimination of hexane), 1 mmol of the corre-
sponding CH-acid dissolved in 2 ml of the same
solvent was added dropwise at the desired tempera-
ture and the reaction mixture was kept stirring for 30
min.
In conclusion the present study contributes to the
understanding of the regioselectivity of addition of
organometallic reagents to cyanine dyes. It seems to
be a function of a subtle balance between the elec-
tronic and steric factors with the predominance of the
latter in the case of bulky reagents. Our results out-
line, in general, the possibility for extending or for
ramifying of the carbon chain by the use of an
appropriate pair of electrophilic substrate, a cyanine
dye- and nucleophilic-organolithium reagent. This new
synthetic approach to differently functionalized hexa-
trienes, key compounds to numerous natural prod-
ucts,8 was achieved as a result of spontaneous or
accelerated on silica gel surface Hofmann type elimi-
nation of the initially formed adducts. A series of
trifunctional ligands were obtained by means of two-
step reduction with Pd/C and LAH.
1.3. Synthesis of III and IV
To 1.2 mmol of the stirred ethereal solution of the
lithium metallate 1 mmol of the corresponding cya-
nine salt, dissolved in 4 ml of dry acetonitrile, was
added at −40°C. After 30 min, the reaction mixture
was allowed to warm to room temperature and the
stirring was continued for 1 h. After evaporation of
the solvent in vacuum with precaution against mois-
ture, the samples for NMR investigations were pre-
pared by the use of CD3CN, dried over molecular
,
sieves 3 A.
1.4. Catalytic reduction of III and IV to V and VI
1. General experimental procedures
After the obtaining of III (IV) the solvents were
removed under vacuum. The residue was dissolved in
dry ethanol (10 ml for 1 mmol of the starting adduct)
and then transferred under argon in a two-necked
round-bottomed flask supplied with stirring bar. The
catalyst (5% Pd/C, 400 mg for 1 mmol of III or IV)
was introduced and the flask was connected with the
system for hydrogenation. The reduction was carried
out under atmospheric pressure at room temperature
and the process was monitored by TLC. The reaction
was completed in 5 h. The catalyst was removed by
filtration and carefully washed with ethanol. After
ethanol removal under vacuum the pure V(VI) were
obtained by means of column chromatography (meth-
ylene chloride/ methanol=95/5).
The reactions were performed under a dry argon
atmosphere. Acetonitrile was dried, distilled and kept
over molecular sieves. Diethyl ether was kept over
sodium and treated with LiAlH4 before use. Merck–
Schuchardt 15% BuLi (in hexane) was used in the
lithiation of diisopropylamine (preparation of LDA).
The 1H and 13C NMR spectra were recorded on a
Bruker 250 MHz spectrometer with TMS as the inter-
nal standard and CDCl3 or CD3CN as the solvent.
The latter was specially dried over molecular sieves.
Column chromatography was performed on silica gel
60 Merck (0.040–0.063 mm).
1.1. Synthesis of symmetrical cyanine dyes II and II%
To a mixture of 10 mmol of the starting aldehyde
and 15 mmol of the corresponding amine (1.5 equiv.),
dissolved in 5 ml of dry ethanol, 15 mmol (1.5
equiv.) of trifluoromethanesulfonic acid was added
drop wise at room temperature under vigorous stir-
ring. The addition resulted in highly exothermic reac-
tion, and the appearance of a deep red-brownish
color of the solution was observed. After the addition
was completed, the reaction mixture was boiled under
1.5. Reduction of V to VII
To an ethereal suspension of 2 mmol LAH in 6 ml of
dry ether, cooled to −78°C, a solution of 1 mmol of
V in 4 ml ether was added drop wise under argon
atmosphere. The reaction mixture was then allowed
to reach room temperature and worked up by a stan-
dard procedure. The adducts VII thus obtained are
TLC and spectroscopically pure (1H, 13C NMR).

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L. Vite6a et al. / Tetrahedron Letters 42 (2001) 7945–7948
2. Physical data of selected compounds
5+H-6), 2.33 (d, 2H, H-7), 2.37–2.66 (m, 10H, H-2+2×
N(CH2CH2)2O); 2.80–2.85 (m, 1H, H-3); 3.62–3.75 (m,
8H, N(CH2CH2)2O); 13C NMR (CDCl3, 250 MHz): l
17.5 (C-2); 24.0, 26.2, 30.3 (C-4, C-5 and C-6), 48.5 and
53.7 (2×N(CH2CH2)2O); 58.6 (C-7); 60.8 (C-3); 66.9
and 67.0 (2×N(CH2CH2)2O); 118.8 (CN).
2.1. II: 1,5-Bis-(morpholino)-pentadienylium triflate
Yield: 68%, red-brownish solid after drying in high
vacuum, strongly hygroscopic. MS (EI) m/z (rel. int.)=
237 (M+, 12). Anal. calcd for C14H21F3N2O5S (386.39):
C, 43.52; H, 5.48; N, 7.25. Found: C, 43.28; H, 5.30, N,
7.47. 1H NMR (CDCl3, 250 MHz): l 3.59 (t, 4H,
N(CH2CH2)2O); 3.66 (t, 4H, N(CH2CH2)2O); 3.77–3.83
(m, 8H, 2×N(CH2CH2)2O); 5.93 (t, 2H, J=12.2, H-2+
H-4); 7.66 (d, 2H, J=11.9, H-1+H-5); 7.73 (t, 1H,
J=12.5, H-3). 13C NMR (CDCl3, 250 MHz, DEPT): l
46.8 and 54.4 (2×N(CH2CH2)2O); 65.7 and 66.8 (2×
N(CH2CH2)2O); 103.4 (C-2+C-4); 160.4 (C-1+C-5);
165.2 (C-3).
2.5. VII: 2-Phenyl,7-morpholino-heptane nitrile
Yield: 83%; oil Rf=0.28 (CH2Cl2:MeOH=95:5). MS
(EI) m/z (rel. int.)=272 (M+, 58). Anal. calcd for
C17H24N2O: C, 74.96; H, 8.88; N, 10.28. Found: C,
1
74.63; H, 8.67; N, 10.40. H NMR (CDCl3, 250 MHz):
l 1.20–1.54 (m, 6H, H-4+H-5+H-6); 1.84–1.99 (m, 2H,
H-3); 2.32–2.48 (m, 6H, N(CH2CH2)2O+H-7), 3.65–
4.36 (m, 5H, N(CH2CH2)2O+H-2); 7.29–7.69 (m, 5H,
C6H5); 13C NMR (CDCl3, 250 MHz): l 26.0, 26.6, 26.7,
35.6 (C-3, C-4, C-5 and C-6); 35.6 (C-2); 53.4
(N(CH2CH2)2O); 58.6 (C-7), 66.7 (N(CH2CH2)2O),
120.7 (CN), 126.8–128.9 (Ph), 135.8 (Ci-Ph).
2.2. IIIc: 3,7-Bis-morpholino-4,6-heptadiene nitrile
1H NMR (CD3CN, 250 MHz): l 2.30–2.47 (m, 4H,
N(CH2CH2)2O); 2.6 (dd, 2H, J=5.0 and 2, H-2); 2.89
(t, 4H, J=5.1, N (CH2CH2)2O,); 3.18–3.30 (m, 1H,
H-3); 5.16 (dd, 1H, J=14.3 and 8.1, H-4); 5.19 (dd, 1H,
H-6, J=13.6 and 9.9, H-6); 6.12 (dd, 1H, J=15.5 and
10.3, H-5); 6.2 (d, 1H, J=13.6, H-7). 13C NMR
(CD3CN, 250 MHz, DEPT): l 21.7 (C-2); 49 and 50.
(2×N(CH2CH2)2O); 64.6 (C-3); 66.5 and 67.3
N(CH2CH2)2O); 118.1 (CN); 100.7 (C-6); 119.7 (C-4);
135.2 (C-5); 144.6 (C-7).
Acknowledgements
This work was supported by an International Coopera-
tion Agreement between the CNRS and the Bulgarian
Academy of Sciences.
2.3. IVc: 1-Cyano-6-morpholino-hexatriene
References
Yield: 73% (as 1:1 mixture of cis/trans isomers around
the new double bond, flash chromatography on silica
gel, ether); deep-dark oil, Rf=0.63 (ether). MS (EI) m/z
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1
(rel. int.)=190 (M+, 65). H NMR (CDCI3, 250 MHz,
for 1:1 mixture of cis and trans isomers): l 3.13 (t, 8H,
N(CH2CH2)2O); 3.72 (t, 8H, N(CH2CH2)2O,); 4.77 (d,
1H, J=10.4, H-6-cis); 4.97 (d, 1H, J=15.3, H-6-trans);
5.22–5.35 (m, 2H), 5.39 (dd, 1H, J=14.3 and 11.2);
6.35–6.60 (m, 5H); 6.75 (t, 1H, J=11.1); 6.94 (dd, 1H,
J=15.9 and 10.2). 13C NMR (CDCI3, 250 MHz, DEPT
for 1:1 mixture of cis and trans isomers): l 48.4.
(N(CH2CH2)2O); 66.1 ( N(CH2CH2)2O); 88.2 (C-6-cis);
89.9 (C-6-trans); 99.5 and 99.7; 118.3 and 118.4 (CN);
118.8 and 119.4; 143.3 and 143.4; 147.5 and 147.6;
150.5 and 151.7.
2.4. Vc: 3,7-Bis-morpholino-heptane nitrile
7. (a) Hafner, K.; Asmus, K. D.; Kro¨hnke, F. Angew. Chem.
1963, 75, 317–329; (b) Kulpe, S.; Schulz, B. Kristal Teck-
nik 1976, 11, 707–728.
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30, 2393–2399.
Yield: 85% (after column chromatography on silica gel,
methylene chloride:methanol=95:5); oil Rf=0.41
(CH2Cl2:MeOH=9:1). MS (EI) m/z (rel. int.)=281
(M+, 63). Anal. calcd for C15H27N3O2: C, 64.02; H,
9.67; N, 14.94. Found: C, 64.30; H, 9.43; N, 14.68. H
NMR (CDCl3, 250 MHz): l 1.20–1.64 (m, 6H, H-4+H-
1