Synthesis of a thiophene-based nonlinear optical chromophore

Article abstract of DOI:10.1080/00397910600943444

This report details an eight-step synthesis of the thiophene-type nonlinear optical chromophore 1 in 38% overall yield. Only one early step required chromatography. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600943444

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Synthesis of a Thiophene‐Based Nonlinear
Optical Chromophore
Matthew C. Davis a , Richard A. Hollins a & Brad Douglas a
a Chemistry and Materials Division, Michelson Laboratory, Naval Air Warfare
Center, China Lake, California, USA
Published online: 24 Nov 2006.
To cite this article: Matthew C. Davis , Richard A. Hollins & Brad Douglas (2006) Synthesis of a
Thiophene‐Based Nonlinear Optical Chromophore, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 36:23, 3515-3523, DOI: 10.1080/00397910600943444
To link to this article: http://dx.doi.org/10.1080/00397910600943444
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Synthetic Communicationsw, 36: 3515–3523, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600943444
Synthesis of a Thiophene-Based Nonlinear
Optical Chromophore
Matthew C. Davis, Richard A. Hollins, and Brad Douglas
Chemistry and Materials Division, Michelson Laboratory, Naval Air
Warfare Center, China Lake, California, USA
Abstract: This report details an eight-step synthesis of the thiophene-type nonlinear
optical chromophore 1 in 38% overall yield. Only one early step required
chromatography.
Keywords: Horner–Wadsworth–Emmons, Knoevenagel, nonlinear optical, thiophene,
Vilsmeier–Haack
As part of a program to develop a nonlinear optical polymer for an optical
modulator application, a consistent supply of the reported chromophore
1[1,2] was needed (see Scheme 1). The chemistry started out similar to
previous work on a CLD-type chromophore.[3] Protection of the hydroxyl
group of 2 was found to proceed in neat acetic anhydride, and the acetylated
product 3 could be purified by distillation directly from the reaction
mixture.[4] The Vilsmeier–Haack formylation to give 4 was run at a molar
scale. Although the reaction is exothermic, generated heat was controlled
by dosing of the phosphorous oxychloride.[5,6] The product was purified by
rapid filtration through a silica-gel plug. Acetate protection of 4 was
easily removed by aqueous sodium hydroxide, and the alcohol 5 was
isolated by precipitation. Using the previously prepared phosponate 6,[7]
the Horner–Wadsworth–Emmons condensation went smoothly to give the
trans-stilbene 7, and trace amounts of the regioisomer were removed by
recystallization.
Received in the USA May 9, 2006
Address correspondence to Matthew C. Davis, Chemistry and Materials Division
(Code 498220 D), Michelson Laboratory, Naval Air Warfare Center, China Lake,
CA 93555, USA. E-mail: matthew.davis@navy.mil
3515

3516
M. C. Davis, R. A. Hollins, and B. Douglas
Scheme 1. Reagents and contions: a) Ac2O, 99%; b) DCE, DMF, POCI3, reflux, 93%;
c) MeOH, H2O, NaOH, 95%; d) KOtBu, THF, 75%; e) TBDMSCI, imidazole, DMF,
100%; f) hexyllithium, DMF, THF, 08C; g) acetone, H2O, conc. HCI, 65% from 7;
h) EtOH, piperidinium acetate, reflux, 89%.
In transforming 7 to 10, attempts were made to avoid using the expensive
tertiary butyldimethylsilyl chloride reagent as a protection strategy. We first
tried to repeat the work of Hu et al.,[2] who were able to make 10 from 7
directly, without the use of any protection. The reaction was successful on a
small scale (200 mg), but when scaling up, the formylation would not go to
completion. The dilithium salt of 7 was found to precipitate under these con-
ditions (2788C, THF, hexyllithium in hexanes) and running the reaction at
higher temperature (08C) or more dilution did not help. Next, we tried
trimethylsilyl protection similar to that of Alcaraz et al.[8] for lithiation of a
thiophene containing a tertiary alcohol. The trimethylsilyl derivative of
alcohol 7 was prepared in situ (trimethylsilyl chloride/hexyllithium)
without isolation because of its labile nature. After silylation, 1 equiv of hex-
yllithium gave 10 along with some 7, which was encouraging. However, in
attempting to drive the formylation to completion with excess base, a new
product was formed, which (by thin-layer chromatography) was probably
the result of the lithiated thiophene attacking a trimethylsilyl ether and
giving a trimethylsilylthiophene derivative. Because we could not find the
correct ratio hexyllithium/trimethylsilyl chloride/N,N-dimethylformamide
to give 10 cleanly on small scale, the idea was abandoned for scale up.
Lastly, we acetylated the alcohol 7 and tried another Vilsmeier–Haack formy-
lation with conditions used previously. The reaction gave the product but also
polar impurities requiring chromatography.

Nonlinear Optical Chromophore
3517
We settled for the expensive but robust tert-butyldimethylsilyl protection
strategy. The tert-butyldimethylsilyl group was put on easily by initially
forming the N-silylimidazole intermediate and then adding alcohol 7. The
lithiation and formylation reactions were found to run cleanly at 08C; no sily-
lation of the thiophene was detected. The silyl-ether 9 could be telescoped into
the deprotection reaction, and 10 precipitated during workup and purification
by recrystallization.
The final Knoevenagel condensation between 10 and the tricyanodihydro-
furan 11[3] went very well, using a catalytic amount of piperidinium acetate in
refluxing ethanol. (The final condensation conditions of refluxing ethanol were
suggested by Dr. Philip A. Sullivan, University of Washington.) The best
results came by using a slight excess of 10 to ensure complete consumption
of 11, which can contaminate the product. The chromophore 1 precipitated
from the reaction mixture in a high-purity, crystalline form that only
required a reslurry to become analytically pure.
In conclusion, we report an eight-step synthesis of the thiophene-type
nonlinear optical chromophore 1, in 38% overall yield. Conditions were
found that gave the final product in high purity without chromatography.
EXPERIMENTAL
Melting points were collected on an electrothermal capillary melting-point
apparatus and are not corrected. All NMR spectra were obtained on a
Bruker AC-200 spectrometer (1H at 200 MHz, 13C at 50 MHz) in CDCl3
and are referenced to solvent or tetramethylsilane. Silica gel (32–63 mm,
˚
60 A) was purchased from Scientific Adsorbents Inc. (Atlanta), (catalog
no. 02826). For the silica gel, plug filtrations used to purify compounds 4,
a
quick separation column/funnel from Chemglass (Vineland, NJ)
(part no. 1412-27) was used. The bottom-drain 20L unjacketed reactor
system (part no. 1966-620) was from Chemglass (Vineland, NJ).
The following reagents were purchased from Aldrich Chemical Co.
(Milwaukee) and used as received: 2 [-(N-ethyl-anilino)ethanol, 99%],
acetic anhydride (ACS reagent, .98%), tert-butyldimethylsilyl chloride
(97%), anhydrous N,N-dimethylformamide (99.8%), phosphorous(III) oxy-
chloride (ReagentPlusTM, 99%), 1,2-dichloroethane (ACS reagent, .99%),
imidazole (ACS reagent, .99%), hexyllithium solution 2.3 M in hexanes,
methylene chloride (ACS reagent, .99%, contains 50 ppm of amylene),
anhydrous THF containing 250 ppm of BHT, and anhydrous THF, Darcow
G-60. The piperidinium acetate was prepared by addition of 1 equiv of
glacial HOAc to a cold, Et2O solution of piperidine and suction filtration
of the product. All other reagents were obtained commercially and used
as received. Elemental analysis was performed by Atlantic Microlabs, Inc.
(Norcross, GA).

3518
M. C. Davis, R. A. Hollins, and B. Douglas
N-Ethyl-N-(2-acetoxyethyl)aniline, 3
A 3-L, two-neck, round-bottomed flask was equipped with a thermometer for
internal temperature and magnetic stirbar. The flask was charged with 400 g
of 2 (2.42 mol), and the other neck of the flask was equipped with a reflux
condenser with a 500-mL addition funnel on top. The addition funnel was
charged with 271.5 g of acetic anhydride (251.4 mL, 1.1 equiv). The reaction
was run open to the atmosphere. A heating mantle was equipped, and the
alcohol was heated to 758C. The anhydride was added over 30 min, and the
internal temperature gradually rose to 1308C. At the halfway point, a liquid
can be seen refluxing, which presumably is acetic acid. The reaction was
complete (measured by thin-layer chromatography) after the addition. The
mixture was allowed to cool to rt. The by-product acetic acid and excess
acetic anhydride were distilled (60–708C, 5 torr) and collected. Stronger
vacuum was applied, and the product was distilled from the pot (120–1308C,
1.5 torr). The colorless liquid obtained weighed 499 g (99%). dH: 7.29
(t, J ¼ 8.3 Hz, 2H), 6.85–6.69 (m, 3H), 4.28 (t, J ¼ 6.5 Hz, 2H), 3.59
(t, J ¼ 6.5 Hz, 2H), 3.46 (q, J ¼ 7.1 Hz, 2H), 2.09 (s, 3H), 1.23 (t, J ¼ 6.9 Hz,
3H); dC: 147.56, 129.28, 116.18, 111.95, 61.64, 48.75, 45.13, 20.76, 12.18.
4-(N-Ethyl-N-(2-acetoxyethyl)amino)benzaldehyde, 4
To a 3-L reactor, 207 g of 3 (1 mol), 128 g of anhydrous DMF (1.75 mol, 1.75
equiv), and 800 mL of 1,2-dichloroethane were added. The mixture was vigor-
ously stirred with a magnetic stirbar while a steady stream of 162.3 mL of
POCl3 (1.75 mol, 1.75 equiv) was added by addition funnel over 25 min.
The temperature within the reaction rose to 788C. The mixture was then
heated to 828C for 6 h. The reaction was cooled to rt and poured onto 2.5 kg
of ice and H2O in a 20-L bottom-drain pilot reactor. The mixture was neutral-
ized (pH 8–9) with 500 g of anhydrous Na2CO3 dissolved in 2 L of H2O. The
mixture was extracted four times with 1-L portions of CH2Cl2. The combined
organic layers were washed with 1 L of H2O followed by 1 L of brine. The
organic layer was then evaporated, leaving a brown oil. The oil was
dissolved in 1 L of Et2O and filtered through 100 g of SiO2 to remove some
of the color. The combined filtrates were evaporated to leave the title
1
compound as a light brown liquid (218.2 g, 93%). H NMR showed that the
material was .97%. dH: 9.78 (s, 1H), 7.76 (d, J ¼ 9.3 Hz, 2H), 6.78
(d, J ¼ 9.3 Hz, 2H), 4.29 (t, J ¼ 6.4 Hz, 2H), 3.67 (t, J ¼ 6.4 Hz, 2H), 3.52
(q, J ¼ 7.1 Hz, 2H), 2.07 (s, 3H), 1.25 (t, J ¼ 7.1 Hz, 3H).
4-(N-Ethyl-N-(2-hydroxyethyl)amino)benzaldehyde, 5
In a 2-L reaction flask, 218.2 g of 4 (0.93 mol) followed by 1 L of MeOH were
added. The solution was magnetically stirred while 10% aqueous NaOH

Nonlinear Optical Chromophore
3519
[37.2 g of NaOH (0.93 mol)/H2O (370 mL)] was added over 10 min. The
mixture becomes warm to the touch, and TLC showed hydrolysis was
complete after the addition was complete. The solvent was rotary evaporated,
leaving a pale orange oil. The oil was partitioned between 500 mL of CH2Cl2
and 500 mL of H2O. The aqueous phase was further extracted twice with 100-
mL portions of CH2Cl2. The combined organic phases were rotary evaporated,
leaving an oil. The oil was stirred with 200 mL of hexanes/Et2O (2 : 1) while
cooling in an ice bath to cause the product to precipitate. The light tan powder
was collected on a medium-porosity glass frit and air-dried overnight (171.4 g,
95%). We were unable to obtain crystals of the low-melting solid for melting-
point determination. dH: 9.59 (s, 1H), 7.64 (d, J ¼ 9.2 Hz, 2H), 6.72
(d, J ¼ 8.9 Hz, 2H), 3.83 (q, J ¼ 5.8 Hz, 2H), 3.62–3.39 (m, 4H), 1.20
(t, J ¼ 7.2 Hz, 3H); dC: 190.45, 152.99, 132.42, 124.67, 111.03, 59.73,
52.28, 45.74, 11.98.
trans-2-[4-(N-Ethyl-N-(2-hydroxyethyl)amino)styryl]thiophene, 7
A 1-L, two-neck flask equipped with magnetic stirbar and reflux condenser
was charged with 47.4 g of 5 (0.245 mol), 53.54 g of 6[7] (0.245 mol, 1
equiv), and 500 mL of anhydrous THF (inhibitor free). The mixture was
stirred until dissolution. Within 15 min, 32.89 g of KOtBu (0.29 mol, 1.2
equiv) were added in 5-g portions to the reaction mixture. The mixture
becomes red in color and reaches reflux temperature. The mixture was
stirred 1 h, slowly cooling to rt, whereby TLC showed the reaction was
complete. The solvent was rotary evaporated, leaving a red oil. Saturated
aqueous NaHCO3 (500 mL) was added to the flask, and the mixture became
a green color. A yellow-green solid precipitated. The mixture was stirred
for 1 h and filtered through a medium-porosity glass frit. The filter cake was
washed four times with 300-mL portions of H2O on the frit and air-dried on
the frit overnight. The mass of the crude product was 50.16 g (75%). The
aqueous washes were not extracted. The crude product was dissolved in
400 mL of CH2Cl2 to give a green solution and washed with 200 mL of
saturated aqueous NaHCO3, 200 mL of H2O, and finally 200 mL of brine.
The organic phase was dried over MgSO4 and filtered. The filtrate was
treated with 5 g of Darcow G-60 for 1 h and filtered through diatomaceous
earth. The yellow filtrate was rotary evaporated to a yellow-orange solid.
The solid was more than 95% by NMR. The title compound can be recrystal-
lized from toluene to give slightly orange, chunky crystals. Mp 93–958C. dH:
7.36 (d, J ¼ 8.9 Hz, 2H), 7.1–7.11 (m, 1H), 7.05 (d, Jab ¼ 16.2 Hz, 1H),
7.01–6.95 (m, 2H), 6.86 (d, Jab ¼ 16.2 Hz, 1H), 6.75 (d, J ¼ 8.9 Hz, 2H),
3.81 (t, J ¼ 5.7 Hz, 2H), 3.54–3.38 (m, 4H), 1.76 (bs, OH), 1.19
(t, J ¼ 7.0 Hz, 3H); dC: 147.84, 143.97, 128.61, 127.73, 127.61, 125.41,
124.72, 123.16, 117.77, 112.62, 60.22, 52.45, 45.68, 12.08. C16H19NOS: C,
70.29; H, 7.00; N, 5.12.

3520
M. C. Davis, R. A. Hollins, and B. Douglas
trans-2-[4-(N-Ethyl-N-(2-tert-butyldimethylsiloxyethyl)amino)
styryl]thiophene, 8
To a magnetically stirred solution of 5.72 g of imidazole (0.084 mol, 1.1
equiv) in 50 mL of anhydrous DMF, 12.68 g TBDMSCl (0.084 mol, 1.1
equiv) were added in one portion. After stirring at rt for 20 min, all the
solids had dissolved, and 20.87 g of 7 (0.076 mol, 1 equiv) were added por-
tionwise over 15 min. The temperature rose to 358C. The reaction was
allowed to stir until rt, whereupon TLC indicated complete reaction. The
mixture was poured into 500 mL of H2O and extracted with 250 mL of
CHCl3. The aqueous was extracted twice more with 100-mL portions of
CHCl3. The organic extracts were combined and washed twice with 200-
mL portions of H2O. The organic extracts were washed with 200 mL of
saturated NaHCO3 and then 200 mL of brine and then dried over MgSO4.
The solvent was rotary evaporated, and volatiles were removed under high
vacuum (608C, 1 torr). The yellow-orange oil (29.6 g, 100%) was more
than 98% by NMR, and no further purification performed. dH: 7.29
(d, J ¼ 9.2 Hz, 2H), 7.1–7.01 (m, 1H), 6.97–6.9 (m, 3H), 6.82
(d, Jab ¼ 15.9 Hz, 1H), 6.62 (d, J ¼ 9.0 Hz, 2H), 3.74 (t, J ¼ 6.1 Hz, 2H),
3.47–3.31 (m, 4H), 1.14 (t, J ¼ 7.2 Hz, 3H), 0.88 (s, 9H), 0.02 (s, 6H); dC:
147.69, 144.27, 128.95, 127.82, 127.64, 124.69, 124.54, 123.04, 117.36,
111.83, 60.86, 52.69, 45.70, 26.14, 18.51, 12.45, 25.13.
trans-[4-(N-Ethyl-N-(2-tert-butyldimethylsiloxyethyl)amino)styryl]
thiophene-5-carboxaldehyde, 9
A two-neck, 2-L, round-bottomed flask was charged with a magnetic stirbar
and equipped with a 100-mL pressure-equalizing addition funnel. The flask
was adapted to a N2 bubbler. The flask was charged with 500 mL of
anhydrous THF (containing 250 ppm of BHT) and 29.7 g of 7 (0.077 mol).
The solution was cooled to 08C with an ice bath. To the addition funnel,
56.5 mL of 2.3 M hexyllithium in hexanes (0.13 mol, 1.7 equiv) were
added, and the base was added dropwise over 20 min. The mixture became
green in color and was stirred a further 15 min. A new pressure-equalizing
addition funnel was equipped and filled with a solution of 11.2 g of
anhydrous DMF (0.15 mol, 2 equiv) in 50 mL of anhydrous THF (containing
250 ppm of BHT), which was added over 10 min. The internal temperature
increased to 68C during the addition. The cooling bath was removed, and
the mixture stirred at rt for 2 h. The addition funnel was charged with
14.9 g of glacial HOAc (0.26 mol, 2 equiv relative to base) dissolved in
100 mL of H2O and was added over 15 min. The internal temperature rose
to 298C, and the mixture became bright orange in color. The mixture was
rotary evaporated, and the red residue was partitioned between 250 mL of
CHCl3 and 200 mL of H2O. The organic phase was washed again with

Nonlinear Optical Chromophore
3521
200 mL of H2O and rotary evaporated. The red oil was placed under vacuum
(rt, 1 torr) to remove residual solvent. NMR showed the crude product was
more than 95% pure and was used in the next step without further purification.
dH: 9.76 (s, 1H), 7.56 (d, J ¼ 4.1 Hz, 1H), 7.30 (d, J ¼ 8.9 Hz, 2H), 7.03
(d, Jab ¼ 15.9 Hz, 1H), 6.98 (d, J ¼ 4.1 Hz, 1H), 6.90 (d, Jab ¼ 16.3 Hz,
1H), 6.60 (d, J ¼ 8.9 Hz, 2H), 3.71 (t, J ¼ 5.9 Hz, 2H), 3.47–3.30 (m, 4H),
1.12 (t, J ¼ 7.4 Hz, 3H), 0.83 (s, 9H), 20.02 (s, 6H).
trans-2-[4-(N-Ethyl-N-(2-hydroxyethyl)amino)styryl]thiophene-5-
carboxaldehyde, 10
A 1-L round-bottomed flask containing 32 g of 9 (0.077 mol) was charged
with a magnetic stirbar and 500 mL of acetone. The mixture was stirred
until dissolution, and a solution of 7 mL of conc. HCl (0.085 mol, 1.1
equiv) in 20 mL of H2O was added in a steady stream over 10 min. The
mixture was stirred at 358C for 3 h, after which time no 9 remained by
TLC. The solvent was rotary evaporated to leave thick red oil. Water
(500 mL) was added to the flask, and the mixture was magnetically stirred
and slowly basified (pH 8) with saturated aqueous Na2CO3. A brick-red
solid precipitated. After stirring 30 min, the mixture was filtered on a
coarse-porosity glass frit. The filter cake was washed on the frit twice with
250-mL portions of H2O and then air dried on the frit 1 h. The brick-red,
granular solid was transferred to a 1-L Erlenmeyer flask and partitioned
between 500 mL of CH2Cl2 and 500 mL of H2O. The phases were split, and
the organic phase was washed again with 500 mL of H2O. The organic
layer was separated, dried over MgSO4, and rotary evaporated to a brick-
red solid. The crude was slurried with 100 mL of EtOAc for 1 h and
filtered. The product was recrystallized from toluene to give 15.0 g of title
compound as clear, garnet-colored crystals (65% from 8). The mother
liquor from the EtOAc slurry carried the remainder of the product. Mp 95–
978C (lit.[1] 106.28C). dH: 9.76 (s, 1H), 7.59 (d, J ¼ 3.9 Hz, 1H), 7.34
(d, J ¼ 8.6 Hz, 2H), 7.07 (d, Jab ¼ 14 Hz, 1H), 7.02 (d, J ¼ 3.9 Hz, 1H),
6.95 (d, Jab ¼ 16 Hz, 1H), 6.7 (d, J ¼ 8.6 Hz, 2H), 3.8 (t, J ¼ 5.9 Hz, 2H),
3.56–3.36 (m, 4H), 2.22 (bs, OH), 1.17 (t, J ¼ 7.1 Hz, 3H); dC: 182.59,
154.49, 148.83, 140.16, 137.93, 133.61, 128.72, 125.19, 123.91, 116.19,
112.29, 60.28, 52.42, 45.65, 12.15. Elemental analysis calculated for
C17H19NO2S: C, 67.8; H, 6.3; N, 4.65. Found: C, 67.74; H, 6.35; N, 4.65.
E,E-[3-Cyano-4-[2-[5-[2-[4-[ethyl(2-hydroxyethyl)amino]phenyl]
ethenyl]-2-thienyl]-ethenyl]-5,5-dimethyl-2(5H)-furanylidene]-
propanedinitrile, 1
A 500-mL round-bottomed flask equipped with magnetic stirbar was charged
with 5.0 g of 10 (0.017 mol, 1.1 equiv), 2.9 g of 11 (0.015 mol, 1.0 equiv),

3522
M. C. Davis, R. A. Hollins, and B. Douglas
200 mg of piperidinium acetate (0.001 mol, 0.06 equiv), and 200 mL of EtOH,
and the mixture was refluxed under an N2 atmosphere protected from light.
After 12 h, the mixture was dark maroon, and TLC (SiO2; EtOAc) showed
all 10 and 11 were consumed. The mixture was cooled in an ice bath and
filtered through a medium-porosity glass frit. The rust-colored, microcrystal-
line powder was washed twice with 50-mL portions of EtOH and air dried on
the frit for 1 h. Residual solvent was removed (608C, 10 torr) to give 6.45 g of
the title compound in 89% yield. NMR showed the material to be more than
97%, and no further purification was performed. Mp 225–2278C (lit.[1]
2398C). dH (DMSO-d6): 8.10 (d, J ¼ 15.9 Hz, 1H), 7.74 (d, J ¼ 3.9 Hz,
1H), 7.46 (d, J ¼ 8.7 Hz, 2H), 7.32–7.11 (m, 3H), 6.70 (d, J ¼ 9.6 Hz, 2H),
6.64 (d, J ¼ 16.9 Hz, 1H), 4.74 (t, J ¼ 4.8 Hz, OH), 3.54 (pent, J ¼ 5.3 Hz,
2H), 3.48–3.34 (m, 2H), 1.79 (s, 6H), 1.10 (t, J ¼ 6.7 Hz, 3H); dC (DMSO-
d6): 176.81, 174.37, 153.60, 148.60, 140.39, 139.00, 137.51, 134.37,
129.03, 127.48, 122.75, 115.65, 113.03, 112.25, 111.64, 111.43, 111.23,
98.46, 96.14, 58.34, 52.63, 51.96, 44.71, 25.55, 12.00. Elemental analysis
calculated for C28H26N4O2S: C, 69.69; H, 5.43; N, 11.61. Found: C, 69.80;
H, 5.31; N, 11.55.
ACKNOWLEDGMENTS
Financial support from the Office of Naval Research is gratefully acknowl-
edged. M. C. D. also thanks Geoffrey A. Lindsay (NAWCWD) for advice
and encouragement throughout the course of this work and Andrew
P. Chafin (NAWCWD) for comments and suggestions in the preparation of
this manuscript.
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