Efficient BOP-mediated synthesis of fulgimides

Article abstract of DOI:10.1016/j.crci.2012.02.001

A mild and efficient method for the synthesis of fulgimides is presented in which the peptide coupling reagent BOP is employed for dehydratation of fulgenic acid monoamides (succinamic acids). The disclosed method proved to be superior to those described in the literature.

Full text of DOI:10.1016/j.crci.2012.02.001

C. R. Chimie 15 (2012) 384–388
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Preliminary communication/Communication
Efficient BOP-mediated synthesis of fulgimides
`
´
Synthese efficace de fulgimides en utilisant le reactif BOP
Krzysztof K. Krawczyk a, Daria Madej a, Jan K. Maurin b, Zbigniew Czarnocki a,
*
a Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warszawa, Poland
b National Drug Institute, Chełmska 30/34, 00-725 Warszawa, Poland
A R T I C L E I N F O
A B S T R A C T
Article history:
A mild and efficient method for the synthesis of fulgimides is presented in which the
peptide coupling reagent BOP is employed for dehydratation of fulgenic acid monoamides
(succinamic acids). The disclosed method proved to be superior to those described in the
literature.
Received 6 December 2011
Accepted after revision 7 February 2012
Available online 10 March 2012
´
ß 2012 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Keywords:
´
´
R E S U M E
Amides
Chirality
Cyclization
Strained molecules
Une me´thode douce et efficace pour la synthe`se de fulgimides est pre´sente´e, dans laquelle
le re´actif de couplage peptidique BOP est utilise´ pour la de´shydratation de monoamides
´
´
´
´
´ ˆ
´
`
d’acide fulgenique (acides succinamiques). Le procede decrit ici s’est avere etre superieur a
´
´
ceux decrits dans la litterature.
ß 2012 Acade´mie des sciences. Publie´ par Elsevier Masson SAS. Tous droits re´serve´s.
1. Introduction
thionyl chloride [6] but there are also literature reports
about the use of carbonyldiimidazole (CDI) [7], carbodii-
Fulgide family compounds are the subject of numerous
publications, mainly due to their photochromic properties
and applications in the synthesis of lignans [1,2]. From the
fulgide-related compounds, fulgimides appear to be the
most interesting for data storage applications because of
their increased fatigue resistance, higher chemical stability
compared to the parent fulgides and the possibility of
functionalisation at the nitrogen atom.
N-substituted fulgimides can be synthesized by func-
tionalisation of simple N-H imides or by the dehydratation
of related succinamic acids. The latter can be obtained
either by the reaction of a fulgide with a primary amine or
by the reaction of a succinic half-ester with the Grignard
salt of the amine [1,3].
mides [1,8] and recently also hexamethyldisilazane
(HMDS) [9].
It is known that DCC (N,N’-dicyclohexylcarbodiimide)
and CDI (1,1’-carbonyldiimidazole) may give unsatisfacto-
ry results due to the formation of isofulgimides instead of
fulgimides [1,8].
The use of acetyl chloride or acetic anhydride proved not
always effective due to the formation of acidic byproducts,
which can lead to decomposition of the material.
Otto et al. [10] have developed another interesting
method for fulgimide formation, where the succinamic
acid is esterified to give a phenacyl ester, which is then
cyclized to the imide by treatment with a base. The
disadvantage of this approach is that it requires additional
steps and the treatment with a strong base (t-BuLi) is
sometimes necessary. Nevertheless, the obtained yields
are much better compared to other methods.
Amongst available dehydrating agents, the most
common is acetyl chloride [4], acetic anhydride [5] and
We have already successfully used benzotriazole-1-yl-
oxy-tris-(dimethylamino)-phosphonium hexafluoropho-
sphate (BOP; Castro’s reagent) for the coupling of amines
* Corresponding author.
E-mail address: czarnoz@chem.uw.edu.pl (Z. Czarnocki).
1631-0748/$ – see front matter ß 2012 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.crci.2012.02.001

K.K. Krawczyk et al. / C. R. Chimie 15 (2012) 384–388
385
R1
R1
R1
R1
R1
R1
O
O
O
OH
H
TEA
BOP, TEA
- H2O
+
H2NR2
N R2
O
R2
N
O
O
O
1a-b
2a-f
R2
R1
R1
2a 3,4,5-trimethoxyphenyl
2b 3,4,5-trimethoxyphenyl
methyl
phenyl
1a 3,4,5-trimethoxyphenyl
1b
H
2c 3,4,5-trimethoxyphenyl 4-methoxyphenyl
2d 3,4,5-trimethoxyphenyl 4-bromophenyl
2e 3,4,5-trimethoxyphenyl (R)-1-phenylethyl
2f
H
2-naphthyl
Scheme 1. General procedure for the BOP-mediated synthesis of fulgimides 2a-f.
or alcohols with carboxylates, and we usually obtained
excellent results [11,12].
Fulgides react almost quantitatively with primary
amines in the presence of one equivalent of tertiary amine
(triethylamine, TEA). TEA can compete in salt formation
between the succinamic acid and the primary amine, thus
its addition was found to be beneficial to the rate of the
reaction and the obtained yield.
Rigorous drying of the resulted amide acid is essential
for the next step, since even traces of residual humidity
significantly lowers the yield of the BOP-mediated reac-
tions. The mixture of the amide acid with 1.05 eq of BOP in
dry tetrahydrofuran (THF) was then treated with 1.1 eq of
TEA, first at À45 8C and then at room temperature. We
found that final warming up of the reaction mixture to
35 8C slightly increased the yield. The usual work-up
affords the product pure enough to crystallize out of the
ethereal solution without additional purification by
column chromatography. However, in the case of the oily
imide 2e, this operation was necessary.
As none of the methods described in the literature
proved successful in the case of the synthesis of chiral
imide 2e due to its instability, we decided to employ BOP.
The good yield of dehydratation and a short reaction time
encouraged us to check this method on a broader scope of
substrates.
2. Results and discussion
The used synthetic procedure is presented in Scheme 1.
Fulgides 1a and 1b were prepared according to the
literature protocols [2b, 2h], involving a double Stobbe
condensation followed by saponification of the 2,3-
bisarylidene succinic acid ester and subsequent treatment
with acetyl chloride. It is noteworthy that BOP could also
successfully be used for the dehydratation of fulgenic acids
to produce fulgides. The yield obtained using this
methodology was always higher than obtained by the
treatment with acetyl chloride and similar to those
observed when DCC was used. In contrast to DCC, the
purification process was much easier. Nevertheless, in the
case of most fulgides, the use of somewhat more expensive
and toxic BOP does not seem to be reasonable.
The described method proved to be the only applicable
for the synthesis of this compound.
Attempted synthesis using acetyl chloride or DCC gave
only trace amounts of the product 2e.
It is also noteworthy that in the case of N-(4-bromo)-
phenyl fulgimide 2d, the yield was increased significantly,
comparing tothe obtained bytraditionalmethods (48%). We
found p-bromophenyl fulgimides of particular interest due
toa possibilitytointroduce other structural modificationsat
the N-phenyl ring e.g. via the Suzuki-Miyaura cross
coupling. The X-ray structure of fulgimide 2d proves the
(E,E) configuration of the double bonds which causes helical
chirality of the molecule (Fig. 1), that can be further
elaborated in stereoselective transformations [12].
The described method will be evaluated for the
synthesis of thermally irreversible heterocyclic fulgimides.
3. Conclusion
We have developed a mild method for the preparation
of fulgimides which can be used for the synthesis of
bisarylidenefulgimides having different N-substituents.
Figure 1. Oak Ridge Thermal Ellipsoid Plot (ORTEP) diagram of molecule
2d.

386
K.K. Krawczyk et al. / C. R. Chimie 15 (2012) 384–388
Table 1
Structure of products 2a–f, the obtained yields and analytical data.
Compound
Isolated yield and analytical data
2a
76%, 78 mg of dense, deep yellow oil, which slowly solidifies to form dark yellow crystals;
Mp 152–154 8C
1H NMR: 3.25 (s, 3H), 3.64 (s, 12H), 3.76 (s, 6H); 6.29 (s, 4H), 7.68 (s, 2H),
13C NMR: 25.09, 55.93, 61.43, 107.87, 122.47, 130.14, 134.65, 140.53, 152.28, 170.67
HRMS: m/z [M + Na]+ calcd for C25H27NNaO8 492.1634; found 492.1626
O
O
O
O
O
N
O
O
O
2b
92%, 107 mg of fine yellow crystals; Mp 174–175 8C
1H NMR: 3.66 (s, 12H), 3.78 (s, 6H), 6.35 (s, 4H), 7.51 (m, 5H), 7.79 (s, 2H)
13C NMR: 55.89, 61.41, 107.93, 122.07, 126.65, 128.59, 129.27, 130.11, 132.16,
135.44, 140.66, 152.24, 169.53
O
HRMS: m/z [M + Na]+ calcd for C30H29NNaO8 554.1791; found 554.1782
O
O
O
O
N
O
O
O
2c
94%; 116 mg of fine yellow crystals; Mp 217–219 8C
1H NMR: 3.65 (s, 12H), 3.78 (s, 6H), 3.87 (s, 3H), 6.34 (s, 4H), 7.05 (d, J = 4.5 Hz, 2H),
7.41 (d, J = 4.5 Hz, 2H), 7.77 (s, 2H)
O
13C NMR: 55.67, 55.93, 61.41, 108.00, 114.63, 122.20, 124.82, 127.89, 130.16, 135.26,
140.69, 152.28, 159.59, 169.82,
HRMS: m/z [M + Na]+ calcd for C31H31NNaO9 584.1897; found 584.1901
O
O
O
O
N
O
O
O
O
2d
82%; 110 mg of fine yellow crystals; Mp 190–191 8C
1H NMR: 3.63 (s, 12H), 3.76 (s, 6H); 6.31 (s, 4H); 7.42 (d, J = 4.4 Hz, 2H), 7.66
(d, J = 4.4 Hz, 2H), 7.76 (s, 2H)
O
13C NMR: 55.92, 61.44, 108.00, 121.79, 122.35, 128.10, 130.00, 131.19, 132.43,
135.77, 140.81, 152.27, 169.21
O
O
HRMS: m/z [M + Na]+ calcd for C30H28BrNNaO8 632.0896; found 632.0878
CCDC nr 847340
O
O
N
Br
O
O
O
20
2e
73%, 89 mg of dense, deep yellow oil; [
a]
+94 (c 1, CHCl3)
D
1H NMR: 1.97 (d, J = 7.4 Hz, 3H), 3.62 (s, 12H); 3.75 (s, 6H); 5.25 (q, J = 7.4 Hz, 1H);
6.25 (s, 4H); 7.26–7.42 (m, 3H); 7.58 (m, 2H); 7.61 (s, 2H)
O
13C NMR: 27.58, 50.59, 55.97, 61.47, 107.88, 117.13, 122.47, 127.89, 127.91, 128.69,
130.24, 134.66, 140.90, 152.28, 171.20
O
O
HRMS: m/z [M + Na]+ calcd for C32H33NNaO8 582.2104; found 582.2099
Ph
O
O
N
O
O
O

K.K. Krawczyk et al. / C. R. Chimie 15 (2012) 384–388
387
Table 1 (Continued )
Compound
Isolated yield and analytical data
2f
60%, 87 mg of fine, yellowish crystals; Mp 234–237 8C
1H NMR: 6.80–6.95 (m, 8H), 7.04–7.13 (m, 2H), 7.51–7.56 (m, 2H), 7.62
(dd, J1 = 2.0 Hz, J2 = 8.8 Hz, 1H), 7.87–7.97 (m, 2H), 7.93 (s, 2H), 7.99
(d, J = 8.6 Hz, 1H), 8.03 (d, J = 1.8 Hz, 1H)
13C NMR: 122.59, 124.18, 125.74, 126.66, 126.90, 127.25, 127.89,
128.43, 129.05, 129.66,
O
N
129.87, 129.99, 132.90, 133.35, 134.81, 135.87, 169.71
HRMS: m/z [M + Na]+ calcd for C28H19NNaO2 424.1313; found 424.1313
O
The yields are superior to those obtained with traditional
dehydratation with AcCl or CDI. For unstable fulgimide 2e,
the BOP-mediated dehydratation proved to be the only
applicable procedure.
solvents were evaporated, and the residue dissolved in
AcOEt and washed with 10% aqueous citric acid solution
and brine. The organic layer was dried with Na2SO4,
filtered and evaporated in vacuo to give the appropriate
succinamic acid as an oily residue. Dry THF was distilled
directly into the reaction mixture (approx. 1 mL/20 mg)
and 1.05 eq of BOP was added under argon. The mixture
was stirred and cooled to À45 8C. Then 1.1 eq of TEA was
added at this temperature and the solution was left to
reach room temperature and then was warmed to 35 8C.
During the time of the reaction, a color change from
slightly yellow to deep yellow or deep orange was
observed. After 30 more minutes of reaction time, the
solvent was evaporated, the residue dissolved in AcOEt and
washed with 10% citric acid solution (2 Â), then 5% NaHCO3
solution (4 Â), water (1 Â) and brine (1 Â). The solution
was dried over Na2SO4, filtered and evaporated to dryness.
Fulgimides 2a–d and 2f started to crystallize after
immediate treatment with diethyl ether.
4. Experimental
The NMR spectra were recorded on a Varian Unity Plus
spectrometer operating at 200 MHz for 1H NMR and at
50 MHz for 13C NMR. The spectra were measured in CDCl3
and are given as
d values (in ppm) relative to TMS. Mass
spectra were collected on Quattro LC Micromass and LCT
Micromass TOF HiRes apparatus. Optical rotations were
measured on Perkin-Elmer 241 polarimeter. TLC analyses
were performed on silica gel plates (Merck Silica Gel 60
F254) and visualized using UV-light. Column chromatogra-
phy was carried out at atmospheric pressure using Silica Gel
60(230–400mesh, Merck). Meltingpointsweredetermined
by a Boetius hot-plate microscope and were uncorrected.
Solvents used in the reactions were anhydrous. CH2Cl2 was
dried with anhydrous CaCl2. THF was dried with CaH2 and
distilled under argon directly into the reaction vessel. The
single-crystal X-ray measurements were carried out on
Fulgimide 2e was subjected to flash column chroma-
tography on Al2O3 (it decomposed immediately on silica)
using diethyl ether as an eluent.
Yields and analytical data for fulgimides 2a–f are
presented in Table 1.
Oxford Diffraction Xcalibur R
k-axis diffractometer with
CCD Ruby detector. In all cases, Cu K
a
characteristic
radiation was applied. After initial corrections and data
reduction, intensities of reflections were used to solve and
consecutively refine structures using SHELXS97 [13] and
SHELXL97 [14] programs. Further absorption corrections
were applied in final steps of refinement. BOP and all other
reactants were purchased from Aldrich.
Acknowledgment
The authors kindly acknowledge the financial support
from the Polish Ministry of Science and Higher Education
(grant No. N204 030636).
The anhydrides 1a and 1b were prepared according to
literature protocols, via double Stobbe condensation/
esterification sequences, followed by saponification and
dehydratation with AcCl at reflux. The analytical data were
in accordance with those presented in the literature for 1a
[2b] and 1b [2g].
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