A new and efficient synthetic route toward 3,4-alkylenedioxypyrrole (XDOP) derivatives via Mitsunobu chemistry

Article abstract of DOI:10.1016/j.tetlet.2006.03.086

A new and high yielding synthetic route toward 3,4-alkylenedioxy-functionalized pyrroles has been achieved by performing tandem Mitsunobu reactions on diethyl 1-benzyl-3,4-dihydroxypyrrole-2,5-dicarboxylate using a variety of 1,2-alkanediols or 1,3-alkane

Full text of DOI:10.1016/j.tetlet.2006.03.086

Tetrahedron Letters 47 (2006) 3521–3523
A new and efficient synthetic route toward 3,4-alkylene-
dioxypyrrole (XDOP) derivatives via Mitsunobu chemistry
Kyukwan Zong,b,* L. ‘Bert’ Groenendaalc and John R. Reynoldsa,*
aDepartment of Chemistry, Center for Macromolecular Science and Engineering, University of Florida,
PO Box 117200, Gainesville, FL 32611-7200, USA
bInstitute of Science Education, Division of Chemical Education, Chonbuk National University, Jeonju 561-756, Republic of Korea
cAGFA-Gevaert N.V., R&D Materials—Chemistry Department, Septestraat 27, B-2640 Mortsel, Belgium
Received 8 February 2006; revised 13 March 2006; accepted 15 March 2006
Abstract—A new and high yielding synthetic route toward 3,4-alkylenedioxy-functionalized pyrroles has been achieved by perform-
ing tandem Mitsunobu reactions on diethyl 1-benzyl-3,4-dihydroxypyrrole-2,5-dicarboxylate using a variety of 1,2-alkanediols or
1,3-alkanediols.
Ó 2006 Elsevier Ltd. All rights reserved.
Heterocycle-based conjugated polymers, such as poly-
pyrrole and polythiophene, have received significant
attention due to their wide range of electrical, electro-
chemical, and optical properties that are controlled by
the heteroatoms within the ring. This is due to their
intrinsic electron-donating or electron-withdrawing
capabilities and hydrogen-bonding and polarizability
properties.1 These polymers have been found to be
useful in many applications including semiconductors
for field-effect transistors2,3 and LEDs,3–5 conductors
for electrostatic charge dissipation and EMI shielding,
and redox active materials for energy storage (batteries
and supercapacitors) and electrochromic devices.6 As
with 3,4-ethylenedioxythiophene (EDOT) and related
derivatives, both the monomer and polymer oxidation
potentials can be decreased by adding an alkylenedioxy
bridge across the 3- and 4-positions of pyrroles which
adds electron density to the aromatic ring resulting in
ease of oxidative polymerization and the formation of
highly stable conducting polymer.7
dioxypyrrole (BuDOP, 3), and [3,4-(2,2-dimethyl-1,3-
propylenedioxy)pyrrole] (ProDOP-Me2, 4). Our studies
have demonstrated that the polymers prepared from
these monomers have high conductivities, long-term sta-
bility, and exhibit unique electrochromic properties.8–11
These promising results have encouraged us to expand
our study to a set of 3,4-alkylenedioxypyrrole deriva-
tives, which will provide a broad family of polymers
having a range of properties.
Me
O
Me
O
O
O
O
O
O
O
N
H
1
N
H
2
N
H
4
N
H
3
ProDOP
EDOP
ProDOP-Me2
BuDOP
To facilitate the successful production of these new
derivatives, a mild and efficient route for monomer
synthesis was needed. Currently, the typical route to
produce these monomers (1, 2, 3, and 4) involves
Williamson etherification of diethyl 1-benzyl-3,4-dihydr-
oxypyrrole-2,5-dicarboxylate with a–x dihaloalkanes or
alkanedisulfonates as a key step. This route is a straight-
forward synthesis for the parent monomers (1 and 2) or
for those with relatively small substituents on the 3,4-
alkylenedioxy bridge, but is limited when more sterically
demanding alkyl substituents are added onto the bridge.
We have synthesized a series of 3,4-alkylenedioxypyr-
roles with varying ring sizes and substituents. Typical
examples include 3,4-ethylenedioxypyrrole (1,4-di-
oxino[2,3-c]pyrrole, EDOP, 1), 3,4-propylenedioxypyrrole
(1,4-dioxepino[2,3-c]pyrrole, ProDOP, 2), 3,4-butylene-
Keywords: 3,4-Alkylenedioxypyrroles; Mitsunobu reaction.
*
Corresponding authors. E-mail addresses: kzong@chonbuk.ac.kr;
reynolds@chem.ufl.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.086

3522
K. Zong et al. / Tetrahedron Letters 47 (2006) 3521–3523
This is demonstrated by the low yields of 4.11 Here we
report a new method for 3,4-alkylenedioxy cyclization
by the reaction of diethyl 1-benzyl-3,4-dihydroxy-
pyrrole-2,5-dicarboxylate with various 1,2-diols and
1,3-diols via double Mitsunobu reactions. This method
produces high yields of the parent products and can be
extended to a wide range of derivatives.
conditions and the desired product was not produced.
It is our opinion that the reaction is highly sensitive to
the degree of steric congestion of the diols employed,
and the secondary hydroxyl group seems to be impracti-
cal with this application.
The reaction was further explored by employing 1,3-
alkanediols where the 7-membered ring is obtained by
reaction (2). The reaction of 5 with 1,3-propanediol
(10), under THF reflux, gave the cyclized product 14
in excellent yield. A systematic study was conducted
by increasing the steric environment around the 1,3-diol
employed. The reaction of 2,2-dimethyl-1,3-propanediol
(11) led to the product in high yield (80%). Similarly,
when 2,2-diethyl-1,3-propanediol (12) and 2,2-dibutyl-
1,3-propanediol (13) were employed, the reaction gave
rise to the desired products in good yield. As with many
examples of Mitsunobu type reactions, it should be
noted that primary alcohols are more reactive than
secondary.
The Mitsunobu reaction is an important synthetic tool
for accomplishing reactions under mild, essentially neu-
tral conditions12–17 and has been used by our group,18
and others,19 in 3,4-alkylenedioxythiophene syntheses.
The reaction of a relatively acidic diol (5) as a nucleo-
phile with an 1,2-alkanediol (6) or 1,3-alkanediol (10)
under standard Mitsunobu conditions is illustrated in
reactions (1) and (2), respectively. The synthesis of the
key intermediate, diethyl 1-benzyl-3,4-dihydroxypyr-
role-2,5-dicarboxylate (5), is well documented in the
literature from the reaction of N-benzyl iminodiacetic
acid diethyl ester with diethyl oxalate in the presence
of sodium ethoxide, followed by acidification to produce
5 in excellent yield.11 With this key intermediate on
hand, subjecting 5 to standard Mitsunobu conditions
[diethyl azodicarboxylate (DEAD), PPh3, THF, room
temperature] using ethylene glycol was sluggish and
gave the desired product only in low yield (<10%), even
with an extended reaction time of three days. However,
when the reaction was heated to reflux, the desired cyc-
lized product was produced via tandem Mitsunobu reac-
tions in excellent yield (95%).18
R
R
HO
EtO2C
OH
CO2Et
R
R
O
O
a
+
EtO2C
N
CO2Et
OH OH
N
Ph
Ph
10 R = H
11 R = Me
12 R = Et
13 R = Bu
5
14 R = H (85%)
15 R = Me (80%)
16 R = Et (75%)
17 R = Bu (60%)
R
HO
EtO2C
OH
CO2Et
O
O
R
Reaction conditions; (a) DEAD, PPh3, THF, reflux, 48 h.
a
ð2Þ
HO
+
OH
EtO2C
CO2Et
N
N
Ph
6 R = H
7 R = Et
Ph
To prove the usefulness of these benzylic intermediates,
compound 16 was further manipulated to isolate the
corresponding monomer as shown in reaction (3).19,20
Debenzylation of 16 via catalytic hydrogenolysis affor-
ded the unsubstituted pyrrole 18 in excellent yield
(95%). Hydrolysis and decarboxylation of the resulting
dicarboxylic acid, under standard conditions, gave the
diethyl substituted ProDOP (19) in good yield (70% over
both steps).21
5
8 R = H (95%)
9 R = Et (10%)
Reaction conditions; (a) DEAD, PPh3, THF, reflux, 48 h.
ð1Þ
In order to define the scope and limitations of this new
method, a more sterically hindered diol, 1,2-butanediol
Et
O
Et
Et
O
Et
Et
O
Et
b, c
CO2Et
O
O
O
a
EtO2C
CO2Et
EtO2C
N
H
ð3Þ
N
N
H
Ph
19
18
16
Reaction conditions; (a) H2 (Pd/C), AcOH, 90 °C,12 h, 95%. (b) 3M NaOH, 70 °C, 6 h.
(c) triethanolamine, 180 °C, 10 min, 70% in two steps.
(7), was attempted. Under various conditions, including
using different azo compounds and phosphines, the reac-
tion led to only a low yield (5–10%) of product 9. Sub-
sequently, 2,3-butanediol underwent these reaction
In conclusion, we have demonstrated that 5 undergoes
double Mitsunobu alkylation using 1,2- and 1,3-diols
to afford the corresponding dioxypyrrole derivatives in
good yields. The corresponding unprotected 3,4-alkylene-

K. Zong et al. / Tetrahedron Letters 47 (2006) 3521–3523
3523
16. Tsunoda, T.; Ozaki, F.; Shirakata, N.; Tamaoka, Y.;
Yamamoto, H.; Ito, S. Tetrahedron Lett. 1996, 37, 2463–
2466.
17. Aristoff, P. A.; Harrison, A. W.; Huber, A. M. Tetra-
hedron Lett. 1984, 25, 3955–3958.
dioxypyrroles, being promising monomers for conduct-
ing and/or electroactive polymers, can subsequently be
isolated in good yields via deprotection/decarboxylation
steps.
18. Zong, K.; Madrigal, L.; Groenendaal, L.; Reynolds, J. R.
Chem. Commun. 2002, 2498–2499.
Acknowledgements
19. Ba¨uerele, P.; Scheib, S. Acta Polym. 1995, 46, 124–129.
20. General procedure for cyclization via double Mitsunobu
reactions: To a solution of diethyl N-benzyl-3,4-dihydr-
oxypyrrole-2,5-dicarboxylate (5) (2.00 g. 6 mmol), ethyl-
ene glycol (6) (0.37 g, 6 mmol), and PPh3 (3.14 g,
12 mmol) in dry THF, was dropwise added diethyl
azodicarboxylate (2.09 g, 12 mmol), under argon at room
temperature. The reaction mixture was stirred for 1 h and
stirred at reflux for 48 h. The reaction was cooled to room
temperature and the THF was removed by a rotary
evaporator. The residue was diluted with ether and stood
for crystallization of triphenylphosphine oxide for 12 h,
which was filtered off and the filtrate was concentrated
again. Purification of the residue by chromatography on
silica gel using hexane/ethyl acetate (3:1) as an eluent gave
the desired product 8. For compounds 8, 9, 14, and 15,
refer to Refs. 10 and 11. The yield of compound 18 is for
crude but the compound was quite pure enough to be used
for next step by judging proton NMR.
We appreciate the efforts of Jessica Hancock and
Aubrey Dyer in the preparation of this manuscript.
References and notes
1. Handbook of Conducting Polymers; 2nd ed.; Skotheim,
T. A., Elsenbaumer, R. L., Reynolds, J. R., Eds.; Marcel
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3. Li, W.; Katz, H. E.; Lovinger, A. J.; Laquindanum, J. G.
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4. Inga¨nas, O. In Organic Electroluminescent materials and
Devices; Miyata, S., Nalwa, H. S., Eds.; Gordon and
Breach: Amsterdam, 1997; pp 147–175.
Diethyl N-benzyl-3,4-(2,2-dibutyl-1,3-propylenedioxy)pyr-
A
colorless oil; 1H NMR
5. Kaminovz, Y.; Smela, E.; Johansson, T.; Brehmer, L.;
Anderson, M. R.; Inga¨nas, O. Synth. Met. 2000, 113, 103–
114.
6. Thompson, B. C.; Schottland, P.; Zong, K.; Reynolds,
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7. Groenendaal, L.; Jonas, F.; Freitag, D.; Pielartzik, H.;
Reynolds, J. R. Adv. Mater. 2000, 12, 481–494.
8. Thomas, C. A.; Zong, K.; Schottland, P.; Reynolds, J. R.
Adv. Mater. 2000, 12, 222–225.
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12. Mitsunobu, O. Synthesis 1981, 1, 1–28.
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role-2,5-dicarboxylate 17.
(300 MHz, CDCl3) d 7.20 (m, 3H), 6.95 (m, 2H), 5.90 (s,
2H), 4.25 (q, J = 7.0 Hz, 4H), 3.94 (s, 4H), 1.50–1.18 (m,
18H), 0.95 (t, J = 7.3 Hz, 6H); HRMS (FAB) calcd for
C28H39NO6 (MH+) 486.2853, found 486.2853; Anal.
Calcd for C28H39NO6: C, 69.25; H, 8.09; N, 2.88. Found:
C, 69.20; H, 8.12; N, 2.85.
Diethyl N-benzyl-3,4-(2,2-diethyl-1,3-propylenedioxy)pyr-
A
colorless oil; 1H NMR
role-2,5-dicarboxylate 16.
(300 MHz, CDCl3) d 7.20 (m, 3H), 6.85 (m, 2H), 5.79 (s,
2H), 4.23 (q, J = 7.0 Hz, 4H), 3.91 (s, 4H), 1.48 (q,
J = 7.5 Hz, 4H), 1.22 (t, J = 7.0 Hz, 6H), 0.90 (t,
J = 7.3 Hz, 6H); HRMS (FAB) calcd for C24H32NO6
(MH+) 430.2230, found 430.2230; Anal. Calcd for
C24H31NO6: C, 67.11; H, 7.27; N, 3.26. Found: C, 67.08;
H, 7.30; N, 3.20.
21. 3,4-(2,2-Diethyl-1,3-propylenedioxy)pyrrole 19. For exper-
imental detail of the reaction, see Refs. 10 and 11; a pale
yellow solid; mp 86 °C; 1H NMR (300 MHz, CDCl3) d
7.15 (br, 1H), 6.26 (d, J = 3.4 Hz, 2H), 3.78 (s, 4H), 1.45
(q, J = 7.5 Hz, 4H), 0.88 (t, J = 7.5 Hz, 6H); HRMS
(FAB) calcd for C11H17NO2 (M+) 195.1295, found
195.1295; Anal. Calcd for C11H17NO2: C, 67.66; H, 8.78;
N, 7.17. Found: C, 67.70; H, 8.80; N, 7.15.