Synthesis of N-substituted 2-arylpyrroles by the reaction of (η2-imine)titanium complexes with 3,3-diethoxypropyne

Article abstract of DOI:10.1016/j.tetlet.2006.06.152

(η²-Imine)Ti(O-i-Pr)₂ complexes generated from arylaldehyde imines and a divalent titanium reagent, Ti(O-i-Pr)₄/2i-PrMgCl, reacted with 3,3-diethoxypropyne to afford 2-arylpyrroles.

Full text of DOI:10.1016/j.tetlet.2006.06.152

Tetrahedron Letters 47 (2006) 6209–6212
Synthesis of N-substituted 2-arylpyrroles by the reaction
of (g2-imine)titanium complexes with 3,3-diethoxypropyne
Mutsumi Ohkubo,a Daisuke Hayashi,a Daisuke Oikawa,a Kouki Fukuhara,b
Sentaro Okamotoa,* and Fumie Satob
aDepartment of Material and Life Chemistry, Kanagawa University, 3-27-1 Rokkakubashi, Kanagawa-ku, Yokohama 221-8686, Japan
bGraduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku,
Yokohama 226-8501, Japan
Received 17 May 2006; revised 20 June 2006; accepted 29 June 2006
Available online 18 July 2006
Abstract—(g2-Imine)Ti(O-i-Pr)2 complexes generated from arylaldehyde imines and a divalent titanium reagent, Ti(O-i-Pr)4/
2i-PrMgCl, reacted with 3,3-diethoxypropyne to afford 2-arylpyrroles.
Ó 2006 Elsevier Ltd. All rights reserved.
We have reported that (g2-imine)Ti(O-i-Pr)2 complexes
(3) generated from arylaldehyde imines 2 and a divalent
titanium reagent, Ti(O-i-Pr)4/2i-PrMgCl (1),1 reacted
with 1-alkynes or propargyl alcohol derivatives to
provide a-aryl allylamines 4 and a-allenylamines 5,
respectively (Scheme 1).2
Based on these results, we planned and investigated syn-
thesis of pyrroles 6 as illustrated in Scheme 2, assuming
that allenylamines 8 having a leaving group X might be
Scheme 2. Synthetic plan for pyrroles
propanes 3.
6 from azatitanacyclo-
obtained by the reaction of 3 with a propargylic com-
pound 7 with two leaving groups at the propargyl posi-
tion and the cyclization of the resulting 8 would provide
6 by elimination of HX.
Since substituted pyrroles are of importance in the syn-
thesis of natural and artificially biologically active com-
pounds, numerous methods for their synthesis have been
developed, and recently metal-mediated and-catalyzed
approaches have been focused on.3 The 2-arylpyrrole
nucleus such as 6 is widely distributed in many natural4
and artificially5 biologically important compounds such
as pentabromopseudilin and selective COX-2 inhibitors,
and also attracts interest as a substructure of organic
electronic materials.6
Scheme 1. Formation of azatitanacyclopropanes 3 from 1 and 2 and
their reactions with alkynes.
*
According to the plan mentioned above, we chose com-
Corresponding author. Tel.: +81 45 481 5661; fax: +81 45 413
9770; e-mail: okamos10@kanagawa-u.ac.jp
mercially available 3,3-diethoxypropyne as 7 and tried
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.152

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M. Ohkubo et al. / Tetrahedron Letters 47 (2006) 6209–6212
2
to prepare 8. Thus, the imine 2a, derived from benzalde-
hyde and benzylamine, was treated with a divalent tita-
nium reagent 1 (1.5 equiv) at À40 °C for 1.5 h to
produce the corresponding (g2-imine)Ti(O-i-Pr)2 com-
plexes in situ. To this was added 3,3-diethoxypropyne
(2.0 equiv) at À40 °C and the mixture was gradually
warmed to room temperature over 3 h. Aqueous work-
up and concentration of the resulting mixture did not
yield the corresponding allenylamine 8 but, interest-
ingly, the procedure gave 2-arylpyrroles 6a in 74% iso-
lated yield after column chromatography (Scheme 3).
The direct formation of 6a can be explained by assuming
that the allenylamine 8 was unstable and could easily cy-
clize and eliminate an ethoxy group from the resulting
pyrroline 10 during the work-up.
the addition of H2O to the reaction mixture of 1, 2a
and 3,3-diethoxypropyne afforded deuterated pyrrole
2H-6a with 24% H-incorporation at the C-4 position.
2
2
Meanwhile, the reaction of deuterated imine H-2a7
(>98% 2H-incorporation) provided 6a with 46% or
73% 2H-incorporation after quenching with H2O or
2H2O, respectively. These results might indicate genera-
tion of the metalated pyrrole of the type 12, however, its
formation may be incomplete and the compound of the
type 9 may remain. It can be assumed that ethoxypyrr-
olines such as 10 and 11 are unstable and quickly elim-
inate EtOH to provide the corresponding pyrroles 6a
and 12, respectively. Generated 12 could be protonated
in situ by eliminated EtOH or EtO2H to give 6a and
2H-6a, respectively, but the protonation may occur par-
tially because EtOH or EtO2H can competitively react
in situ with other compound(s) having a metal–carbon
bond(s) such as Ti–C and Mg–C. The reason for the
incomplete conversion of 9 to 12 is unclear at this time.
Another possible pathway may involve intramolecular
aminotitanation of 9 to 11, which can be protonated
to give 10 and/or eliminate EtOH to generate titanated
pyrrole 12 (Scheme 3). To confirm this possibility, we
carried out the following reactions (Scheme 4). Thus,
Next, we applied the method to one-pot synthesis of 6
from aldehyde and amine. Thus, the imine 2 was pre-
pared from the corresponding arylaldehyde (1.0 mmol)
and amine (1.0 mmol) in situ by dehydrative condensa-
tion and then sequentially treated with 1 (1.5 mmol)
and 3,3-diethoxypropyne (2.0 mmol). Figure 1 shows
the yield of 6 synthesized by this one-pot procedure.8
As revealed from the results, a variety of 2-arylpyrroles
could be synthesized in moderate to good yield, where a
functional group such as bromo and trifluoromethyl
moieties tolerated the reaction conditions. Substituted
and unsubstituted phenyl-pyrroles as well as 2-furyl-
and -naphthyl-pyrroles could also be prepared. Regard-
ing the N-substituent, a variety of alkyl groups such as
Scheme 3. Synthesis of pyrrole 6a from imine 2a and its proposed
mechanism.
Figure 1. Yield of 6 prepared from arylaldehyde, amine and 3,3-
diethoxypropyne by one-pot method.
Scheme 4. Reaction of 2H-2a with 1 and 3,3-diethoxypropyne.

M. Ohkubo et al. / Tetrahedron Letters 47 (2006) 6209–6212
6211
3. For recent examples, see: Gorin, D. J.; Davis, N. R.;
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260; Kamijo,
S.; Kanazawa, C.; Yamamoto, Y. J. Am. Chem. Soc. 2005,
127, 9260; Dhawan, R.; Arndtsen, B. A. J. Am. Chem.
Soc. 2004, 126, 468; Siriwardana, A. I.; Kathriarchchi, K.
K. A. D. S.; Nakamura, I.; Gridnev, I. D.; Yamamoto, Y.
J. Am. Chem. Soc. 2004, 126, 13898; Dhawan, R.;
Arndtsen, B. A. J. Am. Chem. Soc. 2004, 126, 468;
Ramanathan, B.; Keith, A. J.; Armstrong, D.; Odom, A.
L. Org. Lett. 2004, 6, 2957; Gabriele, B.; Salerno, G.;
Fazio, A. J. Org. Chem. 2003, 68, 7853; Nishibayashi, Y.;
Yoshikawa, M.; Inada, Y.; Milton, M. D.; Hidai, M.;
Uemura, S. Angew. Chem., Int. Ed. 2003, 42, 2681; Wang,
Y.; Zhu, S. Org. Lett. 2003, 5, 745.
4. For reviews see: Gilchrist, T. L. J. Chem. Soc., Perkin
Trans. 1 1999, 2849–2866; Pyrroles, Chemistry of Hetero-
cyclic Compounds; Jones, R. A., Ed.; Wiley: New York,
1990; Vol. 48, Pyrroles, Part II; Jones, R. A., Ed.; Wiley:
New York, 1992.
Scheme 5. Limitations of the present pyrrole synthesis.
n-propyl, i-propyl, benzyl, p-methoxybenzyl, and
2-methoxyethyl moieties afforded the corresponding
pyrroles, albeit 6g was obtained in poor yield due to
low solubility of the corresponding imine intermediate
in the solvent (ether).
5. Thompson, R. B. FASEB J. 2001, 15, 1671; Muchowski, J.
M. Adv. Med. Chem. 1992, 1, 109; Cozzi, P.; Mongelli, N.
Curr. Pharm. Des. 1998, 4, 181; Furstner, A.; Szillat, H.;
¨
Gabor, B.; Mynott, R. J. Am. Chem. Soc. 1998, 120, 8305;
Chavatte, P.; Yous, S.; Marot, C.; Baurin, N.; Lesieur, D.
J. Med. Chem. 2001, 44, 3223, and references cited therein.
6. Handbook of Conducting Polymers, 2nd ed.; Skotheim, T.
A., Elsenbaumer, R. L., Reynolds, J. R., Eds.; Marcel
Dekker: New York, 1998.
The results shown in Scheme 5 indicate the limitation of
the present method: the method is restricted to the prep-
aration of N-alkyl-2-arylpyrroles. Thus, the reaction of
2k and 2l gave low yield or a trace amount of the corre-
sponding 6k and 6l, respectively.9 An attempt to synthe-
size 3-susbstituted pyrroles such as 6m using 13 instead
of 3,3-diethoxypropyne also failed, where dibenzyl-
amine, reduction product of 2a, was obtained as a major
product.
7. 2H-2a was prepared according to the procedure illustrated
in the following scheme:
8. Typical procedure: A mixture of benzaldehyde (0.101 mL,
1.0 mmol), benzylamine (0.109 mL, 1.0 mmol) and THF
(5 mL) was stirred for 2 h at room temperature and then
concentrated in vacuo. To this was added THF (5 mL)
and the mixture was concentrated under reduced pressure
for azeotropical removal of water. After purging the flask
with argon gas, to this were added ether (8 mL) and
Ti(O-i-Pr)4 (446 lL, 1.5 mmol). To this solution was
added i-PrMgCl (3.95 mL, 0.76 M in ether, 3.0 mmol) at
À40 °C. After being stirred for 1.5 h at À40 °C, 3,3-
diethoxypropyne (0.29 mL, 2.0 mmol) was added and the
mixture was gradually warmed to room temperature over
3 h. After addition of aqueous saturated NaHCO3
(0.2 mL), NaF (ꢀ1 g) and Celite (ꢀ1 g), the mixture was
filtered through a pad of Celite. The filtrate was concen-
trated in vacuo and chromatographed on silica gel to give
1a (158 mg) in 68% yield.
In summary, we developed a one-pot, convergent
method for preparing N-alkyl-substituted 2-arylpyrroles
610 from three components of arylaldehydes, primary
alkylamines and commercially available 3,3-dieth-
2
oxypropyne.11 The results of the reactions with H-2a
2
and/or quenching with H2O pointed out the formation
of metalated pyrroline and/or pyrrole of the types 11
and 12 through an intramolecular aminotitanation of
a titanium amide 9.
Acknowledgements
We thank the Ministry of Education, Culture, Sports,
Science and Technology (Japan) for financial support.
9. Reductive homocoupling product from 2k and benzyl-
(1-isopropylbutyl)amine from 2l were produced as a
major product.2a
10. 1H NMR data (in CDCl3) of 6. Compound 6a:
(500 MHz): d 5.17 (s, 2H), 6.30 (d, J = 2.3 Hz, 2H), 6.76
(t, J = 2.4 Hz, 1H), 7.02–7.07 (m, 2H), 7.25–7.37 (m, 8H).
Compound 6b: (300 MHz): d 5.14 (s, 2H), 6.29–6.31 (m,
2H), 6.78–6.80 (m, 1H), 7.0–7.49 (m, 9H). Compound 6c:
(500 MHz): d 0.81 (t, J = 7.5 Hz, 3H), 1.62–1.69 (m, 2H),
3.87 (t, J = 6.5 Hz, 2H), 6.16–6.19 (m, 2H), 6.76 (d,
J = 2.3 Hz, 1H), 7.25 (d, J = 7.3 Hz, 2H), 7.51 (d,
J = 7.3 Hz, 2H). Compound 6d: (300 MHz): d 3.64 (s,
3H), 3.89 (s, 3H), 5.15 (s, 2H), 6.26 (dd, J = 1.8, 3.6 Hz,
1H), 6.30 (dd, J = 2.7, 3.6 Hz, 1H), 6.76–7.36 (m, 9H).
Compound 6e: (270 MHz): d 3.84 (s, 3H), 3.92 (s, 3H),
5.51 (s, 1H), 6.86 (d, J = 1.8 Hz, 1H), 7.34–7.46 (m, 17H).
Compound 6f: (300 MHz): d 5.19 (s, 1H), 6.33 (dd,
References and notes
1. Sato, F.; Urabe, H.; Okamoto, S. Chem. Rev. 2000, 100,
2835–2886; Kulinkovich, O. G.; de Meijere, A. Chem. Rev.
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2001, 617–618, 148–157; Sato, F.; Okamoto, S. Adv.
Synth. Catal. 2001, 343, 759–784; Sato, F.; Urabe, H. In
Titanium and Zirconium in Organic Synthesis; Marek, I.,
Ed.; Wiley-VCH: Weinheim, Germany, 2002; pp 319–354.
2. For generation and reactions of (g2-imine)Ti(O-i-Pr)2
complexes, see: (a) Gao, Y.; Yoshida, Y.; Sato, F. Synlett
1997, 1353; (b) Fukuhara, K.; Okamoto, S.; Sato, F. Org.
Lett. 2003, 5, 2145; (c) Quntar, A. A. A. A.; Dembitsky, V.
M.; Srebnik, M. Org. Lett. 2003, 5, 357.

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J = 2.7, 3.6 Hz, 1H), 6.38 (dd, J = 2.1, 3.6 Hz, 1H), 6.83
J = 1.8 Hz, 1H), 6.70 (t, J = 1.8 Hz, 1H), 6.83 (d,
J = 7.1 Hz, 2H), 7.01 (d, J = 8.3 Hz, 2H), 7.40 (d, J =
1.2 Hz, 1H). Compound 6j: (300 MHz): d 4.86 (s, 2H),
6.31 (dd, J = 1.8, 3.6 Hz, 1H), 6.37 (dd, J = 2.7, 3.6 Hz,
1H), 6.83–6.88 (m, 3H), 7.14–7.21 (m, 3H), 7.35–7.52
(m, 4H), 7.75–7.90 (m, 3H).
(dd, J = 1.8, 2.7 Hz, 1H), 7.05–7.10 (m, 2H), 7.25–7.36 (m,
3H), 7.44 (d, J = 7.8 Hz, 2H), 7.59 (d, J = 7.8 Hz, 2H).
Compound 6g: (270 MHz): d 3.52 (s, 3H), 3.51 (m, 4H),
6.21 (m, 2H), 6.83 (dd, J = 1.8, 2.7 Hz, 1H), 7.44 (d, J =
7.8 Hz, 2H), 7.59 (d, J = 7.8 Hz, 2H). Compound 6h:
(300 MHz): d 5.29 (s, 2H), 6.19 (d, J = 3.3 Hz, 1H), 6.24
(dd, J = 2.7, 3.6 Hz, 1H), 6.36 (dd, J = 1.8, 3.3 Hz, 1H),
6.48 (dd, J = 1.8, 3.9 Hz, 1H), 6.73 (dd, J = 1.8, 2.7 Hz,
1H), 7.03–7.34 (m, 5H), 7.38 (dd, J = 0.6, 2.4 Hz, 1H).
Compound 6i: (500 MHz): d 3.77 (s, 3H), 5.21 (s, 2H),
6.21–6.22 (m, 2H), 6.37 (d, J = 1.7 Hz, 1H), 6.48 (d,
11. Indole synthesis from 3,3-diethoxypropyne, see: Zhang,
H.-C.; Ye, H.; Moretto, A. F.; Brumfield, K. K.; Marya-
noff, B. E. Org. Lett. 2000, 2, 89; Larock, R. C.; Yum, E.
K.; Refvik, M. D. J. Org. Chem. 1998, 63, 7652;
Sakamoto, T.; Kondo, Y.; Iwashita, S.; Nagano, T.;
Yamanaka, H. Chem. Pharm. Bull. 1988, 36, 1305.