Two titanium-catalyzed reaction sequences for syntheses of pyrroles from(E/Z)-Chloroenynes or α-Haloalkynols

Article abstract of DOI:10.1021/ol900522g

Titanium-catalyzed intermolecular hydroaminations of (E/Z)-chloroenynes enabled an efficient pyrrole synthesis, which set the stage for the development of a user-friendly one-pot reaction for the regioselective preparation of fully substituted pyrroles fr

Full text of DOI:10.1021/ol900522g

ORGANIC
LETTERS
2009
Vol. 11, No. 9
2031-2034
Two Titanium-Catalyzed Reaction
Sequences for Syntheses of Pyrroles
from (E/Z)-Chloroenynes or
r-Haloalkynols
Lutz Ackermann,* Rene´ Sandmann, and Ludwig T. Kaspar
Institut fu¨r Organische and Biomolekulare Chemie, Georg-August-UniVersitaet,
Tammannstrasse 2, 37077 Goettingen, Germany
lutz.ackermann@chemie.uni-goettingen.de
Received March 13, 2009
ABSTRACT
Titanium-catalyzed intermolecular hydroaminations of (E/Z)-chloroenynes enabled an efficient pyrrole synthesis, which set the stage for the
development of a user-friendly one-pot reaction for the regioselective preparation of fully substituted pyrroles from easily accessible
r-haloalkynols.
Regioselectively substituted pyrroles represent indispensable
structural motifs of among other biologically active natural
products or molecular sensors.1 Therefore, a continued strong
demand exists for flexible syntheses of this five-membered
heterocycle.2 Transition-metal-catalyzed3 C-N bond-forming
reactions have proven highly useful for the preparation of
nitrogen-containing compounds4 in both academia as well
as pharmaceutical industries.5,6 In particular, protocols rely-
ing on addition reactions of N-nucleophiles onto alkynes set
the stage for the development of synthetically useful ap-
proaches.7 In a recent example, Buchwald and co-workers
reported on an elegant application of catalytic C-N coupling/
hydroamidation sequences8 to the synthesis of substituted
pyrroles, employing haloenynes as starting materials.9 This
copper-catalyzed transformation consisted of an initial
intermolecular alkenylation of BocNH2, along with a sub-
sequent intramolecular hydroamidation. Unfortunately, this
reaction was thus restricted to the use of diastereomerically
pure (Z)-iodo- or (Z)-bromoenynes as well as of the less basic
N-nucleophile BocNH2.
(4) For selected representative examples of transition-metal-catalyzed
pyrrole syntheses, see: (a) Fontaine, P.; Masson, G; Zhu, Y. Org. Lett. 2009,
74, 1555–1558. (b) Lu, Y.; Fu, X.; Chen, H.; Du, X.; Jia, X.; Liu, Y. AdV.
Synth. Catal. 2009, 351, 129–134. (c) Lygin, A. V.; Larionov, O. V.;
Korotkov, V. S.; de Meijere, A. Chem.sEur. J. 2009, 15, 227–236. (d)
Dudnik, A. S.; Sromek, A. W.; Rubina, M.; Kim, J. T.; Kel’in, A. V.;
Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 1440–1452. (e) Istrate, F. M.;
Gagosz, F. Org. Lett. 2007, 9, 3181–3184. (f) Yuan, X.; Xu, X.; Zhou, X.;
Yuan, J.; Mai, L.; Li, Y. J. Org. Chem. 2007, 72, 1510–1513. (g) Martin,
R.; Larsen, C. H.; Cuenca, A.; Buchwald, S. L. Org. Lett. 2007, 9, 3379–
3382. (h) Galliford, C. V.; Scheidt, K. A. J. Org. Chem. 2007, 72, 1811–
1813. (i) Smith, C. R.; Bunnelle, E. M.; Rhodes, A. J.; Sarpong, R. Org.
Lett. 2007, 9, 1169–1171. (j) Binder, J. T.; Kirsch, S. F. Org. Lett. 2006,
8, 2151–2153. (k) Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem.
Soc. 2005, 127, 11260–11261. (l) Larionov, O. V.; de Meijere, A. Angew.
Chem., Int. Ed. 2005, 44, 5664–5667. (m) Kamijo, S.; Kanazawa, C.;
Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 9260–9266. (n) Braun, R. U.;
Zeitler, K.; Mueller, T. J. J. Org. Lett. 2001, 3, 3297–3300. (o) Kel’in,
A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074–
2075. (p) Utimoto, K.; Miwa, H.; Nozaki, H. Tetrahedron Lett. 1981, 22,
4277–4278, and references cited therein.
(1) For selected reviews, see: (a) Bellina, F.; Rossi, R. Tetrahedron 2006,
62, 7213–7256. (b) Balme, G. Angew. Chem., Int. Ed. 2004, 43, 6238–
6241. (c) Fuerstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582–3603. (d)
Hoffmann, H.; Lindel, T. Synthesis 2003, 1753–1783. (e) Novak, P.;
Mueller, K.; Santhanam, K. S. V.; Haas, O. Chem. ReV. 1997, 97, 207–
281.
(2) (a) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles, 2nd
ed.; Wiley-VCH: Weinheim, 2003. (b) Joule, J. A.; Mills, K. Heterocyclic
Chemistry, 4th ed.; Blackwell Science Ltd.; Oxford, 2000.
(3) (a) Ackermann, L. Modern Arylation Methods; Wiley-VCH: Wein-
heim, 2009. (b) Beller, M.; Bolm, C. Transition Metals for Organic
Synthesis, 2nd ed.; Wiley-VCH: Weinheim, 2004.
10.1021/ol900522g CCC: $40.75
Published on Web 04/06/2009
 2009 American Chemical Society

Scheme 1
.
Titanium-Catalyzed Pyrrole Synthesis
Table 1. Titanium-Catalyzed Pyrrole Synthesisa
entry 2a diastereomer
[Ti]
T (°C) yield (%)
1
2
3
4
5
6
7
8
Z
E
TiCl4/t-BuNH2
TiCl4/t-BuNH2
TiCl4/t-BuNH2
TiCl4
105
105
105
105
105
105
80
80
83
86
22
82
E/Z
E/Z
E/Z
E/Z
E/Z
E/Z
Ti(NMe2)4
On the contrary, we wondered whether a complementary
approach could be initiated through a catalytic intermolecular
hydroamination of haloenynes 2 (Scheme 1). This should
enable a cyclization, proceeding through a [1,5]H sigmatropic
shift, in essence a tautomerization, followed by an intramo-
lecular nucleophilic substitution.10 Therefore, it should be
possible to employ diastereomers (E)-2, or even, often more
broadly available, mixtures of diastereomers (E/Z)-2. Herein,
we show that the envisioned strategy could be realized with
inexpensive titanium hydroamination catalysts,11,12 which
allowed for the use of more basic amines as well as of chloro-
substituted enynes (E/Z)-2. Furthermore, we disclose a user-
friendly one-pot synthesis of highly substituted pyrroles
starting from easy to prepare R-haloalkynols.
TiCl4/t-BuNH2
TiCl4/t-BuNH2
84
25
a Reaction conditions: 2a (1.00 mmol), 3a (1.25 mmol), [Ti] (20 mol
%), t-BuNH2 (1.20 mmol), PhMe (2.0 mL), 18-24 h; yields of isolated
product.
t-BuNH2 was found to be essential for achieving satisfactory
yields (entry 4). While Ti(NMe2)4 served as an effective
15
alternative as well (entry 5), a titanium hydroamination
catalyst turned out to be mandatory (entry 6). Notably, a
lower reaction temperature of 80 °C gave rise to a syntheti-
cally useful yield of pyrrole 5a (entry 7). On the contrary, a
conversion of the starting materials did not occur at ambient
temperature (entry 8).
At the outset of our studies, we probed our previously
With an effective catalytic system in hand, we explored
its scope and limitations in the one-pot pyrrole synthesis
(Table 2). A variety of (E/Z)-chloroenynes 2 were converted
with anilines 3 in high yields (entries 1-4). However, an
aryl-substituted alkyne gave a lower regioselectivity in the
intermolecular hydroamination,13b which led to a less
satisfactory result (entry 5). Anilines displaying different
halides as functional groups, including 2-iodoaniline (3h),
were chemoselectively transformed into the desired indoles
5g-5k (entries 6-10), a valuable asset for further catalytic
functionalization chemistry. In addition, alkyl amines 3i and
3j could be employed as substrates as well, thereby delivering
pyrroles 5l and 5m, respectively (entries 11 and 12).
Since haloenynes 2 are often tedious to prepare, we desired
to establish a more user-friendly approach, exploiting easily
accessible starting materials. Therefore, we turned our
attention to the use of R-haloalkynols 1, which are available
through nucleophilic addition reactions of acetylides to
developed catalytic system consisting of inexpensive TiCl4
13,14
and t-BuNH2
for the synthesis of pyrrole 5a (Table 1).
Gratifyingly, both diastereomers (Z)-2a and (E)-2a, as well
as their mixtures (E/Z)-2a, provided comparable yields of
desired product 5a (entries 1-3). Furthermore, the additive
(5) (a) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127–2198.
(b) Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104, 2285–2309.
(6) (a) Schlummer, B.; Scholz, U. In Modern Arylation Methods;
Ackermann, L., Ed.; Weinheim, 2009; pp 69-127. (b) Scholz, U. In Amino
Group Chemistry; Ricci, A., Ed.; Wiley-VCH: Weinheim, 2008; pp
333-375. (c) Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. AdV.
Synth. Catal. 2006, 348, 23–39.
(7) Selected reviews on hydroamination reactions: (a) Mu¨ller, T. E.;
Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. ReV. 2008, 108,
3795–3892. (b) Widenhoefer, R. A. Chem.sEur. J. 2008, 14, 5382–5391.
(c) Hultzsch, K. C. AdV. Synth. Catal. 2005, 347, 367–391. (d) Beller, M.;
Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem., Int. Ed. 2004, 43, 3368–
3398. (e) Duncan, A. P.; Bergman, R. G. Chem. Rec. 2002, 2, 431–445.
(8) For related regioselective indole syntheses making use of C-N
coupling/hydroamination sequences, see: (a) Ackermann, L. Org. Lett. 2005,
7, 439–442. (b) Kaspar, L. T.; Ackermann, L. Tetrahedron 2005, 61, 11311–
11316. (c) Sanz, R.; Castroviejo, M. P.; Guilarte, V.; Perez, A.; Fananas,
F. J. J. Org. Chem. 2007, 72, 5113–5118, and references cited therein.
(9) Martin, R.; Rivero, M. R.; Buchwald, S. L. Angew. Chem., Int. Ed.
2006, 45, 7079–7082.
(13) For examples of this system for catalytic hydroaminations, see: (a)
Ackermann, L.; Sandmann, R.; Villar, A.; Kaspar, L. T. Tetrahedron 2008,
64, 769–777. (b) Ackermann, L.; Kaspar, L. T. J. Org. Chem. 2007, 72,
6149–6153. (c) Ackermann, L.; Kaspar, L. T.; Althammer, A. Org. Biomol.
Chem. 2007, 5, 1975–1978. (d) Abbiati, G.; Casoni, A.; Canevari, V.; Nava,
D.; Rossi, E. Org. Lett. 2006, 8, 4839–4842. (e) Ackermann, L.; Kaspar,
L. T.; Gschrei, C. J. Chem. Commun. 2004, 2824–2825. (f) Ackermann, L.
Organometallics 2003, 22, 4367–4368.
(10) Alternatively, an addition/elimination mechanism could be opera-
tive. The feasibility of the proposed [1,5]H sigmatropic shift through
reactions with isotopically labeled compounds was thus far not probed.
(11) For titanium-catalyzed hydroamination reactions for pyrrole syn-
theses, see: (a) Ramanathan, B.; Keith, A. J.; Armstrong, D.; Odom, A. L.
Org. Lett. 2004, 6, 2957–2960. (b) Ackermann, L.; Born, R. Tetrahedron
Lett. 2004, 45, 9541–9544. (c) McGrane, P. L.; Jensen, M.; Livinghouse,
(14) A review: Ackermann, L. Synlett 2007, 507–526.
(15) For representative examples of catalytic hydroaminations with
Ti(NMe2)4, see: (a) Ackermann, L.; Bergman, R. G.; Loy, R. N. J. Am.
Chem. Soc. 2003, 125, 11956–11963. (b) Ackermann, L.; Bergman, R. G.
Org. Lett. 2002, 4, 1475–1478. (c) Shi, Y.; Ciszewski, J. T.; Odom, A. L.
Organometallics 2001, 20, 3967–3969.
T. J. Am. Chem. Soc. 1992, 114, 5459–5460
.
(12) For selected reviews on titanium-catalyzed hydroaminations, see:
(a) Odom, A. L. Dalton Trans. 2005, 225–233. (b) Lee, A. V.; Schafer,
L. L. Eur. J. Inorg. Chem. 2007, 2243–2255, and references cited therein
.
2032
Org. Lett., Vol. 11, No. 9, 2009

Table 2. Scope of Titanium-Catalyzed Pyrrole Synthesisa
Table 3. Regioselective Titanium-Mediated Synthesis of
Fully-Substituted Pyrroles 5a
a Reaction conditions: (a) 1 (1.00 mmol), 3 (1.25 mmol), TiCl4 (1.20
mmol), t-BuNH2 (7.20 mmol), PhMe (2-6 mL), 105 °C, 24 h; (b) AcCl,
TiCl4 (2.00 mmol), 0-23 °C; yields of isolated product.
R-halo ketones. Satisfyingly, inexpensive TiCl4 could be
employed here both as a dehydrating reagent as well as to
ensure the hydroamination reaction, enabling the formation
of tri- or tetrasubstituted pyrroles 5n and 5o (Scheme 2).
a Reaction conditions: (E/Z)-2 (1.00 mmol), 3 (1.25 mmol), TiCl4 (20
mol %), t-BuNH2 (1.20 mmol), PhMe (2.0 mL), 105 °C, 18 h; yields of
isolated product. b GC analysis.
Org. Lett., Vol. 11, No. 9, 2009
2033

tion was not restricted to the use of cyclic starting materials
1 but allowed also for the preparation of nonannulated
pyrroles 5v-5x (entries 7-9).
Scheme 2. Hydroamination-Based Sequence for the
Regioselective Synthesis of Pyrroles 5n and 5o
In conclusion, we developed efficient pyrrole syntheses
relying on titanium-catalyzed intermolecular hydroamination
reactions of diastereomeric mixtures of chloroenynes. Thus,
we described the use of R-haloalkynols for a pyrrole synthesis
through a reaction sequence comprising (a) a dehydration,
(b) an intermolecular hydroamination, (c) a [1,5]H sigmat-
ropic shift, and (d) an intramolecular nucleophilic substitu-
tion. With these two methodologies in hand, a variety of
di-, tri-, tetra-, and pentasubstituted pyrroles proved to be
accessible in a highly modular, yet regioselective, fashion.
Acknowledgment. Support by the DFG is gratefully
acknowledged.
Finally, we probed the regioselective synthesis of fully
decorated pentasubstituted pyrroles. Hence, we functionalized
the remaining C-H bonds of the pyrrole moieties through
electrophilic aromatic substitution reactions within a one-
pot protocol (Table 3). Various annulated pyrroles were
prepared in high yields (entries 1-5), as was product 5u
bearing a valuable halo substituent (entry 6). The transforma-
Supporting Information Available: Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra
for new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL900522G
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Org. Lett., Vol. 11, No. 9, 2009