LIC-KOR-promoted synthesis of alkoxydienyl amines: An entry to 2,3,4,5-tetrasubstituted pyrroles

Article abstract of DOI:10.1021/ol9015018

Figure Presented A stereoselective approach to the synthesis of (E)-alkoxydienylamines (2) is described, starting from α,β- unsaturated acetals (1) and aryl imines, under superbasic conditions. These can be readily converted into α-arylglycine derivatives

Full text of DOI:10.1021/ol9015018

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3914-3917
LIC-KOR-Promoted Synthesis of
Alkoxydienyl Amines: An Entry to
2,3,4,5-Tetrasubstituted Pyrroles
Marco Blangetti,† Annamaria Deagostino, Cristina Prandi,* Silvia Tabasso, and
Paolo Venturello
Dipartimento di Chimica Generale e Chimica Organica, UniVersita` di Torino,
Via P. Giuria 7, 10125 Torino, Italy
cristina.prandi@unito.it
Received July 1, 2009
ABSTRACT
A stereoselective approach to the synthesis of (E)-alkoxydienylamines (2) is described, starting from r,ꢀ-unsaturated acetals (1) and aryl
imines, under superbasic conditions. These can be readily converted into r-arylglycine derivatives (3) by mild acidic hydrolysis or, in turn,
cyclized under oxidative conditions in the presence of a Pd catalyst to 2,3,4,5-tetrasubstituted pyrroles (4).
Compounds containing nitrogen-heterocyclic frameworks
are widespread in many naturally occurring molecules and
find applications both in medicine and agriculture.1
Pyrroles deserve particular attention in this group as they
play crucial roles. Importantly, the construction of multiple
substituted pyrrole rings typically relies on classical
approaches such as the Knorr, Hantzsch, and Paal-Knorr
condensations.2 Many alternative strategies respectively
based on cyclization,3 multicomponent,4 aza-Nazarov
cyclization,5 or transition-metal-catalyzed reactions have
been proposed. Tetrasubstituted pyrroles have recently
been prepared starting from propargylic vinyl ethers and
aromatic amines6 or omopropargylic azides7 in Au-
catalyzed processes. In recent years, Cu-promoted C-N
bond-forming reactions have drawn considerable attention.
Pyrroles with different substitution patterns have been
successfully synthesized starting from iodo enynes,8 bromo
enones,9 and 1,4-halo-1,3-dienes.10 A powerful synthetic
† Partially taken from the Ph.D. thesis of M.B.
(1) For reviews, see: (a) Eicher, T.; Hauptmann, S. The Chemistry of
HeterocyclessStructure, Reactions, Synthesis and Application; (translated
by Suschitzky, H.; Suschitzky, J.); VCH: Weinheim, 2003. (b) Gribble,
G. W. In ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R., Rees,
C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford 1996; Vol. 2, p 207. (c)
Joule, J. A.; Millis, K. In Heterocyclic Chemistry: Blackwell Science:
Oxford, UK 2000. (d) Jones, R. A. The Chemistry of Heterocyclic
Compounds: Pyrroles; Wiley: New York, 1990; Vol. 48. (e) Black, D. S.
In Science of Synthesis; Maas, G., Ed.; Thieme: Stuttgart, 2001; Vol. 5, p
441.
(2) For recent examples, see: (a) Shiner, C. M.; Lash, T. D. Tetrahedron
2005, 61, 11628. (b) Minetto, G.; Raveglia, L. F.; Sega, A.; Taddei, M.
Eur. J. Org. Chem. 2005, 5277. (c) Calvo, L.; Gonzales-Ortega, A.; Sao`udo,
M. C. Synthesis 2002, 2450. (d) Chen, J.; Wu, H.; Zeng, Z.; Jin, C.; Zhang,
X.; Su, W. Tetrahedron Lett. 2006, 47, 5383.
10.1021/ol9015018 CCC: $40.75
Published on Web 08/05/2009
 2009 American Chemical Society

method used to construct nitrogen-containing heterocycles
involves the direct amination of olefins by C-N bond
formation. Unsaturated amines have been successfully
used to synthesize pyrrolidine derivatives via a Pd(II)-
catalyzed cyclization.11 Recently, the aminopalladation
route gained a renewed interest through the introduction
of new Pd catalysts and reaction conditions that turned
out to be compatible with the use of dioxygen as an
oxidant. Since the first nearly simultaneous publication
by Hiemstra and Larock of an aerobic oxidative hetero-
cyclization on a variety of alkenes with Pd(OAc)2/
DMSO,12 new catalysts and conditions have been pro-
posed; among these are N-heterocyclic carbene ligands13
and an asymmetric version of the process.14 Despite
remarkable recent developments in this area, as far as we
are aware 1,3-dienes have been rarely used as substrates.15
Due to our interest in the reactivity and exploitation of
R-metalated 1-alkoxy-1,3-dienes as building blocks in
organic synthesis,16 we recently focused our attention on
electrophiles containing multiple C-N bonds.17 Herein
we report the synthesis of functionalized alkoxydienyl
amines and their use both as precursors of R-aryl glycines
and as substrates in aminopalladation reactions to 2,3,4,5-
tetrasubstituted N-tosylpyrroles.
In the course of these studies, which are aimed at the
addition of the metalated alkoxydienyl moiety, we were
particularly interested in investigating the reactivity of
imines as electrophiles. N-Aryl-, N-tosyl-, and N-Boc-
protected imines were successfully prepared from the
corresponding aldehydes and suitable amines, according
to literature procedures.18 The metalation of 1a and 1b
(Table 1) with 2 equiv of LIC-KOR base (equimolar
Table 1. Synthesis of Alkoxydienyl Amines
entry
product
R
PG
Ar
yielda (%)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2j
H
H
H
H
H
H
H
Me
Me
Ph
Ts
Ts
Ts
Ts
Ts
Boc
Ts
Ts
Ph
Ph
p-Tol
p-MeOC6H4
2-thienyl
p-BrC6H4
Ph
57
86
82
91
79
41
25
74
63
(3) For recent examples, see: (a) St. Cyr, D. J.; Arndtsen, B. A. J. Am.
Chem. Soc. 2007, 129, 12366. (b) Larionov, O. V.; de Meijere, A. Angew.
Chem., Int. Ed. 2005, 44, 5664. (c) Tejedor, D.; Gonzalez-Cruz, D.; Garcia-
Tellado, F.; Marrero-Tellado, J. J.; Rodriguez, M. L. J. Am. Chem. Soc.
2004, 126, 8390. (d) Huang, X.; Shen, R. W.; Zhang, T. X. J. Org. Chem.
2007, 72, 1534. (e) Milgram, B. C.; Eskildsen, K.; Richter, S. M.; Scheidt,
W. R.; Scheidt, K. A. J. Org. Chem. 2007, 72, 3941. (f) Martin, C.;
Maddaluno, J.; Duhamel, L. Tetrahedron Lett. 1995, 36, 9469. Martin,
C.; Maddaluno, J.; Duhamel, L. Tetrahedron Lett. 1996, 37, 8169. (g)
Zhang, Z.; Zhang, J.; Tan, J.; Wang, Z. J. Org. Chem. 2008, 73, 5180. (h)
Kamijo, S.; Kanazawa, C.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127,
9260.
Tol
p-MeOC6H4
a Yields of isolated products.
mixture of BuLi and t-BuOK)19 afforded the (E)-(1-
ethoxybuta-1,3-dienyl)metal (metal ) Li or K); dieny-
lamines 2 were then obtained upon addition of the suitable
imine according to a nucleophilic addition mechanism.20
In view of further elaborations of the products, different
protecting groups were employed, such as phenyl (entry
1, Table 1), tosyl (entries 2-6, 8, and 9), and Boc (entry
7). As expected, the reactivity of N-phenylimine was poor,
due to the low reactivity of the iminic carbon; nevertheless,
the corresponding dienylamine 2a was successfully iso-
lated even though in moderate yield (57%).21 Using these
data as a starting point, we considered the reactivity of
other electrophilic N-protected imines to improve yields
(4) For recent examples, see: (a) St. Cyr, D. J.; Martin, N.; Arndtsen,
B. A. Org. Lett. 2007, 9, 449. (b) Nair, V.; Vinod, A. U.; Rajesh, C. J.
Org. Chem. 2001, 66, 4427.
(5) (a) Dieker, J.; Frohlich, R.; Wurthwein, E. U. Eur. J. Org. Chem.
2006, 5339. (b) Ghavtadze, N.; Frohlich, R.; Wurthwein, E. U. Eur. J. Org.
Chem. 2008, 3656.
(6) Binder, J. T.; Kirsch, S. F. Org. Lett. 2006, 8, 2151.
(7) Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005,
127, 11260.
(8) Martin, R.; Rivero, M. R.; Buchwald, S. L. Angew. Chem., Int. Ed.
2006, 45, 7079.
(9) Pan, Y. J.; Lu, H. J.; Fang, Y. W.; Fang, X. Q.; Chen, L. Q.; Qian,
J. L.; Wang, J. H.; Li, C. Z. Synthesis 2007, 1242.
(10) (a) Yuan, X. Y.; Xu, X. B.; Zhou, X. B.; Yuan, J. W.; Mai, L. G.;
Li, Y. Z. J. Org. Chem. 2007, 72, 1510. (b) Martin, R.; Larsen, C. H.;
Cuenca, A.; Buchwald, S. L. Org. Lett. 2007, 9, 3379.
(11) (a) Ro¨nn, M.; Ba¨ckvall, J. E.; Andersson, P. G. Tetrahedron Lett.
1995, 36, 7749. (b) Michael, F. E.; Cochran, B. M. J. Am. Chem. Soc.
2006, 128, 4246. (c) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem.
Soc. 2005, 127, 7690.
(12) (a) Larock, R. C.; Hightower, T. R. J. Org. Chem. 1993, 58, 5298.
(b) Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J.
Org. Chem. 1996, 61, 3584. (c) Anbenthem, R.; Hiemstra, H.; Michels,
J. J.; Speckamp, W. N. J. Chem. Soc., Chem. Commun. 1994, 357. (d)
Vanbenthem, R.; Hiemstra, H.; Longarela, G. R.; Speckamp, W. N.
Tetrahedron Lett. 1994, 35, 9281.
(18) (a) Taguchi, K.; Westheimer, F. H. J. Org. Chem. 1971, 11, 1570.
(b) Ram, R. N.; Khan, A. A. Synth. Commun. 2001, 31, 841. (c) Kanazawa,
A. M.; Denis, J. N.; Greene, A. E. J. Org. Chem. 1994, 59, 1238.
(19) (a) Schlosser, M. J. Organomet. Chem. 1967, 8, 9. (b) Schlosser,
M. In Modern Synthetic Methods; Scheffold, R., Eds.; VCH: Weinheim,
Germany, 1992; p 227. (c) Mordini, A. In AdVances in Carbanion
Chemistry; Snieckus, V., Ed.; JAI Press, Inc.: Greenwich, CT, 1992; Vol.
1, pp 1-45. (e) Lochmann, L. Eur. J. Inorg. Chem. 2000, 1115.
(20) For a stereoselective approach to dienylamines starting from
enantiomerically enriched stannylated allylamines, see: Reginato, G.;
Gaggini, F.; Mordini, A.; Valacchi, M. Tetrahedron 2005, 61, 6791.
(21) N-Boc-dienylamine 2g has been recovered with an unsatisfac-
tory yield (25%, entry 7, Table 1) along with byproducts coming from
the damage of the Boc protecting group, which turns out to be unsta-
ble under superbasic conditions. N-Protected alkyl imines have not
been considered for this work, as they enolize in the superbasic me-
dium.
(13) Carborough, C. C.; Stahl, S. S. Org. Lett. 2006, 8, 3251.
(14) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 7690. For a
recent example of cascade aminopalladation, see: Yip, K.-T.; Zhu, N.-Y.;
Yang, D. Org. Lett. 2009, 11, 1911.
(15) (a) Bar, G. L. J.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. J. Am.
Chem. Soc. 2005, 127, 7308. (b) Åkermark, B.; Ba¨ckvall, J. E.; Lo¨wbenerg,
K.; Zetterberg, K. J. Organomet. Chem. 1979, 166, C33. (c) Ba¨ckvall, J. E.;
Andersson, P. G. J. Am. Chem. Soc. 1990, 112, 3683.
(16) Deagostino, A.; Prandi, C.; Zavattaro, C.; Venturello, P. Eur. J.
Org. Chem. 2006, 11, 2463, and references therein.
(17) Blangetti, M.; Deagostino, A.; Prandi, C.; Zavattaro, C.; Venturello,
P. Chem. Commun. 2008, 1689.
Org. Lett., Vol. 11, No. 17, 2009
3915

and selectively obtain pure products. Thus, N-tosylaldi-
mines were employed as electrophiles in the above-
mentioned reaction: when (E)-N-benzylidene-4-methyl-
benzenesulfonamide was used as an electrophile the
corresponding N-tosyldienylamine 2b was produced in
86% yield. Once the experimental conditions were set up,
the synthesis was successfully carried out with N-
tosylaldimines bearing various aromatic rings (Table 1).
N-Tosyltolyl, p-methoxyphenyl, and thienyl aldimines all
gave good product yields (entries 3-5, 79-91%), while
p-bromophenyl aldimine proved to be troublesome due
to possible metal-bromine exchange side reactions oc-
curring in the superbasic medium. Furthermore, 3-methyl-
substituted pentadienyl sulfonamides 2h and 2j (entries 8
and 9) were successfully obtained from acetal 1b. Linear
dienylamines 2a-f,h-j were then treated with Amberlyst-
15 in CH2Cl2 or with aqueous 1 N HCl (H2O/THF ) 1:1).
The reaction proceeds toward the hydrolysis of the vinyl
ether moiety, leading to N-protected R-arylglycines de-
rivatives 3a-f,h-j with good to excellent yields as
depicted in Scheme 1.22
takes place according to a 5-exo-trig cyclization and leads
to N-tosyl tri- or tetrasubstituted pyrroles.23 At first, when
the reaction was conducted in the presence of 10 mol % of
PdCl2(CH3CN)2 in THF at 50 °C with benzoquinone as an
oxidant, the desired pyrrole was obtained after 5 h in a 65%
yield (entry 1, Table 2).24 We were particularly interested
in using reaction conditions compatible with an efficient
dioxygen-coupled turnover without requiring the presence
of an external oxidant (benzoquinone, Cu(II), or other redox-
active cocatalyst).
Thus, when the reaction was performed under an O2
atmosphere (1 atm) in THF (entry 4) a good conversion was
obtained. Interestingly, in contrast with the data found in
the literature,12 the use of toluene or DMSO as solvents as
well as Pd(OAc)2 as a catalyst gave unsatisfactory results
both with benzoquinone and with oxygen.
As can be deduced from the data reported in Table 2,
a chloride-bearing Pd(II) catalyst, a weakly coordina-
ting solvent, a base, and LiCl that is supposed to stabilize
the ammonium salt intermediate are all essential for
successful reactions. The results have been rationalized
on the basis of the representative catalytic cycle shown
in Scheme 2.
Scheme 1
.
Deprotection of Alkoxydienylamines into
Arylglycines
Scheme 2. Proposed Catalytic Cycle
Besides the unmasking procedure which affords R-aryl
glycines, dienylamines were successfully used as suitable
substrates for an aminopalladation process (Table 2) that
Aminopalladation of the diene, followed by ꢀ-hydride
elimination, generates the heterocyclic product A and
Pd-H. Then a hydropalladation takes place on the
exocyclic double bond affording an allylic palladium
complex B which undergoes a further ꢀ-hydride elimina-
tion to give the final pyrroles 4.
Table 2. Aminopalladation Reactions on Alkoxydienylamines
The reduced catalyst is then directly oxidized by molecular
oxygen to regenerate the Pd(II) catalyst. To extend the
generality of this coupling reaction, an annulation process
using various functionalized N-tosyl protected dienyl amines
under optimized conditions was examined. The results are
summarized in Table 3. Electronic effects seem to play a
role as 3-ethoxy-5-methyl-2-p-tolyl-1-tosyl-1H-pyrrole 4c
T (°C)/
yieldb
(%)
entry solvent additive/basea oxidant time (h)
1
2
3
THF
LiCl, Na2CO3
LiCl, Na2CO3
LiCl, Na2CO3
LiCl, Na2CO3
PBQ
PBQ
O2
50/5
50/5
80/8
50/8
70/6
70/9
65
10
25
95
15
10
toluene
toluene
THF
4
O2
(22) Enantioselective R-arylglycine synthesis is currently under inves-
tigation in our laboratory.
5c
6c
DMSO
DMSO
O2
O2
(23) We decided to consider only N-tosyldienylamines on the grounds
that less nucleophilic nitrogen atoms are more reactive in aminopalla-
dation reactions. For examples on this subject, see: Beccalli, E. M.;
Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. ReV. 2007, 107, 5318.
(24) Attempts to reduce the amount of Pd(II) by the presence of Cu(II)
salts as cocatalysts led to low yield of pyrroles.
CH3CO2Na
a The reactions were conducted in the presence of 2 equiv of base and
2 equiv of additive. b Yields of isolated products. c Pd(OAc)2 10% as a
catalyst was used.
3916
Org. Lett., Vol. 11, No. 17, 2009

(entry 2, Table 3) was smoothly obtained after 8 h at 50 °C
in a 61% yield, while p-MeOC6H4 4d, thienyl 4e, and
p-bromophenyl 4f derivatives required longer reaction
times.
Table 3. Synthesis of Tri- and Tetrasubstituted Pyrrolesa
Phenyl derivative 2b proved to be the hardest substrate to
cyclize into 4b; however, in this case, the reaction time also
remained reasonable (24 h, entry 1, Table 3). Remarkably,
tetrasubstituted pyrroles 4h and 4j were efficiently obtained
under optimized and mild conditions.
In summary, a new and simple method for the synthesis
of tri- and tetrasubstituted N-tosylpyrroles has been described.
The use of N-tosylalkoxydienylamines as a starting material
is particularly convenient and innovative for the rapid
generation of pharmaceutically interesting pyrroles rapidly
and with high diversity. Moreover, the cyclization reaction
relies on an aminopalladation process under a dioxygen
atmosphere, which has so far rarely been described on dienes
in the literature.
Acknowledgment. We gratefully thank the Italian MIUR
and Regione Piemonte (BioBits project, CIPE 2007) for
financial support.
Supporting Information Available: Typical experimen-
tal procedures and spectroscopic and analytical data for
compounds 2a-f,h,j, 3a-f,h,j, and 4b-f,h,j. This ma-
terial is available free of charge via the Internet at
http://pubs.acs.org.
a All of the reactions have been performed in the presence of
PdCl2(CH3CN)2 10% and THF as a solvent. b Yields refer to isolated
products.
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Org. Lett., Vol. 11, No. 17, 2009
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