Triarylaminium salt induced oxidative cyclizations of tertiary amines. Convenient access to 2-substituted pyrrolidinium salts

Article abstract of DOI:10.1021/ol990735c

(equation presented) Although they are common intermediates, the application of aliphatic tertiary aminium radical cations to organic synthesis has so far been restricted to α-deprotonation and related reactions. We report the very convenient oxidative ge

Full text of DOI:10.1021/ol990735c

ORGANIC
LETTERS
1
999
Vol. 1, No. 6
49-852
Triarylaminium Salt Induced Oxidative
Cyclizations of Tertiary Amines.
Convenient Access to 2-Substituted
Pyrrolidinium Salts
8
Ullrich Jahn* and Susanne Aussieker
Institut f u¨ r Organische Chemie, Technische UniVersit a¨ t Braunschweig, Hagenring 30,
D-38106 Braunschweig, Germany
u.jahn@tu-bs.de
Received June 14, 1999
ABSTRACT
Although they are common intermediates, the application of aliphatic tertiary aminium radical cations to organic synthesis has so far been
restricted to r-deprotonation and related reactions. We report the very convenient oxidative generation and facile 5-exo cyclization of tertiary
amimium radical cations to distonic 2-substituted pyrrolidinium radical cations. These can be further oxidized to 1,3-dications and trapped by
nucleophiles as water, alcohols, or chloride ion. Preliminary mechanistic issues and implications will be presented.
7
8
9
Pyrrolidines and their salts play a pivotal role in many aspects
of organic chemistry. For their synthesis, the development
radicals, generated from N-haloamines, N-sulfenylamines,
1
10
or PTOC-carbamates.
of strategies that exploit reactiVe nitrogen-centered inter-
mediates is an active and attractive area of research. The
most widely applied methods are intramolecular N-alkyl-
However, almost all of these methods are applicable only
1
1
to primary and secondary amine derivatives and require
usually the preparation of N-functionalized precursors.
In a research program, directed to the development of
1
1,2
ations, [3 + 2] cycloadditions, or intramolecular additions
1
2
oxidative electron transfer induced reactions, we became
interested in the activation of amines via single electron
transfer (SET) oxidation. Unsaturated tertiary amines are
especially suitable for the initial exploration of the intramo-
lecular reaction behavior of oxidatively generated aliphatic
to multiple bonds. Most notable for the last strategy are
3
4
4c,5
Li-, Pd- or lanthanoid-catalyzed cyclizations, intramo-
lecular halo- or selenoaminations,1 or cyclizations of aminyl
,6
(
1) Recent reviews: (a) Nadin, A. J. Chem. Soc., Perkin Trans. 1 1998,
493-3513 and earlier reviews in this series. (b) Pichon, M.; Figadere, B.
Tetrahedron: Asymmetry 1996, 7, 927-964.
2) Reviews: (a) Gothelf, K. V.; Jørgensen, K. A. Chem. ReV. 1998,
8, 863-909. (b) Grigg, R. Tetrahedron: Asymmetry 1995, 6, 2475-2486.
3) Fujita, H.; Tokuda, M.; Nitta, M.; Suginome, H. Tetrahedron Lett.
992, 33, 6359-6362.
4) Reviews: (a) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem.
999, 576, 125-146. (b) Yamamoto, Y.; Radhakrishnan, U. Chem. Soc.
3
(7) Reviews: (a) Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53,
17543-17594. (b) Esker, J. L.; Newcomb, M. AdV. Heterocycl. Chem. 1993,
58, 1-45.
(8) Boate, D.; Fontaine, C.; Guittet, E.; Stella, L. Tetrahedron 1993, 49,
8397-8406 and references therein.
(9) Bowman, W. R.; Broadhurst, M. J.; Coghlan, D. R.; Lewis, K. A.
Tetrahedron Lett. 1997, 38, 6301-6304 and references therein.
(10) Horner, J. H.; Musa, O. M.; Bouvier, A.; Newcomb, M. J. Am.
Chem. Soc. 1998, 120, 7738-7748 and references therein.
(11) A few stoichiometric Pd-mediated direct cyclizations of tertiary
amines have been reported: van der Schaaf, P. A.; Sutter, J.-P.; Grellier,
M.; van Mier, G. P. M.; Spek, A. L.; van Koten, G.; Pfeffer, M. J. Am.
Chem. Soc. 1994, 116, 5134-5144 and references therein.
(12) (a) Jahn, U.; Hartmann, P. Chem. Commun. 1998, 209-210. (b)
Jahn, U. J. Org. Chem. 1998, 63, 7130-7131.
(
9
1
1
(
(
ReV. 1999, 28, 199-207. (c) M u¨ ller, T. E.; Beller, M. Chem. ReV. 1998,
8, 675-703. (d) Tamaru, Y.; Kimura, M. Synlett 1997, 749-757.
5) Arredondo, V. M.; Tian, S.; McDonald, F. E.; Marks, T. J. J. Am.
Chem. Soc. 1999, 121, 3633-3639 and references therein.
6) (a) Leading references: Jones, A. D.; Knight, D. W.; Redfern, A.
9
(
(
L.; Gilmore, J. Tetrahedron Lett. 1999, 40, 3267-3270. (b) Clive, D. L.
J.; Farina, V.; Singh, A.; Wong, C. K.; Kiel, W. A.; Menchen, S. M. J.
Org. Chem. 1980, 45, 2120-2126.
1
0.1021/ol990735c CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/25/1999

aminium radical cations.13 So far, only the facile R-depro-
tonation or desilylation of tertiary aminium radical cations
to R-amino radicals has been exploited in synthetic applica-
component to be characterized in the salt product mixture
(entry 5). Attempted oxidation of 1a with ceric ammonium
1
9
nitrate (CAN) (2e) in MeOH or MeCN returned 88% or
48% of the amine, respectively (entry 6).
1
4
tions.
Here, we demonstrate that tertiary 4-pentenylaminium
radical cations can be efficiently generated from amines 1
by tris(p-bromophenyl)aminium salts 2a,b and cyclize di-
Having established that the stable triarylaminium salt 2a
with added base serves as a convenient SET oxidant for
cyclization of tertiary pent-4-enylamines 1, we investigated
the scope and limitations of the method (Scheme 2, Table
15
rectly to functionalized pyrrolidinium salts without interfer-
ence of R-deprotonation (Scheme 1).
Scheme 2. Oxidative Cyclizations of Tertiary
4-Pentenylamines 1
Scheme 1. Screening of Conditions for Aminium Radical
Cation Cyclization of 1a
Initial studies focused on the choice of the oxidant16 and
the establishment of suitable reaction conditions. The results
are summarized in Table 1. Treatment of the 5,5-diphenyl-
Table 1. Oxidant Dependence of the Reactivity of Amine 1a
2
). Variation of the amine substituents showed that N,N-
dialkyl-, N,N-diallyl-, or N,N-dibenzyl-substituted amines
b-d undergo oxidative cyclization to hydroxypyrrolidinium
salts 3ba-3da in high yield in the presence of water (entries
-3). The reaction is applicable to spirocyclization (entry
products (%)
1
entry
2
base
3a a
3a b
1a ‚HX
other
1
2
3
4
5
6
a a
45
88
7
40
1
a a
K2CO3
K2CO3
ba
ca
d b
eb,c
1), and the common N-allyl or N-benzyl amine protecting
44
15
49
K2CO3
K2CO3
23 (Ph2CO)
Table 2. Oxidative Cyclizations of Amines 1 to Pyrrolidinium
Salts 3 Mediated by 2aa
a
Conditions: 50 mM MeCN, -20 °C, 10 equiv of H2O (2 equiv of
b
c
base) under N2. 1 equiv of base. In MeOH at 0 °C according to ref 19c:
8% of 1a recovered. In MeCN, 48% of 1a recovered.
8
entry
1
Y
3 (%)
1‚HX (%)
other (%)
1
2
3
4
5
6
7
8
9
b
c
d
e
f
OH
OH
OH
OH
OHb
OH
OH
ba (74)
ca (82)
d a (88)
ea (-)
fa (79)c
fa (49)c
fa (53)c
h a (26)
ia (-)
k a (51)
la (70)f
m a (46)
n a (51)
4
-pentenylamine compound 1a with tris(p-bromophenyl)-
17
aminium hexafluorophosphate (2a) at -20 °C in 50 mM
acetonitrile solution under a nitrogen atmosphere gave the
pyrrolidinium salt 3aa in a moderate 45% yield accompanied
4 (46)
5 (2)
5 (18)
5 (20)
6 (32)
complex
f
g
h
i
a
f
by 40% 1a‚HPF
and 10 equiv of water improved the yield of 3aa to 88%
entry 2). Treatment with 2b under otherwise identical
conditions yielded the chloropyrrolidinium salt 3ab (entry
). Furthermore, 7% of 3aa and 15% of 1a‚HSbCl were
detected by NMR in the crude reaction mixture. Schmittel’s
6 2 3
(entry 1). Addition of 2 equiv of K CO
HNAcd
d
(
1
1
1
0
1
2
OMeb,e
13
OMeb,e
3fa (6), 5 (6)
3a a (10)
3a a (2)
3
6
OEtb,g
a
a
8
35
13
LiClb,h
18
[Fe(phen)
3 6 3
](PF ) (2c) provided 3aa in 49% isolated yield
a
Conditions: 50 mM MeCN, -20 °C, 10 equiv of H2O, 2 equiv of
(entry 4). The moderate yield is basically due to the
K CO , air, unless otherwise stated. b Under N . c 3:1 diastereomeric
2
3
2
d
e
mixture. 2,6-Di-tert-butylpyridine as base. Reaction in MeOH (50 mM).
extremely difficult separation of the salt 3aa and the reduced
iron(II) complex salt. Nitrosyl hexafluorophosphate 2d
oxidized 1a completely, but benzophenone was the only
f
:1 diastereomeric mixture. g Reaction in EtOH (50 mM). 10 equiv of
h
1
dried LiCl instead of water.
850
Org. Lett., Vol. 1, No. 6, 1999

groups are compatible with the reaction conditions (entries
and 3). Neither R-deprotonation-derived nor possible
bicyclization products were observed.
In contrast to the reactivity of aliphatic tertiary amines,
oxidation of N-(5,5-diphenyl-4-pentenyl)-N-methylaniline
agents, too, as shown by the formation of the chloropyrro-
lidinium salt 3na from 1a and LiCl. 3na is identical in its
properties with 3ab obtained with oxidant 2b (entry 13).
The structure assignment of the products rests on char-
acteristic NMR data and for compounds 3da, 3ka, and 6 on
X-ray analysis, which will be reported separately.
2
(1e) by 2a yielded a mixture of products from which we
were able to isolate the biphenyl derivative 4 in 46% yield
From these results, the following preliminary mechanistic
picture emerges (Scheme 3): Amines 1a-i are oxidized to
(entry 4).
The structure of the alkene acceptor and the presence of
air had a notable influence on the reaction outcome. When
reacted under nitrogen, (E)-5-phenyl-4-pentenylamine (1f)
gave a 3:1 diastereomeric mixture of the 2-(1-hydroxyben-
zyl)pyrrolidinium salt 3fa in 79% yield (entry 5). In addition,
the 2-benzoylpyrrolidinium salt 5 was isolated in 2% yield.
For the reaction in the presence of air, the yield of 3fa
dropped to 49%, while the amount of 5 increased to 18%
Scheme 3. Mechanism of the Oxidative Cyclizations of
Tertiary Amines 1
(entry 6). The Z derivative 1g provided a similar result in
the presence of air (entry 7). Besides alcohol 3fa (53%), 20%
of 5 was isolated. The diastereomeric composition of 3fa is
approximately the same in all cyclization reactions, but we
have not been able to assign the relative configuration so
far.
Surprisingly, the 5-methyl-4-hexenylamine species 1h did
not give the alcohol but a separable mixture of (amido-
methyl)pyrrolidinium salt 3ha and 2-isopropenylpyrroli-
dinium salt 6 in 26 and 32% yields, respectively (entry 8).
To ensure complete conversion, the reaction was conducted
in the presence of 2,6-di-tert-butylpyridine as a homogeneous
base. On the other hand, the 4-hexenylamine 1i led only to
an inseparable salt mixture (entry 9).
aminium radical cations 7 by triarylaminium salts 2. 7a-
d,f-i undergo a 5-exo cyclization to 1,3-radical cations 8a-
d,f-i. This cyclization must be a fast process, since Mariano
et al. determined the rate constants for R-deprotonation of
related anilinium derivatives by acetate ions to be in the range
of 10 M s . Distonic radical cations 8a-d,f-h can be
further oxidized to 1,3-dications 9a-d,f-h. Nucleophilic
trapping or deprotonation finally provide the products 3aa-
5
-1 -1 20
To broaden the synthetic utility further, we studied the
application of trapping reagents other than water. When the
oxidative cyclizations of 1a,f were performed in MeOH or
3
na and 6, respectively.
EtOH under N
obtained in moderate to good unoptimized yields ac-
companied by some protonated starting material 1a‚HPF
and 3aa or 3fa (entries 10-12). Salts may serve as trapping
2
, alkoxypyrrolidinium salts 3ka-3ma were
The dichotomy of nucleophilic trapping of the benzylic
(9a-g) vs aliphatic (9h) carbenium ions in aqueous aceto-
nitrile may be explained by an equilibrium reaction with
excess MeCN that lies to the left with stabilized benzylic
6
2
1
(13) For the general reactivity of aminium radical cations, see ref 7 and
species, thus leading to the alcohols 3aa-ga, but to the
right with tertiary aliphatic carbenium ion 9h, providing the
product of a Ritter-type reaction. In the presence of air, 1,3-
radical cations 8a-d,f,g may be trapped by oxygen in a
parallel pathway to give finally the alcohols 3a-d,f,g and
ketone 5.
the following reviews: (a) Schmittel, M.; Burghart, A. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2550-2589. (b) Chow, Y. L.; Danen, W. C.; Nelsen,
S. F.; Rosenblatt, D. H. Chem. ReV. 1978, 78, 243-274. (c) Wagner, B.
D.; Ruel, G.; Lusztyk, J. J. Am. Chem. Soc. 1996, 118, 13-19.
(14) (a) Tertiary amines do not cyclize under photolytic conditions but
form exciplexes; see: Lewis, F. D.; Bassani, D. M.; Burch, E. L.; Cohen,
B. E.; Engleman, J. A.; Reddy, G. D.; Schneider, S.; Jaeger, W.; Gedeck,
P.; Gahr, M. J. Am. Chem. Soc. 1995, 117, 660-669 and references therein.
In conclusion, we have shown for the first time that tertiary
amines can be cyclized to pyrrolidinium salts in high yields
by applying oxidative SET for N-activation. Depending on
the structure of the alkene acceptor, added nucleophiles, and/
or oxygen, different products 3 can be obtained. Further
studies are clearly warranted to extend the scope of this
methodology to other reaction types and substrates.
(b) For the use of oxidative PET/deprotonation or desilylation, see the
review: Hintz, S.; Heidbreder, A.; Mattay, J. Top. Curr. Chem. 1996, 177,
7-124. (c) For more recent applications, see: Su, Z.; Mariano, P. S.;
Falvey, D. E.; Yoon, U. C.; Oh, S. W. J. Am. Chem. Soc. 1998, 120, 10676-
0686 and references therein.
15) For a classical Bu3SnH-mediated radical cyclization of phenylse-
7
1
(
lenomethylammonium salts to 3-substituted pyrrolidinium salts, see: Della,
E. W.; Smith, P. A. J. Org. Chem. 1999, 64, 1798-1806.
(16) For a very useful review on SET reagents, see: Connelly, N. G.;
Geiger, W. E. Chem. ReV. 1996, 96, 877-910.
17) Prepared by modification of Shine’s procedure: Bandlish, B. K.;
Shine, H. J. J. Org. Chem. 1977, 42, 561-563 (see Supporting Information).
18) (a) Preparation: Schmittel, M.; Levis, M. Synlett 1996, 315-316.
b) Applications: Schmittel, M.; Burghart, A.; Malisch, W.; Reising, J.;
S o¨ llner, R. J. Org. Chem. 1998, 63, 396-400 and references therein.
19) (a) Kim, H. J.; Yoon, U. C.; Jung, Y.-S.; Park, N. S.; Cederstrom,
(
Acknowledgment. We thank the Fonds der Chemischen
Industrie and the Deutsche Forschungsgemeinschaft for
(
(
(
(20) Zhang, X.; Yeh, S.-R.; Hong, S.; Freccero, M.; Albini, A.; Falvey,
D. E.; Mariano, P. S. J. Am. Chem. Soc. 1994, 116, 4211-4220.
(21) Photosolvolysis of diarylmethylcarbenium ions give also the alcohol,
even in the presence of a large excess of MeCN: Bartl, J.; Steenken, S.;
Mayr, H.; McClelland, R. A. J. Am. Chem. Soc. 1990, 112, 6918-6928.
E. M.; Mariano, P. S. J. Org. Chem. 1998, 63, 860-863. (b) Wu, X.-D.;
Khim, S.-K.; Zhang, X.; Cederstrom, E. M.; Mariano, P. S. J. Org. Chem.
1
998, 63, 841-859. (c) Takemoto, Y.; Yamagata, S.; Furuse, S.-i.; Hayase,
H.; Echigo, T.; Iwata, C. Chem. Commun. 1998, 651-652.
Org. Lett., Vol. 1, No. 6, 1999
851

financial support (Liebig-Stipendium and Habilitationssti-
pendium) and Prof. Dr. Henning Hopf for his encouragement
and interest in this project.
material is available free of charge via the Internet at
http://pubs.acs.org.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 1-6. This
OL990735C
852
Org. Lett., Vol. 1, No. 6, 1999