Seleniranium ion-triggered reactions: New aspects of friedel-crafts and N-detosylative cyclizations

Article abstract of DOI:10.1021/ol900961m

Selenlranlum Ions at low temperatures (-90 to -78 0C) will initiate effective Frledel-Crafts cycllzatlon If a suitably placed arene is allowed to react even when the arene is unactivated. These intermediates generated from N-aryl-W-tosylamides undergo a n

Full text of DOI:10.1021/ol900961m

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2924-2927
Seleniranium Ion-Triggered Reactions:
New Aspects of Friedel-Crafts and
N-Detosylative Cyclizations
Hwan Jung Lim and T. V. RajanBabu*
Department of Chemistry, The Ohio State UniVersity,
100 West 18th AVenue, Columbus, Ohio 43210
rajanbabu.1@osu.edu
Received May 1, 2009
ABSTRACT
Seleniranium ions at low temperatures (-90 to -78 °C) will initiate effective Friedel-Crafts cyclization if a suitably placed arene is allowed
to react even when the arene is unactivated. These intermediates generated from N-aryl-N-tosylamides undergo a novel, surprisingly efficient,
detosylative cyclization to form 5- or 6-membered nitrogen heterocycles. A debenzylation route is preferred if both benzyl and tosyl groups
are present in the substrate.
Electrophilic cyclizations of alkenyl carboxylic acids, alco-
hols, amines, amides, and functionalized dienes initiated by
seleniranium ions have been broadly applied for the syntheses
of diverse heterocyclic and carbocyclic compounds.1 Inter-
molecular additions of carbon nucleophiles including electron-
rich aromatic derivatives to seleniranium ions are also known,
and these reactions have been developed to a level that it is
now possible to carry out highly diastereoselective additions,
using enantiopure selenium reagents.2 Even though mecha-
nistically related intramolecular additions of carbon nucleo-
philes to putative seleniranium ion intermediates were among
the earliest examples of selenium-induced cyclizations,3
subsequent developments in this area have been sporadic.
In one such rare example, De´ziel in 19984 reported that
4-arylbutenes (1) with electron-rich aryl groups undergo
(1) (a) Browne, D. M.; Wirth, T. Curr. Org. Chem. 2006, 10, 1893. (b)
Ranganathan, S.; Muraleedharan, K. M.; Vaish, N. K.; Jayaraman, N.
Tetrahedron 2004, 60, 5273. (c) Tiecco, M. Electrophilic Selenium,
Selenocyclizations. In Topics in Current Chemistry: Organoselenium
Chemistry; Wirth, T., Ed.; Springer-Verlag: Berlin, 2000; Vol. 208, pp 7-54.
(d) Wirth, T. Angew. Chem, Int. Ed. 2000, 39, 3740. (e) Paulmier, C.
Selenium Reagents and Intermediates in Organic Synthesis; Pergamon:
Oxford, 1986. (f) Nicolaou, K. C.; Petasis, N. A. Selenium in Natural
Product Synthesis; CIS: Philadelphia, 1984. (g) Organoselenium Chemistry,
A Practical Approach; Back, T. G., Ed.; Oxford University Press: Oxford,
1999. (h) For a recent leading reference, see: Jones, A. D.; Redfern, A. L.;
Knight, D. W.; Morgan, I. R.; Williams, A. C. Tetrahedron 2006, 62, 9247.
(2) (a) Toshimitsu, A. Phosphorus, Sulfur Silicon 2005, 180, 935. (b)
Toshimitsu, A.; Nakano, K.; Mukai, T.; Tamao, K. J. Am. Chem. Soc. 1996,
118, 2756. (c) Okamoto, K.; Nishibayashi, Y.; Uemura, S.; Toshimitsu, A.
Tetrahedron Lett. 2004, 45, 6137. (d) Okamoto, K.; Nishibayashi, Y.;
Uemura, S.; Toshimitsu, A. Angew. Chem., Int. Ed. 2005, 44, 3588.
10.1021/ol900961m CCC: $40.75
Published on Web 06/09/2009
 2009 American Chemical Society

competitive carbocyclization when the reaction is conducted
in a mixture of CH2Cl2 and methanol (Scheme 1). The major
Table 1. Phenylseleniranium Ion-Induced Friedel-Crafts
Cyclizations
product(s)/yield
(%)
reaction conditionsa
Scheme 1. Seleniranium-Ion Initiated Friedel-Crafts Reaction
entry
1
2
3
5a
7a
-90 °C, 2 h, -80 °C, 8 h
-78 °C, 2 h
AgBF4 (3.1 equiv) -90 °C,
2 h, -80 °C, 8 h
AgOTf (3.1 equiv) -90 °C,
2 h, -80 °C, 8 h
-100 °C, 2 h, -80 °C, 8 h
-90 °C, 2 h, -80 °C, 8 h
-90 °C, 2 h, -80 °C,
8 h (no MeOH quench)
-78 °C, 2 h, rt, 8 h
6a (85)
6a (7)
6a (75)
4
6a (61)
5
6
7
8a (55), 9a (30)
8a (48), 9a (15)
8a + 9a (30%)
8
9
8a + 9a (<5%)
8a + 9a (<5%)
PhSeCl, AgSbF6 (3.1 equiv)
-90 °C, 2 h, -80 °C, 8 h
side product, the ꢀ-methoxyselenide 4, is readily converted
into the cyclic product 3 by protic or Lewis acids. Formation
of the methoxylated product 4 cannot be avoided since in
the absence of methanol the reaction gave poor yields. Yet
another limitation of this potentially powerful Friedel-Crafts
cyclization is that nonactivated arenes (e.g., phenyl) do not
participate in this reaction.3j,4,5a
While searching for a general route to 1-methylenetetralin
and analogous heterocyclic compounds in connection with
our asymmetric hydrovinylation approach to 2,3-pyrrolidi-
noindoles (Figure 1), we decided to revisit this area. We
10
11
12
13
14
15
NaBARF 1.2 (equiv), -90 °C, 2 h 8a (38), 9a (15)
-78 °C, 2 h 6b (97)
AgSbF6 (1.05 equiv), -78 °C, 2 h 6b (50)
5b
10a -90 °C, 1 h, -70 °C, 8 h
10b -90 °C, 1 h, -80 °C, 8 h
11a (80)
11b (52)
13 (74)
12
-90 °C, 2 h, -80 °C, 8 h
a See the text and Supporting Information for details. Reactions
performed in CH2Cl2 in the presence of 1.01 equiv of PhSeBr and 3.1 equiv
of AgSbF6 unless otherwise mentioned. At the end of the reaction, excess
MeOH was added and the mixture stirred for 1 h before workup.
Our studies (eqs 1 and 2; Table 1) started with cyclizations
of two prototypical substrates, but-3-enyl 4-methoxyphenyl
ether (5a) and N-phenyl-N-(but-3-enyl)-4-toluenesulfonamide
(7a). A number of studies in the literature have suggested
that counterions and additives in the reaction medium
significantly affect the reactivity and selectivity of the
reactions of seleniranium ions.7 For example, in a study that
is highly pertinent to the present work, it has been reported
that PhSeCl in the presence of a silver salt does not effect
the cyclization of 4-aryl-1-butenes,5a even though such
reactions are known to proceed in moderate yields using
combination of N-(phenylseleno)succinimide and Lewis
acids3j as long as the arene is activated and electron-rich.
We decided to explore the effect of alternate counterions
and reaction conditions on the cyclizations. Initial scouting
experiments to identify the optimal reaction conditions
revealed that the best yields are obtained when a combination
of PhSeBr and a silver salt in anhydrous CH2Cl2 is employed.
Thus, the but-3-enyl aryl ether 5a gave the expected product
6a in 85% isolated yield when the reaction was initiated at
-90 °C and then stirred for 8 h at -80 °C (entry 1, Table
1). Generation of the seleniranium ion and its subsequent
reaction at low temperature are critical for success of this
reaction. Entry 2 shows a reaction that was allowed to
proceed only for a shorter period, resulting in a much lower
yield. Entry 8 is a related example using the substrate 7a.
Presumably, alternate modes of reactivity of the seleniranium
ions have higher energies of activation and they are not
competent at low temperatues where the slow cyclization
ensues. Under the optimized reaction conditions, 3.1 equiv
of the silver salt is used. Highly reproducible results were
Figure 1. Alkene precursors for 2,3-pyrrolidinoindoles.
expected the alkene-forming elimination reaction to be more
facile via a selenide as compared to an iodide5 or sulfide6
arising from alternate cyclizations, especially for the synthesis
of the more sensitive N- and O-containing heterocycles.
Several novel observations that were made during the course
of these investigations form the basis of this paper.
(3) (a) Clive, D. L. J.; Chittatu, G.; Wong, C. K. J. Chem. Soc., Chem.
Commun. 1978, 441. (b) Kametani, T.; Suzuki, K.; Kurobe, H.; Nemoto,
H. J. Chem. Soc., Chem. Commun. 1979, 1128. (c) Nicolaou, K. C.;
Claremon, D. A.; Barnette, W. E.; Seitz, S. P. J. Am. Chem. Soc. 1979,
101, 3704. (d) Jackson, W. P.; Ley, S. V.; Whittle, A. J. J. Chem. Soc.,
Chem. Commun. 1980, 1173. (e) Alderdice, M.; Weiler, L. Can. J. Chem.
1981, 59, 2239. (f) Jackson, W. P.; Ley, S. V.; Morton, J. A. Tetrahedron
Lett. 1981, 22, 2601. (g) Kametani, T.; Suzuki, K.; Kurobe, H.; Nemoto,
H. Chem. Pharm. Bull. 1981, 29, 105. (h) Ley, S. V.; Lygo, B.; Molines,
H.; Morton, J. A. J. Chem. Soc., Chem. Commun. 1982, 1251. (i) Toshimitsu,
A.; Uemura, S.; Okano, M. J. Chem. Soc., Chem. Commun. 1982, 87. (j)
Edstrom, E. D.; Livinghouse, T. Tetrahedron Lett. 1986, 27, 3483.
(4) De´ziel, R.; Malenfant, E.; Thibault, C. Tetrahedron Lett. 1998, 39,
5493.
(5) (a) Appelbe, R.; Casey, M.; Dunne, A.; Pascarella, E. Tetrahedron
Lett. 2003, 44, 7641. (b) Barluenga, J.; Trincado, M.; Rubio, E.; Gonza´lez,
J. M. J. Am. Chem. Soc. 2004, 126, 3416.
(6) Edstrom, E. D.; Livinghouse, T. J. Am. Chem. Soc. 1986, 108, 1334.
Org. Lett., Vol. 11, No. 13, 2009
2925

obtained when the crude reaction mixture was stirred with
methanol for 60 min at the end of the reaction, presumably
resulting in the decomposition of any silver complexes and/
or salts that might be formed. We have noticed that skipping
the methanol quench results in significant loss of material
during isolation and purification by column chromatography
(entry 6 vs 7). As shown in entries 3 and 4, other silver salts
such as AgBF4 and AgOTf also work, giving slightly lower
yields of the product(s). Reactions carried out using PhSeCl
and Ag salts gave lower yields (entry 9). Silver ions are
known to participate in reactions of alkenes including
cyclization reactions.8 To rule out the unlikely involvement
of Ag(I)-alkene intermediates in these reactions, the cy-
clization of 7a was carried out using a putative seleniranium
ion that was generated from PhSeBr and sodium tetrakis[3,5-
di(trifluoromethyl)phenyl]borate (Na BARF).9 The product
distribution is not markedly different from the AgSbF6-
mediated reaction (entry 10), ruling out any special role for
Ag(I) in these reactions. Note that the but-3-enyl-N-sulfon-
amide 7a also gives varying amounts of an unexpected side
product 9a, in which the sulfonyl group has been removed
concomitant with the generation of a pyrrolidine nucleus (eq
2, entries 5-10).
in the cyclization event. Thus, 4-phenylbut-1-ene 10a and a
dimethyl analogue 10b undergo the cyclization under the
standard conditions via a 6-endo-trig cyclization mode (eq
3). BOC-protected N-allylaniline 12 also follows a similar
course giving a single product 13 in 74% yield. Loss of the
BOC protecting group under these highly electrophilic
conditions is no surprise.
Existence of a discrete, long-lived phenylseleniranium ion
under these reaction conditions7a can be inferred from the
reaction of 4-allylanisole 14 (eq 5), a substrate that is resistant
to cyclization because of stereoelectronic considerations.
Upon treatment with PhSeBr and AgSbF6 under conditions
similar to the cyclization (2 h at -90 °C, then 8 h at -80
°C), followed by addition of methanol, 14 yields the expected
methoxyselenated compounds 15 and 16 in 41% and 27%
yields, respectively. Similar products from allylbenzene have
been observed under more standard selenoetherification
conditions.10
N-(But-1-enyl)-N-methylaniline 17 failed to undergo the
cyclization even though cyclization of nonaromatic homoal-
lylamines have been reported to give either an azitidine or a
pyrrolidine upon treatment with PhSeX at room tempera-
ture.11 Allyl ethers 18a and 18b gave products arising from
allylic-O cleavage. Allylic amine derivatives 19a and 19b
gave low yields of the expected cyclization products 20a
and 20b (29% and 39%, respectively).
Since cyclizations of secondary amine substrates carrying
Tos1h,12 and BOC13 protecting groups on nitrogen proceed
without incident, we were surprised to find the partial loss
of the toluenesulfonyl group in the cyclization of 7a to 9a
(eq 2). Even though detosylation14 and dissociative migration
of tosylates15 have been observed under strongly electrophilic
conditions, to the best of our knowledge, this detosylative
cyclization represents a novel transformation. We wondered
Cyclization of but-3-eneyl phenyl ether 5b proceeds to
give a nearly quantitative yield of the 6-exo-cyclization
product 6b (entry 11). As noted before, significantly higher
yields are obtained when more than stoichiometric amounts
of AgSbF6 are used in the reaction (entry 11 vs 12).
(7) (a) Schmid, G. H.; Garratt, D. G. Tetrahedron Lett. 1975, 3991. (b)
Khokhar, S. S.; Wirth, T. Eur. J. Org. Chem. 2004, 4567. (c) Khokhar,
S. S.; Wirth, T. Angew. Chem, Int. Ed. 2004, 43, 631. (d) Denmark, S. E.;
Collins, W. R. Org. Lett. 2007, 9, 3801.
(8) Weibel, J.-M.; Blanc, A.; Pale, P. Chem. ReV. 2008, 108, 3149.
(9) Use of NaBARF to generate non-coordinating counteranions in
homogeneous catalysis is widely practiced. See, for example: (a) Brookhart,
M.; Grant, B.; Volpe, A. F., Jr. Organometallics 1992, 11, 3920. (b)
DiRenzo, G. M.; White, P. S.; Brookhart, M. J. Am. Chem. Soc. 1996,
118, 6225. (c) Nomura, N.; Jin, J.; Park, H.; RajanBabu, T. V. J. Am. Chem.
Soc. 1998, 120, 459.
(10) Tiecco, M.; Testaferri, L.; Temperirini, A.; Bagnoli, L.; Marini,
F.; Santi, C. Synlett 2001, 1767.
(11) (a) Berthe, B.; Outurquin, F.; Paulmier, C. Tetrahedron Lett. 1997,
38, 1393. (b) Pannecoucke, X.; Outurquin, F.; Paulmier, C. Eur. J. Org.
Chem. 2002, 995.
In the most significant departure from previous studies,
under these conditions, even unactivated arenes participate
2926
Org. Lett., Vol. 11, No. 13, 2009

whether placing an electron-withdrawing group on the aryl
ring would divert the reaction away from the Friedel-Crafts
cyclization. Indeed, in substrates carrying a nitro or a
trifluoromethyl group in the arene, the Friedel-Crafts
pathway is completely shut down and all cyclizations now
proceed through the detosylative pathway (eq 2, 7b f 9b).
Other examples of this transformation are shown in Table
2. The efficiency of the detosylative cyclization depends on
the length of the alkene tether and nature of other substituents
on nitrogen. While the N-but-3-enyl derivatives (e.g., 7b and
24) are generally sluggish (∼8 h at -80 °C) in 5-endo-trig
cyclizations, the N-pent-4-enyl derivatives (21 and 26)
undergo more facile reactions giving both the 6-endo and
5-exo cyclization products (entries 2 and 4) in respectable
yields. With a pent-4-enyl substituent, a deactivated aromatic
nucleus is not needed for an effective the detosylative
cyclization (entry 5). The expected Friedel-Crafts cyclization
(compare to 7a, eq 2) would yield a 7-membered ring by
exo cyclization, and presumably this reaction is not competi-
tive with the piperidine formation. As a result, the heterocycle
30 is formed in an astonishing 96% yield! If the substrate
carries N-benzyl and N-tosyl substituents as in 31 and 33,
exclusive loss of the benzyl group is observed in the
formation of the nitrogen heterocycle.16
Table 2. Seleniranium-Ion Initiated Detosylative Cyclizations
In summary, here we disclose new reactions involving
seleniranium ions for intramolecular cyclizations. New
protocols for the Friedel-Crafts cyclizations of nonactivated
arene-alkenes and novel detosylative cyclizations of tertiary
N-p-toluenesulfonamides are described.
Acknowledgment. Financial assistance for this research
by the NSF (CHE-0610349) and NIH (General Medical
Sciences, R01 GM075107) is gratefully acknowledged.
Supporting Information Available: Full experimental
details of synthesis of substrates and cyclization reactions;
spectroscopic and chromatographic data for characterization
of compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL900961M
(12) Jones, A. D.; Knight, D. W.; Redfern, A. L.; Gilmore, J. Tetrahe-
dron Lett. 1999, 40, 3267.
(13) Wirth, T.; Fragale, G. Synthesis 1998, 162.
a See the Supporting Information for details. PhSeBr (1.1 equiv), AgSbF6
(3.1 equiv) CH2Cl2, after reaction, mixture was stirred with MeOH for 1 h
before workup.
(14) Pelkey, E. T.; Gribble, G. W. Can. J. Chem. 2006, 84, 1338.
(15) Lee, Y. T.; Chung, Y. K. J. Org. Chem. 2008, 73, 4698.
(16) In the seleniranium-mediated cyclizations of secondary N-allyl-N-
benzylamines, the benzyl group is retained in the product. See ref 11.
Org. Lett., Vol. 11, No. 13, 2009
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