Diastereoselective synthesis of indanes and tetralins via intramolecular Friedel-Crafts reaction

Article abstract of DOI:10.1021/ol400341p

An easy access to tetralin and indane skeletons has been developed using a diastereoselective intramolecular Friedel-Crafts alkylation. Treatment of diastereomeric mixtures of benzyl carbinols with a catalytic amount of Ca(NTf₂)₂/Bu₄NPF₆ yields the respective tetralin or indane in good yields with high levels of regio- and diastereoselectivity.

Full text of DOI:10.1021/ol400341p

ORGANIC
LETTERS
2013
Vol. 15, No. 6
1370–1373
Diastereoselective Synthesis of Indanes
and Tetralins via Intramolecular
FriedelÀCrafts Reaction
Jeanne-Marie Begouin,† Francesca Capitta,† Xian Wu, and Meike Niggemann*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1,
52074 Aachen, Germany
niggemann@oc.rwth-aachen.de
Received February 5, 2013
ABSTRACT
An easy access to tetralin and indane skeletons has been developed using a diastereoselective intramolecular FriedelÀCrafts alkylation.
Treatment of diastereomeric mixtures of benzyl carbinols with a catalytic amount of Ca(NTf2)2/Bu4NPF6 yields the respective tetralin or indane in
good yields with high levels of regio- and diastereoselectivity.
Tetralin and indane ring structures are present in a wide
range of natural products and pharmaceuticals.1 A variety
of synthetic methods to synthesize these skeletons have
been explored.2 Although intramolecular FriedelÀCrafts
reactions of benzyl carbinols mediated by stoichiometric
protocol to the intramolecular FriedelÀCrafts6 reaction of
benzyl carbinols. The reaction starts with a dehydration of
the hydroxyl function yielding a carbocationic species I
(s. Scheme 1), a process which our calcium catalyst has
proven to promote particularly efficiently. This initially
formed carbocation I might cyclize directly with the arene
moiety. Alternatively, a prior rearrangement, either by a
amounts of Lewis and Brønsted acids (e.g., SnCl4, BF3
3
Et2O, and CF3CO2H) have been described,3 no catalytic
version of this reaction is known to date. Recently, we
developed a Ca(NTf2)2/Bu4NPF6 based catalyst system4
for the intermolecular alkylation of electron-rich arenes
using secondary and tertiary benzylic, allylic, and pro-
pargylic alcohols as environmentally benign alkylating
agents under very mild rt conditions.5 Hence, we became
interested in the possibility of extending the aforementioned
(3) (a) Khalaf, A. A.; Roberts, R. M. J. Org. Chem. 1972, 37, 4227. (b)
Roblin, R. O.; Marston, D., Jr.; Bogert, T. J. Am. Chem. Soc. 1935, 57, 151.
(c) Bright, S. T.; Coxon, J. M.; Steel, P. J. J. Org. Chem. 1990, 55, 1338. (d)
Banik, B. K.; Ghosh, S.; Ghatak, U. R. Tetrahedron 1988, 44, 6947. (e) Axon,
B. W.; Davis, R. B.; Woodgate, P. J. Chem. Soc., Perkin Trans. 1 1981, 2956.
(f) Nasipuri, D.; De Dalai, I. J. Chem. Soc., Perkin Trans. 1 1976, 19. (g)
Bogert, M. T.; Davidson, D.; Apfelbaum, P. M. J. Am. Chem. Soc. 1934, 56,
959. (h) Barrow, C. J.; Bright, S. T.; Coxon, J. M.; Steel, P. J. J. Org. Chem.
1989, 54, 2542. (i) Barclay, L. R. C.; Ginn, B. A.; Milligan, C. E. Can. J.
Chem. 1964, 42, 579. (j) Ganeshpure, P. A.; Stevenson, R. J. Chem. Soc.,
Perkin Trans. 1 1981, 1681. (k) Corey, E. J.; Luo, G.; Lin, L. S. Tetrahedron
Lett. 1998, 39, 2001. (l) Nagumo, S.; Miyoshi, I.; Akita, H.; Kawahara, N.
Tetrahedron Lett. 2002, 43, 2224. (m) Ziegler, F.; Schwartz, J. A. J. Org.
† These authors contributed equally.
(1) For examples of tetralins in medicinal chemistry, see: (a) Perrone, R.;
Berardi, F.; Colabufo, N. A.; Leopoldo, M.; Tortorella, V.; Fiorentini, F.;
Olgiati, V.; Ghiglieri, A.; Govoni, S. J. Med. Chem. 1995, 38, 943. (b)
Brewster, W. K.; Nichols, D. E.; Riggs, R. M.; Mottola, D. M.; Lovenberg,
T. W.; Lewis, M. H.; Mailman, R. B. J. Med. Chem. 1990, 33, 1756. For
examples of indanes in medicinal chemistry, see: (c) Gross, M. F.; Beaudoin,
S.; McNaughton-Smith, G.; Amato, G. S.; Castle, N. A.; Huang, C.; Zou,
A.; Yu, W. Bioorg. Med. Chem. Lett. 2007, 17, 2849.
€
Chem. 1978, 43, 985. (n) Muhlthau, F.; Bach, T. Synthesis 2005, 19, 3428.
(o) Khalaf, A. A.; Roberts, R. M. J. Org. Chem. 1969, 34, 3571. (p) Lednicer,
D.;Emmert,D.E.;Lyster,S.C.;Duncan,G.W.J. Med. Chem. 1969,12, 881.
(q) Bonnet-Delpon, D.; Cambillau, C.; Charpentier-Morize, M.; Jacquot, R.;
Mesureur, D.; Ourevitch, M. J. Org. Chem. 1988, 53, 754. (r) Angle, S. R.;
Louie, M. S. Tetrahedron Lett. 1989, 30, 5741. (s) Blum, R.; Giovannini, E.;
Hengartner, U.; Vallat, G. Helv. Chim. Acta 2002, 85, 1827–1840.
(4) (a) Haubenreisser, S.; Niggemann, M. Adv. Synth. Catal. 2011, 353,
469. (b) Meyer, V. J.; Niggemann, M. Eur. J. Org. Chem. 2011, 3671. (c)
Meyer, V. J.; Niggemann, M. Chem.;Eur. J. 2012, 18, 4687. (d) Niggemann,
M.; Bisek, N. Chem.;Eur. J. 2010, 16, 11246. (e) Niggemann, M.; Diba,
A. K.; Begouin, J.-M.; M. Tetrahedron Lett. 2012, 53, 6629.
(2) (a) Xie, K.; Wang, S.; Li, P.; Li, X. Tetrahedron Lett. 2010, 51,
4466. (b) Youn, S. W.; Pastine, S. J.; Sames, D. Org. Lett. 2004, 6, 581. (c)
Li, G.; Xiao, Q.; Li, C.; Wang, X.; Yin, D. Tetrahedron Lett. 2011, 52,
ꢀ
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Commun. 2010, 46, 7611.
r
10.1021/ol400341p
Published on Web 03/06/2013
2013 American Chemical Society

Table 1. Catalyst Screening for the Intramolecular
FriedelÀCrafts Reaction
Scheme 1. Rearrangements of Initially Formed Carbocation I
temp
yield
(%)b
entrya
catalyst
additive
(°C)
solvent
1
Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
Ca(OTf2)2
Ca(OTf2)2
Ba(NTf2)2
Ba(NTf2)2
Ag(NTf)2
Ag(NTf)2
Sc(OTf)2
Sc(OTf)2
HNTf2
Bu4NPF6
Bu4NPF6
Bu4NPF6
À
rt
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
Et2O
toluene
MeNO2
10
hydride shift or an eliminationÀreprotonation sequence,
might lead to the related carbenium ions II and III, which
in turn can cyclize to give the regioisomeric products. Most
interestingly, throughout this process, residual stereocen-
ters in the starting material can be reset to the thermo-
dynamically most favorable trans-configuration in III
before the final cyclization, thus giving rise to diastereo-
merically pure products even when diastereomeric mix-
tures are used as starting materials. Opposed to the con-
siderable number of reported direct cyclization reactions
of benzyl carbinols,3hÀq only a handful of examples which
involve a prior rearrangement are reported,3aÀg even
though such a rearrangement ring-closure cascade repre-
sents a powerful tool to access diastereomerically pure
compounds from easily accessible benzyl carbinols.
2
80
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
quantc
3
quant
4
0
5
Bu4NPF6
À
0
6
0
7
Bu4NPF6
À
0
8
0
9
Bu4NPF6
À
0
10
11
12
13
14
15
16
17
18
13
22d
0
Bu4NPF6
À
Bu4NPF6
À
0
HNTf2
75d,e
quant
8
Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
Bu4NPF6
Bu4NPF6
Bu4NPF6
Bu4NPF6
12
91
With these considerations in mind we conducted our
initial investigation using benzyl carbinol 1 as a model
compound for the screening of a broad spectrum of reac-
tion conditions (Table 1). When 1 was treated with 5 mol %
Ca(NTf2)2/Bu4NPF6 in 1,2-dichloroethane (DCE) at rt, the
indane 2 was obtained in very low yield (Table 1, entry 1;
10% yield after 12 h) but with complete control of diastereo-
and regioselectivity. As expected, the relative stereochem-
istry was determined to be trans by NOE experiments.
Intrigued by this preliminary result, we sought to establish
reaction conditions in order to improve the yield. To our
delight, after 1 h at 80 °C, the desired product 2was obtained
in almost quantitative yield (entry 2). At lower temperature,
the reaction rate is reduced and conversion ceases after 12 h
(entry 3). The reaction was performed in the presence of
molecular sieves to exclude hydrolysis of the catalyst by
water generated in the deoxygenation process. However, no
influence on the yield was observed. Comparison with other
catalyst systems (entries 5, 7, 9, 11, 13) clearly demonstrates
the superior activity of the Ca(NTf2)2/Bu4NPF6 system for
the intramolecular FriedelÀCrafts cyclization. As already
mentioned in previous publications,4a,5,7 the hexafluoro-
phosphate salt is required to form the highly reactive and
much more soluble CaNTf2PF6 species via an anion
a Reaction conditions: The alcohol (0.25 mmol) was dissolved in
0.75 mL of solvent, catalyst (5 mol %) and additive (5 mol %) were
added, and the reaction mixture was stirred for 12 h at the indicated
temperature. b Isolated yield. c Yield of 2 after 1 h. d 79% yield at 80 °C
after 12 h. e 49% yield with 10 mol % of HNTf2 at 40 °C after 12 h.
exchange reaction.4a In the presence of 5 or 10 mol % of
the superacid HNTf2 (entry 14) the product 2 was obtained
in good but considerably lower yield than under calcium
catalysis. Interestingly, under acidic conditions the presence
of the additive caused the reaction to cease. Among others,
such as Bu4NSbF6 or Bu4NBF4, the initially screened
Bu4NPF6 was the best additive to promote the process
(see Supporting Information (SI)). The reaction rate was
significantly lower in other solvents such as toluene, nitro-
methane, and diethyl ether. Under the thus optimized reaction
conditions a series of different benzyl carbinols were cyclized
(see Table 2). The synthesis of the cyclization precursors was
accomplished by the addition of the appropriate Grignard
reagent (methyl-, benzyl-, or isopropylmagnesiumchloride)
to the corresponding ketone, yielding the respective carbinol
with varying degrees of stereoselectivity. Due to the envi-
sioned redistribution of stereocenters during the ring closure,
the stereoselectivity was not further analyzed at this stage.
When the R-position was substituted by an ethyl group
as in 3, instead of the methyl group in 1, the related indane
compound was obtained in good yield and again with full
trans diastereoselectivity (entry 1).
(5) Niggemann, M.; Meel, M. J. Angew. Chem., Int. Ed. 2010, 49, 1.
(6) (a) Womack, G. B.; Angeles, J. G.; Fanelli, V. E.; Heyer, C. A.
J. Org. Chem. 2007, 72, 7046. (b) Ho, T. L.; Lee, K.-Y.; Chen, C.-K.
J. Org. Chem. 1997, 62, 3365. (c) Suzuki, T.; Ohwada, T.; Shudo, K.
J. Am. Chem. Soc. 1997, 119, 6774. (d) Cai, Q.; Zhao, Z.-A.; You, S.- L.;
T. Angew. Chem., Int. Ed. 2009, 48, 7428. (e) Poulsen, T. B.; Jørgensen,
K. A. Chem. Rev. 2008, 108, 2903. (f) You, S.-L.; Cai, Q.; Zeng, M.
Chem. Soc. Rev. 2009, 38, 2190.
The presence of the additional phenyl group in 5 has no
influence on diastereoselectivity and yield (entry 2). Here,
in addition, the phenyl group at the reactive carbocationic
(7) Qui, H.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew.
Chem., Int. Ed. 2007, 46, 409.
Org. Lett., Vol. 15, No. 6, 2013
1371

Table 2. Catalytic Cyclization of Diastereomeric Mixtures of Benzyl Carbinols
a Reaction conditions: 5 mol % Ca(NTf2)2/Bu4NPF6 were added to the benzyl carbinol (0.25 mmol) in 0.75 mL of DCE and stirred at 40 °C for 20 h.
b Isolated yield. c Reaction at 80 °C. d Mixture 70/30 of trans/cis diastereomers. e The reaction was conducted at 80 °C for 20 h or at 40 °C for 48 h.
f Reaction at 80 °C for 2 h. g Mixture 60/40 of trans/cis diastereomers. h Mixture 90/10 of trans/cis diastereomers. i Mixture 77/23 of trans/cis
diastereomers. j Mixture 85/15 of trans/cis diastereomers.
center is oriented as such that it adopts a trans-configura-
tion after ring closure. The stereoselectivity in the reactions
of benzyl carbinols 7 and 9 is governed by the same
preorientation of the phenyl moiety at the carbocationic
position. Whenthe formation ofregioisomers was prone to
occur, the selectivity of the cyclization was generally high.
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Org. Lett., Vol. 15, No. 6, 2013

Compound 9 shows a preference for closure at the more
stable tertiary benzylic carbon over closure at its secondary
benzylic carbon. The related substrate 11 prefers to close at
the less stabilized secondary position, presumably attrib-
uted to higher steric repulsion induced by the ethyl group
at the tertiary benzylic carbon. Nevertheless, only one out
of the three possible diastereomers of 11 was obtained,
once again with an all-trans-configuration. The regioselec-
tivity was once more exclusive in the cyclization of benzyl
carbinol 13, with steric factors again determining the
closure at the benzyl carbon with the methyl substituent.
Interestingly, substrate 23, with an isopropyl substitutent
in the R-position, afforded the related six-membered ring.
In this case, intramolecular alkylation at the tertiary
carbon resulting in the corresponding tetralin is favored
over ring closure at the benzylic secondary carbon afford-
ing the indane. To investigate the hypothesis that the
formation of six-membered rings is generally preferred,
we tested a range of substrates in which the reaction of the
initially formed carbocation would yield the respective
indanes. In all cases (entries 12À19) solely the tetralins
were obtained, again always with a high level of trans
stereoselectivity. The diastereoselectivity was found to be
reduced in some cases of tetralin formation (entries 11À14,
16), which might be attributed to the higher flexibility of
the cation-bearing carbon chain prior to, and during, the
closure of six-membered rings, thus being able to accom-
modate more than one relative configuration of the resi-
dual stereocenters (cf. mechanistic considerations v.i.).
To complete the evaluation of scope and limitation of
the calcium catalyzed reaction, we investigated the influence
of substituents in the arene. Substrates that incorporate
an electron-donating methoxy or methyl substituent in
the meta-position to the site of electrophilic attack on the
aromatic ring (entries 8/9, 17/18) react readily to the corre-
sponding indanes or tetralins in good yield and trans stereo-
selectivity. The cyclization of m-methoxy and m-methyl
carbinols 21 or 39 produced a mixture of two relative trans-
indanes/tetralins, the regioisomer with the substituent in the
meta-position being predominant. The cyclization of deacti-
vated arenes, such as 41 bearing an electron-withdrawing
group, failed, and only a mixture of different olefins 42 was
obtained. The same result was obtained for a substrate with a
bromide substituent in the para-position (not shown).
Scheme 2. Mechanistic Investigations
sequences the double bond isomers AÀD equilibrate for
some time until the residual stereocenters have adopted a
relative configuration that is favorable for ring closure.
That accomplished, once the reactive carbocationic center
is formed at a suitable position, ring closure occurs. There-
by, all stereocenters settle into an all-trans-configuration.
In summary, we have developed the first catalytic benzyl
carbinol cyclization in the presence of a combination of
5 mol % Ca(NTf2)2 and 5 mol % Bu4NPF6 that provides
indanes and tetralins in good to high yields with high levels
of regio- and diastereoselectivity. The regioselectivity of the
cyclizations was found to be governed by subtle changes of
the substitution pattern in the reactive carbocationic inter-
mediates, where multiple isomeric ring closures are possi-
ble. Cylization to the six-membered tetralins was generally
preferred over indane formation. The reaction was found to
proceed via an equilibrating mixture of different achiral
olefin intermediates after an initial calcium catalyzed dehy-
dration. A ring closure is only encouraged by a single
relative configuration of the residual stereocenters, thus
determining the high diastereoselectivity. Hence, via this
highly elegant self-organizing process diastereomerically
pure compounds are accessed from readily available dia-
stereomeric mixtures of benzyl carbinols.
Preliminary mechanistic investigations were undertaken
to gain deeper insight into the stereoselectivity inducing
rearrangements prior to the ring closure. Therefore, the
distribution of species in the reaction mixture at different
reaction times was analyzed (Scheme 2). After ∼20 min the
starting material 1 is completely converted to different
equilibrating species and a small amount of the final
product 2. The intermediates were separated by semipre-
parative HPLC and identified as A, B, and traces of C and
D. Itisonlyafter 210 min thatthe concentration ofthefinal
product starts to rise. Conversion of the intermediates
to the final product is complete after ∼6 h. Hence, the first
reaction step, the dehydration of the benzyl carbinol
by coordination of the calcium catalyst, is comparatively
fast. Thereafter, in various deprotonation reprotonation
Supporting Information Available. Complete experimen-
tal details and compound characterization data, as well as
copies of 1H NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 6, 2013
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