Diastereoselective intramolecular Friedel-Crafts alkylation of tetralins

Article abstract of DOI:10.1021/ol2008236

An efficient and versatile synthesis of cis-hexahydrobenzophenanthridines starting from readily available tetralins has been developed using an intramolecular Friedel-Crafts alkylation as a key step. The substrates were prepared via a highly stereocontrolled rhodium-catalyzed ring-opening reaction of meso-oxabicyclic alkenes and a hydrogenation sequence. Thus, a wide variety of complex tetracyclic compounds have been isolated with a high level of regio-, diastereo-, and enantioselectivity.

Full text of DOI:10.1021/ol2008236

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3000–3003
Diastereoselective Intramolecular
FriedelÀCrafts Alkylation of Tetralins
†
†
†
‡
ꢀ
ꢀ
Clemence Liebert, Marion K. Brinks, Andrew G. Capacci, Matthew J. Fleming, and
Mark Lautens*,†
Davenport Chemical Laboratories, Department of Chemistry, University of Toronto,
80 St George Street, Toronto, Ontario M5S 3H6, Canada, and Chemical Development
and Catalysis Department, Solvias AG, Roemerpark 2, 4303 Kaiseraugst, Switzerland
mlautens@chem.utoronto.ca
Received March 29, 2011
ABSTRACT
An efficient and versatile synthesis of cis-hexahydrobenzophenanthridines starting from readily available tetralins has been developed using an
intramolecular FriedelÀCrafts alkylation as a key step. The substrates were prepared via a highly stereocontrolled rhodium-catalyzed ring-
opening reaction of meso-oxabicyclic alkenes and a hydrogenation sequence. Thus, a wide variety of complex tetracyclic compounds have been
isolated with a high level of regio-, diastereo-, and enantioselectivity.
Advancedstudies have been recently reportedinthefield
of benzylic arylation using a FriedelÀCrafts (FC) alkyla-
tion protocol. These newly developed methodologies
allowed the use of milder reaction conditions and in-
expensive and relatively nontoxic catalysts.1 Within this
area, there is a growing interest in the utilization of
π-activated alcohols as a replacement of the less widely
available and more toxic organo halides.2 Additionally,
Bach and co-workers made significant progress in the
domain of diastereoselective FC alkylations.3,4 More re-
cently, our group disclosed an FC process for the inter-
molecular trans-selective benzylic arylation of tetralin
systems.5 We next focused our attention on the case of
the intramolecular FC alkylation of tetralins so as to
efficiently and stereoselectively access more complex
hexahydrobenzophenanthridines. Such fused tetracyclic
(3) (a) Stadler, D.; Bach, T. J. Org. Chem. 2009, 74, 4747. (b) Stadler,
D.; Goeppert, A.; Rasul, G.; Olah, G. A.; Surya Prakash, G. K.; Bach, T.
J. Org. Chem. 2009, 74, 312. (c) Stadler, D.; Bach, T. Angew. Chem., Int.
Ed. 2008, 47, 7557. (d) Stadler, D.; Bach, T. Chem. Asian J. 2008, 3, 272.
(e) Rubenbauer, P.; Bach, T. Adv. Synth. Catal. 2008, 350, 1125. (f)
† University of Toronto.
‡ Solvias AG.
€
Stadler, D.; Muhlthau, F.; Rubenbauer, P.; Herdtweek, E.; Bach, T.
(1) (a) Zhang, X.; Rao, W.; Wai Hong Chan, S.; P. Org. Biomol.
Chem. 2009, 7, 4186. (b) Deng, X.; Liang, J. T.; Liu, J.; McAllister, H.;
Schubert, C.; Mani, N. S. Org. Process Res. Dev. 2007, 11, 1043. (c)
Hashmi, A. S. K.; Schwarz, L.; Rubenbauer, P.; Blanco, M. C. Adv.
Synth. Catal. 2006, 348, 705. (d) Liu, J.; Muth, E.; Flc-rke, U.; Henkel,
G.; Merz, K.; Sauvageau, J.; Schwake, E.; Dyker, G. Adv. Synth. Catal.
2006, 348, 456. (e) Rueping, M.; Nachtsheim, B. J.; Ieawsuwan, W. Adv.
Synth. Catal. 2006, 348, 1033. (f) Mertins, K.; Iovel, I.; Kischel, J.; Zapf,
A.; Beller, M. Adv. Synth. Catal. 2006, 348, 691. (g) Iovel, I.; Mertins, K.;
Kischel, J.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 3913.
(h) Mertins, K.; Iovel, I.; Kischel, J.; Zapf, A.; Beller, M. Angew. Chem.,
Int. Ed. 2005, 44, 238.
€
Synlett 2006, 2573. (g) Muhlthau, F.; Stadler, D.; Goeppert, A.; Olah,
G. A.; SuryaPrakash, G. K.; Bach, T. J. Am. Chem. Soc. 2006, 128, 9668.
€
(h) Muhlthau, F.; Schuster, O.; Bach, T. J. Am. Chem. Soc. 2005, 127,
9348.
(4) (a) Chung, J. Y. L.; Mancheno, D.; Dormer, P. G.; Variankaval,
N.; Ball, R. G.; Tsou, N. N. Org. Lett. 2008, 10, 3037. (b) Enders, D.; Del
Signore, G.; Berner, O. M. Chirality 2003, 15, 510.
(5) Davoust, M.; Kitching, J. A.; Fleming, M. J.; Lautens, M.
Chem.;Eur. J. 2010, 17, 50.
(6) (a) Michaelides, M. R.; Hong, Y. (Abbot Laboratories),
US5597832 A, 1997. (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. (c) Lovenberg, T. W.; Brewster, W. K.; Mottola,
D. M.; Lee, R. C.; Riggs, R. M.; Nichols, D. E.; Lewis, M. H.; Mailman,
R. B. Eur. J. Pharmacol. 1989, 166, 111.
(2) (a) Emer, E; Sinisi, R.; Capdevila, M. G.; Petruzziello, D.; De
Vincentis, F.; Cozzi, P. Eur. J. Org. Chem. 2011, 4, 647. (b) Bandini, M.;
Tragni, M. Org. Biomol. Chem. 2009, 7, 1501. (c) Muzart, J. Tetrahedron
2008, 64, 5815.
r
10.1021/ol2008236
Published on Web 05/18/2011
2011 American Chemical Society

skeletons are often found in pharmaceutically relevant
target molecules (Figure 1).6 Therefore, the development
of a versatile and selective method to synthesize highly
substituted hexahydrobenzophenanthridines is warranted.
nitromethane (MeNO2) instead of DCM gave similar
results (Table 1, entries 3 and 4). Interestingly, the use
of iron(III) as LA, previously reported by Beller and co-
workers,1h showed the best results. Indeed, treatment of
tetralin 3 with 2 equiv of FeCl3 6H2O in DCM at 60 °C for
3
24 h provided the desired product in 95% yield (Table 1,
entry 5). Pure cis-hexahydrobenzophenanthridine 4 was
obtained without further purification, and its relative
stereochemistry at the ring junction was confirmed by
NMR 1H NOE experiments. Finally, diminishing the
number of equivalents of LA only led to the recovery of
the starting material (Table 1, entry 8). Coordination of the
LA with the amine and/or with the eliminated water might
consume the LA, making the use of an extra equivalent of
LA necessary.
Figure 1. Pharmaceutically active compounds used in the
treatment of psychiatric and neurological disorders.
Table 1. Optimization Studies
In 2000, our group reported the rhodium(I)-catalyzed
asymmetric ring-opening (ARO) of meso-oxabicyclic alk-
enes 1 (Scheme 1).7,8 Thus, a wide variety of trans-tetralins 2
were readily prepared with a high level of regio- and
diastereoselectivity (>99:1) using numerous amine nucleo-
philes. Excellent ee’s (up to 99% ee) were also achieved
when the achiral ligand DPPF was replaced by the Josiphos-
type ligand PPF-PtBu2. Subsequent hydrogenation of these
tetralins 2 delivered the required substrates for the intra-
molecular FC alkylation study.9
entry
Lewis acid
equiv
solvent
temp (°C) yielda (%)
1b
2
AlCl3
AlCl3
AlCl3
AlCl3
2
2
2
2
2
2
2
1
DCM
rt
60
rt
45
56
32
54
95
0
DCM
3
MeNO2
MeNO2
DCM
4
60
60
60
60
60
5c
6d
7d
8d
FeCl3 6H2O
3
FeCl3 6H2O
MeNO2
dioxane
DCM
Scheme 1. Rh(I)-Catalyzed ARO of meso-Oxabicycles
3
FeCl3 6H2O
0
3
FeCl3 6H2O
0
3
a Yield of pure product obtained after column chromatography and
stirring the reaction for 24 h. b Reaction stirred only for 4 h. c Crude
yield, no purification needed. d No conversion, only starting material
recovered.
We first investigated the conversion of the racemic
tetralin 3 into the hexahydrobenzophenanthridine 4
(Table 1). Although AlCl3 was the best Lewis acid (LA)
to undergo the intermolecular FC alkylation when stirred
in dichloromethane (DCM),5 in the case of the intramole-
cular substrate 3, only moderate yields were achieved
(Table 1, entries 1 and 2). Performing the reaction in
With these results in hand, we next explored the scope
of the reaction, varying first the substituents on the
aromatic ring of the tetralin (Table 2). Of primary
importance, all cis-hexahydrobenzophenanthridines
6À12 were prepared with a high level of diastereo- and
enantioselectivity regardless of the steric and/or elec-
tronic effects (Table 2, entries 1À4). Furthermore, no
loss of ee was observed after both hydrogenation and
FC alkylation steps. The lower yield observed in the case
of the dimethoxytetralin 7 can be explained by the
higher reactivity of the substrate, thus leading to the
formation of side-products under the standard reaction
conditions (Table 2, entry 2).10 Noteworthy is that the
difluorotetralin 9 was readily converted into the desired
cis-hexahydrobenzophenanthridine 10 (Table 2, entry 3).
Another interesting result is the fully substituted
(7) (a) Fleming, M. J.; Lautens, M. CarbonÀHeteroatom Bond For-
mation by Rh(I)-Catalyzed Ring-Opening Reactions in Catalyzed Car-
bonÀHeteroatom Bond Formation; Yudin, A. K., Ed.; Wiley: New York,
2011; pp 411À436. (b) Webster, R.; Boyer, A.; Fleming, M. J.; Lautens,
€
M. Org. Lett. 2010, 12, 5418. (c) Webster, R.; Boing, C.; Lautens, M. J.
Am. Chem. Soc. 2009, 131, 444. (d) Lautens, M.; Fagnou, K.; Yang, D. J.
Am. Chem. Soc. 2003, 125, 14884. (e) Lautens, M.; Schmid, G. A.; Chau,
A. J. Org. Chem. 2002, 67, 8043. (f) Lautens, M.; Fagnou, K. J. Am.
Chem. Soc. 2001, 123, 7170. (g) Lautens, M.; Fagnou, K.; Rovis, T. J.
Am. Chem. Soc. 2000, 122, 5650.
(8) For a review, see: Lautens, M.; Fagnou, K.; Hiebert, S. Acc.
Chem. Res. 2003, 36, 48.
(9) It was mandatory to remove the double bond prior to the FC
alkylation since the tetralin could easily aromatize in the presence of an
acid source.
(10) In this case, the major side product observed was the enamine,
corresponding to the elimination of the alcohol functionality.
Org. Lett., Vol. 13, No. 12, 2011
3001

cis-hexahydrobenzophenanthridine 12 which was iso-
lated in 79% yield and 98% ee (Table 2, entry 4).
In addition, the use of heteroaryls was examined
(Scheme 2). Though the thiophene substrate 23 was easily
transformed into the desired cis-product 24 in 78% yield,11
only decomposition was observed in the case of the furan 21.
Table 2. Scope of the Reaction Varying R1 and R2 Groups
Scheme 2. Intramolecular FC Alkylation with Heteroaryls
entry
substrate
R1, R2
product
yielda (%), ee (%)
1b
2c
3
5
H, H
6
99, 98
59, 92
88, 98
79, 98
7
OMe, H
F, H
8
9
10
12
4
11
Br, Me
To further expand the scope of the reaction, substitution at
the benzylic position was investigated (Table 4). To this end,
racemic branched amines were used for the Rh(I)-catalyzed
ARO reaction, leading to the formation of diastereoisomeric
mixtures. The diastereoisomers were separately subjected to
the hydrogenation step to give compounds (S)-25 and (R)-25
which were readily converted into the corresponding cis-
hexahydrobenzophenanthridines (Table 4, entries 1 and 2).
Treatment of compound (R)-27 with R4 being an ethyl
delivered the desired product (R)-28 in 83% yield (Table 4,
entry 3). To our delight, the reaction proceeded with diaster-
eotopic face differentiation, as cis-hexahydrobenzophenan-
thridine (R)-30 was produced as a single diastereoisomer
starting from substrate 29 (Table 4, entry 5).12
a Yield of pure product after column chromatography. b Crude yield,
no purification needed. c AlCl3 was used as LA.
Substrates bearing substituents on the meta-position of
the reacting aryl were then investigated (Table 3). While the
desired methyl- and chloro-substituted products 14 and 16
were prepared in good yields and excellent regioselectivities
(Table 3, entries 1 and 2), the less sterically hindered fluoro-
and methoxyhexahydrobenzophenanthridines 18 and 20
were generated in 96% and 91% yields but as para:ortho
mixtures (85:15 and 72:18, respectively, Table 3, entries 3
and 4). It is important to mention that the lower ee observed
in the case of product 16 resulted from the reduced ee we
obtained at the Rh(I)-catalyzed ARO reaction using the less
nucleophilic primary amines as coupling partners.
Table 4. Scope of the Reaction with Varying R4 Group
Table 3. Scope of the Reaction with Varying R5 Group
entry
substrate
R4
product
yielda (%), ee (%)
1b,c
2
3c
4
(S)-25
(R)-25
(R)-27
29
Me
Me
Et
(S)-26
(R)-26
(R)-28
(R)-30
99
91, 76
83
entry substrate
R5
product yielda (%), rs (p:o),b, ee (%)
Ph
85, 78
1c,d
2
3c,d
4d
13
15
17
19
Me
Cl
14
16
18
20
99 (>95:5)
88 (>95:5), 74
96 (85:15)
91 (72:28)
a Yield of pure product after column chromatography. b Crude yield,
no purification needed. c No ee determined as no suitable conditions
could be found to achieve a desired peaks separation.
F
OMe
a Yield of pure product after column chromatography. b Regioselec-
tivity (rs) para:ortho relative to the new CÀC bond formed. c Crude
yield, no purification needed. d No ee determined as no suitable condi-
tions could be found to achieve a desired peaks separation.
Interestingly, the presence of suitable protecting groups for
the amine functionality was also tolerated under the reaction
conditions (Table 5). Amines protected by a methyl, an
acetate, or a tosyl group delivered the desired products
32À36 in yields up to 99% (Table 5, entries 1À3). However,
when a Boc or a Cbz group was used, no formation of the
desired cis-hexahydrobenzophenanthridines 38 and 40 was
observed (Table 5, entries 5 and 6). Instead, carbamate 41
was repeatedly isolated in high yields (Figure 2).
(11) No ee could be determined as no suitable conditions could be
found to achieve a desired peak separation.
(12) The stereochemistry of compounds (S)-26, (R)-26, (R)-28, and
(R)-30 was confirmed by NMR 1H NOE experiments.
3002
Org. Lett., Vol. 13, No. 12, 2011

Table 5. Scope of the Reaction with Varying R3 Group
Scheme 3. Chemoselectivity of the Reaction
entry
substrate
R3
product
yielda (%)
1
31
33
35
37
39
Me
Ac
32
34
36
38
40
99
78
49
0
2b
3
Ts
4c,d
5d
Boc
Cbz
0
a Yield of pure product after column chromatography. b Alcohol
functionality was also protected by an acetate group. c Reaction stirred
at rt. d Corresponding side product 41 was isolated in 94% yield
(see Figure 1).
Figure 2. Isolated side product starting from Boc- and Cbz-
protected amines.
and absolute stereochemistry of the tetralins. Subsequent
FC alkylation of the hydrogenated tetralins delivers the
desired cis-hexahydrobenzophenanthridines in high yields
and diastereoselectivities. Of primary importance, no loss
of enantioselectivity is observed under the reaction condi-
tions. Thus, numerous tetracyclic products presenting
various substitution patterns have been prepared, making
this methodology very useful for the rapid synthesis of
analogues.
Finally, we examined the chemoselectivity of the reac-
tion (Scheme 3). Substrates presenting two different aryl
groups were synthesized. While perfect chemoselectivity
was obtained in the case of the electron-poor substrate 44
(the neutral phenyl ring being the only one reacting),
formation of a complex mixture was observed for the
electron-rich substrate 42 (Scheme 3, product 45a vs
products 43a, p-43b, and o-43b). In addition, moderate
chemoselectivity was achieved when one phenyl ring was
replaced by a thiophene.13 However, introducing a
n-propyl group at 4-position of the thiophene drastically
enhanced the chemoselectivity of the reaction as com-
pound 49b was isolated as a single isomer in 80% yield.14
Initial mechanistic studies suggested that the reaction
could proceed via the formation of a stabilized intermedi-
ate carbocation species. Indeed, treatment of both syn-48
Acknowledgment. This work was supported by the
Natural Sciences and Engineering Research Council of
Canada (NSERC), the Merck Frosst Center for Thera-
peutic Research, and the University of Toronto. We thank
Solvias AG for the supply of rhodium catalyst and chiral
ligands as well as initial support of this study. C.L. thanks
the Deutsche Forschungsgemeinschaft (DFG) for a post-
doctoral fellowship. M.K.B. thanksthe GermanAcademic
Exchange Service (DAAD) for a postdoctoral fellowship.
We cordially thank Dr. Jacki A. Kitching and Dr. Marion
Davoust for helpful discussions.
and anti-48 compounds in the presence of FeCl3 6H2O
3
furnished the same cis-product 49b.15 Further investiga-
tions to probe the mechanism of the reaction are currently
underway.
In conclusion, we have developed a new and efficient
route to substituted cis-hexahydrobenzophenanthridines
starting from tetralin systems. The initial Rh(I)-catalyzed
ARO step establishes the regiochemistry and the relative
Supporting Information Available. Full characteriza-
tion details including 1H and 13C NMR, IR, and HRMS.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) AlCl3 was used as Lewis acid.
(14) The reaction was carried out in dioxane at 80 °C for 20 h.
(15) Substrate syn-48 was prepared via an oxidationÀreduction
sequence starting from anti-48.
Org. Lett., Vol. 13, No. 12, 2011
3003