New approach to 4-phenyl-β-aminotetralin from 4-(3-halophenyl)tetralen-2-ol phenylacetate

Article abstract of DOI:10.1016/j.tetlet.2009.06.099

Mixed trifluoroacetyl phenylacetyl anhydride and 3-halostyrenes (fluoro, chloro, and bromo) or vinylcycloalkanes (cyclohexyl and cyclooctyl), undergo cascade Friedel-Crafts cycli-acylalkylation, enolization, and O-acylation to give 4-substituted tetralen-

Full text of DOI:10.1016/j.tetlet.2009.06.099

Tetrahedron Letters 50 (2009) 5107–5109
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New approach to 4-phenyl-b-aminotetralin from
4-(3-halophenyl)tetralen-2-ol phenylacetate
*
Adam S. Vincek, Raymond G. Booth
Department of Medicinal Chemistry, PO Box 100485, College of Pharmacy, University of Florida, Gainesville, FL 32610-0485, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Mixed trifluoroacetyl phenylacetyl anhydride and 3-halostyrenes (fluoro, chloro, and bromo) or vinyl-
cycloalkanes (cyclohexyl and cyclooctyl), undergo cascade Friedel–Crafts cycli-acylalkylation, enoliza-
tion, and O-acylation to give 4-substituted tetralen-2-ol phenylacetates, without additional solvent in
good yields. Base alcoholysis of 4-phenyltetralen-2-ol phenylacetate reveals the tetral-2-one for asym-
metric transfer hydrogenation. Bromophenyltetralen-2-ol phenylacetate undergoes Suzuki coupling,
and provides a short route to trans-4-phenyl-b-aminotetralin.
Received 22 May 2009
Revised 18 June 2009
Accepted 19 June 2009
Available online 25 June 2009
Keywords:
b-Aminotetralin
Cascade
Ó 2009 Elsevier Ltd. All rights reserved.
Halostryene
Phenylacetate
Tetralen-2-ol
The b-aminotetralin moiety is a pharmacophore element recog-
nized by several classes of aminergic neurotransmitter G protein-
coupled receptors (GPCRs). For example, asymmetric (ꢀ)-trans-
4R-phenyl-2S-dimethylaminotetralin (1, Scheme 1) exhibits ano-
rectic and antipsychotic efficacy after peripheral administration
to rodents via actions at brain serotonin (5-hydroxytryptamine,
5-HT) 5-HT2 GPCRs.1 The 4-(3-halophenyl) analogs of 12 are active
at 5-HT2 receptors, important drug targets for many human psy-
chological and physiological disorders. Halophenyltetralen-2-ol
phenylacetate 3 intermediates, from readily available reagents 4
and [5] (Scheme 1), provide these analogs and avoid the require-
ment to isolate corresponding 4-(3-halophenyl)tetral-2-ones 2.
Versatile aryl halide and enol phenylacetate functionalities on 3
make these molecules useful for diversified organic syntheses,
pharmaceuticals, and catalyzed asymmetric transformations.3
Although 4-phenyltetral-2-ones are of great interest to organic
synthesis, methods to synthesize them are low yielding, scarce, dif-
ficult to diversify, and require fast, efficient use to avoid decompo-
sition.4 Direct ring-closure reports to non-halogenated 4-
phenyltetral-2-one 2a include (Scheme 2): (a) dimethylamine
addition to symmetrical dibenzoylethylene 6 gives 2-(N,N-dimeth-
ylamino)-1,4-diphenyl-1,4-butanedione, to reduce and then cy-
clize in refluxing acid;5 (b) enolate addition of phenylacetone 7
to benzaldehyde provides 1,4-diphenylbut-1-en-3-one, to cyclize
under Friedel–Crafts (FCs) conditions with metal Lewis acid or
PPA;6 (c) one-step FC-cycli-acylalkylation (FC-CAA)7 with phenyl-
acetyl chloride 8, styrene 4a (or TMS-activated 4a), and metal Le-
wis acid in dichloromethane.8 Free of many aforementioned
drawbacks one-step FC-CAA; (d) with phenylacetic acid 9, TFAA,
phosphoric acid,9 and 4a, readily dimerizes 4a and furnishes only
a trace amount of 2a by GC–MS.10 While, mixed trifluoroacetyl
phenylacetyl anhydride [5] can esterify alcohols11 or FC-acylate ar-
yls to give 10, one report includes traces of aryl enolates 11.12 Sta-
ble tetralen-2-ol phenylacetates avoid difficulties in handling and
storing expensive 4-phenyltetral-2-ones and are made directly
with one procedure, without additional solvent. We now report a
facile cascade reaction to 4-(3-halophenyl)tetralen-2-ol phenylac-
etates and their utility in asymmetric transfer hydrogenation
NMe2
O
O
ROH
base
Ph
O
R = Me
or
i-Pr
3
R1
R1
R1
(4R,2S)-1
2
H
H
H
F3C
5
O
R1 = H
+
Ph
4
or halogen
see Table
O
O
R1
* Corresponding author. Tel.: +1 352 273 7742; fax: +1 352 392 9455.
E-mail address: booth@cop.ufl.edu (R.G. Booth).
Scheme 1. Retrosynthesis to trans-4-phenyl-b-aminotetralins.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.099

5108
A. S. Vincek, R. G. Booth / Tetrahedron Letters 50 (2009) 5107–5109
(a)
H
H
O
[5] 3 equiv
(d)
Ph
1) (Me)2N, MeOH
2) LiAlH4, Et2O
3) H3O, Δ
Bz
4a
H
O
O
0ºC - rt, 24 h
TFAA, H3PO4
15% by GCMS
Ph
TFAA
2a
6
OH
6 - 29%
Bz
9
n
n
[5]
3e 64%
3f 43%
n = 1
4e,
(b)
(c)
Aryl, H3PO4
4f, n = 3
1) PhCOH, KOH, Δ
2) AlCl3 or PPA
solvent
4a or PhCHCHTMS
ACN, 50 ºC
30-180 min
AlCl3, CH2Cl2
Scheme 3. Cascade reaction with vinylcycloalkanes.
52 - 56%
17 - 28%
O
Ph
Ar
10
(a) RuCl2(benzene)2
OH
OTs
O
Me
O
Cl
Major
Ph
Ph
H2N NHTs
+
(b)
TsCl
75%
Ph Ph
KOH, i-Pr
50 ºC, 3 h
74%
O
Ar O
8
3a R1 = H
3d R1 = Br
cis
7
Ph
cis-13
Ph
-12a
Ph
Ph
pyridine
rt, 24 h
11
Traces
(c)
( )-12a
Pd(OAc)2, H2
aq HNMe2
sealed tube
80 ºC, 24 h
OH
(e)
(d)
Scheme 2. Literature examples for 4-phenyltetral-2-one.
NEt3, MeOH
rt, 2 h
NaBH4, MeOH
0-50 ºC, 15 h
99%
70%
12d
(ATH), palladium cross-coupling, and palladium hydrodebromina-
tion applications.
90% cis:trans
Br
NMe2
(f)
80:20
PhB(OH)2
Cascade FC-CAA, enolization, and O-acylation were investigated
with TFAA-activated phenylacetic acid and 4a, 3-halostyrenes 4b–
d (Table 1), as well as, vinylcycloalkanes 4e, f (Scheme 3). Reactive
4a was heated to 60 °C prior to reaction with [5] in order to accel-
erate the inherently slow enolization13 of 2a in the reaction media
and allow isolation of O-acylated 3a (15%). At rt, or cooling to
ꢀ78 °C, resulted in loss of reactive 2a in a complex mixture. Addi-
tional solvents (ACN, hexanes, and dichloromethane) resulted in
self-condensed phenylacetyl anhydride with styrene persisting,
as did addition of 4a to the activated acid. Surprisingly, moderately
reactive 3-halostyrenes 4b–d14 withstood dimerization in the reac-
tion media and resulted in higher conversions to the desirable tet-
ral-2-one. Equimolar 3-fluorostyrene 4b and [5] gave major 2b
(42%) and minor 3b (8%). Chlorophenyltetral-2-one 2c (70%) was
prepared from 3-chlorostyrene 4c with 3 equiv of [5], and under-
went further treatment with equimolar [5] to provide 3c (38%).
Warming to rt over 24 h 3-bromostyrene 4d with 3 equiv of [5]
gave 3d (50%), over threefold increase in yield from non-haloge-
nated 3a. Vinylcyclohexane 4e and vinylcyclooctane 4f provided
solids 3e (63%) and 3f (40%), respectively, when reacted separately
with [5]. Conformational difference between 4-cycloalkyltetralen-
Pd(OAc)2
(c-Hex)2P(biphen-3-yl)
O
O
Ph
K3PO4, toluene
65 ºC, 24 h
R1
trans-(4R,2S)-1
74% ee
14
70%
Ph
Scheme 4. Utility of 4-(3-bromophenyl)tetralen-2-ol phenylacetate.
2-ol and 4-phenyltetralen-2-ol cores was indicated by allylic pro-
ton coupling in the former. Tetralen-2-ol phenylacetates were iso-
lated with less than 5% of the regioisomer (unlike silyl tetralen-2-ol
ethers15), stable to atm, and enantio-resolvable using chiral sta-
tionary phase (CSP)-HPLC (e.g., for 3e, tR1 = 15.7 ½a D25
ꢁ
ꢀ79.1, tR2
=
16.8 ½a 2D5
ꢁ
+78.8.
Three steps (Scheme 4), (a) ATH,16 (b) tosylation, and (c) SN2
inversion with aq dimethylamine,17 provided enantioenriched
cis-(4R-2R)-12a (74%), cis-(4R-2R)-13 (75%), and trans-(4R-2S)-1
(70%) with b-hydride elimination byproducts.18 Pure trans-4R-2S-
1 was obtained by CSP-HPLC (74% ee). Carbonyl reduction of 3d
Table 1
Cascade reaction with styrene or 3-halostyrenes for 2 and 3, conditions, yields, and UV trace
H
O
O
Ph
H
Conditions
F3C
5
O
H
O
Ph
+
+
O
O
R1
4a-d
R1
R1
3a-d
2a-d
R1
Yield (%)a
Conditions
UVe Trace of 3
4
2
3
[5]:4c
Temp (°C)
t (h)
tR1
tR2
H
F
Cl
Br
a
b
c
0
42
70
0
15
8
3:1
1:1
3:1
3:1
0–60
0
0
0.5
0.5
0.5
24d
17.7
16.0
17.9
18.7
18.1
16.8
18.9
20.1
0(38)b
50
d
0–rt
a
Isolated yield.
From 2c.
Equiv.
Reaction time not minimized.
220/254 nm, CSP-HPLC.
b
c
d
e

A. S. Vincek, R. G. Booth / Tetrahedron Letters 50 (2009) 5107–5109
5109
3. (a) Schreiber, S. L. Nature 2009, 457, 153; (b) Ahn, Y.; Ko, S.-B.; Kim, M.-J.; Park,
J. Coord. Chem. Rev. 2008, 252, 647; (c) Panella, L.; Feringa, B. L.; de Vries, J. G.;
Minnaard, A. J. Org. Lett. 2005, 7, 4177; (d)Palladium in Organic Synthesis; Tsuji,
J., Ed.Topics in Organometallic Chemistry; Springer: Berlin, 2005; Vol. 14, (e)
Nakagawa, H.; Okimoto, Y.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 2003, 44,
103; (f)Cross-Coupling Reactions; Miyaura, N., Ed.Topics in Current Chemistry;
Springer: Berlin, 2002; Vol. 219.
4. (a) Carreño, M. C.; González-López, M.; Latorre, A.; Urbano, A. J. Org. Chem.
2006, 71, 4956; (b) Silveira, C. C.; Machado, A.; Braga, A. L.; Lenardão, E. J.
Tetrahedron Lett. 2004, 45, 4077; (c) Silveira, C. C.; Braga, A. L.; Kaufman, T. S.;
Lenardão, E. J. Tetrahedron 2004, 60, 8295.
with (d) sodium borohydride gave 12d (90%) and (e) hydrodebro-
mination19 provided ( )-12a (99%). Employing brominated 3d in
one additional step gave ( )-12a in 45% yield from reagents, an
improvement over the 11% yield using the non-halogenated 3a. Su-
zuki coupling20 of 3d with (f) phenylboronic acid smoothly pro-
vided 4-(biphenyl-3-yl)tetralen-2-ol phenylacetate 14 (70%).
Thus, simple palladium insertion modifications to bromophenyl
functionality with 3d and 12d were established.
Cascade Friedel–Crafts cycli-acylalkylation, enolization, and O-
acylation with activated phenylacetic acid and moderately reactive
halostyrene or vinylcycloalkanes, provide 4-(3-halophenyl or
cycloalkyl)tetralen-2-ol phenylacetate. An electron-withdrawing
substituted styrene dimerizes less and provides higher yields in
the reaction media than unsubstituted styrene. Base alcoholysis
on 4-phenyltetralen-2-ol phenylacetate reveals 4-phenyltetral-2-
one for use in situ. Simple palladium insertion cross-coupling with
4-(3-bromophenyl)tetralen-2-ol phenylacetate is established and a
short 5-step sequence provides a three times (6–18%) more effi-
cient route to trans-1.
5. (a) Lutz, R. E.; Bailey, P. S.; Shearer, N. H., Jr. J. Am. Chem. Soc. 1946, 68, 2224; (b)
Fine, S. A.; Stern, R. L. J. Org. Chem. 1967, 32, 4132; (c) Fine, S. A.; Stern, R. L. J.
Org. Chem. 1970, 35, 1857; (d) Rhee, S. W.; Tanga, M. J. J. Labelled Compd.
Radiopharm. 2000, 43, 925.
6. (a) Wyrick, S. D.; Booth, R. G.; Myers, A. M.; Owens, C. E.; Kula, N. S.;
Baldessarini, R. J.; McPhail, A. T.; Mailman, R. B. J. Med. Chem. 1993, 36, 2542;
(b) Khalaf, A. A.; El-Khawaga, A. M. A. Rev. Roum. Chim. 1981, 26, 739; (c)
Bertolini, G.; Vecchietti, V.; Mabilia, M.; Norcini, G.; Restelli, A.; Santangelo, F.;
Villa, A. M.; Casagrande, C. Eur. J. Med. Chem. 1992, 27, 663; (d) Gatti, G.;
Piersanti, G.; Spadoni, G. Farmaco 2003, 58, 469.
7. Prakash, S. G. K.; Yan, P.; Török, B.; Olah, G. A. Catal. Lett. 2003, 87, 109.
8. (a) Brook, M. A.; Henry, C.; Jefferson, E.; Jüschke, R.; Sebastian, T.; Tomaszewski,
M.; Wenzel, S. Bull. Soc. Chim. Fr. 1995, 132, 559; (b) Fleming, I.; Pearce, A. J.
Chem. Soc., Perkin Trans. 1 1980, 11, 2485; (c) Lucarini, S.; Bedini, A.; Spadoni,
G.; Piersanti, G. Org. Biomol. Chem. 2008, 6, 147.
9. Galli, C. Synthesis 1979, 4, 303.
10. Gray, A. D.; Smyth, T. P. J. Org. Chem. 2001, 66, 7113.
Acknowledgment
11. Smith, S. M.; Reyes, S. M.; Bravo, O. V.; Herrera, M. A. F.; Pascual, R. M.; Ramírez,
J. S.; Fuente, A.; Reyes, M.; Ruiz, J. A. ARKIVOC 2005, 6, 127.
12. Veeramaneni, V. R.; Pal, M.; Yeleswarapu, K. R. Tetrahedron 2003, 59,
3283.
This work was supported by USPHS (NIH) Grants MH068655,
DA023928, and MH081193.
13. (a) Nevy, J. B.; Hawkinson, D. C.; Blotny, G.; Yao, X.; Pollack, R. M. J. Am. Chem.
Soc. 1997, 119, 12722; (b) Yao, X.; Gold, M. A.; Pollack, R. M. J. Am. Chem. Soc.
1999, 121, 6220.
Supplementary data
14. Matyjaszewski, K.; Sawamoto, M. In Cationic Polymerizations Mechanism,
Synthesis, and Applications; Matyjaszewski, K., Ed.; Marcel Dekker: New York,
1996; p 323.
15. Wang, X.-Z.; Yao, Z.-J.; Liu, H.; Zhang, M.; Yang, D.; George, C.; Burke, T. R., Jr.
Tetrahedron 2003, 59, 6087.
16. (a) Peach, P.; Cross, D. J.; Kenny, J. A.; Mann, I.; Houson, I.; Campbell, L.;
Walsgrove, T.; Wills, M. Tetrahedron 2006, 62, 1864; (b) Mogi, M.; Fuji, K.;
Node, M. Tetrahedron: Asymmetry 2004, 15, 3715; (c) Alcock, N. J.; Mann, I.;
Peach, P.; Wills, M. Tetrahedron: Asymmetry 2002, 13, 2485.
17. Bosse, K.; Marineau, J.; Nason, D. M.; Fliri, A. J.; Segelstein, B. E.; Desai, K.;
Volkmann, R. A. Tetrahedron Lett. 2006, 47, 7285.
18. Lamberts, J. J. M.; Cuppen, T. J. H. M.; Laarhoven, W. H. J. Chem. Soc., Perkin
Trans. 1 1985, 9, 1819.
19. Monguchi, Y.; Kume, A.; Hattori, K.; Maegawa, T.; Sajiki, H. Tetrahedron 2006,
62, 7926.
20. (a) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc.
1999, 121, 9550; (b) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999,
38, 2413.
Supplementary data (general experimental methods, proce-
dures, characterization data, copies of 1H and 13C NMR spectra
for synthesized compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2009.06.099.
References and notes
1. (a) Rowland, N. E.; Crump, E. M.; Nguyen, N.; Robertson, K.; Sun, Z.; Booth, R. G.
Pharmacol., Biochem. Behav. 2008, 91, 176; (b) Ghoneim, O. M.; Legere, J. A.;
Golbraikh, A.; Tropsha, A.; Booth, R. G. Bioorg. Med. Chem. 2006, 14, 6640; (c)
Bucholtz, E. C.; Brown, R. L.; Tropsha, A.; Booth, R. G.; Wyrick, S. D. J. Med. Chem.
1999, 42, 3041; (d) Youngman, M. A.; Willard, N. M.; Dax, S. L.; McNally, J. J.
Synth. Commun. 2003, 33, 2215.
2. SAR for 4-(3-halophenyl)-b-aminotetralin binding, and function at 5-HT2
GPCRs for will be reported in J. Med. Chem.