A very short asymmetric synthesis of enantiomerically pure methyl substituted tetrahydro-3-benzazepines

Article abstract of DOI:10.1016/j.tetasy.2008.06.016

An efficient synthesis of both enantiomers of methyltetrahydro-3-benzazepines 10 and 15 has been elaborated following a very short reaction sequence. The two diastereomeric oxazolo[3]benzazepinones 6 and 7 were prepared by condensation of keto acid 4 with (R)-phenylglycinol 5. Benzylation of 6 and 7 was controlled by the newly established N/O-acetalic stereogenic center leading to products 11 and 12. Reduction of the diastereomeric pairs 6, 7 and 11, 12 with LiAlH₄/AlCl₃ (3:1) occurred under retention of configuration yielding tetrahydro-3-benzazepines 8 and 9 with de >98%, as well as 13 and 14 with complete diastereoselectivity. Hydrogenolytic cleavage of the N-substituent led to the enantiomerically pure 2-methyltetrahydro-3-benzazepines (R)-10 and (S)-10 and 1-benzyl-4-methyltetrahydro-3-benzazepines (R,R)-15 and (S,S)-15. The relative and absolute configuration of the formed products were deduced from X-ray crystal structure analysis of the 3-benzazepine 14·HCl still bearing the original stereochemical information in the N-substituent.

Full text of DOI:10.1016/j.tetasy.2008.06.016

Tetrahedron: Asymmetry 19 (2008) 1613–1616
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A very short asymmetric synthesis of enantiomerically pure methyl
substituted tetrahydro-3-benzazepines
S. Masood Husain a, Roland Fröhlich b, Bernhard Wünsch a,
*
a Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Hittorfstraße 58-62, D-48149 Münster, Germany
b Organisch-Chemisches Institut der Westfälischen Wilhelms-Universität Münster, Corrensstr. 40, D-48149 Münster, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of both enantiomers of methyltetrahydro-3-benzazepines 10 and 15 has been elabo-
rated following a very short reaction sequence. The two diastereomeric oxazolo[3]benzazepinones 6 and
7 were prepared by condensation of keto acid 4 with (R)-phenylglycinol 5. Benzylation of 6 and 7 was
controlled by the newly established N/O-acetalic stereogenic center leading to products 11 and 12.
Reduction of the diastereomeric pairs 6, 7 and 11, 12 with LiAlH4/AlCl3 (3:1) occurred under retention
of configuration yielding tetrahydro-3-benzazepines 8 and 9 with de >98%, as well as 13 and 14 with
complete diastereoselectivity. Hydrogenolytic cleavage of the N-substituent led to the enantiomerically
pure 2-methyltetrahydro-3-benzazepines (R)-10 and (S)-10 and 1-benzyl-4-methyltetrahydro-3-benz-
azepines (R,R)-15 and (S,S)-15. The relative and absolute configuration of the formed products were
deduced from X-ray crystal structure analysis of the 3-benzazepine 14ÁHCl still bearing the original
stereochemical information in the N-substituent.
Received 9 May 2008
Accepted 13 June 2008
Available online 14 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
In order to find novel potent antagonists for the NMDA receptor,
we focused our attention on the tetrahydro-3-benzazepine system
Seven-membered nitrogen heterocycles, such as 3-benzaze-
pines, are constituents of several compounds with interesting
pharmacological properties.1–3 Derivatives with the 3-benzazepine
framework are well known for their agonistic and antagonistic
bearing various substituents in different ring positions. For this
purpose, a general method for the preparation of enantiomerically
pure tetrahydro-3-benzazepines is required allowing the flexible
introduction of various substituents at different ring positions.
Herein, we report on a very short and efficient synthesis of enanti-
omerically pure tetrahydro-3-benzazepines bearing one substitu-
ent at the 2 position or two substituents at the 1 and 4 positions
(see compounds 2 and 3 in Fig. 1).
activity at dopamine D1 and dopamine D3 receptors.6 They also
4,5
show neuroprotective effects by activation of D1 receptors.7 Very
recently, 1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepines have
been described as selective 5-HT2C receptor agonists, which can
be used for the treatment of obesity.8,9 Furthermore, 3-benzaze-
pines are also active in animal models of various neurological
disorders, for example, Parkinson’s disease10 and Alzheimer’s
disease.11
1
R
5
4
Recently, we have shown that racemic12 and enantiomerically
pure 1-substituted 3-benzazepines13,14 1 show moderate to high
affinity to the phencyclidine (PCP) binding site of the NMDA recep-
tor. The NMDA receptor, which is the best investigated subtype of
the class of glutamate receptors, plays a crucial role in processes
such as learning and memory. However, overactivation of the
NMDA receptor results in neuronal damage due to uncontrolled
opening of the NMDA associated Ca2+-channel (excitotoxicity).
Therefore, NMDA receptor antagonists are of great interest for
the prevention of neuronal damage, for example, following ische-
mic conditions and traumatic brain injuries.15,16
3
*
NH
NH
2
NH
R
*
*
*
1
R2
3
R
2
1
Figure 1. Lead compound 1 in comparison with new potential NMDA receptor
antagonists 2 and 3.
2. Results and discussion
2.1. Synthesis
The tricyclic oxazolo[3]benzazepinones 6 and 7 represent key
compounds in the planned asymmetric synthesis. In analogy to
* Corresponding author. Tel.: +49 251 8333311; fax: +49 251 8332144.
E-mail address: wuensch@uni-muenster.de (B. Wünsch).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.06.016

1614
S. Masood Husain et al. / Tetrahedron: Asymmetry 19 (2008) 1613–1616
the procedure of Meyers,17 the keto acid 418,19 was heated at reflux
with (R)-phenylglycinol 5 in toluene for 3 days to provide, in a sin-
gle reaction step, the diastereomeric tricyclic lactams 6 and 7,
which were separated by flash chromatography (6: yield 41%; 7:
yield 31%) (Scheme 1). This transformation occurred without dia-
stereoselectivity leading to a 52:48 mixture of the tricyclic lactams
(1.55 ppm) increased indicating a cis arrangement of these groups.
However, in the control experiment with diastereomer 6, no such
increase in intensity was observed after irradiation at 5.44 ppm
(3-H of 6) confirming the trans-configuration of 3-H and 11a-CH3.
In order to obtain one of the two diastereomers 6 or 7 stereose-
lectively in high yield, the condensation of 4 and 5 was performed
at lower temperatures. Stirring the reaction mixture in toluene for
3 days at room temperature (Fig. 2, spectrum a) and for 3 days at
50 °C (Fig. 2, spectrum b) did not result in formation of either 6
or 7 at all, but gave a side product (or intermediate) exhibiting a
dd at 5.20 ppm. However, heating of the mixture at reflux, even
for 2 h led to the production of both diastereomers 6 and 7
(Fig. 2, spectrum c). Although the conversion was as low as 10%,
the ratio of 6 and 7 was 1:1. The same reaction mixture was heated
at reflux for an additional 3 days giving the same ratio (1:1) of 6
and 7 (Fig. 2, spectrum d). So we assume that the diastereomeric
ratio is not the result of a thermodynamic equilibrium between 6
and 7. This assumption was confirmed by the fact that an intercon-
version of the purified diastereomers 6 and 7 into each other by
refluxing of the corresponding solutions in toluene (3 days)
and CHCl3 (6 days) with trifluoroacetic acid did not take place.
The diastereomeric lactams 6 and 7 were reduced using a 3:1
mixture of LiAlH4 and AlCl3, which forms alane (AlH3) in situ
(Scheme 2). As described in the literature,20 this reduction took
place with retention of configuration and provided the diastereo-
meric 3-benzazepines 8 and 9, respectively. The retention of con-
figuration is explained by coordination of Al of the Lewis acid
AlH3 to the oxygen atom of the oxazolidine ring, and subsequent
delivery of a hydride from the same side as the departing oxygen,
which provides the observed products 8 and 9. Prior to purification,
the diastereomeric excess was 86%21 for crude 8 and 95%21 for
crude 9; after purification the diastereomeric purity was greater
than 98% for both diastereomers (8: de >98%, yield 36%; 9: de
>99%, yield 63%). In the final step, the N-substituent was cleaved
6 and 7. The ratio of the two diastereomers was determined by 1
H
NMR spectroscopy of the crude reaction mixture (Fig. 2, spectrum
e).
CH3
+
H2N
OH
O
CO2H
4
5
(a)
1
O
1
O
H3C
H3C
11
2
11
2
11a
11a
3
+
3
N
N
4
4
O
O
7
6
52:48
Scheme 1. Reagents and conditions: (a) toluene, reflux, 3 d, 72% (6:7 = 52:48); yield
of 6: 41%, yield of 7 31%.
The configuration at position 11a of the two diastereomers 6
and 7 was determined by NOE experiments. After irradiation at
4.93 ppm (3-H of 7), the intensity of the singlet for the CH3-moiety
H3C
O
H3C
O
H
N
H
N
O
O
7
6
reflux, 3 d
e
reflux, 3 d
reflux, 2 h
d
c
50 ºC, 3 days
rt, 3 days
b
a
5.40
5.30
5.20
5.10
5.00
ppm
Figure 2. 1H NMR spectra were recorded after the reaction of 4 with 5 under various reaction conditions using toluene as a solvent. Compound 6 gives a characteristic triplet
at 5.44 ppm (3-H), whereas compound 7 gives a characteristic dd at 4.93 ppm (3-H). The signal at 5.20 ppm is caused by a side product (or intermediate). Spectra a–d were
recorded from the same experiment reacting 4 with 5 in toluene using increasing temperature and time, whereas 1H NMR spectrum e was recorded after heating 4 and 5 at
reflux for 3 days in toluene.

S. Masood Husain et al. / Tetrahedron: Asymmetry 19 (2008) 1613–1616
1615
tive opening of the oxazolidine moiety, the reduced trisubstituted
3-benzazepine 14 was transformed into its HCl salt by the addition
of HCl to a solution of 14 in CH2Cl2. The solid formed was recrystal-
lized from CH2Cl2/n-hexane to give crystals, which were suitable
for X-ray crystal structure analysis. The X-ray crystal structure of
14ÁHCl (Fig. 3) clearly demonstrates (S)-configuration at the 1-po-
sition (corresponds to the 6-position of 12) and an (S)-configura-
tion at the 4-position (corresponds to the 11a-position of 12).
The (S)-configuration at the 4-position confirms the retention of
configuration during AlH3 reduction of the N/O-acetal. Further-
more, the (S)-configuration at the 1-position demonstrates the
attack of benzyl bromide opposite to the 11a-methyl moiety.
H3C
H3C
H
H
OH
OH
(a)
(c)
(b)
(d)
N
NH
6
7
8
(
R
)-10
H
H
CH3
CH3
NH
N
(S)-10
9
Scheme 2. Reagents and conditions: (a) AlCl3 1.0 equiv, LiAlH4 3.0 equiv, THF, 0 °C,
2 h, 67%, dr (8:9) = 93:7; after fc purification dr (8:9) > 99:1, yield 36%;20 (b) H2,
1 bar, Pd/C (10%), aq HCl (1 M) 1.0 mL, MeOH, rt, 88%; (c) AlCl3 1.0 equiv, LiAlH4
3.0 equiv, THF, 0 °C, 2 h, 62%, dr (8:9) = 11:89; after fc purification dr (8:9) = 0.4:99.6,
yield 63%;20 (d) H2, 1 bar, Pd/C (10%), aq HCl (1 M), 1.0 mL, MeOH, rt, 73%.
O13
C12
C101
C15
N1
C10
C11
off with H2 in the presence of Pd/C and HCl to afford the enantio-
meric 2-methyl-3-benzazepines (R)-10 (ee >98%) and (S)-10 (ee
>99%) in 88% and 73% yield (Scheme 2).22
C16
C18
C14
C9
C17
C8
According to the literature13,14 the diastereomeric lactams 6
and 7 were deprotonated with LDA and subsequently trapped with
benzyl bromide to yield the monobenzyl derivatives 11 (80%) and
12 (78%), respectively. The configuration of the new stereogenic
center at the 6-position was determined to be (6R) for 11 and
(6S) for 12 by NOE experiments. Obviously, the formation of the
stereogenic center at the 6-position was controlled by the N/O-
acetalic stereogenic center at the 11a-positions, leading to like con-
figuration at the 6- and 11a-positions, respectively, irrespective of
the configuration of the chiral auxiliary (Scheme 3).
C7
C5
C19
Cl1
C1
C6
C3
C2
C21
C4
C22
C23
C27
C24
C26
C25
Reduction of the benzylated derivatives 11 and 12 with LiAlH4/
AlCl3 (3:1) provided the trisubstituted 3-benzazepines 13 (72%)
and 14 (66%) in diastereomerically pure form, respectively. Finally,
the N-substituent of 13 and 14 was hydrogenolytically removed to
give the enantiomeric 1-benzyl-4-methyl-3-benzazepines (R,R)-15
(73%) and (S,S)-15 (94%).23
Figure 3. X-ray crystal structure analysis of 14ÁHCl.
3. Conclusion
Enantiomerically pure 2-methyl and 1-benzyl-4-methyl substi-
tuted tetrahydro-3-benzazepines were synthesized in good yields,
following a very short procedure (3–4 reaction steps). The config-
uration of the newly formed stereogenic centers was unequivocally
proven by an X-ray crystal structure analysis of 14ÁHCl.
2.2. X-ray crystal structure analysis of 14ÁHCl
In order to unequivocally prove the configuration of the prod-
ucts, in particular the retention of configuration during the reduc-
H3C
H
H3C
O
H3C
H
OH
(c)
(b)
(a)
NH
N
O
6
N
Ph
Ph
Ph
Ph
Ph
11
(
R,
R
)-15
13
H
H3C
H
CH3
NH
O
CH3
OH
Ph
(b)
(c)
(a)
N
O
7
N
Ph
Ph
Ph
Ph
14
12
(S,S)-15
Scheme 3. Reagents and conditions: (a) BnBr 1.0 equiv, LDA 1.2 equiv, THF, 3 h, 11: 80%; 12: 78%; (b) AlCl3 1.0 equiv, LiAlH4 3.0 equiv, THF, 0 °C, 2 h, 13: 72%; 14: 66%; (c) H2,
1 bar, Pd/C (10%), aq HCl (1 M) 1.0 mL, MeOH, rt, (R,R)-15: 73%; (S,S)-15: 94%.

1616
S. Masood Husain et al. / Tetrahedron: Asymmetry 19 (2008) 1613–1616
Radaelli, S.; Tedesco, G.; Terreni, S.; Worby, A.; Heidbreder, C. Bioorg. Med.
4. Experimental
Chem. Lett. 2008, 18, 901–907.
7. Yu, Y.; Wang, J.; Sun, P. H.; Guo, Y.; Zhang, Z.; Jin, G.; Zhen, X. J. Neurochem.
2008, 104, 946–956.
8. Smith, B. M.; Smith, J. M.; Tsai, J. H.; Schultz, J. A.; Gilson, C. A.; Estrada, S. A.;
Chen, R. R.; Park, D. M.; Prieto, E. B.; Gallardo, C. S.; Sengupta, D.; Thomsen, W.
J.; Saldana, H. R.; Whelan, K. T.; Menzaghi, F.; Webb, R. R.; Beeley, N. R. A. Biorg.
Med. Chem. Lett. 2005, 15, 1467–1470.
9. Smith, B. M.; Smith, J. M.; Tsai, J. H.; Schultz, J. A.; Gilson, C. A.; Estrada, S. A.;
Chen, R. R.; Park, D. M.; Prieto, E. B.; Gallardo, C. S.; Sengupta, D.; Dosa, P. I.;
Covel, J. A.; Ren, A.; Webb, R. R.; Beeley, N. R. A.; Martin, M.; Morgan, M.;
Espitia, S.; Saldana, H. R.; Bjenning, C.; Whelan, K. T.; Grottick, A. J.; Menzaghi,
F.; Thomsen, W. J. J. Med. Chem. 2008, 51, 305–313.
4.1. Details for the X-ray crystal structure of 14ÁHCl
Formula
C
26H30ClNO, M = 407.96, colorless crystal 0.20 Â
0.15 Â 0.10 mm, a = 11.3379(1), b = 9.2898(2), c = 12.0980(1) Å,
b = 117.770(1)°,
V = 1127.48(2) Å3,
q
calc = 1.202 g cmÀ3
,
l =
1.61 mmÀ1, empirical absorption correction (0.739 6 T 6 0.856),
Z = 2, monoclinic, space group P21 (No. 4), k = 1.54178 Å,
T = 223(2) K,
x and / scans, 8666 reflections collected ( h, k, l),
[(sinh)/k] = 0.60 ÅÀ1, 2637 independent (Rint = 0.073) and 2637 ob-
10. Gnanalingham, K. K.; Hunter, A. J.; Jenner, P.; Marsden, C. D.
Psychopharmacology 1995, 117, 403–412.
served reflections [I P 2r(I)], 264 refined parameters, R = 0.076,
11. Medhurst, A. D.; Atkins, A. R.; Beresford, I. J.; Brackenborough, K.; Briggs, M. A.;
Calver, A. R.; Cilia, J.; Cluderay, J. E.; Crook, B.; Davis, J. B.; Davis, R. K.; Davis, R.
P.; Dawson, L. A.; Foley, A. G.; Gartlon, J.; Gonzalez, M. I.; Heslop, T.; Hirst, W.
D.; Jennings, C.; Jones, D. N. C.; Lacroix, L. P.; Martyn, A.; Ociepka, S.; Ray, A.;
Regan, C. M.; Roberts, J. C.; Schogger, J.; Southam, E.; Stean, T. O.; Trail, B. K.;
Upton, N.; Wadsworth, G.; Wald, J. A.; White, T.; Witherington, J.; Woolley, M.
L.; Worby, A.; Wilson, D. M. J. Pharm. Exp. Therap. 2007, 321, 1032–1045.
12. Krull, O.; Wünsch, B. Bioorg. Med. Chem. 2004, 12, 1439–1451.
13. Wirt, U.; Fröhlich, R.; Wünsch, B. Tetrahedron: Asymmetry 2005, 16, 2199–2202.
14. Wirt, U.; Schepmann, D.; Wünsch, B. Eur. J. Org. Chem. 2007, 462–475.
15. Watkins, J. C.; Jane, D. E. Br. J. Pharmacol. 2006, 147, 100–108.
16. Bräuner-Osborne, H. B.; Egebjerg, J.; Nielsen, E.; Madsen, U.; Krogsgaard-
Larsen, P. J. Med. Chem. 2000, 43, 2609–2645.
wR2 = 0.210, max. (min.) residual electron density 0.38
(À0.37) e ÅÀ3, Flack parameter 0.05(4), hydrogen atoms calculated
and refined as riding atoms.
Data set was collected with a Nonius KappaCCD diffractometer.
Programs used: data collection COLLECT, ,
24 data reduction DENZO-SMN
25
26
absorption correction DENZO
,
structure solution SHELXS-97,27 struc-
ture refinement SHELXL-97,28 and graphics SCHAKAL
.
29
CCDC 685859 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: (internat.) +44(1223)336-033, E-mail: deposit@
ccdc.cam.ac.uk].
17. Meyers, A. I.; Downing, S. V.; Weiser, M. J. J. Org. Chem. 2001, 66, 1413–1419.
18. Husain, S. M.; Wünsch, B. Synthesis 2008, in press.
19. In the following references, compound 4 is mentioned. However a preparative
procedure and spectroscopic and analytical data are not available. (a)
Bobranski, B.; Konieczny, M. Pol. Roczniki Chemii 1962, 36, 639–644; (b)
Konieczny, M. Pol. Bull Acad. Polon. Sci. Ser. Sci. Chim. 1959, 7, 229–233.
20. Burgess, L. E.; Meyers, A. I. J. Org. Chem. 1992, 57, 1656–1662.
21. The de was determined by chiral HPLC, using CHIRALPAK AD-H column,
isopropanol/n-hexane, flow rate 1 mL/min.
Acknowledgments
22. NMR data of compound 10: 1H NMR (400 MHz, CDCl3): d 1.18 (d, J = 6.1 Hz, 3H,
CH3), 2.72–2.91 (m, 5H, 1-H/2–H/4–H/5–H), 3.01 (ddd, J = 14.7/10.6/1.9 Hz, 1H,
4-H), 3.23 (ddd, J = 12.9/6.5/2.90 Hz, 1H, 5-H), 7.06–7.13 (m, 4H, Ph-CH). A
signal for the NH proton could not be detected.
We wish to thank the NRW Graduate School of Chemistry for a
stipend, which is funded by the Government of the State Nordrh-
ein-Westfalen and the DAAD.
23. NMR data of compound 15: 1H NMR (CDCl3): d 1.13 (d, J = 5.7 Hz, CH3), 2.61
(dd, J = 13.2/8.4 Hz, 1H, 2-H), 2.77 (br s, 1 H, NH), 2.84–2.95 (m, 4H, 4-H/5–H/
CH2Ph), 3.16 (dd, J = 13.3/2.4 Hz, 1H, CH2Ph), 3.23 (dd, J = 13.7/5.4 Hz, 1H, 2-H),
3.32 (m, 1H, 1-H). 7.10–7.32 (m, 9H, arom).
References
1. Weinstock, J.; Hieble, J. P.; Wilson, J. W., III. Drug Future 1985, 10, 645–697.
2. Kawase, M.; Saito, S.; Motohasho, N. Int. J. Antimicrob. Agents 2000, 14, 193–194.
3. Sorbera, L. A.; Castaner, J. Drug Future 2003, 28, 652–658.
4. Pettersson, I.; Liljefors, T.; Bogeso, K. J. Med. Chem. 1990, 33, 2197–2204.
5. Kaiser, C.; Dandridge, P. A.; Garvey, E.; Hahn, R. A.; Sarau, H. M.; Setler, P. E.;
Bass, L. S.; Clardy, J. J. Med. Chem. 1982, 25, 697–703.
24.
‘COLLECT’ data collection software. Nonius, B. V. Delft, The Netherlands, 1998.
25. Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307–326.
26. Otwinowski, Z.; Borek, D.; Majewski, W.; Minor, W. Acta Crystallogr., Sect. A
2003, 59, 228–234.
27. Sheldrick, G. M. Acta Crystallogr., Sect. A 1990, 46, 467–473.
28. Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112–122.
29. Keller, E. SCHAKAL—A Computer Program for the Graphic Representation of
Molecular and Crystallographic Models; Universität Freiburg, 1997.
6. Micheli, F.; Bonanomi, G.; Braggio, S.; Capelli, A. M.; Celestini, P.; Damiani, F.; Di
Fabio, R.; Donati, D.; Gagliardi, S.; Gentile, G.; Hamprecht, D.; Petrone, M.;