A practical synthesis of regioisomeric 6- and 7-methoxytetrahydro-3- benzazepines

Article abstract of DOI:10.1021/op900292j

A concise and versatile synthetic route for 6- and 7-methoxy tetrahydro-3-benzazepines is described. The key feature of the synthesis is a one-pot acylation/cyclization/elimination sequence to construct either of the isomeric dihydrobenzazepine ring syste

Full text of DOI:10.1021/op900292j

Organic Process Research & Development 2010, 14, 380–385
A Practical Synthesis of Regioisomeric 6- and 7-Methoxytetrahydro-3-benzazepines
Jimmy T. Liang,* Jing Liu, Brock T. Shireman, Vi Tran, Xiaohu Deng, and Neelakandha S. Mani
Johnson & Johnson Pharmaceutical Research and DeVelopment, L.L.C., 3210 Merryfield Row, San Diego,
California 92121, U.S.A.
Abstract:
in nonselective opioid receptor antagonists4 as well as novel
antibacterial agents.5 In connection with one of our drug
discovery programs, we were interested in developing a
regioselective and scalable synthesis of both 6- and 7-alkox-
ytetrahydro-3-benzazepine core structures 1a and 2a (Figure
2). In the literature, there are four common synthetic strategies
to assemble the tetrahydrobenzazepine ring (Scheme 1): (a)
Lewis acid-promoted Friedel-Crafts cyclization of acetals 3
followed by reduction of the olefin and carbonyl groups;4,6 (b)
intramolecular Friedel-Crafts acylation of an acid chloride 4
followed by reduction of the carbonyl group;7 (c) intramolecular
Friedel-Crafts alkylation of an alkyl halide 5;3b (d) Ni-catalyzed
high-pressure and high-temperature hydrogenation of o-phe-
nylene diacetonitriles 6 in the presence of ammonia.2c The first
three strategies share a similar bond disconnection probably
because of the easy access to the starting materials. An example
of compound 1 was prepared via route a through the intermedi-
ate acetal 3 in six steps (Scheme 2).4 Regioselective synthesis
of isomer 2, however, has not been reported.
A concise and versatile synthetic route for 6- and 7-methoxy
tetrahydro-3-benzazepines is described. The key feature of the
synthesis is a one-pot acylation/cyclization/elimination sequence
to construct either of the isomeric dihydrobenzazepine ring systems
from the same starting material. The route is high yielding and
chromatography-free.
Introduction
Drugs comprising tetrahydrobenzazepine derivatives have
been thoroughly investigated for their pharmacological and
biological effects (Figure 1). Fenoldopam mesylate, for example,
is the first selective dopamine D1 receptor agonist approved for
severe hypertension.1 Many drug candidates bearing the same
structural motif are also currently under development in a range
of therapeutic areas (Figure 1). For instance, a number of
tetrahydrobenzazepine derivatives are potent modulators of
dopamine D3 receptors, potentially useful for treatment of central
nervous system disorders such as schizophrenia, depression, and
substance abuse.2 Much attention has also been focused on
developing selective 5HT2C agonists for the treatment of obesity,
obsessive-compulsive disorder, sexual dysfunction, glaucoma,
and Alzheimer disease.3 The same structural motif is also found
We envisioned a more redox-efficient cyclization strategy8
through amine intermediate 8 which would minimize oxidation
state manipulation and protecting group exchange, thus signifi-
cantly shortening the overall sequence (Scheme 3). Herein, we
report the successful implementation of this strategy for the
regioselective synthesis of both isomers 1 and 2 through
common precursor 8, which was readily prepared from com-
mercially available starting materials. The key step is a one-
pot transformation that includes N-protection, Friedel-Crafts
cyclization, and elimination. We believe that this sequence
would be applicable to the syntheses of related tetrahydro-3-
benzazepine compounds.
* Author for correspondence. E-mail: jliang4@its.jnj.com.
(1) Murphy, M. B.; Murray, C.; Shorten, G. D. N. Engl. J. Med. 2001,
345, 1548–1557.
(2) (a) Micheli, F.; Bonanomi, G.; Braggio, S.; Capelli, A. M.; Celestini,
P.; Damiani, F.; Fabio, R. D.; Donati, D.; Gagliardi, S.; Gentile, G.;
Hamprecht, D.; Petrone, M.; Radaelli, S.; Tedesco, G.; Terreni, S.;
Worby, A.; Heidbreder, C. Bioorg. Med. Chem. Lett. 2008, 18, 901–
907. (b) Micheli, F.; Bonanomi, G.; Blaney, F. E.; Braggio, S.; Capelli,
A. M.; Cheechia, A.; Curcuruto, O.; Damiani, F.; Fabio, R. D.; Donati,
D.; Gentile, G.; Gribble, A.; Hamprecht, D.; Tedesco, G.; Terreni, S.;
Tarsi, L.; Lightfoot, A.; Stemp, G.; MacDonald, G.; Smith, A.;
Pecoraro, M.; Petrone, M.; Perini, O.; Piner, J.; Rossi, T.; Worby, A.;
Pilla, M.; Valerio, E.; Griffante, C.; Mugnaini, M.; Wood, M.; Scott,
C.; Andreoli, M.; Lacroix, L.; Schwarz, A.; Gozzi, A.; Gifone, A.;
Ashby, C. R.; Hagan, J. J.; Heidbreder, C. J. Med. Chem. 2007, 50,
5076–5089. (c) MacDonald, G. J.; Branch, C. L.; Hadley, M. S.;
Johnson, C. N.; Nash, D. J.; Smith, A. B.; Stemp, G.; Thewlis, K. M.;
Vong, A. K. K.; Austin, N. E.; Jeffrey, P.; Winborn, K. Y.; Boyfield,
I.; Hagan, J. J.; Middlemiss, D. N.; Reavill, C.; Riley, G. J.; Watson,
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46, 4952–4964. (d) Austin, N. E.; Avenell, K. Y.; Boyfield, I.; Branch,
C. L.; Hadley, M. S.; Jeffrey, P.; Johnson, C. N.; MacDonald, G. J.;
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Vong, A. K. K.; Wood, M. Bioorg. Med. Chem. Lett. 2000, 10, 2553–
2555.
Results and Discussion
Commercially available 2-(3-methoxyphenyl)ethylamine (7)
was chosen as the starting material because the electron-donating
alkoxy group should activate the ortho and para positions for
the Friedel-Crafts cyclization, thus potentially providing both
regioisomers of interest. To test this idea, the requisite precursor
(4) Takeuchi, K.; Holloway, W. G.; Mitch, C. H.; Quimby, S. J.;
McKinzie, J. H.; Suter, T. M.; Statnick, M. A.; Surface, P. L.;
Emmerson, P. J.; Thomas, E. M.; Siegel, M. G. Bioorg. Med. Chem.
Lett. 2007, 17, 6841–6846.
(5) Johnson, P. D.; Aristoff, P. A.; Zurenko, G. E.; Schaadt, R. D.; Yagi,
B. H.; Ford, C. W.; Hamel, J. C.; Stapert, D.; Moerman, J. K. Bioorg.
Med. Chem. Lett. 2003, 13, 4197–4200.
(3) (a) Shimada, I.; Maeno, K.; Kondoh, Y.; Kaku, H.; Sugasawa, K.;
Kimura, Y.; Hatanaka, K.; Naitou, Y.; Wanibuchi, F.; Sakamoto, S.;
Tsukamoto, S. Bioorg. Med. Chem. Lett. 2008, 16, 3309–3320. (b)
Mohapatra, S.; Hellberg, M. R.; Feng, Z. U.S. Patent 0293475, 2007.
(c) Behan, D. P.; Smith, B. M.; Bjenning, C. WO/2006/071740, 2006.
(d) Smith, B.; Gilson, C.; Schultz, J.; Estrada, S. WO/2005/042491,
2005.
(6) Snyder, S. E.; Aviles-Garay, F. A.; Chakraborti, R.; Nichols, D. E.;
Watts, V. J.; Mailman, R. B. J. Med. Chem. 1995, 38, 2395–2409.
(7) Kanao, M.; Hashizume, T.; Ichikawa, Y.; Irie, K.; Satoh, Y.; Isoda,
S. Chem. Pharm. Bull. 1982, 30, 180–188.
(8) Deng, X.; Liang, J. T.; Liu, J.; McAllister, H.; Schubert, C.; Mani,
N. S. Org. Process Res. DeV. 2007, 11, 1043–1050.
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10.1021/op900292j  2010 American Chemical Society
Published on Web 01/26/2010

Figure 1. Drug candidates with tetrahydrobenzazepine motif.
Figure 2. Regioisomeric tetrahydro-3-benzazepines of interest.
tivity issues with the Friedel-Crafts cyclization step, one
solution was to pursue intermediate 12 (Scheme 7, route e).
However, it soon became clear to us that the intramolecular
Friedel-Crafts cyclization of 12 was extremely difficult. The
desired product was not observed at all in the presence of strong
acid promoters (HCl, BF3 ·Et2O, TFA, or TfOH), and starting
material 12 eventually decomposed upon prolonged heating.
This was not a total surprise since the meta position was
deactivated by the methoxy substituent via inductive effect. We
then pursued an alternative intermediate 14 (Scheme 7, route
f). With the knowledge that the Friedel-Crafts cyclization of
8 preferentially took place at the para position, we decided to
block the para position with bromine to force the ortho
cyclization. Precursor 14 was synthesized in two steps from
the same starting material 7 as before (Scheme 8). Bromination
of amine 7 with Br2 in AcOH occurred exclusively at the
4-position to give 13, which crystallized out as the HBr salt in
good yield and high purity upon trituration with tert-butylmethyl
ether. In the next step, reductive amination of dimethoxyac-
etaldehyde with amine 13 gave amino acetal 14 in 97% yield.
Compound 14 was isolated after extractive aqueous workup,
and no further purification was needed. With precursor 14 in
hand, the key cyclization step was investigated. Unfortunately,
under the reaction conditions developed previously for acetal
8 (TFAA, CH2Cl2, rt), only N-trifluoroacetylation was observed.
The lower reactivity of acetal 14 relative to that of 8 was
somewhat expected because the ortho position (relative to the
methoxy group) was much less reactive than the para position
as demonstrated by the excellent regioselectivity in the cycliza-
tion of 8. In addition, the bromide substituent also deactivated
14 towards the cyclization reaction.11 This problem was readily
addressed by performing the reaction in TFA as the solvent at
slightly elevated temperature (40 °C). Under these conditions,
the one-pot acylation, cyclization, and elimination again oc-
curred cleanly to provide crude 15 after a simple extractive
workup (Scheme 9). Subsequent hydrogenation in EtOH/EtOAc
reduced enamide 15 with concomitant removal of the bromine
blocking group in a single step to afford compound 2 in good
overall yield. Thus, the regioselective synthesis of both 1 and
2 was accomplished via a similar sequence from the same
starting material 7.
8 was first prepared by reductive amination of compound 7
with dimethoxyacetaldehyde in quantitative crude yield (Scheme
4). With acetal 8 in hand, the Friedel-Crafts cyclization step
was investigated utilizing both Brønsted (AlCl3, BF3 ·Et2O) and
Lewis acids (H2SO4, 6 N HCl, TFA). Unfortunately, none of
these conditions provided either the desired dihydro-3-benza-
zepine 9 or 10 (Scheme 5). We reasoned that the difficulty of
the cyclization reaction stemmed from the coordination of the
acids with the secondary amine, which inductively hindered
the necessary formation of the neighboring carbocation for the
Friedel-Crafts cyclization to occur. Similar cyclization reactions
are also reported to occur in poor yield.3a,6,9 To address this
problem, we intended to install a trifluoroacetyl protecting group
on the nitrogen atom using trifluoroacetic anhydride (TFAA).
To our pleasant surprise, when compound 8 was treated with
TFAA in CH2Cl2 at room temperature, not only did N-protection
occur, but also the subsequent Friedel-Crafts cyclization and
methanol elimination took place to afford compound 11 in
excellent yield. Presumably, the cyclization and elimination
steps were mediated by the trifluoroacetic acid generated in the
N-protection step. Interestingly, the cyclization step occurred
exclusively at the para position relative to the methoxy group.
None of the ortho isomer was isolated. Crude compound 11
was then hydrogenated in EtOAc over Pd/C as catalyst to
provide crude product 1 (Scheme 6). It is worth noting that all
the intermediates were telescoped after simple workup to the
next step without chromatographic purification. Trituration with
1:1 tert-butylmethyl ether/hexanes of the crude product afforded
pure compound 1 in 70% overall yield over three steps.10
Encouraged by these results, we turned our attention to the
regioselective synthesis of isomer 2. To avoid the regioselec-
(9) (a) Draper, R. W.; Hou, D.; Iyer, R.; Lee, G. M.; Liang, J. T.; Mas,
J. L.; Tormos, W.; Vater, E. J.; Gunter, G.; Mergelsberg, I.; Scherer,
D. Org. Process Res. DeV. 1998, 2, 175–185. (b) Draper, R. W.; Hou,
D.; Iyer, R.; Lee, G. M.; Liang, J. T.; Mas, J. L.; Tormos, W.; Vater,
E. J. Org. Process Res. DeV. 1998, 2, 186–193.
(10) The N-trifluoroacetyl protecting group can be easily removed in high
yields. The use of other amide-type N-protecting groups has not been
tested.
(11) Morrison, R. T.; Boyd, R. N. Organic Chemistry, 6th ed.; Prentice
Hall: NJ, 1992.
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Scheme 1. Four common synthetic strategies to construct tetrahydro-3-benzazepine ring
Scheme 2. Six-step literature approach to 6-methoxytetrahydro-3-benzazepine4
Scheme 3. Strategy for the regioisomeric synthesis of 1 and 2
Scheme 4. Reductive amination step
the acylation/cyclization of 14 was already carried out in TFA,
there was the possibility of a one-pot transformation. Indeed,
when the reaction sequence was performed in a one-pot manner
by adding Et3SiH to the reaction mixture containing 15 at 60
°C, compound 16 was formed cleanly (Scheme 10). Thus, four
transformations, N-acylation, cyclization, enamine formation,
and reduction, are all accomplished in a simple one-pot reaction,
and the formation of intermediates at each stage can be
monitored by HPLC. The isolation of compound 16 was
somewhat challenging because of the presence of TFA and
Et3SiOH, the byproduct from the Et3SiH reduction step. After
some optimization, we found that TFA was effectively removed
by dissolving the reaction mixture in toluene and washing
successively with water and saturated NaHCO3 solution. The
toluene layer was concentrated and then triturated with hexanes
to remove the Et3SiOH byproduct. Using this procedure,
benzazepine 16 crystallized out of the solution in good yield
In the above synthesis, the bromide was employed as a
‘protecting group’ for the more reactive para position and was
removed in the last step. However, aryl bromide functionality
would open up many new opportunities for further derivatiza-
tions and structure-activity relationship (SAR) studies. To
preserve the bromide group, an alternative reduction method
was needed. It is known that enamides can be reduced with
silanes, usually in strongly acidic solvents such as TFA.12 Since
(12) (a) Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis 1974, 9,
633–651. (b) Masuno, M. N.; Molinski, T. F. Tetrahedron Lett. 2001,
42, 8263–8266.
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Scheme 5. Friedel-Crafts cyclization
Scheme 6. Synthesis of compound 1
Scheme 7. Two possible synthetic pathways to construct tetrahydro-3-benzazepine 2
Scheme 8. Synthesis of dimethyl acetal 14
Scheme 9. Synthesis of tetrahydrobenzazepine isomer 2
Scheme 10. Three-step, one-pot synthesis
and excellent purity. Thus, we established a highly efficient one-
pot, four-step transformation for the synthesis of tetrahydroben-
zazepine 16 from intermediate 14.
7-methoxytetrahydrobenzazepines 1, 2, and 16 in three chro-
matography-free steps from the same commercially available
amine 7. In the key step, acylation, Friedel-Crafts cyclization,
enamine formation, and reduction (in the case of 16) are all
accomplished with a simple one-pot procedure. Compared to
the literature precedence, this route offers significant advantages
Conclusion
In summary, we have developed a highly efficient and
versatile route for the synthesis of regioisomeric 6- and
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383

and should be applicable to the synthesis of many interesting
tetrahydrobenzazepine building blocks. While we have not
carried out the synthesis beyond 20 g scales, the crystalline
nature of the benzazepines and the simple modifications of
replacing stripping operations with solvent exchanges along with
other minor changes should allow this chemistry to successfully
operate at multikilogram scale.
HRMS (ESI+): calculated for [C13H12F3NO2 + H]+, 272.0893;
m/z found, 272.0881.
7-Methoxy-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-ben-
zo[d]azepine (1)4. In a 1-L, one-neck, Parr bottle, crude
8-methoxy-3-trifluoroacetyl-2,3-dihydro-1H-benzo[d]azepine (7)
(44 g, 0.162 mol) was diluted with EtOAc (250 mL) and then
charged with 10% Pd/C (5 g) and H2 (50 psi). After 18 h at
room temperature, the reaction was approximately 70% com-
plete. The catalyst was filtered off with a pad of Celite. The
filtrate was resubmitted to hydrogenation, utilizing fresh 10%
Pd/C (5 g) to complete the reaction. The catalyst was filtered
off and the filtrate concentrated to an oily solid. The crude
product was slurried in 1:1 TBME/hexane (200 mL) overnight
and then filtered to recover 25.20 g of 7-methoxy-3-trifluoro-
acetyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1) as a white
solid in 70% yield over three steps. The product exists as two
rotamers at room temperature in the NMR spectra. Mp
105-107 °C; 1H NMR (500 MHz, CDCl3, δ): 7.08-7.03 (dd,
J ) 7.7, 3.4 Hz, 1H), 6.72-6.68 (m, 2H), 3.79 (s, 3H),
3.76-3.73 (m, 2H), 3.70-3.65 (m, 2H), 2.96-2.90 (m, 4H);
13C NMR (126 MHz, CDCl3, δ): (158.5, 158.3), (156.2, 155.9),
Experimental Section
General. All reagents were purchased from commercial
suppliers and used without further purification. 1H and 13C NMR
spectra were recorded on a Bruker (1H, 400, 500, 600 MHz;
13C, 126, 151 MHz) NMR spectrometer. HRMS (ESI) was
performed on a Bruker µToF apparatus. Melting points were
determined in open capillaries on a Mel-Temp apparatus and
are uncorrected. Analytical HPLC conditions were the follow-
ing: Agilent ZORBAX Eclipse XDB-C8, 5 µm, 4.6 mm × 150
mm, flow rate 1 mL/min, gradient (acetonitrile/water with
0.05% TFA): 1% acetonitrile/99% water to 99% acetonitrile/
1% water ramp over 8 min, then hold.
N-(2,2-Dimethoxyethyl)-2-(3-methoxyphenyl)ethylamine (8).
A mixture of 2-(3-methoxyphenyl)ethylamine (7) (20.0 g, 0.132
mol, 1.0 equiv), dimethoxyacetaldehyde solution 60 wt % in
H2O (23.9 mL, 0.158 mol, 1.2 equiv), and MeOH (75 mL) was
stirred overnight at room temperature and then cooled to 0 °C.
NaBH4 (4.0 g, 0.106 mol, 0.8 equiv) was added in small
portions over 15 min, and then the mixture was warmed to 25
°C. After stirring for 3 h at room temperature, the reaction was
quenched with H2O (200 mL) and extracted with CH2Cl2 (200
mL). The organic layer was collected, dried over Na2SO4,
filtered, and concentrated to obtain N-(2,2-dimethoxyethyl)-2-
(3-methoxyphenyl)ethylamine (8) as oil (34 g, 107% crude
yield). The material was used in the next step without further
(141.4, 140.7), (132.1, 131.4), (130.9, 130.8), 116.8 (q, JC-F
)
287.7 Hz), (116.0, 115.9), 111.4, 55.2, (48.7, 48.3), (47.2, 46.8),
(38.1, 37.0), (36.9, 35.7); HRMS (ESI+): calculated for
[C13H14F3NO2 + H]+, 274.1049; m/z found, 274.1057.
2-(2-Bromo-5-methoxyphenyl)ethylammonium Bromide
(13). A solution of 3-methoxyphenethylamine (7) (15.0 mL,
0.103 mol, 1.0 equiv) in acetic acid (50 mL) was treated with
a solution of bromine (5.55 mL, 0.108 mol, 1.05 equiv) in acetic
acid (10 mL) over 50 min, during which the internal temperature
never exceeded 25 °C. After stirring for 10 min, Et2O (100 mL)
was added over 5 min. The suspension was cooled to 0 °C and
filtered. The filter cake was rinsed with Et2O and hexanes and
dried in a vacuum oven at 45 °C for 4 h to afford product 13
1
purification. H NMR (500 MHz, CDCl3, δ): 7.21 (dd, J )
8.9, 7.5 Hz, 1H), 6.80 (d, J ) 7.6 Hz, 1H), 6.76-6.74 (m, 2H),
4.45 (t, J ) 5.5 Hz, 1H), 3.79 (s, 3H), 3.36 (s, 6H), 2.89 (t, J
) 6.8 Hz, 2H), 2.79-2.75 (m, 4H); 13C NMR (126 MHz,
CDCl3, δ): 159.7, 141.4, 129.4, 121.0, 114.4, 111.50, 103.8,
55.1, 54.0, 51.0, 36.4; HRMS (ESI+): calculated for
[C13H21NO3 + H]+, 240.1594; m/z found, 240.1596.
1
as a white solid (28.3 g, 88%). Mp 152-154 °C; H NMR
(400 MHz, d6-DMSO, δ): 7.95 (br s, 3H), 7.52 (d, J ) 8.8 Hz,
1H), 6.97 (d, J ) 3.1 Hz, 1H), 6.84 (dd, J ) 8.8, 3.1 Hz, 1H),
3.77 (s, 3H), 3.08-3.01 (m, 2 H), 2.99-2.92 (m, 2H). 13C NMR
(151 MHz, d6-DMSO, δ): 158.8, 137.4, 133.3, 116.7, 114.6,
113.9, 55.4, 38.2, 33.2. HRMS (ESI+): calculated for
[C9H13BrNO + H]+, 230.0175; m/z found, 230.0194.
8-Methoxy-3-trifluoroacetyl-2,3-dihydro-1H-benzo[d]aze-
pine (11). A solution of N-(2,2-dimethoxyethyl)-2-(3-methox-
yphenyl)ethylamine (8) (34 g, 0.142 mol, 1 equiv) in CH2Cl2
(250 mL) was slowly treated with TFAA (100.4 mL, 0.711
mol, 5 equiv) in a cooled ice bath. The ice bath was removed,
and the reaction mixture was stirred for 18 h. The reaction was
quenched with ice cold aq saturated NaCl solution. The organic
layer was separated, dried with Na2SO4, filtered, and concen-
trated to recover 8-methoxy-3-trifluoroacetyl-2,3-dihydro-1H-
benzo[d]azepine (11) as a yellow-orange oil (44.38 g, 115%
crude yield). The material was used in the next step without
further purification. The product exists as two rotamers at room
temperature in the NMR spectra. 1H NMR (500 MHz, CDCl3,
δ): 7.19-6.61 (m, 4H), (5.98, 5.84) (d, J ) 10.4 Hz, 1H), (4.07,
3.96) (t, J ) 4.9 Hz, 2H), 3.82 (s, 3H), (3.13, 3.09) (t, J ) 4.9
Hz, 2H); 13C NMR (126 MHz, CDCl3, δ): 159.0, 154.6 (q, JC-F
) 36.8 Hz), (140.4, 140.1), (133.2, 133.1), 126.0, 121.9, 120.8
(q, JC-F ) 4.5 Hz), 116.4 (q, JC-F ) 287.9 Hz), (116, 115.6),
(115.0, 114.9), (112.0, 111.9), 55.3, (45.8, 44.2), (37.0, 36.5);
N-(2,2-Dimethoxyethyl)-2-(2-bromo-5-methoxyphenyl)-
ethylamine (14). A mixture of 2-(2-bromo-5-methoxyphenyl)-
ethylammonium bromide (13) (20.0 g, 0.064 mol, 1.0 equiv)
in MeOH (200 mL), anhydrous Na2SO4 (20.0 g, 0.141 mol,
2.2 equiv), triethylamine (9.4 mL, 0.067 mol, 1.05 equiv), and
dimethoxyacetaldehyde solution (60 wt % in H2O, 14.5 mL,
0.096 mol, 1.5 equiv) was stirred at room temperature for 18 h.
The reaction was then cooled to -15 °C. Sodium borohydride
(2.4 g, 0.063 mol, 1.0 equiv) was added in small portions over
12 min, during which the internal temperature never exceeded
20 °C. The reaction was warmed to room temperature and
stirred for 30 min and filtered. Saturated NaHCO3 solution (100
mL) was added, and methanol was removed by rotovap. The
solution was diluted with water (150 mL) and extracted with
CH2Cl2 (150 mL). The organic layer was washed with aq
saturated NaHCO3 solution (100 mL) and aq saturated NaCl
(100 mL) solution, dried over Na2SO4, and concentrated to
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afford product 14 as a light-yellow oil (19.8 g, 97%). 1H NMR
(500 MHz, CDCl3, δ): 7.42 (d, J ) 8.8 Hz, 1H), 6.81 (d, J )
3.1 Hz, 1H), 6.65 (dd, J ) 8.7, 3.1 Hz, 1H), 4.49 (t, J ) 5.5
Hz, 1H), 3.78 (s, 3H), 3.40 (s, 6H), 2.90 (s, 4 H), 2.80 (d, J )
5.5 Hz, 2H); 13C NMR (126 MHz, CDCl3, δ): 158.9, 140.2,
133.3, 116.3, 114.9, 113.5, 104.0, 55.4, 54.1, 51.0, 49.5, 36.9;
MS (ESI+): calculated for [C13H21BrNO3 + H]+, 318.1; m/z
found, 318.0.
charged with TFAA (19.6 mL, 0.14 mol, 3.2 equiv) and cooled
to 0 °C. Under neat conditions, N-(2,2-dimethoxyethyl)-2-(2-
bromo-5-methoxyphenyl)ethylamine (14) (14.0 g, 0.044 mol,
1.0 equiv) was added dropwise to TFAA (19.6 mL, 0.14 mol,
3.2 equiv) at 0 °C over 5 min, during which the internal
temperature never exceeded 15 °C. The reaction was warmed
to room temperature and stirred for 20 min. Trifluoroacetic acid
(32.7 mL, 0.440 mol, 10.0 equiv) was added over 3 min, and
the reaction was heated to 40 °C for 2 h. Triethylsilane (31.6
mL, 0.198 mol, 4.5 equiv) was added over 6 min, and the
reaction was heated to 60 °C for 24 h. The reaction was diluted
with toluene (90 mL), washed with water (2 × 200 mL) and
NaHCO3 solution (150 mL), dried over Na2SO4, and concen-
trated. Hexanes (60 mL) was added to the residue over 5 min.
The resulting suspension was cooled to 0 °C and filtered to
afford product 16 as a white solid (10.6 g, 68%). The product
exists as two rotamers (1:1 ratio) at room temperature in NMR
6-Methoxy-3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-ben-
zo[d]azepine (2). Under neat conditions, N-(2,2-dimethoxy-
ethyl)-2-(2-bromo-5-methoxyphenyl)ethylamine (14) (2.3 g, 7.2
× 10-3 mol, 1.0 equiv) was added dropwise to TFAA (3.22
mL, 0.023 mol, 3.2 equiv) at -15 °C over 15 min, during which
the internal temperature never exceeded -10 °C. The reaction
was warmed to room temperature and stirred for 25 min.
Trifluoroacetic acid (5.52 mL, 0.074 mol, 10.3 equiv) was added
over 2 min, and the reaction was heated to 40 °C for 18 h. The
mixture was diluted with toluene (40 mL) and ice/water (40
mL). The organic layer was washed with water (2 × 20 mL)
and passed through a short silica gel pad with CH2Cl2. The
solvents were removed to afford a red oil, which was then
redissolved in 1:1 EtOH/EtOAc (30 mL). The flask was purged
with N2(g) and charged with Pd/C (10%, 0.76 g, 0.71 mmol,
0.1 equiv). The reaction was connected to a H2 balloon and
stirred at room temperature for 3 days. The mixture was filtered
through a Celite pad and concentrated to afford red oil. After
trituration from 1:1 MTBE/hexanes, the product 2 was obtained
as a white solid (1.2 g, 61% yield). The product exists as two
rotamers (1:1 ratio) at room temperature in NMR spectra. Mp
1
spectra. Mp 88-89 °C; H NMR of the mixture (500 MHz,
CDCl3, δ): [7.44 (d, J ) 8.8 Hz, 1H), 7.43 (d, J ) 8.8 Hz,
1H)], 6.69 (d, J ) 8.9 Hz, 1H), [3.82 (s, 3H), 3.81 (s, 3H)],
3.80-3.74 (m, 2H), 3.73-3.65 (m, 2 H), 3.28-3.24 (m, 2H),
3.17-3.11 (m, 2H); 13C NMR (151 MHz, CDCl3, δ): 156.2
(q, JC-F ) 36.5 Hz), 156.1, (140.3, 140.0), (131.6, 131.4),
(130.2, 129.7), 116.7 (q, JC-F ) 288.0 Hz), (115.6, 115.5),
(111.1, 110.8), 55.9, [47.1 (q, JC-F ) 3.1 Hz), 46.6 (q, JC-F
)
3.3 Hz)], (45.4, 45.1), (35.5, 34.6), (27.2, 26.0); HRMS (ESI+):
calculated for [C13H14BrF3NO2 + H]+, 352.0155; m/z found,
352.014. Anal. Calcd for C13H13BrF3NO2: C, 44.34; H, 3.72;
N, 3.98. Found: C, 44.11; H, 3.41; N, 3.91.
1
74-75 °C; H NMR of the mixture (500 MHz, CDCl3, δ):
7.17-7.10 (m, 1H), 6.80 (dd, J ) 8.7, 4.7 Hz, 1H), 6.78-6.72
(m, 1H), 3.81 (s, 3H), 3.79-3.71 (m, 2H), 3.71-3.62 (m, 2H),
3.14-3.05 (m, 2H), 2.99-2.96 (m, 2H); 13C NMR (151 MHz,
CDCl3, δ): 156.9, 156.1 (q, JC-F ) 35.4 Hz), (141.8, 141.2),
(128.3, 127.7), (127.5, 127.3), 122.1, 116.7 (q, JC-F ) 288.0
Hz), (109.5, 109.3), 55.7, [47.9 (q, JC-F ) 3.5 Hz), 47.8 (q,
JC-F ) 3.2 Hz)], (46.4, 46.3), (37.5, 36.3), (27.2, 25.9); HRMS
(ESI+): calculated for [C13H15F3NO2 + H]+, 274.1049; m/z
found, 274.1051.
Acknowledgment
We are grateful to Dr. Nicholas Carruthers for supporting
this work and Dr. Jiejun Wu and Ms. Heather McAllister for
providing analytical assistance.
Supporting Information Available
This material is available free of charge via the Internet at
http://pubs.acs.org.
(6-Bromo-9-methoxy-3-2,2,2-trifluoro-trifluoroacetyl-
2,3,4,5-tetrahydro-1H-benzo[d]azepine (16). A 250-mL, two-
neck, round-bottom flask under a nitrogen atmosphere was
Received for review November 6, 2009.
OP900292J
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