Synthesis of substituted 1-benzazepin-2-ones via ring-closing olefin metathesis

Article abstract of DOI:10.1016/j.tetlet.2009.02.022

The 1-benzazepin-2-one ring system is an important structural feature of marketed drugs, clinical candidates, and other bioactive molecules. We have developed a new benzazepinone synthesis that employs ring-closing olefin metathesis as a key step. This route provides efficient access to substituted benzazepinones that are difficult to synthesize via existing procedures.

Full text of DOI:10.1016/j.tetlet.2009.02.022

Tetrahedron Letters 50 (2009) 1911–1913
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of substituted 1-benzazepin-2-ones via ring-closing olefin metathesis
*
Scott B. Hoyt , Clare London, Min Park
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, RY 123-236, Rahway, NJ 07065-0900, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The 1-benzazepin-2-one ring system is an important structural feature of marketed drugs, clinical candi-
dates, and other bioactive molecules. We have developed a new benzazepinone synthesis that employs
ring-closing olefin metathesis as a key step. This route provides efficient access to substituted benzazepi-
nones that are difficult to synthesize via existing procedures.
Received 9 January 2009
Revised 2 February 2009
Accepted 3 February 2009
Available online 8 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The 1-benzazepin-2-one ring system is an important structural
motif in medicinal chemistry. It is a core feature of the angiotensin
converting enzyme (ACE) inhibitor Benzazepril,1 and of clinical
candidates such as the growth hormone secretagogue L-739,943,2
and the antithrombotic agent CVS-17783 (Fig. 1). 1-Benzazepin-
2-ones have also been employed as Nav1.7 sodium channel block-
ers,4 L-type (Cav1.2) calcium channel blockers,5 and analgesics.6
Their utility notwithstanding, benzazepinones can exhibit phar-
macokinetic liabilities due to their electron-rich nature. For in-
stance, they have been reported to undergo metabolic oxidation
at various sites (C6–C9) on the phenyl ring.7 This oxidation can
lead to higher clearance, lower exposure, and diminished efficacy
when these agents are dosed in vivo. A common strategy for miti-
gating such oxidation involves blocking the site of metabolism,
typically with an electron-withdrawing substituent such as fluo-
rine or trifluoromethyl. A general benzazepinone synthesis that al-
lowed facile substitution of C6–C9 could provide access to more
metabolically stable therapeutic agents, and would thus be highly
desirable.
Figure 1. Benzazepinone clinical agents.
We report herein a general method for benzazepinone synthesis
that employs ring-closing olefin metathesis (RCM) as a key step.
This approach allows facile substitution of C6–C9 and provides
the benzazepinone product in four steps from commercially avail-
able starting materials. In choosing this strategy, we were influ-
enced by the pioneering work of Grubbs, Fürstner, and others
that established RCM as a method of choice for the synthesis of se-
ven-membered rings.15
In principle, the benzazepinone ring system could be con-
structed via metathetic bond formation between C3 and C4, or
C4 and C5. To explore each possibility, we prepared model metath-
esis substrates 3 and 5. As shown in Scheme 1, 4-amino-3-bromo-
benzotrifluoride 2 was heated in the presence of tributylvinyltin
and Pd(PPh3)4 to yield the corresponding Stille coupling product.
Amidation of the anilinic nitrogen with vinylacetic acid then affor-
ded 3. Alternatively, 2 could undergo Stille coupling with allyltri-
butyltin and subsequent amidation with acryloyl chloride to
provide metathesis substrate 5.
Several benzazepinone syntheses have been reported to date.
The parent 1,3,4,5-tetrahydro-1-benzazepin-2-one 1 has been pre-
pared classically via Beckmann rearrangement of the oxime of
a-
tetralone.8 This approach remains in use, and subsequent modifica-
tions have been reported.9 1-Benzazepin-2-ones have also been
more recently prepared via Pd-catalyzed amidation of aryl ha-
lides,10 Rh-catalyzed oxidative cyclization of amino alcohols,11 oxi-
dative cyclization of N-methoxyamides,12 coupling of organozinc
reagents with aryl halides,13 and radical-mediated cyclization.14
While these methods each have various merits, they also suffer
limitations, including lack of availability of substituted starting
materials, a requirement for nitrogen protection and deprotection
in some methods, and lack of generality with regard to substrate.
* Corresponding author. Tel.: +1 732 594 3753; fax: +1 732 594 5350.
E-mail address: scott_hoyt@merck.com (S.B. Hoyt).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.022

1912
S. B. Hoyt et al. / Tetrahedron Letters 50 (2009) 1911–1913
Scheme 1. Reagents and conditions: (a) 5 mol % Pd(PPh3)4, tributylvinyltin, DMF, 80 °C (89%); (b) vinylacetic acid, oxalyl chloride, DMF, CH2Cl2, 0 °C (66%); (c) see Table 1 for
details; (d) 4 mol % Pd(PPh3)4, allyltributyltin, DMF, 80 °C (86%); (e) acryloyl chloride, triethylamine, THF, À10 °C, (70%); (f) see Table 1 for details; (g) 10% Pd:C, H2 (1 atm), 1:1
THF:CH3OH (82%).
Table 2
With substrates 3 and 5 in hand, we were ready to test the via-
Benzazepinone synthesis via two-step RCM/hydrogenation sequence
bility of each ring closure. In these experiments, we employed sec-
Entrya
Substrate
Product
Yieldsb (%)
87, 92
ond generation Grubbs, Grela, and Hoveyda type catalysts 8, 9, and
10 (Fig. 2). These were selected on the basis of their established
high levels of reactivity and stability, and because they were ex-
pected to offer differential and perhaps complementary reactivity
patterns relative to one another. Reactions were conducted under
standard RCM conditions—either at room temperature in dichloro-
methane, or at 70 °C in toluene.
1
We began this series of experiments by exploring bond for-
mation between C4 and C5. As shown in Table 1, exposure of
metathesis substrate 3 to 5 mol % of 8, either at room tempera-
ture (entry 1) or with heating (entry 2), afforded no yield of de-
sired product 4. An increase in the catalyst loading to 20 mol %
did furnish 4, albeit in a modest 35% yield (entry 3). Indenylid-
ene catalyst 9 also proved ineffective in converting 3 to 4 (en-
tries 4 and 5). The Hoveyda type catalyst 10, on the other
hand, delivered a moderate yield of desired product when the
reaction was run at room temperature (entry 6). Unfortunately,
heating did not improve the yield, even when a higher catalyst
loading was employed (entry 7).
2
3
67, 77
80, 81
4
73, 32
In contrast, bond formation between C3 and C4 proceeded
much more readily. Thus, exposure of substrate 5 to 5 mol % of 8
or 10 delivered the desired product 6 in 65% and 89% yields,
respectively (entries 8 and 9). Simple balloon hydrogenation of 6
then furnished the saturated 1-benzazepin-2-one 7 (Scheme 1).
On the basis of these findings, it appeared that an optimal metath-
5
6
7
60, 79
87, 91
89, 82
Figure 2. Second generation metathesis catalysts.
8
9
69, 97
Table 1
Optimization of RCM reactions shown in Scheme 1
86. 90
Entry
Reaction
Conditionsa
Yield (%)
1
2
3
4
5
6
7
8b
9
3 to 4
3 to 4
3 to 4
3 to 4
3 to 4
3 to 4
3 to 4
5 to 6
5 to 6
5 mol % 8, dichloromethane, rt
5 mol % 8, toluene, 70 °C
20 mol % 8, toluene, 70 °C
5 mol % 9, dichloromethane, rt
5 mol % 9, toluene, 70 °C
5 mol % 10, dichloromethane, rt
20 mol %10, toluene, 70 °C
5 mol % 8, dichloromethane, rt
5 mol % 10, dichloromethane, rt
0
0
35
0
10
0
0
42
43
65
89
a
RCM reactions were conducted using 5 mol % 10 in dichloromethane at room
temperature. Hydrogenations were conducted under 1 atm hydrogen with 10% Pd:C
as catalyst in 1:1 tetrahydrofuran:methanol.
a
b
Reactions were stirred for 18 h unless otherwise indicated.
Reaction complete after 2 h.
Yields are shown as (X%, Y%) and are for RCM and hydrogenation reactions,
b
respectively.

S. B. Hoyt et al. / Tetrahedron Letters 50 (2009) 1911–1913
1913
esis procedure would involve the use of catalyst 10 to effect bond
Supplementary data
formation between C3 and C4.
With the site of ring closure established, we next explored the
generality of this strategy. We were most interested in probing
the synthesis of electron-deficient benzazepinones, as clinical
agents that incorporated these would likely be more resistant to
metabolic oxidation. Additionally, electron-deficient substrates
might prove challenging for existing benzazepinone syntheses,
many of which proceed via oxidative mechanisms or cationic inter-
mediates. As shown in Table 2, substrates that incorporated fluo-
rine at the nascent 6, 7, 8, or 9 positions underwent metathesis
and subsequent hydrogenation in good yields to provide the corre-
sponding fluorinated benzazepinones (entries 1–4). Di- and triflu-
orinated substrates could also be employed (entries 5 and 6), as
could those bearing stronger electron-withdrawing groups such
as trifluoromethyl (entry 7), trifluoromethoxy (entry 8), and
methyl sulfone (entry 9). Note that many of these sequences were
conducted on multigram scale, thus confirming the practicality of
this approach.
A final example (entry 10) illustrates the one limitation of this
method that we have encountered thus far, namely its incompati-
bility with substrates that contain basic heteroatoms. Exposure of
the pyridinyl substrate shown to 5 mol % of 10, either at room tem-
perature in dichloromethane or at 70 °C in toluene, resulted in no
conversion to desired product. Similar results were obtained with
catalysts 8 and 9. The incompatibility of Rh-based RCM catalysts
with substrates that can coordinate to the metal center is, by
now, well documented, and likely accounts for the lack of reactiv-
ity observed in this case.16
Representative experimental procedures for the synthesis of 7-
fluoro-1,3,4,5-tetrahydro-1-benzazepin-2-one (Table 2, entry 2)
are included. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/j.tetlet.2009.02.
022.
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be used preparatively on multigram scale. Importantly, it pro-
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The authors would like to thank Jason Cox, Patrick Shao, and Jo-
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