Access to Benzazepinones by Pd-Catalyzed Remote C-H Carbonylation of γ-Arylpropylamine Derivatives

Article abstract of DOI:10.1021/acs.orglett.9b01523

A general method for the construction of seven-membered rings through Pd-catalyzed C(sp²)-H carbonylation at the remote ?-position of γ-arylpropylamine derivatives, including chiral α-amino acids, has been developed using Mo(CO)₆ as the CO source, furnishing richly functionalized benzo[c]azepin-1-one derivatives. The readily removable N-SO₂Py protecting/directing group provides high levels of chemo-, regio- and diastereoselectivity. Furthermore, this method is amenable to the postsynthetic modification of complex molecules such as small peptides.

Full text of DOI:10.1021/acs.orglett.9b01523

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Access to Benzazepinones by Pd-Catalyzed Remote C−H
Carbonylation of γ‑Arylpropylamine Derivatives
,†,‡
Mario Martínez-Mingo,† Nuria Rodríguez,*,†,‡ Ramon Gomez Arrayas,*
́
́
́
and Juan C. Carretero*,†,‡
†
́
́
Departamento de Química Organica, Facultad de Ciencias, Universidad Autonoma de Madrid (UAM), Cantoblanco, 28049
Madrid, Spain
‡Institute for Advanced Research in Chemical Sciences (IAdChem), UAM, Cantoblanco, 28049 Madrid, Spain
S
* Supporting Information
ABSTRACT: A general method for the construction of seven-
membered rings through Pd-catalyzed C(sp2)−H carbonylation at
the remote ε-position of γ-arylpropylamine derivatives, including
chiral α-amino acids, has been developed using Mo(CO)6 as the
CO source, furnishing richly functionalized benzo[c]azepin-1-one
derivatives. The readily removable N-SO2Py protecting/directing group provides high levels of chemo-, regio- and
diastereoselectivity. Furthermore, this method is amenable to the postsynthetic modification of complex molecules such as small
peptides.
he benzazepine skeleton is a privileged scaffold in terms
While the C−H carbonylation of amines is a powerful
method for five- and six-membered-ring benzolactam synthesis
(Scheme 1),11,12 there is no catalytic method for the assembly
T
of biological activity1 (Figure 1). However, access to
Scheme 1. C−H Carbonylation Strategies To Afford
Benzolactams
Figure 1. Bioactive molecules based on a 2-benzazepinone core.
structural diversity around this scaffold is limited by the
availability of general methods for the synthesis of
benzazepines, since classical approaches largely rely on
multistep strategies.2 The asymmetric synthesis of benzaze-
pines is even more underexplored.3
of benzazepinones.13 This lack of precedents likely stems from
the difficulty of forming metallacycles larger than the usual five-
or six-membered rings.13
Given the significant advances in the arsenal of C−H
functionalization strategies concerning the construction of five-
and six-membered heterocyclic ring systems,4 it is surprising
that only a handful of protocols enabling the assembly of
seven-membered rings have been reported.5−10 Most of them
rely on [4 + 3] annulation of benzyl- or phenethylamine
derivatives at various oxidation levels with unsaturated
systems.5 A PdII-catalyzed [3 + 2 + 2]-type oxidative
annulation of isatins with alkynes has appeared for accessing
azepines,6 whereas the assembly of axially chiral dibenzazepi-
nones has been recently achieved via Pd0-catalyzed C−H
intramolecular arylation.7 Some rare examples of azepine
synthesis via intramolecular oxidative C−H coupling8 and C−
H amidation9 have also been reported. Despite these advances,
novel C−H functionalization approaches would be of
substantial utility.
During our studies of Pd-catalyzed γ-C(sp3)−H carbon-
ylative cyclization of aliphatic amines leading to γ-lactams,14 we
observed that the N-SO2Py directing group enabled remote ε-
C(sp2)−H carbonylation to afford the corresponding benza-
zepinones, yet the reaction was heavily dependent on the
substitution and showed modest reactivity. While those results
provided a powerful proof of concept, this elusive chemistry
was far from being solved. Herein we describe the develop-
ment of a practical and general method for the assembly of the
benzazepinone skeleton from γ-arylpropylamines and the study
of its synthetic potential.
Received: April 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01523
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
At the outset, we chose the γ-p-tolyl-substituted L-valine
derivative 115 to study the carbonylative annulation because it
would test the chemoselectivity of the catalyst toward the ε-
C(sp2)−H bond (to form benzazepinone 9a) versus the γ-
C(sp3)−H bond (leading to γ-lactam 9b) (Table 1). Following
Scheme 2. Reaction of γ,γ′-Diarylated Valine Derivatives
a
Table 1. ε-C(sp2)−H versus γ-C(sp3)−H Chemoselectivity
a
b
b
entry
R (substrate)
product
a (%)
b (%)
1
2
3
4
5
6
7
8
4-Me (1)
4-OMe (2)
H (3)
4-Cl (4)
4-Br (5)
4-(CO2Me) (6)
3-Me (7)
2-Me (8)
9
10
11
12
13
14
15
16
80
70
57
−
−
27
21
28
23
−
c
50
a
b
46
49
72
The conditions were identical to those shown in Table 1. Isolated
c
yield when the reaction was scaled-up to a 1.00 mmol scale. 98% ee
(as determined by HPLC using a chiral stationary phase).
c
d
1
35
16
Conversion yield (as determined by H NMR spectroscopy).
a
Conditions: substrate (0.10 mmol), Pd(OAc)2 (10 mol %),
Mo(CO)6 (0.033 mmol), AgOAc (1.50 equiv), BQ (2.00 equiv),
dioxane, 110 °C, 6 h, Ar. Isolated yields. Isolated overall yield upon
subsequent N-deprotection required for chromatographic separation
from the starting material (see the SI).
60% conversion). Moreover, the reaction could be scaled up to
1 mmol scale with even better results (product (−)-30, 96%),
thus emphasizing the robustness of this method.
b
c
The inherent preference for electron-rich aromatics and
trans diastereoselectivity allows selectivity to be achieved in
substrates with two distinct γ-aryl groups. Thus, (2S,3R)-29
with a matched combination of these two requirements led to
trans-42 in 85% yield with complete chemo- and stereo-
selectivity, whereas the mismatched (2S,3S)-29 provided a
mixture of trans and cis products (not shown; see the SI).
The present system could also be extended to γ-arylated
amino acid derivatives different from valine esters, such as
( )-alloisoleucine derivatives (53−58, 45−77%; Scheme 3).
Ethyl (S)-2-amino-4-phenylbutanoate, lacking ramification at
the β-carbon, provided the corresponding benzazepinone 58 in
77% yield (25 mol % Pd catalyst).
some optimization (see the Supporting Information (SI) for
full studies), we were pleased to observe clean carbonylation of
1 with Mo(CO)6 (0.33 equiv)16 using Pd(OAc)2 (10 mol %)
in combination with AgOAc (1.5 equiv) and 1,4-benzoquinone
(BQ) (2.0 equiv) in 1,4-dioxane after 6 h at 110 °C. Under
these conditions, benzazepinone 9a was obtained as the only
product in 80% isolated yield (entry 1). Control experiments
indicated that all of the reaction parameters are essential to
attain significant catalytic activity (see the SI).
The examination of the electronic effects of the aryl
substituents on the chemoselectivity revealed a profound
impact on the reaction outcome. Notably, the desired
benzazepinone was the main product, although complete ε-
C(sp2)−H selectivity was observed only in the derivatives
holding electron-releasing substituents at the para or meta
position (9a, 10a, and 15a, 70−80%). Electron-poor groups
led to modest chemoselectivity, delivering mixtures of both
benzazepinone and γ-lactam products. When a meta sub-
stituent was present, the reaction occurred at the more
sterically accessible ortho position with complete regiocontrol
(15a; entry 7). An ortho substituent was tolerated (16a; entry
8), though it also served to oppose the ε-C(sp2)−H selectivity.
Nevertheless, in all cases useful yields of benzazepinone
products were attained after chromatographic separation. It is
important to note that Cl and Br groups remained intact
(entries 4 and 5).
Simple aliphatic amine derivatives were also amenable to the
reaction, but with lessened reactivity, requiring a higher
loading of Pd (25 mol %) and oxidant to achieve useful yields
Scheme 3. Extension to Amino Acid Derivatives Different
from Valine Esters and Simple Aliphatic Amines
We next examined γ,γ′-diaryl-L-valine derivatives,15 having
two diastereotopic benzyl groups (Scheme 2). Interestingly,
excellent trans diastereoselectivity (>98:2) was observed in all
cases, which likely arises from formation of the more stable
trans-palladacycle. Wide functional group tolerance and
heightened reactivity endowed by electron-rich groups were
maintained. No appreciable racemization took place from
enantioenriched substrates, as demonstrated with substrate 30
(83%, 98% ee). A free COOH group was also tolerated (41,
a
Pd(OAc)2 (25 mol %), AgOAc (2 equiv), and BQ (3 equiv).
B
DOI: 10.1021/acs.orglett.9b01523
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Organic Letters
Letter
(59−62; Scheme 3). The compatibility with a more flexible
substrate lacking branching at both the α- and β-positions (60,
70%) was striking since this constraint is often necessary as a
turning element to maximize the reactive conformation. The
construction of tricyclic skeletons from cyclohexanamine
derivatives is also illustrated, with the trans derivative showing
higher reactivity (61, 71%), than the cis one (62, 33%).17
Overall, the scope highlights the validity of the method for the
efficient construction of benzazepinones with varied sub-
stitution patterns.
Scheme 6. Synthesis of a Chiral Analogue of Rucaparib
Scheme 7. Stoichiometric Experiments
The reductive removal of the N-SO2Py group18 occurs
readily under mild conditions (Zn, THF/sat. NH4Cl),
furnishing the corresponding free lactams in good yields with
full preservation of the stereochemical integrity and high
chemoselectivity (Scheme 4).
Scheme 4. Removal of the N-SO2Py Protecting Group
see the SI for details). The X-ray structure of complex A
showed two units of 43 coordinated to Pd as monoanionic
bidentate N,N-ligands, thus highlighting the bidentate role of
the N-SO2Py group. Either BQ or AgOAc was crucial for
complex A to undergo cyclization. The absence of an external
base in the mixture suggests that one unit of 43 may function
as an inner-sphere base needed for the C−H bond cleavage.
Complex A proved to be a competent catalyst precursor (10
mol %) for the conversion of 43 into 53 (75% yield) (see the
SI).
An HR-ESI-MS analysis of the crude reaction of complex A
with Mo(CO)6 (0.33 equiv) and BQ (2.00 equiv) in dioxane
for 15 min showed a dominant molecular ion peak at m/z
827.2397 ([2M + Na]+) attributable to product 53 (Figure 2).
a
Overall yield from 4 (see Table 1) after C−H carbonylation and
subsequent N-deprotection.
The increased complexity of small peptides represents a
demanding test for the late-stage funcionalization capability of
this method.19 We were delighted to find that the reaction of
both valine-glycine dipeptide derivative 67 and valine-glycine-
valine tripeptide derivative 68 took place efficiently, providing
the corresponding modified peptides 69 and 70 in 78% and
69% yield, respectively (Scheme 5). Again, the reaction
occurred with very high trans diastereoselectivity (trans/cis =
>20:<1).
Scheme 5. Late-Stage Modification of Di- and Tripeptides
This method also enabled the construction of the tricyclic
skeleton of a chiral analogue of rucaparib, a recently approved
drug for ovarian cancer (Figure 1).1c Simple exposure of N-
SO2Py-protected (S)-tryptophan methyl ester 71 to the
standard carbonylation provided azepinoindolone 72 in 98%
yield (Scheme 6). Previous routes to rucaparib relied on
lactamization of a prefunctionalized indole-4-carboxylate
system.1c,20
To gain preliminary mechanistic data, the reactivity of
complex A, prepared from ( )-43, was examined (Scheme 7;
Figure 2. Key area of the HR-ESI-MS spectrum of the crude reaction
mixture of complex A after 15 min.
C
DOI: 10.1021/acs.orglett.9b01523
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Interestingly, two peaks could be assigned to Pd complexes.
The peak at m/z 857.1885 ([M + H]+) corresponds to
complex A (calcd m/z 857.1870 [M + H]+), while the minor
peak B at m/z 481.0417 ([M + H]+) matches with the seven-
membered palladacycle presumably formed upon ε-C(sp2)−H
activation (calcd m/z 481.0413 [M + H]+).
Scheme 9. Plausible Catalytic Cycle
Monitoring the reaction of 43 to give 53 using Pd(OAc)2 (1
equiv), Mo(CO)6 (0.33 equiv), and BQ (2 equiv) at 55 °C in
THF-d8 revealed fast and clean formation of complex A, which
reached its highest concentration after 2 h before it was slowly
consumed at the expense of product formation (Figure 3).
benzazepinone product along with a reduced Pd0 species that
would then be reoxidized back to the active PdII species via the
combined action of BQ and AgOAc.
In conclusion, the method described here provides a
significant advancement to catalytic C−H carbonylation of
amines, as it enables unprecedented general access to the
seven-membered ring of benzazepinones. The excellent
directing ability of the N-SO2Py group under Pd catalysis
and its easy removal under very mild conditions are key points
of this protocol. The capability of this method for late-stage
modification and heterocycle functionalization highlight its
potential to find applications in targeted synthesis.
Figure 3. Carbonylative cyclization of 43 under stoichiometric Pd
monitored by H NMR spectroscopy in THF-d8.
1
Increasing formation of AcOH was observed starting at the
very early stages of the reaction. From these results, it appears
that complex A acts as the resting state of the Pd catalyst.
The carbonylation of 43, conducted in the presence of acetic
acid-d4 (6 equiv) under otherwise standard conditions and
stopped at low conversion, resulted in deuterium incorporation
at the ortho position of both the product (53-D, 55% yield,
31% D) and the recovered starting material 43-D (35% yield,
61% D) (Scheme 8). This may arise from a fast and reversible
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01523.
Experimental procedures and spectral data for all new
compounds (PDF)
Scheme 8. Deuterium Labeling Experiment
Accession Codes
CCDC 1908969 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by e-mailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
metalation/proto(deutero)demetalation step prior to CO
insertion. On the other hand, the strong preference for
electron-rich arenes suggests a partial electrophilic palladation
character for the C−H cleavage mechanism, which is
consistent with literature concerning remote C(sp2)−H
functionalization.21
A simplified catalytic cycle is presented in Scheme 9. Initial
substrate coordination to Pd(OAc)2 would generate complex
A′, in equilibrium with complex A (reversible off-cycle
reservoir). Then PdII-catalyzed C−H activation of A′ would
lead to complex B, which would undergo coordination to CO
(C) followed by carbonyl insertion across the Pd−C bond to
afford complex D. Reductive elimination would release the
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail for N.R.: n.rodriguez@uam.es.
*E-mail for R.G.A.: ramon.gomez@uam.es.
*E-mail for J.C.C.: juancarlos.carretero@uam.es.
ORCID
Nuria Rodríguez: 0000-0002-7174-4555
́
́
́
Ramon Gomez Arrayas: 0000-0002-5665-0905
Juan C. Carretero: 0000-0003-4822-5447
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.9b01523
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
(c) Peneau, A.; Retailleau, P.; Guillou, C.; Chabaud, L. J. Org. Chem.
2018, 83, 2324−2340.
ACKNOWLEDGMENTS
■
(10) For the synthesis of eight-membered lactams via RhIII-catalyzed
formal [4 + 2 + 2] cyclization, see: Wu, S.; Zeng, R.; Fu, C.; Yu, Y.;
Zhang, X.; Ma, S. Chem. Sci. 2015, 6, 2275−2285.
́
We thank the Spanish Ministerio de Economıa y Compet-
itividad (Project CTQ2015-66954-P, MINECO/FEDER, UE)
for financial support. M.M.-M. thanks MINECO for an FPI
Predoctoral Fellowship and the Fondo Social Europeo for
financial support. N.R. thanks the European Commission for a
Marie Curie Career Integration Grant (CIG: CHAAS-
(11) For selected examples of the synthesis of five- and six-
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S.; Tokuda, M. J. Am. Chem. Soc. 2004, 126, 14342−14343.
́
́
304085). Prof. Ines Alonso (Departamento de Quımica
́
(b) Lopez, B.; Rodriguez, A.; Santos, D.; Albert, J.; Ariza, X.;
́
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DOI: 10.1021/acs.orglett.9b01523
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