Modular Access to Azepines by Directed Carbonylative C-C Bond Activation of Aminocyclopropanes

Article abstract of DOI:10.1021/jacs.7b13087

A modular Rh-catalyzed entry to azepines is outlined. Under a CO atmosphere, protecting group directed C-C bond activation of aminocyclopropanes provides rhodacyclopentanones. These intermediates are effective for intramolecular C-H metalation of either an N-aryl or N-vinyl unit en route to azepine ring systems. Thus, byproduct-free heterocyclizations are enabled by sequential C-C activation and C-H functionalization steps.

Full text of DOI:10.1021/jacs.7b13087

Communication
pubs.acs.org/JACS
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Modular Access to Azepines by Directed Carbonylative C−C Bond
Activation of Aminocyclopropanes
Gang-Wei Wang and John F. Bower*
School of Chemistry, University of Bristol, Bristol, BS8 1TS, United Kingdom
S
* Supporting Information
Scheme 1
ABSTRACT: A modular Rh-catalyzed entry to azepines is
outlined. Under a CO atmosphere, protecting group
directed C−C bond activation of aminocyclopropanes
provides rhodacyclopentanones. These intermediates are
effective for intramolecular C−H metalation of either an
N-aryl or N-vinyl unit en route to azepine ring systems.
Thus, byproduct-free heterocyclizations are enabled by
sequential C−C activation and C−H functionalization
steps.
he azepine ring system is present in a wide range of
Tbioactive compounds, with this motif or closely related
variants representing the core structure of over 25 pharma-
ceutical products.1 For example, the drugs Tolvaptan2 and
Benazepril,3 and the beef improvement agent Zilpaterol,4 all
contain the tetrahydrobenzo[b]azepine ring system (Scheme
1A). Despite their established pharmaceutical value, azepines
and other larger (>6-membered) N-heterocyclic rings are
underrepresented in drug discovery libraries,5 primarily because
of a lack of efficient and modular routes for their preparation.
Accordingly, synthetic methods that can address this issue are
in high demand.
Recently, as part of a broader program,6 we outlined an N-
heterocyclization strategy where “capture” of transient
rhodacyclopentanones 2 by tethered nucleophiles occurs in
advance of a C−Nu bond forming “collapse” to the targets
(Scheme 1B).6e Conceptually, this approach is appealing
because it harnesses the strain embodied within readily
available and stereodefined aminocyclopropanes 1 for reaction
initiation, and achieves otherwise challenging ring closures via
the intermediacy of kinetically accessible bicycles 3. In our
proof-of-concept studies, ureas were used as the nucleophile (1,
R3 = NHR), such that intermediates 2 were converted to 1,3-
diazepanes by C−N reductive elimination from 3.6e Outside of
π-insertion processes, the reactivity of rhodacyclopentanones is
relatively unexplored,7−9 rendering further extension of our
approach uncertain. However, it is well-established that
Rh(III)-complexes can promote aryl C−H metalation in
other contexts,10 and we considered whether this type of
process might be exploited from 2 to provide benzazepines 6.
Specifically, for cyclopropanes 1 where R2 = aryl, we envisaged
accessing targets 6 by a sequence of carbonyl directed C−C
oxidative addition, metallacyclobutane carbonylation (to 2),
aryl C−H metalation (to 5), C−C reductive elimination, and
protodemetalation. At the outset, the viability of this design was
considered tentative because of the absence of reports where
rhodacyclopentanones engage in C(sp2)−H metalation or
C(sp2)−C(sp2) reductive elimination processes. Nevertheless,
outlined below is the successful realization of this approach,
which provides striking examples of how metal-catalyzed
carbonylative redistribution of C−C and C−H bonds can be
harnessed in reaction design.
Our investigations commenced by exploring the carbon-
ylative cyclization of 1a, which was readily prepared in two
steps via N-arylation of cyclopropylamine and subsequent Cbz-
protection (see the Supporting Information (SI)). Here we
found that, using 1 atm CO, the combination of [Rh(cod)2]-
OTf (7.5 mol %), P(4-CF3C6H4)3 (15 mol %), Na2SO4 (30
mol %), and 2-NO2C6H4CO2H (100 mol %) enabled the
generation of 6a in 82% isolated yield. Notably, neutral Rh-
Received: December 11, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b13087
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
precatalysts were completely ineffective and electron-neutral/-
rich P-based ligands provided only traces of the product (see
the SI). 6a was formed in less than 30% yield in the absence of
2-NO2C6H4CO2H, with this additive likely acting as a proton
reservoir to facilitate the final protodemetalation step, which
otherwise would rely solely on the proton released during the
conversion of 2 to 5.
At this stage, a series of experiments was undertaken to probe
the mechanism of the process, and this insight proved
fundamental in guiding extensions of the approach outlined
later (Scheme 2). When a 1:1 mixture of 1f and 1c was exposed
Scheme 2. Mechanistic Experiments
With optimized conditions in hand, we explored the scope of
the process with respect to the aromatic unit (Table 1). A
Table 1. Scope of the Aromatic Component
a
Reaction carried out at 140 °C.
to standard conditions, an approximately equimolar ratio of 6f
and 6c was obtained at low conversion (eq 1). A similar
competition experiment involving a 1:1 mixture of 1a and
deuterio-1a revealed a relatively small kinetic isotope effect (kH/
kD = 1.44, eq 2).12 Taken together, these experiments suggest
that aryl C−H metalation is not turnover limiting. Further
insight was gained by running the carbonylative cyclization of
1a in the presence of CD3OD (300 mol %). At full conversion
(eq 3), deuterium incorporation in the product deuterio-6a′ was
observed at C-2 (12%), C-4 (23%), C-6 (9%), and C-9 (15%).
Deuteration at C-2 is consistent with protodemetalation at this
position (to 6) after C−C reductive elimination from 5. At
partial conversion (eq 4), lower levels of C-6 deuteration were
observed (deuterio-6a″), which is consistent with exchange at
this position occurring via ketone directed C−H activation of
the product. In support of this, exposure of product 6a to
standard catalytic conditions in the presence of CD3OD
resulted in 12% deuterium incorporation at C6 (eq 5). In this
experiment, significant exchange also occurred at C-4 (28%),
suggesting that deuterium incorporation observed at this
position in eqs 3 and 4 arises via enolization of the product.
broad range of arenes are tolerated, with electron-rich (e.g., 1f),
electron-poor (e.g., 1d), and heteroaromatic systems (e.g., 1j)
all participating with similar levels of efficiency. For systems
with meta-substituents (1g and 1i), C−C bond formation is
highly regioselective, occurring at the more sterically accessible
ortho-position. In the case of 1h, where both meta-positions are
substituted, cyclization to 6h could be achieved, but the yield of
the process was lower than for other examples. At the present
stage, the protocol does not tolerate acyclic ortho-substituents.
The method exhibits useful levels of flexibility with respect to
the directing group. For example, other classes of carbamate
can be used, as demonstrated by Fmoc-directed cyclization of
1b which provided 6b in 79% yield. Cyclic amides can also
direct the process, and this allowed access to tricyclic systems
6k and 6l in 66% and 62% yield, respectively. However, acyclic
amides and N-urea-based directing groups are ineffective (see
the SI), highlighting the finely balanced nature of the process,
where the DG must be Lewis basic enough to promote C−C
bond activation, but also sufficiently labile to allow aryl C−H
metalation (2 to 5).11
B
DOI: 10.1021/jacs.7b13087
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Accordingly, the key issue remains as to how deuterium
incorporation at C-9 of deuterio-6a′/6a″ occurs? Equation 5
indicates that this is not via C−H activation of the product 6a.
Analysis of recovered starting material in eq 4 revealed
approximately 15% deuterium incorporation at the ortho-
positions (deuterio-1a′); however, a similar exchange experi-
ment involving 7, which lacks a cyclopropyl unit, resulted in no
deuterium incorporation at the ortho-positions (eq 6). This
seemingly rules out an exchange pathway involving carbonyl
directed C−H activation of 1a. Overall, the collective
observations provided in eqs 3−6 indicate that deuterium
exchange at C-9 of deuterio-6a′/6a″ and at the ortho-C−H
bonds of deuterio-1a′ does not occur directly from 1a or 6a, but
instead via reversible formation of another catalytically
generated intermediate, which is most likely bicycle 5.13
Indeed, our previous studies have shown that rhodacyclopenta-
none formation (1 to 2) is highly reversible using cationic Rh-
systems,6b,c,e and the current experiments extend this
reversibility to the aryl C−H metalation step. Accordingly, for
the current process, we favor C−C reductive elimination as the
first irreversible step, and further evidence supporting this
assertion is given later.14
Scheme 3. Benzazepines via trans-1,2-Disubstituted
Cyclopropanes
Substituted aminocyclopropanes can be accessed by Curtius
rearrangement of cyclopropyl carboxylic acids, and these, in
turn, can be synthesized easily in enantioenriched form.15
Consequently, the reaction design outlined in Scheme 1B
potentially allows access to benzazepines bearing stereodefined
substituents that might be challenging to install using
conventional methods. Key requirements for 1,2-disubstituted
cyclopropane-based processes include (a) regioselective gen-
eration of the rhodacyclopentanone intermediate (2) and (b)
transfer of this regiochemistry to the product (vide infra).
Previous studies have revealed that directed rhodacyclo-
pentanone formation from trans-1,2-disubstituted cyclopro-
panes occurs with high selectivity via the less hindered proximal
C−C bond (bond a in 1m−o, Scheme 3A).6c However, as
outlined above, the formation of 2 is likely reversible, such that
product regiochemistry can be subject to Curtin−Hammett
selectivity.16 Indeed, initial attempts to access benzazepine 6m
(R = Me) using the conditions from Table 1 afforded
approximately equal ratios of C-3 and C-4 adducts 6m and
6m′. The former arises from the kinetically favored rhodacyclo-
pentanone 5m; however, subsequent C−C reductive elimi-
nation is likely to be slow because it requires the bulky Rh-
center to move into the proximity of the C-3 methyl
substituent. As such, reversible metallacycle formation provides
kinetically disfavored regioisomer 5m′, which undergoes more
facile C−C reductive elimination to provide C-4 methylated
regioisomer 6m′. Electron-deficient ligand systems are known
to accelerate C−C reductive elimination,17 and so we examined
whether replacement of P(4-CF3C6H4)3 with poorer donors
might enforce selective generation of 6m from 1m (Scheme
3B). These studies revealed that 6m could be generated with
essentially complete selectivity over 6m′ using either As(4-
CNC6H4)3 or P(C6F5)3 as ligand. The latter offered the greatest
efficiencies with 6m isolated in 68% yield and >99:1 e.r. from
enantiopure 1m. These new conditions extended to more
sterically demanding systems 1n and 1o, which cyclized to
provide 6n and 6o as single regioisomers in 52% and 67% yield,
respectively (Scheme 3C); 6o was prepared from racemic 1o,
whereas 6n (99:1 e.r.) was accessed from enantioenriched 1n
(99:1 e.r.). For the processes in Scheme 3C, 3-CNC6H4CO2H
offered higher efficiencies than 2-NO2C6H4CO2H, which was
used earlier (see Table 1). So far, we have been unable to
obtain high selectivity for the formation of C-4 substituted
products (6m′−o′); however, substitution at this position can
be introduced easily using enolate chemistry.18 For example,
highly diastereoselective conversion of 6m to α-functionalized
products 8a and 8b was readily achieved, which demonstrates
the feasibility of introducing C−C or C−heteroatom bonds at
C-4.
The heterocyclizations described so far use an N-aryl unit as
the nucleophilic component, and we questioned whether
further classes of process might be achieved using other types
of π-nucleophile. Specifically, we hoped to access non-
benzofused azepines (6p−t) by harnessing N-vinyl nucleo-
philes (1p−t) (Table 2). In the event, by adapting of our
previously developed conditions, carbonylative heterocycliza-
tion of 1p to 6p and 1q to 6q occurred in 61% yield and 42%
yield, respectively. Here, the carboxylic acid additive was
omitted as it promoted competitive polymerization of 1p and
1q. However, for subsequent examples (6r−t), an acid additive
was beneficial, with the exact choice made on a case-by-case
basis. A key aspect of the method in Table 2 is that the
substrates (1p−t) can be accessed in one pot from the
corresponding ketone (see the SI), which, in turn, allows the
two-step synthesis of a wide variety of interesting and
challenging heterocyclic ring systems. From a mechanistic
viewpoint, these processes are significant; in principle, the
C
DOI: 10.1021/jacs.7b13087
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(Bristol) for contributions during preliminary studies and the
School of Chemistry X-ray Crystallographic Service for analysis
of 6e.
Table 2. Processes Using N-Vinyl Carbamates
REFERENCES
■
(1) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57,
10257.
(2) Kondo, K.; Ogawa, H.; Yamashita, H.; Miyamoto, H.; Tanaka,
M.; Nakaya, K.; Kitano, K.; Yamamura, Y.; Nakamura, S.; Onogawa,
T.; Mori, T.; Tominaga, M. Bioorg. Med. Chem. 1999, 7, 1743.
(3) Towson, J. C.; Wong, S.-C. Patent US20150315195, 2013.
(4) Watthey, J. W. H.; Stanton, J. L.; Desai, M.; Babiarz, J. E.; Finn, B.
M. J. Med. Chem. 1985, 28, 1511.
(5) Hussain, A.; Yousuf, S. K.; Mukherjee, D. RSC Adv. 2014, 4,
43241.
(6) (a) Shaw, M. H.; Melikhova, E. Y.; Kloer, D. P.; Whittingham, W.
G.; Bower, J. F. J. Am. Chem. Soc. 2013, 135, 4992. (b) Shaw, M. H.;
McCreanor, N. G.; Whittingham, W. G.; Bower, J. F. J. Am. Chem. Soc.
2015, 137, 463. (c) Shaw, M. H.; Croft, R. A.; Whittingham, W. G.;
Bower, J. F. J. Am. Chem. Soc. 2015, 137, 8054. (d) Shaw, M. H.;
Whittingham, W. G.; Bower, J. F. Tetrahedron 2016, 72, 2731.
(e) McCreanor, N. G.; Stanton, S.; Bower, J. F. J. Am. Chem. Soc. 2016,
138, 11465. (f) Wang, G.-W.; McCreanor, N. G.; Shaw, M. H.;
Whittingham, W. G.; Bower, J. F. J. Am. Chem. Soc. 2016, 138, 13501.
(7) For a review on rhodacyclopentanone-based catalysis, see:
(a) Shaw, M. H.; Bower, J. F. Chem. Commun. 2016, 52, 10817. For
recent reviews on C−C bond activation-based methodologies, see:
(b) Souillart, L.; Cramer, N. Chem. Rev. 2015, 115, 9410. (c) Fumagalli,
G.; Stanton, S.; Bower, J. F. Chem. Rev. 2017, 117, 9404.
(8) Selected methodologies that exploit π-insertion into rhodacyclo-
pentanones (or related species) derived from C−C bond activation:
(a) Zhou, X.; Dong, G. J. Am. Chem. Soc. 2015, 137, 13715. (b) Ko, H.
M.; Dong, G. Nat. Chem. 2014, 6, 739. (c) Souillart, L.; Parker, E.;
Cramer, N. Angew. Chem., Int. Ed. 2014, 53, 3001. (d) Souillart, L.;
Cramer, N. Angew. Chem., Int. Ed. 2014, 53, 9640. (e) Matsuda, T.;
Tsuboi, T.; Murakami, M. J. Am. Chem. Soc. 2007, 129, 12596.
(f) Murakami, M.; Itahashi, T.; Ito, Y. J. Am. Chem. Soc. 2002, 124,
13976.
carboxylic acid additive could facilitate CMD-type metalation of
the C(sp2)−H bond (2 to 5),19 but the successful synthesis of
6p and 6q in the absence of acid suggests that this is not the
case. Accordingly, we suggest that, for both N-aryl and N-vinyl
systems, C−H metalation occurs by nucleophilic attack of the
electron-rich π-system onto the Rh-center of 2, and that the
primary role of the acid additive is to facilitate the final
protodemetalation step.
To conclude, we outline processes where rhodacyclo-
pentanones generated by directed carbonylative C−C bond
activation are captured by C-based nucleophiles en route to
benzazepines and nonbenzofused variants. Ring systems of this
type are difficult to construct in a modular fashion using
conventional approaches,20 and the methodology addresses this
issue in an atom and step economical manner. Our reaction
design is based on the exploitation of rhodacyclopentanones for
C(sp2)−H metalation and subsequent C(sp2)−C(sp2) bond
forming reductive elimination.9,14 One can easily envisage
harnessing these fundamental mechanistic steps in further
rhodacyclopentanone-based methodologies. Studies toward this
broad goal are ongoing and will be reported in due course.
(9) To the best of our knowledge, C(sp2)−C(sp2) reductive
elimination from C−C activation derived rhodacyclopentanones has
not been demonstrated previously. For C−O reductive elimination,
see: Murakami, M.; Tsuruta, T.; Ito, Y. Angew. Chem., Int. Ed. 2000, 39,
2484. For C−N reductive elimination, see ref 6e.
(10) Selected examples: (a) Schroder, N.; Wencel-Delord, J.; Glorius,
̈
F. J. Am. Chem. Soc. 2012, 134, 8298. (b) Romanov-Michailidis, F.;
Sedillo, K. F.; Neely, J. M.; Rovis, T. J. Am. Chem. Soc. 2015, 137, 8892.
(c) Xia, Y.; Lu, G.; Liu, P.; Dong, G. Nature 2016, 539, 546. (d) Xia,
Y.; Wang, J.; Dong, G. Angew. Chem., Int. Ed. 2017, 56, 2376. The
latter two references outline processes with closing mechanistic steps
that are related to those employed here.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b13087.
■
S
Experimental details, characterization data (PDF)
Crystallographic data for 6e (CIF)
(11) The specific requirements of the DG were noted for earlier
processes developed in our laboratory (see ref 6d).
(12) For a discussion on the interpretation of KIE measurements,
see: Simmons, E. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51,
3066. Consistent with our mechanistic interpretation, an internal
competition experiment using mono-ortho-deuterated 1a revealed a
kH/kD of 0.92 (see the SI). The absolute value must be treated with
caution because eqs 3 and 4 show that H,D exchange can occur under
the reaction conditions.
AUTHOR INFORMATION
Corresponding Author
*john.bower@bris.ac.uk
ORCID
■
John F. Bower: 0000-0002-7551-8221
(13) The similar levels of deuterium incorporation (approximately
15%) observed at C-9 in eq 3 vs 4 (full vs partial conversion) are
consistent with this suggestion.
Notes
The authors declare no competing financial interest.
(14) Alternative mechanistic pathways cannot be discounted based
on available data. For example, protonation of 5 could occur prior to
C−C reductive elimination. We deem this pathway less likely because
(a) it is less consistent with the data in Scheme 3 and (b) a model
neutral rhodacyclopentanone complex does not undergo protonation
when exposed to o-nitrobenzoic acid (see the SI).
ACKNOWLEDGMENTS
■
We thank the Royal Society for a URF (J.F.B.) and a K. C.
Wong Fellowship (G.-W.W.), and the EPSRC (EP/L015366/
1) and the European Research Council (ERC Grant 639594
CatHet) for financial support. We thank Mr. Joe Barker
D
DOI: 10.1021/jacs.7b13087
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(15) An easy approach is by Wadsworth−Emmons cyclopropanation
of the corresponding enantiopure epoxide: (a) Wadsworth, W. S.;
Emmons, W. D. J. Am. Chem. Soc. 1961, 83, 1733. (b) Delhaye, L.;
Merschaert, A.; Delbeke, P.; Brio
689.
̂
ne, W. Org. Process Res. Dev. 2007, 11,
(16) For manifestations of this type of effect see refs 6b, c, and e.
(17) For a discussion within the context of C−C reductive
elimination from Pd-complexes, see: Hartwig, J. F. Inorg. Chem.
2007, 46, 1936.
(18) At the present level of development, cis-1,2-disubstituted and
trisubstituted cyclopropanes are not suitable substrates.
(19) Walsh, A. P.; Jones, W. D. Organometallics 2015, 34, 3400.
(b) Qi, X.; Li, Y.; Bai, R.; Lan, Y. Acc. Chem. Res. 2017, 50, 2799.
(20) Recent methodologies for accessing benzazepines and azepines:
(a) Thullen, S. M.; Rubush, D. M.; Rovis, T. Synlett 2017, 28, 2755.
(b) Mazumdar, W.; Jana, N.; Thurman, B. T.; Wink, D. J.; Driver, T.
G. J. Am. Chem. Soc. 2017, 139, 5031. (c) Claraz, A.; Serpier, F.;
Darses, S. ACS Catal. 2017, 7, 3410. (d) Wang, R.; Jin, R.-X.; Qin, Z.-
Y.; Bian, K.-J.; Wang, X.-S. Chem. Commun. 2017, 53, 12229. (e) Hu,
Y.; Huang, H. Org. Lett. 2017, 19, 5070. (f) Guo, C.; Fleige, M.;
Janssen-Muller, D.; Daniliuc, C. G.; Glorius, F. J. Am. Chem. Soc. 2016,
̈
138, 7840. (g) So, M.; Kotake, T.; Matsuura, K.; Inui, M.; Kamimura,
A. J. Org. Chem. 2012, 77, 4017. (h) Zhou, M.-B.; Song, R.-J.; Wang,
C.-Y.; Li, J.-H. Angew. Chem., Int. Ed. 2013, 52, 10805. (i) Kotha, S.;
Shah, V. R. Eur. J. Org. Chem. 2008, 2008, 1054.
E
DOI: 10.1021/jacs.7b13087
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX