Mild rhodium(III)-catalyzed cyclization of amides with α,β- unsaturated aldehydes and ketones to azepinones: Application to the synthesis of the homoprotoberberine framework

Article abstract of DOI:10.1002/anie.201301426

Seven! The title reaction can be described as an intermolecular annulation involving tandem C-H activation, cyclization to give the seven-membered ring, and condensation steps. Biologically interesting azepinone derivatives can be prepared in this way. Th

Full text of DOI:10.1002/anie.201301426

Angewandte
Chemie
DOI: 10.1002/anie.201301426
À
C H Activation
Mild Rhodium(III)-Catalyzed Cyclization of Amides with a,b-
Unsaturated Aldehydes and Ketones to Azepinones: Application to the
Synthesis of the Homoprotoberberine Framework**
Zhuangzhi Shi, Christoph Grohmann, and Frank Glorius*
The synthesis of azaheterocyclic compounds is a topic of
continued interest due to the presence of this skeletal motif in
countless natural products and synthetic compounds that
display important chemical, biological, and medicinal proper-
ties.[1] Azepine and its derivatives at various oxidation levels
fall into this category. Examples are azepinone-based natural
products such as the checkpoint kinase 2 (Chk2) inhibitor
debromohymenialdisine, the marine sponge constituent
CID755673, which is a highly selective inhibitor of protein
kinase D (PKD), and the matrix metalloproteinase inhibitor
(À)-Cobactin T.[2] Benzazepines such as ribasine, isolated
from Fumariaceae plants in 1983, and homoprotoberberines
alkaloids that exhibit antimalarial and antibacterial proper-
ties (Figure 1).[3] Consequently, extensive research has
focused on the development of effective routes towards
azepine derivatives.[4] Herein, we report a novel method
joining simple and readily available amides with a,b-unsatu-
rated aldehydes and ketones to construct azepinones for the
versatile and efficient preparation of numerous seven-mem-
bered-ring scaffolds.
À
Direct C H activation has advantages over traditional
protocols based on substrate preactivation.[5] The {RhIIICp*}
fragment is one of the most frequently used catalysts for this
transformation[6] and a number of novel C H activation
À
strategies for the synthesis of heterocycles have been
explored.[7] In particular, the RhIII-catalyzed cyclization of
benzamides represents a useful contribution to azahetero-
cycle synthesis. Among these, direct annulations of benza-
mides with CO, isocyanides, olefins, and aldehydes have been
Scheme 1. RhIII-catalyzed cyclization of benzamides to build five- (a),
six- (b), and seven-membered rings (c).
Figure 1. Important compounds containing azepine units.
developed for the synthesis of five-membered heterocycles
(Scheme 1a).[8] Fagnouꢀs,[9] Rovisꢀ,[10] Cramerꢀs,[11] our,[12] and
other groups[13] have reported the synthesis of isoquinolones
and d-lactams by the RhIII-catalyzed coupling of benzamides
with alkynes, alkenes, and allenes. Very recently, Cheng and
co-workers reported the RhIII-catalyzed regioselective syn-
thesis of phenanthridinones from benzamides and aryl
[*] Dr. Z. Shi, C. Grohmann, Prof. Dr. F. Glorius
Universitꢀt Mꢁnster, Organisch-Chemisches Institut
Corrensstrasse 40, 48149 Mꢁnster (Germany)
E-mail: glorius@uni-muenster.de
Homepage: http://www.uni-muenster.de/Chemie.oc/glorius/
index.html
boronic acids through C C/C N bond formation[14] in
a one-pot transformation (Scheme 1b). Although these
methods have been shown to be highly efficacious in the
construction of five- or six-membered azaheterocyclic skel-
etons, there is no report on the more challenging synthesis of
seven-membered nitrogen-containing rings by these Rh-
catalyzed transformations.[15] The proper choice of a suitable
bridging unit is quite challenging due to the requirement of
mild reaction conditions and ready availability.
À
À
[**] We thank Karl Collins for helpful discussions. This work was
supported by the Alexander von Humboldt Foundation (Z.S.) and
the Deutsche Forschungsgemeinschaft (IRTG Mꢁnster-Nagoya).
Generous financial support by the European Research Council
under the European Community’s Seventh Framework Program
(FP7 2007-2013)/ERC Grant agreement no. 25936 is gratefully
acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301426.
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Table 2: RhIII-catalyzed cyclization of venzamides 1 with a,b-unsaturated
aldehydes and ketones 2.[a]
Acrolein is the simplest unsaturated aldehyde, and has
been widely utilized as the electrophilic component in
Michael addition reactions and Diels–Alder reactions. The
initial reaction of N-methoxybenzamide (1a) and acrolein
(2a) was carried out in the presence of 2.5 mol%
[(Cp*RhCl2)2] and 10 mol% AgSbF6 as the catalyst system,
at 808C in dioxane under an Ar atmosphere. This set of
conditions afforded the desired product 3aa in 25% yield
after 12 h without additional oxidant (Table 1, entry 1). We
Table 1: Development of the reaction.[a]
Entry Cat. system
Additive
(equiv)
Solv.
T [8C] Yield
[%][b]
1
2
3
4
5
6
7
8
[(Cp*RhCl2)2] + AgSbF6
[(Cp*RhCl2)2] + AgSbF6 Cu(OAc)2 (1) dioxane 80
–
dioxane 80
25
30
18
26
56
83
75
56
69
35
0
[(Cp*RhCl2)2] + AgSbF6 PivOCs (1)
[(Cp*RhCl2)2] + AgSbF6 AcOH(2)
[(Cp*RhCl2)2] + AgSbF6 PivOH (1)
[(Cp*RhCl2)2] + AgSbF6 PivOH (2)
[RhCp*(MeCN)3](SbF6)2 PivOH (2)
[(Cp*RhCl2)2] + AgSbF6 PivOH (2)
[(Cp*RhCl2)2] + AgSbF6 PivOH (2)
[(Cp*RhCl2)2] + AgSbF6 PivOH (2)
dioxane 80
dioxane 80
dioxane 80
dioxane 60
dioxane 60
dioxane RT
9
THF
EtOAc
60
60
10
11
12
AgSbF6
[(Cp*RhCl2)2]
PivOH (2)
PivOH (2)
dioxane 60
dioxane 60
0
[a] Conditions: 1a (0.20 mmol), 2a (0.24 mmol), 2.5 mol% catalyst,
10 mol% AgSbF6, solvent (1.0 mL), 12 h, under Ar. [b] Yield of isolated
product.
[a] Conditions: 1 (0.20 mmol), 2 (0.24 mmol), 2.5 mol% [(Cp*RhCl2)2],
10 mol% AgSbF6, PivOH (0.4 mmol) in dioxane (1.0 mL) at 608C, 12 h,
under Ar. [b] Using 2 (3.0 equiv). [c] Using 2 (2.0 equiv), at 808C; like
3aa’, 3bc’ contains an additional aliphatic aldehyde in the 6-position.
tested different additives in this system, and observed that
PivOH was the most efficient, affording the cyclization
product 3aa in 56% yield (Table 1, entries 2–5). To our
delight, increasing the amount of the acid additive to 2.0 equiv
improved the yield, providing 83% of the product at lower
temperature (Table 1, entry 6). Using a cationic rhodium
species afforded 3aa in only slightly lower yield (Table 1,
entry 7), suggesting that [Cp*Rh(SbF6)2] is the likely catalyti-
cally active species. Under these conditions, lowering the
reaction temperature or changing the solvent gave lower
yields of 3aa (Table 1, entries 8–10). Control reactions con-
firmed that the transformation does not occur in the absence
of [(Cp*RhCl2)2] or AgSbF6 (Table 1, entries 11 and 12).
With the optimized conditions in hand, we examined the
donating groups such as methoxy (3ea) and methyl (3ma and
3oa) and electron-withdrawing groups such as phenyl (3ja),
carboxylate (3ka), nitro (3la), and trifluoromethyl (3pa).
Halogen-containing substrates (3 fa–3ia and 3na) also
reacted efficiently. This transformation also tolerates ortho
substitution; the corresponding products (3ma and 3na) can
be produced under these optimized conditions in moderate
yield. The naphthamide substrate 1q can also be converted
into the interesting product 3qa in 88% yield as a single
regioisomer. Heterocyclic substrates were also tolerated, and
the thiophene-annulated product 3ra was produced in
moderate yield.
À
scope of this C H activation and cyclization process
(Table 2). First, the effect of N substituents was examined.
We were pleased to find that besides the N-methoxy
derivative, N-alkylbenzamides such as N-methyl- (1b), N-n-
butyl- (1c), and N-benzylbenzamides (1d) were also suitable
substrates for this transformation. However, substrates with
other N substituents such as H, phenyl, and OPiv did not
afford the corresponding products. Interestingly, when
3.0 equiv of acrolein (2a) was used as the reaction partner
of 1a, we selectively obtained the aliphatic aldehyde deriv-
The scope of other a,b-unsaturated aldehydes and
ketones as substrates was also investigated with benzamides
as partners. We found the simplest enone, methyl vinyl ketone
(2b), can also generate the cyclization product 3ab without
any difficulty. Surprisingly, the reaction of N-methoxybenza-
mide (1a) with methacrolein (2c) and benzylacrolein (2d)
only gave trace amounts of the corresponding products, but
under the same reaction conditions, 2c and 2d reacted with N-
methylbenzamide (1b) to afford the desired products 3bc and
3bd in good yield. The reaction of crotonaldehyde (2e) gave
a lower conversion, and cinnamaldehyde (2 f) did not afford
À
ative 3aa’ in 53% yield by means of double C H activation.
The reaction was found to be tolerant of both electron-
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any cyclization product, presumably due to the steric hin-
drance of the phenyl group. Interestingly, a,b-unsaturated
amides such as 1s can also react with acrolein (2a); the
corresponding azepinone product 3sa was obtained in 41%
yield [Eq. (1)].[16] This finding greatly expands the range of
synthetic applications. Interestingly, the subsequent cycliza-
tion step can also be suppressed by the choice of the
N substituent: the coupling of the N-allyloxy derivative 1t
with 2a under the standard conditions yielded the noncyclized
product 4 [Eq. (2)].
yield), which was stable in the presence of PivOH at 608C in
dioxane. However, when the reaction was conducted with
2.5 mol% [(Cp*RhCl2)2] and 10 mol% AgSbF6, dehydration
yielded product 3aa with full conversion (Scheme 3). These
tests indicate that the catalytically active species {RhIIICp*}
Scheme 3. Experiments probing the role of the {RhIIICp*} species.
À
acts simultaneously as a transition-metal catalyst for C H
activation and as a Lewis acid catalyst for dehydration in this
transformation.[18]
Facile manipulation of the enamine units in these
azepinones offers an additional synthetic opportunity. For
example, the double bond in 3aa could be hydrogenated to
yield e-lactam 5 in good yield. It is known that electrophilic
additions to enelactams can provide useful intermediates for
the synthesis of a number of nitrogen-containing natural
products.[19] We employed 3aa in the reactions with NBS/
MeOH and NIS/MeOH systems. Both combinations exclu-
sively produced single diastereomers of the corresponding
halomethoxylation products 6 and 7 in almost quantitative
yields (Scheme 4).
Scheme 2. Plausible reaction mechanism.
On the basis of these investigations, a possible mechanism
is proposed in Scheme 2. Coordination of the benzamide to
a {RhIIICp*} species appears to be crucial for the regioselec-
Scheme 4. Further applications of 3aa.
À
tive C H bond cleavage to afford A. This rhodacycle can
coordinate one equivalent of 2 to form B, which undergoes
alkene insertion giving intermediate C. Subsequently, proto-
nolysis of C delivers the carbonyl intermediate D.[17] The
The total synthesis of homoprotoberberines as exempli-
fied by compound 13 has been reported by several groups.[20]
Very recently, Couture and co-workers developed an efficient
synthetic approach to 13 in 9 steps from readily available
starting materials.[21] Since we had a reliable azepine synthesis
method in hand, we commenced our synthesis with the
preparation of benzamide 10 using the commercially avail-
able substrates veratric acid (8) and homoveratrylamine (9).
Fortunately and surprisingly, reaction of 10 with acrolein (2a)
under the optimized conditions led directly to 13. This
À
formed Rh N bond can add across the carbonyl group
affording the cyclorhodated intermediate E, which undergoes
protonolysis to give the seven-membered-ring hemiaminal F
and the recovered {RhIIICp*} species.[8e] When 1t is used as
substrate, the formed Rh species may coordinate with the
olefin and thus further cyclization is blocked. Finally,
{RhIIICp*}-catalyzed dehydration of F gives access to the
desired enamide product 3. Strong evidence in support of this
step was obtained from the following experiments. Treatment
of 1a and 2a in dioxane containing 5.0 equiv H2O at room
temperature afforded the hemiaminal 3aa-F (isolated in 76%
À
conversion likely involves C H activation and cyclization
for the formation of ring A and subsequent Pictet–Spengler
cyclization for the formation of ring B (Scheme 5).
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
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Scheme 5. Synthesis of the homoprotoberberine framework 13 by
À
a reaction cascade consisting of C H activation, cyclization, and
Pictet–Spengler reaction cascade.
In summary, we have developed a novel and efficient
method for the synthesis of azepinones utilizing benzamides
and a,b-unsaturated aldehydes and ketones as starting
materials. This RhIII-catalyzed intermolecular annulation
À
procedure involving tandem C H activation, cyclization,
and condensation steps, proceeds under mild conditions,
releases H2O as the only byproduct, and displays a broad
substrate scope with respect to the substituents. Furthermore,
the highly efficient construction of the homoprotoberberine
III
À
framework, involving Rh -catalyzed C H activation and
cyclization as a key step, was accomplished.
Received: February 18, 2013
Published online: && &&, &&&&
À
Keywords: amides · azepinones · C H activation ·
homoprotoberberines · rhodium
.
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À
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Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!

.
Angewandte
Communications
Communications
À
C H Activation
Z. Shi, C. Grohmann,
F. Glorius*
&&&& — &&&&
Mild Rhodium(III)-Catalyzed Cyclization
of Amides with a,b-Unsaturated
Aldehydes and Ketones to Azepinones:
Application to the Synthesis of the
Homoprotoberberine Framework
Seven! The title reaction can be described
as an intermolecular annulation involving
azepinone derivatives can be prepared in
this way. The synthetic potential of this
method was demonstrated by the con-
struction of the homoprotoberberine ring
system.
À
tandem C H activation, cyclization to
give the seven-membered ring, and con-
densation steps. Biologically interesting
6
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!