Beyond the five and six: Evaluation of seven-membered cyclic anhydrides in the castagnoli-cushman reaction

Article abstract of DOI:10.1021/acs.orglett.6b03426

The Castagnoli-Cushman reaction with benzo[d]- oxepine-2,4(1H,5H)-dione as an anhydride component allowed for preparation of 2,3-disubstituted 4-oxo-2,3,4,5-tetrahydro-1H-benzo[d]- azepine-1-carboxylic acids in 21-75% yields and with good trans diastereoselectivity. The method worked with imines generated from aromatic or a-branched aliphatic aldehydes and is amenable for both parallel synthesis and scale-up. The procedure for epimerization of the resulting trans-disubstituted tetrahydrobenzo[d]azepines to their cis isomers was also developed.

Full text of DOI:10.1021/acs.orglett.6b03426

Letter
pubs.acs.org/OrgLett
Beyond the Five and Six: Evaluation of Seven-Membered Cyclic
Anhydrides in the Castagnoli−Cushman Reaction
†
,†
‡
‡
Mykhailo I. Adamovskyi, Sergey V. Ryabukhin,* Dmitriy A. Sibgatulin, Eduard Rusanov,
and Oleksandr O. Grygorenko†
†
National Taras Shevchenko University of Kyiv, Volodymyrska Street 64, Kyiv 01601, Ukraine
‡
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine
S Supporting Information
*
ABSTRACT: The Castagnoli−Cushman reaction with benzo[d]-
oxepine-2,4(1H,5H)-dione as an anhydride component allowed for
preparation of 2,3-disubstituted 4-oxo-2,3,4,5-tetrahydro-1H-benzo[d]-
azepine-1-carboxylic acids in 21−75% yields and with good trans
diastereoselectivity. The method worked with imines generated from
aromatic or α-branched aliphatic aldehydes and is amenable for both
parallel synthesis and scale-up. The procedure for epimerization of the
resulting trans-disubstituted tetrahydrobenzo[d]azepines to their cis
isomers was also developed.
horough exploration of the chemical space relevant for
medicinal chemistry requires synthetic methods that open1
principle formed in the CCR since adipic anhydride (3) and its
T
corresponding benzo analogue (4) are known and stable
6
access to potential lead compounds in an efficient manner.
Multicomponent reactions are especially promising in this view
since they provide sufficient diversity of the compound libraries
compounds. Meanwhile, azepanes that can form in such CCR
are in the top 100 most frequently used ring systems in small
7
molecule drugs. For example, the tetrahydrobenzoazepine
2
with minimum synthetic efforts required. In particular, the
derivative ivabradine (5) was approved by the FDA in 2015 for
the symptomatic management of stable angina pectoris,
fenoldopam (6) in 1997 as an antihypertensive agent, and8
lorcaserin (7) in 2012 as an antiobesity drug (Figure 1).
Among other examples, a candidate drug against Alzheimer’s
disease, semagacestat (8), which has reached Phase III clinical
Castagnoli−Cushman reaction (CCR), i.e., a reaction of imines
3
(
1) with cyclic andydrides (Scheme 1), has been considered as
Scheme 1
9
studies, can be mentioned.
In this work, we describe evaluation of the seven-membered
cyclic anhydrides 3 and 4 in Castagnoli−Cushman reaction for
the construction of seven-membered rings, namely, azepane
and tetrahydrobenzo[d]azepine derivatives. The anhydrides 3
and 4 were prepared from the corresponding dicarboxylic acids
6
,10
using modified literature procedures. It should be noted that
adipic anhydride is known to be formed in its polymeric form
(
9), which can be transformed into cyclic (3) upon heating.
Since isolation of pure 3 by vacuum distillation of 9 gives low
yields of the target product (32%), we checked both 3 and 9 in
the CCR with imine 1a (xylene, 140 °C, 20 h). Although no
target product 10 was detected in the reaction mixtures, they
were shown to be nearly identical by LCMS.
an efficient tool for the synthesis of pyrrolidones and
piperidones as well as their fused and heteroatom-substituted
4
analogues. Unlike many other multicomponent reactions, the
3
Moreover, heating of 3 in xylene at 140 °C resulted in its
conversion to 9 (after 3.5 h, the 3 to 9 ratio was 0.8:1 according
CCR leads to the formation of nonflattened sp -enriched cores;
therefore, it is well-compatible with the concept of lead-
1
5
to H NMR). The reverse reaction was slower: a sample of 9
oriented synthesis.
showed 4% conversion to 3 under the same conditions.
Therefore, the polymeric form 9 is obtained from 3 upon
To date, the use of the CCR has been limited to the
construction of five- and six-membered heterocycles. Four-
membered rings are unlikely to be obtained by this reaction due
to instability of malonic anhydride (2). On the contrary, cyclic
systems of larger size such as seven-membered rings could be in
Received: November 16, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03426
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 1. Biologically active tetrahydrobenzo[d]azepines.
Scheme 2
Table 1. Reaction of Imines 1a−j with Anhydride 4
1
2
no.
imine
R1
R2
product
yield (%)
J(H −H ) (Hz)
a
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Bn
Me
Ph
Bn
14a
14b
14c
14d
14e
14f
14g
14h
14i
71
9.5
9.1
8.8
8.3
9.3
10.0
8.8
6.5
6.3
a
75
52
71
71
74
57
4-pyridyl
Ph
2,4-(MeO) C H
2
6
3
4-MeOC H
Bn
Bn
Bn
6
4
1g
1h
1i
t-Bu
i-Pr
i-Pr
Me
a
31
2,4-(MeO) C H
28
2
6
3
a
10
1j
Bn
14j
0
a
Reaction was performed with presynthesized imine.
heating, and we used 9 in further experiments performed at
high temperatures.
reactive than 3 due to increased CH acidity of the
corresponding zwitterionic intermediate. The expected product
14b was obtained as a single diastereomer in 75% yield under
standard thermodynamically controlled CCR conditions
(xylene, 140 °C, 2 h). Relative trans configuration of the
compound 14b was established using X-ray single-crystal
Unfortunately, none of the conditions evaluated for the
reaction of adipic anhydride (9 or 3) with imines 1a−c gave the
target products 10 (see Table S1). Since all of the crude
1
reaction mixtures showed similar patterns in LCMS and H
11
NMR, we performed chromatographic separation only with two
of them. It was shown that amides 11 and 12 were the main
products isolated (Scheme 2). We believe that the intermediate
zwitterion 13 was not reactive enough to give the product of
cyclization 10.
diffraction studies.
Inspired by this result, we studied series of imines 1a−i in the
reaction with 4 under the conditions mentioned above (Table
1). It was found that in the case of imines derived from
nonenolizable aldehydes the products 14a−g were obtained in
52−75% yields as trans diastereomers. We have shown that
both imines 1 and anhydride 4 can be generated and used
without any purification; only filtration (in the case of 4) and
removal of the solvent (in both cases) were needed. This makes
the method compatible with parallel synthesis conditions.
Moreover, this procedure was amenable to scale-up: ∼10 g of
the product 14e was obtained a single run.
We also performed reaction of the monomeric adipic
anhydride (3) with the imine 1a in CHCl at rt; under these
3
conditions, the target product 10 was not obtained.
After the negative results obtained with adipic anhydride, we
turned our attention to its benzo analogue 4. Compound 4 is a
seven-membered analogue of homophthalic anhydride (which
is well-studied in the CCR) and hence should be far more
B
DOI: 10.1021/acs.orglett.6b03426
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Scheme 3
Scheme 4
In the case of the imines 1h,i derived from an enolizable α-
branched aldehyde, the yields of the products 14h,i were
moderate (28−31%). In the case of 14h, we could identify
amide 15a (∼10% by LCMS) as one of the numerous
byproducts. In the case of the imine 1j derived from
acetaldehyde, the target compound 10j was not formed at all;
the compound 15a was the major product isolated in this case.
These results can be possibly explained by the formation of N-
acylenamine byproducts and their further transformations,
The ketimines 1k,l were also evaluated in the reaction with
anhydride 4 (Scheme 3). It was found that if the reaction was
performed in xylene at 140 °C, the amides 15a,b and the N-
acylenamine 16 (isolated in the case of 1k) were the major
13
products formed; no traces of the target compounds 14k,l
were observed. In CHCl at rt, the compounds 15 and 16 were
3
still the main products, but the tetrahydrobenzo[d]azepine
derivatives 14k,l were also isolated (21−24% yields). This is
contrary to the previously reported results on reactions of
ketimines with homophtalic anhydride, where the CCR
3c
which is well-documented for other anhydrides.
The relative stereochemistry of the products 14b−i was
12a
products were formed in high yields upon heating in xylenes.
1
2
In our efforts for further modification of the products 14, we
studied esterification of the compounds 14e,i. Surprisingly, the
reaction of 14e with tert-butyl alcohol, DCC, and DMAP in
CH Cl at 0 °C gave the cis esters 17e (de 70%) instead of the
confirmed by J(H −H ) (6.3−10.0 Hz) (Table 1); these large
values are in accordance with the trans orientation of the
1
1
2
corresponding protons in a pseudoaxial position (H −C −C −
2
2
2
H torsion angle close to 180°), which is observed in the
expected trans isomers 18e. Optimization of the reaction
crystalline state for 14b. Notably, these values are different from
conditions showed that using Boc O−DMAP as a carboxylic
2
those observed for the six-membered analogues, where the
group activator in CH Cl at rt improved de of the product 17e
12
2
2
corresponding protons are in pseudodiequatiorial position.
to 78%, whereas lowering the temperature to −5 °C gave the cis
ester 17e with 90% de and 84% yield (Scheme 4). Under the
same conditions, 14i was transformed to 17i with even slightly
better diastereoselectivity (94% de, 82% yield).
We studied the possibility of improving the yields of 4 with
1
4h in CHCl at rt led to a complex mixture of products,
3
presumably containing 14h, its cis diastereomer, and 15a
1
according to H NMR and LCMS data (see Table 1 for the
The relative configuration of the products 17e and 17i was
1
2
structures of the products). Heating of the crude product in
AcOH led to the epimerization of the cis isomer to 14h;
however, the resulting ratio of 14h and 15a according to LCMS
confirmed by the values of J(H −H ) constants (1.3 and 0 Hz,
respectively), which were considerably different from those
observed in the trans series of the products 14a−i (6.3−10.0
1
1
2
2
(14h/15a = 1:1.74) was less favorable than in the case of
Hz) and apparently corresponded to H −C −C −H torsion
angles close to 90°.
thermodynamically controlled conditions described above.
C
DOI: 10.1021/acs.orglett.6b03426
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The formation of 17e,i possibly included enolization of the
activated intermediate 19 upon action of DMAP (Scheme 5).
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: s.v.ryabukhin@gmail.com. Tel: +380506424763.
Scheme 5
ORCID
Sergey V. Ryabukhin: 0000-0003-4281-8268
Notes
The authors declare no competing financial interest.
REFERENCES
■
(
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H., Eds. Multicomponent reactions; Wiley-VCH:
(
(
3
(
(
́
́
(
̈
̈
2
The protonation of the enolate 20 formed was sterically
unfavorable from the si face; therefore, it occurred from the re
face, which led to the formation of cis diastereomer 21. The
reaction of 21 with tert-butyl alcohol gave the final product 17.
We found that epimerization of the product 17e,i was
possible upon action of a stronger base as compared to DMAP
2
601−2610. (c) Ryabukhin, S. V.; Panov, D. M.; Granat, D. S.;
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between 17e,i and thermodynamically more stable 18e,i was
possible. The corresponding trans isomers 18e,i were isolated
in 81% yield and with 94−98% de. In this case, the J(H −H )
values were consistent with those observed in the trans series
1
2
(
6) (a) Hill, J. W. J. Am. Chem. Soc. 1930, 52, 4110−4114. (b) Wirt,
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̈
(
10.3 and 6.6 Hz for 18e and 18i, respectively).
Since NOESY experiments with the esters 17 and 18 did not
4
(
5
(
confirm unambiguously the configuration of these products, we
performed deprotection of the cis esters 17e,i (TFA, CH Cl ,
2
2
1
2
rt) (Scheme 5). The J(H −H ) values were close to 0 Hz for
both products 22e,i. Under analogous conditions, the starting
carboxylic acids 14e,i gave the products 23e and 23i with
J(H −H ) = 9.9 and 10.2 Hz, respectively. These results
confirm relative configuration of all the above-discussed esters
and also demonstrate configurational stability of the cis isomers
in the acidic media.
(
(
55−69.
1
2
(10) Niwa, H.; Sakata, T.; Yamada, K. Bull. Chem. Soc. Jpn. 1994, 67,
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(
11) Crystallographic data for 14b have been deposited with the
Cambridge Crystallographic Data Centre, 11 Union Road, Cambridge,
CB2 1EZ, UK (fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.
uk). Deposition No. 1513983.
In conclusion, the evaluation of seven-membered cyclic
anhydrides in a Castagnoli−Cushman reaction showed that
adipic anhydride was much less reactive than its five or six-
membered counterparts and did not lead to corresponding
azepanes, whereas its benzo-annelated analogue allowed for the
synthesis of 2,3-disubstituted 4-oxo-2,3,4,5-tetrahydro-1H-
benzo[d]azepine-1-carboxylic acids with preparative yields
(
12) (a) Cushman, M.; Gentry, J.; Dekow, F. W. J. Org. Chem. 1977,
4
2, 1111−1116. (b) Cushman, M.; Cheng, L. J. Org. Chem. 1978, 43,
2
86−288.
(
13) It should be noted that the ratios of 15b to 16 observed by
LCMS might be affected by partial hydrolytic transformation of 16 to
15b during the chromatography.
(
21−75%) and good trans diastereoselectivity. Unusual
epimerization of these products was observed during synthesis
of their tert-butyl esters, which opened access to diastereose-
lective synthesis of cis isomers.
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.6b03426.
Experimental details and copies of NMR spectra (PDF)
X-ray data for compound 14b (CIF)
D
DOI: 10.1021/acs.orglett.6b03426
Org. Lett. XXXX, XXX, XXX−XXX