Catalytic Ynone-Amidine Formal [4 + 2]-Cycloaddition for the Regioselective Synthesis of Tricyclic Azepines

Article abstract of DOI:10.1021/acs.orglett.0c03711

A Ca(OTf)2- and self-promoted ynone-amidine atom-economic formal [4 + 2]-cycloaddition of various ynones with amidines is reported for the construction of highly functionalized tricyclic azepines. High reaction rate, ease of operation, and high product se

Full text of DOI:10.1021/acs.orglett.0c03711

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Letter
Catalytic Ynone−Amidine Formal [4 + 2]-Cycloaddition for the
Regioselective Synthesis of Tricyclic Azepines
T. Prabhakar Reddy,‡ Jagjeet Gujral,‡ Pritam Roy, and Dhevalapally B. Ramachary*
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ABSTRACT: A Ca(OTf)2- and self-promoted ynone−amidine
atom-economic formal [4 + 2]-cycloaddition of various ynones
with amidines is reported for the construction of highly
functionalized tricyclic azepines. High reaction rate, ease of
operation, and high product selectivity with wide substrate scope
are the key advantages of the present annulation protocol.
nones have recently surfaced as Michael acceptors with
versatile reactivity, giving way to the construction of
lies in its use of ynones bearing only aromatic substituents. The
absence of α-acidic hydrogens largely restricts the ynones to
behave only as bielectrophiles (at C-2 and C-4). In contrast,
nucleophilic capabilities of ynones with an enolizable
methylene next to the carbonyl (C-1) have been demonstrated
previously by our group.2,3 Hence, our present experimental
quest is focused on reacting α-enolizable ynones with an
ambiphilic DBU as a substrate, in turn taping into the
complete reactivity competence of ynones with DBU (Scheme
1e). Achieving exclusively a ynone−DBU addition poses a
grave challenge since this addition is in direct competition with
ynone self-addition.2k Such an insertion of DBU to ynones is
further complicated by possibility of diverse cyclization modes
from intermediates 3a, 3b, 3c, and 3d (Scheme 1e).
The preliminary reaction was tested under the self-catalysis
between ynone 1a and 1.3 equiv of DBU 2a at 60 °C in DCE.
To our astonishment, from a plethora of possible products
(Scheme 1e) a single cyclized product 4aa was obtained in
65% yield with 99:1 dr within 1.5 h (Table 1, entry 1). Product
4aa turned out to be quite different from that obtained by
Y
varied hetero/carbocyclic systems.1−3 In this field, pioneering
work has been done by the Tomita and Fu groups exploiting
ynones in trialkylphosphine-catalyzed intramolecular zipper
cyclizations (Scheme 1a).1 Influenced by their work, we
developed a complementary triphenylphosphine-catalyzed
intermolecular Tomita zipper cyclization of ynones with
olefins (Scheme 1b).2f Meticulous analysis of the aforemen-
tioned reaction mechanisms brings to light some salient
features of trialkylphosphine, which rationalizes their excellent
catalytic activity in such reactions. Primarily, the free lone pair
on phosphorus renders the nucleophilic attack on C-4 carbon
of ynones, resulting in a zwitterion. Finally, in the absence of
alternative neutralization pathways, stabilization of this
zwitterion drives the detachment of the catalyst from the
substrate through novel zipper cyclization, hence regenerating
it. These catalytic features that make trialkylphosphine
exceptional catalysts prevent them from becoming good
substrates capable of permanently bonding to its reacting
partner.
Muller (Scheme 1d). To increase the product 4aa yields, an
̈
Such dual behavior, of a catalyst and a substrate, has been
known to be displayed by amidine bases like DBU.4 This is as a
consequence of the fact that, following the nucleophilic attack
by N-8 of DBU on ynones, the resultant zwitterion can be
neutralized by proton loss from C-6 or by nucleophilic attack
on the iminium ion carbon (Scheme 1c,d). These alternative
stabilization routes impart unparalleled nucleophilic capabil-
ities on amidine (DBU), leading to its incorporation into
several acetylenic moieties like alkynoates5a−d and electron-
deficient propargylic alcohols to give fused tricyclic derivatives
extensive solvent screening was carried out (Table 1). To
begin, nonpolar aprotic solvents like DCM, chloroform, and
toluene furnished 4aa in poor yields (Table 1, entries 2−4),
and no reaction was observed in 1,1,2,2-terachloroethane
(Table 1, entry 5). These disappointing results directed our
investigation toward more polar solvents like EtOH (61%
yield, entry 6) and other solvents like THF, DMF, and DMSO
gave just above average yields of 38%, 65%, and 62%,
respectively (Table 1, entries 7−9). Self-catalyzed cyclization
(Scheme 1c).5e
−h
Received: November 8, 2020
Even though such diverse modes of reactivity of DBU with
triple bond exist, stoichiometric addition to ynones has seldom
been explored. An attempt was made in this direction recently,
by Mu
̈
ller’s group,6 where DBU’s binucleophilic nature was
exploited in annulation to ynones yielding tricyclic amino-
pyridinium salts (Scheme 1d). This protocol’s major drawback
https://dx.doi.org/10.1021/acs.orglett.0c03711
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
a
Scheme 1. Previous and Present Reaction Designs for the
Table 1. Reaction Solvent Optimization
Annulation of Ynones with Olefins
b
entry
2 (equiv)
solvent (0.2 M)
time (h)
yield 4aa (%)
1
2
3
4
5
6
7
8
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.5
1.1
1.3
1.3
DCE
DCM
CHCI3
toluene
CI2CHCHCl2
EtOH
1.5
1
2.5
1
65
35
44
13
NR
61
38
65
62
78
73
61
65
73
48
2.5
1.5
0.7
0.5
0.4
0.5
0.6
0.5
2.5
THF
DMF
9
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
10
11
12
13
14
c
d
a
Reactions were carried out in solvent (0.2 M) with 2a relative to 1a
b
c
(0.3 mmol). Yield refers to the column purified product. MeCN
(0.15 M). T = 30 °C. Note: Complete consumption of 1a was
observed in all reactions.
d
a
Table 2. Reaction Additive Optimization
b
entry
additive 5 (mol %)
time (h) yield 4ba (%)
reaction of 1a and 1.3 equiv of 2a in MeCN (0.2 M) at 60 °C
in just 24 min furnished 4aa in very good yield (78%, entry
10). Further, all attempts to improve the yield either by
increasing the 2a equiv to 1.5 or decreasing to 1.1, carrying out
the reaction at a lower temperature (30 °C) or lower
concentration (0.15 M) went in vain (Table 1, entries 11−
14). Thus MeCN (0.2 M) at 60 °C was fixed as the best
condition for the self-catalyzed cyclization of 1a with 2a.
Surprisingly, subjecting the methyl ester 1b to the optimized
self-catalyzed condition (MeCN at 60 °C) with 2a resulted in a
moderate yield of 45% of 4ba (Table 2, entry 1). Even reversal
of reactant equivalents by taking 1.3 equiv of 1b with respect to
2a in MeCN at 60 °C caused a further reduction in yield to
23% (Table 2, entry 2). Such dismal results compelled us to
reanalyze the optimized condition with 1b in the presence of
various additives 5 at 40 °C (Table 2). Catalytic amount of
Brønsted acids 5a−e like CH3CO2H, o-FC6H4CO2H,
PhCO2H, p-MeOC6H4CO2H, and 2-naphthoic acid were
initially employed with the aim of slightly activating the
ynone carbonyl without deactivating DBU. However, all of the
aforementioned additives 5a−e had a detrimental effect on the
product yields, furnishing just 19−64% of 4ba (Table 2, entries
3−7). As a consequence, the reaction was again performed in
the presence of a mild base like DMAP 5f and ( )-BINOL 5g,
both of which gave poor yields of 32% and 41%, respectively
(Table 2, entries 8 and 9). Such discouraging results shifted
c
1
0.3
0.25
2.5
45
23
19
50
64
53
51
32
41
66
36
36
48
51
46
70
d
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
5a: CH3CO2H (20 mol %)
5b: o-FC6H4CO2H (20 mol %)
5c: PhCO2H (20 mol %)
5d: p-MeOC6H4CO2H (20 mol %)
5e: 2-naphthoic acid (20 mol %)
5f: DMAP (20 mol %)
5g: ( )-BINOL (10 mol %)
5h: AgOTf (10 (10 mol %)
5i: Cu(OTf)2 (10 mol %)
5j: Zn(OTf)2 (10 mol %)
5k: ln(OTf)3 (10 mol %)
51: Sc(OTf)3 (10 mol %)
5m: Mg(OTf)2 (10 mol %)
5n: Ca(OTf)2 (10 mol %)
21.0
5.5
4.5
4.5
2.0
3.0
4.0
1.0
2.5
4.0
2.5
3.0
3.0
a
Reactions were carried out in solvent (0.2 M) with 1.3 equiv of 2a
relative to 1b (0.3 mmol) in the presence of additive 5. Yield refers
to the column purified product. T = 60 °C. 1.3 equiv of 1b relative
to 2a (0.3 mmol) at the 60 °C. Note: Complete consumption of 1b
was observed in all reactions.
b
c
d
our focus toward testing Lewis acids like metal triflates 5h−n
for promoting the formation of 4ba in higher yields. Out of all
the metal triflates 5h−n screened, AgOTf 5h and Ca(OTf)2 5n
B
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proved promising as additives by furnishing 4ba in 66% and
70% yields, respectively (Table 2, entries 10−16). Hence, we
narrowed down on 1.3 equiv of 2a with 1b in the presence of
10 mol % of Ca(OTf)2 5n at 40 °C in MeCN (0.2 M) as the
final optimized condition (Table 2, entry 16).
Having established the optimum conditions, a variety of α-
enolizable ynones 1 and amidine bases 2 were tested under the
catalytic protocol to explore the formal [4 + 2]-cycloaddition
scope. Initially, just extending the aliphatic chain as an R2
substituent from methyl to ethyl 1c−d had a negligible effect
on the reaction outcome with 2a yielding the products 4ca−
4da in very good yields of 84 and 83%, respectively (Table 3,
groups gave complete decomposition of the starting material
during the reaction (entry 9). This indicates that increased
reactivity on account of the stabilization of the α-anion
(Scheme 1e, 3b) via electron-withdrawing or delocalizing
groups both lead to occurrence of multiple side reactions.
Surprisingly, reaction of 4-phenylbut-3-yn-2-one or but-3-yn-2-
one with DBU 2a gave an inseparable mixture of compounds
(results not shown in Table 3). Therefore, a fine balance of
ynone reactivity was found to be crucial for success of this
strategy. On similar lines, due to the −I effect of the OCH2Ph
group as R2 diminished the product 4la yield to 38% (Table 3,
entry 10). Subsequently, locking R1 as a Ph or p-FC6H4 group
in conjunction with substituting R2 as methylene esters like
ethyl, benzyl, and isopropyl generated the desired products
4aa−4oa in good to excellent yields of 72−87% (Table 3,
entries 11−14). Even complex chiral substituents like
methylene ester of (−)-menthyl as R2 also fared well under
this reaction strategy, furnishing 4pa and 4′pa in excellent 88%
yield with 1:1 dr (entry 15). Fully aliphatic ynone 1q also
produced the final product 4qa in 42% yield (Table 3, entry
16). This protocol’s scope was further broadened by utilizing
other amidine bases like DBN 2b in reaction with a handful of
ynones 1a−o delivering the respective products 4ab−4ob in
40−70% yields (Table 3, entries 17−20).
Table 3. Reaction Substrate Scope
amidine (n,
2)
time
(h)
yield 4
a
entry
ynone (1)
(%)
1
2
3
4
5
6
1c: R1, R2 = Ph, Me
3, 2a
3, 2a
3, 2a
3, 2a
3, 2a
3, 2a
3, 2a
3, 2a
3, 2a
3, 2a
3, 2a
3, 2a
5.0
5.0
5.0
5.0
5.0
6.0
0.2
5.0
0.5
1.0
3.0
3.0
84 (4ca)
83 (4da)
76 (4ea)
80 (4fa)
68 (4ga)
78 (4ha)
− (4ia)
75 (4ja)
− (4ka)
38 (4la)
87 (4aa)
74 (4ma)
1d: R1, R2 = Ph, CH2Me
1e: R1, R2 = p-FC6H4, Me
1f: R1, R2 = p-ClC6H4, Me
1g: R1, R2 = p-MeC6H4, Me
1h: R1, R2 = p-MeOC6H4, Me
1i: R1, R2 = p-NO2C6H4, Me
1j: R1, R2 = 3-thiophenyl, Me
1k: R1, R2 = Ph, Ph
Further, some unanticipated results were obtained with
other amidine bases like 2c where the reaction with 1b gave a
very poor yield (20%) of the product 4bc (Table 3, entry 21).
However, utilizing the same amidine 2c in reaction with the
ynone 1c proceeded to give a unique open-ring product 7cc via
the intermediate 6cc with incorporation of a molecule of water
from the solvent during the course of reaction. This reaction
path was confirmed by crude NMR analysis (Scheme 2, eq 1).
b
7
8
9
b
10
11
12
1l: R1, R2 = Ph, OCH2Ph
1a: R1, R2 = Ph, CH2CO2Et
1m: R1, R2 = Ph,
CH2CO2CH(Me)2
Scheme 2. Unexpected Reactivity of Ynones with Amidines
13
14
1n: R1, R2 = Ph,
3, 2a
3, 2a
3.0
3.0
72 (4na)
81 (4oa)
CH2CO2CH2Ph
1o: R1, R2 = p-FC6H4,
CH2CO2Et
c
15
16
1p: R1, R2 = Ph, CH2CO2R3
3, 2a
3, 2a
1.5
6.0
88 (4pa)
42 (4qa)
1q: R1, R2 = CH2(CH2)2CH3,
Me
17
18
19
20
1a: R1, R2 = Ph, CH2CO2Et
1c: R1, R2 = Ph, Me
1, 2b
1, 2b
1, 2b
1, 2b
1.0
2.0
3.0
1.0
70 (4ab)
50 (4cb)
40 (4eb)
56 (4ob)
1e: R1, R2 = p-FC6H4, Me
1o: R1, R2 = p-FC6H4,
CH2CO2Et
21
1b: R1, R2 = Ph, CH2CO2Me
2, 2c
1.0
20 (4bc)
Another peculiar reactivity was observed in the interaction of
amidine 2d with the ynone 1b, where a molecule of pyrrolidine
was eliminated from the expected product 8bd to yield the
stable compound 9bd in 28% yield (Scheme 2, eq 2). The
structure and relative stereochemistry of the products 4 were
assigned by NMR analysis and also finally confirmed by X-ray
structure analysis on 4oa as shown in Figure S1 (see the
Supporting Information).
Taking cognizance of the crystal structure of 4oa and
activation of the carbonyl 1 by calcium salts,7 a mechanism was
hypothesized as elucidated in Scheme 3. In the present
mechanism, oxophilicity of calcium drives the coordination of
Ca(OTf)2 5n to ynone carbonyl 1, in turn activating the ynone
toward Michael addition at C-4 by DBU’s N-8. The zwitterion
intermediate 3a thus formed, undergoes a [1,3]-hydrogen shift
to yield resonance hybrid intermediates 3b and 3c.1,2 Such
intermediates could be neutralized through a myriad of
reaction pathways. Loss of an adjacent proton at DBU’s C-6
a
b
Yield refers to the column purified product. Compound 1 totally
c
consumed with formation of multiple spots. R3 = (−)-menthyl and
1:1 dr (4pa:4′pa) obtained.
entries 1 and 2). Hence, our substrate variation was guided
toward varying the R1 group as differently substituted
aromatics with R2 fixed as Me. Phenyl groups bearing halogens
F and Cl at the para positions (Table 3, entries 3 and 4) and
electron-donating substituents like p-Me and p-OMe (Table 3,
entries 5 and 6) delivered good yields of the desired products
4ea−4ha (68−80% yields). Exceptionally, an electron-with-
drawing group like a p-NO2-substituted phenyl ring provided
an inseparable mixture of compounds within a short span of 12
min (Table 3, entry 7).
Heteroaromatics like 3-thiophenyl were also well tolerated
under the present catalytic protocol (Table 3, entry 8).
However, the ynone 1k containing both R1 and R2 as Ph
C
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Letter
Scheme 3. Proposed Reaction Mechanism
Scheme 4. Synthetic Applications
assigned by NMR analysis and also finally confirmed by X-ray
structure analysis on 16ca as shown in Figure S2 (see the
Supporting Information).
In essence, an unprecedented ambiphilic addition of ynones
across a carbon−nitrogen bond of amidines has been achieved
in a formal [4 + 2]-cycloaddition fashion under self- and
calcium catalysis. Furthermore, a single ynone−amidine adduct
was obtained among many possibilities, highlighting the
unique regioselectivity of the present reaction strategy. Our
future efforts will be directed toward applying the profitable
insights gained about the reactivity of amidines and ynones
from the present study to new reactions and substrate designs.
followed by a nucleophilic attack on ynone C-2 could lead to
the addition product 11 similar to that obtained by Mu
group (Scheme 1d) via path A.
̈
ller’s
ASSOCIATED CONTENT
* Supporting Information
■
sı
Path B dictates a selective nucleophilic enolate attack by the
α to the carbonyl moiety on iminium C-7 furnishing the
cyclized products 4. The same intermediate 3b could also yield
the cyclized products 12 through path C. Finally, this reaction
sequence could also be truncated intermolecularly with
addition of water from solvent at C-7, giving entities like 14
through path D. Amidst such manifold reaction possibilities,
the present reaction design yields singularly products 4 via path
B. Reaction pathway D even elucidates the formation of
product 7cc via 6cc. Isolation of 7cc, additionally, is a
testament to the existence of intermediates 3a, 3b, 3c, and 3d
along with the initial regiochemistry of interaction between
DBU 2a and the ynone 1. In the zwitterionic intermediate3c for
reaction with ester ynones, a larger “R” group of ester functionality
sterically locks the ester carbonyl in a conformation favoring
stabilizing interactions between the ester carbonyl’s and the
positively charged iminium nitrogen at the lower temperatures (40
°C), thus rationalizing the decrease in yield on moving from ethyl
ynone ester1a to methyl ynone ester1b.
The Supporting Information is available free of charge on the
ACS Publications Web site. The Supporting Information is
available free of charge at https://pubs.acs.org/doi/10.1021/
acs.orglett.0c03711.
Details of experimental procedures for the catalytic
reactions and spectroscopic data for the products (PDF)
NMR spectral data (PDF)
Accession Codes
CCDC 2024821−2024822 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
The final cyclized products 4 were further scrutinized for
their chemical reactivity, paving the way for their synthetic
applications (Scheme 4). Hence, intentional libraries of
compounds 4 were made to undergo facile bromination
succeeded by bromination addition followed by dehydrohalo-
genation to yield the monobrominated products 16 in good
yields. In addition, compound 4ca underwent C−N bond
cleavage on treatment with aqueous NaOH (6.0 N) in
methanol via formation of the enolate 17ca to generate an 11-
membered fused heterocycle 18ca in excellent yield. The
structure and relative stereochemistry of the products 16 were
Dhevalapally B. Ramachary − Catalysis Laboratory, School of
Chemistry, University of Hyderabad, Hyderabad 500 046,
India; orcid.org/0000-0001-5349-2502; Email: ramsc@
uohyd.ac.in, ramchary.db@gmail.com
Authors
T. Prabhakar Reddy − Catalysis Laboratory, School of
Chemistry, University of Hyderabad, Hyderabad 500 046,
India
Jagjeet Gujral − Catalysis Laboratory, School of Chemistry,
University of Hyderabad, Hyderabad 500 046, India
D
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Letter
Batsanov, A. S.; Howard, J. A. K. J. Chem. Soc., Chem. Commun. 1994,
2055. (p) Fukuyama, T.; Nakashima, N.; Okada, T.; Ryu, I. J. Am.
Chem. Soc. 2013, 135, 1006.
Pritam Roy − Catalysis Laboratory, School of Chemistry,
University of Hyderabad, Hyderabad 500 046, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03711
(5) For interaction of DBU with acetylenic moieties, see: (a) Ma, L.;
Dolphin, D. J. Chem. Soc., Chem. Commun. 1995, 2251. (b) Trofimov,
B. A.; Shemyakina, O. A.; Mal’kina, A. G.; Stepanov, A. V.;
Volostnykh, O. G.; Ushakov, I. A.; Vashchenko, A. V. Eur. J. Org.
Chem. 2016, 2016, 5465. (c) Trofimov, B. A.; Shemyakina, O. A.;
Stepanov, A. V.; Volostnykh, O. G.; Mal’kina, A. G. Russ. J. Org. Chem.
2017, 53, 1893. (d) Shemyakina, O. A.; Volostnykh, O. G.; Stepanov,
A. V.; Mal’kina, A. G.; Ushakov, I. A.; Apartsin, K. A.; Kireeva, V. V.;
Trofimov, B. A. Mendeleev Commun. 2018, 28, 128. (e) Shemyakina,
O. A.; Volostnykh, O. G.; Stepanov, A. V.; Mal’kina, A. G.; Ushakov,
I. A.; Trofimov, B. A. Synthesis 2018, 50, 853.
Author Contributions
‡T.P.R. and J.G. have contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was made possible by a grant from the Department
of Science and Technology (DST), SERB, New Delhi (Grant
No.: CRG/2018/000775). T.P.R. thanks UGC-BSR (New
Delhi) for his senior research fellowship. J.G. thanks CSIR
(New Delhi) for his senior research fellowship. P.R. thanks
UGC (New Delhi) for his senior research fellowship. We thank
Dr. P. Raghavaiah, Central University of Karnataka, Gulbarga,
for X-ray structural analysis.
(6) (a) Bakulina, O.; Merkt, F. K.; Knedel, T.-O.; Janiak, C.; Muller,
̈
T. J. J. Angew. Chem., Int. Ed. 2018, 57, 17240. (b) Trani, G.;
Baddeley, S. M.; Briggs, M. A.; Chuang, T. T.; Deeks, N. J.; Johnson,
C. N.; Khazragi, A. A.; Mead, T. L.; Medhurst, A. D.; Milner, P. H.;
Quinn, L. P.; Ray, A. M.; Rivers, D. A.; Stean, T. O.; Stemp, G.; Trail,
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B. K.; O’Neill, P. M.; Stachulski, A. V. Org. Biomol. Chem. 2013, 11,
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