Aza-Nazarov Cyclization Reactions via Anion Exchange Catalysis

Article abstract of DOI:10.1021/acs.orglett.8b03886

A catalytic aza-Nazarov cyclization between 3,4-dihydroisoquinolines and α,β-unsaturated acyl chlorides has been developed to access α-methylene-?-lactam products in good yields (up to 79%) as single diastereomers. The reactions proceed efficiently when AgOTf is used as an anion exchange catalyst with a 20 mol % loading at 80 °C. Computational studies were performed to investigate the reaction mechanism, and the findings support the role of the ?TMS group in reducing the reaction barrier of the key cyclization step.

Full text of DOI:10.1021/acs.orglett.8b03886

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Aza-Nazarov Cyclization Reactions via Anion Exchange Catalysis
§
,‡
Selin E. Donmez,† Emine Soydas,‡
̧
n Aydın,† Onur S
̆
̈
Gokcȩ ̧ahin, Ugur Bozkaya,*
and Yunus E. Tu
̈
rkmen*,†,∥
†Department of Chemistry, Faculty of Science, Bilkent University, Ankara, 06800, Turkey
‡Department of Chemistry, Hacettepe University, Ankara, 06800, Turkey
§Sinop University, Scientific and Technological Research Application and Research Center, Sinop, 57000, Turkey
∥UNAM - National Nanotechnology Research Center, Institute of Materials Science and Nanotechnology, Bilkent University,
Ankara, 06800, Turkey
S
* Supporting Information
ABSTRACT: A catalytic aza-Nazarov cyclization between 3,4-dihydroisoquinolines and α,β-unsaturated acyl chlorides has
been developed to access α-methylene-γ-lactam products in good yields (up to 79%) as single diastereomers. The reactions
proceed efficiently when AgOTf is used as an anion exchange catalyst with a 20 mol % loading at 80 °C. Computational studies
were performed to investigate the reaction mechanism, and the findings support the role of the −TMS group in reducing the
reaction barrier of the key cyclization step.
eterocyclic chemistry continues to have a pivotal role in
pyrido[1,2-a]indoles were achieved by the Klumpp and Sekar
Hvarious areas of organic chemistry, particularly for the groups with the use of TfOH and formic acid, respectively.13,14
development of new pharmaceuticals and agrochemicals.1 In a
To our knowledge, the only catalytic enantioselective aza-
Nazarov reaction to date was reported by the Tius group in
2010.15 In this work, the racemic azirine reactant 4 was found to
undergo an organocatalytic aza-Nazarov reaction in the form of a
kinetic resolution to afford enantiomerically pure product 6 after
a ring expansion reaction (Scheme 1c). In 2016, Liao and co-
workers reported the aza-Nazarov-type cyclization of in situ
formed azaoxyallyl cations leading to the efficient synthesis of N-
hydroxy oxindoles.16 In addition to these transformations, aza-
Nazarov type cyclizations were proposed to take part in a
number of transition-metal-mediated reactions.17
In this work, we developed a highly efficient aza-Nazarov
reaction between 3,4-dihydroisoquinolines (7) and α,β-
unsaturated acyl chlorides (8) that leads to the formation of a
broad range of α-methylene-γ-lactam products (9) with two
contiguous stereocenters as single diastereomers (Scheme 1d).
The α-alkylidene-γ-lactam unit is an important structural motif
present in many biologically active molecules and natural
products.18,19 In our reaction design, the aza-Nazarov-type
cyclization of the N-acyliminium cation 10, which would be
derived from the acylation of imine 7 with acyl chloride 8, was
anticipated to give intermediate 11 that would eventually
convert to 9 via desilylation. We envisaged that the trimethylsilyl
(−TMS) group at the allylic position of 10 would not only
increase the electron density on the alkene moiety toward the
recent perspective article, discovery of new synthetic methods to
access substituted aliphatic heterocycles stereoselectively from
acyclic precursors has been listed as one of the major synthetic
challenges that could contribute significantly to drug discovery.2
In this respect, cyclization reactions of N-acyliminium ions offer
a plethora of opportunities for the synthesis of a broad range of
nitrogen heterocycles.3−7 In particular, the aza-Nazarov reaction
stands out as a potentially useful transformation for the
construction of five-membered, nitrogen-containing hetero-
cyclic structures.8 However, whereas the catalytic, all-carbon
Nazarov reaction has enjoyed remarkable advances within the
past two decades,9 the analogous aza-Nazarov reaction is still in
its infancy.10 Pioneering studies by Wu
̈
rthwein and co-workers
demonstrated that aza-Nazarov cyclization could be employed
effectively to access a broad range of pyrrole and 2H-pyrrole
derivatives.11 For instance, treatment of oxime and hydrazone
derivatives 1 with trifluoromethanesulfonic acid (TfOH)
followed by trapping with acid anhydrides afforded substituted
pyrrole products 2 in good yields (Scheme 1a).11a In an elegant
work reported by the Klumpp group in 2007, aza-Nazarov
reactions of N-acyliminium salts 3 were shown to be effectively
promoted by TfOH as a superacid (Scheme 1b).12a However,
the reactions investigated in this study generally required the use
of 5 equiv or more of TfOH. This methodology was extended to
the aza-Nazarov reactions of in situ generated iminium ions
starting from benzamides bearing tethered acetal groups.12b
Cyclization reactions of pyridine-containing triarylmethanols to
Received: December 5, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03886
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Organic Letters
Letter
quinoline (17) as the imine component. In the absence of any
catalyst, a mixture of 16 and 17 did not undergo aza-Nazarov
reaction at 23 °C in CH2Cl2 (Table 1, entry 1). On the other
Scheme 1. Examples of Aza-Nazarov Reaction
Table 1. Initial Studies on the Aza-Nazarov Reaction
entry
AgOTf (equiv)
solvent
temp (°C)
isolated yield (%)
1
2
3
4
−
CH2Cl2
CH2Cl2
CH3CN
CH3CN
23
23
80
80
<1
57
79
13
1.3
0.2
−
hand, our initial studies using different Lewis acids for chloride
abstraction revealed AgOTf as a highly effective Lewis acid. We
were gratified to obtain aza-Nazarov product 9a as a single
diastereomer, and in 57% isolated yield when a mixture of 16
and 17 in CH2Cl2 was treated with a stoichiometric amount of
AgOTf (1.3 equiv) at 23 °C (entry 2). We attribute this
enhanced reactivity in the presence of AgOTf to the formation
of an activated iminium cation due to the more noncoordinating
nature of TfO− compared to the Cl− anion. Excitingly, the
reaction was found to proceed well even with the use of 20 mol %
of AgOTf in CH3CN; however, a higher temperature (80 °C) is
required for this process. Under these conditions, aza-Nazarov
product 9a was isolated in 79% yield, again as a single
diastereomer (entry 3). A control experiment under the same
conditions demonstrated that the reaction is much slower when
AgOTf was not used (13% yield, entry 4). Overall, these results
not only supported our initial proposal on the design of the aza-
Nazarov reaction but also showed that the reaction could be
performed comparably well under both stoichiometric and
catalytic conditions depending on the reaction temperature and
solvent. Finally, control experiments between 3,4-dihydroiso-
quinoline (17) and methacryloyl chloride in the absence and
presence of AgOTf at both rt and 80 °C did not result in the
formation of any aza-Nazarov product.24 Hence, our hypothesis
on the importance of the −TMS group is supported by these
observations.
addition to the iminium but also stabilize the carbocation of
intermediate 11 through the β-silicon stabilization effect.20−22
We commenced our studies by the preparation of the α,β-
unsaturated acyl chloride substrates for which the method
developed by Omura and co-workers was followed with slight
modifications.23 The reaction sequence used for the synthesis of
acyl chloride 16 is shown in Scheme 2. Alkylation of the
Scheme 2. Preparation of Acyl Chloride 16
We next studied the substrate scope of the newly developed
aza-Nazarov cyclization (Scheme 3). Initially, the effect of
electron-withdrawing and -donating groups present on the
imine component was investigated under catalytic conditions.
Pleasingly, 3,4-dihydroisoquinolines bearing electron-withdraw-
ing −Br, −Cl, and −NO2 substituents at the 7-position were all
found to be competent substrates giving aza-Nazarov products
9b, 9c, and 9d as single diastereomers, and in 69%, 64%, and
58% isolated yields, respectively. The reaction was found to
tolerate electron-donating MeO− groups on the imine, and
product 9e was isolated in 55% yield. Unsubstituted 3,4-
dihydro-β-carboline was also observed to undergo the aza-
Nazarov cyclization successfully, albeit with a lower yield (9f,
25%). Next, we turned our attention to investigate substitution
at the β-position of acyl halide substrates. When n-propyl-
substituted acyl chloride was tested, product 9g was obtained in
66% yield. The aza-Nazarov product 9h with the branched
isobutyl side chain was isolated in 61% yield on a 1.0 mmol
reaction scale. In addition, both the catalytic and stoichiometric
commercially available triethyl phosphonoacetate (12) with
TMSCH2I gave 13 in 66% yield. Horner−Wadsworth−
Emmons reaction of 13 with propanal afforded α,β-unsaturated
ester 14 in 94% yield and with 3:1 dr (Z/E). Acyl chloride 16
was obtained by the saponification of ester 14 followed by
treatment with oxalyl chloride.
With the acyl chloride 16 in hand, we next sought to test our
hypothesis on the aza-Nazarov reaction using 3,4-dihydroiso-
B
DOI: 10.1021/acs.orglett.8b03886
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Organic Letters
Letter
a
Scheme 3. Substrate Scope of the Aza-Nazarov Reaction
Figure 1. X-ray crystal structure of 9e.
catalytic conditions (Scheme 4). These results clearly
demonstrate the potential of this methodology in accessing a
variety of nitrogen-containing aliphatic heterocycles.
Scheme 4. Aza-Nazarov Reactions Using Acyclic Imines
In order to shed light on the reaction mechanism, the key
cyclization step was investigated computationally with the
density functional theory (DFT). For this purpose, the B3LYP
functional25 was employed along with the 6-311++G(d,p) basis
set.26 Throughout this research, all the relative energies refer to
the zero-point vibrational energy (ZPVE) corrected energies.
Initially, the reaction barriers and reaction energies (ΔE) for the
aza-Nazarov cyclization steps of N-acyliminium cations 25a,
25b, and 28 were studied (Figure 2). The reaction barrier for the
a
Reaction conditions: 1.0 equiv of imine, 1.3 equiv of acyl chloride,
b
20 mol % of AgOTf, CH3CN, 80 °C, N2, 22 h. 1.3 equiv of AgOTf
c
was used at 23 °C in CH2Cl2. 1.3 equiv of AgOTf was used at 80 °C
in CH3CN.
conditions were tested and found to be successful using the n-
hexyl-substituted acyl chloride substrate. Whereas aza-Nazarov
product 9i was isolated in 60% yield under the standard catalytic
conditions, the yield was found to be slightly lower (48%) with
the use of a stoichiometric amount of AgOTf (1.3 equiv) at 23
°C in CH2Cl2. However, the yield increased to 68% when the
reaction mixture was heated at 80 °C in CH3CN with the use of
1.3 equiv of AgOTf. Finally, when compounds 18−21 were
tested as the imine component of the reaction, aza-Nazarov
product formation was not observed. Isoquinoline (18) and
quinoline (19) gave no reaction while complex mixtures of
products were obtained in the reactions of imines 20 and 21.
The relative stereochemistry of the two stereogenic centers of
the aza-Nazarov products was initially determined via the
NOESY analysis of 9a.24 Afterward, this conclusion was
confirmed through the single-crystal X-ray diffraction analysis
of 9e (Figure 1).
Figure 2. Computational studies (at B3LYP/6-311++G(d,p) level) on
the cyclization of 25a, 25b, and 28.
Encouraged by the results obtained with the dihydroisoquino-
line substrates, we next investigated the possibility of using
acyclic imines in the aza-Nazarov reaction. To our delight,
pyrrolidinone products 24a−c were obtained in 35−64% yield
and with dr values ranging from 10:1 to 5:1, when acyclic imines
derived from benzaldehyde derivatives 22a−c and n-propyl-
amine (23) were subjected to aza-Nazarov cyclization under the
cyclization of 25a and 25b, both having a −TMS group, was
calculated to be 17.4 kcal/mol, which is 9.8 kcal/mol lower than
the barrier of cation 28 (27.2 kcal/mol) that has a −Me in place
of the −TMS group.27 Moreover, the reaction energies (ΔE) for
the cyclization of iminium cations 25a and 25b were found to be
much lower than that of 28 (5.0 and 4.8 kcal/mol compared to
C
DOI: 10.1021/acs.orglett.8b03886
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
23.4 kcal/mol). These observations are in perfect agreement
with our initial hypothesis on the β-silicon effect to be imparted
by the −TMS group.
The calculated structures of the transition states (TS) 26b and
29 with selected interatomic distances are shown in Figure 3.
Scheme 5. Proposed Reaction Mechanism
formation of AgCl. Compared to the chloride salt 31, the
iminium salt 33 bearing the OTf− counteranion is expected to be
more active toward the aza-Nazarov cyclization to give
intermediate 34. Finally, abstraction of the −TMS group of 34
by the Cl− anion of another molecule of 31 is proposed to yield
aza-Nazarov product 9 along with TMSCl and regenerate
activated iminium salt 33.
In summary, we have developed a new aza-Nazarov
cyclization between 3,4-dihydroisoquinolines and α,β-unsatu-
rated acyl chlorides, which operates via anion exchange catalysis.
α-Methylene-γ-lactam products were obtained in good yields
(up to 79%) and with high diastereomeric ratios. The reaction
proceeds well at 23 °C when AgOTf is used in a stoichiometric
amount, whereas it can be rendered catalytic with the use of 20
mol % of AgOTf at 80 °C. We have also demonstrated the use of
acyclic imine substrates in this methodology through the
syntheses of pyrrolidinone products 24a−c. The key role of
the −TMS group in reducing the reaction barrier of the aza-
Nazarov cyclization step was revealed by computational studies.
Research to transform this methodology to a catalytic
enantioselective process is currently underway in our laboratory.
Figure 3. Computed structures (at B3LYP/6-311++G(d,p) level) of
the transition states 26b and 29.
The larger distance of 2.106 Å for the newly forming bond
(shown by dashed lines) for TS 26b compared to 1.894 Å for TS
29 is indicative of an earlier TS for 26b. This is in accordance
with the Hammond−Leffler postulate and the higher reaction
energy (ΔE) calculated for the conversion of 28 to 30 compared
to that of 25b to 27b. In addition, the difference in the C−N
bond distances in the TS structures 26b and 29 (1.392 and 1.414
Å, respectively) lends support to this conclusion. Finally, in the
structure of TS 26b, the β-silicon effect due to the presence of
the −TMS group finds reflection in the relatively short C(O)C−
CH2TMS bond distance (1.437 Å) and long CH2−SiMe3 bond
distance (2.028 Å). This situation is even more pronounced in
the calculated structures of 27a and 27b (Figures S6 and S10).24
Finally, we cannot rule out the possibility that the cyclization
reaction discussed here may mechanistically be an intra-
molecular aza-Sakurai-type reaction22 which involves the
nucleophilic attack of an allylsilane moiety to the iminium,
even though this would correspond to a disfavored 5-endo-trig
cyclization according to Baldwin’s rules.28,29
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b03886.
1
Experimental procedures, characterization data, H and
13C NMR spectra, computational details, coordinates and
energies of the computed structures (PDF)
Accession Codes
CCDC 1875287 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 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 Authors
■
In light of our computational studies, observations, and other
reactions reported in the field of anion binding catalysis, we
propose the mechanism shown in Scheme 5 for the catalytic aza-
Nazarov cyclization.22c,30,31 Treatment of imine 7 with acyl
chloride 8 gives iminium chloride salt 31 which may be in
equilibrium with 32.32 Addition of AgOTf is proposed to induce
an anion exchange to afford iminium triflate 33 along with the
*E-mail: yeturkmen@bilkent.edu.tr (Y.E.T.).
*E-mail: ugrbzky@gmail.com (U.B.).
ORCID
̆
Ugur Bozkaya: 0000-0002-5203-2210
rkmen: 0000-0002-9797-2820
Yunus E. Tu
̈
D
DOI: 10.1021/acs.orglett.8b03886
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
51, 17166. (c) Shu, C.; Wang, Y.-H.; Shen, C.-H.; Ruan, P.-P.; Lu, X.;
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Y.; Yonamine, Y.; Terasoma, N.; Matsubara, H. Org. Biomol. Chem.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
́
2011, 9, 3780. (c) Companyo, X.; Geant, P.-V.; Mazzanti, A.; Moyano,
Financial support from the Scientific and Technological
A.; Rios, R. Tetrahedron 2014, 70, 75.
̈
̇
Research Council of Turkey (TUBITAK; Grants Nos.
116Z171 and 116Z506) is gratefully acknowledged. We also
acknowledge Scientific and Technological Research Application
and Research Center, Sinop University, Turkey, for the use of
the Bruker D8 QUEST diffractometer.
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̈
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DOI: 10.1021/acs.orglett.8b03886
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