Altering the Cyclization Modes: Temperature-Dependent Intramolecular 7-Endo-Dig vs 6-Endo-Dig Electrophilic Ring Closures

Article abstract of DOI:10.1021/acs.orglett.7b00472

In an attempt to construct 10-acyl-5H-benzo[e]pyrrolo[1,2-a]azepines via acid-catalyzed intramolecular alkyne carbonyl metathesis, two distinctive modes of cyclization were revealed to depend on the reaction temperatures. 5H-Benzo[e]pyrrolo[1,2-a]azepine-

Full text of DOI:10.1021/acs.orglett.7b00472

Letter
pubs.acs.org/OrgLett
Altering the Cyclization Modes: Temperature-Dependent
Intramolecular 7-Endo-Dig vs 6-Endo-Dig Electrophilic Ring Closures
Maloy Nayak,† Young Kee Kang,*,‡ and Ikyon Kim*,†
†College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University 85 Songdogwahak-ro, Yeonsu-gu, Incheon,
21983, Republic of Korea
‡Department of Chemistry, Chungbuk National University 1 Chungdae-ro, Seowon-gu, Cheongju, Chungbuk 28644, Republic of
Korea
S
* Supporting Information
ABSTRACT: In an attempt to construct 10-acyl-5H-benzo-
[e]pyrrolo[1,2-a]azepines via acid-catalyzed intramolecular
alkyne carbonyl metathesis, two distinctive modes of
cyclization were revealed to depend on the reaction temper-
atures. 5H-Benzo[e]pyrrolo[1,2-a]azepine-1-carbaldehydes
with a substituent at the C11 position were obtained as
major products at 90 °C as a result of intramolecular 7-endo-dig
cyclization, while 6-endo-dig ring closure by electrophilic
addition of nitrogen of the pyrrole to a vinyl cation generated
under acidic medium followed by an unprecedented domino
rearrangement process was observed at 40 °C in some cases,
resulting in 5-aryl-11H-benzo[d]pyrrolo[1,2-a]azepine-1-carbaldehydes along with the former products.
through IACM. In this study, however, we observed the
unexpected outcomes, which is the topic of this paper.
Preparation of the requisite substrate 3 for this study began
with N-alkylation of pyrrole-2-carbaldeyde to afford 5 (Scheme
2). Sonogashira coupling of 5 with phenylacetylene gave 3a in
94% yield.
s part of our research interest in the synthesis of
Aheterocycles with potential biological implications using
intramolecular alkyne carbonyl metathesis (IACM),1,2 we
recently reported a regiospecific synthetic approach to 5-
acylated pyrrolo[1,2-a]quinolines (1 to 2) (Scheme 1, eq 1).3
Scheme 1. IACM Approaches to N-Fused Heterocycles
Scheme 2. Synthesis of 3a
As shown in Scheme 3, treatment of 3a in TFA at 40 °C
produced two new compounds. Contrary to our expectation,
NMR analysis indicated that they both had an aldehyde unit.
No product from IACM was detected. It turned out that the
As an extension of this work, we envisioned that IACM of
benzyl-substituted pyrrole-2-carbaldehyde (3) would give rise
to 10-acyl-5H-benzo[e]pyrrolo[1,2-a]azepine, another N-fused
heterocycle (4) (Scheme 1, eq 2). Compared with other
azepine-containing chemical scaffolds, this tricyclic structure
has been less explored as a pharmacophore in the area of
medicinal chemistry.4 In addition, only a small number of
synthetic works toward this skeleton appeared in the literature.5
A lack of available synthetic methods as well as our continued
research on nitrogen-fused heteroaromatics6 led us to
investigate our designed route to this chemical core structure
Scheme 3. TFA Reaction of 3a
Received: February 16, 2017
© XXXX American Chemical Society
A
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Letter
less polar compound was 6a, a product resulting from
intramolecular 7-endo-dig7 electrophilic cyclization. The struc-
ture of the other one (7a, more polar than 6a) was firmly
established by X-ray crystallographic analysis (Figure 1).8 Much
to our surprise, it had a totally different connectivity from the
starting material.
energy profile of the pathway of the formation of 7a11 at 40 °C
is shown in Figure 2. The barriers (ΔG⧧) to transition states
Figure 2. Gibbs free energy profile of the pathway of the formation of
7a.
Figure 1. ORTEP diagram of 7a with 50% ellipsoid probability.
The plausible mechanism for the formation of 7a is proposed
in Scheme 4. Intramolecular 6-endo-dig electrophilic attack of
ts1, ts2, and ts3 were calculated as 2.15, 17.79, and 9.90 kcal/
mol, respectively. This indicates that the first step of the
intramolecular 6-endo-dig electrophilic attack of nitrogen of the
pyrrole ring to a vinyl cation generated under acidic conditions
seems to be much faster and that the second pathway of A
undergoing a suprafacial [1,5]-sigmatropic alkyl shift to afford B
is the rate-determining step of the reaction. In particular, the
Gibbs free energy of the intermediate decreases in the order A
→ B → C, which may suggest that the formation of 7a is
thermodynamically favored.
Scheme 4. Proposed Mechanism for the Formation of 7a
Interestingly, this domino process initiated by intramolecular
6-endo-dig electrophilic cyclization did not take place at higher
temperatures. Exposure of 3a to TFA at 90 °C only provided
6a in 80% yield.
To examine the effect of the R group on cyclization, several
other alkyne-substituted substrates, 3b−i,12 were submitted to
the same reaction conditions (Table 1). Subjection of 3b to
TFA at 40 °C yielded 75% of 6b and 20% of 7b, while 6b was
the only isolable product at 90 °C, indicating that 7-endo-dig
ring formation was preferred at higher temperatures (entry 1).
X-ray crystallographic analysis confirmed the molecular
structure of 6b (Figure 3).13 When R was an electron-rich
aromatic moiety, 7-endo-dig cyclization products 3c−f were
obtained as major products at 40 °C (entries 2−5).
Surprisingly, exposure of the substrate having a cyclohexenyl
group (3f) to TFA at 40 °C afforded the rearranged product as
a major product (entry 6). The substrate containing a
heterocycle such as thiophene (3h) was also treated with
TFA to give 64% of 6h (entry 7). Interestingly, when R was an
electron-poor aromatic group, the domino process occurred as
a major pathway to furnish 7i in good yields irrespective of the
reaction temperatures (entry 8).
To investigate the generality of this ring formation, indoles
(8 and 9) and pyrroles (10 and 11) were also prepared and
allowed to react with TFA (Scheme 5). A complex mixture of
products was observed in cases of 8 and 9, showing that indoles
are not compatible under these conditions. Decomposition of
10 under TFA also revealed the importance of an electron-
withdrawing group present in pyrrole rings. Exposure of 11a,b
having an ester or an acetyl unit to TFA at 40 °C afforded the
corresponding products 12a,b in good yields as a consequence
nitrogen of the pyrrole ring to a vinyl cation generated under
acidic conditions would occur to give the spirocyclic compound
A, which then would undergo suprafacial [1,5]-sigmatropic
alkyl shift9 to afford B. Neither formal migration of the benzylic
substituent to the C5 position of the pyrrole core nor [1,5]-
vinyl group shift occurred to give the other isomers, D or E,
which is ascribed to the resulting steric clash between the
exocyclic phenyl substituent and the formyl moiety. Another
[1,5]-sigmatropic migration of the formyl group at the ring
juncture of B would lead to C. Final loss of proton to regain
aromaticity would deliver 7a. To the best of our knowledge,
this type of domino sequence10 has never been disclosed.
The populations of 6a and 7a were calculated as 33.5 and
66.5%, respectively, at the M06-2X/cc-pVTZ//M06-2X/6-
31+G(d) level of theory in water, which are consistent with
the observed values of 34 and 50% in TFA at 40 °C. The free-
B
DOI: 10.1021/acs.orglett.7b00472
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Table 1. Synthesis of 6 and 7
Scheme 5. Reactions of 8−11
of intramolecular 7-endo-dig electrophilic ring closure, implying
that formyl moiety is crucial for this unusual domino reaction.
In summary, we have observed temperature-dependent
alteration of cyclization modes (intramolecular 7-endo-dig vs
6-endo-dig electrophilic ring cyclizations) in our effort to
construct N-fused heterocycles. These studies enabled us to
gain access to 11-(hetero)aryl- and 11-alkyl-5H-benzo[e]-
pyrrolo[1,2-a]azepine-1-carbaldehydes via acid-catalyzed intra-
molecular 7-endo-dig cyclization reaction. At lower reaction
temperatures, intramolecular 6-endo-dig electrophilic ring
closure followed by two consecutive suprafacial [1,5]-
sigmatropic alkyl shifts resulted in formation of 5-aryl-11H-
benzo[d]pyrrolo[1,2-a]azepine-1-carbaldehydes in variable
yields depending on the substituent attached to the alkyne of
the cyclization substrates. The plausible mechanism of this
unprecedented domino bond-reorganization process was
proposed, which is consistent with DFT calculations. Expansion
of this work as well as evaluation of these scaffolds for
medicinal use are underway.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00472.
■
a
A solution of 3 (0.1 mmol) in TFA (1 mL) was heated at 40 or 90
S
b
°C. Isolated yield (%).
1H and 13C NMR spectra of synthesized compounds
(PDF)
X-ray data for compound 6b (CIF)
X-ray data for compound 7a (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ykkang@chungbuk.ac.kr.
*E-mail: ikyonkim@yonsei.ac.kr
ORCID
Figure 3. ORTEP diagram of 6b with 50% ellipsoid probability.
Young Kee Kang: 0000-0002-2200-8922
Ikyon Kim: 0000-0002-0849-5517
C
DOI: 10.1021/acs.orglett.7b00472
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government
(MSIP) (2014R1A2A1A11050491) (to I.K.). We thank Mr.
Juwon Kang (Yonsei University) for conducting preliminary
experiments of this study.
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D
DOI: 10.1021/acs.orglett.7b00472
Org. Lett. XXXX, XXX, XXX−XXX