Exploitation of Cyclopropane Carbaldehydes to Prins Cyclization: Quick Access to (E)-Hexahydrooxonine and Octahydrocyclopenta[ b]pyran

Article abstract of DOI:10.1021/acs.orglett.8b02094

A single-step TiX₄-mediated Prins-type cyclization of cyclopropane carbaldehydes with 3-buten-1-ol for the highly stereoselective construction of relatively strained (E)-hexahydrooxonines is reported. Switching the alcohol to 3-butyn-1-ol prompted a similar route, augmented by another cyclization within a nine-membered ring to afford a bicyclized product (4,4-dihalo-5-aryloctahydrocyclopenta[b]pyran). Easy transformation of the resulting geminal dihalide to a vinyl halide and a ketone further supplemented the substance of this approach.

Full text of DOI:10.1021/acs.orglett.8b02094

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Exploitation of Cyclopropane Carbaldehydes to Prins Cyclization:
Quick Access to (E)‑Hexahydrooxonine and
Octahydrocyclopenta[b]pyran
Pankaj Kumar, Raghunath Dey, and Prabal Banerjee*
Department of Chemistry, Indian Institute of Technology Ropar, Nangal Road, Rupnagar, Punjab 140001, India
S
* Supporting Information
ABSTRACT: A single-step TiX4-mediated Prins-type cycliza-
tion of cyclopropane carbaldehydes with 3-buten-1-ol for the
highly stereoselective construction of relatively strained (E)-
hexahydrooxonines is reported. Switching the alcohol to 3-
butyn-1-ol prompted a similar route, augmented by another
cyclization within a nine-membered ring to afford a bicyclized
product (4,4-dihalo-5-aryloctahydrocyclopenta[b]pyran).
Easy transformation of the resulting geminal dihalide to a
vinyl halide and a ketone further supplemented the substance
of this approach.
ver the years, Prins cyclization1 has extensively been used
participant in the Prins cyclization. One interesting approach,
which engaged the cyclopropyl methanol in the synthesis of
Oas a facile tool for the synthesis of various tetrahydropyr-
( )-centrolobine, using the Prins chemistry was reported by
Yadav et al.7 (Scheme 1, eq 2). Although, in its proposed
mechanism, cyclopropane is not directly involved in the Prins
cyclization, it helps in the generation of benzylic carbocation,
which gets captured by the aldehyde to form the active
oxocarbenium ion that ultimately undergoes Prins cyclization.
Similarly, in most of the reports on cyclopropanes in the Prins
reaction, a cyclopropane ring opens up to generate the
carbocation or promote nucleophilic attack on the carbonyl
carbon.8 The donor−acceptor cyclopropane ring opening was
yet to be associated with the Prins cyclization in a direct fashion.
Our group has also been working on the reactivity of donor−
acceptor cyclopropanes,9 and in this regard, a Lewis acid
catalyzed annulation of cyclopropane carbaldehydes with aryl
hydrazines was reported.10a The captivating reactivity of the
cyclopropane carbaldehyde10 is built on the inceptive attack of a
nucleophilic functionality on its carbonyl center. This makes it
an intriguing reactant for possible Prins-type processes. We took
this opportunity and designed a scheme that would implicate the
aryl-substituted cyclopropane carbaldehyde (ACC) and an
alkenol in the synthesis of strained medium-sized ring systems11
via an extended Prins-type cyclization process (Scheme 1, eq 3).
We successfully constructed the nine-membered cyclic
system12 with a trans geometry about the double bond, (E)-4-
chloro-6-aryl-2,3,4,5,6,7-hexahydrooxonine (A) (Scheme 1, eq
3). The trans geometry of the carbon−carbon double bond in
the hexahydrooxonine ring, specifically induced in this pathway,
is quite troublesome to achieve via any other synthetic route, and
the procedures reported for the synthesis of similar systems are
an, tetrahydrofuran, piperidine, and many carbocyclic deriva-
tives which are useful structural motifs of various complex
natural products and bioactive molecules2 like calyxin F,3
zampanolide,4 and clavosolide A.5 The process necessitates the
formation of an oxocarbenium ion (an iminium ion in the case of
aza-Prins cyclization) that undergoes a nucleophilic attack on its
carbon center by an alkene/alkyne, followed by capturing the
carbocation with a nucleophile.
Prins reaction has been thoroughly studied with a variety of
substrates, and the literature is full of reports on the synthesis of
the tetrahydropyran skeleton employing a variety of alkenols
with the carbonyl compounds6 (Scheme 1, eq 1). However,
there are insignificant reports on cyclopropanes being an active
Scheme 1. Classical Prins Cyclization and Its Extension to the
Cyclopropane Carbaldehydes
Received: July 4, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02094
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
very limited.13 With these results, we envisioned a bicyclization
process subject to the use of alkynols14 under identical reaction
conditions. The second cyclization was expected to involve
protonation and an in situ generation of the oxocarbenium ion
that would take part in the classical Prins cyclization, all inside a
nine-membered ring. Accordingly, with 3-butyn-1-ol (4), we
successfully synthesized a bicyclic five-six fused ring system, 4,4-
dihalo-5-aryloctahydrocyclopenta[b]pyran15 (B) (Scheme 1, eq
3).
Scheme 2. Prins-Type Annulation between ACC (1) and 3-
Buten-1-ol (2)
a
We took trans-2-(4-methoxyphenyl)cyclopropane-1-carbal-
dehyde (1a) as a standard substrate and made various attempts
with the alkenols such as allyl alcohol, 3-buten-1-ol, and 4-
penten-1-ol. Following the established literature,16 we screened
the process with Lewis acids like SnCl4, AlCl3, FeCl3, and TiCl4
in varying concentrations, but the expected product was not
found in any of the prototypes. This could be due to
decomposition of cyclopropane carbaldehyde by strong Lewis
acids. We tried the reaction at lower temperatures6,16a and
screened the process with a variety of Lewis acids. We obtained
the nine-membered cyclic product 3a with 3-buten-1-ol (2) by
treatment with 1 equiv of TiCl4 at −78 °C. The reaction was also
carried out in various solvents (Table 1), and it was found that
a
b
Isolated yields and reaction time are illustrated. With 1 equiv of
a
c
d
Table 1. Optimization of the Reaction Conditions
TiCl4. With 1.5 equiv of TiCl4. With 0.1 equiv of TiCl4 and 2 equiv
of TMSCl as an additive (for details, see SI).
dimethoxyphenyl and furan-2-yl-substituted ACCs. In such
cases, the higher electron-releasing effect of the aryl substituent
was expected to promote decomposition of the cyclopropane
with higher concentrations of TiCl4. It was also interesting that
the yield decreased drastically for 1a with increased TiCl4
loading to 1.5 equiv. Again, some decomposition of the ACC
with elevated concentration of TiCl4 could be the possible
reason behind the loss in yield. We also attempted the reaction in
the presence of an external chloride source such as TMSCl,17
using lower concentrations of TiCl4, and successfully obtained
product 3p out of an electron-rich ACC 1p, though the yield was
not satisfactory (Table 1). The geometry of the product was
confirmed from the coupling constant values (J = 15−16 Hz,
suggesting the trans geometry of the double bond) and the 2D-
NOE data for 3a (Scheme 2; also see the Supporting
Information (SI)).
entry
Lewis acid
equiv
solvent
additive (2 equiv)
yield %
1
2
3
4
5
6
7
8
9
TiCl4
TiCl4
TiCl4
AlCl3
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
BF3·OEt2
0.2
1
1.5
1
1
1
1
1
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
DCE
toluene
THF
Et2O
78
38
26
22
52
30
-
-
10
11
12
0.6
0.1
1
CH2Cl2
CH2Cl2
CH2Cl2
TMSCl
TMSCl
TMSCl
36
10
32
To investigate the scope of this approach with the alkynols,
the reaction was screened with propargyl alcohol, 3-butyn-1-ol,
4-pentyn-1-ol, and 3-pentyn-1-ol under the optimized reaction
conditions. Only 4 with 1a underwent the proposed route to
produce the desired bicyclic product 5a in 58% overall yield. It
appeared to be an excellent method for the one-step synthesis of
geminal dichloro-substituted octahydrocyclopenta[b]pyran
(Scheme 3). It was observed that the overall yield increased
with increased TiCl4 loading, and the process was optimized at
1.5 equiv of TiCl4 in CH2Cl2 solvent at −78 °C, except for 1c,
which underwent decomposition upon increased TiCl4 loading.
Screening the process with a variety of ACCs revealed that the
reaction would progress only with the electron-deficient (1g−
1i) cyclopropanes or with those cyclopropane carbaldehydes
that were slightly electron-rich (Scheme 3). Electron-rich
cyclopropanes like those substituted with 3,4-dimethoxyphenyl
1p and furan-2-yl failed to afford the desired bicyclic product.
Among ACCs, 1i offered the maximum yield for the bicyclized
product and afforded 5i in an excellent yield of 80%. Both
diastereomers (5ha/5hb) were isolated in the case of 5h, and
their geometries were determined by the NOE experiment (for
a
The optimum condition involved using 1 equiv of TiCl4 at −78 °C
in CH2Cl2 as a solvent.
3a was obtained in CH2Cl2, CHCl3, (CH2)2Cl2 (DCE), and
toluene. Among these, CH2Cl2 emerged as the solvent of choice.
However, ethereal solvents such as diethyl ether (Et2O) and
THF could not afford the desired product. With 1 equiv of BF3·
OEt2, we could not obtain the fluorinated hexahydrooxinine
derivative because it is difficult to get the fluoride ion from BF3 at
−78 °C, but addition of chlorotrimethylsilane (TMSCl) as an
additive, under the same reaction conditions, afforded the
chlorinated product 3a in 32% yield (Table 1).
With this optimized condition in hand, we investigated the
scope of cyclopropane carbaldehydes consistent with this
protocol (Scheme 2). The results demonstrated that the process
was compatible with cyclopropane carbaldehydes having
moderately electron-releasing groups such as p-methyl, p-
methoxy, p-isopropyl, etc. on the phenyl ring in its vicinal
position. Prominent results were obtained with 1a, affording 3a
in 78% yield. The process was not reconcilable with 3,4-
B
DOI: 10.1021/acs.orglett.8b02094
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Reaction of ACC (1) with 3-Butyn-1-ol (4)
Scheme 4. Plausible Mechanism for Prins-Type Annulation
of 1 with 3-Buten-1-ol (2) and 3-Butyn-1-ol (4)
the chloride ion from TiCl4. The nucleophilic cyclopropane ring
opening may take place either via a less hindered approach (a) of
the double bond (i.e., from the back side of the aryl substituent),
resulting in the formation of 3, or from the sterically hindered
aryl side approach (b) of the double bond, which would afford
3′. However, the sterically unfavored approach (b) was not
feasible here, as only a single isomer 3 was obtained in the
process.
a
Isolated yields, reaction time, and diastereomeric ratios (5xa/5xb)
are illustrated. Hydrogen atoms are omitted in the single-crystal X-ray
structures of 5aa and 5ka for the sake of clarity. With 1.5 equiv of
TiCl4. With 1 equiv of TiCl4. With 1.5 equiv of TiBr4 (for details,
see SI).
b
c
d
With 4, the reaction did not cease at the nine-membered
cyclic product (A or A′) and underwent protonation to give the
oxocarbenium ion II. Intermediate II then encountered the
classical Prins cyclization within the nine-membered ring to give
the fused product 5x (Scheme 4, eq 2). The diastereoselectivity
of this process depends on the approach of the carbon−carbon
triple bond in the initial cyclization. Major isomer 5xa was
obtained by the sterically facile attack of the alkyne on ACC (a′),
and minor isomer 5xb was obtained by the sterically hindered
aryl side attack of the alkyne on the ACC (b′). The sterically
unfavorable approach (b′) was possible here, as the attacking
moiety in this case was less bulky (an alkyne having a linear
geometry). Thus, bicyclization followed a double Prins-type
pathway, involving first the extended Prins cyclization, followed
by the classical Prins cyclization within a nine-membered ring.
As depicted by the stereochemistry of the product, formation of
a stable fused tetrahydropyran derivative 5x (a well-studied
pathway for the classical Prins cyclization), rather than a highly
strained fused THF derivative with a chlorine atom at the ring
fusion, controls the regioselectivity of the second chloride attack.
To showcase the scope of the developed approach, we carried
out some simple transformations with the molecules we isolated.
To examine the possibility of dehydrochlorination18 for the
geminal dichloride, we subjected 5ha to elimination with tBuOK
in methanol, which afforded the vinyl chloride 6 in an excellent
yield of 99% (Scheme 5). When treated with MgO, 5ha also
details, see SI). The structure of major isomer 5aa was also
ascertained by single-crystal X-ray analysis (Scheme 3). We also
explored the reaction with TiBr4 to obtain a geminal dibromo
product. With the optimized conditions, we successfully
synthesized dibromo derivatives 5k−5n but could not separate
the individual diastereomers as they seem to have exactly the
same polarity. The X-ray crystal structure for the major
diastereomer of 5k enabled us to ascertain its stereochemistry
(Scheme 3).
The mechanism we proposed (Scheme 4) is in accordance
with the earlier reports,1,6,14 except that the oxocarbenium ion
ring closing here is coupled with the cyclopropane ring opening.
The mechanism also justified the trans geometry of the carbon−
carbon double bond in 3. It involved a TiCl4-induced
nucleophilic attack of the alcohol on the aldehyde, resulting in
the formation of the oxocarbenium ion I. As demonstrated in the
plausible mechanism (Scheme 4, eq 1), the trans geometry of
ACC is conserved as such in the oxocarbenium ion I.
Intermediate I then encountered an intramolecular nucleophilic
attack by the carbon−carbon double bond on the cyclopropane,
shifting the cyclopropane carbon−carbon bond toward the
oxocarbenium carbon and shaping a trans double bond inside a
nine-membered ring. The resulting cation was then captured by
C
DOI: 10.1021/acs.orglett.8b02094
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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In summary, a versatile technique was developed, where one
can deliberately direct the route to a nine-membered ring or a
fused bicyclic system, simply by picking up an appropriate
alcohol. The protocol provides an excellent method for the
single-step time-efficient construction of (E)-hexahydrooxo-
nines and the octahydrocyclopenta[b]pyrans. The geminal
dichloride was successfully transformed to a vinyl chloride and
a pyranone derivative. Cyclic halides, geminal dihalides, vinyl
halides, and pyranones formulated in this process possess a great
scope for further transformations, and the approach shows
promise in the synthetic chemistry sector. Development of the
asymmetric variant of the present methodology and its further
application are underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b02094.
Experimental procedures, 1H NMR, 13C NMR, IR
spectra, and mass data of all new compounds, single-
crystal X-ray data (PDF)
Accession Codes
CCDC 1845296 and 1845299 contain 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.
́
(b) Miranda, P. O.; Diaz, D. D.; Padrοn, J. I.; Ramírez, M. A.; Martín, V.
S. J. Org. Chem. 2005, 70, 57. (c) Chavre, S. N.; Choo, H.; Lee, J. K.;
Pae, A. N.; Kim, Y.; Cho, Y. S. J. Org. Chem. 2008, 73, 7467.
́
(d) Miranda, P. O.; Ramírez, M. A.; Martín, V. S.; Padrοn, J. I. Chem. -
AUTHOR INFORMATION
■
Eur. J. 2008, 14, 6260. (e) Zhu, C.; Ma, S. Angew. Chem., Int. Ed. 2014,
53, 13532.
Corresponding Author
*E-mail: prabal@iitrpr.ac.in.
ORCID
̌
́
́
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Prabal Banerjee: 0000-0002-3569-7624
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from the
Council of Scientific & Industrial Research, India. We also thank
IIT Ropar for the doctoral fellowship.
(18) Creary, X.; Wang, Y.-X. Tetrahedron Lett. 1989, 30, 2493.
(19) Schmerling, L. J. Am. Chem. Soc. 1946, 68, 1650.
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DOI: 10.1021/acs.orglett.8b02094
Org. Lett. XXXX, XXX, XXX−XXX