Synthesis of tetrahydropyrans from propargyl alcohols and 1,1-cyclopropanediesters: A one-pot ring-opening/Conia-ene protocol

Article abstract of DOI:10.1021/jo9019122

(Chemical Equation Presented) Lewis acid catalyzed ring opening of 1,1-cyclopropanediesters by the hydroxyl group of a propargyl alcohol sets up a subsequent Conia-ene cyclization to afford substituted tetrahydropyrans in a one-pot, high-yielding procedur

Full text of DOI:10.1021/jo9019122

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SCHEME 1. Synthesis of Piperidines and Tetrahydropyrans
Synthesis of Tetrahydropyrans from Propargyl
Alcohols and 1,1-Cyclopropanediesters: A One-Pot
Ring-Opening/Conia-ene Protocol
Andrew B. Leduc, Terry P. Lebold, and Michael A. Kerr*
Department of Chemistry, The University of Western Ontario,
London, Ontario, Canada N6A 5B7
makerr@uwo.ca
Received September 8, 2009
wish to present an extension of this research to a convenient
one-pot synthesis of tetrahydropyrans from propargyl alco-
hols and 1,1-cyclopropanediesters (Scheme 1).
With 1,1-cyclopropanediester 1a and propargyl alcohol 5a
as our exploratory substrates, we set out to find a Lewis acid
capable of promoting both the nucleophilic ring-opening5 of
the cyclopropane and subsequent Conia-ene6-13 cyclization.
While a variety of Lewis acids were screened (Table 1), only
In(OTf)3 was found to perform both functions in an ade-
quate manner. During the screening process, it was noted
that the presence of a base significantly improved the Conia-
ene cyclization (perhaps as a proton shuttle); however,
because of base deactivation of the Lewis acid toward the
cyclopropane ring opening, it was important to use half the
molar quantity with respect to the In(OTf)3.
Lewis acid catalyzed ring opening of 1,1-cyclopropanedie-
sters by the hydroxyl group of a propargyl alcohol sets up a
subsequent Conia-ene cyclization to afford substituted
tetrahydropyrans in a one-pot, high-yielding procedure.
The tetrahydropyran ring is an omnipresent heterocycle in
the chemistry of the natural world owing largely to its presence
in the pyranose sugars. In addition, the tetrahydropyran ring is
a key structural feature of an enormous array of non-carbohy-
drate natural products. With the natural abundance of this
heterocycle, it is not surprising that the synthetic chemists’
repertoire contains numerous methods for its synthesis.1
Annulation reactions of donor-acceptor cyclopropanes2
have received considerable attention in recent years due to
their abiltity to allow rapid access to a variety of heterocycles.3
Our group has had a long-standing interest in this field and
has recently disclosed a tandem ring-opening/Conia-ene se-
quence involving propargyl amines and cyclopropanediesters
allowing access to highly substituted piperidines.4 Herein we
During our studies, it became apparent that soluble amine
bases were most effective. Moreover, it seemed that weaker
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Published on Web 10/06/2009
DOI: 10.1021/jo9019122
r
2009 American Chemical Society

Leduc et al.
JOCNote
TABLE 1. Optimization of Tandem Ring-Opening/Conia-ene Cyclization
entry
base (equiv)
none
none
none
none
none
NEt3 (1.0)
NEt3 (0.1)
DIPEA (0.1)
K2CO3 (0.1)
pyridine (0.1)
PPh3 (0.1)
2,6-lutidine (0.1)
PhN(Me)2 (0.1)
PhN(Me)2 (0.1)
PhN(Me)2 (0.08)
PhN(Me)2 (0.05)
PhN(Me)2 (0.03)
PhN(Me)2 (0.02)
PhN(Me)2 (0.1)
catalyst (equiv)
Zn(OTf)2 (0.1)
Zn(NTf2)2 (0.1)
Sc(OTf)3 (0.1)
ZnBr2 (0.1)
temp
reflux
reflux
rt
reflux
reflux
rt to reflux
reflux
rt to reflux
rt to reflux
rt to reflux
rt to reflux
rt to reflux
rt to reflux
reflux
yielda
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
57%
mixturec
6ab
no rxn
28%
97%
57%
69%
decomp
82%
58%
In(OTf)3 (0.1)
In(OTf)3 (0.2) then ZnBr2 (3.0)
In(OTf)3 (0.2)
In(OTf)3 (0.2)
In(OTf)3 (0.2)
In(OTf)3 (0.2)
In(OTf)3 (0.2)
In(OTf)3 (0.2)
In(OTf)3 (0.2)
In(OTf)3 (0.2)
In(OTf)3 (0.15)
In(OTf)3 (0.1)
In(OTf)3 (0.05)
In(OTf)3 (0.1)
In(OTf)3 (0.1)
77%
86%
88%
82%
reflux
reflux
reflux
reflux
reflux
76%
75%
mixturec
69%
aIsolated yield of 7a. bAcyclic compound 6a was isolated in 88% yield. cProduct was formed as part of an inseparable mixture.
TABLE 2. Reaction Scope for In(OTf)3-Catalyzed Reaction
superstoichiometric in ZnBr2, this metal salt is quite inex-
pensive. Because the initial ring opening was allowed to
proceed at room temperature, little In(OTf)3-promoted
decomposition was observed even for very electron-rich phe-
nylcyclopropanes. In the case of cyclopropanes bearing an
electron-withdrawing aryl substituent, ring opening was
often sluggish. This was overcome by simply increasing the
relative amounts of In(OTf)3 and propargyl alcohol. The
scope of the two-step one-pot protocol is shown in Table 3.
In almost all cases, the yields range from good to excellent.
The cyclopropanediester bearing no substituent vicinal to the
geminal diester moiety performed rather poorly, giving only a
27% yield of product. The reaction is not restricted to
cyclopropanes with phenyl substituents. Cyclopropanes with
methyl, vinyl, naphthyl, and heteroaryl substituents all per-
formed well under these reaction conditions. It should be
noted that the presence of a furan moiety on the cyclopropane
was not tolerated as it underwent decomposition under the
reaction conditions. Compounds 7a and 7f were prepared in
near enantiomerically pure form (as analyzed by chiral
HPLC) beginning with a cyclopropane of similar enantio-
meric purity.14 The reaction proceeded with a presumed15
clean inversion at the cyclopropane stereogenic center.
A plausible mechanism for the two-metal one-pot proce-
dure is shown in Scheme 2, where initial coordination of the
diesters by In(OTf)3 allows nucleophilic ring-opening to occur
and formation of acyclic ether 6a. Addition of NEt3 and
ZnBr2 then allows for sequestering of the In(OTf)3 and
coordination of the diesters by zinc. Subsequent coordination
of the alkyne then facilitates malonate addition to the alkyne
and formation of metalate 8. Protonation of metalate 8 then
leads to the desired tetrahydropyran 7.
bases, such as N,N-dimethylaniline, were superior, perhaps
dueto thelessened ability to deactivatethe Lewis acidcatalyst.
Decreasing the Lewis acid catalyst loading below 20 mol %
resulted in diminished yields (entries 15-17). Using very small
quantities of base was also found to be detrimental to the
reaction course (entry 18). With presumed optimal conditions
in hand (entry 14), we set forth to survey the substrate scope
and demonstrate the utility of this process.
It became apparent early on that the “optimized” condi-
tions were somewhat limited in substrate scope. Only phenyl-
substituted cyclopropanediesters bearing either no phenyl
substituent or an electron-withdrawing substituent behaved
acceptably under these conditions (Table 2). In the case of the
electron-rich aromatic substituents, the reaction led solely to
the decomposition of the acyclic intermediate 6a (vide infra)
via detrimental interaction with In(OTf)3 under the refluxing
conditions necessary to promote the Conia-ene process.
While disappointed at the limited scope of the reaction as
it stood, we decided to reinvestigate the reaction scope of a
two-step one-pot protocol (see Table 1, entry 6). These new
conditions, while straying from the idea of a single catalyst,
are general and technically simple. In addition, although
(14) (R)-Dimethyl 2-phenylcyclopropane-1,1-dicarboxylate 98% ee,
(R)-dimethyl 2-(4-chlorophenyl)cyclopropane-1,1-dicarboxylate 98% ee.
(15) Karadeolian, A.; Kerr, M. A. J. Org. Chem. 2007, 72, 10251.
J. Org. Chem. Vol. 74, No. 21, 2009 8415

Leduc et al.
JOCNote
TABLE 3. Reaction Scope for In(OTf)3/ZnBr2-Catalyzed Method
SCHEME 2. Plausible Mechanism for In(OTf)3/ZnBr2-Cata-
lyzed Method
SCHEME 3. Effects of R-Chirality on the Propargyl Alcohol
In(OTf)3/ZnBr2-Catalyzed Method:. To a solution of 100 mg
of cyclopropane 1a (0.427 mmol) in 1 mL of benzene were added
propargyl alcohol (36 mg, 0.640 mmol) and In(OTf)3 (24 mg,
0.0427 mmol). The reaction was monitored by TLC. Upon
complete consumption of the cyclopropane, the reaction mix-
ture was diluted to a final volume of 3 mL of benzene, and ZnBr2
(288 mg, 1.28 mmol) and NEt3 (44 mg, 0.427 mmol) were then
added. The solution was then heated to reflux and monitored by
TLC. Once the reaction was completed, the solution was diluted
with water and EtOAc. The aqueous layer was then extracted
twice with EtOAc, and the combined organic fractions were
washed once with 5% HCl and once with brine. The solvent was
then removed under reduced pressure, and the resulting crude
residue was preabsorbed onto silica and purified by flash
column chromatography with 10% EtOAc in hexanes. Tetra-
hydropyran 7a (121 mg, 97% yield) was obtained as a pale
aPropargyl alcohol (6 equiv) and In(OTf)3 (0.5 equiv) were employed.
bPropargyl alcohol (3 equiv) and In(OTf)3 (0.2 equiv) were employed.
cProduct obtained in 98% ee. dProduct obtained in 97% ee.
The effect of R-chirality on the propargyl alcohol was also
investigated by treating racemic 1,1-cyclopropanediester 1a
with racemic propargyl alcohol 5b (Scheme 3). Not surpris-
ingly, we obtained tetrahydropyran 7m as an equimolar
mixture of cis and trans isomers. We suspect that, based
on our previous observations,4 through judicious choice of
homochiral starting materials, either diastereomer of the
product tetrahydropyran could be prepared as a single
enantiomer.
In summary, we have reported a technically simple and
general synthesis of tetrahydropyrans from propargyl alco-
hols and 1,1-cyclopropanediesters. A single catalyst system is
useful for some cases, while a two-metal/one-pot protocol
is more general and may be used to prepare a wide variety
of tetrahydropyrans. The application of this methodology
toward the total synthesis of tetrahydropyran-containing
natural products is currently underway.
1
yellow oil: Rf=0.39 (15% EtOAc in hexanes); H NMR (600
MHz, CDCl3) δ (ppm)=7.37-7.32 (m, 4H), 7.30-7.26 (m, 1H),
5.27 (s, 1H), 4.94 (s, 1H), 4.45-4.40 (m, 2H), 4.33 (AB dd, 1H,
J = 8.4 Hz, 0.8 Hz), 3.87 (s, 3H), 3.80 (s, 3H), 2.61 (dd, 1H,
J=9.0 Hz, 1.4 Hz), 2.41 (dd, 1H, J=9.0 Hz, 8 Hz); 13C NMR
(100 MHz, CDCl3) δ (ppm)=170.2, 169.6, 140.9, 139.5, 128.4,
127.8, 125.9, 114.1, 76.3, 71.7, 60.6, 53.2, 52.8, 40.4; IR (thin
film) ν (cm-1)=3091, 3065, 3032, 3005, 2956, 2851, 1735, 1654,
1497, 1456, 1437, 1369, 1337, 1261, 1241, 1214, 1114, 1085, 1071,
1030, 996, 920, 767, 700; HRMS (70 ev) calcd for C16H18O5=
290.1154, found=290.1145.
Experimental Section
Tetrahydropyran 7a was prepared by both methods.
In(OTf)3-Catalyzed Method:. To a solution of 100 mg of
cyclopropane 1a (0.427 mmol) in 3 mL of benzene were added
propargyl alcohol (24 mg, 0.427 mmol), In(OTf)3 (48 mg, 0.0834
mmol), and N,N-dimethylaniline (53 mg, 0.0427 mmol). The
solution was then heated to reflux, and the reaction was
monitored by TLC. Upon completion, the reaction was diluted
with EtOAc and then preabsorbed onto silica and purified by
flash column chromatography with 10% EtOAc in hexanes.
Tetrahydropyran 7a (109 mg, 88% yield) was obtained as a pale
yellow oil.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada for generous
funding of this research. We are grateful to Mr. Doug
Hairsine for performing MS analyses.
Supporting Information Available: Complete experimental
procedures as well as 1H NMR and 13C NMR, IR, MS, data for
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
8416 J. Org. Chem. Vol. 74, No. 21, 2009