Ring expansion of lactones and lactams via propiolate 1-carbon intercalation

Article abstract of DOI:10.1021/ol8014682

(Chemical Equation Presented) Readily available five- and six-membered lactones and N-sulfonyllactams undergo efficient addition of t-butyl propiolate, and the resulting adducts undergo cycloisomerization to six- and seven-membered cyclic ethers or amines in the presence of pyridinium acetate. The ring expansion process occurs in generally good yields and is proposed to involve a nucleophilic catalysis mechanism.

Full text of DOI:10.1021/ol8014682

ORGANIC
LETTERS
2008
Vol. 10, No. 18
3985-3988
Ring Expansion of Lactones and
Lactams via Propiolate 1-Carbon
Intercalation
Tina N. Grant, Chantel L. Benson, and F. G. West*
Department of Chemistry, UniVersity of Alberta, E3-43 Gunning-Lemieux Chemistry
Centre, Edmonton, AB, T6G 2G2, Canada
frederick.west@ualberta.ca
Received June 28, 2008
ABSTRACT
Readily available five- and six-membered lactones and N-sulfonyllactams undergo efficient addition of t-butyl propiolate, and the resulting
adducts undergo cycloisomerization to six- and seven-membered cyclic ethers or amines in the presence of pyridinium acetate. The ring
expansion process occurs in generally good yields and is proposed to involve a nucleophilic catalysis mechanism.
Saturated oxygen and nitrogen heterocycles are found in
many natural products and other medicinally important
compounds. Construction of these rings by direct ring closure
of acyclic precursors is the most straightforward approach1
but is not uniformly effective with seven-membered and
larger rings. We have been interested in the development of
new and general methods for heterocycle synthesis, especially
as applied to the assembly of polycyclic systems such as
those found in the polyether marine ladder toxins.2 An
approach entailing the ring enlargement of simple lactones
or lactams was especially appealing, given their general
availability. In particular, we envisioned a process in which
an acetylide ion substituted with a suitable electron-
withdrawing group could undergo addition to a lactone
carbonyl, with the intermediate tetrahedral adduct 1 then
undergoing a one-atom expansion to furnish a cyclic ether
3 bearing an exocyclic alkene moiety (Scheme 1). Should
the tetrahedral intermediate open to ynone alkoxide 2,
Scheme 1
(1) Recent reviews: (a) Banwell, M. G. Pure Appl. Chem. 2008, 80,
669–679. (b) Larosa, I.; Romea, P.; Urpi, F. Tetrahedron 2008, 64, 2683–
2723. (c) Snyder, N. L.; Haines, H. M.; Peczuh, M. W. Tetrahedron 2006,
62, 9301–9320. (d) Inoue, M. Chem. ReV. 2005, 105, 4379–4405. (e) Deiters,
A.; Martin, S. F. Chem. ReV. 2004, 104, 2199–2238. (f) Zeni, G.; Larock,
R. C. Chem. ReV. 2004, 104, 2285–2309.
(2) (a) Marmsa¨ter, F. P.; Vanecko, J. A.; West, F. G. Tetrahedron 2002,
58, 2027–2040. (b) Marmsa¨ter, F. P.; West, F. G. Chem.-Eur. J. 2002, 8,
4346–4353. (c) Liu, X.; West, F. G. Chem. Commun. 2006, 5036–5038.
10.1021/ol8014682 CCC: $40.75
Published on Web 08/16/2008
2008 American Chemical Society

product 3 might still be attained through an exocyclic
Michael addition directed by the terminal electron-withdraw-
ing group. In effect, the acetylenic nucleophile would
function as a 1,1-dipole, intercalating between the carbonyl
carbon and the oxygen of the lactone ring.3 Described here
are the preliminary results of this study, entailing a conve-
nient method for accessing six- and seven-membered het-
erocycles from lactones and lactams via sequential propiolate
addition and pyridine-mediated rearrangement.
propiolate addition process was first evaluated, using a range
of lactones and lactams 4 (Table 1). In all cases, moderate
Table 1. t-Butyl Propiolate Additions to Lactones and Lactamsa
Initial experiments were designed to determine the optimal
conditions for acetylide addition using δ-valerolactone 4b
as the lactone partner. There is ample precedent for genera-
tion of acetylides derived from propiolate esters and their
addition to various electrophiles,4 and with this in mind,
t-butyl propiolate was chosen as the acetylide precursor.
Deprotonation with n-BuLi or LDA could be effected at low
temperature, and the resulting lithium acetylides or their
transmetallated cerium acetylides underwent addition to the
lactone. However, yields for this process were capricious,
prompting the examination of addition of the lithium
acetylide in the presence of BF3 · OEt2. These conditions have
been applied with success to acetylide additions to esters
and lactones5 and are presumed to operate via an intermediate
lithium alkynyltrifluoroborate salt formed in situ. However,
in contrast to the corresponding potassium organotrifluo-
roborates,6 the lithium salts are not air-stable and have not
been fully characterized, so the exact nature of the reactive
nucleophile remains uncertain. In the event, addition to
valerolactone furnished the adduct 5b as a mixture of open-
chain ynone and the corresponding hemiketal (eq 1). Under
no circumstances was the desired ring-expansion product 3b
observed.
entry
lactone/lactam
X
n
productb
yield (%)c
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
O
O
O
1
2
3
2
1
2
1
2
1
2
5a
5b
5c
5d
5e
5f
5g
5h
5i
63d
82d
83
77
60
NBoc
NTs
NTs
NMs
NMs
NNs
NNs
84
63
57e
37 (39)f
10
4j
5j
37 (40)f
a General procedure: n-BuLi (1.6 M in hexanes; 1.1 equiv) was added
dropwise to a -78 °C solution of t-Bu propiolate in THF (0.2 M). After
stirring for 0.5 h, the reaction temperature was allowed to rise to -50 °C,
and BF3·OEt2 (1.1 equiv) was added dropwise. After 10 min, the reaction
mixture was cooled to -78 °C, and 4 was added neat (entries 1-3, 9-10)
or as a THF solution (entries 4-8). After stirring for 1.5 h, the reaction
was allowed to warm to rt and was quenched with sat. NH4Cl. b Unless
otherwise indicated, product 5 was isolated exclusively as the open-chain
ynone. c All reported yields are for isolated homogeneous product after
chromatographic purification. d Adducts 5a (4:1) and 5b (1.3:1) were isolated
as inseparable mixtures of open-chain and hemiketal forms. e Adduct 5h
was accompanied by 25% of enyne 6h. f Recovered starting material (%).
to good yields of adducts 5 were obtained. With the exception
of five- and six-membered lactones 4a,b, the products were
isolated as the open-chain ynones. The six-membered N-
methanesulfonyllactam 4h furnished a significant quantity
of elimination product 6h along with the desired ynone 5h.
Addition to N-nosyllactams 4i,j did not proceed to comple-
tion even with extended stirring in the presence of several
equivalents of propiolate salt, suggesting competing eno-
lization of the starting lactams.
With the propiolate adducts in hand, conditions for
cyclization to cyclic ethers or amides 3 could be explored.
Inital experiments utilized adduct 5b. Anionic conditions
analogous to those occurring in situ during Schreiber’s two-
carbon ring expansion3 failed to furnish the desired product.
In contrast, treatment with excess pyridine or DMAP at rt
could effect clean conversion of 5b to 3b (Scheme 2),
although the reaction was capricious. Optimally reproducible
conditions employed 1.5 equiv of pyridinium acetate, provid-
ing oxepane 3b in 78% yield. Other pyridinium salts (e.g.,
pyr·HCl or pyr·TsOH) were also more effective than pyridine
alone, presumably due to enhanced rates of proton transfer.7
This transformation is believed to occur via nucleophilic
activation of the ynone to give allenol 7b, which can then
undergo intramolecular Michael addition and expulsion of
With no evidence for spontaneous formation of 3, it
became apparent that a separate step would be required to
effect this conversion. However, the generality of the
(3) For an alternative two-carbon intercalation process involving the
addition of simple acetylides to lactones or lactams followed by endocy-
clization, see: (a) Schreiber, S. L.; Kelly, S. E. Tetrahedron Lett. 1984, 25,
1757–1760. (b) Schreiber, S. L.; Kelly, S. E.; Porco, J. A., Jr.; Sammakia,
T.; Suh, E. M. J. Am. Chem. Soc. 1988, 110, 6210–6218. (c) Suzuki, K.;
Ohkuma, T.; Tsuchihashi, G. J. Org. Chem. 1987, 52, 2929–2930.
(4) (a) Vedejs, E.; Dax, S. L. Tetrahedron Lett. 1989, 30, 2627–2630.
(b) Comins, D. L.; Huang, S.; McArdle, C. L.; Ingalls, C. L. Org. Lett.
2001, 3, 469–471. (c) Trost, B. M.; Crawley, M. L. Chem.-Eur. J. 2004,
10, 2237–2252.
(5) (a) Yamaguchi, M.; Shibato, K.; Fujiwara, S.; Hirao, L. Synthesis
1986, 421–422. (b) Krafft, M. E.; Bon˜aga, L. V. R.; Felts, A. S.; Hirosawa,
C.; Kerrigan, S. J. Org. Chem. 2003, 68, 6039–6042. (c) Doubsky, J.;
Streinz, L.; Leseticky, L.; Koutek, B. Synlett 2003, 7, 937–942. (d) Doubsky,
J.; Streinz, L.; Saman, D.; Zednik, J.; Koutek, B. Org. Lett. 2004, 6, 4909–
4911.
(6) Reviews: (a) Molander, G. A.; Rigueroa, R. Aldrichimica Acta 2005,
38, 49–56. (b) Stefani, H. A.; Cella, R.; Vieira, A. S. Tetrahedron 2007,
63, 3623–3658.
3986
Org. Lett., Vol. 10, No. 18, 2008

Scheme 2
Table 2. Cyclization of Propiolate Adducts 5a
yield
substrate
X
n
conditions
products
ratio (%)b
5a
5b
5c
5d
5e
5f
5g
5h
5i
O
O
O
NBoc
NTs
1
2
3
2
1
2
1
2
1
2
Py · AcOH 3a (E only)
Py · AcOH 3b (E only)
-
-
-
-
1.6:1
1:1.6
82
78
-
28
58
74
60
77
42
55
Py · AcOH
-
Py · AcOH 9d
Py · AcOH 3e (Z + E)
pyridine. An analogous mechanism has been proposed in the
Bu3P-mediated reaction of arylpropiolate esters with bifunc-
tional sulfur nucleophiles.8 Notably, the alternative eight-
membered product 8b was not isolated,9 consistent with
initial attack by pyridine ꢀ to the more electrophilic keto
group rather than the ester. Although this mechanism implies
a catalytic role for pyridine, stoichiometric quantities were
employed to ensure complete reaction within 2.5 h.
NTs
Py
3f (Z + E)
NMs
NMs
NNs
NNs
Py · AcOH 3g (Z + E)/8g 23:6:1
Py 3h (Z + E)/8h 2:5:1
Py · AcOH 3i (Z + E)
Py 3j (Z + E)
1:1.3
1:1.8
5j
a General procedure: Pyridinium acetate (1.5 equiv) or pyridine (1.5
equiv) was added in one portion to a solution of the substrate in CH2Cl2
(0.1 M). The reaction mixture was allowed to stir at room temperature and
monitored for the disappearance of starting material by TLC analysis (1-2.5
h). The reaction was then quenched with 1 N HCl. b Yields given are for
isolated homogeneous product after chromatographic purification.
Cyclization was then attempted using the other propiolate
adducts (Table 2). Butyrolactone adduct 5a underwent clean
conversion to pyranone 3a; however, caprolactone adduct
5c failed to produce the desired oxocane under a wide variety
of conditions. Thus, it appears that this methodology may
not be applicable to eight-membered rings. All of the
N-sulfonyllactam adducts underwent cyclization to provide
the corresponding piperidones or azepinones in 42-77%,
although the three seven-membered examples required the
use of pyridine in place of pyridinium acetate due to rapid
decomposition of 5f,h,j under the standard conditions. While
the cyclic ether products 3a and 3b were formed as single
geometrical isomers,10 the azacycles 3e-j were obtained as
E/Z mixtures, typically inseparable. Fortunately, the seven-
membered N-Ts derivative 3f was subject to chromatographic
separation, and the geometry of the E-isomer was confirmed
by X-ray crystallography. Moreover, catalytic hydrogenation
of a mixture of the Z- and E-isomers of 3f furnished a single
reduction product 10f (Scheme 3), indicating that they only
differ in alkene geometry. Geometrical isomers in the
inseparable mixtures isolated in the other cases were assigned
as E or Z based on 1H NMR spectral analogy, with the alkene
proton of the Z-isomers appearing consistently at lower field
Scheme 3
(7) A similar explanation was given for the superiority of the Keck
lactonization conditions (DMAP/DMAP·HCl): (a) Boden, E. P.; Keck, G. E.
J. Org. Chem. 1985, 50, 2394–2395. (b) See also: Spivey, A. C.;
Arseniyadis, S. Angew. Chem., Int. Ed. 2004, 43, 5436–5441.
(8) Gabillet, S.; Lecercle´, D.; Loreau, O.; Carboni, M.; De´zard, S.;
Gomis, J.-M.; Taran, F. Org. Lett. 2007, 9, 3925–3927.
(9) The seven-membered product 3b could not easily be distinguished
from the alternative isomeric structure 8b by standard 1D NMR techniques.
However, HMBC experiments clearly indicated a correlation between H-4
and C-2, which would not be observable in 8b (see Scheme 2).
(10) 3a,b were tentatively assigned as the E-isomers based on compari-
son of the 1H NMR chemical shifts of the alkene proton to those of 3fZ
and 3fE as well as related literature compounds. See Supporting Information
for a discussion of these assignments.
Org. Lett., Vol. 10, No. 18, 2008
3987

due to anisotropic deshielding from the adjacent ketone
carbonyl. No evidence was seen for interconversion of 3fZ
and 3fE under the standard cyclization conditions. Notably,
divergent reactivity was observed when the inseparable
mixture of 3eZ and 3eE was subjected to prolonged reaction
under the same conditions. After stirring for 3 days, pure
3eZ was isolated, along with comparable amounts of lactone
hemiacetal 11 and minor quantities of spirocyclic dimer 12.
Since the geometric isomers are presumed not to equilibrate
under reactions conditions, 11 could arise only from the
E-isomer. Dimer 12, an apparent Diels-Alder adduct, was
obtained as a single diastereomer. While the trans relation-
ship at the two ester-substituted centers was assigned with
some confidence,11 it was not possible to determine the
relative configuration of the spiro center.
Scheme 4
N-Mesyl substrates 5g,h were notable for being the only
examples in which the corresponding endocyclization prod-
ucts (8g,h) were isolated,12 albeit in very minor amounts. It
is unclear why this alternative regiochemistry was seen only
in these two cases. The divergent behavior of N-Boc
derivative 5d is also notable. In this case, none of the
expected azepinone was isolated, perhaps due to diminished
acidity of the carbamate nitrogen. The only isolable product
was pyridine adduct 9d, which is presumed to form via
tautomerization of the intermediate allenol 7d, followed by
electrocyclization and proton transfer (Scheme 4).13 Isolation
of 9d offers compelling support for the involvement of
pyridine as a nucleophilic catalyst in these reactions.
In summary, a two-step process resulting in a net one-
carbon ring expansion of lactones and lactams has been
developed, providing convenient access to six- and seven-
membered cyclic ethers and amines. This method uses t-butyl
propiolate as a 1,1-dipole equivalent, resulting in the
intercalation of the ꢀ-carbon of the propiolate between the
carbonyl and the adjacent heteroatom, with installation of
an ester-substituted alkylidene unit. The second step appears
to involve nucleophilic catalysis, as shown by the unexpected
incorporation of pyridine in one case. Further applications
of this interesting chemistry will be described in due course.
Acknowledgment. We thank NSERC for support of this
work. T.N.G. and C.L.B. gratefully thank NSERC for PGSD
awards, and T.N.G. thanks the University of Alberta for the
generous award of a Queen Elizabeth II Scholarship. We
also wish to acknowledge Thanh Luu (U. of Alberta) for
early experiments that led to this study and Dr. Bob
McDonald (X-ray Crystallography Lab, Department of
Chemistry, University of Alberta) for the crystal structure
determination of compound 3fE.
(11) A vicinal coupling of 9.5 Hz between the adjacent ester-substituted
methines was observed, consistent with a trans relationship. See Supporting
Information for additional discussion of structural assignments.
(12) The connectivity of endocyclization products 8g,h was established
via HMBC correlations between the alkene proton (H-3) and C-5.
(13) For earlier examples of similar pyridine-ynone adducts, see: (a)
Crabtree, A.; Jackman, L. M.; Johnson, A. W. J. Chem. Soc. 1962, 4417–
4420. (b) Acheson, R. M.; Gagan, J. M. F.; Harrison, D. R. J. Chem. Soc.
1968, 362–378. (c) Acheson, R. M.; Wallis, J. D.; Woollard, J. J. Chem.
Soc., Perkin Trans. I 1979, 584–590.
Supporting Information Available: Experimental pro-
cedures, physical data, and NMR spectra for all compounds
and synthetic intermediates as well as CIF data for 3fE. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL8014682
3988
Org. Lett., Vol. 10, No. 18, 2008