Ring Expansion, Ring Contraction, and Annulation Reactions of Allylic Phosphonates under Oxidative Cleavage Conditions

Article abstract of DOI:10.1021/acs.orglett.8b00791

Oxidative cleavage of cycloalkenylalkylphosphonates 1 followed by treatment with base gives rise to homologated cycloalkenones 2 in good to excellent yields. Subjecting cycloalk-2-enylphosphonates 3 to identical conditions provides the one-carbon ring-contracted compounds 4 in excellent yields. Oxidative cleavage of γ,δ-unsaturated ketophosphonates 6 followed by treatment with base affords 2-cyclopenten-1-ones 7 in good overall yields. This method may offer a practical alternative to existing methods for effecting one-carbon ring expansion, ring contraction, and annulation reactions.

Full text of DOI:10.1021/acs.orglett.8b00791

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ring Expansion, Ring Contraction, and Annulation Reactions of
Allylic Phosphonates under Oxidative Cleavage Conditions
Dupre Orr, Nikolas Yousefi, and Thomas G. Minehan*
Department of Chemistry and Biochemistry, California State University, 18111 Nordhoff Street, Northridge, California 91330-8262,
United States
S
* Supporting Information
ABSTRACT: Oxidative cleavage of cycloalkenylalkylphosphonates 1 followed by treatment with base gives rise to homologated
cycloalkenones 2 in good to excellent yields. Subjecting cycloalk-2-enylphosphonates 3 to identical conditions provides the one-
carbon ring-contracted compounds 4 in excellent yields. Oxidative cleavage of γ,δ-unsaturated ketophosphonates 6 followed by
treatment with base affords 2-cyclopenten-1-ones 7 in good overall yields. This method may offer a practical alternative to
existing methods for effecting one-carbon ring expansion, ring contraction, and annulation reactions.
ing-expansion reactions are a useful synthetic means to
Raccess medium-ring carbocycles, which form the core of
numerous natural products.1 Two of the most popular methods
for accomplishing this transformation include the Saegusa
reaction,2 involving the thermal or FeCl3-mediated cleavage of
silyloxy cyclopropanes, and the addition of diazomethane or its
derivatives to cycloalkanones in the presence of Lewis acids
(Scheme 1).1b Commencing from cyclic ketones, the Saegusa
protocol involves multiple steps (silyl enol ether formation,
cyclopropanation, oxidative cleavage, and elimination of
chloride ion),4 and many procedures combine these processes
into just three separate tranformations.5 Nonetheless, reactivity
issues encountered for any one of the four steps may jeopardize
overall yields for the homologation process. The diazomethane
procedure typically suffers from low regioselectivity, though
appropriate substitution patterns in the starting ketone
substrate may lead to high yields of a single regioisomer.3
Radical-based ring-expansion reactions,1d,e proceeding via
alkoxy-radical fragmentation of strained three-and four-
membered ring intermediates, typically provide low yields of
homologated products and sometimes require the use of toxic
organostannane reagents. Clearly, there is a need for alternative
procedures to achieve this important transformation.
In attempting to access medium-ring enones as intermediates
for natural product synthesis, it became apparent to us that
intramolecular Horner-Wadsworth-Emmons (HWE) olefina-
tion reactions6 were particularly suitable for the preparation of
diversely substituted cycloheptenones from aldehyde-tethered
β-ketophosphonates.7 However, the synthesis of the requisite
β-ketophosphonates from suitable acyclic starting materials
required multiple steps and the preparation and isolation of an
often unstable aldehyde intermediate. To circumvent these
problems, we surmised that oxidative cleavage of a stable cyclic
allylic phosphonate precursor would directly give rise to the β-
ketophosphonate intermediate for the intramolecular olefina-
tion reaction; treatment with base would then provide the
expanded cyclic enone product. However, intramolecular base-
mediated condensation of β-ketophosphonates and aldehydes
or ketones may form two different products (Scheme 1): cyclic
enone 2 (arising from an intramolecular Horner−Wadsworth−
Emmons reaction)6 or cyclic β-ketophosphonate 2′ (arising
from an intramolecular aldol condensation).8 We believed that
a judicious choice of base could control which homologated
product predominated, with stronger bases favoring formation
of enones of the type 2. A benefit of this procedure over using
acyclic starting materials is that investigators could take
advantage of the numerous methods available for control of
stereochemistry in cyclic systems to elaborate their substrates.9
The success of this method would depend on the ease of
synthesis of allylic phosphonates.
A variety of efficient methods are available for the
preparation of cyclic allylic phosphonates. An addition of the
anion of dimethyl methylphosphonate to cyclic enones,
followed by oxidative transposition (PCC, CH2Cl2) gives rise
to enone-β-phosphonates in high overall yields (a, Scheme
1);10 the same products can be accessed directly by addition of
lithiated dimethyl methylphosphonate to 3-methoxycycloalken-
1-ones, followed by a reaction quench under acidic
conditions.11 Reduction of the ketone and protection of the
alcohol or deoxygenation of the allylic alcohol12 then provides
allylic phosphonates suitable for one-carbon ring expansion.
Alternatively, cyclic ketones can be condensed with in situ
prepared β-diphosphonates to give vinyl phosphonates, which
undergo base-mediated isomerization to allylic phosphonates in
DMSO (b, Scheme 1).13 Finally, halogenation of cyclic
alkenes14 or allylic alcohols15 gives rise to halide substrates
Received: March 11, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00791
Org. Lett. XXXX, XXX, XXX−XXX

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Scheme 1. Synthesis and Potential Utility of Allylic
Phosphonates
Table 1. Scope of the Ring-Expansion Reactions of 1
Scheme 2. Ring Expansion of Cyclic Allylic Phosphonate 1a
under Oxidative Cleavage Conditions
that undergo facile Michaelis-Arbuzov reactions16 with
phosphites to produce allylic phosphonates (c, Scheme 1).
With adequate methods available for the preparation of
diverse allylic phosphonates, we first investigated oxidative
cleavage and condensation conditions for the 6 → 7 ring
expansion reaction (Scheme 2). Bubbling ozone through a
solution of silyl ether 1a in 1:1 DCM/MeOH at −78 °C for 15
min, followed by the addition of excess DMS and warming to
room temperature resulted in complete consumption of the
starting material by TLC analysis. Concentration of the
reaction mixture to remove DMS and methanol, followed by
addition of 1.5 equiv of DBU in anhydrous CH2Cl2 (0.2 M, 18
h, rt) resulted in clean conversion to the homologated enone 2a
in 91% yield after purification. No evidence for formation of
a
b
Isolated yields after column chromatography. Yield in parentheses
represents that obtained from oxidative cleavage of 1 with OsO4,
NaIO4, and 2,6-lutidine (3:1 dioxane/water, rt, 24 h) followed by
treatment with Na2SO4, filtration/concentration in vacuo, and dilution
with a solution of 1.5 equiv of DBU in DCM (0.2 M). Starting
material and product obtained as a 3:1 mixture of syn/anti
c
1
d
aldol product 2a’ was seen by H NMR of the crude reaction
diastereomers. Cyclization performed with NaH (1.5 equiv) in
mixture. Similarly, it was found that after concentration of the
THF (0.2 M, rt, 12 h).
B
DOI: 10.1021/acs.orglett.8b00791
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Scheme 3. Ring Contractions of Allylic Phosphonates 3
Table 2. Cyclopentannulations with Phosphonates 8 and 10
Scheme 4. Synthesis and Cyclopentannulation Reactions of
Reagents 8 and 10
ozonolysis reaction mixture, treatment with NaH (1.5 equiv) in
dry THF (0.2 M, 18 h rt) also gave 2a in 85% yield.
Treatment of 1a instead with 2.5 mol % OsO4 and NaIO4 (3
equiv) in dioxane/H2O (3:1) in the presence of 2,6-lutidine
according to Jin’s protocol17 resulted in complete conversion of
the starting material (within 3−12 h) to multiple more polar
compounds. An addition of anhydrous sodium sulfate to the
reaction mixture, concentration in vacuo, and an addition of 1.5
equiv of DBU in DCM (0.2 M) gave rise to 2a, which was
isolated from the reaction mixture in 54% yield. Attempts to
optimize the yields of 2a obtained in this manner by decreasing
reactions times, or using alternate solvents or stoichiometric
oxidants (PhI(OAc)2)18 proved unsuccessful.
a
b
Isolated yields after column chromatography. Starting material
obtained as a 1:1 mixture of diastereomers.
As shown in Table 1, the homologation process was
successful for both 5-membered and 6-membered cyclic allylic
phosphonates (1a−1h, produced from the corresponding 2-
cyclohexen-1-ones and 2-cyclopenten-1-ones via pathway A,
Scheme 1), giving rise to diverse 6- and 7-membered cyclic
enones (2a−h) in good to excellent yields. In entries 1−3, the
ozone/DMS/DBU procedure provided yields superior to those
of the OsO4/NaIO4/DBU protocol. It was found that both
trisubstituted (1a−c,g) and tetrasubstituted (1d−f,h) cyclic
alkenes undergo the homologation process with similar
efficiencies. Furthermore, the α-methyl enone 2b could be
prepared in 69% yield from α-methyl phosphonate 1b, and β-
Figure 1. Some guaiane sesquiterpene natural products possessing
fused 7−5 ring systems potentially accessible by this methodology.
methyl enones 2d, 2e, 2f, and 2h were available in 62−85%
yields from phosphonates 1d, 1e, 1f, and 1h, respectively.
C
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It was apparent that this process could also lead to ring-
contraction reactions19 if the allylic carbon atom of the
phosphonate was incorporated in a ring (Scheme 3). This
possiblility was investigated with cyclic phosphonates 3a and
3b, readily avalable from 1-bromo-2-cyclohexene and 1-bromo-
2-cycloheptene by a Michaelis−Arbuzov reaction (pathway C,
Scheme 1).16 Ozonolysis of 3a, followed by concentration in
vacuo and treatment with 1.5 equiv of NaH in THF, produced
the corresponding ring-contracted enal; due to extreme
volatility, this compound was not isolated but combined
directly with the sodium salt of triethylphosphonoacetate to
provide diene 4a in 86% overall yield. A similar procedure
applied to cycloheptenyl phosphonate 3b gave diene 4b in 91%
yield.
We further realized that this protocol might be of utility in
the formation of cyclopentenones from ketones via an
annulation-type process20 employing a suitable allylic phos-
phonate alkylating agent (Scheme 4). Thus, commercially
available 3-chloro-2-(chloromethyl)-1-propene was combined
with triethyl phosphite (120 °C, 12 h) to provide the
corresponding phosphonate in quantitative yield; treatment of
the crude allyl chloride with NaI in acetone for 12 h gave iodide
8 in 82% overall yield. The α-methyl phosphonate 10 could
also be prepared in 50% overall yield by methylation of silyl
ether 9 (LDA, THF, −78 °C; CH3I)21 followed by silyl ether
hydrolysis22 and iodination. Exposure of the lithium enolate of
cyclohexanone to 8 or 10 (THF, −78 °C, 30 min, then rt, 30
min) gave rise to the alkylated products 6a and 6e cleanly in 60
and 78% yields, respectively. Ozonolysis of 6a, followed by
treatment of the crude reaction mixture after concentration in
vacuo with 1.5 equiv of NaH in THF at 65 °C for 1 h provided
cyclopentenone 7a in 62% yield; a similar treatment of 6e
produced 7e in 72% yield.
The two-step annulation process was explored with both
cyclic (6a,c−f, Table 2) and acyclic (6b) ketones and was
found to provide the corresponding 2-cyclopenten-1ones 7a−f
in good overall yields. Notably, this method also provides
efficient access to 6−5 (7e) and 7−5 (7f) fused 2-methyl-2-
cyclopenten-1-ones.20b
In summary, we have shown that cyclic allylic phosphonates
may serve as precursors of ring-expanded or ring-contracted
compounds via single-flask oxidative cleavage and base-
promoted intramolecular Horner−Wadsworth−Emmons reac-
tions. In addition, alkylation of cyclic and acyclic ketones with
iodides 8 or 10, followed by oxidative cleavage and base
treatment of the intermediate γ,δ-unsaturated ketophospho-
nates, furnishes 2-cyclopenten-1-ones in good overall yields by
an annulation-type process. Application of these procedures to
the total synthesis of guaiane sesquiterpene natural products
(see Figure 1) is currently in progress and will be reported in
due course.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: thomas.minehan@csun.edu.
ORCID
Thomas G. Minehan: 0000-0002-7791-0091
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the National Science Foundation (CHE-
1508070) and the donors of the American Chemical Society
Petroleum Research Fund (53693-URI) for their generous
support of this research.
DEDICATION
■
Dedicated to Professor Yoshito Kishi (Harvard University) on
the occasion of his 80th birthday.
REFERENCES
■
(1) For reviews, see: (a) Donald, J. R.; Unsworth, W. P. Chem. - Eur.
J. 2017, 23, 8780. (b) Candeias, N. R.; Paterna, R.; Gois, P. M. P.
Chem. Rev. 2016, 116, 2937. (c) Roxburgh, C. J. Tetrahedron 1993, 49,
10749. (d) Dowd, P.; Zhang, W. Chem. Rev. 1993, 93, 2091.
(e) Molander, G. A. Acc. Chem. Res. 1998, 31, 603. (f) Kantorowski, E.
J.; Kurth, M. J. Tetrahedron 2000, 56, 4317.
(2) Ito, Y.; Fujii, S.; Nakatsuka, M.; Kawamoto, F.; Saegusa, T. Org.
Synth. 1980, 59, 113.
(3) Kreuzer, T.; Metz, P. Eur. J. Org. Chem. 2008, 2008, 572.
(b) Uyehara, T.; Kabasawa, Y.; Kato, T.; Furuta, T. Tetrahedron Lett.
1985, 26, 2343.
(4) Ito, Y.; Fujii, S.; Saegusa, T. J. Org. Chem. 1976, 41, 2073.
(5) (a) Paquette, L. A.; Ham, W. H.; Dime, D. S. Tetrahedron Lett.
1985, 26, 4983. (b) Blake, A. J.; Highton, A. J.; Majid, T. N.; Simpkins,
N. S. Org. Lett. 1999, 1, 1787.
(6) (a) Ando, K.; Sato, K. Tetrahedron Lett. 2011, 52, 1284.
(b) Ando, K.; Narumiya, K.; Takada, H.; Teruya, T. Org. Lett. 2010,
12, 1460. (c) Krawczyk, H.; Albrecht, L. Synthesis 2008, 2008, 3951.
(d) Nangia, A.; Prasuna, G.; Bheema, R. P. Tetrahedron Lett. 1994, 35,
3755. (e) Saya, J. M.; Vos, K.; Kleinnijenhuis, R. A.; van Maarseveen, J.
H.; Ingemann, S.; Hiemstra, H. Org. Lett. 2015, 17, 3892. (f) Hubert, J.
G.; Furkert, D. P.; Brimble, M. A. J. Org. Chem. 2015, 80, 2231.
(g) Donslund, B. S.; Halskov, K. S.; Leth, L. A.; Paz, B. M.; Jorgensen,
K. A. Chem. Commun. 2014, 50, 13676. (h) Pirrung, M. C.; Biswas, G.;
Ibarra-Rivera, T. R. Org. Lett. 2010, 12, 2402. (i) Chen, C.-A.; Fang, J.-
M. Org. Biomol. Chem. 2013, 11, 7687.
(7) Pan, S.; Gao, B.; Hu, J.; Xuan, J.; Xie, H.; Ding, H. Chem. - Eur. J.
2016, 22, 959.
(8) Wada, E.; Funakoshi, J.; Kanemasa, S. Bull. Chem. Soc. Jpn. 1992,
65, 2456.
(9) Stereochemical Control in Cyclic and Polycyclic Systems. In
Organic Chemistry in Action: the Design of Organic Synthesis; Serratosa,
F., Ed.; Elsevier Science: New York, 1990; Chapter 8.
(10) (a) Mphahlele, M. J. Phosphorus, Sulfur Silicon Relat. Elem. 1996,
118, 145. (b) Hudlicky, J. R.; Werner, L.; Semak, V.; Simionescu, R.;
Hudlicky, T. Can. J. Chem. 2011, 89, 535.
(11) Mphahlele, M. J.; Modro, T. A. J. Org. Chem. 1995, 60, 8236.
(12) Wustrow, D. J.; Smith, W. J.; Wise, L. D. Tetrahedron Lett. 1994,
35, 61.
(13) Kiddle, J. J.; Babler, J. H. J. Org. Chem. 1993, 58, 3572.
(14) Marvel, C. S.; Hartzell, G. E. J. Am. Chem. Soc. 1959, 81, 448.
(15) Hazelden, I. R.; Ma, X.; Langer, T.; Bower, J. F. Angew. Chem.,
Int. Ed. 2016, 55, 11198.
ASSOCIATED CONTENT
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S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00791.
Experimental procedures, spectroscopic and analytical
data, and NMR spectra of new compounds in Tables 1
and 2 and Schemes 3 and 4 (PDF)
(16) (a) Michaelis, A.; Kaehne, R. Ber. Dtsch. Chem. Ges. 1898, 31,
1048. (b) Arbuzov, A. E. J. Russ. Phys. Chem. Soc. 1906, 38, 687.
D
DOI: 10.1021/acs.orglett.8b00791
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(17) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6,
3217.
(18) Nicolaou, K. C.; Adsool, V. A.; Hale, C. R. H. Org. Lett. 2010,
12, 1552.
(19) (a) Silva, L. F. Synlett 2014, 25, 466. (b) Song, Z.-L.; Fan, C.-A.;
Tu, Y.-Q. Chem. Rev. 2011, 111, 7523. (c) Silva, L. F. Tetrahedron
2002, 58, 9137. (d) Silva, L. F. Molecules 2006, 11, 421.
(20) (a) Welch, S. C.; Assercq, J. M.; Loh, J. P.; Glase, S. A. J. Org.
Chem. 1987, 52, 1440. (b) Piers, E.; Abeysekera, B. Can. J. Chem.
1982, 60, 1114. (c) Altenbach, H. J. Angew. Chem. 1979, 91, 1005.
(d) Corey, E. J.; Ghosh, A. K. Tetrahedron Lett. 1987, 28, 175.
(21) Nagase, T.; Kawashima, T.; Inamoto, N. Chem. Lett. 1984, 13,
1997.
(22) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190.
E
DOI: 10.1021/acs.orglett.8b00791
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