A Bronsted acid mediated cascade enone synthesis from aldehydes containing a tethered propargylsilane

Article abstract of DOI:10.1021/jo702351s

(Chemical Equation Presented) MeSO₃H effects the intramolecular allenylation of a series of aldehydes 1 to provide allenyl alcohol product 3 as a single diastereoisomer. Cyclization proceeds rapidly at -78°C. However, when the reaction is perfo

Full text of DOI:10.1021/jo702351s

provide a powerful strategy for intramolecular nucleophile
delivery. For example, we recently used a temporary silicon
connection to tether a propargylsilane nucleophile to a range
of â-hydroxy aldehyde electrophiles.2d Treatment of the resulting
aldehyde 1 with TMSOTf in the presence of the Brønsted acid
scavenger tri-tert-butylpyrimidine (TTBP)9 led to the formation
of a single allenylsilane diastereoisomer 2 in good to very good
yield (Scheme 1).2d
A Brønsted Acid Mediated Cascade Enone
Synthesis from Aldehydes Containing a Tethered
Propargylsilane
Rui Ramalho,† Peter J. Jervis,† Benson M. Kariuki,†
Alexander C. Humphries,‡ and Liam R. Cox*,†
School of Chemistry, The UniVersity of Birmingham, Edgbaston,
Birmingham B15 2TT, U.K., and The Neuroscience Research
Centre, Merck, Sharp and Dohme, Terlings Park,
Harlow, Essex CM20 2QR, U.K.
SCHEME 1. Stereoselective Intramolecular Allenylation
l.r.cox@bham.ac.uk
ReceiVed October 31, 2007
While the reaction of silicon nucleophiles, such as allylsilanes,
propargylsilanes and related systems, with aldehydes is most
commonly effected by Lewis acids,10 Brønsted acids provide a
potentially attractive alternative activation source.11 For our
purposes, using a Brønsted acid in place of TMSOTf would
provide an operationally more simple cyclization method and
remove the need to employ expensive acid scavengers. Reaction
would also generate an alcohol, rather than a silyl ether product,
which is primed for further manipulation and potential use as a
directing group for the diasteroselective functionalization of the
proximal allene.12 From a practical viewpoint, a more polar
alcohol product would also facilitate product purification through
its more straightforward separation from the apolar silyl
byproducts and pyrimidine acid scavenger, which we employed
in our Lewis acid mediated intramolecular allenylation studies.
For these reasons, we were keen to investigate whether Brønsted
acids could also mediate our intramolecular allenylation reaction.
To this end, aldehyde 1a, containing a propargylsilane
tethered through a â-silyl ether connection, was prepared using
our established protocol.2d Although silicon nucleophiles are
MeSO3H effects the intramolecular allenylation of a series
of aldehydes 1 to provide allenyl alcohol product 3 as a single
diastereoisomer. Cyclization proceeds rapidly at -78 °C.
However, when the reaction is performed at room temper-
ature, aldehyde 1 provides enone product 7 instead. A
mechanism for the formation of this product is proposed in
which the initially formed allenyl alcohol 3 undergoes
dehydration to provide an allyl carbocation, which is trapped
with water, thereby installing the enone.
Forming a tether between two reacting partners allows a
subsequent reaction to proceed in an intramolecular fashion and
benefit from the advantages associated with unimolecular
processes. However, if the tether is then cleaved, the product
obtained is the result of a net intermolecular reaction.1 We2 and
others3-8 have demonstrated that temporary silicon tethers
(4) For applications in intramolecular vinylation: (a) Friestad, G. K.;
Jiang, T.; Mathies, A. K. Org. Lett. 2007, 9, 777-780. (b) Friestad, G. K.;
Massari, S. E. Org. Lett. 2000, 2, 4237-4240. (c) Hioki, H.; Izawa, T.;
Yoshizuka, M.; Kunitake, R.; Itoˆ, S. Tetrahedron Lett. 1995, 36, 2289-
2292.
(5) For applications in intramolecular arylation: (a) Rousseau, C.; Martin,
O. R. Org. Lett. 2003, 5, 3763-3766. (b) Huang, P.-Q.; Liu, L.-X.; Wei,
B.-G.; Ruan, Y.-P. Org. Lett. 2003, 5, 1927-1929. (c) Tomooka, K.;
Nakazaki, A.; Nakai, T. J. Am. Chem. Soc. 2000, 122, 408-409. See also
ref 4c.
† The University of Birmingham.
‡ Merck, Sharp and Dohme.
(1) For reviews on the use of the temporary connection in synthesis:
(a) Cox, L. R.; Ley, S. V. In Templated Organic Synthesis; Diederich, F.,
Stang, P. J., Eds.; Wiley-VCH: Weinheim, 2000; Chapter 10, pp 275-
375. (b) Bols, M.; Skrydstrup, T. Chem. ReV. 1995, 95, 1253-1277. (c)
Fensterbank, L.; Malacria, M.; Sieburth, S. M. Synthesis 1997, 813-854.
(d) Gauthier, D. R., Jr.; Zandi, K. S.; Shea, K. J. Tetrahedron 1998, 54,
2289-2338.
(2) (a) Beignet, J.; Cox, L. R. Org. Lett. 2003, 5, 4231-4234. (b)
Simpkins, S. M. E.; Kariuki, B. M.; Arico´, C. S.; Cox, L. R. Org. Lett.
2003, 5, 3971-3974. (c) Beignet, J.; Tiernan, J.; Woo, C. H.; Kariuki, B.
M.; Cox, L. R. J. Org. Chem. 2004, 69, 6341-6356. (d) Ramalho, R.;
Beignet, J.; Humphries, A. C.; Cox, L. R. Synthesis 2005, 3389-3397.
(3) For applications in intramolecular allylation: (a) Robertson, J.; Hall,
M. J.; Green, S. P. Org. Biomol. Chem. 2003, 1, 3635-3638. (b) Wipf, P.;
Aslan, D. C. J. Org. Chem. 2001, 66, 337-343. (c) Pilli, R. A.; Riatto, V.
B. Tetrahedron: Asymmetry 2000, 11, 3675-3686. (d) Fujita, K.; Inoue,
A.; Shinokubo, H.; Oshima, K. Org. Lett. 1999, 1, 917-919. (e) Frost, L.
M.; Smith, J. D.; Berrisford, D. J. Tetrahedron Lett. 1999, 40, 2183-2186.
(f) Hioki, H.; Okuda, M.; Miyagi, W.; Itoˆ, S. Tetrahedron Lett. 1993, 34,
6131-6134. (g) Reetz, M. T.; Jung, A.; Bolm, C. Tetrahedron 1988, 44,
3889-3898. (h) Martin, O. R.; Rao, S. P.; Kurz, K. G.; El-Shenawy, H. A.
J. Am. Chem. Soc. 1988, 110, 8698-8700.
(6) For applications in intramolecular hydride delivery: Anwar, S.; Davis,
A. P. Tetrahedron 1988, 44, 3761-3770.
(7) For applications in intramolecular aglycon delivery: (a) Stork, G.;
La Clair, J. J. J. Am. Chem. Soc. 1996, 118, 247-248. (b) Stork, G.; Kim,
G. J. Am. Chem. Soc. 1992, 114, 1087-1088. (c) Bols, M.; Hansen, H. C.
Chem. Lett. 1994, 1049-1052. (d) Bols, M. Acta Chem. Scand. 1993, 47,
829-834. (e) Bols, M. Tetrahedron 1993, 49, 10049-10060.
(8) See also: (a) Iwamoto, M.; Miyano, M.; Utsugi, M.; Kawada, H.;
Nakada, M. Tetrahedron Lett. 2004, 45, 8647-8651. (b) Robertson, J.; Hall,
M. J.; Stafford, P. M.; Green, S. P. Org. Biomol. Chem. 2003, 1, 3758-
3767. (c) O’Malley, S. J.; Leighton, J. L. Angew. Chem., Int. Ed. 2001, 40,
2915-2917.
(9) Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001, 323-326.
(10) (a) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207-2293. (b)
Fleming, I.; Dunogue`s, J.; Smithers, R. Org. React. (N.Y.) 1989, 37, 57-
575.
(11) For a recent example from our own work: Jervis, P. J.; Cox, L. R.
Org. Lett. 2006, 8, 4649-4652.
(12) Marshall, J. A.; Tang, Y. J. Org. Chem. 1994, 59, 1457-1464.
10.1021/jo702351s CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/16/2008
J. Org. Chem. 2008, 73, 1631-1634
1631

SCHEME 2. Brønsted Acid Mediated Intramolecular
Allenylation
SCHEME 3. Of Brønsted Acids Screened, MeSO3H Was
Most Effective for Accessing Desired Allenyl Oxasilacycle 3a
FIGURE 1. ORTEP plot of the 4-nitrobenzoate derivative of 3a
confirming the relative stereochemistry in the cyclization product.
Atomic displacement parameters at 293 K are drawn at the 30%
probability level.
TABLE 1. Brønsted Acid Mediated Intramolecular Allenylation
Provides an Alternative Cyclization Method to Our Lewis Acid
Mediated Approach
% yield of analogous
TMS ether 2
SCHEME 4. Relative Stereochemistry in Allenyl Alcohol
Cyclization Product 3a Confirmed by Derivatization
obtained using
isolated
yield 3 (%)
TMSOTf activation
entry aldehyde
R
(where available)2d
1
2
3
4
5
1a
1b
1c
1d
1e
iBu
66
57
60
42
61
83
73
85
(E)-styryl
TIPS-alkynyl
Ph-alkynyl
Ph
susceptible to protodesilylation in the presence of Brønsted
acids,13 in related work we recently successfully carried out
intramolecular allylation reactions involving allylsilanes using
methanesulfonic acid without such competing processes being
a problem.11 We were therefore pleased to observe that treating
a solution of 1a in CH2Cl2 with this same Brønsted acid also
led to rapid consumption of starting material at -78 °C and
the formation of a single oxasilacyclic allenyl alcohol, 3a, in
66% yield (Scheme 2). Performing the reaction in the more polar
solvent MeCN led to a complex mixture of products.
We examined a small range of other Brønsted acid activators
in this reaction, although none offered any improvement:
siloxane 4 was the only isolable product when the reaction was
carried out in the presence of the mineral acids hydrochloric
acid and sulfuric acid. This product results from preferential
hydrolysis of the silyl ether connection in the starting material.
When trifluoroacetic acid was employed, the desired allenyl
oxasilacycle 3a was again obtained, albeit in reduced yield
(26%), along with small amounts of siloxane 4 and propargyl
silane 5 (25%). The formation of the latter compound can again
be rationalized by premature cleavage of the silyl ether
connection (Scheme 3).14
80
A small selection of aldehydes, each containing a propar-
gylsilane tethered through a â-silyl ether connection, were
reacted under our optimized conditions. The results suggest this
method is fairly general and provides a useful alternative to
our Lewis acid mediated intramolecular allenylation protocol.
In all cases, the cyclization product is obtained as a single
diastereoisomer; however, in comparison to the yields we
generally obtain with our TMSOTf-mediated cyclizations, the
yields of the allenyl alcohol products 3 are always slightly
depressed owing to the formation of a second, less polar product
(vide infra) (Table 1).
The best yields of allenyl alcohol 3 were obtained by carrying
out the reaction with equimolar quantities of MeSO3H in CH2-
Cl2 at -78 °C. When the temperature of the reaction mixture
was allowed to increase, the yield of allenyl alcohol 3 was
further reduced owing to the formation of more of the second
product, which was identified as the enone 7 in which the
conjugated alkene can also be considered as a vinylsilane owing
to the product’s retention of the silyl ether connection. Careful
monitoring of the reaction by TLC revealed allenyl alcohol 3
to be an intermediate en route to this novel cyclic enone. We
now focused on optimizing the reaction conditions for accessing
this interesting product. The best yields of enone were obtained
by adding 1 equiv of MeSO3H to a solution of the starting
aldehyde 1 in CH2Cl2 in the presence of 4 equiv of water at
ambient temperature and, after 2-3 h, adding a further 1 equiv
of the Brønsted acid to drive the reaction to completion. Using
this procedure, enone 7a was isolated in 78% yield. To probe
the scope of this cascade process, a series of aldehydes 1 was
exposed to our optimized reaction conditions. In most cases
(entries 1, 4-6), the enone products were isolated in very good
The stereochemistry in the allenyl alcohol product 3a was
initially assigned by analogy with similar silyl ether products
obtained from our previous studies employing TMSOTf as the
activator;2d however, confirmation of our stereochemical as-
signment came from an X-ray structure of the 4-nitrobenzoate
derivative 6, which was prepared from alcohol 3a under standard
conditions (Scheme 4, Figure 1).
(13) (a) Chan, T. H.; Fleming, I. Synthesis 1979, 761-786 and references
therein. (b) Fleming, I.; Terrett, N. K. Tetrahedron Lett. 1983, 24, 4153-
4156.
(14) It is not clear why this product was not observed when MeSO3H
was employed as the activator.
1632 J. Org. Chem., Vol. 73, No. 4, 2008

TABLE 2. Enone Synthesis
SCHEME 6. Alternative Mechanism for Formation of
Enone 7, Similar to That Proposed by Wang and
Co-workers
entry
aldehyde
R
method
isolated yield 7 (%)
1
2
3
4
5
6
7
1a
1b
1d
1e
1f
iBu
Aa
Bb
Bb
Aa
Aa
Aa
Cc
78
(E)-styryl
Ph-alkynyl
Ph
42d
29d
73
nBu
78
1g
1h
BnOCH2CH2
Me
71
46d
a 2 equiv of MeSO3H, 4 equiv of H2O, CH2Cl2, rt. b (a) 1 equiv of
MeSO3H, CH2Cl2, -78 °C; (b) 2 equiv of MeSO3H, 4 equiv of H2O,
CH2Cl2, rt. c (a) 1 equiv of Me3SiOTf, TTBP, CH2Cl2, -78 °C; (b) 2 equiv
of MeSO3H, 4 equiv of H2O, CH2Cl2, rt. d Isolated yield of enone over
two steps.
SCHEME 7. Reaction Time Affects Product Distribution
When Aldehyde 15 Is Exposed to MeSO3Ha
SCHEME 5. Possible Mechanism for Formation of Enone 7
yield. In other cases (entries 2, 3, 7), improved yields of enone
product were obtained by performing the transformation in two
stages, i.e., first carrying out the intramolecular allenylation
under Brønsted acid or Lewis acid conditions and then treating
the product from this reaction with MeSO3H to effect enone
formation. The results are summarized in Table 2.
a Reagents and conditions: (a) 1 equiv of MeSO3H, CHCl3, -60 °C, 5
min, 16 (55%), 17 (30%), 18 (trace); 15 min, 16 (trace), 17 (81%), 18
(10%); 30 min, 16 (trace), 17 (trace), 18 (88%); (b) 1 equiv of MeSO3H,
CHCl3, -60 °C, 10 min, 90%; (c) 1 equiv of MeSO3H, CHCl3, -60 °C,
15 min, 91%.
The conversion of aldehyde 1 into enone 7 represents an
interesting cascade process involving a number of bond-forming
and bond-breaking events. The fact that treatment of the first
cyclization product, namely, allenyl alcohol 3 (or its trimeth-
ylsilyl ether 2h (see entry 7, Table 2)), with acid also leads
through to the enone confirms its intermediacy in the reaction.
From here, a number of possible reaction pathways can be
envisaged, which essentially differ in the order in which the
keto group and olefin functionality of the enone are introduced
(Schemes 5 and 6). Allenylsilanes have been shown to react
with Brønsted acids through an SE2′ mechanism.13b If this
happens in our system, reaction of the allenylsilane embedded
within oxasilacycle 3 with acid would generate the carbocationic
intermediate 8, which can then be trapped with water (the
reaction is far more effective when additional water is added)
to provide enol 9 and thence enone 7 on dehydration.
mediated ionization of the alcohol affords a tertiary carbocation,
which is subsequently trapped with water at the allylic position
to provide an enol product and thence enone 13 on tautomer-
ization.
Results from a related study within our group shed more light
on the reaction mechanism.17 We have found that the reaction
of aldehyde 15,18 which contains a propargylsilane nucleophile
tethered through an ether linkage to the electrophilic component,
with MeSO3H in CHCl3 at -60 °C provides a range of products
depending on the reaction time (Scheme 7). When the reaction
is quenched after 5 min, the allenyl alcohol cyclization product
16 is produced with excellent stereoselectivity (>20:1)19 in 55%
isolated yield,20 along with enol mesylate 17 in 30% yield and
Alternatively, protonation of the alcohol functionality in the
first cyclization product 3, followed by ionization, would
generate allyl carbocation 10. Trapping with water at the
exocyclic terminus would afford enol 11 and enone 3 on
tautomerization (Scheme 6). Wang and co-workers have re-
ported that the reaction of trimethylsilyl-substituted R-allenyl
alcohol 12 with aqueous silver(I) nitrate provides an enone 13
in addition to the desired 3-trimethylsilyl-2,5-dihydrofuran
product 14 (Scheme 6).15,16 Although they provide no evidence,
they suggest a plausible mechanism in which Lewis acid
(15) Nikam, S. S.; Chu, K.-H.; Wang, K. K. J. Org. Chem. 1986, 51,
745-747.
(16) Yokozawa has also reported enone byproducts from the reaction of
certain allenylsilanes with aldehydes and methoxytrimethylsilane in the
presence of a Lewis acid; however, since these products contain two
molecules of the aldehyde, they are formed by a pathway that is not
operating in our system: Niimi, L.; Hiraoka, S.; Yokozawa, T. Tetrahedron
2002, 58, 245-252.
(17) See also: Clive, D. L. J.; He, X.; Postema, M. H. D.; Mashimbye,
M. J. J. Org. Chem. 1999, 64, 4397-4410.
(18) Readily prepared from ethyl mandelate; see Supporting Information.
J. Org. Chem, Vol. 73, No. 4, 2008 1633

a trace of enone 18. If the reaction is left for 15 min, enol
mesylate 17 can be isolated in 81% yield, along with enone 18
in 10% yield; extending the reaction time to 30 min provides a
good route to enone 18, which can be isolated under these
conditions in 88% yield. Allenyl alcohol 16 can be converted
separately into enol mesylate 17, and enol mesylate 17 into
enone 18 (Scheme 7), which confirms the intermediacy of 16
and 17 en route to enone 18. The formation of enol mesylate
17 provides good evidence for dehydration preceding keto
formation; were reaction to proceed by initial protonation on
the allene, enol mesylate 17 would not be expected. External
trapping of the intermediate carbocation by the methanesulfonate
conjugate base also rules out the possibility, at least in this
system, that the OH functionality within the allenyl alcohol traps
the cationic intermediate intramolecularly.
In summary, we have shown that a Brønsted acid can be used
to effect the intramolecular allenylation of aldehyde 1 to provide
the corresponding allenyl alcohol oxasilacycle 3 as a single
diastereoisomer, whose relative stereochemistry has been con-
firmed by X-ray crystallography. The best results are obtained
by employing short reaction times and low temperatures. When
the reaction is performed at elevated temperatures and with an
excess of acid, the allenyl alcohol cyclization product reacts
further to provide a cyclic enone 7 in which the conjugated
alkene can also be considered as a vinylsilane. Possible
mechanisms to rationalize the outcome of this cascade process
have been proposed. The isolation of an enol mesylate from a
similar reaction on a related substrate supports a mechanism in
which dehydration and installation of the vinylsilane precede
ketone formation. It is noteworthy that all possible mechanisms
involve cationic intermediates, which possess a â-C-Si bond.
Such species are potentially susceptible to olefination pathways
via cleavage of the C-Si bond; however, the fact that a product
in which the C-Si bond is retained can be rationalized by poor
orbital overlap between the C-Si bond and the leaving group/
positively charged intermediates disfavoring these reaction
pathways. The conversion of aldehyde 1 into enone 7 represents
an unusual cascade process. The enone product is ripe for further
elaboration and a useful starting point for diversity-oriented
synthesis. Future work will investigate the reactivity of the enone
with this in mind.
Experimental Section
General Procedure for the Synthesis of Enone 7 from
Aldehyde 1. MeSO3H (65 µL, 1.0 mmol) was added dropwise over
5 min to a solution of aldehyde 1 (1.0 mmol) in CH2Cl2 (10 mL)
and H2O (72 µL, 4.0 mmol) at room temperature. TLC monitoring
of the reaction generally showed consumption of the starting
material after 5-20 min and full conversion of the intermediate
allenyl alcohol 3 to the desired enone product within 2 h. If
necessary, more MeSO3H (65 µL, 1.0 mmol) was then added. After
a further 2 h, the reaction mixture was cooled to 0 °C and quenched
by the addition of NaHCO3 solution (10 mL), and the biphasic
mixture was allowed to warm to room temperature. The two phases
were separated, and the aqueous phase was extracted with CH2Cl2
(3 × 10 mL). The combined organic extracts were washed with
brine (10 mL) and dried (MgSO4). Removal of the solvent under
reduced pressure and purification of the residue by flash column
chromatography (eluent, EtOAc in hexane) afforded enone 7 as a
colorless oil.
Acknowledgment. We thank Merck, Sharp & Dohme and
the University of Birmingham for a studentship (to R.R.) and
the Engineering and Physical Sciences Research Council and
University of Birmingham for a studentship (to P.J.J.).
Supporting Information Available: General experimental
details, experimental procedures and complete compound charac-
(19) Although it is not significant for the present study, we have assigned
the major diastereoisomer as the anti product by comparison with related
work: Jervis, P. J.; Cox, L. R. Unpublished results (see Supporting
Information).
(20) The yield of this product can be improved to 84% by performing
the reaction in CH2Cl2 at -78 °C for 2 min.
1
terization data for all new compounds, scanned H NMR and 13C
NMR spectra for all new compounds, and a CIF file for 6. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
JO702351S
1634 J. Org. Chem., Vol. 73, No. 4, 2008