Synthesis of β-heteroaryl propionates via trapping of carbocations with π-nucleophiles

Article abstract of DOI:10.1016/j.tetlet.2009.02.018

A variety of heterocyclic alcohols and acetates were coupled with silyl ketene acetals and other π-nucleophiles in the presence of trimethylsilyl trifluoromethanesulfonate to provide an array of substituted β-heteroaryl propionates, including those with c

Full text of DOI:10.1016/j.tetlet.2009.02.018

Tetrahedron Letters 50 (2009) 3253–3257
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Tetrahedron Letters
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Synthesis of b-heteroaryl propionates via trapping of carbocations
with p-nucleophiles
*
Tsung-hao Fu, Amy Bonaparte, Stephen F. Martin
Department of Chemistry and Biochemistry, The University of Texas, Austin, TX 78712, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of heterocyclic alcohols and acetates were coupled with silyl ketene acetals and other p-nucle-
ophiles in the presence of trimethylsilyl trifluoromethanesulfonate to provide an array of substituted
b-heteroaryl propionates, including those with contiguous quaternary centers, as well as vinylogs
Received 26 January 2009
Accepted 4 February 2009
Available online 8 February 2009
thereof. This reaction also proceeds with high diastereoselectivity when the
auxiliary.
p-nucleophile bears a chiral
Ó 2009 Elsevier Ltd. All rights reserved.
In the context of several ongoing projects in alkaloid synthesis,
we were confronted with the task of preparing substituted deriva-
tives of b-heteroaryl propionic acids of the general structure 1.
After examining the literature, it was apparent that there were
two different approaches that might be applied to the synthesis
of such compounds, and these are outlined in Scheme 1.
It was thus evident that there were limitations to existing
methods for preparing compounds generally related to 1, and there
was no direct precedent for a number of possible bond-forming
processes. After considering the available options, we concluded
that the disconnection depicted in Path b offered the greatest
opportunity to develop new chemistry and expand upon that
which was known. We now report some results of our preliminary
studies.
The first approach, which is depicted in Path a, involves the con-
jugate addition of electron-rich heteroaromatic rings to a,b-unsat-
urated carbonyl compounds via a process in which the heterocycle
serves as the nucleophile (Scheme 1, Path a). This approach is well
precedented in the literature, and methods for preparing both achi-
ral and chiral products in high enantioselectivity are known.1,2 The
scope of these methods is, however, limited in several ways. For
example, substitution occurs on the heteroaromatic ring only at
those positions that are favored in classical electrophilic substitu-
tion reactions of electron-rich heterocycles with the vast majority
of examples being pyrroles and indoles. The preparation of com-
pounds of the general structure 1 (R1, R2 = alkyl) is also rather lim-
ited,1b,3 whereas compounds such as 1 (R3, R4 = alkyl) appear to be
inaccessible via this path.
The first objective was to conduct two sets of exploratory exper-
iments to examine the reactivity of indol-3-yl and indol-2-yl carbi-
nol derivatives. Although precedent for the former construction
was reported after we initiated these studies,7 we are aware of
no precedent for the latter. As a prelude to more general studies,
we examined the Lewis acid-catalyzed reaction of the alcohol 6
with the silyl ketene acetal 7 under a variety of conditions to fur-
nish 8, eventually finding that the reaction proceeded in an opti-
mized yield of 92% using THF as the solvent, 0.9 equiv of
trimethylsilyl trifluoromethanesulfonate (TMSOTf) as the Lewis
acid, and a reaction temperature of À40 °C (Scheme 2, method A).
The second option (Scheme 1, Path b) involves a SN1-type reac-
tion in which a compound bearing a benzylic-like leaving group
undergoes ionization, typically in the presence of a suitable Lewis
R1
O
R2
R5
+
Path a
Path b
R3
3
X
acid, and the resulting carbocation is trapped by a
p-nucleophile.
R3 R4
R2
2
Although there are some examples of reactions of cations gener-
ated from a secondary thiophen-2-yl chloride,4 furan-2-yl acetate,5
and several heteroaryl carbinols,6 the scope of this bond construc-
tion appears to be limited to relatively few combinations of hetero-
R5
X
R1
O
OSiR3
R5
Path a Path b
R3
LG
+
aromatic systems and
p-nucleophiles. Moreover, there are no
X
R4
R1 R2
4: LG = OH, OAc
X = N, O, S
1
examples of the enantioselective synthesis of compounds of type
1 by this construction.
5
* Corresponding author. Tel.: +1 512 471 3915; fax: +1 512 471 4180.
E-mail address: sfmartin@mail.utexas.edu (S.F. Martin).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.018

3254
T. Fu et al. / Tetrahedron Letters 50 (2009) 3253–3257
OH
7, TMSOTf
OTMS
OMe
TMSOTf
CO2Me
+
OR
MeCN, –40 °C
N
N
CO2Me
THF, –40 °C
92%
N
N
Me
Me
Me
91% (for 10)
Me
7
6
8
11
9: R = H
10: R = Ac
Scheme 2.
OR
Encouraged by this result, the same conditions (method A)7
were applied to the reactions of other indol-3-yl carbinols with
N
Me
several different
p
-nucleophiles in order to explore the scope of
12: R = H, Ac, CO–C6H4-o-NO2,CONHPh
this route to indol-3-yl propionate derivatives (Table 1). As is evi-
dent from examination of the results in Table 1, the reaction works
well with primary, secondary, and tertiary alcohols. The indole
nitrogen atom may either be unsubstituted or may bear an alkyl
Scheme 3.
residue such as a methyl group. Finally,
p
-nucleophiles having dif-
underwent reaction with 7 under the previously defined condi-
tions to give 11 in moderate yield. After a quick survey of different
solvents and temperatures, it was found that the yield of 11 could
be improved to 91% by changing the solvent to acetonitrile and by
performing the reaction at –40 °C with one full equivalent of
TMSOTf (method B).9
Having optimized the conditions for the reaction of 10 with 7,
the scope of this reaction was further explored (Table 2). The
reaction works well with indol-2-yl, pyrrol-2-yl, furan-2-yl, and
thiophen-2-yl carbinol derivatives. Although the presence of an
N-sulfonyl group on a pyrrole is deactivating, carbon–carbon bond
formation proceeds in modest yield (entry 8).10 In general, the
ferent substitution patterns at the reacting center may be em-
ployed. This feature enables the facile construction of not only
quaternary centers, but also contiguous quaternary centers, argu-
ably one of the most difficult challenges in synthesis.8
The optimized conditions for the reaction of 6 with 7 were then
applied to the reaction of the indol-2-yl carbinol 9 with 7, but 11
was obtained in low yield (Scheme 3). Reasoning that the low yield
in this transformation might be a consequence of the decreased
reactivity toward ionization of 9 relative to 6, we thought that
the corresponding acetate 10 might be more reactive. Accordingly,
acetylation of 9 with acetic anhydride afforded 10, which then
Table 1
Lewis acid-catalyzed reactions of indol-3-yl carbinols with
p
-nucleophiles7
Entry
Alcohol
p
-Nucleophile
Product
Yield (%)
93
OH
CO2Me
CO2Me
CO2Me
CO2Me
CO2Et
1
7
7
7
7
N
Me
N
Me
OH
OH
2
3
4
5
95
76
78
87
N
Me
N
Me
N
H
N
H
OH
OH
N
H
N
H
OTBS
OEt
N
N
Me
Me
OH
O
O
OTMS
O
6
77
N
N
Me
Me

T. Fu et al. / Tetrahedron Letters 50 (2009) 3253–3257
3255
reactions involving tertiary alcohols were most efficient (entries 1,
7, and 12), presumably owing to their relative ease of ionization.
The reactions of secondary acetates were generally superior to
those of their corresponding alcohols. Because the secondary ace-
tates derived from pyrrol-2-yl carbinols are known to be unsta-
ble,11 these were not examined as substrates. The reactions of
primary alcohols appear to be more challenging. For example, in
preliminary experiments, we found that Lewis acid-catalyzed reac-
tions of 7 with the indol-2-yl carbinol derivatives 12 did not afford
isolable quantities of the desired coupling product. It should be
noted, however, that primary furan-2-yl acetates are known to par-
ticipate in such reactions,5 so our findings relative to 12 are clearly
Table 2
Lewis acid-catalyzed reactions of heteroaryl carbinols with
p
-nucleophiles9
-Nucleophile
Entry
Alcohol
p
Product
Yield (%)
93
1
7
OH
N
N
CO2Me
Me
Me
O
O
2
3
4
5
6
7
88
77
68
47
49
88
OH
OTIPS
N
O
N
Me
Me
7
OH
OAc
OAc
N
N
H
CO2Me
CO2Et
H
OTBS
N
N
OEt
Me
Me
12
OTMS
N
N
CO2Me
OMe
Me
Me
OH
OH
OH
OAc
CO2Me
7
7
N
N
Me
Me
CO2Me
CO2Me
CO2Me
N
N
Me
Me
8
9
7
7
42
62
N
N
SO2Ph
SO2Ph
O
O
OH
OAc
OH
CO2Me
CO2Me
CO2Me
10
11
12
7
7
7
45
79
84
O
S
S
O
S
S

3256
T. Fu et al. / Tetrahedron Letters 50 (2009) 3253–3257
not generally applicable to all primary heterocyclic carbinols. Suit-
able -nucleophiles include not only simple enol derivatives such
as 7, but also cyclic and acyclic dienes (entries 2 and 5).
diastereoselectivity using chiral
contiguous quaternary centers may also be easily prepared. This
method will be useful for the synthesis of a wide variety of ,b-
p-nucleophiles. Compounds with
p
a
Having established that heteroaryl carbinol derivatives under-
substituted heterocyclic propionates with defined stereocenters
and alkyl and heteroatom substitution on the carbon backbone.
The expansion and application of this methodology to the synthe-
sis of compounds of biological interest are in progress, and will be
reported in due course.
went facile reactions with several
p-nucleophiles, we were in-
spired to explore such reactions with chiral
p-nucleophiles in
order to develop a diastereoselective variant of this process. That
such a process might be feasible was supported by the findings
of Fuentes and coworkers, who had shown that the presence of a
chiral oxazolidinone on a
lectivity in a reaction involving an N-acyl iminium ion and a
nucleophile.13 We first examined the reaction of the secondary
alcohol 13 with the chiral -nucleophile 14 in the presence of
TMSOTf. Although this reaction proceeded in 76% yield, a mixture
(4.4:1.6:1.6:1) of four stereoisomers was obtained. Toward achiev-
ing a higher level of diastereoselectivity, the enol derivative 15 was
examined as a nucleophile. We were thus gratified that when 15
was allowed to react with 13, a mixture (15.1:1) of stereoisomers
was obtained in 90% yield from which 16 was isolated as the major
product (Scheme 4). A crystal structure of 16 was obtained, thereby
unequivocally establishing its stereochemistry.14
p-nucleophile induced good diastereose-
Acknowledgments
p
-
We thank the National Institutes of Health (GM 25439 and
GM31077), Pfizer, Inc., Merck Research Laboratories, and the Rob-
ert A. Welch Foundation for their generous support of this research.
We also thank Dr. Vince Lynch for performing the X-ray analysis,
and Mr. Travis Turner for preparing some of the starting materials.
p
Supplementary data
Characterization data for all b-heteroaryl propionates. Supple-
mentary data associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2009.02.018.
The efficient synthesis of 16 is noteworthy, because it illustrates
the versatility of Path b in Scheme 1 and its potential for the
enantioselective preparation of b-heteroaryl-a-hydroxy propio-
nates, which are structural subunits of biologically interesting
compounds. For example, 17, which is the N-demethylated analog
of 16, may be envisioned as a precursor of the natural product
(À)-indolmycin (18), which is an antibiotic that exhibits activity
against Staphylococci aureus.15,16 Hydroxy acids related to com-
pounds like 16 are also useful precursors of depsi peptides, which
may be used to probe hydrogen-bonding effects in bimolecular
interactions involving proteins.17 Furthermore, the reactions of
References and notes
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CHCl3, –60 °C
O
TBSO
BnO
+
OH
N
O
90%
dr = 15.1:1
N
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13
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O
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18
Scheme 4.
7. Method A: Freshly distilled TMSOTf (0.47 mL, 2.59 mmol) was slowly added
dropwise to
a solution of silyl ketene acetal (7.20 mmol) and alcohol
(2.88 mmol) in THF (150 mL) at À40 °C (bath temperature) under argon. The
solution was stirred at À40 °C (bath temperature) for 1 h, whereupon H2O
(70 mL) was added. The mixture was extracted with Et2O (4 Â 70 mL), and the
organic layers were combined, dried (Na2SO4), and concentrated under reduced
pressure. The residue was purified by flash chromatography, eluting with a
suitable mixture of EtOAc/hexanes to afford the product in >95% purity.
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the presence of TMSOTf to deliver a number of b-heteroaryl
propionate derivatives and vinylogs thereof, generally in yields
exceeding 75%. The reaction can also be performed with high
p

T. Fu et al. / Tetrahedron Letters 50 (2009) 3253–3257
3257
9. Method B: Freshly distilled TMSOTf (0.42 mL, 2.3 mmol) was slowly added
dropwise to a solution of silyl ketene acetal (3.45 mmol) and alcohol or acetate
(2.3 mmol) in MeCN (23 mL) at À40 °C (bath temperature) under argon. The
solution was stirred at À40 °C (bath temperature) for 1 h, whereupon saturated
NaHCO3 (20 mL) was added. The layers were separated, and the aqueous layer
was washed with Et2O (2 Â 15 mL). The combined organic layers were washed
with brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure.
The residue was purified by flash chromatography, eluting with a suitable
mixture Et2O/pentane to afford the product in >95% purity.
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