Synthesis of Soai aldehydes for asymmetric autocatalysis by desulfurative cross-coupling

Article abstract of DOI:10.1021/ol500189s

Palladium-catalyzed dehydrosulfurative Liebeskind-Srogl coupling of terminal alkynes with 2-mercapto-1,3-pyrimidine-5-carbaldehyde under base-free conditions provides 2-(alkynyl)-1,3-pyrimidine-5-carbaldehydes, which are substrates for autocatalytic ampli

Full text of DOI:10.1021/ol500189s

Letter
pubs.acs.org/OrgLett
Synthesis of Soai Aldehydes for Asymmetric Autocatalysis by
Desulfurative Cross-Coupling
Oleg V. Maltsev, Alexander Pothig, and Lukas Hintermann*
̈
Technische Universitat Munchen, Department Chemie, 85748 Garching bei Munchen, Germany
̈
̈
̈
S
* Supporting Information
ABSTRACT: Palladium-catalyzed dehydrosulfurative Liebes-
kind−Srogl coupling of terminal alkynes with 2-mercapto-1,3-
pyrimidine-5-carbaldehyde under base-free conditions provides
2-(alkynyl)-1,3-pyrimidine-5-carbaldehydes, which are sub-
strates for autocatalytic amplification of chirality according to
Soai et al. The mercapto aldehyde acceptor is obtained by
condensation of Arnold’s vinamidinium salt with thiourea.
with alkynes11 indeed provides convenient access to a range of
Soai-type aldehydes.
oai and co-workers have described a remarkable asym-
metric autocatalytic addition of aldehyde 1a and Zn Pr2 to
i
S
Access to the heterocyclic pro-electrophiles started from
Arnold’s vinamidinium salts12 as triformylmethane12b,13 equiv-
alents: aqueous solutions containing 714 and either urea or
thiourea precipitate enamides 8 or 9, respectively.13 The latter
cyclize to the new pyrimidylaldehydes 5/6 upon brief heating in
acetic acid (Scheme 3).15,16
Scheme 1. Soai’s Asymmetric Autocatalysis
Scheme 3. Synthesis of Aldehydes 5 and 6
form alkoxide 2, which is an asymmetric catalyst of its own
formation (Scheme 1).1,2 The strong asymmetric amplifica-
tion2,3 observed in the process means that addition of minute
amounts of chiral inductors generates product 3 with
considerable enantiomeric excess after hydrolysis.2,4
Some analogues of 1a (R = t-Bu) with variable R groups,
compounds 1, have been prepared and tested in asymmetric
5c
amplification, e.g., R = t-BuMe2Si,5a adamantyl,5b SiMe3 and
others,1,5d but the involved five-step synthesis1,4,6 hampers
wider application and studies of those fascinating compounds.7
It occurred to us that recently introduced “dehydrative”
coupling techniques,8 in the instance with terminal alkynes (4)
and a common electrophile 5, might provide a shortcut access
to targets 1 (Scheme 2).
Initial attempts at Sonogashira-type couplings of 5 via in situ
tosylation8e or phosphonium salt activation8a−d protocols did
not generate any of the desired products.17
Scheme 2. Retrosynthetic Analysis of Soai-Type Aldehydes 1
The focus shifted to mercaptoaldehyde 6 as the potential
starting material in a dehydrosulfurative Liebeskind−Srogl
coupling,9,10 as previously described for alkynes with
oxazolinethione acceptors.10b,d,11 However, established con-
ditions for desulfurative alkynylations involving base11 were
unsatisfactory with the present substrates. After some
experimentation,18 we arrived at base-free alkynylation
While the envisioned dehydrative coupling of 5 has yet to be
realized, we now report that the closely related dehydrosulfur-
ative Liebeskind−Srogl9,10 coupling of mercaptoaldehyde 6
Received: November 19, 2013
Published: February 13, 2014
© 2014 American Chemical Society
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Letter
a
Table 1. Optimization of the Dehydrosulfurative Coupling of 6 with tert-Butylacetylene (4a)
b
yield (%)
entry
cat. (mol %)
none
solvent
temp (°C)
time (h)
1a
14
1
2
3
4
5
6
7
8
THF
65
65
24
24
24
24
24
2
<0.5
44
48
54
57
22
23
39
76
[Pd2Cl2(allyl)2] (5)
Pd(acac)2 (5)
THF
3
2
2
2
THF
65
Pd(dba)2 (5)
THF
65
Pd(OAc)2 (5)
THF
65
Pd(OAc)2 (5)
MeCN
MeCN
MeCN
MeCN
MeCN
65
Pd(OAc)2 + XPhos (5)
Pd(OAc)2 + PPh3 (5)
Pd(OAc)2 + PPh3 (5)
Pd(OAc)2 + PPh3 (1)
65
2
65
2
c
9
110
110
0.5
0.5
2
c
10
79
<1
a
b
Reactions were performed under argon with 6 (0.5 mmol), 4a (0.75 mmol), and CuTC (1 mmol) in the solvent (1.5 mL). Yields of 1 and (E/Z)-
c
14 determined by qNMR with internal standard toluene. Microwave (μW) heating was applied. CuTC = copper(I) thiophene-2-carboxylate; XPhos
= 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.
conditions for 6 with tert-butylacetylene (4a) using various
palladium catalysts and 2 equiv of CuTC (Table 1).
The reaction was performed in solvents such as 1,4-dioxane
or THF with Pd(OAc)2 as best catalyst precursor (Table 1,
entries 1−6). Enol ester 14 is also formed by addition of
thiophene-2-carboxylic acid, released from CuTC, to the triple
bond of 1a; consequently, it is the main product at prolonged
reaction times.18 Reactions in acetonitrile proceeded more
selectively, but rather slowly, at 65 °C (Table 1, entry 6). While
Pd(OAc)2 catalyzes the reaction in the absence of added
ligands (Table 1, entries 5 and 6), the addition of phosphanes
(Table 1, entries 7−10) was preferred because this produced a
homogeneously dissolved in situ catalyst. A metal/ligand ratio
of 1:1 with PPh3 was satisfactory for this purpose, whereas
more specialized ligands provided no advantage (Table 1,
entries 7 and 8).18 To speed up the catalysis, it was performed
in a microwave reactor at 110 °C, where satisfactory
conversions were achieved in 30 min at a catalyst loading
down to 1 mol % (Table 1, entries 9 and 10). Those conditions,
at higher concentration, were then used in preparative
couplings of various alkynes (Table 2).
The synthesis of 1a (Table 2, entry 1) was scaled to 5 mmol
(81% yield) and is limited only by the reactor volume and
stirring efficiency in the heterogeneous reaction mixture of the
microwave reactor. However, the reaction can also be
performed in a pressure tube with thermal heating and
magnetic stirring.19 Alkyl-substituted, nonfunctionalized al-
kynes with variable steric requirements were successfully
coupled (Table 2, entries 2−6), whereas phenylacetylene
appeared to be less reactive and required more forcing
conditions (Table 2, entry 7). However, this was not a general
problem with arylacetylenes, since several substituted deriva-
tives with either electron-attracting or -withdrawing substitu-
ents (entries 8a−e) gave fair yields under standard conditions.20
Compound 1f was amenable to X-ray crystal structure analysis
(Figure 1).
Figure 1. ORTEP representation of the molecular structure of 1f
(CCDC 971916). Ellipsoids are shown at the 50% probability level.
Besides the presence of aldehyde carbonyl, additional
functionality is tolerated, such as ketone carbonyl (Table 2,
entry 9), ester (Table 2, entries 10 and 11), or propargyl
alcohols (Table 2, entry 12). Limitations of the alkyne structure
included medium-chain 1-alkyn-ω-ols and trimethylsilyl
acetylene (Table 2, entry 13) or certain propargyl derivatives
(Table 2, entry 14). Occasionally, the coupling product could
not be readily separated from enol ester side products (cf. 14)
by regular chromatography (examples not included in Table 2).
The mildness of the protocol and its potential for late-stage
functionalization is also shown in the coupling of 6 with the
contraceptive drug mestranol (15) that cleanly proceeds to
aldehyde 16 (Scheme 4).
First experiments show that the nonbasic dehydrosulfurative
alkynylation conditions are also suitable with a range of other
heterocyclic substrates (Figure 2).
In conclusion, a synthesis of alkynylated pyrimidyl aldehydes,
starting from readily accessible Arnold salt, via dehydrosulfur-
ative coupling of alkynes with mercaptoaldehyde 6, has been
developed. This synthesis of Soai-type aldehydes 1 requires
neither cryogenic reaction conditions nor highly air- and water-
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a
Table 2. Synthesis of 2-Alkynylpyrimidine-5-carbaldehydes by Liebeskind−Srogl Alkynyldehydrosulfuration of 6
a
Reactions were performed at the 1 mmol scale under argon in closed glass vessels with 6 (1 equiv), alkyne (1.5−2.0 equiv), CuTC (2.0 equiv),
Pd(OAc)2 (1 mol %), and PPh3 (1 mol %) in dry MeCN (1.5 mL) in a microwave (μW) reactor with variable power setting at 110 °C (hold
b
c
d
temperature) for 22.5 min (hold time). Isolated yield. Performed on a 0.5 mmol scale in MeCN (1.5 mL) for 25 min. Reaction performed with
PhCCH (3.2 equiv), Pd(OAc)2 (3 mol %), and PPh3 (3 mol %) in MeCN (9 mL) under μW irradiation (130 °C, 30 min).
sensitive reagents. This approach illustrates the elegance of
dehydrosulfurative Liebeskind−Srogl-type couplings,9−11 which
start from thio-heterocyclic building blocks as electrophiles
rather than introducing leaving groups in extra synthetic steps.
ASSOCIATED CONTENT
■
S
* Supporting Information
Additional screening results, detailed experimental procedures,
and spectroscopic data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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(7) For mechanistic work using model substrates, see: Buono, F. G.;
Iwamura, H.; Blackmond, D. G. Angew. Chem., Int. Ed. 2004, 43, 2099.
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Org. Lett. 2008, 10, 5043.
Scheme 4. Coupling of 6 with Mestranol
́
(9) (a) Prokopcova, H.; Kappe, C. O. Angew. Chem., Int. Ed. 2009,
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Figure 2. Additional products obtained from mercapto precursors by
the standard protocol (cf. Table 2 for conditions).
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: lukas.hintermann@tum.de.
Notes
The authors declare no competing financial interest.
(14) Crude salt 712e is not exactly the dichloride, but it has the
stoichiometry [C10H23N32+·(Cl−)2·HCl·H2O],12g where part of the
chlorine is furthermore replaced by bromine. This material is
satisfactory for use in the synthesis of 5/6 via 8/9. See the Supporting
Information for details.
ACKNOWLEDGMENTS
This work received support from the Human Frontier Science
Program (RGY0081/2011).
■
REFERENCES
■
(15) According to NMR data in DMSO-d6, 5 and 6 favor the hydroxy
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(16) Prolonged heating of 8/9 in acetic acid produces samples of 5/6
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(17) Reaction of 5 with POCl3 gives 2-chloro-5-dichloromethylpyr-
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(18) See the Supporting Information for additional screening results.
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the parameters of the thermal experiment were chosen to compensate
for a slower heating rate and a temperature gradient. Differences in the
outcome of catalytic reactions between μW and thermal heating are
mostly due to such factors: Obermayer, D.; Gutmann, B.; Kappe, O.
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(20) The limited solubility of PhCCCu might possibly explain the
low reactivity in the case of phenylacetylene.
(6) Spectral data and experimental details of the synthesis of 1a have
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