Synthesis of Soai Type 2-Arylpyrimidine-5-carbaldehydes through Desulfurative Cross-Coupling with Arylboronic Acids

Article abstract of DOI:10.1002/ejoc.201403133

A two-step synthesis of 2-arylpyrimidine-5-carbaldehydes, which are of relevance as substrates for Soai's asymmetric autocatalysis, was realized by exploiting a hidden threefold symmetry in the target core structure. Condensation of Arnold's C ₃-symmetric vinamidinium cation with S-methylisothiouronium sulfate provides 2-methylsulfanyl-pyrimidine-5-carbaldehyde; introduction of aryl groups at C-2 of the latter was accomplished by a Liebeskind-Srogl palladium-catalyzed desulfurative (de-methylsulfanylative) coupling with aryl boronic acids to obtain the target compounds 1 (14 examples, 60-95 % yield). 2-Arylpyrimidine-5-carbaldehydes, which are of relevance as substrates in Soai's asymmetric autocatalysis, are prepared through Liebeskind-Srogl coupling of aryl boronic acids with 2-methylthiopyrimidine-5-carbaldehyde; the latter is obtained in a hydrolytic condensation of two symmetric amidinium salts.

Full text of DOI:10.1002/ejoc.201403133

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FULL PAPER
DOI: 10.1002/ejoc.201403133
Synthesis of Soai Type 2-Arylpyrimidine-5-carbaldehydes through Desulfurative
Cross-Coupling with Arylboronic Acids
Oleg V. Maltsev,[a] Rodger Rausch,[a] Zheng-Jun Quan,[a][‡] and Lukas Hintermann*[a]
Keywords: Asymmetric catalysis / Homogeneous catalysis / Palladium / Cross-coupling / Nitrogen heterocycles
A two-step synthesis of 2-arylpyrimidine-5-carbaldehydes,
which are of relevance as substrates for Soai’s asymmetric
autocatalysis, was realized by exploiting a hidden threefold
symmetry in the target core structure. Condensation of Ar-
carbaldehyde; introduction of aryl groups at C-2 of the latter
was accomplished by a Liebeskind–Srogl palladium-cata-
lyzed desulfurative (de-methylsulfanylative) coupling with
aryl boronic acids to obtain the target compounds 1 (14 ex-
nold’s C3-symmetric vinamidinium cation with S-methyliso- amples, 60–95% yield).
thiouronium sulfate provides 2-methylsulfanyl-pyrimidine-5-
Introduction
Pyrimidine-5-carbaldehydes
1
bearing unsaturated
groups at C-2 have been introduced by Soai and co-workers
as substrates for asymmetric autocatalytic additions of alk-
ylzinc reagents, among which the reaction of the 2-tert-
butylethynyl derivative 1a with diisopropylzinc shows par-
ticularly strong asymmetric amplification (Scheme 1, a).[1,2]
This reaction is an important tool to study processes of
chirality transfer[2] and provides a remarkable example of
absolute asymmetric synthesis.[3] Efficient synthetic ap-
proaches to 1 deserve interest because they will advance re-
search in the field of asymmetric autocatalysis. Until re-
cently, the important C-2-alkynylated aldehydes 1 were ob-
tained in multistep syntheses through coupling of 5-bromo-
2-iodopyrimidine (2) with alkynes, followed by bromine/
lithium exchange and electrophilic formyl transfer
(Scheme 1, b).[1,4]
The same sequence has provided access to 2-alkenyl-sub-
stituted targets through Stille coupling,[5] or to a 2-thio-
phenyl derivative through Negishi coupling.[6] A disadvan-
tage of this approach is that the sequence 2Ǟ3Ǟ1 must
be repeated each time a new group is attached at C-2, which
limits both substance amounts and the number of deriva-
tives available for screening studies in asymmetric auto-
catalysis. Although not fully satisfactory, this synthetic ap-
proach is rather typical for heterocyclic targets bearing car-
bon-substituents at ring-carbon atoms next to the imino-
Scheme 1. Soai-type C-2-substituted pyrimidine-5-carbaldehydes 1:
(a) As substrates in autocatalysis with asymmetric amplification.
(b) General synthetic route to aldehydes 1 through cross-coupling
and formylation from precursor 2.
nitrogen: the condensation of various open-chain precur-
sors A to lactam B or a tautomeric hydroxyimine C is fol-
lowed by nucleophilic halogenation to provide an activated
precursor D for cross-coupling to targets E (Scheme 2).[7]
[a] Department Chemie, Technische Universität München,
Lichtenbergstr. 4, 85748 Garching bei München, Germany
E-mail: lukas.hintermann@tum.de
Scheme 2. Standard route for the synthesis of heterocyclic targets
that bear a carbon substituent at a ring-carbon next to an imino
ring-nitrogen.
http://www.oca.ch.tum.de
[‡] Z.-J. Quan (CSC visiting scholar, 2011). Present address: Gansu
Key Laboratory of Polymer Materials, College of Chemistry
and Chemical Engineering, Northwest Normal University,
Lanzhou, Gansu 730070, P. R. China
The recent introduction of formally “dehydrative” cou-
pling reactions provides a short-cut from B/C directly to
E.[8] The hydroxy moiety is not an actual leaving group in
those couplings, which rely on activation of OH to a phos-
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403133.
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O. V. Maltsev, R. Rausch, Z.-J. Quan, L. Hintermann
FULL PAPER
phonium or sulfonate leaving group in situ. Analogous pal- either PyBrOP[19] as coupling reagent or piperidine as base,
ladium-catalyzed dehydrosulfurative couplings of heterocy- 2-amino aldehydes 10 were detected by GC–MS analysis, in
clic mercapto or thiono substrates have been realized.[9–12] which the amine unit is derived from the coupling reagent
They require thiophilic copper(I) compounds such as cop- or the base, respectively. The failure to realize in situ acti-
per(I) thiophene-2-carboxylate (CuTC) as activators and/or vation led us to investigate the activation of 5 with POCl3/
sulfur sequestering reagents and can be classified as Liebes- N,N-dimethylformamide in a separate step, which resulted
kind–Srogl desulfurative couplings.[9a,13,14] We have recently in the formation of trichloride 11 rather than the expected
shown that C-2-alkynylated pyrimidinecarbaldehydes 1 can aldehyde 12 (Scheme 4, c). The latter compound was only
be accessed in a single step by de-hydrosulfurative coupling detected in trace amounts (by GC–MS analysis) during the
of mercaptoaldehyde
4
with
a
range of alkynes reaction, which might imply that the most nucleophilic cen-
(Scheme 3).[12a] In contrast to other dehydrosulfurative alk- ter of 5 is at the carbonyl oxygen rather than the hydroxyl
ynylations,[12] the reaction proceeded under base-free condi- group, and this may explain the failure to activate the latter
tions.
position in situ. Consequently, the substrate for activation
in situ was changed from 5 to 4 with its more nucleophilic
mercapto group.[12a]
Scheme 3. Synthesis of Soai type aldehydes by dehydrosulfurative
alkynylation of mercaptoaldehyde 4.[12a]
In the present study, we wished to extend the synthetic
methodology towards aldehydes 1 through one-step desul-
furative couplings to other classes of organometallic nucleo-
philes. Boronic acids appeared to be the most promising for
this purpose because of their low toxicity and ready avail-
ability, their expected compatibility with formyl groups, and
because of the interest of C-2-arylated targets 1 as potential
substrates for asymmetric autocatalysis.[2] Although synthe-
ses of 2-aryl-substituted pyrimidine-5-carbaldehydes have
been reported, they take the aryl group through one or sev-
eral intermediates.[15,16] Here, we evaluate the synthetic ap-
proaches towards those targets, and describe an efficient,
new, one-step synthesis through desulfurative Liebeskind–
Srogl boronic acid coupling from a readily available thio-
ether precursor.
Scheme 4. Retrosynthetic strategy and initial reactivity studies.
(a) Retrosynthetic analysis of Soai type aldehydes 1. (b) Attempted
dehydrative couplings. (c) Threefold nucleophilic chlorination of 4.
Extending the successful alkynylation of 4 (Scheme 3) to
dehydrosulfurative couplings with boronic acids looked like
Results and Discussion
At the outset of the project we wanted to realize a short, a promising strategy, considering that similar dehydrosul-
general and (atom-)economic synthesis of Soai type alde- furative arylations of heterocyclic thiono substrates have
hydes 1 by profiting from two innovative elements, namely: been described by Kappe and others.[10,11] However, reac-
(1) the use of dehydrative coupling methodology on tions of mercapto aldehyde 4 with phenylboronic acids un-
hydroxyaldehyde 5 as substrate, and (2) by taking advantage der typical conditions for such couplings[20] were not effec-
of a hidden threefold symmetry in 5, which is revealed by tive (Ͻ 20% yield of 1b). Our attention therefore shifted to
its disconnection to urea (6) and triformylmethane 7 Liebeskind–Srogl de-alkylsulfanylative couplings of aryl-
(Scheme 4, a). We have previously shown that 5 and 4 are boronic acids,[13] which suggested the use of methylthio-al-
obtained by condensing Arnold’s vinamidinium cation 9[17] dehyde 13[16] as a potential substrate. We first obtained the
(see below) – a synthetic equivalent of 7[18] – with urea (6) latter by alkylating 4 with methyl iodide, in the presence of
or thiourea (8), respectively.[12a] Attempts to perform de- a molar equivalent of potassium carbonate (Scheme 5, a).
hydrative couplings of 5 with alkynes through in situ acti-
When a limiting amount of base was used in the alkyl-
vation by either the pTsCl/base[8c,8e] or the phosphonium ation, dimethyl acetal 14 became the major reaction prod-
salt protocol[8a,8b,8d] were unproductive (Scheme 4, b). De- uct, presumably as a result of hydriodic acid catalyzed ace-
fined heterocyclic products were not usually isolated from talization of intermediary 13 (Scheme 5, a).[21] Later, we de-
such experiments, and 1,4-diphenylbutadiyne was the major veloped a second and overall more efficient route to 13 by
product in attempted alkynylations with phenylacetylene. modifying the reported condensation of vinamidinium cat-
Starting with the more activated mercaptoaldehyde 4 and ion 9 with S-methylisothiouronium sulfate (16) (Scheme 5,
2
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Synthesis of Soai Type 2-Arylpyrimidine-5-carbaldehydes
The development of reaction conditions for the desul-
furative coupling of 13 with phenyl boronic acid as test sub-
strate began with a base-free protocol, using Pd(PPh3)4 as
catalyst and 2 equiv. of CuTC as activator.[13] To simplify
the optimization process, we performed the reaction in a
microwave reactor[26] at a fixed heating interval of 30 min.
Under those conditions, product yield was optimized
against reaction temperature rather than reaction time,
which can speed up the discovery process. The conversion
of 13 and the yield of 1b were analyzed in the crude reaction
mixture by qNMR with an internal standard. Satisfactory
conversions and yields were immediately obtained in tetra-
hydrofuran (THF) as solvent by gradually increasing the
temperature, with the best result at 90 °C (Table 1, entries
1–4).
Scheme 5. Syntheses of 2-(methylsulfanyl)pyrimidine-5-carbal-
dehyde (13): (a) By methylation of mercaptoaldehyde 4. (b) By con-
densation of vinamidinium cation 9 with S-methylisothiouronium
sulfate (16).
Reactions in other polar solvents such as dioxane or
N,N-dimethylformamide (DMF) were also suitable, without
offering a major advantage (Table 1, entries 5 and 6). The
reaction also occurred with Pd(OAc)2 as sole catalyst pre-
cursor (entry 7). This allowed a study of the effects of added
b).[16] Instead of obtaining the tetrafluoroborate,[15b,18] ligands by combining the pre-catalyst with several phos-
hexafluorophosphate,[22] or perchlorate salts[17b] of 9, we di- phanes (entries 8–10); however, none of the resulting sys-
rectly applied crude acidic chloride [9]Cl2·HCl·H2O as start- tems was superior to the tetrakis(triphenylphosphane)palla-
ing material.[12a,23] Condensation with 16 in hot ethanol dium catalyst under comparable conditions (entry 5). Given
gave mixtures of 13 (17–31%) and its diethyl acetal 17 (23– that conversions were still incomplete and the yields were
35%), with the composition depending on the mixing ratio confined to the 60% range, we gradually increased the
and reaction time.[24] In aqueous solution (90 °C, 2 h), a quantity of boronic acid and achieved an optimal result
yield of only 29% of 13 resulted at a 9/16 ratio of 1:0.75,[25] when using a twofold excess of that reagent (entries 11–13).
but addition of sodium acetate as buffer increased the yield The remaining problem appeared to be the limited stability
of 13 to Ն 75%, although the conditions also gave rise to of the catalyst. However, increasing the catalyst loading
some 2-(dimethylamino)-pyrimidine-5-carbaldehyde (18) as while lowering the reaction temperature did not increase the
contaminant, more so at extended reaction times. Per- yield or conversion further (entry 14). The conversion and
forming the reaction over a short time in hot, buffered yield could however be raised by performing the reaction in
aqueous solution gave optimal results (Scheme 5, b).
two consecutive heating intervals of 30 min at 90 °C with
Table 1. Screening of reaction parameters in the desulfurative arylation of 13 with phenyl boronic acid.
Entry Catalyst ([mol-%])
PhB(OH)2 [equiv.] Solvent[b]
Temp. [°C]
Time [min]
Conv. [%][a]
Yield [%][a]
1
2
3
4
5
6
7
8
Pd(PPh3)4 (2)
Pd(PPh3)4 (2)
Pd(PPh3)4 (2)
Pd(PPh3)4 (2)
Pd(PPh3)4 (2)
Pd(PPh3)4 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2) + P(oTol)3 (2)
Pd(OAc)2 (2) + SPhos (2)
Pd(OAc)2 (2) + tBuXPhos (2)
Pd(PPh3)4 (2)
Pd(PPh3)4 (2)
Pd(PPh3)4 (2)
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.75
2.00
2.20
2.00
2.00
THF
THF
THF
THF
dioxane
DMF
dioxane
dioxane
dioxane
dioxane
THF
70
90
30
30
30
30
30
30
30
30
30
30
30
30
30
60
30 + 30
58
85
88
85
82
86
76
62
81
72
93
96
97
97
100
45
69
62
62
61
67
51
39
52
60
76
80
78
78
86
110
130
110
110
110
110
110
110
110
110
110
90
9
10
11
12
13
14
15
THF
THF
THF
THF
Pd(PPh3)4 (5)
Pd(PPh3)4 (2.5 + 2.5)
90
[a] Conversion and yield determined by qNMR against internal standard. [b] DMF = N,N-dimethylformamide, THF = tetrahydrofuran.
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renewed addition of catalyst after the first heating phase ation of the relative amount of CuTC nor addition of a base
(entry 15).[26] Further experiments showed that neither vari- were beneficial.[24] The optimized conditions fall within the
known range of parameters of other desulfurative Liebes-
kind–Srogl couplings,[13,14] but each class of thioalkyl sub-
Table 2. Substrate range of the desulfurative boronic acid cou-
pling.[a]
strates requires a specific set of parameters to obtain the
best results. The optimized protocol was applied to the cou-
pling of thioether 13 with a variety of boronic acids on a
preparative scale (Table 2). The desired arylated aldehydes
1 were usually returned in good to excellent yields without
further optimization.
The procedure gives access to alkylated aryl derivatives
(Table 2, entry 2), alkoxy-functionalized aryl derivatives
(entries 3–5), condensed aryl or biaryl derivatives (en-
tries 6–8), heteroaryl (entry 9), and various halogenated
aryl derivatives (entries 10–14). Some limitations were
noted in case of hindered arylboronic acids, or with some
functionalized boronic acids; likewise, alkyl boronic acids
were unreactive (Figure 1).
Figure 1. Limitations of the desulfurative coupling of 13 with bo-
ronic acids. Reaction conditions were those of Table 2, yields were
determined by qNMR spectroscopic analysis of crude reaction
mixtures.
Alternative routes to 2-aryl-pyrimidine-carbaldehydes
through desulfurative coupling have also been considered
and evaluated in the course of this work. In contrast to
boronic acids, boronate esters are not suitable nucleophiles
in the desulfurative coupling reaction with 13 (Scheme 6,
a).
As mentioned, mercaptoaldehyde 4 was unsatisfactory as
an electrophile for coupling with arylboronic acids under
the conditions used for alkynylation of the same sub-
strate.[12a] Even under the optimized conditions of Table 2,
a very low yield of 1b was obtained (Scheme 6, b). Con-
versely, methyl thioether 13 – the preferred substrate for
boronic acid coupling – was not a suitable electrophile for
alkynylation.[27] These results illustrate that desulfurative
couplings of mercapto- (vis. 4) and thioether (vis. 13) deriv-
atives of the same heterocyclic core structure may give com-
plementary results.[28] Finally, acetal 14 proved to be a via-
ble substrate in desulfurative Negishi coupling,[29,30] or un-
der common Liebeskind–Srogl conditions (Scheme 7).[13,14]
In the absence of a formyl group in 14, the choice of
reaction conditions is less constrained by chemoselectivity
issues. Whereas a protecting group approach towards tar-
gets 1 through acetalization (13Ǟ14), cross-coupling
[a] Reactions performed with 13 (1.0 mmol), ArB(OH)2
(2.0 mmol), Pd(PPh3)4 (2.5 + 2.5 mol-%) and CuTC (2.0 mmol) in
THF (1.5 mL) for 2ϫ 30 min at 90 °C with microwave heating.
[b] Isolated yield. [c] 2ϫ 15 min heating intervals. [d] Performed on
a 5 mmol scale with 3ϫ 2.5 mol-% of Pd(PPh3)4 over 3ϫ 30 min
heating. [e] Performed on a 0.5 mmol scale.
4
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Synthesis of Soai Type 2-Arylpyrimidine-5-carbaldehydes
furative coupling route, and methylsulfanyl leaving groups
are often introduced in additional synthetic steps.[34] Our
work highlights the utility of Liebeskind–Srogl type desul-
furative couplings for realizing short synthetic routes to het-
erocyclic targets, if the synthetic strategy is based on a het-
erocyclic condensation event that introduces, at the same
time, a thioalkyl leaving group.[35]
Experimental Section
General: Experimental details are provided in the Supporting Infor-
mation.
2-(Methylthio)pyrimidine-5-carbaldehyde (13): A mixture of 2-(di-
methylamino)methylenepropane-1,3-bis(dimethyliminium) dichlor-
ide hydrochloride monohydrate[12a] (10.38 g, 34.2 mmol), S-methyl
isothiouronium sulfate (16; 7.45 g, 26.8 mmol), and sodium acetate
trihydrate (14.61 g, 107.4 mmol) in water (100 mL) was heated at
90 °C for 1 h. After cooling of the reaction mixture to room temp.,
the product was extracted with dichloromethane (3ϫ 100 mL). The
organic phase was washed with 6 m HCl (6 mL), brine (2ϫ
100 mL), and dried with MgSO4. After filtration, the solvent was
evaporated to give 13 (4.07 g, 77%) as a white or slightly yellow
solid with a purity of 99% (by 1H NMR analysis). 1H NMR
(250 MHz, CDCl3): δ = 2.64 (s, 3 H, SCH3), 8.92 (s, 2 H, CH),
10.02 (s, 1 H, CHO) ppm. 13C NMR (91 MHz, CDCl3): δ = 14.6,
124.6, 158.2, 179.1, 188.5 ppm.
Scheme 6. Unsuccessful approaches to 2-arylpyrimidine-5-carb-
aldehydes. (a) Boronic ester coupling. (b) Dehydrosulfurative aryl-
ation of 4.
General Procedure for the Desulfurative Coupling of 13 with Aryl-
boronic Acids: Into a microwave reactor glass vessel equipped with
a stirring bar (1 cm) were successively added aldehyde 13 (154.2 mg,
1 mmol), the respective boronic acid (2 mmol), Pd(PPh3)4 (29 mg,
2.5 mol-%), and CuTC (381.5 mg, 2.0 mmol). The vessel was closed
with a septum, and evacuated and filled with argon (3 times)
through a steel cannula. Anhydrous THF (3 mL; 4 ppm H2O) was
added by using a syringe, the vessel was sealed with a septum that
was suitable for use in the microwave reactor, and the reaction mix-
ture was subjected to microwave irradiation (target temperature
90 °C, hold for 30 min). After cooling to 50 °C, additional
Pd(PPh3)4 (29 mg, 2.5 mol-%) was added and microwave irradia-
tion (90 °C, 30 min) was repeated. After cooling to room temp., a
saturated solution of aq NH4Cl (3 mL) and EtOAc (25 mL) were
added and the mixture was filtered through Celite to remove insol-
uble solids. The filtrate was transferred into a separating funnel
and the layers were separated. The aqueous phase was extracted
with EtOAc (2ϫ 25 mL) and the combined organic phase was
washed with 2 m NaOH (2 mL) and brine (2ϫ 20 mL), then dried
with MgSO4. After filtration and evaporation, the residue was puri-
fied by column chromatography on SiO2.
Scheme 7. Desulfurative coupling of acetal 14 with boron and zinc
reagents.
(14Ǟ19) and acetal hydrolysis (19Ǟ1b; not performed)
seems viable, it offers no advantage over the direct coupling
reaction (13Ǟ1b; Table 2).
Conclusions
The synthesis of 2-aryl-substituted Soai-type aldehydes 1
as desirable targets of interest for the study of asymmetric
autocatalysis has been achieved in two steps starting from
Arnold’s vinamidinium cation 9, or in one step from the
readily available aldehyde 13 through a palladium-catalyzed
de-methylsulfanylative Liebeskind–Srogl coupling with ar-
ylboronic acids. The literature on desulfurative coupling
methodology points to a number of advantages of coupling
reactions with sulfur-centered leaving groups:[9] (i) The pos-
sibility to perform chemoselective reactions if multiple leav-
ing groups are present in one substrate;[9b,13b,31] (ii) the eas-
ier availability and/or higher stability of thioethers over
some halogenated heterocyclic electrophiles;[13d,14a,14b,30a]
(iii) the potential for stereospecific syntheses of alkenes
when starting from pure (E)- or (Z)-alkenyl sulfides;[9b,31]
(iv) the potential for chemoselective activation of sulfur
leaving groups under mild conditions;[13b,32] (v) the advan-
tage of performing coupling reactions under base-free con-
ditions;[13d,32] (vi) the potential for orthogonal functionali-
zation of thioether substrates (as opposed to more reactive
halogenated substrates) prior to the coupling step.[33] Econ-
2-Phenylpyrimidine-5-carbaldehyde (1b): Prepared according to the
general procedure for 30 min (overall μW heating). Purification by
column chromatography (CH2Cl2), yield 150 mg (82%); colorless
solid. 1H NMR (250 MHz, CDCl3): δ = 7.48–7.62 (m, 3 H, Ph-H),
8.52–8.60 (m, 2 H, Ph-H), 9.23 (s, 2 H, CH), 10.16 (s, 1 H,
CHO) ppm. 13C NMR (63 MHz, CDCl3): δ = 126.5, 128.9, 129.3,
132.3, 136.4, 158.6, 167.9, 188.9 ppm. HRMS (EI): m/z calcd. for
C11H8N2O+ 184.0637; found 184.0639.
2-(p-Tolyl)pyrimidine-5-carbaldehyde (1c): (a) Prepared according
to the general procedure. Purification by column chromatography
(CH2Cl2) gave 1c (177.7 mg, 89%) as a colorless solid. (b) Prepared
according to the general procedure on a 5 mmol scale, with three
omy of steps is seldom an argument for choosing a desul- additions of Pd(PPh3)4 (3ϫ 2.5 mol-%) and 3ϫ 30 min μW-heating
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phases. Purification by column chromatography (CH2Cl2) gave 1c
128.2, 129.1, 130.0, 135.4, 140.3, 145.1, 158.7, 167.9, 189.0 ppm.
(846.1 mg, 85%) as a colorless solid. 1H NMR (250 MHz, CDCl3): HRMS (EI): m/z calcd. for C17H12N2O+ 260.0944; found 260.0945.
δ = 2.45 (s, 3 H, CH3), 7.33 (d, J = 8.2 Hz, 2 H, Ar-H), 8.44 (d, J
2-(Thiophen-2-yl)pyrimidine-5-carbaldehyde (1j): Prepared accord-
= 8.2 Hz, 2 H, Ar-H), 9.18 (s, 2 H, CH), 10.12 (s, 1 H, CHO) ppm.
ing to the general procedure. Purification by column chromatog-
13C NMR (63 MHz, CDCl3): δ = 21.8, 126.4, 129.5, 129.8, 133.8,
143.2, 158.7, 168.3, 189.0 ppm. HRMS (EI): m/z calcd. for
(360 MHz, CDCl3): δ = 7.21 (dd, J = 5.0, 3.8 Hz, 1 H, Ar-H), 7.64
C12H10N2O+ 198.0788; found 198.0794.
1
raphy (CH2Cl2), yield 114 mg (60%); pale-yellow solid. H NMR
(dd, J = 5.0, 1.2 Hz, 1 H, Ar-H), 8.17 (dd, J = 3.8, 1.2 Hz, 1 H,
Ar-H), 9.10 (s, 2 H, CH), 10.08 (s, 1 H, CHO) ppm. 13C NMR
(91 MHz, CDCl3): δ = 126.1, 129.1, 132.1, 133.2, 142.3, 158.9,
164.7, 188.5 ppm. HRMS (ESI): m/z calcd. for C9H6N2OS+
190.0195; found 190.0195.
2-(4-Methoxyphenyl)pyrimidine-5-carbaldehyde (1d): Prepared ac-
cording to the general procedure. Purification by column
chromatography (CH2Cl2), yield 203.1 mg (95%); gray solid. 1H
NMR (250 MHz, CDCl3): δ = 3.91 (s, 3 H, OCH3), 7.03 (d, J =
9.0 Hz, 2 H, Ar-H), 8.52 (d, J = 9.0 Hz, 2 H, Ar-H), 9.15 (s, 2 H,
CH), 10.10 (s, 1 H, CHO) ppm. 13C NMR (63 MHz, CDCl3): δ =
55.6, 114.4, 126.0, 129.2, 131.4, 158.7, 163.4, 167.9, 189.0 ppm.
2-[4-(Trifluoromethyl)phenyl]pyrimidine-5-carbaldehyde (1k): Pre-
pared according to the general procedure. Purification by column
chromatography (CH2Cl2), yield 239.9 mg (95%); colorless solid.
1H NMR (360 MHz, CDCl3): δ = 7.79 (d, J = 8.3 Hz, 2 H, Ar-H),
8.68 (d, J = 8.3 Hz, 2 H, Ar-H), 9.26 (s, 2 H, CH), 10.19 (s, 1 H,
+
HRMS (EI): m/z calcd. for C12H10N2O2 214.0737; found
214.0730.
CHO) ppm. 13C NMR (126 MHz, CDCl3): δ = 124.0 (q, JF,C
=
2-(3-Methoxyphenyl)pyrimidine-5-carbaldehyde (1e): Prepared ac-
cording to the general procedure on a 0.5 mmol scale. Purification
by column chromatography (CH2Cl2), yield 96.5 mg (90%); color-
272.5 Hz, CF3), 125.89 (q, JF,C = 3.7 Hz), 127.1, 129.7, 133.7 (q,
JF,C = 32.5 Hz), 139.6, 158.8, 166.7, 188.9 ppm. HRMS (EI): m/z
1
+
less solid. H NMR (500 MHz, CDCl3): δ = 3.93 (s, 3 H, OCH3),
calcd. for C12H7N2OF3 252.0505; found 252.0501.
7.12 (dd, J = 8.2, 2.4 Hz, 1 H, Ar-H), 7.44 (t, J = 8.0 Hz, 1 H, Ar-
H), 8.11 (s, 1 H, Ar-H), 8.17 (d, J = 7.8 Hz, 1 H, Ar-H), 9.22 (s, 2
H, CH), 10.16 (s, 1 H, CHO) ppm. 13C NMR (63 MHz, CDCl3): δ
= 55.6, 113.6, 119.2, 122.0, 126.7, 130.0, 137.9, 158.7, 160.2, 168.0,
189.0 ppm. HRMS (EI): m/z calcd. for C12H10N2O2 214.0737;
found 214.0729.
2-(3,4,5-Trifluorophenyl)pyrimidine-5-carbaldehyde (1l): Prepared
according to the general procedure. Purification by column
chromatography (CH2Cl2), yield 177.0 mg (75%); colorless solid.
1H NMR (360 MHz, CDCl3): δ = 8.24 (dd, JF,H = 8.6, JF,H
=
+
6.8 Hz, 2 H, Ar-H), 9.22 (s, 2 H, CH), 10.18 (s, 1 H, CHO) ppm.
13C NMR (126 MHz, CDCl3): δ = 113.7 (dd, JF,C = 17.7, JF,C
=
2-(2-Methoxyphenyl)pyrimidine-5-carbaldehyde (1f): Prepared ac-
cording to the general procedure. Purification by column
chromatography (hexanes/EtOAc, 2:1), yield 160.4 mg (74%); yel-
low oil; purity 95% (NMR analysis). 1H NMR (250 MHz, CDCl3):
δ = 3.82 (s, 3 H, OCH3), 6.96–7.06 (m, 2 H, Ar-H), 7.41 (ddd, J =
8.3, 7.4, 1.8 Hz, 1 H, Ar-H), 7.78 (dd, J = 7.6, 1.8 Hz, 1 H, Ar-H),
9.18 (s, 2 H, CH), 10.06 (s, 1 H, CHO) ppm. 13C NMR (63 MHz,
CDCl3): δ = 56.0, 112.1, 120.7, 125.7, 127.0, 132.3, 132.3, 158.0
(br), 158.2, 169.3, 188.9 ppm. HRMS (EI): m/z calcd. for
5.5 Hz), 127.0, 132.5 (td, JF,C = 7.9, JF,C = 4.2 Hz), 142.7 (dt, JF,C
= 258.5, JF,C = 15.6 Hz), 151.6 (ddd, JF,C = 250.3, JF,C = 10.3, JF,C
= 3.7 Hz), 158.8, 165.1 (q, JF,C = 3.0 Hz), 188.7 ppm. HRMS (EI):
+
m/z calcd. for C11H5N2OF3 238.0348; found 238.0345.
2-(4-Fluorophenyl)pyrimidine-5-carbaldehyde (1m): Prepared ac-
cording to the general procedure. Purification by column
chromatography (CH2Cl2), yield 188.5 mg (94%); colorless solid.
1H NMR (360 MHz, CDCl3): δ = 7.14–7.26 (m, 2 H, Ar-H), 8.52–
8.64 (m, 2 H, Ar-H), 9.20 (s, 2 H, CH), 10.15 (s, 1 H, CHO) ppm.
13C NMR (91 MHz, CDCl3): δ = 116.1 (d, JF,C = 22.0 Hz), 126.6,
131.8 (d, JF,C = 9.0 Hz), 132.7 (d, JF,C = 3.0 Hz), 158.8, 165.8 (d,
JF,C = 253.5 Hz), 167.2, 188.9 ppm. HRMS (EI): m/z calcd. for
C11H7N2OF+ 202.0537; found 202.0532.
+
C12H10N2O2 214.0737; found 214.0731.
2-(Naphthalen-2-yl)pyrimidine-5-carbaldehyde (1g): Prepared ac-
cording to the general procedure. Purification by column
chromatography (CH2Cl2), yield 207.0 mg (89%); colorless solid.
1H NMR (250 MHz, CDCl3): δ = 7.49–7.64 (m, 2 H, Ar-H), 7.86–
8.06 (m, 3 H, Ar-H), 8.59 (dd, J = 8.7, 1.8 Hz, 1 H, Ar-H), 9.11
(s, 1 H, Ar-H), 9.24 (s, 2 H, CH), 10.15 (s, 1 H, CHO) ppm. 13C
NMR (63 MHz, CDCl3): δ = 125.4, 126.6, 126.8, 127.9, 128.2,
128.7, 129.7, 130.7, 133.3, 133.8, 135.5, 158.7, 168.2, 189.0 ppm.
HRMS (EI): m/z calcd. for C15H10N2O+ 234.0788; found 234.0792.
2-(4-Chlorophenyl)pyrimidine-5-carbaldehyde (1n): Prepared ac-
cording to the general procedure. Purification by column
chromatography (CH2Cl2), yield 204.9 mg (93%); colorless solid.
1H NMR (360 MHz, CDCl3): δ = 7.50 (d, J = 8.6 Hz, 2 H, Ar-H),
8.50 (d, J = 8.6 Hz, 2 H, Ar-H), 9.20 (s, 2 H, CH), 10.15 (s, 1 H,
CHO) ppm. 13C NMR (91 MHz, CDCl3): δ = 126.7, 129.3, 130.7,
135.0, 138.9, 158.7, 167.2, 188.8 ppm. HRMS (EI): m/z calcd. for
C11H7N2O35Cl+ 218.0241; found 218.0239.
2-(Naphthalen-1-yl)pyrimidine-5-carbaldehyde (1h): Prepared ac-
cording to the general procedure. Purification by column
chromatography (hexanes/EtOAc, 10:1), yield 194.5 mg (83%); col-
1
2-(3-Chlorophenyl)pyrimidine-5-carbaldehyde (1o): Prepared ac-
cording to the general procedure. Purification by column
chromatography (CH2Cl2), yield 203.4 mg (93%); colorless solid.
1H NMR (250 MHz, CDCl3): δ = 7.43–7.56 (m, 2 H, Ar-H), 8.45
(dt, J = 7.5, 1.7 Hz, 1 H, Ar-H), 8.56 (t, J = 1.7 Hz, 1 H, Ar-H),
9.23 (s, 2 H, CH), 10.17 (s, 1 H, CHO) ppm. 13C NMR (63 MHz,
CDCl3): δ = 127.0, 127.5, 129.5, 130.2, 132.3, 135.2, 138.3, 158.7,
166.9, 188.8 ppm. HRMS (EI): m/z calcd. for C11H7N2O35Cl+
218.0241; found 218.0238.
orless solid. H NMR (250 MHz, CDCl3): δ = 7.50–7.66 (m, 3 H,
Ar-H), 7.93 (dd, J = 7.3, 2.4 Hz, 1 H, Ar-H), 8.03 (d, J = 8.3 Hz,
1 H, Ar-H), 8.26 (dd, J = 7.3, 1.3 Hz, 1 H, Ar-H), 8.80 (d, J =
8.3 Hz, 1 H, Ar-H), 9.31 (s, 2 H, CH), 10.17 (s, 1 H, CHO) ppm.
13C NMR (63 MHz, CDCl3): δ = 125.3, 125.7, 126.0, 126.3, 127.6,
128.9, 131.1, 131.2, 132.3, 134.3, 134.4, 158.3, 170.7, 189.0 ppm.
HRMS (EI): m/z calcd. for C15H10N2O+ 234.0788; found 234.0779.
2-([1,1Ј-Biphenyl]-4-yl)pyrimidine-5-carbaldehyde (1i): Prepared ac-
cording to the general procedure. Purification by column
chromatography (CH2Cl2), yield 247.7 mg (60%); colorless solid.
Supporting Information (see footnote on the first page of this arti-
1H NMR (360 MHz, CDCl3): δ = 7.36–7.85 (m, 7 H, Ar-H), 8.62 cle): General information, additional screening data, spectroscopic
(d, J = 8.0 Hz, 2 H, Ar-H), 9.22 (s, 2 H, CH), 10.14 (s, 1 H,
data and copies of 1H and 13C NMR spectra for all synthesized
compounds.
CHO) ppm. 13C NMR (91 MHz, CDCl3): δ = 126.6, 127.4, 127.6,
6
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Job/Unit: O43133
/KAP1
Date: 07-10-14 14:32:23
Pages: 8
Synthesis of Soai Type 2-Arylpyrimidine-5-carbaldehydes
L. S. Liebeskind, Org. Lett. 2001, 3, 91; f) C. Savarin, J. Srogl,
L. S. Liebeskind, Org. Lett. 2000, 2, 3229.
Acknowledgments
[14] a) S. Oumouch, M. Bourotte, M. Schmitt, J. J. Bourguignon,
Synthesis 2005, 25; b) F.-A. Alphonse, F. Suzenet, A. Ker-
omnes, B. Lebret, G. Guillaumet, Org. Lett. 2003, 5, 803; c) F.-
A. Alphonse, F. Suzenet, A. Keromnes, B. Lebret, G. Guil-
laumet, Synlett 2002, 447.
The reported research was partially funded by the Deutsche For-
schungsgemeinschaft (DFG) and the China Scholarship Council.
[15] a) K. Takagi, A. Bajnati, M. Hubert-Habart, Heterocycles
1990, 31, 1105; b) J. A. Ragan, R. E. McDermott, B. P. Jones,
D. J. am Ende, P. J. Clifford, S. J. McHardy, S. D. Heck, S.
Liras, B. E. Segelstein, Synlett 2000, 1172.
[16] J. T. Gupton, J. E. Gall, S. W. Riesinger, S. Q. Smith, K. M.
Bevirt, J. A. Sikorski, M. L. Dahl, Z. Arnold, J. Heterocycl.
Chem. 1991, 28, 1281.
[1]
[2]
T. Shibata, S. Yonekubo, K. Soai, Angew. Chem. Int. Ed. 1999,
38, 659; Angew. Chem. 1999, 111, 746.
a) K. Soai, T. Kawasaki, Top. Curr. Chem. 2008, 284, 1; b) T.
Kawasaki, K. Soai, Bull. Chem. Soc. Jpn. 2011, 84, 879; c) T.
Gehring, M. Busch, M. Schlageter, D. Weingand, Chirality
2010, 22, 173.
[17] a) Z. Arnold, Collect. Czech. Chem. Commun. 1965, 30, 2125;
b) Z. Arnold, M. Budesinsky, J. Org. Chem. 1988, 53, 5353.
[18] M. Keshavarz-K., S. D. Cox, R. O. Angus, F. Wudl, Synthesis
1988, 641.
[19] PyBroP = bromotripyrrolidinophosphonium hexafluorophos-
phate, see: E. Frérot, J. Coste, A. Pantaloni, M.-N. Dufour, P.
Jouin, Tetrahedron 1991, 47, 259.
[20] Conditions: CuTC (1.4 equiv.), PhB(OH)2 (1.4 equiv.),
Pd(PPh3)4 (2 mol-%), THF, 80 °C, 24 h.
[21] Aldehyde 13 was independently shown to undergo standard
acid-catalyzed acetalization with ethylene glycol (toluene,
110 °C, pTsOH) to give a 97% yield of dioxolane acetal 15; see
the Supporting Information.
[22] http://orgprepdaily.wordpress.com/2008/02/24/arnold-salt/, ac-
cessed May 14, 2010.
[23] J. C. McWilliams, E. Buck, K. K. Eng, P. E. Maligres, J. W.
Sager, M. S. Waters, G. R. Humphrey, WO 02/28840 A1, 2002.
[24] Further experimental details are provided in the Supporting
Information.
[3]
[4]
a) D. A. Singleton, L. K. Vo, J. Am. Chem. Soc. 2002, 124,
10010; b) K. Soai, L. Sato, T. Shibata, S. Komiya, M. Hayashi,
Y. Matsueda, H. Imamura, T. Hayase, H. Morioka, H. Tabira,
J. Yamamoto, Y. Kowata, Tetrahedron: Asymmetry 2003, 14,
185.
a) T. Kawasaki, S. Kamimura, A. Amihara, K. Suzuki, K. Soai,
Angew. Chem. Int. Ed. 2011, 50, 6796; Angew. Chem. 2011, 123,
6928; Angew. Chem. 2011, 123, 6928; b) M. Busch, M. Schlag-
eter, D. Weingand, T. Gehring, Chem. Eur. J. 2009, 15, 8251;
c) I. D. Gridnev, J. M. Serafimov, H. Quiney, J. M. Brown, Org.
Biomol. Chem. 2003, 1, 3811; d) F. Lutz, T. Kawasaki, K. Soai,
Tetrahedron: Asymmetry 2006, 17, 486.
[5]
[6]
I. Sato, T. Yanagi, K. Soai, Chirality 2002, 14, 166.
L. Lin, C. Tsai, K. Wong, T. Huang, C. Wu, S. Chou, F. Lin,
S. Chenc, A. Tsaic, J. Mater. Chem. 2011, 21, 5950.
[7] For an early example of the sequence of condensation and
POCl3-mediated chlorination, see: S. Gabriel, J. Colman, Ber.
Dtsch. Chem. Ges. 1899, 32, 1525.
[8] a) F.-A. Kang, J. C. Lanter, C. Cai, Z. Sui, W. V. Murray, Chem.
Commun. 2010, 46, 1347, and references cited therein; b) C.
Shi, C. C. Aldrich, Org. Lett. 2010, 12, 2286; c) Y. Luo, J. Wu,
Tetrahedron Lett. 2009, 50, 2103; d) F.-A. Kang, Z. Sui, W. V.
Murray, J. Am. Chem. Soc. 2008, 130, 11300; e) L. Ackermann,
M. Mulzer, Org. Lett. 2008, 10, 5043.
[9] For reviews, see: a) H. Prokopcová, C. O. Kappe, Angew. Chem.
Int. Ed. 2009, 48, 2276; Angew. Chem. 2009, 121, 2312; Angew.
Chem. 2009, 121, 2312; b) T. Y. Luh, Z.-J. Ni, Synthesis 1990,
89.
[25] Since 16 contains two isothiouronium cations per formula unit,
this ratio corresponds to a 1.5 molar excess of S-methyliso-
thiouronium over 9.
[26] Use of microwave heating in desulfurative cross-coupling and
addition of the catalyst in two separate portions has been re-
commended by Kappe et al., see ref.[10]
[27] Heating of 13 (1 equiv.) with 1-octyne (1.5 equiv.), CuTC
(1.05 equiv.), Pd(OAc)2 (4 mol-%) and PPh3 (4 mol-%) in
MeCN for 23 min at 110 °C gave no alkynylation product;
starting material 13 was largely reisolated.
[10] For RSH and boronic acids, see: a) H. Prokopcová, C. O.
Kappe, J. Org. Chem. 2007, 72, 4440; b) H. Prokopcová, C. O.
Kappe, Adv. Synth. Catal. 2007, 349, 448; c) A. Lengar, C. O.
Kappe, Org. Lett. 2004, 6, 771.
[11] For RSH and various nucleophiles (B, Si, Sn), see: a) Q. Sun,
F. Suzenet, G. Guillaumet, J. Org. Chem. 2010, 75, 3437; b) N.
[28] Complementary coupling behavior of ArSH vs. ArSR sub-
strates was previously reported for 1,3-oxazoline- vs. 1,3-oxazo-
lidine-2-thiones, see ref.[11c]
[29] a) M. E. Angiolelli, A. L. Casalnuovo, T. P. Selby, Synlett 2000,
905; b) K. Lee, C. M. Counceller, J. P. Stambuli, Org. Lett.
2009, 11, 1457.
Arshad, J. Hashim, C. O. Kappe, J. Org. Chem. 2009, 74, 5118; [30] a) L. Melzig, A. Metzger, P. Knochel, Chem. Eur. J. 2011, 17,
c) S. Silva, S. Tardy, S. Routier, F. Suzenet, A. Tatibouet, A. P.
Rauter, P. Rollin, Tetrahedron Lett. 2008, 49, 5583.
2948; b) A. Metzger, L. Melzig, P. Knochel, Synthesis 2010,
2853; c) L. Melzig, A. Metzger, P. Knochel, J. Org. Chem. 2010,
75, 2131; d) A. Metzger, L. Melzig, C. Despotopoulou, P. Kno-
chel, Org. Lett. 2009, 11, 4228.
[12] For RSH and alkynes, see: a) O. V. Maltsev, A. Pöthig, L. Hin-
termann, Org. Lett. 2014, 16, 1282; b) Z.-J. Quan, W.-H. Hu,
X.-D. Jia, Z. Zhang, Y.-X. Da, X.-C. Wang, Adv. Synth. Catal.
2012, 354, 2939; c) X. Guinchard, E. Roulland, Org. Lett. 2009,
11, 4700; d) S. Silva, B. Sylla, F. Suzenet, A. Tatibouet, A. P.
Rauter, P. Rollin, Org. Lett. 2008, 10, 853.
[31] F. Naso, Pure Appl. Chem. 1988, 60, 79.
[32] L. S. Liebeskind, J. Srogl, J. Am. Chem. Soc. 2000, 122, 11260.
[33] K. Itami, D. Yamazaki, J. Yoshida, J. Am. Chem. Soc. 2004,
126, 15396.
[13] a) A. Aguilar-Aguilar, L. S. Liebeskind, E. Peña-Cabrera, J. [34] For an overview of methods available for preparing heterocy-
Org. Chem. 2007, 72, 8539; b) C. Kusturin, L. S. Liebeskind,
H. Rahman, K. Sample, B. Schweitzer, J. Srogl, W. L. Neum-
ann, Org. Lett. 2003, 5, 4349; c) C. L. Kusturin, L. S. Liebes-
kind, W. L. Neumann, Org. Lett. 2002, 4, 983; d) L. S. Liebes-
kind, J. Srogl, Org. Lett. 2002, 4, 979; e) C. Savarin, J. Srogl,
clic methylthio ethers, see ref.[30a]
[35] For other methods of condensation/coupling shortcuts, see: a)
ref.[10c]; b) ref.[12a]; c) ref.[14c]
Received: August 26, 2014
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7

Job/Unit: O43133
/KAP1
Date: 07-10-14 14:32:23
Pages: 8
O. V. Maltsev, R. Rausch, Z.-J. Quan, L. Hintermann
FULL PAPER
Cross-Coupling
O. V. Maltsev, R. Rausch, Z.-J. Quan,
L. Hintermann* ................................ 1–8
Synthesis of Soai Type 2-Arylpyrimidine-5-
carbaldehydes
through
Desulfurative
Cross-Coupling with Arylboronic Acids
2-Arylpyrimidine-5-carbaldehydes, which
are of relevance as substrates in Soai’s
asymmetric autocatalysis, are prepared
through Liebeskind–Srogl coupling of aryl
boronic acids with 2-methylthiopyrimidine-
5-carbaldehyde; the latter is obtained in a
hydrolytic condensation of two symmetric
amidinium salts.
Keywords: Asymmetric catalysis / Homo-
geneous catalysis / Palladium / Cross-cou-
pling / Nitrogen heterocycles
8
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