Catalytic Deprotonative α-Formylation of Heteroarenes by an Amide Base Generated in Situ from Tetramethylammonium Fluoride and Tris(trimethylsilyl)amine

Article abstract of DOI:10.1021/acs.oprd.8b00247

Heteroarene formylations in DMF solution proceed in the presence of an amide base catalyst generated in situ from tetramethylammonium fluoride (TMAF) and tris(trimethylsilyl)amine (N(TMS)₃). The reaction proceeds at room temperature and has an operationally simple procedure. Various heteroarenes, including benzothiophene, thiophene, benzothiazole, oxazole, and indole derivatives, can be formylated with high functional group tolerance.

Full text of DOI:10.1021/acs.oprd.8b00247

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Full Paper
Catalytic Deprotonative #-Formylation of Heteroarenes by
an Amide Base Generated In Situ from TMAF and N(TMS)3
Masanori Shigeno, Yuki Fujii, Akihisa Kajima, Kanako Nozawa-Kumada, and Yoshinori Kondo
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00247 • Publication Date (Web): 29 Oct 2018
Downloaded from http://pubs.acs.org on October 29, 2018
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Catalytic Deprotonative -Formylation of
Heteroarenes by an Amide Base Generated In Situ
from TMAF and N(TMS)3
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Masanori Shigeno*, Yuki Fujii, Akihisa Kajima, Kanako Nozawa-Kumada, Yoshinori Kondo*
Department of Biophysical Chemistry, Graduate School of Pharmaceutical Science, Tohoku
University, Aoba, Sendai, 980-8578, Japan
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Abstract
Heteroarene formylations in DMF solution proceed in the presence of an amide-base catalyst
generated in situ from tetramethylammonium fluoride (TMAF) and N(TMS) . The reaction
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proceeds at room temperature in an operationally simple procedure. Various heteroarenes,
including benzothiophene, thiophene, benzothiazole, oxazole, and indole derivatives, can be
formylated with high functional group tolerance.
KEYWORDS: Formylation, Room temperature deprotonation, Amide-base catalyst, Anions,
Heteroarenes
Introduction
Heteroarenes are ubiquitous in natural products, biologically active compounds, and organic
functional materials. The ability to directly and efficiently functionalize heteroarenes is crucial for
the construction of complex molecules bearing heteroarene scaffolds and for rapid access to
1
diverse molecules. Heteroarene formylation is of great importance in synthetic organic chemistry,
because the introduced formyl group serves as a core motif that can be transformed into a variety
2
of units by olefination, oxidation, reduction, and aldol reactions, among others. Deprotonative
formylation, which involves a two-step procedure, namely the deprotonation of the acidic proton
of the heteroarene and the subsequent coupling with a formylating agent, is a representative and
reliable method in this regard. In the deprotonation step, a stoichiometric amount of a strong base,
such as n-BuLi, lithium diisopropylamide (LDA), or lithium 2,2,6,6-tetramethylpiperidide
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(
LiTMP), is used. It is also noteworthy that these steps involve cryogenic conditions (78 °C) that
prevent temperature rising of the reaction mixture due to the exothermic nature of the
deprotonation step, as well as side reactions involving the nucleophilic carbanion. Such conditions
are of particular importance in reactions of nucleophiles bearing electrophilic moieties. Hence, the
development of deprotonative heteroarene-formylation methodology that is highly functional
group tolerant under ambient conditions is a very attractive objective. A few deprotonative
methods have been used to formylate heteroarenes in the presence of electron-withdrawing
substituents at almost-ambient temperatures (Figure 1, (A)). In pioneering work, Mulzer studied
the formylation of pyridines bearing amide and carbamate groups at 0 °C and room temperature,
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respectively, using (2,2,6,6-tetramethylpiperidino)magnesium chloride (TMPMgCl). We also
reported the formylation of ethyl 2-thiophenecarboxylate at room temperature in the presence of
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i-Pr
2
NMgCl. Recently, Knochel developed a flow procedure that uses TMPMgCl·LiCl at room
temperature for the formylation of bromo- and chloro-substituted pyridines, as well as thiophenes
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possessing chlorines and ethoxycarbonyl groups. Zhao formylated bromo-substituted furan,
benzofuran, thiophene, and benzothiophene at 0 °C using sodium bis(trimethylsilyl)amide
(NaHMDS).7
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Figure 1. Formylations of heteroarenes possessing electrophilic moieties under almost ambient
conditions.
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Our group has been engaged in the development of heteroarene deprotonative functionalization
methodology using amide-base catalysts generated in situ from fluoride or alkoxide salts and
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aminosilanes. Heteroarenes, such as benzothiazole, benzoxazole, triazole, benzothiophene, and
benzofuran derivatives, have been coupled with aldehyde and ketone moieties.8a, 8b Herein, we
report that heteroarene formylation proceeds with DMF using the above-mentioned catalytic
system at room temperature in an operationally simple one-pot procedure in which a solution of
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the heteroarene in DMF is stirred with a catalytic amount of tetramethylammonium fluoride
(
TMAF) and a stoichiometric amount of N(TMS) (Figure 1, (B)). In other words, this reaction
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necessitates neither the conventional two-step protocol involving the dropwise addition of reagents,
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nor cryogenic conditions. A variety of heteroarenes bearing functional groups, including methoxy,
pyridyl, halo, ethoxycarbonyl, (methylphenylamino)carbonyl, and cyano groups can be employed,
the details of which are reported below.
Results and Discussion
A variety of fluoride and alkoxide sources were used to investigate the formylation of
1
0
benzothiophene (1a, pKa = 32.0 at the 2-position ) in DMF (Table 1). A solution of 1a (0.20
mmol) in DMF (0.50 mL) was stirred for 24 h at room temperature in the presence of a salt (0.02
mmol) and N(TMS) (0.40 mmol). The reaction was then quenched with 1 M HCl. A standard
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extractive workup provided the crude material, from which the yield of the formylated product 3a
was determined by NMR spectroscopy. Among alkali-metal fluoride salts, formylation proceeded
smoothly with CsF, to afford 3a in 84% yield (entries 1–3). Sodium alkoxide and phenoxide salts,
namely NaOMe, NaO-t-Bu, and NaOPh, furnished 3a in yields of 84, 76, and 35%, respectively
(entries 4–6). The KOMe and KO-t-Bu potassium alkoxide salts provided 3a in high yields of 91
and 90%, respectively (entries 7 and 8). Ammonium salts were next examined;
tetramethylammonium fluoride (TMAF) was the most effective, affording 3a in 93% isolated yield
(entries 9 and 10). Satisfactory product yields of 88, 85, or 81% respectively, were obtained even
when the reaction was conducted for a shorter time (6 h), or with smaller amounts of TMAF (3
mol %) or DMF (46 L, 0.60 mmol) (entries 11–13). 3a was not obtained in the absence of either
TMAF or N(TMS) (entries 14 and 15).
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Table 1. Optimizing the formylation conditions for 1a.a
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Yield (%)b
Entry
Fluoride or alkoxide salt
KF
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RbF
CsF
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NaOMe
NaO-t-Bu
NaOPh
KOMe
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76
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91
KO-t-Bu
TBAFc
TMAF
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97 (93)d
88e
85f
81g
0h
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TMAF
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14
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TMAF
TMAF
none
TMAF
0i
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Reactions were conducted on a 0.2 mmol scale. b Yields were determined by H-NMR
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c
d
spectroscopy. A 1 M solution of TBAF (tetrabutylammonium fluoride) in THF was used.
e
f
Isolated yield. The reaction time was 6 h. The reaction was conducted on a 1.0 mmol scale with
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g
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TMAF (3 mol %). The reaction was conducted with DMF (46 L). The reaction was attempted
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in the absence of fluoride or alkoxide salt. The reaction was attempted in the absence of N(TMS)
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The optimized conditions were used to formylate a variety of benzothiophenes (Figure 2).
Formylated products 3b and 3c bearing electron-donating methyl and methoxy groups were
obtained in yields of 88 and 83%, respectively, while 5-chlorobenzothiophene (1d) afforded the
corresponding product 3d in 86% yield. Benzothiophenes 1e and 1f bearing bromine atoms at the
5
- and 3-positions, respectively, afforded 3e and 3f in good yields when CsF was used as the
fluoride source.
Figure 2. Formylations of benzothiophenes catalyzed by the TMAF/N(TMS) amide-base
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system.a
a
b
c
d
Reactions were conducted on a 0.20 mmol scale. Isolated yield. DMF (2 mL) was used. CsF
e
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30 mol %) and N(TMS)
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(3 equiv.) were used. CsF (10 mol %) was used instead of TMAF.
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Heteroarenes other than benzothiophenes were also used in the present formylation system
(
Figure 3); thiophenes 4ae bearing aryl groups at their 2-positions were employed; clearly
halogens, as well as methoxy and cyano functional groups are tolerated. 2-(2-Pyridyl)thiophene
4f), bearing a pyridyl group at the 2-position of the thiophene ring, also provided product 5f in
7% yield. Notably, ester and amide moieties on the thiophene ring were also tolerated to afford
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5g and 5h, respectively. The formylations of benzothiazole (4i, pKa = 27.3 at the 2-position ) and
its derivatives 4jl possessing methyl, methoxy, and fluoro groups proceeded to furnish 5il in
good yields. The reaction could be extended to include 2-phenyloxazole (4m), which gave 5m in
90% yield, while 3-cyano-N-methylindole (4n) afforded 5n in 88% yield.
Figure 3. Formylations of heteroarenes other than benzothiophenes by amide-base catalysis
using TMAF and N(TMS)
.a
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(3 equiv.) were used. DMF (1.0 mL) was used. CsF (10 mol %) was used instead of
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TMAF. DMF (3.0 mL) was used. DMF (2.0 mL) was used.
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The scalable nature of the present formylation was demonstrated on a 2.7 g scale (20 mmol) of
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b
our previously reported deprotonative coupling of 4i with pivalaldehyde (6) was also herein
performed on a 1.6 g scale (12 mmol) to produce 2.0 g of 7 in 74% yield (Scheme 1, eq. 2).
Scheme 1. Scale up of the formylation of 1a and our previously reported deprotonative coupling
of 4i with 6.
For comparison with the present catalytic amide-base system, stoichiometric amounts of alkali-
metal bis(trimethylsilyl)amides, namely NaHMDS and KHMDS, and alkali-metal alkoxides,
namely NaOMe, NaO-t-Bu, KOMe, and KO-t-Bu, were used in the one-step protocol involving
1
a at room temperature, which afforded low yields of 3a (Table 2). On the other hand, catalytic
amounts of a variety of alkoxide and fluoride salts, including NaOMe, NaO-t-Bu, KOMe, KO-t-
Bu, CsF, and TMAF, provided 3a in good yields when used with N(TMS) (Table1). It should also
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be noted that, when a catalytic amount of NaHMDS or KHMDS was used in the reaction of 1a
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(Scheme 2). On the basis of these results, we conclude that the current system is driven by the
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formation of strong OSi bonds, as shown in Figures 4 and S1.
Table 2. Reaction of 1a with alkali-metal bis(trimethylsilyl)amide and alkali-metal alkoxide.a
Entry
Base
Yield of 3a (%)b
Recovery of 1a (%)b
1
2
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4
5
6
NaHMDS
KHMDS
NaOMe
NaO-t-Bu
KOMe
13
15
0
39
32
86
81
81
63
0
0
KO-t-Bu
3
a
b
1
Reactions were conducted on a 0.2 mmol scale. Yields were determined by H-NMR analysis.
Scheme 2. Reaction of 1a with a catalytic amount of NaHMDS or KHMDS and a stoichiometric
amount of N(TMS)
3
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1
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8
9
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1
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4
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
1
Yields were determined by H-NMR analysis.
2
-Deuteriobenzothiophene (1a-d) was subjected to our reaction conditions using TMAF (10
mol %), N(TMS) (10 mol %), and HMDS (2 equiv.), to afford a trace amount of 3a and a 85%
3
yield of 1a (78% H-incorporation at the 2-position) (Scheme 3), which reveals that 1a is reversibly
deprotonated and again emphasises that the strong OSi bond formation involved in the current
system (Figures 4 and S1) plays an important role for proceeding the reaction.
Scheme 3. Reaction of 1a-d with a catalytic amount of TMAF and N(TMS) and a stoichiometric
3
amount of NH(TMS) .
2
a
1
Yields were determined by H-NMR analysis.
A plausible formylation mechanism is presented as follows (Figure 4). Amide base A, generated
1
1
from TMAF and N(TMS) , abstracts the acidic proton at the 2-position of 1a. The resulting
3
carbanion B couples with DMF to form the alkoxide intermediate C, which then reacts with
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N(TMS)
3
to provide the silylated product D, regenerating A (path a). As an alternative pathway,
silicate species E, formed by the coordination of C to a silicon atom of N(TMS) , directly
3
1
1
deprotonates 1a to give B and D (path b). Finally, D is desilylated when quenched with 1 M HCl
to afford the formylated product 3a.12
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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5
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5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 4. Plausible reaction mechanism.
Conclusions
In summary, we developed a catalytic heteroarene-formylation system that involves the amide
base generated in situ from TMAF and N(TMS) ; the reaction proceeds at room temperature in a
3
convenient protocol. It should be noted that the present system, which uses a catalytic amount of
a salt and a stoichiometric amount of an aminosilane, facilitates this transformation more
effectively than stoichiometric amounts of an HMDS amide and an alkoxide base. Heteroarenes,
such as benzothiophene, thiophene, oxazole, benzofuran, and indole derivatives, can be formylated
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
3
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4
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5
5
5
5
5
5
6
using this protocol. The reaction is also compatible with heteroarenes bearing a variety of
functionalities, including methoxy groups, esters, amides, nitriles, halogen, and pyridyl groups.
0
1
2
3
4
5
6
7
8
9
0
1
2
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9
0
Experimental section
General Information. All reactions were carried out under N or Ar atmosphere. Flash column
2
chromatography was performed with Kanto silica gel 60 N (spherical, neutral, 70-230 m).
®
Preparative thin-layer chromatography was performed with silica gel (Wakogel B-5F). Melting
points (Mp) were determined with a Yazawa micro melting point apparatus without correction.
Infrared (IR) data were recorded on SensIR ATR (Attenuated Total Reflectance) FT-IR, and
-1
absorbance frequencies are reported in reciprocal centimeters (cm ). NMR data were recorded on
1
13
a JEOL AL400 spectrometer (395.75 MHz for H, 99.50 MHz for C). Chemical shifts are
expressed in  (parts per million, ppm) values, and coupling constants are expressed in herts (Hz).
1H NMR spectra were referenced to tetramethylsilane as an internal standard or to a solvent signal
1
3
(CDCl
3
: 7.26 ppm). C NMR spectra were referenced to tetramethylsilane as an internal standard
or to a solvent signal (CDCl
3
: 77.0 ppm). Low and high resolution mass spectra (LRMS and
HRMS) were obtained from Mass Spectrometry Resource, Graduate School of Pharmaceutical
Sciences, Tohoku University, on a JEOL JMS-DX 303 and JMS-700/JMS-T 100 GC spectrometer,
respectively.
1
3
14
15
15
16
15
16
17
18
19
19
20
21
22
Materials. 1c , 1d , 4a , 4b , 4c , 4d , 4e , 4f , 4h , 4j , 4k , 4l , 4m , 4n , and 1a-
d23 were prepared according to the literature procedures. DMF was distilled over CaH
2
under a
reduced pressure. All other commercially available chemical resources were used as received
without further purification.
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Representative Procedure for Catalytic Deprotonative Formylation of Heteroarenes by an
Amide Base Generated In Situ from TMAF and N(TMS)
Benzo[b]thiophene-2-carboxaldehyde (3a). In a glove box under an Ar atmosphere, to a mixture
of TMAF (1.8 mg, 0.019 mmol) and N(TMS) (91.2 mg, 0.39 mmol) in DMF (0.5 mL) was added
a (26.8 mg, 0.20 mmol) in an oven-dried vial equipped with a stirrer bar. The vial was sealed
3
(Table 1, entry 10).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
1
with a cap containing an inner Teflom film. After stirring at room temperature for 24 h, 1M HCl
aqueous solution (0.5 mL) was added to the reaction mixture. The mixture was stirred at room
temperature for 1.5 h, and H
2
O (10 mL) was added. The mixture was extracted with AcOEt (10
, and concentrated.
mL x 3), washed with H O (10 mL x 2) and brine (10 mL), dried over MgSO
2
4
The residue was purified by column chromatography on silica gel (hexane:AcOEt = 5:1) to afford
24a
3
a (30.2 mg, 0.186 mmol, 93%) as yellow solid: Mp 3435 °C (AcOEt/hexane) (lit. 3435 °C;
2
4b
1
3
335 °C ). H NMR (400 MHz, CDCl /TMS)  7.42 (t, 1H, J = 7.9 Hz), 7.48 (t, 1H, J = 7.6
3
1
3
Hz), 7.87 (d, 1H, J = 7.8 Hz), 7.91 (d, 1H, J = 7.8 Hz), 7.99 (s, 1H), 10.08 (s, 1H). C NMR (100
MHz, CDCl )  123.2, 125.2, 126.2, 128.1, 134.4, 138.5, 142.6, 143.3, 184.6. LRMS (EI) m/z: 162
3
+
(M ). HRMS m/z Calcd for C
9
H
6
OS: 162.0139. Found: 162.0111. IR (neat): 1666, 1513, 1425,
-1
1
320, 1255, 1133, 988, 876, 846, 759, 726 cm . The spectra data matched those reported in the
literature. 24
5-Methylbenzo[b]thiophene-2-carboxaldehyde (3b). According to the procedure analogous to
that described for 3a, 3b (32.1 mg, 0.182 mmol, 88%) was obtained from 1b (30.6 mg, 0.206
25
1
mmol) as white solid: Mp 100101 °C (AcOEt/hexane) (lit. 94.595 °C ). H NMR (400 MHz,
CDCl
3
/TMS)  2.48 (s, 3H), 7.33 (d, 1H, J = 8.3 Hz), 7.72 (s, 1H), 7.77 (d, 1H, J = 8.3 Hz), 7.94
13
(
s, 1H), 10.08 (s, 1H). C NMR (100 MHz, CDCl
3
)  21.3, 122.9, 125.9, 130.1, 134.1, 135.1,
+
1
38.9, 140.0, 143.5, 184.7. LRMS (EI) m/z: 176 (M ). HRMS: Calcd. for C10
8
H OS: 176.0296.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Found: 176.0301. IR (neat): 1669, 1559, 1520, 1441, 1257, 1231, 1155 1132, 895, 850, 774, 718
-1
cm .
4-Methoxylbenzo[b]thiophene-2-carboxaldehyde (3c). According to the procedure analogous to
that described for 3a, 3c (30.9 mg, 0.161 mmol, 83%) was obtained from 1c (31.8 mg, 0.194 mmol)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
26
1
as white solid: Mp 9798 °C (AcOEt/hexane) (lit. 9697 °C ). H NMR (400 MHz, CDCl
3
/TMS)
 3.90 (s, 3H), 7.04 (dd, 1H, J = 9.2 Hz, J = 2.4 Hz), 7.30 (d, 1H, J = 2.0 Hz), 7.79 (d, 1H, J =
13
8
.8 Hz), 7.92 (s, 1H), 10.01 (s, 1H). C NMR (100 MHz, CDCl )  55.6, 104.5, 116.4, 127.1,
3
+
132.5, 134.6, 141.0, 145.1, 160.4, 184.1. LRMS (EI) m/z: 192 (M ). HRMS: Calcd. for C10
H
8
2
O S:
-1
1
92.0245. Found: 192.0238. IR (neat): 1662, 1600, 1512, 1265, 1217, 1139, 1010, 834, 722 cm .
5
-Chlorobenzo[b]thiophene-2-carboxaldehyde (3d). In a glove box under an Ar atmosphere, to
a mixture of 1d (34.6 mg, 0.205 mmol) and N(TMS) (96.2 mg, 0.412 mmol) in DMF (2.0 mL)
3
was added TMAF (2.0 mg, 0.021 mmol) in an oven-dried vial equipped with a stirrer bar. The vial
was sealed with a cap containing an inner Teflom film. After stirring at room temperature for 21
h, 1M HCl aqueous solution (0.5 mL) was added to the reaction mixture. The mixture was stirred
at room temperature for 1.5 h, and H
10 mL x 3), washed with H O (10 mL x 2) and brine (10 mL), dried over MgSO
The residue was purified by preparative thin-layer chromatography of silica gel (hexane:AcOEt =
:1) to afford 3d (34.5 mg, 0.175 mmol, 86%) as yellow solid: Mp 136139 °C (AcOEt/hexane)
2
O (10 mL) was added. The mixture was extracted with AcOEt
(
2
4
, and concentrated.
5
2
7a
27b
1
(
lit. 13435 °C; 135 °C ). H NMR (400 MHz, CDCl
3
/TMS)  7.46 (dd, 1H, J = 8.8 Hz, J =
1
3
2.0 Hz), 7.83 (d, 1H, J = 8.8 Hz), 7.92 (d, 1H, J = 2.0 Hz), 7.96 (s, 1H), 10.11 (s, 1H). C NMR
(
100 MHz, CDCl
3
)  124.4, 125.5, 128.6, 131.6, 133.1, 139.6, 140.6, 145.0, 184.4. LRMS (EI)
ClOS: 196.9750. Found: 196.9724. IR (neat): 1674, 1514,
+
m/z: 196 (M ). HRMS: Calcd. for C
9
H
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425, 1251, 1134, 1077, 905, 870, 799, 714 cm . The spectra data matched those reported in the
literature.27
5-Bromo[b]thiophene-2-carboxaldehyde (3e). According to the procedure analogous to that
described for 3d, except that the reaction was conducted with CsF (9.4 mg, 0.062 mmol) and
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N(TMS)
3
(139.6 mg, 0.598 mmol) in DMF (2.0 mL) for 19 h and that the crude material was
purified by column chromatography on silica gel (hexane:AcOEt = 10:1), 3e (39.8 mg, 0.165 mmol,
7
9%) was obtained from 1e (44.6 mg, 0.209 mmol) as white solid: Mp 129130 °C
1
(AcOEt/hexane). H NMR (400 MHz, CDCl
3
/TMS)  7.59 (dd, 1H, J = 8.8 Hz, J = 1.9 Hz), 7.76
1
3
(d, 1H, J = 8.8 Hz), 7.95 (s, 1H), 8.08 (d, 1H, J = 1.4 Hz), 10.1 (s, 1H). C NMR (100 MHz,
+
CDCl
HRMS: Calcd. for C
1275, 1216, 1134, 1064, 881, 808, 710 cm .
-Bromo[b]thiophene-2-carboxaldehyde (3f). According to the procedure analogous to that
3
)  119.2, 124.6, 128.6, 131.1, 132.9, 140.0, 141.1, 144.8, 184.3. LRMS (EI) m/z: 240 (M ).
9
H BrOS: 239.9244. Found: 239.9221. IR (neat): 1668, 1548, 1511, 1423,
5
-1
3
described for 3a, except that CsF (3.3 mg, 0.022 mmol) was used instead of TMAF, 3f (35.7 mg,
0.148 mmol, 74%) was obtained from 1f (42.6 mg, 0.200 mmol) as yellow solid: Mp 121122 °C
2
8a
28b
1
(
AcOEt/hexane) (lit. 11819 °C; 116117 °C ). H NMR (400 MHz, CDCl /TMS) 
3
1
3
7.497.61 (m, 2H), 7.86 (d, 1H, J = 7.8 Hz), 8.00 (d, 1H, J = 8.1 Hz), 10.27 (s, 1H). C NMR
(
100 MHz, CDCl )  118.8, 123.4, 125.0, 126.0, 129.3, 136.5, 138.0, 140.4, 184.7. LRMS (EI)
3
+
m/z: 240 (M ). HRMS: Calcd. for C
9
H
5
BrOS: 239.9244. Found: 239.9236. IR (neat): 1662, 1501,
-1
28
1304, 1248, 1196, 919, 809, 759 cm . The spectra data matched those reported in the literature.
5
-Phenylthiophene-2-carboxaldehyde (5a). According to the procedure analogous to that
described for 3a, 5a (30.0 mg, 0.159 mmol, 77%) was obtained from 4a (33.2 mg, 0.207 mmol)
2
9a
29b
1
as pale yellow solid: Mp 9596 °C (AcOEt/hexane) (lit. 92 °C; 94.695.1 °C ). H NMR
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
400 MHz, CDCl
3
/TMS)  7.337.50 (m, 4H), 7.637.70 (m, 2H), 7.72 (d, 1H, J = 3.9 Hz), 9.88
1
3
(s, 1H). C NMR (100 MHz, CDCl
3
)  124.1, 126.4, 129.2, 129.4, 133.0, 137.4, 142.4, 154.2,
OS: 188.0296. Found: 188.0287. IR
+
1
82.8. LRMS (EI) m/z: 188 (M ). HRMS: Calcd. for C11
H
8
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
(neat): 1662, 1501, 1304, 1248, 1196, 919, 809, 759 cm . The spectra data matched those reported
in the literature.29
5
-(4-Fluorophenylthiophene)-2-carboxaldehyde (5b). According to the procedure analogous to
that described for 3a, 5b (36.4 mg, 0.176 mmol, 86%) was obtained from 4b (36.4 mg, 0.204
30a
30b
mmol) as pale yellow solid: Mp 114115 °C (AcOEt/hexane) (lit. 103 °C; 114116 °C ).
1H NMR (400 MHz, CDCl
3
/TMS)  7.057.20 (m, 2H), 7.33 (d, 1H, J = 3.9 Hz), 7.587.69 (m,
1
3
2
H), 7.73 (d, 1H, J = 3.9 Hz), 9.88 (s, 1H). C NMR (100 MHz, CDCl
3
)  116.3 (d, J
= 8.2 Hz), 129.3, 137.4, 142.5, 153.0, 163.4 (d, J
FOS: 206.0193. Found: 206.0202. IR
F
= 22.2 Hz),
124.0 (d, J
F
= 1.7 Hz), 128.2 (d, J
F
F
= 249.5 Hz),
+
1
82.7. LRMS (EI) m/z: 206 (M ). HRMS: Calcd. for C11
H
7
-1
(neat): 1635, 1611, 1506, 1442, 1437, 1386, 1232, 1162, 1058, 833, 808 cm . The spectra data
matched those reported in the literature.30
5
-(4-Chlorophenylthiophene)-2-carboxaldehyde (5c). According to the procedure analogous to
that described for 3a, 5c (41.2 mg, 0.185 mmol, 93%) was obtained from 4c (38.8 mg, 0.199 mmol)
3
0a
31
1
as white solid: Mp 8384 °C (AcOEt/hexane) (lit. 74 °C; 8889 °C ). H NMR (400 MHz,
13
CDCl
3
/TMS)  7.337.48 (m, 3H), 7.557.67 (m, 2H), 7.73 (d, 1H, J = 3.9 Hz), 9.88 (s, 1H). C
NMR (100 MHz, CDCl
3
)  124.3, 127.5, 129.4, 131.5, 135.4, 137.3, 142.7, 152.6, 182.7. LRMS
+
(EI) m/z: 222 (M ). HRMS: Calcd. for C11
H
7
ClOS: 221.9906. Found: 221.9898. IR (neat): 1653,
-1
1
530, 1445, 1402, 1223, 1093, 1057, 1008, 824, 799 cm . The spectra data matched those reported
in the literature.30a
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-(4-Methoxyphenylthiophene)-2-carboxaldehyde (5d). According to the procedure analogous
to that described for 3d, except that the reaction was conducted with TMAF (3.7 mg, 0.040 mmol)
and N(TMS) (141.9 mg, 0.608 mmol) in DMF (1.0 mL) for 24 h and that the crude material was
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
purified by column chromatography on silica gel (hexane:AcOEt = 10:1), 5d (28.0 mg, 0.128
mmol, 63%) was obtained from 4d (39.0 mg, 0.205 mmol) as pale yellow solid: Mp 120121 °C
30b
32
1
(AcOEt/hexane) (lit. 120 °C; 110111 °C ). H NMR (400 MHz, CDCl
3
/TMS)  3.86 (s,
3
H), 6.95 (d, 2H, J = 8.8 Hz), 7.30 (d, 1H, J = 4.4 Hz), 7.557.63 (m, 2H), 7.71 (d, 1H, J = 3.9
1
3
Hz), 9.86 (s, 1H). C NMR (100 MHz, CDCl )  55.4, 114.6, 123.0, 125.8, 127.8, 137.7, 141.5,
3
+
1
2
54.5, 160.7, 182.7. LRMS (EI) m/z: 218 (M ). HRMS: Calcd. for C12
H
10
2
O S: 218.0402. Found:
-1
18.3960. IR (neat): 1647, 1602, 1507, 1449, 1436, 1256, 1223, 1181, 1056, 1024, 833, 802 cm .
The spectra data matched those reported in the literature.30b, 32
-(4-Cyanophenylthiophene)-2-carboxaldehyde (5e). According to the procedure analogous to
5
that described for 3a, except that CsF (4.1 mg, 0.027 mmol) was used instead of TMAF, 5e (26.9
mg, 0.126 mmol, 62%) was obtained from 4e (37.9 mg, 0.205 mmol) as red solid: Mp 197198 °C
30b
33
1
(
AcOEt/hexane) (lit. 166 °C;
208210 °C (decomposition) ). H NMR (400 MHz,
1
3
CDCl
CDCl
3
3
/TMS)  7.50 (d, 1H, J = 3.9 Hz), 7.677.81 (m, 5H), 9.94 (s, 1H). C NMR (100 MHz,
)  112.6, 118.3, 125.8, 126.8, 133.0, 137.0, 137.2, 144.1, 151.0, 182.7. LRMS (EI) m/z:
+
2
13 (M ). HRMS: Calcd. for C12
7
H NOS: 213.0248. Found: 213.0244. IR (neat): 2220, 1666, 1604,
-1
1450, 1413, 1227, 1181, 1063, 839, 802 cm . The spectra data matched those reported in the
literature.30b
2
-(Pyridin-2-yl)-5-thiophene carbaldehyde (5f). According to the procedure analogous to that
described for 3a, 5f (25.4 mg, 0.134 mmol, 67%) was obtained from 4f (32.2 mg, 0.200 mmol) as
34a
34b
1
white solid: Mp 125126 °C (AcOEt/hexane) (lit. 122 °C; 119120 °C ). H NMR (400
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2
2
2
2
2
3
3
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3
3
3
3
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4
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5
5
5
5
5
5
5
6
MHz, CDCl
3
/TMS)  7.257.30 (m, 1H), 7.647.68 (m, 1H), 7.707.81 (m, 3H), 8.63 (d, 1H, J =
1
3
3
1
.9 Hz), 9.93 (s, 1H). C NMR (100 MHz, CDCl
3
)  119.7, 123.6, 125.0, 136.8, 136.9, 144.1,
+
49.9, 151.1, 153.9, 183.1. LRMS (EI) m/z: 189 (M ). HRMS: Calcd. for C10
7
H NOS: 189.0248.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
Found: 189.0273. IR (neat): 1646, 1581, 1528, 1447, 1230, 1157, 993, 819, 779 cm . The spectra
data matched those reported in the literature.34
5
-Formyl-thiophene-2-carboxylic acid ethyl ester (5g). According to the procedure analogous to
that described for 3a, except that the reaction was conducted in DMF (3.0 mL), 5g (25.6 mg, 0.139
mmol, 63%) was obtained from 4g (34.6 mg, 0.222 mmol) as white solid: Mp 5758 °C
5
6
1
(AcOEt/hexane) (lit. 5758 °C ; 56.9 °C ). H NMR (400 MHz, CDCl
3
/TMS)  1.40 (t, 3H,
J = 7.3 Hz), 4.40 (q, 2H, J = 7.2 Hz), 7.73 (d, 1H, J = 3.9 Hz), 7.83 (d, 1H, J = 3.9 Hz), 9.97 (s,
1
3
1H). C NMR (100 MHz, CDCl
3
)  14.2, 62.0, 133.1, 135.0, 141.5, 147.6, 161.5, 183.3. LRMS
NO S: 184.0194. Found: 184.0196. IR (neat): 1696,
+
(EI) m/z: 184 (M ). HRMS: Calcd. for C
8
H
8
3
-1
1
665, 1525, 1364, 1280, 1194, 1093, 1040, 1010, 822, 750 cm . The spectra data matched those
reported in the literature.5, 6
-((N-methyl-N-phenyl-amino)carbonyl-2-yl)-thiophenecarboxaldehyde (5h). According to the
5
procedure analogous to that described for 3a, except that the reaction was conducted in DMF (1.0
mL), 5h (43.4 mg, 0.177 mmol, 86%) was obtained from 4h (44.7 mg, 0.206 mmol) as white solid:
1
Mp 104105 °C (AcOEt/hexane). H NMR (400 MHz, CDCl
3
/TMS)  3.47 (s, 3H), 6.92 (d, 1H,
1
3
J = 2.3 Hz), 7.23 (d, 2H, J = 5.0 Hz), 7.387.46 (m, 4H), 9.81 (s, 1H). C NMR (100 MHz,
CDCl
3
)  39.1, 127.8, 128.7, 130.0, 132.2, 134.3, 143.4, 145.9, 161.8, 183.3. LRMS (EI) m/z: 245
S: 245.0510. Found: 245.0498. IR (neat): 1673, 1616, 1586,
+
(
M ). HRMS: Calcd. for C13
H11NO
2
-1
1
491, 1374, 1215, 1070, 828, 703 cm .
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Benzo[d]thiazole-2-carboxaldehyde (5i). According to the procedure analogous to that described
for 3d, except that the reaction was conducted in DMF (3.0 mL) for 19 h and that the crude material
was purified by column chromatography on silica gel (hexane:AcOEt = 6:1), 5i (22.2 mg, 0.136
mmol, 67%) was obtained from 4i (27.4 mg, 0.203 mmol) as yellow solid: Mp 7273 °C
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
35a
1
(
AcOEt/hexane) (lit. 75 °C ). H NMR (400 MHz, CDCl /TMS)  7.557.66 (m, 2H),
3
1
3
7
1
.978.05 (m, 1H), 8.228.27 (m, 1H), 10.17 (s, 1H). C NMR (100 MHz, CDCl
3
)  122.6, 125.8,
NOS:
+
27.4, 128.4, 136.4, 153.5, 165.3, 185.4. LRMS (EI) m/z: 162 (M ). HRMS: Calcd. for C
8
H
5
163.0092. Found: 163.0083. IR (neat): 1693, 1486, 1323, 1204, 1122, 1061, 954, 865, 772, 736
-
1
35b, 35c
cm . The spectra data matched those reported in the literature.
-Methylbenzo[d]thiazole-2-carbaldehyde (5j). According to the procedure analogous to that
6
described for 3a, except that the reaction was conducted in DMF (1.0 mL), 5j (26.4 mg, 0.149
mmol, 74%) was obtained from 4j (30.1 mg, 0.202 mmol) as yellow solid: Mp 7980 °C
1
(
AcOEt/hexane). H NMR (400 MHz, CDCl
3
/TMS)  2.54 (s, 3H), 7.42 (dd, 1H, J = 8.3 Hz, J =
1
3
1.5 Hz), 7.78 (s, 1H), 8.11 (d, 1H, J = 8.8 Hz), 10.14 (s, 1H). C NMR (100 MHz, CDCl )  21.9,
3
+
1
22.1, 125.2, 129.3, 136.7, 139.3, 151.8, 164.4, 185.5. LRMS (EI) m/z: 177 (M ). HRMS: Calcd.
for C
897, 812, 737 cm .
-Methoxybenzo[d]thiazole-2-carbaldehyde (5k). According to the procedure analogous to that
9
H
7
NOS: 177.0248. Found: 177.0234. IR (neat): 1684, 1489, 1318, 1223, 1187, 1131, 1037,
-1
6
described for 3a, except that the reaction was conducted in DMF (1.0 mL), 5k (31.8 mg, 0.165
mmol, 83%) was obtained from 4k (32.7 mg, 0.198 mmol) as yellow solid: Mp 124125 °C
1
(
AcOEt/hexane). H NMR (400 MHz, CDCl
3
/TMS)  3.93 (s, 3H), 7.21 (dd, 1H, J = 8.8 Hz, J =
1
3
2
.4 Hz), 7.38 (d, 1H, J = 2.4 Hz), 8.10 (d, 1H, J = 8.8 Hz), 10.10 (s, 1H). C NMR (100 MHz,
+
CDCl
3
)  55.9, 103.6, 118.2, 126.5, 138.6, 148.2, 160.3, 162.9, 185.1. LRMS (EI) m/z: 193 (M ).
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5
5
6
HRMS: Calcd. for C
9
H
7
NO
2
S: 193.0197. Found: 193.0191. IR (neat): 1683, 1601, 1492, 1452,
-1
36
1
273, 1196, 1118, 1014, 826, 734 cm . The spectra data matched those reported in the literature.
6-Fluorobenzo[d]thiazole-2-carbaldehyde (5l). According to the procedure analogous to that
described for 3d, except that the reaction was conducted for 20 h and that the crude material was
purified by column chromatography on silica gel (hexane:CH Cl = 1:5), 5l (24.8 mg, 0.137 mmol,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
68%) was obtained from 4l (30.9 mg, 0.202 mmol) as yellow solid: Mp 109110 °C
1
(
AcOEt/hexane). H NMR (400 MHz, CDCl
3
/TMS)  7.37 (dt, 1H, J = 2.4 Hz, J = 9.0 Hz), 7.68
1
3
(
dd, 1H, J = 7.8 Hz, J = 2.4 Hz), 8.22 (dd, 1H, J = 9.3 Hz, J = 4.9 Hz), 10.13 (s, 1H). C NMR
)  108.6 (d, J = 26.3 Hz), 116.9 (d, J = 24.7 Hz), 127.2 (d, J = 9.9 Hz),
= 11.5 Hz), 150.2, 162.3 (d, J = 250 Hz), 165.2 (d, J = 3.3 Hz), 184.9. LRMS (EI)
FNOS: 180.9998. Found: 181.0000. IR (neat): 1689, 1599,
(100 MHz, CDCl
3
F
F
F
1
37.73 (d, J
F
F
F
+
m/z: 181 (M ). HRMS: Calcd. for C
8
H
4
-1
1490, 1326, 1247, 1183, 1128, 866, 817, 738 cm .
-Phenyloxazole-5-carboxaldehyde (5m). According to the procedure analogous to that
2
described for 3a, except that the reaction was conducted in DMF (2.0 mL), 5m (31.5 mg, 0.182
mmol, 90%) was obtained from 4m (29.3 mg, 0.202 mmol) as white solid: Mp 6869 °C
37a
37b
1
(AcOEt/hexane) (lit. 74 °C; 6970 °C ). H NMR (400 MHz, CDCl /TMS)  7.487.60
3
1
3
(m, 3H), 7.96 (s, 1H), 8.178.22 (m, 2H), 9.83 (s, 1H). C NMR (100 MHz, CDCl )  125.8,
3
+
1
27.7, 129.1, 132.3, 139.1, 149.6, 165.5, 176.3. LRMS (EI) m/z: 173 (M ). HRMS: Calcd. for
C
9
7
H NOS: 173.0477. Found: 173.0468. IR (neat): 1665, 1529, 1475, 1450, 1347, 1234, 1144, 981,
-1
37
883, 714 cm . The spectra data matched those reported in the literature.
2
-Formyl-1-methyl-1H-indole-3-carbonitrile (5n). According to the procedure analogous to that
described for 3a, except that CsF (2.9 mg, 0.019 mmol) was used instead of TMAF, 5n (32.2 mg,
0.175 mmol, 88%) was obtained from 4n (31.0 mg, 0.198 mmol) as white solid: Mp 142144 °C
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(
AcOEt/hexane). H NMR (400 MHz, CDCl /TMS)  4.14 (s, 3H), 7.37 (t, 1H, J = 6.8 Hz),
3
1
3
7
9
.457.59 (m, 2H), 7.83 (d, 1H, J = 8.3 Hz), 10.15 (s, 1H). C NMR (100 MHz, CDCl
3
)  32.2,
7.0, 111.2, 113.4, 121.3, 123.7, 126.7, 128.3, 137.5, 138.9, 180.6. LRMS (EI) m/z: 184 (M+).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
HRMS: Calcd. for C11
202, 1130, 892, 876, 749 cm .
Scale up of the formylation of 1a and our previously reported deprotonative coupling of 4i
H
8
2
N O: 184.0637. Found: 184.0655. IR (neat): 1678, 1513, 1477, 1405,
-1
1
with 6 (Scheme 1.).
Scale up of the formylation of 1a (Scheme 1, eq. 1). In a glove box under an Ar atmosphere,
to a mixture of 1a (2.697 g, 20.1 mmol) and N(TMS) (7.008 g, 30.0 mmol) in DMF (50 mL) was
3
added TMAF (186.8 mg, 2.01 mmol) in an oven-dried glass screw tube ( = 2.5 cm, 15 cm)
equipped with a stirrer bar. The tube was sealed with a cap containing an inner Teflom film. After
stirring at room temperature for 19 h, 1M HCl aqueous solution (30 mL) was added to the reaction
mixture. The mixture was stirred at room temperature for 1.5 h, and saturated Na
solution (40 mL) was added. The mixture was extracted with AcOEt (20 mL x 3), washed with
brine (40 mL), dried over MgSO , and concentrated. The residue was purified by column
chromatography on silica gel (hexane:AcOEt = 10:1) to afford 3a (2.397 g, 14.8 mmol, 74%).
2
CO
3
aqueous
4
8
b
Scale up of the deprotonative coupling of 4i with 6 (Scheme 1, eq. 2). In a glove box under
an Ar atmosphere, to a mixture of 4i (1.621 g, 12.0 mmol), 6 (1.554 g, 18.0 mmol), and N(TMS)
4.226 g, 18.1 mmol) in DMF (30 mL) was added TMAF (115.3 mg, 1.24 mmol) in an oven-dried
glass screw tube ( = 2.5 cm, 15 cm) equipped with a stirrer bar. The tube was sealed with a cap
containing an inner Teflom film. After stirring at room temperature for 19 h, K CO (1.370 g, 9.91
mmol) and MeOH (20 mL) were added to the reaction mixture. The mixture was stirred at room
3
(
2
3
temperature for 1 h, and H
2
O (30 mL) was added. The mixture was extracted with AcOEt (20 mL
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2
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2
2
2
2
2
2
2
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4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
x 3), washed with brine (40 mL), dried over MgSO
4
, and concentrated. The residue was purified
by column chromatography on silica gel (hexane:AcOEt = 6:1) to afford 7 (1.969 g, 8.90 mmol,
74%).
0
1
2
3
4
5
6
7
8
9
0
1
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9
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1
2
3
4
5
6
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9
0
Reaction of 1a with alkali-metal bis(trimethylsilyl)amide and alkali-metal alkoxide (Table
2
).
Representative procedure (Table 2, entry 1). In a glove box under an Ar atmosphere, 1a (29.8
mg, 0.22 mmol) and DMF (0.5 mL) were added to NaHMDS (73.8 mg, 0.40 mmol) in an oven-
dried vial equipped with a stirrer bar. The vial was sealed with a cap containing an inner Teflom
film. After stirring at room temperature for 24 h, 1M HCl aqueous solution (0.5 mL) was added.
The mixture was stirred at room temperature for 1.5 h, and H O (10 mL) was added. The mixture
2
was extracted with AcOEt (10 mL x 3), washed with H
over MgSO
1,1,2-trichloroethane as an internal standard).
Reaction of 1a with a catalytic amount of NaHMDS or KHMDS and a stoichiometric
amount of N(TMS) (Scheme 2).
Representative procedure. In a glove box under an Ar atmosphere, to a mixture of 1a (30.1
mg, 0.224 mmol) and N(TMS) (97.0 mg, 0.415 mmol) in DMF (0.5 mL) was added NaHMDS
4.1 mg, 0.022 mmol) in an oven-dried vial equipped with a stirrer bar. The vial was sealed with a
2
O (10 mL x 2) and brine (10 mL), dried
1
4
, and concentrated. 3a was obtained in 13% NMR yield (based on H NMR using
3
3
(
cap containing an inner Teflom film. After stirring at room temperature for 24 h, 1M HCl aqueous
solution (0.5 mL) was added to the reaction mixture. The mixture was stirred at room temperature
for 1.5 h, and H
washed with H
2
O (10 mL) was added. The mixture was extracted with AcOEt (10 mL x 3),
2
O (10 mL x 2) and brine (10 mL), dried over MgSO , and concentrated. 3a was
4
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obtained in 71% NMR yield (based on H NMR using 1,1,2-trichloroethane as an internal
standard).
Reaction of 1a-d with a catalytic amount of TMAF and N(TMS)
amount of NH(TMS) (Scheme 3).
In a glove box under an Ar atmosphere, to a mixture of 1a-d (25.8 mg, 0.191 mmol), N(TMS)
4.4 mg, 0.019 mmol), and NH(TMS) (58.6 mg, 0.363 mmol) in DMF (0.5 mL) was added TMAF
1.9 mg, 0.020 mmol) in an oven-dried vial equipped with a stirrer bar. The vial was sealed with a
3
and a stoichiometric
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
3
(
(
2
cap containing an inner Teflom film. After stirring at room temperature for 24 h, 1M HCl aqueous
solution (0.5 mL) was added to the reaction mixture. Then, saturated Na CO aqueous solution
(5.0 mL) was added. The mixture was extracted with AcOEt (10 mL x 3), washed with H O (10
, and concentrated. 1a was obtained in 85% NMR
2
3
2
mL x 2) and brine (10 mL), dried over MgSO
4
1
yield (based on H NMR using 1,1,2-trichloroethane as an internal standard). After the material
was filtered through a pad of silica gel (hexane:CH
2
Cl
2
= 1:1) and concentrated, the ratio of proton
1
and deuterium at the 2-position of 1a was determined by H-NMR analysis.
Confirmation of silylated product D.
A mixture of 1a (26.6 mg, 0.20 mmol), DMF (46 L, 0.60 mmol), TMAF (1.9 mg, 0.02 mmol),
and N(TMS)
3
(96.4 mg, 0.40 mmol) was stirred at room temperature for 24 h. A portion of the
1
mixture was analyzed by H-NMR (CDCl
3
) (Figure S1). The mixture was also analyzed by HRMS:
m/z Calcd for C14H21NOSSi: 279.1113; Found: 279.1113.
ASSOCIATED CONTENT
1
13
Supporting Information. H and C NMR spectra of silylated product D and all isolated products
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AUTHOR INFORMATION
Corresponding Author
*
E-mail: mshigeno@m.tohoku.ac.jp, ykondo@m.tohoku.ac.jp, Fax: (+81) 22-795-6804.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was financially supported by JSPS KAKENHI Grant no. 23105009 in Advanced
Molecular Transformations by Organocatalysis (Y. K.), JSPS KAKENHI Grant no. 16H00997 in
Precisely Designed Catalysts with Customized Scaffolding (Y. K.), JSPS KAKENHI Grant no.
17K15419 (M. S.), Grand for Basic Science Research Projects from The Sumitomo Foundation
(M. S.), and also the Platform Project for Supporting Drug Discovery and Life Science Research
funded by Japan Agency for Medical Research and Development (AMED) (Y. K., M. S., and K.
N.-K.).
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