Development of conjugate addition of lithium dialkylcuprates to thiochromones: Synthesis of 2-alkylthiochroman-4-ones and additional synthetic applications

Article abstract of DOI:10.3390/molecules23071728

Lithium dialkylcuprates undergo conjugate addition to thiochromones to afford 2-alkylthiochroman-4-ones in good yields. This approach provide an efficient and general synthetic approach to privileged sulfur-containing structural motifs and valuable precursors for many pharmaceuticals, starting from common substrates-thiochromones. Good yields of 2-alkyl-substituted thiochroman-4-ones are attained with lithium dialkylcuprates, lithium alkylcyanocuprates or substoichiometric amount of copper salts. The use of commercially available inexpensive alkyllithium reagents will expedite the synthesis of a large library of 2-alkyl substituted thiochroman-4-ones for additional synthetic applications.

Full text of DOI:10.3390/molecules23071728

molecules
Article
Development of Conjugate Addition of Lithium
Dialkylcuprates to Thiochromones: Synthesis of
2-Alkylthiochroman-4-ones and Additional
Synthetic Applications
Shekinah A. Bass 1, Dynasty M. Parker 1, Tania J. Bellinger 1, Aireal S. Eaton 1,
Angelica S. Dibble 1, Kaata L. Koroma 1, Sylvia A. Sekyi 1, David A. Pollard 1 and
Fenghai Guo 1,2,
*
ID
1
Department of Chemistry, Winston Salem State University, 601 S. Martin Luther King Jr. Dr., Winston Salem,
NC 27110, USA; sbass116@rams.wssu.edu (S.A.B.); dparker115@rams.wssu.edu (D.M.P.);
tbellinger115@rams.wssu.edu (T.J.B.); aeaton114@rams.wssu.edu (A.S.E.);
adibble114@rams.wssu.edu (A.S.D.); kkoroma116@rams.wssu.edu (K.L.K.);
ssekyi116@rams.wssu.edu (S.A.S.); pollardda@wssu.edu (D.A.P.)
Biomedical Research Infrastructure Center, Winston Salem State University, Winston Salem, NC 27110, USA
Correspondence: guof@wssu.edu; Tel.: +1-336-750-3158
2
*
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 16 June 2018; Accepted: 13 July 2018; Published: 15 July 2018
Abstract: Lithium dialkylcuprates undergo conjugate addition to thiochromones to afford
2-alkylthiochroman-4-ones in good yields. This approach provide an efficient and general synthetic
approach to privileged sulfur-containing structural motifs and valuable precursors for many
pharmaceuticals, starting from common substrates-thiochromones. Good yields of 2-alkyl-substituted
thiochroman-4-ones are attained with lithium dialkylcuprates, lithium alkylcyanocuprates or
substoichiometric amount of copper salts. The use of commercially available inexpensive alkyllithium
reagents will expedite the synthesis of a large library of 2-alkyl substituted thiochroman-4-ones for
additional synthetic applications.
Keywords: thiochroman-4-ones; conjugate addition; lithium dialkyl cuprates; thiochromones;
2-alkylthiochroman-4-ones
1. Introduction
Sulfur-containing heterocycles are widely present in many bioactive natural products as well
as pharmaceutical active molecules [1–4]. The sulfur-containing heterocycles are an understudied
area when comparing to the oxygen-containing counterparts. In recent years, the development of
efficient synthetic approaches to sulfur-containing compounds has gained much attention due to their
widespread applications in biology, food chemistry, material science, and medicinal chemistry [1–11].
Sulfur-containing heterocycles, such as thiochromanone, thioflavanone, thiochromone, thioflavone,
and their derivatives (Scheme 1) have been reported to display rich biological activities. For example,
thioflavonoids, which are the sulfur analogues of flavonoids [12
activities, such as antimicrobial, antioxidant, inhibiting nitric oxide production, and antifungal
et al. [ 19 27] Thiochroman-4-ones have been reported to display antifungal activities. Some
thiochroman-4-one derivatives have been studied and shown to display the cytotoxic effect on
tumor cells in vitro 28]. Recently, the in vitro antileishmanial and cytotoxic activities of some
–18], display many biological
3, –
[
thiochroman-4-one derivatives have also been reported [29]. Many thiochromanone derivatives
have been known to be effective “bioreductive alkylating agents”, inhibiting Ehrlich ascites tumor
Molecules 2018, 23, 1728; doi:10.3390/molecules23071728
www.mdpi.com/journal/molecules

Molecules 2018, 23, 1728
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growth [21]. Other thiochroman-4-ones have shown the ability to kill tumor cells by inducing
tumor cell apoptosis [30]. Thiochromanones, i.e., thiochroman-4-ones and 2-alkylthiochroman-4-ones,
have become valuable synthons and precursors in organic synthesis in recent years. They are
key precursors for certain bioactive antiproliferative agents [31]. Known as an important class of
heterocycles [
3,4], they are vital precursors of bioactive thiochroman-4-one 1,1-dioxanes, as well as
benzothiazepins [20,21,32–38].
Scheme 1. Structures of Thiochromanone, Thioflavone, Thiochromone, and Thioflavanones.
Although some synthetic approaches to thiochroman-4-ones, thioflavone, and thiochromones
have been reported in literature [28 39 55], research on efficient synthesis of 2-substituted
,
–
thiochroman-4-ones is an underexplored area when compared to O-containing counterparts. Synthetic
approaches to 2-substituted thiochroman-4-ones utilizing Friedel-Crafts acylation of thiopropanoic
acid [56], hydrogenation of thiochromones [57–59], and intramolecular thio-Michael addition [60–66]
have been reported. Recently, a rhodium-catalyzed alkyne hydroacylation/thio conjugate addition
sequence in the synthesis of thiochroman-4-ones, including thioflavanones, has also been reported [67].
In another approach, Wang and coworkers reported an enantioselective Rh-catalyzed conjugate
addition to thiochromones [68]. We also reported a rapid entry to thioflavanones via the conjugate
addition of diarylcuprates to thiochromones recently [69]. While most of these approaches provided
efficient approaches to thioflavanones (2-arylthiochroman-4-ones), they do not work particularly well
in introducing the aliphatic groups to furnish the desired 2-alkylthiochroman-4-ones. For example,
rhodium-catalyzed conjugate addition to thiochromones only works well with arylzinc reagents to
introduce aryl groups to thiochromones and it is not compatible with alkylzinc reagents or aliphatic
groups in general [68]. In an effort to develop a quick entry into 2-alkylthiochroman-4-ones by
taking advantage of the readily available inexpensive alkyllithium reagents and copper salts, we now
report the conjugate addition of lithium dialkylcuprates [70
inexpensive commercially available alkyllithiums, to thiochromones
–
75], prepared from the corresponding
(see Supplementary Material
1
for the preparation of these starting materials) to afford 2-alkylthiochroman-4-ones
(Figure 1).
2 in good yields
Figure 1. Conjugate Addition of Lithium Dialkylcuprates to Thiochromones.

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2. Results and Discussions
We began our study with n-BuLi, copper (I) salt and thiochromone to investigate the reaction
condition. No 1,4-adduct 2-n-butylthiochroman-4-one 4Aa was formed with 0.3 equivalent of CuI or
CuCN without any additive (Table 1, entries 1–2, 0%). Lithium cyanocuprate (i.e., n-BuCuCNLi) also
fail to add to thiochromone with the recovery of unreacted thiochromone (Table 1, entry 3, 0%). Under
similar reaction condition, more reactive Gilman reagents [76] (i.e., n-Bu2CuLi) afforded only a trace
amount of 1,4-adduct 4Aa (Table 1, entry 4). These results indicated that thiochromone is very sluggish
towards the addition of lithium organocopper reagents without other additives/activators.
Table 1. Optimization of 1,4-Conjugate Addition of Alkylcuprates to Thiochromone.
Entries c
Copper (I) Salt/Reagents a
Additive
% Yield b
1
2
3
4
5
6
7
8
9
CuI (0.3 equiv)
CuCN (0.3 equiv)
n-BuCuCNLi
n-Bu2CuLi
CuI (0.3 equiv)
CuCN (0.3 equiv)
n-BuCuCNLi
n-Bu2CuLi
none
none
none
0
0
0
none
trace
66
62
70
86
85
82
TMSCl
TMSCl
TMSCl
TMSCl
TMSI
n-Bu2CuLi
n-Bu2CuLi
10
TMSOTf
a. Reagents were prepared by adding n-BuLi to CuCN or CuI. b. Yields are based on isolated products by flash
column chromatography. c. Reactions were allowed to stir for 12 h and warm up to room temperature before workup.
Lewis acids, such as trimethylsilyl chloride (TMSCl), have been known to accelerate 1,4-conjugate
additions of both stoichiometric organocuprates and catalytic amount of copper (I) salts [77–84]. In our
investigation, we found out that the yield of desired 1,4-adduct 4Aa can be increased to 66% using 0.3
equivalent of CuI with the addition of TMSCl (Table 1, entry 5). Similar enhancement of reactivity was
observed with 0.3 equivalent of CuCN in the presence of TMSCl (Table 1, entry 6). With the addition
of TMSCl, lithium cyanocuprate reagent underwent smooth conjugate addition to thiochromone
3A to afford 2-alkylthiochroman-4-one 4Aa with 70% yield (Table 1, entry 7). Ultimately, lithium
dialkylcuprate (i.e., n-Bu2CuLi) was found to be the most reactive and it afforded the highest yield of
1,4-adduct 4Aa at 86% with the addition of TMSCl (Table 1, entry 8). The effect of other Lewis acid
additives, such as TMSI and TMSOTf, were also investigated. Both TMSI and TMSOTf showed similar
enhancement and promoted the conjugate addition of lithium di-n-butylcuprates to thiochroman-4-one
with good yields (Table 1, entries 9–10, 85% and 82%).
With the optimal reaction condition in hand, we examined the scope of lithium dialkylcuprates
(i.e., R2CuLi) (Scheme 2, 60–86%). In general, a number of lithium dialkylcuprates underwent
conjugate addition to thiochromone 3A to afford 1,4-adducts 4Aa-Am with good chemical yields
(Scheme 2). Simple dialkylcuprates, such as dimethylcuprates, diethyl cuprate, di-n-butylcuprates, and
di-n-hexylcuprates all add to 3A smoothly to afford 1,4-adducts with good yields (Scheme 2, 81–86%).
Lithium di-isopropylcuprate and di-t-buylcuprates also add to thiochromone 3A with slightly lower
yields (Scheme 2, 71% and 60%), indicating that organocuprates that are prepared from more hindered
alkyllithium reagents are less reactive.

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Scheme 2. The Scope of Lithium Dialkylcuprates in Conjugate Addition to Thiochromone. a. All the
reactions were performed using 1.2 equivalentof R2CuLi in the presence of 2.0 equivalent of TMSCl
unless noted otherwise. b. RLi were commercially available. c. Yields are based on isolated products
by flash column chromatography. d. Reactions were stirred for 12 h and warm up to room temperature
before work up.
Having found the optimal reaction condition for conjugate addition to thiochromone 3A, we next
turned our attention to explore the scope of thiochromone substrates for the lithium dialkylcuprate
conjugate addition. A number of substituted thiochromones 3B
that lithium di-n-butylcuprates (i.e., n-Bu2CuLi) readily add to substituted thiochromones 3B
afford 1,4-adducts 4Ba Ja with 74–85% yields (Scheme 3). Thiochromones bearing simple substituents,
such as methyl group, reacted with n-Bu2CuLi to afford 4Ba Da in 81–84% yields (Scheme 3). Bulky
-
J
were investigated. It was found
-J
to
-
-
t-butyl group is also tolerated to afford 1,4-adduct 4Ea with good yield. Thiochromones with halides
F, Br, and Cl also work well with lithium di-n-butylcuprates (Scheme 3, 79–85%). Thiochromones
with electron-donating groups, such as MeO-, also work well to afford 1,4-adduct 4Ia in 76% yield
(Scheme 3). Thiochromane 3J with extended aromatic structure also undergo conjugate addition with
n-Bu2CuLi to afford 1,4-adduct 4Ja in 74% yield.
Synthetic applications of 1,4-adducts: The 1,4-adducts-2-alkylthiochroman-4-ones can be utilized
for additional synthetic applications (Scheme 4). For example, 2-n-butylthiochroman-4-one can be
reduced to corresponding alcohol
with N-chlorosuccinimide (NCS) in dichloromethane, thiochroman-4-one 4Aa was successfully
converted into thiochromone in 71% yield. 2-n-Butylthiochroman-4-one 4Aa can be oxidized
to sulfone with an excess of m-chloroperbenzoic acid (m-CPBA) in dichloromethane (Scheme 4,
79%). It can also be functionalized to chlorinated thiochromone upon treatment with excess of
N-chlorosuccinimide (NCS, 3.0 equivalent) and pyridine (3.0 equivalent) (Scheme 4, 62%).
5 by treatment with sodium borohydride in ethanol. Upon treatment
6
7
8

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Scheme 3. Reactions of Lithium di-n-butylcuprates with Substitututed Thiochromones. a. All the
reactions were performed using 1.2 equivalentof n-Bu2CuLi in the presence of 2.0 equivalent of TMSCl
unless noted otherwise. b. n-BuLi is commercially available. c. Yields are based on isolated products
by flash column chromatography. d. Reactions were stirred for 12 h and warm up to room temperature
before work up.
Scheme 4. Synthetic Applications of 2-n-butyl Thiochroman-4-one.

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3. Materials and Methods
3.1. General Methods
The 1H, 13C, and 19F-NMR spectra were recorded on a BRUKER AscendTM 400 NMR spectrometer
1
(Billerica, MA, USA), operating at 400 MHz for H and 100 MHz for 13C and 376 MHz for 19F.
Samples for NMR spectra were dissolved in deuterated chloroform (with TMS). Analytical thin layer
chromatography (TLC) was performed on silica gel plates, 60
µ mesh with F254 indicator. Visualization
was accomplished by UV light (254 nm), and/or a 10% ethanol solution of phosphomolybdic acid
and/or KMnO4 stain that is prepared by dissolving 1.5 g KMnO4, 10 g potassium carbonate, and
1.25 mL 10% sodium hydroxide in 200 mL water. Flash chromatography was performed with 230–400
µ
silica gel. Infrared (IR) spectra were recorded on a Nicolet iS10 FT-IR spectrometer as neat samples
(thin films).
3.2. Materials
Solvents and chemicals were obtained from commercial sources and used without further
purification unless stated otherwise. Anhydrous tetrahydrofuran (THF) was purchased from
Sigma Aldrich (Milwaukee, WI, USA). TMSCl was distilled from CaH2 under a positive N2
atmosphere. Alkyllithium reagents were purchased from Sigma Aldrich. All of the glassware
was flamed-dried under high vacuum, purged with argon, and then cooled under a dry nitrogen
atmosphere. Low temperature baths were prepared using dry ice-isopropanol slush bath mixtures.
All organocuprate 1,4-conjugate addition reactions were conducted under a positive, dry argon
atmosphere in anhydrous solvents in flasks that were fitted with a rubber septum.
3.3. General Procedure A: Conjugate Addition Reactions of Lithium Alkylcyanocuprates (RCuCNLi) with
Thiochromones
To a flame-dried LiCl (51 mg, 1.2 mmol, 2.4 equivalent) under argon was added CuCN (53 mg,
0.6 mmol, 1.2 equivalent) and THF (1.5 mL◦). The resultant mixture was stirred for 10 mins at
room temperature and then cooled to a
1.2 equivalent). The resultant solution was stirred for additional 30 mins at
−
78 C, followed by addition of alkyl lithium (0.6 mmol,
◦
−
78 C under argon,
followe◦d by addition of thiochromone (0.5 mmol mixed with TMSCl (1.0 mmol) in THF (1.0 mL))
at
−
78 C. The reaction mixture was allowed to warm up to room temperature during overnight
stirring. Then, the reaction mixture was quenched with saturated aqueous NH4Cl (ca. 10.0 mL)
and extracted with ethyl acetate (3 10.0 mL). The combined organic phase was washed with brine
(ca. 15.0 mL), dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and purified by flash
×
column chromatography (silica gel, 0–2% ethyl acetate in hexane, v/v) to give pure compounds.
3.4. General Procedure B: Conjugate Addition Reactions of Lithium Dialkylcuprates (R2CuLi) with
Thiochromones
General procedure B is identical to general procedure A except that double amount of alkyl
lithium reagents (1.2 mmol, 2.4 equivalent) were used.
3.5. General Procedure C: Conjugate Addition Reactions of Alkyl Lithium Reagents with Thiochromone in the
Presence of Substoichiometric Amount of CuI
◦
To a CuI (0.30 equivalent) in THF (1.0 mL) under argon at 0 C, was added a◦lkyl lithium
(1.2 equivalent). The resultant mixture was stirred for 30 min at room temperature 0 C and then
◦
cooled to a
−
78 C, followed by addition of thiochromone [0.5 mmol mixed with TMSCl (1.0 mmol) in
THF (1.0 mL)]. The reaction mixture was allowed to warm up to room temperature during overnight
stirring. Then, the reaction mixture was quenched with saturated aqueous NH4Cl (ca. 10.0 mL)
and extracted with ethyl acetate (3
×
8.0 mL). The combined organic phase was washed with brine

Molecules 2018, 23, 1728
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(ca. 10.0 mL), dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and purified by flash
column chromatography (silica gel, 0–2% ethyl acetate in hexane, v/v) to give pure compounds.
HRMS data for compounds 4Aa, 4Ba–4Ja, 5, 7, and 8 were analyzed by TOF MS. Compounds
4Ab–Ac, 4Ad–Af, and 6 have been fully characterized and reported [39,43,48,67].
3.5.1. Synthesis of 2-n-Butylthiochroman-4-one (4Aa)
Employing General Procedure B, using n-BuLi (2.8 M, 0.43 mL, 1.2 mmol) and thiochromone
(81 mg, 0.5 mmol), after purification by flash column chromatography (silica gel, 0–2% ethyl
acetate:hexanes, v/v) gave light yellow oil 4Aa (95 mg, 86%).
Alternatively, 2-n-butylthiochroman-4-one (4Aa) was prepared by employing General Procedure
A, using n-BuLi (2.8 M, 0.22 mL, 0.6 mmol) and thiochromone (81 mg, 0.5 mmol), after purification
by flash column chromatography (silica, 0–2% ethyl acetate:hexanes, v/v) gave light yellow oil 4Aa
(77 mg, 70%);
2-n-butylthiochroman-4-one (4Aa) was also prepared by employing General Procedure C, using
n-BuLi (2.8 M, 0.22 mL, 0.6 mmol), CuI (29 mg) and thiochromone (81 mg, 0.5 mmol), after purification
by flash column chromatography (silica gel, 0–2% ethyl acetate:hexanes, v/v) gave light yellow oil 4Aa
(72 mg, 66%): IR (neat) 3058 (w), 2955 (s), 2927 (s), 2857 (s), 1676 (s), 1588 (s), 1457 (m), 1435 (s), 1286
(s), 1231 (w), 1088 (m), 758 (m) cm−1; 1H-NMR (400 MHz, CDCl3)
δ 0.94 (t, J = 7.2 Hz, 3H), 1.31–1.41
(m, 2H), 1.46 (quintet, J = 7.6 Hz, 2H), 1.74 (q, J = 7.6 Hz, 2H), 2.82 (dd, J = 11.2, 16.4 Hz, 1H), 3.07 (dd,
J = 3.2, 16.4 Hz, 1H), 3.46–3.55 (m, 1H), 7.14–7.21 (m, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.37–7.43 (m, 1H),
7.14 (ddd, J = 0.4, 0.8, 8.0 Hz, 1H); 13C-NMR (100 MHz, CDCl3)
δ 13.9, 22.3, 28.8, 34.2, 41.6, 46.3, 124.9,
127.6, 128.9, 130.7, 133.4, 141.7, 194.8; HRMS (EI-ion trap) m/z: [M]+ calcd. for C13H16OS, 220.0922;
found 220.0918.
3.5.2. Synthesis of 6-Methyl-2-n-butylthiochroman-4-one (4Ba)
Employing General Procedure B and using 6-methylthiochromone (176 mg, 1.00 mmol) and
n-BuLi (2.8 M, 0.86 mL, 2.40 mmol), after purification by flash column chromatography (silica gel, 0–2%
ethyl acetate:hexanes, v/v) gave light yellow oil 4Ba (190 mg, 81%); IR (neat) 3046 (w), 2955 (s), 29−214
(s), 2856 (s), 1675 (s), 1602 (m), 1468 (m), 1398 (m), 1299 (w), 1278 (m), 1231 (w), 1097 (w), 814 (w) cm
;
1H-NMR (400 MHz, CDCl3)
δ 0.70 (t, J = 7.2 Hz, 3H), 1.03–1.14 (m, 2H), 1.17–1.30 (m, 2H), 1.50 (q,
J = 7.6 Hz, 2H), 2.11 (s, 3H), 2.57 (dd, J = 11.2, 16.4 Hz, 1H), 2.82 (dd, J = 2.8, 16.4 Hz, 1H), 3.21–3.30 (m,
2H), 6.95 (d, J = 8.0 Hz, 1H), 7.00 (ddd, J = 0.4, 2.0, 8.4 Hz, 1H), 7.67–7.70 (m, 1H); 13C-NMR (100 MHz,
CDCl3) δ 13.9, 20.8, 22.3, 28.9, 34.2, 41.7, 46.5, 127.6, 129.0, 130.5, 134.6, 134.7, 138.3, 195.1; HRMS (EI-ion
trap) m/z: [M]+ calcd. for C14H18OS, 234.1078; found 234.1082.
3.5.3. Synthesis of 6,7-Dimethyl-2-n-butylthiochroman-4-one (4Ca)
Employing General Procedure B and using 6,7-dimethylthiochromone (190 mg, 1.00 mmol) and
and n-BuLi (2.8 M, 0.86 mL, 2.40 mmol), after purification by flash column chromatography (silica
gel, 0–2% ethyl acetate:hexanes, v/v) gave light yellow solid 4Ca (208 mg, 84%): m.p. 64.0–64.9 ◦C;
IR (neat) 2956 (s) 2920 (s), 2860 (s), 1669 (s), 1599 (s), 1470 (m), 1447 (m), 1383 (m), 1370 (m), 1262 (s),
1
1147 (m), 1100 (m), 1023 (w), 864 (w) cm−1; H-NMR (400 MHz, CDCl3)
δ 0.84 (t, J = 7.2 Hz, 3H),
1.21–1.31 (m, 2H), 1.36 (dt, J = 5.2, 7.6 Hz, 2H), 1.63 (q, J = 7.6 Hz, 2H), 2.16 (s, 3H), 2.17 (s, 3H), 2.68
(dd, J = 11.2, 16.4 Hz, 1H), 2.93 (dd, J = 3.2, 16.4 Hz, 1H), 3.30–3.43 (m, 1H), 7.14–7.21 (m, 1H), 7.28 (d,
J = 8.0 Hz, 1H), 7.37–7.43 (m, 1H), 6.97 (s, 1H), 7.77 (s, 1H); 13C-NMR (100 MHz, CDCl3)
δ 13.9, 19.2,
20.0, 22.3, 28.9, 34.2, 41.8, 46.4, 128.4, 128.6, 129.5, 133.8, 138.6, 143.7, 194.8; HRMS (EI-ion trap) m/z:
[M]+ calcd. for C15H20OS, 248.1235; found 248.1236.
3.5.4. Synthesis of 8-Methyl-2-n-butylthiochroman-4-one (4Da)
Employing General Procedure B and using 8-methylthiochromone (176 mg, 1.0 mmol) and n-BuLi
(2.8 M, 0.43 mL, 1.2 mmol), after purification by flash column chromatography (silica gel, 0–2% ethyl

Molecules 2018, 23, 1728
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acetate:hexanes, v/v) gave light yellow oil 4Da (194 mg, 83%); IR (neat) 3061 (w), 2955 (m) 2926 (s),
2857 (m), 1676 (s), 1583 (m), 1449 (m), 1401 (m), 1379 (w), 1295 (m), 1279 (m), 1248 (w), 1056 (w), 1000
(w), 841 (w) 784 (w), 722 (w) cm−1; 1H-NMR (400 MHz, CDCl3)
δ 0.73 (t, J = 7.2 Hz, 3H), 1.11–1.21 (m,
2H), 1.22–1.35 (m, 2H), 1.51–1.60 (m, 2H), 2.12 (s, 3H), 2.58 (dd, J = 11.6, 16.0 Hz, 1H), 2.83 (dd, J = 2.8
,
,
16.0 Hz, 1H), 3.21–3.29 (m, 1H), 6.88 (t, J = 7.6 Hz, 1H), 7.09 (qd, J = 0.8, 8.0 Hz, 1H), 7.78 (qd, J = 0.4
8.0 Hz, 1H); 13C-NMR (100 MHz, CDCl3)
δ 13.9, 20.1, 22.4, 28.8, 34.4, 40.7, 45.7, 123.9, 126.6, 130.8,
134.5, 135.4, 141.3, 195.2; HRMS (EI-ion trap) m/z: [M]+ calcd. for C14H18OS, 234.1078; found 234.1075.
3.5.5. Synthesis of 6-(tert-Butyl)-2-n-butylthiochroman-4-one (4Ea)
Employing General Procedure B and using 6-tert-butylthiochromone (86 mg, 0.42 mmol) and and
n-BuLi (2.8 M, 0.36 mL, 1.01 mmol), after purification by flash column chromatography (silica gel,
0–2% ethyl acetate:hexanes, v/v) gave light yellow oil 4Ea (89 mg, 77%); IR (neat) 3054 (w), 2955 (s),
2928 (s), 2869 (m), 1678 (s), 1596 (m), 1479 (m), 1463 (m), 1463 (m), 1252 (s), 1119 (m), 824 (m) cm−1
;
1H-NMR (400 MHz, CDCl3)
δ 0.84 (t, J = 7.2 Hz, 3H), 1.24 (s, 9H), 1.21–1.30 (m, 2H), 1.32–1.46 (m, 2H),
1.64 (q, J = 7.6 Hz, 2H), 2.72 (dd, J = 11.2, 16.4 Hz, 1H), 2.97 (dd, J = 3.2, 16.4 Hz, 1H), 3.35–3.45 (m, 1H),
7.13 (d, J = 8.40 Hz, 1H), 7.37 (dd, J = 2.4, 8.4 Hz, 1H), 8.04 (d, J = 2.40 Hz, 1H); 13C-NMR (100 MHz,
CDCl3)
δ 13.9, 22.3, 28.9, 31.1, 34.3, 34.6, 41.6, 46.5, 125.4, 127.4, 130.2, 131.2, 138.5, 148.1, 195.2; HRMS
(EI-ion trap) m/z: [M]+ calcd. for C17H24OS, 276.1548; found 276.1544.
3.5.6. Synthesis of 6-Chloro-2-n-butylthiochroman-4-one (4Fa)
Employing General Procedure B, and using 6-chlorothiochromone (130 mg, 0.66 mmol) and
n-BuLi (2.8 M, 0.57 mL, 1.58 mmol), after purification by flash column chromatography (silica gel,
0–2% ethyl acetate:hexanes, v/v) gave light yellow oil 4Ea (143 mg, 85%); IR (neat) 3057 (w), 2955 (s),
2927 (s), 2857 (m), 1682 (s), 1582 (m), 1452 (s), 1391 (m), 1293 (w), 1253 (m), 1224 (w), 1157 (w), 1094
(m), 898 (w), 815 (w), 730 (w) cm−1; 1H-NMR (400 MHz, CDCl3)
δ 0.94 (t, J = 7.2 Hz, 3H), 1.32–1.40 (m,
2H), 1.41–1.50 (m, 2H), 1.74 (q, J = 7.6 Hz, 2H), 2.81 (dd, J = 11.2, 16.4 Hz, 1H), 3.06 (dd, J = 3.2, 16.4 Hz,
1H), 3.45–3.54 (m, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.36 (dd, J = 2.4, 8.4 Hz, 1H), 8.06 (d, J = 2.4 Hz, 1H);
13C-NMR (100 MHz, CDCl3)
δ 13.9, 22.3, 28.8, 34.1, 41.7, 45.9, 128.5, 129.1, 131.1, 131.6, 133.4, 140.1,
193.6; HRMS (EI-ion trap) m/z: [M]+ calcd. for C13H15OSCl, 254.0532; found 254.0534.
3.5.7. Synthesis of 6-Bromo-2-n-butylthiochroman-4-one (4Ga)
Employing General Procedure B and using 6-bromothiochromone (130 mg, 0.54 mmol) and n-BuLi
(2.8 M, 0.39 mL, 1.08 mmol), after purification by flash column chromatography (silica gel, 0–2% ethyl
acetate:hexanes, v/v) gave light yellow oil 4Ga (132 mg, 82%); IR (neat) 3054 (w), 2955 (m) 2926 (s),
2856 (m), 1679 (s), 1574 (m), 1474 (m), 1450 (m), 1386 (m), 1291 (w), 1254 (m), 1224 (w), 1091 (m), 1054
(w), 898 (w), 813 (w) cm−1; 1H-NMR (400 MHz, CDCl3)
δ 0.84 (t, J = 7.2 Hz, 3H), 1.21–1.31 (m, 2H),
1.32–1.41 (m, 2H), 1.64 (q, J = 7.6 Hz, 2H), 2.71 (dd, J = 11.2, 16.4 Hz, 1H), 2.97 (dd, J = 2.8, 16.4 Hz,
1H), 3.36–3.45 (m, 1H), 7.07 (d, J = 8.4 Hz, 1H), 7.40 (dd, J = 2.0, 8.4 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H);
13C-NMR (100 MHz, CDCl3)
δ 13.9, 22.3, 28.8, 34.1, 41.7, 45.8, 118.6, 129.3, 131.5, 131.9, 136.2, 140.7,
193.5; HRMS (EI-ion trap) m/z: [M]+ calcd. for C13H15OSBr, 298.0027; found 298.0033.
3.5.8. Synthesis of 6-Fluoro-2-n-butylthiochroman-4-one (4Ha)
Employing General Procedure B and using 6-fluorothiochromone (100 mg, 0.56 mmol) and n-BuLi
(2.8 M, 0.48 mL, 1.34 mmol), after purification by flash column chromatography (silica gel, 0–2% ethyl
acetate:hexanes, v/v) gave light yellow oil 4Ha (105 mg, 79%); IR (neat) 3066 (w), 2957 (m) 2928 (s),
2858 (m), 1682 (s), 1601 (m), 1464 (s), 1404 (s), 1303 (m), 1262 (s), 1223 (w), 1196 (w), 1089 (w), 895 (w),
817 (w) cm−1; 1H-NMR (400 MHz, CDCl3)
δ 0.94 (t, J = 7.2 Hz, 3H), 1.32–1.41 (m, 2H), 1.42–1.50 (m,
2H), 1.74 (q, J = 7.6 Hz, 2H), 2.81 (dd, J = 11.2, 16.4 Hz, 1H), 3.07 (dd, J = 2.8, 16.4 Hz, 1H), 3.46–3.55
(m, 1H), 7.15 (ddd, J = 2.8, 8.0, 8.4 Hz, 1H), 7.27 (dd, J = 5.2, 8.8 Hz, 1H), 7.79 (dd, J = 3.2, 9.6 Hz, 1H);
13C-NMR (100 MHz, CDCl3) δ 13.9, 22.3, 28.8, 34.0, 41.8, 46.0, 114.9 (d, J = 22 Hz), 121.4 (d, J = 22 Hz),

Molecules 2018, 23, 1728
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129.4 (d, J = 7 Hz), 132.0 (d, J = 6 Hz), 136.9 (d, J = 3 Hz), 160.4 (d, J = 244 Hz), 193.8; 19F NMR (376
MHz, CDCl3)
- 116.8 (quintet, J = 3.76 Hz); HRMS (EI-ion trap) m/z: [M]+ calcd. for C13H15OSF,
δ
238.0828; found 238.0827.
3.5.9. Synthesis of 6-Methoxy-2-n-butylthiochroman-4-one (4Ia)
Employing General Procedure B and using 6-methoxydimethylthiochromone (76 mg, 0.4 mmol)
and and n-BuLi (2.8 M, 0.34 mL, 0.96 mmol), after purification by flash column chromatography (silica
gel, 0–2% ethyl acetate:hexanes, v/v) gave light yellow oil 4Ia (76 mg, 76%); IR (neat) 3065 (w), 2955
(m) 2925 (s), 2854 (m), 1675 (s), 1599 (m), 1471 (s), 1403 (m), 1323 (w), 1273 (s), 1222 (s), 1180 (w), 1099
(w), 1027 (m), 870 (w), 820 (w) cm−1; 1H-NMR (400 MHz, CDCl3)
(m, 2H), 1.39 (td, J = 2.0, 14.8 Hz, 2H), 1.64 (q, J = 7.6 Hz, 2H), 2.71 (dd, J = 11.2, 16.4 Hz, 1H), 2.97
(dd, J = 2.8, 16.4 Hz, 1H), 3.30–3.49 (m, 1H), 3.75 (s, 3H), 6.94 (dd, J = 2.8, 8.8 Hz, 1H), 7.11 (dd, J = 0.4
δ 0.84 (t, J = 7.2 Hz, 3H), 1.21–1.31
,
8.8 Hz, 1H), 7.52 (d, J = 2.8 Hz, 1H); 13C-NMR (100 MHz, CDCl3)
δ 13.9, 22.3, 28.9, 34.1, 41.9, 46.5,
55.6, 111.0, 122.5, 129.0, 131.4, 133.1, 157.3, 194.8; HRMS (EI-ion trap) m/z: [M]+ calcd. for C14H18O2S,
250.1028; found 250.1029.
3.5.10. Synthesis of 2-n-Butyl-2,3-dihydro-4H-benzo[g]thiochromen-4-one (4Ja)
Employing General Procedure B and using 6,7-dimethylthiochromone (106 mg, 0.5 mmol) and
and n-BuLi (2.8 M, 0.43 mL, 1.2 mmol), after purification by flash column chromatography (silica gel,
0–2% ethyl acetate:hexanes, v/v) gave light yellow oily liquid 4Ja (100 mg, 74%); IR (neat) 3051 (w),
2954 (s) 2926 (s), 2856 (m), 1660 (s), 1613 (m), 1590 (m), 1549 (w), 1504 (m), 1464 (w), 1422 (m), 1335
(m), 1215 (m), 1111 (m), 872 (w), 813 (m), 779 (w), 746 (m) cm−1; 1H-NMR (400 MHz, CDCl3)
δ 0.86 (t,
J = 7.2 Hz, 3H), 1.25–1.35 (m, 2H), 1.36–1.46 (m, 2H), 1.70 (q, J = 7.6 Hz, 2H), 2.87 (dd, J = 11.2, 15.2 Hz,
1H), 3.09 (dd, J = 3.6, 15.2 Hz, 1H), 3.45–3.54 (m, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.34–7.40 (m, 1H), 7.52
(ddd, J = 1.6, 6.8, 8.8 Hz, 1H), 7.64–7.68 (m, 1H), 7.71 (d, J = 8.8 Hz, 1H), 9.12 (dd, J = 0.8, 8.8 Hz, 1H);
13C-NMR (100 MHz, CDCl3)
δ 13.9, 22.4, 28.8, 34.2, 41.3, 47.7, 125.1, 125.4, 125.6, 125.8, 128.4, 129.2,
131.7, 132.3, 133.7, 144.7, 197.0; HRMS (EI-ion trap) m/z: [M]+ calcd. for C17H18OS, 270.1078; found
270.1074.
3.6. Synthesis of 2-n-Buylthiochroman-4-ol (5)
To a dry ethanol solution (1.5 mL) of 2-n-butylthiochroman-4-one (0.5 mmol, 110 mg) under
argon, sodium borohydride (0.25 mmol, 10 mg) was added portion-wise. The resultant mixture was
stirred at room temperature for 2 h. Then solvent was evaporated, ice water (10 mL) was added,
and the mixture was acidified with 10% HCl to pH = 1–2. It was then extracted with ethyl acetate
(3
×
8 mL) and organic layers were combined, washed with brine (15 mL). The organic layer was
dried (Na2SO4), filtered and evaporated under vacuum to give crude product. The crude product
was then purified by flash column chromatography (silica gel, 10% ethyl acetate:hexanes, v/v) to give
2-n-butylthiochroman-4-ol
5
as white solid (91 mg, 82%): m.p. 64.1–65.2 ◦C; IR (neat) 3317 (br s), 3065
(w), 2958 (s), 2924 (s), 2855 (s), 1591 (w), 1566 (w), 1466 (m), 1433 (s), 1349 (w), 1308 (m), 1263 (m),
1196 (w), 1059 (m), 1034 (m), 1016 (m), 978 (w), 759 (m), 750 (s), 730 (m), 688 (w) cm−1; 1H-NMR (400
MHz, CDCl3)
δ 0.96 (t, J = 7.2 Hz, 3H), 1.36–1.50 (m, 3H), 1.60–1.75 (m, 2H), 1.75–1.86 (m, 1H), 2.27 (d,
J = 8 Hz, 1H), 2.46 (ddd, J = 3.2, 4.4, 12.8 Hz, 1H), 3.38–3.48 (m, 1H), 7.07–7.16 (m, 3H), 7.53–7.59 (m,
1H); 13C-NMR (100 MHz, CDCl3)
δ 14.0, 22.5, 28.9, 36.3, 40.0, 40.3, 69.2, 124.4, 126.1, 126.2, 127.6, 133.3,
137.1; HRMS (EI-ion trap) m/z: [M]+ calcd. for C13H18OS, 222.1078; found 222.1084.
3.7. Synthesis of 2-n-Butyl-thiochromen-4-one 1,1-dioxide (7)
To a dry DCM (dichloromethane) solution of 2-n-butylthiochroman-4-one (0.5 mmol) under Ar
atmosphere in a 50 mL RB (round-bottom) flask, was added excess 3-meta-chloroperoxybenzoic acid
(m-CPBA, 3.0 equivalent, 1.5 mmol, 259 mg). The resultant mixture was stirred at room temperature
until the reaction is complete by TLC monitoring (5 h). Then the reaction mixture was quenched

Molecules 2018, 23, 1728
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with NaHCO3 (10 mL) and diluted with DCM (8 mL). The organic layer were separated and aqueous
layer was extracted with DCM (2 X 8 mL). The organic layers were combined and washed with brine
and dried over anhydrous Na2SO4. It was filtered and concentrated in vacuum. The crude product
was purified by flash column chromatography (silica gel, 20% ethyl acetate:hexanes, v/v) to give
transparent/clear yellow liquid
(s), 1588 (m), 1571 (w), 1466 (w), 1443 (w), 1300 (s), 1279 (s), 1231 (m), 1150 (s), 1125 (m), 1045 (w),
936 (w), 751 (m), 722 (m) cm−1; 1H-NMR (400 MHz, CDCl3)
0.96 (t, J = 7.2 Hz, 3H), 1.35–1.43 (m,
7 (100 mg, 79%): IR (neat) 3067 (w), 2956 (s), 2930 (s), 2869 (m), 1691
δ
2H), 1.46–1.59 (m, 2H), 1.61–1.72 (m, 2H), 2.22–2.33 (m, 1H), 3.28 (dd, J = 10, 17.6 Hz, 1H), 3.39 (dd,
J = 3.6, 17.6 Hz, 1H), 3.58–3.67 (m, 1H), 7.76 (td, J = 1.2, 7.6 Hz, 1H), 7.85 (td, J = 1.2, 7.6 Hz, 1H), 8.07
(dd, J = 0.8, 7.6 Hz, 1H), 8.13 (dd, J = 0.8, 7.6 Hz, 1H); 13C-NMR (100 MHz, CDCl3)
δ 13.7, 22.3, 25.8,
28.2, 42.0, 59.1, 124.2, 128.5, 130.5, 133.2, 135.0, 141.1, 190.7; HRMS (EI-ion trap) m/z: [M]+ calcd. for
C13H16O3S, 252.0820; found 252.0823.
3.8. Synthesis of 3-Chloro-2-n-butyl-4H-thiochromen-4-one (8)
To a DCM solution of 2-n-butylthiochroman-4-one (1.0 equivalent, 0.5 mmol) was added NCS
(N-chlorosuccinimide) (3.0 equivalent, 1.5 mmol, 200 mg) and pyridine (3.0 equivalent, 1.5 mmol, 119).
The reaction mixture was stirred at room temperature for 3 h and then concentrated under vacuum
to give the crude product, which was purified by flash column chromatography (silica gel, 5% ethyl
◦
acetate:hexanes, v/v) to give
8
as a white solid (78 mg, 62%): m.p. 40.5–41.3 C; IR (neat) 3062 (w), 2959
(m), 2928 (m), 2858 (m), 1622 (s), 1567 (s), 1585 (m), 1532 (s), 1464 (m), 1437 (m), 1321 (m), 1254 (w),
1156 (w), 1098 (m), 1070 (w), 834 (m), 739 (m) cm−1; 1H-NMR (400 MHz, CDCl3)
0.92 (t, J = 7.2 Hz
3H), 1.41 (sextet, J = 7.2 Hz, 2H), 1.65–1.74 (m, 2H), 2.80–2.86 (m, 2H), 7.45–7.59 (m, 3H), 8.48 (ddd,
δ
,
J = 0.8, 1.6, 8.0 Hz, 1H); 13C-NMR (100 MHz, CDCl3)
δ 13.7, 22.5, 30.7, 36.4, 125.6, 126.5, 127.8, 129.6,
130.4, 131.5, 135.8, 150.9, 174.3; HRMS (EI-ion trap) m/z: [M]+ calcd. for C13H13OSCl, 252.0376; found
252.0381.
4. Conclusions
In conclusion, we have successfully developed the conjugate addition of lithium dialkylcuprates
to thiochromones in the presence of chlorotrimethylsilane (TMSCl) and other Lewis acids, such as TMSI
and TMSOTf, to afford 2-alkylthiochroman-4-ones in good yields utilizing commercially available
inexpensive alkyllithium reagents. This reaction works well with simple dialkylcuprates as well as
bulky dialkylcuprates (i-Pr2CuLi, t-Bu2CuLi). Lithium di-n-butylcuprate undergoes smooth conjugate
addition to a broad range of substituted thiochromones. The 1,4-adducts (2-alkylthiochroman-4-ones)
can be utilized for additional synthetic applications to access privileged sulfur-heterocycles. Further
synthetic applications using these 1,4-adducts as key intermediates are ongoing in our lab.
Supplementary Materials: The following are available online, 1H, and 13C-NMR spectra for compounds: 4Aa
4Ba, 4Ca, 4Da, 4Ea, 4Fa, 4Ga, 4Ha, 4Ia, 4Ja, 5, 6, 7 and 8; 19F-NMR spectra for compounds: 4Ha.
,
Author Contributions: S.A.B., D.M.P., T.J.B., A.S.E., A.S.D., K.L.K., and S.A.S. performed the experiments. D.A.P.
assisted in GC-MS analysis. F.G. conceived and designed the experiments; F.G. secured funding and wrote
the paper.
Funding: This research was funded by National Science Foundation HBCU-UP RIA award grant number
[1600987].
Acknowledgments: We thank National Science Foundation HBCU-UP RIA award (NSF award no. 1600987)
for generous financial support. D.M.P., A.S.E., T.J.B., K.L.K., S.A.S. are NIH RISE scholars. We also like to
thank NIH RISE (R25GM113774) Programs for generous financial support. We thank Dr. Marcus Wright from
Chemistry Department, Wake Forest University, Winston Salem for access to NMR facility and assistance in
attaining NMR spectra.
Conflicts of Interest: The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds are not available from the authors.
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