Rhodium(I)-complexes catalyzed 1,4-conjugate addition of arylzinc chlorides to N-boc-4-pyridone

Article abstract of DOI:10.3390/molecules22050723

Rhodium(I)-complexes catalyzed the 1,4-conjugate addition of arylzinc chlorides to N-Boc-4-pyridone in the presence of chlorotrimethylsilane (TMSCl). A combination of [RhCl(C₂H₄)₂]₂ and BINAP was determined to be the most effective catalyst to promote the 1,4-conjugate addition reactions of arylzinc chlorides to N-Boc-4-pyridone. A broad scope of arylzinc reagents with both electron-withdrawing and electron-donating substituents on the aromatic ring successfully underwent 1,4-conjugate addition to N-Boc-4-pyridone to afford versatile 1,4-adducts 2-substituted- 2,3-dihydropyridones in good to excellent yields (up to 91%) and excellent ee (up to 96%) when (S)-BINAP was used as chiral ligand.

Full text of DOI:10.3390/molecules22050723

molecules
Article
Rhodium(I)-Complexes Catalyzed 1,4-Conjugate
Addition of Arylzinc Chlorides to N-Boc-4-pyridone
Fenghai Guo 1,*, Matthew A. McGilvary 1, Malcolm C. Jeffries 1, Briana N. Graves 1,
Shekinah A. Graham 1 and Yuelin Wu 2
1
Department of Chemistry, Winston-Salem State University, Winston Salem, NC 27110, USA;
mcgilvary336@gmail.com (M.A.M.); mjeffries115@rams.wssu.edu (M.C.J.);
bgraves114@rams.wssu.edu (B.N.G.); sgraham113@rams.wssu.edu (S.A.G.)
School of Chemical and Environmental Engineering, Shanghai Institute of Technology,
2
Shanghai 201418, China; wuyuelin517@hotmail.com
*
Correspondence: guof@wssu.edu; Tel.: +1-336-750-3158
Academic Editor: Wim Dehaen
Received: 15 March 2017; Accepted: 27 April 2017; Published: 1 May 2017
Abstract: Rhodium(I)-complexes catalyzed the 1,4-conjugate addition of arylzinc chlorides to
N-Boc-4-pyridone in the presence of chlorotrimethylsilane (TMSCl). A combination of [RhCl(C2H4)2]2
and BINAP was determined to be the most effective catalyst to promote the 1,4-conjugate addition
reactions of arylzinc chlorides to N-Boc-4-pyridone. A broad scope of arylzinc reagents with
both electron-withdrawing and electron-donating substituents on the aromatic ring successfully
underwent 1,4-conjugate addition to N-Boc-4-pyridone to afford versatile 1,4-adducts 2-substituted-
2,3-dihydropyridones in good to excellent yields (up to 91%) and excellent ee (up to 96%) when
(S)-BINAP was used as chiral ligand.
Keywords: N-boc-4-pyridone; rhodium (I)-complexes; conjugate addition; 2,3-dihydropyridones
1. Introduction
1,4-conjugate addition of organometallic reagents to enones is one of the most reliable and widely
used carbon-carbon bond formation processes to afford
highly useful synthons for further organic transformations [
with an organometallic reagent has been particularly effective in promoting 1,4-addition to enones.
Among the metal catalysts, copper is the most commonly used species [ ]. Other metal catalysts
including nickel and palladium have also been reported to be effective in 1,4-conjugate addition of
organozinc, organoaluminum, organoziconium, and organomercury compounds to -unsaturated
β-substituted carbonyl compounds, which are
1–5
]. The combination of metal catalysts
3
α,β
enones. Organometallic reagents such as organolithiums, Grignard reagents and diorganozinc reagents
have also been widely used in this regard and high yields of 1,4-adducts can be achieved in most cases.
However, the competing 1,2-additions as well as 1,6-additions accompanied with these organometallic
reagents have limited their applications [
been made in asymmetric 1,4-conjugate additions, especially in the addition of organozinc or
Grignard reagents using copper(I) catalysts in combination with chiral phosphorous ligands [12 14].
Although high yields and high entioselectivity can be achieved in these copper-catalyzed reactions, the
substituents introduced to the -position are limited to alkyl groups [12 14]. In recent years, there has
been a growing interest in rhodium-catalyzed C-C bond forming reactions of organometallic reagents,
due to the mild reaction conditions and toleration of various functional groups [15 16]. Since the first
6–11]. Over the last 30 years, significant progresses have
–
β
–
,
report by Miyaura in 1997 [17], rhodium-catalyzed 1,4-conjugate addition of organometallic reagents to
unsaturated substrates has emerged as a versatile and efficient methodology for the formation of C-C
bonds due to their tolerance with water and a wide range of substrates [18,19]. Rhodium-catalyzed
Molecules 2017, 22, 723; doi:10.3390/molecules22050723
www.mdpi.com/journal/molecules

Molecules 2017, 22, 723
2 of 10
1,4-conjugate addition reactions utilize mild organometallic reagents such as organoboron and arylzinc
reagents under mild reaction conditions, which are extremely useful in introducing versatile aromatic
groups to the β-position. For the abovementioned reasons, considerable efforts have been devoted
to developing the rhodium-catalyzed 1,4-conjugate addition of alkenyl(aryl)boronic acids as well
as arylzinc reagents. A broad scope of substrates such as cyclic or acyclic enones and enoates have
been reported [18,19]. Rhodium(I) complexes have been demonstrated to be excellent catalysts for
1,4-conjugate addition of alkenyl- and arylboronic acids to
less reactive amides [18–27].
α,β-unsaturated ketones, esters, and even
In the course of our investigation on access to highly versatile 2-substituted-2,3-dihydropyridones
, we are intrigued by the possibility of rhodium(I)-complex catalyzed 1,4-addition of arylzinc
2
cholorides or arylboronic acids to N-protected-4-pyridones
N-heterocycles such as 2-substituted-2,3-dihyrdopyrdones
of medicinal compounds, and many medicinally important compounds in clinical or pre-clinical
studies contain piperidine subunits [28 31]. 2-Substituted-2,3-dihyrdopyrdines are precursors for
1
(Scheme 1). We are interested in
2
because they are an important class
–
medicinally important N-heterocycles such as pyridines, piperidones, piperidines, indolizidenes,
and quinolizidenes.
Scheme 1. Rh(I)-catalyzed C-C bond formation.
Due to their importance in medicinal chemistry, considerable efforts have been devoted to develop
efficient synthetic strategies for the synthesis of piperidine derivatives. Most of these strategies involve
using chiral auxiliaries/chiral starting materials and have been developed into effective methods for
the synthesis of a wide variety of N-heterocycles [32
via conjugate addition reactions have also been reported [38
using dialkylzinc reagents in conjunction with copper catalysts, but challenges still remain in
increasing reactivity and general applicability [40 46]. Recent developments in copper-catalyzed
asymmetric conjugate additions of Grignard reagents [47 50 51] and rhodium-catalyzed 1,4-addition
of arylboroxines/boronic acids promise greater reactivity and versatility [40]. Recent advances in the
NHC-Cu-catalyzed conjugate arylation of -substututed cyclic enones to afford quaternary stereogenic
–
40]. The synthesis of 2,3-dihydro-4-pyridones
–
51]. Great progress has been made
–
,
,
β
centers has also been reported [52]. Despite the fact that rhodium(I)-complexes-catalyzed 1,4-conjugate
addition of boronic acids is one of the most potent methods for C-C bond formation, there are no
reported examples on 1,4-conjugate addition of boronic acids to N-Boc-4-pyridones or substrates that
contain piperidine subunits, presumably due to the unreactive nature of these nitrogen-containing
substrates with boronic acids [20–27].
2. Results and Discussions
As a starting point, we employed the standard rhodium(I)-BINAP reaction conditions
(Scheme 2) [20
acid 4a was carried out in dioxane/water (10 to 1 ratio) in the presence of 1.5 mol % of [RhCl(C2H4)2]2
and 3 mol % of ligands such as phosphoramidite ligands (A, B) [12 14], 1,5-diphenyl-1,5-cyclooctadiene
,53]. Initially, the reaction of N-Boc-4-pyridone 3A with 2.0 equiv of p-tolylboronic
–
(C) [54], and BINAP (D) [18,19]. Under these standard reactions conditions, no 1,4-adduct 5Aa was
formed (Scheme 2, entries 1–2, 5, 7). No desired 1,4-adduct 5Aa was formed even after 24 h at 100 ◦C
in dioxane/water (10 to 1 ratio) with the increased catalyst loading of 15 mol % of [RhCl(C2H4)2]2 and

Molecules 2017, 22, 723
3 of 10
30 mol % of ligands (Scheme 2, entries 3–4, 6). Only a trace amount of 1,4-adduct 5Aa was observed
◦
after extended heating with 15 mol % [RhCl(C2H4)2]2 and 30 mol % of BINAP at 100 C for 48 h
(Scheme 2, entry 8). The substituents on nitrogen were also investigated (Scheme 2, entries 9–10). With
ethyl carbonate as a protecting group, a trace amount of 1,4-adduct 5Ba was observed. No 1,4-adduct
5Ca was attained with N-methylated substrate 3C (Scheme 2, entry 10).
Scheme 2. Rh-catalyzed conjugate addition of arylboronic acid.
We then turned our attention to arylzinc chlorides, which have been reported to be more reactive
nucleophiles towards 1-benzyloxycarbonyl-4-quinolone and structurally similar 2,3-dihydro-4-pyridones
under rhodium(I)-complexes-catalyzed reaction conditions [18,19]. There is also one isolated example
on rhodium(I)-BINAP-catalyzed 1,4-conjugate addition to N-tert-butoxycarbonyl-4-pyridone [55].
Other approaches involving 2,3-dihydro-4-pyridones via direct conjugate addition of organocuprates
and Grignard reagents have also been reported [56
ligands (A, B) [12 14], 1,5-diphenyl-1,5-cyclooctadiene (C) [54], and BINAP (D) [18
studied in rhodium(I)-catalyzed conjugate addition of p-tolylZnCl 6a to N-Boc 4-pyridone 3A at
5 ◦C. As shown in Scheme 3, p-tolylZnCl 6a underwent 1,4-conjugate addition to N-Boc-4-pyridone
,
57]. In our study, ligands such as phosphoramidite
–
,19] were initially
−
3A catalyzed by rhodium(I)-phosphoramidite in the presence of chlorotrimethyl silane (TMSCl)
with low chemical yield (Scheme 3, entry 1). Slightly higher chemical yield was observed when
phosphoramidite B was used as a ligand (Scheme 3, entry 2). When 1,5-diphenyl-1,5-cyclootadiene
was used with [RhCl(C2H4)2]2, a higher chemical yield 32% can be attained under similar reaction
conditions (entry 4). With both ligands A and B, no significant increases in chemical yields were
obtained, even with 15 mol % [RhCl(C2H4)2]2 and 30 mol % of ligands (Scheme 3, entries 3 and 5). This
ligand screening showed that when 3 mol % of BINAP was used as a ligand, 1,4-adduct 5Aa can be
attained in good chemical yield (89%, Scheme 3, entry 6). We also investigated the effect of substituents
on nitrogen (Scheme 3, entries 8–9). With ethyl carbonate as a protecting group, the yield of 1,4-adduct
5Ba was much lower (Scheme 3, entry 8). No 1,4-adduct 5Ca was attained with N-methylated substrate
3C (Scheme 3, entry 9). Notably no desired 1,4-adduct was observed without the addition of TMSCl
(Scheme 3, entry 7). It has been reported that the addition of chlorotrimethylsilane as a Lewis acid may
facilitate the activation of the substrate toward 1,4-addition and also stabilize the product by forming a
silyl enol ether, which is then converted to the carbonyl group under acidic work-up conditions [58].

Molecules 2017, 22, 723
4 of 10
Scheme 3. Optimization of Rh-catalyzed conjugate addition.
With the optimized reaction conditions in hand, we next examined the scope of rhodium-BINAP-
catalyzed arylzinc reagents conjugate addition (Scheme 4). In general, arylzinc reagents underwent
smooth conjugate addition to N-Boc-4-pyridone with good to excellent chemical yields. Simple
arylzinc reagents such as phenylzinc and naphthylzinc chlorides added to N-Boc-4-pyridone with
excellent chemical yields (Scheme 4, entries 3–5). The arylzinc reagents with electron donating
substituents usually showed higher reactivity (Scheme 4, entries 1, 2, 6–9). The arylzinc reagents with
strong electron withdrawing groups such as fluoro, trifluoromethyl, and bistrifluromethyl groups also
underwent conjugate addition but with lower chemical yields (entries 10–12). Compared to para- and
meta-substituted arylzinc reagents, the ortho-substituted arylzinc reagents gave lower yields due to
steric hindrance (entries 2, 8). We also conducted asymmetric conjugate addition of arylzinc reagents
to N-Boc-4-pyridone. When (S)-BINAP was used as the chiral ligand, excellent ee can be achieved
(entries 1 and 3, up to 96% ee).
Scheme 4. Rh(I)-BINAP-catalyzed conjugate addition reaction.

Molecules 2017, 22, 723
5 of 10
3. Materials and Methods
3.1. General Procedures, Materials and Intrumentation
The 1H- and 13C-NMR spectra were recorded on a BRUKER 300 NMR spectrometer (BRUKER,
Winston Salem, NC, USA), operating at 300 MHz for 1H, 75 MHz for 13C and 282 MHz for 19F. Samples
for NMR spectra were dissolved in deuterated chloroform (with TMS). Infrared (IR) spectra were
recorded on a Nicolet iS10 FT-IR spectrometer as neat samples (thin films). 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 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 200–400 µ silica gel.
3.1.1. Materials
Unless stated otherwise, solvents and chemicals were obtained from commercial sources and
used without further purification. Anhydrous tetrahydrofuran (THF) was purchased from Sigma
Aldrich. TMSCl was distilled from CaH2 under a positive nitrogen atmosphere. Arylzinc reagents
were prepared from the corresponding aryllithium reagent and ZnCl2. Aryllithium reagents were
prepared from the corresponding arylhalides and t-BuLi (1.70 M in pentane). t-BuLi (1.70 M in pentane)
was commercially available and titrated using sec-BuOH and 1,10-phenanthroline monohydrate in
THF. All glassware was flamed-dried under high vacuum and purged with argon and then cooled
under a dry nitrogen atmosphere. Low temperature baths were prepared using ice NaCl water bath, or
dry ice-isopropanol slush bath mixtures. All ArZnCl 1,4-conjugate addition reactions were conducted
under a positive, dry argon atmosphere in anhydrous solvents in flasks fitted with rubber septa.
3.1.2. General Procedure A
Rh(I)-BINAP-catalyzed 1,4-conjugate addition reactions. This method was modified from the
procedure reported by Hayashi [18]. Starting N-Boc-4-pyridone (0.5 mmol) was added to a solution
of [RhCl(C2H4)◦2]2 (0.015 mol %, 0.0075 mmol) and BINAP (0.033 mol %, 0.0165 mmol) in dry THF
(1.0 mL) at
−
5 C under argon with continuous stirring. After stirring for 15 min, ArZnCl (1.0 M
in THF, 3.0 quiv, 1.5 mmol, prepared from corresponding arylbromides in a separate flask [59]) and
TMSCl (1.0 M in THF, 3.0 equiv, 1.5 mmol) were added simultaneously dropwise over 10 min to this
solution. The resulting mixture was then warmed up to room temperature and stirred for 20 h at room
temperature. Then, the reaction mixture was diluted with dichloromethane (4.0 mL), quenched with
saturated aqueous NH4Cl (4.0 mL) and extracted with dichloromethane (3
×
8.0 mL). The combined
organic phase was washed with water (8.0 mL), brine (8.0 mL), then dried over anhydrous Na2SO4,
filtered, concentrated in vacuo, and purified by flash column chromatography (silica, 10%–20% ethyl
acetate in hexanes, v/v) to give pure compounds.
HRMS data for compounds 5Aa
see supplementary. Compounds 5Ab
reported [55,57,60].
,
–
5Ad
,
5Af−Ag
, 5Ai, 5Ak–Al were analyzed by TOF MS,
5Ah, and 5Aj have been fully characterized and
Ac 5Ae,
,
3.2. Synthesis of Adducts 5Aa, 5Ad, 5Af–Ag, 5Ai, 5Ag, 5Ak–Al
N-Boc-2-(4-methylphenyl)-2,3-dihydro-4-pyridone (5Aa). Employing General Procedure A and using
N-Boc-4-pyridone (97 mg, 0.5 mmol), [RhCl(C2H4)2]2 (2.92 mg, 0.0075 mmol), (S)-BINAP (10.3 mg,
0.0165 mmol), ArZnCl (1.0 M in THF, 3.0 equiv, 1.5 mmol), TMSCl (163 mg, 1.5 mmol) and the resultant
◦
◦
reaction mixture was slowly warmed to 0 C and stirred for an additional 24 h at 0 C, after purification
by flash column chromatography (silica, 10%–20% ethyl acetate:hexanes, v/v) gave white solid 5Aa
(128 mg, 89%). The ee was determined on a Daicel Chiralcel OD-H column with a solvent system
of hexanes/2-propanol (9:1 ratio), flow rate = 1.0 mL/min. tr(major) = 7.1 min., tr(minor) = 7.8 min.
92% ee. m.p. 82.6–84.3 ◦C; IR (neat) 3081 (w), 2982 (w), 2926 (w), 1729 (s), 1661 (s), 1597 (s), 1412 (w),

Molecules 2017, 22, 723
6 of 10
1369 (m), 1339 (s), 1299 (s), 1253 (m), 1210 (m), 1145 (s), 1096 (m), 1010 (m), 923 (m), 845 (m), 815 (m),
774 (m) cm−1; 1H-NMR
1.33 (s, 9 H), 2.17 (s, 3H), 2.63 (td, J = 1.5, 16.5 Hz, 1 H), 2.98 (dd, J = 7.50,
16.5 Hz, 1 H), 5.20 (dd, J = 1.17, 8.4 Hz, 1 H), 5.49 (d, J = 7.50 Hz, 1 H), 6.96 (s, 4 H), 7.79 (d, J = 8.4 Hz,
δ
1 H); 13C-NMR
δ 21.0, 28.0, 41.9, 55.4, 83.6, 107.0, 125.8, 129.4, 135.8, 137.6, 142.9, 151.5, 192.3. HRMS
(EI-ion trap) m/z: [M]+ calcd. for C17H21NO3, 287.1520; found 287.1521.
N-Boc-2-(2-napthanyl)-2,3-dihydro-4-pyridone (5Ad). Employing General Procedure A and using
N-Boc-4-pyridone (97 mg, 0.5 mmol), [RhCl(C2H4)2]2 (2.92 mg, 0.0075 mmol), BINAP (10.3 mg,
0.0165 mmol), ArZnCl (1.0 M in THF, 3.0 equiv, 1.5 mmol) and TMSCl (163 mg, 1.5 mmol) after
purification by flash column chromatography (silica, 10%–20% ethyl acetate:hexanes, v/v) gave white
solid 5Ad (147 mg, 91%): mp 113.8–115.1 ◦C; IR (neat) 3065 (w), 2981 (w), 1717 (s), 1667 (s), 1606 (s),
1
1451 (m), 1369 (m), 1309 (s), 1257 (m), 1222 (m), 1142 (s), 950 (m), 851 (m), 757 (s) cm−1; H-NMR
(300 MHz, CDCl3)
δ 1.40 (br s, 9H), 2.84 (d, J = 16.5 Hz, 1H), 3.16 (dd, J = 7.8, 16.5 Hz, 1H), 5.34 (d,
J = 8.4 Hz, 1H), 5.76 (d, J = 7.2 Hz, 1H), 7.30 (dd, J = 1.5, 8.4 Hz, 1H), 7.35–7.43 (m, 2H), 7.68–7.76 (m,
3H), 7.97 (d, J = 8.4 Hz, 1H); 13C-NMR (75 MHz, CDCl3)
δ 28.0, 41.8, 55.9, 83.8, 107.1, 123.9, 124.6, 126.2,
126.4, 127.6, 128.0, 128.9, 132.9, 133.2, 136.2, 142.9, 151.5, 192.0. HRMS (EI-ion trap) m/z: [M]+ calcd. for
C20H21NO3, 323.1521; found 323.1529.
N-Boc-2-(3,5-dimethylphenyl)-2,3-dihydro-4-pyridone (5Af). Employing General Procedure A and using
N-Boc-4-pyridone (97 mg, 0.5 mmol), [RhCl(C2H4)2]2 (2.92 mg, 0.0075 mmol), BINAP (10.3 mg,
0.0165 mmol), ArZnCl (1.0 M in THF, 3.0 equiv, 1.5 mmol) and TMSCl (163 mg, 1.5 mmol) after
purification by flash column chromatography (silica, 10%–20% ethyl acetate:hexanes, v/v) gave white
solid 5Af (129 mg, 86%): mp 100.0–101.7 ◦C; IR (neat) 3012 (w), 2978 (w), 2918 (w), 1713 (s), 1663 (s),
1596 (s), 1460 (w), 1418 (m), 1369 (m), 1337 (m), 1315 (s), 1257 (m), 1220 (m), 1142 (s), 1017 (m), 843
(s), 762 (s), 703 (w) cm−1; 1H-NMR (300 MHz, CDCl3)
16.5 Hz, 1H), 2.98 (dd, J = 7.8, 16.5 Hz, 1H), 5.21 (dd, J = 1.2, 8.4 Hz, 1H), 5.44 (d, J = 7.8 Hz, 1H), 6.65
δ 1.32 (br s, 9H), 1.13 (s, 6H), 2.64 (td, J = 1.5,
(s, 2H), 6.75 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H); 13C-NMR (75 MHz, CDCl3)
δ 21.4, 28.0, 41.9, 55.6, 83.6,
107.0, 123.5, 128.2, 129.0, 129.5, 138.3, 138.8, 143.0, 151.5, 192.3. HRMS (EI-ion trap) m/z: [M]+ calcd. for
C18H23NO3, 301.1678; found 301.1683.
N-Boc-2-(4-methoxylphenyl)-2,3-dihydro-4-pyridone (5Ag). Employing General Procedure A and using
N-Boc-4-pyridone (97 mg, 0.5 mmol), [RhCl(C2H4)2]2 (2.92 mg, 0.0075 mmol), BINAP (10.3 mg,
0.0165 mmol), ArZnCl (1.0 M in THF, 3.0 equiv, 1.5 mmol) and TMSCl (163 mg, 1.5 mmol) after
purification by flash column chromatography (silica, 10%–20% ethyl acetate:hexanes, v/v) gave white
amorphous solid 5Ag (138 mg, 91%): mp 70.0
(s), 1663 (s), 1594 (s), 1508 (s), 1508 (w), 1366 (w), 1342 (s), 1285 (s), 1246 (s), 1171 (s), 1104 (s), 1027 (s),
981 (m), 852 (w), 787 (m), 769 (s), 645 (m) cm−1; 1H-NMR (300 MHz, CDCl3)
1.47 (br s, 9H), 2.74 (td,
J = 1.5, 16.5 Hz, 1H), 3.11 (dd, J = 7.5, 16.5 Hz, 1H), 3.77 (s, 3H), 5.34 (dd, J = 1.5, 8.4 Hz, 1H), 5.61 (d,
J = 7.5 Hz, 1H), 6.81 (d, J = 8.7 Hz, 2H), 7.14 (dd, J = 8.7 Hz, 2H),7.90 (d, J = 8.4 Hz, 1H); 13C-NMR
−
71.9 ◦C; IR (neat) 2984 (w), 2932 (w), 2836 (w), 1719
δ
δ
28.0, 41.9, 55.1, 55.3, 83.7, 106.9, 114.1, 127.2, 131.1, 142.8, 151.5, 159.2, 192.4. HRMS (EI-ion trap) m/z:
[M]+ calcd. for C17H21NO4, 303.1471; found 303.1471.
N-Boc-2-(3,5-dimethoxylphenyl)-2,3-dihydro-4-pyridone (5Ai). Employing General Procedure A and using
N-Boc-4-pyridone (97 mg, 0.5 mmol), [RhCl(C2H4)2]2 (2.92 mg, 0.0075 mmol), BINAP (10.3 mg,
0.0165 mmol), ArZnCl (1.0 M in THF, 3.0 equiv, 1.5 mmol) and TMSCl (163 mg, 1.5 mmol) after
purification by flash column chromatography (silica, 10%–20% ethyl acetate:hexanes, v/v) gave clear
sticky oil 5Ai (141 mg, 85%): IR (neat) 2975 (w), 2838 (w), 1719 (s), 1664 (s), 1592 (s), 1457 (m), 1420
(m), 1368 (m), 1288 (s), 1203 (m), 1144 (s), 1066 (m), 999 (m), 940 (w); 833 (m), 759 (m), 697 (m) cm−1
1H-NMR (300 MHz, CDCl3)
1.46 (br s, 9H), 2.76 (d, J = 16.5 Hz, 1H), 3.11 (dd, J = 7.8, 16.5 Hz, 1H),
3.74 (s, 6H), 5.33 (d, J = 8.4 Hz, 1H), 5.58 (d, J = 7.8 Hz, 1H), 6.33 (s, 3H), 7.94 (d, J = 8.4 Hz, 1H);
13C-NMR (75 MHz, CDCl3)
28.0, 41.9, 55.3, 55.7, 83.8, 99.3, 104.1, 107.0, 125.3, 128.2, 129.0, 141.3, 142.9,
151.4, 161.1, 192.0. HRMS (EI-ion trap) m/z: [M]+ calcd. for C18H23NO5, 333.1576; found 333.1578.
;
δ
δ

Molecules 2017, 22, 723
7 of 10
N-Boc-2-(4-trifluoromethylphenyl)-2,3-dihydro-4-pyridone (5Ak). Employing General Procedure A and
using N-Boc-4-pyridone (97 mg, 0.5 mmol), [RhCl(C2H4)2]2 (2.92 mg, 0.0075 mmol), BINAP (10.3 mg,
0.0165 mmol), ArZnCl (1.0 M in THF, 1.5 equiv, 0.75 mmol) and TMSCl (163 mg, 1.5 mmol) after
purification by flash column chromatography (silica, 10%–20% ethyl acetate:hexanes, v/v) gave white
amorphous solid 5Ak (80 mg, 47%): mp 78.1
(s), 1661 (s), 1604 (s)1474 (w), 1454 (m), 1394 (m), 1309 (s), 1258 (m), 1217 (m), 1147 (s), 1110 (s), 1069
(s), 1017 (m), 979 (w), 839 (m), 759 (m) cm−1; 1H-NMR (300 MHz, CDCl3)
1.42 (br s, 9H), 2.71 (d,
J = 16.8 Hz, 1H), 3.14 (dd, J = 7.2, 16.8 Hz, 1H), 5.32 (d, J = 8.4 Hz, 1H), 5.66 (d, J = 7.2 Hz, 1H), 7.28 (d,
−
79.5 ◦C; IR (neat) 3076 (w), 2980 (w), 2930 (w), 1728
δ
J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H),7.92 (d, J = 8.4 Hz, 1H); 13C-NMR (75 MHz, CDCl3)
δ 28.0, 41.6,
55.4, 84.2, 107.2, 125.87, 125.93, 126.2, 130.1, 130.5, 142.8, 151.2, 191.3. 19F-NMR (282 MHz, CDCl3)
δ
−62.7; HRMS (EI-ion trap) m/z: [M]+ calcd. for C17H18NO3F3, 341.1239; found 341.1242.
N-Boc-2-(3,5-ditrifluoromethylphenyl)-2,3-dihydro-4-pyridone (5Al). Employing General Procedure A and
using N-Boc-4-pyridone (97 mg, 0.5 mmol), [RhCl(C2H4)2]2 (2.92 mg, 0.0075 mmol), BINAP (10.3 mg,
0.0165 mmol), ArZnCl (1.0 M in THF, 1.5 equiv, 0.75 mmol) and TMSCl (163 mg, 1.5 mmol) after
purification by flash column chromatography (silica, 10%–20% ethyl acetate:hexanes, v/v) gave yellow
sticky oil 5Al (84 mg, 41%): IR (neat) 2981 (w), 1725 (m), 1671 (m), 1601 (m), 1459 (w), 1417 (w), 1372
(w), 1303 (m), 1275 (s), 1213 (m), 1125 (s), 1014 (m), 897 (m), 846 (m), 766 (m) cm−1; 1H-NMR (300 MHz,
CDCl3)
δ 1.41 (br s, 9H), 2.73 (d, J = 16.5 Hz, 1H), 3.15 (dd, J = 7.8, 16.5 Hz, 1H), 5.34 (d, J = 8.4 Hz,
1H), 5.69 (d, J = 7.8 Hz, 1H), 7.57 (s, 2H), 7.90 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H); 13C-NMR (75 MHz,
CDCl3)
δ 27.9, 41.2, 55.0, 84.8, 107.4, 117.6, 121.2, 122.2, 124.8, 126.1, 132.2, 132.6, 141.7, 142.6, 150.9,
190.6. 19F-NMR (282 MHz, CDCl3) δ −63.0; HRMS (EI-ion trap) m/z: [M]+ calcd. for C18H17NO3F6,
409.1113; found 409.1119.
4. Conclusions
We have successfully developed rhodium(I)-complexes-catalyzed 1,4-conjugate additions of
arylzinc chlorides to N-Boc-4-pyridone in the presence of chlorotrimethylsilane (TMSCl).
A
combination of [RhCl(C2H4)2]2 and BINAP was determined to be the most effective catalyst for
1,4-conjugate addition of arylzinc chlorides to N-Boc-4-pyridones. We also demonstrated that
this reaction is compatible with a broad scope of substrates with both electron-withdrawing
and electron-donating substituents on the aromatic ring to afford 1,4-adducts 2-substituted-2,3-
dihydropyridones in high yields. Excellent ee can be achieved when (S)-BINAP is used as the
chiral ligand. These 1,4-adducts are versatile intermediates that can be utilized for the synthesis
of medicinally important N-heterocycles such as pyridines, piperidones, piperidines, indolizidenes,
and quinolizidenes.
Supplementary Materials: Supplementary materials are available online.
Acknowledgments: This work was generously supported in part by the National Science Foundation HBCU-UP
RIA (NSF award no. 1600987). We also thank Winston Salem State University for start-up fund and Research
Initiation Program for providing seed funding for this project. We also like to thank Marcus Wright from Chemistry
Department, Wake Forest University, Winston Salem for assistance in attaining NMR spectra.
Author Contributions: Fenghai Guo conceived and designed the experiments; Matthew McGilvary, Malcolm
Jeffries, Briana Graves, Shekinah Graham performed the experiments; Yuelin Wu analyzed the data and helped in
results and discussion; Fenghai Guo wrote the paper.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
Boc
tert-Butyloxycarbonyl
C-C
Carbon carbon
BINAP
2,2’-bis(diphenylphosphino)-1,1’-binaphthyl

Molecules 2017, 22, 723
8 of 10
References and Notes
1.
2.
Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Pergamon: Oxford, MS, USA, 1992.
Lipshutz, B.H. Organometallics in Organic Synthesis, 2nd ed.; Schlosser, M., Ed.; John Wiley & Sons: Chichester,
UK, 2002; pp. 665–815.
3.
4.
5.
6.
7.
Alexakis, A.; Benhaim, C. Enantioselective Copper-Catalyzed Conjugate Addition. Eur. J. Org. Chem. 2002,
3221–3236. [CrossRef]
Christoffers, J.; Koripelly, G.; Rosiak, A.; Rossle, M. Recent Advances in Metal-Catalyzed Asymmetric
Conjugate Additions. Synthesis 2007, 1279–1300. [CrossRef]
Alexakis, A.; Backvall, J.-E.; Krause, N.; Pamies, O.; Dieguez, M. Enantioselective copper-catalyzed conjugate
addition and allylic substitution reactions. Chem. Rev. 2008, 108, 2796–2823. [CrossRef] [PubMed]
Perez, M.; Ayad, T.; Maillos, P.; Poughon, V.; Fahy, J.; Ratovelomanana-Vidal, V. Highly Diastereoselective
1,6-Conjugate Addition of Arylboronic Acids to Securinine. Synlett 2016, 27, 1077–1082.
Wei, Y.; Liu, Z.; Wu, X.; Fei, J.; Gu, X.; Yuan, X.; Ye, J. Remote Construction of Chiral Vicinal Tertiary and
Quaternary Centers by Catalytic Asymmetric 1,6-Conjugate Addition of Prochiral Carbon Nucleophiles to
Cyclic Dienones. Chem. Eur. J. 2015, 21, 18921–18924. [CrossRef] [PubMed]
8.
Magrez-Chiquet, M.; Morin, M.S.T.; Wencel-Delord, J.; Amraoui, S.D.; Basle, O.; Alexakis, A.; Crevisy, C.;
Mauduit, M. Enantioselective 1,6-Conjugate Addition of Dialkylzinc Reagents to Acyclic Dienones Catalyzed
by Cu-DiPPAM Complex—Extension to Asymmetric Sequential 1,6/1,4-Conjugate Addition. Chem. Eur. J.
2013, 19, 13663–13667. [CrossRef] [PubMed]
9.
Hayashi, T.; Yamamoto, S.; Tokunaga, N. Rhodium-Catalyzed Asymmetric 1,6-Addition of Aryl Zinc
Reagents to Dienones. Angew. Chem. 2005, 117, 4296–4299. [CrossRef]
10. Hayashi, T.; Yamamoto, S.; Tokunaga, N. Rhodium-Catalyzed Asymmetric 1,6-Addition of Aryl Zinc
Reagents to Dienones. Angew. Chem. Int. Ed. 2005, 44, 4224–4227. [CrossRef] [PubMed]
11. Hayashi, T.; Tokunaga, N.; Inoue, K. Rhodium-Catalyzed Asymmetric 1,6-Addition of Aryltitanates to
Enynones Giving Axially Chiral Allenes. Org. Lett. 2004, 6, 305–307.
12. Phosphoramidite ligands and their application in copper catalyzed conjugate addition reactions: Feringa, B.L.
Phosphoramidites: Marvellous ligands in catalytic asymmetric conjugate addition. Acc. Chem. Res. 2000, 33,
346–353.
13. Phosphoramidite ligands and their application in copper catalyzed conjugate addition reactions: Yang, B.;
Xie, F.; Yu, H.; Shen, K.; Ma, Z.; Zhang, W. Enantioselective Synthesis of Chiral
γ-aryl α-keto Ester
by Copper-catalyzed 1,4-conjugate Addition Using D2-symmetric Biphenyl Phosphoramidite Ligand.
Tetrahedron 2011, 67, 6197–6201.
14. Chiral phosphite ligands: Xing, A.P.; Bai, C.B.; Wang, L.L. Chiral phosphite ligands derived from
L-(+)-tartaric acid: synthesis and application in the Cu-catalyzed 1, 4-conjugate addition of organozincs to
cyclic enones. Tetrahedron 2013, 69, 455–459. [CrossRef]
15. Fagnou, K.; Lautens, M. Rhodium-Catalyzed Carbon-Carbon Bond Forming Reactions of Organometallic
Compounds. Chem. Rev. 2003, 103, 169–196. [CrossRef] [PubMed]
16. Hayashi, T.; Yamasaki, K. Rhodium-Catalyzed Asymmetric 1,4-Addition and Its Related Asymmetric
Reactions. Chem. Rev. 2003, 103, 2829–2844. [CrossRef] [PubMed]
17. Sakai, M.; Hayashi, H.; Miyaura, N. Rhodium-Catalyzed Conjugate Addition of Aryl- or 1-Alkenylboronic
Acids to Enones. Organometallics 1997, 16, 4229–4231. [CrossRef]
18. Shintani, R.; Tokunaga, N.; Doi, H.; Hayashi, T. A New Entry of Nucleophiles in Rhodium-Catalyzed
Asymmetric 1,4-Addition Reactions: Addition of Organozinc Reagents for the Synthesis of 2-Aryl-4-
piperidones. J. Am. Chem. Soc. 2004, 126, 6240–6241. [CrossRef] [PubMed]
19. Shintani, R.; Yamagami, T.; Kimura, T.; Hayashi, T. Asymmetric Synthesis of 2-Aryl-2,3-dihydro-4-quinolones
by Rhodium-Catalyzed 1,4-Addition of Arylzinc Reagents in the Presence of Chlorotrimethylsilane. Org. Lett.
2005, 7, 5317–5319. [CrossRef] [PubMed]
20. Sakuma, S.; Miyaura, N. Rhodium(I)-Catalyzed Asymmetric 1,4-Addition of Arylboronic Acids to
α,β-Unsaturated Amides. J. Org. Chem. 2001, 66, 8944–8946. [CrossRef] [PubMed]
21. Sakuma, S.; Sakai, M.; Itooka, R.; Miyaura, N. Asymmetric Conjugate 1,4-Addition of Arylboronic Acids to
α
,
β-Unsaturated Esters Catalyzed by Rhodium(I)/(S)-BINAP. J. Org. Chem. 2000, 65, 5951–5955. [CrossRef]
[PubMed]

Molecules 2017, 22, 723
9 of 10
22. Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds.
Chem. Rev. 1995, 95, 2457–2483. [CrossRef]
23. Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. A Chiral Chelating Diene as A New Type of Chiral
Ligand for Transition Metal Catalysts: Its Preparation and Use for the Rhodium-Catalyzed Asymmetric
1,4-Addition. J. Am. Chem. Soc. 2003, 125, 11508–11509. [CrossRef] [PubMed]
24. Defieber, C.; Paquin, J.-F.; Serna, S.; Carreira, E.M. Chiral [2.2.2] Dienes as Ligands for Rh(I) in Conjugate
Additions of Boronic Acids to a Wide Range of Acceptors. Org. Lett. 2004, 6, 3873–3876. [CrossRef] [PubMed]
25. Kuuloja, N.; Vaismaa, M.; Franzén, R. Rh-IndOlefOx Catalyzed Conjugate Addition/Heck-type Coupling of
Organoboronics to a Lactam or a Lactone. Tetrahedron 2012, 68, 2313–2318. [CrossRef]
26. Glorius, F. Chiral Olefin Ligands-New “Spectators” in Asymmetric Catalysis. Angew. Chem. Int. Ed. 2004, 43,
3364–3366. [CrossRef] [PubMed]
27. Croix, C.; Prié, G.; Chaulet, C.; Viaud-Massuard, M.-C. Rhodium-Catalyzed 1,4-Addition of Arylboronic
Acids to 3-Benzylidene-1H-pyrrolo[2,3-b]pyridin-2(3H)-one Derivatives. J. Org. Chem. 2015, 80, 3264–3269.
[CrossRef] [PubMed]
28. Asano, N.; Nash, R.J.; Molyneux, R.J.; Fleet, G.W.J. Sugar-mimic Glycosidase Inhibitors: Natural Occurrence,
Biological Activity and Prospects for Therapeutic Application. Tetrahedron Asymmetry 2000, 11, 1645–1680.
[CrossRef]
29. Watson, P.S.; Jiang, B.; Scott, B. A Diastereoselective Synthesis of 2,4-Disubstituted Piperidines: Scaffolds for
Drug Discovery. Org. Lett. 2000, 2, 3679–3681. [CrossRef] [PubMed]
30. Stinson, S.C. Driven by the Needs of the Drug Industry and Fueled by the Ingenuity of Chemists, Sales of
Single-enantiomer Chiral Compounds Keep Accelerating. C&EN 2001, 79, 45–57.
31. Thayer, A.M. Centering on Chirality. C&EN 2007, 85, 11–19.
32. Pearson, M.S.M.; Mathe-Allainmat, M.; Fargeas, V.; Lebreton, J. Recent Advances in the Total Synthesis of
Piperidine Azasugars. Eur. J. Org. Chem. 2005, 2159–2191. [CrossRef]
33. Cossy, J. Selective Methodologies for the Synthesis of Biologically Active Piperidinic Compounds. Chem. Rec.
2005, 5, 70–80. [CrossRef] [PubMed]
34. Zhou, P.; Chen, B.C.; Davis, F.A. Recent Advances in Asymmetric Reactions Using Sulfinimines (N-sulfinyl
imines). Tetrahedron 2004, 60, 8003–8030. [CrossRef]
35. Buffat, M.G.P. Synthesis of Piperidines. Tetrahedron 2004, 60, 1701–1729. [CrossRef]
36. Weintraub, P.M.; Sabol, J.S.; Kane, J.M.; Borcherding, D.R. Recent Advances in the Synthesis of Piperidones
and Piperidines. Tetrahedron 2003, 59, 2953–2989. [CrossRef]
37. Laschat, S.; Dickner, T. Stereoselective Synthesis of Piperidines. Synthesis 2000, 1781–1813. [CrossRef]
38. Bailey, P.D.; Millwood, P.A.; Smith, P.D. Asymmetric Routes to Substituted Piperidines. Chem. Commun. 1998
.
[CrossRef]
39. Šebesta, R.; Pizzuti, M.; Boersma, A.J.; Minnaard, A.J.; Feringa, B.L. Catalytic Enantioselective Conjugate
Addition of Dialkylzinc Reagents to N-Substituted-2,3-dehydro-4-piperidones. Chem. Commun. 2005
1711–1713.
,
40. Jagt, R.B.C.; de Vries, J.G.; Feringa, B.L.; Minnaard, A.J. Enantioselective Synthesis of 2-Aryl-4-piperidones via
Rhodium/Phosphoramidite-Catalyzed Conjugate Addition of Arylboroxines. Org. Lett. 2005, 7, 2433–2435.
[CrossRef] [PubMed]
41. Alexakis, A.; Backvall, J.E.; Krause, N.; Pamies, O.; Dieguez, M. Enantioselective Copper-Catalyzed
Conjugate Addition and Allylic Substitution Reactions. Chem. Rev. 2008, 108, 2796–2823. [CrossRef]
[PubMed]and references cited therein.
42. Feringa, B.L.; Naasz, R.; Imbos, R.; Arnold, L.A. Modern Organocopper Chemistry; Krause, N., Ed.; John Wiley
& Sons: New York, NY, USA, 2002; Volume 7, pp. 224–258.
43. Krause, N.; Hoffmann-Röder, A. Recent Advances in Catalytic Enantioselective Michael Additions. Synthesis
2001, 171–196. [CrossRef]
44. Sibi, M.P.; Manyem, S. Enantioselective Conjugate Additions. Tetrahedron 2000, 56, 8033–8061. [CrossRef]
45. Duncan, A.P.; Leighton, J.L. Enantioselective Cu-Catalyzed Conjugate Addition of Diethylzinc to Acyclic
Aliphatic Enones. Org. Lett. 2004, 6, 4117–4119. [CrossRef] [PubMed]and references cited therein.
46. Brown, M.K.; Degrado, S.J.; Hoveyda, A.H. Highly Enantioselective Cu-Catalyzed Conjugate Addition of
Dialkylzinc Reagents to Unsaturated Furanones and Pyranones: Preparation of Air-Stable and Catalytically
Active Cu-Peptide Complexes. Angew. Chem. Int. Ed. 2005, 44, 5306–5310. [CrossRef] [PubMed]

Molecules 2017, 22, 723
10 of 10
47. Lopóz, F.; Harutyunyan, S.R.; Meetsma, A.; Minnaard, A.J.; Feringa, B.L. Copper-Catalyzed Enantioselective
Conjugate Addition of Grignard Reagents to
2752–2756. [CrossRef] [PubMed]
α,β-Unsaturated Esters. Angew. Chem. Int. Ed. 2005, 44,
48. Brown, M.K.; Hoveyda, A.H. Enantioselective Total Synthesis of Clavirolide C. Applications of Cu-Catalyzed
Asymmetric Conjugate Additions and Ru-Catalyzed Ring-Closing Metathesis. J. Am. Chem. Soc. 2008, 130,
12904–12906. [CrossRef] [PubMed]
49. Alexakis, A.; Albrow, V.; Biswas, K.; d’Augustin, M.; Prieto, O.; Woodward, S. Highly Enantioselective
Copper(I)-phosphoramidite-catalysed Additions of Organoaluminium Reagents to Enones. Chem. Comm.
2005, 2843–2845. [CrossRef] [PubMed]
50. For reviews on Grignard reagents and copper catalysis, see; Harutyunyan, S.R.; den Hartog, T.; Geurts, K.;
Minnaard, A.J.; Feringa, B.L. Catalytic Asymmetric Conjugate Addition and Allylic Alkylation with Grignard
Reagents. Chem. Rev. 2008, 108, 2824–2852. [CrossRef] [PubMed] and references cited therein.
51. For reviews on Grignard reagents and copper catalysis, see; López, F.; Minnaard, A.J.; Feringa, B.L. Catalytic
Enantioselective Conjugate Addition with Grignard Reagents. Acc. Chem. Res. 2007, 40, 179–188.
52. Lee, K.-S.; Brown, M.K.; Hird, A.W.; Hoveyda, A.H. A Practical Method for Enantioselective Synthesis of
All-Carbon Quaternary Stereogenic Centers through NHC-Cu-Catalyzed Conjugate Additions of Alkyl-
and Arylzinc Reagents to
[PubMed]
β-Substituted Cyclic Enones. J. Am. Chem. Soc. 2006, 128, 7182–7184. [CrossRef]
53. Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. Catalytic Cycle of Rhodium-Catalyzed Asymmetric
1,4-Addition of Organoboronic Acids. Arylrhodium, Oxa- -allylrhodium, and Hydroxorhodium
Π
Intermediates. J. Am. Chem. Soc. 2002, 124, 5052–5058. [CrossRef] [PubMed]
54. Kina, A.; Ueyame, K.; Hayashi, T. Enantiomerically Pure Rhodium Complexes Bearing 1,5-Diphenyl-1,5-
cyclooctadiene as a Chiral Diene Ligand. Their Use as Catalysts for Asymmetric 1,4-Addition of Phenylzinc
Chloride. Org. Lett. 2005, 7, 5889–5892. [CrossRef] [PubMed]
55. Guo, X.; Singh, R.P.; Corey, E.J. Enantioselective Synthesis of a Chiral C3-Symmetric Bridgehead Amine.
Org. Lett. 2010, 12, 1812–1814. [CrossRef] [PubMed]
56. Dieter, R.K.; Guo, F. Conjugate Addition Reactions of N-Carbamoyl-4-Pyridones with Organometallic
Reagents. J. Org. Chem. 2009, 74, 3843–3848. [CrossRef] [PubMed]
57. Guo, F.; Dhakal, R.C.; Dieter, R.K. Conjugate Addition Reactions of N-Carbamoyl-4-pyridones and
2,3-Dihydropyridones with Grignard Reagents in the Absence of Cu(I) Salts. J. Org. Chem. 2013, 78,
8451–8464. [CrossRef] [PubMed]
58. Hayashi, T.; Yamamoto, S.; Tokunaga, N. Rhodium-Catalyzed Asymmetric 1,6-Addition of Aryl Zinc
Reagents to Dienones. Angew. Chem. Int. Ed. 2005, 44, 4224–4227. [CrossRef] [PubMed]
59. Liang, Y.; Fu, G. Catalytic Asymmetric Synthesis of Tertiary Alkyl Fluorides: Negishi Cross-Couplings of
Racemic α,α-Dihaloketones. J. Am. Chem. Soc. 2014, 136, 5520–5524. [CrossRef] [PubMed]
60. Li, H.; Wu, J. Rhodium(II)-Catalyzed Formal [3 + 2] Cycloaddition of N-Sulfonyl-1,2,3-triazoles with
Isoxazoles: Entry to Polysubsituted 3-Aminopyrroles. Org. Lett. 2015, 17, 5424–5427. [CrossRef] [PubMed]
Sample Availability: Samples of the compounds 5Ad
, 5Ae, 5Af, 5Ag, 5Ah, and 5Ai are available from the authors.
©
2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).