Conjugate Addition Routes to 2-Alkyl-2,3-dihydroquinolin-4(1H)-ones and 2-Alkyl-4-hydroxy-1,2-dihydroquinoline-3-carboxylates

Article abstract of DOI:10.1002/ejic.201901036

Under CuBr·SMe2/PPh3 catalysis (5/10 mol-%) RMgCl (R = Me, Et, nPr, CH=CH₂, nBu, iBu, nC₅H₁₁, cC₆H₁₁, Bn, CH₂Bn, nC₁₁H₂₃) readily (–78 °C) undergo 1,4-addition to Cbz or Boc protected quinolin-4(1H)-ones to provide 2-alkyl-2,3-dihydroquinolin-4(1H)-ones (14 examples, 54–99 % yield). Asymmetric versions require AlEt₃ to Boc-protected ethyl 6-substituted 4(1H)-quinolone-3-carboxylates (6-R group = all halogens, n/i/t-alkyls, CF₃) and provide 61–91 % yield, 30–86 % ee; any halogen, Me, or CF₃ provide the highest stereoselectivities (76–86 % ee). Additions of AlMe₃ or Al(nC₈H₁₇)₃ provide ≈ 45 and ≈ 75 % ee on addition to the parent (6-R = H). Ligand (S)-(BINOL)P–N(CHPh₂)(cC₆H₁₁) provides the highest ee values engendering addition to the Si face of the 4(1H)-quinolone-3-carboxylate. Allylation and deprotection of a representative 1,4-addition product example confirm the facial selectivity (X-ray crystallography).

Full text of DOI:10.1002/ejic.201901036

DOI: 10.1002/ejic.201901036
Full Paper
Copper-Catalyzed 1,4-Addition | Very Important Paper |
Conjugate Addition Routes to 2-Alkyl-2,3-dihydroquinolin-
4(1H)-ones and 2-Alkyl-4-hydroxy-1,2-dihydroquinoline-3-
carboxylates
Alex Kingsbury,[a][‡] Steve Brough,[b] Antonio Pedrina McCarthy,[a] William Lewis,[a][‡‡] and
Simon Woodward*[a]
Abstract: Under CuBr·SMe2/PPh3 catalysis (5/10 mol-%) RMgCl gen, Me, or CF3 provide the highest stereoselectivities (76–86 %
(R = Me, Et, nPr, CH=CH2, nBu, iBu, nC5H11, cC6H11, Bn, CH2Bn, ee). Additions of AlMe3 or Al(nC8H17)3 provide ≈ 45 and ≈ 75 %
nC11H23) readily (–78 °C) undergo 1,4-addition to Cbz or Boc ee on addition to the parent (6-R = H). Ligand (S)-(BINOL)P–
protected quinolin-4(1H)-ones to provide 2-alkyl-2,3-dihydro- N(CHPh2)(cC6H11) provides the highest ee values engendering
quinolin-4(1H)-ones (14 examples, 54–99 % yield). Asymmetric addition to the Si face of the 4(1H)-quinolone-3-carboxylate.
versions require AlEt3 to Boc-protected ethyl 6-substituted Allylation and deprotection of a representative 1,4-addition
4(1H)-quinolone-3-carboxylates (6-R group = all halogens, n/i/t- product example confirm the facial selectivity (X-ray crystallog-
alkyls, CF3) and provide 61–91 % yield, 30–86 % ee; any halo- raphy).
Introduction
Pd-catalysed[7] ArM (M = ZnCl, BAr3) addition providing 6c (R =
aryl) in 40–99+% ee, or by a variety of organocatalytic closures
(0–99+% ee) leading to the same core but from different 2-
aminochalcone and related intermediates.[8] As both these ap-
proaches do not presently allow access to more biologically
interesting sp3 substituents (e.g. 3–4 etc.) we sought to study
presently less explored alkyl organometallic additions to 6c.
This seemed potentially profitable as catalytic enantioselective
1,4-alkyl additions to related 6a–b (Y = O, S with R = alkyl) are
already known (9–96 % ee).[9]
Quinolone sub-structure cores 1a and their dihydro-analogues
1b (Scheme 1) constitute privileged starting materials in medic-
inal and natural product chemistry. The former core has been a
lynchpin in antibiotic development for more than 50 years,[1]
most recently in quorum sensing approaches, e.g. the modera-
tion of bacterial activity engendered by species such as 2.[2]
The latter core 1b has been deployed in the syntheses of a
range of natural and biologically active molecules, for example
Ma's intermediate (3),[3] used in the synthesis of martinellic acid
(a natural Bradykinin antagonist); and in the related 4; active at
7 n
towards 5-HT6 serotonin receptors.[4] Compounds 3–4 are
M
exemplary of the recent move to explore sp3 rich heterocycles
in medicinal chemistry.[5] Such concepts are poorly explored
for dihydroquinolones, with 5 being the only common “model
compound” encountered, providing significant stereoselec-
tivities for aryl additions and being attained by either Rh-[6] or
[a] GSK Carbon Neutral Laboratories for Sustainable Chemistry,
University of Nottingham,
Jubilee Campus, Nottingham NG7 2TU, United Kingdom
E-mail: simon.woodward@nottingham.ac.uk
http://www.nottingham.ac.uk/~pczsw/SWGroup/
[b] Key Organics Ltd,
Highfield Road Industrial Estate, Camelford, Cornwall PL32 9RA,
United Kingdom
[‡] Present address: School of Chemical and Physical Sciences,
Keele University,
Staffordshire ST5 5BG, United Kingdom
E-mail: a.kingsbury@keele.ac.uk
[‡‡] Present address: School of Chemistry, The University of Sydney,
Eastern Avenue, Sydney, NSW 2006 Australia
E-mail: w.lewis@sydney.edu.au
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejic.201901036.
Scheme 1. Quinolone and derived dihydro-analogues of relevance to this
publication.
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Results and Discussion
7b while 7c did not participate in the same reaction; (ii) the
catalytic reaction is sensitive to α-branching in the Grignard
(e.g. iPrMgBr and PhMgBr do not react and cC6H11MgBr give
a reduced yield); (iii) Allyl Grignard did not participate in the
reaction.
Additions to Protected Quinolin-4(1H)-ones (7)
The protected acceptors 7a–d (within Table 1) are readily acces-
sible from commercial quinolin-4(1H)-one, which is itself also
available from 2-nitroacetophenone via standard heterocyclic
chemistry.[10] As stoichiometric copper reagents had already
been used in copper-promoted additions to 7a (for aza ana-
logues of the natural product Wrightiadione.[11]), we tested this
substrate under catalytic conditions, but it proved too deacti-
vated to react. The more electron deficient 7b still performed
poorly with ZnEt2 or AlEt3, under typical conjugate addition
conditions. Runs 1–2 were the best outcomes we could attain
from a range of conditions. As we could readily confirm that
the stoichiometric cuprate MgBr[CuEt2] readily added to 7b in
THF upon reaction at –78 to –20 °C affording a 65 % isolated
yield of 8b we trialled catalytic versions of this chemistry. In the
absence of added ligands conversions were modest in THF
(Run 3), and worse upon addition of Et2O (Run 4) due to the
insolubility of 7b in this solvent. Remarkably, although 7b is
also insoluble in 2-MeTHF at low temperature, this solvent pro-
duced a very rapid 1,4-addition (within 5 min), which could
be somewhat further promoted by simple phosphorus ligand
addition (Runs 5–7). Simply increasing the overall reaction time
to 1 h led to complete conversion in both the Cbz and Boc
protected quinolin-4(1H)-ones (7b–c) (Runs 8–9) while the
methyl carbamate (7d) was inferior (Run 10). By employing
these optimal conditions of Table 1 we could show the syn-
thetic scope of the 2-MeTHF reaction conditions (Scheme 2);
Scheme 2. Scope and limitations of CuBr·SMe2/PPh3 catalysed 1,4 Grignard
addition to acceptors 7. Isolated yields.
Having established viable catalysis, we turned our attention
which contains compounds of clear synthetic and biological to the potential for an asymmetric version. Using the conditions
utility. Species 8b–c and 9 have only been mentioned passingly of Scheme 2 but truncating the reaction time to just 2.5 min-
in alternative methodology aimed at biologically active tar- utes for the EtMgBr 1,4-addition to 7b is instructive. In the ab-
gets,[12] while all other isolated examples in Scheme 2 are novel. sence of any added ligand CuBr·SMe2 (5 mol-%) a 35 % conver-
Certain limitations were noted in the chemistry of Scheme 2: (i) sion to 8b is already realised. In the presence the same copper
the lowest yields were associated with addition of MeMgX to loading and conditions, but with added phosphine ligands
Table 1. Optimisation of EtMgBr addition to N-protected quinolin-4(1H)-ones 7.
[a] Determined by 1H NMR on the crude reaction mixture. [b] Isolated yield 80 %. [c] Isolated yield 99 %.
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(10 mol-%) improved conversions are realised: P(OPh)3 (88 %),
PPh3 (73 %) and P(cC6H11)3 (92 %). This indicates that any ligand
accelerated catalysis[13] is modest and not strongly affected by
the σ/ϖ-donor characteristics of the phosphine. In line with
these observations screening of a small diverse library of chiral
ligands (exemplars LA-LF)[10] produced at best 1–11 % ee at con-
versions of 21–76 %. The low levels of asymmetric induction
realised are likely due to diverse substrate coordination shown
by MgII in 2-MeTHF.[14]
Additions to Boc-Protected Ethyl 6-Substituted 4(1H)-
Quinolone-3-carboxylates (26)
One way to overcome the issues raised by substrates 7 is to
add additional coordinative groups to the acceptor to provide
both greater control of the asymmetric transition state confor-
mation and increase its reactivity allowing the use of more se-
lective (more covalent) organometallics (ZnR2, AlR3). Substrates
23[15]–24[16] (Scheme 3) represent examples of such ap-
proaches. We therefore initiated study of acceptors 26 which
are attractive due to their similarity to Schmalz's asymmetric
synthesis of Vitamin E (94 % ee for 1,4 AlMe3 addition);[17] and
as Scammells has described very short preparation of the par-
ent precursor 25a.
Scheme 3. Preferred heterocyclic motifs for improved selectivity in asymmet-
ric additions and the synthesis of preferred acceptor 26.[18]
protection of 25, washing with LiCl(aq) to remove DMF avoids
the degradation that even mildly acidic washes would cause.
Preliminary investigations focused of asymmetric catalytic
Synthesis of the acceptor library 26a–k proceeded as ex-
pected,[10] but two points are worth noting: (i) the use of studies on 26a (Table 2). Previous studies had already revealed
Eaton's reagent to cyclise the 6-substituted 4-oxo-1,4-dihydro- the ethyl ester is preferred over both smaller and larger groups
quinolines 25 is much preferred over traditional phosphoric (Me, CHPh2) and that phosphoramidites are the optimal ligand
acids or high temperature cyclisations in Ph2O and we found class. The ligand structures used in the final optimisation are
this can be telescoped into a one-pot procedure; (ii) in Boc shown in Scheme 4.
Table 2. Optimisation of AlEt3 addition to Boc-protected 4(1H)-quinolone-3-carboxylate 26a.
[a] Determined by 1H NMR on the crude reaction mixture. [b] Isolated yield 68 %. [c] Isolated yield 73 %. [d] 77–82 % ee at 4 mol-% Cu(OTf)2 and 8 mol-%
LN.
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Scheme 4. Ligands used for catalytic asymmetric additions of MR to acceptor
26a.
Initial trials (Table 2) identified Et2O as an optimal solvent
(Runs 1–3) and that copper(II) triflate was the optimal pre-cata-
lyst for asymmetric AlEt3 1,4-addition (Runs 4–6) using (S,R,R)
Feringa's ligand LG as a starting phosphoramidite. Alternative
additions of ZnEt2 provided poorer performance (Run 7 is repre-
sentative). For AlEt3 additions cooling the reaction to –40 °C led
to the highest ee value, but an increase in reaction time is re-
quired (Runs 8–9). We postulate that the success of the ether
solvent is due to the relative insolubility of 26a in it at low
temperature which somewhat moderates background (uncata-
lysed) reactions. At –40 °C in the absence of any catalyst a 74 %
conversion of 25a is seen at 24 h. Lower temperatures could
not be used to further moderate this, as all reactions (catalysed
or background) shut down at –50 °C. We have seen similar ef-
fects before.[16] Ligand modification to include addition coordi-
nation (LI, Run 11), increase in steric bulk of both the amine
(LJ) or atropisomeric diol (L K) (Runs 12–13) had detrimental
effects on the selectivity. The performance of the dissymmetric
ligands (LL-LN) was maximised for a cyclohexyl substituent
(Runs 14–16). Finally, as the reaction is close to viability at
–40 °C we assured its reproducibility, performance and conver-
sion by increasing the catalyst loadings to 4 mol-% Cu(OTf)2
and 8 mol-% LN. Using these optimised conditions we investi-
gated the effect of the 6-substituent on the catalytic reaction
performance (Scheme 5).
Scheme 5. Scope and limitations of substitution patterns for 4(1H)-quinolone-
3-carboxylate acceptors.
ucts 27 we encountered were oils. However, we could over-
come this issue and attain a crystalline derivative by manipula-
tion of 27a (Scheme 6).
The behaviour of 27a–k indicate that electron withdrawing
groups in the 6-position increase the stereoselectivity of AlEt3
1,4-addition. Steric demand in the 6-position has a detrimental
effect on the selective transition state, but less so than electron
factors. With respect to the alane, AlMe3 reversed the sense of
asymmetric induction (28), but longer linear alkyl chains were
tolerated and behaved similarly to AlEt3 (29). Disubstituted 30–
31 are clearly not accepted by the reaction transition state, but
the root cause of this issue is not apparent at present. Due to
the apparent reversals of enantioselectivity (e.g. 27a vs. 28),
based on sign of optical rotation and HPLC enantiomer elution
order, it became important to identify the absolute sense of the
asymmetric induction engendered by (S)-LN in AlEt3 addition to
26a, and by implication other combinations of acceptors and
alanes. Unfortunately, all of the direct conjugate addition prod-
Scheme 6. Stereo-correlation of (+)-27a to crystallographically characterised
(2S,3R)-33 via selective allylation, to anti-32, and Boc-deprotection. Only
hydrogens on the allyl, amine and C2-methine groups of 33 are shown. Se-
lected bond lengths: N1–C2 1.450(6), 1.439(6); C2–C3 1.555(6), 1.558(6); C3–
C4 1.524(7), 1.543(7) Å and N1–C1–C2–C3 torsion angle: 43.4(5), 48.2(5).
There are two independent molecules in the unit cell of 33 (CCDC 1967992).
A sample of 77 % ee (+)-27a was allylated under non-polar
mild conditions leading to the formation of a major allyl anti
diastereomer 32 with the same optical purity, within experi-
mental error as the starting material. Deprotection of 32 with
trifluoroacetic acid leads to formation of a similar mixture of
stereoisomers, of which the anti-(33) species is significantly the
most abundant. Fortunately, slow addition of pentane to con-
centrated ether solutions of the 33 mixture leads to the forma-
tion of modest crops of yellow needles of (+)-33, which by crys-
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tallography are the single isomer anti-(+)-(2S,3R)-33.[10] Thus
(+)-27a also has the 2S configuration presented throughout this
paper. Based on the similarity of their chiral (Chiralpak AD-H)
HPLC enantiomer elution and the homology of their polarime-
try results we tentatively suggest that 27a–k and 28–31 have
the stereochemistry implied herein.
by column chromatography (silica, 9:1 pentane/Et2O) to afford the
products 8b–d as described. The catalytic trials of Table 1 were
performed in a similar manner but at 0.1–0.3 mmol scales with
estimations of the conversions made by 1H NMR spectroscopy prior
to chromatography (runs 8–9 only).
Benzyl 2-Ethyl-4(1H)-quinolone-1-carboxylate (8b): The general
procedure was followed with compound 7b (903 mg, 3.23 mmol)
and ethylmagnesium bromide (3.0
M in THF) (2.7 mL, 8.1 mmol) to
afford compound 8b as a colourless solid (798 mg, 2.58 mmol,
80 %); m.p. 74–76 °C; 1H NMR (400 MHz, CDCl3) δH = 8.00 (dd,
J = 7.8, 1.7 Hz, 1 H, , C5H), 7.81 (d, J = 8.2 Hz, 1H, C8H), 7.54 (ddd,
J = 8.2, 7.8, 1.7 Hz, 1H), 7.46–7.33 (m, 5H, 2 × C12H, 2 × C13H, C14H),
7.19 (dd, J = 7.8 Hz, 7.8 Hz, 1H, C6H), 5.32 (s, 2H, C10H2), 4.94 (dtd,
J = 9.9, 5.8, 1.7 Hz, 1H, C2H), 3.07 (dd, J = 17.6, 5.8 Hz, 1H, C3HAHB),
2.67 (dd, J = 17.6, 1.8 Hz, 1H, C3HAHB), 1.73–1.38 (m, 2H, C15H2), 0.90
(t, J = 7.4 Hz, 3H, C16H3); 13C{1H} NMR (101 MHz, CDCl3) δC = 193.4
(C), 154.2 (C), 140.9 (C), 135.8 (C), 134.4 (C), 128.7 (CH), 128.4 (CH),
128.1 (CH), 126.8 (CH), 125.0 (CH), 124.7 (CH), 124.2 (CH), 68.2 (CH2),
Conclusions
While new 1,4-addition of akyl Grignard reagents to protected
quinolin-4(1H)-ones (7) proceed efficiently (54–99 % yield) un-
der CuBr·SMe2/PPh3 catalysis (5/10 mol-%) attempts to render
the process asymmetric are not successful (eemax ≈ 11 %). How-
ever, modification of the quinolin-4(1H)-one core by addition
of an ester directing/activating group at the 3-position allows
asymmetric additions of AlR3 (R = Me, Et, nC8H17) under
Cu(OTf)2/phosphoramidite (4/8 mol-%) catalysis. The best li-
gands are the dis-symmetric ligands introduced by Fletcher, es-
pecially (S)-LN.[19] Stereoselectivities in the range from: –45 to
+86 % ee are observed, with the highest selectivities being as-
sociated with those 4(1H)-quinolone-3-carboxylate acceptors
(26) bearing small electron withdrawing substituents at the
6-position. The sense of asymmetric induction, due to (S)-LN,
could be determined by C3-allylation and subsequent N-depro-
tection to afford crystals of ethyl (2S,3R)-3-allyl-2-ethyl-2,3-di-
hydro-4(1H)-quinolone-3-carboxylate (2S,3R)-(33). As no gen-
eral ligand providing > 90 % ee over a range of 4(1H)-quino-
lone-3-carboxylates was identified it is likely that individual sub-
strate optimisation will be required. Rather than ad hoc screen-
ing we propose in silico ligand screening of a test transition
state, modelled out of our own mechanistic studies,[20] but us-
ing the substrates employed here may be an attractive alterna-
tive strategy to the discovery of such systems. Such investiga-
tions are our next target.
55.4 (CH), 43.2 (CH2), 24.6 (CH2), 10.7 (CH3); IR (CHCl3): νmax = 3051,
˜
2968, 1685 (C=O), 1602, 1481, 1461, 1395, 1341, 1323, 1304, 1272,
1240, 1127, 909; HRMS m/z calcd. for C19H20NO3 [M + H]: 310.1438,
found 310.1451 (σ = 3.70 ppm). An alternative method to 8b has
appeared, but no data were presented.[10]
tert-Butyl 2-Ethyl-4(1H)-quinolone-1-carboxylate (8c): The gen-
eral procedure was followed with compound 7c (245 mg,
1.00 mmol) and ethylmagnesium bromide (3.0
M solution in THF)
(0.85 mL, 2.55 mmol) to afford compound 8c as a colourless solid
(273 mg, 0.991 mmol, 99 %); m.p. 65–66 °C; 1H NMR (400 MHz,
CDCl3) δH = 7.98 (dd, J = 7.8, 1.6 Hz, 1H, C5H), 7.79 (app. d, J =
8.6 Hz, 1H, C8H), 7.52 (ddd, J = 8.6, 7.3, 1.6 Hz, 1H, C7H), 7.15 (dd,
J = 7.8, 7.3 Hz, 1H, C6H), 4.85 (app. dtd, J = 7.3, 5.8, 1.6 Hz, 1H, C2H),
3.06 (dd, J = 17.5, 5.8 Hz, 1H, C3HAHB), 2.65 (dd, J = 17.5, 1.7 Hz, 1H,
C3HAHB), 1.79–1.37 (m, 11H, 3 × C11H3, C12H2), 0.91 (t, J = 7.3 Hz,
3H, C13H3); 13C{1H} NMR (101 MHz, CDCl3) δC = 193.8 (C), 153.3 (C),
141.5 (C), 134.1 (C, CH), 126.7 (CH), 124.8 (CH), 123.6 (CH), 82.0 (C),
55.0 (CH), 43.2 (CH2), 28.3 (CH3), 24.7 (CH2), 10.7 (CH3); IR (CHCl3):
νmax = 3078, 3011, 2976, 2934, 2879, 1683 (C=O), 1601, 1576, 1480,
˜
1461, 1370, 1348, 1304, 1284, 1256, 1163, 1127, 1066, 1047, 1025,
1003; HRMS m/z calcd. for C16H21NNaO3 [M + Na]: 298.1404, found
298.1407 (σ = 1.40 ppm). An alternative method to 8c has appeared,
but no data were presented.[10]
Experimental Section
General: Details of our general laboratory set-up and instrumenta-
tion have been already published.[21] In brief, 2-Me-THF and Et2O
were distilled from sodium-benzophenone. For catalytic procedures
Grignard and alane reagents and copper salts were commercial
products. Ligands and starting materials were prepared by literature
procedures.[10] Further details for the processes and compounds de-
scribed in this paper are within the Supporting Information.
Methyl 2-Ethyl-4(1H)-quinolone-1-carboxylate (8d): The general
procedure was followed with compound 7d (88 mg, 0.43 mmol)
and ethylmagnesium bromide (3.0
M in THF) (0.35 mL, 1.05 mmol)
to afford compound 8d as a colourless oil (79 mg, 0.339 mmol,
1
79 %); m.p. 74–76 °C; H NMR (400 MHz, CDCl3) δH = 7.99 (dd, J =
7.8, 1.2 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.58–7.51 (m, 1H), 7.19 (t,
J = 7.5 Hz, 1H), 4.94–4.86 (m, 1H, C2H), 3.87 (s, 3H, C10H3), 3.06 (dd,
J = 17.6, 5.8 Hz, 1H, C3HAHB), 2.66 (dd, J = 17.6, 1.0 Hz, 1H, C3HAHB),
1.68–1.43 (m, 1H, C11HAHB), 1.22 (app. t, J = 7.2 Hz, 1H, C11HAHB),
Optimised General Procedure for Conjugate Addition of Gri-
gnard Reagents to Acceptors 7 (Table 1 and Scheme 2): To a
solution of the protected quinolone substrate (7b–d, 1 equiv.) in 2-
0.90 (app. t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δC
=
193.5 (C), 154.9 (C), 140.9 (C), 134.4 (C), 126.8 (CH), 125.0 (CH), 124.7
(CH), 124.2 (CH), 55.4 (CH), 53.3 (CH3), 43.1 (CH2), 24.6 (CH2), 10.7
methyl tetrahydrofuran (0.2
M solution), copper bromide dimethyl
sulfide complex (0.05 equiv.) and triphenylphosphine (0.1 equiv.)
were added with stirring at –78 °C. Under an argon atmosphere
was added a solution of the Grignard reagent (2.5 equiv.). The reac-
tion mixture was stirred at –78 °C under an argon atmosphere for
1 hour. Water (0.1 mL per mmol of 7b–d) was added to the reaction
mixture which was warmed to r.t. whilst stirring over 10 minutes.
The reaction mixture was partitioned between Et2O and water and
the phases separated. The aqueous phase was re-extracted with
Et2O (3 × 10 mL). The combined organic phases were washed with
water (15 mL), dried (MgSO4), concentrated in vacuo and purified
(CH3); IR (CHCl3): νmax = 3011, 2972, 1684, 1603, 1481. 1461, 1442,
˜
1389, 1348, 1304, 1282, 1193; HRMS m/z calcd. for C13H16NO3 [M +
H]: 234.1125, found 234.1120 (σ = 2.20 ppm).
Representative Procedure for AlR3 Conjugate Addition Product
(S)-27 and Their Subsequent acetylation (Table 2 and Scheme 5):
A suspension of protected quinolone derivative (1 equiv.), Cu(OTf)2
(2 or 4 mol-%; 2 or 4 for 26a, 4 for all other 26) and ligand (typically
L
N 4 or 8 mol-%; 2 or 4 for 26a, 4 for all other 26) in freshly distilled
anhydrous Et2O (0.1 in acceptor 25) was stirred under an argon
M
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atmosphere at r.t. for 30 minutes. The suspension was then cooled
to –40 °C and stirred at this temperature under an argon atmos-
phere for a further 15 minutes. To the suspension was added AlEt3
C12HAHB), 1.35 (t, J = 7.1 Hz, 3H, C16H3), 0.89 (t, J = 7.4 Hz, 3H,
C13H3); 13C{1H} NMR (101 MHz, CDCl3): δC = 168.0 (C), 163.4 (C),
152.7 (C), 149.2 (C), 137.2 (C), 130.5 (CH), 124.8 (CH), 123.8 (CH),
123.6 (CH), 123.4 (C), 118.1 (C), 81.7 (C), 60.8 (CH2), 53.8 (CH), 28.3
(1.3
M solution in heptane) (2.5 equiv.) via dropwise addition allow-
ing the organometallic solution to cool prior to contact with the
suspension by running down the side of the reaction vessel. The
reaction mixture was stirred under an atmosphere of argon at
–40 °C until completion (see specified times). A saturated solution
(CH3), 25.5 (CH2), 20.9 (CH3), 14.2 (CH3), 10.0 (CH3); IR (ATR): νmax =
˜
2974, 2933, 2875, 1773 (C=O), 1700 (C=O), 1635, 1602, 1572, 1485,
1456, 1368, 1329, 1249, 1223, 1184, 1156, 1133, 1106, 1069, 1020,
1005, 904, 887, 870, 855, 759, 732, 646, 584, 521, 459, 433; HRMS
of potassium sodium tartrate was then added to the reaction mix- m/z calcd. for C21H27NNaO6 [M + Na]: 412.1731, found 412.1732
ture and warmed to r.t. whilst stirring over 30 minutes. The reaction
mixture was partitioned between CH2Cl2 and water and the phases
were separated. The aqueous phase was extracted with CH2Cl2 (3
times). The combined organics were washed with water (once),
dried (MgSO4), concentrated in vacuo and purified either by column
chromatography (silica, 97:3 pentane/Et2O) or preparative thin layer
chromatography (silica, CH2Cl2) to afford the conjugate addition
products 27 as described. The preparation of 28–29 was attained
in an equivalent manner. Enol tautomers dominate (enol:keto 95:5–
80:20). Only signals relating to enol form are reported. Exchange of
the products with minor keto tautomers can cause signal broaden-
ing in chiral HPLC assays and higher error bars ( 4 vs. ≈ 1 % ee
error for acetate assay).
(σ = 0.40 ppm); HPLC Chiralpak AD-H; mobile phase: hexane:2-prop-
anol (95:5 v/v); flow rate: 0.5 mL min–1; retention times: major
enantiomer: 10.1 min (88.5 %), minor enantiomer: 13.0 min (11.5 %),
77 % ee; [α]2D0 = +295.5 (c = 1.0 in CHCl3, 77 % ee).
1-tert-Butyl 3-Ethyl (2S,3R)-3-Allyl-2-ethyl-2,3-dihydro-4(1H)-
quinolone-1,3-dicarboxylate (32): To a stirred solution of com-
pound (+)-27a (224 mg, 0.645 mmol, assayed as 77 % ee) in CH2Cl2
(4.3 mL, 0.15
M solution) at –78 °C was added potassium hydroxide
(145 mg, 2.58 mmol), tetrabutylammonium iodide (24 mg,
0.065 mmol) and allyl bromide (112 μL, 1.29 mmol). The reaction
vessel was shielded from light to prevent decomposition of the
tetrabutylammonium iodide and the suspension was warmed
slowly to r.t. whilst stirring over 18 h. The reaction mixture was
partitioned between CH2Cl2 (10 mL) and H2O (5 mL). The phases
were separated and the aqueous phase was extracted with CH2Cl2
(3 × 10 mL). The combined organic phases were dried (MgSO4),
concentrated in vacuo and purified by column chromatography (sil-
ica, CH2Cl2) to afford a mixture of four stereoisomers (≈ 3:10:76:10),
of which anti (2S,3R)-32 was the major component, as a colourless
oil (203 mg, 0.524 mmol, 81 %); anti/syn ratio = 6.3:1 (only data for
the major diastereomer are reported). 1H NMR (400 MHz, CDCl3):
δH = 8.05 (dd, J = 7.9, 1.7 Hz, 1H, C5H), 7.79 (br d, J = 8.4 Hz, 1H,
C8H), 7.55 (ddd, J = 8.4, 7.2, 1.7 Hz, 1H, C7H), 7.19 (ddd, J = 7.9, 7.2,
1.1 Hz, 1H, C6H), 5.77 (dddd, J = 17.3, 10.2, 7.3, 7.0 Hz, 1H, C18H),
5.12–5.03 (m, 2H, C19H2), 4.85 (dd, J = 10.7, 4.8 Hz, 1H, C2H), 4.32–
4.23 (2 × q, J = 7.1 Hz, 2H, C15H2), 2.88 (dddd, J = 14.2, 7.0, 1.3,
1.3 Hz, 1H, C17HAHB), 2.60 (dddd, J = 14.2, 7.3, 1.2, 1.2 Hz, 1H,
C17HAHB), 1.59 (s, 9H, 3 × C11H3) overlapped by 1.61–1.52 (m, 2H,
C12H2), 1.33 (t, J = 7.1 Hz, 3H, C16H3), 0.88 (t, J = 7.3 Hz, 3H, C13H3);
13C{1H} NMR (101 MHz, CDCl3): δC = 190.0 (C), 169.4 (C), 153.6 (C),
139.9 (C), 134.2 (CH), 131.8 (CH), 127.9 (CH), 124.4 (CH), 124.3 (C),
124.0 (CH), 119.3 (CH2), 82.4 (C), 63.0 (C), 61.4 (CH2), 61.2 (CH), 38.7
Conversion of Scalemic (S)-27 Into Derived Acetates: The conju-
gate addition product was dissolved in 1:1 mixture of Ac2O/pyridine
(0.5
M solution) and stirred at r.t. for 24 h. Isolated acetate products
were confirmed by 1H NMR spectroscopy. HPLC chromatograms
were obtained on small amounts of acetylated material isolated via
thin layer chromatography on the remainder of the products.
1-tert-Butyl 3-Ethyl (S)-2-Ethyl-4-hydroxy-1,2-dihydroquinoline-
1,3-dicarboxylate (27a): The general procedure was followed us-
ing the protected quinolone carboxylate 26a (2.54 g, 8.00 mmol)
and triethylaluminium (1.3
M in heptane) (15.5 mL, 20.2 mmol, 24 h)
to afford compound 27a as a colourless oil (2.03 g, 5.84 mmol,
73 %); 1H NMR (400 MHz, CDCl3): δH = 12.12 (s, 1H, OH), 7.78 (dd,
J = 7.7, 1.6 Hz, 1H, C5H), 7.63 (br s, 1H, C8H), 7.40 (ddd, J = 8.4, 7.4,
1.6 Hz, 1H, C7H), 7.17 (ddd, J = 7.7, 7.4, 1.1 Hz, 1H, C6H), 5.39 (dd,
J = 9.7, 4.9 Hz, 1H, C2H), 4.42–4.25 (m, 2H, C15H2), 1.55 (s, 9H, 3 ×
C11H3) overlapped by 1.56–1.45 (m, 1H, C12HAHB), 1.38 (t, J = 7.1 Hz,
3H, C16H3) overlapped by 1.42–1.34 (m, 1H, C12HAHB), 0.87 (t, J =
7.4 Hz, 3H, C13H3); 13C{1H} NMR (101 MHz, CDCl3): δC = 170.5 (C),
162.3 (C), 152.9 (C), 137.9 (C), 130.7 (CH), 125.0 (CH), 124.2 (CH),
123.8 (CH), 123.1 (C), 100.7 (C), 81.4 (C), 60.8 (CH2), 51.9 (CH), 28.3
(CH ), 28.3 (CH ), 22.3 (CH ), 14.1 (CH ), 10.6 (CH ); IR (ATR): ν =
˜
2
3
2
3
3
max
3078, 2976, 2935, 2877, 1689 (C=O), 1600, 1479, 1459, 1367, 1332,
1253, 1218, 1154, 1127, 1078, 1013, 991, 923, 886, 758, 643, 582,
451; HRMS m/z calcd. for C22H30NO5 [M + H]: 388.2118, found
388.2120 (σ = 0.30 ppm); HPLC Chiralpak AD-H; mobile phase: hex-
ane/2-propanol (99:1 v/v); flow rate: 0.5 mL min–1; retention times:
major product (2S,3R)-32: 26.9 min (76.1 %), 76 % ee; minor syn-
allylation product (2S,3S)-32: 31.1 min (10.3 %), enantiomer of major
product (2R,3S)-32: 20.0 min (10.3 %), enantiomer of minor syn-allyl-
ation product (2R,3R)-32: 10.8 min (3.4 %). The ee value of the minor
syn diastereomer of 32 could not be accurately determined due to
peak overlap, measured at ≥ 50 % ee; [α]2D0 = +68.0 (c = 1.0 in CHCl3,
for a ≈ 3:10:76:10 mixture of the 2R,3R/2R,3S/2S,3R/2S,3S isomers).
(CH3), 26.7 (CH2), 14.3 (CH3), 10.3 (CH3); IR (ATR): νmax = 3488, 2977,
˜
2933, 2875, 1702 (C=O), 1651, 1624, 1569, 1488, 1457, 1403, 1368,
1350, 1328, 1280, 1252, 1232, 1145, 1094, 1074, 1023, 904, 818, 766,
675, 521, 457; HRMS m/z calcd. for C19H25NNaO5 [M + Na]: 370.1625,
found 370.1625 (σ = 0.10 ppm); HPLC Keto–enol tautomerism led
to broad signals in the chromatograms and increased error bars.
Accurate ee measurement was attained on the derived acetate (See
below for data). Chiralpak AD-H; mobile phase: hexane:2-propanol
(99:1 v/v); flow rate: 0.8 mL min–1; retention times: major enantio-
mer: 5.3 min (91.2 %), minor enantiomer: 14.2 min (8.8 %), 82 % ee;
[α]2D0 = +256.3 (c = 1.0 in CHCl3, 82 % ee).
1-tert-Butyl 3-Ethyl (S)-4-Acetoxy-2-ethyl-1,2-dihydroquinoline- Ethyl
(2S,3R)-3-Allyl-2-ethyl-2,3-dihydro-4(1H)-quinolone-3-
carboxylate (33): To a stirring solution of the mixture of stereoiso-
mers 32 (310 mg, 0.80 mmol) in CH2Cl2 (2.4 mL, 0.33 solution) at
r.t. was added trifluoroacetic acid (1.6 mL). The solution was stirred
at r.t. for 24 h then diluted with CH2Cl2 (9.6 mL) and added slowly
to a saturated aqueous solution of NaHCO3 (12 mL). The aqueous
phase was extracted with CH2Cl2 (3 × 12 mL). The combined organ-
ics were washed with H2O (24 mL), dried (MgSO4), concentrated in
vacuo and purified by column chromatography (silica, CH2Cl2) to
1,3-dicarboxylate (27a derived acetate): The general procedure
was followed using the conjugate addition product 26a (278 mg,
0.800 mmol) to afford the derived acetate as a pale yellow oil
(229 mg, 0.588 mmol, 74 %); 1H NMR (400 MHz, CDCl3): δH = 7.71
(br s, 1H, C8H), 7.42–7.32 (m, 2H), 7.13 (ddd, J = 8.2, 7.4, 1.1 Hz, 1H,
C6H), 5.56 (dd, J = 10.0, 4.4 Hz, 1H, C2H), 4.33–4.21 (m, 2H, C15H2),
2.39 (s, 3H, C18H3), 1.68–1.59 (m, 1H, C12HAHB) overlapped by water
peak, 1.56 (s, 9H, 3 × C11H3), 1.47 (dtd, J = 14.1, 7.2, 2.7 Hz, 1H,
M
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afford 33 as a bright yellow solid (198 mg, 0.689 mmol, 86 %; as a
mixture of four stereoisomers ≈ 14:3:73:10). The major species was
assigned to anti (2S,3R)-33. The mixture was recrystallised from ≈
5:1 pentane/Et2O at r.t. to afford stereo enriched (2S,3R)-33 as bright
yellow needles (≈ 30 % yield, > 91 % ee, > 90:1 dr by HPLC, > 20:1
by NMR); X-ray crystallographic analysis confirmed the 2S,3R stereo-
chemistry of the major stereoisomer; NMR data for only major 2S,3R
isomer. M.p. 83–85 °C; 1H NMR (400 MHz, CDCl3): δH = 7.94 (dd, J =
8.0, 1.6 Hz, 1H, C5H), 7.33 (ddd, J = 8.2, 7.1, 1.6 Hz, 1H, C7H), 6.80
(td, J = 8.0, 7.1, 1.0 Hz, 1H, C6H), 6.70 (dd, J = 8.2, 1.0 Hz, 1H, C8H),
5.74 (dddd, J = 17.1, 10.2, 9.2, 5.4 Hz, 1H, C15H), 5.19 (ddd, J = 17.1,
1.7, 0.9 Hz, 1H, C16HAHB), 5.11 (ddd, J = 10.2, 1.7, 0.9 Hz, 1H,
C16HAHB), 4.37 (s, 1H, NH), 4.14 (dq, J = 10.8, 7.1 Hz, 1H, C12HAHB),
4.05 (dq, J = 10.8, 7.1 Hz, 1H, C12HAHB), 3.47 (dd, J = 10.6, 2.3 Hz,
1H, C2H), 3.19 (ddt, J = 14.2, 5.5, 1.7 Hz, 1H, C14HAHB), 2.66 (dd, J =
14.2, 9.2 Hz, 1H, C14HAHB), 2.01 (ddd, J = 14.4, 7.5, 2.3 Hz, 1H,
C9HAHB), 1.78 (ddd, J = 14.4, 10.6, 7.5 Hz, 1H, C9HAHB), 1.10 (t, J =
7.1 Hz, 3H, C13H3), 1.07 (t, J = 7.5 Hz, 3H, C10H3); 13C{1H} NMR
(101 MHz, CDCl3): δC = 191.0 (C), 170.2 (C), 150.4 (C), 134.8 (CH),
133.1 (CH), 128.4 (CH), 119.8 (C), 118.9 (CH2), 118.3 (CH), 115.5 (CH),
61.1 (CH2), 60.0 (C), 59.6 (CH), 34.5 (CH2), 21.6 (CH2), 13.9 (CH3), 11.2
Keywords: Alanes · Copper · Asymmetric catalysis ·
Michael addition · Phosphane ligands
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(CH3); IR (ATR): νmax = 3370, 3075, 2978, 2927, 1727 (C=O), 1661,
˜
1638, 1608, 1505, 1484, 1464, 1435, 1388, 1344, 1307, 1258, 1222,
1203, 1158, 1111, 1093, 1048, 1031, 994, 921, 860, 781, 754, 650,
621, 529, 491, 444; HRMS m/z calcd. for C17H22NO3 [M + H]:
288.1594, found 288.1599 (σ = 1.80 ppm); HPLC (before crystallisa-
tion) on Chiralpak AD-H; mobile phase: hexane:2-propanol (99:1 v/
v); flow rate: 0.5 mL min–1; retention times for purified sample: ma-
jor product anti (2S,3R)-33-24.7 min (73.1 %), 76 % ee; minor anti
enantiomer (2R,2S)-33-28.3 min (10.0 %), minor syn-allylation prod-
uct (2S,3S)-33-18.2 min (3.2 %), 66 % ee, enantiomer of syn product
(2R,3S)-175-20.6 min (13.6 %); anti/syn ratio = 5.0:1 by HPLC. After
recrystallisation the bulk sample showed anti (2S,3R)-33 with
> 91 % ee and > 90:1 vs. all other diastereomers from which the
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chromatography (c = 1.0 in CHCl3, for a ≈ 14:3:73:10 mixture of the
2S,3S/2R,3R/2S,3R/2R,3S isomers); recrystallised sample: +24.0 (c =
1.0 in CHCl3, > 91 % ee, > 90:1 dr).
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CCDC 1967992 (for 33) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre.
Acknowledgments
A. K. thanks Key Organics Ltd, the Engineering and Physical
Sciences Research Council (EPSRC CASE Award 1507028) and
the University of Nottingham for financial support. S. W. is very
grateful to Dr David Robinson (Nottingham Trent University, UK)
for discussions on stereochemistry and to Profs H.-G. Schmalz
(University of Cologne, Germany) and Alex Alexakis (University
of Geneva, Switzerland) for providing small initial samples of
some of the ligands used in this study.
Received: September 25, 2019
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Copper-Catalyzed 1,4-Addition
A. Kingsbury, S. Brough,
A. P. McCarthy, W. Lewis,
S. Woodward* ..................................... 1–8
Conjugate Addition Routes to 2-
Alkyl-2,3-dihydroquinolin-4(1H)-
ones and 2-Alkyl-4-hydroxy-1,2-di-
hydroquinoline-3-carboxylates
Directing ester functions (R = CO2Et) addition of EtMgBr. In the presence of
“give a big hand” to copper catalysed the CO2Et activating group, AlEt3 may
1,4-additions of organometallics to be added in up to 82 % ee providing
medicinally relevant quinolin-4(1H)- 6-halo building block starting materi-
ones. In the absence of any directing als for quinolone species.
group only 11 % ee is realised for the
DOI: 10.1002/ejic.201901036
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