CuI-Catalysed Enantioselective Alkyl 1,4-Additions to (E)-Nitroalkenes and Cyclic Enones with Phosphino-Oxazoline Ligands

Article abstract of DOI:10.1002/ejoc.201800476

Catalytic enantioselective conjugate additions of simple alkyl groups to nitroalkenes or cyclic enones that result in the formation of tertiary C–C bonds are described. For these stereoselective addition reactions, new chiral phosphino-oxazoline ligands w

Full text of DOI:10.1002/ejoc.201800476

DOI: 10.1002/ejoc.201800476
Full Paper
Asymmetric Catalysis
CuI-Catalysed Enantioselective Alkyl 1,4-Additions to
(E)-Nitroalkenes and Cyclic Enones with Phosphino-Oxazoline
Ligands
Minkyeong Shin,[a] Minji Gu,[b] Sung Soo Lim,[c] Min-Jae Kim,[a][‡] JuHyung Lee,[a][‡]
HyeongGyu Jin,[a][‡] Yun Hee Jang,[c] and Byunghyuck Jung*[a]
Abstract: Catalytic enantioselective conjugate additions of promoted by a Cu-based catalyst (2 mol-%), and gave the chiral
simple alkyl groups to nitroalkenes or cyclic enones that result products in up to 92 % yield with 95 % ee. A larger-scale synthe-
in the formation of tertiary C–C bonds are described. For these sis was demonstrated, and the origin of the stereoselectivity
stereoselective addition reactions, new chiral phosphino-oxaz- was proposed based on DFT calculations.
oline ligands were synthesized and used. The reactions were
Introduction
co-worker developed the peptide-based ligand 1, and found
that the Cu complex formed from ligand 1 and a Cu salt gave
efficient enantioselective conjugate additions to form nitro-
alkanes containing tertiary stereogenic centres. Surprisingly, a
reaction time of 1 h at ambient temperature was enough for
the successful conversion. The Hoveyda group also reported a
protocol for the construction of quaternary carbon stereogenic
centres through enantioselective conjugate additions to trisub-
stituted nitroalkenes with the same peptide ligand 1.[9]
Charette's group used Me-DuPHOS monoxide 2 as a source of
chirality, and obtained the desired nitroalkenes in 70–91 % yield
with 95–98 % ee. A copper complex of diphenylmethane-based
phosphoramidite 3, developed by Mikami's group, catalysed
the enantioselective conjugate addition to aryl-substituted (E)-
Amine-containing chiral molecules, such as Thalidomide®, show
various kinds of biological activities that allow their commer-
cialization as drugs to cure patients.[1] In contrast to the thera-
peutic (+)-enantiomer of Thalidomide®, which acts as a sedative
drug, the (–)-enantiomer, if administered to pregnant women,
results in birth defects in babies due to malformation of the
embryos. This case drew attention to the need for the synthesis
of chiral drugs with high enantiopurities.[1,2] The development
of catalytic enantioselective C–C-bond-forming reactions is very
important for the synthesis of nitrogen-containing optically ac-
tive natural products and pharmaceuticals.[1,3,4] In particular,
enantioselective conjugate additions to (E)-nitroalkenes under
organocatalytic or transition-metal-catalysed conditions have
played important roles in the preparation of amine-containing
chiral compounds.[5,6]
Cu-catalysed enantioselective conjugate additions to nitro-
alkenes using organozinc reagents as the source of alkyl nucleo-
philes have been well investigated since first reports ap-
peared.[7,8] Among the protocols that have been reported for
the construction of tertiary carbon stereogenic centres, the rep-
resentative examples shown in Scheme 1 give high stereo-
selectivities and have broad substrate scopes. Hoveyda and a
[a] School of Basic Science, Daegu Gyeongbuk Institute of Science and
Technology (DGIST),
Daegu 42988, Republic of Korea
E-mail: byunghyuck.jung@dgist.ac.kr
https://sites.google.com/site/byunghyuckjung/
[b] LG Chem,
Daejeon 34122, Republic of Korea
[c] Department of Energy, Science, & Engineering, Daegu Gyeongbuk Institute
of Science and Technology (DGIST),
Daegu 42988, Republic of Korea
[‡] Contributed equally.
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201800476.
Scheme 1. Examples of Cu-catalysed enantioselective conjugate additions to
nitroalkenes with (alkyl)2Zn reagents.
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nitroalkenes to give the ethyl-addition products with 91–99 % such as ethyl acetate or dichloromethane, the amides were
ee. Although these methods have broad substrate scopes and used directly in the following step, which involved tosyl-
give excellent stereoselectivities, the necessity of cryogenic con-
ditions for Charette's method (–70 °C) and Mikami's method
(–78 °C) is hardly avoidable, and Mikami's protocol is not appli-
cable to alkyl-substituted nitroalkenes. Moreover, despite the
above-mentioned notable advances in catalytic enantioselec-
tive conjugate additions to nitroalkenes, the number of exam-
ples of asymmetric addition reactions of simple alkyl groups to
nitroalkenes, especially those containing a small alkyl substitu-
ent at a prochiral centre, is still small. For this reason, it is still
necessary to develop methods for Cu-catalysed enantioselec-
tive conjugate additions to nitroalkenes with new chiral ligands.
ation and subsequent intramolecular cyclization under basic
conditions. N-Cbz-protected monoxazolines 6a–6d were ob-
tained in 80–88 % overall yield. Heterogeneous Pd-catalysed
hydrogenolysis of 6a–6d gave the corresponding free primary
amines. These were converted into the final P,N ligands 7a–7d
through CDMT-mediated peptide synthesis with diphenylphos-
phinobenzoic acid in 57–66 % yield.
To evaluate the performance of the synthesized P,N ligands
in Cu-catalysed enantioselective conjugate additions to (E)-
nitroalkenes with dialkylzinc reagents, substrate 8a was tested
with Et2Zn (Table 1). We found that Et2Zn was not sufficiently
nucleophilic for the conjugate addition; the desired 1,4-addition
product 9a was formed in <2 % yield (Table 1, entry 1). A com-
plex of Trost's ligand and a Cu salt was similarly inefficient in
this system. The addition of the Cu complex of (R,R)-Ph-bisox-
azoline (3 mol-%) resulted in the efficient formation of 9a in
84 % yield, but the optical purity of 9a was low (10 % ee;
Table 1, entry 3). In sharp contrast to the Trost ligand and Ph-
bisoxazoline, the newly developed P,N ligand 7a showed supe-
rior efficiency and enantioselectivity, and 9a was formed in
90 % yield with 75 % ee (Table 1, entry 4). A complex of 7e, a
diastereomer of 7a, with a Cu salt did not efficiently catalyse
the enantioselective conjugate addition reaction (37 % yield
and 6 % ee; Table 1, entry 5). A change from an iPr group (7a)
to a tBu (7b) group in the P,N ligand gave a slight increase in
the stereoselectivity for the formation of 9a (Table 1, entry 6),
but replacement of the phenyl group with a benzyl or methyl
group resulted in a decrease in the optical purity of 9a (Table 1,
entries 6–8). A reaction carried out with 7b at –50 °C was not
efficient or stereoselective (Table 1, entry 9), but when the reac-
Results and Discussion
Our initial study focussed on the design of new chiral ligands.
Our phosphino-oxazoline ligands were based on versatile
chiral ligands, particularly Trost's ligand and bisoxazolines
(Scheme 2).[10] The 2-diphenylphosphinobenzamide moiety was
derived from Trost's ligand (red circle in Scheme 2), and the
oxazoline part from bisoxazolines (blue circle in Scheme 2). An
amino acid (violet box in Scheme 2) was used to connect the
2-diphenylphosphinobenzamide and oxazoline moieties.[11] The
two stereogenic carbons in the chiral ligands originate from
naturally abundant L-amino acids; the ligands were prepared
from commercially available N-protected amino acids 4a
(valine) and 4b (tert-leucine) in four steps. The synthesis began
with an amide-forming reaction between N-Cbz-protected L-
amino acids 4a and 4b and amino alcohols 5a–5c, mediated
by 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT).[12] Because of
the poor solubility of the amide products in organic solvents
Scheme 2. Design and synthesis of phosphino-oxazoline ligands. DMAP = 4-dimethylaminopyridine; NMM = N-methylmorpholine.
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tion temperature was raised to 0 °C, the reaction was complete In contrast, BnOCH2-substituted nitroalkene 8j was converted
within 2 h, and 9a was formed in 91 % yield with 86 % ee (en- into 1,4-addition product 9j in 91 % yield, but the optical purity
try 10). When the same reaction was carried out at 22 °C, the decreased to 77 % ee. To investigate the behaviour of highly
reaction was complete within 10 min, and 9a was obtained activated nitroalkenes, phenyl-substituted (8k) and EtO2C-sub-
with a similar yield and ee (Table 1, entry 11). Increasing the stituted (8l) nitrostyrenes were examined. Disappointingly, the
loading of the 7b–Cu(OTf) catalyst resulted in a decrease in the Cu-catalysed enantioselective conjugate additions to 8k and 8l
optical purity of 9a to 76 % ee (Table 1, entry 12). However, were not stereoselective, and the corresponding products 9k
changing the counterion from triflate (OTf) to thiophen-2-carb- and 9l were generated in 50–87 % yield with 3–26 % ee. We
oxylate (Tc) enhanced the performance of the catalyst, and 9a suspect that a planar substituent such as Ph- or EtO2C- cannot
was obtained in 92 % yield with 90 % ee (Table 1, entry 13). We generate enough steric hindrance in the transition state to give
observed that the background reaction with CuTc (2 mol-%) a significant difference between the ΔG‡ values of the (R)-form-
gave a significant amount of 9a (14 % yield) within 2 h.
ing pathway and (S)-forming pathway.
Table 2. Substrate scope.[a]
Table 1. Optimization of the Cu-catalysed enantioselective conjugate addition
to 8a with Et2Zn.[a]
[a] All reactions were carried out on a 0.2 mmol scale of 8a in toluene (0.1 M)
under a nitrogen atmosphere. [b] Yield of purified product. [c] Determined
by GLC analysis. [d] N.A. = not applicable. [e] 5 mol-% of Cu and 6 mol-% of
the ligand were used. [f] CuTc was used instead of Cu(OTf).
Using the optimized reaction conditions using the Cu–7b
complex (2 mol-%; formed from CuTc) with Et2Zn (2 equiv.) at
0 °C for 2 h, we examined a range of (E)-nitroalkenes (Table 2).
Nitroalkenes with a small alkyl substituent such as Me, nPr, or
nBu were converted into the respective 1,4-addition products
9b, 9c, and 9e in 69–82 % yield with 90 % ee. The more steri-
[a] All reactions were carried out on a 0.2 mmol scale of 8b–8l in toluene
(0.1 M) under a nitrogen atmosphere. [b] Yield of purified product. [c] Deter-
mined by GLC analysis. [d] The reaction was carried out at –45 °C for 16 h.
Next, we explored the range of dialkylzinc reagents that
cally hindered substituents iPr, iBu, and cyclohexyl (Cy) did not could be used in the Cu-catalysed enantioselective conjugate
adversely affect the stereoselectivity of the Cu-catalysed reac- additions to nitroalkene 8a. As shown in Table 3, the use of Me,
tion, and the ethyl-addition products 9d, 9f, and 9h were gen- iPr, and nBu as alternative alkyl groups resulted in significant
erated in 72–88 % yield with 86–90 % ee. However, the high decreases in the stereoselectivity of the reaction.[13] For com-
steric hindrance of the tBu group resulted in a drop in the opti- parison, ethyl-addition product 9a was obtained in 92 % yield
cal purity of the corresponding product 9g to 59 % ee, although with 90 % ee (Table 1, entry 13), whereas methyl-addition
the reactivity of 8g was similar to those of 8b–8f and 8h. To product 9m was generated in 74 % yield with 65 % ee. The Cu-
evaluate the functional-group compatibilities of the Cu-cata- catalysed reaction of 8a with (nBu)2Zn resulted in the formation
lysed reaction, acetal-containing (8i) and ether-containing (8j) of 9o in 85 % yield with 76 % ee. However, the sterically hin-
nitroalkenes were used under the optimized conditions. The Cu dered (iPr)2Zn reagent showed relatively poor stereoselectivity
catalyst did not interfere with the acetal moiety in 8i, and the in the addition reaction with 8a, and compound 9n was ob-
desired nitroalkane 9i was obtained in 73 % yield with 90 % ee. tained with 32 % ee.[14]
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Table 3. Scope of the reaction in terms of dialkyl zinc reagents.[a]
optimized reaction conditions using the Cu complex of 7a and
CuTc (2 mol-%) with dialkylzinc (3 equiv.) at –35 °C for 4 h.
Table 4. Optimization of the Cu-catalysed enantioselective conjugate addition
to 11a with Et2Zn.[a]
[a] All reactions were carried out on a 0.2 mmol scale of 8a in toluene (0.1 M)
under a nitrogen atmosphere. [b] Yield of purified product. [c] Determined
by GLC analysis.
To examine the synthetic utility of the method, a reaction
with (E)-nitroalkene 8e was carried out on a 5 mmol scale
(Scheme 3). A catalyst loading of the 7b–CuTc complex of
1 mol-% resulted in the complete conversion of 8e within a
reaction time of 24 h, and nitroalkane 9e was obtained in 78 %
yield with 91 % ee. Reduction of the nitro group in 9e through
Pd/C-catalysed hydrogenation resulted in quantitative conver-
sion into the amine. Because of the volatility of the amine, a
CDMT-mediated amide-coupling reaction with N-(4-bromo-
benzoyl)proline was then carried out to generate amide 10 in
64 % yield.
[a] All reactions were carried out on a 0.2 mmol scale of 11a in toluene (0.1 M)
under a nitrogen atmosphere. [b] Yield of purified product. [c] Determined
by GLC analysis. [d] The reaction was carried out in Et2O. [e] CuTc was used
instead of Cu(OTf). [f] 3 mol-% of 7a and 2 mol-% of CuTc were used.
As shown in Table 5, the Cu-catalysed 1,4-addition of an
ethyl group to 2-cycloheptenone (11c) proceeded less effi-
ciently than for 2-cyclohexeneone (11a); compound 12b was
obtained in 51 % yield, but with a high optical purity of 94 %
ee. Cu-catalysed enantioselective conjugate additions to 11a
and 11b with (iPr)2Zn proceeded smoothly, and the corre-
sponding products 12c and 12d were obtained in 71–84 %
yield with 83–94 % ee. Thus, there is a remarkable contrast be-
tween the Cu-catalysed enantioselective conjugate additions to
(E)-nitroalkenes and those to cyclic enones. The addition of an
iPr group to nitroalkene 8a gave the desired product with 32 %
ee, but the addition of an iPr group to cyclic enone 11a gave
12d with 94 % ee. The stereoselective addition of (nBu)2Zn to
cyclic enone 11b proceeded successfully to generate 12e in
67 % yield with 87 % ee.
The stereoselectivity observed in the formation of 12a can
be rationalized by the stereochemical model shown in
Scheme 3. A larger-scale synthesis of 10.
The synthetic utility of the complexes of the P,N ligands with
Cu salts was examined further by testing Cu-catalysed enantio-
selective conjugate additions to cyclic enone 11a with Et2Zn
(Table 4).[1,15] Ligand 7b was found to be optimal in terms of
reactivity for Cu-catalysed enantioselective conjugate additions
to (E)-nitroalkenes, but was gave worse results than 7a in terms
of stereoselectivity for the formation of 12a (Table 4, entries 1
and 2). In contrast to the enantioselective conjugate additions
to nitroalkenes, the replacement of the phenyl group with Bn,
Me, or iPr did not influence the stereoselectivity in the forma-
tion of 12a (Table 4, entries 2–5). The use of weakly coordinat-
ing Et2O as a solvent resulted in a lower optical purity and lower
yield of 12a (32 % yield and 65 % ee; Table 4, entry 6). When
CuTc was used instead of CuOTf, and the loading of 7a–CuTc
was decreased, the stereoselectivity of the formation of 12a
increased (77 % yield and 95 % ee). Some enantioselective
conjugate additions to cyclic enones were explored under the
Table 5. Substrate scope.[a]
[a] All reactions were carried out on a 0.2 mmol scale of 11a–11c in toluene
(0.1
M) under a nitrogen atmosphere. [b] Yield of purified product. [c] Deter-
mined by GLC analysis.
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Scheme 4. This model is supported by density functional theory sis can explain why valine-based ligand 7a is better than tert-
(DFT; M06/LACVP**) calculations carried out in toluene at 253 K leucine-based ligand 7b for enantioselective conjugate addi-
using Jaguar v8.8.[16] The calculations showed that monoden- tions to cyclic enones. The alkyl substituent — iPr or tBu — in
tate Cu species II was more prone than bidentate Cu species I the bridging moiety is relatively close to 11a during the reac-
to interact with the π* orbital of 11a. A similar trend of bident- tion, and steric repulsion would be expected between the tBu
ate vs. monodentate ligand–metal complexes for allylic substi- group and 11a in transition state III.
tutions with NHC–Cu (NHC = N-heterocyclic carbene) com-
plexes was also reported by Hoveyda and co-workers.[17] They
proposed that it was the monodentate NHC–Cu complex, rather
than the bidentate form, that was involved in the addition step
of a Cu catalyst to an allylic phosphate, as supported by compu-
tational studies. Transition states III and IV of the enantioselec-
tive conjugate addition of Cu complex II are shown in
Scheme 4. Computations suggest that the energy level of tran-
Conclusions
We have demonstrated Cu-catalysed enantioselective conjugate ad-
ditions to nitroalkenes and cyclic enones with simple alkylzinc rea-
gents. To facilitate these reactions, new phosphino-oxazoline li-
gands 7a–7h were synthesized. We found that the 7a–CuTc com-
plex was optimal for enantioselective conjugate additions to cyclic
enones, and that the 7b–CuTc complex was optimal for enantio-
selective conjugate additions to nitroalkenes. Even a 1 mol-% cata-
lyst loading of 7b–CuTc facilitated the desired reactions in good
yield with high stereoselectivity. Further investigations will focus on
computational studies to determine the origin of the high stereo-
selectivity in the formation of the chiral nitroalkanes. In addition,
the expansion of the substrate scope, especially to aryl-substituted
(E)-nitroalkenes, will be investigated further.
sition state III is lower than that of transition state IV as a result
of steric repulsion between the iPr group and 11a (ΔΔG‡
=
253
1.53 kcal/mol); this is consistent with the experimental results.
This stereochemical model also clarifies why the substituents
on the chiral centre in the oxazoline moiety of P,N ligands, such
as Me, iPr, Ph, or Bn, are not crucial for the stereoselectivity in
the formation of 12a (Table 4, entries 2–5). As shown in
Scheme 4, the substituent in question is well removed from the
Cu centre, so it is unlikely to influence the enantioselectivity.
The role of the substituent is presumably to block the bottom-
face approach of 11a to Cu complex II. Moreover, this hypothe-
Experimental Section
General Remarks: Melting points of solid compounds were meas-
ured with a Metler Toledo MP50 instrument. H NMR spectra were
1
recorded with a Bruker Avance III 400 (400 MHz) spectrometer.
Chemical shifts are reported in ppm from tetramethylsilane, with
the solvent resonance as an internal standard (CDCl3: δ = 7.26 ppm).
Data are reported as follows: chemical shift, multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, br. s = broad singlet, m =
multiplet), coupling constant [Hz], and integration. 13C NMR spectra
were recorded with a Bruker Avance III 400 (100 MHz) spectrometer
with complete broadband decoupling. Chemical shifts are reported
in ppm from tetramethylsilane, with the solvent resonance as an
internal standard (CDCl3: δ = 77.16 ppm). High-resolution mass
spectrometry was carried out with a Bruker Daltonics 7 T SolariX
XR instrument in positive mode at the department of Chemistry,
Kyungpook National University. Unless otherwise stated, all reac-
tions were carried out under an atmosphere of dry N2 in oven-dried
(100 °C) glassware using vacuum-line techniques. Distilled solvents,
including CH2Cl2, Et2O, tetrahydrofuran, benzene, toluene, and di-
methylformamide, were purchased from Sigma–Aldrich sealed with
Sure/SealTM, and used directly. All work-up and purification proce-
dures were carried out with reagent-grade solvents (purchased from
Daejung Chemicals & Metals Co., Ltd) in air. Enantiomeric ratios
were determined by GLC analysis [Alltech Associated lipodex E
column (30 m × 0.25 mm), γ-dex column (30 m × 0.25 mm)], or
HPLC analysis [Chiral Technologies Chiralpak® OJ-H column
(250 × 4.6 mm)] in comparison with authentic racemic materials.
Specific rotations were measured with a Kruss P3000 automatic po-
larimeter.
Representative Procedure for the Synthesis of P,N Ligands: An
oven-dried round-bottomed flask (250 mL) equipped with a mag-
netic stirrer bar was sealed with a septum and evacuated using a
Schlenk line. The reaction vessel was filled with inert N2 gas using
an N2 balloon. Cbz-protected valine (2.51 g, 10 mmol), 2-chloro-4,6-
dimethoxy-1,3,5-triazine (CDMT; 1.93 g, 11 mmol), and THF (50 mL)
were added to the flask. N-Methylmorpholine (NMM; 3.3 mL,
30 mmol) was added by syringe, and the mixture was stirred at
Scheme 4. Stereochemical model.
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22 °C for 2 h. (S)-Phenylglycinol (1.38 g, 10 mmol) was added, and N-{(S)-2,2-Dimethyl-1-[(S)-4-phenyl-4,5-dihydrooxazol-2-
the resulting solution was stirred at 22 °C for 10 h. The reaction was
quenched with a saturated aqueous solution of ammonium chlor-
ide (30 mL). The solution was diluted with ethyl acetate (EtOAc),
and the organic layer was transferred into a beaker (200 mL) by
using a separatory funnel. The aqueous layer was washed with
EtOAc (3 × 20 mL). The combined organic layers were dried with
anhydrous MgSO4, and concentrated in vacuo. The crude product
was used directly in the next step without further purification.
yl]propyl}-2-(diphenylphosphanyl)benzamide (7b): White solid
(64 %). M.p. 98 °C. H NMR (400 MHz, CDCl3): δ = 7.61 (qd, J = 3.6.
1
1.2 Hz, 1 H), 7.37–7.26 (m, 17 H), 7.00 (qd, J = 3.6. 1.2 Hz, 1 H), 6.74
(d, J = 9.6 Hz, 1 H), 5.21 (dd, J = 10.2, 8.2 Hz, 1 H), 4.84 (d, J = 9.6 Hz,
1 H), 4.63 (dd, J = 10.0, 8.4 Hz, 1 H), 4.16 (t, J = 8.2 Hz, 1 H), 1.03 (s,
9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 167.7, 142.0, 134.6, 133.9,
133.7, 130.3, 128.8, 128.6, 128.6, 128.5, 128.5, 128.5, 128.4, 127.7,
127.5, 126.7, 75.0, 69.4, 55.9, 35.2, 26.7 ppm. [α]2D3 = –12.3 (c = 0.16,
CHCl3). HRMS (ESI+): calcd. for C33H33N2NaO2P [M + Na]+ 543.2177;
found 543.2171.
The crude product was dissolved in CH2Cl2 (100 mL) in a round-
bottomed flask (250 mL) equipped with a magnetic stirrer bar. 4-
(Dimethylamino)pyridine (DMAP; 122 mg, 1 mmol), p-toluenesulf-
onyl chloride (2.09 g, 11 mmol), and triethylamine (4.18 mL,
30 mmol) were added sequentially. The mixture was stirred at 22 °C
for 24 h, and then the reaction was quenched with a saturated
aqueous solution of ammonium chloride (30 mL). The organic layer
was transferred into a beaker (200 mL) by using a separatory funnel,
and the aqueous layer was washed with CH2Cl2 (3 × 20 mL). The
combined organic layers were dried with anhydrous MgSO4, and
concentrated in vacuo. The residue was purified by silica gel chro-
N-{(S)-1-[(S)-4-Benzyl-4,5-dihydrooxazol-2-yl]-2,2-dimethyl-
propyl}-2-(diphenylphosphanyl)benzamide (7c): White solid
1
(66 %). M.p. 90 °C. H NMR (400 MHz, CDCl3): δ = 7.67 (qd, J = 4.0,
1.2 Hz, 1 H), 7.42 (td, J = 7.6, 1.2 Hz, 1 H), 7.37–7.21 (m, 16 H), 7.01
(qd, J = 4.0, 0.8 Hz, 1 H), 6.70 (d, J = 9.6 Hz, 1 H), 4.70 (d, J = 9.6 Hz,
1 H), 4.42–4.35 (m, 1 H), 4.18 (t, J = 9.0 Hz, 1 H), 4.06–3.98 (m, 1 H),
3.07 (dd, J = 13.6, 5.6 Hz, 1 H), 2.65 (dd, J = 13.8, 8.6 Hz, 1 H), 0.96
(s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.3, 166.6, 141.5,
137.9, 137.4, 136.7, 134.6, 133.9, 133.9, 133.7, 133.7, 130.3, 129.2,
matography (CH2Cl2/acetone, 95:5; note the products are less solu- 128.8, 128.6, 128.6, 128.5, 128.4, 127.7, 127.6, 126.6, 71.9, 67.0, 55.9,
ble in an EtOAc/hexanes eluent system) to give Cbz-protected
mono-oxazoline 6a (3.10 g, 8.8 mmol, 88 %).
41.9, 35.2, 26.7 ppm. [α]D23 = –12.0 (c = 0.17, CHCl3). HRMS (ESI+):
calcd. for C34H35N2NaO2P [M + Na]+ 557.2334; found 557.2329.
N-Cbz-protected mono-oxazoline 6a (700 mg, 1.98 mmol), Pd/C
(10 %; 70 mg, 10 wt.-%), and anhydrous methanol (5 mL) were
added to an oven-dried round-bottomed flask (50 mL) equipped
with a magnetic stirrer bar. The flask was evacuated and then filled
with H2 gas using an H2 balloon. The solution was stirred at 22 °C
N-{(S)-2,2-Dimethyl-1-[(S)-4-methyl-4,5-dihydrooxazol-2-
yl]propyl}-2-(diphenylphosphanyl)benzamide (7d): White solid
(57 %). M.p. 109 °C. H NMR (400 MHz, CDCl3): δ = 7.64 (qd, J = 3.6.
1.2 Hz, 1 H), 7.41 (td, J = 7.6, 1.2 Hz, 1 H), 7.36–7.25 (m, 11 H), 7.00
(qd, J = 4.0, 0.8 Hz, 1 H), 6.67 (d, J = 9.6 Hz, 1 H), 4.70 (d, J = 9.6 Hz,
1
for 3 h, and then the balloon was removed. The hydrogenolysis 1 H), 4.31 (dd, J = 9.2, 8.0 Hz, 1 H, 1 H), 4.2–4.14 (m, 1 H), 3.84 (dd,
reaction was quenched by passing the mixture through a short
plug of Celite, which was then washed with methanol (3 × 2 mL).
The filtrate was concentrated in vacuo to give the amino-oxazoline,
which was used directly in the next step without further purifica-
tion.
J = 8.0, 6.8 Hz, 1 H), 1.26 (d, J = 6.4 Hz, 3 H), 0.96 (s, 9 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 168.4, 165.7, 141.5, 137.6, 137.5, 137.4,
134.5, 134.0, 133.9, 133.8, 133.7, 130.3, 128.7, 128.6, 128.5, 128.5,
128.4, 127.7, 127.6, 73.9, 61.2, 55.8, 35.3, 26.6, 21.6 ppm. [α]D23
=
–27.3 (c = 0.11, CHCl3). HRMS (ESI+): calcd. for C28H31N2NaO2P [M +
Na]+ 481.2021; found 481.2018.
2-Diphenylphosphinobenzoic acid (606 mg, 1.98 mmol), CDMT
(382 mg, 2.18 mmol), and THF (5 mL) were added to an oven-dried
round-bottomed flask (25 mL) equipped with a magnetic stirrer bar.
NMM (0.65 mL, 5.94 mmol) was added by syringe, and the mixture
was stirred at 22 °C for 1 h. A solution of the amino-oxazoline in
THF (3 mL) was added by cannula, and the resulting solution was
2-(Diphenylphosphanyl)-N-{(S)-2-methyl-1-[(R)-4-phenyl-4,5-di-
hydrooxazol-2-yl]propyl}benzamide (7e): White solid (62 %). M.p.
111 °C. 1H NMR (400 MHz, CDCl3): δ = 7.64–7.61 (m, 1 H), 7.37–7.21
(m, 16 H), 6.96 (qd, J = 4.0, 0.8 Hz, 1 H), 6.72 (d, J = 8.4 Hz, 1 H),
5.17 (t, J = 10.4 Hz, 1 H), 4.81 (ddd, J = 7.2, 4.8, 1.2 Hz, 1 H), 4.67
stirred at 22 °C for 12 h. The reaction was quenched with a satu- (dd, J = 10.4, 8.4 Hz, 1 H), 4.10–4.00 (m, 1 H), 2.21–2.14 (m, 1 H),
rated aqueous solution of ammonium chloride (8 mL). The solution
0.96 (d, J = 6.8 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.7,
was diluted with EtOAc, and the organic layer was transferred into 167.7, 141.9, 137.5, 134.5, 134.0, 133.9, 133.8, 130.3, 128.8, 128.7,
a beaker (50 mL) by using a separatory funnel. The aqueous layer
was washed with EtOAc (3 × 10 mL). The combined organic layers
were dried with anhydrous MgSO4, and concentrated in vacuo. The
residue was purified by silica gel chromatography (EtOAc/hexanes,
1:3) to give ligand 7a (590 mg, 1.16 mmol, 59 %) as a white solid.
128.5, 127.8, 126.8, 75.4, 69.5, 53.1, 31.8, 18.8 ppm. [α]2D3 = +4.25
(c = 0.23, CHCl3). HRMS (ESI+): calcd. for C32H31N2NaO2P [M + Na]+
529.2021; found 529.2016.
N-{(S)-1-[(S)-4-Benzyl-4,5-dihydrooxazol-2-yl]-2-methylpropyl}-
2-(diphenylphosphanyl)benzamide (7f): White solid (64 %). M.p.
1
1
The H and 13C NMR spectroscopic data of 6a–6c[12] and 6d–6e[18]
97 °C. H NMR (400 MHz, CDCl3): δ = 7.65 (ddd, J = 7.6, 3.6, 1.2 Hz,
were consistent with those reported in the literature.
1 H), 7.39 (td, J = 7.6, 1.2 Hz, 1 H), 7.32–7.26 (m, 13 H), 7.20 (t, J =
5.2 Hz, 2 H), 6.97 (ddd, J = 7.6, 3.6, 0.8 Hz, 1 H), 6.63 (d, J = 8.8 Hz,
1 H), 4.71 (dd, J = 8.8, 4.4 Hz, 1 H), 4.39–4.31 (m, 1 H), 4.20 (t, J =
8.8 Hz, 1 H), 4.01–3.99 (m, 1 H), 3.00 (dd, J = 13.8, 5.6 Hz, 1 H), 2.66
(dd, J = 13.8, 8.0 Hz, 1 H), 2.10–2.02 (m, 1 H), 0.85 (t, J = 6.8 Hz, 6
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.5, 166.7, 141.4, 141.2,
137.8, 137.6, 137.4, 136.4, 134.5, 133.9, 133.8, 130.3, 129.3, 128.7,
128.6, 128.5, 128.4, 127.7, 126.6, 72.6, 67.1 53.0, 41.8, 31.5, 18.6,
17.9 ppm. [α]2D3 = –20.5 (c = 0.39, CHCl3). HRMS (ESI+): calcd. for
C33H33N2NaO2P [M + Na]+ 543.2177; found 543.2172.
2-(Diphenylphosphanyl)-N-{(S)-2-methyl-1-[(S)-4-phenyl-4,5-di-
hydrooxazol-2-yl]propyl}benzamide (7a): White solid (59 %). M.p.
105 °C. 1H NMR (400 MHz, CDCl3): δ = 7.63–7.60 (m, 2 H), 7.35–7.24
(m, 16 H), 6.96 (qd, J = 4.0, 0.8 Hz, 1 H), 6.72 (d, J = 8.8 Hz, 1 H),
5.17 (dd, J = 10.0, 8.4 Hz, 1 H), 4.86 (dd, J = 8.8, 4.8 Hz, 1 H), 4.64
(dd, J = 10.0, 8.4 Hz, 1 H), 4.16–4.09 (m, 1 H), 2.19–2.1 (m, 1 H), 0.94
(dd, J = 6.8, 2.0 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.7,
167.7, 141.9, 137.4, 136.3, 134.5, 133.9, 133.7, 130.2, 128.8,
128.6, 128.5, 128.4, 127.7, 126.7, 75.4, 69.2, 53.0, 31.6, 18.7,
18.0 ppm. [α]2D3 = +6.54 (c = 0.31, CHCl3). HRMS (ESI+): calcd. for 2-(Diphenylphosphanyl)-N-{(S)-2-methyl-1-[(S)-4-methyl-4,5-di-
C32H31N2NaO2P [M + Na]+ 529.2021; found 529.2015.
hydrooxazol-2-yl]propyl}benzamide (7g): White solid (58 %). M.p.
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1
132 °C. 1H NMR (400 MHz, CDCl3): δ = 7.66 (qd, J = 8.0. 1.2 Hz, 1
H), 7.41 (td, J = 7.6, 1.2 Hz, 1 H), 7.35–7.27 (m, 11 H), 6.99 (qd, J =
4.0, 1.2 Hz, 1 H), 6.67 (d, J = 8.4 Hz, 1 H), 4.73 (dd, J = 8.6, 4.6 Hz, 1
H), 4.35 (dd, J = 9.2, 8.0 Hz, 1 H), 4.20–4.14 (m, 1 H), 3.84 (dd, J =
8.0, 7.6 Hz, 1 H), 2.10 (quintet of doublets, J = 6.8, 4.8 Hz, 1 H), 1.26
(d, J = 6.8 Hz, 3 H), 0.89 (dd, J = 7.2, 4.8 Hz, 6 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 168.4, 165.9, 137.5, 137.4, 134.4, 133.9, 133.8,
130.3, 128.7, 128.7, 128.6, 128.5, 128.4, 127.7, 127.7, 74.4, 61.1, 52.9,
31.6, 21.5, 18.6, 18.1 ppm. [α]2D3 = –18.5 (c = 0.11, CHCl3). HRMS
(ESI+): calcd. for C27H29N2NaO2P [M + Na]+ 467.1864; found
467.1858.
tminor = 31.191 min, tmajor = 32.346 min]. H NMR (400 MHz, CDCl3):
δ = 4.31 (d, J = 6.8 Hz, 2 H), 2.19–2.13 (m, 1 H), 1.44–1.29 (m, 6 H),
0.95–0.92 (m, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 79.5, 38.8,
33.2, 24.1, 19.6, 14.2, 10.6 ppm. [α]2D3 = +3.83 (c = 0.27, CHCl3). HRMS
(ESI+): calcd. for C7H15NNaO2 [M + Na]+ 168.1000; found 168.0995.
2-Methyl-3-(nitromethyl)pentane (9d): Colourless oil (72 % yield);
86 % ee determined by GC [Lipodex E column (30 m × 0.25 mm),
70 °C, FID; tminor = 59.186 min, tmajor = 61.336 min]. 1H and 13C
NMR spectroscopic data were consistent with those reported in the
literature.[20] [α]D23 = +3.11 (c = 0.24, CHCl3).
3-(Nitromethyl)heptane (9e): Colourless oil (82 % yield); 90 % ee
2-(Diphenylphosphanyl)-N-{(S)-1-[(S)-4-isopropyl-4,5-di-
hydrooxazol-2-yl]-2-methylpropyl}benzamide (7h): White solid
determined by GC [Lipodex E column (30 m × 0.25 mm), 70 °C, FID;
1
tminor = 94.872 min, tmajor = 96.787 min]. H NMR (400 MHz, CDCl3):
1
(61 %). M.p. 88 °C. H NMR (400 MHz, CDCl3): δ = 7.64 (qd, J = 8.0.
δ = 4.30 (d, J = 6.8 Hz, 2 H), 2.17–2.11 (m, 1 H), 1.44–1.37 (m, 2 H),
1.2 Hz, 1 H), 7.38 (td, J = 7.6, 1.2 Hz, 1 H), 7.33–7.25 (m, 10 H), 6.98
(qd, J = 4.0, 1.2 Hz, 1 H), 6.66 (d, J = 8.4 Hz, 1 H), 4.72 (dd, J = 8.8,
4.8 Hz, 1 H), 4.25 (dt, J = 8.8, 1.2 Hz, 1 H), 4.00 (t, J = 8.0 Hz, 1 H),
3.89–3.84 (m, 1 H), 2.11–2.04 (m, 1 H), 1.72 (septet, J = 6.8 Hz, 3 H),
0.96 (d, J = 6.8 Hz, 3 H), 0.89 (d, J = 6.8 Hz, 6 H), 0.87 (d, J = 6.8 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.5, 166.0, 141.6, 141.3,
137.6, 137.5, 137.4, 136.7, 136.4, 134.4, 134.0, 133.9, 133.7, 130.2,
128.7, 128.6, 128.5, 128.4, 127.6, 127.5, 71.6, 70.7, 53.0, 32.7, 31.5,
18.8, 18.6, 18.3, 18.0 ppm. [α]2D3 = –22.7 (c = 0.66, CHCl3). HRMS
(ESI+): calcd. for C29H33N2NaO2P [M + Na]+ 495.2177; found
495.2171.
1.35–1.27 (m, 6 H), 0.94–0.88 (m, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 79.4, 38.3, 30.4, 28.4, 23.9, 22.7, 13.9, 10.4 ppm. [α]D23
=
+5.56 (c = 0.18, CHCl3). HRMS (ESI+): calcd. for C8H17NNaO2 [M +
Na]+ 182.1157; found 182.1151.
2-Methyl-4-(nitromethyl)hexane (9f): Colourless oil (87 % yield);
89 % ee determined by GC [Lipodex E column (30 m × 0.25 mm),
90 °C, FID; tminor = 18.627 min, tmajor = 21.315 min]. 1H NMR
(400 MHz, CDCl3): δ = 4.29 (dd, J = 6.6, 3.0 Hz, 2 H), 2.42–2.18 (m,
1 H), 1.67–1.60 (m, 1 H), 1.46–1.37 (m, 2 H), 1.30–1.22 (m, 1 H), 1.16–
1.11 (m, 1 H), 0.92–0.87 (m, 9 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 79.7, 40.5, 36.8, 25.2, 24.4, 22.8, 22.6, 10.4 ppm. [α]2D3 = +3.70
(c = 0.27, CHCl3). HRMS (ESI+): calcd. for C8H17NNaO2 [M + Na]+
182.1157; found 182.1152.
Representative Procedure for the Cu-Catalysed Enantioselective
Conjugate Addition to (E)-Nitroalkenes with R2Zn Reagents: An
oven-dried round-bottomed flask (10 mL) equipped with a mag-
netic stirrer bar was sealed with a septum, and evacuated using a
Schlenk line. The reaction vessel was filled with inert N2 gas using
an N2 balloon. Compound 7b (3.1 mg, 6 μmol), copper(I) thiophene-
2-carboxylate (CuTc; 0.77 mg, 4 μmol), and toluene (1.6 mL) were
then added. The mixture was stirred for 1 h at 22 °C, then it was
2,2-Dimethyl-3-(nitromethyl)pentane (9g): Colourless oil
(84 % yield); 59 % ee determined by GC [Lipodex E column
(30 m × 0.25 mm), 80 °C, FID; tmajor = 31.831 min, tminor
=
33.242 min]. 1H NMR (400 MHz, CDCl3): δ = 4.47 (dd, J = 12.8, 5.2 Hz,
1 H), 4.18 (dd, J = 12.8, 7.0 Hz, 1 H), 2.00–1.95 (m, 1 H), 1.67 (ddd,
J = 14.4, 7.6, 3.6 Hz, 1 H), 1.25–1.13 (m, 1 H), 0.96 (t, J = 7.2 Hz, 3
H), 0.92 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 77.8, 49.4,
33.7, 28.7, 27.6, 22.1, 13.3 ppm. HRMS (ESI+): calcd. for C8H17NNaO2
[M + Na]+ 182.1157; found 182.1151.
cooled to 0 °C in an ice bath, and Et2Zn (1.0
M in hexanes; 0.4 mL,
0.4 mmol) was added slowly by syringe. Compound 8a (35.4 mg,
0.2 mmol) was then added by microsyringe, and the solution was
stirred at 0 °C for 2 h. The reaction was quenched with a saturated
aqueous solution of ammonium chloride (4 mL). The solution was
diluted with Et2O, and the organic layer was separated by using a
pipette with a bulb. The aqueous layer was extracted with Et2O
(3 × 3 mL). The combined organic layers were dried with anhydrous
MgSO4, and concentrated in vacuo. The residue was purified by
silica gel chromatography (Et2O/hexanes, 1:30) to give [3-(nitro-
methyl)pentyl]benzene (9a; 38.1 mg, 0.18 mmol, 92 %) as a colour-
less oil.
(1-Nitrobutan-2yl)cyclohexane (9h): Colourless oil (88 % yield);
90 % ee determined by GC [Lipodex E column (30 m × 0.25 mm),
120 °C, FID; tminor = 23.265 min, tmajor = 23.998 min]. 1H and 13C
NMR spectroscopic data were consistent with those reported in the
literature.[7e] [α]D23 = +6.47 (c = 0.29, CHCl3).
(R)-1,1-Dimethoxy-2-(nitromethyl)butane (9i): Colourless oil
(73 % yield); 90 % ee determined by GC [Lipodex E column
(30 m × 0.25 mm), 100 °C, FID; tminor = 24.562 min, tmajor
=
[3-(Nitromethyl)pentyl]benzene (9a): Colourless oil (92 % yield);
90 % ee determined by HPLC [Daicel Chiralcel OJ-H column
27.148 min]. 1H and 13C NMR spectroscopic data were consistent
with those reported in the literature.[7e] [α]D23 = –4.72 (c = 0.26,
CHCl3); lit.[7e] value for the (S) enantiomer [α]2D3 = +4.44 (c = 0.54,
CHCl3).[7e]
(250 × 4.6 mm), n-hexane/iPrOH, 95:5, 1.0 mL min–1, 225 nm; tminor
=
1
8.768 min, tmajor = 9.156 min]. H NMR (400 MHz, CDCl3): δ = 7.33–
7.31 (m, 2 H), 7.24–7.20 (m, 3 H), 4.40 (dd, J = 6.6, 1.4 Hz, 2 H), 2.69
(td, J = 8.0, 2.0 Hz, 2 H), 2.27–2.20 (m, 1 H), 1.77–1.70 (m, 2 H), 1.59–
1.48 (m, 2 H), 0.99 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 141.4, 128.5, 128.3, 126.1, 79.0, 38.5, 32.7, 32.6, 23.9,
10.4 ppm. [α]2D3 = –6.17 (c = 0.33, CHCl3). HRMS (ESI+): calcd. for
C12H17NNaO2 [M + Na]+ 230.1157; found 230.1152.
{[2-(Nitromethyl)butoxy]methyl}benzene (9j): Colourless oil
(91 % yield); 77 % ee determined by GC [Lipodex E column
(30 m × 0.25 mm), 120 °C, FID; tmajor = 129.759 min, tminor
=
132.681 min]. 1H NMR (400 MHz, CDCl3): δ = 7.38–7.26 (m, 5 H),
4.58–4.46 (m, 3 H), 4.38 (dd, J = 12.2, 6.6 Hz, 1 H), 3.52 (dd, J = 9.6,
4.4 Hz, 1 H), 3.43 (dd, J = 9.6, 6.8 Hz, 1 H), 2.42 (ddd, J = 14.0, 6.4,
4.4 Hz, 1 H), 1.54–1.40 (m, 2 H), 0.95 (t, J = 7.6 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 138.1, 128.6, 127.9, 127.7, 77.4, 73.4,
69.6, 39.9, 22.0, 11.2 ppm. [α]2D3 = –12.3 (c = 0.24, CHCl3). HRMS
(ESI+): calcd. for C12H17NNaO3 [M + Na]+ 246.1106; found 246.1102.
2-Methyl-1-nitrobutane (9b): Colourless oil (69 % yield); 90 % ee
determined by GC [Lipodex E column (30 m × 0.25 mm), 65 °C, FID;
1
tmajor = 23.280 min, tminor = 27.935 min]. H and 13C NMR spectro-
scopic data were consistent with those reported in the literature.[19]
[α]2D3 = +6.06 (c = 0.18, CHCl3).
3-(Nitromethyl)hexane (9c): Colourless oil (79 % yield); 91 % ee
determined by GC [Lipodex E column (30 m × 0.25 mm), 80 °C, FID;
(1-Nitrobutan-2yl)benzene (9k): Colourless oil (87 % yield);
26 % ee determined by HPLC [Daicel Chiralcel OJ-H column
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(250 × 4.6 mm), n-hexane/iPrOH, 95:5, 1.0 mL min–1, 225 nm; tminor
=
balloon was removed. The hydrogenolysis reaction was quenched
10.014 min, tmajor = 10.861 min]. 1H and 13C NMR spectroscopic by passing the mixture through a short plug of Celite, which was
data were consistent with those reported in the literature.[7c]
then washed with methanol (3 × 5 mL). The filtrate was concen-
trated in vacuo to give the corresponding amine, which was used
directly in the next step without further purification.
Ethyl 2-(Nitromethyl)butanoate (9l): Colourless oil (50 % yield);
3 % ee determined by GC [Lipodex E column (30 m × 0.25 mm),
100 °C, FID; tmajor = 42.328 min, tminor = 43.328 min]. 1H NMR
(400 MHz, CDCl3): δ = 4.74 (dd, J = 14.4, 9.2 Hz, 1 H), 4.42 (dd, J =
14.4, 5.0 Hz, 1 H), 4.21 (q, J = 7.2 Hz, 2 H), 3.17–3.10 (m, 1 H), 1.77–
1.64 (m, 2 H), 1.28 (t, J = 7.0 Hz, 3 H), 0.98 (t, J = 7.6 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 172.2, 75.1, 61.5, 44.4, 22.7, 14.3,
11.1 ppm. HRMS (ESI+): calcd. for C7H13NNaO4 [M + Na]+ 198.0742;
found 198.0737.
N-(4-Bromobenzoyl)-L-proline (936 mg, 3.14 mmol), CDMT (551 mg,
3.14 mmol), and THF (10 mL) were added to an oven-dried round-
bottomed flask (50 mL) equipped with a magnetic stirrer bar. NMM
(1.03 mL, 9.42 mmol) was added by syringe, and the mixture was
stirred at 22 °C for 2 h. A solution of the amine in THF (8 mL) was
added by cannula, and the resulting solution was stirred at 22 °C
for 12 h. The reaction was quenched with a saturated aqueous solu-
tion of ammonium chloride (15 mL). The solution was diluted with
EtOAc, and the organic layer was transferred into a beaker (50 mL)
by using a separatory funnel. The aqueous layer was washed with
CH2Cl2 (3 × 20 mL). The combined organic layers were dried with
anhydrous MgSO4, and concentrated in vacuo. The residue was pu-
rified by silica gel chromatography (EtOAc/hexanes) to give amide
10 (823 mg, 2.01 mmol, 64 % over two steps) as a white solid.
(3-Methyl-4-nitrobutyl)benzene (9m): Colourless oil (74 % yield);
65 % ee determined by HPLC [Daicel Chiralcel OJ-H column
(250 × 4.6 mm), n-hexane/iPrOH, 95:5, 1.0 mL min–1, 225 nm; tminor
=
10.998 min, tmajor = 11.860 min]. 1H and 13C NMR spectroscopic
data were consistent with those reported in the literature.[21] [α]D23
+16.4 (c = 0.31, CHCl3).
=
[4-Methyl-3-(nitromethyl)pentyl]benzene (9n): Colourless oil
(88 % yield); 32 % ee determined by HPLC [Daicel Chiralcel OJ-H
(2S)-1-(4-Bromobenzoyl)-N-(2-ethylhexyl)pyrrolidine-2-carbox-
amide (10): White solid. M.p. 87 °C, H NMR (400 MHz, CDCl3): δ =
1
column (250 × 4.6 mm), n-hexane/iPrOH, 95:5, 1.0 mL min–1
,
7.56 (d, J = 8.4 Hz, 2 H), 7.37 (d, J = 8.4 Hz, 2 H), 6.97 (s, 1 H), 4.74
(dd, J = 8.0, 5.2 Hz, 1 H), 3.53–3.50 (m, 1 H), 3.46–3.40 (m, 1 H), 3.21
(t, J = 6.0 Hz, 2 H), 2.53–2.47 (m, 1 H), 2.11–1.98 (m, 2 H), 1.86–1.80
(m, 1 H), 1.46–1.43 (m, 1 H), 1.32–1.24 (m, 8 H), 0.89–0.85 (m, 6 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 170.9, 170.3, 135.2, 131.8,
128.9, 124.9, 60.1, 50.6, 42.5, 39.4, 31.2, 29.0, 27.1, 25.6, 24.5, 23.1,
14.2, 11.1 ppm. [α]2D3 = –123.8 (c = 0.72, CHCl3). HRMS (ESI+): calcd.
for C20H29BrN2NaO2 [M + Na]+ 431.1310; found 431.1305.
1
225 nm; tminor = 8.246 min, tmajor = 8.795 min]. H NMR (400 MHz,
CDCl3): δ = 7.25–7.23 (m, 2 H), 7.22–7.19 (m, 3 H), 4.45 (dd, J = 12.0,
6.8 Hz, 1 H), 4.35 (dd, J = 12.0, 7.2 Hz, 1 H), 2.67 (t, J = 8.2 Hz, 2 H),
2.25–2.22 (m, 1 H), 1.88–1.75 (m, 2 H), 1.66–1.57 (m, 1 H), 0.96 (dd,
J = 13.2, 8.2 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 141.4,
128.5, 128.3, 126.1, 77.7, 42.9, 33.3, 30.5, 28.5, 18.9, 18.7 ppm.
[α]2D3 = +2.07 (c = 0.29, CHCl3). HRMS (ESI+): calcd. for C13H19NNaO2
[M + Na]+ 244.1313; found 244.1307.
Representative Procedure for the Cu-Catalysed Enantioselective
Conjugate Addition to Cyclic Enones with R2Zn Reagents: An
oven-dried round-bottomed flask (10 mL) equipped with a mag-
netic stirrer bar was sealed with a septum and evacuated using a
Schlenk line. The reaction vessel was filled with inert N2 gas using
an N2 balloon. Ligand 6a (3.1 mg, 6 μmol), copper(I) thiophene-2-
carboxylate (CuTc; 0.77 mg, 4 μmol), and toluene (1.4 mL) were
added to the flask. The mixture was stirred for 1 h at 22 °C, then it
[3-(Nitromethyl)heptyl]benzene (9o): Colourless oil (85 % yield);
76 % ee determined by HPLC [Daicel Chiralcel OJ-H column
(250 × 4.6 mm), n-hexane/iPrOH, 95:5, 1.0 mL min–1, 225 nm; tminor
=
1
6.974 min, tmajor = 7.495 min]. H NMR (400 MHz, CDCl3): δ = 7.31–
7.26 (m, 2 H), 7.22–7.16 (m, 3 H), 4.36 (d, J = 6.8 Hz, 2 H), 2.65 (t,
J = 8.0 Hz, 2 H), 2.28–2.21 (m, 1 H), 1.73–1.68 (m, 2 H), 1.45–1.38
(m, 2 H), 1.33–1.29 (m, 4 H), 0.91 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 141.4, 128.5, 128.3, 126.1, 79.4, 37.1, 33.2,
32.6, 30.9, 28.3, 22.7, 13.9 ppm. [α]2D3 = +4.24 (c = 0.24, CHCl3). HRMS
(ESI+): calcd. for C14H21NNaO2 [M + Na]+ 258.1470; found 258.1464.
was cooled to –35 °C in a dry ice/acetone bath. Et2Zn (1.0
M in
hexanes; 0.6 mL, 0.6 mmol) was added slowly by syringe. 2-Cyclo-
hexen-1-one (11a; 19.3 μL, 0.2 mmol) was added by microsyringe,
and the solution was stirred at –35 °C for 4 h. The reaction was
quenched with a saturated aqueous solution of ammonium chlor-
ide (4 mL). The solution was diluted with Et2O, and the organic layer
was separated by using a pipette with a bulb. The aqueous layer
was extracted with Et2O (3 × 3 mL). The combined organic layers
were dried with anhydrous MgSO4, and concentrated in vacuo. The
residue was purified by silica gel chromatography (Et2O/petroleum
ether, 1:20) to give 3-ethylcyclohexanone (12a; 18.9 mg, 0.15 mmol,
77 %) as a colourless oil.
Larger-Scale Synthesis and Preparation of Amide 10: An oven-
dried round-bottomed flask (100 mL) equipped with a magnetic
stirrer bar was sealed with a septum, and evacuated using a Schlenk
line. The reaction vessel was filled with inert N2 gas using an N2
balloon. Ligand 6b (28.6 mg, 55 μmol), copper(I) thiophene-2-carb-
oxylate (CuTc; 9.53 mg, 50 μmol), and toluene (10 mL) were added
to the flask. The mixture was stirred for 2 h at 22 °C, then additional
toluene (30 mL) was added. The mixture was cooled to 0 °C in an
ice bath. Et2Zn (1.0
M in hexanes; 10 mL, 10 mmol) was added
3-Ethylcyclohexanone (12a): Colourless oil (77 % yield); 95 % ee
slowly by syringe. (E)-1-Nitrohex-1-ene (8e; 645.8 mg, 5 mmol) was
added by syringe, and the solution was left in a fridge for 24 h.
The reaction was quenched with a saturated aqueous solution of
ammonium chloride (30 mL). The solution was extracted with Et2O
(3 × 20 mL). The combined organic layers were dried with anhy-
drous MgSO4, and concentrated in vacuo. The residue was purified
by silica gel chromatography (Et2O/petroleum ether, 1:30) to give
3-(nitromethyl)heptane (9e; 620 mg, 3.90 mmol, 78 %).
determined by GC [Lipodex E column (30 m × 0.25 mm), 85 °C, FID;
1
tmajor = 13.738 min, tminor = 15.394 min]. H and 13C NMR spectro-
scopic data were consistent with those reported in the literature;[22]
[α]2D3 = +17.4 (c = 0.92, CHCl3); lit.[23] value for the (S) enantiomer
[α]2D3 = –15.6 (c = 1.00, CHCl3).
3-Ethylcycloheptanone (12b): Colourless oil (51 % yield); 94 % ee
determined by GC [Lipodex E column (30 m × 0.25 mm), 85 °C, FID;
1
tminor = 24.872 min, tmajor = 25.267 min]. H and 13C NMR spectro-
Compound 9e (500 mg, 3.14 mmol), Pd/C (10 %; 50 mg, 10wt.-%),
and anhydrous methanol (10 mL) were added to an oven-dried
round-bottomed flask (25 mL) equipped with a magnetic stirrer bar.
The flask was evacuated and filled with H2 gas by using an H2
balloon. The solution was stirred at 22 °C for 12 h, and then the
scopic data were consistent with those reported in the literature.[22]
[α]2D3 = +55.9 (c = 0.42, CHCl3).
3-(1-Methylethyl)cyclopentanone (12c): Colourless oil
(71 % yield); 83 % ee determined by GC [Lipodex E column
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(30 m × 0.25 mm), 70 °C, FID; tminor = 24.466 min, tmajor
=
24.911 min]. 1H and 13C NMR spectroscopic data were consistent
with those reported in the literature.[22] [α]D23 = +152 (c = 0.25,
CHCl3).
3-(1-Methylethyl)cyclohexanone (12d): Colourless oil (84 % yield);
94 % ee determined by GC [Lipodex E column (30 m × 0.25 mm),
85 °C, FID; tmajor = 21.116 min, tminor = 25.165 min]. 1H and 13C
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3-Butylcyclohexanone (12e): Colourless oil (67 % yield); 87 % ee
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1
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[α]2D3 = +26.4 (c = 0.32, CHCl3).
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Keywords: Asymmetric catalysis · Michael addition ·
Nucleophilic addition · N,P ligands · Ligand design · Zinc
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Received: March 24, 2018
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Full Paper
Asymmetric Catalysis
New phosphino-oxazoline ligands
have been developed, and the ligands
have been used for Cu-catalysed enan-
tioselective conjugate additions to (E)-
nitroalkenes.
M. Shin, M. Gu, S. S. Lim,
M.-J. Kim, J. Lee, H. Jin,
Y. H. Jang, B. Jung* ........................ 1–10
CuI-Catalysed Enantioselective Alkyl
1,4-Additions to (E)-Nitroalkenes
and Cyclic Enones with Phosphino-
Oxazoline Ligands
DOI: 10.1002/ejoc.201800476
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