Isoquinoline-based diimine ligands for Cu(II)-catalyzed enantioselective nitroaldol (Henry) reactions

Article abstract of DOI:10.1016/j.tetasy.2011.05.018

A series of isoquinoline-based chiral diimine ligands are conveniently prepared via Bischler-Napieralski cyclization. The C₂-symmetric diimine ligand 1a is effective in Cu(II)-catalyzed enantioselective Henry reactions between nitromethane and

Full text of DOI:10.1016/j.tetasy.2011.05.018

Tetrahedron: Asymmetry 22 (2011) 1097–1102
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Isoquinoline-based diimine ligands for Cu(II)-catalyzed enantioselective
nitroaldol (Henry) reactions
⇑
Michael J. Rodig, Hwimin Seo, Dimitri Hirsch-Weil, Khalil A. Abboud, Sukwon Hong
Department of Chemistry, University of Florida, PO Box 117200, Gainesville, FL 32611-7200, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of isoquinoline-based chiral diimine ligands are conveniently prepared via Bischler–Napieralski
cyclization. The C2-symmetric diimine ligand 1a is effective in Cu(II)-catalyzed enantioselective Henry
reactions between nitromethane and various aldehydes (11 examples), showing 50–89% yield and 75–
93% ee.
Received 27 April 2011
Accepted 26 May 2011
Available online 15 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Diimine Ligands
Ph
The nitroaldol (Henry) reaction constitutes an important C–C
bond formation that yields b-nitroalcohols from carbonyl com-
pounds and nitroalkanes. The b-nitroalcohols produced contain at
least one newly formed stereogenic center and are valuable interme-
diates in the construction of synthetically important building blocks.1
The value of these reaction products has prompted the development
of a number of successful asymmetric variants including organocat-
alysts2 and numerous Lewis acid based catalysts employing metals,
such as lanthanides,3 Cr(III),4 Co(II),5 Zn(II),6 Cu(I),7 and Cu(II).8–10
Of the Lewis acids described, copper in particular has gained consid-
erable attention, due in part to its availability, low toxicity and ease of
handling. The Cu metal center is often supported by nitrogen-based
chiral ligands bearing amine,7a–f,8 imine (or pyridine),7h,i,9 oxazo-
line,7j,10a–h oxazolidine,7k,10i or imidazoline10j–l moieties.
N
N
N
N
Ar
R
3
R
R
1
Ph
N
N
N
N
Ar
C
C
R
R
R
2 (BIQ)
4 (MIQ)
Figure 1. Isoquinoline-based chiral carbene ligands.
Recently, we developed synthetic routes to isoquinoline-based
chiral diaminocarbenes via Bischler–Napieralski cyclization and
several chiral diimines such as 111a and 311b were prepared as pre-
cursors to those carbenes (Fig. 1). The aforementioned literature
precedence of imine-containing ligands for the asymmetric Henry
reaction as well as our experience in this reaction,5a,7j led us to
question whether the isoquinoline-based imine ligands 1 and 3
could be effective in the enantioselective Henry reaction. Herein
we report the applications of isoquinoline-based chiral diimines
in Cu(II)-catalyzed asymmetric Henry reactions.
diimine 3a11b were prepared by the procedures previously re-
ported by our group. The isoquinoline-based diimine ligands were
evaluated in the copper catalyzed Henry reaction of nitromethane
and 4-nitrobenzaldehyde (Table 1). A C2-symmetric diimine with
an iBu group 1a gave higher enantioselectivity than a structurally
related C1-symmetric diimine 3a (entry 2 vs entry 1). When the
R group in the C2-symmetric diimines was varied, more sterically
demanding substituents resulted in lower enantioselectivities
and longer reaction time (iBu ꢀ CH2Cy > iPr ꢁ tBu, entries 2–5).
Thus, the best result was obtained when using the C2-symmetric
diimine with an iBu substituent 1a, affording nitroaldol product
10a in 89% yield and 77% ee after 24 h.
2. Results and discussion
Attempts were made to further optimize the reaction condi-
tions by changing the Lewis acid metal and the solvent (Table 2).
Replacing Cu(OAc)2 with another divalent metal acetate such as
Ni(OAc)2 or Zn(OAc)2 resulted in lower enantioselectivities (entry
1 vs entries 2–3). Protic solvents (EtOH or iPrOH) proved to be bet-
ter than aprotic solvents (THF or CH2Cl2), giving higher yields and
ees (entries 1 and 4 vs entries 5–6).
Scheme 1 summarizes a concise synthesis of various isoquino-
line-based diimines 1 and 3 from phenethylamine precursors
5a–d. The C2-symmetric diimines 1a–d11a as well as a C1-symmetric
⇑
Corresponding author. Fax: +1 352 846 0296.
E-mail address: sukwon@ufl.edu (S. Hong).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.05.018

1098
M. J. Rodig et al. / Tetrahedron: Asymmetry 22 (2011) 1097–1102
Table 2
Optimization of reaction conditionsa
O
O
Ph
Ph
b)
a)
NH HN
CH3NO2 (10 equiv)
OH
O
NH2
N
N
Lewis Acid (5 mol %)
R
R
NO2
Ligand 1a (5 mol %)
H
R
R
R
5a: R = iBu
6a (46%)
6b (92%)
6c (81%)
6d (80%)
1a (85%, Ref.11a)
Solvent, rt, 24 h
O2N
O2N
5b:
1b (91%)
R = CH2C6H11
1c (83%, Ref.11a)
1d (82%)
5c: R = iPr
9a
Lewis acid
10a
5d: R = tBu
Entry
Solvent
Yieldb (%)
eec (%)
5a
1
2
3
4
5
6
Cu(OAc)2ꢂH2O
Ni(OAc)2ꢂ4H2O
Zn(OAc)2ꢂ2H2O
Cu(OAc)2ꢂH2O
Cu(OAc)2ꢂH2O
Cu(OAc)2ꢂH2O
EtOH
EtOH
EtOH
iPrOH
THF
89
91
64
84
59
38
77
30
0
72
40
54
c) 75%
O
Ph
Ph
Ph
Ph
d)
e)
iPr
NH
O
98%
71%
N
N
CH2Cl2
N
O
a
All reactions were performed on a 0.5 mmol scale at a 0.4 M concentration.
iPr
Reactions were run at room temperature in a screw-capped vial.
b
3a (Ref. 11b)
7
8
Values are isolated yields after chromatographic purification.
c
Enantiomeric excess was determined by HPLC using Chiralpak IB column.
Scheme 1. Synthesis of isoquinoline-containing chiral imine ligands. Reagents and
conditions: (a) oxalyl chloride, Et3N, THF, 0 °C to rt, 12 h; (b) PCl5, Zn(OTf)2, toluene,
85 °C, 12 h; (c) 2-oxo-2-phenylacetic acid, EDC, HOBt, rt, 12 h; (d) Tf2O, DMAP,
toluene, 90 °C, 8 h; (e) 2,6-diisopropylaniline, TiCl4, Et3N, toluene, rt, 12 h.
Table 3
Substrate scopea
Table 1
Ligand surveya
CH3NO2 (10 equiv)
Cu(OAc)2⋅H2O (5 mol %)
O
OH
Ligand 1a (5 mol %)
CH3NO2 (10 equiv)
Cu(OAc)2⋅H2O (5 mol %)
Diimine ligand (5 mol %)
OH
O
NO2
N
N
R
H
NO2
R
EtOH, rt, 24 h
H
iBu
iBu
1a
9
10
O2N
EtOH, rt
O2N
Yieldb (%)
eec (%)
9a
10a
Entry
R
Product
1
Ph
Ph
10b
10b
10c
10d
10e
10f
10g
10h
10a
10i
55
80
57
87
52
51
59
78
89
78
68
50
91
90
77
90
93
91
90
88
77
81
87
75
Entry
Ligand
Time
(h)
Yieldb
(%)
eec
(%)
2d
3
2-MeO–C6H4
2-Cl–C6H4
2-F–C6H4
3-F–C6H4
4-F–C6H4
4-Cl–C6H4
4-NO2–C6H4
4-Ph–C6H4
1-Naphthyl
PhCH@CH
4
5
6
7
8
9
10
11
12
Ph
iPr
1
3a (R = iBu)
48
84
11
N
N
N
R
R
iPr
10j
10k
2
3
1a (R = iBu)
1b
(R = CH2Cy)
1c (R = iPr)
1d (R = tBu)
24
24
89
90
77
75
a
All reactions were performed on a 0.5 mmol scale at a 0.4 M concentration.
Reactions were run at room temperature in a screw-capped vial.
Values are isolated yields after chromatographic purification.
Enantiomeric excess was determined by HPLC using Chiralpak IB or Whelk-O1
columns.
4
5
48
48
90
48
65
5
N
b
c
R
a
d
All reactions were performed on a 0.5 mmol scale at a 0.4 M concentration.
Reactions were run at room temperature in a screw-capped vial for the indicated
time.
10 mol % of Cu(OAc)2ꢂH2O and 10.0 mol % of ligand 1a were used.
b
Values are isolated yields after chromatographic purification.
Enantiomeric excess was determined by HPLC using Chiralpak IB column.
c
gave uniformly good enantiomeric excesses (77–93% ee, entries
3–11). It is interesting to note that the substrate scope is not lim-
ited to benzaldehydes, as cinnamaldehyde was an effective sub-
strate, affording nitro-aldol product 10k in 75% ee (entry 12).
The X-ray structure of 1a–PdCl2 shed some light on the unique
structural features of the isoquinoline-based C2-symmetric
diimines. The iBu substituent takes the axial position on the
six-membered azacycle, that is, folded into a boat-like conforma-
tion. In addition, helical (or axial) chirality seems to exist due to
the severe steric repulsion between two phenyl rings. Compound
1a–PdCl2 shows P helicity (or axial chirality) as well as (S)-
stereogenic centers.
With the optimal ligand structure and reaction conditions
selected, we decided to explore the scope of the reaction. (Table 3)
In general, high enantiomeric excesses (75–93% ee) were observed
at room temperature with various substrates. While yields were
decreased in some cases, additional reaction time was not found
to improve those yields. It was observed however that increasing
the catalyst loading to 10 mol % for a sluggish substrate such as
benzaldehyde 9b, could improve the yield without a loss of selec-
tivity (entry 2). Ortho-, meta- and para-substituted benzaldehydes

M. J. Rodig et al. / Tetrahedron: Asymmetry 22 (2011) 1097–1102
1099
CH2Cl2 (20 mL), p-toluenesulfonyl chloride (2.260 g, 11.9 mmol)
was added portionwise at ꢃ30 °C. The cooled mixture was stirred
for 2 h at ꢃ30 °C and then for 1 h at room temperature. The stirred
mixture was cooled to ꢃ30 °C, and methanesulfonyl chloride
(0.84 mL, 11 mmol) was added. After stirring for 2 h at ꢃ30 °C,
the reaction mixture was stirred for 10 h at room temperature.
The reaction solution was diluted with CH2Cl2 (100 mL) and
washed with 1 M aqueous HCl solution (100 mL) and then with a
saturated NaHCO3 solution (50 mL). The organic solution was dried
over anhydrous MgSO4, and the solvent was removed under re-
duced pressure. The residue was purified by flash column chroma-
tography (silicagel, 5:1 hexane/EtOAc) to afford the aziridine
(2.298 g, 7.84 mmol, 76% yield). ½a D24
ꢄ
¼ ꢃ6:4 (c 0.22, CHCl3). 1H
NMR (300 MHz, CDCl3)
d 7.83 (d, J = 8.2 Hz, 2H), 7.34 (d,
J = 8.2 Hz, 2H), 2.82–2.69 (m, 1H), 2.65 (d, J = 2.8 Hz, 1H), 2.44 (s,
3H), 2.02 (d, J = 4.8, 1H), 1.73–1.47 (m, 5H), 1.43–0.94 (m, 6H),
0.93–0.69 (m, 2H); 13C NMR (75 MHz, CDCl3) d 144.6, 135.5,
129.9, 128.2, 39.4, 39.2, 36.3, 34.1, 33.6, 32.8, 26.5, 26.3, 26.2,
21.9. HRMS (ESI) calcd for C16H23NO2S (M+Na)+: 316.1342; found:
316.1356.
4.2.2. (S)-1-Cyclohexyl-3-phenylpropan-2-amine 5b
Figure 2. X-ray structure of 1a–PdCl2. Thermal ellipsoids are drawn at the 50%
probability level. Selected bond lengths (Å), angles (°), and torsion angles (°): Pd–
N1: 2.0095(18), N1–C1: 1.302 (3), N1–Pd–N1A: 79.32(7), N1–C1–C1A: 113.9(2),
Pd–N1–C1–C1A: 11.1(2), C2–C1–C1A–C2A:-25.1(3).
4.2.2.1. Synthesis of (S)-N-(1-cyclohexyl-3-phenylpropan-2-yl)-
4-methylbenzenesulfonamide. To a suspension of CuI (0.276 g,
1.45 mmol) in THF (5.0 mL), PhMgCl solution (2.0 M in THF,
4.8 mL, 9.6 mmol) was slowly added at ꢃ30 °C. After 30 min stirring
at ꢃ30 °C, (S)-2-(cyclohexylmethyl)-1-toluenesulfonylaziridine
(1.42 g, 4.84 mmol) was added. The reaction temperature was
slowly increased to room temperature for 3 h. The reaction was
cautiously quenched by a saturated aqueous NH4Cl solution
(20 mL). The organic layer was separated and the aqueous layer
was extracted with EtOAc (3 ꢅ 20 mL). The combined organic mix-
ture was dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The residue was filtered through a column
of silica gel with EtOAc as an eluent to afford the sulfonamide.
3. Conclusion
In conclusion, a series of chiral isoquinoline-based imine li-
gands have been conveniently prepared via Bischler–Napieralski
cyclization. The iBu-substituted, C2-symmetric diimine ligand 1a
is effective in Cu(II)-catalyzed enantioselective Henry reactions be-
tween nitromethane and various aldehydes (11 examples), show-
ing 50–89% yield and 75–93% ee. The application of these
diimine ligands in other asymmetric catalysis is currently ongoing.
4.2.2.2. Synthesis of (S)-1-cyclohexyl-3-phenylpropan-2-ami-
ne. To a suspension of Li (0.50 g, 72 mmol) in THF (30 mL) under
argon, naphthalene (50 mg, 0.39 mmol) was added at room tem-
perature. After 30 min, the solution turned dark blue. (S)-N-
(1-Cyclohexyl-3-phenylpropan-2-yl)-4-methylbenzenesulfonamide
was added at ꢃ78 °C, and the reaction temperature was slowly
warmed to room temperature. After 12 h, the solution was trans-
ferred through a canula to another flask to remove the remaining
Li. The solution was quenched by a saturated aqueous NH4Cl solution
(50 mL) and rinsed with water (100 mL). To the organic solution was
added 1 M HCl aqueous solution (15 mL), and the organic layer was
discarded. To the acidic aqueous solution was added 20% NaOH
aqueous solution (20 mL). The aqueous layer was extracted by
Et2O (3 ꢅ 20 mL) and was dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure to afford the phenethyl-
4. Experimental
4.1. General
All reactions were conducted in flame-dried glassware under an
inert atmosphere of dry argon unless otherwise specified. THF,
CH2Cl2, CH3CN and Et2O were passed through two packed columns
of neutral alumina under positive pressure of argon prior to use.
All otherchemicalsusedwerecommerciallyavailableand wereused
as received without further purification. NMR spectra were recorded
using an FT-NMR machine, operating at 300 MHz for 1H NMR and at
75.4 MHz for 13C NMR. All chemical shifts for 1H and 13C NMR spec-
troscopy were referenced to Me4Si (d 0.0 ppm) for 1H and 13C or
residual signals from (CDCl3) (d 7.24 ppm) for 1H and (d 77.23) for
13C. High resolution mass spectra were recorded on a DIP-CI-MS
spectrometer, an APCI-TOF spectrometer, an ESI-TOF spectrometer,
or a TOF-LC/MS spectrometer. Specific optical rotations were
obtained on a JASCO P-2000 Series Polarimeter (wavelength =
589 nm). Enantiomeric ratios were determined by chiral HPLC
analysis (Shimadzu) using Chiralpak IB and (S,S) Whelk-O1 column.
Known compounds have been identified by comparison of spectral
data (1H NMR, and 13C NMR) with those previously reported.
amine (0.600 g, 2.76 mmol, 57% yield). ½a D23
¼ þ9:7 (c 0.27, CHCl3);
ꢄ
1H NMR (300 MHz, CDCl3) d 7.39–7.02 (m, 5H), 3.10 (br. s, 1H), 2.78
(dd, J = 4.3, 13.3 Hz, 1H), 2.41 (dd, J = 8.8, 13.5 Hz, 1H), 1.89–0.71
(m, 13H); 13C NMR (75 MHz, CDCl3) d 140.0, 129.5, 128.6, 126.3,
49.9, 45.9, 45.5, 34.7, 34.4, 33.2, 26.9, 26.6, 26.5. HRMS (ESI) calcd
for C15H23N (M+H)+: 218.1903; found: 218.1906.
4.2.3. N,N0-Bis((S)-1-cyclohexyl-3-phenylpropan-2-yl)oxalamide
6b
To a cooled, magnetically stirred solution of (S)-1-cyclohexyl-3-
phenylpropan-2-amine 5b (90.2 mg, 0.415 mmol) and triethyl-
4.2. Preparation of ligands
amine (65
chloride (17.6
l
L, 0.46 mmol) in THF (5.0 mL) under argon, oxalyl
L, 0.202 mmol) was added dropwise at 0 °C. The
4.2.1. (S)-2-(Cyclohexylmethyl)-1-toluenesulfonylaziridine
l
To
a
solution of (S)-2-amino-3-cyclohexylpropan-1-ol12
reaction mixture was allowed to warm to room temperature and
(1.620 g, 10.3 mmol) and triethylamine (7.2 mL, 52 mmol) in
was then stirred for 12 h. The reaction mixture was cooled to

1100
M. J. Rodig et al. / Tetrahedron: Asymmetry 22 (2011) 1097–1102
0 °C before quenching with water (10 mL). The mixture was ex-
tracted with CHCl3 (3 ꢅ 15 mL). The combined organic extracts
were dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash column chromatography
(silica gel, 3:1 chloroform/hexane) to afford the oxalamide
4.2.9. Dichloro[(3S,30S)-3,30-diisobutyl-3,30,4,40-tetrahydro-1,10-
biisoquinoline]-palladium(II) 1a–PdCl2
To a solution of 1a (0.205 g, 0.550 mmol) in toluene (3 mL),
PdCl2(CH3CN)2 (0.130 g, 0.500 mmol) was added, and the solution
was stirred at room temperature for 12 h. The precipitated product
was filtered and washed with hexanes (20 mL). (0.271 g, 98.6%)
(90.1 mg, 0.184 mmol, 92% yield) ½a D23
¼ ꢃ21:9 (c 0.29, CHCl3);
ꢄ
1H NMR (300 MHz, CDCl3) d 7.33–7.10 (m, 12H), 4.32–4.11 (m,
2H), 2.78 (d, J = 6.4 Hz, 4H), 1.89–1.49 (m, 12H), 1.43–1.05 (m,
11H), 1.01–0.63 (m, 4H); 13C NMR (75 MHz, CDCl3) d 159.4,
137.7, 129.6, 128.6, 126.7, 48.7, 41.9, 41.6, 34.5, 34.0, 32.8, 26.7,
26.4, 26.3. HRMS (ESI) calcd for C32H44N2O2 (M+Na)+: 511.3295;
found: 511.3308.
½
a 2D3
ꢄ
¼ ꢃ702:5 (c 0.43, CHCl3); 1H NMR (300 MHz,CDCl3) d 7.55
(m, 2H), 7.34 (d, J = 7.4 Hz, 2H), 7.13 (m, 2H), 6.86 (d, J = 7.6 Hz,
2H), 5.04–4.86 (m, 2H), 3.26–3.06 (m, 2H), 3.04–2.84 (m, 2H),
2.11–1.87 (m, 2H), 1.67–1.40 (m, 2H), 1.00 (d, J = 6.8 Hz, 6H),
0.91–0.80 (m, 2H), 0.78 (d, J = 6.5 Hz, 6H); 13C NMR (75 MHz,
CDCl3) d 170.9, 135.7, 134.4, 129.4, 129.2, 126.8, 126.7, 56.4,
35.1, 29.3, 25.9, 24.2. Anal. Calcd for C26H32Cl2N2Pd: C, 56.79; H,
5.87; N, 5.09. Found: C, 57.00; H, 6.00; N, 5.01.
4.2.4. (3S,30S)-3,30-Bis(cyclohexylmethyl)-3,30,4,40-tetrahydro-
1,10-biisoquinoline 1b
To a solution of N,N-Bis((S)-1-cyclohexyl-3-phenylpropan-2-yl)
oxalamide 6b (0.450 g, 0.921 mmol) in toluene (45 mL) under
nitrogen was added Zn(OTf)2 (1.00 g, 2.76 mmol) and PCl5
(1.15 g, 5.52 mmol). The reaction mixture was heated at 85 °C for
12 h and then was cooled to room temperature before quenching
with a 30% aqueous NH4OH solution (20 mL). The mixture was ex-
tracted with EtOAc (3 ꢅ 30 mL). The combined organic extracts
were dried over MgSO4, filtered, and concentrated under reduced
pressure. Purification of the crude product by flash column chro-
matography (silica gel, 5:1 hexanes/EtOAc) afforded the biisoquin-
4.3. General procedure for the enantioselective Henry reaction
To a 3.0 mL screw cap vial, a magnetic stirrer bar and ligand
(0.025 mmol) were added followed by absolute EtOH (1.25 mL).
After the ligand was fully dissolved, Cu(OAc)2ꢂH2O (4.99 mg,
0.025 mmol) was then added and allowed to stir at room temper-
ature for 1 hour. Next, CH3NO2 was added (0.27 mL, 5.0 mmol)
followed by aldehyde (0.50 mmol) and allowed to stir for the
indicated time. The reaction mixture was purified by flash column
chromatography on silica gel and the enantiomeric ratios were
determined by chiral HPLC analysis (Shimadzu) using Chiralpak
IB and (S,S) Whelk-O1 columns
oline (0.380 g, 0.839 mmol, 91% yield)
½
a 2D3
ꢄ
¼ ꢃ12:9 (c 0.37,
CHCl3); 1H NMR (300 MHz, CDCl3) d 7.44–7.04 (m, 8H), 3.98–
3.75 (m, 2H), 2.93 (dd, J = 5.6, 15.8 Hz, 2H), 2.64 (dd, J = 11.1,
15.8 Hz, 2H), 1.98–1.48 (m, 16H), 1.38–1.06 (m, 6H), 1.06–0.75
(m, 4H); 13C NMR (75 MHz, CDCl3) d 164.0, 137.5, 131.1, 128.6,
128.0, 127.1, 126.9, 54.5, 43.5, 34.6, 34.1, 33.3, 31.6, 26.9, 26.6.
4.3.1. (S)-2-Nitro-1-(4-nitrophenyl)ethanol 10a
Enantiomeric excess was determined by HPLC with a Chiralpak
IB column (85:15 hexanes/isopropanol, 1.0 mL/min, 254 nm); min-
or tr = 12.87 min; major tr = 14.47 min; 77% ee. Configuration
assignment: absolute configuration of the major isomer was deter-
mined to be (S) by comparison of the retention time with literature
data.7j
HRMS (ESI) calcd for
453.3286.
C
32H40N2 (M+H)+: 453.3264; found:
4.2.5. (S)-2-(tert-Butyl)-1-touenesulfonylaziridine13
88%. 1H NMR (300 MHz, CDCl3) d 7.82 (d, J = 8.0 Hz, 2H), 7.32 (d,
J = 8.0 Hz, 2H), 2.46–2.60 (m, 2H), 2.43 (s, 3H), 2.16 (d, J = 4.25 Hz,
1H), 0.78 (s, 9H); 13C NMR (75 MHz, CDCl3) d 144.6, 135.4, 129.8,
128.4, 49.1, 30.5, 26.4, 21.9.
4.3.2. (S)-2-Nitro-1-phenylethanol 10b
Enantiomeric excess was determined by HPLC with a Chiralpak
IB column (85:15 hexanes/isopropanol, 0.8 mL/min, 215 nm);
minor tr = 8.94 min; major tr = 9.82 min; 91% ee. Configuration
assignment: absolute configuration of the major isomer was deter-
mined to be (S) by comparison of the retention time with litera-
ture data.7j
4.2.6. (R)-3,3-Dimethyl-1-phenylbutan-2-amine 5d
93%. ½a 2D2
ꢄ
¼ þ48:6 (c 0.88, CHCl3); 1H NMR (300 MHz, CDCl3) d
7.35–7.27 (m, 2H), 7.25–7.18 (m, 3H), 2.98 (dd, J = 2.3, 13.3 Hz,
1H), 2.69 (dd, J = 2.4, 10.9 Hz, 1H), 2.21 (dd, J = 11.0, 13.3 Hz, 1H),
1.00 (s, 9H); 13C NMR (75 MHz, CDCl3) d 141.3, 129.4, 128.7,
4.3.3. (S)-1-(4-Methoxyphenyl)-2-nitroethanol 10c
Enantiomeric excess was determined by HPLC with a Chiralpak
IB column (85:15 hexanes/isopropanol, 0.8 mL/min, 215 nm); min-
or tr = 8.64 min; major tr = 9.32 min; 77% ee. Configuration assign-
ment: absolute configuration of the major isomer was determined
to be (S) by comparison of the retention time with literature
data.5a,7j
126.3, 62.3, 39.0, 34.5, 26.6. HRMS (ESI) calcd for
C12H19N
(M+H)+: 178.1590; found: 178.1582.
4.2.7. N,N0-Bis((R)-3,3-dimethyl-1-phenylbutan-2-yl)oxalamide
6d
80%. ½a 2D2
ꢄ
¼ þ36:3 (c 0.54, CHCl3); 1H NMR (300 MHz, CDCl3) d
7.21–7.00 (m, 12H), 3.86 (td, J = 2.8, 11.0 Hz, 2H), 3.01 (dd,
J = 2.8, 14.2 Hz, 2H), 2.36 (dd, J = 11.3, 14.2 Hz, 2H), 0.97 (s, 18H);
13C NMR (75 MHz, CDCl3) d 159.5, 138.8, 129.0, 128.5, 126.4,
60.1, 36.6, 35.1, 26.7. HRMS (ESI) calcd for C26H36N2O2 (M+Na)+:
431.2669; found: 431.2671.
4.3.4. (S)-1-(2-Chlorophenyl)-2-nitroethanol 10d
Enantiomeric excess was determined by HPLC with a (S,S)
Whelk-O1 column (95:5 hexanes/isopropanol, 1.0 mL/min,
215 nm); minor tr = 8.53 min; major tr = 9.39 min; 90% ee. Configu-
ration assignment: absolute configuration of the major isomer was
determined to be (S) by comparison of the retention time with lit-
erature data.5a,7j
4.2.8. (3R,30R)-3,30-Di-tert-butyl-3,30,4,40-tetrahydro-1,10-
biisoquinoline 1d
82%. ½a 2D2
ꢄ
¼ þ204:8 (c 0.62, CHCl3); 1H NMR (300 MHz, CDCl3) d
7.49 (d, J = 7.9 Hz, 2H), 7.35–7.27 (m, 2H), 7.24–7.11 (m, 4H), 3.23
(dd, J = 5.0, 15.1 Hz, 2H), 2.86–2.56 (m, 4H), 1.09 (s, 18 H); 13C NMR
(75 MHz, CDCl3) d 163.2, 139.1, 130.5, 128.9, 127.7, 127.5, 126.5,
66.4, 34.3, 27.1, 26.9. HRMS (ESI) calcd for C26H32N2 (M+H)+:
373.2638; found: 373.2639.
4.3.5. (S)-1-(2-Fluorophenyl)-2-nitroethanol 10e
Enantiomeric excess was determined by HPLC with a (S,S)
Whelk-O1 column (95:5 hexanes/isopropanol, 0.8 mL/min,
215 nm); major tr = 10.6 min; minor tr = 11.5 min; 93% ee. Configu-
ration assignment: absolute configuration of the major isomer was

M. J. Rodig et al. / Tetrahedron: Asymmetry 22 (2011) 1097–1102
1101
Table 4
determined to be (S) by comparison of the retention time with lit-
erature data.5a,7j
Crystal data and structure refinement for 1a–PdCl2
Identification code
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
Unit cell dimensions
a (Å)
1a–PdCl2
C28H36Cl6N2Pd
719.69
173(2)
0.71073
4.3.6. (S)-1-(3-Fluorophenyl)-2-nitroethanol 10f
½
a 2D2
ꢄ
¼ þ26:8 (c 0.26, CH2Cl2). 1H NMR (300 MHz, CDCl3) d 7.29–
7.45 (m, 1H), 7.10–7.21 (m, 2H), 7.04 (td, J = 8.4, 2.5 Hz, 1H), 5.46 (dd,
J = 8.8, 3.4 Hz, 1H), 4.43–4.64 (m, 2H), 3.11 ppm (s, 1H); 13C NMR
(75 MHz, CDCl3) d 163.3 (d, JCF = 246.0 Hz), 140.8 (d, JCF = 6.8 Hz),
130.9 (d, JCF = 8.3 Hz), 121.7 (d, JCF = 3.0 Hz), 116.1 (d, JCF = 21.0 Hz),
113.3 (d, JCF = 22.5 Hz), 81.2, 70.5 (d, JCF = 1.5 Hz); HRMS (DART)
calcd for C8H26FN2O3 [M+NH4]+: 203.0826, found: 203.0809; Enan-
tiomeric excess was determined by HPLC with a Chiralpak IB column
(85:15 hexanes/isopropanol, 1.0 mL/min, 215 nm); minor
tr = 6.84 min; major tr = 7.42 min; 91% ee; Configuration assign-
ment: absolute configuration of major isomer was determined to
be (S) by analogy of the retention time with other products.
Tetragonal
P41212
12.8898(3)
12.8898(3)
19.4625(9)
90
90
90
3233.63(18)
4
1.478
1.090
1464
0.32 ꢅ 0.32 ꢅ 0.26
1.89–27.49
ꢃ16 ꢆ h ꢆ 14,
ꢃ8 ꢆ kꢆ16,
ꢃ25 ꢆ l ꢆ 20
18011
b (Å)
c (Å)
a
(°)
b (°)
c
(°)
Volume (Å3)
Z
Density (calculated) (Mg/m3)
Absorption coefficient (mmꢃ1
F(0 0 0)
)
4.3.7. (S)-1-(4-Fluorophenyl)-2-nitroethanol 10g
Enantiomeric excess was determined by HPLC with a Chiralpak
IB column (90:10 hexanes/isopropanol, 1.0 mL/min, 215 nm);
minor tr = 9.11 min; major tr = 9.97 min; 90% ee. Configuration
assignment: absolute configuration of the major isomer was deter-
mined to be (S) by comparison of the retention time with literature
data.5a,7j
Crystal size (mm3)
h range for data collection (°)
Index ranges
Reflections collected
Independent reflections
Completeness to h = 27.49° (%)
Absorption correction
Max. and min. transmission
Refinement method
3722 [R(int) = 0.0591]
100.0
Integration
0.7995 and 0.7030
4.3.8. (S)-1-(4-Chlorophenyl)-2-nitroethanol 10h
Full-matrix least-squares on F2
3722/0/168
Enantiomeric excess was determined by HPLC with a Chiralpak
IB column (85:15 hexanes/isopropanol, 1.0 mL/min, 254 nm);
minor tr = 7.38 min; major tr = 8.15 min; 88% ee. Configuration
assignment: absolute configuration of the major isomer was deter-
mined to be (S) by with literature data.8g,10g,14
Data/restraints/parameters
Goodness-of-fit on F2
1.078
Final R indices [I > 2
r
(I)]
R1 = 0.0248, wR2 = 0.0640 [3615]
R1 = 0.0259, wR2 = 0.0646
ꢃ0.03(3)
R indices (all data)
Absolute structure parameter
Largest diff. peak and hole (e Åꢃ3
)
0.447 and ꢃ0.533
4.3.9. (S)-1-(Biphenyl-4-yl)-2-nitroethanol 10i
Enantiomeric excess was determined by HPLC with a (S,S)
Whelk-O1 column (85:15 hexanes/isopropanol, 1.0 mL/min,
215 nm); minor tr = 8.53 min; major tr = 10.51 min; 81% ee. Config-
uration assignment: absolute configuration of the major isomer
was determined to be (S) by comparison with literature data.14
using full-matrix least squares. The non-H atoms were treated
anisotropically, whereas the hydrogen atoms were calculated in
ideal positions and were riding on their respective carbon atoms.
The asymmetric unit consists of a half complex (located on a two-
fold rotation symmetry element) and a dichloromethane molecule.
A total of 168 parameters were refined in the final cycle of refine-
4.3.10. (S)-1-(Naphthalen-1-yl)-2-nitroethanol 10j
Enantiomeric excess was determined by HPLC with a Chiralpak
IB column (85:15 hexanes/isopropanol, 1.0 mL/min, 215 nm); min-
or tr = 8.15 min; major tr = 10.7 min; 87% ee. Configuration assign-
ment: absolute configuration of the major isomer was determined
to be (S) by comparison of the retention time with literature
data.5a,7j
ment using 3615 reflections with I > 2r(I) to yield R1 and wR2 of
2.48% and 6.40%, respectively. These data can be obtained free of
charge from the Cambridge Crystallographic Data Center via
www.ccdc.cam.ac.uk/data_request/cif (CCDC 812994). The thermal
ellipsoid drawing (Fig. 2) was produced using OLEX2.16
Acknowledgments
4.3.11. (S,E)-1-Nitro-4-phenylbut-3-en-2-ol 10k
We thank the James
& Esther King Biomedical Research
Enantiomeric excess was determined by HPLC with a Chiralpak
IB column (85:15 hexanes/isopropanol, 0.8 mL/min, 215 nm); min-
or tr = 18.56 min; major tr = 17.16 min; 75% ee. Configuration
assignment: absolute configuration of the major isomer was deter-
mined to be (S) by comparison with literature data.6a
Program, Florida Department of Health (08KN-04) and the
Petroleum Research Fund administered by the American Chemical
Society (PRF 46157-G1). K.A.A. wishes to acknowledge the National
Science Foundation and the University of Florida for funding for the
new X-ray equipment. We also thank Mr. Jongwoo Park and
Mr. Kai Lang for discussion.
4.4. Crystal structure analysis
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ꢄ
(b) The enantiomeric purity of this amino alcohol compound was confirmed
by
(cyclohexylmethyl)oxazolidin-2-one:
literature value [
derivatization
to
the
known
cyclic
carbamate,
(S)-4-
½ ꢄ
a 2D2
¼ ꢃ15:3 (c 1.0, CHCl3) versus
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