Highly regioselective synthesis of chiral diamines via a Buchwald-Hartwig amination from camphoric acid and their application in the Henry reaction

Article abstract of DOI:10.1002/aoc.3162

In this work the synthesis of new asymmetric diamine ligands from camphoric acid is described. The new diamines can be directly prepared in a regioselective arylation of the less hindered primary amine group of (+)-cis-1,2,2-trimethylcyclopentane-1,3-diam

Full text of DOI:10.1002/aoc.3162

Full Paper
Received: 24 March 2014
Revised: 3 April 2014
Accepted: 9 April 2014
Published online in Wiley Online Library: 29 May 2014
(wileyonlinelibrary.com) DOI 10.1002/aoc.3162
Highly regioselective synthesis of chiral
diamines via a Buchwald–Hartwig amination
from camphoric acid and their application in
the Henry reaction
Magdalena Uzarewicz-Baig, Maximilian Koppenwallner, Sobia Tabassum†
and René Wilhelm*
In this work the synthesis of new asymmetric diamine ligands from camphoric acid is described. The new diamines can be di-
rectly prepared in a regioselective arylation of the less hindered primary amine group of (+)-cis-1,2,2-trimethylcyclopentane-
1,3-diamine via a Buchwald–Hartwig amination in high yields. The resulting diamines incorporate a secondary and primary
amine group and were successfully applied as ligands in a copper-catalyzed Henry reaction. Copyright © 2014 John Wiley &
Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
Keywords: Buchwald–Hartwig amination; palladium; diamines; camphor; Henry reaction
Introduction
Experimental
General Remarks
The development of new chiral ligands is an important task in the
research field of asymmetric catalysis.[1] One class of asymmetric
ligand that is being continuously reported is based on diamines.
The latter have been studied as ligands with several different
metals in a broad range of reactions.[2]
Among those transformations that have been explored is
the asymmetric Henry reaction or nitro-aldol reaction, which
is an important method to obtain enantiomer-enriched β-nitro
alcohols from nitroalkanes and aldehydes.[3] The reaction can
be catalyzed with chiral organocatalysts and metal-based
systems with chiral ligands.[4] New diamine ligands for the
copper-catalyzed Henry reaction are constantly being devel-
oped.[5] For several of these ligand systems (+)-camphor from
the chiral pool proved to be a valuable starting material for
their synthesis.[5d,5n–p]
One interesting way to utilize (+)-camphor is in the develop-
ment of ligands via (+)-cis-1,2,2-trimethylcyclopentane-1,3-di-
amine (2), which can be prepared in one step from (+)-
camphoric acid (1) via the Schmidt reaction (Scheme 1).[6] The di-
amine 2 has been the starting point of several attractive ligand
targets over recent years.[7] Ligands 3[7a] and 4[7c] can be pre-
pared by exploiting the different reactivity of the two amine
groups attached to secondary and tertiary carbon atoms with
carboxylic acid chlorides.
Diamine 2 was prepared according to the literature[6] from
(+)-camphoric acid (1), which was purchased from commercial
sources. The diamines 18[9] and 19[9] were prepared according
to the literature. Melting points were taken with an apparatus
after Dr Tottoli and are uncorrected. IR spectra were recorded
on a Bruker VERTEX 70 FT-IR spectrometer. 1H NMR spectra were
acquired at ambient temperature on a Bruker Avance 500
(500 MHz) in deuterated solvents as stated. 13C NMR spectra were
recorded at ambient temperature at 125 MHz and 15N spectra at
51 Hz in deuterated solvents. Mass spectra (EI) were recorded
with a Hewlett Packard 5989B at 70 eV. High-resolution mass
spectra (ESI) were recorded on a Waters Quadrupole-ToF Synapt
2G. EI mass spectra were recorded on a Thermo Scientific
double-focusing sector field-MS DFS. Enantiomeric excess was
determined on a Merck Hitachi HPLC system. Flash column
chromatography was performed on Sorbisil C-60. Reactions were
monitored by TLC with Merck Silica gel 60 F254 plates. THF and
diethyl ether were distilled from sodium benzophenone ketyl.
Toluene was distilled from sodium. CH2Cl2 and acetonitrile were
distilled from calcium hydride.
Here, we explore the possibility of differentiating between the
different amine groups with a Buchwald–Hartwig amination.[8]
This N-aryl amination has found an increased interest over the
last 20 years. In the present study it gives a direct access to new
diamine ligands, whose potential is explored in the copper-cata-
lyzed asymmetric Henry reaction.
*
Correspondence to: René Wilhelm, Department of Chemistry, University of
Paderborn, Warburgerstr. 100, 33098 Paderborn, Germany. E-mail: rene.
wilhelm@uni-paderborn.de
Department of Chemistry, University of Paderborn, 33098, Paderborn, Germany
†
Current address: COMSATS Institute of Information Technology, Lahore, Pakistan
Appl. Organometal. Chem. 2014, 28, 552–558
Copyright © 2014 John Wiley & Sons, Ltd.

Regioselective synthesis of diamines via a Buchwald–Hartwig amination
toluene (360 ml). After workup, the product was obtained as a
yellow solid (5.2 g, 20.94 mmol, 99%).
1
M.p. 65°C. H NMR (500 MHz, CDCl3) δ = 6.85 (ddd, J = 7.7, 6.1,
1.4 Hz, 1H, H-5′), 6.77 (dd, J = 7.9, 1.3 Hz, 1H, H-3′), 6.66–6.59
(m, 2H, H-6′, H-4′), 4.96 (bs, 1H, H-N1), 3.85 (s, 3H, 2′-OCH3),
3.73–3.66 (m, 1H, H-1), 2.24 (dddd, J = 13.6, 10.3, 8.5, 4.9 Hz, 1H,
H-5), 1.76 (ddd, J = 13.2, 10.3, 6.1 Hz, 1H, H-4), 1.66 (ddd, J = 13.3,
11.0, 4.9 Hz, 1H, H-4), 1.54 (ddt, J = 13.7, 11.0, 6.0 Hz, 1H, H-5),
1.15 (s, 3H, H-8), 0.97 (s, 3H, H-6), 0.96 (s, 3H, H-7) ppm. 13C NMR
(126 MHz, CDCl3) δ = 146.9 (C-2′), 138.7 (C-1′), 121.3 (C-5′), 115.5
(C-4′), 110.0 (C-6′), 109.8 (C-3′), 61.8 (C-1), 61.0 (C-3), 55.6
(2′-OCH3), 47.1 (C-2), 38.3 (C-4), 29.3 (C-5), 26.3 (C-8), 23.7 (C-6),
17.2 (C-7) ppm. 15N NMR (51 MHz, CDCl3) δ = 70.5 (bs, 1N, N1),
47.7 (bs, 1N, N3) ppm. IR (KBr) = 3435, 3062, 2961, 2869, 2284,
1601, 1515, 1454, 1428, 1368, 1341, 1311, 1223, 1179, 1119,
1026, 879, 839, 737, 551 cmÀ1. MS (EI, 70 eV): m/z (%) = 248 (16)
[M]+, 216 (10), 123 (100), 108 (15), 70 (10). HRMS (ESI): calcd for
C13H25N2O: 249.1967 [M+H]+; found: 249.1976. Anal. Calcd for
C15H24N2O: C, 72.54; H, 9.74; N, 11.28; found: C, 72.41; H, 9.71; N,
11.21. [α]20D = +51 (c = 2.7, CHCl3).
Scheme 1. Camphor diamines based on camphoric acid.
General Experimental for the Regioselective Arylation of
Diamine (2)
In a dried Schlenk tube Pd2(dba)3 (2–4 mol%), ( )-BINAP (6–9 mol%)
and NaOtBu (3 equiv.) were dissolved in toluene under a nitrogen
atmosphere and stirred for 20 min. Diamine 2 (1 equiv.) and a
bromoaryl (1 equiv.) were added and the solution was stirred for
48 h at 100°C. The solution was filtered through a plug of silica
and the plug was eluted with additional toluene. Thereafter, the
plug was eluted with CH2Cl2/MeOH (9:1) until all the product was
removed from the silica plug. The solvent was evaporated under re-
duced pressure and the crude product was dissolved in CH2Cl2. The
organic phase was extracted with 12 M HCl. The aqueous phase was
separated and washed three times with CH2Cl2. Thereafter, the
aqueous phase was cooled to 0°C and 12M NaOH was slowly added
until the solution had a pH of 14. The basic solution was extracted
five times with CH2Cl2 and the combined organic phases were
dried over Na2SO4, filtered and the solvent was removed. The crude
product was dissolved in pentane and the solution was filtered to
remove insoluble impurities. The solvent was removed and the
product was further purified via chromatography.
(1R,3S)-1,2,2-Trimethyl-N3-(o-tolyl)cyclopentane-1,3-diamine (7)
From Pd2(dba)3 (0.8 g, 0.87 mmol, 4 mol%), ( )-BINAP (1.2 g,
1.93 mmol, 9 mol%), NaOtBu (6.1 g, 63.48 mmol), diamine 2
(3.0 g, 21.09 mmol), 2-bromotoluene (2.5 ml, 20.79 mmol) in
toluene (360 ml). After workup, the product was obtained as a
yellow solid (4.0 g, 17.21 mmol, 82%).
M.p. 95°C. 1H NMR (500 MHz, CDCl3) δ = 7.10–7.05 (m, 1H, H-4′),
7.03 (dd, J = 7.3, 0.6 Hz, 1H, H-6′), 6.61–6.55 (m, 2H, H-5′, H-3′), 5.11
(s, 1H, H-N3), 3.68 (d, J = 4.5 Hz, 1H, H-3), 2.28–2.18 (m, 1H, H-4),
2.13 (s, 3H, 2′-CH3), 1.86–1.77 (m, 1H, H-5), 1.69–1.56 (m, 2H, H-5,
H-4), 1.18 (s, 3H, H-8), 1.02 (s, 3H, H-7), 0.98 (s, 3H, H-6) ppm. 13C
NMR (126 MHz, CDCl3) δ = 146.6 (C-1′), 130.1 (C-6′), 126.9 (C-4′),
122.3 (C-2′), 115.7 (C-3′), 109.6 (C-5′), 62.6 (C-3), 61.7 (C-1), 47.2
(C-2), 38.2 (C-5), 29.4 (C-4), 26.5 (C-8), 25.0 (C-6), 17.9 (2′-CH3),
17.3 (C-7) ppm. 15N-NMR (51 MHz, CDCl3) δ = 82.4 (bs, 1N, N3),
52.1 (bs, 1N, N1) ppm. IR (ATR) = 3288, 2967, 1602, 1580, 1502,
1448, 1386, 1364, 1314, 1262, 1227, 1144, 1049, 980, 953, 909,
856, 745, 715, 654 cmÀ1. MS (EI, 70 eV): m/z (%) = 248 (16) [M]+,
216 (10), 123 (100), 108 (15), 70 (10). HRMS (ESI): calcd for
C15H25N2: 233.2018 [M+H]+; found: 233.2017. Anal. Calcd for
C15H24N2: C, 77.53; H, 10.41; N, 12.06; found: C, 77.43; H, 10.31;
N, 12.00. [α]20D = +112 (c = 6, CHCl3).
(1R,3S)-1,2,2-Trimethyl-N3-(pyridin-2-yl)cyclopentane-1,3-diamine (5)
From Pd2(dba)3 (0.1 g, 0.11 mmol, 2 mol%), ( )-BINAP (0.3 g,
0.48 mmol, 6 mol%), NaOtBu (2.0 g, 20.81 mmol), diamine 2
(1.0 g, 7.03 mmol), 2-bromopyridine (0.7 ml, 7.34 mmol) in toluene
(100 ml). After workup, the product was purified via column
chromatography (CH2Cl2/Et2O, 9:1 with 4% Et3N) and obtained
as a yellow oil (1.4 g, 6.38 mmol, 91%).
1H NMR (500 MHz, CDCl3) δ = 7.97 (d, J = 5.0 Hz, 1H, H-6′),
7.30–7.23 (m, 1H, H-4′), 6.42–6.35 (m, 1H, H-5′), 6.28 (dd,
J = 8.4, 0.9 Hz, 1H, H-3′), 6.01 (d, J = 9.5 Hz, 1H, H-N3), 4.03–3.94
(m, 1H, H-3), 2.25–2.12 (m, 1H, H-4), 1.78–1.65 (m, 1H, H-5),
1.62–1.48 (m, 2H, H-5, H-4), 1.08 (s, 3H, H-8), 0.88 (s, 6H, H-7,
H-6) ppm. 13C NMR (126MHz, CDCl3) δ = 159.0 (C-2′), 148.1 (C-6′),
137.0 (C-4′), 111.6 (C-5′), 107.2 (C-3′), 61.6 (C-1), 60.8 (C-3), 47.2
(C-2), 38.1 (C-5), 29.4 (C-4), 26.5 (C-8), 24.5 (C-6), 17.1 (C-7) ppm.
15N NMR (51 MHz, CDCl3) δ = 260.4 (bs, 1N, N-1′), 97.0 (bs, 1N, N3),
53.2 (bs, 1N, N1) ppm. IR (ATR) = 2962, 1621, 1584, 1471, 1435,
1315, 1249, 1207, 1162, 1018, 860, 772, 716, 617 cmÀ1. MS (EI,
70 eV): m/z (%) = 219 (74) [M]+, 187 (49), 149 (81), 127 (83), 126
(100), 110 (88), 96 (43), 95 (94), 93 (43), 79 (74), 70 (80), 57 (74), 42
(38). HRMS (ESI): calcd for C13H22N3: 220.1814 [M+H]+; found:
220.1813. Anal. Calcd for C13H21N3: C, 71.19; H, 9.65; N, 19.16; found:
C, 70.99; H, 9.30; N, 18.64. [α]20D = +71.4 (c = 1.2, CH2Cl2).
(1S,3R)-N1-([1,1′-Biphenyl]-2-yl)-2,2,3-trimethylcyclo-pentane-1,3-diamine (8)
From Pd2(dba)3 (0.8 g, 0.87 mmol, 4 mol%), ( )-BINAP (1.2 g,
1.93 mmol, 9 mol%), NaOtBu (6.2 g, 64.52 mmol), diamine 2
(3.1 g, 21.79 mmol), 2-bromo-1,1′-biphenyl (3.7 ml, 20.26 mmol)
in toluene (360 ml). After workup the product was obtained as a
yellow oil (4.7 g, 15.96 mmol, 73%).
1H NMR (500 MHz, CDCl3) δ = 7.47–7.38 (m, 4H, H-6″, H-5″, H-3″,
H-2″), 7.34–7.29 (m, 1H, H-4″), 7.19 (ddd, J = 8.2, 7.4, 1.7 Hz, 1H,
H-6′), 7.08 (dd, J = 7.6, 1.7 Hz, 1H, H-4′), 6.72–6.67 (m, 2H, H-5′,
H-3′), 4.90 (s, 1H, H-N1), 3.64 (s, 1H, H-1), 2.19 (tdt, J = 10.6, 8.2,
5.4 Hz, 1H, H-5), 1.72 (ddd, J = 13.4, 10.5, 6.0Hz, 1H, H-4), 1.61–1.52
(m, 1H, H-4), 1.49–1.38 (H-5), 1.11 (s, 3H, H-8), 0.91 (s, 3H, H-7),
0.78 (s, 3H, H-6) ppm. 13C NMR (126 MHz, CDCl3) δ = 145.5 (C-2′),
140.0 (C-1″), 130.3 (C-4′), 129.5 (C-5″, C-3″), 128.6 (C-6′), 128.6 (C-6″,
C-2″), 127.9 (C-1′), 126.9 (C-4″), 116.0 (C-5′), 110.5 (C-3′), 62.2 (C-1),
61.2 (C-3), 47.1 (C-2), 37.9 (C-4), 29.0 (C-5), 26.1 (C-8), 23.8 (C-7),
17.2 (C-6) ppm. 15N-NMR (51 MHz, CDCl3) δ = 79.6 (bs, 1N, N1), 50.4
(bs, 1N, N3) ppm. IR (ATR) = 3296, 3057, 2959, 2867, 1597, 1576,
(1S,3R)-N1-(2-Methoxyphenyl)-2,2,3-trimethylcyclo-pentane-1,3-diamine (6)
From Pd2(dba)3 (0.8 g, 0.87 mmol, 4 mol%), ( )-BINAP (1.2 g,
1.93 mmol, 9 mol%), NaOtBu (6.1 g, 63.48 mmol), diamine 2
(3.0 g, 21.09 mmol), 2-bromoanisole (2.6 ml, 20.88 mmol) in
Appl. Organometal. Chem. 2014, 28, 552–558
Copyright © 2014 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

M. Uzarewicz-Baig et al.
1506, 1489, 1462, 1436, 1387, 1368, 1319, 1283, 1161, 1144, 1063,
1007, 994, 927, 879, 841, 769, 734, 701, 615 cmÀ1. MS (EI, 70eV):
m/z (%) = 294 (9) [M]+, 258 (34), 248 (15), 216 (12), 169 (99), 123
(100), 110 (70), 70 (58), 57 (65). HRMS (ESI): calcd for C20H27N2:
295.2174 [M+H]+, found: 295.2162. Anal. Calcd for C20H26N2: C,
81.59; H, 8.90; N, 9.51; found: C, 80.95; H, 8.98; N, 9.43. [α]20D = +44
(c = 7, CHCl3).
toluene (350 ml). After workup, the product was obtained as a
brown oil (1.8g, 6.91mmol, 49%).
1H NMR (500 MHz, CDCl3) δ = 7.13–7.03 (m, 2H, H-5′, H-3′),
6.67–6.59 (m, 2H, H-6′, H-4′), 5.41 (s, 1H, H-N1), 3.66 (s, 1H, H-1),
2.92–2.87 (m, 1H, 2′-CH(CH3)2), 2.25–2.17 (m, 1H, H-5), 1.84–1.78
(m, 1H, H-4), 1.64–1.56 (m, 2H, H-5, H-4), 1.25 (t, J = 7.1 Hz, 6H, 2′-
CH(CH)3), 1.16 (s, 3H, H-8), 1.02 (s, 3H, H-7), 0.97 (s, 3H, H-6) ppm.
13C NMR (126 MHz, CDCl3) δ = 145.3 (C-1′), 132.5 (C-2′), 126.6
(C-4′), 124.9 (C-6′), 115.9 (C-3′), 110.1 (C-5′), 62.8 (C-3), 61.5 (C-1),
47.3 (C-2), 38.5 (C-5), 29.3 (2′-CH(CH3)2), 27.5 (C-4), 26.8 (2′-CHCH3),
25.1 (2′-CHCH3), 22.5 (C-8), 22.1 (C-7), 17.3 (C-6) ppm. 15N-NMR
(51 MHz, CDCl3) δ = 80.6 (br, 1N, N1), 51.1 (br, 1N, N3) ppm. IR
(ATR) = 3306, 2957, 2870, 1602, 1579, 1509, 1451, 1364, 1258,
1056, 886, 735 cmÀ1. MS (EI, 70 eV): m/z (%) = 261 (6) [M]+, 260
(26), 243 (5), 228 (16), 201 (2), 200 (6), 186 (3), 161 (4), 146 (24),
135 (100), 120 (57), 110 (71), 93 (11), 71 (15), 70 (43), 57 (56), 42
(22). HRMS (ESI): calcd for C17H29N2: 261.2331 [M+H]+, found:
261.2324. Anal. Calcd for C17H28N2: C, 78.41; H, 10.84; N, 10.76;
found: C, 78.38; H, 10.34; N, 10.90. [α]20D = +172 (c = 0.55, CH2Cl2).
(1R,3S)-1,2,2-Trimethyl-N3-(naphthalen-1-yl)cyclo-pentane-1,3-diamine (9)
From Pd2(dba)3 (0.5 g, 0.55 mmol, 4 mol%), ( )-BINAP (0.5 g,
0.80 mmol, 6 mol%), NaOtBu (4.1 g, 42.66 mmol), diamine 2
(2.0 g, 14.06 mmol), 1-bromonaphthalene (1.9 ml, 13.58 mmol)
in toluene (180 ml). After workup, the product was further
purified via column chromatography (CH2Cl2/MeOH, 99:1) on
neutral aluminum oxide and obtained as a white solid (2.4 g,
8.94 mmol, 64%).
M.p. 126°C. 1H NMR (500 MHz, CDCl3) δ = 7.92 (d, J = 8.0 Hz, 1H,
H-8′), 7.81–7.74 (m, 1H, H-5′), 7.46–7.37 (m, 2H, H-7′, H-6′), 7.34
(t, J = 7.9 Hz, 1H, H-3′), 7.15 (d, J = 8.2 Hz, 1H, H-4′), 6.64–6.48
(m, 2H, H-N3, H-2′), 3.84 (d, J = 5.0 Hz, 1H, H-3), 2.37–2.25 (m, 1H,
H-4), 1.93–1.85 (m, 1H, H-5), 1.85–1.76 (m, 1H, H-4), 1.75–1.66
(m, 1H, H-5), 1.23 (s, 3H, H-8), 1.13 (s, 3H, H-7), 1.05 (s, 3H, H-6)
ppm. 13C NMR (126 MHz, CDCl3) δ = 144.1 (C-1′), 134.7 (C-4′a),
128.5 (C-5′), 126.8 (C-3′), 125.5 (C-6′), 124.2 (C-7′), 124.0 (C-8′a),
120.9 (C-8′), 115.7 (C-4′), 103.6 (C-2′), 63.3 (C-3), 62.2 (C-1), 47.5
(C-2), 38.2 (C-5), 29.2 (C-4), 26.4 (C-8), 25.7 (C-6), 17.4 (C-7) ppm.
15N NMR (51 MHz, CDCl3) δ = 83.6 (bs, 1N, N3), 54.4 (bs, 1N, N1)
ppm. IR (ATR) = 1258, 1227, 1153, 1028, 633, 574, 517 cmÀ1. MS
(EI, 70 eV): m/z (%) = 268 (34), 157 (36), 143 (100), 112 (49), 97
(44), 95 (24), 83 (66), 71 (53), 70 (58), 69 (58), 57 (84), 55 (63), 44
(42), 43 (57), 41 (56). HRMS (ESI): calcd for C18H24N2Na: 291.1837
[M+H+Na]+; found: 291.1829. Anal. Calcd for C18H24N2: C, 80.55;
H, 9.01; N, 10.44; found: C, 80.55; H, 9.13; N, 10.43. [α]20D = +137
(c = 2.1, CHCl3).
(1S,3R)-N1-([1,1′-Biphenyl]-3-yl)-2,2,3-trimethylcyclopentane-1,3-diamine (12)
From Pd2(dba)3 (0.08 g, 0.09 mmol, 4 mol%), ( )-BINAP (0.1 g,
0.16 mmol, 9 mol%), NaOtBu (0.6 g, 6.24 mmol), diamine 2 (0.3 g,
2.11 mmol), 3-bromobiphenyl (0.4 ml, 2.40 mmol) in toluene
(60 ml). After workup, the product was obtained as a yellow oil
(0.3 g, 1.02 mmol, 48%).
1H NMR (500 MHz, CDCl3) δ = 7.67-7.64 (m, 2H, H-6″, H-5″),
7.50–7.45 (m, 2H, H-2″, H-3″), 7.40–7.36 (m, 1H, H-4″), 7.29–7.25
(m, 1H, H-6′), 6.93 (ddd, J = 7.5, 1.6, 0.9 Hz, 1H, H-5′), 6.90–6.87
(m, 1H, H-4′), 6.66 (ddd, J = 8.1, 2.4, 0.8Hz, 1H, H-2′), 5.19 (br s, 1H,
H-N3), 3.76 (d, J = 4.6Hz, 1H, H-1), 2.32–2.25 (m, 1H, H-5), 1.87–1.80
(m, 1H, H-4), 1.71–1.63 (m, 2H, H-5, H-4), 1.19 (s, 3H, H-8), 1.04
(s, 3H, H-7), 1.02 (s, 3H, H-6) ppm. 13C NMR (126 MHz, CDCl3)
δ = 149.1 (C-3′), 142.4 (C-1″), 142.2 (C-5′), 129.6 (C-5″, C-3″), 128.6
(C-6′), 127.3 (C-6″, C-2″), 127.1(C-1′), 115.6 (C-4″), 112.2 (C-5′), 112.1
(C-4′), 62.8 (C-1), 61.4 (C-3), 47.4 (C-2), 38.3 (C-4), 29.3 (C-5), 26.6
(C-8), 24.8 (C-7), 17.3 (C-6) ppm. 15N-NMR (51 MHz, CDCl3) δ = 84.1
(bs, 1N, N1), 51.1 (bs, 1N, N3) ppm. IR (ATR) = 3286, 3051, 2940,
2866, 1577, 1523, 1480, 1466, 1425, 1374, 1346, 1253, 1161, 1140,
1076, 1011, 927, 899, 845, 759, 713, 616 cmÀ1. MS (EI, 70 eV): m/z
(%) = 294 (15) [M]+, 277 (4), 262 (9), 250 (3), 234 (8), 208 (4), 195
(8), 194 (4), 170 (17), 169 (100), 155 (13), 152 (6), 126 (11), 93 (5),
70 (5), 41 (4). HRMS (ESI): Calcd for C20H27N2: 295.2174 [M+H]+;
found: 295.2172. Anal. Calcd for C20H28N2: C, 81.59; H, 8.90; N,
9.51; found: C, 80.70; H, 9.17; N, 9.52. [α]20D = +88 (c = 0.49, CH2Cl2).
(1S,3R)-N1-Mesityl-2,2,3-trimethylcyclopentane-1,3-diamine (10)
From Pd2(dba)3 (0.8 g, 0.87 mmol, 4 mol%), ( )-BINAP (1.2 g,
1.93 mmol, 9 mol%), NaOtBu (6.1g, 63.48 mmol), diamine 2 (3.0g,
21.09 mmol), 2-bromo-1,3,5-trimethylbenzol (3.2 ml, 20.90 mmol)
in toluene (360ml). The product was obtained as a yellow oil
(5.3g, 20.35 mmol, 97%).
1H NMR (500 MHz, CDCl3) δ = 6.78 (s, 2H, H-5′, H-3′), 4.21 (bs, 1H,
H-N1), 3.42 (dd, J = 7.7, 4.9 Hz, 1H, H-1), 2.25 (s, 6H, 6′-CH3, 2′-CH3),
2.21 (s, 3H, 4′-CH3), 1.90–1.81 (m, 1H, H-5), 1.75–1.60 (m, 2H, H-4),
1.54–1.45 (m, 1H, H-5), 1.12 (s, 3H, H-8), 1.09 (s, 3H, H-7), 0.94
(s, 3H, H-6) ppm. 13C NMR (126 MHz, CDCl3) δ = 143.5 (C-1′),
129.7 (C-6′, C-2′), 129.6 (C-5′, C-3′), 128.7 (C-4′), 66.4 (C-1), 61.2
(C-3), 47.0 (C-2), 38.2 (C-4), 28.6 (C-5), 26.8 (C-8), 23.9 (C-6), 20.5
(C-4′), 19.4 (C-6′, C-2′), 17.1 (C-7) ppm. 15N NMR (51 MHz, CDCl3)
δ = 68.8 (bs, 1N, N1), 50.6 (bs, 1N, N3) ppm. IR (ATR) = 3319, 2961,
2866, 1584, 1481, 1386, 1370, 1300, 1237, 1156, 1137, 1110,
1059, 1026, 927, 890, 851, 810, 763 cmÀ1. MS (EI, 70 eV): m/z
(%) = 260 (24) [M]+, 228 (22), 161 (8), 146 (21), 135 (100), 120 (8),
86 (9), 70 (46), 57 (30), 41 (11). HRMS (EI): calcd for C17H28N2:
260.2247 [M]+; found: 260.2248. Anal. Calcd for C17H28N2: C,
78.41; H, 10.84; N, 10.76; found: C, 78.39; H, 10.80; N, 10.75.
[α]20D = +79 (c = 4.3, CHCl3).
1,2,2-Trimethyl-N3-(2-(1-naphthyl)phenyl)cyclopentane-1,3-diamine (13)
From Pd2(dba)3 (0.03 g, 0.03 mmol, 4 mol%), ( )-BINAP (0.04 g,
0.06 mmol, 9 mol%), NaOtBu (0.2 g, 2.08 mmol), diamine 2 (0.1 g,
0.71 mmol), 1-(2-bromophenyl)naphthalene (0.2 mg, 0.70 mmol)
in toluene (100 ml). After workup, the product was obtained
as a mixture of diastereoisomers as a yellow solid (0.08 g,
0.23 mmol, 33%).
1H NMR (500 MHz, CDCl3) δ = 7.86 (dd, J = 16.7, 8.1 Hz, 4H, H-8″D1
H-8″D2, H-2″D1, H-2″D2), 7.72–7.62 (m, 2H, H-5″D1, H-5″D2), 7.58–7.28
(m, 10H, H-4″D1, H-4″D2, H-3″D1, H-3″D2, H-6′D1, H-6′D2, H-6″D1
,
,
H-6″D2, H-7‴D1, H-7″D2), 7.15 (dt, J = 7.5, 1.7 Hz, 2H, H-4′D1, H-4′D2),
6.79–6.74 (m, 4H, H-5′D1, H-5′D2, H-3′D1, H-3′D2) 4.67 (d, J = 9.1Hz,
(1S,3R)-N1-(2-Isopropylphenyl)-2,2,3-trimethylcyclopentane-1,3-diamine (11)
1H, H-N1D1), 4.50 (d, J = 9.1 Hz, 1H, H-ND12), 3.81–3.48 (m, 2H, H-1D1
,
From Pd2(dba)3 (0.5 g, 0.55 mmol, 4 mol%), ( )-BINAP (0.8 g,
1.29 mmol, 9 mol%), NaOtBu (4.1g, 42.66 mmol), diamine 2 (2.0g,
14.06 mmol), 1-bromo-2-isopropylbenzene (2.2ml, 14.37 mmol) in
H-1D2), 2.24–1.90 (m, 2H, H-5D1, H-5D2), 1.67–1.55 (m, 2H, H-4D1,
H-4D2), 1.42–1.20 (m, 4H, H-5D1, H-5D2, H-4D1, H-4D2), 0.96 (s, 3H,
CH3, H-8D1), 0.94 (s, 3H, CH3, H-8D2), 0.82 (s, 3H, CH3, H-7D1), 0.78
wileyonlinelibrary.com/journal/aoc
Copyright © 2014 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2014, 28, 552–558

Regioselective synthesis of diamines via a Buchwald–Hartwig amination
(s, 3H, CH3, H-7D2), 0.53 (s, 3H, CH3, H-6D1), 0.37 (s, 3H, CH3, H-6D2
)
General Procedure for the Henry Reaction
ppm. 13C NMR (126 MHz, CDCl3) δ = 146.6 (C-2′D1), 146.4 (C-2′D2),
137.7 (C-1″D1, C-1″D2), 133.9 (C-4″aD1), 133.7 (C-4″aD2), 132.3 (C-8″
aD1), 132.1 (C-8″aD2), 130.8 (C-4′aD1, C-4′aD2), 128.8 (C-5″D1, C-5″D2),
128.1 (C-8″D1), 128.1 (C-8″D2), 127.8 (C-4″D1), 127.8 (C-4″D2), 127.7
(C-6″D1), 127.6 (C-6″D2), 126.9 (C-7″D1, C-7″D2), 126.4 (C-3″D1, C-3″D2),
126.1 (C-2″D1, C-2″D2), 125.9 (C-6′D1), 125.8 (C-6′D2), 125.8 (C-5′D1, C-5′
D2), 115.7 (C-1′D1), 115.6 (C-1′D2), 110.2 (C-3′D1), 110.1 (C-3′D2), 62.4
(C-1D1), 62.2 (C-1D2), 60.7 (C-3D1), 60.6 (C-3D2), 46.9 (C-2D1, C-2D2),
38.2 (C-4D1, C-4D2), 29.1 (C-5D1), 28.8 (C-5D2), 26.3 (C-8D1), 26.2
(C-8D2), 24.2 (C-6D1), 23.9 (C-6D2), 16.8 (C-7D1), 16.7 (C-7D2).
The appropriate ligand (1–1.5 equiv.) and Lewis acid (0–1.5
equiv.) were dissolved in a solvent (1 ml) and the mixture was
stirred for 1 h at room temperature under an argon atmosphere.
A solution of aldehyde (10 equiv.) and base (0.2 equiv.) in a
solvent (0.5 ml) was added and the reaction mixture was stirred
at various temperatures over 15 min. Nitroalkane (100–200
equiv.) was added and the solution was stirred for the specific
time at various temperatures. The resulting mixture was filtered
through a silica gel column (10 cm3) with EtOAc (100 ml) to
remove the catalyst. The solvent was removed under reduced
pressure at <30°C and the crude product was purified by silica
gel flash column chromatography to give the corresponding
β-nitro alcohol. The enantiomeric excess was determined by
chiral HPLC analysis. The absolute configuration was assigned
by comparison to literature values (for yields and enantiomeric
excess see Tables 3 and 4).
(1R,3S)-1,2,2-Trimethyl-N3-phenylcyclopentane-1,3-diamine (14)
From Pd2(dba)3 (0.3 g, 0.33 mmol, 2.5 mol%), ( )-BINAP (0.5 g,
0.80 mmol, 6 mol%), NaOtBu (1.7g, 17.69 mmol), diamine 2 (2.5 g,
17.57 mmol), bromobenzene (1.8mL, 17.14 mmol) in toluene
(180ml). After workup, the product was obtained as a brown oil
(2.3g, 10.53 mmol, 60%).
(S)-2-Nitro-1-phenylethanol (16)
1H NMR (500 MHz, CDCl3) δ = 7.15 (dd, J = 8.6 Hz, H-6′, H-2′), 6.62
( m, 3H, H-3′, H-4′, H-5′), 5.2-4.7 (s (br), 1H, H-N1), 3.65 (m, 1H, H-3),
2.21 (m, 1H, H-4), 1.77 (m, 1H, H-5), 1.59 (m, 2H, H-5, H-4),
1.38–1.20 (s (br), 2H, H-N3), 1.14 (s, 3H, H-8), 0.96 (s, 3H, H-7),
0.95 (s, 3H, H-6) ppm. 13C NMR (126 MHz, CDCl3) δ = 148.7 (C-1′),
129.2 (C-6′, C-2′), 116.3 (C-4′), 113.1 (C-5′, C-33), 62.6 (C-3), 61.3
(C-1), 47.2 (C-2), 38.2 (C-5), 29.1 (C-4), 26.5 (C-8), 24.5 (C-6), 17.2
(C-7) ppm. 15N NMR (51 MHz, CDCl3) δ = 83.8 (bs, 1N, N3), 51.0
(bs, 1N, N1) ppm. IR (ATR) = 3401, 3360, 3300, 3083, 3052, 3020,
2959, 2867, 1909, 1595, 1500, 1468, 1312, 854, 742, 690,
502 cmÀ1. MS (EI, 70 eV): m/z (%) = 218 (85) [M]+, 201 (27), 186
(77), 132 (40), 126 (97), 119 (72), 109 (68), 93 (100), 77 (32), 70
(72), 57 (65), 41 (30). HRMS (ESI): calcd for C14H23N2: 219.1861
[M+H]+; found: 219.1854. Anal. Calcd for C14H22N2: C, 77.01;
H, 10.16; N, 12.83; found: C, 76.86; H, 10.11; N, 12.69.
[α]20D = +112.2 (c = 1.05, CH2Cl2).
The compound was prepared according to the general procedure
and purified by column chromatography (n-hexane/EtOAc, 8:2) to
give a colorless oil (93% yield). HPLC (Chiralcel OD-H, n-hexane/
i-PrOH, 85/15 v/v, 1 ml minÀ1, 25°C, UV = 250nm): tminor = 11.76 min,
t
major = 14.05 min; 77% ee. Spectral data were consistent with
literature values.[5h,o]
(S)-1-(2-Methoxyphenyl)-2-nitroethanol (23)
The compound was prepared according to the general procedure
and purified by column chromatography (n-hexane/EtOAc, 8:2)
to give a yellow oil (65% yield). HPLC (Chiralcel OD-H, n-hexane/
i-PrOH, 85:15 v/v, 1 ml minÀ1, 25°C, UV = 250 nm): tminor = 10.32
min, tmajor = 11.55 min; 83% ee. Spectral data were consistent
with literature values.[5h,o]
(S)-2-Nitro-1-(2-nitrophenyl)ethanol (21)
The compound was prepared according to the general procedure
and purified by column chromatography (n-hexane/EtOAc, 7:3) to
give an orange solid (68% yield). HPLC (Chiralcel OD-H, n-hexane/
i-PrOH, 85:15 v/v, 1 mlminÀ1, 25°C, UV= 250 nm): tminor = 13.36 min,
(1R,3S)-1,2,2-Trimethyl-N3-(quinolin-2-yl)cyclopentane-1,3-diamine (15)
From Pd2(dba)3 (0.3 g, 0.33 mmol, 4 mol%), ( )-BINAP (0.4 g,
0.64 mmol, 9 mol%), NaOtBu (2.0 g, 20.81 mmol), diamine 2
(1.0 g, 7.03 mmol), 2-chloroquinoline (1.2 g, 7.34 mmol) in toluene
(180 ml). After workup, the product was obtained as a yellow
solid (1.0 g, 3.71 mmol, 53%).
t
major = 14.61 min; 82% ee. Spectra data were consistent with
literature values.[5h,o]
(S)-2-Nitro-1-(3-nitrophenyl)ethanol (22)
1
M.p. 81°C. H-NMR (500 MHz, CDCl3) δ = 7.71 (d, J = 8.9 Hz, 1H,
The compound was prepared according to the general procedure
and purified by column chromatography (n-hexane/EtOAc, 8:2) to
give a yellow solid (57% yield). HPLC (Chiralcel OD-H, n-hexane/
i-PrOH, 85:15 v/v, 1 ml minÀ1, 25°, UV = 250 nm): tminor = 20.56 min,
H-4′), 7.61 (d, J = 8.4 Hz, 1H, H-8′), 7.52 (dd, J = 7.9, 1.3 Hz, 1H,
H-5′), 7.47 (ddd, J = 8.4, 7.0, 1.5 Hz, 1H, H-7′), 7.13 (ddd, J = 8.0,
7.0, 1.2 Hz, 1H, H-6′ ), 6.57 (d, J = 8.9 Hz, 1H, H-3′), 6.41 (bs, 1H,
H-N3), 4.44 (s, 1H, H-3), 2.38–2.26 (m, 1H, H-4), 1.87–1.76
(m, 1H, H-5), 1.70–1.58 (m, 2H, H-5, H-4), 1.16 (s, 3H, H-8),
0.99 (s, 3H, H-7), 0.95 (s, 3H, H-6) ppm. 13C NMR (126 MHz,
CDCl3) δ = 157.0 (C-2′), 148.5 (C-8′a), 136.6 (C-4′), 129.2 (C-7′),
127.3 (C-5′), 126.1 (C-8′), 123.3 (C-4′a), 121.3 (C-6′), 112.2 (C-3′),
61.8 (C-1), 60.4 (C-3), 47.6 (C-2), 38.2 (C-5), 29.7 (C-4), 26.6
(C-8), 24.7 (C-7), 17.3 (C-6) ppm. 15N NMR (51 MHz, CDCl3)
δ = 237.8 (bs, 1N, N-1′), 105.1 (bs, 1N, N3), 52.5 (bs, 1N, N1)
ppm. IR (ATR) = 3308, 2961, 2868, 1658, 1615, 1563, 1515,
1487, 1421, 1398, 1367, 1307, 1255, 1211, 1140, 1119, 1062,
1021, 928, 885, 814, 779, 752, 618 cmÀ1. MS (EI, 70 eV): m/z
(%) = 269 (11) [M]+, 252 (21), 237 (5), 199 (21), 183 (12), 169
(21), 144 (100), 128 (24), 117 (14), 101 (5), 70 (8), 57 (10), 41
(7). HRMS (EI): calcd for C17H23N3: 269.1886 [M]+; found:
269.1877. [α]20D = +19 (c = 2.7, CHCl3).
t
major = 22.72 min; 59% ee. Spectral data were consistent with
literature values.[5h,o]
(S)-1-(3-Chlorophenyl)-2-nitroethanol (20)
The compound was prepared according to the general procedure
and purified by column chromatography (n-hexane/EtOAc, 8:2)
to give a yellow oil (65% yield). HPLC (Chiralcel OD-H, n-hexane/
i-PrOH, 85:15 v/v, 1 ml minÀ1, 25°C, UV = 250 nm): tminor = 11.44
min, tmajor = 13.97 min; 63% ee. Spectral data were consistent
with literature values.[5h,o]
2-Nitro-1-(2-nitrophenyl)propan-1-ol (24)
The compound was prepared according to the general procedure
and purified by column chromatography (n-hexane/EtOAc, 8:2)
Appl. Organometal. Chem. 2014, 28, 552–558
Copyright © 2014 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

M. Uzarewicz-Baig et al.
to give a brown oil (73% yield as a mixture of diastereoisomers),
dr (anti/syn) = 38:62 determined by 1H NMR analysis. HPLC
(combination of Chiralpak AD-H column + Chiralpak AS-H col-
umn, n-hexane/i-PrOH, 95/5 v/v, 0.5 ml minÀ1, 25°C, UV = 250 nm):
t
major = 59.65 min, tminor = 63.41 min for anti-isomer, tminor = 74.88
Scheme 2. Asymmetric addition of nitromethane to benzaldehyde cata-
lyzed by copper(II) acetate and ligands 5–11.
min, tmajor = 81.81 min for syn-isomer; 53% ee for anti-isomer,
57% ee for syn-isomer. Spectra data were consistent with
literature values.[5h,o]
benzaldehyde and 10 equiv. of nitromethane the reaction was
stirred at 0°C for 24 h. The results are summarized in Table 2. Next
to the new prepared ligands, the diamines 18[9] and 19[9] with
two secondary amine functions were also explored in the reac-
tion. While 18 and 19 resulted in a small enantiomeric excess
of the R enantiomer of the Henry product (Table 2, entries 11
and 12), the other diamines gave the S enantiomer in excess.
The highest enantiomeric excess was obtained with diamine
8 (Table 2, entry 4). As can be seen from Table 2, in general a
sterically demanding substituent at one ortho position of the
arene ring increases the enantiomeric excess. If the aryl substitu-
ent becomes too large, as in the case of ligand 10, the yield de-
creases (Table 2, entry 6).
In order to further optimize the reaction conditions with the new
ligands, different influences of solvents, copper sources and bases
were explored with ligand 7. The results are summarized in Table 3.
From the table it is evident that methanol is the best solvent for
the presented system. The use of ethanol and isopropanol resulted
in a lower yield (Table 3, entries 2 and 3). When copper chlorides
were used, lower yields and enantioselectivities were obtained
(Table 3, entries 4, 15 and 16). A decrease in temperature from
0 to À25°C increased the enantiomeric excess only slightly. How-
ever, the yield decreased from 82% to 39% (Table 3, entry 11).
Results and Discussion
In order to explore the different reactivities of the two amine
groups of 2 in a Buchwald–Hartwig amination, the diamine 2
was treated in a modified literature procedure[10] with 1 equiv.
of different bromoarenes in the presence of Pd2(dba)3, BINAP
and NaOtBu.
The results are summarized in Table 1. In general, good to
excellent yields could be obtained of the desired regioisomers.
The reaction tolerated arenes with various substitution patterns.
The sterically hindered 2-bromomesitylene, for example, gave
an excellent yield of 97% (Table 1, entry 6). Bromobiphenyls
(Table 1, entries 4 and 8) as well as 2-bromonaphthyl (Table 1,
entry 5) could be applied. Heteroaromatic compounds could be
also used. 2-Bromopyridine resulted in a yield of 91% (Table 1,
entry 1). In order to explore also chloroarenes in the reaction,
2-chloroquinoline was applied in the reaction and compound
15 was isolated in a yield of 53% (Table 1, entry 11). Due to
the axial chirality of 1-(2-bromophenyl)naphthalene the product
13 was isolated as a mixture of diastereomers in 33% yield.
In all cases only the desired regioisomers were observed and
identified by 1H–13C NMR-HMBC. The high regioselectivity is
remarkable considering the high reaction temperature of 100°C.
With these new diamines available their potential as ligands in
the copper-catalyzed asymmetric Henry reaction was explored
(Scheme 2). First, different ligands were explored under the same
conditions. 10 mol% Cu(OAc)2.H2O and 10 mol% ligand were
mixed in methanol and after the addition of 3 mol% DABCO,
Table 2. Asymmetric Henry reaction of benzaldehyde with
nitromethane in the presence of various diamine ligands, 10 mol%
Cu(OAc)2.H2O and DABCO in methanol at 0°C for 24 h
Entry
Ligand
Yield (%)
ee (%)
Config.
1
5
6
18
60
82
56
41
34
64
32
84
78
57
4
38
45
69
37
47
45
30
48
31
7
S
S
S
S
S
S
S
S
S
S
R
2
3
7
Table 1. Regioselective arylation of diamine
bromoarenes via the Buchwald–Hartwig amination
2 with various
4
8
5
9
4 mol% Pd2(dba)3
6
10
11
12
13
14
Ar
NH
NH2
9 mol% ( )-BINAP
NH2
NH2
7
ArX
+
NaOtBu
8
48 h, 110 °C
toluene
2
5-15
9
10
11
Entry
Arene
Product
Yield (%)
1
2-Bromopyridine
2-Bromoanisole
2-Bromotoluene
5
6
91
99
82
73
64
97
49
48
33
60
53
2
3
7
4
2-Bromo-1,1′-biphenyl
1-Bromonaphthalene
2-Bromo-1,3,5-trimethylbenzol
1-Bromo-2-isopropylbenzene
3-Bromobiphenyl
8
12
26
11
R
5
9
6
10
11
12
13
14
15
7
8
9
1-(2-Bromophenyl)naphthalene
Bromobenzene
10
11
2-Chloroquinoline
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Copyright © 2014 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2014, 28, 552–558

Regioselective synthesis of diamines via a Buchwald–Hartwig amination
Table 3. Asymmetric Henry reaction of benzaldehyde with
nitromethane in the presence of 10 mol% diamine ligand 7, 10 mol
% copper salt, and 3 mol% DABCO under different reaction conditions
for 24 h
Table 4. Asymmetric Henry reaction of aryl aldehydes with nitro-
methane in the presence of 10 mol% diamine ligand 7, 10 mol%
copper(II)-2-ethylhexanoate and 3 mol% DABCO for 24 h
10 mol% Ligand 7
Entry Solvent
Copper salt
T (°C) Yield (%) ee (%)
10 mol% Cu[CH3
(CH2)3CH(C2H5)CO2]2
Ar
NO2
ArCHO
1
MeOH
EtOH
Cu(OAc)2.H2O
0
0
82
53
47
65
69
75
60
68
63
59
39
42
11
21
56
60
92
26
9
45
49
46
34
47
41
47
0
OH
DABCO
MeOH, MeNO2
2
Cu(OAc)2.H2O
Cu(OAc)2.H2O
CuCl
3
iPrOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
THF
0
4
0
Entry
Ar
T (°C)
Product
Yield (%)
ee (%)
5a
6b
7c
8
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
—
0
0
1
2
3
4
5
Ph
0
0
0
0
0
16
20
21
22
23
93
65
68
57
65
77
63
82
59
83
0
3-Cl-C6H4
0
2-NO2-C6H4
3-NO2-C6H4
2-MeO-C6H4
9
Cu(OAc)2.H2O
—
r.t.
0
38
0
10
11
12d
13
14
15
16
17
18
19
20
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
CuCl
À25
À25
À25
r.t.
0
53
54
73
31
36
16
52
72
56
77
H2O
l
l
l
THF
MeOH
MeOH
THF
CuCl2
0
Cu[C6H11(CH2)3CO2]2
Cu[C6H11(CH2)3CO2]2
Cu[C6H11(CH2)3CO2]2
Cu[CH3(CH2)3
CH(C2H5)CO2]2
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu[C6H11(CH2)3CO2]2
Cu[C6H11(CH2)3CO2]2
Cu[C6H11(CH2)3CO2]2
Cu[CH3(CH2)3
CH(C2H5)CO2]2
0
0
CH2Cl2
MeOH
0
0
93
21e
22f
23f
24f
25f
26f
MeOH
MeOH
THF
0
0
0
0
0
0
69
56
21
74
5
46
69
84
72
76
74
Scheme 3. Asymmetric Henry reaction of 2-nitrobenzene with nitroethane.
Electron-rich and electron-poor benzaldehydes were explored.
While the yield decreased slightly, the enantioselectivities
increased with substituents in the ortho position up to 83%
(Table 4, entries 3 and 5).
Finally, a reaction was carried out with nitroethane and ortho-
nitrobenzaldehyde as depicted in Scheme 3 and the desired
product was isolated in 73% yield. The resulting syn/anti
selectivity of the diastereomers was 34/66. The syn diastereomer
had an enantiomeric excess of 57% and the anti diastereomer
had an enantiomeric excess of 53%.
MeOH
CH2Cl2
MeOH
59
a3 mol% Et3N.
b15 mol% diamine 7.
cCu(OAc)2.H2O 15 mol%.
dreaction time 48 h.
e200 equiv. MeNO2.
freaction was carried out with ligand 8.
Conclusion
A highly regioselective arylation of diamine 2, via a Buchwald–
Hartwig amination, gave new chiral diamine ligands incorpo-
rating a primary and arylated secondary amine function. The
resulting ligands were explored first in an asymmetric Henry
reaction. Enantiomeric excesses of up to 84% could be
obtained. In the case of ligands incorporating two secondary
amine functions the opposite enantiomer was obtained,
although in low excess.
A longer reaction time of 48h did not increase the yield (Table 3,
entry 12). The use of THF could increase the enantiomeric excess
but resulted in a lower yield (Table 3, entry 13). Next, the influence
of different carboxylate counter-anions was investigated. With
copper(II)-cyclohexanebutyrate a slight increase in the yield and
enantioselectivity was found (Table 3, entry 17) compared to cop-
per(II)-acetate. Interestingly, copper(II)-2-ethylhexanoate resulted
in the same increase in yield but the enantioselectivity increased
even further to 77% ee. Obviously, the presence of a racemic
stereocenter in the ethylhexanoate would result in the formation
of two diastereomeric complexes in the case where one carbo-
xylate ligand is replaced with the diamine ligand. Whether
both diastereomeric complexes have the same catalytic reactivity
and selectivity cannot be determined. Finally, ligand 8 was
investigated under different reaction conditions (Table 3, entries
22–26). Although the obtained enantioselectivities were slightly
higher, the obtained yields were lower than with ligand 7. Hence,
ligand 7 was further used in the reaction of nitromethane with dif-
ferent aldehydes, as show in Table 4.
Acknowledgments
The authors would like to thank the DFG for financial support.
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