An evaluation of some hindered diamines as chiral modifiers of metal-promoted reactions

Article abstract of DOI:10.1071/CH03238

Diamino analogues of the C₂-symmetric chiral diphosphine ligands DuPHOS and BPE have been prepared and evaluated as chiral modifiers of the osmium tetraoxide dihydroxylation of stilbene. NMR experiments showed that these ligands were too bulky to coordinate to osmium. Less hindered analogues of these ligands were prepared and some were shown to act as ligands in dihydroxylation reactions but with poor enantioselectivity (e.e. < 10%). The diamines have also been briefly evaluated as ligands in rhodium-catalyzed hydroformylation and copper-catalyzed phenolic coupling reactions. Once again, only low enantioselectivity was obtained.

Full text of DOI:10.1071/CH03238

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2004, 57, 167–176
An Evaluation of Some Hindered Diamines as Chiral Modifiers
of Metal-Promoted Reactions
Jayamini Illesinghe,A Richard Ebeling,A Brett Ferguson,A Jim Patel,B Eva M. Campi,A
W. Roy Jackson,A,B and Andrea J. RobinsonA,C
A School of Chemistry, Box 23, Monash University, Melbourne VIC 3800, Australia.
B Centre for Green Chemistry, Box 23, Monash University, Melbourne VIC 3800, Australia.
C Author to whom correspondence should be addressed (e-mail: andrea.robinson@sci.monash.edu.au).
Diamino analogues of the C2-symmetric chiral diphosphine ligands DuPHOS and BPE have been prepared and
evaluated as chiral modifiers of the osmium tetraoxide dihydroxylation of stilbene. NMR experiments showed that
these ligands were too bulky to coordinate to osmium. Less hindered analogues of these ligands were prepared and
some were shown to act as ligands in dihydroxylation reactions but with poor enantioselectivity (e.e. < 10%). The
diamines have also been briefly evaluated as ligands in rhodium-catalyzed hydroformylation and copper-catalyzed
phenolic coupling reactions. Once again, only low enantioselectivity was obtained.
Manuscript received: 5 September 2003.
Final version: 4 November 2003.
Introduction
Me-DuPHOS 1[1] and Me-BPE 2[1,2] (Diagram 1) are
readily prepared, commercially available, C2-symmetric
diphosphine ligands which have been used in enantio-
selective RhI-catalyzed hydrogenation reactions.[3] Recently,
a RhI–DuPHOS complex has also been shown to act as
a hydroformylation catalyst in a tandem hydrogenation–
hydroformylation–cyclization sequence to produce cyclic
amino acids.[4] The nitrogen analogue 4 of the phosphine 2
has been prepared previously.[5] Few experimental details
were given and the compound was only evaluated as a chi-
ral ligand for enantioselective Pd-catalyzed allylic alkylation
where enantiomeric excesses of >90% were reported. Chiral
diamines have been shown to be effective ligands in a wide
range of metal-modified reactions.[6] It thus seemed worth-
while to explore the effectiveness of the chiral diamines 3
and 4, Diagram 2, as ligands in other potentially enantio-
selective reactions. One such reaction is the dihydroxylation
of alkenes, e.g. stilbene, using osmium tetraoxide. Tomioka
has reported the preparation and use of the 3,4-diphenyl
analogues of 3 and 4,[7,8] and shown that the BPE ana-
logue 5 gave a high yield (85%) of the stilbene diol with
97% e.e. in a reaction of stilbene with osmium tetraoxide at
−110◦C.[7] Perhaps, surprisingly, it has been reported that
only a low yield (5%) of the stilbene diol was obtained using
the DuPHOS analogue of 5 as a ligand in the dihydroxylation
of stilbene with osmium tetraoxide at −78◦C.[8,9]
P
P
P
P
1
2
Diagram 1.
N
N
Ph
N
N
N
N
Ph
Ph
Ph
3
4
5
Diagram 2.
Results and Discussion
Synthesis of Diamines
Di-tertiary Amines
The (R,R)-Me-BPE diamine analogue 4 was prepared
from the cyclic sulfate 6, which was prepared using a
sequence involving the yeast reduction of hexane-2,5-dione
as described by Burk[2] (Scheme 1). The (2S,5S)-hexanediol
was shown to have an e.e. of >99.9% by HPLC of the
diacetate. Reaction of the cyclic sulfate 6 with benzylamine
followed by Pd-catalyzed hydrogenolysis gave the (2R,5R)-
dimethylpyrrolidine salt 7. The chiral pyrrolidine 7 was con-
verted into 4 by reaction with oxalyl chloride and reduction
of the resulting diamide with lithium aluminium hydride.
Two other reactions, rhodium-catalyzed hydroformyla-
tion[10] and copper-catalyzed phenolic coupling,[11] have
been briefly explored.
© CSIRO 2004
10.1071/CH03238
0004-9425/04/020167

168
J. Illesinghe et al.
The DuPHOS analogue 3 was prepared from the cyclic
Mixed Tertiary and Secondary/Primary Diamines
sulfate 6 by reaction with o-nitroaniline and hydrogenation
of the resulting nitro compound 8 to give the aniline 9, which
was reacted with the cyclic sulfate 6 (Scheme 2). The struc-
ture of 9 was confirmed by a single-crystal X-ray structure
determination of its hydrochloride salt (Fig. 1).
The related homologous tertiary amine 10 was prepared
as shown in Scheme 3. The unsubstituted homologue 12[12]
was prepared from pyrrolidine by the sequence shown in
Scheme 1.
The secondary amine 14 was prepared from the alcohol 11 via
the primary amine 13. The secondary amine 15 was prepared
from the primary amine 9 (Scheme 4).
Diamine–Osmium Tetraoxide Dihydroxylation of Stilbene
Stilbene was reacted with osmium tetraoxide in the presence
of the diamine ligands at a range of temperatures (Scheme 5;
see Table 1). Reactions involving the DuPHOS 3 and BPE
analogues 4, at both −78◦C and room temperature, gave no
conversion into diol 16 (entries 1–4). N-Alkylated pyrrolid-
ines have been successfully used as ligands in this reaction by
several research groups but none involved 2,5-disubstitution
of the pyrrolidine ring. The successful ligands include di-
N-alkylated (Hirama[13] and Corey[14]) and 3,4-disubstituted
(Tomioka[7]) ligands. Several other, less sterically, demand-
ing diamines, e.g. a 1,1ꢀ-binaphthyl-derived azepine,[15] have
given good to excellent yields and enantioselectivity. The
bis(2,5-dibenzylpyrrolidin-1-yl)ethane analogue of 4 has
also been prepared and shown to lead to no conversion in
the osmium tetraoxide oxidation of stilbene.[8]
C11
C8
C7
C9
N1
C6
C1
C10
Cl1
C5
C12
1H NMR experiments were then conducted to establish a
reason for the failure of these reactions. The BPE analogue 4
was added to a solution of the bis(pyridine) osmium glyco-
late 17 in deuterated chloroform at room temperature as it has
been shown that the labile pyridine ligands can be displaced
byaddeddiamineligands.[8] NochangeintheNMRspectrum
was observed when chiral diamine ligand 4 was used. Signals
observed corresponded to either the ligand 4 or the osmium
C4
N2
C2
C3
Fig. 1. ORTEP diagram of the hydrochloride salt of 1-amino-
2-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]benzene 9.
ClϪ
Nϩ
H
H
(i) PPh3, DIAD,
phthalimide
(i) (COCl)2, Py
(i) PhCH2NH2
(i) CH3COCl
NH2
N
N
HN
4
11
9
(ii) Pd/C, H2
(iii) HCl
77%
O
O
(ii) LiAlH4
73%
.
(ii) H2NNH2 H2O
51%
(ii) LiAlH4
38%
S
13
14
O
O
6
7
(i) CH3COCl
Scheme 1.
(ii) LiAlH4
62%
N
HN
15
H2N NO2
63%
6
Pd/C
H2
Scheme 4.
H2N
N
3
6
O2N
N
71%
100%
Ph
OH
Ph
Ph
8
9
diamine-OsO4
Scheme 2.
Ph
HO
16
(i) PPh3, CBr4
(i) ClCOCO2Et
Scheme 5.
N
OH
7
(ii) LiAlH4
42%
(ii)
N
H
Ph
Ph
O
11
31%
diamine
12
N
N
Py
O
O
O
O
Os
O
ϩ
Os
O
N
Py
N
N
O
N
N
(2 equiv.)
Ph
Ph
10
12
17
18
Scheme 3.
Scheme 6.

Hindered Diamines as Chiral Modifiers of Metal-Promoted Reactions
169
glycolate 17. In contrast, when the unsubstituted dipyrroli-
dine 12 was added, peaks due to 17 and 12 were immediately
replaced by a new set of resonances attributed to free pyri-
dine and a new osmium–glycolate complex 18. This reaction
was repeated on a preparative scale (Scheme 6) and 1,2-
di(pyrrolidin-1-yl)ethane osmium(vi) 1,2-diphenylglycolate
18 was isolated and characterized by elemental analysis, and
1H and 13C NMR spectroscopy.
−78◦C but reduced yields from reactions carried out at tem-
peratures above −30◦C due to some decomposition of the
in-situ formed Os–diamine complex.
Molecular modelling of the osmate ester (L–OsO4) of the
BPE analogue 4 and 3,4-diphenyl analogue 5 using Insight II
gave the space-filling molecular mechanics structures shown
in Fig. 2.
The flanking methyl groups in the osmate ester derived
from 4 clearly impede access to the axial oxygen atoms
(only one visible) but allow free access to the equato-
rial oxygens. The osmate ester formed from diamine 5,
in contrast, allows clear access to both equatorial and
axial oxygens. The lack of activity of osmium compounds
derived from 4 thus appears to be associated with lack
of access to an axial oxygen. This result is in agree-
ment with a mechanism proposed by Corey et al.[16] in
which one axial and one equatorial oxygen are involved in
forming a five-membered transition state with the alkene.
Tomioka’s earlier mechanistic suggestion was based on an
X-ray crystal structure of the diamine osmium glycolate
formed from 5, OsO4 and stilbene which showed glycolate
formation via two equatorial oxygen atoms.[7,9,17] Mech-
anistic models have been extensively examined by several
researchers[18] but full agreement on reaction profile has not
yet been achieved.
Reactions of the mixed ligand 10 bearing one 2,5-dimethyl
and one unsubstituted pyrrolidine also gave no conversion
into diol 16 at −78◦C and room temperature (entries 7
and 8), but at −15◦C gave 50% conversion with a small
but observable e.e. (9%) (entry 9). A related diamine, con-
taining 2,5-diphenylpiperazine rings, gave good-to-excellent
enantiomeric excesses at −78◦C.[19]
Use of the diamine 12 in the dihydroxylation reaction led
to complete conversion into the diol 16 at −78◦C (entry 5)
and 37% conversion at room temperature (entry 6). Similar
1
dramatic changes in the H NMR spectrum were observed
during the reaction of 3,4-diphenyl analogue 5 and 17.[8]
This ligand gave high conversions of stilbene at −100 and
Table 1. Amine-modified osmium tetraoxide dihydroxylations of
stilbeneA
Entry
No.
Amine
used
T
[◦C]
Conversion
into 16B
e.e.C
(R,R)
1
2
3
3
3
4
4
−78
RTD
−78
RT
0
0
0
–
–
–
4
0
–
5
6
7
8
12
12
10
10
−78
100
37
0
–
–
–
–
RT
−78
RT
0
9
10
15
−15
50
0
9
–
10
11
12
13
14
15
16
17
18
19
20
RT
14
14
9
9
13
13
–
–
−78
RT
0
0
–
–
–
<1
–
6
–
–
89
66
−60
<5
66
0
28
0
100
100
100
RT
−78
RT
The use of diamines incorporating one 2,5-dimethylpyrro-
lidine and a secondary amine, 14 and 15, also gave no
conversion into the diol 16 at −78◦C or room temperature
(entries 10–12). In contrast, some conversion was achieved
with the two diamines incorporating one 2,5-dimethylpyrro-
lidine and a primary amine, 9 and 13, but no significant
enantiomeric excesses were achieved (<6%; entries 13–16).
These results are consistent with reactions involving pyrro-
lidine (2 equivalents) and OsO4 which under our conditions
gave no diol at −78◦C or room temperature. In contrast, both
butylamine (2 equivalents) and aniline (2 equivalents) gave
100% conversion at room temperature.
−78
RT
(–)-DHQD–PHNE
(–)-DHQD–PHN
RT
RT
A Reactions carried out in THF using a molar ratio of stilbene/
OsO4/ligand of 0.8 : 0.9 : 1.
B Conversion (%) determined from the 1H NMR spectrum of the crude
product.
C Enantiomeric excess (%) determined by HPLC of the purified diol on a
CHIRALCEL OJ chiral column.
D RT refers to room temperature.
E Ratio of stilbene/OsO4/ligand of 0.8 : 0.9 : 2.
Equatorial oxygen
Axial oxygen
Equatorial oxygen
Axial oxygen
CH3
CH3
Ph
Ph
4-OsO4
5-OsO4
Fig. 2. Structures of the osmium complexes of 4 and 5 minimized by molecular mechanics.

170
J. Illesinghe et al.
ReactionsofOsO4 withstilbenewerecarriedoutat−78◦C
air, gave quinone products similar to those obtained by pre-
vious workers.[24] Other attempted reactions of 19a and 19b,
in both air and oxygen atmosphere, led to recovered starting
material.
and room temperature in the absence of added ligand. No
conversion was obtained at −78◦C (entry 17) but 100% con-
version was achieved at room temperature (entry 18). Use
of the Sharpless ligand (–)-DHQD–PHN[20] at room temper-
ature with ligand-to-OsO4 ratios of 2 : 1 or 1 : 1 gave quan-
titative conversions and high enantiomeric excesses (entries
19 and 20).
Use of the mixed pyrrolidine/primary aliphatic amine lig-
and 13 with β-naphthol in air gave a small amount of coupled
product (9%) together with quinones; reactions performed
under an oxygen atmosphere led to only quinones. Use of
this ligand with 19b gave 17% of the coupled product 20b
from a reaction under an oxygen atmosphere for 3 days at
room temperature. The product 20b had an e.e. of 23% (S).
Complete conversion into 20b was obtained from a reac-
tion with air under reflux but the e.e. dropped to 6%. These
results are comparable to those obtained by other workers
using other diamine ligands.[23,24] The use of the trans-
2,5-dimethylpyrrolidine as a chiral motif is therefore not as
successful as the use of either proline-derived diamines[23] or
1,5-diaza-cis-decalins.[24]
The above results are in agreement with our attempted
dihydroxylation reactions at −78◦C. Ligands 3 and 4 show
poor coordination to OsO4 and uncomplexed OsO4 is unre-
active at this temperature. Attempted reactions involving the
hindered diamines as ligands at room temperature led to
ligand–OsO4 reaction in preference to alkene–OsO4 reac-
tion. In support of this proposal, it was found that unreacted
ligands could not be recovered from these reactions. 1H NMR
spectra showed evidence for extensive ligand decomposition
with many new signals being observed.
Conclusion
Use of Diamine Ligands as Chiral Modifiers of Other
Metal-Promoted Reactions
Chiral diamines based on trans-2,5-dimethylpyrrolidine
appear to be too hindered to be of use as chiral modifiers
of osmium tetraoxide dihydroxylations of stilbene. Some
of these diamines show moderate promise as ligands for
enantioselective Rh-catalyzed hydroformylation of styrene
and Cu-catalyzed oxidative coupling of methyl 3-hydroxy-
2-naphthoate 19b.
The diamine 3 was used as a ligand in the rhodium-catalyzed
hydroformylation of styrene. Reaction for 20 h at 50◦C using
400 psi of H2/CO gave a 50% conversion into a 90 : 10
mixture of branched-to-linear aldehydes. Complete conver-
sion into a 88 : 12 branched-to-linear aldehyde mixture was
obtained when a reaction time of 48 h was used.The branched
aldehyde had a 15% e.e. This branched-to-linear ratio and
e.e. are comparable with the results obtained from reactions
involving numerous phosphorus-containing ligands.[10,21,22]
No chiral diamines have previously been reported as ligands
in enantioselective hydroformylation reactions.
Experimental
Syntheses
Melting points are uncorrected. Infrared spectra were recorded on a
Perkin–Elmer 1600 Fourier-transform IR spectrophotometer. 1H and
13C NMR spectra were recorded using Bruker AM-300 and DRX-400
spectrometers for solutions in CDCl3 unless otherwise stated. Mass
spectra (ESI+) were measured on a Bruker BioApex 47 e− Fourier-
transform mass spectrometer with a 4.7 Tesla magnet and an Analytica
electrospraysource. MicroanalyseswereperformedbyCampbellMicro-
analytical Laboratory, Dunedin, New Zealand. Merck Silica Gel 60
(230–400 mesh, No. 9385) was used for flash chromatography.
Diamines 4, 12, and 13 were used as ligands in copper-
catalyzed oxidative coupling of β-naphthol 19a and methyl
3-hydroxy-2-naphthoate 19b under conditions described
previously[11,23,24] (Scheme 7).
The hydroxycopper complex formed from the unsubsti-
tuted dipyrrolidine ligand 12 gave quantitative conversion of
19a into the coupled product 20a when used as a catalyst
for a reaction at room temperature for 18 h. Similar oxidative
coupling of the ester-substituted naphthol 19b needed more
forcing conditions and 100% conversion was only achieved
when the reaction mixture was heated under reflux for 2 days.
In contrast, the BPE analogue 4 formed a ligand–
Cu(OH)Cl complex which failed to act as a catalyst for
oxidative coupling of either 19a or 19b. Reaction of
β-naphthol using 4 as a ligand, under oxygen rather than
(2S,5S)-Hexane-2,5-diol
Hexane-2,5-dione (10.26 mL, 87.6 mmol) was reduced using Baker’s
yeast(105 g;Kitchencollection)asdescribedbyLeiser[25] andShort.[26]
The mixture was filtered through a Celite plug and the filtrate was con-
tinuously extracted for 2 days with dichloromethane. The extract was
dried (MgSO4), filtered, and evaporated under reduced pressure to yield
a light brown oil (8.93 g). The 1H NMR spectrum of this crude oil
showed hexane-2,5-diol together with butane-2,3-diol (<10%). Purifi-
cation by column chromatography (SiO2; ethyl acetate/hexane, 1:1)
initially afforded butane-2,3-diol as a mixture with the desired prod-
uct. δH (300 MHz) 2.73 (2 H, br s, 2 × OH), 3.58–3.46 (2 H, m, H2
and H3), 1.17 (6 H, d, J 6.1, H1 and H4). δC (100 MHz) 72.7 (C2 and
C3), 19.5 (C1 and C4). m/z (ESI+, MeOH) 112.8 [M + Na]+•. Analy-
sis by GC indicated only two components: (Chrompack–WCOT Fused
silica coating, CP Chirasil-Dex CB DF = 0.25; 50–200◦C, 5◦C min−1):
Rt 12.4 min [89% for (2R,5R)] and Rt 13.2 min [11% for (2S,5S)].
The spectroscopic data were consistent with the literature.[27]
R
R
.
CuCl(OH) diamine
OH
OH
2
Oxidant
OH
19a R = H
19b R = CO2Me
Further elution gave (2S,5S)-hexane-2,5-diol which solidified upon
R
25
25
standing (4.77 g, 46%). [α]D +33.4◦ (c 8.6 in CHCl3) (lit.[25,26] [α]D
+35◦) (c 9 in CHCl3). mp 52–54◦C (lit.[25] 50–53◦C). δH (300 MHz)
3.86–3.74 (2 H, m, H2 and H5), 1.60–1.42 (4 H, m, H3 and H4),
20
Scheme 7.

Hindered Diamines as Chiral Modifiers of Metal-Promoted Reactions
171
1.20 (6 H, d, J 6.3, H1 and H6). δC (100 MHz) 68.6 (C2 and C5),
36.4 (C3 and C4), 24.1 (C1 and C6). Mass spectrum (ESI+, MeOH)
m/z 140.9 [M + Na]+•. The spectroscopic data were consistent with
literature data.[25,26]
Using the modified method of Masamune et al.,[26] the
N-benzylpyrrolidine (2.31 g, 12.22 mmol) was dissolved in methanol
(20 mL) and the solution transferred to a Fisher–Porter tube to which
10% Pd/C (30 mg) was added. The mixture was stirred under hydrogen
(100 psi) for 18 h.The catalyst was removed by filtration through a Celite
pad with cooling (0◦C). Dry HCl gas was bubbled into the filtrate for
1 h and the solution was evaporated to dryness to give the amine salt 7
The (2S,5S)-hexane-2,5-diol (500 mg, 4.24 mmol) was acetylated
using acetyl chloride (0.6 mL, 8.47 mmol) in dichloromethane (25 mL)
at room temperature for 18 h to give (2S,5S)-hexane-2,5-diiyl diacetate
as a yellow oil (810 mg, 95%). δH (300 MHz) 4.96–4.82 (2 H, m, H2
and H5), 2.04 (6 H, s, 2 × COCH3), 1.70–1.42 (4 H, m, H3 and H4),
1.22 (6 H, d, J 6.3 H1 and H6). δC (100 MHz) 170.7 (CO), 70.7 (C2
and C5), 31.9 (C3 and C4), 21.6 (COCH3), 20.2 (C1 and C6). m/z
(ESI+, MeOH) 225.0 [M + Na]+•. Analysis by GC indicated one com-
ponent (Chrompack–WCOT fused silica coating, CP Chirasil-Dex CB
DF = 0.25; 50–200◦C, 5◦C min−1): 17.04 min [>99.9% for (2S,5S);
>99.9% e.e.].
25
as a colourless solid (1.50, 90%). [α]D +5.01◦ (c 3.0, CH2Cl2) (lit.[26]
25
[α]D +5.57◦) (c 1.18, CH2Cl2). mp 196–202◦C (lit.[26] 197–200◦C).
δH (300 MHz) 9.52 (2 H, br s, 2 × NH), 3.94–3.72 (2 H, m, H2 and H5),
2.30–2.14 (2 H, m, H3 and H4), 1.78–1.60 (2 H, m, H3 and H4), 1.53
(6 H, d, J 6.7, 2 × CH3). δC (100 MHz) 55.3 (C2 and C5), 32.7 (C3 and
C4), 18.7 (2 × CH3). m/z (GCMS, MeOH) 99 [M + H − HCl]+•. The
spectroscopic data were consistent with literature data.[26]
1,2-Bis[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]ethane 4
(2S,5S)-Hexane-2,5-diol Cyclic Sulfite
Pyridine (15.7 mL, 195.8 mmol) was added to
a solution of
the dimethylpyrrolidine hydrochloride 7 (2.67 g, 19.58 mmol) in
dichloromethane (150 mL) at −78◦C under a N2 atmosphere, and
the resulting mixture stirred for 15 min. Oxalyl chloride (0.85 mL,
9.79 mmol) was added dropwise and the mixture stirred for 2 days.
The reaction was quenched with water (100 mL) and diluted with
dichloromethane (150 mL). The organic layer was separated and
washed successively with 1 M HCl (3 × 150 mL), water (150 mL), and
brine (150 mL), dried over MgSO4, filtered, and evaporated to give
the diamide, namely 1,2-bis[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]-1,2-
Synthesis of the cyclic sulfite was achieved using the method described
by Caron and Kazlauskas.[28] Thionyl chloride (1.41 mL, 19.37 mmol)
was added dropwise to a cooled solution (0◦C) of (2S,5S)-hexane-2,5-
diol (1.53 g, 12.95 mmol) in tetrachloromethane (25 mL). The reaction
mixture was brought to ambient temperature and stirred at reflux for
a further hour. The mixture was allowed to cool to 25◦C before being
evaporatedunderreducedpressuretogivethecyclicsulfiteasabrownoil
(1.85 g, 87%). vmax (neat)/cm−1 2997s, 2922m, 1450m, 1378s, 1350w,
1200s, 1122m, 1089m, 905s, 856s, 816m, 739s. δH (300 MHz) 5.16
(1 H, m, H2 or H5), 4.33 (1 H, m, H2 or H5), 1.90–1.50 (4 H, m, H3
and H4), 1.32 (6 H, d, J 6.4, H1 and H6). δC (100 MHz), 73.1, 70.0 (C2
and C5), 36.0, 34.1 (C3 a•nd C4), 22.6, 22.3 (C1 and C6). m/z (ESI+,
25
dioxoethane as a colourless solid (1.81 g, 74%). [α]D −220.5◦ (c 1.03
•
in CHCl3), mp 184–186◦C (Found: 275.1727. [M + Na]+ requires
275.1735). vmax (KBr)/cm−1 2963s, 2874m, 1654m, 1629s, 1602m,
1560m, 1481s, 1444s, 1375s, 1308s, 1209m, 1163s, 1087s, 1033s, 967w,
916w, 800w, 772s, 694s. δH (300 MHz) 4.48–4.38 (2 H, m, H2ꢀ and H5ꢀ),
4.34–4.24 (2 H, m, H2ꢀ and H5ꢀ), 2.34–2.00 (4 H, m, H3ꢀ and H4ꢀ), 1.66–
1.52 (4 H, m, H3ꢀ and H4ꢀ), 1.24 (6 H, d, J 6.4, 2 × CH3), 1.14 (6H,
d, J 6.6, 2 × CH3). δC (100 MHz) 163.0 (C1 and C2), 54.1, 53.8 (C2ꢀ
MeOH) 186.8 [M + Na]+
.
(2S,5S)-Hexane-2,5-diol Cyclic Sulfate 6
The cyclic sulfate 6 was prepared using to the method described by
Burk et al.[3] Tetrachloromethane (20 mL), acetonitrile (20 mL), and
water (25 mL) were added to the cyclic sulfite (1.85 g, 11.25 mmol) and
the mixture cooled to 0◦C. Ruthenium(iii) chloride (30 mg, 0.14 mmol)
and sodium periodate (4.81 g, 22.5 mmol) were added and the mixture
was stirred at 25◦C for 1 h. After quenching the reaction with water
(100 mL), the mixture was extracted with diethyl ether (4 × 50 mL).
The combined ether extracts were washed with brine (2 × 25 mL), dried
(MgSO4), filtered, and evaporated. The resulting solid was filtered
through a silica plug to remove any ruthenium salts. The filtrate was
evaporated under reduced pressure to afford the cyclic sulfate (6) as
and C5ꢀ), 31.4, 29.2 (C3ꢀ and C4ꢀ), 22.8, 18.9 (4 × CH3). m/z (ESI+,
•
MeOH) 253.2 [M + H]+
.
A solution of the diamide (1.21 g, 4.77 mmol) dissolved in THF
(10 mL) was added to a refluxing solution of LiAlH4 (900 mg,
23.85 mmol) in THF (200 mL). The reaction mixture was vigorously
stirred at this temperature for a further 2 h. The mixture was cooled to
0◦C and sodium sulfate decahydrate (NaSO4 · 10H2O) was added until
no further gas evolution was observed. The resulting precipitate was
filtered off and washed with THF (100 mL). The filtrate was evaporated
25
to give the diamine 4 as a yellow oil (1.07 g, 99%), [α]D −181.1◦ (c 3.0
25
colourless crystals (1.32 g, 65%). [α]D +33.0◦ (c 1.15, CHCl3) (lit.[3]
25
in CHCl3) (lit.[5] [α]D −183◦) (c 3.05 in CHCl3) (Found: 225.2321.
25
[α]D +32.4◦) (c 1 in CHCl3). mp 108–112◦C (lit.[3] 109.5–110.5◦C).
•
[M + H]+ requires 225.2331). vmax (neat)/cm−1 2955s, 2877s, 2811s,
δH (300 MHz) 4.82 (2 H, m, H2 and H5), 2.08–1.82 (4 H, m, H3 and H4),
2688w, 1667w, 1638w, 1455m, 1300s, 1350m, 1322m, 1294m, 1194w,
1166w, 1116m, 1005w, 966w, 866m. δH (300 MHz) 3.24–3.02 (4 H, m,
H2ꢀ and H5ꢀ), 2.79–2.54 (4 H, m, H1 and H2), 2.08–1.92 (4 H, m, H3ꢀ
and H4ꢀ), 1.45–1.33 (4 H, m, H3ꢀ and H4ꢀ), 1.01 (12 H, d, J 6.4, 4 ×
CH3). δC (100 MHz) 55.2 (C2ꢀ and C5ꢀ), 47.1 (C1 and C2), 31.0 (C3ꢀ
and C4ꢀ), 17.2 (4 × CH3). m/z (ESI+, MeOH) 225.2 [M + Na]+•. The
NMR data were consistent with the literature.[5]
1.44 (6 H, d, J 6.4, H1 and H6). δC (100 MHz) 82.1 (C2 and C5), 35.3
•
(C3 and C4), 22.4 (C1 and C6). m/z (ESI+, MeOH) 202.9 [M + Na]+
.
The spectroscopic data were consistent with the literature.[3]
(2R,5R)-2,5-Dimethylpyrrolidine Hydrochloride 7
A mixture of cyclic sulfate 6 (7.78 g, 43.2 mmol) and benzylamine
(23.16 mL, 216 mmol) was stirred at ambient temperature over 96 h
using a modification to the method of Masamune et al.[26] The reaction
was quenched with sodium hydroxide (2 M, 300 mL) and the resulting
solution was extracted with dichloromethane (3 × 250 mL) to remove
the excess benzylamine. The aqueous layer was continuously extracted
overnight to give (2R,5R)-N-benzyl-2,5-dimethylpyrrolidine as a
2-[(2R,5R)-2,5-Dimethylpyrrolidin-1-yl]-1-nitrobenzene 8
The nitrophenyl pyrrolidine 8 was prepared using the modified method
of Cahill et al.[29] 2-Nitroaniline (77 mg, 0.56 mmol) was added to a
solution of the cyclic sulfate 6 (100 mg, 0.56 mmol) in THF (20 mL).
The resulting yellow solution was refluxed for 2 days, after which time
80% sodium hydride (101 mg, 3.30 mmol) was added. After reflux-
ing for a further 24 h, the reaction was quenched with 10% NH4Cl
(20 mL). The THF was removed under reduced pressure and the result-
ing aqueous solution extracted with dichloromethane (3 × 100 mL).
The combined organic extracts were successively washed with water
(100 mL) and brine (100 mL), dried with MgSO4, and filtered, and evap-
orated to afford an orange semi-solid (95 mg). Purification by column
chromatography (SiO2; ethyl acetate/hexane, 1 : 10) gave the nitro com-
25
25
yellow oil (7.05 g, 86%). [α]D −112.0◦ (c 2.1, MeOH) (lit.[26] [α]D
−109.7◦) (c 1.97 in MeOH). δH (300 MHz) 7.40–7.17 (5 H, m, ArH),
3.84 (1 H, d, J 13.7, CH2Ph), 3.51 (1 H, d, J 13.7, CH2Ph), 3.10–2.98
(2 H, m, H2 and H5), 2.01–1.91 (2 H, m, H3 and H4), 1.44–1.29 (2 H, m,
H3 and H4), 0.97 (6 H, d, J 6.4, 2 × CH3). δC (100 MHz) 140.9 (C1ꢀ),
128.7, 128.2 (C2ꢀ, C3ꢀ, C5ꢀ, and C6ꢀ), 126.6 (C4ꢀ), 55.3 (C2 and C5),
52.0 (CH2Ph), 31.3 (C3 and C4), 17.4 (2 × CH3). m/z (ESI+, MeOH)
190.1 [M + H]+•.The spectroscopic data were consistent with literature
data.[26]
25
pound 8 as a yellow oil (78 mg, 63%). [α]D −1803.7◦ (c 0.41 in CHCl3)

172
J. Illesinghe et al.
•
(Found: 243.1101. [M + Na]+ requires 243.1109). vmax (neat)/cm−1
2956s, 2855s, 2356s, 1600s, 1561m, 1505s, 1477m, 1450m, 1350m,
1272s, 1172m, 1150m, 1044m, 922w, 838m. δH (300 MHz) 7.82 (1 H,
dd, J 8.2, 1.7, H3), 7.39 (1 H, t, J 7.0, H5), 7.06 (1 H, dd, J 8.5, 1.2, H6),
6.80 (1 H, t, J 7.0, H4), 4.10–3.82 (2 H, br s, H2ꢀ and H5ꢀ), 2.28–2.10
(2H, m, H3ꢀ and H4ꢀ), 1.68–1.46 (2 H, m, H3ꢀ and H4ꢀ), 1.22–0.80 (6 H,
br m, 2 × CH3). δC (100 MHz) 140.9 (ArC), 132.9, 126.7, 121.7, 117.6
(2 H, m, H2ꢀ and H5ꢀ), 2.20–2.02 (4 H, m, H3ꢀ and H4ꢀ), 1.58–1.32 (4
H, m, H3ꢀ and H4ꢀ), 1.10 (6 H, d, J 5.8, 2 × CH3), 0.58 (6 H, d, J 6.4,
2 × CH3). δC (100 MHz) 140.4 (C1 and C2), 120.6 (C4 and C5), 120.0
(C3 and C6), 52.1, 51.9 (C2ꢀ and C5ꢀ), 33.2, 32.3 (C3ꢀ and C4ꢀ), 19.9,
•
19.6 (2 × CH3). m/z (ESI+, MeOH) 273.2 [M + H]+
recently.[30]
.
The single-crystal X-ray structure of the diamine 3 has been reported
(ArCH), 55.8 (C2ꢀ and C5ꢀ), 30.1 (C3ꢀ and C4ꢀ), 20.1 (2 × CH3). m/z
•
(ESI+, MeOH) 221.1 [M + H]+
.
2-[(2R,5R)-2,5-Dimethylpyrrolidin-1-yl]ethanol 11
Pyridine(7.0 mL, 87.0 mmol)wasaddeddropwisetoastirredsolutionof
(2R,5R)-2,5-dimethylpyrrolidine hydrochloride 7 (2.38 g, 17.47 mmol)
in dichloromethane/ether (2 : 1, 100 mL) at 0◦C. After stirring for
15 min, ethyl oxalyl chloride (1.94 mL, 17.4 mmol) was added drop-
wise and an immediate formation of white precipitate was observed.
The reaction was allowed to stir at room temperature for 18 h. It was
acidified with 1 M HCl (75 mL) and extracted with dichloromethane
(3 × 75 mL).The combined organic layers were dried (MgSO4), filtered,
and evaporated to give ethyl 2-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]-
1-Amino-2-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]benzene 9
The nitrophenyl pyrrolidine 8 (441 mg, 2.00 mmol) was dissolved in
benzene (10 mL) and placed in a Fisher–Porter tube to which 10% Pd/C
(10 mg) was added.The reaction mixture was pressurized with hydrogen
gas to 60 psi and stirred overnight.The Pd/C was removed using a Celite
plug and the filtrate concentrated to give an orange oil. The residual oil
was purified using column chromatography (SiO2; ethyl acetate/hexane,
1 : 10) to give the aminophenyl pyrrolidine 9 as a red/orange oil (380 mg,
•
25
100%). [α]D +79.5◦ (c 0.86 in CHCl3). (Found: 191.1535. [M + H]+
25
2-oxoethanoate as a yellow oil (2.87 g, 83%). [α]D −88.4◦ (c 2.0
requires 191.1548). vmax (neat)/cm−1 3433s, 3333s, 3055w, 3022w,
2955s, 2855s, 2822m, 2600w, 1605s, 1500s, 1455s, 1366s, 1322m,
1277s, 1250s, 1150s, 1133m, 1050m, 1016w, 922w, 844w, 744s. δH
(300 MHz) 6.95–6.82 (2 H, m, H4 and H5), 6.75–6.65 (2 H, m, H3 and
H6), 3.98–3.60 (4 H, m, H2ꢀ, H5ꢀ, and NH2), 2.24–2.00 (2 H, m, H3ꢀ
and H4ꢀ), 1.58–1.38 (2 H, m, H3ꢀ and H4ꢀ), 1.02–0.90 (3 H, m, CH3),
0.80–0.60 (3 H, m, CH3). δC (100 MHz) 143.2, 133.5 (C1 and C2),
123.6, 123.2 (C3 and C6), 118.1, 115.2 (C4 and C5), 54.3, 52.8 (C2ꢀ
•
in CHCl3) (Found: 222.1093. [M + Na]+ requires 222.1106). vmax
(neat)/cm−1 2967s, 2878s, 1738s, 1650s, 1433s, 1383m, 1300m, 1277s,
1183s, 1161s, 1088s, 1017s, 983m, 911m, 861s. δH (300 MHz) 4.42–
4.24 (4 H, m, H2ꢀ, H5ꢀ, and OCH2CH3), 2.34–2.04 (2 H, m, H3ꢀ and
H4ꢀ), 1.68–1.55 (2 H, m, H3ꢀ and H4ꢀ), 1.37 (3 H, t, J 7.2, OCH2CH3),
1.22 (3 H, d, J 6.4, CH3), 1.15 (3 H, d, J 6.3, CH3). δC (100 MHz)
162.5, 159.2 (C1 and C2), 61.9 (OCH2CH3), 53.9 (C2ꢀ and C5ꢀ), 30.8,
28.8 (C3ꢀ and C4ꢀ), 22.3, 18.6 (2 × CH3), 14.0 (OCH2CH3). m/z (ESI+,
and C5ꢀ), 32.8, 32.1 (C3ꢀ and C4ꢀ), 18.6 (2 × CH3). m/z (ESI+, MeOH)
•
MeOH) 222.1 [M + Na]+
.
•
191.0 [M + H]+
.
The LiAlH4 reduction was carried out as described previously using
ethyl 2-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]-2-oxoethanoate (1.78 g,
8.92 mmol). Workup gave an orange oil which was purified using col-
umn chromatography (SiO2; ethyl acetate followed by NH3 in methanol)
Dry HCl gas was passed through a stirred solution of 1-amino-2-
[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]benzene 9 (200 mg, 1.05 mmol)
in methanol (20 mL). The mixture was concentrated to give 1-amino-
2-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]benzene hydrochloride salt as
a colourless solid (269 mg, 93%), mp 182–184◦C (Found: 191.1541.
25
to obtain the pyrrolidinylethanol 11 (660 mg, 52%), [α]D −55.1◦
•
(c 2.3 in CHCl3) (Found: 144.1382. [M + H]+ requires 144.1388).
•
[M + H − HCl]+ requires 191.1548). vmax (KBr)/cm−1 3322s, 3200s,
vmax (NaCl)/cm−1 3383bs, 2963s, 2360s, 2341m, 1654s, 1560w, 1456s,
1379s. δH (300 MHz) 3.63–3.48 (1 H, m, H1), 3.23 (1 H, br s, OH), 3.23–
3.05 (1 H, m, H2), 2.80–2.64 (2 H, m, H2ꢀ and H5ꢀ), 2.07–1.89 (2 H,
m, H3ꢀ and H4ꢀ), 1.46–1.30 (2 H, m, H3ꢀ and H4ꢀ), 0.97 (6 H, d, J 6.3,
2977m, 2822w, 2733w, 2556bm, 1661s, 1605s, 1500s, 1466m, 1444s,
1383w, 1311w, 1277w, 1022m, 783s, 755s. δH (300 MHz, CD3OD) 7.32
(1 H, ddd, J 8.4, 6.9, 1.3, H6), 7.26 (1 H, d, J 7.3, 1.5, H4), 7.11 (1 H, ddd,
J 8.4, 6.9, 1.3, H3), 7.03 (1 H, d, J 7.3, 1.5, H5), 4.35–4.20 (1 H, m, H2ꢀ
or H5ꢀ), 4.20–4.13 (1 H, m, H2ꢀ or H5ꢀ), 2.55–2.40 (1 H, m, H3ꢀ or H4ꢀ),
2.40–2.25 (1 H, m, H3ꢀ or H4ꢀ), 2.08–1.88 (1 H, m, H3ꢀ or H4ꢀ), 1.88–
1.72 (1 H, m, H3ꢀ or H4ꢀ), 1.32 (3 H, d, J 6.1, CH3), 0.86 (3 H, d, J 6.7,
CH3). δC (100 MHz, CD3OD) 141.2, 130.0 (C1 and C2), 131.8, 127.0,
124.9, 123.5 (ArCH), 63.6, 61.9 (C2ꢀ and C5ꢀ), 33.7 (C3ꢀ and•C4ꢀ), 19.9,
2 × CH3). δC (100 MHz) 59.2 (C1), 55.2 (C2ꢀ and C5ꢀ), 48.4 (C2), 31.2
•
(C3ꢀ and C4ꢀ), 17.7 (2 × CH3). m/z (ESI+, MeOH) 144.0 [M + H]+
.
1,2-Di(pyrrolidin-1-yl)ethane 12
Oxalyl chloride (6.1 mL, 70.1 mmol) was added dropwise to a stirred
solution of pyrrolidine (11.4 mL, 142 mmol) and triethylamine (25 mL,
185 mmol) in dichloromethane (70 mL) at 0◦C. The solution was stirred
for 12 h and then diluted with dichloromethane (50 mL). The mix-
ture was acidified with 1 M HCl and extracted with dichloromethane
(3 × 50 mL). The combined organic layers were washed with water
(50 mL) and brine (50 mL) dried (MgSO4), filtered, and evaporated to
give 1,2-dioxo-1,2-di(pyrrolidin-1-yl)ethane as a cream solid (11.7 g,
85%), mp 73–75◦C (lit.[31] 77–78◦C). δH (400 MHz) 3.58–3.47 (8 H, m,
H1ꢀ and H4ꢀ), 2.05–1.88 (8 H, m, H2ꢀ and H3ꢀ). δC (100 MHz) 163.3 (C1
and C2), 47.1, 42.3 (C1ꢀ and C4ꢀ), 26.1, 24.1 (C2ꢀ and C3ꢀ). m/z (ESI+,
MeOH) 218.8 [M + Na]+•. The spectroscopic data were consistent with
literature data.[31]
18.7 (2 × CH3). m/z (ESI+, MeOH) 190.8 [M + H − HCl]+
.
Slow evaporation of a solution of the hydrochloride salt in a
diethyl ether/hexane mixture gave crystals suitable for X-ray structure
determination.
1,2-Bis[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]benzene 3
The aminophenyl pyrrolidine 9 (400 mg, 2.11 mmol) was added to a
solution of the cyclic sulfate 6 (379 mg, 2.11 mmol) in THF (100 mL).
The resulting orange solution was refluxed for 2 days after the addition
of 80% sodium hydride (633 mg, 21.10 mmol). As TLC indicated the
presence of unreacted aminophenyl pyrrolidine 9, more cyclic sulfate 6
(379 mg, 2.11 mmol) dissolved inTHF (30 mL) was added. The mixture
was stirred at reflux for a further 2 days and quenched with 10% NH4Cl
(30 mL).TheTHF was removed under reduced pressure and the aqueous
mixture extracted with dichloromethane (3 × 100 mL). The combined
organic layers were washed with water (100 mL) and brine (100 mL),
dried with MgSO4, filtered, and evaporated to afford a brown semi-solid.
Purification using column chromatography (ethyl acetate/hexane, 1 : 10)
A suspension of LiAlH4 (4.81 g, 127.4 mmol) in THF (70 mL) was
added to a stirred solution of 1,2-dioxo-1,2-di(pyrrolidin-1-yl)ethane
(5.00 g, 25.5 mmol) in THF (50 mL) at 0◦C under an atmosphere of
nitrogen. The mixture was stirred for 2 h at reflux. The mixture was
cooled to 0◦C before NaSO4 · 10H2O was added until no further gas
evolution was observed. The resulting suspension was filtered off and
washed withTHF (50 mL). The filtrate was evaporated to afford the title
compound as a pale yellow oil (2.00 g, 47%). δH (400 MHz) 2.65 (4 H,
s, H1 and H2), 2.48–1.82 (8 H, m, H1ꢀ and H4ꢀ), 1.82–1.74 (8 H, m,
H2ꢀ and H3ꢀ). δC (100 MHz) 55.9 (C1 and C2), 54.8 (C1ꢀ and C4ꢀ), 23.7
25
gave the diamine 3 as a colourless solid (408 mg, 71%). [α]D +18◦
•
(c 0.51 in CHCl3), mp 108–112◦C (Found: 273.2320. [M + H]+
requires 273.2331). vmax (KBr)/cm−1 2955s, 2922s, 2867s, 2811s,
1583s, 1494s, 1450s, 1367s, 1322m, 1294s, 1256m, 1194w, 1150s,
1100w, 1044w, 994m, 956w, 916w, 744s. δH (300 MHz) 6.84 (4 H,
s, H3, H4, H5, and H6), 4.18–4.06 (2 H, m, H2ꢀ and H5ꢀ), 3.80–3.68
•
(C2ꢀ and C3ꢀ). m/z (ESI+, MeOH) 190.8 [M + Na]+ . The 1H NMR
data were consistent with literature.[12]

Hindered Diamines as Chiral Modifiers of Metal-Promoted Reactions
173
1-[(2R,5R)-2,5-Dimethylpyrrolidin-1-yl]-2-(pyrrolidin-
1-yl)ethane 10
with dichloromethane (3 × 20 mL). The combined organic layers were
washed with water, dried with MgSO4, filtered, and evaporated to
25
afford the amine 13 as a orange oil (513 mg, 99%), [α]D −112◦
A solution of triphenylphosphine (915 mg, 3.49 mmol) in anhydrous
diethyl ether (15 mL) was added to a cooled (0◦C) and stirred solu-
tion of 2-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]ethanol 11 (500 mg,
3.49 mmol) and carbon tetrabromide (1.16 g, 3.49 mmol) in anhydrous
diethyl ether (20 mL). External cooling was discontinued and the reac-
tion mixture was heated at reflux for 1 h. The mixture was then cooled
in ice before a small sample was removed and concentrated under
vacuumtogive2-bromo-1-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]ethane
and triphenylphosphine oxide (identified by 1H NMR spectroscopy of
the crude residue) as a pale brown solid. δH (300 MHz) 3.41 (2 H, t, J 7.9,
H1), 3.16–3.06 (2 H, m, H1ꢀ and H5ꢀ), 2.93 (2 H, dt, J 7.9, 2.1, H2),
•
(c 0.5 in CHCl3) (Found: 143.1546. [M + H]+ requires 143.1548).
vmax (neat)/cm−1 3288bs, 3189bs, 2953s, 2866s, 2822s, 1718s, 1664s,
1534m, 1450s, 1375s, 1238s, 1112s, 1036s, 927s. δH (300 MHz) 3.10–
2.98 (2 H, m, H2ꢀ and H5ꢀ), 2.77 (2 H, br s, NH2), 2.68–2.48 (2 H, m,
H1 and H2), 2.08–1.92 (2 H, m, H1 and H2), 1.42–1.20 (4 H, m, H3ꢀ
and H4ꢀ), 0.96 (6 H, d, J 6.4, 2 × CH3). δC (100 MHz) 55.2 (C2ꢀ and
C5ꢀ), 31.04 (C1, C2, C3ꢀ, and C4ꢀ), 17.2 (2 × CH3). m/z (ESI+, MeOH)
•
142.8 [M + H]+
.
2-[(2R,5R)-Dimethylpyrrolin-1-yl]-1-ethylaminoethane 14
2.08–1.98 (2 H, m, H3ꢀ and H4ꢀ), 1.45–1.35 (2 H, m, H3ꢀ and H4ꢀ), 1.01
Acetyl chloride (0.15 mL, 2.05 mmol) was added dropwise to a cooled
(0◦C) stirred solution of 1-amino-2-[(2R,5R)-2,5-dimethylpyrrolidin-
1-yl]ethane 13 (292 mg, 2.05 mmol) and pyridine (0.18 mL, 2.26 mmol)
in dichloromethane/ether (2 : 1, 20 mL). The mixture was brought to
room temperature and stirred for 4 h. The reaction was quenched with
water (20 mL) and extracted with dichloromethane (3 × 20 mL). The
combined organic layers were dried with MgSO4, filtered, and eva-
porated to give a black oil (100 mg). The 1H NMR spectrum of this
oil showed mainly unreacted pyridine, together with other impuri-
ties. The aqueous layer was basified using NaOH (4 M) and extracted
with dichloromethane (3 × 20 mL). The organic extract was dried
(MgSO4), filtered, and evaporated to give 1-acetylamino-2-[(2R,5R)-
2,5-dimethylpyrrolidin-1-yl]ethane as an orange oil (192 mg, 51%),
•
(6 H, d, J 6.3, 2 × CH3). m/z (ESI+, MeOH) 208.0 [M(81Br) + H]+
,
206.0 [M(79Br) + H]+•. The bromo compound was extremely unstable
and the crude solution was used immediately in the next step.
Pyrrolidine (0.32 mL, 3.84 mmol) was added to this cold reaction
mixture and the mixture brought to room temperature. The mixture was
stirred for 18 h before the solvent was evaporated. The resulting brown
oil was dissolved in methanol (50 mL) and dry HCl gas was bubbled
through it (20 min).The methanol was evaporated, the resulting black oil
was dissolved in water (30 mL) and dichloromethane (30 mL), and the
layers were separated and extracted with dichloromethane (3 × 30 mL).
The aqueous layer was reduced under vacuum, the pH was adjusted to
11 using NaOH pellets and the mixture extracted with dichloromethane
(3 × 50 mL). The combined organic layers were washed with water,
brine, dried (MgSO4), filtered, and evaporated to give a dark brown
oil. This oil was run through a silica plug (ethyl acetate followed
by NH3 in methanol) to give the amine 10 as a brown oil (214 mg,
[α]D −127.6◦ (c 0.21 in CHCl3) (Found: 185.1653. [M + H]+• requires
25
185.1653). vmax (neat)/cm−1 3289bs, 3089w, 2967s, 2922s, 2867s,
2822s, 1722s, 1650s, 1550s, 1450s, 1372s, 1277s, 1167m, 1111m,
1033w. δH (300 MHz) 3.56–3.44 (1 H, m, H2ꢀ or H5ꢀ), 3.18–2.98 (3 H,
m, H1 and H2ꢀ or H5ꢀ), 2.69–2.61 (2 H, m, H2), 2.08–1.92 (5 H, m,
COCH3, H3ꢀ and H4ꢀ), 1.44–1.32 (2 H, m, H3ꢀ and H4ꢀ), 0.97 (6 H, d,
J 6.3, 2 × CH3). δC (100 MHz) 170.5 (CO), 55.1 (C2ꢀ and C5ꢀ), 45.8
•
25
31%), [α]D −80.5◦ (c 0.2 in CHCl3) (Found: 197.2010. [M + H]+
requires 197.2018). vmax (neat)/cm−1 2955s, 2800s, 2689m, 1456s,
1372s, 1344m, 1327m, 1294m, 1238w, 1194s, 1122s, 1000m, 967s,
922m, 887m, 722s, 694s. δH (300 MHz) 3.12–3.00 (2 H, m, H2ꢀ and
H5ꢀ), 2.86–2.52 (8 H, m, H2ꢀꢀ, H5ꢀꢀ, H1 and H2), 1.88–1.72 (4 H, m,
H3ꢀꢀ and H4ꢀꢀ), 2.08–1.92 (2 H, m, H3ꢀ and H4ꢀ), 1.46–1.32 (2 H, m, H3ꢀ
and H4ꢀ), 0.99 (6 H, d, J 6.2, 2 × CH3). δC (100 MHz) 55.7 (C2ꢀ and
(C2), 37.9 (C1), 31.0 (C3ꢀ and C4ꢀ), 23.6 (CH3CO), 17.3 (2 × CH3).
•
m/z (ESI+, MeOH) 184.9 [M + H]+
.
1-Acetylamino-2-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]ethane
(192 mg, 1.05 mmol) was reduced with LiAlH4 (199 mg, 5.27 mmol) as
described above. The reaction mixture was refluxed for 24 h and worked
up with Na2SO4 · 10H2O as described previously to give the amine 14
C5ꢀ), 54.6 (C2ꢀꢀ and C5ꢀꢀ), 55.1, 46.4 (C1 and C2), 30.6, 23.4 (C3ꢀ, C4ꢀ,
•
C3ꢀꢀ, and C4ꢀꢀ), 16.7 (2 × CH3). m/z (ESI+, MeOH) 196.9 [M + H]+
.
25
as a yellow oil (133 mg, 75%), [α]D −94.7◦ (c 0.95 in CHCl3) (Found:
•
171.1855. [M + H]+ requires 171.1861). vmax (neat)/cm−1 3300bs,
1-Amino-2-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]ethane 13
1455s, 1372s, 1327m, 1133m, 1122s, 733w. δH (300 MHz) 3.08–2.98
(2 H, m, H2ꢀ and H5ꢀ) and 2.82–2.48 (6 H, m, CH2CH3, H1 and H2),
2.08–1.90 (2 H, m, H3ꢀ and H4ꢀ), 1.42–1.28 (2 H, m, H3ꢀ and H4ꢀ), 1.12
(3 H, t, J 7.2, CH2CH3), 0.96 (6 H, d, J 6.2, 2 × CH3). δC (100 MHz)
55.3 (C2ꢀ and C5ꢀ), 48.1, 46.8, 44.3 (CH2CH3, C1 and C2), 31.0 (H3ꢀ
Solutionsof2-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]ethanol11(746 mg,
5.21 mmol) dissolved in distilled THF (5 mL) and diisopropyl azodi-
carboxylate (DIAD; 1.03 mL, 5.21 mmol) dissolved in distilled THF
(5 mL) were added dropwise simultaneously under a nitrogen atmo-
sphere to a stirred mixture of phthalimide (767 mg, 5.21 mmol) and
triphenylphosphine (1.37 g, 5.21 mmol) in freshly distilledTHF (20 mL)
at 0◦C. Stirring was continued at ambient temperatures for 3 days
and the solvent was removed under reduced pressure to give a yel-
low oil. The oil was redissolved in methanol (50 mL) before adding
hydrazine hydrate (0.3 mL, 6.25 mmol) and refluxing for a further 8 h.
Concentrated HCl (5 mL) was added and the mixture was refluxed
for 2 h. After cooling the mixture, the methanol was removed under
reduced pressure. The resulting semi-solid was dissolved in water
and extracted with dichloromethane (3 × 100 mL). The aqueous layer
was concentrated to give 1-amino-2-[(2R,5R)-2,5-dimethylpyrrolidin-
and H4ꢀ), 17.1 (2 × CH3), 15.4 (CH2CH3). m/z (ESI+, MeOH) 171.1
•
[M + H]+
.
2-[(2R,5R)-Dimethylpyrrolidin-1-yl]-1-ethylaminobenzene 15
Acetyl chloride (0.07 mL, 1.05 mmol) was added dropwise to a cooled
(0◦C) stirred solution of 1-amino-2-[(2R,5R)-2,5-dimethylpyrrolidin-
1-yl]benzene 9 (200 mg, 1.05 mmol) and pyridine (0.09 mL, 1.16 mmol)
in dichloromethane/ether (2 : 1, 20 mL). The mixture was brought to
room temperature and stirred for 1.5 h. The reaction was quenched with
1 M HCl (20 mL) and extracted with dichloromethane (6 × 20 mL).
The combined organic layers were dried (MgSO4), filtered, and
evaporated to give 1-acetylamino-2-[(2R,5R)-2,5-dimethylpyrrolidine-
25
1-yl]ethane hydrochloride as a yellow semi-solid (887 mg, 96%), [α]D
•
−41.3◦ (c 0.62 in H2O) (Found: 143.1545. [M + H − HCl]+ requires
25
143.1548). vmax (KBr)/cm−1 3411bs, 2989s, 1728s, 1650m, 1455s,
1394s, 1278s, 1150w, 1100m, 1055m, 800w. δH (300 MHz, D2O) 4.01
(1 H, m, H2ꢀ or H5ꢀ), 3.68 (1 H, m, H2ꢀ or H5ꢀ), 3.54–3.24 (4 H, m,
H1 and H2), 2.39 (1 H, m, H3ꢀ or H4ꢀ), 2.18 (1 H, m, H3ꢀ or H4ꢀ), 1.85
(1 H, m, H3ꢀ or H4ꢀ), 1.71 (1 H, m, H3ꢀ or H4ꢀ), 1.40 (3 H, d, J 6.6, CH3),
1.27 (3 H, d, J 6.8, CH3). δC [100 MHz, (CD3)2SO] 60.1, 57.9 (C2ꢀ and
1-yl]benzene as an orange solid (158 mg, 63%), [α]D −62.3◦ (c 0.942
•
in CHCl3), mp 158–168◦C (Found: 233.1641. [M + H]+ requires
233.1654). vmax (KBr)/cm−1 3411bs, 3309s, 3166s, 3111s, 2989s,
2956s, 2544s, 2447s, 2355s, 1700s, 1600s, 1533s, 1489s, 1439s, 1367m,
1289s, 1239s, 1117m, 1072m, 1033m. δH (300 MHz) 10.97 (1 H, br s,
NH), 7.94 (1 H, d, J 8.1, H6), 7.50 (1 H, t, J 7.5, H4), 7.30 (1 H, t, J 7.2,
H5), 7.20 (1 H, d, J 7.6, H3), 4.62–4.48 (1 H, m, H2ꢀ or H5ꢀ), 4.16–
4.02 (1 H, m, H2ꢀ or H5ꢀ), 2.78–2.42 (2 H, m, H3ꢀ or H4ꢀ), 2.34 (3 H, s,
CH3CO), 1.82–1.68 (2 H, m, H3ꢀ or H4ꢀ), 1.66 (3 H, d, J 6.3, CH3), 0.86
(3 H, d, J 7.0, CH3). δC (100 MHz) 170.5 (CO), 133.6 (C1), 130.2 (C6),
C5ꢀ), 43.3 (C2), 34.4 (C1), 28.5 (C3ꢀ and C4ꢀ), 15.9, 13.4 (2 × CH3).
•
m/z (ESI+, MeOH) 142.7 [M + H − HCl]+
.
A saturated sodium bicarbonate solution was added to the amine
hydrochloride salt (600 mg, 3.37 mmol) and the mixture extracted

174
J. Illesinghe et al.
128.3 (C3), 126.2 (C2), 125.9 (C4), 122.4 (C5), 62.1, 60.1 (C2ꢀ and
7.40–7.10 (10 H, m, H2ꢀ, H3ꢀ, H4ꢀ, H5ꢀ, and H6ꢀ), 5.36 (2 H, s, 2H, H1
and H2). δC (100 MHz) 149.8 (C2ꢀꢀ and C6ꢀꢀ), 141.0 (C1ꢀ), 140.7, 128.2
(C3ꢀꢀ, C4ꢀꢀ, and C5ꢀꢀ), 128.0 (C2ꢀ and C6ꢀ), 127.7 (C4ꢀ), 125.6 (C3ꢀ and
C5ꢀ), 99.4 (C1 and C2).
C5ꢀ), 30.5, 30.0 (C3ꢀ and C4ꢀ), 24.0 (CH3CO), 17.6, 14.9 (2 × CH3).
•
m/z (ESI+, MeOH) 233.2 [M + H]+
.
Reduction as described above of 1-acetylamino-2-[(2R,5R)-2,5-
dimethylpyrrolidin-1-yl]benzene (137 mg, 1.04 mmol) using LiAlH4
(392 mg, 10.37 mmol) after reflux for 24 h and workup with Na2SO4·
10H2O as described previously gave a yellow oil which was puri-
fied by column chromatography (SiO2; ethyl acetate/hexane, 1 : 10).
Reaction between 17 and 4
A solution of the bis(pyridine)osmium(vi) glycolate 17 (16 mg, 2.8 ×
10−2 mmol) was dissolved in base-washed CDCl3 and transferred by
syringe into an NMR tube.After data acquisition was complete, the con-
tents were transferred into an NMR tube containing 1,2-bis[(2R,5R)-
2,5-dimethylpyrrolidin-1-yl]ethane 4 (7.0 mg, 3.09 × 10−2 mmol). A
1H NMR spectrum of the mixture showed no significant differences to
the corresponding spectrum of the ligand 4 or the osmium complex 17.
25
This gave the amine 15 as a yellow oil (120 mg, 98%), [α]D +14.6◦
•
(c 0.56 in CHCl3) (Found: 219.1861. [M + H]+ requires 219.1861).
vmax (neat)/cm−1 3355bs, 3044m, 2967s, 1650w, 1595s, 1505s, 1455m,
1433s, 1372s, 1322s, 1261s, 1156s, 1044m. δH (300 MHz) 6.99 (1 H, t,
J 7.5, H4), 6.92 (1 H, dd, J 7.6, 1.4, H6), 6.68–6.60 (2 H, m, H3 and
H5), 4.38 (1 H, br s, NH), 3.94–3.86 (1 H, m, H2ꢀ or H5ꢀ), 3.74–3.62
(1 H, m, H2ꢀ or H5ꢀ), 3.30–3.02 (2 H, m, CH2CH3), 2.28–2.04 (2 H,
m, H3ꢀ and H4ꢀ), 1.58–1.40 (2 H, m, H3ꢀ and H4ꢀ), 1.27 (3 H, t, J 7.2,
CH2CH3), 0.99 (3 H, d, J 5.3, CH3), 0.70 (3 H, d, J 6.4, CH3). δC
(100 MHz) 145.5 (C1), 132.9 (C2), 124.1, 123.1, 116.7, 110.2 (C3, C4,
C5, and C6), 54.3, 53.1 (C2ꢀ and C5ꢀ), 38.9 (CH2CH3), 32.8, 32.2 (C3ꢀ
Reaction between 17 and 12
A solution of the bis(pyridine)osmium(vi) glycolate 17 (16 mg, 2.8 ×
10−2 mmol) and 1,2-di(pyrrolidin-1-yl)ethane 12 (5.2 mg, 3.09 ×
10−2 mmol) in CDCl3 was prepared as described above. A 1H NMR
spectrum was then recorded which showed the displaced pyridine
together with the 1,2-di(pyrrolidin-1-yl)ethane osmium(vi) 1,2-
diphenylglycolate · CH2Cl2 18. The displaced pyridine was removed
under vacuum and the resulting pink solid was dissolved in fresh, based-
washed CDCl3. An additional 1H NMR spectrum was then recorded
which showed the presence of 1,2-di(pyrrolidin-1-yl)ethaneosmium(vi)
1,2-diphenylglycolate · CH2Cl2 18.
and C4ꢀ), 18.7, 15.5 (2 × CH3 and CH2CH3). m/z (ESI+, MeOH) 219.2
•
[M + H]+
.
Asymmetric Dihydroxylations
)-1,2-Diphenylethane-1,2-diol 16 [( )-hydrobenzoin]
(
Benzoin (50 mg, 0.236 mmol) was dissolved in ethanol (10 mL) and
placed in a Fisher Porter tube. PtO2 (10 mg) was added, the mixture was
pressurized with hydrogen to 30 psi, and stirred overnight. The PtO2
was removed using a Celite plug and the filtrate concentrated to afford
the crude diol 16 as a colourless solid (50 mg, 99%), mp 145–149◦C
(lit.[32] 148–149◦C). δH (300 MHz) 7.25–7.20 (6 H, m, H2ꢀ, H4ꢀ, and
H6ꢀ), 7.14–7.07 (4 H, m, H3ꢀ and H5ꢀ), 4.68 (2 H, s, H1 and H2), 2.93
(2 H, br s, 2 × OH). δC (100 MHz) 140.0 (C1ꢀ), 128.3 (C2ꢀ and C6ꢀ),
1,2-Di(pyrrolidin-1-yl)ethaneosmium(VI)
1,2-Diphenylglycolate · CH2Cl2 18
The bis(pyrrolidine) 12 (27 mg, 0.16 mmol) was added to a stirring solu-
tion of the pyridine complex 17 (87 mg, 0.15 mmol) in dry toluene
(5 mL). The brown suspension was stirred for 10 min before the sol-
vent was removed. The resulting solid was washed with pentane
(3 × 3 mL), dissolved in dichloromethane, and the solvent evaporated
to afford a light brown solid which was washed with pentane (3 × 3 mL)
and dicloromethane (3 × 3 mL) to afford the 1,2-di(pyrrolidin-1-
yl)ethaneosmium( vi) 1,2-diphenylglycolate · CH2Cl2 18 as a pink solid
(75 mg, 90%) (Found: C 44.3, H 4.9, N 4.1. C25H34Cl2N2O4Os requires
C43.7, H4.9, N4.1%). vmax (KBr)/cm−1 3044w, 3022m, 2966w, 2900w,
2856s, 1650s, 1638s, 1600w, 1444s, 1333w, 1277m, 1105m, 1055s,
1000s, 955s, 827s, 730m, 686s, 672s, 605s, 583s. δH (300 MHz) 7.08–
7.32 (10 H, m, ArH), 5.30 (s, CH2Cl2), 5.03 (2 H, s, H1 and H2),
4.00–3.80 (4 H, m, H1ꢀꢀ and H2ꢀꢀ), 3.40–3.24 (2 H, m, H2ꢀꢀꢀ or H5ꢀꢀꢀ),
2.94–2.76 (2 H, m, H2ꢀꢀꢀ or H5ꢀꢀꢀ), 2.34–2.12 (2 H, m, H3ꢀꢀꢀ or H4ꢀꢀꢀ),
2.00–1.78 (2 H, m, H3ꢀꢀꢀ, H4ꢀꢀꢀ). δC (100 MHz) 142.0 (C1ꢀ), 127.9 (C3ꢀ
andꢀꢀC5ꢀ), 127.6 (C2ꢀ and C6ꢀ), 127.2 (C5ꢀ), 99.0 (C1 and C2), 63.12
128.1 (C4ꢀ), 127.2 (C3ꢀ and C5ꢀ), 79.4 (C1 and C2). m/z (ESI+, MeOH)
•
237.1 [M + Na]+
.
The crude diol 16 was purified for HPLC analysis using prepara-
tive TLC (silica gel 60F254, glass plate 2.5 by 7.5 cm, 250 µm; ethyl
acetate/hexane, 1 : 1). The silica containing the diol was scraped off the
plate as a powder. Isopropyl alcohol (HPLC grade; 1 mL) was added
to the silica and the resulting suspension was filtered through a syringe
filter (25 mm, 0.46 by 25 cm, 0.2 U) to give a solution of the purified
hydrobenzoin 16. The solution of diol in isopropyl alcohol (20 µL) was
injected into the HPLC apparatus containing a Chiralcel OJ column
(1.0 mL/min, detection at 250 nm, 10% isopropyl alcohol/90% hexane)
to give two peaks: T1 12.0 min (S,S), T2 13.3 min (R,R).
Asymmetric Dihydroxylations of Stilbene
(C1 and C2ꢀꢀ), 61.1, 61.1 (C1ꢀꢀꢀ and C4ꢀꢀꢀ), 55.7 (CH2Cl2), 22.0, 22.1
•
(C2ꢀꢀꢀ and C3ꢀꢀꢀ). m/z (ESI+, MeOH) 627.2 [M + Na]+
.
Reactions were carried out using the general method described by
Tomioka et al.,[7] and a typical procedure using 1,2-bis[(2R,5R)-2,5-
dimethylpyrrolidin-1-yl]ethane 4 is outlined below.
Asymmetric Hydroformylation of Styrene Using 1,2-Bis[(2R,5R)-
2,5-dimethylpyrrolidin-1-yl]benzene 3
OsO4 (51 mg, 0.201 mmol) was added to a stirred solution of chiral
diamine 4 (50 mg, 0.223 mmol) in THF (10 mL) at the desired temper-
ature (e.g. room temperature, −78◦C, 0◦C) and the mixture stirred for
15 min before stilbene (32 mg, 0.178 mmol) was added. The mixture
was stirred at the same temperature for 6 h. LiAlH4 (59 mg, 1.56 mmol)
was added, the mixture was stirred for 18 h at ambient temperature, and
NaSO4 · 10H2O was added until no further gas evolution was observed.
The resulting precipitate was filtered through a Celite plug and the fil-
trate was evaporated. 1H NMR spectroscopy of the crude sample was
used to identify the products isolated.
Hydroformylation was carried out using the general procedure
described previously.[4] Styrene (100 mg, 0.96 mmol), diamine 3
(5 mg, 1.9 × 10−2 mmol), and rhodium(ii) acetate dimer (4 mg,
9.8 × 10−3 mmol) were dissolved in deoxygenated benzene (10 mL) in
a 100 mL Parr autoclave which was pressurized with CO/H2 (1 : 1 molar
ratio, 400 psi). The reaction mixture was heated at 50◦C for 48 h. The
autoclave was cooled to ambient temperature before the pressure was
released. The mixture was concentrated to give an oil (104 mg), and
a
1H NMR spectrum of the crude material showed a mixture of the
branched and linear aldehydes in a ratio of 88 : 12. For (R)-2-methyl-
2-phenylpropanal and (S)-2-methyl-2-phenylpropanal: δH (300 MHz)
9.88 (1 H, d, J 1.4, H1), 7.45–7.17 (5 H, m, ArH), 3.63 (1 H, dq, J 7.0,
1.2, H2), 1.44 (3 H, d, J 7.0, H3). For 3-phenylpropanal: δH (300 MHz)
9.83 (1 H, t, J 1.4, H1) 7.45–7.17 (5 H, m, ArH), 2.97 (2 H, t, J 7.5,
H3), 2.78 (2 H, t, J 7.3, H2). The enantiomeric excess of the branched
aldehyde was determined using the shift base [Eu(hfc)3].
1H NMR Spectroscopy Displacement Studies Using the Bispyridine
Osmium Glycolate 17
Synthesis of Bis(pyridine)osmium(VI)
1,2-Diphenylethyleneglycolate 17
The glycolate was prepared following the method described by Nelson
et al. (yield 87%).[18f] δH (300 MHz) 9.00 (4 H, dt, J 5.2, 1.5, H2ꢀꢀ and
H6ꢀꢀ), 7.87 (2 H, tt, J 7.7, 1.5, H4ꢀꢀ), 7.53–7.48 (4 H, m, H3ꢀꢀ and H5ꢀꢀ),
A similar reaction for 18 h gave a 1 : 1 mixture of starting material
and aldehydes with a branched-to-linear aldehyde ratio of 90 : 10.

Hindered Diamines as Chiral Modifiers of Metal-Promoted Reactions
175
Copper–Diamine Complexes
gave recovered starting material. A similar reaction under an oxygen
atmosphere at room temperature for 2 days gave a mixture of 1,2-
naphthoquinone and 2ꢀ-hydroxy-1,1ꢀ-binaphthalene-3,4-dione in a ratio
of 60 : 40. The crude product was purified using column chromatog-
raphy (SiO2; ethyl acetate/hexane, 1 : 5) to give 1,2-naphthoquinone
as a yellow solid (47 mg, 24%), mp 135–138◦C (lit.[34] 143◦C). The
spectroscopic data were consistent with literature data.[34]
Reactions were carried out using the general method described by
Nakajima et al.,[23] and a typical procedure using 1,2-di(pyrrolidin-1-
yl)ethane 12 is outlined.
Cu(OH)Cl · 1,2-di(pyrrolidin-1-yl)ethane
Further elution gave 2ꢀ-hydroxy-1,1ꢀ-binaphthalene-3,4-dione as a
red/orange solid (29 mg, 27%), mp 138–148◦C (lit.[24] 148–149◦C).
The spectroscopic data were consistent with literature data.[24]
Reactions using the catalyst (2 mg, 4.95 × 10−3 mmol) and the ester
19b (100 mg, 0.495 mmol) at room temperature or reflux, and in air or
under an atmosphere of oxygen, gave only starting material.
A mixture of CuICl (59 mg, 0.595 mmol) and 1,2-di(pyrrolidin-1-
yl)ethane12(200 mg, 1.19 mmol)inmethanol(20 mL)wasstirredunder
an oxygen atmosphere at room temperature for 2 days. After reducing
the methanol volume to 5 mL, the reaction mixture was centrifuged.The
filtrate was decanted and the resulting solid was washed with a small
amount of cold methanol. The copper complex was isolated as a green
solid (99 mg, 59%), mp 110–115◦C.
Reactions using Cu(OH)Cl · 1-amino-2-[(2R,5R)-
2,5-dimethylpyrrolidin-1-yl]ethane
Cu(OH)Cl · 1,2-bis[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]ethane
Reaction of a mixture of CuICl (70 mg, 0.711 mmol) and 1,2-
bis[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]ethane4(319 mg, 1.42 mmol)
as described above gave the copper complex as a chocolate brown solid
(166 mg, 69%), mp 100–105◦C.
Reactions of 2-naphthol 19a (100 mg, 0.694 mmol) and the cata-
lyst (2 mg, 6.94 × 10−2 mmol) at room temperature in air for 7 days
gave mainly recovered starting material, with 9% conversion into
1,1ꢀ-binaphthalene-2,2ꢀ-diol 20a, and a small amount of 2ꢀ-hydroxy-
1,1ꢀ-binaphthalene-3,4-dione.
A similar reaction under an atmosphere of oxygen at room tem-
perature for 3 days gave complete conversion into a 3 : 1 mixture of
1,2-naphthoquinone and 2ꢀ-hydroxy-1,1ꢀ-binaphthalene-3,4-dione.
Reaction of the ester 19b (100 mg, 0.495 mmol) using the catalyst
(2 mg, 4.95 × 10−3 mmol) at room temperature under an atmosphere of
oxygen for 3 days gave 17% conversion into dimethyl 2,2ꢀ-dihydroxy-
Cu(OH)Cl · 1-amino-2-[(2R,5R)-2,5-dimethylpyrrolidin-
1-yl]ethane
Reaction of a mixture of CuICl (179 mg, 1.81 mmol) and 1-amino-2-
[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]ethane 13 (514 mg, 3.61 mmol)
in dichloromethane (10 mL) as described above gave a solid which was
washed with a small amount of cold dichloromethane to give the copper
complex as a khaki green solid (260 mg, 71%), mp 107–110◦C.
25
1,1ꢀ-binaphthalene-3,3ꢀ-dicarboxylate[23] 20b, [α]D −38.4◦ (c 0.44, in
THF). (lit.[23] for (R)-20b +172◦) (c 0.82 in THF). The (S)-20b had an
e.e. of 23%. A similar reaction in air at reflux for 7 days gave complete
conversion into 20b with an e.e. of 6%.
Oxidative Coupling Reactions of 2-Naphthol 19
and Methyl 3-Hydroxy-2-naphthoate 19b
Molecular Modelling
Reactions were carried out using the general method described by
Nakajima et al.,[23] and a typical procedure using 1,2-di(pyrrolidin-1-
yl)ethane 12 is outlined below.
Molecular modelling was carried out using Insight II 4.0 P+ (Accelrys,
San Diego, CA, USA) with Discover Minimization Module (97.0) using
CVFF force fields.[35] The structures were minimized using the conju-
gate gradients algorithm with a convergence criterion of the average
Oxidative Coupling of 19a using Cu(OH)Cl · 1,2-
derivative being less than 0.001 kcal mol−1
.
di(pyrrolidin-1-yl)ethane
A mixture of the catalyst (10 mg, 3.47 × 10−2 mmol) and 2-naphthol
19a (500 mg, 3.47 mmol) in dichloromethane (10 mL) was stirred at
room temperature for 18 h in open air. The mixture turned dry over the
course of the reaction to afford a brown solid which was purified using
column chromatography (SiO2; ethyl acetate) to give 1,1ꢀ-binaphthyl-
2,2ꢀ-diol 20a asacolourlesssolid(450 mg, 90%), mp206–210◦C(lit.[33]
208–210◦C). The spectroscopic data were consistent with those of an
authentic sample.
Crystal Data for the HCl Salt of 9
C
12H19ClN2,
a 8.0618(1), b 9.4707(1), c 16.0182(2) Å, β 90◦, V 1223.00(3) Å3, Z 4,
Dc 1.231 g cm−3, F(000) 488, MoKα (λ 0.71073 Å), µ 0.284 mm−1
M 226.74, orthorhombic, space group P212121,
.
For intensity measurements, a colourless prismatic crystal having
approximate dimensions of 0.20 by 0.16 by 0.14 mm was mounted on a
glass fibre and measurements were made on a Nonius KappaCCD area
detector with graphite-monochromated MoKα radiation. Data were col-
lected at a temperature of −150 2◦C; unique data 3018 (Rint 0.0400).
DatawereprocessedusingNoniussoftware.[36] Thestructurewassolved
by and expanded using Fourier techniques[37] and refined with the full-
matrix least-squares technique. The non-hydrogen atoms were refined
anisotropically. Hydrogen atoms were included but not refined. The
final Rw ([ꢀw(|Fo|–|Fc|)2/ꢀw(|Fo|)2]1/2) value for 139 parameters
and 3018 reflections was 0.092; the R (ꢀ||Fo|–|Fc||/ꢀ|Fo|) value was
0.0326 [I > 2.00σ(I)].
Oxidative Coupling of 19 using Cu(OH)Cl · 1,2-
di(pyrrolidin-1-yl)ethane
The reaction of methyl 3-hydroxy-2-naphthoate 19b (100 mg,
0.694 mmol) with the copper complex under reflux in air as described
above for 2 days gave a brown solid. Purification using column
chromatography gave dimethyl 2,2ꢀ-dihydroxy-1,1ꢀ-binaphthalene-3,3ꢀ-
dicarboxylate[23] 20b as a colourless solid (100 mg, 100%), mp 280–
283◦C. δH (300 MHz) 10.72 (2 H, s, 2 × OH), 8.68 (2 H, s, H4 and H4ꢀ),
7.96–7.88 (2 H, m, ArH), 7.38–7.30 (4 H, m, ArH), 7.19–7.05 (2 H, m,
ArH), 4.05 (6 H, s, 2 × OCH3). δC (100 MHz) 170.7 (2 × CO), 154.1
(C3 and C3ꢀ), 133.1 (C4 and C4ꢀ), 130.0, 129.6, 124.9, 124.2 (ArCH),
137.3, 127.4, 117.2 (C1, C1ꢀ, C4a, C4aꢀ, C8a, and C8aꢀ), 114.4•(C2 and
All the bond lengths and angles were in the expected range. Listings
of bond lengths, bond angles, atomic coordinates and anisotropic ther-
mal parameters have been deposited at the Cambridge Crystallographic
Data Centre (file No. CCDC 218994).
C2ꢀ), 53.1 (2 × OCH3). m/z (ESI+, MeOH) 425.2 [M + Na]+
.
Acknowledgments
Similar reactions at room temperature under air or under an atmo-
sphere of oxygen for 3 days gave only approximately 20% conversion.
We thank the Australian Research Council for the award of a
Discovery Grant and for provision of a postgraduate research
award (to J.I.) and Johnson Matthey for a loan of precious
metals. We also thank Dr G. Fallon (Monash University) for
X-ray diffraction studies.
Reactions using Cu(OH)Cl · 1,2-bis[(2R,5R)-
2,5-dimethylpyrrolidin-1-yl]ethane
Reaction of 2-naphthol 19a (100 mg, 0.694 mmol) and the cata-
lyst (3 mg, 6.94 × 10−2 mmol) in air at room temperature or reflux

176
J. Illesinghe et al.
References
[19] K. Fuji, K. Tanaka, H. Miyamoto, Tetrahedron Lett. 1992, 33,
4021. doi:10.1016/0040-4039(92)88090-R
[20] Y. Ogino, H. Chen, E. Manoury, T. Shibata, M. Beller,
D. Lübben, K. B. Sharpless, Tetrahedron Lett. 1991, 32, 5761.
doi:10.1016/S0040-4039(00)93549-4
[21] (a) S. Gladiali, J. C. Bayon, C. Claver, Tetrahedron: Asymmetry
1995, 6, 1453. doi:10.1016/0957-4166(95)00178-R
(b) F. Agbossou, J.-F. Carpentier, A. Mortreux, Chem. Rev. 1995,
95, 2485.
[22] M. Noji, M. Nakajima, K. Koga, Tetrahedron Lett. 1994, 35,
7983.
[23] M. Nakajima, I. Miyosi, K. Kanayama, S. Hashimoto, J. Org.
Chem. 1999, 64, 2264. doi:10.1021/JO981808T
[24] L. Xiaolin, J. Yang, M. C. Kozlowski, Org. Lett. 2001, 3, 1137.
doi:10.1021/OL015595X
[25] J. K. Lieser, Synth. Commun. 1983, 13, 765.
[26] R. P. Short, R. M. Kennedy, S. Masamune, J. Org. Chem. 1989,
54, 1755.
[27] F. B. Gallwey, J. E. Hawkes, P. Haycock, D. Lewis, J. Chem.
Soc., Perkin Trans. 2 1990, 1979.
[28] G. Caron, R. J. Kazlauskas, Tetrahedron: Asymmetry 1994, 5,
657. doi:10.1016/0957-4166(94)80028-6
[29] J. P. Cahill, F. M. Bohnen, R. Goddard, C. Kruger, P. J. Guiry,
Tetrahedron: Asymmetry 1998, 9, 3831. doi:10.1016/S0957-
4166(98)00393-0
[30] G. D. Fallon, J. Illesinghe, E. M. Campi, W. R. Jackson,
A. J. Robinson, Acta Crystallogr. E 2003, 59, O1163. doi:
10.1107/S160053680301537X
[31] D. S. Crumrine, T. A. Dieschbourg, J. G. O’Toole, B. A. Tassone,
S. C. Vandeburg, J. Org. Chem. 1987, 52, 3699.
[32] G. Berti, F. Bottari, J. Org. Chem. 1960, 25, 1286.
[33] B. Feringa, H. Wynberg, Tetrahedron Lett. 1977, 4447.
doi:10.1016/S0040-4039(01)83533-4
[34] C. Cavallotti, F. Orsini, G. Sello, P. Di Gennaro, E. Galli,
G. Bestetti, Tetrahedron 1999, 55, 4467. doi:10.1016/S0040-
4020(99)00135-0
[1] M. J. Burk, J. Am. Chem. Soc. 1991, 113, 8518.
[2] M. J. Burk, J. E. Feaster, R. L. Harlow, Tetrahedron: Asymmetry
1991, 2, 569. doi:10.1016/S0957-4166(00)86109-1
[3] M. J. Burk, J. E. Feaster, W. A. Nugent, R. L. Harlow, J. Am.
Chem. Soc. 1993, 115, 10 125.
[4] E. Teoh, E. M. Campi, W. R. Jackson, A. J. Robinson, New J.
Chem. 2003, 27, 387. doi:10.1039/B209087M
[5] H. Kubota, M. Nakajima, K. Koga, Tetrahedron Lett. 1993, 34,
8135. doi:10.1016/S0040-4039(00)61472-7
[6] Catalytic Asymmetric Synthesis (Ed. I. Ojima) 2000 (Wiley–
VCH: New York, NY).
[7] K. Tomioka, M. Nakajima, K. Koga, J. Am. Chem. Soc. 1987,
109, 6213.
[8] M. Nakajima, K. Tomioka, Y. Iitaka, K. Koga, Tetrahedron
1993, 49, 10 793. doi:10.1016/S0040-4020(01)80234-9
[9] K. Tomioka, M. Nakajima, K. Koga, Tetrahedron Lett. 1990,
31, 1741. doi:10.1016/S0040-4039(00)88869-3
[10] K. Nozaki, I. Ojima, in Catalytic Asymmetric Synthesis
(Ed. I. Ojima) 2000, Ch. 7, pp. 429–463 (Wiley–VCH:
New York, NY).
[11] T. Rovis, D. A. Evans, in Progress in Inorganic Chemistry (Ed.
K. D. Karlin) 2001, Vol. 50, pp. 1–150 (Wiley: New York, NY).
[12] G. Bitsi, E. Schleiffer, F. Antoni, G. Jenner, J. Organomet.
Chem. 1989, 373, 343. doi:10.1016/0022-328X(89)85063-6
[13] (a) M. Hirama, T. Oishi, J. Chem. Soc., Chem. Commun. 1989,
665.
(b) T. Oishi, M. Hirama, J. Org. Chem. 1989, 54, 5834.
[14] E. J. Corey, S. Sarshar, M. D. Azimiora, R. C. Newbold,
M. C. Noe, J. Am. Chem. Soc. 1996, 118, 7851. doi:10.1021/
JA960536D
[15] C. Rosini, R. Tanturli, P. Pertici, Tetrahedron: Asymmetry 1996,
7, 2971. doi:10.1016/0957-4166(96)00388-6
[16] E. J. Corey, P. D. Jardine, S. Virgil, P.-W. Yven, R. D. Connell,
J. Am. Chem. Soc. 1989, 111, 9243.
[17] K. Tomioka, M. Nakajima, K. Koga, Tetrahedron Lett. 1988,
29, 573. doi:10.1016/S0040-4039(00)80153-7
[18] (a) M. Schröder, Chem. Rev. 1980, 80, 187.
(b) K. A. Jørgensen, R. Hoffmann, J. Am. Chem. Soc. 1986,
108, 1867.
[35] Insight II (Discover) 1998 (Molecular Simulations: San Diego,
CA).
[36] Denzo-SMN Z. Otwinowski, W. Minor, Methods Enzymol.
Vol. 276: Macromolecular Crystallography, Part
A (Eds
C. W. Carter, Jr, R. M. Sweet) 1997, pp. 307–326 (Academic
Press: London).
(c) K. A. Jørgensen, Tetrahedron: Asymmetry 1991, 2, 515.
doi:10.1016/S0957-4166(00)86105-4
(d)Y.-D.Wu,Y.Wang, K. N. Houk, J. Org. Chem. 1992, 57, 1362.
(e) B. B. Lohray, Tetrahedron: Asymmetry 1992, 3, 1317.
doi:10.1016/0957-4166(92)80001-D
[37] G. M. Sheldrick, SHELXS97 and SHELXL97 1997 (University
of Göttingen: Göttingen).
(f) D. W. Nelson, A. Gypser, P. T. Ho, H. C. Kolb, T. Kondo,
H.-L. Kwong, D. V. McGrath, A. E. Rubin, et al., J. Am. Chem.
Soc. 1997, 119, 1840. doi:10.1021/JA961464T