The use of a [4 + 2] cycloaddition reaction for the preparation of a series of 'tethered' Ru(ii)-diamine and aminoalcohol complexes

Article abstract of DOI:10.1039/b700744b

A series of catalysts have been prepared for use in the asymmetric transfer hydrogenation of ketones. The complexes were prepared using a [4 + 2] cycloaddition reaction at a key step in the reaction sequence. This provides a means for the synthesis of cat

Full text of DOI:10.1039/b700744b

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www.rsc.org/obc | Organic & Biomolecular Chemistry
The use of a [4 + 2] cycloaddition reaction for the preparation of a series of
‘tethered’ Ru(II)–diamine and aminoalcohol complexes†
Fung Kei Cheung, Aidan M. Hayes, David J. Morris and Martin Wills*
Received 17th January 2007, Accepted 12th February 2007
First published as an Advance Article on the web 1st March 2007
DOI: 10.1039/b700744b
A series of catalysts have been prepared for use in the asymmetric transfer hydrogenation of ketones.
The complexes were prepared using a [4 + 2] cycloaddition reaction at a key step in the reaction
sequence. This provides a means for the synthesis of catalysts with modifications at specific sites.
on to transfer these subsequently to the ketone substrate to
form the product thereby regenerating 6/7 which re-enters the
Introduction
catalytic cycle.4 Formic acid is generally preferred to isopropanol
in this application because the reactions are essentially irreversible,
and may be carried out at high concentrations. However this
limits the ligand to the monotosylated diamines, since the Ru(II)–
aminoalcohol complexes are not stable to formic acid conditions.
The asymmetry of the ketone reduction is controlled by the
approach of the ketone to the hydrides 8 or 9, which are
known to be formed predominantly in the diastereoisomeric forms
illustrated (supported by X-ray crystallography and molecular
modeling studies).4 Crucial to the high enantioselectivity is a
favourable CH–p interaction between the hydrogen atoms of the
g6-arene and the aryl ring of a substrate, such as an acetophenone
derivative (illustrated for 9 in Fig. 1). This interaction accounts
for the high degree of enantiocontrol observed for acetophenone
derivatives. In contrast, substrates which contain a combination
of two alkyl groups flanking the ketone are generally reduced
in poor enantioselectivity, as the key stabilizing interaction does
not exist. There is evidence that dispersion and steric effects4e
also contribute to the enantiocontrol of the reduction process,
however these forces are not by themselves sufficiently strong
to effectively control the reduction of dialkyl ketones with high
enantioselectivity.
Recent research has led to the development of a number of
highly active catalysts for asymmetric transfer hydrogenation
(ATH) of ketones.1–6 The popular Ru(II)–arene based catalysts
1 and 2 contain an g6-coordinated arene ring which occupies
three vertices of an octahedrally-complexed metal.2–5 An enan-
tiomerically pure bidentate ligand, most commonly an amino
alcohol2 such as ephedrine 3 or a monotosylated diamine3 such as
N-tosyl-1,2-diphenylethane-1,2-diamine (TsDPEN) 4 or N-tosyl-
1,2-diaminocyclohexane (TsDAC) 5, and a chloride, complete the
structure of the ‘pre-catalyst’ which may be isolated prior to use
or formed in situ. Upon addition to the reaction, which typically
consists of a solution of ketone substrate in either isopropanol–
alkoxide or formic acid–triethylamine (FA–TEA), HCl is lost
from the pre-catalyst to generate the 16-electron species 6 or
7. This intermediate removes two hydrogen atoms from either
isopropanol or formic acid to give hydride 8 or 9 which goes
Fig. 1 Reduction of acetophenone derivatives by catalyst RR-9.
Some investigations into the modification of the g6-arene rings
have been reported, although these have been largely limited to
methyl substitution.2a,3a,c,4 In the case of the amino alcohol com-
plexes, it has been clearly demonstrated that the CH–p interaction
can be productively extended through a methyl group on the
arene ring, and indeed can even increase the enantioselectivity in
some cases.2a However for the monotosylated diamine complexes,
the situation is slightly more complicated. This is because an
additional N-Ts–g6-arene nonbonded interaction results in a
reduction of reaction rate,4d when hexamethylbenzene is used
instead of benzene as the g6-arene component.
The Department of Chemistry, The University of Warwick, Coventry, UK
CV4 7AL. E-mail: m.wills@warwick.ac.uk; Fax: 024 7652 3260; Tel: 024
7652 3260
† Electronic supplementary information (ESI) available: General experi-
mental details, preparation of precursor molecules and ketone reductions,
1H and 13C-NMR of all new compounds lacking elemental analyses, and
synthetic procedures. See DOI: 10.1039/b700744b
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A
comparison between the closely related Rh(III)–
cyclohexadiene precursor (e.g. 12), coupling to the chiral ligand to
give intermediate 13, and finally complexation with ruthenium(III)
chloride. However, this route is difficult to pursue on a large scale,
and requires an appropriately-substituted aryl substrate, which
may not be readily available.
In order to prepare derivatives of 10 and 11 on a larger scale and
with substituents in specific positions, we chose to investigate an
alternative approach based on a [4 + 2] cycloaddition strategy
between a diene and a functionalized alkyne 14 (Fig. 3). If
successful, this would permit the large scale synthesis of large
quantities of the required functionalized catalysts.
pentamethylcyclopentadienyl transfer hydrogenation catalysts
is also of value.7 Rhodium(III) catalysts offer advantages in the
reduction of certain substrates, notably a-chloroacetophenones
and related substrates, for which they appear to give better
conversions and e.e. compared to the Ru(II) complexes.7 For the
Rh(III) complexes, however, the investigations have focused (with
the exception of some of our own studies) on the pentamethylated
complexes, which are widely assumed to operate through an
analogous transition state to that illustrated in Fig. 1, again
suggesting that the CH–p interaction works productively through
methyl groups on the g5-coordinated ring. We are not aware of
Rh(III) catalysts which lack the methyl groups on the Cp ring
having been reported for ATH of ketones or imines, however this
may be due to the increased stability of complexes containing Cpꢀ
over Cp.
Results and discussion
In order to make the catalysts such as 1 and 2 effective at
enantioreduction of dialkyl ketones, it would be desirable to be
able to substitute the arene ring with large functional groups.
A large group such as t-butyl, positioned in the region close to
the substrate in the reduction, may be able to change the basis of
enantiocontrol from primarily electronic to steric. A substrate such
as acetocyclohexane, for example, might be expected to approach
the catalyst in a manner that positions the larger substituent
away from the bulky group on the arene, thus forcing delivery
of hydrogen to predominantly one face of the carbonyl group
(Fig. 2). One difficulty with this, however, is ensuring that the
‘bulky’ group is correctly positioned relative to the substrate; this
is difficult to control due to the high conformational flexibility of
the arene group.
Fig. 3 Established and proposed alternative approaches to complex 10
and its derivatives.
We first examined the synthetic approach to derivatives of
the monotosylated catalyst 11, and our final route is shown in
Scheme 1. Alkyne-containing sulfonyl chloride 15 was combined
with RR-DPEN 4 to give sulfonamide 16 in 62% yield. Studies
revealed that it was necessary to protect the free amine group in 16,
which was achieved by reaction with Boc2O to give 17 in 97% yield.
The cycloaddition reaction with isoprene required the use of a
catalyst. In our studies we examined the use of two catalysts which
have been reported for this application, the cobalt based 18 9 and
Fig. 2 Changing the basis of stereocontrol from electronic to steric.
In our research work on Ru(II) complexes, we have sought
to address this problem by preparing modified catalysts which
contain a ‘tether’ between the chiral ligand component and the
arene.8 This tether serves to increase the stability of the catalyst and
to restrict the conformations available to the arene, thus permitting
it to be selectively functionalized. Two of our ‘tethered’ catalysts,
are 10 and 11, containing an aminoalcohol and a sulfonylated
diamine respectively.8b In order to prepare derivatives of these with
functional groups on the arene ring, the conventional approach
has been to use a Birch reduction to prepare the appropriate 1,4-
Scheme 1 Reagents and conditions: i) 4, Et3N, DCM, 0 ◦C. ii) tBoc2O,
THF, rt. iii) Catalyst 19 (2 mol%), DCM, rt. iv) HCl, Et2O, DCM, rt then
RuCl3, EtOH, reflux o/n.
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the rhodium complex 19.10 In the event, only the Rh(I) complex 19
proved to be successful, yielding 20a from the acetylene 17 in 65%
isolated yield. Following the success of this protocol, a series of
derivatives 20b–20d were also prepared. In the cases of 20a–20c,
the products were formed predominantly as the 1,4-disubstituted
dienes (1,4- : 1,3- ca. 5–6 : 1), however 20d contained ca. 25% of
the 1,3-isomer, which was not separable by flash chromatography.
Each of these was converted into the dimeric catalyst precursors
21a–21d in good yield through tBoc deprotection followed by
complexation with RuCl3. At the complexation stage, only the 1,4-
disubstituted products were isolated, except for the case of 21d,
which retained ca. 25% of the 1,3- isomer. In the final step, yields
were low to moderate, reflecting an incomplete crystallization of
the product from solution rather than an inherently low yielding
reaction. It is anticipated that these yields can be optimized
through modification of our isolation procedure.
increase of the steric hindrance around the metal. Alternatively the
effect may be due to electronic factors. The complexes containing
the larger groups, 21b and 21c gave products in even lower
conversions, and ca. 17–18% e.e. The phenyl-substituted catalyst
21d gave a product in the best observed e.e. of 36%, although
only 50% conversion. The extra phenyl ring therefore appears to
have a beneficial effect, although it is not clear which isomer of
the catalyst may be giving the improved result, since the catalyst
was a mixture of 1,3- and 1,4-disubstituted arene derivatives. This
remains to be established.
By way of literature comparison, the reduction of acetophenone
under the same conditions with catalyst [(mesitylene)RuCl(SS-
TsDPEN)] gives a product of 98% e.e. (S configuration) in
◦
>99% yield after 20 h at S/C = 200, 28 C.3a Although no
systematic comparison of [(benzene)RuCl(SS-TsDPEN)] against
[(hexamethylbenzene)RuCl(SS-TsDPEN)] has been reported, it is
known that the additional methyl groups in the latter complex
reduce the reaction rate, in accord with our findings.
We also prepared a series of derivatives of the amino alcohol
catalyst 10, through the sequence in Scheme 2. The required alkyne
25 was prepared by the reaction of (1R, 2S)-norephedrine 3 with
tosylate 26 followed by N-protection in 40% yield for the two steps.
Experiments revealed that, as well as N-protection, it was also nec-
essary to protect the oxygen atom of the norephedrine in order for
the cycloaddition to be successful. This was achieved in 98% using
TBDMSCl, to furnish 27, which was subsequently reacted with
a series of four dienes to give the predominantly 1,4-cyclodienes
28a–28d. Following the precedent previously established, each of
these complexes was deprotected and converted to the catalyst
precursor dimers 29a–29d. Diene 28a and catalyst 29a have been
reported by us in an earlier publication, and the data obtained in
this study matched that previously obtained.8c Again, since our
We have previously demonstrated that dimers such as 21a–d are
converted directly to the respective monomers 22a–d in situ during
the reaction in FA–TEA. This process involves neutralization
of the salt, splitting of the dimer and ‘wrapping’ of the ligand
around the metal. In practice, the dimers give identical results in
reduction reactions to the monomers. We therefore employed 21a–
21d directly in reduction reactions without prior isolation of the
monomers. Results of ketone reduction using our new catalysts are
given in Table 1, with examples of reduction of both acetophenone
23 and acetocyclohexane 24. The introduction of substituents
results in the reduction of enantioselectivity and conversion for
acetophenone reduction. It therefore appears that the substituents
have an effect on the catalysts, but not a productive one. For the
reduction of acetocyclohexane 24, there is a more complex pattern.
The parent catalyst 11 gave a reduction product of only 19% e.e.,
in 84% yield. The methyl-substituted derivative 21a reduced the
ketone in slightly higher e.e. (27%) but at a significantly reduced
rate, only 20% yield after 166 hours. It appears that the new group
has a significant effect on reactivity, possibly due to an overall
Table 1 Reductions of ketones using catalysts RR-11 and 21a–da
Substrate
Catalyst
T/h
Conversion (%)b
Eec (R/S)d
Acetophenone 23
Acetophenone 23
Acetophenone 23
Acetophenone 23
Acetophenone 23
c-C6H11COMe 24
c-C6H11COMe 24
c-C6H11COMe 24
c-C6H11COMe 24
c-C6H11COMe 24
11
24
96
96
96
96
63
166
72
91
72
99
88
35
44
63
84
20
10
< 10
50
96 (R)
63 (R)
35 (R)
25 (R)
68 (R)
19 (R)
27 (R)
17 (R)
18 (R)
36 (R)
21a
21b
21c
21d
11
21a
21b
21c
21d
a Monomer RR-11(0.5 mol%) or dimer 21a–d (0.25 mol%) (200 : 1 S/C),
1 M solution of ketone in HCO2H–NEt3 (5 : 2), 40 ◦C. b Determined
by GC or 1H NMR analysis. c Determined by GC analysis using a
chrompac cyclodextrin-b-236M-19 50 m column unless otherwise spec-
ified. d Determined from the sign of rotation of the isolated product.
Scheme 2 Reagents and conditions: i) 3, Et3N, MeCN, rt, then tBoc2O,
THF, rt. ii) TBSCl, Im, DMF, rt. iii) Catalyst 19 (2 mol%), DCM, rt. iv)
TBAF, THF, rt. v) HCl, Et2O, DCM, rt, then RuCl3, EtOH, reflux o/n.
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previous studies had revealed that the dimers are converted to
monomers 30a–30d in situ in the reduction reactions,8 complexes
29a–29d were directly employed in the reduction of acetophenone
and acetocyclohexane. For the aminoalcohol ligands, however,
the reductions were carried out in isopropanol with 5 mol%
KOH as base to form the activated catalysts. In contrast to the
monotosylated diamines, the amino alcohol complexes do not
appear to be stable to formic acid–triethylamine.
However, again caution should be maintained here before reading
too much into the results, because the same reduction using
pseudoephedrine is reported to give a product of 75% e.e.3a
The sense of the ketone reduction using 10 and 29a–d is worthy
of comment. In all the acetophenone reductions, the products
of R-configuration were obtained, which matches that reported
for these configurations of chiral ligand, thus suggesting that the
CH–p interaction continues to dominate these (Fig. 1). In the case
of the acetocyclohexane 24, the product of S-configuration was
obtained in every case, suggesting that the ketone is approaching
the catalyst with the larger (cyclohexyl) substituent orientated
away from the g6-arene ring. This appears to be in contrast to the
mode of reduction operated by the sulfonylated diamine catalysts
11 and 21a–d (Fig. 4). Although the reversed substrate approach to
the aminoalcohol derivatives is what we had hoped to build into
the catalyst design, it is surprising that the parent structure 10,
with no arene substituent, appears to enforce this approach most
effectively. It appears that sterics are not the only factors here, but
possibly also a combination of electronic effects from the various
substituents which lead to subtle shifts in the enantiocontrol.
All the complexes proved to be competent reduction catalysts
(Table 2). In the case of acetophenone, the product e.e.s were
similar or in some cases a little higher than that obtained using the
parent complex 10, however the conversions were lower, possibly
due to increased steric hindrance. In the case of acetocyclohexane
24, the e.e.s were slightly below that obtained using 10, but in
the same sense. Again the reactions proceeded at significantly
reduced rates compared to the parent 10, which suggests that
the substituents are indeed in a position to influence the reaction,
although not at present in a productive manner. A small series of
dialkyl ketones were also reduced (Table 2) using 10 however in all
cases the e.e.s were moderate or rather poor.
The results can be compared with published results ob-
tained using the untethered [(benzene)RuCl(1R, 2S-N-methyl-
1,2-diphenylaminoethanol)] and [(hexamethyl)RuCl(1R, 2S-N-
methyl-1,2-diphenylaminoethanol)] complexes.2a In these systems,
the more substituted complex gives an acetophenone reduction
product of 13% e.e. in only 3% yield compared to 64% yield and
52% e.e. for the benzene complex. However this trend completely
reverses when the (S,S)-aminoalcohol ligand is employed; the
e.e. is 17% (91% yield) with the benzene complex and 92% (94%
yield) with the hexamethylbenzene complex. In our own studies
we have found that [(benzene)RuCl(1R, 2S-ephedrine)] reduces
acetylhexane in only 6% e.e. under comparable conditions.8c
Fig. 4 Modes of asymmetric reduction of acetylcyclohexane.
Conclusion
In conclusion, we have developed a new approach to the synthesis
of ‘tethered’ catalysts for ATH reductions of ketones using a
variant of a [4 + 2] cycloaddition reaction to create the required
1,4-cyclohexadiene ring for complexation to ruthenium. This
process provides a means for the preparation of Ru(II) catalysts
on a larger scale than would be possible using the traditional
approaches. Using this method, it was possible to prepare a
small series of catalysts for evaluation in ATH of acetophenone
derivatives and dialkyl ketones. In all cases, the sense of reduction
for acetophenone was opposite to that for acetocyclohexane,
however the conversions and e.e.s were lower for the derivatives
than for the parent complexes, possibly reflecting the increased
steric hindrance. We are currently investigating the development
of ‘tethered’ catalysts in synthesis and are aided by the availability
of this new method for their preparation.
Table 2 Reductions of ketones using catalysts (1R, 2S)-10 and 29a–da
Substrate
Catalyst T/h Conversion (%)b Eec (R/S)d
Acetophenone 23
Acetophenone 23
Acetophenone 23
Acetophenone 23
Acetophenone 23
c-C6H11COMe 24
c-C6H11COMe 24
c-C6H11COMe 24
c-C6H11COMe 24
c-C6H11COMe 24
tBuCOMe
10
2
2
2
2
2
2
2
2
2
2
2
2
2
2
94
56
77
64
37
78
22
15
12
43
100
21
68
19
62 (R)
72 (R)
77 (R)
64 (R)
37 (R)
69 (S)
62 (S)
45 (S)
54 (S)
16 (S)
63 (S)
61 (S)
24 (S)
28 (S)
29a
29b
29c
29d
10
29a
29b
29c
29d
10
10
10
Experimental
Enantiomeric excesses were measured using chiral HPLC or chiral
GC methods, details of which are given in the experimental
section below. Absolute configurations were established by optical
rotation and comparison to literature data. Racemic standards of
all alcohol products were prepared by reduction of the precursor
ketone with sodium borohydride. General experimental details
are given in the ESI.† Compounds 28a, 29a and the desilylated
derivative of 28a have been reported in a previous publication.8c
AdCOMe
n-C6H11COMe
c-C6H11COCH2CH3 10
a Monomer (1R, 2S)-10(0.5 mol%) or dimer 29a–d (0.25 mol%) (200 :
1 S/C), 0.1 M solution of ketone in iPrOH, 28 ◦C. b Determined
by GC or 1H NMR analysis. c Determined by GC analysis using a
chrompac cyclodextrin-b-236M-19 50 m column unless otherwise spec-
ified. d Determined from the sign of rotation of the isolated product.
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Synthesis of but-3-yne-1-sulfonic acid
((R,R)-2-amino-1,2-diphenylethyl)-amide 16
Synthesis of {(R,R)-2-[2-(4-methylcyclohexa-1,4-dienyl)-ethane-
sulfonylamino]-1,2-diphenylethyl} tert-butyl carbamate 20a
Catalyst 19 (0.005 g, 0.01 mmol), DCM (3 cm3), isoprene (0.080 g,
1.17 mmol) and 17 (0.250 g, 0.58 mmol) were reacted according
to the general procedure above to give 20a (0.185 g, 65%) as a
white solid; mp 158–166 ◦C (EtOH); [a]D24 +11.8 (c 0.9 in CHCl3);
To a stirred solution of R,R-diphenylethylene diamine 4 (0.795 g,
3.75 mmol) and triethylamine (0.757 g, 7.50 mmol) in DCM
(20 cm3) at 0 ◦C was added dropwise 15 (0.570 g, 3.75 mmol).
The reaction mixture was stirred overnight at room temperature
and concentrated under vacuum to give the crude product. The
residue was purified by flash chromatography (20% EtOAc–hexane
to 80% EtOAc–hexane) to give 16 (0.757 g, 62%) as a white solid
(Found: C, 65.65; H, 6.1; N, 8.◦30. C18H20N2O2S requires C, 65.85;
H, 6.15; N, 8.55%); mp 148 C (EtOH); [a]2D4 +10.5 (c 1.25 in
CHCl3); mmax/cm−1 (solid) 3352 (NH), 3310 (NH2), 3145 (≡C–
H), 1603 (NH2), 1314 and 1133 (SO2N), 767 and 697 (Ph); dH
(300 MHz; CDCl3; Me4Si) 1.93 (1 H, t, J 2.6, ≡CH), 2.35 (2 H, dt,
J 8.3 and 2.6, ≡CCH2), 2.49–2.66 (2 H, m, CH2SO2N), 2.85–4.05
(2 H, br s, NH2), 4.28 (1 H, d, J 5.8, PhCHNH2), 4.57 (1 H, d,
J 5.8, PhCHNHTs), 7.21–7.40 (11 H, m, 2 × Ph and NH); dC
(75.5 MHz; CDCl3; Me4Si) 14.1 (t), 52.0 (t), 60.6 (d), 63.0 (d), 70.4
(d), 80.4 (s), 127.1 (2 × d), 127.3 (2 × d), 128.4 (2 × overlapping
s), 129.1 (2 × d), 129.2 (2 × d), 139.8 (s), 141.7 (s). Found (EI)
329.1321 [MH]+, C18H21N2O2S requires 329.1324 (0.9 ppm error);
m/z (EI) 329 (MH+, 60%), 312 (30), 196 (30), 106 (100), 79 (40),
77 (30).
mmax/cm−1 (solid) 3300 (NH), 3262 (NH), 1686 (C O), 1318 and
=
1145 (SO2N), 756 and 696 (Ph); dH (400 MHz; CDCl3; Me4Si) 1.48
(9 H, s, C(CH3)3), 1.59 (0.5 H, s, CH3 minor isomer), 1.61 (2.5 H, s,
CH3 major isomer), 2.08–2.29 (4 H, m, 2 × CH2), 2.42–2.45 (2 H,
m, CH2), 2.54–2.62 (1 H, m, CHaHbNHSO2), 2.70–2.77 (1 H, m,
CHaHbNHSO2), 4.69 (1 H, dd, J 10.3 and 6.8, PhCHNHCO2),
4.84 (1 H, dd, J 10.3 and 10.0, PhCHNHSO2), 5.16–5.33 (3 H, m,
=
NHCO2 and 2 × CH), 6.03 (1 H, m, NHSO2), 6.99–7.07 (4 H, m,
Ph), 7.15–7.22 (6 H, m, Ph); dC (100.6 MHz; CDCl3; Me4Si) 22.9
(q, major isomer), 23.0 (q, minor isomer), 28.3 (3 × q), 29.4 (s),
30.6 (t), 31.4 (t), 52.3 (t), 60.0 (d), 64.0 (d), 80.8 (t), 118.0 (d, major
isomer), 118.2 (d, minor isomer), 120.3 (d, minor isomer), 120.4
(d, major isomer), 127.4 (2 × d), 127.5 (2 × d), 127.9 (d), 128.0 (d),
128.6 (overlapping 2 × (2 × d)), 131.0 (overlapping 2 × s), 138.2 (s),
138.9 (s); Found (LSIMS) 495.2334 [M-H]+, C28H35N2O4S requires
495.2318 (3.4 ppm error); m/z (EI) 495 (M-H+, 10%), 419 (100),
395 (75), 240 (75).
Synthesis of {(R,R)-2-[2-(4-tert-butylcyclohexa-1,4-dienyl)-
ethanesulfonylamino]-1,2-diphenylethyl}-tert-butyl carbamate 20b
Synthesis of [(R,R)-2-(but-3-yne-1-sulfonylamino)-1,
2-diphenylethyl]-tert-butyl carbamate 17
Catalyst 19 (0.006 g, 0.02 mmol), DCM (5 cm3), 2-tBu-butadiene
(0.163 g, 1.48 mmol) and 17 (0.317 g, 0.74 mmol) were reacted
according to the general procedure above to give 20b (0.329 g,
83%) as a white solid; mp 99–100 ◦C; [a]D18 +15.3 (c 1.35 in CHCl3);
To a stirred solution of 16 (1.170 g, 3.57 mmol) in THF (20 cm3)
was added di-tert-butyl dicarbonate (0.770 g, 3.57 mmol). The
reaction mixture was stirred overnight, diluted with 1 M potassium
hydrogen sulfate (aq.) (50 cm3) and extracted with DCM (2 ×
75 cm3). The combined extracts were dried (MgSO4), filtered
and concentrated under◦vacuum to give 17 (1.48 g, 97%) as a
white solid; mp 161–162 C (EtOH); [a]2D4 +5.2 (c 0.90 in CHCl3);
mmax/cm−1 (solid) 3350 (NH), 3250 (NH), 1686 (C O), 1319 and
=
1145 (SO2N), 755 and 697 (Ph); dH (400 MHz; CDCl3; Me4Si) 0.90
=
=
(2.1 H, s, CC(CH3)3 minor isomer), 0.98 (6.9 H, s, CC(CH3)3
major isomer), 1.48 (9 H, s, C(CH3)3), 2.11–2.33 (4 H, m, 2 × CH2),
2.53–2.63 (3 H, m, CH2 and CHaHbNHSO2), 2.69–2.79 (1 H, m,
CHaHbNHSO2), 4.70 (1 H, dd, J 10.0 and 6.8, PhCHNHCO2),
4.84 (1 H, dd, J 10.0 and 10.0, PhCHNHSO2), 5.18–5.42 (3 H, m,
mmax/cm−1 (solid) 3385 (NH), 3304 (NH), 1684 and 1672 (C O),
=
1323 and 1135 (SO2N), 697 (Ph); dH (400 MHz; CDCl3; Me4Si)
1.47 (9 H, s, 3 × CH3), 1.92 (1 H, t, J 2.5, ≡CH), 2.45 (2 H, dt, J
7.8 and 2.5, CH2CH2SO2), 2.64–2.89 (2 H, m, CH2SO2), 4.71 (1 H,
dd, J 10.0 and 6.8, PhCHNHCO2), 4.86 (1 H, dd, J 10.0 and 8.0,
PhCHNHSO2), 5.30 (1 H, br s, NHCO2), 6.28 (1 H, br s, NHSO2),
7.02–7.20 (10 H, m, 2 × Ph); dC (100.6 MHz; CDCl3; Me4Si) 13.8
(t), 28.3 (3 × q), 52.1 (t), 60.1 (d), 64.4 (d), 70.7 (d), 79.8 (s), 81.1 (s),
127.4 (2 × overlapping (2 × d)), 128.1 (d), 128.2 (d), 128.6 (2 × d),
128.8 (2 × d), 137.9 (2 × overlapping s), 138.5 (s); Found (LSIMS)
429.1835 [MH]+, C23H29N2O4S requires 429.1848 (3.1 ppm error);
m/z (EI) 329 ([MH-CO2C4H9]+, 5%), 222 (30), 206 (25), 150(50),
106 (100).
=
NHCO2 and 2 × CH), 6.03 (1 H, m, NHSO2), 6.99–7.07 (4 H, m,
Ph), 7.15–7.22 (6 H, m, Ph); dC (100.6 MHz; CDCl3; Me4Si) 28.7
(3 × q), 29.2 (3 × q, minor isomer), 29.3 (3 × q, major isomer),
30.1 (t), 30.9 (t), 31.3 (s), 35.2 (s), 52.7 (t), 60.5 (d), 64.6 (d), 81.3
(t), 115.1 (d, major isomer), 115.3 (d, minor isomer), 120.3 (d,
minor isomer), 121.3 (d, major isomer), 127.8 (2 × d), 127.9 (2 ×
d), 128.3 (d), 128.4 (d), 128.9 (2 × d), 129.1 (2 × d), 130.9 (s),
135.1 (s), 139.2 (s), 142.8 (s); Found (LSIMS) 537.2769 [M-H]+,
C31H41N2O4S requires 537.2787 (3.3 ppm error); m/z (LSIMS) 537
(M-H+, 40%), 439 (80), 240 (65), 196 (90), 106 (100).
Synthesis of {(R,R)-2-[2-(4-adamantan-1-ylcyclohexa-1,4-dienyl)-
ethanesulfonylamino]-1,2-diphenylethyl}-tert-butyl carbamate 20c
General procedure for the synthesis of compounds 20a–d
Catalyst 19 (0.009 g, 0.02 mmol), DCM (5 cm3), 2-adamantyl-
butadiene (0.404 g, 2.15 mmol) and 17 (0.460 g, 1.08 mmol)
were reacted according to the general procedure above to give 20c
(0.550 g, 83%) as a white solid; mp 119–121 ◦C; [a]D24 +19.0 (c 1.4
To a stirred solution of catalyst 19 (0.02 eq.) in DCM was
added the required diene (2.00 eq.) followed by 17 (1.00 eq.).
The reaction mixture was stirred for 2 hours and concentrated
under vacuum to give the crude product. The residue was purified
by flash chromatography (DCM to 2% DCM–MeOH) to give
cyclohexadienes 20a–d.
in CHCl3); mmax/cm−1 (solid) 3340 (NH), 3268 (NH), 1682 (C O),
=
1319 and 1146 (SO2N), 755 and 698 (Ph); dH (400 MHz; CDCl3;
Me4Si) 1.47 (9 H, s, C(CH3)3), 1.56–1.85 (12 H, m, adamantyl
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6 × CH2), 1.95–2.08 (3 H, m, adamantyl 3 × CH), 2.10–2.32 (4
H, m, 2 × CH2), 2.52–2.95 (4 H, m, 2 × CH2), 4.65–4.75 (1 H, m,
PhCHNHCO2), 4.83–4.91 (1 H, m, PhCHNHSO2), 5.18 (0.1 H,
ruthenium trichloride trihydrate (0.065 g, 0.25 mmol) were reacted
according to the general procedure above to give 21a (0.098 g, 48%)
as a dark green solid; mp >300 ◦C; mmax/cm−1 (solid) 3442 (NH),
+
=
=
m, CH minor isomer), 5.21 (0.9 H, m, CH major isomer), 5.31–
1602 and 1496 (NH3 ), 1321 and 1137 (SO2N), 764 and 699 (Ph);
=
5.41 (2 H, m, NHCO2 and CH), 6.08–6.24 (1 H, m, NHSO2),
dH (400 MHz; DMSO-d6) 2.07 (6 H, s, 2 × CH3), 3.20–3.50 (8
7.01–7.24 (10 H, m, Ph); dC (100.6 MHz; CDCl3; Me4Si) 24.8 (s),
28.4 (3 × q), 28.7 (3 × d), 29.8 (t), 30.5 (s), 37.1 (3 × t), 40.9
(3 × t), 43.2 (t), 52.4 (t), 60.2 (d), 64.2 (d), 80.9 (t), 114.9 (d,
major isomer), 115.0 (d, minor isomer), 120.0 (d, minor isomer),
121.0 (d, major isomer), 127.4 (2 × d), 127.5 (2 × d), 128.0 (d),
128.1 (d), 128.6 (2 × d), 128.7 (2 × d), 130.6 (s), 138.9 (s), 143.0
(s); Found (LSIMS) 616.3287 [M-H]+, C3613CH47N2O4S requires
616.3290 (0.5 ppm error); m/z (LSIMS) 615 (M+, 3%), 559 (4),
515 (20), 408 (10), 240 (30), 196 (55).
H, m, 2 × CH2CH2SO2 (peaks obscured by overlap with H2O
+
resonance)), 4.50 (2 H, m, 2 × PhCHNH3 ), 4.70 (2 H, t, J 9.6,
2 × PhCHNH), 5.36 (2 H, d, J 6.0, 2 × ArH on Ru-Ph), 5.69 (2
H, d, J 6.0, 2 × ArH on Ru-Ph), 5.75 (4 H, d, J 6.0, 4 × ArH
on Ru-Ph), 7.10–7.32 (20 H, m, 4 × Ph), 8.43 (2 H, d, J 9.6, 2 ×
+
NH), 8.65 (6 H, m, 2 × NH3 ); dC (75.5 MHz; DMSO-d6) 18.4
(2 × q), 26.4 (2 × t), 52.1 (2 × t), 58.7 (2 × d), 61.4 (2 × d),
86.1 (2 × d), 86.3 (2 × d), 88.6 (2 × d), 89.0 (2 × d), 96.7 (2 ×
s), 101.6 (2 × s), 128.3 (2 × (2 × d)), 128.4 (2 × d), 128.8 (2 ×
(2 × d)), 128.9 (overlapping 2 × (2 × d) and 2 × (2 × d)), 129.2
(2 × d), 134.7 (2 × s), 138.3 (2 × s). Found (LSIMS): 531.0440
(monomeric species formed in situ), 102RuC23H26N2O2SCl requires
531.0447 (1.2 ppm error); m/z (LSIMS) 531 (monomer+, 40%),
522 (60), 495 (M-HCl+, 20), 397 (100), 196 (100).
Synthesis of {(R,R)-1,2-diphenyl-2-[2-(4-phenylcyclohexa-1,
4-dienyl)-ethanesulfonylamino]-ethyl}-tert-butyl carbamate 20d
Catalyst 19 (0.008 g, 0.02 mmol), DCM (5 cm3), 2-phenylbutadiene
(0.250 g, 1.92 mmol) and 17 (0.412 g, 0.96 mmol) were reacted
according to the general procedure above to give 20d (0.521 g,
97%) as a white solid (Found: C, 70.8; H, 6.8; N, 4.95. C33H38N2O4S
requires C, 70.95; H, 6.85; N, 5.0%); mp 164–168 ◦C (dec.);
[a]D24 +23.7 (c 1.1 in CHCl3); mmax/cm−1 (solid) 3388 (NH), 3303
Synthesis of 2-(4-tert-butyl-phenyl)-ethanesulfonic acid
((R,R)-2-amino-1,2-diphenylethyl)-amide ammonium chloride
ruthenium dimer 21b
=
(NH), 1685 (C O), 1320 and 1142 (SO2N), 745 and 696 (Ph);
Diene 20b (0.600 g, 1.12 mmol), DCM (10 cm3), 1 M solution of
HCl in diethyl ether (20 cm3, 40.0 mmol), ethanol (10 cm3) and
ruthenium trichloride trihydrate (0.142 g, 0.55 mmol) were reacted
according to the general procedure above to give 21b (0.242 g, 68%)
as a dark green solid; mp >300 ◦C; mmax/cm−1 (solid) 3492 (NH),
dH (400 MHz; CDCl3; Me4Si) 1.47 (9 H, s, C(CH3)3), 2.16–2.39
(2 H, m, CH2), 2.44–2.52 (1.5 H, m, CH2), 2.57–2.68 (1.5 H, m,
CH2), 2.73–2.84 (1.5 H, m, CH2), 2.94–3.00 (1.5 H, m, CH2) (NB
unable to determine major/minor isomers of CH2 groups), 4.73
(1 H, dd, J 9.5 and 7.3, PhCHNHCO2), 4.84 (1 H, dd, J 9.5 and
+
1606 and 1496 (NH3 ), 1319 and 1137 (SO2N), 765 and 699 (Ph);
=
8.3, PhCHNHSO2), 5.26–5.39 (2 H, m, NHCO2 and CH2C CH),
5.97–6.01 (0.7 H, m, PhC CH major isomer), 6.03–6.06 (0.3 H,
m, PhC CH minor isomer), 6.18 (1 H, m, NHSO2), 7.01–7.37
dH (300 MHz; DMSO-d6) 1.33 (18 H, s, 2 × C(CH3)3), 3.20–3.50
=
(8 H, m, 2 × CH2CH2SO2 (peaks obscured by overlap with H2O
=
+
resonance)), 4.49 (2 H, m, 2 × PhCHNH3 ), 4.70 (2 H, m, 2 ×
(15 H, m, Ph); dC (100.6 MHz; CDCl3; Me4Si) 28.3 (3 × q), 28.7
(t), 30.0 (t), 30.5 (s), 52.3 (t), 60.1 (d), 64.3 (d), 81.0 (t), 119.9 (d,
minor isomer), 120.5 (d, major isomer), 121.0 (d, major isomer),
121.3 (d, minor isomer), 124.9 (2 × d), 127.0 (d), 127.4 (2 × d),
127.5 (2 × d), 128.0 (d), 128.1 (d), 128.3 (2 × d), 128.6 (2 × d),
128.7 (2 × d), 130.6 (s), 131.2 (s), 133.3 (s, minor isomer), 133.6
(s, major isomer), 138.0 (s, minor isomer), 138.9 (s, major isomer),
141.0 (s); Found (LSIMS) 557.2471 [M-H]+, C33H37N2O4S requires
557.2474 (0.5 ppm error); m/z (LSIMS) 559 (MH+, 5%), 503 (15),
459 (55), 351 (20), 240 (65), 196 (60).
PhCHNH), 5.34 (2 H, d, J 5.8, 2 × ArH on Ru-Ph), 5.72 (2 H,
d, J 6.0, 2 × ArH on Ru-Ph), 6.04 (4 H, m, 2 × (2 × ArH) on
Ru-Ph), 7.10–7.36 (20 H, m, 4 × Ph), 8.45 (2 H, d, J 9.8, 2 ×
+
NH), 8.59–8.78 (6 H, m, 2 × NH3 ); dC (125.8 MHz; DMSO-d6)
27.0 (2 × t), 30.6 (2 × (3 × q)), 52.6 (2 × t), 59.2 (2 × d), 61.9
(2 × d), 84.1 (2 × overlapping 2 × d), 87.7 (2 × d), 87.9 (2 × d),
98.6 (2 × s), 112.5 (2 × s), 128.8 (2 × (2 × d)), 128.9 (2 × d),
129.3 (2 × (2 × d)), 129.4 (2 × overlapping 2 × (2 × d)), 129.7
(2 × d), 135.3 (2 × s), 138.9 (2 × s). Found (LSIMS): 573.0920
(monomeric species formed in situ), 102RuC26H32N2O2SCl requires
573.0917 (0.6 ppm error); m/z (LSIMS) 573 (monomer+, 40%),
551 (100), 537 (M-HCl+, 50).
General procedure for the synthesis of compounds 21a–d
To a stirred solution of cyclohexadiene 20a–d (1.00 eq.) in DCM
was added an excess of a 2 M solution of HCl in diethyl ether and
the reactants stirred overnight. The solvent was removed from
the resulting precipitate under vacuum, dissolved in ethanol and
ruthenium trichloride trihydrate (typically 0.75 eq.) was added.
The reaction mixture was heated at reflux overnight and then
cooled to room temperature. The precipitate was collected by
filtration and washed with ethanol (5 × 10 cm3) to give ruthenium
dimers 21a–d.
Synthesis of 2-(4-adamantan-1-yl-phenyl)-ethanesulfonic acid
((R,R)-2-amino-1,2-diphenylethyl)-amide ammonium chloride
ruthenium dimer 21c
Diene 20c (0.500 g, 0.81 mmol), DCM (5 cm3), 2 M solution of
HCl in diethyl ether (10 cm3, 20.0 mmol), ethanol (12 cm3) and
ruthenium trichloride trihydrate (0.154 g, 0.59 mmol) were reacted
according to the general procedure above to give 21c (0.098 g, 23%)
as a dark green solid; mp >300 ◦C; mmax/cm−1 (solid) 3424 (NH),
Synthesis of 2-p-tolyl-ethanesulfonic acid ((R,R)-2-amino-1,
2-diphenylethyl)-amide ammonium chloride ruthenium dimer 21a
+
1605 and 1495 (NH3 ), 1318 and 1136 (SO2N), 763 and 699 (Ph);
dH (400 MHz; DMSO-d6) 1.67–2.05 (30 H, m, 2 × adamantyl),
Diene 20a (0.170 g, 0.34 mmol), DCM (2 cm3), 2 M solution
3.20–3.50 (8 H, m, 2 × CH2CH2SO2 (peaks obscured by overlap
+
of HCl in diethyl ether (8 cm3, 8.00 mmol), ethanol (5 cm3) and
with H2O resonance)), 4.49 (2 H, m, 2 × PhCHNH3 ), 4.71 (2 H,
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m, 2 × PhCHNH), 5.30 (2 H, d, J 6.0, 2 × ArH on Ru-Ph),
5.68 (2 H, d, J 5.3, 2 × ArH on Ru-Ph), 6.07 (4 H, m, 4 ×
ArH on Ru-Ph), 7.09–7.35 (20 H, m, 4 × Ph), 8.44 (2 H, d, J
extracted with DCM (3 × 100 cm3). The combined extracts were
concentrated under vacuum, dissolved in THF (110 cm3) and di-
tert-butyl dicarbonate (3.65 g, 16.7 mmol) added. The mixture was
stirred at room temperature overnight, diluted with 1 M KHSO4
(220 cm3) resulting in formation of a precipitate, to which water
(500 cm3) was added, extracted with DCM (2 × 500 cm3) and the
organic layers combined, dried (MgSO4), filtered and concentrated
under vacuum to give crude product. The residue was purified by
flash column chromatography (5% EtOAc–hexane to 20% EtOAc–
hexane) to give 25 (3.02 g, 40%) as a colourless oil; [a]2D7 +2.8 (c
2.1 in CHCl3); mmax/cm−1 (thin film) 3427 (OH), 3306 (≡CH),
+
10.0, 2 × NH), 8.63–8.72 (6 H, m, 2 × NH3 ); dC (125.8 MHz;
DMSO-d6) 26.7 (2 × t), 28.5 (2 × (3 × d)), 36.3 (2 × (3 × t)),
41.0 (2 × (3 × t)), 43.0 (2 × s), 52.0 (2 × t), 58.7 (2 × d), 61.4
(2 × d), 84.3 (2 × overlapping 2 × d), 85.9 (2 × d), 86.2 (2 ×
d), 128.3 (2 × d), 128.4 (2 × (2 × d)), 128.8 (2 × (2 × d)), 128.9
(2 × (2 × d)), 129.0 (2 × (2 × d)), 129.2 (2 × d), 134.6 (2 × s),
138.0 (2 × s) (NB not all quaternary carbons distinctly observed).
Found (LSIMS): 652.1399 (monomeric species formed in situ),
102RuC3113CH38N2O2SCl requires 652.1420 (3.2 ppm error); m/z
(LSIMS) 651 (monomer+, 10%), 615 (M-HCl+, 15), 515 (100), 196
(100).
=
1664 (C O), 770 and 701 (Ph); dH(300 MHz; CDCl3; Me4Si)
1.27–1.30 (3 H, m, CH3), 1.46 (9 H, s, C(CH3)3), 1.58–1.76 (2
H, m, CH2CH2C≡CH), 1.95–1.97 (1 H, m, ≡CH), 2.12–2.17 (2
H, m, CH2C≡CH), 3.09–3.18 (2 H, m, NCH2), 3.56 (1 H, br s,
CH3CHN), 4.58 (0.4 H, br s, PhCH rotamer A), 5.01 (0.6 H, br s,
PhCH rotamer B), 7.10–7.41 (5 H, m, Ph); dH(400 MHz; DMSO-
d6; 373 K) 1.27 (3 H, d, J 7.0, CH3), 1.38 (9 H, s, C(CH3)3),
1.47–1.65 (2 H, m, CH2CH2C≡CH), 2.05 (2 H, dt, J 7.0 and
2.6, CH2C≡CH), 2.48–2.51 (1 H, m, ≡CH), 2.91–2.98 (1 H, m,
NCHaHb), 3.05–3.12 (1 H, m, NCHaHb), 3.77 (1 H, apparent
quintet, dq, J 7.0 and 7.0, CH3CH), 4.72 (1 H, d, J 7.0, CHPh),
7.19–7.34 (5 H, m, Ph); dC(75.5 MHz; CDCl3; Me4Si) 10.8 (d),
14.2 (t), 26.6 (q), 27.4 (3 × q), 29.9 (d), 46.9 (t), 60.9 (d), 75.8 (t),
79.2 (s), 82.5 (s), 125.3 (2 × d), 126.3 (d), 127.1 (2 × d), 141.7 (s),
155.6 (s). Found (LSIMS) 318.2060 [MH]+, C19H28NO3 requires
318.2069 (2.8 ppm error); m/z (LSIMS) 318 (MH+, 90%), 262 (65),
244 (100), 210 (75).
Synthesis of 2-biphenyl-4-yl-ethanesulfonic acid ((R,R)-2-amino-1,
2-diphenylethyl)-amide ammonium chloride ruthenium dimer 21d
Diene 20d (0.500 g, 0.90 mmol), DCM (5 cm3), 2 M solution
of HCl in diethyl ether (5 cm3, 20.0 mmol), ethanol (15 cm3) and
ruthenium trichloride trihydrate (0.195 g, 0.75 mmol) were reacted
according to the general procedure above to give 21d (0.145 g, 29%)
as a dark green solid; mp >300 ◦C; mmax/cm−1 (solid) 3465 (NH),
+
1600 and 1495 (NH3 ), 1321 and 1138 (SO2N), 764 and 698 (Ph);
dH (400 MHz; DMSO-d6) 3.20–3.50 (8 H, m, 2 × CH2CH2SO2
(peaks obscured by overlap with H2O resonance)), 4.44–4.55 (2
+
H, m, 2 × PhCHNH3 ), 4.73 (2 H, t, J 9.8, 2 × PhCHNH), 5.48
(1.5 H, d, J 6.2, 2 × ArH on Ru-Ph major isomer), 5.87 (1.5 H, d,
J 6.2, 2 × ArH on Ru-Ph major isomer), 6.06–6.12 (1 H, m, 4 ×
ArH on Ru-Ph minor isomer), 6.26–6.29 (1 H, m, 4 × ArH on Ru-
Ph minor isomer), 6.47 (3 H, d, J 6.2, 4 × ArH on Ru-Ph major
isomer), 7.18–7.52 (30 H, m, 6 × Ph), 8.24 (0.5 H, d, J 9.8, 2 ×
NH minor isomer), 8.46 (1.5 H, d, J 9.8, 2 × NH major isomer),
Synthesis of tert-butyl (1R,2S)–1-(tert-butyldimethylsilyloxy)-
1-phenylpropan-2-yl (pent-4-ynyl)carbamate 27
To a solution of 25 (2.153 g, 6.79 mmol) and imidazole (0.740 g,
10.86 mmol) in anhydrous DMF (22 cm3), was added tert-
butyldimethylsilyl chloride (1.535 g, 10.19 mmol). The reaction
mixture was stirred overnight, diluted with water (50 cm3) and
extracted with diethyl ether (2 × 100 cm3). The combined extracts
were dried (MgSO4), filtered, and concentrated under vacuum
to give the crude product. The residue was purified by flash
chromatography (2% EtOAc–hexane to 4% EtOAc–hexane) to
give 27 (2.856 g, 98%) as a colourless oil (Found: C, 69.5; H, 9.5,
N, 3.05. C25H41NO3Si requires C, 69.55; H, 9.55, N, 3.25%); [a]D27
+10.1 (c 1.45 in CH2Cl2); mmax/cm−1 (thin film) 3250 (≡CH), 1688
+
8.60–8.72 (6 H, m, 2 × NH3 ); dC (100.6 MHz; DMSO-d6) 26.5
(2 × t), 51.8 (2 × t), 58.4 (2 × d), 61.0 (2 × d), 85.6 (2 × d), 85.8
(2 × d), 86.9 (2 × d), 87.0 (2 × d), 97.5 (2 × s), 101.8 (2 × s), 128.0
(2 × (2 × d)), 128.3 (2 × d), 128.5 (2 × (2 × d)), 128.7 (2 × (2 × d)),
128.8 (2 × (2 × d)), 128.9 (2 × (2 × d)), 129.0 (2 × (2 × d)), 129.1
(2 × d), 129.8 (2 × d), 133.2 (2 × s), 134.3 (2 × s), 137.7 (2 × s,
major isomer), 137.8 (2 × s, minor isomer) (NB not all carbons
of minor isomer distinctly observed). Found (LSIMS): 557.0841
(monomeric species formed in situ), 102RuC28H27N2O2SCl requires
557.0837 (0.7 ppm error); m/z (LSIMS) 557 (monomer+, 75%),
551 (90), 523 (100).
=
(C O), 1253 and 865 (Si(CH3)2), 774 and 701 (Ph); dH(300 MHz;
1
Note: the H-NMR spectra for compounds containing tBoc
CDCl3; Me4Si) −0.25 (6 H, s, Si(CH3)2), 0.89 (9 H, s, SiC(CH3)3),
1.26–1.35 (3 H, m, CH3CHN), 1.41 (9 H, s, OC(CH3)3), 1.45
(2 H, s, CH2CH2C≡CH), 1.92 (1 H, s, ≡CH), 1.95–2.10 (2 H,
m, CH2C≡CH), 2.91–3.07 (2 H, m, NCH2), 3.64 (1 H, br s,
CH3CHN), 4.79 (0.4 H, br s, PhCH rotamer A), 4.98 (0.6 H, br s,
PhCH rotamer B), 7.20–7.35 (5 H, m, Ph); dH(400 MHz; DMSO-
d6; 373 K) −0.24 (6 H, s, Si(CH3)2), 0.84 (9 H, s, SiC(CH3)3), 1.29
(3 H, d, J 7.0, CH3CHN), 1.35 (9 H, s, OC(CH3)3), 1.45–1.55
(1H, m, ≡CH), 1.95–1.99 (2 H, m, CH2CH2C≡CH), 2.44–2.48
(2 H, m, CH2C≡CH), 2.75–2.82 (1 H, m, NCHaHb), 2.92–2.99
(1 H, m, NCHaHb), 3.58 (1 H, apparent quintet, dq, J 7.3 and
7.0, CH3CH), 4.88 (1 H, d, J 7.3, PhCH), 7.19–7.27 (5 H, m, Ph);
dC(125.8 MHz; DMSO-d6) −4.4 (2 × q), 15.6 (t), 18.1 (s), 26.0 (3 ×
q), 28.4 (3 × q), 40.4 (t), 55.3 (d), 71.5 (s), 71.6 (d), 76.3 (d), 78.7 (t),
79.1 (s), 84.1 (s), 126.7 (2 × d), 127.6 (d), 127.7 (2 × d), 143.1 (s),
protecting groups obtained at rt were subject to significant
broadening due to restricted rotation effects. The data for these
spectra have been quoted along with the best spectra obtained
using elevated temperatures where this was possible.
Synthesis of tert-butyl (1R,2S)-1-hydroxy-1-phenylpropan-2-yl-
(pent-4-ynyl) carbamate 25
To a solution of 1R,2S-norephedrine 3 (3.57 g, 23.6 mmol) and
triethylamine (2.63 g, 26.0 mmol) in acetonitrile (70 cm3) was
added 26 (5.63 g, 23.6 mmol). The reaction mixture was refluxed
overnight, cooled to room temperature and concentrated under
vacuum. The residue was dissolved in DCM (150 cm3), washed
with sat. NaHCO3 solution (100 cm3) and the aqueous layer
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154.5 (s) (NB signal due to CH3CHN not observed possibly due
to restricted rotation effects). Found (LSIMS): 432.2916 [MH]+,
C25H42NO3Si requires 432.2934 (4.2 ppm error); m/z (LSIMS) 432
(MH+, 15%), 358 (25), 332 (65), 318 (50), 244 (100), 221 (75), 210
(60), 147 (55).
1.78–1.83 (2 H, m, CH2CH2CH2N), 2.52–2.56 (2 H, m, diene
CH2), 2.63–2.69 (2 H, m, diene CH2), 2.85–2.97 (2 H, m, NCH2),
3.63 (1 H, m, CH3CHN), 4.79 (0.4 H, br s, PhCH rotamer A),
=
4.95 (0.6 H, br s, PhCH rotamer B), 5.34 (0.15 H, m, CH minor
=
=
isomer), 5.38 (0.85 H, m, CH major isomer), 5.48 (1 H, m, CH),
7.17–7.33 (5 H, m, Ph); dC(125.8 MHz; CDCl3; Me4Si) −5.7 (2 ×
q), 13.1 (q), 17.0 (s), 24.9 (3 × q), 27.5 (3 × q), 27.9 (3 × q),
29.2 (t), 31.8 (t), 33.3 (t), 33.9 (t), 41.2 (t), 51.7 (d), 75.4 (d), 77.8
(s), 78.3 (s), 114.2 (d), 117.9 (d), 125.5 (2 × d), 125.9 (d), 126.6
(2 × d), 132.8 (s), 142.2 (s), 147.6 (s), 154.1 (s). Found (LSIMS):
540.3889 [M-H]+, C33H54NO3Si requires 540.3873 (3.0 ppm error);
m/z (LSIMS) 540 (M-H+, 45%), 440 (95), 352 (60), 318 (55), 262
(100), 218 (85). A satisfactory 1H-NMR to improve the resolution
of peaks at elevated temperatures could not be obtained due to
facile oxidation of the cyclohexadiene ring to the corresponding
aromatic ring.
General procedure for the synthesis of compounds 28a–d
To a stirred solution of 19 (0.02 eq.) in DCM was added the
appropriate diene (2.00 eq.) followed by 27 (1.00 eq.). The reaction
mixture was stirred for 2 hours and concentrated under vacuum
to give the crude product. The residue was purified by flash
chromatography (2% EtOAc–hexane) to give cyclohexadienes
28a–d.
Synthesis of [(1S,2R)-2-(tert-butyldimethylsilanyloxy)-1-methyl-2-
phenylethyl]-[3-(4-methylcyclohexa-1,4-dienyl)-propyl]-tert-butyl
carbamate 28a7c
Synthesis of [3-(4-adamantan-1-ylcyclohexa-1,4-dienyl)-propyl]-
[(1S,2R)–2-(tert-butyldimethylsilanyloxy)-1-methyl-2-phenyl-
ethyl]-tert-butyl carbamate 28c
Catalyst 19 (0.050 g, 0.12 mmol), DCM (30 cm3), isoprene (0.317 g,
4.66 mmol) and 27 (1.00 g, 2.33 mmol) were reacted according
to the general procedure above to give 28a (0.853 g, 73%) as a
thick colourless oil; [a]2D7 +5.9 (c 1.2 in DCM); mmax/cm−1 (thin
Catalyst 19 (0.034 g, 0.08 mmol), DCM (22 cm3), 2-adamantyl-
butadiene (0.600 g, 3.19 mmol) and 27 (0.685 g, 1.60 mmol)
were reacted according to the general procedure above to give
28c (0.730 g, 74%) as a thick colourless oil; [a]2D5 −15.4 (c 0.15
=
film) 1689 (C O), 1252 and 865 (Si(CH3)2), 774 and 700 (Ph);
dH(300 MHz; CDCl3; Me4Si) −0.25 (6 H, s, Si(CH3)2), 0.88 (9
H, s, SiC(CH3)3), 1.19–1.29 (3 H, m, CH3CHN), 1.40 (9 H, s,
in DCM); mmax/cm−1 (thin film) 1689 (C O), 1251 and 864
=
=
OC(CH3)3), 1.45 (2 H, m, CH2CH2N), 1.66 (3 H, s, CH3C ),
(Si(CH3)2), 774 and 700 (Ph); dH(300 MHz; CDCl3; Me4Si) −0.27
(6 H, s, Si(CH3)2), 0.86 (9 H, s, SiC(CH3)3), 1.21–1.23 (3 H, m,
CH3CHN), 1.28–1.83 (26 H, m, OC(CH3)3, 6 × adamantyl CH2,
3 × adamantyl CH and CH2CH2N), 2.35–2.68 (4 H, m, 2 × diene
CH2), 2.86–2.92 (2 H, m, NCH2), 3.61 (1 H, m, CH3CHN), 4.77
(0.4 H, br s, PhCH rotamer A), 4.95 (0.6 H, br s, PhCH rotamer B),
1.82–1.85 (2 H, m, CH2CH2CH2N), 2.22–2.27 (2 H, m, diene
CH2), 2.53 (2 H, m, diene CH2), 2.80–3.00 (2 H, m, NCH2), 3.63
(1 H, m, CH3CHN), 4.79 (0.4 H, br s, PhCH rotamer A), 4.97
=
(0.6 H, br s, PhCH rotamer B), 5.35 (1 H, m, CH), 5.39 (1 H, m,
=
CH), 7.00–7.20 (5 H, m, Ph); dH(500 MHz; DMSO-d6; 373 K)
−0.24 (6 H, s, Si(CH3)2), 0.84 (9 H, s, SiC(CH3)3), 1.27–1.29 (3 H,
=
=
5.32 (0.2 H, m, CH minor isomer), 5.36 (0.8 H, m, CH major
d, J 7.5, CH3CHN), 1.36 (9 H, s, OC(CH3)3), 1.41–1.45 (2 H, m,
=
isomer), 5.41 (1 H, m, CH), 7.16–7.24 (5 H, m, Ph); dC(75.5 MHz;
=
CH2CH2N), 1.62 (3 H, s, CH3C ), 1.77 (2 H, m, CH2CH2CH2N),
CDCl3; Me4Si) −4.2 (2 × q), 18.5 (s), 26.2 (t), 26.3 (3 × q), 29.2
(3 × q), 29.4 (3 × d), 30.6 (t), 33.2 (s), 34.7 (t), 37.0 (t), 37.2 (3 × t),
41.4 (3 × t), 43.6 (t), 58.0 (d), 76.8 (d), 79.2 (s), 115.7 (d), 119.4 (d),
126.9 (2 × d), 127.4 (d), 128.0 (2 × d), 134.2 (s), 134.4 (s), 143.6 (s),
154.1 (s) (NB signal due to CH3CHN not observed possibly due
to restricted rotation effects). Found (LSIMS): 618.4319 [M-H]+,
C39H60NO3Si requires 618.4342 (3.8 ppm error); m/z (LSIMS) 618
(M-H+, 10%), 518 (65), 430 (40), 340 (75), 296 (100), 221 (55), 210
(60), 135 (50). A satisfactory 1H-NMR to improve the resolution
of peaks at elevated temperatures could not be obtained due to
facile oxidation of the cyclohexadiene ring to the corresponding
aromatic ring.
2.16–2.39 (2 H, m, diene CH2), 2.59–2.70 (2 H, m, diene CH2),
2.89–2.94 (2 H, m, NCH2), 3.56–3.61 (1 H, m, CH3CHN), 4.88
=
=
(1 H, d, J 7.3, PhCH), 5.35 (1 H, m, CH), 5.38 (1 H, m, CH),
7.20–7.29 (5 H, m, Ph); dC(75.5 MHz; CDCl3; Me4Si) −4.9 (2 × q),
17.8 (s), 22.8 (q), 25.7 (3 × q), 28.3 (3 × q), 29.7 (t), 31.4 (t), 34.0
(t), 34.2 (t), 41.4 (t), 51.2 (d), 76.2 (d), 79.8 (s), 118.3 (d), 118.4 (d),
126.7 (2 × d), 127.0 (d), 127.6 (2 × d), 133.2 (s), 133.4 (s), 136.1 (s),
161.0 (s) (NB signal due to CH3CHN not observed possibly due
to restricted rotation effects). Found (LSIMS): 498.3415 [M-H]+,
C30H48NO3Si requires 498.3403 (2.4 ppm error); m/z (LSIMS) 498
(M-H+, SS 5%), 426 (20), 400 (80), 312 (55), 222 (100), 178 (90).
Synthesis of [3-(4-tert-butyl-cyclohexa-1,4-dienyl)-propyl]-
[(1S,2R)-2-(tert-butyldimethylsilanyloxy)-1-methyl-2-
phenylethyl]-tert-butyl carbamate 28b
Synthesis of [(1S,2R)-2-(tert-butyldimethylsilanyloxy)-1-methyl-2-
phenylethyl]-[3-(4-phenylcyclohexa-1,4-dienyl)-propyl]-tert-butyl
carbamate 28d
Catalyst 19 (0.009 g, 0.02 mmol), DCM (10 cm3), 2-tBu-butadiene
(0.192 g, 1.75 mmol) and 27 (0.441 g, 1.53 mmol) were reacted
according to the general procedure above to give 28b (0.428 g, 52%)
as a thick colourless oil; [a]2D5 +0.9 (c 0.95 in CHCl3); mmax/cm−1
Catalyst 19 (0.02 g, 0.04 mmol), DCM (30 cm3), 2-phenyl-
butadiene (0.579 g, 4.46 mmol) and 27 (1.00 g, 2.23 mmol) were
reacted according to the general procedure above to give 28d
(1.20 g, 96%) as a thick colourless oil; [a]2D5 −2.7 (c 0.15 in DCM);
=
(thin film) 1690 (C O), 1253 and 865 (Si(CH3)2), 774 and 700
mmax/cm−1 (thin film) 1688 (C O), 1252 and 864 (Si(CH3)2),
=
(Ph); dH(400 MHz; CDCl3; Me4Si) −0.27 (6 H, s, Si(CH3)2), 0.87
=
(9 H, s, SiC(CH3)3), 1.02 (9 H, s, (CH3)3CC ), 1.21–1.32 (3 H, m,
775 and 698 (Ph); dH(300 MHz; CDCl3; Me4Si) −0.26 (6 H, s,
Si(CH3)2), 0.86 (9 H, s, SiC(CH3)3), 1.23–1.26 (3 H, m, CH3CHN),
CH3CHN), 1.38 (9 H, s, OC(CH3)3), 1.44 (2 H, m, CH2CH2N),
1100 | Org. Biomol. Chem., 2007, 5, 1093–1103
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1.39 (9 H, s, OC(CH3)3), 1.48 (2 H, m, CH2CH2N), 1.83–1.88 (2
H, m, CH2CH2CH2N), 2.72–2.88 (4 H, m, 2 × diene CH2), 3.01–
3.05 (2 H, m, NCH2), 3.62 (1 H, m, CH3CHN), 4.70 (0.4 H, br s,
PhCH rotamer A), 4.97 (0.6 H, br s, PhCH rotamer B), 5.41 (0.3
Synthesis of [3-(4-tert-butylcyclohexa-1,4-dienyl)-propyl]-
((1S,2R)-2-hydroxy-1-methyl-2-phenylethyl)-tert-butyl carbamate
Diene 28b (0.400 g, 0.74 mmol), THF (6 cm3), and a 1 M solution
of TBAF in THF (1.1 cm3) were reacted according to the general
procedure above to give the alcohol (0.283 g, 90%) as a thick
colourless oil; [a]D21 +6.1 (c 0.95 in CHCl3); mmax/cm−1 (thin film)
=
=
H, m, CH a to Ph, minor isomer), 5.48 (0.7 H, m, CH a to Ph,
=
major isomer), 6.09 (1 H, m, CH b to Ph), 7.16–7.40 (10 H, m,
2 × Ph); dH(400 MHz; DMSO-d6; 373 K) −0.25 (6 H, s, Si(CH3)2),
0.84 (9 H, s, SiC(CH3)3), 1.30 (3 H, d, J 7.0, CH3CHN), 1.37 (9
H, s, OC(CH3)3), 1.42–1.50 (2 H, m, CH2CH2N), 1.82–1.86 (2 H,
m, CH2CH2CH2N), 2.69–2.74 (4 H, m, 2 × diene CH2), 2.97 (2 H,
m, NCH2), 3.58 (1 H, dq (app. quintet), J 7.7 and 7.0 CH3CHN),
=
3440 (OH), 1665 (C O), 760 and 701 (Ph); dH(300 MHz; CDCl3;
=
Me4Si) 1.04 (9 H, s (CH3)3CC ), 1.22–1.28 (3 H, m, CH3CHN),
1.45 (9 H, s, OC(CH3)3), 1.48–1.68 (2 H, m, CH2CH2N), 1.88–
1.93 (2 H, m, CH2CH2CH2N), 2.48–2.72 (4 H, m, 2 × diene
CH2), 2.95–3.08 (2 H, m, NCH2), 3.50 (1 H, m, CH3CHN), 5.00
=
4.90 (1 H, d, J 7.7, PhCH), 5.40 (0.3 H, m, CH a to Ph, minor
=
(PhCH), 5.39 (0.15 H, m, CH minor isomer), 5.44 (0.85 H, m,
=
isomer), 5.47 (0.7 H, m, CH a to Ph, major isomer), 6.09 (1 H,
=
=
CH major isomer), 5.51 (1 H, m, CH), 7.21–7.40 (5 H, m, Ph);
=
m, CH b to Ph), 7.16–7.39 (10 H, m, 2 × Ph); dC(75.5 MHz;
dC(125.8 MHz; CDCl3; Me4Si) 14.2 (q), 25.6 (t), 29.0 (3 × q), 29.0
(t), 31.4 (t), 31.6 (3 × q), 32.2 (t), 48.9 (t), 49.1 (s), 62.1 (d), 77.4
(d), 80.1 (s), 115.2 (d), 119.2 (d), 125.3 (d), 126.4 (2 × d), 127.9
(2 × d), 138.4 (s), 142.5 (s), 148.8 (s), 156.8 (s). Found (LSIMS):
426.2997 [M-H]+, C27H40NO3 requires 426.3008 (2.7 ppm error);
m/z (LSIMS) 426 (M-H+, 50%), 370 (40), 352 (80), 318 (50), 262
(100), 218 (85). A satisfactory 1H-NMR to improve the resolution
of peaks at elevated temperatures could not be obtained due to
facile oxidation of the cyclohexadiene ring to the corresponding
aromatic ring.
CDCl3; Me4Si) −4.8 (2 × q), 13.9 (q), 17.9 (s), 25.7 (3 × q), 27.1
(t), 28.5 (3 × q), 28.6 (t), 30.1 (t), 31.0 (t), 34.1 (t) 53.2 (d), 76.2 (d),
78.7 (s), 118.3 (d), 121.5 (d), 124.8 (2 × d), 126.3 (2 × d), 126.8
(d), 127.4 (2 × d), 127.7 (d), 128.064 (2 × d), 133.6 (s), 134.1 (s),
141.2 (s), 143.0 (s), 154.8 (s). Found (LSIMS): 560.3554 [M-H]+,
C35H50NO3Si requires 560.3560 (1.0 ppm error); m/z (LSIMS) 560
(M-H+, 30%), 460 (70), 372 (60), 338 (40), 282 (95), 238 (100), 221
(50), 136 (65).
General procedure for the desilylation of compounds 28a–d
To a stirred solution of 28a–d (1.00 eq.) in THF was added a
1 M solution of TBAF in THF (1.50 eq.). The reaction mixture
was stirred overnight, diluted with water, extracted with EtOAc,
dried (MgSO4) and concentrated under vacuum to give the crude
product. The residue was purified by flash chromatography (2.5%
to 20% EtOAc–hexane) to give the corresponding alcohols.
Synthesis of [3-(4-adamantan-1-yl-cyclohexa-1,4-dienyl)-propyl]-
((1S,2R)-2-hydroxy-1-methyl-2-phenylethyl)-tert-butyl carbamate
Diene 28c (0.730 g, 1.18 mmol), THF (10 cm3), and a 1 M solution
of TBAF in THF (1.8 cm3) were reacted according to the general
procedure above to give the alcohol (0.450 g, 65%) as a thick
colourless oil; [a]D25 +2.9 (c 0.1 in DCM); mmax/cm−1 (thin film)
Synthesis of ((1S,2R)-2-hydroxy-1-methyl-2-phenylethyl)-[3-(4-
methylcyclohexa-1,4-dienyl)-propyl]-tert-butyl
carbamate7c
=
3441 (OH), 1665 (C O), 758 and 700 (Ph); dH(300 MHz; CDCl3;
Me4Si) 1.15–1.17 (3 H, m, CH3CHN), 1.34 (9 H, s, OC(CH3)3),
1.57–2.05 (19 H, m, CH2CH2CH2N, 6 × adamantyl CH2 and 3 ×
adamantyl CH), 2.38–2.61 (4 H, m, 2 × diene CH2), 2.84–3.01
(2 H, m, NCH2), 3.41 (1 H, m, CH3CHN), 4.77 (0.4 H, br s,
PhCH rotamer A), 4.99 (0.6 H, br s, PhCH rotamer B), 5.35–
Diene 28a (0.800 g, 1.60 mmol), THF (8 cm3), and a 1 M solution
of TBAF in THF (2.4 cm3) were reacted according to the general
procedure above to give the product (0.386 g, 63%) as a thick
colourless oil; [a]D27 +14.3 (c 1.05 in DCM); mmax/cm−1 (thin film)
=
5.38 (2 H, m, 2 × CH), 7.02–7.24 (5 H, m, Ph); dC(75.5 MHz;
CDCl3; Me4Si) 11.3 (q), 24.6 (t), 28.3 (3 × q), 28.8 (3 × d), 30.0
(t), 32.5 (s), 34.0 (t), 36.6 (t), 36.9 (3 × t), 40.7 (3 × t), 43.0 (t),
61.9 (d), 77.2 (d), 79.9 (s), 115.0 (d), 119.0 (d), 125.9 (2 × d),
127.0 (d), 127.9 (2 × d), 133.4 (s), 142.6 (s), 143.0 (s), 155.4 (s).
Found (LSIMS): 504.3460 [M-H]+, C33H46NO3 requires 504.3478
(3.5 ppm error); m/z (LSIMS) 432 (M-H+, 45%), 430 (70), 396
(30), 340 (90), 296 (100). A satisfactory 1H-NMR to improve
the resolution of peaks at elevated temperatures could not be
obtained due to facile oxidation of the cyclohexadiene ring to
the corresponding aromatic ring.
=
3391 (OH), 1664 (C O), 759 and 700 (Ph); dH(300 MHz; CDCl3;
Me4Si) 1.22–1.26 (3 H, m, CH3CHN), 1.45 (9 H, s, OC(CH3)3),
1.52–1.64 (2 H, m, CH2CH2N), 1.67 (3 H, s, CH3), 1.88–1.91 (2
H, m, CH2CH2CH2N), 2.49–2.62 (4 H, m, 2 × diene CH2), 2.93–
2.98 (2 H, m, NCH2), 3.49 (1 H, m, CH3CHN), 4.87 (0.4 H, br s,
PhCH rotamer A), 4.99 (0.6 H, br s, PhCH rotamer B), 5.40 (2 H,
=
m, 2 × CH), 7.25–7.37 (5 H, m, Ph); dH(400 MHz; DMSO-d6;
363 K) 1.20 (3 H, d, J 6.6, CH3CHN), 1.34 (9 H, s, OC(CH3)3),
1.34–1.53 (2 H, m, CH2CH2N), 1.59 (3 H, s, CH3), 1.79 (2 H,
t, J 6.4, CH2CH2CH2N), 2.55–2.62 (4 H, m, 2 × diene CH2),
2.88–2.95 (2 H, m, NCH2), 3.68 (1 H, dq (app. quintet), J 6.6
and 5.8, CH3CHN), 4.66 (1 H, t, J 5.8 and 4.8), 4.99 (1 H, d, J
Synthesis of ((1S,2R)-2-hydroxy-1-methyl-2-phenylethyl)-
[3-(4-phenylcyclohexa-1,4-dienyl)-propyl]-tert-butyl carbamate
=
4.8, OH), 5.31–5.38 (2 H, m, 2 × CH), 7.12–7.28 (5 H, m, Ph);
dC(125.8 MHz; DMSO-d6) 13.9 (q), 23.3 (q), 27.5 (3 × q), 29.7 (t),
31.4 (t), 34.3 (t), 40.4 (t), 45.9 (t), 58.6 (d), 75.0 (d), 78.4 (s), 118.2
(d), 118.8 (d), 126.7 (2 × d), 127.9 (d), 128.4 (2 × d), 131.1 (s),
134.2 (s), 144.5 (s), 154.4 (s). Found (LSIMS): 384.2520 [M-H]+,
C24H34NO3 requires 384.2539 (4.9 ppm error); m/z (LSIMS) 384
(M-H+, 25%), 330 (45), 312 (95), 310 (90), 242 (65), 222 (80), 220
(60), 178 (100), 176 (60).
Diene 28d (1.00 g, 1.79 mmol), THF (10 cm3), and a 1 M solution
of TBAF in THF (2.7 cm3) were reacted according to the general
procedure above to give the alcohol (0.740 g, 94%) as a thick
colourless oil; [a]D25 +9.7 (c 0.1 in DCM); mmax/cm−1 (thin film) 3434
=
(OH), 1662 (C O), 756 and 698 (Ph); dH(300 MHz; CDCl3; Me4Si)
1.24–1.28 (3 H, m, CH3CHN), 1.43 (9 H, s, OC(CH3)3), 1.52–1.64
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+
(2 H, m, CH2CH2N), 1.98–2.03 (2 H, m, CH2CH2CH2N), 2.56–
3.07 (6 H, m, 2 × diene CH2 and NCH2), 3.48 (1 H, m, CH3CHN),
4.77 (0.4 H, br s, PhCH rotamer A), 4.99 (0.6 H, br s, PhCH
(OH), 1603 (NH2 ), 745 and 701 (Ph); dH(400 MHz; DMSO-d6)
0.94 (6 H, d, J 6.0, 2 × CH3CHN), 1.39 (18 H, s, 2 × ArC(CH3)3),
1.96–2.03 (4 H, m, 2 × CH2CH2N), 2.53–2.58 (4 H, m, 2 ×
CH2CH2CH2N), 3.08–3.17 (4 H, m, 2 × NCH2), 3.48 (2 H, m,
2 × CH3CHN), 5.10 (2 H, m, 2 × PhCH), 5.86 (4 H, d, J 6.0,
2 × (2 × ArH on Ru-arene)), 6.14 (4 H, d, J 6.0, 2 × (2 × ArH
on Ru-arene)), 7.33 (2 H, br s, 2 × OH), 7.38–7.45 (10 H, m, 2 ×
=
rotamer B), 5.38 (0.3 H, m, CH a to Ph, minor isomer), 5.44 (0.7
=
=
H, m, CH a to Ph, major isomer), 6.06 (1 H, m, CH b to Ph),
7.24–7.48 (10 H, m, 2 × Ph); dC(75.5 MHz; CDCl3; Me4Si) 12.1
(q), 27.9 (t), 28.9 (3 × q), 31.3 (t), 33.3 (t), 33.8 (t), 47.0 (t), 57.5
(d), 77.8 (d), 80.6 (s), 120.8 (d), 125.4 (d), 126.6 (2 × d), 127.4 (2 ×
d), 127.6 (2 × overlapping d), 128.6 (2 × d), 129.2 (2 × d), 137.8
(s), 141.4 (s), 143.1 (s) (NB not all quaternary carbons distinctly
observed). Found (LSIMS): 446.2711 [M-H]+, C29H36NO3 requires
446.2695 (3.5 ppm error); m/z (LSIMS) 446 (M-H+, 30%), 372
+
Ph), 8.41–8.68 (4 H, m, 2 × NH2 ); dC(100.6 MHz; DMSO-d6)
9.8 (2 × q), 25.8 (2 × t), 29.5 (2 × t), 30.3 (2 × (3 × q)), 34.8 (s),
44.7 (2 × t), 58.5 (2 × d), 69.9 (2 × d), 84.7 (2 × (2 × d)), 86.1
(2 × (2 × d)), 101.7 (2 × s), 111.1 (2 × s), 126.3 (2 × (2 × d)),
127.8 (2 × d), 128.6 (2 × (2 × d)), 141.5 (2 × s). Found (LSIMS):
462.1148 (monomeric species formed in situ), 102RuC22H31NOCl
requires 462.1138 (2.1 ppm error); m/z (LSIMS) 462 (monomer+,
30%), 326 (100), 232 (80).
1
(100), 318 (30), 282 (85), 238 (95). A satisfactory H-NMR to
improve the resolution of peaks at elevated temperatures could
not be obtained due to facile oxidation of the cyclohexadiene ring
to the corresponding aromatic ring.
Synthesis of (1R,2S)-2-[3-(4-adamantan-1-yl-phenyl)-
propylamino]-1-phenylpropan-1-ol ruthenium dimer 29c
General procedure for the synthesis of compounds 29a–d
To a stirred solution of the precursor alcohol prepared as described
above (1.00 eq.) in DCM was added an excess of a 2 M solution
of HCl in diethyl ether and the reactants stirred overnight.
The solvent was removed from the resulting precipitate under
vacuum, dissolved in ethanol and ruthenium trichloride trihydrate
(typically 0.75 eq.) was added. The reaction mixture was heated
at reflux overnight and then cooled to room temperature. The
precipitate was collected by filtration and washed with ethanol
(5 × 10 cm3) to give ruthenium dimers 29a–d.
The precursor alcohol (0.450 g, 0.90 mmol), DCM (10 cm3),
2 M solution of HCl in diethyl ether (15 cm3, 30.00 mmol),
ethanol (12.5 cm3) and ruthenium trichloride trihydrate (0.157 g,
0.60 mmol) were reacted according to the general procedure above
to give 29c (0.149 g, 28%) as a dark green solid; mmax/cm−1 (thin
+
film) 3396 (OH), 1602 (NH2 ), 746 and 701 (Ph); dH(300 MHz;
DMSO-d6) 0.92 (6 H, m, 2 × CH3CHN), 1.60–2.05 (34 H, m,
2 × (CH2CH2N, 6 × adamantyl CH2 and 3 × adamantyl CH)),
2.48–2.53 (4 H, m, 2 × CH2CH2CH2N), 3.08–3.19 (4 H, m, 2 ×
NCH2), 3.50 (2 H, m, 2 × CH3CHN), 5.10 (2 H, m, 2 × PhCH),
5.81 (4 H, m, 2 × (2 × ArH on Ru-arene)), 6.05–6.18 (6 H, m, 2 ×
(2 × ArH on Ru-arene) and 2 × OH), 7.31–7.43 (10 H, m, 2 ×
Synthesis of (1R,2S)-1-phenyl-2-(3-p-tolylpropylamino)-
propan-1-ol ruthenium dimer 29a7c
+
Ph), 8.38–8.61 (4 H, m, 2 × NH2 ); dC(125.8 MHz; DMSO-d6)
The precursor alcohol (0.350 g, 0.94 mmol), DCM (10 cm3), 2 M
solution of HCl in diethyl ether (15 cm3, 30.00 mmol), ethanol
(15 cm3) and ruthenium trichloride trihydrate (0.196 g, 0.75 mmol)
were reacted according to the general procedure above to give
29a (0.182 g, 42%) as a dark green solid; mmax/cm−1 (thin film)
9.9 (2 × q), 25.7 (2 × t), 28.5 (2 × (3 × d)), 29.7 (2 × t), 36.6
(2 × (3 × t)), 41.2 (2 × (3 × t)), 43.1 (2 × s), 44.8 (2 × t), 58.4
(2 × d), 70.0 (2 × d), 81.8 (2 × d), 84.6 (2 × d), 85.0 (2 × d),
85.5 (2 × d), 103.2 (2 × s), 109.7 (2 × s), 126.3 (2 × (2 × d)),
127.8 (2 × d), 128.6 (2 × (2 × d)), 141.4 (2 × s). Found (LSIMS):
540.1599 (monomeric species formed in situ), 102RuC28H37NOCl
requires 540.1607 (1.6 ppm error). m/z (LSIMS) 510 (monomer+,
75%), 504 (M-HCl+, 100).
+
3422 (OH), 1602 (NH2 ), 749 and 703 (Ph); dH(400 MHz; DMSO-
d6) 0.93 (6 H, d, J 6.3, 2 × CH3CHN), 2.00–2.03 (4 H, m, 2 ×
CH2CH2N), 2.13 (6 H, s, 2 × ArCH3), 2.53–2.58 (4 H, m, 2 ×
CH2CH2CH2N), 3.07–3.15 (4 H, m, 2 × NCH2), 3.45 (2 H, m,
2 × CH3CHN), 5.11 (2 H, m, 2 × PhCH), 5.84–5.88 (8 H, m, 2 ×
(4 × ArH on Ru-arene)), 6.13 (2 H, br s, 2 × OH), 7.29–7.45 (10
H, m, 2 × Ph), 8.50 (2 H, m, 2 × NHaHb+), 8.56 (2 H, m, 2 ×
NHaHb+); dC(100.6 MHz; DMSO-d6) 9.8 (2 × q), 18.6 (2 × q),
25.8 (2 × t), 29.1 (2 × t), 45.0 (2 × t), 58.3 (2 × d), 69.7 (2 × d),
87.4 (2 × (2 × d)), 88.2 (2 × (2 × d)), 99.8 (2 × s), 100.4 (2 ×
s), 126.2 (2 × (2 × d)), 127.5 (2 × d), 128.4 (2 × (2 × d)), 141.0
(2 × s). Found (LSIMS): 420.0670 (monomeric species formed
in situ), 102RuC19H25NOCl requires 420.0668 (0.5 ppm error); m/z
(LSIMS) 420 (monomer+, 100%).
Synthesis of (1R,2S)-2-(3-biphenyl-4-yl-propylamino)-
1-phenylpropan-1-ol ruthenium dimer 29d
The precursor alcohol (0.600 g, 1.35 mmol), DCM (10 cm3),
2 M solution of HCl in diethyl ether (2 cm3, 4.00 mmol),
ethanol (15 cm3) and ruthenium trichloride trihydrate (0.186 g,
0.712 mmol) were reacted according to the general procedure
above to give 29d (0.180 g, 20%) as a dark green solid;
mmax/cm−1 (thin film) 3403 (OH), 1601 (NH2 ), 764 and 699 (Ph);
+
dH(400 MHz; DMSO-d6) 0.95 (6 H, d, J 6.3, 2 × CH3CHN), 1.31
(2 H, d, J 6.0, 2 × OH), 2.06–2.10 (4 H, m, 2 × CH2CH2N),
2.60–2.63 (4 H, m, 2 × CH2CH2CH2N), 3.06–3.19 (4 H, m, 2 ×
NCH2), 3.46 (2 H, m, 2 × CH3CHN), 5.13 (2 H, m, 2 × PhCH),
5.99–6.02 (4 H, m, 2 × (2 × ArH on Ru-arene)), 6.15 (2 H, m, 2 ×
ArH on Ru-arene), 6.54 (2 H, d, J 5.8, 2 × ArH on Ru-arene),
Synthesis of (1R,2S)-2-[3-(4-tert-butylphenyl)-propylamino]-
1-phenylpropan-1-ol ruthenium dimer 29b
The precursor alcohol (0.235 g, 0.58 mmol), DCM (10 cm3), 2 M
solution of HCl in diethyl ether (15 cm3, 30.00 mmol), ethanol
(10 cm3) and ruthenium trichloride trihydrate (0.125 g, 0.48 mmol)
were reacted according to the general procedure above to give 29b
(0.038 g, 13%) as a dark green solid; mmax/cm−1 (thin film) 3354
+
7.36–7.84 (20 H, m, 2 × (2 × Ph)), 8.43–8.64 (4 H, m, 2 × NH2 );
dC(100.5 MHz; DMSO-d6) 9.1 (2 × q), 25.8 (2 × t), 29.8 (2 ×
t), 45.2 (2 × t), 58.4 (2 × d), 69.7 (2 × d), 84.8 (2 × (2 × d)),
1102 | Org. Biomol. Chem., 2007, 5, 1093–1103
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85.3 (2 × (2 × d)), 96.6 (2 × s), 105.3 (2 × s), 124.8 (2 × (2 ×
d)), 127.5 (2 × d), 128.4 (2 × (2 × d)), 129.0 (2 × overlapping
(2 × (2 × d))), 129.8 (2 × d), 141.1 (2 × s). Found (LSIMS):
482.0826 (monomeric species formed in situ), 102RuC24H27NOCl
requires 482.0825 (0.3 ppm error); m/z (LSIMS) 482 (monomer+,
30%), 446 (M-HCl+,15), 346 (100).
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Acknowledgements
We thank the EPSRC for postdoctoral fellowship support (to
DJM) and Warwick University for the award of a Warwick
Postgraduate Research Fellowship (to AMH). We thank Dr
B. Stein of the EPSRC National Mass Spectrometry Service Centre
(Swansea) for HRMS analysis of certain compounds, Johnson-
Matthey Ltd for loans of ruthenium salts and Arran chemical
(Ireland) for generous donation of enantiopure diamines. We
acknowledge the use of the EPSRC’s Chemical Database Service
at Daresbury.11
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