The development of highly active acyclic chiral hydrazides for asymmetric iminium ion organocatalysis

Article abstract of DOI:10.1039/c3ob41719k

Double asymmetric induction has been employed as a tool to optimise pyrazolidinone-derived organocatalysts for the asymmetric iminium ion catalysed Diels-Alder reaction. Mechanistic studies revealed a superior hydrazide catalyst deriving from methanolysis of the chiral pyrazolidinone precursor. This catalyst displays unusually high endo diastereoselectivity and good enantioselectivity with a range of β-arylenals and cyclic dienes at catalyst loadings as low as 1 mol%.

Full text of DOI:10.1039/c3ob41719k

Organic &
Biomolecular Chemistry
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The development of highly active acyclic chiral
hydrazides for asymmetric iminium ion
Cite this: Org. Biomol. Chem., 2013, 11,
7877
organocatalysis†
Eoin Gould,a Tomas Lebl,a Alexandra M. Z. Slawin,a Mark Reid,b Tony Daviesb and
Andrew D. Smith*a
Double asymmetric induction has been employed as a tool to optimise pyrazolidinone-derived organo-
catalysts for the asymmetric iminium ion catalysed Diels–Alder reaction. Mechanistic studies revealed a
superior hydrazide catalyst deriving from methanolysis of the chiral pyrazolidinone precursor. This catalyst
displays unusually high endo diastereoselectivity and good enantioselectivity with a range of β-arylenals
and cyclic dienes at catalyst loadings as low as 1 mol%.
Received 22nd August 2013,
Accepted 27th September 2013
DOI: 10.1039/c3ob41719k
www.rsc.org/obc
Introduction
Iminium ion-mediated organocatalysis represents a rapidly
maturing area of research, beginning with the seminal work of
MacMillan in 2000.1 Within the field, the recurring catalytic
motif is that of a secondary amine constrained within a five-
membered ring and,2 although often displaying outstanding
levels of enantioselectivity, most reactions require relatively
high catalyst loadings (>10 mol%)3 and extended reaction
times (>24 h).1,4,5 Acyclic iminium ion catalysts have the poten-
tial to overcome the limited reactivity of their cyclic counter-
parts by decreasing the steric hindrance around the reactive
centre.6 Tomkinson et al. first demonstrated this reactivity
benefit when they showed that acyclic acyl hydrazides, such as
1, acted as highly reactive iminium ion organocatalysts in
Diels–Alder reactions.7 Subsequently Ogilvie and co-workers
introduced the first asymmetric (cyclic) hydrazide catalyst 2,
derived from camphor (Fig. 1).5 The enantioselectivity was
optimised by the addition of an additional exocyclic stereo-
directing group that served to rigidify the catalyst and thus
control the iminium ion geometry. Lee8 and Langlois9 later
reported related sulfonyl hydrazides, with Lee further develop-
ing primary sulfonyl hydrazide catalyst 3 for the cycloaddition
of ketones.10 More recently Suzuki et al. reported the first
Fig. 1 New hydrazide iminium ion organocatalysts.
acyclic chiral hydrazide organocatalyst 4 that displayed good
reactivity and enantioselectivity (though typically modest dia-
stereocontrol) in Diels–Alder reactions at 5 mol% catalyst
loading (up to 96% ee, endo product).11 Ishihara and co-
workers have also reported primary amine acyclic catalysts
specifically for the Diels–Alder reaction of demanding
α-substituted acroleins.12
We have previously reported one example of pyrazolidi-
nones acting as iminium ion organocatalysts in Diels–Alder
cycloadditions with modest induced enantioselectivity.13
Building upon these studies, we now report our efforts towards
an improved asymmetric variant, employing the concept of
double asymmetric induction as a tool in catalyst design
(Fig. 1). These studies led from initial catalyst 5 to the discov-
ery of catalytically efficient acyclic hydrazide organocatalyst 6
that displays an unusual endo diastereoselectivity preference as
aEaStCHEM, School of Chemistry, University of St Andrews, North Haugh,
St Andrews KY16 9ST, UK. E-mail: ads10@st.andrews.ac.uk
bMerck Sharp & Dohme Limited, Hertford Road, Hoddesdon, Hertfordshire EN11
9BU, UK
†Electronic supplementary information (ESI) available: Spectroscopic details for
all novel compounds. Supplementary crystallographic data available for com-
pounds 6, 11, 17, 18, 19, 20, 21, and 29. CCDC 915107, 956166, 956167, 956168,
956169, 956170, 956171, and 925705. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c3ob41719k
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well as good enantioselectivity (up to 86% ee) in the Diels–
Alder reaction of β-arylenals with dienes at catalyst loadings
as low as 1 mol%.
Table 1 Initial diastereoisomeric catalyst screen
Results and discussion
Catalyst synthesis and evaluation
Yield
(%)
Following our previously reported synthetic approach, a broad
range of catalyst structures could be accessed via a single
straightforward synthetic protocol (Fig. 2). The appropriate
α,β-unsaturated ester can be condensed with hydrazine to
generate the desired pyrazolidinone, followed by regioselective
amide coupling with an enantiomerically pure acid to give di-
astereoisomeric products that are readily separated by either
chromatography or recrystallisation.13
Entry Catalyst
1
exo : endo exo % ee endo % ee
89
66 : 34
48
28
2
3
4
82
62 : 38
54 (ent)
45 (ent)
Initially, diastereoisomeric pyrazolidinone catalysts bearing
a stereogenic C(5)-phenyl substituent were synthesised by this
method and screened as potential catalysts for the Diels–Alder
reaction of cinnamaldehyde and cyclopentadiene (Table 1).
(R)-Mandelic acid derived catalyst 7 shows an improvement in
ee over both 5 and its diastereoisomer 8, the (5S,2′R) configur-
ation leading to a synergistic enhancement of stereoselectivity
(entries 1–3). O-Methyl protected analogues 9 and 10 displayed
the same trends with marginally enhanced stereoselectivity
(entries 4 and 5). More prominent structural changes to the
acyl unit were also well tolerated, with (S)-naproxen derived
catalyst 12 displaying moderate enantioselectivity when
matched with the (5S)-pyrazolidinone configuration (entry 7
superior to entry 6). However, superior stereocontrol came
from incorporation of a CBz-protected proline, yielding cata-
lysts 13 and 14, with (5R)-configured 14 giving the better
enantioselectivity of the two (entries 8 and 9). Catalysts 13 and
14 were also significant in that they displayed little or no exo
diastereoselectivity compared to the other catalysts tested.
The influence of the pyrazolidinone C(5)-stereodirecting
group was next explored using a common (S)-naproxen-derived
acyl unit (Table 2). Again, for each diastereoisomeric pair a
superior ee was observed with the ‘matched’ combination of
stereocentres. Nonetheless, the incorporation of a tert-butyl
(entries 1 and 2) or benzyl stereodirecting group (in analogy to
the imidazolidinone catalysts of the MacMillan group, entries 3
and 4),1 gave no selectivity benefit compared to a phenyl substi-
tuent (see Table 1). The highest overall enantioselectivity
came when a (5S)-trifluoromethyl group was present with (2S)-
86
77
62 : 38
67 : 33
28
22
63 (ent)
44 (ent)
5
6
7
8
9
81
69
71
82
80
65 : 35
66 : 34
58 : 42
56 : 44
50 : 50
33
31
26
<5
45 (ent)
27 (ent)
57
52 (ent)
18
67
Ar = 6-methoxynaphthalen-2-yl.
products produced in 61% (exo) and 71% (endo) ee (entry 6).
Alternatively the gem-dimethyl catalyst 21 allowed us to examine
the extent of enantioinduction in the absence of a C(5)-pyrazoli-
dinone stereodirecting group, with the poor ee’s observed (13%
exo and 27% endo) illustrating the value of a second, suitably
matched stereodirecting group (entry 7). Again, diastereo-
selectivity was generally similar across the series with a small
exo preference for all but trifluoromethyl catalyst 20 which
displayed modest endo preference (46 : 54 exo : endo, entry 6).
With these results in hand, the diastereoisomeric catalysts
22 and 23 that combined a C(5)-trifluoromethyl substituent
with an N-carboxyproline unit were prepared and evaluated
(Fig. 3). Unsurprisingly, “matched” catalyst 23 proved the more
Fig. 2 Route to diastereoisomeric catalysts.
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For this reason, combined with the high observed enantio-
selectivity, catalyst 23 was selected for further study.
Table 2 Variation in enantioselectivity with change in stereodirecting group at
C(5)14
Mechanistic insights
We next investigated the stability of catalyst 23 under the reac-
tion conditions; 23 was treated with triflic acid (1 eq.) in
CD3OD and the reaction monitored by 19F NMR spectroscopy
(Fig. 4). Interestingly, 23 underwent rapid competitive
methanolysis (orange line, t1/2 1.2 h) at both the C(3) and N(2)
carbonyl groups, giving compounds 6 (red line) and 24 (blue
line) respectively. Further breakdown of 6 to give 25 was not
observed, but subsequent in situ methanolysis of 24 did lead
to hydrazide 25 (green line).16,17
Yield
(%)
Entry Catalyst
1
exo : endo exo % ee endo % ee
93
59 : 41
53 : 47
63 : 37
58 : 42
51 : 49
46 : 54
56 : 44
13
42
33
39
3
30
40
44
49
32
71
27
This complex product distribution led us to question the
dominant catalytic species present in the iminium ion
mediated process utilising catalyst 23 and other pyrazolidi-
none catalysts and so we attempted to isolate and evaluate
these intermediates. Acyclic hydrazides 6, 26 and 27 were pre-
pared by acid-mediated methanolysis of their respective pyr-
azolidinones and tested in catalysis along with racemic
pyrazolidinone 24 (Table 3). Isolated catalyst 6 gave superior
enantioselectivity to 23 at standard 10 mol% catalyst loading
but, more significantly, also at a low 1 mol% loading while
maintaining good catalytic activity (Table 3, entries 1 and 2).18
By contrast, another catalyst degradation product, racemic pyra-
zolidinone 24, displayed very limited catalytic activity with only
82% conversion reached after an extended time (24 h) and
giving products with no diastereoselectivity (entry 4). Alternative
hydrazides 26 and 27 were both catalytically active at 1 mol%
loading and gave modest improvements in enantioselectivity
over their cyclic precursors (entries 5 and 6). Catalyst 27 in par-
ticular gave similar enantioselectivities to 6 though with mark-
edly less diastereocontrol. In order to compare catalysts 23 and
6 in the absence of interconversion, the reaction solvent was
changed to non-nucleophilic DMF. While both catalysts showed
reduced reactivity compared with their respective reactions in
2
3
4
5
6
7
74
82
95
88
79
69
61
13
Ar = 6-methoxynaphthalen-2-yl.
Fig. 3 Screening of optimised catalyst 20 and its diastereoisomer 19.
enantioselective of the two compounds giving the (2R)-pro-
ducts in 65% (exo) and 75% (endo) ee. Interestingly, the cata-
lyst proved to be significantly endo diastereoselective (35 : 65
exo : endo), an unusually high selectivity in comparison with
the majority of other known iminium ion organocatalysts.15
Fig. 4 Triflic acid-mediated methanolysis of 23 as monitored by 19F NMR
spectroscopy.14,17
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Table 3 Testing of methanolysis products of 23 using both methanol and DMF as solvent
Entry
Catalyst
Solvent
Yield (%)
exo : endo
exo % ee
endo % ee
1
MeOH
MeOH
DMF
81
71
40
37 : 63
35 : 65
41 : 59
62
60
57
81
79
69
2a
3a
4
MeOH
82b
50 : 50
n/a
n/a
5a
MeOH
41
61 : 39
27 (ent)
43 (ent)
6a
7
MeOH
DMF
83
25
45 : 55
45 : 55
63
21
77
38
Ar = 6-methoxynaphthalen-2-yl. a 1 mol% catalyst loading (0.01 eq. triflic acid). b % conversion after 24 h.
methanol, catalysis by 10 mol% 23 was particularly sluggish, Table 4 Competition experiments between ent-23 and 6
with only 25% yield and significantly lower enantioselectivities
after extended reaction time (48 h, entry 7). By comparison, just
1 mol% of catalyst 6 gave superior yield after 24 h (40%), while
maintaining reasonable enantioselectivity (entry 3).
To compare the catalytic activities of 6 and 23 under cata-
lytically relevant conditions, competition experiments in
methanol utilising varying mixtures of 6 and ent-23 were
undertaken (amounting to 10 mol% in total) to catalyse the
model cycloaddition (Table 4). With each catalyst favouring the
opposite product enantiomers, the observed ee of the products
serves as a partial measure of the relative reaction rates of the
two species (although ent-23 inevitably undergoes in situ ring- Entry
ent-23 : 6 (mol%)
Yield (%)
exo : endo
endo % ee
opening during the experiments, leading to formation of ent-
6). Notably at both 5 : 5 and 9 : 1 ratios of ent-23 : 6, the (2R)-
enantiomer of the endo product is still favoured (68% and 50%
ee respectively, entries 2 and 3) indicating the dominance of 6
as a catalyst, even at 9 times lower concentration than catalytic
species arising from ent-23.
1
2
3
0 : 10
5 : 5
1 : 9
81
93
95
37 : 63
38 : 62
37 : 63
81
68
50
is not an effective catalyst for this transformation and that the
As a final comparison, the rate of exo and endo product for- principle active species when 23 is employed is in fact acyclic 6.
mation (as the di-CD3 acetals) in d4-methanol under catalysis by
With regards to the origin of enantiocontrol, iminium ion
23 (4 mol%, orange line) and 6 (2 mol%, red line) was moni- salt 28, derived from the combination of 6 and cinnamalde-
tored by 1H NMR spectroscopy (Fig. 5).19 The rate of product for- hyde, was successfully isolated and characterised (Fig. 6a).
mation with catalyst 6 was appreciably faster compared to 23 Although we have been unable to obtain an X-ray crystal struc-
after 256 min (4.27 h), reaction with 4 mol% 23 having reached ture of 28, nOe spectroscopic analysis in d3-acetonitrile indi-
76% conversion whereas 2 mol% 6 gave 75% conversion in just cated a Z-geometry in the key carbon–nitrogen double bond. A
98 min (1.63 h). These studies as a whole indicate that 23 itself racemic iminium ion derived from ring-opened 5 (compound
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29) was successfully crystallised and this was also found to
display a Z-configuration in the CvN bond in both the solu-
tion and solid phase (Fig. 6b). Such a geometry is consistent
with reaction upon the Re face of the dienophile, anti to the tri-
fluoromethyl stereodirecting group (as drawn) leading to the
observed (2R)-enantioselectivity in the cycloaddition products.
Substrate scope
Finally, the substrate scope of catalyst 6 at low catalyst loadings
(1–5 mol%) was explored, initially by changing the β-substitu-
ent of the enal (Table 5). Catalysis using 6 tolerated a range of
β-aryl substituted enals, including electron-donating and with-
drawing groups while maintaining good ee and endo diastereo-
selectivity (entries 1–3). ortho-Substitution on the aromatic
ring was also tolerated with high endo selectivity (entries 4 and
5), however, more modest enantioselectivities were observed
Table 5 Diels–Alder reactions catalysed by 6
Fig. 5 Graph of % conversion (against standard) vs. time (min) for Diels–Alder
reactions catalysed by 6 (red) and 23 (orange).
Yield
(%)
exo
% ee
endo
% ee
Product
exo : endo
1
71
35 : 65
60
79
2a
86
36 : 64
36 : 64
15 : 85
21 : 79
71
86
3b
4b
5
91
78
83
62
67
62
75
83
81
6
90
43
31 : 69
6 : 94
38
54
85
7c
—
Fig. 6 (a) Key nOe correlations for iminium ion 28.14 (b) Crystal structure of
compound 29.
a Reaction run at 5 °C. b 5 mol% catalyst loading.20 c 10 mol% catalyst
(0.1 eq. triflic acid), yield is for endo product only.
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with an aliphatic aldehyde (entry 6). Further studies allowed
General procedure C: acetalisation of products with
extension of this protocol to other dienes, with the reaction of (+)-(R,R)-hydrobenzoin. Following the method of Fujioka
cinnamaldehyde and cyclohexadiene giving the endo product et al.,23 to a suspension of aldehyde (1 eq.) in toluene (0.1 M)
in 85% ee (entry 7). Notably, the successful organocatalysed was added (+)-(R,R)-hydrobenzoin (1.1 eq.) and tosic acid
Diels–Alder reaction of these two components has not been (20 mol%) and the resulting mixture stirred at room tempera-
reported previously and cannot be realised with MacMillan’s ture until reaction was complete by TLC analysis. The reaction
first or second-generation imidazolidinone catalysts.21,22
was quenched with saturated ammonium chloride solution
and extracted with ethyl acetate (×3). The combined organic
layer were washed with brine (40 mL), dried (MgSO4), filtered
and concentrated in vacuo.
Conclusions
Screening of catalysts in Diels–Alder reaction of (E)-cinnam-
aldehyde and cyclopentadiene. To a suspension of catalyst
(20 mol%, 0.378 mmol) in methanol (2 mL) was added triflic
acid (35.0 μl, 0.378 mmol). After 2 min of stirring, (E)-cinna-
maldehyde (0.240 mL, 1.89 mmol) was added, followed by a
In summary, double asymmetric induction was used to maxi-
mise the enantioselectivity of a series of chiral pyrazolidinones
in the iminium ion catalysed Diels–Alder reaction. Subsequent
investigations on optimised structure 23 led to the discovery
that acyclic hydrazide 6 represented the active catalytic species,
giving Diels–Alder products with preferential endo diastereo-
selectivity and good enantioselectivity (up to 86% ee). Current
investigations are focused on other uses of pyrazolidinones
and hydrazides in asymmetric catalysis.
further
5
min of stirring. Cyclopentadiene (370 mg,
5.60 mmol) was then added and the resulting mixture left to
stir at rt. Reaction was monitored by TLC. Upon completion,
the reaction mixture was concentrated in vacuo then worked-
up as in general procedure B. The crude material was purified
by column chromatography, eluting with 5% diethyl ether in
petrol to yield the cycloaddition products as an inseparable
mixture of exo and endo diastereoisomers, with spectroscopic
data in accordance with the literature.7 Enantiomeric excesses
were determined by acetalisation with (+)-(R,R)-hydrobenzoin
The authors acknowledge the Royal Society for a URF (ADS),
MSD (Case award to EG) and the EPSRC National Mass
Spectrometry Service Centre (Swansea).
following general procedure
C
and 1H NMR analysis:
(500 MHz, C6D6) exo isomers δ 5.74 (d, J 4.8, CHO2, 2R) and
5.72 (d, J 5.8, CHO2, 2S), endo isomers δ 5.37 (d, J 8.1, CHO2,
2R) and 5.33 (d, J 8.2, CHO2, 2S).
Experimental
General experimental
For general experimental details see ESI.† The ESI also con-
tains spectroscopic data for compounds 6–8, 11–23 and 25–29.
Experimental procedures
General procedure A: amide coupling of pyrazolidin-3-one to The synthesis of compounds 5, 9, 10 and 24 have been
chiral acid. N-(3-Dimethylaminopropyl)-N′-ethylcarbodi- reported previously.13
a
imide hydrochloride (1 eq.), 1-hydroxybenzotriazole (1 eq.) and
(R)-Methyl
3-(2-((S)-1′-((benzyloxy)carbonyl)pyrrolidine-2′-
the appropriate chiral acid (1 eq.) were combined in DMF carbonyl)hydrazinyl)-4,4,4-trifluorobutanoate 6. To a solution
(0.1 M) and stirred at room temperature for 15 minutes. The of (R)-2-((S)-1′-((benzyloxy)carbonyl)pyrrolidine-2′-carbonyl)-5-
appropriate pyrazolidin-3-one (1 eq.) was then added and the (trifluoromethyl)-pyrazolidin-3-one (300 mg, 0.779 mmol) in
resultant solution stirred at rt overnight. The reaction mixture methanol (5 mL) was added triflic acid (0.140 mL, 1.56 mmol)
was then concentrated in vacuo and the resultant residue taken and the resulting mixture stirred at rt overnight. The excess
up in dichloromethane, washed twice with 0.1 M hydrochloric acid was then quenched with saturated sodium hydrogen
acid solution followed by single washes with saturated sodium carbonate solution (25 mL) and extracted with ethyl acetate
bicarbonate solution and brine before being dried (MgSO4), fil- (3 × 25 mL). The combined organic layers were dried (MgSO4),
tered and concentrated in vacuo.
filtered and concentrated in vacuo. The crude material was pur-
General procedure B: screening of aldehyde substrates with ified by column chromatography on silica gel, eluting with
catalyst 6. Catalyst 6 (X mol%) was suspended in a solution of 60% ethyl acetate in petrol to give the title compound as a col-
triflic acid (X mol%) in methanol. After 2 min of stirring, the ourless solid (120 mg, 39%).
appropriate aldehyde (1 eq.) was added, followed by a further
[α]2D0 −33.2 (c 0.5, methanol); mp 90–91 °C; νmax (KBr disc)/
15 min of stirring. Cyclopentadiene (3 eq.) was then added cm−1 3299 (N–H), 3271 (N–H), 3125 (Ar–H), 3033 (Ar–H), 2986
and the resulting mixture left to stir at the appropriate temp- (C–H), 2953 (C–H), 1737 (CvO), 1709 (CvO), 1646 (N–H bend)
erature overnight. The reaction mixture was concentrated and 1578 (Ar CvC); δN ((CD3)2S(O)) 138 (NHC(O)), 96.5 (NProC-
in vacuo then hydrolysed in a chloroform (2 mL), water (1 mL), (O)O), 65.9 (NHCHCF3); δF (376 MHz, CD3OD, rotamers A : B
trifluoroacetic acid (1 mL) mixture for 2 h. Saturated sodium 1.1 : 1) −76.86 (B, 3F, d, J 7.7, CF3) and −76.89 (A, 3F, d, J 7.7,
hydrogen carbonate solution (20 mL) was then added and the CF3); δH (300 MHz, CD3OD, rotamers A : B 1.1 : 1) 7.37–7.28 (A,
resulting biphasic mixture extracted with chloroform (2 × 5H, m, ArH & B, 5H, m, ArH), 5.11 (B, 2H, br s, PhCH2), 5.09
20 mL). The combined organic layer were washed with brine (A, 2H, br s, PhCH2), 4.25–4.21 (A, 1H, m, NProCH & B, 1H, m,
(40 mL), dried (MgSO4), filtered and concentrated in vacuo.
N
ProCH), 3.93 (B, 1H, app sext, J 7.0, CHCF3), 3.80–3.68 (A, 1H,
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m, CHCF3), 3.72 (A, 3H, s, OCH3 & B, 3H, s, OCH3), 3.62–3.45 yl)propanoyl)-5-phenylpyrazolidin-3-one
12. N-(3-Dimethyl-
(A, 2H, m, NProCH2 & B, 2H, m, NProCH2), 2.69 (B, 2H, d, J 6.2, aminopropyl)-N′-ethylcarbodiimide hydrochloride (26.5 g.
C(O)CH2), 2.61 (A, 2H, d, J 6.5, C(O)CH2), 2.31–2.13 (A, 1H, m, 138 mmol), 1-hydroxybenzotriazole (18.7 g, 138 mmol),
N
ProCHCHAHB & B, 1H, m, NProCHCHAHB) and 2.04–1.86 (S)-naproxen (31.9 g, 138 mmol) and (RS)-5-phenylpyrazolidin-
(A, 3H, m, NProCHCHAHBCH2 & B, 3H, m, NProCHCHAHBCH2); 3-one13 (22.5 g, 138 mmol) were combined according to
δC (75 MHz, CD3OD) 174.8 (C(O)NH), 174.7 (C(O)NH), 171.8 general procedure A. The crude material was purified by
(C(O)OCH3), 171.6 (C(O)OCH3), 156.3 (NProC(O)O), 138.0 Biotage Isolera on silica gel, eluting with a gradient of 10–90%
(CAripso), 137.9 (CAripso), 129.5 (CAr), 129.1 (CAr), 128.9 (CAr), ethyl acetate in heptane to give title compound 11 as a colour-
128.8 (CAr), 123.6 (q, J 218, CF3), 68.3 (CH2Ph), 60.5 (NProCH), less solid (7.20 g, 14%) and 20.9 g of mixed fractions (28.1 g of
60.0 (NProCH), 59.6 (q, J 28.1, CHCF3), 59.4 (q, J 28.3, CHCF3), compounds 11 and 12 over all fractions, 54% combined yield).
52.7 (OCH3), 48.0 (NProCH2), 32.9 (C(O)CH2), 32.5 In order to access pure compound 12, 2.02 g of mixed fractions
(NProCHCH2), 31.4 (NProCHCH2) 25.4 (NProCHCH2CH2) and were further purified by column chromatography on silica gel,
24.6 (NProCHCH2CH2); m/z HRMS (ESI+) C18H23N3O5F3 ([M + eluting with 1–2% ethyl acetate in dichloromethane to give
H]+) requires 418.1584, found 418.1586 (+0.4 ppm).
480 mg of fractions enriched in 12 and 1.50 g mixed fractions.
(S)-2-((R)-2′-Hydroxy-2′-phenylacetyl)-5-phenylpyrazolidin-3-one These enriched fractions were further purified by column
and (R)-2-((R)-2′-hydroxy-2′-phenylacetyl)-5-phenylpyrazoli- chromatography on silica gel, eluting with 1–2% ethyl acetate
7
din-3-one 8. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide in dichloromethane to give pure compound 12 as a colourless
hydrochloride (250 mg, 1.54 mmol), 1-hydroxybenzotriazole oil (60.0 mg, 0.1%).
(208 mg, 1.54 mmol), (R)-mandelic acid (234 mg, 154 mmol)
Compound 11 (upper spot): [α]2D0 +64.8 (c 1.0, dichloro-
and (RS)-5-phenylpyrazolidin-3-one13 (250 mg, 1.54 mmol) methane); νmax (KBr disc)/cm−1 3255 (N–H) 3050 (Ar–H), 2966
were combined in THF according to general procedure A. The (C–H), 2956 (C–H), 1744 (CvO), 1686 (CvO), 1630 (N–H bend)
crude material was purified by column chromatography, and 1603 (Ar CvC); mp 157–160 °C; δN (CDCl3) 193 (N(2)C(O)),
eluting with 25% ethyl acetate in petrol then 50% ethyl acetate 104 (N(1)H); δH (300 MHz, CDCl3) 7.74–7.68 (3H, m, ArH), 7.48
in petrol to give title compound 7 as a white solid (59 mg, (1H, dd, J 8.5, 1.8, ArH), 7.38–7.32 (5H, m, ArH), 7.10–7.05 (2H,
13%) and title compound 8 as a clear yellow oil (67 mg, 15%). m, ArH), 5.04 (1H, q, J 6.9, CH(CH3)), 4.58 (1H, dd, J 10.0, 8.2,
24 mg of mixed fractions were also collected (150 mg of com- C(5)H), 3.91 (3H, s, OCH3), 2.95 (1H, d, J 8.2, C(4)HAHB), 2.93
pounds 7 and 8 over all fractions, 33% combined yield).
(1H, d, J 10.0, C(4)HAHB) and 1.56 (3H, d, J 7.0, CH(CH3)); δC
Compound 7 (upper spot): [α]2D0 −77.0 (c 0.2, chloroform); (75 MHz, CDCl3) 171.0 (N(2)C(O)), 169.7 (C(3)O), 157.8 (OCAr-
νmax (KBr disc)/cm−1 3422 (O–H), 3228 (N–H), 3038 (Ar–H), ipso), 137.8 (CAripso), 135.8 (CAripso), 133.8 (CAripso), 129.5 (CAr),
3025 (Ar–H), 2947 (C–H), 1751 (CvO) and 1686 (CvO); mp 129.0 (CAr), 128.7 (CAr), 127.2 (CAr), 127.0 (CAr), 126.7 (CAr),
143–145 °C; δN (CDCl3) 189 (N(2)C(O)), 105 (N(1)H); δH 119.0 (CAr), 105.7 (CAr), 57.2 (C(5)H), 55.0 (OCH3), 44.2 (CH-
(300 MHz, CDCl3) 7.47–7.32 (10H, m, ArH), 6.00 (1H, s, (CH3)), 42.0 (C(4)H2) and 19.4 (CH(CH3)); m/z HRMS (ESI+)
CH(OH)), 5.17 (1H, bs, OH), 4.68 (1H, app dt, J 10.1, 7.7, C(5)- C23H23N2O3 ([M + H]+) requires 375.1703, found 375.1702
H), 4.06 (1H, d, J 7.4, N(2)H), 3.01 (1H, dd, ABX system, (−0.3 ppm).
JAB 17.2, JAX 10.1, C(4)HAHB) and 2.90 (1H, dd, ABX system, JBA
Compound 12 (lower spot): [α]2D0 +20.8 (c 0.25, chloroform);
17.2, JBX 7.7, C(4)HAHB); δC (100 MHz, CDCl3) 170.8 (C(O)), νmax (KBr disc)/cm−1 3266 (N–H) 3059 (Ar–H), 2916 (C–H),
170.3 (C(O)), 138.3 (CAripso), 137.0 (CAripso), 129.2 (CAr), 129.0 2842 (C–H), 1744 (CvO), 1692 (CvO), 1631 (N–H bend) and
(CAr), 128.9 (CAr), 128.8 (CAr), 127.8 (CAr), 126.6 (CAr), 73.4 1604 (Ar CvC); mp 47–51 °C; δH (300 MHz, CDCl3) 7.72–7.68
(CH(OH)), 58.0 (C(5)H) and 41.0 (C(4)H2); m/z HRMS (ESI+) (3H, m, ArH), 7.47 (1H, dd, J 8.5, 1.7, ArH), 7.28–7.21 (5H, m,
C17H17N2O3 ([M + H]+) requires 297.1234, found 297.1237 ArH), 7.15–7.11 (2H, m, ArH), 5.60 (1H, d, J 6.8, N(1)H), 5.07
(+1.1 ppm).
(1H, q, J 7.0, CH(CH3)), 4.66 (1H, app dt, J 9.3, 7.1, C(5)H), 3.92
Compound 8 (lower spot): [α]2D0 −47.3 (c 0.1, chloroform); (3H, s, OCH3), 3.05 (1H, dd, ABX system, JAB 17.0, JAX 7.3, C(4)-
νmax (KBr disc)/cm−1 3424 (O–H), 3226 (N–H), 3058 (Ar–H), HAHB), 2.80 (1H, dd, JBA 17.0, JBX 9.3, C(4)HAHB) and 1.58 (3H,
3025 (Ar–H), 1752 (CvO) and 1700 (CvO); mp 125–126 °C; δH d, J 7.0, CH(CH3)); δC (75 MHz, CDCl3) 170.8 (N(2)C(O)), 169.6
(300 MHz, CDCl3) 7.39–7.24 (8H, m, ArH), 7.22–7.16 (2H, m, (C(3)O), 157.8 (OCAripso), 138.3 (CAripso), 135.6 (CAripso), 133.9
ArH), 5.96 (1H, s, CH(OH)), 5.41 (1H, bs, OH), 4.62 (1H, app t, J (CAripso), 129.5 (CAr), 129.1 (CAripso), 129.0 (CAr), 128.6 (CAr),
8.0, C(5)H), 3.92 (1H, bs, N(2)H), 2.99 (1H, dd, ABX system, JAB 127.3 (CAr), 127.1 (CAr), 126.6 (CAr), 126.5 (CAr), 119.0 (CAr),
17.2, JAX 7.4, C(4)HAHB) and 2.77 (1H, dd, ABX system, JBA 17.2, 105.7 (CAr), 57.6 (C(5)H), 55.5 (OCH3), 44.2 (CH(CH3)), 42.1
JBX 8.9, C(4)HAHB); δC (75 MHz, CDCl3) 170.6 (C(O)), 170.0 (C(4)H2) and 19.4 (CH(CH3)); m/z HRMS (ESI+) C23H22N2O3Na
(C(O)), 138.1 (CAripso), 137.7 (CAripso), 129.1 (CAr), 128.9 (CAr), ([M + Na]+) requires 397.1528, found 375.1529 (+0.2 ppm).
128.84 (CAr), 128.82 (CAr), 127.8 (CAr), 126.5 (CAr), 73.4
(S)-2-((S)-1′-((Benzyloxy)carbonyl)pyrrolidine-2′-carbonyl)-
(CH(OH)), 58.2 (C(5)H) and. 41.2 (C(4)H2); m/z HRMS (ESI+) 5-phenylpyrazolidin-3-one 13 and (R)-2-((S)-1′-((benzyloxy)carbo-
C17H17N2O3 ([M + H]+) requires 297.1234, found 297.1237 nyl)pyrrolidine-2′-carbonyl)-5-phenylpyrazolidin-3-one 14.
(+1.1 ppm).
Benzyl chloroformate (9.5 mL, 65 mmol) and 4 M sodium
(R)-2-((S)-2′-(6-Methoxynaphthalen-2-yl)propanoyl)-5-phenyl- hydroxide solution (18.0 mL, 70 mmol) were added dropwise
pyrazolidin-3-one 11 and (S)-2-((S)-2′-(6-methoxynaphthalen-2- simultaneously (using addition funnels) over 30 min with
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vigorous stirring to an ice-cooled solution of (S)-proline 127.9 (CAr), 126.9 (CAr), 126.7 (CAr), 67.2 (CH2Ph), 67.1
(5.80 g, 50 mmol) in 2 M sodium hydroxide solution (30.0 mL, (CH2Ph), 59.8 (NProCH), 58.7 (NProCH), 58.2 (C(5)H), 58.0
60 mmol). The reaction was then left to stir at room temp- (C(5)H), 47.4 (NProCH2), 47.0 (NProCH2), 42.0 (C(4)H2), 41.9
erature for 1 h. The solution was then extracted with diethyl (C(4)H2), 30.7 (NProCHCH2CH2), 29.8 (NProCHCH2CH2), 24.1
ether (2 × 50 mL) and the aqueous layer retained and acidified (NProCHCH2CH2) and 23.6 (NProCHCH2CH2); m/z HRMS (ESI+)
to approximately pH 4 with 2 M HCl. The resulting solution C22H24N3O4 ([M + H]+) requires 394.1761, found 394.1765
was extracted with ethyl acetate (3 × 50 mL), the organic layers (+0.9 ppm).
dried (MgSO4) and concentrated in vacuo to give crude (S)-N-
Compound 14 (lower spot): [α]2D0 −40.3 (c 0.9, chloroform);
(benzyloxycarbonyl)-proline (10.1 g) as a colourless oil with νmax (KBr disc)/cm−1 3226 (N–H), 3059 (Ar–H), 3029 (Ar–H),
spectroscopic data in accordance with the literature.24 Product 2956 (C–H), 2926 (C–H), 1744 (CvO), 1708 (CvO), 1695
was used without further purification.
(CvO) and 1605 (N–H bend); δH (300 MHz, CDCl3, rotamers
δH (300 MHz, CDCl3, rotamers A : B 1.4 : 1) 7.39–7.27 (A, 5H, A : B 1 : 1) 7.56–7.19 (A, 10H, m, ArH & B, 10H, m, ArH), 5.40
m, ArH & B, 5H, m, ArH), 5.18 (A, 1H, d, AB system, JAB 12.4, (A, 1H, d, J 8.7, NProCH), 5.39 (B, 1H, d, J 8.5, NProCH), 5.17 (A,
PhCHAHB), 5.15 (A, 1H, d, AB system, JAB 12.4, PhCHAHB), 5.13 1H, d, AB system, JAB 12.5, PhCHAHB), 5.10 (A, 1H, d, AB
(B, 2H, s, PhCH2), 4.42 (A, 1H, dd, J 8.2, 3.4, NProCH), 4.38 (B, system, JBA 12.5, PhCHAHB), 5.09 (B, 1H, d, AB system, JAB 12.3,
1H, dd, J 8.7, 3.5, NProCH), 3.67–3.42 (A, 2H, m, NProCH2 & B, PhCHAHB), 5.03 (B, 1H, d, AB system, JBA 12.3, PhCHAHB), 4.75
2H, m, NProCH2) and 2.35–1.86 (A, 4H, m, CH2CH2 & B, 4H, m, (A, 1H, app t, J 8.8, C(5)H), 4.64 (B, 1H, app t, J 8.6, C(5)H),
CH2CH2).
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide
3.74–3.49 (A, 2H, m, NProCH2 & B, 2H, m, NProCH2), 3.039 (A,
hydro- 1H, d, J 8.6, C(4)HAHB), 3.038 (A, 1H, d, J 9.4, C(4)HAHB), 2.97
chloride (1.09 g, 5.67 mmol), 1-hydroxybenzotriazole (766 mg, (B, 1H, dd, ABX system, JAB 17.0, JAX 7.3, C(4)HAHB), 2.74
5.67 mmol), (S)-N-(benzyloxycarbonyl)-proline (1.55 g, 6.24 mmol, (B, 1H, dd, ABX system, JBA 17.0, JBX 10.5, C(4)HAHB), 2.44–2.30
added as solution in 5 mL DMF) and (RS)-5-phenylpyrazolidin- (A, 1H, m, NProCHCHAHB & B, 1H, m, NProCHCHAHB) and
3-one13 (1.00 g, 5.67 mmol) were combined according to general 2.08–1.89 (A, 3H, m,
N
ProCHCHAHBCH2
& B, 3H, m,
procedure A. The crude material was purified by column
NProCHCHAHBCH2); δC (100 MHz, CDCl3) 170.9 (C(3)O), 170.7
chromatography, eluting with 40% ethyl acetate in petrol to give (C(3)O), 169.6 (N(2)C(O)), 169.1 (N(2)C(O)), 155.0 (C(O)O),
title compound 13 as a clear yellow oil (382 mg, 17%) and frac- 154.2 (C(O)O), 137.6 (CAripso), 137.5 (CAripso), 136.9 (CAripso),
tions containing title compound 14 and a minor impurity 129.2 (CAr), 129.1 (CAr), 129.0 (CAr), 128.9 (CAr), 128.6 (2 ×
(176 mg). 392 mg of mixed fractions were also collected. The CAr), 128.05 (CAr), 128.03 (CAr), 128.0 (CAr), 127.9 (CAr), 126.8
fractions containing impure 14 were purified by further (CAr), 126.6 (CAr), 67.2 (2 × CH2Ph), 60.1 (NProCH), 59.2
column chromatography, eluting with diethyl ether to give title (NProCH), 57.8 (C(5)H), 57.4 (C(5)H), 47.4 (NProCH2), 46.9
compound 14 as a colourless oil (100 mg, 4%) (668 mg of com- (NProCH2), 41.5 (C(4)H2), 41.3 (C(4)H2), 31.0 (NProCHCH2CH2),
pounds 13 and 14 over all fractions, 30% combined yield).
30.1 (NProCHCH2CH2), 24.1 (NProCHCH2CH2) and 23.5
Compound 13 (upper spot): [α]D20 −82.2 (c 0.6, chloroform); (NProCHCH2CH2); m/z HRMS (ESI+) C22H24N3O4 ([M + H]+)
νmax (KBr disc)/cm−1 3248 (N–H), 3063 (Ar–H), 3033 (Ar–H), requires 394.1761, found 394.1755 (−1.6 ppm).
2978 (C–H), 2955 (C–H), 2883 (C–H), 1771 (CvO), 1746 (CvO),
(R)-2-((S)-2′-(6-Methoxynaphthalen-2-yl)propanoyl)-5-(tert-butyl)-
1695 (CvO), 1605 (N–H bend) and 1586 (Ar CvC); δN (CDCl3) pyrazolidin-3-one 15 and (S)-2-((S)-2′-(6-methoxynaphthalen-2-
192 (N(2)C(O)), 103 (N(1)H), 97.8 (NProC(O)O); δH (500 MHz, yl)propanoyl)-5-(tert-butyl)-pyrazolidin-3-one 16. To a solution
(CD3)2S(O), rotamers A : B 1.1 : 1) 7.46 (A, 2H, d, J 7.3, ArH), of hydrazine hydrate (5.00 mL, 101 mmol) in absolute ethanol
7.39–7.36 (A, 4H, m, ArH & B, 4H, m, ArH), 7.33–7.27 (A, 4H, (140 mL) was added crude (E)-ethyl 4,4-dimethylpent-2-enoate
m, ArH & B, 4H, m, ArH), 7.24 (B, 2H, d, J 6.8, ArH), 6.54 (B, (13.3 g, 85.1 mmol) and the resulting solution stirred at reflux
1H, d, J 9.0, N(1)H), 6.53 (A, 1H, d, J 8.9, N(1)H), 5.22–5.14 (A, overnight before concentration in vacuo. The crude oil was
1H, m, NProCH & B, 1H, m, NProCH), 5.08 (A, 2H, s, PhCH2), then purified by trituration in diethyl ether followed by fil-
5.03 (B, 1H, d, AB system, JAB 13.1, PhCHAHB), 4.97 (B, 1H, d, tration to give 3.68 g of (RS)-5-(tert-butyl)pyrazolidin-3-one as a
AB system, JBA 13.1, PhCHAHB), 4.67 (A, 1H, app q, J 8.3, C(5)- colourless solid. The filtrate was concentrated in vacuo and
H), 4.58 (B, 1H, br s, C(5)H), 3.53–3.38 (A, 2H, m, NProCH2 & B, purified by column chromatography on silica gel, eluting with
2H, m, NProCH2), 3.10 (B, 1H, dd, ABX system, JAB 16.9, JAX 9.0, 8% methanol in dichloromethane to give a further 3.20 g of
C(4)HAHB), 3.08 (A, 1H, dd, ABX system, JAB 16.7, JAX 7.1, the product (6.68 g in total, 53% combined yield).
C(4)HAHB), 2.92 (A, 1H, dd, ABX system, JBA 16.7, JBX 9.6,
νmax (KBr disc)/cm−1 3270 (N–H), 3219 (N–H), 2958 (C–H),
C(4)HAHB), 2.81 (B, 1H, dd, ABX system, JBA 16.7, JBX 8.7, 2870 (C–H) and 1667 (CvO); mp 85–89 °C; δH (300 MHz,
C(4)HAHB), 2.31–2.19 (A, 1H, m, NProCHCHAHB & B, 1H, m, CDCl3) 4.95 (2H, bs, N(1)H and N(2)H), 3.47 (1H, app t, J 8.6, C
N
ProCHCHAHB) and 1.95–1.84 (A, 3H, m, NProCHCHAHBCH2 & (5)H), 2.45 (1H, dd, ABX system, JAB 16.7, JAX 8.2, C(4)HAHB),
B, 3H, m, NProCHCHAHBCH2); δC (100 MHz, CDCl3) 169.8 (C(3)- 2.38 (1H, dd, ABX system, JBA 16.7, JBX 8.9, C(4)-HAHB) and 0.95
O), 169.7 (C(3)O), 169.1 (N(2)C(O)), 168.5 (N(2)C(O)), 155.0 (9H, s, C(CH3)3); δC (75 MHz, CDCl3) 176.8 (C(3)O), 67.5 (C(5)
(C(O)O), 154.1 (C(O)O), 137.9 (CAripso), 137.7 (CAripso), 136.9 H), 33.1 (C(4)H2), 33.0 (C(CH3)3) and 37.3 (C(CH3)3); m/z HRMS
(CAripso), 136.8 (CAripso), 129.1 (CAr), 128.79 (CAr), 128.77 (CAr), (ESI+) C7H14N2ONa ([M + Na]+) requires 165.1004, found
128.6 (CAr), 128.5 (CAr), 128.3 (CAr), 128.2 (CAr), 128.1 (CAr), 165.1001 (−1.7 ppm).
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N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide
hydro- 63.1 mmol) and the resulting solution stirred at reflux for
chloride (5.03 g, 25.9 mmol), 1-hydroxybenzotriazole (3.56 g, 90 min. The suspension was then concentrated in vacuo and
25.9 mmol), (S)-naproxen (6.00 g, 25.9 mmol) and (RS)-5-(tert- redissolved in toluene (120 mL) and stirred at reflux for a
butyl)pyrazolidin-3-one (3.68 g, 25.9 mmol) were combined further 90 min. The resulting solution was concentrated
according to general procedure A. The crude material was par- in vacuo and purified by column chromatography on silica gel,
tially purified by column chromatography on silica gel, eluting eluting with a gradient of 1–10% methanol in dichloro-
with 60% diethyl ether in petrol to give first 700 mg of frac- methane to give (RS)-5-benzylpyrazolidin-3-one as an off-white
tions enriched in title compound 15 (15 : 16 85 : 15) then solid (6.96 g, 63%).
710 mg of fractions enriched in title compound 16 (15 : 16
νmax (KBr disc)/cm−1 3234 (N–H), 3165 (N–H), 3054 (Ar–H),
9 : 91). 2.24 g of mixed fractions were also collected (15 : 16 1698 (CvO) and 1655 (N–H bend); mp 81–83 °C; δH (300 MHz,
42 : 58) (3.65 g of compounds 15 and 16 over all fractions, 40% CDCl3) 7.37–7.17 (5H, m, ArH), 5.12 (1H, br s, NH), 3.95 (1H,
combined yield). The fractions enriched in title compound 15 app quin, J 7.2, C(5)H), 2.98 (1H, dd, ABX system, JAB 13.8, JAX
were further purified by column chromatography on silica gel, 6.9, CHAHBPh), 2.84 (1H, dd, ABX system, JBA 13.8, JBX 7.0,
eluting with 40% diethyl ether in petrol to give title compound CHAHBPh), 2.55 (1H, dd, ABX system, JAB 16.4, JAX 7.2,
15 as an amorphous white solid (360 mg, 4%) and 300 mg of C(4)HAHB) and 2.32 (1H, dd, ABX system, JBA 16.4, JBX 7.5,
mixed fractions. The fractions enriched in title compound 16 C(4)HAHB); δC (75 MHz, CDCl3) 177.0 (C(3)O), 137.3 (CAripso),
were further purified by dissolution in diethyl ether followed 129.2 (CAr), 128.8 (CAr), 127.0 (CAr), 61.0 (C(5)H), 39.6 (C(4)H2)
by cooling to 0 °C. Collection by filtration then gave title com- and 37.3 (CH2Ph); m/z HRMS (ESI+) C10H13N2O ([M + H]+)
pound 16 as a colourless solid (264 mg, 3%).
requires 177.1022, found 177.1019 (−1.9 ppm).
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide
Compound 15 (upper spot): [α]2D0 −1.0 (c 0.5, chloroform);
hydro-
νmax (KBr disc)/cm−1 3281 (N–H), 2960 (C–H), 2931 (C–H), chloride (3.27 g, 17.0 mmol), 1-hydroxybenzotriazole (2.30 g,
1744 (CvO), 1678 (CvO), 1631 (N–H bend) and 1607 (Ar 17.0 mmol), (S)-naproxen (3.93 g, 17.0 mmol) and (RS)-5-benzyl-
CvC); mp 45–46 °C; δH (300 MHz, CDCl3) 7.73–7.67 (3H, m, pyrazolidin-3-one (3.00 g, 17.0 mmol) were combined according
ArH), 7.47 (1H, dd, J 8.5, 1.8, ArH), 7.14–7.09 (2H, m, ArH), to general procedure A. The crude material was dissolved in
5.27 (1H, br s, N(1)H), 5.04 (1H, q, J 7.0, CH(CH3)), 3.91 (3H, s, diethyl ether and a minimum of dichloromethane, cooled to
OCH3), 3.21 (1H, dd, J 11.3, 7.6, C(5)H), 2.63 (1H, dd, ABX 0 °C overnight and the resulting mixture filtered to give title
system, JAB 17.2, JAX 11.3, C(4)HAHB), 2.50 (1H, dd, JBA 17.2, JBX compound 17 as a colourless solid (1.20 g, 18%). The filtrate
7.6, C(4)HAHB), 1.56 (3H, d, J 7.0, CH(CH3)) and 0.92 (9H, s, was concentrated in vacuo and taken up in diethyl ether and a
C(CH3)3); δC (75 MHz, CDCl3) 170.8 (N(2)C(O)), 170.2 (C(3)O), minimum of methanol. 560 mg of colourless solid composed
157.7 (OCAripso), 135.9 (CAripso), 133.8 (CAripso), 129.4 (CAr), of a 14 : 86 mixture of title compounds 17 and 18 respectively,
129.0 (CAripso), 127.1 (CAr), 127.0 (CAr), 126.6 (CAr), 119.0 was collected (1.76 g of compounds 17 and 18 over all frac-
(CAr), 105.6 (CAr), 62.3 (C(5)H), 55.4 (OCH3), 43.9 (CH(CH3)), tions, 27% combined yield). In order to access pure compound
35.9 (C(4)H2), 32.4 (C(CH3)3), 25.7 (C(CH3)3) and 19.4 18, this mixture was subjected to recrystallisation from metha-
(CH(CH3)); m/z HRMS (ESI+) C21H27N2O3 ([M + H]+) requires nol and the minimum quantity of dichloromethane to give
355.2016, found 355.2015 (−0.3 ppm).
title compound 18 as a colourless solid (342 mg, 5%).
Compound 16 (lower spot): [α]2D0 +28.2 (c 0.5, chloroform);
Compound 17 (upper spot): [α]2D0 +31.2 (c 0.3, chloroform);
νmax (KBr disc)/cm−1 3290 (N–H), 2869 (C–H), 1741 (CvO), νmax (KBr disc)/cm−1 3265 (N–H), 3060 (Ar–H), 2976 (C–H),
1679 (CvO), 1634 (N–H bend) and 1606 (Ar CvC); mp 2935 (C–H), 1723 (CvO), 1687 (CvO), 1630 (N–H bend) and
86–87 °C; δH (300 MHz, CDCl3) 7.71–7.66 (3H, m, ArH), 7.46 1605 (Ar CvC); mp 147–148 °C; δN (CDCl3) 193 (N(2)C(O)), 103
(1H, dd, J 8.5, 1.8, ArH), 7.14–7.08 (2H, m, ArH), 5.35 (1H, br s, (N(1)H); δH (500 MHz, CDCl3) 7.70–7.68 (3H, m, ArH), 7.45 (1H,
N(1)H), 5.03 (1H, q, J 6.9, CH(CH3)), 3.90 (3H, s, OCH3), 3.26 dd, J 8.5, 1.3, ArH), 7.33–7.25 (3H, m, ArH), 7.16–7.10 (4H, m,
(1H, dd, J 10.1, 8.0, C(5)H), 2.58 (1H, dd, ABX system, JAB 17.2, ArH), 5.19 (1H, br s, N(1)H), 4.98 (1H, q, J 6.9, CH(CH3)), 3.91
JAX 8.0, C(4)HAHB), 2.51 (1H, dd, JBA 17.2, JBX 10.1, C(4)HAHB), (3H, s, OCH3), 3.69 (1H, app dq, J 9.4, 6.7, C(5)H), 2.89 (1H, dd,
1.56 (3H, d, J 6.9, CH(CH3)) and 0.85 (9H, s, C(CH3)3); δC ABX system, JAB 13.7, JAX 6.8, CHAHBPh), 2.83 (1H, dd, JBA 13.7,
(75 MHz, CDCl3) 170.6 (N(2)C(O)), 170.4 (C(3)O), 157.7 JBX 6.3, CHAHBPh), 2.64 (1H, dd, ABX system, JAB 17.0, JAX 6.9,
(OCAripso), 135.5 (CAripso), 133.7 (CAripso), 129.4 (CAr), 129.0 C(4)HAHB), 2.55 (1H, dd, JBA 17.0, JBX 9.4, C(4)HAHB) and 1.56
(CAripso), 127.1 (CAr), 127.0 (CAr), 126.6 (CAr), 118.9 (CAr), (3H, d, J 6.8, CH(CH3)); δC (75 MHz, CDCl3) 170.9 (N(2)C(O)),
105.6 (CAr), 62.7 (C(5)H), 55.4 (OCH3), 43.9 (CH(CH3)), 35.9 170.1 (C(3)O), 157.8 (OCAripso), 136.4 (CAripso), 135.8 (CAripso),
(C(4)H2), 32.7 (C(CH3)3), 25.7 (C(CH3)3) and 19.4 (CH(CH3)); m/ 133.8 (CAripso), 129.5 (CAr), 129.2 (CAr), 129.1 (CAripso), 129.0
z HRMS (ESI+) C21H26N2O3Na ([M + Na]+) requires 377.1841, (CAr), 127.3 (CAr), 127.2 (CAr), 126.9 (CAr), 126.6 (CAr), 119.0
found 377.1826 (−4.0 ppm).
(CAr), 105.7 (CAr), 55.4 (OCH3), 55.0 (C(5)H), 44.1 (CH(CH3)),
(S)-2-((S)-2′-(6-Methoxynaphthalen-2-yl)propanoyl)-5-benzyl- 40.1 (CH2Ph), 39.6 (C(4)H2) and 19.4 (CH(CH3)); m/z HRMS
pyrazolidin-3-one 17 and (R)-2-((S)-2′-(6-methoxynaphthalen- (ESI+) C24H24N2O3Na ([M + Na]+) requires 411.1685, found
2-yl)propanoyl)-5-benzylpyrazolidin-3-one 18. To a solution of 411.1675 (−2.4 ppm).
hydrazine hydrate (9.20 mL, 189 mmol) in absolute ethanol
Compound 18 (lower spot): [α]2D0 +68.0 (c 0.5, chloroform);
(120 mL) was added (E)-ethyl 4-phenylbut-2-enoate (12.0 g, νmax (KBr disc)/cm−1 3241 (N–H), 2970 (C–H), 2946 (C–H),
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1769 (CvO), 1682 (CvO), 1629 (N–H bend) and 1604 (Ar J 8.2, CF3); δH (300 MHz, (CD3)2S(O)) 7.78 (1H, d, J 9.0, CAr(8)H),
CvC); mp 133–134 °C; δH (300 MHz, CDCl3) 7.71–7.68 (3H, m, 7.76 (1H, d, J 8.6, CAr(4)H), 7.60 (1H, d, J 1.6, CAr(1)H), 7.33
ArH), 7.44 (1H, dd, J 8.4, 1.9, ArH), 7.30–7.21 (3H, m, ArH), (1H, dd, J 8.6, 1.6, CAr(3)H), 7.27 (1H, d, J 2.4, CAr(5)H), 7.14
7.15–7.06 (4H, m, ArH), 4.99 (1H, q, J 7.0, CH(CH3)), 3.91 (3H, (1H, dd, J 9.0, 2.4, CAr(7)H), 6.87 (1H, d, J 7.2, N(1)H), 4.88
s, OCH3), 3.79 (1H, app quin, J 7.3, C(5)H), 2.79 (1H, dd, ABX (1H, q, J 6.8, CH(CH3)), 4.35–4.22 (1H, m, C(5)H), 3.86 (3H, s,
system, JAB 13.8, JAX 7.4, CHAHBPh), 2.75 (1H, dd, ABX system, OCH3), 3.25 (1H, dd, ABX system, JAB 18.3, JAX 10.1, C(4)HAHB),
JAB 17.0, JAX 7.0, C(4)HAHB), 2.70 (1H, dd, JBA 13.8, JBX 6.7, 2.67 (1H, dd, JBA 18.3, JBX 2.7, C(4)HAHB) and 1.42 (3H, d, J 6.8,
CHAHBPh), 2.48 (1H, dd, JBA 17.0, JBX 8.4, C(4)HAHB) and 1.54 CH(CH3)); δC (75 MHz, (CD3)2S(O)) 170.7 (N(2)C(O)), 170.5
(3H, d, J 7.0, CH(CH3)); δC (75 MHz, CDCl3) 170.9 (N(2)C(O)), (C(3)O), 157.6 (OCAripso), 136.0 (CAripso), 133.6 (CAripso), 129.5
170.1 (C(3)O), 157.8 (OCAripso), 136.6 (CAripso), 135.6 (CAripso), (CAr), 128.7 (CAripso), 127.3 (CAr), 126.9 (CAr), 126.0 (CAr),
133.8 (CAripso), 129.5 (CAr), 129.1 (CAr), 129.0 (CAripso), 128.9 125.6 (q, J 280, CF3), 119.1 (CAr), 106.0 (CAr), 55.5 (OCH3), 51.9
(CAr), 127.24 (CAr), 127.21 (CAr), 127.0 (CAr), 126.7 (CAr), (q, J 30.7, C(5)H), 43.8 (CH(CH3)), 33.6 (C(4)H2) and 19.2
119.0 (CAr), 105.7 (CAr), 55.5 (OCH3 & C(5)H), 44.1 (CH(CH3)), (CH(CH3)); m/z HRMS (ESI+) C18H17N2O3F3Na ([M + Na]+)
40.1 (C(4)H2), 39.7 (CH2Ph) and 19.4 (CH(CH3)); m/z HRMS requires 389.1089, found 389.1094 (+1.2 ppm).
(ESI+) C24H25N2O3 ([M
389.1858 (−0.4 ppm).
+
H]+) requires 389.1860, found
(S)-2-(2′-(6-Methoxynaphthalen-2-yl)propanoyl)-5,5-dimethyl-
pyrazolidin-3-one 21. To a solution of hydrazine hydrate
(S)-2-((S)-2′-(6-Methoxynaphthalen-2-yl)propanoyl)-5-(trifluoro- (2.35 mL, 48.2 mmol) in absolute ethanol (50 mL) was added
methyl)pyrazolidin-3-one 19 and (R)-2-((S)-2′-(6-methoxy- methyl 3-methyl-2-butenoate (5.30 mL, 43.8 mmol) by drop-
naphthalen-2-yl)propanoyl)-5-(trifluoromethyl)-pyrazolidin-3-one wise addition. The resulting solution was stirred for 1 h at rt
20. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide
hydro- and then at reflux for 4 h before concentration in vacuo to give
chloride (1.55 g, 8.11 mmol), 1-hydroxybenzotriazole (1.10 g, 5,5-dimethylpyrazolidin-3-one as a colourless oil with spectro-
8.11 mmol), (S)-naproxen (1.87 g, 8.11 mmol) and (RS)-5-(tri- scopic data in accordance with the literature (4.95 g, 99%).25
fluoromethyl)pyrazolidin-3-one 2413 (1.25 g, 8.11 mmol) were
δH (400 MHz, CDCl3) 7.28 (1H, br s, N(2)H), 4.08 (1H, br s,
combined according to general procedure A. The crude material N(1)H), 2.31 (2H, s, C(4)H2) and 1.29 (6H, s, C(CH3)2).
was purified by column chromatography, eluting with 25% N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide
hydro-
ethyl acetate in petrol then pure ethyl acetate to give impure chloride (1.11 g, 5.80 mmol), 1-hydroxybenzotriazole (784 mg,
fractions of title compound 19 (766 mg) and fractions of title 5.80 mmol), (S)-naproxen (1.34 g, 5.80 mmol) and 5,5-
compound 20 contaminated with residual (S)-naproxen dimethylpyrazolidin-3-one (662 mg, 5.80 mmol) were com-
(474 mg). The fractions of 19 were purified by recrystallisation bined according to general procedure A. The crude material
in methanol and the minimum of ethyl acetate to give title com- was purified by column chromatography on silica gel, eluting
pound 19 as a colourless solid (229 mg, 8%). The fractions of 20 with 75% diethyl ether in petrol to give the title compound as
were taken up in dichloromethane (100 mL) and washed with a colourless solid (1.15 g, 61%).
saturated sodium bicarbonate solution (2 × 100 mL), brine
[α]D20 +20.8 (c 0.25, chloroform); νmax (KBr disc)/cm−1 3226
(100 mL), dried (MgSO4) and concentrated in vacuo to give title (N–H) 2967 (C–H), 2927 (C–H), 1764 (CvO), 1747 (CvO), 1673
compound 20 as a colourless solid (219 mg, 7%) (448 mg of (N–H bend), 1633 (Ar CvC) and 1609 (Ar CvC); mp
compounds 19 and 20 over all fractions, 15% combined yield).
109–111 °C; δN (CDCl3) 190 (N(2)C(O)), 117 (N(1)H); δH
Compound 19 (upper spot): [α]2D0 +3.3 (c 0.6, chloroform); (400 MHz, CDCl3) 7.71–7.66 (3H, m, ArH), 7.44 (1H, dd, J 8.6,
νmax (KBr disc)/cm−1 3259 (N–H), 2938 (C–H), 1760 (CvO), 1.7, ArH), 7.14–7.08 (2H, m, ArH), 4.99 (1H, q, J 6.9, CH(CH3)),
1672 (CvO), 1635 (N–H bend) and 1610 (Ar CvC); mp 3.90 (3H, s, OCH3), 2.53 (1H, d, AB system, JAB 16.8, C(4)HAHB),
162–165 °C; δF (282 MHz, CDCl3) −78.2 (3F, d, J 6.8, CF3); δH 2.45 (1H, d, AB system, JBA 16.8, C(4)HAHB), 1.55 (3H, d, J 7.0,
(300 MHz, CDCl3) 7.70–7.67 (3H, m, ArH), 7.44 (1H, dd, J 8.5, ArCH(CH3)), 1.28 (3H, s, (C((CH3)A(CH3)B)) and 1.14 (3H, s,
1.8, ArH), 7.15–7.09 (2H, m, ArH), 5.66 (1H, d, J 6.3, N(1)H), (C((CH3)A(CH3)B)); δC (100 MHz, CDCl3) 171.8 (C(O)), 171.7
4.99 (1H, q, J 7.0, CH(CH3)), 4.00 (1H, app dsext, J 8.8, 6.6, C(5) (C(O)), 157.7 (OCAripso), 135.9 (CAripso), 133.8 (CAripso), 129.5
H), 3.90 (3H, s, OCH3), 3.00 (1H, dd, ABX system, JAB 17.9, JAX (CAr), 129.1 (CAripso), 127.2 (CAr), 127.0 (CAr), 126.5 (CAr), 119.0
8.8, C(4)HAHB), 2.91 (1H, dd, JBA 17.9, JBX 6.3, C(4)HAHB) and (CAr), 105.7 (CAr), 55.5 (C(CH3)2), 55.4 (OCH3), 47.9 (C(4)H2),
1.57 (3H, d, J 7.0, CH(CH3)); δC (75 MHz, CDCl3) 170.8 (N(2)- 44.5 (CH(CH3)), 26.2 (C((CH3)A(CH3)B)), 26.1 (C((CH3)A(CH3)B))
C(O)), 167.0 (C(3)O), 157.8 (OCAripso), 135.1 (CAripso), 133.8 and 19.4 (CH(CH3)); m/z HRMS (ESI+) C19H22N2O3Na ([M + Na]+)
(CAripso), 129.4 (CAr), 128.9 (CAripso), 127.2 (CAr), 126.9 (CAr), requires 349.1528, found 349.1534 (+0.6 ppm).
126.8 (CAr), 124.3 (q, J 280, CF3), 119.1 (CAr), 105.6 (CAr), 55.4
(S)-2-((S)-1′-((Benzyloxy)carbonyl)pyrrolidine-2′-carbonyl)-5-(tri-
(OCH3), 52.8 (q, J 32.5, C(5)H), 43.9 (CH(CH3)), 33.8 (C(4)H2) fluoromethyl) pyrazolidin-3-one 22 and (R)-2-((S)-1′-((benzyloxy)-
and 19.3 (CH(CH3)); m/z HRMS (ESI+) C18H17N2O3F3Na ([M + carbonyl)pyrrolidine-2′-carbonyl)-5-(trifluoromethyl)-pyrazoli-
Na]+) requires 389.1089, found 389.1094 (+1.2 ppm).
din-3-one 23. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide
Compound 20 (lower spot): [α]2D0 +18.5 (c 0.5, acetonitrile); hydrochloride (1.57 g, 8.21 mmol), 1-hydroxybenzotriazole
νmax (KBr disc)/cm−1 3292 (N–H), 2988 (C–H), 2944 (C–H), (1.10 g, 8.21 mmol), crude (S)-N-(benzyloxycarbonyl)-proline
1757 (CvO), 1677 (CvO), 1631 (N–H bend) and 1605 (Ar (1.87 g, 9.03 mmol, added as solution in 5 mL DMF) and (RS)-5-
CvC); mp 161–162 °C; δF (282 MHz, (CD3)2S(O)) −77.5 (3F, d, (trifluoromethyl)pyrazolidin-3-one 2413 (1.26 g, 8.21 mmol)
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were combined according to general procedure A. The crude (C(O)O), 154.1 (C(O)O), 136.6 (CAripso), 136.5 (CAripso), 128.6
material was purified by column chromatography, eluting with (CAr), 128.5 (CAr), 128.0 (CAr), 127.9 (CAr), 127.6 (CAr), 124.6
85% diethyl ether in petrol to give title compound 22 as a col- (q, J 279, CF3), 124.5 (q, J 279, CF3), 67.2 (CH2Ph), 67.1
ourless oil (305 mg, 10%) and fractions containing title com- (CH2Ph), 59.7 (NProCH), 59.2 (NProCH), 53.3 (q, J 32.3, C(5)H),
pound 23 and a minor impurity (286 mg). 135 mg of mixed 53.2 (q, J 32.6, C(5)H), 47.3 (NProCH2), 47.0 (NProCH2), 33.3
fractions were also collected. The fractions containing title (C(4)H2), 33.1 (C(4)H2), 30.6 (NProCHCH2CH2), 29.5
compound 23 were purified by further column chromato- (NProCHCH2CH2),
24.0
(NProCHCH2CH2)
and
23.0
graphy, eluting with 60% ethyl acetate in petrol to give title (NProCHCH2CH2); m/z HRMS (ESI+) C17H22N4O4F3 ([M + NH4]+)
compound 23 as a colourless foam (190 mg, 6%) (630 mg of requires 403.1599, found 403.1589 (−2.4 ppm).
compounds 22 and 23 over all fractions, 20% combined yield).
Upon heating to 100 °C, the observed rotamers coalesced:
δF (282 MHz, (CD3)2S(O), H decoupled) −77.1 (3F, s, CF3);
1
Compound 22 (upper spot): [α]2D0 −46.1 (c 0.6, chloroform);
νmax (KBr disc)/cm−1 3256 (N–H), 3064 (Ar–H), 3034 (Ar–H), δH (300 MHz, (CD3)2S(O)) 7.36–7.26 (5H, m, ArH), 6.74 (1H, d,
2980 (C–H), 2957 (C–H), 1786 (CvO), 1757 (CvO), 1707 J 7.4, N(1)H), 5.13 (1H, d, J 9.5, NProCH), 5.05 (1H, s, PhCH2),
(CvO) and 1587 (N–H bend); δF (376 MHz, CDCl3, rotamers 4.41–4.26 (1H, m, C(5)H), 3.49 (2H, app t, J 6.8, NProCH2), 3.30
A : B 1.5 : 1) −78.2 (B, 3F, d, J 6.5, CF3), −78.3 (A, 3F, d, J 6.6, (1H, dd, ABX system, JAB 18.1, JAX 9.9, C(4)HAHB), 2.75 (1H, dd,
CF3); δH (300 MHz, CDCl3, rotamers A : B 1.5 : 1) 7.42–7.27 (A, ABX system, JBA 18.1, JBX 3.6, C(4)HAHB), 2.36–2.21 (1H, m,
5H, m, ArH & B, 5H, m, ArH), 5.85 (A, 1H, d, J 7.2, N(1)H),
5.34–5.28 (A, 1H, m, NProCH & B, 2H, m, NProCH & N(1)H), 5.14
N
ProCHCHAHB) and 1.94–1.78 (3H, m, NProCHCHAHBCH2).
2-(1,1,1-Trifluoro-4-methoxy-4-oxobutan-2-yl)hydrazin-1-ium
(A, 1H, d, AB system, JAB 12.6, PhCHAHB), 5.13 (B, 1H, d, AB trifluoromethanesulfonate 25. To a solution of crude (RS)-5-
system, JAB 12.1, PhCHAHB), 5.11 (A, 1H, d, AB system, JBA 12.6, (trifluoromethyl)pyrazolidin-3-one 2413 (90.0 mg, 0.570 mmol)
PhCHAHB), 4.94 (B, 1H, d, AB system, JBA 12.1, PhCHAHB), in methanol (1 mL) was added triflic acid (101 μL, 1.14 mmol)
4.21–4.07 (A, 1H, m, C(5)H), 3.74–3.47 (A, 2H, m, NProCH2 & B, and the mixture stirred at rt overnight. The resulting solution
3H, m, NProCH2 & C(5)H), 3.19 (A, 1H, dd, ABX system, JAB 18.0, was then concentrated in vacuo for 4 h to remove excess triflic
JAX 9.6, C(4)HAHB), 2.88 (A, 1H, dd, ABX system, JBA 18.0, JBX acid to give the title compound as a colourless solid (175 mg,
5.2, C(4)HAHB), 2.75 (B, 1H, d, J 7.4, C(4)H2), 2.37–2.27 (A, 1H, 91%).
m, NProCHCHAHB & B, 1H, m, NProCHCHAHB) and 2.03–1.86
νmax (ATR)/cm−1 3300 (N–H), 3144 (N–H), 2990 (C–H), 2968
(A, 3H, m, NProCHCHAHBCH2 & B, 3H, m, NProCHCHAHBCH2); (C–H) and 1717 (CvO); mp 73–77 °C; δF (375 MHz, CD3OD)
δC (100 MHz, CDCl3) 169.6 (N(2)C(O)), 168.3 (N(2)C(O)), 168.9 −77.3 (3F, d, J 6.9, CHCF3) and −80.7 (3F, s, SO3CF3); δH
(C(3)O), 168.5 (C(3)O), 155.1 (C(O)O), 154.1 (C(O)O), 136.9 (400 MHz, CD3OD) 4.06 (1H, dqd, J 10.1, 6.9, 3.5, CHCF3), 3.77
(CAripso), 136.7 (CAripso), 128.7 (2 × CAr), 128.6 (CAr), 128.3 (3H, s, OCH3), 2.91 (1H, dd, ABX system, JAB 17.5, JAX 3.5, C(O)
(CAr), 128.1 (CAr), 127.4 (CAr), 124.5 (q, J 279, CF3), 124.2 (q, HAHB) and 2.69 (1H, dd, ABX system, JBA 17.5, JBX 10.1, C(O)
J 279, CF3), 67.2 (CH2Ph), 67.1 (CH2Ph), 59.9 (NProCH), 58.8 HAHB); δC (75 MHz, CD3OD) 172.0 (C(O)OCH3), 126.4 (q, J 281,
(NProCH), 53.3 (q, J 32.6, C(5)H), 53.2 (q, J 33.0, C(5)H), 47.3 CF3), 121.8 (q, J 320, SO3CF3), 58.2 (q, J 30.1, CHCF3), 53.0
(NProCH2), 47.0 (NProCH2), 33.5 (C(4)H2), 33.4 (C(4)H2), (OCH3) and 33.2 (C(O)CH2); m/z HRMS (ESI+) C5H10F3N2O2 ([M
30.5
(NProCHCH2CH2) and 23.4 (NProCHCH2CH2); m/z HRMS (ESI+)
C17H19N3O4F3 ([M + H]+) requires 386.1323, found 386.1322 hydrazinyl)-3-methylbutanoate 26. To a solution of (S)-2-(2′-(6-
(+0.9 ppm). methoxynaphthalen-2-yl)propanoyl)-5,5-dimethylpyrazolidin-3-
(NProCHCH2CH2),
29.7
(NProCHCH2CH2),
24.0 − OTf]+) requires 187.0689, found 187.0686 (−1.5 ppm).
(S)-Methyl 3-(2-(2-(6-methoxynaphthalen-2-yl)propanoyl)-
Compound 23 (lower spot): [α]2D0 −34.1 (c 0.5, chloroform); one 21 (300 mg, 0.920 mmol) in methanol (5 mL) was added
mp 50 °C; νmax (KBr disc)/cm−1 3240 (N–H), 3036 (Ar–H), 2985 triflic acid (0.160 mL, 1.85 mmol) and the resulting mixture
(C–H), 2957 (C–H), 2886 (C–H), 1786 (CvO), 1761 (CvO) and stirred at rt for 3 days. The resulting heterogeneous mixture
1701 (CvO); δN (CD3OD) 184 (N(2)C(O)), 97.6 (NProC(O)O), 86.4 was quenched with saturated sodium hydrogen carbonate
(N(1)H); δF (282 MHz, (CD3)2S(O)), 1H decoupled, rotamers solution (20 mL) and extracted with ethyl acetate (3 × 20 mL).
A : B 1.1 : 1) −77.3 (A, 3F, s, CF3), −77.5 (B, 3F, s, CF3); δH The combined organic layers were washed with brine (50 mL),
(300 MHz, (CD3)2S(O), rotamers A : B 1.1 : 1) 7.38–7.19 (A, 5H, dried (MgSO4), filtered and concentrated in vacuo. 1H NMR
m, ArH & B, 5H, m, ArH), 6.92 (B, 1H, d, J 8.6, N(1)H), 6.89 (A, spectroscopic analysis indicated incomplete reaction so the
1H, d, J 7.8, N(1)H), 5.14 (B, 1H, dd, J 8.7, 2.5, NProCH), 5.07 (A, material was re-dissolved in dichloromethane (5 mL), more
2H, s, PhCH2), 5.03 (A, 1H, dd, J 8.9, 1.9, NProCH), 4.98 (B, 2H, triflic acid (0.400 mL, 4.60 mmol) added and the mixture
s, PhCH2), 4.45–4.31 (A, 1H, m, C(5)H & B, 1H, m, C(5)H), stirred for a further 3 days while being monitored by TLC. The
3.49–3.27 (A, 3H, m, NProCH2 & C(4)HAHB & B, 3H, m, NProCH2 resulting mixture was worked up as above. The crude material
& C(4)HAHB), 2.81 (B, 1H, dd, ABX system, JBA 18.3, JBX 3.1, was purified by column chromatography on silica gel, eluting
C(4)HAHB), 2.78 (A, 1H, dd, ABX system, JBA 18.4, JBX 3.0, with 60% ethyl acetate in petrol to give the title compound as
C(4)HAHB), 2.35–2.16 (A, 1H, m, NProCHCHAHB & B, 1H, m, a colourless oil (48 mg, 15%).
N
ProCHCHAHB) and 1.93–1.69 (A, 3H, m, NProCHCHAHBCH2 &
[α]D20 +18.1 (c 0.26, chloroform); νmax (ATR)/cm−1 3277 (N–H)
B, 3H, m, NProCHCHAHBCH2); δC (75 MHz, CDCl3) 169.7 2971 (C–H), 2934 (C–H), 1732 (CvO), 1653 (N–H bend), 1635
(N(2)C(O)), 169.6 (N(2)C(O)), 169.4 (C(3)O), 169.0 (C(3)O), 154.9 (Ar CvC) and 1605 (Ar CvC); δN (CDCl3) 190 (N(2)C(O)), 117
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(N(1)H); δH (400 MHz, CDCl3) 7.73–7.69 (3H, m, ArH), 7.49 (1H, and triflic acid (68.0 mM) in deuterated acetonitrile (2 mL)
br s, NH), 7.41 (1H, dd, J 8.5, 1.9, ArH), 7.17–7.09 (2H, m, ArH), and the mixture stirred at room temperature for 1 h. Analysis
3.92 (3H, s, OCH3), 3.77 (1H, q, J 7.1, CH(CH3)), 3.56 (3H, s, by 1H NMR spectroscopy indicated full conversion to the
C(O)OCH3), 2.31 (2H, s, CH2), 1.62 (3H, d, J 7.1, CH(CH3)), 1.09 iminium ion. The mixture was concentrated in vacuo, taken up
(3H, s, (C((CH3)A(CH3)B)) and 1.08 (3H, s, (C((CH3)A(CH3)B)); δC in dichloromethane and filtered to remove insoluble impuri-
(100 MHz, CDCl3) 173.8 (C(O)NH), 172.1 (C(O)O), 157.9 ties. Concentration in vacuo gave the product as a brown foam
(OCAripso), 135.9 (CAripso), 133.9 (CAripso), 129.4 (CAr), 129.1 (73 mg, 89%).
(CAripso), 127.6 (CAr), 126.24 (CAr), 126.20 (CAr), 119.3 (CAr),
[α]2D0 +129 (c 1.0, dichloromethane); mp 38–41 °C; νmax
105.8 (CAr), 57.4 (C(CH3)2), 55.5 (OCH3), 51.7 (C(O)OCH3), 45.6 (ATR)/cm−1 3150 (N–H), 2972 (C–H), 2926 (C–H), 1732 (CvO),
(CH(CH3)), 44.4 (CH2), 25.5 (C(CH3)2) and 18.5 (CH(CH3)); m/z 1717 (CvO), 1694 (CvO), 1684 (CvN), 1599 (Ar CvC) and
HRMS (ESI+) C20H27N2O4 ([M + H]+) requires 359.1965, found 1576 (N–H bend); δF (376 MHz, CD3CN) −72.9 (3F, d, J 6.6,
359.1968 (+0.7 ppm).
CHCF3) and −79.9 (3F, s, SO3CF3); δH (500 MHz, CD3CN) 10.4
(R)-Methyl 3-(2-((S)-1′-((benzyloxy)carbonyl)pyrrolidine-2′- (1H, br s, NH), 9.17 (1H, d, J 10.2, C(N)H)), 8.53 (1H, d, J 15.0,
carbonyl)hydrazinyl)-3-phenylbutanoate 27. To a solution of C(N)HCHCH), 8.13 (2H, d, J 14.9, ArH), 7.75–7.68 (2H, m, C(N)
(R)-2-((S)-1′-((benzyloxy)carbonyl)pyrrolidine-2′-carbonyl)-5-phe- HCH & ArH), 7.60–7.57 (2H, m, ArH), 7.34–7.29 (5H, m, ArH),
nylpyrazolidin-3-one 14 (500 mg, 1.60 mmol) in methanol 5.50–5.43 (1H, m, CHCF3), 5.26 (1H, d, AB system, JAB 12.5,
(10 mL) was added triflic acid (0.300 mL, 3.20 mmol) and the PhCHAHB), 5.11 (1H, d, AB system, JBA 12.5, PhCHAHB), 4.40
resulting mixture stirred at rt overnight. The resulting solution (1H, dd, J 8.0, 4.4, NProCH), 3.70 (3H, s, OCH3), 3.60–3.52 (2H,
was concentrated in vacuo then the excess acid was quenched m, NProCH2), 3.10 (1H, dd, ABX system, JAB 18.2, JAX 2.7,
with saturated sodium hydrogen carbonate solution (30 mL) C(O)HAHB), 3.01 (1H, dd, ABX system, JBA 18.2, JBX 10.3,
and extracted with ethyl acetate (3 × 30 mL). The combined C(O)CHAHB), 2.42–2.33 (1H, m, NProCHCHAHB) and 2.06–1.99
organic layers were washed with brine (50 mL), dried (MgSO4), (3H, m, NProCHCHAHBCH2); δC (100 MHz, CD3CN) 179.7
filtered and concentrated in vacuo. The crude material was (C(N)), 173.5 (C(N)CHCH), 172.2 (C(O)NH), 169.3 (C(O)OCH3),
purified by column chromatography on silica gel, eluting with 156.6 (NProC(O)O), 137.8 (CAr), 137.6 (OCH2CAripso), 134.6
60% ethyl acetate in petrol to give the title compound as a col- (CHCHCAripso), 133.9 (CAr), 130.8 (CAr), 129.5 (CAr), 129.1
ourless oil (235 mg, 43%).
(CAr), 128.7 (CAr), 123.5 (q, J 282, CHCF3), 121.8 (q, J 320,
[α]2D0 −40.4 (c 0.5, chloroform); νmax (ATR)/cm−1 3279 (N–H), SO3CF3), 118.1 (C(N)CH), 68.2 (CH2Ph), 68.1 (q, J 33.2, CHCF3),
3063 (Ar–H), 3032 (Ar–H), 2974 (C–H), 2953 (C–H), 2881 (C–H), 60.7 (NProCH), 53.4 (OCH3), 47.8 (NProCH2), 31.0 (NProCHCH2),
1734 (CvO), 1699 (CvO) and 1684 (CvO); δN ((CD3)2S(O)) 138 30.3 (C(O)CH2), and 25.6 (NProCHCH2CH2); m/z HRMS (ESI+)
(NHC(O)), 96.5 (NProC(O)O), 65.9 (NHCH); δH (300 MHz, C27H29N3O5F3 ([M − OTf]+) requires 532.2054, found 532.2054
CDCl3, rotamers A : B 1.3 : 1) 7.40–7.28 (A, 5H, m, ArH & B, 5H, (+0.0 ppm).
m, ArH), 5.09 (B, 2H, s, PhCH2), 5.05 (A, 2H, s, PhCH2), 4.41 (B,
1H, app t, J 7.1, CHPh), 4.32 (A, 1H, app t, J 7.2, CHPh), propyl)hydrazinecarboxylate
(Z)-Iminium ion of (RS)-benzyl 2-(3-methoxy-3-oxo-1-phenyl-
trifluoromethane- sulfonate
4.13–4.09 (A, 1H, m, NProCH & B, 1H, m, NProCH), 3.59 (A, 3H, 29. To a solution of (RS)-benzyl 5-oxo-3-phenylpyrazolidine-1-
s, OCH3 & B, 3H, s, OCH3), 3.53–3.37 (A, 2H, m, NProCH2 & B, carboxylate 5 (100 mg, 0.337 mmol) in dichloromethane
2H, m, NProCH2), 2.89 (B, 1H, dd, ABX system, JAB 15.7, JAX 6.9, (1 mL) was added triflic acid (42.0 μL, 0.337 mmol) and the
C(O)CHAHB), 2.80 (A, 1H, dd, ABX system, JAB 15.5, JAX 7.3, mixture stirred at room temperature for 2 h. Upon addition of
C(O)CHAHB), 2.65 (B, 1H, dd, ABX system, JBA 15.7, JBX 7.2, petrol, 105 mg of the triflate salt precipitated as a colourless
C(O)CHAHB), 2.60 (A, 1H, dd, ABX system, JBA 15.5, JBX 7.2, C solid and was collected by filtration. This solid was taken up in
(O)CHAHB), 2.13–1.96 (A, 1H, m, NProCHCHAHB & B, 1H, m, dry methanol (2 mL) and (E)-cinnamaldehyde (35.0 μL,
N
ProCHCHAHB) and 1.81–1.64 (A, 3H, m, NProCHCHAHBCH2 & 0.260 mmol) added. The resulting mixture was left to stir at
B, 3H, m, NProCHCHAHBCH2); δC (75 MHz, CD3OD) 174.0 room temperature with occasional sampling and analysis by
(C(O)NH), 173.9 (C(O)NH), 173.3 (C(O)OCH3), 173.2 (C(O) 1H NMR spectroscopy to monitor reaction progress. After
OCH3), 156.3 (NProC(O)O), 141.5 (CHCAripso), 141.4 (CHCAripso), 3 weeks, the resultant dark red oil was triturated in diethyl
138.0 (CH2CAripso), 129.5 (CAr), 129.4 (CAr), 129.0 (CAr), 128.9 ether and a minimum of dichloromethane to precipitate
(CAr), 128.6 (CAr), 68.2 (CH2Ph), 68.1 (CH2Ph), 62.3 (CHPh), 10 mg of the title compound as a yellow solid. The filtrate was
62.2 (CHPh), 60.5 (NProCH), 60.1 (NProCH), 52.2 (OCH3), 48.0 concentrated in vacuo and trituration repeated to yield a
(NProCH2), 40.8 (C(O)CH2), 40.5 (C(O)CH2), 32.5 (NProCHCH2), further 3 mg of title compound (13 mg in total, 9%).
31.3 (NProCHCH2) 25.2 (NProCHCH2CH2) and 24.4
(NProCHCH2CH2); m/z HRMS (ESI+) C23H28N3O5 ([M + H]+) 1751 (CvO), 1732 (CvO), 1613 (N–H bend) and 1588 (Ar
requires 426.2023, found 426.2022 (−0.3 ppm). CvC); mp 114–116 °C; δF (376 MHz, CD3CN) −79.9 (3H, s,
νmax (KBr disc)/cm−1 3427 (N–H), 2925 (C–H), 2854 (C–H),
Iminium ion of (R)-methyl 3-(2-((S)-1′-((benzyloxy)carbonyl)- SO3CF3); δH (300 MHz, CD3CN) 9.08 (1H, d, J 10.2, C(N)H)),
pyrrolidine-2′-carbonyl)hydrazinyl)-4,4,4-trifluorobutanoate 28. 8.96 (1H, br s, NH), 8.29 (1H, d, J 15.4, C(N)HCHCH), 7.81 (2H,
(R)-Methyl 3-(2-((S)-1′-((benzyloxy)carbonyl)pyrrolidine-2′-carbo- d, J 7.4, ArH), 7.73–7.68 (1H, m, ArH), 7.59–7.31 (12H, m, ArH),
nyl)hydrazinyl)-4,4,4-trifluorobutanoate 6 (52 mg, 0.124 mmol) 7.07 (1H, dd, J 15.4, 10.2, C(N)HCH), 5.81 (1H, dd, J 10.1, 4.4,
was dissolved in a solution of (E)-cinnamaldehyde (62.0 mM) CHCH2), 5.07 (2H, bs, CH2Ph), 3.67 (3H, s, OCH3), 3.48 (1H,
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dd, ABX system, JAB 17.9, JAX 10.1, C(O)HAHB) and 3.16 (1H, dd, J 5.6, 3.2, CHAvCHB), 6.16 (1H, dd, J 5.6, 2.8, CHAvCHB), 3.79
ABX system, JBA 17.9, JBX 4.4, C(O)CHAHB); δC (125 MHz, (3H, s, OCH3), 3.33–3.29 (1H, m, CHAr), 3.08–3.04 (1H, m,
CD3CN) 174.1 (C(N)), 170.9 (C(O)CH3), 167.8 (C(N)CHCH), CHCH2), 3.04–3.01 (1H, m, CHCH2), 2.94 (1H, ddd, J 5.1, 3.2,
136.3 (CAr), 134.3 (CAripso), 132.7 (CAripso), 132.4 (CAr), 131.6 2.3, CHCHO), 1.79 (1H, app dt, J 8.7, 1.5, CHAHB) and
(CAr), 130.3 (CAr), 129.6 (2 × CAr), 129.4 (CAr), 129.1 (CAr), 1.64–1.58 (1H, m, CHAHB).
116.9 (C(N)CH), 72.5 (CHCH2), 69.6 (CH2Ph), 52.9 (OCH3) and
34.8 (C(O)CH2); m/z HRMS (ESI+) C27H27N2O4 ([M − OTf]+) (+)-(R,R)-hydrobenzoin following general procedure C and 1H
requires 443.1965, found 443.1966 (+0.1 ppm).
NMR analysis:8 (500 MHz, C6D6) exo isomers δ 5.76 (d, J 4.9,
Enantiomeric excess was determined by acetalisation with
exo-(1R,2R,3R,4S)-3-Phenylbicyclo[2.2.1]hept-5-ene-2-carbox- CHO2, 2R) and 5.75 (d, J 7.0, CHO2, 2S), endo isomers δ 5.39 (d,
aldehyde and endo-(1S,2R,3R,4R)-3-phenylbicyclo[2.2.1]hept- J 8.2, CHO2, 2R) and 5.35 (d, J 8.2, CHO2, 2S).
5-ene-2-carboxaldehyde (Table 5, entry 1). (E)-Cinnamaldehyde
exo-(1R,2R,3R,4S)-3-(4-Nitrophenyl)bicyclo[2.2.1]hept-5-ene-
(0.120 mL, 0.950 mmol), triflic acid (19.0 mM solution in 2-carboxaldehyde and endo-(1S,2R,3R,4R)-3-(4-nitrophenyl)-
methanol, 0.5 mL, 9.50 μmol), catalyst 6 (1 mol%, 4.0 mg, bicyclo[2.2.1]hept-5-ene-2-carboxaldehyde (Table 5, entry 3).
9.50 μmol) and cyclopentadiene (188 mg, 2.80 mmol) were 4-Nitrocinnamaldehyde (84.0 mg, predominantly (E)-,
combined according to general procedure B. The crude 0.480 mmol), triflic acid (95.0 mM solution in methanol,
material was then purified by column chromatography, eluting 0.25 mL, 24.0 μmol), catalyst 6 (5 mol%, 10.0 mg, 24.0 μmol)
with 5% diethyl ether in petrol to yield the title compounds as and cyclopentadiene (94.0 mg, 1.40 mmol) were combined
a 35 : 65 mixture of diastereoisomers, with spectroscopic data according to general procedure B. The crude material was then
in accordance with the literature (133 mg, 71%).7
Compound (2R)-exo: δH (300 MHz, CDCl3) 9.93 (1H, d, J 2.1, acetate in petrol to yield the title compounds as
purified by column chromatography, eluting with 15% ethyl
a
CHO), 7.34–7.13 (5H, m, ArH), 6.34 (1H, dd, J 5.8, 3.6, 36 : 64 mixture of diastereoisomers, with spectroscopic data in
CHAvCHB), 6.08 (1H, dd, J 5.8, 3.3, CHAvCHB), 3.73 (1H, dd, accordance with the literature (106 mg, 91%).5
J 5.2, 3.4, CHPh), 3.24–3.21 (2H, m, CHCH2), 2.60 (1H, app dt,
J 5.2, 2.1, CHCHO) and 1.62–1.53 (2H, m, CH2).
(2R)-exo: δH (300 MHz, CDCl3) 9.92 (1H, d, J 1.7, CHO),
8.13–8.08 (2H, m, ArH), 7.32–7.27 (2H, m, ArH), 6.41 (1H, dd,
Compound (2R)-endo: δH (300 MHz, CDCl3) 9.60 (1H, d, J 5.7, 3.2, CHAvCHB), 6.05 (1H, dd, J 5.7, 2.8, CHAvCHB), 3.88
J 2.2, CHO), 7.34–7.13 (5H, m, ArH), 6.42 (1H, dd, J 5.7, 3.2, (1H, dd, J 5.0, 3.5, CHAr), 3.36–3.32 (1H, m, CHCH2), 3.27–3.33
CHAvCHB), 6.18 (1H, dd, J 5.7, 2.8, CHAvCHB), 3.36–3.32 (1H, (1H, m, CHCH2), 2.62 (1H, br d, J 5.0, CHCHO) and 1.62–1.60
m, CHCH2), 3.14–3.12 (1H, m, CHCH2), 3.09 (1H, dd, J 4.8, 1.5, (2H, m, CH2).
CHPh), 2.98 (1H, ddd, J 4.8, 3.4, 2.2, CHCHO), 1.84–1.79 (1H,
m, CHAHB) and 1.65–1.63 (1H, m, CHAHB).
(2R)-endo: δH (300 MHz, CDCl3) 9.64 (1H, d, J 1.7, CHO),
8.19–8.14 (2H, m, ArH), 7.45–7.40 (2H, m, ArH), 6.44 (1H, dd,
Enantiomeric excess was determined by acetalisation with J 5.9, 3.6, CHAvCHB), 6.20 (1H, dd, J 5.7, 2.8, CHAvCHB),
(+)-(R,R)-hydrobenzoin following general procedure C and 1H 3.45–3.41 (1H, m, CHCH2), 3.22–3.18 (2H, m, CHAr and CHCH2),
NMR analysis:5 (500 MHz, C6D6) exo isomers δ 5.74 (d, J 4.8, 2.95 (1H, ddd, J 5.0, 3.5, 1.7, CHCHO) and 1.78–1.68 (2H, m, CH2).
CHO2, 2R) and 5.72 (d, J 5.8, CHO2, 2S), endo isomers δ 5.37 (d,
J 8.1, CHO2, 2R) and 5.33 (d, J 8.2, CHO2, 2S).
Enantiomeric excess was determined by acetalisation with
(+)-(R,R)-hydrobenzoin following general procedure C and 1H
exo-(1R,2R,3R,4S)-3-(4-Methoxyphenyl)bicyclo[2.2.1]hept-5-ene- NMR analysis:5 (500 MHz, C6D6) exo isomers δ 5.60 (d, J 5.2,
2-carboxaldehyde and endo-(1S,2R,3R,4R)-3-(4-methoxyphenyl)- CHO2, 2R) and 5.58 (d, J 5.9, CHO2, 2S), endo isomers δ 5.26 (d,
bicyclo[2.2.1]hept-5-ene-2-carboxaldehyde (Table 5, entry 2). J 8.1, CHO2, 2R) and 5.19 (d, J 8.2, CHO2, 2S).
(E)-4-Methoxycinnamaldehyde (77.0 mg, 0.480 mmol), triflic
exo-(1R,2R,3R,4S)-3-(2-Nitrophenyl)bicyclo[2.2.1]hept-5-ene-
acid (0.0190 M solution in methanol, 0.25 mL, 4.80 μmol), 2-carboxaldehyde and endo-(1S,2R,3R,4R)-3-(2-nitrophenyl)-
catalyst 6 (1 mol%, 2.00 mg, 4.80 μmol) and cyclopentadiene bicyclo[2.2.1]hept-5-ene-2-carboxaldehyde (Table 5, entry
(94 mg, 1.40 mmol) were combined at 5 °C according to 4). (E)-2-Nitrocinnamaldehyde (168 mg, 0.950 mmol), triflic acid
general procedure B. The crude material was then purified by (95.0 mM solution in methanol, 0.5 mL, 9.50 μmol), catalyst 6
column chromatography, eluting with 10% diethyl ether in (5 mol%, 20.0 mg, 47.5 μmol) and cyclopentadiene (188 mg,
petrol to yield the title compounds as a 36 : 64 mixture of di- 2.80 mmol) were combined according to general procedure
astereoisomers, with spectroscopic data in accordance with the B. The crude material was then purified by column chromato-
literature (94 mg, 86%).8
graphy, eluting with 15% ethyl acetate in petrol to yield the title
(2R)-exo: δH (400 MHz, CDCl3) 9.91 (1H, d, J 2.0, CHO), compounds as a 15 : 85 mixture of diastereoisomers, with spec-
7.09–7.05 (2H, m, ArH), 6.81–6.78 (2H, m, ArH), 6.34 (1H, dd, troscopic data in accordance with the literature (180 mg, 78%).5
J 5.6, 3.2, CHAvCHB), 6.07 (1H, dd, J 5.6, 2.9, CHAvCHB), 3.77
(2R)-exo: δH (300 MHz, CDCl3) 9.80 (1H, d, J 2.1, CHO), 7.72
(3H, s, OCH3), 3.66 (1H, dd, J 5.2, 3.5, CHAr), 3.22–3.19 (1H, m, (1H, dd, J 8.0, 1.4, ArH), 7.46–7.30 (2H, m, ArH), 7.17 (1H, dd,
CHCH2), 3.19–3.15 (1H, m, CHCH2), 2.53 (1H, app dt, J 5.2, J 8.0, 1.0, ArH), 6.46 (1H, dd, J 5.6, 3.0, CHAvCHB), 6.01 (1H,
2.0, CHCHO), 1.64–1.58 (1H, m, CHAHB) and 1.56–1.53 (1H, m, dd, J 5.6, 2.9, CHAvCHB), 4.09 (1H, dd, J 5.3, 3.1, CHAr),
CHAHB).
3.39–3.36 (1H, m, CHCH2), 3.30–3.25 (1H, m, CHCH2),
(2R)-endo: δH (400 MHz, CDCl3) 958 (1H, d, J 2.3, CHO), 2.62–2.59 (1H, app dt, J 5.3, 2.1, CHCHO), 1.69–1.62 (1H, m,
7.20–7.17 (2H, m, ArH), 6.87–6.81 (2H, m, ArH), 6.41 (1H, dd, CHAHB) and 1.61–1.55 (1H, m, CHAHB).
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(2R)-endo: δH (300 MHz, CDCl3) 9.40 (1H, d, J 3.7, CHO), d, J 8.4, ArH), 6.45 (1H, dd, J 5.6, 3.2, CHAvCHB), 5.82 (1H, dd,
7.82 (1H, dd, J 8.1, 1.2, ArH), 7.61–7.51 (2H, m, ArH), 7.46–7.30 J 5.6, 3.0, CHAvCHB), 4.58 (1H, dd, J 5.1, 3.5, CHAr), 3.37–3.33
(1H, m, ArH), 6.50 (1H, dd, J 5.7, 3.3, CHAvCHB), 6.21 (1H, dd, (1H, m, CHCH2), 3.33–3.28 (1H, m, CHCH2), 2.92 (1H, app dt,
J 5.7, 2.8, CHAvCHB), 3.43 (1H, dd, J 5.2, 1.2, CHAr), 3.34–3.29 J 5.1, 1.7, CHCHO), 1.81 (1H, app dt, J 8.8, 1.5, CHAHB) and
(1H, m, CHCH2), 3.14–3.10 (1H, m, CHCH2), 2.95 (1H, app dt, 1.62 (1H, ddd, J 8.8, 3.5, 1.8, CHAHB); δC (75 MHz, CDCl3)
J 5.2, 3.7, CHCHO), 1.84 (1H, app dt, 9.0, 1.6, CHAHB) and 202.6 (CHO), 139.2 (CHAvCHB), 137.6 (CAripso), 136.2 (CAripso),
1.69–1.62 (1H, m, CHAHB).
134.1 (CHAvCHB), 132.5 (CAripso), 129.1 (CAr), 127.2 (CAr),
Enantiomeric excess was determined by acetalisation with 126.2 (CAr), 125.6 (CAr), 125.1 (CAr), 123.4 (CAr), 58.4
(+)-(R,R)-hydrobenzoin following general procedure C and 1H (CHCHO), 48.6 (CHCH2), 47.9 (CH2), 46.0 (CHCH2) and 40.4
NMR analysis:5 (300 MHz, C6D6) exo isomers δ 5.59 (d, J 4.5, (CHAr).
CHO2, 2R) and 5.51 (d, J 5.1, CHO2, 2S), endo isomers δ 5.21 (d,
J 7.6, CHO2, 2R) and 5.13 (d, J 7.6, CHO2, 2S).
endo-(2R): δH (300 MHz, CDCl3) 9.69 (1H, d, J 2.3, CHO),
8.05 (1H, dd, J 6.7, 2.5, ArH), 7.89–7.84 (1H, m, ArH), 7.76–7.70
exo-(1R,2R,3R,4S)-3-(Naphthalen-1-yl)bicyclo[2.2.1]hept-5-ene- (1H, m, ArH), 7.61–7.42 (4H, m, ArH), 6.58 (1H, dd, J 5.7, 3.2,
2-carbaldehyde and endo-(1S,2R,3R,4R)-3-(naphthalen-1-yl)- CHAvCHB), 6.22 (1H, dd, J 5.7, 2.7, CHAvCHB), 3.82 (1H, dd,
bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (Table 5, entry 5). Fol- J 4.9, 1.1, CHAr), 3.44–3.38 (1H, m, CHCH2), 3.22 (1H, ddd,
lowing the method of Moitessier et al.,26 to a suspension of J 4.9, 3.5, 2.3, CHCHO), 3.20–3.17 (1H, m, CHCH2), 1.92 (1H,
(E)-3-(naphthalen-1-yl)acrylic acid (990 mg, 5.00 mmol) and app dt, J 8.7, 1.5, CHAHB) and 1.67 (1H, ddd, J 8.7, 3.2, 1.6,
DMF (0.0400 mL, 0.500 mmol) in dichloromethane (30 mL) CHAHB); δC (75 MHz, CDCl3) 203.5 (CHO), 139.1 (CHAvCHB),
was added oxalyl chloride (0.65 mL, 7.500 mmol) dropwise, 136.9 (CAripso), 135.9 (CAripso), 134.2 (CHAvCHB), 132.5
leading to significant gas evolution. The resulting mixture was (CAripso), 129.0 (CAr), 127.3 (CAr), 126.3 (CAr), 125.8 (CAr),
stirred at room temperature for 1 h then concentrated in vacuo 125.4 (CAr), 123.8 (CAr), 123.0 (CAr), 59.1 (CHCHO), 49.7
to a yellow solid which was subsequently dissolved in THF (CHCH2), 47.6 (CH2), 45.7 (CHCH2) and 41.4 (CHAr); m/z
(30 mL) and cooled to −78 °C. Lithium tri-tert-butoxyaluminium HRMS (ESI+) C18H17O ([M + H]+) requires 249.1279, found
hydride (1.33 g, 5.25 mmol) was then added portionwise and 249.1287 (+3.0 ppm).
the resulting mixture left to stir for 1 h. The mixture was then
Enantiomeric excess was determined by acetalisation with
allowed to warm to 0 °C and stirred for a further 2 h before (+)-(R,R)-hydrobenzoin following general procedure C and 1H
being quenched by addition of water (30 mL). The resulting sus- NMR analysis: (500 MHz, C6D6) exo isomers δ 5.79 (d, J 3.8,
pension was passed through a layer of Ceilte and the cake CHO2, 2R) and 5.77 (d, J 5.1, CHO2, 2S), endo isomers δ 5.51 (d,
washed with dichloromethane (50 mL). The filtrate was diluted J 7.5, CHO2, 2R) and 5.43 (d, J 7.7, CHO2, 2S).
further with water (50 mL) and the resulting biphasic mixture
exo-(1R,2R,3R,4S)-3-Propylbicyclo[2.2.1]hept-5-ene-2-carbox-
extracted. The aqueous layer was washed with dichloromethane aldehyde and endo-(1S,2R,3R,4R)-3-propylbicyclo[2.2.1]hept-5-
(50 mL) and the combined organic layers were washed with ene-2-carboxaldehyde (Table 5, entry 6). (E)-2-Hexen-1-al
water (100 mL), brine (100 mL), dried (MgSO4), filtered and con- (0.110 mL, 0.950 mmol), triflic acid (19.0 mM solution in
centrated in vacuo. The crude material was purified by column methanol, 0.5 mL, 9.50 μmol), catalyst 6 (1 mol%, 4.00 mg,
chromatography on silica gel, eluting with 60% dichloro- 9.50 μmol) and cyclopentadiene (188 mg, 2.80 mmol) were
methane in petrol to give (E)-3-(naphthalen-1-yl)acrylaldehyde combined according to general procedure B. The crude
as a yellow solid with spectroscopic data in accordance with the material was then purified by column chromatography, eluting
literature (463 mg, 51%).27
with 2.5% diethyl ether in petrol to yield the title compounds
Mp 43–44 °C; δH (300 MHz, CDCl3) 9.87 (1H, d, J 7.7, CHO), as a 31 : 69 mixture of diastereoisomers, with spectroscopic
8.35 (1H, d, J 15.7, CHCHCHO), 8.20 (1H, d, J 8.5, ArH), data in accordance with the literature (140 mg, 90%).1,28
7.98–7.91 (2H, m, ArH), 7.84 (1H, d, J 7.1, ArH), 7.66–7.52 (3H,
m, ArH) and 6.86 (1H, dd, J 15.7, 7.7, CHCHO).
exo: δH (300 MHz, CDCl3) 9.78 (1H, d, J 2.8, CHO), 6.21 (1H,
dd, J 5.7, 3.1, CHAvCHB), 6.13 (1H, dd, J 5.7, 2.9, CHAvCHB),
(E)-3-(Naphthalen-1-yl)acrylaldehyde
(87.5
mg, 3.03–2.98 (1H, m, CHCH2), 2.89–2.85 (1H, m, CHCH2), 2.28
0.480 mmol), triflic acid (19.0 mM solution in methanol, (1H, tdd, J 7.6, 4.7, 3.1 CHCH2CH2), 1.76 (1H, ddd, J 4.7, 2.8,
0.25 mL, 4.80 μmol), catalyst 6 (1 mol%, 2.00 mg, 4.80 μmol) 1.7, CHCHO), 1.77–1.06 (6H, m, CHCH2CH & CH2CH2) and
and cyclopentadiene (94 mg, 1.40 mmol) were combined 0.88 (3H, t, J 7.2, CH3).
according to general procedure B. The crude material was then
endo: δH 9.37 (1H, d, J 3.4, CHO), 6.27 (1H, dd, J 5.7, 3.2,
purified by column chromatography, eluting with 40% CHAvCHB), 6.06 (1H, dd, J 5.7, 2.8, CHAvCHB), 3.14–3.10 (1H,
dichloromethane in petrol to yield the title compounds as a m, CHCH2), 2.68–2.64 (1H, m, CHCH2), 2.38 (1H, dt, J 4.4, 3.4,
21 : 79 mixture of diastereoisomers (99 mg, 83%).
CHCHO), 1.72 (1H, m, CHCH2CH2), 1.77–1.06 (6H, m,
[α]2D0 −47.3 (c 0.5, chloroform); νmax (film)/cm−1 3051 (Ar– CHCH2CH & CH2CH2) and 0.88 (3H, t, J 7.2, CH3).
H), 2975 (C–H), 2872 (C–H), 2815 (C–H), 2717 (C–H), 1716
(CvO), 1597 (CvC) and 1578 (Ar CvC)).
Enantiomeric excess was determined by acetalisation with
(+)-(R,R)-hydrobenzoin following general procedure C and 1H
exo-(2R): δH (300 MHz, CDCl3) 9.95 (1H, d, J 1.7, CHO), 8.32 NMR analysis:8 (300 MHz, C6D6) exo isomers δ 5.62 (d, J 6.1,
(1H, d, J 8.4, ArH), 7.89–7.84 (1H, m, ArH), 7.76–7.70 (1H, m, CHO2, 2R) and 5.60 (d, J 6.2, CHO2, 2S), endo isomers δ 5.24 (d,
ArH), 7.61–7.42 (2H, m, ArH), 7.35 (1H, t, J 7.7, ArH), 7.09 (1H, J 8.3, CHO2, 2R) and 5.18 (d, J 8.3, CHO2, 2S).
7890 | Org. Biomol. Chem., 2013, 11, 7877–7892
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endo-(1S,2R,3R,4R)-3-Phenylbicyclo[2.2.2]oct-5-ene-2-carb- (CHO), 139.1 (CHAvCHB), 136.9 (CAripso), 135.9 (CAripso), 134.2
aldehyde (Table 5, entry 7). (E)-Cinnamaldehyde (60.0 μL, (CHAvCHB), 132.5 (CAripso), 129.0 (CAr), 127.3 (CAr), 126.3
0.480 mmol), triflic acid (0.190 M solution in methanol, (CAr), 125.8 (CAr), 125.4 (CAr), 123.8 (CAr), 123.0 (CAr), 59.1
0.250 mL, 47.5 μmol), catalyst
6 (10 mol%, 20.0 mg, (CHCHO), 49.7 (CHCH2), 47.6 (CH2), 45.7 (CHCH2) and 41.4
47.5 μmol) and cyclohexadiene (140 μL, 1.40 mmol) were com- (CHAr); m/z HRMS (ESI+) C22H26NO2 ([M + NH4]+) requires
1
bined according to general procedure B. After 3 days, H NMR 336.1958, found 336.1963 (+1.5 ppm).
spectroscopic analysis indicated reaction had achieved 51%
Enantiomeric excess was determined by HPLC with Chiral-
conversion (exo : endo 6 : 94) and reaction was quenched as out- Cel OJ-H column (0.5% isopropanol : hexane, flow rate =
lined in general procedure B. The crude material was then pur- 1.0 mL min−1, 211 nm), tR(2S) 15.3 min and tR(2R) 24.7 min.
ified by column chromatography, eluting with 7.5% diethyl
ether in petrol to yield the title compound as a colourless solid endo-3-phenylbicyclo[2.2.2]oct-5-ene-2-carbaldehyde
with spectroscopic data in accordance with the literature obtained following the method of Deutsch, et al.,30 and deriva-
(43 mg, 43%).21
tised to the benzoyl ester by the same method described
[α]2D0 −35.7 (c 0.3, chloroform) (lit. [α]2D0 +82 ((1R,2S,3S,4S) above.
enantiomer, >95% ee,
1.0, dichloromethane));21 mp
In order to carry out HPLC analysis, a racemic sample of
was
c
54–55 °C; δH (300 MHz, CDCl3) 9.42 (1H, d, J 1.3, CHO),
7.29–7.12 (5H, m, ArH), 6.45 (1H, ddd, J 8.1, 6.8, 1.3,
CHAvCHB), 6.12 (1H, ddd, J 8.1, 6.5, 1.2, CHAvCHB), 3.13 (1H,
app dt, J 6.3, 2.2, CHPh), 3.03–2.98 (1H, m, CHCHCHO), 2.76
(1H, app dt, J 6.3, 1.5, CHCHO), 2.58–2.54 (1H, m, CHCHPh),
1.72–1.58 (2H, m, CHAHBCHCHCHO and CHAHBCHCHPh),
1.44–1.32 (1H, m, CHAHBCHCHCHO) and 1.07–0.94 (1H, m,
CHAHBCHCHPh).
Notes and references
1 K. A. Ahrendt, C. J. Borths and D. W. C. MacMillan, J. Am.
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Synthesis, 2010, 1–26.
For the purpose of HPLC analysis, the product was deriva-
tised to the benzoyl ester according to the method of Maruoka
et al.15,29
To a solution of endo-(1S,2R,3R,4R)-phenylbicyclo[2.2.2]oct-
5-ene-2-carbaldehyde (31.0 mg, 0.146 mmol) in methanol
(1 mL) was added sodium borohydride (17.0 mg, 0.450 mmol)
and the resulting suspension stirred at room temperature for
2 h. The reaction mixture was concentrated in vacuo before
being suspended in a mixture of water and brine and extracted
with dichloromethane (2 × 10 mL). The combined organic
layers were dried (MgSO4), filtered and concentrated in vacuo.
The resulting material was dissolved in dichloromethane
(1 mL) and treated with triethylamine (30.0 µL, 0.216 mmol),
DMAP (18.0 mg, 0.150 mmol) and benzoyl chloride (20.0 µL,
0.175 mmol) then stirred at room temperature overnight. Reac-
tion was quenched with saturated ammonium chloride solu-
tion (10 mL) and extracted with diethyl ether (3 × 10 mL). The
combined organic layers were washed with brine, dried
(MgSO4), filtered and concentrated in vacuo. The crude
material was purified by column chromatography on silica gel,
eluting with 5% diethyl ether in petrol to give the desired
product as a colourless solid (22 mg, 47%).
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[α]D20 −10.6 (c 0.5, chloroform); νmax (KBr disc)/cm−1 2931
(C–H), 2867 (C–H), 1711 (CvO), 1658 (Ar CvC) and 1601 (Ar
CvC); mp 82–84 °C; δH (300 MHz, CDCl3) 7.81 (2H, dd, J 8.3,
1.4, ArH), 7.50 (1H, tt, J 7.4, 1.4, ArH), 7.37–7.32 (5H, m, ArH),
7.27–7.19 (2H, m, ArH), 6.53 (1H, app t, J 7.4, CHAvCHB), 6.25
(1H, app t, J 7.3, CHAvCHB), 4.08 (1H, dd, ABX system, JAB
10.6, JAX 8.2, CHAHBO), 3.96 (1H, dd, ABX system, JBA 10.6, JBX
6.6, CHAHBO), 2.80–2.75 (1H, m, CHPh), 2.51–2.39 (3H, m,
CHCHCH2O & CHCHPh), 1.74–1.68 (2H, m, CHAHBCHCHCHO
8 H. He, B. J. Pei, H.-H. Chou, T. Tian, W.-H. Chan and
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9 Y. Langlois, A. Petit, P. Rémy, M.-C. Scherrmann and
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1.12–1.00 (1H, m, CHAHBCHCHPh); δC (100 MHz, CDCl3) 203.5
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Organic & Biomolecular Chemistry
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7892 | Org. Biomol. Chem., 2013, 11, 7877–7892
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