The chemical reactivity of a known anti-psoriasis drug. Part 1: Further insights into the products resulting from oxidative cleavage

Article abstract of DOI:10.1016/j.tet.2010.10.044

The oxidative cleavage of the known anti-psoriasis drug 1 to give 2 has been reported previously. Due to the importance of accessing medium-sized ring containing systems via oxidative cleavage, this reaction has been revisited revealing additional informa

Full text of DOI:10.1016/j.tet.2010.10.044

Tetrahedron 66 (2010) 9667e9674
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The chemical reactivity of a known anti-psoriasis drug. Part 1: Further insights
into the products resulting from oxidative cleavage
Alan M. Jones y, Magali M. Lorion y, Tomas Lebl, Alexandra M.Z. Slawin, Douglas Philp,
*
Nicholas J. Westwood
School of Chemistry and Biomedical Sciences Research Complex, University of St Andrews, St Andrews, Fife KY16 9ST, Scotland, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The oxidative cleavage of the known anti-psoriasis drug 1 to give 2 has been reported previously. Due to
the importance of accessing medium-sized ring containing systems via oxidative cleavage, this reaction
has been revisited revealing additional information about the structure of 2. Alternative reaction prod-
ucts were identified when the reaction was carried out in the presence of water. The conversion of 1 to 2
has also been carried out using ruthenium tetroxide. A detailed variable temperature NMR and com-
putational study of the restricted rotation of the N-aryl ring in 2 is presented.
Received 30 September 2009
Received in revised form 28 September 2010
Accepted 18 October 2010
Available online 10 November 2010
Keywords:
Heterocycle
Ó 2010 Elsevier Ltd. All rights reserved.
Oxidative fragmentation
Macrocycle
VT NMR analysis
Mechanism
1. Introduction
opening of an initially formed epoxide. Attack of the second
equivalent of m-CPBA was proposed to occur from the opposite face
The preparation of compounds containing medium-sized ring
systems continues to provide a considerable synthetic challenge.
One approach that has proved a particularly robust method of
accessing medium-sized rings is the oxidative cleavage of bicyclic
ring systems.1 Once formed, the presence in these systems of
a number of functional groups in close proximity often results in
the restricted interconversion of ring conformers leading, in some
cases, to atropisomerism.2
As a result of our interest in reaction sequences that deliver
medium-sized rings using oxidative cleavage reactions, our
attention was drawn to the anti-psoriasis drug, 10-(3-chlor-
ophenyl)-6,8,9,10-tetrahydrobenzo[b][1,8]naphthyridin-5(7H)-one
1 (Scheme 1). In particular, the m-CPBA mediated cleavage of the
central double bond in 1 to afford 2 has been reported.3 1 is also of
interest from a stereochemical perspective, as it possesses a ster-
eogenic axis due to restricted rotation about the N(10)eC(10) bond
and isolation of the short-lived enantiomers of 1 has been achieved
by HPLC using a chiral stationary phase.4 The oxidative fragmen-
tation of 1 was proposed to occur via reaction of a second equiva-
lent of m-CPBA with iminium ion 3,3 which may result from
to the hydroxyl functional group in 3 leading to the anti-arrange-
ment of the alcohol and the peroxyester groups shown in anti-4
(Scheme 1). Subsequent Grob-fragmentation5 of 4 was then sug-
gested to lead to 2 as shown. Interestingly, the 1H NMR spectrum
reported for 2 included diastereotopic protons that were assigned
to methylene groups that were remote from the N(12)eC(10) ster-
eogenic axis (C7 and C8 in 2, Scheme 1). Furthermore, an experi-
ment was described in support of the proposed mechanism. 1 was
reported to give 5, via 3 and anti-6 (Scheme 1), when the reaction
was carried out in the presence of only 1 equiv of m-CPBA and
a large excess of water. The proposed formation of 5 was also in-
teresting as 5 might be expected to contain at least one non-clas-
sical stereogenic element in addition to its classical stereogenic
centre and several issues relating to stereo- and potentially regio-
chemical control arise in this reaction. To explore this further, we
decided to revisit the oxidative fragmentation of 1 by m-CPBA and
other reagents. Part I of this study details the results of our attempts
to prepare 5 and a detailed study of the rotation of the N-aryl ring
about the N(12)eC(10) bond in 2. In the following paper,6 we
present the synthesis and analysis of ring-expanded analogues of 2.
Part II describes a detailed NMR and computational study of the
non-classical stereogenic element associated with the medium-
sized ring present in 2 and its analogues.6
* Corresponding author. E-mail address: njw3@st-andrews.ac.uk (N.J. Westwood).
y
These authors contributed equally.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.044

9668
A.M. Jones et al. / Tetrahedron 66 (2010) 9667e9674
H
H
O
O
O
H
Ar
O
O
O
R
10
N
N
N
N
R
Ar
4
anti-6
anti-
1'
O
H
O
Cl
1
H
Ar
-
m
O
-
O
C
+
H2
P
m
m-CPBA
B
+
-
A
O
C
H 2
P
B
-
A
H
O
OH
O
O
O
O
O
7
8
R
9
N
N
N
6'
N
N
R
10
3
Ar
O
2'
Cl
2
5
Cl
Scheme 1. A proposed3 rationalisation of the formation of 2 and 5.
2. Results and discussion
from restricted rotation about the N(12)eC(10) bond on the basis of
a 2D EXSYexperiment.10 Fig.1B(i) shows the dramatic differences in
chemical shifts experienced by the C20 (signals labelled 20a and 20b,
Scheme 1 for numbering system) and C60 (60a and 60b) protons in
the two rotameric forms as well as the two signals assigned to the
C7-diastereotopic protons in 2. Warming the sample to 293 K
resulted in coalescence of the signals corresponding to all the ar-
omatic protons whereas both at this temperature and at 363 K no
coalescence of the signals corresponding to the C7-diastereotopic
protons was observed despite the fact that the frequency difference
between the two C7 signals (Dn¼515 Hz) is comparable to that
observed at 233 K for the C20 and C60 protons (Dn¼496 and 419 Hz,
respectively).
These variable temperature NMR studies indicated that 2 pos-
sesses (at least) one additional stereogenic axis due to restricted
bond rotation in the medium-sized ring. In addition, it is clear that
the activation barrier associated with this additional dynamic pro-
cess is higher than that associated with the restricted rotation about
theN(12)eC(10)bond in 2. Adetailed discussionof this observationis
provided in the following paper in this issue.6 Here, as restricted
rotationabout the N(12)eC(10)bond in 1 enabled isolation of thetwo
enantiomeric atropisomers of 1,4 it was decided to investigate the
restricted rotation about the N(12)eC(10) bond in 2 in more detail.
Therateconstantsfor restricted rotationabout the N(12)eC(10)bond
in 2 were determined by lineshape analysis of the C20 and/or C60
In order to repeat the reported oxidative cleavage reactions with
m-CPBA, 1 was prepared from 7 by reaction of 8 with commercially
available 9 in accordance with literature precedent (Scheme 2).7
This reaction probably proceeds via the initial formation of 10 fol-
lowed by an intramolecular transamination reaction. 1 was then
subjected to the previously reported oxidative cleavage conditions
to afford 2 in an analogous yield to that previously reported (65% cf.
75%3).8 The structure of our sample of 2 was confirmed by X-ray
crystallographic studies.9
Analysis of our sample of 2 in CDCl3 by 1H NMR spectroscopy at
293 K revealed a set of aliphatic signals corresponding to diaster-
eotopic protons, as expected. These signals were assigned to the
protons of the four methylene carbons in 2 (C7, C8, C9 and C10,
Scheme 1). A detailed analysis using 2D NMR experiments, in-
cluding 1H,1H-COSY, 1H,13C-HSQC and 1H,13C-HMBC10 led us to
a different assignment of these signals compared to the original
report3 (Fig. 1A). Further analysis of 2 was carried out using variable
temperature NMR techniques. These experiments were carried out
in toluene-d8 to extend the range of temperatures that could be
accessed compared to studies in deuterochloroform. When the 1H
NMR spectrum was recorded at 223 K, two sets of signals in a ratio
of 1:0.7 were visible in the aromatic region of the spectrum (Fig. 1B
(i)). The two sets of signals were assigned to two rotamers resulting
CO2H
SOCl2, cat. DMF
COCl
NH
N
NH
N
O
N
rt, 1 h, 96%
NEt3, PhMe
0 oC to 80 oC,
54%
2.2 eq. m-CPBA
2
1
Cl
7
8
Cl
DCM, rt, 65%
N
NH
Cl
N
10
9
Scheme 2. Synthesis of 1 and the corresponding medium-sized ring containing compound 2.

A.M. Jones et al. / Tetrahedron 66 (2010) 9667e9674
9669
Fig. 1. A The reported3 assignment of the aliphatic region of the 1H NMR spectrum of 2 and the corrected assignment; B Comparison of selected regions of the aliphatic and aromatic
region of the 1H NMR (500 MHz) spectrum of 2 recorded in toluene-d8 at (i) 223, (ii) 293 and (iii) 363 K.
proton resonances in 1H NMR spectra recorded between 223 and
273 K. In this temperature range the dynamic process associated
with the medium-sized ring was in the slow exchange limit and did
not contribute to broadening of resonances in the aromatic region.
The temperature dependence of the experimentally determined
rate constants was used to determine the activation parameters by
fitting the experimental data to the Eyring equation. The plots of ln
(k/T) against 1/Tshowed a good overall linear dependence (Fig. S7)10
excellent agreement with the 1:0.7 ratio of rotamers observed in
the 1H NMR analysis of 2 at 223 K.10 Furthermore, the 1NMR
analysis of 2 at 223 K shows that in the most abundant rotamer the
chemical shift of the H20 proton is lower and the chemical shift of
proton H60 is higher than the same signals in the less abundant
rotamer by (ꢀ) 0.99 and (þ) 0.84 ppm, respectively.10 The calcu-
lated chemical shift differences (B3LYP/6-31G** level of theory)
associated with the H20 and H60 signals between the computa-
tionally predicted more stable rotamer (ii) and the less stable
rotamer (i) are smaller ((ꢀ) 0.64 and (þ) 0.61 ppm) but show the
same trend.10
The two transition states that connect rotamers (i) and (ii) with
torsional angles (C12aeN12eC10eC20) of ꢀ17.98ꢂ and 161.15ꢂ, re-
spectively, were located using semi-empirical RM1 method and the
geometries were refined at B3LYP/6-31G** level of theory (Fig. 2D).
In addition, the calculations showed that the two transition states
and the resulting activation parameters
D
Gz
,
D
Hz
and D
Sz
298 298
were55.6 kJ molꢀ1, 56.1 kJ molꢀ1 and 1.7 kJ Kꢀ129m8 olꢀ1, respectively. A
half life for this dynamic process was therefore calculated to be
3.11ꢁ10ꢀ4 s at 298 K. Interestingly, the Gibbs free energy of activa-
tion (D
Gz298) for racemisation of 1, a process that involves the
analogous rotation about the N(12)eC(10) bond, was determined by
dynamic high-performance liquid chromatography to be
88.7 kJ molꢀ1 with a corresponding half life of 3.5 min4 Whilst dif-
ferent techniques were used to determine the two
D
Gz298 values, the
have nearly the same energy (
D
ETS1ꢀTS2¼0.45 kJ molꢀ1). The cal-
clearly increased barrier to this rotation in 1 compared to 2, whilst
perhaps not surprising, was of interest to us. To investigate this
further, the energy profile for rotation about the N(12)eC(10) bond in
2 was calculated at the RM1 level of theory. This revealed two pre-
ferred low energy orientations for the chlorophenyl ring (Fig. 2A).
Both of these rotamers were also found in the X-ray structure of 2
(Fig. 2B). Calculation of the ground state structures at the B3LYP/6-
31G** level of theory afforded geometries that were in good agree-
ment with the structures obtained experimentally. Selected torsion
angles for the experimentally determined and calculated structures
are shown for comparison in Fig. 2C.
culated geometries (Fig. 2D) indicate that in order to pass through
the transition states, the chlorophenyl ring is forced to adopt an
orientation in which it is nearly perpendicular with respect to the
pyridine ring (C4aeC12aeN12eC10¼ꢀ104ꢂ in (iii)). The calculated
enthalpy of activation of the process (D
Hz298 61.0 kJ molꢀ1) for 2 is
only slightly higher than the experimentally determined one
(D
Hz 56.1 kJ molꢀ1). By reorienting the chlorophenyl ring in 2,
298
a process, that is, not possible in 1, rotation about the N(12)eC(10)
bond is facilitated by avoiding interactions with the lone pair on the
pyridine nitrogen and/or the C10 methylene group. The amide bond
remains trans throughout aryl ring rotation with the
C12aeC12eC11eC10 torsional angle remaining approximately
constant.
The energy of structure (ii) (Fig. 2A) was calculated to be only
0.37 kJ molꢀ1 lower than that of the rotameric form (i). This is in

9670
A.M. Jones et al. / Tetrahedron 66 (2010) 9667e9674
Fig. 2. A Ground state structures of 2 calculated at the B3LYP/6-31G** level of theory. B The analaogous two rotamers observed on X-ray crystallographic analysis of 2. C Comparison
of the torsion angles in ꢂ for structures (i) and (ii) of 2 determined and calculated (see Fig. 2A) and the numbering system used for 2. The values are in relatively close agreement.
D The two transition states ((iii) and (iv)) for restricted rotation about the N(12)eC(10) bond in 2.
3. Reinvestigation of the reaction of compound 1 with
m-CPBA
provided for 5 in the literature.3 Interestingly, in our hands, the
minor product we obtained in this reaction was also a yellow
compound. Extensive 2D NMR analysis of the minor product
resulted in its structural assignment as the enamine 12 formed via
dehydration of 11.10 Interestingly, in the case of 12, an IR signal was
We next turned our attention to the reported conversion of 1 to
5 (Scheme 1).3 Compound 1 was proposed to react with 1 equiv of
m-CPBA to give iminium ion 3. Reaction of 3 with water was then
proposed to lead to anti-diol 6 (Scheme 1), which was converted to
5 via a retro-aldol reaction. The reported analytical data for 5 in-
cluded some 13C data, IR, MS and microanalysis.3 In our hands, the
procedure described for the synthesis of 5 repeatedly gave two
main products in addition to recovered 1. The structure of the major
product was assigned as syn-diol 11 based on X-ray crystallographic
analysis (Scheme 3).9 The 13C NMR spectrum of 11 in CDCl3 showed
a carbonyl resonance was present at 197.9 ppm,10 0.1 ppm different
from that quoted in the literature for the C5 carbonyl 13C NMR
resonance in the proposed product 5.3 Mass spectroscopic analysis
of 11 was consistent with the structural assignment 11 or 5, as they
are isomers. The IR stretch associated with the carbonyl group in 11
was observed at
n n )
1665 cmꢀ1 (compared with ( 1685 cmꢀ1
reported 5). In addition, a broad signal assigned to the presence of
an OH group in 11 was observed at
reported signals in this region for 5 were
n
3482 cmꢀ1 whereas the
3530 and 3460 cmꢀ1. The
n
colourless crystals of 11 obtained by us, changed to yellow crystals
Scheme 3. Conversion of 1 to syn-diol 11 (X-ray structure) and enamine 12.
on prolonged exposure to air, in accordance with the description

A.M. Jones et al. / Tetrahedron 66 (2010) 9667e9674
9671
observed at
n
1684 cmꢀ1, one wavenumber away from the value
membered ring is rigid, as suggested by VT 1H NMR (see discussion
above), then it would initially be expected to give the 3 carbonyl
groups in the relative orientation shown in 2a (Fig. 3A), that is,
different from the orientation 2b seen in the crystal structure of 2
(Fig. 2B).9 However, according to computational studies at the
B3LYP/6-31G** level of theory, 2a is some 36.0 kJ molꢀ1 higher in
energy than 2b. Attempts to calculate a pathway by which 2a could
be converted to 2b, (for example, by flipping of the C5eC6 dicar-
bonyl functionality) were made. Using the semi-empirical RM1
method, the torsion angle O5eC5eC6eO6 was driven in 2ꢂ steps
fromþ140ꢂ to ꢀ140ꢂ. Unsurprisingly, the maximum energy struc-
ture was located when the O5eC5eC6eO6 torsion angle was
approaching 0ꢂ, that is, when the dipoles associated with two
carbonyl groups are aligned. The maximum energy structure was
used as an initial guess for refinement of the transition state
structure at the B3LYP/6-31G** level of theory. The calculated
ground and transition state structures together with the corre-
sponding O5eC5eC6eO6 torsion angles and relative energies are
shown in Fig. 3B. The Gibbs free energy of activation
reported for the apparently unstable 5.3
The chemical reactivity of 11 was as expected for a syn-diol with
rapid and quantitative conversion of 11 to 2 occurring on treatment
with either lead tetraacetate11 in dichloromethane at 0 ꢂC or phe-
nyliododiacetate (97% yield, Scheme 3).12 Amongst several possible
explanations for the highly stereoselective formation of syn-diol 11
on treatment of 1 with m-CPBA and water, we currently favour the
hydrogen-bond directed addition of water to the reactive iminium
ion 3 to give 11 directly (Scheme 3). This proposal would be in line
with previous literature reports.13
One possible explanation for the observed difference in the re-
action outcome in our hands compared to the literature may be the
purity of the m-CPBA used in these reactions.14 The major con-
taminant in m-CPBA, apart from water,15 is likely to be the corre-
sponding carboxylic acid (m-CBA) and so attempts were made to
repeat this reaction in the presence of additional m-CBA or an al-
ternative acid, trifluoroacetic acid. In both cases only the formation
of 11 and increased amounts of 12 were observed. To date we have
been unable to detect the formation of 5 under any reaction
conditions.
If the mechanism proposed in Scheme 3 is correct, it might also
be expected that m-CPBA adds to give syn-4 (Fig. 3A) as opposed to
anti-4 (Scheme 1). Whilst isomerisation of syn-4 to anti-4 is clearly
feasible,15 and Grob-fragmentation of anti-4 is the most likely
method by which 2 can be accessed, it remains possible that 2 is
formed via syn-4 as the two bonds that would break during frag-
mentation can adopt an anti-periplanar arrangement in syn-4. If
formation of 2 does occur via syn-4 and the conformation of the 10-
(D
Gz ¼41.5 kJ molꢀ1) calculated for this process using standard
298
methods suggests that flipping of the C5eC6 dicarbonyl function-
ality in 2a to give 2b can occur very readily at room temperature
with a half life of 2a of 1.2ꢁ10ꢀ6 s.
Ruthenium-based reagents are known for their ability to cleave,
epoxidise and dihydroxylate alkenes,16 although to the best of our
knowledge reagents of this type have very rarely been used in
conjunction with
b-enaminones of the general type discussed
here.17 Interestingly, it proved possible to convert 1 to 2 in rea-
sonable yield using ruthenium tetroxide, generated in situ by
Fig. 3. A An alternative proposal for the mechanism of the conversion of 1 to 2 via syn-4. B Ball and stick representations of ground state (2a and 2b) and transition state (TS) for
flipping of C5eC6 dicarbonyl functionality. The table shows corresponding O5eC5eC6eO6 torsion angles and relative energies.

9672
A.M. Jones et al. / Tetrahedron 66 (2010) 9667e9674
reaction of RuCl3$xH2O (0.5 mol %) with sodium periodate
(6.0 equiv) as the oxidant.18 Attempts to analyse the progress of this
reaction at early time points and in the presence of lower quantities
of sodium periodate led to the observation that syn-diol 11 was the
major product. As 11 has been shown by us to be readily cleaved to
2 by sodium periodate (as well as lead tetraacetate and phenyl-
iododiacetate, Scheme 3), it seems very likely that 2 is formed from
1 not by ruthenium-catalysed direct cleavage of the double bond in
1,19 but by either direct dihydroxylation of 1 or by epoxidation of 1
by RuO4 followed by epoxide opening to give 11 (Fig. 3A).
1.0 M Na2CO3(aq) (10.0 mL) and H2O (10.0 mL). The aqueous washes
were back extracted with dichloromethane (2ꢁ30.0 mL). The
combined organic phase was dried (MgSO4), filtered and concen-
trated in vacuo. The residue was purified by column chromatog-
raphy over silica gel (1:1, ethyl acetate/hexane). An analytically
pure sample of 2 (223 mg, 0.652 mmol, 65%) was obtained as yel-
low needles by recrystallisation from ethanol.
Method 2: Sodium periodate (642 mg, 3.00 mmol, 6.00 equiv)
was stirred in H2O (0.750 mL) and 2 N sulfuric acid (100 mL). After
the solid had dissolved, the solution was cooled to 0 ꢂC. Ruthenium
(III) chloride hydrate (0.622 mg, 0.003 mmol, 0.5 mol %) was then
added and the reaction was stirred until the colour turned bright
yellow. Ethyl acetate (3.00 mL) and acetonitrile (3.00 mL) were
added and stirring was continued for a further 5 min. Compound 1
(155 mg, 0.500 mmol, 1.00 equiv) was then added to the reaction
and the slurry was stirred at room temperature for 24 h. The re-
action mixture was poured into a mixture of saturated NaHCO3
solution (10.0 mL) and saturated sodium thiosulfate solution
(10.0 mL). The phases were separated, and the aqueous layer was
extracted with ethyl acetate (3ꢁ20.0 mL). The combined organic
layers were dried (Na2SO4) and concentrated in vacuo. The crude
product was purified by flash column chromatography using silica
gel (1:9e3:7, ethyl acetate/hexane), which afforded two fractions.
The fraction eluting at 1:9 ethyl acetate/hexane was 2 (68.4 mg,
0.200 mmol, 40%) as a yellow solid. The fraction eluting at 3:7 ethyl
acetate/hexane was 11 (103 mg, 0.300 mmol, 60%) as a cream solid.
Method 3: To a cooled solution of 11 (20.6 mg, 0.0600 mmol,
1.00 equiv) in anhydrous DCM (5.00 mL) at 0 ꢂC (ice/water bath)
was added lead tetraacetate (53.2 mg, 0.120 mmol, 2.00 equiv) and
the reaction was stirred for 20 min. The solvent was removed in
vacuo and the crude residue was purified by flash column chro-
matography over silica gel (2:3, ethyl acetate/hexane) to afford 2
(20.5 mg, 0.060 mmol, 99%) as a yellow solid.
4. Conclusion
The synthesis of compounds containing medium-sized rings
remains a challenge. One robust approach for their synthesis in-
volves the use of oxidative cleavage reactions in which the central
double bond in a polycyclic compound is cleaved. A previously
reported example of this approach involves the fragmentation of
the anti-psoriasis drug 1 resulting in the formation of 2, a com-
pound containing a highly functionalised 10-membered ring. Here
we have revisited this report and extended the level of un-
derstanding associated with this reaction. In Part II of this study,6
the nature of the non-classical stereogenic axis in this system is
explored through the use of ring-expanded analogues of 2.
5. Experimental10
5.1. 1 10-(3-Chlorophenyl)-6,8,9,10-tetrahydrobenzo[b][1,8]
naphthyridin-5(7H)-one3,7
A solution of triethylamine (4.81 mL, 34.5 mmol, 1.10 equiv) and
9 (5.21 g, 34.5 mmol, 1.10 equiv) in toluene (18.0 mL) was added
dropwise over 10 min to a stirred, cooled (ice-acetone, ꢀ10 ꢂC bath)
suspension of the crude acid chloride 8 (8.35 g, 31.4 mmol,
1.00 equiv) in toluene (140 mL). As the solid dissolved the dark red
reaction mixture was kept between ꢀ5 ꢂC and þ5 ꢂC for 2 h. The
reaction mixture was allowed to warm to room temperature over
30 min and then heated at 80 ꢂC for 4 h. The reaction mixture was
allowed to cool and to stand at room temperature for 12 h, after
which the toluene was removed under reduced pressure. The res-
idue was dissolved in dichloromethane (150 mL) and the solution
was washed with H2O (100 mL), 1.0 M HCl(aq) (100 mL), 1.0 M
Na2CO3(aq) (100 mL) and H2O (100 mL). Aqueous extracts were back
extracted with dichloromethane (2ꢁ150 mL), and the combined
organic portion was dried over Na2SO4, filtered and evaporated. The
residue was purified by column chromatography over silica gel (3:2,
ethyl acetate/hexane). An analytically pure sample of 1 (5.27 g,
17.0 mmol, 54%) was obtained as a cream solid by recrystallisation
from acetonitrile. Mp 187e188 ꢂC (lit.3, 199e201 ꢂC); 1H NMR
Method 4: To a solution of 11 (127 mg, 0.370 mmol,1.00 equiv) in
anhydrous dichloromethane (10 mL) was added portion-wise
(diacetoxyiodo)benzene (238 mg, 0.740 mmol, 2.00 equiv) and the
reaction was stirred at room temperature for 1 h. The reaction
mixture was washed with a saturated NaHCO3 solution (10.0 mL)
and a saturated sodium thiosulfate solution (10.0 mL). The aqueous
washes were back extracted with dichloromethane (2ꢁ30.0 mL)
and the combined organic phase was dried (MgSO4), filtered and
concentrated in vacuo. The residue was purified by flash column
chromatography over silica gel (2:3, ethyl acetate/hexane) to afford
2 (123 mg, 0.360 mmol, 97%) as a yellow solid.
Mp 157.5e157.9 ꢂC (lit.3, 173e175 ꢂC); 1H NMR (300 MHz,
CDCl3):
d
8.49 (dd, 3J¼5.0 Hz, 4J¼2.0 Hz, 1H, C2eH), 8.28 (dd,
3J¼8.0 Hz, 4J¼2.0 Hz,1H, C4eH), 7.43e7.34 (m, 3H, AreH), 7.31e7.27
(m, 1H, C3eH), 7.26e7.21 (m, 1H, AreH), 3.33e3.25 (m, 1H, C7eHa),
2.56e2.50 (m, 1H, C7eHb), 2.43e2.38 (m, 1H, C10eHa), 2.16e2.04
(m, 2H, C10eHb, C9eHa), 1.95e1.82 (m, 2H, C9eHb, C8eHa),
(300 MHz, CDCl3):
d
8.84 (dd, 3J¼8.0 Hz, 4J¼2.0 Hz, 1H, C4eH), 8.62
(dd, 3J¼4.5 Hz, 4J¼2.0 Hz, 1H, C2eH), 7.62e7.60 (m, 2H, AreH),
7.38e7.34 (m, 2H, AreH, C3eH), 7.29e7.23 (m, 1H, AreH),
2.85e2.80 (m, 2H, C6eH2), 2.42e2.36 (m, 2H, C9eH2), 1.88e1.81
1.76e1.66 (m, 1H, C8eHb); 13C NMR (75.5 MHz, CDCl3):
d 202.1 (C6),
190.5 (C5), 176.1 (C11), 153.1 (C12a), 152.7 (C2), 142.4 (C10), 139.5
(C4), 135.5 (C30), 130.7 (Ar), 129.0 (Ar), 128.7 (Ar), 127.1 (Ar), 125.2
(C4a), 122.1 (C3), 37.6 (C7), 36.0 (C10), 25.5 (C9), 25.2 (C8); IR (KBr):
nmax¼2951 (m), 2870 (w), 1701 (s), 1684 (s), 1653 (s), 1592 (m), 1424
(m), 1287 (m), 1160 (w), 760 (m) cmꢀ1; LRMS (ESþ): m/z (%) 365.10
(100) [M35ClþNa]þ; HRMS (ESþ): m/z calcd for C18H1535ClN2NaO3
[M35ClþNa]þ: 365.0669; found 365.0666.
(m, 4H, C7eH2, C8eH2); 13C NMR (75.5 MHz, CDCl3):
d 177.6 (C5),
152.0 (C2), 151.2 (C10a), 149.1 (C9a), 139.9 (C10), 135.6 (C4), 135.3
(C30), 130.6 (Ar), 129.8 (Ar), 129.4 (Ar), 127.7 (Ar), 119.9 (C4a), 119.3
(C3), 118.6 (C5a), 29.6 (C6), 22.5 (C7 and C8), 21.4 (C9); LRMS (ESþ):
m/z (%) 311.79 (100) [M35ClþH]þ.
5.2. 2 12-(3-Chlorophenyl)-7,8,9,10-tetrahydropyrido[2,3-b]
azecine-5,6,11(12H)-trione3
5.3. 7 2-((3-Chlorophenyl)amino)-3-pyridinecarboxylic acid20
A
mixture of 2-chloronicotinic acid (15.8 g, 100 mmol,
Method 1: To a solution of 1 (310 mg, 1.00 mmol) in anhydrous
dichloromethane (16.0 mL) was added portion-wise m-CPBA
(345 mg, 2.00 mmol, 2.00 equiv) and the reaction was stirred at
room temperature for 40 h. The reaction mixture was washed with
1.00 equiv), 3-chloroaniline (25.5 g, 200 mmol, 2.00 equiv), p-tol-
uenesulfonic acid$H2O (1.90 g, 10.0 mmol, 0.100 equiv) and H2O
(100 mL) was heated at reflux for 4 h. The cooled mixture was fil-
tered, and the collected yellow precipitate was washed with cold

A.M. Jones et al. / Tetrahedron 66 (2010) 9667e9674
9673
H2O (2ꢁ50.0 mL) and dried overnight (60 ꢂC) in an oven to afford
the title compound 7 (24.1 g, 970 mmol, 97%) as a bright yellow
solid. Mp 195e196 ꢂC (lit.20, 199e201 ꢂC); 1H NMR (300 MHz,
Mp 167.1e168 ꢂC; 1H NMR (400.1 MHz, CDCl3):
d
8.32e8.27 (m,
1H, C2eH), 8.16 (dd, 3J¼7.6 Hz, 4J¼1.9 Hz, 1H, C4eH), 7.63e7.60 (m,
0.5H, C20eH), 7.52e7.47 (m, 0.5H, C60eH), 7.44e7.35 (m, 2.5H,
C50eH, C40eH, C20eH), 7.34e7.30 (m, 0.5H, C60eH), 6.83 (dd, 3J¼7.6,
1.9 Hz, 1H, C3eH), 4.02 (s, 1H, C5aeOH), 3.07 (s, 1H, C9aeOH),
2.00e1.89 (m, 1H, C6eHa), 1.81e1.46 (m, 7H, C9eH2, C8eH2, C6eHb,
CD3OD):
d
8.43e8.36 (m, 2H, C6eH, C4eH), 8.03 (dd, 4J¼2.0, 2.0 Hz,
1H, C20eH), 7.48e7.44 (m, 1H, C50eH), 7.35e7.28 (m, 1H, C60eH),
7.09e7.04 (m, 1H, C40eH), 6.91 (dd, 3J¼7.5, 5.0 Hz, 1H, C5eH); IR
3059 (s), 1671 (s), 1567 (m), 1426 (m), 1241 (m), 1094 (m), 763 (m)
cmꢀ1; LRMS (ESꢀ): m/z (%) 247.67 (100) [M35ClꢀH]ꢀ.
C7eH2); 13C NMR (100.1 MHz, CDCl3, 298 K):
d 198.1 (C5), 158.7
(C10a), 155.6 & 155.5 (C1), 141.2 (C10), 136.6 (2ꢁC4), 135.1 & 134.0
(C30), 131.9 (C50), 130.5 (C40), 130.0 (C20), 129.8 (C60), 129.4 (C50),
128.1 (C40), 128.1 (C60), 128.0 (C20), 115.7 (C3), 111.6 & 111.5 (C4a),
89.5 (C9a), 77.3 (C5a), 33.6 (2ꢁC6), 32.9 & 32.8 (C9), 22.2 & 22.1
(C7), 18.9 (2ꢁC8); IR (KBr): nmax¼3482 (s) (OH), 2926 (s) (CH2),
2944 (s) (CH2), 2865 (m) (CH2), 1665 (s) (C]O), 1598 (m), 1470 (m),
1196 (m) (CeO), 722 (m) (CeCl) cmꢀ1; LRMS (ESþ): m/z (%) 367.04
(100) [M35ClþNa]þ; HRMS (ESþ): m/z calcd for C18H1735ClN2 NaO3
[M35ClþNa]þ: 367.0825; found 367.0827.
5.4. 8 2-((3-Chlorophenyl)amino)-3-pyridinecarbonyl
chloride7b
2-((3-Chlorophenyl)amino)-3-pyridinecarboxylic acid 7 (8.18 g,
33.0 mmol, 1.0ꢂ equiv) was added to thionyl chloride (13.3 mL,
182 mmol, 5.50 equiv) and DMF (catalytic 100 mL) and stirred at
25 ꢂC for 1 h. Concentration of the reaction mixture in vacuo
afforded the crude acid chloride 8 (8.35 g, 31.4 mmol, 96%), which
was used without further purification. 1H NMR (300 MHz, CDCl3):
5.6. 12 (S)-10-(3-Chlorophenyl)-5a-hydroxy-5a,6,7,8-
tetrahydrobenzo[b][1,8]naphthyridin-(10H)-one
d
9.65 (s, NH), 8.51 (dd, 3J¼4.5 Hz, 4J¼2.0 Hz, 1H, C6eH), 8.46 (s, 1H,
C4eH), 7.85 (br s, 1H, C20eH), 7.50e7.25 (m, 3H, C50eH, C60eH,
1H NMR (300 MHz, CDCl3):
d
8.27 (dd, 3J¼4.7 Hz, 4J¼2.1 Hz, 1H,
C40eH), 6.92 (dd, 3J¼7.5, 4.5 Hz, 1H, C5eH).
C2eH), 8.18 (m, 3J¼7.7 Hz, 4J¼2.1 Hz, 1H, C4eH), 7.45 (dd, 3J¼7.5,
7.6 Hz, 1H, C50eH), 7.40e7.37 (m, 1H, C40eH), 7.30 (dd, 4J¼2.0,
2.0 Hz, 1H, C20eH), 7.19 (ddd, 3J¼7.5 Hz, 4J¼2.0, 1.3 Hz, 1H, C60eH),
6.82 (dd, 3J¼7.7, 4.7 Hz, 1H, C3eH), 5.11 (dd, 3J¼5.7 Hz, 4J¼3.1 Hz,
1H, C9eH), 2.45 (br s, 1H, OH), 2.27e1.91 (m, 4H, C6eH2, C8eH2),
5.5. 11 (5aS, 9aR)-10-(3-Chlorophenyl)-5a,9a-dihydroxy-
6,7,8,9,9a,10-hexahydrobenzo[b][1,8]-naphthyridin-5(5aH)-
one
1.87e1.47 (m, 2H, C7eH2); 13C NMR (75.5 MHz, CDCl3):
d 192.1 (C5),
154.7 (C10a), 154.6 (C2), 141.9 (C10), 139.4 (C9a), 137.5 (C4), 135.3
(C30), 130.8 (C50), 130.3 (C20), 128.3 (C60), 128.2 (C40), 119.4 (C9),
115.6 (C3), 112.4 (C4a), 69.6 (C5a), 30.2 (C6), 25.3 (C8), 18.0 (C7); IR
(KBr): nmax¼3484 (s) (OH), 2945 (m) (CH2), 1684 (s) (C]O), 1567
(m), 1361 (m), 1174 (m) (CeO), 748 (m) (CeCl) cmꢀ1; LRMS (ESþ):
m/z (%) 349.04 (100) [M35ClþNa]þ; HRMS (ESþ): m/z calcd for
C18H1535ClN2NaO2 [M35ClþNa]þ: 349.0725; found 349.0724.
Repurification of 12 by column chromatography eluting with
MeOH/DCM (1:99) yielded only 12.15
Method 1: To a solution of 1 (311 mg, 1.00 mmol, 1.00 equiv) in
dimethyl formamide (6.00 mL) diluted with H2O (2.00 mL) was
added purified m-CPBA (173 mg, 1.00 mmol, 1.00 equiv) and the
reaction was stirred at room temperature for 94 h. The reaction
mixture was poured into H2O (100 mL) and extracted with ethyl
acetate (3ꢁ150 mL). The combined organic extracts were washed
with H2O (100 mL), 1.0 M NaHCO3(aq) solution (100 mL) and brine
(100 mL), dried (MgSO4) and concentrated in vacuo to give a yellow
oil. Purification by column chromatography using silica gel
(1:10e4:6, ethyl acetate/hexane) afforded three fractions. The
fraction eluting at 1:10 ethyl acetate/hexane was 11 (110 mg,
0.320 mmol, 32%) as a white solid. The fraction eluting at 15:85
ethyl acetate/hexane was 12 (48.9 mg, 0.150 mmol, 15%) as a yellow
oil. The fraction eluting at 4:6 ethyl acetate/hexane was the starting
pyridinone 1 (164 mg, 0.530 mmol, 53%) as a cream solid. This
experiment was also repeated using an unpurified batch of m-
CPBA. No change in the products identified from this reaction was
observed. In addition attempts to purify either the crude reaction
by column chromatography eluting with MeOH/DCM (1:99) yiel-
ded the same products as when ethyl acetate/hexane mixtures
were used.15 Repurification of 11 by column chromatography
eluting with MeOH/DCM (1:99) yielded only 11.15
Acknowledgements
The authors thank BBSRC (A.M.J.) and the Royal Society (Re-
search Fellowship to N.J.W.) for funding.
Supplementary data
VT NMR data, 2D NMR spectra associated with 2 and 12, low
temperature NMR assignment for 11, general and computational
experimental and 1H and 13C NMR spectra of all new compounds.
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2010.10.044.
Method 2: Sodium periodate (321 mg, 1.50 mmol, 3.00 equiv)
was stirred in H2O (0.750 mL) and 2 N sulfuric acid (100 mL). After
the solid had dissolved, the solution was cooled to 0 ꢂC. Ruthenium
(III) chloride hydrate (0.622 mg, 0.00300 mmol, 0.5 mol %) was then
added and the reaction was stirred until the colour turned bright
yellow. Ethyl acetate (3 mL) and acetonitrile (3 mL) were added and
stirring was continued for a further 5 min. Compound 1 (155 mg,
0.500 mmol, 1.00 equiv) was then added to the reaction and the
slurry was stirred at room temperature for 24 h. The reaction
mixture was poured into a mixture of saturated NaHCO3 solution
(10.0 mL) and saturated sodium thiosulfate solution (10.0 mL). The
phases were separated, and the aqueous layer was extracted with
ethyl acetate (3ꢁ20.0 mL). The combined organic layers were dried
(Na2SO4) and concentrated in vacuo. The crude product was puri-
fied by flash column chromatography using silica gel (2:3, ethyl
acetate/hexane) to afford 11 (127 mg, 0.370 mmol, 74%) as a white
solid.
References and notes
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A.M. Jones et al. / Tetrahedron 66 (2010) 9667e9674
hands there was a considerable difference in the melting point of 1 compared
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Smith, A. D. Synlett 2003, 1659e1662; (b) Aciro, A.; Davies, S. G.; Garner, A. C.;
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Butterworth-Heinemann: Oxford, UK, 2003.
15. We thank the reviewers for raising these issues during the assessment of this
manuscript. We would also like to thank the authors of Ref. 3 for help and
advice throughout the review process.
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with the value reported previously.3
8. A discrepancy in the melting point of 2 prepared by us and that reported
previously3 was observed.
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