Synthesis and structure determination of 8- and 9-iodocamphorquinone bis(ethylene ketal)

Article abstract of DOI:10.3184/030823407X209714

The structures of 8- and 9-iodocamphorquinone bis(ethylene ketal) have been confirmed by spectroscopic and single crystal X-ray analysis. The unexpected formation of the latter isomer is attributed to intramolecular rearrangement of the camphor skeleton, the mechanistic details of which have been explored using coset analysis.

Full text of DOI:10.3184/030823407X209714

240 RESEARCH PAPER
APRIL, 240–243
JOURNAL OF CHEMICAL RESEARCH 2007
Synthesis and structure determination of 8- and 9-iodocamphorquinone
bis(ethylene ketal)
Nceba Magqia, Kevin A. Lobba, Perry T. Kayea* and Mino R. Cairab
aDepartment of Chemistry, Rhodes University, Grahamstown, 6140, South Africa
bDepartment of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa
The structures of 8- and 9-iodocamphorquinone bis(ethylene ketal) have been confirmed by spectroscopic and single
crystal X-ray analysis. The unexpected formation of the latter isomer is attributed to intramolecular rearrangement
of the camphor skeleton, the mechanistic details of which have been explored using coset analysis.
Keywords: camphor, skeletal rearrangement, 8- and 9-iodocamphorquinone bis(ethylene ketal)
Various camphor derivatives have been targeted in our
research on the development of multidentate ligands.1,2
Such systems readily undergo acid-catalysed intramolecular
rearrangement,3 often resulting in complete reorganisation of
the camphor skeleton. Selective bromination of camphor at C-8
requires pre-functionalisation at C-3 to prevent intramolecular
rearrangements that lead to undesirable by-products.4 Thus,
following Money’s procedure,4 3-bromocamphor 1 was treated
with neat bromine to afford 3,3-dibromocamphor 2. Selective
C-8 bromination and Zn-catalysed debromination then gave 8-
bromocamphor 6 in 38% yield, together with 3,3,4-trimethyl-
1,7-dibromonorbornan-2-one 7 (ca 6%) (Scheme 1). Prior
to the debromination step, a sample was chromatographed
and fractions were subjected to NMR analysis. This
revealed the presence of 3,3,8-tribromocamphor 3, 3,3,8,10-
tetrabromocamphor 4 and 1,7-dibromo-4-dibromomethyl-
3,3-dimethylnorbornan-2-one 5 in a 7:1:5 ratio. While all
of these camphor derivatives have been previously isolated
and characterised by Money and co-workers,4 our particular
interest lay in the conversion of 8-bromocamphor 6 to the
previously unreported 8-iodocamphorquinone 9, which was
expected to provide access, via the diketal 10, to chiral,
tridentate ligands, such as compound 11 (Scheme 2).
Before attempting to introduce an intrinsically nucleophilic
phosphine donor into the 8-iodo diketone 9, the carbonyl
groups were protected by acid-catalysed ketalisation following
a
procedure described by Komarov and co-workers.5
Spectroscopic analysis of the crude material recovered
after the reaction indicated the presence of a mixture of
compounds, chromatographic separation of which afforded
five different ketal products, viz., the 8-iodo monoketals 12
and 13, the known diketal 146 and a pair of isomers. Both
isomers exhibited spectroscopic properties consistent with the
desired 8-iodocamphorquinone bis(ethylene ketal) 10.
Single crystal X-ray analysis (Fig. 1) permitted assignment
of structure 10 to the major product (24%). Interestingly,
the X-ray crystal structure reveals a particular orientation of
the 8-methylene hydrogens relative to the ketal groups such
Br
Br
3
Br
Br
O
Br
Br
6
Br
Br
Br
Br
O
H
Br2, ClSO3H
O
Br2
Zn, HOAc
4
+
H
Br
Br
O
Br
O
1
2
O
Br
Br
O
7
5
Br
Br
Scheme 1
I
PR2
Br
Br
PTSA
ethylene
glycol
I
O
OH
OH
SeO2
O
O
KI, DMF
O
O
O
O
O
O
6
10
9
11
8
+
By-products
Scheme 2
* Correspondent. E-mail: p.kaye@ru.ac.za
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JOURNAL OF CHEMICAL RESEARCH 2007 241
I
I
I
9
9
8
8
7
1
7
4
4
2
O
O
O
O
O
O
O
O
3
3
5
O
5
I
6
6
1
O
2
10
10
O
O
O
O
9
8
7
1
15
14
13
12
O
(b)
(a)
4
3
that one of these atoms participates in strong, bifurcated
hydrogen bonds C10–HA O12 and C10–HA O16 (H
and C O distances ~2.2 and 2.9 Å respectively). If a similar
conformation is favoured in CDCl3, this could account for the
significant H NMR chemical shift difference (ca 1.2 ppm)
5
O
O
º
º
º
O
2
º
6
O
10
1
observed for these protons. Thus, the hydrogen-bonded atom
(HA) would be deshielded by the electronegative oxygens
while the other (HB) would be shielded by the 9- and 10-
methyl groups. In the molecule of 10, the C–I bond length is
2.167(3) Å and the torsion angle C9–C8–C10–I11 is –67.5(3)°.
One of the ketal rings adopts an envelope conformation (flap
at C14) while the other is a twist form (twisted around the
bond O16–C17).
Fig. 1 (a) X-ray crystal structure of 8-iodocamphorquinone
bis(ethylene ketal) 10, showing the crystallographic numbering
and thermal ellipsoids at the 50% probability level, and (b) the
corresponding wire-frame structure showing the systematic
numbering.
The only significant differences between the 1H NMR spectra
of compound 10, and the isomeric diketal lay in the chemical
shifts of the diastereotopic 8-methylene protons. In the diketal
10, these protons resonate as doublets at 3.13 and 4.33 ppm,
while the corresponding protons in the isomer resonate at 3.42
and 3.92 ppm. The isomeric diketal was initially thought to be
structure 15, the rationale being that either diketal could, in
principle, be formed from 8-iodocamphorquinone 9. However,
single crystal X-ray analysis revealed the isomeric diketal to
be 9-iodocamphorquinone bis(ethylene ketal) 16 (Fig. 2).
The crystallographic asymmetric unit of 16 comprises
three molecules (A, B, C) of which the representative
molecule A is shown in Fig. 2. Molecules A, B and C adopt
slightly different conformations, the C9–C8–C10–I11 torsion
angle values spanning the narrow range 70.1(4)–73.6(4)°,
suggesting that the common C–I bond orientation observed is
energetically favoured. In contrast to 10, in the crystal of 16,
the methylene hydrogen atoms on the respective atoms C10A–
C10C do not engage in significant intra- or intermolecular
interactions. C–I distances are in the narrow range 2.159(5)–
2.166(5) Å.
I
8
9
7
O
4
3
5
O
O
1
(a)
(b)
6
2
O
10
Fig. 2 (a) X-ray crystal structure of 9-iodocamphorquinone
bis(ethylene ketal) 16, showing one of the three molecules
in the asymmetric unit with thermal ellipsoids drawn at the
50% probability level, and the crystallographic numbering,
and (b) the corresponding wire-frame structure showing the
systematic numbering.
and possible intramolecular rearrangement pathways to the
9-iodocamphorquinone cation 18 were explored using a fine-
tuned version7 of Johnson and Collins’computer-assisted coset
analysis.8 This analysis permits the identification of all possible
pathways between a given substituted bicyclo[2.2.1]heptyl
cation and a designated isomeric norbornyl cation via
common intramolecular rearrangements (the “generator
permutations”). Intermediate cations are mapped on coset
graphs, which permit assessment of alternative pathways to the
designated norbornyl cation. Rearrangement sequences were
limited to a maximum of 13 steps, and two pathways were
generated involving the following “permutation operators”:-
Wagner–Meerwein rearrangements (WM), 2,3-exo-methyl
In order to explore the possibility that the 9-iodomethyl
diketal 16 might be formed as a minor product during the
ketalisation of 8-iodocamphorquinone 9, the latter compound
was thoroughly purified by semi-preparative HPLC and
then reacted with ethylene glycol in the presence of p-
1
toluenesulfonic acid. Surprisingly, H NMR analysis of the
crude material collected after the repeated reaction revealed
that both diketal isomers 10 and 16 were again present.
Since the ketalisation is acid-catalysed, protonation of
the substrate, 8-iodocamphorquinone 9, can be expected to
afford the resonance-stabilised cation 17 (Scheme 3). Such
bicyclic cations readily undergo skeletal rearrangement,4
WM, 23e, 23x, WM
I
I
or
O
WM, 23x, 62, WM, 62, WM, 62,
WM, 23x, 23e, 23x, WM
H+
O
Ethylene glycol
9
16
+
OH
+
+
H
[
]
-
OH
Where:
17
18
WM = Wagner–Merwein
23e = 2,3-endo methyl shift
23x = 2,3-exo methyl shift
62 = 6,2-hydride shift
Scheme 3
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242 JOURNAL OF CHEMICAL RESEARCH 2007
O
O
O
I
I
I
I
O
O
23e
23x
WM
WM
+
I
+
+
+
HO
+
OH
HO
HO
OH
17
19
20
Scheme 4
M+– I: 253.14204. C14H21O4 - I requires M, 253.14398); [α]D
21
18
22
=
(23x), 2,3-endo-methyl (23e) and 6,2-hydride (62) shifts.
These pathways for achieving the transformation 17→18 are
summarised in Scheme 3, while the shorter, 4-step pathway is
detailed in Scheme 4.
The shorter pathway (Scheme 4) involves rearrangements
common to norbornane systems, whereas the longer pathway
requires the unusual 6,2-hydride shifts. Moreover, coset
analysis of the analogous C-3 carbocation failed to afford a
feasible rearrangement pathway. Consequently, we tentatively
attribute formation of the 9-iodo diketal 16 to acid-catalysed,
skeletal rearrangement of 8-iodocamphorquinone during the
ketalisation process via the shorter mechanistic sequence
detailed in Scheme 4.
+15.8°(c1.00,CHCl3);δH0.82(3H,s,10-CH3),1.10(3H,d,J=1.1Hz,
9-CH3), 1.56 (2H, m, 5Ha and 6-Ha), 1.78 (1H, m, 6-Hb), 1.98 (1H, d,
J = 4.2 Hz, 4-H), 2.20 (1H, m, 5-Hb), 3.13 (1H, d, J = 9.7 Hz, 8-Ha),
3.92 (8H, m, 2xOCH2CH2O) and 4.33 (1H, dd, J = 9.7 and 1.2 Hz,
8-Hb); δC 9.9, 19.5, 19.8, 20.7, 31.9, 48.5, 51.9, 53.2, 64.2, 64.6, 65.2,
66.1, 113.0 and 113.5; m/z 380 (M+, 9.2%) and 253 (100);
The residual material from flash chromatography was
chromatographed further [HPLC on Partisil 10; elution hexane–
EtOAc (4:1)] to afford four fractions.
(i) (1R,4S,7R)-(+)-9-Iodocamphorquinone bis(ethylene ketal)
16 as white crystals (102 mg, 6%), m.p. 57–60°C; [α]D = + 6.4°
22
(c 1.00, CHCl3); δH 0.83 (3H, s, 10-CH3), 1.34 (3H, s, 8-CH3), 1.46
(2H, m, 5Ha and 6-Ha), 1.83 (1H, m, 6-Hb), 1.87 (1H, d, J = 4.0 Hz,
4-H), 2.06 (1H, m, 5-Hb), 2.96 (1H, d, J = 9.7 Hz, 9-Ha), 3.42 (1H,
dd, J = 9.7 and 1.3 Hz, 9-Hb) and 3.92 (8H, m, 2xOCH2CH2O); δC
10.1, 18.5, 18.8, 20.6, 29.1, 48.5, 52.6, 53.7, 64.4, 64.6, 65.0, 66.0,
113.0 and 115.6; m/z 380 (M+, 17.6%) and 253 (100).
Experimental
NMR spectra were recorded on a Bruker AVANCE 400 MHz
spectrometer at 303 K in CDCl3, and calibrated using solvent signals.
IR spectra were recorded on a Perkin Elmer FT-IR Spectrum 2000
spectrometer. Low-resolution (EI) mass spectra were obtained on a
Finnigan-Mat GCQ mass spectrometer and high-resolution (EI) mass
spectraonaVG70-SEQdouble-focusingmagneticsectorspectrometer
(Department of Chemistry, University of the Witwatersrand). Optical
rotations were measured on a Perkin Elmer 141 polarimeter using
a 1 dm cell, with concentrations cited in g/100 ml. Optically pure
compounds were derived from commercially available, homochiral,
(1R)-(+)-camphor.
(ii) (1R,4S,7S)-(+)-2,2-(Ethylenedioxy)-8-iodocamphorquinone 12
as a yellow oil (19.4 mg, 1.4%), (Found M+– CH2O: 307.02175.
C11H16O2I – CH2O requires M, 307.01951); νmax(thin film)/cm-1 1749
(C=O); [α]D22 = + 137° (c 1.9, CHCl3); δH 0.92 (3H, s, 10-CH3), 1.16
(3H, d, J = 1.0 Hz, 9-CH3), 1.90 (4H, m, 5-CH2 and 6-CH2), 2.23
(1H, d, J = 3.9 Hz, 4-H), 3.07 (1H, d, J = 9.9 Hz, 8-Ha), 3.43 (1H,
dd, J = 9.9 and 1.1 Hz, 8-Hb) and 4.16 (4H, m, OCH2CH2O); δC 9.2,
16.5, 18.2, 20.3, 33.7, 47.8, 50.9, 58.2, 64.7, 66.3, 106.4 and 215.9.
(iii) (1R,4S,7S)-(–)-3,3-(Ethylenedioxy)-8-iodocamphorquinone 13
(trace amount) as a pale yellow oil; νmax (thin film)/cm-1 1757 (C=O);
[α]D22 = –16.0 (c 0.12 CHCl3); δH 1.07 (3H, s, 10-CH3), 1.08 (3H, s,
9-CH3), 1.76–2.06 (5H, series of overlapping multiplets, 4-H, 5-CH2
and 6-CH2), 3.05 (1H, d, J = 10.5 Hz, 8-Ha), 3.25 (1H, d, J = 10.5 Hz,
8-Hb), 4.17 (4H, m, OCH2CH2O); δC 11.4 (C-8), 18.7 (C-10), 19.4
(C-9) 20.0 (C-6), 31.5 (C-5), 45.1 (C-7), 52.7 (C-4), 59.7 (C-1), 64.5
and 66.3 (OCH2CH2O), 106.4 (C-2) and 213.3 (C=O).
(1R,4S,7S)-(–)-8-Iodocamphorquinone 9
A solution of 8-bromocamphorquinone 64 (4.00 g, 16.3 mmol)
and KI (13.5 g) in DMF (50 ml) was stirred under argon at 110°C
overnight. The mixture was then cooled to room temperature, diluted
with water (200 ml) and extracted with diethyl ether (2 × 100 ml).
The organic extracts were combined, washed with water (3 × 100 ml),
dried (anhydrous Na2SO4) and concentrated in vacuo. The
residue was chromatographed [flash chromatography on silica;
elution with hexane–ethyl acetate (3:1)] to afford (1R,4S,7S)-8-
iodocamphorquinone 9, as yellow crystals (1.50 g, 27.3%), m.p.
78–85°C (Found M+: 291.99603. C10H13O2I requires M, 291.99603);
(iv) Camphorquinone bis(ethylene ketal) 14, as colourless crystals
(trace amount), m.p. 59–63°C (lit.6 58–59°C); δH 0.80, 0.87 and 1.18
(9H, 3xs, 8-, 9- and 10-CH3), 1.31–2.00 (4H, series of multiplets,
5- and 6-CH2), 1.68 (1H, d, J = 4.6, 4-H), 3.74–4.00 (8H, m,
2xOCH2CH2O); δC 9.9, 20.7, 21.0, 21.1, 29.3, 44.5, 52.7, 53.3, 64.2,
64.5, 65.0, 65.9, 113.5 and 114.7.
22
[α]D = –76.5° (c 1.1, CHCl3); νmax(thin film)/cm-1 1754 (C=O);
X-ray analysis of (1R,4S,7S)-(+)-8-iodocamphorquinone bis(ethylene
ketal) 10 and (1R,4S,7R)-(+)-9-iodocamphorquinone bis(ethylene
ketal) 16
δH 1.13 (3H, s, 10-CH3), 1.23 (3H, d, J = 1.0 Hz, 9-CH3), 1.66 (1H,
m, 5-Ha), 1.87 (1H, m, 6-Ha), 2.10 (2H, m, 5-Hb and 6-Hb), 2.76 (1H,
dd, J = 11.1 and 1.0 Hz, 8-Ha), 2.89 (1H, d, J = 5.1 Hz, 4-H), 3.14
(1H, d, J = 11.1 Hz, 8-Hb); δC 9.02, 11.9, 16.3, 21.5, 32.7, 46.8, 58.3,
58.6, 201.2 and 203.3 (C=O); m/z 292 (100%).
Crystal data 10: C14H21IO4, Mr
= 380.21, monoclinic, C2,
a = 16.3127(4), b = 7.1753(2), c = 12.5202(4) Å, b = 97.618(1)°,
V = 1452.54(7) Å3, Dx = 1.739 g cm-3, Z = 4, m = 2.212 mm-1, T = 113K.
The final refinement was based on 2643 reflections and 174 variable
parameters and converged at R1 = 0.0204 (2586 reflections with I >
2s(I)), wR2 = 0.0503 and S = 1.112. The final maximum difference
electron density peak (1.27 eÅ-3, not modelled) was attributed to
an alternative, minor site for atom C17, the two disordered
components giving rise to two slightly different ring conformations.
The correct assignment of absolute structure was indicated by the
Flack parameter value of –0.02(2). Full crystallographic details
have been deposited at the Cambridge Crystallographic Data Centre
(CCDC 639803).
Crystal data 16: C14H21IO4, Mr = 380.21, monoclinic, P21,
a = 7.227(1), b = 22.840(5), c = 13.149(3) Å, b = 92.18(3)°,
V = 2168.9(8) Å3, Dx = 1.747 g cm-3, Z = 6, m = 2.223 mm-1,
T = 113K. Final refinement was based on 7847 reflections and 520
variables and converged at R1 = 0.0343 (6459 reflections with I >
2s(I)), wR2 = 0.0566 and S = 0.973. The final difference electron
density was 0.59 eÅ-3. The Flack parameter value –0.04(1) indicated
the correct assignment of absolute structure. Full crystallographic
details have been deposited at the Cambridge Crystallographic Data
Centre (CCDC 639804).
(1R,4S,7S)-(+)-8-Iodocamphorquinone bis(ethylene ketal) 10, (1R,
4S,7R)-(+)-9-iodocamphorquinone bis(ethylene ketal) 16, (1R,4S,
7S)-(–)-2,2-(ethylenedioxy)-8-iodocamphorquinone 12, (1R,4S,7S)-
(+)-3,3-(ethylenedioxy)-8-iodocamphorquinone13andcamphorquin-
one bis(ethylene ketal) 14
A mixture of 8-iodocamphorquinone 9 (1.30 g, 4.44 mmol), ethylene
glycol (13.4 ml), p-toluene-sulfonic acid (1.40 g, 6.83 mmol) and
benzene (42 ml) was boiled under reflux under nitrogen in a flask
fitted with a Dean-Stark trap containing 5Å molecular sieves.
After 5 days, the mixture was cooled to room temperature, diluted
with diethyl ether (100 ml), washed sequentially with brine (100 ml)
and water (3 × 100 ml), and dried (anhydrous Na2SO4). The solvent
was removed in vacuo, and the crude product was chromatographed
[flash chromatography on silica; elution with hexane–ethyl acetate
(3:1)] to afford (1R,4S,7S)-(+)-8-iodocamphorquinone bis(ethylene
ketal) 10 (400 mg, 24%) as white crystals. An analytical sample
was prepared by further chromatography [HPLC on Partsil 10;
elution with hexane–ethyl acetate 4:1] to give (1R,4S,7S)-(+)-8-
iodocamphorquinone bis(ethylene ketal) 10, m.p. 98–104°C (Found
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JOURNAL OF CHEMICAL RESEARCH 2007 243
References
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program SADABS.10 The structures were solved using SHELXS-8611
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in difference electron density maps but were added in idealised
positions in a riding model with isotropic displacement parameters
1.2–1.5 times those of their parent atoms. All non-hydrogen atoms
1
2
3
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7
8
K.A. Lobb, unpublished work.
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and Sasol Technology Ltd., the Technology and Human
Resources for Industry Programme (THRIP; Project no.
2642), Rhodes University and the University of Cape Town
for generous financial support. M.R.C also acknowledges
research funding from the NRF (Pretoria).
9
10 G.M. Sheldrick, SADABS, Program for Empirical Absorption Correction
of Area Detector Data; University of Göttingen, Germany, 1996.
11 SHELXS-86: G.M. Sheldrick, in Crystallographic Computing 3,
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Received 26 March 2007; accepted 23 April 2007
Paper 07/4560 doi: 10.3184/030823407X209714
12 G.M. Sheldrick, SHELXL-97, Program for refinement of crystal structures,
University of Göttingen, Germany, 1997.
PAPER: 07/4560