A route to a wide range of cyclopentanecarboxylic acids via 4-substituted camphors

Article abstract of DOI:10.1016/j.tet.2011.12.053

4-Carboxycamphor, easily obtainable starting from camphor, is used as a versatile precursor in high-yielding syntheses of a wide range of cyclopentanecarboxylic acids using just a few steps. Regioselective bromination of 4-carboxy- and 4-methoxycarbonyl-3-bromocamphors leads to 10-bromomethyl derivatives in good yields. Grob-type fragmentation reactions proceed smoothly for 10-bromocamphor-4-carboxylic acid, 10-bromocamphorquinone-4-carboxylic acid and 3,4-dibromocamphor with the formation of unsaturated cyclopentanecarboxylic acids. Detailed studies of bromination and rearrangement reactions of brominated camphor-4-carboxylic acid and its derivatives, reported herein, highlight the unique chemistry of substituted camphor and offer easy access to a wide range of 2,2-dimethyl-3-methylenecyclopentanecarboxylic acid derivatives.

Full text of DOI:10.1016/j.tet.2011.12.053

Tetrahedron 68 (2012) 1972e1978
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A route to a wide range of cyclopentanecarboxylic acids via 4-substituted
camphors
,
a,
Volodymyr O. Knizhnikov a, Zoya V. Voitenko a, Vladimir B. Golovko b , Marian V. Gorichko
*
*
a Department of Chemistry, Kiev University, Volodimirska St. 64, Kiev 01033, Ukraine
b Department of Chemistry, University of Canterbury, P.B. 4800, Christchurch 8140, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 October 2011
Received in revised form 3 December 2011
Accepted 19 December 2011
Available online 28 December 2011
4-Carboxycamphor, easily obtainable starting from camphor, is used as a versatile precursor in high-
yielding syntheses of a wide range of cyclopentanecarboxylic acids using just a few steps. Re-
gioselective bromination of 4-carboxy- and 4-methoxycarbonyl-3-bromocamphors leads to 10-bromo-
methyl derivatives in good yields. Grob-type fragmentation reactions proceed smoothly for 10-bromo
camphor-4-carboxylic acid, 10-bromocamphorquinone-4-carboxylic acid and 3,4-dibromocamphor with
the formation of unsaturated cyclopentanecarboxylic acids. Detailed studies of bromination and re-
arrangement reactions of brominated camphor-4-carboxylic acid and its derivatives, reported herein,
highlight the unique chemistry of substituted camphor and offer easy access to a wide range of 2,2-
dimethyl-3-methylenecyclopentanecarboxylic acid derivatives.
Keywords:
Camphor
Bromination
Grob fragmentation
Cyclopentanecarboxylic acids
Ó 2012 Published by Elsevier Ltd.
1. Introduction
chemistry of camphor, unlike many other relatively simple mole-
cules, has many uncharted domains (as highlighted by the research
The chemistry of camphor has excited and inspired many gener-
ations of chemists since the dawn of organic chemistry. The huge
variety of unusual and even unique reactions characteristic of this
terpenoid ketone, combined with its natural occurrence, explains
such interestonly partially. Camphorhasbeen successfully utilized as
a versatile starting material in a number of approaches toward the
total synthesis of both complex natural compounds, such as
Paquette’s approach to taxol1e3 and Steven’s syntheses of vitamins
B12 and D4,4e6 as well as deceptively simple structurally yet hard-to-
synthesize molecules, such as sarkomycin made via the Martinez
approach.7 Notably, cyclopentanoid compounds obtained starting
from the camphor are now recognized as versatile intermediates in
the synthesis of terpenoids8e16 and steroids.17e19 Many other natural
and synthetic biologically active compounds feature five-membered
carbocycles as important structural moiety’s. Thus, the development
of new synthetically important pathways to novel cyclopentanoids
starting from simple natural starting materials, such as camphors,
will ensure further advances in this area and will be of interest for
synthetic organic chemists and biochemists.20 A comprehensive and
up-to-date overview of all aspects of the chemistry of camphor and
the use of its derivatives would warrant a dedicated and very detailed
review and is outside the scope of this paper. Even today, the
presented here), which offer a diligent explorer access to novel and
potentially very useful molecular building blocks.
The chemistry of 4-substituted camphor is quite unique, as is
the case for many other camphor derivatives. A wide range of 4-
substituted derivatives of isoborneol and camphor can be easily
prepared from 1- or 4-substituted camphenes under acidic con-
ditions.21e26 4-Carboxycamphor27,28 is by far the most accessible
and convenient starting material, and can be further transformed
into a range of other 4-substituted camphors (e.g., NH2, Cl, Br, OH,
CN, COCH3).24 However, there are important obstacles to further
exploration of chemical transformations of 4-substituted camphor
compared with camphors substituted in other positionsdfacile
racemization under synthetically useful conditions is a challenge
unsurpassable to many. Indeed, Scheme 1 illustrates the Wag-
nereMeerwein rearrangement of 2,3,3-trimethylnorbornane-2-yl
carbocations accompanied by a competitive Nametkin rearrange-
ment and consecutive 6,2-hydride shift between enantiomeric
carbocations. As a net result these processes lead to the formation
of racemic mixtures or product mixtures with a low optical purity,
also known as scalemic mixtures.21,29,30 It should be noted that
camphenes bearing electron donating substituents (e.g., NH2 or
OH) in the bridgehead positions undergo rearrangement via a dif-
ferent pathway, forming camphor under acidic conditions.31,32
Despite the above mentioned synthetic challenges in the explo-
ration of the advanced chemistry of 4-substituted camphor, the high
yield of 4-carboxycamphor starting from easily sourced natural
* Corresponding authors. E-mail addresses: vladimir.golovko@canterbury.ac.nz
(V.B. Golovko), gorichko@chem.univ.kiev.ua (M.V. Gorichko).
0040-4020/$ e see front matter Ó 2012 Published by Elsevier Ltd.
doi:10.1016/j.tet.2011.12.053

V.O. Knizhnikov et al. / Tetrahedron 68 (2012) 1972e1978
1973
Scheme 1. Reactions leading to the racemization of the 4-substituted isoborneols and
camphors.
racemic camphor makes it a very attractive starting compound for
further modification for the reasons discussed in detail below.
Racemic camphor is usually produced from natural pinene or
camphene with racemization affecting the 2-bornyl cation in
a fashion similar to that mentioned above for the substituted
camphenes.33 Racemic camphor is substantially cheaper than the
R-(þ) enantiomer, which is, in turn, cheaper than the S-(ꢀ) enan-
tiomer. Additionally, it should be noted that commercially available
natural camphor enantiomers are not absolutely enantiomerically
pure.34 Thus, from both the commercial and practical point of view,
using an expensive enantiomerically enriched source as a starting
material could be disadvantageous compared to an alternative
pathway via separation of the enantiomers from the final mixture
of products obtained using the racemic starting material, (which, of
course, could also be a challenge).
Bromination is a very important approach for the functionali-
zation of camphor at all positions of the camphor skeleton and
opens avenues to further modifications via nucleophilic sub-
stitutions or various skeletal rearrangements and cyclizations.
In this paper we report our findings on the bromination of
camphor-4-carboxylic acid and the Grob-type rearrangements of
the bromination products, leading to the formation of a range of
novel unsaturated cyclopentanecarboxylic acids.
Scheme 2. Bromination of camphor-4-carboxylic acid and formation of 1-
carboxymethyl-2,2-dimethyl-3-methylene-1-cyclopentanecarboxylic acid.
transformations of this compound in the reaction with an excess of
sodium hydroxide resulted in a complicated mixture of numerous
products. This prompted us to obtain the crystal structure of 3a
(Fig. 1) to confirm its structure directly in order to remove any
doubts about potential simultaneous skeletal rearrangements.
Selective removal of the bromine atom at the 3-position of the
camphor skeleton yielded 4a, simplifying the molecule for further
transformations. Indeed, the reaction of 4a with an excess of
aqueous sodium hydroxide yields the 1-(carboxymethyl)-2,2-
dimethyl-3-methylenecyclopentanecarboxylic acid 5. The forma-
tion of cyclopentanecarboxylic acids with terminal alkene groups
via Grob-type fragmentation is characteristic for 10-
bromocamphor derivatives under these conditions.18,39
2. Results and discussion
We report a series of novel compounds easily and selectively
accessible starting from a cheap natural camphor precursor. endo-
3-Bromo-4-carboxycamphor 2a was synthesized from 4-
carboxycamphor 1 under standard acetic acid bromine reaction
conditions (Scheme 2).27,28 The NOE experiment indicated an endo-
orientation of the bromine atom in 2a. Further selective bromina-
tion of this compound in chlorosulfonic acid media yielded a single
product 3a with one bromomethyl group.
Assuming that the camphor skeleton is preserved, there are
three possible pathways for the bromination reaction as depicted in
Scheme 2. For example, 3-bromo- and 3,3-dibromocamphors un-
dergo brominations at positions C-9 and C-8, respectively, under
similar conditions.35e37 The only known example of bromination of
camphor that bears a substituent at the C-4 carbon was reported for
endo-3-bromo-4-methyl-camphor, in which case the reaction also
takes place at C-9.38 Long-range NMR CeH correlation spectra
provide evidence of the formation of the C-10 substitution product
3a. Yet, attempts to affirm structure of 3a by further chemical
Fig. 1. Crystal structure of 3,10-dibromo-4-carboxycamphor 3a.
Similarly, bromination of the methyl ester of 3-bromocamphor-4-
carboxylic acid 2b yields 3,10-dibromo-4-methoxycarbonylcamphor
3b as the main product. The structure of 3b was verified by compar-
ison with the esterification product of 3a; the two methyl esters
proved to be identical. Furthermore, NOE experiments provide evi-
dence for the endo-orientation of bromine atom at the 3-position of
the camphor skeleton in 3a,b, which is confirmed in the case of 3a by
its crystal structure.
The regioselectivity of the rearrangements under the bromina-
tion conditions reported here can be rationalized using a mecha-
nism proposed for the bromination of camphor,40 relevant parts of
which are shown in the Scheme 3. The presence of the electron
withdrawing groups (EWG) at the 4-position of the camphor

1974
V.O. Knizhnikov et al. / Tetrahedron 68 (2012) 1972e1978
skeleton significantly increases the energy of formation of cation II.
Thus, the high selectivity of bromination can be explained by
carboxy or carboxymethyl groups. Yet, the reaction does not proceed
via this mechanism since the formation of four-membered rings in
corresponding intermediates is presumably significantly less fa-
vorable in the case of this molecular structure with its rigid skeleton.
The 4-carboxycamphor 1 is an excellent starting material for
a range of other camphors with substituents at the 4-position. For
example, we have synthesized 4-bromocamphor 6 via the Ag salt of
4-carboxycamphor, which is a major improvement compared with
preferential formation of intermediate cation
I via Wag-
nereMeerwein rearrangement of the protonated forms of the
starting 3-bromocamphors. This explanation fits with a previously
reported observation that camphor derivatives bearing EWGs at the
8- or 9-position of the camphor skeleton also reacted at C-10 atom
for the same reason.18,41,42
Scheme 3. Intermediate carbocations enforce the regioselectivity of bromination of camphor.
Known examples of electrophilic functionalization at C-10 of
camphor derivatives not bearing substituents at the methyl groups
(e.g., direct sulfonation or bromination)43 usually require use of
acetic anhydride as a reaction medium. In these reactions, carbo-
cations of types I and III are stabilized by interaction with the lone
pair of the oxygen atom of the carbonyl group in the five-
membered cyclic intermediates (Scheme 4).44,45
the previously reported six-stage process.24,26 The 4-
bromocamphor was brominated further in acetic acid to yield
endo-3,4-dibromocamphor 7 (Scheme 5). Interestingly, the Grob
fragmentation has not been previously reported for camphors with
a halide substituent at the 4-position. It was hypothesized that
Grob-type fragmentation, yielding products containing the cyclo-
pentane moiety (as was previously described for 10- and 6-
bromocamphor),18,39 in principle, could work in the case of the 4-
bromocamphor. More precisely, such fragmentation should in-
volve an intermediate resulting from 4-bromocamphor via nucle-
ophilic addition at the carbonyl group since this intermediate
would have almost antiparallel C2eC3 and C4eBr bonds, which is
a prerequisite for successful Grob fragmentation. Yet, all of our ef-
forts to carry out this fragmentation of 6 have failed, even when
harsh conditions, such as prolonged treatment with strong bases
(NaOHaq or NaOEt) at elevated temperatures, have been used.
In contrast, endo-3,4-dibromocamphor 7 undergoes fragmenta-
tion rather readily, yielding cyclopentanecarboxylic acid 8. The
presence of the electron withdrawing bromine substituent at the 3-
endo position is likely to facilitate the nucleophilic attack on car-
bonyl group of 7. The NOE correlation between the proton of the
bromomethylene group and protons of the methyl groups in com-
pounds 7 and 8 supports the endo-orientation of the bromine atom
in 7 and the E-configuration at the double bond in 8, respectively.
The endo-3,4-dibromocamphor 7 does not undergo Favorskii
Scheme 4. Intramolecular stabilization of the intermediate carbocations I, II, and III.
It could be hypothesized that carbocations of type II, generated
from compounds 2a,b, could also be stabilized in a similar way due
to interaction with lone electron pairs of oxygen atoms in the
rearrangement despite presence of the Br substituent at the
carbon atom relative to the keto-group.
a-

V.O. Knizhnikov et al. / Tetrahedron 68 (2012) 1972e1978
1975
Oxidation of the 4-bromocamphor 6 using SeO2 in acetic acid
results in selective formation of 4-bromocamphorquinone 1147 in
high yield. This molecule is particularly interesting in light of the
chemical rearrangements discussed in this paper since it could, in
principle, undergo Favorskii rearrangement if attacked by a nucle-
ophile at the carbonyl at C-3 (pathway A, Scheme 8) as well as Grob
fragmentation if attacked by a nucleophile at the carbonyl at C-2
(pathway B, Scheme 8). The C2eC3 and C4eBr bonds are involved
in both of these processes.
Our attempt to explore the potential dual reactivity of the
4-bromocamphorquinone 11 demonstrated that the Favorskii
rearrangement reaction does not proceed. Indeed, treatment
of 11 with NaOH in methanol at room temperature results in
an initial loss of the yellow coloration characteristic of
4-bromocamphorquinone, yet acidification of the reaction mixture
allows close to quantitative recovery of the starting material.
However, when refluxed with NaOHaq, 4-bromocamphorquinone
11 probably undergoes Grob fragmentation to an intermediate 12,
which, under the conditions of this experiment, converts to the
camphoric acid 13.48
Scheme 5. Formation of the novel cyclopentanecarboxylic acid via series of 4-
bromocamphors starting from easily available precursor.
The parent unsubstituted endo-3-bromocamphor also did not
undergo Favorskii rearrangement even under very harsh condi-
tions. This observation can be explained by the unfavorable (see the
next paragraph) orientation of CeC and CeBr bonds highlighted in
Scheme 6.
Interestingly, another bromocamphorquinone 14a that was
synthesized from 4 undergoes fragmentations under mild condi-
tions (Scheme 8), such as treatment with an aqueous NaOH solu-
tion at 5 ꢁC with formation of sodium salt of dicarboxylic acid 15.
We followed this reaction by variable-temperature 1H and 13C NMR
experiments, which confirmed that 1 equiv of 14a dissolved in
a solution of 4 equiv of NaOD in D2O at 5 ꢁC quantitatively yields 15,
which, under heating, undergoes ketonic cleavage leading to
complete conversion (at 60 ꢁC) to the sodium salt of corresponding
deuterated acid (Na salt-D-16), we have developed a complemen-
tary approach to synthesis of the same compound 16 in two easy
steps, this time starting from 10-bromocamphorquinone 1749
(Scheme 9). This convergent synthesis of the same novel cyclo-
pentanecarboxylic acid in two steps from two different bromo-
camphorquinones confirms the correctness of our assignment of
the structure of cyclopentanecarboxylic acid 16. It is noteworthy
that, in contrast to the parent acid 14a, a product of its simple es-
terification 14b yields, following acidic cleavage, an ester derivative
of yet another cyclopentanecarboxylic acid 18 upon treatment with
NaOMe in methanol (Scheme 9).
Scheme 6. Unfavorable orientation of CeC and CeBr bonds prevents Favorskii re-
arrangement of endo-3,4-dibromocamphor.
Notably, 3-bromo-3,8-cyclocamphor 9 containing CeC and CeBr,
which have almost antiparallel orientation does undergo rear-
rangement, yielding very strained derivatives of tricyclic carboxylic
acid 10 when treated with potassium anilide46 or under even milder
conditions as was discovered in our laboratory (Scheme 7).
Compound 18 was previously reported, but only as a component
of a complex product mixture.50 These transformations of bromo-
camphorquinones 14a, 14b, 17 and earlier-mentioned chemistry of
11 highlight the versatility of the synthetic pathway via bromo-
camphorquinones in the synthesis of
pentanecarboxylic acids.
a range of cyclo-
In conclusion, we have reported a series of selective and high-
yielding brominations of camphor derivatives and explored
unique rearrangements of the resulting brominated camphor
Scheme 7. Rearrangement of 3-bromo-3,8-cyclocamphor under mild conditions.
Scheme 8. Observed reactivity of the 4-bromocamphorquinone 11.

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V.O. Knizhnikov et al. / Tetrahedron 68 (2012) 1972e1978
1.76e1.84 (m, 1H), 2.04e2.10 (m, 1H), 2.23e2.32 (m, 1H), 5.20 (s,
1H), 13.02 (br s, 1H). 13C{1H} NMR (100.70 MHz, DMSO-d6):
d¼9.7,
18.0, 18.1, 24.9, 29.3, 49.7, 55.7, 59.4, 60.1, 171.0, 209.6. IR (KBr,
cmꢀ1): 2968, 1760, 1700, 1284. Anal. Calcd for C11H15BrO3: C, 48.02;
H, 5.50; found: C, 47.96; H, 5.58.
3.1.2. endo-2-Bromo-4-bromomethyl-7,7-trimethyl-3-oxobicyclo
[2.2.1]heptane-1-carboxylic acid (endo-3,10-dibromo-4-
carboxycamphor) (3a). Bromine (1.600 g, 10.01 mmol) was added
to a stirred solution of 2a (2.751 g, 10.00 mmol) in 10 mL of freshly
distilled chlorosulfonic acid. After stirring for 4 days at room tem-
perature, reaction mixture was poured carefully onto crushed ice
(200 g). The resultant mixture was extracted with chloroform
(3ꢂ50 mL). Organic extracts were dried over Na2SO4, filtered, and
solvent was removed under reduced pressure. The crude yellow
product was crystallized from a small amount of absolute ethanol
resulting in white crystals. Yield 3.102 g (90%). Mp: 191e192 ꢁC. 1H
NMR (400.45 MHz, DMSO-d6):
d
¼1.00 (s, 3H), 1.16 (s, 3H), 1.37e1.44
(m, 1H), 2.06e2.13 (m, 2H), 2.28e2.36 (m, 1H), 3.55 (d, 2J¼11.2 Hz,
Scheme 9. Bromocamphorquinones as starting materials for cyclopentanecarboxylic
acids.
1H), 3.60 (d, 2J¼11.2 Hz, 1H), 5.27 (s, 1H), 13.16 (br s, 1H). 13C{1H}
NMR (100.70 MHz, DMSO-d6):
d
¼18.7, 18.8, 24.6, 27.7, 28.6, 50.8,
54.9, 60.5, 61.6, 170.3, 206.3. IR (KBr, cmꢀ1): 2972, 1760, 1698, 1288,
1264. Anal. Calcd for C11H14Br2O3: C, 37.32; H, 3.99; found: C, 37.27;
H, 4.04.
skeletons to give a series of novel cyclopentanecarboxylic acids.
New synthetically important pathways to bromo-derivatives
of camphor and easy access to a range of novel cyclopen-
tanecarboxylic acids should be of interest for a wide community of
chemists.
3.1.3. 4-Bromomethyl-7,7-trimethyl-3-oxobicyclo[2.2.1]heptane-1-
carboxylic acid (10-bromo-4-carboxycamphor) (4a). Zinc dust
(1.150 g, 17.59 mmol) was added in small portions to a stirred so-
lution of 3a (1.770 g, 5.00 mmol) in glacial acetic acid (15 mL).
During the addition care was taken to keep the temperature of
reaction mixture under 25 ꢁC. When addition of zinc dust was
completed, the resulting mixture was stirred for 45 min at room
temperature. The excess of zinc and inorganic precipitate was fil-
tered off and washed twice with acetic acid. Solvent was removed
from the filtrate under reduced pressure. Deionized water (15 mL)
and ether (15 mL) were added to the residue. The organic layer was
separated, aqueous layer was extracted with another portion of
ether (15 mL). The combined ether extracts were dried over Na2SO4.
The removal of the solvent under reduced pressure afforded a white
solid. Yield 1.248 g (91%). Mp: 180e181 ꢁC. 1H NMR (400.45 MHz,
3. Experimental section
3.1. General
4-Camphorcarboxylic acid 1 and 3-bromo-3,8-cyclocamphor 9
were prepared according to the literature procedures.27,28,46 All
other starting materials were purchased from major supplier of
chemicals. All solvents were distilled before use.51 Melting points
are uncorrected. 1H and 13C NMR spectra were recorded on
400 MHz spectrometers. Temperature-dependent 1H and 13C NMR
experiments were recorded on a 600 MHz spectrometer. Tetra-
methylsilane was used as an internal standard in organic solvents,
and 1,4-dioxane as an internal standard in D2O in NMR experi-
ments. nmax (cmꢀ1) values in IR spectra are given for the main ab-
sorption bands. Mass spectra were recorded on the LCMS
instrument with chemical ionization. All experiments, unless oth-
erwise stated, were carried under a nitrogen atmosphere. Crystal-
lographic measurements were performed at room temperature on
a Bruker Smart Apex II diffractometer. Full crystallographic data for
the structure of 3a in this paper have been deposited with the
Cambridge Crystallographic Data Centre under registration number
855317. Copy of the data can be obtained, free of charge, on ap-
plication to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44
1223336033 or e-mail: deposit@ccdc.cam.ac.uk).
DMSO-d6):
d
¼0.87 (s, 3H), 1.06 (s, 3H), 1.46e1.53 (m, 1H), 1.65e1.71
(m, 1H), 1.99e2.07 (m, 1H), 2.23 (d, 2J¼18.0 Hz, 1H), 2.21e2.31 (m,
1H), 2.66 (dd, 2J¼18.0 Hz, 4J¼3.6 Hz, 1H), 3.49 (d, 2J¼10.8 Hz, 1H),
3.57 (d, 2J¼10.8 Hz, 1H), 12.54 (br s, 1H). 13C{1H} NMR (100.70 MHz,
DMSO-d6):
d
¼17.8, 18.7, 27.0, 29.2, 29.8, 44.7, 51.2, 54.7, 61.8, 173.0,
211.9. IR (KBr, cmꢀ1): 2966, 1754, 1700, 1426, 1288. Anal. Calcd for
C11H15BrO3: C, 48.02; H, 5.50; found: C, 47.95; H, 5.56.
3.1. 4. 1-Carboxymethyl-2, 2-dimethyl-3-methylene-1-
cyclopentanecarboxylyc acid (5). Compound 4a (1.000 g,
3.635 mmol) was added to an aqueous solution of sodium hy-
droxide (1.000 g, 25.00 mmol in 10 mL of deionized H2O). The so-
lution was refluxed for 20 min, cooled to room temperature and
acidified using concentrated HCl. The resultant precipitate was fil-
tered and washed with small amount of cold water. Yield 0.613 g
3.1.1. endo-2-Bromo-4,7,7-trimethyl-3-oxobicyclo[2.2.1]heptane-1-
carboxylic acid (endo-3-bromo-4-carboxycamphor) (2a). A stirred
solution of 1 (3.130 g, 15.95 mmol) in glacial acetic acid (8 mL) was
warmed to 80 ꢁC and maintained at that temperature using
a temperature controller. Bromine (2.560 g, 16.02 mmol) was added
slowly over a period of ca. 3 h. After 30 min the liberation of hy-
drogen bromide started. Heating was continued until de-
colorization of solution occurred (ca. 5 h). After cooling to room
temperature, the reaction mixture was poured into ice cold water
(80 mL), and the resulting precipitate was filtered off. The crude
product was recrystallized from ethanol, affording white crystals.
Yield 3.520 g (80%). Mp: 183e184 ꢁC. 1H NMR (400.45 MHz, DMSO-
(77%). Mp: 202 ꢁC. 1H NMR (400.45 MHz, DMSO-d6):
d
¼0.90 (s, 3H),
1.02 (s, 3H), 1.58e1.66 (m, 1H), 2.04 (d, 2J¼16.4 Hz, 1H), 2.26e2.39
(m, 3H), 2.71 (d, 2J¼16.4 Hz,1H), 4.76 (s,1H), 4.78 (s, 2H),12.33 (br s,
2H). 13C{1H} NMR (100.70 MHz, DMSO-d6):
d¼22.5, 25.5, 28.0, 28.5,
37.9, 47.5, 55.9, 104.2, 159.1, 172.9, 175.1. IR (KBr, cmꢀ1): 2986, 1714,
1424, 1264, 1218, 888. Anal. Calcd for C11H16O4: C, 62.25; H, 7.60;
Found: C, 62.19; H, 7.68.
3.1.5. Methyl endo-2-bromo-4,7,7-trimethyl-3-oxobicyclo[2.2.1]hep-
tane-1-carboxylate (methyl ester of endo-3-bromocamphor-4-
carboxylic acid) (2b). A stirred solution of 2a (500 mg 1.82 mmol)
d6):
d
¼0.89 (s, 3H), 0.91 (s, 3H), 1.05 (s, 3H), 1.20e1.28 (m, 1H),

V.O. Knizhnikov et al. / Tetrahedron 68 (2012) 1972e1978
1977
in thionyl chloride (3 mL) was refluxed for 2 h. The excess thionyl
chloride was removed and the residue dissolved in dry methanol
(5 mL). The resulting solution was refluxed for 30 min. The removal
of the solvent resulted in the methyl ester 2b (525 mg, 100%). Mp:
(m, 1H), 2.12e2.23 (m, 1H), 2.56e2.65 (m, 1H), 4.65 (d, 4J¼1.6 Hz,
1H). 13C{1H} NMR (100.70 MHz, CDCl3):
d
¼10.8,11.9,18.3, 29.8, 32.9,
50.3, 56.7, 60.4, 68.1, 207.5. IR (KBr, cmꢀ1): 2966, 1755, 1443, 1287,
1187, 1026, 775. Anal. Calcd for C10H14Br2O: C, 38.74; H, 4.55; found:
C, 38.71; H, 4.57.
100e101 ꢁC. 1H NMR (400.45 MHz, DMSO-d6):
d
¼0.88 (s, 3H), 0.91
(s, 3H), 1.04 (s, 3H), 1.22e1.29 (m, 1H), 1.79e1.86 (m, 1H), 2.06e2.13
(m, 1H), 2.28e2.36 (m, 1H), 3.72 (s, 3H), 5.29 (d, 4J¼1.6 Hz, 1H). 13
C
3.1.10. (3E)-3-(Bromomethylene)-1,2,2-trimethylcyclopentanecar-
boxylic acid (8). The same procedure as described for the synthesis
of 10 starting from 9 using 7 as a starting material gives corre-
{1H} NMR (100.70 MHz, DMSO-d6):
d
¼9.7, 17.9, 18.0, 25.0, 29.2, 50.1,
52.1, 55.1, 59.3, 60.1, 169.8, 209.1. IR (KBr, cmꢀ1): 2964, 1752, 1730,
1270, 1230, 1074. Anal. Calcd for C12H17BrO3: C, 49.84; H, 5.93;
found: C, 49.80; H, 5.96.
sponding compound
8 as white crystals. Yield (80%). Mp:
162e163 ꢁC. 1H NMR (400.45 MHz, DMSO-d6):
d¼0.94 (s, 3H), 1.01
(s, 3H), 1.11 (s, 3H), 1.51e1.58 (m, 1H), 2.20e2.29 (m, 2H), 2.35e2.42
3.1.6. Methyl endo-2-bromo-4-(bromomethyl)-7,7-dimethyl-3-
oxobicyclo[2.2.1]heptane-1-carboxylate (endo-3,10-dibromo-4-
carboxymethylcamphor) (3b). Synthesized by the same procedure
described above for the synthesis of 2b from 2a using 3a as
a starting material gives the corresponding methyl ester 3b as
white crystals. Yield (98%). Mp: 65e66 ꢁC. 1H NMR (400.45 MHz,
(m, 1H), 6.15 (s, 1H), 12.24 (s, 1H). 13C{1H} NMR (100.70 MHz,
DMSO-d6):
d
¼20.2, 22.2, 25.9, 29.2, 31.1, 49.6, 55.8, 99.3, 156.2,
182.5. IR (KBr, cmꢀ1): 3432, 2971, 1694, 1640, 1301, 1276, 1104. Anal.
Calcd for C10H15BrO2: C, 48.60; H, 6.12; found: C, 48.57; H, 6.15.
3.1.11. 2,6-Dimethyltricyclo[3.2.0.02,6]heptane-1-carboxylic acid (10).
Compound 946 (1.00 g, 4.36 mmol) was added to a stirred solution of
sodium isopropoxide in 2-propanol, made by addition of sodium
(0.50 g, 21.74 mmol) to 40 mL of dry 2-propanol. The resulting
mixture was refluxed until disappearance of the starting 9 (moni-
tored by TLC, ca. 30 min). The mixture was then cooled to room
temperature and water (90 mg, 5.00 mmol) was added before
restarting reflux until full hydrolysis of the intermediate isopropyl
ester (monitored by TLC, ca. 3 h). The solvent was removed from the
reaction mixture under reduced pressure. Deionized water (15 mL)
and ether (15 mL) were added to the residue. The organic layer was
separated; the aqueous layer was extracted with another portion
of ether (15 mL). The aqueous layer was separated and acidified
using concentrated HCl. The resultant precipitate was filtered off
and washed with a small amount of cold water. White solid. Yield
0.652 g (90%). Mp: 132e133 ꢁC. 1H NMR (400.45 MHz, CDCl3):
DMSO-d6):
d
¼0.99 (s, 3H), 1.15 (s, 3H), 1.39e1.47 (m, 1H), 2.09e2.16
(m, 2H), 2.33e2.41 (m, 1H), 3.55 (d, 2J¼11.6 Hz, 1H), 3.61 (d,
2J¼11.6 Hz, 1H), 3.73 (s, 3H), 5.34 (s, 1H). 13C{1H} NMR (100.70 MHz,
DMSO-d6):
d
¼18.6, 18.8, 24.7, 27.6, 28.4, 51.2, 52.3, 54.3, 60.5, 61.5,
169.1, 205.7. IR (KBr, cmꢀ1): 2954,1754,1734,1262,1216,1068. Anal.
Calcd for C12H16Br2O3: C, 39.16; H, 4.38; found: C, 39.10; H, 4.44.
3.1.7. Methyl
4-(bromomethyl)-7,7-dimethyl-3-oxobicyclo[2.2.1]
heptane-1-carboxylate (10-bromo-4-carboxymethylcamphor) (4b).
Synthesized bythe same procedure described above for the synthesis
of 2b from 2a using 4a as a starting material gives the corresponding
substance 4b as white crystals. Yield (95%). Mp: 46e47 ꢁC. 1H NMR
(400.45 MHz, DMSO-d6):
d
¼0.87 (s, 3H), 1.05 (s, 3H), 1.48e1.55 (m,
1H), 1.70e1.76 (m, 1H), 2.021e2.09 (m, 1H), 2.26e2.35 (m, 2H), 2.70
(dd, 2J¼18.4 Hz, 4J¼3.6 Hz, 1H), 3.50 (d, 2J¼11.2 Hz, 1H), 3.57 (d,
2J¼11.2 Hz, 1H), 3.67 (s, 3H). 13C{1H} NMR (100.70 MHz, DMSO-d6):
d
¼0.80 (s, 3H), 1.17 (s, 3H), 1.46e1.54 (m, 1H), 1.57e1.65 (m, 1H),
d
¼17.6, 18.5, 26.8, 29.1, 29.5, 44.5, 51.4, 51.7, 54.6, 61.6, 171.4, 211.0. IR
1.68e1.77 (m, 1H), 1.82e1.91 (m, 1H), 2.00 (d, 2J¼3.2 Hz, 1H), 2.24
(KBr, cmꢀ1): 2962, 1750, 1732, 1224, 1086, 1060. Anal. Calcd for
C12H17BrO3: C, 49.84; H, 5.93; found: C, 49.80; H, 5.97.
(d, 2J¼3.2 Hz, 1H), 2.66 (s, 1H), 10.94 (br s, 1H). 13C{1H} NMR
(100.70 MHz, CDCl3):
d¼9.7, 10.3, 22.2, 32.8, 41.2, 42.9, 45.3, 66.2,
70.2, 176.0. IR (KBr, cmꢀ1): 3412, 2954, 2615, 1693, 1424, 1311, 1219,
956, 750. Anal. Calcd for C10H14O2: C, 72.26; H, 8.49; found: C, 72.18;
H, 8.58.
3.1.8. 4-Bromo-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (4-
bromocamphor) (6). Concentrated solution of AgNO3 (1.699 g,
10.00 mmol) in distilled water was added to a stirred solution of 1
(1.963 g, 10.00 mmol) in 50 mL 0.2 N NaOHaq. The resulting mixture
was stirred for 5 min, the precipitate was filtered off, washed with
distilled water (2ꢂ30 mL) and dried overnight in a desiccator over
P2O5 in the dark. Resulting Ag salt was grinded and added in small
portions to 15 mL dry Br2, which was vigorously stirred and cooled.
The mixture was stirred further for 30 min and the excess of Br2
was removed in vacuum. The residue was extracted with CH2Cl2
(3ꢂ50 mL). CH2Cl2 extracts were combined and washed with
NaHCO3aq., then water and dried over Na2SO4. Removal of CH2Cl2
under reduced pressure yielded crude product, which was recrys-
tallized from a mixture of n-hexane/2-propanol. Yield: 1.825 g
(78%) The product is identical to previously reported 6.24
3.1.12. 4-(Bromomethyl)-7,7-dimethyl-2,3-dioxobicyclo[2.2.1]hep-
tane-1-carboxylic acid (14a). To a stirred solution of 4a (6.000 g,
21.81 mmol) in 20 mL of glacial acetic acid was added finely ground
SeO2 (5.326 g, 48.00 mmol) in one portion. This mixture was then
refluxed with stirring for 24 h. The resulting mixture was filtered off
and the residue was washed twice with acetic acid. The filtrate was
evaporated under reduced pressure yielding oily product. This crude
product was then grinded in water. The resulting mixture was
extracted with chloroform (3ꢂ50 mL), dried over Na2SO4, and fil-
tered. Solvent was removed under reduced pressure leaving yellow
solid. Yield 5.668 g (90%). Mp 189e190 ꢁC. 1H NMR (400.45 MHz,
DMSO-d6):
d
¼1.01 (s, 3H), 1.13 (s, 3H), 1.78e1.93 (m, 2H), 2.12e2.19
(m, 1H), 2.40e2.47 (m, 1H), 3.67 (d, 2J¼11.2 Hz, 1H), 3.74 (d,
3.1.9. endo-3,4-Dibromo-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one
(endo-3,4-dibromocamphor) (7). A stirred solution of 6 (3.000 g,
12.98 mmol) in glacial acetic acid (8 mL) was warmed to 80 ꢁC and
maintained at that temperature using a temperature controller.
Bromine (2.427 g, 15.00 mmol) was added slowly over a period of
ca. 3 h. Heating was continued until the solution became trans-
parent (ca. 5 h). After cooling to room temperature the reaction
mixture was poured into ice cold water (50 mL), and the resultant
precipitate was filtered off. The crude product was recrystallized
from a small amount of absolute ethanol yielding white crystals.
Yield 3.210 g (80%). Mp: 125e126 ꢁC. 1H NMR (400.45 MHz, CDCl3):
2J¼11.2 Hz,1H),13.1 (br s,1H).13C{1H} NMR (100.70 MHz, DMSO-d6):
d
¼16.7, 20.8, 25.5, 26.7, 28.9, 47.4, 61.5, 68.8, 169.3, 196.4, 199.9. IR
(KBr, cmꢀ1): 3501, 2955, 1776, 1757, 1708, 1287, 933. Anal. Calcd for
C11H13BrO4: C, 45.70; H, 4.53; found: C, 45.68; H, 4.56.
3.1.13. The sodium salts of 1-(carboxycarbonyl)-2,2-dimethyl-3-
methylenecyclopentanecarboxylic acid (15) and deuterio-(2,2-
dimethyl-3-methylenecyclopentyl)(oxo)acetic acid (Na salt-D-
16). The experiment was conducted in an NMR ampoule, with
degassed low-paramagnetic D2O used as solvent. 14a (40.0 mg,
0.14 mmol) was added to a solution of NaOD (24.8 mg, 0.61 mmol)
in 0.6 mL of D2O at 5 ꢁC. The mixture was warmed to room
d¼0.95 (s, 3H), 1.05 (s, 3H), 1.10 (s, 3H), 1.37e1.47 (m, 1H), 1.67e1.76

1978
V.O. Knizhnikov et al. / Tetrahedron 68 (2012) 1972e1978
temperature and the NMR spectrum corresponding to 15 was
recorded. 1H NMR (400.45 MHz, D2O):
¼1.05(s, 3H), 1.14(s, 3H),
2.02e2.12(m, 1H), 2.33e2.45(m, 2H), 2.55e2.65(m, 1H), 4.78(s, 1H),
4.83(s, 1H). 13C{1H} NMR (150 MHz, D2O):
48.6, 72.0, 102.7, 162.6, 170.9, 178.6, 206.6. Upon further slow
heating to 60 ꢁC the NMR signals due to 15 disappeared while ones
due to the Na salt of deuterated 16 appeared. 1H NMR (400.45 MHz,
Supplementary data
d
1H NMR and 13C NMR of all new compounds, 1-D NOE difference
spectra of compounds 2a, 2b, 3a, 3b, 7, and 8, 2-D NMR (NOESY and
heteronuclear CeH correlations), cif file and thermal ellipsoid plots
(several styles) for the crystal structure for the compound 3a, LCMS,
GCeMS, and IR spectra. Supplementary data associated with this
article can be found in the online version, at doi:10.1016/
j.tet.2011.12.053. These data include MOL files and InChiKeys of the
most important compounds described in this article.
d¼23.5, 27.3, 28.9, 30.3,
D2O):
d
¼0.92 (s, 3H), 1.26 (s, 3H), 1.75e1.85 (m, 1H), 1.85e1.97 (m,
1H), 2.35e2.47 (m, 1H), 2.47e2.60 (m, 1H), 4.83 (s, 1H), 4.85 (s, 1H).
13C{1H} NMR (150 MHz, D2O):
d¼24.1, 24.6, 28.4, 30.5, 46.0, 57.7 (t,
1JCeD¼19.6 Hz), 103.9, 162.4, 172.5, 209.7.
References and notes
3.1.14. (2,2-Dimethyl-3-methylenecyclopentyl)(oxo)aceticacid(16). To
a stirred solution of NaOH (0.920 g, 23.00 mmol) in 15 mL of
deionized water was added 14a (1.500 g, 5.19 mmol) and the mixture
was then refluxed for 1 min. The cooled reaction mixture was acid-
ified by addition of concentrated HCl. The product was extracted
with dichloromethane (2ꢂ15 mL), the dichloromethane extract was
dried over Na2SO4, filtered, and solvent was removed in vacuum
leaving a colorless liquid. Yield 0.852 g (97%). 1H NMR (400.45 MHz,
1. Paquette, L.; Zeng, Q.; Wang, H.-L.; Shih, T.-L. Eur. J. Org. Chem. 2000, 2187e2194.
2. Paquette, L. A.; Zhao, M. J. Am. Chem. Soc. 1998, 120, 5203e5212.
3. Paquette, L. A.; Zhao, M. Z.; Montgomery, F.; Zeng, Q. B.; Wang, T. Z.; Elmore, S.;
Combrink, K.; Wang, H. L.; Bailey, S.; Su, Z. A. Pure Appl. Chem. 1998, 70,
1449e1457.
4. Stevens, R. V.; Beaulieu, N.; Chan, W. H.; Daniewski, A. R.; Takeda, T.; Waldner,
A.; Williard, P. G.; Zutter, U. J. Am. Chem. Soc. 1986, 108, 1039e1049.
5. Stevens, R. V.; Chang, J. H.; Lapalme, R.; Schow, S.; Schlageter, M. G.; Shapiro, R.;
Weller, H. N. J. Am. Chem. Soc. 1983, 105, 7719e7729.
6. Stevens, R. V.; Lawrence, D. S. Tetrahedron 1985, 41, 93e100.
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Osuna, S.; Lora Maroto, B. Tetrahedron Lett. 2001, 42, 7795e7799.
8. Jacobs, R. T.; Feutrill, G. I.; Meinwald, J. J. Org. Chem. 1990, 55, 4051e4062.
9. Rowley, M.; Kishi, Y. Tetrahedron Lett. 1988, 29, 4909e4912.
10. Rowley, M.; Tsukamoto, M.; Kishi, Y. J. Am. Chem. Soc. 1989, 111, 2735e2737.
11. John, H.; Hutchinson, T. M. Can. J. Chem. 1985, 63, 3182e3185.
12. Hutchinson, J. H.; Money, T.; Piper, S. E. Can. J. Chem. 1986, 64, 1404e1406.
13. Williams, D. R.; Coleman, P. J.; Henry, S. S. J. Am. Chem. Soc. 1993, 115,
11654e11655.
14. Money, T.; Richardson, S. R.; Wong, M. K. C. Chem. Commun. 1996, 667e668.
15. Money, T.; Wong, M. K. C. Tetrahedron 1996, 52, 6307e6324.
16. Vaillancourt, V.; Agharahimi, M. R.; Sundram, U. N.; Richou, O.; Faulkner, D. J.;
Albizati, K. F. J. Org. Chem. 1991, 56, 378e387.
CDCl3):
d
¼0.92 (s, 3H), 1.25 (s, 3H), 1.80e1.89 (m, 1H), 1.93e2.03 (m,
1H), 2.39e2.47 (m, 1H), 2.53e2.59 (m, 1H), 3.61 (t, 3J¼8 Hz, 1H), 4.74
(s, 1H), 4.81 (s, 1H), 10.07 (br s, 1H). 13C{1H} NMR (100.70 MHz,
CDCl3):
d
¼24.3, 24.7, 28.8, 30.4, 46.8, 55.4, 104.1, 159.1, 162.0, 197.9. IR
(KBr, cmꢀ1): 3170, 2967, 1743, 1720, 1652, 1324, 1082. Anal. Calcd for
C10H16O2: C, 71.39; H, 9.59; found: C, 71.37; H, 9.61.
3.1.15. Methyl 4-(bromomethyl)-7,7-dimethyl-2,3-dioxobicyclo[2.2.1]
heptane-1-carboxylate (14b). A stirred solution of 14a (3.000 g
10.38 mmol) in thionyl chloride (20 mL) was refluxed for 2 h. The
excess thionyl chloride was removed under reduced pressure and
the residue dissolved in dry methanol (30 mL). The resulting so-
lution was refluxed for 30 min. Solvent was removed under reduced
pressure leaving yellow solid methyl ester 14b (3.139 g, 100%). Mp
17. Clase, J. A.; Money, T. Synthesis 1989, 934e936.
18. Clase, J. A.; Money, T. Can. J. Chem. 1992, 70, 1537e1544.
19. Stevens, R. V.; Gaeta, F. C. A.; Lawrence, D. S. J. Am. Chem. Soc. 1983, 105,
7713e7719.
80e82 ꢁC. 1H NMR (400.45 MHz, CDCl3):
d
¼1.14 (s, 3H), 1.21 (s, 3H),
20. Martinez, A. G.; Vilar, E. T.; Fraile, A. G.; Fernandez, A. H.; Cerero, S. D.; Jimenez,
F. M. Tetrahedron 1998, 54, 4607e4614.
1.77e1.84 (m, 1H), 1.94e2.01(m, 1H), 2.29e2.37 (m, 1H), 2.54e2.62
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94, 4615e4628.
(m, 1H), 3.47 (d, 2J¼11.2 Hz, 1H), 3.70 (d, 2J¼11.2 Hz, 1H), 3.82 (s,
3H). 13C{1H} NMR (100.70 MHz, CDCl3):
d¼16.7, 20.2, 25.1, 26.2,
26.3, 47.1, 52.4, 61.1, 68.1, 167.5, 194.2, 198.4. IR (KBr, cmꢀ1): 2959,
1779, 1761, 1730, 1274, 1261. Anal. Calcd for C12H15BrO4: C, 47.54; H,
4.99; found: C, 47.50; H, 5.01.
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3.1.16. Methyl 2,2-dimethyl-3-methylenecyclopentanecarboxylate
(18). To a solution of sodium methoxide in methanol, made by
addition of sodium (0.200 g, 8.69 mmol) to 10 mL of dry methanol,
was added 14b (2.000 g, 6.59 mmol) and the mixture was refluxed
for 10 min. The resulting clear, colorless solution was cooled to
room temperature and glacial acetic acid (0.600 g, 10.00 mmol) was
added in one portion. The solvents were removed from the
resulting mixture under reduced pressure on a rotary evaporator
and the product was extracted with dichloromethane (2ꢂ15 mL)
from a water/dichloromethane mixture. The dichloromethane ex-
tract was dried over Na2SO4, filtered, and the solvent was removed
in vacuum leaving yellow liquid. Yield 0.952 g (86%). 1H NMR
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€
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37. Eck, C. R.; Mills, R. W.; Money, T. J. Chem. Soc., Chem. Commun. 1973, 911e912.
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rahedron 1996, 52, 14661e14672.
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40. Cachia, P.; Darby, N.; Eck, C. R.; Money, T. J. Chem. Soc., Perkin Trans. 1 1976,
359e362.
41. Dadson, W. M.; Lam, M.; Money, T.; Piper, S. E. Can. J. Chem. 1983, 61, 343e346.
42. Hutchinson, J. H.; Money, T. Can. J. Chem. 1987, 65, 1e6.
43. Reychler, A. Bull. Soc. Chim. Fr. 1898, 19, 120e128.
44. Hart, H.; Tomalia, D. A. Tetrahedron Lett. 1966, 3383e3388.
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(400.45 MHz, CDCl3):
d
¼0.91 (s, 3H), 1.22 (s, 3H), 1.80e1.88 (m, 1H),
1.92e2.02 (m, 1H), 2.29e2.38 (m, 1H), 2.50e2.58 (m, 2H), 3.65 (s,
3H), 4.76 (s, 1H), 4.80 (s, 1H). 13C{1H} NMR (100.70 MHz, CDCl3):
d
¼24.7, 24.9, 28.0, 30.5, 44.9, 51.0, 55.1, 103.8, 159.9, 174.1. IR (KBr,
cmꢀ1): 2964, 1737, 1731, 1652, 1204, 1153. Anal. Calcd for C10H16O2:
C, 71.39; H, 9.59; found: C, 71.16; H, 9.74.
Acknowledgements
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Oxford, 2003.
We thank Professor Igor Komarov, Department of Chemistry,
Kiev University, Ukraine for valuable discussions. We thank Tetiana
Matviiuk for her help with graphic design.