Unknown Camphor: Regioselective Rearrangement under Acylation in a CF3SO3H/(CF3CO)2O System

Article abstract of DOI:10.1002/ejoc.201501581

The utility of camphor in the chemical sciences is vast and well documented, yet the creation of camphor-derived potentially useful bicyclo[2.2.1]heptane scaffolds still remains one of the great challenges of synthetic organic chemistry. Herein, we show that CF₃SO₃H/(CF₃CO)₂O-mediated acylation of camphor with benzoic acids is accompanied by a cascade of alkyl and hydride shifts and opens access to a new type of polyfunctional isoborneol. In case of salicylic acids, camphor feels the presence of the ortho-hydroxy group in the aryl moiety, the influence of which provokes cleavage of the bicycloheptane skeleton to lead to monocyclic carvenone. The trifluoromethanesulfonic acid (TfOH)/trifluoroacetic anhydride (TFAA) mediated acylation of camphor with benzoic acids gives rise to a cascade of regioselective rearrangements of the bicycloheptane skeleton and allows the synthesis of a new type of previously unknown isoborneol. If salicylic acids are used as the acylating agents, the camphor is isomerized to give carvenone.

Full text of DOI:10.1002/ejoc.201501581

DOI: 10.1002/ejoc.201501581
Communication
Regioselective Rearrangement
Unknown Camphor: Regioselective Rearrangement under
Acylation in a CF3SO3H/(CF3CO)2O System
Vladimir Kovalev,*[a] Elvira Shokova,[a] Vyacheslav Chertkov,[a] and Victor Tafeenko[a]
Abstract: The utility of camphor in the chemical sciences is alkyl and hydride shifts and opens access to a new type of
vast and well documented, yet the creation of camphor-derived
potentially useful bicyclo[2.2.1]heptane scaffolds still remains
one of the great challenges of synthetic organic chemistry.
Herein, we show that CF3SO3H/(CF3CO)2O-mediated acylation
of camphor with benzoic acids is accompanied by a cascade of
polyfunctional isoborneol. In case of salicylic acids, camphor
feels the presence of the ortho-hydroxy group in the aryl moi-
ety, the influence of which provokes cleavage of the bicyclo-
heptane skeleton to lead to monocyclic carvenone.
Introduction
Camphor is a natural compound that exerts a significant influ-
ence on the development of synthetic and theoretical organic
chemistry. Owing to its unique chemical properties, a wide
range of synthetic methods for the regiospecific and stereo-
specific functionalization of the different carbon atoms of cam-
phor and its derivatives, various bond-cleavage reactions, and
rearrangements have been reported.[1] So, camphor has been
proven to be an attractive starting material for the preparation
of numerous natural and synthetic biologically active com-
pounds,[1,2] as well as for the construction of chiral catalysts,[3]
chiral auxiliaries,[4] NMR shift reagents, and others.[5]
The ability of camphor to undergo easy carbocationic trans-
formations is one of its unique features.[1] As far back as 1902
the English chemists Armstrong and Lowry wrote: “No sub-
stance known to us suffers rearrangement of its parts and un-
dergoes a complete change of type more readily than does
camphor”.[6] Its chemical modification is often accompanied by
fascinating Wagner–Meerwein and Nametkin rearrangements,
as well as by 2,6-hydride shifts, and leads to unpredictable
products. Therefore, camphor and its derivatives, relative to
other simple organic molecules, have considerable potential for
the creation of new molecular scaffolds.[7] However, syntheti-
cally useful methods for the stereo- and regioselective modifi-
cation of camphor on the basis of skeletal rearrangements are
limited to C9 and C10 sulfonation,[8,9] C9 bromination,[10] and
transformation into 1-substituted camphenes under the action
of phosphorus chlorides (e.g., PCl3/PCl5),[11] trichloroacetic an-
hydride or trifluoromethanesulfonic anhydride (Scheme 1).[12,13]
Scheme 1. Known methods for the chemical modification of camphor on the
basis of rearrangements. DTBMP = 2,6-di-tert-butyl-4-methylpyridine.
The last of these methods, the stereoselective synthesis of 1-
camphenyl triflate,[13] was discovered almost three decades
ago. Evidently, to create new synthetic applications of camphor,
the development of new methods for its regio- and stereose-
lective modification is undoubtedly interesting for synthetic or-
ganic chemistry.
In the present work, the unexpected transformation of cam-
phor (1) under CF3SO3H/(CF3CO)2O-mediated acylation with
benzoic acids is disclosed. Our recent synthesis of ꢀ-diketones
by the selective α-acylation of alkyl aryl ketones with carboxylic
acids in trifluoromethanesulfonic acid (TfOH)/trifluoroacetic an-
hydride (TFAA) was the motivation for this research.[14] TFAA,
which was used as a medium and an activating agent, eagerly
formed acyl trifluoroacetates from the carboxylic acids. The
presence of TfOH promoted enolization and increased the acyl-
ating ability of the acyl trifluoroacetates.
[a] Chemistry Department, Moscow State University
Lenin's Hills, Moscow 119991, Russia
E-mail: kovalev@petrol.chem.msu.ru
http://www.chem.msu.ru
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501581.
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Results and Discussion
carboxylic acids,[14] the yields of 3a–d were considerably re-
duced. In the absence of the carboxylic acids, camphor was
returned from the reactions, practically without change. Hydrol-
ysis of the obtained trifluoroacetates under very mild condi-
tions gave dihydroxy ketones 4a–d in excellent yields.
Our aim was to synthesize camphor-derived ꢀ-diketones by us-
ing benzoic acids 2 [ArCOOH; Ar = Ph (a), 4-MeC6H4 (b), 4-
ClC6H4 (c), 4-PhC6H4 (d), 2-HOC6H4 (e), 2-HO-5-BrC6H3 (f), 4-
HOC6H4 (g)] as acylating agents by this method. Taking into
consideration the ease with which bornyl cation rearrange-
ments occur, we expected that the TfOH/TFAA-mediated acyla-
tion of enantiomerically pure camphor would occur with race-
mization; therefore, substantially cheaper racemic camphor was
used.
Surprisingly, we found that acylation of camphor with ben-
zoic acids 2a–d was followed by rearrangement of the bicyclic
skeleton to give 3a–d as previously unknown functional deriva-
tives of isoborneol, e.g., exo-4-(2-aryl-2-oxoethyl)-3-hydroxy-7,7-
dimethyl-1-(trifluoroacetoxy)bicyclo[2.2.1]heptanes (Scheme 2).
Notably, under classic conditions of the Claisen condensation,
the reaction of camphor with acyl halides and acid esters gives
1,3-diketones and is not accompanied by rearrangement.[15]
Our reactions were performed with a camphor (1)/acid 2/TfOH/
TFAA molar ratio of 1:2:1.5:8 in dichloromethane at room tem-
perature for 48 h. One molecule of benzoic acid is involved in
the reaction, and the utilization of a smaller excess (1.5 equiv.)
of 2 did not reduce the yields of isoborneols 3. By using 1 equiv.
of benzoic acids 2 and/or 0.5 equiv. of TfOH, under the condi-
tions used to synthesize diketones from alkyl aryl ketones and
The structures of bicyclo[2.2.1]heptanes 3 and 4, previously
unknown, were determined by a combination of conventional
1D and 2D NMR spectroscopy experiments (1H NMR and 13C
NMR, DEPT90, 135COSY, HSQC, and HMBC) and elemental anal-
yses, in addition to X-ray structure analysis data for 3a, 3b, 4b,
1
and 4c.[16] To gain patterns for the assignment of the H and
13C signals in the NMR spectra of compounds 3 and 4, full as-
signment of the 1H and 13C signals for compound 3a as a repre-
sentative example was accomplished (see the Supporting Infor-
1
mation for the H and 13C NMR spectroscopy data).
The exo configuration of the secondary hydroxy group of 3-
hydroxy-7,7-dimethyl-4-phenacyl-1-(trifluoroacetoxy)bicyclo-
[2.2.1]heptane (3a) was determined on the basis of the magni-
3
3
tudes of the vicinal JH2n-H3n and JH2x-H3n coupling constants
4
and the long-rang JH2x-H6x coupling constant. Generally, the
magnitude of the 3JH,H coupling constant for protons with a cis
configuration is much larger (7–12 Hz) than that for protons
with a trans orientation (2–6 Hz), and the presence of the appre-
4
ciable long-range JH,H coupling constant is specific for W-ar-
ranged protons.[17] The observed magnitudes of JH2n-H3n
=
3
8.6 Hz, 3JH2x-H3n = 4.0 Hz, and 4JH2x-H6x = 4.1 Hz allowed the exo
configuration for the hydroxy group at C3 to be unambiguously
ascribed and allowed assignment of the methylene protons at
C2 (Figure 1).
Figure 1. 1H–1H COSY correlations to determine the position of the OH group
in 3a.
Luckily, we were able to grow crystals of bicycloheptanes 3a,
3b, 4b, and 4c that were suitable for X-ray diffraction analysis
to prove their structures definitively.[16]
The molecular structures of trifluoroacetate 3b and diol 4b
are shown in Figures 2 and 3 as representative examples. Nota-
Scheme 2. Acylation of camphor (1) with benzoic acids 2a–d.
Figure 2. Molecular structure of 3b.
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bly, the spatial arrangement of the benzoyl moiety is different can be explained by hydrolysis of the formed triflic acid esters
in the structures of these compounds. The torsion angles C4– of alcohols 3 upon treatment of the reaction mixture with wa-
C10–C11–O2 are equal to 3.67° for 3b and 75.52° for 4b. This ter.
difference is the result of an O3–H3···O2 intramolecular
hydrogen bond in 4b.
Reaction of (+)-(R)-1 with benzoic acid (2a) yielded racemic
isoborneol rac-3a. Therefore, trapping of the corresponding car-
bocation E with water follows a racemizing 6,2-hydride shift
(Figure 4). This confirmed the ease of racemization of the bornyl
cations under the TfOH/TFAA conditions for the acylation of
camphor.
Figure 3. Molecular structure of 4b.
Figure 4. Racemization of precursor carbocations E.
The obtained structural data allowed a plausible mechanism
for the TfOH/TFAA-mediated acylation of camphor with benzoic
acids to be assumed (Scheme 3).
At the first stage, O-trifluoroacylation of a carbonyl group
with acyl trifluoroacetate I generated in situ leads to 4-(tri-
fluoroacetoxy)camphene II and probably proceeds through suc-
cessive formation of carbocations A, B, and C as a result of
Wagner–Meerwein (W.-M.) and Nametkin rearrangements, with
following deprotonation of C. Next, benzoylation of the methyl-
ene group of II with anhydride I gives intermediate D, which
The acylation of camphor with benzoic acids 2a–d proved
to yield not only trifluoroacylated products 3a–d but also a
small amount of carvenone (5; 5–8 %), which has a chromato-
graphic mobility similar to that of trifluoroacetates 3. After re-
moval of the trifluoroacetyl group, 5 could be easily separated
from keto diols 4a–d. The analogous course of camphor reac-
tions under acidic conditions is well known.[19,20]
Unexpectedly, carvenone (5) became the main reaction
easily undergoes Wagner–Meerwein rearrangement to give cat- product in the reactions of camphor with salicylic acids 2e and
ion E. Final treatment of the mixture with water yields isobornyl 2f, and the formation of bicyclic compounds 3 was not ob-
product 3. The interaction of cations of type E with nucleo- served at all. The yield of 5 was 35–40 % after 48 h and in-
philes usually affords isobornyl products such as 3 despite the creased to 51–55 % after 72 h for both salicylic acids 2e and 2f.
thermodynamic preference for the formation of bornyl deriva- It can be assumed that the acylation of camphor with trifluoro-
tives.[13,18] Curiously, in this reaction we observed dual reactivity acetyl salicylates formed in situ leads to carbocations F, which
of anhydride I – trifluoroacetylation of the carbonyl group of undergo cleavage of the C1–C7 bond with subsequent hydride
camphor (hard nucleophilic center) and benzoylation of the shift and deprotonation (Scheme 4). Such a transformation may
double bond of camphene II (soft nucleophilic center) – in full be related to the fact that the ortho-OR group in the salicylic
compliance with the hard–soft acid–base principle. The forma- fragment of intermediate F complicates the Wagner–Meerwein
tion of the hydroxy (NOT trifluoroacetate or triflate) group at rearrangement and makes cleavage of the C1–C7 bond the pre-
the C3 atom is another peculiarity of the acylation process. This ferred process.
Scheme 3. Plausible mechanism for the formation of isoborneols 3a–d in the acylation of camphor (1) with benzoic acids 2a–d.
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(1.07 mL, 8 mmol), and TfOH (132 μL, 1.5 mmol). Yield: 62 %
1
(230 mg), white solid, m.p. 122–124 °C, Rf = 0.27 (CH2Cl2). H NMR
(600 MHz, CDCl3, 303 K): δ = 7.98 (m, 2 H, ArHo), 7.61 (m, 1 H, ArHp),
3
3
7.50 (m, 2 H, ArHm), 4.08 (dd, JH2n-H3n = 8.6 Hz, JH2x-H3n = 4.0 Hz,
H3n), 3.30 (br. s, OH), 3.22 (d, 2J = –14.3 Hz, 1 H, CH2CO), 2.95 (d,
2J = –14.3 Hz, 1 H, CH2CO), 2.77 (dd, 2JH2n-H2x = –12.7 Hz, 3JH2n-H3n
=
3
3
8.6 Hz, H2n), 2.15 (ddd, JH5n-H6n = 9.8 Hz, JH5x-H6n = 4.1 Hz,
2JH6n-H6x = –12.3 Hz, H6n), 1.94 (dt, JH2n-H2x = –12.7 Hz, JH2x-H3n
=
=
2
3
4.0 Hz, 4JH2x-H6x = 4.1 Hz, H2x), 1.73 (tt, 4JH2x-H6x = 4.1 Hz, 3JH5n-H6x
3
2
4.1 Hz, JH5x-H6x = 12.5 Hz, JH6n-H6x = –12.3 Hz, H6x), 1.65 (ddd,
2JH5n-H5x = –12.6 Hz, 3JH5x-H6n = 4.1 Hz, 3JH5x-H6x = 12.5 Hz, H5x), 1.30
(ddd, 2JH5n-H5x = –12.6 Hz, 3JH5n-H6n = 9.8 Hz, 3JH5n-H6x = 4.1 Hz, H5n),
1.21 (s, 3 H, Mes), 0.99 (s, 3 H, Mea) ppm. 13C NMR (150 MHz, CDCl3,
303 K): δ = 201.9 (CO), 156.8 (q, JCF = 41.6 Hz, OCO), 137.5 (CAri),
2
133.7 (CHArp), 128.8 (2 CHArm), 128.4 (2 CHAro), 114.4 (q, JCF
=
1
–286.4 Hz, CF3), 90.5 (C1), 74.7 (C3), 48.6 (C7), 48.4 (C4), 40.0 (C2),
34.5 (C10), 29.5 (C6), 29.1 (C5), 17.9 (C9, Mea), 17.2 (C8, Mes) ppm.
C19H21F3O4 (370.37): calcd. C 61.62, H 5.72; found C 61.30, H 5.42.
exo-1,3-Dihydroxy-7,7-dimethyl-4-(2-oxo-2-phenylethyl)bicy-
clo[2.2.1]heptane (4a): A mixture of 3a (200 mg, 0.54 mmol),
NaOH (50 mg, 1.3 mmol), ethanol (9 mL), and water (1 mL) was
kept at room temperature for ca. 15 min. Upon completion of the
reaction (TLC control), the solvent was evaporated, and the residue
Scheme 4. TFAA/TfOH-mediated isomerization of camphor by salicylic acids.
The proposed mechanism is speculative and requires proof.
Interestingly, 4-hydroxybenzoic acid was polymerized under the
same conditions as a result of self-acylation, and camphor was
returned from the reaction without change.
was acidified with 1
N HCl (pH ≈ 5) and extracted with CH2Cl2. The
organic phase was washed with H2O, dried (MgSO4), and concen-
trated under vacuum. Purification of the product was performed by
column chromatography (silica gel; CH2Cl2/MeOH, 98:2). Yield: 91 %
(135 mg), white solid, m.p. 80–82 °C, Rf = 0.17 (CH2Cl2/MeOH, 98:2).
1H NMR (400 MHz, CDCl3, 298 K): δ = 7.98 (m, 2 H, HAr), 7.59 (m, 1
H, HAr), 7.48 (m, 2 H, HAr), 3.93 (dd, J = 8.4, 3.9 Hz,1 H, H3), 3.24 (d,
J = 13.8 Hz, 1 H, CH2CO), 2.87 (d, J = 13.8 Hz, 1 H, CH2CO), 2.59
(br. s, 2OH), 2.05 (dd, J = 8.4, 12.6 Hz, 1 H of CH2), 1.86 (m, 1 H of
Conclusions
In this study we found that the trifluoromethanesulfonic acid/
trifluoroacetic anhydride mediated acylation of camphor with
benzoic acids radically depends on the nature of the acid used. CH2), 1.64 (m, 1 H of CH2), 1.53 (m, 1 H of CH2), 1.43 (m, 1 H of
CH2), 1.11 (s, 3 H, CH3), 1.09 (m, 1 H of CH2), 0.91 (s, 3 H, CH3) ppm.
13C NMR (100 MHz, CDCl3, 298 K): δ = 202.3 (CO), 137.2 (CAr), 133.2
(CHAr), 128.3 (CHAr), 128.1 (CHAr), 81.0 (C1), 73.9 (C3), 50.7 (C), 47.0
(C), 43.6 (CH2), 34.9 (CH2), 32.5 (CH2), 28.5 (CH2), 17.4 (Me), 16.8 (Me)
ppm. C17H22O3 (274.36): calcd. C 74.42, H 8.08; found C 74.31, H8.21.
In whole, the reaction is accompanied by regioselective
Wagner–Meerwein and Nametkin rearrangements and provides
access to previously unknown polyfunctional isoborneols. How-
ever, the presence of an ortho-hydroxy group in the benzoic
acid changes the course of the reaction: the interaction of cam-
phor with the salicylic acids proceeds through cleavage of the
bicycloheptane skeleton and leads to carvenone. These results
once again show the unique chemical properties of camphor
in its transformations in electrophilic reactions and the wide
possibilities of its modification.
Carvenone (5): Obtained from camphor (1; 1 mmol), salicylic acid
(2e; 207 mg, 1.5 mmol), TFAA (1.07 mL, 8 mmol), and TfOH (132 μL,
1.5 mmol), 72 h. Yield: 51 % (78 mg), oil, Rf = 0.28 (CH2Cl2). 1H NMR
(400 MHz, CDCl3, 298 K): δ = 5.83 (s, 1 H, CH=C), 2.38–2.25 (m, 4 H),
2.04 (m, 1 H), 1.68 (m, 1 H), 1.10 (d, J = 6.8 Hz, CH3), 1.07 (d, J =
6.8 Hz, CH3), 1.05 (d, J = 6.8 Hz, CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 202.2 (CO), 170.3 (C=CH), 122.6 (C=CH), 40.6 (CH), 35.1
(CH), 30.6 (CH2), 26.8 (CH2), 20.4 (CH3), 20.1 (CH3), 14.7 (CH3) ppm.
Experimental Section
Data for 5 from ref.[21] 13C NMR (20 MHz, CDCl3, room temp.): δ =
:
201.9, 170.5, 123.0, 41.1, 35.5, 31.3, 27.3, 20.9, 20.5, 15.1 ppm.
General Procedure for the TfOH/TFAA-Mediated Acylation of
Camphor: A solution of camphor (1 mmol), carboxylic acid (1.5–
2 mmol), and TFAA (1.07 mL, 8 mmol) in dichloromethane (3 mL)
was stirred at room temp. for 15 min. Triflic acid (132 μL, 1.5 mmol)
was then added, and the resulting solution was kept under the
conditions indicated in Scheme 2 (TLC monitoring). Volatile compo-
nents of the mixture were evaporated under reduced pressure, and
after quenching with water, the residue was redissolved in CH2Cl2
(20 mL), washed with 5 % NaHCO3 (2 × 5 mL) and water (2 × 5 mL),
and dried with MgSO4. The solvent was removed in vacuo, and the
crude mixture was purified by silica gel chromatography (column
20 × 1.5 cm, n-hexane/CH2Cl2).
Acknowledgments
Financial support for this work was provided by the Russian
Foundation of Basic Researches (15-03-05381). We are grateful
to J. K. Kim for experimental assistance.
Keywords: Acylation · Isoborneols · Natural products ·
Rearrangement · Regioselectivity
exo-3-Hydroxy-7,7-dimethyl-4-(2-oxo-2-phenylethyl)-1-(tri-
fluoroacetoxy)bicyclo[2.2.1]heptane (3a): Obtained from cam-
phor (1; 152 mg, 1 mmol), benzoic acid (2a; 244 mg, 2 mmol), TFAA
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Received: December 16, 2015
Published Online: February 29, 2016
Eur. J. Org. Chem. 2016, 1508–1512
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim