Stereo- and regioselectivity in dynamic gas-phase thermoisomerization (DGPTI): Novel route to α-campholanic acid and derivatives

Article abstract of DOI:10.1021/ol034882t

(Matrix presented) Dynamic gas-phase thermoisomerization (DGPTI) of (-)-2-phenylisoborneols effects stereo- and regioselective ring opening under formation of (+)-trans-α-campholanic acid derivatives. Similarly, (-)-α-2-phenylfenchol underwent under DGPTI conditions ring opening to (-)-fencholic acid derivatives. In both cases, DGPTI led to cleavage of the weakest bond in the isomeric bicyclic structures. A reaction mechanism involving a diradical intermediate is supported by a deuterium labeling study.

Full text of DOI:10.1021/ol034882t

ORGANIC
LETTERS
2003
Vol. 5, No. 15
2691-2693
Stereo- and Regioselectivity in Dynamic
Gas-Phase Thermoisomerization
(DGPTI): Novel Route to r-Campholanic
Acid and Derivatives
Georg Ru1edi,* Matthias Nagel,† and Hans-Ju1rgen Hansen
Organisch-Chemisches Institut der UniVersita¨t, 8057 Zu¨rich, Switzerland
georg@access.unizh.ch
Received May 20, 2003
ABSTRACT
Dynamic gas-phase thermoisomerization (DGPTI) of (−)-2-phenylisoborneols effects stereo- and regioselective ring opening under formation
of (+)-trans-r-campholanic acid derivatives. Similarly, (−)-r-2-phenylfenchol underwent under DGPTI conditions ring opening to (−)-fencholic
acid derivatives. In both cases, DGPTI led to cleavage of the weakest bond in the isomeric bicyclic structures. A reaction mechanism involving
a diradical intermediate is supported by a deuterium labeling study.
Alkyl esters of R-campholanic acid (1) are reported to reveal
organoleptic properties of fruity and floral quality, which
make them interesting for fragrance chemisty.1 Although the
skeleton of 1 has been prepared chemically2 as well as
photochemically,3 the thermal chemistry of this chiral
building block has apparently not yet been investigated.
Among the four possible stereoisomers of 1, mainly mixtures
of cis/trans isomers were reported, predominantly obtained
via hydrogenation of R-campholenic acid derivatives 2.4
only one configuration but with unsatisfactory yields.5 More
recent methods involving the cleavage of the C1-C2 bond
of camphor by hydrosilylation6 or fragmentation of initially
generated camphoriminyl radicals4 lack diastereoselectivity.
As we recently discovered in our laboratory, large-ring
1-phenylcycloalkanols react under DGPTI conditions cleanly
to open-chain phenones, whereas the small-ring analogues
undergo only H2O elimination.7 Were 2-phenylisoborneol (3)
to behave like a bicyclic small-ring 1-phenylcycloalkanol
analogue, elimination of H2O under formation of 2-phenyl-
bornene would be expected to occur under DGPTI. In sharp
contrast to this expectation, pyrolysis of (-)-2-phenyl-
isoborneol8 (3) at 630 °C afforded a monocyclic isomeric
product that was easily removed from highly volatile side
products, characterized, and proved to be (+)-trans-2-(2,2,3-
trimethyl-cyclopentyl)-1-phenyl-ethanone9 (4) (Scheme 1,
A further approach, by heating camphor imine in the
presence of oxygen, is reported to deliver the amide of 1 in
(1) Rohr, M.; Flynn, C. U.S. Patent 4 547 315, 1985; Chem. Abstr. 1986,
105, 11868.
(2) Harispe, M.; Mea, D. Bull. Soc. Chim. Fr. 1962, 1340.
(3) El Kaim, L.; Meyer, C. J. Org. Chem. 1996, 61, 1556.
† Current address: Swiss Federal Laboratories for Materials Testing and
Research (EMPA), CH-8600 Du¨bendorf, Switzerland.
10.1021/ol034882t CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/20/2003

3-d-4, which exhibited a broad singlet in its 2H NMR
spectrum at δ 1.66.
Scheme 1
The investigation has led to the conclusion that this
thermally promoted cleavage reaction proceeds via a diradical
species as we found earlier for the transformation of
1-phenylcycloalkanols.7 Moreover, the label has been proved
to be transferred both stereospecifically (retention of con-
figuration) and regiospecifically from the O-atom of O-d-3
to C3 of 4 (Scheme 2). The labeling experiment reveals that
Table 1). This thermal behavior might be explained by the
strain incorporated in the bicyclic bornane system. The
Scheme 2
Table 1. Effects of Para Substituents on DGPTI of
2-Phenylisoborneols 3
R
product
T (°C)
yield (%)
dr (%)
H
CH3
OCH3
CF3
a
b
c
d
630
620
610
630
73
45
62
71
>99
>99
>99
>99
initial homolysis of the C1-C2 bond of isoborneol 3 results
in the formation of a monocyclic hydroxybenzyl alkyl
diradical 5, which then undergoes a disproportionation
reaction via 1,7-H shift. However, cleavage of the C2-C3
bond under formation of the lower substituted alkyl radical
moiety could not be detected.
assignment of the trans configuration is based on the
observed NOE correlations as shown in Figure 1.
Substituents at the aromatic ring affected both the yield
and the required optimal temperature for the DGPTI process,
but not the diastereoisomeric ratio. As summarized in Table
1, a series of readily prepared isoborneols 3a-d was
thermally converted to the isomeric phenones 4a-d in
moderate to good yields. The lower yields of 4-methyl- and
(7) Ru¨edi, G.; Nagel, M.; Hansen, H.-J. Synlett 2003, 1210.
(8) Prepared from (+)-camphor with PhMgBr in the presence of CeCl3;
see: Dimitrov, V.; Brabantov, S.; Simova, S.; Kostova, K. Tetrahedron
Lett. 1994, 35, 6713.
(9) (a) DGPTI process was performed in a flow reactor system using a
quartz tube (110 cm length) heated in a tube furnace (100 cm lengths with
six different temperature zones separately adjustable). (b) For details, see:
Nagel, M.; Fra´ter, G.; Hansen, H.-J. Synlett 2002, 275, 280. Nagel, M.;
Fra´ter, G.; Hansen, H.-J. Chimia 2003, 57, 196 and references therein. (c)
The following procedure is illustrative. After evacuation of the apparatus
with a high-vacuum oil pump, (-)-2-phenylisoborneol (3) (2.0 g, 8.68 mmol)
was distilled slowly through the preheated reactor tube (contact time
estimated at about 1-2 s). A flow of N2 was adjusted from 1.2 L/h. At the
end of the reactor unit, the isomerization products were collected in a trap
cooled with liquid N2 (90-95% recovery). Purification by flash chroma-
tography (silica gel, 30:1 hexanes/ethyl acetate) followed by bulb-to-bulb
distillation (kugelrohr) afforded (+)-trans-2-(2,2,3-trimethyl-cyclopentyl)-
1-phenyl-ethanone (4) (1.46 g, 73% yield) as a colorless oil: [a]23D +54.7
(c 0.6, MeOH); FTIR (film) 3060, 3027, 2958, 2871, 1687, 1598, 1580,
Figure 1. 1H-NOE correlations of compound (+)-4 showing its
trans configuration.
We have studied the mechanism and the origin of this
unique stereoselectivity in the pyrolysis of isoborneol 3 by
means of deuterium labeling experiments. The thermal
isomerization of O-deuterated isoborneol O-d-310 gave
(4) (a) Lipp, P. Ber. Dtsch. Chem. Ges. 1922, 55, 1883. (b) Cason, J.;
Khodair, A. I. A. J. Org. Chem. 1967, 32, 575. (c) Gream, G. E.; Wege,
D.; Mular, M. Aust. J. Chem. 1974, 27, 567. (d) Treibs, W.; Mu¨hlsta¨dt,
M.; Megges, R.; Klotz-Herdmann, I. Justus Liebigs Ann. Chem. 1960, 634,
118. (e) Ichikawa, S. Bull. Chem. Soc. Jpn. 1936, 11, 759.
(5) (a) Mahla, F.; Tiemann, F. Ber. Dtsch. Chem. Ges. 1900, 33, 1929.
(b) Blanc, G.; Desfontaines, M. Bull. Soc. Chim. Fr. 1903, 29, 608. (c)
Bonnett, R.; Raleigh, J. A.; Redman, D. G. J. Am. Chem. Soc. 1965, 87,
1600.
1448, 1366, 1285, 1215, 1180, 1016, 1002 cm-1 1H NMR (600 MHz,
;
CDCl3) δ 7.95 (dd, J ) 8.3 and 1.4 Hz, 2H); 7.54 (tt, J ) 7.4 and 1.3 Hz,
1H); 7.45 (t, J ) 7.9 Hz, 2H); 3.03 (dd, J ) 16.2 and 4.0 Hz, 1H); 2.73
(dd, J ) 16.0 and 10.4 Hz, 1H); 2.20 (m, 1H); 1.93 (m, 1H); 1.85 (m, 1H);
1.66 (sext, J ) 7.1 Hz, 1H); 1.25-1.20 (m, 2H); 0.89 (s, 3H); 0.88 (s, 3H);
0.86 (d, J ) 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 201.1, 137.6,
133.0, 128.7, 128.3, 44.3, 43.7, 42.4, 40.7, 31.6, 29.7, 24.4, 23.8, 16.5 ppm;
MS m/z (rel intensity) 230 (12), 221 (2), 187 (1), 173 (45), 145 (7), 120
(82), 105 (100), 95 (23), 77 (30), 69 (11).
(6) Brunner, H.; Becker, R. Angew. Chem., Int. Ed. Engl. 1985, 24, 703;
Angew. Chem. 1985, 97, 713.
(10) Prepared by iterative treatment of 3 with MeOD/D2O.
2692
Org. Lett., Vol. 5, No. 15, 2003

4-methoxy-substituted substrates 3b and 3c, respectively, are
due to increased susceptibility to dehydration. The corre-
sponding bornenes could be isolated in 20-30% yield.
The enantioselective thermoisomerization reaction sum-
marized in Table 1 can widely be exploited in the synthesis
of a broad variety of chiral monoterpenes derived from
phenones of type 4. For instance, the large difference in
electronic properties between the electron-donating methoxy
group (4c) and the electron-withdrawing trifluoromethyl
group (4d) allows selective Baeyer-Villiger rearrangement.
According to Scheme 3, treatment of 4c with m-chloroper-
cyclopentyl methyl ester 7, which upon hydrolysis led to
cyclopentyl carbinol 8 in comparable yields. Oxidation of 8
with Jones reagent13 furnished (+)-trans-R-dihydrocam-
pholytic acid (9). On the other hand, the Baeyer-Villiger
reaction of both 4a and 4b gave, after hydrolysis, 3:1
mixtures of 1 and 8, which could easily be separated.
Scheme 4
Scheme 3
It was of interest to extend our studies to (-)-fenchone,
which upon treatment with PhLi in Et2O gave (1R,2R,4S)-
2-phenyl fenchol14 (10). AM1 calculations of 10 show that
the C2-C3 bond is longer than the C1-C2 bond, which is
in agreement with X-ray crystallographic analyses of reported
2-arylfenchol derivatives.15 Indeed, thermal isomerization of
10 at 630 °C provided fencholic acid derivative 1116 in 48%
yield. In contrast to the transformation of 3 to 4, a reaction
pathway involving the cleavage of the C2-C3 bond was
observed.
Further investigations on the DGPTI-induced rearrange-
ment of fencholic derivatives of type 10 are in progress.
In conclusion, the observed stereoselective conversion of
camphor and fenchone derivatives to campholanic and
fencholic acid derivatives by DGPTI is novel and demon-
strates the potential of pyrolytic methods.
Acknowledgment. This work was generously supported
by the Swiss National Science Foundation (SNF).
Supporting Information Available: Experimental pro-
cedures and complete spectral data for all new compounds
(4a-d, 6-9, and 11). This material is available free of charge
via the Internet at http://pubs.acs.org.
OL034882T
benzoic acid and an aequimolar amount of TFA in CH2Cl2,11
followed by hydrolysis of the intermediate phenyl ester 6,
afforded campholanic acid12 (1) in almost quantitative yields,
whereas treatment of 4d under equivalent conditions provided
(13) Welch, J. T.; Lin, J. Tetrahedron 1996, 52, 291.
(14) Lecompte, V.; Ste´phane, E.; Japuen, G. Tetrahedron Lett. 2002,
43, 3463.
(15) Allen, F. H. Acta Crystallogr. 2002, B52, 380.
(16) Phenone 11: [a]23D -6.7 (c 1.0, hexane); FTIR (film) 3060, 2957,
2871, 1674, 1598, 1579, 1447, 1384, 1367, 1284, 1236, 1181, 1159, 1077,
1
(11) Koch, S. S. C.; Chamberlin, A. R. Synth. Commun. 1989, 19, 829.
(12) -trans-R-Campolanic acid (1): [a]23D +40.6 (c 1.0, hexane); FTIR
(CHCl3) 3517, 2961, 2874, 2680, 1704, 1470, 1452, 1412, 1389, 1368,
1003, 975, 942, 797, 714, 656 cm-1; H NMR (600 MHz, CDCl3) δ 7.86
(dd, J ) 7.2 and 1.4 Hz, 2H); 7.47 (tt, J ) 7.4 and 1.2 Hz, 1H); 7.41 (t, J
) 7.5 Hz, 2H); 2.45 (ddd, J ) 13.2, 9.4, and 3.7 Hz, 1H); 1.88 (m, 1H);
1.89 (d, J ) 8.9 Hz, 2H); 1.75 (sext., J ) 7.9 Hz, 1H); 1.66 (ddd, J )
16.9, 8.7, and 3.7 Hz, 1H); 1.42 (s, 3H); 1.38 (sext × d, J ) 6.7 and 1.7
Hz, 1H); 1.26 (m, 1H); 0.90 (d, J ) 6.6 Hz, 3H); 0.89 (d, J ) 6.6 Hz, 3H);
13C NMR (150 MHz, CDCl3) δ 206.7, 136.9, 131.8, 129.2, 128.3, 54.7,
46.9, 43.2, 37.6, 33.6, 30.6, 28.0, 21.8, 21.7 ppm; MS m/z (rel intensity)
230 (4), 212 (1), 187 (10), 124 (25), 105 (100), 81 (63), 69 (80), 55 (28).
Anal. Calcd for C16H22O (230.35): C, 83.43; H, 9.63. Found: C, 83.39;
H, 9.66.
1
1296, 1230, 1178, 1136 cm-1; H NMR (300 MHz, CDCl3) δ 2.43 (dd, J
) 15.1 and 3.5 Hz, 1H); 2.12 (dd, J ) 15.6 and 10.4 Hz, 1H); 2.06-1.91
(m, 2H); 1.85 (m, 1H); 1.62 (sext, J ) 7.1 Hz, 1H); 1.31-1.17 (m, 2H);
0.86 (d, J ) 6.9 Hz, 3H); 0.84 (s, 3H); 0.81 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 180.6, 44.5, 43.3, 42.0, 36.2, 31.1, 29.1, 23.7, 23.3, 16.0 ppm;
MS m/z (rel intensity) 170 (10), 127 (11), 114 (37), 110 (26), 95 (42), 84
(67), 69 (100), 55 (23). Anal. Calcd for C16H22O (230.35): C, 83.43; H,
9.63. Found: C, 83.31; H, 9.62.
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