Pyridinium chlorochromate mediated oxidative cyclisation of sterically crowded γ,δ-unsaturated alcohols

Article abstract of DOI:10.1016/j.tetlet.2007.08.112

Pyridinium chlorochromate (PCC) mediated oxidative cyclisation of sterically crowded γ,δ-unsaturated alcohols (primary, secondary, allylic, benzylic as well as tertiary) is described.

Full text of DOI:10.1016/j.tetlet.2007.08.112

Tetrahedron Letters 48 (2007) 7610–7613
Pyridinium chlorochromate mediated oxidative cyclisation
of sterically crowded c,d-unsaturated alcohols
A. Srikrishna,* B. Vasantha Lakshmi and A. V. S. Sudhakar
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 5 August 2007; revised 23 August 2007; accepted 30 August 2007
Available online 5 September 2007
Abstract—Pyridinium chlorochromate (PCC) mediated oxidative cyclisation of sterically crowded c,d-unsaturated alcohols (pri-
mary, secondary, allylic, benzylic as well as tertiary) is described.
ꢀ 2007 Elsevier Ltd. All rights reserved.
c,d-Unsaturated alcohols 1 have been employed as start-
ing materials for the construction of 2-acyltetrahydro-
furans 2 in natural product synthesis, either via the
corresponding epoxide or by employing a haloetheri-
fication (or its equivalent) reaction. However, there is
no report in the literature on the direct one-step oxida-
tive conversion of c,d-unsaturated primary and second-
ary alcohols 1a to generate 2-acyltetrahydrofurans 2a, as
oxidation to the corresponding aldehyde or ketone 3 is
preferred (Eq. 1). A few scattered examples of oxidative
cyclisation of c,d-unsaturated tertiary alcohols 1b to the
corresponding 2-acyltetrahydrofurans 2b (Eq. 2) have
been reported in the literature.1 Pyridinium chlorochro-
mate (PCC) is a versatile oxidising agent, which has
been employed in the selective oxidation of a variety
of alcohols.2 It has also been utilised in the transposition
of tertiary alcohols and cyclopropyl methanols.2 During
our investigations on the synthesis of enantiopure bicyclo-
[n.3.1]alkanes from derivatives of carvone, we have
discovered a novel PCC mediated oxidative cyclisation
of sterically crowded c,d-unsaturated alcohols, which
is the subject of this Letter.
O
R"
R
R'
R
R
R'
R'
oxdn
R"
R'
oxdn
X
ð1Þ
ð2Þ
OH
R
O
2a
O
3
1a
R' &/or R" = H
O
R'
oxdn
R"
R
O
OH
R"
1b
2b
O
O
O
CO2Me
OH
a,b
c
d
5
6
7
4a
Scheme 1. Reagents and conditions: (a) LiAlH4, Et2O, ꢀ70 ꢁC, 2 h, 96%; (b) Me2CHCO2H, DCC, DMAP, CH2Cl2, rt, 3 h, 94%; (c) (i) LDA, THF,
TMSCl, NEt3, ꢀ70 ꢁC, 30 min; rt, 2 h; reflux, 8 h; (ii) dil HCl, 30 min; (iii) CH2N2, Et2O, 0 ꢁC, 30 min, 92%; (d) LiAlH4, Et2O, 0 ꢁC, 2 h, 97%.
*
Corresponding author. Tel.: +91 80 22932215; fax: +91 80 23600529; e-mail: ask@orgchem.iisc.ernet.in
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.112

A. Srikrishna et al. / Tetrahedron Letters 48 (2007) 7610–7613
7611
Neopentyl alcohol 4a was prepared from (R)-carvone 5
O
as depicted in Scheme 1 via the Ireland ester Claisen
rearrangement3 of carvyl 2-methylpropanoate 6,
followed by reduction of the resulting ester 7. Oxidation
of neopentyl alcohol 4a with 2.5 equiv4 of PCC and
silica gel in methylene chloride at room temperature for
40 minutes furnished the bicyclic ketone 8a in addition
to aldehyde 9a, in a combined 85% yield and 1:1 ratio.
X
O
OH
H
O
+
9a X=H
10 X=OH
4a
8a
reagent
yield
ratio of 8a and 9a
PCC, silica gel
PCC
PCC, NaOAc
PDC
Jones' reagent
85%
90%
81%
76%
90%
1:1
1:1.2
1:1.2
Compounds 8a and 9a were separated by column chro-
matography on silica gel. The structure of the bicyclic
ketone 8a was established from its spectral data, in par-
ticular, from the presence of a carbonyl absorption band
at 1724 cmꢀ1 in the IR spectrum, the absence of signals
due to the trisubstituted olefin and aldehyde protons
and carbons in the NMR spectra, and the presence of
1:6
only 9a and 10
Scheme 2.
a quaternary carbon resonance at d 211.4 due to the
ketone carbon and two oxygen bearing carbons (one
quaternary at 86.6 and one methylene at 78.1 ppm) in
the 13C NMR spectrum. The reaction was further investi-
gated, Scheme 2. The bicyclic ketone 8a was formed
on oxidation of alcohol 4a under various conditions,
viz. pyridinium dichromate (PDC) in methylene
chloride, PCC in the absence of silica gel and PCC
and sodium acetate. However, Jones’ reagent failed to
generate ketone 8a, and furnished only a mixture of
aldehyde 9a and the corresponding acid 10, which ruled
out the role of the acidity of PCC in the formation of the
bicyclic ketone 8a from alcohol 4a.
Yields refer to isolated and chromatographically pure compounds.
All the compounds exhibited spectral data (IR, 1H and 13C NMR and
mass) consistent with their structures. Selected spectral data for the
23
bicyclic ketone 8a: ½aꢁD +7.4 (c 2.6, CHCl3); IR (neat): mmax/cmꢀ1
1724, 1646, 1072, 891; 1H NMR (300 MHz, CDCl3): d 4.76 (2H, s),
3.49 and 3.41 (2H, 2 · d, J 9.0 Hz), 2.75–2.60 (2H, m), 2.20–1.95 (2H,
m), 1.85–1.70 (1H, m), 1.74 (3H, s), 1.46 (3H, s), 1.40–1.00 (1H, m),
1.12 (3H, s), 0.89 (3H, s); 13C NMR (75 MHz, CDCl3): d 211.4 (C),
146.9 (C), 110.3 (CH2), 86.6 (C), 78.1 (CH2), 56.5 (CH), 42.2 (C), 41.5
(CH2), 39.8 (CH), 29.6 (CH2), 27.1 (CH3), 26.3 (CH3), 21.2 (CH3),
20.1 (CH3); HRMS: m/z calcd for C14H22O2Na (M+Na): 245.1517.
22
Found: 245.1515. For the bicyclic ketone 8d: ½aꢁD +11.0 (c 1.2,
CHCl3); IR (neat): mmax/cmꢀ1 3081, 1723, 891; 1H NMR (300 MHz,
CDCl3): d 5.77 (1H, ddd, J 17.4, 10.2 and 6.6 Hz), 5.26 (1H, d, J
17.4 Hz), 5.22 (1H, d, J 10.2 Hz), 4.75 (2H, s), 3.66 (1H, d,J 6.3 Hz),
2.73–2.58 (2H, m), 2.25–2.00 (2H, m), 1.90–1.70 (1H, m), 1.73 (3H, s),
1.51 (3H, s), 1.25–1.10 (1H, m), 0.98 (3H, s), 0.85 (3H, s); 13C NMR
(75 MHz, CDCl3): d 211.9 (C), 147.2 (C), 133.7 (CH), 118.1 (CH2),
110.3 (CH2), 86.4 (CH), 85.5 (C), 57.6 (CH), 44.5 (C), 41.5 (CH2),
39.9 (CH), 31.0 (CH2), 26.5 (CH3), 25.6 (CH3), 20.1 (CH3), 20.0
(CH3); HRMS: m/z calcd for C16H24O2Na (M+Na): 271.1675.
The PCC mediated oxidative cyclisation was further
investigated with several secondary alcohols 4b–g and
the results are summarised in Table 1. The alcohols
4b–g were prepared from aldehyde 9a. Oxidation was
carried out with PCC in methylene chloride at room
temperature.5 It is worth noting that even the allyl
alcohol (entry d) and benzyl alcohol (entry g) furnished
the bicyclic ketones. The exo isomer was found to pre-
dominate (>8:1) in all the bicyclic compounds 8b–g,
indicating that one of the isomers of 4b–g preferentially
cyclises and the other generates both the bicyclic ketone
8 and aldehyde 9.
24
Found: 271.1675. For the bicyclic ketone 8g: ½aꢁD ꢀ17.9 (c 5.5,
CHCl3); IR (neat): mmax/cmꢀ1 1723, 1071, 764; 1H NMR (300 MHz,
CDCl3): d 7.15 and 7.05 (4H, 2 · d, J 8.1 Hz), 4.76 (2H, s), 4.26 (1H,
s), 2.80–2.50 (2H, m), 2.32 (3H, s), 2.20–2.10 (2H, m), 1.90–1.70 (1H,
m), 1.74 (3H, s), 1.59 (3H, s), 1.40–1.25 (1H, m), 0.89 (3H, s), 0.72
(3H, s); 13C NMR (75 MHz, CDCl3): d 211.3 (C), 147.1 (C), 136.5
(C), 134.0 (C), 128.1 (2C, CH), 126.5 (2C, CH), 110.2 (CH2), 86.1
(CH), 84.8 (C), 57.7 (CH), 44.5 (C), 41.4 (CH2), 39.8 (CH), 31.2
(CH2), 26.4 (CH3), 26.0 (CH3), 21.2 (CH3), 20.2 (CH3), 20.0 (CH3);
HRMS: m/z calcd for C21H28O2Na (M+Na): 335.1987. Found:
Since it is already well established that the primary alco-
hol 11a undergoes smooth oxidation to the correspond-
ing aldehyde6 with PCC, it is obvious that the presence
of the quaternary carbon (thereby increasing the steric
crowding) in alcohol 4a is responsible for the generation
of ketone 8a, perhaps due to the Thorpe–Ingold (or
reactive rotamer) effect.7 The oxidative cyclisation was
carried out with an epimeric mixture of propyl alcohol
12 in the presence of PCC and silica gel in methylene
chloride in order to establish the role of the two methyl
groups in 4a in the cyclisation. Alcohol 12 was readily
available from carvone 5 and the stereochemistry of
the secondary methyl group has been established.8 It
was observed that the major isomer (R)-12 leads to a
mixture of the bicyclic ketone 13 and aldehyde 14,
whereas the minor isomer (S)-12 exclusively gives alde-
hyde 14. This was further established by the oxidation
of the tertiary alcohols 11b and 15. The reaction was
found to be very slow with alcohol 11b (only 20% con-
version after 5 h) and produced the bicyclic ketone
25
335.1986. For the bicyclic ketone 13: ½aꢁD +4.5 (c 1.5, CHCl3); IR
(neat): mmax/cmꢀ1 1717, 1015, 893; 1H NMR (300 MHz, CDCl3): d
4.80 (1H, br s), 4.74 (1H, s), 4.02 (1H, dd, J 8.1 and 8.1 Hz), 3.48 (1H,
dd, J 9.9 and 8.1 Hz), 2.80–2.60 (1H, m), 2.55–2.39 (3H, m), 2.16 (1H,
quintet, J 6.6 Hz), 1.80–1.65 (1H, m), 1.75 (3H, s), 1.35–1.21 (1H, m),
1.27 (3H, s), 1.01 (3H, d, J 6.6 Hz); 13C NMR (75 MHz, CDCl3): d
209.0 (C), 147.3 (C), 110.3 (CH2), 85.1 (C), 72.6 (CH2), 50.1 (CH),
42.9 (CH), 42.5 (CH2), 36.7 (CH), 29.0 (CH2), 22.1 (CH3), 20.4
(CH3), 11.6 (CH3); HRMS: m/z calcd for C13H20O2Na (M+Na):
24
231.1361. Found: 231.1360. For the bicyclic ketone 16: ½aꢁD +20.0 (c
3.0, CHCl3); IR (neat): mmax/cmꢀ1 1722, 891; 1H NMR (300 MHz,
CDCl3): d 4.71 (2H, s), 2.60–2.25 (4H, m), 2.10–1.90 (2H, m), 1.69
(3H, s), 1.58 (1H, dd, J 12.3 and 7.2 Hz), 1.50–1.40 (1H, m), 1.36 (3H,
s), 1.26 (3H, s), 1.23 (3H, s); 13C NMR (75 MHz, CDCl3): d 210.5 (C),
147.0 (C), 110.7 (CH2), 85.8 (C), 81.3 (C), 47.6 (CH), 46.2 (CH2), 42.1
(CH2), 41.5 (CH), 34.0 (CH2), 30.5 (CH3), 30.1 (CH3), 26.1 (CH3),
20.8 (CH3); HRMS: m/z calcd for C14H22O2Na (M+Na): 245.1517.
Found: 245.1509.

7612
A. Srikrishna et al. / Tetrahedron Letters 48 (2007) 7610–7613
Table 1. PCC mediated oxidative cyclisation of neopentyl alcohols 4a–g
Entry Alcohol 4
Productsa 8 and 9
Yield/%
(ratiob of 8:9)
O
O
O
O
O
H
H
a
85 (1:1)
OH
H
+
9a
4a
8a
Me
O
b
93 (1:1.2)
OH
Me
+
9b
4b
8b
Bu
O
O
O
OH
O
O
O
O
c
79 (1.6:1)
H
Bu
4c
Bu
9c
+
8c
O
OH
d
86 (1:1.6)
H
+
9d
4d
8d
OH
O
e
81 (1.2:1)
H
+
9e
4e
8e
( )2
H
O
OH
O
O
f
94 (1.5:1)
( )2
4f
( )2
9f
+
8f
p
-tolyl
+
O
O
OH
O
g
84 (1.8:1)
H
9g
4g
8g
a All the compounds were separated by column chromatography on silica gel.
b Ratio is based on the isolated pure compounds.
16. On the other hand, the major isomer of alcohol (R)-
15 was cyclised to the bicyclic ketone 17 and the minor
isomer (S)-15 remained unreacted under these condi-
tions. The reaction was also investigated with alcohol
18 containing two competing olefins at the c-position
for the alcohol to cyclise. As expected, bicyclic ketone
19 was formed, clearly establishing the preference for
the electron rich olefin to cyclise.

A. Srikrishna et al. / Tetrahedron Letters 48 (2007) 7610–7613
7613
CHO
O
OH
O
PCC, silica gel
H
+
CH2Cl2, rt
86%
(
R:S 3:1)
14
( 3 : 5 )
O
12
13
R
R
O
PCC, silica gel
CH2Cl2, rt
OH
H
11a R = H
11b R = Me
16
OH
O
O
PCC, silica gel
OH
H
+
CH2Cl2, rt
95%
15
15
17
O
O
PCC, silica gel
H
H
OH
+
O
CH2Cl2, rt
84%
( 1.1 : 1 )
18
19
20
3. Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94,
5897.
In conclusion, we have reported a novel oxidative
cyclisation of sterically crowded alcohols (primary,
secondary, allyl, homoallyl, benzyl, tertiary) to gener-
ate annulated tetrahydrofurans. Currently, we are
investigating the utility of this oxidative cyclisation in
the synthesis of perhydrobenzofuran based natural
products.
4. It was found that a minimum of 2 equiv of PCC was
required for completion of the reaction. For example,
reaction of alcohol 4a with 1.5 equiv of PCC furnished the
bicyclic alcohol i in addition to the bicyclic ketone 8a and
aldehyde 9a (i:8a:9a 3:2:5), suggesting the secondary
alcohol i (or its equivalent chromium containing species)
as the intermediate in the sequence.
O
O
H
HO
O
1.5 eq. PCC
silica gel
H
H
+
+
OH
O
CH2Cl2, 0.5 h
91%
9a
i
8a
4a
5. General experimental procedure: To a magnetically stirred
solution of alcohol 4a (250 mg, 1.2 mmol) in anhydrous
CH2Cl2 (4 ml) was added a homogeneous mixture of PCC
(775 mg, 3.6 mmol) and silica gel (775 mg), and the reaction
stirred for 30 min at rt. The reaction mixture was then
filtered through a small silica gel column using CH2Cl2
as eluent. Evaporation of the solvent and purification of
the residue on a silica gel column using ethyl acetate–
hexane (1:20) as eluent furnished aldehyde 9a (106 mg,
43%) as an oil. Further elution of the column with ethyl
acetate–hexane (1:10) furnished the ketoether 8a (134 mg,
42%) as an oil.
Acknowledgements
We thank Ms. Hema Sivaramakrishnan for checking the
reproducibility of some of the reactions. We are grateful
to the Department of Biotechnology, New Delhi, for the
financial support, and the Indian Institute of Science for
a fellowship to BVL.
References and notes
6. Srikrishna, A.; Dinesh, C.; Anebouselvy, K. Tetrahedron
Lett. 1999, 40, 1031.
7. Jung, M. E. Synlett 1999, 843; Jung, M. E.; Trifunovich, I.
D.; Lensen, N. Tetrahedron Lett. 1992, 33, 6719.
8. Ireland, R. E.; Wipf, P.; Armstrong, J. D. J. Org. Chem.
1988, 53, 640.
1. Schlecht, M. F.; Kim, H.-J. Tetrahedron Lett. 1986, 27,
4889; Waddell, T. G.; Carter, A. D.; Miller, T. J.; Pagni, R.
M. J. Org. Chem. 1992, 57, 381.
2. Wietzerbin, K.; Bernadou, J.; Meunier, B. Eur. J. Org.
Chem. 2000, 1391; Buchi, G.; Egger, B. J. Org. Chem. 1971,
36, 2021.