Selective ring expansion alkylation of formyl[2.2.1]bicyclic carbinols with c-nucleophiles: A unique route to cyclopentane derivatives

Article abstract of DOI:10.1021/jo070730q

(Chemical Equation Presented) Reactions of camphor-, and camphene-derived formyl [2.2.1]-bicyclic carbinols with Grignard and organolithium reagents afford the corresponding regio- and stereospecific alkyl/aryl [3.2.1]bicyclic diols. Some of these bicycli

Full text of DOI:10.1021/jo070730q

Selective Ring Expansion Alkylation of
Formyl[2.2.1]bicyclic Carbinols with
C-Nucleophiles: A Unique Route to Cyclopentane
Derivatives
Te-Fang Yang,* Chih-Hao Tseng, Kuan-I Wu, and
Chung-Nien Chang
Department of Applied Chemistry, Chaoyang UniVersity of
Technology, Wufong, 413, Taichung, Taiwan, ROC
tfyang@cyut.edu.tw
ReceiVed April 26, 2007
FIGURE 1. Some bridged bicyclic alcohols that undergo various ring-
expansion reactions.
and Koser’s reagent4 did afford 2-[(Z)-bromoiodomethylidene]-
bicyclo-[3.2.1]octan-3-one and its regioisomer.5 Several years
ago, another example of halogen-containing ring expansion of
[2.2.1]bicyclocarbinol framework was presented by Ruggles and
Maleczka.6 They successfully carried out the ring expansion of
isopropenyl[2.2.1]bicyclocarbinol 4 in 6 h at 0 °C, utilizing a
bleach-acetic acid system as the promoter.6 Recently, a catalytic
rearrangement of cyclic R-ketol has been investigated by
Brunner et al.7a,b On the other hand, ring expansion reactions
of R-hydroxy ketones with sodium methoxide and that of
aminomethyl bicyclio[2.2.1]heptan-2-ol with sodium nitrite
under acidic condition also take place.7c-e In 1974, Sisti and
Rusch8 had reported that [2.2.1]bicyclic carbinol 5 (Figure 1),
derived from camphor, underwent ring expansion in the presence
of one equivalent of i-propyl magnesium bromide to afford
[3.2.1]bicyclooctanones (Scheme 1).
Reactions of camphor-, and camphene-derived formyl [2.2.1]-
bicyclic carbinols with Grignard and organolithium reagents
afford the corresponding regio- and stereospecific alkyl/aryl
[3.2.1]bicyclic diols. Some of these bicyclic diols have been
treated with lead tetraacetate to provide new chiral cyclo-
pentane derivatives. A plausible mechanism of the ring
expansion-alkylation reaction is proposed.
Bridged bicyclic alcohols are prone to rearrangement to form
various bicyclic ketones under appropriate conditions. Espe-
cially, owing to its potential application to the synthesis of
natural products or derivatives, the ring expansion of [2.2.1]-
bicyclocarbinols has drawn much attention from organic chem-
ists.1 For example, the ring expansion of endo-norbornanol 1
(Figure 1) had been reported by Paquette, et al.2 in 1992. They
concluded that the bridge-head carbon atom of 1 migrated
exclusively in the presence of toluenesulfonic acid. Furthermore,
Paquette, Houk, and co-workers3 found that exo-norbornanol 2
and its heterosubstituted derivatives could undergo an anionic
oxy-Cope rearrangement to provide corresponding bicyclo[6.2.1]-
undecenone analogues when the reactants were individually
treated with potassium hexamethyldisilazide at low temperatures.
The specialty of this reaction is that one of the sp3-hybridized
bridgehead carbon atoms became an sp2-hybridized one upon
the rearrangement. In addition, reaction of borneol 3 with iodine
SCHEME 1
All the reactions mentioned above and, as we reported very
recently,9 the reaction of formyl isoborneol with MeMgBr
primarily gave ring-expanded bridged bicyclic ketones. How-
ever, the reaction of formyl borneol (6) with either 1 or 2.5
(4) Moriaty, R. M.; Vaid, R. K.; Koser, G. F. Synlett 1990, 365-383.
(5) Djuardi, E.; Bovonsombat, P.; McNelis, E. Tetrahedron 1994, 50,
11793-11802.
(6) (a) Ruggles, E. L.; Maleczka, R. E., Jr. Org. Lett. 2002, 4, 3899-
3902. Johnson, C. R.; Herr, R. W. J. Org. Chem. 1973, 38, 3153-3159.
(b) Johnson, C. R.; Cheer, C. J.; Goldsmith, D. J. J. Org. Chem. 1964, 29,
3320-3323.
(7) (a) Brunner, H.; Kagan, H. B.; Kreutzer, G. Tetrahedron: Asymmetry
2001, 12, 497-499. (b) Brunner, H.; Kagan, H. B.; Kreutzer, G.
Tetrahedron: Asymmetry 2003, 14, 2177-2187. (c) Creary, X.; Inocencio,
P. A.; Underiner, T. L.; Kostromin, R. J. Org. Chem. 1985, 50, 1932-
1938. (d) Creary, X.; Geiger, C. C. J. Am. Chem. Soc. 1982, 104, 4151-
4162. (e) McKinney, M. A.; Patel, P. P.; J. Org. Chem. 1973, 38, 4059-
4064.
(8) Sisti, A.; Rusch, G. M. J. Org. Chem. 1974, 39, 1182-1186.
(9) Yang, T.-F.; Zhang, Z.-N.; Tseng, C.-H.; Chen, L.-H. Tetrahedron
Lett. 2005, 46, 1917-1920.
(1) (a) John, C. R.; Cheer, C. J.; Goldsmith, D. J. J. Org. Chem. 1964,
29, 3320-3323. (b) Krow, G. R. Tetrahedron 1987, 43, 3-38. (c) Paquette,
L. A.; Lawhorn, D. E.; Teleha, C. A. Heterocycles 1990, 30, 765-769. (d)
Guo, X.; Paquette, L. A. J. Org. Chem. 2005, 70, 315- 320.
(2) (a) Paquette, L. A.; Andrews, J. F. P.; Vanucci, C.; Lawhorn, D. E.;
Negri, J. T.; Rogers, R. D. J. Org. Chem. 1992, 57, 3956-3965. (b) Negri,
J. T.; Rogers, R. D.; Paquette, L. A. J. Am. Chem. Soc. 1991, 113, 5073-
5075.
(3) (a) Paquette, L. A.; Reddy, Y. R.; Haeffner, F.; Houk, K. N. J. Am.
Chem. Soc. 2000, 122, 740-741. (b) Paquette, L. A.; Pegg, N. A.; Toops,
D.; Maynard, G. D.; Rogers, R. D. J. Am. Chem. Soc. 1990, 112, 277-
283.
10.1021/jo070730q CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/04/2007
7034
J. Org. Chem. 2007, 72, 7034-7037

TABLE 1. Ring Expansion-Alkylation Results of Carbinol 6
SCHEME 2
time
(min)
yield
entry
RM(X)a
productc
(%)e
1
2
3
4
5
6
MeMgBrb
MeLi
30
30
30
30
30
30
11 (R ) Me)d
11 (R ) Me)d
12 (R ) Ph)
91
90
67
65
63
77
PhMgBrb
PhLi
12 (R ) Ph)
n-BuMgClb
n-BuLi
13 (R ) n-Bu)d
13 (R ) n-Bu)d
SCHEME 3
a All the reagents were purchased from commercial suppliers and used
without further purification. b Data have been shown in ref 9. c >99% de.
d The configuration of each new chiral center was determined with X-ray
diffraction. e Yields of isolated products.
carbinol 6 also reacted with lithium reagents and gave the same
products as those provided by the reactions with corresponding
Grignard reagents (Table 1). Thus, individual reactions of 6 with
both types of C-nucleophile donors showed the same chemose-
lectivity and regio- and stereochemical (>99% de) behaviors.
Although the reaction time of some experiments (entries 5 and
6) has been prolonged for 60 min, the yield of each product
was not improved. In addition, it showed that the nucleophi-
licities of methyl and phenyl lithium compounds (entries 2 and
4) were close to those of corresponding Grignard reagents
(entries 1 and 3). The mechanism of reaction of 6 with Grignard
reagents has been previously illustrated.9 Thus, it is expected
that the mechanism of the reaction of 6 with alkyl/aryl lithium
compounds is similar to that of the reaction of 6 with Grignard
reagents.
As shown in Table 2, the reactions of formyl carbinol 7 with
various Grignard and organolithium reagents were carried out
individually under conditions similar to those adopted for the
reaction of 6. In each case, among all possible regio- and
stereoisomers of the [3.2.1]bicyclic diol structure, the isomer
containing two vicinal exo-hydroxyl groups and possessing the
new alkyl group attached to the ring carbon, which is the closest
one to the bridgehead carbon, is the only product isolated and
determined (>99% de). In order to search for a shorter reaction
time for 7, some experiments have been carried out in 15 min.
After the time period for the reactions with MeMgBr and
EtMgBr was prolonged from 15 to 30 min, the yields of 10
and 14 (entries 1, 2, 4, and 5) were not obviously improved.
However, the yields of products 15, 21, and 22 were signifi-
cantly improved after the reaction time was increased (entries
6, 7, 14, 15, 17, and 18). Although the reactions with allylMgCl,
n-BuMgCl, vinylMgBr, and CH3CCMgBr (entries, 8, 9, 11, and
12) were individually carried out in 15 and 30 min, the yields
of the corresponding products given in both time periods were
almost the same. Interestingly, the reaction with phenyl ethynyl
magnesium bromide (entry 13) also afforded the expected
product in good yield. However, cyclopentyl magnesium
bromide (entry 19) was not a good C-nucleophile donor for the
reaction. This phenomenon is probably due to the steric effect
caused by the nonplanar cyclopentyl moiety.9 Some lithium
reagents (entries 3 and 10) showed almost the same reactivity
as their corresponding Grignard reagents did. Nevertheless,
phenyl lithium (entry 16) was more reactive than phenyl
magnesium bromide (entry 15).
equiv of various Grignard reagents provided alkyl[3.2.1]bicyclic
diols instead of ketones.9 It should be emphasized that 5
underwent ring expansion only,8 whereas 6 did consecutively
undergo a ring expansion-alkylation reaction when both of them
were individually treated with 1 equiv of the same reagent.
These interesting results impelled us to further study the
reactions of other formyl[2.2.1]bicyclic carbinol analogues with
some C-nucleophiles. We herein report the individual ring
expansion alkylation of camphor- and camphene-based
formyl[2.2.1]bicyclic carbinols (6 and 7) with Grignard reagents
(RMgX) and alkyl/aryl lithium compounds (RLi), which were
both adopted as the C-nucleophile donors for the reaction.
In order to obtain carbinol 7 (Scheme 2), (+)-camphene (8),
which is commercially available, was adopted as the starting
material. Treatment of 8 with N,N-dimethyl-methanamine
oxide10 in the presence of a catalytic amount of OsO4 (Scheme
2) provided diol 9 (91% yield, 98% de). It is noteworthy that
Uchida, et al. had reported the preparation of the enantiomer of
9,11 which could be obtained in slight or low yields (2-39%)
from the electrochemical oxidation reaction of camphene in
acetic acid followed by the treatment with aqueous sodium
bicarbonate. In addition, treatment of camphene with KMnO4
in aqueous acetone11c also gave the enantiomer of 9 in low
(∼12%) yield. In our lab, then, the primary hydroxyl group in
9 was further oxidized with NaOCl and TEMPO in the presence
of KBr to afford formyl carbinol 7 in good (90%) yield.
As mentioned above, the reactions of camphor-based formyl-
[2.2.1]bicyclic carbinol (6) with various Grignard reagents have
been previously described.9 Now, the new finding is that
(10) (a) Gream, G. E.; Pincombe, C. F.; Wege, D. Aust. J. Chem. 1974,
27, 603-628. (b)Yang, T.-F.; Chao, H.-H.; Lu, Y.-H.; Tsai, C.-J. Tetra-
hedron, 2003, 59, 8827-8831.
(11) (a) Uchida, T.; Matsubara, Y.; Nishiguchi, I.; Hirashima, T.; Ohnishi,
T.; Kanehira, K. J. Org. Chem. 1990, 55, 2938-2943. (b) Matsubara, Y.;
Uchida, T.; Ohnishi, T.; Kanehira, K.; Fujita, Y.; Hirashima, T.; Nishiguchi,
I. Tetrahedron Lett. 1985, 4513-4516. (c) Kozlov, N. G.; Kovalskaya, S.
S.; Kalechits, G. V. Zhurnal Obshchei Khimii 1993, 63, 1124-1133. (d)
Ren, W. Y.; Brown, D. A. W.I.O.P. Patent WO/2001/068576, 2001. (e)
Ren, W. Y.; Brown, D. A. W.I.O.P. Patent WO/2000/044368, 2000.
J. Org. Chem, Vol. 72, No. 18, 2007 7035

TABLE 2. Ring Expansion-Alkylation Results of Carbinol 7
RM(X)
(C-Nu donor)
time
(min)
yield
(%)b
entry
producta
1
2
3
4
5
6
7
8
MeMgBr
MeMgBr
MeLi
EtMgBr
EtMgBr
i-PrMgCl
i-PrMgCl
allylMgCl
n-BuMgCl
n-BuLi
vinylMgBr
CH3CCMgBr
PhCCMgBr
PhMgBr
15
30
30
15
30
15
30
15
15
30
15
15
30
15
30
30
15
30
30
10 (R ) Me)
10 (R ) Me)
92
94
91
82
85
45
70
77
79
80
76
78
83
52
70
82
63
79
23
10 (R ) Me)
14 (R ) Et)
14 (R ) Et)
15 (R ) i-Pr)
15 (R ) i-Pr)
16 (R ) Allyl)
17 (R ) n-Bu)
17 (R ) n-Bu)
18 (R ) CHCH2)
19 (R ) CHCH3)
20 (R ) CCPh)
21 (R ) Ph)
FIGURE 2. Plausible mechanism for the ring expansion-alkylation
reaction of 7.
9
Polysantol.14 Thus, the C-C bonds between vicinyl hydroxyl
groups on diols 10, 14, 16, 17, and 21 (Seheme 3) were also
oxidatively cleaved with Pb(OAc)4 at room temperature to
provide fencholic acid derivatives 2415-28, respectively. The
application of these disubstituted cyclopentanes (2415-28) to
the synthesis of some natural product analogues is under
investigation.
10
11
12
13
14
15
16
17
18
19
PhMgBr
PhLi
BnMgCl
BnMgCl
cyclopentylMgBr
21 (R ) Ph)
21 (R ) Ph)
22 (R ) Bn)
22 (R ) Bn)
23 (R ) cyclopentyl)
Experimental Section
a >99% de given by each experiment. b Yields of isolated products.
Procedure for Dihydroxylation of 8. To a mixture of 8 (2.0
g, 14.7 mmol), N,N-dimethylmethanamine oxide (2.48 g, 22.3
mmol) in t-BuOH (30 mL), water (5 mL), and pyridine (2.0
mL) was added dropwise osmium tetroxide (2.5% in t-BuOH,
1.48 mL, 0.114 mmol). The reaction mixture was heated at
reflux for 5 h, then cooled to room temperature and quenched
with sodium bicarbonate (20%, 10 mL). The mixture was
extracted with petroleum ether, washed with water, dried (Na2-
SO4), and concentrated under reduced pressure. The residue was
purified with flash column chromatography (1:1 hexane/EtOAc)
to give 9 (2.2 g, 90% yield, 90% de) as a white solid: mp 194-
A plausible mechanism of the ring expansion-alkylation
reaction of 7 is illustrated in Figure 2. Presumably, as described
in the reaction of 69, the alkyl/aryl moiety of the first molecule
of organometallic reagent functioned as a base instead of a
nucleophile and attacked the proton of hydroxyl group on 7 at
the beginning of reaction. It is deduced that the ring-carbon
atom which possesses two methyl groups was forced to migrate
and attack the formyl moiety from the si-face right after the
first molecule of the organometallic reagent chelated12 to the
hydroxyl and formyl groups as shown in structure 7a. This
phenomenon is a sharp contrast to that observed in the reaction
of 6 but consistent with that shown by the ring expansion of
the dihydrofuranyl carbinol-bearing fenchone skeleton under
acidic conditions, which forced the bridgehead carbon atom to
migrate exclusively.2a The migration of the ring-carbon atom
in 7a resulted in formation of the new carbonyl group shown
in structure 7b. The alkyl/aryl moiety of second molecule of
organometallic reagent, then, functioned as a nucleophile and
attacked the newly formed carbonyl group in 7b from the si-
face, too. Finally, the [3.2.1]bicyclic syn-diols (Scheme 2) were
exclusively obtained after workup.
27
196 °C; [R]D ) +12.1 (0.01, CH2Cl2); IR (KBr) 3369 (br),
1
2963, 2881, 1464 cm-1; H NMR (200 MHz, CDCl3): δ 3.71
(dd, J ) 6.0 Hz, 11.2 Hz, 1H), 3.58 (dd, J ) 4.4 Hz, 11.2 Hz,
1H), 2.81(dd, J ) 4.4 Hz, 6.0 Hz, OH), 2.48 (s, OH), 2.13-
1.11 (m, 8H), 1.02 (s, 3H), 0.93 (s, 3H); 13C NMR (50 MHz,
CDCl3): δ 81.9, 63.9, 49.7, 47.2, 43.4, 34.5, 25.3, 23.7, 22.7,
21.6. Anal. Calcd for C10H18O2: C, 70.55; H, 10.66. Found:
C, 70.88; H, 10.36.
Procedure for Preparation of 7. To a mixture of 9 (1.0 g,
5.87 mmol), TEMPO (0.03 g, 0.19 mmol), KBr (0.13 g, 1.10
mmol), NaHCO3 (0.13 g, 1.55 mmol) in CH2Cl2 (40 mL) and
H2O (5 mL) at 0 °C was added dropwise NaOCl (5.2 mL, 10.76
mmol). After the reaction mixture was stirred at 0 °C for 1 h,
NaHSO3 (5%, 10 mL) was added. Then, the mixture was
extracted with CH2Cl2, washed with H2O, dried (Na2SO4), and
filtered. The filtrate was concentrated under reduced pressure
to give 7 as a white solid: mp 98-100 °C; [R]D27 ) +9.4 (0.01,
CH2Cl2); IR (KBr) 3483 (br), 2957, 2880, 1709, 1461, 1338
In order to search for the application of the title reaction,
diol 11 has been previously converted to new, highly substituted
chiral cyclopentanes,9,13 which could be potential valuable
synthons for the preparation of R-campholanic acid and
1
cm-1; H NMR (200 MHz, CDCl3): δ 10.07 (s, 1H), 3.56 (br
(12) Still, W. C.; Schneider, J. A. Tetrahedron Lett. 1980, 21, 1035-
1038.
s, 1H), 2.23-1.17 (m, 2H), 1.92-1.30 (m, 6H), 1.10 (s, 3H),
(13) For the synthesis of chiral substituted cyclopentanes, see: (a) Clark,
M. A.; Georing, B. K.; Li, J.; Ganem, B. J. Org. Chem. 2000, 65, 4058-
4069. (b) Hubbard, R. D.; Miller, B. L. Tetrahedron 2003, 59, 8143-8152.
(c) Ishii, S.; Zhao, S.; Mehta, G.; Knors, C. J.; Helquist, P. J. Org. Chem.
2001, 66, 3449-3458. (d) Aurrecoechea, J. M.; Lopez, B.; Arrate, M. J.
Org. Chem. 2000, 65, 6493-6510. (e) Garcia Martinez, A.; Teso Vilar, E.;
Garcia Fraile, A.; de la Moy, Cerero, S.; Lora Maroto, B. Tetrahedron Lett.
2005, 46, 5157-5159.
(14) (a) Ruedi, G.; Nagel, M.; Hansen, H.-J. Org. Lett. 2003, 5, 2691-
2693. (b) El Kaim, L.; Meyer, C. J. Org. Chem. 1996, 61, 1556-1557. (c)
Castro, J. M.; Linares-Palomino, P. J.; Salido, S.; Altarejos, J.; Nogueras,
M.; Sanches, A. Tetrahedron Lett. 2004, 45, 2619-2622. (d) Frater, G.;
Bajgrowwicz, J. A.; Kraft, P. Tetrahedron 1998, 54, 7633-7703.
(15) Matsubara, Y. Nippon Kagaku Sasshi 1957, 78, 903-906.
7036 J. Org. Chem., Vol. 72, No. 18, 2007

0.99 (s, 3H); 13C NMR (50 MHz, CDCl3): δ 207.4, 84.0, 49.9,
48.9, 48.6, 37.3, 25.6, 24.0, 22.4, 21.5. HRMS calcd for
C10H16O2: 168.1150; found: 168.1155.
were combined and washed with water, dried (Na2SO4), and
concentrated under reduced pressure. The residue was purified
with flash column chromatography (3:1 hexane/EtOAc) to give
the corresponding cyclopentane derivative.
General Procedure for the Reaction of Carbinol 6 or 7
with the Grignard and Organolithium Reagents. To a
solution of carbinol 6 (0.45 g, 2.47 mmol) or 7 (0.50 g, 2.98
mmol) in diethyl ether (10 mL) was added dropwise a Grignard
or lithium reagent (2.5 equiv). The reaction mixture was stirred
at room temperature for 30 min and then quenched with aqueous
NH4Cl and extracted with ethyl acetate (3 × 10 mL). The
organic layers were combined and washed with water, dried
(Na2SO4), and concentrated under reduced pressure. The residue
was purified with flash column chromatography (6:1 hexane/
EtOAc) to give the corresponding [3.2.1]bicyclic diol.
General Procedure for the Ring-Cleavage of Bicyclic Diols
10, 14 ,16, 17, and 21. A solution of [3.2.1]bicyclic diol (0.43
mmol) in ethyl acetate (5 mL) was treated with lead tetraacetate
(0.56 mmol). The reaction mixture was stirred at room tem-
perature for 5 min and then quenched with water (10 mL) and
extracted with ethyl acetate (3 × 10 mL). The organic layers
Acknowledgment. This work was supported by National
Science Council of Taiwan, ROC, which is gratefully acknowl-
edged. We also thank the Instrumental Center at National
Taiwan University and the Regional Instruments Center at
National Chung-Hsing University for the X-ray crystallography,
HRMS, and elemental analyses.
Supporting Information Available: Procedure for prepara-
tion of camphene-based formyl[2.2.1]bicyclic carbinol, experimental
details for the ring expansion-alkylation reaction and the pre-
paration of cyclopentane derivatives 24-28, 1H and 13C NMR
spectra and characterization data of the products (7, 9-28). This
material is available free of charge via the Internet at http://
pubs.acs.org.
JO070730Q
J. Org. Chem, Vol. 72, No. 18, 2007 7037