A versatile indium trichloride mediated Prins-type reaction to unsaturated heterocycles

Article abstract of DOI:10.1021/jo034981k

A versatile and high-yielding indium trichloride mediated cyclization reaction of silylated homoallylic alcohols, thiols, or amines with aldehydes or epoxides is described as a rapid route to a range of unsaturated heterocycles. The excellent diastereosel

Full text of DOI:10.1021/jo034981k

A Ver sa tile In d iu m Tr ich lor id e Med ia ted
P r in s-Typ e Rea ction to Un sa tu r a ted
Heter ocycles
Adrian P. Dobbs,*,† Sebastien J . J . Guesne´,†
Sasˇa Martinovic´,† Simon J . Coles,‡ and
Michael B. Hursthouse‡
F IGURE 1. Target range of heterocycles.
School of Chemistry, University of Exeter, Stocker Road,
Exeter EX4 4QD, UK, and EPSRC National
Crystallographic Service, Department of Chemistry,
University of Southampton,
SCHEME 1
Highfield, Southampton SO17 1BJ , UK
a.dobbs@exeter.ac.uk
Received J uly 8, 2003
Abstr a ct: A versatile and high-yielding indium trichloride
mediated cyclization reaction of silylated homoallylic alco-
hols, thiols, or amines with aldehydes or epoxides is de-
scribed as a rapid route to a range of unsaturated hetero-
cycles. The excellent diastereoselectivity observed offers a
method of wide scope and generality.
olefin may serve as a handle for further synthetic
manipulation.
We have recently reported the indium trichloride
mediated silyl-Prins reaction as a rapid route to the
dihydropyran skeleton.3 Herein, we report that a similar
methodology may be employed for the synthesis of a
range of heterocycles, using this mild Lewis acid.
The silyl-Prins reaction is the cyclo-condensation reac-
tion of a silylated homoallylic alcohol with a suitable
partner in the presence of a Lewis acid. Typically, the
cyclization partner has been either a carbonyl compound
or epoxide, and of various Lewis acids screened for
promoting this reaction, indium trichloride has been
shown to be the most efficient (Scheme 1).4
Results are presented herein to complement our previ-
ous report3 and prove the previously postulated stereo-
selectivity of the silyl-Prins cyclization. Further, we shall
describe the extension of this method to the preparation
of heterocycles containing sulfur and nitrogen, as well
as oxygen.
The silyl-Prins reaction proceeds at room temperature
and occurs with complete diastereocontrol, obtaining
exclusively the cis-2,6-dihydropyran product, as demon-
strated both by NOE data and X-ray crystallography. A
6.5% enhancement was observed of the C6 proton on
irradiation of the C2 proton in 2-benzhydryl-6-methyl-
5,6-dihydro-2H-pyran, 2. Dihydroxylation with osmium
tetraoxide/NMO proceeded exclusively from the least
hindered lower face, and diacetylation of the diol gave a
colorless crystalline solid, the crystal structure of which
is shown in Scheme 2. No epimerization of the dihydro-
pyran was observed by NMR during the hydroxylation/
protection steps.
The pyran and piperidine skeletons are found abun-
dantly in many natural products. Over the years, there
has been a plethora of elegant methodologies developed
independently for the synthesis of each of these hetero-
cycles1,2 but very few general methods that are equally
applicable to the synthesis of both functionalized ring
systems, starting from a common precursor. Much of our
research effort therefore has been devoted to developing
a synthetic approach to a range of heterocycles of the type
shown in Figure 1, where the heteroatom may be oxygen,
sulfur, or nitrogen, there is a stereocontrolled incorpora-
tion of substituents during a cyclization process, and an
* Corresponding author.
† University of Exeter.
‡ University of Southampton.
(1) Representative examples of the synthesis of unsaturated oxygen-
containing heterocycles: (a) Hoffmann, R. W.; Giesen, V.; Fuest, M.
Liebigs Ann. Chem. 1993, 629-639. (b) Carbonyl allylation-Prins
cyclization: Viswanathan, G. S.; Yang, J .; Li, C.-J . Org. Lett. 1999, 1,
993-995. (c) Sakurai reaction: Marko, I. E.; Bayston, D. J . Tetrahedron
1994, 50, 7141-7156. (d) Marko, I. E.; Dobbs, A. P.; Scheirmann, V.;
Chelle´, F.; Bayston, D. J . Tetrahedron Lett. 1997, 38, 2899-2902. (e)
Olefin metathesis: Schmidt, B.; Westhus, M. Tetrahedron 2000, 56,
2421-2426. (f) Sonogashira-selenoetherification approach: Brimble,
M. A.; Pavia, G. S.; Stevenson, R. J . Tetrahedron Lett. 2002, 43, 1735-
1738.
(2) Representative examples of the synthesis of unsaturated nitrogen-
containing heterocycles: (a) Overman, L. E.; Malone, T. C.; Meier, G.
P. J . Am. Chem. Soc. 1983, 105, 6993-6994. Overman, L. E.; Burk,
R. M. Tetrahedron Lett. 1984, 25, 5739-5742. Flann, C.; Malone, T.
C.; Overman, L. E. J . Am. Chem. Soc. 1987, 109, 6097-6107. Daub,
G. W.; Heerding, D. A.; Overman, L. E. Tetrahedron 1988, 44, 3919-
3930. Kværnø, L.; Norrby, P.-O.; Tanner, D. Org. Biomol. Chem. 2003,
1, 1041-1048. (b) Agami, C.; Comesse, S.; Kadouri-Puchot, C. J . Org.
Chem. 2002, 67, 2424-2428. (c) Ring-closing metathesis: Cooper, T.
S.; Larigo, A. S.; Laurent, P.; Moody, C. J .; Takle, A. K. Synlett, 2002,
1730-1732. Kumareswaran, R.; Hassner, A. Tetrahedron: Asymmetry
2001. 12, 2269-2276. (d) Chackalamannil, S.; Wang, Y. Tetrahedron
1997, 53, 11203-11210.
The silyl-Prins methodology could easily be adapted
for the preparation of enantiomerically pure products,
starting from either R- or S-propylene oxide. After
(3) Dobbs, A. P.; Martinovic´, S. Tetrahedron Lett. 2002, 43, 7055-
7057.
(4) Babu, G.; Perumal, P. T. Aldrichim. Acta 2000, 33, 16-22. Babu,
S. A. Synlett 2002, 531-532.
10.1021/jo034981k CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/06/2003
7880
J . Org. Chem. 2003, 68, 7880-7883

TABLE 1. Syn th esis of Dih yd r oth ia p yr a n s via th e
Silyl-P r in s Rea ction a
SCHEME 2
entry
R
R1
% yieldb
1
2
3
4
H
H
Me
Me
PhCH2
51
53
68
54
n-C5H11
PhCH2CH2
n-C5H11
a
Reaction conditions: aldehyde (typically 3 mmol), thiol (1
equiv), indium trichloride (1 equiv), CH2Cl2 (20 mL), reflux, 5-12
b
h. Yield of pure product after chromatographic separation; all
compounds gave satisfactory spectroscopic and analytical data.
but simple elevation of the reaction to reflux temperature
gave a smooth transformation to the dihydrothiapyran
product.
SCHEME 3
When the methyl-substituted thiol precursor is used,
the same cis-diastereoselectivity was observed as previ-
ously reported with the dihydropyran series.3 The selec-
tivity is believed to arise from a chair-like transition
state, with equatorially orientated substituents in the
developing six-membered ring. During NOE experiments,
significant enhancement of the C6 proton was observed
for both compounds (Table 1, entries 3 (4.4%) and 4
(3.1%)) on irradiation of the C2 proton.
Finally, attention was focused on the formation of
tetrahydropyridines. The indium trichloride mediated
cyclization of any of the amines 5 also failed to proceed
at room temperature or indeed at reflux temperature in
dichloromethane. The solvent was switched to the higher
boiling polar aprotic solvent, acetonitrile and the reaction
then proceeded smoothly in 3-24 h. Employing indium
trichloride as the Lewis acid gave significantly higher
yields than any alternative Lewis acid (boron trifluoride
etherate, trimethylsilyl triflate, or aluminum trichloride).
As reported with the oxygen series, an epoxide could
be substituted in place of the aldehyde. As with the
previous heterocycles, only a single diastereomer was
produced in each case, but surprisingly, NOE data
suggested that the tetrahydropyridines produced were
the trans diastereomers, i.e., there was complete reversal
of diastereocontrol compared to the alcohol and thiol
reactions. A 2.2% enhancement of the C6 methyl group
was observed on irradiation of the C2 proton, which
suggested that the methyl group was orientated axial in
these compounds, a finding confirmed by the X-ray
structure of 1-benzyl-2-methyl-6-phenyl-1,2,3,6-tetrahy-
dropyridine, 6 (Figure 2). The origin of the trans selectiv-
ity is believed to be unfavorable A1,3 interactions between
the N-alkyl group, the methyl group, and the R group
from the aldehyde. Similar NOE enhancements were
observed for each entry in Table 2.
epoxide ring-opening using lithium trimethylsilylacetyl-
ide/boron trifluoride etherate and subsequent reduction
with DIBAL-H, giving enantiomerically pure 1 (R ) Me),
the reaction sequence could be repeated in full without
racemization.5
Due to the easy preparation of the cyclization precur-
sors, it occurred to us that it might be possible to extend
this method to the synthesis of heterocycles other than
those containing oxygen. Therefore, the sulfur- and
nitrogen-containing analogues of 1 were prepared in good
yields. Mitsunobu reaction of 1 with thioacetic acid and
subsequent treatment with lithium aluminum hydride
gave 4-trimethylsilyl-3-butene-1-thiol in good yield over
the two steps. Alternatively, starting from the same
precursor 1, quantitative tosylation followed by displace-
ment with an amine gave a range of 4-trimethylsilyl-3-
butenyl-1-amines. The same two reaction sequences were
repeated starting from 4-pentyn-2-ol, to give the 2-meth-
yl-substituted homoallylic thiol and amines (Scheme 3).
Despite considerable current interest in sulfur-contain-
ing heterocycles and sugar analogues, methods for the
synthesis of dihydrothiapyrans and thiapyrans are rela-
tively rare.6 The method employed for dihydropyran
synthesis was slow with the thiols at room temperature,
In summary, we have developed a general and efficient
indium trichloride mediated route to a range of unsatur-
(6) (a) Lewis acid mediated synthesis of thiacyclohexanes: Yang,
X.-F.; Li, C.-J . Tetrahedron Lett. 2000, 41, 1321-1325. Yang, X.-F.;
Mague, J . T.; Li, C.-J J . Org. Chem. 2001, 66, 739-747. (b) Synthesis
of thiasugars: Fuzier, M.; Le Merrer, Y.; Depezay, J .-C. Tetrahedron
Lett. 1995, 36, 6443-6446. Le Merrer, Y.; Fuzier, M.; Dosbaa, I.;
Foglietti, M.-J .; Depezay, J .-C. Tetrahedron 1997, 53, 16731-16746.
(5) The absence of racemization was judged by NMR experiments
using Eu(hfc)3 doping and comparison with the racemic series, where
separation occurred.
J . Org. Chem, Vol. 68, No. 20, 2003 7881

3027 [Ar(CH)], 2970 (OCH), 1654 (CdC), 1598, 1495, 1449, 1388,
1183 (CO), 1086; δH (400 MHz; CDCl3) 7.19-7.39 (10H, m, Ar-
H), 5.77 (1H, m, C(4)H), 5.58 (1H, dt, J 10.3, 1.9, C(3)H), 4.87
(1H, m, C(2)H), 4.02 (1H, d, J 8.1, Ph2CH), 3.75 (1H, m, C(6)H),
1.95 (2H, m, C(5)H2), 1.23 (3H, d, J 6.4, C(6)CH3); δC (100 MHz;
CDCl3) 142.5 (Cipso), 142.0 (Cipso), 127.9-128.9 [overlapping 8 ×
(C-Ar), C(3)H], 126.3 (C(4)H), 126.1 (C-Ar), 125.9 (C-Ar), 77.3
(C(2)H), 70.3 (C(6)H), 56.3 (Ar2CH), 32.8 (C(5)H2), 21.7 (C(6)-
CH3); m/z (CI) 265 [(MH)+, 90], 247 [(MH)+ - H2O, 100]. Anal.
Calcd for C19H20O: C, 86.3; H, 7.6. Found: C, 86.3; H, 7.7.
(()-2â-Ben zh yd r yl-3r,4r-d ia cet oxy-6â-m et h ylt et r a h y-
d r op yr a n (3). (()-cis-2-Benzhydryl-6-methyl-5,6-dihydro-2H-
pyran (0.09 g, 0.3 mmol) was dissolved in acetone/water 2:1 (9
mL) and 4-methylmorpholine N-oxide added (0.09 g, 0.7 mmol,
2 equiv), followed by two crystals of osmium tetraoxide. The flask
was sealed with a stopper and the reaction mixture stirred for
48 h at room temperature. After this time, the reaction mixture
was cooled to 0 °C, saturated aqueous sodium bisulfite (6 mL)
was added, and the reaction mixture was allowed to warm to
room temperature. The aqueous layer was extracted with ethyl
acetate. The combined organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated in vacuo to give
(()-2â-benzhydryl-3R,4R-dihydroxy-6â-methyltetrahydropyran
(0.06 g, 61%), which was used without further purification. (()-
2â-Benzhydryl-3R,4R-dihydroxy-6â-methyltetrahydropyran (0.06
g) was dissolved in pyridine/DCM 1:1 (10 mL), acetic anhydride
was added (0.61 mL, 6.4 mmol, 16 equiv), and the reaction
mixture was stirred overnight (19 h). After this time, the reaction
mixture was quenched with saturated aqueous sodium hydrogen
carbonate solution (5 mL), the layers were separated, and the
aqueous layer was extracted with dichloromethane. The organic
layer was washed with 2 M hydrochloric acid and saturated
brine solution (10 mL) and dried over magnesium sulfate. The
solvent was removed in vacuo to give (()-2â-benzhydryl-3R,4R-
diacetoxy-6â-methyltetrahydropyran as colorless crystals (0.04
g, 57%; overall yield 35%): mp 144-146 °C (from hexane/diethyl
ether); found [M + H]+ 383.1851, C23H26O5 + H requires
383.1858; νmax/cm-1 (KBr) 3088, 3052, 3027 [Ar(CH)], 2883
(OCH), 1736, (CdO), 1598, 1495, 1449, 1367, 1137 (CO), 1055;
δH (400 MHz; CDCl3) 7.19-7.44 (10H, m, Ar-H), 5.40 (1H, m,
Ph2CH), 4.48 (2H, m, C(2)H, C(3)H), 4.09 (1H, m, C(4)H), 3.96
(1H, m, C(6)H), 2.11 (3H, s, OCOCH3), 1.96 (3H, s, OCOCH3),
1.79 (1H, m, C(5)HH), 1.58 (1H, m, C(5)HH), 1.20 (3H, d, J 6.2,
C(6)CH3); δC (100 MHz; CDCl3) 170.3 [Cquat(OCOCH3)], 169.6
[Cquat(OCOCH3)], 143.1 (Cipso), 139.7 (Cipso), 130.2 [overlapping
2 × C(Ar)], 128.7 [overlapping 2 × C(Ar)], 128.2 [overlapping 2
× C(Ar)], 128.0 [overlapping 2 × C(Ar)], 126.6 C(Ar), 126.2 C(Ar),
74.9 and 69.8 [C(3 and 2)H], 68.4 (C(6)H), 67.7 (Ph2CH), 51.1
(C(4)H), 37.4 (C(5)H2), 21.1 [overlapping C(3 and 4)CHOCOCH3],
20.8 [C(6)CH3]; m/z (CI) 383 [(MH)+, 5], 323 [(MH)+ - C2H4O2,
10], 263 [(MH)+ - 2 × (C2H4O2), 35], 245 [(MH)+ - C4H10O5,
25], 215 [(MH)+ - C6H16O5, 25], 143 [(MH)+ - C12H16O5, 100].
Anal. Calcd for C23H26O5: C, 72.2; H, 6.8. Found: C, 72.3; H,
6.8.
F IGURE 2. Typical NOE and X-ray crystallographic data for
trans-tetrahydropyridines obtained from InCl3-mediated cy-
clizations.
TABLE 2. Syn th esis of Tetr a h yd r op yr id in es via th e
Silyl-P r in s Rea ction a
entry
R
R2
Bn
Bn
Ph
n-Pr
Bn
Bn
n-Pr
n-Pr
R1
PhCH2
styrene oxide
n-C5H11
PhCH2
% yieldb
1
2
3
4
5
6
7
8
H
H
H
H
Me
Me
Me
Me
95
79
94
55
68
70
73
85
PhCH2
n-C5H11
n-C5H11
PhCH2
a
Reaction conditions: aldehyde (typically 1 mmol), amine (1
equiv), indium trichloride (1 equiv), acetonitrile (20 mL), reflux,
b
5-24 h. Yield of pure product after chromatographic separation;
all compounds gave satisfactory spectroscopic and analytical data.
ated heterocycles, starting from a common precursor and
employing a mild Lewis acid. The heterocycles produced
may contain oxygen, sulfur, or nitrogen and are obtained
in excellent diastereoselectivities; as such, we believe this
will become a highly efficient and widely applicable
methodology. Extensions of this methodology to more
highly substituted ring systems and to an asymmetric
version and the application of these combined features
to the total synthesis of various natural products will be
the subject of future publications.
Typ ica l Exp er im en ta l P r oced u r e for th e Syn th esis of
cis-Dih yd r oth ia p yr a n s. Indium chloride (1 mmol) was added
to a solution of aldehyde (1 mmol) in dry dichloromethane (20
mL), under an atmosphere of nitrogen, and the reaction mixture
was stirred for 1 h. After this time, the homoallylic thiol (1 mmol)
was added and the reaction mixture stirred at reflux tempera-
ture for a further 5-16 h. The reaction was monitored by TLC.
Upon completion, the reaction mixture was cooled and quenched
with distilled water (10 mL). The water layer was extracted with
dichloromethane and the combined organic layer dried with
magnesium sulfate. The solvent was removed in vacuo and the
reaction mixture purified by flash column chromatography
(hexane/diethyl ether 10:1) affording the cyclization product as
an oil.
Typ ica l Exp er im en ta l P r oced u r e for th e Syn th esis of
tr a n s-Tetr a h yd r op yr id in es. The secondary amine (1.0 mmol)
was added dropwise to a solution of indium trichloride (221 mg,
1.0 mmol) and an aldehyde (1.0 mmol) in anhydrous acetonitrile
(20 mL) at reflux. Once the reaction was completed (monitored
by TLC), the solution was cooled and concentrated and the
Exp er im en ta l Section
(()-cis-2-Ben zh yd r yl-6-m eth yl-5,6-d ih yd r o-2H-p yr a n (2).
Indium(III) chloride (0.44 g, 2 mmol) was added to diphenylac-
etaldehyde (1 equiv, 0.39 g, 2 mmol) dissolved in dry DCM (20
mL) under an atmosphere of nitrogen, and the resulting solution
was stirred for 1 h. After this time, (Z)-5-trimethylsilylpent-4-
en-2-ol (1 equiv, 0.32 g, 2 mmol) was added, and the reaction
mixture was stirred at room temperature for a further 16 h. The
reaction mixture was then quenched with distilled water (10
mL), and the water layer was extracted with dichloromethane.
The combined organic extracts were dried with magnesium
sulfate. The solvent was removed in vacuo and the reaction
mixture purified by flash column chromatography (hexane/
diethyl ether 10:1) to give the title compound isolated as a
colorless solid (0.41 g, 78%): Rf 0.43 (petroleum ether/diethyl
ether 10:1); mp 75-77 °C (from petroleum ether); found [M +
H]+ 265.1590, C19H20O + H requires 265.1592; νmax/cm-1 (KBr)
7882 J . Org. Chem., Vol. 68, No. 20, 2003

residue obtained partitioned between dichloromethane and 1 M
NaOH. The aqueous layer was extracted with dichloromethane,
and the combined organic layers were washed with 1 M NaOH
and water, dried (MgSO4), and concentrated under reduced
pressure. The residue obtained was then purified by flash
chromatography to give the corresponding tetrahydropyridine.
tallography Service (Southampton) for structure deter-
mination and the EPSRC Mass Spectrometry Service
(Swansea) for some mass spectral data.
Su p p or tin g In for m a tion Ava ila ble: Representative ex-
perimental procedures; characterization and spectral data for
compounds 2-4 and 6 and those in Tables 1 and 2; crystal-
lographic data for compounds 3 and 6 (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. We thank the University of
Exeter (studentship to S.J .J .G.), CVPC (ORS award to
S.M.), and The Royal Society (small equipment grant)
for funding. We also thank the EPSRC National Crys-
J O034981K
J . Org. Chem, Vol. 68, No. 20, 2003 7883