Intramolecular nucleophilic substitution at the C-4 position of functionalized oxetanes: A ring expansion for the construction of various heterocycles

Full text of DOI:10.1021/jo961436t

7642
J . Org. Chem. 1996, 61, 7642-7643
Sch em e 1
In tr a m olecu la r Nu cleop h ilic Su bstitu tion
a t th e C-4 P osition of F u n ction a lized
Oxeta n es: A Rin g Exp a n sion for th e
Con str u ction of Va r iou s Heter ocycles†
Sch em e 2a
Thorsten Bach* and Kristian Kather
Organisch-Chemisches Institut der Westfa¨lischen
Wilhelms-Universita¨t Mu¨nster, D-48149 Mu¨nster, Germany
Received J uly 30, 1996
The intramolecular ring opening of epoxides by het-
eroatom nucleophiles has been frequently exploited for
the construction of five- and six-membered heterocycles.1,2
Depending on the substitution pattern, the reaction
conditions, and the length of the side chain the nucleo-
philic attack occurs in an exo1 or endo2 fashion. Contrary
to that, similar ring expansion reactions of oxetanes have
been rarely observed. Monosubstituted oxetanes can be
ring-opened intramolecularly by carbon nucleophiles.3 A
Lewis acid-mediated intramolecular ring opening of
monosubstituted oxetanes has also been reported.4 In
systems in which the stereochemical array enables a
facile approach SN2-type reactions of oxygen nucleophiles
have been described.5 An SN1-type substitution has been
achieved at the higher substituted position of an oxet-
ane.6 Moreover, 2-oxetanones (â-lactones) have been
used extensively for ring expansions.7 In this case the
â-cleavage is facilitated by the acyloxy leaving group.
We have recently shown that 2-aryl-3-(silyloxy)oxet-
anes are readily obtained in diastereomerically pure form
by the photocycloaddition of silyl enol ethers and aro-
matic aldehydes.8 Our plan was to use these products
as substrates for ring expansion reactions, and we
speculated that the preferred site of attack for a strong
nucleophile should be the least crowded carbon atom C-4
(Scheme 1).
a
Reagents and conditions: (a) MeLi, 25 °C (Et2O); (b) PPh3,
DEAD, 25 °C (THF).
tive group (Piv) can be readily removed upon treatment
with MeLi in Et2O at ambient temperature to yield the
alcohols 2a and 2b, which in turn were converted to the
oxetanes 3 and 5 (Scheme 2), which carry sulfur- and
nitrogen-based nucleophiles. The Mitsunobu reaction
with thiolacetic acid proceeded cleanly according to the
modified procedure of Volante.10 For the construction of
oxetane 5 we initially used the tert-butyloxycarbonyl
(Boc)-protected p-toluenesulfonamide (HNBocTs) de-
scribed by Weinreb et al.11 to introduce the amide.
Cleavage of the Boc-group in the presence of the (silyl-
oxy)oxetane moiety proved difficult, however. Only the
thermal deprotection12 (185 °C, 30 min, Ar) gave the
desired compound 5. Unfortunately, this method proved
to be not very reliable for this particular example as the
yields varied considerably (55% at best) and the isolation
of pure material was complicated by several byproducts.
A better solution was found by employing the 9-fluore-
nylmethyloxycarbonyl (Fmoc)-protected amide 4.13 To
our surprise, its reaction with alcohol 2a gave directly
the desired oxetane 5. Although we have not yet made
an effort to elucidate what causes the cleavage of the
Fmoc-group under Mitsunobu conditions, the amide 4
appears to be a generally useful substitute for TsNH2.
The ring-opening experiments were conducted upon in
situ generation of the corresponding heteroatom anion.
In the case of oxetanes 1 and 3 the acyl protective group
was removed with MeLi in dimethoxyethane (DME), and
the reaction mixture was subsequently heated to induce
the nucleophilic substitution.14 As Table 1 reveals, the
best result was obtained with a sulfur nucleophile
forming a six-membered ring (Table 1, entry 3). The
corresponding thiotetrahydropyran 7a (91%) was isolated
in diastereomerically pure form (Scheme 3). In none of
the described experiments was an epimerization to be
detected. Starting from compound 1a the analogously
liberated oxygen nucleophile yielded tetrahydropyran 6a .
The known oxetanes 1a 8b and 1b9 already bear a side
chain with a latent oxygen nucleophile and served as a
versatile entry for other substrates. The pivaloyl protec-
† This paper is dedicated to Professor Rolf Gleiter on the occasion
of his 60th birthday.
(1) Some selected examples of an exo ring opening by heteroatom
nucleophiles follow. (a) N-Nucleophiles: Kozikowski, A. P.; Schmiesing,
R. J . Chem. Soc., Chem. Commun. 1979, 106. Tanner, D.; Somfai, P.
Tetrahedron Lett. 1985, 26, 3883. McIntosh, J . M.; Matassa, L. C. J .
Org. Chem. 1988, 53, 4452. Pearson, W. H.; Bergmeier, S. C. ibid. 1991,
56, 1976. (b) O-Nucleophiles: Kitamura, M.; Isobe, M.; Ichikawa, Y.;
Goto, T. J . Am. Chem. Soc. 1984, 106, 3252. Corey, E. J .; Ha, D.-C.
Tetrahedron Lett. 1988, 29, 3171. Paterson, I.; Craw, P. A. Ibid. 1989,
30, 5799.
(2) Some selected examples of an endo ring opening by heteroatom
nucleophiles follow. (a) N-Nucleophiles: Setoi, H.; Takeno, H.; Hash-
imoto, M. Tetrahedron Lett. 1985, 26, 4617. Ratovelomanana, V.; Vidal,
L.; Royer, J .; Husson, H.-P. Heterocycles 1991, 32, 879. (b) O-
Nucleophiles: Chmielewski, M.; Guzik, P. Heterocycles 1984, 22, 7.
Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. J . Am.
Chem. Soc. 1989, 111, 5330.
(3) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1984, 25, 4549.
(4) Itoh, A.; Hirose, Y.; Kashiwagi, H.; Masaki, Y. Heterocycles 1994,
38, 2165.
(5) Danishefsky, S. J .; Masters, J . J .; Young, W. B.; Link, J . T.;
Snyder, L. B.; Magee, T. V.; J ung, D. K.; Isaacs, R. C. A.; Bornmann,
W. G.; Alaimo, C. A.; Coburn, C. A.; Di Grandi, M. J . J . Am. Chem.
Soc. 1996, 118, 2843.
(6) Khan, N.; Morris, T. H.; Smith, E. H.; Walsh, R. J . Chem. Soc.,
Perkin Trans. 1 1991, 865.
(10) Volante, R. P. Tetrahedron Lett. 1981, 22, 3119.
(11) Henry, J . R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.;
Harris, G. D., J r.; Weinreb, S. M. Tetrahedron Lett. 1989, 30, 5709.
(12) Rawal, V. H.; J ones, R. J .; Cava, M. P. J . Org. Chem. 1987, 52,
19.
(13) The amide 4 was prepared from TsNCO and 9-fluorenylmetha-
nol (solvent: toluene; 93% yield) in full analogy to a previously
described procedure (cf. ref 11).
(7) (a) Mead, K. T.; Yang, H.-L. J . Org. Chem. 1990, 55, 2991. (b)
Mead, K. T.; Lu, J . Tetrahedron Lett. 1994, 35, 8947.
(8) (a) Bach, T.; J o¨dicke, K. Chem. Ber. 1993, 126, 2457. (b) Bach,
T. Liebigs Ann. 1995, 855 and references cited therein.
(9) Kather, K. Ph.D. thesis, University of Mu¨nster, 1996. Starting
from ethyl 5-oxohexanoate the procedure is identical to the one
employed for the construction of oxetane 1a (cf. ref 8b).
S0022-3263(96)01436-3 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 22, 1996 7643
Sch em e 4a
Ta ble 1. Rin g Op en in g of Oxeta n es w ith Va r iou s
In tr a m olecu la r Nu cleop h iles
timea
(h) product
yieldb
(%)
entry oxetane
n
X
PG reagent
1
2
3
4
5
1a
1b
3a
3b
5
1
2
1
2
1
O
O
S
S
Piv MeLi
Piv MeLi
Ac MeLi
Ac MeMgBr
6
5
4
5
5
6a
6b
7a
7b
8
54
91
54
52
NTs
H
MeMgBr
a
Time required for complete conversion at reflux in DME (cf.
typical procedure14). Refers to isolated yield of analytically pure
b
product.
Sch em e 3
a
Reagents and conditions: (a) PivCl, NEt3, DMAP, 25 °C
(CH2Cl2); (b) LDA, TMSCl, -78 f 25 °C (THF); (c) PhCHO, hν,
30 °C (PhH); (d) MeLi, 25 f 85 °C (DME); (e) MeMgBr, 25 f 85
°C (DME).
If oxetane 1b was used as precursor the reaction failed
and the seven-membered ring was not formed. Prolonged
heating gave decomposition products that arise most
likely from oxetane fragmentation. Nitrogen nucleo-
philes were generated from oxetane 5 by deprotonation.
The choice of the counterion appears to be crucial for the
success of the ring opening. Whereas lithium (MeLi in
DME) and sodium (NaH in DMF) failed to induce a
reaction the magnesium amide generated with MeMgBr
in DME yielded the desired piperidine 8 (Table 1, entry
5).15 Obviously, the magnesium ion activates the ether
bond by complexation to the oxetane oxygen. The same
effect was advantageously employed in the case of the
seven-membered thiepane 7b, which was formed in low
yield (16%) by treating compound 3b with MeLi in DME
and subsequent reflux. Repeating the procedure with
MeMgBr as reagent gave the desired heterocycle in 54%
yield (Table 1, entry 4).
phile we prepared the diastereomerically pure oxetane
10 from 2-hydroxyacetophenone (9).8a Due to the cis-
arrangement of the enolate in the aromatic side chain
this substrate seems to be predisposed toward an effec-
tive ring expansion. Indeed, treatment of compound 10
with MeLi in DME and subsequent reflux yielded the
desired diol 11 in combination with its monosilylated
derivative 12. MS data clearly revealed that the silyl
group had migrated and was found at the least hindered
position. Contrary to that, the analogous procedure
conducted with MeMgBr in DME gave directly the
benzofuran 13. There is no indication that a silyl shift
occurs. The only byproduct found is the alcohol 14 in
which the tertiary alcohol is still silyl-protected. This
observation helps to explain why the elimination in the
latter example is so facile. The silyl ether 14 is prone to
an elimination by an E1cB- or an E2-mechanism, whereas
the alkoxide formed from compound 11 or 12 will not be
able to react along this pathway. In a control experiment
the diol 11 was subjected to the reaction conditions of
the MeMgBr-initiated ring opening. No elimination
product was observed.
The regiochemistry of the ring opening was docu-
1
mented by H-NMR studies of the heterocyclic diols in
d6-DMSO. One of the alcohol OH protons appears as a
singlet and the other as a doublet. If the ring opening
had occurred at C-2 a tertiary (singlet) and a primary
(triplet) alcohol would have been expected. In some
instances, O-silyl-protected products were also obtained
in minor amounts. They could be quantitatively con-
verted to the diols by treatment with K2CO3 in MeOH.16
In order to test a phenolate as intramolecular nucleo-
In summary, the intramolecular ring opening of dias-
tereomerically pure oxetanes leads to several interesting
heterocycles that bear a side chain in the 3-position. In
the described cases a diol unit is established at this site.
An extension to other functionalized oxetanes is pro-
jected. Further studies are directed toward this goal and
toward the application of this methodology to the syn-
thesis of biologically relevant compounds.
(14) Typical procedure: To a stirred solution of 0.9 mmol of oxetane
3a (315 mg) in 15 mL of DME was added 1.4 mL of a 1.6 M solution
of MeLi (2.3 mmol) in Et2O by syringe at ambient temperature. The
mixture was stirred for 1 h at room temperature and subsequently
heated to reflux for 4 h. After that time, 0.3 mL of a saturated NH4Cl
solution was added. Upon dilution with ether (20 mL) Na2SO4 was
added, and the mixture was filtered. After evaporation of the solvent
in vacuo the crude product was treated with 10 mL of a saturated
solution of K2CO3 in MeOH at room temperature. As soon as the
desilylation was complete (1 h), the mixture was diluted with water.
Solid NaCl was added until the solution was saturated. After extraction
with CH2Cl2 (3 × 50 mL), the combined organic layers were dried over
Na2SO4. Filtration and solvent removal gave 281 mg of crude material,
which was purified by flash chromatography (eluent: cyclohexane/ethyl
acetate ) 85/15). The desired compound 7a was obtained as a colorless
oil (183 mg, 91%). The same procedure was followed while working
with MeMgBr as nucleophile/base. A 3.0 M solution in Et2O was used.
If no silylated product was detected by TLC and NMR the desilylation
procedure was omitted.
Ack n ow led gm en t. This work was generously sup-
ported by the Deutsche Forschungsgemeinschaft (Ba
1372/1-2), by the Fonds der Chemischen Industrie, and
by the Gesellschaft zur Fo¨rderung der Westfa¨lischen
Wilhelms-Universita¨t. We thank Prof. Dr. D. Hoppe for
his continuing support.
Su p p or tin g In for m a tion Ava ila ble: Procedures and
analytical data (NMR, MS) for compounds 2, 3, 5-8, 10-13
(14 pages).
J O961436T
(15) For the biological relevance of closely related compounds, see:
Hite, G.; Lokhandwala, M.; Patel, D. B.; Patel, H.; Merker, P. C.;
Shafi’ee, A. J . Pharm. Sci. 1971, 60, 685.
(16) Hurst, D. T.; McInnes, A. G. Can. J . Chem. 1965, 43, 2004.