- Email: [email protected]
Synthesis of medium size rings containing oxygen and sulfur by ring expansion of halodioxolanes, dioxanes and oxathiolanes
Synthesis of Medium Size Rings Containing Oxygen and Sulfur by Ring Expansion of Haiodioxolanes, Dioxanes and Oxathiolanes James J. De Yom and Zhibua Sui*f
Smprisiagly, we also found that dioxaner and dioxolanes (1, Z = 0) undergo analogous ring expansion rcBctiolls (Scheme 1). Although the conditions necessary for the oxygen xing expansion an harsher than those employed~thelrUlCtiOIlOfdle~kisStillagtlltralneactionasshowninTablel(Entries610).
Thus.
nfl~the~s(l,Z=O)ovwnightiaDMFinthtpresenoeddfiroplopylethylamine~,infairO good yield, to the dioxacycloalkenes (2.2 = 0). For the chIo&etals
(1, Z = 0, X = Cl) it was necessary to
addpotassiumiodideasacatalyst. Table 1. Ring &pa&m EmpChpd
of Various Halo Oxathiolaaes, Dioe
R
n
m
X
Z
Ph
0
2
cl
s
Ph
0
2
cl
s
Ring
and Dioxanes. Product
Yieldb (‘fib)
8
Z-2a
82
8
Z-2b
80
Size 1
2c 3a 4
la lb lc Id
Ph
0
2
Q
S
8
Z-2c
78
p-FPh
0
2
Cl
0
8
Z-2d
86
5
le
Ph
0
2
Cl
0
8
Z-2e
55e
6
If
Ph
0
3
Br
0
9
Z-2f
24f
7 8
lg lh
Ph
1
3
cl
0
10
z-2g
6oc
Ph
1
2
cl
0
9
Z-2h
9
li
ma2
0
3
Q
0
9
z-&
50 37f*
10
lj
PhCH2
1
3
Q
0
10
exo 21 z- &
38fa
aF’or entry 1 and 4-10 R’ = R” = H. bwlated yield. CR’ = H: R” = w. dw s r-Butyldimethyl&qmethyl: R” = EL CEFydrolysis of the ring cxpwialpmdllc~wasabavedin-20% yield. fHlMoat&n of hydmga b&e and the ring tkagmenmdon pmducv (4) were obaawd dioxa~ycl~n~nanein 10% overall yield tim 11. bIscdated yield of reduced
We believe that the mechanism of this reaction is analogous to that of the sulfur ring expansion.4 Thus, intramolecular alkylation of one of the oxygen atoms by the primary halide yields an oxo&um intermediate (Scheme 1,3) which fragments to the dioxacycloalkenes (Scheme 1) with overall loss of the hydrogen haIide. As was the case in the sulfur ring expansion we also occasionally isolated the ring fragmentation products (4). These may arise f&m an alternative breakdown of the oxonium intermdiatc
3, and so lend support to our
postulatedm&auism. When the ketal is formed from an alkyl ketone (e.g. 1i.j) both enda and cxo double bond isomers result. Inordertosimplifytheanalysisofthesereactions,thccndcringe~~~wae~~totbe -ding
saturated cyclic ethers. Conventional magents such as Hz/pd and aiethylsilan&&omacetic
failed to give the de&&
acid
products. However, reaction with sodium cyanoborohydridc/ tritluoroacetic acid in
51
O-+PC
NaBH&N -
TFA
PhU
n - 0.1 !icheme2
Tablelalsoindicaaesthatbree~ofadiaxolaaewithafourcarbon~chaingivesa~yield (enaies 6 and 9) than all other combinations.
Consistently more elhnination of the halide to give the
cotresponding termhml alkene is also seen in these reactions. This partitioning into other pathwaysis perhaps due to two unfavorable effects that occur in this type of ketal. First, the intermediate oxonium ion requites the formation of a six memhemd ring which would occur mote slowly than the comsponding five memheted ring. Secondly, the lone pairs on the oxygens of a dioxolane may have less p chamcter, and so he less mtcleophilic. thanthoseofadioxanebecauseofchangesinorbitslmixingto
accommodate the different ring angles. Such an
explanation has been suggested to account for the differences in complex formation of tetrshydrofuran and tetrahydropyran with dimethylziuc.7 The dioxolan~
sidechain system is the only one in which both effects
occur, allowing other pathways such as elimination to compete with ring expansion. In summary, we have inuoduced novel methodology Earthe conversion ofoxathioketaIsandketslsiuto medium sixed heterocycles containing two heteroatoms.
The reaction occurs in fair to good yields under
relatively mild conditions. The scope and utility of this reaction, as well as the synthetic transformations of the produced hetemcycks, are currently being investigated. Gcnerul Procedure for Oxygen Ring Expansion.
Diisopropylethylsmine
(5 mmol) was added to a
solution of the haloketal(1 mmol) in dry DMF (5 ml) and the solution stirred under reflux for 16 h. (For chloroketsls, catalytic potassium iodide (1 mmol) was added to the reaction.)
After cooling, water and ether
were added. The orgsnic phase was separated washed with brine and dried over MgSO4. After evaporation of the solvent, the residue was purified by flash column chromatography (silica gel, typical eluent: hexane:ethyl acetate = 9:l).
All products had physical data (NMR (lH and %),
MWHRMS and/a elemental analysis)
consistent with the assigned structures. Reducrion of rk CycbdhwuZkenes.
To a ‘IFIF solution (10 ml) of the crude ring expansion product
(from 1 mmol of the corresponding haloketat) and sodium qanokuohydride
(5 mmol), trifluoroacetic acid (10
52
mmol)wasaddaislowlyat
0°C. lllcmixtumwasstimdatmxnntcm~ovcmightanddilutcdwithcthcr*
washefIwithtKduttlbicathxme and brim. and driedover Mgs04.
After Eve
of tk SolvelItthe dduc
waspurifidbycolumn~atogIapily.
AckmowMgement. rnstitum ofHdtb
The wthars thank Dr. F%ulOaiz de Mona&no
hr his encoumgunentand National
Gtant GM39552 fm financialsuppa
REFERENCES
AND NOTES
1.
Illuminati. G.; Mandolini. L. Act. C&em. Res. 19Sl. 14.95-102.
2.
Fduhop. J.; penzlin, G. Orgadc SyiuhesisConcepts,Metha&, Stan@
3.
Hcsse, M. Ring Rnlargement in Organic Chemistry; Vedag Chcmic: Wcinheim. 1991.
4.
Sui, Z., Furth, P. S., De Vow; J. J. J. Org. Chem. 1992,57,
5.
a. Qika, M.; Nemoto, T.; Yamada, K. Tetrahedron Later8 19!&34,3461-3462,
Materials Vdag
Chnk
Weinheim, 1983, pp. 80-82. 6658-6662.
b. Naetc. hi.; Gondlez, A. G.; Cataldo, F.; Roddgucz. M. L.; Brim 1. Tetrahedron 199k47.941 9418; c. Notaro, CL; Piccialli, V.; Sica, D. J. Nat. Prod. 1992.55.626-632.
6.
lllcprocedmdcscribcdinfcf.4wasuscd.
7.
Sea&a, S. Jr.; Tamres, M Baskity and ComplexingAbility of Ethersin The Chemistry of the Ether
Linkage; Mai S. E& Intasiena
Publishers:New York, 1967; pp. 295-297.
(Received in USA 1 September 1993; revised 8 October 1993;accepted 25 October 1993)
l-
Smprisiagly, we also found that dioxaner and dioxolanes (1, Z = 0) undergo analogous ring expansion rcBctiolls (Scheme 1). Although the conditions necessary for the oxygen xing expansion an harsher than those employed~thelrUlCtiOIlOfdle~kisStillagtlltralneactionasshowninTablel(Entries610).
Thus.
nfl~the~s(l,Z=O)ovwnightiaDMFinthtpresenoeddfiroplopylethylamine~,infairO good yield, to the dioxacycloalkenes (2.2 = 0). For the chIo&etals
(1, Z = 0, X = Cl) it was necessary to
addpotassiumiodideasacatalyst. Table 1. Ring &pa&m EmpChpd
of Various Halo Oxathiolaaes, Dioe
R
n
m
X
Z
Ph
0
2
cl
s
Ph
0
2
cl
s
Ring
and Dioxanes. Product
Yieldb (‘fib)
8
Z-2a
82
8
Z-2b
80
Size 1
2c 3a 4
la lb lc Id
Ph
0
2
Q
S
8
Z-2c
78
p-FPh
0
2
Cl
0
8
Z-2d
86
5
le
Ph
0
2
Cl
0
8
Z-2e
55e
6
If
Ph
0
3
Br
0
9
Z-2f
24f
7 8
lg lh
Ph
1
3
cl
0
10
z-2g
6oc
Ph
1
2
cl
0
9
Z-2h
9
li
ma2
0
3
Q
0
9
z-&
50 37f*
10
lj
PhCH2
1
3
Q
0
10
exo 21 z- &
38fa
aF’or entry 1 and 4-10 R’ = R” = H. bwlated yield. CR’ = H: R” = w. dw s r-Butyldimethyl&qmethyl: R” = EL CEFydrolysis of the ring cxpwialpmdllc~wasabavedin-20% yield. fHlMoat&n of hydmga b&e and the ring tkagmenmdon pmducv (4) were obaawd dioxa~ycl~n~nanein 10% overall yield tim 11. bIscdated yield of reduced
We believe that the mechanism of this reaction is analogous to that of the sulfur ring expansion.4 Thus, intramolecular alkylation of one of the oxygen atoms by the primary halide yields an oxo&um intermediate (Scheme 1,3) which fragments to the dioxacycloalkenes (Scheme 1) with overall loss of the hydrogen haIide. As was the case in the sulfur ring expansion we also occasionally isolated the ring fragmentation products (4). These may arise f&m an alternative breakdown of the oxonium intermdiatc
3, and so lend support to our
postulatedm&auism. When the ketal is formed from an alkyl ketone (e.g. 1i.j) both enda and cxo double bond isomers result. Inordertosimplifytheanalysisofthesereactions,thccndcringe~~~wae~~totbe -ding
saturated cyclic ethers. Conventional magents such as Hz/pd and aiethylsilan&&omacetic
failed to give the de&&
acid
products. However, reaction with sodium cyanoborohydridc/ tritluoroacetic acid in
51
O-+PC
NaBH&N -
TFA
PhU
n - 0.1 !icheme2
Tablelalsoindicaaesthatbree~ofadiaxolaaewithafourcarbon~chaingivesa~yield (enaies 6 and 9) than all other combinations.
Consistently more elhnination of the halide to give the
cotresponding termhml alkene is also seen in these reactions. This partitioning into other pathwaysis perhaps due to two unfavorable effects that occur in this type of ketal. First, the intermediate oxonium ion requites the formation of a six memhemd ring which would occur mote slowly than the comsponding five memheted ring. Secondly, the lone pairs on the oxygens of a dioxolane may have less p chamcter, and so he less mtcleophilic. thanthoseofadioxanebecauseofchangesinorbitslmixingto
accommodate the different ring angles. Such an
explanation has been suggested to account for the differences in complex formation of tetrshydrofuran and tetrahydropyran with dimethylziuc.7 The dioxolan~
sidechain system is the only one in which both effects
occur, allowing other pathways such as elimination to compete with ring expansion. In summary, we have inuoduced novel methodology Earthe conversion ofoxathioketaIsandketslsiuto medium sixed heterocycles containing two heteroatoms.
The reaction occurs in fair to good yields under
relatively mild conditions. The scope and utility of this reaction, as well as the synthetic transformations of the produced hetemcycks, are currently being investigated. Gcnerul Procedure for Oxygen Ring Expansion.
Diisopropylethylsmine
(5 mmol) was added to a
solution of the haloketal(1 mmol) in dry DMF (5 ml) and the solution stirred under reflux for 16 h. (For chloroketsls, catalytic potassium iodide (1 mmol) was added to the reaction.)
After cooling, water and ether
were added. The orgsnic phase was separated washed with brine and dried over MgSO4. After evaporation of the solvent, the residue was purified by flash column chromatography (silica gel, typical eluent: hexane:ethyl acetate = 9:l).
All products had physical data (NMR (lH and %),
MWHRMS and/a elemental analysis)
consistent with the assigned structures. Reducrion of rk CycbdhwuZkenes.
To a ‘IFIF solution (10 ml) of the crude ring expansion product
(from 1 mmol of the corresponding haloketat) and sodium qanokuohydride
(5 mmol), trifluoroacetic acid (10
52
mmol)wasaddaislowlyat
0°C. lllcmixtumwasstimdatmxnntcm~ovcmightanddilutcdwithcthcr*
washefIwithtKduttlbicathxme and brim. and driedover Mgs04.
After Eve
of tk SolvelItthe dduc
waspurifidbycolumn~atogIapily.
AckmowMgement. rnstitum ofHdtb
The wthars thank Dr. F%ulOaiz de Mona&no
hr his encoumgunentand National
Gtant GM39552 fm financialsuppa
REFERENCES
AND NOTES
1.
Illuminati. G.; Mandolini. L. Act. C&em. Res. 19Sl. 14.95-102.
2.
Fduhop. J.; penzlin, G. Orgadc SyiuhesisConcepts,Metha&, Stan@
3.
Hcsse, M. Ring Rnlargement in Organic Chemistry; Vedag Chcmic: Wcinheim. 1991.
4.
Sui, Z., Furth, P. S., De Vow; J. J. J. Org. Chem. 1992,57,
5.
a. Qika, M.; Nemoto, T.; Yamada, K. Tetrahedron Later8 19!&34,3461-3462,
Materials Vdag
Chnk
Weinheim, 1983, pp. 80-82. 6658-6662.
b. Naetc. hi.; Gondlez, A. G.; Cataldo, F.; Roddgucz. M. L.; Brim 1. Tetrahedron 199k47.941 9418; c. Notaro, CL; Piccialli, V.; Sica, D. J. Nat. Prod. 1992.55.626-632.
6.
lllcprocedmdcscribcdinfcf.4wasuscd.
7.
Sea&a, S. Jr.; Tamres, M Baskity and ComplexingAbility of Ethersin The Chemistry of the Ether
Linkage; Mai S. E& Intasiena
Publishers:New York, 1967; pp. 295-297.
(Received in USA 1 September 1993; revised 8 October 1993;accepted 25 October 1993)
l-