Cyclopentyl and carbohydrate derivatives of N-hydroxy-4-methylthiazole-2(3H)-thione: Synthesis by Mitsunobu reaction and highly selective photochemical conversion into aldehydes

Article abstract of DOI:10.1055/s-2001-14598

Substituted N-cyclopentoxy- and carbohydrate-derived thiazole-2(3H)-thiones 3 were prepared from alcohols 2 or from 2,3:5,6-di-O-isopropylidene mannose in the presence of PPh ₃, diethyl azodicarboxylate (DEAD), and N-hydroxy-4-methylthiazole-2(3H)-thione (1). Alkoxyl radical precursors 3 were photoreacted with hydrogen atom donors to afford substituted aldehydes 7 or formyl esters 10-11 via highly regioselective alkoxyl radical fragmentations.

Full text of DOI:10.1055/s-2001-14598

LETTER
749
Cyclopentyl and Carbohydrate Derivatives of N-Hydroxy-4-methyl-
thiazole-2(3H)-thione: Synthesis by Mitsunobu Reaction and Highly Selective
Photochemical Conversion into Aldehydes
Jens Hartung,* Thomas Gottwald, Rainer Kneuer
Institut für Organische Chemie, Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
Fax +49 (0)931/888 4606; E-mail: hartung@chemie.uni-wuerzburg.de
Received 2 April 2001
is used as solvent (Table 1, entry 1).8 Neither a change in
Abstract: Substituted N-cyclopentoxy- and carbohydrate-derived
solvents to CH2Cl2, THF, or CH3NO2, nor the use of diiso-
propyl azodicarboxylate or bis(1,1,1-trichloro)ethyl
azodicarboxylate led to an improvement of yields for
thiazole-2(3H)-thiones 3 were prepared from alcohols 2 or from
2,3:5,6-di-O-isopropylidene mannose in the presence of PPh3, di-
ethyl azodicarboxylate (DEAD), and N-hydroxy-4-methylthiazole-
2(3H)-thione (1). Alkoxyl radical precursors 3 were photoreacted thione 3a. A comparison with the hitherto "best yield"
with hydrogen atom donors to afford substituted aldehydes 7 or
(87%) for the synthesis of N-cyclopentoxythiazolethione
formyl esters 10 11 via highly regioselective alkoxyl radical frag-
3a from cyclopentyl tosylate in a phase transfer-catalyzed
mentations.
alkylation of 19 indicates that the new method is highly
Key words: alkoxyl radical, carbohydrate, -cleavage, Mitsunobu
reaction, thiazolethione
competitive and certainly more convenient since it safes
an additional step.10
The unsubstituted cyclopentoxyl radical undergoes a regi-
Table 1 Synthesis of N-Alkoxy-4-methylthiazole-2(3H)thiones 3
under Mitsunobu Conditions
oselective -C C cleavage which leads to the -formyl-
butyl radical.1 It is a reversible reaction with the
equilibrium shifted towards the acyclic intermediate since
the cyclopentane ring strain of ~ 26 kJ mol−1 is relieved by
the ring opening reaction and a strong C O -bond is
formed at the expense of a C C -bond. The kinetics of
this radical rearrangement have been thoroughly investi-
gated by Beckwith and Hay.2 In open chain alkoxyl radi-
cals the regioselectivity of -C C cleavage is generally
governed by thermochemical effects. According to theo-
retical studies by Houk et al. the same guidelines should
apply for cyclic systems.3 Experimental evidences for
such radical based transformations under neutral (i.e. non
oxidative) conditions, however, are rare in the literature.4
Selected examples of ring opening reactions of anomeric
oxyl radicals have only recently been been studied by
Suárez et al.5 In view of this issue we have addressed two
aspects of oxygen radical induced C C-cleavages: (i) a
versatile and short access to substituted N-cyclopentoxy-
4-methylthiazolethiones 3 as alkoxyl radical precursors
(Table 1) and (ii) a concise study on the regioselectivity of
-C C fission in substituted cyclopentoxyl radicals and in
carbohydrate-derived radicals (Table 2).
Besides cyclopentanol (1a), 1,2-trans-disubstituted deriv-
atives 2b and 2c were reacted with DEAD, PPh3 and acid
1 in benzene to afford the corresponding diastereomeri-
cally pure cis-substituted N-cyclopentoxy-substituted
We have applied the Mitsunobu-reaction6 for the synthe-
sis of N-alkoxy 4-methylthiazole-2(3H)-thiones 3 since
these radical precursors have recently been successfully
applied for synthetic purposes.7 Based on structural anal-
thiones 3b and 3c in good yields (Table 1, entries 2 and 3).
ogy to the chosen substrates, cyclopentanol (2a) was se-
Substrates with two vicinal substituents adjacent to the re-
lected for elucidation of suitable conditions for the
active C O bond, for example the four different diastere-
omers of 2-phenyl 5-methyl substituted cyclopentanols
synthesis of 3. Our experiments showed that the conver-
sion of 2a with diethyl azodicarboxylate, PPh3, and
2d g11 are sterically significantly more demanding which
N-hydroxy-4-methylthiazole-2(3H)-thione (1) affords
caused a severe drop in yields of O-radical precursors
N-cyclopentoxythiazolethione 3a in 79% yield, if benzene
(synthesis of 3d, 3f; Table 1, entries 4, 6).12 Syntheses of
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750
J. Hartung et al.
LETTER
compounds 3e and 3g using the conditions which are giv-
en in Table 1 failed, presumably due to competing elimi-
nation reactions leading to phenyl substituted
cyclopentenes13. Relative configurations of all di- or
trisubstituted N-cyclopentoxy derivatives 3 were estab-
lished by NOE-experiments.
Table 2 Photolysis of N-Alkoxy-4-methylthiazole-2(3H)thiones 3
The conditions which are given in Table 1 were applied to
prepare mannosyl thiazolethione 3h (31%, Figure) from
2,3:5,6-di-O-isopropylidene- -D-mannofuranose.
For
reasons which are unclear at the moment, the synthesis of
glucosyl thiazolethione 3i from 2,3,4,6-tetra-O-acetyl- -
D-glucose failed. This compound, however, is readily
available from 2,3,4,6-tetra-O-acetyl- -D-glucopyranosyl
bromide and acid 1 in 72% yield using the phase transfer
alkylation method.9
(a) The configuration at Cα in 2 in this Scheme is opposite to those of
alcohols 2 which were used for the synthesis of radical precurors 3.
(b) Photoreaction in o-C6H4Cl2; the yield was determined by GC
using n-tetradecane as internal standard.
(c) Photoreaction in C6D6, the yield was measured by NMR using
anisole as internal standard.
Figure Yields of mannosyl thizaolthione 3h and glucosyl thiazo-
lethione 3i. [a] Mitsunobu reaction.6,12 [b] Phase transfer alkylation.9
(d) Photoreaction in C6H6. Y = Bu3Sn or (Me3Si)3Si, Tz = 4-me-
thyl thiazyl-3-sulfanyl.
In the second part of this study, thiazolethiones 3 (Table
1, Figure) and reactive hydrogen donors, either Bu3SnH or
(Me3Si)3SiH (for Y H: co = 0.18 M; 3.7 equiv.), were
dissolved in C6H6 or C6D6 and were photolyzed 30 min at
room temperature in a Rayonet® apparatus ( = 350 nm,
Table 2).14 Analytical data (1H NMR) from the crude re-
action mixture indicated, that only aldehydes which orig-
The second unexpected result from our data was the fact
that no alcohols 2 were discovered by NMR or by GC in
the crude reaction mixtures. After consumption of 1 equiv
of Bu3SnH in photoreactions of 3, a final concentration of
Bu3SnH of 0.13 M should remain. According to kinetic
data from the literature this concentration is sufficient to
convert the cyclopentoxyl radical (Rβ = Rε = H in Table 2)
into a 1: 2 mixture of cyclopentanol (1a) and pentanal un-
der pseudo-first order conditions.2 However, the fact that
no alcohols 2b f were obtained in our experiments means
that either ring opening reactions in substituted cyclopen-
toxyl radicals 2b f are faster than the the hydrogen atom
transfer from the stannane to the cyclopentoxyl radical, or
the rate constant of 5-exo-trig cyclizations of radicals
5b f is substantially slower than the reference value of
the -formylbutyl radical.
inated from
-cleavage, e.g. compounds 6b d, were
obtained from these experiments. Alcohols 2 which could
have been formed by a direct trapping of 4 and carbonyl
compounds from the alternative
-fission, were absent.
Except of volatile hexanal (6b) (NMR, GC analysis, Table
2, entries 1,2) all products were purified by column chro-
matography.
The data in Table 2 confirm the well-known preference of
O-radical mediated -C C-cleavages to afford the most
stabilized of all possible intermediate carbon radicals. For
further mechanistic discussions it should be noted that a
possible reverse reaction 5 4 has been omitted from the
illustration in Table 2, since it has not yet been investigat-
ed. Thus, 2-phenyl substituted radicals 4c and 4d regiose-
lectively afford substituted benzyl radicals 5c and 5d as
intermediates which are then trapped by Bu3SnH to yield
aldehydes 6c and 6d. We were surprised to note, that the
2-methyl substituted radical reacts similar selectively to
afford hexanal (6b) as single detectable product.15
In a final set of experiments, mannosyl thiazolethione 3h
and glucosyl derivative 3i were photoreacted with
Bu3SnH [co(Bu3SnH) = 0.18 M, 3.7 equiv.] to afford via
-C C cleavage of the intermediate O-radicals (not
shown in Scheme 1) either symmetrically substituted ara-
binitol derivative 7 or the unsymmetrically substituted ar-
abinitol 8 in excellent yields (Scheme).
Synlett 2001, No. 6, 749–752 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of Aldehydes from N-Alkoxythiazole-2(3H)-thiones
751
(5) (a) Francisco, C.G.; León, E.I. Moreno, P.; Suárez, E.
Tetrahedron: Asymmetry 1998, 9, 2975; (b) Martín, A.
Rodríguez, M.S., Suárez, E. Tetrahedron Lett. 1999, 40, 7525.
(6) (a) Grochowski, E.; Jurczak, J. Synthesis 1976, 682;
(b) Mitsunobu, O. Synthesis 1981, 1; (c) Hughes, D.L. Org.
React. 1992, 42, 335.
(7) Hartung, J. Eur. J. Org. Chem. 2001, 619.
(8) Typical procedure: A 10 mL Schlenk flask was charged with
N-hydroxy-4-methylthiazole-2(3H)thione (1) (221 mg, 1.50
mmol), dry C6H6 (5 mL), triphenylphosphine (525 mg, 2.00
mmol), alcohol 2 (1 mmol) and a magnetic stirring bar. After
cooling in an ice bath DEAD (0.33 mL, 366 mg, 2.10 mmol)
was added dropwise through a rubber septum cap during a
period of 5 min with agitation. Stirring of the brownish-red
solution was continued at 20 °C for 36 h. Afterwards the
reaction mixture was diluted with CH2Cl2 (10 mL) and
extracted with 2 M aqueous NaOH (10 mL). The aqueous
phase was washed CH2Cl2 (2 10 mL) and the combined
organic phases are dried (MgSO4) and concentrated in vacuo
to afford a brown oil which was purified by column
chromatography (SiO2).12
(9) Hartung, J.; Kneuer, R.; Schwarz. M.; Svoboda, I.; Fuess, H.
Eur. J. Org. Chem. 1999, 97.
(10) Hartung, J.; Hünig, S.; Kneuer, R.; Schwarz, M.; Wenner, H.
Synthesis 1997, 1433.
(11) Tartarova, L.E.; Yarovaya, O.I.; Volcho, K.P.; Korchagina,
D.V.; Salakhutdinov, N.F.; Ione, K.G.; Barkhash, V.A. Russ.
J. Org. Chem. 1995, 31, 982.
Scheme Photochemical conversion of carbohydrate-derived thia-
zolethiones 3h and 3i into arabinitol derivatives 7 and 8.
In summary, we have applied the Mitsunobu reaction for
the first time in the synthesis of N-alkoxythiazole-2(3H)-
thiones 3 from substituted cyclopentanols 2 and a man-
nose derivative (i.e. lactol). These compounds 3 serve as
efficient alkoxyl radical precursors which were applied in
the photochemical synthesis of aldehydes 6 under mild
and neutral conditions.
(12) Thiazolethiones 3b i are new compounds. Characteristic
analytical data are provided for two examples: N-(cis-2-
phenylcyclopentoxy)-4-methylthiazole-2(3H)-thione cis-
(3c): colorless solid; yield: 577 mg (66%); dec. 123 °C (DTA;
differential thermoanalysis); Rf = 0.42 [petroleum ether/
diethyl ether = 1/1(v/v)]; 1H NMR (CDCl3, 250 MHz):
= 1.68 2.40 (m, 6 H, 3'-H 5’-H), 1.94 (d, 3 H, 4J = 1.2 Hz,
4-CH3), 3.32 (ddd, 1 H, 3J = 7.3 Hz, 6.3 Hz, 4.0 Hz, 2'-H), 5.99
(dt, 1H, 3Jd = 4.0 Hz, 3Jt = 1.0 Hz, 1'-H), 6.05 (q, 1 H, 5-H,
4J = 1.2 Hz, 5-H), 7.19 7.39 (m, 3 H, 3''-5''-H), 7.46 7.52 (m,
2 H, 2''-H, 5''-H).13C NMR (CDCl3, 250 MHz): = 13.5, 21.7,
28.3, 29.6, 50.2, 88.5, 102.8, 126.4, 126.5, 128.0, 128.5,
128.6, 128.8, 138.4, 181.3. UV/VIS (EtOH) : max (lg ) = 320
nm (3.920); C15H17NOS2 (291.4): calcd. C 61.82, H 5.88, N
4.81, S 22.00; found C 61.56, H 5.74, N 4.66, S 21.81.
N-(2,3:5,6-Di-O-isopropyliden- -D-mannofuranosyl)-4-
methylthiazole-2(3H)-thione (3i): colorless solid; yield 464
Acknowledgement
Generous financial support was provided by the Deutsche For-
schungs-gemeinschaft (Normalverfahren, Ha 1705/5-1, 5 2) and
the Fonds der Chemischen Industrie (Sachbeihilfen).
References and Notes
(1) Walling, C.; Padwa, A. J. Am. Chem. Soc. 1963, 85, 1593.
(2) Beckwith, A.L.J.; Hay, B.P. J. Am. Chem. Soc. 1989, 111,
230.
(3) S. Wilsey, P. Dowd, K.N. Houk J. Org. Chem. 1999, 64,
8801 8811.
(4) For reviews and fundamental work on alkoxyl radical induced
-C C cleavages: (a) Nussbaum, A.L.; Robinson, C.H.
Tetrahedron 1962, 17, 35; (b) Suginome, H.; Sato, N;
Masamone, T. Tetrahedron Lett. 1967, 1557; (c) Nickon, A.;
Iwadare, T.; McGuire, F.J.; Mahajan, J.R.; Narang, S.A.;
Umezawa, B. J. Am. Chem. Soc. 1970, 92, 1688; Walling, C.;
Clark, R.T. J. Am. Chem. Soc. 1974, 96, 4530. (d) Druliner,
J.D.; Kitson, F.G.; Rudat, M.A.; Tolman, C.A. J. Org. Chem.
1983, 48, 4951; (e) Kalvoda, J.; Heusler, K. Synthesis 1985,
501; (f) Tsang, R.; Fraser-Reid, B. J. Am. Chem. Soc. 1986,
108, 8102; (g) Kobayashi, K.; Itoh, M.; Suginome, H.
Tetrahedron Lett. 1987, 28, 3369; (h) Beckwith, A.L.J.; Hay.
B.P; Williams, G.M. J. Chem. Soc., Chem. Commun. 1989,
1202); (i) Curran, D.P. Radical Cyclizations and Sequential
Radical Reactions in Comprehensive Organic Synthesis;
Trost, B.M., Fleming, I., Eds.; Pergamon Press: New York,
1991; Vol. 4, pp. 812 818; (j) Dowd, P.; Zhang, W. Chem.
Rev. 1993, 93, 2091; (k) Batsanov, A.S.; Begley, M.J.;
Fletcher, R.J.; Murphy, J.A.; Sherburn, M.S. J. Chem. Soc.,
Perkin Trans 1 1995, 1281; (l) Kim, S.; Lee, T.A. Synlett
1997, 950; (m) Easton, C.J.; Ivory, A.J. Smith, C.A. J. Chem.
Soc., Perkin Trans. 2 1997, 503; (n) Francisco, C.G.; Martin,
C.G.; Suárez, E. J. Org. Chem. 1998, 63, 2099.
mg (31%); [ ]D
= 35.2 (c 1.0 in CHCl3); mp 87 °C (dec.);
20
Rf = 0.51 [petroleum ether/diethylether/methanol = 10/10/1
(v/v/v)]; 1H NMR (CDCl3, 250 MHz): = 1.37 (s, 3 H, 7'-CH3
or 8'-CH3), 1.39 (s, 3 H, 7'-CH3 or 8'-CH3), 1.41 (s, 3 H, 7'-CH3
or 8'-CH3), 1.56 (s, 3 H, 7'-CH3 or 8'-CH3), 2.31 (d, 3 H,
4J = 1.2 Hz, 4-CH3), 3.66 (dd, 1 H, 3J = 6.7 Hz, 3.7 Hz, 4'-H),
4.01 4.16 (m, 2 H, 6'-H), 4.46 (dt, 1 H, 3Jt = 1.2 Hz, 3Jd = 6.7
Hz, 5'-H), 4.76 (dd, 1 H, 3J = 6.0 Hz, 3.7 Hz, 3'-H), 5.05 (dd,
1H, 3J = 6.0 Hz, 4.0 Hz, 2'-H), 5.85 (d, 1 H, 3J = 4.0 Hz, 1'-H),
6.12 (q, 1 H, 4J = 1.2 Hz, 5-H); 13C NMR (CDCl3, 63 MHz):
= 13.8, 24.8, 25.2, 25.8, 26.8, 66.4, 73.1, 77.1, 78.7, 78.9,
101.8, 104.9, 109.3, 114.0, 139.0, 180.2. UV/VIS (EtOH) :
max (lg ) = 318 nm (3.897); C16H23NO6S2 (389.5): calcd. C
49.34, H 5.95, N 3.60, S 16.47; found C 49.37, H 5.81, N 3.40,
S 16.19.
(13) For example, 10% of a 6: 1 mixture of 1-phenyl-3-methyl
cyclopentene and 1-methyl-3-phenyl cyclopentene (see
Wolinsky, J. J. Org. Chem. 1976, 41, 754 750) were isolated
besides 85% of alcohol 2g from the reaction of 2g, PPh3,
DEAD, and thiazolethione 1.
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J. Hartung et al.
LETTER
(14) A 10 mL Schlenk flask was charged with N-alkoxy-4-
methylthiazole-2(3H)thione 3 (0.5 mmol) and dry C6H6
(10 mL). The reaction vessel was sealed with a rubber septum
and cooled to liquid nitrogen temperature. After thorough
evaporation the flask was flushed with argon and Bu3SnH
(0.48 mL, 531 mg, 1.83 mmol) was added. The reaction
mixture was degassed by three consecutive freeze-pump-thaw
cycles and then thermostated in a water bath to 18 °C. The
solution was photolyzed for 30 min in a Rayonet® apparatus
( = 350 nm). Afterwards, the solvent was evaporated in
vacuo and the remaining oil purified by column
chromatography (SiO2). Rf-values of selected products: 0.57
(6c) 0.66 (6d), both: petroleum ether/methyl tert-butyl ether 3/
1 (v/v), 0.62 (7) in petroleum ether/ methyl tert-butyl ether 1/
1 (v/v).
(15) (a) Kabasakalian, P.; Townley, E.R. J. Org. Chem. 1962, 27,
3562; (b) Grossi, L.; Strazzari, S. J. Org. Chem. 1999, 64,
8076.
Article Identifier:
1437-2096,E;2001,0,06,0749,0752,ftx,en;G01301ST.pdf
Synlett 2001, No. 6, 749–752 ISSN 0936-5214 © Thieme Stuttgart · New York