Preparation of spiro hydroxy S-methylisothioureas from cyclic ketones

Full text of DOI:10.1021/jo960657w

5674
J . Org. Chem. 1996, 61, 5674-5676
Sch em e 1
P r ep a r a tion of Sp ir o Hyd r oxy
S-Meth ylisoth iou r ea s fr om Cyclic Keton es
Indrawan J . McAlpine and Robert W. Armstrong*
Department of Chemistry and Biochemistry, University of
California, Los Angeles, California 90095
Received April 9, 1996
R-Hydroxyguanidines appear as a functionality in a
number of natural products such as tetrodotoxin1 and
crambine B.2 We were interested in synthesizing a
blocked version of the spirohydroxyguanidinium portion
of the natural products styloguanidine3 and palau’amine.4
A methodology was sought which would allow for the
generation of this moiety starting from a ketone precur-
sor under sufficiently mild conditions to be compatible
with a multifunctional natural product intermediate. Ugi
has reported the four-component condensation of a
ketone, the thiocyanate salt of an amine, and an isocya-
nide to create 2-thiohydantoin 4-imines.5 The ease of
making 2-thiohydantoin 4-imines via an Ugi condensa-
tion and the fact that they are a single oxidation state
away from hydroxyguanidines makes them attractive
precursors for spirohydroxyguanidines.6,7 Appropriate
choice of amine such as p-methoxybenzylamine leads to
an attractive protecting group on the 2-thiohydantoin
4-imine and consequently, also on the spirohydroxy-
guanidine. This overall concept is represented in Scheme
1.
The main issue in developing this methodology is
converting the oxidation state of 2-thiohydantoin 4-imi-
nes to that of R-hydroxyguanidines. A masked version
of R-hydroxyguanidines could be obtained if suitable
conditions could be found for the reduction of 2-thiohy-
dantoin 4-imines to the corresponding R-aminothiourea
as represented by the second transformation in Scheme
1. Meyers has shown many examples of hydride reduc-
tion of oxazolines to carbinols using activators such as
methyl triflate and iodine.8,9 An example of the types of
functionality amenable to these conditions includes a Boc-
protected 1,3-imidazolidin-4-one which is reduced to the
corresponding Boc-protected 1,3-imidazolidine.10 We felt
that this presented an opportunity to probe suitable
reducing conditions. Here we report the synthesis of
spiro hydroxy S-methylisothioureas using an Ugi four-
component condensation followed by the reduction of the
resultant spiro-2-thiohydantoin 4-imines using sodium
cyanoborohydride and iodine as an activator of the
amidine carbon.
Sch em e 2
To address the accessibility of this masked spirohy-
droxyguanidine, the spiro-2-thiohydantoin 4-imine 1 was
prepared in 37% yield by adding methyl isocyanoacetate
to a solution of cyclopentanone and the thiocyanate salt
of p-methoxybenzylamine in methanol (Scheme 2). The
thiocyanate salt is formed by heating the hydrochloride
salt of the amine with potassium thiocyanate in metha-
nol. Subjecting 2-thiohydantoin 4-imine 1 to standard
hydride reductions using lithium aluminum hydride or
sodium borohydride resulted only in the reduction of the
methyl ester. By using conditions described by Meyers,10
treatment of 2-thiohydantoin 4-imine 1 with sodium
borohydride followed by activation with iodine resulted
in the formation of the overreduced cyclic thiourea 2 in
quantitative yield (Scheme 2). Attempts at effecting the
single reduction to the aminal by using the less reactive
sodium cyanoborohydride or running the reaction at a
lower temperature resulted either in overreduction to the
cyclic thiourea 2 or no reaction at all.
The mechanism of reduction might proceed via the
association of iodide with the amidine nitrogen and
resultant reduction of the amidine carbon yielding the
R-amino thiourea. Assistance from the thiourea nitrogen
may also result in elimination and subsequent reduction
to the thiourea due to the lability of the glycylamino
group. Therefore, using an electron-rich isocyanide in
the 2-thiohydantoin 4-imine formation should lead to a
more robust amino group which might in turn result in
an aminal stable to further reduction. With this in mind,
2-thiohydantoin 4-imine 3 was prepared in 65% yield via
an Ugi condensation using benzyl isocyanide in place of
methyl isocyanoacetate (Scheme 3). Reduction with
sodium cyanoborohydride and iodine in methylene chlo-
ride and tetrahydrofuran at 0 °C for 20 min was suc-
cessful in giving a 40% yield of the desired R-benzylamino
thiourea 4 (48% yield based on recovered thiohydantoin
3) after chromatography. Prolonged exposure to the
reduction conditions resulted in overreduction to the
cyclic thiourea 2. Conversion to the R-hydroxy thiourea
5 was accomplished in 68% yield by dissolving 4 in an
acetone/water mixture with a catalytic amount of p-
toluenesulfonic acid.11
(1) Goto, T.; Kishi, Y.; Takahashi, S.; Hirata, Y. Tetrahedron Lett.
1963, 4, 2105, 2115.
(2) Berlink, R. G. S.; Braekman, J . C.; Daloze, D.; Hallenga, K.;
Ottinger, R.; Bruno, I.; Ricco, R. Tetrahedron Lett. 1990, 31, 6531.
(3) Kato, T.; Shizuri, Y.; Izumida, H.; Yokoyama, A.; Endo, M.
Tetrahedron Lett. 1995, 36, 2133.
(4) Kinnel, R. B.; Gehrken, H.-P.; Scheuer, P. J . J . Am. Chem. Soc.
1993, 115, 3376.
(5) Interestingly, Ugi points out that 2-thiohydantoin 4-imines are
formed in high yield only from ketones and not from aldehydes,
whereas, hydantoin 4-imines are formed from aldehydes but not very
well from ketones (see ref 6).
(6) Ugi, I. Isonitrile Chemistry; Academic Press: New York, 1971;
Vol. 20, pp 145-155.
(7) Ugi, I.; Rosendahl, F. R.; Bodesheim, F. J ustus Liebigs Ann.
Chem. 1963, 666, 54.
(8) Meyers, A. I.; Shimano, M. Tetrahedron Lett. 1993, 34, 4893.
(9) Robichaud, A. J .; Meyers, A. I. J . Org. Chem. 1991, 56, 2607.
(10) McKennon, M. J .; Meyers, A. I. J . Org. Chem. 1993, 58, 3568.
(11) The hydroxythiourea 5 is somewhat unstable and rearranges
upon standing, presumably to the 4-hydroxy-2-imino-3,1-thiazaspiro-
[4]nonane.
S0022-3263(96)00657-3 CCC: $12.00 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 16, 1996 5675
ucts, the combined organic layers were dried with Na2SO4 and
concentrated in vacuo before further treatment.
Sch em e 3
Gen er a l P r oced u r e for Sp ir o 2-th ioh yd a n toin 4-im in e
F or m a tion . To a solution of the 4-methoxybenzylamine hy-
drochloride (100 mg, 0.575 mmol) in methanol (3 mL) was added
potassium thiocyanate (55 mg, 0.570 mmol), and the mixture
was heated to 60 °C for 1 h. The reaction mixture was passed
over a cotton plug to remove the KCl. To the filtrate was then
added distilled cyclopentanone (50 µL, 0.570 mmol) followed by
isocyanide (1.1 equivalent) and the reaction was allowed to stir
at room temperature for 18 h. The methanol was removed in
vacuo, and the remaining residue was subjected to chromatog-
raphy using a gradient of hexane and ethyl acetate.
1 -(4 -M e t h o x y b e n z y l )-4 -(m e t h y l a c e t o i m i n o )-1 ,3 -
d ia za sp ir o[4.4]n on a n e-2-th ion e (1). Chromatography af-
forded 1 in 37% yield as a white powder: mp 187-188 °C; IR
(KBr pellet) 3233, 2957, 1749, 1611, 1516, 1235 cm-1; 1H NMR
(360 MHz) δ 7.25 (d, J ) 9.0 Hz, 2H), 6.8 (d, J ) 9.0 Hz, 2H),
6.5 (bs, 1H), 4.9 (s, 2H), 4.3 (bs, 2H), 3.7 (s, 3H), 3.7 (s, 3H), 1.9
(m, 4H), 1.8 (m, 4H); 13C NMR (101 MHz) δ 194.9, 182.2, 169.8,
158.8, 129.5, 128.4, 113.8, 77.7, 55.2, 52.6, 46.4, 43.7, 36.1 26.5;
HRFAB calcd for C18H23N3O3S [(M + H)+] 362.1532, found
362.1538.
1-(4-Meth oxyben zyl)-4-(ben zylim in o)-1,3-diazaspir o[4.4]-
n on a n e-2-th ion e (3). Chromatography afforded 3 in 65% yield
as a white powder: mp 227-229 °C; IR (KBr pellet) 3253, 2957,
1611, 1515, 1244 cm-1 1H NMR (360 MHz) δ 7.3 (m, 7H), 6.8
;
(d, J ) 9.0 Hz, 2H), 4.9 (s, 2H), 4.7 (s, 2H), 3.8 (s, 3H), 1.9 (m,
4H), 1.7 (m, 4H); 13C NMR (101 MHz) δ 158.9, 137.0, 129.7,
128.9, 128.5, 128.0, 127.9, 114.0, 77.6, 55.3, 47.4, 46.6, 36.8, 26.6;
HRFAB calcd for C22H25N3OS [(M + H)+] 380.1810, found
380.1797.
In an attempt to optimize the yield of the reduction,
2-thiohydantoin 4-imine 7 was prepared in 73% yield
using p-methoxybenzyl isocyanide. Reduction conditions
were identical to that used for 2-thiohydantoin 4-imine
3 except the reaction was allowed to proceed for 1 h.
Isolation of the corresponding R-(p-methoxybenzyl)amino
thiourea was difficult as chromatography usually re-
sulted in partial conversion to the R-hydroxy thiourea.
Therefore, the crude material from the reduction of 7 was
treated with catalytic p-toluenesulfonic acid in acetone
and water to yield 48% of the R-hydroxy thiourea 5 on
the basis of the two-step conversion (61% based on
recovered starting 2-thiohydantoin 4-imine 7). Treat-
ment of 5 with iodomethane followed by basic workup
gave the desired R-hydroxy S-methylisothiourea 6 in
quantitative yield.
In conclusion, we have developed a mild synthetic route
for building spiro R-hydroxy S-methylisothioureas from
cyclic ketones via a 2-thiohydantoin 4-imine. We have
shown that the reduction of 2-thiohydantoin 4-imine can
be controlled by the appropriate choice of nitrogen
substituent. The mild conditions of this procedure should
be useful for the synthesis of spiroguanidines in the
presence of additional functional groups.
1-(4-Met h oxyb en zyl)-4-[(4-m et h oxyb en zyl)im in o]-1,3-
d ia za sp ir o[4.4]n on a n e-2-th ion e (4). Chromatography af-
forded 4 in 73% yield as a white powder. mp 211-214 °C; IR
(KBr pellet) 3247, 2955, 1613, 1514, 1245, 1179 cm-1; 1H NMR
(360 MHz) δ 7.3 (d, J ) 9.0 Hz, 2H), 7.2 (d, J ) 9.0 Hz, 2H),
6.85 (d, J ) 9.0 Hz, 2H), 6.80 (d, J ) 9.0 Hz, 2H), 5.6 (bs, 1H),
5.0 (s, 1H), 4.6 (d, J ) 5.0 Hz, 1H), 3.8 (s, 3H), 1.90-1.95 (m,
2H), 1.75-1.80 (m, 4H), 1.63-1.68 (m, 2H); 13C NMR (101 MHz)
δ 195.3, 182.0, 159.4, 158.9, 129.8, 129.5, 128.9, 128.5, 114.3,
113.9, 77.5, 55.3, 55.2, 46.5, 36.5, 26.7; HRFAB calcd for
C
23H27N3O2S [(M + H)+] 410.1892, found 410.1902.
1-(4-Me t h o x y b e n zy l)-1,3-d ia za s p ir o [4.4]n o n a n e -2-
th ion e (2). To a solution of 1 (19 mg, 0.052 mmol) in THF (2
mL) was added an excess of NaBH4 which was stirred for 30
min. To this mixture was added dropwise a solution of iodine
(15 mg, 0.059 mmol) in THF (0.5 mL) and the reaction was
allowed to stir for 10 h. The reaction mixture was quenched
with 1 N HCl and then poured into saturated NaHCO3 solution.
The aqueous layer was extracted with CH2Cl2 (3 × 50 mL), and
the combined organic phase was dried and evaporated to give 2
(15 mg) as a yellow solid in quantitative yield: mp 148-151 °C;
IR (KBr pellet) 3219, 2954, 1613, 1513, 1453, 1245 cm-1 1H
;
NMR (360 MHz) δ 7.3 (d, J ) 9.0 Hz, 2H), 6.8 (d, J ) 9.0 Hz,
2H), 4.7 (s, 2H), 3.8 (s, 3H), 3.4 (s, 2H), 1.65-1.75 (m, 4H), 1.5-
1.6 (m, 4H); 13C NMR (101 MHz) δ 183.2, 158.6, 130.6, 128.1,
113.7, 73.8, 56.1, 55.1, 45.5, 34.7, 22.7; HRFAB calcd for
C
15H20N2OS [(M + H)+] 277.1369, found 277.1375.
Exp er im en ta l Section
1-(4-Meth oxyben zyl)-4-(ben zylam in o)-1,3-diazaspir o[4.4]-
Gen er a l. 1H and 13C NMR spectra were obtained at room
temperature. 1H NMR chemical shifts are referenced to CDCl3
(7.26 ppm), and those for 13CMR to CDCl3 (77.0 ppm). High-
resolution mass spectroscopy (HRMS) was performed at UCLA.
For EI, CI, and FAB methods, 2σ ) 4 ppm.
All water-sensitive reactions were conducted in oven- or flame-
dried glassware under a nitrogen atmosphere. Solvents were
distilled immediately prior to use: CH2Cl2 from P2O5, MeOH
from magnesium metal, and THF from sodium benzophenone
ketyl. Most commercially available reagents were distilled
before use including methyl isocyanoacetate and cyclopentanone.
Benzyl isocyanide and 4-methoxybenzyl isocyanide were pre-
pared by standard methods described in ref 6. Thin-layer
chromatography (TLC) was performed on silica gel-coated plates
(0.25 mm thickness for analytical and preparative TLC) and
visualized by UV light and/or p-anisaldehyde or ninhydrin
staining. After all aqueous extractions of crude reaction prod-
n on a n e-2-th ion e (5). To a solution of 3 (30 mg, 0.079 mmol)
in CH2Cl2 (2 mL) was added an excess of NaCNBH3, and the
reaction was left to stir for 10 min. The reaction mixture was
cooled to 0 °C and a solution of iodine (20 mg, 0.079 mmol) in
THF (1 mL) was added dropwise. After 20 min at 0 °C, the
reaction was quenched with 1 N HCl solution and then poured
into saturated NaHCO3 solution. The aqueous layer was
extracted with CH2Cl2 (3 × 60 mL), and the combined organic
phase was dried and evaporated. The crude residue was
subjected to preparative TLC using 1:1 hexanes/ethyl acetate
and gave 5 (12 mg) as a yellow oil in 40% yield and 3 (5 mg) in
13% yield: IR (neat) 3215, 2960, 1729, 1612, 1514, 1455, 1249
cm-1; 1H NMR (360 MHz) δ 7.3 (m, 7H), 6.8 (d, J ) 9.0 Hz, 2H),
5.0 (d, J ) 16.0 Hz, 1H), 4.5 (d, J ) 16.0 Hz, 1H), 4.1 (s, 1H),
3.9 (d, J ) 13.0 Hz, 1H), 3.8 (d, J ) 13.0 Hz, 1H), 3.8 (s, 3H),
2.0 (m, 1H), 1.5-1.7 (m, 7H); 13C NMR (101 MHz) δ 181.7, 158.7,
139.3, 130.6, 128.5, 128.3, 128.0, 127.3, 113.9, 76.3, 76.0, 55.2,

5676 J . Org. Chem., Vol. 61, No. 16, 1996
Notes
49.5, 45.9, 34.9, 28.3, 23.8, 22.6; HRFAB calcd for C22H27N3OS
[(M + H)+] 382.1961, found 382.1953.
The aqueous layer was extracted with CH2Cl2 (3 × 50 mL) and
the combined organic phase was dried and evaporated. The
residue was subjected to preparative TLC to give 6 (9 mg, 0.033
mmol) as a yellow oil in 48% yield. The spectral data matched
that of the previous procedure.
4-H yd r oxy-1-(4-m e t h oxyb e n zyl)-1,3-d ia za sp ir o[4.4]-
n on a n e-2-th ion e (6) fr om 5. To a solution of 5 (12 mg, 0.031
mmol) in acetone (1 mL) and water (1 mL) was added p-TSA (5
mg, 0.026 mmol). After 10 h of stirring, the reaction mixture
was poured into a saturated NaHCO3 solution, and the aqueous
layer was extracted with CH2Cl2 (3 × 50 mL). The combined
organic phase was dried and evaporated. The crude residue was
subjected to preparative TLC using ethyl acetate and gave 6 (6
mg) as a yellow oil in 68% yield: IR (KBr pellet) 3323, 3205,
2970, 2460, 2401, 1619, 1514, 1465 cm-1; 1H NMR (360 MHz) δ
7.3 (d, J ) 9.0 Hz, 2H), 7.0 (s, 1H), 6.8 (d, J ) 9.0 Hz, 2H), 5.0
(d, J ) 16.0 Hz, 1H), 4.8 (s, 1H), 4.6 (d, J ) 16.0 Hz, 1H), 3.8 (s,
3H), 2.0 (m, 1H), 1.5-1.7 (m, 7H); 13C NMR (101 MHz) δ 181.5,
158.7, 130.0, 128.1, 113.8, 84.2, 55.2, 45.6, 33.2, 27.5, 23.4, 22.4;
4-H y d r o x y -2-(m e t h y lt h io )-1-(4-m e t h o x y b e n zy l)-1,3-
d ia za sp ir o[4.4]n on -2-en e (7). To a solution of 6 (6 mg, 0.022
mmol) in CH2Cl2 (2 mL) was added excess MeI (10 µL, 0.161
mmol). The reaction mixture stirred for 14 h at rt after which
the solution was poured into saturated NaHCO3. The aqueous
layer was extracted with CH2Cl2 (3 × 50 mL) and the combined
organic phase was dried and evaporated to give 7 (7 mg) as a
yellow oil in quantitative yield: IR (neat) 3176, 2960, 1729, 1612,
1249, 1033 cm-1; 1H NMR (360 MHz) δ 7.2 (d, J ) 9.0 Hz, 2H),
6.9 (d, J ) 9.0 Hz, 2H), 5.1 (s, 1H), 4.3 (s, 2H), 3.8 (s, 3H), 2.5 (s,
3H), 2.3 (m, 1H), 1.5-1.7 (m, 7H); 13C NMR (101 MHz) δ 167.0,
158.7, 130.6, 127.7, 113.9, 93.8, 55.2, 44.7, 34.5, 29.7, 27.0, 23.6,
22.5, 13.9; HREI calcd for C16H22N2O2S [(M + H)+] 306.1402,
found 306.1402.
HREI calcd for
292.1241.
C
15H20N2O2S [(M + H)+] 292.1246, found
4-H yd r oxy-1-(4-m e t h oxyb e n zyl)-1,3-d ia za sp ir o[4.4]-
n on a n e-2-th ion e (6) fr om 4. To a solution of 4 (27 mg, 0.067
mmol) in CH2Cl2 (2 mL) was added iodine (18 mg, 0.071 mmol),
and the reaction mixture was then cooled to 0 °C. After 15 min,
an excess of NaCNBH3 was added, and the reaction mixture was
stirred for 1 h. The mixture was then quenched with 1 N HCl
solution and poured into a saturated NaHCO3 solution. The
aqueous layer was extracted with CH2Cl2 (3 × 60 mL), and the
combined organic phase dried and evaporated. The crude
residue was passed over a silicia gel plug using ethyl acetate,
and the resulting solution was evaporated. The residue was
dissolved in acetone (2 mL) and water (1 mL), and p-TSA (5 mg,
0.026 mmol) was added. The reaction mixture was stirred for 6
h at rt and then was poured into a saturated NaHCO3 solution.
Ack n ow led gm en t. This work was made possible by
financial support from UCLA and NIH grant GM51095.
I.J .M. was supported on an NSF Fellowship.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR data for reported compounds (14 pages). This material
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