Chemistry of N-hydroxyguanidines: Photo-sensitized oxygenation and reaction with nitric oxide

Article abstract of DOI:10.1002/1522-2675(200209)85:9<2636::AID-HLCA2636>3.0.CO;2-L

The chemistry of N-hydroxyguanidines, focusing on photo-sensitized oxygenation and reaction with nitric oxide (NO), was examined. In the former reaction, a urea derivative was obtained as the main product together with the generation of NO. On the other hand, in the latter case, oxidative nitrosation occurred under aerobic conditions to give a nitrosourea derivative, which was also obtained from urea by the same treatment.

Full text of DOI:10.1002/1522-2675(200209)85:9<2636::AID-HLCA2636>3.0.CO;2-L

2636
Helvetica Chimica Acta Vol. 85 (2002)
Chemistry of N-Hydroxyguanidines: Photo-Sensitized Oxygenation and
Reaction with Nitric Oxide
by Hiroyo Kabasawaa), Masako Ikenoa), Masahiro Suzukawaa), Keiro Higuchib), Keiko Yanagisawab),
Hiroko Sekic), Tatsuhiro Tokunagad), and Tsutomu Ishikawa*a)
a) Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, Japan
b) FIA Instruments Co., Ltd, 6-15-9 Toshima, Kita 114-0003, Japan
c) Chemical Analysis Center, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, Japan
d) Molecular Chemistry Analysis and Metabolism Laboratories, Institute for Drug Discovery Research,
Yamanouchi Pharmaceutical Co., Ltd, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan
(Tel. and fax: ‡81-43-290-2910; e-mail: benti@p.chiba-u.ac.jp)
The chemistry of N-hydroxyguanidines, focusing on photo-sensitized oxygenation and reaction with nitric
oxide (NO), was examined. In the former reaction, a urea derivative was obtained as the main product together
with the generation of NO. On the other hand, in the latter case, oxidative nitrosation occurred under aerobic
conditions to give a nitrosourea derivative, which was also obtained from urea by the same treatment.
1. Introduction. It is well-known that nitric oxide (NO) in vivo plays important
roles in the cardiovascular and central and peripheral nervous systems, and modulates
immunological responses [1], in spite of its being one of the air-polluting nitrogen
oxides. NO is biosynthesized during the conversion of l-arginine (1) to l-citrulline (3)
through N-hydroxy-l-arginine (NOHA; 2) [2]. We have examined the photo-sensitized
oxygenation of N-hydroxyguanidine derivatives as a chemical model for the biological
NO generation and preliminarily reported that 2-hydroxy-1-(2-phenylethyl)guanidine
(4) was photochemically oxidized to produce (2-phenylethyl)urea (5) and (2-phenyl-
ethyl)cyanamide (6) with the evolution of NO [3].
On the other hand, Zembowicz et al. [4] proposed that an alternative active
principle, derived from a further reaction between NOHA (2) and NO, was possibly
responsible for biological activity based on the observation that a product resulting
H
HO2C
N
NH2
H
N
NH2
H2N
X
X
4 X=NOH
5 X=O
7 X=NH
1 X=NH
2 X=NOH
3 X=O
NOH
CH3
H
N
CN
6
8

Helvetica Chimica Acta Vol. 85 (2002)
2637
from reaction of hydroxyguanidine with HONO had caused vasorelaxation. However,
our trials for the reaction of 4 with aqueous HONO according to the reported
procedure [4] resulted only in formation of a complex mixture1). Instead, reaction with
NO gas in place of HONO under aerobic conditions led unexpectedly to the production
of an N-nitrosourea derivative 12 (see the Table).
In this paper, we present further photo-sensitized oxygenation with the NOHA
derivative 9 as a substrate, in addition to experimental details of the preliminary
reactions of 2-hydroxy-1-(2-phenylethyl)guanidine 4, and the results of reactions of 4
and its related compounds with NO gas.
2. Results and Discussion.
2.1. Photo-Sensitized Oxygenation.
The singlet-
oxygen (1O2) ene reaction [6] has been shown to be a powerful method for allylic
oxyfunctionalization of cyclic and acyclic olefin systems. We assumed that, when a
1
2-hydroxyguanidine was used as a substrate in the O2 ene reaction, the oxime bond
(CˆNÀOH) could act as an ene to give a nitrosohydroperoxide (like B1 in Scheme 1),
structurally related to a peroxyheme complex [7], which may spontaneously be
degraded to a urea derivative with the evolution of NO or its equivalent. As stated in a
preliminary communication [3], the photo-sensitized oxygenation of 2-hydroxy-1-(2-
phenylethyl)guanidine (4) in AcOEt for 1 h with a high-pressure Hg lamp (400 W) as a
Scheme 1. Proposed Mechanisms for the Photo-Sensitized Oxygenation of 2-Hydroxyguanidines
1
)
During our study, Southan et al. [5] reported the successful isolation of zwitterionic diazenium diolates as
reaction products between hydroxyguanidines and HONO, supporting Zembowicz×s proposal [4].

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Helvetica Chimica Acta Vol. 85 (2002)
light source through a Pyrex filter in the presence of a catalytic amount of rose bengal
(RB) as a sensitizer with bubbling O2 under water-cooling smoothly gave the expected
(2-phenylethyl)urea (5) in 58% isolated yield together with (2-phenylethyl)cyanamide
(6) as a minor oxidation product (4% yield). Nearly the same product distribution had
been observed when tetraphenylporphine (TPP) was used instead of RB as a sensitizer.
The failure of photo-oxygenation with (2-phenylethyl)guanidine (7) or 4-phenyl-
butan-2-one oxime (8) indicated that the presence of a whole 2-hydroxyguanidine
function [RNHC(NH2)ˆNOH], not the limited functionalities such as CˆNÀOH or
NˆCÀNH, was essential for the photo-oxidative production of not only a urea but
also a cyanamide. Analysis of the reaction mixture obtained in the RB-sensitized
photoreaction of 2-hydroxy-1-(2-phenylethyl)guanidine (4) by application of the
Griess reaction [8] after irradiation for 1.5 h, followed by extraction with H2O, led to
identification of NOÀ2 and NO3À, albeit in low 4 and 9% yields, respectively, strongly
indicating that NO should be generated during the reaction. Based on these
experimental observations, we proposed a plausible mechanism for the photo-
oxygenation of 2-hydroxyguanidines A to yield ureas D and cyanamides E with
evolution of NO or its equivalent through C- and N-hydroperoxides B1 and B2 (or
endoperoxides C) as shown in Scheme 1.
To further confirm the photoreactivity of an 2-hydroxyguanidyl function, we next
examined the photoreaction with tert-butyl Na-Boc-Nw-hydroxy-l-arginate (9), an N-
Boc-protected NOHA ester, which was prepared according to the method described in
[9], with some modifications [10], as a more structurally-closed model substrate for the
biological oxidation of NOHA (2). The photo-irradiation of the protected NOHA 9 for
2h in the presence of RB under the same conditions mentioned above, as expected,
afforded the corresponding urea 10 and cyanamide 11 in 51 and 10% isolated yields,
respectively (Scheme 2). The use of TPP in place of RB as a sensitizer also led to
effective formation of both products (10: 41%; 11: 5%). Thus, it was clear that the
CˆNÀOH group of an 2-hydroxyguanidine function was smoothly cleaved by an
2
activated O2 ) to effectively yield a urea derivative as a main product.
Scheme 2. The Photo-Sensitized Reaction of NOHA Derivative 9
2
)
During our study, the chemical oxidation of 2-hydroxy-1-arylguanidines with a superoxide was reported
[11]. However, no mechanistic consideration was given.

Helvetica Chimica Acta Vol. 85 (2002)
2639
Table. Reactions of 2-Hydroxy-1-(2-phenylethyl)guanidine (4), (2-Phenylethyl)urea (5), and 1-(2-Phenyl-
ethyl)guanidine (7) with NO under Various Conditions
Entry
Substrate
Time [h]
Workupa)
Product
1b)
2c)
3c)
4b)
5c)
6b)
4
4
4
5
5
7
3
4
0.3
0.8
5.7
7.6
A
B
C
B
B
B
12: 64%
12: 36%
Recovery of 4
12: 100%
12: 100%
12: 9%
a) A: Evaporation after washing with H2O, B: passing Ar before treatment of A, C: evaporation after passing
Ar without washing with H2O. b) Commercially available NO gas was used. c) NO gas was purified through
30% aq. NaOH soln.
2.2. Reactions with NO. It is known that some N-containing compounds such as
amines3) react with NO to give various types of product depending on the conditions
used. N-Nitrosation has occurred in the cases of amides [15]; however, there have been
no reports on 2-hydroxyguanidines. We tried reactions of 2-hydroxy-1-(2-phenyl-
ethyl)guanidine (4) and its related compounds with NO for chemical approaches
(Table) to the possible production of the vasorelaxation-active principle [4] in the
reaction of NOHA (2) with NO in vivo.
An ice-cooled solution of 4 in AcOEt was saturated with NO through bubbling
commercially available NO gas for 5 min after passing Ar for 10 min, and then the
mixture was stirred for 3 h under ice-cooling. After removal of the excess NO by
passing Ar (10 min), the solution was washed with H2O, dried, and evaporated. An N-
nitrosated urea 12 was obtained in 64% yield as a crystalline product (Entry 1). Its
structure was confirmed by spectroscopic means, including 1H,15N-HMQC and 1H,15N-
HMBC experiments. In the HMQC experiment, cross-peaks due to an NH2 group
appeared between a N-atom at d À296 ppm and two exchangeable H-atoms (d 7.80 and
8.12ppm). In the HMBC experiment, cross-peaks between a N-atom at d À106 ppm
and two methylene H-atoms (d 2.62 and 3.94 ppm) were observed through three- and
two-bonds correlation. Among them, the CH2 signal at lower field additionally showed
a cross-peak between a N-atom at d 184 ppm through three-bonds correlation,
indicating the presence of a partial structure of CH2CH2N(N)CNH2 in its molecule.
We carried out the reaction with NO gas purified by passing through 30% aqueous
NaOH solution under the same conditions mentioned above (Entry 2). The same 12
was obtained in a lower 36% yield. On tracing this reaction, the appearance of a new
3
)
Aromatic primary amines were either reductively deaminated or diazotized by NO in the absence [12] or
in the presence [13] of O2, respectively, whereas aromatic secondary amines afforded N-nitroso derivatives
under aerobic conditions [13]. Recently, it was reported that Li salts of secondary amines could be reacted
with NO to give N-nitroso derivatives [14].

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Helvetica Chimica Acta Vol. 85 (2002)
spot on TLC was noted after disappearance of the starting 4 (ca. 15 min). The
intermediate was different from the urea derivative 5, an expected precursor for 12
(vide infra); however, it was converted to 12 after further reaction for 2h. Attempts at
isolation of the intermediate after a short reaction (20 min) by bubbling Ar into the
reaction mixture, followed by evaporation of the solvent without washing with H2O,
resulted in the recovery of the starting 4 (Entry 3). On the other hand, an N-
nitrosourea 12 was produced in the case of omission of the Ar treatment in the above
reaction, whereas decomposition of the reaction products was observed when the
reaction mixture was bubbled with O2 after the Ar treatment. Furthermore, the starting
4 was found to be quite stable under the conditions in the absence of NO. These results
allowed us to interpret the reaction of 4 with NO as follows: 1) the intermediate may be
in equilibrium with the starting 2-hydroxyguanidine 4 under anaerobic conditions, and
2) O2, even in a catalytic amount, in addition to NO should be needed for the
conversion of the intermediate to an N-nitrosourea 12 (Scheme 3).
Scheme 3. Reaction of 2-Hydroxy-1-(2-phenylethyl)guanidine (4) with NO
Next, we examined the reaction using (2-phenylethyl)urea (5) as a starting
substrate under the conditions described in Entries 1 and 2 (Entries 4 and 5,
respectively). In both reactions, a nitrosated product 12 was, as expected, formed in
quantitative yields; however, a longer reaction time (5.7 h) was needed when degassing
was performed with purified NO (Entry 5), indicating that O2 dissolved in the reaction
system plays an important role for this nitrosation reaction. On the other hand, the
reaction of 1-(2-phenylethyl)guanidine (7) with NO under the conditions of Entry 1
resulted in low conversion to the nitrosourea 12 (9%) (Entry 6).
In the case of the oxime 8, the corresponding ketone 13 was smoothly obtained in
64% yield (Scheme 4). Thus, it was found that an N-hydroxy imine (oxime) function is
susceptible to being converted to the corresponding carbonyl function by NO gas under
aerobic conditions.
Scheme 4. Reaction of 4-Phenylbutan-2-one Oxime (8) with NO under Aerobic Conditions
It is known that NO is a less-reactive nitrosation agent than other nitrogen oxides
such as NO2, N2O3, and N2O4, among which NO2 is easily generated from NO with O2
[16]. Therefore, it could be reasonably assumed that NO2 is the actual nitrosating

Helvetica Chimica Acta Vol. 85 (2002)
2641
agent4) because O2 dissolved in the solvent clearly plays an important role in these
reactions mentioned above.
3. Conclusions. We examined two types of reactions of 2-hydroxyguanidines,
photo-sensitized oxygenation and reaction with NO gas, as chemical models for
biological NO generation from NOHA (2) and for chemical approaches to the possible
production of an alternative, biologically active principle by the reaction of 2 with NO.
The former photo-sensitized oxygenations are often used as chemical mimics for
oxygenase-catalyzed biological oxidations (see, e.g., [18]). The smooth conversion of
an 2-hydroxyguanidine to urea and NO (or its equivalent) in the photo-sensitized O2
oxidation may allow us to consider the oxygenation reaction as a possible chemical
model5) for the NOS-catalyzed oxidation of NOHA (2) to citrulline (3).
In the latter reaction, an 2-hydroxyguanidyl residue is oxidatively nitrosated with
NO gas under aerobic conditions to give an N-nitrosourea function, which can be
smoothly obtained by treatment of a urea with NO under the same conditions.
However, detection of a new spot on TLC, but not that of urea during the reaction,
suggested that this oxidative nitrosation is not composed of simple stepwise reactions of
oxidation of the hydroxy imine function to a CˆO function, followed by N-nitrosation
of the formed ureido function, or even smooth conversion of an oxime group into the
corresponding ketone function by action of NO. Biological tests of vasorelaxation on
N-nitrosourea derivatives are planned to be performed in the future.
Experimental Part
General. Reactions were monitored by TLC on Kieselgel 60 F 254 (Merck, 5715). Column chromatography
(CC): silica gel (Fuji Silysia, FL100D). In the photoreaction, Toshiba HLS-4002 (400 W) was used as a light
source. Both ions of NOÀ2 and NOÀ3 were analyzed by TCI-NOX 5000S (Tokyo Kasei Kogyo Co., Ltd). M.p.: a
micro melting-point hot stage (Yanagimoto), uncorrected. IR Spectra: JASCO FT/IR-300E spectrophotometer.
1H-, 13C-, and 15N-NMR spectra: in CDCl3 on a JEOL JNM-LA500; in the former two cases, TMS (0.00 ppm)
and the middle resonance of CDCl3 (77.0 ppm) were used as an internal standard, respectively, whereas 15N
chemical shifts were referenced to 0 ppm for MeNO2 as an external standard. EI-MS (MS) and HR-FAB-MS
(HR-MS): JEOL Automass 20 and JMS-HX110 with m-nitrobenzyl alcohol as a matrix, respectively.
(2-Phenylethyl)cyanamide (6). A soln. of bromocyan (95%, 1.84 g, 16.5 mm) in dry MeOH (6 ml) was
added to a mixture of 2-phenylethylamine (1.95 g, 16.1 mm) and AcONa (1.65 g, 20.2 mm) in dry MeOH (12ml)
at À108, and the whole was stirred at the same temp. for 1 h. After evaporation of MeOH, the residue was
partitioned with AcOEt and H2O. The org. soln. was washed with H2O and brine, dried (K2CO3), and
evaporated to give 6 (1.74 g, 74%) as a yellow oil, which was used in the next reaction without further
purification. IR (neat): 3404, 2224. 1H-NMR: 2.89 (t, J ˆ 6.9, CH2(2)); 3.30 (q, J ˆ 6.9, CH2(1)); 3.99 (br. s, NH);
‡
7.21 ( d, J ˆ 7.0, HÀC(2')); 7.25 (t, J ˆ 7.4, HÀC(4')); 7.32( t, J ˆ 7.0, HÀC(3')). MS: 146 (53, M ).
2-Hydroxy-1-(2-phenylethyl)guanidine (4). A mixture of 6 (0.805 g, 5.51 mm), NH2OH ¥ HCl (0.460 g,
6.61 mm), and Et3N (1 ml, 7.17 mm) in EtOH (6.4 ml) was stirred at r.t. for 3.5 h. After evaporation of EtOH, the
residue was adjusted to pH 8 9 with sat. aq. Na2CO3 soln. and extracted with AcOEt. After workup,
recrystallization of the crude product with AcOEt afforded 4 (0.435 g, 44%). Colorless powder. M.p. 106 110.
IR (nujol): 3418, 3354. 1H-NMR (CD3OD): 2.80 (t, J ˆ 7.2, CH 2(2)); 3.26 (t, J ˆ 7.2, CH 2(1)); 7.15 7.30
4
)
During our study, Collet et al. [17] reported the decarbamoylation of monoalkylurea derivatives with NO
and O2 under aqueous conditions, in which N-nitroso derivatives were supposed to be key intermediates.
During preparation of this paper, Oecal and Erden [19] reported the successful oxygenation of the CˆN
5
)
1
bond in amidoximates by O2. Unfortunately, they had not seen our paper [3].

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Helvetica Chimica Acta Vol. 85 (2002)
‡
(m, ArH). 13C-NMR (CD3OD): 36.9; 43.7; 127.3; 129.5; 129.8; 140.7; 158.9. HR-MS: 180.1156 (C9H14N3O ; calc.
180.1137). Anal. calc. for C9H14N3O: C 60.32, H 7.31, N 23.45; found: C 60.08, H 7.24, N 23.38.
Photo-Sensitized Oxygenation of 4: Isolation of (2-Phenylethyl)urea (5) and (2-Phenylethyl)cyanamide (6).
A mixture of RB (2.4 mg) in AcOEt (100 ml) was stirred at 758 (bath temp.) for 1 h. Compound 4 (0.018 g,
0.1 mm) was added to the supernatant soln. (6 ml, RB < 0.018 mol/l) prepared above, and the whole was stirred
at 758 for 1 h. After cooling, a part of the mixture (5 ml) was subjected to photo-irradiation for 1 h through a
Pyrex filter under ice-cooling. During the photoreaction, O2 was bubbled into the reaction mixture. After
evaporation of the solvent, the residue was dissolved in excess MeOH, and Norit (0.014 g) was added. The
mixture was stirred at r.t. for 10 min, and the insoluble materials were filtered off. After evaporation of the
filtrate, purification of the residue by prep. TLC (CHCl3/MeOH 10 :1) afforded 5 (Rf 0.45; 0.008 g, 58%). The
less polar product (Rf > 0.45, 0.0041 g) was further purified by prep. TLC (hexane/AcOEt 2:1) to give
6
(0.0005 g, 4%), which was identified with authentic sample prepared above.
Photo-Sensitized Oxygenation of 4: Identification of NO by the Griess Reagent. The same photoreaction
described above with 4 (0.012g, 0.07 m m) was carried out for 1.5 h, and the mixture was extracted twice with
H2O. Each aq. soln. was analyzed with the Griess reagent, a soln. of sulfanilamide and N-(naphthalen-1-
yl)ethylenediamine in HCl, after passing through a CdÀCu column. The first extract showed the presence of
NOÀ2 (1.955 mmol) and NO3À (5.750 mmol), and the second extract the presence of NO2À (0.465 mmol) and NO3À
(0.265 mmol). Thus, total nitrogen oxide ions was 8.43 mmol.
tert-Butyl Na-Boc-l-citrullinate (10). A mixture of TsOH ¥ H2O (0.0069 g, 0.0036 mm) in dry toluene (5 ml)
was refluxed in a Dean-Stark apparatus. To the soln. were added a soln. of tert-butyl Na-Boc-l-ornithinate [9]
(0.0915 g, 0.32m m) in toluene (2.5 ml) and then a soln. of Me3SiNCO in dry toluene (0.2ml, 0.52m m as
Me3SiNCO), which was prepared from Me3SiNCO (0.35 ml, 2.6 mm) and toluene (1.0 ml). The soln. was stirred
at r.t. for 4.8 h and extracted with AcOEt after addition of sat. NaHCO3 (pH 9). The org. soln. was washed with
brine, dried (K2CO3), and evaporated to dryness. Purification of the residual oil by CC (CHCl3/MeOH 25 :1)
afforded 10 (0.0892g, 85%). Yellow oil. IR (neat): 1679. 1H-NMR (CD3OD): 1.44 (s, t-Bu); 1.47 (s, t-Bu); 1.56
1.69 (br., CH2(3)); 1.70 1.87 (m, CH2(4)); 3.20 (t, J ˆ 5.9, CH2(5)); 4.14 (br., HÀC(2)); 4.62 (s, CONH2); 5.26
(s, 2CONH). 13C-NMR: 25.64; 28.0; 28.4; 30.7; 40.1; 53.5; 80.0; 82.2; 155.76, 159.0, 171.8. HR-MS: 322.2180
‡
(C15H29N3O5 ; calc. 332.2180).
Photo-Sensitized Oxygenation of the Protected NOHA 9. A mixture of RB (2.1 mg) in AcOEt (100 ml) was
stirred at 758 (bath temp.) for 1 h and filtered. Compound 9 (0.0193 g, 0.06 mm), which was prepared according
to the method described in [9] with some modification [10], was dissolved in the filtrate (6 ml) with heating at
758 (bath temp.). A part of the soln. (5 ml) was photo-irradiated for 2h under the conditions described above
and worked up. Purification of crude products by prep. TLC (CHCl3/MeOH 10 :1) afforded the urea 10 (0.008 g,
51%) as a more-polar product (Rf 0.30). Further purification of the less-polar fraction (Rf 0.66) by prep. TLC
(hexane/AcOEt 2:1) gave the cyanamide 11 (0.002g, 10%). These products were identified with authentic
samples.
Reaction with NO. A soln. of the starting material in AcOEt was saturated with NO by bubbling for 5 min
under ice-cooling after pre-bubbling with Ar for 10 15 min. The NO-saturated soln. was stirred for an
appropriate time under the same conditions, and Ar was passed through for 20 min in order to expel the
remaining NO. The mixture was washed with H2O and brine, dried (MgSO4), and evaporated. Purification of
the residue afforded the product.
Reaction of 4 with NO: 1-(2-Phenylethyl)-1-nitrosourea (12). A soln. of 4 (0.050 g, 0.28 mm) in AcOEt
(30 ml) was treated for 40 min and worked up. Purification of the residue by prep. TLC (AcOEt/hexane 1:2),
followed by recrystallization from Et2O/hexane, afforded 12 (0.026 g, 48%). Yellow prisms. M.p. 101 1028. IR
(Nujol): 3529, 3412, 1740. 1H-NMR ((D6)DMSO): 2.62 (t, J ˆ 7.6, CH2(1)); 3.94 (t, J ˆ 7.6, CH2(2)); 7.15 (d, J ˆ
7.3, HÀC(2')); 7.21 (d, J ˆ 7.3, HÀC(4')); 7.28 (t, J ˆ 7.6, HÀC(3')); 7.80, 8.12(2 s, NH2). 13C-NMR ((D6)DMSO):
32.8; 39.9; 30.2; 126.5; 128.4; 128.6; 137.9; 158.8. 15N-NMR (50.55 MHz, (D6)DMSO): À296 (NAH2), À106
‡
(NB), 184 (NO). HR-MS: 194.0931 (C9H12N3O2 ; calc. 194.0929). Anal. calc. for C9H11N3O2: C 55.96, H 5.70,
N 21.76; found: C 55.79, H 5.69, N 21.76.
Reaction of 5 with NO: 12. A soln. of 5 (0.050 g, 0.31 mm) in AcOEt (50 ml) was treated for 50 min to give
12 (0.061 g, quant.).
Reaction of 1-(2-Phenylethyl)guanidine (7) with NO: 12. A soln. of 7 (0.050 g, 0.24 mm) in AcOEt (50 ml)
was treated for 7.5 h to give 12 (0.004 g, 9%) after purification by prep. TLC (AcOEt/hexane 1:2).
Reaction of 4-Phenylbutan-2-one Oxime (8) with NO: 4-Phenylbutan-2-one (13). A soln. of 8 (0.040 g,
0.24 mm) in AcOEt (10 ml) was treated for 3 h to give 13 (0.023 g, 64%) after purification by prep. TLC
(AcOEt/hexane 1:4).

Helvetica Chimica Acta Vol. 85 (2002)
2643
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Received May 29, 2002