Reactions of in situ generated N-Boc nitrones with aromatic and heteroaromatic Grignard reagents: Application to the synthesis of zileuton

Article abstract of DOI:10.1021/jo7025838

(Chemical Equation Presented) A new class of α-aromatic-N- hydroxylamines has been prepared by reaction of tert-butyl (phenylsulfonyl) alkyl-N-hydroxycarbamates with aromatic and heteroaromatic Grignard reagents. Reactions proceed via a base-assisted elimination of the phenylsulfonyl group leading to N-Boc nitrones. This methodology has been applied to the synthesis of zileuton.

Full text of DOI:10.1021/jo7025838

N-oxides, present advantages of being both more electrophilic
and more stable than their imines derivatives. That is why
numerous additions of organometallic reagents have been
performed on nitrones over the last years, leading to N-
hydroxylamine derivatives, which are valuable building blocks
in organic synthesis.4b,c,5 We recently developed an original
method to prepare N-(tert-butoxycarbonyl) (N-Boc)-protected
propargylic, allylic, and homoallylic N-hydroxylamines via in
situ generation of N-Boc-protected nitrones by reaction between
tert-butyl (phenylsulfonyl)alkyl-N-hydroxycarbamates 1 and
organometallic reagents (Figure 1).6 The undeniable advantage
of using the N-(tert-butoxycarbonyl) group resides in the fact
that it can be easily cleaved under mild conditions allowing
synthesis of hydrogenolysis-sensitive compounds and/or primary
N-hydroxy amino moiety.
Reactions of In Situ Generated N-Boc Nitrones
with Aromatic and Heteroaromatic Grignard
Reagents: Application to the Synthesis of
Zileuton
Xavier Guinchard and Jean-Noe¨l Denis*
De´partement de Chimie Mole´culaire (SERCO), UMR-5250,
ICMG FR-2607, CNRS, UniVersite´ Joseph Fourier, BP-53,
38041 Grenoble Cedex 9, France
jean-noel.denis@ujf-grenoble.fr
ReceiVed December 3, 2007
FIGURE 1. Reaction of in situ generated N-Boc nitrones 2 with
unsaturated organometallics.
Herein, we wish to report the reactions of these N-Boc
nitrones precursors with aromatic and heteroaromatic Grignard
reagents, leading to R-aromatic and R-heteroaromatic-N-Boc-
N-hydroxylamines 4, 6, 7, and 11 in good to excellent yields
and an application in the synthesis of zileuton.
A new class of R-aromatic-N-hydroxylamines has been
prepared by reaction of tert-butyl (phenylsulfonyl)alkyl-N-
hydroxycarbamates with aromatic and heteroaromatic Grig-
nard reagents. Reactions proceed via a base-assisted elimi-
nation of the phenylsulfonyl group leading to N-Boc nitrones.
This methodology has been applied to the synthesis of
zileuton.
Compounds 1a-e were easily prepared from aldehydes, tert-
butyl N-hydroxycarbamate, and sodium benzenesulfinate in
MeOH/H2O or H2O/THF in the presence of formic acid
according to our previous report.6 We first studied the reaction
of monocyclic heteroaromatic and aromatic Grignard reagents,
such as 2-thienyl- and 2-furylmagnesium bromides 3a7 and 3b,8
respectively, and arylmagnesium bromides 5a,b with various
tert-butyl (phenylsulfonyl)alkyl-N-hydroxycarbamates 1 (Table
1). Best conditions were found when sulfone 1a was reacted
with 3a in toluene during 45 min at room temperature leading
to compound 4a in 88% yield, versus 51% in THF. The
application of these conditions to sulfones 1b-d gave corre-
sponding R-thienyl-N-(Boc)-N-hydroxylamines 4b-d in 74%,
47%, and 54% yields, respectively. When the reaction was
Creation of the carbon-carbon bond remains a major
challenge for organic chemists. The use of organometallic
reagents is particularly attractive due to their huge nucleophi-
licity and structural diversity. Among them, Grignard reagents
are powerful tools for the synthetic chemist since they are in
most cases readily available, well-known, and very reactive
toward numerous electrophilic entities.1 In particular, the
addition of such reagents to the carbon-nitrogen double bond
of imines and their derivatives (hydrazones, oximes) is a
powerful method to prepare a wide range of amino compounds
which are used in organic synthesis as important intermediates.2
However, the basicity of Grignard reagents is often a problem
encountered when performing nucleophilic additions to imines,
promoting competitive enolization. This side reaction can be
overcome by the use of more electrophilic imines, bearing an
electron-withdrawing group on the nitrogen atom.3 However,
because of their intrisic high reactivity, these electrophilic imines
are more sensitive to moisture, they are unstable,3g and/or the
deprotection of the reaction products sometimes requires harsh
conditions. Nitrones,4 which can be considered as imine
(3) (a) Trost, B. M.; Marrs, C. J. Org. Chem. 1991, 56, 6468. (b) Weinreb,
S. M. Top. Curr. Chem. 1997, 190, 131. (c) Sisko, J.; Weinreb, S. M. J.
Org. Chem. 1990, 55, 393. (d) Murry, J. A.; Frantz, D. E.; Soheili, A.;
Tillyer, R.; Grabowski, E. J. J.; Reider, P. J. J. Am. Chem. Soc. 2001, 123,
9696. (e) Chemla, F.; Hebbe, V.; Normant, J.-F. Synthesis 2000, 75. (f)
Mecozzi, T.; Petrini, M. Tetrahedron Lett. 2000, 41, 2709. (g) Mecozzi,
T.; Petrini, M. Synlett 2000, 73. (h) Ballini, R.; Petrini, M. Tetrahedron
Lett. 1999, 40, 4449. (i) Lee, K. Y.; Lee, C. G.; Kim, J. N. Tetrahedron
Lett. 2003, 44, 1231. (j) Speekamp, W. N.; Moolenaar, M. J. Tetrahedron
2000, 56, 3817. (k) Petrini, M. Chem. ReV. 2005, 105, 3949.
(4) (a) Hamer, J.; Macaluso, A. Chem. ReV. 1964, 64, 473. (b) Merino,
P. C. R. Chim. 2005, 8. (c) Merino, P. In Science of Synthesis; Padwa, A.,
Ed.; Georg Thieme Verlag: Stuttgart, 2004; Vol. 27, Chapter 13, pp 511-
580. (d) Lombardo, M.; Trombini, C. Synthesis 2000, 759.
(5) Merino, P. Targets Heterocycl. Syst. 2003, 7, 140.
(6) Guinchard, X.; Valle´e, Y.; Denis, J.-N. Org. Lett. 2005, 7, 5147.
(7) Commercialy available from Sigma-Aldrich Co.
(1) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp,
F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42,
4302 and references cited therein.
(2) (a) Bloch, R. Chem. ReV. 1998, 98, 1407. (b) ComprehensiVe Organic
Synthesis; Heathcock, C. H., Ed.; Pergamon: Oxford, 1991; Vol. 2.
(8) Jung, M. E.; Gervay, J. J. Am. Chem. Soc. 1991, 113, 224.
10.1021/jo7025838 CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/13/2008
2028
J. Org. Chem. 2008, 73, 2028-2031

TABLE 1. Reactions of Sulfones 1 with Heteroaromatic and
Aromatic Grignard Reagents
SCHEME 1. Reaction of Sulfones 1b and 1f with
2-Benzothienylmagnesium Bromide: Synthesis of Zileuton 9
SCHEME 2. Reaction of Sulfone 1b with Indolylmagnesium
Bromides 10
2-benzothienyl Grignard 15 with sulfones 1b and 1f6 afforded
the corresponding R-benzothien-2-yl-N-Boc-N-hydroxylamines
7a and 7b in 76% and (unoptimized) 29% yields, respectively
(Scheme 1).
N-Boc N-hydroxylamine 7a was then engaged in the synthesis
of zileuton 9 (Ziflo),11 a compound belonging to the N-
hydroxyurea class.12 Zileuton is the first selective, orally active
inhibitor of the 5-lipoxygenase, an enzyme implicated in the
biosynthesis of leukotrienes which are implicated as mediators
in disease states13 such as asthma, allergy, psoriasis, and
inflammatory bowel disease. Several syntheses of zileuton have
been described within either racemic14 or enantioselective
pathways.10,15
a 51% yield when the reaction was performed in THF. b 3 equiv of
Grignard reagent. c dr: 0.7/1. d Reaction performed in THF/PhMe (1/5)
solution.
performed on â-chiral sulfone 1e, N-hydroxylamine 4e was
obtained with a poor level of diastereoselectivity. These
conditions were then applied to the reaction of sulfone 1a with
2-furylmagnesium bromide 3b, prepared by metalation of furan
with n-butyllithium in the presence of TMEDA followed by
transmetalation with magnesium bromide diethyl etherate.8
R-Furyl-N-(Boc)-N-hydroxylamine 4f was obtained in excellent
yield. Finally, the reaction of tolylmagnesium bromide 5a and
4-methoxyphenylmagnesium bromide 5b with sulfones 1a and
1b afforded the corresponding R-phenyl-N-(Boc)-N-hydroxyl-
amines 6a-d in good yields (Table 1).
We then focused on the reaction of N-Boc nitrones with
bicyclic heteroaromatic Grignard reagents such as 2-benzothien-
ylmagnesium bromide 15 (Scheme 1) and various indolylmag-
nesium bromides 10 (Scheme 2). Indeed, the benzothiophene
and the indole moieties are widely represented in bioactive
products.9 Compound 15 was prepared by metalation of ben-
zothiophene with n-butyllithium followed by transmetalation
with magnesium bromide diethyl etherate.10 Reactions of
(9) Selected references: (a) For bioactive indolic compounds, see: Gul,
W.; Hamman, M. T. Life Sci. 2005, 78, 442 and references cited therein.
Alvarez, M.; Salas, M. Heterocycles, 1991, 32, 1391 and references cited
therein. (b) For bioactive thiophene-based compounds, see: Fedi, V.;
Altamura, M.; Catalioto, R.-M.; Giannotti, D.; Giolitti, A.; Giuliani, S.;
Guidi, A.; Harmat, N. J. S.; Lecci, A.; Meini, S.; Nannicini, R.; Pasqui, F.;
Tramontana, M.; Triolo, A.; Maggi, C. A. J. Med. Chem. 2007, 50, 4793.
Filzen, G. F.; Bratton, L.; Cheng, X.-M.; Erasga, N.; Geyer, A.; Lee, C.;
Lu, G.; Pulaski, J.; Sorenson, R. J.; Unangst, P. C.; Trivedi, B. K.; Xu, X.
Bioorg. Med. Chem. Lett. 2007, 17, 3630. Fournier dit Chabert, J.; Marquez,
B.; Neuville, L.; Joucla, L.; Broussous, S.; Bouhours, P.; David, E.; Pellet-
Rostaing, S.; Marquet, B.; Moreau, N.; Lemaire, M. Bioorg. Med. Chem.
2007, 15, 4482 and references cited therein.
(10) Basha, A.; Henry, R.; McLaughlin, M. A.; Ratajczyk, J. D.;
Wittenberger, S. J. J. Org. Chem. 1994, 59, 6103.
(11) (a) McGill, K. A.; Busse, W. W. Lancet 1996, 348, 519. (b) Brooks,
D. W.; Carter, G. W. Search Anti-Inflammatory Drugs 1995, 129. (c)
Wenzel, S. E.; Kamada, A. K. Ann. Pharmacother. 1996, 30, 858.
(12) Bell, R. L. NoVel Inhib. Leukotrienes 1999, 235.
(13) Lewis, R. A.; Austen, K. F.; Soberman, R. J. N. Engl. J. Med. 1991,
323, 645.
J. Org. Chem, Vol. 73, No. 5, 2008 2029

SCHEME 3. Synthesis of Di-N-Boc Indolic
1,2-Diaminoethanes 12a-c
Experimental Section
1-[N-(tert-Butoxycarbonyl)-N-hydroxyamino]-3-methyl-1-(thien-
2-yl)butane (4a). To a stirred solution of sulfone 1a (200 mg, 0.58
mmol) in toluene (4 mL) under inert atmosphere was added 2 equiv
of 2-thienylmagnesium bromide (1.16 mL, 1.16 mmol, 1 M solution
in toluene) at room temperature. The resulting mixture was stirred
during 45 min before being quenched by addition of an aqueous
saturated solution of ammonium chloride. The mixture was then
extracted three times with EtOAc. The organic layers were washed
with brine and dried over anhydrous magnesium sulfate. After the
removal of the solvent, the crude mixture was then purified by
column chromatography on silica gel (eluent: CH2Cl2) to give the
pure product 4a (145 mg, 0.51 mmol). Yield: 88%. IR (film): 3211,
2961, 2931, 2871, 1686, 1476, 1399, 1319, 1236, 1170, 1136, 1096,
1
1043 cm-1. H NMR (CDCl3, 300 MHz): δ 0.94 (d, J ) 5.9 Hz,
3H, CH3), 0.96 (d, J ) 5.9 Hz, 3H, CH3), 1.46 (s, 9H, C(CH3)3),
1.55-1.75 (m, 2H, CH2), 2.05-2.20 (m, 1H, CH), 5.33 (dd, J )
5.6 and 9.8 Hz, 1H, CHN), 6.93 (dd, J ) 3.7 and 4.9 Hz, 1H, H
arom), 7.00 (d, J ) 3.2 Hz, 1H, H arom), 7.10 (s, 1H, OH), 7.18
(d, J ) 4.9 Hz, 1H, H arom). 13C NMR (CDCl3, 75.5 MHz): δ
21.7 (CH3), 22.9 (CH3), 24.8 (CH), 28.3 (C(CH3)3), 41.7 (CH2),
56.1 (CHN), 82.1 (C(CH3)3), 124.5 (CH arom), 125.2 (CH arom),
126.3 (CH arom), 142.6 (C arom), 156.7 (CdO). LRMS (ESI):
m/z ) 292 [(M + Li)+], 577 [(dimer + Li)+]. Anal. Calcd for
C14H23NO3S: C, 58.92; H, 8.13; N, 4.91. Found: C, 59.27; H, 8.22;
N, 4.83.
N-Hydroxylamine 7a was deprotected with hydrochloric acid
in Merino’s conditions,16 and the reaction of the resulting
primary N-hydroxylamine 8 with trimethylsilyl isocyanate
afforded racemic zileuton 9 in the excellent overall yield of 31%
in four steps from the commercially available tert-butyl N-
hydroxycarbamate.
Finally, we studied the reactions of sulfone 1b with indolyl-
magnesium bromides 10, obtained by metalation of the corre-
sponding indolic cores with methylmagnesium bromide.17 We
prepared R-indol-3′-yl-N-Boc-N-hydroxylamines 11a-e in ex-
cellent yields (Scheme 2). It is noteworthy that no transmetal-
ation occurred when halogenated indoles were used, allowing
access to halogenated products. The reduction of the N-OH bond
in compounds 11a, 11b, and 11e with samarium(II) diiodide
afforded 1,2-diamino indolic compounds 12a-c which could
be key intermediates in the synthesis of marine sponge
alkaloids18,19 of the spongotine and topsentin classes 13 and 14
(Scheme 3).
In conclusion, we have developed a novel method for the
synthesis of R-aryl-N-hydroxyamino compounds via the reaction
of N-Boc nitrone precursors 1a-e with aromatic and heteroaro-
matic Grignard reagents. We have shown that this reaction is
very general concerning the choice of the organometallic
reagent. We have applied this new methodology to the synthesis
of zileuton in an overall yield of 31% in four steps from the
commercially available tert-butyl N-hydroxycarbamate. Finally,
we have prepared the di-N-Boc indolic 1,2-diaminoethanes
12a-c, potential building blocks in the total syntheses of
spongotine and topsentin marine sponge products 13 and 14.
1-[N-(tert-Butoxycarbonyl)-N-hydroxyamino]-1-(benzothien-
2-yl)ethane (7a). To a solution of thianaphthene (89 mg, 0.66
mmol) in ether (1 mL) at room temperature was added n-BuLi (1.28
M in hexane 0.52 mL, 0.66 mmol). After 55 min of reaction,
MgBr2‚OEt2 (171 mg, 0.66 mmol) was added in three portions to
give a suspension of 2-benzothienylmagnesium bromide. To this
solution was added a solution of sulfone 1f (100 mg, 0.33 mmol)
in toluene (4 mL) and THF (1 mL). The resulting mixture was
allowed to stir at room temperature during 1 h. It was then quenched
by addition of a saturated aqueous solution of ammonium chloride.
Aqueous layers were extracted twice with EtOAc. The combined
organic layers were washed with brine, dried over anhydrous
magnesium sulfate, and filtered. The solvents were removed under
reduced pressure, and the residue was purified by column chro-
matography on flash silica gel (eluent: CH2Cl2). The product 7a
was obtained as a pale amorphous solid (73 mg, 0.25 mmol).
Yield: 76%. IR (KBr): 3213, 3150, 2962, 2869, 1681, 1408, 1389,
1
1325, 1157, 1101, 1011 cm-1. H NMR (CDCl3, 300 MHz): δ
1.47 (s, 9H, C(CH3)3), 1.71 (d, J ) 6.9 Hz, 3H, CH3), 5.48 (dq, J
) 1.0 and 7.0 Hz, 1H, CHN), 7.20 (s, 1H, H arom), 7.18-7.35
(m, 2H, H arom), 7.65-7.80 (m, 2H, H arom). 13C NMR (CDCl3,
75.5 MHz): δ 18.0 (CH3), 28.2 (C(CH3)3), 54.5 (CHN), 82.6
(C(CH3)3), 121.5, (CH arom), 122.2 (CH arom), 123.4 (CH arom),
124.2 (CH arom),139.4 (C arom), 139.5 (C arom),144.5 (C arom),
156.6 (CdO). Anal. Calcd for C15H19NO3S: C, 61.41; H, 6.53; N,
4.78. Found: C, 61.19; H, 6.70; N, 4.70.
1-(N-Hydroxyamino)-1-(benzothien-2-yl)ethane (8). A cold
solution of hydrochloric acid was prepared at 0 °C by adding 271
µL (300 mg, 3.82 mmol) of freshly distilled acetyl chloride to 1
mL of dry methanol. The resulting solution was stirred for 15 min
at 0 °C. A solution of N-hydroxylamine 7a (80 mg, 0.273 mmol)
in 0.7 mL of methanol was then added to the acidic solution at 0
°C, and the resulting mixture was stirred for an additional 2 h.
Methanol was then slowly evaporated under vacuum (temperature
<20 °C). The residue was dissolved in EtOAc, and to the resulting
mixture was added a saturated solution of sodium hydrogenocar-
bonate. It was then extracted twice with CH2Cl2. The combined
organic layers were washed with brine and dried over anhydrous
magnesium sulfate. After removal of the solvents, the residue was
purified by column chromatography on silica gel (eluent: CH2-
Cl2). The product 8 was obtained as a yellow amourphous solid
(34 mg, 0.18 mmol). Yield: 66%. IR (KBr): 3171, 3049, 2977,
(14) (a) Kolasa, T.; Brooks, D. W. Synth. Commun. 1993, 23, 743. (b)
Basha, A.; Ratajczyk, J. D.; Brooks, D. W. Tetrahedron Lett. 1991, 32,
3783.
(15) (a) Hsiao, C.-N.; Kolasa, T. Tetrahedron Lett. 1992, 33, 2629. (b)
Rohloff, J. C.; Alfredson, T. V.; Schwartz, M. A. Tetrahedron Lett. 1994,
35, 1011.
(16) Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero, T. Tetrahedron:
Asymmetry 1997, 8, 2381.
(17) Bodwell, G. J.; Li, J. Org. Lett. 2002, 4, 127.
(18) (a) Guinchard, X.; Valle´e, Y.; Denis, J.-N. J. Org. Chem. 2007, 72,
3972. (b) Guinchard, X.; Valle´e, Y.; Denis, J.-N. Org. Lett. 2007, 9, 3761
and references cited therein.
(19) For a general review on bis(indole) alkaloids, see: Yang, C.-G.;
Huang, H.; Jiang, B. Curr. Org. Chem. 2004, 8, 1691.
2030 J. Org. Chem., Vol. 73, No. 5, 2008

2865, 1453, 1366, 1310, 1082 cm-1. 1H NMR (CDCl3, 300 MHz):
δ 1.51 (d, J ) 6.6 Hz, 3H, CH3), 4.45 (q, J ) 6.6 Hz, 1H, CHN),
7.19 (s, 1H, H arom), 7.24-7.39 (m, 2H, H arom), 7.69-7.74 (m,
1H, H arom), 7.74-7.81 (m, 1H, H arom). 13C NMR (CDCl3, 75.5
MHz): δ 19.7 (CH3), 57.9 (CHN), 121.3 (CH arom), 122.3 (CH
arom), 123.3 (CH arom), 124.1 (CH arom), 124.2 (CH arom), 139.3
(C arom), 139.5 (C arom), 146.6 (C arom). LRMS (ESI): m/z 194
[(M + H)+], 217 [(M + Na)+]. Anal. Calcd for C10H11NOS: C,
62.15; H, 5.74; N, 7.25. Found: C, 61.88; H, 5.77; N, 7.05.
Zileuton (9). To a solution of primary hydroxylamine 8 (30 mg,
0.155 mmol) in THF (10 mL) was added TMSNCO (89 mg, 0.77
mmol) at room temperature, and the resulting solution was stirred
for 16 h. Several drops of water were then introduced, and the
resulting mixture was stirred for an additional 30 min. The mixture
was concentrated in vacuo, and the residue was triturated with CH2-
C12, collected, washed with CH2Cl2, and dried to give zileuton (9)
as a white solid (30 mg, 0.127 mmol). Yield: 82%. IR (film): 3468,
over a few hours and was stirred overnight. It was then quenched
by addition of an aqueous saturated solution of ammonium chloride.
The crude mixture was extracted three times by EtOAc. The organic
layers were washed by an aqueous saturated solution of sodium
chloride and then dried over anhydrous magnesium sulfate. After
removal of the solvent, the crude mixture was purified by column
chromatography on silica gel (eluent: CH2Cl2 then EtOAc) to yield
11a as a colorless solid (103 mg, 0.28 mmol). Yield: 78%. IR
(film): 3332, 3057, 2980, 2932, 2872, 1695, 1515, 1457, 1395,
1366, 1288, 1251, 1169, 1111 cm-1. 1H NMR (CDCl3, 300 MHz):
δ 1.38 (s, 9H, C(CH3)3), 1.41 (s, 9H, C(CH3)3), 3.20-3.28 (m,
1H, CH of CH2N), 3.85-4.05 (m, 1H, CH of CH2N), 5.06 (br s,
1H, NHBoc), 5.44 (dd, J ) 4.2 and 11.4 Hz, 1H, CHN), 7.04 (dt,
J ) 1.0 and 7.2 Hz, 1H, H indol), 7.10 (t, J ) 6.9 Hz, 1H, H
indol), 7.18 (s, 1H, H indol), 7.26 (d, J ) 7.8, 1H, H indol), 7.63
(d, J ) 7.5 Hz, 1H, CH indol), 8.28 (s, 1H, NH indol). 13C NMR
(CDCl3, 75.5 MHz): δ 28.4 (2 C(CH3)3), 41.4 (CH2N), 55.1 (CHN),
80.6 (C(CH3)3), 81.1 (C(CH3)3), 111.2 (CH indol), 112.2 (C indol),
119.1 (CH indol), 119.7 (CH indol), 122.1 (CH indol), 123.1 (CH
indol), 126.4 (C indol), 135.7 (C indol), 156.4 (CdO), 158.0 (Cd
O). LRMS (ESI): m/z 398 [(M + Li)+], 414 [(M + Na)+], 789
[(dimer + Li)+], 805 [(dimer + Na)+]. HRMS (ESI): calcd for
C20H29N3O5Na [(M + Na)+] 414.2005, found 414.2007.
1
3318, 3270, 3191, 2876, 1651, 1573, 1456, 1434, 1157 cm-1. H
NMR (DMSO, 300 MHz): δ 1.51 (d, J ) 6.9 Hz, 1H, CH3), 5.57
(q, J ) 6.9 Hz, 1H, CHN), 6.41 (s, 2H, NH2), 7.26 (s, 1H, H arom),
7.25-7.37 (m, 2H, H arom), 7.73-7.79 (m, 1H, H arom), 7.85-
7.90 (m, 1H, H arom), 9.22 (s, 1H, H arom). 13C NMR (DMSO,
75.5 MHz): δ 17.8 (CH3), 52.3 (CHN), 121.2 (CH arom), 122.1
(CH arom), 123.2 (CH arom), 123.9 (CH arom), 124.0 (CH arom),
138.9 (C arom), 139.0 (C arom), 146.1 (C arom), 163.3 (CdO).
LRMS (ESI): m/z 237 [(M + H)+], 259 [(M + Na)+], 275 [(M +
K)+].
1-[N-(tert-Butoxycarbonyl)-N-hydroxyamino]-2-[N-(tert-but-
oxycarbonyl)amino]-1-(indol-3′-yl)ethane (11a). To a solution of
indole (127 mg, 1.08 mmol) in THF (3 mL) at -78 °C under inert
atmosphere was added methylmagnesium bromide (0.36 mL, 1.08
mmol, 3 M solution in Et2O), and the resulting solution was stirred
during 15 min. A solution of the sulfone 1b dissolved into THF
was slowly added, and the reaction was allowed to reach -5 °C
Acknowledgment. We thank ACI no. 02L0525, “Nouvelles
approches the´rapeutiques du cancer”, for financial support. This
research work was supported by a grant from the Ministe`re de
la Jeunesse, de l’Education Nationale et de la Recherche to X.G.
Supporting Information Available: Experimental procedures
and full characterization of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO7025838
J. Org. Chem, Vol. 73, No. 5, 2008 2031