Acyclic oxyiminium ions. Mannich reactions and addition of grignard reagents

Article abstract of DOI:10.1016/S0040-4020(00)00721-3

Acyclic oxyiminium ion generation from secondary hydroxylamines (4a,b and 6a,b) and formaldehyde in the presence of acetic acid is reported. Trapping these electrophiles with 2-methyl furan, pyrrole or indole affords a series of novel O-benzyl tertiary hydroxylamines in good to excellent yield. Benzotriazole mediated synthetic methodology has also been successfully developed to generate oxyiminium ions which react with Grignard reagents, to give novel O-benzyl tertiary hydroxylamines. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00721-3

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 8025±8032
Acyclic Oxyiminium Ions. Mannich Reactions and Addition of
Grignard Reagents
b
a
R. Grigg,a, Z. Rankovic and M. Thoroughgood
*
aLeeds University, School of Chemistry, Woodhouse Lane, Leeds, LS2 9JT, UK
bOrganon Laboratories, Newhouse, Motherwell, ML1 5SH, UK
Received 30 May 2000; revised 20 July 2000; accepted 10 August 2000
AbstractÐAcyclic oxyiminium ion generation from secondary hydroxylamines (4a,b and 6a,b) and formaldehyde in the presence of acetic
acid is reported. Trapping these electrophiles with 2-methyl furan, pyrrole or indole affords a series of novel O-benzyl tertiary hydroxyl-
amines in good to excellent yield. Benzotriazole mediated synthetic methodology has also been successfully developed to generate
oxyiminium ions which react with Grignard reagents, to give novel O-benzyl tertiary hydroxylamines. q 2000 Elsevier Science Ltd. All
rights reserved.
Introduction
We now report Mannich reactions of secondary hydroxyl-
amine (4a,b and 6a,b), formaldehyde, and 5-membered
heterocycles to give the corresponding Mannich bases in
moderate to excellent yield. We also report the utilisation
of benzotriazole for the generation of oxyiminium ions and
their subsequent reactions with a range of Grignard reagents
to give novel tertiary O-benzyl hydroxylamine derivatives.
Tertiary O-alkyl hydroxylamines exhibit a variety of bio-
logical properties, often similar to that of their analogous
tertiary amines. For example, recent studies of the biologi-
cal activity of tertiary O-alkyl hydroxylamines report anti-
bacterial activity,1 anticonvulsant activity,2 inhibition of
human plasma renin,3 promotion of chlorophyll retention
in rice leaves/growth of soybean hypocotyl sections4 and
insecticidal activity.5 As part of our ongoing interest in
the sparsely studied chemistry of oxyiminium ions (or
oxoiminium ions) we have been developing effective routes
for the preparation of O-benzyl tertiary hydroxylamines
with the view to the coupling this methodology with our
hydroxylamine linker for the solid-phase synthesis of
tertiary amines.6 Whilst there have been examples in the
literature reporting the Mannich reaction of oxyiminium
ions (generated in situ from secondary hydroxylamines
and an appropriate carbonyl compound) with aceto-
phenone,7 N-methyl piperazine,8 1,2,4,5-tetrahydro-3,2-
benzoxazepine8 and cyanide,9 to our knowledge there are
no examples in the literature using aromatic heterocycles as
the nucleophilic component.
Results and Discussion
Thus, O-benzyl hydroxylamine hydrochloride (1) was
reacted with Boc anhydride (Scheme 1)10 to give Boc
protected O-benzyl hydroxylamine hydrochloride (2) in
excellent yield. This was then alkylated with alkyl halides11
to give carbamates (3a and b) in excellent yields. Deprotec-
tion with TFA/DCM proceeded smoothly to give secondary
O-benzyl hydroxylamines (4a and b) in excellent yield.
Alternatively, secondary O-benzyl hydroxylamines were
prepared via the reduction of oxime ethers (Scheme 2).12,13
Using secondary hydroxylamine (4a), formaldehyde and a
range of nucleophiles a series of O-benzyl Mannich bases
Scheme 1.
Keywords: acyclic oxyiminium ion; Mannich reaction; Grignard reagent.
* Corresponding author. Tel.: 144-113-2336501; fax: 144-113-2336501; e-mail: r.grigg@chem.leeds.ac.uk
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00721-3

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R. Grigg et al. / Tetrahedron 56 (2000) 8025±8032
Scheme 2.
were successfully synthesised (Scheme 3). The nucleophiles
chosen to map out the reaction's scope were those that
would lead to Mannich bases of pharmacological interest,
e.g. 2-methylfuran, pyrrole, indole, phenol, 1,3-dimethoxy
benzene, thiophene and 2-methoxythiophene.14 Initial
reactions gave predominately the aminal (11), an unwanted
side product,15 by reaction of the oxyiminium ion inter-
mediate (7) with unreacted (4a), together with a very poor
yield of the Mannich base (,10%). However, with opti-
misation (excess nucleophile and acetic acid) it was possible
to minimise the formation of (11) (,15%) and obtain the
O-benzyl Mannich bases in good to excellent yield.
DCM at r.t. proceeded smoothly to give the expected
Mannich base (8) in excellent yield via oxyiminium ion
(7). The reaction could be repeated with indole under
analogous conditions using methanol as the solvent to
give (9) (82%). The use of DCM as solvent for this
particular nucleophile resulted in greater formation of
aminal (11) than with pyrrole. Moreover, using 2-methyl-
furan as nucleophile required more forcing conditions.
Conditions analogous to pyrrole, resulted in exclusive
formation of aminal (11). However, boiling (4a)
(1 equiv.), paraformaldehyde (1 equiv.), 2-methyl furan
(5 equiv.) and acetic acid (10 equiv.) in DCE under re¯ux
proceeded smoothly to give (10) (72%). Unfortunately, the
use of phenol, 1,3-dimethoxybenzene, thiophene and
2-methoxythiophene, under a variety of conditions resulted
in virtually exclusive formation of (11) showing that these
nucleophiles were less reactive.
Surprisingly, the use of excess formaldehyde actually
promoted formation of (11). A typical reaction of (4a)
(1 equiv.), formaldehyde (1 equiv.) (37% soln, in
methanol), pyrrole (5 equiv.) and acetic acid (10 equiv.) in
Scheme 3.
Scheme 4.

R. Grigg et al. / Tetrahedron 56 (2000) 8025±8032
8027
The scope of the secondary hydroxylamine component in
the reaction was then explored with several analogues of
Mannich bases using pyrrole as the common nucleophile
(Scheme 4). Thus reaction of (6a), formaldehyde (37%
soln, in methanol), pyrrole and acetic acid in DCM at r.t.
proceeded smoothly to give (13) in good yield via oxy-
iminium ion (12). However, using aliphatic secondary
hydroxylamines (4b) and (6b) under analogous conditions
resulted in large amounts of the secondary hydroxylamine
being left unreacted even after two days, suggesting that
oxyiminium ion formation in this low polarity solvent
mixture was slow. Using a more polar solvent (methanol)
at 2108C, complete reaction of the starting material could
be achieved affording (14) (69%) and (15) (55%), respec-
tively. 1H NMR monitoring of reactions at ambient tempera-
ture showed that other compounds were being formed such
as the isomers (16) and (19) and the dimers (17) and (20),
illustrating the high reactivity of the oxyiminium ion inter-
mediates. Interestingly, the 1H NMR spectra showed no sign
of the dimers (18) or (21). It was found that repeating the
reaction at 2108C minimised the formation of the side
products.
The scope of the carbonyl component in the reaction was
explored by substituting formaldehyde by acetaldehyde,
acetone or benzaldehyde. Unfortunately, reacting secondary
hydroxylamine (4a) and pyrrole with any of these alterna-
tive carbonyl compounds, under a variety of conditions was
unsuccessful. The 1H NMR spectra of the reaction mixtures
showed the presence of large quantities of starting material
along with small amounts of unidenti®ed products.
Benzotriazole has been used in place of a halogen sub-
stituent in many reactions. A recent review16 indicates
a-benzotriazolylalkyl amines and a-benzotriazolylalkyl
ethers are of considerable synthetic utility in aminoalkyl-
ation (amines, hydroxylamines, hydrazines, amides, thio-
amides and sulphonamides) and alkoxyalkylation
reactions (ethers and esters) when used in conjunction
with nucleophiles such as Grignard reagents and lithium
enolates. In addition, these benzotriazole derivatives are
frequently more stable and less toxic than their chloro or
bromo analogues. Benzotriazole has not previously been
utilised for oxyiminium ion generation from O-alkyl
hydroxylamines (only O-unsubstituted hydroxylamine)
and offers methodology for increased N-alkyl diversity for
the development of a hydroxylamine linker for the synthesis
Scheme 5.

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R. Grigg et al. / Tetrahedron 56 (2000) 8025±8032
Scheme 6.
of N-methyl tertiary amines.6 Additionally, benzotriazole
chemistry offers the potential for mild conditions and
solvents viable for chemistry on polymer supports e.g.
DCM, THF.
the reaction mixture showed a small quantity (,5%) of
aminal (11) (Scheme 5). The water by-product can be
removed from the reaction by adding magnesium sulphate
just before work up and isolation of (22). In solution, (22)
enters into equilibrium with the oxyiminium ion (23) which
can be trapped with a range Grignard reagents in dry THF to
give the corresponding tertiary hydroxylamines (24±27) in
69±78% overall yield from (4a). The use of excess Grignard
reagent and long reaction times (24 h) were required to push
the reactions to completion.
Thus, vigorous stirring of secondary O-benzyl hydroxyl-
amine (4a) (1 equiv.), benzotriazole (1 equiv.) and formal-
dehyde (37% in methanol) (1 equiv.) in DCM gave the
a-benzotriazolylalkyl O-benzyl hydroxylamine (22) in
1
near quantitative yield, although the H NMR spectra of
Scheme 7.
Scheme 8.

R. Grigg et al. / Tetrahedron 56 (2000) 8025±8032
8029
The scope of the carbonyl component of the reaction was
then explored by substituting formaldehyde with acetalde-
hyde, cyclopropane carboxaldehyde, benzaldehyde, furfur-
aldehyde, cyclohexane carboxaldehyde, acetone and
cyclohexanone.
by ¯ash chromatography, eluting with 10:1 v/v petroleum
ether±diethyl ether to give the product (4.98 g, 89%), as a
pale yellow oil. Found: C, 73.3; H, 7.5; N, 4.35. C20H25NO3
requires C, 73.35; H, 7.7; N, 4.3%. m/z (%) (FAB): 328
(M11, 14), 272 (70), 228 (17), 210 (18), 182 (7) and 91
(100). nmax 2980, 1700, 1360, 1150, 740 and 690 cm21. d:
7.42±7.17 (m, 10H, ArH), 4.82 (s, 2H, OCH2), 3.62 (t, 2H,
Jˆ7.3 Hz, NCH2CH2Ph), 2.88 (t, 2H, Jˆ7.3 Hz,
NCH2CH2Ph) and 1.45 (s, 9H, 3£Me).
Carbamate (3b).11 No further puri®cation was required.
The product (98%), a pale yellow oil, was used directly
for the next step. d: 7.44±7.32 (m, 5H, Ar H), 4.85 (s,
2H, OCH2), 3.07 (s, 3H, NMe) and 1.50 (s, 9H, 3£Me).
The a-benzotriazolylalkyl O-benzyl hydroxylamines (28)
and (30) were successfully prepared in excellent yield in
DCM under analogous conditions (Scheme 6), but
analogous reactions using benzaldehyde, furfuraldehyde,
cyclohexane carboxaldehyde and cyclohexanone were less
successful, giving mixtures of the desired compound
(60±80%) and starting material (20±40%) even when
using molecular sieves to remove water. The reaction with
acetone gave exclusively starting material.
General procedure for Boc deprotection. The appropriate
carbamate was added to a stirred solution of 3: 1 v/v DCM-
TFA (2.5 ml mmol21 of carbamate). The reaction mixture
was stirred at r.t. for 20 h, made alkaline with 1 M sodium
hydrogen carbonate solution and extracted with DCM. The
combined organic extracts were dried (MgSO4), ®ltered and
the solvent removed under reduced pressure to give the
product.
Reaction of benzotrialzole derivative (28) (Scheme 7) or
(30) (Scheme 8) with the vinyl and phenyl magnesium
bromides (3 equiv.) in dry THF gave the novel O-benzyl
tertiary hydroxylamines (32±35) in good yield, via trapping
of the corresponding oxyiminium ions (29) and (31)
(Scheme 6).
Experimental
O-Benzyl-N-phenethyl-hydroxylamine (4a). No further
puri®cation was necessary. The product (94%) was obtained
as a pale yellow oil. Found: C, 79.0; H, 7.45; N, 6.3,
C15H17NO requires C, 79.25; H, 7.55; N, 6.15%. m/z (%):
228 (M11, 5), 182 (23), 136 (65), 104 (11), 91 (100) and
77 (26). nmax 3260, 3020, 2900, 1490, 1450, 1360, 1010,
740 and 690 cm21. d: 7.36±7.17 (m, 10H, ArH), 5.55 (br
s, 1H, NH), 4.72 (s, 2H, OCH2), 3.17 (t, 2H, Jˆ
7.0 Hz, NCH2CH2Ph) and 2.84 (t, 2H, Jˆ7.0 Hz,
NCH2CH2Ph).
Melting points were obtained on a Ko¯er hot-stage
apparatus and are uncorrected. Infrared spectra were
recorded on a PU 9706 infrared spectrometer using
potassium bromide discs. Microanalyses were obtained
using a Carlo Erba Elemental Analyser MOD 1106. Mass
spectral data were obtained using a VG-AutoSpec spectro-
meter operating at 70 eV using per¯uorokerosine for
accurate molecular weights. Nuclear magnetic resonance
spectra were recorded at 250 or 300 MHz using Bruker
AC 250 or General Electric QE300. Column chromato-
graphy employed Silica Gel 60 (Merck 9385). Flash
chromatographic columns were run using air pressure to
maintain a column ¯ow rate of the solvent of ca.
5 cm3 min21. The term ether (Et2O) refers to diethyl ether,
and petroleum ether refers to the fraction with boiling point
40±608C.
O-Benzyl-N-methyl-hydroxylamine (4b).11 The pale
yellow oily residue was puri®ed by ¯ash chromatography,
eluting with 1:1 v/v petroleum ether±diethyl ether to give
the product (89%) as a pale yellow oil. d: 7.39±7.20 (m, 5H,
ArH), 5.55 (br s, 1H, NH), 4.67 (s, 2H, OCH2) and 2.71 (s,
3H, Me).
Oxime ethers (5a) and (5b).12 Prepared as described in the
literature.
Synthesis of the O-benzyl secondary hydroxylamines
(4a,b) and (6a,b)
(5a). The E-isomer (98%) was obtained as a colourless oil.
d: 7.40±7.20 (m, 11H, 10£ArH and imine H) and 5.20 (s,
2H, OCH2).
Boc protected O-benzyl hydroxylamine (2).10 Prepared
(98%) as described in the literature as colourless crystals,
mp 42±458C, (lit. 45±468C). d: 7.41±7.32 (m, 5H, ArH),
7.24 (br s, 1H, NH), 4.83 (s, 2H, OCH2) and 1.48 (s, 9H,
3£Me).
(5b). The product (99%) was obtained as a colourless oil. d:
7.38±7.25 (m, 5H, ArH), 5.05 (s, 2H, OCH2) and 1.87 (s,
6H, 2£Me).
General procedure for synthesis of carbamates (3a) and
(3b). Sodium hydride (1.1 equiv.) was added to a stirred
solution of (2) (1 equiv.) in anhydrous DMF and the result-
ing solution stirred at r.t. for 30 min. The appropriate alkyl
halide (1.1 equiv.) was added and the reaction mixture stir-
red at r.t. for a further 16 h, then poured into water and the
product extracted with hexane. The combined extracts were
dried (MgSO4), ®ltered and the solvent removed under
reduced pressure.
General procedure for reduction of O-benzyl oxime
ethers (5a,b).13 Sodium cyanoborohydride (5 equiv.) was
added to a stirred solution of the appropriate oxime ether
(1 equiv.) in methanol. Two drops of methyl orange
indicator were added followed by dropwise addition of
concentrated hydrochloric acid, until the solution remained
pink for at least half an hour. The reaction mixture was
stirred at r.t. for 16 h and the solvent removed. The residue
was taken up in DCM and washed until alkaline with 1 M
potassium hydroxide solution and extracted with DCM. The
Carbamate (3a). The pale yellow oily residue was puri®ed

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R. Grigg et al. / Tetrahedron 56 (2000) 8025±8032
combined organic extracts were dried (MgSO4), ®ltered and
the solvent removed to give the product.
(%): 357 (M11, 28), 240 (11), 220 (20), 207 (9), 130 (100),
103 (12), and 91 (49). nmax 3420, 2920, 1450, 1360, 1090,
1010, 740, and 690 cm21. d: 7.96 (br s, 1H, NH), 7.70±7.04
(m, 15H, ArH and 5£indole H), 4.60 (s, 2H, OCH2), 4.11 (s,
2H, NCH2) and 3.02±2.93 (m, 4H, NCH2CH2Ph).
N,O-Dibenzyl-hydroxylamine (6a).13 Puri®cation by
column chromatography, eluting with diethyl ether afforded
the product (86%) as a pale yellow oil. d: 7.35±7.18 (m,
10H, ArH), 5.67 (br s, 1H, NH), 4.61 (s, 2H, OCH2) and 3.98
(s, 2H, NCH2).
O-Benzyl-N-(5-methylfuran-2-ylmethyl)-N-phenethyl-
hydroxylamine (10). 2-Methylfuran (180 mg, 2.2 mmol)
was added to a stirred solution of secondary hydroxylamine
(4a) (100 mg, 0.44 mmol), paraformaldehyde (14 mg,
0.44 mmol) and acetic acid (270 mg, 4.4 mmol) in DCE
(10 ml). The reaction mixture was stirred under re¯ux for
20 h. The solvent was removed under reduced pressure and
the residue was taken up in DCM (5 ml), washed until
alkaline with 1 M sodium hydrogen carbonate solution
and extracted with DCM (3£15 ml). The combined organic
extracts were dried (MgSO4), ®ltered and the solvent
removed under reduced pressure. The pale orange oily
residue was puri®ed by ¯ash chromatography, eluting with
10:1 v/v petroleum ether±diethyl ether to give the product
(103 mg, 72%), as a pale yellow oil. Found: C, 78.2; H,
7.25; N, 4.3. C21H23NO2 requires C, 78.45; H, 7.2; N,
4.35%. m/z (%) (FAB): 322 (M11, 8), 240 (7), 230 (13),
214 (8), 105 (8) and 91 (100). nmax 2920, 1450, 1360, 1220,
1020, 790, 740 and 690 cm21. d: 7.32±7.19 (m, 10H, ArH),
6.15 (m, 1H, furan H), 5.93 (m, 1H, furan H), 4.56 (s, 2H,
OCH2), 3.85 (s, 2H, NCH2), 2.99 (s, 4H, NCH2CH2Ph) and
2.31 (s, 3H, Me).
O-Benzyl-N-isopropyl-hydroxylamine (6b). Puri®cation
by column chromatography, eluting with diethyl ether
afforded the product (92%) as a pale yellow oil. Found: C,
72.9; H, 9.15; N, 8.5. C10H15NO requires C, 72.7; H, 9.15;
N, 8.5 %. m/z (%): 165 (M11, 2), 108 (2), 105 (4), 98 (2), 92
(9), 91 (100) and 54 (11). nmax 3250, 2960, 1450, 1360,
1050, 740 and 700 cm21. d: 7.40±7.23 (m, 5H, ArH),
5.36 (br s, 1H, NH), 4.71 (s, 2H, OCH2), 3.19 (sept, 1H,
NCHMe2), and 1.08 (d, 6H, Jˆ6.3 Hz, 2£Me).
Synthesis of O-benzyl tertiary hydroxylamines (8±10, 13,
14 and 15)
O-Benzyl-N-phenethyl-N-(pyrrol-2-ylmethyl)-hydroxyl-
amine (8). Formaldehyde (37% solution methanol, 36 mg,
0.44 mmol) was added to a stirred solution of secondary
hydroxylamine (4a) (100 mg, 0.44 mmol), pyrrole
(150 mg, 2.2 mmol) and acetic acid (270 mg, 4.4 mmol) in
DCM (10 ml). The ¯ask was wrapped in foil and the stirred
at r.t. for 16 h and washed with aqueous sodium hydrogen
carbonate solution. The organic layer was separated and the
aqueous layer extracted with DCM (3£15 ml). The
combined organic extracts were dried (MgSO4), ®ltered
and the solvent removed under reduced pressure. The
residue was puri®ed by ¯ash chromatography, eluting with
4:1 v/v petroleum ether±diethyl ether to give the product
(112 mg, 83%) as a pale yellow oil, which solidi®ed slowly
to colourless needles, mp 62±648C. Found: C, 78.25; H,
7.35; N, 9.4. C20H22N2O requires C, 78.4; H, 7.25; N,
9.15%. m/z (%): 306 (M11, 1), 227 (1), 215 (4), 182 (1),
170 (25), 157 (8), 91 (47) and 80 (100). nmax 3460, 2930,
1450, 1370, 1020, 910, and 730 cm21. d: 8.27 (br s, 1H,
NH), 7.38±7.15 (m, 10H, ArH), 6.69 (m, 1H, Ha), 6.14±6.07
(m, 2H, Hb), 4.58 (s, 2H, OCH2), 3.90 (s, 2H, NCH2) and
2.92 (s, 4H, NCH2CH2Ph).
N,O-Dibenzyl-N-(pyrrol-2-ylmethyl)-hydroxylamine (13).
Formaldehyde (37% solution in methanol, 37 mg,
0.47 mmol) was added to a stirred solution of secondary
hydroxylamine (6a) (100 mg, 0.47 mmol), pyrrole
(160 mg, 2.4 mmol) and acetic acid (280 mg, 4.7 mmol) in
DCM (10 ml). The ¯ask was wrapped in foil and stirred at
r.t. for 16 h and washed with aqueous sodium hydrogen
carbonate solution until alkaline. The organic layer was
separated and the aqueous layer extracted with DCM
(3£15 ml). The combined organic extracts were dried
(MgSO4), ®ltered and the solvent removed under reduced
pressure. The residue was puri®ed by ¯ash chromatography,
eluting with 4:1 v/v petroleum ether±diethyl ether to give
the product (105 mg, 78%) as a pale yellow oil, which
solidi®ed slowly to colourless needles, mp 72±758C.
Found: C, 77.95; H, 6.95; N, 9.55. C19H20N2O requires C,
78.05; H, 6.9; N, 9.6%. m/z (%): 292 (M11, 2), 170 (25),
157 (8), 91 (60) and 80 (100). nmax 3400, 2930, 1450, 1360,
1020, 970, 720 and 700 cm21. d: 8.38 (br s, 1H, NH), 7.37±
7.10 (m, 10H, ArH), 6.72 (m, 1H, Ha), 6.17±6.05 (m, 2H,
Hb), 4.33 (s, 2H, OCH2), 3.90 (s, 2H, NCH2) and 3.82 (s, 2H,
NCH2Ph).
O-Benzyl-N-(indole-3-ylmethyl)-N-phenethyl-hydroxyl-
amine (9). Formaldehyde (37% solution in methanol,
36 mg, 0.44 mmol) was added to a stirred solution of
secondary hydroxylamine (4a) (100 mg, 0.44 mmol), indole
(260 mg, 2.2 mmol) and acetic acid (270 mg, 4.4 mmol) in
methanol (10 ml). The ¯ask was wrapped in foil and the
stirred at r.t. for 21 h and the solvent removed under reduced
pressure. The residue was taken up in DCM (10 ml) and
washed with aqueous sodium hydrogen carbonate solution
until alkaline. The organic layer was separated and the
aqueous layer extracted with DCM (3£15 ml). The
combined organic extracts were dried (MgSO4), ®ltered
and the solvent removed under reduced pressure. The
residue was puri®ed by ¯ash chromatography, eluting with
3:1 v/v petroleum ether±diethyl ether to give the product
(130 mg, 82%) as a pale yellow oil, which solidi®ed slowly
to colourless needles, mp 76±788C. Found: C, 80.7; H, 6.9;
N, 7.95. C24H24N2O requires C, 80.85; H, 6.8; N, 7.85%. m/z
O-Benzyl-N-methyl-N-(pyrrol-2-ylmethyl)-hydroxyl-
amine (14). Formaldehyde (37% solution in methanol,
60 mg, 0.73 mmol) was added to a stirred solution of
secondary hydroxylamine (4b) (100 mg, 0.73 mmol),
pyrrole (250 mg, 3.7 mmol) and acetic acid (440 mg,
7.3 mmol) in methanol (10 ml) at 2108C. The ¯ask was
wrapped in foil and allowed to return to r.t. with stirring
over 16 h. The solvent was removed under reduced pressure,
the residue taken up in DCM (10 ml) and washed with
aqueous sodium hydrogen carbonate solution until alkaline.
The organic layer was separated and the aqueous layer

R. Grigg et al. / Tetrahedron 56 (2000) 8025±8032
8031
extracted with DCM (3£15 ml). The combined organic
extracts were dried (MgSO4), ®ltered and the solvent
removed under reduced pressure. The residue was puri®ed
by ¯ash chromatography, eluting with 2:1 v/v petroleum
ether±diethyl ether to give the product (104 mg, 69%) as
a pale yellow oil, which solidi®ed slowly to colourless
needles, mp 36±388C. Found: C, 72.2; H, 7.6; N, 13.2.
C13H16N2O requires C, 72.2; H, 7.45; N, 12.95%. m/z (%):
216 (M11, 2), 187 (2), 170 (14), 157 (5), 91 (35), and 81
(100). nmax 3380, 2930, 1450, 1360, 1030, 730, and
700 cm21. d: 8.34 (br s, 1H, NH), 7.35±7.20 (m, 5H,
ArH), 6.70 (m, 1H, Ha), 6.12 (m, 2H, Hb), 4.56 (s, 2H,
OCH2), 3.82 (s, 2H, NCH2) and 2.57 (s, 3H, Me).
oil. HRMS: 372.195. C23H24N4O requires 372.197. m/z (%):
373 (M11, 0.5), 162 (2), 119 (30), 105 (36), 91 (59), 77 (42)
and 56 (100). nmax 3040, 2940, 1610, 1450, 1370, 1280,
1150, 1020, 740 and 700 cm21. d: 8.05±7.12 (m, 14H,
ArH), 5.94 (q, 1H, Jˆ6.8 Hz, Ha), 4.67 (AB, 2£d, 2H,
Jˆ10.8 Hz, OCH2), 2.90 (m, 4H, NCH2CH2Ph) and 1.93
(d, 3H, Jˆ6.8 Hz, Me).
Benzotriazole derivative (30). No further puri®cation was
necessary. The product (90%) was obtained as a light brown
oil. HRMS: 398.213. C25H26N4O requires: 398.211. m/z
(%): 399 (M11, 1), 280 (100), 172 (10), 144 (7), 105 (26)
and 91 (52).nmax 3020, 2920, 1600, 1440, 1360, 1260, 1000,
740 and 690 cm21. d: 8.08±7.12 (m, 14H, ArH), 4.87 (d,
1H, Jˆ9.7 Hz, Ha), 4.61 (AB, 2£d, 2H, Jˆ10.5 Hz, OCH2),
3.06 (m, 4H, NCH2CH2Ph), 2.04 (m, 1H, Hb), 0.89, 0.70,
0.58 and 0.29 (4£m, 4£1H, cyclopropyl H).
O-Benzyl-N-isopropyl-N-(pyrrol-2-ylmethyl)-hydroxyl-
amine (15). Formaldehyde (37% solution in methanol,
50 mg, 0.61 mmol) was added to a stirred solution of
secondary hydroxylamine (6b) (100 mg, 0.61 mmol),
pyrrole (210 mg, 3.1 mmol) and acetic acid (370 mg,
6.1 mmol) in methanol (10 ml) at 2108C. The ¯ask was
wrapped in foil and the mixture stirred and allowed to return
to r.t. over 18 h. The solvent was removed under reduced
pressure, the residue taken up in DCM (10 ml) and washed
with aq. sodium hydrogen carbonate solution until neutral.
The organic layer was separated and the aqueous layer
extracted with DCM (3£15 ml). The combined organic
extracts were dried (MgSO4), ®ltered and the solvent
removed under reduced pressure. The residue was puri®ed
by ¯ash chromatography, eluting with 4:1 v/v petroleum
ether±diethyl ether to give the product (82 mg, 55%) as a
pale yellow oil, which solidi®ed slowly to give colourless
needles, mp 46±488C. Found: C, 73.75; H, 8.3; N, 11.2.
C15H20N2O requires C, 73.75; H, 8.25; N, 11.45%. m/z
(%): 244 (M11, 2), 170 (15), 157 (6), 91 (51), and 81
(100). nmax 3420, 2940, 1440, 1350, 1030, 740 and
690 cm21. d: 8.47 (br s, 1H, NH), 7.38±7.23 (m, 5H,
ArH), 6.73 (m, 1H, Ha), 6.12 (m, 2H, Hb), 4.54 (s, 2H,
OCH2), 3.96 (s, 2H, NCH2), 3.80 (sept, 1H, NCHMe2) and
1.20 (d, 6H, Jˆ6.3 Hz, 2£Me).
General procedure for the synthesis of tertiary
hydroxylamines (24±27) and (32±35) from benzotriazole
derivatives and Grignard reagents. The appropriate
Grignard reagent (3 equiv.) was added to a stirred solution
of the appropriate benzotriazole derivative (1 equiv.) in dry
THF at r.t. under nitrogen. The reaction mixture was stirred
for 24 h and quenched with 20% w/w ammonium chloride
solution (2 ml per 0.1 mmol of benzotriazole derivative).
The aqueous layer was extracted with ether, the organic
extracts combined and washed twice with 5% w/w sodium
hydroxide solution (1 ml per 0.1 mmol of benzotriazole
derivative) and then water until neutral, then dried
(MgSO4), ®ltered and the solvent removed under reduced
pressure.
O-Benzyl-N-phenethyl-N-propyl-hydroxylamine (24).
Puri®cation of the residue by column chromatography,
eluting with 10:1 v/v petroleum ether±diethyl ether afforded
the product (70%) as a pale yellow oil. Found: C, 80.0; H,
8.55; N, 4.9. C18H23NO requires C, 80.25; H, 8.6; N, 5.2%.
m/z (%) (FAB): 270 (M11, 23), 240 (16), 178 (100), 162
(12), 105 (12) and 91 (54). nmax 2960, 1460, 1370, 1030, 740
and 690 cm21. d: 7.4±7.17 (m, 10H, ArH), 4.74 (s, 2H,
OCH2), 2.99 (s, 4H, NCH2CH2Ph), 2.73 (t, 2H, Jˆ7.2 Hz,
NCH2CH2Me), 1.65 (sext, 2H, NCH2CH2Me) and 0.94 (t,
3H, Jˆ7.2 Hz, Me).
General procedure for the synthesis of benzotriazole
derivatives (22), (28) and (30) from secondary hydroxyl-
amine (4a). Benzotriazole (1 equiv.) and secondary
hydroxylamine (4a) (1 equiv.) were dissolved in dry DCM
and the solution stirred at r.t. for 5 min. The appropriate
aldehyde (1 equiv.) was then added and stirring continued
at r.t. for 18 h. Magnesium sulphate was then added and the
mixture stirred for a further 0.5 h, ®ltered and the magne-
sium sulphate copiously washed with DCM. The ®ltrate was
evaporated under reduced pressure to afford the product.
O-Benzyl-N-allyl-N-phenethyl-hydroxylamine (25). Puri-
®cation of the residue by column chromatography, eluting
with 10:1 v/v petroleum ether±diethyl ether afforded the
product (69%) as a pale yellow oil. Found: C, 80.8; H,
7.75; N, 5.15. C18H21NO requires C, 80.85; H, 7.9; N,
5.25%. m/z (%) (FAB): 268 (M11, 53), 176 (100), 160
(19), 105 (11) and 91 (57). nmax 2930, 1730, 1450, 1360,
1000, 930, 750 and 700 cm21. d: 7.4±7.15 (m, 10H, ArH),
6.00 (m, 1H, Hb), 5.72 (m, 2H, Ha), 4.74 (s, 2H, OCH2), 3.42
(d, 2H, Jˆ6.6 Hz, NCH2) and 2.94 (s, 4H, NCH2CH2Ph).
Benzotriazole derivative (22). No further puri®cation was
necessary. The product (99%) was obtained as a light brown
oil which solidi®ed slowly on standing to give a tan solid,
mp 49±538C. HRMS: 358.179. C22H22N4O requires
358.183. m/z (%): 358 (M11, 7), 223 (19), 210 (17), 180
(25), 132 (35), 104 (43) and 91 (100). nmax 3040, 2920,
1450, 1270, 1150, 1030, 100, 740 and 700 cm21. d: 8.11±
7.12 (m, 14H, ArH), 5.50 (s, 2H, NCH2N), 4.55 (s, 2H,
OCH2) and 3.00 (m, 4H, NCH2CH2Ph).
N,O-Dibenzyl-N-phenethyl-hydroxylamine (26). Puri®ca-
tion of the residue by column chromatography, eluting with
10:1 v/v petroleum ether±diethyl ether afforded the product
(76%) as a pale yellow oil. Found: C, 83.05; H, 7.2; N, 4.35.
C22H23NO requires C, 83.25; H, 7.3; N, 4.4%. m/z (%)
(FAB): 318 (M11, 3), 226 (71), 181 (21), 136 (8), 105
(21), 91 (100) and 77 (27). nmax 3020, 2920, 2840, 1450,
Benzotriazole derivative (28). No further puri®cation was
necessary. The product (93%) was obtained as a light brown

8032
R. Grigg et al. / Tetrahedron 56 (2000) 8025±8032
1360, 1020, 750 and 700 cm21. d: 7.37±7.16 (m, 15H,
ArH), 4.48 (s, 2H, OCH2), 3.87 (s, 2H, NCH2Ph) and 2.97
(s, 4H, NCH2CH2Ph).
amine (35). Puri®cation of the residue by column chromato-
graphy, eluting with 10:1 v/v petroleum ether±ether
afforded the product (70%) as a pale yellow oil, which
slowly solidi®ed to give colourless needles, mp 37±408C.
Found: C, 83.95; H, 7.5; N, 3.7. C25H27NO requires C, 84.0;
H, 7.6; N, 3.9%. m/z (%) (FAB): 358 (M11, 4), 266 (8), 250
(7), 131 (100), 105 (9) and 91 (17). nmax 3070, 3040, 2940,
2880, 1490, 1460, 1360, 1030, 750 and 700 cm21. d: 7.38±
7.11 (m, 15H, ArH), 4.67 (d, 1H, Jˆ9.9 Hz, one H from
OCH2), 4.53 (br s, 1H, one H from OCH2), 3.18 (br s, 1H,
Ha), 2.96 (s, 4H, NCH2CH2Ph) 1.31 (m, 1H, Hb), 0.75 and
0.06 (2£m, 2£1H, cyclopropyl H), and 0.59±0.49 (m, 2H,
cyclopropyl H).
O-Benzyl-N-(4-¯uoro-benzyl)-N-phenethyl-hydroxyl-
amine (27). Puri®cation of the residue by column chromato-
graphy, eluting with 10:1 v/v petroleum ether±diethyl ether
afforded the product (78%) as a pale yellow oil. Found: C,
78.9; H, 6.6; N, 4.1. C22H22FNO requires C, 78.8; H, 6.6; N,
4.2%. m/z (%) (FAB): 336 (M11, 22), 244 (100), 228 (18),
109 (89) and 91 (49). nmax 3040, 2930, 1600, 1500, 1220,
740 and 690 cm21. d: 7.38±6.93 (m, 14H, ArH), 4.50 (s,
2H, OCH2), 3.83 (s, 2H, NCH2) and 2.96 (s, 4H,
NCH2CH2Ph).
O-Benzyl-N-(1-methyl-allyl)-N-phenethyl-hydroxylamine
(32). Puri®cation of the residue by column chromatography,
eluting with 10:1 v/v petroleum ether±diethyl ether afforded
the product (82%) as a pale yellow oil. Found: C, 81.35; H,
8.5; N, 5.0. C19H23NO requires C, 81.1; H, 8.25; N, 5.0%.
m/z (%) (FAB): 282 (M11, 19), 254 (6), 190 (100), 174 (15)
136 (10), 105 (26) and 91 (63). nmax 2940, 1460, 1360, 1030,
920, 750 and 700 cm21. d: 7.43±7.12 (m, 10H, Ar H), 5.92
(m, 1H, Hb), 5.13 (m, 2H, Ha), 4.76 (s, 2H, OCH2), 3.42 (s,
1H, Hc), 2.96 (s, 4H, NCH2CH2Ph) and 1.29 (d, 3H,
Jˆ6.5 Hz, Me).
Acknowledgements
We thank the EPSRC, Leeds University and Organon
Laboratories for support.
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(10), 105 (13), 91 (22) and 81 (100). nmax 3400, 3080, 3030,
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O-Benzyl-N-(1-cyclopropyl-benzyl)-N-phenethyl-hydroxyl-