when toluene is the solvent. The reaction is efficient and can be
8c,10 8d,11 8e,12 8f,9 8h13 and 8i14 were known compounds, and
applied to aromatic, allylic and aliphatic Grignard reagents.
characterised by comparison of NMR spectra. Compounds
8g, 8k, 8l and 8m had the following data.
1-Ethoxy-1-phenylbutane (8g). 1H NMR (200 MHz, CDCl3):
δ 0.9 (t, 3H), 1.1 (t, 3H), 1.2–1.7 (m, 4H), 3.25 (m, 2H), 4.1 (dd,
1H), 7.1–7.3 (m, 5H).
Experimental
ꢀ-Azidobenzyl (؊)-menthyl ether (2c)
A solution of ICl (1.01 g, 6 mmol) in CH3CN (50 mL) was
cooled down to Ϫ10 ЊC to which NaN3 (1.07 g, 14 mmol) was
added with continuous stirring. After 15 minutes, the cooling
bath was removed and benzyl (Ϫ)-menthyl ether (492 mg,
2 mmol) was added. The mixture was heated to 80 ЊC for 1 h or
until disappearance of the starting material was observed
(monitored by TLC). Then the mixture was cooled to room
temperature, CH2Cl2 (200 mL) was added, and the mixture
was washed with 5% Na2S2O3 solution (150 mL). The dried
(Na2SO4) organic layer was evaporated and the residue was
purified by flash chromatography on silica (pentane–ethyl
acetate 20 : 1) to give the pure azide 2c (470 mg) in 82% yield.
1H NMR (200 MHz; CDCl3): δ 0.79 (d, 3H, J 6.3 Hz), 0.98
(d, 6H, J 6.9 Hz), 1.0 (m, 2H), 1.2 (m, 1H), 1.4 (m, 2H), 1.65
(m, 2H), 2.1 (m, 1H), 2.2 (m, 1H), 3.65 (dt, 1H), 5.45 (s, 1H), 7.4
(m, 5H); MS(ES): m/z: 310.1877 (calcd. for C17H25N3O ϩ Na:
310.1895).
1-N-Acetyl-4-(ꢀ-methylbenzyloxy)piperidine (8k). 1H NMR
(200 MHz, CDCl3): δ 1.20–1.27 (d, 3H, J 6.7 Hz), 1.20–1.85 (m,
4H), 2.0 (s, 3H), 3.0–3.2 (m, 2H), 3.25–3.64 (m, 2H), 3.8–4.0
(m, 1H), 4.4–4.6 (q, 1H), 7.1–7.3 (m, Ar); MS (ES, positive
mode): 270.1469, calcd. for C15H21NO2 ϩ Na: 270.1469.
1-N-Acetyl-4-(ꢀ-propylbenzyloxy)piperidine (8l). MS (ES,
positive mode): 298.1775, calcd. for C17H25NO2
298.1782.
ϩ Na:
1-N-Acetyl-4-(ꢀ-hexylbenzyloxy)piperidine (8m). 1H NMR
(200 MHz, CDCl3): δ 0.6–0.8 (t, 3H, J 6.6 Hz), 1.0–1.3 (m, 8H),
1.4–1.85 (m, 6H), 2.0 (s, 3H), 3.0–3.2 (m, 2H), 3.4–3.6 (m, 2H),
3.7–3.9 (m, 1H), 4.2–4.4 (q, 1H), 7.1–7.3 (m, aromatic); MS
(ES, positive mode): m/z: 340.2257, calcd. for C20H31NO2 ϩ Na:
340.2252.
Reaction of ꢀ-azido compounds with multicomponent Grignard
reagents
1-Acetyl-4-benzyloxypiperidine (1d)
To a suspension of NaH (240 mg,10 mmol) in dry DMF
(10 mL) was slowly added (over 10 minutes) a solution of the
1-acetyl-4-oxypiperidine5 (1.14 g, 8 mmol) in DMF (5 mL) at
r.t. Stirring was continued for 30 minutes at the same temper-
ature. Then benzyl bromide (1.36 g, 8 mmol) was slowly added,
and the reaction mixture was stirred for 16 h. After completion
of the reaction, DMF was evaporated in vacuo, and 10 mL of
water was added. Then the product was extracted with CH2Cl2
(2 × 75 mL). The dried (Na2SO4) organic layer was concen-
trated and purified by flash chromatography on silica (ethyl
Preparation of a multicomponent Grignard reagent. Mg turn-
ings (600 mg) were suspended in diethyl ether (12 mL) in a three
necked round-bottomed flask fitted with a reflux condenser in
the middle. All four halides i.e. PhBr (1.5 g, 1 mL); CH3I (1.3 g,
0.5 mL); CH3CH2CH2Br (1.3 g, 1 mL) and allyl bromide (1.2 g,
0.9 mL) were mixed together and added slowly by continuous
stirring. When the reflux started the flask was cooled in an
ice–water bath, and the mixture was stirred for another 1.5 h.
Then the solution was directly taken out by syringe and used.
1
acetate) to give pure 1d (1.2 g, 60%). H NMR (200 MHz,
4-Member libraries. 163 mg (1 mmol) of the α-azidobenzyl
methyl ether (2a), or 177 mg (1 mmol) of the α-azidobenzyl
ethyl ether (2b), was dissolved in 10 mL of dry toluene and
1 mL of the mixture of Grignard reagents was added slowly
(ca 2 h) with constant stirring. After completion of the addition
of reagents the reaction mixture was worked up in the way
described above. The composition of the library was confirmed
CDCl3): δ 1.42–1.62 (m, 2H), 1.63–1.91 (m, 2H), 2.0 (s, 3H),
3.1–3.28 (m, 2H), 3.45–3.65 (m, 2H), 3.79–3.88 (m, 1H), 4.45
(s, 2H), 7.2–7.4 (m, 5H, Ar); MS(ES): m/z: 256.1 ([M ϩ Na]ϩ).
1-N-Acetyl-4-(ꢀ-azidobenzyloxy)piperidine (2d)
A solution of ICl (1.01 g, 6 mmol) in CH3CN (50 mL) was
cooled to Ϫ10 ЊC to which NaN3 (1.07 g, 14 mmol) was added
with continuous stirring. After 15 minutes, the cooling bath was
removed and the substrate (350 mg, 1.5 mmol) was added. The
mixture was heated to 80 ЊC for 40 minutes or until disappear-
ance of the starting material was observed (TLC). Then the
mixture was cooled to room temperature, CH2Cl2 (200 mL) was
added, and the mixture was washed with 5% Na2S2O3 solution
(150 mL). The dried (Na2SO4) and evaporated organic layer
was purified by flash chromatography on silica (ethyl acetate) to
give pure azide 2d (226 mg) in 55% yield. 1H NMR (200 MHz,
CDCl3): δ 1.45–1.65 (m, 2H), 1.66–1.88 (m, 2H), 2.08, (s, 3H),
3.18–3.45 (m, 2H), 3.46–3.84 (m, 2H), 3.89–4.09 (m, 1H), 5.41
(s, 1H), 7.30–7.42 (m, 5H); MS(ES): m/z: 297.1331, calcd. for
C14H18N4O2 ϩ Na: 297.1327.
1
by comparing the H NMR spectrum with the spectra of the
individual compounds.
8-Member libraries. An 8 component Grignard reagent was
prepared as previously described7 by adding a mole equivalent
mixture of alkyl halides (CH3I, CH2CH2Br, CH3(CH2)2Br,
CH3(CH2)3Br, CH3(CH2)4Br, CH3(CH2)5Br, CH3(CH2)6Br, CH3-
(CH2)7Br, 30 mmol total) to the suspension of Mg metal
(2 equivalents, 60 mmol) in diethyl ether (20 mL).
1 mL (1.5 mmol) of this freshly prepared Grignard reagent
was slowly added through a syringe to the solution of α-
azidobenzyl (Ϫ)-menthyl ether (2c, 287 mg, 1 mmol), or 1-N-
acetyl-4-(α-azidobenzyloxy)piperidine (2d, 274 mg, 1 mmol),
in dry toluene (10 mL). The reaction mixture was stirred for
30 minutes at room temperature. Then aqueous NH4Cl (1 mL)
was added and the product was extracted by diethyl ether. The
dried (Na2SO4), and concentrated organic phase contained the
library of 8 compounds.
Library from 2c: MS (ES, positive mode): m/z: 283.2036
(calcd. for 8i ϩ Na 283.2037); 297.2183 (calcd. for 8n ϩ Na:
297.2194); 311.2370 (calcd. for 8j ϩ Na: 311.2350); 325.2564
(calcd. for 8o ϩ Na: 325.2507); 339.2656 (calcd. for 8p ϩ Na:
339.2663); 353.2847 (calcd. for 8q: 353.2820); 367.2990 (calcd.
for 8r: 367.2976); 381.3111 (calcd. for 8s: 381.3133).
Substitution of azide by Grignard reagents
The reactions were carried out by dissolving 0.5 mmol of the
azide 2 in 5 mL of dry toluene. A freshly prepared ether sol-
ution (0.4 mL) of the desired Grignard reagents (2 equivalents)
was slowly added with continuous stirring at room temperature.
After stirring for 10–20 minutes (monitored by TLC) the reac-
tions were quenched by adding 1 mL saturated solution of
NH4Cl and 1 mL of water. Then the product was extracted with
diethyl ether (2 × 10 mL), dried over Na2SO4 and evaporated
in vacuo to obtain 8 in 82–94% yields. The products 8a,8 8b,9
Library from 2d: MS (ES, positive mode), m/z: 270.1464
(calcd. for 8k ϩ Na: 270.1469), 284.1716 (calcd. for 8t ϩ Na:
J. Chem. Soc., Perkin Trans. 1, 2002, 509–512
511