Substitution of α-azido ethers with Grignard reagents and its use in combinatorial chemistry

Article abstract of DOI:10.1039/b110428b

α-Azidobenzyl ethers were reacted with alkyl or arylGrignard reagents in toluene to produce α-alkylbenzyl or diarylmethyl ethers in 82-94% yield. α-Azidobenzyl ethers were also reacted with multicomponent Grignard reagents to produce libraries of α-alkylbenzyl ethers.

Full text of DOI:10.1039/b110428b

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Substitution of ꢀ-azido ethers with Grignard reagents and its use
in combinatorial chemistry
Mukulesh Baruah and Mikael Bols*
1
Department of Chemistry, University of Aarhus, Langelandsgade 140 Aarhus C, DK-8000,
Denmark. E-mail: mb@kemi.aau.dk
Received (in Cambridge, UK) 14th November 2001, Accepted 7th January 2002
First published as an Advance Article on the web 22nd January 2002
α-Azidobenzyl ethers were reacted with alkyl or arylGrignard reagents in toluene to produce α-alkylbenzyl or
diarylmethyl ethers in 82–94% yield. α-Azidobenzyl ethers were also reacted with multicomponent Grignard
reagents to produce libraries of α-alkylbenzyl ethers.
Table 1 The results from the reaction shown in Scheme 3
Introduction
Recently we reported that benzyl ethers (1) react with IN3 in
refluxing acetonitrile to give the corresponding α-azido ether 2
(Scheme 1).1 This radical reaction is high-yielding, efficient and
Substrate
Product
R
RЈ
Time/min
Yield (%)
2a
2a
2a
2a
2b
2b
2b
2b
2c
2c
2d
2d
2d
8a
8b
8c
8d
8e
8f
Me
Me
Me
Me
Et
Et
Et
Me
Ph
Pr
Allyl
Me
Ph
20
20
30
90
20
20
30
90
30
50
10
10
10
90
89
88
85
89
87
87
85
82
82
94
90
90
8g
8h
8i
Pr
Et
All
Me
Pr
Me
Pr
Mn
Mn
Pip
Pip
Pip
8j
Scheme 1 Radical azidonation of benzyl ether.
8k
8l
8m
n-C6H13
simple to carry out and has the advantage that the monosubsti-
tuted azido ether is selectively obtained probably because the
azide destabilises a radical cation intermediate. A related reac-
tion has been reported by Magnus et al., who were able to
directly azidonate in the α-position of amines using TMSN3–
PhI(OAc)2 to obtain compounds like 3.2 They also reported
that reaction between 3 and phenylmagnesium bromide gave
the adduct 4 Scheme 2. A similar substitution reaction could
structures could also be useful. In this paper we report our
findings regarding the reaction between Grignard reagents and
α-azidobenzyl ethers, and also report the synthesis of libraries
of diphenylpyraline analogues using multicomponent Grignard
reagents.
Results and discussion
Initially reaction of methylmagnesium bromide with α-azido-
benzyl methyl ether was attempted (2a, Scheme 3 and Table 1) in
Scheme
bromide.
2
Substitution of α-azidoamine with phenylmagnesium
potentially be useful on α-azidobenzyl ethers like 2, since this
would lead to diaryl or alkylaryl ethers, which are quite abund-
ant among bioactive compounds. Thus antihistamines diphenyl-
pyraline (5), ebastine (6) and medrylamine (7) are examples of
such compounds (Fig. 1). Combinatorial approaches to such
Scheme 3 Substitution of α-azido ethers with alkyl or arylmagnesium
bromide. Reaction and substituent details are given in Table 1.
THF similar to the reaction described by Magnus et al (Scheme
2), but no reaction was observed at all. Obviously the azido
ether 2a is much less reactive than the azidoamine 3 which is
also witnessed by a much greater stability of 2a. However
a review of the literature revealed that the reactivity of the
Grignard reagent might be increased if toluene was used as
solvent.3,4 Indeed when the Grignard reagent in ether was added
to the azido ether 2a in toluene an excellent yield of 1-
phenylethyl methyl ether (8a) was obtained (Scheme 3, Table 1)
after 20 min at room temperature.
Fig. 1 The antihistamines diphenylpyraline (5), ebastine (6) and
medrylamine (7).
DOI: 10.1039/b110428b
J. Chem. Soc., Perkin Trans. 1, 2002, 509–512
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509

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The reaction was now attempted on the series of azido ethers
2a–2d of which 2a and 2b were previously known,1 while 2c and
2d were new. These were made by treatment of the correspond-
ing benzyl ethers, made by benzylation (NaH–BnBr) of
menthol and known N-acetyl-4-oxypiperidine5 (1d), with IN3
in refluxing acetonitrile, which gave the azido ethers 2c and 2d
in 82% and 55% yield, respectively (Fig. 2).
We also carried out a similar reaction with an 8 component
Grignard reagent consisting of MeMgI and CH3(CH2)nMgBr
with n being from 1 to 7. The reagent was prepared from an
equimolar mixture of the corresponding halides and excess Mg,
and then in two separate experiments reacted with the azides 2c
and 2d (Fig. 2). While, in both cases, NMR of the product
mixture was consistent with the presence of the 8 possible
products (Fig. 3), it could not ensure their presence due to the
Fig. 2 The azido ethers 2c and 2d. In parentheses is given the yield of
the azide obtained from reaction of the corresponding benzyl ether
with IN3.
Reaction between azido ethers 2a–2d and MeMgI, PrMgBr,
PhMgBr or CH ᎐CHCH MgBr in toluene–ether at 25 ЊC gave
᎐
2
2
Fig. 3 The possible products from the reaction of an 8 component
Grignard reagent, consisting of CH3(CH2)nMgX (n = 0–7), with azides
2c and 2d, respectively.
the adducts 8a–8m in 82–94% yield (Table 1). The reaction
appears to have a broad scope with respect to the Grignard
reagent. The reactions were monitored by TLC and interestingly
some variation in reaction times were observed. Particularly the
allyl Grignard reagent was considerably more sluggish towards
number of very similar compounds. However mass spectro-
scopy of the two libraries gave signals corresponding to the
products 8i, 8j and 8n–8s being obtained from 2c, and products
8k–8m and 8t–8y being obtained from 2d. The mass spectrum
of the library obtained from 2d is shown in Fig. 4. While the
the azido ethers, which is surprising because CH ᎐CHCH MgBr
᎐
2
2
reacts with acetone much faster than both MeMgI and PrMgBr.6
We have recently found that it is possible to prepare multi-
component Grignard reagents and add them to aldehydes,
esters and ketones to create uniform libraries of secondary and
tertiary alcohols.7 We now investigated whether similar chem-
istry would be feasible here; if so libraries of analogues of the
drugs 5–7 could essentially be made in one step. Since the reac-
tions between individual Grignard reagents and α-azido ethers
had revealed a considerable difference in rate of reaction
between allylmagnesium bromide and the other Grignard
reagents it was clear that such experiments would fail and no
allyl product would be formed unless precautions were made
to ensure formation of allyl product. This was done by slow
addition of the multicomponent Grignard reagent to the azide
solution. Thus a 4 component Grignard reagent was made by
reaction of a mixture of MeI, PhBr, CH CH CH Br and CH ᎐
᎐
2
3
2
2
CHCH2Br with excess magnesium and added over 2 h to a
solution of 2a (Scheme 4). This gave the products 8a–8d in an
essentially uniform mixture. The ratio was 3 : 4 : 3 : 4, which
1
could be seen from H NMR since the absorptions of sub-
stituents in 8a–8d are widely different. The reaction was also
carried out with 2b giving a 1 : 1 : 1 : 1 ratio of 8e–8h.
Fig. 4 Electrospray mass-spectrum of the products obtained from
reaction of 2d with an 8 component Grignard reagent. The spectrum
shows the presence of 8k–8m and 8t–8y.
intensity of the peaks appears to suggest that some of the com-
pounds 8k–8m and 8t–8y are present in larger amounts the
peak intensity cannot be taken as significant. HPLC of the
product mixture suggested that the products were present in
roughly equal amounts (Fig. 5).
Scheme 4 Solution-phase combinatorial reactions between the 4
Grignard reagents MeMgI, PhMgBr, CH3CH2CH2MgBr and CH2᎐᎐
CHCH2MgBr, and the azides 2a or 2b.
In summary we have shown that the azido group in α-
azidobenzyl ethers can be substituted with Grignard reagents
510
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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
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Acknowledgements
We thank the Danish National Science Research Council
(SNF) and the Lundbeck foundation for financial support.
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