Synthesis of α-silylalkylbenzoxazoles and oxazoles from stable silylketenes

Article abstract of DOI:10.1016/j.tet.2009.03.105

Stable silylketenes, prepared by rhodium-catalysed decomposition of silyldiazoketones, undergo addition/cyclocondensation sequences with aminophenols and aminomalonate to give α-silylalkylbenzoxazoles and oxazoles, respectively. The silicon can be retaine

Full text of DOI:10.1016/j.tet.2009.03.105

Tetrahedron 65 (2009) 5503–5512
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of
a
-silylalkylbenzoxazoles and oxazoles from stable silylketenes
,
b
c
Stephen P. Marsden a , James T. Steer , Barry S. Orlek
*
a School of Chemistry, University of Leeds, Leeds LS2 9JT, UK
b Department of Chemistry, Imperial College London, London SW7 2AY, UK
c GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow CM19 5AW, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Stable silylketenes, prepared by rhodium-catalysed decomposition of silyldiazoketones, undergo addition/
cyclocondensation sequences with aminophenols and aminomalonateto give -silylalkylbenzoxazoles and
oxazoles, respectively. The silicon can be retained throughout functional group interconversions or can be
removed by protodesilylation under acidic conditions as desired.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 12 December 2008
Received in revised form 14 March 2009
Accepted 15 March 2009
a
Available online 14 April 2009
1. Introduction
synthetic intermediates (e.g., for use in Peterson olefinations8).
Additionally, the incorporation of silicon into pharmaceutical can-
Ketenes are generally highly reactive, unisolable species, and
synthetic applications are therefore usually based upon their in situ
generation and subsequent reaction.1 By contrast, silylketenes are
stable, isolable entities,2,3 a property attributed to a combination of
electronic stabilisation (most convincingly as a consequence of the
didates is an area of growing interest,9 and this chemistry would
provide convenient entry to potentially pharmacologically active
targets. In this paper, we describe the facile synthesis of
alkylbenzoxazoles and oxazoles from silylketenes.
a-silyl-
excellent hyperconjugative donation possible from a C–Si s
-bond4)
2. Results and discussion
and steric hindrance to attack on the ketene LUMO by the bulk of
the silyl substituent. Amongst the various methods for the prepa-
ration of silyl ketenes,2 we reported a convenient method based
upon an unexpected Wolff rearrangement of silylated diazoketones
upon treatment with a rhodium(II) dicarboxylate catalyst.5 This
allows for the preparation of silylketenes with ready variation of
both the silicon and carbon substituents. We have exploited these
ketenes as synthetic intermediates, for example, in the synthesis of
novel tri- and tetrasubstituted allenylsilanes.6
We chose benzoxazoles as our initial targets, since they occur in
a diverse range of biologically active natural products10 and phar-
maceutical targets.11 We commenced our study by reaction of
o-aminophenol with n-heptyl(triethylsilyl)ketene 1a, generated by
decomposition of (triethylsilyl)diazonanone 2a according to our
previously reported method.5 We were pleased to find that addi-
tion of the aminophenol to the crude ketene gave a good yield of
the expected amide 3a (Scheme 1). We next sought to find condi-
tions whereby heterocyclisation to the benzoxazole could be
Silylketenes react readily with nucleophilic species, acting as
synthetic equivalents of activated
a-silylcarboxylic acids to give the
O
corresponding
a
-silylesters or amides.2,3 However, the further
O
nC7H15
SiEt3
1 mol% Rh2(oct)4
PhH, rt
synthetic potential of intermediates prepared by this route has
been little studied. One such example is the synthesis of coumarins
by addition of o-acylphenols to trimethylsilylketene followed by
nC7H15
SiEt3
N2
1a
2a
intramolecular condensation of the resulting
a-silylacetate and
aldehyde.7 In this chemistry, however, the silicon substituent is lost
in the condensation process. We were interested to investigate
whether silylketenes could be used as acyl cation equivalents for
the assembly of heterocyclic motifs in which the silicon was
retained on the alkyl substituent adjacent to the new heterocycle.
2-aminophenol,
THF, heat
80% (2 steps)
O
O
nC7H15
Et3Si
nC7H15
Et3Si
PPh3, DEAD
Et3N, THF, 50oC
81%
N
H
The resulting
a-silylalkylheterocycles could potentially be useful
N
OH
3a
-silylalkylbenzoxazoles.
4a
Scheme 1. Development of a synthesis of
* Corresponding author.
E-mail address: s.p.marsden@leeds.ac.uk (S.P. Marsden).
a
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.105

5504
S.P. Marsden et al. / Tetrahedron 65 (2009) 5503–5512
effected whilst retaining the silicon substituent. The use of stan-
dard cyclodehydration reagents such as PPh3/I2 was successful in
achieving benzoxazole formation but gave substantial amounts of
protodesilylated material, likely as a result of the acidic by-products
liberated in such reactions. The use of the neutral Mitsunobu con-
resulting amide then proceeded in near-quantitative yield (entry g).
Finally, we examined the use of aminophenols bearing (allylox-
ycarbonyl)amino substituents, in the expectation that subsequent
removal of the allyloxycarbonyl group could be achieved under mild
enough conditions to prevent protodesilylation. These highly nucle-
ophilic aminophenols gave addition and cyclisation to alkyl-
(triethylsilyl)ketenes without any difficulties (entries h–k).
ditions for cyclodehydration,12 however, gave the
a-silylalkyl-
benzoxazole 4a in 81% yield with no trace of the desilylated
product.
With the ring-functionalized a-silylalkylbenzoxazoles 4g–k in
We then set out to establish the scope and limitations of these
conditions with respect to both the silylketene substituents and
substitution in the aminophenol coupling partner. The silyldiazo-
ketones 2a–g (prepared from the parent diazoketone according
to the method of Regitz13) were therefore decomposed under
rhodium octanoate catalysis, and the crude ketenes condensed
with the appropriate o-aminophenol. The resulting amides were
treated under Mitsunobu conditions to give the substituted
benzoxazoles. The findings of this survey are reported in Table 1.
The alkyl-substituted ketenes derived from 2a and 2b behaved
well in the heterocyclisations (entries a and b), though we found that
the amides from aryl-substituted ketenes (from 2c–2e) gave sub-
stantially lower yields in the heterocyclisation (entries c–e). We at-
tribute this to competing protodesilylation in the cyclisation reaction
(ca. 20% of the desilylated benzoxazole was observed in these cases)
rather than any diminished reactivity of the arylketenesdfull con-
sumption of ketene was seen in all cases. The presence of an aryl
substituent would be expected to labilise the C–Si bond to cleavage,
since amide protonation and desilylationwould give rise to an enol in
conjugation with the aryl substituent. However, use of the tert-
butyldimethylsilylketene 2f gave an amide 3f that was more robust in
the heterocyclisation event, giving a higher yield of the desired
benzoxazole without protodesilylation (entry f). In terms of variation
in the aminophenol nucleophile, we elected to incorporate nitrogen
substitution, since substituted 5- and 6-aminobenzoxazoles are
found in natural products (e.g., calcimycin10) and drug substances
such as the orexin-1 receptorantagonist SB-334867-A.14 The use of 4-
nitro-2-aminophenol as a nucleophile proved problematic: the at-
tenuated nucleophilicity of the nitrogen slowed addition to the
silylketene and required prolonged heating (five days) to effect good
conversions. The potential for competing protodesilylation meant
that the tert-butyldimethylsilyl-substituted ketenes were required to
give good yields in the addition; Mitsunobu cyclisation of the
hand, we next investigated whether conditions could be found for
the manipulation and functionalisation of the nitrogen substituents
without suffering competing protodesilylation. Deprotection of the
allyloxycarbonyl groups of 4h–k was carried out under the Kunz
conditions,15 using palladium(0) catalysis with N,N0-dimethyl-
barbituric acid to scavenge the resulting p-allyl palladium electrophile.
Good to excellent yields of the resulting 5- and 6-amino-
benzoxazoles 5a–d were obtained (Scheme 2). Alternatively, the
tert-butyldimethylsilyl-substituted 5-aminobenzoxazole 5e could
be accessed by reduction of the nitro group of 4g using copper
acetylacetonate and sodium borohydride.16 The resulting amine
was reacted with a range of electrophilic reagents representative of
those widely used in medicinal chemistry (sulfonyl chlorides, car-
bamoyl chlorides, chloroformates, acid chlorides, isocyanates and
isothiocyanates). In all cases, good yields of the functionalized
products 6–11 were obtained without significant desilylation
occurring.
Finally, we demonstrated that desilylation of the
a-silyl-
benzoxazoles could be deliberately achieved by treatment under
acidic conditions. Thus, exposure of compounds 4a, 4f and 5b to
trifluoroacetic acid in dichloromethane returned the desilylated
benzoxazoles 12–14 in moderate to good yield (Scheme 3).
Mechanistically, the reaction presumably occurs by protonation of
the basic ring nitrogen, followed by loss of silicon (generating an
exo-alkylidenebenzoxazoline) and rearomatising tautomerisation.
We also wished to demonstrate that silylketenes have the
potential to act as electrophilic templates for the construction of
a-silylalkylheterocycles other than benzoxazoles. We elected to
NH2
O
5 mol% Pd(PPh3)4
4h-k
R
N
N,N'-dimethylbarbituric
Et3Si
acid, THF, rt
Table 1
Synthesis of
R = nC7H15, 5-NH2
5a
86%
83%
70%
72%
a
-silylalkylbenzoxazoles
5b R = nC7H15, 6-NH2
R2
R2
5c
R = PhCH2, 5-NH2
O
O
O
(a)
R1
(b)
R1
5d R = PhCH2, 6-NH2
SiR3
R1
N
H
N
R3Si
OH
R3Si
N2
O
NH2
nC7H15
20 mol% Cu(acac)2
2a-g
3a-k
4a-k
4g
N
NaBH4, EtOH
64%
5e
tBuMe2Si
(a) 1 mol% Rh2(oct)4, PhH, then (substituted) 2-amino-
phenol,THF; (b) PPh3, DEAD, Et3N, THF, 50oC
Electrophile
Et3N, CH2Cl2,
rt or reflux
O
Entry
SiR3
R1
nC7H15
PhCH2
4-MeOC6H4
2-Furyl
R2
Yield 3a (%)
Yield 4 (%)
NHX
nC7H15
a
b
c
d
e
f
g
h
i
TES
TES
TES
TES
TES
TBS
TBS
TES
TES
TES
TES
H
H
H
H
H
H
5-NO2
80
73
52
45
66
69
79
75
78
75
77
81
67
34
42
47
67
95
56
70
54
73
N
tBuMe2Si
(N-Boc)Indolyl
(N-Boc)Indolyl
nC7H15
6
7
8
X = SO2Me
X = CONMe2
X = CONHEt
68%
79%
71%
65%
74%
60%
b
nC7H15
5-NHAllocb
6-NHAllocb
5-NHAllocb
6-NHAllocb
nC7H15
9
X = CSNHEt
j
k
PhCH2
PhCH2
i
10 X = CO2 Bu
11 X = COtBu
a
Yield over two steps from 2.
Numbering refers to position of substituent in benzoxazoles 4.
b
Scheme 2. Synthesis and functionalisation of (a-silylalkyl)aminobenzoxazoles.

S.P. Marsden et al. / Tetrahedron 65 (2009) 5503–5512
5505
R2
4. Experimental
R2
O
O
R1
TFA
R1
4.1. General information
N
N
CH2Cl2
R3Si
Tetrahydrofuran and diethyl ether were freshly distilled from
sodium benzophenone ketyl, benzene and toluene from sodium
and dichloromethane from calcium hydride. Triethylamine and
N,N-diisopropylethylamine were distilled from and stored over
potassium hydroxide. All other solvents and reagents were used
without purification. All glassware was oven dried at 130 ꢀC prior to
use. Reactions were carried out under an atmosphere of nitrogen,
unless otherwise stated. Thin layer chromatography was performed
on precoated glass backed plates (Merck Kieselgel 60 F254) and
visualised with ultraviolet light (254 nm), potassium permanga-
nate, acidic ammonium molybdate(IV) or ninhydrin solution. Flash
column chromatography was performed on Merck Kieselgel 60
(200–300 mesh) under pressure.
R1
1 = indolyl, R2 = H, R3Si = TBS
nC7H15, R2 = 6-NH2, R3Si = TES
=
nC7H15, R2 = H, R3Si = TES
12
4a
4f
67%
13 57%
14
79%
R
=
5b
R1
Scheme 3. Desilylation of -silylalkylbenzoxazoles.
a
study the formation of non-benzannulated systems, and specifi-
cally focused on oxazoles, given their widespread occurrence in
bioactive natural products17 and synthetic drug substances such as
the non-steroidal anti-inflammatory Oxaprozin. Moody has
reported the formation of oxazoles by cyclodehydration of acyla-
minomalonates, which he prepared via rhodium-catalysed N–H
insertion of diazomalonates to primary amides.18 We recognised
that condensation of commercial aminomalonate esters with
silylketenes would afford similar intermediates, and were pleased
to find that addition to ketenes derived from 2a and 2f gave the
desired products 15a and 15b in excellent yields. In contrast to the
benzoxazole series, cyclisation using PPh3/I2 (as used by Moody)
proceeded without significant desilylation to give the desired
oxazoles 16a and 16b. Finally, we showed that protodesilylation of
16a could be achieved, if desired, using trifluoroacetic acid, giving
a 74% yield of oxazole 17 (Scheme 4).
1H and 13C NMR spectra were recorded at the cited frequency.
Coupling constants (J) were recorded in Hertz (Hz). Where two
signals in the 13C NMR are coincident they are labelled with an
asterisk ( ).
*
Melting points were determined using a Gallenkamp melting
point apparatus. Elemental analyses were performed at the Uni-
versity of North London analytical laboratory.
4.2. Synthesis and nucleophilic trapping of silylketenes
with aminophenols
4.2.1. N-(2-Hydroxyphenyl)-2-triethylsilylnonamide (3a)
Silyl diazoketone 2a (464 mg, 1.65 mmol) and Rh2(oct)4 (13 mg,
1 mol %) were dissolved in benzene (10 mL) and stirred at rt until
complete consumption of starting material was observed by TLC
(10 min). The solvent was removed in vacuo and the silylketene
dissolved in THF (10 mL). 2-Aminophenol (360 mg, 3.29 mmol) was
added and the reaction mixture heated at 40 ꢀC for 16 h, after which
the solvent was removed in vacuo. The crude yellow oil was purified
by column chromatography (8/15% ether/petrol) to give the amide
3a (477 mg, 80%) as a colourless oil. Rf 0.22 (10% ether/petrol).
Found: C, 69.6; H, 10.1; N, 3.7. C21H37NO2Si requires C, 69.35; H,
10.25; N, 3.85%. nmax (NaCl/film)/cmꢁ13291 br, 2956 s, 2924 s, 2876 s,
2855 s,1644 s,1601 s,1520 s,1453 s,1362 s,1309 s,1243 s and 1018 s;
dH (270 MHz, CDCl3) 0.68 (6H, q, J 7.5, Si(CH2CH3)3), 0.85 (3H, t, J 7.0,
(CH2)6CH3), 0.98 (9H, t, J 7.5, Si(CH2CH3)3), 1.13–1.38 (10H, m,
(CH2)5), 1.41–1.52 (2H, m, 3-H), 2.03 (1H, dd, J 2.0 and 12.0, 2-H),
6.78–6.89 (2H, m, PhH), 6.97–7.14 (2H, m, PhH), 7.17 (1H, br s, NH)
and 9.40 (1H, br s, OH); dC (67.5 MHz, CDCl3) 2.6 (Si(CH2CH3)3), 7.4
(Si(CH2CH3)3), 14.2 ((CH2)6CH3), 22.7, 27.5, 29.2, 29.5, 30.7 and 31.9
((CH2)6), 8.0 (C-2), 120.2, 120.3, 122.0 and 127.1 (C-30, 40, 50 and 6),
137.1 (C-10), 149.4 (C-20) and 176.3 (C]O); m/z (CIþ) 364.2685
([MþH]þ, C21H38NO2Si requires 364.2672), 364 ([MþH]þ,100%), 290
(64), 255 (25) and 132 (43).
O
O
R
SiR3
1 mol% Rh2(oct)4
PhH, rt
R
SiR3
N2
2a, 2f
EtO2C
CO2Et
NH3Cl
Et3N, CH2Cl2
R3Si
R
R3Si
R
N
H
PPh3, I2
CO2Et
OEt
N
CO2Et
Et3N, CH2Cl2
O
O
CO2Et
15a, b
16a, b
TFA,
CH2Cl2
15a 85%, 16a 90%
15b 61%, 16b 57%
N
nC7H15
CO2Et
O
74%
OEt
17
Scheme 4. Synthesis and reactions of
a
-silylalkyloxazoles.
4.2.2. N-(2-Hydroxyphenyl)-3-phenyl-2-triethylsilyl-
propanamide (3b)
Prepared according to the method for 3a on a 0.51 mmol scale.
Purification by column chromatography (15/25% ether/petrol)
gave amide 3b (132 mg, 73%) as a colourless oil. Rf 0.28 (30% ether/
petrol). nmax (NaCl/film)/cmꢁ1 3346 m, 3062 w, 3027 w, 2953 s,
2876 m, 1746 m, 1640 m, 1515 s, 1497 s, 1453 s, 1241 m, 1040 m; dH
(300 MHz, CDCl3) 0.81 (6H, q, J 8.0, Si(CH2CH3)3), 1.08 (9H, t, J 8.0,
Si(CH2CH3)3), 2.39 (1H, dd, J 2.5 and 12.0, 2-H), 2.85 (1H, dd, J 2.5
and 14.0, 3-H), 3.32 (1H, dd, J 12.0 and 14.0, 3-H), 6.76–6.79 (2H, m,
ArH), 6.95 (1H, d, J 7.5, ArH), 7.08 (1H, m, ArH), 7.20–7.31 (6H, m,
5ꢂPhH and NH) and 9.23 (1H, s, OH); dC (75 MHz, CDCl3) 2.6
(Si(CH2CH3)3), 7.5 (Si(CH2CH3)3), 33.5 (C-3), 40.6 (C-2), 119.8, 120.2,
122.0, 125.9, 126.4 and 126.9 (C-10, 30, 40, 50, 60 and 4-PhH), 128.1 and
3. Conclusions
In summary, we have demonstrated that silylketenes can be
used as electrophilic templates for the construction of -silyl-
alkylbenzoxazoles and oxazoles. Conditions for the manipulation of
these intermediates with retention of the silicon function can be
a
found, allowing the preparation of diverse functionalised a-silyl-
alkylheterocycles. The silicon function is found to be labile towards
acidic reaction conditions, however, and this can be exploited to
effect deliberate protodesilylation in good yield if desired. Further
applications of this chemistry will be reported in due course.

5506
S.P. Marsden et al. / Tetrahedron 65 (2009) 5503–5512
128.7 (4C, PhH), 141.9 and 149.1 (PhC and C-20) and 175.4 (C]O);
m/z (CIþ) 356.2041 ([MþH]þ, C21H30NO2Si requires 356.2046), 356
([MþH]þ, 100%), 247 (20) and 109 (45).
ꢁ40 ꢀC to rt. Purification by column chromatography (30/50%
ether/petrol) gave amide 3f (122 mg, 69%) as a white foam. Rf 0.33
(50% ether/petrol). nmax (NaCl/film)/cmꢁ1 3304 br, 3047 w, 2957 m,
2933 m, 2861 m, 1732 s, 1643 m, 1527 m, 1478 m, 1453 s, 1368 s,
1257 s, 1156 s and 1075 m; dH (300 MHz, CDCl3) 0.11 (3H, s, SiCH3),
0.32 (3H, s, SiCH3), 0.95 (9H, s, SiC(CH3)3), 1.72 (9H, s, Boc), 3.81 (1H,
s, 2-H), 6.78–6.87 (2H, m, PhH), 7.01 (1H, d, J 9.0, PhH), 7.10 (1H, t, J
8.0, PhH), 7.28 (1H, t, J 8.0, IndH), 7.37 (1H, t, J 7.0, IndH), 7.54 (1H, d,
J 7.0, IndH), 7.77 (2H, br s, IndH and NH), 8.17 (1H, d, J 8.0, IndH) and
9.07 (1H, br s, OH); dC (75 MHz, CDCl3) ꢁ5.9 (SiCH3), ꢁ5.7 (SiCH3),
18.0 (SiC(CH3)3), 27.0 (SiC(CH3)3), 28.3 (Boc), 34.5 (C-2), 84.1 (Boc),
115.5, 116.1, 118.8, 119.9, 120.3, 122.1, 122.8, 123.7, 124.9, 125.8 and
127.1 (C-10, 30, 40, 50, 60, 200, 300, 400, 500, 600 and 700), 130.1 (C-3a00), 135.1
(C-7a00), 149.1 (Boc), 149.7 (C-20) and 173.4 (C]O, amide); m/z (CIþ)
481.2522 ([MþH]þ, C27H37N2O4Si requires 481.2523), 481
([MþH]þ, 97%), 349 (100), 253 (56), 236 (95) and 134 (46).
4.2.3. N-(2-Hydroxyphenyl)-2-(4-methoxyphenyl)-2-
triethylsilylethanamide (3c)
Prepared according to the method for 3a on a 0.52 mmol scale,
with the first step carried out at 40 ꢀC and the second step from
ꢁ40 ꢀC to rt. Purification by column chromatography (30% ether/
petrol) gave amide 3c (100 mg, 52%) as a very viscous yellow oil.
nmax (NaCl/film)/cmꢁ1 3304 m, 2953 s, 2910 m, 2882 m, 2836 m,
1638 m, 1508 s, 1454 m, 1246 m, 1179 m, 1033 m and 746 m; dH
(300 MHz, CDCl3) 0.72 (6H, q, J 7.5, Si(CH2CH3)3), 0.97 (9H, t, J 7.5,
Si(CH2CH3)3), 3.51 (1H, s, 2-H), 3.84 (3H, s, OCH3), 6.68–6.88 (2H, m,
PhH), 6.93 (2H, d, J 8.0, 300- and 500-H), 7.02 (1H, d, J 7.5, PhH), 7.09
(1H, m, PhH), 7.29 (2H, d, J 8.0, 200- and 600-H), 7.62 (1H, br s, NH) and
9.29 (1H, br s, OH); dC (75 MHz, CDCl3) 3.3 (Si(CH2CH3)3), 7.4
(Si(CH2CH3)3), 44.3 (C-2), 55.3 (OCH3), 114.5 (2C, C-300 and 500), 120.1,
120.2, 122.0, 125.9, 127.0 and 128.7 (C-10, 30, 40, 50, 60 and 100), 130.0
(2C, C-200 and 600), 149.0 and 158.3 (C-20 and 400) and 174.2 (C]O); m/z
(CIþ) 372.1998 ([MþH]þ, C21H30NO3Si requires 372.1995), 372
([MþH]þ, 100%), 258 (28) and 240 (34).
4.2.7. N-(2-Hydroxy-5-nitro)-2-(tert-butyldimethylsilyl)-
nonamide (3g)
Prepared according to the method for 3a on a 4.36 mmol scale,
with the second step carried out at reflux. Purification by column
chromatography (10/30% ether/petrol) gave amide 3g (1.40 g,
79%) as a yellow solid. Rf 0.14 (30% ether/petrol); mp 144–145 ꢀC.
nmax (NaCl/film)/cmꢁ1 3124 br, 3035 w, 2956 s, 2929 s, 2858 s, 1649
m, 1595 m, 1529 m, 1340 m, 1286 m and 1080 m; dH (300 MHz,
CDCl3) 0.11 (3H, s, SiCH3), 0.16 (3H, s, SiCH3), 0.85 (3H, t, J 7.0,
(CH2)6CH3), 0.98 (9H, s, SiC(CH3)3), 1.19–1.54 (10H, m, (CH2)5), 1.64
(1H, m, 3-H), 1.98 (1H, m, 3-H), 2.27 (1H, dd, J 1.5 and 11.5, 2-H), 7.13
(1H, d, J 9.0, 30-H), 7.99 (1H, dd, J 2.5 and 9.0, 40-H), 8.15 (1H, d, J 2.5,
60-H), 8.69 (1H, br s, NH) and 10.93 (1H, br s, OH); dC (75 MHz,
CDCl3) ꢁ7.0 (SiCH3), ꢁ6.6 (SiCH3), 14.1 ((CH2)6CH3), 17.7 (SiC(CH3)3),
22.7 (CH2), 26.8 (SiC(CH3)3), 28.5, 29.2, 29.5, 30.6 and 31.8 (5ꢂCH2),
4.2.4. N-(2-Hydroxyphenyl)-2-(2-furyl)-2-triethylsilyl-
ethanamide (3d)
Prepared according to the method for 3a on a 0.79 mmol scale,
with the first step carried out at 50 ꢀC and the second step from
ꢁ40 ꢀC to rt. Purification by column chromatography (20/25%
ether/petrol) gave amide 3d (118 mg, 45%) as a yellow solid. nmax
(NaCl)/cmꢁ1 3378 br, 2953 m, 2912 m, 2878 m, 1620 s, 1512 m, 1452
m, 1350 m, 1240 m, 1102 m and 1017 s; dH (300 MHz, CDCl3) 0.76
(6H, q, J 8.0, Si(CH2CH3)3), 0.98 (9H, t, J 8.0, Si(CH2CH3)3), 3.76 (1H, s,
2-H), 6.22 (1H, d, J 2.5, FurH), 6.34 (1H, d, J 2.5, FurH), 6.85 (1H, t, J
8.0, PhH), 7.02 (2H, d, J 8.0, PhH), 7.12 (1H, t, J 8.0, PhH), 7.47 (1H, s,
FurH), 8.11 (1H, s, NH) and 9.10 (1H, s, OH); dC (75 MHz, CDCl3) 3.2
(Si(CH2CH3)3), 7.1 (Si(CH2CH3)3), 38.9 (C-2), 107.7 and 111.4 (C-300
and 400), 119.6, 120.3, 122.1, 125.7 and 126.9 (C-10, 30, 40, 50 and 6þ0),
142.0 (C-500), 148.7 (C-20), 150.5 (C-200) and 171.6 (C]O); m/z (CI )
332.1679 ([MþH]þ, C18H26NO3Si requires 332.1682), 332 ([MþH]þ,
100%), 233 (17), 218 (32), 200 (21) and 120 (19).
38.4 (C-2), 117.0
*
(2C, C-30 and 60), 121.8 (C-40þ), 126.3 (C-10), 140.5 (C-
50), 153.7 (C-20) and 177.3 (C]O); m/z (CI ) 409.2540 ([MþH]þ,
C21H37N2O4Si requires 409.2523), 426 ([MþNH4]þ, 58%), 409
([MþH]þ, 39) and 379 (100).
4.2.8. N-(5-Allyloxycarbonylamino-2-hydroxyphenyl)-2-
triethylsilylnonamide (3h)
Prepared according to the method for 3a on a 0.72 mmol scale,
with the second step carried out at 50 ꢀC. Purification by column
chromatography (30/50% ether/petrol) gave amide 3h (246 mg,
75%) as a pale yellow oil. Rf 0.33 (50% ether/petrol). nmax (NaCl/film)/
cmꢁ1 3311 m, 2954 s, 2923 s, 2874 m, 2854 m, 1705 s, 1646 m, 1609
w, 1528 s, 1504 s, 1234 s and 1064 w; dH (300 MHz, CDCl3) 0.69 (6H,
q, J 8.0, Si(CH2CH3)3), 0.88 (3H, t, J 7.0, (CH2)6CH3), 1.00 (9H, t, J 8.0,
Si(CH2CH3)3), 1.20–1.39 (10H, m, (CH2)5), 1.45 (1H, m, 3-H), 1.97 (1H,
m, 3-H), 2.05 (1H, d, J 12.0, 2-H), 4.67 (2H, d, J 5.5, Alloc), 5.29
(1H, dd, J 1.0 and 10.5, Alloc), 5.38 (1H, dd, J 1.5 and 17.0, Alloc), 5.98
(1H, ddt, J 10.5, 17.0 and 5.5, Alloc), 6.60 (1H, br s, NH or 60-H),
6.85 (1H, dd, J 2.0 and 8.5, 40-H), 6.95 (1H, d, J 8.5, 30-H), 7.37 (2H, br
s, 2ꢂNH or NH and 60-H) and 9.17 (1H, s, OH); dC (75 MHz, CDCl3)
2.5 (Si(CH2CH3)3), 7.4 (Si(CH2CH3)3), 14.1 ((CH2)6CH3), 22.7, 27.4,
29.1, 29.5, 30.6 and 31.9 ((CH2)6), 37.9 (C-2), 65.9 (Alloc), 113.8 and
117.7 (C-60 and C-30 or 40), 118.1 (Alloc), 119.3 (C-30 or 40), 126.5 and
130.3 (C-10 and 50),132.4 (Alloc),145.0 (C-20),154.0 (Alloc) and 176.4
(C]O, amide); m/z (CIþ) 463.3003 ([MþH]þ, C25H43N2O4Si requires
463.2992), 480 ([MþNH4]þ, 100%) and 463 ([MþH]þ, 87).
4.2.5. N-(2-Hydroxyphenyl)-2-[3-(1-tert-butoxycarbonyl)indolyl]-
2-triethylsilylethanamide (3e)
Prepared according to the method for 3a on a 0.49 mmol scale,
with the first step carried out at 40 ꢀC and the second step from
ꢁ40 ꢀC. Purification by column chromatography (10/40% ether/
petrol) gave amide 3e (156 mg, 66%) as a yellow oil. nmax (NaCl/
film)/cmꢁ1 3307 br, 3110 w and 3052 w, 2948 m, 2930 m, 2913 m,
2877 m, 1734 s, 1642 m,1601 m, 1526 s, 1497 s,1371 s, 1257 s, 1156 s,
1075 m and 1018 m; dH (300 MHz, CDCl3) 0.82 (6H, q, J 7.5,
Si(CH2CH3)3), 1.00 (9H, t, J 7.5, Si(CH2CH3)3), 1.73 (9H, s, Boc), 3.80
(1H, s, 2-H), 6.76–6.82 (2H, m, PhH), 7.00–7.13 (2H, m, PhH), 7.30
(1H, m, IndH), 7.40 (1H, t, J 7.5, IndH), 7.54 (1H, d, J 7.5, IndH), 7.69
(1H, s, NH), 7.77 (1H, s, IndH), 8.18 (1H, d, J 7.5, IndH) and 9.14 (1H, s,
OH); dC (75 MHz, CDCl3) 3.5 (Si(CH2CH3)3), 7.4 (Si(CH2CH3)3), 28.3
(Boc), 34.1 (C-2), 84.2 (Boc), 115.5, 115.7, 118.8, 120.0, 120.2, 122.1,
122.9, 123.8, 125.1, 125.7 and 127.1 (C-10, 30, 40, 50, 60, 200, 300, 400, 500, 600
and 700), 130.2 (C-3a00), 135.1 (C-7a00), 149.6 (C-20), 149.2 (Boc) and
173.3 (C]O, amide); m/z (CIþ) 481.2522 ([MþH]þ, C27H37N2O4Si
requires 481.2523), 481 ([MþH]þ, 100%), 430 (16), 381 (37), 349
(87), 248 (30) and 130 (16).
4.2.9. N-(4-Allyloxycarbonylamino-2-hydroxyphenyl)-2-
triethylsilylnonamide (3i)
Prepared according to the method for 3a on a 0.57 mmol scale,
with the second step carried out at 55 ꢀC. Purification by column
chromatography (30/50% ether/petrol) gave amide 3i (206 mg,
78%) as a yellow oil. Rf 0.29 (50% ether/petrol). nmax (NaCl/film)/
cmꢁ1 3308 br, 2953 s, 2925 s, 2875 s, 2855 s, 1708 s, 1644 s, 1611 s,
4.2.6. N-(2-Hydroxyphenol)-2-[3-(1-tert-butoxycarbonyl)indolyl]-
2-(tert-butyldimethylsilyl)ethanamide (3f)
Prepared according to the method for 3a on a 0.37 mmol scale,
with the first step carried out at 40 ꢀC and the second step from

S.P. Marsden et al. / Tetrahedron 65 (2009) 5503–5512
5507
1514 s, 1458 m, 1428 m, 1363 m, 1299 m, 1227 s, 1063 s and 733 m;
dH (300 MHz, CDCl3) 0.69 (6H, q, J 8.0, Si(CH2CH3)3), 0.88 (3H, t, J 7.0,
(CH2)6CH3), 1.00 (9H, t, J 8.0, Si(CH2CH3)3), 1.18–1.37 (10H, m,
(CH2)5), 1.46 (1H, m, 3-H), 1.98 (1H, m, 3-H), 2.07 (1H, d, J 11.5, 2-H),
4.67 (2H, d, J 5.5, Alloc), 5.28 (1H, dd, J 1.0 and 10.5, Alloc), 5.37 (1H,
dd, J 1.0 and 17.0, Alloc), 5.97 (1H, ddt, J 10.5, 17.0 and 5.5, Alloc),
6.74 (1H, br s, NH or PhH), 6.83–6.94 (2H, m, PhH), 7.02 (1H, br s, NH
or PhH), 7.39 (1H, br s, NH) and 9.53 (1H, br s, OH); dC (75 MHz,
CDCl3) 2.5 (Si(CH2CH3)3), 7.4 (Si(CH2CH3)3), 14.1 ((CH2)6CH3), 22.7,
27.4, 29.2, 29.5, 30.7 and 31.9 ((CH2)6), 37.8 (C-2), 65.9 (Alloc), 109.6
and 111.0 (C-30 and 50), 118.2 (Alloc), 122.4 (C-60), 122.4 (C-10), 132.3
(Alloc), 135.9 (C-40), 149.0 (C-20), 153.6 (Alloc) and 176.0 (C]O,
amide); m/z (CIþ) 463.2984 ([MþH]þ, C25H43N2O4Si requires
463.2292), 463 ([MþH]þ, 100%), 405 (32) and 208 (22).
DEAD (22 mL, 0.14 mmol) were added and the solution heated at
55 ꢀC for 4 h. The reaction mixture was washed with water (2 mL)
and extracted with DCM (2ꢂ5 mL). The organic layer was dried
over MgSO4, filtered and the solvent removed in vacuo. The com-
pound was purified by column chromatography (2% ether/petrol) to
give the benzoxazole 4a (30 mg, 81%) as a colourless oil. nmax (NaCl/
film)/cmꢁ1 2954 s, 2876 s, 2555 s, 1610 w, 1556 s, 1456 s, 1243 s and
742 s; dH (300 MHz, CDCl3) 0.65 (6H, q, J 7.5, Si(CH2CH3)3), 0.86 (3H,
t, J 4.5, (CH2)6CH3), 0.95 (9H, t, J 7.5, Si(CH2CH3)3), 1.12–1.43 (10H, m,
(CH2)5), 1.74 (1H, m, 2-H), 2.14 (1H, m, 2-H), 2.65 (1H, dd, J 2.5 and
12.0, 1-H), 7.24–7.30 (2H, m, BenzH), 7.46 (1H, dd, J 2.0 and 6.5,
BenzH) and 7.65 (1H, dd, J 2.0 and 7.0, BenzH); dC (75 MHz, CDCl3)
2.6 (Si(CH2CH3)3), 7.3 (Si(CH2CH3)3), 14.1 ((CH2)6CH3), 22.7 and 28.0
(2ꢂCH2), 28.7 (C-1), 29.2, 29.3, 30.3 and 31.9 (4ꢂCH2), 109.9 (C-70),
118.9 (C-40), 123.5 and 123.8 (C-50 and 60), 142.0 (C-3a0), 150.6 (C-
7a0) and 170.5 (C-20); m/z (CIþ) 346.2561 ([MþH]þ, C21H36NOSi
requires 346.2566), 346 ([MþH]þ, 100%), 232 (28), 153 (33) and 104
(58).
4.2.10. N-(5-Allyloxycarbonylamino-2-hydroxyphenyl)-3-phenyl-
2-triethylsilylpropanamide (3j)
Prepared according to the method for 3a on a 0.88 mmol scale,
with the second step carried out at reflux. Purification by column
chromatography (40/50% ether/petrol) gave amide 3j (300 mg,
75%) as a yellow oil. Rf 0.26 (50% ether/petrol). nmax (NaCl/film)/
cmꢁ1 3310 br, 3085 w, 3061 w, 3025 w, 2954 s, 2911 m, 2876 m,
1703 s, 1646 m, 1606 m, 1530 s, 1505 s, 1454 m, 1235 s and 1064 m;
dH (300 MHz, CDCl3) 0.78 (6H, q, J 8.0, Si(CH2CH3)3), 1.06 (9H, t, J 8.0,
Si(CH2CH3)3), 2.34 (1H, dd, J 2.0 and 12.0, 2-H), 2.82 (1H, dd, J 2.0
and 14.0, 3-H), 3.30 (1H, dd, J 12.0 and 14.0, 3-H), 4.63 (2H, d, J 5.5,
Alloc), 5.27 (1H, dd, J 1.5 and 10.5, Alloc), 5.36 (1H, dd, J 1.5 and 17.0,
Alloc), 5.95 (1H, ddt, J 10.5, 17.0 and 5.5, Alloc), 6.51 (1H, br s, NH or
60-H), 6.81 (1H, dd, J 2.5 and 8.5, 40-H), 6.89 (1H, d, J 8.5, 30-H), 7.09–
7.23 (4H, m, NH, 2ꢂPhH and NH or 60-H), 7.25–7.32 (3H, m, 3ꢂPhH)
and 8.95 (1H, s, OH); dC (75 MHz, CDCl3) 2.6 (Si(CH2CH3)3), 7.4
(Si(CH2CH3)3), 33.3 (C-3), 40.4 (C-2), 65.9 (Alloc), 113.4 (C-30 or 40 or
60), 118.2 (Alloc), 119.7 (C-30 or 40 or 60), 128.3 (C-30 or 40 or 60), 126.0
(C-10 or 50), 126.4 (4-PhH), 128.1 and 128.7 (4C, PhH), 130.0 (C-10 or
50), 132.4 (Alloc), 142.0 (PhC), 145.3 (C-20), 153.9 (Alloc) and 175.3
(C]O, amide); m/z (CIþ) 455.2371 ([MþH]þ, C25H35N2O4Si requires
455.2367), 472 ([MþNH4]þ, 25%) and 455 ([MþH]þ, 68).
4.3.2. 2-[1-(2-Phenyl-1-triethylsilyl)ethyl]benzoxazole (4b)
Prepared according to the method for 4a on a 0.25 mmol scale.
Purification by column chromatography (10% DCM/petrol) gave
benzoxazole 4b (57 mg, 67%) as a colourless oil. nmax (NaCl/film)/
cmꢁ1 3062w, 2953 m, 2910 m, 2876 m, 1609 w, 1555 s, 1496 w, 1455
s, 1242 s and 1003 m. dH (300 MHz, CDCl3) 0.74 (6H, q, J 7.5,
Si(CH2CH3)3), 1.02 (9H, t, J 7.5, Si(CH2CH3)3), 3.05 (1H, dd, J 3.0 and
12.0, 1-H), 3.11 (1H, dd, J 3.0 and 14.5, 2-H), 3.51 (1H, dd, J 12.0 and
14.5, 2-H), 7.13–7.31 (7H, m, 5ꢂPhH and 2ꢂBenzH), 7.44 (1H, dd, J
2.0 and 6.5, BenzH), 7.64 (1H, dd, J 2.5 and 7.0, BenzH); dC (75 MHz,
CDCl3) 2.6 (Si(CH2CH3)3), 7.3 (Si(CH2CH3)3), 30.8 (C-2), 33.8 (C-1),
109.9 (C-70), 119.0 (C-40), 123.5, 123.8 and 126.2 (4-PhH and C-50 and
60), 128.1 and 128.4 (4C, PhH), 141.6 and 141.9 (PhC anþd C-3a0), 150.5
(C-7a0) and 169.4 (C-20); m/z (CIþ) 338.1946 ([MþH] , C21H28NOSi
requires 338.1940) and 338 ([MþH]þ, 100%).
4.3.3. 2-[(4-Methoxyphenyl)triethylsilylmethyl]benzoxazole (4c)
Prepared according to the method for 4a on a 0.50 mmol scale.
Purification by column chromatography (5% ether/petrol) gave
benzoxazole 4c (60 mg, 34%) as a colourless oil. nmax (NaCl/film)/
cmꢁ1 3055 w, 3024 w, 2952 s, 2910 m, 2879 s, 2834 m, 1609 m, 1553
s, 1510 s, 1456 s, 1244 s, 1180 m, 1138 m, 1036 m, 1000 m and 826 m;
dH (270 MHz, CDCl3) 0.64 (6H, q, J 8.0, Si(CH2CH3)3), 0.86 (9H, t, J 8.0,
Si(CH2CH3)3), 3.78 (3H, s, OCH3). 3.97 (1H, s, 1-H), 6.86 (2H, d, J 9.0,
300 and 500-H), 7.20–7.29 (2H, m, BenzH), 7.39 (2H, d, J 9.0, 200 and 600-
H), 7.45 (1H, m, BenzH) and 7.65 (1H, m, BenzH); dC (75 MHz, CDCl3)
2.7 (Si(CH2CH3)3), 7.1 (Si(CH2CH3)3), 35.8 (C-1), 55.3 (OCH3), 110.0
(C-70), 113.9 (2C, C-300 and 500), 119.4 (C-40), 123.9 (C-50 or 60), 129.2
4.2.11. N-(4-Allyloxycarbonylamino-2-hydroxyphenyl)-3-phenyl-2-
triethylsilylpropanamide (3k)
Prepared according to the method for 3a on a 0.57 mmol scale,
with the second step carried out at reflux. Purification by column
chromatography (30/50% ether/petrol) gave amide 3k (182 mg,
77%) as a yellow oil. Rf 0.27 (50% ether/petrol). nmax (NaCl/film)/
cmꢁ1 3298 br, 3084 w, 3062 w and 3026 w, 2954 m, 2910 m, 2876
m, 1705 s, 1644 m, 1611 m, 1524 s, 1226 s and 1062 m; dH (300 MHz,
CDCl3) 0.79 (6H, q, J 8.0, Si(CH2CH3)3),1.06 (9H, t, J 8.0, Si(CH2CH3)3),
2.33 (1H, dd, J 2.0 and 12.0, 2-H), 2.82 (1H, dd, J 2.0 and 14.0, 3-H),
3.29 (1H, dd, J 12.0 and 14.0, 3-H), 4.65 (2H, d, J 5.5, Alloc), 5.27 (1H,
dd, J 1.0 and 10.5, Alloc), 5.37 (1H, dd, J 1.0 and 17.0, Alloc), 5.97
(1H, ddt, J 10.5, 17.0 and 5.5, Alloc), 6.60 (1H, br s, NH or 50-H), 6.63
(1H, d, J 8.5, 60-H), 6.83 (1H, d, J 2.0, 30-H), 6.94–7.11 (2H, m, 2ꢂNH
or NH and 50-H), 7.17–7.23 (2H, m, 2ꢂPhH), 7.24–7.32 (3H, m,
3ꢂPhH) and 9.37 (1H, br s, OH); dC (75 MHz, CDCl3) 2.6
(Si(CH2CH3)3), 7.5 (Si(CH2CH3)3), 33.3 (C-3), 40.1 (C-2), 65.9 (Alloc),
109.4 and 111.1 (C-30 and 50), 118.3 (Alloc), 122.0 (C-10), 122.5 (C-60),
126.3 (4-PhH), 128.2 and 128.6 (4C, PhH), 132.3 (Alloc), 136.0 (C-40),
142.2 (PhC), 149.0 (C-20), 153.6 (Alloc) and 175.1 (C]O, amide); m/z
(CIþ) 455.2372 ([MþH]þ, C25H35N2O4Si requires 455.2366), 455
([MþH]þ, 100%), 397 (66) and 323 (48).
(C-100), 129.4 (3C, C-50 or 60, 200 and 600), 141.8 (C-3a0), 150.6 (C-7a0),
*
157.8 (C-400) and 167.9 (C-20); m/z (CIþ) 354.1889 ([MþH]þ,
C21H28NO2Si requires 354.1889), 354 ([MþH]þ, 100%), 240 (14) and
104 (12).
4.3.4. 2-[(2-Furyl)triethylsilylmethyl]benzoxazole (4d)
Prepared according to the method for 4a on a 0.36 mmol
scale. Purification by column chromatography (5/30% ether/
petrol) gave benzoxazole 4d (47 mg, 42%) as a colourless oil. nmax
(NaCl/film)/cmꢁ1 3115 w, 3056 w, 2954 s, 2912 s, 2890 m, 1557 s,
1563 m, 1455 s, 1384 w, 1240 s, 1144 m, 1009 s, 946 m and 810
m; dH (300 MHz, CDCl3) 0.73 (6H, q, J 8.0, Si(CH2CH3)3), 0.93 (9H,
t, J 8.0, Si(CH2CH3)3), 4.25 (1H, s, 1-H), 6.34 (1H, d, J 3.0, FurH),
6.38 (1H, d, J 3.0, FurH), 7.25–7.33 (2H, m, BenzH), 7.40 (1H, s,
FurH), 7.49 (1H, m, BenzH) and 7.70 (1H, m, BenzH); dC (75 MHz,
CDCl3) 2.9 (Si(CH2CH3)3), 7.0 (Si(CH2CH3)3), 30.2 (C-1), 106.5
(FurH), 110.1 and 110.7 (C-70 and FurH), 119.5 (C-40), 124.0* (2C, C-
50 and 60), 141.1 (FurH), 141.8 þ(C-3a0), 150.6 and 150.8 (C-7a0 and
200) and 165.8 (C-20); m/z (CI ) 314.1575 ([MþH]þ, C18H24NO2Si
4.3. Cyclodehydration to a-silylalkylbenzoxazoles
4.3.1. 2-[1-(1-Triethylsilyl)octyl]benzoxazole (4a)
Amide 3a (42 mg, 0.12 mmol) was dissolved in THF (2 mL).
Triethylamine (34 mL, 0.24 mmol), PPh3 (36 mg, 0.14 mmol) and

5508
S.P. Marsden et al. / Tetrahedron 65 (2009) 5503–5512
requires 314.1576), 314 ([MþH]þ, 100%), 200 (15), 132 (10) and
(300 MHz, CDCl3) 0.62 (6H, q, J 8.0, Si(CH2CH3)3), 0.85 (3H, t, J 7.0,
(CH2)6CH3), 0.92 (9H, t, J 8.0, Si(CH2CH3)3), 1.16–1.39 (10H, m,
(CH2)5), 1.68 (1H, m, 2-H), 2.11 (1H, m, 2-H), 2.62 (1H, dd, J 3.0 and
12.0, 1-H), 4.69 (2H, d, J 5.5, Alloc), 5.26 (1H, dd, J 1.0 and 10.5,
Alloc), 5.36 (1H, dd, J 1.5 and 17.0, Alloc), 5.98 (1H, ddt, J 10.5, 17.0
and 5.5, Alloc), 6.95 (1H, br s, NH or BenzH), 7.31 (1H, br s, NH or
BenzH), 7.36 (1H, d, J 8.5, 70-H) and 7.64 (1H, s, NH or BenzH); dC
(75 MHz, CDCl3) 2.5 (Si(CH2CH3)3), 7.2 (Si(CH2CH3)3), 14.1
((CH2)6CH3), 22.6, 27.9, 29.1, 29.2, 30.3 and 31.8 ((CH2)6), 28.8 (C-1),
65.9 (Alloc), 109.7, 110.0 and 115.7 (C-40, 60 and 70), 118.2 (Alloc),
132.5 (Alloc), 134.1 (C-50), 142.5 (C-3a0), 147.2 (C-7a0), 153.7 (Alloc)
and 171.5 (C-20); m/z (CIþ) 445.2885 ([MþH]þ, C25H41N2O3Si
requires 445.2886), 445 ([MþH]þ, 100%) and 387 (28).
104 (12).
4.3.5. 2-{[3-(1-tert-Butoxycarbonyl)indolyl]-triethylsilylmethyl}-
benzoxazole (4e)
Prepared according to the method for 4a on a 0.088 mmol scale.
Purification by column chromatography (5/20% ether/petrol)
gave benzoxazole 4e (19 mg, 47%) as a colourless oil. nmax (NaCl/
film)/cmꢁ1 3053 w, 2954 s, 2930 s, 2884 s, 1730 s, 1608 m, 1553 s,
1453 s, 1368 s, 1248 m, 1013 m and 859 w; dH (300 MHz, CDCl3) 0.72
(6H, q, J 8.0, Si(CH2CH3)3), 0.92 (9H, t, J 8.0, Si(CH2CH3)3), 1.73 (9H, s,
Boc), 4.32 (1H, s, 1-H), 7.26–7.33 (4H, m, 2ꢂBenzH and 2ꢂIndH),
7.49 (1H, m, BenzH), 7.58 (1H, d, J 7.5, IndH), 7.66 (1H, m, BenzH),
7.95 (1H, s, IndH) and 8.11 (1H, d, J 8.0, IndH); dC (75 MHz, CDCl3) 2.9
(Si(CH2CH3)3), 7.2 (Si(CH2CH3)3), 25.8 (C-1), 28.3 (Boc), 83.7 (Boc),
110.1 (C-70), 115.3 (C-700), 115.8 (C-300), 118.8 (IndH), 119.4 (C-40),
122.4 (IndH), 123.8, 123.9, 124.0 and 124.4 (C-50, 60 and 2ꢂIndH),
130.5 (C-3a00), 134.8 (C-7a0þ0), 141.9 (C-3a0), 150.0 (Boc), 150.7 (C-7a0)
and 167.5 (C-20); m/z (CI ) 463.2401 ([MþH]þ, C27H35N2O3Si re-
quires 463.2417), 463 ([MþH]þ, 100%), 406 (27), 363 (21) and 349
(15).
4.3.9. 6-Allyloxycarbonylamino-2-[1-(1-triethylsilyl)octyl]-
benzoxazole (4i)
Prepared according to the method for 4a on a 0.64 mmol scale,
using DIAD in place of DEAD. Purification by column chromato-
graphy (25/35% ether/petrol) gave benzoxazole 4i (133 mg, 70%)
as a colourless oil. Rf 0.21 (25% ether/petrol). nmax (NaCl/film)/cmꢁ1
3318 br, 3075 w, 2953 s, 2926 s, 2875 m, 2855 m, 1735 s, 1710 s, 1617
s, 1546 s, 1496 s, 1431 m, 1220 s and 1051 m; dH (270 MHz, CDCl3)
0.59 (6H, q, J 8.0, Si(CH2CH3)3), 0.82 (3H, t, J 7.0, (CH2)6CH3), 0.90
(9H, t, J 8.0, Si(CH2CH3)3), 1.12–1.39 (10H, m, (CH2)5), 1.65 (1H, m, 2-
H), 2.10 (1H, m, 2-H), 2.57 (1H, dd, J 3.5 and 12.5, 1-H), 4.66 (2H, d, J
5.5, Alloc), 5.24 (1H, dd, J 1.5 and 10.5, Alloc), 5.35 (1H, dd, J 1.5 and
17.5, Alloc), 5.96 (1H, ddt, J 10.5, 17.5 and 5.5, Alloc), 6.90 (1H, br s,
NH or 70-H), 6.98 (1H, dd, J 2.0 and 8.5, 50-H), 7.47 (1H, d, J 8.5, 40-H)
and 7.86 (1H, br s, NH or 70-H); dC (67.5 MHz, CDCl3) 2.6
(Si(CH2CH3)3), 7.3 (Si(CH2CH3)3), 14.1 ((CH2)6CH3), 22.6 and 27.9
(2ꢂCH2), 28.7 (C-1), 29.1, 29.3, 30.3 and 31.8 (4ꢂCH2), 65.9 (Alloc),
101.5 and 115.4 (C-70 and C-40 or 50), 118.2 (Alloc), 118.5 (C-40 or 50),
132.5 (Alloc), 134.5 and 137.8 (C-3a0, 60), 151.0 (C-7a0), 153.7 (Alloc)
and 170.4 (C-20); m/z (CIþ) 445.2878 ([MþH]þ, C25H41N2O3Si re-
quires 445.2886) and 445 ([MþH]þ, 100%).
4.3.6. 2-{[3-(1-tert-Butoxycarbonyl)indolyl]tert-
butyldimethylsilylmethyl}benzoxazole (4f)
Prepared according to the method for 4a on a 0.11 mmol scale.
Purification by column chromatography (5/20% ether/petrol)
gave benzoxazole 4f (33 mg, 67%) as a colourless oil. Rf 0.51 (30%
ether/petrol). nmax (NaCl/film)/cmꢁ1 3053 w, 2957 s, 2934 s, 2863 s,
1730 s, 1608 m, 1555 s, 1453 s, 1367 s, 1252 s, 1202 s, 1082 s and 1011
m; dH (300 MHz, CDCl3) 0.07 (3H, s, SiCH3), 0.22 (3H, s, SiCH3), 0.88
(9H, s, SiC(CH3)3), 1.72 (9H, s, Boc), 4.37 (1H, s, 1-H), 7.25–7.37 (4H,
m, 2ꢂBenzH and 2ꢂIndH), 7.52 (1H, m, BenzH), 7.63–7.69 (2H, m,
BenzH and IndH), 7.91 (1H, s, IndH) and 8.10 (1H, d, J 8.0, IndH); dC
(75 MHz, CDCl3) ꢁ6.9 (SiCH3), ꢁ5.8 (SiCH3), 17.8 (SiC(CH3)3), 25.4
(C-1), 26.7 (SiC(CH3)3), 28.3 (Boc), 83.8 (Boc), 110.2 (C-70), 115.3 (C-
700), 116.5 (C-300), 119.0 (IndH), 119.4 (C-40), 122.5 (IndH), 123.8,
124.0* and 124.4 (4C, C-50, 60 and 2ꢂIndH), 130.4 (C-3a00), 134.8 (C-
7a00), 141.7 (C-3a0), 150.0 (Boc), 150.7 (C-7a0) and 167.5 (C-20); m/z
(CIþ) 463.2408 ([MþH]þ, C27H35N2O3Si requires 463.2417), 463
([MþH]þ, 100%), 406 (18) and 362 (23).
4.3.10. 5-Allyloxycarbonylamino-2-[1-(2-phenyl-1-triethylsilyl)-
ethyl]benzoxazole (4j)
Prepared according to the method for 4a on a 0.96 mmol scale.
Purification by column chromatography (35/50% ether/petrol)
gave benzoxazole 4j (152 mg, 54%) as a yellow oil. Rf 0.41 (50%
ether/petrol). nmax (NaCl/film)/cmꢁ1 3323 br, 3082 w, 3063 w, 3027
w, 2954 s, 2911 s, 2877 s,1731 s,1709 s,1621 m,1554 s,1486 m,1224
s and 1053 m; dH (300 MHz, CDCl3) 0.70 (6H, q, J 7.5, Si(CH2CH3)3),
0.98 (9H, t, J 7.5, Si(CH2CH3)3), 2.99 (1H, dd, J 3.0 and 12.0, 1-H), 3.06
(1H, dd, J 3.0 and 14.5, 2-H), 3.44 (1H, dd, J 12.0 and 14.5, 2-H), 4.69
(2H, d, J 5.5, Alloc), 5.28 (1H, dd, J 1.0 and 10.5, Alloc), 5.38 (1H, dd, J
1.0 and 17.0, Alloc), 5.99 (1H, ddt, J 10.5, 17.0 and 5.5, Alloc), 6.81
(1H, br s, NH or BenzH), 7.08–7.28 (6H, m, BenzH and 5ꢂPhH), 7.33
(1H, d, J 8.5, 70-H) and 7.62 (1H, br s, NH or BenzH); dC (75 MHz,
CDCl3) 2.5 (Si(CH2CH3)3), 7.3 (Si(CH2CH3)3), 30.9 (C-1), 33.7 (C-2),
66.9 (Alloc), 109.8, 110.1 and 115.9 (C-40, 60 and 70), 118.2 (Alloc),
126.2 (4-PhH), 128.1 and 128.5 (4C, PhH), 132.5 (Alloc), 134.2 (C-50),
141.5 and 142.3 (C-3a0 and PhC), 147.1 (þC-7a0), 153.8 (Alloc) and
170.5 (C-20); m/z (CIþ) 437.2259 ([MþH] , C25H33N2O3Si requires
437.2260), 437 ([MþH]þ, 98%) and 379 (100).
4.3.7. 2-[1-(1-tert-Butyldimethylsilyl)octyl]-5-nitro-
benzoxazole (4g)
Prepared according to the method for 4a on a 3.40 mmol scale.
Purification by column chromatography (1/5% ether/petrol) gave
benzoxazole 4g (1.26 g, 95%) as a colourless oil. Rf 0.55 (20% ether/
petrol). nmax (NaCl/film)/cmꢁ1 3109 w, 2929 m, 2956 s, 2858 m, 1416
m, 1552 m, 1531 s, 1460 m, 1346 m, 1257 m, 1147 w and 1108 w; dH
(300 MHz, CDCl3) ꢁ0.10 (3H, s, SiCH3), 0.14 (3H, s, SiCH3), 0.79 (3H,
t, J 7.0, (CH2)6CH3), 0.83 (9H, s, SiC(CH3)3), 1.15–1.31 (10H, m,
(CH2)5), 1.75 (1H, m, 2-H), 2.09 (1H, m, 2-H), 2.67 (1H, dd, J 2.5 and
12.5, 1-H), 7.53 (1H, d, J 9.0, 70-H), 8.20 (1H, dd, J 2.0 and 9.0, 60-H)
and 8.48 (1H, d, J 2.0, 40-H); dC (75 MHz, CDCl3) ꢁ7.1 (SiCH3), ꢁ6.9
(SiCH3), 14.1 ((CH2)6CH3), 17.5 (SiC(CH3)3), 22.6 (CH2), 26.5
(SiC(CH3)3), 28.9, 29.0
*
, 29.1, 30.3 and 31.7 (6C, 5ꢂCH2 and C-1),
109.9, 115.1 and 119.9 (C-40, 60 and 70), 142.3 and 145.0 (C-3a0 and
50), 154.1 (C-7a0) and 174.1 (C-20); m/z (CIþ) 391.2428 ([MþH]þ,
C21H35N2O3Si requires 391.2417) and 391 ([MþH]þ, 100%).
4.3.11. 6-Allyloxycarbonylamino-2-[1-(2-phenyl-1-triethylsilyl)-
ethyl]benzoxazole (4k)
4.3.8. 5-Allyloxycarbonylamino-2-[1-(1-triethylsilyl)octyl]-
benzoxazole (4h)
Prepared according to the method for 4a on a 0.59 mmol scale.
Purification by column chromatography (30/50% ether/petrol)
gave benzoxazole 4k (128 mg, 73%) as a colourless oil. Rf 0.42 (50%
ether/petrol). nmax (NaCl/film)/cmꢁ1 3318 br, 3083 w, 3063 w, 3026
w, 2953 s, 2911 m, 2876 m, 1713 s, 1710 s, 1617 s, 1546 s, 1494 s, 1455
m, 1431 m, 1222 s and 1051 s; dH (300 MHz, CDCl3) 0.71 (6H, q, J 8.0,
Si(CH2CH3)3), 0.98 (9H, t, J 8.0, Si(CH2CH3)3), 2.98 (1H, dd, J 3.0 and
Prepared according to the method for 4a on a 0.20 mmol scale.
Purification by column chromatography (25/35% ether/petrol)
gave benzoxazole 4h (50 mg, 56%) as a colourless oil. Rf 0.35 (30%
ether/petrol). nmax (NaCl/film)/cmꢁ1 3252 br, 2956 s, 2935 s, 2876
m, 2855 m, 1734 m, 1706 m, 1550 s, 1262 w, 1221 m and 1054 w; dH

S.P. Marsden et al. / Tetrahedron 65 (2009) 5503–5512
5509
12.0, 1-H), 3.07 (1H, dd, J 3.0 and 14.0, 2-H), 3.43 (1H, dd, J 12.0 and
14.0, 2-H), 4.70 (2H, d, J 5.5, Alloc), 5.29 (1H, dd, J 1.5 and 10.0,
Alloc), 5.39 (1H, dd, J 1.5 and 17.0, Alloc), 5.99 (1H, ddt, J 10.0, 17.0
and 5.5, Alloc), 6.82 (1H, br s, NH or 70-H), 6.97 (1H, dd, J 2.0 and 8.5,
50-H), 7.08–7.22 (5H, m, 5ꢂPhH), 7.47 (1H, d, J 8.5, 40-H) and 7.87
(1H, br s, NH or 70-H); dC (75 MHz, CDCl3) 2.5 (Si(CH2CH3)3), 7.3
(Si(CH2CH3)3), 30.8 (C-1), 33.8 (C-2), 65.9 (Alloc), 101.4, 115.4 (C-70
and C-40 or 50), 118.2 (Alloc), 118.6 (C-40 or 50), 126.2 (4-PhH), 128.1
and 128.5 (4C, PhH), 132.4 (Alloc), 134.4 (C-60), 137.7 and 141.5 (C-
3a0 and PhC), 150.9 (C-7a0), 153.6 (Alloc) and 169.4 (C-20); m/z (CIþ)
437.2266 ([MþH]þ, C25H33N2O3Si requires 437.2260), 437 ([MþH]þ,
100%) and 379 (65).
and 8.5, 60-H), 6.91 (1H, d, J 2.5, 40-H) and 7.08–7.22 (6H, m, 5ꢂPhH
and 70-H); dC (75 MHz, CDCl3) 2.6 (Si(CH2CH3)3), 7.3 (Si(CH2CH3)3),
30.8 (C-1), 33.8 (C-2), 104.7, 109.9 and 111.8 (C-40, 60 and 70), 126.5
(4-PhH), 128.1 and 128.4 (4C, PhH), 141.7, 142.9, 143.þ2 and 144.5
(PhC, C-3a0, 50 and 7a0) and 169.9 (C-20); m/z (CI ) 353.2047
([MþH]þ, C21H29N2OSi requires 353.2049) and 353 ([MþH]þ,100%).
4.4.4. 6-Amino-2-[1-(2-phenyl-1-triethylsilyl)ethyl]-
benzoxazole (5d)
Prepared from 4k according to the method for 5a on
a 0.25 mmol scale. Purification by column chromatography (50/
80% ether/petrol) gave aminobenzoxazole 5d (64 mg, 72%) as
a beige coloured solid. Rf 0.32 (75% ether/petrol); mp 102–103 ꢀC.
nmax (NaCl/film)/cmꢁ1 3320 br, 3214 br, 3082 w, 3061 w, 3023 w,
2953 s, 2910 m, 2876 s, 1623 s, 1608 s, 1560 m, 1491 s, 1450 s and
1138 s; dH (300 MHz, CDCl3) 0.71 (6H, q, J 8.0, Si(CH2CH3)3), 0.98
(9H, t, J 8.0, Si(CH2CH3)3), 2.92 (1H, dd, J 3.0 and 12.0, 1-H), 3.04 (1H,
dd, J 3.0 and 14.5, 2-H), 3.42 (1H, dd, J 12.0 and 14.5, 2-H), 3.71 (2H,
br s, NH2), 6.61 (1H, dd, J 2.0 and 8.5, 50-H), 6.75 (1H, d, J 2.0, 70-H),
7.08–7.21 (5H, m, 5ꢂPhH) and 7.36 (1H, d, J 8.5, 40-H); dC (75 MHz,
CDCl3) 2.6 (Si(CH2CH3)3), 7.3 (Si(CH2CH3)3), 30.5 (C-1), 33.9 (C-2),
96.6, 112.1 and 119.1 (C-40, 50 and 70), 126.1 (4-PhH), 128.2 and 128.4
(4C, PhH), 134.4, 141.7 and 143.2 (PhC, C-3a0 and 60), 151.7 (C-7a0)
and 167.2 (C-20); m/z (CIþ) 353.2041 ([MþH]þ, C21H29N2OSi re-
quires 353.2049) and 353 ([MþH]þ, 100%).
4.4. Deprotection of allyloxycarbonyl groups
4.4.1. 5-Amino-2-[1-(1-triethylsilyl)octyl]benzoxazole (5a)
Protected aminobenzoxazole 4h (20 mg, 45.0 mmol) was dis-
solved in THF (1 mL) with N,N0-dimethylbarbituric acid (70 mg,
0.45 mmol). Tetrakis(triphenylphosphine) palladium (3 mg,
5 mol %) was added to the solution and the mixture stirred at rt for
3.5 h. The solution was diluted with ether (10 mL) and washed with
NaHCO3 (satd, aq, 5 mL) and brine (satd, aq, 5 mL), dried over
MgSO4, filtered and the solvent removed in vacuo. The crude
compound was purified by column chromatography (30/70%
ether/petrol) to give the aminobenzoxazole 5a (14 mg, 86%) as
a colourless oil. Rf 0.27 (70% ether/petrol). nmax (NaCl/film)/cmꢁ1
3339 br, 2953 s, 2925 s, 2874 s, 2854 m,1624 w,1551 s,1487 m,1450
m,1184 m,1009 w and 798 w; dH (300 MHz, CDCl3) 0.63 (6H, q, J 8.0,
Si(CH2CH3)3), 0.86 (3H, t, J 7.0, (CH2)6CH3), 0.93 (9H, t, J 8.0,
Si(CH2CH3)3), 1.17–1.41 (10H, m, (CH2)5), 1.75 (1H, m, 2-H), 2.12 (1H,
m, 2-H), 2.58 (1H, dd, J 3.0 and 12.5, 1-H), 3.67 (2H, br s, NH2), 6.59
(1H, dd, J 2.0 and 8.5, 60-H), 6.94 (1H, d, J 2.0, 40-H) and 7.22 (1H, d, J
8.5, 70-H); dC (75 MHz, CDCl3) 2.5 (Si(CH2CH3)3), 7.2 (Si(CH2CH3)3),
14.1 ((CH2)6CH3), 22.6, 27.9 (2ꢂCH2), 28.7 (C-1), 29.1, 29.2, 30.3 and
31.8 (4ꢂCH2),104.7,109.9 and 111.7 (C-40, 60 and 70),143.0,143.2 and
144.5 (C-3a0, 50 and 7a0) and 170.9 (C-20); m/z (CIþ) 361.2666
([MþH]þ, C21H37N2OSi requires 361.2675) and 361 ([MþH]þ, 100%).
4.4.5. 5-Amino-2-[1-(1-tert-butyldimethylsilyl)octyl]-
benzoxazole (5e)
Nitrobenzoxazole 4g (63 mg, 0.16 mmol) was dissolved in eth-
anol (2 mL). Copper acetylacetonate (8 mg, 20 mol %) and sodium
borohydride (61 mg, 1.62 mmol) were added and the solution was
stirred for 4 h. The solution was washed with water (2 mL) and the
solvent removed in vacuo. The crude compound was purified by
column chromatography (50/70% ether/petrol) to give the ami-
nobenzoxazole 5e (37 mg, 64%) as a colourless oil. Rf 0.11 (50%
ether/petrol). nmax (NaCl/film)/cmꢁ1 3352 w, 3340 m, 3224 w, 3031
w, 2956 s, 2929 s, 2858 s, 1625 m, 1552 m, 1488 m, 1452 m, 1361 w,
1268 m and 1184 m; dH (300 MHz, CDCl3) ꢁ0.08 (3H, s, SiCH3), 0.13
(3H, s, SiCH3), 0.78–0.90 (12H, m, SiC(CH3)3 and (CH2)6CH3), 1.15–
1.33 (10H, m, (CH2)5), 1.70 (1H, m, 2-H), 2.05 (1H, m, 2-H), 2.58 (1H,
dd, J 3.0 and 12.5, 1-H), 3.63 (2H, br s, NH2), 6.59 (1H, dd, J 2.0 and
8.5, 60-H), 6.93 (1H, d, J 2.0, 40-H) and 7.21 (1H, d, J 8.5, 70-H); dC
(75 MHz, CDCl3) ꢁ7.1 (SiCH3), ꢁ6.8 (SiCH3), 14.1 ((CH2)6CH3), 17.5
(SiC(CH3)3), 22.6 (CH2), 26.7 (SiC(CH3)3), 28.6, 29.0, 29.1, 29.2, 30.2
and 31.8 (5ꢂCH2 and C-1), 104.6, 110.0 and 111.8 (C-40, 60 and 7þ0),
142.9, 143.3 and 144.4 (C-3a0, 50 and 7a0) and 170.9 (C-20); m/z (CI )
361.2681 ([MþH]þ, C21H37N2OSi requires 361.2675) and 361
([MþH]þ, 100%).
4.4.2. 6-Amino-2-[1-(1-triethylsilyl)octyl]benzoxazole (5b)
Prepared from 4i according to the method for 5a on a 0.30 mmol
scale. Purification by column chromatography (40/60% ether/
petrol) gave aminobenzoxazole 5b (88 mg, 83%) as a yellow oil. Rf
0.42 (75% ether/petrol). nmax (NaCl/film)/cmꢁ1 3463 br w, 3334 br,
3219 br w, 3031 w, 2953 s, 2927 s, 2875 s, 2855 s, 1630 s, 1608 s,
1561 s, 1494 s and 1141 m; dH (300 MHz, CDCl3) 0.63 (6H, q, J 8.0,
Si(CH2CH3)3), 0.86 (3H, t, J 7.0, (CH2)6CH3), 0.93 (9H, t, J 8.0,
Si(CH2CH3)3), 1.14–1.42 (10H, m, (CH2)5), 1.42 (1H, m, 2-H), 2.09 (1H,
m, 2-H), 2.56 (1H, dd, J 3.0 and 12.0, 1-H), 3.73 (2H, br s, NH2), 6.64
(1H, dd, J 2.0 and 8.5, 50-H), 6.79 (1H, d, J 2.0, 70-H) and 7.39 (1H, d, J
8.5, 40-H); dC (75 MHz, CDCl3) 2.5 (Si(CH2CH3)3), 7.3 (Si(CH2CH3)3),
14.1 ((CH2)6CH3), 22.6 and 28.0 (2ꢂCH2), 28.3 (C-1), 29.1, 29.3, 30.2
and 31.8 (4ꢂCH2), 96.6, 112.0 and 118.9 (C-40, 50 and 70), 134.4 (C-60),
143.6 (C-3a0), 151.7 (C-7a0) and 168.2 (C-20); m/z (CIþ) 361.2666
([MþH]þ, C21H37N2OSi requires 361.2675) and 361 ([MþH]þ, 100%).
4.5. Electrophilic trapping of (
benzoxazoles
a-silylalkyl)amino-
4.5.1. 5-Methylsulfonylamino-2-[1-(1-tert-butyldimethylsilyl)-
octyl]benzoxazole (6)
Aminobenzoxazole 5e (84 mg, 0.23 mmol) was dissolved in
4.4.3. 5-Amino-2-[1-(2-phenyl-1-triethylsilyl)ethyl]-
benzoxazole (5c)
DCM (2 mL) with pyridine (21
m
l, 0.26 mmol). The mixture was
cooled to 0 ꢀC and mesyl chloride (20
ml, 0.26 mmol) was added
Prepared from 4j according to the method for 5a on a 0.24 mmol
scale. Purification by column chromatography (50/80% ether/
petrol) gave aminobenzoxazole 5c (58 mg, 70%) as a yellow oil. Rf
0.20 (75% ether/petrol). nmax (NaCl/film)/cmꢁ1 3349 br w, 3040 br,
3222 w, 3083 w, 3061 w and 3026 w, 2953 s, 2909 m, 2875 s, 1624
m, 1551 s, 1488 s, 1451 s, 1188 s and 1006 m; dH (300 MHz, CDCl3)
0.69 (6H, q, J 8.0, Si(CH2CH3)3), 0.98 (9H, t, J 8.0, Si(CH2CH3)3), 2.95
(1H, dd, J 3.0 and 12.0, 1-H), 3.05 (1H, dd, J 3.0 and 14.5, 2-H), 3.44
(1H, dd, J 12.0 and 14.5, 2-H), 3.64 (2H, br s, NH2), 6.58 (1H, dd, J 2.5
over 5 min. The solution was allowed to warm to rt and stirred for
6 h, after which it was quenched with water (5 mL) and extracted
with DCM (3ꢂ4 mL), dried over MgSO4, filtered and the solvent
removed in vacuo. The crude compound was purified by column
chromatography (50/80% ether/petrol) to give the sulfonamide 6
(70 mg, 68%) as a colourless oil. Rf 0.24 (75% ether/petrol). Found: C,
60.35; H, 8.95; N, 6.2. C22H38N2O3SSi requires C, 60.25; H, 8.75; N,
6.4%. nmax (NaCl/film)/cmꢁ1 3262 br, 2954 s, 2928 s, 2856 s, 1617 w,
1551 s, 1465 s, 1403 m, 1336 s, 1252 s, 1147 s, 974 m, 824 m, 761 m

5510
S.P. Marsden et al. / Tetrahedron 65 (2009) 5503–5512
and 669 w; dH (300 MHz, CDCl3) ꢁ0.09 (3H, s, SiCH3), 0.14 (3H, s,
SiCH3), 0.84 (3H, t, J 7.0, (CH2)6CH3), 0.85 (9H, s, SiC(CH3)3), 1.10–
1.34 (10H, m, (CH2)5), 1.73 (1H, m, 2-H), 2.07 (1H, m, 2-H), 2.63 (1H,
dd, J 2.5 and 12.5, 1-H), 3.05 (3H, s, SO2CH3), 7.21 (1H, dd, J 2.0 and
8.5, 60-H), 7.42 (1H, s, NH), 7.43 (1H, d, J 8.5, 70-H) and 7.58 (1H, d, J
2.0, 40-H); dC (75 MHz, CDCl3) ꢁ7.0 (SiCH3), ꢁ6.9 (SiCH3), 14.1
((CH2)6CH3), 17.5 (SiC(CH3)3), 22.6 (CH2), 26.6 (SiC(CH3)3), 28.8,
29.0, 29.1, 29.2, 30.3 and 31.8 (5ꢂCH2 and C-1), 39.2 (SO2CH3),110.5,
113.1 and 119.0 (C-40, 60 and 7þ0), 132.7, 142.7 and 148.6 (C-3a0, 50 and
7a0) and 172.3 (C-20); m/z (CI ) 439.2456 ([MþH]þ, C22H39N2O3SSi
requires 439.2451) and 439 ([MþH]þ, 100%).
solution was stirred for 3 days, then washed with water (5 mL),
extracted with DCM (3ꢂ5 mL), dried over MgSO4, filtered and the
solvent removed in vacuo. The crude compound was purified by
column chromatography (40/50% ether/petrol) to give the thio-
urea 9 (29 mg, 65%) as a colourless oil. Rf 0.41 (75% ether/petrol).
Found: C, 64.6; H, 9.25; N, 9.25. C24H41N3OSSi requires C, 64.4; H,
9.25; N, 9.4%. nmax (NaCl/film)/cmꢁ1 2954 m, 2927 s, 2856 m, 1546 s,
1473 s, 1336 m, 1251 s and 1232 m; dH (300 MHz, CDCl3) ꢁ0.07 (3H,
s, SiCH3), 0.16 (3H, s, SiCH3), 0.85 (3H, t, J 7.0, (CH2)6CH3), 0.88 (9H, s,
SiC(CH3)3), 1.17–1.35 (10H, m, (CH2)5), 1.20 (3H, t,
J 7.5,
CSNHCH2CH3), 1.73 (1H, m, 2-H), 2.09 (1H, m, 2-H), 2.66 (1H, dd, J
3.0 and 12.5, 1-H), 3.69 (2H, dq, J 5.5 and 7.5, CSNHCH2CH3), 5.98
(1H, br t, J 5.5, CSNHCH2CH3), 7.11 (1H, dd, J 2.0 and 8.5, 60-H), 7.47–
7.54 (2H, m, 40 and 70-H) and 7.81 (1H, s, BenzNHCS); dC (75 MHz,
CDCl3) ꢁ7.0 (SiCH3), ꢁ6.9 (SiCH3), 14.1 ((CH2)6CH3), 14.4
(CSNHCH2CH3), 17.5 (SiC(CH3)3), 22.6 (CH2), 26.7 (SiC(CH3)3), 28.9,
29.0, 29.1, 29.2, 30.3 and 31.8 (5ꢂCH2 and C-1), 40.5 (CSNHCH2CH3),
111.2, 116.6 and 121.8 (C-40, 60 and 70), 131.9, 143.2 and þ149.4 (C-3a0,
50 and 7a0), 172.8 (C-20) and 180.9 (C]S); m/z (CI ) 448.2813
([MþH]þ, C24H42N3OSSi requires 448.2818) and 448 ([MþH]þ,
39%).
4.5.2. 2-[1-(1-tert-Butyldimethylsilyl)octyl]-5-dimethylamino-
carbonylaminobenzoxazole (7)
Aminobenzoxazole 5e (82 mg, 0.23 mmol) was dissolved in
DCM (2 mL) with Et3N (63
ml, 0.46 mmol). Dimethyl carbamoyl
chloride (31 l, 0.34 mmol) was added and the solution stirred for
m
16 h, washed with water (5 mL), extracted with DCM (3ꢂ5 mL),
dried over MgSO4, filtered and the solvent removed in vacuo. The
crude compound was purified by column chromatography (100%
ether) to give the urea 7 (78 mg, 79%) as a colourless oil. Rf 0.20
(100% ether). Found: C, 66.65; H, 9.7; N, 9.55. C24H41N3O2Si requires
C, 66.75; H, 9.6; N, 9.75%. nmax (NaCl/film)/cmꢁ1 3322 s, 2952 s,
2933 s, 2858 s, 1646 s, 1619 m, 1544 s, 1479 s, 1427 m, 1367 m, 1255
m, 1199 m and 1112 m; dH (300 MHz, CDCl3) ꢁ0.12 (3H, s, SiCH3),
0.10 (3H, s, SiCH3), 0.81 (3H, t, J 6.5, (CH2)6CH3), 0.82 (9H, s,
SiC(CH3)3), 1.10–1.32 (10H, m, (CH2)5), 1.69 (1H, m, 2-H), 2.03 (1H,
m, 2-H), 2.58 (1H, dd, J 2.5 and 12.5, 1-H), 2.95 (6H, N(CH3)2), 6.78
(1H, s, NH or BenzH), 7.27 (2H, s, NH and BenzH or 2ꢂBenzH) and
7.52 (1H, s, NH or BenzH); dC (75 MHz, CDCl3) ꢁ7.1 (SiCH3), ꢁ6.8
(SiCH3), 14.1 ((CH2)6CH3), 17.4 (SiC(CH3)3), 22.6 (CH2), 26.6
(SiC(CH3)3), 28.6, 28.9, 29.1, 29.2, 30.2 and 31.8 (5ꢂCH2 and C-1),
36.5 (N(CH3)2), 109.5, 111.7 and 118.1 (C-40, 60 and 70), 135.6, 142.0
and 146.9 (C-3a0, 50 and 7a0), 156.4 (C]O) and 171.0 (C-20); m/z (CIþ)
432.3052 ([MþH]þ, C24H42N3O2Si requires 432.3046), 432
([MþH]þ, 100%), 387 (84) and 336 (87).
4.5.5. 2-[1-(1-tert-Butyldimethylsilyl)octyl]-5-(2-
methylpropyloxycarbonylamino)benzoxazole (10)
To a solution of aminobenzoxazole 5e (38 mg, 106
Et3N (29 l, 0.21 mmol) in DCM (1 mL) was added isobutyl chloro-
formate (27 l, 0.21 mmol). The solution was stirred for 40 min
mmol) and
m
m
after which it was washed with water (3 mL), extracted with DCM
(3ꢂ5 mL), dried over MgSO4, filtered and the solvent removed in
vacuo. The crude compound was purified by column chromatog-
raphy (20% ether/petrol) to give the carbamate 10 (36 mg, 74%) as
a colourless oil. Rf 0.30 (30% ether/petrol). nmax (NaCl/film)/cmꢁ1
3316 br, 3075 w, 2956 s, 2929 s, 2858 s, 1731 s, 1708 s, 1623 m, 1554
s, 1471 s, 1429 m, 1346 m, 1224 s, 1056 s and 825 s; dH (300 MHz,
CDCl3) ꢁ0.08 (3H, s, SiCH3), 0.14 (3H, s, SiCH3), 0.84 (3H, t, J 7.0,
(CH2)6CH3), 0.85 (9H, s, SiC(CH3)3), 0.97 (6H, d, J 7.0, CH(CH3)2),
1.15–1.36 (10H, m, (CH2)5), 1.72 (1H, m, 2-H), 1.98 (1H, m, 200-H),
2.07 (1H, m, 2-H), 2.62 (1H, dd, J 2.5 and 12.5, 1-H), 3.97 (2H, d, J 6.5,
100-H), 6.85 (1H, s, NH), 7.28–7.37 (2H, m, 60 and 70-H) and 7.64 (1H,
s, 40-H); dC (75 MHz, CDCl3) ꢁ7.1 (SiCH3), ꢁ6.8 (SiCH3), 14.1
((CH2)6CH3), 17.5 (SiC(CH3)3), 19.1 (CH(CH3)2), 22.6 (CH2), 26.6
(SiC(CH3)3), 28.0 and 28.7 (C-1 and C-200), 29.0, 29.1, 29.2, 30.2, 31.8
4.5.3. 2-[1-(1-tert-Butyldimethylsilyl)octyl]-5-ethylaminocarbonyl-
aminobenzoxazole (8)
To a solution of aminobenzoxazole 5e (27 mg, 75
mmol) in DCM
(1 mL) was added ethyl isocyanate (12 l, 150 mol). The solution
m
m
was stirred for 10 h, after which it was washed with water (3 mL),
extracted with DCM (3ꢂ5 mL), dried over MgSO4, filtered and the
solvent removed in vacuo. The crude compound was purified by
column chromatography (80% ether/petrol) to give the urea 8
(23 mg, 71%) as a colourless oil. Rf 0.12 (75% ether/petrol). nmax
(NaCl/film)/cmꢁ1 3332 br, 2954 s, 2929 s, 2858 s, 1648 s, 1619 m,
1554 s, 1481 s, 1429 w, 1261 m and 1189 m; dH (300 MHz, CDCl3)
ꢁ0.09 (3H, s, SiCH3), 0.14 (3H, s, SiCH3), 0.84 (3H, t, J 7.0, (CH2)6CH3),
0.85 (9H, s, SiC(CH3)3), 1.07 (3H, t, J 7.0, CONHCH2CH3), 1.15–1.35
(10H, m, (CH2)5), 1.72 (1H, m, 2-H), 2.06 (1H, m, 2-H), 2.61 (1H, dd, J
2.5 and 12.5, 1-H), 3.25 (2H, dq, J 6.0 and 7.0, CONHCH2CH3), 5.29
(1H, br t, J 6.0, CONHCH2CH3), 7.23 (1H, dd, J 2.0 and 8.5, 60-H), 7.26
(1H, br s, BenzNHCO), 7.34 (1H, d, J 8.5, 70-H) and 7.53 (1H, d, J 2.0,
40-H); dC (75 MHz, CDCl3) ꢁ7.0 (SiCH3), ꢁ6.8 (SiCH3), 14.1
((CH2)6CH3), 15.4 (CONHCH2CH3), 17.5 (SiC(CH3)3), 22.6 (CH2), 26.6
(SiC(CH3)3), 28.7 (C-1), 29.0, 29.1, 29.2, 30.3 and 31.8 (5ꢂCH2), 35.1
(CONHCH2CH3), 110.0, 112.2 and 118.5 (C-40, 60 and 70), 135.0, 142.4
and 147.3 (C-3a0, 50 and 7a0), 156.7 (C]O) and 171.6 (C-20); m/z (CIþ)
432.3050 ([MþH]þ, C24H42N3O2Si requires 432.3046) and 432
([MþH]þ, 100%).
(5ꢂCH2), 71.4 (C-100), 109.8
*
and 115.8 (3C, C-40, 60 and 70), 134.4,
142.3 and 147.0 (C-3a0, 50 and 7a0),154.2 (C]O) and 171.5 (C-20); m/z
(CIþ) 461.3201 ([MþH]þ, C26H45N2O3Si requires 461.3199) and 461
([MþH]þ, 100%).
4.5.6. 2-[1-(1-tert-Butyldimethylsilyl)octyl]-5-(1,1-
dimethylethylcarbonylamino)benzoxazole (11)
Trimethylacetyl chloride (33
ml, 0.27 mmol) was added to a so-
lution of aminobenzoxazole 5e (48 mg, 133
m
mol) and Et3N (37 l,
m
0.27 mmol) in DCM (1 mL). The solution was stirred for 1 h and
washed with NaHCO3 (satd, aq, 4 mL), extracted with DCM
(3ꢂ5 mL), dried over MgSO4, filtered and the solvent removed in
vacuo. The crude compound was purified by column chromatog-
raphy (30/40% ether/petrol) to give the amide 11 (35 mg, 60%) as
a colourless oil. Rf 0.28 (40% ether/petrol). Found: C, 70.3; H, 9.85; N,
6.15. C26H44N2O2Si requires C, 70.2; H, 9.95; N, 6.3%. nmax (NaCl/
film)/cmꢁ1 3334 br, 3070 w, 2952 s, 2929 s, 2858 s, 1656 s, 1619 m,
1544 s, 1477 s, 1363 m, 1253 s, 1191 s, 919 s and 823 s; dH (300 MHz,
CDCl3) ꢁ0.08 (3H, s, SiCH3), 0.13 (3H, s, SiCH3), 0.83 (3H, t, J 6.5,
(CH2)6CH3), 0.84 (9H, s, SiC(CH3)3), 1.17–1.30 (10H, m, (CH2)5), 1.33
(9H, s, COC(CH3)3), 1.72 (1H, m 2-H), 2.06 (1H, m, 2-H), 2.62 (1H, dd,
J 2.0 and 12.5, 1-H), 7.36 (1H, d, J 8.5, 70-H), 7.43 (1H, dd, J 2.0 and
8.5, 60-H), 7.46 (1H, s, NH) and 7.72 (1H, d, J 2.0, 40-H); dC (75 MHz,
CDCl3) ꢁ7.1 (SiCH3), ꢁ6.8 (SiCH3), 14.1 ((CH2)6CH3), 17.5 (SiC(CH3)3),
4.5.4. 2-[1-(1-tert-Butyldimethylsilyl)octyl]-5-ethylaminothio-
carbonylaminobenzoxazole (9)
Ethyl isothiocyanate (10
ml, 0.11 mmol) was added to a solution
of aminobenzoxazole 5e (37 mg, 100
m
l) in DCM (1 mL). The

S.P. Marsden et al. / Tetrahedron 65 (2009) 5503–5512
5511
23.0 (CH2), 26.6 (SiC(CH3)3), 27.7 (COC(CH3)3), 28.7 (C-1), 28.9, 29.1,
29.2, 30.2, 31.8 (5ꢂCH2), 39.5 (COC(CH3)3), 109.7, 111.4 and 117.2 (C-
40, 60 and 70), 134.2, 142.2 and 147.4 (C-3a0, 50 and 7a0), 171.4 (C-2)
and 176.7 (C]O); m/z (CIþ) 445.3250 ([MþH]þ, C26H45N2O2Si re-
quires 445.3250) and 445 ([MþH]þ, 100%).
this solution diethyl aminomalonate hydrochloride (114 mg, 0.54 mmol)
was added in one portion and it was stirred for 2 h. The solution
was diluted with ether (10 mL), washed with NH4Cl (satd, aq,
10 mL) and brine (satd, aq, 10 mL), dried over MgSO4, filtered and
the solvent was removed in vacuo. The crude material was purified
by column chromatography (15/50% ether/petrol) to give the
amide 15a (179 mg, 85%) as a colourless oil. Rf 0.34 (30% ether/
petrol). nmax (NaCl/film)/cmꢁ1 3316 w, 2954 s, 2929 s, 2875 m, 2856
m, 1758 s, 1743 s, 1666 s, 1504 m, 1465 m, 1371 m, 1201 s, 1180 s and
1022 m; dH (300 MHz, CDCl3) 0.57 (6H, q, J 8.0, Si(CH2CH3)3), 0.79
(3H, t, J 5.5, (CH2)6CH3), 0.89 (9H, t, J 8.0, Si(CH2CH3)3) 1.10–1.25
(10H, m, (CH2)5), 1.22 (6H, t, J 7.0, 2ꢂCO2CH2CH3), 1.30–1.40 (2H, m,
3-H), 1.83 (1H, m, 2-H), 4.10–4.27 (4H, m, 2ꢂCO2CH2CH3), 5.09 (1H,
d, J 6.5, 20-H) and 6.24 (1H, d, J 6.5, NH); dC (75 MHz, CDCl3) 2.3
(Si(CH2CH3)3), 7.3 (Si(CH2CH3)3), 13.9 and 14.0 (3C, (CH2)6CH3 and
2ꢂCO2CH2CH3), 22.6, 27.2, 29.1, 29.4, 30.4 and 31.8 ((CH2)6), 36.4 (C-
2), 56.4 (C-10), 62.3 (2ꢂCO2CH2CH3), 166.6 and 166.7 (C]O, esters)
and 174.5 (C]O, amide); m/z (CIþ) 430.2976 ([MþH]þ, C22H44NO5Si
requires 430.2989), 430 ([MþH]þ, 95%), 255 (33), 135 (37) and 102
(100).
4.6. Desilylation of a-silylalkylbenzoxazoles
4.6.1. 2-(1-Octyl)benzoxazole (12)
Benzoxazole 4a (31 mg, 89.9
mmol) was dissolved in DCM
(1 mL), TFA (35 ml, 0.45 mmol) was added and the solution stirred
for 18 h. The solvent was removed in vacuo and the crude com-
pound purified by column chromatography (5/10% ether/petrol)
to give the benzoxazole 12 (14 mg, 67%) as a colourless oil. Rf 0.45
(30% ether/petrol). nmax (NaCl/film)/cmꢁ1 3058 w, 2955 s, 2934 s,
2855 s, 1717 w, 1615 m, 1573 m, 1455 m, 1242 m, 1147 w and 758 m;
dH (300 MHz, CDCl3) 0.89 (3H, t, J 7.0, (CH2)6CH3), 1.21–1.50 (10H, m,
(CH2)5), 1.90 (2H, pentet, J 7.5, 2-H), 2.94 (2H, t, J 7.5, 1-H), 7.26–7.35
(2H, m, BenzH), 7.50 (1H, m, BenzH) and 7.70 (1H, m, BenzH); dC
(75 MHz, CDCl3) 14.1 ((CH2)6CH3), 22.7, 26.8, 28.7, 29.1, 29.2 and
*
31.8 (7C, (CH2)7), 110.3 (C-70), 119.5 (C-40), 124.1 and 124.4 (C-50 and
60), 141.4 (C-3a0), 150.8 (C-7a0) and 167.4 (C-20); m/z (CIþ) 232.1706
([MþH]þ, C15H22NO requires 232.1701), 232 ([MþH]þ, 100%), 189
(21), 175 (42) and 133 (16).
4.7.2. N-(2-Diethylmalonyl)-2-[3-(1-tert-butoxycarbonyl)indolyl]-
2-(tert-butyldimethylsilyl)ethanamide (15b)
Silyl diazoketone 2f (145 mg, 0.36 mmol) was reacted with
Rh2(oct)4 (3 mg, 1 mol %) in benzene (4 mL) for 10 min at 40 ꢀC. The
solvent was removed in vacuo and the silylketene redissolved in
4.6.2. 2-(3-Indolylmethyl)benzoxazole (13)
Benzoxazole 4f (62 mg, 0.13 mmol) was dissolved in DCM
DCM (4 mL) with Et3N (56
m
l, 0.40 mmol) and cooled to ꢁ40 ꢀC. To
(2 mL), TFA (66
ml, 0.86 mmol) was added and the solution heated
this solution diethyl aminomalonate hydrochloride (85 mg,
0.40 mmol) was added and it was warmed to rt over 15 min. The
solution was washed with water (10 mL), extracted with DCM
(3ꢂ10 mL), dried over MgSO4, filtered and the solvent removed in
vacuo. The crude material was purified by column chromatography
(30/50% ether/petrol) to give the amide 15b (122 mg, 61%) as
a white foam. Rf 0.38 (50% ether/petrol). nmax (NaCl/film)/cmꢁ1 3293
br, 3069 w, 3006 m, 2944 m, 2911 m, 2858 s, 1758 s, 1733 s, 1677 s,
1465 m, 1368 s, 1255 m, 1158 s, 1074 m and 1020 m; dH (300 MHz,
CDCl3) 0.07 (3H, s, SiCH3), 0.24 (3H, s, SiCH3), 0.88 (9H, s, SiC(CH3)3),
1.24 (3H, t, J 7.0, CO2CH2CH3), 1.26 (3H, t, J 7.0, CO2CH2CH3), 1.68,
(9H, s, Boc), 3.62 (1H, s, 2-H), 4.14–4.33 (4H, m, 2ꢂCO2CH2CH3), 5.13
(1H, d, J 6.5, 20-H), 6.66 (1H, d, J 6.5, NH), 7.23–7.36 (2H, m, IndH),
7.53 (1H, d, J 7.0, IndH), 7.69 (1H, s, IndH) and 8.15 (1H, d, J 7.0,
IndH); dC (75 MHz, CDCl3) ꢁ6.2 (SiCH3), ꢁ6.0 (SiCH3), 14.0
(2ꢂCO2CH2CH3), 17.9 (SiC(CH3)3), 27.0 (SiC(CH3)3), 28.2 (Boc), 33.5
(C-2), 56.7 (C-20), 62.6 (2ꢂCO2CH2CH3), 83.6 (Boc), 115.3 (C-700),
116.2 (C-300), 118.9, 122.4, 123.4 and 124.5 (C-200, 400, 500 and 600), 130.3
(C-3a00), 135.0 (C-7a00), 149.7 (Boc), 166.4 and 166.5 (C]O, esters)
and 172.0 (C]O, amide); m/z (CIþ) 547.2845 ([MþH]þ,
C28H43N2O7Si requires 547.2840), 547 ([MþH]þ,100%) and 490 (36).
at reflux for 10 h. The solvent was removed in vacuo and the crude
material purified by column chromatography (20/80% ether/
petrol) to give the desilylated and Boc deprotected benzoxazole 13
(19 mg, 57%). Rf 0.08 (40% ether/petrol); mp 132–133 ꢀC. nmax (NaCl/
film)/cmꢁ1 3425 br; dH (300 MHz, CDCl3) 4.46 (2H, s, 1-H), 7.14–7.38
(6H, m, 2ꢂBenzH and 4ꢂIndH), 7.49 (1H, m, BenzH), 7.65–7.76 (2H,
m, BenzH and IndH) and 8.41 (1H, br s, NH); dC (75 MHz, CDCl3) 25.5
(C-1), 109.1 (C-300), 110.5 (C-70), 111.4 (C-700), 118.9, 119.7, 119.8, 122.4,
123.2, 124.2 and 124.6 (C-40, 50, 60, 200, 400, 500 and 600), 127.0 (C-3a0þ0),
136.3 (C-7a00), 141.4 (C-3a0), 151.0 (C-7a0) and 165.9 (C-20); m/z (CI )
249.1022 ([MþH]þ, C16H13N2O requires 249.1028) and 249
([MþH]þ, 100%).
4.6.3. 6-Amino-2-(1-octyl)benzoxazole (14)
Aminobenzoxazole 5b (80 mg, 0.22 mmol) was dissolved in
DCM (2.5 mL) with TFA (86 ml, 1.11 mmol) and stirred at rt for 2 h.
The solvent was removed in vacuo and the crude compound puri-
fied by column chromatography (80/100% ether/petrol) to give
the benzoxazole 5b (43 mg, 79%) as a pale yellow oil. Rf 0.44 (100%
ether). nmax (NaCl/film)/cmꢁ1 3362 br, 3322 br, 3219 br, 2974 s, 2956
s, 2927 s, 2854 s,1632 s,1612 s,1570 m,1492 s,1450 m,1381 m,1139
s and 1121 s; dH (300 MHz, CDCl3) 0.89 (3H, t, J 7.0, (CH2)6CH3), 1.18–
1.48 (10H, m, (CH2)5), 1.85 (2H, pentet, J 7.5, 2-H), 2.86 (2H, t, J 7.5, 1-
H), 3.78 (2H, br s, NH2), 6.65 (1H, dd, J 2.0 and 8.5, 50-H), 6.79 (1H, d,
J 2.0, 70-H) and 7.42 (1H, d, J 8.5, 40-H); dC (75 MHz, CDCl3) 14.1
4.8. Formation of a-silylalkyloxazoles
4.8.1. 5-Ethoxy-4-ethoxycarbonyl-2-[1-(1-triethylsilyl)-
octyl]oxazole (16a)
((CH2)7CH3), 22.7, 26.8, 28.6, 29.1, 29.2
*
and 31.8 (7C, (CH2)7), 96.5,
A solution of triphenylphosphine–iodine was preformed by
adding iodine (122 mg, 0.48 mmol) to a solution of PPh3 (125 mg,
0.48 mmol) in DCM (2 mL). The resulting solution was added to
a solution of amide 15a (106 mg, 0.25 mmol) and Et3N (0.14 mL,
0.98 mmol) in DCM (1 mL) and stirred for 18 h at rt. The solution
was washed with water (5 mL), extracted with DCM (2ꢂ5 mL),
dried over MgSO4, filtered and the solvent removed in vacuo. The
crude compound was purified by column chromatography (15/
30% ether/petrol) to give the oxazole 16a (91 mg, 90%) as a colour-
less oil. Rf 0.33 (30% ether/petrol). nmax (NaCl/film)/cmꢁ1 2955 s,
2928 s, 2876 s, 2863 s, 1717 s, 1631 s, 1576 w, 1465 w, 1382 m, 1347
w, 1221 m, 1201 m, 1102 s and 1015 w; dH (300 MHz, CDCl3) 0.55
(6H, q, J 8.0, Si(CH2CH3)3), 0.82 (3H, t, J 6.0, (CH2)6CH3), 0.87 (9H, t, J
112.5 and 119.6 (C-40, 50 and 70þ), 133.9 (C-60), 144.3þ(C-3a0), 152.0 (C-
7a0) and 165.3 (C-20); m/z (CI ) 247.1809 ([MþH] , C15H23N2O re-
quires 247.1810) and 247 ([MþH]þ, 100%).
4.7. Synthesis of silylketenes and nucleophilic trapping
with aminomalonates
4.7.1. N-(2-Diethylmalonyl)-2-triethylsilylnonamide (15a)
Silyl diazoketone 2a (138 mg, 0.49 mmol) was dissolved in
benzene (5 mL) with Rh2(oct)4 (4 mg, 1 mol %) and stirred for
30 min. The solvent was removed in vacuo and the silylketene
redissolved in DCM (5 mL) with Et3N (75 ml, 0.54 mmol). To

5512
S.P. Marsden et al. / Tetrahedron 65 (2009) 5503–5512
8.0, Si(CH2CH3)3), 1.18 (10H, m, (CH2)5), 1.31 (3H, t, J 7.0, CO2CHCH3
or OCH2CH3), 1.42 (3H, t, J 7.0, CO2CHCH3 or OCH2CH3), 1.52 (1H, m,
2-H), 1.80 (1H, m, 2-H), 2.36 (1H, dd, J 3.0 and 12.5,1-H), 4.31 (2H, q,
J 7.0, CO2CH2CH3 or OCH2CH3) and 4.37 (2H, q, J 7.0, CO2CH2CH3 or
OCH2CH3); dC (75 MHz, CDCl3) 2.5 (Si(CH2CH3)3), 7.2 (Si(CH2CH3)3),
14.0, 14.5 and 14.9 ((CH2)6CH3, CO2CH2CH3 and OCH2CH3), 22.6,
t, J 7.0, (CH2)6CH3), 1.14–1.40 (10H, m, (CH2)5), 1.34 (3H, t, J 7.0,
CO2CH2CH3 or OCH2CH3), 1.45 (3H, t, J 7.0, CO2CH2CH3 or OCH2CH3),
1.65–1.74 (2H, m, 2-H), 2.64 (2H, t, J 8.0, 1-H), 4.32 (2H, q, J 7.0,
CO2CH2CH3 or OCH2CH3) and 4.45 (2H, q, J 7.0, CO2CH2CH3 or
OCH2CH3); dC (75 MHz, CDCl3) 14.1, 14.5 and 15.0 ((CH2)5CH3,
CO2CH2CH3 and OCH2CH3), 22.6, 26.8, 28.2, 29.0, 29.1 and 31.8 (7C,
*
27.7
*
, 29.0, 29.1, 30.0 and 31.8 (7C, (CH2)6 and C-1), 60.3 and 67.4
(CH2)7), 60.5 and 69.7 (CO2CH2CH3 and OCH2CH3), 106.8 (C-40) and
154.4, 161.2 and 161.7 (C]O, ester, C-20 and 50); m/z (CIþ) 298.2010
([MþH]þ, C16H28NO4 requires 298.2018) and 298 ([MþH]þ), 100%.
(CO2CH2CH3 and OCH2CH3), 106.9 (C-40) and 157.0, 160.8 and 161.9
(C]O, C-20 and 50); m/z (CIþ) 412.2882 ([MþH]þ, C22H42NO4Si re-
quires 412.2883), 412 ([MþH]þ, 100%), 102 (64) and 52 (56).
Acknowledgements
4.8.2. 5-Ethoxy-4-ethoxycarbonyl-2-{[3-(1-tert-butoxycarbonyl)-
indolyl]-(tert-butyldimethylsilyl)methyl}oxazole (16b)
We thank the EPSRC and GlaxoSmithKline for an Industrial CASE
award to J.T.S.
Prepared according to the method for 3a on a 0.22 mmol scale.
Purification by column chromatography (20/40% ether/petrol)
gave oxazole 16b (67 mg, 57%) as a pale yellow oil. Rf 0.40 (50%
ether/petrol). nmax (NaCl/film)/cmꢁ1 2979 m, 2961 m, 2932 m, 2859
m, 1730 s, 1631 s, 1582 w, 1452 m, 1369 s, 1308 m, 1257 m, 1156 s,
1077 s and 1014 w; dH (300 MHz, CDCl3) ꢁ0.03 (3H, s, SiCH3), 0.17
(3H, s, SiCH3), 0.86 (9H, s, SiC(CH3)3), 1.34 (3H, t, J 7.0, CO2CH2CH3 or
OCH2CH3), 1.52 (3H, t, J 7.0, CO2CH2CH3 or OCH2CH3), 1.68 (9H, s,
Boc), 4.14 (1H, s, 1-H), 4.33 (2H, dq, J 3.0 and 7.0, CO2CH2CH3 or
OCH2CH3), 4.50 (2H, dq, J 2.5 and 7.0, CO2CH2CH3 or OCH2CH3),
7.22–7.35 (2H, m, IndH), 7.54 (1H, d, J 7.0, IndH), 7.61 (1H, s, IndH)
and 8.07 (1H, br s, IndH); dC (75 MHz, CDCl3) ꢁ6.9 (SiCH3), ꢁ5.9
(SiCH3), 14.5 and 15.1 (CO2CH2CH3 and OCH2CH3), 17.6 (SiC(CH3)3),
24.8 (C-1), 26.6 (SiC(CH3)3), 28.3 (Boc), 60.5 and 69.8 (CO2CH2CH3
and OCH2CH3), 83.8 (Boc), 107.0 (C-40), 115.2 (C-700), 116.7 (C-300),
119.1, 122.5, 122.9 and 124.6 (C-200, 400, 500 and 600), 130.1 (C-3a00),
134.7 (C-7a00), 149.8 þ(Boc) and 154.4, 161.2þand 161.8 (C]O, ester, C-
20 and 50); m/z (CI ) 529.2737 ([MþH] , C28H41N2O6Si requires
529.2734) and 529 ([MþH]þ, 100%).
References and notes
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2. Pons, J.-M.; Kocienski, P. J. J. Chem. Soc., Perkin Trans. 1 1998, 2105.
3. (a) Pons, J.-M.; Kocienski, P. J. Product Subclass 31: Silylketenes. Science of
Synthesis; Georg Thieme: Stuttgart, 2002; Vol. 4, pp 657–668; (b) George, D.
M.; Danheiser, R. L. Product Class 2: Silylketenes. Science of Synthesis: Georg
Thieme: Stuttgart, 2006; Vol. 23, pp 53–99.
4. Allen, A. A.; Egle, I.; Janoschek, R.; Liu, H. W.; Ma, J.; Marra, R. M.; Tidwell, T. T.
Chem. Lett. 1996, 45.
5. Marsden, S. P.; Pang, W.-K. Chem. Commun. 1999, 1199.
6. Marsden, S. P.; Ducept, P. C. Beilstein J. Org. Chem. 2005, 1, 5.
7. Taylor, R. T.; Cassel, R. A. Synthesis 1982, 672.
8. For an example of the use of branched a-aryl-a-silylalkyl compounds in Pe-
terson olefinations, see: Chenard, B. L.; Slapak, C.; Anderson, D. K.; Swento, J. S.
J. Chem. Soc., Chem. Commun. 1981, 179.
9. Showell, G. A.; Mills, J. S. Drug Discov. Today 2003, 8, 551.
10. See, for example, UK-1 (Ueki, M.; Ueno, K.; Miyadoh, S.; Abe, K.; Shibata, K.;
Taniguchi, M.; Oi, S. J. Antibiot. 1993, 46, 1089), the boxazomycins (Kusumi, T.;
Ooi, T.; Wa¨lchli, M. R.; Kakisawa, H. J. Am. Chem. Soc. 1998, 110, 2954) and
calcimycin (Chaney, M. O.; Demarco, P. V.; Jones, N. D.; Occolowitz, J. L. J. Am.
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J.; Brodkin, J. D.; Jiang, X.; Gardner, M. F.; Yang, X.; Munoz, B. Bioorg. Med. Chem.
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1979, 2409.
17. Jin, Z. Nat. Prod. Rep. 2006, 23, 464 and references to earlier reports cited therein.
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825; (b) Bagley, M. C.; Buck, R. T.; Hind, S. L.; Moody, C. J. J. Chem. Soc., Perkin
Trans. 1 1998, 591.
4.9. 5-Ethoxy-4-ethoxycarbonyl-2-(1-octyl)oxazole (17)
Oxazole 16a (71 mg, 0.17 mmol) was dissolved in DCM (2 mL).
TFA (39 ml, 0.51 mmol) was added and the reaction mixture stirred
for 24 h. The solution was diluted with ether (10 mL) and washed
with NaHCO3 (satd, aq, 5 mL) and brine (satd, aq, 5 mL), dried over
MgSO4, filtered and the solvent removed in vacuo. The crude
compound was purified by column chromatography (30/50%
ether/petrol) to give the oxazole 17 (38 mg, 74%) as a colourless oil.
Rf 0.10 (30% ether/petrol). nmax (NaCl/film)/cmꢁ1 2999 m, 2957 m,
2928 m, 2855 m, 1718 s, 1632 s, 1596 m, 1466 m, 1425 m, 1390 m,
1296 m, 1201 m, 1081 s and 1017 m; dH (300 MHz, CDCl3) 0.85 (3H,