Synthesis of 2-oxazolines mediated by N,N′-diisopropylcarbodiimide

Article abstract of DOI:10.1016/j.tetlet.2004.10.143

Heating N-(β-hydroxyethyl)amides with DIC and Cu(OTf)₂ (5 mol %) leads to the formation of 2-oxazolines in good to excellent yields. N-(β-Hydroxy)amides can be cyclised by reaction with diisopropylcarbodiimide (DIC) to give the corresponding 2-

Full text of DOI:10.1016/j.tetlet.2004.10.143

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9611–9615
Synthesis of 2-oxazolines mediated by
N,N0-diisopropylcarbodiimide
Stefano Crosignani, Abigail C. Youngà and Bruno Linclau*
Combinatorial Centre of Excellence, School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK
Received 29 August 2004; revised 15 October 2004; accepted 26 October 2004
Available online 11 November 2004
Abstract—N-(b-Hydroxy)amides can be cyclised by reaction with diisopropylcarbodiimide (DIC) to give the corresponding 2-oxa-
zolines in high yields. The reaction requires only very mild Lewis-acid catalysis (5mol% Cu(OTf)2) and can be accomplished with
simple heating, or in very short reaction times under microwave irradiation.
Ó 2004 Elsevier Ltd. All rights reserved.
Over the years, 2-oxazolines have emerged as a very
interesting class of heterocycles with an astonishingly
wide range of applications in synthetic organic chemis-
try.1 Carboxylic acids as well as b-amino alcohols can
be protected as a 2-oxazoline,1,2 and 2-oxazolines have
been used as building blocks in organic synthesis.3
Homochiral 2-oxazolines have been used as auxiliaries
for a number of applications.4 Many examples of useful
homochiral ligands based on 2-oxazolines for a wide
range of transformations have been reported.4c,5 In
addition, the 2-oxazoline ring occurs in natural products
and in drug-like compounds,6 and has been employed as
nyl chloride/Et3N.6a,9e Other methods include the reac-
tion between an aldehyde and a b-hydroxy azide.10
As part of a research programme investigating the syn-
thetic utility of isoureas,11 we were intrigued by the pos-
sibility of using isoureas as intermediates in 2-oxazoline
synthesis. O-Alkylisoureas are easily formed by the
addition of an alcohol to a dialkylcarbodiimide under
copper catalysis.12 Isoureas, as such, are poor leaving
groups, and need to be activated by protonation. A typ-
ical example is the protonation of an O-alkylisourea by
a carboxylic acid, leading to the formation of a carboxyl-
ate anion that subsequently displaces the protonated
isourea moiety to give a carboxylic ester (Scheme 1).12
We have reported an alternative activation of isoureas
using acetyl halides (Cl, Br), ultimately leading to a
one-pot conversion of alcohols into alkyl halides.11b
Isoureas derived from chiral, secondary alcohols are dis-
placed with inversion of configuration.11b,13
a
hydrolysable precursor for carboxylic acids in
prodrugs.7
Many synthetic procedures exist for the formation of 2-
oxazolines and new ones continue to be devel-
oped.1,4d,5a,c Starting from amino alcohols, reaction
with carboxylic acids,7,8a,b ortho esters,8c nitriles,8d,e,f
imino ethers8g and acyl benzotriazoles8h have been re-
ported. The other major synthetic methods start from
b-hydroxy amides, with cyclisation achieved with a
number of reagents including BurgessÕ reagent,9a,b
DAST,9c PPh3/DIAD9d and immobilised p-toluenesulfo-
There are very few examples of isoureas being used in
cyclisation reactions. Alexandre reported that heating
isoureas derived from c-hydroxyketones leads to
O
+
R
N
R
R"
R'
O
R
O
O
R"COOH
OOCR"
Keywords: 2-Oxazoline; Isourea; Lewis acid; Microwave irradiation;
Carbodiimide.
R'
R'
R'
R'
O
N
N
N
H
H
H
*
Corresponding author. Tel.: +44 23 8059 3816; fax: +44 23 8059
6805; e-mail: bruno.linclau@soton.ac.uk
R'
N
N
H
H
Present address: Serono Pharmaceutical Research Institute, 14
Chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland.
à Southampton undergraduate project student.
Scheme 1. Typical reaction of isoureas by protic activation, followed
by nucleophilic substitution.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.143

9612
S. Crosignani et al. / Tetrahedron Letters 45 (2004) 9611–9615
Table 1. Formation of 2-oxazolines in THF (reflux) with DIC (1equiv)
and Cu(OTf)2 (5mol%)
iPr
N
O
H
N
Ph
iPr
OH
Yielda
(%)
N
+
∆
O
DIC
Entry
Starting material
Time
(h)
Product
3a
O
O
Cu(OTf)2
Ph
N
H
O
1
2
3
1a
1a
1a
24
48
72
3a
3a
63
92
Ph
N
iPr
iPr
H
1a
N
N
68b
H
H
2a
3a
4
OH
O
O
Ph
N
4
48
97
Scheme 2. Planned cyclisation of amide isoureas 2 to 2-oxazolines 3.
Ph
N
H
1c
a Isolated yield after chromatography.
b 6mol% Cu(OTf)2.
3c
a,b-cyclopropyl ketones and 2,3-dihydrofurans.14 Gray-
son recently reported the synthesis of 2,5-dihydrofurans
from (Z)-1,4-dihydroxyalk-2-enes by monoaddition of
DCC, followed by heating the hydroxyisourea interme-
diate with 13mol% of trifluoroacetic acid.15
Table 2. Formation of 2-oxazolines in 1,4-dioxane (reflux) with DIC
(1equiv) and Cu(OTf)2 (5mol%)17
It is known that amides do not react with isoureas. Nev-
ertheless, as amides have a similar acidity to ketones, we
envisioned that intra- or intermolecular activation of
isoureas 2 would be possible, and that the cyclisation
to form 2-oxazolines 3 as depicted in Scheme 2 would
be feasible without added acid. In this communication,
we report our results regarding this novel isourea trans-
formation.16 From the outset, it was envisioned that the
process would not be investigated starting from isolated
isoureas 2, but that 2 would be made in situ from the
corresponding N-(b-hydroxyethyl)amides 1, which are
easily synthesised from 2-aminoalcohols.
Entry
Starting material
Time
(h)
Product
Yielda
(%)
1
2
3
1a
1a
20
18
5
3a
3a
3a
O
81b
96c
97
1a
OH
O
4
5
97
Ph
Ph
1b
N
H
N
3b
3c
5
6
1c
5
6
93
OH
O
O
98b
Ph
N
3d
Ph
1d
N
H
Ph
Ph
Ph
Ph
OH
O
O
To this end, N-(2-hydroxy-1,1-dimethylethyl)benzamide
1b was reacted with 1equiv of diisopropylcarbodiimide
(DIC) under Cu(II) catalysis to give the corresponding
O-alkylisourea 2b. The reaction could easily be moni-
tored by IR for disappearance of the carbodiimide band
at 2110cmꢀ1 and the appearance of the isourea band at
1655cmꢀ1. When judged complete, and without remov-
ing the copper salt, the isourea intermediate was heated
at 60°C for 2days. The appearance of a white crystalline
diisopropylurea precipitate 4 signalled that the reaction
had occurred. Purification by filtration followed by col-
umn chromatography gave 4,4-dimethyl-2-phenyl-2-
oxazoline 3b in 74% yield.
7
6
78d
Ph
N
3e
Ph
1e
N
Ph
Ph
H
a Isolated yield after chromatography.
b 6mol% Cu(OTf)2.
c 8mol% Cu(OTf)2.
d Trans:cis ratio: >95:<5.
reducing the reaction time to just 5h (entry 3). A num-
ber of other N-(b-hydroxyethyl)amide substrates were
investigated under these conditions, with excellent re-
sults when a-substitution was present (entries 4–6).
The yield was somewhat decreased when b-substitution
was present (entry 7).
With this preliminary result in hand, further optimisa-
tion was carried out (Table 1). N-(b-Hydroxy-
ethyl)amide 1a in THF was mixed with DIC (1equiv)
and Cu(OTf)2, and refluxed for the times indicated.
The reaction was incomplete after 24h, with 63% iso-
lated yield after chromatography (entry 1). However,
complete reaction could be achieved after refluxing for
48h (92%, entry 2), but when the reaction time was
too long, product degradation was observed (entry 3).
Subjecting N-(b-hydroxyethyl)amide 1c to the optimal
conditions (48h) yielded the corresponding oxazoline
3c in 97% yield (entry 4). Despite the high yields, the
reaction time required was a drawback to the utility of
the process. Hence, the reaction was investigated in
1,4-dioxane as a higher boiling solvent (Table 2).
We have demonstrated in earlier work that both isourea
formation, as well as isourea displacements, can be
achieved efficiently, with very short reaction times, un-
der microwave irradiation.11 Hence, we were keen to
investigate whether the whole reaction sequence from
1 to 3 could be carried out in this way in the hope of
shortening reaction times further (Table 3).
We were delighted to find that mixing 1a or 1b with DIC
and Cu(OTf)2, followed by heating for only 5min at
150°C in a focused microwave oven, yielded 3a,b in
87% and 93% isolated yields, respectively, after chroma-
tography (entries 1and 2). Performing the reaction at
lower temperatures gave lower yields despite doubling
the reaction time (entry 3 vs 2). When 1a was heated
in a microwave oven in the absence of DIC, no reaction
was observed. Substitution at the a-position generally
When the reaction was carried out at reflux for 20h, a
yield of 81% was obtained (entry 1). This was improved
after increasing the amount of catalyst (entry 2) or

S. Crosignani et al. / Tetrahedron Letters 45 (2004) 9611–9615
9613
Table 3. Microwave-assisted cyclisation to 2-oxazolines in THF with DIC (1equiv) and Cu(OTf)2 (5mol%)18
Entry
Starting material
Time (temp) (min,°C)
Product
Yielda (%)
1
2
3
4
5
1a
1b
1b
1c
1d
5 (150)
5 (150)
10 (120)
5 (150)
5 (150)
3a
3b
3b
3c
3d
87
93
61
92
87
OH
Ph
O
N
O
6
5 (100) + 10 (175)
79
PhCH2
PhCH2
1f
N
Ph
H
3f
7
1g
15 (150)
3g
83b
8
9
1h
1i
5 (150)
5 (150)
3h
3i
88b
86c
a Isolated yield after chromatography.
b Trans:cis ratio: >95:<5.
c Trans:cis ratio: 1:4. Combined yield of both isomers.
posed no problem (entries 2–5). However, cyclisation of
substrates with an aliphatic R1-substituent (PhCH2–)
was slightly more difficult and required higher reaction
temperatures and/or longer reaction times (entries 6
and 7). Cyclisation of 1g and 1h (derived from
(1R,2S)-norephedrine) yielded a single diastereoisomer,
with slightly lower yields because of the b-substitution
(entries 7 and 8 and Scheme 3). As a trans-substituted
oxazoline was obtained (as confirmed by comparison
with literature data), the cyclisation must have occurred
with inversion of configuration, consistent with the ex-
pected SN2 process.
iPr
NH
iPr
NH
HN iPr
Ph
H
Ph
O
O
O
O
Ph
O
NH
iPr
O
NH
iPr
N
Ph
N
Ph
N
H
H
iPr
Ph
N
OMe
OMe
H
5
6
4
OMe
2i
- H
rotation
- H
H
Ph
3i
O
- H
3j
Ph
N
H
OMe
7
However, a lower level of diastereoselectivity was ob-
served with amide 1i, derived from (1S,2S)-2-amino-3-
methoxy-1-phenyl-1-propanol. Only a 4:1 ratio in
favour of the expected cis-substituted oxazoline over
the trans-substituted isomer was observed in this case
(entry 9 and Scheme 3).
Scheme 4. Suggested mechanism for the 2-oxazoline formation.
diimide and 1a had been consumed, forming the corre-
sponding isourea 2a (major) plus a minor amount of
cyclised product 3a. At this point the copper catalyst
was removed by filtration through an alumina plug,
using DCM as eluant. The solution was concentrated
under vacuum, placed in a microwave vial and subjected
to the usual conditions. TLC analysis indicated com-
plete conversion of the isourea to the oxazoline, and
subsequent column chromatography afforded pure 3a
in 84% yield. This suggests that the copper species does
not play a significant role in the second step of the
reaction.
We also sought to verify whether the copper(II) Lewis
acid, in addition to catalysing the isourea formation,
played a role in the cyclisation step. In the event, amide
1a was reacted with DIC at room temperature in the
presence of the usual quantity of copper(II) triflate.
After 4h, IR and TLC analysis showed that both carbo-
DIC
Ph
Ph
OH
O
N
Based on the above, and on the stereochemical findings
described in Scheme 3, we suggest a mechanism in which
the isourea moiety necessarily has to be activated before
cyclisation takes place (Scheme 4).
Cu(OTf)2
O
R
only one diastereomer
observed
THF, µω
R
N
H
3g R = CH2Ph
3h R = Ph
1g R = CH2Ph
1h R = Ph
Given the basicity of isoureas, an intermolecular acid–
base reaction would take place leading to the protonated
intermediate 5, upon which cyclisation can occur to give
the 2-oxazoline product 3i with inversion of configura-
tion at the reacting centre. However, because the urea
is a good leaving group, the reaction could proceed
through an SN1-type mechanism featuring 6, especially
when the cation is stabilised by a phenyl group. The for-
mation of 3j can thus be explained by a subsequent rota-
tion about the C–C bond to give 7, followed by
DIC
Ph
O
Ph
O
Ph
OH
O
Cu(OTf)2
Ph
+
Ph
N
N
Ph
N
H
THF, µω
OMe
OMe
OMe
3j
3i
1i
4:1 ratio
Scheme 3. Diastereoselective formation of oxazolines derived from
(1R,2S)-norephedrine and (1S,2S)-2-amino-3-methoxy-1-phenyl-1-
propanol.

9614
S. Crosignani et al. / Tetrahedron Letters 45 (2004) 9611–9615
5. (a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetra-
cyclisation. Given the pKa value of ureas, we believe it is
very unlikely that an unactivated isourea can dissociate,
even when benzylic. Interestingly however, only one
oxazoline diastereomer was observed starting from 1e,
g and h, which also contain a secondary benzylic alcohol
moiety. Hence, the actual cyclisation mechanism is
dependent on structural features. With primary alcoh-
ols, a true SN2 process will take place. With secondary
benzylic alcohols, an SN2 mechanism still operates but
if a-substitution is present, unfavourable steric interac-
tions may tilt the balance towards an SN1-type process.
In this way, rotation can relieve steric strain that other-
wise would build up in the formation of cis-substituted
2-oxazolines. Given that 3j is still the minor diastereo-
isomer, the inversion process is still the major pathway
even with 5 (Scheme 4). Further research to investigate
these mechanistic aspects is in progress.
´
hedron: Asymmetry 1998, 9, 1–45; (b) Gomez, M.; Muller,
G.; Rocamora, M. Coord. Chem. Rev. 1999, 193–195, 769–
835; (c) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev.
1996, 96, 835–875; Recent examples: (d) Inoue, M.;
Suzuki, T.; Nakada, M. J. Am. Chem. Soc. 2003, 125,
1140–1141; (e) Duffey, M. O.; LeTiran, A.; Morken, J. P.
J. Am. Chem. Soc. 2003, 125, 1458–1459.
6. (a) Pirrung, M. C.; Tumey, L. N.; McClerren, A. L.;
Raetz, C. R. H. J. Am. Chem. Soc. 2003, 125, 1575–1586;
(b) Li, Q.; Woods, K. W.; Claiborne, A.; Gwaltney, S. L.,
II; Barr, K. J.; Liu, G.; Gehrke, L.; Credo, R. B.; Hua
Hui, Y.; Lee, J.; Warner, R. B.; Kovar, P.; Nukkala, M.
A.; Zielinski, N. A.; Tahir, S. K.; Fitzgerald, M.; Kim, K.
H.; Marsh, K.; Frost, D.; Ng, S.-C.; Rosenberg, S.; Sham,
H. L. Bioorg. Med. Chem. Lett. 2002, 12, 465–469; (c)
Campani, G.; De Angelis, M.; Armaroli, S.; Fattorusso,
C.; Catalanotti, B.; Ramunno, A.; Nacci, V.; Novellino,
E.; Grewer, C.; Ionescu, D.; Rauen, T.; Griffiths, R.;
Sinclair, C.; Fumagalli, E.; Mennini, T. J. Med. Chem.
2001, 44, 2507–2510.
In conclusion, we have discovered that N-(b-hydroxy-
ethyl)amides can be cyclised to the corresponding 2-
oxazolines by converting them into the corresponding
O-alkylisoureas in situ, followed by thermally induced
cyclisation. It was shown that the cyclisation proceeded
in good to excellent yields after 5h reflux in 1,4-diox-
ane,17 and in merely 5min under microwave irradiation
(150°C).18 The reaction is easier with aromatic amides,
and substitution on the other carbon atoms of the ring
is allowed. Inversion of configuration is observed with
good to excellent selectivity. Based on the stereochemi-
cal observations with chiral substrates, we propose a se-
quence in which the isourea moiety is protonated prior
to the actual cyclisation reaction, which proceeds via
an SN2 mechanism, however, in particular cases having
appreciable SN1character.
7. Bandgar, B. P.; Pandit, S. S. Tetrahedron Lett. 2003, 44,
2331–2333.
´
¨
8. (a) Cwik, A.; Hell, Z.; Hegedus, A.; Finta, Z.; Horvath, Z.
¨
Tetrahedron Lett. 2002, 43, 3985–3987; (b) Vorbruggen,
H.; Krolikiewicz, K. Tetrahedron 1993, 49, 9353–9372; (c)
Kamata, K.; Agata, I. J. Org. Chem. 1998, 63, 3113–3116;
(d) Jnaneshwara, G. K.; Deshpande, V. H.; Lalithambika,
M.; Ravindranathan, T.; Bedekar, A. V. Tetrahedron Lett.
1998, 39, 459–462; (e) Clarke, D. S.; Wood, R. Synth.
Commun. 1996, 26, 1335–1340; (f) Bolm, C.; Weickhardt,
K.; Zehnder, M.; Ranff, T. Chem. Ber. 1991, 124, 1173–
1180; (g) Oussaid, B.; Berlan, J.; Soufiaoui, M.; Garrigues,
B. Synth. Commun. 1995, 25, 659–665; (h) Katritzky, A.
R.; Cai, C.; Suzuki, K.; Singh, S. K. J. Org. Chem. 2004,
69, 811–814.
9. (a) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 907–
910; (b) Wipf, P.; Venkatraman, S. Tetrahedron Lett. 1996,
37, 4659–4662; (c) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno,
M. J.; Williams, D. R. Org. Lett. 2000, 2, 1165–1168; (d)
Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 6267–
6270; (e) Pirrung, M. C.; Tumey, L. N. J. Comb. Chem.
2000, 2, 675–680.
Acknowledgements
The authors thank Personal Chemistry for the donation
of a Smith SynthesizerTM, and acknowledge the support-
ing partners of the Southampton Combinatorial Centre
of Excellence: AstraZeneca, GlaxoSmithKline and Evo-
tec OAI. The authors thank Dr Joan Street and Dr Neil
Wells for assistance with NMR and Ms Julie Herniman
and Dr John Langley for assistance with the mass
spectrometry. We also wish to acknowledge the use of
the EPSRCÕs Chemical database Service at Daresbury.19
´
10. Badiang, J. G.; Aube, J. J. Org. Chem. 1996, 61, 2484–
2487.
11. (a) Crosignani, S.; White, P. D.; Linclau, B. J. Org. Chem.
2004, 69, 5897–5905; (b) Crosignani, S.; Nadal, B.; Li, Z.;
Linclau, B. Chem. Commun. 2003, 260–261; (c) Li, Z.;
Crosignani, S.; Linclau, B. Tetrahedron Lett. 2003, 44,
8143–8147.
12. Mathias, L. J. Synthesis 1979, 561–576.
13. Kaulen, J. Angew. Chem., Int. Ed. Engl. 1987, 26, 773–774.
14. Alexandre, A.; Rouessac, F. Bull. Soc. Chim. Fr. 1971,
1837–1840.
References and notes
15. Duffy, M. G.; Grayson, D. H. J. Chem. Soc., Perkin
Trans. 1 2002, 1555–1563.
16. During the course of this research, we found that a similar
reaction to the one reported here has been suggested as an
intermediate step in the reaction of acetic acid with the
isourea of a-chymotrypsin (obtained by reaction of a-
chymotrypsin with a water-soluble carbodiimide). How-
ever, no proof of the proposed reaction pathway was given
and the reaction has never been exploited in synthesis
Banks, T. E.; Blossey, B. K.; Shafer, J. A. J. Biol. Chem.
1969, 244, 6323–6333.
17. Typical procedure: To a solution of amide 1b (999mg,
5.2mmol) and Cu(OTf)2 (100mg, 0.28mmol) in anhy-
drous 1,4-dioxane (10mL) was added DIC (654mg,
5.2mmol) and the solution was heated at reflux for 5h.
1. Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297–
2360.
2. Saravanan, P.; Corey, E. J. J. Org. Chem. 2003, 68, 2760–
2764.
3. Wiedemann, S. H.; Bergman, R. G.; Ellman, J. A. Org.
Lett. 2004, 6, 1685–1687.
4. (a) Meyers, A. I. J. Heterocycl. Chem. 1998, 35, 991–1001;
(b) Scott, A. Aust. J. Chem. 2003, 56, 953; (c) Glos, M.;
Reiser, O. In Organic Synthesis Highlights IV; Schmalz,
H.-G., Ed.; Wiley-VCH, 2000; (d) Reuman, M.; Meyers,
A. I. Tetrahedron 1985, 41, 837–860; (e) Luisi, R.;
Capriati, V.; Florio, S.; Piccolo, E. J. Org. Chem. 2003,
68, 10187–10190.

S. Crosignani et al. / Tetrahedron Letters 45 (2004) 9611–9615
9615
The resulting white precipitate was filtered (washed with
ethyl acetate), and the solution evaporated under reduced
pressure. The oily residue was purified by column chro-
matography (hexane:ethyl acetate 60:40), to give 880mg
(97%) of 3b.
drous THF. The resulting solution was heated at 150°C
for 5min by microwave irradiation. The resulting white
precipitate was filtered (washed with ethyl acetate), and
the solution evaporated under reduced pressure. The oily
residue was purified by column chromatography (hex-
ane:ethyl acetate 60:40), to give 163mg (93%) of 3b.
19. Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J. Chem.
Inf. Comput. Sci. 1996, 36, 746–749.
18. Typical procedure: amide 1b (193mg, 1mmol), DIC
(126mg, 1mmol) and Cu(OTf)2 (ca. 20mg, 0.05mmol)
were placed in a microwave vial and dissolved in anhy-