The use of phosphonium anhydrides for the synthesis of 2-oxazolines, 2-thiazolines and 2-dihydrooxazine under mild conditions

Article abstract of DOI:10.1039/b818310d

β-Hydroxy amides 6 and 7 were treated with triphenylphosphonium anhydride trifluoromethane sulfonate (3), or the cyclic analogue 4, to generate 2-oxazolines 5 and 8 under mild conditions. The reaction was optimised by examining the number of equivalents of reagents 3 or 4, or diisopropylethyl amine required to best effect cyclisation. The effects of altering the reaction temperature, reaction time, concentration, solvent, and addition rate also were investigated. However, it was found that use of a trityl group to block reaction at the hydroxyl or thiol group of the starting amides, and subsequent in situ detritylation, in the absence of base, led to greatly improved yields. Reagent 4 offered significant advantages in the purification of products and was used to dehydrate a range of trityl derivatives to form simple oxazolines, thiazolines, and a dihydro-1,3-oxazine, in high yield (85-99%), as well as a tetrahydro-1,3-oxazepine (31%).

Full text of DOI:10.1039/b818310d

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
The use of phosphonium anhydrides for the synthesis of 2-oxazolines,
2-thiazolines and 2-dihydrooxazine under mild conditions†
Maria J. Petersson,a Ian D. Jenkinsa and Wendy A. Loughlin*a,b
Received 16th October 2008, Accepted 12th November 2008
First published as an Advance Article on the web 18th December 2008
DOI: 10.1039/b818310d
b-Hydroxy amides 6 and 7 were treated with triphenylphosphonium anhydride trifluoromethane
sulfonate (3), or the cyclic analogue 4, to generate 2-oxazolines 5 and 8 under mild conditions. The
reaction was optimised by examining the number of equivalents of reagents 3 or 4, or diisopropylethyl
amine required to best effect cyclisation. The effects of altering the reaction temperature, reaction time,
concentration, solvent, and addition rate also were investigated. However, it was found that use of a
trityl group to block reaction at the hydroxyl or thiol group of the starting amides, and subsequent
in situ detritylation, in the absence of base, led to greatly improved yields. Reagent 4 offered significant
advantages in the purification of products and was used to dehydrate a range of trityl derivatives to
form simple oxazolines, thiazolines, and a dihydro-1,3-oxazine, in high yield (85–99%), as well as a
tetrahydro-1,3-oxazepine (31%).
reagent (triphenylphosphonium anhydride trifluoromethane sul-
Introduction
fonate 3), which has been used to convert N-acyl serines24 and
N-acyl cysteines,25‡ into the corresponding heterocyclic analogues
2-Oxozalines and 2-thiazolines are heterocycles that have attracted
a wide range of interest from synthetic and medicinal chemists over
under very mild conditions with little or no racemisation. This pa-
per reports that phosphonium anhydride 326,27 and the cyclic ana-
the last 20 years. Oxazoline and thiazoline rings occur in natural
products and in drug like compounds,1–7 and derivatives have
logue, 1,1,3,3-tetraphenyl-2-oxa-1,3-phospholanium bis(trifluoro
been identified as anti-HIV,6,8 antimitotic,4,5 anti-cancer,4,7 and
antibiotic agents.9,10 In synthesis, 2-oxazolines and 2-thiazolines
have been used as building blocks,9,11,12 protecting groups for
b-amino alcohols,13 and as auxiliaries and ligands14,15 in a num-
ber of applications. Synthetic procedures to 2-oxazolines and
2-thiazolines have been developed from a range of precursors.3,15–17
One of the more common approaches is the synthesis of oxazolines
and thiazolines from acylamino alcohols or acylamino thiols,
respectively (Scheme 1). A variety of reagents1,12,17–23 have been
used to carry out such transformations, however, typically harsh
conditions {as with [bis(2-methoxylethyl)amino]sulfur trifluoride
(Deoxo-Fluor)20 or DAST17,21} and low to moderate yields (as with
PPh3/DIAD12,18,22 or Burgess’ reagent12,18,19) are observed.
methanesulfonate) (4),28 can be used for the synthesis of simple
oxazolines and thiazolines, as well as a dihydrooxazine and a
tetrahydro-1,3-oxazepine. The use of the cyclic analogue 4 offers
significant advantages in some cases. The importance of protection
of the terminal hydroxyl or thiol group in the starting amide, by
a group that can be deprotected in situ (i.e. trityl) by the expelled
triflic acid in the absence of base, was established.
Results and discussion
The Hendrickson reagent (3), brings about dehydrations and
coupling reactions (such as ester and amide formation29), in a
similar manner to the Mitsunobu reaction,30 and along with the
cyclic analogue 4, is useful for the synthesis of simple esters
and amides, and conversion of primary alcohols to azides.28,29
Reagent 3 was prepared as previously reported,27,29 by treatment of
triphenylphosphine oxide with triflic anhydride at 0 ◦C under an
atmosphere of nitrogen. Likewise, the cyclic analogue 4 was pre-
pared under the same conditions by reaction of the corresponding
bis-phosphine oxide with triflic anhydride.28 Initially, we examined
the use of reagent 3, and the cyclic analogue 4 for oxazoline
synthesis using in situ formation of the benzamide intermediate
and subsequent cyclisation (Scheme 2). Accordingly, the acy-
loxyphosphonium intermediate C6H5COOP+Ph3 was generated by
stirring a mixture of 3 (2 equiv.) and benzoic acid for 60 minutes
in dry dichloromethane (DCM) at room temperature, followed
by addition of 2-amino-1-ethanol and diisopropylethylamine
Scheme 1 General synthesis of thiazolines and oxazolines from acy-
lamino thiols or acylamino alcohols.
One of the mildest reagents for this type of cyclisa-
tion/cyclodehydration appears to be the Hendrickson ‘POP’
aEskitis Institute for Cell and Molecular Therapies, Griffith University,
Nathan, Brisbane, QLD, 4111, Australia. E-mail: w.loughlin@griffith.
edu.au; Fax: +61 07 3735 7656; Tel: +61 07 3735 7567
bSchool of Biomolecular and Physical Sciences, Griffith University, Nathan,
Brisbane, QLD, 4111, Australia
† Electronic supplementary information (ESI) available: General proce-
dures; further experimental procedures; 1H NMR spectra of compounds
17–22, 25, 27, 29. See DOI: 10.1039/b818310d
‡ Although the literature states that Hendrickson reagent (3), converts a
N-acyl cysteine into the corresponding thiazoline, no experimental
evidence is reported.
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Scheme 2 Formation of oxazoline 5 from benzoic acid.
(DIPEA). Oxazoline 5 was isolated (54%). Similarly, use of reagent
4 also gave oxazoline 5 (50%). When reagent 3 or 4 was used in
excess, oxazoline 5 was formed in reduced yields (2.4 equiv. of 3,
47%; 2.4 equiv. of 4, 38%; 2.8 equiv. of 4, 15%).
The moderate yields suggested that in the two-step process
reagent 3 (or 4) was reacting with not only the benzoic acid, but
also the amino group of the amino alcohol. Cyclisation of amide 6
potentially would circumvent this. Reaction of benzoyl chloride or
nitrobenzoyl chloride with 2-amino-1-ethanol in the presence of
triethylamine, gave amide 6 (73%) and amide 7 (99%), respectively.
Treatment of one equivalent of reagent 3 or 4 with amide 6
and DIPEA gave oxazoline 5§ in 60% or 57% isolated yield,
respectively (Scheme 3). In a similar manner, treatment of 3 or
4 with nitroamide 7 gave the corresponding nitrooxazoline 8 in
56% or 52% isolated yield, respectively (Scheme 3). Compared to
oxazoline 5, the oxazoline 8 offered the advantage of separation
of the aromatic peaks in the 1H NMR spectra for crude product
analysis. Thus, amide 7 was extensively used in subsequent studies.
Fig. 1 Equivalents of reagent 3 versus % yield of oxazoline 5 (filled
circles), or 8 (open squares) based on recovery of unreacted amide 6 or 7
respectively.
Next, reagent 3 was generated at 0 ◦C and subsequent reaction
with amide 7 in the presence of DIPEA, was carried out at 0, 10,
22 and 40 ◦C. The optimal reaction temperature was found to be
22 ◦C which gave the best yield of oxazoline 8 (56%) and best
overall recovery of mass (97% mass recovery).
The influence of the solvent was examined by carrying out the
reaction of reagent 3 with amide 7 in the presence of DIPEA (at
◦
22 C, with 1 equivalent of 3) in either DCM, CH3CN or THF
as the solvent. A complex mixture was obtained with THF and a
reduced yield of product 8 (30%) with 67% recovery of amide 7
was obtained with CH3CN. DCM gave the best yield of 8 (56%)
with the least amount of recovered amide 7 (40%). The chlorinated
solvent appears to be best for the formation and use of 3.27
Using DCM, the effect of reaction concentration on the
formation of 8 was examined (Table 1). Dilution (entries 4 and
5, Table 1) or increased concentration (entries 1 and 2, Table 1)
of the reactants 3 and 7, led to decreased yields of 8. The optimal
concentration was around 0.05 mM, which gave moderate yields
of 8 (entry 3, Table 1).
Scheme 3 Formation of oxazolines 5 and 8 from amides 6 and 7.
Firstly, the effect of altering the number of equivalents of reagent
3 was examined. Thus, between 0.5 and 2.0 equivalents of 3 were
reacted with amides 6 or 7 (Fig. 1). The best conversion of amides
6 and 7 to oxazolines 5 and 8, respectively, was achieved when only
one equivalent of reagent 3 was used.
As an example, oxazoline 8 (56%) was isolated along with
recovered amide 7 (42%), giving an adjusted yield of 97% for
oxazoline 8 based on reacted amide 7 (Fig. 1). Reduced yields of
oxazolines 5 and 8 were obtained when excess reagent 3 was used.
This correlated with an increase in decomposition products, as
observed in the 1H NMR spectra of the crude products, along with
reduced isolated yields [e.g. use of 1.2 equivalents of 3 or 4, gave 5
(33% and 37%, respectively) or 8 (49% and 39%, respectively), not
adjusted for recovery of 6 or 7.
Next, the reaction time was altered. Reagent 3 was reacted
with amide 7 in the presence of DIPEA. At 2 and 24 hours
1
an aliquot of the reaction mixture was analysed by H NMR
spectroscopy. Oxazoline 8 was present in 56% and 57% yield,
Table 1 Reaction of 7 with reagent 3 with variation in solvent (DCM)
volume
Conc. of 7
and 3 (mM)
Reaction
Entry
volume (mL) Yield 8a (%) Recovered 7 (%)
1
2
3
4
5
0.095
0.095
0.048
0.024
0.005
2.5
2.5
5.0
10.0
50.0
42
46b
56
13
13
47
42
40
78
84
§ The stability of oxazoline 5 to acid conditions was tested by stirring
oxazoline 5 with silica gel in DCM for 16 hours, or with aqueous
hydrochloric acid (2M) for 1 hour. In the silica experiment, no significant
1
a Yield from analysis of 1H NMR spectra of crude product. b Isolated yield;
separate reaction from entry 1.
decomposition of oxazoline 5 was observed by H NMR analysis of the
crude mixture. The hydrochloric acid test showed some decomposition, a
91:9 ratio of oxazoline 5 and amide 6 was observed.
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Table 2 Reaction of 7 with reagent 3 with variation in equivalents of
DIPEA
Table 3 Heterocycles generated from amides 6, 13, 14, 17–23 with reagent
4
Equiv. of
7 and 3
Equiv. of
DIPEA
Entry
Starting material
Product
Yield
Entry
Yield 8 (%)
Recovered 7 (%)
1
2
3
benzoic acid
6
17
50%
72%
94%
1
2
3
4
1.0
1.0
1.0
1.0
1.1
2.2
3.0
4.4
47
56
19
0
42
40
67
88
4
5
6
benzoic acid
13
20
55%
71%
99%
respectively. Complete reaction workup at 2 hours gave 57% of
8, indicating that 2 hours is sufficient for reaction.
7
8
14
21
11%
31%
The effect of excess DIPEA was considered. Reagent 3 was
reacted with amide 7 and 1.1, 2.2, 3.0 or 4.4 equivalents of DIPEA
then the solvent removed. The ratio of 7 and 8 was analysed by 1H
NMR spectroscopy (Table 2). These results indicate that the use of
2.2 equivalents of DIPEA was preferred for formation of oxazoline
8. Amide 7 was generally recovered during the course of the
above studies. Inverse addition of reagent 3 was also investigated.
9
18
19
85%
98%
10
◦
Generation of reagent 3 at 0 C and addition of the suspensi◦on
of 3 to a solution of amide 7 in the presence of DIPEA at 0 C
over 30 minutes, gave oxazoline 8 (25%) and amide 7 (33%), as
determined by 1H NMR analysis of the crude product. Difficulties
in the control of temperature and transfer of reagent 3 could
account for the reduced recovery of 7 and yield of 8.
11
12
15
22
57%
95%
13
23
88%
Reaction conditions that allowed easy isolation of oxazoline 5
were also investigated. When reagent 3 is used, the triphenylphos-
phine oxide by-product (Rf = 0.54; EtOAc:Hexane, 3:1) co-elutes
with a significant amount of 5 during chromatography leading
to lower isolated yields of oxazoline 5, unless a second chro-
matography step is carried out. By comparison, the corresponding
bis-phosphine oxide by-product from reagent 4 is significantly
more polar (Rf = 0.11; EtOAc:Hexane, 3:1) and thus more easily
removed by chromatography. Thus, amide 6 was treated with
reagent 4 using the optimized reactions conditions (1.0 equiv.
reagent 4, 22 oC, DCM, 0.05 mM of 6, 2 hours, 2.2 equiv. DIPEA)
and oxazoline 5 was easily isolated in 57% yield.
Fig. 2 Structures 9 and 10.
Finally, the rate of addition of the amide was varied, using 6
as the example. Direct addition of amide 6 as a solid to reagent 4
gave oxazoline 5 in moderate yield (56%). However, co-addition of
amide 6 with DIPEA in DCM to reagent 4 dropwise over 5 minutes
gave oxazoline 5 in an increased yield (70%). Delivery of 6 and
DIPEA in DCM via syringe pump over 30 or 60 minutes, gave 5
in 72% (entry 2, Table 3) or 64% yields, respectively. The optimal
mode of addition was as a pre-made solution of 6 and DIPEA with
a rate of addition of between 5 and 30 minutes. These conditions
led to improved yields of 5 (72% cf ~57%) as compared to the
previous experiments.
During the course of the optimisation work we considered that
the reduced yields of oxazoline 8 (and 5) and the recovery of amide
7 (or 6) may be due to a side reaction where aziridine 9 (Fig. 2)
is formed, which is then hydrolysed upon workup to give amide 7
(or 6). In an attempt to trap the proposed by-product 9, amide 7
was treated with reagent 4 (1.0 equiv. of 4, 22 ◦C, DCM, 0.05 mM
of 7, 16 hours, 2.2 equiv. DIPEA) followed by addition of propyl
amine. In situ trapping of an intermediate such as aziridine 9 with
propyl amine should generate amide 10 (Fig. 2). Upon workup,
amide 7 (46%) and oxazoline 8 (51%) were isolated, confirming
the absence of aziridine 9.
A plausible explanation for the recovery of amide 7 (or 6) in the
optimisation reactions is that both the hydroxyl and amide groups
are blocked as oxyphosphonium salts and therefore the cyclisation
reaction cannot take place. Upon workup these phosphonium salts
would be hydrolysed back to amide 7 (or 6).
Using the optimized conditions and reagent 4 we sought to
extend this reaction to the preparation of other heterocycles.
Benzoyl chloride was reacted with 3-amino-1-propanol, 4-amino-
1-butanol or cysteamine in the presence of triethylamine to give
amides 13, 14 and 15 (99%, 81% and 93% yield respectively).
Cyclisation of amides 13 and 14 with reagent 4 in the presence of
DIPEA with slow addition of amide and DIPEA gave dihydro-
1,3-oxazine 26, and tetrahydro-1,3-oxazepine 27 (entries 5 and 7,
Table 3). In contrast, cyclisation of amide 15 with reagent 4 gen-
erated thiazoline 30 (57%, entry 11, Table 3) in conjunction with
disulfide 24 (8%, Fig. 3). Disulfide 24 was formed through mono
reduction of the bis-phosphine oxide, as reported elsewhere.31
To improve the yields we considered the use of an acid-labile
protecting group on the hydroxyl or thiol group of amides 6, 13,
14 and 15, which would be deprotected in situ by the expelled
triflic acid if no base is present in the reaction. There is a literature
report of the formation of a thiazoline ring within peptides from
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A mechanism for these cyclodehydrations is suggested in
Scheme 5 (illustrated for the reaction of 17 with reagent 3). Attack
of the amide carbonyl in 17 on the phosphonium anhydride 3
would result in formation of the oxyphosphonium intermediate
32 with expulsion of Ph3PO and triflic acid. Expulsion of a
second molecule of Ph3PO from 32 would generate the nitrilium
intermediate 33 (analogous to the formation of benzonitrile when
benzamide is treated with 3).33 Detritylation of 33 would generate
34, which would undergo a (favoured) 5-endo-dig cyclisation to
give the oxazoline 5.
Fig. 3 Structures 24 and 25.
cyclisation of Tr-S-cysteine peptides.32 We therefore applied the
trityl protecting group to our hydroxy and thiol amides. Treatment
of amides 6, 13, 14 and 15, with trityl chloride and DIPEA or
triethylamine gave trityl derivatives 17, 20, 21 and 22 (93%, 99%,
65% and 84% respectively, Scheme 4). Trityl derivatives 17 and 20
were stable upon standing in CDCl3 for 24 hours, whereas trityl
derivative 21 converted to a 62:38 mixture of amide 14 and 21, as
1
determined by H NMR spectroscopy. However, trityl derivative
21 was stable in the solid form.
Scheme 5 Suggested mechanism for the cyclodehydration of 17.
Alternatively, if detritylation of 32 were to occur, this interme-
diate could also undergo loss of Ph3PO to generate 34 (a 5-endo-
trig cyclisation at this stage is possible, but this is disfavoured
by Baldwin’s rules).34 Another possibility is that intermediate 33
could form 5 directly (attack by the trityl oxygen on the nitrilium
carbon, followed by loss of the trityl cation). However, based on
related work on the synthesis of cyclic amidines (e.g., using 3, X =
NTr, R = Ph),35 it was found that the reaction failed when carried
out in the presence of DIPEA. This suggests that detritylation is
required for the reaction to proceed.
Scheme 4 Synthesis of trityl derivatives 17–23.
Conclusions
Cyclisation of trityl derivatives 17, 20, 21 and 22 with reagent
4, in the absence of base, gave oxazoline 5 (94%), dihydro-1,3-
oxazine 26 (99%), tetrahydro-1,3-oxazepine 27 (31%; perhaps
due to the instability of 21 as noted before) and thiazoline
30 (95%) (entries 3, 6, 8 and 12, Table 3). Further examples,
using commercially available starting materials, were considered.
1-Amino-2-propanol, and D,L-serine methyl ester were converted
to amides 11 (95%) and 12 (94%), respectively, with benzoyl
chloride in the presence of triethylamine. However, treatment of
L-cysteine methyl ester with benzoyl chloride and triethylamine
gave unwanted dibenzoyl product 25 (98%, Fig. 3). Instead,
treatment of L-cysteine methyl ester with benzoic anhydride, and
triethylamine at -78 ◦C, gave both amide 16 (67%) and amide 25
(30%). Amides 11, 12, and 16 were converted to trityl derivatives
18 (97%), 19 (97%), and 23 (72%), as described above (Scheme 4).
Cyclisation of 18, 19 and 23 with reagent 4, in the absence of base,
gave oxazolines 28 and 29, and thiazoline 31 in excellent yields
(entries 9, 10, 13; Table 3).
In summary, the versatility of reagent 4 as a general dehydrating-
type reagent to access simple heterocycles has been demonstrated
by the synthesis of oxazolines, thiazolines, a dihydro-1,3-oxazine
and a tetrahydro-1,3-oxazepine. The preferred conditions for
dehydration (1.0 equiv. reagent 3 or 4, 22 ◦C, DCM, 0.05 mM
of 6 or 7, 2 hours, 2.2 equiv. DIPEA) were established, using the
reaction between b-hydroxy amides 6 or 7 and reagents 3 or 4.
Oxazolines 5 and 8 were obtained in moderate to good yields
(typically 50–72%). Use of the acid-labile trityl protecting group
on the hydroxyl or thiol group of the amide precursor significantly
improved the yield of heterocycle obtained. Using reagent 4,
a range of trityl derivatives (such as 17–23) were converted to
the above mentioned heterocycles, in high yields (85–99%, apart
from tetrahydro-1,3-oxazepine 27). This identifies reagent 4 as an
effective mild dehydrating reagent, with further potential for the
synthesis of other heterocycles. Reagent 4 has the advantage over
reagent 3 of much easier removal of the bis-phosphine oxide by-
product.
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(30 mL) according to the representative procedure above. N-
(2-hydroxyethyl)benzamide (6) (300 mg, 1.82 mmol) and DI-
PEA (692 mL, 4.0 mmol) in dry CH2Cl2 (5 mL) were added
dropwise (over 5 minutes) to the reaction mixture. The pale
yellow mixture was warmed to room temperature and then
stirred for 2 hours. The reaction mixture was washed with
sodium hydrogen carbonate (5% aqueous solution, 2 ¥ 30 mL),
dried (anhydrous Na2SO4) and filtered. The solvent was removed
under reduced pressure and the residue purified by silica gel
column chromatography (ethyl acetate/hexane, gradient from
10:90 to 100:0). Compound 536,37 (188 mg, 70%) was obtained
Experimental
For general experimental procedures see ESI.† Preparation of
reagents 329 and 428 are described elsewhere.
Representative example for the preparation of
2-phenyl-4,5-dihydro-1,3-oxazole (5) from benzoic acid and
2-amino-1-ethanol using reagent 4
Freshly distilled triflic anhydride (276 mL, 1.64 mmol) was added
slowly to a solution of 1,2-bis(diphenylphosphinyl)ethane (980 mg,
2.46 mmol) in dry CH2Cl2 (20 mL) at 0 ◦C under a nitrogen
atmosphere. A thick white precipitate was formed and left to stir
at 0 ◦C for 30 minutes. Benzoic acid (100 mg, 0.82 mmol) was
added and the mixture was warmed to room temperature and
then stirred for 1 hour. 2-Amino-1-ethanol (49 mL, 0.82 mmol)
and DIPEA (426 mL, 2.46 mmol) were added simultaneously to
the reaction mixture (over 5 minutes). The pale yellow mixture was
stirred for 16 hours. The reaction mixture was washed with sodium
hydrogen carbonate (5% aqueous solution, 2 ¥ 30 mL), dried
(anhydrous Na2SO4) and filtered. The solvent was removed under
reduced pressure and the residue purified by silica gel column
chromatography (ethyl acetate/hexane, gradient from 25:75 to
100:0). Compound 536,37 (61 mg, 50%) was obtained as a colour-
less oil.
1
as a colourless oil, identical by TLC and H NMR spectroscopy
to that obtained previously. Amide 638 (88 mg, 29%) was also
recovered.
Representative example for the preparation of trityl derivatives:
synthesis of N-[(2-trityloxy)ethyl] benzamide (17)
Tritylchloride (1.69 g, 6.05 mmol) was added to N-(2-
hydroxyethyl)benzamide (6) (500 mg, 3.03 mmol) and DIPEA
(1.58 mL, 9.08 mmol) in dry CH2Cl2 (25 mL), and the mixture
stirred at room temperature under a nitrogen atmosphere for
16 hours. The solvent was removed under reduced pressure and
the residue purified by silica gel column chromatography (ethyl
acetate/hexane, gradient from 10:90 to 50:50). Compound 1739
(1.15 g, 93%) was obtained as an amorphous white solid. Mp
Representative example for the preparation of amides: synthesis of
N-(2-hydroxyethyl)benzamide (6)
◦
139–141 ◦C. (lit.,39 mp 135–136 C); nmax/cm-1 3270, 3070, 2917,
Benzoyl chloride (1.65 mL, 14.2 mmol) was added dropwise
to 2-amino-1-ethanol (859 mL, 14.2 mmol) and triethylamine
(1.9 mL, 14.2 mmol) in dry CH2Cl2 (100 mL), and the mixture
stirred at room temperature under a nitrogen atmosphere for
16 hours. The solvent was removed under reduced pressure and
the residue purified by silica gel column chromatography (ethyl
acetate/hexane, gradient from 10:90 to 100:0). Compound 638
(1.71 g, 73%) was obtained as an amorphous white solid. Mp
56–58 ◦C (lit.,38 mp 56–57 ◦C).
1642, 1556 and 1317. dH(400 MHz; CDCl3) 3.37 (2 H, t, J 5.3,
H-2), 3.67 (2 H, dt, J 5.3 and 5.3, H-1), 6.45 (1 H, br s,
NH), 7.22–7.32 [9 H, m, m-C(C6H5)3 and p-C(C6H5)3], 7.43–
7.47 [8 H, m, m-C6H5 and o-C(C6H5)3], 7.50–7.54 (1 H, m, p-
C6H5), 7.73–7.76 (2 H, m, o-C6H5); dC(100 MHz; CD3OD) 41.2
(C-1), 63.7 (C-2), 87.9 [C(C6H5)3], 128.1 [p-C(C6H5)3], 128.3 (o-
C6H5), 128.8 [m-C(C6H5)3], 129.6 (m-C6H5), 129.8 [o-C(C6H5)3],
=
132.7 (p-C6H5), 135.8 (i-C6H5), 145.5 [i-C(C6H5)3], 170.4 (C O);
m/z (ES+) 430.1756 (M + Na+ C28H25NO2Na requires 430.1777),
430.2 (M + Na+, 100%), 414.3 (M + Li+, 100%), 243.0 [C(C6H5)3 ,
+
Representative example for the cyclisation of amides via direct
addition: synthesis of 2-phenyl-4,5-dihydro-1,3-oxazole (5)
76%].
Triflic anhydride (102 mL, 0.61 mmol) and 1,2-bis(diphenyl-
phosphinyl)ethane (313 mg, 0.73 mmol) were reacted in dry
CH2Cl2 (10 mL) according to the representative procedure above.
N-(2-Hydroxyethyl)benzamide (6) (100 mg, 0.61 mmol) and
DIPEA (231 mL, 1.33 mmol) were added to the reaction mixture.
The pale yellow mixture was warmed to room temperature and
then stirred for 16 hours. The reaction mixture was washed with
sodium hydrogen carbonate (5% aqueous solution, 2 ¥ 30 mL),
dried (anhydrous Na2SO4) and filtered. The solvent was removed
under reduced pressure and the residue purified by silica gel
column chromatography (ethyl acetate/hexane, gradient from
25:75 to 100:0). Compound 536,37 (51 mg, 57%) was obtained as
N-Benzoyl-O-tritylserine methyl ester (18)
Tritylchloride (936 mg, 3.36 mmol), N-benzoylserine methyl ester
(11) (500 mg, 2.24 mmol) and triethylamine (624 mL, 4.48 mmol)
were reacted in dry CH2Cl2 (30 mL) according to the representative
procedure above. Compound 18 (1.01 g, 97%) was obtained as an
amorphous white solid. Mp 132–134 ◦C; nmax/cm-1 3248, 3060,
2942, 1746, 1635 and 1207. dH(400 MHz; CDCl3) 3.53 (1 H, dd,
J 2.9 and 9.2, CH2), 3.68 (1 H, dd, J 2.9 and 9.2, CH2), 3.81
(3 H, s, CH3), 4.92 (1 H, ddd, J 2.9, 5.4 and 8.0, a-CH), 7.01 (1 H,
br d, J 8.0, NH), 7.20–7.29 [9 H, m, p-C(C6H5)3 and m-C(C6H5)3],
7.36–7.39 [6 H, m, o-C(C6H5)3], 7.44–7.48 (2 H, m, m-C6H5), 7.52–
7.55 (1 H, m, p-C6H5), 7.77–7.79 (2 H, m, o-C6H5); dC(100 MHz;
CDCl3) 52.6 (CH3), 53.1 (a-CH), 63.7 (CH2), 86.6 [C(C6H5)3],
127.1 (o-C6H5), 127.2 [p-C(C6H5)3], 127.9 [m-C(C6H5)3], 128.5 [o-
C(C6H5)3], 128.6 (m-C6H5), 131.8 (p-C6H5), 134.0 (i-C6H5), 143.4
[i-C(C6H5)3], 166.9 [C(O)N], 171.1 [C(O)O]; m/z (ES+) 488.1819
(M + Na+ C30H27NO4Na requires 488.1832), 488.3 (M + Na+,
1
a colourless oil, identical by TLC and H NMR spectroscopy to
that obtained previously.
Representative example for the cyclisation of amides with slow
addition time: synthesis of 2-phenyl-4,5-dihydro-1,3-oxazole (5)
Triflic anhydride (306 mL, 1.82 mmol) and 1,2-bis(diphenyl-
phosphinyl)ethane (938 mg, 2.2 mmol) were reacted in dry CH2Cl2
+
58%), 243.0 [C(C6H5)3 , 100%].
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N-[(2-Trityloxy)propyl]benzamide (19)
(1 H, br s, NH), 7.20–7.32 [9 H, m, m-C(C6H5)3 and p-C(C6H5)3],
7.37–7.52 [9 H, m, o-C(C6H5)3, p-C6H5 and m-C6H5], 7.69–7.73
(2 H, m, o-C6H5); dC(100 MHz; CDCl3) 26.1 (C-2), 27.1 (C-3),
39.9 (C-1), 62.8 (C-4), 85.8 [C(C6H5)3], 126.9 [p-C(C6H5)3], 127.1
(o-C6H5), 127.9 [o-C(C6H5)3], 128.2 [m-C(C6H5)3], 128.2 (m-C6H5),
Trityl chloride (1.63 g, 5.86 mmol), N-(2-hydroxypropyl) benza-
mide (12) (700 mg, 3.91 mmol) [with approximately 6% of N-
(2-hydroxy-1-methylethyl)benzamide present] and triethylamine
(1.1 mL, 7.8 mmol) were reacted in dry CH2Cl2 (40 mL) according
to the representative procedure above. Compound 19 (1.59 g, 97%)
was obtained as an amorphous white solid containing 6% of N-
(2-triphenylmethoxy-1-methylethyl)benzamide. Mp 110–112 ◦C
(decomposed); nmax/cm-1 3322, 3047, 2929, 1639, 1541 and 1075.
dH(400 MHz; CDCl3) 1.05 (3 H, d, J 6.0, CH3), 2.87–2.93 (1 H,
m, H-1), 3.29–3.36 (1 H, m, H-1), 3.79–3.85 (1 H, m, H-2), 6.35
(1 H, br s, NH), 7.23–7.32 [9 H, m, p-C(C6H5)3 and m-C(C6H5)3],
7.38–7.42 (2 H, m, m-C6H5), 7.44–7.53 [7 H, m, p-C6H5 and
o-C(C6H5)3], 7.65–7.67 (2 H, m, o-C6H5); dC(100 MHz; CDCl3)
19.9 (CH3), 45.0 (C-1), 69.0 (C-2), 87.0 [C(C6H5)3], 126.8 (o-C6H5),
127.3 [p-C(C6H5)3], 127.9 [m-C(C6H5)3], 128.5 (m-C6H5), 128.7
=
131.0 (p-C6H5), 134.7 (i-C6H5), 144.1 [i-C(C6H5)3], 166.1 (C O);
m/z (ES+) 458.2076 (M + Na+ C30H29NO2Na requires 458.2091),
458.3 (M + Na+, 40%), 243.0 [C(C6H5)3 , 100%].
+
N-[2-(Triphenylmethylsulfanyl)ethyl] benzamide (22)
Tritylchloride (308 mg, 1.10 mmol), N-(2-sulfanylethyl) benza-
mide (15) (100 mg, 0.55 mmol) and DIPEA (288 mL, 1.66 mmol)
were reacted in dry CH2Cl2 (5 mL) according to the representative
procedure above. Compound 22 (195 mg, 84%) was obtained as
an amorphous white solid. Mp 134–136 ◦C; nmax/cm-1 3326, 3273,
3044, 2921, 1632, 1541 and 1310. dH(400 MHz; CDCl3) 2.53 (2 H,
t, J 6.2, H-2), 3.30 (2 H, dt, J 6.2 and 6.2, H-1), 6.24 (1 H,
br s, NH), 7.18–7.28 [9 H, m, p-C(C6H5)3 and m-C(C6H5)3], 7.40–
7.44 [8 H, m, o-C(C6H5)3 and m-C6H5], 7.47–7.52 (1 H, m, p-
C6H5), 7.69–7.72 (2 H, m, o-C6H5); dC(100 MHz; CDCl3) 32.1
(C-2), 38.5 (C-1), 66.8 [C(C6H5)3], 126.8 [p-C(C6H5)3], 126.9 (o-
C6H5), 127.9 [m-C(C6H5)3], 128.5 (m-C6H5), 129.5 [(o-C(C6H5)3)],
[o-C(C6H5)3], 131.3 (p-C6H5), 134.6 (i-C6H5), 144.8 [i-C(C6H5)3],
+
=
167.2 (C O); m/z (ES+) 444.1924 (M + Na C29H27NO2Na
requires 444.1934), 444.2 (M + Na+, 39%), 243.0 [C(C6H5)3 ,
+
100%].
N-[(3-Trityloxy)propyl]benzamide (20)
=
131.4 (p-C6H5), 134.4 (i-C6H5), 144.6 [i-C(C6H5)3], 167.2 (C O);
Trityl chloride (1.85 g, 6.64 mmol), N-(3-hydroxypropyl) ben-
zamide (13) (793 mg, 4.42 mmol) and triethylamine (1.24 mL,
8.90 mmol) were reacted in dry CH2Cl2 (40 mL) according to the
representative procedure above. Compound 20 (1.84 g, 99%) was
obtained as an amorphous white solid. Mp 111–113 ◦C; nmax/cm-1
3365, 3047, 2934, 2868, 1634, 1534 and 1090. dH(400 MHz; CDCl3)
1.91 (2 H, tt, J 5.6 and 5.6, H-2), 3.31 (2 H, t, J 5.6, H-3), 3.57
(2 H, dt, J 5.6 and 6.4, H-1), 6.70 (1 H, br s, NH), 7.22–7.32 [11 H,
m, m-C6H5, m-C(C6H5)3, and p-C(C6H5)3], 7.41–7.46 [7 H, m, o-
C(C6H5)3 and p-C6H5], 7.59–7.62 (2 H, m, o-C6H5); dC(100 MHz;
CDCl3) 29.0 (C-2), 38.9 (C-1), 62.8 (C-3), 87.2 [C(C6H5)3], 126.9
(o-C6H5), 127.1 [p-C(C6H5)3], 127.9 [m-C(C6H5)3], 128.3 (m-
m/z (ES+) 446.1555 (M + Na+ C28H25NOSNa requires 446.1549),
446.2 (M + Na+, 100%), 430.3 (M + Li+, 44%), 243.0 [C(C6H5)3 ,
+
100%].
N-Benzoyl-S-tritylcysteine methyl ester (23)
Tritylchloride (365 mg, 1.31 mmol), N-benzoylcysteine methyl
ester (16) (209 mg, 0.87 mmol) and triethylamine (243 mL,
1.75 mmol) were reacted in dry CH2Cl2 (15 mL) according to the
representative procedure above. Compound 2341 (301 mg, 72%)
was obtained as an amorphous white solid. Mp 130–133 ◦C (lit.,41
mp 132–134 ◦C). dH(300 MHz; CDCl3) 2.78 (2 H, m, CH2), 3.75
(3 H, s, CH3), 4.84 (1 H, dt, J 6.7 and 10.4, CH), 6.72 (1 H, br d,
J 10.4, NH), 7.19–7.28 [8 H, m, m-C(C6H5)3 and m-C6H5], 7.37–
7.56 [9 H, m, o-C(C6H5)3, p-C(C6H5)3 and p-C6H5], 7.76–7.79 (2 H,
m, o-C6H5); m/z (ES+) 482.3 (M + H+, 8%), 504.2 (M + Na+, 8%),
C6H5), 128.6 [o-C(C6H5)3], 131.1 (p-C6H5), 134.6 (i-C6H5), 143.8
+
=
[i-C(C6H5)3], 167.3 (C O); m/z (ES+) 444.1935 (M + Na
C29H27NO2Na requires 444.1934), 444.2 (M + Na+, 46%), 243.0
+
[C(C6H5)3 , 100%].
488.2 (M + Li+, 100%), 243.0 [C(C6H5)3 , 100%].
+
N-[(4-Trityloxy)butyl]benzamide (21)
Trityl chloride (995 mg, 3.57 mmol), N-(4-hydroxybutyl) ben-
zamide (14) (230 mg, 1.19 mmol) and triethylamine (497 mL,
3.57 mmol) were reacted in dry CH2Cl2 (20 mL) according
to the representative procedure above. TLC indicated complete
conversion of compound 14 to the desired product 21, however
upon purification by silica gel column chromatography (ethyl
acetate/hexane with 0.5% triethylamine, gradient from 5:95 to
50:50) part of the product decomposed and compound 21 (335 mg,
65%) was therefore obtained only in moderate yield as an
amorphous white solid. Amide 1440 (161 mg, 31%) was also
isolated.
Representative example for the cyclisation of trityl derivatives:
synthesis of 2-phenyl-4,5-dihydro-1,3-oxazole (5)
Triflic anhydride (186 mL, 1.10 mmol) was added slowly to a solu-
tion of 1,2-bis(diphenylphosphinyl)ethane (539 mg, 1.25 mmol) in
dry CH2Cl2 (10 mL) at 0 ◦C under a nitrogen atmosphere. N-(2-
Triphenylmethoxyethyl)benzamide (17) (300 mg, 0.74 mmol) in
dry CH2Cl2 (15 mL) was added dropwise to the reaction mixture.
The reaction was stirred at room temperature for 2 hours. The
reaction mixture was washed with sodium hydrogen carbonate
(5% aqueous solution, 2 ¥ 20 mL), dried (anhydrous Na2SO4)
and filtered. The solvent was removed under reduced pressure and
the residue purified by silica gel column chromatography (ethyl
acetate/hexane, gradient from 10:90 to 100:0). Compound 536,37
(102 mg, 94%) was obtained as a colourless oil, identical by TLC
and 1H NMR spectroscopy to that obtained previously.
N-[(4-Trityloxy)butyl]benzamide (21)
Mp 153–154 ◦C; nmax/cm-1 3287, 3056, 2946, 2856, 1629, 1537
and 1070. dH(300 MHz; CDCl3) 1.66–1.77 (4 H, m, H-2 and H-3),
3.14 (2 H, t, J 5.8, H-4), 3.46 (2 H, dt, J 5.8 and 6.8, H-1), 6.20
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2-Phenyl-5,6-dihydro-4H-1,3-oxazine (26)
(2H, m, m-C6H5), 7.46–7.49 (1H, m, p-C6H5), 7.94-7.96 (2H, m,
o-C6H5); dC(100 MHz; CDCl3) 21.4 (CH3), 62.0 (C-4), 74.0 (C-5),
128.1 (o-C6H5), 128.2 (i-C6H5), 128.3 (m-C6H5), 131.2 (p-C6H5),
163.7 (C-2).
Triflic anhydride (180 mL, 1.07 mmol), 1,2-bis(diphenylpho-
sphinyl)ethane (521 mg, 1.21 mmol) and N-(3-triphenylmetho-
xypropyl)benzamide (20) (300 mg, 0.71 mmol) were reacted in dry
CH2Cl2 (15 mL) according to the representative procedure above.
Compound 2642 (113 mg, 99%) was obtained as a colourless oil.
2-Phenyl-4,5-dihydro-1,3-thiazole (30)
Triflic anhydride (179 mL, 1.06 mmol), 1,2-bis(diphenylpho-
sphinyl)ethane (518 mg, 1.20 mmol) and N-[2-(triphenylmethyl-
sulfanyl)ethyl]benzamide (22) (300 mg, 0.71 mmol) were reacted
in dry CH2Cl2 (15 mL) according to the representative procedure
above. Compound 3045,46 (110 mg, 95%) was obtained as a pale
yellow oil.
2-Phenyl-4,5,6,7-tetrahydro-1,3-oxazepine (27)
Triflic anhydride (55 mL, 0.33 mmol), 1,2-bis(diphenylpho-
sphinyl)ethane (160 mg, 0.37 mmol) and N-(4-triphenylmetho-
xybutyl)benzamide (21) (95 mg, 0.22 mmol) were reacted in
dry CH2Cl2 (5 mL) according to the representative procedure
above. Compound 27 (12 mg, 31%) was obtained as a colourless
oil. nmax/cm-1 3436, 3052, 2974, 2880, 1626, 1426 and 1266.
dH(400 MHz; CDCl3) 1.91 (4 H, br s, H-5 and H-6), 3.44 (2 H,
br s, H-7), 3.65 (2 H, br s, H-4), 7.38–7.42 (3 H, m, m-C6H5 and p-
C6H5), 7.50–7.53 (2 H, m, o-C6H5); dC(100 MHz; CDCl3) 24.5 (C-5
or C-6), 26.1 (C-5 or C-6), 46.1 (C-4), 49.6 (C-7), 127.1 (o-C6H5),
128.2 (m-C6H5), 129.7 (p-C6H5), 137.2 (i-C6H5), 169.7 (C-2); m/z
(ES+) 175.0997 (M + H+ C11H13NO requires 175.0997), 175.8 (M
+ H+, 100%), 181.9 (M + Li+, 100%).
Methyl 2-phenyl-4,5-dihydro-1,3-thiazole-4-carboxylate (31)
Triflic anhydride (89 mL, 0.53 mmol), 1,2-bis(diphenylpho-
sphinyl)ethane (257 mg, 0.60 mmol) and N-[2-(triphenylmethyl-
sulfanyl)ethyl]benzamide (23) (169 mg, 0.35 mmol) were reacted
in dry CH2Cl2 (10 mL) according to the representative procedure
above. Compound 3146,47 (68 mg, 88%) was obtained as a pale
yellow oil.
Acknowledgements
Methyl 2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate (28)
Financial support for this work was provided by Griffith Univer-
sity, and the Eskitis Institute for Cell and Molecular Therapies,
Griffith University.
Triflic anhydride (163 mL, 0.97 mmol), 1,2-bis(diphenylpho-
sphinyl)ethane (472 mg, 1.10 mmol) and methyl N-benzoyl-O-
(triphenylmethylethyl)serinate (18) (300 mg, 0.64 mmol) were
reacted in dry CH2Cl2 (13 mL) according to the representative
procedure above. Compound 2843 (112 mg, 85%) was obtained as
a pale yellow oil. dH(400 MHz; CDCl3) 3.83 (3 H, s, CH3), 4.61
(1 H, dd, J 8.3 and 10.7, H-5), 4.71 (1 H, dd, J 8.3 and 8.3, H-5),
4.97 (1 H, dd, J 8.3 and 10.7, H-4), 7.40–7.44 (2 H, m, m-C6H5),
7.49–7.53 (1 H, m, p-C6H5), 7.98–8.00 (2 H, m, o-C6H5); m/z (ES+)
206.0803 (M + H+ C11H12NO3 requires 206.0812), 205.9 (M + H+,
52%).
Notes and references
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746 | Org. Biomol. Chem., 2009, 7, 739–746
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