(Thio)urea-mediated benzoxazinone opening: Mild approach towards synthesis of o-(substituted amido)benzamides

Article abstract of DOI:10.1039/c3ra45903a

C-terminal activation of N-acylated o-aminobenzoic acids and their derivatives during coupling reactions with amines would often pose a challenge due to the formation of a benzoxazinone intermediate, which may resist reacting with amines. This communication reports a mild approach towards the installation of an amide bond via benzoxazinone ring opening utilizing Schreiner's (thio)urea organocatalyst. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c3ra45903a

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(Thio)urea-mediated benzoxazinone opening: mild
approach towards synthesis of o-(substituted
amido)benzamides†
Cite this: RSC Adv., 2014, 4, 7058
Received 17th October 2013
Accepted 21st November 2013
*
Roshna V. Nair and Gangadhar J. Sanjayan
DOI: 10.1039/c3ra45903a
www.rsc.org/advances
C-terminal activation of N-acylated o-aminobenzoic acids and their of anthranilic acid and their derivatives due to the intra-
derivatives during coupling reactions with amines would often pose a molecular cyclization of the benzamide oxygen, resulting in
challenge due to the formation of a benzoxazinone intermediate, trace or no coupling.2 Strategies meant either to avert its
which may resist reacting with amines. This communication reports formation in situ or to react it with amines have been attempted
a mild approach towards the installation of an amide bond via through heating the reactants at elevated temperatures3 and/or
benzoxazinone ring opening utilizing Schreiner's (thio)urea in the presence of bases.2b,c However, such drastic conditions
organocatalyst.
may cause quinazoline formation as well, owing to a second
cyclodehydration of the coupled product. Moreover, applying
such drastic conditions to amino acids may not be advisable
due to the possibility of epimerization.
Peptide coupling reactions oen encounter major hurdles
because of the formation of side products during carbonyl
activation of various amino acids, like N-carboxyanhydride,
diketopiperazine etc.1 1,3-benzoxazinones (Fig. 1) are a class of
heterocyclic side products obtained upon C-terminal activation
We have been interested for quite some time in the devel-
opment of foldamers containing the Ant–Pro reverse-turn motif
(Ant ¼ anthranilic acid, Pro ¼ proline), Fig. 1.4 The striking
feature of this motif is its robust 9-membered-ring intra-
molecular H-bonding network. Occasionally, the formation of a
benzoxazinone intermediate causes a drastic fall in the yield of
coupled products.5 Owing to the reduced reactivity of benzox-
azinones towards amine nucleophiles, we attempted different
conditions, such as heating the reaction mixture and under
microwave conditions. Unfortunately, these procedures led to
only partial conversion of the oxazinone into the product. Aer
extensive effort, we were successful in developing an efficient
method for coupling a range of isolated benzoxazinone inter-
mediates via nucleophilic ring-opening utilizing DBU (1,8-dia-
5
˚
zabicycloundec-7-ene) in DMF containing 4 A molecular sieves.
However, in a few cases, this method produced only meagre
yields of the coupled product. One such instance was the reac-
tion of 2-(2-azidopropan-2-yl)-2H-benzo[d][1,3]oxazin-4-one 1a,
Table 1 (isolated as the major by-product on activation of 2-(2-
azido-2-methylpropanamido)benzoic acid) with H-LPro-OBn to
obtain compound 2a. Scanty yields of the product isolated
under DBU-mediated opening conditions impelled us to explore
a carbonyl activation route to open the azlactone moiety. Hence,
we employed some lactone activating agents, such as Sc(OTf)3,
Ti(OiPr)4 etc., but none of the trials were rewarding (see ESI,
page S8,† Table 1).
Fig.
1 Schematic representation of the possible routes for the
synthesis of the Ant–Pro dipeptide unit. Note: numbering of the
positions of the benzoxazinone moiety is shown in pink.
Division of Organic Chemistry, National Chemical Laboratory, Dr Homi Bhabha Road,
Pune 411 008, India. E-mail: gj.sanjayan@ncl.res.in; Fax: +91-020-2590-2629; Tel:
+91-020-2590-2082
† Electronic supplementary information (ESI) available: General experimental
procedures, 1H, 13C, DEPT-135 NMR spectra and ESI mass spectra of all new
compounds are included. See DOI: 10.1039/c3ra45903a
Following the trend, we subsequently exploited the property
of explicit non-covalent double hydrogen-bonding donor-based
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Table 1 Organocatalytic ring opening of 2-(2-azidopropan-2-yl)-2H-
benzo[d][1,3]oxazin-4-one 1a (1 equiv.) with H-LPro-OBn (1.5 equiv.)
making polar solvents more preferable following the trend
DMSO > DCM > toluene. Strangely, the reaction failed to reach
completion in solvents like DMF, acetonitrile, THF etc., even
under a prolonged reaction time. The reaction optimisation
revealed 10 mol% of the catalyst in DMSO at room temperature
to be the best condition, providing the best yields. The reaction
was also attempted in water, which sluggishly completed in 48 h
at 25 ꢀC, affording a 67% yield of the product. However, a slight
reduction in the yield was observed with an elevated tempera-
ture. This examination substantiated the rate dependence of
the reaction on the solvent polarity, but that it was independent
of temperature.
Aer successful installation of the amide link between
H-LPro-OBn with benzoxazinone 1a, by applying similar reac-
tion conditions, we further explored the coupling of a range of
stable oxazinones that are oen isolated during oligopeptide
synthesis. Different 2-(aliphatic/aromatic) substituted-[1,3]-oxazi-
nones, like 6,7-diuoro-2-phenyl-substituted 1b, 2-nitrophenyl-
substituted 1c, etc. were subjected to (thio)urea mediated
opening, which provided good to quantitative yields of the
coupled products without the formation of any by-products (Table
2). The investigations conrmed that the stability of the oxazi-
Catalyst (mol%)
Solvent
Time (h)
Product (%)a,b
1
2
3
4
5
6
7
8
0
DMSO
DCM
Toluene
THF
24
36
36
48
48
48
24
48
24
0.5
24
24
0
10
10
10
10
10
10
10
5
76
65
30c
40c
36c
53
67
71
48
81
79
DMF
ACN
H2Od
H2O
9
DMSO
DMSO
DMSO
DMSO
10
11
12
10
10
15
a
b
Yield refers to the column-puried product. Unless specied, the none imparted no inuence on the coupling tendency, possibly
c
reaction was carried out at room temperature (25 ꢀC). Conversion
due to the efficient activation of the carbonyl functionality.
calculated from NMR of the crude reaction mixture (see ESI, page
According to earlier investigations on acylanthranils,16
d
S45–S47†). Reaction was carried out at 40 ꢀC.
having electron withdrawing groups at the 6th position or
positioning any electron decient group on the phenyl ring is
(thio)urea organocatalysis.6 Since its inception, rate enhance-
ments for a wide range of reactions, like the Michael reac-
Table
2 Comparison of the coupling of oxazinones 1a–e with
tion,7a–f Claisen rearrangements,7g,h Morita–Baylis–Hillman,7i–l
Diels–Alder reactions7m etc., have been observed. Amongst
them, Schreiner's N,N0-bis[(3-uoromethyl) phenyl]-based (thio)
urea has emerged as a very efficient catalyst. The requirement of
low catalyst loading,8 high competency, moderate binding
tendency to the basic sites (unlike Lewis acids),9 improved
enantioselectivity10 and possible structure diversication has
made it an easy choice for several reactions. The other features
include good air and water stability/compatibility and synthetic
accessibility.11 Moreover, Schreiner's (thio)urea is well known to
act as a modular catalyst in many organic reactions, like the
Strecker synthesis, Mannich reaction, Henry reaction, etc.,12 and
also in dynamic kinetic resolution of azlactones.13
H-LPro-OBn in DMSO
–R
–R1
–R2 Time (h) Conversion (%) Yield (%)a
2a
2b
H
F
H
F
24
36
100
92
81
70b
This desirable (thio)urea catalyst bears rigid hydrogen-
bonding sites between the positively polarized ortho-hydrogen
atom, the basic thiocarbonyl sulphur and the electron-decient
–CF3 substitution at the meta or para position of the phenyl
ring.14 It readily activates the carbonyl group of the substituted
2H-benzo[d][1,3]oxazin-4-one unit, involving the ortho CH bond
that binds with the oxygen (Lewis basic site) and facilitates
nucleophilic attack of the amine, preferably at the 4th position
of the benzoxazinone.
2c
H
H
H
H
9
100
100
97
75
2d
24
It was observed that the reaction of 1a with H-LPro-OBn
proceeded in a reasonable time period, furnishing good yields
of the product at room temperature with no racemisation.15 The
reaction was carried out in a range of solvents, like toluene,
DCM, acetonitrile, THF, DMF, DMSO and water, etc. (Table 1).
The rate of the reaction revealed a solvent polarity dependence,
2e
OiBu
H
48
52
91c
a
Unless specied, the reaction was carried out at 25 ꢀC with oxazinone
(1 equiv.) and H-LPro-OBn (1.5 equiv.). Yield calculated aer 8%
b
oxazinone recovery. c Yield calculated aer 48% oxazinone recovery.
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considered to disfavour o-acetamidobenzamide formation furnishing excellent yields to afford 2f and 2g, respectively. On
(required for the desired reaction). This is due to the fact that comparing primary and secondary amines, the reaction rate was
the introduction of electron withdrawing groups at the 6th observed to be faster for the primary amine i.e. propylamine. On
position would in turn increase the electrophilicity of the 2nd the other hand, the reaction of 1c with H-DVal-OMe provided a
position of the benzoxazinone, making it more susceptible good yield, furnishing up to 89% of the product 2i, but
towards nucleophile attack (undesirable reaction). On the other completion of the reaction needed 36 h. Steric hindrance
hand, the introduction of electron releasing groups at the same imparted by germinal dimethyl groups of H-Aib-OMe (a-ami-
position presumably enhances the electron density at the 2nd noisobutyric acid methyl ester) also affected the rate drastically,
position and would favour nucleophilic attack at the 4th posi- where 82% of the product was isolated from the slow reaction,
tion.16b Interestingly, activation by (thio)urea was shown to with only 60% conversion of the reactants into product 2h. The
selectively activate the carbonyl of the oxazinone moiety, reactivity of the amines is presumably negatively inuenced by
making the carbonyl carbon more electrophilic and thereby the methoxycarbonyl group. However, the smooth reactivity of
facilitating the desired coupling reaction, irrespective of the chiral (S)-phenylethylamine in 10 min revealed that the
electron density of the phenyl ring.
hindrance at the a-position didn't affect the reactivity at the 2nd
The reactivity pattern of different oxazinones that follows the position of the oxazinone, but imparted a drastic inuence on
order: 1c > 1a > 1d > 1b > 1e with amine H-Pro-OBn evidently the reaction time. Primary amines without any a-substitution,
supports our predictions (considering the completion time of like propylamine, proceeded to completion, affording a 97%
the reaction and the yield of the isolated product).
yield of the product 2j within a short duration of 3 min.
Proline is a very well known organocatalyst used in various
reactions that involve carbonyl activation as the key step.17
Thus, our next concern was to assess the role of proline in
Conclusions
catalysis. We therefore carried out a set of reactions with the In summary, we have developed an efficient strategy for the
selected stable oxazinone 1c and a series of different chiral/ ring opening of benzoxazinones by amines using Schreiner's
achiral amines and a few exible/constrained amino acids (thio)urea. This method provides a convenient route to Ant
(Table 3). Interestingly, the reaction of 1c with piperidine and (anthranilic acid) incorporated peptides, which are otherwise
(S)-phenyl-ethylamine proceeded rapidly towards completion, difficult to synthesise using the conventional method of
peptide coupling. By employing a mere 10% of the (thio)urea
catalyst, the reactions are found to furnish good-to-excellent
yields of the coupled products at ambient conditions. This
work extends the application of organocatalysis in the area of
Table 3 Comparison of the coupling of different amines with oxazi-
none 1c
peptide coupling.
General methods
Unless otherwise stated, all the chemicals and reagents were
obtained commercially. Dry solvents were prepared by the
standard procedures. Analytical Thin Layer Chromatography
was done on precoated silica gel plates (Kieselgel 60F254,
Merck). Unless otherwise stated, column chromatographic
purications were done with 100–200 Mesh Silica gel.
–R
Time (h)
0.5
Conversion (%)
100
Yield (%)a
94
2f
Synthetic Procedure for 2a–k: 1,3-bis(3,5-bis(triuoro-
methyl)phenyl)thiourea (10 mol%) was added to a solution of
oxazinone (1 equiv.) and amine (1.5 equiv.) in DMSO (1 mL). The
reaction was stirred and constantly monitored by TLC. Aer
maximum conversion of the oxazinones, water (2 mL) was added
to the reaction mixture. The product was extracted into DCM (3 ꢁ
5 mL) from the aqueous layer. The organic layers were pooled
together and washed with a KHSO4 solution, followed by brine.
The organic layer was then dried over Na2SO4 and was evaporated
in vacuo to afford the coupled product. The crude product was
then puried by column chromatography.
2g
2h
0.12
48
100
60
94
82b
89
2i
36
100
2j
0.05
100
97
Acknowledgements
RVN is thankful to CSIR, New Delhi, for a Senior Research
Fellowship. GJS thanks NCL-IGIB (New Delhi) for nancial
support.
a
Unless specied, the reaction was carried out at 25 ꢀC with oxazinone
(1 equiv.) and amine (1.5 equiv.). b Yield calculated aer 40% oxazinone
recovery.
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