Synthesis and isolation of 5,6-dihydro-4 H -1,3-oxazine hydrobromides by autocyclization of N -(3-bromopropyl)amides

Article abstract of DOI:10.1021/jo101955q

5,6-Dihydro-4H-1,3-oxazine hydrobromides have been synthesized by the nucleophilic autocyclo-O-alkylation of N-(3-bromopropyl)amides under neutral conditions in chloroform. It is found that electron-donating amide α-substituents influence the autocyclizat

Full text of DOI:10.1021/jo101955q

pubs.acs.org/joc
acetylcholine esterase inhibitors,10 choline acetyl transferase
Synthesis and Isolation of 5,6-Dihydro-4H-1,3-
Oxazine Hydrobromides by Autocyclization of N-(3-
Bromopropyl)amides
inhibitors,11 and cardenolide analogues.12 Recently, 1,3-
benzoxazines have also found applications as stimulus re-
sponsive quantum dots,13 molecular switches,14 and detectors.15
The 5,6-dihydro-4H-1,3-oxazine hydrobromide salts 2, on
the other hand, have received much lesser attention as
electrophilic synthons in organic transformations. This is
mainly because, unlike the relatively stable 1,3-oxazines (1)
which can be synthesized from a variety of starting materials
such as ketones,16 nitriles,17 azides,18 olefins,19 ketimines,20
amido alcohols,21 amido propylbromides,22 and amino
alcohols,23 the highly reactive salts 2 can only be synthesized
in situ by reacting oxazines 1with the desired acids (Scheme 1 A).
Under these conditions however, the yields of the salts 2 are
poor and they ring open to yield 3-hydroxypropylamide and
3-aminopropylesters (3).1 Hence, a method to synthesize and
isolate the salts 2 will have several applications.
Damodara N. Reddy and Erode N. Prabhakaran*
Department of Organic Chemistry, Indian Institute of Science,
Bangalore, India 560012.
eprabhak@orgchem.iisc.ernet.in
Received October 15, 2010
We envisioned that, if the amide carbonyl in amides 4 is
rendered sufficiently nucleophilic to undergo an autocyclo-
O-alkylation reaction (Scheme 1 B) under neutral condi-
tions, then the in situ generated hydrobromic acid can be
trapped by the resulting 1,3-oxazines (1) to yield the desired
salts 2. This may be best achieved in a nonpolar solvent such
as chloroform. In this endeavor, we synthesized the benza-
1
mide 4g (Table 1) and monitored its H NMR in CDCl3
5,6-Dihydro-4H-1,3-oxazine hydrobromides have been
synthesized by the nucleophilic autocyclo-O-alkylation
of N-(3-bromopropyl)amides under neutral conditions in
chloroform. It is found that electron-donating amide R-
substituents influence the autocyclization efficiency.
(60 mM) as a function of time. Indeed, 4g was converted
exclusively to 2g (Scheme 2), following first-order kinetics as
expected for an intramolecular nucleophilic cyclization reaction.
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(24) T1/2 were determined by following the time-dependent disappearance
of the triplet for -CH2-Br (in 4) at δ ≈ 3.40 ( 0.2 ppm and the simultaneous
growth of the triplet for -CH2-O- (in 2) at δ ≈ 4.60 ( 0.2 ppm in the 1H NMR
spectra.
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680 J. Org. Chem. 2011, 76, 680–683
Published on Web 12/21/2010
DOI: 10.1021/jo101955q
r
2010 American Chemical Society

Reddy and Prabhakaran
JOCNote
SCHEME 1. Synthesis of 1,3-Oxazine Hydrobromides 2
TABLE 1. Autocyclization of N-(3-Bromopropyl)amides 4
The reaction had a half-life (t1/2
)
24 of 97 h25 (32 °C). Notably,
the moisture-sensitive hydrobromide 2g, which was insolu-
ble in ether, was isolated from a mixture (56:44) of 2g and 4g
by simple trituration of the concentrated mixture with dry
ether.
There are no reports of such autocyclization of 4 to 2 under
neutral conditions,26 although the bromooxazinization27 of
amido γ-olefins have been reported. In fact, several benza-
mides (4) are known to be very stable in the absence of base in
solvents such as THF, acetonitrile, and ether. Hence, gen-
eralization of the current method will provide direct access to
a variety of synthons, 2, which are otherwise difficult to
isolate.1 In the current work we report the propensity of the
N-(3-bromopropyl)acetamides (4a-e, i), the benzamides (4f-h),
and the peptidylamides (4j-r), with electronically varying
amide R-substituents, to undergo autocyclo-O-alkylation
and form the salts 2a-r under neutral conditions in
chloroform.
The starting materials, amides (4a-r), were synthesized in
good yields by coupling the corresponding carboxylic acids
and anhydrides with 3-bromopropylamine28 5 (Scheme 3).
Time-dependent 1H NMR of the acetamides 4b-e revealed
that they underwent clean autocyclization to form the corre-
sponding 2-alkyl-5,6-dihydro-4H-1,3-oxazine hydrobro-
mides (2b-e, Table 1). The salts were easily isolated by
trituration of the mixtures with ether.
aT1/2’s were calculated from time-dependent 1H NMR studies.
c
bAmide 4 is unchanged after >100 h. Estimated t1/2
.
dIsolated yields
after ether wash. eYield based on 1H NMR.
SCHEME 2. Synthesis of 2g by Autocyclization of 4g
The t1/2 of autocycliation of 4b-e (Table 1) decreased in
the order (4b > 4c > 4d > 4e) of increase in electron density
on the R-carbon. Notably, 4e with the tert-butyl substituent
cyclized significantly faster than 4a-c which have enolizable
hydrogens at the R-carbon. Thus, the cyclization rate is
affected predominantly by the inductive effect of the R-
carbon substituents. The benzamides 4f-h cyclize more
slowly than the acetamides, but the electronic effects are
similar (Table 1). The formamide 4a remained stable and
unchanged due to the poor electron-donating ability of
hydrogen. Surprisingly, the autocyclization of the peptides,
including the R-disubstituted, R,β-bis(disubstituted) and
cyclic amides (4j-p) was extremely slow. Their rates de-
creased significantly with time, as the concentration of the
hydrobromide salts (2j-p) increased, implying the poor
nucleophilicity of their amide carbonyl oxygens. The
R-(Boc-NH-) substituent seems to be sufficiently electron
withdrawing to significantly decrease the autocyclization
rates of the peptidyl amides 4j-p. Hence, electron-donating
R-substituents on the amide are essential for the nucleophilic
autocyclo-O-alkylation of 4 to proceed at a reasonable rate.
Solution FTIR (CHCl3, 10 mM) spectral analysis of the
amides showed that the amide CdO stretch bands of 4j-p
(26) Rehlander Ber. 1894, 27, 2157.
(27) (a) Kapferer, P.; Vasella, A. Helv. Chim. Acta 2004, 87, 2764–2789.
(b) Nakoji, M.; Kanayama, T.; Okino, T.; Takemoto, Y. J. Org. Chem. 2002,
67, 7418–7423. (c) Kok, G. B.; van Phan, T.; von Itzstein, M. J. Carbohydr.
Chem. 2001, 20, 359–374.
(28) (a) Kazemekaite, M.; Bulovas, A.; Talaikyte, Z.; Railaite, V.;
Niaura, G.; Butkus, E.; Razumas, V. Tetrahedron Lett. 2008, 49, 6212–
ꢀ
6216. (b) Clave, G.; Bernardin, A.; Massonneau, M.; Renard, P.-Y.; Romieu,
A. Tetrahedron Lett. 2006, 47, 6229–6233.
J. Org. Chem. Vol. 76, No. 2, 2011 681

Reddy and Prabhakaran
JOCNote
SCHEME 3. Synthesis of N-(3-Bromopropyl)amides 4
Experimental Section
General Procedure for Synthesis of N-(3-Bromopropyl)-
amides. Method i. Under N2 atmosphere was added ethylchloro-
formate (ECF) (1.03 mmol) to a cold (-20 °C) solution of the
carboxylic acid (1 mmol) and N-methyl morpholine (NMM)
(1.5 mmol) in tetrahydrofuran (THF) (6 mL), and this mixture
was vigorously stirred. After 2 min of stirring, a solution of
3-bromopropylamine hydrobromide (1 mmol) in a mixture of
THF/DMF (1:4 - v/v) was added to the mixture followed by
NMM (2.5 mmol) and stirred. After 10 min the mixture was
warmed to 25 °C and stirred further until TLC indicated
complete consumption of the starting acid. THF was removed
under reduced pressure, and the resulting viscous solution was
diluted with water (5 mL) and thoroughly extracted with ethyl
acetate (15 mL). The combined organic extracts were washed
with saturated aqueous citric acid (5 mL) and saturated aqueous
sodium bicarbonate (NaHCO3) (5 mL) and were dried over
anhydrous sodium sulfate (Na2SO4) and concentrated to give a
residue, which was purified by silica gel (100-200 mesh) flash
column chromatograph using ethyl acetate/hexanes as eluting
solvents.
TABLE 2. Effect of Temperature on Autocyclization of 4q,r
Method ii. To a cooled (0 °C) suspension of 3-bromopropyl-
amine hydrobromide (1 mmol) and the acylchloride (1 mmol) in
methylene chloride (DCM) (5 mL) was slowly added triethyla-
mine (2 mmol), such that the temperature was maintained at
0 °C. After 10 min the mixture was warmed to 25 °C and stirred
further until TLC indicated the complete consumption of the
acylchloride. The mixture was diluted with DCM (5 mL) and
washed with water (5 mL), 1N HCl (5 mL), saturated NaHCO3
(5 mL) and dried over Na2SO4 and concentrated under vacuum
to give a residue, which was purified by silica gel flash column
chromatograph.
Method iii. To a cooled (5 °C) solution of 3-bromopropyl-
amine hydrobromide (1 mmol) and acetic anhydride (1 mmol)
in distilled water (1 mL) was slowly added sodiumbicarbonate
(2.5 mmol). The mixture was stirred at 5 °C for 10 min, extracted
with ethyl acetate (15 mL), dried over Na2SO4 and concentrated
to give a residue, which was purified by silica gel flash column
chromatograph.
N-(3-Bromopropyl)formamide (4a). Amide 4a was synthesized
by following the procedure in method i. Purification by silica gel
flash column chromatograph (EtOAc/hexane, 1:1) yielded the
desired product as a viscous oil (253 mg, 1.5 mmol, 50% yield).
(TLC - EtOAc, Rf = 0.27). IR (NaCl, neat): 3282, 3055, 2943,
2876, 1668, 1540, 1386, 1260 cm-1; IR (NaCl, 10 mM in CHCl3):
3445, 3014, 2866, 1689, 1509, 1392, 1216, 805, 786, 667 cm-1; 1H
NMR (400 MHz, CDCl3) δ: 8.20 (s, 1H), 5.95 (bs, 1H), 3.49-3.43
(m, 4H), 2.15-2.03 (m, 2H); 13C NMR (100 MHz, CDCl3) δ:
161.5, 36.8, 31.9, 30.5; HRMS m/z Calcd for C4H8BrNONa
187.9687, Found 187.9709.
aDetermined by time-dependent 1H NMR analysis. bYield based on
1H NMR.
appear at higher values (>1683 cm-1), similar to that for the
unreactive formamide 4a (1689 cm-1), than that for the
acetamides 4b-e (∼1672-1654 cm-1). The lower bond order
of the amide CdO in 4b-e than in peptides 4j-p suggested that
the electron-donating R-susbstituents probably facilitate the
stabilization of the amide in the more nucleophilic enolate
resonance form than do the electron-withdrawing substituents.
The β- and γ-(Boc-NH-)-substituted amides 4q and 4r,
however, underwent faster autocyclization reactions (Table 2,
entries 1, 4). The t1/2 of these reactions were halved upon
increasing the reaction temperature from 32 to 40 °C and
to 50 °C (Table 2). Thus, the rates of the autocyclization
reactions can be controlled by varying the reaction tempera-
ture. The temperature dependence of the t1/2 and the sig-
nificant difference in rates of autocyclization between 4i-p
and 4q, r, can have advantages for the design of peptides that can
undergo residue-selective cyclizations along the chain length.29
In summary, we have identified that N-(3-bromopropyl)-
amides undergo clean autocyclization reaction in chloro-
form, following first-order kinetics, to yield the 5,6-dihydro-
4H-1,3-oxazine hydrobromides. The progress of the reaction
N-(3-Bromopropyl)acetamide (4b). Amide 4b was synthesized
by following the procedure in method iii. Purification by silica
gel flash column chromatograph (EtOAc/hexane, 1:1) yielded
the desired product as a viscous oil (135 mg, 0.8 mmol, 76%
yield). (TLC - EtOAc, Rf = 0.33). IR (NaCl, neat): 3416, 3287,
3086, 2966, 2936, 2878, 1756 (weak), 1652, 1557, 1436, 1370,
1296, 1261 cm-1; IR (NaCl, 10 mM in CHCl3): 3455, 3014, 1672,
1
can be easily monitored in real time by H NMR. The
moisture-sensitive hydrobromide salts can be isolated simply
by trituration with dry ether. Electron-donating R-substitu-
ents on the amide facilitate the progress of the autocycliza-
tion reaction. The scope of the reaction has been expanded
by the synthesis of β- and γ-peptide-derived 1,3-oxazine
hydrobromides.
1
1602, 1520, 1437, 1368, 1221, 762, 667 cm-1; H NMR (300
MHz, CDCl3) δ: 6.01 (bs, 1H), 3.41 (t, J=6.6 Hz, 2H), 3.37 (q,
J=6.6 Hz, 2H), 2.05 (quin, J= .6 Hz, 2H), 1.98 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ: 170.8, 37.8, 32.0, 30.8, 22.9; HRMS
m/z Calcd for C5H10BrNONa 201.9843, Found 201.9849.
N-(30-Bromopropyl)-2,2-dimethylpropionamide (4e). Amide 4e
was synthesized by following the procedure in method ii. Purifica-
tion by silica gel flash column chromatography (EtOAc/hexane,
1:5) yielded the desired product as a viscous oil (234 mg, 1.2 mmol,
64% yield). (TLC - EtOAc, Rf = 0.71). IR (NaCl, neat): 3345,
(29) Dos Santos, S.; Chandravarkar, A.; Mandal, B.; Mimna, R.; Murat,
ꢁ
K.; Saucede, L.; Tella, P.; Tuchscherer, G.; Mutter, M. J. Am. Chem. Soc.
2005, 127, 11888–11889.
682 J. Org. Chem. Vol. 76, No. 2, 2011

Reddy and Prabhakaran
JOCNote
2964, 2931, 2871, 1640, 1534, 1481, 1438, 1367, 1298, 1211 cm-1
IR (NaCl, 10 mM in CHCl3): 3472, 3013, 2970, 1654, 1602, 1515,
1213, 795, 698, 668 cm-1; 1H NMR (400 MHz, CDCl3) δ: 5.88 (bs,
1H), 3.41 (t, J = 6.4 Hz, 2H), 3.38 (q, J=6.4 Hz, 2H), 2.08 (quin,
J =6.4 Hz, 2H), 1.18 (s, 9H); 13C NMR (100 MHz, CDCl3) δ:
178.7, 38.9, 38.1, 32.1, 31.0, 27.5; HRMS m/z Calcd for C8H16-
BrNONa 244.0313, Found 244.0316.
General Procedure for the Autocyclization and Purification of
2-Substituted-5,6-dihydro-4H-1,3-oxazine Hydrobromides. A so-
lution of the amide (4) in CHCl3 (60 mM) in a clean, dry, round-
bottomed flask was shaken in a constant temperature incubator
at 32 °C. The progress of the reaction was periodically mon-
itored (1H NMR). After completion of the reaction, CHCl3 was
removed under reduced pressure to get a thick residue, which
was triturated with cold, dry diethylether (3 ꢀ 4 mL). The
resulting insoluble precipitate was dried under vacuum to get
the desired 2-substituted-5,6-dihydro-4H-1,3-oxazine hydro-
bromides (2).
2-Ethyl-5,6-dihydro-4H-1,3-oxazine Hydrobromide (2c). Fol-
lowing the general ether-wash procedure, 2c was isolated from a
mixture of 4c (5%) and 2c (95%), as an oil (88 mg, 0.46 mmol,
88% yield). IR (NaCl, neat): 3447, 2984, 2948, 2925, 1671, 1655,
1541, 1288, 1275, 1084, 829 cm-1; IR (NaCl, 10 mM in CHCl3):
3019, 2968, 2654 (br), 2434, 1672, 1602, 1529, 1217, 1086, 695
cm-1; 1H NMR (300 MHz, CDCl3) δ: 12.81 (bs, 1H), 4.63 (t, J=
5.7 Hz, 2H), 3.66 (t, J=5.7 Hz, 2H), 2.84 (q, J=7.8 Hz, 2H), 2.21
(quin, J=5.7 Hz, 2H), 1.24 (t, J=7.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ: 176.7, 69.3, 38.1, 27.0, 18.8, 9.5; HRMS m/z
Calcd for C6H12NO 114.0919, Found 114.0937.
.
from a mixture of 4e (10%) and 2e (90%), as a hygroscopic solid
(86 mg, 0.39 mmol, 87% yield); mp=145-146 °C. IR (NaCl,
neat): 3468, 3418, 2977, 2941, 1656, 1510, 1297, 1191, 1050, 836
cm-1; IR (NaCl, 10 mM in CHCl3): 3018, 2961, 2820, 1652,
1
1499, 1293, 1049, 768 cm-1; H NMR (300 MHz, CDCl3) δ:
13.12 (bs, 1H), 4.68 (t, J = 5.4 Hz, 2H), 3.86 (q, J = 5.9 Hz, 2H),
2.23 (quin, J = 5.7 Hz, 2H), 1.42 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ: 181.2, 69.6, 39.3, 39.0, 27.1, 18.8; HRMS m/z Calcd
for C8H16NO 142.1232, Found 142.1232.
2-Phenyl-5,6-dihydro-4H-1,3-oxazine Hydrobromide (2g).
Following the general ether-wash procedure, 2g was isolated
from a mixture of 2g and 4g (53: 47%), to get 2g (56 mg, 56%
yield) as a hygroscopic solid; mp=136-137 °C. IR (KBr, neat):
3061, 2918, 1651, 1602, 1512, 1489, 1376, 1298, 1147 cm-1; 1H
NMR (400 MHz, CDCl3) δ: 13.08 (bs, 1H), 8.34-8.30 (m, 2H),
7.70-7.63 (m, 1H), 7.56-7.50 (m, 2H), 4.87 (t, J =5.3 Hz, 2H),
3.95-3.94 (m, 2H), 2.35-2.33 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ: 167.8, 135.7, 129.3, 129.0, 124.8, 69.8, 38.9, 19.1;
HRMS m/z Calcd for C10H12NO 162.0919, Found 162.0912.
Acknowledgment. We thank the Department of Science
and Technology for funding this work. D.N.R. thanks the
Council of Scientific and Industrial Research, India, for
Junior Research Fellowship.
Supporting Information Available: Experimental methods
and spectral data for all the amides 4 and the oxazine hydro-
bromides 2; time-dependent H NMR spectra of the amides;
1
2-(tert-Butyl)-5,6-dihydro-4H-1,3-oxazine hydrobromide (2e).
Following the general ether-wash procedure, 2e was isolated
kinetic data for the autocyclization reactions. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 76, No. 2, 2011 683