Retro-Mannich reactions of 3-alkyl-3,4-dihydro-2H-1,3-benz[e]oxazines and the synthesis of axially chiral resorcinarenes

Article abstract of DOI:10.1016/S0040-4039(03)00393-9

Intermediates involved in the conversion of 3-alkyl-3,4-dihydro-2H-1,3-benz[e]oxazines into 2-N,N-dialkylaminomethylphenol derivatives, using morpholine and other high boiling secondary amines, have been identified and characterised. Additional experiments have established the involvement of o-quinone methide intermediates in the retro-Mannich reactions. Axially chiral resorcinarenes have been prepared by utilising the exchange reactions.

Full text of DOI:10.1016/S0040-4039(03)00393-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2965–2970
Retro-Mannich reactions of
3-alkyl-3,4-dihydro-2H-1,3-benz[e]oxazines and the synthesis of
axially chiral resorcinarenes
Philip C. Bulman Page, Harry Heaney,* Matthew J. McGrath, Edward P. Sampler and
Robert F. Wilkins
Department of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, UK
Received 8 January 2003; revised 28 January 2003; accepted 7 February 2003
Abstract—Intermediates involved in the conversion of 3-alkyl-3,4-dihydro-2H-1,3-benz[e]oxazines into 2-N,N-dialkyl-
aminomethylphenol derivatives, using morpholine and other high boiling secondary amines, have been identified and character-
ised. Additional experiments have established the involvement of o-quinone methide intermediates in the retro-Mannich reactions.
Axially chiral resorcinarenes have been prepared by utilising the exchange reactions. © 2003 Elsevier Science Ltd. All rights
reserved.
The chemistry of 3-alkyl-3,4-dihydro-2H-1,3-benz[e]-
oxazines, has been studied in some detail.1–8 Acid-
catalysed hydrolyses that result in the formation of
secondary amines by loss of formaldehyde,2,5 undoubt-
edly result from initial fragmentations to iminium ions.
The reductive cleavage of cyclic aminol ethers, including
3-alkyl-3,4-dihydro-2H-1,3-benz[e]oxazines, for exam-
ple using formic acid,7 also involves iminium ion interme-
diates. Although iminium ion involvement was not
discussed, such an intermediate is implicated in the
reaction that occurred when 3,8-dimethyl-3,4-dihydro-
2H-1,3-benz[e]oxazine and 2,4-dimethylphenol were
mixed and melted at 25°C and which resulted in the
formation of a tertiary amine in 87% yield.4 Fragmenta-
tion of the aminol ether moiety to an iminium ion using
other electrophiles provides routes to variously function-
alised phenols. More recent results have focused on
reactions using aprotic conditions. Thus, the interaction
of dichlorodimethylsilane with 3-benzyl-6,8-dichloro-
3,4-dihydro-2H-1,3-benz[e]oxazine in the presence of
2-methylfuran gave a tertiary amine in 94% yield.6
Similarly, a reaction in which 3,4-dihydro-3,6-dimethyl-
2H-1,3-benz[e]oxazine (1) was allowed to react with
methyltrichlorosilane in the presence of N-methylindole,
shown in Eq. (1), gave the product 2†,‡ in 72%
yield and when 3,4-dihydro-3,8-dimethyl-2H-1,3-benz-
[e]oxazine was allowed to interact with methyltri-
chlorosilane in the presence of N-methylindole the
expected product, N-(2-hydroxy-3-methylbenzyl)-N-
methyl-(1-methyl-3-indolylmethyl)amine, was obtained
in 83% yield.
† New compounds have been fully characterised by elemental analysis
or by accurate mass measurement of the molecular ion by high
resolution mass spectrometry and by spectroscopic methods includ-
ing appropriate 1H and 13C NMR studies on homogeneous material
and by infrared measurements.
‡ m/z (M+) 294.1728, C19H22N2O requires 294.1732: lH 400 MHz
(CDCl3) 2.24 (s, 3H, Me), 2.27 (s, 3H, Me), 3.74 (s, 2H), 3.77 (s, 3H,
Me), 3.79 (s, 2H), 6.73 (d, 1H, J=8 Hz), 6.79 (d, 1H, J=1.6 Hz),
6.95 (m, 1H), 7.02 (s, 1H), 7.16 (m, 1H), 7.23 (m, 1H), 7.31 (d×t,
1H, J=8.0 and 0.8 Hz), and 7.66 (d×t, 1H, J=8.0 and 1.2 Hz) ppm:
lC 100 MHz (CDCl3) 20.48 (Me), 32.77 (Me), 41.35 (Me), 51.55
(CH2), 60.46 (CH2), 109.31 (CH), 109.83 (CH), 115.70 (CH), 118.91
(CH), 119.43 (CH), 121.78 (CH), 121.84 (CH), 127.90 (C), 128.05
(C), 128.86 (CH), 128.93 (CH), 129.00 (CH), 136.94 (C), and 155.60
(C) ppm.
Keywords: heterocycles; aminol ethers; o-quinone methides; axially
chiral resorcinarenes.
* Corresponding author. Fax: 44 + 1509 223926; e-mail: h.heaney@
lboro.ac.uk
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00393-9

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However, the fragmentation and exchange reactions
that involve heating the 3-alkyl-3,4-dihydro-2H-1,3-
benz[e]oxazines with an excess of morpholine that
result in the formation of N-o-hydroxybenzyl morpho-
line derivatives, exemplified in Eq. (2), are much less
well known.9 The latter reactions are carried out in the
absence of electrophilic reagents that are presumably
required for the generation of iminium ions. In an
earlier study we converted a diastereoisomerically pure
resorcin[4]arene derived tetramethoxytetrakis(2-N-a-
methylbenzyl-3,4-dihydro-2H-1,3-benz[e]oxazine) into
an axially chiral non-racemic derivative, in an overall
yield of 33% for the four reactions, by heating the
compound in an excess of morpholine for 24 h in order
to remove the chiral auxiliary.10 The high yielding
thermally induced exchange reactions, for example of
1-N,N-dimethylaminomethyl-2-naphthol with morpho-
line and piperidine,11 may be related and have been
suggested to proceed by Michael addition of the sec-
ondary amine to a quinone methide.12 The involvement
of a quinone methide has been implicated further in
thermal reactions of 1-N,N-dimethylaminomethyl-2-
naphthol with enamines, such as 1-N-pyrrolidinylcyclo-
hexene, and which resulted in the isolation of
1,2-naphthopyran derivatives after treatment with
water.13,14 The capture of other quinone methides by
morpholine has also been reported.15,16 o-Quinone
methides have also been generated photochemically
from Mannich bases derived from phenols including
2-naphthol.17 o-Hydroxybenzyl ethers,18,19 o-[(1-alkyl-
thio)alkyl]phenols,20 and 2-phenyl-4H-1,3,2-benzodi-
oxaborin21 also have been shown to provide valuable
routes to o-quinone methides. Recent studies include a
computational analysis of o-quinone methide towards
the prototype nitrogen-, oxygen-, and sulfur-centred
nucleophiles, the role of hydrogen bonding and solvent
effects,22 and the preparation of differentially o-preny-
lated phenols.23 Michael reactions with amines and
sulfides, including amino acids and glutathione, have
also been studied.24 We now report the results of a
series of experiments designed to delineate the possible
reaction pathways involved in the reactions of
3-alkyl-3,4-dihydro-2H-1,3-benz[e]oxazines with sec-
ondary amines together with a series of retro-Mannich
reactions including examples that give axially chiral
resorcinarenes.
Because of our earlier work, our initial choice of a
model compound for the present study was 6-methyl-3-
[(1R)-1-phenylethyl]-3,4-dihydro-2H-1,3-benz[e]oxazine
3, which was prepared in 70% yield by the interaction
of p-cresol with (R)-(+)-a-methylbenzylamine and
paraformaldehyde in methanol together with a catalytic
amount of potassium hydroxide. When the compound
3 was heated under reflux with an excess of morpholine
for 30 min, and then excess morpholine removed under
high vacuum, we were able to isolate the unstable
aminal 4§ in an almost quantitative yield. Although the
1H NMR spectrum was relatively uninformative the 13
C
NMR spectrum was diagnostic. Chromatography of
the aminal 4 on silica gel resulted in its quantitative
conversion into the secondary amine 5¶, which was also
(2)
§ wmax: 2960, 2852, 1599, 1499, 1452, 1116, and 867 cm−1: lC 100 MHz (CDCl3) 20.42 (Me), 23.29 (Me), 50.39 (CH2), 52.05 (CH2), 57.28 (CH),
67.06 (CH2), 81.71 (CH2), 116.13, 121.43 (C), 126.50 (CH), 127.55 (CH), 128.12 (C), 128.81 (CH), 128.88 (CH), 129.09 (CH), 143.48 (C), and
155.78 (C) ppm.
¶ m/z (M+) 241.14694, C16H19NO requires 241.14666: wmax: 3289, 2967, 1599, 1498, 1252, and 700 cm−1: lH 400 MHz (CDCl3) 1.44 (d, 3H, J=7.5
Hz), 2.21 (s, 3H, Me), 3.73 (d, 1H JAB=14.2 Hz), 3.77 (d, 1H, JBA=14.2 Hz), 3.78 (q, 1H, J=7.5 Hz), 6.69 (d, 1H, J=8 Hz), 6.73 (d, 1H, J=1.6
Hz), 6.94 (d×d, 1H, J=8 and 1.6 Hz) and 7.26–7.39 (m, 5H) ppm: lC 100 MHz (CDCl3) 14.2 (Me), 23.38 (Me), 50.36 (CH2), 57.24 (CH), 116.11
(CH), 122.03 (C), 126.94 (CH), 128.41 (CH), 128.48 (C), 128.90(CH), 129.22 (CH), 129.35 (CH), 140.99 (C), and 155.99 (C) ppm.

P. C. B. Page et al. / Tetrahedron Letters 44 (2003) 2965–2970
2967
Scheme 1. Reagents and conditions: (i) morpholine, reflux, 30 min, 99%; (ii) morpholine, rt, 3 weeks; (iii) silica gel, 100%; (iv)
morpholine, reflux, 12 h, 85%; (v) morpholine, reflux 24 h, 51%.
isolated by heating the benzoxazine 3 under reflux in
a mixture of ethanol and aqueous hydrochloric acid
(5 M). Both the aminal 4 and the secondary amine 5
were converted into 4-methyl-2-N-morpholinyl-
methylphenol 6 in ca. 85% yield when they were
heated under reflux in morpholine for 12 h. 6-Methyl-
3-[(1R)-1-phenylethyl]-3,4-dihydro-2H-1,3-benz[e]-
oxazine 3 gave the tertiary amine 6 in 51% yield
using similar reaction conditions. It is interesting to
note that after a sample of the aminal 4 was stored
at room temperature for 3 weeks it was reconverted
was heated under reflux in morpholine (82%), or with
secondary amines with higher boiling points than
morpholine such as piperazine (58% yield), or di-n-
butylamine (78% yield) (Eqs. (3)–(5)), but not when
the Mannich base 7 was heated under reflux in pipe-
ridine. The boiling point of piperidine is 106°C
whereas that of morpholine is 129°C.
We have also carried out experiments with derivatives
of the Mannich base 7. The amine 7 was converted
into its quaternary methiodide 8 in 99% yield. When
the quaternary salt 8 was stirred with morpholine at
room temperature for 12 h the amine 6 was isolated
in 85% yield. Protection of the phenolic hydroxyl
group in 7 as the t-butyldiphenylsilyl (TBDPS) ether
gave the compound 9 in 65% yield and 9 was con-
verted in essentially quantitative yield into the quater-
nary methiodide 10. When the compound 9 was
heated under reflux in morpholine for 12 h it was
recovered in 82% yield. A similar result was obtained
when using the quaternary salt 10. In neither experi-
ment did we detect any product that resulted from
direct amine exchange although 4-methyl-2-N-mor-
pholinylmethylphenol 6 was formed in 85% yield
when the quaternary methiodide 10 was heated under
reflux in morpholine for 36 h. We reasoned that the
amine 6 resulted from the addition of morpholine to
into the benzoxazine
3
and morpholine. N,N-
Dimethylbenzylamine does not undergo an exchange
reaction when heated under reflux in morpholine for
12 h. These results (Scheme 1) suggest that the inter-
mediates 4 and 5 were converted thermally into 4-
methyl-o-quinone methide which was captured by
morpholine.
We speculated that the reason why morpholine had
been chosen most frequently as the secondary amine
with which to carry out the exchange reactions is
related to the temperature at which o-quinone
methides are generated from the Mannich bases
derived from phenols.11,15,16 We found, for example,
that products from exchange reactions were obtained
when 2-N,N-dimethylaminomethyl-4-methylphenol
7

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P. C. B. Page et al. / Tetrahedron Letters 44 (2003) 2965–2970
Scheme 2. Reagents and conditions: (i) TBDPSCl, Et3N, DMAP, DCM, 65%; (ii) methyl iodide, Et2O, 24 h, 99%; (iii) morpholine,
rt, 12 h, 85%; (iv) piperidine, TBAF, rt, 12 h, 81%; (v) morpholine, TBAF, rt, 12 h, 100%.
a quinone methide following slow desilylation of the
quaternary methiodide 10 induced by iodide ions. The
quaternary salt 10 was therefore stirred with an
excess of morpholine containing TBAF at room tem-
perature for 12 h after which time the amine 6 was
isolated in a quantitative yield. When piperidine was
used in place of morpholine in a reaction with the
quaternary salt 10, 4-methyl-2-N-piperidinylmethyl-
phenol 11 was isolated in 81% yield. Thus, the
involvement of a mechanism involving an o-quinone
methide is supported by the results of the experiments
shown in Scheme 2.
amine and 2-hydroxy-5-methyl-N,N-dimethylbenzyl-
amine under reflux in xylene with 1-morpholino-
cyclopentene, followed by a hydrolytic work-up, we
obtained 2-(2-hydroxy-5-methylbenzyl)cyclopentanone
12 in 40 and 34% yields, respectively. Although we
did not isolate a cyclo adduct in those reactions,
spectroscopic data obtained from crude reaction mix-
tures indicated the presence of a small amount of a
cyclic aminol.
Finally, the C4 symmetric chiral non-racemic (R,S)-
diastereoisomer 16 was prepared from the achiral C4v
symmetric resorcinarene 13 as shown in Scheme 3,
using the protocols outlined previously.10 When the
compound 16 was heated under reflux in morpholine
it was converted into the chiral non-racemic (S)-mor-
pholino-resorcinarene derivative 17** in 73% yield.
Thus, the product 17 was obtained in four steps, each
of which involved four identical reactions, in an over-
all yield of 47% starting from the resorcinarene 13. In
a similar reaction the chiral non-racemic (S)-tetra-
We have also studied reactions of potential quinone
methide precursors with enamines. When the quater-
nary salt 10 was heated for 48 h under reflux in
tetrahydrofuran in the presence of TBAF and 1-N-
morpholinocyclopentene, 2-(2-hydroxy-5-methylbenzyl)-
cyclopentanone
yield after a hydrolytic work-up, as shown in Eq. (6).
12ꢀꢀ
was
isolated
in
87%
When we heated 2-hydroxy-5-methyl-N-methylbenzyl-
(6)
ꢀꢀ m/z (M+) 204.11513, C13H16O2 requires 204.11503: wmax: 3364, 2961, 2873, 1718, 1611, 1510, 1262, 1157, 1125, and 814 cm−1: lH 400 MHz
(CDCl3) 1.31 (m, 1H), 1.47 (m, 1H), 1.80–1.90 (m, 2H), 2.08–2.22 (m, 2H), 2.27 (s, 3H), 2.40 (m, 1H), 2.48 (m, 1H), 2.77 (d×d, 1H, J=12.5
and 5.6 Hz), 2.91 (d×d, 1H, J=12.5 and 5.6 Hz), 6.78 (d, 1H, J=8.0 Hz), 6.87 (m, 1H), and 6.93 (d×d, 1H, J=8.0 and 1.6 Hz) ppm: lC 100
MHz (CDCl3) 20.89 (CH2), 21.27 (Me), 29.34 (CH2), 29.74 (CH2), 37.99 (CH2), 52.12 (CH), 117.29 (CH), 126.22 (C), 128.80 (CH), 129.72 (C),
132.14 (CH), 152.50 (C) and 224.58 ppm.
** Mp 146–148°C: [h]2D3=−30 (c 0.92, CHCl3): Found: C, 80.64; H, 6.95; N, 3.50%; C84H100N4O12 requires C, 80.99; H, 7.07; N, 3.63%: m/z (FAB)
(MH+) 1357.7466, (M+) 1356.7407, (MH+) requires 1357.7416, (M+) requires 1356.7338: wmax: 3423, 2933, 2852, 2361, 1455, 1117 cm−1: lH 400
MHz (CDCl3) 2.04–2.35 (m, 8H), 2.47–2.77 (m, 24H), 3.43 (s, 12H), 3.61–3.77 (m, 24H), 4.61 (t, 4H, J=7.4 Hz), 6.86 (s, 4H) and 7.05–7.25 (m,
20H) ppm: lC 100 MHz (CDCl3) 34.62 (CH2), 35.61 (CH), 38.01 (CH2), 52.83 (CH2), 55.26 (CH2), 61.09 (Me), 66.77 (CH2), 112.66 (C), 125.47
(CH), 125.70 (CH), 127.37 (C), 128.08 (C), 128.19 (CH), 128.42 (CH), 142.78 (C), 154.14 (C) and 154.83 (C) ppm.

P. C. B. Page et al. / Tetrahedron Letters 44 (2003) 2965–2970
2969
Scheme 3. Reagents and conditions: (i) N,N-bis(methoxymethyl)-N-(R)-(+)-a-methylbenzylamine, EtOH, D, 12 h, 83% R=H; (ii)
THF, −78°C, n-BuLi (5 equiv.), then MeOTf (5 equiv.), then to rt, 94% R=Me; (iii) HCO2H, D, 12 h, 83%; (iv) morpholine, D,
48 h, 73%.
kis(benzoxazine) derivative 18 was prepared from the
analogue of the compound 16 after removal of the
chiral auxiliary by hydrogenolysis using hydrogen in
the presence of palladium hydroxide followed by refor-
mation of a tetrakis(benzoxazine) by treatment with
formaldehyde. The enantiomer 18 was heated under
reflux in morpholine and gave the related chiral non-
racemic morpholino-resorcinarene derivative 19 in 74%
yield. The final step is shown in Eq. (7) in which the
axially chiral (S)-enantiomer was converted into the
axially chiral (R)-product.
In summary we have established the nature of the
intermediates involved in the fragmentation-exchange
reactions of 3-alkyl-3,4-dihydro-2H-1,3-benz[e]oxazines
and made use of the processes in the synthesis of the
resorcinarene derivatives 17 and 19, both of which
possess only axial chirality.

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