Novel synthesis of 2,2-dialkyl-3-dialkylamino-2,3-dihydro-1H-naphtho[2,1-b]pyrans

Article abstract of DOI:10.1016/j.tetlet.2008.10.083

2,2-Dialkyl-3-dialkylamino-2,3-dihydro-1H-naphtho[2,1-b]pyrans were prepared from 2-naphthol, a secondary amine, and 3-hydroxy-2,2-dialkylpropanal in the presence of a catalytic amount of p-toluenesulfonic acid. This one-pot reaction involves retro-aldol

Full text of DOI:10.1016/j.tetlet.2008.10.083

Tetrahedron Letters 50 (2009) 51–54
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Tetrahedron Letters
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Novel synthesis of 2,2-dialkyl-3-dialkylamino-2,3-dihydro-1H-
naphtho[2,1-b]pyrans
Po-Jung Jimmy Huang a, T. Stanley Cameron b, Amitabh Jha a,
*
a Department of Chemistry, Acadia University, Wolfville, NS, Canada B4P 2R6
b Department of Chemistry, Dalhousie University, Halifax, NS, Canada B3H 4R2
a r t i c l e i n f o
a b s t r a c t
Article history:
2,2-Dialkyl-3-dialkylamino-2,3-dihydro-1H-naphtho[2,1-b]pyrans were prepared from 2-naphthol, a
secondary amine, and 3-hydroxy-2,2-dialkylpropanal in the presence of a catalytic amount of p-toluene-
sulfonic acid. This one-pot reaction involves retro-aldol disintegration of 3-hydroxy-2,2-dialkylpropanal
followed by formation of a Mannich base intermediate from 2-naphthol, a secondary amine, and formal-
dehyde (retro-aldol product). This Mannich base then disproportionates into a quinone methide interme-
diate and the secondary amine is regenerated. It then forms an enamine intermediate with 2,2-
dialkylacetaldehyde (another retro-aldol product). Finally, the quinone methide intermediate undergoes
electrocyclic ring closure with enamines to produce the title compounds.
Received 17 September 2008
Revised 14 October 2008
Accepted 16 October 2008
Available online 22 October 2008
Dedicated to Professor Kelvin K. Ogilvie on
his retirement from Acadia University
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
2-Naphthol
Naphthopyrans
3H-Benzo[f]chromenes
2,2-Dialkyl-3-dialkylamino-1,2-dihydro-
1H-naphtho[2,1-b]pyrans
Quinone methide
Microwave-assisted synthesis
Cyclization
3H-Naphtho[2,1-b]pyrans, also known as 3H-benzo[f]chrom-
enes, are well documented for their photochromic character.1–3
This characteristic leads to their application in transition lenses
which tint upon exposure to sunlight.4 Naphthopyrans are also
prevalent in numerous natural products with significant biological
and medicinal properties.5,6 They have been shown to exhibit po-
tent mutagenic,5 cytotoxic,5,6 anticancer,7–9 and antiproliferative10
activities. Hence, synthesizing novel naphthopyran derivatives of-
fers the possibility of uncovering new biological activities and
other applications are yet to be found.
Since this investigation primarily deals with novel procedures
for the synthesis of 2,3-dihydro-1H-naphtho[2,1-b]pyran deriva-
tives, it is imperative to review previously reported synthetic pro-
cedures which were found to generally lack simplicity and
satisfactory yields. 2,3-Dihydro-1H-naphtho[2,1-b]pyran was pre-
pared in 31% yield from 2-allyloxy-1-bromonaphthalene and AIBN,
using a modified stannane reagent;11 conventional Bu3SnH gave
only 17% yield.12 In a similar endeavor, 1-bromo-2-but-3-enyl-
oxy-naphthalene resulted in formation of 2-methyl-2,3-dihydro-
1H-naphtho[2,1-b]pyran as one of the products.13 Suzuki et al.
published the synthesis of 2,3-dihydro-1H-naphtho[2,1-b]pyran
in ꢀ70% yield from 2-allyloxy-1-iodonaphthalene using 9-BBN
and palladium dichloride.14 Use of phosphinic acid, AIBN and NaH-
CO3 on 2-allyloxy-1-iodonaphthalene leading to same product is
also known.15,16 Chow et al. discovered that singlet excited-state
proton transfer on 1-allyl-2-naphthols causes cyclization and re-
sults in formation of 2,3-dihydro-1H-naphtho[2,1-b]pyran in 13%
yield.17 In another electron transfer reaction, methylene blue-cata-
lyzed photodecarboxylation of 1-allyl-2-naphthoxy acetic acid led
to formation of 2-methyl-2,3-dihydro-1H-naphtho[2,1-b]pyran in
55% yield.18,19 2,3-Dihydro-1H-naphtho[2,1-b]pyran was also ob-
tained from 2-naphthol and acrylonitrile by a 6-step reaction se-
quence in low overall yield.20 Reaction of 2-naphthol and 3-
methylbut-2-enoyl chloride in nitrobenzene and a small amount
of anhydrous aluminum chloride led to formation of the corre-
sponding naphthopyranone derivative after 12 days.21 Various
dihydronaphthopyrans were prepared by synthetic manipulations
on the double bond of 3,3-dimethyl-3H-naphtho[2,1-b]pyran.22
A
multi-step synthesis of 2,3-dihydro-1H-naphtho[2,1-b]pyran from
2,3-dihydro-1H-naphtho[2,1-b]pyran-1-one involves sodium boro-
hydride reduction followed by a dehydration and di-imide reduc-
tion sequence.23 The same research article also reported the
* Corresponding author. Tel.: +1 902 585 1515; fax: +1 902 585 1114.
E-mail address: ajha@acadiau.ca (A. Jha).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.083

52
P.-J. J. Huang et al. / Tetrahedron Letters 50 (2009) 51–54
synthesis of 3-ethoxy-2,3-dihydro-3-methyl-1H-naphtho[2,1-
b]pyran from 2-naphthol, methyl iodide, and 1-(N,N-diethyl-
amino)butan-3-one in dry ethanol.23 Use of expensive Au(III) to
catalyze intramolecular carbon-carbon bond formation in 2-naph-
thyloxy-propyl triflate or mesylate ester led to formation of
2,3-dihydro-1H-naphtho[2,1-b]pyran in ꢀ90% yield.24 The group
subsequently reported Au(III)-catalyzed intramolecular cycloalky-
lation of 2-(2-naphthyloxymethyl)oxirane to 2,3-dihydro-1H-
naphtho[2,1-b]pyran-2-ol in 76% yield.25 Multiple step syntheses,
poor yields, formation of by-products, and/or use of expensive
reagents are some of the serious drawbacks of most of the proce-
dures described above.
In pursuit of molecules with novel carbon skeletons making use
of 2-tetralone and 2-naphthol analogs,26–31 our research group has
also developed novel procedures for the one-pot syntheses of 12H-
benzo[a]xanthenes26 and 2,2-dialkyl-2,3-dihydro-1H-naphtho[2,1-
b]pyrans27 from substituted ortho-hydroxy aromatic aldehydes
and 2,2-dialkyl-3-hydroxypropanals, respectively, with 2-tetralone
analogs under acidic conditions with high yields.
All compounds were completely characterized by spectroscopic
means. Compounds 1a,b,d–g, and 3a,b are new to chemical litera-
ture. The NMR data of series 1 compounds would bear substantial
resemblance to those of expected isomeric products 5 (Scheme 3,
vide infra), unequivocal support of their structure came from
X-ray crystal structures of representative compounds 1d and 1g
(Fig. 1A and B, respectively).36 As expected, compounds 1e and 1f
were obtained as diastereomeric mixtures with relatively low dia-
stereoselectivity (de 10–12%) which we wish to study in future.
We originally had expected to synthesize 2,2-dialkyl-1-dial-
kylamino-2,3-dihydro-naphtho[2,1-b]pyrans (5) using 2,2-disub-
stituted-3-hydroxypropanals, 2-naphthol, and cyclic secondary
amines utilizing a Mannich reaction-cyclization sequence. Instead,
we obtained 2,2-dialkyl-3-dialkylamino-2,3-dihydro-1H-naph-
O
O
O
N
R'
R'
R''
N
H
O
HO
OH
O
R"
OH N
Two synthetic approaches reported in the literature were found
to be most closely related to the present investigation.32-34 One in-
volved reaction of 2-naphthol Mannich bases and enamines to pro-
pTSA (cat.)
microwave
3a,b
4
duce
2,2-dialkyl-3-dialkylamino-2,3-dihydro-1H-naphtho[2,1-
simple method of
b]pyrans.32,33 The second one reported
a
Scheme 2. Microwave-assisted reaction of 3,3-dialkyl-2-morpholino-3,4-dihydro-
2H-naphtho[1,2-b]pyrans.
preparing
2,2-dialkyl-3-dialkylaminonaphtho[2,1-b]pyran-1-ols
from 2-hydroxy-1-naphthaldehyde and enamines.34 We herein
report a novel microwave-assisted synthesis of 2,2-dialkyl-3-dial-
kylamino-2,3-dihydro-1H-naphtho[2,1-b]pyrans
(1a–g)
from
Table 2
2-naphthol, a secondary amine and 3-hydroxy-2,2-dialkylpropanal
in the presence of a catalytic amount of pTSA.
Physical data of 3,3-dialkyl-2-morpholino-3,4-dihydro-2H-naphtho[1,2-b]pyran
(3a,b) and Mannich base 4a
No R0
R00
–NR2
3
4
The solvent-free microwave-assisted reaction (Scheme 1)
between 2-naphthol, 2,2-disubstituted-3-hydroxypropanals, and
cyclic secondary amines in the presence of catalytic amounts of
pTSA resulted in the formation of 2,2-dialkyl-3-dialkylamino-2,3-
dihydro-1H-naphtho[2,1-b]pyrans (1a–g) along with 2-naphthol
Mannich bases (2a–c).35 The physical data of seven reactions
involving 2-naphthol are indicated in Table 1.
% Yield mp (°C)
% Yield m.p (°C)
a
–CH3
–CH3
Morpholino 42
106–107 N.C.
Liquid
73–74
—
b
–CH2CH3 –CH2CH3 Morpholino 37
N.C.
N.C. = Obtained but not calculated.
Two reactions were performed using 1-naphthol as the starting
material in place of 2-naphthol. Two 3,3-dialkyl-2-morpholino-
3,4-dihydro-2H-naphtho[1,2-b]pyran analogs were synthesized
(Scheme 2). Physical data of these compounds are presented in
Table 2.
R
H
R
O
R
R
NH
N
OH
OH
OH
OH
R' R"
R' R"
NR2
R
R
R
R
O
NR2
OH
N
N
N
HNR2
OH O
OH
O
O
OH
+
pTSA (cat.)
microwave
1a-g
2a-c
2
1
5
Obtained
Expected
Scheme 1. Microwave-assisted reaction of 2,2-dialkyl-3-dialkylamino-2,3-dihy-
dro-1H-naphtho[2,1-b]pyrans.
Scheme 3. Expected and obtained products were shown side by side.
Table 1
Physical data of 2,2-dialkyl-3-dialkylamino-2,3-dihydro-1H-naphtho[2,1-b]pyrans (1a–g) and corresponding Mannich bases (2a–c)
No
R0
R00
–NR2
1
2
% Yield
mp (°C)
% Yield
mp (°C)
a
b
c
d
e
f
–CH3
–CH3
–CH3
–CH2CH3
–CH2CH3
–CH3
–CH3
–CH3
–CH3
–CH2CH3
–(CH2)3CH3
–C6H5
Pyrrolidino
Piperidino
Morpholino
Morpholino
Morpholino
Morpholino
72
45
57
57
47
48
60
153–155
101–103
50–53
140–142
102–104
Liquid
42
33
40
39
N.C.
N.C.
N.R.
86–88
88–90
114–116
N.R.
N.R.
N.R.
Liquid
N.C.
g
–CH2(CH2)3CH2–
Morpholino
N.C. = Obtained but not calculated; N.R. = Not recorded.

Po-Jung Jimmy Huang et al. / Tetrahedron Letters 50 (2009) 51–54
53
Figure 1. ORTEP diagrams of X-ray crystal structures of 1d (A) and 1g (B).
tho[2,1-b]pyrans (1a–g) as one of the products. In addition, 1-dial-
kylaminomethyl-2-naphthols (2) was invariably obtained in all
cases (Scheme 3).
formaldehyde will be more amenable to Mannich reaction while
enolizable 2,2-disubstituted acetaldehydes will be more so to the
formation of enamines. Under the employed reaction conditions,
the Mannich bases deaminated to quinone methides. Perycyclic
cycloaddtion between electron deficient quinone methide and
electron rich enamine resulted in 2,2-dialkyl-3-dialkylamino-2,3-
dihydro-1H-naphtho[2,1-b]pyrans (1a–g) with aromatization
being the driving force (Scheme 4).
To substantiate this mechanistic pathway, a pTSA-catalyzed
four-component reaction involving 2-naphthol, paraformaldehyde,
isobutyraldehyde, and morpholine (1 M equiv each) was carried
out under microwave-assisted conditions identical to the original
three component reaction. This indeed led to the formation of
2,2-dimethyl-3-morpholino-2,3-dihydro-1H-naphtho[2,1-b]pyran
(1c, 52%) and 1-morpholinomethyl-2-naphthol (2c, 43%). Reaction
of 2-naphthol, 2,2-dimethyl-3-hydroxypropanal, and morpholine
was also carried out using conventional conditions. The mixture
was dissolved in DMF and refluxed for 3 h. Compounds 1c and 2c
were obtained in 22% and 38% yields, respectively. Based on these
results, the microwave-assisted procedure was found to be a more
efficient method to synthesize 2,2-dialkyl-3-dialkylamino-2,3-
dihydro-1H-naphtho[2,1-b]pyrans.
In summary, the synthesis of novel 2,2-dialkyl-3-dialkylamino-
2,3-dihydro-1H-naphtho[2,1-b]pyrans from 2,2-disubstituted-3-
hydroxypropanals, 2-naphthol, and cyclic secondary amines was
achieved in moderate to good yields under controlled microwave
heating in the presence of pTSA. The overall mechanism of forma-
tion of the title compounds (1a–g) involves two disproportionation
steps (retro-aldol and deamination of Mannich bases) and a pericy-
clic cycloaddition step. A simpler pTSA-catalyzed four-component
reaction was also developed to produce the title compounds which
validated the proposed mechanism.
At the first instance, it appeared as if the product was formed
via a mechanism where the imminium ion formed by the reaction
of the amine and the aldehyde is attacked by nucleophilic hydroxyl
group of ambidentate 2-naphthol leading to a hemiaminal rather
than the nucleophilic C-1 carbon attacking the imminium ion
which would have resulted in a Mannich base, as initially expected.
A subsequent cyclization–dehydration–aromatization sequence of
the hemiaminal intermediate yielding the 2,2-dialkyl-3-dialkyla-
mino-2,3-dihydro-1H-naphtho[2,1-b]pyrans under acid catalyzed
SN2-type conditions also appeared reasonable. This mechanism,
however, does not explain the formation of Mannich base side
products 2a–c. Presence of formaldehyde (or its equivalent) is
mandatory for the formation of these side products. This led us
to speculate if 2,2-disubstituted-3-hydroxypropanals underwent
retro-aldol disproportionation to formaldehyde and 2,2-disubsti-
tuted acetaldehyde in situ. Formaldehyde (a non-enolizable alde-
hyde) is known to give facile reaction with 2-naphthol to
produce Mannich bases (2) in the presence of secondary
amines.30–32 This evidence of retro-aldol disproportionation led
to a reassessment of the mechanism for the formation of com-
pounds 1 as shown in Scheme 3. A report by Strandtmann
et al.32 described the formation of 2,2-dialkyl-3-dialkylamino-
2,3-dihydro-1H-naphtho[2,1-b]pyrans from 2-naphthol Mannich
bases and enamines via deamination followed by cycloaddition.
Based on this report, it became apparent that the retro-aldol break-
down products of 2,2-disubstituted-3-hydroxypropanals, namely,
formaldehyde and 2,2-disubstituted acetaldehydes, met different
fates resulting in facile formation of 2-naphthol Mannich bases
and enamines, respectively. This is expected as non-enolizable
H
N R
R
N
R
R
N
R
H
pTSA H
H
H
N
H
R
R
R
OH
OH2
O
O
O
R
N
H
R
N
R
N
R
R
H
R
HN
OH
R
N
R
H
R
H
O
R
OH
O
O
O
-HNR2
Scheme 4. Most plausible mechanism of formation of 2,2-dimethyl-3-dialkylamino-2,3-dihydro-1H-naphtho[2,1-b]pyrans.

54
P.-J. J. Huang et al. / Tetrahedron Letters 50 (2009) 51–54
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The authors thank the Natural Sciences and Engineering Re-
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.10.083.
29. Jha, A.; Padmanilayam, M. P.; Dimmock, J. R. Synthesis 2002, 463–465.
30. Jha, A.; Paul, N. K.; Trikha, S.; Cameron, T. S. Can. J. Chem. 2006, 84, 843–853.
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35. In a typical procedure, a mixture of 1- or 2-naphthol (0.01 mol), an appropriate
b-hydroxypropionaldehyde (0.0105 mol), and a secondary amine (0.0105 mol)
with catalytic amount of p-toluenesulfonic acid (pTSA) were reacted under
neat microwave conditions (CEM Discover S-Class) in a closed vessel at 190 °C
for 5 min. The crude product was purified by column chromatography (silica
gel mesh size 230–400; eluent 5–10% MeOH/DCM). Data for a representative
compound is presented here. Compound 1a: Yield: 45%; mp: 101–103 °C. 1H
NMR (300 MHz; CDCl3): d 1.22 (s, 3H, CH3), 1.26 (s, 3H, CH3), 1.81–1.85 (m, 4H,
2 ꢁ –CH2), 2.94 (d, J = 5.4 Hz, 2H, ArCH2), 3.00–3.05 (m, 2H, NCH2a), 3.10–3.15
(m, 2H, NCH2b), 4.77 (s, 1H, OCHN), 7.13 (d, J = 9.0 Hz, 1H, Ar-H), 7.37 (t,
J = 7.8 Hz, 1H, Ar-H), 7.52 (t, J = 7.8 Hz, 1H, Ar-H), 7.67 (d, J = 8.7 Hz, 1H, Ar-H),
7.81 (d, J = 8.7 Hz, 2H, Ar-H). 13C NMR (75 MHz; CDCl3): d 23.48, 25.19, 27.98,
33.48, 39.64, 49.16, 95.69, 113.15, 119.10, 122.24, 123.24, 126.52, 128.00,
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128.80, 129.19, 133.60, 153.13. IR (KBr; mmax): 3060, 2964, 2871, 1623, 1468,
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