A convenient one-pot synthesis of 2,2-dialkyl-2,3-dihydro-1H-naphtho[2,1-b] pyrans

Article abstract of DOI:10.1055/s-2007-992380

This work describes a convenient one-pot procedure for the synthesis of 2,2-disubstituted 2,3-dihydro-177-naphtho[2,1-b]pyrans {i.e. 2,2-disubstituted 1H-benzo[f]chromans} by the reaction of 2-tetralones and α,α- disubstituted β-hydroxy propionaldehydes under acidic conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-992380

LETTER
3127
A Convenient One-Pot Synthesis of 2,2-Dialkyl-2,3-dihydro-1H-naphtho[2,1-
b]pyrans
S
ynthesis of 2,2-D
m
ialkyl-2,3-dihydro-1
i
H
-na
p
t
htho[2,
a
1-
b
]pyransbh Jha,* Po-Jung Jimmy Huang, Chandrani Mukherjee, Nawal K. Paul
Department of Chemistry, Acadia University, Wolfville, NS, B4P 2R6, Canada
Fax +1(902)5851114; E-mail: ajha@acadiau.ca
Received 28 August 2007
material, 2-methyl-2,3-dihydro-1H-naphtho[2,1-b]pyran
Abstract: This work describes a convenient one-pot procedure for
the synthesis of 2,2-disubstituted 2,3-dihydro-1H-naphtho[2,1-
b]pyrans {i.e. 2,2-disubstituted 1H-benzo[f]chromans} by the reac-
tion of 2-tetralones and a,a-disubstituted b-hydroxy propionalde-
hydes under acidic conditions.
was obtained as one of the products.5c A similar example
starting from 2-allyloxy-1-iodonaphthalene involved use
of 9-BBN and palladium-catalyzed intramolecular cross-
coupling reaction.5d Another related reaction on 2-allyl-
oxy-1-iodonaphthalene using phosphinic acid, AIBN, and
NaHCO3 is also known.5e,f Photoexcitation of 1-allyl-2-
naphthols resulted in formation of 2,3-dihydro-1H-naph-
tho[2,1-b]pyran in 13% yield among several byproducts.5g
2,3-Dihydro-1H-naphtho[2,1-b]pyran was also obtained
from 1-(3-hydroxypropyl)naphthalen-2-ol by intramolec-
ular cyclization in low yields.5h,i A multistep synthesis of
2,3-dihydro-1H-naphtho[2,1-b]pyran from 2,3-dihydro-
1H-naphtho[2,1-b]pyran-1-one following a reduction, de-
hydration, and hydrogenation sequence is also known.5j In
an electron-transfer reaction, methylene blue catalyzed
photodecarboxylation of 1-allyl-2-naphthoxy acetic acid
led to formation of 2-methyl-2,3-dihydro-1H-naph-
tho[2,1-b]pyran in 55% yield.5k,l Impressive results were
reported by Sih and He5m who synthesized 2,3-dihydro-
1H-naphtho[2,1-b]pyran in 90% yield by expensive
Au(III)-catalyzed C–C bond formation of 2-naphthyloxy-
propyl triflate or methane sulfonate ester. In a related en-
deavor, the same group reported Au(III)-catalyzed
intramolecular cycloalkylation of 2-(2-naphthyloxymeth-
yl)oxirane to 2,3-dihydro-1H-naphtho[2,1-b]pyran-1-ol
in 89% yield.5n All these procedures suffer from draw-
backs such as multiple step syntheses, poor yields, signif-
icant amounts of byproducts, and/or use of expensive
reagents.
Key words: naphthopyran, aromatization, cyclizations, fused-ring
systems, alkylation, rearrangements
Naphtho[2,1-b]pyrans, also known as 1H-ben-
zo[f]chromenes, are well known for their photochromic
properties.1 This property is the result of a facile electro-
cyclic pyran ring opening to yield a mixture of yellow- or
purple-colored geometrical isomers that gradually cyclize
back to the colorless pyran ring upon removal of the
source of irradiation:1 leading to their importance in pho-
tochromic lenses which darken upon exposure to sun-
light.2 Furthermore, naphthopyrans are prevalent in
numerous natural products with significant biological and
medicinal properties.3 Hence, the syntheses of naphthopy-
rans are of importance as they are of value for a variety of
applications.
Several synthetic approaches to naphthopyrans have been
described but they generally lack simplicity and satisfac-
tory yields. Some methodologies for preparing naphtho-
pyrans with photochromic properties4 involve multistep
strategies initiating from chromanones4a or via Grignard
reactions on benzocoumarins followed by dehydration.4b
Other methods involve the Claisen rearrangement of pro-
pargyl aryl ethers obtained in situ from reaction of a,a-
disubstituted propargyl alcohols with phenols under acid-
ic conditions.4c–g In some reports, catalysts like pyridini-
um p-toluenesulfonate have been employed to improve
the yield.4
It is quite clear from the above discussion that simple and
cost-effective synthesis of 2,3-dihydro-1H-naphtho[2,1-
b]pyran-type compounds has thus far proved elusive. We
report herein a convenient and one-pot synthesis of 2,3-di-
hydro-1H-naphtho[2,1-b]pyrans 4a–o starting from a,a-
disubstituted b-hydroxy propionaldehydes 2a–e and com-
mercially available 2-tetralones 3a–c (Scheme 1).
Numerous related procedures are known for the synthesis
of the 2,3-dihydro-1H-naphtho[2,1-b]pyran analogues
with a saturated pyran ring {1H-benzo[f]chromans}
which are devoid of photochromic behavior.5 2,3-Dihy-
dro-1H-naphtho[2,1-b]pyran was prepared in 31% yield
by heating 2-allyloxy-1-bromonaphthalene and AIBN in
benzene using a modified stannane reagent;5a the conven-
tional reagent Bu3SnH gave only ca. 17% yield.5b When 1-
bromo-2-but-3-enyloxy-naphthalene was used as starting
We have previously reported the synthesis of 2-alkoxy-1-
arylmethylnaphthalenes from 2-tetralone, aldehydes, and
alcohols under acidic conditions.6 The most plausible
mechanism of formation involves mixed aldol condensa-
tion of the most active methylene of 2-tetralone with alde-
hyde, then vinyl ether formation followed by
rearrangement to produce the more stable species through
aromatization. Subsequently, 12H-benzo[a]xanthenes
were prepared from 2-tetralone and substituted ortho-hy-
droxy aromatic aldehydes in a related endeavor.7
SYNLETT 2007, No. 20, pp 3127–3130
x
x
.x
x
.2
0
0
7
Advanced online publication: 21.11.2007
DOI: 10.1055/s-2007-992380; Art ID: S06507ST
© Georg Thieme Verlag Stuttgart · New York

3128
A. Jha et al.
LETTER
R1
H
R2
O
O
+
H
H
1a–e
R1
R2
O
aq K2CO3
R2
R1
O
R4
R4
O
HCl (g), AcOH
5–10 °C, 1 h
+
OH
R3
R3
2a–e
3a–c
4a–o
Scheme 1 Synthetic scheme for preparing 1H-benzo[f]chromenes 4a–o. Refer to Table 1 for R1–R4 substituents.
The present work constitutes an extension of our previous This result implies that extended conjugation, as we pre-
results describing the synthesis of 12H-benzo[a]xan- viously suggested,7 may not be the sole factor in facilitat-
thenes.7 It was proposed that the aldehyde-active methyl- ing cyclization.
ene condensation led to (E)-1-arylidene-2-tetralones8 as
After close examination, three possibilities were noted by
intermediates where the position of the hydroxyl group
which this cyclization may have resulted. Either a self-as-
was such that concomitant cyclization was unlikely; the
sembly (due to H-bonding) or reversible addition–elimi-
presence of the extended conjugation from the hydroxyl
nation of HCl across the newly created E double bond
group to carbonyl function made the conversion of E-iso-
leads to the formation of the Z-isomer of the 1-alkylidene-
mer to Z-isomer possible and therefore cyclization en-
2-tetralone intermediate. The hydroxyl and carbonyl func-
sued.7 We decided to react 2-tetralone and b-hydroxy
tional groups in the resulting Z-enone are in excellent
aliphatic aldehydes under similar conditions to confirm if
proximity and orientation for the cyclization to occur via
the presence of the extended conjugation is an absolute re-
nucleophilic attack, followed by dehydration and rear-
quirement.
rangement. Alternatively, the aldol initially formed cy-
The synthesis involves anhydrous conditions using dry clizes to
a hemiacetal which undergoes double
HCl gas in acetic acid (Scheme 1). The necessary a,a-di- dehydration and rearrangement leading to the formation
substituted b-hydroxy propionaldehydes 2a–e were ob- of aromatic naphtho[2,1-b]pyrans 4a–o (Scheme 2). This
tained by simple base-promoted mixed aldol appears to be the most reasonable possibility as it elimi-
condensations of appropriately substituted aliphatic alde- nates the geometrical prerequisites for intermediate
hydes 1a–e and formalin following literature procedures.9 enones (vide supra) to cyclize.
All the final compounds (4a–o, Scheme 1) are new to
Another puzzling aspect of this chemistry involves the use
of primary alcohols with a quaternary b-position. These
chemical literature and completely characterized by spec-
troscopic data.10 Table 1 reports the yields, melting
substrates are well known to undergo facile rearrange-
points, and HRMS data of the final naphthopyran prod-
ment involving 1,2-alkyl shift, leading to tertiary carboca-
ucts where appropriate.
tion under acidic conditions.11 It was therefore expected
It is documented (X-ray crystallographic studies) that the that the formation of conjugated tertiary carbocations in
reaction of 2-tetralone with one equivalent of aromatic al- present scenario would eventually lead to naphthofuran
dehydes under suitable conditions exclusively produce 1- derivatives. However, this was not observed. Solvent po-
arylidene-2-tetralones with more stable E-geometry.8 larity plays an important role in reactions involving car-
Only the Z-isomer of the intermediate 1-alkylidene-2-te- bocation intermediates – use of acetic acid (e = 6) as a
tralone can cyclize to the corresponding naphtho[2,1- solvent is not most conducive; more polar solvents such as
b]pyrans. When a,a-disubstituted b-hydroxy propional- formic acid (e = 58) and water (e = 78) lead to faster reac-
dehydes 2a–e were reacted with 2-tetralone or its ana- tion rates.12 This prompted us to replicate the reactions of
logues 3a–c, naphtho[2,1-b]pyrans 4a–o were the only 2,2-dimethyl-3-hydroxypropanal (2a) with 2-tetralone in
products isolated in satisfactory to good yields (Table 1). anhydrous formic acid13 as well as in 50% aqueous formic
HO
H+
HO
OH
O
OH
O
O
H+
O
O
O
OH
4a
H
Scheme 2 Most plausible mechanism of formation of representative 2,3-dihydro-2,2-dimethyl-1H-benzo[f]chromene (4a) from 2-tetralone
and 3-hydroxy-2,2-dimethylpropanal.
Synlett 2007, No. 20, 3127–3130 © Thieme Stuttgart · New York

LETTER
Synthesis of 2,2-Dialkyl-2,3-dihydro-1H-naphtho[2,1-b]pyrans
3129
Table 1 Physical Data of Compounds 4a–o
Compd
4a
R1
R2
R3
R4
mp (°C)
96-98
–
HRMS Calcd
212.1201
242.1307
242.1307
240.1514
270.1620
270.1620
252.1514
282.1620
282.1620
268.1827
298.1933
298.1933
274.1358
304.1463
304.1463
HRMS Found
212.1193
242.1302
242.1291
240.1530
270.1633
270.1610
252.1508
282.1623
282.1624
268.1815
298.1931
298.1935
274.1352
304.1480
304.1472
Yield (%)a
70b
61
Me
Me
Me
Me
Et
H
H
4b
4c
Me
OMe
H
H
Me
OMe
H
–
58
4d
4e
Et
H
–
79
Et
Et
OMe
H
H
93–95
61–63
96–98
91–93
130–132
–
51
4f
Et
Et
OMe
H
63
4g
-(CH2)5-
-(CH2)5-
-(CH2)5-
Et
H
75
4h
4i
OMe
H
H
50
OMe
H
62
4j
n-Bu
n-Bu
n-Bu
Ph
H
75
4k
4l
Et
OMe
H
H
–
63
Et
OMe
H
–
58
4m
4n
4o
Me
H
102–104
88–91
102–105
70
Me
Ph
OMe
H
H
59
Me
Ph
OMe
63
a Isolated yields.
b Compound 1 was obtained in 96.4% and 89.6% isolated yields when reaction was performed in anhyd formic acid and 50% aq formic acid,
respectively.
acid. Both reactions yielded compound 1 as the only prod-
uct in significantly higher yields (Table 1, footnote b) and
there was no trace of any naphthofuran product. Upon ret-
rospection it was discerned that the prospective carboca-
tion would be destabilized by the vicinal carbonyl
functionality preventing this mechanistic possibility.
References and Notes
(1) (a) Nakatsuji, S. Chem. Soc. Rev. 2004, 33, 348.
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In conclusion, we have successfully synthesized fifteen
new 2,3-dihydronaphtho[2,1-b]pyrans from 2-tetralone
analogues and a,a-disubstituted b-hydroxy propionalde-
hydes. The synthetic methodology involves facile acid-
catalyzed aldol condensation, cyclization, and aromatiza-
tion sequence. This procedure is completely unrelated to
any known procedure for the preparation of 2,3-dihy-
dronaphtho[2,1-b]pyrans. Following a similar protocol,
the synthesis of optically pure novel glyconaphthopyrans
is under investigation using 2-tetralone analogues and b-
hydroxyaldehydes obtained from sugars.
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Acknowledgment
The authors thank the Natural Sciences and Engineering Research
Council of Canada and Acadia University for financial support for
this project. Mr. Arun Sehgal of Chempro Exports (India) is
thanked for providing the complimentary samples of 5-methoxy-2-
tetralone and 7-methoxy-2-tetralone.
Synlett 2007, No. 20, 3127–3130 © Thieme Stuttgart · New York

3130
A. Jha et al.
LETTER
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hydroxypropionaldehyde (0.01 mol) and a 2-tetralone
analogue (0.0105 mol) were stirred in AcOH (ca. 50 mL) at
0 °C. Freshly prepared dry HCl gas was briskly passed
through the mixture for 1 h. Stirring was continued at r.t. for
17 h. Then, AcOH was removed under vacuum and the
residue was extracted with CH2Cl2 (2 × 100 mL) and H2O (2
× 50 mL). The organic layer was dried and rotary evaporated
to dryness to yield crude product, which was purified by
column chromatography (silica gel mesh size 230–240;
eluent 1–2% EtOAc–hexane). Spectroscopic Data for a
Representative Compound
Compound 4o: 1H NMR (300 MHz, CDCl3): d = 1.53 (3 H,
s, CH3), 3.10 and 3.46 (1 H each, d, J = 16.2 Hz, ArCHa and
ArCHb), 3.97 (3 H, s, OCH3), 4.19 and 4.33 (1 H each, d,
J = 10.5 Hz, OCHa and OCHb), 6.99 (1 H, d, J = 8.7 Hz,
ArH), 7.08 (1 H, m, ArH), 7.15 (1 H, s, ArH), 7.32 (1 H, d,
J = 6.9 Hz, ArH), 7.39–7.50 (4 H, m, ArH), 7.61 (1 H, d,
J = 8.7 Hz, ArH), 7.73 (1 H, d, J = 8.7 Hz, ArH) ppm. 13
C
NMR (75 MHz, CDCl3,): d = 25.00, 35.84, 36.36, 55.75,
74.42, 101.48, 112.70, 115.65, 116.56, 124.80, 126.31,
127.09, 127.91, 129.03, 130.51, 134.82, 146.17, 152.33,
158.81 ppm. IR (KBr): n = 2963, 1624, 1515, 1233, 1222,
1028, 830, 699 cm–1.
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