Chelation control in the [3+3] annulation reaction of alkoxy-substituted 1,1-diacylcyclopropanes with 1,3-bis(trimethylsilyloxy)-1,3-butadienes. Diversity-oriented synthesis of isochromanes

Article abstract of DOI:10.1021/jo902334q

(Chemical Equation Presented) Functionalized arenes were prepared by chelation-controlled [3 + 3] cyclization/cyclopropane opening reactions of 1-trimethylsilyloxy-1,3-butadienes with benzyloxy- or methoxy-substituted 1,1-diacylcyclopropanes. A number of benzyloxy-substituted derivatives were transformed into isochromanes by deprotection and subsequent cyclization. Mixed chromanes-isochromanes were prepared starting with 1,3-bis(silyloxy)-1,3- butadienes containing a remote chloride group. 2010 American Chemical Society.

Full text of DOI:10.1021/jo902334q

pubs.acs.org/joc
Chelation Control in the [3 þ 3] Annulation Reaction of Alkoxy-
Substituted 1,1-Diacylcyclopropanes with 1,3-Bis(trimethylsilyloxy)-
1,3-butadienes. Diversity-Oriented Synthesis of Isochromanes
Vahuni Karapetyan,† Satenik Mkrtchyan,† Jennifer Hefner,† Christine Fischer,‡ and
Peter Langer*,†,‡
†
€
Institut fu€r Chemie der Universitat Rostock, Albert-Einstein-Strasse 3a, D-18059 Rostock, Germany and
€
‡
Leibniz Institut fu€r Katalyse e.V. an der Universitat Rostock, Albert-Einstein-Strasse 29a,
D-18059 Rostock, Germany
peter.langer@uni-rostock.de
Received November 1, 2009
Functionalized arenes were prepared by chelation-controlled [3 þ 3] cyclization/cyclopropane
opening reactions of 1-trimethylsilyloxy-1,3-butadienes with benzyloxy- or methoxy-substituted
1,1-diacylcyclopropanes. A number of benzyloxy-substituted derivatives were transformed into
isochromanes by deprotection and subsequent cyclization. Mixed chromanes-isochromanes were
prepared starting with 1,3-bis(silyloxy)-1,3-butadienes containing a remote chloride group.
Introduction
Kock et al. from Pseudoanguillospora, show antibacterial and
antifungal activity.5
3,4-Dihydro-2H-chromenes (chromanes) represent phar-
macologically relevant heterocycles which occur in a variety
of natural products (Scheme 1).1,2 For example, bavachro-
manol has been isolated from leaves of Maclura tinctoria L.
(Venezuela).2a The chromanol moiety of vitamin E (R-toco-
pherol) exhibits antiandrogen properties.3 Natural products
containing an isochromane substructure are also of pharma-
cological relevance. For example, the natural product pseudo-
deflectusine, which has been isolated from Aspergillus pseudo-
deflectus, exhibits selective cytotoxic activity against several
human cancer cell lines.4 The isochromane derivatives pseudo-
anguillosporines A and B, which have been isolated first time by
Finn et al. have prepared chromanes from salicylic alde-
hydes and vinylboronic acids in the presence of catalytic
amounts of dibenzylamine.6 Jones et al. reported the synth-
esis of chromanes by Diels-Alder reactions of o-quinone
methides, which were generated from salicylic aldehydes and
alcohols.7 We have reported the synthesis of 6-(2-hydroxy-
benzoyl)-3,4-dihydro-2H-chromenes based on sequential
[3þ3]-cyclization/Williamson reactions of 1,3-bis(trimethyl-
silyloxy)-7-chlorohepta-1,3-dienes with 3-silyloxy 2-en-1-ones
and 3-formylchromones.8
Recently, we have reported9 the synthesis of functionalized
phenols by TiCl4-mediated [3 þ 3] cyclization10 of 1,3-bis(tri-
methylsilyloxy)-1,3-butadienes11 with 1,1-diacylcyclopropanes.
*To whom correspondence should be addressed. Fax: þ49-381-498-6411.
(1) Hepworth, J. Comprehensive Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., eds.; Elsevier Science: Oxford, 1984; Vol. 3, p 737.
(2) (a) Bavachromanol: Sohly, H. N.; Joshi, A. S.; Nimrod, A. C.;
Walker, L. A.; Clark, A. M. Planta Med. 2001, 67, 87. (b) Calyxin L:
Tezuka, Y.; Gewali, M. B.; Ali, M. S.; Banskota, A. H.; Kadota, S. J. Nat.
Prod. 2001, 64, 208.
€
(5) Kock, I.; Draeger, S.; Schulz, B.; Elsasser, B.; Kurtan, T.; Kenez, A.;
Antus, S.; Pescitelli, G.; Salvadori, P.; Speakman, J.-B.; Rheinheimer, J.;
Krohn, K. Eur. J. Org. Chem. 2009, 1427.
(6) Wang, Q.; Finn, M. G. Org. Lett. 2000, 2, 4063.
(7) Jones, R. M.; Selenski, C.; Pettus, T. R. R. J. Org. Chem. 2002, 67,
6915.
(3) Ro€mpp-Lexikon Naturstoffe; Fugmann, B., Ed.; Georg Thieme Verlag:
Stuttgart, 1997.
(4) (a) Vismiaguianone E: Seo, E.-K.; Wani, M. C.; Wall, M. E.;
Navarro, H.; Mukherjee, R.; Farnsworth, N. R.; Kinghorn, A. D. Phyto-
chemistry 2000, 55, 35. (b) Grandinal: Singh, I. P.; Hayakawa, R.; Etoh, H.;
Takasaki, M.; Konoshima, T. Biosci. Biotechnol. Biochem. 1997, 61, 921.
(c) Calomelanol A: Asai, F.; Iinuma, M.; Tanaka, T.; Mizuno, M. Phyto-
chemistry 1991, 30, 3091. (d) Iryantherin E: Conserva, L. M.; Yoshida, M.;
Gottlieb, O. R.; Martinez V., J. C.; Gottlieb, H. E. Phytochemistry 1990, 29,
3911.
(8) Nguyen, V. T. H.; Appel, B.; Langer, P. Tetrahedron 2006, 62, 7674.
(9) (a) Langer, P.; Bose, G. Angew. Chem., Int. Ed. 2003, 42, 4033.
€
(b) Bose, G.; Nguyen, V. T. H.; Ullah, E.; Lahiri, S.; Gorls, H.; Langer, P.
J. Org. Chem. 2004, 69, 9128.
(10) For a review of [3þ3] cyclizations, see: Feist, H.; Langer, P. Synthesis
2007, 327.
(11) For a review of 1,3-bis(silyl enol ethers), see: Langer, P. Synthesis
2002, 441.
DOI: 10.1021/jo902334q
r
Published on Web 01/11/2010
J. Org. Chem. 2010, 75, 809–814 809
2010 American Chemical Society

Karapetyan et al.
JOCArticle
SCHEME 1. Structures of Bavachromanol, Flemistrictin F,
Vitamin E, Pseudodeflectusine, and Pseudoanguillosporine B
SCHEME 2. Synthesis of 2a-d
TABLE 1. Synthesis of 2a-d
1, 2
R1
R2
% (2)a
a
b
c
Me
Me
Bn
Bn
Me
Ph
Me
Ph
40
40
42
40
d
aYields of isolated products.
SCHEME 3. Possible Mechanism of the Formation of 4a
Although symmetrical cyclopropanes were employed in most
cases, some unsymmetrical substrates have also been studied.
The cyclization of 1,3-bis(silyloxy)-1,3-butadienes with 1-acetyl-
1-formylcyclopropane and with 1-acetyl-1-benzoylcyclopro-
pane proceeded by regioselective attack of the terminal carbon
atom of the diene onto the more reactive carbonyl group (i.e.,
the formyl and the acetyl group, respectively). Recently, we have
reported preliminary results related to the regiodirecting effect
of chelating12,13 alkoxy groups present in 1,1-diacylcyclopro-
pane.14 Herein, we report full details and a comprehensive study
of the scope of our methodology. In addition, we report its
application to the synthesis of various functionalized chromanes
and isochromanes.
Results and Discussion
1-Methoxypentane-2,4-dione,15 1-benzyloxypentane-2,4-
dione,16 and 4-methoxy-1-phenylbutane-1,3-dione17 are known
compounds which were prepared according to the literature.
Hitherto unknown 4-benzyloxy-1-phenylbutane-1,3-dione
was prepared, in analogy to the synthesis of 1-benzyloxy-
pentane-2,4-dione, by Claisen condensation of benzyl 2-(benzyl-
oxy)acetate with acetophenone in 50% yield. The potassium
carbonate-mediated reaction of the four 1,3-diketones with
1,2-dibromoethane in DMSO afforded the cyclopropanes
2a-d in moderate yields (Scheme 2, Table 1).
The TiCl4-mediated cyclization of 2a with 1,3-bis(trimethyl-
silyloxy)-1,3-butadiene 3a, readily available in two steps from
methyl acetoacetate,18 afforded the 5-chloroethyl-4-(methoxy-
methyl)salicylate 4a (Scheme 3). The moderate yield of 4a can
be explained by practical problems during the chromatographic
purification. The best yields of 4a were obtained when 1.0 equiv
of 2a, 1.5 equiv of 3a, and 2.0 equiv of TiCl4 were employed.
The low concentration (c(2a) = 0.01 M) and the presence of
˚
molecular sieves (4 A) (for the removal of water) also played an
important role.
(12) For reviews of chelation control in Lewis acid-mediated reactions,
see: (a) Yamamoto, H. Lewis Acid Chemistry: A Practical Approach; Oxford
University Press: Oxford, 1999. (b) Mahrwald, R. Chem. Rev. 1999, 99, 1095.
(c) Santelli, M.; Pons, J. M. Lewis Acids and Selectivity in Organic Synthesis;
CRC Press: Boca Raton, 1996. (d) Shambayati, S.; Schreiber, S. L. In Compre-
hensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,
1991; Vol. 1, pp 283-324.
(13) Chelation control has been reported for the [4 þ 3] annulation
reaction of benzyloxy-substituted 1,4-dicarbonyl compounds with bis(silyl
enol ethers): Molander, G. A.; Eastwood, P. R. J. Org. Chem. 1996, 61, 1910.
(14) Hefner, J.; Langer, P. Tetrahedron Lett. 2008, 49, 4470.
The regioselectivity can be explained by the Lewis acid-
directing effect of the methoxy group of the substrate. The
chelation of TiCl4 by the methoxy and the neighboring
carbonyl group of 2a results in the formation of intermediate
A. The TiCl4-mediated attack of the terminal carbon atom of
3a onto 2a gives rise to the formation of intermediate B which
(15) Bruce, W. F.; Coover, H. W. J. Am. Chem. Soc. 1944, 66, 2092.
(16) Wenner, W.; Plati, J. T. J. Org. Chem. 1946, 11, 751.
(17) Gault, H.; Viout, A. Bull. Soc. Chim. Fr. 1951, 713.
(18) (a) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980, 102, 3534.
(b) Brownbridge, P.; Chan, T.-H.; Brook, M. A.; Kang, G. J. Can. J. Chem.
1983, 61, 688.
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SCHEME 4. Synthesis of 4a-p
TABLE 2. Synthesis of Salicylates 4a-p
undergoes a cyclization via the central carbon atom of the
1,3-dicarbonyl unit (intermediate C). The product is subse-
quently formed by Lewis acid-assisted cleavage of the spiro-
cyclopropane moiety and aromatization by attack of a
chloride ion onto the cyclopropane (intermediate D) and
hydrolysis upon aqueous workup. The process can be re-
garded as a domino [3þ3] cyclization/cyclopropane opening
reaction.18
The TiCl4- or TiBr4-mediated cyclization of 2a and 2b with
1,3-bis(trimethylsilyloxy)-1,3-butadienes 3a-j, prepared
from the corresponding 1,3-dicarbonyl compounds in two
steps,18 afforded the 4-chloroethyl- and 4-bromoethyl-
3-(methoxymethyl)phenols 4a-p in 30-73% yields (Scheme 4,
Table 2). The employment of TiCl4 or TiBr4 is equally efficient in
terms of yield. All reactions proceeded with very good regio-
selectivity. Although some products were isolated in only mode-
rate yields, only one regioisomer could be isolated in all reactions.
Only hydrolyzed 1,3-bis(silyl enol ether) could be isolated as a
side product (which is understandable because the diene was
used in a slight excess, 1.5 equiv). The low yields are a result of
practical problems during the chromatographic purification.
The yields of the products derived from 2b were in many cases
better than those of the products derived from 2a. Relatively low
yields were obtained for products 4h,j,k derived from dienes 3h
and 3j. These dienes, which have been prepared from 1,3-
diketones, are less reactive than the other dienes which have
been prepared from β-ketoesters.
Depending on the position of the attack of the 1,3-bis(silyl
enol ether) onto the 1,1-diacylcyclopropane the formation of
two regioisomers is possible. Substituent R1 can be located
ortho or para to R3. The two possible regioisomers of pro-
duct 4a are depicted in Scheme 5. The structures of the
products were established by 2D NMR experiments
(1H,1H-NOESY, 1H,13C-HMBC). A NOESY experiment
shows an interaction between the methylene group CH2OMe
(δ = 4.43 ppm) and the aromatic proton (δ = 6.90 ppm),
which proves the presence of isomer A. An HMBC experi-
ment exhibits a 3JC,H-coupling between the methylene group
CH2OMe (1H: δ = 4.43 ppm; 13C: δ = 73.8 ppm) and the
aromatic CH-group (1H: δ=6.90 ppm; 13C: δ=116.8 ppm).
In contrast, an NOE interaction between the methyl group
(δ = 2.50 ppm) and the aromatic proton (δ = 6.90 ppm),
which would be diagnostic for isomer B, was not observed.
The low-field shift of the hydroxyl proton shows that the
latter is involved in solution in an intramolecular hydrogen
bond to the neighbored ester carbonyl group.
The novel benzyloxy-substituted 1,1-diacylcyclopropanes
2c and 2d were prepared by cyclopropanation of 1-benzyloxy-
pentane-2,4-dione and 4-benzyloxy-1-phenylbutane-1,3-dione,
respectively. The cyclization of 2c,d with 1,3-bis(trimethyl-
silyloxy)-1,3-butadienes 3a-m in the presence of TiCl4 or TiBr4
aYields of isolated products.
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SCHEME 5. Possible Regioisomers of 4a
TABLE 3. Synthesis of Salicylates 4q-ai, 5a-k, and Isochromanes
6a-h
SCHEME 6. Synthesis of Isochromanes 6a-h
afforded the functionalized phenols 4q-ai (Scheme 6, Table 3).
All products were again formed with very good regioselectivity
by attack of the terminal carbon atom of the diene onto the
carbonyl group located next to the benzyloxy group. The
debenzylation of 4q-ai afforded the alcohols 5a-k, which
were transformed by Williamson reaction into the isochro-
manes 6a-h (Scheme 6, Table 3).
Treatment of salicylates 4g, 4y, and 4ah, which contain
two chloride groups, with NaH/TBAI afforded chromanes
7a-c (Scheme 7, Table 4). The benzyloxy-substituted deri-
vatives 7b,c were hydrogenated to give the free alcohols 8a,b.
The base-mediated cyclization of 8a,b afforded heterocycles
9a,b containing a chromane and an isochromane moiety.
In conclusion, we have reported the first chelation-con-
trolled domino [3 þ 3] cyclization/cyclopropane opening
reactions of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with
1,1-diacylcyclopropanes. These reactions provide a conve-
nient approach to highly functionalized phenols which are
not readily available by other methods. The regioselectivity
can be explained by the Lewis acid-directing effect of the
alkoxy groups of the substrates.
Experimental Section
General Methods. Chemical shifts of the 1H and 13C NMR are
reported in parts per million using the solvent internal standard
(chloroform, 7.26 and 77.0 ppm, respectively). Infrared spectra
were recorded on an FTIR spectrometer. Mass spectrometric
data (MS) were obtained by electron ionization (EI, 70 eV),
chemical ionization (CI, isobutane), or electrospray ionization
(ESI). Melting points are uncorrected. The solvent CH2Cl2
(anhydrous, 99.8%) was purchased directly from ACROS and
used without further purification, and TiCl4 was purchased
from Aldrich and freshly destilled prior to use. Analytical
thin-layer chromatography was performed on 0.20 mm 60 A
aYields of isolated products.
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silica gel plates. Column chromatography was performed using
60A silica gel (60-200 mesh). All cyclization reactions were
carried out in Schlenk tubes under an argon atmosphere. 1-Meth-
oxypentane-2,4-dione, 1-benzyloxypentane-2,4-dione, 4-methoxy-
1-phenylbutane-1,3-dione, and 4-benzyloxy-1-phenylbutane-1,3-
dione were prepared according to the literature.15-17
1,2-Dibromomethane (1.3 equiv) was dropwise added with
stirring. The reaction mixture was stirred at 20 °C for approxi-
mately 18 h, and subsequently water (300 mL) was added. The
organic and the aqueous layers were separated, and the latter
was extracted with diethyl ether (3 ꢀ 50 mL). The combined
organic layers were washed with water (3 ꢀ 30 mL) and brine.
The aqueous and the organic layers were separated, the latter
was dried (Na2SO4) and filtered, and the filtrate was concen-
trated in vacuo. The residue was purified by vacuum distillation
or by chromatography (heptanes/EtOAc =100:1 f 5:1).
1-Acetyl-1-(methoxymethyl)carbonylcyclopropane (2a). Start-
ing with 1-methoxypentane-2,4-dione 1a (5.011 g, 38.50 mmol),
1,2-dibromoethane (9.402 g, 50.0 mmol), and K2CO3 (15.96 g,
115.50 mmol) in DMSO (100 mL), 2a was obtained as a pale
yellow oil (2.41 g, 40%). Bp= 46 °C (p=0.15 Torr). 1H NMR
(300 MHz, CDCl3): δ=1.43-1.46 (m, 2H), 1.50-1.52 (m, 2H),
2.10 (s, 3H), 3.38 (s, 3H), 4.31 (s, 2H). 13C NMR (75.5 MHz,
CDCl3): δ=17.4, 26.3, 41.0, 59.1, 77.1, 202.9, 203.6. IR (ATR,
cm-1): ν=2827 (w), 1687 (s), 1195 (m), 1125 (s). MS (GC, 70 eV):
m/z=111 (100), 69 (85), 45 (81), 43 (94). HRMS (ESIþ): calcd
for C8H12NaO3 ([M þNa]þ) 179.06787, found 179.06790.
General Procedure for the Synthesis of Salicylates 4a-ai. To a
CH2Cl2 solution (100 mL) of 2 (1.0 mmol) and 1,3-bis(silyl enol
4-Benzyloxy-1-phenylbutane-1,3-dione (1d). This compound
was prepared according to the literature.16,17 Starting with
benzyl 2-(benzyloxy)acetate (10.25 g, 40.0 mmol), acetophenone
(6.01 g, 50.0 mmol), and sodium ethoxide (3.40 g, 50.0 mmol) in
diethyl ether (40 mL), 4-benzyloxy-1-phenylbutane-1,3-dione
was obtained as a pale yellow oil (5.37 g, 50%), Rf = 0.58
(heptane/EtOAc=1:1). The product was purified by chromato-
graphy (heptane/EtOAc=100:1 f 15:1). 1H NMR (250 MHz,
CDCl3): δ = 4.19 (s, 2H), 4.66 (s, 2H), 6.56 (s, 1H), 7.28-7.57
(m, 8H), 7.89-7.94 (m, 2H), 15.92 (s, 1H). 13C NMR (62.9 MHz,
CDCl3): δ = 71.7, 73.4, 93.5, 127.1, 127.9, 128.0, 128.5, 128.6,
132.5, 134.4, 137.2, 183.1, 194.6. IR (ATR, cm-1): ν=3467 (w),
3030 (w), 2863 (w), 1682 (s), 1451 (m), 1264 (s), 1103 (s), 688 (s).
MS (EI, 70 eV): m/z = 162 (86), 161 (19), 147 (100), 105 (67),
91 (87). HRMS (ESIþ): calcd for C17H16NaO3 ([M þ Na]þ)
291.09917, found 291.09902.
Synthesis of Cyclopropanes 2a-d. To a DMSO solution
(2.5 mL per 1 mmol of 1,3-diketone) of the 1,3-diketone 1 was
added powdered K2CO3 (3.0 equiv) under argon atmosphere.
˚
ether) 3 (1.5 mmol) in the presence of molecular sieves (4 A, 1.00 g)
was dropwise added TiCl4 (0.22 mL, 2.0 mmol) at -78 °C under
argon atmosphere. The solution was allowed to warm to 20 °C
within 18 h with stirring and subsequently filtered. The filtrate was
poured into hydrochloric acid (10%, 100 mL), the organic and the
aqueous layers were separated, and the latter was extracted with
CH2Cl2 (3 ꢀ 100 mL). The combined organic layers were dried
(Na2SO4) and filtered, and the filtrate was concentrated in vacuo.
The residue was purified by chromatography (silica gel, heptanes/
EtOAc=15:1 f 7:1).
SCHEME 7. Synthesis of Heterocycles 9a,b
5-(2-Chloroethyl)-4-methoxymethyl-6-methylsalicylic Acid
Methyl Ester (4a). Starting with 2a (0.156 g, 1.00 mmol), 3a
(0.391 g, 1.50 mmol), and TiCl4 (0.22 mL, 2.00 mmol) in CH2Cl2
(100 mL), 4a was obtained as a pale yellow solid (0.120 g, 44%).
Mp = 77-78 °C. Rf = 0.38 (heptane/EtOAc = 3:1). 1H NMR
(300 MHz, CDCl3): δ=2.50 (s, 3H), 3.06-3.12 (m, 2H), 3.42 (s,
3H), 3.52-3.57 (m, 2H), 3.97 (s, 3H), 4.43 (s, 2H), 6.90 (s, 1H),
10.61 (s, 1H). 13C NMR (75.5 MHz, CDCl3): δ = 14.5, 32.9,
43.3, 52.7, 59.9, 73.8, 113.9, 116.8, 127.3, 140.0, 143.8, 160.7,
172.0. IR (KBr, cm-1): ν=3025 (m), 2892 (w), 1660 (s), 1445 (s),
1198 (m), 1100 (s), 710 (m). MS (EI, 70 eV): m/z = 274 (Mþ,
37Cl, 16), 272 (Mþ, 35Cl, 46), 240 (100), 133 (96). HRMS (EI):
calcd for C13H17ClO4 ([M]þ, 35Cl) 272.08099, found 272.08061.
TABLE 4. Synthesis of Chromanes 7a-c, 8a,b, and 9a,b
aYields of isolated products.
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Karapetyan et al.
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Anal. Calcd for C13H17ClO4 (272.72): C, 57.25; H, 6.28. Found:
C, 57.24; H, 6.39.
(m), 1283 (s), 1201 (m), 1118 (m), 1079 (s), 792 (m), 728 (m). MS
(EI, 70 eV): m/z = 314 (Mþ, 37Cl, 14), 312 (Mþ, 35Cl, 47), 280
(100), 245 (97), 233 (90), 213 (71), 201 (54). HRMS (EI): calcd
for C16H21ClO4 ([M]þ, 35Cl) 312.11229, found 312.11187. Anal.
Calcd for C16H21ClO4 (312.79): C, 61.44; H, 6.77. Found: C,
61.34; H, 6.82.
4-Benzyloxymethyl-5-(2-chloroethyl)-6-methylsalicylic Acid
Methyl Ester (4q). Starting with 2c (0.232 g, 1.00 mmol), 3a
(0.391 g, 1.50 mmol), and TiCl4 (0.22 mL, 2.00 mmol) in CH2Cl2
(100 mL), 4q was obtained as a pale yellow solid (0.162 g, 46%).
Mp = 90-93 °C. Rf = 0.54 (heptane/EtOAc = 1:1). 1H NMR
(250 MHz, CDCl3): δ = 2.50 (s, 3H), 3.07-3.14 (m, 2H),
3.50-3.57 (m, 2H), 3.97 (s, 3H), 4.52 (s, 2H), 4.60 (s, 2H), 6.95
(s, 1H), 7.31-7.34 (m, 5H), 10.63 (s, 1H). 13C NMR (62.9 MHz,
CDCl3): δ=18.3, 32.6, 42.9, 52.3, 70.9, 72.8, 113.5, 116.6, 127.0,
127.9, 128.0, 128.5, 137.6, 139.6, 143.4, 160.3, 171.6. IR (ATR,
cm-1): ν=3030 (w), 2834 (w), 1651 (s), 1435 (s), 1197 (m), 1111
(m), 737 (m). MS (EI, 70 eV): m/z=348 (Mþ, 35Cl, 4), 242 (43),
210 (100), 161 (34), 91, (99). HRMS (EI): calcd for C19H21-
ClO4 ([M]þ, 35Cl) 348.11229, found 348.11328. Anal. Calcd
for C19H21ClO4 (348.82): C, 65.42; H, 6.07. Found: C, 64.56;
H, 5.97.
General Procedure for the Synthesis of Products 5 and 8. To
a EtOAc solution (10 mL) of 4 or 7 (1.0 mmol) was added Pd/C
(10 wt % Pd, 10 mol %) at 20 °C under argon atmosphere. The
flask was evacuated and filled with hydrogen (3ꢀ), and the
mixture was stirred under hydrogen atmosphere for 48 h. The
mixture was filtered (Celite) and washed with EtOAc (300 mL),
and the aqueous and the organic layers were separated. The
latter was dried (Na2SO4) and filtered, and the filtrate was
concentrated in vacuo. The residue was purified by chromato-
graphy (silica gel, heptanes/EtOAc = 10:1f5:1).
5-(2-Chloroethyl)-4-hydroxymethyl-6-methylsalicylic Acid
Methyl Ester (5a). Starting with 4q (0.091 g, 0.26 mmol) and
Pd/C (0.028 g, 0.026 mmol Pd) in ethyl acetate (3 mL), 5a was
obtained as a colorless solid (0.041 g, 61%). Mp = 86-88 °C.
Rf=0.20 (heptane/EtOAc=1:1). 1H NMR (250 MHz, CDCl3):
δ=1.92 (s, 1H), 2.49 (s, 3H), 3.08-3.14 (m, 2H), 3.52-3.59 (m,
2H), 3.97 (s, 3H), 4.71 (s, 2H), 6.94 (s, 1H), 10.67 (s, 1H). 13C
NMR (62.9 MHz, CDCl3): δ=18.3, 32.2, 42.9, 52.3, 63.6, 113.3,
115.0, 126.2, 139.6, 145.9, 160.5, 171.6. IR (ATR, cm-1): ν =
3374 (m), 3020 (w), 2918 (w), 1661 (s), 1445 (m), 1383 (w), 1182
(m), 1138 (m), 699 (m), 599 (w). MS (GC, 70 eV): m/z=260 (Mþ,
37Cl, 7), 258 (Mþ, 35Cl, 22), 226 (64), 177 (100). HRMS (EI):
calcd for C12H15ClO4 ([M]þ, 35Cl) 258.06534, found 258.06482.
General Procedure for the Synthesis of Products 6, 7, and 9. To
a DMF solution (20 mL) of 4, 5, or 8 (1.0 mmol) was added
TBAI (2.0 mmol) under argon atmosphere, and the reaction
mixture was cooled to -78 °C. The cooling bath was replaced by
an ice/NaCl mixture (-23 °C), and NaH (2.3 mmol) was added.
After the mixture was stirred for 14-20 h, EtOAc (5 mL) and
ice/water (5 mL) were added, and the solution was neutralized
with hydrochloric acid (10%). The organic and the aqueous
layers were separated, and the latter was extracted with ethyl
acetate (3 ꢀ 20 mL). The combined organic layers were dried
(Na2SO4) and filtered, and the filtrate was concentrated in
vacuum. The residue was purified by chromatography (silica
gel, heptanes/EtOAc =10:1f3:1).
6-(2-Chloroethyl)-5-methoxymethyl-7-methylchromane-8-carb-
oxylic Acid Methyl Ester (7a). Starting with 4g (0.050 g, 0.14
mmol), TBAI (0.106 g, 0.29 mmol), and NaH (0.009 g, 0.22
mmol NaH) in DMF (2 mL), 7a was obtained as a colorless solid
(0.031 g, 69%). Mp = 92-93 °C. Rf = 0.36 (heptane/EtOAc =
1:1). 1H NMR (250 MHz, CDCl3): δ=1.96-2.06 (m, 2H), 2.21
(s, 3H), 2.82 (t, 3J=6.5 Hz, 2H), 3.09-3.16 (m, 2H), 3.43 (s, 3H),
3.50-3.56 (m, 2H), 3.89 (s, 3H), 4.11-4.15 (m, 2H), 4.40 (s, 2H).
13C NMR (75.5 MHz, CDCl3): δ = 16.4, 22.0, 22.1, 32.9, 43.3,
52.3, 58.6, 66.1, 68.1, 120.7, 124.5, 128.2, 132.1, 136.5, 150.5,
169.2. IR (ATR, cm-1): ν = 2989 (w), 2918 (w), 1725 (s), 1446
6-(2-Chloroethyl)-5-hydroxymethyl-7-methylchromane-8-car-
boxylic Acid Methyl Ester (8a). Starting with 7b (0.114 g, 0.29
mmol) and Pd/C (0.031 g, 0.029 mmol Pd) in ethyl acetate
(3 mL), 8a was obtained as a colorless solid (0.083 g, 96%). Rf=
0.09 (heptane/EtOAc=1:1). 1H NMR (300 MHz, CDCl3): δ=
1.65 (s, 1H), 1.98-2.06 (m, 2H), 2.21 (s, 3H), 2.88 (t, 3J=6.6 Hz,
2H), 3.14-3.20 (m, 2H), 3.54-3.60 (m, 2H), 3.90 (s, 3H),
4.13-4.16 (m, 2H), 4.69 (s, 2H). 13C NMR (75.5 MHz, CDCl3):
δ = 16.4, 22.0, 22.1, 32.5, 43.5, 52.3, 58.5, 66.1, 120.3, 124.6,
127.7, 132.3, 138.7, 150.7, 169.2. IR (ATR, cm-1): ν=3435 (br,
w), 2950 (w), 1727 (s), 1440 (m), 1197 (m), 1114 (s), 804 (m), 724
(m). MS (EI, 70 eV): m/z = 300 (Mþ, 37Cl, 16), 298 (Mþ, 35Cl,
60), 280 (53), 267 (37), 249 (100). HRMS (EI): calcd for
C15H19ClO4 ([M]þ, 35Cl) 298.09664, found 298.09631. Anal.
Calcd for C15H19ClO4 (298.76): C, 60.30; H, 6.41. Found: C,
60.71; H, 6.39.
7-Hydroxy-5-methylisochromane-6-carboxylic Acid Methyl
Ester (6a). Starting with 5a (0.100 g, 0.39 mmol), TBAI (0.288 g,
0.78 mmol), and NaH (0.036 g, 0.90 mmol NaH) in DMF (10 mL),
6a was obtained as a colorless solid (0.054 g, 62%). Mp = 89-
90 °C. Rf =0.36 (heptane/EtOAc=1:1). An alternative synthesis
of 5a is based on the use of Me3SiOTf rather than TiCl4 in 10 mL of
CH2Cl2. Starting with 1a (0.156 g, 1.00 mmol), 2a (0.391 g, 1.50
mmol), and Me3SiOTf (0.36 mL, 2.00 mmol) in CH2Cl2 (10 mL),
5a was obtained as a colorless solid (0.045 g, 20%). Rf = 0.45
(heptane/EtOAc=3:1). 1H NMR (250 MHz, CDCl3): δ=2.40 (s,
3H), 2.67 (t, 3J=5.8 Hz, 2H), 3.96 (s, 3H), 3.97 (t, 3J=5.8 Hz, 2H),
4.70 (s, 2H), 6.50 (s, 1H), 10.65 (s, 1H). 13C NMR (62.9 MHz,
CDCl3): δ=17.6, 26.3, 52.2, 65.7, 68.3, 110.6, 112.2, 123.9, 139.4,
141.8, 159.4, 171.8. IR (ATR, cm-1): ν=3014 (w), 2849 (w), 1662
(s), 1445 (m), 1201 (m), 1120 (s), 804 (m). MS (GC, 70 eV): m/z=
222 (Mþ, 39), 190 (100), 160 (31), 104 (25). HRMS (EI): calcd for
C12H14O4 ([M]þ) 222.08866, found 222.08853.
1,3,4,8,9,10-Hexahydropyrano[3,4-f]chromene-6-carboxylic
Acid Methyl Ester (9a). Starting with 8a (0.060 g, 0.20 mmol),
TBAI (0.155 g, 0.42 mmol), and NaH (0.012 g, 0.30 mmol NaH)
in DMF (3 mL), 9a was obtained as a colorless solid (0.025 g,
47%). Mp=145-147 °C. Rf=0.07 (heptane/EtOAc=1:1). 1H
NMR (250 MHz, CDCl3): δ=1.96-2.06 (m, 2H), 2.10 (s, 3H),
2.46 (t, 3J=6.6 Hz, 2H), 2.62 (t, 3J=5.7 Hz, 2H), 3.90 (s, 3H),
3.92 (t, 3J = 5.7 Hz, 2H), 4.11-4.15 (m, 2H), 4.61 (s, 2H). 13
C
NMR (62.9 MHz, CDCl3): δ=15.4, 20.3, 21.7, 25.8, 52.2, 64.9,
66.1, 66.1, 115.5, 121.9, 123.8, 131.6, 134.8, 149.3, 169.3. IR
(ATR, cm-1): ν = 2963 (w), 2849 (w), 1721 (s), 1453 (m), 1284
(s), 1203 (m), 1102 (s), 866 (m), 734 (w). MS (GC, 70 eV): m/z=
262 (Mþ, 100), 247 (22), 232 (50), 203 (22). HRMS (EI): calcd
for C15H18O4 ([M]þ) 262.11996, found 262.11980. Anal. Calcd
for C15H18O4 (262.30): C, 68.68; H, 6.92. Found: C, 68.44;
H, 7.02.
Acknowledgment. Financial support by the State of Meck-
lenburg-Vorpommern (scholarships for V.K. and S.M.) is
gratefully acknowledged.
Supporting Information Available: Experimental proce-
dures, compound characterization, and copies of NMR spectra.
This material is available free of charge via the Internet at http://
pubs.acs.org.
814 J. Org. Chem. Vol. 75, No. 3, 2010