Synthesis of substituted benzoxacycles via a domino ortho-alkylation/heck coupling sequence

Article abstract of DOI:10.1021/jo060552l

The synthesis of a variety of alkylidene benzoxacycles via a domino palladium-catalyzed ortho-alkylation/intramolecular Heck reaction is described. Under the optimized conditions [Pd(OAc)₂ (10 mol %), P(2-Furyl) ₃ (20 mol %), norborn

Full text of DOI:10.1021/jo060552l

Synthesis of Substituted Benzoxacycles via a Domino
Ortho-Alkylation/Heck Coupling Sequence
Andrew Martins, Udo Marquardt,† Neema Kasravi, Dino Alberico, and Mark Lautens*
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto, 80 St. George Street,
Toronto, Ontario, M5S 3H6 Canada
mlautens@chem.utoronto.ca
ReceiVed March 13, 2006
The synthesis of a variety of alkylidene benzoxacycles via a domino palladium-catalyzed ortho-alkylation/
intramolecular Heck reaction is described. Under the optimized conditions [Pd(OAc)2 (10 mol %), P(2-
Furyl)3 (20 mol %), norbornene (4 equiv), Cs2CO3 (2 equiv), CH3CN, 80 °C], aryl iodides with oxygen-
tethered Heck acceptors are coupled with alkyl bromides (5 equiv) to generate a variety of six- and
seven-membered-ring benzoxacyclic products.
SCHEME 1. Tandem Ortho-Alkylation/Heck Approach
toward Benzoxacycles
Introduction
Chromans (2,3-dihydrobenzopyrans) and benzoxepines rep-
resent families of oxygen-containing natural products that
demonstrate activity toward a variety of biological targets.1
Structure activity relationships of these compounds have been
studied;2 however, the effect of substituents on the aromatic
ring remains to be fully explored. We sought to develop a
method that could efficiently prepare substituted chromans and
benzoxepines in a direct way. Domino3 palladium catalysis4
represents a class of reaction that can fulfill this objective. Herein
we describe that the norbornene-mediated, palladium-catalyzed
domino ortho-alkylation/Heck reaction initially reported by
Catellani5 and further developed in our laboratories6 can be
applied to the synthesis of chromen-4-ylidenes and 1-benz-
oxepin-5-ylidenes (Scheme 1). The modularity of this reaction
can be demonstrated by employing a variety of alkyl halides
(R3-X) and aryl iodides containing ortho oxygen-tethered Heck
acceptors (1). This approach is particularly interesting as it forms
(2) As kappa opioid receptor agonists, see: (a) Chu, G.-H.; Gu, M.;
Cassel, J. A.; Belanger, S.; Graczyk, T. M.; DeHaven, R. N.; Conway-
James, N.; Koblish, M.; Little, P. J.; DeHaven-Hudkins, D. L.; Dolle, R.
E. Bioorg. Med. Chem. Lett. 2005, 15, 5114-5119. As estrogen receptor
ligands, see: (b) Tan, Q.; Blizzard, T. A.; Morgan, J. D.; Birzin, E. T.;
Chan, W.; Yang, Y. T.; Pai, L.-Y.; Hayes, E. C.; DaSilva, C. A.; Warrier,
S.; Yudkovitz, J.; Wilkinson, H. A.; Sharma, N.; Fitzgerald, P. M. D.; Li,
S.; Colwell, L.; Fisher, J. E.; Adamski, S.; Reszka, A. A.; Kimmel, D.;
DiNinno, F.; Rohrer, S. P.; Freedman, L. P.; Schaeffer, J. M.; Hammond,
M. L. Bioorg. Med. Chem. Lett. 2005, 15, 1675-1681. For redox
inactivation of human 15-lipoxygenase, see: (c) Cichewicz, R. H.; Kenyon,
V. A.; Whitman, S.; Morales, N. M.; Arguello, J. F.; Holman, T. R.; Crews,
P. J. Am. Chem. Soc. 2004, 126, 14910-14920. As novel pesticides, see:
(d) Yang, G.; Jiang, X.; Yang, H. Pest Manage. Sci. 2002, 58, 1063-1067.
As nicotine agonists, see: (e) Efange, S. M. N.; Tu, Z.; von Hohenberg,
K.; Francesconi, L.; Howell, R. C.; Rampersad, M. V.; Todaro, L. J.; Papke,
R. L.; Kung, M.-P. J. Med. Chem. 2001, 44, 4704-4715. As IKs channel
blockers, see: (f) Gerlach, U.; Brendel, J.; Lang, H.-J.; Paulus, E. F.;
Weidmann, K.; Brueggemann, A.; Busch, A. E.; Suessbrich, H.; Bleich,
M.; Greger, R. J. Med. Chem. 2001, 44, 3831-3837.
* To whom correspondence should be addressed.
† Current address: Green Hills Biotechnology, Gersthofer Strasse 29-31,
A-1180 Vienna, Austria.
(1) Chromans are typically found as the core of the tocopherols, most
importantly Vitamin E (R-tocopherol). For the subtype-specific translocation
and activation of diacylglycerol kinase R by D-R-tocopherol, see: (a)
Fukunaga-Takenaka, R.; Shirai, Y.; Yagi, K.; Adachi, N.; Sakai, N.; Merino,
E.; Merida, I.; Saito, N. Genes Cells 2005, 10, 311-319. For the inhibition
of LPS-induced nitric oxide production by chromans, see: (b) Kim, B.-H.;
Reddy, A. M.; Lee, K.-H.; Chung, E. Y.; Cho, S. M.; Lee, H.; Min, K. R.;
Kim, Y. Biochem. Biophys. Res. Commun. 2004, 325, 223-228. For the
use of chromans in the treatment of cancer and inflammation, see: (c)
Salvatore, B. A.; Solis, F. C. WO 2004103985, 2004. For the use of
chromans as antiinflammatory agents, see: (d) Salman, M.; Arora, P. K.;
Ray, S.; Srimal, R. C. Indian J. Pharm. Sci. 1987, 49, 43-47. For the use
of 1-benzoxepines as inhibitors of farnesyl protein transferase, see: Wolin,
R.; Connolly, M.; Kelly, J.; Weinstein, J.; Rosenblum, S.; Afonso, A.; James,
L.; Kirschmeier, P.; Bishop, W. R. Biorg. Med. Chem. Lett. 1998, 8, 2521-
2526.
10.1021/jo060552l CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/19/2006
J. Org. Chem. 2006, 71, 4937-4942
4937

Martins et al.
SCHEME 3. Generalized Preparation of Cyclization
SCHEME 2. Proposed Reaction Mechanism
Precursors
SCHEME 4. Optimized Reaction Conditions
palladium sources and phosphine ligands, we found that Pd-
(OAc)2 and tri(2-furyl)phosphine8 in acetonitrile was the ideal
catalyst system. Screening of inorganic bases found Cs2CO3 to
be optimal. Testing different alkyl halides, we found that alkyl
bromides performed better than alkyl iodides, and that alkyl
chlorides were inert to the reaction conditions. Substrate
concentration had a small effect on the yield, and 0.35 M 1a in
CH3CN was optimal. Varying the equivalents of each reagent
led to the optimized conditions shown in Scheme 4. Finally, it
was found that the order and the timing of addition of reagents
were crucial to the efficiency of the reaction. We observed that
the best yields were obtained if Pd(OAc)2 and tri(2-furyl)-
phosphine were added together and pre-stirred in CH3CN for
10 to 15 minites under N2(g) until a homogeneous solution was
obtained, followed by addition of Cs2CO3, norbornene, and a
mixture of alkyl halide and aryl iodide in CH3CN. The reaction
vessel was then flushed with N2(g) and heated to 80 °C. Omitting
the pre-stirring of the catalyst generally gave yields 5% to 10%
lower, while under “open flask” conditions, yields were gener-
ally 30% lower. Under the optimized conditions, using n-BuBr
as alkyl halide, 2a was obtained in 68% yield, as solely the E
isomer, as determined by 2D-ROESY experiments. Formation
of the desired product and avoiding the “Heck-only” product
indicates that the intermolecular ortho-alkylation reaction is
a 1,2,3-trisubstituted aromatic, which would be difficult to access
via classical methods. Our previous studies suggest that the
ortho-alkylation step benefits from the presence of electron-
donating groups on the aryl iodide.6b,d This approach would thus
benefit from electron-rich phenol-based systems.
The proposed mechanism and catalytic cycle (Scheme 2),
based upon the findings of Catellani and Pregosin,5b begins with
the oxidative addition of Pd(0) to 1, forming arylpalladium(II)
species 3. Carbopalladation of norbornene forms species 4,
followed by ortho C-H activation to generate palladacycle 5.
An alkyl bromide oxidatively adds to 5, giving Pd(IV) species
6. Reductive elimination of 6 forms a C(sp3)-C(sp2) bond, and
subsequent extrusion of norbornene generates 7, which further
undergoes an intramolecular Heck reaction to afford 2.
Results and Discussion
To create an efficient route toward the desired benzoxacycles,
cyclization precursors should be accessible through common
transformations with use of commercially available starting
materials. For the most part, the substrates were attained through
a two-step alkylation/olefin metathesis (n ) 1), or direct
alkylation with ethyl 6-bromohex-2-enoate (n ) 2) (Scheme
3).
Synthesis of Chromen-4-ylidenes. (a) Optimization. With
substrate 1a in hand, the synthesis of chromen-4-ylidenes was
explored. On the basis of the proposed reaction mechanism
(Scheme 2), a suitable catalytic Pd0 source,7 norbornene, base,
and alkyl halide are required. Through the examination of
(5) (a) Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem., Int. Ed.
Engl. 1997, 36, 119-122. (b) Catellani, M.; Mealli, C.; Motti, E.; Paoli,
P.; Perez-Carreno, E.; Pregosin, P. S. J. Am. Chem. Soc. 2002, 124, 4336-
4346. (c) Catellani, M. Synlett 2003, 298-313. (d) Catellani, M. Top.
Organomet. Chem. 2005, 14, 21-53.
(6) (a) Lautens, M.; Piguel, S. Angew. Chem., Int. Ed. 2000, 39, 1045-
1046. (b) Lautens, M.; Paquin, J.-F.; Piguel, S.; Dahlmann, M. J. Org. Chem.
2001, 66, 8127-8134. (c) Lautens, M.; Paquin, J.-F.; Piguel, S. J. Org.
Chem. 2002, 67, 3972-3974. (d) Pache, S.; Lautens, M. Org. Lett. 2003,
5, 4827-4830. (e) Alberico, D.; Paquin, J.-F.; Lautens, M. Tetrahedron
2005, 61, 6283-6297. (f) Bressy, C.; Alberico, D.; Lautens, M. J. Am.
Chem. Soc. 2005, 127, 13148-13149. (g) Wilhelm, T.; Lautens, M. Org.
Lett. 2005, 7, 4053-4056.
(7) For investigations into “Pd0” formation from PdII salts, see: (a)
Amatore, C.; Jutand, A. J. Organomet. Chem. 1999, 576, 254-278. (b)
Amatore, C.; Jutand, A. Acc Chem. Res. 2000, 33, 314-321.
(8) For a review of the use of tri(2-furyl)phosphine in transition metal
mediated reactions, see: Andersen, N. G.; Keay, B. G. Chem. ReV. 2001,
101, 997-1030.
(3) Tietze, L. F. Chem. ReV. 1996, 96, 115-136.
(4) (a) Negishi, E. Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., Ed.; Wiley: New York, 2002. (b) Tsuji, J. Palladium
Reagents and Catalysts: New PerspectiVes for the 21st Century; Tsuji, J.,
Ed.; Wiley: New York, 2004.
4938 J. Org. Chem., Vol. 71, No. 13, 2006

Synthesis of Substituted Benzoxacycles
TABLE 1. Scope of Alkyl Halides
TABLE 2. Scope of Heck Acceptors
faster than an intramolecular 6-exo-trig Heck reaction under
these reaction conditions. It should also be noted that when the
analogous reaction was attempted with the intent of making
4-substituted benzofurans (n ) 0), only intramolecular Heck
product was obtained, with no ortho-alkylation observed.
(b) Scope of Alkyl Halides. The scope of the reaction was
explored through variation of the alkyl halides used (Table 1).
We elected to introduce n-alkyl chains containing remote
reactive functional groups as potential handles for product
elaboration. As mentioned above, alkyl chlorides were inert to
the reaction conditions, thus introduction of a chloroalkyl chain
by using 1-bromo-3-chloropropane was accomplished, affording
product 2b in 80% yield (entry 2). Furthermore, esters can be
incorporated, as 2c was obtained in 71% yield (entry 3). This
reaction affords two easily differentiated ester moieties. When
a phenyl ring was included at the 3-position of the alkyl bromide,
2d was obtained in 96% yield (entry 4). Introduction of an
epoxyalkyl chain, such as in 2e (entry 5), is particularly
interesting, as epoxides can undergo a variety of reactions.9
Finally, the incorporation of nitrogen-containing side chains was
demonstrated as 2f and 2g were synthesized in 75% and 70%
yields, respectively (entries 6 and 7). These cases demonstrate
that the ortho-alkylation and intramolecular Heck reactions are
faster than aryl amination (either intramolecular or intermo-
lecular), which is known to proceed under similar reaction
conditions.10
containing a nitrogen atom were examined (entries 4 and 5).
Amide 1d afforded product 2j in 65% yield, with significant
amounts of “Heck-only” product observed. The synthetically
useful Weinreb amide11 1e afforded the desired product 2k in
75% yield with no direct Heck reaction product observed. When
Heck acceptors containing strongly Lewis basic functionalities
were tried, such as in entries 6 and 7, only traces of product
were observed. The low yield with 1f may be attributed to
catalyst poisoning by the pyridyl nitrogen, as this was one of
the only cases where starting material was recovered. For vinyl
sulfone 1g, the Lewis basicity of sulfones may have led to
catalyst poisoning, or other reactions12 of phenyl vinyl sulfones
under Pd-catalysis may have formed undesired products,
although no such products could be isolated and identified.
(d) Aromatic Substitution. Aromatic substituents can have
a profound effect on the rates of oxidative addition and
carbopalladation, and thus can greatly affect the catalytic cycle.
As previously mentioned, the ortho-alkylation reaction benefits
from electron-rich aromatic rings, so methoxy-substituted 1h
was subjected to the reaction conditions (Scheme 5) and afforded
2l in 55% yield. This lower than expected yield may be
attributed to a slower rate of oxidative addition to 1h,13 or to
the effect of steric crowding by the methoxy substituent.
Conversely, electron-poor species 1i gave 2m in 74% yield,
showing that electron-withdrawing groups are tolerated. In
(c) Scope of Heck Acceptors. In an effort to further
demonstrate the flexibility of this approach, a variety of Heck
acceptors were examined. As 1-bromo-3-phenylpropane afforded
the best results during the screening of alkyl halides, it was
used to examine the scope of Heck acceptors (Table 2). With
alkyl esters as electron withdrawing groups (entries 1-3), it
was observed that the lability of the ester factored into the
product yield. Methyl ester 1b afforded 2h in 74% yield,
whereas more stable ethyl and tert-butyl esters afforded 2i and
2d in 90% and 96% yields, respectively. Next, Heck acceptors
(9) Hassner, A. In Heterocyclic Compounds; Vol. 42, Part 3, Small Ring
Heterocycles; Hassner, A., Ed.; John Wiley & Sons: Toronto, Canada, 1985;
pp 3-152.
(10) We have preliminary results for a domino ortho-alkylation/aromatic
amination reaction.
(11) For synthetic applications of Weinreb amides, see: (a) Sibi, M. P.
Org. Prep. Proc. Int. 1993, 25, 15-42. (b) Keck, G. E.; McHardy, S. F.;
Murry, J. A. Tetrahedron Lett. 1993, 34, 6215-6218.
(12) Mauleo´n, P.; Alonso, I.; Carretero, J. C. Angew. Chem., Int. Ed.
2001, 40, 1291-1293.
J. Org. Chem, Vol. 71, No. 13, 2006 4939

Martins et al.
SCHEME 5. Aromatic Substitution
Conclusion
We have developed a concise route toward the synthesis of
alkylidene benzoxacyclic products. This method utilizes pal-
ladium-catalyzed ortho-alkylation with an intramolecular Heck
reaction as the ring-forming step. In this sequence, two carbon-
carbon bonds are formed in one pot, one from an unactivated
aryl C-H bond. For six- and seven-membered rings, the
intramolecular Heck reaction was slow enough for the reaction
to proceed smoothly in the desired sequence. The modularity
of this reaction was demonstrated by the variety of chroman-
4-ylidenes and 1-benzoxepin-5-ylidenes which could be syn-
thesized through variation of the alkyl halide and Heck acceptor
moieties.
SCHEME 6. Synthesis of 1-Benzoxepin-5-ylidenes
Experimental Section
The following represents experimental procedures toward the
synthesis of products 2a-q. This includes experimental details and
characterization data for the aforementioned compounds. The
information for all other compounds can be found in the Supporting
Information.
General Procedure. In a round-bottom flask with a fused, water-
cooled condenser were combined Pd(OAc)2 (7.80 mg, 0.0350 mmol,
10 mol %) and P(2-Furyl)3 (16.2 mg, 0.0700 mmol, 20 mol %),
then the flask was capped and flushed with N2(g). Dry CH3CN (0.5
mL) was added, and the mixture was stirred for 10-15 minutes at
room temperature, until a homogeneous, orange-red solution was
obtained. Next, Cs2CO3 (228 mg, 0.700 mmol, 2 equiv) was added,
and the solution turned a dark brown color. Norbornene (132 mg,
1.40 mmol, 4 equiv) was added, followed by a mixture of 1 (0.350
mmol) and alkyl bromide (1.75 mmol, 5 equiv) in CH3CN (0.5
mL). The system was capped, flushed with N2(g), and then stirred
at 80 °C for 18 h. The mixture was quenched with 10 mL of
saturated NH4Cl(aq) and extracted with 3 × 10 mL of Et2O. The
combined organic phases were dried over MgSO4, filtered, and
concentrated in vacuo. The crude mixture was then purified by flash
chromatography on silica gel to afford product 2.
tert-Butyl (2E)-(5-Butyl-2,3-dihydro-4H-chromen-4-ylidene)-
acetate (2a). Following the general procedure, 1a (80.0 mg, 0.210
mmol) and 1-bromobutane (113 µL, 1.05 mmol) were reacted. The
crude mixture was purified by flash chromatography on silica gel
(Rf 0.42 in 10% Et2O/hexane), using 0-10% Et2O/hexane, to afford
product 2a as a viscous, clear oil. Isolated yield: 43 mg (68%). 1H
NMR (300 MHz, CDCl3) δ 0.96 (t, J ) 7.3 Hz, 3H), 1.37-1.44
(m, 2H), 1.51 (s, 9H), 1.59-1.67 (m, 2H), 2.73-2.80 (m, 2H),
3.36 (td, J ) 6.1, 1.2 Hz, 2H), 4.23-4.29 (m, 2H), 5.96 (s, 1H),
6.67 (dd, J ) 8.2 1.2 Hz, 1H), 6.81 (dd, J ) 7.6, 1.2 Hz, 1H),
7.09-7.15 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 13.8, 22.6,
27.5, 28.3, 32.9, 33.9, 66.7, 80.1, 114.6, 118.1, 122.9, 129.8, 141.3,
147.2, 156.6, 166.2; IR neat, ν (cm-1) 734 (m), 753 (m), 861 (w),
885 (w), 1058 (m), 1144 (s), 1256 (m), 1367 (m), 1630 (m), 1707
(s), 2254 (w), 2872 (m), 2931 (m), 2959 (m); HRMS (EI) calcd
for C19H26O3 302.1882 (M+), found 302.1874.
tert-Butyl (2E)-[5-(3-Chloropropyl)-2,3-dihydro-4H-chromen-
4-ylidene]acetate (2b). Following the general procedure, 1a (80.0
mg, 0.210 mmol) and 1-bromo-3-chloropropane (104 µL, 1.05
mmol) were reacted. The crude mixture was purified by flash
chromatography on silica gel (Rf 0.40 in 10% Et2O/hexane), using
0-10% Et2O/hexane, to afford product 2b as a viscous, clear oil.
Isolated yield: 54 mg (80%). 1H NMR (300 MHz, CDCl3) δ 1.51
(s, 9H), 2.04-2.15 (m, 2H), 2.93-3.00 (m, 2H), 3.37 (t, J ) 6.3
Hz, 2H), 3.57 (t, J ) 6.5 Hz, 2H), 4.28 (t, J ) 6.3 Hz, 2H), 5.96
(s, 1H), 6.70 (dd, J ) 8.2, 1.1 Hz, 1H), 6.81 (dd, J ) 7.7, 0.8 Hz,
1H), 7.14 (t, J ) 8.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 27.7,
28.5, 30.7, 34.3, 44.7, 67.1, 80.6, 115.4, 118.6, 123.1, 123.4, 130.2,
139.2, 147.2, 157.0, 166.2; IR neat, ν (cm-1) 1076 (w), 1144 (s),
1249 (m), 1367 (m), 1448 (m), 1598 (w), 1632 (m), 1705 (s), 2976
(m); HRMS (EI) calcd for C18H23ClO3 322.1336 (M+), found
322.1330.
addition, the nitro group can act as a precursor to a variety of
transformations.14 Finally, the presence of an aryl halide was
examined. Our previous work demonstrated that extraneous I,
Br, and OTf aromatic substitutents were not tolerated under the
reaction conditions;6b thus an aromatic Cl was tried. Gratifyingly,
aryl chlorides are inert to the reaction conditions, and 2n was
isolated in 77% yield. This is a useful result, as the aryl chloride
can serve as a functional handle for a variety of recently
developed cross-coupling reactions.15
Synthesis of 1-Benzoxepin-5-ylidenes. Our final effort was
placed upon the synthesis of seven-membered rings through the
intramolecular Heck reaction. Our previous efforts demonstrated
success synthesizing benzoxepinylidenes;6c however, benz-
oxepines with phenolic oxygens could not be accessed by that
method. This method provides access to a different family of
benzoxepines with a different substitution pattern. With use of
the optimized conditions listed in Scheme 3, 1k was used to
synthesize several 1-benzoxepin-5-ylidenes (Scheme 6). Yields
were generally lower than those for the chromanylidene
analogues; however, there was greater uniformity of isolated
yield with a variety of alkyl halides.
(13) For a discussion on the effect of electron donating and withdrawing
groups on the rate of oxidative addition, see: Amatore, C.; Pflu¨ger, F.
Organometallics 1990, 9, 2276-2282.
(14) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH:
Chichester, UK, 2001.
(15) Palladium-catalyzed cross-coupling of aryl chlorides: Selected
examples in aromatic amination, see: (a) Shen, Q.; Shekhar, S.; Stambuli,
J. P.; Hartwig, J. F. Angew. Chem., Int. Ed. 2005, 44, 1371-1375. (b)
Urgaonkar, S.; Verkade, J. G. J. Org. Chem. 2004, 69, 9135-9142. In
Sonogashira coupling, particularly with ortho-substituted aryl chlorides,
see: (c) Gelman, D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2003, 42,
5993-5996. In Suzuki-Miyaura coupling, see: (d) Shen, W. Tetrahedron
Lett. 1997, 38, 5575-5578. (e) Anderson, K. W.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2005, 44, 6173-6177. (f) Ozdemir, I.; Gurbuz, N.; Gok,
Y.; Cetinkaya, E.; Cetinkaya, B. Synlett 2005, 2394-2396. In Stille
coupling, see: (g) Su, W.; Urgaonkar, S.; McLaughlin, P. A.; Verkade, J.
G. J. Am. Chem. Soc. 2004, 126, 16433-16439. In Heck coupling, see:
(h) Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10-11. In Negishi
coupling, see: (i) Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004,
126, 13028-13032. In Kumada coupling, see: (j) Huang, J.; Nolan, S. P.
J. Am. Chem. Soc. 1999, 121, 9889-9890.
4940 J. Org. Chem., Vol. 71, No. 13, 2006

Synthesis of Substituted Benzoxacycles
Ethyl 4-[(4E)-4-(2-tert-Butoxy-2-oxoethylidene)-3,4-dihydro-
2H-chromen-5-yl]butanoate (2c). Following the general procedure,
1a (131 mg, 0.350 mmol) and ethyl 4-bromobutyrate (252 µL, 1.75
mmol) were reacted. The crude mixture was purified by flash
chromatography on silica gel (Rf 0.36 in 20% Et2O/hexane), using
0-20% Et2O/hexane, affording product 2c as a clear, pale yellow
1701 (s, br), 2933 (m), 2978 (m), 3337 (m, br); HRMS (EI) calcd
for C20H27NO5 362.1967 (M+), found 362.1964.
tert-Butyl (2E)-(5-{3-[(Ethoxycarbonyl)amino]propyl}-2,3-di-
hydro-4H-chromen-4-ylidene)acetate (2g). Following the general
procedure, 1a (131 mg, 0.350 mmol) and ethyl 3-bromopropylcar-
bamate (368 mg, 1.75 mmol) were reacted. The crude mixture was
purified by flash chromatography on silica gel (Rf 0.47 in 30%
EtOAc/hexane), using 15-35% Et2O/hexane, to afford product 2g
as a clear, pale yellow oil. Isolated yield: 92 mg (70%). 1H NMR
(400 MHz, CDCl3) δ 1.24 (t, J ) 6.9 Hz, 3H), 1.52 (s, 9H), 1.79-
1.89 (m, 2H), 2.80-2.86 (m, 2H), 3.20-3.29 (m, 2H), 3.36 (t, J )
6.3 Hz, 2H), 4.11 (q, J ) 6.9 Hz, 2H), 4.27 (t, J ) 6.1 Hz, 2H),
4.65 (br s, 1H), 5.91 (s, 1H), 6.70 (d, J ) 8.1 Hz, 1H), 6.81 (d, J
) 7.2 Hz, 1H), 7.13 (t, J ) 7.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 14.7, 27.6, 28.3, 30.4, 31.7, 40.6, 60.7, 66.8, 80.4, 115.1,
118.1, 122.8, 123.0, 130.0, 139.7, 147.3, 156.7, 156.8, 166.0; IR
neat, ν (cm-1) 778 (m), 883 (m), 947 (w), 1039 (s), 1143 (s), 1250
(s), 1367 (s), 1537 (s), 1699 (s), 2977 (s), 3065 (w), 3334 (br, s);
HRMS (ESI) calcd for C20H27NO5Na 398.1937 (M + Na+), found
398.1952.
Methyl (2E)-[5-(3-Phenylpropyl)-2,3-dihydro-4H-chromen-4-
ylidene]acetate (2h). Following the general procedure, 1b (70.0
mg, 0.210 mmol) and Ph(CH2)3Br (159 µL, 1.05 mmol) were
reacted. The crude mixture was purified by flash chromatography
on silica gel (Rf 0.36 in 10% Et2O/hexane), using 0-10% Et2O/
hexane, to afford product 2h as a viscous, clear oil. Isolated yield:
50 mg (74%). 1H NMR (300 MHz, CDCl3) δ 1.90-2.02 (m, 2H),
2.66-2.72 (m, 2H), 2.78-2.85 (m, 2H), 3.37-3.42 (m, 2H), 3.76
(s, 3H), 4.24-4.29 (m, 2H), 5.99 (s, 1H), 6.69 (dd, J ) 8.2, 1.1
Hz, 1H), 6.82 (dd, J ) 7.8, 1.1 Hz, 1H), 7.11-7.21 (m, 4H), 7.26-
7.32 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 28.0, 33.2, 33.4, 36.0,
51.4, 66.9, 115.2, 115.9, 123.1, 126.0, 128.6, 128.7, 130.4, 142.1,
149.3, 157.0, 167.2; IR neat, ν (cm-1) 700 (m), 753 (m), 787 (w),
878 (w), 1047 (w), 1081 (m), 1158 (s), 1250 (m), 1309 (m), 1353
(m), 1447 (m), 1474 (m), 1573 (m), 1597 (m), 1631 (m), 1714 (s),
2946 (m), 3024 (m); HRMS (ESI) calcd for C21H23O3 323.1641
(M + H+), found 323.1642.
1
oil. Isolated yield: 90 mg (71%). H NMR (300 MHz, CDCl3) δ
1.26 (t, J ) 7.1 Hz, 3H), 1.52 (s, 9H), 1.90-2.01 (m, 2H), 2.34 (t,
J ) 7.4 Hz, 2H), 2.80-2.87 (m, 2H), 3.36 (t, J ) 6.2 Hz, 2H),
4.13 (q, J ) 7.1 Hz, 2H), 4.27 (t, J ) 6.2 Hz, 2H), 5.92 (s, 1H),
6.69 (dd, J ) 8.0, 1.1 Hz, 1H), 6.83 (d, J ) 7.5 Hz, 1H), 7.13 (t,
J ) 8.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 14.5, 26.8, 27.9,
28.5, 32.5, 34.1, 60.5, 67.0, 80.5, 115.2, 118.6, 122.9, 123.4, 130.1,
139.9, 147.3, 156.9, 166.3, 173.5; IR neat, ν (cm-1) 734 (m), 861
(w), 885 (w), 1045 (m), 1078 (m), 1143 (s), 1250 (s), 1368 (s),
1447 (m), 1574 (m), 1598 (m), 1631 (m), 1705 (s), 1732 (s), 2876
(m), 2934 (m), 2977 (s), 3447 (w); HRMS (ESI) calcd for C21H29O5
361.2009 (M + H+), found 361.2018.
tert-Butyl (2E)-[5-(3-Phenylpropyl)-2,3-dihydro-4H-chromen-
4-ylidene]acetate (2d). Following the general procedure, 1a (187
mg, 0.500 mmol) and Ph(CH2)3Br (380 µL, 2.50 mmol) were
reacted. The crude mixture was purified by flash chromatography
on silica gel (Rf 0.33 in 10% Et2O/hexane), using 0-10% Et2O/
hexane, to afford product 2d as a viscous, clear oil, slowly
solidifying to a waxy, white solid with needlelike crystals (mp 42-
45 °C). Isolated yield: 175 mg (96%). 1H NMR (300 MHz, CDCl3)
δ 1.53 (s, 9H), 1.90-2.02 (m, 2H), 2.65-2.72 (m, 2H), 2.78-
2.85 (m, 2 H), 3.34-3.39 (m, 2H), 4.26 (t, J ) 6.1 Hz, 2H), 5.94
(s, 1H), 6.67 (dd, J ) 8.1, 1.2 Hz, 1H), 6.81 (dd, J ) 7.7, 1.1 Hz,
1H), 7.11 (t, J ) 8.0 Hz, 1H), 7.15-7.22 (m, 3H), 7.24-7.32 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 27.8, 28.6, 33.3, 33.7, 36.1,
67.0, 80.5, 115.0, 118.3, 122.9, 123.2, 126.0, 128.6 (2 C), 130.1,
140.9, 142.3, 147.5, 156.9, 166.4; IR neat, ν (cm-1) 695 (s), 760
(m), 794 (m), 861 (m), 883 (m), 944 (m), 1080 (s), 1140 (s), 1248
(s), 1311 (m), 1699 (s), 2971 (s); HRMS (ESI) calcd for C24H29O3
365.2111 (M + H+), found 365.2124.
tert-Butyl (2E)-[5-(2-Oxiran-2-ylethyl)-2,3-dihydro-4H-chromen-
4-ylidene]acetate (2e). Following the general procedure, 1a (131
mg, 0.350 mmol) and 2-(2-bromoethyl)oxirane (264 mg, 1.75
mmol) were reacted. The crude mixture was purified by flash
chromatography on silica gel (Rf 0.55 in 10% Et2O/hexane), using
0-5% Et2O/hexane, affording product 2e as a clear, pale yellow
Ethyl (2E)-[5-(3-Phenylpropyl)-2,3-dihydro-4H-chromen-4-
ylidene]acetate (2i). Following the general procedure, 1c (118 mg,
0.340 mmol) and Ph(CH2)3Br (258 µL, 1.70 mmol) were reacted.
The crude mixture was purified by flash chromatography on silica
gel (Rf 0.30 in 10% Et2O/hexane), using 5-10% Et2O/hexane, to
afford product 2i as a viscous, clear oil. Isolated yield: 103 mg
1
oil. Isolated yield: 55 mg (50%). H NMR (400 MHz, CDCl3) δ
1
(90%). H NMR (400 MHz, CDCl3) δ 1.33 (t, J ) 7.1 Hz, 3H),
1.52 (s, 9H), 1.79-1.96 (m, 2H), 2.53 (dd, J ) 4.9, 2.7 Hz, 1H),
2.76-2.79 (m, 1H), 2.94-3.00 (m, 3H), 3.30-3.44 (m, 2H), 4.27
(t, J ) 6.2 Hz, 2H), 5.94 (s, 1H), 6.70 (dd, J ) 8.1, 1.1 Hz, 1H),
6.83 (dd, J ) 7.7, 1.1 Hz, 1H), 7.13 (t, J ) 7.9 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 27.8, 28.5, 29.7, 34.5, 47.4, 52.0, 67.0, 80.6,
115.4, 118.5, 122.9, 123.2, 130.2, 139.6, 147.4, 157.0, 166.2; IR
neat, ν (cm-1) 750 (m), 858 (m), 1079 (m), 1144 (s), 1251 (m),
1367 (m), 1475 (m), 1574 (m), 1597 (m), 1633 (m), 1704 (s), 2975
(m); HRMS (EI) calcd for C19H24O4 316.1675 (M+), found
316.1674.
tert-Butyl (2E)-(5-{2-[(Ethoxycarbonyl)amino]ethyl}-2,3-di-
hydro-4H-chromen-4-ylidene)acetate (2f). Following the general
procedure, 1a (131 mg, 0.350 mmol) and ethyl 2-bromoethylcar-
bamate (343 mg, 1.75 mmol) were reacted. The crude mixture was
purified by flash chromatography on silica gel (Rf 0.49 in 30%
EtOAc/hexane), using 15-35% Et2O/hexane, to afford product 2f
as a clear, pale yellow oil. Isolated yield: 95 mg (75%). 1H NMR
(300 MHz, CDCl3) δ 1.19-1.27 (m, 3H), 1.52 (s, 9H), 3.04 (t, J
) 7.1 Hz, 2H), 3.37 (t, J ) 5.8 Hz, 2H), 3.41-3.51 (m, 2H), 4.11
(q, J ) 7.0 Hz, 2H), 4.28 (t, J ) 6.2 Hz, 2H), 4.64 (br s, 1H), 5.92
(s, 1H), 6.72 (d, J ) 8.2 Hz, 1H), 6.83 (d, J ) 7.4 Hz, 1H), 7.15
(t, J ) 8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 14.7, 27.6,
28.3, 29.8, 33.2, 41.7, 60.8, 67.0, 80.5, 92.0, 107.2, 115.6, 118.7,
122.6, 130.1, 156.5, 156.8, 165.9; IR neat, ν (cm-1) 778 (m), 942
(w), 1051 (m), 1145 (s), 1253 (s), 1367 (m), 1448 (m), 1534 (s),
1.91-2.01 (m, 2H), 2.66-2.71 (m, 2H), 2.79-2.84 (m, 2H), 3.39
(t, J ) 6.3 Hz, 2H), 4.21 (q, J ) 7.0 Hz, 2H), 4.26 (t, J ) 6.3 Hz,
2H), 6.00 (s, 1H), 6.68 (d, J ) 8.3 Hz, 1H), 6.81 (d, J ) 7.7 Hz,
1H), 7.13 (t, J ) 7.9 Hz, 1H), 7.15-7.21 (m, 3H), 7.24-7.30 (m,
2H); 13 C NMR (100 MHz, CDCl3) δ 14.5, 28.0, 33.2, 33.5, 36.0,
60.2, 66.9, 115.1, 116.4, 123.0, 126.0, 128.5, 128.6, 130.3, 140.9,
142.2, 148.9, 157.0, 166.8; IR, neat, ν (cm-1) 700 (s), 751 (s), 787
(w), 883 (w), 909 (w), 1050 (m), 1081 (m), 1157 (s), 1249 (s),
1366 (m), 1447 (s), 1475 (s), 1496 (m), 1574 (m), 1597 (s), 1632
(s), 1709 (s), 1738 (s), 2935 (m); HRMS (EI) calcd for C22H24O3
336.1725 (M+), found 336.1726.
1-{(2E)-2-[5-(3-Phenylpropyl)-2,3-dihydro-4H-chromen-4-
ylidene]ethanoyl}pyrrolidine (2j). Following the general proce-
dure, 1d (31.0 mg, 0.0850 mmol) and Ph(CH2)3Br (65.0 µL, 0.425
mmol) were reacted. The crude mixture was purified by flash
chromatography on silica gel (Rf 0.21 in 50% EtOAc/hexane), using
50-60% EtOAc/hexane, to afford product 2j as a viscous, clear,
1
colorless oil. Isolated yield: 20 mg (65%). H NMR (400 MHz,
CDCl3) δ 1.85-2.03 (m, 6H), 2.69 (t, J ) 7.5 Hz, 2H), 2.80-2.86
(m, 2H), 3.28 (t, J ) 6.1 Hz, 2H), 3.32 (t, J ) 6.5 Hz, 2H), 3.54
(t, J ) 6.6 Hz, 2H), 4.28 (t, J ) 6.1 Hz, 2H), 6.08 (s, 1H), 6.68
(dd, J ) 8.1, 1.1 Hz, 1H), 6.82 (dd, J ) 7.5, 1.1 Hz, 1H), 7.11 (t,
J ) 7.9 Hz, 1H), 7.15-7.21 (m, 3H), 7.25-7.30 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 24.4, 26.2, 27.8, 32.8, 33.1, 35.8, 45.6, 46.9,
67.3, 114.8, 118.8, 122.5, 125.8, 128.3, 128.4, 129.4, 140.1, 141.9,
J. Org. Chem, Vol. 71, No. 13, 2006 4941

Martins et al.
142.8, 156.3, 165.5; IR neat, ν (cm-1) 699 (m), 747 (m), 1080 (m),
1248 (m), 1343 (m), 1418 (s), 1450 (s), 1615 (s), 1640 (s), 2926
(s); HRMS (ESI) calcd for C24H27NO2 361.2042 (M+), found
361.2047.
Ethyl (2E)-[6-(3-Chloropropyl)-3,4-dihydro-1-benzoxepin-
5(2H)-ylidene]acetate (2o). Following the general procedure, 1k
(178 mg, 0.500 mmol) and 1-bromo-3-chloropropane (247 µL, 2.50
mmol) were reacted. The crude mixture was purified by flash
chromatography on silica gel (Rf 0.13 in 70% CH2Cl2/hexane), using
70-80% CH2Cl2/hexane, to afford product 2o as a clear, colorless
(2E)-N-Methoxy-N-methyl-2-[5-(3-phenylpropyl)-2,3-dihydro-
4H-chromen-4-ylidene]acetamide (2k). Following the general
procedure, 1e (180 mg, 0.500 mmol) and Ph(CH2)3Br (380 µL,
2.50 mmol) were reacted. The crude mixture was purified by flash
chromatography on silica gel (Rf 0.35 in 25% EtOAc/hexane), using
10-45% EtOAc/hexane, to afford product 2k as a viscous, red-
1
oil. Isolated yield: 73 mg (47%). H NMR (400 MHz, CDCl3) δ
1.31 (t, J ) 7.1 Hz, 3H), 1.94-2.09 (m, 4H), 2.83 (br s, 2H), 3.50
(t, J ) 6.5 Hz, 2H), 4.09 (br s, 2H), 4.21 (q, J ) 7.0 Hz, 2H), 5.78
(s, 1H), 6.88 (dd, J ) 7.9, 1.1 Hz, 1H), 7.00 (dd, J ) 7.6, 0.8 Hz,
1H), 7.16 (t, J ) 7.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
14.3, 29.2, 30.1, 30.4, 34.0, 44.2, 59.9, 72.9, 119.4, 119.9, 125.3,
128.8, 135.9, 138.2, 156.5, 157.8, 166.0; IR neat, ν (cm-1) 755
(w), 881 (w), 998 (w), 1044 (m), 1068 (m), 1174 (s), 1236 (m),
1275 (m), 1368 (m), 1444 (m), 1571 (w), 1639 (m), 1713 (s), 2956
(m); HRMS (EI) calcd for C17H21ClO3 308.1179 (M+), found
308.1183.
1
orange oil. Isolated yield: 132 mg (75%). H NMR (300 MHz,
CDCl3) δ 1.94-2.05 (m, 2H), 2.69 (t, J ) 7.7 Hz, 2H), 2.83-2.88
(m, J ) 6.3 Hz, 2H), 3.26 (s, 3H), 3.36 (t, J ) 6.2 Hz, 2H), 3.63
(s, 3H), 4.28 (t, J ) 6.3 Hz, 2H), 6.49 (s, 1H), 6.69 (dd, J ) 8.2,
1.2 Hz, 1H), 6.83 (dd, J ) 7.6, 1.2 Hz, 1H), 7.10-7.20 (m, 4H),
7.25-7.30 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 27.8, 33.0, 33.2,
35.7, 61.7, 67.1, 100.0, 114.8, 115.1, 122.6, 123.4, 125.8, 128.3 (4
C), 129.7, 140.4, 141.9, 156.6; IR neat, ν (cm-1) 700 (s), 1080
(m), 1456 (s), 2935 (s); HRMS (EI) calcd for C22H26NO3 352.1913
(M + H+), found 352.1909.
Ethyl 4-[(5E)-5-(2-Ethoxy-2-oxoethylidene)-2,3,4,5-tetrahy-
dro-1-benzoxepin-6-yl]butanoate (2p). Following the general
procedure, 1k (178 mg, 0.500 mmol) and ethyl 4-bromobutyrate
(358 µL, 2.50 mmol) were reacted. The crude mixture was purified
by flash chromatography on silica gel (Rf 0.32 in 20% Et2O/hexane),
using 10-25% Et2O/hexane, to afford product 2p as a clear,
tert-Butyl (2E)-[6-Methoxy-5-(3-phenylpropyl)-2,3-dihydro-
4H-chromen-4-ylidene]acetate (2l). Following the general pro-
cedure, 1h (134 mg, 0.330 mmol) and Ph(CH2)3Br (251 µL, 1.65
mmol) were reacted. The crude mixture was purified by flash
chromatography on silica gel (Rf 0.41 in 50% CH2Cl2/hexane), using
40-60% CH2Cl2/hexane, affording product 2l as a clear, colorless
1
colorless oil. Isolated yield: 77 mg (45%). H NMR (400 MHz,
CDCl3) δ 1.18-1.29 (m, 2H), 1.24 (t, J ) 7.1 Hz, 3H), 1.31 (t, J
) 7.1 Hz, 3H), 1.80-1.89 (m, 2H), 1.96, 2.04 (m, 2H), 2.28 (t, J
) 7.5 Hz, 2H), 2.70 (br s, 2H), 4.09 (br s, 2H), 4.11 (q, J ) 7.2
Hz, 2H), 4.21 (q, J ) 7.0 Hz, 2H), 5.77 (s, 1H), 6.86 (dd, J ) 7.9,
1.1 Hz, 1H), 6.99 (dd, J ) 7.7, 0.9 Hz, 1H), 7.15 (t, J ) 7.8 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 14.2, 14.3, 26.5, 29.1, 30.4,
32.2, 33.9, 59.9, 60.3, 72.9, 119.2, 119.7, 125.3, 128.7, 135.8, 138.9,
156.3, 158.1, 166.0, 173.2; IR neat, ν (cm-1) 755 (w), 880 (w),
997 (w), 1044 (m), 1068 (m), 1096 (w), 1174 (s), 1242 (s), 1275
(m), 1369 (m), 1445 (m), 1638 (m), 1713 (s), 1732 (s), 2941 (m);
HRMS (EI) calcd for C20H26O5 346.1780 (M+), found 346.1797.
Ethyl (2E)-[6-(3-Phenylpropyl)-3,4-dihydro-1-benzoxepin-
5(2H)-ylidene]acetate (2q). Following the general procedure, 1k
(178 mg, 0.500 mmol) and 1-bromo-3-phenylpropane (380 µL, 2.50
mmol) were reacted. The crude mixture was purified by flash
chromatography on silica gel (Rf 0.21 in 10% Et2O/hexane), using
5-12% Et2O/hexane, to afford product 2q as a clear, colorless oil.
Isolated yield: 79 mg (45%). 1H NMR (300 MHz, CDCl3) δ 1.17-
1.31 (m, 2H), 1.31 (t, J ) 7.1 Hz, 3H), 1.80-1.88 (m, 2H), 1.96-
2.03 (m, 2H), 2.59-2.64 (m, 2H), 2.68 (br s, 2H), 3.96-4.17 (m,
2H), 4.21 (t, J ) 7.0 Hz, 2H), 5.76 (s, 1H), 6.85 (dd, J ) 7.9, 1.3
Hz, 1H), 6.97 (dd, J ) 7.7, 1.1 Hz, 1H), 7.14 (t, J ) 7.8 Hz, 1H),
7.14-7.20 (m, 3H), 7.23-7.29 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 14.3, 29.1, 30.4, 32.8, 33.2, 35.7, 59.9, 72.9, 119.0, 119.6,
125.3, 125.8, 128.3, 128.6, 135.7, 139.9, 142.0, 156.3, 158.2, 166.1;
IR neat, ν (cm-1) 700 (m), 751 (m), 880 (w), 998 (m), 1044 (m),
1173 (s), 1243 (m), 1275 (m), 1368 (m), 1445 (m), 1639 (m), 1713
(s), 2940 (m); HRMS (EI) calcd for C23H26O3 350.1882 (M+), found
350.1873.
1
viscous oil. Isolated yield: 71 mg (55%). H NMR (300 MHz,
CDCl3) δ 1.54 (s, 9H), 1.88-2.01 (m, 2H), 2.69-2.82 (m, 4H),
3.36 (t, J ) 5.9 Hz, 2H), 3.76 (s, 3H), 4.21 (t, J ) 6.2 Hz, 2H),
5.97 (s, 1 H), 6.67 (d, J ) 8.8 Hz, 1H), 6.78 (d, J ) 9.1 Hz, 1H),
7.14-7.31 (m, 7H); 13C NMR (125 MHz, CDCl3) δ 16.9, 27.7,
28.2, 28.4, 32.1, 36.3, 56.2, 66.7, 80.2, 110.0, 113.1, 114.4, 118.6,
125.7, 128.2, 128.4, 142.4, 147.5, 150.7, 152.5, 166.1; IR thin film,
ν (cm-1) 699 (m), 807 (w), 884 (w), 946 (w), 1064 (m), 1081 (m),
1142 (s), 1231 (m), 1366 (m), 1461 (s), 1634 (m), 1705 (s), 2935
(s); HRMS (EI) calcd for C25H30O4 394.2144 (M+), found 394.2141.
tert-Butyl (2E)-[7-Nitro-5-(3-phenylpropyl)-2,3-dihydro-4H-
chromen-4-ylidene]acetate (2m). Following the general procedure,
1i (145 mg, 0.350 mmol) and Ph(CH2)3Br (266 µL, 1.75 mmol)
were reacted. The crude mixture was purified by flash chromatog-
raphy on silica gel (Rf 0.37 in 10% Et2O/hexane), using 0-12%
Et2O/hexane, affording product 2m as a yellow oil. Isolated yield:
106 mg (74%). 1H NMR (300 MHz, CDCl3) δ 1.54 (s, 9H), 1.93-
2.05 (m, 2H), 2.71 (t, J ) 7.6 Hz, 2H), 2.87 (m, 2H), 3.37 (t, J )
6.3 Hz, 2H), 4.34 (t, J ) 6.1 Hz, 2H), 6.00 (s, 1H), 7.16-7.23 (m,
3H), 7.25-7.33 (m, 2H), 7.49 (d, J ) 2.3 Hz, 1H), 7.66 (d, J )
2.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 26.9, 28.5, 33.2 (2C),
35.9, 67.7, 81.3, 110.2, 116.8, 121.1, 126.3, 128.6, 128.7, 129.2,
141.6, 142.3, 145.1, 148.3, 157.0, 165.6; IR neat, ν (cm-1) 700
(s), 1145 (s), 1347 (s), 1523 (s), 1603 (m), 1636 (m), 1708 (s),
1739 (m), 2935 (s), 2976 (s); HRMS (EI) calcd for C24H27NO5
409.1889 (M+), found 409.1885.
tert-Butyl (2E)-[6-Chloro-5-(3-phenylpropyl)-2,3-dihydro-4H-
chromen-4-ylidene]acetate (2n). Following the general procedure,
1j (143 mg, 0.350 mmol) and Ph(CH2)3Br (266 µL, 1.75 mmol)
were reacted. The crude mixture was purified by flash chromatog-
raphy on silica gel (Rf 0.54 in 10% Et2O/hexane), using 0-4%
Et2O/hexane, to afford product 2n as a clear, pale pink oil. Isolated
yield: 107 mg (77%). 1H NMR (400 MHz, CDCl3) δ 1.54 (s, 9H),
1.95-2.04 (m, 2H), 2.74 (dd, J ) 8.1, 8.0 Hz, 2H), 2.86-2.90 (m,
2H), 3.36 (t, J ) 6.0 Hz, 2H), 4.27 (t, J ) 6.2 Hz, 2H), 5.98 (s,
1H), 6.64 (d, J ) 8.8 Hz, 1H), 7.16-7.21 (m, 2H), 7.23-7.31 (m,
4H); 13C NMR (100 MHz, CDCl3) δ 27.1, 28.3, 31.1, 31.6, 35.9,
67.0, 80.6, 116.1, 118.9, 124.8, 125.9, 127.2, 128.3, 128.4, 131.1,
137.7, 141.9, 147.0, 155.2, 165.8; IR neat, ν (cm-1) 815 (m), 885
(m), 1081 (m), 1144 (s), 1446 (s), 1634 (s), 1709 (s), 1870 (w),
2976 (s); HRMS (EI) calcd for C24H27ClO3 398.1649 (M+), found
398.1645.
Acknowledgment. We thank the National Science and
Engineering Research Council of Canada and Merck Frosst
Canada & Co. for financial support in the form of an Industrial
Research Chair. A.M. thanks the Government of Ontario for
financial support in the form of an Ontario Graduate Scholarship.
U.M. thanks the Boehringer-Ingleheim Foundation for financial
support in the form of a postdoctoral fellowship. We also thank
Dr. Alex Young for help with mass spectrometry analysis and
Dr. Sandrine Pache for helpful discussions.
Supporting Information Available: Experimental details and
characterization data for compounds 1a to 1k and their precursors.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO060552L
4942 J. Org. Chem., Vol. 71, No. 13, 2006