Tandem Henry/oxa-Michael route to the 1,3-disubstituted-1,3-dihydrobenzo[c] furan system

Article abstract of DOI:10.1016/j.tetlet.2011.09.123

The reaction of ortho-formyl cinnamates and ortho-formyl-α- benzalketones with suitably substituted alkylnitro compounds in the presence of 1,1,3,3-tetramethylguanidine results in the formation of 1,3-disubstituted dihydroisobenzofurans. The reaction mechanism entails a base-mediated nitronate addition to the aryl formyl group followed by intramolecular alcoholate addition to the unsaturated component that then affords the isobenzofuran system.

Full text of DOI:10.1016/j.tetlet.2011.09.123

Tetrahedron Letters 52 (2011) 6530–6533
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Tandem Henry/oxa-Michael route to the
1,3-disubstituted-1,3-dihydrobenzo[c]furan system q
⇑
Frederick A. Luzzio , Otome E. Okoromoba
Department of Chemistry, University of Louisville, 2320 South Brook Street, Louisville, KY 40292, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of ortho-formyl cinnamates and ortho-formyl-a-benzalketones with suitably substituted
Received 24 August 2011
Revised 26 September 2011
Accepted 27 September 2011
Available online 4 October 2011
alkylnitro compounds in the presence of 1,1,3,3-tetramethylguanidine results in the formation of 1,
3-disubstituted dihydroisobenzofurans. The reaction mechanism entails a base-mediated nitronate addi-
tion to the aryl formyl group followed by intramolecular alcoholate addition to the unsaturated compo-
nent that then affords the isobenzofuran system.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Isobenzofurans
Henry reaction
Alkylnitro compounds
1,1,3,3-Tetramethylguanidine
Heck reaction
1. Introduction
the aromatic and dihydrofuran rings. For example, the 1,3-disubsti-
tuted-1,3-dihydroisobenzofuran system may act as extended
When considering the Henry reaction, a number of cyclic motifs
are possible when employing alkylnitro compounds in conjunction
with the reacting partners having multiple carbonyl components.2
The sequential process of anion generation followed by C–C bond
formation facilitates these so called ‘tandem’ processes whereby
five and six-membered carbocycles may be assembled from the
appropriate 1,4- or 1,5-dicarbonyl compounds and nitroalkanes.3
The accompanying side products, in contrast to the carbocyclic
products, are those in which closure does not result in C–C bond for-
mation giving the nitroaldol but rather ethereal bond formation
giving an acetal or ketal. Interestingly, a similar process may be
pursued by replacing the second carbonyl component with an elec-
tron-poor double bond thereby enabling an intramolecular alkox-
ide Michael addition. Hence, the resulting cyclic ether may take
the form of 1,3-dihydrobenzo[c]furan system when the starting
substrates have the carbonyl and EWG substituents disposed ortho
on the aryl system. The 1,3-dihydrobenzo[c]furan system is a repre-
sentative oxygen heterocycle whose derivatives display diverse
biological activities such as those associated with antifungal4a, anti-
depressive4b, antisecretory4c, and antitumor function.4d In addition,
the multi-functionalized 1,3-dihydroisobenzofuran system consti-
tutes a unique benzoheterocyclic scaffold for elaboration on both
scaffold analogous to the more structurally abbreviated 1,3-disub-
stituted-2,5-dihydrofurans as in the case of 20,30-benzo-fused
didehydronucleoside analogs.5 A number of previous routes to the
dihydroisobenzofuran system are tandem conversions such as
diene generation-cycloaddition,4d o-metalation-epoxide open-
ing,6a
,
iodocyclization,6b o-metalation-addition-displacement6c
,
and telluration-epoxide opening.6d We are presently exploring
the tandem Henry/oxa-Michael reaction of ortho-formyl cinna-
mates, 20-(ortho-formyl) chalcones, ortho-formylbenzalacetones,
and analogous ortho-formylarylenones with nitroalkanes (Eq. 1).
When reacting the difunctional formyl derivatives with alkylnitro
compounds of 1–3 carbons under basic conditions, a Henry-type at-
tack on the aldehyde occurs first. The intermediate b–nitroalkoxide
then cyclizes on the electron-deficient alkene thereby forming the
R1
O
COR3
NO2
H
R3
R2
R4
O
R4
H
ð1Þ
TMG/THF/rt
H
R1
R2
2a-j
O
NO2
1a-e
diastereomeric 1,3-disubstituted 1,3-dihydroisobenzofurans
(Scheme 1). The tandem reaction utilizes 1,1,3,3-tetramethylguani-
dine (TMG)7 as the catalyst in THF at room temperature and is oper-
ationally simple and amenable to scale-up.
q
See Ref. 1.
⇑
Corresponding author.
E-mail address: faluzz01@gwise.louisville.edu (F.A. Luzzio).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.123

F. A. Luzzio, O. E. Okoromoba / Tetrahedron Letters 52 (2011) 6530–6533
6531
finic substitution within the substrate aldehyde. In all cases, the
tandem reaction affords chromatographically-inseparable mix-
tures of diastereomeric products which may be clearly identified
through inspection of 400 or 500 MHz 1H NMR data. Through cor-
relating our spectral data with that of earlier workers who reported
stereospecific preparations of 1,3-disubstituted-1,3-dihydroiso-
benzofurans, we were able to confirm the 1H NMR peak assign-
ments of the diastereotopic ring protons.6a,10b The distribution of
1,3- cis and trans diastereomers ranged from 1.3/1 to 4/1 as deter-
mined by proton integration whereby the farthest downfield pro-
tons on the dihydrofuran ring are situated trans and exhibited
the characteristic H–C–O–C–H coupling.10,11 Using nitromethane
and formyl cinnamate 1a or formylchalcone 1c, the yield of the ex-
pected isobenzofurans 2i and 2j comprised less than 20% of very
complicated reaction mixtures (Table 1). Presumably, the compet-
ing Michael addition of the more reactive nitromethane results in
an adduct giving a multiple anion manifold. The intramolecular
addition of either anion would then yield carbocyclic products of
the Henry type as well as those of the standard intramolecular al-
dol addition (Scheme 2). Although the competing side reactions
O
O
R
TMG
THF
R
(R)2CHNO2
2
O-
O
R
H
NO2
(R)2C-NO2
R
Scheme 1. Tandem Henry–Michael mechanism to iso benzofurans.
2. Results and discussion
The tandem Henry/oxa-Michael reaction was tested on a range
of difunctional o-formyl derivatives 1a–e and nitroalkanes (Ta-
ble 1). The nitroalkane co-reactants were commercially available
save for 3-methyl-4-nitrobutane.8 All the reactions were run in
capped vessels at room temperature in THF without scrupulous
precaution to exclude air or moisture.9 The reaction time varied
from 2–16 h, depending on the alkylnitro compound and the ole-
Table 1
Tandem Henry–Michael reactants and products
Aldehyde
Nitro
compound
Producta,c
Yieldb
Aldehyde
Nitro
compound
Product
Yieldb
(ratio)e
(ratio)e
COOEt
COOEt
NO2
COC6H5
NO2
NO2
NO2
CHO
1a
O
O
87 (1.5:1) 1c
68 (4:1)
2a
2f
COCH3
COCH3
CO-t-Bu
CHO
CO-t-Bu
NO2
NO2
NO2
NO2
CHO
1b
O
O
82 (2:1)
86 (1.7:1)
1d
NO2
2b
2c
2g
NO2
COCH3
COCH3
COCH3
O
O
O
O
O
O
CHO
1e
76
(1:1:1:1)
1b
79 (2:1)
NO2
NO2
2h
COCH3
COOEt
NO2
O
O
1b
90 (1.3:1) 1a
CH3NO2
<20d
NO2
NO2
2i
2j
2d
COC6H5
COC6H5
COC6H5
NO2
CHO
O
O
65 (4:1)
1c
CH3NO2
<20d
1c
NO2
NO2
2e
a
b
c
Products are a chromatographically-homogenous diastereomeric mixture.
Isolated yields.
With the exception of conversion of 1d–2d, the reactions were run with commercially-available nitro compounds.
d
e
Yields were estimated by 1H NMR.
Diastereomeric ratio of trans to cis.

6532
F. A. Luzzio, O. E. Okoromoba / Tetrahedron Letters 52 (2011) 6530–6533
O
NO2
COR
H2C-NO2 (Michael)
CH2OH
a
CHO
CH2OTBDMS
b
R
COR
NO2
-
-
COR
CH2OTBDMS
CH2OTBDMS
H
H
H
O
O
c
O
a. PCC/SiO2/CH2Cl2/rt;
b. Ph3PCHCOR/CH2Cl2;
c. PCC/SiO2/TBAF/CH2Cl2
(Henry)
(aldol)
1a
NO2
COR
COR
NO2
Scheme 3. Selective synthesis of coupling components via Witting.
substituted isobenzofuranyl ketone 3 in 68% yield (Eq. 4).16 In sum-
mary, we have detailed a tandem ‘Henry/oxa-Michael’ route to the
1,3-disubstituted-1,3-dihydrobenzo[c]furan system. The key reac-
tion utilizes nitroalkanes and difunctional aryl substrates bearing
a formyl group and suitably-disposed unsaturation in the form of
an enoate or enone. Presently, the reaction is limited to mainly sec-
ondary nitro compounds and the scope of the reaction has yet to be
expanded with electron withdrawing groups such as nitrile, sulfo-
nyl, or nitro as well as primary nitro compounds. Further experi-
ments entailing stereocontrol and the application of the overall
strategy to natural product synthesis are presently underway and
will be reported in due course.
OH
OH
Scheme 2. Competing carbon–carbon bond formation during the tandem reaction
with nitromethane.
depicted in Scheme 2 are nonexistent using secondary alkylnitro
compounds, we were gratified to obtain 2c in respectable yield
using the primary alkylnitro compound, 3-methyl-4-nitrobutane
(Table 1). Presumably, there is enough steric influence so that
the Henry attack is favored over the Michael attack during the first
step of the tandem reaction in yielding 2c. Our synthetic route to-
ward the products listed in Table 1 necessitated the preparation of
the
a,b-unsaturated-b-phenyl (ortho-formyl) esters/ketones 1a–
Acknowledgments
e.12,13 These compounds are not commercially-available, but can
be prepared from o-phthalaldehyde through a semi-Wittig reac-
tion (Eq. 2) or from 2-bromo-4,5-methylenedioxybenzaldehyde
through a Heck reaction (Eq. 3). In a few instances, the utilization
of ortho-phthalaldehyde presented problems as an impurity during
We thank Dr. Bogdan Bogdanov for running high-resolution
mass spectra and Mr. Joel Ott and Mr. Steve Shang for preliminary
results. Use of the Texas A&M University Laboratory for Biological
Mass Spectrometry and Ms. Vanessa Santiago are acknowledged.
We thank Juan Chen for technical contributions.
the isolation and purification of the product
a,b-unsaturated for-
myl esters or ketones. A more selective route which avoided
o-phthalaldehyde entailed preparation of the half-silyl ether of
1,2-benzenedimethanol followed by oxidation with PCC/SiO2 and
Wittig olefination (Scheme 3).14 Oxidation-desilylation of the
TBDMS-protected cinnamate with PCC/SiO2 in the presence of
tetra-n-butylammonium fluoride (TBAF) then affords the 2-formyl-
cinnamate 1a. Overall, we found the Heck reaction of the 2-halo-
methylenedioxy aldehydes and methyl vinyl ketone as the
greatest expedient toward substrate (1e) with aryl substitution al-
ready in place, albeit with the lowest yields. Depending on the
requirements of a typical synthetic plan the 3-substituted nitro-
methylisobenzofuran may only be intermediary, thus, it may be-
come necessary to remove the nitro group and replace it with
hydrogen or even deuterium. We found that the replacement of
the nitro group with hydrogen is easily facilitated using the free
References and notes
1. Presented by FAL at the 240th National Meeting of the American Chemical
Society, Boston, MA; August 22, 2010 (ORGN 161).
2. For
a review which includes tandem Henry processes, see: Luzzio, F. A.
Tetrahedron 2001, 57, 915–945.
3. (a) Ruano, J. L. G.; Marcos, V.; Suanzes, J. A.; Marzo, L.; Aleman, J. Chem. Eur. J.
2009, 15, 6576–6580; (b) Ballini, R.; Petrini, M. ARKIVOC 2009, ix, 195–223; (c)
Ballini, R.; Barboni, L.; Fiorini, D.; Giarlo, G.; Palmieri, A. Green Chem. 2005, 7,
828–829; (d) Luzzio, F. A.; Fitch, R. W. J. Org. Chem. 1999, 64, 5485–5493; (e)
Sasai, H.; Hiroi, M.; Yamada, Y. M. A.; Shibasaki, M. Tetrahedron Lett. 1997, 38,
6031–6034; (f) Fitch, R. W.; Luzzio, F. A. Ultrason. Sonochem. 1997, 4, 99–107;
(g) Chou, W.; Fotsch, C.; Wong, C.-H. J. Org. Chem. 1995, 60, 1917–2916; (h)
Defaye, J.; Gadelle, A.; Movilliat, F.; Nardin, R. Carbohyd. Res. 1991, 212, 129–
157; (i) Eberle, M.; Missbach, M.; Seebach, D. In Organic Synthesis; Paquette, L.
A., Ed.; Wiley: New York, 1990; Vol. 69, pp 19–30 (Coll. Vol. VII); (j) Weller, T.;
Seebach, D. Tetrahedron Lett. 1982, 23, 935–938; (k) Lichtenthaler, F. W. Angew.
Chem. Int. Ed. Engl. 1964, 3, 211–224.
4. (a) Lovey, R. G.; Elliot, A. J.; Kaminski, J. J.; Loebenberg, D.; Parmegiani, R. M.;
Rane, D. F.; Girijavallabhan, V. M.; Pike, R. M.; Guzik, H.; Antonacci, B.; Tomaine,
T. Y. J. Med. Chem. 1992, 35, 4221–4229; (b) Agranat, I.; Caner, H.; Caldwell, J.
Nat. Rev. Drug. Disc. 2002, 1, 753–768; (c) Klohs, M. W.; Petracek, F. J. U.S. Patent
3 471 519, 1969; Chem. Abstr. 1969, 71, 124212.; (d) Martin, C.; Maillet, P.;
Maddaluno, J. J. Org. Chem. 2001, 66, 3797–3805; (e) Karmakar, R.; Pahari, P.;
Mal, D. Tetrahedron Lett. 2009, 50, 4042–4045.
R
Ph3P
CHO
O
ð2Þ
1a-d (Table 1)
CH2Cl2/rt
CHO
R
5. Ewing, D. F.; Len, C.; Mackenzie, G.; Ronco, G.; Villa, P. Tetrahedron: Asymmetry
2000, 11, 4995–5002.
Br
O
O
O
ð3Þ
1e (Table 1)
6. (a) Capriati, V.; Florio, S.; Luisi, R.; Perna, F. M.; Salomone, A. J. Org. Chem. 2006,
71, 3984–3987; (b) Mancusco, R.; Mehta, S.; Gabriele, B.; Salerno, G.; Jencks, W.
S.; Larock, R. C. J. Org. Chem. 2010, 75, 897–901; (c) Parham, W. E.; Bradsher, C.
K.; Reames, D. C. J. Org. Chem. 1981, 46, 4804–4806; (d) Delacroix, T.; Berillon,
L.; Cahiez, G.; Knochel, P. J. Org. Chem. 2000, 65, 8108–8110; (e) Cjao, B.;
Dittmer, D. C. Tetrahedron Lett. 2000, 41, 6001–6004.
Pd(OAc)2
NaOAc/DMA
CHO
radical method of Ono.15 For example, after removal of the TMG by
flash chromatography, the complex diastereomeric mixture 2c
(Table 1) was directly treated with tri-n-butyltin hydride/
AIBN in refluxing toluene (110 °C) and furnished the 3-isopentyl-
7. Luzzio, F. A.; Fitch, R. W. Tetrahedron Lett. 1994, 35, 6013–6016.
8. Zhang, Z.; Schreiner, P. R. Synthesis 2007, 2559–2564.
9. Preparation of 1,3-Dihydroisobenzofurans (2a–h, Table 1). General Procedure: To
a solution of formyl enone or enoate 1a–e (0.2–0.5 mmol) and nitroalkane
(0.24–0.6 mmol, 1.2 equiv) in dry THF (2.0–3.0 mL) was added 1,1,3,3-
tetramethylguanidine (0.2 equiv) by syringe at room temperature. Upon
addition of the base, the solution turned yellow or yellow–orange. The
reaction mixture was then capped and stirring was continued (rt) while
monitoring by thin layer chromatography (hexane/EtOAc, 2:1?hexane/EtOAc,
6:1). The product starts to form within an hour, exhibits a less-mobile spot, and
as the reaction progresses, the color begins to lighten but does not completely
COCH3
HSnBu3AIBN
2c
O
ð4Þ
toluene/110 oC
68%
3

F. A. Luzzio, O. E. Okoromoba / Tetrahedron Letters 52 (2011) 6530–6533
6533
discharge. Upon complete consumption of starting material, the THF is
removed by rotary evaporation and the oily residue is dissolved in
minimum of dichloromethane. The CH2Cl2 solution of the crude product is
then directly applied to a silica gel flash column and eluted with hexane/ethyl
acetate (4:1). The pure fractions were then combined and concentrated under
vacuum to afford the pure 1,3-dihydro-isobenzofurans 2a–h.
minor), 7.96 (d, 2H, J = 8.5 Hz, major), 7.58 (t, 2H, J = 7.5 Hz), 7.48 (m, 4H), 7.30
(m, 6H), 7.17 (d, 1H, J = 7.5 Hz, minor), 7.08 (d, 1H, J = 7.0 Hz, major), 5.96 (dt,
1H, J = 3.6 Hz, major), 5.93 (d, 1H, J = 2.5, major), 5.86 (t, 1H, J = 6.5 Hz, minor),
5.72 (s, 1H, minor), 3.58 (dd, 1H, J = 7, 12.5 Hz, minor), 3.56 (dd, 1H, J = 5.5,
16.5, major), 3.30 (dd, 1H, J = 6.0, 11, minor), 3.29 (dd, 1H, J-6, 17 Hz, major),
2.62 (m, 1H, minor), 2.55 (m, 1H, minor), 2.49 (m, 1H, major), 2.30 (m, 1H,
major), 2.13 (m, 2H, minor/major), 1.98 (m, 1H, minor), 1.82 (m, 1H, major),
1.71 (m, 8H, minor/major); 13C NMR (100 MHZ, CDCl3) d: 197.64, 197.49,
142.71, 142.41, 136.93, 136.89, 136.86, 136.81, 133.40, 133.37, 128.96, 128.86,
128.65 (overlap), 128.64 (overlap), 128.33 (overlap), 128.26, 128.20 (overlap),
128.16, 122.23, 122.17, 121.93, 121.78, 102.62, 102.16, 86.29, 85.26, 80.39,
79.64, 46.12, 46.03, 35.16, 35.02, 33.63, 31.90, 24.62, 24.58, 24.49, 24.26;
a
10. (a) Barfield, M.; Spear, R. J.; Sternhell, S. J. Am. Chem. Soc. 1971, 93, 5322–5327;
(b) Petracek, F. J.; Sugisaka, N.; Klohs, M. W.; Parker, R. G.; Bordner, J.; Roberts,
J. D. Tetrahedron Lett. 1970, 10, 707–710.
11. Ethyl 2-(3-(2-nitropropan-2-yl)-1,3-dihydroisobenzofuran-1-yl) acetate. (2a,
Table 1): (oil, 1.5:1 diastereomeric mixture) Rf 0.44 (hexane/EtOAc, 2:1);
FTIR 2986, 1730, 1536, 1348, 1159, 1042 cmꢀ1 1H NMR (500 MHz, CDCl3) d:
;
7.35 (m, 2H), 7.30 (m, 2H), 7.21 (m, 2H), 5.77 (s, 1H, major), 5.71(m, 1H, minor),
5.70 (s, 1H, major), 5.62 (m, 1H, minor), 4.21 (q, 2H), 4.19 (q, 2H), 2.81 (dd, 1H),
2.68 (m, 3H), 1.24 (t, 1H, major), 1.3 (t, 1H, minor), 1.46 (s, 3H, major), 1.52 (s,
3H, minor), 1.58 (s, 3H, major), 1.62 (s, 3H, minor); 13C NMR (125 MHz, CDCl3)
d: 170.59 (overlap), 142.24, 142.10, 136.78, 136.62, 129.25, 129.20, 128.67,
128.61, 122.64, 122.51, 121.75, 121.73, 91.47, 90.45, 87.36, 87.16, 81.02, 80.15,
61.08, 60.92, 42.25, 42.17, 23.57, 22.84, 21.44, 20.98, 14.44, 14.37; HRMS calcd
for C15H20NO5 (M+H)+ 294.1341; found 294.1349. 1-(3-(2-Nitropropan-2-yl)-
1,3-dihydroisobenzofuran-1-yl)propan-2-one (2b, Table 1): (oil, 2:1
diastereomeric mixture) Rf 0.38 (hexane/EtOAc, 2:1); FTIR 2997, 1712, 1534,
HRMS calcd for C
21H21NaNO4 374.1362 (M+Na)+, Found 374.1363. 3,3-
Dimethyl-1-(3-(2-nitropropan-2-yl)-1,3-dihydroiso benzofuran-1-yl) butan-2-
one. (2 g, Table 1): (oil, 1.7:1 diastereomeric mixture) Rf 0.56 (hexane/EtOAc,
2:1); FTIR 1702, 1536, 1460, 1369, 1348, 1041 cmꢀ1 1H NMR (CDCl3) d: 7.28
;
(m, 4H), 7.26 (m, 2H), 7.06 (m, 2H), 5.78 (dt, 1H, J = 2.8, 5.6 Hz, major), 5.74 (d,
1H, J = 2.8 Hz, major), 5.70 (t, 1H, J = 5.6 Hz, minor), 5.62 (s, 1H, minor), 3.11
(dd, 1H, J = 7.2, 17.2 Hz, minor), 3.08 (dd, 1H, J = 6, 17.2 Hz, major), 2.77 (dd,
1H, J = 5.6, 17.2 Hz, minor), 2.72 (dd, 1H, J = 6.4, 16.8 Hz, major), 3.28 (s, 3H,
minor), 1.55 (s, 6H, overlap, minor, major), 1.43 (s, 3H, major); 13C NMR
(100 MHz, CDCl3) d: 213.37, 212.92, 143.02, 142.68, 136.52, 136.35, 129.31,
128.98, 128.85, 128.16 (overlap), 122.29, 122.11, 121.77, 121.60, 91.35, 90.21,
86.83 (overlap), 80.84 (overlap), 79.57, 44.31, 43.86, 26.07 (overlap), 23.12,
1396, 1348, 1049 cmꢀ1 1H NMR (400 MHz, CDCl3) d: 7.31 (m, 4H), 7.18 (t, 2H),
;
7.09 (t, 2H), 5.75 (s, 1H, major), 5.73 (m, 1H, major), 5.65 (s, 1H, minor), 5.62
(m, 1H, minor), 2.9 (dd, 2H), 2.77 (dd, 2H), 2.26 (s, 3H, minor), 2.20 (s, 3H,
major), 1.61 (s, 3H, minor), 1.56 (s, 6H, minor, major, overlap), 1.45 (s, 3H,
major); 13C NMR (100 MHz, CDCl3) d: 206.25, 206.11, 142.40, 142.19, 136.23
(overlap), 129.07, 128.97, 128.31, 128.28, 122.37, 122.19, 121.61, 121.53,
91.31, 90.25, 87.12, 87.06, 80.46, 79.53, 50.67 (overlap), 30.93 (overlap), 22.89,
22.29, 21.76, 20.88; HRMS calcd for C14H17NNaO4 (M+Na)+ 286.1055; Found
286.1049. 1-(3-(3-Methyl-1-nitrobutyl)-1,3-dihydroisobenzo furan-1-yl)propan-
2-one. (2c, Table 1): (oil, 1:1:1:1 diastereomeric mixture) Rf 0.42 (hexane/
22.50, 21.75, 20.69; HRMS calcd for
C
17H24NO4 306.1705 (M+H)+, Found
306.1697. 1-(7-(2-Nitropropan-2-yl)-5,7-dihydroisobenzo furo[5,6-d][1,3]dioxol-
5-yl)propan-2-one. (2h, Table 1): (oil, 2:1 diastereomeric mixture) Rf 0.30
(hexane/EtOAc, 2:1); FTIR 2996, 2898, 1708, 1536, 1476, 1347, 1259,
1034 cmꢀ1 1H NMR (400 MHz, CDCl3) d: 6.58 (d, 2H, J = Hz), 6.47 (d, 2H,
;
J = 8 Hz), 5.97 (s, 4H), 5.61 (m, 1H, major), 5.58 (m, 1H, major), 5.51 (s, 1H,
minor), 5.49 (m, 1H, minor), 2.86 (dd, 1H, J = 6.8, 16.8 Hz, major), 2.85 (dd, 1H,
J = 7.2, 16.4 Hz minor), 2.76 (dd, 1H, J = 5.2, 16.4 Hz, minor), 2.70 (dd, 1H,
J = 5.2, 16.8 Hz, major), 2.23 (s, 3H, minor), 2.17 (s, 3H, major), 1.59 (s, 3H,
minor), 1.54 (s, 3H, major), 1.53 (s, 3H, minor), 1.42 (s, 3H, major); 13C NMR
(100 MHz, CDCl3) d: 206.39, 206.21, 148.91, 148.87, 148.40, 148.36, 135.72,
135.53, 128.90 (overlap), 102.70, 102.54, 102.05 (overlap), 101.92 (overlap),
91.37, 90.31, 87.16, 87.04, 80.39, 79.49, 50.91, 50.87, 30.98, 30.96, 22.98, 22.50,
21.67, 20.69; HRMS calcd for C15H17LiNO6 (M+Li)+ 314.1216, Found 314.1208.
12. (a) Fustero, S.; Moscardo, J.; Sanchez-Rosello, M.; Rodriguez, F.; Barrio, P. Org.
Lett. 2010, 12, 5494–5497; (b) Suwa, T.; Nishino, K.; Miyatake, M.; Shibata, I.;
Baba, A. Tetrahedron Lett. 2000, 41, 3403–3406; (c) Suwa, T.; Shibata, I.;
Nishino, K.; Baba, A. Org. Lett. 1999, 1, 1579–1581; (d) Dai, W.-M.; Lee, M. Y. H.
Tetrahedron Lett. 1998, 39, 8149–8152; (e) Shigematsu, N.; Hayashi, K.;
Kayakiri, N.; Takase, S.; Hashimoto, M.; Tanaka, H. J. Org. Chem. 1993, 58,
170–175.
EtOAc, 2:1); FTIR 1960, 2874, 1713, 1545, 1460, 1371 cmꢀ1 1H NMR (400 MHz,
;
CDCl3) d: 7.32 (m, 2H), 7.18 (m, 1H), 7.10 (m, 1H), 5.73 (m, 2H), 5.66 (t, 2H,
J = 6 Hz), 5.56 (m, 1H), 5.50 (m, 2H), 5.43 (d, 1H, J = 5.6), 4.76 (m, 3H), 4.63 (m,
1H), 2.90 (m, 8H), 2.27 (s, 3H), 2.26 (s, 3H), 2.24 (m, 4H), 2.21 (s, 6H), 1.61 (m,
8H), 0.94 (m, 24H); 13C NMR (100 MHz, CDCl3) d: 218.66, 218.45, 218.20,
218.02, 142.23 (overlap), 141.52 (overlap), 136.95 (overlap), 136.58 (overlap),
129.18 (overlap), 129.11, 128.47, 128.40, 128.08 (overlap), 122.56, 122.31,
121.87, 121.79 (overlap), 121.70 (overlap), 121.63 (overlap), 90.46, 90.04,
89.79, 89.55, 83.91, 83.70, 83.61 (overlap), 80.16, 79.99, 79.93, 79.50, 51.15,
51.02, 50.32, 50.17, 38.31, 38.08, 37.78, 37.71, 31.28, 31.03, 30.94, 30.80, 25.05
(overlap), 24.97, 23.19, 23.08. 21.33, 21.12 (overlap), 21.04 (overlap), 20.89,
20.82; HRMS calcd for C16H22NO4 (M+H)+ 292.1549, Found 292.1543. HRMS
calcd for
C
16H22NO4 (M+H)+ 292.1549, Found 292.1543. 1-(3-(1-
Nitrocyclopentyl)-1, 3-dihydroisobenzofuran-1-yl) propane-2-one. (2d, Table 1):
(oil, 1.3:1 diastereomeric mixture) Rf 0.4 (hexane/EtOAc, 2:1); FTIR 2962, 2878,
13. The a,b-unsaturated-b-(ortho-formyl)phenyl substrates such as those listed in
Table 1 have recently been synthesized and used as key intermediates in the
stereoselective synthesis of 1,3-disubstituted isoindolines; see Ref. 12a.
14. Banfi, L.; Basso, A.; Casuscelli, F.; Guanti, G.; Naz, F.; Riva, R.; Zito, P. Synlett
2010, 85–88.
15. Ono, N.; Miyake, H.; Tamura, R.; Kaji, A. Tetrahedron 1981, 22, 1705–1708.
16. 1-(3-Isopentyl-1,3-dihydroisobenzofuran-1-yl)propan-2-one. 3: To a solution of
1-(3-(3-Methyl-1-nitrobutyl)-1,3-dihydroiso-benzofuran-1-yl) propan-2-one
2c (62.5 mg, 0.21 mmol) in dry toluene (3.0 mL) was added tri-n-butyltin
1713, 1532, 1359, 1160, 1049 cmꢀ1 1H NMR (400 MHz, CDCl3) d:7.3 (m, 2H),
;
7.27 (m, 2H), 7.15 (m, 3H), 7.05 (d, 1H, J = 7.2 Hz), 5.87 (d, 1H, J=2.4 Hz, major),
5.70 (m, 1H, major), 5.68 (s, 1H, minor), 5.59 (s, 1H, minor), 2.88 (dd, 2H, J = 7.2,
16.4 Hz, overlap), 2.76 (dd, 2H, J = 4.8, 16 Hz, overlap), 2.55 (m, 3H), 2.3 (m,
1H), 2.56 (s, 3H, minor), 2.19 (s, 3H, major), 2.04 (m, 3H), 1.82 (m, 1H), 1.72 (m,
8H); 13C NMR (100 MHz, CDCl3) d: 206.39, 206.25, 142.31, 142.09, 136.64,
136.62, 128.97, 128.86, 128.24, 128.17, 122.25, 122.19, 121.54, 121.45, 102.56,
102.18, 86.41, 85.37, 80.13, 79.42, 50.79, 50.64, 34.82, 34.68, 33.74, 32.14,
31.06, 30.89, 24.63, 24.53, 24.41, 24.29; HRMS calcd for C16H19NaNO4 (M+Na)+
312.1212, Found 312.1206. 2-(3-(2-Nitropropan-2-yl)-1,3-dihydroisobenzo
furan-1-yl)-1-phenylethanone. (2e, Table 1): (oil, 4:1 diastereo-meric mixture)
hydride (93.6
(10.5 mg, 0.064 mmol). The mixture was then refluxed under nitrogen (3 h, oil
bath) and another portion of n-butyltin hydride (93.6 l) and AIBN (10.5 mg)
lL, 0.32 mmol) by syringe followed by azobisisobutyronitrile
l
was added. Stirring was continued (2 h) where upon TLC analysis (hexane/
EtOAc, 10:1) indicated full consumption of 2c and the more mobile product.
Toluene was then removed under rotary evaporation and the oily yellow
residue was then flash-chromatographed on silica gel (hexane/EtOAc, 10:1) to
afford 3 (35 mg, 68%) as a 50/50 mixture of diastereomers (colorless oil): Rf
0.19 (hexane/EtOAc, 10:1); FTIR 2955, 2931, 2869, 1714, 1460, 1365,
Rf 0.5 (hexane /EtOAc, 2:1); FTIR 2922, 1678, 1541, 1447, 1212, 1053 cmꢀ1 1H
;
NMR (400 MHz, CDCl3) d: 8.0 (d, 2H, J = 6 Hz), 7.95 (d, 2H, J = 6 Hz), 7.57 (m,
2H), 7.48 (m, 4H), 7.30 (m, 6H), 7.09 (d, 2H, J = 6 Hz), 5.98 (m, 1H, major), 5.86
(m, 1H, minor), 5.79 (s, 1H, major), 5.67 (s, 1H, minor), 3.59 (dd, 1H, overlap,
minor), 3.57 (dd, 1H, J = 4.8, 13.6 Hz, major), 3.35 (dd, 1H, 4.8, 13.6 Hz, minor),
3.28 (dd, 1H, J = 5.2, 13.6 Hz, major), 1.63 (s, 3H, minor), 1.58 (s, 3H, major),
1.56 (s, 3H, minor), 1.47 (s, 3H, major); 13C NMR (100 MHz, CDCl3) d: 197.49,
197.38, 142.82, 142.56, 136.87, 136.38, 133.48, 133.41, 129.08 (overlap),
128.96 (overlap), 128.73 (overlap), 128.66 (overlap), 128.30 (overlap), 128.27
(overlap), 128.22 (overlap), 122.34, 122,19, 122.03, 121.90, 91.39, 90.29, 87.04,
86.98, 80.72, 79.69, 46.18, 45.95, 23.33, 22.59, 21.65, 20.75; HRMS calcd for
1161 cmꢀ1 1H NMR (500 MHz, CDCl3) d: 7.28 (m, 4H), 7.16 (m, 4H), 5.68 (m,
;
1H), 5.59 (t, 1H, J = 6.5), 5.26 (m, 1H), 5.18 (t, 1H, J = 5 Hz), 2.91 (dd, 1H, J = 7.5,
17 Hz), 2.89 (d, 2H, J = 5.5), 2.80 (dd, 1H, J = 5,16 Hz), 2.72 (s, 3H), 2.23 (s, 3H),
1.91 (m, 1H), 1.83 (m, 1H), 1.69 (m, 2H), 1.57 (m, 2H), 1.34 (m, 4H); 13C NMR
(125 MHz, CDCl3) d: 206.94, 206.91, 142.35, 142.24, 141.57, 141.47, 127.32,
127.70, 127.52 (overlap), 121.24, 121.19, 121.14, 121.10, 83.47, 83.27, 78.88,
78.83, 51.29, 50.62, 34.44, 34.29, 34.19, 33.93, 31.11, 30.95, 28.11, 28.03, 22.62,
22.58, 22.46, 22.45; HRMS calcd for C16H22NaO2 (M+Na)+ 269.1512, Found
269.1513.
C
19H20NO4 326.1392 (M+H)+, Found: 326.1405. 2-(3-(1-Nitrocyclopentyl)-1,3-
dihydroisobenzofuran-1-yl)-1-phenylethan one. (2f, Table 1): (oil, 4:1
diastereomeric mixture) Rf 0.52 (hexane/EtOAc, 2:1); FTIR 2961, 2876, 1681,
1531, 1448, 1209 cmꢀ1 1H NMR (500 MHz, CDCl3) d: 8.02 (d, 2H, J = 8.5 Hz,
;