Electroreductive intramolecular coupling of phthalimides with aromatic aldehydes: Application to the synthesis of lennoxamine

Article abstract of DOI:10.1021/jo2018735

The electroreductive intramolecular coupling of phthalimides with aromatic aldehydes in the presence of chlorotrimethylsilane and triethylamine led to five-, six-, and seven-membered cyclized products (58 - 84%). The electroreductive cyclization was applied to the total synthesis of lennoxamine.

Full text of DOI:10.1021/jo2018735

Note
pubs.acs.org/joc
Electroreductive Intramolecular Coupling of Phthalimides with
Aromatic Aldehydes: Application to the Synthesis of Lennoxamine
Naoki Kise,* Shinsaku Isemoto, and Toshihiko Sakurai
Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101, Koyama-cho Minami,
Tottori 680-8552, Japan
S
* Supporting Information
ABSTRACT: The electroreductive intramolecular coupling of
phthalimides with aromatic aldehydes in the presence of
chlorotrimethylsilane and triethylamine led to five-, six-, and
seven-membered cyclized products (58−84%). The electro-
reductive cyclization was applied to the total synthesis of
lennoxamine.
In order to apply the electroreductive cyclization to the
ecently, we have reported the electroreductive intra-
Rmolecular coupling of phthalimides with ketones and synthesis of lennoxamine 7, we explored the dehydroxylation of
aldehydes1 and α,β-unsaturated esters2 in the presence of
diols 5 and 6 (Scheme 3). Reduction of 5 and 6 with Et3SiH/
BF3·Et2O in CH2Cl2 gave 11 and 12, respectively. Alcohol 11
chlorotrimethylsilane (TMSCl) and triethylamine (TEA). In
this context, we report herein that the electroreductive
intramolecular coupling of phthalimides with aromatic
aldehydes in the presence of TMSCl and TEA produced
tetracyclic compounds 4−6 incorporating an isoindolinone ring
(Scheme 1). It is worth noting that the seven-membered
cyclized product 6 was also obtained in high yield (82%),
whereas the intramolecular coupling with aliphatic aldehydes
gave the corresponding seven-membered cyclized product in
low yield (34%).1 Because of these results, we planned the
synthesis of lennoxamine 7 utilizing this electroreductive
intramolecular coupling. Lennoxamine 7 and chilenine 8,
naturally occurring isoindolobenzazepine alkaloids,3 have
attracted much attention from synthetic chemists because of
their unique structures.4 Although the reductive cyclization of 9
to 10 with the expensive SmI2 reagent has been reported for the
formal synthesis of chilenine 8 (Scheme 2),5 we were able to
achieve the reaction by electroreduction, which is an
inexpensive process, without using rare-earth reagents. In
addition, we improved more conveniently the preparation of
the precursor 9 for the cyclized product 10. Consequently, the
present method provides a practical method for the
construction of the isoindolobenzazepine skeleton of 7
compared to the other synthetic strategies employing late-
stage formation of the C12b−C13 bond of the benzoazepine
ring.4j,l,m,5,6
was formed as a single stereoisomer (76% yield), and the
1
relative stereochemistry was assigned to be trans by its H
NMR coupling constant (J = 9.2 Hz). On the other hand,
alcohol 12 was obtained as a 50:50 diastereomeric mixture
(70% yield). Both isomers of 12 could be separated by column
chromatography, and the structure of each stereoisomer was
determined by X-ray crystallographic analysis. Dehydration of
alcohols 11 and 12 with KHSO4 in refluxing xylene and
subsequent hydrogenation of the resulting alkenes 13 and 14
afforded the saturated products 15 and 16 in high yields.
The synthesis of lennoxamine 7 was then performed as
depicted in Scheme 4. The preparation of substrate 9 for the
electroreductive cyclization was achieved from known com-
pounds, aldehyde 177 and acid anhydride 20.8 Aldehyde 17 was
transformed to β-nitrostyrene 18 by addition with nitro-
methane and subsequent dehydration in 64% yield. LiAlH4
reduction of 18 led to β-arylethylamine 19 quantitatively. On
the other hand, acid anhydride 20 was converted to N-
ethoxycarbonylimide 21 by heating with aq NH3 and following
N-ethoxycarbonylation of the resulting imide in 78% yield.
Reaction of 19 and 21 with TEA in DMF gave the substrate 9
(60% yield) after subsequent deacetalization with 3 M HCl.
Electroreduction of 9 in the presence of TMSCl and TEA
followed by desilylation with TBAF led to diol 10 as a 50:50
diastereomeric mixture (68% yield). The diastereomeric
mixture of 10 was reduced by Et3SiH/BF3·Et2O to give alcohol
22 in 66% yield with a 50:50 diastereomeric ratio. Dehydration
of the mixture of 22 with KHSO4 in refluxing toluene afforded
dehydrolennoxamine 23 (82% yield), which was subjected to
hydrogenation4j,l to produce lennoxamine 7 in 97% yield.
The electroreduction of 1−3 in the presence of TMSCl and
TEA was carried out using Et4NOTs/acetonitrile as a catholyte
according to our reported method.1 The electrogenerated
products were obtained as disilyl ethers of cyclized diols 4−6.
Desilylation of the disilyl ethers with TBAF in THF gave 4−6
as diastereomeric mixtures (Scheme 1). The major isomer of 5
could be separated by recrystallization, and its stereostructure
was confirmed to be cis by X-ray crystallographic analysis.
Received: September 10, 2011
Published: October 24, 2011
© 2011 American Chemical Society
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Note
Scheme 1
Scheme 2
Scheme 3
H), 7.75−7.85 (m, 3 H), 7.96−8.04 (m, 3 H), 9.96 (s, 1 H); 13C NMR
(CDCl3) δ 123.9 (d), 129.5 (d), 130.0 (d), 131.6 (s), 131.8 (s), 132.2
(s), 132.6 (d), 134.5 (d), 134.6 (d), 167.2 (s), 189.3 (s). Anal. Calcd
for C15H9NO3: C, 71.71%; H, 3.61%; N, 5.58%. Found: C, 71.66%; H,
3.62%; N, 5.53%.
2: White solid; Rf 0.5 (hexanes/EtOAc, 2:1); mp 183−185 °C
(recryst. from hexanes/EtOAc, 1:2, lit.12 183−185 °C); IR (KBr)
1771, 16945, 1599, 1574, 1481, 1466, 962, 939, 854, 772, 762, 721,
712, 685, 660 cm−1; 1H NMR (CDCl3) δ 5.37 (s, 2 H), 7.25−7.28 (m,
1 H), 7.45−7.54 (m, 2 H), 7.73−7.78 (m, 2 H), 7.86−7.92 (m, 3 H),
10.35 (s, 1 H); 13C NMR (CDCl3) δ 38.7 (t), 123.5 (d), 127.5 (d),
127.9 (d), 131.9 (s), 133.4 (s), 133.7 (d), 133.9 (d), 134.2 (d), 137.8
(s), 168.0 (s), 192.9 (s). Anal. Calcd for C16H11NO3: C, 72.45%; H,
4.18%; N, 5.28%. Found: C, 72.40%; H, 4.21%; N, 5.22%.
Incidentally, the synthesis of chilenine 8 from 10 and 23 has
been reported by Danishefsky et al.6
In conclusion, the electroreduction of 1−3 in the presence of
TMSCl and TEA gave five-, six-, and seven-membered cyclized
products 4−6 respectively. The diols 5 and 6 were transformed
to the dehydroxylated compounds 15 and 16. Lennoxamine 7,
an isoindolobenzazepine alkaloid, was synthesized utilizing the
electroreductive cyclization of 9 as a key step (in five steps with
an overall yield of 36% from 9).
EXPERIMENTAL SECTION
■
General Methods. Column chromatography was performed on
silica gel 60. Solvents, TMSCl, and TEA were distilled from CaH2.
Starting Materials. 2-(1,3-Dioxoisoindolin-2-yl)benzaldehyde
(1) was prepared from o-aminobenzaldehyde ethylene acetal9 by
usual phthaloylation with phthalic anhydride in refluxing toluene and
following deacetalization with 3 M HCl. 2-((1,3-Dioxoisoindolin-2-
yl)methyl)benzaldehyde (2) and 2-(2-(1,3-dioxoisoindolin-2-yl)-
ethyl)benzaldehyde (3) were synthesized from o-bromomethylbenzal-
dehyde10 and o-(2-bromoethyl)benzaldehyde,11 respectively, by treat-
ment with potassium phthalimide in DMF at 50 °C.
3: White solid; Rf 0.5 (hexanes/EtOAc, 2:1); mp 156−157 °C
(recryst. from hexanes/EtOAc, 1:2); IR (KBr) 1769, 1697, 1676, 1599,
1572, 1491, 1464, 943, 858, 839, 773, 718, 656 cm−1 1H NMR
;
(CDCl3) δ 3.44 (t, 2 H, J = 7.1 Hz), 4.00 (t, 2 H, J = 7.1 Hz), 7.20−
7.23 (m, 1 H), 7.39−7.45 (m, 2 H), 7.67−7.72 (m, 2 H), 7.78−7.82
(m, 2 H), 7.82−7.85 (m, 1 H), 10.28 (s, 1 H); 13C NMR (CDCl3) δ
31.5 (t), 38.6 (t), 123.1 (d), 127.4 (d), 131.5 (d), 131.8 (s), 133.4 (d),
133.6 (d), 133.8 (d), 134.2 (s), 140.2 (s), 168.0 (s), 192.6 (s). Anal.
Calcd for C17H13NO3: C, 73.11%; H, 4.69%; N, 5.02%. Found: C,
73.00%; H, 4.69%; N, 4.99%.
1: White solid; Rf 0.5 (hexanes/EtOAc, 2:1); mp 163−164 °C
(recryst. from hexanes/EtOAc, 2:1); IR (KBr) 1780, 1709, 1688, 1655,
1599, 1578, 1514, 1487, 1464, 889, 874, 856, 816, 799, 772, 721, 708,
692 cm−1; 1H NMR (CDCl3) δ 7.41−7.46 (m, 1 H), 7.64−7.69 (m, 1
Synthesis of 18. To a solution of 6-(1,3-dioxolan-2-yl)benzo[d]-
[1,3]dioxole-5-carbaldehyde (17)7 (4.44 g, 20 mmol) and CH3NO2
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Note
Scheme 4
(3.2 mL) in MeOH (30 mL) was added 3 M aq NaOH (15 mL) at 0
°C. After being stirred for 3 h at this temperature, the mixture was
neutralized with 3 M HCl (15 mL), extracted with CH2Cl2, and dried
over MgSO4. After the solvent was removed in vacuo, the residue was
dissolved in CH2Cl2 (20 mL). To the solution were successively added
DMAP (100 mg), pyridine (8 mL), and Ac2O (4 mL) at 0 °C. After
being stirred for 6 h at this temperature, the mixture was diluted with
saturated aq NaHCO3 (30 mL) and extracted with CH2Cl2. The
extract was successively washed with 1 M HCl and saturated aq NaCl
and then dried over MgSO4. After the solvent was removed in vacuo,
the residue was recrystallized from hexanes/EtOAc (1:2) to give 3.39 g
of (E)-5-(1,3-dioxolan-2-yl)-6-(2-nitrovinyl)benzo[d][1,3]dioxole
(18) in 64% yield.
35.8 (t), 43.5 (t), 65.0 (t), 100.8 (d), 100.9 (t), 106.4 (d), 109.6 (d),
128.8 (s), 132.3 (s), 146.0 (s), 147.9 (s).
Synthesis of 21. A solution of 4,5-dimethoxyisobenzofuran-1,3-
dione (20)8 (2.08 g, 10 mmol) in aq NH3 (40 mL) was stirred at 120
°C until almost all of the water evaporated and then heated at 180 °C
for 1.5 h. The residue was dissolved in DMF (20 mL), and the solution
was added dropwise to a suspension of NaH (12 mmol) in DMF (20
mL) at 0 °C. After the mixture was stirred for 1 h at room
temperature, ClCO2Et (1.2 mL, 12.5 mmol) was added to the mixture
at 0 °C. After being stirred for 12 h at room temperature, the mixture
was diluted with water (80 mL) and extracted with EtOAc. The extract
was washed with saturated aq NaCl and then dried over MgSO4. After
the solvent was removed in vacuo, the residue was recrystallized from
hexanes/EtOAc (1:1) to give 2.18 g of ethyl 1-hydroxy-4,5-dimethoxy-
3-oxoisoindoline-2-carboxylate (21) in 78% yield.
18: Yellow solid; Rf 0.6 (hexanes/EtOAc, 2:1); mp 179−180 °C
(recryst. from hexanes/EtOAc, 1:2); IR (KBr) 1632, 1603, 1501, 1483,
21: White solid; Rf 0.45 (hexanes/EtOAc, 1:1); mp 150−151 °C
1
972, 945, 924, 903, 883, 833, 804, 737, 716, 669 cm−1; H NMR
(recryst. from hexanes/EtOAc, 1:1); IR (KBr) 1759, 1709, 1599, 1492,
(CDCl3) δ 4.05−4.21 (m, 4 H), 5.95 (s, 1 H), 6.06 (s, 2 H), 7.00 (s, 1
H), 7.16 (s, 1 H), 7.43 (d, 1 H, J = 13.7 Hz), 8.43 (d, 1 H, J = 13.7
Hz); 13C NMR (CDCl3) δ 65.4 (t), 101.2 (t), 102.2 (d), 106.6 (d),
107.8 (d), 122.9 (s), 134.0 (s), 135.9 (d), 136.6 (d), 148.7 (s), 150.8
(s). Anal. Calcd for C12H11NO6: C, 54.34%; H, 4.18%; N, 5.28%.
Found: C, 54.45%; H, 4.24%; N, 5.03%.
1
928, 889, 833, 775, 662 cm−1; H NMR (CDCl3) δ 1.44 (t, 3 H, J =
7.2 Hz), 3.98 (s, 3 H), 4.14 (s, 3 H), 4.48 (q, 2 H, J = 7.2 Hz), 7.22 (d,
1 H, J = 8.0 Hz), 7.67 (d, 1 H, J = 8.0 Hz); 13C NMR (CDCl3) δ 14.1
(q), 56.7 (q), 62.6 (q), 64.0 (t), 117.4 (d), 120.7 (d), 121.3 (s), 123.4
(s), 148.0 (s), 148.5 (s), 158.6 (s), 161.7 (s), 163.1 (s). Anal. Calcd for
C13H13NO6: C, 55.91%; H, 4.69%; N, 5.02%. Found: C, 55.96%; H,
4.70%; N, 4.91%.
Synthesis of 9. To a solution of crude 19 (5 mmol) and 21 (1.4 g,
5 mmol) in DMF (20 mL) was added triethylamine (1.4 mL, 10
mmol), and the mixture was stirred for 6 h at room temperature. To
the mixture was added 3 M HCl (40 mL) and acetone (40 mL), and
the mixture was stirred for 12 h at 40 °C. After acetone was removed
in vacuo, the mixture was diluted with saturated aq NaCl (60 mL) and
extracted with EtOAc. The extract was washed successively with 1 M
NaOH and saturated aq NaCl and then dried over MgSO4. After the
solvent was removed in vacuo, the residue was recrystallized from
hexanes/EtOAc (1:5) to give 1.15 g of 6-(2-(4,5-dimethoxy-1,3-
Synthesis of 19. To a suspension of LAH (0.57 g, 15 mmol) in
THF (20 mL) was added dropwise a solution of 18 (1.33 g, 5 mmol)
in THF (20 mL) at room temperature, and the mixture was refluxed
for 12 h. After the mixture was cooled to 0 °C, to the mixture were
added H2O (1.0 mL) and 3 M aq NaOH (1.0 mL). The mixture was
filtered and evaporated in vacuo to give 1.25 g (quantitative yield) of
crude 19, which was employed in the next step without further
purification.
1
Crude 19: Yellow paste; H NMR (CDCl3) δ 2.80 (t, 2 H, J = 7.2
Hz), 2.94 (t, 2 H, J = 7.2 Hz), 3.99−4.06 (m, 2 H), 4.11−4.18 (m, 2
H), 5.94 (s, 3 H), 6.68 (s, 1 H), 7.08 (s, 1 H); 13C NMR (CDCl3) δ
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Note
dioxoisoindolin-2- yl)ethyl)benzo[d][1,3]dioxole-5-carbaldehyde (9)
in 60% yield.
3.84 (s, 3 H), 3.91 (s, 3 H), 4.26−4.40 (m, 1 H), 4.77 (s, 0.5 H), 4.94
(s, 0.5 H), 5.87−5.98 (m, 2 H), 6.64 (s, 0.5 H), 6.66 (s, 0.5 H), 6.79
(brs, 0.5 H), 6.83 (brs, 0.5 H), 6.99−7.04 (m, 1 H), 7.31−7.35 (m,
0.5), 7.45−7.50 (m, 0.5 H); 13C NMR (CDCl3, DMSO-d6) δ 32.1 (t),
32.6 (t), 34.2 (t), 35.0 (t), 54.8 (q), 60.29 (q), 60.31 (q), 74.3 (d),
75.0 (d), 87.1 (s), 87.4 (s), 99.2 (t), 99.3 (t), 106.8 (d), 107.9 (d),
109.1 (d), 113.9 (d), 114.1 (d), 116.0 (d), 120.6 (d), 121.8 (s), 122.7
(s), 130.0 (s), 131.4 (s), 131.5 (s), 132.4 (s), 138.6 (s), 139.2 (s),
143.7 (s), 144.0 (s), 144.2 (s), 144.3 (s), 144.4 (s), 144.8 (s), 151.3
(s), 151.5 (s), 162.2 (s), 162.9 (s); HRMS (ESI) m/z calcd. for
C20H19NO7 (M + H)+ 385.1162, found 385.1166.
Typical Procedure for Reduction with Et3SiH. To a solution of
5 (134 mg, 0.5 mmol) in CH2Cl2 (10 mL) were added Et3SiH (0.32
mL, 2 mmol) and BF3·Et2O (0.26 mL, 20 mmol) at 0 °C, and the
mixture was stirred for 1.5 h at this temperature. After addition of
triethylamine (0.3 mL), the solvent was removed in vacuo. From the
residue, trans-11 was isolated in 76% yield by column chromatography
on silica gel (hexanes/EtOAc).
9: White solid; Rf 0.5 (hexanes/EtOAc, 1:1); mp 182−184 °C
(recryst. from hexanes/EtOAc, 1:5); IR (KBr) 1755, 1701, 1665, 1609,
1
1497, 1477, 997, 986, 924, 878, 849, 797, 770, 750, 669 cm−1; H
NMR (CDCl3) δ 3.31 (t, 2 H, J = 7.2 Hz), 3.89 (t, 2 H, J = 7.2 Hz),
3.95 (s, 3 H), 4.13 (s, 3 H), 6.02 (s, 2 H), 6.74 (s, 1 H), 7.08−7.11 (m,
1 H), 7.31 (s, 1 H), 7.51−7.53 (m, 1 H), 10.20 (s, 1 H); 13C NMR
(CDCl3) δ 30.9 (t), 39.3 (t), 56.6 (q), 62.5 (q), 102.0 (t), 109.4 (d),
110.9 (d), 115.8 (d), 119.4 (d), 121.6 (s), 124.3 (s), 128.9 (s), 138.0
(s), 147.20 (s), 147.23 (s), 152.3 (s), 157.7 (s), 166.0 (s), 167.3 (s),
189.3 (d). Anal. Calcd for C20H17NO7: C, 62.66%; H, 4.47%; N,
3.65%. Found: C, 62.62%; H, 4.52%; N, 3.58%.
Typical Procedures for Electroreduction and Subsequent
Desilylation. A 0.3 M solution of Et4NOTs in CH3CN (15 mL) was
placed in the cathodic chamber of a divided cell (40 mL beaker, 3 cm
diameter, 6 cm height) equipped with a lead cathode (5 × 5 cm2), a
platinum anode (2 × 1 cm2), and a ceramic cylindrical diaphragm (1.5
cm diameter). A 0.3 M solution of Et4NOTs in DMF (4 mL) was
placed in the anodic chamber (inside the diaphragm). Substrate 2 (265
mg, 1 mmol), TMSCl (0.64 mL, 5 mmol), and TEA (0.70 mL, 5
mmol) were added to the cathodic chamber. After 300 C of electricity
was passed at a constant current of 100 mA at room temperature, the
catholyte was evaporated in vacuo. The residue was dissolved in ethyl
acetate (20 mL), and insoluble Et4NOTs was filtered off. After
removal of the solvent, the residue was dissolved in THF (10 mL). To
the solution was added 1 M TBAF in THF (1 mL) at 0 °C, and the
mixture was stirred for 15 min. After removal of the solvent, the crude
product was purified by column chromatography on silica gel
(hexanes/EtOAc) to give 5 in 84% yield with a 82:18 dr. The major
isomer of 5 (cis-5) was isolated as a single crystal by recrystallization
from EtOAc.
trans-11: White solid; Rf 0.45 (hexanes/EtOAc, 1:2); mp 214−215
°C (recryst. from EtOAc); IR (KBr) 3246, 1663, 1616, 1580, 1493,
1
1470, 758, 743, 709, 689 cm−1; H NMR (CDCl3, DMSO-d6) δ 4.27
(t, 1 H, J = 9.2 Hz), 4.43 (d, 1 H, J = 9.2 Hz), 4.55 (d, 1 H, J = 17.2
Hz), 5.22 (d, 1 H J = 17.2 Hz), 6.22 (d, 1 H, J = 9.2 Hz), 7.25−7.36
(m, 3 H), 7.51−7.56 (m, 1 H), 7.60−7.64 (m, 1 H), 7.72−7.76 (m, 1
H), 7.81−7.85 (m, 1 H), 7.93−7.97 (m, 1 H); 13C NMR (CDCl3,
DMSO-d6) δ 39.8 (t), 58.4 (d), 68.5 (d), 121.0 (d), 122.5 (d), 124.2
(d), 124.3 (d), 125.1 (d), 125.5 (d), 126.6 (d), 129.4 (s), 129.5 (d),
130.4 (s), 136.6 (s), 143.3 (s), 164.9 (s). Anal. Calcd for C16H13NO2:
C, 76.48%; H, 5.21%; N, 5.57%. Found: C, 76.28%; H, 5.24%; N,
5.38%.
trans-12: White solid; Rf 0.5 (hexanes/EtOAc, 1:2); mp 215−216
°C (recryst. from EtOAc); IR (KBr) 3258, 1659, 1591, 1470, 937, 908,
1
800, 773, 760, 735, 692, 669 cm−1; H NMR (CDCl3, DMSO-d6) δ
4 (70:30 diastereomeric mixture): Colorless paste; Rf 0.55
1
(hexanes/EtOAc, 1:2); H NMR (CDCl3, DMSO-d6) δ 3.65 (d, 0.3
2.92−3.10 (m, 3 H), 4.39 (d, 1 H, J = 8.2 Hz), 4.61 (dd, 1 H, J = 5.4,
8.2 Hz), 4.75−4.82 (m, 1 H), 5.06 (d, 1 H J = 5.4 Hz), 7.19−7.23 (m,
1 H), 7.24−7.29 (m, 1 H), 7.31−7.37 (m, 1 H), 7.47−7.52 (m, 1 H),
7.55−7.60 (m, 1 H), 7.78−7.88 (m, 2 H), 7.92−7.96 (m, 1 H); 13C
NMR (CDCl3, DMSO-d6) δ 33.4 (t), 33.8 (t), 63.3 (d), 71.8 (d),
120.8 (d), 124.1 (d), 124.8 (d), 125.6 (d), 126.4 (d), 127.5 (d), 129.0
(d), 130.1 (s), 136.5 (s), 140.6 (s), 141.9 (s), 165.2 (s). Anal. Calcd
for C17H15NO2: C, 76.96%; H, 5.70%; N, 5.28%. Found: C, 76.87%;
H, 5.78%; N, 5.15%.
cis-12: White solid; Rf 0.3 (hexanes/EtOAc, 1:2); mp 199−200 °C
(recryst. from EtOAc); IR (KBr) 3316, 1651, 1616, 1597, 1491, 1470,
914, 808, 750, 737, 721, 712, 686, 667 cm−1; 1H NMR (CDCl3) δ 1.77
(d, 1 H, J = 3.7 Hz), 2.83 (dd, 1 H, J = 5.1, 14.8 Hz), 3.10 (t, 1 H, J =
14.8 Hz), 3.49−3.57 (m, 1 H), 4.71 (s, 1 H), 4.81−4.88 (m, 1 H), 5.18
(d, 1 H, J = 3.7 Hz), 7.21−7.25 (m, 1 H), 7.27−7.34 (m, 2 H), 7.36−
7.41 (m, 1 H), 7.50−7.55 (m, 1 H), 7.59−7.66 (m, 2 H), 7.88−7.92
(m, 1 H); 13C NMR (CDCl3, DMSO-d6) δ 33.6 (t), 40.5 (t), 63.9 (d),
75.1 (d), 121.2 (d), 122.3 (d), 125.8 (d), 127.3 (d), 127.6 (d), 128.7
(d), 129.8 (d), 130.6 (d), 132.2 (s), 139.6 (s), 140.1 (s), 142.8 (s),
167.2 (s). Anal. Calcd for C17H15NO2: C, 76.96%; H, 5.70%; N,
5.28%. Found: C, 76.90%; H, 5.68%; N, 5.21%.
H, J = 7.2 Hz), 4.71 (d, 0.7 H, J = 9.8 Hz), 5.09 (d, 0.3 H, J = 7.2 Hz),
5.27 (d, 0.7 H, J = 9.8 Hz), 5.69 (brs, 0.3 H), 6.47 (brs, 0.7 H), 7.15−
7.86 (m, 8 H); 13C NMR (CDCl3, DMSO-d6) δ 73.7 (d), 73.8 (d),
95.5 (s), 97.9 (s), 114.9 (d), 115.0 (d), 121.5 (d), 121.8 (d), 122.0
(d), 122.5 (d), 122.9 (d), 123.0 (d), 123.3 (d), 125.1 (d), 126.8 (d),
127.5 (d), 127.8 (d), 128.1 (d), 130.3 (s), 131.1 (d), 131.3 (s), 131.5
(d), 136.1 (s), 136.2 (s), 137.8 (s), 137.9 (s), 143.8 (s), 145.4 (s),
164.5 (s), 165.8 (s); HRMS (ESI) m/z calcd. for C15H12NO3 (M +
H)+ 254.0817, found 254.0820.
cis-5: White solid; Rf 0.4 (hexanes/EtOAc, 1:2); mp 187−189 °C
(recryst. from EtOAc); IR (KBr) 3439, 3215, 1672, 1612, 1580, 1466,
758, 737, 712, 694 cm−1; 1H NMR (CDCl3, DMSO-d6) δ 4.51 (d, 1 H,
J = 17.0 Hz), 4.52 (brs, 1 H), 5.18 (d, 1 H, J = 17.0 Hz), 8.31 (brs, 1
H), 7.21−7.36 (m, 3 H), 7.52−7.57 (m, 1 H), 7.60−7.66 (m, 1 H),
7.44−7.66 (m, 1 H), 7.74−7.79 (m, 1 H), 7.81−7.85 (m, 1 H), 7.95−
8.00 (m, 1 H); 13C NMR (CDCl3, DMSO-d6) δ 38.4 (t), 71.3 (d),
84.5 (s), 121.8 (d), 123.0 (d), 124.4 (d), 125.7 (d), 125.9 (d), 126.2
(d), 128.3 (d), 130.3 (s), 130.5 (s), 130.9 (d), 135.3 (s), 146.5 (s),
164.6 (s). Anal. Calcd for C16H13NO3: C, 71.90%; H, 4.90%; N,
5.24%. Found: C, 71.98%; H, 4.88%; N, 5.07%.
6 (50:50 diastereomeric mixture): Colorless paste; Rf 0.35 and 0.25
(hexanes/EtOAc, 1:2); 1H NMR (CDCl3, DMSO-d6) δ 2.71−2.82 (m,
0.5 H), 2.88−2.98 (m, 0.5 H), 3.05−3.25 (m, 1 H), 3.26−3.36 (m, 0.5
H), 3.34−3.58 (m, 0.5 H), 4.16 (brs, 0.5 H), 4.46−4.59 (m, 1 H), 4.81
(d, 0.5 H, J = 6.0 Hz), 5.08−5.13 (m, 1 H), 5.50 (brs, 0.5 H), 5.73
(brs, 1 H), 7.12−7.28 (m, 3 H), 7.31−7.36 (m, 0.5 H), 7.45−7.51 (m,
1 H), 7.56−7.63 (m, 1.5 H), 7.72−7.80 (m, 1.5 H), 7.94−7.99 (m, 0.5
H); 13C NMR (CDCl3, DMSO-d6) δ 32.7 (t), 34.7 (t), 35.0 (t), 35.3
(t), 74.5 (d), 76.8 (d), 88.47 (s), 88.54 (s), 120.4 (d), 120.7 (d), 120.8
(d), 124.6 (d), 124.8 (d), 125.2 (d), 125.6 (d), 126.0 (d), 126.3 (d),
127.3 (d), 127.4 (d), 127.5 (d), 128.6 (d), 129.69 (d), 129.74 (s),
130.2 (d), 131.0 (s), 136.5 (s), 138.0 (s), 138.5 (s), 145.8 (s), 146.4
(s), 164.2 (s), 164.8 (s); HRMS (ESI) m/z calcd. for C17H16NO3 (M
+ H)+ 282.1130, found 282.1135.
22a (upper isomer): White solid; Rf 0.55 (hexanes/EtOAc, 1:5);
mp 258−260 °C (recryst. from EtOAc); IR (KBr) 3416, 1668, 1591,
1495, 1479, 1470, 995, 961, 941, 920, 878, 854, 845, 827, 806, 791,
754, 729, 664 cm−1; 1H NMR (CDCl3, DMSO-d6) δ 2.80−2.98 (m, 3
H), 3.91 (s, 3 H), 4.04 (s, 3 H), 4.21 (d, 1 H, J = 7.9 Hz), 4.48 (dd, 1
H, J = 5.3, 7.9 Hz), 4.66−4.72 (m, 1 H), 5.04 (d, 1 H, J = 5.3 Hz), 5.96
(s, 2 H), 6.69 (s, 1 H), 7.12 (d, 1 H, J = 8.2 Hz), 7.30 (brs, 1 H), 7.55
(d, 1 H, J = 8.2 Hz); 13C NMR (CDCl3, DMSO-d6) δ 33.4 (t), 39.1
(t), 54.8 (q), 60.3 (q), 62.6 (d), 72.1 (d), 99.3 (t), 105.3 (d), 108.2
(d), 114.1 (d), 120.4 (d), 122.6 (s), 130.2 (s), 134.7 (s), 135.0 (s),
144.3 (s), 144.5 (s), 144.6 (s), 150.7 (s), 163.8 (s). Anal. Calcd for
C20H19NO6: C, 65.03%; H, 5.18%; N, 3.79%. Found: C, 64.95%; H,
5.22%; N, 3.58%.
22b (lower isomer): White solid; Rf 0.35 (hexanes/EtOAc, 1:5);
mp 253−256 °C (recryst. from EtOAc); IR (KBr) 3372, 3291, 1647,
1618, 1599, 1489, 980, 962, 930, 897, 854, 824, 810, 797, 768, 745,
10 (50:50 diastereomeric mixture): Colorless paste; Rf 0.4
1
(hexanes/EtOAc, 1:5); H NMR (CDCl3) δ 2.55−3.35 (m, 5 H),
9859
dx.doi.org/10.1021/jo2018735|J. Org. Chem. 2011, 76, 9856−9860

The Journal of Organic Chemistry
Note
694, 685, 656 cm−1; 1H NMR (CDCl3) δ 2.98−3.08 (m, 1 H), 3.42−
3.53 (m, 1 H), 3.79 (brs, 1 H), 3.92 (s, 3 H), 4.08 (s, 3 H), 4.55 (brs, 1
H), 4.67−4.76 (m, 1 H), 4.98 (d, 1 H, J = 3.1 Hz), 5.96 (s, 2 H), 6.69
(s, 1 H), 6.86 (s, 1 H), 7.14 (d, 1 H, J = 8.1 Hz); 7.25 (d, 1 H, J = 8.1
Hz); 13C NMR (CDCl3, DMSO-d6) δ 32.4 (t), 39.6 (t), 55.1 (q), 60.6
(q), 62.2 (d), 74.0 (d), 99.6 (t), 108.7 (d), 109.6 (d), 114.5 (d), 116.2
(d), 123.7 (s), 132.7 (s), 133.0 (s), 135.5 (s), 144.1 (s), 144.9 (s),
145.3 (s), 150.8 (s), 164.6 (s). Anal. Calcd for C20H19NO6: C, 65.03%;
H, 5.18%; N, 3.79%. Found: C, 65.05%; H, 5.19%; N, 3.65%.
Typical Procedure of Dehydration. A mixture of trans-11 (126
mg, 0.5 mmol) and KHSO4 (50 mg) in xylene (10 mL) was refluxed
using a Dean−Stark apparatus for 6 h. After the solvent was removed
in vacuo, the residue was purified by column chromatography on silica
gel to give 13 in 88% yield.
Org. Chem. 2009, 74, 5486−5495. (b) Kim, G.; Jung, P.; Tuan, L. A.
Tetrahedron Lett. 2008, 49, 2391−2392. (c) Kim, G.; Lee, K. Y.; Yoo,
C.-H. Synth. Commun. 2008, 38, 3251−3259. (d) Fuwa, H.; Sasaki, M.
Heterocycles 2008, 76, 521−539. (e) Couty, S.; Meyer, C.; Cossy, J.
Tetrahedron Lett. 2006, 47, 767−769. (f) Couty, S.; Liegault, B.;
Meyer, C.; Cossy, J. Tetrahedron 2006, 62, 3882−3895. (g) Taniguchi,
T.; Iwasaki, K.; Uchiyama, M.; Tamura, O.; Ishibashi, H. Org. Lett.
2005, 7, 4389−4390. (h) Comins, D. L.; Schilling, S.; Zhang, Y. Org.
Lett. 2005, 7, 95−98. (i) Honda, T.; Sakamaki, Y. Tetrahedron Lett.
2005, 46, 6823−6825. (j) Sahakitpichan, P.; Ruchirawat, S.
Tetrahedron 2004, 60, 4169−4172. (k) Kim, G.; Kim, J. H.; Kim,
W.-J.; Kim, Y. A. Tetrahedron Lett. 2003, 44, 8207−8209. (l) Koseki,
Y.; Katsura, S.; Kusano, S.; Sakata, H.; Sato, H.; Monzene, Y.;
Nagasaka, T. Heterocycles 2003, 59, 527−540. (m) Yoda, H.; Inoue, K.;
Ujihara, Y.; Mase, N.; Takabe, K. Tetrahedron Lett. 2003, 44, 9057−
9060. (n) Montano, R. G.; Zhu, J. Chem. Commun. 2002, 2448−2449.
(o) Fuchs, J. R.; Funk, R. L. Org. Lett. 2001, 3, 3923−3925.
(5) Yoda, H.; Nakahama, A.; Koketsu, T.; Takabe, K. Tetrahedron
Lett. 2002, 41, 4667−4669.
13: Yellow solid; mp 157−158 °C (lit.13 157−158 °C).
14: Yellow solid; mp 128−129 °C (lit.14 128−130 °C).
Dehydrolennoxamine 23: Yellow solid; mp 208−209 °C (lit.15
208−209 °C).
Typical Procedure for Hydrogenation. A suspension of 13 (93
mg, 4 mmol) and 10% Pd−C (40 mg) in EtOAc (10 mL) was stirred
for 6 h under an atmospheric pressure of hydrogen. After the catalyst
was filtered off, the solvent was removed in vacuo. The residue was
purified by column chromatography on silica gel to give 15 in 95%
yield.
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2750.
(7) Dwayne, A. D.; Kerr, M. A. Org. Lett. 2009, 11, 3694−3697.
(8) Wasserman, H. H.; Amici, R.; Frechette, R. H.; van Duzer, J. H.
Tetrahedron Lett. 1989, 30, 869−872.
(9) Wani, M. C.; Ronman, P. E.; Lindley, J. T.; Wall, M. E. J. Med.
Chem. 1980, 23, 554−560.
(10) Zhang, X.-X.; Lippard, J. J. Org. Chem. 2000, 65, 5298−5305.
(11) Page, P. C. B.; Rassias, G. A.; Barros, D.; Ardakani, A. J. Org.
Chem. 2001, 66, 6926−6931.
(12) Bornstein, J.; Bedell, S. F.; Drummond, P. E.; Kosloski, C. L. J.
Am. Chem. Soc. 1956, 78, 83−86.
(13) Machida, M.; Nakamura, M.; Oda, K.; Takechi, H.; Ohno, K.;
Nakai, H.; Sato, Y.; Kanaoka, Y. Heterocycles 1987, 26, 2683−2690.
(14) Scartoni, V.; Fiaschi, R.; Catalano, S.; Morelli, I.; Marsili, A. J.
Chem. Soc., Perkin Trans. 1 1979, 1547−1551.
(15) Ruchirawat, S.; Sahakitpichan, P. Tetrahedron Lett. 2000, 41,
8007−8010.
15: White solid; mp 134−136 °C (lit.14 126−128 °C).
16: White solid; mp 197−198 °C (lit.14 193−195 °C).
Lennoxamine 7: White solid; mp 234−235 °C (lit.4l 235−235.5
°C).
X-ray Crystallographic Analysis of cis-5, trans-12, and cis-
12. All measurements of X-ray crystallographic analysis were made on
a Rigaku RAXIS imaging plate area detector with graphite
monochromated Mo Kα radiation. The structure was solved by direct
methods with SIR-97 and refined with SHELXL-97. The non-
hydrogen atoms were refined anisotropically. Hydrogen atoms were
refined isotropically. All calculations were performed using the
YADOKARI-XG software package.
cis-5 (CCDC 838890): C16H13NO3, FW = 267.27, mp 187−189
°C, monoclinic, P21/c (No. 14), colorless block, a = 17.296(3) Å, b =
9.0264(16) Å, c = 17.030(3) Å, β = 28.664(4), V = 1275.3(4) Å3, T =
298 K, Z = 4, Dcalcd = 1.392 g/cm3, μ = 0.97 cm−1, GOF = 1.062.
trans-12 (CCDC 838891): C17H15NO2, FW = 265.30, mp 215−
216 °C, monoclinic, P21/c (No. 14), colorless block, a = 14.500(2) Å, b
= 7.1527(12) Å, c = 25.930(4) Å, β = 99.797(9), V = 2650.1(7) Å3, T
= 298 K, Z = 8, Dcalcd = 1.330 g/cm3, μ = 0.87 cm−1, GOF = 0.942.
cis-12 (CCDC 838889): C17H15NO2, FW = 265.30, mp 199−200
°C, monoclinic, P21/c (No. 14), colorless block, a = 10.8606(16) Å, b
= 8.0593(8) Å, c = 15.861(2) Å, β = 105.485(6), V = 1337.9(3) Å3, T
= 298 K, Z = 4, Dcalcd = 1.317 g/cm3, μ = 0.87 cm−1, GOF = 1.026.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of 1−7, 9−16, 18, 19, and 21−23
and X-ray crystallographic structures (Ortep) of cis-5, trans-12,
and cis-12 (PDF), as well as crystallographic CIF files. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: kise@bio.tottori-u.ac.jp.
■
REFERENCES
■
(1) Kise, N.; Sakurai, T. Tetrahedron Lett. 2010, 51, 70−74.
(2) Kise, N.; Isemoto, S.; Sakurai, T. Org. Lett. 2009, 11, 4902−4905.
(3) Valencia, E.; Freyer, A. J.; Shamma, M.; Fajardo, V. Tetrahedron
Lett. 1984, 25, 599−602.
(4) For recent syntheses of lennoxamine and chilenine, see:
(a) Onozaki, Y.; Kurono, N.; Senboku, H.; Tokuda, M.; Orito, K. J.
9860
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