A novel and efficient synthesis of dihydrexidine

Article abstract of DOI:10.1055/s-0028-1083359

An efficient synthesis of the dopamine D₁ selective full agonist dihydrexidine has been achieved in high yields and requiring no chromatographic separations via a facilitated intramolecular Henry cyclization of a (nitropropyl)benzophenone and subsequent diastereomerically selective reduction of the resulting tricyclic ni- troalkene. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083359

PAPER
715
A Novel and Efficient Synthesis of Dihydrexidine
A
N
ew Sy
u
nthesis of
D
i
hydrexidin
n
e
Pablo Cueva, David E. Nichols*
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University,
West Lafayette, IN 47907, USA
Fax +1(765)4941414; E-mail: drdave@pharmacy.purdue.edu
Received 25 September 2008; revised 12 November 2008
to effect the transformation, making the process less than
Abstract: An efficient synthesis of the dopamine D1 selective full
ideal for production-scale chemistry.
agonist dihydrexidine has been achieved in high yields and requir-
ing no chromatographic separations via a facilitated intramolecular
Henry cyclization of a (nitropropyl)benzophenone and subsequent
diastereomerically selective reduction of the resulting tricyclic ni-
troalkene.
More recently, Tomioka and co-workers reported an
asymmetric synthesis of 1 based on the 1,4-addition of an
aryllithium reagent to nitroalkene 7 (Scheme 1), mediated
by a chiral lithium-chelating ligand.6 Although this meth-
odology is elegant and impressive, the synthesis entails
the use of the somewhat dangerous and costly tetrani-
tromethane for the preparation of the required nitroalkene
7. Furthermore, our initial attempts to follow this route
were less than satisfactory.
Key words: acylations, intramolecular Henry reaction, nitroalkene,
total synthesis.
Exploration of the structure–activity relationships of
dopamine analogues in our laboratories led to the identifi-
cation in 1990 of dihydrexidine (1, Scheme 2), a selective
dopamine D1 receptor full agonist.1 Selective ligands for
the dopamine D1 receptor have been used as neurophar-
macological tools to investigate D1 receptor function2 and
have been posited as novel treatments both for Parkin-
son’s disease and to treat the cognitive deficits of schizo-
phrenia.3 Thus, there exists practical and commercial
interest in the preparation of dihydrexidine on a large
scale.
Seeking to improve upon the approach of Tomioka et al.,
in part by devising a more efficient route to nitroalkene 7,
we envisioned a simpler, more direct strategy for the syn-
thesis of dihydrexidine. We now report the successful re-
sult of our efforts to this end.
With the idea of using the 1,4-addition of arylmetal re-
agents to nitroalkene 7 as the pivotal operation in the syn-
thesis of dihydrexidine, we evaluated methodologies for
an improved synthesis of 7. Known routes for the prepa-
ration of cyclic nitroalkenes typically involve nitration of
cyclic styrenes using tetranitromethane,7 iodine and po-
tassium nitrite,8 or through the action of nitrogen monox-
ide in acidic media.9 In our hands these methodologies all
proved to be either low-yielding or unsuitable for large-
scale chemistry.
We next reasoned that an intramolecular Henry reaction10
might provide a more facile and scalable route to nitroalk-
ene 7. Our successful approach is shown in Scheme 1,
where the key synthon proved to be nitroalkane 5.
Several methodologies have been reported for the synthe-
sis of 1. The original preparation of dihydrexidine by
Brewster, Nichols, and co-workers1 constructed the trans-
fused benzo[a]phenanthridine framework starting from a
difficultly accessible b-tetralone via a low-yielding photo-
chemical cyclization, which rendered this process ineffi-
cient and not amenable to large-scale production.
Ehrlich et al.4 subsequently developed a general strategy
for the synthesis of hexahydrobenzo[a]phenanthridines
based on Friedel–Crafts acylation of veratrole with N-(tri-
fluoroacetyl)-D-aspartic anhydride. This procedure pro-
vided a chiral route towards the construction of these
types of compounds, but in the case of dihydrexidine it-
self, the final Pictet–Spengler closure of the heterocyclic
C ring could not be employed due to the low reactivity of
the unsubstituted phenyl D ring.
Starting from readily accessible 3,4-dimethoxycinnamic
acid (2),11 we prepared alcohol 3 in nearly quantitative
yield by a two-step-reduction sequence employing cata-
lytic hydrogenation followed by treatment with borane.
Conversion of this alcohol into bromide 4 was then
achieved in high yield using tetrabromomethane and
triphenylphosphine. Displacement of bromide with nitrite
salts is a well-established procedure to provide nitroal-
kanes, but most often affords only very modest yields, due
mainly to the ambident character of the nitrite anion.12 In-
deed, an efficient scalable high-yielding procedure for
preparing nitroalkanes from the corresponding alkyl ha-
lides has never appeared in the literature. Accordingly, we
could only obtain the required nitroalkane in less than ide-
al yields by halting the reaction at the point where nitrite
ester formation was minimal and did not significantly ef-
fect the nitrosation of 5 into its corresponding nitrolic
Negash and Nichols5 offered an alternate synthesis of di-
hydrexidine by cyclization of an N-tosylglycine moiety
into the b-phenyl ring through release of carbon monoxide
from an intermediate acylium ion. Although this proce-
dure effectively circumvented the problematic Pictet–
Spengler cyclization, it also required four additional steps
SYNTHESIS 2009, No. 5, pp 0715–0720
x
x
.
x
x
.2
0
0
9
Advanced online publication: 11.02.2009
DOI: 10.1055/s-0028-1083359; Art ID: M05708SS
© Georg Thieme Verlag Stuttgart · New York

716
J. P. Cueva, D. E. Nichols
PAPER
MeO
MeO
MeO
MeO
MeO
MeO
1. Pd/C, H2
CBr4, Ph3P
2. BH3, THF
98%
OH
CH2Cl2, 92%
Br
COOH
2
3
4
MeO
MeO
NO2
MeO
MeO
CHO
MeO
NO2
NaNO2
Cl2CHOMe
AcOH
1
DMF
54%
SnCl4, CH2Cl2
98%
NO2
MeO
92%
Tomioka et al.6
5
6
7
N
H
Et3SiH
TFA
90%
O
MeO
MeO
O
O
HO
O
SOCl2
95%
NO2
MeO
AlCl3,
CH2Cl2
r.t., 36 h
79%
Cl
NO2
NO2
65%
H
MeO
10
9
8
Scheme 1
acid.13 Although significant amounts of starting material duced in excellent yield by stirring with triethylsilane and
could be recovered, we found that chromatographic sepa- trifluoroacetic acid for five days. The undesirable long re-
ration of the resulting mixture was an unavoidable neces- action time was more than offset by the economy of the re-
sity. Clearly, this approach was not one that would be agents and the high yields.
useful for large-scale synthesis of 7.
Thus, we achieved an economical synthesis of key inter-
Given these results, we envisioned a new route to nitroalk- mediate 5, and were then able to effect its formylation us-
ene 7 based on the Friedel–Crafts acylation of veratrole ing dichloromethyl methyl ether with tin(IV) chloride to
with 3-nitropropanoyl chloride. A survey of the literature yield aldehyde 6, which smoothly underwent intramolec-
revealed an efficient method for the preparation of 3- ular Henry ring closure with piperidinium acetate in acetic
nitropropanoic acid (8) starting from readily available acid. This scheme represents an efficient synthesis of 7
acrolein.14 This nitro acid was converted into the acid from veratrole in only four steps and in an overall yield of
chloride, which was used to acylate veratrole in good 70%.
yield. The resulting ketone 10 was then selectively re-
COCl
COOH
NO2
COOMe
NO2
1. SOCl2
2. MeOH
COCl
MeO
MeO
MeO
MeO
MeO
MeO
O
O
SnCl4, CH2Cl2
NO2
5
11, 88%
12, 86%
O
1. DCC, DMAP
CH2Cl2, MeOH
COOH
NO2
COOH
NO2
H
NaBH4
i-PrOH
DBU
O
H
MeO
MeO
NO2
MeO
MeO
MeO
MeO
THF
MeOH
2. Zn, AcOH
3. MeOH, reflux
13, 97%
14, 71%
O
NH
1. BBr3, THF
reflux, 12 h
1. BH3, THF
reflux, 12 h
H
H
H
MeO
MeO
MeO
MeO
NH
HO
HO
NH
2. NaHCO3
3. HCl
2. HCl
H
H
H
HCl
HCl
15, 91%
16, 71%
1⋅HCl, 79%
Scheme 2
Synthesis 2009, No. 5, 715–720 © Thieme Stuttgart · New York

PAPER
A New Synthesis of Dihydrexidine
717
We anticipated employing nitroalkene 7 as an electrophile nipulations, with an overall yield of 11%, and requiring no
that would be very reactive toward arylmetal nucleo- chromatographic separations.
philes. We found, however, that treating 7 with ortho-sub-
stituted aryllithium and aryl Grignard reagents led only to
All reactions were performed under a dry inert atmosphere. All re-
product mixtures that were complex, affording only small
agents were obtained commercially and used without further purifi-
amounts of the desired adducts after tedious workup pro-
cation, unless otherwise noted. Anhyd THF was obtained by
distillation from a benzophenone/Na still kept under N2. Flash col-
cedures. This result can most likely be attributed to the
acidity of the conjugated benzylic proton (C4H), and by
the occurrence of polymerization reactions that are well
documented for nitroalkenes.
umn chromatography was carried out using silica gel having a par-
ticle size of 40–65 mm. J. T. Baker flexible TLC (IB2-F) sheets were
used to monitor reactions. Melting points were obtained using a
Meltemp apparatus and are uncorrected. 1H NMR spectra were ob-
tained using a 300 MHz Bruker ARX-300 spectrometer unless oth-
erwise noted. MS information was obtained by the Purdue
University Campus-wide Mass Spectrometry Center. Elemental
analyses were performed by the Purdue University Microanalysis
Laboratory and all values are within 0.4% of calculated values.
These complications led us to consider new potential
routes toward the synthesis of 1. We were especially in-
trigued by the ease and high efficiency of the intramolec-
ular Henry strategy, which we believed might be
exploited in view of the high reactivity and regioselectiv-
ity of nitroalkane 5 to Friedel–Crafts acylation. We thus
developed a completely novel synthesis of dihydrexidine,
which is detailed in part in Scheme 2.
3-(3,4-Dimethoxyphenyl)propan-1-ol (3)17
3,4-Dimethoxycinnamic acid (10.00 g, 48.03 mmol) was dissolved
in warm EtOH, mixed with 10% Pd/C (0.5 g), and shaken under H2
(2.4 bar) in a Parr hydrogenator for 3 h. This soln was then filtered,
and the solvents were removed under reduced pressure to obtain the
saturated acid in quantitative yield. This material was sufficiently
pure to proceed to the next step.
We initially attempted to install the b-phenyl moiety by
treatment of nitroalkane 5 with phthalic anhydride and
various Lewis acid catalysts, but obtained only small
amounts of the acylation product. Treating 5 with phtha-
loyl chloride, however, proved very successful, furnishing
high yields of crystalline benzophenone 11. Although we
were able to effect intramolecular Henry reaction with this
keto acid, providing modest yields, we discovered that
A soln of 3-(3,4-dimethoxyphenyl)propanoic acid (0.961 g, 4.58
mmol) in anhyd THF (30 mL) was placed under a dry N2 atmo-
sphere at 0 °C. Dropwise, 1 M BH3 in THF (5 mL, 5 mmol) was
added to this soln and it was allowed to stir for 4 h. The soln was
concentrated to one third of its volume under reduced pressure and
much milder conditions would promote a nearly quantita- H2O (40 mL) was carefully added. This mixture was extracted with
CH2Cl2 (3 × 20 mL); the combined extracts were washed with H2O
(2 × 10 mL) and then brine, dried (MgSO4), and filtered and the sol-
vents were removed under reduced pressure to give 3 as an oil that
solidified upon long standing or cooling; yield: 0.879 g (98%).
1H NMR (300 MHz, CDCl3): d = 6.77–6.72 (m, 3 H, ArH), 3.86 (s,
3 H, OCH3), 3.85 (s, 3 H, OCH3), 3.67 (t, 2 H, CH2OH), 2.65 (t, 2
H, ArCH2), 1.86 (q, 2 H, CH2), 1.73 (br s, 1 H, OH).
tive transformation of methyl ester 12 into nitroalkene 13.
Curiously, the reaction had proceeded with loss of the
methyl ester moiety under conditions where ester hydro-
lysis should not have occurred. After a variety of experi-
ments, we established that the ester was not lost during
workup and had not simply fortuitously hydrolyzed. It
was evident therefore, that the reaction must have taken
place through an intermediate lactone, which then rapidly
underwent elimination to acid 13, facilitating the overall
ring closure. Thus, we obtained the cyclic nitroalkene in
excellent yield.
MS (ESI): m/z (%) = 219 (100) [M + Na]+, 197 (28) [M + H]+.
Anal. Calcd for C11H16O3.: C, 67.32; H, 8.22. Found: C, 67.18; H,
8.24.
4-(3-Bromopropyl)-1,2-dimethoxybenzene (4)18
We then treated 13 with sodium borohydride in isopropyl
alcohol to reduce the alkene. The conjugate reduction of
13 was very sluggish and required high temperatures and
dilution to proceed efficiently, but gave exclusively trans-
nitroalkane 14, presumably by equilibration of the result-
ing nitronate anion.15 We were then best able to form lac-
tam 15 by esterification of the free acid, reduction of the
nitro moiety using zinc and acetic acid, and heating of the
resulting amino ester freebase to effect cyclization. This
lactam was easily reduced with borane, and the dimethoxy
protecting groups were subsequently cleaved by treatment
with boron tribromide. Isolation of dihydrexidine hydro-
chloride (1·HCl), was then carried out as described previ-
ously.16
Alcohol 3 (3.00 g, 15.3 mmol) was dissolved in CH2Cl2 (30 mL)
along with CBr4 (5.08 g, 15.3 mmol). This soln was then cooled to
0 °C and Ph3P (4.01 g, 15.1 mmol) was added. The soln stirred for
2 h, and the solvents were removed under reduced pressure. A quick
elution through a short column (silica gel, EtOAc–hexanes, 1:1)
gave a soln that was Ph3PO-free and that was concentrated and
placed under vacuum at 50 °C for 8 h to give 4 as a pale yellow oil;
yield: 3.64 g (92%).
1H NMR (300 MHz, CDCl3): d = 6.76 (m, 3 H, ArH), 3.87 (2 s, 6 H,
OCH3), 3.40 (t, 2 H, CH2Br), 2.73 (t, 2 H, ArCH2), 2.15 (q, 2 H,
CH2).
MS (CI): m/z (%) = 259 (100) [M + H]+, 261 (98) [M + H]+.
Anal. Calcd for C11H15BrO2: C, 50.98; H, 5.83. Found: C, 50.84; H,
5.79.
1,2-Dimethoxy-4-(3-nitropropyl)benzene (5)
Thus, we have succeeded in developing an uncomplicated
scalable methodology enabling the preparation of racemic
dihydrexidine (1) from inexpensive starting materials (ve-
ratrole, acrolein, phthalic anhydride, and sodium nitrite).
From acrolein, this process leads to 1 in 14 synthetic ma-
From 4: In a round-bottom flask 4 (1.82 g, 7.02 mmol) was stirred
with DMF (40 mL) and cooled to 0 °C. To this mixture, NaNO2
(629 mg, 9.12 mmol) were added and the mixture was removed
from cooling and stirred at r.t. for 4 h. The mixture was then poured
over ice and extracted with CH2Cl2 (4 × 15 mL). The organic ex-
Synthesis 2009, No. 5, 715–720 © Thieme Stuttgart · New York

718
J. P. Cueva, D. E. Nichols
PAPER
tracts were pooled and washed with H2O (10 × 20 mL). The organic
layer was dried (Na2SO4) and filtered and the solvents were re-
moved under reduced pressure to yield an oil that was a mixture of
4 and 5. This mixture was then separated by column chromatogra-
phy (silica gel, hexanes–EtOAc, 2:1) to yield pure 5 as a yellow oil;
yield: 0.848 g (54%).
hyd toluene, the soln was azeotropically distilled to remove excess
SOCl2. The residue was then slowly distilled at 80 °C/0.133 mbar to
afford pure 3-nitropropanoyl chloride (9) as a clear liquid; yield:
11.13 g (95%). The acid chloride was dissolved in CH2Cl2 (150 mL)
along with AlCl3 (11.87 g, 89.13 mmol) and cooled to 0 °C in an ice
bath. Veratrole (12.30 g, 89.13 mmol) was added in a slow stream
and the soln was removed from cooling and allowed to stir for 36 h.
The mixture was then poured onto ice, acidified by addition of 2 M
HCl (40 mL), and extracted with CH2Cl2. The combined organic ex-
tracts were washed again with 2 M HCl (30 mL) and then H2O (30
mL), dried (MgSO4), and filtered, and the solvent was removed un-
der reduced pressure to yield a brown solid that was recrystallized
(MeOH) to give 10 as cream-colored crystals; yield: 16.77 g (79%);
mp 121–123 °C.
From 10: Under an inert atmosphere, 10 (16.77 g, 70.16 mmol) was
dissolved in TFA (100 mL) and Et3SiH (30 mL). This mixture was
stirred at r.t. for 5 d, and then concentrated under reduced pressure.
After standing for 3 h the top clear layer (Et3SiOH) was carefully
decanted and discarded. The bottom layer was then distilled at 70
°C/0.133 mbar. After collecting an initial fraction that was mostly
Et3SiOH, the pot temperature was increased to 130 °C. After 6 h of
distillation, 5 (14.179 g, 90%) was obtained as a pale yellow oil.
1H NMR (300 MHz, CDCl3): d = 6.81 (d, 1 H, ArH), 6.73–6.68 (m,
2 H, ArH), 4.37 (t, 2 H, CH2NO2), 3.87 (2 s, 6 H, OCH3), 2.67 (t, 2
H, ArCH2), 2.30 (q, 2 H, CH2).
1H NMR (300 MHz, CDCl3): d = 7.59 (dd, 1 H, ArH), 7.50 (d, 1 H,
ArH), 6.90 (d, 1 H, ArH), 4.81 (t, 2 H, CH2NO2), 3.93 (2s, 6 H,
OCH3), 3.62 (t, 2 H, CH2).
MS (CI): m/z (%) = 240 (76) [M + H]+, 193 (100) [M – NO2]+.
MS (CI): m/z (%) = 226 (100) [M + H]+.
Anal. Calcd for C11H13NO5: C, 55.23; H, 5.48; N, 5.86. Found: C,
55.15; H, 5.28; N, 5.80.
Anal. Calcd for C11H15NO4: C, 58.66; H, 6.71; N, 6.22. Found: C,
58.77; H, 6.61; N, 6.11.
2-[4,5-Dimethoxy-2-(3-nitropropyl)benzoyl]benzoic Acid (11)
A soln of phthaloyl dichloride (1.35 g, 6.66 mmol) in CH2Cl2 (25
mL) was placed in a dry flask and cooled to 0 °C. Next, SnCl4 (0.52
mL, 4.44 mmol) was added, followed by nitroalkane 5 (1.00 g, 4.44
mmol) added dropwise. The flask was removed from external cool-
ing and the contents allowed to stir for 36 h. The soln was then
poured onto ice. The organic layer was separated and washed with
2 M HCl (2 × 10 mL) to remove tin salts, followed by extraction
with sat. NaHCO3 soln (4 × 30 mL). The aqueous extracts were
combined, washed with Et2O (1 × 10 mL), and then carefully acid-
ified with concd HCl while vigorously stirring. The mixture was
then extracted into CH2Cl2 and the extracts were washed with H2O
(1 ×), dried (MgSO4), and filtered and the solvent was removed un-
der reduced pressure to give 11 as a yellow crystalline product;
yield: 1.462 g (88%). An analytical sample was obtained by crystal-
lization (MeOH); mp 129–132 °C.
4,5-Dimethoxy-2-(3-nitropropyl)benzaldehyde (6)
In a two-necked flask equipped with a condenser, a soln of 5 (2.85
g, 12.7 mmol) in CH2Cl2 (50 mL) was cooled to 0 °C. Through a sy-
ringe, anhyd SnCl4 (1.48 mL, 12.7 mmol) was added, and then,
through an addition funnel, Cl2CHOMe (1.16 mL, 12.8 mmol) was
added dropwise to the flask. The mixture was stirred for 4 h and
poured over ice. The heavy organic layer was separated and washed
with 2 M HCl (2 × 50 mL) and then with brine (10 mL). The soln
was dried (MgSO4) and filtered and the solvent was removed under
reduced pressure to yield 6 as a brown solid; yield: 3.13 g (98%).
An analytical sample was obtained by recrystallization (EtOH); mp
80–82 °C.
1H NMR (300 MHz, CDCl3): d = 10.05 (s, 1 H, CHO), 7.30 (s, 1 H,
ArH), 6.69 (s, 1 H, ArH), 4.41 (t, 2 H, CH2NO2), 3.91 (2 s, 6 H,
OCH3), 3.07 (t, 2 H, ArCH2), 2.29 (q, 2 H, CH2).
MS (CI): m/z (%) = 254 (100) [M + H]+.
1H NMR (500 MHz, CDCl3): d = 8.05 (dd, 1 H, ArH), 7.66 (td, 1 H,
ArH), 7.57 (td, 1 H, ArH), 7.39 (dd, 1 H, ArH), 6.77 (s, 1 H, ArH),
6.69 (s, 1 H, ArH), 4.45 (t, 2 H, CH2NO2), 3.94 (s, 3 H, OCH3), 3.60
(s, 3 H, OCH3), 3.09 (t, 2 H, CH2), 2.42 (q, 2 H, CH2).
Anal. Calcd for C12H15NO5: C, 56.91; H, 5.97; N, 5.53. Found: C,
56.79; H, 6.09; N, 5.39.
1,2-Dihydro-6,7-dimethoxy-3-nitronaphthalene (7)7
MS (ESI): m/z (%) = 396 (100) [M + Na]+.
A soln of 6 (3.12 g, 12.3 mmol) in glacial AcOH (50 mL) was pre-
pared in a two-necked flask equipped with a condenser. Through a
syringe, piperidine (2.40 mL, 24.7 mmol) was added and the mix-
ture was stirred with heating at 100 °C for 4 h. The soln was then
reduced to one half of its volume under reduced pressure, H2O (50
mL) was added, and this mixture was extracted with CH2Cl2 (3 × 20
mL). These extracts were pooled and washed with 2 M NaOH
(5 × 20 mL) and then brine (10 mL). The organic phase was dried
(MgSO4) and filtered and the solvent was removed to yield pure 7
as a bright yellow solid; yield: 2.67 g (92%). An analytical sample
was obtained by recrystallization (i-PrOH); mp 99–100 °C.
Anal. Calcd for C19H19NO7: C, 61.12; H, 5.13; N, 3.75. Found: C,
61.10; H, 5.09; N, 3.65.
Methyl 2-[4,5-Dimethoxy-2-(3-nitropropyl)benzoyl]benzoate
(12)
In a dry flask containing benzoic acid 11 (4.89 g, 13.1 mmol) was
added SOCl2 (30 mL) and the soln was stirred overnight. Benzene
was added to the reaction, followed by azeotropic distillation to re-
move excess SOCl2. The residue was dissolved in anhyd MeOH,
whereupon the product immediately crystallized. The crystals were
collected by filtration and air dried to yield the ester 12 as cream-
colored crystals; yield: 4.372 g (86%); mp 70–72 °C.
1H NMR (300 MHz, CDCl3): d = 7.94 (dd, 1 H, ArH), 7.63–7.51
(m, 2 H, 2 ArH), 7.40 (dd, 1 H, ArH), 6.77 (s, 1 H, ArH), 6.70 (s, 1
H, ArH), 4.48 (t, 2 H, CH2NO2), 3.94 (s, 3 H, COOCH3), 3.65 (s, 3
H, OCH3), 3.60 (s, 3 H, OCH3), 3.08 (t, 2 H, ArCH2), 2.44 (q, 2 H,
CH2).
1H NMR (300 MHz, CDCl3): d = 7.82 (s, 1 H, ArCHCNO2), 6.82 (s,
1 H, ArH), 6.75 (s, 1 H, ArH), 3.93 (s, 3 H, OCH3), 3.89 (s, 3 H,
OCH3), 2.98 (m, 4 H, ArCH2, CH2CNO2).
MS (ESI): m/z (%) = 236 (100) [M + H]+.
Anal. Calcd for C12H13NO4: C, 61.27; H, 5.57; N, 5.95. Found: C,
61.34; H, 5.52; N, 5.81.
MS (CI): m/z (%) = 388 (100) [M + H]+.
1-(3,4-Dimethoxyphenyl)-3-nitropropan-1-one (10)
Anal. Calcd for C20H21NO7: C, 62.01; H, 5.46; N, 3.62. Found: C,
61.63; H, 5.43; N, 3.65.
In a dry flask, 3-nitropropanoic acid14 8 (10.15 g, 85.24 mmol) was
stirred overnight with SOCl2 (100 mL). Following addition of an-
Synthesis 2009, No. 5, 715–720 © Thieme Stuttgart · New York

PAPER
A New Synthesis of Dihydrexidine
719
2-(3,4-Dihydro-6,7-dimethoxy-2-nitronaphthalen-1-yl)benzoic
Acid (13)
Concentration and cooling of the mother liquor yielded a second
crop to afford the lactam 15; total yield: 1.10 g (91%); mp 258–260
°C.
1H NMR (300 MHz, CDCl3): d = 8.08 (dd, 1 H, ArH), 7.67 (d, 1 H,
ArH), 7.50 (td, 1 H, ArH), 7.40 (t, 1 H, ArH), 6.98 (s, 1 H, ArH),
6.72 (br s, 1 H, CONH), 6.68 (s, 1 H, ArH), 4.24 (d, J = 12 Hz, 1 H,
ArCHAr), 3.88 (2s, 6 H, 2 OCH3), 3.66 (dt, Jtrans = 12.3 Hz, Jvic = 3
Hz, 1 H, CHN), 2.90–2.75 (m, 2 H, ArCH2), 2.11 (m, 1 H, CH2),
1.92 (dq, Jtrans = 12.3 Hz, Jvic = 5.1 Hz, 1 H, CH2).
Ester 12 (4.61 g, 11.9 mmol) was dissolved in a warm mixture of
THF (100 mL) and MeOH (100 mL). DBU (4.45 mL, 29.7 mmol)
was added and the mixture was stirred overnight. The mixture was
then diluted with H2O (200 mL), and extracted with Et2O (2 × 50
mL). The aqueous soln was acidified to pH 6 and extracted with
EtOAc–CH2Cl2 (20:1) (to aid phase separation). The combined or-
ganic extracts were washed with 2 M HCl (1 ×), then with brine (1
×). The soln was dried (Na2SO4) and filtered and the solvents were
removed to leave a bright yellow solid that was dried under vacuum;
crude yield: 4.12 g (97%). An analytical sample was prepared by re-
crystallization (EtOAc–hexanes); mp 148–154 °C.
MS (ESI): m/z (%) = 310 (100) [M + H]+.
Anal. Calcd for C19H19NO3: C, 73.77; H, 6.19; N, 4.53. Found: C,
73.39; H, 6.21; N, 4.58.
1H NMR (300 MHz, CDCl3): d = 8.20 (dd, 1 H, ArH), 7.64 (td, 1 H,
ArH), 7.51 (td, 1 H, ArH), 7.16 (dd, 1 H, ArH), 6.77 (s, 1 H, ArH),
5.99 (s, 1 H, ArH), 3.91 (s, 3 H, OCH3), 3.49 (s, 3 H, OCH3), 3.07–
2.94 (m, 4 H, 2CH2).
trans-5,6,6a,7,8,12b-Hexahydro-10,11-dimethoxyben-
zo[a]phenanthridine Hydrochloride (16)16
To a suspension of lactam 15 (460 mg, 1.49 mmol) in anhyd THF
(30 mL) was added 1 M BH3 in THF (5 mL). This mixture was heat-
ed at reflux and stirred for 18 h. The clear soln was then cooled,
quenched with H2O, and its volume reduced to one-third under re-
duced pressure. H2O was added, and the mixture was extracted with
EtOAc (4 × 10 mL). The combined organic extracts were washed
with H2O, dried (MgSO4), and filtered and the solvents were re-
moved under reduced pressure. The residue was dissolved in 2 M
HCl in EtOH (10 mL). This soln was stirred at 40 °C for 1 h and then
concentrated to dryness under vacuum. The residue was crystallized
(MeCN) to afford the HCl salt in two batches; yield: 350 mg (71%);
mp 243 °C. The NMR spectrum and other properties were identical
to those reported previously.16
MS (ESI): m/z (%) = 378 (100) [M + Na]+.
Anal. Calcd for C19H17NO6: C, 64.22; H, 4.82; N, 3.94. Found: C,
64.54; H, 4.78; N, 3.63.
trans-2-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-nitronaphthalen-
1-yl)benzoic Acid (14)
Nitroalkene 13 (2.00 g, 5.63 mmol) was dissolved in i-PrOH (250
mL), NaBH4 (638 mg, 16.9 mmol) was added, and the mixture was
stirred and heated at reflux for 12 h. Additional NaBH4 (275 mg,
24.1 mmol total) was then added and the mixture was stirred for an
additional 6 h at reflux, at which time the yellow color had been
completely discharged. The suspension was concentrated to one-
third of its original volume under reduced pressure and a concen-
trated soln of urea in 1% AcOH was then added until pH 6. The mix-
ture was then extracted with CH2Cl2 (3 × 50 mL); the combined
organic extracts were washed with H2O (2 ×), dried (MgSO4), and
filtered and the solvents were removed under reduced pressure. The
residual light green solid was triturated under warm EtOAc, cooled,
and filtered to yield 14; yield: 1.44 g (71%); mp 185–190 °C.
trans-5,6,6a,7,8,12b-Hexahydro-10,11-dihydroxyben-
zo[a]phenanthridine Hydrochloride (1·HCl)16
Compound 1 was prepared following the procedure by Knoerzer et
al.16 and had identical properties to those reported therein.
Acknowledgment
1H NMR (300 MHz, DMSO-d6): d = 7.85 (d, 1 H, ArH), 7.47 (t, 1
H, ArH), 7.37 (t, 1 H, ArH), 6.99 (d, 1 H, ArH), 6.75 (s, 1 H, ArH),
6.24 (s, 1 H, ArH), 5.56 (d, J = 5.7 Hz, 1 H, ArCHAr), 5.21 (m, 1
H, CHNO2), 3.74 (s, 3 H, OCH3), 3.46 (s, 3 H, OCH3), 2.97 (m, 1
H, CH2), 2.73 (m, 1 H, CH2), 2.29 (m, 2 H, ArCH2).
This work was supported by NIH Grant MH42705. The work was
conducted in a facility constructed with support from Research Fa-
cilities Improvement Program Grant No. C06-14499 from the Na-
tional Center for Research Resources of the National Institutes of
Health. The authors also acknowledge Ms. Lisa Bonner for conduc-
ting NMR spectroscopy studies of many of the compounds repor-
ted.
MS (ESI): m/z (%) = 380 (100) [M + Na]+.
Anal. Calcd for C19H19NO6: C, 63.86; H, 5.36; N, 3.92. Found: C,
63.59; H, 5.52; N, 3.78.
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