Development of an Efficient Synthesis of rac-3-Demethoxyerythratidinone via a Titanium(III) Catalyzed Imine-Nitrile Coupling

Article abstract of DOI:10.1002/ejoc.201801479

We herein describe the evolution of a rapid, high-yielding synthesis of the erythrina alkaloid 3-demethoxyerythratidinone. The natural product is assembled in six steps from commercial precursors in 30–35 % overall yield and with only two chromatographical purification operations. The key step is a titanium(III) catalyzed umpolung reaction in form of a reductive imine–nitrile coupling that can be combined with a subsequent cyclization reaction on a 50 mmol scale. Furthermore, optimized Wacker oxidation conditions enable the selective alkene oxidation in the presence of a tertiary amine functionality, which has been a problem in previous syntheses of erythrina alkaloids. The racemic route can be used to prepare the natural product on gram scale and the results may be useful for the synthesis of related alkaloids.

Full text of DOI:10.1002/ejoc.201801479

A Journal of
Accepted Article
Title: Development of an Efficient Synthesis of rac-3-
Demethoxyerythratidinone via a Titanium(III) Catalyzed Imine-
Nitrile Coupling
Authors: Hieu-Trinh Luu and Jan Streuff
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801479
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801479
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10.1002/ejoc.201801479
European Journal of Organic Chemistry
FULL PAPER
Development of an Efficient Synthesis of rac-3-Demethoxy-
erythratidinone via a Titanium(III) Catalyzed Imine-Nitrile Coupling
Hieu-Trinh Luu[a] and Jan Streuff*[a]
Abstract: We herein describe the evolution of a rapid, high-yielding
synthesis of the erythrina alkaloid 3-demethoxyerythratidinone. The
natural product is assembled in six steps from commercial
precursors in 30–35% overall yield and with only two
As part of our ongoing research program for the development of
unconventional C-C coupling methods, we have developed a
series of titanium(III) catalyzed intra- and intermolecular
reductive umpolung reactions.[5–8] This included a reductive
iminonitrile cyclization to a-aminoketones or pyrrolidinones and
corresponding intermolecular imine-nitrile couplings to acyclic
a-aminoketones.[9] Recently, this approach has been advanced
to a selective reductive C1-acylation of dihydroisoquinolines,
which was applied to the synthesis of functionalized
chromatographical purification operations. The key step is
a
titanium(III) catalyzed umpolung reaction in form of a reductive
imine-nitrile coupling that can be combined with a subsequent
cyclization reaction on a 50 mmol scale. Furthermore, optimized
Wacker oxidation conditions enable the selective alkene oxidation in
the presence of a tertiary amine functionality, which has been a
problem in previous syntheses of erythrina alkaloids. The racemic
route can be used to prepare the natural product on gram scale and
the results may be useful for the synthesis of related alkaloids.
tetrahydroisoquinolines
and
a
total
synthesis
of
3-demethoxyerythratidinone (1).[10] In this full paper, we describe
in detail the synthetic efforts to 1 via an intramolecular and an
intermolecular titanium(III)-catalyzed imine-nitrile coupling, the
latter of which ultimately evolved into an operationally
convenient and protecting group free six-step synthesis. It
demonstrates the viability and strengths of titanium(III)-catalyzed
reductive couplings for applications in alkaloid synthesis.[11]
Furthermore, it was highlighted in previous synthetic studies to
erythrina alkaloids that attempts to carry out Wacker oxidation
reactions on advanced intermediates would fail. We herein
demonstrate that this limitation can be overcome by using
modified acidic conditions or by a preceding transformation of
the tertiary amine into the corresponding hydrochloride.
Introduction
Erythrina alkaloids exhibit
a
number of interesting
pharmacological properties and have been common targets for
the exploration of new synthetic methodology.[1] In particular,
3-demethoxyerythratidinone (1), which is one of the less
complex family members, has served as a benchmark substrate,
although no particular biological activity has been reported for
this compound (Figure 1).[2] Hence, a number of racemic and
asymmetric approaches to 1 have been developed to date.[3,4]
The molecule contains a fully substituted tertiary benzylic carbon
The two retrosynthetic analyses of 1 are outlined in Scheme 1.
Following
a
common
retro-aldol
condensation
and
deoxygenation, intermediate 2 was disconnected by a retro-
Friedel-Crafts alkylation and N-dealkylation, resulting in the
removal of a C2 fragment. The pyrrolidinone 3 could then be
transformed by a deacylating C-C cleavage into the readily
available imine 4, which would be an ideal precursor for a
titanium(III)-catalyzed cyclization to 3.
stereocenter bearing
tetrahydroisoquinoline motif and
a
tertiary amine, an oxygenated
cyclohexenone subunit.
a
These functions are found in other members of this natural
product class and in a range of other alkaloids, which renders 1
a reasonable candidate for probing the applicability of new
methods to the synthesis of alkaloids in general.
MeO
N
MeO
MeO
D
C
A
N
N
MeO
rac-1
O
B
3
MeO
MeO
MeO
MeO
MeO
MeO
O
H
erythrina alkaloid
skeleton
(+)-3-demethoxy-
erythratidinone (1)
N
N
NH
X
O
O
O
+
Figure 1. The erythrina alkaloid framework and target molecule 1.
3
2
5
intramolecular
intermolecular
coupling
coupling
MeO
MeO
MeO
X
N
N
MeO
[a]
Dr. H.-T. Luu, Dr. J. Streuff
Institut für Organische Chemie
Albert-Ludwigs-Universität Freiburg
Albertstraße 21, 79104 Freiburg im Breisgau
E-mail: jan.streuff@ocbc.uni-freiburg.de
http://portal.uni-freiburg.de/streuff
N
N
4
6
7
Scheme 1. Key retrosynthetic steps for the disconnection of 1. The
intermediates 3 and 5 were to be constructed by applying a titanium(III)-
catalyzed intra- or intermolecular imine-nitrile coupling.
Supporting information for this article is given via a link at the end of
the document.
1
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10.1002/ejoc.201801479
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Alternatively, the pyrrolidinone part of compound 2 was opened
by a retro-N-alkylation to give tetrahydroisoquinoline 5, which
could then be disconnected by an intermolecular deacylating
C-C coupling into the literature-known dihydroisoquinoline 6 and
a substituted propionitrile 7.3d In a forward sense, the assembly
of 5 would be then possible by a direct titanium(III)-catalyzed
reductive acylation of 6.
Afterwards, the oxidation of 3 to diketone 12 was attempted
(Scheme 3). However, even when the secondary amine was first
transformed into the corresponding hydrochloride, only complex
product mixtures were obtained. As an alternative approach,
pyrrolidinone 3 was N-alkylated using bromoacetonitrile as well
as methyl and tert-butyl a-bromoacetate in very good yield (13–
15). But
a subsequent Houben-Hoesch or Friedel-Crafts
cyclization to product 17 did not take place, although various
Lewis acids were tested as promoters. This was also the case
for the TFA salt of the unprotected glycin derivative (16).
Results and Discussion
Compund 13, was then converted into a hydrochloride and
immediately submitted to Wacker oxidation conditions. In the
presence of catalytic amounts of Pd(CH3CN)2Cl2 and
stoichiometric 1,4-benzoquinone (1,4-BQ), diketone 18 was
formed in 80% yield. However, all attempts to forge the AB ring
system 19 by an aldol condensation under basic equilibrium
conditions were unsuccessful. At this point, it was decided to
discard the intramolecular strategy since further attempts to
assemble the full ABCD ring system would lead to a significantly
increased step count of the synthesis.
We first tested the intramolecular titanium(III) catalyzed
cyclization in presence of the bis-methoxylated arene unit
(Scheme 2). Starting from 3,4-dimethoxyacetophenone (8),
imine 9 was prepared by condensation with 3-aminopropionitrile
in presence of Ti(OEt)4 and used after filtration without further
purification as substrate for the titanium catalyzed cyclization.
With 10 mol-% Cp2TiCl2 and zinc as reducing agent, the
cyclization to pyrrolidinone 10 readily occurred, giving a 93%
yield over two steps. The cyclization proceeded smoothly even
in presence of the residual titanium(IV) salts, which underlined
the robustness of the reaction.
MeO
H
Encouraged by this result, the synthetic study towards 1 was
N
a) HCl in Et2O
started
with
the
preparation
of
pyrrolidinone
3.
MeO
3
then
3,4-Dimethoxyacetophenone was first allylated in presence of
potassium hydride and triethyl borane to give ketone 11 in 35%
yield (not optimized). Careful reaction monitoring was required to
avoid double allylation. It should be noted that a similar
monoallylation of less electron-rich benzodioxol-5-yl methyl
ketone gave 81% yield.[12] Then, the imine condensation was
carried out, giving quantitative conversion to 4 as was indicated
by 1H NMR of the crude product mixture. The cyclization of
crude 4 then took place as planned in presence of 10 mol-%
Cp2TiCl2 and the analytically pure pyrrolidinone 3 was isolated
after an acid-base extraction in 87% yield over two steps.
O
Pd(CH3CN)2Cl2
1,4-BQ
O
CH3CN-H2O
12
O
Br
EWG
EWG
b)
MeO
MeO
MeO
MeO
Na2CO3
N
3
N
O
O
13, EWG = CN, >99%
17
14, EWG = CO2Me, 93%
15, EWG = CO2tBu, 84%
16, EWG = CO2H, TFA salt
c) TFA, (99%)
a) Ti(OEt)4
CN
MeO
MeO
MeO
MeO
MeO
CN
CN
H2N
MeO
N
R
HCl in Et2O
d)
R
CN
MeO
c)
N
THF, reflux
filtration
13
N
9: R = Me
4: R =
MeO
then
Pd(CH3CN)2Cl2
1,4-BQ
CH3CN-H2O
(80%)
O
8: R = Me
O
O
O
11: R =
18
19
(not purified)
MeO
MeO
b) Cp2TiCl2 (10 mol-%)
Zn, TMSCl, Et3N•HCl
Scheme 3. Studies towards the assembly of the erythrina alkaloid core using
3. a) HCl in Et2O (2 M), CHCl3, 23 ºC; then Pd(CH3CN)Cl2 (10 mol-%), 1,4-
benzoquinone (1.1 equiv), CH3CN-H2O 4:1, 23 ºC, 24 h; b) EWG-CH2Br (1.3
equiv), Na2CO3 (2.0 equiv), CH3CN, reflux, 48 h; c) TFA (66 equiv), CH2Cl2, –
78→23 ºC, 3 d; d) HCl in Et2O (2 M), CHCl3, 23 ºC; then Pd(CH3CN)Cl2 (10
mol-%), 1,4-benzoquinone (1.1 equiv), CH3CN-H2O 4:1, 70 ºC, 24 h.
H
N
THF, 23 ºC
R
O
Me, 93% (2 steps)
10: R =
3: R =
, 87% (2 steps)
The intermolecular approach, on the other hand, led to a very
short and modular synthesis of 1. Following a literature protocol,
4-pentenoyl chloride (20), commercially available or synthesized
from 4-pentenoic acid with SOCl2, was treated with
homoveratrylamine (21) in the presence of triethylamine to form
the corresponding amide (Scheme 4). This amide was then
transformed into literature-known dihydroisoquinoline 6 by a
Bischler-Napieralski cyclization with POCl3.[3d,13] On a 90 mmol
Scheme 2. Imine-condensation and intramolecular cyclization sequence. a)
Ti(OEt)4 (1.1 equiv), 3-aminopropionitrile (1.1 equiv), THF (c = 1.0 M), reflux,
48 h (8) or 24 h (11), then filtration; b) Cp2TiCl2 (10 mol-%), Zn dust (2.0 equiv),
TMSCl (3.0 equiv), Et3N•HCl (0.5 equiv), THF (c = 0.4 M), 23 ºC, 25 h; c) KH
(1.4 equiv), BEt3 (1.2 equiv), allyl bromide (1.5 equiv), THF, 0 → 23 ºC, 3 h,
35%.
2
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10.1002/ejoc.201801479
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scale, this sequence gave analytically pure 6 after extraction in
Table 1. Optimization of the titanium(III) catalyzed reductive coupling of 6 and
7d.
an overall yield of 88%. Dihydroisoquinoline
6 was then
subjected to the titanium(III)-catalyzed reductive acylation
conditions with chloro-, bromo-, or hydroxypropionitriles 7a–c as
coupling partners. But it was found that these nitriles were not
tolerated under the reaction conditions. Neither ketone 5 nor
pyrrolidinone 2 were observed. Gratifyingly, it was found that
trimethylsiloxy-substituted propionitrile 7d was an appropriate
coupling partner and the reaction occurred in 48% after 72 h
reaction time. The silyl group was cleaved during the acid-base
workup sequence, releasing the free primary alcohol (5c).
catalyst (10 mol-%)
Zn (2.0 equiv)
Et3N•HCl (0.5 equiv)
TMSCl
MeO
NH
MeO
CN
O
6
+
OTMS
7d
THF, 35 ºC
acid-base extraction
OH
5c
Ph
H
H
Cl Ti Cl
Cl Ti Cl
H
Cl Ti Cl
H
MeO
a)
Ph
NH2
MeO
22
23
24
21
MeO
Et3N
POCl3
O
Entry
catalyst
equiv 7d
5.0
equiv TMSCl
t / h
72
72
72
24
24
24
24
24
24
24
Yield / %
b)
N
MeO
Cl
(88%, 2 steps)
90 mmol scale
1
Cp2TiCl2
Cp2TiCl2
Cp2TiCl2
Cp2TiCl2
Cp2TiCl2
3.0
3.0
1.5
0
48
20
6
2
1.5
32
MeO
MeO
3
1.5
48
MeO
MeO
X
c)
NC
NH
O
7a–d
N
4
1.5
0
or
Cp2TiCl2 (10 mol-%)
Zn, Et3N•HCl, TMSCl
acid-base extraction
5[a]
6
1.5
1.5
1.5
1.5
1.5
1.5
1.5
14
O
X
Cp2Ti(OPh)2
1.5
72
7a, X = Cl
7b, X = Br
5a, X = Cl, 0%
5b, X = Br, 0%
5c, X = OH, 0%
5c, X = OH, 48%
2
(not observed)
7c, X = OH
7d, X = OTMS
7[b]
8[c]
9[c]
10[c]
Cp2Ti(OPh)2
1.5
22
22
23
24
1.5
52 (9% ee)
45 (16% ee)
74 (16% ee)
Scheme 4. Synthesis of 6 and first TiIII-catalyzed interomlecular couplings. a)
22 (1.0 equiv), Et3N (1.5 equiv), CH2Cl2, 0 ºC, 30 min, then 23 ºC, 20 h; b)
POCl3 (7.4 equiv), CH3CN, 95 ºC, 4 h; c) nitrile 7 (5.0 equiv), Cp2TiCl2
(10 mol-%), Zn (2.0 equiv), TMSCl (3.0 equiv), Et3N•HCl (0.5 equiv), THF
(c = 0.1 M), 35 ºC, 72 h; then acid-base extraction.
1.5
1.5
[a] Reaction without Et3N•HCl. [b] Reaction with Mn (2.0 equiv) instead of Zn.
[c] Determined by chiral HPLC.
Apart from the prolonged reaction time, the initial reaction
conditions were identical to the cyclizations of 9 and 4, and
consisted of Cp2TiCl2 (10 mol-%), Et3N•HCl (0.5 equiv), as well
as a significant excess of nitrile 7d (5.0 equiv) and TMSCl (3.0
equiv). In order to achieve more economic conditions, a careful
optimization was carried out (Table 1). It was found that the
amounts of 7d and TMSCl could be drastically reduced to 1.5
equivalents each, while maintaining a yield of 48% (entries 1–3).
No reaction took place if the silyl chloride was absent and the
yield was significantly reduced if no hydrochloride was present
(entries 4 and 5). With Cp2Ti(OPh)2 as catalyst precursor the
optimized yield of 72% was achieved (entry 6). Using
manganese instead of zinc gave a reduced yield of 22% under
the same conditions (entry 7). We also tested chiral titanocene
catalysts 22–24 and all of them gave the desired cross-coupling
product 5c in moderate to good yields. The asymmetric
induction that was observed in each case was low (9–16% ee,
entries 8–10).
Product 5c was then cyclized in order to complete the BCD ring
system (Scheme 5). Using Mitsunobu conditions, the tricyclic
intermediate 2 was formed in 66% yield, but the separation of 2
from the hydrazine dicarboxylate byproduct by chromatography
proved to be particularly difficult. Alternatively, treatment of 5c
with mesyl chloride and pyridine led to the quantitative formation
of 2. Furthermore, the product could then be conveniently
isolated after aqueous extraction in analytically pure form.
Pyrrolidinone
2 was then subjected to Wacker oxidation
conditions with the goal to transform the terminal alkene into a
ketone. However, a number of literature protocols employing
PdCl2 and
a variety of oxidants such as CuCl2, 1,4-
benzoquinone or aerobic conditions failed. This also applied to
recently developed conditions employing Pd(II)-sparteine or
Pd(II)-Quinox catalysts.[14] Based on our previous observations,
it was reasoned that the tertiary amine could have poisoned the
catalyst, preventing the oxidation of the alkene. In fact, it was
previously described by others that attempts to perform Wacker
oxidations on related intermediates in erythrina alkaloid
synthesis were unsuccessful.[4d] In order to overcome this
limitation, 2 was converted into the corresponding hydrochloride
salt 25, which could be isolated in quantitative yield by filtration.
3
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a) PPh3, DIAD
MeO
MeO
MeO
as oxidant, a set of conditions that was previously successful for
the oxidation of internal and cyclic olefins (Table 3).[15] While a
(66%)
NH
or
N
MeO
temperature of 70 ºC and
a dioxane-water mixture were
b) MsCl, pyridine
(>99%)
O
insufficient, a temperature of 80 ºC and a acetonitrile-water gave
the desired product in 55% yield (entries 1 and 2). Changing the
precatalyst to Pd(TFA)2 slightly reduced the yield to 41% (entry
3). With Pd(CH3CN)2 at 70 ºC, on the other hand, the result was
increased to 59% yield. The final improvement to 64% yield
could be achieved by increasing the amount of catalyst to 20
mol-% and by optimization of the amount of acid and oxidant
(entry 5).
O
OH
5c
2
MeO
MeO
Cl–
+
c) HCl in Et2O
(>99%)
N
H
O
25
Scheme 5. Closure of the BCD ring system, attempted Wacker oxidation, and
conversion of into its hydrochloride salt. a) PPh3 (1.3 equiv), DIAD
2
(1.3 equiv), THF (c = 0.17 M), 23 ºC, 16 h; b) MsCl (1.5 equiv), pyridine (4.3
equiv), 1,2-dichloroethane (c = 0.1 M), 10 ºC, 30 min, then 23 ºC, 2 h, then
50 ºC, 16 h; c) HCl in Et2O (2 M, 1.5 equiv), CHCl3, 0 ºC; filtration. DIAD =
diisopropyl azodicarboxylate
Table 3. Optimization of the direct Wacker oxidation of 2.
catalyst (10 mol-%)
oxidant
2
26
conditions
additives oxidant solvent
Entry catalyst
T / ºC Yield / %
Using 25 as precursor, the desired oxidation to ketone 26 took
place in 14% yield (Table 2, entry 1). A further investigation of
oxidation conditions then showed that a yield of 78% could be
achieved after optimization of the acetronitrile-water ratio and
the reaction concentration (entries 2–3). Using a higher amount
(equiv)
(equiv) (ratio)
HBF4
(2.5)
1.4-BQ dioxane-H2O
(2.2) (7:1)
1
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
70
80
80
70
70
0
HBF4
(2.5)
1.4-BQ CH3CN-H2O
(2.2) (7:1)
2
55
41
59
64
of oxidant was inferior (entry 4), but in presence of
a
stoichiometric ammount of palladium(II), diketone 26 was
obtained in quantitative yield (entry 5).
HBF4
(2.5)
1.4-BQ CH3CN-H2O
(2.2) (7:1)
3
HBF4
(2.5)
1.4-BQ CH3CN-H2O
(2.2) (7:1)
4
Pd(CH3CN)2Cl2
5[a]
Pd(CH3CN)2Cl2
Table 2. Optimization of the Wacker oxidation of 25.[a]
HBF4
(3.2)
1.4-BQ CH3CN-H2O
(4.0) (7:1)
MeO
Pd(CH3CN)2Cl2 (10 mol-%)
1,4-BQ
N
[a] With 20 mol-% palladium catalyst.
MeO
25
conditions
O
O
26
The final step in the synthesis of 1 was then a literature-known
aldol condensation reaction of 26, which give in our hands 57%
yield (54% on a 5 mmol scale).[3i,4d] The overall sequence from
commercially available 20 and 21 to 3-demethoxytratidinone
consisting of 6 steps was then further streamlined. After the two-
step formation of 6, it was found to be most convenient to
directly use the crude product 5c obtained from the titanium(III)
catalyzed cyclization in the subsequent mesylation/cyclization/
hydrochloride formation sequence (Scheme 6). The consecutive
steps from 6 to 25 were carried out on a 50 mmol scale and the
tricyclic product was isolated in pure form by simple precipitation
and filtration (63%). This yield was increased to 72%, if the
intermediary product 5c was isolated in between (see Table 1).
Only the last two steps (Wacker oxidation and aldol
condensation) required a chromatographical separation. Overall,
1 was prepared in a total yield of 30–35%, which marks one of
the most efficient routes towards this natural product to date.
Entry
1
equiv BQ
1.1
ratio CH3CN-H2O c / M
Yield / %
7:1
7:1
4:1
4:1
7:1
1.0
0.1
0.1
0.1
0.2
14
50
78
37
99
2
1.1
3[b]
4
1.1
2.2
5[c]
1.1
[a] Conditions: Pd(CH3CN)2Cl2 (10 mol-%), 1,4-benzoquinone (1.1–2.2 equiv),
80 ºC, 24 h. [b] Reaction on a 5 mmol scale. [c] Reaction with 100 mol-%
Pd(CH3CN)2Cl2 at 70 ºC.
It was then tested whether the conversion of 2 to 26 could be
achieved in a single step by carrying out the Wacker oxidation in
presence of a strong acid. We started with the addition of HBF4
to reactions using Pd(OAc)2 as catalyst and 1,4-benzoquinone
4
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10.1002/ejoc.201801479
European Journal of Organic Chemistry
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a)
7d (1.5 equiv)
Cp2Ti(OPh)2 (10 mol-%)
Zn, Et3N•HCl, TMSCl
absorption. Low and high resolution mass analyses were performed by
the service department at the Institute for Organic Chemistry and
Biochemistry, Freiburg University using a Thermo Finnigan TSQ 700 for
electron impact ionization (EI) at 70 eV, 200 ºC. High resolution mass
analyses (HRMS) were carried out on a Thermo Exactive with Orbitrap-
Analyzer using atmospheric pressure chemical ionization (APCI or ESI).
HPLC analyses were carried out by the Analytics Service of the Institute
of Organic Chemistry of the University of Freiburg using a Merck Hitachi
LaChrom HPLC system.
Cl–
H
MeO
MeO
b) MsCl, pyridine
DCE
N
6
then: HCl / Et2O
THF, 35 ºC
acid-base extraction
O
50 mmol scale:
63% from 6
25
(filtration only)
c)
Pd(CH3CN)2Cl2
1,4-BQ
d) KOH
diphenoxide:[10,18]
Titanocene
26
rac-1
Bis(cyclopentadienyl)titanium(IV)
MeOH
(57%)
CH3CN-H2O
(>99%)
dichloride (1.0 g, 4.0 mmol) and phenol (0.75 g, 8.0 mmol, 2 eq) were
dissolved in benzene (40 mL). While stirring, sodium hydride (290 mg, 12
mmol, 3 equiv) suspended in benzene (20 mL) was added and gas
evolution was observed. The reaction mixture was heated to reflux for 3
hours, which resulted in a color change from red to orange. The mixture
was allowed to cool to 23 ºC and filtered over celite (5 cm pad) and the
filter cake was rinsed with additional benzene (50 mL). The combined
organic mother liquors were concentrated and an orange solid (1.2 g)
was received. The crude product was suspended in n-hexane (4 mL) and
sonicated for 1 min in an ultrasonic bath. The solution was decanted off
and the suspension/sonication/decanting procedure was repeated. The
remaining solid was dried under high vacuum and Cp2Ti(OPh)2 was
received in 69% yield (1.0 g, 2.75 mmol) as a yellow solid. The analytical
data matched the previously reported values.
5 mmol-scale: 54%
Scheme 6. Optimized synthesis of rac-1. a) 7d (1.5 equiv), Cp2Ti(OPh)2
(10 mol-%), Zn (2.0 equiv), TMSCl (1.5 equiv), Et3N•HCl (0.5 equiv), THF (c =
1.0 M), 35 ºC, 24 h; b) MsCl (1.5 equiv), pyridine (4.3 equiv), 1,2-
dichloroethane (c = 0.1 M), 10 ºC, 30 min, then 23 ºC, 2 h, then 50 ºC, 16 h;
then HCl in Et2O (2.0 M, 1.5–1.6 equiv), CHCl3, 0 ºC; c) Pd(CH3CN)2Cl2 (1.0
equiv), 1,4-BQ (1.1 equiv), CH3CN-H2O (7:1, c = 0.2 M), 70 ºC, 24 h; d) aq.
KOH (20% w/w, 53.5 equiv), MeOH, 120 ºC, 16 h.
Conclusion
A short racemic total synthesis of 3-demethoxyerythratidinone
was developed that demonstrates the efficient application of a
titanium(III)-catalyzed reductive umpolung reaction in alkaloid
synthesis. With only six steps and two chromatographic
purification steps this synthesis constitutes one of the most
straightforward and operationally convenient approaches to the
erythrina alkaloid family. Furthermore, an optimized Wacker
oxidation protocol was developed that will be useful for future
applications in the presence of tertiary amines.
Bis(acetonitrile)dichloropalladium(II):[19] PdCl2 (2.0 g, 11.3 mmol) was
suspended in dry CH3CN (450 mL). The reaction mixture was heated to
reflux for 3 hours under argon atmosphere. After cooling down to room
temperature (23 ºC) the solvent was removed under reduced pressure.
The remaining solid was dried under high vacuum and Pd(CH3CN)2Cl2
was received in 99% yield (2.9 g, 11.2 mmol) as an orange-yellow solid.
The dried product was used without further purification and stored under
argon in the dark.
rac-2-(3,4-Dimethoxyphenyl)-2-methylpyrrolidin-3-one
(10):
3,4-
Dimethoxyacetophenone (1.802 g, 10.0 mmol) was dissolved in THF (10
ml) and 3-aminopropionitrile (805 µL, 11.0 mmol, 1.1 equiv) was added
while stirring. The mixture was cooled to 0 ºC in an ice bath and Ti(OEt)4
(2.51 g, 11.0 mmol, 1.1 equiv) was added. The ice bath was removed
and the reaction was heated to reflux for 48 h. After allowing the mixture
to cool to room temperature, it was filtered over Celite and the filter cake
was rinsed with CH2Cl2 (40 ml). The solvents were removed under
reduced pressure to give 9 as a white-yellow solid (2.35 g), which was
used as such in the next step. E-isomer only. 1H NMR (400.1 MHz,
CDCl3): d = 2.22 (t, J = 0.7 Hz, 3H), 2.78 (t, J = 6.9 Hz, 2H), 3.66 (td, J =
0.7, 6.9 Hz, 2H), 3.88 (s, 3H), 3.90 (s, 3H), 6.82 (d, J = 8.5 Hz, 1H), 7.29
(dd, J = 2.1, 8.5 Hz, 1H), 7.51 (d, J = 2.1 Hz, 1H). 13C NMR (100.6 MHz,
CDCl3): d = 15.65, 20.03, 47.43, 55.93, 55.98, 109.50, 110.26, 119.14,
120.09, 133.19, 148.91, 150.99, 166.42. MS (EI, 70 eV): m/z (%) = 180.0
[M–C3H3N+H]+ (51), 165.0 (100), 137.0 (7). HRMS (APCI, MeOH) calcd
Experimental Section
General remarks: All reactions have been carried out in flame-dried
Schlenk–tubes equipped with
a magnetic stir bar under argon
atmosphere (argon 5.0) using dry solvents unless noticed otherwise. For
reactions run under refluxing conditions, the reaction vessel was
equipped with an appropriate reflux condenser. Absolute THF was dried
over potassium under argon atmosphere and freshly distilled prior to use.
Ethyl acetate and cyclohexane for column chromatography were
purchased in technical quality and purified by destillation with a rotary
evaporator. Triethylamine hydrochloride was purchased from Aldrich and
purified by crystallization from chloroform. 1,4-Benzoquinone was
purchased from Aldrich and purified by chromatography over Al2O3 using
CH2Cl2 as eluent. Titanocene dichloride (Cp2TiCl2) was purchased from
Alfa Aesar and used as received. Titanocene catalysts 22 and 23 were
prepared according to literature procedures.[16] Titanocene catalyst 24
was purchased from mcat, Konstanz, Germany (www.mcat.de).
Pd(sparteine)Cl2 and Pd(Quinox)Cl2 were prepared according to
literature procedures.[14c,17] All other chemicals were purchased from
Aldrich, AlfaAesar, or Acros and used as received unless noted
otherwise. An IKAmag temperature modulator in combination with an oil
bath or stainless steel heating block was used to control the reaction
temperatures. NMR spectra were recorded on a Bruker 250 DRX (250
MHz), a Bruker Avance III 300 (300 MHz) or a Bruker Avance II 400 (400
MHz and 100 MHz) spectrometer and reported to CDCl3 (1H: d = 7.26
ppm;13C: d = 77.16 ppm). The following abbreviations were used: s =
singlet, d = doublet, t = triplet, q = quartet, br = broad signal. IR spectra
were recorded on a Thermo Scientific Nicolet iS10 FT-IR spectrometer
equipped with a diamond ATR unit and are reported in frequency of
for C13H17N2O2 [M+H]+: 233.12845, found: 233.12845. IR (ATR): n [cm−1
]
= 3178, 3076, 2963, 2934, 2840, 1666, 1586, 1511, 1452, 1414, 1358,
1265, 1222, 1171, 1147, 1081, 1020, 874, 849, 806, 761. A flame-dried
100 ml Schlenk-tube equipped with a magnetic stir bar was charged with
Cp2TiCl2 (226.8 mg, 0.9 mmol, 10 mol-%), Et3N•HCl (612.9 mg, 4.5
mmol, 0.5 equiv) and zinc dust (1.177 g, 18.0 mmol, 2.0 equiv). The
reaction vessel was evacuated and back-filled with argon three times.
THF (22.5 ml) was added and stirring was started. After about 2 min at
23 ºC, the color of the mixture had changed from red to green and crude
9 (2.09 g, 9.0 mmol) was added followed by TMSCl (3.45 ml, 27.0 mmol,
3.0 equiv). The vessel was sealed with a greased glass stopper and
stirring was continued for 24 h at 23 ºC. The reaction mixture was
transferred with 5–8 ml of CH2Cl2 into a separation funnel containing ice-
cold Et2O (100 ml) and ice-cold aq. HCl (1 M, 20 ml). After a quick
shaking, the aqueous layer was separated and the organic layer
extracted six more times with aq. HCl as before (1 M, 6 × 20 ml). The
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801479
European Journal of Organic Chemistry
FULL PAPER
combined aqueous layers were carefully neutralized (pH 8–9) by addition
of sat. aq. NaHCO3 solution (~400 ml) and then extracted with CH2Cl2 (4
× 50 ml). The combined CH2Cl2 layers wer dried (Na2SO4), filtered, and
concentrated to give pure 10 as a yellow oil in 93% yield over 2 steps
(1.97 g, 8.37 mmol). 1H NMR (400.1 MHz, CDCl3): d = 1.25 (s, 3H), 2.09
(br. s, NH), 2.13 (ddd, J = 4.8, 7.7, 18.6 Hz, 1H), 2.19 (ddd, J = 7.8, 7.8,
18.6 Hz, 1H), 2.93 (ddd, J = 7.7, 7.8, 11.6 Hz, 1H), 3.09 (ddd, J = 4.8,
7.8, 11.6 Hz, 1H), 3.65 (s, 3H), 3.70 (s, 3H), 6.65 (d, J = 8.5 Hz, 1H),
6.91 (dd, J = 2.1, 8.5 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H). 13C NMR (100.6
MHz, CDCl3): d = 25.34, 36.40, 39.63, 55.45, 65.58, 77.35, 108.96,
110.84, 117.64, 132.81, 147.87, 148.68, 217.12. MS (EI, 70 eV): m/z (%)
= 235.1 [M]+ (7), 206.1 (100), 192.1 (58), 178.1 (28), 176.1 (24), 164.0
(64), 148.0 (21), 133.1 (11), 120.0 (9). HRMS (APCI, MeOH) calcd for
C13H18NO3 [M+H]+: 236.12867, found: 236.12870. IR (ATR): n [cm−1] =
3056, 2965, 2936, 2837, 2361, 2255, 2020, 1739, 1603, 1589, 1507,
1464, 1405, 1369, 1324, 1257, 1230, 1177, 1143, 1128, 1074, 1026,
961, 909, 865, 811, 763, 729, 702, 647, 602.
2.04 (m, 4H), 2.17 (br. s, NH), 2.32 (ddd, J = 4.7, 8.0, 18.7 Hz, 1H), 2.37
(ddd, J = 7.7, 8.5, 18.7 Hz, 1H), 3.11 (ddd, J = 8.0, 8.3, 11.7 Hz, 1H),
3.31 (ddd, J = 4.6, 7.4, 11.7 Hz, 1H), 3.85 (s, 3H), 3.88 (s, 3H), 4.88-4.97
(m, 2H), 5.72 (ddt, J = 6.4, 10.2, 17.2 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H),
7.07 (dd, J = 2.1, 8.3 Hz, 1H), 7.14 (d, J = 2.1 Hz, 1H). 13C NMR (100.6
MHz, CDCl3): d = 28.63, 37.37, 38.26, 40.31, 56.01, 56.08, 69.26,
109.74, 111.17, 114.93, 118.53, 130.91, 138.20, 148.46, 149.27, 217.29.
MS (EI, 70 eV): m/z (%) = 275.1 [M]+ (18), 247.2 (100), 232.1 (45), 220.1
(24), 218.2 (35), 216.1 (16), 204.1 (20), 192.1 (46), 164.1 (26), 151.1 (6),
148.1 (9), 105.1 (7). HRMS (APCI, MeOH) calcd for C16H22NO3 [M+H]+:
276.15942, found: 276.15948. IR (ATR): n [cm−1] = 3074, 2941, 2844,
2253, 1740, 1595, 1511, 1455, 1254, 1254, 1134, 1025, 906, 724, 644.
rac-N-Cyanomethyl-2-(but-3-en-1-yl)-2-(3,4-
dimethoxyphenyl)pyrrolidin-3-one (13): Pyrrolidinone 3 (137.7 mg,
0.50 mmol) was dissolved in CH3CN (1.0 ml). While stirring,
bromoacetonitrile (45.0 µl, 0.65 mmol, 1.3 equiv) and Na2CO3 (106.0 mg,
1.0 mmol, 2.0 equiv) were added. The reaction was heated to reflux for
24 h and then allowed to cool to room temperature. The mixture was
treated with sat. aq. NaHCO3 (5.0 ml). The organic and aqueous layer
was separated and the aqueous layer was extracted with CH2Cl2 (4 × 5.0
ml). The combined organic layers were dried (Na2SO4), filtered, and
concentrated. The residue was purified by flash chromatography
(CH2Cl2/EtOAc, 20:1, Rf = 0.58) and 13 was received as a yellow oil in
>99% yield (158 mg, 0.50 mmol). 1H NMR (400.1 MHz, CDCl3): d = 1.86-
2.04 (m, 2H), 2.13-2.23 (m, 2H), 2.58 (ddd, J = 6.6, 8.1, 18.8 Hz, 1H),
2.66 (ddd, J = 5.3, 8.0, 18.8 Hz, 1H), 3.26 (ddd, J = 6.6, 8.1, 9.0 Hz, 1H),
3.39 (ddd, J = 5.3, 8.1, 8.2 Hz, 1H), 3.43 (d, J = 17.2 Hz, 1H), 3.54 (d, J =
17.2 Hz, 1H), 3.82 (s, 3H), 3.83 (s, 3H), 4.94-4.98 (m, 1H), 5.01-5.06 (m,
1H), 5.73-5.83 (m, ddt, J = 6.2, 10.3, 17.0 Hz, 1H), 6.70 (d, J = 2.3 Hz,
1H), 6.73 (dd, J = 2.3, 8.3 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H). 13C NMR
(100.6 MHz, CDCl3): d = 28.91, 32.10, 36.73, 37.09, 45.92, 55.91, 56.09,
71.73, 110.76, 111.24, 115.28, 116.43, 119.83, 130.21, 137.49, 149.05,
149.15, 214.34. MS (EI, 70 eV): m/z (%) = 314.1 [M]+ (52), 287.2 (9),
285.2 (82), 271.1 (29), 259.1 (100), 257.1 (95), 246.1 (28), 244.1 (14),
231.1 (55), 218.1 (17), 215.1 (9), 203.1 (27), 188.1 (6), 178.1 (10), 165.1
(10), 163.0 (89), 151.1 (14), 148.0 (24), 132.1 (7), 130.0 (6), 120.0 (11),
92.0 (14), 77.0 (13), 65.0 (7), 55.0 (7). HRMS (APCI, MeOH) calcd for
C18H22N2O3 [M+H]+: 315.17032, found: 315.17023. IR (ATR): n [cm−1] =
3060, 2937, 2840, 2353, 2162, 2016, 1753, 1594, 1515, 1453, 1416,
1259, 1145, 1024, 913, 805, 729.
1-(3,4-Dimethoxyphenyl)pent-4-en-1-one (11): KH (1.65 g, 40.5 mmol,
1.35 equiv) was suspended in THF (60 ml). While stirring, the suspension
was cooled to 0 ºC using an ice bath and 3,4-dimethoxyacetophenone
(5.41 g, 30.0 mmol) was added. The yellow suspension was then allowed
to warm to room temperature (23 ºC) and stirred for 30 min. After cooling
the mixture to 15 ºC, a solution of BEt3 in THF (1.0 M, 36.0 ml, 36.0 mmol,
1.2 equiv) was slowly added over 15 min. After 15 min stirring at room
temperature, freshly destilled allyl bromide (4.20 ml, 45.0 mmol, 1.5
equiv) was added over 10 min in a dropwise fashion. The suspension
was stirred for another 3 h and then cooled to –10 ºC. A mixture of aq.
NaOH (30%, 10 ml) and aq. H2O2 (30%, 10 ml) was added dropwise and
stirring was continued at 0 ºC for 15 min. Water (30 ml) was added and
the organic layer was separated using a separation funnel. The organic
layer was diluted with Et2O (200 ml) and washed with water (2 × 50 ml).
The combined aqueous layers were extracted with CH2Cl2 (2 × 40 ml).
The combined organic layers were then dried (Na2SO4), filtered, and the
solvents were removed under reduced pressure. The crude material was
purified by flash chromatography (hexanes/EtOAc, 20:3, Rf = 0.25) and
11 was received as a colorless oil in 35% yield (2.34 g, 10.6 mmol). 1H
NMR (400.1 MHz, CDCl3): d = 2.44-2.50 (m, 2H), 2.99-3.02 (m, 2H), 3.91
(s, 3H), 3.92 (s, 3H), 4.98 (ddt, J = 1.3, 1.8, 10.2 Hz, 1H), 5.06 (ddt, J =
1.7, 1.8, 17.1 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H),
7.56 (dd, J = 2.0, 8.3 Hz, 1H). 13C NMR (100.6 MHz, CDCl3): d = 28.58,
37.36, 56.05, 56.12, 110.13, 110.32, 115.25, 122.70, 130.33, 137.53,
149.16, 153.33, 198.07. MS (EI, 70 eV): m/z (%) = 220.1 [M]+ (15), 165.0
(100), 137.0 (14), 79.1 (13), 77.1 (12). HRMS (APCI, MeOH) calcd for
C13H17O3 [M+H]+: 221.11722, found: 221.11722. IR (ATR): n [cm−1] =
3075, 2932, 2841, 2606, 2027, 1837, 1671, 1588, 1512, 1451, 1417,
1346, 1258, 1148, 1018, 1018, 910, 878, 764, 618.
rac-N-Methoxycarbonylmethyl-2-(but-3-en-1-yl)-2-(3,4-
dimethoxyphenyl)pyrrolidin-3-one (14): Synthesized from 3 (137.7 mg,
0.5 mmol) in analogy to 13. Methyl bromoacetate (62.0 µl, 0.65 mmol, 1.3
equiv) was used instead of bromoacetonitrile. The crude material was
purified by flash chromatography (CH2Cl2/EtOAc, 20:1, Rf = 0.54) and 14
was received as a colorless oil in 93% yield (161 mg, 0.46 mmol). 1H
NMR (400.1 MHz, CDCl3): d = 1.83-1.96 (m, 2H), 2.15-2.28 (m, 2H), 2.51
(ddd, J = 5.2, 7.9, 18.6 Hz, 1H), 2.63 (ddd, J = 6.3, 8.5, 18.6 Hz, 1H),
3.29 (ddd, J = 6.3, 8.1, 8.8 Hz, 1H), 3.34 (d, J = 16.8 Hz, 1H), 3.35-3.41
(m, 1H), 3.38 (d, J = 16.8 Hz, 1H), 3.68 (s, 3H), 3.82 (s, 3H), 3.83 (s, 3H),
4.93 (ddt, J = 1.0, 2.0, 10.2 Hz, 1H), 5.01 (ddt, J = 1.4, 2.0, 17.1 Hz, 1H),
5.76 (ddt, J = 6.2, 10.2, 17.1 Hz, 1H), 6.79 (d, J = 8.5 Hz, 1H), 6.79 (dd, J
= 2.1, 8.5 Hz, 1H), 6.97 (d, J = 2.1 Hz, 1H). 13C NMR (100.6 MHz,
CDCl3): d = 29.22, 33.80, 36.70, 46.53, 50.57, 51.77, 55.90, 55.97,
71.88, 110.72, 111.12, 114.97, 119.56, 132.67, 137.94, 148.47, 148.91,
171.51, 215.23. MS (EI, 70 eV): m/z (%) = 347.1 [M]+ (5), 319.2 (82),
304.1 (31), 292.1 (100), 290.1 (29), 288.1 (20), 264.1 (81), 260.2 (13),
246.1 (8), 232.1 (13), 218.1 (10), 203.1 (8), 190.1 (6), 163.1 (18), 151.1
(31), 148.1 (8), 136.1 (6), 117.1 (5), 114.9 (5), 91.1 (7), 77.1 (5), 42.1 (7).
HRMS (APCI, MeOH) calcd for C19H26NO5 [M+H]+: 348.18055, found:
348.18045. IR (ATR): n [cm−1] = 3019, 2947, 2838, 2253, 1746, 1593,
1513, 1450, 1216, 1150, 1023, 909, 742, 664.
rac-2-(But-3-en-1-yl)-2-(3,4-dimethoxyphenyl)pyrrolidin-3-one
(3):
This compound was prepared in analogy to pyrrolidinone 10 with the
following modifications. The imine condensation reaction (10 mmol scale)
was heated to reflux for 24 h. Crude imine 4 was received in form of a
brownish oil that consisted of a mixture of E/Z isomers (3:1) and it was
used as without further purification in the next step. The titanium
catalyzed cyclization was carried out on a 10 mmol scale (using all of
crude 4) in presence of 5 mol-% Cp2TiCl2 (124 mg). An alternative
workup procedure was carried out as follows. After 24 h reaction time,
the mixture was filtered to remove the excess zinc metal and the filter
cake was rinsed with CH2Cl2 (200 ml). Aq. HCl (1 M, 100 ml) was added
to the filtrate and the organic solvents of the resulting biphasic mixture
were removed under reduced pressure. The remaining aqueous layer
was washed with Et2O (3 × 50 ml), neutralized with NaHCO3 (pH 8–9),
and the precipitated solid was collected by filtration. The filter cake was
washed with CH2Cl2 (100 ml) and the aqueous layer was extracted with
CH2Cl2 (5 × 100 ml). The combined CH2Cl2 layers were dried (Na2SO4),
filtered, and concentrated to give pure 3 as a red-brown oil in 87% yield
over 2 steps (2.40 g, 8.72 mmol). 1H NMR (400.1 MHz, CDCl3): d = 1.76-
rac-N-(tert-Butoxycarbonylmethyl)-2-(but-3-en-1-yl)-2-(3,4-
dimethoxyphenyl)pyrrolidin-3-one (15): Synthesized from 3 (137.7 mg,
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801479
European Journal of Organic Chemistry
FULL PAPER
0.5 mmol) in analogy to 13. tert-Butylbromoacetate (89.0 µl, 0.60 mmol,
1.2 equiv) was used instead of bromoacetonitrile. The crude material was
purified by flash chromatography (CH2Cl2/EtOAc, 20:1, Rf = 0.53) and 15
was received as a yellowish oil in 84% yield (163 mg, 0.42 mmol). 1H
NMR (400.1 MHz, CDCl3): d = 1.44 (s, 9H), 1.83-1.96 (m, 2H), 2.17-2.30
(m, 2H), 2.50 (ddd, J = 5.1, 7.8, 18.6 Hz, 1H), 2.62 (ddd, J = 6.5, 8.5,
18.6 Hz, 1H), 3.25 (d, J = 16.7 Hz, 1H), 3.30 (ddd, J = 6.4, 7.8, 8.6 Hz,
1H), 3.37 (d, J = 16.7 Hz, 1H), 3.41 (ddd, J = 5.2, 8.7, 8.7 Hz, 1H), 3.82
(s, 3H), 3.84 (s, 3H), 4.94 (ddt, J = 1.1, 1.9, 10.2 Hz, 1H), 5.01 (ddt, J =
1.4, 1.8, 17.1 Hz, 1H), 5.77 (ddt, J = 6.1, 10.2, 17.1 Hz, 1H), 6.80 (d, J =
8.5 Hz, 1H), 6.89 (dd, J = 2.1, 8.5 Hz, 1H), 7.02 (d, J = 2.1 Hz, 1H). 13C
NMR (100.6 MHz, CDCl3): d = 28.18, 29.29, 34.20, 36.71, 46.45, 51.49,
55.93, 56.01, 71.92, 81.13, 110.76, 111.14, 114.93, 119.56, 133.07,
138.06, 148.42, 148.92, 170.37, 215.40. MS (EI, 70 eV): m/z (%) = 389.3
[M]+ (7), 361.2 (48), 334.2 (20), 304.2 (49), 288.2 (38), 278.2 (100), 276.2
(18), 260.2 (26), 250.1 (68), 246.2 (13), 232.1 (25), 220.1 (10), 203.2 (9),
165.0 (45), 163.1 (14), 151.1 (24), 146.1 (27), 57.1 (11), 42.2 (8). HRMS
(APCI, MeOH) calcd for C22H32NO5 [M+H]+: 390.22750, found:
390.22763. IR (ATR): n [cm−1] = 3018, 2836, 1740, 1594, 1513, 1456,
1371, 1217, 1146, 1025, 919, 846, 746, 666.
120.19, 128.67, 149.37, 149.47, 207.45, 215.08. MS (EI, 70 eV): m/z (%)
= 330.2 [M]+ (5), 301.2 (36), 287.1 (8), 259.1 (34), 244.1 (12), 231.1 (13),
219.1 (13), 203.1 (19), 190.1 (7), 177.1 (10), 163.1 (100), 151.1 (15),
148.0 (35), 131.0 (10), 120.1 (13), 110.1 (10), 102.0 (10), 92.1 (19), 43.1
(29). HRMS (ESI, MeOH) calcd for C18H22N2O4Na [M+Na]+: 353.14718,
found: 353.14734. IR (ATR): n [cm−1] = 3057, 2982, 2840, 2307, 1753,
1715, 1596, 1516, 1422, 1262, 1148, 1026, 895, 728.
Pent-4-enoyl chloride (20):[20] This compound was also commercially
available. In a flame-dried 50 mL round-bottom flask equipped with a
magnetic stirrer bar and a reflux-condenser, pent-4-enoic acid (9.4 mL,
90.0 mmol) was treated with a catalytic amount of DMF (20 μL) and
thionyl chloride (16.4 mL, 224.0 mmol, 2.8 equiv). The reaction mixture
was heated to reflux for 16 h. After cooling down to room temperature (23
°C) the excess of thionyl chloride was removed under reduced pressure.
The acid chloride 20 was received as a brown liquid in 99% yield (10.680
g, 90.0 mmol) and used immediately. The analytical data matched the
previously reported values. 1H NMR (400.1 MHz, CDCl3): d = 2.46 (tdt, J
= 1.4, 6.5, 7.2 Hz, 2H), 2.99 (t, J = 7.2 Hz, 2H), 5.09 (ddt, J = 1.4, 1.5,
10.3 Hz, 1H), 5.11 (ddt, J = 1.4, 1.5, 17.0 Hz, 1H), 5.79 (ddt, J = 6.5,
10.3, 17.0 Hz, 1H). 13C NMR (100.6 MHz, CDCl3): d = 29.06, 46.40,
117.06, 134.80, 173.26.
rac-2-(But-3-en-1-yl)-1-(carboxymethyl)-2-(3,4-dimethoxyphenyl)-3-
oxopyrrolidin-1-ium 2,2,2-trifluoroacetate (16): A solution of 15 (77.9
mg, 0.2 mmol) in CH2Cl2 (20.0 ml) was stirred and cooled to –78 ºC. TFA
(1.0 ml, 13.1 mmol, 65.5 equiv) was added and the mixture was allowed
to warm to room temperature (23 ºC). Stirring was continued for 72 h.
Then, the solvent and excess TFA were removed under reduced
pressure and the TFA salt 16 was obtained as a brown solid in >99%
yield (98 mg, 0.2 mmol). 1H NMR (400.1 MHz, CDCl3): d = 1.85-1.96 (m,
1H), 2.10-2.25 (m, 2H), 2.43-2.51 (m, 1H), 2.95 (t, J = 6.5 Hz, 2H), 3.46
(d, J = 16.8 Hz, 1H), 3.60 (ddd, J = 8.0, 8.0, 10.7 Hz, 1H), 3.71 (d, J =
16.8 Hz, 1H), 3.85 (s, 3H), 3.88 (s, 3H), 4.99 (dd, J = 1.5, 10.1 Hz, 1H),
5.02 (dd, J = 1.5, 17.1 Hz, 1H), 5.73 (ddt, J = 6.3, 10.1, 17.1 Hz, 1H),
6.83-6.90 (m, 3H), 11.27 (br. s, NH, COOH). 13C NMR (100.6 MHz,
CDCl3): d = 27.78, 31.17, 35.44, 48.06, 51.80, 56.09, 56.23, 76.06,
111.63, 111.82, 115.80 (q, J = 288 Hz) 116.03, 121.72, 124.05, 136.33,
149.67, 150.54, 161.28 (q, J = 41 Hz), 169.33, 208.57. 19F NMR (235.3
MHz, CDCl3): d = 75.76 (m, 3F). MS (EI, 70 eV): m/z (%) = 334.3 [M–
C2F3O2]+ (10), 304.2 (59), 290.2 (24), 288.2 (21), 278.1 (100), 276.2 (22),
274.1 (11), 260.2 (24), 250.2 (78), 246.2 (20), 232.2 (21), 218.1 (12),
205.1 (25), 192.2 (8), 165.1 (34), 163.1 (20), 151.1 (35), 69.1 (15), 45.1
(11), 42.2 (6). HRMS (ESI, MeOH) calcd for C18H24NO5 [M–C2F3O2]+:
334.16490, found: 334.16519. IR (ATR): n [cm−1] = 2255, 1752, 1519,
1460, 1260, 1156, 1026, 903, 723, 647.
1-(But-3-en-1-yl)-6,7-dimethoxy-3,4-dihydroisoquinoline
(6):[3d,10]
Homoveratrylamine (21,15.2 mL, 90.0 mmol, 1.0 equiv) was dissolved in
a mixture of CH2Cl2 (90 ml) and NEt3 (18.9 ml, 135.0 mmol, 1.5 equiv).
While stirring, pent-4-enoyl chloride 20 (10.68 g, 90.0 mmol, 1.0 equiv)
was added dropwise at 0 ºC. After an additional 30 min at 0 ºC, the
mixture was allowed to warm to room temperature (23 ºC) and stirring
was continued for another 20 h. The mixture was concentrated under
reduced pressure and the residue was successively dissolved in EtOAc
and aq. HCl (1 M) and transferred to a separation funnel. EtOAc was
added (total amount 300 ml) and the mixture was washed with aq. HCl (1
M, 300 ml) and brine (100 ml). The organic layer was dried (Na2SO4),
filtered, and concentrated to give pure N-(3,4-dimethoxyphenethyl)pent-
4-enamide as a brown oil in >99% yield (23.730 g, 90.0 mmol). The NMR
data matched the previously reported values. 1H-NMR (300.1 MHz,
CDCl3): d = 2.21 (t, J = 7.2 Hz, 2H), 2.31-2.38 (m, 2H), 2.74 (t, J = 7.0 Hz,
2H), 3.48 (td, J = 6.2, 7.0 Hz, 2H), 3.84 (s, 3H), 3.85 (s, 3H), 4.93-5.05
(m, 2H), 5.58 (br, NH), 5.77 (ddt, J = 6.6, 10.3, 16.8 Hz, 1H), 6.69-6.72
(m, 2H), 6.79 (d, J = 8.8 Hz, 1H). The N-(3,4-dimethoxyphenethyl)pent-4-
enamide (23.730 g, 90.0 mmol) was redissolved in CH3CN (550 ml) and
POCl3 (63.5 ml, 667 mmol, 7.4 equiv) was added at room temperature
(23 °C). The resulting mixture was heated to 95 °C for 4 h. After allowing
the reaction to cool down to room temperature (23 ºC), the solvent was
removed under reduced pressure and the residue was added carefully to
an ice-cold aqueous saturated K2CO3 solution (500 ml), resulting in a pH
10–14. This aqueous solution was then extracted with CH2Cl2 (5 × 200
ml). The combined organic layers were dried (K2CO3), filtered, and
concentrated to give 6 as a brown oil in 88% yield (19.451 g, 79.3 mmol).
The material was directly used in the titanium-catalysis. 1H NMR (400.1
MHz, CDCl3): d = 2.35-2.42 (m, 2H), 2.54-2.58 (m, 2H), 2.71-2.75 (m,
2H), 3.59 (tt, J = 1.4, 7.5 Hz, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 4.93 (ddt,
J = 1.3, 1.9, 10.1 Hz, 1H), 5.01 (ddt, J = 1.7, 1.9, 17.1 Hz, 1H), 5.87 (ddt,
J = 6.7, 10.1, 17.1 Hz, 1H), 6.65 (s, 1H), 6.95 (s, 1H). 13C NMR (100.6
MHz, CDCl3): d = 25.91, 31.16, 35.16, 46.96, 55.96, 56.31, 108.90,
110.48, 114.85, 121.97, 131.63, 138.06, 147.54, 150.85, 165.85. MS (EI,
70 eV): m/z (%) = 213.1 (100), 185.1 (57), 180.0 (14), 168.1 (13), 152.1
(27), 141.0 (12), 139.1 (19), 128.1 (19), 115.1 (18), 102.1 (9), 97.1 (7),
89.1 (9), 77.1 (20), 63.3 (9), 58.3 (5), 51.4 (8), 45.6 (7). HRMS (APCI,
corona) calcd for C15H20O2N+ [M+H]+: 246.14886, found: 246.14890. IR
(ATR): n [cm−1] = 3004 ,2937, 2835, 2254, 2191, 1625, 1605, 1572, 1513,
1464, 1406, 1359, 1321, 1267, 1231, 1207, 1144, 1074, 1027, 959, 907,
860, 809, 725.
rac-N-Cyanomethyl-2-(3,4-dimethoxyphenyl)-2-(3-
oxobutyl)pyrrolidin-3-one (18): Pyrrolidinone 13 (157.2 mg, 0.5 mmol)
was dissolved in CHCl (1.0 ml) and, while stirring at 0 ºC, HCl in Et2O (2
M, 0.5 ml, 2.0 equiv) was added. The reaction was concentrated under
reduced pressure and the residue was dissolved in CH3CN-H2O (4:1 v/v,
2.0 ml). After stirring for 15 min at 23 ºC, 1,4-benzoquinone (60.0 mg,
0.55 mmol, 1.0 equiv) and Pd(CH3CN)2Cl2 (13.5 mg, 0.05 mmol, 10 mol-
%) were subsequently added. The reaction was stirred at room
temperature (23 ºC) for 24 h. Afterwards, CH2Cl2 (15 ml) and sat. aq.
NaHCO3 (5 ml) were added and the mixture was transferred into a
separation funnel. The aqueous layer was separated and extracted with
CH2Cl2 (4 × 15 ml). The combined organic layers were dried (Na2SO4),
filtered, and concentrated. The crude product was purified by flash
chromatography (cyclohexane/EtOAc, 1:1, Rf = 0.28) to give 18 as red-
brown oil in 80% yield (132 mg, 0.40 mmol). 1H NMR (500.3 MHz,
CDCl3): d = 2.14 (s, 3H), 2.18-2.27 (m, 1H), 2.32-2.38 (m, 1H), 2.47-2.61
(m, 2H), 2.64 (ddd, J = 7.8, 7.8, 18.9 Hz, 1H), 2.71 (ddd, J = 4.1, 7.6,
18.9 Hz, 1H), 3.11-3.16 (m, 1H), 3.22 (d, J = 16.9 Hz, 1H), 3.45 (ddd, J =
4.3, 8.2, 9.3 Hz, 1H), 3.50 (d, J = 16.9 Hz, 1H), z3.858 (s, 3H), 3.864 (s,
3H), 6.62 (d, J = 2.3 Hz, 1H), 6.67 (dd, J = 2.3, 8.4 Hz, 1H), 6.83 (d, J =
8.4 Hz, 1H). 13C NMR (125.8 MHz, CDCl3): d = 25.10, 30.50, 37.21,
37.24, 38.49, 45.69, 56.04, 56.27, 71.66, 110.93, 111.24, 116.19,
3-((Trimethylsilyl)oxy)propanenitrile (7d):[10,21] In a flame-dried 250 ml
round-bottom flask equipped with
a
magnetic stirrer bar,
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801479
European Journal of Organic Chemistry
FULL PAPER
chlorotrimethylsilane (7.66 mL, 60.0 mmol, 1.01 equiv) was dissolved in
Et2O (50 ml). While stirring, the solution was cooled to 0 ºC and 3-
hydroxypropionitrile (4.03 mL, 59.0 mmol) dissolved in Et3N (8.45 ml,
61.0 mmol) was added dropwise over 20 minutes. The mixture was
slowly allowed to warm to room temperature (23 ºC) and stirred for 16 h.
The mixture was filtered and the filter cake was rinsed with Et2O (100 ml).
The combined filtrates were concentrated to afford analytically pure 7d
as a pale-yellow oil in 98% yield (8.31 g, 58.0 mmol). The 1H NMR data
matched the literature values. 1H-NMR (300.1 MHz, CDCl3): d = 0.15 (s,
9H), 2.55 (t, J = 6.4 Hz, 2H), 3.81 (t, J = 6.4 Hz, 2H).
stirring at -10°C for 30 min, the mixture was allowed to warm to room
temperature (23 ºC) and stirred for additional 2 h. After stirring for
additional 16 h at 50 °C, the reaction was allowed to cool to room
temperature and the mixture was transferred with CH2Cl2 (5–8 ml) into a
separation funnel containing ice-cold Et2O (100 ml) and aqueous HCl (1
M, 50 mL). It was shaken until both layers became clear and the aqueous
layer was separated. The organic layer was extracted with additional aq.
HCl (1 M, 2 × 25 ml). The combined aqueous layers were carefully
saturated with solid NaHCO3 after which 10–20 mg of solid NaOH were
added. The aqueous layer was extracted with CH2Cl2 (at least 3 × 50 ml,
TLC control of the aqueous phase) and the combined EtOAc layers were
dried (Na2SO4), filtered and concentrated. The remaining pale yellow oil
was dried under high vacuum at 50°C. Analytically pure 2 was received
in 99% yield (90.2 mg, 0.299 mmol) and was used as such in the next
step. However, if desired it can be purified by flash chromatography
(CH2Cl2:AcOEt, 15:1, Rf=0.31) to give a colorless oil. The nmr data
matched the previously reported values. 1H NMR (400.1 MHz, CDCl3):
d = 1.75-1.82 (m, 1H), 1.84-1.92 (m, 1H), 2.09 (ddd, J = 4.3, 11.5,
13.3 Hz, 1H), 2.17-2.26 (m, 1H), 2.31-2.45 (m, 3H), 3.03-3.20 (m, 4H),
3.29 (ddd, J = 5.1, 12.6, 14.1 Hz, 1H), 3.83 (s, 3H), 3.85 (s, 3H), 4.90
(ddt, J = 1.2, 2.2, 10.2 Hz, 1H), 4.98 (ddt, J = 1.5, 2.2, 16.9 Hz, 1H), 5.78
(ddt, J = 6.3, 10.1, 16.9 Hz, 1H), 6.52 (s, 1H), 6.97 (s, 1H). 13C NMR
(100.6 MHz, CDCl3): d = 21.25, 29.41, 36.57, 38.24, 41.73, 43.82, 55.96,
56.11, 68.60, 110.01, 111.84, 114.56, 126.01, 126.07, 138.67, 147.81,
148.21, 216.12. MS (EI, 70 eV): m/z (%) = 301.1 [M]+ (9), 273.2 [M-CO]+
(32), 272.2 (19), 258.2 (14), 246.1 (100), 244.1 (49), 230.1 (22), 216.1 (4),
214.1 (5), 202.1 (11), 200.1 (4), 190.1 [M-(C4H7+C3H4)]+ (7), 188.0 (7),
185.1 (5), 172.0 (6), 123.0 (5), 119.0 (8), 115.8 (4), 109.0 (24) 79.0 (7).
HRMS (APCI, MeOH) calcd for C18H24O3N+ [M+H]+: 302.17562, found:
302.17560. IR (ATR): n [cm−1] = 3055, 2935, 2849, 2360, 2340, 1747,
1640, 1608, 1510, 1465, 1443, 1401, 1324, 1264, 1225, 1211, 1178,
1120, 1104, 1057, 1004, 967, 909, 869, 778, 731, 703.
rac-1-(1-(But-3-en-1-yl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-
1-yl)-3-hydroxypropan-1-one (5c):[10] Representative procedure: Table
1, entry 6. A flame-dried Schlenk-tube was charged under argon with a
magnetic stir bar, Cp2Ti(OPh)2 (18.2 mg, 0.05 mmol, 10 mol %),
Et3N•HCl (34.4 mg, 0.25 mmol, 0.5 equiv) and zinc dust (65.4 mg,
1.0 mmol, 2.0 equiv). The reaction vessel was evacuated and back-filled
with argon three times. THF (0.2 ml) was added and the mixture was
stirred for 2 min, upon which a color changed from red to green occurred.
Then, under a positive pressure of argon, TMSCl (95 µL, 0.75 mmol,
1.5 equiv) and nitrile 7d (107.5 mg, 0.75 mmol, 1.5 equiv) were added
successively followed by addition of a solution of 6 (122.7 mg, 0.5 mmol)
in THF (0.2 ml) via syringe. The syringe was rinsed with THF (0.1 ml) and
the resulting solution was added to the reaction mixture leading to a total
amount of 0.5 ml of THF. The reaction vessel was sealed with a greased
glass stopper and the mixture was stirred at 35 ºC for 24 h. The reaction
was allowed to cool to room temperature and the mixture was transferred
with CH2Cl2 (5–8 mL) into a separation funnel containing ice-cold Et2O
(100 ml) and aqueous HCl (1 M, 50 ml). The mixture was shaken until
both layers became clear and the aqueous layer was separated. The
organic layer was extracted with additional aq. HCl (1 M, 2 × 25 ml). The
combined aqueous layers were carefully saturated with solid NaHCO3
after which 10–20 mg of solid NaOH were added. The aqueous layer was
extracted with EtOAc (at least 3 × 50 ml, TLC control of the aqueous
phase) and the combined EtOAc layers were dried (Na2SO4), filtered and
concentrated to give 5c. Purification by flash chromatography
(CH2Cl2/EtOAc, 1:1, Rf = 0.21) gave the title compound as a pale-yellow
oil in 72% yield (114.9 mg, 0.36 mmol). 1H NMR (400.1 MHz, CDCl3): d =
1.81-1.94 (m, 1H), 2.02-2.14 (m, 3H), 2.53 (ddd, J = 4.4, 5.3, 16.4 Hz,
1H), 2.67-2.84 (m, 5H), 3.06 (ddd, J = 4.9, 6.2, 12.0 Hz, 1H), 3.13 (ddd,
J = 4.5, 7.2, 12.0 Hz, 1H), 3.66-3.72 (m, 2H), 3.79 (s, 3H), 3.84 (s, 3H),
4.93 (ddt, J = 1.3, 1.6, 10.1, 1H), 4.99 (ddt, J = 1.6, 1.6, 17.2 Hz, 1H),
5.77 (ddt, J = 6.3, 10.1, 17.2 Hz, 1H), 6.54 (s, 1H), 6.59 (s, 1H). 13C-NMR
(100.6 MHz, CDCl3): d = 28.57, 29.67, 37.29, 40.11, 41.23, 55.92, 56.26,
58.87, 67.75, 109.75, 112.08, 115.01, 126.50, 128.45, 138.21, 147.83,
148.34, 212.55. MS (EI, 70 eV): m/z (%) = 319.1 [M]+ (<1), 246.1
[M-C3H5O2]+ (100), 244.1 (18), 230.1 (10), 205.1 (5), 204.1 (5), 190.0 (5).
HRMS (APCI, MeOH) calcd for C18H26O4N+ [M+H]+: 320.18618, found:
320.18610. IR (ATR): n [cm−1] = 3019, 2937, 1699, 1640, 1610, 1515,
1465, 1403, 1347, 1327, 1260, 1215, 1134, 1050, 910, 862, 746. HPLC
(OD-3, heptane/EtOH, 95:5, 1 ml min–1, 22 ºC): t1 = 11.25 min (major), t2
= 12.95 min (minor).
rac-10b-(But-3-en-1-yl)-8,9-dimethoxy-1-oxo-2,3,4,5,6,10b-
hexahydro-1H-pyrrolo[2,1-a]isoquinolin-4-ium
chloride
(25):[10]
Compound 2 (60.3 mg, 0.200 mmol) was dissolved in CHCl3 (2 ml) and
HCl in Et2O (2.0 M, 150 µl, 0.300 mmol, 1.5 equiv) was added dropwise
at 0 °C. A precipitate was formed. The supernatant solvent was removed
carefully and the remaining solid was dried under high vacuum at 50°C.
The analytical pure title compound was received in 99% yield (67.5 mg,
0.200 mmol) as a colorless, highly hygroscopic solid. M.p. 58°C. 1H NMR
(400.1 MHz, CDCl3): d = 2.16-2.31 (m, 3H), 2.48-2.57 (m, 1H), 2.66 (ddd,
J = 2.3, 7.9, 19.0 Hz, 1H), 3.01-3.19 (m, 3H), 3.39 (dt, J = 8.0, 10.8 Hz,
1H), 3.63-3.70 (m, 2H), 3.84 (s, 3H), 3.85 (s, 3H), 4.02-4.07 (m, 1H), 4.93
(dd, J = 1.4, 10.4 Hz, 1H), 5.00 (dd, J = 1.4, 17.2 Hz, 1H), 5.63-5.73 (m,
1H), 6.61 (s, 1H), 6.90 (s, 1H), 13.57 (br s, NH). 13C NMR (100.6 MHz,
CDCl3): d = 21.75, 28.46, 33.57, 36.62, 43.81, 45.32, 56.13, 56.27, 71.08,
108.88, 111.36, 116.31, 118.39, 122.73, 136.07, 149.30, 149.95, 205.73.
MS (EI, 70 eV): m/z (%) = 302.2 [M-Cl-]+ (1), 301.1 [M-HCl]+ (6), 273.2
[M-(HCl+CO)]+ (31), 272.2 (17), 258.2 (15), 246.1 (100), 244.1 (53),
232.1 (10), 230.1 (24), 216.1 (4), 214.1 (5), 202.1 (11), 190.1
[M-(HCl+C4H7+C3H4)]+ (7), 188.0 (7), 185.1 (4), 172.0 (5). HRMS (APCI,
MeOH) calcd for C18H24O3N+ [M-Cl]+: 302.17562, found: 302.17530. IR
(ATR): n [cm−1] = 2254, 1766, 1611, 1520, 1465, 1265, 1232, 1162, 113,
1068, 1013, 905, 726.
rac-10b-(But-3-en-1-yl)-8,9-dimethoxy-2,3,6,10b-tetrahydropyrrolo-
[2,1-a]isoquinolin-1(5H)-one (2):[4d,10] Mitsunobu conditions. PPh3 (34.1
mg, 0.13 mmol, 1.3 equiv) and tetrahydroisoquinoline 5c (31.9 mg, 0.1
mmol) were dissolved in THF (0.3 ml). After stirring for 5 min, a solution
of DIAD (25.5 µl, 0.13 mmol, 1.3 equiv) in THF (0.3 ml) was added and
the mixture was stirred for 16 h at room temperature (23 ºC). The solvent
was removed under reduced pressure and the residue was purified by
flash chromatography (CH2Cl2/EtOAc, 15:1, Rf = 0.31). Compound 2 was
obtained as a colorless oil in 66% yield (20.0 mg, 0.066 mmol).
Direct transformation of 6 to 25 (large scale, see Scheme 6). A flame-
dried 250 ml Schlenk-flask was charged under argon with a magnetic
stirrer bar, Cp2Ti(OPh)2 (1.8213 g, 5.0 mmol, 10 mol %), Et3N•HCl
(3.410 g, 25.0 mmol, 0.5 equiv) and zinc dust (6.540 g, 100.0 mmol,
2.0 equiv). The reaction vessel was evacuated and back-filled with argon
three times. Absolute THF (20 ml) was added and the mixture was stirred
for
2 min. Under a positive pressure of argon, TMSCl (9.50 ml,
75.0 mmol, 1.5 equiv), 3-Trimethylsiloxypropionitrile (7d) (10.75 g,
75.0 mmol, 1.5 equiv) were added successively in this order followed by
addition of a solution of 6 (12.266 g, 50.0 mmol) dissolved in THF (20 ml)
via syringe. The syringe was rinsed with THF (10 ml) and the liquid was
Mesylation-cyclization (alternative protocol). Compound 5c (95.8 mg, 0.3
mmol) was dissolved in 1,2-dichloroethane (3.0 ml) and added dropwise
at -10°C to
a stirred solution of methanesulfonyl chloride (36 µl,
0.465 mmol, 1.55 equiv) in pyridine (117 µl, 1.45 mmol, 4.8 equiv). After
8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801479
European Journal of Organic Chemistry
FULL PAPER
added to the reaction mixture (total amount of THF 50 ml). The vessel
was sealed with a greased glass stopper and the mixture was stirred at
35 ºC for 24 h. The mixture was filtered and the filter cake was rinsed
with CH2Cl2 (2 × 100 ml) and aq. HCl (1 M, 750 ml). This simplified the
following extraction. The organic solvents (CH2Cl2 and THF) of the
combined filtrate were removed under reduced pressure and the
remaining aqueous layer was washed with Et2O (3 × 300 ml) and
saturated carefully with solid NaHCO3. The basic aqueous layer was then
extracted with EtOAc (10 × 200 ml) and the combined EtOAc layers were
then dried (Na2SO4), filtered and concentrated to give crude 5c as a
brownish oil (16.540 g) that was employed in the next step without further
purification. On this larger scale, the crude material still contained traces
of 3-hydroxypropionitrile, which did not interfere with the subsequent
cyclization. The crude material was dissolved in 1,2-dichloroethane
(100 ml) and this solution was added slowly at -10 °C to a solution of
methanesulfonyl chloride (4.4 ml, 60.0 mmol, 1.2 equiv) in pyridine
(17.4 ml, 215.0 mmol, 4.3 equiv). After further stirring for 30 min at
-10 °C, the mixture was allowed to warm to room temperature (23 ºC).
After 2 h, the mixture was then heated to 50 °C for 16 h. After cooling the
reaction to 23 ºC, the solvent was removed under reduced pressure. The
residue was dissolved in aq. HCl (1 M, 500 ml) and the resulting aqueous
layer was washed with Et2O (3 ´ 300 mL) using a separation funnel. The
aqueous layer was carefully saturated with solid NaHCO3 and then
extracted with EtOAc (6 × 150 ml). The combined EtOAc layers were
dried (Na2SO4), filtered and concentrated. The remaining oil was then
dried under high vacuum at 50°C to give pure 2 in 63% yield over two
15 min stirring at room temperature (23 °C) 1,4-benzoquinone (23.8 mg,
0.22 mmol, 1.1 equiv) and Pd(CH3CN)2Cl2 (51.9 mg, 0.2 mmol, 1 equiv)
were added and the resulting mixture was heated to 70°C for 24 h. The
reaction was allowed to cool to room temperature and the mixture was
transferred with CH2Cl2 (5–8 ml) into a separation funnel containing ice-
cold Et2O (100 mL) and aqueous HCl (1 M, 50 ml). The mixture was
shaken until both layers became clear and the aqueous layer was
separated. The organic layer was extracted with additional aq. HCl (1 M,
2 × 25 ml). The combined aqueous layers were carefully saturated with
solid NaHCO3. The aqueous layer was extracted with CH2Cl2 (3 × 50 ml)
and the combined CH2Cl2 layers were dried (Na2SO4), filtered and
concentrated to give the crude product. Purification by flash
chromatography (CH2Cl2:AcOEt, 2:1, Rf = 0.46) gave 26 as a pale-yellow
oil in >99% yield (63.4 mg, 0.2 mmol).
Direct oxidation of 2 to 26 (Table 3, entry 9). Compound 2 (716.8 mg,
2.38 mmol) was dissolved in a solution of HBF4 in CH3CN-H2O 7:1 (0.5
M, 15.0 ml, 7.5 mmol, 3.15 equiv). After stirring for 15 min at room
temperature (23 ºC), 1,4-benzoquinone (1.029 g, 9.52 mmol, 4.0 equiv)
was added, followed by Pd(CH3CN)2Cl2 (123.5 mg, 0.476 mmol, 20 mol-
%). The mixture was stirred for 72 h at 70 ºC and then allowed to cool to
room temperature. It was transferred with CH2Cl2 (5–8 ml) into
a
separation funnel containing ice-cold Et2O (50 ml) and aq. HCl (1 M, 10
ml). After briefly shaking the mixture, the aqueous layer was separated
and the organic layer was extracted with aq. HCl (1 M, 6 ´ 10 ml). The
combined aq. layers were neutralized by addition of sat. aq. NaHCO3
solution (pH 8–9) and then extracted with CH2Cl2 (4 ´ 20 ml). The
combined CH2Cl2 layers were dried (Na2SO4), filtered and concentrated
to give the crude product. Purification by flash chromatography
(CH2Cl2:AcOEt, 2:1, Rf = 0.46) gave 26 as a pale-yellow oil in 64% yield
(482.8 mg, 1.52 mmol).
steps (9.4935 g, 31.5 mmol) as
a brown oil. This material was
redissolved in CHCl3 (300 ml) and HCl in Et2O (2.0 M, 25.0 ml, 50.0 mmol,
1.58 equiv.) was added at 0°C dropwise. This led to the precipitation of
hydrochloride 25. The supernatant solvent was carefully decanted and
the remaining solid was dried under high vacuum at 50°C. Compound 25
was received in 63% yield over two steps (10.64 g, 31.5 mmol) as a
brownish solid, which showed no impurities by nmr and was used as
such in the subsequent Wacker oxidation.
rac-3-Demethoxyerythratidinone (1):[2–4,10] Diketone 26 (31.7 mg,
0.10 mmol) was dissolved in degassed MeOH (30 ml) and degassed
aqueous 20% KOH solution (1.5 ml, 5.35 mmol, 53.5 equiv) was added
at room temperature (23 °C). The resulting mixture was put into a
preheated oil bath (120 °C) and was heated to reflux for 16 hours under
argon atmosphere. After cooling down to room temperature the reaction
mixture was concentrated and extracted with CH2Cl2 (50 ml). The organic
layer was washed with brine (5 ml), dried over Na2SO4. and concentrated
to give the crude product. Purification by flash chromatography
(CH2Cl2/MeOH, 100:8; Rf = 0.35) gave 1 as a yellow oil in 57% yield
(17.0 mg, 0.057 mmol). This reaction was also carried out on a 5 mmol
scale at higher concentration (300 ml MeOH, extraction: 250 ml CH2Cl2,
10 ml brine). 1 was received as a brown oil in 54% yield (808.3 mg,
2.7 mmol). The nmr data matched the previously reported values. 1H-
NMR (400.1 MHz, CDCl3/TMS): d = 2.20 (ddd, J = 5.6, 12.4, 14.1, 1H),
2.31 (ddd, J = 2.1, 5.6, 12.5 Hz, 1H), 2.42-2.61 (m, 4H), 2.68-2.77 (m,
1H), 2.82-2.89 (m, 1H), 3.00-3.11 (m, 2H), 3.23 (ddd, J = 1.3, 7.6,
14.5 Hz, 1H), 3.48 (ddd, J = 6.6, 11.7, 14.5 Hz, 1H), 3.74 (s, 3H), 3.85 (s,
3H), 6.10 (t, J = 1.9 Hz, 1H), 6.56 (s, 1H), 6.65 (s, 1H). 13C-NMR
(100.6 MHz, CDCl3/TMS): d = 21.63, 28.82, 32.98, 36.29, 40.32, 45.97,
56.05, 56.21, 63.72, 110.59, 113.07, 123.81, 124.98, 125.86, 147.11,
148.61, 169.11, 199.50. MS (EI, 70 eV): m/z (%) = 299.1 [M]+ (17), 271.2
[M-CO]+ (100), 256.1 (58), 246.2 (10), 242.2 (45), 240.2 (14), 228.2 (21),
214.2 (14), 212.2 (17), 197.2 (23), 184.2 (10), 182.2 (5), 170.2 (4), 168.2
(4), 156.2 (4), 154.2 (4). HRMS (APCI, MeOH) calcd for C18H22O3N+
[M+H]+: 300.15942, found: 300.15960 IR (ATR): n [cm−1] = 2936, 2851,
2253, 1664, 1608, 1510, 1465, 1422, 1400, 1331, 1291, 1253, 1230,
1207, 1165, 1150, 1107, 1048, 1037, 999, 904, 805, 783, 724, 648, 588,
576, 553, 532, 473.
rac-8,9-Dimethoxy-10b-(3-oxobutyl)-2,3,6,10b-tetrahydropyrrolo[2,1-
a]isoquinolin-1(5H)-one (26):[4d] Catalytic oxidation procedure (Table 2,
entry 3 and Scheme 6). Hydrochloride 25 (1.689 g, 5.0 mmol) was
dissolved in CH3CN-H2O (4:1, 100 ml). After stirring for 15 min at room
temperature (23 °C), 1,4-benzoquinone (594.5 mg, 5.5 mmol, 1.1 equiv)
and Pd(CH3CN)2Cl2 (129.7 mg, 0.5 mmol, 10 mol %) were added and the
resulting mixture was heated to 80 °C for 24 h. The reaction was allowed
to cool to room temperature (23 °C) and about 80% of the solvent was
removed under reduced pressure. H2O (250 ml) was added and the
mixture was transferred into a separation funnel. The aqueous solution
was washed with Et2O (5 ´ 100 ml) and the combined Et2O layers were
extracted with H2O (2 ´ 100 ml). The combined aqueous layers
containing the protonated product were filtered to remove unsoluble
material. It was then saturated with Na2CO3 and extracted with CH2Cl2
(10 ´ 50 ml). The combined CH2Cl2 layers were then dried (Na2SO4),
filtered and concentrated to give the crude product. After purification by
flash chromatography (cyclohexane/EtOAc, 1:2; Rf = 0.289) product 26
was received as a brown oil in 78% yield (1.238 g, 3.9 mmol). The nmr
data matched the previously reported values. 1H-NMR (400.1 MHz,
CDCl3): d = 2.12 (s, 3H), 2.12-2.28 (m, 3H), 2.35-2.44 (m, 3H), 2.46-2.57
(m, 1H), 3.00-3.26 (m, 5H), 3.83 (s, 3H), 3.83 (s, 3H), 6.52 (s, 1H), 6.91
(s, 1H). 13C-NMR (100.6 MHz, CDCl3): d = 21.30, 30.36, 32.76, 36.41,
39.40, 41.49, 43.66, 55.97, 56.09, 68.28, 109.89, 111.88, 125.23, 126.17,
147.85, 148.38, 208.03, 215.96. MS (EI, 70 eV): m/z (%) = 317.1 [M]+ (1),
289.2 [M-CO]+ (12), 246.1 (100), 244.1 (4), 230.1 (9), 202.0 (6). HRMS
(APCI, MeOH) calcd for C18H24O4N+ [M+H]+: 318.16998, found:
318.17030. IR (ATR): n [cm−1] = 2936, 2850, 2254, 1746, 1711, 1608,
1510, 1465, 1442, 1401, 1324, 1254, 1226, 1211, 1189, 1120, 1106,
1051, 1005, 904, 779, 724.
Acknowledgements
Procedure with stoichiometric Pd (Table 2, entry 5). Hydrochloride 25
(67.6 mg, 0.2 mmol) was dissolved in CH3CN-H2O (7:1, 1.0 ml). After
This work was funded by the Deutsche Forschungsgemeinschaft (DFG) –
project 240508776.
9
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10.1002/ejoc.201801479
European Journal of Organic Chemistry
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European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Alkaloid Synthesis
MeO
MeO
MeO
TiIII
-
TiIII
-
MeO
MeO
catalysis
catalysis
Hieu-Trinh Luu, Jan Streuff*
N
N
N
MeO
N
+
Page No. – Page No.
intramolecular
coupling?
intermolecular
coupling?
3-demethoxy-
erythratidinone
N
X
O
Development of an Efficient
Synthesis of rac-3-
The development of an efficient synthesis of the erythrina alkaloid 3-
Demethoxyerythratidinone via a
Titanium(III) Catalyzed Imine-Nitrile
Coupling
demethoxyerythratidinone is described. A titanium(III) catalyzed umpolung in form
of an imine-nitrile coupling reaction serves as key step for the construction of the
highlighted C-C bond.
11
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