Formal Total Synthesis of (±)-Rhazinal: Evaluating the Radical Approach

Article abstract of DOI:10.1055/s-0036-1588956

We describe a formal total synthesis of the racemic natural product rhazinal by a rapid elaboration of a recently reported tetrahydroindolizine intermediate into the cyclization precursor reported by Trauner. The synthesis focuses on the early and convergent introduction of functional groups while the synthetic challenges encountered by this approach are described.

Full text of DOI:10.1055/s-0036-1588956

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–E
paper
A
S. Hildebrandt et al.
Paper
Synthesis
Formal Total Synthesis of (±)-Rhazinal: Evaluating the Radical
Approach
Sven Hildebrandt
Hendrik Weißbarth
Andreas Gansäuer*
OHC
N
N
?
Kekulé-Institut für Organische Chemie und Biochemie, Univer-
sität Bonn, Gerhard-Domagk-Straße 1, 53121 Bonn, Germany
andreas.gansaeuer@uni-bonn.de
?
H
N
H
O
OH
Received: 29.12.2016
Accepted after revision: 06.02.2017
Published online:
construct tetrahydroindolizine scaffolds, as part of our pro-
gram directed towards the development of efficient catalyt-
ic radical reactions.3,4 By our titanocene(III)-catalyzed
transformation we obtained alcohol 5 from epoxide 6 and,
ultimately, from the readily available 4-pyrrolylbutanoic
acid5 in a minimum number of operational steps with max-
imum atom-economy (Scheme 1) and without the forma-
tion of undesired side products.
DOI: 10.1055/s-0036-1588956; Art ID: ss-2016-z0894-op
Abstract We describe a formal total synthesis of the racemic natural
product rhazinal by a rapid elaboration of a recently reported tetrahy-
droindolizine intermediate into the cyclization precursor reported by
Trauner. The synthesis focuses on the early and convergent introduc-
tion of functional groups while the synthetic challenges encountered by
this approach are described.
Here, we report an efficient route to the Trauner inter-
mediate 3 starting from 5.6 Moreover, we investigated a
protecting-group-free radical cyclization of intermediate 3
to form rhazinal (1), which would constitute a desirable key
step for the construction of the nine-membered lactam.
A retrosynthetic analysis of 3 suggests that it can either
be accessed via traditional homologation utilizing the
Horner–Wadsworth–Emmons (HWE) reaction or through a
state-of-the-art ‘borrowing hydrogen/hydrogen autotrans-
fer’ methodology for the alkylation of 4 with alcohol 5
(Scheme 1).7 A potential advantage of our approach is the
introduction of the unprotected amide functionality that
has, as yet, not been realized due to potential reagent or
catalyst incompatibilities.
Key words rhazinal, natural products, catalysis, radicals, pyrroles
The tetracyclic tetrahydroindolizine alkaloids rhazinal
and rhazinilam have attracted considerable attention in the
synthetic community as challenging targets for the evalua-
tion of new synthetic methodologies.1 A recent comprehen-
sive review has summarized the numerous strategies de-
vised for the synthesis of these alkaloids.2 This article seeks
to add a complementary approach to the existing routes
that employs modern catalytic methodologies for the effi-
cient synthesis of these natural products.
We recently reported on the catalytic C–H functional-
ization of pyrroles, proceeding via radical intermediates to
OHC
R
N
N
TiIII
N
N
O
6
( )-5
OH
O
+
H
I
H
I
'borrowing
hydrogen'
radical
cyclization
N
N
N
N
O
H
O
3
4
CO2H
R = CHO, ( )-1
R = H, ( )-2
Scheme 1 Retrosynthesis of rhazinal and rhazinilam employing a radical macrocyclization and the borrowing hydrogen methodology for amide alkylation
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E

B
S. Hildebrandt et al.
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Synthesis
Attempts of alkylating 2-iodoacetanilide (4) with alco-
hol 5 were initially conducted with the iridium pincer com-
plex cat-Ir, which has been introduced as an efficient alco-
hol oxidation catalyst under high temperature conditions
(Table 1).8 The strong base KOtBu facilitates enolate forma-
tion and subsequent condensation with the formed alde-
hyde. Unfortunately, no conversion to 8 could be observed
under the conditions investigated (entry 1). Changing the
pronucleophile to the corresponding diethyl phosphonate 7
to conduct the condensation under HWE conditions did not
lead to any conversion either (entry 2). The recently intro-
duced cobalt catalyst cat-Co, which is active under similar
conditions, also did not show aldehyde or product forma-
tion, even at higher catalyst loadings (entry 3).9 These find-
ings indicate that the bulky transition-metal catalysts are
unable to induce the oxidation of the neopentylic alcohol.
the Swern oxidation of 5.12 In our hands the only viable
method for efficient oxidation of 5 proved to be a Ley–
Griffith oxidation that produced aldehyde 9 in good yield
(entry 5).13 The sensitive pyrrole moiety remained un-
changed by the mild terminal oxidant NMO. The catalyst
loading could be lowered to 5 mol% when carefully activat-
ed molecular sieves were used.
Table 2 Reaction Conditions Screening for the Efficient Oxidation of
Alcohol 5
N
N
( )-5
9
OH
O
Entry
Conditions
Yield (%)
Table 1 Borrowing Hydrogen/Hydrogen Autotransfer Conditions Ex-
amined for the Conversion of Alcohol 5 into Amide 8a,b
1
2
3
4
5
DMP, H2O, CH2Cl2
32
26
6
DMP, NaHCO3, CH2Cl2
PCC, NaOAc, CH2Cl2
PDC, MS, MeCN
O
N
R
Ar
3
N
N
H
TPAP (5 mol%), NMO, MS, MeCN
81
R = H, 4
R = P(O)(OEt)2, 7
O
8
HWE reaction of aldehyde 9 with diethyl phosphonate
7, which can be prepared easily from 2-bromo-N-(2-io-
dophenyl)acetamide (see experimental section) via an
Arbuzov reaction, furnished the unsaturated amide 10 in
excellent yield at room temperature (Scheme 2).14 From this
point, reduction of the conjugated double bond in 10 leads
to a direct cyclization precursor. The reduction of the un-
saturated amide posed multiple problems. First, the pyrrole
moiety can still react under Lewis acid catalysis, leading to
inhibition or decomposition of reagents and the substrate.
Second, the approach to the α,β-unsaturated amide is steri-
cally hindered due to the adjacent quaternary carbon. This
may lead either to prolonged reaction times or, in the worst
case, the prevention of catalyst binding. Additionally, the
iodoarene functionality is prone to undergoing defunction-
alization under reductive conditions. With these potential
restrictions in mind, only a few reduction methods seemed
to be viable options (Table 3). Reduction of the conjugated
double bond with Stryker’s reagent (entry 1) or borane-cat-
alyzed hydrosilylation (entry 2) led to no conversion to
8.15,16 Also, the cobalt-mediated conjugate reduction with
stoichiometric NaBH4 (entry 3) did not lead to the desired
product, but to the dehalogenated arene arising from reac-
tion with in situ formed Co(I).17 NaBH4 itself (entry 4) led to
slight conversion to the product, because NaBH4 decom-
posed in methanol before completion of the reduction or
was only poorly soluble in aprotic solvents. Eventually, hy-
drogenation with catalysts inert to carbon–halogen bonds
led to success. Wilkinson’s catalyst [RhCl(PPh3)3] gave poor
conversion in the presence of H2 (4 bar).18 Crabtree’s cata-
lyst [Ir(COD)(PCy3)py]PF6] led to about 50% conversion to 8
OH
( )-5
HN
Ar
HN PiPr2
HN PtBu2
Cl
N
N
Cl
Cl
HN
N Co
N
Ir COE
HN PiPr2
HN PtBu2
cat-Ir
cat-Co
Entry
Conditionsb
1
2
3
4 (1.5 equiv), KOtBu (2.5 equiv), cat-Ir (2 mol%)c
7 (2 equiv), K2CO3 (2 equiv), cat-Ir (5 mol%)c
4 (3 equiv), KOtBu (2 equiv), cat-Co (15 mol%)d
a Ar = 2-iodophenyl; COE = cyclooctene.
b No conversion was observed under these conditions.
c Toluene, 100 °C, 20 h.
d THF, 100 °C, 20 h.
These results foreshadow the problems encountered in
the oxidation of 5 to provide 9 when using more common
reagents (Table 2). The Dess–Martin periodinane gave un-
satisfactory yields under water-accelerated as well as buff-
ered conditions (entries 1 and 2) and the chromium(VI)-
based reagents PCC and PDC resulted in an even lower con-
version to 9 (entries 3 and 4).10,11 These reactions were al-
ways monitored for complete substrate consumption and,
thus, decomposition of the substrate or the product by the
reagents employed seems likely. Presumably, this is due to
the high nucleophilicity of the pyrrole. In a formal synthesis
of rhazinal, Chandrasekhar reported a moderate yield for
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E

C
S. Hildebrandt et al.
Paper
Synthesis
with H2 (4 bar) and, gratifyingly, full conversion occurred at
higher H2 pressure (40 bar) with a catalyst loading of 2
mol% (entry 7). The high pressure might be necessary to
overcome product inhibition and to ensure regeneration of
the active catalyst from inactive catalyst dimers.19
Table 4 Attempts to Initiate a Free-Radical Cyclization of 3 and 8 onto
the Pyrrole Aromatic System
OHC
N
N
POCl3
DMF
Trauner
N
( )-1
via N-MOM-
protection/
cyclization/
deprotection
72%
H
H
N
I
I
O
P
O
N
N
NaH
Ar
+
O
O
EtO
EtO
N
THF
92%
O
8
H
3
O
HN
9
7
10
Ar
Scheme 2 HWE reaction to form the unsaturated amide 10 (Ar = 2-
iodophenyl)
( )-2
Substrate Conditionsa
( )-1
Entry
Table 3 Reaction Conditions Screening for the Selective Reduction of
Unsaturated Amide 10a
1
2
3
4
3
3
3
8
[Ir(dtbbpy)(ppy)2]PF6 (2 mol%), Et3N, 15 W lampb
[Ir(ppy)3] (5 mol%), Et3N, 15 W lampb
Et3B, (Me3Si)3SiH, airc
N
N
[Ir(dtbbpy)(ppy)2]PF6 (2 mol%), Et3N, 15 W lampd
a dtbbpy = 4,4′-bis(tert-butyl)-2,2′-bipyridine; ppy = 2-(2-pyridyl)phenyl.
b No conversion.
c Full conversion to an unidentified mixture of products.
d Decomposition of starting material.
O
O
HN
HN
10
Entry Conditions
8
Ar
Ar
aryl iodides by Ir photoredox catalysts has been described
by Stephenson.21 Therefore, [Ir(ppy)3], which also shows
oxidative quenching from Ir(III)* to Ir(IV), as well as
[Ir(dtbbpy)(ppy)2]PF6 were tested for the conversion of 3 to
1 (entries 1 and 2) under visible-light irradiation. Unfortu-
nately, neither 1 nor the defunctionalized arene could be
detected in the crude reaction mixture. To evaluate the rad-
ical cyclization strategy itself, stoichiometric radical gener-
ation was performed with Et3B and (Me3Si)3SiH (TTMSS, en-
try 3).22 While full consumption of the starting material
was observed, we were unable to detect 1 in the crude reac-
tion mixture. Treatment of 8 under the same conditions as
3 led to decomposition of the starting material (entry 4).
In conclusion, we have devised a simple and efficient
route to Trauner’s intermediate 3 in the total synthesis of
rhazinal from the readily available alcohol 5. The synthesis
features an early incorporation of the necessary iodoacet-
anilide moiety that posed several synthetic challenges, all
of which could be solved. A direct radical macrocyclization
of 3 and 8 that would have provided a more direct access to
1 and 2 via photoredox catalysis or classical radical chain
reaction methodology failed.
Conversion (%)
1
2
3
4
5
6
7
[CuH(PPh3)]6, toluene
–
b
B(C6F5)3 (0.5 mol%), PHMS, CH2Cl2
CoCl2, NaBH4, MeOH–DMF
NaBH4, MeOH–THF
–
100c
35
20
55
92d
RhCl(PPh3)3 (5 mol%), H2 (4 bar), toluene
[Ir(COD)(PCy3)py]PF6 (5 mol%), H2 (4 bar), CH2Cl2
[Ir(COD)(PCy3)py]PF6 (2 mol%), H2 (40 bar)
a Ar = 2-iodophenyl.
b PHMS = poly(hydromethylsiloxane).
c Defunctionalization of the iodoarene.
d Yield of product 8.
With an efficient synthesis of 8 in hand, we prepared
Trauner’s intermediate 3 via Vilsmeier formylation (Table
4). This reaction completes the formal total synthesis of
rhazinal. Trauner’s successful synthesis of 1 proceeds via
Pd-catalyzed macrolactamization that requires MOM-pro-
tection of the amide nitrogen and, as a consequence, an ad-
ditional deprotection step.6,20 We were attracted by the idea
of radical macrocyclizations of the unprotected amides 3
and 8 for a protecting-group-free conclusion of the total
syntheses of 1 and 2.
All reactions involving air- or moisture-sensitive compounds were
carried out in oven-dried glassware under argon using standard
Schlenk and vacuum-line techniques. All solvents were either dried
and deoxygenated by distillation (THF over Na/K alloy) before use or
purified inside an M-Braun MB-SPS-800 solvent purification system
To this end, we focused on the visible-light-mediated
generation of aryl radicals from the corresponding iodides
through photoredox catalysts. The defunctionalization of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E

D
S. Hildebrandt et al.
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and used after degasification. Commercially available chemicals were
used without further purification. 1H NMR and 13C NMR spectra were
recorded on Bruker spectrometers. 1H NMR chemical shifts were cali-
brated by using the residual undeuterated solvent as internal refer-
ence (CHCl3, δ = 7.26; C6HD5, δ = 7.16). 13C NMR chemical shifts were
calibrated by using the solvent peak as internal reference (CDCl3, δ =
77.16; C6D6, δ = 128.06). IR spectra of samples prepared as neat films
were recorded on a Nicolet 380 ATR IR spectrometer. High-resolution
mass spectra were obtained on a Thermoquest MAT 95 CL instru-
ment. Column chromatography was carried out on silica gel (230–400
mesh) supplied by Merck and Macherey-Nagel. TLC was performed on
silica gel on aluminum plates and the compounds were detected with
the Seebach staining mixture. Solvent mixtures consisting of EtOAc
and cyclohexane were used as eluents for silica gel chromatography.
(0.056 g, 0.16 mmol, 0.05 equiv) was added in one portion and the
mixture was stirred at r.t. for 1 h. The solids were removed by filtra-
tion and the solvent was removed under reduced pressure. The crude
was purified by column chromatography.
Yield: 0.453 g (2.6 mmol, 81%); colorless oil; Rf = 0.6 (cyclohexane–
EtOAc, 80:20).
IR (neat): 2960, 1720, 1450 cm–1
.
1H NMR (400 MHz, C6D6): δ = 9.26 (d, J = 1.5 Hz, 1 H), 6.36–6.31 (m, 2
H), 6.05 (dd, J = 3.6, 1.7 Hz, 1 H), 3.22–3.06 (m, 2 H), 2.10 (dddd, J =
13.4, 5.7, 3.1, 1.0 Hz, 1 H), 1.67–1.39 (m, 3 H), 1.36–1.26 (m, 1 H), 1.06
(dddd, J = 13.4, 11.9, 3.3, 1.5 Hz, 1 H), 0.65 (t, J = 7.5 Hz, 3 H).
13C NMR (100 MHz, C6D6): δ = 198.9, 127.4, 120.8, 108.7, 106.4, 51.4,
44.8, 29.2, 24.6, 21.2, 8.1.
HRMS (ESI): m/z [M + Na]+ calcd for C11H15NONa: 200.1051; found:
200.1046.
2-Bromo-N-(2-iodophenyl)acetamide
To a solution of commercially available 2-iodoaniline (5.356 g, 24.5
mmol, 1.00 equiv) in CH2Cl2 (60 mL) cooled to 0 °C was added Et3N
(4.2 mL, 29.4 mmol, 1.20 equiv) followed by bromoacetyl bromide
(2.5 mL, 29.4 mmol, 1.20 equiv). The mixture was stirred at 0 °C for 1
h and warmed to r.t. The organic phase was washed with 1 N aq HCl
(60 mL), sat. aq NaHCO3 (60 mL), and brine (60 mL) and dried over an-
hyd MgSO4. The solvent was removed under reduced pressure to yield
the product as a colorless powder, which was used without further
purification.
rac-3-(8-Ethyl-5,6,7,8-tetrahydroindolizin-8-yl)-N-(2-iodophe-
nyl)prop-2-enamide (10)
NaH (60 wt% in mineral oil, 0.493 g, 12.3 mmol, 2.00 equiv) was add-
ed portionwise to a solution of 7 (2.693 g, 6.8 mmol, 1.10 equiv) in
anhyd THF (36 mL) under argon over 15 min at r.t., and the mixture
was stirred until gas evolution ceased. A solution of 9 (1.092 g, 6.2
mmol, 1.00 equiv) in anhyd THF (36 mL) was added and the mixture
was stirred for 2 d at r.t. H2O (70 mL) was added and the mixture was
extracted with EtOAc (3 × 70 mL). The combined organic phase was
dried over anhyd MgSO4 and the volatiles were removed under re-
duced pressure. The crude was purified by column chromatography.
Yield: 7.330 g (21.6 mmol, 88%); colorless powder; mp 113–115 °C.
IR (neat): 3240, 1660, 1530, 1175 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.59 (br s, 1 H), 8.21 (dd, J = 8.3, 1.6 Hz,
1 H), 7.81 (dd, J = 8.0, 1.5 Hz, 1 H), 7.45–7.32 (m, 1 H), 6.90 (ddd, J =
8.0, 7.4, 1.6 Hz, 1 H), 4.08 (s, 2 H).
Yield: 2.382 g (5.7 mmol, 92%); white solid; Rf = 0.4 (cyclohexane–
EtOAc, 80:20); mp 119–121 °C.
IR (neat): 3270, 2925, 1670, 1635, 1510, 1430 cm–1
.
13C NMR (75 MHz, CDCl3): δ = 163.8, 139.2, 137.7, 129.4, 126.8, 121.8,
1H NMR (300 MHz, CDCl3): δ = 8.35–8.24 (m, 1 H), 7.76 (dd, J = 7.9, 1.4
Hz, 1 H), 7.40–7.30 (m, 2 H), 7.06 (d, J = 15.2 Hz, 1 H), 6.83 (ddd, J =
7.9, 7.3, 1.6 Hz, 1 H), 6.19 (d, J = 3.5 Hz, 1 H), 5.99 (d, J = 3.5 Hz, 1 H),
5.65 (d, J = 15.2 Hz, 1 H), 4.04–3.95 (m, 1 H), 3.91–3.79 (m, 1 H), 2.03–
1.73 (m, 6 H), 0.95 (t, J = 7.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 164.3, 154.4, 138.9, 138.5, 132.1, 129.4,
126.0, 123.2, 122.2, 119.4, 107.8, 105.5, 90.2, 45.5, 42.6, 33.9, 30.9,
20.3, 8.9.
90.0, 29.8.
HRMS (ESI): m/z [M + Na]+ calcd for C8H7BrINONa: 361.8653; found:
361.8648.
Diethyl [(2-Iodophenyl)carbamoyl]methylphosphonate (7)
P(OEt)3 (4.8 mL, 28.1 mmol, 1.30 equiv) was added to a solution of 2-
bromo-N-(2-iodophenyl)acetamide (7.330 g, 21.6 mmol, 1.00 equiv)
in DCE (20 mL) at r.t. and then the mixture was heated to 90 °C for 4 h
under stirring. The solvent was removed under reduced pressure and
the remaining oil was purified by column chromatography.
HRMS (ESI): m/z [M + Na]+ calcd for C19H21IN2ONa: 443.0596; found:
443.0591.
Yield: 7.200 g (18.1 mmol, 84%); beige solid; Rf = 0.1 (cyclohexane–
EtOAc, 50:50); mp 75–77 °C.
rac-3-(8-Ethyl-5,6,7,8-tetrahydroindolizin-8-yl)-N-(2-iodophe-
nyl)propanamide (8)
IR (neat): 1675, 1530, 1225 cm–1
.
Crabtree’s catalyst [Ir(COD)(PCy3)py]PF6 (0.097 g, 0.12 mmol, 0.02
equiv) was added to a solution of 10 (2.545 g, 6.1 mmol, 1.00 equiv) in
CH2Cl2 (40 mL) inside a Parr 5500 microreactor hydrogenation appa-
ratus. The apparatus was flushed with argon and finally placed under
H2 (40 atm) pressure; the solution was stirred for 7 h at r.t. Upon com-
pletion of the reaction, the solvent was removed under reduced pres-
sure. The crude was purified by column chromatography.
1H NMR (300 MHz, CDCl3): δ = 8.50 (s, 1 H), 8.14–8.07 (m, 1 H), 7.79
(dd, J = 8.0, 1.3 Hz, 1 H), 7.32 (ddd, J = 8.4, 7.2, 1.4 Hz, 1 H), 6.89–6.81
(m, 1 H), 4.21 (p, J = 7.3 Hz, 4 H), 3.06 (d, J = 20.8 Hz, 2 H), 1.42–1.27
(m, 6 H).
13C NMR (75 MHz, CDCl3): δ = 162.6, 139.3, 138.6, 129.1, 126.5, 122.9,
90.1, 63.2, 63.1, 37.7, 36.0, 16.6, 16.5.
HRMS (ESI): m/z [M + Na]+ calcd for C12H17INO4PNa: 419.9838; found:
419.9832.
Yield: 2.354 g (5.6 mmol, 92%); yellow oil; Rf = 0.4 (cyclohexane–
EtOAc, 80:20).
IR (neat): 3270, 2935, 1665, 1510, 1285 cm–1
.
rac-8-Ethyl-5,6,7,8-tetrahydroindolizine-8-carbaldehyde (9)
1H NMR (300 MHz, CDCl3): δ = 8.30–8.09 (m, 1 H), 7.76 (dd, J = 8.0, 1.4
Hz, 1 H), 7.43–7.28 (m, 2 H), 6.91–6.75 (m, 1 H), 6.14 (s, 1 H), 5.92 (br
s, 1 H), 3.90 (t, J = 6.1 Hz, 2 H), 2.37 (dd, J = 9.6, 7.3 Hz, 2 H), 2.02 (dtd,
J = 14.6, 7.0, 6.4, 4.8 Hz, 4 H), 1.84–1.56 (m, 4 H), 0.88 (t, J = 7.4 Hz, 3
H).
A Schlenk tube was charged with activated 4 Å MS (1.5 g) and anhyd
4-methylmorpholine N-oxide (0.768 g, 6.3 mmol, 2.00 equiv) under
argon. A solution of rac-53 (0.565 g, 3.2 mmol, 1.00 equiv) in anhyd
MeCN (15 mL) was added and the mixture was stirred at r.t. TPAP
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E

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S. Hildebrandt et al.
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Synthesis
13C NMR (75 MHz, CDCl3): δ = 171.8, 138.9, 138.4, 134.8, 129.3, 125.9,
125.1, 122.2, 118.9, 107.5, 104.3, 90.1, 45.5, 37.8, 35.3, 33.7, 30.8,
20.3, 8.8.
(2) Crossley, S. W. M.; Shenvi, R. A. Chem. Rev. 2015, 115, 9465.
(3) Hildebrandt, S.; Gansäuer, A. Angew. Chem. Int. Ed. 2016, 55,
9719.
(4) Examples of efficient titanocene(III)-catalyzed radical reac-
tions: (a) Gansäuer, A.; Rinker, B.; Ndene-Schiffer, N.; Pierobon,
M.; Grimme, S.; Gerenkamp, M.; Mück-Lichtenfeld, C. Eur. J. Org.
Chem. 2004, 2337. (b) Gansäuer, A.; Fleckhaus, A.; Lafont, M. A.;
Okkel, A.; Kotsis, K.; Anoop, A.; Neese, F. J. Am. Chem. Soc. 2009,
131, 16989. (c) Gansäuer, A.; Worgull, D.; Knebel, K.; Huth, I.;
Schnakenburg, G. Angew. Chem. Int. Ed. 2009, 48, 8882.
(d) Gansäuer, A.; Behlendorf, M.; von Laufenberg, D.; Fleckhaus,
A.; Kube, C.; Sadasivam, D. V.; Flowers, R. A. II Angew. Chem. Int.
Ed. 2012, 51, 4739. (e) Streuff, J.; Feurer, M.; Bichovski, P.; Frey,
G.; Gellrich, U. Angew. Chem. Int. Ed. 2012, 51, 8661.
(f) Gansäuer, A.; Klatte, M.; Brandle, G. M.; Friedrich, J. Angew.
Chem. Int. Ed. 2012, 51, 8891. (g) Gansäuer, A.; Hildebrandt, S.;
Michelmann, A.; Dahmen, T.; von Laufenberg, D.; Kube, C.;
Fianu, G. D.; Flowers, R. A. II Angew. Chem. Int. Ed. 2015, 54,
7003. (h) Streuff, J.; Feurer, M.; Frey, G.; Steffani, A.; Kacprzak,
S.; Weweler, J.; Leijendekker, L. H.; Krakert, D.; Plattner, D. A.;
Dietmar, H. J. Am. Chem. Soc. 2015, 137, 14396. (i) Henriques, D.
S. G.; Zimmer, K.; Klare, S.; Meyer, A.; Rojo-Wiechel, E.; Bauer,
M.; Sure, R.; Grimme, S.; Schiemann, O.; Flowers, R. A. II Angew.
Chem. Int. Ed. 2016, 55, 7671. (j) Funken, N.; Mühlhaus, F.;
Gansäuer, A. Angew. Chem. Int. Ed. 2016, 55, 12030.
HRMS (ESI): m/z [M + H]+ calcd for C19H23IN2OH: 423.0933; found:
423.0935.
rac-3-(8-Ethyl-3-formyl-5,6,7,8-tetrahydroindolizin-8-yl)-N-(2-io-
dophenyl)propanamide (3)
DMF (2.1 mL, 26.8 mmol, 5.00 equiv) was dissolved in CH2Cl2 (25 mL),
and POCl3 (0.55 mL, 5.9 mmol, 1.10 equiv) was added at r.t. The solu-
tion was stirred for 15 min and then cooled to 0 °C. A solution of 8
(2.264 g, 5.4 mmol, 1.00 equiv) in CH2Cl2 (25 mL) was added over 5
min and the mixture was stirred for 3 h while allowed to warm to r.t.
Half-saturated K2CO3 solution (50 mL) was added and the mixture
was stirred for 30 min. The mixture was extracted with CH2Cl2 (3 × 50
mL), washed with H2O (100 mL), and dried over anhyd MgSO4. The
solvent was removed under reduced pressure and the crude was puri-
fied by column chromatography.
Yield: 1.739 g (3.9 mmol, 72%); foamy semi-solid; Rf = 0.6 (cyclohex-
ane–EtOAc, 50:50).
IR (neat): 3270, 2935, 1735, 1645 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 9.41 (s, 1 H), 8.15 (d, J = 8.9 Hz, 1 H),
7.76 (dd, J = 8.0, 1.4 Hz, 1 H), 7.35 (br s, 1 H), 7.32 (ddd, J = 8.5, 7.4, 1.5
Hz, 1 H), 6.90 (d, J = 4.1 Hz, 1 H), 6.86–6.80 (m, 1 H), 6.09 (d, J = 4.2 Hz,
1 H), 4.40 (dt, J = 14.1, 5.9 Hz, 1 H), 4.31 (dt, J = 13.6, 6.4 Hz, 1 H),
2.44–2.32 (m, 1 H), 2.27 (dq, J = 15.1, 7.9, 7.1 Hz, 1 H), 2.13–2.06 (m, 2
H), 2.04–1.97 (m, 2 H), 1.82–1.64 (m, 4 H), 0.87 (t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 178.7, 171.0, 146.2, 138.9, 138.2,
131.0, 129.4, 126.1, 124.8, 122.2, 107.6, 90.2, 45.6, 38.4, 35.4, 33.7,
33.4, 29.0, 19.7, 8.7.
(5) Dinsmore, A.; Mandy, K.; Michael, J. P. Org. Biomol. Chem. 2006,
4, 1032.
(6) Bowie, A. L.; Trauner, D. J. Org. Chem. 2009, 74, 1581.
(7) (a) Nixon, T. D.; Whittlesey, M. K.; Williams, J. M. J. Dalton Trans.
2009, 753. (b) Huang, F.; Liu, Z.; Yu, Z. Angew. Chem. Int. Ed.
2016, 55, 862.
(8) Guo, L.; Liu, Y.; Yao, W.; Leng, X.; Huang, Z. Org. Lett. 2013, 15,
1144.
HRMS (ESI): m/z [M + Na]+ calcd for C20H23IN2O2Na: 473.0702; found:
(9) Deibl, N.; Kempe, R. J. Am. Chem. Soc. 2016, 138, 10786.
(10) Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549.
(11) Corey, E. J.; Suggs, J. Tetrahedron Lett. 1975, 16, 2647.
(12) Sailu, M.; Muley, S. S.; Das, A.; Mainkar, P. S.; Chandrasekhar, S.
Tetrahedron 2015, 71, 1276.
(13) (a) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D.
J. Chem. Soc., Chem. Commun. 1987, 1625. (b) Zhang, H.;
Boonsombat, J.; Padwa, A. Org. Lett. 2007, 9, 279.
(14) Gois, P. M. P.; Afonso, C. A. M. Eur. J. Org. Chem. 2003, 3798.
(15) Lee, D.-W.; Yun, J. Tetrahedron Lett. 2005, 46, 2037.
(16) Chandrasekhar, S.; Chandrashekar, G.; Reddy, M. S.; Srihari, P.
Org. Biomol. Chem. 2006, 4, 1650.
(17) Jagdale, A.; Paraskar, A.; Sudalai, A. Synthesis 2009, 660.
(18) Campbell, A. L.; McChesney, J. D. Synth. Commun. 1979, 9, 471.
(19) Crabtree, R. H.; Felkin, H.; Morris, G. E. J. Organomet. Chem.
1977, 141, 205.
473.0701.
The data are in agreement with the literature.6
Acknowledgment
We thank the DFG (SFB 813 ‘Chemistry at Spin Centers’) for
support. S.H. thanks the Jürgen Manchot Stiftung for a PhD fellow-
ship.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588956.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(20) Bowie, A. L.; Hughes, C. C.; Trauner, D. Org. Lett. 2005, 7, 5207.
(21) (a) Nguyen, J. D.; D’Amato, E. M.; Narayanam, J. M. R.;
Stephenson, C. R. J. Nat. Chem. 2012, 4, 854. (b) Staveness, D.;
Bosque, I.; Stephenson, C. R. J. Acc. Chem. Res. 2016, 49, 2295.
(22) Wyler, B.; Brucelle, F.; Renaud, P. Org. Lett. 2016, 18, 1370.
References
(1) Neier, R.; Kholod, I.; Vallat, O.; Buciumas, A.-M. Heterocycles
2010, 82, 917.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E