Pyrrole-Protected β-Aminoalkylzinc Reagents for the Enantioselective Synthesis of Amino-Derivatives

Article abstract of DOI:10.1002/chem.202000870

Chiral β-aminoalkylzinc halides were prepared starting from optically pure commercial β-amino-alcohols. These amino-alcohols were converted to the corresponding N-pyrrolyl-protected alkyl iodides which undergo a zinc insertion in the presence of LiCl (THF, 25 °C, 10–90 min). Subsequent Negishi cross-coupling or acylation reactions with acid chlorides produced amino-derivatives with retention of chirality. Diastereoselective CBS-reductions of some prepared N-pyrrolyl-ketones provided 1,3-subsituted N-pyrrolyl-alcohols with high diastereoselectivity. Additionally, a deprotection procedure involving an ozonolysis allowed the conversion of the pyrrole-ring into a formamide without loss of optical purity.

Full text of DOI:10.1002/chem.202000870

A Journal of
Accepted Article
Title: Pyrrole Protected β-Aminoalkylzinc Reagents for the
Enantioselective Synthesis of Amino-Derivatives
Authors: Marcel Leroux, Wan-Yun Huang, Yannick Lemke, Thaddäus
Koller, Konstantin Karaghiosoff, and Paul Knochel
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To be cited as: Chem. Eur. J. 10.1002/chem.202000870
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Pyrrole Protected β-Aminoalkylzinc Reagents for the
Enantioselective Synthesis of Amino-Derivatives
Marcel Leroux, Wan-Yun Huang, Yannick Lemke, Thaddäus Koller, Konstantin Karaghiosoff and Paul
Knochel*
Abstract: Chiral β-aminoalkylzinc halides were prepared starting
from optically pure commercial β-amino-alcohols. These amino-
alcohols were converted to the corresponding N-pyrrolyl-protected
alkyl iodides which undergo a zinc insertion in the presence of LiCl
(THF, 25 °C, 10–90 min). Subsequent Negishi cross-couplings or
acylations with acid chlorides produced amino-derivatives with
retention of chirality. Diastereoselective CBS-reductions of some
prepared N-pyrrolyl-ketones provided 1,3-subsituted N-pyrrolyl-
alcohols with high diastereoselectivity. Additionally, a deprotection
procedure involving an ozonolysis allowed the conversion of the
pyrrole-ring into a formamide without loss of optical purity.
the presence of an appropriate transition-metal catalyst
(Scheme 1a).
Results and Discussion
Preliminary results showed that the choice of the protecting group
was essential for the success of the proposed reaction sequence
(Scheme 1a). Whereas most electron-withdrawing amino-
protecting groups[6] will enhance elimination side reactions for the
resulting organozinc reagent of type 4, most donating amino-
protecting groups on the other hand will favor aziridination of the
starting iodide 3. After some experimentation, we have found that
the use of a pyrrole ring as protecting group is an excellent
compromise which allows to accomplish the proposed sequence
with high efficiency (Scheme 1b).
Introduction
The preparation of chiral amino-derivatives is of great synthetic
importance for the development of new pharmaceuticals and
agrochemicals.[1] In this context, the preparation of organometallic
intermediates bearing an amino group in β-position may provide
a powerful tool for the synthesis of functionalized amino-
derivatives. Organozinc compounds are known to tolerate a broad
range of functional groups[2] and are therefore well suited for
synthesis of chiral amino-derivatives. Jackson has demonstrated
the utility of serine derived chiral organozinc reagents for the
preparation of novel amino-acids using Negishi cross-couplings.[3]
Furthermore, chiral β-aminoalkylzinc reagents derived from the
corresponding amino-alcohols have been already used for the
synthesis of functionalized amines.[4,5]
In this work, we have envisioned to prepare stable zinc
organometallics bearing an amino group in β-position as key
organometallic intermediates. Thus, 2-amino-alcohols of type 1,
readily available by reduction of the corresponding natural amino-
acid, will afford after protection of the amino group the
corresponding amino-alcohol of type 2 and after functional group
interconversion the corresponding alkyl iodides of type 3.
Treatment of these functionalized alkyl iodides (3) with zinc dust
in the presence of LiCl should provide 2-aminoalkylzinc
halides (4) which should readily react with various electrophiles in
Dr. Marcel Leroux, Wan-Yun Huang, Yannick Lemke, Thaddäus
Koller, Prof. Dr. K. Karaghiosoff, Prof. Dr. P. Knochel;
Department Chemie, Ludwig-Maximilians-Universität München
Butenandtstrasse 5–13, Haus F, 81377 München (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
Scheme 1. Preparation of chiral β-aminoalkylzinc halides of type 4 from
optically pure amino-alcohols of type 1. [a] Zinc insertion conditions:
LiCl (1.0 equiv), Zn dust (1.5 equiv, activated with DBE/TMSCl) in THF at 25 °C.
[b] Complexed with LiCl. [c] Determined by titration against iodine.[7]
Supporting information for this article is given via a link at the end of
the document.
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Therefore, the treatment of commercially available 1,2-amino-
alcohols (1a–e) derived from optically enriched amino-acids[8] with
2,5-dimethoxytetrahydrofuran in the presence of NaOAc/AcOH in
1,2-dichloroethane (DCE) and water (90 °C, 1–16 h) produced the
pyrrol-1-yl-alcohol derivatives 2a–e in 71–92% yield.[9] An Appel-
reaction[10] (PPh3, I2, imidazole in dichloromethane (DCM))
allowed the conversion of the alcohols 2a–e to the corresponding
primary iodides 3a–e in 71–91% yield. Direct insertion of zinc
powder (1.5 equiv, >325 mesh) previously activated with
1,2-dibromoethane (DBE) and Me3SiCl (TMSCl) to the alkyl
iodides 3a–e in presence of LiCl[11] proceeded smoothly in THF at
25 °C (10–90 min) furnishing the desired alkylzinc halides (4a–e)
in 71–93% yield. These alkylzinc reagents showed no tendency
to undergo elimination reactions and were stable at 25 °C for
several days without decomposition.
In preliminary experiments, 2-(1H-pyrrol-1-yl)ethylzinc iodide (4a)
was used to determine the optimum cross-coupling and acylation
conditions. Negishi cross-coupling reactions[12] of 4a were best
performed using 2 mol% Pd(OAc)2 and 4 mol% SPhos[13] as
catalyst with both electron-rich or electron-poor aryl- and
heteroaryl bromides or iodides in THF (25 °C, 16 h) affording the
pyrrole derivatives 5a–h in 83–98% yield. Negishi acylation
reactions[14] of 4a were also readily performed using aryl-,
heteroaryl- and cyclopropyl-substituted acyl chlorides in the
presence of 4 mol% Pd(PPh3)4 in THF (25–50 °C, 16 h) providing
the β-pyrrolyl-ketones (5i–l) in 73–87% yield (Scheme 2). No
significant amount of β-hydride elimination was observed in these
cross-couplings.
Scheme 3. Negishi cross-coupling reactions of chiral β-N-pyrrolyl alkylzinc
reagents 4b–e with various functionalized aryl halides. [a] Yield of analytically
pure isolated products.
With these optimized conditions in hand, we have extended these
reactions to the chiral organozinc reagents 4b–e. Various chiral
arylated pyrroles (6a–d, 7a–e, 8a–d, 9a–e) were obtained after
Negishi cross-couplings with aryl iodides and bromides in 75–
99% isolated yield with full retention of configuration (ee = 99%,
Scheme 3).
Similarly, the reagents 4b–e were used in palladium-catalyzed
acylation reactions with several aryl-, heteroaryl- and alkyl-
substituted acyl chlorides providing the desired chiral ketones (7f,
7i–j and 8e–h) in 66–86% yield. Furthermore, as a cheap
alternative to palladium-catalysis and to prevent cross-coupling
side reactions, copper(I) iodide was used as catalyst for
acylations.[15] Chiral halogenated ketones (6e–g, 7g–h, 9f) and a
2-thienyl-ketone (6h) were obtained in 59–80% yield (Scheme 4).
All ketones, whether prepared by using palladium- or copper-
derivatives as catalyst, were obtained with full retention of
configuration (ee = 99%).
Scheme 2. Palladium-catalyzed Negishi cross-coupling and acylation reactions
of 4a with various aryl halides and acid chlorides leading to functionalized
pyrrole derivatives 5a–l. [a] Yield of analytically pure isolated products.
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Additionally,
a
tyrosine-based alkylzinc compound was
prepared.[16] For this purpose, the acidic phenolic hydroxyl group
of L-tyrosine was protected by methylation with MeI. Starting from
L-tyrosine, a straightforward synthesis pathway including pyrrole
formation, phenol protection, methyl esterification and
subsequent reduction of the methyl ester was performed in 40%
yield over three steps providing the pyrrol-1-yl-alcohol (S)-2g
(Scheme 6). A subsequent conversion into the alkyl iodide (S)-3g
using Appel-reaction conditions was proceeding in 95% yield and
92% ee. After oxidative addition of zinc dust into this alkyl iodide,
the corresponding chiral N-pyrrolyl-alkylzinc halide (S)-4g was
obtained after 15 min at 25 °C in 99% yield. Negishi cross-
coupling reactions using electron-rich and electron-poor aryl
iodides afforded the functionalized tyrosine derivatives (S)-11a–c
in 93–96% yield. Additional copper- and palladium-catalyzed
acylation reactions were performed providing ketones (S)-11d–f
bearing halogens in ortho-, meta- or para-position in 75–84% yield
(Scheme 6). All products were obtained with retention of
configuration with 92% ee as determined previously for the
starting alkyl iodide (S)-3g.
Scheme 4. Palladium- and copper-catalyzed acylation reactions using chiral
organozinc reagents 4b–e with various acyl chlorides. [a] Palladium-catalyzed
acylation. [b] Copper-catalyzed acylation. [c] Yield of analytically pure isolated
products.
To further extend these reactions, we have prepared an indolyl-
substituted zinc reagent.[16] Starting from tryptophanol (R)-1f,
successive pyrrole-protection leading to (R)-2f and iodination
using our standard procedures[17] provided the optically pure alkyl
iodide (R)-3f which was converted to the corresponding
organozinc reagent (R)-4f. Interestingly, the presence of a
secondary amine of the indole side-chain did not interfere with the
zinc insertion and the resulting organozinc reagent (R)-4f was
prepared in 91% yield.[18] Palladium-catalyzed Negishi cross-
couplings with various aryl and heteroaryl iodides or bromides
were performed and functionalized indole derivatives 10a–f were
obtained in 68–98% yield without racemization (Scheme 5).
Scheme 6. Preparation of a chiral N-pyrrolyl-alkylzinc iodide ((S)-4g) derived
from L-tyrosine and its use in Negishi cross-coupling and acylation reactions.
In addition to the organozinc reagents derived from amino-acids,
we have also prepared a chiral zinc reagent derived from trans-
(1S,2S)-2-aminocyclohexanol ((S,S)-1h). After protection as a
pyrrole ring, the corresponding N-pyrrolyl-alkylalcohol (S,S)-2h
was obtained in 83% yield and further Appel-iodination led to the
desired cycloalkyl iodide (S,R)-3h at 50 °C in 76% yield after 30 h.
Following zinc insertion of (S,R)-3h provided the alkylzinc reagent
(S)-4h in 79% yield. The stereochemistry of the carbon bearing
zinc is lost due to the radical insertion reaction.[19] However, cross-
coupling reactions of the organozinc reagent (S)-4h using
Pd(OAc)2 and SPhos as catalyst with different substituted
electron-rich and electron-deficient electrophiles provided the
cross-coupling products 12a–d in 84–97% yield (Scheme 7).
Remarkably, using this palladium system, the trans-cross-
coupling products were formed selectively (dr = 99:1) and all
products exhibit a high optical purity (99% ee).[19]
Scheme 5. Preparation of a chiral pyrrole-protected alkylzinc reagent ((R)-4f)
derived from tryptophanol (R)-1f bearing an unprotected indolyl-moiety and its
use in Negishi cross-coupling reactions.
Reaction of (S)-4h with 4-fluorobenzoyl chloride using Pd(PPh3)4
as acylation catalyst led solely to the trans-ketone (S,S)-12e in
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93% yield (dr = 99:1, 99% ee). The same reaction using copper(I)
providing selectively the trans-products 13a–f in 75–93% yield
iodide as catalyst resulted in a diastereomeric mixture (dr = 83:17). with high enantiopurity (Scheme 8). Determination of the crystal
structure of (S,R)-13a by X-ray analysis confirmed the trans-
configuration.[20]
A
post-functionalization of some chiral pyrrole-containing
products was performed providing chiral amino-alcohol
derivatives. Thus, the acylation products (R)-8f and (S)-8f were
selectively reduced to optically pure 1,3-substituted N-pyrrolyl-
alcohols
using
the
Corey-Bakshi-Shibata
asymmetric
reduction.[21] Therefore, the CBS catalyst ((R)- or (S)-2-methyl-
CBS-oxazaborolidine) was mixed with BH3·SMe2 at 0 °C and the
ketone 8f was slowly added. The desired alcohols 14a–d were
obtained in 92–98% yield with a diastereomeric ratio of 99:1 and
an enantiomeric excess of 99% (Scheme 9).
To confirm the absolute configuration, the alcohol (R,S)-14d was
esterified with the (R)- as well as the (S)-Mosher acid (MTPA) and
the resulting two diastereomeric esters were analyzed by NMR-
spectroscopy. The chemical shifts were compared and evaluated
as reported in the literature (see Supporting Information).[22] The
analysis confirmed the configuration previously predicted by the
CBS-model. Thus, the (R)-CBS catalyst provided the (S)-alcohols
(14b, 14c) and vice versa the (S)-CBS catalyst led to the
(R)-alcohols (14a, 14d).
Scheme 7. Preparation of a chiral N-pyrrolyl-alkylzinc reagent starting from the
1,2-cis substituted iodocyclohexyl derivative (S,R)-3h providing exclusively
trans-configured products using palladium-catalysis.
Furthermore, this method was extended to a N-pyrrolyl-alkylzinc
reagent derived from trans-(1R,2R)-2-aminocyclopentanol
((R,R)-1i). After protection of the amino group as a pyrrole ring,
the corresponding N-pyrrolyl-alcohol (R,R)-2i was obtained in
77% yield. Its iodination was rather difficult due to the increased
formation of an elimination product and the cis-iodide[20] (R,S)-3i
was obtained at 50 °C in only 43% yield after 16 h reaction time.
Subsequent insertion of zinc dust in the presence of LiCl led to
the secondary organozinc reagent (R)-4i at 25 °C after 10 min
reaction time in 96% yield (Scheme 8).
Scheme 9. Enantioselective CBS-reduction of the ketones (R)-8f and (S)-8f
provides a pathway towards the 1,3-substituted N-pyrrolyl-alcohols 14a–d.
A deprotection procedure for the pyrrole group was developed
based on literature procedures.[23] Ozonolysis converted pyrroles
into solid formamides, which were easier to handle than the
corresponding alkylamines. Thus, treatment of
a pyrrole
derivative with ozone at –78 °C in a DCM/MeOH mixture for 5 min,
followed by a reductive work-up with methyl sulfide led to a
mixture of the corresponding formamide and diformylamine. This
mixture was then stirred in a diluted potassium hydroxide solution
in ethanol (0.1 M) for 1 h leading selectively to formamides of
type 15 (Table 1).[24]
Scheme 8. Preparation of the 2-N-pyrrolyl-cyclopentlyzinc reagent (R)-4i.
Exclusively trans-configured products of type 13 were obtained after palladium-
catalyzed Negishi cross-coupling.
This deprotection protocol was applied to selected cross-coupling
products (5g, 8c, 8d, 11a, 12c, 13f) as well as the CBS-reduced
alcohol (S,R)-14a and the corresponding formamide derivatives
15a–g were obtained 62–76% yield (Table 1). The stereocenters
A
stereo-converging reaction occurred when using the
diastereomeric mixture of organozinc reagent (R)-4i in palladium-
catalyzed Negishi cross-couplings with aryl iodides bearing
various functional groups in ortho-, meta- or para-position
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were not affected by this treatment and full retention of
configuration was achieved for all compounds.
Table 1. Deprotection of the pyrroles via ozonolysis and subsequent reductive
and basic workup leading to the formamides 15a–g with retention of
configuration.
entry
1
functionalized pyrrole
formamide 15a–15g
15a, 71% yield
5g
Figure 1. Molecular structure of the deprotected formamide (S,R)-15e. Thermal
ellipsoids are drawn at 50% probability level. The fluorine atoms of both CF3
groups are disordered.
2
Furthermore, the crystal structure of (R,S)-15g (Figure 2) showed
an anti-configuration. This was in accordance with the results of
the Mosher’s ester analysis using NMR-spectroscopy described
above.
(S)-8c, 99% ee
(S)-15b, 74% yield, 99% ee
3
4
(S)-8d, 99% ee
(S)-11a, 92% ee
(S)-15c, 65% yield, 99% ee
(S)-15d, 62% yield, 92% ee
5
6
7
(S,R)-12c
dr = 99:1, 99% ee
(S,R)-15e, 74% yield
dr = 99:1, 99% ee
Figure 2. Molecular structure of the deprotected formamide (R,S)-15g. Thermal
ellipsoids are drawn at 50% probability level.
(R,S)-13f
dr = 99:1, 99% ee
(R,S)-15f, 71% yield,
dr = 99:1, 99% ee
Conclusion
In conclusion, we have developed a straightforward preparation
of pyrrole-protected β-aminoalkylzinc halides starting from
optically pure β-amino-alcohols. The pyrrole moiety was a
suitable protecting group for the preparation of such organozinc
reagents. These β-aminoalkylzinc reagents underwent palladium-
catalyzed Negishi cross-coupling reactions and acylation
reactions with a broad range of functionalized electrophiles
providing a range of chiral amino-derivatives. Similarly, secondary
cycloalkylzinc halides were prepared from the corresponding
iodides. Subsequent cross-coupling and acylation reactions
produced various chiral 1,2-cyclohexyl- and cyclopentyl-amines.
An amino-ketone prepared via acylation reaction was reduced
using an asymmetric CBS-reduction providing optically pure 1,3-
substituted N-pyrrolyl-alcohols. A deprotection procedure was
also developed involving an ozonolysis with subsequent reductive
work-up. This allowed to convert these pyrrole derivatives into
diastereomerically and enantiomerically enriched formamides.
(S,R)-14a
dr = 99:1, 99% ee
(R,S)-15g, 76% yield,
dr = 99:1, 99% ee
Additionally, the crystal structures of (S,R)-15e and (R,S)-15g
were obtained by X-ray diffraction of single-crystals. The structure
of (S,R)-15e (Figure 1) confirmed the trans-configuration of the
formamide group to the aryl moiety which was determined for
pyrrole derivative (S,R)-12c via NMR-spectroscopy.
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Typical procedure for palladium-catalyzed cross-coupling
reactions: Preparation of ethyl (S)-4-(3-phenyl-2-(1H-pyrrol-
1-yl)propyl)benzoate ((S)-8c)
Experimental Section
Typical procedure for the preparation of N-pyrrolyl-alcohols
of type 2 from amino-alcohols of type 1: Preparation of (S)-
3-phenyl-2-(1H-pyrrol-1-yl)propan-1-ol ((S)-2d)
In a dry Schlenk-flask, Pd(OAc)2 (2.3 mg, 10 µmol, 2 mol%) and
SPhos (8.2 mg, 20 µmol, 4 mol%) were dissolved in freshly
distilled dry THF (1 mL) and stirred for 10 min at 25 °C. Ethyl
4-iodobenzoate (140 mg, 0.5 mmol, 1.0 equiv) was added and to
this mixture, the alkylzinc reagent (S)-4d in THF (1.3 mL, 0.47 M,
0.6 mmol, 1.2 equiv) was added dropwise. The reaction mixture
was stirred for 16 h at 25 °C and then quenched with
sat. aq. NH4Cl solution (1 mL). The mixture was extracted three
times with EtOAc, the combined organic phases were dried over
MgSO4 and solvents were evaporated. Purification via flash
column chromatography (i-hexanes/ethyl acetate 95:5) provided
the cross-coupling product (S)-8c (162 mg, 0.49 mmol, 96% yield,
99% ee).
(S)-2-Amino-3-phenyl-1-propanol (S)-1d (3.8 g, 25 mmol,
1.0 equiv) and NaOAc⋅3H2O (3.4 g, 25 mmol,1.0 equiv) were
dissolved in a DCE/water mixture (1:1, 75 mL) and glacial acetic
acid (12.5 mL). 2,5-Dimethoxytetrahydrofuran (cis/trans mixture,
3.3 g, 25 mmol, 1.0 equiv) was added and the two-phase mixture
was refluxed at 90 °C under vigorous stirring for 16 h. The organic
phase was separated, the aqueous phase was extracted three
times with EtOAc and the combined organic phases were
neutralized with sat. aq. NaHCO3 solution, washed with brine and
dried over MgSO4. After evaporation of solvents, the residue was
purified by flash column chromatography (i-hexanes/ethyl
acetate 8:2 + 1 vol% Et3N) and the corresponding pyrrol-1-yl-
alcohol (S)-2d (4.3 g, 21 mmol, 85% yield) was obtained.
Typical procedure for palladium-catalyzed acylation
reactions: Preparation of (S)-1-(3-chlorophenyl)-4-phenyl-3-
(1H-pyrrol-1-yl)butan-1-one ((S)-8f)
Typical procedure for the preparation of alkyl iodides of
type 3: Preparation of (S)-1-(1-iodo-3-phenylpropan-2-yl)-1H-
pyrrole ((S)-3d)
In a dry Schlenk-flask, Pd(PPh3)4 (23 mg, 20 µmol, 4 mol%) was
dissolved in freshly distilled dry THF (1 mL) and 3-chlorobenzoyl
chloride (88 mg, 0.5 mmol, 1.0 equiv) was added. To this mixture,
the alkylzinc reagent (S)-4d in THF (1.3 mL, 0.47 M, 0.6 mmol,
1.2 equiv) was added dropwise. The reaction mixture was stirred
for 16 h at 50 °C and then quenched with sat. aq. NH4Cl solution
(1 mL). The mixture was extracted three times with EtOAc, the
combined organic phases were dried over MgSO4 and solvents
were evaporated. Purification via flash column chromatography
(i-hexanes/ethyl acetate 95:5) provided the acylation product
(S)-8f (138 mg, 0.43 mmol, 85% yield, 99% ee).
In a dry Schlenk-flask, PPh3 (6.1 g, 23 mmol, 1.1 equiv) and
imidazole (1.6 g, 23 mmol, 1.1 equiv) were dissolved in dry DCM
(44 mL) and cooled to 0 °C. Iodine (5.9 g, 23 mmol, 1.1 equiv)
was added in three portions over a period of 10 min. The
corresponding pyrrol-1-yl-alcohol (S)-2d (4.3 g, 21 mmol,
1.0 equiv) dissolved in dry DCM (40 mL) was added dropwise to
the reaction mixture at 0 °C over a period of 30 min. The mixture
was stirred for 30 min at this temperature and then warmed to
25 °C and stirred additionally for 1 h. After quenching with sat. aq.
Na2S2O3 solution, the organic phase was separated and the
aqueous phase extracted three times with DCM. The combined
organic phases were dried over CaCl2 and solvents were
evaporated. Purification by flash column chromatography (i-
hexanes/ethyl acetate 99:1) afforded the corresponding alkyl
iodide (S)-3d (5.5 g, 18 mmol, 84% yield, 99% ee).
Typical procedure for deprotection of the pyrrole-group:
Preparation of ethyl (S)-4-(2-formamido-3-
phenylpropyl)benzoate ((S)-15b)
In a Schlenk-flask, (S)-8c (334 mg, 1.0 mmol, 1.0 equiv) was
dissolved in DCM (8 mL) and methanol (2 mL) and then cooled to
–78 °C. Ozone was passed through the solution for 5 min and
afterwards flushed with nitrogen for 10 min. Dimethyl sulfide
(621 mg, 10 mmol, 10 equiv) was added and the reaction mixture
stirred for 4 h at 25 °C. After evaporation of the solvents, the
residue was stirred for 1 h in 10 mL KOH in ethanol (0.1 M) and
afterwards ethanol was removed under reduced pressure. The
crude product was purified by via flash column chromatographic
purification (i-hexanes/ethyl acetate 1:1) and formamide
derivative (S)-15b (230 mg, 0.74 mmol, 74% yield, 99% ee) was
obtained.
Typical procedure for the zinc insertion into pyrrole-
containing alkyl iodides: Preparation of (S)-(3-phenyl-2-(1H-
pyrrol-1-yl)propyl)zinc(II) iodide ((S)-4d)
In a Schlenk-flask, LiCl (340 mg, 8.0 mmol 1.0 equiv) and zinc
dust (785 mg, 12 mmol, 1.5 equiv) were dried in vacuo. Under
argon atmosphere, freshly distilled dry THF (12 mL) was added
and the zinc dust was activated using 1,2-dibromoethane (35 µl,
5 mol%) and Me3SiCl (50 µL, 5 mol%). The suspension was
slightly heated with a heat-gun until a gas formation started.
Afterwards, the alkyl iodide (S)-3d (2.5 g, 8.0 mmol, 1.0 equiv)
was added slowly and the mixture stirred at 25 °C. The reaction
progress was monitored by gas chromatographic analysis of
small aliquots quenched with sat. aq. NH4Cl solution. After 10 min,
the solution was passed through a syringe filter and the
concentration of the organozinc reagent (S)-4d was determined
by titration against iodine (13 mL, 6.5 mmol, 82% yield).[7]
Acknowledgements
We thank the LMU Munich and the DFG for financial support.
Furthermore, we like to thank Albemarle (Frankfurt a. M.) and the
BASF (Ludwigshafen) for the generous gift of chemicals.
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[17] For the experimental procedure, see Supporting Information.
Keywords: organozinc reagents · palladium · cross-coupling
[18] H. P. Knoess, M. T. Furlong, M. J. Rozema, P. Knochel, J. Org. Chem.
1991, 56, 5974.
·amines · heterocycles
[19] T. Thaler, B. Haag, A. Gavryushin, K. Schober, E. Hartmann, R. M.
Gschwind, H. Zipse, P. Mayer, P. Knochel, Nat. Chem. 2010, 2, 125.
[20] Structure and configuration was determined by single-crystal x-ray
analysis; see Supporting Information.
[1]
a) T. C. Nugent, M. El-Shazly, Adv. Synth. Catal. 2010, 352, 753; b) T.
C. Nugent, Chiral Amine Synthesis, Wiley-VCH Verlag GmbH & Co.
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M. Kesseler, R. Stürmer, T. Zelinski, Angew. Chem. Int. Ed. 2004, 43,
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10.1002/chem.202000870
Chemistry - A European Journal
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Marcel Leroux, Wan-Yun Huang,
Yannick Lemke, Thaddäus Koller,
Konstantin Karaghiosoff and Paul
Knochel
Page No. – Page No.
Pyrrole Protected β-Aminoalkylzinc
Reagents for the Enantioselective
Synthesis of Amino-Derivatives
Chiral β-Aminoalkylzinc Halides for Enantioselective Amine-Synthesis: Chiral β-N-pyrrolyl-alkyl iodides prepared from commercial
β-amino-alcohols undergo zinc insertion in the presence of LiCl (THF, 25 °C, 10–90 min). Negishi cross-coupling or acylation quenching
reactions produced a range of chiral β-N-pyrrolyl derivatives that may be converted into 1,3-amino-alcohols and other chiral amino-derivatives.
Subsequent ozonolysis allowed the conversion of the pyrrole moiety into formamides without loss of optical purity.
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