Magnesium Aldimines Prepared by Addition of Organomagnesium Halides to 2,4,6-Trichlorophenyl Isocyanide: Synthesis of 1,2-Dicarbonyl Derivatives

Article abstract of DOI:10.1002/chem.201900903

The selective addition of organomagnesium reagents to 2,4,6-trichlorophenyl isocyanide leading to magnesiated aldimines is reported. These aldimines react with Weinreb amides, ketones, or carbonates to provide the corresponding carbonyl derivatives after acidic cleavage. This allows for an efficient synthesis of 1,2-dicarbonyl compounds and α-hydroxy ketones.

Full text of DOI:10.1002/chem.201900903

A Journal of
Accepted Article
Title: Magnesium Aldimines Prepared by Addition of
Organomagnesium Halides to 2,4,6-Trichlorophenyl Isocyanide .
Synthesis of 1,2-Dicarbonyl Derivatives.
Authors: Kuno Schwärzer, Andreas Bellan, Maximilian Zöschg,
Konstantin Kargaghiosoff, and Paul Knochel
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To be cited as: Chem. Eur. J. 10.1002/chem.201900903
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Magnesium Aldimines Prepared by Addition of
Organomagnesium Halides to 2,4,6-Trichlorophenyl
Isocyanide. Synthesis of 1,2-Dicarbonyl Derivatives
Kuno Schwärzer, Andreas Bellan, Maximilian Zöschg, Konstantin Karaghiosoff, and Paul Knochel*[a]
Dedicated to Armin de Meijere in celebration of his 80th birthday
Abstract: We report the selective addition of organomagnesium
reagents to 2,4,6-trichlorophenyl isocyanide leading to magnesiated
aldimines which react with Weinreb amides, ketones or carbonates to
provide the corresponding carbonyl derivatives after acidic cleavage.
This allows an efficient synthesis of 1,2-dicarbonyl compounds and
-hydroxy ketones.
conversion (entry 3). In order to determine the E/Z-stereo-
chemistry, we have prepared the crystalline thioimidate 4b from
p-dimethylaminophenylmagnesium bromide (2b) and determined
its structure by X-ray analysis (Figure 2) showing that only E-4b
was formed.[8]
Table 1. Condition screening for the reaction of 2,4,6-trichlorophenyl
isocyanide 1 with the phenylmagnesium halide 2a.
Isocyanides are widely used in heterocyclic synthesis.[1] These
unsaturated compounds show carbenoic behaviour (Figure 1)[2]
and Walborsky has shown in pioneer work that organometallics of
lithium or magnesium added to tertiary or aryl isocyanides leading
to metallo aldimines that were readily trapped with several classes
of electrophiles.[3] Based on this reactivity several intramolecular
ring closing reactions have been developed.[4]
Entry
Time [min]
Yield [%][a]
60
1
2
3
4
2
5
97[b]
Figure 1. Representation of an isocyanide as a linear carbene stabilized via
delocalization of the nitrogen lone pair.[2]
10
20
96 (6)[c]
82
Herein, we wish to report the selective addition of Grignard
reagents to isocyanides. An optimization study showed that
2,4,6-trichlorophenyl isocyanide (1) was an excellent acceptor for
arylmagnesium halide additions.[5] This is most likely due to the
strong inductive electron-withdrawing effect of the chloride
substituents which increases the carbenoic character of the
isocyanide.[2] Thus, the reaction of phenylmagnesium halide (2a),
prepared by the reaction of phenyl bromide with magnesium
turnings in the presence of LiCl (0 °C to 25 °C, 15 h),[6] with the
isocyanide 1 was performed in THF at 20 °C using various
reaction times (Table 1, entries 1 – 4).
[a] GC yields using undecane as internal standard. [b] Isolated yield of
analytically pure product [c] Using a Grignard reagent prepared without LiCl.
It was found that the addition was completed within 5 min at
20 °C providing the magnesiated aldimine 3a which was trapped
with PhSO2SMe[7] (1.1 equiv., 25 °C, 10 min) leading to the
thioimidate 4a in almost quantitative yield (entry 2). Using a
Grignard reagent prepared without LiCl resulted in a very low
[a]
K. Schwärzer, A. Bellan, M. Zöschg, Prof. Dr. Konstantin
Karaghiosoff, Prof. Dr. Paul Knochel
Department Chemie, Ludwig-Maximilians-Universität München
Butenandtstraße 5-13, Haus F, 81377 München (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
Figure 2. X-ray structure of the thioimidate 4b, DIAMOND representation,
thermal ellipsoids are drawn at 50% probability level.
Supporting information for this article is given via a link at the end of
the document.
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Thus, we have explored the scope of the reaction between the
magnesiated aldimines
3 and various electrophiles. Both
7
2b
MeI
electron-rich arylmagnesium halides such as 2b and an
alkylmagnesium halide like n-butylmagnesium bromide
complexed with LiCl (2c) added to the aryl isocyanide 1. The
resulting aldimines were successfully trapped with PhSO2SMe to
afford the thioimidates 4b and 4c in 56 and 65% yield respectively
(Table 2, entries 1 – 2). It should be noted, that electron-poor aryl-
magnesium halides bearing functional groups such as an ester or
a nitrile, as well as arylmagnesium halides with substituents in
ortho position did not add to the isocyanide 1 under various
conditions. Nevertheless, we have found that magnesiated
aldimines 3 reacted readily with various carbonyl derivatives such
as the Weinreb amide 5a,[9] dimethyl or diethyl carbonate and
diethyl ketone leading to the expected products 4d – 4g in
59 – 91% yield (entries 3 – 6). The reaction with methyl iodide
provided the imine 4h in 35% yield (entry 7), while benzaldehyde
did not react at all.
4h, 35%
[a] Complexated LiCl omitted for clarity. [b] Ar = 2,4,6-trichlorophenyl.
[c] Isolated yields of analytically pure products.
These preliminary results showed that the addition to Weinreb
amides was especially efficient. Therefore, we have treated a
range of magnesiated aldimines 3 with Weinreb amides followed
by direct acidic cleavage of the imino function leading to
1,2-diketones of type 6 (Table 3).
Table 3. Reaction of magnesiated aldimines 3 with various Weinreb amides
followed by acidic cleavage leading to 1,2-diketones 6.
Table 2. Reaction of the isocyanide 1 with Grignard reagents followed by
trapping of the formed magnesiated aldimines 3 with various electrophiles.
Entry
Grignard
reagent 2[a]
Weinreb amide 5
Product[b]
Entry
Grignard
Electrophile E+
PhSO2SMe
Product[b], [c]
1
2b
2d
2d
5a
reagent 2[a]
6a, 76%
6b, 91%
1
2
3
4
5a
4b, 56%
4c, 65%
2b
nBuMgBr
2
3
PhSO2SMe
2c
5b
5c
6c, 76%
6d, 63%
2b
2b
2b
2a
5a
4d, 91%
4e, 66%
4
(MeO)2CO
5
6
2d
2d
6e, 59%
6f, 42%
5d
5e
5
6
(EtO)2CO
4f, 72%
4g, 59%
2d
Et2CO
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of various alkyl-substituted Weinreb amides (5f – 5h) was
successfully employed, yielding the corresponding 1,2-diketones
6g – 6i in 64 – 69% yield (entries 7 – 9). The scope of Grignard
reagents was also further explored including n-butylmagnesium
bromide (2c), t-butylmagnesium chloride (2e) as well as meta-
anisylmagnesium bromide (2f) and para-fluorophenylmagnesium
bromide (2g), which led to the respective 1,2-diketones 6j – 6m
in 48 – 82% yields (entries 10 – 13). Heterocyclic Grignard
reagents such as thiophen-2-ylmagnesium bromide (2h) and
thiophen-3-ylmagnesium bromide (2i) underwent the addition to
the isocyanide 1 leading to the 1,2-diketones 6n and 6o in 61%
and 38% yield respectively (entries 14 – 15). In addition, the
Boc-protected para-phenol Grignard reagent 2j[10] provided the
corresponding magnesiated aldimine which was trapped with the
Weinreb amide 5a. Subsequent treatment with concentrated
aqueous HCl for 15 h led to a complete cleavage of both the imino
function as well as the Boc protecting group providing the
1,2-diketone 6p in 68% yield (entry 16).
7
2b
5f
6g, 69%
6h, 69%
6i, 64%
6j, 71%
8
2b
2d
2c
5g
9
5h
5b
10
Table 3. Reaction of magnesiated aldimines 3 with various electrophiles
tBuMgCl
2e
followed by acidic cleavage.
11
12
13
5b
5a
5a
6k, 48%
6l, 65%
2f
Entry
Grignard
Electrophile E+
Product[a]
reagent 2
6m, 82%
6n, 61%
6o, 38%
1
2b
2b
2g
7a, 40%
BrMg
S
O
14
15
5a
5b
OH
2h
2
Me2N
F
7b, 58%
2i
3
4
5
2b
2d
2b
7c, 55%
16
5a
6p, 68%[d]
2j[c]
(EtO)2CO
[a] Complexated LiCl omitted for clarity. [b] Isolated yields of analytically
pure products. [c] Formed via magnesium insertion at 10 °C over 1 h.
[d] Stirred for 15 h with HCl to ensure cleavage of the Boc-group.
7d, 58%[b]
A one-pot reaction sequence consisting of the magnesium
aldimine formation, subsequent trapping with the Weinreb amide
5a and acidic cleavage of the imino function using concentrated
aqueous HCl proceeded well with the electron-rich Grignard
reagents 2b and 2d, providing the expected 1,2-diketones 6a and
6b in 76 and 91% yield respectively (entries 1 – 2). This reaction
sequence tolerated electron-rich as well as electron-poor aryl-
substituted Weinreb amides (entries 3 – 6). Furthermore, a range
PhSO2SMe
7e, 67%
[a] Isolated yields of analytically pure products. [b] 3 M HCl was used instead
of conc. HCl.
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[3]
[4]
a) H. M. Walborsky, G. E. Nizik, J. Am. Chem. Soc. 1969, 91, 7778;
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5405-5407.
Finally, we extended the one-pot procedure to reactions with
various other electrophiles (Table 3). Thus, by using alkyl and aryl
ketones, we have achieved the formation of the -hydroxy
ketones 7a – 7c in 40 – 58% yield (entries 1 – 3). In the case of
diethyl carbonate the cleavage of the imino function was achieved
using 3 M aqueous HCl in order to avoid the decomposition of
resulting -keto ester 7d (entry 4). The cleavage of the imino bond
in the thioimidate 4b required concentrated aqueous HCl, leading
to the formation of the thioester 7e in 67% yield (entry 5).
In summary, we have reported an efficient addition of
organomagnesium halides to 2,4,6-trichlorophenyl isocyanide (1).
This isocyanide gave much better results than related aryl
isocyanides.[5] Quenching reactions with Weinreb amides as well
as ketones provided the desired functionalized carbonyl
derivatives (1,2-diketones of type 6 and -hydroxy ketones
7a – 7c). Further extensions of this method are underway.
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[5]
[6]
For a detailed screening see supporting information.
a) F. M. Piller, P. Appukkuttan, A. Gavryushin, M. Helm, P. Knochel,
Angew. Chem. Int. Ed. 2008, 47, 6802; b) A. Metzger, F. M. Piller,
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J. Am. Chem. Soc. 2007, 129, 12358; e) A. Metzger, M. A. Schade,
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Chem. Int. Ed. 2008, 47, 7648; g) Y.-H. Chen, M. Sun, P. Knochel,
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Acknowledgements
We wish to thank the Ludwig-Maximilians-Universität München
for financial support. We also thank Albemarle (Germany) for the
generous gift of chemicals.
[7]
[8]
K. Fujiki, N. Tanifuji, Y. Sasaki, T. Yokoyama, Synthesis 2002, 3,
343-348.
Keywords: Organomagnesium halides • Isocyanides •
CCDC 1899170 (4b) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
Magnesium aldimines • Weinreb amides• 1,2-Diketones
[9]
a) S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3815-3818;
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Entry for the Table of Contents
COMMUNICATION
Kuno Schwärzer, Andreas Bellan,
Maximilian Zöschg, Konstantin
Karaghiosoff, Paul Knochel*
Page No. – Page No.
Magnesium Aldimines Prepared by
Addition of Organomagnesium
Halides to 2,4,6-Trichlorophenyl
Isocyanide. Synthesis of 1,2-
Dicarbonyl Derivatives.
A selective addition of organomagnesium halides to 2,4,6-trichlorophenyl isocyanide leads
to magnesium aldimines. Subsequent trapping with Weinreb amides or ketones and acidic
cleavage gives access to functionalized 1,2-diketones or -hydroxy ketones (see Figure).
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