Regio- and stereoselective carbometallation reactions of N-alkynylamides and sulfonamides

Article abstract of DOI:10.3762/bjoc.9.57

The carbocupration reactions of heterosubstituted alkynes allow the regio- and stereoselective formation of vinyl organometallic species. N-Alkynylamides (ynamides) are particularly useful substrates for the highly regioselective carbocupration reaction, as they lead to the stereodefined formation of vinylcopper species geminated to the amide moiety. The latter species are involved in numerous synthetically useful transformations leading to valuable building blocks in organic synthesis. Here we describe in full the results of our studies related to the carbometallation reactions of N-alkynylamides.

Full text of DOI:10.3762/bjoc.9.57

Regio- and stereoselective carbometallation
reactions of N-alkynylamides and sulfonamides
Yury Minko, Morgane Pasco, Helena Chechik and Ilan Marek*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 526–532.
The Mallat Family Organic Chemistry Laboratory, Schulich Faculty of
Chemistry, and the Lise Meitner-Minerva Center for Computational
Quantum Chemistry, Technion – Israel Institute of Technology, Haifa
32000, Israel
doi:10.3762/bjoc.9.57
Received: 14 January 2013
Accepted: 21 February 2013
Published: 13 March 2013
Email:
Ilan Marek* - chilanm@tx.technion.ac.il
This article is part of the Thematic Series "Carbometallation chemistry".
Associate Editor: C. Stephenson
* Corresponding author
Keywords:
© 2013 Minko et al; licensee Beilstein-Institut.
License and terms: see end of document.
carbometallation; enamides; organocopper; regiochemistry; ynamides
Abstract
The carbocupration reactions of heterosubstituted alkynes allow the regio- and stereoselective formation of vinyl organometallic
species. N-Alkynylamides (ynamides) are particularly useful substrates for the highly regioselective carbocupration reaction, as
they lead to the stereodefined formation of vinylcopper species geminated to the amide moiety. The latter species are involved in
numerous synthetically useful transformations leading to valuable building blocks in organic synthesis. Here we describe in full the
results of our studies related to the carbometallation reactions of N-alkynylamides.
Introduction
Due to a strong differentiation of electron density on the two substituted alkenes is the carbometallation reaction of alkynes
sp-hybridized carbon atoms, N-alkynylamides (ynamides) have [16-18], ynamide should be a suitable substrate for the regio-
become attractive substrates involved in many synthetically and stereoselective synthesis of enamide through carbometalla-
useful transformations [1-4]. The remarkable renaissance of tion reaction [19-22]. Although the stereoselectivity of the
N-substituted alkynes in synthesis is primarily due to the combi- carbocupration is usually controlled through a syn-addition of
nation of the easy and straightforward access to these com- the organocopper reagent on the triple bond [23], the regioselec-
pounds with their notable stability [5-7]. A rather large variety tivity is dependent on the nature of the α-substituent on the
of synthetic approaches have been therefore developed in the alkyne 1. The presence of a donor substituent (XR = OR, NR2,
last decade that allow ynamides to be of easy access to the Path B, Scheme 1) leads generally to the β-isomer in which the
whole synthetic community [8-14]. Similarly, enamides are copper atom adds to the carbon β of the heteroatom [16,17],
another important class of substrates involved in numerous whereas an acceptor substituent (XR = SR, SOR, SO2R, SiMe3,
applications in organic synthesis [5,15]. As one of the most PR2, P(O)R2, Path A, Scheme 1) would preferably give the
straightforward and well-developed methods to generate poly- α-isomer [16,17] (copper geminated to the heteroatom,
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Beilstein J. Org. Chem. 2013, 9, 526–532.
Scheme 1: Possible regioisomers obtained in the carbocupration reaction of α-heterosubstituted acetylenes 1.
Scheme 1). Although N-substituted alkynes are known to give
Table 1: Carbometallation reactions of the N-alkynylsulfonamide 2.
Entry Conditionsa R2 E–X Product Yield (%)b
the β-isomer, we thought that a precomplexation of the
organometallic species (i.e., copper) with a polar functional
group in the vicinity of the reactive center should be able to
reverse the regioselectivity of the carbometallation, as we have
shown for the carbocupration of ethynyl carbamate (XR =
OCONR2, Path C, Scheme 1) [24].
1
2
3
4
5
A
A
A
B
B
n-Bu H3O+
Me H3O+
3a
3b
3c
3a
3b
93
30
50
90
70
n-Bu AllylBr
n-Bu H3O+
Me
H3O+
aConditions A: 2.0 equiv of R2Cu (prepared from an equimolar amount
of R2MgBr and CuBr at −50 °C to rt in Et2O. Conditions B: 2.0 equiv of
R2MgBr with 10 mol % of CuBr·Me2S in Et2O from −30 °C to rt. bYields
of isolated product after flash column chromatography (based on 2).
Herein we describe our results for the regio- and stereoselective
carbometallation reaction of N-alkynylsulfonyl amides and
various N-alkynylcarbamates [25].
Results and Discussion
Carbocupration of sulfonyl-substituted
ynamides
lower. The presence of the vinylcopper was proved by the reac-
tion with allyl bromide as a classical electrophile used in
organocopper chemistry to give 3c (Table 1, entry 3). Although
N-heterosubstituted alkynes were used in all cases, the α-isomer
is regioselectively obtained, as confirmed by 1H NMR analysis
of the crude reaction mixture after hydrolysis, through an
intramolecular chelation between the N-sulfonamide moiety and
the organocopper species. To improve the chemical yield of this
transformation, we considered the copper-catalyzed carbomag-
nesiation reaction. However, such catalytic reaction requires a
transmetallation reaction of the intermediate vinylcopper into
vinylmagnesium halide, and due to the intramolecular chelation,
it is usually performed at higher temperature. Thus, a thermally
Our initial experiments were directed towards the carbometalla-
tion reaction of N-alkynylsulfonylamides, as the coordination of
the organometallic species by the sulfonyl group should control
the regioselectivity of the carbometallation reaction in favor of
the α-isomer. When 2 was added to an organocopper (easily
prepared by the addition of one equivalent of R2MgBr to one
equivalent of CuBr in Et2O at −50 °C), the carbometalated
products 3 were obtained in good isolated yields after hydroly-
sis (Scheme 2, conditions A and Table 1, entries 1–3). Some of
these results were published as a preliminary note in [25].
The reaction proceeds smoothly for classical primary alkyl- more stable organocopper species [formed from copper(I) bro-
copper species (Table 1, entry 1), but for groups that are known mide–dimethylsulfide complex (CuBr·Me2S)], was used for this
to be sluggish in carbocupration reaction, such as the introduc- copper-catalyzed carbomagnesiation reaction. We were pleased
tion of a Me group (Table 1, entry 2), yield is significantly to see that the reaction is very efficient for the addition of
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Beilstein J. Org. Chem. 2013, 9, 526–532.
Scheme 2: Regioselective carbometallation of N-alkynylsulfonamide 2.
BuMgBr, as 3a was obtained in 90% yield as a unique reaction could also be performed on N-alkynylcarbamate 4 with
α-isomer. More importantly, the copper-catalyzed methylmag- primary and secondary alkylcopper species (still obtained in
nesiation now proceeded in good yield to lead to the carbometa- diethyl ether from 1.0 equiv of a Grignard reagent and 1.0 equiv
lated product 3b in 70% yield after hydrolysis (Table 1, entry 5) of CuBr, conditions A) to give the corresponding vinylcopper
[25,26].
intermediate 5. Simple hydrolysis led to the enamide 6a,c in
good isolated yields after purification by column chromatog-
raphy (Scheme 3 and Table 2, entries 1 and 3). The vinylcopper
species could also be successfully trapped at low temperature
with allylbromide to give the functionalized adduct 6b
(Scheme 3, Table 2, entry 2) [25]. The addition of the Me and
Ph groups proceeds more easily on the N-alkynylamide 4 than
N-alkynylsulfonamide 2 as yields could reach 68 and 84%, res-
Carbocupration reaction of acyclic N-alkynyl-
carbamates
As the carbocupration of an N-alkynylsulfonamide could be
easily achieved, we were interested to see whether such a
carbocupration reaction could be extended to ynamide 4 bearing
an acyclic carbamate moiety. We were pleased to find that this
Scheme 3: Regioselective carbometallation of ynamide 4.
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Beilstein J. Org. Chem. 2013, 9, 526–532.
Table 2: Carbometallation reactions of alkynylcarbamates 4.
Entry
Conditionsa
R1
R2
E–X
Product
Yield (%)b
1
2
A
A
Et
Me
Me
Et
n-Bu
n-Bu
c-C6H11
Me
H3O+
Allyl–Br
H3O+
H3O+
H3O+
H3O+
H3O+
H3O+
H3O+
H3O+
6a
6b
6c
6d
6e
6a
6a
6d
6e
6c
72
55
50
68
84
94
81
60
90
81
3
A
4
Ac
Ac
Ac
B
5
Et
Ph
6
Et
n-Bu
n-Bu
Me
7
Et
8
B
Me
Et
9
B
Ph
10
B
Me
c-C6H11
aConditions A: 2.0 equiv of R2Cu (prepared from equimolar amount of R2MgBr and CuBr at −50 °C to rt in Et2O. Conditions B: 2.0 equiv R2MgBr with
10 mol % of CuI in Et2O from −30 °C to rt. bYields of isolated product after flash column chromatography (based on 4). cCuBr·Me2S complex was
used as a copper source.
pectively (Table 2, entries 8 and 9). Yield could be further im- transformation requires higher temperature, yields are usually
proved when CuBr·Me2S was used as the copper source better than in reactions with the preformed organocopper
(Table 2, compare entries 1 and 6) [25]. In all cases, the species (Table 2, entries 7–10) [25].
expected α-isomer of 6 was exclusively formed and the regio-
Carbocupration of cyclic N-alkynylcarbamate
chemistry was determined by NOE (nuclear Overhauser effect)
between the methyl substituent and the corresponding vinylic (chiral oxazolidinone moiety)
proton (E = H, Table 2, entry 4). However, such selectivity can Recently, our group was particularly interested in the carbomet-
only be achieved in nonpolar solvent, such as Et2O, since the allation reaction of ynamides bearing chiral cyclic carbamates 7,
same reaction performed in THF leads mainly to the formation particularly the Evans's oxazolidinone [27], as vinylmetal
of the β-isomer in a α/β ratio of 18:82.
species could subsequently react with a large variety of elec-
trophiles leading to diastereomerically enriched functionalized
When N-alkynylamide 4 was treated under our copper- adducts [28-30]. Thus, the carbometallation reaction of
catalyzed carbomagnesiation conditions (conditions B), enam- N-alkynylamide 7 was performed with several organometallic
ides 6 were similarly obtained as a pure α-isomer. Although this species as described in Scheme 4 and Table 3.
Scheme 4: Regioselective carbometallation of cyclic N-alkynylcarbamate 7.
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Beilstein J. Org. Chem. 2013, 9, 526–532.
Table 3: Carbometallation reactions of cyclic N-alkynylcarbamates 7 (Scheme 4).
Entry
Conditionsa
R1
R2
M
CuX
α/β
Product
Yield (%)b
1
2
A
B
B
B
B
C
B
B
B
B
B
Hex (7a)
Bu (7b)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
MgBr
Li
CuI
CuI
>95:5
>95:5
>95:5
90:10
9a
9b
9b
9b
9b
9b
9c
9d
9e
9f
75
59
69
80
80
86
51
90
50
71
60
3
Bu (7b)
Li
CuBr
CuCN
4
Bu (7b)
Li
5
Bu (7b)
Li
CuBr·Me2S >95:5
CuI >95:5
6
Bu (7b)
MgBr
Li
7
(iPr)3SiO(CH2)2 (7c)
Ad1CO2(CH2)3 (7d)
Ph (7e)
CuBr·Me2S >95:5
CuBr·Me2S 80:20
CuBr·Me2S 90:10
CuBr·Me2S >95:5
CuBr·Me2S >95:5
8
Li
9
Li
10
11
p-FC6H4 (7f)
p-MeOC6H4 (7g)
Li
Li
9g
aConditions A: 2.0 equiv of R2Cu (prepared from an equimolar amount of R2MgBr and CuBr at −50 °C to rt in Et2O. Conditions B: 2.4 equiv MeLi, 1.2
equiv CuX, Et2O, −30 to −20 °C, 2 h. Conditions C: 1.2 equiv MeMgBr with 10 mol % of CuI in Et2O from −20 to 0 °C. bYields of isolated product after
flash column chromatography (based on 7).
Our initial attempt was performed with organocopper species (ca. 20 vol %) as a co-solvent used to dissolve the starting
prepared from alkylmagnesium halide and CuBr (1:1 ratio) and ynamide 7d. When the reaction was performed with aryl-substi-
ynamide 7a (R1 = Hex), which cleanly led to the enamide 9a in tuted ynamides (7e–g), THF had to be added as a co-solvent to
very good isolated yield for the addition of MeCu, and with improve the solubility of the starting materials as well, which
excellent regioselectivities (α/β > 95:5, Table 3, entry 1). For may affect the resulting selectivity. Indeed, in the case of
subsequent reaction of 8Cu, we were also interested in evalu- phenylsubstituted ynamine 7e, a 1:1 mixture of Et2O and THF
ating the regioselectivity of the carbometallation reaction of an was used to avoid precipitation of the starting material, which
organocuprate, and we were pleased to see that the same led to a 9:1 ratio in favor of the α-isomer (Table 3, entry 9).
α-regioisomer was obtained. However, yields are lower with However, for substrates bearing p-fluoro and p-methoxyphenyl
CuI and CuBr (Table 3, entries 2 and 3) than that with a more substituents (7f and 7g respectively), only around 8 vol % of
soluble complex CuBr·Me2S (Table 3, entry 5). However, when THF was necessary to add to the reaction mixture to obtain a
CuCN was employed, only an α/β ratio of 9:1 was obtained, homogeneous solution. In such circumstances, the α-adduct was
probably due to the decreased chelating effect of the resulting detected as the sole product of the carbocupration (Table 1,
mixed organometallic species (Table 3, entry 4). When the entries 10 and 11) as confirmed by NMR spectroscopy and
copper-catalyzed carbomagnesiation reaction was performed X-ray crystallographic analysis of the major isomer of 9f
(Table 3, entry 6), results were very similar to those from the (Figure 1).
addition of copper or cuprate reagents (Table 3, entries 1 and 5,
respectively).
Thus, the best compromise we found for the regioselective addi-
tion of a methyl group on ynamides 7a and 7b was through the
addition of a cuprate Me2CuLi·Me2S prepared from the addi-
tion of methyllithium (2 equiv) to Me2S·CuBr (1 equiv). These
experimental conditions were used for the stereo- and regiose-
lective carbocupration of several functionalized ynamides 7c–g.
With a TIPS-protected alcohol 7c (Table 3, entry 7), the
carbocupration gave only the α-regioisomer, albeit in moderate
yield. On the other hand, in the presence of the
1-adamantylester substituted substrate 7d, the two α/β-isomers
were formed in a 8:2 ratio (Table 3, entry 8). This loss of selec-
Figure 1: Molecular structure of 9f (hydrogen atoms except of H9 and
H10 are omitted for clarity).
tivity may be explained either by a competitive chelation of the
carbonyl group of the ester functionality or the presence of THF
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Beilstein J. Org. Chem. 2013, 9, 526–532.
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Acknowledgements
This research was supported by the Israel Science Foundation
administrated by the Israel Academy of Sciences and Humani-
ties (140/12) and by the Fund for promotion of Research at the
Technion. IM is holder of the Sir Michael and Lady Sobell
Academic Chair.
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