Arylsulfonylacetylenes as alkynylating reagents

Article abstract of DOI:10.1080/10426507.2012.748054

The unexpected anti-Michael addition of RLi to β-substituted sulfonylacetylenes, followed by in situ elimination of the ion sulfinate, allows the alkynylation of C(sp²) and C(sp³). Aryl and heteroaryl acetylenes, enynes, and mono and dialkyl alkynes can be obtained in very high yields under very mild conditions, avoiding the use of transition metals as catalysts and, in many cases, haloderivatives as starting materials. Furthermore, the use of lithium 2-p-tolylsulfinyl benzylcarbanions as nucleophiles of these reactions allows their stereocontrolled alkynylation, affording enantiomerically pure alkynes or enantioenriched allenes depending on the protonating agent (NH4Cl or H2O).

Full text of DOI:10.1080/10426507.2012.748054

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Phosphorus, Sulfur, and Silicon and the Related
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Arylsulfonylacetylenes as Alkynylating Reagents
Leyre Marzo a , José Alemán a & José Luis García Ruano a
a Departamento de Química Orgánica (Módulo 1), Universidad Autónoma de Madrid,
Cantoblanco, 28049, Madrid, Spain
Accepted author version posted online: 14 Nov 2012.
To cite this article: Leyre Marzo, José Alemán & José Luis García Ruano (2012): Arylsulfonylacetylenes as Alkynylating
Reagents, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:10.1080/10426507.2012.748054
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ARYLSULFONYLACETYLENES AS ALKYNYLATING REAGENTS
Leyre Marzo, José Alemán,* José Luis García Ruano*
Departamento de Química Orgánica (Módulo 1), Universidad Autónoma de Madrid,
Cantoblanco, 28049-Madrid, Spain
joseluis.garcia.ruano@uam.es, jose.aleman@uam.es
Abstract: The unexpected “anti-Michael” addition of RLi to -substituted sulfonylacetylenes,
followed by in situ elimination of the ion sulfinate, allows the alkynylation of C(sp2) and C(sp3).
Aryl and heteroaryl acetylenes, enynes, and mono and dialkyl alkynes can be obtained in very
high yields under very mild conditions, avoiding the use of transition metals as catalysts and, in
many cases, haloderivatives as starting materials. Furthermore, the use of lithium 2-p-
tolylsulfinyl benzylcarbanions as nucleophiles of these reactions allows their stereocontrolled
alkynylation, affording enantiomerically pure alkynes or enantioenriched allenes depending on
the protonating agent (NH4Cl or H2O).
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Keyworks: Alkynylation, C(sp2)-C(sp) and C(sp3)-C(sp) bonds, organolithiums,
sulfonylacetylenes, “anti-Michael” reactions
INTRODUCTION
With the aim of obtaining enantiomerically enriched benzyl-alkenyl centers, we studied
the reactions of the ortho-sulfinyl benzylcarbanions 1 with sulfonyl acetylenes 2. To our
surprise, instead of the expected Michael addition alkene 3 (left, Scheme 1), the alkynylation
product 4 at the benzylic position was obtained, presumably resulting by desulfonylation of the
“anti-Michael” addition intermediate. This result prompted us to investigate the ability of the
sulfonylacetylenes as alkynylating reagents of organyllithiums.
RESULTS
First we studied the alkynylation methods of sp3 carbons, because of the no existence of
general methods for the direct preparation of acetylenes joined to secondary and tertiary alkyl
groups.[1] Results obtained in the reactions of organolithiums derived from sp3 carbons (5) with
different sulfonylacetylenes (2), affording alkynes (6) are collected in Table 1.[2] Aryl alkyl
alkynes, TIPS derivatives (precursors off terminal alkyl alkynes) and any kind of 1,2-dialkyl
alkynes can be obtained in high yields regardless the primary, secondary o tertiary character of
the alkyl residues.
We next investigated the alkynylation of sp2 carbons, usually prepared by using Sonogashira
cross-coupling reaction,[3] and less frequently inverse-Sonogashira,[4] and gold-catalyzed Friedel-
Crafts type reactions.[5] All of them requires the presence of a transition metals generating a
large amount of waste, seriously limiting their use by the industry. As Li scarcely generates
2
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waste, we were interested in evaluating the potential usefulness of the reaction of aryllithiums
with sulfonylacetylenes as a general method for creating the C(sp2)-C(sp). Results are indicated
in Table 2.[2]
Starting from arylsulfonylacetylenes and alkylsulfonylacetylenes lacking of propargylic
protons, diarylalkynes are obtained in high yields under mild conditions. When acidic protons
are present, their abstraction is competitive resulting in complex mixtures. The TIPS derivative
also produces the precursors of the terminal arylacetylenes in high yields. Changes in the
electronic density of the reagents scarcely affect the reactivity or the yield of these reactions,
which usually are completed in 5 minutes at -78 ºC. Similar results were obtained in the
alkynylation of the 2-bromopyridine which allowed us to conclude that the method is efficient
for preparing any kind of aryl and heteroarylacetylenes starting from the corresponding halo
derivative.
Our method could be also applied to the synthesis of enynes[2] which are easily obtained from
alkenyllithiums under the standard conditions maintaining the configuration of the double bond
(Scheme 2).
Reactions of the organolithiums resulting in the ortho-litiation processes were interesting
because they did not require the use of haloderivatives as starting materials. Alkynylation of
anisol and other ortho directing groups, such as diethylcarbamate and N,N-diisopropyl
carboxamide gave good results with different sulfonylated arylacetylenes,[6] regardless the
electronic density of the aryl ring (Scheme 3).
Interestingly, the alkynylation process is sensitive to electronic and steric factors, which
allows controlling their regioselectivity. Thus, 1,3-dimethoxybenzene mainly yielded the 2-
3
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alkynyl derivative (position doubly activated by the two methoxy groups) and the 2-
methoxynaphthalene almost exclusively afforded the 3-alkynyl derivative due to the steric
hindrance of the hydrogen at C-8.[6]
Furan, thiophene and N-methylpyrrole were efficiently alkynylated in -position (Scheme 4).
Interestingly, N-methylindole is alkynylated at C-2, whereas the regioselectivity changes starting
from the bulkier TIPS derivative, which is alkynylated at C-3 (Scheme 4).[6] Finally,
benzothiazole also react under very mild conditions (Scheme 4).
The unexpected electrophilic behavior of substituted sulfonylacetylenes was explained by
theoretical calculations,[5,6] which suggests the formation of a complex with the lithium
associated to one of the sulfonyl oxygens, which can evolve by attacking to the  and -
positions, with the first one being more favorable by around 4.4 Kcal/mol, thus explaining the
complete selectivity observed in these reactions.
Finally, reactions of the sulfinylated benzylcarbanions with different sulfonylated
arylacetylenes followed by protonation with NH4Cl are completely stereoselective (Scheme 5),
affording enantiomerically pure benzylacetylenes (4)[7]. When the protonation was performed
with H2O at -98 ºC, allenes (7) are exclusively obtained in high diastereomeric excess (Scheme
5). Resulting acetylenes and allenes were desulfinylated with t-BuLi, without affecting the
enantiomeric purity.[7] The change in the reaction course depending on the protonating agent
could be rationalized by theoretical calculation and deuteration studies.
4
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Acknowledgements: Financial support from Spanish Government (CTQ-2009-12168) and CAM
(“programa AVANCAT CS2009/PPQ-1634”) is gratefully acknowledged. J. A. thanks the
MICINN for “Ramon y Cajal” contract, and L. M. thanks the Ministerio de Educación y Ciencia
for a predoctoral fellowship.
References:
[1] (a) Dehmlow, E. V.; Fastabend, U. Gazzetta Chimica Italiana 1996, 126, 53-55. (b) Dotz, K.
H.; Gerhardt, A. J. Organomet. Chem. 1999, 578, 223–228. (c) Hayashi, N.; Noguchi, H.;
Tsuboi, S. Tetrahedron 2000, 56, 7123-7137. d) Uck, M.; Chong, J. M. Tetrahedron Lett. 2001,
42, 5825-7137.
[2] García Ruano, J. L.; Alemán, J.; Marzo, L.; Alvarado, C.; Tortosa, M.; Díaz-Tendero, S.;
Fraile, S. Chem. Eur. J. 2012, 18, 8245-8422.
[3] For recent reviews, see: a) Chichilla, R.; Nájera, C. Chem. Rev. 2007, 107, 874-922. b)
Heravi, M. M.; Sadjavi, S. Tetrahedron 2009, 65, 7761-7775. c) Doucet, H.; Hierso, J. –C.
Angew. Chem. Int. Ed. 2007, 46, 834-871.
[4] For a highlight article, see: a) Dudnik, A. S.; Gevorgyan, V. Angew. Chem. Int. Ed. 2010, 49,
2096-2098; b) For a pioneering work, see: Kobayashi, K.; Arisawa, M.; Yamaguchi, M. J. Am.
Chem. Soc. 2002, 124, 8528-8529.
[5] See e.g.; a) Haro, T.; Nevado, C. J. Am. Chem. Soc. 2010, 132, 1512-1513. b) Brand, J. P.;
Waser, J. Angew. Chem. Int. Ed. 2010, 49, 7304-7307.
[6] García Ruano, J. L.; Alemán, J.; Marzo, L.; Alvarado, C.; Tortosa, M.; Díaz-Tendero, S.;
Fraile, S. Angew. Chem. Int. Ed. 2012, 51, 2712-2716.
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[7] Garcia Ruano, J. L.; Marzo, L.; Marcos, V.; Alvarado, C.; Aleman, J. Chem. Eur. J. 2012, 18,
9775-9779.
O
SO2Ph
R2
S
:
R2
LDA, THF
-78ºC
LDA, THF
-78ºC
Tol
+
SO2Ph
R2
TolOS
R1
R1
TolOS
R1
3
1
2
4
Scheme 1
n-Hex
Li
Li
5I
5K
n-Hex
Ph
SO2Tol
THF, -78 ºC
THF, -78 ºC
Ph
2a
Ph
6aK (40%)
6aI (97%)
Scheme 2
Y
Ph
Y
n-BuLi, -78ºC
5 min, then 2a
Y = OMe, OCONMe2, CONiPr2
(>81-96% yield)
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Scheme 3
S
n-BuLi, -78ºC
2a
S
N
n-BuLi, -78ºC
2a
Ph
5 min, then
X
X
N
A
5 min, then
Ph
X = O, S, NMe
(70-90%)
(64%)
Ph
n-BuLi, -78ºC
2a
n-BuLi, -78ºC
2a
5 min, then
N
5 min, then
N
N
N
TIPS
Me
Ph
Me
H
(80%)
(32%)
Scheme 4
O
S
O
S
SOTol
LDA, -78 ºC
20-30 min
SO2Ar
LDA, -78 ºC
20-30 min
Tol
H
Tol R´
+
•
then H2O
-98 ºC
then NH4Cl
-78 ºC
R´
R
R´
R
H
R
7
(dr up to 98:2)
2
4
(dr>98:2)
1
Scheme 5
Table 1. Synthesis of alkylacetylenes derivatives 8.
THF,-78 ºC
SO2Tol +
R1
R2-Li
R2
R1
5 min
5A-D
6
2a-e
Entr Sulfone Reagent
y
Product
Entr Sulfone Reagent
y
Reagent
(R1)
(R2)
(%)[b]
(R1)
(R2)
(R2)
1
2a (Ph)
5A (n-
6aA (68)
9
2c (t-
5A (n-
6cA (>99)[c]
7
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Bu)
Bu)
Bu)
2
3
4
6aB (91)
6aC (85)
6aD(83)
10
11
12
6dA (90)
6dC (90)
6dD (92)
5B (Me)
5A (n-
Bu)
2d
(Chx)
5C (s-
Bu)
5C (s-
Bu)
5D (t-
Bu)
5D (t-Bu)
5
6
7
8
2b(TIP
5A (n-
Bu)
6bA (90)
6bC (91)
6bD (96)
13
14
15
2e (n-
Bu)
5A (n-
Bu)
6eA (60)
S)
6eC (38)
5C (s-
Bu)
5C (s-
Bu)
-[d]
8cD(>99)[
5D (t-
Bu)
5D (t-Bu)
c]
4c (t-
Bu)
7D (t-
Bu)
[a] All the reactions were performed with 0.2 mmol of 2a-e and 0.4 mmol of 5A-D. [b]% Isolated
yield after flash chromatography. [c] Conversion measured by 1H-NMR. [d] Only the Michael
product could be identified (20% yield) in the complex mixture.
Table 2. Formation of Csp2-Csp bonds by reaction of aryl or alkenyllithiums with 2-substituted p-
tolylsulfonylacetylenes.[a]
THF,-78 ºC
R1
2a-h
R2-Li
R2
R1
SO2Tol
+
5 min
5E-H
6
Entry
Sulfone (R1)
2b (TIPS)
Reagent (R2)
5E (Ph)
5E (Ph)
5E (Ph)
5E (Ph)
5E (Ph)
5E (Ph)
5E (Ph)
Product (%)[b]
6bE (80)
6cE (81)
6eE (-[c])
6aE (98)
6fE (99)
1
2
3
4
5
6
7
2c (t-Bu)
2e (n-Bu)
2a (Ph)
2f (p-Tol)
2g (p-CF3-C6H4)
2h [3,5-di(p-CF3)-C6H4]
6gE (99)
6hE (89)
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8
2f (p-Tol)
2a (Ph)
5F (p-MeO-C6H4)
5F (p-MeO-C6H4)
5F (p-MeO-C6H4)
5G (p-CF3- C6H4)
5H (2-Py)
6fF (60)
6aF (78)
6hF (88)
6hG (81)
6aH (95)
6bH (90)
9
10
11
12
13
2h [3,5-di(p-CF3)-C6H3]
2h [3,5-di(p-CF3)-C6H3]
2a (Ph)
2b (TIPS)
5H (2-Py)
[a] All the reactions were performed with 0.2 mmol of 2a-h and 0.4 mmol of 5E-H. [b] % Isolated
yield after flash chromatography. [c] Complex mixture.
9
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