Trans-Selective Radical Silylzincation of Ynamides

Article abstract of DOI:10.1002/anie.201407002

The silylzincation of terminal ynamides is achieved through a radical-chain process involving (Me₃Si)₃SiH and R₂Zn. A potentially competing polar mechanism is excluded on the basis of diagnostic control experiments. The un

Full text of DOI:10.1002/anie.201407002

Angewandte
Chemie
DOI: 10.1002/anie.201407002
Radical Chemistry
Trans-Selective Radical Silylzincation of Ynamides**
Elise Romain, Carolin Fopp, Fabrice Chemla, Franck Ferreira, Olivier Jackowski,
Martin Oestreich,* and Alejandro Perez-Luna*
Abstract: The silylzincation of terminal ynamides is achieved
through a radical-chain process involving (Me3Si)3SiH and
R2Zn. A potentially competing polar mechanism is excluded
on the basis of diagnostic control experiments. The unique
ꢀ
feature of this addition across the C C bond is its trans
ꢁ
selectivity. One-pot electrophilic substitution of the Csp2 Zn
I
ꢁ
bond by Cu -mediated C C bond formation and subsequent
manipulation of the Csp2 Si bond provides a modular access to
ꢁ
Z-a,b-disubstituted enamides.
ꢁ
ꢀ
T
he addition of Si Met bonds across C C bonds is an area of
intense ongoing research as it offers the possibility to prepare
=
in a single operation 1,2-difunctionalized C C bonds, i.e., b-
Scheme 1. Diastereocontrolled silylmetalation of terminal ynamides.
metalated vinylic silanes, ideally suited for the subsequent
introduction of two different substituents.[1,2] However, the
success of this approach is dependent on the regio- and
stereoselectivity of the addition reaction. Popular procedures
to perform the silylmetalation of alkynes are the direct
silylcupration[3] and silylzincation[4] as well as the CuI-
catalyzed silylmagnesiation[5] and silylzincation.[6,7] The use
of silylstannanes or silylboronic esters for this purpose is also
well established.[1] The classic silylmetalation pathway is
entered by transmetalation, whereas oxidative addition
chemistry allows for silylstannylation and silylboration reac-
tions. The above-cited methods offer a range of options to
control the sense of regiochemistry. By contrast, tuning of
stereochemistry is rarely feasible, because these are usually
syn-addition processes and, hence, provide access to cis-
silylmetalated alkenes.[8,9] Thus, finding a method to achieve
the silylmetalation of alkynes in a trans-stereoselective
manner is highly relevant. The demonstration that the trans
carbozincation[10,11] of alkynes can be achieved by a radical
mechanism led us to consider a radical-based silylzincation
approach to address this issue.
Here we focus on ynamides, because the functionalization
of these nitrogen-substituted alkynes through addition reac-
ꢀ
tions across their C C bond is currently attracting atten-
tion.[12] A number of protocols was developed for the
silylmetalation of ynamides (Scheme 1). Silylcupration[13]
and the Pd0-catalyzed silylstannylation[14] afford a-metalated
Z-b-silylenamides. Conversely, the Pd0-catalyzed silylbora-
tion reaction gives b-metalated Z-a-silylenamides.[15] To date,
the available synthetic tools only offer the possibility to
determine the site selectivity invariably leading to Z-meta-
lated silylenamides. Here we describe the regio- and stereo-
selective preparation of a-metalated E-b-silylenamides
through the silylzincation of ynamides by reaction with
a combination of a hydrosilane and a dialkylzinc reagent.
This system leads to an unprecedented trans stereoselectivity
and represents the first example of a radical-based silylme-
talation reaction.[16] As part of this work, we demonstrate the
synthetic potential of this stereodefined construction of
orthogonally metalated enamides.
Our idea, outlined in Scheme 2 (top), was inspired by
a report on the formation of silyl radicals by the reaction of
various silyl-substituted hydrosilanes with dialkylzinc
reagents in the presence of radical initiators.[17] We reasoned
that radical II, produced in such a way from (Me3Si)3SiH (I!
II),[18] would add across ynamide III to provide regioselec-
tively Z-configured a-amino vinylic radical IV (II!IV).[19]
Reaction of IV with the dialkylzinc by homolytic substitution
(SH2) at the Zn atom would afford a-zincated b-silylenamides
V concomitant with the formation of an alkyl radical that
would propagate a radical chain (IV!I). According to this
picture, the stereoselectivity of the process would be that of
the zincation step. By deliberate installation of a donor group
at the ynamide nitrogen atom (Figure 1), we hoped to activate
the dialkylzinc reagent toward SH2 by Lewis pair formation,
thereby outcompeting the Z-to-E isomerization of the vinylic
[*] E. Romain, Prof. Dr. F. Chemla, Dr. F. Ferreira, Dr. O. Jackowski,
Dr. A. Perez-Luna
Sorbonne Universitꢀs
UPMC Univ Paris 06, CNRS, UMR 8232, IPCM, CC 183
4, place Jussieu, 75005 Paris (France)
E-mail: alejandro.perez_luna@upmc.fr
C. Fopp, Prof. Dr. M. Oestreich
Institut fꢁr Chemie, Technische Universitꢂt Berlin
Strasse des 17. Juni 115, 10623 Berlin (Germany)
E-mail: martin.oestreich@tu-berlin.de
[**] This research was supported by the Agence Nationale de la
Recherche (SATRAZ Project, grant n8 2011-INTB-1015-01) and by
the Deutsche Forschungsgemeinschaft (Oe 249/7-1). X-ray crystal-
lography was performed by Lise-Marie Chamoreau and Geoffrey
Gontard (UPMC).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407002.
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closure (VII!VIII, left), whereas the alternative polar
addition would form a fragile b-alkoxy anion prone to rapid
b-elimination (VII!X, right). Subjecting VII to the later
established procedure yielded cyclized [2H]-VIII and [2H]-IX
exclusively (as a result of competing ethyl radical addition).
Conversely, (Me2PhSi)2Zn that is unlikely to form radicals led
to quantitative fragmentation (VII!X); X reacted with the
remaining zinc reagent furnishing XI.[21] In agreement with
the requirement for a silyl group at the silicon atom,[17,18]
treatment of III with Me2PhSiH and Et2Zn was not effective.
These findings strongly support the proposed mechanism
(Scheme 2, top).
Ynamide 1 was selected as test substrate (Table 1). The
initial conditions, involving Et2Zn (3.0 equiv) and
(Me3Si)3SiH (1.3 equiv) at 08C in CH2Cl2, led to substrate
Table 1: Optimization of the silylzincation of ynamide 1.
Entry Conditions
E
Product[a] Yield [%][b] d.r. (Z:E)[c]
1
2
3
4
Et2Zn, CH2Cl2, 08C
H
H
D
D
6
6
6[d]
–
Et2Zn, n-hexane, 08C
Et2Zn, n-hexane, 08C
Et2Zn,[g] n-hexane,
08C
97
>98:2
[2H]-6
[2H]-6
95[e]
98[e]
>98(79%[f]):2
>98(78%[f]):2
5
6
(cHex)2Zn,
D
H
[2H]-6
95[e]
77
>98(86%[f]):2
n-hexane/Et2O, 08C
Me2Zn, n-hexane,
08C
6
37:63
Scheme 2. Anticipated radical approach to the trans-selective silylzinca-
tion of ynamides (top) and verification of the radical mechanism
(bottom).
[a] Only b-silylated regioisomers were detected (b:a>98:2). [b] Com-
bined yield of isolated diastereomers. [c] Determined by 1H NMR
analysis prior to purification. [d] 33% of starting material recovered.
[e] Yield determined by 1H NMR spectroscopy using butadiene sulfone
as internal standard. [f] Deuteration grade estimated by NMR analysis.
[g] 5.0 equiv Et2Zn were used.
degradation, and the desired b-silylenamide 6 was isolated in
6% yield at 67% conversion (entry 1). A significant improve-
ment was obtained in n-hexane, and Z-6 was formed in 97%
yield as a single regio- and diastereoisomer (entry 2). We
Figure 1. Ynamides considered in this work.
radical IV.[10a] That would secure the trans stereoselectivity of
the overall process. A key requirement is that radical IV must
undergo Zn-atom transfer faster than competitive H-atom
transfer from (Me3Si)3SiH (kIV!V > kIV!VI). If not, hydro-
silylation[20] of III will occur (III!VI) and the Zn function-
ality is lost.
As previously demonstrated by Apeloig and co-workers,
the combination of a dialkylzinc reagent, for example, Et2Zn,
and a silyl-substituted hydrosilane such as (Me3Si)3SiH indeed
yields [(Me3Si)3Si]2Zn in the absence of a deliberately added
radical initiator.[17] Hence, its polar addition across triple
bonds had to be excluded. To distinguish between radical and
polar pathways, we employed VII as a mechanistic probe
(Scheme 2, bottom). Radical 1,4-addition would proceed
through a b-alkoxy radical followed by a 5-exo-dig ring
emphasize here that the Z double bond geometry of 6 (3Jcis
=
11.2 Hz) is opposite to that of the product of the polar
addition of (Me2PhSi)2Zn across 1 (3Jtrans = 17.9 Hz, not
shown), lending clear evidence for the radical mechanism.
To discriminate between the two possible reaction pathways
leading to Z-6, that is, silylzincation (IV!V) versus hydro-
silylation (IV!VI), the reaction was quenched with ND4Cl.
[2H]-6 was recovered with 79% deuterium incorporation at
the a-position (entry 3), thereby providing strong evidence
for zinc intermediate V. We attribute the strong solvent effect
to a more favorable complexation of Et2Zn to the carbonyl
group of the oxazolidinone. The formation of such a complex
would provide a more efficient radical chain by activating the
starting ynamide toward silyl radical addition and at the same
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time by facilitating the SH2 step. Whereas an increase of the
amount of Et2Zn did not make any difference (entry 4), the
ease of the dialkylzinc reagent to undergo Zn-atom transfer
was important. With (cHex)2Zn, a secondary dialkylzinc
reagent, more susceptible toward SH2 than Et2Zn, Z-6 was
obtained as a single isomer with a slightly improved level of
zincation (entry 5). In turn, the use of Me2Zn gave enamide 6
as a mixture of double bond isomers (entry 6), consistent with
a more difficult SH2 step that is not fast enough to occur prior
to Z-to-E isomerization of IV. Finally, it is worthy of mention
that in every case, the initiation of the silylzincation process
by oxidation of the dialkylzinc reagent by traces of oxygen
present in the reaction media is sufficient to achieve full
conversion, and the introduction of additional air or radical
initiators is not required. This indicates that the radical chain
involved in the process is remarkably efficient.
We next considered the scope of this new silylzincation
reaction. Ynamides substituted at the alkyne terminus by
a phenyl or an alkyl group failed to react. Conversely, the
modification of the nitrogen group was well tolerated
(Table 2). Ynamides 2–4 reacted smoothly in the presence
Table 2: Reaction scope for the silylzincation of ynamides.
Entry Substrate
E
Product[a] Yield [%] d.r. (Z:E)[b] [2H] [%][c]
Scheme 3. CuI-mediated electrophilic trapping of vinylic zinc intermedi-
ate V. [a] Partial isomerization observed on silica gel. [b] 14% of the E
isomer isolated. [c] Contaminated with approx. 5% of the E isomer.
Si=Si(SiMe3)3.
1
2
3
4
5
6
7
2
2
3
3
4
4
5
H
D
H
D
H
D
H
Z-7
87
>98:2
>98:2
97:3
–
85
–
75
–
88
–
Z-[2H]-7
Z-8
85[d]
93[d,f]
72[d]
83[d,g]
64[d]
62
Z-[2H]-8
Z-9
95:5
87:13
78:22
96:4
Z-[2H]-9
Z-10
readily reacted with various electrophiles to afford the
corresponding a-substituted b-silylenamides (Scheme 3).[22]
Methyl-substituted Z-11 was obtained by electrophilic trap-
ping with MeI. Primary and secondary allylic halides as well
as propargyl bromide were particularly well-suited and
proved to be useful to introduce an array of alkene
functionalities (Z-12–Z-20, Scheme 3). Full regiocontrol was
observed for the allylic and propargylic displacements leading
to Z-15, Z-16, and Z-19, this being indicative of SN’-selective
processes. Finally, a-carbonylated b-silylenamides Z-21–Z-25
were prepared by reaction with aromatic, vinylic, or aliphatic
acyl chlorides. The Z configuration of Z-13 was established by
X-ray crystallographic analysis[23] (see the Supporting Infor-
mation).
Finally, the (Me3Si)3Si group was used as a linchpin for the
installation of carbon substituents in the b position of selected
enamides by means of a two-step bromodesilylation/Pd0-
catalyzed cross-coupling sequence (Scheme 4).[24] Reaction of
Z-21 with Br2 in CH2Cl2 afforded Z-26 in 97% yield with
almost complete retention of the double bond geometry.
Conversely, NBS emerged as a better alternative to achieve
the transformation of Z-24 to Z-28 because the competitive
allylic bromination was avoided. Full retention of configu-
ration was observed. Moreover, the reaction of Br2 with b-
[a] Only b-silylated regioisomers were detected (b:a>98:2). [b] Deter-
mined by 1H NMR analysis prior to purification. [c] Deuteration grade
estimated by 1H NMR spectroscopy. [d] Determined by 1H NMR spec-
troscopy using butadiene sulfone as internal standard. [e] 37% of Z-8
and 56% of E-8 were isolated after silica gel chromatography. [f] 26% of
Z-9 and 57% of E-9 were isolated after silica gel chromatography.
of (Me3Si)3SiH and Et2Zn to provide the corresponding
enamides Z-7, Z-8, and Z-9 in good to excellent yields and
stereoselectivity after aqueous quench (entries 1, 3, and 5).
Formation of V rather than VI was again established by
deuterium labeling (entries 2, 4, and 6). The silylzincation
reaction was also well-suited for acyclic ynamides such as 5
(entry 7); the regio- and stereoselective formation of Z-10
was observed in 62% yield. It must be noted that, as a general
trend, the sensitivity of the Z-b-silylenamides toward acid
made them prone to Z-to-E isomerization. For Z-8 and Z-9,
significant isomerization during purification by chromatog-
raphy on silica gel could not be avoided and led to a decrease
in the isolated yields of the stereochemically pure adducts.
Our next efforts were then devoted to assess the value of
ꢁ
zinc intermediates V as nucleophiles in C C bond-forming
reactions. In the presence of CuCN·2LiCl, these reagents
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Keywords: copper · radical reactions · silicon · silylmetalation ·
.
zinc
[1] For an authoritative review of vinylic silanes, see: D. S. W. Lim,
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ꢁ
Scheme 4. The Csp2 Si bond as a linchpin for the elaboration of the b
position of selected a-substituted Z-b-silylenamides. NBS=N-bromo-
succinimide.
silylenamide Z-11 allowed combining bromodesilylation and
allylic bromination to afford dibromide E-30 in 74% yield. Its
E-configuration was confirmed by X-ray crystallographic
analysis.[23,25] The prepared b-bromoenamides participated
readily in Suzuki–Miyaura-type cross couplings. Reaction of
Z-26 with 4-anisylboronic acid afforded a-carbonyl b-sub-
stituted enamide Z-27[23,26] in 73% isolated yield in spite of
a partial isomerization during the coupling reaction. Z-29 was
prepared similarly from Z-28 and phenylboronic acid in 50%
yield, and no isomerization was observed. Additionally, the
potential of dibrominated E-30 as a template for stereoselec-
tive enamide synthesis by means of sequential intermolecular
cross-coupling reactions was demonstrated.[27] We combined
an allylic alkylation reaction and a Sonogashira cross-
coupling reaction in a one-pot sequence to obtain E-31 in
59% yield.
[8] Stereoselective access to E-2-borylated vinylic silanes by Z-to-E
isomerization was reported in one case: T. Ohmura, K. Oshima,
M. Suginome, Chem. Commun. 2008, 1416 – 1418.
[9] CuI-catalyzed conjugate addition of silicon nucleophiles released
ꢁ
from a Si B interelement compound to ynoates affords alle-
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Vercruysse, L. Cornelissen, F. Nahra, L. Collard, O. Riant,
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Ferreira, A. Perez-Luna, Beilstein J. Org. Chem. 2013, 9, 236 –
245.
In conclusion, we described here the completely regio-
and stereoselective silylzincation of terminal ynamides using
a combination of (Me3Si)3SiH and a dialkylzinc reagent. The
procedure is operationally simple, utilizes readily available
reagents, and provides a straightforward and modular access
to Z-configured a,b-disubstituted enamides by means of
[11] J. Maury, L. Feray, M. P. Bertrand, Org. Lett. 2011, 13, 1884 –
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[12] For most recent examples of ynamide carbometalation, see:
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Soc. Jpn. 2008, 81, 373 – 379.
ꢁ
subsequent sequential functionalization of the Csp2 Zn and
ꢁ
Csp2 Si bonds introduced. Most significantly, with this reac-
ꢁ
tion we uncover a new entry to the silylzincation of C C
multiple bonds based on the merger of silyl radical chemistry
and radical Zn-atom transfer chemistry. The decisive feature
of this approach is the possibility to achieve trans selectivity in
ꢀ
the addition across the C C bond.
[14] a) S. Miniꢁre, J.-C. Cintrat, Synthesis 2001, 705 – 707; b) L.
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Received: July 8, 2014
Revised: August 6, 2014
Published online: && &&, &&&&
[15] N. Saito, K. Saito, H. Sato, Y. Sato, Adv. Synth. Catal. 2013, 355,
853 – 856.
4
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=
[16] Organosilyl radical addition to C C bonds following UV
[23] CCDC 1009934 (Z-13), 1009935 (Z-27) and 1009936 (E-30)
irradiation of organosilylboranes was reported: A. Matsumoto,
Y. Ito, J. Org. Chem. 2000, 65, 5707 – 5711.
[17] R. Dobrovetsky, Y. Kratish, B. Tumanskii, M. Botoshansky, D.
Bravo-Zhivotovskii, Y. Apeloig, Angew. Chem. Int. Ed. 2012, 51,
4671 – 4675; Angew. Chem. 2012, 124, 4749 – 4753.
[18] C. Chatgilialoglu, Chem. Eur. J. 2008, 14, 2310 – 2320.
[19] For a related radical addition of thiyl radicals, see: A. Sato, H.
Yorimitsu, K. Oshima, Synlett 2009, 28 – 31.
[20] B. Kopping, C. Chatgilialoglu, M. Zehnder, B. Giese, J. Org.
Chem. 1992, 57, 3994 – 4000.
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
ꢁ
[24] Little is known about the Hiyama cross-coupling of Csp2
Si(SiMe3)3 bonds, and existing protocols rely on H2O2 as an
additive: Z. Wang, J.-P. Pitteloud, L. Montes, M. Rapp, D.
Derane, S. F. Wnuk, Tetrahedron 2008, 64, 5322 – 5327. These
reaction conditions were not compatible with our enamides and
led to protodesilylation.
[21] For the conjugate addition of (Me2PhSi)2Zn, see: G. Auer, B.
Weiner, M. Oestreich, Synthesis 2006, 2113 – 2116; the b-
elimination had been observed by us previously: R. K. Schmidt,
M. Oestreich, F. Chemla, A. Perez-Luna, unpublished results
from our laboratories, 2009.
[25] The reasons for this inversion are not clear but may be the result
of a participating effect of the Lewis basic bromine atom
introduced in allylic position prior to the bromodesilylation
reaction.
[26] For recent applications of a-carbonyl b-substituted enamides,
see: a) D. J. Kerr, M. Miletic, J. H. Chaplin, J. M. White, B. L.
Flynn, Org. Lett. 2012, 14, 1732 – 1735; b) D. J. Kerr, M. Miletic,
N. Manchala, J. M. White, B. L. Flynn, Org. Lett. 2013, 15, 4118 –
4121.
[22] The motif of a-zincated enamides, prepared by RhI-catalyzed
carbo- and hydrozincation of ynamides, was engaged in Negishi
cross-coupling reactions by Lam and co-workers: a) B. Gourdet,
H. W. Lam, J. Am. Chem. Soc. 2009, 131, 3802 – 3803; b) B.
Gourdet, M. E. Rudkin, C. A. Watts, H. W. Lam, J. Org. Chem.
2009, 74, 7849 – 7858. Yields were decent but not excellent.
Application of this and modified protocols to V was likely
thwarted by the bulk of the (Me3Si)3Si group.
[27] M. G. Organ, J. T. Cooper, L. R. Rogers, F. Soleymanzadeh, T.
Paul, J. Org. Chem. 2000, 65, 7959 – 7970.
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Communications
Radical Chemistry
E. Romain, C. Fopp, F. Chemla,
F. Ferreira, O. Jackowski, M. Oestreich,*
A. Perez-Luna*
&&&& — &&&&
Trans-Selective Radical Silylzincation of
ꢁ
ꢁ
Ynamides
A radical transformation: Z-configured
a,b-disubstituted enamides are obtained
through a regio- and stereoselective
silylzincation of terminal ynamides and
subsequent sequential functionalization
of the resulting Csp2 Zn and Csp2 Si
bonds (see Scheme). The trans-selective
silylzincation proceeds through a radical
process combining organosilyl radical
and radical Zn-atom transfer chemistry.
6
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
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