Radical-polar crossover domino reaction involving alkynes: A stereoselective zinc atom radical transfer

Article abstract of DOI:10.1002/chem.200801451

The radical-polar crossover domino reaction involving alkynes was investigated. Dialkylzinc reagent R₂Zn was added to a stirred solution of β-(propargyloxy)enoate in Et₂O at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction was hydrolyzed with an aqueous solution of HCl. The layers were separated, the aqueous one being extracted twice with Et₂O. The combined organic layers were washed with brine, dried over MgSO₄ and the solvents evaporated under reduced pressure. The product was purified by flash chromatography on silica gel. The experiment offered a new possibility to retain functionality following 5-exo-dig radical cyclizations.

Full text of DOI:10.1002/chem.200801451

DOI: 10.1002/chem.200801451
Radical-Polar Crossover Domino Reaction Involving Alkynes:
AStereoselective Zinc Atom Radical Transfer
Alejandro PØrez-Luna,*[a, b] Candice Botuha,[a, b] Franck Ferreira,[a, b] and
Fabrice Chemla*[a, b]
Intramolecular radical cyclization has become over the
years one of the most powerful strategies to synthesize car-
bocyclic and heterocyclic compounds.[1] In this context, cycli-
zation of 5-hexynyl radicals has found widespread applica-
tion for the preparation of exo-alkylidene derivatives. The
most common protocols involve the use of metal hydrides
(generally tin) as radical mediators and thus termination af-
fords directly an alkene, which results in a loss of functional-
ity. Halide atom transfer cyclization conditions leading to
vinyl halides provide an elegant solution to retain function-
ality,[2] but further elaboration requires an additional syn-
thetic step. Alternatively, processes where the intermediate
vinyl radical is captured by reaction with a metallic reagent
As part of our ongoing interest in carbometallation of
zinc enolates,[12] we have recently disclosed a new access to
(pyrrolidylmethyl) zinc and (tetrahydrofuranylmethyl) zinc
derivatives by reaction of dialkylzinc, organozinc and
copper-zinc mixed reagents with (N-allyl)aminoenoates[9a–c]
and b-(allyloxy)enoates[9e] through a zinc atom transfer in-
volving a domino 1,4-addition/carbocyclization sequence.
We reasoned that addition on b-(propargyloxy)enoates,
readily prepared by reaction of the corresponding propar-
gylic alcohol with methyl 2-(bromomethyl)acrylate, might
lead to (exo-methylene tetrahydrofuranyl) zinc[13,14] deriva-
tives which can be functionalized further in-situ by reaction
with an electrophile and afford polysubstituted alkenyl tet-
rahydrofurans (Scheme 1).
À
to generate a new carbon metal bond, have also been dis-
closed.[3] In principle such a strategy is highly attractive
since subsequent ionic reactions should offer multibond-
forming events, however examples where the vinyl metal is
retained and reacted further are scarce.[3c,e,f]
The use of organozinc reagents as non-toxic radical pre-
cursors or mediators is a field of growing interest.[4–6] Of par-
ticular interest are zinc atom transfer reactions which enable
the transformation of simple readily available organozinc re-
agents into more elaborated ones via a radical chain transfer
mechanism. This approach has already been applied for the
preparation of zinc enolates[7,8] and alkylzinc reagents,[9–11]
but to our knowledge never for vinyl zinc derivatives.
Scheme 1. New multicomponent approach to polysubstituted alkylidene
tetrahydrofurans.
We have found that reaction of primary dialkylzincs pro-
ceeds smoothly in diethyl ether at room temperature with a
number of b-(propargyloxy)enoates bearing diversely substi-
tuted alkynes to afford the corresponding exo-alkylidene tet-
rahydrofurans after acidic quench (Table 1).
[a] Dr. A. PØrez-Luna, Dr. C. Botuha, Dr. F. Ferreira, Prof. F. Chemla
UPMC Univ Paris 06, UMR 7611, Laboratoire de Chimie Organique
Institut de Chimie MolØculaire (FR 2769), Case 183, 4 place Jussieu
75005 Paris (France)
Addition of Bu2Zn (or Et2Zn) on enoate 1a bearing a ter-
minal alkyne leads to exo-methylene tetrahydrofuran 2 (or
3) in 54% (or 55%) yield (entries 1–2). Starting from TMS-
substituted b-(propargyloxy)enoate 1b, diastereomerically
pure vinylsilanes (Z)-4 and (Z)-5 are obtained in good to
excellent yields (entries 3–4). The sequence is also highly ef-
fective and stereoselective with substrates bearing conjugat-
ed alkynes. Reaction of Bu2Zn and Et2Zn with 1c yields
styrenes 7 and 8 in 81 and 79% yield, respectively, in a
90:10 Z/E ratio (entries 6–7), whereas enyne 1d leads to dia-
stereomerically pure diene (Z)-9 in 59% yield (entry 8). Ste-
Fax : (+33)144-277-567
E-mail: fabrice.chemla@upmc.fr
alejandro.perez_luna@upmc.fr
[b] Dr. A. PØrez-Luna, Dr. C. Botuha, Dr. F. Ferreira, Prof. F. Chemla
CNRS, UMR 7611, Laboratoire de Chimie Organique
Institut de Chimie MolØculaire (FR 2769), Case 183
4 place Jussieu, 75005 Paris (France)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801451.
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Chem. Eur. J. 2008, 14, 8784 – 8788

COMMUNICATION
Table 1. Reaction of dialkylzincs on b-(propargyloxy)enoates 1a–e.
for the E isomers, as for the non-substituted case (entries 3–
4).
Functionalization of the intermediate vinylzinc species
was thus considered with substrates affording high degrees
of Z selectivity. The intermediate gem Si/Zn bimetallated
alkene resulting from the addition of Bu2Zn or Et2Zn on 1b
was trapped with iodine to afford iodo vinylsilane (E)-15 in
72% as a single diastereomer or allylated with allyl bromide
following transmetallation with CuCN·2LiCl to give trisub-
stituted vinylsilane (Z)-16 (entries 6–7). As confirmed by
NOE experiments on 15 (Scheme 2), full retention of con-
figuration was observed.[15] Likewise, electrophilic trapping
of the intermediate vinyl zinc was also possible starting from
enoate 1c bearing a phenylacetylene moiety (Table 2, en-
tries 8–9). Reaction with Bu2Zn followed by iodolysis af-
forded 17 in 79% yield in a 93:07 E/Z ratio, whereas reac-
tion with Et2Zn followed by transmetallation and trapping
with allyl bromide gave tetrasubstituted alkene 18 in 42%
as a single Z diastereomer. Here again, as evidenced by the
slight increase in diastereoselectivity with respect to simple
acidic quench (Table 1, entries 6–7) the alkenyl intermediate
leading to the Z product seems to be fully metallated but
not the one leading to the E product.
Entry Substrate R1
R2Zn (equiv) Product Yield [%][a] dr[b]
Z/E
1
2
3
4
5
6
7
8
9
1a
1a
1b
1b
1b
1c
1c
1d
1e
H
H
TMS
TMS
TMS
Ph
Bu2Zn (3)
Et2Zn (3)
Bu2Zn (5)
Et2Zn (3)
iPr2Zn (3)
Bu2Zn (5)
Et2Zn (3)
2
3
4
5
6
7
8
9
54
55
67
91
49[c]
81
79
59
64
–
–
>95:05
>95:05
>95:05
88:12
90:10
>95:05
64:36
Ph
1-Cx[d] Bu2Zn (3)
Et
Bu2Zn (3)
10
[a] Combined yield of isolated diastereomers. [b] Determined by NMR
analysis of the crude material. [c] 40% of 3-(trimethylsilyl)prop-2-yn-1-ol
was isolated. [d] 1-Cx/ 1-cyclohexenyl.
reochemical assignment for products 4 and 8 arouse from
NOE experiments (Scheme 2).[15]
The observed transformations are believed to follow a
radical-polar crossover mechanism similar to the one we evi-
denced for the related reactions involving (N-allyl)amino-
enoates and b-(allyloxy)enoates (Scheme 3).[9a,b,e] Initial oxi-
dation of the organometallic species by traces of oxygen
produces a radical that undergoes 1,4-addition onto the Mi-
chael acceptor 1a–e to afford an enoxy radical 19.[17] Subse-
quent 5-exo-dig cyclization on the alkyne moiety and reduc-
tion of the resulting vinyl radical 20 by the organometallic
species gives the (tetrahydofuranylalkenyl)zinc intermediate
21 and a new radical that propagates the chain. The forma-
tion of the non-metallated compounds 2 and (E)-10 is unex-
pected. In the case of 1a (R1 =H), we initially considered a
possible deprotonation of the starting terminal alkyne by
the formed vinylzinc 21.[18] To be consistent with the ob-
served yields higher than 50%, this possibility would imply
the formation of a gem-Zn,Zn bimetallated species which
was not detected after a deuterium quench.[19] Moreover,
such a possibility would not account for the formation of the
reduced product even with internal alkynes. It therefore
seems reasonable to consider that non-metallated com-
pounds 2 and (E)-10 arise from reduction of the intermedi-
ate vinyl radicals by hydrogen abstraction. Since a possible
intramolecular hydrogen shift was ruled out by the fact that
Scheme 2. Selected NOE signals for products (Z)-4, (Z)-8 and (E)-15.
Reaction with alkyl substituted alkynes is also possible as
evidenced by the addition of Bu2Zn on 1e (entry 9). Howev-
er, in this case, a significant drop in diastereoselectivity is
observed as a mixture of alkylidene furans 10 is obtained in
a 64:36 Z/E ratio.
The domino sequence is not limited to primary dialkyl-
zincs. For example, salt free iPr2Zn prepared from
iPrMgCl[16] reacts with 1b to afford diastereomerically pure
vinylsilane (Z)-6 in 49% yield (Table 1, entry 5). Neverthe-
less, as evidenced by the recovery of 40% of 3-TMS-prop-
argyl alcohol, a competitive addition/b-elimination process
hampers the overall efficiency in this case.
In order to develop a three-component approach, we next
investigated the subsequent functionalization of the vinyl-
zinc resulting from the 1,4 addition/cyclization sequence
(Table 2). Much to our surprise, deuteration of the inter-
mediate obtained from Bu2Zn and enoate 1a afforded 11 as
a mixture of two diastereomers in a 51:49 E/Z ratio but also
50% of non-deuterated methylene–tetrahydrofuran 2 (en-
tries 1–2). On the contrary, complete deuterium labeling was
observed starting with TMS-substituted enoate 1b and (Z)-
14 was isolated (entry 5). The case of substrate 1e bearing
an ethyl substituted internal alkyne lies between the two
previous cases. As expected, a mixture of diastereomers is
obtained, but whereas complete deuterium labeling is ob-
served for the Z isomers, only partial labeling is observed
2
no deuterium incorporation was detected by H-NMR else-
where in the molecule,[19] H abstraction must in consequence
occur intermolecularly, though the hydrogen donor still re-
mains unidentified.[20]
Vinyl zinc derivatives being known to be configurationally
stable,[21] the diastereoselectivity of the process arises from
the stereoselectivity of the kinetically controlled SH2 step.[22]
Building on models reported for reductive cyclization of
hexynyl radicals[23] and iodine atom transfer cyclization of
hex-5-ynyl iodides,[2b] we propose an interpretation of the
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8785

F. Chemla, A. PØrez-Luna et al.
sidered to be sp2 hybridized
and to invert with a very low
barrier. The Z/E ratio depend-
ing on the size of R1, with
“small” substituents, the con-
centration of (E)-20 increases
and its reduction, not only by
non pre-complexed dialkylzinc
but also by intermolecular H-
transfer, becomes more impor-
tant, thus leading to a selectivi-
ty drop and partial loss of the
metal. Interestingly, for H-sub-
stituted vinyl radical 20, H-
transfer seems to compete
both with syn and anti substitu-
tion to the same extent, per-
haps as a consequence of a
higher reactivity of the unsub-
stituted radical (Scheme 5).
In summary, we have dis-
closed a new efficient stereose-
lective multicomponent ap-
proach to polysubstituted alkyl-
idene tetrahydrofurans from
dialkylzincs and b-(propargyl-
oxy)enoates, by means of a
radical-polar domino 1,4-addi-
tion/carbocyclization sequence.
From a mechanistic point of
view, the transformation is re-
lated to carbozincations of
non-activated alkynes by zinc
Table 2. In situ functionalization of vinyl zinc reaction products of dialkylzincs with b-(propargyloxy) enoates.
Entry Substrate R2Zn E-X Product
Yield[a] [%] dr[b]
11 66
1
2
1a
1a
Bu2Zn D2O
Bu2Zn DCl
51 ([D] 51%[c]):49 ([D] 49%[c]
51 ([D] 49%[c]):49 ([D] 47%[c]
)
)
11 67
3
4
5
6
1e
1e
1b
1b
Bu2Zn D2O
Et2Zn D2O
Bu2Zn D2O
Bu2Zn I2, THF
12 78
66 ([D] 92%[c]):34 ([D] 47%[c]
62 ([D] 94%[c]):38 ([D] 60%[c]
>95 ([D] 94%[c]):05
>95:05
)
)
13 64
14 83
15 72
7
1b
Et2Zn allylBr,[c] THF
16 51
>95:05
8
9
1c
1c
Bu2Zn I2, THF
17 79
18 42
93:07
Et2Zn allylBr,[c] THF
>95:05
[a] Combined yield of isolated diastereomers after chromatography. [b] Determined by NMR analysis of the
crude material. [c] Percentage of deuteration determined by NMR analysis. [d] Transmetallation with CuCN·2
LiCl (1.1 equivalent) was performed.
Scheme 4. Origin of diastereoselectivity in the case of “linear” vinyl radi-
cals (R1 =Ph, 1-cyclohexene).
Scheme 3. Mechanism of the radical-polar crossover domino reaction.
stereoselectivity based on the structure of the vinyl radical
(linear or bent).
Both for linear (R1 =Ph, 1-cyclohexenyl) (Scheme 4) and
bent (R1 =TMS, Et) radicals (Scheme 5), reduction occurs
selectively from the more sterically hindered syn side, pre-
sumably as a result of pre-coordination to the ester group of
the dialkylzinc involved in the SH2.[24] anti Reduction is nev-
ertheless obtained to a significant extent for ethyl-substitut-
ed and unsubstituted vinyl radicals. These radicals are con-
Scheme 5. Origin of diastereoselectivity in the case of “bent” vinyl radi-
cals (R1 =TMS, Et).
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Chem. Eur. J. 2008, 14, 8784 – 8788

Domino Reaction Involving Alkynes
COMMUNICATION
enolates which are rare.[18,25] It is remarkable by the fact that
an alkylzinc derivative is transformed into a more basic vi-
nylzinc in what represents, to our knowledge, the first exam-
ple of a zinc atom radical transfer involving the formation
of a vinylzinc species.[26] Synthetically, a new possibility to
retain functionality following 5-exo-dig radical cyclizations is
offered, and in our particular case, subsequent in situ trans-
formation of the intermediate organozinc compound results
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À
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Experimental Section
General procedure for the radical-polar crossover domino reaction
(Table 1): Under argon, to a stirred solution of b-(propargyloxy)enoate
(0.2 mmol) in Et2O (5 mL) was added dialkylzinc reagent R2Zn (0.6 mL,
~1n in heptane or hexane, 0.6 mmol) at room temperature. The reaction
mixture was stirred at room temperature for 16 h. The reaction was hy-
drolyzed with an aqueous solution of HCl (1m). The layers were separat-
ed, the aqueous one being extracted twice with Et2O. The combined or-
ganic layers were washed with brine, dried over MgSO4 and the solvents
evaporated under reduced pressure. The product was purified by flash
chromatography on silica gel.
For detailed experimental procedures and characterization data for com-
pounds 1a–e, 2–10, and 15–18 see Supporting Information.).
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Acknowledgements
The authors thankDr. E. Caytan for help with 2H NMR and J. Bell for
synthesis of some starting materials.
Keywords: cyclization · domino reactions · multicomponent
reactions · organozinc reagents · radical-polar reactions
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[19] See Supporting Information.
Chem. Eur. J. 2008, 14, 8784 – 8788
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F. Chemla, A. PØrez-Luna et al.
[20] Prof. M. P. Bertrand suggested alkylzincperoxides as possible hydro-
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Received: July 18, 2008
Published online: August 27, 2008
8788
www.chemeurj.org
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Chem. Eur. J. 2008, 14, 8784 – 8788