Unprecedented noncatalyzed anti-carbozincation of diethyl acetylenedicarboxylate through alkylzinc group radical transfer

Article abstract of DOI:10.1021/ol200419x

The radical carbozincation of diethyl acetylenedicarboxylate, performed at room temperature in the presence of air, leads to fumaric derivatives through a selective alkylzinc group radical transfer controlled by coordination. The total trans stereocontrol

Full text of DOI:10.1021/ol200419x

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1884–1887
Unprecedented Noncatalyzed anti-
Carbozincation of Diethyl
Acetylenedicarboxylate through Alkylzinc
Group Radical Transfer
ꢀ
Julien Maury, Laurence Feray,* and Michele P. Bertrand*
Laboratoire Chimie Provence, UMR 6264, Equipe CMO, case 562,
ꢁ
Universite Aix-Marseille, FST Saint-Jerome, av. Escadrille Normandie Niemen,
13397 Marseille cedex 20, France
ꢁ ^
laurence.feray@univ-cezanne.fr; michele.bertrand@univ-cezanne.fr
Received February 15, 2011
ABSTRACT
The radical carbozincation of diethyl acetylenedicarboxylate, performed at room temperature in the presence of air, leads to fumaric derivatives
through a selective alkylzinc group radical transfer controlled by coordination. The total trans stereocontrol is unprecedented, carbocupration is
well-known to give the reversal selectivity at low temperature, while classical radical addition methodologies lead to mixtures of isomers.
Stereocontrolled anti-carbometalation of the triple bond
of dialkyl acetylenedicarboxylates remains a challenge for
organic chemists.1 To achieve the addition of organome-
tallic reagents to these substrates, specific organocopper
reagents are needed. The syn-carbocupration of dialkyl
acetylenedicarboxylates can be realized by using organocop-
per-organoborane complexes (RCu•BR03),2 organocopper
reagents derived from cuprous bromide-dimethyl sulfide
complex (RCu(Me2S)•MgBr2),3 and also mixed copper-
zinc species (RCu(CN)ZnBr).4 In all cases, maleic deriva-
tives are formed at low temperature (Scheme 1). Additional
functionalization has been applied to the synthesis of
natural and unnatural maleic acids5 and anhydrides.6
Scheme 1. Alkylation of Dialkyl Acetylenedicarboxylates
(1) For general reviews on carbometalation and carbocupration of
alkynes, see: (a) Fallis, A. G.; Forgione, P. Tetrahedron 2001, 57, 5899–
5913. (b) Chemla, F.; Ferreira, F. In Chemistry of Organocopper
Compounds; Rappoport, Z., Marek, I., Eds.; Wiley & Sons: Hoboken,
2009; pp 527-584. (c) Basheer, A.; Marek, I. Beilstein J. Org. Chem.
2010, 6 (77), 10.3762/bjoc.6.77. (d) Wipf, P.; Kendall, C. Chem.;Eur. J.
2002, 8, 1778–1784.
(2) Yamamoto, Y.; Yatagai, H.; Maruyama, K. J. Org. Chem. 1979,
44, 1744–1746.
(3) Nishiyama, H.; Sasaki, M.; Itoh, K. Chem. Lett. 1981, 905–908.
(4) (a) Chou, T.-S.; Knochel, P. J. Org. Chem. 1990, 55, 4791–4793.
(b) Sidduri, A. R.; Knochel, P. J. Am. Chem. Soc. 1992, 114, 7579–7581.
r
10.1021/ol200419x
Published on Web 03/09/2011
2011 American Chemical Society

The alkylation of the triple bond of dialkyl acetylenedi-
carboxylates can also be achieved by using radical chem-
istry. Most reactions are nonstereoselective. Due to the fast
isomerization of the intermediate vinylic radicals, the
stereochemical outcome is mainly governed by steric ef-
fects in the atom transfer step.
We report in this paper the highly stereoselective di-
alkylzinc-mediated addition of alkyl radicals to diethyl
acetylenedicarboxylate at room temperature.
The addition of ethyl radical was achieved by using 2
equiv of Et2Zn and air in dichloromethane at room
temperature (entry 1, Table 1).14 The ratio of 97:3 in favor
The photoinduced addition of cyclic ethers,7 alcohols,8
2,2-dialkyldioxolanes,9 and cycloalkanes10 to dimethyl
acetylenedicarboxylate (DMAD), usually ends with non
stereoselective hydrogen atom abstraction. Theaddition of
adamantane to diethyl acetylenedicarboxylate catalyzed
by N-hydroxyphtalimide and Co(II) species under O2
atmosphere gives the Z and E adducts in a ratio close to
70:30.11
Table 1. Dialkylzinc-Mediated Alkyl Radical Addition to
Diethyl Acetylenedicarboxylate
A radical process is also involved in the photostimulated
formation of vinylmercurial from the reaction of organo-
mercury halides with diethyl acetylenedicarboxylate. The
latter can be reduced by NaBH4 or cleaved by I2 to form in
each case the expected product as a mixture of Z and E
isomers in a 62:38 ratio.12
Similarly, functionalized maleic and fumaric derivatives
can be obtained via Atom Transfer Radical Additions
(ATRA).13 the pioneering work in the field is due to
Curran, who was the first to investigate the iodine atom
transfer methodology.13a
entry A (equiv)
R1I (equiv)
1 yield (%)
1a (89)
1b (32)b
1c (96)
1d (97)
1e (99)
E:Z
1
2
3
4
5
6
7
Et2Zn (2) none
Me2Zn (5) none
100:0a
100:0
100:0c
98:2
Me2Zn (3) t-BuI (5)
Me2Zn (3) i-PrI (5)
Me2Zn (3) s-BuI (5)
Me2Zn (3) EtI (5)
Me2Zn (3) EtI (10)
100:0
1a (34) 1b (35) 100:0
1a (51) 1b (33) 100:0
1a (59) 1b (27) 100:0
8d Me2Zn (3) EtI (10)
9d Me2Zn (3) ICH(Me)CH2CO2Et (10) 1f (75)
100:0
a Crude E:Z: 97:3. b Sixty-one percent of starting material was
recovered. c Crude E:Z: 96:4. d Me2Zn was added portionwise.
However, the alkylation of dialkyl acetylenedicarboxy-
lates leading to the exclusive formation of fumaric deriva-
tives through either polar or radical chemistry is without
precedent.
of the E isomer, measured from the proton NMR spectra
of the crude mixture, increased after purification and (E)-
1a was isolated in 89% yield. Lower yields were obtained
when diethylzinc was replaced by dimethylzinc, even in the
presence of an excess (5 equiv) of the reagent (entry 2).
Methyl derivative 1b was isolated in 32% yield whereas
61% of starting material was recovered.15 This behavior is
in agreement with the poor reactivity of methyl radical
regarding conjugate addition.16
(5) (a) Ratemi, E. S.; Dolence, J. M.; Poulter, C. D.; Vederas, J. C.
J. Org. Chem. 1996, 61, 6296–6301. (b) Garneau, S.; Qiao, L.; Chen, L.;
Walker, S.; Vederas, J. C. Bioorg. Med. Chem. 2004, 12, 6473–6494.
(6) (a) Baldwin, J. E.; Beyeler, A.; Cox, R. J.; Keats, C.; Pritchard,
G. J.; Adlington, R. M.; Watkin, D. J. Tetrahedron 1999, 55, 7363–7374.
(b) Baldwin, J. E.; Adlington, R. M.; Roussi, F.; Bulger, P. G.; Marquez,
R.; Mayweg, A. V. W. Tetrahedron 2001, 57, 7409–7416. (c) Adlington,
R. M.; Baldwin, J. E.; Cox, R. J.; Pritchard, G. J. Synlett 2002, 820–
822.
The additions of secondary and tertiary alkyl radicals
were achieved by using dimethylzinc in the presence of the
(7) Singh, P. J. Org. Chem. 1972, 37, 836–841.
(8) Geraghty, N. W. A.; Hernon, E. M. Tetrahedron Lett. 2009, 50,
570–573.
(9) Fagnoni, M.; Mella, M.; Albini, A. J. Org. Chem. 1998, 63, 4026–
4033.
(14) A typical procedure: diethylzinc (2 equiv, 1.24 mL, 1 M in
hexane) was added to a solution of diethyl acetylenedicarboxylate (100
μL, 0.62 mmol) 0.3 M in dichloromethane at room temperature. Air was
introduced in the reaction mixture through a syringe pump (40 mL for
1 h). After stirring for 18 h at room temperature, the reaction was
quenched with saturated NH4Cl. The layers were separated and the
aqueous layer was extracted twice with CH2Cl2. The combined organic
phases were dried (MgSO4), filtered and concentrated in vacuo. Flash
column chromatography on silica gel using pentane/ethyl acetate as
eluent afforded (E)-2-ethyl-but-2-enedioic acid diethyl ester (1a) in 89%
yield (110 mg, >99:1 ratio for E:Z isomers). 1H NMR (400 MHz,
CDCl3) δ: 1.06 (3H, t, J = 7.5 Hz), 1.28 (3H, t, J = 7.0 Hz), 1.29 (3H, t,
J = 7.0 Hz), 2.76 (2H, q, J = 7.5 Hz), 4.19 (2H, q, J = 7.0 Hz), 4.22 (2H,
q, J = 7.0 Hz), 6.68 (1H, s). 13C NMR (100 MHz, CDCl3) δ: 13.6 (CH3),
14.2 (CH3), 14.3 (CH3), 21.5 (CH2), 60.7 (CH2), 61.5 (CH2), 126.1
(dCH), 149.7þ(dC), 165.8 (CdO), 166.9 (CdO). HRMS (ESI): m/z:
calcd for [MH ] C10H17O4: 201.1121; found: 201.1122.
(10) The best result was obtained for the addition of cyclopentane in
the presence of benzophenone as the photomediator under solar radia-
tion. In this case the Z isomer was formed selectively (Z:E, 98:2), see: (a)
Doohan, R. A.; Geraghty, N. W. A. Green Chem. 2005, 7, 91–96. (b)
Doohan, R. A.; Hannan, J. J.; Geraghty, N. W. A. Org. Biomol. Chem.
2006, 4, 942–952.
(11) Kagayama, T.; Nakayama, M.; Oka, R.; Sakaguchi, S.; Ishii, Y.
Tetrahedron Lett. 2006, 47, 5459–5461.
(12) (a) Russell, G. A.; Hu, W. J. S. S.; Khanna, R. K. J. Org.
Chem. 1986, 51, 5499–5501. For the addition of t-Bu2Hg, see also: (b)
Blaukat, U.; Neumann, W. P. J. Organomet. Chem. 1973, 49, 323–
332.
(13) For examples of iodine atom transfer radical reaction involving
dialkyl acetylenedicarboxylates, see: (a) Curran, D. P.; Kim, D. Tetra-
hedron 1991, 47, 6171–6188. (b) Araki, Y.; Endo, T.; Tanji, M.;
Nagasawa, J.; Ishido, Y. Tetrahedron Lett. 1987, 28, 5853–5856. (c)
Araki, Y.; Endo, T.; Tanji, M.; Nagasawa, J.; Ishido, Y. Tetrahedron
Lett. 1988, 29, 351–354. (d) Harendza, M.; Lesmann, K.; Neumann,
W. P. Synlett 1993, 283–285. (e) Fang, X.; Yang, X.; Yang, X.; Mao, S.;
Wang, Z.; Chen, G.; Wu, F. Tetrahedron 2007, 63, 10684–10692. For
tellurium atom transfer addition of carbamotelluroates to DMAD, see:
(f) Fujiwara, S.-I.; Shimizu, Y.; Shin-Ike, T.; Kambe, N. Org. Lett. 2001,
3, 2085–2088.
(15) When the reaction was conducted with 9 equiv of dimethylzinc in
the presence of a large excess of air, 1b was isolated in 44% yield.
(16) (a) Fischer, H.; Radom, L. Angew. Chem., Int. Ed. 2001, 40,
ꢁ
1340–1371. (b) Gomez-Balderas, R.; Coote, M. L.; Henry, D. J.; Fischer,
ꢁ
H.; Radom, L. J. Phys. Chem. A 2003, 107, 6082–6090. (c) Gomez-
Balderas, R.; Coote, M. L.; Henry, D. J.; Radom, L. J .Phys. Chem. A
2004, 108, 2874–2883.
Org. Lett., Vol. 13, No. 7, 2011
1885

corresponding alkyl iodides (entries 3-5, 9). It is to be
noted that the number of equivalents of alkyl iodide per
mole of substrate is rather low compared to the amounts
generally used in similar reactions in the literature.17,18
High stereocontrol and yields were reached again in these
cases even when a functionalized alkyl iodide was used as
the radical precursor (entry 9).
Optimization was necessary to perform the addition of a
primary alkyl radical from a primary alkyl iodide. Tested
as a model reaction, the addition of ethyl radical mediated
by the couple Me2Zn/EtI led to a mixture of adducts 1a
and 1b (entries 6-8). Dimethylzinc had to be added
portionwise to increase the ratio of adduct 1a which could
be isolated as the major product in 59% yield (entry 8).
alkyl radical which adds to the activated triple bond to give
a vinylic radical. We speculate that the reaction proceeds
thenthrough alkylzinc group transfer. The coordination of
Zn(II) with the oxygen atom of the ester group explains the
stereoselectivity of this transfer, which occurs in position
cis relative to the carboxylate.19 It is important to note that
this is the first example of noncatalyzed formation of a
vinylzinc from an alkyne bearing two ester groups.20,21 The
stabilized vinylzinc intermediate can then either be proto-
nated or allowed to react with other electrophiles (the
examples are not limitative) added to the reaction
mixture.22 We assume that the Z-isomers of products 1,
that are detected in trace amount in the crude reaction
mixture, result from hydrogen atom transfer from any
hydrogen atom donor present in the reaction medium and
not from the protonation of the vinylzinc.23
AsshowninScheme 3, whenI2 was added tothe reaction
mixture, the vinylzinc intermediate was transformed in the
corresponding vinylic iodide. Whatever the alkylgroup,
primary, secondary, or tertiary, the iodides 2 were formed
in good yields without any loss in selectivity.24
Scheme 2. Proposed Mechanism
Phenylselenyl chloride was also shown to be a good
trap for the vinylzinc intermediate (Scheme 3), 3a and 3d
were isolated in satisfactory yields still with a total
stereoselectivity.25
Scheme 3
To explain the high stereochemical outcome of the reac-
tion, we propose the mechanism depicted in Scheme 2.
The reaction between the dialkylzinc and oxygen generates
an alkyl radical.18 In the presence of an alkyl iodide, the
transfer of the iodine atom allows the formation of a new
(17) While this work was being revised the Et3B-mediated radical
additions to activated alkynyl oxime ethers were reported, see: Ueda,
M.; Matsubara, H.; Yoshida, K.-I.; Sato, A.; Naito, T.; Miyata, O.
Chem.;Eur. J. 2011, 17, 1789–1792.
(18) For reviews on dialkylzincs in radical chemistry, see: (a) Bazin,
S.; Feray, L.; Bertrand, M. P. Chimia 2006, 60, 260–265. (b) Akindele, T.;
Yamada, K.-I.; Tomioka, K. Acc. Chem. Res. 2009, 42, 345–355. For
recent reports on the subject see also: (c) Giboulot, S.; Perez-Luna, A.;
Botuha, C.; Ferreira, F.; Chemla, F. Tetrahedron Lett. 2008, 49, 3963–
3966. (d) Maury, J.; Feray, L.; Perfetti, P.; Bertrand, M. P. Org. Lett.
2010, 12, 3590–3593. (e) Akindele, T.; Mamamoto, Y.; Maekawa, M.;
Umeki, H.; Yamada, K.-I.; Tomioka, K. Org. Lett. 2006, 8, 5729–5732.
(19) For recent reports on the stereoselective formation of vinylzinc
(21) The addition of allylzinc bromide to acetylenic sulfone without
any additive such as copper salt was reported, see: (a) Xie, M.; Wang, J.;
Gu, X.; Sun, Y.; Wang, S. Org. Lett. 2006, 8, 431–434. Direct
carbozincation reaction of trifluoromethylated acetylenic phosphonates
mediated by dialkylzinc was also reported, see: (b) Konno, T.; Morigaki,
A.; Ninomiya, K.; Miyabe, T.; Ishihara, T. Synthesis 2008, 564–572. In
these cases, a vinylzinc was formed in alpha position to an electronwith-
drawing group.
(22) The formation of a zinc allenoate intermediate cannot be ruled
out. We assume that the coordination of the zinc atom to the carboxylate
stabilizes the vinylzinc intermediate and therefore displaces the equili-
brium toward the latter. This explains the high stereoselectivity of the
reaction whatever the bulk of the alkyl group is.
ꢁ
species through SH2 process see: (a) Perez-Luna, A.; Botuha, C.;
Ferreira, F.; Chemla, F. Chem.;Eur. J. 2008, 14, 8784–8788. (b) Feray,
L.; Bertrand, M. P. Eur. J. Org. Chem. 2008, 3164–3170. (c) Chen, Z.;
Zhang, Y.-X.; An, Y.; Song, X.-L.; Wang, Y.-H.; Zhu, L.-L.; Guo, L.
Eur. J. Org. Chem. 2009, 5146–5152.
(23) This was supported by treating the reaction with ND4Cl instead
of NH4Cl. Whatever the conditions (with or without the alkyliodide) the
E-isomer was deuterated up to 95% whereas the traces of Z-isomer
remained non deuterated.
(24) Note that in the presence of (Bu3)2Sn2 under sunlamp irradia-
tion, the addition of t-BuI and i-PrI to DMAD led to the formation of
fumaric and maleic adducts in 76:24 and 16:84 relative ratios, respec-
tively, see ref 13a.
(20) Vinylzinc are usually prepared through transmetalation of
differents vinylmetal. Here are selected examples: for transmetalation
€
involving vinylnickel species, see: (a) Studemann, T.; Ibrahim-Ouali, M.;
Knochel, P. Tetrahedron 1998, 54, 1299–1316. For alkene transfer from
zirconium to zinc, see: (b) Wipf, P.; Kendall, C.; Stephenson, C. R. J. J.
Am. Chem. Soc. 2003, 125, 761–768. For transmetalation involving
vinyllithium species, see: (c) Agami, C.; Couty, F.; Evano, G. Org. Lett.
2000, 2, 2085–2088. (d) Dieter, R. K.; Guo, F. Org. Lett. 2006, 8, 4779–
4782. For reactions involving vinylborane, see: (e) Wang, S.; Seto, C. T.
Org. Lett. 2006, 8, 3979–3982. (f) Valenta, P.; Carroll, P. J.; Walsh, P. J.
J. Am. Chem. Soc. 2010, 132, 14179–14190 and previous refs therein.
(25) Attempts to trap the vinylzinc intermediate with reactive alde-
hydes such as benzaldehyde or methyl glyoxylate failed even after
transmetalation with CuI.
1886
Org. Lett., Vol. 13, No. 7, 2011

In addition, transmetalation with CuI enabled an indir-
ect anti-carbocupration to be achieved at room tempera-
ture. Subsequent trapping with allylbromide led to the
corresponding diene 4a in 89% yield (Scheme 4).
ate vinylic radical.26 The latter abstracted the iodine atom
from t-butyliodide leading to vinyl iodide 2c isolated in
80% yield.27 Homolytic substitution at zinc by a vinylic
radical can thus be claimed as a distinctive property of
dialkylzincs that are often compared to alkylboron deri-
vatives as mediators of radical reactions.
Scheme 4
Scheme 6
Additional experiments performed on substrate 5 con-
firmed that the transfer of the alkylzinc group is controlled
by coordination (Scheme 5). The alkyl radical adds regio-
selectively to the triple bond. The resulting vinyl radical
stereoselectively transfers the alkylzinc group at the ex-
pense of any iodine atom transfer.
In conclusion, we have shown that direct anticarbozin-
cation of diethyl acetylenedicarboxylate can be performed
through dialkylzinc-mediated alkyl radical addition. This
process led to the highly stereoselective formation of
diethylfumarate derivatives in good yields at room tem-
perature. The keystep relies on the ability of dialkylzincs to
undergo homolytic substitution by vinylic radicals. The
high selectivity observed in the transfer of the alkylzinc
group is controlled by the coordination of Zn(II) to the
ester group. The formation of a vinylzinc intermediate
enabled further functionalization. The trapping of the
latter with various electrophiles led to the corresponding
fumaric derivatives in good yields without any loss in the
stereoselectivity.
Scheme 5
Finally, we decided to perform the reaction in the
presence of triethylborane as the initiator. The addition
oft-butyliodide led to a mixture of 1cand 2cinquantitative
overall yield (Scheme 6). Compound 1c, isolated as a 1:1
mixture of isomers, became the minor product of the
reaction. In all likelihood, it resulted from hydrogen atom
abstraction, possibly from boron derivatives. Contrary to
zinc, the boron atom was not transferred to the intermedi-
Acknowledgment. We gratefully acknowledgethe ANR
(D2R2; ANR-09-JCJC-0081) for financial support.
Supporting Information Available. Experimental pro-
cedures and characterization data of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(26) When DMAD was reacted with selenoborane, the authors
concluded that the intermediate formed was not a vinylborane but a
vinyl radical, see: Kataoka, T.; Yoshimatsu, M.; Shimizu, H.; Hori, M.
Tetrahedron Lett. 1990, 31, 5927–5930.
(27) The E/Z ratio was more or less the same as the one reported by
Curran under standard iodine atom transfer radical addition of t-butyl
iodide to DMAD, see ref 13a.
Org. Lett., Vol. 13, No. 7, 2011
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