Regiodivergent addition of carbon units to dual-activated alkynes for stereoselective construction of tetrasubstituted alkenes

Article abstract of DOI:10.1002/chem.201002744

The discovery of potential synthons and reagent systems that allow the selective synthesis of target compounds is crucial for advances to be made in organic synthesis. Development of a simple methodology for preparing both regioisomers from a single subst

Full text of DOI:10.1002/chem.201002744

COMMUNICATION
DOI: 10.1002/chem.201002744
Regiodivergent Addition of Carbon Units to Dual-Activated Alkynes for
Stereoselective Construction of Tetrasubstituted Alkenes
Masafumi Ueda,[a] Hiroshi Matsubara,[b] Kin-ichi Yoshida,[a] Aoi Sato,[a]
Takeaki Naito,[a] and Okiko Miyata*[a]
The discovery of potential synthons and reagent systems
that allow the selective synthesis of target compounds is cru-
cial for advances to be made in organic synthesis. Develop-
ment of a simple methodology for preparing both regioisom-
ers from a single substrate with highly tunable selectivity, by
designing and controlling of reagents, is an attractive and
challenging task. A plethora of stereoselective conjugate ad-
dition reactions to a,b-unsaturated carbonyl compounds
have been invented.[1] In addition, a,b-unsaturated imines
have been reported as a substrate for a number of transfor-
mations such as 1,4- and 1,2-addition reaction and cycloaddi-
tion reaction.[2] However, switchable regiodivergent addition
to an electron-deficient olefins is quite rare. During the
course of our studies on radical addition to a variety of a,b-
unsaturated imine derivatives,[3] we were interested in the
reactivity of alkyne 1 that is doubly activated by an ester
and an oxime ether.[4] The alkynyl oxime ether 1 has several
reaction sites such as electrophilic carbon atoms and the ni-
trogen, radicophilic carbon atoms and an acidic hydrogen,
therefore, it is one of the most challenging organic com-
pounds [Eq. (1)].
We anticipated that an alkyl radical would react exclusive-
ly at the b-position to generate the allenaminyl radical A be-
cause it is stabilized by a two-center, three-electron bonding
effect.[5] On the other hand, the reaction with a alkynophilic
nucleophile such as organocuprate would lead to the genera-
tion of a-adduct B through addition of an alkyl anion at the
more electrophilic a-position. Furthermore, both intermedi-
ates could be transformed stereoselectively to a tetrasubsti-
tuted alkene by electrophilic trapping under suitable condi-
tions. Herein, we report the reagent-controlled regiodiver-
gent addition reaction of a dual activated alkyne and its ap-
plication to stereoselective domino and one-pot reactions
for the construction of tetrasubstituted alkenes. Owing to
their simplicity, convenience, complete positional selectivity,
and generally high levels of regiochemical control, both tun-
able regioselective addition reactions provide a new entry to
highly functionalized alkenes.[6] Regiochemically and geo-
metrically defined alkenes are not only ubiquitous structural
motifs in biologically relevant molecules, but also serve as a
foundation for a broad range of chemical transformations.[7]
In order to test our hypothesis, we started to investigate
the reaction of Z-alkynyl oxime ether 1[8] in the presence of
a range of alkyl iodides as carbon radical precursors in the
iodine-atom-transfer reaction initiated by Et3B (Table 1).
When Z-1 was treated with cyclohexyl iodide and Et3B at
room temperature, the expected regioselective radical addi-
tion reaction proceeded to give b-adduct 4a in high yield
but with low stereoselectivity (Table 1, entry 1). To control
the double bond geometry, the radical reaction and the pro-
tonation of boryl aminoallene C, generated by trapping of
allenaminyl radical A with Et3B, were carried out in the
presence of alcohol at À808C. Addition of tBuOH improved
the stereoselectivity of the C=N double bond, but not of the
C=C double bond (Table 1, entry 2). Interestingly, both
double bonds were successfully controlled by the presence
[a] Dr. M. Ueda, K. Yoshida, A. Sato, Prof. Dr. T. Naito,
Prof. Dr. O. Miyata
Kobe Pharmaceutical University, Motoyamakita
Higashinada, Kobe 658-8558 (Japan)
Fax : (+81)78-441-7554
E-mail: miyata@kobepharma-u.ac.jp
[b] Dr. H. Matsubara
Graduate School of Science, Osaka Prefecture University
Sakai, Osaka 599-8531 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002744.
Chem. Eur. J. 2011, 17, 1789 – 1792
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1789

Table 1. Regio- and stereoselective radical addition to alkynyl oxime
6d as a sole product in 77% yield (Table 2, entry 4). It is
noteworthy that reversal of stereoselectivity in the aldol re-
action step was observed compared with the radical addi-
tion–protonation reaction because of thermodynamic con-
trol. The reaction with the bulky tert-butyl radical also pro-
duced exclusively anti-adduct 6e in excellent yield (Table 2,
entry 5). The domino reaction with enolizable cyclohexane-
carboxaldehyde proceeded effectively to provide the corre-
sponding furanones 6 f–h in good yields and in a stereoselec-
tive manner (Table 2, entries 6–8).
ether (Z)-1.[a]
Entry R1I
R2OH
T
[8C]
Product
(yield [%][b]
)
Ratio[c] [2Z,4E/2E,4E/
2Z,4Z/2E,4Z]
U
1
2
3
4
5
6
c-C6H11I none
RT 4a (93)
1:1:2:2
c-C6H11I tBuOH À80 4a (55)
0:0:3:2
0:0:10:1
0:0:15:1
0:0:9:1
0:0:10:1
The stereoselectivity could be explained with the six-
membered transition states D and E shown in Scheme 1.
The tetrasubstituted olefin 5 would be formed through a
c-C6H11I MeOH À80 4a (85)
sBuI
MeOH À80 4b (49)
c-C5H9I MeOH À80 4c (69)
iPrI
MeOH À80 4d (52)
[a] The reactions were carried out with R1I (20 equiv), Et3B (2 equiv),
and R2OH (2 equiv). [b] Combined yield of all isomers. [c] Determined
1
by H NMR spectroscopy.
of MeOH to furnish (2Z,4Z)-4a in high yield (Table 1,
entry 3). Other secondary alkyl iodides worked well to
afford the 2Z-adducts 4b–d stereoselectively (Table 1, en-
tries 4–6).
The new finding of this regioselective addition to 1
prompted us to explore a new domino radical addition–
aldol-type reaction[9] and we succeeded in developing a
novel method for constructing the tetrasubstituted olefins 5
and the highly substituted butenolides 6 (Table 2). In the
presence of Me3Al as a Lewis acid, the domino reaction of 1
with benzaldehyde and Et3B afforded 5a and 6a through a
sequential process involving a regioselective ethyl radical
addition and a aldol-type reaction of intermediate N-boryl
aminoallene C, but with low selectivity (Table 2, entry 1). In
the case of the reaction with aliphatic aldehydes, slightly
Scheme 1. Explanation for the stereoselective outcome of the aldol-type
reaction of N-boryl aminoallene.
predominant formation of furanone
6 was observed
(Table 2, entries 2 and 3). Interestingly, employment of
more bulky secondary isopropyl iodide afforded furanone
syn-addition of N-borylaminoallene C to a Me3Al-activated
aldehyde via transition state D. An anti-trapping of C with
an aldehyde and subsequent lactonization of borate G
would afford furanone 6 via transition state E. Relatively
large alkyl group for R1 and R2 would led to a preference
for conformation E with less steric repulsion between the
ester group and the aldehyde part, and eventually led to the
formation of furanone 6 through anti-addition of an electro-
phile. Because the aldol reaction in principle is reversible,
the irreversible lactonization enforced an equilibrium favor-
ing the formation of furanone 6.
Table 2. Domino alkyl radical addition–aldol-type reaction of (Z)-1.
Entry
R1I
R2CHO
Product (R1 =) (yield [%][a]
)
5a–c
6a–h
The usefulness of dual activated alkyne 1 as a synthon
was proved by reversed regioselective addition of organo-
cuprates. The conjugate addition of organocopper reagents
to the alkynyl ester is a prime method for constructing iso-
merically pure, trisubstituted a,b-unsaturated esters.[10] Un-
fortunately, extensions toward synthesizing tetrasubstituted
alkenes[11] have been hampered by the low reactivity of the
1-alkoxycarbonyl vinylcopper(I) intermediate and its ten-
dency to isomerize via a copper allenoate at temperatures
above À308C.[12] Although many examples of nucleophilic
addition to a,b-acetylenic ketones and esters have been re-
1[b]
2[b]
3[b]
4[c]
5[c]
6[c]
7[c]
8[c]
–
–
–
PhCHO
5a (Et)
5b (Et)
5c (Et)
(36)
(28)
(31)
6a (Et)
6b (Et)
6c (Et)
6d
6e
6 f
(21)
(55)
(49)
(77)
(93)
(63)
(68)
(68)
Me2CHCHO
c-C6H11CHO
PhCHO
iPrI
tBuI
iPrI
c-C6H11I
tBuI
nd[d]
PhCHO
nd
nd
nd
nd
c-C6H11CHO
c-C6H11CHO
c-C6H11CHO
6g
6h
[a] Yield of isolated product. [b] Reactions were carried out with Et3B
(2.5 equiv), aldehyde (1.2 equiv), and Me3Al (1.2 equiv) for 3 h. [c] Reac-
tions were carried out with Et3B (2.5 equiv), R1I (20 equiv), aldehyde
(1.2 equiv), and Me3Al (1.2 equiv) for 3 h. [d] Not detected.
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Chem. Eur. J. 2011, 17, 1789 – 1792

Stereoselective Construction of Tetrasubstituted Alkenes
COMMUNICATION
ported,[13] the reaction of a,b-acetylenic imines has not been
reported so far.
stereoselectivities (Table 3, entries 4 and 5). It should be
noted that methylation and bromination by 2,4,4,6-tetrabro-
mo-2,5-cyclohexadienone gave highly functionalized olefin
7e, which is a useful synthon for further transformation.
Computational studies were carried out by using density
functional theory (DFT) to understand the reversal of regio-
selectivity with the same substrate (Scheme 2). Addition of
a methyl radical to the model oxime ether 8 is predicted to
be a highly exothermic process. The activation energy for
transition state K, which is involved in the addition reaction
at the b-carbon of 8, is calculated to be 23.0 kJmolÀ1 and,
therefore, 12.5 kJmolÀ1 lower than that for transition state I,
which is involved in the reaction at the a-carbon. Intermedi-
ate L, which is involved in the b-addition, is also calculated
to be more stable than adduct J, which is involved in the a-
addition, by 63.5 kJmolÀ1. Thus, the b-addition of the
methyl radical is both kinetically and thermodynamically
preferable to the a-addition. In the case of carbocupration,
transition states M and O, which are involved in the carbo-
cupration of oxime ether 8 with Me2CuLi, were formed in
the presence of LiBr. Inspection of the transition structures
reveals that in both structures the lithium atom coordinates
with the oxygen of the carbonyl group, and the copper atom
coordinates with the nitrogen of the oxime moiety. The car-
bocupration reaction is predicted to commence from com-
plex 9 in which a lithium atom of the cyclic cluster of
Me2CuLi and LiBr coordinates to the carbonyl group of 8.
The a-addition involving transition state M is calculated to
be energetically favored over the b-addition involving transi-
tion state O by 15.9 kJmolÀ1. In addition, the a-adduct N is
calculated to be more stable than the b-adduct P by
10.5 kJmolÀ1. Therefore, the a-addition is both kinetically
and thermodynamically preferable to the b-addition.[15]
In summary, reagent-dependent regioselective additions
to dual activated alkynes have been carried out for the first
time. The reactions display complete reagent selectivity in
that the reversal of the orientation of the addition to the al-
kynes is controlled. Finally, the present regioselective addi-
tion reaction to alkynes can provide a new synthetic access
to tetrasubstituted and functionalized alkenes including
highly substituted furanones.
The regioselective addition reaction of (E)-1[14] with MeLi
in the presence of CuBr·SMe2 proceeded successfully to give
the expected a-addition product (2Z,4E)-7a in moderate
yield with high stereoselectivity (Table 3, entry 1). It is note-
Table 3. Regio- and stereoselective nucleophilic addition to alkynyl
oxime ether (E)-1.
Entry RM
Electrophile Product
Yield
[%][a]
Ratio[b] [2Z,4E/
isomers]
(E=)
1[c]
2[c]
3[c]
4[d]
5[d]
6[d]
MeLi
EtLi
EtMgBr H2O
EtLi
EtLi
MeLi
H2O
H2O
7a (H)
7b (H)
7b (H)
7c (Me)
7d (Bz)
7e (Br)
46
75
60
63
66
45
>10:1
10:1
1:1
8:1
>10:1
7:1
MeI
BzCl[e]
TBCHD[f]
[a] Combined yield of the different isomers. [b] Determined by 1H NMR
spectroscopy. [c] Reactions were carried out with RM (2.2 equiv) and
CuBr·SMe2 (1.1 equiv). [d] Reactions were carried out with RM
(2.2 equiv), CuBr·SMe2 (1.1 equiv), and an electrophile (2.2 equiv).
[e] Bz: benzoyl. [f] TBCHD: 2,4,4,6-tetrabromo-2,5-cyclohexadienone.
worthy that the alkylation occurred at the opposite position
compared with that of the radical addition, which is consis-
tent with our hypothesis. EtLi worked better than MeLi to
afford 7b in good yield (Table 3, entry 2). The Grignard re-
agents underwent the same type of a-addition but with no
stereoselectivity (Table 3, entry 3). Encouraged by the regio-
selective nucleophilic a-addition to 1, we were challenged to
explore the one-pot nucleophilic–electrophilic addition reac-
tion and succeeded in constructing tetrasubstituted olefins.
Treatment of 1 with R2CuLi in THF followed by addition of
an electrophile such as MeI and PhCOCl, produced the ex-
pected tetrasubstituted alkenes 7c and 7d with good to high
Scheme 2. Reaction profile for the regioselective addition reaction of oxime ether 8. Energies [kJmolÀ1] were calculated on the BHandHLYP/6-31+G*
level for the radical reactions and on the BHandHLYP/6-31+G*+LanL2DZ ECP level (Cu, Br) for the carbocupration.
Chem. Eur. J. 2011, 17, 1789 – 1792
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1791

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Experimental Section
General procedure for radical additions: MeOH (0.011 mL, 0.26 mmol),
R1I (2.6 mmol), and Et3B (1.0m in hexane, 0.26 mL, 0.26 mmol) were
added to a solution of alkynyl oxime ether (Z)-1 (30 mg, 0.13 mmol) in
CH2Cl2 (3 mL) under a N2 atmosphere at À808C. After being stirred for
15 h at the same temperature, the reaction mixture was diluted with H2O
(10 mL) and extracted with CHCl3 (3ꢁ20 mL). The combined organic
layers were dried over MgSO4 and concentrated under reduced pressure.
Purification by preparative TLC (hexane/AcOEt 15:1) afforded 4a–d.
[3] a) M. Ueda, E. Iwasada, H. Miyabe, O. Miyata, T. Naito, Synthesis
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General procedure for domino alkyl radical addition–aldol-type reac-
tions: R2CHO (0.26 mmol), R1I (4.40 mmol), Me3Al (1.03m in hexane,
0.25 mL, 0.26 mmol), and Et3B (1.05m in hexane, 0.52 mL, 0.55 mmol)
were added to a solution of (Z)-1 (50 mg, 0.22 mmol) in CH2Cl2 (5 mL)
under an Ar atmosphere at room temperature. After being stirred under
a N2 atmosphere at the same temperature for 3 h, the reaction mixture
was washed with saturated aqueous NaHSO3 (10 mL) and extracted with
ethyl acetate (3ꢁ20 mL). The organic phase was washed with saturated
aqueous NaHCO3 (20 mL) and saturated aqueous NaCl (20 mL), dried
over MgSO4, and concentrated at reduced pressure. The residue was pu-
rified by preparative TLC (hexane/AcOEt 5:1) to afford 6d–h.
[5] a) S. E. Booth, P. R. Jenkins, C. J. Swain, J. B. Sweeney, J. Chem.
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General procedure for nucleophilic and electrophilic addition reactions:
RLi (0.48 mmol) was added dropwise to a suspension of CuBr·Me2S
(50 mg, 0.24 mmol) in THF (1 mL) under an Ar atmosphere at À408C.
The resulting dark brown suspension was stirred at the same temperature
for 1 h. A solution of (E)-1 (50 mg, 0.22 mmol) in THF (1 mL) was
added dropwise to the reaction mixture at À788C and then the reaction
mixture was stirred at the same temperature for 1 h. After a solution of
an electrophile (0.48 mmol) was added dropwise, the reaction mixture
was stirred at À788C for 1 h, and then 08C for 1 h. After being stirred at
room temperature overnight, the reaction was quenched with saturated
aqueous NH4Cl (5 mL), diluted with H2O (10 mL), and extracted with
ethyl acetate (3ꢁ20 mL). The organic phase was washed with saturated
aqueous NaCl (20 mL), dried over MgSO4, and concentrated at reduced
pressure. The residue was purified by preparative TLC (hexane/AcOEt=
10:1) to afford 7c–e.
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stereoselectivity.
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Acknowledgements
This work was supported in part by Grants-in Aid from the Ministry of
Education, Culture, Sports, Science and Technology of Japan, and the
Science Research Promotion Fund of the Japan Private School Promo-
tion Foundation. M.U. is grateful for the Research Foundation for Phar-
maceutical Science.
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Keywords: addition reactions · computational chemistry ·
domino reactions · radical reactions · regioselectivity
[14] The E isomer of the oxime ether should be used, because the reac-
tion of (Z)-1 with organometallic reagent produced the conjugated
nitrile by the elimination of benzyl alcohol.
[1] a) M. E. Jung in Comprehensive Organic Synthesis, Vol. 4 (Eds.:
B. M. Trost, I. Fleming), Pergamon, Oxford, 1999, pp. 1–67; b) P.
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[15] For details of calculations see the Supporting Information.
[2] For a review, see: a) M. Shimizu, I. Hachiya, I. Mizota, Chem.
Commun. 2009, 874; for selected examples, see: b) L.-Q. Lu, J.-J.
Received: September 24, 2010
Published online: January 5, 2011
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Chem. Eur. J. 2011, 17, 1789 – 1792