Regioselective 1,4-conjugate addition of grignard reagents to nitrodienes in the presence of catalytic amounts of Zn(II) salts

Article abstract of DOI:10.1021/ol500114m

Grignard reagents undergo facile regioselective 1,4-conjugate addition to nitrodienes in the presence of catalytic amounts of Zn(II) salts with excellent yields. A wide range of ligands such as alkyl, aryl, heteroaryl, allyl, vinyl, 1-alkynyl, and alkoxy ligands were transferred, while a thiolate ligand afforded 1,6-regioselectivity. The reactions were successfully carried out on δ-alkyl- or aryl-substituted α,β,γ,δ-diunsaturated nitrodiene substrates. Regioselectivity is minimally influenced by temperature or choice of solvent.

Full text of DOI:10.1021/ol500114m

Letter
pubs.acs.org/OrgLett
Regioselective 1,4-Conjugate Addition of Grignard Reagents to
Nitrodienes in the Presence of Catalytic Amounts of Zn(II) Salts
Ramesh C. Dhakal and R. Karl Dieter*
Hunter Laboratory, Department of Chemistry, Clemson University, Clemson, South Carolina 29634-0973, United States
S
* Supporting Information
ABSTRACT: Grignard reagents undergo facile regioselective
1,4-conjugate addition to nitrodienes in the presence of
catalytic amounts of Zn(II) salts with excellent yields. A wide
range of ligands such as alkyl, aryl, heteroaryl, allyl, vinyl, 1-
alkynyl, and alkoxy ligands were transferred, while a thiolate
ligand afforded 1,6-regioselectivity. The reactions were
successfully carried out on δ-alkyl- or aryl-substituted α,β,γ,δ-diunsaturated nitrodiene substrates. Regioselectivity is minimally
influenced by temperature or choice of solvent.
he control of regio-, stereo-, and chemoselectivity in the
reactions of small, highly functionalized molecules
chiral ligands.8d,12c We now report our results on the
regioselective 1,4-conjugate addition of Grignard reagents to
nitrodienes in the presence of catalytic amounts of zinc(II)
salts.
T
provides rich opportunities for generating highly substituted
and functionalized molecular synthons.1,2 The conjugate
addition of carbon nucleophiles to Michael acceptors is a
ubiquitous reaction for construction of carbon−carbon bonds
in organic chemistry,3 and Michael acceptors containing
conjugated dienes4−6 pose problems of regioselective control.
Numerous developments have been reported for the conjugate
addition reactions of nitroalkene−Michael acceptors for the
synthesis of nitrogen-containing molecules, which are often
richly endowed with biological activity.7 The most widely
studied nitro alkene-Michael acceptors include simple nitro-
alkenes,8 α,β,γ,δ-nitrodienes,8d,9−11 and nitroenynes8d,12 where
the conjugated nitrodienes and nitroenynes give a mixture of
products in the absence of catalysts arising from competitive
nonregioselective 1,4- and 1,6-addition pathways.9−11
Although a large number of organocatalytic procedures for
the regio- and stereoselective conjugate addition of nucleo-
philes to nitrodienes have been developed, they have largely
involved soft nucleophiles such as enolates, enamines, and silyl
enol ethers. Chiral proline,9a−d bifunctional amine−thiourea
derivatives,9e−i cinchona alkaloids,9j,k and amino acid9l,m
catalysts have been employed for enantioselective 1,4-conjugate
addition reactions of carbonyl substrates to nitrodienes with
high efficiency. The utilization of nitrodienes in transition-
metal-catalyzed enantioselective 1,4-conjugate addition reac-
tions of malonate enolates,9n Friedel−Crafts alkylation of
indole,9o diastereoselective Morita−Baylis−Hillman reactions10
of carbonyl compounds, and the Rauhut−Currier reaction11 of
methyl vinyl ketone (MVK) have also been reported recently.
The use of organometallic reagents for regio- and stereo-
selective 1,4-conjugate additions to nitrodienes is rather limited.
A singular report on 1,4-additions of triorganoaluminum
reagents13 to nitroalkenes was followed recently by a report
for the regio- and enantioselective 1,4- or 1,6-conjugate
addition reactions of trialkylaluminum reagents to nitrodienes
employing catalytic amounts of Cu(I) salts and ferrocene based
We first examined the 1,4-conjugate addition reactions of
stoichiometric organozincate reagents to (E)-1-nitro-2,4-
pentadiene (1). Although 1,4-conjugate addition was the
favored pathway, a mixture of 1,4- and 1,6-addition products
was observed (Table 1, entries 1−5 and 8−14) when
trialkylzincate reagents were employed. Treatment of nitro-
n
diene 1 with Bu3ZnLi gave slightly better regioselectivity at
lower temperatures (entry 1 vs 2) and in less polar solvents
(entries 3 and 4), but slightly decreased regioselectivity was
observed when the counterion was changed from Li+ to MgBr+
(entries 5 and 9). As expected, the dialkyl or alkyl(cyano)-
cuprate reagents gave exclusively the 1,6-addition product
(entries 6 and 7).6 Although slightly higher regioselectivity was
obtained with the less reactive Me3ZnLi (entry 8), little to no
t
regioselectivity was observed for Bu3ZnLi in either polar
(entries10 and 11) or nonpolar (entry 12) solvents. Good
regioselectivity could be achieved by utilization of the mixed
t
triorganozinate BuZnMe2Li (entries 13 and 14), which was
i
also observed for PrZnMe2MgBr (entry 9). Surprisingly, the
reaction of sodium tributoxy zincate with nitrodiene 1 also gave
exclusively the 1,4-adduct in good yield and without a trace of
the 1,6-addition product being formed (entry 15), while the
utilization of (nPrS)3ZnNa under identical reaction conditions
gave the 1,6-adduct with minor amounts of the 1,4-addition
product (entries 16 and 17).14
Encouraged by these preliminary results involving the
reaction of stoichiometric organozincate reagents with nitro-
diene 1, we sought to reduce the amounts of organometallic
reagents used [RLi or Grignard reagent (3.0 equiv), ZnBr2 (1.0
equiv)] by developing a procedure catalytic in the Zn(II) salt
Received: January 13, 2014
Published: February 19, 2014
© 2014 American Chemical Society
1362
dx.doi.org/10.1021/ol500114m | Org. Lett. 2014, 16, 1362−1365

Organic Letters
Letter
Table 1. Regioselective Conjugate Addition of
Organozincate/Organocuprate Reagents to Nitrodiene 1
Table 2. 1,4-Conjugate Addition of Grignard Reagents to 1
Catalyzed by Zn(II) Salts
R3ZnM or
a
temp °C
% yield
regio
e
b
c
d
entry
RCuLLi
solvent
(h)
(2 + 3)
(2:3)
1
nBu3ZnLi
nBu3ZnLi
nBu3ZnLi
nBu3ZnLi
nBu3ZnMgBr
nBu2CuLi
nBuCuCNLi
A
A
B
C
A
A
A
A
A
A
A
C
A
A
A
A
A
−40 (12)
78
81
78
72
74
77
55
71
78
80
72
71
73
69
81
78
79
82:18
84:16
87:13
88:12
78:22
0:100
0:100
90:10
88:12
50:50
56:44
55:45
78:22
92:8
f
temp °C
% yield
regio
e
2
−78 (3)
−78 (3)
−78 (3)
a
b
c
d
entry
R
solvent
(h)
(2 + 3)
(2:3)
f
3
f
1
nBu-
nBu-
nBu-
nBu-
nBu-
Me-
iPr-
A
A
A
B
−78 (3)
−40 (12)
−78 (2)
−78 (2)
−78 (2)
−78 (3)
−78 (3)
−78 (3)
0 (12)
65
81
83
87
86
75
76
77
85
86
89
72
74
85
89
83
77
85
83
87
73
72
73
70
83
75
81
79
83
76
87
65:35
88:12
90:10
91:9
f
4
2
5
−78 (12)
−78 (12)
−78 (12)
−78 (12)
−78 (12)
−40 (3)
3
6
4
7
5
C
A
A
A
D
D
D
C
A
D
B
92:8
8
Me3ZnLi
6
91:9
9
iPrZnMe2MgBr
tBu3ZnLi
7
90:10
95:5
10
11
12
13
14
15
16
17
8
Bn-
tBu3ZnLi
tBu3ZnLi
tBuZnMe2Li
tBuZnMe2Li
(nBuO)3ZnNa
(nPrS)3ZnNa
(nPrS)3ZnNa
−78 (3)
−78 (3)
9
Bn-
67:33
76:24
82:18
78:22
95:5
f
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Bn-
−20 (12)
−78 (3)
−78 (3)
−78 (2)
−78 (3)
−78 (3)
−78 (12)
−40 (3)
−40 (3)
−20 (12)
−78 (3)
−20 (12)
−78 (12)
−20 (12)
0 (12)
−78 (6)
−78 (3)
Bn-
f
Bn-
−20 (12)
25 (1)
100:0
6:94
CH2CHCH2-
CH2CHCH2-
CH2CHCH2-
Ph-
96:4
−78 (6)
b
5:95
96:4
a
1−1.5 equiv of reagents was used. Solvent: A = THF, B = CH2Cl2, C
= toluene. Reaction was run at the indicated temperature and allowed
to warm to room temperature over the indicated time unless otherwise
noted. Combined yield of both regioisomers. Regioisomeric ratio
was determined from integration of the 1H NMR absorptions of vinyl
hydrogens or peak height of the vinyl carbon absorptions in the 13C
D
B
80:20
93:7
c
Ph-
g
Ph-
B
98:2
d
e
1-naphthyl-
2-MeC6H4-
D
B
100:0
92:8
g
f
p-MeOC6H4-
B
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
72:28
93:7
NMR spectrum. Reaction was run and quenched at the indicated
p-Me2NC6H4-
5-(1-Me)indolyl-
2-furyl-
E
temperature.
D
D
D
D
D
F
n
(Table 2). In a control experiment, reaction of BuMgCl (1.0
2-furyl-
−40 (12)
0 (12)
equiv) with nitrodiene 1 in the absence of Zn(II) salts gave
2-thienyl-
moderate yields of conjugate adducts with poor regioselectivity
2-thienyl-
−20 (12)
−20 (12)
−78 (3)
−20 (12)
−20 (12)
−20 (12)
n
(Table 2, entry 1). When BuMgCl (1.2 equiv) was reacted
2-(1-Me)pyrrolyl-
nBuCHCH-
nBuCC-
with nitrodiene 1 in the presence of catalytic amounts of zinc
bromide (0.1 equiv), good yields and regioselectivity for the
1,4-conjugate adduct was observed (entries 2−5) with the
degree of regioselectivity being largely independent of solvent
polarity but slightly higher when conducted at lower temper-
atures. Similar results were obtained for the methyl, isopropyl,
and benzyl Grignard reagents (entries 6−8), although the
benzyl Grignard reagent gave significantly lower regioselectivity
at higher temperatures (entries 9 and 10) in Et2O with the poor
or noncoordinating solvents Et2O and PhMe giving slightly
lower regioselectivities (entries 11 and 12) than the more
coordinating THF (entry 8) at −78 °C. Allyl Grignard reagents
gave good yields and good regioselectivity in both coordinating
(e.g., THF or Et2O) and noncoordinating (e.g., CH2Cl2)
solvents (entries 13−15).
These encouraging results involving regioselective 1,4-
conjugate addition reactions of alkyl Grignard reagents with
nitrodiene 1 mediated by ZnBr2 catalysis prompted us to
examine the reaction of aryl Grignard reagents with nitrodiene
1 in the presence of catalytic amounts of zinc(II) salts.
Contrary to prior observations,2a the reaction of PhMgBr with
nitrodiene 1 in Et2O or CH2Cl2 gave excellent yields of the
D
D
D
D
PhCC-
g
PhCC-
83
b
a
ZnBr2 (0.1 equiv) was used unless otherwise noted. Solvent: A =
THF. B = CH2Cl2. C = toluene. D = Et2O. E = THF:CH2Cl2 (1:1). F
= THF:Et2O (1:3). Reagents were added at the indicated temperature
c
d
and warmed to 25 °C over the indicated time. Combined yield of
e
both regioisomers. Regioisomeric ratios were determined from
integration of 1H NMR absorptions of vinyl hydrogens or peak height
f
of the vinyl carbon absorptions in 13C NMR spectrum. Reaction run
g
in the absence of Zn(II) salts. Zn(CN)2 (0.1 equiv) was used.
conjugate adduct with modest regioselectivity in Et2O (entry
16) and excellent regioselectivity at −40 °C in CH2Cl2 (entries
17 and 18). Significant production of biphenyl was not
observed in these reactions, and Zn(CN)2 offered no
advantages over ZnBr2 (entries 17 and 18). The protocol
could be readily extended to polyaromatic (entry 19), electron-
rich aryl (entries 20−23), and heteroaryl (entries 24−28)
Grignard reagents affording exclusively the 1,4-adducts. In these
1363
dx.doi.org/10.1021/ol500114m | Org. Lett. 2014, 16, 1362−1365

Organic Letters
Letter
reactions, the regioselectivity did not appear sensitive to
temperature (entries 17−19, 21, 23−28, and 30−32).
Surprisingly, an alkynyl Grignard reagent was also successfully
transferred to nitrodiene 1 when the catalytic procedure was
employed since in prior work2a the alkynyl ligand acted as a
nontransferable ligand. Although, nBuCCMgBr gave ex-
clusively the 1,4-adduct in Et2O (entry 30), the more electron
deficient PhCCMgBr gave good yields but poor regiose-
lectivity (entry 31) under identical reaction conditions.
Utilization of Zn(CN)2 (0.1 equiv) in the reaction of PhC
CMgBr with nitrodiene 1, however, gave excellent yields and
regioselectivity for the major 1,4-adduct (entry 32).
exclusively the 1,4-conjugate addition product (entry 9, 73%,
1,4:1,6; 100:0) under identical reaction conditions.
Although complex 10 has been invoked15 to account for the
tendency of organozinc reagents to undergo 1,4-addition to
α,β-unsaturated carbonyl compounds in contrast to the 1,2-
addition reactivity pathway of Grignard and organolithium
reagents and could explain the preference for 1,4-selectivity, the
model does not fully comport with our experimental data.
Contrary to expectations, the 1,4:1,6-regioselectivity is relatively
insensitive to solvent-coordinating ability [e.g., THF vs CH2Cl2
or PhMe (DN = 20−0):16 Table 1, entries 2 vs 3−4, 11 vs 12;
Table 2, entries 3 vs 4−5, 8 vs 11−12, and 13 vs 14−15; Table
3, entries 2 vs 3−4, 5 vs 6] where a contact ion-pair (CIP) for
the zincate reagent17 in CH2Cl2 or PhMe should favor greater
1,4:1,6-selectivity and a solvent separated ion-pair (SSIP) in
THF16 should induce lower selectivity.2a,17
In an attempt to extend substrate scope of the reactions, (E)-
1-nitro-4-phenyl-1,3-butandiene (4) and (E)-1-nitro-4-(4-me-
thoxyphenyl)-1,3-butandiene (7) were synthesized and reacted
with Grignard reagents using a procedure with catalytic zinc(II)
n
salts. The reaction of BuMgCl (1.2 equiv) with 4 in the
Calculations indicate that the d-orbitals on organo-Zn(II)
species are low lying in comparison15,18 to those of organo-
cuprates (e.g., R2CuM) so that the organo ligands act as the
nucleophiles in the former while the Cu atom acts as the
nucleophile in the latter. Thus, the zinc reagents follow a
pathway of carbozincation18 while the cuprate reagents undergo
oxidative addition and favor 1,6-addition via σ−π-allyl-σ-
Cu(III) rearrangements. The preference for zincate 1,4-
addition could be rationalized by differential charge density
or orbital coefficient magnitudes at the γ- and δ-positions
(Scheme 1). The latter correctly rationalizes regiochemistry in
presence of catalytic amounts of zinc cyanide (0.1 equiv) in
both coordinating (i.e., THF) and noncoordinating solvents
(i.e., CH2Cl2, toluene) was investigated. In all of these solvents,
moderate yields but poor regioselectivity of the 1,4-adduct were
observed (Table 3, entries 1−3, 63−67%, 1,4 vs 1,6; 78:22−
Table 3. 1,4-Conjugate Addition of Grignard Reagents to
Aryl Nitrodienes Catalyzed by Zn(II) Salts
Scheme 1. Mechanistic Rationale for 1,4-Addition
c
d
% yield
regio
a
b
entry diene
R-
solvent
(A + B)
(A:B)
1
2
3
4
5
6
7
8
9
4
4
4
4
4
4
7
7
7
nBu-
nBu-
nBu-
A
B
C
A
A
C
A
A
A
65
67
63
66
77
58
73
71
73
78:22
80:20
78:22
60:40
65:35
60:40
78:22
100:0
100:0
frontier molecular orbital (FMO) models.19 Simple semi-
empirical calculations20 support this view and correctly predict
lower 1,4:1,6-regioselectivity for the aryl-substituted nitrodienes
4 and 7. Charge density considerations also appear consistent
with the 1,6-preference of (nPrS)3ZnNa and 1,4-preference of
(nBuO)3ZnNa (Table 2, entries 16 and 17) in line with HSAB
considerations.15
e
Ph-
Ph-
Ph-
nBu-
e
Ph-
e,f
nBuCHCH
a
Zn(CN)2 (0.1 equiv) was used as catalyst unless otherwise noted.
Solvent: A = THF. B = CH2Cl2. C = toluene. Combined yield of
both regioisomer. Regioisomeric ratios were determined from
In summary, we have successfully developed the first method
for the 1,4-conjugate addition of Grignard reagents to α,β,γ,δ-
unsaturated nitrodienes in the presence of catalytic amounts of
Zn(II) salts and in the absence of Cu(I) salts. The method is
highly 1,4-regioselective for δ-alkyl-substituted nitrodiene 1
showing excellent 1,4-selectivity for alkyl (90:10 to 92:8),
benzyl (82:18 to 95:5), allyl (95:5 to 96:4), and alkynyl (93:7
to 100:0) Grignard reagents while displaying exclusive to nearly
exclusive 1,4-selectivity for aryl (98:2 to 100:0), heteroaryl
(100:0), and vinyl (100:0) Grignard reagents. Although there
are no uniform patterns, choice of solvent, Zn(II) salt, and
reaction temperature can be manipulated to increase 1,4-
regioselectivity in those cases where initial experimenation led
to 1,4:1,6 ratios below 90:10. δ-Substituted aryl nitrodienes 4
and 7 generally display reduced 1,4-selectivity, although a 4-
methoxyphenyl substituent (i.e., 7) did afford exclusive 1,4-
selectivity with phenyl and alkenyl Grignard reagents. The
scope of the method was also expanded to heteroatom ligands
wherein alkoxyzincate reagents gave exclusive 1,4-addition and
alkylthiolatozincates gave high 1,6-selectivity (95:5). The
b
c
d
1
integration of the H NMR absorptions of the vinyl hydrogen or the
peak height of the vinyl carbon absorptions in the 13C NMR spectrum.
e
f
ZnBr2 (0.1 equiv) was used. Grignard reagent was prepared by
halogen−metal exchange of the corresponding vinyl iodide with nBuLi
(1.0 equiv) followed by treatment with MgBr2.
80:20). Application of identical reaction conditions for the
reaction of PhMgCl (1.2 equiv) with 4 in THF gave moderate
yields but poor regioselectivity (entry 4, 66%, 1,4:1,6; 60:40).
Utilization of zinc cyanide as a source of Zn(II) ion or use of a
noncoordinating solvent (i.e., toluene) did not change the
yields or regioselectivity of the conjugate addition product
n
(entries 5 and 6). The reaction of BuMgCl with 7 gave good
yields of conjugate addition products with poor regioselectivity
(entry 7, 73%, 1,4:1,6; 78:22), while PhMgCl gave exclusive
1,4-conjugate adduct in good yield (entry 8, 71%, 1,4:1,6;
100:0). Vinyl Grignard reagents also gave good yields and
1364
dx.doi.org/10.1021/ol500114m | Org. Lett. 2014, 16, 1362−1365

Organic Letters
Letter
(i) Tan, B.; Lu, Y.; Zeng, X.; Chua, P. J.; Zhong, G. Org. Lett. 2010, 12,
2682−2685. (j) Tan, B.; Chua, P. J.; Li, Y.; Zhong, G. Org. Lett. 2008,
10, 2437−2440. (k) Tripathi, C. B.; Kayal, S.; Mukherjee, S. Org. Lett.
2012, 14, 3296−3299. (l) Nugent, T. C.; Shoaib, M.; Shoaib, A. Org.
Biomol. Chem. 2011, 9, 52−56. (m) Biswas, A.; De Sarkar, S.; Tebben,
L.; Studer, A. Chem. Commun. 2012, 48, 5190−5192. (n) Evans, D. A.;
Mito, S.; Seidel, D. J. Am. Chem. Soc. 2007, 129, 11583−11592.
(o) Peng, J.; Du, D. Eur. J. Org. Chem. 2012, 2012, 4042−4151.
(10) Deb, I.; Shanbhag, P.; Mobin, S. M.; Namboothiri, I. N. N. Eur.
J. Org. Chem. 2009, 2009, 4091−4101.
conjugate addition of alkynyl and heteroatom ligands are
particularly challenging for Cu(I) salts. Control experiments
confirmed that the reactions were indeed catalyzed by zinc(II)
salts.
ASSOCIATED CONTENT
* Supporting Information
General experimental procedures, data reduction, H and 13C
■
S
1
NMR spectra for 1, 2a−t, 3a,g,i,t, 4, 5a,b, 7, and 8a−c are
included. This material is available free of charge via the
Internet at http://pubs.acs.org.
(11) Shanbhag, P.; Nareddy, P. R.; Dadwal, M.; Mobin, S. M.;
Namboothiri, I. N. N. Org. Biomol. Chem. 2010, 8, 4867−4873.
(12) (a) Trost, B. M.; Hisaindee, S. Org. Lett. 2006, 8, 6003−6005.
(b) Belot, S.; Vogt, K.; Besnard, C.; Krause, N.; Alexakis, A. Angew.
AUTHOR INFORMATION
Corresponding Author
̀
Chem., Int. Ed. 2009, 48, 8923−8926. (c) Tissot, M.; MuIller, D.;
■
Belot, S.; Alexakis, A. Org. Lett. 2010, 12, 2770−2773. (d) Uraguchi,
D.; Kinoshita, N.; Kizu, T.; Ooi, T. Synlett 2011, 2011, 1265−1267.
(13) Menicagli, R.; Guagnano, V.; Malanga, C. Gazz. Chim. Ital.
1992, 122, 487−488.
*E-mail: dieterr@clemson.edu.
Notes
(14) For organocatalytic 1,4-addition of aliphatic thiols to nitrodiene,
see: Kowalczyk, R.; Nowak, A. E.; Skarzewski, J. Tetrahedron:
Asymmetry 2013, 24, 505−514.
(15) Uchiyama, M.; Nakamura, S.; Furuyama, T.; Nakamura, E.;
Morokuma, K. J. Am. Chem. Soc. 2007, 129, 13360−13361.
(16) For donor numbers (DN), see: Gutmann, V. Coord. Chem. Rev.
1976, 18, 225−255.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support of the NSF Chemical Instrumentation Program for
purchase of a JEOL 500 MHz NMR instrument is gratefully
acknowledged (CHE-9700278).
(17) (a) Hevia, E.; Chua, J. Z.; Garcia-Alvarez, P.; Kennedy, A. R.;
McCall, M. D. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 5294−5299.
(b) Armstrong, D. R.; Clegg, W.; Garcia-Alvarez, P.; McCall, M. D.;
Nuttall, L.; Kennedy, A. R.; Russo, L.; Hevia, E. Chem.Eur. J. 2011,
17, 4470−4479.
REFERENCES
■
(1) For a review on divergent synthetic strategy, see: Serba, C.;
Winssinger, N. Eur. J. Org. Chem. 2013, 4195−4214.
(2) (a) Dhakal, R. C.; Dieter, R. K. J. Org. Chem. 2013, 78, 12426−
12439. (b) Guo, F.; Dhakal, R. C.; Dieter, R. K. J. Org. Chem. 2013, 78,
8451−8464. (c) Dieter, R. K.; Huang, Y.; Guo, F. J. Org. Chem. 2012,
77, 4949−4967. (d) Dieter, R. K.; Guo, F. J. Org. Chem. 2009, 74,
3843−3848. (e) Dieter, R. K.; Guo, F. Org. Lett. 2008, 10, 2087−2090.
(3) (a) Perlmutter, P. Conjugate Addition Reactions in Organic
Reactions; Pergamon: Oxford, 1992. (b) Ballini Bosica, G.; Fiorini, D.;
Palmieri, A.; Petrini, M. Chem. Rev. 2005, 105, 933−971.
(4) For reviews on conjugate addition to electron-deficient dienes,
see: (a) Silva, E. M. P.; Silva, A. M. S. Synthesis 2012, 44, 3109−3128.
(b) Csaky, A. G.; de le Herran, G.; Murcia, M. C. Chem. Soc. Rev.
2010, 39, 4080−4102.
(18) Mori, S.; Hirai, A.; Nakamura, M.; Nakamura, E. Tetrahedron
2000, 56, 2805−2809.
(19) Fleming, I. Molecular Orbitals and Organic Chemical Reactions,
reference ed.; John Wiley & Sons: Chichester, UK, 2010; Chapter 4,
pp 183−199.
(20) MacSpartan PM3 (WAVEFUNCTION, Inc.: Irvine, CA)
calculations give charge differences between C2 and C4 [compound
Δ(C2−C4): 1 (+ 0.126), 4 (+ 0.079), and 7 (+ 0.071)] and orbital
coefficient differences [compound Δ(C2-C4): 1 (+ 0.7419), 4 (+
0.00254) and 7 (+ 0.00201)] that qualitatively mirror the observed
1,4:1,6-regioselectivity trends with aryl-substituted nitrodienes giving
lower regioselectivity. Hartree−Fock (6-31G**) calculations for 1
gave small negative charge values for C2 and C4 where C4 was less
negative than C2 by 0.029 charge units, and the orbital coefficient
difference Δ(C2−C4) was +0.03468 so that semiempirical PM3 and
ab initio Hartree−Fock calculations gave the same qualitative picture.
Caution should be exercised when applying simple MO calculations to
rationalize chemical reactivity by “electrostatic terms and electron
density alone”. See: Schwarz, W. H. E.; Schmidbaur, H. Chem.Eur. J.
2012, 18, 4470−4479.
(5) For a review on conjugated nitrodienes, see: Ballini, R.; Araujo,
N.; Gil, M. V.; Roman, E.; Serrano, J. A. Chem. Rev. 2013, 113, 3493−
3515.
(6) For a review on copper-mediated 1,6-conjugate additions, see:
Krause, N.; Aksin-Artok, O. In Chemistry of Organocopper Compounds;
Rappoport, Z., Marek, I., Eds.; Wiley: New York, 2009; Part 2, pp
857−879. For mechanistic studies, see: (a) Ueerdingen, M.; Krause,
N. Tetrahedron 2000, 56, 2799−2804. (b) Yoshikai, N.; Yamashita, T.;
Nakamura, E. AsianJ. Chem. 2006, 1, 322−330.
(7) (a) Backvall, J.; Karlsson, U.; Chinchilla, R. Tetrahedron Lett.
̈
1991, 32, 5607−5610 and references cited therein. (b) Ballini, R.;
́
Bosica, G.; Gil, M. V.; Roman, E.; Serrano, J. A. Tetrahedron:
Asymmetry 2002, 13, 1773−1787.
(8) (a) Schafer, H.; Seebach, D. Tetrahedron 1995, 51, 2305−2324.
̈
(b) Alexakis, A.; Benhaim, C. Org. Lett. 2000, 2, 2579−2581.
(c) Rimkus, A.; Sewald, N. Synthesis 2004, 2004, 135−146. (d) Tissot,
M.; Alexakis, A. Chem.Eur. J. 2013, 19, 11352−11363.
(9) (a) List, B.; Pojarliev, P.; Martin, H. Org. Lett. 2001, 3, 2423−
2425. (b) Hayashi, Y.; Okana, T.; Aratake, S.; Hazelard, D. Angew.
Chem., Int. Ed. 2007, 46, 4922−4925. (c) Belot, S.; Massaro, A.; Tenti,
A.; Mordini, A.; Alexakis, A. Org. Lett. 2008, 10, 4557−4560. (d) Belot,
S.; Quintard, A.; Krause, N.; Alexakis, A. Adv. Synth. Catal. 2010, 352,
667−695. (e) He, T.; Qian, J.; Song, H.; Wu, X. Synlett 2009, 2009,
3195−3197. (f) Ma, H.; Liu, K.; Zhang, F.; Zhu, C.; Nei, J.; Ma, J. J.
Org. Chem. 2010, 75, 1402−1409. (g) Chen, J.; Fu, L.; Zou, Y.; Chang,
N.; Rong, J.; Xiao, W. Org. Biomol. Chem. 2011, 9, 5280−5287.
(h) Tsakos, M.; Kokotos, C. G. Eur. J. Org. Lett. 2012, 2012, 576−580.
1365
dx.doi.org/10.1021/ol500114m | Org. Lett. 2014, 16, 1362−1365