Controllable highly stereoselective reaction of in situ generated magnesium dienolate intermediates with different electrophiles

Article abstract of DOI:10.1021/ol8012815

(Chemical Equation Presented) In this paper, we have described an efficient controllable stereoselective a-acylation and -allylation reaction of the magnesium dienolate intermediates generated in situ from the Fe(lll)-catalyzed reaction between 2,3-allenoates and Grignard reagents with different electrophiles to afford 2-acylated or allylated 3(Z)- or (E)-alkenoates depending on the nature of the electrophiles and reaction conditions. The distinct stereoselectivity may be caused by the isomerization of metallic Z-1,3-dienoate to E-1,3-dienoate via the intermediacy of anti-allylic MgCl and syn-metallic species.

Full text of DOI:10.1021/ol8012815

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3517-3520
Controllable Highly Stereoselective
Reaction of in situ Generated
Magnesium Dienolate Intermediates with
Different Electrophiles
Zhan Lu, Guobi Chai, Xiaobing Zhang, and Shengming Ma*
Laboratory of Molecular Recognition and Synthesis, Department of Chemistry,
Zhejiang UniVersity, Hangzhou 310027, Zhejiang, People’s Republic of China
masm@mail.sioc.ac.cn
Received June 6, 2008
ABSTRACT
In this paper, we have described an efficient controllable stereoselective r-acylation and -allylation reaction of the magnesium dienolate
intermediates generated in situ from the Fe(III)-catalyzed reaction between 2,3-allenoates and Grignard reagents with different electrophiles to
afford 2-acylated or allylated 3(Z)- or (E)-alkenoates depending on the nature of the electrophiles and reaction conditions. The distinct
stereoselectivity may be caused by the isomerization of metallic Z-1,3-dienoate to E-1,3-dienoate via the intermediacy of anti-allylic MgCl and
syn-metallic species.
1,3-Dienolates 1 are useful intermediates in organic synthesis,
in which both the R- and γ-position may react with
electrophiles to afford the corresponding ꢀ,γ- or R,ꢀ-
unsaturated products 2 or 3 (Scheme 1).1–3 It has been
reported that the reaction of 2-lithiated 3(Z)- or (E)-alkenoates
with water,4a alkyl iodide,4a,b or aldehyde4b afforded the
R-protonated, alkylated, or aldolated 3(Z) or (E)-alkenoate
with moderate to high stereoselectivity. However, to the best
of our knowledge, there is no report on stereocontrollable
reaction of the same metal dienolate with different electro-
philes to afford ꢀ,γ-unsaturated (E)- or (Z)-alkenoates in high
regio- and stereoselectivity, respectively. On the other hand,
recently an iron-catalyzed conjugate addition reaction of 2,3-
allenoates with Grignard reagents affording 3(Z)-alkenoates
* To whom correspondence should be addressed. Phone: 86-21-549-
25147. Fax: 86-21-641-67510.
(1) (a) Fuson, R. C. Chem. ReV. 1935, 16, 1. (b) Denmark, S. E.;
Heemstra, J. R., Jr.; Beutner, G. L. Angew. Chem., Int. Ed. 2005, 44, 4682.
(c) Zhao, D.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006,
128, 14440
.
(2) For some recent typical examples of reactions of dienolate at
R-position, see: (a) Reutrakul, V.; Jaratjaroonphong, J.; Tuchinda, P.;
Kuhakarn, C.; Kongsaeree, P.; Prabpai, S.; Pohmakotr, M. Tetrahedron Lett.
2006, 47, 4753. (b) Davis, F. A.; Qi, H.; Sundarababu, G. Tetrahedron
2000, 56, 5303. (c) Baza´n-Tejeda, B.; Bluet, G.; Broustal, G.; Campagne,
J.-M. Chem.-Eur. J. 2006, 12, 8358. (d) Alexander, P. A.; Marsden, S. P.;
Subtil, D. M. M.; Reader, J. C. Org. Lett. 2005, 7, 5433. (e) Fukuhara, K.;
Urabe, H. Tetrahedron Lett. 2005, 46, 603. (f) Otaka, A.; Yukimasa, A.;
Watanabe, J.; Sasaki, Y.; Oishi, S.; Tamamura, H.; Fujii, N. Chem. Commun.
Scheme 1. Reaction of 1,3-Dienolates
2003, 1834
.
10.1021/ol8012815 CCC: $40.75
Published on Web 07/16/2008
2008 American Chemical Society

Table 1. Reaction of in situ Generated Dienolate 5 with Acyl Chlorides or Allyl Carboxylic Estersa
conditions A
conditions B
yield of
Z-6 (%)b
ratio
(Z/E)c
yield of
E-6 (%)b
ratio
(E/Z)c
entry
R1
R2
R3
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
p-FC6H4
p-ClC6H4
p-BrC6H4
Me (4a)
Me (4a)
Me (4a)
n-Pr (4b)
Me (4c)
Me (4d)
Me (4e)
Me
Bn
Ph
Me
Me
Me
Me
68 (Z-6a)
87 (Z-6b)
70 (Z-6c)
69 (Z-6d)
76 (Z-6e)
84 (Z-6f)
87 (Z-6g)
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
50 (E-6a)
47 (E-6b)
57 (E-6c)
50 (E-6d)
69 (E-6e)
50 (E-6f)
62 (E-6g)
95/5
>98/2
>98/2
>98/2
98/2
98/2
97/3
a Conditions A: acyl chloride (2 mmol) was added to the solution of in situ generated magnesium dienolate (0.4 mmol) at -78 °C. Conditions B: allyl
carboxylic acid ester (2 mmol) was added to the solution of in situ generated magnesium dienolate (0.4 mmol) at -78 °C followed by warming up to rt
c
naturally. b Isolated yield. Tatio was determined by H NMR analysis of the crude products.
1
with very high regio- and stereoselectivity has been reported
by this group.5 In this paper, we wish to report our recent
observation that the magnesium 1,3(Z)-dienolate intermedi-
ates in situ generated in this reaction may react with different
electrophiles to afford R-allylated or acylated 3(Z)- or (E)-
alkenoates highly stereoselectively under different reaction
conditions.
Conditions A, the reaction with acyl chloride provided the
Z-6 in 68-87% yields with Z/E ratio >99/1 while the
corresponding opposite stereoisomers E-6 may be formed
under the Conditions B with E/Z ratio of g95/5.
Furthermore, we are quite happy to observe that under
the catalysis of Pd(PPh3)4, instead of forming the R- acylated
3(E)-alkenoate 6, the reaction of magnesium dienolate 5a
with allylic acetate afforded the R-allylated alk-3(Z)-enoate
Z-7a in 67% yield with high stereoselectivity (Z/E ) 96/4),
which was established by NOE study of Z-7a (Figure 1)
(Conditions C, entry 1, Table 2). The structure of the products
Z-7 was further established by the X-ray diffraction study
of Z-7h7 (Figure 2). Obviously, the oxidative addition
reaction of Pd(PPh3)4 with allyl acetate forms a π-allyl
palladium species, which reacted with the magnesium
dienolate to provide the corresponding R-allylated products.8
The reaction of the magnesium dienolates with 2- or
As originally noted,5 the reaction of the in situ generated
magnesium dienolate intermediate 5a with acyl chloride at
-78 °C afforded R-acylated alk-3(Z)-enoate Z-6a in 61%
yield (Conditions A). The configuration of the carbon-carbon
double bond was determined by NOE analysis (Figure 1).
(3) For some recent typical examples of reactions of dienolate at
γ-position, see: (a) Denmark, S. E.; Heemstra, J. R., Jr. J. Org. Chem. 2007,
72, 5668. (b) Denmark, S. E.; Xie, M. J. Org. Chem. 2007, 72, 7050. (c)
Denmark, S. E.; Heemstra, J. R., Jr. J. Am. Chem. Soc. 2006, 128, 1038.
(d) Denmark, S. E.; Beutner, G. L. J. Am. Chem. Soc. 2003, 125, 7800. (e)
Saito, S.; Nagahara, T.; Shiozawa, M.; Nakadai, M.; Yamamoto, H. J. Am.
Chem. Soc. 2003, 125, 6200. (f) Denmark, S. E.; Heemstra, J. R., Jr. Synlett
2004, 2411.
Figure 1. NOE Study of the Z- and E-Isomers of 6a and 7a.
(4) (a) Kende, A. S.; Toder, B. H. J. Org. Chem. 1982, 47, 163. (b) He,
Y.; Yang, H.; Yao, Z. Tetrahedron 2002, 58, 8805.
Further screening led us to observe that the reaction of the
in situ generated magnesium dienolate 5a with allyl acetate
afforded R-acylated alk-3(E)-enoate E-6a in 50% yield with
a reversal stereoselectivity (E/Z ) 95/5),6 which was also
established by NOE analysis (Figure 1) (Conditions B, entry
1, Table 1). Some such examples are shown in Table 1. It
can be noted that R1 may be aryl, R2 may be alkyl, and R3
may be alkyl, benzyl, or phenyl. In conclusion, under
(5) Lu, Z.; Chai, G.; Ma, S. J. Am. Chem. Soc. 2007, 129, 14546.
(6) Solomons, T. W. G.; Fryhle, C. B. Organic Chemistry, 7th ed.; John
Wiley & Sons: New York, 2000; pp 880-883.
(7) Crystal data for compound Z-7h: C23H26O2, Mw 334.46, triclinic,
j
P1, Mo KR, final R indices [I > 2σ(I)], R1 ) 0.0812, wR2 ) 0.2081, a )
8.2770 (6) Å, b ) 8.6143 (7) Å, c ) 14.1523 (13) Å, R ) 103.444 (2)°, ꢀ
) 91.662 (2)°, γ ) 95.1097 (19)°, V ) 976.23 (14), Z ) 2, number of
reflections measured/unique 4336/1886 (Rint ) 0.028) number of observa-
tions 4336 [I > 2σ(I)], parameter 227, CCDC 676332.
3518
Org. Lett., Vol. 10, No. 16, 2008

Table 2. Transition Metal-Catalyzed Allylation Reactions of in situ Generated Dienolates 5 with Different Allylic Reagentsa
conditions C
conditions D
yield of
Z-7 (%)b
ratio
(Z/E)c
yield of
E-7 (%)b
ratio
(E/Z)c
entry
R1
R2
R3
R4
1
2
3
4
5
6
7
8
Ph
Me (4a)
Me (4c)
Me (4d)
Me (4e)
Me(4f)
Me (4a)
n-Pr (4b)
Me (4a)
H
H
H
H
H
H
H
Ph
H
H
H
H
67 (Z-7a)
74 (Z-7b)
66 (Z-7c)
80 (Z-7d)
72 (Z-7e)
61 (Z-7f)
58 (Z-7g)
77 (Z-7h)
96/4
94/6
96/4
93/7
98/2
89/11
91/9
94/6
51 (E-7a)
72 (E-7b)
71 (E-7c)
65 (E-7d)
53 (E-7e)
58 (E-7f)
39 (E-7g)
39 (E-7h)
96/4
97/3
97/3
97/3
97/3
p-FC6H4
p-ClC6H4
p-BrC6H4
p-MeOC6H4
Ph
H
Ph
Ph
H
>99/1
>99/1
Ph
Ph
d
-
a Conditions C: Pd(PPh3)4 (5 mol %) and allylic acetate (5 equiv) were added to the solution of in situ generated magnesium dienolate (0.4 mmol) at -78
°C for 1 h followed by warming up to rt naturally. Conditions D: CuI (10 mol %) and allylic bromide (5 equiv) were added to the solution of in situ
generated magnesium dienolate (0.4 mmol) at rt. b Isolated yield. c Ratio was determined by 1H NMR analysis of the crude products. d Other isomer was not
isolated.
3-substituted allylic acetate under the catalysis of Pd(PPh3)4
all afforded the R-allylated Z-products Z-7 in 58-77% yields
with an Z/E ratio of 89/11∼94/6 (Conditions C, entries 6-8,
Table 2). Quite surprisingly, under the catalysis of CuI, the
related reaction with allyl bromide afforded the opposite
stereoisomer E-7a in 51% yield (E/Z ) 96/4), which was
confirmed by NOE study (Figure 1)(Conditions D, entry 1,
Table 2).9 Based on the results shown in Table 2, it should
also be noted that the reversed E-stereoselectivity (Conditions
D) is higher than the original Z-stereoselectivity (Conditions
C). Not only simple allyl bromide but also 2- or 3-substituted
allylic bromides react with the magnesium dienolates 5 under
the catalysis of CuI to afford the corresponding stereo-
reversed R-allylated E-products with high selectivity (Condi-
tions D, entries 6-8, Table 2).
It has been reported that the syn-allylic metallic species
is thermodynamically more stable as compared to the anti-
allylic metallic species due to the steric interaction of the
metal and the substituent(s) at the 1- and/or 3-positions,10
thus, we reasoned that due to the presence of the carbon-
carbon double bond, the in situ formed 1,3(Z)-dienoate5 is
prone to isomerize to the thermodynamically more stable
1,3(E)-dienoate via the intermediacy of anti-allylic MgCl and
syn-allylic metallic species (Scheme 2).
When allylic acetate or allylic bromide with CuI was added
as the electrophile at -78 °C, the carbon-carbon double
bond11 and/or the carbonyl oxygen may act as the coordina-
tion ligand to the metal, which increases the steric interaction
between the coordinated metal and the substituent R1 leading
(8) (a) Trost, B. M. Acc. Chem. Res. 1980, 13, 385. (b) Trost, B. M.;
Van Vranken, D. L. Chem. ReV. 1996, 96, 395. (c) Trost, B. M.; Crawley,
M. L. Chem. ReV. 2003, 103, 2921. (d) Trost, B. M. J. Org. Chem. 2004,
69, 5813. (e) Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 258.
(9) Flynn, A. B.; Ogilvie, W. W. Chem. ReV. 2007, 107, 4698.
(10) For a review in this area, see: (a) Frost, C. G.; Howarth, J.; Williams,
J. M. J. Tetrahedron: Asymmetry 1992, 3, 1089. For some typical reports,
see: (b) Akermark, B.; Hansson, S.; Vitagliano, A. J. J. Am. Chem. Soc.
1990, 112, 4587. (c) Hayashi, T.; Yamamoto, A.; Hagihara, T. J. Org. Chem.
1986, 51, 723.
Figure 2. ORTEP structure of Z-7h.
Org. Lett., Vol. 10, No. 16, 2008
3519

Scheme 2
.
Rationale for Observed Stereoselectivity
Scheme 3. Mechanistic Study
to the complete conversion of 1,3-(Z)-dienoate to 1,3(E)-
dienoate. Subsequent reaction with the allylic carboxylate
or allylic bromide leads to the formation of E-6 and E-7. Of
course, in the latter case the isomerization may also be
promoted by the presence of Cu, which is more sterically
demanding due to its relatively bigger radius.12 The reaction
with acyl chloride or allylic acetate under the catalysis of
Pd is believed to be very fast, occurring before the Z to
E-isomerization at lower reaction temperature, which was
further confirmed by the fact that addition of acyl chloride
or 5 mol% Pd(PPh3)4 and allylic acetate at rt led to the
formation of an E/Z mixture (Scheme 3).
Grignard reagents with acyl chloride, allyl carboxylic acid
esters, allylic acetate catalyzed by Pd(PPh3)4, or allylic
bromide catalyzed by CuI to afford alk-3(Z or E)-enoates
highly stereoselectively. Further studies including the scope,
synthetic application, and the mechanism for such an
isomerization are being conducted in our laboratory.
Acknowledgment. We greatly acknowledge the financil
support from the NSF of China (20732005) and the Major
State Basic Research Development Program (2006CB806105).
S.M. is a Qiu Shi Adjunct Professor at Zhejiang University.
We thank Mr. Guofei Chen in this group for reproducing
the results presented in entry 5 in Table 1 and entry 4 in
Table 2.
In summary, we have observed an efficient controllable
stereoselective R-acylation or -allylation reaction of the in
situ generated magnesium dienolate intermediate from the
Fe-catalyzed conjugate addition of 4-aryl-2,3-allenoates and
Supporting Information Available: Experimental pro-
(11) For most recent reports on using optically active olefin as ligand
in Rh- or Ir-catalyzed reactions, see: (a) Hayashi, T.; Ueyama, K.; Tokunaga,
N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508. (b) Fischer, C.;
Sefieber, C.; Suzuki, T.; Carreira, E. M. J. Am. Chem. Soc. 2004, 126, 1628.
(c) Wang, Z.-Q.; Feng, C.-G.; Xu, M.-H.; Lin, G.-Q. J. Am. Chem. Soc.
2007, 129, 5336.
1
cedures and copies of H and 13C NMR spectra of all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) The radius of Mg2+ is 0.65 Å and the radius of Cu+ is 0.96 Å.
OL8012815
3520
Org. Lett., Vol. 10, No. 16, 2008