Iron-catalyzed δ-selective conjugate addition of methyl and cyclopropyl Grignard reagents to α,β,γ,δ-unsaturated esters and amides

Article abstract of DOI:10.1016/j.tetlet.2018.12.043

Iron-catalyzed δ-selective conjugate addition of methyl and cyclopropyl Grignard reagents to α,β,γ,δ-unsaturated esters and amides took place in good yields to give products exclusively with cis-β,γ-olefinic bond.

Full text of DOI:10.1016/j.tetlet.2018.12.043

Accepted Manuscript
Iron-catalyzed δ-Selective Conjugate Addition of Methyl and Cyclopropyl
Grignard Reagents to α,β,γ,δ -Unsaturated Esters and Amides
Goshi Sugano, Kojiro Kawada, Masayuki Shigeta, Takeshi Hata, Hirokazu
Urabe
PII:
S0040-4039(18)31486-2
https://doi.org/10.1016/j.tetlet.2018.12.043
TETL 50506
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 November 2018
13 December 2018
18 December 2018
Please cite this article as: Sugano, G., Kawada, K., Shigeta, M., Hata, T., Urabe, H., Iron-catalyzed δ-Selective
Conjugate Addition of Methyl and Cyclopropyl Grignard Reagents to α,β,γ,δ -Unsaturated Esters and Amides,
Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.12.043
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Iron-catalyzed -Selective Conjugate Addition of Methyl and Cyclopropyl
Grignard Reagents to ,,,-Unsaturated Esters and Amides
Goshi Sugano, Kojiro Kawada, Masayuki Shigeta, Takeshi Hata, and Hirokazu Urabe*
*Corresponding author: Fax: (+81) (0)45 924 5849; E-mail: hurabe@bio.titech.ac.jp.
School of Life Science and Technology, Tokyo Institute of Technology, 4259-B-59 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501 Japan
Keywords:
catalytic reaction
conjugate addition
cyclopropane
Grignard reagent
iron
methylation
Abstract:
Iron-catalyzed -selective conjugate addition of methyl and cyclopropyl Grignard reagents to ,,,-unsaturated
esters and amides took place in good yields to give products exclusively with cis-,-olefinic bond.
1. Introduction
Conjugate addition of Grignard reagents to ,-unsaturated carbonyl compounds (1), giving solely product 2, is one of the
most fundamental methods for carbon-carbon bond formation in organic synthesis (Scheme 1) [1]. Recently, the substrates in
this reaction have been actively extended to homologous ,,,-unsaturated carbonyl compounds 3 [2], additional issues of
both regiochemistry of the addition (4 vs. 5 + 6) and the regio- (5 vs. 6) and stereochemistry (cis- vs. trans-5 or cis- vs. trans-6)
of the remaining olefin arise, making the straightforward formation of a single product among 4-6 quite difficult.
Scheme 1. Conjugate addition to unsaturated carbonyl compounds.
Although appropriate combinations of the substrates, Grignard reagents, and catalysts could solve the above difficulty, the
successful cases are still not many [3-5].
Among these, the iron-catalyzed reaction shown in eq 1 exhibits unique
characteristics such as the exclusive -addition of Grignard reagents and the exclusive formation of cis-,-olefin as can be seen
in products 10 [5-7]. Therefore, this transformation demonstrates a practical and dependable conjugate addition to ,,,-
unsaturated carbonyl and related compounds.
However, as shown in eq 1, this iron-catalyzed reaction is so far limited to aromatic Grignard reagents, and aliphatic ones do
not give the desired products like 10. Thus, we focused our attention on the issue to expand the applicability of Grignard

reagents in eq 1 to aliphatic ones. As we conceived that the failure of aliphatic Grignard reagents comes from the instability
of the intermediate alkyl-iron complexes [8] amenable to -hydride elimination, we chose methyl Grignard reagent, which
lacks -hydrogens and is free from the above side reaction, as the first candidate. Although a couple of relevant iron-
catalyzed additions have been reported by us and others (eqs 2 [9a] and 3 [9b,c]), they should be facilitated by a favorable
carbometallation to acetylene in 11 and an irreversible addition/elimination sequence to 13, giving 12 and 14 in good yields.
Contrary to these, the addition of methyl Grignard reagent to fundamental diene 3 in Scheme 1 has not yet been disclosed.
2. Result and Discussion
The reaction of 3 with methyl Grignard reagent was first attempted under the similar conditions as those of the previous aryl
addition. After brief modification of the reaction conditions such as equivalents of the Grignard reagent, the amount of
catalyst load, or reaction temperature, ethyl ester 15 afforded the desired product 19 in 57% yield, albeit accompanied with
some by-products (eq 4). As the yield and the regio- and stereoselectivities themselves were, gratifyingly, not worse than
what we had expected, we tried to suppress the formation of the by-products by changing the ethyl ester to more robust tert-
butyl ester. Actually, tert-butyl ester 16 effected a cleaner reaction to give desired product 20 in 52% yield without
contaminated by impurities. Switching tert-butyl ester 16 to amide 17 further increased the product yield (21) as well as the
cis/trans ratio of the remaining olefin to those of the aryl addition. The presence of magnesiated intermediate 18 (X = NEt )
2
was verified by deuteration ( 21-d ) and eventually utilized for the second carbon-carbon bond formation via alkylation as
1
exemplified in the formation of products 22 and 23 in good yields.
The preliminary study shown above led us to broaden the variation of substrates involving esters and amides. More results
are summarized in Table 1. Esters derived from sterically demanding alcohols 24, 16, and 25 afforded products 32, 20, and 33
with excellent cis olefinic selectivity (entries 1-3). Exceptionally, bulky aryl ester 26 underwent the similar regioselective
addition to give product 34, but its olefin became an almost equimolar mixture of cis- and trans-isomers (entry 4). Amides 17
and 27-30 (entries 5-9) uniformly furnished products 21 and 35-38 as single isomers in good yields. Functional groups in the
side chain of 28 and 29 proved compatible with the reaction conditions to afford desired products 36 and 37 (entries 7 and 8).
An additional substituent on the conjugated diene moiety of 30 did not interfere the reaction to form regio- and stereodefined
tri-substituted olefin 38 (entry 9). Diarylamide 31 is also a good substrate in this reaction with a slight decrease in the cis-
purity of the resulting olefin 39 (entry 10).

Table 1.
Iron-catalyzed regio- and stereoselective addition of methyl Grignard reagent.
Isolated
Yield (%)
Cis/trans
Entry
1
Starting Ester or Amide
Product
a
(24)
(16)
(25)
(32)
(20)
(33)
57
52
56
cis only
96:4
2
3
97:3
4b
(26)
(34)
51
47:53
5
6
(27)
(17)
(28)
(29)
(30)
(31)
(35)
(21)
(36)
(37)
(38)
(39)
81
73
82
73
77
69
cis only
cis only
cis only
cis only
cis only
93:7
7
8
9
10
a This value was also observed at the crude stage.
b Reaction was performed under the following conditions: -78 to 0 °C, 3 h; 0 °C, 2 h.
Having established the methyl addition, we continued to seek for other possible candidates of Grignard reagents. Benzyl,
2-phenyl-2-methylpropyl, and (trimethylsilyl)methyl Grignard reagents, which all lack -hydrogens, did not meet with success
(eq 5). Meanwhile we happened to attest the feasibility of cyclopropyl or cyclobutyl Grignard reagent. While cyclobutyl

Grignard reagent afforded messy products, cyclopropyl Grignard reagent fortunately did fit this reaction, giving the same type
of adduct as the aryl or methyl addition as shown in Table 2, which summarizes the optimization of reaction conditions.
Under the standard conditions of the former methyl addition yet using 2 equiv of cyclopropyl Grignard reagent, desired product
41 was produced in moderate yield and a small amount of the starting material 24 was recovered (entry 1). The change in the
reaction temperature did not increase the product yields (entries 2-4). However, when the equivalent of the Grignard reagent
was increased (entry 5) and, to the contrary, the catalyst load was decreased (entry 6), the marginally best yield was attained
with retaining the exclusively high regio- and stereoselectivities. The retarding -hydride elimination of cyclopropylmetal
intermediates owing to the unfavorable formation of strained cyclopropene may account for the above success.
Table 2.
Optimization of reaction conditions of the cyclopropyl addition.
40
(equiv)
FeCl2
(mol%)
Yield of
Recovery of
Entry
1
Conditions
41 (%)a,b
24 (%)a
-45 to 0 °C, 3 h;
0 °C, 2 h
2
20
64
9
2
3
4
2
2
2
20
20
20
-45 °C to r.t., 5 h
-45 ~ -30 °C, 9 h
-15 °C, 9 h
48
41
18
18
19
6
-45 to 0 °C, 3 h;
0 °C, 2 h
5
6
3
3
20
10
70
0
0
-45 to 0 °C, 3 h;
0 °C, 2 h
97 (70)
a Yields were determined by 1H NMR analysis. Isolated yield is shown in parentheses.
b The formation of single isomer was also observed at the crude stage.
In the above investigation, the yield of 41 was recorded after hydrolysis. However, the metallated intermediate 42 after the
cyclopropyl addition was identified by deuteration to give 41-d with high deuterium incorporation (eq 6). Upon alkylation
1
with MeI or allyl bromide, the three-component coupling of 24, 40, and an alkyl halide was viable in one pot to give product 43
or 44 in good yield.

More variation of the products of the cyclopropyl addition is shown in Table 3. Esters and amides could be used equally
well, except for a case where ethyl ester 45 (entry 1) was again an inferior substrate to tert-butyl esters as pointed out in the
methyl addition. A couple of functional groups in the side chains of 46 and 47 (entries 5 and 6) survived the reaction
conditions to give 53 and 54 in good yields. The steric hindrance at -position as exemplified by 48 (entry 7) appears to block
the -addition of the Grignard reagent to decrease the yield of 55. An additional substituent at the -position on diene 49 did
not lower the yield of 56 (entry 8). In all entries of Table 3, the products were formed virtually as a single isomer.
Table 3.
Iron-catalyzed regio- and stereoselective addition of cyclopropyl Grignard reagent.
Isolated
Yield
(%)a
40
(equiv)
FeCl2
(mol%)
Entry
Starting Ester or Amide
Product
1
(45)
(24)
3
3
10
10
(50)
(41)
51
2
70
3
4
(27)
(16)
(46)
3
3
10
10
10
(51)
(52)
(53)
82
72
66
5b
3.5

6b
(47)
(48)
(49)
3.5
10
30
15
(54)
(55)
(56)
68
47
97
7
4
8
3
a The formation of single isomer was also observed at the crude stage.
b Reaction was performed under the following conditions: -45 to 0 °C, 3 h; 0 °C, 7 h.
In the above experiments, cyclopropyl Grignard reagent (40) was prepared from the corresponding bromide and magnesium
turnings in a standard manner [10]. Alternatively, cyclopropyl Grignard reagent (58) prepared by a different method, the
transmetallation between cyclopropyllithium (57) and MgBr as shown in eq 7, was found good enough for this purpose to give
2
41 in good yield. It is interesting to note that cyclopropyllithium (57) itself was definitely useless as illustrated in eq 8.
3. Conclusion
As a methyl substituent is very common in artificial and natural organic compounds, this concise synthetic method is useful
to impart a methyl substituent at the defined position on the functionalized carbon chains starting from readily available
,,,-unsaturated carbonyl compounds. In addition to methyl group, cyclopropane ring, a versatile structure for many
unique synthetic transformations [11], can be also introduced to the carbon linkage in a regio- and stereoselective manner.
Acknowledgments
This work was supported partially by JSPS KAKENHI Grant Number 26810019, The Kurata Memorial Hitachi Science and
Technology Foundation, The Sumitomo Electric Group Basic Policies on Social Contributions, and the PRESTO Program on
Molecular Technology from JST Grant Number JPMJPR14KC.18.
Supplementary data
Supplementary data to this article can be found online at https://doi.org/xxxxxxxxx.

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Graphical Abstract
Iron-catalyzed -Selective Conjugate Addition of
Methyl and Cyclopropyl Grignard Reagents to
,,,-Unsaturated Esters and Amides
Goshi Sugano, Kojiro Kawada, Masayuki Shigeta, Takeshi Hata, and Hirokazu Urabe
cis
COX
MeMgBr or
FeCl2 cat.
El+


MgBr
COX
R1
El
R1


Me
or
X = OR2, NR2
2
-addition

Highlights for:
Iron-catalyzed -Selective Conjugate Addition of Methyl and Cyclopropyl Grignard Reagents to
,,,-Unsaturated Esters and Amides
Goshi Sugano, Kojiro Kawada, Masayuki Shigeta, Takeshi Hata, and Hirokazu Urabe*
School of Life Science and Technology, Tokyo Institute of Technology, 4259-B-59 Nagatsuta-cho,
Midori-ku, Yokohama, Kanagawa 226-8501 Japan
• A strictly ordered combination of three different units is attained in one flask
• Iron and Copper play complementary roles to determine the structure of olefins
• Iron leads environmentally friendly and economical synthesis of valuable compounds
• Superior production of a single isomer among possible five is artificially realized