Iron-catalyst-switched selective conjugate addition of grignard reagents: α,β,γ,δ-unsaturated amides as versatile templates for asymmetric three-component coupling processes

Article abstract of DOI:10.1002/anie.200801928

(Figure Presented) Diene for conjugate addition: Iron(II) chloride switches the reaction course of the three-component coupling of a Grignard reagent, an alkyl halide, and a dienamide, thus making the amide a simple yet versatile chiral template.

Full text of DOI:10.1002/anie.200801928

Communications
DOI: 10.1002/anie.200801928
Homogeneous Catalysis
Iron-Catalyst-Switched Selective Conjugate Addition of Grignard
Reagents: a,b,g,d-Unsaturated Amides as Versatile Templates for
Asymmetric Three-Component Coupling Processes**
Satoshi Okada, Kyohei Arayama, Ryuji Murayama, Takumi Ishizuka, Keiichi Hara,
Naoki Hirone, Takeshi Hata, and Hirokazu Urabe*
Conjugate addition of Grignard reagents to a,b-unsaturated
carbonyl compounds is one of the most fundamental methods
for carbon–carbon bond formation and is usually carried out
with copper catalysis.[1,2] Among the various kinds of carbonyl
compounds employed for this procedure, dienic substrates
have not been amply investigated, presumably as a result of
the accumulated difficulties in controlling both regio- and
stereoselections, as shown in Scheme 1.[3,4] We report herein
allowed us to explore asymmetric 1,4-addition by using a
chiral amide group.[6] Among several such candidates,[7] amide
3, incorporating
a
sugar-derived pyrrolidine unit
(Scheme 2),[8] showed exclusive 1,4-regioselectivity and sat-
Scheme 1. Conjugate addition to dienic carbonyl compounds.
Scheme 2. 1,4-Addition of Grignard reagent and successive alkylation.
that a,b,g,d-unsaturated amides work as a simple yet versatile
template to circumvent this problem, where the absence or
presence of an iron catalyst, rather than the aforementioned
copper catalyst, is another key to achieving clear-cut reac-
tions.
While 1,4-regioselective addition of Grignard reagents to
a,b,g,d-unsaturated amides was documented almost twenty-
five years ago, we revisited this reaction using (E,E)-N,N-
diethyl-2,4-hexadienamide as a dienic substrate.[5] After
surveying various Grignard reagents, we found that using
isopropenylmagnesium bromide (1) results in an excellent
1,4-:1,6-selectivity of 94:6 in THF without any other addi-
tive(s) to give (E)-N,N-diethyl-3-isopropenyl-4-hexenamide
(2) in a synthetically acceptable 65% yield. This result
isfactory product yield (4, 84%), both of which were more
enhanced than those of 2, probably as a result of the ether
functionality present in the chiral auxiliary (see below). We
also found that conjugate addition was highly stereoselective,
giving 4 in 93:7 diastereoselectivity. More importantly, the
subsequent alkylation of the resultant enolate also proceeded
in a highly stereoselective manner to give 5 (Scheme 2), which
consists of a 94:6 mixture of two major diastereoisomers with
two other isomers being formed in trace amounts.[9,10] This
ratio (94:6) reflects that of the addition product 4 (93:7), thus
suggesting that the stereochemistry of methylation is perfectly
controlled by the proximate chiral amide auxiliary, which is
further evidenced by the fact that the isomeric ratio of 5 did
not change after the removal of amide auxiliary, as shown in
Equation (1).
Scheme 3 illustrates a proposed reaction course. The
reaction should proceed via a less hindered conformation 3
(rather than 3’), in which the reacting Grignard reagent 1 is
fixed at the depicted position in 6 by the chelation of
magnesium to the carbonyl and acetal oxygen atoms. From
the intermediate 6, the alkenyl (R) group migrates to the
diene carbon b to the carbonyl group, to account for the
higher 1,4-selectivity and better product yield (of 4) than for
the simple diethylamide 2. In addition, alkylation of the
resulting enolate 7 most likely proceeds from the side where
the magnesium coordinates (as in 8), to produce 5.
Results for the above three-component coupling process,
incorporating different amides, Grignard reagents, and
organic halides, are listed in Table 1. The chiral enolate
generated by the 1,4-addition was alkylated with activated
halides, such as methyl iodide, allyl bromide, propargyl
[*] S. Okada,[+] K. Arayama,[+] R. Murayama, T. Ishizuka, K. Hara,
N. Hirone, Dr. T. Hata, Prof. Dr. H. Urabe
Department of Biomolecular Engineering, Graduate School of
Bioscience and Biotechnology
Tokyo Institute of Technology
4259-B-59 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-
8501 (Japan)
Fax: (+81)45-924-5849
E-mail: hurabe@bio.titech.ac.jp
Homepage: http://www.urabe-lab.bio.titech.ac.jp
[+] These authors contributed equally to this work.
[**] This work was supported by a Grant-in-Aid for Scientific Research on
Priority Area (No.16073208) and a Grant-in-Aid for Young Scientists
(B) (No. 20750071, to T.H.) from the Ministry of Education, Culture,
Sports, Science and Technology (Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801928.
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also gave the products 12 and 13 with high asym-
metric induction (Table 1, entries 5 and 6). Variation
in the amide substrates (14–16) further illustrated the
synthetic flexibility of this method (Table 1,
entries 7–9).
The chiral auxiliary in 5 was readily removed by
acidic hydrolysis, as shown in Equation (1),[11] to give
lactone 20, which has thermodynamically less stable
cis-substituents on its five-membered ring. This
stereochemical outcome and the separately con-
firmed structure of 4 were used to assign the depicted
absolute stereochemistry to 5.
Scheme 3. Proposed reaction course for 1,4-addition.
bromide, and benzyl bromide (other than entry 4), and also a
less reactive primary-alkyl iodide (Table 1, entry 4) in good
yields with exclusive regioselectivity and excellent diastereo-
selectivities.[10] a-Hexyl- and a-silylvinyl Grignard reagents
Regio- and stereoselective 1,6-
Table 1: Three-component coupling process based on 1,4-addition of Grignard reagents according to
Scheme 2.[a]
addition of Grignard reagents to
a,b,g,d-unsaturated amides is com-
plementary to the above 1,4-addi-
tion as illustrated in Scheme 1.
While we reported that the exclu-
sive 1,6-selective addition of aryl
Grignard reagents to a,b,g,d-unsa-
turated esters and amides was
viable with an iron catalyst,[12–15]
the remote asymmetric induction
from a chiral amide portion to the
carbon d to the carbonyl, which is
categorized as 1,7-chirality trans-
fer,[16] appeared quite difficult.
Nonetheless, of the chiral esters
and amides tested,[17] amide 21[18]
(see Scheme 4) was most promising.
The iron-catalyzed 1,6-addition of
PhMgBr to 21 proceeded with
exclusive regioselectivity and high
diastereoselectivity to give 22, or
the same addition followed by the
stereoselective alkylation of the
resulting enolate gave 23 as a 95:5
mixture of two (of a possible four)
diastereoisomers.
Entry
Substrate
Grignard Alkylation
Reagent
Product[b]
Yield [%][c] d.r.[d]
1
2
3
MeI
:65 7494
3
3
9
66
95:5
94:6
3
10 44
4
5
6
3
3
3
C6H13I
MeI
11 62
12 73
13 53
94:6
92:8
97:3
MeI
7[e]
14
BnBr[f]
17 65
94:6
8[e]
15
16
MeI
MeI
18 76
19 87
95:5
93:7
In these products, the amide
moiety and the incoming aryl
group are cis to each other about
the carbon–carbon double bond,
which suggests that the reaction
most likely proceeds via the s-cis-
diene iron complex 24[12,19] to gen-
erate 25 (and subsequently 22 or 23)
as shown in Scheme 5. This olefin
geometry is in stark contrast to that
9[e]
[a] Molar ratio: dienamide/Grignard reagent/alkylating agent=1:2:4. [b] The most abundant diastereo-
isomer is depicted. Absolute stereochemistries of 9–13 and 17–19 were deduced based on that of 5 by
analogy. [c] Yields that are not necessarily optimized. [d] The ratio of two major diastereoisomers. Two
other isomers, which were formed in less than trace amounts and could not be isolated nor
characterized, are omitted. [e] NR2* is the same as that in 3. [f] Alkylation was performed at room
temperature for 12 h.
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In conclusion, switching between exclusive 1,4- and 1,6-
additions of Grignard reagents to a,b,g,d-unsaturated amides
is now possible, owing to the absence or presence of an iron
catalyst. Moreover, a,b,g,d-unsaturated amides can be uti-
lized as a simple yet versatile template for asymmetric three-
component coupling process by the present one-pot reaction.
Scheme 4. Iron-catalyzed 1,6-addition and successive alkylation.
Experimental Section
(2S,3R,E)-2-Methyl-3-(1-methylethenyl)-4-hexenamide (5, derived
from 1,3:4,6-di-O-benzylidene-2,5-dideoxy-2,5-imino-l-iditol): iso-
propenylmagnesium bromide (1) (0.53m in THF, 0.377 mL,
0.200 mmol) was added to
a stirred solution of 3 (43.4 mg,
0.100 mmol, ca. 100% ee) in THF (2.0 mL) at ꢀ208C under argon.
The solution was rapidly warmed to room temperature and was
stirred at the same temperature for 1 h. Iodomethane (0.025 mL,
0.400 mmol) was added to this solution at room temperature, and the
solution was stirred at 608C for 1 h. The reaction was cooled to room
temperature and was terminated by the addition of an aqueous
saturated NH4Cl solution (2.0 mL). The organic layer was separated
and the aqueous layer was extracted with ethyl acetate. The combined
organic layers were dried over Na2SO4, and concentrated in vacuo to
give a crude oil, which was purified by column chromatography on
silica gel (hexane/ethyl acetate) to afford 5 (36.5 mg, 74%) as a white
Scheme 5. Proposed reaction course for 1,6-addition. Ln =ligands.
1
solid. H NMR spectroscopic analysis of isolated 5 revealed that the
diastereoselectivity was 94:6, which is comparable to the value
detected at the crude stage.
in copper-catalyzed reactions, where the carbonyl and the
introduced alkyl groups are usually
trans.[4a–c,f,g] The same intermediate
Table 2: Three-component coupling process based on the iron-catalyzed 1,6-addition according to
Scheme 4.[a]
24 could account for the anoma-
lously high level of 1,7-chirality
transfer, because the amide auxil-
iary efficiently blocks one plane of
the s-cis-diene, whereas the iron
complexation takes place from
another side (21!24, Scheme 5) to
promote efficient asymmetric deliv-
ery of the Ph group (24!25), which
is followed by highly stereoselective
alkylation (26!23). Thus, through-
out the reaction, the iron catalyst
should play three roles; to control
1) the regiochemistry of the conju-
gate addition, 2) the olefinic geom-
etry of the product, and 3) the
efficient remote chiral induction.
Table 2 shows the generality of
this reaction. The 1,6-addition and
the subsequent alkylation of 21
could be carried out with a variety
of aryl Grignard reagents and alky-
lating agents to produce the desired
products, 23 and 27–31 (Table 2,
entries 1–6). The same reaction
sequence with differently substi-
tuted amides 32 and 33 gave the
products 34 and 35, in very high
diasteromeric ratios, without any
complication (Table 2, entries 7
and 8).
Entry
Substrate
ArMgBr
Alkylation
MeI
Product[b]
Yield [%][c] d.r.[d]
1
21 PhMgBr
27 67
95:5
95:5
2
21
PhMgBr
28 58
3
4
21
21
PhMgBr
PhMgBr
29 55
23 69
94:6
95:5
C6H13I
C6H13I
5
6
21
21
30 63
31 70
96:4
94:6
C6H13I
7[e]
32 PhMgBr
33 PhMgBr
C6H13I
MeI[f]
34 71
35 68
96:4
97:3
8[e]
[a] Molar ratio: dienamide/FeCl2/ArMgBr/alkylating agent=1:0.1:2.5:5. [b] The most abundant diaste-
reoisomer is depicted. Absolute stereochemistries of 27–31, 34 and 35 were deduced by analogy based
on that of 23. [c] Yields that are not necessarily optimized. [d] The ratio of two major diastereoisomers.
Two other isomers, which were formed in trace amounts and could not be isolated or characterized, are
omitted. [e] NR2* is the same as that in 21. [f] Alkylation was performed at 08C for 12 h.
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(2R,5R,Z)-N,N-[(1’S,4’S)-1’,4’-Diphenyl-1’,4’-butylidene]-2-
hexyl-5-phenyl-3-hexenamide (23): PhMgBr (1.0m in THF, 0.250 mL,
0.250 mmol) was added over 7 min to a stirred solution of 21 (31.7 mg,
0.100 mmol, 97% ee[20]) and FeCl2 (1.3 mg, 0.010 mmol) in THF
(1.0 mL) in a 30 mL round-bottomed flask at ꢀ208C under argon to
give a dark brown to black homogeneous solution. After the solution
was stirred at the same temperature for 1 h, 1-iodohexane (0.074 mL,
0.500 mmol) was added. The solution was warmed to room temper-
ature and stirred for 12 h. The reaction was terminated by the
addition of 1m aqueous HCl (1.0 mL) at room temperature. The
reaction mixture was diluted with ethyl acetate and the organic layer
was separated. The aqueous layer was extracted with ethyl acetate.
The combined organic layers were washed with an aqueous saturated
NaHCO3 solution, dried over Na2SO4, and concentrated in vacuo to
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[5] Although 1,4-addition of Grignard reagents to a,b,g,d-unsatu-
rated amides was reported (reference [3b]), the precise regiose-
lectivities were not described and low to moderate product
yields were reported. In our group, among alkyl, alkenyl, and
aryl Grignard reagents, only isopropenyl-like reagents proved
satisfactory for this study. For Grignard conjugate addition to
a,b-unsaturated amides, see reference [1b].
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1
give a crude oil, H NMR spectroscopic analysis of which revealed
that the diastereoselectivity was 95:5 and that the regio- and olefinic
stereoisomers were absent. The product was purified by column
chromatography on silica gel (hexane/ethyl acetate) to afford 23
(33.3 mg, 69%) as a white solid, having the same isomeric compo-
sition as above.
Products 5 and 23 were fully characterized by 1H NMR, 13C NMR
spectroscopy, IR, elemental analyses, and appropriate derivatizations.
Their spectroscopic data and detailed structural determinations are
shown in the Supporting Information.
Received: April 24, 2008
Published online: July 29, 2008
[7] Similar amides derived from prolinol or a,a-diphenylprolinol
and amide 21 showed lower product yields and/or diastereose-
lectivities.
[8] a) Y. Masaki, H. Oda, K. Kazuta, A. Usui, A. Itoh, F. Xu,
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J. Chem. Soc. Perkin Trans. 1 1977, 1123 – 1126. The antipode of 3
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[9] For reviews on three-component coupling reactions based on
conjugate addition, see: a) M. J. Chapdelaine, M. Hulce in
Organic Reactions, Vol. 38 (Ed.: L. A. Paquette), Wiley, New
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[10] Precedents of three-component coupling process based on
conjugate addition of organometallic reagents to acyclic chiral
a,b-unsaturated carbonyl compounds followed by alkylation are
as follows. In these reactions, the alkylation was achieved with
reactive halides and a less reactive, higher primary-alkyl iodide,
such as C6H13I, was not included; a) L. S. Liebeskind, M. E.
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Asano, K. Takao, K. Tadano, Synlett 2001, 1772 – 1776; c) Y.
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Keywords: amides · asymmetric reaction · conjugate addition ·
Grignard reagents · iron
.
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