Cross-metathesis of allyl halides with olefins bearing an α-alkoxy amide group

Article abstract of DOI:10.1016/j.tetlet.2011.02.043

We have examined whether the allyl halide cross-metathesis reaction tolerates α-alkoxy amide groups. Ruthenium-based catalysts I-III did not catalyze the cross-metathesis of allyl halides in the presence of an α-alkoxy N,N-dimethylamide group to any appreciable extent, but the reaction could tolerate either a bulky N,N-diisopropylamide or Weinreb amide group. In particular, the Grubbs-Hoveyda-Blechert 2nd generation catalyst (III) efficiently catalyzed the cross-metathesis of allyl halides with olefins bearing a Weinreb amide group.

Full text of DOI:10.1016/j.tetlet.2011.02.043

Tetrahedron Letters 52 (2011) 1928–1930
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Tetrahedron Letters
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Cross-metathesis of allyl halides with olefins bearing an a
-alkoxy amide group q
Jeong In Yun a,b, Deukjoon Kim c, Jongkook Lee a,
⇑
a Bio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Yuseong, Daejeon 305-600, Republic of Korea
b Department of Chemistry, Korea University, Anam-dong, Seongbuk-Ku, Seoul 136-701, Republic of Korea
c The Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, San 56-1, Shillrim-Dong, Kwanak-Ku, Seoul 151-742, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
We have examined whether the allyl halide cross-metathesis reaction tolerates a-alkoxy amide groups.
Ruthenium-based catalysts I–III did not catalyze the cross-metathesis of allyl halides in the presence of
Received 5 January 2011
Revised 8 February 2011
Accepted 10 February 2011
Available online 13 February 2011
an -alkoxy N,N-dimethylamide group to any appreciable extent, but the reaction could tolerate either a
a
bulky N,N-diisopropylamide or Weinreb amide group. In particular, the Grubbs–Hoveyda–Blechert 2nd
generation catalyst (III) efficiently catalyzed the cross-metathesis of allyl halides with olefins bearing a
Weinreb amide group.
Keywords:
Cross-metathesis
Ó 2011 Elsevier Ltd. All rights reserved.
Allyl halide
Weinreb amide
Grubbs–Hoveyda–Blechert 2nd generation
catalyst
A great deal of progress in olefin cross-metathesis (CM) has
been achieved over the last decade. Many organic chemists have
utilized CM in their syntheses1 following the emergence of ruthe-
nium-based catalysts, such as the Grubbs catalyst (I),2 Grubbs 2nd
generation catalyst (II)3 and Grubbs–Hoveyda–Blechert 2nd gener-
ation catalyst (III).4 These catalysts are highly active, relatively sta-
ble, and tolerant of a variety of organic functional groups (Fig. 1).
In natural product syntheses, an allyl halide moiety is fre-
quently incorporated by building onto an existing aldehyde group
via an olefination–reduction–halogenation sequence,5 while the
CM of an allyl halide offers a synthetic shortcut that can substitute
for several functional group transformations in the sequence.
Ruthenium-based catalysts I–III have been used in a number of
cases over the past decade to promote the CM of allyl halides for
the synthesis of functionalized allyl halides.6–14 The reaction toler-
ates a variety of functional groups including ester, cyanide, benzyl
ether, silyl ether, and the hydroxyl group. The CM of allyl halides
has also been employed successfully in the syntheses of several
natural products. For example, Hong and co-workers developed
an elegant tandem allyl halide CM/SN20 reaction methodology for
the construction of O-heterocycles, and applied this tandem reac-
tion in the syntheses of subglutinol B15 and ( )-diospongin A.16
Ghosh and Xu synthesized a segment of (ꢀ)-spongidepsin utilizing
N
N
Mes
Mes
Cl
PCy3
Ru
N
N
Mes
Mes
Cl
Cl
Cl
Ru
Ru
Cl
Cl
O
Cy3P
Cy3P
I
III
II
Figure 1. Grubbs catalyst (I), Grubbs 2nd generation catalyst (II) and Grubbs–
Hoveyda–Blechert 2nd generation catalyst (III).
metal cations, such as Li+, Na+, Mg2+, and K+,18 but no reports have
yet appeared that address whether the CM of allyl halides can
tolerate an
of allyl halide CM to synthesize functionalized allyl halides that
bear an -alkoxy amide group.
Our initial attempt to determine whether the CM of allyl halides
would tolerate such a group involved the preparation of -alkoxy
amide 6b by the SN2 reaction of pentenol 3 with chloroacetamide
1 (Scheme 1).19 The CM of allyl chloride with
-alkoxy N,N-dimeth-
a-alkoxy amide. We now describe our successful use
a
a
a
ylamide 6b was carried out in the presence of ruthenium com-
plexes I–III. Contrary to our expectation, this reaction with amide
6b did not afford allyl halides 11a–b, and most of the starting
material was recovered (Table 1, entry 1). We considered that
the N,N-dimethylamide group of 6b could act as a ligand for cata-
lysts I–III,20 and reasoned that bulky alkyl substituents or electron-
withdrawing groups might hinder any disfavorable interactions
with I–III. Williamson ether synthesis of pentenol 3 with chloro-
acetamide 7 and the coupling of acid 9b with N-methoxy-
N-methylamine yielded amides 8 and 10b, respectively. Although
the CM of allyl chloride.17 Frequently,
a-alkoxy amide groups are
used in natural product synthesis due to their strong chelation of
q
Taken in part from the Master’s Thesis of J.I. Yun, Korea University, 2011.
⇑
Corresponding author. Tel.: +82 42 860 7178; fax: +82 42 860 7160.
E-mail address: jongkook@krict.re.kr (J. Lee).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.043

J. I. Yun et al. / Tetrahedron Letters 52 (2011) 1928–1930
1929
(Table 1, entries 11 and 12). These results strongly indicated that
the N,N-dimethylamide group of 6b is responsible for the putative
inactivation of ruthenium complexes I–III. In contrast to catalyst
III, Grubbs catalyst (I) or Grubbs 2nd generation catalyst (II) did
not catalyze the CM of allyl halides with Weinreb amide 10b to
any appreciable extent (Table 1, entry 6).21
O
O
i
O
O
Cl
Me2N
O
Me2N
n
1
6a-d
O
i
Cl
(i-Pr)2N
(i-Pr)2N
We next sought to investigate the effect of the distance between
the amide group and terminal olefin moiety on the success of CM
of allyl halides catalyzed by III. Williamson ether synthesis of alco-
hols 2, 4, and 5 with chloroacetamide 1 led to the formation of the
corresponding N,N-dimethylamides 6a,c–d. Readily available car-
boxylic acids 9a,c–d22 were transformed into 10a,c–d by coupling
with N-methoxy-N-methylamine (Scheme 1). The CM of allyl ha-
lides with N,N-dimethylamides 6a,c–d furnished no 12a–c, but
the Weinreb amides 10a,c–d underwent smooth CM to produce
12d–i in good yields, with little effect due to the distance between
the amide group and the terminal olefin moiety (Table 2). Interest-
7
8
O
O
ii
O
O
HO
Me(MeO)N
10a-d
n
n
9a-d
a
b
: n = 1
: n = 3
c: n = 5
d
: n = 8
Scheme 1. Reagent and conditions: (i) NaH, THF, prop-2-en-1-ol (2)/pent-4-en-1-ol
(3)/hept-5-en-1-ol (4)/dec-9-en-1-ol (5), rt, overnight, 63-94%; (ii) Me(MeO)NH,
hydroxybenzotriazole (HOBt), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
(EDCI), Et3N, CH2Cl2, rt, overnight, 78–90%.
ingly, the E/Z selectivity of the reactions with a-allyloxyamide 10a
was superior to that obtained in the reactions with 10b–d (16–
20:1 vs 6:1, Table 2, entries 2 and 3). The results further substan-
tiate our hypothesis that an N,N-dimethylamide group impedes
the CM of allyl halides catalyzed by I–III.
conversion was incomplete, the CM of allyl halides with bulky N,N-
diisopropylamide 8 generated allyl halides 11c–d in the presence
of catalyst III in 53% and 44% yields, respectively (50–60% conver-
sion, Table 1, entries 4 and 5).
In summary, we have prepared functionalized allyl halides that
possess an
a-alkoxy amide group by the CM of allyl halides cata-
lyzed by the Grubbs–Hoveyda–Blechert 2nd generation catalyst
(III) in good yield with good E/Z selectivity. The findings from this
investigation indicate that ruthenium complexes I–III do not toler-
ate olefins that bear an N,N-dimethylamide group. This problem
We then turned our attention to the CM of allyl halides with
Weinreb amide 10b. To our delight, amide 10b was converted
completely to allyl halides 11e–f by the CM of allyl halides
promoted by catalyst III, in 69% and 90% yields, respectively
Table 1
Cross-metathesis of allyl halides in the presence of substituted amides
O
O
allyl halides
I-III, CH2Cl2, reflux
O
O
R
R
X
11a-f
6b, 8, 10b
Entry
Compound #
R
X
Conditions
Yield (%)
Ratio E:Za
1
2
3
4
5
6
7
8
6b
8
8
8
8
10b
10b
10b
NMe2
N(i-Pr)2
N(i-Pr)2
N(i-Pr)2
Cl, or Br
I, II or III (10 mol %), 24 h
I (10 mol %), 24 h
11a-b, Nb
11c, 8
Cl
Cl
Cl
Br
Cl
Cl
Br
3:1
7:1
8:1
5:1
II (10 mol %), 24 h
III (20 mol %),c 4 h
III (20 mol %),c 4 h
I or II (10 mol %), 3 h
III (20 mol %),c 5 h
III (10 mol %), 2 h
11c, 10
11c, 53
11d, 44
11e, Nb
11e, 69
11f, 90
N(i-Pr)2
N(OMe)Me
N(OMe)Me
N(OMe)Me
9:1
7:1
a
b
c
The ratio was determined by the analysis of 1H 500 MHz NMR spectra.
No product formation was detected and most of the starting material was recovered.
Total 20 mol % (time 0, 10 mol %; time 2 h, 10 mol %) of III was used to complete the reaction.
Table 2
Effect of the distance between an amide group and olefin moiety on the cross-metathesis of allyl halides
O
O
allyl halides
O
O
R
X
R
n
n
III, CH2Cl2, reflux
12a-i
6a,c-d, 10a,c-d
Entry
Compound #
R
X
Conditions
Yield (%)
Ratio E:Za
1
2
3
4
5
6
7
6a,c or d (n = 1, 5, or 8)
10a, n = 1
10a, n = 1
10c, n = 5
10c, n = 5
NMe2
Cl
Cl
Br
Cl
Br
Cl
Br
10 mol %, 24 h
20 mol %,c 3 h
10 mol %, 3 h
20 mol %,c 3 h
10 mol %, 2 h
20 mol %,c 2 h
10 mol %, 2 h
12a–c, Nb
12d, 74
12e, 65
12f, 97
12g, 89
12h, 95
12i, 88
N(OMe)Me
N(OMe)Me
N(OMe)Me
N(OMe)Me
N(OMe)Me
N(OMe)Me
20:1
16:1
6:1
6:1
6:1
10d, n = 8
10d, n = 8
6:1
a
b
c
The ratio was determined by the analysis of 1H 500 MHz NMR spectra.
No product formation was detected and most of the starting material was recovered.
Total 20 mol % (time 0, 10 mol %; time 2 h, 10 mol %) of III was used to complete the reaction.

1930
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