Application of organocerium reagents for the efficient conversion of Z-α,β-unsaturated Weinreb amides to Z-α,β-unsaturated ketones

Article abstract of DOI:10.1246/cl.2005.470

The reactions of Z-rich unsaturated Weinreb amides with organolithium and organocerium reagents were examined. Taking in consideration both the extent of geometry retention and cleanness of the reaction, organocerium reagents were more effective for the conversion to Z-α,β-unsaturated ketones. Copyright

Full text of DOI:10.1246/cl.2005.470

470
Chemistry Letters Vol.34, No.4 (2005)
Application of Organocerium Reagents for the Efficient Conversion
of Z-ꢀ,ꢁ-Unsaturated Weinreb Amides to Z-ꢀ,ꢁ-Unsaturated Ketones
Satoshi Kojima,ꢀy;yy Tsugihiko Hidaka,y and Atsushi Yamakaway
yDepartment of Chemistry, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima 739-8526
yyCenter for Quantum Life Sciences, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima 739-8526
(Received December 24, 2004; CL-041590)
Table 1. HWE reaction with R1CHOa
The reactions of Z-rich unsaturated Weinreb amides with or-
ganolithium and organocerium reagents were examined. Taking
Yield
in consideration both the extent of geometry retention and clean-
ness of the reaction, organocerium reagents were more effective
for the conversion to Z-ꢀ,ꢁ-unsaturated ketones.
Entry
R1
Reagent
Base
Product Z:Eb
/%c
1d
2
Ph
Ph
Ph
1a
1b
1c
1a
1b
1c
1b
1c
1b
1c
KHMDS
n-BuLie
t-BuOKf
NaH
3a
3a
3a
3b
3b
3b
3c
3c
3d
3d
72:28 67
88:12 71
3
97:3
83:17 83
91:9 97
88
4d Ph(CH2)2
The conjugated carbonyl unit is a versatile building block,
and the geometry of the double bond often dictates the stereo-
chemical outcome of reactions to this unit. For the less available
Z-olefins, however, only a limited number of practical methods
which accompany carbon–carbon double bond formation have
been reported.1–5 As for Z-ꢀ,ꢁ-unsaturated ketones, there is only
one that can be coined general, and it only deals with methyl ke-
tones.4 In order to gain access to a wider range of Z-ꢀ,ꢁ-unsat-
urated ketones, we figured that utilization of ꢀ,ꢁ-unsaturated
Weinreb amides might be practical.6 That is, the use of a Wit-
tig-type reaction to prepare Z-ꢀ,ꢁ-unsaturated Weinreb amides
and treatment of these amides with organometallic reagents to
complete the transformation. The success of such a tandem reac-
tion relies on high Z-selectivity for the olefination reaction and
retention of geometry in the second step. If the second process
does not lead to a high degree of retention, efforts to gain high
Z-selectivity in the first step would be useless. Thus, it would
be very important to assess the ketone-forming step. For the
E-counterparts, prevention of isomerization is not a critical is-
sue, since they are highly favored. In fact, there are quite a
few examples involving the transformation of aldehydes to E-
ꢀ,ꢁ-unsaturated Weinreb amides7 followed by further transfor-
mation to E-ꢀ,ꢁ-unsaturated aldehydes and ketones.8 Herein,
we report on the reaction of Z-ꢀ,ꢁ-unsaturated Weinreb amides
with organo-lithium and -cerium reagents.
5
6
Ph(CH2)2
Ph(CH2)2
c-Hexyl
c-Hexyl
PhMe2C
PhMe2C
NaH
KHMDSf
NaHf
t-BuOKf,g
NaHf
t-BuOKf,g
85:15 87
86:14 99
68:32 98
84:16 58
43:57 35
7
8
9
10
aAll of the reactions were run in THF at ꢁ78 ꢂC. bDetermined by
the 1H NMR (500 MHz) measurement of the crude mixture.
cCombined isolated yield of Z and E olefins. The isomers of the
products other than 3a could be separated by chromatography,
although with much difficulty in the case of 3d. dFrom
e
f
reference 5(c). TMEDA was used as an additive. 18-Crown-6
g
was used as an additive. The temperature was gradually raised
to 0 ꢂC.
steric demand tended to give lower selectivity.
The obtained ꢀ,ꢁ-Unsaturated Weinreb amides were not al-
ways separable by column chromatography, and thus were not
necessarily separated upon examination with organometals.
With organolithium reagents, MeLi, n-BuLi, and phenyllithium,
the reactions were found to be rather messy as a whole and be-
sides the desired ꢀ,ꢁ-unsaturated ketones arising from 1,2-addi-
tion, the crude reaction mixtures showed the presence of multi-
ple saturated products in varying amounts, making purification
somewhat tedious (Table 2).10 The latter apparently formed by
1,4-addition or by secondary reactions to the 1,4-adducts. This
is in contrast with E-ꢀ,ꢁ-unsaturated Weinreb amides, which re-
portedly undergo high yielding reactions.7 However, the geom-
etry of the olefin was found to be essentially intact during the re-
actions regardless of the identity of the substrate or organolithi-
um reagent. The use of PhMgBr was found to lead to a high
percentage of the E-olefin (Entry 7). The product ketones, espe-
cially those bearing a phenyl group, were prone to undergo some
degree of isomerization.11 Thus, in some cases, the product
ketone was further reduced to the corresponding alcohol. This
not only assured reaction selectivity (by reducing the possibility
of adventituous isomerization) for isomerizable ketones, but also
demonstrated that further transformations may be realized with
minimal change in E–Z ratio.
R1
R1
O
O
1) base, THF, -78 °C
2) R1CHO (2)
R2O P
R2O
OMe
O
O
N
N
N
OMe
OMe
1a: R2=Ph
1b: R2=o-tolyl
1c: R2=CF3CH2
3c: R1=c-hexyl
3d: R1=PhMe2C
3a: R1=Ph
3b: R1=Ph(CH2)2
Since our primary objective was to determine the efficacy of
the second step, efforts to obtain the Z-ꢀ,ꢁ-unsaturated Weinreb
amides with high selectivity were carried out only briefly. Com-
pared with the previously examined amide analog of Ando’s es-
ter reagent,2 i.e., (PhO)2P(O)CH2CON(Me)OMe (1a),5 the steri-
cally more demanding (2-MeC6H4O)2P(O)CH2CON(Me)OMe
(1b) was more effective for alkyl aldehydes, whereas the amide
analog of Still’s reagent,1 i.e., (CF3CH2O)2P(O)CH2CON(Me)-
OMe (1c),9 was superior for aromatic aldehydes. Representative
results are given in Table 1. Aliphatic aldehydes with higher
With the intention of reducing the amount of the 1,4-addi-
tion products, the use of CeCl3 as an additive was next examined
(Table 3).12,13
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.4 (2005)
471
R1
O
R1
O
R3Li or R3Li, CeCl3
THF
4aa: R1=Ph, R3=Me
4ab: R1=Ph, R3=n-Bu
4ac: R1=Ph, R3=Ph
Besides those involving PhCeCl2 where biphenyl formation
was inevitable, the reactions were found to be rather clean ones,
and other than the desired 1,2-product, practically only the un-
reacted starting material could be observed in the crude reaction
mixtures. As for the geometry of the product ketones, compared
with the organolithium reactions, there was a slight leakage in
stereochemistry, but it was very minimal.
In summary, from a comprehensive point of view, we have
found that organocerium reagents are very useful for the conver-
sion of Z-ꢀ,ꢁ-unsaturated Weinreb amides to Z-ꢀ,ꢁ-unsaturated
ketones. Efforts to increase selectivity in the olefination step for
an efficient one-pot reaction, are currently in progress.
OMe
N
R3
4ca: R1=c-hexyl, R3=Me
4cb: R1=c-hexyl, R3=n-Bu
4cc: R1=c-hexyl, R3=Ph
4da: R1=PhMe2C, R3=Me
4db: R1=PhMe2C, R3=n-Bu
4dc: R1=PhMe2C, R3=Ph
3a-d
4ba: R1=Ph(CH2)2, R3=Me
4bb: R1=Ph(CH2)2, R3=n-Bu
4bc: R1=Ph(CH2)2, R3=Ph
R1 OH
NaBH4, CeCl3-7H2O
MeOH
5ab: R1=Ph, R3=n-Bu
5ac: R1=Ph, R3=Ph
R3
5bc: R1=Ph(CH2)2, R3=Ph
5cc: R1=c-hexyl, R3=Ph
5dc: R1=PhMe2C, R3=Ph
This work was supported in part by Grants-in-Aid for
Scientific Research (Nos. 14540497 and 16550098) from the
Japan Society for the Promotion of Science.
Table 2. Reaction of unsaturated amides with RLia
Yield
/%e
d
Entry
R1
R3 Product
Z:Eb (Z:E)c
Z=ðZÞ
References and Notes
1
2
W. C. Still and C. Gennari, Tetrahedron Lett., 24, 4405 (1983).
a) K. Ando, J. Org. Chem., 64, 8406 (1999) and references therein. b)
T. Y. Zhang, J. C. O’Toole, and J. M. Dunigan, Tetrahedron Lett., 39,
1461 (1998).
For example: a) S. Kojima, R. Takagi, and K.-y. Akiba, J. Am. Chem.
Soc., 119, 5970 (1997). b) S. Kojima, K. Kawaguchi, S. Matsukawa,
K. Uchida, and K.-y. Akiba, Chem. Lett., 2002, 170. c) S. Kojima, H.
Inai, T. Hidaka, and K. Ohkata, Chem. Commun., 2000, 1795. d) S.
Kojima, H. Inai, T. Hidaka, T. Fukuzaki, and K. Ohkata, J. Org. Chem.,
67, 4093 (2002). e) S. Kojima, T. Fukuzaki, A. Yamakawa, and Y.
Murai, Org. Lett., 6, 3917 (2004), and references therein.
W. Yu, M. Su, and Z. Jin, Tetrahedron Lett., 40, 6725 (1999).
a) K. Ando, Synlett, 2001, 1272. b) S. Kojima, T. Hidaka, Y. Ohba, and
K. Ohkata, Phosphorus, Sulfur Silicon, 177, 729 (2002). c) S. Kojima, T.
Hidaka, and Y. Ohba, Heteroat. Chem., 15, 515 (2004).
a) S. Nahm and S. M. Weinreb, Tetrahedron Lett., 22, 3815 (1981). For
reviews see: b) M. P. Sibi, Org. Prep. Proced. Int., 25, 15 (1993). c) M.
Mentzel and H. M. R. Hoffmann, J. Prakt. Chem., 339, 517 (1997). d) J.
Singh, N. Satyamurthi, and I. S. Aidhen, J. Prakt. Chem., 342, 340
(2000).
a) J. M. Nuzillard, A. Boumendjel, and G. Massiot, Tetrahedron Lett., 30,
3779 (1989). b) D. A. Evans, S. W. Kaldor, T. K. Jones, J. Clardy, and
T. J. Stout, J. Am. Chem. Soc., 112, 7001 (1990). c) D. F. Netz and
J. L. Seidel, Tetrahedron Lett., 33, 1957 (1992). d) M. Murakami, Y.
Hoshino, H. Ito, and Y. Ito, Chem. Lett., 1998, 163. e) C. Beney, A.
Boumendjel, and A.-M. Mariotte, Tetrahedron Lett., 39, 5779 (1998).
For example: a) Y. L. Bennani and K. B. Sharpless, Tetrahedron Lett.,
34, 2083 (1993). b) M. Groesbeek, G. A. Rood, and J. Lugtenburg, Recl.
Trav. Chim. Pays-Bas, 111, 149 (1992).
The reagent 1c was prepared from (CF3CH2O)2P(O)H and ClCH2CON-
(Me)OMe in the presence of NaH. During our efforts on this project, the
preparation of the same reagent by a different method and a single exam-
ple of the use of this reagent was reported. Contrary to our results, the
reaction with an unbranched alkyl aldehyde was reported to give perfect
Z-selectivity. S. Fortin, F. Dupont, and P. Deslongchamps, J. Org.
Chem., 67, 5437 (2002).
1
2
3f
4
5
Ph
Ph
Ph
Me
n-Bu 4ab
Ph 5ac
4aa
63:37 (69:31)
68:32 (69:31)
97:3 (96:4)
0.91
0.99
1.00
44
66
70
82
71
46
68
3
Ph(CH2)2 Me
Ph(CH2)2 n-Bu 4bb >99:1 (>99:1) 1.00
5bc >97:3 (97:3) 1.00
4bc 70:30 (>99:1) 0.70
4ba >99:1 (>99:1) 1.00
6f Ph(CH2)2 Ph
7g,h Ph(CH2)2 Ph
aAll of the reactions were run in THF at ꢁ78 ꢂC with 3 equiv. of
RLi except where noted otherwise. The yields were not optimized.
bDetermined by the 1H NMR (500 MHz) measurement of the
crude mixtures. cThe ratios of the unsaturated Weinreb amide sub-
strates are in parentheses. dZ ratio of products divided by Z ratio of
substrates. These values are rough indications of the degree of ge-
4
5
6
7
e
ometry retention. Combined isolated yields of Z and E olefins.
The isomers of the ketone products could be separated by chroma-
tography, although somewhat less readily for 4aa and 4ab.
fFurther reduction was carried out on the crude ketone mixture.
gThe temperature was gradually raised to 0 ꢂC. hPhMgBr (10
equiv.) was used.
a
Table 3. Reaction of unsaturated amides with RLi–CeCl3
8
9
Yield
/%e
d
Entry
R1
R3 Product
Z:Eb (Z:E)c
Z=ðZÞ
1
Ph
Ph
Ph
Me
n-Bu 5ab
Ph 5ac
4aa
67:33 (73:27)
94:6 (94:6)
94:6 (94:6)
0.92 77
1.00 93
1.00 93
2f
3f
4
Ph(CH2)2 Me 4ba >99:1 (>99:1) 1.00 34(76)
Ph(CH2)2 n-Bu 4bb >99:1 (>99:1) 1.00 95
5
6f Ph(CH2)2 Ph
5bc
4ca
96:4 (97:3)
0.99 80
10 The saturated products could not be isolated in pure form.
11 C. Dugave and L. Demange, Chem. Rev., 103, 2475 (2003).
12 An isolated example on the use of an organocerium reagent for ketone
synthesis via a saturated Weinreb amide has been reported: R. G. Carter
and D. J. Weldon, Org. Lett., 2, 3913 (2000).
7
c-Hexyl Me
95:5 (>99:1) 0.95 38(90)
96:4 (>99:1) 0.96 56(85)
5cc >99:1 (>99:1) 1.00 99
8
c-Hexyl n-Bu 4cb
9f c-Hexyl Ph
10 PhMe2C Me
13 Typical procedure: To a suspension of anhydrous CeCl314 (0.3 mmol) in
THF (1 mL) was added RLi (0.3 mmol) at ꢁ78 ꢂC under N2. To the sus-
pension was added a solution of an ꢀ,ꢁ-unsaturated Weinreb amide (0.1
mmol) in THF (2.5 mL) and stirring was continued at the same temper-
ature for 3 h. The reaction was quenched with saturated NH4Cl, and the
aqueous layer was extracted with ether. The combined organic layer was
washed with brine, dried over MgSO4, and concentrated. Purification of
the crude product by PTLC gave a mixture of Z and E olefins.
14 a) T. Imamoto, T. Kusumoto, Y. Tawarayama, Y. Sugiura, T. Mita,
Y. Hatanaka, and M. Yokoyama, J. Org. Chem., 67, 3904 (1984). b)
D. Vladimir, K. Kostova, and M. Genov, Tetrahedron Lett., 37, 6787
(1996).
4da
65:35 (71:29)
69:31 (71:29)
96:4 (>99:1) 0.96 76
0.92 49(86)
0.97 90
11 PhMe2C n-Bu 4db
12f PhMe2C Ph
5dc
aTypical reactions were run in THF at ꢁ78 ꢂC with 3 equiv. each
of RLi and CeCl3. b{dSee footnotes of Table 2. eCombined isolated
yields of Z and E olefins. Yields based on recovered starting ma-
terial are in parentheses. The isomers of the ketone products could
be separated by chromatography, although somewhat less readily
f
for 4aa. Further reduction was carried out on the crude ketone
mixture.
Published on the web (Advance View) February 26, 2005; DOI 10.1246/cl.2005.470