Zinc-mediated allylation of aldoxime esters

Article abstract of DOI:10.1016/j.tetlet.2011.01.032

A facile zinc-mediated Barbier-type allylation of aromatic aldoxime esters, producing the corresponding protected homoallylic hydroxylamines, which are readily converted into homoallylic hydroxamic acids, is described.

Full text of DOI:10.1016/j.tetlet.2011.01.032

Tetrahedron Letters 52 (2011) 1195–1198
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Zinc-mediated allylation of aldoxime esters
⇑
Andrzej Wolan , Alicja Joachimczak, Marcin Budny, Anna Kozakiewicz
´
Department of Chemistry, Nicolaus Copernicus University, Gagarina 7, 87-100 Torun, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile zinc-mediated Barbier-type allylation of aromatic aldoxime esters, producing the corresponding
protected homoallylic hydroxylamines, which are readily converted into homoallylic hydroxamic acids, is
described.
Received 3 November 2010
Revised 17 December 2010
Accepted 7 January 2011
Available online 14 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Allylation of carbonyl compounds with allylic organometallic
reagents is a well known process with a broad spectrum of syn-
thetic applications.1 It provides an approach to secondary and ter-
tiary homoallylic alcohols, as valuable building blocks in the
synthesis of natural products.2 In 1985, Luche and Pétrier3 reported
the zinc-mediated Barbier-type allylation of aldehydes and ketones
in aqueous media. Since then, the addition of allylmetal reagents to
carbonyl groups in aqueous systems has been the subject of exten-
sive development.4,5 The C@N bond of imines can also be allylated
effectively to give homoallylic amines, which are important build-
ing blocks for the synthesis of nitrogen-containing natural prod-
ucts and bioactive molecules.4,6,7
However, the number of papers concerning the allylation of oxi-
mes and their derivatives under aqueous Barbier conditions is lim-
ited. Due to the poor electrophilicity of oximes, only certain oxime
ethers derived from glyoxylic acid and 2-pyridinecarboxaldehyde
can be allylated efficiently in the presence of zinc or indium metal.8
However, the addition of allylzinc reagents to simple aromatic
aldoximes has been less explored.9
unreacted starting material, and (E)-benzaldehyde oxime was not
detected. It should be noted that an excess of the reagents (Table
1, entries 5 and 6) and vigorous stirring of the heterogeneous reac-
tion mixture were required in order to obtain the product in a sat-
isfactory yield.
The allylation of (E)-benzaldehyde oxime benzoate (1e) can be
explained assuming coordination of a zinc atom with the nitrogen
atom and the carbonyl group activating the C@N bond to nucleo-
philic attack by the allyl group via a chair-like transition state
(Fig. 1). Earlier, Ricci and co-workers8d proposed the chelation ef-
fect of the ring nitrogen atom of 2-pyridinecarboxaldehyde oxime
ether or the carbonyl group of glyoxylic acid oxime ether.
Coordination of the carbonyl group is influenced by substitu-
ents on the aromatic ring of the ester group. An electron-with-
drawing CF3 group at the para-position of the benzoate ring
decreases the yield to 48% (Table 1, entry 7). In contrast, an elec-
tron-donating methoxy group at the para-position increases the
Table 1
Herein we present a practical and efficient approach to the syn-
thesis of homoallylic hydroxylamine esters by the zinc-mediated
allylation of aldoxime esters under Barbier conditions.
Allylation of (E)-benzaldehyde oxime and derivatives
OR
OR
H
Initially, we applied the procedure described by Hanessian and
Yang8a and examined the reaction of (E)-benzaldehyde oxime (1a)
with allyl bromide in the presence of zinc in THF/aqueous ammo-
nium chloride (Table 1). We observed zinc disappearing, but even
after 24 h, no allylation product was detected. Similarly, (E)-benz-
aldehyde oxime benzyl ether (1b) was unreactive. However, when
(E)-benzaldehyde oxime acetate (1c) was used under the same
reaction conditions, after 30 min, homoallylic hydroxylamine ace-
tate 2c was obtained in 81% yield. The product was contaminated
with the starting material and (E)-benzaldehyde oxime which
was formed by competing ester hydrolysis in the aqueous medium.
Fortunately, benzoate 1e, which is more stable in aqueous solution,
produced 2e in 67% yield which was easily separated from the
HN
N
Zn
Br
THF, aq .NH4Cl
1a-g
2a-g
Entry
R
Time (h)
Product
No reaction
No reaction
2c
Yielda (%)
1
2
3
4
5
6
7
8
1a, H
24
24
—
—
1b, Bn
1c, Ac
1d, Piv
1e, Bz
1e, Bz
0.5
24
0.5
0.5
0.5
0.5
81
—
67
56b
48
78
No reaction
2e
2e
2f
1f, 4-F3CC6H4CO
1g, 4-MeOC6H4CO
2g
a
⇑
3.0 equiv of allyl bromide, 3.5 equiv of zinc.
1.5 equiv of allyl bromide, 2 equiv of zinc.
Corresponding author. Tel.: +48 56 6114861; fax: +48 56 6542477.
E-mail address: wolan@chem.umk.pl (A. Wolan).
b
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.032

1196
A. Wolan et al. / Tetrahedron Letters 52 (2011) 1195–1198
As shown in Table 2, the yields were higher in the case of esters
Ph
containing electron-withdrawing groups (Table 2, entries 1–3 and
6). Electron-donating groups lowered the yields significantly (Ta-
ble 2, entries 4 and 5). ortho-Substituted esters 3g and 3h gave
the corresponding products in moderate yields. Presumably, for-
mation of the six-membered transition state with esters 3g and
3h is more difficult, due to a steric hindrance. In the case of nitro-
and dimethylamino substituents, side reactions involving reduc-
tion and allylation at the nitrogen atom led to complex mixtures
of products.
Allylation with trans-cinnamyl bromide was also carried out,
and the results are summarized in Table 3.
Esters with electron-withdrawing groups 3a–c and 3f gave
products in higher yields, the corresponding homoallylic hydroxyl-
N
Zn
O
O
Br
H
Ph
Figure 1. Chelation of the carbonyl group to the zinc atom in the transition state.
yield to 78% (Table 1, entry 8). The pivaloyl ester 1d was unreac-
tive, presumably due to a steric hindrance in the transition state.
The results presented above point to chelation of the carbonyl
group with the zinc atom (Fig. 1).
A series of 4-methoxybenzoates of various aromatic oximes
(3a–j) were prepared by reaction of 4-methoxybenzoyl chloride
with the appropriate oxime in the presence of triethylamine. The
allylation reactions of the esters are summarized in Table 2.10
amine esters being obtained in yields up to 84%. The
c-addition
products were formed selectively, and no a-products were found.
X-ray analysis of a single crystal of 5c (Fig. 2)11 showed it to be
Table 2
Allylation of aromatic aldoxime 4-methoxybenzoates
OMe
OMe
O
O
O
O
HN
N
Zn
THF, aq .NH4Cl
Br
H
R
R
4a-j
3a-j
Entry
R
Product
Yielda (%)
1
2
3
4
5
6
7
8
9
3a, p-F
3b, p-Cl
3c, p-Br
3d, p-Me
3e, p-MeO
3f, p-F3C
3g, o-Br
3h, o-MeO
3i, p-O2N
3j, p-Me2N
4a
4b
4c
4d
4e
4f
4g
4h
4i
73
81
72
68
53
72
48
51
b
—
b
10
4j
—
a
Isolated yields.
Complex mixtures of inseparable products.
b
Table 3
Stereoselective allylation of oximes 3a–c and 3f with (E)-cinnamyl bromide
OMe
OMe
OMe
O
O
O
O
Zn, Ph
Br
O
O
N
HN
HN
aq. NH4Cl, THF
R
X
X
3a-c, 3f
syn-5a-d
anti-5a-d
Entry
Oxime ester
Product
Yield (%)
Syn/antia
1
2
3
4
3a
3b
3c
3f
5a
5b
5c
5d
81
74
76
84
91/9
89/11
91/9
90/10
a
Determined on the basis of 1H NMR spectroscopic analysis of the crude products.

A. Wolan et al. / Tetrahedron Letters 52 (2011) 1195–1198
1197
The zinc-mediated allylation reaction of aldoxime benzoates
with allyl bromide under Barbier conditions produces the corre-
sponding homoallylic hydroxylamine esters in good yields. The
advantage of this reaction is that it is effective with non-activated
aromatic aldoximes. The products are readily transformed into
homoallylic hydroxamic acids, which are valuable products both
in organic synthesis and medicinal chemistry.14 This tandem trans-
formation provides a convenient access to hydroxamic acids from
readily available aromatic aldoxime esters. Further application of
this methodology in divergent synthesis is in progress.
Acknowledgment
We gratefully acknowledge the Ministry of Science and Higher
Education, Warsaw, for financial support Grant No. 2683/3/H03/
2010/38.
Supplementary data
Figure 2. ORTEP diagram of the single-crystal X-ray structure of syn-5c.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.01.032.
the syn-adduct. The stereochemical assignment of 5a, 5b, and 5d
was made by comparison of the methine vinylic proton chemical
shifts with that of 5c. The favored syn diastereoselectivities were
previously reported in the case of indium-mediated allylation of
2-pyridinecarboxaldehyde and glyoxylic acid,12 or related oximes
ethers.8d
References and notes
1. For general reviews on allylation, see: (a) Denmark, S. E.; Fu, J. Chem. Rev. 2003,
103, 2763–2793; (b) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207–2293;
ˇ
´
(c) Malkov, A. V.; Kocovsky, P. Eur. J. Org. Chem. 2007, 29–36; (d) Tietze, L. F.;
Knizel, T.; Brazel, C. C. Acc. Chem. Res. 2009, 42, 367–378.
2. For selected examples, see: (a) Nicolaou, K. C.; Kim, D. W.; Baati, R. Angew.
Chem., Int. Ed. 2002, 41, 3701–3704; (b) Girard, S.; Robins, R. J.; Villiéras, J.;
Lebreton, J. Tetrahedron Lett. 2000, 48, 9245–9249; (c) Makita, N.; Hoshino, Y.;
Yamamoto, H. Angew. Chem., Int. Ed. 2002, 41, 3701–3704; (d) Lee, K.-Ch.; Loh,
T.-P. Chem. Commun. 2006, 4209–4211; (e) Smith, A. B., III; Adams, C. M.;
Barbosa, S. A. L.; Degnan, A. P. J. Am. Chem. Soc. 2003, 125, 350–351; (f)
Hornberger, K. R.; Hamblet, C. L.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122,
12894–12895.
Next, 4c was transformed into the corresponding homoallylic
hydroxamic acids 7 and 8 (Scheme 1). Thus, acetylation of 4c pro-
duced amide 6 in good yield, which was treated with sodium
methoxide in methanol to cleave the ester group. After acidificat-
ion and flash chromatography, homoallylic hydroxamic acid 7
was isolated in high yield (87%). Its structure was confirmed by
NMR spectroscopy and the presence of the hydroxamic acid group
was also detected by a simple color test with iron(III) chloride.
Other attempts to cleave the ester group of hydroxylamine es-
ters, either in acidic (TFA, PTSA) or in basic conditions, failed. How-
ever, the use of potassium tert-butoxide resulted in the transfer of
the acyl group from oxygen to nitrogen and hydroxamic acid 8 was
obtained in 40% yield. A similar rearrangement was reported ear-
lier by Yamamoto and co-workers13 who described isomerization
of a hydroxylamine ester into a hydroxamic acid by treatment with
tert-butyllithium under mild conditions.
3. Pétrier, Ch.; Luche, J.-L. J. Org. Chem. 1985, 50, 910–912.
4. (a) Li, Ch.-J. Chem. Rev. 1993, 93, 2023–2035; (b) Li, Ch.-J. Chem. Rev. 2005, 105,
3095–3165; (c) Li, Ch.-J.; Chan, T.-H. Comprehensive Organic Reactions in
Aqueous Media, 2nd ed.; John Wiley & Sons: Hoboken, New Jersey, 2007.
5. For mechanistic studies, see: Dam, J. H.; Fristrup, P.; Madsen, R. J. Org. Chem.
2008, 73, 3228–3235.
6. Bloch, R. Chem. Rev. 1998, 98, 1407–1438.
7. For selected reviews and examples, see: (a) Friestad, G. K.; Mathies, A. K.
Tetrahedron 2007, 63, 2541–2569; (b) Basile, T.; Bocoum, A.; Savoia, D.; Umani-
Ronchi, A. J. Org. Chem. 1994, 59, 7766–7773; (c) Pachamuthy, K.; Vankar, Y. D.
J. Organomet. Chem. 2001, 624, 359–363; (d) Sugimoto, Y.; Imamura, H.; Sakoh,
H.; Yamada, K.; Morishima, H. Synlett 2001, 1747–1750; (e) Samanta, D.;
Kargbo, R. B.; Cook, G. R. J. Org. Chem. 2009, 74, 7183–7186.
OMe
OMe
O
O
O
1. MeONa
MeOH
O
O
O
OH
AcCl, Py
RT, 0.5 h
HN
N
N
0
–
20°C, 18 h
2. aq. HCl
83%
87%
Br
Br
Br
4c
6
7
OMe
t-BuOK
OH
Et2O, RT, 0.5 h
O
N
40%
Br
8
Scheme 1. Synthesis of hydroxamic acids 7 and 8.

1198
A. Wolan et al. / Tetrahedron Letters 52 (2011) 1195–1198
8. (a) Hanessian, S.; Yang, R. –Y. Tetrahedron Lett. 1996, 37, 5273–5276; (b)
Hanessian, S.; Lu, P.-P.; Sancéau, J. –Y.; Chemla, P.; Gohda, K.; Fonne-Pfister, R.;
Prade, L.; Cowan-Jacob, S. W. Angew. Chem., Int. Ed. 1999, 38, 3160–3162; (c)
Miyabe, H.; Nishimura, A.; Ueda, M.; Naito, T. Chem. Commun. 2002, 1454–
1455; (d) Bernardi, L.; Cerè, V.; Femoni, C.; Pollicino, S.; Ricci, A. J. Org. Chem.
2003, 68, 3348–3351; (e) Ritson, D. J.; Cox, R. J.; Berge, J. Org. Biomol. Chem.
2004, 2, 1921–1933.
9. One example of benzaldoxime acetate crotylation under Barbier conditions can
be found in Cheng, H.-S.; Seow, A.-H.; Loh, T.-P. Org. Lett. 2008, 10, 2805–2807.
10. Typical procedure for the allylation of oxime esters: Zinc powder (3.50 equiv,
7 mmol, 0.46 g) and (E)-4-bromobenzaldehyde O-4-methoxybenzoyl oxime
(3c) (1.00 equiv, 2 mmol, 0.67 g) were placed in a flask (100 mL), then THF
(7 mL) was added followed by saturated aqueous NH4Cl solution (28 mL). Allyl
bromide (3.00 equiv, 6 mmol) was added in one portion with vigorous stirring
which was continued for an additional 30 min. Next, 2 M NaOH (15 mL) was
added followed with Et2O (15 mL). The organic phase was separated, and the
aqueous layer extracted by Et2O (3 Â 10 mL). The combined organic phases
were washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered,
and concentrated to give the crude product which was purified by flash
chromatography on silica gel (PE/AcOEt; 4:1) to give N-[1-(4-
bromophenyl)but-3-enyl]-O-(4-methoxybenzoyl)hydroxylamine (4c) as
colorless crystals; 0.54 g, yield 72%, mp 55–56 °C. IR (KBr): 3413, 3231, 1701,
1607, 1511, 1317, 1261, 1171, 1116, 1027 cmÀ1 1H NMR (200 MHz, CDCl3): d
2.54 (m, 2H), 3.84 (s, 3H), 4.13 (dt, J = 7.0, 4.4 Hz, 1H), 5.18 (m, 2H), 5.77 (m,
1H), 6.88 (d, J = 9.0 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.83
(d, J = 9.0 Hz, 2H), 8.00 (d, J = 4.4 Hz, 1H). 13C NMR (50.3 MHz, CDCl3): d 38.6,
55.4, 64.5, 113.8, 118.6, 120.4, 121.6, 129.1, 131.3, 131.6, 133.4, 139.3, 163.7,
166.5. Anal. Calcd for C18H18BrNO3: C, 57.46; H, 4.82; N, 3.72. Found: C, 57.19;
H, 4.60; N, 3.61.
.
11. The structural data for syn-5c have been deposited at the Cambridge
Crystallographic Data Centre: (CCDC No. 771504).
12. Paquette, L. A.; Rothhaar, R. R. J. Org. Chem. 1999, 64, 217–224.
13. (a) Murase, N.; Hoshino, Y.; Oishi, M.; Yamamoto, H. J. Org. Chem. 1999, 64,
338–339; (b) Hoshino, Y.; Murase, N.; Oishi, M.; Yamamoto, H. Bull. Chem. Soc.
Jpn. 2000, 73, 1653–1658.
14. The Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids; Rappoport, Z.,
Liebman, J. F., Eds.; Wiley: Chichester, 2009.