Palladium-catalyzed addition of hydroxylamine derivatives to Baylis-Hillman acetate adducts

Article abstract of DOI:10.1016/j.tetlet.2006.11.061

The first use of hydroxylamine derivatives as the aminoxy equivalent of nucleophiles in palladium catalyzed addition to Baylis-Hillman acetate adducts is described. The reaction proceeds smoothly to give the substituted allyloxy amines in good yield and s

Full text of DOI:10.1016/j.tetlet.2006.11.061

Tetrahedron Letters 48 (2007) 215–218
Palladium-catalyzed addition of hydroxylamine derivatives
to Baylis–Hillman acetate adductsI
Ch. Raji Reddy,a,* N. Kiranmai,a G. S. Kiran Babu,a G. Dattatreya Sarma,b
B. Jagadeeshb and S. Chandrasekhara
aOrganic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
bNuclear Magnetic Resonance Division, Institute of Chemical Technology, Hyderabad 500 007, India
Received 4 October 2006; revised 2 November 2006; accepted 9 November 2006
Abstract—The first use of hydroxylamine derivatives as the aminoxy equivalent of nucleophiles in palladium catalyzed addition to
Baylis–Hillman acetate adducts is described. The reaction proceeds smoothly to give the substituted allyloxy amines in good yield
and selectivity.
Ó 2006 Elsevier Ltd. All rights reserved.
Palladium-catalyzed allylic substitution has been used in
a wide variety of synthetically useful reactions involving
various nucleophiles.1 However, few studies have been
reported in which hydroxylamines are used as oxygen
atom (aminoxy equivalent) nucleophiles for allylic sub-
stitution reactions.2 Interestingly, there is no report in
the literature on allylic substitution of Baylis–Hillman
acetate adducts using hydroxylamines. These findings
encouraged us to study the reaction of hydroxylamines
with Baylis–Hillman acetates. The products obtained
also serve as intermediates for making useful allyloxy
amines/aminoxy esters and their derivatives.3
as precursors in synthesizing several useful compounds.4
In particular, the acetates of Baylis–Hillman adducts
have proved to be very useful synthons for addition
reactions with different nucleophilic reagents.5 In contin-
uation of our interest in the reactions involving Baylis–
Hillman adducts,6 we studied the nucleophilic addition
of hydroxylamine derivatives to Baylis–Hillman acetate
adducts in the presence of 10 mol % Pd(PPh3)4 (Scheme
1).
We first examined the reaction of N-hydroxyphthal-
imide 1b with Baylis–Hillman adduct 1a in the presence
of 10 mol % Pd(PPh3)4 in acetonitrile at room tempera-
ture to afford the corresponding allyloxy phthalimide 1c.
The reaction was complete in 1 h and product 1c was
The products of Baylis–Hillman reactions (BH adducts)
are multifunctional allylic alcohols and have been used
CO2Et
O
X=CO2Et
R
O
N
O
OAc
O
Pd(PPh3)4 (10 mol%)
CH3CN, 20 oC
X
HO
N
+
R
O
O
X=CN
O
N
R
CN
O
Scheme 1.
Keywords: Palladium; Baylis–Hillman adduct; Hydroxylamines.
q IICT Communication No. 060912.
*
Corresponding author. Tel.: +91 40 27193434; fax: +91 40 27160512; e-mail: rajireddy@iict.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.061

216
Ch. Raji Reddy et al. / Tetrahedron Letters 48 (2007) 215–218
Table 1. Addition of hydroxylamines to Baylis–Hillman acetate adducts9
Entry
1
BH acetate adduct (a)
Hydroxylamine derivative (b)
Time (h)
1
Product (c)a
Yieldb (%)
O
OAc
CO2Et
CO2Et
HO N
1c
2c
3c
4c
80
O NPhth
O
1a
1b (HO-NPhth)
OAc
CN
NPhth
O
2
3
4
1b
1b
1b
1
2
2
71
68
70
CN
2a
OAc
Br
Br
CO2Et
Br
Br
CO2Et
O NPhth
3a
OAc
NPhth
CN
O
CN
4a
Br OAc
Br
CN
NPhth
NPhth
5
6
7
1b
1b
1b
2
5c
6c
7c
62
68
71
O
O
5a
CN
CN
NO2 OAc
NO2
CN
1.5
1
6a
OAc
CO2Et
CO2Et
O NPhth
7a
O
HO N
O
CO2Et
8
9
1a
1.5
2
8c
70
65
66
O NSu
(HO-NSu)
2b
O NSu
2a
3a
2b
9c
CN
Br
CO2Et
10
2b
2b
2
10c
O NSu
CO2Et
11
12
13
7a
3a
3a
1
11c
12c
13c
67
34
28
O NSu
Br
Br
CO2Et
HO–NHBoc
3b
1.5
1.5
O NHBoc
CO2Et
HO–NHBn
4b
O NHBn
a The products were characterized by 1H NMR, mass and IR spectra.
b Isolated yields.
obtained in 80% yield with exclusive (E)-selectivity
(entry 1). The stereochemistry of the product was estab-
lished based on extensive 2D NMR studies including
DQCOSY, NOESY and TOCSY experiments.7
In the absence of a catalyst, no reaction occurred even at
reflux. Next, the reaction of Baylis–Hillman acetate
adduct 2a, derived from acrylonitrile, with N-hydroxy-
phthalimide under similar reaction conditions gave the

Ch. Raji Reddy et al. / Tetrahedron Letters 48 (2007) 215–218
217
1689; (c) Frost, C. G.; Howarth, J.; Williams, J. M. J.
Tetrahedron: Asymmetry 1992, 3, 1089; (d) Tsuji, J.
Transition Metal Reagents and Catalysts; Wiley: New York,
2000.
O
CO2Et
O N
2. (a) Miyabe, H.; Yoshida, K.; Yamaguchi, M.; Takemoto,
Y. J. Org. Chem. 2005, 70, 2148; (b) Miyabe, H.; Matsu-
mura, A.; Moriyama, K.; Takemoto, Y. Org. Lett. 2004, 6,
4631; (c) Miyabe, H.; Yoshida, K.; Matsumura, A.;
Yamaguchi, M.; Takemoto, Y. Synlett 2003, 567.
3. (a) Ishikawa, T.; Kawakami, M.; Fukui, M.; Yamashita,
A.; Urano, J.; Saito, S. J. Am. Chem. Soc. 2001, 123, 7734;
(b) Yang, D.; Zhang, Y.-H.; Li, B.; Zhang, D.-W. J. Org.
Chem. 2004, 69, 7577.
O
1c
N H H O
.
2
4
2
CH2Cl2:MeOH (1:1)
rt
CO2Et
O NH2
1d
4. (a) Basavaiah, D.; Satyanarayana, T. Chem. Commun.
2004, 32; (b) Basavaiah, D.; Rao, A. J.; Satyanarayana,
T. Chem. Rev. 2003, 103, 811; (c) Frank, S. A.;
Mergott, D. J.; Rousch, W. R. J. Am. Chem. Soc. 2002,
124, 2404; (d) Yang, K.-S.; Chen, K. Org. Lett. 2000, 2,
729; (e) Drews, S. E.; Ross, G. H. P. Tetrahedron 1988, 44,
4653.
5. (a) Kabalka, G. W.; Dong, G.; Venkataiah, B.; Chen, C. J.
Org. Chem. 2005, 70, 9207; (b) Seung, C. K.; Gowrisankar,
S.; Kim, J. N. Bull. Korean Chem. Soc. 2005, 26, 799; (c)
Basavaiah, D.; Rao, J. S. Tetrahedron Lett. 2004, 45, 1621;
(d) Saxena, R.; Patra, A.; Batra, S. Synlett 2003, 1439; (e)
Shanmugam, P.; Singh, P. R. Synlett 2001, 1314.
6. (a) Chandrasekhar, S.; Saritha, B.; Jagadeeshwar, V.;
Narsihmulu, Ch.; Vijay, D.; Sarma, G. D.; Jagadeesh, B.
Tetrahedron Lett. 2006, 47, 2981; (b) Chandrasekhar, S.;
Chandrasekhar, G.; Vijeender, K.; Reddy, M. S. Tetra-
hedron Lett. 2006, 47, 3475; (c) Chandrasekhar, S.; Basu,
D.; Rambabu, Ch. Tetrahedron Lett. 2006, 47, 3059.
7. (a) The (E)-stereochemistry of 1c was assigned on the basis
of 1H and 13C NMR chemical shifts in comparison with
literature values.8 The structure was supported by NOE
cross peaks between H7–H9, H1–H16 and H1–H17.
Spectral data for 1c: Off white solid; mp 74–78 °C; 1H
NMR (500 MHz, CDCl3): d 8.13 (1H, s, H1), 7.83 (2H, dd,
J = 3.5, 5.5 Hz, H11, 14), 7.73 (2H, dd, J = 3.5, 5.5 Hz,
H12, 13), 7.70 (2H, d, J = 7.0 Hz, H3, 7), 7.43–7.45 (3H, m,
H4, 5, 6), 5.11 (2H, s, H9), 4.28 (2H, q, J = 7.0 Hz, H16),
1.32 (3H, t, J = 7.0 Hz, H17); 13C NMR (75 MHz, CDCl3);
d 166.7, 163.2, 148.1, 134.3, 133.8, 129.9, 129.8, 128.7,
128.6, 125.4, 123.3, 71.5, 61.3, 14.0. IR (CHCl3): m 1727,
1620, 1106, 794 cmÀ1; LC MS (m/z): 352 (M+H)+; HRMS
(EI): m/z Calcd for C20H18NO5 352.1185 [M+H]+. Found
352.1181.
aq. NaHCO3
Ph-CHO
DCM, rt
Piv-Cl, DCM, rt
CO2Et
O N
CO2Et
O NHPiv
1f
Ph
1e
Scheme 2.
corresponding product, 2c in 71% yield with exclusive
(E)-selectivity (entry 2).7 To prove the generality of the
method, we reacted other Baylis–Hillman acetate
adducts with N-hydroxyphthalimide 1b and succinimide
2b (entries 3–11). The results are summarized in Table 1.
In all cases, the reaction proceeded smoothly and affor-
ded the products in reasonably good yields with good
selectivity. As shown in Table 1, Baylis–Hillman acetate
adducts derived from ethyl acrylate gave the correspond-
ing products having the aryl group trans to the ester,
whereas the adducts derived from acrylonitrile gave
products having the aryl group cis to the nitrile. The
1
olefin geometry was established based on H and 13C
NMR chemical shifts and by comparison with literature
values.8 However, reaction with N-Boc-hydroxylamine
and N-benzyl hydroxylamine gave low yields of the
desired products with (E)-selectivity (entries 12 and 13).
We also investigated the transformations of 1c into use-
ful substituted allyloxy amine/aminoxy ester 1d and its
derivatives 1e and 1f (Scheme 2). Further applications
of these products to prepare pseudo-c-amino acids are
underway.
17
CH3
H
H
16
O
In conclusion, we have developed a palladium-catalyzed
addition of hydroxylamine derivatives to Baylis–Hill-
man acetate adducts.9 The selective formation of substi-
tuted allyloxy amine products was observed and these
products may find use in organic synthesis.
H
H
H
2
O
H
3
1
8
O
11
10
15
H
9
H
12
O
N
7
H
H
4
H
H
13
14
6
5
H
O
H
1c
(b) The structure was supported by NOE cross peaks
Acknowledgements
between H1–H3 and H1–H9. Spectral data for 2c: Off white
1
solid; mp 158–161 °C H NMR (500 MHz, CDCl3): d 7.85
N.K., G.S.K.B. and G.D.S. thank CSIR and UGC,
New Delhi, for financial assistance.
(2H, dd, J = 3.0, 5.38 Hz, H11, 14), 7.82–7.80 (2H, m, H3,
7), 7.76 (2H, dd, J = 3.0, 5.38 Hz, H12, 13), 7.44 (3H, dd,
J = 2.1, 5.1 Hz H4, 5, 6), 7.37 (1H, s, H1), 4.93 (2H, s, H9);
13C NMR (75 MHz, CDCl3): d 163.3, 149.7, 134.7, 132.4,
131.4, 129.4, 128.9, 128.7, 123.7, 117.2, 104.7, 78.5. IR
(CHCl3): m 2230, 1725, 1502, 1219, 771 cmÀ1; LC MS (m/z):
327 (M+Na)+; HRMS (EI): m/z Calcd for C18H12N2O3Na
327.0746 [M+Na]+. Found 327.0749.
References and notes
1. (a) Trost, B. M.; Crawly, M. L. Chem. Rev. 2003, 103, 2921;
(b) Johannsen, M.; Jorgenson, K. A. Chem. Rev. 1998, 98,

218
Ch. Raji Reddy et al. / Tetrahedron Letters 48 (2007) 215–218
reaction (monitored by TLC), the solvent was evaporated
H
O
11
in vacuo and the crude was purified by column chroma-
tography to afford the corresponding product. Spectro-
scopic data for selected products: Product 3c: Pale yellow
solid; mp 110–114 °C; H NMR (300 MHz, CDCl3): d 8.00
10
H
12
H H
H
3
9
H
O N
15
1
H
H
2
8
1
H
13
14
4
CN
O
H
7
(1H, s), 7.20–7.85 (6H, m), 7.55 (1H, d, J = 8.6 Hz), 7.4
(1H, t, J = 7.8 Hz), 5.05 (2H, s), 4.3 (2H, q, J = 7.2 Hz),
1.35 (3H, t, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3): d
166.3, 163.1, 146.1, 135.9, 134.3, 132.6, 132.4, 130.2, 128.7,
128.4, 126.9, 123.3, 122.6, 71.1, 61.46, 14.0; IR (CHCl3): m
1733, 1637, 770, 665 cmÀ1; LC MS (m/z): 430 (M+H)+, 432
[(M + 2)+H]+; HRMS (EI): m/z Calcd for C20H17BrNO5
430.0290 [M+H]+. Found 430.0286. Product 4c: Pale
yellow solid; mp 143–146 °C; 1H NMR (500 MHz, CDCl3):
d 7.75–7.87 (6H, m), 7.55 (1H, d, J = 8.6 Hz), 7.32–7.36
(2H, m), 4.9 (2H, s); 13C NMR (100 MHz, CDCl3): d 163.3,
147.5, 134.8, 134.2, 130.5, 128.6, 127.4, 123.8, 122.9, 116.6,
106.5, 78.1; IR (CHCl3): m 2213, 1618, 698, 622 cmÀ1; LC
MS (m/z): 405 (M+Na)+, 407[(M + 2)+Na]+; HRMS (EI):
m/z Calcd for C18H11BrN2O3Na 404.9851 [M+Na]+.
Found 404.9848.
H
5
6
H
2c
8. (a) Basavaiah, D.; Muthukumaran, K.; Sreenivasulu, B.
Synthesis 2000, 545; (b) Basavaiah, D.; Krishnamacha-
ryulu, M.; Hyma, R. S.; Sarma, P. K. S.; Kumaraguru-
baran, M. J. Org. Chem. 1999, 64, 1197.
9. General experimental procedure: To a stirred solution of
Baylis–Hillman acetate adduct (1 mmol) in acetonitrile
(3 mL) was added N-hydroxyphthalimide (148 mg,
0.9 mmol) and the reaction mixture was cooled to 20 °C.
Palladium tetrakis(triphenyl-phosphine) (0.1 mmol) was
added to the above reaction mixture which was stirred for
the given time (see Table 1). After completion of the