Iminonitroso ene reactions: experimental studies on reactivity, regioselectivity, and enantioselectivity

Article abstract of DOI:10.1016/j.tetlet.2009.11.015

Ene reactions of iminonitroso agents with olefins were investigated in both solution and solid phase. Reactions afforded allyl hydroxylamine products in up to 99% yield and with high regioselectivity. A Cu(I)-mediated enantioselective nitroso ene reaction gave an ene product with up to 40% ee.

Full text of DOI:10.1016/j.tetlet.2009.11.015

Tetrahedron Letters 51 (2010) 328–331
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Iminonitroso ene reactions: experimental studies on reactivity, regioselectivity,
and enantioselectivity
*
Baiyuan Yang, Marvin J. Miller
Department of Chemistry and Biochemistry, 251 Nieuwland Science Hall, University of Notre Dame, Notre Dame, IN 46556, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Ene reactions of iminonitroso agents with olefins were investigated in both solution and solid phase.
Reactions afforded allyl hydroxylamine products in up to 99% yield and with high regioselectivity. A
Cu(I)-mediated enantioselective nitroso ene reaction gave an ene product with up to 40% ee.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 2 October 2009
Accepted 4 November 2009
Available online 10 November 2009
The nitroso ene reaction with alkenes constitutes a mild, valu-
able method for generation of allylamines, versatile and fundamen-
tal building blocks in organic synthesis, in an atom economical
fashion (Scheme 1).1 However, this method has received relatively
little attention compared to ene reactions with other enophiles
such as singlet oxygen (1O2),2 azo compounds,3 and carbonyl func-
tionalities4 presumably due to the labile nature of the resulting
hydroxylamine products.5 To minimize such problems, a frequently
employed strategy involves the introduction of electron-withdraw-
ing groups at the nitroso functionality to not only increase the eno-
philic reactivity, but also afford relatively stable hydroxylamine
products that are useful for further transformation. In this regard,
To begin our investigation, a panel of iminonitroso agents 1a–e
were synthesized based on a literature-reported procedure.11 The
unsymmetrical alkene, 2-methyl-2-butene 2a, was used as a model
olefin substrate to examine the reactivity of enophiles 1a–e in the
ene reaction. The results are summarized in Table 1.13 While low
yields were observed when 6-methyl-2-nitrosopyridine 1a and 2-
nitrosopyridine 1b were used (entries 1 and 2), the introduction
of a bromo substituent on the pyridine ring increased the reactivity
of nitroso species 1c–d. Thus, ene products 3c and 3d were gener-
ated in 64% and 53% yields, respectively (entries 3 and 4). Clearly,
use of electron-poorer enophiles increased the reactivity. On the
other hand, we were pleased to find that reaction of 1e, 5-
methyl-3-nitrosoisoxazole, afforded ene product 3e in 94% yield
within 10 min (entry 5). In all foregoing ene reactions, single re-
gio-isomeric ene adducts 3a–e derived from abstraction of the
allylic hydrogen on the more substituted side of olefin 2a were ob-
served and isolated.
Geraniol (4) was also used as a substrate to test the relative
reactivity of allylically functionalized olefins versus simple al-
kenes. The results are summarized in Table 2.14 In general, reac-
tions of nitroso agents 1a–e with 2.0 equiv of geraniol gave both
regioisomeric ene products, 6,7-adducts 5a–e and 2,3-adducts
6a–e, in moderate to good yields, with compounds 5a–e as the ma-
jor products (entries 1–5). The regioselective preference for ad-
ducts 5a–e is consistent with ene reactions of simple olefin 2a.
The formation of compounds 6a–e can be rationalized by steric ef-
fects in the transition state of the ene reaction (Fig. 1).15 The best
yield and highest intramolecular double bond regioselectivity were
observed when 5-methyl-3-nitrosoisoxazole 1e was employed,
electron-poor enophiles, such as pentafluoronitrosobenzene,6
a-
chloronitroso agents,7 acylnitroso agents,8 and p-nitronitosoben-
zene9 are often used.
Enantioselective nitroso ene reactions would offer an attractive
pathway to valuable, optically active amines from readily available
olefins. However, only limited examples of asymmetric nitroso ene
reactions have been reported, by either using a chiral auxiliary for
stereo control10 or using a-chloronitroso sugar derivatives as chiral
nitrosyl reagents.7 Recently, iminonitroso agents have attracted a
great deal of interest. Unlike the transient acylnitroso species, most
iminonitroso agents, in particular, pyridinylnitroso derivatives, can
be synthesized from commercially available amine precursors and
stored in pure form.11 Their successful application in Diels–Alder
reactions, including enantioselective versions,12 encouraged us to
examine their reactivity in ene chemistry, which surprisingly has
not been disclosed. Herein, we report studies of the reactivity
and regioselectivity of iminonitroso agents with various olefins in
ene reactions. We also describe preliminary results from solid
phase-supported nitroso ene reactions as well as enantioselective
nitroso ene reactions.
3
3
R
2
1
2
1
N
O
O
N
+
H
H
R
ene
enophile
* Corresponding author. Tel.: +1 574 631 7571; fax: +1 574 631 6652.
E-mail address: mmiller1@nd.edu (M.J. Miller).
Scheme 1. Nitroso ene reaction with olefins.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.015

B. Yang, M. J. Miller / Tetrahedron Letters 51 (2010) 328–331
329
Table 1
Ene Reactions of 2-methyl-2-butene 2a with iminonitroso agents
H
Ar
OH
1,2A
O
ArNO
N
Genraniol (4)
+
OH
N
OH
7
N
7
6
2
6
2
O
N
H
R
+
O
DCM, 0 o
C
R
Ar
N
N
2a
1a-e
ArNO: iminonitroso
3a-e
Product
Yieldc (%)
steric unfavored
6a-e
Entrya
1
Nitroso
Timeb
Figure 1. Steric encounters in the formation of geraniol 2,3-adducts 6a–e.
1a
20 min
3a
3b
38
48
O
N
N
ated ene adduct 3f in quantitative yield in less than 1 min (entry
1)! Two isomeric ene products 3g and 3h were isolated in an
80:20 ratio and 31% yield, when 1-methylcyclohexene 2c was used
(entry 2). Reaction with cyclohexene 2d, itself, afforded <10% yield
of product 3i based on LC/MS analysis (entry 3). Compared to al-
kenes 2a–c, 2d represented a relatively electron-poor olefin, which
corresponded to low reactivity in the ene reaction. When a-meth-
ylstyrene 2e was employed, ene product 3j was isolated in 23%
yield (entry 4). Reactions with functionalized alkene 2f gave ene
products 3k as a single regioisomer in 89% yield (entry 5).
A close look at the low yielding ene reactions revealed that, in
those cases, a competing decomposition of the initially formed
hydroxylamine product in the presence of the nitroso species oc-
curred. As a result, an azoxy compound5 was generated as the ma-
jor byproduct, which was not active in the ene reaction. In order to
potentially minimize these problems, a solid phase-supported
pyridinylnitroso ene reaction strategy was proposed and con-
ducted.17 As depicted in Scheme 2, a commercially available resin
7 was treated with piperidine to give resin-bound free amine 8,
which was further coupled with 2-fluoro-5-pyridinecarboxylic acid
to afford resin 9. A subsequent nucleophilic substitution with
hydroxylamine under basic conditions gave resin-bound pyridyl
2
3
1b
1c
15 min
10 min
O
N
Br
N
3c
3d
3e
64
53
94
O
O
N
N
N
Br
O
4
5
1d
1e
10 min
10 min
N
O
N
N
a
b
c
2.0 equiv of 2a used.
Time recorded based on the consumption of nitroso enophile.
Isolated yields reported.
affording an 80:20 ratio of ene adducts 5e and 6e in 80% total yield
(entry 5).
We next explored the ene reactions of 5-methyl-3-nitrosoisox-
azole 1e with five different alkenes of varying structures (Table
3).16 Interestingly, reaction with 2,3-dimethyl-2-butene 2b gener-
Table 2
Ene reactions of geraniol 4 with iminonitroso agents
R
+
O
7
DCM, 0 o
C
3
OH
N
N
6
2
1a-e
4
2
6
OH
OH
+
N
N
HO
6a-e
HO
R
R
N
N
5a-e
Entrya
1
Nitroso
Timeb (min)
30
Product
Yieldc (%)
46
Ratiod 5:6
1a
5a + 6a
68:32
O
N
N
2
3
1b
1c
25
20
5b + 6b
5c + 6c
71
70
72:28
70:30
O
N
Br
N
O
O
N
N
N
Br
4
1d
1e
20
10
5d + 6d
5e + 6e
60
80
66:34
80:20
N
O
5
O
N
N
a
b
c
2.0 equiv of 4 used.
Time recorded based on the consumption of nitroso enophile.
Isolated yields reported.
d
Ratio determined by 1H NMR of the crude product mixture.

330
B. Yang, M. J. Miller / Tetrahedron Letters 51 (2010) 328–331
Table 3
Iminonitroso ene reactions of 5-methyl-3-nitrosoisoxazole 1e with various olefins
Entrya
Nitroso 1e
Olefin
Timeb
Product
Yieldc (%)
99
OH
N
O
O
N
O
1
2b
1 min
3f
N
O
N
N
OH
N
OH
N
N
N
N
N
N
O
2
3
4
5
2c
2d
2e
2f
2 h
3g + 3h
31d
<10e
23
N
O
O
O
O
O
+
OH
N
O
O
O
O
O
O
12 h
3i
N
N
N
N
N
N
OH
N
20 min
5 min
3j
OH
N
O
O
3k
89
a
b
c
2.0 equiv of 2a–f used.
Time recorded based on the consumption of nitroso enophile.
Isolated yields reported.
d
e
Ratio of 3g:3h = 80:20, determined by 1H NMR of the crude mixture.
Based on LC/MS analysis.
O
HO
O
Fmoc
NH2
O
NH
O
N
F
piperidine
DMF
HN
HOBT, DMF/DCM
O
O
N
F
O
O
9
8
OH
7
N
N
N
N
O
O
NH2OH HCl
DIEA
(2b)
DCM, rt
50% TFA
H
N
H2N
Dess-Martin
DCM
HN
DMSO
92% from 10
O
O
N
NHOH
> 99%
12
11
10
Scheme 2. Resin-bound pyridinylnitroso ene reaction with 2b.
hydroxylamine 11 in excellent yield. In situ oxidation of 11 in the
presence of a representative olefin, 2b, afforded ene product 12 in
92% yield after acid cleavage from the resin. On the other hand, the
solution ene reactions of nitroso agents 1a and 1c with 2b gave the
corresponding ene products in 78% and 85% yields, respectively.
These preliminary results showed that solid phase-supported ene
reactions might afford an alternative method for efficient nitroso
ene chemistry.
Encouraged by the previous results, enantioselective ene reac-
tions between iminonitroso agents 1a–e and unsymmetrical olefin
2a were investigated using a chiral Cu(I)PF6(MeCN)4-biphosphine
catalyst.12b The reaction was conducted at À78 °C and gradually
warmed to 0 °C.18 The results are summarized in Table 4. Reaction
of 2a with 1e in the presence of Cu(I)-(S)-DifluoroPhos indeed gen-
erated ene adduct 3e in 81% yield but only with a 12% ee value.
Separate use of 6-methyl-2-nitrosopyridine 1a with (S)-BINAP
and (S)-DifluoroPhos increased the enantioselectivity, generating
ene product 3a with 25% and 40% ee, respectively, although in
relatively low chemical yields (entries 2 and 3). The major R-enan-
tiomer was proposed based on the relevant mechanistic model.12b
When nitroso enophile 1c was used, the yield increased as ex-
pected; however, a dramatically decreased ee value was observed
(entry 4). The trend of increased enantioselectivity with nitroso
enophile having a 6-substitutent close to nitrogen is consistent
with the results of asymmetric nitroso Diels–Alder reactions.12b
6-Methyl-5-bromo-2-nitrosopyridine 1d, as a combination of 1a
and 1c, was also used in ene reaction with (S)-DifluoroPhos. Unfor-
tunately, low conversion and ee values were observed.
In summary, we have demonstrated an unprecedented ene
reaction using iminonitroso agents. The allyl hydroxylamine ene
products were obtained in various yields and with high regioselec-
tivity. A solid phase-supported iminonitroso ene reaction and
asymmetric nitroso ene reactions were also attempted for the first
time. Despite the low enantioselectivity, the methodology pre-
sented here holds promise for the development of potentially valu-
able preparative methods for useful allylamine compounds.

B. Yang, M. J. Miller / Tetrahedron Letters 51 (2010) 328–331
331
Table 4
Trans. 1 1985, 1961; (c) Quadrelli, P.; Mella, M.; Caramella, P. Tetrahedron Lett.
1998, 39, 3233; (d) Adam, W.; Bottke, N.; Krebs, O.; Saha-Moller, C. R. Eur. J. Org.
Chem. 1999, 1963; (e) Fakhruddin, A.; Iwasa, S.; Nishiyama, H.; Tsutsumi, K.
Tetrahedron Lett. 2004, 45, 9323; (f) Keck, G. E.; Webb, R. R.; Yates, J. B.
Tetrahedron 1981, 37, 4007; (g) Quadrelli, P.; Mella, M.; Piccanello, A.; Romano,
S.; Caramella, P. J. Org. Chem. 2007, 72, 1807; (h) Quadrelli, P.; Romano, S.;
Piccanello, A.; Caramella, P. J. Org. Chem. 2009, 74, 2301; (i) Keck, G. E.; Webb, R.
Tetrahedron Lett. 1979, 20, 1185.
Enantioselective ene reactions of 2a with various iminonitroso agents
OH
CuPF6(MeCN)4
-(S)-ligand (10 mol%)
N
N
*
+
R
O
R
DCM
N
N
-78 oC to 0 o
C
1a, 1c-d, 1e
2a
3a, 3c-d, 3e
9. (a) Adam, W.; Bottke, N.; Engels, B.; Krebs, O. J. Am. Chem. Soc. 2001, 123, 5542;
(b) Adam, W.; Bottke, N.; Krebs, O. J. Am. Chem. Soc. 2000, 122, 6791; (c) Adam,
W.; Bottke, N.; Krebs, O. Org. Lett. 2000, 2, 3293; (d) Adam, W.; Bottke, N. J. Am.
Chem. Soc. 2000, 122, 9846; (e) Adam, W.; Krebs, O.; Orfanopoulos, M.;
Stratakis, M. J. Org. Chem. 2002, 67, 8395. and Ref. 1a.
O
F
F
O
PPh2
PPh2
PPh2
PPh2
10. Adam, W.; Degen, H. G.; Krebs, O.; Saha-Moeller, C. R. J. Am. Chem. Soc. 2002,
124, 12938.
O
F
11. Taylor, E. C.; Tseng, C. P.; Rampal, J. B. J. Org. Chem. 1982, 47, 552.
12. For a review, see: (a) Yamamoto, H.; Momiyama, N. Chem. Commun. 2005,
3514; For relevant publications, see: (b) Yamamoto, Y.; Yamamoto, H. J. Am.
Chem. Soc. 2004, 126, 4128; (c) Jana, C. K.; Studer, A. Angew. Chem., Int. Ed. 2007,
46, 6542; (d) Yamamoto, Y.; Yamamoto, H. Angew. Chem., Int. Ed. 2005, 44,
7082; (e) Yang, B. Y.; Miller, P.; Mollmann, U.; Miller, M. J. Org. Lett. 2009, 11,
2828; (f) Li, F. Z.; Yang, B. Y.; Miller, M. J.; Zajicek, J.; Noll, B. C.; Mollmann, U.;
Dahse, H.-M.; Miller, P. Org. Lett. 2007, 9, 2923; (g) Lin, W. M.; Gupta, A.; Kim, K.
H.; Mendel, D.; Miller, M. J. Org. Lett. 2009, 11, 449.
F
O
(S)-DifluoroPhos
(S)-BINAP
Nitroso
Entrya
1
Ligand
3b (%)
eec (%)
12
O
1e
(S)-DifluoroPhos
3e, 81
O
N
13. General procedure for the nitroso ene reaction: To
a
solution of olefin 2a
solution of
N
(0.89 mmol) in 1 mL of DCM at 0 °C was slowly added
a
iminonitroso 1e (50 mg, 0.44 mmol) in 0.5 mL of DCM. The resulting reaction
mixture was stirred at 0 °C until 1e was consumed (TLC analysis). The solvent
was removed under reduced pressure and the crude product was purified by
silica gel chromatography (hexanes/EtOAc = 2:1) to afford nitroso ene adduct
3e (75 mg, 94% yield) as a white solid. Mp: 80–82 °C; 1H NMR (500 MHz,
DMSO-d6) d 8.95 (s, 1H), 5.94 (m, 1H), 4.90 (br m, 1H), 4.87 (m, 1H), 4.09 (dd,
J = 13.2, 6.4 Hz, 1H), 2.28 (s, 3H), 1.75 (s, 3H), 1.19 (d, J = 6.6 Hz, 3H); 13C NMR
(125 MHz, DMSO-d6) d 169.6, 168.2, 144.5, 111.9, 94.6, 61.3, 20.7, 12.8, 11.7;
HRMS (ESI) [M+H]+ calcd for C9H15N2O2 183.1128, found 183.1131.
2
3
1a
1a
(S)-BINAP
3a,11
25
40
O
O
N
N
N
(S)-DifluoroPhos
3a, 14
N
Br
Br
4
5
1c
(S)-BINAP
3c, 36
3d, 37
4
O
O
N
N
N
N
14. Representative spectroscopic data of nitroso ene adducts: 5b (white solid): mp:
108–110 °C; 1H NMR (600 MHz, DMSO-d6) d 8.81 (s, 1H), 8.10 (ddd, J = 4.7, 1,8,
0.9 Hz, 1H), 7.57 (ddd, J = 9.1, 7.0, 1.7 Hz, 1H), 7.01 (dt, J = 8.2, 0.9 Hz, 1H), 6.66
(ddd, J = 7.0, 4.7, 0.9 Hz, 1H), 5.23 (m, 1H), 4.94 (t, J = 7.3 Hz, 1H), 4.85 (br m,
1H), 4.80 (m, 1H), 4.40 (t, J = 5.3 Hz, 1H), 3.91 (t, J = 5.9 Hz, 2H), 2.00 (m, 1H),
1.90–1.74 (m, 3H), 1.66 (s, 3H), 1.56 (s, 3H); 13C NMR (150 MHz, DMSO-d6) d
163.0, 146.9, 144.4, 137.4, 135.6, 125.1, 113.8, 112.6, 107.8, 62.6, 57.5, 36.1,
27.2, 21.4, 16.1; HRMS (ESI) [M+H]+ calcd for C15H23N2O2 263.1754, found
263.1768. Compound 5e (yellow oil): 1H NMR (600 MHz, DMSO-d6) d 9.04 (s,
1H), 5.91 (s, 1H), 5.25 (m, 1H), 4.87 (m, 1H), 4.84 (m, 1H), 4.43 (br s, 1H), 3.93–
3.90 (m, 3H), 2.27 (s, 3H), 2.02 (m, 1H), 1.92 (m, 1H), 1.84 (m, 1H), 1.73 (m, 1H),
1.71 (s, 3H), 1.58 (s, 3H); 13C NMR (150 MHz, DMSO-d6) d 169.9, 168.3, 143.4,
135.4, 125.4, 113.8, 94.6, 66.4, 57.5, 35.8, 27.1, 20.9, 16.1, 12.1; HRMS (ESI)
[M+Na]+ calcd C14H22N2Na O3 289.1523, found 289.1538.
1d
(S)-DifluoroPhos
16
a
b
c
1.2 equiv of 2a used.
Isolated yields reported.
Determined by Chiralcel OD-H analyses.
Further development of enantioselective nitroso ene reactions are
in progress.
15.
A
rationale for regioselectivity in the ene reaction between 4-
nitronitrosobenzene and trisubstituted olefins has been reported, see Ref. 1a,
and references therein.
Acknowledgments
16. An example of solid-supported nitroso hetero Diels–Alder reactions, see:
Krchnak, V.; Moellmann, U.; Dahse, H.-M.; Miller, M. J. J. Comb. Chem. 2008, 10,
104.
We gratefully acknowledge support from the NIH(GM 075855).
We thank Dr. Viktor Krchnak for helpful discussions. We also thank
the Lizzadro Magnetic Resonance Research Center at Notre Dame
for NMR facilities and Nonka Sevova for mass spectroscopic
analyses.
17. Representative spectroscopic data of nitroso ene adducts: 3f (white solid): mp:
64–66 °C; 1H NMR (500 MHz, DMSO-d6) d 9.10 (s, 1H), 5.90 (m, 1H), 4.84 (m,
1H), 4.77 (m, 1H), 2.27 (s, 3H), 1.78 (s, 3H), 1.29 (s, 6H); 13C NMR (125 MHz,
DMSO-d6) d 169.2, 167.5, 149.9, 110.4, 96.6, 65.6, 23.2, 19.4, 11.9; HRMS (ESI)
[M+H]+ calcd for C10H17N2O2 197.1285, found 197.1288. Compound 3j (white
glass): 1H NMR (600 MHz, DMSO-d6) d 9.40 (s, 1H), 7.52 (m, 2H), 7.35 (m, 2H),
7.29 (m, 1H), 5.99 (d, J = 0.9 Hz, 1H), 5.60 (d, J = 1.2 Hz, 1H), 5.35 (d, J = 1.2 Hz,
1H), 4.30 (s, 2H), 2.30 (d, J = 0.9 Hz, 3H); 13C NMR (150 MHz, DMSO-d6) d 170.7,
169.0, 142.1, 138.6, 128.2, 127.6, 125.8, 115.7, 94.9, 58.7, 12.1; HRMS (ESI)
[M+Na]+ calcd for C13H14N2NaO2 253.0947, found 253.0965.
18. General procedure for enantioselective nitroso ene reaction: To a flame-dried
round-bottomed flask were added Cu(I)PF6(CH3CN)4 (9.0 mg, 0.024 mmol) and
chiral biphosphine ligand (0.025 mmol). The mixture was dried under vacuum
for 10 min. Anhydrous DCM (1.0 mL) was added and the mixture was stirred
for 1 h. The reaction mixture was cooled to À78 °C, and then nitroso agent 1a
(30 mg, 0.24 mmol) in anhydrous DCM (0.5 mL) was added dropwise. The
References and notes
1. For selected reviews, see: (a) Adam, W.; Krebs, O. Chem. Rev. 2003, 103, 4131;
(b) Leach, A. G.; Houk, K. N. Chem. Commun. 2002, 1243; For relevant
publications of nitroso ene reactions in total synthesis of natural products,
see: (c) Keck, G. E.; Webb, R. R., II J. Am. Chem. Soc. 1981, 103, 3173; (d) Keck, G.
E., ; Webb, R. R., II J. Org. Chem. 1982, 47, 1302; (e) Zhang, F. L.; Vasella, A. Helv.
Chim. Acta 2008, 91, 2351.
2. (a) Sratakis, M.; Orfanopoulos, M.; Foote, C. S. J. Org. Chem. 1998, 63, 1315; (b)
Stephenson, L. M.; Grdina, M. J.; Orfanopoulos, M. Acc. Chem. Res. 1980, 13, 419;
(c) Orfanopoulos, M.; Stratakis, M. Tetrahedron 2000, 56, 1595; (d) Clennan, E. L.
Tetrahedron 2000, 56, 9151.
3. (a) Cheng, C. C.; Seymour, C. A.; Petty, M. A.; Greene, F. D.; Blount, J. F. J. Org.
Chem. 1984, 49, 2910; (b) Singleton, D. A.; Hang, C. J. Am. Chem. Soc. 1999, 121,
11885; (c) Stratakis, M.; Hatzimarinaki, M.; Froudakis, G. E.; Orfanopoulos, M. J.
Org. Chem. 2001, 66, 3682.
4. For selected reviews, see: (a) Clarke, M. L.; France, M. B. Tetrahedron 2008, 64,
9003; (b) Dias, L. C. Curr. Org. Chem. 2000, 4, 305.
resulting dark blue mixture was stirred for 10 min, then olefin 2a (31 lL,
0.3 mol) in anhydrous DCM (1 mL) was added via a syringe pump over 1 h. The
solution was gradually warmed to 0 °C over 3 h, and then the solvent was
removed under reduced pressure. The crude product was purified by silica gel
chromatography (hexanes/EtOAc = 5:1) to afford nitroso ene adduct 3a
(6.8 mg, 14% yield) as a white solid. Enantiomeric excess was determined by
HPLC using a Chiralcel OD-H column (95:5 hexanes/2-propanol), 1.0 mL/min,
major enantiomer tR = 5.6 min, minor enantiomer tR = 6.4 min; mp: 106–
108 oC; IR (neat, cmÀ1) 3430, 3074, 2987, 1592, 1421, 1265, 896, 738, 705;
1H NMR (600 MHz, DMSO-d6) d 8.64 (s, 1H), 7.47 (dd, J = 8.2, 7.0 Hz, 1H), 6.84
(d, J = 8.2 Hz, 1H), 6.57 (d, J = 7.0 Hz, 1H), 5.09 (dd, J = 13.2, 6.5 Hz, 1H), 4.87 (br
m, 1H), 4.84 (m, 1H), 2.32 (s, 3H), 1.72 (s, 3H), 1.15 (d, J = 6.5 Hz, 3H); 13C NMR
(150 MHz, DMSO-d6) d 162.6, 155.3, 146.0, 137.8, 113.4, 111.6, 105.5, 58.1,
24.2, 21.5, 13.5; HRMS (ESI) [M+Na]+ calcd for C11H16N2NaO 215.1155, found
215.1141.
5. (a) Johannsen, M.; Jørgensen, K. A. Chem. Rev. 1998, 98, 1689; (b) Knight, G. T.;
Pepper, B. Tetrahedron 1971, 27, 6201.
6. Seymour, C. A.; Greene, F. D. J. Org. Chem. 1982, 47, 5226.
7. Braun, H.; Felber, H.; Krebe, G.; Ritter, A.; Schmidtchen, F. P.; Schneider, A.
Tetrahedron 1991, 47, 3313.
8. (a) Corrie, J. E. T.; Kirby, G. W.; Mackinnon, J. W. M. J. Chem. Soc., Perkin. Trans. 1
1985, 883; (b) Kirby, G. W.; McGuigan, H.; McLean, D. J. J. Chem. Soc., Perkin