Chiral Lewis acid catalyzed enantioselective conjugate radical additions to α,β-unsaturated 2-pyridyl ketones

Article abstract of DOI:10.1055/s-2007-992386

We have investigated the utility of a pyridine-based achiral template in enantioselective conjugate radical additions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-992386

LETTER
83
Chiral Lewis Acid Catalyzed Enantioselective Conjugate Radical Additions to
a,b-Unsaturated 2-Pyridyl Ketones
C
onjugate Radical Add
u
itions to
a
,
b
k
-Unsaturated
u
2-Pyridyl
K
n
etones d P. Sibi,* Yong-Hua Yang
Department of Chemistry, North Dakota State University, Fargo, ND 58105, USA
E-mail: Mukund.Sibi@ndsu.edu
Received 7 August 2007
To our colleague Prof. Melvin Morris for his outstanding achievements as an educator
appended to a,b-unsaturated carboxylic acids are excel-
Abstract: We have investigated the utility of a pyridine-based
achiral template in enantioselective conjugate radical additions.
lent substrates in enantioselective radical reactions.8,9 Re-
cently, we have also shown that substrates possessing
template E are good for conjugate radical additions.10 In
an effort to investigate alternate templates and also poten-
tially improve the selectivity in the radical reactions, we
sought to explore pyridyl ketones as substrates. This class
of compounds has received some attention in enantiose-
lective transformations.11 In this work we report conjugate
radical additions to substrates appended to template G and
address aspects of their utility.
Key words: conjugate radical reactions, chiral Lewis acids, pyridyl
ketones, catalysis, achiral templates
Achiral templates play an important role in a variety of
enantioselective transformations.1 They have features
which include ready availability, ease of introduction of
the desired substrate, ease of removal of the auxiliary
from the product, donor atom(s) for potential coordination
to Lewis acids, and rotamer control elements.2 The tradi-
tional templates are well suited for incorporating sub-
strates at the carboxylic acid oxidation state (templates A–
D, Figure 1).3 A large fraction of these compounds show
modest to good reactivity in enantioselective transforma-
tions such as cycloadditions and conjugate additions.
Lewis acid activation can alleviate the reactivity problem
to some extent.4 One solution to this dilemma is to use
more reactive substrates at the keto oxidation state. This
would require a substrate appended to an achiral auxiliary
that incorporates the features discussed above with the ad-
ditional ability for easy conversion to products at the car-
boxylic acid oxidation state. Templates that meet these
requirements are shown in Figure 1 (structures E–G).5–7
Lewis Acid/ligand
(100 mol%)
O
O
N
N
i-PrI, Bu3SnH, Et3B, O2
CH2Cl2, –78 °C
3a
O
O
O
O
Ph
Ph
N
N
N
N
Ph
Ph
R
R
L6
L1 R = t-Bu
L2 R = Me
L3 R = i-Pr
L4 R = Ph
L5 R = Bn
O
O
O
O
N
N
O
N
O
O
O
O
O
O
N
N
N
N
O
N
L7
L8
N
R
N
H
Ph
Ph
N
R
Scheme 1
A
B
C
D
O
O
Our work began with an effort to identify reaction condi-
tions using a standard set of chiral Lewis acids to achieve
good chemical efficiency and enantioselectivity in conju-
gate radical addition to azachalcones (Scheme 1). Results
from these studies are tabulated in Table 1. For initial ex-
ploration we chose the azachalcone 1a as the starting ma-
terial, isopropyl iodide as the radical precursor, tin
hydride as the H-atom source as well as the chain carrier
and triethylborane/oxygen as the initiator.12 One equiva-
lent of the chiral Lewis acid was employed in the radical
reactions. Reaction with copper triflate as the Lewis acid
and the bisoxazoline L1 as a ligand gave only 15% of the
desired product (entry 1). The product was nearly racem-
ic. Magnesium perchlorate in combination with L1 also
N
N
HO
O
N
E
G
F
Figure 1
Our group has reported on the development of novel
achiral templates that have broad utility in enantioselec-
tive transformations. We have shown that templates A–D
SYNLETT 2008, No. 1, pp 0083–0088
Advanced online publication: 03.12.2007
DOI: 10.1055/s-2007-992386; Art ID: S05607ST
x
x.
x
x.
2
0
0
7
© Georg Thieme Verlag Stuttgart · New York

84
M. P. Sibi, Y.-H. Yang
LETTER
lectivity in this series (entry 6). Changing the counter ion
of the Lewis acid to a triflimide was not rewarding giving
the product in low yield and selectivity (entry 10). Other
Lewis acid and ligand combinations were either ineffec-
tive or gave the product in low yield and/or selectivity (en-
tries 11–13).
Table 1 Optimization of Reaction Conditions for Conjugate Radi-
cal Addition to a,b-Unsaturated 2-Pyridyl Ketone 1aa
Entry Lewis acid
Ligand Reaction time Yield
ee
(%)
(min)
120
180
60
(%)b
1
2
Cu(OTf)2
Mg(ClO4)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(NTf2)2
Mg(NTf2)2
Mg(NTf2)2
Sc(OTf)3
L1
L1
L1
L2
L3
L4
L5
L6
L7
L4
L4
L7
L8
15
2 (–)
After identifying a Lewis acid–ligand combination that
gave high yield and good selectivity, we examined the ef-
fect of catalyst loading, tin hydride–triethyl borane con-
centration, and temperature on the reaction (Scheme 2).
Results from these experiments are tabulated in Table 2.
36
4 (–)
19 (S)
17 (S)
9 (S)
64 (S)
45 (S)
57 (R)
0
3
73
4
60
40
5
60
42
Reactions with 10 mol% chiral Lewis acid gave lower
yield for the product (entry 1). Of the different variations
tried (entries 2–6), reaction with 30 mol% of the chiral
Lewis acid and excess radical precursor (10 equiv), tin hy-
dride (5 equiv), and triethylborane (5 equiv) gave the best
result (entry 6). Use of stoichiometric amount of the chiral
Lewis acid did not lead to improvement in selectivity (en-
try 7). Reaction temperature had a significant impact on
efficiency and selectivity (entries 8–12). Of these experi-
ments, reaction at room temperature was the least efficient
with respect to yield and selectivity (entry 8). Lowering
the temperature to 0 °C and –30 °C led to improvements
in yield and selectivity (entries 9 and 10) and the optimal
conditions were at –78 °C (entry 11). A further lowering
of reaction temperature to –90 °C did not lead to improve-
ment in selectivity and gave a lower yield for the product
(entry 12).
6
60
98
7
60
95
8
60
88
9
60
51
10
11
12
13
60
85
51 (S)
50 (S)
35 (S)
–
180
60
85
63
120
trace
a Typical reaction conditions: substrate (1 equiv), chiral Lewis acid (1
equiv), alkyl iodide (10 equiv), Bu3SnH (5 equiv), Et3B (5 equiv), and
O2 (10 mL) were used.
b 0.1 mmol scale reactions, isolated yield.
Next we examined the scope of the azachalcone substrates
in conjugate addition using zinc triflate–L4 as the chiral
Lewis acid (Scheme 3). Results from these experiments
are tabulated in Table 3. As illustrated earlier, isopropyl
radical addition to the parent azachalcone was highly effi-
cient but proceeded with only modest selectivity (entry 1).
gave low yield and selectivity (entry 2). Zinc triflate and
L1 proved to be a better combination and gave the product
in good yield (73%) and low selectivity (entry 3). Other
box ligands with zinc triflate were also investigated (en-
tries 4–9). Of these, the phenylglycine-derived box ligand
L4 gave 98% yield of the product with the best enantiose-
Table 2 Impact of Catalyst Loading and Temperature on Reaction Efficiencya
Entry
1
LA (equiv)
0.1
Temp (°C)
–78
–78
–78
–78
–78
–78
–78
25
i-PrI (equiv)
10.0
Bu3SnH (equiv) Et3B (equiv)
Yield (%)
ee (%)
58
5.0
5.0
2.5
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
3.0
2.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
79
66
76
75
67
97
98
66
68
74
97
80
2
0.3
5.0
65
3
0.3
10.0
64
4
0.3
10.0
68
5
0.3
10.0
70
6
0.3
10.0
64
7
1.0
10.0
64
8
0.3
10.0
36
9
0.3
0
10.0
54
10
11
12
0.3
–30
–78
–90
10.0
66
0.3
10.0
64
0.3
10.0
56
a 0.2 mmol scale reactions, isolated yield, 10 mL of O2 were used in all the reactions.
Synlett 2008, No. 1, 83–88 © Thieme Stuttgart · New York

LETTER
Conjugate Radical Additions to a,b-Unsaturated 2-Pyridyl Ketones
85
O
O
Zn(OTf)2/L4
N
N
i-PrI, Bu3SnH, Et3B, O2
CH2Cl2, –78 °C
3a
1a
Scheme 2
O
O
R2
Zn(OTf)2/L4 (30 mol%)
R2I, Bu3SnH, Et3B, O2
N
N
R1
R1
CH2Cl2, –78 °C
1
3
Scheme 3
Reactions with electron-rich aromatics were facile giving
the products in high yield and modest selectivity (entries
2 and 3). In contrast, conjugate addition to an azachalcone
with an electron-poor aromatic b-substituent gave low
yield of the product with modest selectivity (entry 4). A
minor amount of the ethyl radical addition product was
also obtained. Similarly, reactions with aromatics con-
taining ortho substituents were also less efficient giving
both isopropyl and ethyl radical addition products (entries
5 and 6). Addition of various nucleophilic radicals to the
p-methoxyphenyl-substituted substrate 1c was investigat-
ed. Reactions with primary alkyl radicals were only mod-
estly efficient and the level of enantioselectivity was
similar to that obtained with the secondary isopropyl rad-
ical (compare entries 7 and 8 with 3). Addition of the more
reactive tert-butyl radical was highly efficient and gave
the product in high yield but with lower selectivity than
that observed with a secondary radical (compare entry 9
with 3). Cyclic secondary radicals gave addition products
in modest to good yield and selectivity (entries 10 and 11).
Conjugate radical additions to b-alkyl substituted sub-
strates gave high chemical yields for the products but the
selectivities were low (entries 12–14). These results dem-
onstrate that both aryl- and alkyl-substituted substrates are
competent in the conjugate additions but the enantioselec-
tivities are only modest.
Table 3 Enantioselective Conjugate Additions to 2-Pyridyl Ketones
with Various Radicalsa
Entry R1
R2
Reaction time Yield
(min)
ee
(%)
(%)b
1
1a, Ph
i-Pr
40
3a, 97
3b, 99
3c, 97
3d, 60
3e, 72
3f, 75
3h, 50
3i, 53
3j, 88
3k, 59
3l, 79
3m, 91
3n, 92
3g, 92
64
66
66
53
62
46
69
61
43
54
59
33
17
42
2
1b, p-ClC6H4
1c, p-OMeC6H4
1d, 4-CO2MePh
1e, o-MeC6H4
1f, o-ClC6H4
1c, p-OMeC6H4
1c, p-OMeC6H4
1c, p-OMeC6H4
1c, p-OMeC6H4
1c, p-OMeC6H4
1g, Me
i-Pr
40
3
i-Pr
40
4d
5c,e
6c,f
7c
8c,e
9
i-Pr
40
i-Pr
180
180
300
300
40
i-Pr
Et
i-Pr
t-Bu
c-Hex
c-Pent
c-Hex
c-Pent
i-Pr
10c
300
120
60
11
12
13
14
1g, Me
60
1h, 3-PhPr
40
a Typical reaction conditions: substrate (1 equiv), chiral Lewis acid
(0.3 equiv), alkyl iodide (10 equiv), Bu3SnH (5 equiv), Et3B (5 equiv),
and O2 (10 mL) were used.
In an effort to understand the origins of the selectivity
with the azachalcones, we carried out control experiments
(Scheme 4). To assess if the nitrogen atom of the azachal-
cone was necessary for reactivity and selectivity, conju-
gate radical additions to chalcone were carried out under
the optimal conditions. This reaction was very inefficient
b 0.2 mmol scale reactions, isolated yield.
c After 2 h, additional Bu3SnH (2.5 equiv), Et3B (2.5 equiv) and O2 (10
mL) were added.
d i-Pr/Et radical adduct = 90:10 (from NMR).
and gave only a trace of the desired product. This suggests e i-Pr/Et radical adduct = 88:12 (from NMR).
f i-Pr/Et radical adduct = 80:20 (from NMR).
that the nitrogen atom of the pyridine is essential for reac-
tivity allowing the Lewis acid to chelate the carbonyl ox-
To arrive at a working model for reactions with azachal-
ygen and the pyridine nitrogen. Previous authors have
suggested that reaction with azachalcones may proceed
through an s-trans rotamer of the substrate.13 To get a bet-
ter handle on this issue, we carried out reaction with
3-methyl-substituted azachalcone 1i, which when chelat-
ed to a Lewis acid is unable to attain an s-trans-rotamer
conformation. Reaction with 2a under the optimal condi-
tions gave the product in 73% yield and modest selectivi-
ty.
cone, the absolute stereochemistry for the conjugate addi-
tion product was determined by converting compounds 3a
and 3o to a known compound (Scheme 5). Interestingly,
both the products showed the same sense of stereoinduc-
tion (S product).14
A number of potential complexes could account for the
product stereochemistry. We present two options. Reac-
Synlett 2008, No. 1, 83–88 © Thieme Stuttgart · New York

86
M. P. Sibi, Y.-H. Yang
LETTER
O
O
Zn(OTf)2/L4 (30 mol%)
i-PrI, Bu3SnH, Et3B, O2
CH2Cl2, –78 °C, 3 h
4
5
<5% yield
O
O
Zn(OTf)2/L4 (30 mol%)
i-PrI, Bu3SnH, Et3B, O2
N
N
CH2Cl2, –78 °C, 1 h
Me
Me
3o
1i
73% yield
37% ee
Scheme 4
O
O
N
1. MeOTf, MeCN, r.t.
2. aq NaOH, 90 °C
HO
S
3a
6a 95%
[α]D25 –21.4
64% ee
O
O
N
1. MeOTf, MeCN, r.t.
2. aq NaOH, 90 °C
HO
S
3o
6a 88%
[α]D25 –10.0
37% ee
Scheme 5
tions could occur via an s-trans rotamer of the substrate products to the carboxylic acid oxidation state demon-
with a tetrahedral or a cis-octahedral zinc geometry strates the utility of these templates. Development of new
(Figure 2, H). This is consistent with what is proposed in enantioselective transformations using the azachalcones
the literature for reactions with azachalcones proceeding is under way.
via an s-trans-rotamer geometry. Alternatively, the prod-
uct stereochemistry is also consistent with reactions pro-
ceeding via an s-cis rotamer with the zinc complex in a
Acknowledgment
We thank the NIH (GM-54656) for financial support.
cis-octahedral geometry (Figure 2, I). The observed low
selectivity with azachalcones in our experiments suggests
poor rotamer control.
References and Notes
(1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley-Interscience: New York, 1994. (b) Gawley, R.;
Aube, J. Asymmetric Synthesis; Pergamon: New York, 1996.
(2) (a) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem.
Soc. 1988, 110, 1238. (b) Castellino, S.; Dwight, W. J.
J. Am. Chem. Soc. 1993, 115, 2986. (c) Montaudo, G.;
Librando, V.; Caccamese, S.; Maravigna, P. J. Am. Chem.
Soc. 1973, 95, 6365. (d) Corminboeuf, O.; Renaud, P. Org.
Lett. 2002, 4, 1731. (e) Gnas, Y.; Glorius, F. Synthesis 2006,
1899.
(3) Oxazolidinones: (a) Evans, D. A.; Miller, S. J.; Lectka, T. J.
Am. Chem. Soc. 1993, 115, 6460. (b) Evans, D. A.; Miller,
S. J.; Lectka, T.; von Matt, P. J. Am. Chem. Soc. 1999, 121,
7559. Acyl pyrazoles: (c) Sibi, M. P.; Shay, J. J.; Liu, M.;
Jasperse, C. P. J. Am. Chem. Soc. 1998, 120, 6615. (d) Itoh,
K.; Kanemasa, S. J. Am. Chem. Soc. 2002, 124, 13394.
Imides: (e) Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc.
re-face addition
re-face addition
Ph
X
N
X
X
O
Zn
X
Zn
O
O
N
N
O
N
N
Ph
N
O
O
H
I
Figure 2
In conclusion we have shown that azachalcones have po-
tential as substrates with enone-like reactivity in enantio-
selective transformations. The ready conversion of
Synlett 2008, No. 1, 83–88 © Thieme Stuttgart · New York

LETTER
Conjugate Radical Additions to a,b-Unsaturated 2-Pyridyl Ketones
87
1999, 121, 8959. (f) Sammis, G. M.; Jacobsen, E. N. J. Am.
Chem. Soc. 2003, 125, 4442. Pyrazolidinones: (g) Sibi, M.
Compound 3a
Colorless liquid. The enantiomeric purity was determined by
HPLC analysis (254 nm, 25 °C): tR(minor) = 13.8 min;
tR(major) 15.0 min [Chiracel AD-H (0.46 cm × 25 cm; from
Daicel Chemical Ind., Ltd.) hexane–i-PrOH (99:1), 0.5 mL/
min] as 64% ee. [a]D25 14.2 (c 1.39, CH2Cl2). 1H NMR (500
MHz, CDCl3): d = 0.84 (d, J = 6.5 Hz, 3 H), 1.02 (d, J = 6.5
Hz, 3 H), 1.95–1.99 (m, 1 H), 3.21–3.25 (m, 1 H), 3.61 (dd,
J = 17.5, 5.0 Hz, 1 H), 3.77 (dd, J = 17.5, 9.5 Hz, 1 H), 7.12–
7.22 (m, 3 H), 7.22–7.40 (m, 2 H), 7.41–7.43 (m, 1 H), 7.73–
P.; Stanley, L. M.; Nie, X.; Venkatraman, L.; Liu, M.;
Jasperse, C. P. J. Am. Chem. Soc. 2007, 129, 395.
(4) For a study on achiral templates in Diels–Alder reactions,
see: Sibi, M. P.; Chen, J.; Stanley, L. Synlett 2007, 298.
(5) Acyl imidazoles: (a) Evans, D. A.; Fandrick, K. R.; Song,
H.-J. J. Am. Chem. Soc. 2005, 127, 8942. (b) Evans, D. A.;
Fandrick, K. R. Org. Lett. 2006, 8, 2249. (c) Evans, D. A.;
Song, H.-J.; Fandrick, K. R. Org. Lett. 2006, 8, 3351.
(6) a-Hydroxy ketones: (a) Palomo, C.; Oiarbide, M.; Kardak,
B. G.; Garcia, J. M.; Linden, A. J. Am. Chem. Soc. 2005,
127, 4154. (b) Palomo, C.; Oiarbide, M.; Garcia, J. M.;
Gonzalez, A.; Arceo, E. J. Am. Chem. Soc. 2003, 125,
13942.
(7) Aza chalcones: (a) Matsumoto, K.; Jitsukawa, K.; Masuda,
H. Tetrahedron Lett. 2005, 46, 5687. (b) Otto, S.;
Boccaletti, G.; Engberts, J. B. F. N. J. Am. Chem. Soc. 1998,
120, 4238. (c) Wittkopp, A.; Schreiner, P. R. Chem. Eur. J.
2003, 9, 407. (d) Rispens, T.; Engberts, J. B. F. N. J. Org.
Chem. 2002, 67, 7369. (e) Otto, S.; Engberts, J. B. F. N.;
Kwak, J. C. T. J. Am. Chem. Soc. 1998, 120, 9517.
(8) For selected reviews on enantioselective radical reactions,
see: (a) Sibi, M. P.; Manyem, S.; Zimmerman, J. Chem. Rev.
2003, 103, 3263. (b) Zimmerman, J.; Sibi, M. P. Top. Curr.
Chem. 2006, 263, 107. (c) Sibi, M. P.; Porter, N. A. Acc.
Chem. Res. 1999, 32, 163.
7.76 (m, 1 H), 7.89–7.91 (m, 1 H), 8.68–8.69 (m, 1 H). 13
C
NMR (125 MHz, CDCl3): d = 20.5, 20.8, 33.5, 41.1, 47.6,
121.8, 125.9, 126.9, 127.9, 128.5, 136.7, 143.9, 148.8,
153.6, 201.0. IR (neat): 995, 1641, 1697, 2960, 3426 cm–1.
ESI-HRMS: m/z calcd for C17H19NONa+: 276.1364; found:
276.1349.
Compound 3b
Colorless liquid. The enantiomeric purity was determined by
HPLC analysis (254 nm, 25 °C): tR(minor) = 14.9 min;
tR(major) = 17.9 min [Chiracel AD-H (0.46 cm × 25 cm;
from Daicel Chemical Ind., Ltd.) hexane–i-PrOH (99:1) 0.5
mL/min] as 66% ee. [a]D25 13.8 (c 1.11, CH2Cl2). 1H NMR
(500 MHz, CDCl3): d = 0.79 (d, J = 6.5 Hz, 3 H), 0.98 (d,
J = 6.5 Hz, 3 H), 1.88–1.93 (m, 1 H), 3.14–3.18 (m, 1 H),
3.52 (dd, J = 17.5, 5.0 Hz, 1 H), 3.73 (dd, J = 17.5, 5.0 Hz, 1
H), 7.14 (d, 3 H), 7.19 (d, 3 H), 7.42–7.45 (m, 1 H), 7.75–
7.88 (m, 1 H), 7.89–7.90 (m, 1 H), 8.66–8.67 (m, 1 H). 13
C
(9) Enantioselective conjugate radical additions using different
achiral templates. For oxazolidinones, see: (a) Sibi, M. P.;
Ji, J.; Wu, J. H.; Gurtler, S.; Porter, N. A. J. Am. Chem. Soc.
1996, 118, 9200. Imides: (b) Sibi, M. P.; Petrovic, G.;
Zimmerman, J. J. Am. Chem. Soc. 2005, 127, 2390.
Pyrazoles: (c) Sibi, M. P.; Shay, J. J.; Ji, J. Tetrahedron Lett.
1997, 38, 5955. Pyrazolidinones: (d) Sibi, M. P.;
NMR (125 MHz, CDCl3): d = 20.3, 20.7, 33.4, 41.0, 47.1,
121.8, 127.0, 128.0, 129.8, 131.6, 136.8, 142.3, 148.8,
153.4, 200.8. IR (neat): 996, 1490, 1584, 1642, 1697, 2959,
3431 cm–1. ESI-HRMS: m/z calcd for C17H18ClNONa+:
310.0975; found: 310.0962.
Compound 3g
Colorless liquid. The enantiomeric purity was determined by
HPLC analysis (254 nm, 25 °C): tR(major) = 16.4 min;
tR(minor) = 18.9 min [Chiracel OJ-H (0.46 cm × 25 cm;
from Daicel Chemical Ind., Ltd.) hexane–i-PrOH (99:1), 0.5
mL/min] as 43% ee. [a]D25 1.0 (c 0.87, CH2Cl2). 1H NMR
(400 MHz, CDCl3): d = 0.85 (d, J = 6.0 Hz, 3 H), 0.87 (d,
J = 6.0 Hz, 3 H), 1.24–1.30 (m, 1 H), 1.32–1.44 (m, 1 H),
1.60 (dt, J = 8.0, 7.6 Hz, 2 H), 1.74–1.78 (m, 1 H), 2.08–2.13
(m, 1 H), 2.56 (t, J = 7.6 Hz, 2 H), 3.08 (dd, J = 16.8, 6.1 Hz,
1 H), 3.15 (dd, J = 16.8, 6.1 Hz, 1 H), 7.11–7.14 (m, 3 H),
7.20–7.24 (m, 2 H), 7.42–7.45 (m, 1 H), 7.78–7.83 (m, 1 H),
8.00 (d, J = 7.6 Hz, 1 H), 8.65–8.67 (m, 1 H). 13C NMR (100
MHz, CDCl3): d = 18.7, 19.6, 29.3, 30.0, 31.2, 36.1, 38.9,
39.3, 121.8, 125.5, 126.9, 128.2, 128.3, 136.8, 142.7, 148.8,
153.8, 202.4. IR (neat): 995, 1583, 1642, 1692, 2957, 3431
cm–1. ESI-HRMS: m/z calcd for C20H25NONa+: 318.1834;
found: 318.1814.
Prabagaran, N. Synlett 2004, 2421. Naphthosultams:
(e) Sibi, M. P.; Sausker, J. B. J. Am. Chem. Soc. 2002, 124,
984. Pyrones: (f) Sibi, M. P.; Zimmerman, J. J. Am. Chem.
Soc. 2006, 128, 13346.
(10) Lee, S.; Lim, C. J.; Kim, S.; Subramaniam, R.; Zimmerman,
J.; Sibi, M. P. Org. Lett. 2006, 8, 4311.
(11) (a) de Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2374. (b) G u, C.-L.; Liu, L.;
Sui, Y.; Zhao, J.-L.; Wang, D.; Chen, Y.-J. Tetrahedron:
Asymmetry 2007, 18, 455. (c) Zhang, Z.; Dong, Y.-w.;
Wang, G.-w.; Komatsu, K. Synlett 2004, 61.
(12) All new compounds showed analytical and spectral
characteristics consistent with their structure. An experi-
mental procedure and spectral data for select products are
provided.
General Procedure for Conjugate Radical Addition
A solution of the appropriate Lewis acid (0.06 mmol) and
bisoxazoline ligand (0.06 mmol) in CH2Cl2 (3 mL) was to
stirred at r.t. for 30 min under N2. Then, the substrate (0.20
mmol) in CH2Cl2 (1 mL) was added. After stirring for
another 30 min, the solution was cooled to –78 °C in a dry
ice–acetone bath. To the solution was added the radical
precursor RX (2.0 mmol), Bu3SnH (1.0 mmol), and Et3B
(1.0 M in hexane, 1.0 mL, 1.0 mmol) at –78 °C. A 10 mL
aliquot of O2 was then added via syringe. The reaction
mixture was stirred at –78 °C for the time shown in Table 3.
After completion (TLC), ethylenediamine tetraacetic acid
disodium salt solution (1.0 M in H2O, 10 mL) was added to
the reaction mixture. It was then extracted with CH2Cl2 (2 ×
30 mL) and dried with Na2SO4. The crude product was
purified by flash column chromatography to yield the
alkylated products.
Compound 3h
Colorless liquid. The enantiomeric purity was determined by
HPLC analysis (254 nm, 25 °C): tR(minor) = 21.2 min;
tR(major) = 23.9 min [Chiracel AD-H (0.46 cm × 25 cm;
from Daicel Chemical Ind., Ltd.) hexane–i-PrOH (99:1), 0.5
mL/min] as 69% ee. [a]D25 2.9 (c 1.00, CH2Cl2). 1H NMR
(500 MHz, CDCl3): d = 0.81 (t, J = 7.5 Hz, 3 H), 1.62–1.65
(m, 1 H), 1.72–1.76 (m, 1 H), 3.19–3.22 (m, 1 H), 3.49 (dd,
J = 17.5, 4.5 Hz, 1 H), 3.57 (dd, J = 17.5, 4.2 Hz, 1 H), 3.76
(s, 3 H), 6.80 (dd, J = 7.0, 2.5 Hz, 2 H), 7.16 (dd, J = 7.0, 2.5
Hz, 2 H), 7.41–7.44 (m, 1 H), 7.58–7.79 (m, 1 H), 7.93–7.95
(m, 1 H), 8.65–8.67 (m, 1 H). 13C NMR (125 MHz, CDCl3):
d = 12.0, 29.7, 41.9, 44.4, 55.1, 113.6, 121.8, 126.9, 128.6,
136.8, 136.9, 148.8, 153.6, 157.8, 200.9. IR (neat): 995,
1035, 1247, 1512, 1584, 1612, 1640, 1691, 2961, 3436
cm–1. ESI-HRMS: m/z calcd for C17H19NO2Na+: 292.1313;
found: 292.1325.
Synlett 2008, No. 1, 83–88 © Thieme Stuttgart · New York

88
M. P. Sibi, Y.-H. Yang
Compound 3i
LETTER
The reaction temperature was increased to 90 °C and
Colorless liquid. The enantiomeric purity was determined by
HPLC analysis (254 nm, 25 °C): tR(minor) = 22.9 min;
tR(major) = 24.9 min [Chiracel AD-H (0.46 cm × 25 cm;
from Daicel Chemical Ind., Ltd.) hexane–i-PrOH (99:1), 0.5
mL/min] as 61% ee. [a]D25 2.8 (c 1.20, CH2Cl2). 1H NMR
(500 MHz, CDCl3): d = 0.85 (t, J = 7.0 Hz, 3 H), 1.16–1.25
(m, 2 H), 1.56–1.74 (m, 2 H), 3.29–3.35 (m, 1 H), 3.48 (dd,
J = 17.0, 6.0 Hz, 1 H), 3.55 (dd, J = 17.0, 7.5 Hz, 1 H), 3.75
(s, 3 H), 6.79 (dt, J = 6.5, 2.5 Hz, 2 H), 7.16 (dt, J = 6.5, 2.0
Hz, 2 H), 7.41–7.44 (m, 1 H), 7.76–7.79 (m, 1 H), 7.94 (dd,
J = 8.0, 1.0 Hz, 1 H), 8.65–8.66 (m, 1 H). 13C NMR (125
MHz, CDCl3): d = 14.0, 20.6, 39.1, 39.9, 44.7, 55.1, 113.6,
121.8, 126.9, 128.5, 136.8, 137.2, 148.8, 153.6, 157.8,
200.8. IR (neat): 995, 1036, 1178, 1247, 1512, 1612, 1696,
2930, 2956, 3435 cm–1. ESI-HRMS: m/z calcd for
C18H21NO2Na+: 306.1465; found: 306.1466.
maintained at this temperature for 5 h. The reaction was
cooled to r.t. and quenched with 2 M HCl (10 mL). The
reaction was diluted with EtOAc and partitioned between
EtOAc and H2O. The combined organic phase was dried
over anhyd Na2SO4, filtered, and evaporated. The residue
was chromatographed on a silica gel column to give 6a in
95% yield (eluant: MeOH–CH2Cl2, 5:95).
Compound 6a
[a]D25 –21.4 (c 1.62, CHCl3) {Lit.15 data for R-isomer (97%
ee): [a]D25 +33.54 (c 2.75, CHCl3)}. 1H NMR (400 MHz,
CDCl3): d = 0.74 (d, J = 6.8 Hz, 3 H), 0.92 (d, J = 6.8 Hz, 3
H), 1.83–1.87 (m, 1 H), 2.60 (dd, J = 15.6, 9.6 Hz, 1 H), 2.78
(dd, J = 6.8, 15.6 Hz, 1 H), 2.83–2.87 (m, 1 H), 7.11–7.27
(m, 5 H), 10.39 (br, 1 H). 13C NMR (100 MHz, CDCl3): d =
20.1, 20.5, 33.1, 38.1, 48.4, 126.4, 128.1, 128.2, 142.5,
179.0.
Experimental Procedure for Cleavage of 2-Acylpyridine
3a
(13) (a) Reetz, M. T.; Jiao, N. Angew. Chem. Int. Ed. 2006, 45,
2416. (b) Roelfes, G.; Boersma, A. J.; Feringa, B. L. Chem.
Commun. 2006, 635. (c) For computational data on zinc
triflate mediated Diels–Alder reaction using azachalcones
with s-cis-rotamer geometry, see: Domingo, L. R.; Andres,
J.; Alves, C. N. Eur. J. Org. Chem. 2002, 2557.
To an oven-dried 6-dram vial containing a magnetic stirring
bar, 4 Å MS (100 mg) and 3a (50.6 mg, 0.2 mmol), was
added 2 mL of freshly distilled MeCN and MeOTf (0.6
mmol, 77 mL) successively under N2 atmosphere. After
stirring for 2 h at r.t., 6 M NaOH (50 mL) was added at 0 °C.
(14) Sibi, M. P.; Ji, J. J. Org. Chem. 1997, 62, 3800.
Synlett 2008, No. 1, 83–88 © Thieme Stuttgart · New York

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