Chlorosilane-promoted addition reaction of isocyanides to 3,4-dihydroisoquinoline N -oxides

Article abstract of DOI:10.1021/jo301791m

The addition reaction of isocyanides to 3,4-dihydroisoquinoline N-oxides in the presence of TMSCl has been demonstrated, with the corresponding 1,2,3,4-tetrahydroisoquinoline-1-carboxylamides being obtained in moderate to high yields. A wide range of 3,4-dihydroisoquinoline N-oxides and isocyanides were applicable to this reaction.

Full text of DOI:10.1021/jo301791m

Note
pubs.acs.org/joc
Chlorosilane-Promoted Addition Reaction of Isocyanides to 3,4-
Dihydroisoquinoline N‑Oxides
Takahiro Soeta,* Shuhei Fujinami, and Yutaka Ukaji*
Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa
920-1192, Japan
S
* Supporting Information
ABSTRACT: The addition reaction of isocyanides to 3,4-
dihydroisoquinoline N-oxides in the presence of TMSCl has
been demonstrated, with the corresponding 1,2,3,4-tetrahydroi-
soquinoline-1-carboxylamides being obtained in moderate to high
yields. A wide range of 3,4-dihydroisoquinoline N-oxides and
isocyanides were applicable to this reaction.
Scheme 1. Hypothetical Modified Ugi-Type Reaction
Mechanism
soquinoline alkaloids, especially 1,2,3,4-tetrahydroisoquino-
Ilines (THIQs), have long attracted significant attention due
to their biological activity and also because they are important
building blocks in natural product synthesis and drug
discovery.1 The majority of these compounds have a
substituent at the C1 position of the isoquinoline moiety, and
therefore the development of practical methods for the
synthesis of THIQs bearing substituents at this position is
important. Various reliable methods involving asymmetric
synthesis have been reported to date.2 The compound
1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid and its deriva-
tives are of particular interest as potential building blocks of
modified peptides or other pharmacologically active com-
pounds.3 Such derivatives have been produced via Ugi-type
reactions, which have also been applied to the synthesis of
medicinally relevant heterocycles,4 although the practical
applications of this approach remain limited.5 Herein, we
report the addition of isocyanides to 3,4-dihydroisoquinoline
N-oxides via an innovation of the Ugi reaction utilizing a
chlorosilane without a carboxylic acid, to give the correspond-
ing 1,2,3,4-tetrahydroisoquinoline-1-carboxylamide derivatives
in good to high yields.
In general, Ugi reactions require a carboxylic acid that
activates an imine and traps a nitrilium ion to form an
acyloxylated intermediate. Subsequent acyl transfer leads to the
corresponding α-amino amide. A carboxylic acid is therefore
typically a necessary component of the sequence within the Ugi
synthesis involving a reaction of an isocyanide with an imine.
This requirement for a carboxylic acid, however, limits the
applications of the reaction and prevents the synthesis of a
broad range of molecules. To overcome this limitation, we have
reasoned that a compound (which we write in the generic
format as Z−X) composed of an electrophile (Z) and a
nucleophilic group (X), could essentially perform the same
function as the carboxylic acid in an Ugi-type reaction (Scheme
1). On the basis of this hypothesis, we have previously
developed an O-silylative Passerini reaction and the borinic
acid-catalyzed α-addition of isocyanide.6
We initially investigated the feasibility of using metal halides
as the Z−X species to induce the addition reaction of an
isocyanide to a nitrone.7 Among the imine analogues, nitrones
appear to be a promising candidate8 since they possess an
electronegative oxygen that can activate the CN bond and
strongly coordinate to metals.
Our initial attempts involved using 3,4-dihydroisoquinoline
N-oxide (1a) and tert-butyl isocyanide (2a) in the presence of
MgCl2, ZnCl2, and other metal halides in dichloromethane.
However, none of these reactions were successful; the reactions
either did not proceed and only starting materials were
recovered, or the reactions gave a very complex mixture of
products. In contrast, when this reaction was carried out in the
presence of chlorotrimethylsilane (TMSCl) in dichloromethane
at −20 °C, the reaction resulted in the 1,2,3,4-tetrahydroiso-
quinoline-1-carboxylamide 3aa in 53% yield, as well as the
dehydrated compound 4aa in 23% yield (Table 1, entry 1).9
With the use of toluene and THF as solvents, mixtures of 3aa
and 4aa were again obtained, but in lower yields. Reactions
carried out in DMF and acetonitrile (MeCN), however, gave
3aa as the sole product in 78% and 82% yields, respectively
Received: August 25, 2012
Published: October 16, 2012
© 2012 American Chemical Society
9878
dx.doi.org/10.1021/jo301791m | J. Org. Chem. 2012, 77, 9878−9883

The Journal of Organic Chemistry
Note
Table 1. Reaction Conditions and Results for Ugi-Type
Reactions
Table 2. Summary of Isocyanides and Nitrones Investigated
time
(h)
yield of yield of yield of 5
3aa (%) 4aa (%) or 5′ (%)
entry
ZX
solvent
1
2
3
4
5
6
7
8
9
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TESCl
CH2Cl2
toluene
THF
8
12
12
12
12
12
12
24
24
53
7
23
12
9
23
78
82
59
47
11
DMF
MeCN
MeCN
MeCN
MeCN
MeCN
29
TIPSCl
TBDMSCl
TBDPSCl
51
76
(entries 2−5). The structure of product 3aa was obtained by X-
ray crystallography.
Having established an efficient method for the addition of an
isocyanide to a nitrone, we set out to evaluate the use of
chlorosilane derivatives bearing other substituents (entries 6−
9). Using chlorotriethylsilane (TESCl), a mixture of 3aa and
4aa was obtained with yields of 59% and 29%, respectively
(entry 6), whereas chlorotriisopropylsilane (TIPSCl) exhibited
decreased reactivity and gave solely 3aa in 47% yield (entry 7).
When employing the more sterically hindered silyl compounds
tert-butylchlorodimethylsilane (TBDMSCl) and tert-butylchlor-
odiphenylsilane (TBDPSCl), the O-silylated products 5 and 5′
were obtained with yields of 51% and 76%, respectively (entries
8 and 9). These results indicate that minimal steric hindrance at
the Si atom is crucial for the reaction to proceed efficiently.
We subsequently attempted to expand the scope of
isocyanides and nitrones to which this Ugi-type reaction
utilizing TMSCl might be applied, as detailed in Table 2. In
these reactions, optimal molar quantities of nitrones 1a−h (1.0
equiv) and isocyanides 2a−h (1.5 equiv) were used in the
presence of 1.05 equiv of TMSCl. From this work we
determined that these reaction conditions were applicable to
a wide variety of nitrones and isocyanides and that most
reactions were complete within 24 h at either −20 or 0 °C. The
reaction of the aliphatic isocyanides 2a and 2b (R2 = t-Bu, c-
Hex) with 1a in the presence of TMSCl resulted in the product
in good to high yields (entries 1 and 2). In the case of the
primary alkyl isocyanide 2c, however, lower reactivity was
observed with the corresponding product 3ac produced in 73%
yield (entry 3). The chiral isocyanide 2d, which was prepared
from the corresponding amino acid,10 gave the product 3ad in
good yield; however, no chiral induction was observed (entry
4). Aromatic isocyanides were also investigated, although low
reactivities resulted from their use (entries 5−8). When
phenylisocyanide (2e) was used, only the corresponding
dehydrated compound 4ae was obtained in 32% yield (entry
5). Aromatic isocyanides bearing an electron-donating group at
the para position also exhibited low reactivities with the
corresponding products produced in 42% and 53% yields,
respectively (entries 6 and 7). In the case of an aromatic
isocyanide bearing an electron-withdrawing group at the para
position, the reaction did not proceed at all (entry 8). The
reactivity of various nitrones in conjuction with tert-
a
Reaction was carried out at 0 °C.
butylisocyanide (2a) was next examined, via the reaction of
1.0 equiv of nitrones 1a−h with 1.5 equiv of 2a in the presence
of 1.05 equiv of TMSCl. With regard to the substituents of the
nitrones, those nitrones having 5-, 7-, and 8-methyl substituents
were all reactive, furnishing the corresponding heterocycles
(entries 9, 11, and 12). The only exception was the
incorporation of the 6-methyl substituent, which resulted in a
very sluggish reaction to give the product 3ca in 26% yield
(entry 10). The nitrones 1f and 1g with dimethoxy groups
showed low reactivity with 2a and TMSCl at −20 °C, but at 0
°C both compounds reacted to give the corresponding
products 3fa and 3ga in 75% and 78% yields, respectively
(entries 13 and 14). In addition, the nitrone 1g with an
electron-withdrawing group on the aromatic ring reacted to
afford the product 3ha in 77% yield (entry 15).
The hydroxyl group of 3aa was easily removed by the
reaction with Raney nickel to give the corresponding 1,2,3,4-
tetrahydroisoquinoline-1-carboxylamide 6 in 92% yield (eq 1).
1
To elucidate the reaction mechanism, we performed H and
13C NMR analyses in MeCN-d3. Treatment of nitrone 1a with
1.0 equiv of TMSCl induced a downfield shift of the iminium
hydrogen atom from 7.65 to 8.10 ppm. The same behavior was
observed with 13C NMR, where the carbon of the imino group
(at 133.6 ppm) moved downfield (to 148.1 ppm). In contrast,
treatment of 2a with 1.0 equiv of TMSCl did not result in the
shift of any hydrogen or carbon atoms. On the basis of these
results and the data presented in Table 1 (entries 8 and 9), we
propose a mechanism for this Ugi-type reaction as shown in
9879
dx.doi.org/10.1021/jo301791m | J. Org. Chem. 2012, 77, 9878−9883

The Journal of Organic Chemistry
Note
123.6, 127.3, 128.2, 128.4, 131.5, 134.4, 135.2. IR (KBr): 3370, 2910,
1610, 1580, 1450, 1250, 1170 cm−1. HRMS−FAB (m/z): calcd for
C10H12NO [M+ + H] 162.0919; found 162.0923.
Scheme 2. We propose that this reaction likely proceeds by
initial activation of the nitrone via coordination of its oxygen
6-Methyl-3,4-dihydroisoquinoline 2-Oxide (1c). Silica gel
column chromatography (ethyl acetate/MeOH = 10/1) gave 1c
(507 mg, 63%, 5.0 mmol scale) as a white solid of mp = 109−110 °C.
1H NMR (400 MHz, CDCl3): 2.32 (s, 3H), 3.12 (t, J = 7.7 Hz, 2H),
4.06 (t, J = 7.7 Hz, 2H), 7.02 (d, J = 7.7 Hz, 1H), 7.06 (d, J = 7.7 Hz,
1H), 7.15 (t, J = 7.7 Hz, 1H), 7.97 (s, 1H). 13C NMR (100 MHz,
CDCl3): 18.4, 28.1, 57.6, 124.9, 126.7, 129.1, 129.4, 130.5, 132.2,
133.7. IR (KBr): 3380, 2970, 1600, 1560, 1470, 1260, 1190 cm−1.
HRMS−FAB (m/z): calcd for C10H12NO [M+ + H] 162.0919; found
162.0918.
Scheme 2. Plausible Reaction Mechanism
7-Methyl-3,4-dihydroisoquinoline 2-Oxide (1d). Silica gel
column chromatography (ethyl acetate/MeOH = 10/1) gave 1d
(515 mg, 64%, 5.0 mmol scale) as a white solid of mp = 90.5−91.5 °C.
1H NMR (400 MHz, CDCl3): 2.27 (s, 3H), 3.07 (t, J = 7.8 Hz, 2H),
4.02 (t, J = 7.8 Hz, 2H), 6.84 (s, 1H), 7.03 (s, 2H), 7.64 (s, 1H). 13C
NMR (100 MHz, CDCl3): 20.9, 27.3, 58.1, 126.0, 127.1, 128.2, 130.1,
134.2, 137.3. IR (KBr): 3430, 2960, 1590, 1570, 1500, 1280, 1200
cm−1. HRMS−FAB (m/z): calcd for C10H12NO [M+ + H] 162.0919;
found 169.0922.
8-Methyl-3,4-dihydroisoquinoline 2-Oxide (1e). Silica gel
column chromatography (ethyl acetate/MeOH = 10/1) gave 1e
(572 mg, 71%, 5.0 mmol scale) as a white solid of mp = 75−76 °C. 1H
NMR (400 MHz, CDCl3): 2.33 (s, 3H), 3.12 (t, J = 7.7 Hz, 2H), 4.06
(t, J = 7.7 Hz, 2H), 6.97−7.01 (m, 2H), 7.05 (d, J = 7.8 Hz, 1H), 7.71
(s, 1H). 13C NMR (100 MHz, CDCl3): 21.4, 27.7, 57.8, 125.4, 125.7,
128.1, 128.2, 130.0, 134.2, 139.9. IR (KBr): 3360, 2980, 1600, 1560,
1440, 1270, 1170 cm−1. HRMS−FAB (m/z): calcd for C10H12NO [M+
+ H] 162.0919; found 162.0920.
with TMSCl. This is followed by stabilization of the nitrilium
intermediate by the addition of the chloride anion to form the
imidoyl chloride,11 which is then hydrolyzed by water to give
the final product. In the case of phenyl isocyanide (R2 = Ph;
2e), conjugation between CN bond and aromatic ring on the
nitrogen atom of imidoyl chloride might make C1 proton of the
tetrahydroisoquinoline ring more acidic. Therefore, deprotona-
tion at the C1 position readily occurred followed by elimination
of the silyloxy anion to give 4ae. On the other hand,
introduction of an electron-donating group on the aromatic
ring such as 2f and 2g made the C1 proton of the
corresponding imidoyl chloride less acidic to prevent the
deprotonation.
In conclusion, we have designed and demonstrated the
addition reaction of isocyanides to nitrones in the presence of
TMSCl to afford the corresponding 1,2,3,4-tetrahydroisoquino-
line-1-carboxylamides in moderate to high yields. A wide range
of 3,4-dihydroisoquinoline N-oxides and isocyanides were
applicable to this reaction.
5,6-Dimethoxy-3,4-dihydroisoquinoline 2-Oxide (1f). Silica
gel column chromatography (ethyl acetate/MeOH = 10/1) gave 1f
(672 mg, 65%, 5.0 mmol scale) as a white solid of mp = 124.5−125
1
°C. H NMR (400 MHz, CDCl3): 3.14 (t, J = 7.7 Hz, 2H), 3.77 (s,
3H), 3.82 (s, 3H), 3.98 (t, J = 7.7 Hz, 2H), 6.74 (d, J = 8.3 Hz, 1H),
6.80 (d, J = 8.3 Hz, 1H), 7.62 (s, 1H). 13C NMR (100 MHz, CDCl3):
21.9, 55.8, 57.0, 60.6, 110.9, 121.7, 121.9, 123.9, 133.8, 145.8, 154.0. IR
(KBr): 3430, 2940, 1590, 1490, 1310, 1270, 1090 cm−1. HRMS−FAB
(m/z): calcd for C11H14NO3 [M+ + H] 208.0974; found 208.0979.
7-Chloro-3,4-dihydroisoquinoline 2-Oxide (1h). Silica gel
column chromatography (ethyl acetate/MeOH = 10/1) gave 1h
(288 mg, 78%, 2.0 mmol scale) as a white solid of mp = 109−110 °C.
1H NMR (400 MHz, CDCl3): 3.09 (t, J = 7.8 Hz, 2H), 4.04 (t, J = 7.8
EXPERIMENTAL SECTION
General Method. H NMR was recorded on a 400 MHz NMR
■
1
spectrometer. Chemical shifts δ are reported in ppm using TMS as an
internal standard. Data are reported as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet), coupling constant (J) and integration. 13C NMR spectra
were recorded on 100 MHz NMR spectrometer. The chemical shifts
were determined in the δ-scale relative to CDCl3 (δ = 77.0 ppm). The
wave numbers of maximum absorption peaks of IR spectroscopy are
presented in cm−1. HRMS (FAB, positive) was measured with a
quadrupole mass spectrometer. All of the melting points were
measured with a micro melting point apparatus. Toluene was dried
and distilled over sodium. THF was freshly distilled from sodium
diphenylketyl. All other solvents were distilled and stored over drying
agents.
Hz, 2H), 7.04−7.09 (m, 2H), 7.15−7.19 (m, 1H), 7.62 (s, 1H). 13C
NMR (100 MHz, CDCl3): 27.3, 58.2, 124.9, 128.2, 128.5, 129.0,
130.0, 132.8, 133.5. IR (KBr): 3360, 3030, 2830, 1590, 1490, 1410,
1270, 1190 cm−1. HRMS−FAB (m/z): calcd for C9H9ClNO [M+ +
H] 182.0373; found 182.0369.
General Procedure for the Addition of Isocyanide to
Nitrones in the Presence of TMSCl. To a solution of nitrone
(0.5 mmol) in MeCN (1.0 mL) was added TMSCl (0.525 mmol) in
MeCN (0.5 mL) at −20 °C. After 10 min, isocyanide (1.0 mmol) in
MeCN (0.5 mL) was added dropwise at −20 °C and stirred at that
temperature. After reaction completion (monitored by TLC), water (3
mL) was added at −20 °C and warmed to room temperature, and then
ethyl acetate was added. Aqueous layer was separated and extracted
with ethyl acetate (5 mL × 3). Combined organic layers were washed
with brine and dried over Na2SO4. The residue was purified by silica
gel column chromatography to give the corresponding products.
N-(tert-Butyl)-2-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-
carboxamide (3aa). Silica gel column chromatography (hexane/
ethyl acetate = 3/1−1/1) gave 3aa (151 mg, 82%) as a white solid of
mp = 156−157 °C. 1H NMR (400 MHz, CDCl3): 1.31 (s, 9H), 2.76−
2.80 (m, 1H), 2.94−3.01 (m, 1H), 3.06−3.14 (m, 1H), 3.39−3.43 (m,
1H), 4.21 (s, 1H), 5.70 (br, 1H), 6.42 (brs, 1H), 7.02 (d, J = 6.9 Hz,
1H), 7.09−7.12 (m, 2H), 7.41 (d, J = 6.9 Hz, 1H). 13C NMR (100
MHz, CDCl3): 28.6, 29.1, 50.8, 54.2, 74.0, 126.2, 126.4, 127.2, 128.2,
132.0, 132.3, 170.5. IR (KBr): 3370, 2970, 2830, 1650, 1530, 1450,
3,4-Dihydroisoquinoline 2-oxides were prepared according to the
reported procedure.12
General Procedure. To a solution of 2-(2-bromoethyl)-
benzaldehyde derivative (2.0 mmol) in MeOH (2.0 mL) was added
hydroxylamine hydrogenchloride (4.0 mmol) at room temperature,
and the whole was refluxed for 1 h. The 1 N NaOH aq (5 mL) was
added at room temperature. After removal of the MeOH under
reduced pressure, the aqueous solution was extracted with CHCl3 (3
mL × 3). The combined organic layers were washed with brine and
dried over Na2SO4, followed by evaporation.
5-Methyl-3,4-dihydroisoquinoline 2-Oxide (1b). Silica gel
column chromatography (ethyl acetate/MeOH = 10/1) gave 1b
(595 mg, 74%, 5.0 mmol scale) as a white solid of mp = 84.5−85.0 °C.
1H NMR (400 MHz, CDCl3): 2.28 (s, 3H), 3.10 (t, J = 7.8 Hz, 2H),
4.09 (t, J = 7.8 Hz, 2H), 6.96 (d, J = 7.1 Hz, 1H), 7.15 (t, J = 7.1 Hz,
2H), 7.70 (s, 1H). 13C NMR (100 MHz, CDCl3): 18.9, 24.7, 57.4,
9880
dx.doi.org/10.1021/jo301791m | J. Org. Chem. 2012, 77, 9878−9883

The Journal of Organic Chemistry
Note
1360, 1230 cm−1. HRMS−FAB (m/z): calcd for C14H21N2O2 [M+ +
H] 249.1603; found 249.1609.
(d, J = 8.7 Hz, 2H), 7.06 (d. J = 7.3 Hz, 1H), 7.09−7.13 (m, 2H), 7.34
(d, J = 8.7 Hz, 2H), 7.52 (d, J = 7.3 Hz, 1H), 8.25 (s, 1H). 13C NMR
(100 MHz, CDCl3): 29.2, 41.0, 54.2, 73.6, 113.1, 121.4, 126.4, 126.5,
127.4, 127.7, 128.2, 131.5, 132.5, 147.8, 169.1. IR (KBr): 3340, 2950,
2840, 1640, 1540, 1360, 1230 cm−1. HRMS−FAB (m/z): calcd for
C18H22N3O2 [M+ + H] 312.1712; found 312.1716.
N-Cyclohexyl-2-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-
carboxamide (3ab). Silica gel column chromatography (hexane/
ethyl acetate = 3/1−1/1) gave 3ab (118 mg, 86%) as a white solid of
1
mp = 178−179 °C. H NMR (400 MHz, CDCl3): 0.73−1.90 (m, 10
H), 2.78−2.82 (m, 1H), 2.96−3.02 (m, 1H), 3.08−3.17 (m, 1H),
3.41−3.45 (m, 1H), 3.68−3.77 (m, 1H), 4.31 (s, 1H), 5.36 (brs, 1H),
6.41 (d, J = 6.3 Hz, 1H), 7.03 (d, J = 6.9 Hz, 1H), 7.07−7.14 (m, 2H),
7.41 (d, J = 6.9 Hz, 1H). 13C NMR (100 MHz, CDCl3): 24.7, 24.9,
25.5, 29.1, 32.7, 32.9, 48.0, 54.3, 73.3, 126.2, 126.4, 127.2, 128.2, 131.9,
132.4, 170.6. IR (KBr): 3230, 2970, 2920, 1640, 1560, 1450, 1370,
1250 cm−1. HRMS−FAB (m/z): calcd for C16H23N2O2 [M+ + H]
275.1770; found 275.1760.
N-(tert-Butyl)-2-hydroxy-5-methyl-1,2,3,4-tetrahydroisoqui-
noline-1-carboxamide (3ba). Silica gel column chromatography
(hexane/ethyl acetate = 4/1−2/1−1/1) gave 3ba (102 mg, 78%) as a
white solid of mp = 173−174 °C. 1H NMR (400 MHz, CDCl3): 1.26
(s, 9H), 2.16 (s, 3H), 2.72−2.76 (m, 1H), 2.82−2.90 (m, 1H), 2.94−
3.00 (m, 1H), 3.44−3.49 (m, 1H), 4.20 (s, 1H), 5.31 (brs, 1H), 6.29
(brs, 1H), 6.98−7.04 (m, 2H), 7.25 (d, J = 7.3 Hz, 1H). 13C NMR
(100 MHz, CDCl3): 19.4, 26.9, 28.6, 50.8, 54.1, 74.4, 123.8, 126.3,
128.6, 131.0, 131.9, 135.8, 170.7. IR (KBr): 3360, 2970, 2830, 1650,
1530, 1360, 1230 cm−1. HRMS−FAB (m/z): calcd for C15H23N2O2
[M+ + H] 263.1760; found 263.1755.
N-(tert-Butyl)-2-hydroxy-6-methyl-1,2,3,4-tetrahydroisoqui-
noline-1-carboxamide (3ca). Silica gel column chromatography
(hexane/ethyl acetate = 4/1−2/1−1/1) gave 3ca (102 mg, 26%) as a
white solid of mp = 160−170 °C. 1H NMR (400 MHz, CDCl3): 1.26
(s, 9H), 2.22 (s, 3H), 2.72−2.76 (m, 1H), 2.95−2.98 (m, 1H), 3.01−
3.03 (m, 1H), 3.38−3.43 (m, 1H), 4.16 (s, 1H), 5.48 (brs, 1H), 6.37
(brs, 1H), 6.84 (brs, 1H), 6.91 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz,
1H). 13C NMR (100 MHz, CDCl3): 20.9, 28.6, 29.1, 50.7, 54.3, 73.9,
126.1, 127.3, 128.7, 129.0, 132.1, 136.9, 170.1 IR (KBr): 3370, 2970,
2840, 1650, 1540, 1360, 1230 cm−1. HRMS−FAB (m/z): calcd for
C15H23N2O2 [M+ + H] 263.1760; found 263.1765.
N-(tert-Butyl)-2-hydroxy-7-methyl-1,2,3,4-tetrahydroisoqui-
noline-1-carboxamide (3da). Silica gel column chromatography
(hexane/ethyl acetate = 4/1−2/1−1/1) gave 3da (108 mg, 82%) as a
white solid of mp = 114−115 °C. 1H NMR (400 MHz, CDCl3): 1.27
(s, 9H), 2.21 (s, 3H), 2.72−2.77 (m, 1H), 2.91−2.98 (m, 1H), 3.01−
3.09 (m, 1H), 3.38−3.42 (m, 1H), 4.16 (s, 1H), 5.50 (brs, 1H), 6.38
(brs, 1H), 6.90−6.92 (m, 2H), 7.21 (brs, 1H). 13C NMR (100 MHz,
CDCl3): 21.1, 28.6, 28.7, 50.8, 54.4, 74.0, 126.5, 128.0, 128.1, 129.5,
131.2, 136.0, 170.7. IR (KBr): 3330, 2970, 2830, 1660, 1530, 1360,
1230 cm−1. HRMS−FAB (m/z): calcd for C15H23N2O2 [M+ + H]
263.1760; found 263.1764.
N-(tert-Butyl)-2-hydroxy-8-methyl-1,2,3,4-tetrahydroisoqui-
noline-1-carboxamide (3ea). Silica gel column chromatography
(hexane/ethyl acetate = 4/1−2/1−1/1) gave 3ea (84 mg, 64%) as a
white solid of mp = 162−164 °C. 1H NMR (400 MHz, CDCl3): 1.26
(s, 9H), 2.23 (s, 3H), 2.72−2.76 (m, 1H), 2.92−2.98 (m, 1H), 3.02−
3.11 (m, 1H), 3.38−3.42 (m, 1H), 4.16 (s, 1H), 5.49 (brs, 1H), 6.37
(brs, 1H), 6.84 (brs, 1H), 6.91 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 7.8 Hz,
1H). 13C NMR (100 MHz, CDCl3): 20.9, 28.6, 29.0, 50.7, 54.3, 73.9,
126.1, 127.3, 128.7, 129.1, 132.1, 136.9, 170.7. IR (KBr): 3300, 2970,
2840, 1650, 1530, 1530, 1230. cm−1. HRMS−FAB (m/z): calcd for
C15H23N2O2 [M+ + H] 263.1760; found 263.1759.
N-Benzyl-2-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-car-
boxamide (3ac). Silica gel column chromatography (hexane/ethyl
acetate = 3/1−1/1) gave 3ac (103 mg, 73%) as a white solid of mp =
176−177 °C. 1H NMR (400 MHz, CDCl3): 2.75−2.79 (m, 1H),
2.95−3.00 (m, 1H), 3.04−3.13 (m, 1H), 3.38−3.41 (m, 1H), 4.26 (dd,
J = 15.5, 5.5 Hz, 1H), 4.42 (s, 1H), 4.50−4.56 (m, 1H), 5.54 (brs,
1H), 6.97 (brs, 1H), 7.02−7.04 (m, 1H), 7.12−7.22 (m, 7H), 7.48 (d,
J = 7.3 Hz, 1H). 13C NMR (100 MHz, CDCl3): 29.2, 43.0, 54.3, 73.1,
126.4, 126.5, 127.4, 127.4, 127.5, 128.2, 128.6, 138.3, 171.4. IR (KBr):
3290, 2930, 2840, 1660, 1530, 1490, 1360, 1250 cm−1. HRMS−FAB
(m/z): calcd for C17H19N2O2 [M+ + H] 283.1447; found 283.1446.
N-((S)-1-((tert-Butyldimethylsilyl)oxy)-3-methylbutan-2-yl)-
2-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide
(3ad). Silica gel column chromatography (hexane/ethyl acetate = 5/
1−1/1) gave 3ad (138 mg, 70%). Diastereomeric ratio was
1
determined to be 1:1 by H NMR.
Diastereomer (Rf = 0.4, hexane/ethyl acetate = 7/1 × 2). 1H NMR
(400 MHz, CDCl3): −0.28 (s, 3H), −0.14 (s, 3H), 0.74 (s, 9H), 0.96
(d, J = 6.6 Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H), 1.93 (sep, J = 6.6 Hz,
1H), 2.83−2.88 (m, 1H), 3.03−3.19 (m, 2H), 3.35 (dd, J = 10.5, 3.2
Hz, 1H), 3.48−3.52 (m, 1H), 3.64−3.70 (m, 2H), 4.43 (s, 1H), 5.34
(brs, 1H), 6.86 (d, J = 9.2 Hz, 1H), 7.06−7.08 (m, 1H), 7.12−7.18 (m,
2H), 7.48−7.51 (m, 1H). 13C NMR (100 MHz, CDCl3): −6.1, −5.8,
18.0, 19.5, 19.7, 25.7, 28.8, 29.2, 54.2, 55,4, 62.6, 73.3, 126.3, 126.5,
127.3, 128.2, 131.8, 132.3, 170.8. IR (KBr): 3360, 2930, 2820, 1640,
1530, 1260, 1100 cm−1 HRMS−FAB (m/z): calcd for C21H37N2O3Si
[M+ + H] 393.2573; found 393.2566.
Diastereomer (Rf = 0.55, hexane/ethyl acetate = 7/1 × 2). 1H NMR
(400 MHz, CDCl3): 0.09 (s, 3H), 0.10 (s, 3H), 0.75 (d, J = 6.9 Hz,
3H), 0.86 (d, J = 6.9 Hz, 3H), 0.91 (s, 9H), 2.6−2.90 (m, 1H), 3.03−
3.09 (m, 1H), 3.18−3.26 (m, 1H), 3.47−3.50 (m, 1H), 3.63−3.66 (m,
1H), 3.74−3.81 (m, 2H), 4.40 (s, 1H), 6.07 (s, 1H), 6.86 (d, J = 9.2
Hz, 1H), 7.11 (d, J = 7.3 Hz, 1H), 7.13−7.20 (m, 3H), 7.49 (d, J = 7.3
Hz, 1H). 13C NMR (100 MHz, CDCl3): −5.5, −5.4, 18.3, 19.0, 19.5,
25.8, 29.3, 29.3, 53.3, 55.6, 63.4, 73.9, 126.1, 126.4, 127.3. 128.2, 131.8,
132.2, 171.3. IR (KBr): 3360, 2930, 2820, 1640, 1530, 1260, 1100
cm−1. HRMS−FAB (m/z): calcd for C21H37N2O3Si [M+ + H]
393.2573; found 393.2562
2-Hydroxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoqui-
noline-1-carboxamide (3af). Silica gel column chromatography
(hexane/ethyl acetate = 3/1−1/1) gave 3af (63 mg, 42%) as a white
solid of mp = 158−159 °C. 1H NMR (400 MHz, CDCl3): 2.81−2.86
(m, 1H), 3.02−3.08 (m, 1H), 3.15−3.23 (m, 1H), 3.47−3.52 (m, 1H),
3.70 (s, 3H), 4.45 (s, 1H), 5.58 (brs, 1H), 6.76 (d, J = 8.9 Hz, 2H),
7.05−7.16 (m, 3H), 7.39 (d, J = 8.9 Hz, 2H), 7.51 (d, J = 6.9 Hz, 1H),
8.37 (s, 1H). 13C NMR (100 MHz, CDCl3): 29.2, 54.2, 55.4, 73.5,
114.0, 121.5, 126.3, 126.6, 127.5, 128.3, 130.8, 131.3, 132.5, 156.2,
169.4. IR (KBr): 3330, 2960, 2840, 1650, 1510, 1460, 1250 cm−1.
HRMS−FAB (m/z): calcd for C17H19N2O3 [M+ + H] 299.1396;
found 299.1397.
N-(tert-Butyl)-2-hydroxy-5,6-dimethoxy-1,2,3,4-tetrahydroi-
soquinoline-1-carboxamide (3fa). Silica gel column chromatog-
raphy (hexane/ethyl acetate = 5/1−2/1−1/1) gave 3fa (115 mg,
1
75%) as a white solid of mp = 158−159 °C. H NMR (400 MHz,
CDCl3): 1.27 (s, 9H), 2.81−2.98 (m, 3H), 3.40−3.43 (m, 1H), 3.75
(s, 3H), 3.77 (s, 3H), 4.11 (s, 1H), 5.31 (brs, 1H), 6.34 (brs, 1H), 6.70
(d, J = 8.7 Hz, 1H), 7.10 (d, J = 8.7 Hz, 1H). 13C NMR (100 MHz,
CDCl3): 23.8, 28.6, 50.8, 53.9, 55.7, 60.0, 73.5, 110.9, 121.7, 125.1,
126.9, 145.7, 151.3, 170.5. IR (KBr): 3380, 2970, 2840, 1650, 1540,
1280, 1230 cm−1. HRMS−FAB (m/z): calcd for C16H25N2O4 [M+ +
H] 309.1814; found 309.1818.
N-(tert-Butyl)-2-hydroxy-6,7-dimethoxy-1,2,3,4-tetrahydroi-
soquinoline-1-carboxamide (3ga). Silica gel column chromatog-
raphy (hexane/ethyl acetate = 5/1−2/1−1/1) gave 3ga (120 mg,
1
78%) as a white solid of mp = 194−195 °C. H NMR (400 MHz,
N-(4-(Dimethylamino)phenyl)-2-hydroxy-1,2,3,4-tetrahy-
droisoquinoline-1-carboxamide (3ag). Silica gel column chroma-
tography (hexane/ethyl acetate = 8/1−5/1−1/1) gave 3ag (82 mg,
CDCl3): 1.27 (s, 9H), 2.68−2.72 (m, 1H), 2.92−2.98 (m, 1H), 3.01−
3.09 (m, 1H), 3.37−3.42 (m, 1H), 3.75 (s, 3H), 3.78 (s, 3H), 4.12 (s,
1H), 5.21 (brs, 1H), 6.37 (brs, 1H), 6.49 (s, 1H), 6.93 (s, 1H). 13C
NMR (100 MHz, CDCl3): 28.6, 28.8, 50.7, 54.4, 55.8, 55.9, 73.8,
108.6, 110.4, 123.8, 124.3, 147.6, 148.2, 170.6. IR (KBr): 3360, 2970,
1
53%) as a white solid of mp = 173−175 °C. H NMR (400 MHz,
CDCl3): 2.83 (s, 6H), 2.85−2.88 (m, 1H), 3.03−3.08 (m, 1H), 3.15−
3.23 (m, 1H), 3.47−3.51 (m, 1H), 4.44 (s, 1H), 5.48 (brs, 1H), 6.61
9881
dx.doi.org/10.1021/jo301791m | J. Org. Chem. 2012, 77, 9878−9883

The Journal of Organic Chemistry
Note
2840, 1650, 1520, 1300, 1220 cm−1. HRMS−FAB (m/z): calcd for
ASSOCIATED CONTENT
■
C16H25N2O4 [M+ + H] 309.1814; found 309.1823.
S
* Supporting Information
N-(tert-Butyl)-7-chloro-2-hydroxy-1,2,3,4-tetrahydroisoqui-
noline-1-carboxamide (3ha). Silica gel column chromatography
(hexane/ethyl acetate = 5/1−2/1−1/1) gave 3ha (108 mg, 77%) as a
white solid of mp = 137−138 °C. 1H NMR (400 MHz, CDCl3): 1.27
(s, 9H), 2.72−2.77 (m, 1H), 2.92−3.06 (m, 2H), 3.37−3.40 (m, 1H),
4.17 (s, 1H), 6.17 (brs, 1H), 6.52 (brs, 1H), 6.95 (d, J = 8.1 Hz, 1H),
7.09 (d, J = 8.1 Hz, 1H), 7.42 (s, 1H). 13C NMR (100 MHz, CDCl3):
28.3, 28.6, 51.0, 53.9, 73.2, 126.2, 127.5, 129.5, 131.0, 132.2, 133.8,
170.0. IR (neat): 3360, 2970, 2830, 1650, 1530, 1290, 1230 cm−1.
HRMS−FAB (m/z): calcd for C14H20ClN2O2 [M+ + H] 283.1213;
found 283.1220.
1
Copies of H NMR and 13C NMR spectra of products and X-
ray crystallographic data of 3aa in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: soeta@se.kanazawa-u.ac.jp; ukaji@se.kanazawa-u.ac.jp.
Notes
■
The authors declare no competing financial interest.
N-(tert-Butyl)-3,4-dihydroisoquinoline-1-carboxamide (4aa).
Silica gel column chromatography (hexane/ethyl acetate = 10/1−5/1)
ACKNOWLEDGMENTS
1
■
gave 4aa as a pale yellow oil. H NMR (400 MHz, CDCl3): 1.45 (s,
This work was supported by a Grant-in-Aid for Young Scientist
(B) (24750037) and a Grant in-Aid for Scientific Research (B)
from the Japan Society for the Promotion of Science
(24350022).
9H), 2.70 (t, J = 7.3 Hz, 2H), 3.73 (t, J = 7.3, 2H), 7.17 (d, J = 7.3 Hz,
1H), 7.28−7.38 (m, 3H), 8.17 (d, J = 7.3 Hz, 1H). 13C NMR (100
MHz, CDCl3): 25.6, 28.5, 46.9, 50.8, 126.1, 126.6, 126.9, 128.4, 130.9,
137.9, 160.3, 163.6. IR (neat): 3360, 2970, 1680, 1610, 1510, 1360.
1250, 1130 cm−1. HRMS−FAB (m/z): calcd for C14H19N2O [M+ +
H] 231.1497; found 231.1499.
N-(Phenyl)-3,4-dihydroisoquinoline-1-carboxamide (4ae).
Silica gel column chromatography (hexane/ethyl acetate = 10/1−5/
1) gave 4ae (40 mg, 32%) as brown oil. 1H NMR (400 MHz, CDCl3):
2.70 (t, J = 7.3 Hz, 2H), 3.79 (t, J = 7.3 Hz, 2H), 7.07 (t, J = 7.8 Hz,
1H), 7.15 (d, J = 7.8 Hz, 1H), 7.26−7.36 (m, 4H), 7.63 (d, J = 8.2 Hz,
2H), 8.26 (d, J = 7.8 Hz, 1H). 9.43 (brs, 1H). 13C NMR (100 MHz,
CDCl3): 25.9, 47.2, 119.6, 124.2, 126.0, 127.0, 127.2, 128.7, 129.0,
131.4, 137.7, 138.1, 159.3, 161.6. IR (neat): 3320, 2920, 1690, 1600,
1520, 1440, 1290 cm−1. HRMS−FAB (m/z): calcd for C16H15N2O
[M+ + H] 251.1184; found 251.1180.
REFERENCES
■
(1) (a) Bentley, K. W. Nat. Prod. Rep. 2006, 23, 444−463.
(b) Bentley, K. W. Nat. Prod. Rep. 2005, 22, 249−268. (c) Scott, J.
D.; Williams, R. M. Chem. Rev. 2002, 102, 1669−1730. (d) Bentley, K.
W. Nat. Prod. Rep. 2001, 18, 148−170.
(2) (a) Xie, J.-H.; Yan, P.-C.; Zhang, Q.-Q.; Yuan, K.-X.; Zhou, Q.-L.
ACS Catal. 2012, 2, 561−564. (b) Chang, M.; Li, W.; Zhang, X.
Angew. Chem., Int. Ed. 2011, 50, 10679−10681. (c) Hashimoto, T.;
Omote, M.; Maruoka, K. Angew. Chem., Int. Ed. 2011, 50, 8952−8955.
(d) Sasamoto, N.; Dubs, C.; Hamashima, Y.; Sodeoka, M. J. Am. Chem.
Soc. 2006, 128, 14010−14011. (e) Wu, T. R.; Chong, J. M. J. Am.
Chem. Soc. 2006, 128, 9646−9647. (f) Seayad, J.; Seayad, A. M.; List,
B. J. Am. Chem. Soc. 2006, 128, 1086−1087. (g) Itoh, T.; Miyazaki, M.;
Fukuoka, H.; Nagata, K.; Ohsawa, A. Org. Lett. 2006, 8, 1295−1297.
(h) Taylor, A. M.; Schreiber, S. L. Org. Lett. 2006, 8, 143−146.
(i) Frisch, K.; Landa, A.; Saaby, S.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2005, 44, 6058−6063. (j) Taylor, M. S.; Jacobsen, E. N. J. Am.
Chem. Soc. 2004, 126, 10558−10559. (k) Funabashi, K.; Ratni, H.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 10784−10785.
(l) Ukaji, Y.; Yoshida, Y.; Inomata, K. Tetrahedron: Asymmetry 2000,
11, 733−736. (m) Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2000, 122, 6327−6328. (n) Ukaji, Y.; Shimizu, Y.;
Kenmoku, Y.; Ahmed, A.; Inomata, K. Bull. Chem. Soc. Jpn. 2000, 73,
447−452. (o) Ukaji, Y.; Shimizu, Y.; Kenmoku, Y.; Ahmed, A.;
Inomata, K. Chem. Lett. 1997, 59−60. (p) Uematsu, N.; Fujii, A.;
Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118,
4916−4917 and references therein.
N-(tert-Butyl)-2-((tert-butyldimethylsilyl)oxy)-1,2,3,4-tetra-
hydroisoquinoline-1-carboxamide (5). Silica gel column chroma-
tography (hexane/ethyl acetate = 10/1−5/1) gave 5 (55 mg, 51%, 0.3
1
mmol scale) as a pale yellow oil. H NMR (400 MHz, CDCl3): 0.08
(s, 3H), 0.10 (s, 3H), 0.81 (s, 9H), 1.29 (s, 9H), 2.43−2.46 (m, 1H),
3.02−3.12 (m, 3H), 4.36 (s, 1H), 6.68 (brs, 1H), 6.96−6.99 (m, 1H),
7.07 (m, 2H), 7.29 (m, 1H). 13C NMR (100 MHz, CDCl3): −4.8,
−3.6, 17.8, 25.6, 26.0, 28.7, 50.8, 51.5, 71.4, 125.6, 126.8, 128.0, 129.3,
130.4, 133.2, 169.0. IR (KBr): 3290, 2930, 1660, 1550, 1450, 1360,
1250 cm−1. HRMS−FAB (m/z): calcd for C20H35N2O2Si [M+ + H]
363.2468; found 363.2471.
N-(tert-Butyl)-2-((tert-butyldiphenylsilyl)oxy)-1,2,3,4-tetra-
hydroisoquinoline-1-carboxamide (5′). Silica gel column chro-
matography (hexane/ethyl acetate = 10/1−5/1) gave 5′ (110 mg,
76%, 0.3 mmol scale) as a pale yellow oil. 1H NMR (400 MHz,
CDCl3): 0.98 (s, 9H), 1.01 (s, 9H), 2.43−2.47 (m, 1H), 3.02−3.12
(m, 3H), 4.36 (s, 1H), 6.15 (brs 1H), 6.98−7.00 (m, 1H), 7.07−7.10
(m, 2H), 7.26−7.41 (m, 6H), 7.60−7.66 (m, 5H). 13C NMR (100
MHz, CDCl3): 0.98, 19.1, 27.2, 28.3, 50.5, 50.7, 70.8, 125.5, 126.8,
127.6, 127.6, 127.9, 129.5, 129.7, 129.9, 129.9, 133.2, 133.3, 133.6,
134.8, 136.0, 168.3. IR (neat): 3390, 2930, 2820, 1690, 1510, 1430,
1220, 1110 cm−1. HRMS−FAB (m/z): calcd for C30H39N2O2Si [M+ +
H] 487.2781; found 487.2777.
N-(tert-Butyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide
(6). To a solution of 3aa (59.5 mg, 0.24 mmol) in MeOH (1.1 mL)
were subsequently added potassium hydroxide (26.9 mg, 0.48 mmol)
in H2O and nickel/aluminum alloy (421 mg) at room temperature.13
The whole was stirred at room temperature for 2 h and filtrated
through Celite. The filtrate was concentrated to afford the crude
prodtct. Silica gel column chromatography (ethyl acetate/MeOH =
10/1) gave 6 (51 mg, 92%) as a pale yellow oil. 1H NMR (400 MHz,
CDCl3): 1.25 (s, 9H), 2.03 (brs, 1H), 2.63−2.70 (m, 1H), 2.74−2.81
(m, 1H), 2.98 (t, J = 5.9 Hz, 2H), 4.34 (s, 1H), 6.97 (brs, 1H), 7.00−
7.02 (m, 1H), 7.09−7.11 (m, 2H), 7.40−7.44 (m, 1H). 13C NMR
(100 MHz, CDCl3): 28.6, 29.2, 41.1, 50.6, 60.6, 125.8, 126.8, 127.9,
129.0, 132.9, 134.4, 171.7. IR (neat): 3310, 2970, 1660, 1510, 1390,
1230 cm−1. HRMS−FAB (m/z): calcd for C14H21N2O [M+ + H]
233.1654; found 233.1658.
(3) (a) Imae, Y.; Takada, K.; Murayama, S.; Okada, S.; Ise, Y.;
Matsunaga, S. Org. Lett. 2011, 13, 4798−4801. (b) Fang, X.; Yin, Y.;
Chen, Y.-T.; Yao, L.; Wang, B.; Cameron, M. D.; Lin, L.; Khan, S.;
Ruiz, C.; Schroter, T.; Grant, W.; Weiser, A.; Pocas, J.; Pachori, A.;
̈
Schurer, S.; LoGrasso, P.; Feng, Y. J. Med. Chem. 2010, 53, 5727−
̈
5737. (c) Li, J. J.; Wang, H.; Qu, F.; Musial, C.; Tino, J. A.; Robl, J. A.;
Slusarchyk, A.; Golla, R.; Seethala, R.; Dickinson, K.; Giupponi, L.;
Grover, G.; Sleph., P.; Flynn, N.; Murphy, B. J.; Gordon, D.; Kung, M.;
Stoffel, R. Bioorg. Med. Chem. Lett. 2005, 15, 1799−1802. (d) Toth, B.
́
E.; Bodnaar, I.; Homicsko, K. G.; Fulop, F.; Fekete, M.; Nagy, G. M.
́
́
̈
̈
Neurotoxicol. Teratol. 2002, 24, 655−666.
(4) Recent reviews: (a) Banfi, L.; Riva, R.; Basso, A. Synlett 2010,
23−41. (b) El Kaim, L.; Grimaud, L. Tetrahedron 2009, 65, 2153−
2171. (c) Domling, A. Curr. Opin. Chem. Biol. 2002, 6, 306−313.
̈
(d) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3169−3210.
̈
́ ́
(5) (a) Schuster, I.; Lazar, L.; Fulop, F. Synth. Commun. 2010, 40,
̈
̈
2488−2498. (b) Jiang, G.; Chen, J.; Huang, J.-S.; Che, C.-M. Org. Lett.
2009, 11, 4568−4571. (c) Shaabani, A.; Soleimani, E.; Khavasi, H. R.
Tetrahedron Lett. 2007, 48, 4743−4747. (d) Schuster, I.; Sztojkov-
́ ́
Ivanov, A.; Lazar, L.; Fulop, F. Lett. Org. Chem. 2007, 4, 102−108.
̈
̈
(e) Ngouansavanh, T.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 5775−
9882
dx.doi.org/10.1021/jo301791m | J. Org. Chem. 2012, 77, 9878−9883

The Journal of Organic Chemistry
Note
5778. (f) Díax, J. L.; Miguel, M.; Lavilla, R. J. Org. Chem. 2004, 69,
3550−3553. (g) Tron, G. C.; Zhu, J. Synlett. 2005, 532−534.
(6) (a) Soeta, T.; Kojima, Y.; Ukaji, Y.; Inomata, K. Tetrahedron Lett.
2011, 52, 2557−2559. (b) Soeta, T.; Kojima, Y.; Ukaji, Y.; Inomata, K.
Org. Lett. 2010, 12, 4341−4343.
(7) (a) Pirali, T.; Mossetti, R.; Galli, S.; Tron, G. C. Org. Lett. 2011,
13, 3734−3737. (b) Bouma, M.; Masson, G.; Zhu, J. J. Org. Chem.
2010, 75, 2748−2751.
(8) (a) Ukaji, Y.; Inomata, K. Chem. Rec. 2010, 10, 173−187 and
references therein. (b) Grigor’ev, I. A. Nitrones: Novel Strategies in
Synthesis. In Nitrile Oxides. Nitrones, and Nitronates in Organic
Synthesis; Feuer, H., Ed.; John Wiley & Sons, Inc., New Jersey, 2008;
pp 129−434. (c) Breuer, E. Nitrones and Nitric Acid Derivatives: An
Update. In Nitrones, Nitronates and Nitroxides; Patai, S., Ed.; John
Wiley & Sons, Inc.: Chichester, 1989; pp 245−312. (d) Breuer, E.
Nitrones and Nitric Acid Derivatives: Their Structure and Their Roles
in Synthesis. In Nitrones, Nitronates and Nitroxides; Patai, S., Ed.; John
Wiley & Sons, Inc.: Chichester, 1989; pp 139−244.
(9) (a) Denmark, S. E.; Fan, Y. J. Org. Chem. 2005, 70, 9667−9676.
(b) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2003, 125, 7825−7827.
(10) (a) Bauer, M.; Kazmaier, U. J. Organomet. Chem. 2006, 691,
2155−2158. (b) Bauer, M.; Kazmaier, U. Eur. J. Org. Chem. 2009,
2360−2366.
(11) Banfi, L.; Riva, R. Org. React. 2005, 65, 1−140.
(12) Schmitz, E. Chem. Ber. 1958, 91, 1488−1494.
(13) Lunn, G.; Sansone, E. B.; Keefer, L. K. Synthesis 1985, 1104−
1108.
9883
dx.doi.org/10.1021/jo301791m | J. Org. Chem. 2012, 77, 9878−9883