Carbamoyl anion addition to nitrones

Article abstract of DOI:10.1021/jo500848a

The addition of carbamoyl anions derived from N,N-disubstituted formamides and LDA to N-tert-butyl nitrones is described. The reaction was demonstrated with a variety of formamides and nitrones and provided a direct route to α-(N-hydroxy)amino amides. The use of a tert-leucinol derived chiral auxiliary on the nitrone provided products in good diastereoselectivity. Derivatization of the products by tert-butyl deprotection or N-deoxygenation was demonstrated.

Full text of DOI:10.1021/jo500848a

Note
pubs.acs.org/joc
Carbamoyl Anion Addition to Nitrones
Jonathan T. Reeves,* Chris Lorenc,† Kaddy Camara,† Zhibin Li, Heewon Lee, Carl A. Busacca,
and Chris H. Senanayake
Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut
06877-0368, United States
S
* Supporting Information
ABSTRACT: The addition of carbamoyl anions derived from
N,N-disubstituted formamides and LDA to N-tert-butyl nitrones is
described. The reaction was demonstrated with a variety of
formamides and nitrones and provided a direct route to α-(N-
hydroxy)amino amides. The use of a tert-leucinol derived chiral
auxiliary on the nitrone provided products in good diastereose-
lectivity. Derivatization of the products by tert-butyl deprotection
or N-deoxygenation was demonstrated.
he α-(N-hydroxy)amino amide moiety is present in many
Scheme 1. Synthesis of α-(N-Hydroxy)amino Amides
T
pharmaceutically important synthetic and naturally
occurring peptides (Figure 1).1 The natural product azino-
Figure 1. Selected bioactive natural and synthetic products containing
α-(N-hydroxy)amino amides.
thricin (1) and related cyclodepsipeptides have demonstrated
powerful antibiotic and antitumor activities.2 Callyspongidipep-
tide A (2) is a marine sponge derived diketopiperazine.3
Synthetic N-hydroxylated peptides such as 3 have been
developed as HIV protease inhibitors.4
Our initial work was focused on the addition of carbamoyl
anions to N-alkyl aldimines, specifically derivatives of chiral α-
arylethylamines. The addition of N,N-diisopropylformamide to
imines 4a−c proceeded to give the desired products 5a−c in
good yields and with diastereoselectivities as high as 90:10 for
5b (Scheme 2).11 Unfortunately, the use of less bulky
formamides such as N,N-dimethylformamide, N,N-diethylfor-
mamide, N,N-dibutylformamide, 4-formylmorpholine, and 1-
formylpyrrolidine gave little to no product. Inclusion of Lewis
acid additives such as ZnBr2, Cu(OTf)2, or BF3·OEt2 did not
lead to any improvement. This lack of reactivity can be
attributed to both the lesser stability of carbamoyl anions
Several procedures have been employed for the synthesis of
α-(N-hydroxy)amino amides (Scheme 1). These methods
include the N-oxidation of amino amides (method a) via Schiff
base intermediates,5 the Ugi reaction employing O-protected
hydroxylamine derivatives (method b),6 and the reduction of α-
ketoamide derived oximes (method c).7 We recently reported
the addition of carbamoyl anions to N-sulfinyl imines to
provide N-sulfinyl α-aminoamide products in high diaster-
eoselectivity.8 Carbamoyl anions are readily generated by
deprotonation of N,N-disubstituted formamides with strong
bases such as LDA.9 Their synthesis and utility in additions to a
variety of electrophiles was described in the pioneering reports
of Schollkopf, Seebach, and Enders.10 Herein we report that
̈
carbamoyl anions react with aldehyde derived nitrones to
Received: April 15, 2014
Published: May 28, 2014
provide α-(N-hydroxy)amino amides (method d).
© 2014 American Chemical Society
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a
Scheme 2. Carbamoyl Anion Addition to N-Alkyl Imines
Table 1. Scope of Carbamoyl Anion Addition to Nitrone 7
derived from smaller formamides, which undergo dimerization
in the absence of a suitably reactive electrophile, and the
relatively low electrophilicity of N-alkyl imines 4a−c.12 The
bulky N,N-diisopropylcarbamoyllithium is comparatively stable
and its addition to 4a−c is competitive relative to dimerization.
It is known that nitrones have increased reactivity toward
nucleophilic attack relative to the corresponding N-alkyl
imines.13 We hoped that this increased electrophilicity could
facilitate the addition of a broad spectrum of formamides to
nitrones. To test the reaction feasibility, N-benzyl nitrone 6 was
reacted with N,N-diisopropylformamide and LDA in toluene at
0 °C (Scheme 3). No product formation was observed. On
Scheme 3. Reactions with N-Benzyl and N-tert-Butyl
Nitrones
a
Typical reaction conditions: 1 equiv nitrone, 6.1 equiv formamide, 6.0
b
c
equiv LDA, PhMe, 0 °C. Isolated yield. LiTMP used instead of LDA.
d
Isolated yield of oxalic acid salt.
isolated as its crystalline oxalate salt in 79% yield by treatment
of the crude reaction mixture with oxalic acid. The reactions
with DMF employed LiTMP as base instead of LDA to
minimize transformylation. The addition of N,N-dimethylth-
ioformamide (entry 3) gave access to the uncommon α-(N-
hydroxy)amino thioamide moiety. The use of a cyclic
formamide (entry 4) and an N-alkyl-N-aryl formamide (entry
5) were also possible.
The scope of the reaction was next explored with respect to
variation in nitrone structure (Table 2). The ortho-substituted
aryl nitrone 13 reacted with N,N-diethylformamide to give
adduct 14 in 88% yield (entry 1). The electron rich aryl nitrone
15 reacted smoothly, giving adduct 16 in 72% yield (entry 2).
Heterocyclic (entries 3 and 4) and aliphatic (entries 5 and 6)
nitrones were amenable to carbamoyl anion addition. The
hindered pivaldehyde derived nitrone 21 gave α-(N-hydroxy)-
amino amide 22 in 56% yield (entry 5). Finally, the enolizable
nitrone 23 could be converted to amide 24 (entry 6).
The use of a chiral nitrone was examined to see if the
carbamoyl anion addition could occur in a diastereoselective
manner. The synthesis of chiral nitrone 28 is outlined in
Scheme 4. Thus, O-benzyl R-tert-leucinol 2515 was treated with
benzoyl peroxide to give the O-benzoyl hydroxylamine 26.16
Subsequent exposure to NH4OH caused debenzoylation to
yield hydroxylamine 27.16 Condensation of 27 with 4-
bromobenzaldehyde provided the chiral nitrone 28.
addition of LDA, the reaction mixture became bright red in
color. Since carbamoyllithium formation is not accompanied by
such color changes, we suspected that under the strongly basic
reaction conditions benzylic deprotonation of the nitrone
occurred. A similar competitive benzylic deprotonation of an N-
benzyl nitrone with MeLi was observed by Coates and
Chang.13a In order to prevent this side reaction, N-tert-butyl
nitrone 7, bearing no protons α to the nitrogen, was subjected
to the same conditions.14 In this case, the desired reaction
proceeded smoothly to give amide 8 in 72% isolated yield. The
use of 6 equiv of carbamoyl anion proved necessary to achieve
complete conversion of the nitrone.
The reaction of nitrone 7 with a variety of formamides was
explored (Table 1). In contrast to the N-alkyl imines 4a−c, 7
reacted with both large and small formamides. The reaction
with DMF (entry 2) gave the adduct 9 in 67% yield after
purification by chromatography. Alternatively, 9 could be
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Note
a
Table 2. Scope of Carbamoyl Anion Addition to Various
Nitrones
Table 3. Diastereoselective Carbamoyl Anion Additions
a
a
Typical reaction conditions: 1 equiv nitrone, 6.1 equiv formamide, 6.0
b
c
1
equiv LDA, PhMe, 0 °C. Isolated yield. Determined from H NMR
of crude product. LiTMP used instead of LDA.
d
Scheme 5. Stereochemical Assignment of 31
a
Typical reaction conditions: 1 equiv nitrone, 6.1 equiv formamide, 6.0
b
equiv LDA, PhMe, 0 °C. Isolated yield.
Scheme 4. Chiral Nitrone Synthesis
stereochemistry and are drawn accordingly in Table 3. The
stereochemistry of the reaction is consistent with that observed
for the addition of MeLi to valinol O-alkyl ether derived aryl
nitrones and can be rationalized by a chelation controlled
transition state.13a
The α-(N-hydroxy)amino amide products could be further
elaborated as shown in Scheme 6. The tert-butyl group was
deprotected by heating 11 in MsOH at 60 °C, giving
hydroxylamine 32 in 68% yield. Alternatively, the hydroxyl-
amine moiety could be reduced under mild conditions by
treatment of 11 with carbon disulfide at rt, providing amine 33
in 84% yield.18
In conclusion, the addition of carbamoyl anions to nitrones
has been demonstrated. The use of N-tert-butyl nitrones allows
for the addition of a variety of formamides to aldehyde derived
nitrones. Aryl, heteroaryl, and aliphatic nitrones were amenable
to the addition reaction. The extension of the reaction to a tert-
leucinol derived chiral nitrone was shown to proceed with
diastereoselectivity up to 89:11. Finally, the products could be
derivatized by either tert-butyl deprotection under acidic
conditions or deoxygenation with CS2.
The results of the addition of carbamoyl anions to chiral
formamide 28 are shown in Table 3. For the addition of DMF,
LiTMP was employed as the base, and the product 29 was
formed in a modest diastereomeric ratio of 80:20 (entry 1).
The reactions of the more bulky formamides N,N-diisopro-
pylformamide (entry 2) and N-methyl-N-tert-butylformamide
(entry 3) proceeded with higher selectivity, yielding adducts 30
and 31 in diastereomeric ratios of 88:12 and 89:11,
respectively.17
The stereochemistry of the newly formed chiral center in
adduct 31 was assigned as (S) from single crystal X-ray
structure determination (Scheme 5). By analogy, adducts 29
and 30 are assumed to have been formed with the same
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Note
washed with CH2Cl2, and the filtrate was concentrated to a solid. The
solid was dissolved in a minimal amount of warm CH2Cl2, and the
product was crystallized out by the addition of heptane. The solid was
filtered, rinsed with heptane, and dried under vacuum to afford 4c
(15.9 g, 87%) as a white solid. mp 138−140 °C; 1H NMR (400 MHz,
CDCl3) δ 8.38 (s, 1 H), 8.29 (d, J = 8.4 Hz, 1 H), 7.93−7.91 (m, 1 H),
7.86−7.84 (m, 1 H), 7.81 (d, J = 8.2 Hz, 1 H), 7.71−7.68 (m, 2 H),
7.61−7.51 (m, 5 H), 5.39 (q, J = 6.6 Hz, 1 H), 1.79 (d, J = 6.6 Hz, 3
H); 13C NMR (100 MHz, CDCl3) δ 158.4, 141.0, 135.4, 134.1, 131.8,
130.7, 129.8, 129.1, 127.5, 126.0, 125.8, 125.5, 125.0, 124.1, 123.6,
65.8, 24.6; HRMS: calcd for C19H17BrN [M + H]: 338.0539. Found:
338.0536.
Scheme 6. Deprotection and Deoxygenation of Products
2-(4-Bromophenyl)-N,N-diisopropyl-2-(((S)-1-phenylethyl)-
amino)acetamide (5a). A flask was charged with 4a (0.500 g, 1.74
mmol), N,N-diisopropylformamide (0.780 mL, 5.38 mmol), and
toluene (10 mL). The solution was cooled to −78 °C and treated
dropwise with LDA (2.60 mL, 5.21 mmol, 2.0 M solution in THF/
heptane/ethylbenzene). After the LDA addition, the reaction mixture
was stirred at −78 °C for 10 min and then warmed to 0 °C, at which
point the reaction was quenched with water. The mixture was
extracted with EtOAc, and the organic phase dried (Na2SO4), filtered,
and concentrated. 1H NMR analysis of the crude product mixture
showed a reaction diastereoselectivity of 83:17. The crude product was
purified by chromatography on SiO2 (hexanes/MTBE, 75:25) to
afford the pure major diastereomer of 5a (572 mg, 79%) as a colorless
EXPERIMENTAL SECTION
■
General Information. All starting materials and reagents were
purchased from commercial sources and used as received unless
otherwise noted. Melting points are uncorrected. NMR spectra were
recorded on 400 or 500 MHz instruments. All 1H and 13C NMR data
were referenced to the internal deuterated solvent relative to TMS at 0
ppm. High resolution mass spectroscopy (HRMS) was performed on a
TOF instrument with ESI in positive ionization mode. Flash
chromatography was performed on an automated system with silica
columns. The following nitrones have been described in the literature
with either no characterization data or partial characterization data:
4a,19 6,20 7,21 13,22 15,23 21,24 and 23.25 Melting point ranges, 1H and
13C NMR data and copies of spectra, and HRMS data are provided for
1
oil. H NMR (400 MHz, CDCl3) δ 7.42−7.38 (m, 4 H), 7.36−7.32
(m, 2 H), 7.27−7.24 (m, 1 H), 7.07−7.06 (m, 2 H), 4.11 (s, 1 H), 3.76
(q, J = 6.5 Hz, 1 H), 3.56−3.48 (m, 1 H), 3.36−3.32 (m, 1 H), 2.79
(br, 1 H), 1.53 (d, J = 6.8 Hz, 3 H), 1.43 (d, J = 6.8 Hz, 3 H), 1.35 (d,
J = 6.8 Hz, 3 H), 0.91 (d, J = 6.8 Hz, 3 H), 0.65 (d, J = 6.8 Hz, 3 H);
13C NMR (100 MHz, CDCl3) δ 170.4, 145.3, 139.1, 131.9, 129.4,
these known compounds for completeness.
128.6, 127.3, 127.2, 121.5, 60.6, 57.3, 47.9, 46.3, 25.2, 20.9, 20.5, 20.2,
19.8; HRMS: calcd for C22H30BrN2O [M + H]: 417.1536. Found:
417.1539.
(S)-1-(4-Bromophenyl)-N-(1-phenylethyl)methanimine (4a).
A flask was charged successively with 4-bromobenzaldehyde (10.0 g,
54.0 mmol), MgSO4 (26.0 g, 0.216 mol), CH2Cl2 (100 mL), and (S)-
α-methylbenzylamine (6.88 mL, 54.0 mmol). The resultant slurry was
stirred at rt for 18 h and then filtered through a medium porosity stone
frit filter. The solid was washed with CH2Cl2, and the filtrate was
concentrated to a solid. The solid was dissolved in a minimal amount
of warm CH2Cl2, and the product was crystallized out by the addition
of heptane. The solid was filtered, rinsed with heptane, and dried
under vacuum to afford 4a (8.20 g, 53%) as a white solid. mp 86.5−
88.0 °C; 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1 H), 7.62 (d, J = 8.4
Hz, 2 H), 7.50 (d, J = 8.4 Hz, 2 H), 7.41−7.39 (m, 2 H), 7.34−7.30
(m, 2 H), 7.24−7.20 (m, 1 H), 4.51 (q, J = 6.6 Hz, 1 H), 1.57 (d, J =
6.6 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 158.2, 145.0, 135.4,
131.8, 129.8, 128.6, 127.0, 126.7, 125.0, 69.8, 24.9; HRMS: calcd for
C15H15BrN [M + H]: 288.0382. Found: 288.0379.
(S)-1-(4-Bromophenyl)-N-(1-(4-methoxyphenyl)ethyl)-
methanimine (4b). A flask was charged successively with 4-
bromobenzaldehyde (10.0 g, 54.0 mmol), MgSO4 (26.0 g, 0.216
mol), CH2Cl2 (100 mL), and (S)-1-(4-methoxyphenyl)ethylamine
(8.58 g, 56.8 mmol). The resultant slurry was stirred at rt for 18 h and
then filtered through a medium porosity stone frit filter. The solid was
washed with CH2Cl2, and the filtrate was concentrated to a solid. The
solid was dissolved in the minimal amount of warm CH2Cl2, and the
product was crystallized out by the addition of heptane. The solid was
filtered, rinsed with heptane, and dried under vacuum to afford 4b
(11.1 g, 64%) as a white solid. mp 103−104 °C; 1H NMR (400 MHz,
CDCl3) δ 8.26 (s, 1 H), 7.61 (d, J = 8.4 Hz, 2 H), 7.50 (d, J = 8.4 Hz,
2 H), 7.32 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 4.48 (q, J =
6.6 Hz, 1 H), 3.77 (s, 3 H), 1.55 (d, J = 6.6 Hz, 3 H); 13C NMR (100
MHz, CDCl3) δ 158.6, 157.9, 137.1, 135.4, 131.8, 129.7, 127.7, 124.9,
113.9, 69.2, 55.3, 24.8; HRMS: calcd for C16H17BrNO [M + H]:
318.0488. Found: 318.0490.
2-(4-Bromophenyl)-N,N-diisopropyl-2-(((S)-1-(4-
methoxyphenyl)ethyl)amino)acetamide (5b). A flask was
charged with 4b (1.00 g, 3.14 mmol), N,N-diisopropylformamide
(1.41 mL, 9.74 mmol), and toluene (20 mL). The solution was cooled
to −78 °C and treated dropwise with LDA (4.71 mL, 9.43 mmol, 2.0
M solution in THF/heptane/ethylbenzene). After the LDA addition,
the reaction mixture was stirred at −78 °C for 10 min and then
warmed to 0 °C, at which point the reaction was quenched with water.
The mixture was extracted with EtOAc, and the organic phase dried
1
(Na2SO4), filtered, and concentrated. H NMR analysis of the crude
product mixture showed a reaction diastereoselectivity of 90:10. The
crude product was purified by chromatography on SiO2 (hexanes/
MTBE, 75:25) to afford the pure major diastereomer of 5b (1.18 g,
84%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.42−7.38 (m,
2 H), 7.31−7.27 (m, 2 H), 7.06−7.04 (m, 2 H), 6.91−6.87 (m, 2 H),
4.11 (s, 1 H), 3.82 (s, 3 H), 3.71 (q, J = 6.4 Hz, 1 H), 3.59−3.49 (m, 1
H), 3.39−3.28 (m, 1 H), 2.76 (br, 1 H), 1.53 (d, J = 6.8 Hz, 3 H), 1.43
(d, J = 6.8 Hz, 3 H), 1.33 (d, J = 6.8 Hz, 3 H), 0.95 (d, J = 6.8 Hz, 3
H), 0.65 (d, J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 170.4,
158.8, 139.2, 137.3, 131.9, 129.4, 128.3, 121.5, 113.9, 60.5, 56.6, 55.3,
47.9, 46.3, 25.2, 20.9, 20.6, 20.2, 19.8; HRMS: calcd for C23H32BrN2O2
[M + H]: 447.1642. Found: 447.1646.
2-(4-Bromophenyl)-N,N-diisopropyl-2-(((S)-1-(naphthalen-1-
yl)ethyl)amino)acetamide (5c). A flask was charged with 4c (1.00 g,
2.96 mmol), N,N-diisopropylformamide (1.33 mL, 9.16 mmol), and
toluene (20 mL). The solution was cooled to −78 °C and treated
dropwise with LDA (4.43 mL, 8.87 mmol, 2.0 M solution in THF/
heptane/ethylbenzene). After the LDA addition, the reaction mixture
was stirred at −78 °C for 10 min and then warmed to 0 °C, at which
point the reaction was quenched with water. The mixture was
extracted with EtOAc, and the organic phase dried (Na2SO4), filtered,
and concentrated. 1H NMR analysis of the crude product mixture
showed a reaction diastereoselectivity of 77:23. The crude product was
purified by chromatography on SiO2 (hexanes/MTBE, 75:25) to
afford the pure major diastereomer of 5c (967 mg, 70%) as a waxy
solid. 1H NMR (400 MHz, CDCl3) δ 8.32 (br, 1 H), 7.88−7.76 (m, 3
(S)-1-(4-Bromophenyl)-N-(1-(naphthalen-1-yl)ethyl)-
methanimine (4c). A flask was charged successively with 4-
bromobenzaldehyde (10.0 g, 54.0 mmol), MgSO4 (26.0 g, 0.216
mol), CH2Cl2 (100 mL), and (S)-1-(1-naphthyl)ethylamine (9.25 g,
54.0 mmol). The resultant slurry was stirred at rt for 18 h and then
filtered through a medium porosity stone frit filter. The solid was
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H), 7.52−7.40 (m, 5 H), 7.08−7.06 (m, 2 H), 4.66 (q, J = 6.4 Hz, 1
H), 4.11 (s, 1 H), 3.38−3.23 (m, 2 H), 2.87 (br, 1 H), 1.54 (d, J = 6.7
Hz, 3 H), 1.51 (d, J = 6.7 Hz, 3 H), 1.43 (d, J = 6.7 Hz, 3 H), 0.54 (d, J
= 6.7 Hz, 3 H), 0.50 (d, J = 6.7 Hz, 3 H); 13C NMR (100 MHz,
CDCl3) δ 170.5, 140.6, 139.1, 134.0, 131.9, 131.7, 129.4, 128.9, 127.5,
125.8, 125.7, 124.6, 123.4, 121.5, 60.8, 53.0, 47.8, 46.2, 24.3, 20.8, 20.2,
20.0, 19.7; HRMS: calcd for C26H32BrN2O [M + H]: 467.1693.
Found: 467.1689.
(Z)-N-Benzyl-1-(4-bromophenyl)methanimine oxide (6). A
flask was charged with benzyl hydroxylamine (2.95 g, 18.5 mmol, 1.0
equiv), 4-bromobenzaldehyde (3.42 g, 18.5 mmol, 1.0 equiv), sodium
carbonate (1.96 g, 18.5 mmol, 1.0 equiv), and DCM (40 mL), and the
mixture was stirred overnight at room temperature. The reaction
mixture was diluted with DCM, filtered through a thin layer of silica
gel, and concentrated in vacuo to give 6 (3.95 g, 82%) as a white solid.
mp 129−130 °C; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.6 Hz,
2H), 7.51 (d, J = 8.6 Hz, 2H), 7.49−7.37 (m, 5H), 7.35 (s, 1H), 5.04
(s, 2H); 13C NMR (100 MHz, CDCl3) δ 133.1, 133.0, 131.7, 129.9,
129.3, 129.1 (2), 129.0, 124.3, 71.4; HRMS: calcd for C14H13BrNO
[M + H]: 290.0175. Found: 290.0160.
stirred for 20 min at −78 °C. The reaction mixture was quenched with
water, extracted with ethyl acetate, dried over Na2SO4, filtered, and
concentrated in vacuo. A solution of oxalic acid dihydrate (0.260 g,
2.05 mmol, 1.5 equiv) in methanol (5 mL) was added to the
concentrate. The solution was diluted with MTBE (30 mL) and
filtered to give the oxalic acid salt of 9 (490 mg, 79%) as light brown
1
solid. mp 158−161 °C; H NMR (400 MHz, D2O) δ 7.63 (d, J = 8.5
Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 5.62 (s, 1H), 2.89 (s, 3H), 2.86 (s,
3H), 1.34 (s, 9H); 13C NMR (100 MHz, D2O) 166.6, 132.7, 131.0,
127.0, 124.9, 71.1, 67.0, 36.7, 36.2, 23.5; HRMS: calcd for
C14H22BrN2O2 [M + H − HO2CCO2H]: 329.0860. Found: 329.0851.
2-(4-Bromophenyl)-2-(tert-butyl(hydroxy)amino)-N,N-dime-
thylethanethioamide (10). A flask was charged with nitrone 7
(0.500 g, 1.95 mmol, 1.0 equiv), N,N-dimethylthioformamide (1.01
mL, 11.9 mmol, 6.1 equiv), and toluene (5 mL), and the solution was
cooled to −78 °C and treated dropwise with LDA (11.7 mL, 11.7
mmol, 1.0 M, 6.0 equiv). The reaction mixture was stirred for 20 min
at −78 °C. The reaction was quenched with water, extracted with ethyl
acetate, dried over Na2SO4, filtered, and concentrated in vacuo. The
crude product was purified by flash chromatography (MTBE/hexanes)
to give 10 (400 mg, 59%) as a yellow oil. 1H NMR (400 MHz,
CDCl3) δ 7.51 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 7.42 (br s,
1H), 5.33 (s, 1H), 3.44 (s, 3H), 3.30 (s, 3H), 1.13 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 203.7, 135.7, 131.9, 131.2, 122.2, 68.4, 60.2,
45.1, 42.2, 27.4; HRMS: calcd for C14H20BrN2S [M + H − H2O]:
327.0525. Found: 327.0513.
(Z)-1-(4-Bromophenyl)-N-(tert-butyl)methanimine oxide (7).
A flask was charged with tert-butylhydroxylamine acetate (2.00 g, 13.4
mmol, 1.0 equiv), 4-bromobenzaldehyde (2.48 g, 13.4 mmol, 1.0
equiv), sodium carbonate (1.42 g, 13.4 mmol, 1.0 equiv), and DCM
(20 mL), and the mixture was stirred overnight at room temperature.
The reaction mixture was diluted with DCM, filtered through a pad of
Celite, and concentrated in vacuo. The crude material was purified by
column chromatography (hexanes/MTBE) to give 7 (2.54 g, 74%) as
a white solid. mp 62−64 °C; 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J
= 8.6 Hz, 2H), 7.55−7.50 (m, 3H), 1.61 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 131.6, 130.1, 129.9, 128.8, 123.7, 71.2, 28.3; HRMS:
calcd for C11H15BrNO [M + H]: 256.0332. Found: 256.0320.
2-(4-Bromophenyl)-2-(tert-butyl(hydroxy)amino)-N,N-diiso-
propylacetamide (8). A flask was charged with nitrone 7 (0.400 g,
1.56 mmol, 1.0 equiv), N,N-diisopropylformamide (1.38 mL, 9.53
mmol, 6.1 equiv), and toluene (4 mL), and the solution was cooled to
0 °C and treated dropwise with LDA (4.68 mL, 9.37 mmol, 2.0 M, 6.0
equiv). The reaction mixture was stirred for 20 min at 0 °C. The
reaction was quenched with water, extracted with ethyl acetate, dried
over Na2SO4, filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography (MTBE/hexanes) to give 8 (430
2-(4-Bromophenyl)-2-(tert-butyl(hydroxy)amino)-1-morpho-
linoethan-1-one (11). A flask was charged with nitrone 7 (0.500 g,
1.95 mmol, 1.0 equiv), 4-formylmorpholine (1.19 mL, 11.9 mmol, 6.1
equiv), and toluene (5 mL), and the solution was cooled to −78 °C
and treated dropwise with LDA (5.85 mL, 11.7 mmol, 2.0 M, 6.0
equiv). The reaction mixture was stirred for 20 min at −78 °C. The
reaction was quenched with water, extracted with ethyl acetate, dried
over Na2SO4, filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography (MTBE/hexanes) to give 11
1
(500 mg, 70%) as a white solid. mp 123−124 °C; H NMR (400
MHz, CDCl3) δ 7.80 (s, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4
Hz, 2H), 4.88 (s, 1H), 3.82−3.65 (m, 2H), 3.63−3.41 (m, 4H), 3.35−
3.20 (m, 2H), 1.50 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.5,
135.8, 131.7, 130.9, 122.3, 66.6, 66.2, 60.7, 59.9, 46.1, 42.0, 27.0;
HRMS: calcd for C16H24BrN2O3 [M + H]: 371.0965. Found:
371.0944.
1
mg, 72%) as a white solid. mp 113−115 °C; H NMR (400 MHz,
2-(4-Bromophenyl)-2-(tert-butyl(hydroxy)amino)-N-methyl-
N-phenylacetamide (12). A flask was charged with nitrone 7 (0.300
g, 1.17 mmol, 1.0 equiv), N-methyl formanilide (0.880 mL, 7.14 mmol,
6.1 equiv), and toluene (5 mL), and the solution was cooled to 0 °C
and treated dropwise with LDA (3.51 mL, 7.02 mmol, 2.0 M, 6.0
equiv). The reaction mixture was stirred for 20 min at 0 °C. The
reaction was quenched with water, extracted with ethyl acetate, dried
over Na2SO4, filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography (MTBE/hexanes) to give 12
(350 mg, 76%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.57
(s, 1H), 7.43−7.32 (m, 5H), 7.11 (d, J = 8.4 Hz, 2H), 6.99 (br s, 2H),
4.55 (s, 1H), 3.25 (s, 3H), 1.00 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 173.5, 142.5, 136.7, 131.3, 131.1, 129.8, 128.6, 127.4, 122.0, 61.9,
59.9, 37.4, 26.6; HRMS: calcd for C19H24BrN2O2 [M + H]: 391.1016.
Found: 391.0997.
(Z)-N-tert-Butyl-1-(o-tolyl)methanimine oxide (13). A flask
was charged with tert-butyl-hydroxylamine acetate (2.00 g, 13.4 mmol,
1.0 equiv), o-tolualdehyde (1.55 mL, 13.4 mmol, 1.0 equiv), sodium
carbonate (1.42 g, 13.4 mmol, 1.0 equiv), and DCM (20 mL), and the
mixture was stirred overnight at room temperature. The reaction
mixture was diluted with DCM, filtered through a pad of Celite, and
concentrated in vacuo. The crude material was purified by column
chromatography to give 13 (1.95 g, 76%) as a white solid. mp 68−69
°C; 1H NMR (400 MHz, CDCl3) δ 9.18−9.13 (m, 1H), 7.73 (s, 1H),
7.29−7.25 (m, 2H), 7.22−7.17 (m, 1H), 2.39 (s, 3H), 1.63 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 136.4, 130.1, 129.8, 129.3, 127.9,
CDCl3) δ 9.07 (s, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz,
2H), 4.76 (s, 1H), 3.86−3.70 (m, 1H), 3.44−3.29 (m, 1H), 1.46 (d, J
= 6.8 Hz, 3H), 1.43 (d, J = 6.8 Hz, 3H), 1.24−1.18 (m, 12H), 0.79 (d,
J = 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.1, 136.9, 131.6,
130.8, 121.8, 59.8, 59.7, 48.9, 46.3, 27.4, 20.8, 20.4, 20.0, 19.9; HRMS:
calcd for C18H30BrN2O2 [M + H]: 385.1485. Found: 385.1470.
2-(4-Bromophenyl)-2-(tert-butyl(hydroxy)amino)-N,N-dime-
thylacetamide (9). A flask was charged with nitrone 7 (0.300 g, 1.17
mmol, 1.0 equiv), N,N-dimethylformamide (0.550 mL, 7.14 mmol, 6.1
equiv), and toluene (3 mL), and the solution was cooled to 0 °C and
treated dropwise with a solution of lithium 2,2,6,6-tetramethylpiper-
idide in THF (12.9 mL, 7.03 mmol, 0.54 M in THF, 6.0 equiv). The
reaction mixture was stirred for 20 min at 0 °C. The reaction was
quenched with water, extracted with ethyl acetate, dried over Na2SO4,
filtered, and concentrated in vacuo. The crude product was purified by
flash chromatography (MTBE/hexanes) to give 9 (260 mg, 67%) as a
white solid. mp 158−160 °C; 1H NMR (400 MHz, CDCl3) δ 8.24 (s,
1H), 7.47 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 4.88 (s, 1H),
2.97 (s, 3H), 2.94 (s, 3H), 1.16 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 174.5, 135.8, 131.7, 130.9, 122.1, 60.1, 59.7, 37.2, 35.7, 27.0; HRMS:
calcd for C14H22BrN2O2 [M + H]: 329.0860. Found: 329.0845.
2-(4-Bromophenyl)-2-(tert-butyl(hydroxy)amino)-N,N-dime-
thylacetamide Oxalic Acid Salt (9·HO2CCO2H). A flask was
charged with nitrone 7 (0.350 g, 1.37 mmol, 1.0 equiv), N,N-
dimethylformamide (0.650 mL, 8.34 mmol, 6.1 equiv), and toluene
(3.5 mL), and the solution was cooled to −78 °C and treated dropwise
with a solution of lithium 2,2,6,6-tetramethylpiperidide in THF (14.5
mL, 7.82 mmol, 0.54 M in THF, 6.0 equiv). The reaction mixture was
126.6, 126.3, 71.2, 28.4, 19.9; HRMS: calcd for C12H18NO [M + H]:
192.1383. Found: 192.1376.
5899
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Note
2-(tert-Butyl(hydroxy)amino)-N,N-diethyl-2-(o-tolyl)-
acetamide (14). A flask was charged with nitrone 13 (0.500 g, 2.61
mmol, 1.0 equiv), N,N-diethylformamide (1.79 mL, 15.95 mmol, 6.1
equiv), and toluene (5 mL), and the solution was cooled to −78 °C
and treated dropwise with LDA (7.84 mL, 15.68 mmol, 2.0 M, 6.0
equiv). The reaction mixture was stirred for 20 min at −78 °C. The
reaction was quenched with water, extracted with ethyl acetate, dried
over Na2SO4, filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography (MTBE/hexanes) to give 14
3.35 (m, 2H), 3.26−3.17 (m, 1H), 3.15−3.05 (m, 1H), 1.55−1.45 (m,
3H), 1.34−1.22 (m, 5H), 1.14 (s, 9H), 0.93−0.86 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 173.6, 157.8, 148.8, 136.3, 124.5, 122.7, 64.2,
59.7, 47.6, 45.9, 30.9, 29.3, 26.8, 20.2, 20.1, 13.8; HRMS: calcd for
C19H34N3O2 [M + H]: 336.2646. Found: 336.2634.
(Z)-N-tert-Butyl-1-(9-ethyl-9H-carbazol-3-yl)methanimine
Oxide (19). A flask was charged with tert-butylhydroxylamine acetate
(2.00 g, 13.4 mmol, 1.0 equiv), 9-ethyl-3-carbazole carboxaldehyde
(2.99 g, 13.4 mmol, 1.0 equiv), sodium carbonate (1.42 g, 13.4 mmol,
1.0 equiv), and DCM (20 mL), and the mixture was stirred overnight
at room temperature. The reaction mixture was diluted with DCM,
filtered through a pad of Celite, and concentrated in vacuo. The crude
material was purified by column chromatography to give 19 (1.01 g,
1
(670 mg, 88%) as a white solid. mp 110−112 °C; H NMR (400
MHz, CDCl3) δ 9.20 (s, 1H), 7.42 (d, J = 7.0 Hz, 1H), 7.22−7.12 (m,
3H), 4.96 (s, 1H), 3.47−3.36 (m, 1H), 3.36−3.25 (m, 1H), 3.11−3.00
(m, 1H), 3.00−2.89 (m, 1H) 2.44 (s, 3H), 1.27 (s, 9H), 1.23 (t, J = 7.1
Hz, 3H), 1.03 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
175.3, 136.3, 134.8, 131.1, 129.2, 128.1, 126.1, 60.6, 56.4, 41.8, 40.2,
27.3, 19.8, 14.0, 12.4; HRMS: calcd for C17H29N2O2 [M + H]:
293.2224. Found: 293.2211.
1
26%) as an off-white solid. mp 123−125 °C; H NMR (400 MHz,
CDCl3) δ 9.59 (d, J = 1.5 Hz, 1H), 8.16 (d, J = 7.8 Hz, 1H), 8.05 (dd,
J = 1.7, 8.7 Hz, 1H), 7.70 (s, 1H), 7.51−7.45 (m, 1H), 7.43−7.39 (m,
2H), 7.28−7.23 (m, 1H), 4.37 (q, J = 7.2 Hz, 2H), 1.67 (s, 9H), 1.45
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 140.9, 140.4,
130.8, 127.8, 126.0, 123.4, 122.9, 122.3, 121.5, 121.0, 119.6, 108.7,
108.1, 69.9, 37.7, 28.4, 13.9; HRMS: calcd for C19H23N2O [M + H]:
295.1805. Found: 295.1790.
(Z)-N-tert-Butyl-1-(4-methoxyphenyl)methanimine Oxide
(15). A flask was charged with tert-butyl-hydroxylamine acetate (2.00
g, 13.4 mmol, 1.0 equiv), 4-methoxybenzaldehyde (1.62 mL, 13.4
mmol, 1.0 equiv), sodium carbonate (1.42 g, 13.4 mmol, 1.0 equiv),
and DCM (20 mL), and the mixture was stirred overnight at room
temperature. The reaction mixture was diluted with DCM, filtered
through a pad of Celite, and concentrated in vacuo. The crude material
was purified by column chromatography (MTBE/hexanes) to give 15
2-(tert-Butyl(hydroxy)amino)-2-(9-ethyl-9H-carbazol-3-yl)-
N,N-diisopropylacetamide (20). A flask was charged with nitrone
19 (0.300 g, 1.02 mmol, 1.0 equiv), N,N-diisopropylformamide (0.900
mL, 6.22 mmol, 6.1 equiv), and toluene (3 mL), and the solution was
cooled to −78 °C and treated dropwise with LDA (0.310 mL, 6.11
mmol, 2.0 M, 6.0 equiv). The reaction mixture was stirred for 20 min
at −78 °C. The reaction was quenched with water, extracted with ethyl
acetate, dried over Na2SO4, filtered, and concentrated in vacuo. The
crude product was purified by flash chromatography (MTBE/hexanes)
to give 20 (260 mg, 60%) as a white solid. mp 165−167 °C; 1H NMR
(500 MHz, CDCl3) δ 9.20 (s, 1H), 8.11 (s, 1H), 8.07 (d, J = 7.8 Hz,
1H) 7.55 (d, J = 8.4 Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.9
Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 5.00 (s, 1H), 4.35 (q, J = 7.2 Hz,
2H), 4.01−3.90 (m, 1H), 3.39−3.29 (m, 1H), 1.50 (t, J = 7.1 Hz, 6H),
1.40 (t, J = 7.2 Hz, 3H), 1.27 (s, 9H), 1.20 (d, J = 6.5 Hz, 3H), 0.63 (d,
J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 175.1, 140.2, 139.6,
127.9, 127.0, 125.5, 123.0 (2), 121.1, 120.5, 118.7, 108.5, 108.4, 60.9,
59.6, 48.8, 46.2, 37.6, 27.5, 20.9, 20.6, 19.9, 19.8, 13.8; HRMS: calcd
for C26H38N3O2 [M + H]: 424.2959. Found: 424.2940.
1
(2.44 g, 88%) as a white solid. mp 94−96 °C; H NMR (400 MHz,
CDCl3) δ 8.28 (d, J = 8.8 Hz, 2H), 7.47 (s, 1H), 6.93 (d, J = 8.8 Hz,
2H), 3.85 (s, 3H), 1.61 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
160.9, 130.8, 129.6, 124.0, 113.8, 70.1, 55.3, 28.3; HRMS: calcd for
C12H18NO2 [M + H]: 208.1332. Found: 208.1324.
N-(tert-Butyl)-2-(tert-butyl(hydroxy)amino)-2-(4-methoxy-
phenyl)-N-methylacetamide (16). A flask was charged with nitrone
15 (0.500 g, 2.41 mmol, 1.0 equiv), N-methyl-N-tert-butylformamide
(1.69 g, 14.7 mmol, 6.1 equiv), and toluene (5 mL), and the solution
was cooled to 0 °C and treated dropwise with LDA (7.23 mL, 14.5
mmol, 2.0 M, 6.0 equiv). The reaction mixture was stirred for 20 min
at 0 °C. The reaction was quenched with water, extracted with ethyl
acetate, dried over Na2SO4, filtered, and concentrated in vacuo. The
crude product was purified by flash chromatography (MTBE/hexanes)
1
to give 16 (560 mg, 72%) as a white solid. mp 96−97 °C; H NMR
(400 MHz, CDCl3) δ 8.91 (s, 1H), 7.34 (d, J = 8.5 Hz, 2H), 6.87 (d, J
= 8.5 Hz, 2H), 4.74 (s, 1H), 3.79 (s, 3H), 2.76 (s, 3H), 1.43 (s, 9H),
1.20 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 176.8, 159.2, 130.3,
129.4, 114.0, 61.2, 59.5, 57.6, 55.3, 31.5, 28.0, 27.4; HRMS: calcd for
C18H31N2O3 [M + H]: 323.2329. Found: 323.2312.
(Z)-N-(tert-Butyl)-2,2-dimethylpropan-1-imine Oxide (21). A
flask was charged with tert-butylhydroxylamine acetate (2.00 g, 13.4
mmol, 1.0 equiv), trimethylacetaldehyde (1.45 mL, 13.4 mmol, 1.0
equiv), sodium carbonate (1.42 g, 13.4 mmol, 1.0 equiv), and DCM
(20 mL), and the mixture was stirred overnight at room temperature.
The reaction mixture was diluted with DCM, filtered through a pad of
Celite, and concentrated in vacuo. The crude material was purified by
column chromatography to give 21 (1.84 g, 87%) as a white solid. mp
80−82 °C; 1H NMR (400 MHz, CDCl3) δ 6.57 (s,1H), 1.47 (s, 9H),
1.26 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 139.7, 69.7, 32.6, 28.3,
26.2; HRMS: calcd for C9H20NO [M + H]: 158.1539. Found:
158.1543.
(Z)-N-tert-Butyl-1-(pyridin-2-yl)methanimine Oxide (17). A
flask was charged with tert-butylhydroxylamine acetate (2.00 g, 13.4
mmol, 1.0 equiv), 2-pyridinecarboxaldehyde (1.27 mL, 13.4 mmol, 1.0
equiv), sodium carbonate (1.42 g, 13.4 mmol, 1.0 equiv), and DCM
(20 mL), and the mixture was stirred overnight at room temperature.
The reaction mixture was diluted with DCM, filtered through a pad of
Celite, and concentrated in vacuo. The crude material was purified by
1
column chromatography to give 17 (1.70 g, 71%) as a red oil. H
2-(tert-Butyl(hydroxy)amino)-3,3-dimethyl-1-(pyrrolidin-1-
yl)butan-1-one (22). A flask was charged with nitrone 21 (0.500 g,
3.18 mmol, 1.0 equiv), 1-formylpyrrolidine (1.85 mL, 19.4 mmol, 6.1
equiv), and toluene (5 mL), and the solution was cooled to −78 °C
and treated dropwise with LDA (9.50 mL, 19.1 mmol, 2.0 M, 6.0
equiv). The reaction mixture was stirred for 20 min at −78 °C. The
reaction was quenched with water, extracted with ethyl acetate, dried
over Na2SO4, filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography (MTBE/hexanes) to give 22
NMR (400 MHz, CDCl3) δ 9.22 (d, J = 8.1 Hz, 1H), 8.65−8.61 (m,
1H), 7.92 (s, 1H), 7.79 (td, J = 1.5, 7.7 Hz, 1H), 7.30−7.26 (m, 1H),
1.64 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 150.1, 149.4, 137.0,
131.6, 124.1, 123.7, 71.7, 28.3; HRMS: calcd for C10H15N2O [M + H]:
179.1179. Found: 179.1169.
N,N-Dibutyl-2-(tert-butyl(hydroxy)amino)-2-(pyridin-2-yl)-
acetamide (18). A flask was charged with nitrone 17 (0.270 g, 1.51
mmol, 1.0 equiv), N,N-dibutylformamide (1.68 mL, 9.24 mmol, 6.1
equiv), and toluene (2.7 mL), and the solution was cooled to −78 °C
and treated dropwise with LDA (4.54 mL, 9.09 mmol, 2.0 M, 6.0
equiv). The reaction mixture was stirred for 20 min at −78 °C. The
reaction was quenched with water, extracted with ethyl acetate, dried
over Na2SO4, filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography (MTBE/hexanes) to give 18
1
(460 mg, 56%) as a white solid. mp 135−136 °C; H NMR (400
MHz, CDCl3) δ 8.51 (s, 1H), 3.57−3.44 (m, 4H), 3.34 (s, 1H), 2.01−
1.85 (m, 4H), 1.11 (s, 9H), 1.09 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 174.4, 63.4, 59.5, 47.5, 45.8, 36.0, 28.3, 26.6, 26.2, 23.9;
HRMS: calcd for C14H29N2O2 [M + H]: 257.2224. Found: 257.2220.
(Z)-N-tert-Butyl-1-cyclohexylmethanimine Oxide (23). A flask
was charged with tert-butylhydroxylamine acetate (3.0 g, 20.1 mmol,
1.0 equiv), cyclohexane carboxaldehyde (2.43 mL, 20.1 mmol, 1.0
equiv), sodium carbonate (2.13 g, 20.1 mmol, 1.0 equiv), and DCM
1
(240 mg, 53%) as a colorless oil. H NMR (400 MHz, CDCl3) δ
8.55−8.50 (m, 1H), 8.40 (s, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.66 (td, J
= 1.8, 7.6 Hz, 1H), 7.19 (ddd, J = 1.2, 4.9 Hz, 1H), 5.16 (s, 1H), 3.44−
5900
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The Journal of Organic Chemistry
Note
(30 mL), and the mixture was stirred overnight at room temperature.
The reaction mixture was diluted with DCM, filtered through a pad of
Celite, and concentrated in vacuo. The crude material was purified by
column chromatography to give 23 (2.08 g, 57%) as a white solid. mp
MHz, CDCl3) δ 138.1, 134.4, 131.6, 129.9, 129.5, 128.4, 127.7, 127.6,
123.7, 84.7, 73.6, 67.1, 33.3, 27.4; HRMS: calcd for C20H25BrNO2 [M
+ H]: 390.1063. Found: 390.1043.
(S)-2-(((R)-1-(Benzyloxy)-3,3-dimethylbutan-2-yl)(hydroxy)-
amino)-2-(4-bromo-phenyl)-N,N-dimethylacetamide (29). A
flask was charged with nitrone 28 (0.270 g, 0.690 mmol, 1.0 equiv),
N,N-dimethylformamide (0.330 mL, 4.22 mmol, 6.1 equiv), and
toluene (2.7 mL), and the solution was cooled to 0 °C and treated
dropwise with lithium 2,2,6,6-tetramethylpiperidide (6.10 mL, 4.15
mmol, 0.68 M, 6.0 equiv). The reaction mixture was stirred for 20 min
at 0 °C. The reaction was quenched with water, extracted with ethyl
1
60−61 °C; H NMR (400 MHz, CDCl3) δ 6.61 (d, J = 7.2 Hz, 1H),
3.05−2.93 (m, 1H), 1.92−1.85 (m, 2H), 1.75−1.64 (m, 3H), 1.48 (s,
9H), 1.43−1.33 (m, 2H), 1.30−1.21 (m, 1H), 1.19−1.08 (m, 2H); 13
C
NMR (100 MHz, CDCl3) δ 138.2, 68.8, 35.2, 28.9, 28.0, 26.0, 25.4;
HRMS: calcd for C11H22NO [M + H]: 184.1696. Found: 184.1696.
2-(tert-Butyl(hydroxy)amino)-2-cyclohexyl-N,N-diisopropy-
lacetamide (24). A flask was charged with nitrone (0.500 g, 2.73
mmol, 1.0 equiv), N,N-diisopropylformamide (2.42 mL, 16.6 mmol,
6.1 equiv), and toluene (5 mL), and the solution was cooled to −78
°C and treated dropwise with LDA (8.19 mL, 16.4 mmol, 2.0 M, 6.0
equiv). The reaction mixture was stirred for 20 min at −78 °C. The
reaction was quenched with water, extracted with ethyl acetate, dried
over Na2SO4, filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography (MTBE/hexanes) to give the
1
acetate, dried over Na2SO4, filtered, and concentrated in vacuo. H
NMR analysis of the crude product showed a reaction diastereose-
lectivity of 80:20. The crude product was purified by flash
chromatography (MTBE/hexanes) to give the major diastereomer of
1
29 (180 mg, 56%) as a colorless oil. H NMR (400 MHz, CDCl3) δ
7.45−7.27 (m, 9H), 5.95 (s, 1H), 5.41 (s, 1H), 4.52 (s, 2H), 4.28 (dd,
J = 8.0, 10.0 Hz, 1H), 3.57 (dd, J = 2.4, 9.9 Hz, 1H), 2.84 (s, 3H), 2.75
(s, 3H), 2.38 (dd, J = 2.4, 7.9 Hz, 1H), 0.84 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 171.3, 138.8, 134.7, 131.4, 128.4, 127.8, 127.7, 122.2,
73.3, 69.2, 66.7 (2), 36.7, 36.1, 34.2, 28.3; HRMS: calcd for
C23H32BrN2O3 [M + H]: 463.1591. Found: 463.1550.
1
pure product (520 mg, 61%) as a white solid. mp 111−112.5 °C; H
NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 4.12−4.02 (m, 1H), 3.46 (d,
J = 9.3 Hz, 1H), 3.43−3.34 (m, 1H), 2.38 (d, J = 13.1 Hz, 1H), 2.18−
2.06 (m, 1H), 1.77−1.57 (m, 4H), 1.43 (d, J = 3.8 Hz, 3H), 1.41 (d, J
= 3.8 Hz, 3H), 1.37−1.23 (m, 8H), 1.21−1.12 (m, 1H), 1.11 (s, 9H),
1.00−0.84 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 177.0, 60.1, 58.5,
48.9, 46.5, 39.3, 31.3, 30.5, 26.8, 26.7, 26.6, 26.3, 20.9, 20.8, 20.3, 19.7;
HRMS: calcd for C18H37N2O2 [M + H]: 313.2850. Found: 313.2860.
(R)-O-Benzoyl-N-(1-(benzyloxy)-3,3-dimethylbutan-2-yl)-
hydroxylamine (26). O-Benzyl R-tert-leucinol (10.0 g, 48.3 mmol,
1.0 equiv) was added to a flask containing a mixed buffer solution (235
mL) of sodium bicarbonate (0.75 M) and sodium hydroxide (1.5 M).
A solution of benzoyl peroxide (23.4 g, 96.5 mmol, 2.0 equiv) in water
(220 mL) and DCM (60 mL) was then added, and the mixture was
stirred 18 h at room temperature. The reaction mixture was extracted
with DCM, and the organic layer was washed with brine and dried
over Na2SO4. The crude product was concentrated in vacuo and
purified by column chromatography with hexanes/MTBE to give 26
(S)-2-(((R)-1-(Benzyloxy)-3,3-dimethylbutan-2-yl)(hydroxy)-
amino)-2-(4-bromo-phenyl)-N,N-diisopropylacetamide (30). A
flask was charged with nitrone (0.400 g, 1.02 mmol, 1.0 equiv), N,N-
diisopropylformamide (0.910 mL, 6.25 mmol, 6.1 equiv), and toluene
(4 mL), and the solution was cooled to 0 °C and treated dropwise
with LDA (3.07 mL, 6.15 mmol, 2.0 M, 6.0 equiv). The reaction
mixture was stirred for 20 min at 0 °C. The reaction was quenched
with water, extracted with ethyl acetate, dried over Na2SO4, filtered,
1
and concentrated in vacuo. H NMR analysis of the crude product
showed a reaction diastereoselectivity of 88:12. The crude product was
purified by flash chromatography (MTBE/hexanes) to give the major
1
diastereomer of 30 (390 mg, 73%) as a colorless oil. H NMR (400
MHz, CDCl3) δ 7.45−7.31 (m, 7H), 7.23 (d, J 7.97 Hz, 2H), 6.09 (s,
1H), 5.36 (s, 1H), 4.53 (dd, J = 11.4, 15.6 Hz, 2H), 4.31 (t, J = 9.3 Hz,
1H), 4.02−3.91 (m, 1H), 3.57 (d, J = 9.8 Hz, 1H), 3.26−3.16 (m,
1H), 2.36 (d, J = 7.7 Hz, 1H), 1.42 (d, J = 6.6 Hz, 3H), 1.24 (d, J = 6.8
Hz, 3H), 1.08 (d, J = 6.5 Hz, 3H), 0.82 (s, 9H), 0.48 (d, J = 6.5 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 169.8, 138.9, 135.4, 131.9,
131.4, 128.4, 127.8, 127.6, 121.9, 73.3, 70.4, 66.9, 66.0, 47.5, 46.1, 34.2,
28.3, 20.7, 20.5, 19.8, 19.5; HRMS: calcd for C27H40BrN2O3 [M + H]:
519.2217. Found: 519.2205.
1
(7.09 g, 45%) as a light yellow oil. H NMR (400 MHz, CDCl3) δ
7.99−7.95 (m, 2H), 7.58−7.53 (m, 1H), 7.46−7.41 (m, 2H), 7.34−
7.27 (m, 4H), 7.25−7.21 (m, 1H), 4.51 (dd, J = 12.0, 21.2 Hz, 2H),
3.67 (dd, J = 3.6, 10.0 Hz, 1H), 3.54 (dd, J = 8.1, 10.0 Hz, 1H), 3.01
(dd, J = 3.6, 8.1 Hz, 1H), 1.07 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 166.3, 137.9, 133.1, 129.3, 128.8, 128.5, 128.4, 127.7, 127.6, 73.3,
69.1, 66.9, 33.4, 27.7; HRMS: calcd for C20H26NO3 [M + H]:
328.1907. Found: 328.1884.
(R)-N-(1-(Benzyloxy)-3,3-dimethylbutan-2-yl)hydroxylamine
(27). A flask was charged with 26 (10.0 g, 48.3 mmol, 1.0 equiv) and
methanol (7 mL). Ammonium hydroxide solution (28−30%, 5 mL)
was added dropwise, and the solution was stirred for 18 h at room
temperature. The reaction mixture was concentrated in vacuo, and the
residue was dissolved in ethyl acetate, washed with brine, and dried
over Na2SO4. The solution was concentrated in vacuo and purified by
column chromatography to give 27 (1.03 g, 32%) as a colorless oil. 1H
NMR (500 MHz, CDCl3) δ 7.36−7.27 (m, 5H), 5.63 (br s, 1H), 4.55
(dd, J = 12.0, 15.8 Hz, 2H), 3.73 (dd, J = 3.6, 9.8 Hz, 1H), 3.59 (dd, J
= 7.6, 9.7 Hz, 1H), 2.79 (dd, J = 3.7, 7.6 Hz, 1H), 0.97 (s, 9H); 13C
NMR (125 MHz, CDCl3) δ 138.1, 128.4, 127.7, 127.6, 73.4, 69.6, 68.2,
33.0, 27.7; HRMS: calcd for C13H20NO2 [M − H2 + H]: 222.1489.
Found: 222.1470.
(R,Z)-N-(1-(Benzyloxy)-3,3-dimethylbutan-2-yl)-1-(4-
bromophenyl)methanimine oxide (28). A flask was charged with
27 (2.15 g, 9.63 mmol, 1.0 equiv), 4-bromobenzaldehyde (1.78 g, 9.63
mmol, 1.0 equiv), MgSO4 (5.0 g), and DCM (21.5 mL), and the
mixture was stirred for 18 h at room temperature. The reaction
mixture was diluted with DCM, filtered through a pad of Celite, and
concentrated in vacuo. The crude material was purified by column
chromatography to give 28 (3.10 g, 83%) as a white solid. mp 82−84
°C; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.6 Hz, 2H), 7.54 (d, J
= 8.6 Hz, 2H), 7.34 (s, 1H), 7.30−7.27 (m, 1H), 7.25−7.21 (m, 3H),
4.58 (d, J = 11.9 Hz, 1H), 4.48 (d, J = 11.9 Hz, 1H), 4.26 (t, J = 10.0
Hz, 1H), 3.74 (dd, J = 2.3, 10.0 Hz, 2H), 1.08 (s, 9H); 13C NMR (100
(S)-2-(((R)-1-(Benzyloxy)-3,3-dimethylbutan-2-yl)(hydroxy)-
amino)-2-(4-bromophenyl)-N-(tert-butyl)-N-methylacetamide
(31). A flask was charged with nitrone 28 (0.400 g, 1.02 mmol, 1.0
equiv), N-methyl-N-tert-butylformamide (0.720 g, 6.25 mmol, 6.1
equiv), and toluene (4 mL), and the solution was cooled to 0 °C and
treated dropwise with LDA (3.07 mL, 6.15 mmol, 2.0 M, 6.0 equiv).
The reaction mixture was stirred for 20 min at 0 °C. The reaction was
quenched with water, extracted with ethyl acetate, dried over Na2SO4,
1
filtered, and concentrated in vacuo. H NMR analysis of the crude
product showed a reaction diastereoselectivity of 89:11. The crude
product was purified by flash chromatography (MTBE/hexanes) to
give the major diastereomer of 31 (380 mg, 72%) as an off-white solid.
mp 104−106 °C; 1H NMR (400 MHz, CDCl3) δ 7.44−7.29 (m, 8H),
7.26−7.24 (m, 1H), 5.89 (s, 1H), 5.35 (s, 1H), 4.53 (dd, J = 11.5, 20.7
Hz, 2H), 4.29 (dd, J = 7.9, 10.0 Hz, 1H), 3.57 (dd, J = 2.6, 10.0 Hz,
1H), 2.64 (s, 3H), 2.35 (dd, J = 2.6, 7.8 Hz, 1H), 1.32 (s, 9H), 0.82 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 171.6, 138.8, 134.9, 132.0,
131.3, 128.4, 127.8, 127.6, 122.0, 73.3, 71.4, 66.8, 66.2, 57.4, 34.2, 31.0,
28.2, 28.0; HRMS: calcd for C26H38BrN2O3 [M + H]: 505.2060.
Found: 505.2030.
2-(4-Bromophenyl)-2-(hydroxyamino)-1-morpholinoethan-
1-one (32). A flask was charged with (N-hydroxy)amino amide 11
(100 mg, 0.280 mmol) and methanesulfonic acid (2 mL), and the
solution was stirred at 60 °C for 5 h. The reaction mixture was cooled
to room temperature and then diluted with DCM. The solution was
washed with saturated aqueous Na2CO3, and the organic layer was
dried over Na2SO4, filtered, and concentrated in vacuo. Purification by
5901
dx.doi.org/10.1021/jo500848a | J. Org. Chem. 2014, 79, 5895−5902

The Journal of Organic Chemistry
Note
flash chromatography (MTBE/hexanes) gave 32 (60.0 mg, 68%) as a
light brown film. H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.4 Hz,
2H), 7.21 (d, J = 8.4 Hz, 2H), 6.03 (br s, 1 H), 4.86 (s, 1H), 3.86−
3.69 (m, 2H), 3.64−3.52 (m, 3H), 3.42−3.33 (m, 1H), 3.26−3.13 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 169.1, 132.7, 132.5, 130.1,
123.3, 66.7, 66.6, 66.1, 45.5, 42.6; HRMS: calcd for C12H16BrN2O3 [M
+ H]: 315.0339. Found: 315.0320.
(14) For other organometallic additions to tert-butyl nitrones:
(a) Drockenmuller, E.; Catala, J.-M. Tetrahedron Lett. 2001, 42, 9011.
(b) Pyne, S. G.; Hajipour, A. R. Tetrahedron 1992, 48, 9385.
(c) Annunziata, R.; Cinquini, M. Synthesis 1982, 929.
(15) Tang, T. P.; Volkman, S. K.; Ellman, J. A. J. Org. Chem. 2001, 66,
8772.
(16) (a) Smithen, D. A.; Mathews, C. J.; Tomkinson, N. C. O. Org.
Biomol. Chem. 2012, 10, 3756. (b) Biloski, A. J.; Ganem, B. Synthesis
1983, 537.
(17) For the removal of a related valinol ether auxiliary, see: Negoro,
N.; Yanada, R.; Okaniwa, M.; Yanada, K.; Fujita, T. Synlett 1998, 835.
(18) Schwartz, M. A.; Gu, J.; Hu, X. Tetrahedron Lett. 1992, 33, 1687.
(19) Mostowicz, D.; Belzecki, C. J. Org. Chem. 1977, 42, 3917.
(20) Yang, Y.-S.; Shen, Z.-L.; Loh, T.-P. Org. Lett. 2009, 11, 1209.
(21) Boyd, D. R.; Campbell, R. M.; Coulter, P. B.; Grimshaw, J.;
Neill, D. C.; Jennings, W. B. J. Chem. Soc., Perkin Trans. 1 1985, 849.
(22) Hinton, R. D.; Janzen, E. G. J. Org. Chem. 1992, 57, 2646.
(23) Huie, R.; Cherry, W. R. J. Org. Chem. 1985, 50, 1531.
(24) Aurich, H. G.; Franzke, M.; Kesselheim, H. P.; Rohr, M.
Tetrahedron 1992, 48, 669.
1
2-(4-Bromophenyl)-2-(tert-butylamino)-1-morpholinoethan-
1-one (33). A flask was charged with (N-hydroxy)amino amide 11
(0.180 g, 0.470 mmol) and carbon disulfide (3 mL), and the solution
was stirred at room temperature overnight. The reaction mixture was
concentrated in vacuo, and the residue was purified by flash
chromatography (MTBE/hexanes) to give 33 (140 mg, 84%) as a
1
waxy solid. H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.4 Hz, 2H),
7.14 (d, J = 8.4 Hz, 2H), 4.48 (s, 1H), 3.81−3.62 (m, 2H), 3.62−3.52
(m, 4H), 3.52−3.41 (m, 1H), 3.40−3.29 (m, 1H), 3.29−3.19 (m, 1H),
1.10 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.2, 140.2, 132.2,
129.0, 121.5, 66.7, 66.2, 56.2, 51.2, 45.8, 42.8, 29.6; HRMS: calcd for
C16H24BrN2O2 [M + H]: 355.1016. Found: 355.0997.
ASSOCIATED CONTENT
(25) Cummins, C. H.; Coates, R. M. J. Org. Chem. 1983, 48, 2070.
■
S
* Supporting Information
1H and 13C NMR spectra, thermal ellipsoid plot, and CIF data
for 31. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jonathan.reeves@boehringer-ingelheim.com.
■
Present Address
†(C.L. and K.C.) Department of Chemistry, University of
Connecticut, Storrs, CT 06269.
Notes
The authors declare no competing financial interest.
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dx.doi.org/10.1021/jo500848a | J. Org. Chem. 2014, 79, 5895−5902