Highly regioselective nitrile oxide dipolar cycloadditions with ortho-nitrophenyl alkynes

Article abstract of DOI:10.1039/c2ob26267c

The dipolar cycloadditions of ortho-nitrophenyl alkynes with aryl nitrile oxides has been demonstrated. A range of substituents are tolerated on the alkyne. These reactions proceed with excellent levels of regioselectivity. Subsequent functionalization of the isoxazole scaffold has been demonstrated.

Full text of DOI:10.1039/c2ob26267c

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PAPER
Highly regioselective nitrile oxide dipolar cycloadditions with
ortho-nitrophenyl alkynes†
Melissa L. McIntosh,a Michael R. Naffziger,a Bradley O. Ashburn,a Lev N. Zakharovb and Rich G. Carter*a
Received 4th July 2012, Accepted 4th October 2012
DOI: 10.1039/c2ob26267c
The dipolar cycloadditions of ortho-nitrophenyl alkynes with aryl nitrile oxides has been demonstrated.
A range of substituents are tolerated on the alkyne. These reactions proceed with excellent levels of
regioselectivity. Subsequent functionalization of the isoxazole scaffold has been demonstrated.
Isoxazoles serve as a valuable class of heterocyclic structures
found in natural products and medicinally relevant compounds.
Pinho e Melo has written a recent detailed review of the syn-
thesis and reactivity of isoxazoles.1 This functional group is
generally constructed via two major methods – condensation of
hydroxylamine with a 1,3-dicarbonyl compound and cyclo-
addition of an alkyne with a nitrile oxide.2 The cycloaddition
strategy is of particular interest to our laboratory.3,4
the use of an alkynyliodide in the cycloaddition reaction with
nitrile oxides to provide 3,4,5-trisubstituted isoxazoles.10 In most
cases, dimerization pathways of the nitrile oxides could be
avoided by in situ formation of the nitrile oxides.5,8,9
Our laboratory has demonstrated the powerful and under-
exploited directing ability of ortho-nitrophenyl-substituted
alkynes to access densely functionalized biaryls through a net
[4 + 2] cycloaddition/cycloreversion process of substituted
2-halo-6-nitrophenyl acetylenes (e.g. 1) with cyclic dienes (e.g.
2) as shown in Scheme 1 (eqn (1)).3 These transformations
proved highly regioselective – routinely giving the biaryl 4 as
the single regioisomer. Recently, we began to extend the scope
of these reactions to include [3 + 2] cycloadditions. Earlier this
year, we published a full account of the thermal, dipolar cyclo-
addition of ortho-nitrophenyl alkynes (e.g. 1) with a series of
azides with up to 11 : 1 regiomeric ratio (rr) (Scheme 1,
eqn (2)).4 Unlike what was observed in the [4 + 2] series, we
found that the regioselectivity of this reaction was highly
A variety of regioselective syntheses of isoxazoles using
[3 + 2] cycloadditions have been reported. Fokin and co-
workers5 used a copper(I) catalyst to access 3,5-disubsubstituted
isoxazoles regioselectively. Although a computational study
suggested that the 3,5-regioisomer was strongly favoured
(100 : 1) under thermal, uncatalyzed conditions,6 Fokin observed
a mixture of regioisomers in the absence of catalyst. Grecian and
Fokin7 optimized a ruthenium-catalyzed reaction to access the
3,5-disubstituted, 3,4-disubstituted and 3,4,5-trisubstituted isoxa-
zoles. The regioselectivity was controlled by the complexation
of the different dipoles to the ruthenium catalysts. Access to
3,4,5-trisubstituted isoxazoles could also be accomplished
through a cycloaddition of an alkynyldimethylsilyl ether with an
aryl or alkyl nitrile oxide.8 This method uses the inherent bias of
the dipole and dipolarophile to control regioselectivity. There are
limited examples of the cycloaddition process employing
haloalkynes to access 3,4,5-trisubstituted isoxazoles. Ohlmeyer
and co-workers accessed 5-aryl-4-bromo-3-carboxyisoxazoles
through a cycloaddition of aryl alkynes with alkyl and THP
ether nitrile oxides in modest yields.9 A separate study employed
aDepartment of Chemistry, Oregon State University, 153 Gilbert Hall,
Corvallis, Oregon 97331, USA. E-mail: rich.carter@oregonstate.edu;
Fax: +1 541-737-2062; Tel: +1 541-737-9486
bDirector of the X-ray Crystallographic Facility of the Departments of
Chemistry at Oregon State University and the University of Oregon,
USA. E-mail: lev@uoregon.edu
†Electronic supplementary information (ESI) available: Copies of 1H
and 13C NMR spectra, for all new compounds and X-ray data for 13b,
13d (Fig. 1), 13g and 13h are provided. CCDC reference numbers
880837–880840, 904545. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c2ob26267c
Scheme 1 Prior work in [4 + 2] and [3 + 2] cycloadditions with ortho-
nitrophenyl alkynes.
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Table 1 Exploration of scope in nitrile oxide/alkyne dipolar
cycloaddition
Entry
R1
R2
R3
% Yielda
a
b
c
d
e
f
g
h
i
Cl
Cl
Cl
Cl
Cl
H
Me
H
Me
Me
H
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
88
87
83
68
70
69
73
90
92
74
Me
CO2Me
Br
Cl
Cl
Cl
H
H
Me
j
a Regioselectivity in each case was >20 : 1 as determined by crude 1H
NMR.
Scheme 2 Initial exploration of nitrile oxide dipolar cycloadditions.
Fig. 2 ORTEP representations of compound 13d (Note: only one posi-
tion for disordered nitro moiety and chloro group are shown for clarity).
Fig. 1 ORTEP representation of isolated dimer 11.
Presence of nitrile oxide dimer 11 (Fig. 1) was confirmed by
X-ray crystallographic analysis. We have previously observed a
related reduction in reactivity for alkyl substituted alkynes (e.g.
1b) in dipolar cycloadditions with benzyl azides.4 Attempts to
minimize this unwanted side reaction through the use of slow
addition techniques proved ineffective. The reduced reactivity
imparted by the addition of a methyl group on the alkyne likely
increases the transition state energy for the [3 + 2] dipolar cyclo-
addition sufficiently so that the dimerization pathway is more
energetically favourable.
In order to minimize the dimerization pathway, a more steri-
cally hindered nitrile oxide was selected. 2,4,6-Trimethyl deriva-
tive 1214 has been shown to minimize dimerization pathways
with nitrile oxides (Table 1).13 We screened this nitrile oxide pre-
cursor with our parent alkyne 1a (entry a) and again observed
excellent chemical yield and regioselectivity for the isoxazole
product 13a (88% yield, sole regioisomer). Fortunately, the pre-
viously problematic alkynyl methyl isomer 1b proved equally
effective with 87% yield of the desired isoxazole 13b. Similar
high levels of regioselectivity and chemical yield were observed
for a series of both mono- and di-substituted alkynes3 (entries
c–j). We were particularly pleased to see once again that halo-
genated alkynes (entries d–g) all proved highly effective in the
dependent on the nature of the second substitution on the alkyne
(R2) – giving low selectivity with hydrogen, alkyl or ester substi-
tution but high selectivity with halogens (R2 = Cl, Br). In parallel
with the experimental work on these azide dipolar cycloadditions,
we computationally explored these transformations – including a
detailed analysis of the dipolarophile.4 In this Article, we extend
this exploration of dipolar cycloadditions to include nitrile oxides
as a highly regioselective method to access densely functionalized
isoxazoles. As observed in the [4 + 2] series, we are aware of only
a single study utilizing ortho-nitrophenyl alkynes in [3 + 2]
cycloadditions to access isoxazoles.11
We first selected 2-chloro-6-nitrophenyl acetylene (1a) and the
oximyl acid chloride 812 to screen for both reactivity and selec-
tivity in the cycloaddition process (Scheme 2). To our delight,
we found that clean conversion to the desired isoxazole occurred
in high yield (82%) and as a single regioisomer. Unfortunately,
when a more challenging substrate such as the di-substituted
alkyne 1b4 was employed in this transformation, less than 10%
of impure desired product 10b was produced (tentatively ident-
ified by mass spectroscopy). We attributed this divergence in
reactivity to competitive dimerization of the nitrile oxide.13
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Scheme 4 Derivatization of isoxazoles.
Scheme 3 Important effect of the ortho-nitro acetylene and variation
of the nitrile oxide.
restricted rotation around the mesityl group on the NMR time
scale. The ortho-chloride moiety could be cross coupled using
PEPPSI-IPr16 under our previously reported boroxine coupling
conditions3g to provide the biaryls 24 and 25.
cycloaddition process. Assignment of the regiochemistry of the
reactions was confirmed by X-ray crystallographic analysis of
compounds 13b, 13d (Fig. 2), 13g and 13h. The high level of
regioselectivity observed in Table 1 is in stark contrast to the
azide series in which the R2 substituent had a dramatic impact
on the regioselective outcome of the transformation.4
In summary, we have demonstrated a highly regioselective
method for the construction of densely functionalized isoxazoles
through the use of dipolar cycloaddition with ortho-nitrophenyl
alkynes and in situ generated nitrile oxides. Avariety of substitu-
ents on the alkyne is tolerated. The importance of the ortho-nitro
moiety on the alkyne and the R group on the nitrile oxide was
demonstrated. The subsequent derivatization of the isoxazoles
has been demonstrated. Additional applications of the cyclo-
addition strategy for the construction of sterically congested lin-
kages will be reported in due course.
It is important to note the critical role that substituents play in
the success of these dipolar cycloadditions (Scheme 3). For
example, the ortho-nitro moiety provides a key activating role in
the cycloaddition – leading to improved yields as compared to
the des-nitro alkynes 14a and 14b which provided the products
15a and 15b in 76% and 27% yield respectively. In both cases,
these yields were lower than the corresponding nitro series (90%
for 13h and 74% for 13j) which clearly demonstrated the elec-
tronic benefits of the nitro moiety to override the steric penalty
for its presence. Variation of the dipole component also led to a
divergence in chemical yields. Cycloaddition of nitrile oxide pre-
cursor 16a with alkyne 1a provided a much lower yield (17a,
29%) than the less sterically hindered variant 16b with alkyne
1a (17b, 75%). The cycloaddition using nitrile oxide precursor
16c with 1a provided a 39% yield of the desired product 17c.
These yields are all lower than the parent mesityl series 13a
(88%, see Table 1).
Experimental section
Oxime 27
Scheme 4 illustrates that it is possible to derivatize both the
halogen and the ester moieties in the isoxazole scaffold. Sapo-
nification4 of the methyl ester 13c under optimized conditions
provided the acid 18. This acid could be easily converted15 to
the corresponding acid chloride 19 using PCl5 in high yield.
Subsequent coupling with benzyl amine or (+)-α-methyl benzyl
amine cleanly generated the desired amide bond. Interesting,
careful analysis of the 1H NMR spectra of amide 23 reveals dou-
bling of both the ortho-methyl moieties and the meta-aryl
protons on the mesityl ring, which indicates that there is
To a stirred solution of ice (46 g) in H2O–ethanol (40 mL, 1 : 1)
was added mesitylaldehyde 26 (6.0 g, 6.0 mL, 40.7 mmol),
hydroxylamine hydrochloride (4.2 g, 61.0 mmol) and NaOH
(17 mL, 100 mmol, 6.0 M in H2O). After 2 h, the reaction was
quenched with 1 M HCl (50 mL), extracted with Et2O (3 ×
30 mL), and washed with brine (30 mL). The dried (MgSO4)
extract was concentrated in vacuo and purified by recrystalliza-
tion with Et2O and Hexanes to give known oxime 2714 (6.05 g,
1
37.1 mmol, 91%) as a white solid. H NMR (400 MHz, CDCl3)
δ 8.44 (s, 1H), 6.91 (s, 2H), 2.39 (s, 6H), 2.30 (s, 3H) ppm.
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Oximyl acid chloride 12
(400 MHz, CDCl3) δ 8.46 (bs, 1H), 2.50 (t, J = 7.3 Hz, 2H),
1.70 (sextet, J = 7.4 Hz, 6H), 0.98 (t, J = 7.3, 3H) ppm.
Oximyl acid chloride 16c
To a stirred solution of oxime 27 (3.0 g, 18.4 mmol) in DMF
(18.5 mL) at 0 °C, was added 4 portions of NCS (0.75 g × 4,
20 min apart). Upon warming to rt over 4 h, the reaction was
quenched with H2O/ice (50 mL), extracted with Et2O (4 ×
25 mL), and washed with brine (2 × 10 mL). The dried
(Na2SO4) extract was concentrated in vacuo to give known 1214
(3.6 g, 18.4 mmol, 99%) as a white semi-solid. 1H NMR
(400 MHz, CDCl3) δ 6.92 (s, 2H), 2.27 (s, 9H) ppm.
To a stirred solution of ice (15 g) in H2O–ethanol (14 mL, 1 : 1)
was added aldehyde 32 (1.8 g, 1.8 mL, 14 mmol), hydroxyl-
amine hydrochloride (1.5 g, 21 mmol) and NaOH (5.8 mL,
35 mmol, 6.0 M in H2O). After 4.5 h, the reaction was quenched
with 1 M HCl (12 mL), extracted with Et2O (3 × 20 mL), and
washed with brine (50 mL). The dried (MgSO4) extract was con-
centrated in vacuo to give crude oxime 33 as a yellow solid
which was used without further purification. To a stirred solution
of oxime 33 (2.06 g, 14 mmol) in DMF (14 mL) at 0 °C, was
added 4 portions of NCS (0.49 g × 4, 20 min apart). After 11 h
at rt, the reaction was diluted with H2O (50 mL), extracted with
Et2O (2 × 40 mL), and washed with H2O (3 × 60 mL). The
dried (Na2SO4) extract was concentrated in vacuo to give known
16c17 (2.49 g, 13.7 mmol, 98%) as a yellow solid. 1H NMR
(400 MHz, CDCl3) δ 8.07 (bs, 1H), 7.51 (d, J = 7.6 Hz, 2H),
7.48–7.31 (overlapping m, 4H), 6.88 (d, J = 15.6, 1H) ppm.
Oximyl acid chloride 16a
To a stirred solution of ice (15 g) in H2O–ethanol (14 mL, 1 : 1)
was added aldehyde 28 (1.0 g, 1.3 mL, 14 mmol), hydroxyl-
amine hydrochloride (1.5 g, 21 mmol) and NaOH (5.8 mL,
35 mmol, 6.0 M in H2O). After 21 h, the reaction was quenched
with 1 M HCl (10 mL), extracted with DCM (3 × 25 mL), and
washed with brine (50 mL). The dried (MgSO4) extract was con-
centrated in vacuo to give crude oxime 29 as a yellow liquid
which was used without further purification. To a stirred solution
of oxime 29 (1.2 g, 14 mmol) in DMF (14 mL) at 0 °C, was
added 4 portions of NCS (0.49 g × 4, 20 min apart). After 18 h
at rt, the reaction was diluted with H2O (20 mL), extracted with
Et2O (3 × 20 mL), and washed with brine (1 × 50 mL). The
dried (Na2SO4) extract was concentrated in vacuo to give known
16a17 (1.63 g, 13.4 mmol, 96%) as a pale yellow liquid.
1H NMR (400 MHz, CDCl3) δ 8.51 (bs, 1H), 2.82 (septet, J =
6.8 Hz, 1H), 1.23 (d, J = 6.8 Hz, 6H) ppm.
Isoxazole 10a
Oximyl acid chloride 16b
To a pressure vessel containing 1a3c (63.2 mg, 348 μmol) was
added dry PhMe (600 μL), NEt3 (109 mg, 150 μL, 1.08 mmol)
and 82,12 (208.5 mg, 1.123 mmol) sequentially, and heated to
80 °C. Immediately after addition of 8, a white solid formed
along with a mild exotherm. After 1 h, the reaction was cooled
to rt, filtered, concentrated in vacuo, and purified via flash
chromatography over silica gel, eluting with 10–25% EtOAc/
hexanes to give 10a (101.4 mg, 306.6 μmol, 82%) as a yellow
solid. Mp 82–84 °C; IR (neat) 3087, 2839, 1612, 1534, 1434,
1255, 1029, 809, 738 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.97
(d, J = 8.2 Hz, 1H), 7.82 (m, 3H), 7.64 (t, J = 8.2 Hz, 1H), 7.02
(m, 2H), 6.82 (s, 1H), 3.89 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ 162.3, 162.2, 161.2, 150.4, 136.2, 134.3, 131.6, 128.4,
123.0, 122.2, 121.0, 114.4, 104.0, 55.4 ppm; HRMS (ES+)
calcd for C16H12N2O4Cl (M + H) 331.0486, found 331.0476.
To a stirred solution of ice (15 g) in H2O–ethanol (14 mL, 1 : 1)
was added aldehyde 30 (1.0 g, 1.3 mL, 14 mmol), hydroxyl-
amine hydrochloride (1.5 g, 21 mmol) and NaOH (5.8 mL,
35 mmol, 6.0 M in H2O). After 2.5 h, the reaction was quenched
with 2 M HCl (10 mL), extracted with Et2O (3 × 20 mL), and
washed with brine (50 mL). The dried (MgSO4) extract was con-
centrated in vacuo to give crude oxime 31 as a colorless liquid
which was used without further purification. To a stirred solution
of oxime 31 (1.2 g, 14 mmol) in DMF (14 mL) at 0 °C, was
added 4 portions of NCS (0.49 g × 4, 20 min apart). After
18.5 h at rt, the reaction was diluted with H2O (20 mL), extracted
with Et2O (3 × 20 mL), and washed with brine (1 × 50 mL). The
dried (Na2SO4) extract was concentrated in vacuo to give known
1
16b18 (1.7 g, 14 mmol, 99%) as a colorless liquid. H NMR
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Dimer 11
over 5 h. After 10 h, the crude mixture was cooled to rt, filtered,
concentrated in vacuo, and purified via flash chromatography
over silica gel, eluting with 5–15% EtOAc/hexanes to give
impure 13b as a yellow oil. The impure oil was triturated and
recrystallized from hexanes/methanol to give pure 13b (65.6 mg,
184 μmol, 87%) as a pale yellow solid. Mp 151–153 °C; IR
(thin film) 1609, 1535, 1456, 1437, 1348, 901, 852, 808, 759,
1
735 cm−1; H NMR (400 MHz, CDCl3) δ 8.08 (dd, J = 8.2,
To a stirred solution of 1b4 (19.4 mg, 99 μmol) and 82,12
(184 mg, 990 μmol) in PhMe (500 μL) at 80 °C was added NEt3
(800 μL, 1.19 mmol, 1.50 M in PhMe) via syringe pump over
5 h. After 14 h, the crude mixture was cooled to rt, filtered, con-
centrated in vacuo, and purified via flash chromatography over
silica gel, eluting with 0–50% EtOAc/hexanes to give undesired
dimer 11 (64.6 mg, 216 μmol, 22%) as a yellow solid. Mp
105–107 °C; IR (neat) 2938, 2840, 1611, 1591, 1574, 1520,
1.2 Hz, 1H), 7.85 (dd, J = 8.1, 1.2 Hz, 1H), 7.68 (t, J = 8.2 Hz,
1H), 7.00 (s, 2H), 2.37 (s, 3H), 2.18 (s, 6H), 1.75 (s, 3H) ppm;
13C NMR (100 MHz, CDCl3) δ 163.4, 159.0, 150.3, 139.0,
137.5, 137.0, 134.5, 131.8, 128.3, 124.8, 123.3, 122.8, 114.8,
21.2, 19.7, 7.1 ppm; HRMS (EI+) calcd for C19H17N2O3Cl
(M+) 356.0928, found 356.0926.
1450, 1258, 1179, 835 cm−1 1H NMR (300 MHz, CDCl3)
;
Isoxazole 13c
δ 7.49 (m, 4H), 6.97 (m, 4H), m, 3H), 3.88 (s, 3H), 3.87 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3) δ 161.6, 161.1, 155.9,
130.2, 129.8, 199.0, 114.9, 114.5, 55.4 ppm; HRMS (EI+) calcd
for C16H14N2O4 (M+) 298.0953, found 298.0952.
Isoxazole 13a
To a stirred solution of 1c3c (50 mg, 208 μmol) and 1214
(411 mg, 2.08 mmol) in PhMe (1.5 mL) at 80 °C, was added
NEt3 (1.7 mL, 2.55 mmol, 1.5 M in PhMe) via syringe pump
over 5 h. After 14 h, the crude mixture was cooled to rt, filtered,
concentrated in vacuo, and purified via flash chromatography
over silica gel, eluting with 10–20% EtOAc/hexanes to give
impure 13c as a yellow solid. Repurification via trituration with
hexanes gave impure 13c as a pale yellow solid. Repurification
via flash chromatography over silica gel, eluting 20–40%
EtOAc/hexanes gave impure 13c. Repurification via trituration
with hexanes and EtOAc gave 13c (69.5 mg, 173 μmol, 83%) as
a white solid. Mp 177–178 °C; IR (neat) 1730, 1534, 1456,
To a stirred solution of 1a3c (63.8 mg, 351 μmol) and NEt3
(500 μL, 363 mg, 3.59 mmol) in PhMe (700 μL) at 80 °C was
added 1214 (15.4 mL, 3.846 mmol, 250 mM in PhMe) via
syringe pump over 5 h. After 10 h, the crude mixture was cooled
to rt, filtered, concentrated in vacuo, and purified via flash
chromatography over silica gel, eluting with 2–8% EtOAc/
hexanes gave pure 13a (105.9 mg, 309.0 μmol, 88%) as a yellow
oil. IR (thin film) 1750, 1613, 1536, 1464, 1439, 1382, 1353,
1400, 1348, 1310, 1120 cm−1 1H NMR (400 MHz, CDCl3)
;
δ 8.25 (dd, J = 0.8, 8.3 Hz, 1H), 7.89 (dd, J = 0.8, 8.1 Hz, 1H),
7.75 (t, J = 8.2 Hz, 1H), 6.98 (s, 2H), 3.51 (s, 3H), 2.37 (s, 3H),
2.81 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 168.2, 162.0,
160.7, 149.2, 139.1, 136.6, 134.9, 132.2, 128.1, 124.2, 123.4,
123.0, 111.9, 51.9, 21.3, 19.9 ppm; HRMS (EI+) calcd for
C20H17N2O5Cl (M+) 400.0826, found 400.0838.
906, 882, 808, 757, 737 cm−1 1H NMR (300 MHz, CDCl3)
;
δ 8.02 (dd, J = 8.2, 1.2 Hz, 1H), 7.83 (dd, J = 8.2, 1.2 Hz, 1H),
7.65 (t, J = 8.2 Hz, 1H), 7.00 (s, 2H), 6.49 (s, 1H), 2.36 (s, 3H),
2.25 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 162.3, 162.2,
150.2, 139.1, 137.3, 136.3, 134.4, 131.7, 128.4, 125.5, 123.1,
122.4, 107.6, 21.8, 20.2 ppm; HRMS (EI+) calcd for
C18H15N2O3Cl (M+) 342.0771, found 342.0759.).
Isoxazole 13d
Isoxazole 13b
To a stirred solution of 1d4 (42.8 mg, 164 μmol) and 1214
(353.8 mg, 1.790 mmol) in PhMe (1.00 mL) at 80 °C was added
NEt3 (1.43 mL, 2.15 mmol, 1.5 M in PhMe) via syringe pump
over 5 h. After 10 h, the crude mixture was cooled to rt, filtered,
concentrated in vacuo, and purified via flash chromatography
over silica gel, eluting with 2–10% EtOAc/hexanes to give
To a stirred solution of 1b4 (41.4 mg, 212 μmol) and 1214
(446.3 mg, 2.258 mmol) in PhMe (1.00 mL) at 80 °C was added
NEt3 (1.72 mL, 2.58 mmol, 1.50 M in PhMe) via syringe pump
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impure 13d as a yellow solid. The impure solid was recrystal-
lized from methanol to give pure 13d (46.8 mg, 111 μmol, 68%)
(s, 3H), 2.21 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3)
δ 161.7, 161.5, 148.2, 139.8, 137.8, 133.4, 131.8, 131.6, 128.4,
125.3, 122.7, 121.0, 109.6, 21.3, 19.8 ppm; HRMS (EI+) calcd
for C18H15N2O3Cl (M+) 342.0771, found 342.0772.
as a light brown oil. IR (thin film) 1527, 1356, 1116 cm−1
;
1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.2 Hz, 1H),
7.90 (d, J = 8.2 Hz, 1H), 7.74 (t, J = 8.2 Hz, 1H), 7.02 (s, 2H),
2.38 (s, 3H), 2.23 (s, 3H), 2.20 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3) δ 162.9, 161.7, 149.6, 139.8, 138.0, 137.3,
135.0, 132.6, 128.4, 128.3, 123.6, 121.4, 97.3, 21.3, 19.7 ppm;
HRMS (EI+) calcd for C18H14N2O3ClBr (M+) 419.9876, found
419.9880.
Isoxazole 13g
Isoxazole 13e
To a stirred solution of 1g4 (240.9 mg, 1.231 mmol) and 1214
(2.369 g, 11.98 mmol) in PhMe (6.10 mL) at 80 °C was added
NEt3 (10.1 mL, 15.1 mmol, 1.50 M in PhMe) via syringe pump
over 5 h. After 10 h, the crude mixture was cooled to rt, filtered,
concentrated in vacuo, and purified via flash chromatography
over silica gel, eluting with 10–30% EtOAc/hexanes to give
impure 13g as a yellow solid. The impure solid was recrystal-
lized from methanol to give pure 13g (346.8 mg, 977.5 μmol,
73%) as a yellow solid. Mp 178–180 °C; IR (thin film) 1538,
1455, 1384, 1339, 912, 880, 854, 803, 748, 735 cm−1; 1H NMR
(300 MHz, CDCl3) δ 8.11 (dd, J = 7.4, 2.0 Hz, 1H), 7.70 (d, J =
5.7 Hz, 1H), 7.66 (t, J = 7.2 Hz, 1H), 7.02 (s, 2H), 2.39 (s, 3H),
2.38 (s, 3H), 2.23 (s, 6H) ppm; 13C NMR (75 MHz, CDCl3)
δ 161.7, 161.4, 149.0, 141.5, 139.8, 135.5, 131.5, 128.4, 122.8,
122.8, 120.4, 110.0, 21.3, 19.7, 19.5 ppm; HRMS (EI+) calcd
for C19H17N2O3Cl (M+) 356.0928, found 356.0913.
To a stirred solution of 1e4 (41.1 mg, 190 μmol) and 1214
(386.8 mg, 1.957 mmol) in PhMe (1.00 mL) at 80 °C was added
NEt3 (1.67 mL, 2.51 mmol, 1.5 M in PhMe) via syringe pump
over 5 h. After 10 h, the crude mixture was cooled to rt, filtered,
concentrated in vacuo, and purified via flash chromatography
over silica gel, eluting with 10–30% EtOAc/hexanes to give
impure 13e as a yellow solid. The impure solid was recrystallized
from methanol to give pure 13e (50.2 mg, 133 μmol, 70%) as a
light brown oil. IR (thin film) 1528, 1353 cm−1 1H NMR
;
(400 MHz, CDCl3) δ 8.21 (dd, J = 8.2, 1.2 Hz, 1H), 7.90
(dd, J = 8.2, 1.2 Hz, 1H), 7.74 (t, J = 8.2 Hz, 1H), 7.02 (s, 2H),
2.38 (s, 3H), 2.23 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3)
δ 161.5, 159.4, 149.7, 139.8, 137.9, 137.4, 134.9, 132.6,
128.4, 123.6, 122.6, 120.9 111.2, 21.2, 19.7 ppm; HRMS
(EI+) calcd for C18H14N2O3Cl2 (M+) 376.0382, found
376.0400.
Isoxazole 13h
Isoxazole 13f
To a stirred solution of 1h (50 mg, 340 μmol) and 1214
(672 mg, 3.40 mmol) in PhMe (1.5 mL) at 80 °C, was added
NEt3 (2.7 mL, 4.05 mmol, 1.5 M in PhMe) via syringe pump
over 5 h. After 11.5 h, the crude mixture was cooled to rt,
filtered, concentrated in vacuo, and purified via flash chromato-
graphy over silica gel, eluting with 10% EtOAc/hexanes to give
impure 13h as a yellow solid. Repurification via flash chromato-
graphy over silica gel, eluting 20% EtOAc/hexanes gave impure
13h. Repurification via trituration with hexanes gave 13h
(94.4 mg, 0.306 mmol, 90%) as a white solid. Mp 122–123 °C;
To a stirred solution of 1f4 (50 mg, 276 μmol) and 1214
(545 mg, 2.76 mmol) in PhMe (1.5 mL) at 80 °C, was added
NEt3 (2.2 mL, 3.30 mmol, 1.5 M in PhMe) via syringe pump
over 5 h. After 16.5 h, the crude mixture was cooled to rt,
filtered, concentrated in vacuo, and purified via flash chromato-
graphy over silica gel, eluting with 5–10% EtOAc/hexanes to
give impure C as a yellow oil. Purification via flash chromato-
graphy over silica gel, eluting 10% EtOAc/hexanes gave impure
13f as a yellow oil. Repurification via flash chromatography over
silica gel, eluting 20% Et2O/pentane gave 13f (66 mg,
0.193 mmol, 69%) as a beige solid. Mp 89–92 °C; IR (neat)
1
IR (neat) 1534, 1353 cm−1; H NMR (400 MHz, CDCl3) δ 7.93
(td, J = 1.2, 8.1 Hz, 2H), 7.75 (td, J = 1.2, 7.6 Hz, 1H), 7.66 (td,
J = 1.3, 7.7 Hz, 1H), 6.98 (s, 2H), 6.46 (s, 1H), 2.35 (s, 3H),
2.12 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 164.6, 162.7,
148.2, 139.1, 137.3, 132.6, 131.0, 130.4, 128.4, 125.5, 124.4,
121.8, 105.4, 21.2, 20.3 ppm; HRMS (EI+) calcd for
C18H16N2O3 (M+) 308.1161, found 308.1162.
1534, 1351, 1129, 852 cm−1 1H NMR (400 MHz, CDCl3)
;
δ 8.20 (d, J = 8.0 Hz, 1H), 7.76–7.86 (m, 3H), 7.01 (s, 2H), 2.37
This journal is © The Royal Society of Chemistry 2012
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Isoxazole 13i
Isoxazole 15a
To a stirred solution of 14a (46.4 mg, 50 μL, 455 μmol) and
1214 (900 mg, 4.55 mmol) in PhMe (3.0 mL) at 80 °C was
added NEt3 (3.6 mL, 5.46 mmol, 1.5 M in PhMe) via syringe
pump over 5 h. After 20 h, the crude mixture was cooled to rt,
filtered, concentrated in vacuo, and purified via flash chromato-
graphy over silica gel, eluting with 0–10% EtOAc/hexanes to
give impure 15a as a yellow solid. The impure solid was recrys-
tallized from EtOAc/hexanes to give known 15a10 (89.4 mg,
To a stirred solution of 1i4 (47.2 mg, 293 μmol) and 1214
(519.9 mg, 2.630 mmol) in PhMe (1.50 mL) at 80 °C was added
NEt3 (2.40 mL, 3.60 mmol, 1.50 M in PhMe) via syringe pump
over 5 h. After 10 h, the crude mixture was cooled to rt, filtered,
concentrated in vacuo, and was purified via flash chromato-
graphy over silica gel, eluting with 10–25% EtOAc/hexanes to
give impure 13i as a solid. The impure solid was recrystallized
from hexanes/methanol to give pure 13i (87.1 mg, 269 μmol,
92%) as a pale yellow oil. IR (thin film) 1613, 1528, 1457,
1381, 1354, 906, 855, 832, 802, 707 cm−1; 1H NMR (300 MHz,
CDCl3) δ 7.92 (dd, J = 7.7, 1.0 Hz, 1H), 7.63 (d, J = 6.5 Hz,
1H), 7.58 (t, J = 7.7 Hz, 1H), 6.99 (s, 2H), 6.29 (s, 1H), 2.40
(s, 3H), 2.36 (s, 3H), 2.24 (s, 6H) ppm; 13C NMR (75 MHz,
CDCl3) δ 164.8, 162.3, 149.6, 140.8, 139.0, 137.2, 134.9, 130.8,
128.4, 125.7, 122.3, 122.1, 106.1, 21.2, 20.2, 20.0 ppm; HRMS
(EI+) calcd for C19H18N2O3 (M+) 322.1317, found 322.1304.
1
340 μmol, 75%) as a white solid. H NMR (700 MHz, CDCl3)
δ 7.88 (d, J = 7.1 Hz, 2H), 7.53 (t, J = 7.1 Hz, 2H), 7.48 (t, J =
7.1 Hz, 1H), 6.99 (s, 2H), 6.50 (s, 1H), 2.36 (s, 3H), 2.22 (s,
6H) ppm; 13C NMR (125 MHz, CDCl3) δ 169.8, 162.7, 138.8,
137.2, 130.1, 129.0, 128.4, 127.6, 126.2, 125.9, 100.9, 21.1,
20.2 ppm.
Isoxazole 15b
Isoxazole 13j
To a stirred solution of 14b19 (50.0 mg, 384 μmol) and 1214
(759 mg, 3.84 mmol) in PhMe (1.5 mL) at 80 °C was added
NEt3 (3.1 mL, 4.61 mmol, 1.5 M in PhMe) via syringe pump
over 5 h. After 15 h, the crude mixture was cooled to rt, filtered,
concentrated in vacuo, and purified via flash chromatography
over silica gel, eluting with 0–20% EtOAc/hexanes to give
impure 15b. Repurification via trituration with hexanes and
EtOAc gave 15b (29.9 mg, 103 μmol, 27%) as a white solid. Mp
96–99 °C; IR (neat) 2923, 1614, 1450, 1145, 1006, 898, 852,
766, 741 cm−1; H NMR (400 MHz, CDCl3) δ 7.44–7.31 (over-
1
To a stirred solution of 1j4 (80.9 mg, 462 μmol) and 1214
(845.6 mg, 4.278 mmol) in PhMe (2.30 mL) at 80 °C was added
NEt3 (3.70 mL, 5.55 mmol, 1.50 M in PhMe) via syringe pump
over 5 h. After 10 h, the crude mixture was cooled to rt, filtered,
concentrated in vacuo, and purified via flash chromatography
over silica gel, eluting with 2–10% EtOAc/hexanes to give
impure 13j as a yellow solid. The impure solid was recrystallized
from methanol to give pure 13j (115.7 mg, 349.3 μmol, 74%) as
a light brown solid. Mp 133–135 °C; IR (thin film) 1643, 1613,
lapping m, 4H), 6.99 (s, 2H), 2.41 (s, 3H), 2.37 (s, 3H), 2.16 (s,
6H), 1.80 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 166.7,
163.4, 138.7, 137.8, 137.3, 130.8, 129.8, 129.6, 128.2, 128.0,
125.7, 111.4, 21.2, 20.1, 19.8, 7.6 ppm. HRMS (ES+) calcd for
C20H22NO (M + H) 292.1701, found 292.1689.
Isoxazole 17a
1533, 1457, 1347, 914, 853, 804, 741 cm−1
;
1H NMR
(400 MHz, CDCl3) δ 7.99 (dd, J = 8.4, 1.3 Hz, 1H), 7.65 (dd,
J = 7.7, 1.9 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.00 (s, 2H), 2.36
(s, 3H), 2.33 (s, 3H), 2.18 (s, 6H), 1.67 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3) δ 163.3, 161.3, 149.6, 141.4, 138.9, 137.3,
135.0, 130.7, 128.2, 125.0, 122.5, 122.3, 113.4, 21.2, 19.7, 19.6,
6.9 ppm; HRMS (EI+) calcd for C20H20N2O3 (M+) 336.1470,
found 336.1462.
To a stirred solution of 1a3c (69.7 mg, 384 μmol) and 16a17
(467 mg, 3.84 mmol) in PhMe (1.5 mL) at 80 °C was added
9210 | Org. Biomol. Chem., 2012, 10, 9204–9213
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NEt3 (3.1 mL, 4.61 mmol, 1.5 M in PhMe) via syringe pump
over 5 h. After 15 h, the crude mixture was cooled to rt, filtered,
concentrated in vacuo, and purified via flash chromatography
over silica gel, eluting with 0–30% EtOAc/hexanes to give
impure 17a. Repurification via flash chromatography over silica
gel, eluting with 0–10% EtOAc/hexanes gave 17a (29.5 mg,
111 μmol, 29%‡) as a yellow oil. IR (neat) 3089, 2970, 1537,
impure 17c. Repurification via trituration with hexanes and
EtOAc gave 17c (49.4 mg, 151 μmol, 39%‡) as a yellow solid.
Mp 117–120 °C; IR (neat) 1535, 1425, 1353, 965, 884, 755,
737, 696 cm−1 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J =
;
8.2 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.64 (t, J = 8.2 Hz, 1H),
7.57 (d, J = 7.1 Hz, 2H), 7.44–7.33 (overlapping multiplets,
3H), 7.27, 7.20 (ABq, J = 16.5 Hz, 2H), 6.80 (s, 1H) ppm; 13C
NMR (100 MHz, CDCl3) δ 162.0, 161.9, 150.4, 136.6, 136.3,
135.7, 134.3, 131.7, 129.1, 128.9, 127.1, 123.0, 122.1, 155.6,
103.3 ppm. HRMS (ES+) calcd for C17H12N2O3Cl (M + H)
327.0536, found 327.0543.
1352, 1124, 950, 883, 759, 739 cm−1 1H NMR (400 MHz,
;
CDCl3) δ 7.91 (dd, J = 8.2, 1.0 Hz, 1H), 7.78 (dd, J = 8.2,
1.1 Hz, 1H), 7.60 (t, J = 8.2 Hz, 1H), 6.42 (s, 1H), 3.16 (septet,
J = 7.1 Hz, 1H), 1.37 (d, J = 7.0 Hz, 6H) ppm; 13C NMR
(100 MHz, CDCl3) δ 169.4, 161.5, 150.4, 136.0, 134.2, 131.4,
122.9, 122.4, 104.4, 26.7, 21.6 ppm. HRMS (EI+) calcd for
C12H11N2O3Cl (M+) 266.0458, found 266.0462.
Carboxylic acid 18
Isoxazole 17b
To a stirred solution of 13c (100 mg, 249 μmol) stirring in
THF–H2O (2 : 1, 0.2 M, 1.2 mL) was added LiOH·H2O
(36.2 mg, 863 μmol). After 5 days the reaction mixture was
quenched with 6 M HCl (1.5 mL) and the aqueous layer
extracted with EtOAc (3 × 10 mL ea.). The combined organic
layers were washed with brine (30 mL), dried over MgSO4 and
concentrated in vacuo to yield 18 as a beige solid (91.9 mg,
238 μmol, 95%). Mp 195–197 °C; IR (neat) 2919, 1691, 1536,
To a stirred solution of 1a3c (69.7 mg, 384 μmol) and 16b18
(467 mg, 3.84 mmol) in PhMe (1.5 mL) at 80 °C was added
NEt3 (3.1 mL, 4.61 mmol, 1.5 M in PhMe) via syringe pump
over 5 h. After 15 h, the crude mixture was cooled to rt, filtered,
concentrated in vacuo, and purified via flash chromatography
over silica gel, eluting with 0–30% EtOAc/hexanes to give
impure 17b. Repurification via flash chromatography over silica
gel, eluting with 0–10% EtOAc/hexanes gave 17b (76.8 mg,
288 μmol, 75%) as a yellow oil. IR (neat) 3090, 2964, 2875,
1
1348, 1139, 753 cm−1; H NMR (400 MHz, CDCl3) δ 8.26 (d,
J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.73 (t, J = 8.4 Hz,
1H), 6.98 (s, 2H), 2.36 (s, 3H), 2.18 (s, 6H) ppm; 13C NMR
(175 MHz, CDCl3) δ 169.7, 162.9, 161.9, 148.8, 139.3, 137.4,
137.1, 136.6, 135.1, 132.4, 128.3, 128.1, 123.9, 123.6, 122.8,
111.2, 21.3, 19.9 ppm; HRMS (ES+) calcd for C19H16ClN2O5
(M + H) 387.0762, found 387.0748.
1
1538, 1417, 1354, 1125, 950, 883, 808, 738 cm−1; H NMR
(400 MHz, CDCl3) δ 7.92 (d, J = 8.2 Hz, 1H), 7.78 (d, J =
8.2 Hz, 1H), 7.60 (t, J = 8.1 Hz, 1H), 6.40 (s, 1H), 2.75 (t, J =
7.3 Hz, 2H), 1.77 (sextet, J = 7.4 Hz, 2H), 1.02 (t, J = 7.4 Hz,
3H) ppm; 13C NMR (100 MHz, CDCl3) δ 164.0, 161.6, 150.3,
136.0, 134.2, 131.5, 122.9, 122.4, 105.8, 28.0, 21.5, 13.6 ppm.
HRMS (EI+) calcd for C12H11N2O3Cl (M+) 266.0458, found
266.0469.
Acid chloride 19
Isoxazole 17c
To a stirred solution of 18 (10 mg, 25.8 μmol) in CH2Cl2
(100 μL) was added PCl5 (6.4 mg, 30.7 μmol). After 2 h at
reflux the crude mixture was cooled to rt and concentrated
in vacuo to give 19 as a beige solid (9.8 mg, 24.2 μmol, 94%).
Crude materials were used without further purification. Mp
To a stirred solution of 1a3c (69.7 mg, 384 μmol) and 16c17
(697 mg, 3.84 mmol) in PhMe (1.5 mL) at 80 °C was added
NEt3 (3.1 mL, 4.61 mmol, 1.5 M in PhMe) via syringe pump
over 5 h. After 14 h, the crude mixture was cooled to rt, filtered,
concentrated in vacuo, and purified via flash chromatography
over silica gel, eluting with 0–20% EtOAc/hexanes to give
132–136 °C; IR (neat) 2925, 1733, 1536, 1315, 1124, 737 cm−1
;
1H NMR (700 MHz, CDCl3) δ 8.37 (d, J = 8.4 Hz, 1H), 7.95 (d,
J = 7.7 Hz, 1H), 7.82 (t, J = 8.4 Hz, 1H), 7.02 (m, 2H), 2.83 (s,
3H), 2.22 (s, 3H), 2.19 (s, 3H) ppm; 13C NMR (175 MHz,
CDCl3) δ 170.8, 161.6, 157.9, 148.5, 139.9, 137.4, 137.1, 136.6,
135.5, 133.0, 128.5, 128.4, 123.9, 123.0, 122.4, 116.5, 21.1,
19.9 ppm; HRMS (EI+) calcd for C19H14Cl2N2O4 (M+)
404.0331, found 404.0330.
‡This product contains a small (<10% impurity) which is inseparable.
This journal is © The Royal Society of Chemistry 2012
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Amide 22
Isoxazole 24
To a pressure vessel containing 13a (83.4 mg, 243 μmol) and
dioxane (1.00 mL), was sequentially added PEPPSI-IPr
(16.8 mg, 24.7 μmol), (PhBO)3 (124.3 mg, 340 μmol), K2CO3
(127.6 mg, 923 μmol). The solution was sealed under Ar and
heated to 80 °C. After 48 h, the reaction was cooled to rt, and
filtered through a Celite pad with CH2Cl2 (40 mL). The elutant
was concentrated in vacuo, and purified via flash chromato-
graphy over silica gel, eluting with 0–15% EtOAc/hexanes to
give 24 (74.1 mg, 19.3 μmol, 79%) as a pale yellow solid. Mp
To a stirred solution of 19 (14.5 mg, 35.8 μmol) in CH2Cl2
(360 μL) was added NEt3 (7.2 mg, 10 μL, 71.6 μmol) and ben-
zylamine 20 (7.8 mg, 8 μL, 73.2 μmmol) at rt. After 15 h the
crude materials were concentrated in vacuo and purified via flash
chromatography over silica gel, eluting 0–40% EtOAc/hexanes
to give 22 as a beige solid (10.2 mg, 21.4 μmol, 60%). Mp
139–141 °C; IR (neat) 3400, 2922, 1666, 1531, 1350, 1150,
1
1
738 cm−1; H NMR (700 MHz, CDCl3) δ 8.26 (d, J = 8.4 Hz,
168–170 °C; H NMR (400 MHz, CDCl3) δ 8.12 (dd, J = 2.1,
7.3 Hz, 1H), 7.76 (m, 2H), 7.35 (m, 3H), 7.24 (m, 2H), 6.92 (s,
2H), 5.85 (s, 1H), 2.32 (s, 3H), 2.02 (s, 6H) ppm; 13C NMR
(100 MHz, CDCl3) δ 164.5, 162.0, 149.5, 145.3, 138.8, 138.4,
137.3, 134.6, 130.9, 128.9, 128.4, 128.21, 128.20, 125.7, 123.6,
121.7, 107.0, 21.1, 20.0 ppm; HRMS (EI+) calcd for
C24H20N2O3 (M+) 384.1474, found 384.1465.
1H), 7.87 (d, J = 8.4 Hz, 1H), 7.70 (t, J = 8.4 Hz, 1H), 7.23 (m,
3H), 6.93 (s, 2H), 6.86 (m, 2H), 5.52 (s, 1H), 4.25 (d, J =
4.6 Hz, 1H), 4.18 (d, J = 4.1 Hz, 1H), 2.30 (s, 3H), 2.17 (s, 6H)
ppm; 13C NMR (175 MHz, CDCl3) δ 168.2, 159.2, 159.1,
149.2, 140.7, 138.0, 137.3, 136.8, 136.6, 134.8, 131.9, 129.2,
129.0, 128.5, 127.5, 127.2, 123.6, 123.4, 123.3, 113.6, 43.2,
21.2, 19.7 ppm; HRMS (ES+) calcd for C26H23ClN3O4 (M + H)
476.1377, found 476.1358.
Isoxazole 25
Amide 23
To a pressure vessel containing 13c (50 mg, 125 μmol) was
added sequentially K2CO3 (52 mg, 374 μmol), (PhBO)3
(117 mg, 374 μmol), and PEPPSI-IPr (3.8 mg, 5.6 μmol). The
vessel was evacuated and backfilled with argon 3 times. Dioxane
was added and the reaction was let stir at 100 °C. After 15 h, the
crude material was cooled to rt, filtered through Celite and con-
centrated in vacuo. Purification via flash chromatography over
silica gel, eluting 5–20% EtOAc/hexanes gave 25 as a yellow
solid (37.4 mg, 84.5 μmol, 63%). mp 175–178 °C; IR (neat)
To a stirred solution of 19 (4.8 mg, 11.8 μmol) in CH2Cl2
(120 μL) was added NEt3 (2.4 mg, 3.3 μL, 23.6 μmol) and (R)-
(+)-α-methyl benzylamine 21 (2.8 mg, 3 μL, 23.6 μmmol) at rt.
After 7 h the crude materials were concentrated in vacuo and
purified via flash chromatography over silica gel, eluting 0–30%
EtOAc/hexanes to give 23 as a beige solid (3.8 mg, 7.75 μmol,
66%). Mp 51–53 °C; IR (neat) 3388, 2924, 1667, 1534, 1351,
1
2953, 1732, 1534, 1123, 737, 703 cm−1; H NMR (400 MHz,
CDCl3) δ 8.32 (t, J = 4.8 Hz, 1H), 7.82 (d, J = 4.8 Hz, 2H), 7.32
(m, 3H), 7.21 (m, 2H), 6.92 (s, 1H), 6.86 (s, 1H), 3.41 (s, 3H),
2.31 (s, 3H), 2.13 (s, 3H) 1.76 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3) δ 170.3, 161.8, 160.6, 148.3, 145.6, 138.8,
137.9, 137.1, 136.9, 135.1, 131.3, 128.6, 128.4, 128.3, 128.2,
128.0, 127.8, 124.4, 123.9, 122.1, 111.7, 51.6, 21.2, 19.8,
19.7 ppm; HRMS (EI+) calcd for C26H22N2O5 (M+) 442.1529,
found 442.1531.
1
757, 699 cm−1; H NMR (700 MHz, CDCl3) δ 8.24 (bs, 1H),
7.85 (dd, J = 7.6, 14.8 Hz, 1H), 7.68 (t, J = 8.2 Hz, 1H), 7.22
(m, 3H), 7.13 (s, 1H of rotamer), 7.10 (s, 1H of rotamer), 6.96
(s, 1H of rotamer), 6.94 (s, 1H of rotamer), 6.80 (m, 2H), 5.65
(bs, 1H), 4.89 (s, 1H), 2.39 (s, 3H), 2.28 (s, 3H of a rotamer),
2.26 (s, 3H of a rotamer), 2.09 (s, 3H), 1.16 (m, 3H) ppm; 13C
NMR (175 MHz, CDCl3) δ 168.0, 159.1, 158.3, 149.2, 142.4,
142.2, 140.8, 138.3, 138.1, 137.7, 137.4, 136.6, 134.8, 131.8,
129.4, 129.2, 128.9, 128.5, 127.3, 125.4, 123.6, 123.4, 113.7,
48.6, 22.2, 21.3, 19.8, 19.7 ppm; HRMS (ES+) calcd for
C27H25ClN3O4 (M + H) 490.1534, found 490.1524.
Acknowledgements
Financial support was provided by the Oregon State University
(OSU) and the National Science Foundation (CHE-0848704).
We thank Professor Claudia Maier and Dr Jeff Morré (OSU) for
9212 | Org. Biomol. Chem., 2012, 10, 9204–9213
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6 F. Himo, T. Lovell, R. Hilgraf, V. V. Rostovstev, L. Noodleman,
K. B. Sharpless and V. V. Fokin, J. Am. Chem. Soc., 2005, 127, 210–216.
7 S. Grecian and V. V. Fokin, Angew. Chem., Int. Ed., 2008, 47,
8285–8287.
mass spectra data. Finally, we are grateful to Dr Roger Hansel-
mann (Rib-X Pharmaceuticals) for his helpful discussions.
8 S. E. Denmark and J. M. Kallemeyn, J. Org. Chem., 2005, 70,
2839–2842.
Notes and references
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