A sequential enantioselective, organocatalytic route to chiral 1,2-oxazines and chiral pyridazines

Article abstract of DOI:10.1039/b708646f

A sequential, organocatalysed asymmetric reaction to access chiral 1,2-oxazines and chiral pyridazines is reported, which proceeds in moderate to good yields and good to excellent enantioselectivities. The Royal Society of Chemistry.

Full text of DOI:10.1039/b708646f

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
A sequential enantioselective, organocatalytic route to chiral 1,2-oxazines and
chiral pyridazines†
Sirirat Kumarn, Alexander J. Oelke, David M. Shaw, Deborah A. Longbottom and Steven V. Ley*
Received 7th June 2007, Accepted 20th June 2007
First published as an Advance Article on the web 10th July 2007
DOI: 10.1039/b708646f
A sequential, organocatalysed asymmetric reaction to access chiral 1,2-oxazines and chiral pyridazines
is reported, which proceeds in moderate to good yields and good to excellent enantioselectivities.
Introduction
The synthetic potential of multicomponent, tandem or domino
reactions has been exploited for the efficient and stereoselective
construction of a variety of complex structures from simple
starting materials.1 These one-pot sequential transformations
avoid lengthy purification or protection procedures and thus
Scheme 1 Synthesis of chiral 1,2-oxazines from aldehyde and ketone
substrates.
greatly reduce both the cost and time taken for chemical syn-
theses. In recent years, spectacular advances have been made in
organocatalytic processes2 and one significant advantage is their
ability to promote several types of reactions through different
activation modes.3 In particular, tandem reactions mediated by
organocatalysts can be applied to generate useful enantiomerically
pure building blocks in the synthesis of biologically active natural
products.4 It was envisaged that such a process might be used
in the preparation of both optically active 1,2-oxazines and 3,6-
dihydropyridazines.
useful class of compound has been demonstrated, namely 3,6-
dihydropyridazines.13 In a similar manner, these may be obtained
by applying an initial a-amination using an azo compound instead
of a nitroso component (Scheme 2).
Conventionally, these compounds are prepared by the [4 +
2] cycloaddition of nitroso or azo compounds and dienes,5
or the ring-closing metathesis of suitable alkene precursors.6
However, their asymmetric preparation7 can be difficult to achieve
without control induced by chiral substrates8 or chiral auxiliaries.9
Therefore, the development of an asymmetric organocatalytic
route, which would lead to a variable substitution pattern, was
very attractive.
Scheme 2 Synthesis of chiral 3,6-dihydropyridazines.
Results and discussion
Following optimisation studies, we first demonstrated an effi-
cient new route to enantiopure 1,2-oxazines from commercially
available achiral precursors using (S)-pyrrolidinyl-tetrazole cata-
lyst 1a (Scheme 1).10 The transformation involves an asymmetric
organocatalytic a-oxyamination11 with nitrosobenzene to afford
an intermediate, which undergoes base-promoted conjugate addi-
tion to a vinylphosphonium salt.12 The resulting ylide then cyclises
to the 1,2-oxazine via an intramolecular Wittig process.
Through this new method, by varying any one of the three
components, a wide range of potentially useful enantiomerically
enriched heterocycles can be accessed. Indeed, by changing the
carbonyl component from aldehyde to ketone or varying the
vinylphosphonium salt used in the Wittig step, more substituted
enantiopure 1,2-oxazines can be obtained. Moreover, alteration
of the electrophilic component to provide a related, synthetically
We have recently demonstrated an efficient new route to enan-
tiopure 1,2-oxazines from commercially available aldehydes10a
and ketones.10b To achieve this, extensive optimisation studies
were conducted. Initial work centred on finding conditions most
appropriate for the organocatalytic a-oxyamination reaction,
while remaining compatible with the subsequent steps in the
one-pot procedure. Solvents, temperatures, order of addition,
reaction times and equivalents of reagents used, were screened.
It was found that conditions similar to those developed by
Zhong,11a where only a small excess of aldehyde partner in
DMSO was required, were optimum for the use of pyrrolidinyl-
tetrazole catalyst 1a. NaH (2 eq.) was needed in the subsequent
intramolecular Wittig process in a mixed solvent system (1 : 1,
DMSO–THF). Interestingly, increased yields were observed with
more substituted aldehydes, suggesting competing homo-aldol
reactions (Table 1). In support of this hypothesis is the observed
reduction in overall yield as the number of equivalents of aldehyde
were increased. The matched/mismatched effect was investigated
using citronellal as the chiral aldehyde to create dihydro-1,2-
oxazines with pendant chirality (Entries 9 and 10). Although yields
Department of Chemistry, University of Cambridge, Lensfield Road, Cam-
bridge, UK CB2 1EW. E-mail: svl1000@cam.ac.uk; Fax: +44 1223 336442;
Tel: +44 1223 336398
† Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b708646f
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Table 1 Synthesis of 1,2-oxazines from aldehydes
a Isolated yields of material after chromatography. b The ee values were determined directly by chiral HPLC. c The de values were determined directly by
1H NMR of crude material. d The ee value was determined directly by chiral SFC.
were similar, diastereoselectivity did differ with a diastereomeric
excess of only 83% in the mismatched compared with 99% in the
matched case (Entry 9).
The use of (S)-pyrrolidinyl-tetrazole 1a as a catalyst for this
process was based on its improved properties, especially solu-
bility, when compared, for example, to L-proline. As with other
chemistries developed independently by ourselves,14 Yamamoto
et al.,11f,11g,15 Hartikka and Arvidsson16 and others17 where 1a was
an especially effective catalyst, it also proved to be the compound
of choice in this work.18
In order to probe the synthetic scope of the method, linear
Scheme 3 Preparation of protected hydroxyaldehydes.
aldehydes with various protecting groups and chain lengths were
prepared by oxidising a suitable mono-protected diol (Scheme 3).19
However, under the optimised reaction conditions although the
enantiomeric excesses were still excellent, the yields were no longer
as high. Most notably, it was found that only traces of the 1,2-
oxazine products 3k and 3l from protected b-hydroxyaldehydes
were observed (Entries 11–12, Table 1). For reasons which are not
entirely clear, this suggests a critical aldehyde chain length of four
carbons or more for successful a-oxyamination.
An alternative nitroso compound, 4-nitrosoanisole 4 (Table 2),20
has also been investigated. Under similar reaction conditions, with
slow addition of the nitroso compound, generally lower yields but
excellent enantioselectivities were observed, in comparison with
their nitrosobenzene counterparts (Table 2). It is believed that this
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Table 2 Synthesis of 1,2-oxazines from 4-nitrosoanisole20
Table 3 Synthesis of 1,2-oxazines from ketones
a Isolated yields of material after chromatography. b The ee values were
determined directly by chiral HPLC. c 6% obtained without NH4Cl work-
up.
is due to the much more facile dimerisation of the nitroso reagent
during the a-oxyamination step caused by the additional electron-
donating substituent.
Slight alterations in reaction conditions were required to pro-
duce enantiopure 1,2-oxazines from ketone starting materials.10b
The conditions employed for the a-oxyamination were similar to
those used by Yamamoto et al.11g Crucially, these use a much
smaller excess of ketone (3 eq.), such that the subsequent steps may
be carried out in a single pot with greatly reduced catalyst loading
(5 mol%). The problems from the sequential Wittig process were
resolved by the use of KH as a base instead of NaH. Remarkably,
an excess of KH did not cause racemisation of the stereogenic
centre generated during the a-oxyamination process (99% ee). We
were pleased to find that the reaction conditions developed were
then applicable to a range of ketones to give moderate to good
yields of products with excellent ee’s throughout (Table 3).
Use of the more substituted vinylphosponium bromide 6b21 gave
the tri- and tetrasubstituted 1,2-oxazines 9a (Entry 1, Table 4)
and 8f (Entry 6, Table 3) from aldehyde and ketone starting
materials, respectively. When phosphonium salt 6c22 was used,
a diastereomeric ratio of 6 : 1 was observed in the reaction
of isovaleraldehyde, catalysed by (S)-pyrrolidinyl-tetrazole 1a,
compared with 4 : 1 when L-proline was used (Entry 2, Table 4)
each with 9d as a by-product.23 It is also of note that the 1,2-
oxazine 8g from cyclohexanone 7a was generated with complete
diastereoselectivity24 and excellent enantioselectivity (Entry 7,
Table 3).
a Isolated yields of material after chromatography. b The ee values were
determined directly by chiral HPLC. c Reaction of 20 eq. 7e was conducted
with 20 mol% of 1a. d Compound 8f generated using 6b. e Compound 8g
generated using 6c.
The enantiomer of the pyrrolidinyl-tetrazole catalyst, 1b was
also applied to selected aldehyde and ketone examples to verify
its equivalent utility in these transformations. As expected, this
was successful in providing the corresponding enantiomeric 1,2-
oxazine products (Table 5).
Cleavage of the N–O bond of selected 1,2-oxazines liberated the
synthetically useful cis-allylic alcohols in high yield using zinc in
methanolic HCl, with retention of enantiopurity (Table 6). It is
also worth noting that when N–O cleavage of 3a was performed
on a larger scale (3.38 mmol), the yield significantly increased
from 83% (1.02 mmol) to 93%, highlighting the practicality of the
transformation.
The reactions between nitrosobenzene and activated carbonyl
compounds, for example enamines, are known to provide a-
oxyamination11 or a-hydroxyamination25 products, depending
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Table 4 Synthesis of 1,2-oxazines using alternative Wittig reagents
jugate addition to a vinylphosphonium salt, intramolecular Wittig
cyclisation thus yields dihydro-1,2-oxazines with the stereogenic
centre alpha to nitrogen (Table 7). This illustrates that regioisomers
of these compounds can be generated by simply changing the
catalyst used.26
It has also been shown that an organocatalytic a-amination,27
to provide a-hydrazinocarbonyl compounds, can furnish 3,6-
dihydropyridazines by a similar route.13 Reaction conditions
similar to those developed by Jørgensen et al.27a where
dichloromethane was used as the solvent of choice, were cho-
sen to facilitate the sequential Wittig process. Importantly, a
reduced excess of aldehyde (1.2 eq.) was found to give good
yields, further aiding the following intramolecular Wittig step
by minimising side reactions. Using isovaleraldehyde and diethyl
azodicarboxylate (DEAD, 17a, Table 8) as our model system,
it was found that the use of a mixed solvent system (1 : 1,
CH2Cl2–THF) was optimum, and also provided for an easier
work-up. Comparison of the catalytic activity of L-proline 1c and
(S)-pyrrolidinyl-tetrazole 1a shows that although the ee values
were very similar, the yields varied significantly (Entries 3–6,
Table 8). (S)-Pyrrolidinyl-tetrazole demonstrated much higher
activity leading to significantly reduced reaction times, especially
when low catalyst loadings were applied (Entries 5–8, Table 8).
The reaction scope was then evaluated by examining a variety of
aldehydes and azodicarboxylates under these optimised reaction
conditions (Table 9) and indeed a selection of aldehydes reacted
with DEAD 17a giving the 3,6-dihydropyridazines 18a-18k in
good to excellent yields and enantioselectivities. These results
further support our homo-aldol coupling hypothesis, with un-
branched aldehydes showing lower yields and surprisingly lower
selectivities (Entries 3–5, Table 9). The study has also indicated
that the reaction can successfully be scaled up (Entry 1, Table 9).
Notably, the 3,6-dihydropyridazine product 18k can be obtained
a Isolated yields of material after chromatography. b The ee was determined
directly by chiral GC. c 4 : 1 dr obtained when catalysed by L-proline. d The
ees for both 9b and 9c are 99% and were determined directly by chiral
HPLC and chiral SFC, respectively.
on the catalyst used. Maruoka and co-workers have recently
developed an axially chiral secondary amine catalyst 14 (Table 7)
to direct enantioselective hydroxyamination of aldehydes.25
By applying catalyst 14, the a-hydroxyaminated intermediate
can be generated chemoselectively. Following base-promoted con-
Table 5 Synthesis of 1,2-oxazines catalysed by (R)-pyrrolidinyl-tetrazole from aldehydes and ketones
a Isolated yields of material after chromatography. b The ee values were determined directly by chiral HPLC.
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Table 6 Synthesis of cis-allylic alcohols through N–O bond cleavage
Table 7 Synthesis of 1,2-oxazines from aldehydes catalysed by the
Maruoka catalyst
a Isolated yields of material after chromatography. b The ee values were
assigned according to Maruoka’s values at the hydroxyamination stage25
assuming no epimerisation in the following steps as found in all previous
reactions.
Table 8 Catalyst and solvent screening
a Isolated yields of material after chromatography. b The ee values were
determined directly by chiral HPLC. c Reaction carried out on 1.02 mmol
scale. d Reaction carried out on 3.38 mmol scale.
from the TBS-protected b-silyloxypropanal 2k (Entry 8, Table 9).
This indicates that no critical aldehyde chain length exists as it
does in the a-oxyamination case. Interestingly, with L-proline as
catalyst, elimination product 19 (Fig. 1) was obtained as the sole
reaction product.
a a-Amination reaction time. b Isolated yields of material after chromatog-
raphy. c The ee values were determined directly by chiral SFC.
Fig. 1 Elimination product 19.
Using both enantiomers of citronellal as the chiral aldehyde,
although yields were similar, this mismatched case showed not
only lower diastereoselectivity, but also a much longer reaction
time (compare Entry 6 with Entry 7, Table 9).
A comparison of azodicarboxylates was carried out us-
ing isovaleraldehyde under the optimised reaction conditions
(Table 10). It was found that the di-tert-butyl derivative (Entry 1)
provided an improved ee whilst the benzyl analogue (Entry 2) gave
notably reduced selectivity. An alternative aminating agent, N-
phenyltriazoline dione (PTAD, 17d) was also investigated (Entry 3)
and the reagent was completely consumed in only 20 minutes
in the a-amination step, despite its rather low solubility in
dichloromethane. However, a much longer reaction time (4 h)
was required in the sequential cyclisation step, which could be due
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Table 9 Synthesis of 3,6-dihydropyridazines from aldehydes
Table 10 Alternative aminating agents
a Isolated yields of material after chromatography. b The ee values were
determined directly by chiral SFC. c Complete reaction sequence carried
out at 0 ◦C. d The relative stereochemistry was confirmed by X-ray
crystallography: CCDC reference number 649830. For crystallographic
data in CIF or other electronic format see DOI: 10.1039/b708646f, see
the ESI† for details. e A 4 h reaction time was required for the cyclisation
step.
precursors did not initially prove very effective. a-Amination
was firstly investigated using cyclohexanone and DEAD in
dichloromethane. Compared with the literature values (79% ee,
11 h)27b using L-proline as catalyst, (S)-pyrrolidinyl-tetrazole 1a
provided a definite improvement in both enantioselectivity (84%
ee) and reaction time (5.5 h). An optimisation study was then cen-
tred on the tandem Wittig process. The optimum conditions were
with KH as the base in a mixed solvent system (1 : 1 : 1, CH2Cl2–
DMSO–THF) where a reduced amount of ketone (1.2 eq.) was
key in minimising intermolecular Wittig side reactions (Entry 4,
Table 11).
With this information in hand, the scope of the ketone substrates
was then examined (Table 12). It was pleasing to find that
the reaction conditions developed were indeed applicable to a
range of ketones (1.2 eq.) using (S)-pyrrolidinyl-tetrazole catalyst
(20 mol%) to give generally moderate yields of product and good
enantioselectivities. In only one case (Entry 5, Table 12), that of the
linear butan-2-one substrate, was it necessary to use a higher excess
of ketone (5 eq.) and higher catalyst loading (30 mol%). A mixture
of regioisomers was obtained with this substrate. Interestingly, a
better ratio of 10 : 1 was achieved using L-proline whilst (S)-
pyrrolidinyl-tetrazole gave only 2 : 1.
a Isolated yields of material after chromatography. b The ee values were
determined directly by chiral SFC. c Reaction carried out on 5 mmol
scale. d 20 mol% of catalyst used. e 330 min required for a-amination.
f Determining the de values directly by 1H NMR of crude material was
difficult due to the number of rotameric forms present in the spectra.
g 83 min required in a-amination. h The product obtained was 19 when
catalysed by L-proline.
to the increased steric bulk of the reagent and might explain the
reduced enantioselectivity.
Following the successful synthesis of chiral 3,6-dihydropyrida-
zines from aldehyde starting materials, application to ketone
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Table 11 Optimisation study of ketone substrates
Table 12 Synthesis of pyridazines from ketones
a Co-solvents used in a 1 : 1 ratio with CH2Cl2. b Isolated yields of material
after chromatography. c The ee values were determined directly by chiral
SFC.
Conclusions
A sequential one-pot synthesis of chiral 1,2-oxazines from achiral
aldehyde and ketone starting materials has been developed. A
range of molecular decoration can be successfully achieved by
varying the substitution pattern of the reagents involved. Similarly,
chiral pyridazines can be prepared by applying a-amination
instead of a-oxyamination in the first part of the transformation.
The 1,2-oxazine products undergo facile N–O bond cleavage to
provide cis-allylic alcohols, which are synthetically useful building
blocks. Further efforts to evaluate the use of these methods and
their application to natural product synthesis and related processes
are underway.
Experimental
Solvents: diethyl ether and tetrahydrofuran were distilled from
sodium calcium hydride and lithium aluminium hydride (tetrahy-
drofuran using triphenylmethane as indicator); chloroform,
dichloromethane, methanol and toluene from calcium hydride
prior to use. Anhydrous dimethylsulfoxide was used as supplied.
Petrol refers to petroleum ether b.p. 40–60 ◦C, and ether to diethyl
ether, which were distilled before use. Reagents: all reactions
were performed under an argon atmosphere unless otherwise
stated. Reagents: were used as supplied or purified using standard
procedures as necessary. Chromatography: flash column chro-
matography was carried out using silica gel 60 (0.040–0.063 mm)
230–400 mesh under pressure unless otherwise indicated. Analyt-
ical thin layer chromatography was performed using pre-coated
glass-backed plates (Merck Kieselgel 60 F254) and visualised by
ultraviolet radiation (254 nm), acidic ceric ammonium molybdate,
or basic potassium permanganate solutions as appropriate. Data
collection: melting points were performed on a Reichert hot-stage
apparatus, and are uncorrected. Optical rotations were measured
on a Perkin Elmer 343 digital polarimeter using a sodium lamp
(589 nm) as the light source, [a]D values are reported in 10−1
deg cm2 g−1. Infrared spectra were recorded as thin films on a
Perkin Elmer Spectrum One FT-IR 1600 spectrometer fitted with
a Isolated yields of material after chromatography. b The ee values were
determined directly by chiral SFC. c 67% with ratio of 10 : 1, 21e–21f
obtained when L-proline used.
400, 500 and 600 MHz on Bruker Advance DPX-400, Bruker
Advance DRX-500 (cryoprobe) and Bruker Advance DRX-600
spectrometers, respectively with residual protic solvent CDCl3
as the internal reference (dH = 7.26 ppm) and are reported as
follows: chemical shift d/ppm (number of protons, multiplicity,
coupling constant J/Hz, assignment). 13C NMR spectra were
recorded at 100, 125 and 150 MHz on Bruker Advance DPX-
400, Bruker Advance DRX-500 (cryoprobe) and Bruker Advance
DRX-600 spectrometers, respectively. The resonance of CDCl3
(dC = 77.0 ppm, t) was used as an internal reference. 13C DEPT-
135 and two-dimensional (COSY, HMQC, HMBC and NOESY)
NMR experiments were used where appropriate, to support the
assignment of signals in the 1H and 13C spectra. Two-dimensional
NOESY experiments were performed on a Bruker Advance
1
an ATR sampling accessory. H NMR spectra were recorded at
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DPX-700 spectrometer at 700 MHz to assign through-space
correlation where appropriate. NMR resolution enhancement was
also used to assist coupling assignment in most 1H NMR spectra.
The 31P NMR spectrum was recorded on a Bruker Advance DPX-
400 spectrometer at 162 MHz. Mass spectra and accurate mass
data were obtained on an LCT Premier spectrometer by Waters
using a Micromass MS software at the Department of Chemistry,
University of Cambridge. The enantiomeric excesses (ee) were
determined by high performance liquid chromatography (HPLC),
performed on Hewlett–Packard Agilent 1100 chromatographs,
or by supercritical fluid chromatography (SFC) on a Berger
Minigram using a Chiralpak AD (0.46 × 25 cm), Chiralpak AD-
H (0.46 × 25 cm), Chiralcel OD (0.46 × 25 cm) or Chiralcel
OD-H (0.46 × 25 cm) column as noted, or gas chromatography
(GC), performed on an Agilent 6890N chromatograph using
an Astec Chiraldex column. The diastereomeric excesses (de)
14.3, 8.2, 6.3, 4.3 Hz, CHHꢀCH2OCH2Ph), 2.05 (1H, app
ddt, J 14.3, 8.9, 5.2 Hz, CHHꢀCH2OCH2Ph), 3.65 (1H, ddd,
J 9.4, 6.3, 5.2 Hz, CH2CHHꢀOCH2Ph), 3.72–3.88 (3H, m,
ꢀ
=
PhNCH2CH CHCHCH2CHH O), 4.55 (1H, d, J 12.0 Hz,
OCHHꢀPh), 4.58 (1H, d,
J
12.0 Hz, OCHHꢀPh), 4.76–
=
4.82 (1H, m, PhNCH2CH CHCHCH2), 5.89–5.97 (2H, m,
=
PhNCH2CH CH), 6.97 (1H, tt, J 7.3, 1.2 Hz, PhH-para),
7.06 (2H, dd, J 8.8, 1.2 Hz, 2 × PhH-ortho), 7.28 (2H,
dd, J 8.8, 7.3 Hz, 2 × PhH-meta), 7.32–7.38 (5H, m, 5 ×
OCH2PhH); dC (100 MHz, CDCl3) 33.7 (CH2CH2OCH2Ph), 51.7
=
(PhNCH2CH CH), 66.7 (CH2CH2OCH2Ph), 73.1 (OCH2Ph),
=
75.1 (PhNCH2CH CHCH), 115.4 (2 × PhC-ortho), 121.9
=
(PhC-para), 123.0 (PhNCH2CH CH), 127.6, 127.7, 128.4 (5 ×
=
OCH2PhC), 128.8 (2 × PhC-meta), 129.9 (PhNCH2CH CH),
138.5 (OCH2PhC-ipso), 150.6 (PhC-N); m/z (ES) found 296.1645
([M+H]+ C19H22NO2), requires 296.1651; HPLC (Chiralpak AD-
H, 99 : 1, hexane–iPrOH, 0.5 ml min−1, 254 nm) tR(major) 19.9 min,
tR(minor) 23.0 min.
1
were determined by H NMR spectroscopy of crude products.
The racemic materials were prepared using DL-proline or a
50 : 50 mixture of (2S) and (2R)-5-pyrrolidin-2-yl-1H-tetrazoles
as catalyst in the same procedure as their corresponding optically
active compounds. In the experimental section, compounds are
divided according to general reaction type, rather than table by
table.
For full experimental data of compounds 3a–3j, 9a and
12a–12d see10a: http://pubs3.acs.org/acs/journals/supporting_
information.page?in_manuscript=ol051577u. General experi-
mental procedures and full characteristic data of representative
compounds of each class are supplied here. Full experimental and
characteristic details of all compounds featured in this article can
be found in the ESI†.
General procedure for the synthesis of 1,2-oxazines using
4-nitrosoanisole
To a stirred solution of (2S)-5-pyrrolidin-2-yl-1H-tetrazole
(28 mg, 0.20 mmol, 20 mol%) in DMSO (2 ml) was added a
solution of 4-nitrosoanisole (0.15 g, 1.00 mmol, 1.0 eq.) and
the appropriate aldehyde (1.20 mmol, 1.2 eq.) in DMSO (3 ml)
dropwise via syringe over 1 h. The mixture was allowed to stir
for further 1 h and then cooled to 0 ◦C and THF (5 ml) was
added. Vinyltriphenylphosphonium bromide (0.57 g, 1.50 mmol,
1.5 eq.) was added, followed by sodium hydride (0.08 g, 2.00 mmol,
2.0 eq.). After stirring for 20 min at 0 ◦C, the reaction mixture was
quenched using saturated aqueous NH4Cl (20 ml) and extracted
with ether (3 × 20 ml). The combined organic layers were washed
with saturated aqueous LiCl (20 ml) and dried over MgSO4,
filtered and concentrated in vacuo. The resulting residue was
purified by flash column chromatography (solvents noted) to
provide the title compounds.
General procedure for the synthesis of 1,2-oxazines from aldehydes
To a stirred solution of the appropriate aldehyde (1.2 eq.) in
DMSO (5 ml per 1 mmol of nitrosobenzene) was added (2S)-5-
pyrrolidin-2-yl-1H-tetrazole (20 mol%). The resulting suspension
was stirred vigorously for 1 min before addition of nitrosobenzene
(1.0 eq.). The bright green reaction mixture was stirred at room
temperature until the reaction was determined to be complete by
TLC and the disappearance of green colour, resulting in a yellow
solution. The reaction mixture was then cooled to 0 ◦C and THF
(1 ml per ml of DMSO) was added. Vinyltriphenylphosphonium
bromide (1.5 eq.) was added, followed by sodium hydride (2.0 eq.).
After stirring for 20 min at 0 ◦C, the reaction mixture was quenched
using saturated aqueous NH4Cl (2 ml per ml of reaction volume)
and extracted with ether (3 × 2 ml per ml of reaction volume).
The combined organic layers were dried over MgSO4, filtered and
concentrated in vacuo. The resulting residue was purified by flash
column chromatography (solvents noted) to provide the title com-
pounds.
(6R)-6-Isopropyl-2-(4-methoxyphenyl)-3,6-dihydro-2H-1,2-oxa-
zine (5a). Prepared according to the general procedure from
isovaleraldehyde (0.13 ml, 1.20 mmol) to provide the title com-
pound as a pale yellow solid (84 mg, 36%, >98% ee) after flash
column chromatography (10 : 1, petrol–EtOAc). Rf 0.55 (3 : 1,
petrol–EtOAc); m.p. 54–55 ◦C; [a]D25 +11.5 (c 0.48 in CHCl3); mmax
(film) 3676, 2971, 2902, 1505, 1463, 1385, 1245, 1210, 1175, 1066,
1037, 991, 867, 832, 726, 714, 659 cm−1; dH (600 MHz, CDCl3)
1.01 (3H, d, J 6.8 Hz, (CH3)(CHꢀ3)CH), 1.03 (3H, d, J 6.8 Hz,
(CH3)(CHꢀ3)CH), 1.94 (1H, app oct, J 6.8 Hz, (CH3)(CHꢀ3)CH),
ꢀ
=
3.67 (1H, app ddt, J 15.7, 5.0, 1.7 Hz, ArNCHH CH CH),
ꢀ
=
3.74–3.80 (1H, m, ArNCHH CH CH), 3.78 (3H, s, OCH3),
4.31–4.34 (1H, m, (CH3)2CHCHCH CH), 5.92–5.98 (2H, m,
=
=
(6R)-6-(2-(Benzyloxy)ethyl)-2-phenyl-3,6-dihydro-2H-1,2-oxa-
zine (3n). Prepared according to the general procedure from
4-(benzyloxy)butanal (0.22 g, 1.21 mmol) to provide the title
compound as a yellow oil (94 mg, 32%, 99% ee) after flash
column chromatography (20 : 1, petrol–EtOAc). Rf 0.58 (3 : 1,
(CH3)2CHCHCH CH), 6.86 (2H, d, J 9.0 Hz, 2 × ArH-
ortho), 7.10 (2H, d, J 9.0 Hz, 2 × ArH-meta); dC (150 MHz,
CDCl3) 18.3 ((CH3)(CHꢀ3)CH), 18.4 ((CH3)(CHꢀ3)CH), 31.5
ꢀ
=
((CH3)(CH 3)CH), 52.7 (ArNCH2CH CH), 55.5 (OCH3), 82.4
=
((CH3)2CHCHCH CH), 114.1 (2 × ArC-ortho), 117.7 (2 ×
25
=
=
petrol–EtOAc); [a]D +43.6 (c 0.39 in CHCl3); mmax (film)
ArC-meta), 123.8 (ArNCH2CH CH), 128.5 (ArNCH2CH CH),
144.6 (ArCN), 155.3 (ArCO); m/z (ES) found 234.1490 ([M+H]+
C14H20NO2), requires 234.1494; HPLC (Chiralcel OD-H, 99 : 1,
2859, 1598, 1491, 1454, 1363, 1212, 1093, 1029, 1005, 888,
753, 690 cm−1; dH (400 MHz, CDCl3) 1.96 (1H, dddd, J
This journal is
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Org. Biomol. Chem., 2007, 5, 2678–2689 | 2685
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hexane–iPrOH, 1.0 ml min−1, 254 nm) tR(minor) 6.9 min, tR(major)
9.3 min.
was stirred at 0 ◦C for 1 h until the reaction was determined to be
complete by TLC. Vinyltriphenylphosphonium bromide (34 mg,
0.090 mmol, 1.5 eq.) was added, followed by additional THF
(0.2 ml), DMSO (0.3 ml) and sodium hydride (5 mg, 0.132 mmol,
General procedure for the synthesis of 1,2-oxazines from ketones
◦
2.2 eq.). After 1.5 h of stirring at 0 C, the reaction mixture was
quenched using saturated aqueous NH4Cl (5 ml) and extracted
with ether (3 × 5 ml). The combined organic layers were washed
with saturated aqueous LiCl (10 ml), then H2O (10 ml), dried over
MgSO4, filtered and concentrated in vacuo. The resulting residue
was purified by flash column chromatography (solvents noted) to
provide the title compounds.
To a stirred solution of (2S)-5-pyrrolidin-2-yl-1H-tetrazole (7 mg,
0.05 mmol, 5 mol%) and the appropriate ketone (3.00 mmol,
3.0 eq.) in DMSO (3 ml) was added a solution of nitrosobenzene
(0.11 g, 1.00 mmol, 1.0 eq.) in DMSO (2 ml) dropwise via syringe
over 1 h. The reaction mixture was allowed to stir for a further
1 h, then vinyltriphenylphosphonium bromide (0.57 g, 1.50 mmol,
1.5 eq.) was added. The resulting solution was added to a stirred
suspension of KH (0.40 g, 30% in mineral oil, washed with
hexane, 3.00 mmol, 3.0 eq.) in THF (5 ml) at 0 ◦C. After 2 h
(3R)-3-Methyl-2-phenyl-3,6-dihydro-2H-1,2-oxazine
(16a).
Prepared according to the general procedure from
propionaldehyde (0.13 ll, 0.180 mmol) to provide the title
compound as a yellow oil (4 mg, 33%) after flash column
chromatography (3 : 1, petrol–CH2Cl2). Rf 0.72 (3 : 1, petrol–
◦
of vigorous stirring at 0 C, the reaction mixture was quenched
using saturated aqueous NH4Cl (20 ml), extracted with ether (3 ×
30 ml), and washed with saturated aqueous LiCl (20 ml). The
combined organic phase was dried using MgSO4, filtered and
concentrated in vacuo. The resulting residue was purified by flash
column chromatography (solvent noted) to provide the oxazine
products.
25
EtOAc); [a]D + 183.3 (c 0.06 in CHCl3); mmax (film) 2959, 2928,
2859, 1726, 1599, 1492, 1460, 1379, 1268, 1121, 1072, 1057,
958, 878, 754, 693 cm−1; dH (600 MHz, CDCl3) 1.11 (3H, d, J
=
=
6.6 Hz, CH3CHCH CH), 4.09–4.14 (1H, m, CH3CHCH CH),
ꢀ
=
4.37 (1H, dddd, J 15.6, 3.2, 1.8, 1.8 Hz, CH CHCHH O),
ꢀ
=
(8aR)-2-Phenyl-3,5,6,7,8,8a-hexahydro-2H-benzo[e][1,2]oxa-
zine (8a). Prepared according to the general procedure from
cyclohexanone (0.32 ml, 3.00 mmol) to provide the title
compound as an orange solid (0.13 g, 60%, 99% ee) after
flash column chromatography (20 : 1, petrol–EtOAc). Rf 0.64
4.57 (1H, app dq, J 15.6, 1.8 Hz, CH CHCHH O), 5.89 (1H,
dddd, J 10.0, 3.2, 1.8, 1.8 Hz, CH CHCH2O), 5.94 (1H, dddd,
J 10.0, 4.1, 1.8, 1.8 Hz, CH CHCH2O), 6.98 (1H, tt, J 7.3,
=
=
1.1 Hz, PhH-para), 7.09 (2H, dd, J 8.7, 1.1 Hz, 2 × PhH-ortho),
7.30 (2H, dd, J 8.7, 7.3 Hz, 2 × PhH-meta); dC (150 MHz,
(3 : 1, petrol–EtOAc); m.p. 51–53 ◦C; [a]D +133.3 (c 0.73
CDCl3) 14.6 (CH3CHCH CH), 55.5 (CH3CHCH CH), 68.7
25
=
=
=
in CHCl3); mmax (film) 3059, 2934, 2854, 2818, 1597, 1486,
1445, 1437, 1361, 1342, 1220, 1193, 1180, 1149, 1093, 1064,
1014, 993, 921, 880, 860, 835, 820, 785, 751, 722, 689 cm−1;
(CH CHCH2O), 116.8 (2 × PhC-ortho), 122.0 (PhC-para), 124.9
=
=
(CH CHCH2O), 128.8 (2 × PhC-meta), 129.4 (CH CHCH2O),
148.8 (PhC-N); m/z (ES) found 176.1078 ([M+H]+ C11H14NO),
requires 176.1075.
ꢀ
=
dH (600 MHz, CDCl3) 1.25–1.33 (1H, m, CH CCH2CHH ),
ꢀ
ꢀ
=
1.36–1.48 (2H, m, CH C(CH2)2CHH CHH ), 1.76–1.80 (1H,
ꢀ
ꢀ
=
=
m, CH CCH2CHH ), 1.85–1.89 (1H, m, CH C(CH2)2CHH ),
General procedure for the synthesis of cis-allylic alcohols through
N–O cleavage
ꢀ
=
2.02–2.09 (1H, m, CH CCHH (CH2)3), 2.14–2.18 (1H, m,
CH C(CH2)3CHH ), 2.38 (1H, dddd, J 14.2, 4.2, 2.1, 2.1 Hz,
J 15.4, 2.7 Hz,
PhNCHH CH C), 3.88 (1H, dddd, J 15.4, 5.1, 2.5, 2.5 Hz,
PhNCHH CH C), 4.49–4.54 (1H, m, PhNOCH(CH2)4), 5.58–
5.60 (1H, m, PhNCH2CH C), 6.98 (1H, tt, J 7.3, 1.0 Hz,
ꢀ
=
ꢀ
=
CH CCHH (CH2)3), 3.72 (1H, app dq,
To a stirred solution of the 1,2-oxazine (1 eq.) in MeOH was added
zinc powder (5 eq.) and 3N aqueous HCl (20 eq.). The resulting
suspension was stirred vigorously at room temperature until the
reaction was determined to be complete by TLC. The reaction
mixture was quenched using saturated aqueous NaHCO3, diluted
with H2O and extracted with EtOAc three times. The combined
organic phase was dried (MgSO4), filtered and concentrated in
vacuo. The resulting residue was purified by flash column chro-
matography (solvents noted) to provide the desired compound.
ꢀ
=
ꢀ
=
=
PhH-para), 7.14 (2H, dd, J 8.7, 1.0 Hz, 2 × PhH-ortho), 7.30
(2H, dd, J 8.7, 7.3 Hz, 2 × PhH-meta); dC (150 MHz, CDCl3)
=
=
23.9 (CH C(CH2)2CH2CH2), 26.8 (CH CCH2CH2(CH2)2),
=
=
31.4 (CH C(CH2)3CH2), 32.2 (CH CCH2(CH2)3), 52.1
=
=
(PhNCH2CH C), 78.3 (NOCH(CH2)4), 114.8 (PhNCH2CH C),
115.9 (2 × PhC-ortho), 122.0 (PhC-para), 128.7 (2 × PhC-meta),
=
140.3 (PhNCH2CH C), 150.6 (PhC-N); m/z (ES) found 216.1380
(R,Z)-2-(2-(Phenylamino)ethylidene)cyclohexanol (13a). Pre-
pared according to the general procedure from (6R)-2-
phenyl-3,5,6,7,8,8a-hexahydro-2H-benzo[e][1,2]oxazine (19 mg,
0.084 mmol) for 48 h to provide the title compound as a brown
solid (15 mg, 83%, 99% ee) after flash column chromatography
(3 : 1, petrol–EtOAc with 1% triethylamine). Rf 0.28 (3 :
1, petrol–EtOAc with 1% triethylamine); m.p. 56–57 ◦C;
([M+H]+ C14H18NO), requires 216.1388; HPLC (Chiralpak AD–
H, 99 : 1, hexane–iPrOH, 0.5 ml min−1, 254 nm) tR(major)
10.1 min, tR(minor) 10.8 min.
General procedure for the synthesis of 1,2-oxazines catalysed by
the Maruoka catalyst
25
[a]D −48.4 (c 0.55 in CHCl3); mmax (film) 3675, 3257, 2930,
To a stirred solution of the Maruoka catalyst (4 mg, 0.006 mmol,
10 mol%) in THF (0.5 ml) was added nitrosobenzene (7 mg,
0.060 mmol, 1.0 eq.) in one portion at 0 ◦C. The resulting solution
was stirred vigorously for 10 min before dropwise addition of the
appropriate aldehyde (0.180 mmol, 3.0 eq.). The reaction mixture
2901, 2808, 1601, 1522, 1497, 1439, 1408, 1301, 1251, 1234,
1146, 1089, 1060, 1037, 986, 914, 857, 749, 691 cm−1; dH
ꢀ
=
(500 MHz, CDCl3) 1.37 (1H, m, CH CCH2CHH (CH2)2),
ꢀ
ꢀ
=
1.49–1.61 (2H, m, CH C(CH2)2CHH CHH ), 1.69–1.90 (3H, m,
CH CCH2CHH CHH CHH ), 2.00 (1H, app dt, J 13.5, 4.2 Hz,
ꢀ
ꢀ
ꢀ
=
2686 | Org. Biomol. Chem., 2007, 5, 2678–2689
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©

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ꢀ
ꢀ
=
=
CH CCHH (CH2)3), 2.39–2.46 (1H, m, CH CCHH (CH2)3),
butyldimethylsilyloxy)propanal (226 mg, 1.2 mmol) and diethyl
azodicarboxylate (97% purity, 162 ll, 179 mg, 1.0 mmol) and
proline as a catalyst. Reaction time for the a-amination was 48 h.
Purification by gradient flash column chromatography (10 : 1 →
2 : 1, hexane–EtOAc) gave the title compound as a colourless oil
(105 mg, 44%). Rf 0.50 (3 : 1, hexane–EtOAc); mmax (film) 2983,
2937, 2910, 1713, 1646, 1600, 1466, 1398, 1372, 1327, 1282, 1257,
1207, 1172, 1127, 1090, 1037, 1022, 952, 910, 872, 754 cm−1; dH
(600 MHz, CDCl3) 1.13–1.31 (6H, m, 2 × CO2CH2CH3), 3.67–
3.95 (1H, m, NCHHꢀ), 4.04–4.31 (4H, m, 2 × CO2CH2CH3),
=
3.73–3.82 (2H, m, PhNHCH2CH C), 4.70 (1H, t, J 3.7 Hz,
=
=
CH CCHOH), 5.38–5.42 (1H, m, PhNHCH2CH C), 6.64 (2H,
dd, J 8.6, 1.1 Hz, 2 × PhH-ortho), 6.73 (1H, tt, J 7.3, 1.1 Hz,
PhH-para), 7.18 (2H, dd, J 8.6, 7.3 Hz, 2 × PhH-meta);
=
dC (125 MHz, CDCl3) 20.8 (CH C(CH2)2 CH2CH2), 27.8
=
=
(CH CCH2CH2(CH2)2),
32.7
(CH CCH2(CH2)3),
34.6
=
=
(CH C(CH2)3CH2), 40.9 (PhNHCH2), 65.5 (CH CCHOH),
113.4 (2 × PhC-ortho), 118.0 (PhC-para), 120.9 (PhNHCH2-
=
=
CH C), 129.2 (2 × PhC-meta), 144.3 (PhNHCH2CH C), 147.9
(PhC–N); m/z (ES) found 240.1365 ([M+Na]+ C14H19NONa),
requires 240.1364; HPLC (Chiralcel OD-H, 90 : 10, hexane–
iPrOH, 1.0 ml min−1, 254 nm) tR(minor) 28.6 min, tR(major)
35.1 min.
ꢀ
ꢀ
=
4.37–4.67 (1H, m, NCHH ), 4.93 (1H, s, C CHH ), 5.21–5.56
ꢀ
=
=
=
(1H, m, C CHH ), 5.85 (1H, br s, CH CHC CH2), 6.06
=
=
(1H, d, CH CHC CH2); dC (150 MHz, CDCl3) 14.4 (2 ×
CO2CH2CH3), 43.8 (NCH2), 62.5 and 62.6 (2 × CO2CH2CH3),
=
=
=
=
108.0 (CH CHC CH2), 124.5 and 125.0 (CH CHC CH2),
=
=
137.2 (CH CHC CH2), 155.7 (2 × CO2CH2CH3); m/z (ESI)
General procedure for the synthesis of 3,6-dihydropyridazines from
aldehydes
found 263.1000 ([M+Na]+ C11H16N2O4Na), requires 263.1008.
To a stirred solution of the appropriate aldehyde (1.2 eq.) and
aminating agent (1.0 eq.) in CH2Cl2 (3 ml per mmol of the
aminating agent) was added (2S)-5-pyrrolidin-2-yl-1H-tetrazole
catalyst (10 mol%). The resulting suspension was stirred at room
temperature until the yellow colour of the azodicarboxylate
or the red colour of the N-phenyltriazolinedione, respectively,
disappeared. The mixture was then cooled to 0 ◦C, THF (1 ml
per ml of CH2Cl2) added. Vinyltriphenylphosphonium bromide
(1.5 eq.) was added, followed by NaH (2.5 eq.). After 45 min of
stirring at 0 ◦C, the reaction mixture was quenched using saturated
aqueous NH4Cl (2 ml per ml reaction volume) and extracted with
CH2Cl2 (3 × 1 ml per ml reaction volume). The combined organic
layers were washed with brine (2 ml per ml reaction volume)
and dried over MgSO4, filtered and concentrated in vacuo. The
resulting residue was purified by flash column chromatography
(solvents noted) to provide the title compounds.
General procedure for the synthesis of pyridazines from ketones
To a stirred solution of the appropriate ketone (1.2 eq.) and
diethyl azodicarboxylate (1.0 eq.) in CH2Cl2 (5 ml per mmol of
diethyl azodicarboxylate) was added (2S)-5-pyrrolidin-2-yl-1H-
tetrazole catalyst (20 mol%). The reaction mixture was stirred
at room temperature for 24 h. DMSO (1 ml per ml of CH2Cl2)
and vinyltriphenylphosphonium bromide (1.5 eq.) were added.
◦
The solution was cooled to 0 C and then added in one portion
via syringe to a suspension of KH (2.5 eq., 30%, in mineral oil,
washed with hexane (2 × 3 ml)) in THF (1 ml per ml of CH2Cl2)
at 0 ◦C. The reaction mixture was slowly allowed to warm to
room temperature and quenched after 270 min with saturated
aqueous NH4Cl (2 ml per ml reaction volume) and extracted with
CH2Cl2 (2 × 1 ml per ml reaction volume). The combined organic
layers were washed with saturated aqueous LiCl (2 ml per ml
reaction volume), brine (2 ml per ml reaction volume) and dried
over MgSO4, filtered and concentrated in vacuo. The resulting
residue was purified by flash column chromatography (solvents
noted) to provide the title compounds.
(3R)-3-Isopropyl-3,6-dihydro-pyridazine-1,2-dicarboxylic acid
diethyl ester (18a). Prepared according to the general procedure
from isovaleraldehyde (130 ll, 103 mg, 1.2 mmol) and diethyl
azodicarboxylate (97% purity, 162 ll, 179 mg, 1.0 mmol).
Purification by gradient flash column chromatography (10 : 1 →
2 : 1, petrol–EtOAc) gave the title compound as a colourless
(8aR)-3,5,6,7,8,8a-Hexahydrocinnoline-1,2-dicarboxylic acid di-
ethyl ester (21a). Prepared according to the general procedure
from cyclohexanone (124 ll, 118 mg, 1.2 mmol) to provide the
title compound as a colourless oil (147 mg, 52%, 76% ee) after
flash column chromatography (5 : 1, petrol–EtOAc). Rf 0.62
25
oil (241 mg, 89%, 94% ee). Rf 0.45 (3 : 1, petrol–EtOAc); [a]D
−98.3 (c 1.00 in CHCl3); mmax (film) 2961, 2872, 1705, 1467,
1407, 1378, 1337, 1287, 1211, 1173, 1111, 1059, 1024, 926, 872,
826, 755, 707 cm−1; dH (400 MHz, CDCl3) 0.95–1.02 (3H, m,
CH(CH3)(CHꢀ3)), 1.06 (2.25H, d, J 6.6 Hz, CH(CH3)(CHꢀ3) of
major rotamer), 1.11 (0.75H, d, J 6.6 Hz, CH(CH3)(CHꢀ3) of
minor rotamer), 1.19–1.33 (6H, m, 2 × CH2CH3), 1.71–1.85 (1H,
m, CH(CH3)2), 3.62–3.95 (1H, m, NCHHꢀ), 4.02–4.30 (5H, m,
NCH and 2 × CO2CH2CH3), 4.30–4.40 (1H, m, NCHHꢀ), 5.66–
25
(2:1, petrol–EtOAc); [a]D −101.2 (c 2.00 in CHCl3); mmax (film)
2933, 2856, 2295, 1704, 1415, 1382, 1342, 1298, 1240, 1216, 1172,
1141, 1115, 1094, 1070, 1047, 1026, 960, 884, 799, 755 cm−1; dH
(400 MHz, CDCl3) 1.08–1.35 (7H, m, one of (CH2)4 and 2 ×
CH2CH3), 1.38–1.52 (2H, m, two of (CH2)4), 1.71–1.90 (2H, m,
two of (CH2)4), 1.91–2.10 (2H, m, two of (CH2)4), 2.20–2.32 (1H,
m, one of (CH2)4), 3.55–3.90 (1H, m, NCHHꢀ), 4.15–4.22 (4H,
m, 2 × CO2CH2CH3), 4.22–4.46 (2H, m, NCH and NCHHꢀ),
=
5.82 and 5.83–5.95 (2H, m, CH CH); dC (100 MHz, CDCl3) 14.5
and 14.6 (CH2CH3), 19.1 and 20.1 (CH(CH3)2), 32.2 (CH(CH3)2),
42.5 (NCH2), 60.7 (NCH), 62.0 and 62.3 (2 × CO2CH2CH3),
=
5.42 (1H, br s, C CH); dC (100 MHz, CDCl3) 14.9 and 15.0 (2 ×
=
122.8 and 127.1 (CH CH), 155.4 (2 × CO2CH2CH3); m/z (ESI)
CO2CH2CH3); 25.5, 28.1, 32.6 and 35.1 ((CH2)4), 43.2 (NCH2),
found 293.1476 ([M+Na]+ C13H22N2O4Na), requires 293.1477;
SFC (Chiralcel OD-H, 10% iPrOH in CO2, 1.0 ml min−1, 100 bar,
200 nm) tR(major) 6.0 min, tR(minor) 4.9 min.
=
57.1 (NCH), 62.3 and 62.5 (2 × CO2CH2CH3), 114.4 (C CH),
=
139.5 (C CH), 155.7 and 156.0 (2 × CO2CH2CH3); m/z (ESI)
found 305.1486 ([M+Na]+ C14H22N2O4Na), requires 305.1477;
SFC (Chiralcel OD-H, 10% iPrOH in CO2, 1.0 ml min−1, 100 bar,
200 nm) tR(major) 9.2 min, tR(minor) 7.9 min.
Diethyl 3-methylenepyridazine-1,2(3H,6H)-dicarboxylate (19).
Prepared according to the general procedure from 3-(tert-
This journal is
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10 (a) S. Kumarn, D. M. Shaw, D. A. Longbottom and S. V. Ley, Org.
Lett., 2005, 7, 4189; (b) S. Kumarn, D. M. Shaw and S. V. Ley, Chem.
Commun., 2006, 3211.
Acknowledgements
We gratefully acknowledge the Royal Thai Government (to S.K.),
the Studienstiftung des Deutschen Volkes (to A.J.O.), AstraZeneca
(to D.M.S.), EPSRC and Trinity College (to D.A.L.) and Novartis
for a Research Fellowship (to S.V.L.). We thank Dr G. Sedelmeier
and V. Aureggi for the kind donation of (2R)-5-pyrrolidin-2-
yl-1H-tetrazole and Prof. Keiji Maruoka for kindly supplying
a quantity of his catalyst, 14. We also thank Dr J. Davies for
determining the crystal structure of 20d and the EPSRC for
financial assistance towards the purchase of the Rikagu AFC7R
diffractometer. Thanks also to Dr Matthew Ball, Dr Alejandro
Dieguez, Dr Steve Lanners and Dr Matthew O’Brien for useful
discussions.
11 For representative papers, see: (a) G. Zhong, Angew. Chem., Int. Ed.,
2003, 42, 4247; (b) S. P. Brown, M. P. Brochu, C. J. Sinz and D. W. C.
MacMillan, J. Am. Chem. Soc., 2003, 125, 10808; (c) A. Bøgevig, H.
Sunde´n and A. Co´rdova, Angew. Chem., Int. Ed., 2004, 43, 1109; (d) Y.
Hayashi, J. Yamaguchi, T. Sumiya and M. Shoji, Angew. Chem., Int. Ed.,
2004, 43, 1112; (e) Y. Hayashi, J. Yamaguchi, K. Hibino and M. Shoji,
Tetrahedron Lett., 2003, 44, 8293; (f) Y. Yamamoto, N. Momiyama and
H. Yamamoto, J. Am. Chem. Soc., 2004, 126, 5962; (g) N. Momiyama,
H. Torii, S. Saito and H. Yamamoto, Proc. Natl. Acad. Sci. U. S. A.,
2004, 101, 5374; (h) W. Wang, J. Wang, H. Li and L. Liao, Tetrahedron
Lett., 2004, 45, 7235; (i) D. B. Ramachary and C. F. Barbas, III, Org.
Lett., 2005, 7, 1577; (j) S. P. Mathew, H. Iwamura and D. G. Blackmond,
Angew. Chem., Int. Ed., 2004, 43, 3317.
12 E. E. Schweizer, J. E. Hayes and E. M. Hanawalt, J. Org. Chem., 1985,
50, 2591.
13 A. J. Oelke, S. Kumarn, D. A. Longbottom and S. V. Ley, Synlett, 2006,
2548.
Notes and references
14 (a) A. J. A. Cobb, D. M. Shaw and S. V. Ley, Synlett, 2004, 558;
(b) A. J. A. Cobb, D. A. Longbottom, D. M. Shaw and S. V. Ley,
Chem. Commun., 2004, 1808; (c) A. J. A. Cobb, D. M. Shaw, D. A.
Longbottom, J. B. Gold and S. V. Ley, Org. Biomol. Chem., 2005, 3,
84; (d) C. E. T. Mitchell, S. E. Brenner and S. V. Ley, Chem. Commun.,
2005, 5346; (e) K. R. Knudsen, C. E. T. Mitchell and S. V. Ley, Chem.
Commun., 2006, 66; (f) C. E. T. Mitchell, S. E. Brenner, J. Garc´ıa-
Fortanet and S. V. Ley, Org. Biomol. Chem., 2006, 4, 2039; (g) V.
Franckevicˇius, K. R. Knudsen, M. Ladlow, D. A. Longbottom and
S. V. Ley, Synlett, 2006, 889; (h) V. Franckevicˇius, D. A. Longbottom,
R. M. Turner and S. V. Ley, Synthesis, 2006, 19, 3215; (i) H. M.
Hansen, D. A. Longbottom and S. V. Ley, Chem. Commun., 2006,
4838; (j) V. Aureggi, V. Franckevicˇius, M. O. Kitching, S. V. Ley, D. A.
Longbottom, A. J. Oelke, G. Sedelmeier, Org. Synth., 2007, submitted;
(k) D. A. Longbottom, V. Franckevicˇius, S. Kumarn, A. J. Oelke, V.
Wascholowski, S. V. Ley, Aldrichimica Acta, 2007, submitted.
15 H. Torii, M. Nakadai, K. Ishihara, S. Saito and H. Yamamoto, Angew.
Chem., Int. Ed., 2004, 43, 1983.
16 (a) A. Hartikka and P. I. Arvidsson, Tetrahedron: Asymmetry, 2004,
15, 1831; (b) A. Hartikka and P. I. Arvidsson, Eur. J. Org. Chem., 2005,
4287.
17 For examples, see: (a) N. S. Chowdari, M. Ahmad, K. Albertshofer, F.
Tanaka and C. F. Barbas, III, Org. Lett., 2006, 8, 2839; (b) S.-G. Kim
and T.-H. Park, Tetrahedron Lett., 2006, 47, 9067.
18 The absolute configuration of a-oxyaminated ketone intermediates and
oxazine products from both aldehydes and ketones was determined by
correlation with the aD values found from the analogous reactions using
L-proline as catalyst.
1 (a) L. F. Tietze, Chem. Rev., 1996, 96, 115; (b) L. F. Tietze and U.
Beifuss, Angew. Chem., Int. Ed. Engl., 1993, 32, 131; (c) C. Simon, T.
Constantieux and J. Rodriguez, Eur. J. Org. Chem., 2004, 4957; (d) D. J.
Ramon and M. Yus, Angew. Chem., Int. Ed., 2005, 44, 1602; (e) H.
Guo and J. Ma, Angew. Chem., Int. Ed., 2006, 45, 354; (f) H. Pellisier,
Tetrahedron, 2006, 62, 2143; (g) K. C. Nicolaou, T. Montagnon and
S. A. Synder, Chem. Commun., 2003, 551; (h) B. M. Trost, Angew.
Chem., Int. Ed. Engl., 1995, 34, 259; (i) L. F. Tietze and A. Modi, Med.
Res. Rev., 2000, 20, 304; (j) D. Enders, C. Grondal and M. R. M. Hu¨ttl,
Angew. Chem., Int. Ed., 2007, 46, 1570.
2 For representative papers, see: (a) D. Enders, M. R. M. Hu¨ttl, C.
Grondal and G. Raabe, Nature, 2006, 441, 861; (b) U. Eder, G. Sauer
and R. Wiechert, Angew. Chem., Int. Ed. Engl., 1971, 10, 496; (c) Z. G.
Hajos and D. R. Parrish, J. Org. Chem., 1974, 39, 1615; (d) G. Zhong,
T. Hoffmann, R. A. Lerner, S. J. Danishefsky and C. F. Barbas, III,
J. Am. Chem. Soc., 1997, 119, 8131; (e) B. List, R. A. Lerner and C. F.
Barbas, III, Org. Lett., 1999, 1, 59; (f) T. Bui and C. F. Barbas, III,
Tetrahedron Lett., 2000, 41, 6951; (g) T. Itoh, M. Yokoya, K. Miyauchi,
K. Nagata and A. Ohsawa, Org. Lett., 2003, 5, 4301; (h) N. Halland,
P. S. Aburel and K. A. Jørgensen, Angew. Chem., Int. Ed., 2004, 43,
1272; (i) J. Pukkinen, P. S. Aburel, N. Halland and K. A. Jørgensen,
Adv. Synth. Catal., 2004, 346, 1077; (j) Y. Yamamoto, N. Momiyama
and H. Yamamoto, J. Am. Chem. Soc., 2004, 126, 5962; (k) Y. Huang,
A. Walji, C. H. Larsen and D. W. C. MacMillan, J. Am. Chem. Soc.,
2005, 127, 15051; (l) J. W. Yang, M. T. Hechavarria Fonseca and B.
List, J. Am. Chem. Soc., 2005, 127, 15036; (m) M. Marigo, S. Bertelsen,
A. Landa and K. A. Jørgensen, J. Am. Chem. Soc., 2006, 128, 5475;
(n) M. Marigo, T. Schulte, J. Franze´n and K. A. Jørgensen, J. Am.
Chem. Soc., 2005, 127, 15710; (o) H. Sunde´n, I. Ibrahem, L. Erikson
and A. Co´rdova, Angew. Chem., Int. Ed., 2005, 44, 4877; (p) W. Wang,
H. Li, J. Wang and L. Zu, J. Am. Chem. Soc., 2006, 128, 10354.
3 For recent reviews on organocatalysis, see: (a) P. I. Dalko and L.
Moisan, Angew. Chem., Int. Ed., 2004, 43, 5138; (b) A. Berkessel,
H. Gro¨ger, Asymmetric Organocatalysis, Wiley-VCH, Weinheim, Ger-
many, 2005; (c) J. Seayad and B. List, Org. Biomol. Chem., 2005, 3, 719;
(d) M. J. Gaunt, C. C. C. Johansson, A. McNally and N. T. Vo, Drug
Discovery Today, 2007, 12, 9; (e) Acc. Chem. Res., 2004, 37(8), special
issue on organocatalysis.
19 For TBS mono-protection of diols, see: (a) P. G. McDougal, J. G. Rico,
Y.-I. Oh and B. D. Condon, J. Org. Chem., 1986, 51, 3388; (b) For
2k and its corresponding alcohol, see: A. Fu¨rstner, M. D. B. Fenster,
B. Fasching, C. Godbout and K. Radkowski, Angew. Chem., Int. Ed.,
2006, 45, 5506, or (a); (c) For 2l and its corresponding alcohol, see:
L. Coppi, A. Ricci and M. Taddei, J. Org. Chem., 1988, 53, 911; C.
Gennari and P. G. Cozzi, J. Org. Chem., 1988, 53, 4015; (d) For 2m
and its corresponding alcohol, see: Y. Ikeda, J. Ukai, N. Ikeda and H.
Yamamoto, Tetrahedron, 1987, 43, 731, or (a); (e) For 2n, see: K. A.
Parker and T. Iqbal, J. Org. Chem., 1987, 52, 4369; for its corresponding
alcohol, see: C. Garc´ıa, T. Mart´ın and V. S. Mart´ın, J. Org. Chem., 1988,
53, 4015; (f) For 2o and its corresponding alcohol, see: J. A. Marshall,
B. G. Shearer and S. L. Crooks, J. Org. Chem., 1987, 52, 1236, or (a);
(g) For 2p and its corresponding alcohol, see: L. Bo¨rjesson, I. Cso¨regh
and C. J. Welch, J. Org. Chem., 1995, 60, 2989.
4 (a) D. R. Williams, P. A. Jass, H. L. A. Tse and R. D. Gaston, J. Am.
Chem. Soc., 1990, 112, 4552; (b) D. E. Ward, V. Jheengut and G. E.
Beye, J. Org. Chem., 2006, 71, 8989; (c) D. Enders, A. Lenzen and M.
Mu¨ller, Synthesis, 2004, 9, 1486.
20 A. Defoin, Synthesis, 2004, 5, 706.
5 (a) J. Hamer, A. Ahmad and R. E. Holliday, J. Org. Chem., 1963, 28,
3034; (b) G. Kresze, J. Firl, H. Zimmer and U. Wollnik, Tetrahedron,
1964, 20, 1605.
21 (a) D. Seyferth and J. Fogel, J. Organomet. Chem., 1966, 6, 205; (b) E. E.
Schweizer, A. T. Wehman and D. M. Nycz, J. Org. Chem., 1973, 38,
1583.
6 Y.-K. Yang and J. Tae, Synlett, 2003, 1043.
22 P. T. Keough and M. Grayson, J. Org. Chem., 1964, 29, 631.
23 Diastereomeric ratio was obtained by crude 1H NMR and relative
stereochemistry was assigned from 700 MHz NOESY spectra.
24 Assigned by 700 MHz NOESY spectrum.
7 (a) H. Yamamoto and M. Kawasaki, Bull. Chem. Soc. Jpn., 2007, 80,
595; (b) N. Momiyama, Y. Yamamoto and H. Yamamoto, J. Am. Chem.
Soc., 2007, 129, 1190.
8 (a) P. F. Vogt and M. J. Miller, Tetrahedron, 1998, 54, 1317; (b) J.
Streith and A. Defoin, Synlett, 1996, 189; (c) S. E. Denmark and A.
Thorarensen, Chem. Rev., 1996, 96, 137.
25 T. Kano, M. Ueda, J. Takai and K. Maruoka, J. Am. Chem. Soc., 2006,
128, 6046.
26 No further experiments were conducted owing to small amount of
catalyst available to us via a generous gift from Prof. Keiji Maruoka.
9 X. Ding, Y. Ukaji, S. Fujinami and K. Inomata, Chem. Lett., 2003, 32,
582.
2688 | Org. Biomol. Chem., 2007, 5, 2678–2689
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27 (a) For the a-amination of aldehydes, see: A. Bøgevig, K. Juhl, N.
Kumaragurubaran, W. Zhuang and K. A. Jørgensen, Angew. Chem.,
Int. Ed., 2002, 41, 1790; (b) B. List, J. Am. Chem. Soc., 2002, 124,
5656; (c) H. Vogt, S. Vanderheiden and S. Brase, Chem. Commun.,
2003, 2448; (d) For a-amination on other substrates or its use in total
synthesis, see: N. Kumaragurubaran, K. Juhl, W. Zhuang, A. Bøgevig
and K. A. Jørgensen, J. Am. Chem. Soc., 2002, 124, 6254; (e) K. Juhl
and K. A. Jørgensen, J. Am. Chem. Soc., 2002, 124, 2420; (f) M. Marigo,
K. Juhl and K. A. Jørgensen, Angew. Chem., Int. Ed., 2003, 42, 1367;
(g) S. Saaby, M. Bella and K. A. Jørgensen, J. Am. Chem. Soc., 2004,
126, 8120; (h) W. Pei, H.-X. Wei, D. Chen, A. D. Headley and G. Li,
J. Org. Chem., 2003, 68, 8404; (i) H. Iwamura, S. P. Mathew and D. G.
Blackmond, J. Am. Chem. Soc., 2004, 126, 11770; (j) X. Liu, H. Li and
L. Deng, Org. Lett., 2005, 7, 167; (k) N. S. Chowdari and C. F. Barbas,
III, Org. Lett., 2005, 7, 867; (l) J. T. Suri, D. D. Steiner and C. F. Barbas,
III, Org. Lett., 2005, 7, 3885.
This journal is
The Royal Society of Chemistry 2007
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