Regioisomeric and Substituent Effects upon the Outcome of the Reaction of 1-Borodienes with Nitrosoarene Compounds

Article abstract of DOI:10.1021/acs.joc.5b00593

A study of the reactivity of 1-borodienes with nitrosoarene compounds has been carried out showing an outcome that differs according to the hybridization state of the boron moiety. Using an sp² boron substituent, a one-pot hetero-Diels-Alder/ring contraction cascade occurred to afford N-arylpyrroles with low to good yields depending on the electronic properties of the substituents on the borodiene, whereas an sp³ boron substituent led to the formation of stable boro-oxazines with high regioselectivity in most of the cases, in moderate to good yields. ¹H and ¹¹B NMR studies on two boro-oxazine regioisomers showed that selective deprotection can be performed. Formation of either the pyrrole or the furan derivative is pH- and regioisomer-structure-dependent. The results obtained, together with previous B3LYP calculations, support mechanistic proposals which suggest that pyrrole, or furan, formation proceeds via oxazine formation, followed by a boryl rearrangement and an intramolecular addition-elimination sequence.

Full text of DOI:10.1021/acs.joc.5b00593

Article
pubs.acs.org/joc
Regioisomeric and Substituent Effects upon the Outcome
of the Reaction of 1‑Borodienes with Nitrosoarene Compounds
Ludovic Eberlin,†,‡ Bertrand Carboni,*,† and Andrew Whiting*,‡
†Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS-Universite
35042 Rennes Cedex, France
́
de Rennes 1, Campus de Beaulieu, CS 74205,
‡Centre for Sustainable Chemical Processes, Department of Chemistry, Durham University, South Road, Durham DH1 3LE, U. K.
S
* Supporting Information
ABSTRACT: A study of the reactivity of 1-borodienes with
nitrosoarene compounds has been carried out showing an
outcome that differs according to the hybridization state of
the boron moiety. Using an sp2 boron substituent, a one-pot
hetero-Diels−Alder/ring contraction cascade occurred to
afford N-arylpyrroles with low to good yields depending on the electronic properties of the substituents on the borodiene,
whereas an sp3 boron substituent led to the formation of stable boro-oxazines with high regioselectivity in most of the cases, in
moderate to good yields. 1H and 11B NMR studies on two boro-oxazine regioisomers showed that selective deprotection can be
performed. Formation of either the pyrrole or the furan derivative is pH- and regioisomer-structure-dependent. The results
obtained, together with previous B3LYP calculations, support mechanistic proposals which suggest that pyrrole, or furan,
formation proceeds via oxazine formation, followed by a boryl rearrangement and an intramolecular addition−elimination
sequence.
of both steric and electronic effects on both the nitroso and the
diene partners. For example, Houk et al. examined mono-
substituted dienes and their addition to numerous nitroso
derivatives6 and established a correlation between regioselec-
tivity and (1) the properties and position of substituents on the
diene and (2) the nature of the nitroso compound. More
recently, Kouklovsky et al. examined 1,2-disubstituted dienes
and their reaction with Boc-nitroso compounds to derive
nitroso Diels−Alder cycloadducts with high regioselectivity.7
To predominantly obtain the distal isomer, it is necessary for
the diene to bear a bulky substituent at C1 and an electron-
donating group at the C2 position. For the proximal isomer, a
nonbulky substituent at C1 and an electron-withdrawing group
at C2 are required. Nevertheless, regioselectivity is also
dependent upon the nature of the nitroso compound.
INTRODUCTION
■
The hetero-Diels−Alder reaction between a nitroso hetero-
dienophile and a diene is a useful tool in organic chemistry.
Since 1947 and the pioneering work of Wichterle,1 this reaction
has been widely studied and numerous nitroso and diene
partners have been used to enlarge its scope and efficiency.
A large range of nitroso reagents, including acylnitroso, nitro-
soarene, chloronitroso, etc., have been used, as well as
substituted acyclic, cyclic, and heterocyclic dienes to provide
3,6-dihydro-1,2-oxazine scaffolds.2 The resulting oxazine
skeleton is a key intermediate in the synthesis of natural
products, such as alkaloid derivatives,3 heterocycles,4 and
saccharide mimetics.5 However, the modest regioselectivity
encountered with some types of unsymmetric dienes can
constitute an important limitation for applications in organic
synthesis. The nitroso [4 + 2]-cycloaddition can provide two
regioisomers: the distal isomer (major substituent close to the
nitrogen of the oxazine cycloadduct) and the proximal isomer
(major substituent close to the oxygen of the oxazine
cycloadduct) (Scheme 1). Several studies on the regiocontrol
of this reaction have shown that it results from a combination
Despite the synthetic utility of borodienes,8 especially in
multicomponent and cascade processes, no investigation of the
reaction of borodienes has been carried out with nitroso com-
pounds until our recent preliminary communication, which fo-
cused on the reaction of 1,3-dienylboronic esters 1 (Scheme 1,
R1 = Bpin) with aryl nitroso derivatives 2.9 In addition to the
possible postfunctionalization of the resulting cycloadducts, we
expected that tuning of the electronic properties of the
boronated group through the introduction of various
substituents on boron10 would provide an insight into the
control of the regioselectivity of the [4 + 2] cycloaddition
reaction and, therefore, the subsequent transformation of the
resulting cycloadducts. Herein, we report the full details of
Scheme 1. Regioselectivity of Nitroso Diels−Alder Reaction
with Mono- and Disubstituted Dienes
Received: March 16, 2015
© XXXX American Chemical Society
A
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these studies, especially the impact of varying the nature of both
the borodiene and the dienophile substituents upon the
reaction outcome, and, hence, discuss the mechanistic
implications of the results.
Table 1. Pyrrole Formation from the Reaction of
Nitrosoarenes with Diene 1
RESULTS AND DISCUSSION
■
Reaction of 1-Dienylboronate Pinacolate Esters with
Nitrosoarene Compounds. As reported previously,9 initial
investigations into the reaction between the dienyl boronate
1 and nitrosobenzene 2 resulted in the formation of the
unexpected N-phenylpyrrole 3a instead of a mixture of
regioisomeric oxazine cycloadducts (Scheme 2). Given that
Scheme 2. N-Phenylpyrrole Formation from the Reaction of
Boronated Diene 1 and Nitrosobenzene 2
such reactions tend to lack high regiocontrol,2 the efficiency of
the pyrrole formation was intriguing and clearly required
further study and explanation. Indeed, even when the reaction
1
was followed by H NMR, only 3-methyl-1-phenyl-pyrrole 3a,
together with some azoxybenzene 4, was identified. There was
a notable absence of any oxazine cycloadducts, and the re-
action was complete after 5 h to afford 3a in 82% isolated yield
(Table 1, entry 3).
Further studies to address the scope of this reaction were
conducted, the results of which are summarized in Table 1.
Differently substituted nitrosoarene compounds were reacted
with borodiene 1 to afford N-arylpyrroles 3 in moderate to
good yields. Use of either a protic solvent (MeOH) or an
aprotic solvent (DCM) had no significant effect (entries 1 and
2, Table 1). Because of the formation of the azoxybenzene
byproduct, an excess of nitrosoarene reagent (2.5 equiv) was
used in order to increase the isolated yield, for example, by
15% in the cases of comparing entries 1 and 3 (Table 1).
Modification of the nature or the location of the aromatic ring
substituent on the nitrosoarene moiety showed no notable
effect on the formation of the N-arylpyrrole products 3a−g,
which were isolated in 52−82% yields (entries 4−9, Table 1).
Other dienes, prepared according to literature procedures,11
were also examined, as summarized in Table 2.
a
b
Reaction with 1.5 equiv of ArNO in MeOH at rt for 5 h. Reaction
c
with 1.5 equiv of ArNO in DCM at rt for 48 h. Reaction with
2.5 equiv of ArNO in MeOH at rt for 5 h.
Table 2. Reaction of Dienes 5−7 with Nitrosobenzene
Unsubstituted 1-borobutadiene 5 reacted efficiently with
nitrosobenzene to give the corresponding pyrrole 3h in 78%
yield (entry 1, Table 2). However, there was a major decrease
in yield observed in the case of the more substituted and cyclic
borodiene 6 (entry 2, Table 2). The acyclic, 2-substituted
diene 7 also resulted in a reduced yield (entry 3, Table 2),
though the yield was not quite as low as that for cyclic diene 6.
The corresponding pyrroles were nevertheless isolated in only
34% and 16% yields, respectively, and despite the extended
reaction times.
Next, the influence of substituents on the borodiene was
examined, possessing aromatic or electron-withdrawing groups
in position 4. Diene 8 was prepared via a three-step pathway,
involving a Sonogashira reaction of β-bromostyrene with
a
b
Reaction with 2.5 equiv of ArNO in MeOH at rt for 5 h. Reaction
with 2.5 equiv of ArNO in MeOH at rt for 16 h.
B
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trimethylsilylacetylene, followed by proto-desilylation, to give
4-phenyl-3-buten-1-yne as an E/Z mixture (91/9).12 Hydro-
boration using pinacolborane and Schwartz’s catalyst11a
provided the desired diene 8 as a mixture of two stereo-
isomers (E,E:E,Z = 91:9) in a 56% overall yield. The
subsequent reactions of diene 8 with nitrosobenzene are
shown in Table 3.
Table 4. Study of the Reactivity of Diene 9 with
Nitrosobenzene
Table 3. Study of the Reactivity of Diene 8 with
Nitrosobenzene
E,E-isomer conversion
(isolated yield) (%)
entry solvent temperature (°C) time (h)
a
1
2
3
4
5
MeOH
MeOH
toluene
toluene
toluene
rt
16
16
0
a
a
a
b
reflux
rt
0
16
0
reflux
reflux
64
15
128
100 (26)
a
b
Reactions with 2.5 equiv of nitrosobenzene. Reaction with 5 equiv of
nitrosobenzene.
conversion
(isolated yield) (%)
entry solvent temperature (°C) time (h)
a
1
2
3
4
5
6
7
8
MeOH
toluene
MeOH
toluene
MeOH
MeOH
MeOH
MeOH
rt
16
16
5
0
reaction time were required in toluene at reflux, and only the
E,E-stereoisomer reacted. Indeed, even under longer reaction
times, the other isomers were still unreacted and present in the
reaction mixture (entry 5, Table 4). Nevertheless, 26% of the
corresponding pyrrole 3l was isolated after silica gel chro-
matography (entry 5, Table 4).
a
a
a
a
b
c
rt
0
reflux
70
50
16
22
22
22
22
50 (14)
72 (19)
77 (20)
82 (24)
100 (36)
reflux
reflux
reflux
reflux
Reaction of Tetracoordinated 1-Borodienes to Nitro-
soarene Compounds. Since the various 1-borodienes with
pinacol esters all resulted in reactions in which the oxazine was
not observed, we turned our attention to the study of the
influence of boron substituents that might result in the oxazine
cycloadducts being isolated. The impact of replacing the
pinacol ester of boronate 1 by diethanolamine was studied, as
outlined in Scheme 3.
d
a
b
Reactions with 2.5 equiv of nitrosobenzene. Reaction with 2.5 equiv
c
of nitrosobenzene added in portions. Reaction with 2.5 equiv of
nitrosobenzene added slowly by syringe pump. Reaction with
3.5 equiv of nitrosobenzene.
d
In the presence of nitrosobenzene, no reaction of diene 8 was
observed at room temperature in either toluene or MeOH
(entries 1 and 2, Table 3). Heating triggered reaction ac-
Scheme 3. Reactivity of Dienyl Diethanolamine Esters 10
with Nitrosobenzene
1
cording to H NMR in both MeOH and toluene (entries 3
and 4, Table 3), and the starting nitrosobenzene was fully
consumed after an extended 22 h reaction time, resulting in
72% conversion of diene 8 (entry 5, Table 3). No further
improvement was observed if the nitrosobenzene was added in
portions in an attempt to decrease azo-byproduct formation
(1 equiv at the outset - 1 equiv after 4 h - 0.5 equiv after 4 h), or
by slow addition of a MeOH solution by syringe pump (see
entries 6 and 7, Table 3). Finally, the use of 3.5 equiv of
nitrosobenzene (entry 8, Table 3) was required in order to
achieve the complete conversion of both stereoisomers of
diene 8, resulting in the formation of pyrrole 3k and a 36%
isolated yield.
The introduction of an electron-withdrawing group (methyl
carboxylate function) in position 4 of the borodiene was
next examined. Diene 9 was, therefore, synthesized by a
Wittig route from an ester-stabilized ylide and β-borylacrolein
pinacol ester, resulting in a mixture of three stereo-
isomers (E,E:E,Z:Z,E = 83:10:7) in an unoptimized 30%
overall yield.13 The subsequent reactions of diene 9 are shown
in Table 4.
Reaction of 1-borodiene 10 with nitrosobenzene resulted in
the identification of the [4 + 2]-cycloadduct 11 in the 1H NMR
spectrum of the crude mixture.14 After 2 h, all the diene 10 was
consumed and the intermediate boro-1,2-oxazine 11 had also
disappeared, resulting in only pyrrole 3a formation, to-
gether with small amounts of azoxybenzene 4 (Scheme 3).15
This cycloaddition (Scheme 4) was notably faster with this
tetracoordinated boron substituent (50% conversion after
5 min at room temperature compared with 5 h for com-
plete conversion of the corresponding pinacol ester (Table 1,
entry 3).
Diene 9 proved even less reactive than diene 8, and longer
reaction times and higher temperatures were required to give
an improved conversion (see Table 4, entries 1−5). In order to
form the pyrrole 3l, 5 equiv of nitrosobenzene and a 128 h
Indeed, this increased reactivity was confirmed by the
reaction of cyclic diene 12,16 which provided pyrrole 3i after
only 2 h and in a 46% yield, as shown in eq 1 (compared with
C
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16% over 16 h for the corresponding pinacol ester derivative,
entry 2, Table 2).
Table 5. Reactivity of MIDA-Substituted Diene 13 with
Nitrosoarene Compounds
Most interestingly of course, the observation of the transient
[4 + 2]-hetero-Diels−Alder cycloadduct 11 (Scheme 3)
confirms the key role of the oxazine cycloadduct in the sub-
sequent formation of the pyrrole. Diethanolamine esters are
known for their facile hydrolysis or methanolysis to regenerate
the corresponding boronic acid or ester;17 however, simply the
reversibility of B-N chelation could be responsible for allowing
the facile rearrangement to the pyrrole (vide infra). We can
also observe in these results the beneficial effect of the
tetracoordinated boronate ester, which is presumably less
electron-withdrawing then a pinacol ester, and, therefore, more
reactive toward the electron-deficient dienophile.
Prompted by these results, we, therefore, examined the
behavior of the corresponding MIDA (N-methyliminodiacetic)-
borodiene derivatives. Because of their high stability toward air
and moisture, these compounds have been used as flexible
scaffolds for the synthesis of a wide range of functionalized
small molecules.18 It was our expectation that such dienes
would make it possible to isolate and study the intermediate
oxazine cycloadducts. The presence of an sp3- versus an
sp2-hybridized borodiene would also be expected to be a useful
tool to examine the regioselectivity of the cycloaddition
reaction. The scope of the reaction of the MIDA diene 13
was, therefore, examined with various nitrosoarene compounds,
as outlined in Table 5. Reactions were carried out in AcOEt for
a better solubility of the diene B-MIDA 13.
The reaction of the MIDA-borodiene 13 provided the
corresponding oxazine cycloadducts in moderate to good yields
with the different nitrosoarene compounds, without obvious
electronic effects from the aryl substituent. However, single
regioisomeric products were obtained, as exemplified by the
formation of the stable [4 + 2]-cycloadduct 14a, obtained from
reaction of diene 13 with nitrosobenzene and isolated in 64%
yield (entry 1, Table 5). Only the boron-oxygen 1,2-related
regioisomer (in red in Table 5) was observed, and its structure
was assigned by NOESY NMR by correlation between the o-
phenyl Hs and one of the NCHs on the oxazine ring. The
introduction of different nitrosoarene substituents, i.e., electron-
donating and withdrawing-groups in positions 2 and 4, did not
change the resulting regiochemical outcome (entries 2−5, Table
5), and yields ranged between 47% and 77%. It is also
noteworthy that little or no dimerization of the nitrosoarene
took place during these reactions, reflecting the short reaction
times and more reactive diene, reducing the potential for
competitive byproduct formation from the nitroso compound.
The impact of different MIDA borodiene substituents was
then examined, i.e., dienes 15−18, which were synthesized by
Stille or Suzuki−Miyaura couplings of (E)-(2-bromovinyl)-
MIDA boronate with either vinyltributyltin (72%), (E)-hex-1-
ene boronic acid (79%), (1-bromovinyl)benzene (68%), or 1-
phenylvinylboronic acid (76%), respectively.19 The resulting
nitroso addition reactions are summarized in Table 6.
Similar to the results observed with the MIDA derivative 13,
the first three dienes (15−17) gave the same single
regioisomeric boron-oxygen 1,2-related products at room
temperature (in red in Table 6), with the boron occupy-
ing the α-position relative to the ring oxygen of the oxazine
(entries 1−3, Table 6). The introduction of a phenyl group
at C4 noticeably reduced the reactivity of the borodiene 18 with
D
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the resulting oxazine. Consequently, borodienes 1, 5−9, and
dienyl diethanolamine esters 10, 12 react with the nitroso
compounds to afford the corresponding 3,6-dihydro-1,2-
oxazines 24 and 23, respectively. The subsequent boryl
rearrangement would give 26, followed by an intramolecular
aza-boryl addition to the aldehyde generating 27, and finally,
borate elimination provides the pyrroles 3a−l.
Table 6. Reactivity of MIDA-Substituted Dienes 15−18 with
Nitrosobenzene
Further investigations into this process to support our
supposition and DFT calculations9 have now been provided by
experimental investigations. Therefore, the replacement of the
boronate pinacol ester on the diene component by diethanol-
amine (vide supra) resulted in the identification of the [4 + 2]-
14
1
cycloadduct in the H NMR spectrum of the crude mixture.
Reacting diene 10 or 12 with nitrosobenzene for 2 h resulted in
complete diene consumption, and even the boro-1,2-oxazine
11 had totally disappeared to afford only pyrrole 3a with only
small amounts of azoxybenzene 4 (Scheme 4) produced. The
pyrrole formation under these conditions can be explained
by an facile equilibrium between the dioxazaborocane 23
and the corresponding methyl ester 24 due to solvolysis.17
This equilibrium releases the vacant orbital on boron, and
consequently, the subsequent rearrangement occurs to access
the pyrrole (Scheme 4). The enhanced reactivity of the
borodiene possessing a diethanolamine ester (50% conversion
after 5 min at rt for 10 vs 5 h for complete conversion for 1,
Table 1, entry 1) is consistent with similar observations already
reported in the literature,17 i.e., a more electron-rich diene,
reacting with an electron-deficient nitroso compound, in a
“normal” electron, frontier-orbital-controlled [4 + 2]-cyclo-
addition reaction. It is noteworthy that even diene 12 provided
a 48% yield of pyrrole 3i after 2 h at rt (c.f. 16% in 16 h, entry 2,
Table 2), which further demonstrates the advantages of the
more electron-rich diene. Indeed, these conclusions are further
supported by the MIDA boronate ester derivatives, as outlined
in Scheme 5.
The reaction of nitrosobenzene with the MIDA boronate 18
results in the formation of the two regioisomers 22 and 22′ (vide
supra). Under the same conditions (Scheme 5), regioisomer 22
reacted cleanly to give the pyrrole 3k, whereas the other
regioisomer 22′ gave a mixture of unidentified products. We,
therefore, decided to test another method to deprotect the
MIDA boronate ester function of these types of oxazine
cycloadducts. Hence, under acidic conditions (DCl 1 M,
1 equiv) in acetone-d6, 2-phenylfuran 31 was cleanly and
quantitatively produced after 15 min at room temperature from
regioisomer 22′, as shown in eq 2. Under the same acidic
conditions, the regioisomer 22 did not lead to the formation of
the pyrrole 3k. Instead, only the hydrochloride salt of the MIDA
system was clearly identified. Thus, it is possible to selectively
and cleanly deprotect each regioisomer depending on the
conditions. Pyrrole formation requires a regioisomer like 22, and
to be released in a basic medium, whereas furan formation
requires a regioisomer like 22′ and an acidic medium.
a
Reaction with 2.5 equiv of nitrosobenzene in AcOEt at rt for 6 h.
Reaction with 5 equiv of nitrosobenzene AcOEt at reflux for 24 h.
b
reaction only occurring at reflux in EtOAc over 24 h. In
addition, a mixture of regioisomers 22 and 22′ (ratio 40:60)
was isolated in an 89% combined yield (entry 4, Table 6). The
structure of the major boron-oxygen 1,3-related regioisomer
22′ (in blue in Table 6) was secured by single-crystal X-ray
structure analysis (see the Supporting Information), confirming
the cis-stereochemistry of the boron and phenyl ring
substituents. Both steric and electronic effects of the phenyl
ring can explain this observed preferred regiochemistry (as
discussed by Houk et al. for 1-phenylbutadiene compared with
penta-1,3-diene20).
Mechanistic Aspects of the Reaction of 1-Borodienes
with Nitrosoarene Compounds. The mechanism which was
hypothesized and subsequently supported by DFT calculations9
to rationalize the observed formation of pyrroles 3a−l is shown
in Scheme 4, which involves a [4 + 2]-Diels−Alder cyclo-
addition intermediate 23 or 24, followed by rearrangement of
E
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Scheme 4. Proposed Mechanism for the Formation of Pyrroles from the Reaction of 1-Borodienes with Nitrosoarene
Compounds
Scheme 5. Proposed Reaction Sequence for the Formation of Pyrrole 3k from MIDA Boronate Oxazine Derivative 22
Moreover, the byproduct 36 was isolated by extracting the
reaction mixture with DCM (see Scheme 6) in 25% yield,
whose structure was established by 1H, 13C, and 11B NMR, and
mass spectroscopy. These experimental observations are in
agreement with the proposed mechanism outlined in Scheme 4.
In addition, a preliminary and essential protonation of the
nitrogen atom of the MIDA boronate 22′ results in the de-
coordination of the nitrogen from boron, leading to the
intermediate 32. Formation of this BX2 moiety 32 enables the
facile boryl rearrangement 33−35 to take place and, in this
case, to form the furan 31 (Scheme 6).
Scheme 6. Proposed Mechanism for the Formation of Furan
31 from 22′
Transformations of Boro-1,6-dihydro-1,2-oxazine
Derivatives. To explore the synthetic importance of B-MIDA
oxazine derivatives, we decided to carry out a Suzuki−Miyaura
coupling with the cycloadduct 14a as a model substrate. Under
classical experimental conditions for this class of reaction,
1H NMR of the crude reaction mixture (see the Supporting
Information) shows a full conversion of the starting material
into the pyrrole 3a that showed that 14a is not stable enough to
survive under Suzuki−Miyaura coupling conditions (Scheme 7).
To confirm that this is indeed the location of the boronated
group that is responsible for this failure, the diene 37 was
synthesized from (1-bromovinyl)-MIDA boronate and
1-bromostyrene.21 The reaction with nitrosobenzene regiose-
lectively provided the cycloadduct 38 in a 73% isolated yield
with only traces of the second isomer.22 To confirm the
structure of the major regioisomer, it was engaged in a Suzuki−
Miyaura cross-coupling with 1-bromotoluene in the presence of
palladium acetate and SPhos (Scheme 8). The 2,4,5-
trisubstituted dihydrooxazine 39 was isolated in a 71% yield.
F
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dried solvents were used; THF and toluene were distilled on sodium,
benzophenone and DCM on P2O5. Reactions were monitored by TLC
analysis using Silica Gel 60 F254 plates. Purifications on silica gel were
carried out on silica gel 0.060−0.200 mm, 60 Å. NMR spectra
Scheme 7. Reactivity of Oxazine 14a and Iodobenzene under
Suzuki−Miyaura Coupling Conditions
1
were recorded on apparatus at 300, 400, or 500 MHz for H, 75 or
1
101 MHz for 13C, and 96 MHz for 11B. H and 13C NMR chemical
shifts were referenced to Me4Si as internal reference, and 11B NMR
chemical shifts to external BF3·OEt2 (0.0 ppm). Deuterated chloro-
form CDCl3 and acetone-d6 were used for NMR spectra. NMR data
are reported as chemical shift (ppm), multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, dd = doublet of doublet, ddd = doublet
of doublet of doublet, dt = doublet of triplet, m = multiplet, b =
broad), coupling constant J (Hz), and integration. High-resolution
mass spectra (HMRS) were obtained on a Q-TOF instrument and
measured using either electrospray ionization (ESI) or electron impact
(EI). Melting points were measured and reported in °C.
General Procedure for Pyrrole Synthesis. To a solution of
diene (1 equiv) (pinacol boronate or diethanolamine esters) in the
solvent was added nitrosoarene compound (2.5−5 equiv). The re-
action mixture was stirred at the temperature indicated in the experi-
mental procedure. The solvent was evaporated, and the crude product
was purified by silica gel chromatography.
Scheme 8. Synthesis of Triarylated Oxazine 39 from the
Nitrosobenzene Cycloadduct 38 after Suzuki−Miyaura
Cross-Coupling Reaction Sequence
Characterization and Experimental Procedure of Com-
pounds 3a−j.9 1,2-Diphenyl-1H-pyrrole 3k.23 To a solution of
diene 8 (65 mg, 0.25 mmol) in MeOH (1 mL) was added nitro-
sobenzene (94.9 mg, 0.76 mmol). The reaction mixture was heated to
boiling and stirred for 22 h. The solvent was evaporated and the crude
product was purified by silica gel chromatography (cyclohexane/
toluene 98/2, Rf = 0.3) to give compound 3k (19.7 mg, 36%).
1H NMR (400 MHz, CDCl3) δ ppm 7.33−7.31 (m, 2H), 7.28−7.26
(m, 1H), 7.21−7.14 (m, 7H), 6.99 (dd, J = 2.7, 1.8 Hz, 1H), 6.47
(dd, J = 3.4, 1,8 Hz, 1H), 6.41 (dd, J = 3.4, 3.0 Hz, 1H); 13C NMR
(101 MHz, CDCl3) δ ppm 140.7, 134.0, 133.1, 129.1, 128.4, 128.2,
126.7, 126.4, 125.9, 124.5, 110.8, 109.4.
Methyl-1-phenyl-1H-pyrrole-2-carboxylate 3l.24 To a solution of
diene 9 (65 mg, 0.25 mmol) in MeOH (0.5 mL) was added
nitrosobenzene (94.9 mg, 0.76 mmol). The reaction mixture was
heated to boiling and stirred for 22 h. The solvent was evaporated and
the crude product was purified by silica gel chromatography
(cyclohexane/toluene 98/2, Rf = 0.3) to give compound 3l (15 mg,
A NOESY NMR experiment (correlation between H’s of the
methyl group of the toluene moiety and H’s on the oxazine ring
at C6) established the structure of this compound and
consequently the orientation of the first cycloaddition. No
ring contraction product was observed in this case.
1
26%). H NMR (400 MHz, CDCl3) δ ppm 7.45−7.29 (m, 5H), 7.10
(dd, J = 3.9, 1.8 Hz, 1H), 6.95 (dd, J = 2.7, 1.8 Hz, 1H), 6.29 (dd, J =
3.9, 2.7 Hz, 1H), 3.71 (s, 3H); 13C NMR (101 MHz, CDCl3), δ ppm
161.1, 140.6, 130.0, 128.7, 128.0, 126.5, 119.1, 109.3, 51.3.
CONCLUSIONS
■
This study revealed that hetero-Diels−Alder cycloadditions of
nitroso compounds and boronated dienes can afford either
pyrrole derivatives or oxazine cycloadducts. The most critical
parameter to guide these reactions remains the ability of the
boron to keep, or not, its sp3 hybridization state, the presence
of a boronate function α to the oxygen or the nitrogen atom
of the oxazine ring being responsible for the fate of the ring
contraction. Different experimental observations led us to
propose a mechanism to rationalize these results, also in
agreement with previous theoretical investigations. In the case
of 2-MIDA borodienes, the formation of the corresponding
[4 + 2]-cycloadduct is highly regioselective, and notably, these
more electron-rich dienes react faster with the nitrosoarene
compounds. Indeed, this increased reactivity directly results in a
decrease in the amount of nitrosoarene compound which can
competitively degrade to azo byproducts. No decomposition of
the oxazine ring was observed during a Suzuki−Miyaura
coupling. A 2,4,5-triaryl-3,6-dihydro-1,2-oxazine was isolated in
good yield, thus showing the interest of this approach to
prepare this class of heterocycles with complete control of the
position of the different substituents.
(E,E)-1,3-Butadienyl-(4-butyl)-1-boronate MIDA Ester 16. Com-
pound 16 was synthesized using the procedure of Burke et al.15 mp =
1
122 °C; H NMR (400 MHz, acetone-d6) δ ppm 6.53 (dd, J = 17.5,
10.2 Hz, 1H), 6.18−6.07 (m, 1H), 5.81−5.72 (m, 1H), 5.54 (d, J =
17.5 Hz, 1H), 4.19 (d, J = 16.8 Hz, 2H), 4.01 (d, J = 16.8 Hz, 2H),
2.98 (s, 3H), 2.09 (q, J = 6.9 Hz, 2H), 1.45−1.27 (m, 4H), 0.89 (t, J =
7.2 Hz, 3H); 13C NMR (101 MHz, acetone-d6) δ ppm 169.1, 143.7,
136.4, 133.6, 62.2, 47.3, 32.9, 32.1, 22.9, 14.1 (boron−carbon bound
was not visible); 11B NMR (96 MHz, acetone-d6) δ ppm 10.8; HRMS
(ESI) calcd. for C16H22N [M + H]+: 265.1485 found: 265.1484.
General Procedure for [4 + 2] Cycloaddition of B-MIDA
Dienes to Nitrosoarene Compounds. To a solution of diene
(1 equiv) (MIDA ester) in AcOEt was added aryl nitroso (2.5 equiv).
The reaction mixture was stirred at room temperature or in reflux
conditions. The solvent was evaporated, and the crude product was
purified by silica gel chromatography.
14a. For oxazine 14a, see ref 9.
Oxazine 14b. To a suspension of diene 13 (50 mg, 0.22 mmol)
in AcOEt (2 mL) was added 4-methoxynitrosobenzene (61.5 mg,
0.45 mmol). The reaction mixture was stirred at room temperature
overnight. The solvent was evaporated, and the crude product was
purified by solid phase silica gel chromatography (Et2O:MeCN 8/2,
1
Rf = 0.4). 14b (37.2 mg, 47%). mp = 164 °C; H NMR (400 MHz,
EXPERIMENTAL SECTION
General Information and Materials. Reagents and solvents were
used as received from the supplier, unless specified. When specified,
acetone-d6) δ ppm 7.09−7.05 (m, 2H), 6.87−6.83 (m, 2H), 5.71 (ddd,
J = 3.2, 1.7, 1.6 Hz, 1H), 4.47 (bs, 1H), 4.26 (dd, J = 16.8, 6.8 Hz, 2H),
4.01 (dd, J = 33.6, 16.8 Hz, 2H), 3.75 (s, 3H) 3.74−3.69 (m, 1H),
■
G
DOI: 10.1021/acs.joc.5b00593
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3.57−3.51 (m, 1H), 3.27 (s, 3H), 1.79 (s, 3H); 13C NMR (101 MHz,
acetone-d6) δ ppm 168.8, 168.5, 156.4, 145.6, 129.6, 122.3, 119.1,
114.8, 63.19, 63.17, 57.1, 55.7, 55.0, 46.8, 20.6 (boron−carbon bound
was not visible); 11B NMR (96 MHz, acetone-d6) δ ppm 9.9; HRMS
(ESI) calcd. for [M + Na]+ (C17H21N2O611BNa): 383.1385 found:
383.1382.
7.28−7.21 (m, 2H), 7.02 (m, 1H), 6.86 (m, 1H), 6.06 (ddd, J = 10.3,
5.2, 2.8 Hz, 1H), 5.91 (dt, J = 10.3, 1.4 Hz, 1H), 4.37 (bd, J = 1.4 Hz,
1H), 4.31 (dd, J = 19.2, 16.9 Hz, 2H), 4.10 (dd, J = 16.9, 10.7 Hz, 2H),
4.10−4.07 (m, 1H), 3.35 (s, 3H), 1.68−1.62 (m, 2H), 1.44−1.21 (m,
4H), 0.85 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, acetone-d6)
δ ppm 169.0, 168.1, 149.9, 129.6, 127.6, 126.3, 121.4, 116.8, 69.6, 63.2,
58.1, 46.8, 31.9, 23.4, 14.3; 11B NMR (96 MHz, acetone-d6) δ ppm
10.2; HRMS (ESI) calcd. for [M + H]+ (C19H25N2O511B): 373.1935
found: 373.1933.
Oxazine 14c. To a suspension of diene 13 (60 mg, 0.27 mmol) in
AcOEt (2 mL) was added 2-nitrosotoluene (48.9 mg, 0.40 mmol).
The reaction mixture was stirred at room temperature overnight. The
solvent was evaporated, and the crude product was purified by solid
phase silica gel chromatography (Et2O/MeCN 8/2, Rf = 0.5). 14c
(52 mg, 56%). mp = 169 °C; 1H NMR (400 MHz, acetone-d6) δ ppm
7.23 (m, 1H), 7.16 (m, 2H), 7.15 (m, 1H), 5.74 (s, 1H), 4.51 (bs,
1H), 4.21 (dd, J = 16.8, 11.1 Hz, 2H), 3.94 (dd, J = 19.5, 16.8 Hz, 2H),
3.69−3.65 (m, 1H) 3.45−3.41 (m, 1H), 3.17 (s, 3H), 2.30 (s, 3H),
1.80 (s, 3H); 13C NMR (101 MHz, acetone-d6) δ ppm 168.7, 168.6,
149.7, 133.6, 131.4, 130.2, 127.1, 125.7, 122.2, 119.0, 63.21, 63.16,
56.7, 46.8, 20.6, 18.5 (boron−carbon bound was not visible);
11B NMR (96 MHz, acetone-d6) δ ppm 9.9; HRMS (ESI) calcd. for
[M + Na]+ (C17H21N2O511BNa): 367.1436 found: 367.1439.
Oxazine 14d. To a suspension of diene 13 (50 mg, 0.22 mmol) in
AcOEt (2 mL) was added 4-chloronitrosobenzene (47.6 mg, 0.34
mmol). The reaction mixture was stirred at room temperature
overnight. The solvent was evaporated, and the crude product was
purified by solid phase silica gel chromatography (Et2O:MeCN 8/2,
Oxazine 21. To a suspension of diene 17 (30 mg, 0.11 mmol) in
AcOEt (2 mL) was added nitrosobenzene (23 mg, 0.21 mmol). The
reaction mixture was stirred at room temperature for 6 h. The solvent
was evaporated, and the crude product was purified by silica gel
chromatography (Et2O:MeCN 8/2, Rf = 0.4). 21 (32 mg, 78%). mp =
207 °C; 1H NMR (400 MHz, acetone-d6) δ ppm 7.59−7.57 (m, 2H),
7.40−7.36 (m, 2H), 7.33−7.23 (m, 5H), 7.00−6.96 (m, 1H), 6.51 (m,
1H), 4.74 (bs, 1H), 4.57 (ddd, J = 15.8, 2.8, 1.8 Hz, 1H), 4.33 (d,
J = 16.8 Hz), 4.10 (dd, J = 26.0, 16.8 Hz) 4.01 (ddd, J = 15.8, 2.8,
1.1 Hz, 1H), 3.36 (s, 3H); 13C NMR (101 MHz, acetone-d6) δ ppm
169.8, 169.6, 152.7, 140.4, 133.5, 130.6, 130.4, 129.2, 126.6, 126.2,
123.8, 118.0, 64.3, 54.8, 48.0 (boron−carbon bound was not visible);
11B NMR (96 MHz, acetone-d6) δ ppm 10.2; HRMS (ESI) calcd. for
[M + H]+ (C21H21N2O511B): 393.1622 found: 393.1618.
Oxazine 22 and 22′. To a suspension of diene 18 (50 mg,
0.18 mmol) in AcOEt (2 mL) was added nitrosobenzene (38 mg,
0.35 mmol). The reaction mixture was stirred under reflux during 24 h.
The solvent was evaporated, and the crude product was purified by
solid phase silica gel chromatography (Et2O:MeCN 8/2, Rf = 0.4).
22 + 22′ (40/60) (62.8 mg, 89%). The mixture of isomer was
solubilized in the minimum amount of CHCl3 and left overnight in a
fridge at +5 °C. The precipitate was filtered, washed with Et2O, and
recrystallized in MeOH to afford pure isomer 22′ as white crystals.
The filtrate was evaporated and diluted in CHCl3 (1 mL). Aqueous
HCl (1 M) (0.5 mL) was added, and the heterogeneous mixture was
vigorously stirred for 24 h to decompose the residual 22′. The organic
phase was separated, dried over MgSO4, filtered, and concentrated
under vacuum. After purification by silica gel chromatography, 22 was
obtained as a pale yellow solid.
1
Rf = 0.5). 14d (61 mg, 77%). mp = 224 °C; H NMR (400 MHz,
acetone-d6) δ ppm 7.31−7.23 (m, 2H), 7.16−7.08 (m, 2H), 5.74 (s,
1H), 4.51 (bs, 1H), 4.29 (dd, J = 16.8, 0.7 Hz, 2H), 4.05 (dd, J = 20.8,
16.8 Hz, 2H), 3.94−3.89 (m, 1H), 3.62−3.54 (m, 1H), 3.29 (s, 3H),
1.81 (s, 3H); 13C NMR (101 MHz, acetone-d6) δ ppm 168.7, 168.5,
150.6, 129.4, 129.3, 126.9, 122.3, 118.1, 63.24, 63.23, 55.9, 46.9,
20.5 (boron−carbon bound was not visible); 11B NMR (96 MHz,
acetone-d6) δ ppm 9.9; HRMS (ESI) calcd. for [M + Na]+
(C16H18N2O535Cl11BNa): 387.0889 found: 367.0888.
Oxazine 14e. To a suspension of diene 13 (30 mg, 0.13 mmol) in
AcOEt (1 mL) was added 4-nitrosobenzoate (33.9 mg, 0.19 mmol).
The reaction mixture was stirred at room temperature overnight. The
solvent was evaporated, and the crude product was purified by solid
phase silica gel chromatography (Et2O:MeCN 8/2, Rf = 0.4). 14e
1
Isomer 22: mp = 174 °C; 1H NMR (400 MHz, acetone-d6) δ ppm
7.44−7.40 (m, 2H), 7.17−7.09 (m, 5H), 7.00−6.95 (m, 2H), 6.81−
6.75 (m, 1H), 6.17 (ddd, J = 10.0, 1.7, 1.6 Hz, 1H), 6.04 (ddd,
J = 10.0, 5.2, 2.9 Hz, 1H) 5.24 (ddd, J = 4.8, 2.9, 1.7 Hz, 1H), 4.59 (m,
1H), 4.36 (dd, J = 29.6, 16.9 Hz, 2H), 4.10 (dd, J = 39.7, 16.9 Hz, 2H),
3.33 (s, 3H); 13C NMR (101 MHz, acetone-d6) δ ppm 169.1, 167.9,
150.1, 139.1, 130.5, 129.2, 128.4, 127.9, 127.8, 125.9, 121.9, 117.3,
72.8, 64.3, 63.21, 63.16, 46.7; 11B NMR (96 MHz, acetone-d6) δ ppm
10.3; HRMS (ESI) calcd. for [M + H]+ (C21H22N2O511B): 393.1622
found: 393.1624.
(31.9 mg, 61%). mp = 210 °C; H NMR (400 MHz, acetone-d6) δ
ppm 7.93−7.90 (m, 2H), 7.17−7.14 (m, 2H), 5.76 (s, 1H), 4.56 (bs,
1H), 4.35−4.29 (dd, J = 16.8, 0.8 Hz, 2H), 4.29 (q, J = 7.1 Hz, 2H),
4.14−4.04 (ddd, J = 16.8, 10.1, 1.1 Hz, 2H), 4.12−4.05 (m, 1H),
3.70−3.65 (m, 1H), 3.33 (s, 3H), 1.83 (s, 3H), 1.33 (t, J = 7.1 Hz,
3H); 13C NMR (101 MHz, acetone-d6) δ ppm 168.7, 168.5, 166.5,
155.0, 131.4, 129.1, 123.6, 122.2, 114.9, 63.28, 63.25, 60.9, 54.6,
47.0, 20.4, 14.7 (boron−carbon bound was not visible); 11B NMR
(96 MHz, acetone-d6) δ ppm 10.0; HRMS (ESI) calcd. for [M + Na]+
(C19H23N2O711BNa): 425.1490 found: 425.1491.
Isomer 22′: mp = 152 °C; 1H NMR (400 MHz, acetone-d6) δ ppm
7.60−7.58 (m, 2H), 7.37−7.31 (m, 5H), 7.22−7.20 (m, 2H), 6.98−
6.94 (m, 1H), 6.19 (ddd, J = 10.5, 4.8, 2.4 Hz, 1H), 5.68 (ddd, J =
10.5, 1.7, 1.5 Hz, 1H), 5.11 (m, 1H), 4.19 (dd, J = 88.8, 16.9 Hz, 2H),
4.11 (dd, J = 54.0, 16.9 Hz, 2H), 4.11−4.07 (m, 1H), 3.13 (s, 3H); 13C
NMR (101 MHz, acetone-d6) δ ppm 169.4, 167.8, 149.9, 139.9, 130.2,
129.6, 129.1, 129.0, 127.0, 125.1, 122.1, 117.1, 72.8, 63.08, 63.03, 49.8,
47.3, 45.4; 11B NMR (96 MHz, acetone-d6) δ ppm 10.6; HRMS (ESI)
calcd. for [M + H]+ (C21H22N2O511B): 393.1622 found: 393.1632.
Conversion of 22 to 1,2-Diphenyl-1H-pyrrole 3k under Basic
Conditions. Oxazine 22 (6.0 mg, 0.015 mmol) was dissolved in
acetone-d6 (0.4 mL). NaOD (1 M in water, 15 μL, 0.015 mmol) was
Oxazine 19. To a suspension of diene 15 (40.0 mg, 2.21 mmol) in
AcOEt (2 mL) was added nitrosobenzene (59.1 mg, 5.52 mmol). The
reaction mixture was stirred at room temperature for 6 h. The solvent
was evaporated, and the crude product was purified by solid phase
silica gel chromatography (Et2O:MeCN 8/2, Rf = 0.4). 19 (28 mg,
1
43%). mp = 161 °C; H NMR (400 MHz, acetone-d6) δ ppm 7.29−
7.25 (m, 2H), 7.12−7.08 (m, 2H), 6.96−6.92 (m, 1H), 6.06 (dddd,
J = 10.1, 2.4, 1.7, 1.6 Hz, 1H), 5.93 (dddd, J = 10.1, 5.2, 2.8, 1.7 Hz,
1H), 4.61(bs, 1H), 4.29 (dd, J = 16.8, 0.7 Hz, 2H), 4.10−4.04 (m,
1H), 4.06 (dd, J = 22.6, 16.8 Hz, 2H), 3.70−3.64 (m, 1H), 3.32 (s,
3H); 13C NMR (101 MHz, acetone-d6) δ ppm 168.7, 168.5, 152.0,
129.6, 127.9, 122.6, 122.2, 116.5, 63.2, 52.6, 46.9 (boron−carbon
bound was not visible); 11B NMR (96 MHz, acetone-d6) δ ppm 9.9;
HRMS (ESI) calcd. for [M + Na]+ (C15H17N2O511BNa): 339.1128
found: 339.1125.
1
then added, and the reaction was directly followed by H and 11B
NMR. After one night, a 32% conversion was observed with no further
evolution if the reaction was left longer at room temperature. NaOD
(1 M, 30 μL, 0.030 mmol) was finally added to observe complete
consumption of the starting oxazine, followed by DCl (1 M in D2O,
15 μL, 0.015 mmol). After 15 min, a full conversion into the
corresponding pyrrole was observed. The reaction mixture was poured
into DCM (2 mL), and water (1 mL) was added. The aqueous layer
was extracted with DCM (3×). The organic phase was dried over
Oxazine 20. To a suspension of diene 16 (63 mg, 0.24 mmol) in
AcOEt (3 mL) was added nitrosobenzene (64 mg, 0.60 mmol). The
reaction mixture was stirred at room temperature for 6 h. The solvent
was evaporated, and the crude product was purified by solid phase
silica gel chromatography (Et2O:MeCN 8/2, Rf = 0.7). 20 (61 mg,
68%). mp = 188 °C; 1H NMR (400 MHz, acetone-d6) δ ppm
H
DOI: 10.1021/acs.joc.5b00593
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
MgSO4, filtered over a pad of silica gel, and eluted with DCM to give
pyrrole 3k (2.8 mg, 85%).
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: bertrand.carboni@univ-rennes1.fr (B.C.).
*E-mail: andy.whiting@durham.ac.uk (A.W.).
Conversion of 22′ to 2-Phenylfuran 31 under Acidic
Conditions. Oxazine 22′ (6.8 mg, 0.017 mmol) was dissolved in
acetone-d6 (0.4 mL), followed by the addition of DCl in D2O (1 M,
18 μL, 0.018 mmol). After full conversion of the starting oxazine, the
reaction mixture was poured into DCM (1 mL). NaOH (1M, 0.2 mL)
was added. The aqueous layer was extracted with DCM (3×), dried
over MgSO4, filtered, and purified over a pad of silica (DCM).
Furan 31 was isolated. (2.4 mg, quantitative)
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Isolation of Byproduct 36. Oxazine 22′ (25.2 mg, 0.064 mmol)
L.E. thanks Durham University and the Reg
́
ion Bretagne for a
was dissolved in acetone-d6 (0.7 mL). DCl (1 M in D2O, 64 μL,
1
Ph.D. grant. This work has been performed as part of the LIA
Rennes-Durham (Molecular Materials and Catalysis). We thank
Durham University, CNRS, and University of Rennes 1 for
support of this research.
0.064 mmol) was then added, and the reaction was followed by H
and 11B NMR. After full conversion of the starting oxazine, the
reaction mixture was extracted with DCM (3×), dried over MgSO4,
filtered, and concentrated. The crude yellow solid was suspended in
CHCl3 (0.5 mL) and filtered. The resulting solid was washed with
CHCl3 (3×). (4 mg of 36, 25%).
REFERENCES
2-Phenylfuran 31.25 1H NMR (400 MHz, CDCl3) δ ppm 1H NMR
(400 MHz, CDCl3) δ 7.71−7.66 (m, 2H), 7.48 (dd, J = 1.8, 0.7 Hz,
1H), 7.42−7.36 (m, 2H), 7.27 (m, 1H), 6.66 (dd, J = 3.4, 0.7 Hz, 1H),
6.48 (dd, J = 3.4, 1.8 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ ppm
154.1, 142.2, 131.0, 128.8, 127.5, 123.9, 111.8, 105.1.
■
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6-Methyl-2-(phenylamino)-1,3,6,2-dioxazaborocane-4,8-dione
1
36. H NMR (400 MHz, acetone-d6) δ ppm 7.07 (m, 2H), 6.85 (d,
J = 7.7 Hz, 2H), 6.62 (m, 1H), 4.74 (bs, 1H), 4.25 (d, J = 17.2 Hz,
2H), 4.09 (d, J = 17.2 Hz, 2H), 3.01 (s, 3H); 13C NMR (101 MHz,
acetone-d6) δ ppm 167.6, 147.2, 129.0, 117.4, 116.2, 62.1, 45.8,
boron−carbon bound was not visible; 11B NMR (96 MHz, acetone-d6)
δ ppm 9.9; HRMS (ESI) calcd. for [M + H]+ (C11H14N2O411B):
249.1047 found: 249.1042.
Synthesis and Suzuki−Miyaura Coupling of Boronated
Oxazine MIDA Ester 38 with 2-Bromotoluene. To a suspension
of diene 37 (229 mg, 0.80 mmol) in AcOEt (10 mL) was added nitro-
sobenzene (221 mg, 2.06 mmol). The reaction mixture was stirred at
50 °C for 22 h. The solvent was evaporated, and the crude product
product was purified by solid phase silica gel chromatography
1
(Et2O:MeCN 8/2, Rf = 0.4). 38 (229 mg, 73%). mp = 153 °C; H
NMR (400 MHz, acetone-d6) δ ppm 7.40−7.25 (m, 7H), 7.17 (m,
2H), 6.94 (m, 1H), 4.67 (t, J = 2.4 Hz, 2H), 3.97 (t, J = 2.4 Hz, 2H),
3.94 (d, J = 16.8 Hz, 2H), 3.43 (d, J = 16.8 Hz, 2H), 3.07 (s, 3H); 13C
NMR (101 MHz, acetone-d6) δ ppm 168.2, 151.5, 144.4, 141.9, 129.7,
129.5, 129.4, 128.2, 122.5, 116.2, 72.2, 63.0, 58.3, 47.3 (boron−carbon
bound was not visible); 11B NMR (96 MHz, acetone-d6) δ ppm 10.4;
HRMS (ESI) calcd. for [M + H]+ (C21H22N2O511B): 393.1618 found:
393.1622.
In a flask under an inert atmosphere were added oxazine 38 (41 mg,
0.10 mmol), Pd(OAc)2 (1.2 mg, 0.0053 mmol), SPhos (4.3 mg,
0.010 mmol), and 2-bromotoluene (14 μL, 0.11 mmol) in dioxane
(2 mL). An aqueous solution of K3PO4 (3 M, 190 mL, 0.57 mmol)
previously degassed with Ar for 15 min was then added. The orange
reaction mixture was stirred at 60 °C overnight. Et2O (5 mL) and
NaOH (1M, 5 mL) were added in the reaction mixture. The aqueous
phase was extracted with Et2O (3×), and the organic layer was dried
over MgSO4, filtered, and concentrated under vacuum. The crude
compound was purified by silica gel chromatography (hexane/AcOEt
95/5, Rf = 0.4). 39 (27 mg, 71%). mp = 161 °C; 1H NMR (400 MHz,
CDCl3) δ ppm 7.40−6.83 (m, 14H), 4.58 (s, 2H), 4.12 (s, 2H), 2.00
(s, 3H); 13C NMR (101 MHz, CDCl3) δ ppm 150.2, 138.9, 137.1,
136.1, 134.1, 131.0, 130.3, 130.0, 129.1, 128.2, 128.1, 127.6, 127.2,
125.8, 122.8, 116.2, 72.0, 55.4, 19.7; HRMS (ESI) calcd. for [M + H]+
(C23H22NO): 328.1689 found: 328.1701.
ASSOCIATED CONTENT
■
S
* Supporting Information
Spectral data of all pyrrole and oxazine compounds; X-ray
structural data of 22′. The Supporting Information is available
free of charge on the ACS Publications website at DOI:
10.1021/acs.joc.5b00593.
I
DOI: 10.1021/acs.joc.5b00593
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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DOI: 10.1021/acs.joc.5b00593
J. Org. Chem. XXXX, XXX, XXX−XXX