Stereodivergent access to all four stereoisomers of chiral tetrahydrobenzo[f] [1,4]oxazepines, through highly diastereoselective multicomponent Ugi-Joullié reaction

Article abstract of DOI:10.1039/c9ra10689h

Starting from easily accessible chiral enantiopure 1,2-amino alcohols and salicylaldehydes, a concise route to cyclic imines has been developed. These chiral cyclic imines undergo a highly diastereoselective Ugi-Joullié reaction to give trans tetrahydrobe

Full text of DOI:10.1039/c9ra10689h

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Stereodivergent access to all four stereoisomers of
chiral tetrahydrobenzo[f][1,4]oxazepines, through
highly diastereoselective multicomponent Ugi–
Cite this: RSC Adv., 2020, 10, 965
Joullie reaction†
´
a
a
a
Alessandro Pinna,a Andrea Basso,
Chiara Lambruschini,
Lisa Moni,
b
a
Valeria Roccaa and Luca Banfi
*
Renata Riva,
Starting from easily accessible chiral enantiopure 1,2-amino alcohols and salicylaldehydes, a concise route
to cyclic imines has been developed. These chiral cyclic imines undergo a highly diastereoselective Ugi–
Received 28th November 2019
Accepted 20th December 2019
Joullie reaction to give trans tetrahydrobenzo[f][1,4]oxazepines with the introduction of up to 4 diversity
´
inputs. The cis isomer may also be attained, thanks to a thermodynamically controlled base catalysed
epimerization. Free secondary amines have been obtained using an unprecedented “removable”
carboxylic acid.
DOI: 10.1039/c9ra10689h
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Better results have been accomplished with the so called Ugi–
Introduction
18,19
´
Joullie reaction.
This is a 3-component variant of the Ugi
reaction that employs preformed cyclic imines. When these cyclic
imines are chiral and enantiopure, racemization at the a-position
is less likely, although yet possible.20 Furthermore, thanks to
a higher rigidity, several examples of highly diastereoselective
Multicomponent reactions (MCRs) are processes where three or
more substrates are combined in a single step, to give a product
that contains all the essential parts of the used components.1
Thanks to their high step economy and to the possibility to
introduce several diversity inputs in a single step, they are
considered a very powerful tool for the construction of libraries
of drug-like entities.2–4 While the use of MCRs in medicinal
chemistry is well assessed, their application in other elds is
less pronounced. Recently, MCRs were found to be successful in
the synthesis of functionalized uorophores.5–7 On the other
hand, only a few papers deal with the use of MCRs for the
combinatorial assembly of chiral organocatalysts.8–10 For this
latter goal, the control of stereochemistry is clearly essential.
Isocyanide-based processes (e.g. the Ugi and Passerini reac-
tions) are among the most popular MCRs. However, they suffer
from a typical lack of diastereoselection when chiral inputs are
employed. This limits their utility, because of the generation of
diastereomeric mixtures.
´
Ugi–Joullie reactions have been reported. Most of the previous
studies involve 5-membered (pyrrolines, thiazolines and so
on),9,21–31 or 6-membered cyclic imines (e.g. tetrahydropyr-
idines).32–38 The use of compounds with other ring size is much
´
less investigated. Only recently an Ugi–Joullie reaction of a 3-
membered azirine was reported.39 In our group we are particu-
larly interested in applying MCRs for the synthesis of benzo-fused
7-membered nitrogen heterocycles,40 whose interest in medicinal
chemistry is steadily growing.41 Towards this goal, we have
´
already studied the diastereoselective Ugi–Joullie reaction of
some 7-membered chiral enantiopure cyclic imines.20,42
We thought that enantiopure dihydrobenzoxazepines of
general formula 3 could be very useful intermediates for the
diastereoselective synthesis of a variety of tetrahydrobenzox-
azepines 4 or 5, through multicomponent processes. For
Recently, some examples of diastereoselective Passerini
reactions on chiral enantiopure aldehydes or ketones have been
reported,11–16 but the related Ugi reaction is more problematic,
not only because of the low diastereoselectivity typically ach-
ieved, but also for the easy racemization of aldehydes with a-
stereogenic centres.17
´
example, the Ugi–Joullie reaction would give peptide-like
compounds 4. Removal of the acyl group from 4 will then
afford secondary amines 5. Secondary amines 5 might also be
directly obtained by exploiting other MCRs, such as the Betti, or
the Ugi-tetrazole reactions. Compounds 4 and 5, containing
a typical privileged structure, may be interesting for library
production, whereas chiral enantiopure amines 5 may be
investigated as potential organocatalysts (Scheme 1).
a
`
Department of Chemistry and Industrial Chemistry, Universita di Genova, Italy.
E-mail: ban@chimica.unige.it
In order to make the whole methodology highly practical, it
was essential to develop a fast and diversity-oriented synthesis
of chiral imines 3 in enantiopure form. Our plan was to employ
b
`
Department of Pharmacy, Universita di Genova, Italy
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra10689h
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Scheme 1 General strategy.
amino alcohols 2, in turn derived from widely available a-amino
acids.
In this paper we report the successful accomplishment of
a quite short synthesis of imines 3, and their diastereodivergent
´
conversion into both diastereomers of 4, through an Ugi–Joullie
reaction. Since a-amino acids are available in both enantio-
meric forms, this means the possibility to get all four stereo-
isomers of 4. Furthermore, the efficient obtainment of
secondary amines 5 is demonstrated as well.
Results and discussion
The key step for the synthesis of cyclic imines 3 is the Mitsu-
nobu coupling of salicylaldehydes 1 with Boc-protected ami-
noalcohols 7. All employed alcohols 7 are known,43–45 and they
can be easily synthesized by reduction of Boc-protected a-amino
acids, in turn commercially available in both enantiomeric
forms with a wide variety of R2 substituents. Alternatively, some
of them (7d, 7e) have been obtained by protection of the
commercially available enantiopure amino alcohols (see ESI†).
We have previously shown42 that protection of the aldehyde
group was essential. Thus, salicylaldehydes 1 were quantita-
tively converted into the acetals 6. They were not isolated but,
aer a very simple work-up, directly coupled with amino alco-
hols 7a–e. This step proved to be very critical and was optimized
using 1a and 7a. Working on Boc-protected 1-amino-2-alkanols,
we had previously selected di-tert-butylazodicarboxylate (TBAD)
and PPh3 as the best reagents. However, in the present case, the
yield was rather poor (25%) and the known aziridine 9a46 was
Scheme 2 Synthetic sequence from salicyladehydes 1 to Ugi adducts
10–11 (or ent-10–ent-11).
azodicarboxylates such as DEAD or DIAD, the yield remained
unsatisfactory, due to the formation of substantial amounts of
9a. This result was not completely unexpected, taking into
account some literature precedents on Mitsunobu reactions of
phenols with this type of Boc-amino alcohols, where yields are
oen low and strongly depend on the nature of the starting
phenol.47–49 Aer some investigation (see ESI for details†), we
obtained as
a major product. Shiing to other typical
Table 1 Synthesis of ethers 8a–h
Boc-amino alcohol
(cong.)
Entry
Salicyl-aldehydea (equiv.)
Product
Yieldb %
1
2
3
4
5
6
1a (1.2)
1a (1.0)
1a (1.1)
1a (1.1)
1b (1.1)
1b (1.1)
7a (S)
7b (S)
7c (S)
7d (R)
7e (S)
7e (R)
8a
8b
8c
8d
8e
ent-8e
78
65
55
42
60
60
a
Relative to Boc-amino alcohol. b Isolated yield from Boc-amino alcohol.
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found out that the formation of 9a could be nearly completely including also formation of the cyclic imines 3 by removal of the
suppressed by using a special azodicarboxylate, namely 1,10- protecting groups. In some instances, the Ugi–Joullie reactions
´
(azodicarbonyl)dipiperidine (ADDP).50 Its use led to a 78% yield were incomplete, and thus a higher yield could probably be
of the desired product 8a. With other amino alcohols the yields obtained by using a higher excess of isocyanide or by longer
were somehow lower (see Table 1), but still satisfactory. Chro- reaction times.
matographic separation from aziridines 9 were quite easy,
whereas the remaining excess of phenol 6 was conveniently synthesize enantiopure trans tetrahydrobenzo[f][1,4]oxazepines
removed by basic extraction (Scheme 2). 10, introducing up to four diversity inputs: the salicylaldehyde
The results reported in Scheme 3 show that it is possible to
Ethers 8 were then converted very easily into the cyclic 1, the amino alcohol 7, the isocyanide, and the carboxylic acid.
imines 3, by acid promoted removal of both protecting group. The methodology is operationally simple (just two chromatog-
The crude imines were subjected, without any intermediate raphies) and highly diastereoselective. Finally, both enantio-
´
purication, to the Ugi–Joullie reaction with a variety of iso- meric series are accessible, thanks to the easy availability of 1,2-
cyanides and carboxylic acids. It is worth noting that the whole amino alcohols or a-amino acids in either enantiomeric form.
sequence from 1 to the Ugi adducts 10–11 required just a single Tetrahydrobenzoxazepines 10 may be useful in the medicinal
intermediate purication, at the level of ethers 8. This chemistry realm, since several N-acylated tetrahydrobenzo[f]
straightforward route to enantiopure cyclic imines 3 allows the [1,4]oxazepines have been reported to be endowed with very
introduction of two diversity inputs and, due to the wide interesting pharmacological properties.51–55 On the other hand,
availability of both (S) and (R) a-amino acids, gives an access to the 5-substituted compounds are largely unexplored from this
both enantiomeric series.
point of view, although some stimulating examples can be
As for the Ugi–Joullie reaction, we tried different reaction found in the literature.56–58 The possibility to control stereo-
conditions, as detailed in the ESI,† eventually nding that the chemistry in their synthesis will facilitate the exploration of
best conditions, both in terms of isolated yield and of diaster- their chemical space.
´
eoselectivity, involved the use of methanol as solvent with no
additive at room temperature.
However, apart from medicinal chemistry applications, we
also wanted to use this chemistry for the combinatorial
As shown in Scheme 3, the diastereoselectivities were in all synthesis of chiral enantiopure secondary amines, to be used as
cases excellent. The yields were moderate to good, but it should organocatalysts. A possibility to obtain amines like 13 or 14
be stressed that they refer to the overall yield of two steps, would be to apply a “truncated” Ugi on cyclic imines 3. In the
Scheme 3 Scope of the methodology. Ugi–Joullie reaction were carried out at rt for 48 h, unless otherwise noted. All reactions were carried out
´
on 200–400 mmol of starting 8. Yield ¼ isolated yield of 10 from 8. Combined yield ¼ isolated or calculated yield of 10 + 11 from 8. D.r. were
determined by HPLC on the crude product.
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literature we could nd only few examples of “truncated” Ugi
Our initial plan was to use tetrabutylammonium uoride to
reaction of aldehydes, primary amines and isocyanides,59–61 promote desilylation of the alcohol and to catalyse the subse-
employing either Lewis or Brønsted acids (or enzymes). quent intramolecular acyl transfer to give g-butyrolactone and
However, to our knowledge, no example of “truncated” Ugi the free secondary amine 13. With our surprise, not only the
applied to cyclic imines was reported.
reaction stopped at the level of free alcohols 10m–11m, TBAF
We tried various Lewis acids (e.g. ZnBr2 or ZnCl2),62 obtain- being unable to promote intramolecular acyl transfer, but
ing in all cases poor results in terms of yields. Similar unsatis- a nearly complete epimerization took place, converting trans
factory outcomes were obtained using boric acid63 or sulphinic 10m into cis epimer 11m (d.r. ¼ 90 : 10). Alcohol 11m can be
acid.64
isolated in diastereomerically pure form by chromatography.
Thus, we decided to follow a different approach, performing
On the other hand, by treatment of 10l with an acid catalyst in
´
a normal Ugi–Joullie reaction, but using an easily removable methanol, the desilylation reaction takes place quickly without
carboxylic acid. While there are many examples of “convertible” any epimerization at rt. Then, by raising the temperature to 40 ꢀC
isocyanides, the use of removable carboxylic acids in the Ugi or intramolecular acyl transfer leads to the release of g-butyr-
´
Ugi–Joullie reaction is less explored. An acid component olactone and to the formation of diastereomerically pure amine
sometimes used for this scope is 4-pentenoic acid, that can be 13. The same conditions convert cis alcohol 11m to diaster-
removed by treatment with iodine.28,65
eomerically pure amine 14. Thus, thanks to the TBAF promoted
However, as removable carboxylic acid, we selected known epimerization, it is possible to stereodivergently convert trans 10
compound 12 (Scheme 4), that was prepared by a modication into both trans and cis amines 13 and 14, depending on reaction
of the reported procedures (see ESI†).66,67 The Ugi–Joullie reac- conditions. Since both enantiomers of amino alcohols 7 are
´
tion using this acid proceeded as usual, affording adduct 10l available, this means that all four stereoisomers of these
with high d.r.
secondary amines are easily accessible. This fact is quite useful in
view of investigation of these secondary amines as organo-
catalysts: we can explore both decoration diversity (up to 3
diversity inputs) and stereochemical diversity. It is worth noting
that amines 13 and 14 are completely stable against epimeriza-
tion under basic conditions (TBAF or KOH), indicating that only
N-acylated compounds are prone to epimerization.
In order to get some additional information on the epime-
rization mechanism, we submitted 10j (obtained from imine
(S)-3e) to basic conditions (KOH in MeOH) (Scheme 5). Again,
epimerization took place, giving a cis : trans ratio of 68 : 32.
Analysis by HPLC on chiral stationary phase of the two crudes,
showed that both 10j and 11j were enantiomerically pure, and
´
different from ent-10j and ent-11j obtained from Ugi–Joullie
reaction of imine (R)-3e. This fact clearly demonstrates that
epimerization occurs at carbon 5 and not at carbon 3, otherwise
10j would have been converted into ent-11j.
Scheme 4 Synthesis of diastereomeric amines 13 and 14. c.y. ¼
combined yield of both diastereomers. CSA ¼ camphorsulphonic acid.
TBAF ¼ tetrabutylammonium fluoride.
Scheme 5 Epimerization of 10j and ent-10j.
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Treatment of isolated pure cis compound 11j under the same
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Experimental section
conditions again affords a 68 : 32 cis : trans ratio, proving that
this is the thermodynamic ratio. Finally, also in the case of
compound 10a epimerization takes place under these condi-
tions, affording a cis : trans ratio ¼ 68 : 32.
Typical procedure for the Mitsunobu reaction: (S)-tert-butyl
(1-(2-(dimethoxymethyl)phenoxy)-3-phenylpropan-2-yl)
carbamate 8a
These experiments demonstrate that, for 10a–11a, 10j–11j,
A solution of salicylaldehyde (0.770 mL, 901 mg, 7.38 mmol) in
dry MeOH (8.1 mL) was treated with trimethyl orthoformate
(3.50 mL, 32.0 mmol) and Amberlyst 15 (100 mg). The resulting
mixture was stirred at room temperature for 20 h, then diluted
with CH2Cl2 and ltered. The ltrate was treated with solid
NaHCO3 (25 mg) and ltered again. The ltrate was evaporated,
and the residue was taken up in CH2Cl2/toluene, and again
evaporated to azeotropically remove all methanol. The crude
acetal 6a was obtained as a yellow oil (1.380 g). This acetal
(301.7 mg, theoretical 1.61 mmol, 1.2 equiv.) was dissolved in
dry THF (2.60 mL), cooled to 0 ꢀC, and treated sequentially with
Boc-amino alcohol 7a (330.5 mg, 1.31 mmol, 1 equiv.), PPh3
(171.8 mg, 0.655 mmol, 0.5 equiv.) and 1,10-(azodicarbonyl)
dipiperidine (ADDP) (165.5 mg, 0.656 mmol, 0.5 equiv.). Aer
stirring at 0 ꢀC for 60 min, further PPh3 (171.8 mg, 0.655 mmol)
and ADDP (165.5 mg, 0.656 mmol) were added. Finally, aer 60
minutes, an identical amount of both reagents was added. The
mixture was further stirred overnight at rt and evaporated to
dryness. The crude was taken up in Et2O and washed with 1 M
NaOH, to remove excess of 6a. The organic phase was washed
with aqueous saturated NH4Cl, evaporated and puried by
chromatography (PE/AcOEt 11 : 1) to give pure 8a as an oil
(411.4 mg, 78% from 7a). For characterization data, see ESI.†
´
or 10m–11m (and probably also for all the other Ugi–Joullie
products here described) the “kinetic” product is not the most
stable one. Furthermore, the thermodynamic preference for
the cis isomer is stronger for 10m–11m than for 10a–11a or
10j–11j. This suggest some inuence of the free hydroxy
group.
The relative conguration was established, at the level of
amines 13 and 14, by a very clear NOE effect between H-5 and H-
3, which is present only in the cis compound. Although the
conformational equilibrium of these benzoxazepines is rather
complex (see a discussion in the ESI†), no conformation of the
trans compound would be able to experience this NOE.
We could not nd in the literature conformational studies
on these systems, apart from our own paper on products
similar to 10–11, but with the substituent bound at carbon 2,
instead of at carbon 3.42 The ESI† contains a discussion on
these complex conformational equilibria, applied to 10j–11j.
The most stable conformations are either half-chair or twist,
where the substituent at C-5 occupies an axial position. Among
them, the best one is a twist conformation of the cis stereo-
isomer 11j where the methyl group is in equatorial position.
This result agrees with the thermodynamic preference for the
cis product.
The conformation of imine 3e is a sort of half-chair, where
the C]N bond is coplanar with the benzene ring. Among the
two possible half-chairs, the one with the methyl in pseudo-
equatorial position seems more stable. In any case the face
opposite to the substituent is less encumbered, leading to
a kinetic preference for the trans compound.
´
Typical procedure for the Ugi–Joullie reaction: (3S,5R)-4-
acetyl-3-benzyl-N-(tert-butyl)-2,3,4,5-tetrahydrobenzo[f][1,4]
oxazepine-5-carboxamide 10a
Acetal 8a (312.4 mg, 778 mmol) was dissolved in CH2Cl2 (3.0 mL)
and treated with 37% aqueous HCl (640 mL, 7.73 mmol). The
mixture was stirred at rt for 5 h. Then it was diluted with
CH2Cl2, and cautiously treated with 5% aqueous Na2CO3 (25
mL). Aer checking that pH > 9, the two phases were separated,
washed with brine, and evaporated to dryness. The resulting
crude imine 3a (oil) was taken up in dry methanol (3.90 mL),
and treated with acetic acid (53 mL, 927 mmol), and tert-butyl
isocyanide (106 mL, 937 mmol). The mixture was stirred at rt for
45 h and evaporated to dryness. It was taken up in AcOEt,
washed with saturated aqueous NaHCO3 (to remove excess
carboxylic acid), evaporated, and chromatographed (PE/AcOEt
2 : 1) to give pure 10a (237 mg, 80%). The ratio 10a : 11a was
determined by HPLC on the crude product and resulted ¼
95 : 5. For HPLC conditions and characterization data, see ESI.†
Conclusions
In conclusion we have developed a concise and diversity-
oriented methodology to obtain both N-acylated, and N-free
tetrahydrobenzo[f][1,4]oxazepines with
a high control of
conguration of the two stereogenic centres. The enantio-
meric purity is granted by the starting materials (1,2-amino
alcohols of a-amino acids), which are easily accessible from
the chiral pool. The methodology is based on a highly dia-
´
stereoselective Ugi–Joullie reaction that strongly favours the
trans products. However, also the thermodynamically favoured
cis isomers can be obtained thanks to a base mediated epi-
merization. These seven-membered nitrogen heterocycles can
nd applications in medicinal chemistry, because tetrahydro-
1,4-benzoxazepines are typical privileged structures. On the
(3S,5R)-7-Bromo-N-(tert-butyl)-3-methyl-2,3,4,5-
tetrahydrobenzo[f][1,4]oxazepine-5-carboxamide 13
other hand, secondary amines such as 13, 14 or their Compound 10l (75.2 mg, 139 mmol) was dissolved in a 1.0 M
analogues may be explored as asymmetric organocatalysts. An solution of camphorsulfonic acid in dry MeOH (0.60 mL), and
ꢀ
easy combinatorial synthesis of such potential catalysts, stirred overnight at 40 C. Then it was diluted with AcOEt and
exploring both decoration and stereochemical diversity, is washed with a 1 : 1 mixture of saturated aqueous NaHCO3 and
indeed possible. Studied directed towards this goal are in brine. The nal pH of aqueous phase was 8. The phases were
progress.
separated, and the organic one evaporated to dryness and
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chromatographed (PE/AcOEt 2 : 1 + 1% EtOH / PE/AcOEt 1 : 1
+ 1% EtOH) to give pure 13 as a white solid (29 mg, 62%). Rf ¼
0.55 (PE/AcOEt 2 : 1). [a]D ¼ +28.6 (c 0.6, CHCl3). Mp: 154.0–
156.2 ꢀC. 1H NMR (300 MHz, CDCl3, 20 ꢀC): d ¼ 7.34 (1H, dd, J ¼
8.4, 2.4 Hz), 7.29 (1H, d, J ¼ 2.4 Hz), 6.92 (1H, d, J ¼ 8.4 Hz), 5.96
(1H, broad s, NH), 4.40 (1H, s, CHC]O), 4.12 (1H, dd, J ¼ 11.6,
2.0 Hz, CHHO), 3.50–3.31 (2H, m, CHHO, CHN), 1.32 (9H, s,
C(CH3)3), 1.07 (3H, d, J ¼ 6.3 Hz, CH3CH). 13C NMR (75 MHz,
CDCl3, 25 ꢀC): d ¼ 169.3 (C]O), 157.7, 133.7, 116.2 (quat.),
133.6, 132.3, 123.4 (aromatic CH), 78.4 (CH2O), 64.3 (CHC]O),
51.5 (CNH), 50.8 (CHN), 28.7 (C(CH3)3), 17.8 (CH3CH). IR (ATR):
nmax 3320, 3295, 2995, 2970, 2930, 2869, 1745, 1673, 1520, 1502,
1483, 1452, 1391, 1363, 1345, 1298, 1268, 1243, 1222, 1194,
1166, 1114, 1080, 1045, 1016, 985, 941, 928, 907, 874, 819, 786,
761, 726, 661 cmꢁ1. HRMS (ESI+): found 341.0870 [calcd for
Acknowledgements
We thank Mr Francesco Bellina for his collaboration to this
work, Dr Giuliana Ottonello and Dr Andrea Armirotti for HRMS.
Notes and references
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(3S,5S)-7-Bromo-N-(tert-butyl)-3-methyl-2,3,4,5-
tetrahydrobenzo[f][1,4]oxazepine-5-carboxamide 14
Compound 10l (103.7 mg, 191 mmol) was dissolved in dry THF
(1.22 mL) and treated with a 1 M solution of tetrabutylammo-
nium uoride (TBAF) in THF (230 mL, 230 mmol). The mixture
was stirred at rt for 2 h. Then it was diluted with AcOEt and
washed with a 1 : 1 mixture of brine and water. The organic
phases were evaporated. HPLC analysis of this crude product
indicated a d.r. of 90 : 10 (see ESI for details†). This crude
product was chromatographed (PE/AcOEt 1 : 2 + 1% EtOH) to
give pure cis compound 11m as a colorless oil (58 mg, 71%). The
overall yield, calculated from d.r., was 79%. This intermediate
was dissolved in a 1.0 M solution of camphorsulfonic acid in dry
MeOH (0.63 mL), and stirred overnight at 40 ꢀC. Then it was
diluted with AcOEt and washed with a 1 : 1 mixture of saturated
aqueous NaHCO3 and brine. The nal pH of aqueous phase was
8. The phases were separated, and the organic one evaporated to
dryness and chromatographed (PE/AcOEt 2 : 1 + 1% EtOH /
PE/AcOEt 1 : 1 + 1% EtOH) to give pure 14 as a white solid
(36 mg, 77%). Rf ¼ 0.55 (PE/AcOEt 2 : 1). [a]D ¼ ꢁ57.0 (c 1.0,
CHCl3). Mp: 107.6–110.0 ꢀC. 1H NMR (300 MHz, CDCl3, 20 ꢀC):
d ¼ 7.39 (1H, d, J ¼ 2.4 Hz), 7.30 (1H, dd, J ¼ 8.4, 2.4 Hz), 7.10
(1H, broad s, NH), 6.90 (1H, d, J ¼ 8.4 Hz), 4.53 (1H, s, CHC]O),
4.24 (1H, d, J ¼ 9.0 Hz, CHHO), 3.32–3.18 (2H, m, CHHO, CHN),
1.43 (9H, s, C(CH3)3), 1.03 (3H, d, J ¼ 5.6 Hz, CH3CH). 13C NMR
17 L. Moni, L. Ban, A. Basso, L. Carcone, M. Rasparini and
R. Riva, J. Org. Chem., 2015, 80, 3411–3428.
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20 L. Moni, L. Ban, A. Basso, A. Galatini, M. Spallarossa and
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ꢀ
(75 MHz, CDCl3, 25 C): d ¼ 169.6 (C]O), 158.0, 137.0, 116.8
(quat.), 131.6, 130.4, 123.3 (aromatic CH), 78.6 (CH2O), 61.4
(CHC]O), 54.5 (CHNH), 51.1 (CNH), 28.8 (C(CH3)3), 17.7
(CH3CH). IR (ATR): nmax 3338, 3286, 2965, 2931, 2875, 1661,
1513, 1477, 1457, 1392, 1365, 1316, 1300, 1286, 1264, 1245,
1223, 1164, 1144, 1104, 1085, 1047, 1009, 994, 939, 915, 903,
884, 874, 852, 829, 823, 805, 774, 751, 730, 675, 623 cmꢁ1. HRMS
+
(ESI+): found 341.0866 [calcd for C15H22BrN2O2 (M + H)+
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341.0865].
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Conflicts of interest
There are no conicts to declare.
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