Journal of Molecular Structure 1194 (2019) 204e210

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Journal of Molecular Structure

journal homepage: http://www.elsevier.com/locate/molstruc

Synthesis and stereochemistry assignment of (3R,5R)- and (3S,5R)-4-

benzyl-3-(3,4-dimethoxyphenyl)-5-phenyl-1,4-oxazin-2-ones
Agnieszka Grajewska a, *, Maria D. Rozwadowska a, Andrzej Gzella b
a
Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznan
skiego 8, 61-614, Poznan

, Poland
b
Poznan
University of Medical Sciences, Pharmaceutical Faculty, Organic Chemistry Department, Grunwaldzka 6, 60-780, Poznan

, Poland

a r t i c l e i n f o a b s t r a c t

Article history: The diastereoselective synthesis of 3,5-disubstituted 1,4-oxazin-2-ones, the valuable intermediates on
Received 18 April 2019 the route to tetrahydroisoquinoline derivatives, was based on the Petasis reaction in which (R)-(
)-N-
Received in revised form benzyl-2-phenylglycinol was used as the amine component. It was demonstrated that the configuration
21 May 2019
of the newly generated C3 stereogenic centers in synthesized compounds, as well as in other 3,5-
Accepted 22 May 2019
Available online 25 May 2019
disubstituted 1,4-oxazin-2-ones, could be established simply by 1H NMR spectral data analysis. The
absolute configuration of the major isomer was additionally confirmed by single crystal X-ray analysis.
© 2019 Elsevier B.V. All rights reserved.
Keywords:
Petasis reaction
Diastereoselective synthesis
1,4-Oxazin-2-one
Configuration determination
NMR
X-ray

1. Introduction on the type of boronic acid and/or N-substituent [3,10e16] applied.

Recently, we have reported [1e3] a new approach to the syn-
thesis of tetrahydroisoquinoline derivatives based on a combina-
tion of two synthetic methodologies: the three-component
(boronic acid, carbonyl derivative and amine) Petasis synthesis of
various nitrogen-containing systems [4e6] and the Pomeranz-
Fritsch-Bobbitt cyclization of aminoacetals [7e9]. In this approach
the key intermediate of the synthesis, which is the “Pomeranz-
Fritsch aminoacetal” is prepared in one single operation by
coupling of an aromatic boronic acid, a carbonyl derivative and an
aminoacetaldehyde acetal, then subjected to cyclization followed
by reduction to construct the tetrahydroisoquinoline skeleton.
(Scheme 1).
Chiral amines used as components of the Petasis reaction can act
as chiral inductors at the same time, allowing for stereoselective
synthesis.
In most cases of the stereoselective Petasis reactions, (R)- and
(S)- enantiomers of a-phenylethylamine or their N-substituted
derivatives have been used, affording products in fair to good yields
with various degree of diastereoselectivity (0e99% d.e.), depending
* Corresponding author.
E-mail address: agako@amu.edu.pl (A. Grajewska).
When 1,2-aminoalcohols containing a primary amine group
were applied in reaction with boronic and glyoxylic acid, a-amino
acids were formed [10,16,17], while the N-substituted 1,2-
aminoalcohols led directly to 1,4-oxazin-2-one derivatives [13,18].
Petasis and Zavialov [10] starting with styrenyl boronic acid 1,
glyoxylic acid hydrate 2 and (S)-2-phenylglycinol 3, prepared hy-
droxy amino acid 4 in high yield with 99% d.e. which, after removal
of the chiral auxiliary, was transformed into (R)-homo-
phenylalanine hydrochloride 5, also in high yield and with 99% e.e.
(Scheme 2). The high enantioselectivity of this reaction could not be
reached by Churches et al. [16] who, after analysis of the crude
reaction product, established the diastereomeric ratio as 3:1. Yet,
after fractional crystallization it could be increased to 95:5 d.r.
In reactions, in which N-substituted 2-phenylglycinol was
applied, the initially formed Petasis products, the corresponding
hydroxy amino acids, undergo direct cyclization, leading to 3,5-
disubstituted 1,4-oxazin-2-one derivatives.
Jiang and Xu [13] applying (S)-(
)-N-propargyl-2-
phenylglycinol 6, styrenyl boronic acid 1 and glyoxylic acid hy-
drate 2, obtained oxazinones 7 and 8 as a 1.5:1 mixture of di-
astereomers in 87% yield. By conducting the reaction in the
presence of triethylamine a single diastereomer was formed, for
which cis-(3R,5S)-7 configuration was established by X-ray crystal

https://doi.org/10.1016/j.molstruc.2019.05.091
0022-2860/© 2019 Elsevier B.V. All rights reserved.
 A. Grajewska et al. / Journal of Molecular Structure 1194 (2019) 204e210 205

Scheme 1. Synthesis of tetrahydroisoquinoline derivatives based on two synthetic methods: the Petasis reaction and the Pomeranz-Fritsch-Bobbitt cyclization.

Scheme 2. Synthesis of (R)-homophenylalanine hydrochloride 5 by applying (S)-2-phenylglycinol 3.

analysis. (Scheme 3).

In a related to that described by Jiang and Xu [13] synthesis,
Hutton and co-workers [16,18] used (R)-N-benzyl-2-phenylglycinol
9 and various para substituted styrenyl boronic acids for the
preparation of highly functionalized dihydroxyhomoarylalanine
derivatives. Only in the case of unsubstituted styrenyl boronic acid
1, the oxazinone product 10 with high, 20:1 d.r., was obtained.
(Scheme 4). Its configuration established by X-ray crystal analysis,
was determined to be trans-(3R,5R). In the presence of para sub-
stituents in the phenyl ring of styrenyl boronic acid, the diaste-
reomeric ratio of the products was much lower (from 1:1 to 3:1 Scheme 4. Synthesis of oxazinone 10 by applying (R)-(þ)-N-benzyl-2-phenylglycinol
d.r.), independently on the nature of the substituent attached. 9.
It should be mentioned that by employing glyoxal 12 as the
carbonyl component in the Petasis reaction and 1,2-amino alcohols,
2. Results and discussion
1-hydroxymorpholine derivatives could be prepared [19e21]. Ac-

e and co-workers [19], performed an
cording to this protocol, Berre
In continuation of our experiments on the asymmetric synthesis
efficient synthesis of series of 1-hydroxymorpholines with high
of tetrahydroisoquinoline derivatives according to the Petasis/
yields. A stereochemical version of this approach in which (R)-N-
Pomeranz-Fritsch-Bobbitt approach [1e3], a model reaction was
methyl-2-phenylglycinol 11, glyoxal 12 and phenyl boronic acid 13
conducted to establish the diastereoselectivity of the Petasis step.
were used is shown in Scheme 5. In this reaction a mixture of
Thus, coupling of (R)-N-benzyl-2-phenylglycinol 9, with boronic
diastereomeric morpholinols 14 and 15 was formed, among which
acid 18 and glyoxylic acid hydrate 2 afforded two diastereomeric
trans-(3R,5R) diastereomer was the major product (93:7 d.r.).
oxazinones 19 and 20 in 98% yield with 58:42 diastereomeric ratio
Configuration of the both diastereomers (3R,5R)-14 and (3S,5R)-15
(determined by HPLC analysis), which were separated by column
as trans and cis, respectively, was assigned on the basis of optical
chromatography. (Scheme 6).
rotation of known aminodiols 16, [a]D ¼ þ86.5, and 17 [a]D ¼ 0,
The same reaction was conducted in the presence of
obtained by LAH reduction of 14 and 15.

Scheme 3. Synthesis of oxazinones 7 and 8 with the use of (S)-(
)-N-propargyl-2-phenylglycinol 6.

206 A. Grajewska et al. / Journal of Molecular Structure 1194 (2019) 204e210
Scheme 5. Synthesis of 1-hydroxymorpholine derivatives 14 and 15 and aminodiols 16 and 17.
Scheme 6. Synthesis of oxazinones 19 and 20.
triethylamine, which has been found to increase the diaster-
eoselectivity of Petasis reaction [13] leading to oxazinones 7
(Scheme 3) and in the presence of transition-metal-based Lewis
acids [FeCl3 and Cu(OTf)2] as the catalysts, playing an important
role in Petasis reaction stereocontrol between vinyl boronic acids,
N-tert-butanesulfinamide and glyoxylic acid [22].
When triethylamine was used as an additive to the reaction
between 2, 18 and 9 no formation of the oxazinones 19 and 20 was
observed, only starting materials 18 and 9 were isolated from the
reaction mixture.
The reaction conducted in the presence of 10% mol of FeCl3 and
Cu(OTf)2, respectively, gave the desired products, but interestingly
the isomer 20 was favoured over the isomer 19 in a 54:46 and 56:44
diastereomeric ratio respectively, the reverse diastereomeric ratio
to that observed for uncatalyzed Petasis reaction.
In order to assign the configuration of the newly generated C3
stereogenic center in 19 and 20, after careful analysis of spectral
data (1H NMR, 13C NMR, IR, MS), we have noticed that this problem
could be solved simply by comparing 1H NMR spectra of both di-
astereomers, recorded in CDCl3. (Fig. 1, Table 1).
Our attention was paid to a difference in the splitting pattern of
signals of methylene group protons in the N-benzyl substituent and
of the H6/H60 ring protons. In the spectrum of the diastereomer 19
Fig. 1. The structure and numbering of oxazinones 19 and 20.
the signals of the benzyl methylene group protons were found as
two doublets at 3.35 ppm and 3.64 ppm with J ¼ 14.1 Hz and
14.0 Hz, respectively, while the signal of the ring methylene protons
is represented as a doublet of doublets at 4.71 ppm with J ¼ 11.1 Hz
and J’ ¼ 5.5 Hz and 4.90 ppm with J ¼ 11.2 Hz and J’ ¼ 4.1 Hz. In the
case of the isomer 20 the signal of the benzylic protons is repre-
sented as an AB quartet at 3.76 ppm and 3.81 ppm with J ¼ 13.8 Hz,
and the signal of the ring methylene protons appears also as
doublet of AB quartet at 4.15 ppm with J ¼ 11.8 Hz and 8.0 Hz,
suggesting a symmetrical environment around these protons, and
thus a symmetrical structure of the molecule of the isomer 20.
The pattern of signals described above is however specific for
the spectra recorded in CDCl3. The spectra of 19 and 20 in DMSO‑d6
were also recorded and are presented in Table 2.
In the spectrum of the diastereomer 19 measured in DMSO‑d6
the signals of the benzyl methylene group protons were found as a
doublet at 3.43 ppm, overlapped with the signal of water traces in
DMSO‑d6 and a doublet at 3.55 ppm with J ¼ 14.3 Hz. In the case of
the isomer 20 the signals of the benzyl methylene group protons
overlapped with each other and were found as a doublet at
3.74 ppm with J ¼ 3.3 Hz. In the spectrum of isomer 19, the signals
of the H6/H60 ring protons were represented as a doublet at
4.68 ppm, overlapped with the signal of H-3 proton at 4.66 ppm,
and doublet at 4.98 ppm with J ¼ 10.2 Hz. The signals of the same
protons in 20 were found as a doublet of doublets at 4.23 ppm with
J ¼ 9.4 Hz and J’ ¼ 2.3 Hz and 4.38 ppm with J ¼ 10.8 Hz and
J’ ¼ 2.5 Hz.
The above results show that the relative configuration in 19 and
20 cannot be determined directly from their 1H NMR spectra
recorded in DMSO‑d6 because of overlapping signals of benzyl
methylene group protons with water (in 19) or with each other (in
20) and because of the fact that there is no significant difference
between the signals of the H6/H6’ ring protons in both
diastereomers.
 A. Grajewska et al. / Journal of Molecular Structure 1194 (2019) 204e210 207

Table 1
Comparison of selected 1H NMR chemical shifts, coupling constants and splitting patterns of N-benzyl-3,5-disubstituted 1,4-oxazin-2-ones 19 and 20. Spectra recorded in
CDCl3.

Compound d/J/(splitting pattern)

H3 NeCH2C6H5 H5 H6/H60

19 4.60/(s) 3.35/14.1 Hz/(d) 4.28/4.7 Hz/(t) 4.71/11.1; 5.5 Hz/(dd)

3.64/14.0 Hz/(d) 4.90/11.2; 4.1 Hz/(dd)
20 4.72/(s) 3.76/13.8 Hz/(ABq) 4.25/11.8 Hz/(t) 4.15/11.8; 8.0 Hz/(dABq)
3.81/13.8 Hz/(ABq)

Table 2
Comparison of selected 1H NMR chemical shifts, coupling constants and splitting patterns of N-benzyl-3,5-disubstituted 1,4-oxazin-2-ones 19 and 20. Spectra recorded in
DMSO‑d6.

Compound d/J/(splitting pattern)

H3 NeCH2C6H5 H5 H6/H60

19 4.66/(s) 3.43/
/(d)[a] 4.28/[b]/(s) 4.68/4.9 Hz/(d)[c]

3.55/14.3 Hz/(d) 4.98/10.2 Hz/(d)
20 4.68/(s) 3.74/3.3 Hz/(d) 4.29/10.8 Hz/(t) 4.23/9.4; 2.3 Hz/(dd)
4.38/10.8; 2.5 Hz/(dd)

[a] overlapped signal of NeCH2C6H5 and H2O.

[b] broad.
[c] overlapped signal of H6/H60 and H3.

In our opinion, the conclusions from the spectra recorded in

CDCl3 seem to have a more general meaning for assignment of
stereochemistry of other 3,5-disubstituted-1,4-oxazin-2-ones con-
taining a benzyl substituent as well as for their NH congeners.
We have undertaken a literature review and found other com-
pounds of this type with proven relative configuration and assigned
1
H NMR data showing a similar splitting pattern characteristic of
the trans-3,5-diastereomers, the dominating Petasis products
[16,18,23].
On the other hand, Boa, Russel et al. [24] in spectral character-
ization of a series of cis-3,5-disubstituted oxazine-2-ones of type 23
(R ¼ Me, Bn, CH2CH]CH2, CH2CH¼CMe2, CH2CH¼CHPh), prepared
by N- and C3- benzylation of 21 and then C3-alkylation of 22,
proved the presence of ABq systems corresponding to the N-benzyl
methylene group protons as well as to H6/H6’ ring protons in
spectra of all compounds synthesized. (Scheme 7). Similar ABq
splitting pattern was also reported by Dellaria and Santarsiero [23]
in 1H NMR spectra of cis-oxazinones with C-benzyl substituent, e.g. Fig. 2. The molecular structure of 19, showing the atomic labelling scheme.
Displacement ellipsoids are drawn at the 30% probability level.
24.
Additional support for our suggestions concerning the correla-
tion between 3,5-stereochemistry in 3,5-disubstituted 1,4-oxazin-
established by the structure refinement using 1817 Bijvoet-pair
2-ones and the shape of the signals of both the benzyl and the H6/
reflections. The research have shown that the H atoms at the
H6’ methylene groups protons, followed from X-ray structure
asymmetric C3 and C5 centres occupy a pseudoequatorial and axial
analysis of the crystalline (3R,5R) diastereomer 19.
positions, respectively, with respect to the 1,4-oxazine-2-one het-
The molecular structure and atom labeling scheme are illus-
erocyclic system. The torsion angle H3eC3/C5eH5 of 152 reveals
trated in Fig. 2. Studies have shown that 19 crystallizes in the
a trans configuration for atoms H3 and H5. The 1,4-oxazine-2-one
orthorhombic system and noncentrosymmetric space group
system has a chair conformation distorted towards the form in-
P212121 and its molecules have an absolute configuration of (3R,5R).
termediate between half-chair and envelope, with puckering
The absolute configuration of the tetrahedral C3 and C5 atoms was

Scheme 7. Synthesis of cis-3,5-disubstituted oxazine-2-ones of type 23 and structure of cis-oxazinone 24 with C-benzyl substituent.
208 A. Grajewska et al. / Journal of Molecular Structure 1194 (2019) 204e210
parameters [25] of Q ¼ 0.4674(16) Å, q ¼ 35.4(2) , 4 ¼ 224.5(3) .
3,4-Dimethoxyphenyl substituent is almost perpendicular to the
mean plane of 1,4-oxazine-2-one system [dihedral
angle ¼ 89.00(4) ], while the phenyl and benzyl substituents make
with it dihedral angles of 72.75(5) and 62.88(4) . A spatial orien-
tation of 3,4-dimethoxyphenyl, phenyl and benzyl substituents is
additionally determined by torsion angles O1eC2eC3eC8 and
C2eC3eC8eC9 of
107.44(16) and
126.34(14) , O1eC6eC5eC25
and C6eC5eC25eC26 of
173.67(14) and
94.94(17) , and
C3eC4eC18eC19 and C4eC18eC19eC20 of
64.08(15)
and
27.62(18) , respectively.
The molecules in the crystal structure of 19 are linked via non-
classical CeH/O hydrogen bonds, forming a three-dimensional
hydrogen bond network. Between molecules
C15eH15B$$$p(Ph2iv), C21eH21$$$p(Ph1iv), C28eH28$$$p(Ph3v)
contacts are also observed (Table 3, Fig. 3).
3. Conclusion
In conclusion, a diastereoselective synthesis of oxazinones 19
and 20, which were chosen as model compounds to test the steric
outcome of the Petasis step of the Petasis/Pomeranz-Fritsch-
Bobbitt synthesis of tetrahydroisoquinolines, was performed. It
was shown, that the configuration of the new stereogenic center at
C3 could be easily determined by 1H NMR spectral data analysis,
without special measurements or derivatization, which was sup-
ported by spectral data of other 3,5-disubstituted oxazin-2-ones
found in literature. Absolute configuration of 19, established by X-
ray crystal analysis, confirmed also the above finding.
4. Experimental section
4.1. General methods
Melting points were determined on a Koffler block and are
uncorrected. IR spectra: Bruker FT-IR IFS 113V. NMR spectra: Bruker
ASCEND 400 (1H: 400 MHz, 13C: 100 MHz). Mass spectra: AMD402.
HRMS: Impact HD (Bruker Daltonics). Optical rotation: Perkin-
Elmer polarimeter 242B at 20  C. HPLC: Waters HPLC system with
Kromasil 3-Amycoat 4.6  250 mm column, hexane: 2-PrOH 9:1,
flow rate 0.5 mL/min. Merck DC-Alufolien Kieselgel 60254 were
used for TLC and silica gel (100e200 mesh ASTM) for column
chromatography. All compounds were purchased from Aldrich
Chemical Co. and used as received.
4.2. Synthesis of (3R,5R)- and (3S, 5R)-4-benzyl-3-(3,4-
dimethoxyphenyl)-5-phenyl-1,4-oxazin-2-ones 19 and 20
4.2.1. Petasis reaction without additives
3,4-Dimethoxyphenyl boronic acid 18 (0.728 g, 4 mmol) and
glyoxylic acid hydrate 2 (0.368 g, 4 mmol) in DCM (5 mL) were
stirred at room temperature for 10 min then (R)-N-benzyl-2-
Table 3
Hydrogen bond geometry in the crystal lattice of 19.
Hydrogen bonds Donor
H (Å)
C5eH5/O7i 1.00
C6eH6A$$$O14ii 0.99
C22eH22/O1iii 0.95
C15eH15B$$$p(Ph2iv) 0.98
C21eH21$$$p(Ph1iv) 0.95
C28eH28$$$p(Ph3v) 0.95
Symmetry codes: (i)
0.5 þ x,1.5ey,1ez; (ii) x,e1þy,z; (iii) 1.5ex,1ey,e0.5 þ z; (iv) 0.5 þ x,0.5ey,1ez; (v) 1ex, 0.5 þ y,0.5ez; Ph1: C8 e C13; Ph2: C25 e C30; Ph3: C19 e C24
(Fig. 3).
phenylglycinol 9 (0.908 g, 4 mmol) was added and the mixture
was stirred at room temperature for 72 h. After this time, the
inorganic solid was removed by filtration, then the solvent was
evaporated in vacuo to give partially crystalline residue (1.58 g, 98%)
with 58:42 d.r. [by HPLC: tR (major isomer) ¼ 23.5 min, tR (minor
isomer) ¼ 17.7 min]. The crude product was recrystallized from
methanol to deposit pure crystalline isomer 19 (0.86 g, 53%), m.p.

1
159e160  C, [a]20D
206.6 (c 1.08, DCM). IR (KBr, cm ): 2992, 2960,

1 1
2940, 2833, 1731(br), 1515 cm . H NMR (CDCl3), d: 3.35 (d, J
14.1 Hz, 1H), 3.64 (d, J 14.0 Hz, 1H), 3.90 (2s, 6H), 4.28 (t, J 4.7 Hz,
1H), 4.6 (s, 1H), 4.71 (dd, J 11.1, 5.5 Hz, 1H), 4.90 (dd, J 11.1, 4.1 Hz,
1H), 6.91 (d, J 8.3 Hz, 1H), 6.97 (d, J 2.0 Hz, 1H), 7.09 (dd, J 8.3, 2.0 Hz,
1H), 7.28e7.31 (m, 1H), 7.33e7.39 (m, 7H), 7.41e7.44 (m, 2H). 13C
NMR (CDCl3), d: 52.6, 54.9, 55.8, 55.9, 64.8, 72.7, 111.1, 111.8, 121.0,
127.4, 128.4, 128.4, 128.4, 128.6, 128.9, 128.9, 135.8, 137.4, 149.0,
149.1, 169.2. 1H NMR (DMSO‑d6), d: 3.43 (d, overlapped with water,
1H), 3.55 (d, J 14.3 Hz, 1H), 3.79 (2s, 6H), 4.28 (s, broad, 1H), 4.66 (s,
1H), 4.68 (d, J 4.9 Hz, 1H), 4.98 (d, J 10.2 Hz, 1H), 7.02 (d, J 8.3 Hz, 1H),
7.07 (s, 1H), 7.11 (d, J 8.3 Hz, 1H), 7.29e7.31 (m, 3H), 7.35e7.41 (m,
5H), 7.45e7.48 (m, 2H). 13C NMR (DMSO‑d6), d: 53.3, 55.4, 56.4, 56.5,
65.4, 73.2, 112.6, 113.0, 121.7, 128.2, 128.9, 129.0, 129.0, 129.5, 129.7,
130.6, 137.7, 138.5, 149.6, 169.6. MS (EI): m/z (%): 404 (2) [Mþ1]þ,
403 (8) [M]þ, 402 (3), 359 (26), 358 (18), 357 (4), 255 (56), 254
(100), 253 (37), 178 (30), 177 (17), 164 (8), 104 (7), 91 (58). HRMS
(ESI) calcd. for C25H26NO4 [Mþ1]þ 404.18603, found: 404.1874.
HPLC: tR ¼ 23.5 min.
The isomer 20 was isolated as an oil by column chromatography
of mother liquor, (0.065 g, 4%), [a]D þ80.5 (c 1.03, DCM).
IR (KBr, cm
1): 2951, 2933, 2834, 1746 (br), 1513 cm
1. 1H NMR
(CDCl3), d: 3.76 and 3.81 (ABq, J 13.8 Hz, 2H), 3.87 (s, 3H), 3.88 (s,
3H), 4.15 (dABq, J 11.8, 8.0 Hz, 2H), 4.25 (t, J 11.8 Hz, 1H), 4.72 (s, 1H),
6.86 (d, J 8.3 Hz, 1H), 7.06 (d, J 1.7 Hz, 1H), 7.11e7.14 (m, 3H),
7.23e7.27 (m, 3H), 7.37e7.39 (m, 1H), 7.44 (t, J 7.5 Hz, 2H), 7.55 (d, J
7.4 Hz, 2H). 13C NMR (CDCl3), d: 55.9, 57.4, 63.2, 64.3, 71.0, 110.7,
111.0, 119.0, 127.7, 128.1, 128.3, 128.6, 129.0, 129.8, 130.7, 135.9, 137.5,
148.7, 149.0, 170.0. 1H NMR (DMSO‑d6), d: 3.74 (d, J 3.3 Hz, 2H), 3.78
(s, 3H), 3.78 (s, 3H), 4.23 (dd, J 9.4, 2.3 Hz, 1H), 4.29 (t, 10.8 Hz, 1H),
4.38 (dd, J 10.8, 2.5 Hz, 1H), 4.68 (s, 1H), 6.98 (d, J 8.3 Hz, 1H), 7.05 (d,
J 8.5 Hz, 1H), 7.10 (s, 1H), 7.16 (d, J 7.2 Hz, 2H), 7.21e7.30 (m, 3H), 7.38
(t, J 7.2 Hz, 1H), 7.46 (t, J 7.4 Hz, 2H), 7.62 (d, J 7.6 Hz, 2H). 13C NMR
(DMSO‑d6), d: 56.4, 56.4, 58.1, 62.5, 65.5, 71.0, 112.2, 112.6, 120.2,
128.2, 128.9, 129.0, 129.1, 129.6, 130.2, 131.7, 137.6, 139.2, 149.3,
149.5, 170.6. MS (EI): m/z (%): 404 (4) [Mþ1]þ, 403 (16) [Mþ], 402
(6), 359 (29), 358 (32), 357 (10), 344 (10), 255 (55), 254 (100), 253
(50), 240 (10), 239 (7), 178 (25), 177 (10), 164 (12), 104 (6), 91 (52),
90 (33). HRMS (ESI) calcd. for C25H26NO4 [Mþ1]þ 404.18603, found:
404.1864. HPLC: tR ¼ 17.7 min.
4.2.2. Petasis reaction performed in the presence of Lewis acids
(general procedure)
3,4-Dimethoxyphenyl boronic acid 18 (1 equiv.), glyoxylic acid
hydrate 2 (1 equiv.) and Lewis acid (0.01 equiv.) in DCM (5 mL per
H$$$Acceptor (Å) Donor$$$Acceptor (Å) Donor
H$$$Acceptor (º)
2.53 3.383(2) 142
2.54 3.451(2) 153
2.52 3.278(2) 136
2.87 3.6331(19) 136
2.84 3.6534(19) 145
2.58 3.4434(19) 152
 A. Grajewska et al. / Journal of Molecular Structure 1194 (2019) 204e210
Fig. 3. The CeH/O and C21eH21$$$p(Ph) hydrogen bonding in the crystal structure of 19. The H atoms not involved in hydrogen bonds have been omitted for clarity.
1 mmol of substrates) were stirred at room temperature for 10 min
then (R)-N-benzyl-2-phenylglycinol 9 (1 equiv.) was added and the
reaction mixture was stirred at room temperature for 24 h. After
this time, water was added and the aqueous phase was extracted
with DCM (3 x 5 mL). The combined organic extracts were dried
over anhydrous Na2SO4 then the solvent was evaporated in vacuo to
give partially crystalline residue. The diastereomeric ratio of the
products was measured by HPLC analysis.
Following the general procedure, 19 and 20 were obtained in
90% yield with d.r. 44:56 from the reaction of 18, 2 and 9 carried out
in the presence of Cu(OTf)2 in a 0.30 mmol scale.
Following the general procedure, 19 and 20 were obtained in
89% yield with d.r. 46:54 from the reaction of 18, 2 and 9 carried out
in the presence of FeCl3 in a 0.25 mmol scale.
4.3. Crystal structure determination of 19
Crystal data: C25H25NO4, Mr ¼ 403.46, orthorhombic, space
group P212121, a ¼ 10.45975(11), b ¼ 10.67288(13), c ¼ 18.8643(2)
Å, V ¼ 2105.93(4) Å3, T ¼ 130.0(1) K, Z ¼ 4.
Data collection. A colourless plate (methanol) crystal of 0.20 x
0.17  0.07 mm was used to record 21872 (Cu Ka radiation,
qmax ¼ 76.49 ) intensities on a SuperNova Dual A diffractometer
[26]. Accurate unit cell parameters were determined by least-
squares techniques from the q values of 12011 reflections, q range
4.17e76.24 . The data were corrected for Lorentz, polarization and
for absorption effects [26]. The 4392 total unique reflections
(Rint ¼ 0.028) were used for structure determination.
Structure solution and refinement. The structure was solved by
dual-space algorithm (SHELXT) [27] and refined against F2 for all
data (SHELXL-97) [28]. The positions of the H atoms were posi-
tioned geometrically and were refined using a riding model, with
CeH ¼ 0.98 Å (CH3), 0.99 Å (CH2), 1.00 Å, (Csp3H), 0.95 Å, (CarH), and
Uiso(H) ¼ 1.2Ueq(C) or 1.5Ueq(C) for methyl H atoms. The methyl
groups were refined as rigid group, which was allowed to rotate.
Final refinement converged with R ¼ 0.0289 (for 4275 data with
F2 > 4s(F2)), wR ¼ 0.0745 (on F2 for all data), and S ¼ 1.057 (on F2 for
all data). The largest difference peak and hole was 0.129 and
0.182
eÅ3. The molecular illustrations were drawn using ORTEP-3 for
Windows [29]. Software used to prepare material for publication
was WINGX [29], OLEX [30] and PLATON [31].
The crystallographic data in the CIF form are available as Elec-
tronic Supplementary data from the Cambridge Crystallographic
209
Data Centre, deposition number CCDC-1880981; http://www.ccdc.
cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK; fax:
ţ44 1223 336033; e-mail: deposit@ccdc.cam.uk).
Conflicts of interest
The authors declare no competing conflict of interests.
Acknowledgement
This work was supported by the research grant from the Polish
National Science Centre (NCN) No. 2011/01/D/ST5/06627.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.molstruc.2019.05.091.
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