A short and elegant synthesis of (±)-streptopyrrolidine

Article abstract of DOI:10.1002/jhet.1078

A brief and efficient approach for the synthesis of (±)-5-benzyl-4- hydroxy-2-pyrrolidine () from phenylalanine racemate is described. The key step is the stereocontrolled reduction of the keto functionality of benzylated pyrrolidinone intermediate () via sodium borohydride in carboxylic acid medium furnishing both (R,R)- and (S,S)-configured diastereomers. The natural (R,R) enantiomer (), however, crystallized out from its racemic mixture. Structure of was confirmed by NMR, IR, elemental analyzer, and single crystal X-ray crystallographic techniques.

Full text of DOI:10.1002/jhet.1078

Month 2013
A Short and Elegant Synthesis of ( )‐Streptopyrrolidine
Zurina Shaameri,a Sharifah Hidayah Sharif Ali,a Mohd Fazli Mohamat,a
b
a
*
Bohari M. Yamin, and Ahmad Sazali Hamzah
aOrganic Synthesis Laboratory, Institute of Science,Universiti Teknologi MARA, 40450 Shah Alam, Selangor, Malaysia
bSchool of Chemical Sciences & Food Technology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia,
43600 Bangi, Selangor, Malaysia
*
E-mail: asazali@salam.uitm.edu.my
Received May 7, 2011
DOI 10.1002/jhet.1078
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
A brief and efficient approach for the synthesis of ( )‐5‐benzyl‐4‐hydroxy‐2‐pyrrolidine (1) from phenyl-
alanine racemate is described. The key step is the stereocontrolled reduction of the keto functionality of
benzylated pyrrolidinone intermediate (6) via sodium borohydride in carboxylic acid medium furnishing
both (R,R)‐ and (S,S)‐configured diastereomers. The natural (R,R) enantiomer (2), however, crystallized
out from its racemic mixture. Structure of 2 was confirmed by NMR, IR, elemental analyzer, and single crys-
tal X‐ray crystallographic techniques.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
Because of its promising bioactivities and unique struc-
ture, streptopyrrolidine (2) is used as a target molecule in
this study. Herein, we report a short and concise synthetic
route to racemate (1) by using first the convenient way of
preparing pyrrolidinone ring moiety via condensation and
Dieckmann cyclisation, subsequently utilizing a one‐pot
manner of deacylation and stereocontrolled reduction
onto a key intermediate benzylated β,β‐diketoester, 6, as
outlined in Scheme 1.
Numerous approaches have been developed for the
synthesis of cis‐5‐benzyl‐4‐hydroxy‐2‐pyrrolidine [6–8].
However, the absolute configurations of the synthesized
5‐benzyl‐4‐hydroxy‐2‐pyrrolidines were reported to be
(4S,5S), as there are significant differences in the magni-
tude of the specific rotation of the synthetic samples [7a,
8] compared with that of the natural compound (2) [1].
We verify the structure of our target compound, which
crystallized out to be identical to the natural 2 with the cor-
rect stereochemistry as the 1H‐ and 13C‐NMR spectral
values are the same as those reported by Shin et al. [1].
Moreover, single crystal X‐ray data have confirmed the
absolute configuration of our natural 2 to be (4R,5R).
Streptopyrrolidine, (4R,5R)‐5‐benzyl‐4‐hydroxy‐2‐pyr-
rolidine (2) (Fig. 1), was isolated from the fermentation
broth of the deep sea bacterium Spectromyces sp. KORDI‐
3973 by Shin et al. [1]. It has been reported to
exhibit substantial antiangiogenesis activity with the same
potency as the known angiogenesis inhibitor SU11248 [2].
This hydroxypyrrolidine compound is therefore expected
to be a significant small molecule bioprobe for sudying
angiogenesis [1].
In our continuing efforts toward the synthesis of bioac-
tive pyrrolidine type compounds, our group successfully
synthesized some novel substituted 2‐pyrrolidinone and
spiroisoxazoline compounds [3]. Some of these com-
pounds are shown to exhibit potential anticancer and
neuroprotective activities against a panel of normal and
cancer cell lines [4]. The 4‐hydroxy‐2‐pyrrolidine ring
skeleton in streptopyrrolidine (2; Fig. 1) is currently being
much investigated in our laboratory due to its significant
presence in many biologically active compounds, which
include the nootropic drug oxiracetam (Fig. 1). This
ring moiety could also act as a versatile intermediate
for synthesizing important natural compounds such as
the antifungal alkaloid preussin [5] as well as a series
of γ‐amino acids (GABA). Several research groups
had successfully developed asymmetric synthesis of 5‐
alkyl‐4‐hydroxy‐2‐pyrrolidines toward such natural
products [6]. Some had specifically synthesized cis‐5‐
benzyl‐4‐hydroxy‐2‐pyrrolidine as a synthetic intermedi-
ate [7] but more recently as the target natural compound
(2) [8].
RESULTS AND DISCUSSION
Our synthetic approach to 1 began with the esterification
of readily available DL‐phenylalanine with thionyl chloride
in methanol at 0°C to give the required phenylalanine
methyl ester in a quantitative yield, 99% (Scheme 2).
Condensation of the methyl ester with methyl malonate
potassium salt in an equimolar amount gave an intermediate
diester 5 in excellent yield, 94%. The condensation between
© 2013 HeteroCorporation

Z. Shaameri, S. H. S. Ali, M. F. Mohamat, B. M. Yamin, and A. S. Hamzah
Vol 000
Scheme 3. Keto‐enol tautomerism of 6.
Figure 1. Chemical structures of (R,R)‐streptopyrrolidine (2) and
oxiracetam.
one‐pot reaction manner as described by Poncet et al.
[7a] (Scheme 4). The diketoester 6 was initially refluxed
with sulfuric acid of pH = 1.6 for 10 min to deacylate the
methyl ester functionality at C3, then the resulting
unpurified benzylated pyrrolidinone was dissolved in a
mixture of 1 : 9 ratio of acetic acid‐dichloromethane,
cooled to 0°C and reduced by sodium borohydride to give
racemate 1, in a quantitative yield. This synthetic strategy
furnished both natural (R,R)‐streptopyrrolidine (2) and its
unnatural (S,S) configured enantiomer. However, the natural
2 was successfully separated out via enantiomeric crystalli-
zation, which was obtained by slow evaporation of a
methanol‐diisopropyl ether (1 : 9 v/v) solution, from its
racemic mixture in 90% yield.
The key stereoselectivity was alleged to occur in the
final step of the synthetic strategy mediated by the
triacetoxyborohydride generated from NaBH4 with excess
glacial acetic acid [11]. The incoming hydride comes from
the less hindered side of the keto group, away from the
benzyl, forcing the hydroxyl to be in cis‐position to the
benzyl substituent (Scheme 5). Therefore, in our system,
the two reagents was carried out in the presence of
dicyclohexylcarbodiimide (DCC), which acts as both a cat-
alyst and a peptide coupling agent, in acetonitrile following
the method described by Heinicke [9]. Dieckmann cycliza-
tion of diester 5 with sodium methoxide, in situ generated
from sodium metal and anhydrous methanol in toluene
under reflux gave 6, methyl 5‐benzyl‐2,4‐dioxopyrrolidine‐
3‐carboxylate, as the advanced intermediate toward com-
pound 1 in 87% yield.
As anticipated, in two different solvents of disparate
polarities, 6 has shown to exist as either its keto tautomer,
6, or its enol form, 7 [10]. The β,β‐diketoester, 6, is favored
in a more polar solvent, in view of the fact that the reduced
polarity of the enol tautomer is induced by the tautomer’s
intramolecular hydrogen bonding (Scheme 3). The pres-
ence of these different tautomers was observed during
NMR analysis.
Our synthetic strategy, however, did not require further
isolation of the tautomers. Compound 6 was directly
subjected to demethoxycarbonylation and reduction in a
Scheme 1. Synthesis of ( )‐streptopyrrolidine (1).
Scheme 2. Synthesis of β,β‐diketoester 6.
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A Short and Elegant Synthesis of ( )‐Streptopyrrolidine
Scheme 4. One‐pot deacylation‐reduction of 6.
such transformation leads to the production of only (R,R)‐
and (S,S)‐configured isomers, favoring the formation of
the former diastereomer. The presence of both diastereo-
mers was markedly observed in NMR analysis of the oil
1
residue of racemate 1. The H‐NMR spectrum shows two
separate sets of signals for H‐4 and H‐5 methines: a set
of 4.33 and 3.91 ppm for H‐4 and H‐5, respectively, in
the (R,R) isomer, and another of 4.20 and 3.76 ppm for
the (S,S) isomer (Fig. 2). The chemical shifts of the H‐3
methylene are also distinct: 2.25 and 2.62 ppm for (R,R);
2.08 and 2.42 ppm for (S,S). The peak intensity of these
signals gave the ratio of (4R,5R)/(4S,5S) as 5 : 1 (Fig. 2).
For comparison purposes, both 1H‐NMR spectra in Figure
2 were obtained in deuterated methanol. They were not
measured in deuterated DMSO to avoid any interference
from the residual DMSO‐d6 which are at the chemical
shifts of 2.48 and 3.28 ppm.
The (4R,5R)‐streptopyrrolidine (2) obtained was light
yellow crystals with melting point of 134–136°C (lit. Mp
134–135°C [1]). The 1H‐NMR spectroscopic data of 2
(Table 1), which were measured in deuterated DMSO, in-
dicate resonances for aromatic protons, two methylenes,
two downfield methines at δ 3.68 and δ 4.09, amide NH
Figure 2. 1H‐NMR spectra of 1 and 2 in MeOD.
at δ 7.49, and hydroxy OH at δ 5.13. The nonequivalent
protons of C‐3 appear to be doublet of doublets at a much
upfield region of δ 1.97 (J = 16.5 and 2.7 Hz) and δ 2.38
(J = 16.5 and 6.0 Hz). Likewise, the doublet of doublets
of the nonequivalent benzylic protons appear at δ 2.65
(J = 13.5 and 6.0 Hz) and δ 2.95 (J = 13.5 and 7.8 Hz).
The olefinic hydrogens of the aromatic ring system appear
between δ 7.12 and δ 7.32 as multiplets, indicate the
presence of a monosubstituted benzene ring. The 13C
spectroscopic data (Table 1) suggest that compound 2
contains one carbonyl carbon, one quaternary aromatic
Scheme 5. Stereocontrolled reduction of 8.
NaBH
Natural (4R,5R) isomer ( 2)
5R (favoured intermediate)
HOAc/DCM
8
Unnatural (4S,5S) isomer
5S (disfavoured intermediate)
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Z. Shaameri, S. H. S. Ali, M. F. Mohamat, B. M. Yamin, and A. S. Hamzah
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Table 1
The whole molecule is not planar instead the pyrrolidine
ring adopts a twist conformation with N1-C5-C4-C3 and
N1-C2-C3-C4 torsion angles of −30.99(14)° and −17.58
(17)°, respectively (Fig. 3). The gauche conformation about
the C4-C5 bond leads to the formation of (R,R) relative
configuration as compared to (S,S) in the previously
reported synthesized compound [7a, 8].
The C5/N1/C2/C3/O13 fragment of the pyrrolidinone
ring is planar with maximum deviation of 0.032(1) Å for
N1 atom from the least square plane. It makes dihedral
angle of 59.53° with the benzyl C6/C7/C8/C9/C10/C11/
C12 (max deviation 0.025(2) Å for C6 atom) fragment.
The bond lengths and angles are in normal ranges [13] with
C2-O13 and C4-O14 bond lengths of 1.2257(2) and 1.3403
(11) Å, respectively. In the crystal structure, the mole-
cules are linked by N1-H1A···O13 and O14-H14A···O13
to form centrosymmetric dimers that are linked to form
one‐dimensional chains along the a‐axis (Fig. 4). The C-
H···pi interaction between the methylene hydrogen atom
of the pyrrolidinone ring and the benzene centroid is
also present.
In conclusion, a short synthesis of natural (4R,5R)‐
streptopyrrolidine (2) and its unnatural (4S,5S) configured
enantiomer was accomplished by demethoxycarbonylation
followed by stereoselective reduction of a key intermediate
benzylated β,β‐diketoester in a one‐pot reaction. The
overall yield was 73% over four steps. This synthetic strat-
egy is potentially applicable to members of natural prod-
ucts with a similar ring moiety. Further transformations
of ( )‐streptopyrrolidine (1) toward bioactive natural prod-
ucts are currently underway in our laboratory.
1H‐ and 13C‐NMR spectroscopic assignments for 2 in DMSO‐d6.
Position
1H (mult, J = Hz)
13C
NH
2
3
7.49 (1H, s)
–
1.97 (1H, dd, 16.5, 2.7)
2.38 (1H, dd, 16.5, 6.0)
4.09 (1H, m)
3.68 (1H, q, 6.2)
2.65 (1H, dd, 13.5, 6.0)
2.95 (1H, dd, 13.5, 7.8)
–
–
175.36
41.20
4
5
6
67.39
60.53
35.00
7
8
9
10
OH
139.13
129.68
128.65
126.43
–
7.15–7.27 (5H, m)
}
5.13 (1H, d, 4.8)
carbon, three aromatic methines, two saturated methines,
and two methylenes. The 1H‐1H COSY spectrum of 2 also
shows the correlation between the methine proton H‐4 at
δ 4.09 and the hydroxyl proton at δ 5.13. These NMR
values complement those of the isolated and purified
natural streptopyrrolidine as reported by Shin et al. [1].
Furthermore, the structure of 2 was confirmed by X‐ray
investigation. The compound crystallized in monoclinic
system with space group P 21/n, a = 5.945(2), b = 9.001
(4), c = 18.712(8), β = 94.100(8), V = 100.4(7) and Z = 4.
EXPERIMENTAL
General procedures.
1H‐ and 13C‐NMR spectra were
measured at 300 and 75 MHz, respectively. All NMR spectra
were recorded in deuterated solvents on Varian NMR 300 MHz
or Bruker NMR 300 MHz Spectrometers with tetramethylsilane
Figure 3. The molecular structure of 2 drawn in the crystals at 50% prob-
ability ellipsoid.
Figure 4. Molecular packing of compound 2 viewed down the b‐axis. The dashed lines denote the intermolecular hydrogen bonds.
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DOI 10.1002/jhet

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A Short and Elegant Synthesis of ( )‐Streptopyrrolidine
as an internal standard. Chemical shifts are expressed in δ (ppm)
units downfield from TMS. Infrared spectra were measured on
Varian Excalibur 3100. All samples were run neat on a single
refraction ZnSe crystal plate via ATR sampling accessory.
Elemental analyses were performed on Flash EA 110 instrument.
Melting points were determined by either an Electrothermal
melting point apparatus or an automatic B‐545 melting point
apparatus from Büchi and were uncorrected.
Crystals suitable for X‐ray investigation were obtained by slow
evaporation of a methanol‐diethyl ether (1 : 9 v/v) solution. The
measurements were performed at 273(2) or 298(2) K on Bruker
SMART APEX CCD diffraction using graphite‐monochromated
Mo‐Kα radiation (λ = 0.71073 Å). Orientation matrix and unit
cell parameters were obtained from the setting angles of 25‐cen-
ters reflection. The structure was solved using direct method
and refined by full‐matrix least‐square method on F2 using the
SHELXTL software package [14]. All non‐H atoms were aniso-
tropically refined. The hydrogen atoms were located in a differ-
ence Fourier map and then were fixed geometrically and treated
as riding atom on the parent C or N atoms, with C-H distances be-
tween 0.86 and 0.97 Å.
Methyl 5‐benzyl‐2,4‐dioxopyrrolidine‐3‐carboxylate, 6, as
the keto tautomer and methyl 5‐benzyl‐4‐hydroxy‐2‐oxo‐2,5‐
dihydro‐1H‐pyrrole‐3‐carboxylate, 7, as the enol tautomer.
A
solution of methyl 3‐(1‐methoxy‐1‐oxo‐3‐phenylpropan‐2‐ylamino)‐
3‐oxopropanoate, 5 (1.00 g, 3.58 mmol), in toluene (18 mL) was
added to a solution of sodium methoxide, which was prepared from
sodium (0.08 g, 3.58 mmol) in dry methanol (3 mL). The mixture
was refluxed at 90°C for 6 h under nitrogen. The reaction mixture
was cooled and diluted with H2O and the combined aqueous layers
were acidified with concentrated HCl. The product, methyl 5‐
benzyl‐2,4‐dioxopyrrolidine‐3‐carboxylate, 6 slowly precipitated out
as light yellow powder (0.76 g, 87%), m.p. 140.4°C. IR v cm−1:
3375 (N-H), 1684 (C═O), 1641 (C═O), 1226 (C═O); In
deuterated methanol, 6 was present as the keto tautomer; δH
(CD3OD, 300 MHz): 2.97 (1H, dd, J = 5.7 and 5.7 Hz, PhCHH),
3.18 (1H, dd, J = 4.2 and 4.2 Hz, PhCHH), 3.30 (1H, s,
COCHCO), 3.72 (3H, s, OCH3), 4.38 (1H, t, J = 5.1 and 5.1 Hz,
NCH), 7.18–7.23 (5H, m, Ar H), 13C (CD3OD, 75 MHz): 36.5
(CH2), 50.2 (OCH3), 58.1 (CHNH), 96.2 (COCHCO), 126.6–129.3
(aromatic C), 135.0 (quat. aromatic C), 164.6 (C═O), 171.7
(C═O), 186.1 (C═O). In deuterated chloroform, methyl 5‐benzyl‐4‐
hydroxy‐2‐oxo‐2,5‐dihydro‐1H‐pyrrole‐3‐carboxylic methyl ester
was present as the enol tautomer, 7; δH (CDCl3, 300 MHz): 3.77
(1H, dd, J = 8.7 and 8.7 Hz, PhCHH), 3.28 (1H, dd, J = 3.9 and 3.9
Hz, PhCHH), 3.78 (3H, s, OCH3), 4.33 (1H, d, J = 5.4 Hz, NCH),
6.16 (1H, br, s, OH), 7.18–7.32 (5H, m, Ar H); 13C (CDCl3, 75
MHz): 37.7 (CH2), 51.1 (OCH3), 57.9 (CHNH), 97.9 (COCHCO),
127.2–129.2 (aromatic C), 135.3 (quat. aromatic C), 167.7 (C-O),
187.6 (C═O); CHN: Found C, 63.11; H, 5.19; N, 5.27; O, 26.43
%; requires C, 63.15; H, 5.30; N, 5.67; O, 25.88 %.
Methyl 2‐amino‐3‐phenylpropanoate, 3.
To a stirred
solution of phenylalanine (16.63 g, 100.67 mol) in 118.23 mL
of methanol, under ice‐cooled condition of −20°C, thionyl
chloride (8.05 mL, 110.73 mol) was added dropwise over 10
min and stirred for 30 min. The ice bath was removed and
stirred for another 2.5 h. The reaction mixture was then refluxed
for 30 min and then evaporated to give the product, methyl
2‐amino‐3‐phenylpropanoate,
3 as white precipitate. The
precipitate was filtered and washed with diethyl ether and dried
(20.52 g, 99%), m.p. 155°C. IR v cm−1: 2994 (N-H), 1745
(C═O), 1148 (C-N), 1233 (C-O); δH (D2O, 300 MHz): 3.13
(1H, dd, J = 7.2, 7.5, 7.2, and 7.5 Hz, PhCHH ), 3.23 (1H, dd,
6.0, 6.3, 6.0, and 6.3 Hz, PhCHH), 3.72 Hz (3H, s, OCH3 ),
4.32 (1H, t, J = 6.6 Hz, NCH), 7.16–7.34 (5H, m, Ar H). 13C
(D2O, 75 MHz): 35.8 (CH2), 53.5 (OCH3), 54.0 (CHNH),
128.0–129.3 (aromatic C), 133.6 (quat. aromatic C), 169.9
(C═O); CHN: Found C, 67.48; H, 7.59; N, 8.31; O, 16.62 %;
requires C, 67.02; H, 7.31; N, 7.82; O, 17.85 %.
Formation of ( )‐streptopyrrolidine, 1.
A solution of
methyl 5‐benzyl‐2,4‐dioxopyrrolidine‐3‐carboxylate (2.0 g, 8.08
mmol) in 0.025M H2SO4 (pH = 1.6; 32 mL) was refluxed for
10 min. The solution was rapidly cooled in an ice‐bath and
extracted three times with ethyl acetate (40 mL). The organic
phase was dried over anhydrous sodium sulphate, filtered, and
concentrated under reduced pressure. The resulting unpurified
compound, 8, was dissolved in acetic acid‐dichloromethane (10
: 90; 40 mL), cooled to 0°C, and NaBH4 (0.32 g, 8.40 mmol)
was added in three batches. The solvent was removed under
reduced pressure furnishing an oily residue, 1, which consists of
both (4R,5R) and (4S,5S) isomers. The residue was then
recrystallized from methanol‐diisopropyl ether solution (1 : 9 v/v)
to give the natural (4R,5R)‐5‐benzyl‐4‐hydroxypyrrolidin‐2‐one
(streptopyrrolidine), 2 as light yellow crystals (2.79 g, 90%), m.p.
134–136°C. IR v cm−1: 3459 (N-H), 3195 (O-H), 1688 (C═O),
1185 (C-O); δH (DMSO‐d6, 300 MHz): 1.97 (1H, dd, J = 16.5
and 2.7 Hz, COCHHCHOH), 2.38 (1H, dd, J = 16.5 and 6.0 Hz,
COCHHCHOH), 2.65 (1H, dd, J = 13.5 and 6.0 Hz, PhCHH),
2.95 (1H, dd, J = 13.5 and 7.8 Hz, PhCHH), 3.68 (1H, q, J =
6.6, 5.4, and 6.6 Hz, NCH), 4.09 (1H, m, CHOH), 5.13 (1H, d, J
= 4.8 Hz, COH), 7.15–7.27 (5H, Ar H), 7.49 (1H, s, NH), 13C
(DMSO‐d6, 75 MHz): 35.0 (CH2), 41.2 (CH2), 60.5 (CHNH),
67.3 (COH), 126.4–129.6 (aromatic C), 139.1 (quat. aromatic C),
175.3 (C═O); CHN: Found C, 69.07; H, 6.84; N, 7.12; O, 16.97
%; requires C, 69.09; H, 6.85; N, 7.32; O, 16.73 %.
Methyl 3‐(1‐methoxy‐1‐oxo‐3‐phenylpropan‐2‐ylamino)‐3‐
oxopropanoate, 5.
Dicyclohexylcarbodiimide (1.14 g, 5.57
mmol) was added to a solution of phenylalanine methyl ester, 3
(1.00 g, 5.57 mmol) and methyl malonate potassium salt (0.87
g, 5.57 mmol) in acetonitrile/water (13/4 mL) at 0°C and stirred
for 2 h. The white precipitate formed was filtered and washed
with DCM. The combined filtrates were evaporated, and the
residue was partitioned between H2O and DCM. The DCM
fraction was washed with H2O, dried over anhydrous MgSO4,
and evaporated. The white powder was recrystallized from
acetone/petroleum ether to give the methyl 3‐(1‐methoxy‐1‐
oxo‐3‐phenylpropan‐2‐ylamino)‐3‐oxopropanoate, 5 as light
yellow oily (1.47 g, 94%), IR v cm−1: 3310 (N-H), 1741
(C═O), 1664 (C═O), 1203 (C═O); δH (CDCl3, 300 MHz):
3.12 (1H, dd, J = 6 and 6 Hz, PhCHH), 3.13 (1H, dd, J = 5.4
and 5.4 Hz, PhCHH), 3. 25 (2H, s, COCH2CO), 3.64 (6H, s,
2 × OCH3), 4.78 (1H, q, J = 6.6, 7.2, and 6.3 Hz, NCH),
7.02–7.25 (5H, m, Ar H), 7.34 (1H, br, s, NH); 13C (CDCl3,
75 MHz): 37.7 (CH2), 41.0 (CH2), 52.3 (OCH3), 52.4 (OCH3),
53.4 (CHNH), 127.1–129.2 (aromatic C), 135.7 (quat. aromatic
C), 164.6 (C═O), 169.1 (C═O), 171.6 (C═O); CHN: Found
C, 59.13; H, 6.16; N, 4.75; O, 29.96 %; requires C, 60.21; H,
6.14; N, 5.02; O, 28.64 %.
Acknowledgments. The authors acknowledge the generous
support of Universiti Teknologi MARA and Universiti
Kebangsaan Malaysia, as well as the financial support of
Ministry of Higher Education Malaysia (FRGS grant No. 600‐
IRDC/ST/FRGS 5/3/FST(1/2008)‐1). Crystal data are in CIF
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format. This supplementary crystallographic data have been
deposited with the Cambridge Crystallographic Data Centre,
CCDC No. 805759. Copies of this information may be obtained
free of charge from The Director, CCDC, 12 Union Road,
Cambridge CB2 IEZ, UK (Fax: +44 1223 336033; E‐mail:
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet