Organocatalyzed stereoselective construction of N-formylpiperidines via a Michael-aza-Henry-hemiaminalization reaction cascade

Article abstract of DOI:10.1016/j.tetlet.2012.07.097

An efficient asymmetric synthesis of N-formylpiperidines via an organocatalytic Michael-aza-Henry-hemiaminalization reaction cascade of an aldehyde, a nitroalkene, and an N-arylideneformamide is reported. The reaction is triggered by diphenylprolinol trim

Full text of DOI:10.1016/j.tetlet.2012.07.097

Tetrahedron Letters 53 (2012) 5323–5326
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Organocatalyzed stereoselective construction of N-formylpiperidines via
a Michael-aza-Henry-hemiaminalization reaction cascade
⇑
Ruchi Chawla, Ankita Rai, Atul K. Singh, Lal Dhar S. Yadav
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient asymmetric synthesis of N-formylpiperidines via an organocatalytic Michael-aza-Henry-
hemiaminalization reaction cascade of an aldehyde, a nitroalkene, and an N-arylideneformamide is
reported. The reaction is triggered by diphenylprolinol trimethylsilyl ether and creates two C–C and
one C–N bonds leading to the formation of highly enantio-enriched N-formylpiperidines with five contig-
uous chiral centers in a one-pot operation.
Received 19 June 2012
Revised 18 July 2012
Accepted 22 July 2012
Available online 27 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalysis
Piperidines
Nitroalkenes
Stereoselective synthesis
Cascade reactions
Organocatalysis has become a thriving area of general concepts
and has contributed greatly to the past decade’s advances in syn-
thetic organic chemistry.1 One of its impressive and current appli-
cations is in the construction of cyclic molecules via domino/
cascade reactions.2 In our earlier investigations on organocascade
reactions, we have reported the synthesis of cyclic systems with
up to five stereocenters.3 A study on further potential of organocas-
cade reactions via the enamine activation employing the same
class of pyrrolidine-based catalysts to generate variously substi-
tuted piperidine ring system appears an interesting area of
research.4–7 The ubiquitous molecular skeleton of a piperidine ring
with one or more substituents finds important application in the
construction of natural products and pharmaceuticals. Efficient
new approaches for the preparation of chemically and biologically
relevant piperidines are of great significance in chemical research,
especially those with an intriguing mechanism and good stereose-
lectivity. Hence, such a framework has attracted the attention of
synthetic chemists tremendously over the recent years.4–7
Although a number of methods for the synthesis of polysubsti-
tuted piperidines are known,5–7 only a few reports on their chiral
versions are available in the literature.2g,7,8 The previously reported
methods are lengthy, whereas the recently reported one-pot asym-
metric organocascade reaction approaches employ N-sulfonyli-
mines for incorporating the nitrogen atom into the piperidine
ring. N-sulfonylimines are relatively unstable compounds and their
reactions, in most of the cases, are carried out in dry solvents and
under inert atmosphere. In order to present an alternative to such
procedures, we decided to employ N-( -tosylaryl)formamides in
a
place of N-sulfonylimines for the organocatalyzed stereoselective
construction of the piperidine skeleton. N-(aryl(tosyl)methyl)for-
mamides are stable, readily accessible substrates which can under-
go elimination of sulfinic acid to afford an N-arylideneformamide
under very mild conditions.9 In fact, N-arylideneformamides are
not only potential substitute for N-sulfonylimines but they also
offer an additional advantage of synthesizing substituted N-form-
ylpiperidines. Most of the available synthetic methods for N-form-
ylpiperidines are tedious and require harsh conditions.10 To the
best of our knowledge, N-formylpiperidines have never been
prepared using N-(aryl(tosyl)methyl)formamides in conjunction
with enamine catalysis.
The N-formylpiperidines are valuable compounds as their CHO
group can be utilized for the direct synthesis of various analogs.
For example, N-formylpiperidines can be either thionized with
Lawesson’s reagent to N-CHS piperidines or selenized with P/Se
or Woollins’ reagent to N-CHSe piperidines.11 N-methyl com-
pounds can be also easily obtained from N-formyl derivatives.12
All of these analogs show useful biological activities such as excel-
lent antifungal, herbicidal, insecticidal, bactericidal, anti-inflam-
matory, antihistaminic, hypotensive, anticancer, CNS stimulant
and depressant, and nerve activities.10,11 Furthermore, N-formylpi-
peridine moiety is used for the synthesis of drugs for treatment of
neurological disorders.13
The literature survey reveals that the synthesis of numerous
compounds bearing multiple stereogenic centers involves organoc-
atalysis.7,8 In the context of our continued investigations on new
⇑
Corresponding author. Tel.: +91 532 2500652; fax: +91 532 2460533.
E-mail address: ldsyadav@hotmail.com (L.D.S. Yadav).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.097

5324
R. Chawla et al. / Tetrahedron Letters 53 (2012) 5323–5326
O
tivity (Table 1, entries 1 and 2). Gratifyingly, the use of 20 mol %
Ts
R3
R2
N
NH
of catalyst 4a gave the best results and was used as the catalyst
in the following exploration. With optimal catalyst in hand, differ-
ent organic solvents were screened to investigate their effect on
the reaction. As recorded in Table 1, the efficiency of solvents
was of overwhelming distinction. An inference has been drawn
that polar aprotic solvents give good results (Table 1, entries 2
and 8–14) in terms of yield and stereoselectivity. Thus, among
CH2Cl2, THF, DCE, 1,4-dioxane, and acetonitrile, the best solvent
was CH2Cl2 (Table 1, entry 2) to carry out the reaction.
3
R1
R2
O2N
R3
O
catalyst (S)-4a, Et3N
R1
CH2Cl2, rt
H
OH
O2N
1
2
5
O
single diastereomer
Scheme 1. Synthesis of N-formylpiperidines.
organocatalytic strategies for the synthesis of chiral heterocycles,3
we herein disclose the first chiral amine-triggered cascade reaction
that allows the construction of highly enantio-enriched N-form-
ylpiperidines with five contiguous chiral centers (Scheme 1).
The feasibility of the proposed synthesis was examined using
propionaldehyde 1a, trans-b-nitrostyrene 2a, N-(phenyl(tosyl)
methyl)formamide 3a, and a range of pyrrolidine-based organocat-
alysts along with Et3N in varying solvents. Our initial endeavor was
to evaluate appropriate conditions for the Michael addition of
propionaldehyde 1a to nitrostyrene 2a and to screen a range of cat-
alysts 4 and solvents.
Thus, we first focused on the search for an efficient catalyst for
the one-pot three-component reaction. Interestingly, the desired
product 5a was obtained in excellent diastereo- and enantioselec-
tivities apparently depending upon the catalyst used. The results of
this assessment are summarized in Table 1. The conditions that
gave the best result in terms of yield and stereoselectivity, used
20 mol % of catalyst 4a at room temperature (Table 1, entry 2).
On lowering the catalyst loading from 20 mol % to 15 mol %, there
was considerable decrease in the yield and stereoselectivity (Table
1, entries 2 and 3). Moreover, an increase in catalyst loading from
20 mol % to 25 mol % neither improved the yield nor stereoselec-
Consequently, considering the overall effects of catalyst, sol-
vent, and catalyst loading, finally the synthetic strategy was estab-
lished and applied to the present study to transform a series of
substrates to the corresponding products.14 Further studies on
the exploration of substrate scope and limitations were carried
out. As shown in Table 2, regardless of the presence of an elec-
tron-withdrawing or -donating group in the aryl rings at ortho,
meta, or para positions almost similar reactivity and selectivity in
the formation of 5 were observed (Table 2).
A tentative mechanism for the formation of N-formylpiperi-
dines is depicted in Scheme 2. In the first step, the catalyst trimeth-
ylsilyl ether 4a activates aldehyde 1 by enamine formation, which
then selectively adds to nitroalkene 2 in a Michael type reaction.
The addition takes place through the transition state 8 as proposed
by Hayashi et al.1e The following in situ hydrolysis forms nitroal-
kane 6 and liberates the catalyst to complete the catalytic cycle
of the first step (Michael reaction). The subsequent aza-Henry
reaction followed by hemiaminalization furnishes the product 5.
The present reaction cascade forms a single diastereomer with a
high enantioselectivity. The main reason for the high stereoselec-
tivity is the chiral diphenylprolinol trimethylsilyl ether (S)-4a cat-
alyzed Michael addition, which is known to proceed with high
Table 1
Optimization of the reaction conditionsa
O
O
Ts
Ph
Ph
N
NH
H3C
Ph
Ph
catalyst (S)-4
O2N
Ph
CH3
O
H
3a
H
Et3N, CH2Cl2
rt, 15 h
CH2Cl2, rt, 7 h
OH
O2N
NO2
6a
1a
2a
O
5a
single diastereomer
Ph
OH
Ph
Bn
N
Ph
OTMS
Ph
Ph
OTES
Ph
O
N
N
N
N
N
N
N
H
H
H
H
H
OH
4e
4a
4c
4b
4d
S. No.
Catalyst (mol %)
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4a (25)
4a (20)
4a (15)
4b (20)
4c (20)
4d (20)
4e (20)
4a (20)
4a (20)
4a (20)
4a (20)
4a (20)
4a (20)
4a (20)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
DCE
91
91
84
73
62
69
65
81
79
69
71
85d
78d
80d
97
97
90
92
86
88
89
90
94
96
96
99d
96d
95d
THF
1,4-Dioxane
n-Hexane
Isooctane
Toluene
a
b
c
For the experimental procedure, see Ref. 14.
Isolated yield of the product 5a.
Determined by HPLC analysis on a chiral Eurocel column (250 Â 4.6 mm, 5
l
).
d
Yield and ee of compound 6a, product 5a was formed only in traces. The HPLC data of 6a, determined with a OD-H column at 237 nm (2-propanol/hexane = 1:10) and
1.0 mL/min flow rate, are in agreement with those reported in the literature,1e which confirm its absolute configuration (2R, 3S).

R. Chawla et al. / Tetrahedron Letters 53 (2012) 5323–5326
5325
Table 2
Scope of the synthesis of N-formylpiperidinesa
O
O
R2
N
Ts
R1
R2
catalyst (S)-4a
CH2Cl2, rt, T1
R1
NH
O2N
R3
O
H
3
R3
R1
R2
H
Et3N, CH2Cl2
rt, T2
OH
O2N
NO2
1
2
O
5
6
single diastereomer
S. No.
R1
R2
R3
T1b (h)
T2b (h)
Product
Yieldc,d (%)
eee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
iPr
iPr
Ph
Ph
p-ClC6H4
Ph
p-ClC6H4
Ph
Ph
Ph
Ph
p-ClC6H4
Ph
p-ClC6H4
Ph
7
8
7
15
15
17
16
19
20
20
17
15
18
17
16
18
19
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
91
90
88
88
74
80
86
85
87
72
83
81
89
85
97
95
95
96
90
93
88
92
89
85
91
94
90
84
p-MeOPh
p-BrC6H4
o-ClC6H4
2-Furyl
p-MeC6H4
m-MeOC6H4
Ph
p-BrC6H4
2-Furyl
p-MeOPh
o-ClC6H4
p-ClC6H4
p-MePh
6
10
10
9
6
8
10
9
9
7
8
PhCH2
PhCH2
Ph
p-ClC6H4
a
b
c
For the experimental procedure, see Ref. 14.
Time taken (T1) for the generation of 6 and the time elapsed (T2) for the synthesis of products 5.
Isolated yield of the product 5.
d
e
All compounds gave C, H, N analyses within 0.35% and satisfactory spectral (IR, 1H NMR, 13C NMR, and EIMS) data.
Determined by HPLC analysis on a chiral Eurocel column (250 Â 4.6 mm, 5
l).
R2
O2N
R3
R1
Ph
OTMS
Ph
O
R1
N
H
Hemiaminalization
H
N
OH
1
catalyst (S)-4a
R2
5
O
O2N
R1
Ph
OTMS
Ph
δ
N
R3
10
N
O
Enamine-catalyzed
cycle
δ
7
O
R1
R2
Et3N
O
Aza-Henry Reaction
R1
R2
O
O
H
O
2
NO2
N
TMSOPh2C
N
N
Et3N
R3
NH
Ts
O
3
Michael reaction
NO2
-TsH
R3
R2
6
8
R1
Scheme 2. Tentative mechanism for the synthesis of N-formylpiperidines 5.
in situ generated N-arylideneformamide from N-(aryl(tosyl)
methyl)formamide 3 and the nitroalkane 6 followed by intramo-
lecular hemiaminalization to afford 5. The possibility of controlling
the absolute configuration up to five contiguous stereocenters on
the piperidine ring offers a useful methodology for a short synthe-
sis of several differently substituted piperidine derivatives with
excellent yields and high diastereo- and enantioselectivities.
The relative stereochemistry of 5 was determined by NOE
experiments and coupling constants (Fig. 1). Strong NOE between
2-H and 6-H; 4-H and 6-H shows that 2-H, 4-H, and 6-H are on
the same face of the molecule. The coupling constants (J = 10.4–
11.9 Hz) of these protons clearly indicate that they occupy axial
(ax) positions, hence the other substituents at positions 2, 4, and
6 must be equatorial (eq). A significant NOE between 3-H and
hydroxylic proton shows that they are cis to each other, which
H
H
H
O
H
R1
O
R2
NO2
N
R3
H
H
Figure 1. Selected NOE.
H
diastereo- and enantioselectivities; clearly this selectivity is kept
or enhanced in the subsequent steps probably owing to the chiral-
ity of 6 along with a sterically favorable interaction between the

5326
R. Chawla et al. / Tetrahedron Letters 53 (2012) 5323–5326
Chem. Sci. 2012, 3, 384; (d) Chen, Y.; Zhong, C.; Peterson, J. L.; Akhmedov, N. G.;
Shi, X. Org. Lett. 2009, 11, 2333.
confirms the trans-stereochemistry at all the vicinal carbons of the
piperidine ring in products 5 as shown in Scheme 2.
9. (a) Dahmen, S.; Brase, S. J. Am. Chem. Soc. 2002, 124, 5940; (b) Mennen, S. M.;
Gipson, J. D.; Kun, Y. R.; Muller, J. J. Am. Chem. Soc. 2005, 127, 1654; (c) Van
Leusen, A. M.; Wildeman, J.; Oldenziel, O. H. J. Org. Chem. 1977, 42, 1153; (d)
Sisko, J.; Mellinger, M.; Sheldrake, P. W.; Baine, N. H. Tetrahedron Lett. 1996, 37,
8113.
10. (a) Zakrewski, J.; Krawczyk, M. Bioorg. Med. Chem. Lett. 2011, 21, 514; (b)
Sekhar, A. C.; Kumar, A. R.; Sathaiah, G.; Paul, V. L.; Sridhar, M.; Rao, P. S.
Tetrahedron Lett. 2009, 50, 7099; (c) Das, B.; Krishnaiah, M.; Balasubramanyam,
P.; Veeranjaaneyulu, B.; Kumar, D. N. Tetrahedron Lett. 2008, 49, 2225; (d)
Jayabarthi, J.; Manimekalai, A.; Vani, T. C.; Padmavathy, M. Eur. J. Med. Chem.
2007, 42, 593.
In summary, we have developed the first one-pot chiral amine-
triggered asymmetric synthesis of highly substituted N-formylpi-
peridines via a [2+2+2]-annulation of an aldehyde, a nitroalkene,
and an N-(aryl(tosyl)methyl)formamide. The merit of this method
is highlighted by its efficiency to install five contiguous chiral
centers into the piperidine structure. No by-product formation,
operational simplicity, ambient temperature, and high stereoselec-
tivity are the salient features of the present protocol, which would
encourage chemical and pharmaceutical applications of N-formylpi
peridines.
11. (a) Zakrzewski, J.; Krawczyk, M. Heteroat. Chem. 2006, 17, 393; (b) Zakrzewski,
J.; Krawczyk, M. Heteroat. Chem. 2008, 19, 549.
12. (a) Kizuka, H.; Elmaleh, D. R. Nucl. Med. Biol. 1993, 20, 239; (b) Kraus, N. A.
Synthesis 1973, 361.
13. Labas, R.; Gilbert, G.; Nicole, O.; Dhilly, M.; Abbas, A.; Tirel, O.; Buisson, A.;
Henry, J.; Barré, L.; Debruyne, D.; Sobrio, F. Eur. J. Med. Chem. 2011, 46, 2295.
14. General procedure for the synthesis of N-formylpiperidines 5: Diphenylprolinol
trimethylsilyl ether 4a (0.2 mmol) was added to a solution of nitroalkene 2
(1 mmol) and aldehyde 1 (1.2 mmol) in CH2Cl2 (2 mL) at 23 °C under nitrogen
atmosphere and the mixture was stirred for 6–10 h at rt. Then, N-
(aryl(tosyl)methyl)formamide 3 (1.2 mmol) and triethylamine (2 mmol) in
CH2Cl2 (4 mL) were added to the reaction mixture at rt under nitrogen
atmosphere. The resulting mixture was stirred for 15–20 h at rt, then,
quenched with saturated aqueous citric acid, and extracted three times with
ethyl acetate. The combined organic layer was washed with water followed by
saturated aqueous sodium chloride, dried over sodium sulfate, and
concentrated under reduced pressure. The residue was purified by silica gel
column chromatography (EtOAc-hexane; 1:9 as eluent) to afford an
analytically pure sample of N-formylpiperidines 5. Characterization data of
representative compounds 5. Compound 5a: Yellow liquid, yield 91%. IR (KBr)
Acknowledgments
We sincerely thank the DST, Govt. of India, for financial support
(DST File No. SR/S1/OC-22/2010) and the SAIF, Punjab University,
Chandigarh, for providing microanalyses and spectra.
References and notes
1. (a) Asymmetric Organocatalysis; Berkessel, A., Groger, H., Eds.; Wiley-VCH:
Weinheim, Germany, 2005; (b) Enantioselective Organocatalysis; Dalko, P. I., Ed.;
Wiley-VCH: Weinheim, Germany, 2007; (c) Melchiorre, P.; Margio, M.;
Armando, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138; (d) Marcelli, T.;
Hiemstra, H. Synthesis 2010, 1229; (e) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji,
M. Angew. Chem., Int. Ed. 2005, 44, 4212.
2. (a) Enders, D.; Grondal, C.; Hüttl, M. R. M. Angew. Chem. Int. Ed. 2007, 46, 1570;
(b) Bui, T.; Barbas, C. F., III Tetrahedron Lett. 2000, 41, 6951; (c) Halland, N.;
Aburel, P. S.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2004, 43, 1272; (d) Rueping,
M.; Antonchick, A. P.; Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 3683; (e)
Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005,
127, 15051; (f) Marigo, M.; Schulte, T.; Franzén, J.; Jørgensen, K. A. J. Am. Chem.
Soc. 2005, 127, 15710; (g) Enders, D.; Hüttl, M. R. M.; Grondal, C.; Raabe, G.
Nature 2006, 441, 861.
3. (a) Singh, A. K.; Chawla, R.; Rai, A.; Yadav, L. D. S. Chem. Commun. 2012, 48,
3766; (b) Rai, A.; Singh, A. K.; Singh, S.; Yadav, L. D. S. Synlett 2011, 335; (c) Rai,
A.; Singh, A. K.; Singh, P.; Yadav, L. D. S. Tetrahedron Lett. 2011, 52, 1354.
4. Watson, P. S.; Jiang, B. Org. Lett. 2000, 2, 3679.
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Angew. Chem., Int. Ed. 2009, 48, 5474; (c) Hayashi, Y.; Gotoh, H.; Masui, R.;
Ishikawa, H. Angew. Chem. 2008, 120, 4076. Angew. Chem., Int. Ed. 2008, 47,
4012.
m
max 3444, 2963, 1660, 1554, 1450, 1330, 1154, 1021, 924, 813, 704, 676 cmÀ1
.
1H NMR (400 MHz; DMSO-d6) d: 1.05 (d, J = 6.9 Hz, 3H), 1.68 (bs, exch. D2O,
1H), 2.42–2.51 (m, 1H), 2.82 (dd, J = 11.8, 8.5 Hz, 1H), 3.43 (t, J = 11.8 Hz, 1H),
5.08 (d, J = 10.4 Hz, 1H), 5.46 (dd, J = 10.8, 2.5 Hz, 1H), 6.99–7.46 (m, 10 H), 8.81
(s, CHO, 1H). 13C NMR (100 Hz, DMSO-d6) d: 8.9, 27.9, 32.6, 40.7, 72.9, 85.5,
125.4, 126.3, 127.2, 128.1, 129.2, 130.5, 139.6, 141.7, 163.2 ppm. EIMS m/z 340
(M+). Anal. Calcd for C19H20N2O4: C, 67.05; H, 5.92; N, 8.23. Found: C, 66.73; H,
6.17; N, 8.57. Compound 5c: Yellow liquid, yield 88%. IR (KBr)
m
max 3447, 2961,
1652, 1548, 1453, 1329, 1156, 1021, 921, 817, 707, 672, 541 cmÀ1
.
1H NMR
(400 MHz; DMSO-d6) d: 1.12 (d, J = 6.6 Hz, 3H), 1.87 (bs, exch. D2O, 1H), 2.48–
2.59 (m, 1H), 2.89 (dd, J = 11.6, 8.9 Hz, 1H), 3.42 (t, J = 11.6 Hz, 1H), 5.12 (d,
J = 10.7 Hz, 1H), 5.44 (dd, J = 10.9, 2.8 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.40–7.68
(m, 5 H), 7.74 (d, J = 8.2 Hz, 2H), 8.79 (s, CHO, 1H). 13C NMR (100 MHz, DMSO-
d6) d: 8.8, 27.7, 32.8, 40.4, 72.3, 85.5, 120.2, 125.4, 127.5, 128.8, 130.6, 131.5,
138.2, 140.7, 162.0 ppm. EIMS m/z 418, 420 (M+, M++2). Anal. Calcd for
C
19H19BrN2O4: C, 54.43; H, 4.57; N, 6.68. Found: C, 54.78; H, 4.90; N, 6.37.
Compound 5f: Yellow liquid, yield 80%. IR (KBr) mmax 3441, 2968, 1657, 1551,
1454, 1332, 1152, 1020, 925, 810, 709, 679 cmÀ1 1H NMR (400 MHz; DMSO-
.
6. Nara, S.; Tanaka, R.; Eishima, J.; Hara, M.; Takahashi, Y.; Otaki, S.; Foglesong, R.
J.; Hughes, P. F.; Turkington, S.; Kanda, Y. J. Med. Chem. 2003, 46, 2467.
7. (a) Urushima, T.; Sakamoto, D.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2010, 12,
4588; (b) Wang, Y.; Yu, D.-F.; Liu, Y.-Z.; Wei, H.; Luo, Y.-C.; Dixon, D. J.; Xu, P.-F.
Chem. Eur. J. 2010, 16, 3922.
8. (a) Ishikawa, H.; Saweno, S.; Yasui, Y.; Shibata, Y.; Hayashi, Y. Angew. Chem., Int.
Ed. 2011, 50, 3774; (b) Davies, S. G.; Roberts, P. M.; Smith, A. D. Org. Biomol.
Chem. 2007, 5, 1405; (c) Rajkumar, S.; Shankland, K.; Brown, G. D.; Cobb, A. J. A.
d6) d: 0.98 (d, J = 7.1 Hz, 3H), 1.72 (bs, exch. D2O, 1H), 2.36–2.43 (m, 1H), 2.45
(s, 3H), 2.91 (dd, J = 11.9, 8.3 Hz, 1H), 3.37 (t, J = 11.9 Hz, 1H), 5.03 (d,
J = 10.5 Hz, 1H), 5.40 (dd, J = 10.7, 2.6 Hz, 1H), 7.10–7.42 (m, 5 H), 8.01–8.04 (m,
2H), 8.10–8.15 (m, 2H), 8.72 (s, CHO, 1H). 13C NMR (100 MHz, DMSO-d6) d: 7.6,
25.1, 28.8, 30.6, 41.1, 71.9, 85.7, 126.0, 127.2, 128.1, 129.2, 130.3, 134.7, 137.8,
141.1, 162.5 ppm. EIMS m/z 354 (M+). Anal. Calcd for C20H22N2O4: C, 67.78; H,
6.26; N, 7.90. Found: C, 68.03; H, 5.96; N, 8.17.