Stereoselective preparation of chiral compounds in Mannich-type reactions of a bicyclic imine and phenols or indole Dedicated to Professor Jacek Skarzewski on the occasion of his 65th birthday

Article abstract of DOI:10.1016/j.tetlet.2014.10.081

Mannich-type reactions of a chiral bicyclic imine and various nucleophiles yield the corresponding adducts with good to high diastereoselectivity. The influence of the reaction conditions on the yield and stereochemical outcome is investigated. The configuration of the products is established by ¹H NMR spectroscopy, and the major isomers of two adducts are characterized by X-ray crystallography.

Full text of DOI:10.1016/j.tetlet.2014.10.081

Tetrahedron Letters 55 (2014) 6619–6622
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective preparation of chiral compounds in Mannich-type
reactions of a bicyclic imine and phenols or indole
a
a,
b
c
⇑
_
´
´
Jakub Iwanejko , Elzbieta Wojaczynska , Jacek Wojaczynski , Julia Ba˛kowicz
a
_
Department of Organic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzeze Wyspian´skiego 27, 50-370 Wrocław, Poland
b Department of Chemistry, University of Wrocław, 14 F. Joliot-Curie St., 50-383 Wrocław, Poland
c
_
´
Institute of Physical and Theoretical Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzeze Wyspianskiego 27, 50-370 Wrocław, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Mannich-type reactions of a chiral bicyclic imine and various nucleophiles yield the corresponding
adducts with good to high diastereoselectivity. The influence of the reaction conditions on the yield
and stereochemical outcome is investigated. The configuration of the products is established by 1H
NMR spectroscopy, and the major isomers of two adducts are characterized by X-ray crystallography.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 26 July 2014
Revised 1 October 2014
Accepted 14 October 2014
Available online 18 October 2014
_
Dedicated to Professor Jacek Skarzewski on
the occasion of his 65th birthday
Keywords:
Mannich reaction
Betti reaction
Bicyclic imines
Stereoselectivity
The Mannich reaction is a very important method for the forma-
tion of new C–C bonds, and is used as a key step in the synthesis of
many pharmaceuticals and natural products. The classical version
of this transformation, the nucleophilic addition of carbonyl com-
pounds to imine derivatives (typically formed in situ from the
respective amines and formaldehyde), leads to b-amino carbonyl
compounds (Mannich bases).1 Modern variants of the reaction
have been developed,2,3 including vinylogous4 and nitro-Mannich
reactions.5 In its stereoselective version, the process can employ
chiral auxiliaries or can be catalyzed by chiral metal complexes
or organocatalysts; the recent progress on asymmetric Mannich
reactions has been thoroughly reviewed.1,5–8
Mannich-type condensation of phenols with amines and alde-
hydes (also referred to as the Betti reaction9) has been explored
as a route to benzylamine derivatives.10–13 This methodology has
been applied to the synthesis of multidendate aminophenol
ligands,14,15 chitosan derivatives,16 heterocalixarenes,17 and tyro-
sine bioconjugates.18 Alternatively, phenols have been reacted
with 1,3,5-trialkylhexahydro-1,3,5-triazine (a product of the con-
densation of primary amines with formaldehyde).19 Cyclic imines
have been also reacted with naphthols and activated phenols,
and the resulting racemic derivatives of the Betti bases were
resolved with (R,R)-tartaric acid.20 The use of a bicyclic imine in
water also afforded Mannich products and this methodology was
used for protein-labeling with fluorophores.21–23
In our previous paper, we described the stereoselective prepara-
tion of imine (1R,6R)-1 from ethyl glyoxylate and (1R,2R)-diamino-
cyclohexane (Scheme 1).24 Under conditions optimized by
Minakawa et al. for the addition of phenols to racemic 1 (phos-
phate buffer, pH = 8),21 we tested the possibility of chiral induction
in its reaction with pyrrole. The conversion was quantitative, and
two diastereomeric adducts were obtained in 58:42 ratio. 1H
NMR measurements and comparison with the X-ray data for prod-
uct 2a, obtained as the unexpected product of an attempted aza-
Diels–Alder reaction, revealed an S configuration of the newly
formed stereogenic center (C4) of the major product. A similar
reaction with p-cresol resulted in a modest yield and diastereose-
lectivity (Scheme 1). In this contribution, we decided to concen-
trate on the possible application of chiral imine (1R,6R)-1 as a
useful precursor for the synthesis of enantiopure adducts of vari-
ous phenols and indole. In each case we explored the influence
of the substrate structure and reaction conditions on the yield,
and the regio- and stereoselectivity of the Mannich-type reaction.
Having in hand the enantiopure imine 1, we performed the Man-
nich reaction with three different phenols, bearing substituents at
ortho, meta, or para positions: 4-tert-butylphenol, 2,4-di-tert-butyl-
phenol, and 2-isopropyl-5-methylphenol (thymol).25 Additionally,
⇑
Corresponding author. Tel.: +48 71 3202410; fax: +48 71 3202427.
E-mail address: elzbieta.wojaczynska@pwr.edu.pl (E. Wojaczyn´ ska).
http://dx.doi.org/10.1016/j.tetlet.2014.10.081
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

6620
J. Iwanejko et al. / Tetrahedron Letters 55 (2014) 6619–6622
HN
H
HN
N
S
R
O
O
NH
+
NH
HN
HN
O
NH2
COOEt
OH
OH
N
phosphate
buffer
COOEt
O
2a
2b
HIO4
H
H
NH2
-EtOH
HN
Me
Me
(pH = 8.0)
H
COOEt
1
OH
OH
NH
Me
OH
R
S
O
O
+
NH
HN
HN
2a 2b
:
= 58:42, Y = 100%
3a
3a:3b = 63:37, Y = 40%
3b
Scheme 1.
R1
R2
R1
R2
R1
HO
R2
R3
R3
NH
HO
O
R3
NH
HO
O
R
S
+
HN
HN
4a: R1, R3 = H, R2 = t-Bu
5a: R1, R2 = t-Bu, R3 = H
4b: R1, R3 = H, R2 = t-Bu
5b: R1, R2 = t-Bu, R3 = H
O
N
HN
6a: R1 = i-Pr, R2 = H, R3 = Me 6b: R1 = i-Pr, R2 = H, R3 = Me
1
HN
HN
HN
R
S
O
O
+
NH
NH
HN
HN
7a
Scheme 2.
7b
indole was also tested as a nucleophile (Scheme 2). In each case the
obtained adducts were separated using column chromatography.
Their identification was based on high resolution mass spectrome-
try and NMR measurements, including 2D techniques (1H–1H COSY,
1H–1H NOESY, 1H–13C HMQC, 1H–13C HMBC), which led to a com-
plete signal assignment, and indicated the reaction’s regioselectiv-
ity. In addition, the NOESY experiment revealed the configuration of
the newly created stereogenic center, since a cross peak due to the
contact between H4 and H6 (for S diastereomers) or H4 and H1 (a
weaker one, for R isomers) in the bicyclic fragment was observed
(see Supplementary data for details). For products 6a and 7a, the
structure was additionally confirmed by X-ray crystallographic
studies.
The reaction conditions were varied. The process can be per-
formed in buffered aqueous solution, which is beneficial from eco-
nomical and ecological points of view. We used phosphate buffer of
pH = 8, which was previously shown to give optimum results for
the additions to racemic imine 1.21 In two cases, the addition of
5% DMSO was necessary to improve the solubility of the substrates.
All the reactions were also conducted in dichloromethane. For cer-
catalyst. As can be seen from Scheme 2 and Table 1, only the prod-
ucts of ortho-substitution (with respect to the hydroxyl group)
were isolated, even in the case of thymol, for which steric demands
would suggest a preference for the para attack. This regioselectivity
is in agreement with the results obtained for the reaction of cyclic
imines with activated phenols, and can be attributed to hydrogen
bond formation in the transition state.20 The reaction of 4-tert-
butylphenol (with two vacant ortho positions) led also to the prod-
ucts of double substitution (vide infra). The stereoselectivity of the
reaction was medium to high, with predominant formation of the S
diastereomer with a de exceeding 90%; only the indole adduct 7a
with R configuration at the newly formed stereogenic center was
formed preferentially. This difference is also probably due to the
participation of the phenol OH group in hydrogen bonding with
the imine nitrogen atom (this interaction is also visible in the crys-
tal structure of adduct 6a). The use of dichloromethane instead of
water as the reaction medium resulted in an increase in the overall
yield, while the diastereoselectivity was higher when phenols were
used as substrates, but lower in the case of indole. Our observa-
tions are in contrast to the findings of Minakawa et al. who did
not isolate any product of the reaction of racemic imine 1 with cre-
sol conducted in organic solvents.21 The highest diastereomeric
excess was obtained with thymol (one isomer was exclusively
formed) and is apparently connected with the presence of the
methyl group next to the reacting carbon atom. Neither conducting
tain substrates, we also tested the influence of additives (L-proline,
or CF3COOH and BF3ÁEt2O) and investigated the effect of decreasing
the temperature. Results are given in Table 1.
Since imine 1 contains a lactam function as well, the reaction
proceeds with nonactivated phenols and indole without any

J. Iwanejko et al. / Tetrahedron Letters 55 (2014) 6619–6622
6621
Table 1
Results of the reaction of imine 1 with various nucleophiles performed for 48 h at 20 °C
Entry
Nucleophile
Conditions
Yield (%)
de (%)
1
2
3
4
5
6
7
8
4-tert-butylphenol
4-tert-butylphenol
2,4-Di-tert-butylphenol
2,4-Di-tert-butylphenol
Thymol
Indole
Indole
Indole
Phosphate buffer (pH = 8), 5% DMSO
CH2Cl2
55
58
44
66
40
47
91
45
54 (77S:23R)
60 (80S:20R)
45 (72S:28R)
90 (95S:5R)
100 (100S)
91 (95R:5S)
70 (85R:15S)
49 (75R:25S)
Phosphate buffer (pH = 8), 5% DMSO
a
CH2Cl2
CH2Cl2
Phosphate buffer (pH = 8)
b
CH2Cl2
CH2Cl2, CF3COOH, BF3ÁEt2O
a
Addition of 20 mol % of L-proline gave 58% yield and dr = 63% (82S:18R).
Reaction conducted at 0 °C, yield >90%, de = 68% (84S:16R).
b
the reaction at low temperature (0 °C) nor the use of 20 mol % of
-proline as an additional chirality source led to an improvement
two positions with occupancy 0.79:0.21. Molecules A and B differ
only slightly in bond distances and angles, for example, the angle
between the mean plane of the lactam ring and the phenol moiety
L
of the diastereomeric excess. We also tested the effect of the addi-
tion of CF3COOH/BF3ÁEt2O, since previously its use in an attempted
Diels–Alder reaction of imine (1R,6R)-1 with pyrrole yielded
instead the product of a Mannich reaction with high diastereose-
lection.24 However, in the case of indole, both the yield and diaste-
reomeric excess decreased significantly when the acids were
present in the solution.
X-ray structures of compounds 6a (the only isolated product of
thymol addition to imine 1) and 7a (the major diastereomer
obtained in the reaction of indole) are shown in Figure 1. Com-
pound 6a crystallizes in the P21 space group with two symmetri-
cally independent molecules, A and B, in the asymmetric unit
(Fig. 1a); in one of these the isopropyl group is disordered over
for
A (81.6°) is a little bit larger than for B (76.9°). Both
intra- (–OHÁÁÁN) and intermolecular hydrogen bonds (NHÁÁÁO@C)
are observed in which the amine nitrogen atom (N1 in Fig. 1a) of
6a is engaged, making separate chains of linked molecules of a
given type (A or B) along the crystallographic b axis. Adduct 7a
crystallized in the P212121 space group with two water molecules
in the asymmetric unit (Fig. 1b). One of them forms four hydrogen
bonds with different molecules serving as a donor for the C@O and
lactam nitrogen atom, and as a donor for the amine NH and
another H2O molecule. This is in turn engaged in two other
interactions: with the carbonyl group and the indole NH. As a con-
sequence, a three-dimensional hydrogen bond network is formed.
The geometry of the hydrogen bonds in 6a and 7a is presented in
Table S2 and Figures S1 and S2 (Supplementary data). The X-ray
structures confirmed the configurations of the newly formed stere-
ogenic centers (C8 in Fig. 1) which were originally established by
NMR measurements (S for 6a, R for 7a).
As already mentioned, in addition to the products of monosub-
stitution of 4-tert-butylphenol, compounds resulting from the dou-
ble ortho-substitution were isolated in 14% (for the reaction in
dichloromethane) or 17% yield (phosphate buffer/DMSO). When
the imine/phenol stoichiometry was changed to 2:1, compounds
4a and 4b were not observed and two diasteromeric products 4c
and 4d (Fig. 2) were obtained in 47% yield (in CH2Cl2). The first dia-
stereomer possesses C2 symmetry which is reflected in the reduced
number of NMR signals while the other product, of C1 symmetry, is
characterized by two sets of NMR signals of equal intensity. In par-
ticular, two H4 resonances were found at 4.68 and 5.05 ppm; one
of them exhibited an NOE correlation with H1, and the other—with
the H6 signal of another bicyclic fragment of the molecule, indicat-
ing the opposite configurations of the newly created stereogenic
centers (Fig. S3, Supplementary data). For 4c isomer, a NOESY
experiment revealed S configurations for both C4 atoms; the third
possible isomer, with (R,R) configurations, was not isolated. The
ratio of 4c to 4d was found to be equal to 63:37 (de = 26%), which
is in good agreement with the theoretical predictions for an
independent reaction at two ortho positions, and the observed
NH OH HN
NH OH HN
HN
NH
HN
NH
S
S
S
R
O
O
O
O
4c
4d
Figure 1. ORTEP views26 of (a) the two crystallographically independent molecules
in the crystal of 6b, and (b) of compound 7a, showing the atom-numbering scheme.
Displacement ellipsoids are drawn at 20% probability level.
Figure 2. Products of the double substitution reaction of 4-tert-butylphenol with
imine 1.

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J. Iwanejko et al. / Tetrahedron Letters 55 (2014) 6619–6622
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stereochemical preference for monosubstitution [S:R = 80:20
implies (S,S):(S,R):(R,R) = 64:32:4]. The mutual orientation of the
hydroxyl group and amine fragments makes 4c and 4d good
candidates for application as chiral chelating ligands in asymmet-
ric catalysis.
In summary, we have shown the utility of the Mannich-type
reaction as a route to enantiopure phenol and indole derivatives
which might be useful for asymmetric synthesis. Imine (1R,6R)-1
can thus serve as a versatile tool for the conversion of various achi-
ral nucleophiles into chiral compounds containing additional
donor atoms; their configuration can be adjusted by the proper
choice of substrates [(1S,6S)-1 can be used in place of its enantio-
mer]. The presence of functional groups in the structures of the
obtained adducts opens the route to further modifications. In addi-
tion, these compounds offer various possibilities for interactions
with biologically important molecules (for example, they can serve
both as hydrogen bond donors and acceptors). Studies on the
potential biological activities of the selected prepared derivatives
are in progress.
19. Bujnowski, K.; Adamczyk-Woz´niak, A.; Synoradzki, L. Arkivoc 2008, 13, 106–
114.
20. Cimarelli, C.; Fratoni, D.; Mazzanti, A.; Palmieri, G. Eur. J. Org. Chem. 2011,
2094–2100.
21. Minakawa, M.; Guo, H.-M.; Tanaka, F. J. Org. Chem. 2008, 73, 8669–8672.
22. Guo, H.-M.; Minakawa, M.; Tanaka, F. J. Org. Chem. 2008, 73, 3964–3966.
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19, 1210–1213.
Acknowledgments
_
24. Wojaczyn´ ska, E.; Ba˛kowicz, J.; Dorsz, M.; Skarzewski, J. J. Org. Chem. 2013, 78,
2808–2811.
25. In a typical procedure, 0.152 g (1 mmol) of chiral imine (1R,6R)-1 was added to
a stirred solution of 0.150 g (1 mmol) of 4-tert-butylphenol in 5 mL of CH2Cl2
and the stirring was continued for 24 h at room temperature. The solvent was
evaporated and chromatography on a silica column (5% CH3OH in CHCl3 was
This work was financed by a statutory activity subsidy from the
Polish Ministry of Science and Higher Education for the Faculty of
Chemistry of the Wrocław University of Technology.
used as eluent) was then performed, yielding fractions containing products 4a–
20
4d. Analytical data for the major products: 4a: mp 173-174 °C. [
a
]
D
+194.6 (c
Supplementary data
0.42, CH2Cl2). 1H NMR (500 MHz, CDCl3): d 1.31–1.43 (m, 4H), 1.34 (s, 9H), 1.79–
1.85 (m, 4H), 2.67–2.71 (m, 1H), 3.23–3.27 (m, 1H), 4.76 (s, 1H), 6.30 (s, 1H), 6.82
(d, 1H, J = 8.5 Hz), 7.23 (dd, 1H, J1 = 8.4 Hz, J2 = 2.5 Hz), 7.30 (d, 1H, J = 2.4 Hz), 9.9
(bs, 1H).13C NMR (125 MHz, CDCl3): 23.6, 24.3, 30.4, 31.1, 31.6, 34.1, 57.3, 58.5,
Supplementary data (experimental section, details for X-ray
structures, and fragments of NOESY spectra) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2014.10.081.
63.5, 116.9, 122.5, 126.4, 127.1, 142.2, 153.8, 169.8. [a]
20 +194.6 (c 0.42, CH2Cl2).
D
IR (film): 732, 802, 1121, 1308, 1341, 1452, 1670, 2859, 2933, 3213 cm1. HRMS
(ESI-TOF): m/z [M+H]+ calcd for (C18H27N2O2)+ 303.2072; found 303.2068. 4b:
20
mp 101–102 °C. [
a
]
+13.9 (c 0.14, CH2Cl2). 1H NMR (500 MHz, CDCl3): d 1.27–
D
1.43 (m, 4H), 1.30 (s, 9H), 1.76–1.79 (m, 1H), 1.83–1.86 (m, 2H), 1.99–2.01 (m,
1H), 2.68–2.74 (m, 1H), 3.11–3.16 (m, 1H), 5.01 (s, 1H), 6.59 (s, 1H), 6.86 (d, 1H,
J = 8.4 Hz), 7.24 (dd, 1H, J1 = 8.4 Hz, J2 = 2.1 Hz), 7(d, 1H, J = 2.1 Hz), 10.7 (bs, 1H).
13C NMR (125 MHz, CDCl3): d 23.7, 24.9, 29.7, 30.6, 31.6, 34.2, 53.7, 58.9, 59.3,
117.3, 121.7, 123.5, 126.0, 142.2, 154.5, 171.2. IR (film): 822, 1121, 1271, 1362,
1463, 1496, 1664, 2861, 2937, 3201 cm1. HRMS (ESI-TOF): m/z [M+H]+ calcd for
(C18H27N2O2)+ 303.2072; found 303.2079.
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