A complicated path of salicylaldehyde through the Biginelli reaction: A case of unexpected spiroketalization

Article abstract of DOI:10.1016/j.tet.2014.09.003

Cyclocondensation of salicylaldehydes with alkyl acetoacetates and 2-aminobenzothiazoles or 2-amino-5-methylthiazole under classical Biginelli reaction conditions gives rare hetarylamino substituted 2,2′-spirobischromanecarboxylate derivatives. The mechanism and observed stereoselectivity of the unexpected pseudo-four-component process are discussed.

Full text of DOI:10.1016/j.tet.2014.09.003

Tetrahedron 70 (2014) 8354e8360
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A complicated path of salicylaldehyde through the Biginelli reaction:
a case of unexpected spiroketalization
,
c
d
ꢀ b
Jan Svĕtlík a , Nad’a Pronayova , Lubomír Svorc , Vladimír Frecer
ꢁ
*
ꢀ
a Department of Pharmaceutical Analysis and Nuclear Pharmacy, Faculty of Pharmacy, Comenius University, Odbojarov 10, 832 32 Bratislava, Slovakia
b Department of NMR Spectroscopy and Mass Spectrometry, Faculty of Chemical and Food Technology, Slovak University of Technology,
812 37 Bratislava, Slovakia
c Institute of Analytical Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinskeho 9, 812 37 Bratislava, Slovakia
d Department of Physical Chemistry of Drugs, Faculty of Pharmacy, Comenius University, Odbojarov 10, 832 32 Bratislava, Slovakia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 May 2014
Received in revised form 18 August 2014
Accepted 2 September 2014
Available online 6 September 2014
Cyclocondensation of salicylaldehydes with alkyl acetoacetates and 2-aminobenzothiazoles or 2-amino-
5-methylthiazole under classical Biginelli reaction conditions gives rare hetarylamino substituted 2,20-
spirobischromanecarboxylate derivatives. The mechanism and observed stereoselectivity of the un-
expected pseudo-four-component process are discussed.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Biginelli reaction
Spiroketalization
2,20-Spirobischromane
Salicylaldehyde
1. Introduction
4''
3''
5'' Y
2''
6''
Spiroketals are prominent structural subunits embedded in
numerous natural products of plant, fungi, bacterial, insect and
marine origin. Most of the naturally occurring substances with
various complexity, such as steroidal saponins, polyketide antibi-
otics, polyether ionophores, macrolides and pheromones exhibit
important biological properties.1 In this respect even relatively
simple spiroketal structures display useful pharmacological effects.
Not only potential medicinal importance but also rather delicate
relationship between anomeric and non-anomeric configurations,
access to less stable isomers, development of general and stereo-
controlled methods to ‘contrathermodynamic’ (non-anomeric)
congeners and generation of stereodiversified libraries make spi-
roketal ring system an attractive target.1
In the course of our research focused on salicylaldehyde (1a) as
a fundamental constituent of oxygen-bridged pyrimidines2 we
have recently found that the replacement of urea/thiourea by 3-
amino-1,2,4-triazole in the Biginelli reaction led quite un-
expectedly to novel spirocyclic structure 22d (Fig. 1). For a better
understanding of the pseudo-four-component process, we selected
some substituted 2-aminobenzothiazoles 4aee and 2-amino-5-
HO
1''
5'
7
5
2: a Y = H
b Y = 8-OMe, 3"-OMe
c Y = 6-OMe, 5"-OMe
d Y = 6-Br, 5"-Br
8
O 6'
NH
6
7'
3'a
2
Y
N
N
3
4
N
2'
CO2Me
Fig. 1. Unconventional product of the Biginelli-like reaction with 3-amino-1,2,4-
triazole.
methylthiazole (5) substrates to reduce the number of reaction
centres acting in the above aminotriazole educt. The present paper
reports on the unexpected formation of a benzannelated spiroketal
ring system in the Biginelli-like reaction using salicylaldehydes 1,
alkyl acetoacetates 3 and the chosen isothiourea analogues.
2. Results and discussion
We began our investigations with the heterocyclization of
methyl acetoacetate (3a), 2-aminobenzothiazole (4a) with
2 M equiv of salicylaldehyde (1a) under similar conditions as re-
ported for the transformation of aminotriazole.2d Thus, ethanolic
solution of the reactants was allowed to reflux gently in the pres-
ence of the HCl catalyst for 14 h, at the end of which period a white
* Corresponding author. E-mail address: svetlik@fpharm.uniba.sk (J. Svĕtlík).
http://dx.doi.org/10.1016/j.tet.2014.09.003
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

J. Svĕtlík et al. / Tetrahedron 70 (2014) 8354e8360
8355
precipitate separated. The molecular formula, C26H20N2O4S, of
isolated compound 6a corresponds to an adduct combining the
above ester 3a, amine 4a and aldehyde 1a in a 1:1:2 manner by loss
of three molecules of water. Although the NMR spectra of the
product 6a are similar to those of spiro-fused heterocycle 2a,
thereby showing the presence of some common structural ele-
ments, the diagnostic N,O-spiro 13C resonance (dC 85.6 for C-2 in 2a)
was lacking. Instead, a new quaternary sp3 carbon atom was ob-
served at dC 98.1. Such a peculiar downfield shift is anticipated for
a OeCeO moiety where increased substituent electronegativities
would induce a higher degree of deshielding. This assumption was
supported by comparison of the critical 13C chemical shift value
with literature data reported for ketals and spiroketals typically
lying close to 100 ppm.3 In addition, the absence of free hydroxyl
groups permitted the deduction that both of the phenolic func-
tionalities have been incorporated in the formation of the key
spiroketal substructure. According to a careful NMR analysis, the
other part of the molecule contains a CH2CHNH segment of which
a two-carbon link belonging to the oxacyclic system is tethered to
the phenylene skeleton via the methine carbon on the one hand
and to the spiro centre through the methylene terminus on the
other. Hence, the secondary amino group must be flanked by the
spiroketal and benzothiazole pendants. Two types of 15N nuclei
were differentiated by means of 1H, 15N correlation spectroscopy
(HSQC for the protonated nitrogen, HMBC for the heteroaromatic
ring nitrogen atom). Not surprisingly, the second half of the [6,6]-
spiroketal core consists of an unsaturated chromene ring carrying
a methoxycarbonyl function, thus being reminiscent of 2a. Having
collected the above molecular features, we concluded that the
product structure is spiro[chroman-2,20-chromene]-30-carboxylate
6a as outlined in Scheme 1. A complete 1H and 13C signal assign-
ment of 6a was achieved using 2D NMR methods (COSY, HSQC,
HMBC). Nevertheless, the 1H NMR spectrum of the crude product
showed that two diastereomers, 6a and 60a were formed. Both
isomers could be easily recognized mainly due to different posi-
tions of their H-4 (Dd 0.34 ppm) resonances. Integration of the
corresponding signals, being well separated from the rest of the
spectrum, allowed us to estimate the isomer relation 6a/60a in
a ratio 37:1. Evidently, the explored multicomponent condensation
is highly diastereoselective. Based on the NMR spectra, the exam-
ined diastereomers retain the same configuration at the spiro car-
bon while the amine residue alternates between two possible
positions on the C-4 ring carbon. The relative stereochemistry of 6a
was established from the 1D-NOESY and ROESY measurements. In
particular, the ROESY experiment displayed convincing and even
complementary dipoleedipole interactions between the aliphatic
methine H-4 and aromatic H-80 protons. As seen from the Dreiding
model of 6a, H-4 faces the oxygen atom belonging to the chromene
ring whereas the secondary amine moiety, which is also bonded to
C-4 has to occupy the opposite side of the partially saturated oxa-
cyclic skeleton. Besides that, the NeH bond became aligned with
one of the neighbouring methylene hydrogen linkages. The former
H-4 proton was found downfield from that of the epimer 60a, which
by contrast is characterized by a reverse arrangement. The observed
deshielding seems to reflect a relationship between the H-4 and O-
10 atoms. Accordingly, the higher chemical shift of H-4 in 6a is
possibly due to the anisotropy effect of this proximal and eclipsing
oxygen, thereby parallelling the situation in some spiroketal
derivatives.3b Note that the presented structural findings have been
confirmed by single crystal X-ray diffraction analysis made on other
derivatives (see below).
To exploit the synthetic potential of the multicomponent cycli-
zation, we examined other aminobenzothiazole substrates. The
treatment of salicylaldehyde (1a) and methyl ester 3a with 2-
amino-6-methoxy- (4b) or 2-amino-6-methyl-benzothiazole (4c)
provided, under similar conditions, the desired spiroketals 6b and
6c, respectively. Besides the target products, small amounts of
azomethines 7b and 7c, arising from aldehyde and amine con-
densation, were isolated from the filtrate (Fig. 2). As for stereo-
selectivity, cyclocondensation of 4b resulted in a single isomer 6b
whereas reaction of 4c gave an epimeric mixture of 6c/60c in a ratio
5:1. Moreover, we found that longer time led to a decrease of
7
8
6
5
7'
X
8'
8a
8'a
O
6'
O
4a
4
CH3COCH2COOR
H
2
2'
S
X
5'
4'a
N
H
3
3'
3 a: R = Me, b: R = isoPr, c: R = CH2CH2OMe
Y
4'
N
CO2R
6a-h (major, except for 6h)
Y
S
O
X
+
NH2
N
OH
X
4
1 a: X = H, c: X = 3-OMe
b: X = 5-Br
a: Y = H,
b: Y = OMe, e: Y = NO2
c: Y = Me
d: Y = Cl
S
O
O
H
N
Y
X
N
H
6/6' a: X = H, R = Me, Y = H (37:1)
b: X = H, R = Me, Y = OMe (only 6b)
c: X = H, R = Me, Y = Me (5:1)
CO2R
6'a,c-h
d: X = H, R = Me, Y = Cl (2.5:1)
e: X = H, R = isoPr, Y = H (17:1)
f: X = H, R = CH2CH2OMe, Y = H (50:1)
g: X = 6,6'-Br, R = Me, Y = H (15:1)
h: X = 8,8'-OMe, R = Me, Y = H (1:14)
O
O
O
H
N
S
O
Me
H
S
Me
N
H
H
N
(21%, 50:1)
N
CO2Me
CO2Me
8
8'
Scheme 1. Biginelli-like condensation of salicylaldehydes with aminobenzothiazoles and 2-amino-5-methylthiazole.

8356
J. Svĕtlík et al. / Tetrahedron 70 (2014) 8354e8360
60g 15:1, together with 3-acetyl-6-bromocoumarin (10) (Fig. 2), the
O
HetHN
H
H
Y
3-methoxy representative 1c gave the opposite diastereomer 60h as
the dominant form (6h/60h 1:14) (Scheme 1). As expected, the
methine H-4 signal in 60h moved upfield (dH 5.61) when compared
to that of 6h (dH 5.79). The relative stereochemistry of the major
isomer 60h was again assigned on the basis of NOESY exhibiting
a significant correlation of the NH with the spatially adjacent MeO-
80 protons and afterwards confirmed by a single crystal X-ray dif-
fraction4 (Fig. 3).
Br
S
Me
COOisoPr
OH
Me
N
N
OH
O
O
O
7 b: Y = OMe, c: Y = Me
9 Het = benzothiazol-2-yl
10
Fig. 2. Isolated by-products 7b,c, 9 and 10.
diastereoselectivity. In contrast to the above amines, the cyclization
with 2-amino-6-chlorobenzothiazole (4d) appeared to be more
complex and was less diastereoselective (6d/60d ratio of 2.5:1). On
the other hand, 2-amino-6-nitrobenzothiazole (4e), which is rather
insoluble in ethanol, proved to be resistant to spiroketalization
under the given conditions (Scheme 1).
Of the thiazole series, just 2-amino-5-methyl member 5 was
successfully converted to provide the expected spiroketal with
excellent diastereoselectivity, 8/80¼50:1 (Scheme 1). Since this
compound occurred in a single crystal form, we determined its X-
ray structure4 to support our postulated assignment and to estab-
lish the overall molecular conformation. The crystal structure un-
equivocally confirmed that the spatial features (Fig. 3) are in
accordance with the above conclusions judged from the NMR
spectra.
The prepared spiroketals were obtained as stable crystalline
colourless compounds. Generally, the achieved yields were modest
and almost constant regardless of the nature of the substituent
(20e29%), except for the condensation between salicylaldehyde, 2-
aminobenzothiazole and methyl acetoacetate displaying a slightly
higher efficiency (36%). By contrast, in most cases the determined
stereoselectivities were found to be good to high.
A plausible mechanism for the studied reaction can be envi-
sioned to involve the generation of analogous initial condensation
adducts, azomethine A and butenone B (Scheme 2), which have
been proposed as precursors of the aforementioned spiro-
pyrimidine 2.2d Then, the enol form of the constituent B attacks
the aldimine A forming intermediate C via a Mannich-like process.
Fig. 3. Perspective views of (a) spiroketal 8 (left), and (b) 60h (right).
Next, we tested the applicability of the studied reaction with
two other acetoacetates. Both esters, isopropyl 3b and 2-
methoxyethyl 3c, produced the corresponding spiroketals in
a highly diastereoselective fashion, 6e/60e 17:1 and 6f/60f 50:1, re-
spectively (Scheme 1). Furthermore, in the former case the minor
chromane by-product 9 (Fig. 2) was isolated from the mother li-
quor. The relative stereochemistry of 9 followed from X-ray crys-
tallography4 (Fig. 4).
The postulated dihydroxy ketone structure C, being similar to the
widely used building blocks for the spiroketal synthesis,1 un-
dergoes subsequent dehydrative cyclization to yield the desired
spiro derivative 8. It is noteworthy that the two feasible intervening
carboxonium ions, D and D0, originating from both phenolic hy-
droxyl functionalities, can be implicated in the spiroketalization
(Scheme 2). Interestingly, although the formation of the species D
by more nucleophilic aminobenzyl phenol in C0 should be favoured,
the final SN1 closure5 might also occur through the alternative
pyrylium cation D0 considering its aromatic character and hence an
inherent higher thermodynamic stability. Indeed, the significant
energy difference of 15.1 kcal/mol between both carboxonium in-
termediates was obtained by using ab initio MP2/6-31G(d)//HF/6-
31G(d) calculations. Recently similar mechanisms have also been
described by research groups of Zhu6 and Pyne7 to explain the
formation of related amino substituted spiroketal structures.
Theoretically, the spiroketalization sequence might also occur
via initial formation of a chromenylium structure E (Scheme 2)
whose acidic methyl group would then add to the aldimine A.
Nevertheless, this route can be ruled out since the condensation
between salicyladehyde and
b-ketoesters to the ion E requires
a strong acid medium (HClO4/HOAc/Ac2O).8
It was somewhat surprising that the opposite isomer 60h sig-
nificantly prevailed over isomer 6h, which typically predominates.
Nevertheless, this dramatic change in the diastereoselectivity may
be due to hydrogen bonding between the NH group and the two
available adjacent acceptors, the O-10 atom along with the OMe
oxygen situated on the C-80. This so-called bifurcated hydrogen
Fig. 4. Perspective view of chromane 9.
It was also of interest to inspect the behaviour of some
substituted salicylaldehydes in the cyclocondensation with amine
4a and ester 3a. Whereas 5-bromo-2-hydroxybenzaldehyde 1b
reacted in an usual mode furnishing a mixture of epimers 6g and

J. Svĕtlík et al. / Tetrahedron 70 (2014) 8354e8360
8357
OH
OH
O
OH
O
Me
OH
CH2
MeOOC
MeOOC
MeCOCH2COOMe
+
H
3a
B
B'
OH
O
NH2
+
Me
OH
HO
O
NH
OH
S
S
N
+
H
S
+
N
-
H
N
N
Me
H
COOMe
Me
5
A
C
OH
HO
Me
HO
+O
OH
O +
O
+
H
S
Me
Me
8
S
S
H O
N
-
or
N
N
N
H
COOMe
H
N
COOMe
COOMe
H
N
D'
C'
D
COOR
-
X
O
+
Me
E
Scheme 2. Plausible spirocyclization mechanism leading to compound 8.
bond was chaꢀracterized by the bond lengths and angles, NH/O-10:
involvement of the carboxonium intermediate D. Its two possible
stereochemical models, D1 and D2, possessing o-hydroxystyryl and
secondary amine groups in an anti or syn relationship were pos-
tulated for final ring closure (Fig. 5). However, due to steric re-
pulsion between these large moieties, the amine functionality
0
ꢀ
ꢂ
ꢂ
2.163 A, 121.1 ; NH/OMe-8 : 2.449A, 169.6 , and is believed to be
a medium strength hydrogen bond.9 Consequently, the observed
hydrogen bond could be capable of steering the reaction towards
formation of ‘anomalous’ diastereomer 60h. It seems therefore
likely that 60h is a product of thermodynamic control. Likewise, ab
initio MP2/6-31G(d)//HF/6-31G(d) calculations predicted the
structure 60h to be more stable than its counterpart 6h
HetHN
OH
H
NHHet
H
OH
(
D
Erel¼ꢁ5.9 kcal/mol). Such an energy difference can be attributed
to the existence of the bifurcated hydrogen bond in 60h. To elucidate
the reversed situation when the ‘normal’ diastereomers predomi-
nated, we carried out calculations for a model pair of 8/80. In this
instance the ‘anomalous’ minor isomer 80 was found only 1.6 kcal/
mol lower in energy than 8 as computed at the same level of theory
as above. Although the obtained results support again the ther-
modynamic preference of the opposite isomer 80, the estimated
value is, however, not large enough to guarantee its preferential
formation. As expected, the diastereomer couple 6a/60a also
+
+
O
O
H
H
COOR
COOR
D1
D2
H
NHHet
HO
+
HO
O
O
H
+
E
showed an analogous energy difference (
D
Erel¼ꢁ1.7 kcal/mol).
COOR
NHHet
H
Disregarding the thermodynamic stabilities of the products, the
observed diastereomeric ratios suggest that the determined ster-
eoselectivities might be the consequence of a kinetically governed
process. Correspondingly, treatment with a catalytic amount of HCl
in ethanol for 6 days at rt converted 6e into 60e, setting their
population at a ratio of 60:40. Thus, the observed slow equilibration
towards the opposite isomer was consistent with the kinetic con-
trol of the reaction.
D'1
H
NHHet
H
HO
O
HO
+
O
H
H
+
E
COOR
HetHN
D
Since the formation of the Mannich adduct C is not diaster-
eoselective, the resulting stereochemistry must be established only
in the course of the spirocyclization. We have therefore presumed
that the observed stereoselectivity could be explained by the
'
2
H
E = COOR Het = hetaryl
Fig. 5. Transition state conformations leading to spiro products 6 or 8.

8358
J. Svĕtlík et al. / Tetrahedron 70 (2014) 8354e8360
prefers to occupy the opposite face of the forming oxonium ring,
thus adopting a more advantageous distal equatorial position as
viewed by the D1 assemblage. This anti type configuration of the
intermediate satisfies the stereochemistry of the kinetic product 6.
It should be noted that a shorter interatomic distance between the
phenolic oxygen and the contiguous amine hydrogen in D2
and trituration of an oily residue with a small volume of MeCN. The
by-products 7b, 7c, 9, 102d and another crop of spiroketals were
isolated from the filtrate upon standing. The crude spiro products
were then recrystallized from MeCN (dioxane for 60h) to give pure
diastereomer as white crystalline solids.
ꢂ
(w2.3 A) enables the O/HN hydrogen bonding. Nevertheless, the
4.2.1. Methyl (2R
2,20-chromene]-30-carboxylate (6a). Yield 36%; mp 235e237 ꢀC; IR:
nmax 1716, 1612, 1575, 1450, 1207, 1191, 1032, 753 cmꢁ1 1H NMR:
2.77 (dd, 1H, J¼13.2, 6.0 Hz, Ha-3), 3.22 (t, 1H, J¼13.2 Hz, Hb-3),
*
,4R
*
)-4-(benzothiazol-2-ylamino)spiro[chroman-
benefit arising from the mentioned steric relief overrides the sta-
bilization of the syn form by the potential hydrogen bonding. Be-
sides, the oxygen atom involved in hydrogen bonding would
certainly become less nucleophilic.
;
d
3.78 (s, 3H, OMe), 5.80e5.86 (m, 1H, H-4), 6.73 (d, 1H, J¼8.4 Hz, H-
8), 7.00 (d, 1H, J¼8.4 Hz, H-80), 7.01 (t, 1H, J¼8.4 Hz, H-6), 7.06 (t, 1H,
J¼7.8 Hz, H-600), 7.13 (t, 1H, J¼8.4 Hz, H-60), 7.18 (t, 1H, J¼8.4 Hz, H-
7), 7.25 (t, 1H, J¼7.8 Hz, H-500), 7.38e7.42 (m, 2H, H-5 and H-70), 7.45
(d, 1H, J¼7.8 Hz, H-400), 7.61 (d, 1H, J¼8.4 Hz, H-50), 7.72 (d, 1H,
J¼7.8 Hz, H-700), 8.01 (s, 1H, H-40), 8.57 (d, 1H, J¼9.0 Hz, NH); 13C
Alternatively, final spirocyclization may also be rationalized in
terms of two transition states derived from the carboxonium ion D0.
Due to a higher conformational freedom, the saturated side chain in
D0 enables the placement of the 2-hydroxyphenyl functionality in
a better bonding contact than does the 2-hydroxystyryl moiety in
the species D. Accordingly, the proposed arrangement D01 with
a gauche positioned chromene and aryl moieties (Fig. 5) is expected
to yield the major isomer 6. On the other hand, pre-transition state
conformer D02 involving two unfavourable gauche interactions
should lead to the minor diastereomer 60. The steric encumbrance
imposed by the position of the oxygen ring and the two vicinal
bulky groups makes D02 somewhat less favoured than D01. For that
reason the reaction channel through D01 appears to be the pathway
with a lower overall activation energy leading to the dominant
kinetic isomer 6.
NMR:
d 34.2 (CH2), 45.8 (CH), 52.0 (OMe), 98.1 (C-2 spiro), 116.3
(CH-80), 116.6 (CH-8), 118.2 (CH-400), 118.8 (C-40a), 121.0 (CH-700),
121.2 (CH-600), 121.7 (CH-6), 122.6 (CH-60), 122.7 (C-30), 123.9 (C-4a),
125.6 (CH-500), 126.8 (CH-5), 128.9 (CH-7), 129.4 (CH-50), 130.4 (C-
700a), 132.9 (CH-70), 136.3 (CH-40), 150.9 (C-8a), 151.0 (C-80a), 152.3
(C-300a), 164.0 (COO), 166.3 (C-200); ESI MS: (m/z) 1009
[2MþDMSOþNH4þH]2þ, 913 [2MþH]þ, 457 [MþH]þ. Anal. Calcd
for C26H20N2O4S (456.52): C, 68.41; H, 4.42; N, 6.14%. Found: C,
68.28; H, 4.20; N, 6.33%.
4.2.2. Methyl (2R
*
,4R )-4-(6-methoxybenzothiazol-2-ylamino)spiro
*
3. Conclusion
[chroman-2,20-chromene]-30-carboxylate (6b). Yield 24%; mp
232e233 ꢀC; IR: nmax 1711, 1615, 1471, 1216, 1187, 1030, 928, 881,
In summary, we have elucidated the structures of un-
conventional products formed in the Biginelli-like reaction of sal-
icylaldehydes with alkyl acetoacetates and 2-aminobenzothiazoles
or 2-amino-5-methylthiazole. The identified alkyl 4-hetarylamino
substituted spiro[chroman-2,20-chromene]-30-carboxylates consti-
tute a group of hitherto unreported compounds obtained in the
name reaction using salicylaldehyde as an aldehyde component.
Formation of these heterocycles contrasts the pyrimidine de-
rivatives produced normally by the Biginelli cyclization. The prop-
erly functionalized spiroketals are considered to be valuable
bioactive preparates, being primarily suitable for screening as po-
tential Akt inhibitors for cancer treatment.10
753 cmꢁ1; 1H NMR:
d
2.75 (dd, 1H, J¼13.2, 6.0 Hz, Ha-3), 3.19 (t, 1H,
J¼13.2 Hz, Hb-3), 3.75 (s, 3H, OMe), 3.78 (s, 3H, ester OMe),
5.74e5.80 (m, 1H, H-4), 6.71 (dd, 1H, J¼7.8, 1.2 Hz, H-8), 6.85 (dd,
J¼7.8, 1.8 Hz, H-500), 7.00 (dd, 1H, J¼7.8, 1.8 Hz, H-80), 7.01 (dt, 1H,
J¼7.8, 1.2 Hz, H-6), 7.13 (dt, 1H, J¼7.8, 1.8 Hz, H-60), 7.17 (t, 1H,
J¼7.8 Hz, H-7), 7.35 (d, 1H, J¼7.8 Hz, H-400), 7.36 (d, 1H, J¼1.8 Hz, H-
700), 7.38e7.41 (m, 2H, H-5 and H-70), 7.61 (dd,1H, J¼7.8,1.8 Hz, H-50),
8.01 (s, 1H, H-40), 8.34 (d, 1H, J¼9.0 Hz, NH); 13C NMR:
d 34.3 (CH2),
45.7 (CH), 52.1 (ester OMe), 55.6 (OMe), 98.1 (C-2 spiro), 105.7 (CH-
700),113.1 (CH-500),116.4 (CH-80),116.6 (CH-8),118.6 (CH-400),118.8 (C-
40a),121.7 (CH-6),122.6 (C-30),122.7 (CH-60),124.1 (C-4a),126.9 (CH-
5), 128.9 (CH-7), 129.5 (CH-50), 131.5 (C-700a), 132.9 (CH-70), 136.3
(CH-40), 146.4 (C-300a), 150.9 (C-8a), 151.0 (C-80a), 154.5 (C-600), 164.0
(COO), 164.7 (C-200). Anal. Calcd for C27H22N2O5S (486.54): C, 66.65;
H, 4.56; N, 5.76%. Found: C, 66.38; H, 4.42; N, 5.93%.
4. Experimental
4.1. General
4.2.3. Methyl
(2R
*
,4R )-4-(6-methylbenzothiazol-2-ylamino)spiro
*
The melting points (uncorrected) were determined with a Kofler
hot stage microscope. The IR spectra were recorded on a Nicolet
Impact 400D spectrophotometer (taken as KBr discs). The NMR
spectra were measured in DMSO-d6 on a Varian VNMRS 600 (for
6aec, eeh and 8) or Varian Unity-Inova 300 (for 6d and 9) in-
struments using TMS as internal standard. The MS (ESIþ) spectrum
was obtained on an Agilent 6520 Q-TOF mass spectrometer. Ele-
mental analyses were taken on a Carlo-Erba Elemental Analyzer
1012 apparatus. The X-ray diffraction data were collected on an
Oxford Diffraction Xcalibur (Ruby, Gemi) diffractometer.
[chroman-2,20-chromene]-30-carboxylate (6c). Yield 22%; mp
224e227 ꢀC; IR: nmax 1708, 1594, 1537, 1445, 1219, 1111, 1030, 884,
758 cmꢁ1; 1H NMR:
d
2.33 (s, 3H, Me), 2.75 (dd, 1H, J¼12.6, 6.0 Hz,
Ha-3), 3.19 (t, 1H, J¼12.6 Hz, Hb-3), 3.78 (s, 3H, OMe), 5.76e5.82 (m,
1H, H-4), 6.72 (dd, 1H, J¼7.8, 1.8 Hz, H-8), 7.00 (dt, 1H, J¼7.8, 1.8 Hz,
H-6), 7.01 (d, 1H, J¼7.8 Hz, H-80), 7.06 (d, 1H, J¼7.8 Hz, H-500), 7.13 (t,
1H, J¼7.8 Hz, H-60), 7.17 (t, 1H, J¼7.8 Hz, H-7), 7.33 (d, 1H, J¼7.8 Hz,
H-400), 7.39 (d, 1H, J¼7.8 Hz, H-5), 7.40 (dt, 1H, J¼7.8, 1.8 Hz, H-70),
7.52 (s, 1H, H-700), 7.61 (dd, 1H, J¼7.8, 1.8 Hz, H-50), 8.01 (s, 1H, H-40),
8.44 (d, 1H, J¼8.4 Hz, NH); 13C NMR:
d 20.7 (Me), 34.3 (CH2), 45.7
(CH), 52.0 (ester OMe), 98.1 (C-2 spiro), 116.4 (CH-80), 116.6 (CH-8),
117.9 (CH-400), 118.8 (C-40a),120.9 (CH-700), 121.7 (CH-6),122.6 (C-30),
122.7 (CH-60), 124.0 (C-4a), 126.6 (CH-500), 126.9 (CH-5), 128.9 (CH-
7), 129.4 (CH-50), 130.3 (C-600), 130.5 (C-700a), 132.9 (CH-70), 136.2
(CH-40), 150.2 (C-300a), 150.9 (C-8a), 151.0 (C-80a), 164.0 (COO), 165.6
(C-200). Anal. Calcd for C27H22N2O4S (470.54): C, 68.92; H, 4.71; N,
5.95%. Found: C, 69.19; H, 4.52; N, 5.77%.
4.2. General procedure for the synthesis of spiroketal de-
rivatives 6 and 8
To a solution of amine 4 or 5 (4.0 mmol) in dry EtOH (15 mL)
were added alkyl acetoacetate 3 (4.0 mmol) and aldehyde 1
(8.0 mmol). The mixture containing four drops of concd HCl was
refluxed for 14e17 h until the completion of reaction was con-
firmed by TLC. While compound 6a precipitated during the re-
action, the other products crystallized after removal of the solvent
4.2.4. Methyl
(2R
*
,4R )-4-(6-chlorobenzothiazol-2-ylamino)spiro
*
[chroman-2,20-chromene]-30-carboxylate (6d). Yield 21%; mp

J. Svĕtlík et al. / Tetrahedron 70 (2014) 8354e8360
8359
214e215 ꢀC; IR: nmax 1716, 1614, 1465, 1212, 1194, 1024, 926, 886,
753 cmꢁ1; 1H NMR:
J¼12.9 Hz, Hb-3), 3.78 (s, 3H, OMe), 5.75e5.85 (m, 1H, H-4), 6.72 (d,
1H, J¼8.1 Hz, H-8), 6.97e7.50 (m, 8H, Har), 7.61 (d, 1H, J¼7.5 Hz, H-
50), 7.78 (d, 1H, J¼2.1 Hz, H-700), 8.01 (s, 1H, H-40), 8.73 (d, 1H,
J¼8.7 Hz, NH). Anal. Calcd for C26H19ClN2O4S (490.96): C, 63.61; H,
3.90; N, 5.71%. Found: C, 63.30; H, 4.21; N, 6.00%.
C26H18Br2N2O4S (611.94): C, 50.99; H, 2.96; N, 4.58%. Found: C, 50.74;
H, 3.23; N, 4.77%.
d
2.77 (dd, 1H, J¼12.9, 6.0 Hz, Ha-3), 3.20 (t, 1H,
4.2.8. Methyl (2R
*
,4S
)-4-(benzothiazol-2-ylamino)-8,80-dimethox-
*
yspiro[chroman-2,20-chromene]-30-carboxylate (60h). Yield 20%; mp
231e232 ꢀC; IR: nmax 3385, 1715, 1541, 1481, 1459, 1441, 1265,
1203, 1188, 1109, 1028, 977, 947, 782, 757 cmꢁ1 1H NMR:
; d 2.67
(dd, 1H, J¼15.0, 3.0 Hz, Ha-3), 3.37 (overlapped by HDO signal, Hb-
3), 3.61 (s, 3H, 8-OMe), 3.79 (s, 3H, ester OMe), 3.86 (s, 3H, 80-
OMe), 5.59e5.63 (m, 1H, H-4), 6.91 (dd, 1H, J¼7.8, 1.2 Hz, H-7),
6.95 (t, 1H, J¼7.8 Hz, H-6), 7.07 (t, 1H, J¼7.8 Hz, H-60), 7.08 (t, 1H,
J¼7.8 Hz, H-600), 7.13 (dd, 1H, J¼7.8, 1.2 Hz, H-5), 7.18 (d, 1H,
J¼7.8 Hz, H-70), 7.21 (d, 1H, J¼7.8 Hz, H-50), 7.28 (t, 1H, J¼7.8 Hz, H-
500), 7.50 (d, 1H, J¼7.8 Hz, H-400), 7.56 (d, 1H, J¼9.6 Hz, NH), 7.72 (d,
4.2.5. Isopropyl (2R
*
,4R )-4-(benzothiazol-2-ylamino)spiro[chroman-
*
2,20-chromene]-30-carboxylate (6e). Yield 29%; mp 210e212 ꢀC; IR:
nmax 1707, 1604, 1573, 1456, 1445, 1207, 1193, 1099, 1014, 918, 887,
753 cmꢁ1
;
1H NMR:
d
1.27 (d, 3H, J¼6.6 Hz, Me), 1.30 (d, 3H,
J¼6.6 Hz, Me), 2.75 (dd, 1H, J¼13.2, 6.0 Hz, Ha-3), 3.21 (t, 1H,
J¼13.2 Hz, Hb-3), 5.04 (sep, 1H, J¼6.6 Hz, OCH), 5.78e5.84 (m, 1H,
H-4), 6.73 (dd, 1H, J¼8.4, 1.2 Hz, H-8), 6.99 (dd, 1H, J¼7.8, 1.8 Hz, H-
80), 7.00 (dt, 1H, J¼8.4, 1.2 Hz, H-6), 7.06 (dt, 1H, J¼7.8, 1.2 Hz, H-600),
7.13 (dt, 1H, J¼7.8, 1.8 Hz, H-60), 7.17 (dt, 1H, J¼8.4, 1.2 Hz, H-7), 7.25
(dt, 1H, J¼7.8, 1.2 Hz, H-500), 7.38 (dd, 1H, J¼8.4, 1.2 Hz, H-5), 7.39
(dt, 1H, J¼7.8, 1.8 Hz, H-70), 7.45 (dd, 1H, J¼7.8, 1.2 Hz, H-400), 7.61
(dd, 1H, J¼7.8, 1.8 Hz, H-50), 7.72 (dd, 1H, J¼7.8, 1.2 Hz, H-700), 7.94 (s,
1H, J¼7.8 Hz, H-700), 7.99 (s, 1H, H-40); 13C NMR:
d 34.6 (CH2), 46.4
(CH), 52.1 (ester OMe), 55.5 (8-OMe), 56.2 (80-OMe), 98.7 (C-2
spiro), 112.0 (CH-7), 115.4 (CH-70), 118.5 (C-40a and CH-400), 120.5
(CH-5), 121.07 (CH-50), 121.13 (CH-700), 121.5 (CH-600), 121.8 (CH-6),
122.4 (CH-60), 122.5 (C-30), 124.1 (C-4a), 125.8 (CH-500), 130.1 (C-
700a), 136.1 (CH-40), 139.7 (C-80a), 139.8 (C-8a), 147.0 (C-80), 148.3
(C-8) 152.4 (C-300a), 164.0 (COO), 165.3 (C-200). Anal. Calcd for
1H, H-40), 8.57 (d, 1H, J¼8.7 Hz, NH); 13C NMR:
d 21.5 (Me), 21.6
(Me), 34.3 (CH2), 45.8 (CH), 68.3 (OCH), 98.2 (C-2 spiro), 116.3 (CH-
80), 116.6 (CH-8), 118.2 (CH-400), 118.8 (C-40a), 121.0 (CH-700), 121.2
(CH-600), 121.7 (CH-6), 122.7 (CH-60), 123.2 (C-30), 123.9 (C-4a), 125.6
(CH-500), 126.8 (CH-5), 128.9 (CH-7), 129.4 (CH-50), 130.4 (C-700a),
132.7 (CH-70), 135.7 (CH-40), 150.9 (C-8a), 151.0 (C-80a), 152.3 (C-
300a), 163.0 (COO), 166.3 (C-2000). Anal. Calcd for C28H24N2O4S
(484.57): C, 69.40; H, 5.00; N, 5.78%. Found: C, 69.33; H, 4.90; N,
5.73%.
C
28H24N2O6S (516.14): C, 65.10; H, 4.69; N, 5.43%. Found: C, 65.34;
H, 4.43; N, 5.67%.
4.2.9. Methyl (2R
*
,4R )-4-(5-methylthiazol-2-ylamino)spiro[chroman-
*
2,20-chromene]-30-carboxylate (8). Yield 21%; mp 216e217 ꢀC; IR:
nmax 1717, 1593, 1484, 1448, 1293, 1207, 1135, 1113, 1091, 1035,
1028, 995, 948, 886, 770, 757 cmꢁ1 1H NMR:
; d 2.34 (d, 1H,
J¼1.2 Hz, Me), 2.66 (dd, 1H, J¼13.2, 6.0 Hz, Ha-3), 3.12 (t, 1H,
J¼13.2 Hz, Hb-3), 3.77 (s, 3H, OMe), 5.52e5.62 (m, 1H, H-4), 6.69
(dd, 1H, J¼7.8, 1.2 Hz, H-8), 6.72 (d, 1H, J¼1.2 Hz, H-400), 6.96 (dd,
1H, J¼7.8, 1.2 Hz, H-80), 6.99 (dt, 1H, J¼7.8, 1.2 Hz, H-6), 7.11 (dt,
1H, J¼7.8, 1.2 Hz, H-60), 7.15 (t, 1H, J¼7.8 Hz, H-7), 7.37 (dt, J¼7.8,
1.2 Hz, H-70), 7.38 (d, 1H, J¼7.8 Hz, H-5), 7.59 (dd, 1H, J¼7.8, 1.2 Hz,
4.2.6. 2-Methoxyethyl (2R
*
,4R )-4-(benzothiazol-2-ylamino)spiro[chro
*
man-2,20-chromene]-30-carboxylate (6f). Yield 20%; mp 186e187 ꢀC;
IR: nmax 1708,1607,1573,1485,1447,1210,1190,1163,1131,1060,1003,
916, 885, 752 cmꢁ1; 1H NMR:
d
2.77 (dd,1H, J¼13.2, 6.0 Hz, Ha-3), 3.22
(t, 1H, J¼13.2 Hz, Hb-3), 3.28 (s, 3H, OMe), 3.62 (t, 2H, J¼4.8 Hz,
CH2OMe), 4.29e4.33 (m, 2H, OCH2), 5.79e5.86 (m, 1H, H-4), 6.72 (d,
1H, J¼8.4 Hz, H-8), 7.00 (d,1H, J¼7.8 Hz, H-80), 7.01 (t, 1H, J¼8.4 Hz, H-
6), 7.06 (t, 1H, J¼7.8 Hz, H-600), 7.13 (t, 1H, J¼7.8 Hz, H-60), 7.17 (t, 1H,
J¼8.4 Hz, H-7), 7.25 (t, 1H, J¼7.8 Hz, H-500), 7.40 (d, 1H, J¼8.4 Hz, H-5),
7.41 (t, 1H, J¼7.8 Hz, H-70), 7.46 (d, 1H, J¼7.8 Hz, H-400), 7.63 (d, 1H,
J¼7.8 Hz, H-50), 7.72 (d, 1H, J¼7.8 Hz, H-700), 7.98 (s, 1H, H-40), 8.57 (d,
H-50), 7.84 (d, 1H, J¼9.0 Hz, NH), 7.98 (s, 1H, H-40); 13C NMR:
d 12.2
(Me), 34.9 (CH2), 46.1 (CH), 52.6 (OMe), 98.8 (C-2 spiro), 116.9
(CH-80), 117.1 (CH-8), 119.4 (C-40a), 120.4 (C-500), 122.1 (CH-6),
123.2 (CH-60), 123.3 (C-4a), 125.3 (C-30), 127.4 (CH-5), 129.2 (CH-
7), 130.0 (CH-50), 133.4 (CH-70), 135.9 (CH-400), 136.7 (CH-40), 151.5
(C-8a), 151.6 (C-80a), 164.6 (COO), 167.9 (C-200). Anal. Calcd for
C
23H20N2O4S (420.48): C, 65.70; H, 4.79; N, 6.66%. Found: C,
1H, J¼9.0 Hz, NH); 13C NMR:
d 34.2 (CH2), 45.8 (CH), 58.1 (OMe), 63.8
65.78; H, 4.82; N, 6.73%.
(OCH2), 69.6 (CH2OMe), 98.2 (C-2 spiro), 116.4 (CH-80), 116.6 (CH-8),
118.2 (CH-400), 118.8 (C-40a), 121.0 (CH-700), 121.2 (CH-600), 121.7 (CH-6),
122.6 (C-30), 122.7 (CH-60), 123.9 (C-4a), 125.6 (CH-500), 126.8 (CH-5),
128.9 (CH-7),129.5 (CH-50),130.4 (C-700a),132.9 (CH-70),136.2 (CH-40),
150.9 (C-8a), 151.0 (C-80a), 152.3 (C-300a), 163.4 (COO), 166.3 (C-200).
Anal. Calcd for C28H24N2O5S (500.57): C, 67.19; H, 4.83; N, 5.60%.
Found: C, 67.31; H, 4.93; N, 5.67%.
4.2.10. Isopropyl (2R
*
,3S
*
,4S )-4-(benzothiazol-2-ylamino)-2-hydro
*
xy-2-methyl-3,4-dihydro-2H-chromene-3-carboxylate (9). Yield 6%;
mp 145e146 ꢀC (toluene); IR: nmax 3304, 1709, 1558, 1447, 1249,
1179, 1102, 926, 753 cmꢁ1; 1H NMR:
d
1.04 (d, 3H, J¼6.0 Hz, Me),1.11
(d, 3H, J¼6.0 Hz, Me),1.61 (s, 3H, Me-2), 2.94 (d,1H, J¼12.0 Hz, H-3),
4.91 (sep, 1H, J¼6.0 Hz, OCH), 5.68e5.78 (m, 1H, H-4), 6.78 (d, 1H,
J¼7.8 Hz, H-8), 6.88 (t,1H, J¼7.8 Hz, H-6), 7.05 (t, 1H, J¼7.8 Hz, H-60),
7.06 (br s,1H, OH), 7.16 (t,1H, J¼7.8 Hz, H-7), 7.21 (d,1H, J¼7.8 Hz, H-
5), 7.25 (t,1H, J¼7.8 Hz, H-50), 7.42 (d,1H, J¼7.8 Hz, H-40), 7.69 (d,1H,
4.2.7. Methyl (2R
[chroman-2,20-chromene]-30-carboxylate
243e245 ꢀC; IR: nmax 1717, 1604, 1562, 1474, 1447, 1265, 1209, 1198,
1114, 1023, 926, 901, 888, 817, 755 cmꢁ1 1H NMR:
2.80 (dd, 1H,
*
,4R
*
)-4-(benzothiazol-2-ylamino)-6,60-dibromospiro
(6g). Yield 20%; mp
J¼7.8 Hz, H-70), 8.41 (d, 1H, J¼9.0 Hz, NH); 13C NMR:
d 21.2 (Me),
;
d
21.5 (Me), 27.0 (Me-2), 49.5 (CH-4), 53.7 (CH-3), 67.7 (OCH), 97.0 (C-
2), 116.5 (CH-8), 118.2 (CH-40), 120.7 (CH-6), 120.9 (CH-70), 121.1
(CH-60), 123.9 (C-4a), 125.6 (CH-50), 126.8 (CH-5), 128.5 (CH-7),
130.3 (C-70a), 151.2 and 152.5 (C-8a/C-30a), 168.8 (COO), NeCeS(]
N) not observed. Anal. Calcd for C21H22N2O4S (398.13): C, 63.30; H,
5.57; N, 7.03%. Found: C, 63.09; H, 5.34; N, 7.22%.
J¼13.2, 6.0 Hz, Ha-3), 3.17 (t, 1H, J¼13.2 Hz, Hb-3), 3.78 (s, 3H, OMe),
5.74e5.85 (m, 1H, H-4), 6.73 (d, 1H, J¼8.7 Hz, H-8), 7.01 (d, 1H,
J¼8.7 Hz, H-80), 7.07 (t, 1H, J¼7.8 Hz, H-600), 7.26 (t, 1H, J¼7.8 Hz, H-500),
7.35 (dd, 1H, J¼8.7 and 2.1 Hz, H-7), 7.46 (d, 1H, J¼7.8 Hz, H-400), 7.48
(d, 1H, J¼2.1 Hz, H-5), 7.54 (dd, 1H, J¼8.7 and 2.1 Hz, H-70), 7.72 (d, 1H,
J¼7.8 Hz, H-700), 7.86 (d, 1H, J¼2.1 Hz, H-50), 8.00 (s, 1H, H-40), 8.60 (d,
1H, J¼8.7 Hz, NH); 13C NMR:
d 33.7 (CH2), 45.6 (CH), 52.3 (OMe), 98.4
(C-2 spiro), 113.5 and 114.2 (C-6/C-60), 118.4 (CH-400), 118.8 (CH-80),
119.2 (CH-8), 120.9 (C-40a), 121.1 (CH-700), 121.4 (CH-600), 123.5 (C-30),
125.8 (CH-500), 126.5 (C-4a), 129.3 (CH-5), 130.5 (C-700a), 131.5 (CH-50),
131.8 (CH-7), 135.2 (CH-40 and CH-70), 149.9 and 150.1 (C-8a/C-80a),
152.1 (C-300a), 163.7 (COO), 166.2 (C-200). Anal. Calcd for
Acknowledgements
This work was supported by the Slovak Research and De-
velopment Agency (APVV 0204-10 and APVV-0797-11) and the
Grant Agency of the Slovak Republic (VEGA 1/0051/13).

8360
J. Svĕtlík et al. / Tetrahedron 70 (2014) 8354e8360
4. Crystallographic data (excluding structures factors) for the structures in this
References and notes
paper have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication nos. CCDC 992475 for 8, 992476 for 60h and 992477
for 9. Copies of the data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK, fax: þ44 (0)1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk.
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