Synthesis and reactions of 5-[amino(thiomethyl)methylene]-2,2-dimethyl-1,3- dioxane-4,6-dione

Article abstract of DOI:10.1515/znb-2009-0113

5-[Amino(thiomethyl)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (4) is obtained from 5-[bis-(thiomethyl)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (1) and aqueous ammonia in excellent yield. Its reaction with m-chloroperbenzoic acid gives the sulfoxi

Full text of DOI:10.1515/znb-2009-0113

Synthesis and Reactions of 5-[Amino(thiomethyl)methylene]-
2,2-dimethyl-1,3-dioxane-4,6-dione
Ahmad Al-Sheikha, Kamal Sweidanb, Ca¨cilia Maichle-Mo¨ßmerc, Manfred Steimannc, and
Norbert Kuhnc
a Faculty of Pharmacy, Petra University, P. O. Box 961343, Amman, Jordan
b Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P. O. Box 130, Amman, Jordan
c Institut fu¨r Anorganische Chemie der Universita¨t Tu¨bingen, Auf der Morgenstelle 18,
D-72076 Tu¨bingen, Germany
Reprint requests to Dr. A. Al-Sheikh. E-mail: aalsheikh@uop.edu.jo or
Prof. Dr. N. Kuhn. E-mail: norbert.kuhn@uni-tuebingen.de
Z. Naturforsch. 2009, 64b, 101 – 105; received October 9, 2008
Dedicated to Professor Otto J. Scherer on the occasion of his 75th birthday
5-[Amino(thiomethyl)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (4) is obtained from 5-[bis-
(thiomethyl)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (1) and aqueous ammonia in excellent
yield. Its reaction with m-chloroperbenzoic acid gives the sulfoxide derivative 5-[amino(sulfinylmeth-
yl)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (5). With triphenylphosphine, 5 reacts to give tri-
phenyl(thiomethyl)phosphonium 5-cyano-2,2-dimethyl-1,3-dioxane-4,6-dionate (6) from which the
methyltriphenylphosphonium salt 6a is obtained with excess triphenylphosphine. The crystal struc-
tures of 4, 5 and 6a are discussed.
Key words: Meldrum’s Acid, Heterocycles, Hydrogen Bonds, Sulfur, Zwitterionic States
Introduction
Meldrum’s acid (1) derivatives play an impor-
tant role in organic and pharmaceutical synthe-
sis [1]. 5-[Bis(thiomethyl)methylene]-2,2-dimethyl-
1,3-dioxane-4,6-dione(2), first prepared by Huang and
Chen [2], may serve as a useful precursor for the prepa-
ration of a series of methylene compounds (3) [3 – 8].
In the light of our interest in studying intra- and in-
termolecular hydrogen bonds in Meldrum’s acid and
barbituric acid derivatives [9 – 11] and in the chemistry
of these compounds we report now on the exchange of
one thiomethyl substituent by an amino group and sub-
sequent reactions.
Fig. 1. View of the molecule of C8H11NO4S (4) in the crys-
tal.
amines to form compounds of the type 3 (X = SMe;
Y = NHR, NR1R2) [3, 4]. With aqueous ammonia,
2 reacts readily to give 5-[amino(thiomethyl)methyl-
ene]-2,2-dimethyl-1,3-dioxane-4,6-dione (4) as a sta-
ble solid in excellent yield. Its crystal structure (Ta-
bles 1 and 2, Figs. 1 and 2) reveals the presence of an
intramolecular N–H···O bond [O(01)···H(8b) 1.86,
◦
˚
N(8)–H(8b) 0.856 A; N(8)–H(8b)···O(01) 142.1 ]
The bond lengths of the six-membered ring indicate a
π electron distribution with a strong enolate contribu-
tion [O(01)–C(1) 1.225(2), C(1)–C(6) 1.441(2), C(6)–
Results and Discussion
The well known reaction of compound 2 with
amines is restricted to the use of primary and secondary
˚
C(7) 1.425(2), C(7)–N(8) 1.322(2) A]. Consequently,
c
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102
A. Al-Sheikh et al. · 5-[Amino(thiomethyl)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione
Table 1. Crystal data and structure refine-
ment for C8H11NO4S (4), C8H11NO5S
(5), and C26H24NO4P (6a).
4
5
6a
Empirical formula
Formula weight
Temperature, K
λ, A
Crystal system
Space group
C8H11NO4S
217.24
C8H11NO5S
233.24
173
C26H24NO4P
445.43
˚
0.71073
triclinic
P1
triclinic
P1
monoclinic
P21/c
¯
¯
Unit cell dimensions
˚
a, A
5.826(1)
7.172(1)
11.199(2)
93.99(1)
90.59(1)
91.84(1)
466.5(2)
2
7.203(1)
8.574(2)
8.799(2)
106.62(1)
103.99(1)
98.64(1)
490.89
2
9.209(1)
16.525(1)
15.000(2)
90
92.08(1)
90
2281.1(4)
4
1.297
0.153
˚
b, A
˚
c, A
α, deg
β, deg
γ, deg
3
˚
Volume, A
Z
Dcalcd, g cm−3
1.546
0.335
228
1.578
0.331
244
µ(MoKα ), mm−1
F(000), e
936
θ, deg
3.27 – 26.37
6699
1901
3.29 – 26.37
6988
3.31 – 26.37
31701
4660
Refls. coll.
Refls. indep.
1991
Refinement method
Param. refined
Full-matrix least-squares on F2
172
1.137
0.0309/0.0677
0.0365/0.0700
0.026(3)
+0.28/−0.20
181
1.069
0.0289/0.0740
0.0312/0.0752
0.014(4)
+0.53/−0.25
386
1.117
0.0617/0.1073
0.0786/0.1099
0.002(1)
+0.46/−0.32
Goodness-of-fit on F2
Final R1/wR2 [I ≥ 2σ (I)]
Final R1/wR2 (all data)
Extinction coeff.
−3
˚
∆ρfin (max/min), e A
˚
Table 2. Bond lengths (A) and angles (deg) for C8H11NO4S (4), and C8H11NO5S (5).
C8H11NO4S (4)
C8H11NO5S (5)
C8H11NO4S (4)
C8H11NO5S (5)
C(1)–O(01)
C(1)–O(2)
C(1)–C(6)
O(2)–C(3)
C(3)–O(4)
O(4)–C(5)
C(5)–O(05)
C(5)–C(6)
C(6)–C(7)
C(7)–N(8)
C(7)–S(9)
S(9)–C(10)
S(9)–O(11)
1.225(2)
1.347(2)
1.441(2)
1.436(2)
1.439(2)
1.371(2)
1.216(2)
1.441(2)
1.425(2)
1.322(2)
1.736(2)
1.801(2)
1.214(2)
1.357(2)
1.448(2)
1.438(2)
1.448(2)
1.361(2)
1.216(2)
1.446(2)
1.386(2)
1.308(2)
1.837(2)
1.805(2)
1.494(1)
O(2)–C(1)–C(6)
C(1)–O(2)–C(3)
O(2)–C(3)–O(4)
C(5)–O(4)–C(3)
O(05)–C(5)–O(4)
O(05)–C(5)–C(6)
O(4)–C(5)–C(6)
C(7)–C(6)–C(5)
C(7)–C(6)–C(1)
C(5)–C(6)–C(1)
N(8)–C(7)–C(6)
N(8)–C(7)–S(9)
C(6)–C(7)–S(9)
C(7)–S(9)–C(10)
C(7)–S(9)–O(11)
C(10)–S(9)–O(11)
118.35(13)
119.86(12)
110.22(11)
119.12(11)
116.36(13)
126.99(14)
116.55(13)
121.00(13)
119.25(13)
119.39(14)
120.31(14)
119.05(12)
120.64(11)
101.51(8)
–
116.75(12)
117.60(11)
109.76(11)
118.56(10)
117.85(12)
125.68(13)
116.42(12)
120.98(13)
118.65(13)
120.13(13)
126.26(14)
110.58(11)
123.13(11)
94.99(7)
O(01)–C(1)–O(2)
O(01)–C(1)–C(6)
115.78(14)
125.85(15)
117.50(13)
125.64(13)
102.91(7)
105.11(7)
–
the orientation of the fragments N(8)H(8a)H(8b) and
The oxidation of organic sulfides is a stan-
C(6)C(7)S(9) is almost coplanar (interplanar angle dard method for the synthesis of sulfoxides and
6.8◦). The second NH proton is incorporated into an in- sulfones [12]. We obtained 5-[amino(sulfinylmeth-
termolecular hydrogen bond which links the molecule yl)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (5)
to the second carbonyl oxygen atom of a neighbor- from 2 and m-chloroperbenzoic acid as the final prod-
ing molecule thus forming a polymeric chain structure uct; apparently, further oxidation of 5 to the corre-
˚
[O(05B)···H(8a) 2.407, N(8)–H(8a) 0.884 A; N(8)– sponding sulfone does not proceed under mild con-
H(8a)···O(05B) 135.2◦]. For further bond lengths and ditions. The crystal structure of 5 (Tables 1 and 2,
angles see Table 2.
Fig. 3) parallels that of 4 apart from a slight shorten-
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A. Al-Sheikh et al. · 5-[Amino(thiomethyl)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione
103
Fig. 2. View of the polymeric
chain of C8H11NO4S (4) in the
crystal.
Fig. 3. View of the molecule of C8H11NO5S (5) in the crys-
tal.
ing of the central exocyclic olefinic bond [N(8)–C(7)
Fig. 4. View of the ion pair of C26H24NO4P (6a) in the crys-
1.308(2), C(6)–C(7) 1.386(2), C(1)–C(6) 1.448(2),
tal.
˚
C(1)–O(61) 1.214(2) A]. Also, the angle between the
fragments N(8)H(8a)H(8b) and C(6)C(7)S(9) (1.6◦)
The enhanced acidity of the sulfoxide center in 5,
and the parameters of the intramolecular N–H···O however, allows its nucleophilic attack. Surprisingly,
˚
bond [O(01)···H(8b) 2.035, N(8)–H(8b) 0.875 A; triphenylphosphine attacks the sulfur atom to split the
O(01)···H(8b)–N(8) 129.9◦] are very similar to those methylene carbon to sulfur bond to give the triphen-
of 4. Instead of intermolecular contacts, H(8a) forms ylthiomethylphosphonium salt 6, in which the meth-
a second intramolecular O···H–N bridge including yleneamino fragment has been transformed to a nitrile
the sulfinyl oxygen atom [O(11)···H(8a) 2.083, N(8)– function under elimination of water. The mechanism of
◦
˚
H(8a) 0.869 A; O(11)···H(8a)–N(8) 121.7 ].
this fast reaction needs further investigation since no
We did not succeed in substituting the second thio- by-products were detected. Excess of triphenylphos-
methyl group in 2 with excess ammonia. Apparently, phine causes dealkylation of the thiomethylphosphon-
the electrophilic nature of 4 is reduced, in comparison ium ion in 6, its methyltriphenylphosphonium salt 6a
with 2, by the strong +M effect of the amino group. being formed.
Similarly, 4 does not react with triphenylphosphineun-
der ambient conditions.
The crystal structure analysis of 6a (Table 1, Fig. 4)
reveals the presence of isolated ions. The structure of
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104
A. Al-Sheikh et al. · 5-[Amino(thiomethyl)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione
˚
Table 3. Bond lengths (A) and angles (deg) for C26H24NO4P
creases upon the exchange of thiomethyl substituents
by amino groups which have stronger π-donating prop-
erties as demonstrated by the different reactivity of 2
and 4 towards ammonia. Nevertheless, π donation of
the thiomethyl substituent in 4 seems to be present
as indicated by its uncommon resistance to oxidation
which stops at the sulfoxide derivative 5.
In 5, the soft base triphenylphosphine attacks the
soft sulfur center under mild conditions according to
the HSAB concept [14] while 4, owing to its lower
acidity, does not react. The mechanism of the interest-
ing formation of 6 as well as the reaction of 5 with
harder bases are currently under investigation.
(6a).
P(1)–C(11)
P(1)–C(31)
O(3)–C(2)
O(5)–C(6)
O(21)–C(2)
N(10)–C(10)
C(1)–C(6)
C(4)–C(42)
1.790(2)
1.794(2)
1.371(2)
1.372(3)
1.219(2)
1.148(3)
1.415(3)
1.503(3)
P(1)–C(01)
P(1)–C(21)
O(3)–C(4)
O(5)–C(4)
O(61)–C(6)
C(1)–C(10)
C(1)–C(2)
C(4)–C(41)
1.790(2)
1.794(2)
1.441(2)
1.437(2)
1.220(2)
1.417(3)
1.424(3)
1.506(3)
C(11)–P(1)–C(01)
C(01)–P(1)–C(31)
C(01)–P(1)–C(21)
C(2)–O(3)–C(4)
C(10)–C(1)–C(6)
C(6)–C(1)–C(2)
O(21)–C(2)–C(1)
O(5)–C(4)–O(3)
O(3)–C(4)–C(42)
O(3)–C(4)–C(41)
O(61)–C(6)–O(5)
O(5)–C(6)–C(1)
108.9(1)
109.6(1)
108.0(1)
117.1(2)
118.7(2)
122.4(2)
126.7(2)
110.5(2)
106.3(2)
110.0(2)
117.3(2)
116.1(2)
C(11)–P(1)–C(31)
C(11)–P(1)–C(21)
C(31)–P(1)–C(21)
C(6)–O(5)–C(4)
C(10)–C(1)–C(2)
O(21)–C(2)–O(3)
O(3)–C(2)–C(1)
O(5)–C(4)–C(42)
O(5)–C(4)–C(41)
C(42)–C(4)–C(41)
O(61)–C(6)–C(1)
N(10)–C(10)–C(1)
110.2(1)
110.7(1)
109.4(1)
117.6(2)
118.5(2)
117.2(2)
116.1(2)
106.5(2)
110.5(2)
113.0(2)
126.5(2)
179.5(2)
Experimental Section
All starting materials were purchased from commercial
sources and used without purification. Experiments were per-
formed in purified solvents under argon. Compound 2 was
prepared according to a published procedure [2]. Crystals of
4, 5 and 6a were obtained by recrystallization from CH2Cl2 /
diethyl ether.
CCDC 698445 (4), CCDC 698444 (5), and CCDC 703897
(6a) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data request/cif.
the cation agrees with published results [13]. Though
being negatively charged, the structure of the anion re-
sembles closely those found in the neutral molecules
4 and 5 indicating similar charge distributions. Bond
lengths and angles around the cyano substituent are
in the expected range [C(1)–C(10) 1.417(3), C(10)–
◦
˚
N(10) 1.148(3) A; C(1)–C(10)–N(10) 179.5(2) ]. For
more details see Table 3.
C8H11NO4 (4)
1 g (4 mmol) of 2 was added to 10 mL of aqueous
ammonia (25 %). The suspension was stirred for 30 min
at r. t. The precipitate was filtered and recrystallized from
CH2Cl2/diethyl ether to give 0.72 g (82 %) of 4 as pale yel-
Concluding Remarks
Our results confirm the electrophilic nature of the
exocyclic 5-methylene substituent in Meldrum’s acid
derivatives. In fact, the propensity of the methylene
carbon atom to allow an attack by nucleophiles de-
1
low crystals. – H NMR (400 MHz, [D6]DMSO): δ = 1.57
(s, 6 H, 2-Me), 2.41 (s, 3 H, SMe), 8.8, 10.8 (2 s, 2 H,
NH2). – 13C NMR (400 MHz, [D6]DMSO): δ = 17.0 (SMe),
25.88 (2-Me), 82.75 (C5), 102.2 (C2), 163.3 (C=O), 177.6
(C-SMe). – MS (EI, 70 eV): m/z (%) = 217 (75) [M]+,
186 (65) [M–2 Me]+, 160 (80) [M–2 Me, CO]+, and further
fragments.
O
H
O
H
N
O
O
N
H
O
O
H
O
SMe
S
C8H11NO5S (5)
O
O
H3C
To a solution of 0.5 g (2.30 mmol) of 4 in 10 mL of
CH2Cl2 0.52 g (2.30 mmol) m-chloroperbenzoic acid (77 %)
5
4
◦
was added at −60 C. The suspension was stirred overnight
O
O
and CH2Cl2 evaporated in vacuo. To the resulting precipitate
20 mL of diethyl ether was added at r. t., and the solution was
stirred for 5 min. The precipitate was filtered and recrystal-
lized from CH2Cl2 / diethyl ether to give 0.48 g (92 %) of 5 as
O
O
Ph3P
S
CH3
C
N
1
colorless crystals. – H NMR (400 MHz, CDCl3): δ = 1.57
6
(s, 6 H, 2-Me), 2.86 (s, 3 H, SMe), 8.8, 10.8 (2 s, 2 H, NH2). –
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A. Al-Sheikh et al. · 5-[Amino(thiomethyl)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione
105
13C NMR (400 MHz, CDCl3): δ = 25.88 (2-Me), 42.30 CH2Cl2 / diethyl ether to give 0.91 g (89 %) of 6 as col-
(S(O)Me), 82.44 (C5), 105.5 (C2), 164.31 (C=O), 178.77 (C orless crystals. – 1H NMR (400 MHz, CDCl3): δ = 1.52
S(O)Me). – MS (EI, 70 eV): m/z (%) = 234 (15) [M]+, 192 (s, 6 H, 2-Me), 2.41 (d, 3 H, SMe), 7.69 – 7.82 (m, 15 H,
(55) [M–2Me, C]+, 176 (80) [M–2 Me, CO]+, and further Ph). – 13C NMR (400 MHz, CDCl3): δ = 13.75 (SMe),
fragments.
26.12 (2-Me), 57.29 (C5), 102.24 (C2), 117.66 (CN), 120.00,
130.85, 133.45, 136.12 (Ph), 166.27 (C=O). – MS (FAB
neg.): m/z (%) = 167.9 (100) [M]−, 152.9 (10) [M–Me]−,
121.9 (5) [M – 2 Me, CO]−. – MS (FAB): m/z (%) = 309.1
(100) [M]+, 262.2 (5) [M–MeS]+, 183.0 (5) [M–MeS, Ph]+.
C26H24NO4PS (6)
To a solution of 0.5 g (2.15 mmol) of 5 in 10 mL of
CH2Cl2 0.56 g (2.15 mmol) triphenylphosphine was added
at r. t. The suspension was stirred overnight, and CH2Cl2 was
evaporated in vacuo. To the resulting precipitate 20 mL of di-
ethyl ether was added at r. t., and the solution was stirred for
5 min. The precipitate was filtered and recrystallized from
Acknowledgement
Financial support by the Deutsche Forschungsgemein-
schaft and the Higher Council for Science and Technology
of Jordan is gratefully acknowledged.
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1991, 113, 1954.
Unauthenticated
Download Date | 5/27/18 11:03 AM