Novel dithia-aza-norbornanes as 'stiff' bicyclic dithiazines

Article abstract of DOI:10.1055/s-2003-41431

Addition of lithiated 4,5-dihydro-1,3,5-dithiazines to in situ generated N-silylimines in THF produces 2-(α-aminoalkyl)dithiazines, which rearrange into 3,5-dithia-1-azabicyclo[2.2.1]heptanes upon aqueous workup. These novel bicyclic dithiazines can in tu

Full text of DOI:10.1055/s-2003-41431

LETTER
1731
Novel Dithia-aza-norbornanes as ‘Stiff’ Bicyclic Dithiazines
N
ovel Bicyclic Dit
l
hiazine
e
s
xei N. Kurchan, Edmir Wade, Andrei G. Kutateladze*
Department of Chemistry and Biochemistry, University of Denver, Denver, CO 80208-2436, USA
Fax +1(303)8712254; E-mail: akutatel@du.edu
Received 28 March 2003
R
7
4
Abstract: Addition of lithiated 4,5-dihydro-1,3,5-dithiazines to in
situ generated N-silylimines in THF produces 2-(a-ami-
noalkyl)dithiazines, which rearrange into 3,5-dithia-1-azabicy-
clo[2.2.1]heptanes upon aqueous workup. These novel bicyclic
dithiazines can in turn be lithiated at the position 4 and added to car-
bonyl compounds.
S
S
1. n-BuLi
S
S
1
R
N
6
Me
N
2
N
2. RCH=N-SiMe3
3. H3O+
- MeNH2
H2N
5
S
S
Me
3
3
1
2
a R = Ph, 55 %
b R = Py, 39 %
c R = t-Bu, 30 %
Key words: heterocycles, sulfur, carbanions, nucleophilic addi-
tions, diastereoselectivity, desulfurization
Scheme 1
celerates the transformation of the initial reaction mixture.
For example, treatment of 2b with aqueous ammonium
chloride/HCl at pH 3 for 15 min and extraction with ethyl
acetate gives almost pure 3b, while a similar work-up at
pH 6 gives a mixture of unreacted 2b and the product 3b
even after 1–2 hours. The caveat is that the overall isolat-
ed yield of 3b at pH 3 is less than 10%, smaller than that
of the much slower reaction at near neutral pH.
Reactions of sulfur-stabilized carbanions with various
electrophiles have found numerous applications in organ-
ic synthesis. Stereochemical aspects of these reactions
have been studied in depth and several ingenious ap-
proaches that utilize chiral auxiliaries have been imple-
mented. Examples include both external auxiliaries, such
as sparteine,1 and internal auxiliaries, such as menthol es-
ters,2 chiral dithiane-S-oxides3 etc.
H+
H
N
S
S
R
S
R
It was long recognized that sulfur can potentially serve a
dual function - it can stabilize the carbanion and, at the
same time, it is easily removable when no longer needed.4
In this Letter we report a novel transformation of 2-ami-
noalkyl-1,3,5-dithiazines into substituted 3,5-dithia-1-
azabicyclo[2.2.1]heptanes, and their subsequent lithiation
and reaction with carbonyl compounds. This is an experi-
mentally simple synthetic sequence that, when augmented
with desulfurization reactions (e.g. Raney-Ni), offers ac-
cess to diastereomeric 1,n-diamines or aminoalcohols.
Me
Me
N
H2N
S
H2N
2
R
NH2Me
NHMe
S
R
~H+
S
S
R
N
S
HN
S
S
H2N
3
Scheme 2
Earlier we found that lithiated dithianes add to in situ gen-
erated N-silyl imines, furnishing 2-(a-aminoalkyl)-1,3-
dithianes.5 We now report that addition of lithiated dithi-
azines to N-silylated imines produces similar 2-(a-ami-
noalkyl)-1,3,5-dithiazines 2, which rearrange into 3,5-
dithia-1-azabicyclo[2.2.1]heptanes 3 upon aqueous work-
up or during chromatography on silica gel, Scheme 1.
This transformation gives access to bicyclic dithiazines 3,
in which the auxiliary group R is locked in proximity to
the latent anionic center C4.
Conceivably, this is due to the competing complete hy-
drolysis of the dithiazine ring at low pH. Under optimal
conditions 3a, the rearranged product of addition to benz-
aldimine, was obtained in 55% yield by hydrolysis over-
night at pH 6.6 Compounds 3b,c were obtained similarly
by reacting lithiated N-methyldithiazine with silylated py-
ridine-2-carboxaldimine and pivalaldimine respectively.
The isolated yield of 7-tert-butyl substituted 3b was low
(30%). Generally, we found that increased substitution in
the carbonyl component lowered the yield of bicyclic
dithiazines. For example, addition of methyldithiazine to
N-silylated benzophenone imine produced adduct of type
2 that did not rearrange into 3.
The most probable mechanism for the conversion of 2 into
3 is a stepwise acid-catalyzed intramolecular nucleophilic
substitution shown in Scheme 2. Alternatively, the actual
substitution steps 2 and 4 in Scheme 2 may proceed via an
SN1-like mechanism, i.e. formation of a sulfur-stabilized
carbocation. Judging by NMR, an increase in acidity ac-
The structure of the bicyclic dithiazines 3 was elucidated
by NMR. Compounds 3a–c all lacked the original dithiaz-
ine methyl group. In 3a (Figure 1), six aliphatic protons
produce three two-proton spin systems, H2x-H2n, H6x-H6n
and H4-H7. Additionally, H2x-H6x are weakly W-coupled
(J2x-6x = 1.9 Hz). The geminal coupling constants are
Synlett 2003, No. 11, Print: 02 09 2003. Web: 25 08 2003.
Art Id.1437-2096,E;2003,0,11,1731,1733,ftx,en;S04003ST.pdf.
DOI: 10.1055/s-2003-41431
J
2x-n = 9.4 Hz and J6x-n = 9.0 Hz. The benzylic (H7) and the
© Georg Thieme Verlag Stuttgart · New York

1732
A. N. Kurchan et al.
LETTER
bridgehead (H4) protons are coupled with J7-4 = 1.2 Hz, departure. Subsequent enamine-imine tautomerization
which is expected in a bicyclo[2.2.1] framework. The produces 4a.
exo-proton H2x is almost half a ppm upfield of H6x. The
The reaction, however, takes a different path with very
geometry, optimized at a DFT level (B3LYP/3-21G*),
strong bases in aprotic solvents. Our further investigation
shows that H2x is positioned below the phenyl ring – it is
showed that 3a,c are readily deprotonated with butyllithi-
um at C-4, not at the benzylic position. The generated sul-
in the shielding part of the aromatic anisotropy cone. The
NOE values are in very good agreement with the calculat-
fur-stabilized carbanions are reactive toward various
ed inter-proton distances (Figure 1). The computed ‘hori-
electrophiles, including carbonyl compounds. Shown in
zontal’ conformation of the phenyl is supported by the
Scheme 4 are such reactions with aldehydes, producing
diastereomers 5–8 in moderate to good yields, although
observation that the H4-Hortho NOE effect (5.4%) is much
greater than that of H7-Hortho (1.2%).
with no diastereoselectivity.7
R
R
R
N
N
1. n-BuLi/THF, –30 °C
+
N
S
S
S
H
S
2. R'CHO
HO
H
OH
S
S
R'
5-RS(SR) R = Ph,R' = Ph
R'
5-RR(SS) (1:1, 81%)
3a,c
6-RS(SR) R = Ph, R' = Py 6-RR(SS) (1:1.5, 35%)
7-RS(SR) R = t-Bu, R' = Ph 7-RR(SS) (1:1, 80%)
8-RS(SR) R = Ph, R' = t-Bu 8-RR(SS) (1:1, 57%)
Scheme 4
For example, reaction with benzaldehyde produced dia-
stereomers 5-RS(SR) and 5-RR(SS), which are separated
readily by column chromatography, in a 1:1 ratio,
Scheme 4. Expansions of the aliphatic region of their
NMR spectra are shown in Figure 2. The left-most doub-
lets shown in Figure 2 are benzylic protons. Their splitting
is due to spin-spin coupling on the respective protons of
the hydroxy groups (not shown in the expansion of ali-
phatic region). The RS(SR) diastereomer has its C7-ben-
zylic proton at 4.02 ppm, about 0.9 ppm upfield of the
respective benzylic proton in the RR(SS), 4.92 ppm. Sim-
ilar large chemical shift differences are also observed in
pairs 6 and 8, which, by analogy, can be used to assign
stereochemistry in these diastereomers.
1
Figure 1 (a) H NMR coupling constants and chemical shifts (bo-
xed) for 3a; (b) B3LYP/3-21G* geometry (c) NOE (%) with DFT
inter-proton distances; (d) expansion of the aliphatic region of the
spectrum.
Like the parent dithiazines, 3,5-dithia-1-azabicyc-
lo[2.2.1]heptanes are solvolytically unstable in the pres-
ence of strong acids. They are relatively stable in basic
aprotic solutions but lose one mole of thioformaldehyde
and convert into thiazolines upon extended refluxing with
bases in protic solutions. For example, refluxing 3a with
sodium bicarbonate in ethanol yields 4-phenyl-2,5-dihy-
drothiazole 4a nearly quantitatively.
The stereochemical configuration of the diastereomers of
5 was established indirectly, by reductive desulfurization
with Raney nickel to the corresponding 1,3-amino-
A plausible mechanism for this transformation is shown in
Scheme 3. It involves elimination of the benzylic proton
and expulsion of thioformaldehyde, which is accelerated
by the protic solvent acting as a general acid. Judging by
the DFT geometry, the H7-C7-C1-S3 fragment is almost
anti-periplanar, 169.4o, which should facilitate the thiolate
Ph
Ph
NaHCO3/EtOH
N
N
reflux
S
S
S
4a
3a
B
Ph
N
Ph
H
Ph
S
H
Solv
HN
N
-CH2S
S
S
S
S
Figure 2 1H NMR spectrum expansion of the aliphatic region in the
diastereomers of 5.
Scheme 3
Synlett 2003, No. 11, 1731–1733 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Novel Bicyclic Dithiazines
1733
3a–c. (a) N-Silyl benzaldimine: A solution of 5.32 g
alcohols, for which the stereochemical assignment was
previously described,8 Scheme 5. Desulfurization with
W2 Raney nickel lead to over-reduction, as did the reac-
tion with in situ generated nickel boride.
(33 mmol) of 1,1,1,3,3,3-hexamethyldisilazane in 100 mL of
freshly distilled THF was cooled to 0 °C, and 21.46 mL of
n-butyllithium (1.6 M solution in hexanes, 34 mmol) was
added with stirring under N2 atmosphere. The reaction
mixture was stirred at this temperature for 1.5 h. Next, 3.49
g (33 mmol) of benzaldehyde was slowly added, and the
resulting mixture was stirred at 0 °C for 1.5 h; see also:
Gyenes, F.; Bergmann, K. E.; Welch, J. T. J. Org. Chem.
1998, 63, 2824. (b) Lithiated methyldithiazine was prepared
by addition of 20.35 mL of 1.6 M n-BuLi in hexane (32
mmol) under nitrogen to a solution of 4 g dithiazine (30
mmol) in 100 mL of anhydrous THF at –78 °C. The reaction
mixture was stirred for 2 h at –78 °C and a solution of
silylated benzaldimine (33 mmol) in 100 mL of anhydrous
THF was added dropwise. The solution was stirred at –78 °C
for one hour and then allowed to warm to room temperature.
The solvent was removed under reduced pressure to give
orange oil, to which 150 mL of saturated NH4Cl was added.
The resulting two phase system was stirred for 12 hours at
room temperature. The insoluble residue was dissolved in
EtOAc, and the water phase was additionally extracted with
EtOAc (2 × 50 mL). The organic extracts were combined
and dried over Na2SO4. The solvent was removed under
reduced pressure and the product was purified by column
chromatography (EtOAc–hexanes, 1:20) resulting in 3.4 g of
colorless crystals (54.7% yield). 1H NMR (CDCl3, 400
MHz), d 7.48–7.28 (5 H, m), 5.16 (1 H, d, J = 1.4 Hz), 4.80
(1 H, s), 4.73 (1 H, dd, J1 = 9.0 Hz, J2 = 1.9 Hz), 4.28 (1 H,
dd, J1 = 9.4 Hz, J2 = 2.3 Hz), 4.16 (1 H, d, J = 9.0 Hz), 3.95(1
H, d, J = 9.4 Hz). C13 NMR (CDCl3, 100 MHz), d (ppm)
135.3, 128.5,127.6, 127.2, 82.4, 61.7, 59.5, 56.2. MS (EI)
m/z (relative intensity) 209 (M+ 40), 142 (20), 134 (35), 118
(50), 91 (100), 77 (20), 64 (20). Calcd. for C10H11NS2, %:
C 57.38, H 5.30; Found, %: C 57.72, H 5.53.
The best results were achieved with deactivated Raney
nickel, treated with acetic acid. In each case we observed
only one diastereomer of the amino-alcohol 9 being
formed along with by-product 1,3-diphenyl-1-propanol.
The reported chemical shifts of the H-C-NMe2 protons in
9-SR(RS) and 9-SS(RR) differ by 0.8 ppm making it rel-
atively straightforward to distinguish between the two di-
astereomers.
Ph
N
Ph
Ph
NMe2
Raney Ni
S
S
HO
OH
H
Ph
9-SR(RS)
5-RS(SR)
Ph
N
Raney Ni
Ph
Ph
NMe2
9-SS(RR)
S
H
S
OH
OH
Ph
5-RR(SS)
Scheme 5
In conclusion, we found that addition of lithiodithiazines
to N-silylated imines is accompanied by a transformation
into novel 3,5-dithia-1-azabicyclo[2.2.1]heptanes, which
in turn can be deprotonated at position 4 and added to car-
bonyl compounds, furnishing diastereomeric adducts. The
diastereomers are readily separated by column chroma-
tography, providing easy access to both RR(SS)- and
RS(SR)-diastereomers. In conjunction with sulfur-remov-
ing reactions, for example desulfurization with Raney
nickel, this approach can potentially be used to synthesize
diastereomeric 1,3-aminoalcohols and related com-
pounds, thus making bicyclic dithiazines 3 a synthon for
(7) General procedure. 2.8 mmol of 3a or 3c was dissolved in
30 mL of freshly distilled THF and cooled to –78 °C, under
nitrogen atmosphere. Then 2.0 mL (3.2 mmol) of n-BuLi 1.6
M solution in hexane was added dropwise. The reaction
mixture was stirred for 2 hours at –30 °C and 3.6 mmol of
the respective aldehyde in 10 mL of THF was added
dropwise. The temperature was maintained at –78 °C for one
more hour and then allowed to warm up overnight. The
resulting red solution was washed with 50 mL of saturated
NH4Cl, the organic layer separated and the water phase
extracted with 30 mL of CHCl3. The organic layers were
combined, dried over Na2SO4 and the solvent was removed
in vacuum to give a yellow oil, which was purified by
column chromatography. Additional column separation was
required to isolate the diastereomers in a pure state.
–
b-aminoethyl carbanions, RCH(NMe2)-CH2 .
Diastereomers 5: (the stereochemistry is assigned based on
Raney-Ni desulfurization) 5-RR(SS): 1H NMR (CDCl3, 400
MHz), d (ppm) 7.86–7.80 (2 H, m), 7.46–7.40 (3 H, m),
7.31–7.20 (3 H, m), 7.16–7.12 (2 H, m), 5.61 (1 H, d, J = 3.2
Hz), 4.61 (1 H, d, J = 8.8 Hz), 4.59 (1 H, d, J = 8.8 Hz), 4.27
(1 H, d, J = 8.8 Hz), 4.11 (1 H, d, J = 8.8 Hz), 4.02 (1 H, s),
2.45 (1 H, d, J = 3.2 Hz). 13C NMR (CDCl3, 100 MHz), d
140.4, 134.9, 129.7, 129.1, 129.0, 128.7, 128.0, 127.4, 85.9,
83.1, 75.4, 62.2, 60.1 5-RS(SR): 1H NMR (CDCl3, 400
MHz), d (ppm) 7.84 (2 H, d, J = 7.4 Hz), 7.52–7.36 (7 H, m),
7.33–7.28 (1 H, m), 5.41 (1 H, d, J = 8.1 Hz), 4.92 (1 H, s),
4.73 (1 H, d, J = 9.5 Hz), 4.70 (1 H, d, J = 9.5 Hz), 4.19 (1
H, d, J = 9.5 Hz), 4.18 (1 H, d, J = 8.8 Hz), 2.87 (1 H, d, J =
7.3 Hz). 13C NMR (CDCl3, 100 MHz), d 143.6, 134.6, 129.0,
128.9, 128.8, 128.6, 126.6, 87.2, 83.3, 72.8, 62.1, 61.5.
(8) Liguori, A.; Romeo, G.; Sindona, G.; Uccella, N. Chem. Ber.
1988, 121, 105.
Acknowledgment
Support of this research by the National Science Foundation (Career
Award CHE-9876389) is gratefully acknowledged.
References
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(6) Synthesis of 3a as an example of a general procedure for
Synlett 2003, No. 11, 1731–1733 ISSN 1234-567-89 © Thieme Stuttgart · New York