A versatile synthetic route to 1,5-dithiocins from o-mercapto aromatic aldehydes

Article abstract of DOI:10.1139/v98-230

An earlier procedure for the facile preparation of benzo-fused 1,5-dithiocins 2a-2c from o-mercaptobenzaldehydes has been improved and shown to be capable of extension to the preparation of several naphthalene-derived analogues. The general method also afforded several N-alkylated 1,5-dithiocins 4, 5 by replacing NH₃ with the appropriate primary amine. It was found that N-acylation of the 1,5-dithiocins was successful only with methyl chloroformate. Attempted N-phenylation met with limited success but was shown to be unnecessary since even the less reactive aniline readily undergoes the general reaction of primary amines. When simple α-amino acids, or their methyl esters, were employed as the primary amine in the reaction with o-mercaptobenzaldehyde, the formation of the N-alkylated 1,5-dithiocins 4a, 17a, 17b with accompanying loss of -COOH or -COOMe was observed, in preparatively useful yields. A mechanism is proposed for this interesting transformation.

Full text of DOI:10.1139/v98-230

113
A versatile synthetic route to 1,5-dithiocins from
o-mercapto aromatic aldehydes1
Ian W.J. Still, Rosanne Natividad-Preyra, and F. Dean Toste
Abstract: An earlier procedure for the facile preparation of benzo-fused 1,5-dithiocins 2a–2c from o-mercapto-
benzaldehydes has been improved and shown to be capable of extension to the preparation of several
naphthalene-derived analogues. The general method also afforded several N-alkylated 1,5-dithiocins 4, 5 by replacing
NH3 with the appropriate primary amine. It was found that N-acylation of the 1,5-dithiocins was successful only with
methyl chloroformate. Attempted N-phenylation met with limited success but was shown to be unnecessary since even
the less reactive aniline readily undergoes the general reaction of primary amines. When simple α-amino acids, or their
methyl esters, were employed as the primary amine in the reaction with o-mercaptobenzaldehyde, the formation of the
N-alkylated 1,5-dithiocins 4a, 17a, 17b with accompanying loss of -COOH or -COOMe was observed, in preparatively
useful yields. A mechanism is proposed for this interesting transformation.
Key words: 1,5-dithiocins, α-amino acids, N-acylation, decarboxylation.
Résumé : On a amélioré une méthode proposée antérieurement pour préparer facilement des benzo-1,5-dithiocines,
2a–2c, à partir des o-mercaptobenzaldéhydes et on a démontré qu’on peut l’étendre à la préparation de plusieurs
dérivés du naphtalène. La méthode générale permet aussi d’obtenir plusieurs 1,5-dithiocines N-alkylées (4, 5) en
remplaçant le NH3 par l’amine primaire appropriée. On a observé que la N-acylation des 1,5-dithiocines ne se fait
correctement qu’avec du chloroformiate de méthyle. Des essais en vue d’effectuer une N-phénylation ont conduit à des
résultats mitigés; toutefois, cette limitation ne présente pas de problèmes puisque l’on peut obtenir le même produit en
procédant à la réaction générale en présence d’aniline, même si celle-ci est moins réactive. Lorsqu’on utilise des acides
α-aminés simples ou leurs esters méthyliques comme amine primaire dans la réaction avec l’o-mercaptobenzaldéhyde,
on observe la formation des 1,5-dithiocines N-alkylées, 4a, 17a, 17b, avec des rendements préparativement utiles. On
propose un mécanisme pour cette transformation intéressante.
Mots clés : 1,5-dithiocines, acides α-aminés, N-acylation, décarboxylation.
[Traduit par la Rédaction] Still et al. 121
to their chiral properties (4, 5). We felt that it would be ad-
vantageous to prepare this type of compound containing a
readily functionalized group (such as a secondary amine) for
which a variety of derivatives could easily be produced. The
preparation of the racemic 6,12-imino-6H,12H-dibenzo[b,f]-
1,5-dithiocins 2a–2c, representing easily obtained examples
of such compounds, was reported earlier by us (6).
The preparation of the imino-bridged, 1,5-dithiocin ring
system was reported as early as 1958 (7) and that of the
dibenzo[b,f] analog 2b by Gol’dfarb et al. (8) in 1966. These
synthetic procedures, and the later serendipitous prepara-
tions of dibenzo[b,f]-1,5-dithiocins by Corrigan and West (9)
and, more recently, Brieaddy and Donaldson (10), were of
limited utility. Moreover, structural proof, notably the ab-
sence of NMR spectra in the earlier papers cited, was inade-
quate. Our previous work (6) was therefore important not
only in establishing the structure of 2b and its analogues by
X-ray analysis but also in making available a general syn-
thetic approach to such molecules.
Molecules possessing
a
structurally well-defined,
V-shaped molecular cleft have recently attracted consider-
able attention due to their application toward problems in
the areas of molecular recognition, self-assembly, and supra-
molecular chemistry (1, 2). Molecules possessing molecular
chirality in addition are of interest as potential chiral ligands
and solvating agents. Chiral molecules that lock two aro-
matic rings in almost perpendicular planes, such as Tröger’s
base 1 (3) are of special interest as DNA probes owing to
their different possible modes of interaction with DNA and
Received August 4, 1998.
I.W.J. Still,2 R. Natividad-Preyra, and F.D. Toste.
Department of Chemistry, University of Toronto at
Mississauga, 3359 Mississauga Road, Mississauga,
ON L5L 1C6, Canada.
1Taken in part from the M.Sc. thesis of R. Natividad,
University of Toronto, l997.
2Author to whom correspondence may be addressed.
Telephone: (905) 828-5354. Fax: (905) 828-5425.
e-mail: istill@credit.erin.utoronto.ca
We describe herein an improved experimental procedure
for the preparation of 2a–2c that also allows the facile prep-
aration of N-alkyl and N-aryl analogues of these molecules.
We also describe our attempts to prepare N-acyl analogues
and the ready extension of our methodology to several
Can. J. Chem. 77: 113–121 (1999)
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114
Can. J. Chem. Vol. 77, 1999
naphtho-fused analogues of 2a. Finally, the results of our at-
tempts to prepare chiral N-alkylated analogues of 2a directly
by utilizing natural α-amino acids or their methyl esters in
our general approach will be discussed.
the right balance between acid and base catalysis, which
seems to be crucial.
By modifying the reaction of 3a or 3b and replacing the
ammonium acetate with a mixture of primary amine and
acetic acid (1:4) we have been able to prepare the N-alkyl
analogues 4a–4c and 5a, 5b in excellent yields (83–91%).
Interestingly, 4a could also be obtained in the absence of
acetic acid but in a very much lower yield (27%).
It was felt that the creation of the naphtho-fused ana-
logues of these 1,5-dithiocins would provide molecules with
more pronounced clefts and potentially more interesting
solvating effects. We accordingly undertook the synthesis of
the three isomeric ortho-mercaptonaphthaldehydes 6–8.
Compound 6 was readily obtained from 1-naphthalenethiol,3
by our general procedure using N-formylpiperidine, in 43%
yield. It was found in the naphthalene series that a slightly
higher molar ratio of both the n-butyllithium and the
TMEDA complexing agent gave the best results (2.5 equiv.
of each, vs. 2.2 equiv. for the benzene analogues).
The benzo-fused 1,5-dithiocins 2a–2c were prepared, as
reported previously (6), starting from the appropriate thiol
and carrying out a selective ortho formylation via a doubly
lithiated (S,C-) intermediate. We have found that yields in
the formylation could be almost doubled (to 63–81%) if
N-formylpiperidine was used as the formylating agent, in
place of DMF. We have also discovered that the subsequent
cyclization step converting 3a–3c into 2a–2c is more conve-
niently achieved with NH4OAc in refluxing ethanol rather
than in nitromethane, presumably by the mechanism we had
previously outlined (6). The reaction was also attempted us-
ing other amonium salts (e.g., NH4Cl, NH4SCN) but, with
the exception of NH4HCO3, only the acetate seems to offer
R′
10
N
11S
HN
12
H3C
1
R
2
9
CH3
3
N
8
R
4
7
S
6
5
1
R′
2a R= R′= H
b R= CH3 , R′= H
c R= CH3 , R′= StBu
SH
R
S
NR
CHO
R′
S
4a R= CH2 CH2C6H5
b R= CH2 CH(CH3)2
c R= C(CH3)3
3a R= R′= H
b R= CH3 , R′ = H
c R = CH3, R′= StBu
d R= C6 H5
S
CH3
NR
CH3
S
5a R= CH2 CH2C6H5
b R= CH2 CH(CH3)2
SH
CHO
SH
SH
CHO
CHO
8
6
7
3 1-Naphthalenethiol is a relatively expensive reagent, which may be conveniently prepared, in 89% yield, by reduction of 1-naphtha-
lenesulfonyl chloride with tin and concentrated HCl (see experimental section).
© 1999 NRC Canada

Still et al.
115
Scheme 1.
CHO
CHO
t
OH
SSiMe2 Bu
TBAF, THF
(Ref. 14)
Tf2O
KSTBDMS
Pdº (PPh3 )4
(Ref. 13)
7
(Ref. 12)
9
10
Application of our general formylation procedure to the
isomeric 2-naphthalenethiol afforded the two isomeric alde-
hydes 7 and 8, in isolated yields of 45% and 30%, respec-
tively. That the major isomer was the (expected) result of
1-formylation of the naphthalene nucleus was confirmed by
an unambiguous synthesis of 7 from 2-hydroxy-1-naphthal-
dehyde 9 in 42% overall yield, by the three-step sequence
shown in Scheme 1 (11), slightly modified in Step 2 (see
Experimental).
With the necessary three naphthaldehydes in hand, we
were able to complete our synthesis of the three isomeric
naphtho-fused 1,5-dithiocins 11–13, from 6, 7, and 8, re-
spectively. The same experimental procedure was used as
for the benzo-fused analogues 2a–2c and excellent yields
(>90%) of these crystalline solids were obtained for all three
cases. Recently, Biehl et al. (15) reported the synthesis of
the 1,5-dioxocin 14a (analogous to 12) by the reaction of 9
with ammonium acetate, accompanied by a small amount of
the O-bridged derivative 14b. The mechanism proposed by
these authors for the formation of 14a is essentially identical
to that which we had earlier proposed (6), differing only in
the order of the steps involved.
Attempts have been made to introduce an N-acyl group
into these imino-bridge molecules. Using 4b as a representa-
tive example, we sought to introduce N-benzoyl and
N-propanoyl groups by reaction of 4b with benzoyl chloride
and propanoic acid–DCC, respectively, but failed to obtain
the amides in preparatively useful yields. When methyl
chloroformate was used, however, in refluxing acetone with
K2CO3 (or, better still, Cs2CO3 (16)) as the base, we ob-
S
S
NH
NH
S
S
11
12
S
NH
S
13
S
CH3
O
NR
X
CH3
S
O
15
R = CO2Me
14a X = NH
b X =
O
S
S
CH3
NR
S
NR
CH3
S
17a R = CH2CH2CH(CH3)2
b R = CH2CH2OH
16 R = CH(CH3)C6H5
c R = CHCH2CH(CH3)2
t
CO2 Bu
© 1999 NRC Canada

116
Can. J. Chem. Vol. 77, 1999
Scheme 2.
H
SH
COOH
SH NH
R
CHO
COOH
+
RCHNH2
R = CH2CH(CH3)2
3a
3a
H
O
SH R
C
COOH
SH NH
O
R
H+
S
O
H
N
S
18
SH
SH R
R
N
H
N
17a
S
S
20
19
tained the expected carbamate 15 in over 60% yield. Unlike
the starting imino analogue and its congeners, 15 shows the
two methine protons, in addition to the expected downfield
shift, as nonequivalent (δH = 6.74, 6.57), presumably due to
restricted bond rotation in the N—CO2Me bond.
We have also attempted to introduce an N-phenyl sub-
stituent in the 1,5-dithiocins. Using a procedure described by
Barton et al. (17) we first attempted this with 2a, using
Ph3Bi as phenylating agent, with Cu(OAc)2 as the catalyst.
The reaction mixtures obtained in various trials were com-
plex and in no case was more than 25% of the desired 4d
present. Accordingly, we reverted to our standard methodol-
ogy, using 3a, aniline, and a somewhat longer reflux period,
and were rewarded by obtaining the crystalline 4d in 75%
yield.
One potential application of our 1,5-dithiocins was in the
area of asymmetric base-catalyzed reactions. The early work
of Noyori and coworkers (18) established (–)-sparteine, a
readily available alkaloid, as a potential agent for enantio-
induction at carbanion centres and several recent reports
have made good use of this type of methodology (refs. 19
(for recent reviews) and 20). For our compounds to be use-
ful in this type of application, it will be necessary to prepare
enantiomerically pure 1,5-dithiocins. As one approach to this
problem we decided to investigate the use of enantiomeri-
cally pure amines in our general method since, in principle,
the diastereomeric dithiocins so obtained should be readily
separable.
Our first attempt along these lines employed R-1-phenyl-
ethylamine as the derivatizing amine, in a reaction with 3b.
Disappointingly, however, we were unable to achieve a com-
plete separation of the diastereomeric pair of dithiocins 16
so formed, under a variety of conditions. We next decided to
use one of the readily available, inexpensive, α-amino acids
to achieve our purpose. Reaction of 3a with L-leucine under
the usual conditions led, much to our surprise, to a
benzo-fused dithiocin which showed no evidence for
-COOH either in the IR or the proton NMR. The structure of
the product has been established as 17a, the
N-(3′-methylbutyl) analogue of the N-alkylated series,
formed here in 68% yield. When the reaction was repeated
using L-leucine methyl ester the same product was obtained.
Thus, formation of the N-alkylated 1,5-dithiocins in these re-
actions from α-amino acids or their methyl esters is accom-
panied by loss of the carboxylate moiety.
Confirmation that the structural assignment to the prod-
ucts of this new reaction was correct came from the reaction
of 3a with L-phenylalanine methyl ester. The product, ob-
tained in 63% yield, was identical in all respects with 4a,
obtained independently as described above. A further exam-
ple of this interesting reaction was shown by the formation
of the 2′-hydroxyethyl analogue 17b in 75% yield when 3a
was allowed to react with L-serine methyl ester under the
usual conditions.
We propose that this novel reaction may proceed by a
mechanism akin to the known enzymatic decarboxylation of
© 1999 NRC Canada

Still et al.
Table 1. Physical data and H NMR chemical shifts for 1,5-dithiocins 2, 4, 5, 11–13, 15.
117
1
δ
Compound
Yield (%)
Melting point (°C)
ϭNCH2 or ϭNH
Aromatic
ϭCH—S
2a
2b
2c
4a
4b
4c
4d
5a
5b
11
89
91
90
84
83
87
75
83
86
92
131–133
205–206
45–47
147–150
129–131
136–138
70–72
132–134
Oil
168–170
2.88
2.83
4.33
3.01
2.87, 2.48
—
—
2.94
2.83, 2.46
Not observed
7.28(2H), 7.04(6H)
7.08(2H), 6.91(4H)
7.15(4H)
5.73
5.67
5.66
5.45
5.38
5.87
6.15
4.92
5.31
6.05
7.24(2H), 7.05(6H)
7.25(2H), 7.00(6H)
7.28(2H), 6.69(6H)
7.32(4H), 7.13(4H)
7.04(2H), 6.88(4H)
7.05(2H), 6.89(4H)
7.95(4H), 7.78(2H)
7.75(2H), 7.53(2H),
7.44(2H)
12
13
15
94
96
67
160–163
170–172
143–146
Not observed
Not observed
—
7.83(4H), 7.62(4H)
7.48(2H), 7.02(2H)
7.76(4H), 7.62(4H)
7.38(4H)
6.45
6.03
7.18(2H), 6.93(4H)
6.74, 6.57
α-amino acids, catalyzed by pyridoxal phosphatase (21). The
key intermediate in our proposed mechanism for the reaction
with L-leucine (Scheme 2) is the initial iminium ion 18,
which, under the approximately neutral pH conditions em-
ployed, leads to decarboxylation and a second iminium spe-
cies 19, which undergoes a protropic rearrangement to the
more stable iminium ion 20 and is trapped by thiol (thiolate),
leading to the 1,5-dithiocin in the usual way. Since thiolate
ions are known to be excellent nucleophiles it is quite con-
ceivable that intramolecular demethylation could first occur
in the analogous reaction with the methyl ester, leading to
the same carboxylate species 18. Indirect support for this hy-
pothesis came from a preliminary reaction using L-leucine
tert-butyl ester, which should be stable to thiolate ion attack.
Gratifyingly, the N-alkylated dithiocin 17c, obtained in 71%
yield, showed no loss of the -COOtBu group. As expected,
signals for the diastereomeric methine protons in 17c were
diethyl ether were distilled from sodium – benzophenone
ketyl. Triethylamine and TMEDA were distilled from cal-
cium hydride prior to use. Alkyllithium solutions were ob-
tained from Fluka and were titrated regularly (22). Work-up
procedures involving the drying of organic extracts utilized
Na2SO4. Purification was initially carried out by (flash) col-
umn chromatography, using Merck 40–60 µm silica gel or
aluminum oxide and the appropriate solvent system (q.v.)
IR spectra were obtained as neat films or as KBr pellets,
1
as indicated, and data were recorded in cm–1. H NMR spec-
tra were recorded at 200 MHz in CDCl3, unless otherwise
stated. 13C NMR and DEPT spectra were run at 100.6 MHz.
High- and low-resolution mass spectra were obtained at 70 eV.
Elemental analyses were performed by the Guelph Chemical
Laboratories Ltd., Guelph, Ontario. Compounds for which
high-resolution mass measurements are given were homoge-
neous by TLC analysis and gave satisfactory 1H and (or) 13
NMR spectra indicative of their purity. H NMR data for
compounds 2a–2c, 4a–4d, 5a, 5b, 11, 12, 13, and 15 have
been collected in Table 1.
C
1
1
observable (δH = 5.78, 5.70) in the H NMR spectrum, indi-
cating a 70:30 ratio of the diastereomers. Further work is un-
der way to optimize this finding using the tert-butyl esters of
other natural amino acids. Effective separation of the pre-
sumably scalemic diastereomers is also a prerequisite for the
successful application of this approach.
2-Mercaptobenzaldehyde 3a
To a solution of thiophenol (2.00 mL, 19.47 mmol) in
45 mL of dry hexanes under argon, TMEDA (6.43 mL,
42.83 mmol) was added via addition funnel. The clear solu-
tion was stirred for 5 min and cooled to 0°C. The 2.2 M
n-BuLi (19.47 mL, 42.83 mmol) was added with a syringe
over a period of 20 min, giving the solution a yellow colour.
The mixture was stirred for an additional 0.5 h at 0°C,
warmed to room temperature, and stirred for 17 h. The re-
sulting solution turned white and became very thick in ap-
pearance. On cooling to 0°C, N-formylpiperidine (4.34 mL,
38.94 mmol) was slowly added, forming a red solution and
an orange pastelike precipitate. The reaction mixture was
stirred at 25°C for 18 h, then acidified with 1 M HCL (2 ×
25 mL), extracted with CH2Cl2 (4 × 25 mL), and washed
with saturated NaCl (25 mL). The solution was dried and
concentrated to afford a dark orange-brown oil (2.77 g,
Work is continuing in our attempts to prepare enantio-
merically pure examples of the 1,5-dithiocins from readily
accessible starting materials. We also plan to investigate the
solvating and metal-complexing properties of these interest-
ing molecules.
General information
For all anhydrous reactions, glassware was dried in the
oven overnight at 120°C prior to its use. All anhydrous reac-
tions were run under an argon atmosphere. DMF and
nitromethane were distilled from P2O5 and stored over 3Å
sieves. Methanol was distilled from magnesium turnings and
stored over activated 3Å sieves. Hexanes, THF, toluene, and
© 1999 NRC Canada

118
Can. J. Chem. Vol. 77, 1999
93%). Flash chromatography, eluting with CH2Cl2 (Rf =
0.35) afforded an oil (2.42 g, 81%). IR (film), ν: 3085, 2839,
2750, 1680, 1590, 1560, 850, 750; H NMR, δ: 10.25
(s, 1H), 7.89 (dd, 1H, J = 7.5, 1.6 Hz), 7.80 (dd, 1H, J = 7.8,
1.6 Hz), 7.50 (td, 1H, J = 7.8, 1.6 Hz), 7.39 (td, 1H, J = 7.5,
1.6 Hz), 5.49 (s, 1H).
2,8-Dimethyl-6,12-imino-6H,12H-dibenzo[b,f]-1,5-dithioci
n 2b
The same procedure as that used for the preparation of 2a
was employed. A white solid was obtained directly from the
reaction mixture (0.85 g, 91%), mp 205–206°C (lit. (6) mp
206–206.5°C). IR (KBr), ν: 3358, 3056, 2965, 1482, 796.
1
4,10-Bis(tert-butylthio)-2,8-dimethyl-6,12-imino-6H,12H-
dibenzo[b,f]-1,5-dithiocin 2c
The same procedure as that used for the preparation of 2a
was employed. A yellow solid was obtained from the reac-
tion mixture (0.05 g, 90%), mp 45–47°C (lit. (6) mp
44–46°C). IR (KBr), ν: 3054, 2920, 2874, 1493, 804, 737.
2-Mercapto-5-methylbenzaldehyde 3b
This aldehyde was prepared according to the same proce-
dure. A crude orange-brown oil (1.19 g, 88%) was obtained
from the solution. Flash chromatography, eluting with
CH2Cl2 (Rf = 0.39), afforded a yellow oil (1.01 g, 75%). IR
1
(film), ν: 3018, 2925, 2875, 2545, 1665, 815, 780; H NMR,
δ: 9.99 (s, 1H), 7.52 (d, 1H, J = 2.6 Hz), 7.19 (m, 2H), 5.31
(s, 1H), 2.37 (s, 3H).
N-(2′-Phenylethyl)-6,12-imino-6H,12H-dibenzo[b,f]-1,5-di
thiocin 4a
Method A
3-(tert-Butylthio)-2-mercapto-5-methylbenzaldehyde 3c
To a solution of p-thiocresol (0.30 g, 2.40 mmol) in
30 mL of dry hexanes under argon, TMEDA (0.80 mL,
5.32 mmol) was added via addition funnel. The clear solu-
tion was stirred for 5 min and was cooled to 0°C. The 1.6 M
n-BuLi (3.32 mL, 5.32 mmol) was added with a syringe,
over a period of 20 min, giving the solution a yellow colour.
The mixture was stirred for an additional 0.5 h at 0°C,
warmed to room temperature, and stirred for 17 h. The re-
sulting solution turned white and, was cooled to –10°C. Slow
addition of freshly distilled tert-butyl disulfide (0.74 mL,
3.84 mmol) turned the mixture red in colour and stirring was
continued for 16 h. The solution was washed with 1 M HCl
(2 × 20 mL), saturated NaCl (20 mL), dried, and evaporated
to afford a brown oil (0.38 g, 81%). Kugelrohr distillation
afforded 2-(tert-butylthio)-4-methylbenzenethiol (0.33 g, 70%),
bp 130–134°C/7 Torr (1 Torr = 133.3 Pa). IR (film), ν: 2961,
To a solution of thiosalicylaldehyde 3a (0.04 g, 0.28 mmol)
in absolute ethanol (10 mL), 0.5 mL of HOAc was added.
Addition of the phenethylamine (0.02 mL, 0.15 mmol) to the
above reaction vessel immediately turned the yellow solu-
tion orange in colour. The mixture was refluxed for 3.5 h,
quenched with H2O (5 mL), and extracted with CH2Cl2 (2 ×
10 mL). The organic layer was dried and concentrated to af-
ford a brown oil. Flash chromatography, eluting with
CH2Cl2–hexanes (4:1) (Rf = 0.52), yielded a light yellow
solid, (0.04 g, 84%), mp 147–150°C. IR (KBr), ν: 3116,
3032, 2996, 1625, 1487, 815. Exact Mass calcd. for
C22H19NS2: 361.0959; found: 361.0954. Anal. calcd. for
C22H19NS2: S 17.74; found: S 18.14.
Method B
A mixture of 3a (0.14 g, 1.03 mmol), L-phenylalanine
methyl ester hydrochloride (0.09 g, 0.57 mmol), and abso-
lute ethanol (15 mL) was refluxed for 2.5 h. The clear yel-
low solution was cooled to room temperature and the
solvent was evaporated to yield a yellow-brown oil. The oil
was dissolved in CH2Cl2 (15 mL) and the organic layer
washed with saturated NaHCO3 (15 mL). Drying and con-
centration afforded a white powdery solid (0.12 g, 63%).
Flash chromatography, eluting with CH2Cl2–hexanes (85:15)
(Rf = 0.57) gave white crystals (0.10 g, 51%), mp
149–151°C, identical in all respects with 4a prepared above.
1
2934, 2518, 818; H NMR, δ: 7.41 (d, 1H, J = 1.5 Hz), 7.29
(d, 1H, J = 7.8 Hz), 7.04 (dd, 1H, J = 7.8, 1.5 Hz), 4.77
(s, 1H), 2.33 (s, 3H), 1.39 (s, 9H).
The thiol so obtained (0.20 g, 0.94 mmol) was lithiated in
dry hexanes (20 mL) and TMEDA (0.33 mL, 2.17 mmol),
using 2.2 M n-BuLi (0.98 mL, 2.17 mmol) as in the general
procedure. The resulting orange mixture was treated with
N-formylpiperidine (0.21 mL, 1.88 mmol) at 25°C. The mix-
ture turned yellow and was stirred for 18 h. The solution
was washed with 1 M HCl (2 × 15 mL), saturated NaCl
(15 mL), dried, and concentrated to afford a brown oil (0.16 g,
74%). Flash chromatography, eluting with CH2Cl2 (Rf = 0.45),
yielded a yellow oil (0.13 g, 63%). IR (film), ν: 2960, 2925,
N-(Isobutyl)-6,12-imino-6H,12H-dibenzo[b,f]-1,5-dithioci
n 4b
To a solution of 3a (0.05 g, 0.35 mmol) in absolute etha-
nol (8 mL), 0.5 mL of HOAc was added. Addition of
isobutylamine (0.02 mL, 0.19 mmol) to the above reaction
vessel immediately turned the yellow solution orange in col-
our. Reaction was carried out as in Method A above and, af-
ter flash chromatography, eluting with CH2Cl2–hexanes
(4:1) (Rf = 0.52), gave 4b as a yellow solid (0.04 g, 83%),
mp 129–131°C. IR (film), ν: 3053, 2456, 1515, 1489, 792,
743. Exact Mass calcd. for C18H19NS2: 313.0958; found:
313.0956.
1
2893, 2480, 1684, 1672, 769; H NMR, δ: 10.05 (s, 1H),
7.63 (d, 1H, J = 1.6 Hz), 7.56 (d, 1H, J = 1.6 Hz), 6.98 (s,
1H), 2.15 (s, 3H), 1.33 (s, 9H).
6,12-Imino-6H,12H-dibenzo[b,f]-1,5-dithiocin 2a
The thiosalicylaldehyde 3a (0.90 g, 6.52 mmol) dissolved
in absolute ethanol (30 mL) was treated with ammonium ac-
etate (0.55 g, 7.17 mmol), the solution turning a yellow col-
our. The solution was refluxed for 3.5 h and cooled to room
temperature, resulting in the formation of a white precipi-
tate. Filtration and drying afforded a yield of (0.75 g, 89%),
mp 131–133°C (lit. (6) mp 130–132°C). IR (KBr), ν: 3334,
3115, 3005, 1595, 1499, 763.
N-(tert-Butyl)-6,12-imino-6H,12H-dibenzo[b,f]-1,5-dithioc
in 4c
To a solution of 3a (0.06 g, 0.40 mmol) in absolute etha-
nol (10 mL), 0.5 mL of HOAc and tert-butylamine
© 1999 NRC Canada

Still et al.
119
(0.02 mL, 0.22 mmol) were added. Reaction and work-up
procedure identical with those for 4a, 4b afforded, on flash
chromatography, eluting with CH2Cl2–hexanes (4:1) (Rf =
0.56), 4c as a yellow solid (0.04 g, 87%), mp 136–138°C. IR
(film), ν: 3322, 3057, 2970, 2924, 1695, 1589, 1463, 819.
Exact Mass calcd. for C18H19NS2: 313.0958; found:
313.0968.
piperidine (1.11 mL, 9.98 mmol) was added via syringe and
a dark red paste resulted. Vigorous stirring for 10 h formed a
yellow mixture, which was then washed with 1 M HCl (2 ×
25 mL) and extracted with CH2Cl2 (4 × 25 mL). Additional
washing with saturated NaCl (25 mL), drying, and concen-
tration yielded a brown oil (0.62 g, 56%). Chromatography
on aluminum oxide, eluting with CH2Cl2–MeOH (95:5) (Rf
= 0.45), gave a yellow oil (0.47 g, 43%), bp 139–142°C/7
Torr. IR (film), ν: 3050, 2924, 2864, 1682, 1495, 825, 753;
1H NMR, δ: 9.82 (s, 1H), 8.33 (m, 2H), 7.95 (m, 2H), 7.66
(m, 1H), 7.31 (m, 1H), 5.31 (s, 1H). Exact Mass calcd. for
C11H8OS: 188.0288; found: 188.0283.
N-Phenyl-6,12-imino-6H,12H-dibenzo[b,f]-1,5-dithiocin
4d
A mixture of 3a (0.23 g, 1.64 mmol), aniline (0.08 g,
0.90 mmol), acetic acid (0.5 mL), and absolute ethanol
(15 mL) was refluxed for 6.5 h. The clear yellow solution
was cooled to room temperature and the solvent was evapo-
rated to yield a brown oil (0.24 g, 87%). Flash chromatogra-
phy, eluting with CH2Cl2–hexanes (4:1) (Rf = 0.58), resulted
in a white solid (0.20 g, 75%), mp 70–72°C. IR (KBr), ν:
3075, 2961, 835; 13C NMR, δ: 147.1s, 133.3s, 130.3s,
129.5d, 128.6d, 128.0d, 127.9d, 125.0d, 123.0d, 119.5d,
61.1d. Exact Mass calcd. for C20H15NS2: 333.0645; found:
333.0651. Anal. calcd. for C20H15NS2: C 72.12, H 4.54, N
4.20, S 19.25; found: C 71.63, H 4.51, N 3.93, S 19.78.
2-Mercapto-1-naphthaldehyde 7 and
3-mercapto-2-naphthaldehyde 8
2-Naphthalenethiol (2.00 g, 12.48 mmol) was ground and
dissolved in dry hexanes (80 mL), under argon, and TMEDA
(4.69 mL, 31.20 mmol) was added to the mixture. The mix-
ture was cooled to 0°C and 1.6 M n-BuLi (19.50 mL,
31.20 mmol) was added dropwise. The solution initially
turned a cloudy white colour and eventully became yellow
and clear. The mixture was then stirred for 0.5 h at 0°C and
warmed to room temperature before stirring for an addi-
tional 16 h. N-Formylpiperidine (2.78 mL, 24.96 mmol) was
added via syringe and a dark red paste resulted. Vigorous
stirring for 10 h formed a yellow mixture, which was
washed with 1 M HCl (2 × 30 mL) and extracted with
CH2Cl2 (4 × 30 mL). Washing with saturated NaCl (30 mL),
drying, and concentration afforded a brown oil (1.76 g,
75%). Chromatography on aluminum oxide, eluting with
CH2Cl2–MeOH (95:5) (Rf = 0.64), resulted in compound 7
(0.70 g, 45%), mp 122–124°C. IR (film), ν: 2957, 2924,
2851, 2725, 2555, 1722,774; 1H NMR, δ: 11.03 (s, 1H), 8.66
(d, 1H, J = 7.5 Hz), 7.84 (d, 1H, J = 7.6 Hz), 7.63 (m, 1H),
7.48 (m, 1H), 7.34 (d, 1H, J = 7.5 Hz), 7.31 (d, 1H, J =
7.7 Hz), 4.85 (s, 1H). Exact Mass calcd. for C11H8OS:
188.0288; found: 188.0285.
N-(2′-Phenylethyl)-2,8-dimethyl-6,12-imino-6H,12H-dibe
nzo[b,f]-1,5-dithiocin 5a
The same procedure was used as in the formation of 4a. A
crude yellow oil was obtained (0.06 g, 96%). Flash chroma-
tography, eluting with CH2Cl2–hexanes (4:1) (Rf = 0.58),
yielded a beige solid (0.05 g, 83%), mp 132–134°C. Exact
Mass calcd. for C24H23NS2: 389.1272; found: 389.1263.
N-Isobutyl-2,8-dimethyl-6,12-imino-6H,12H-dibenzo[b,f]-
1,5-dithiocin 5b
The same procedure as for the formation of 4b was used.
Flash chromatography of the crude product, eluting with
CH2Cl2–hexanes (4:1) (Rf = 0.60), yielded a yellow oil
(0.06 g, 86%) bp 150–153°C/5 Torr. Exact Mass calcd. for
C20H23NS2: 341.1272; found: 341.1270.
An earlier fraction obtained on eluting with CH2Cl2 –MeOH
(95:5) (Rf = 0.33) resulted in 8 (0.47 g, 30%), mp
134–136°C. IR (film), ν: 2970, 2930, 2850, 2578, 1708,
1-Naphthalenethiol
1
1525, 734; H NMR, δ: 10.15 (s, 1H), 8.26 (s, 1H), 7.89
Concentrated hydrochloric acid (11.40 mL) was added to
crushed ice (30 g) in a round-bottom flask, with stirring.
1-Naphthalenesulfonyl chloride (1.00 g, 4.41 mmol) was
added portionwise via spatula, making sure that the solution
was kept below 0°C. Tin (6.30 g, 53.04 mmol) was added to
the vessel, turning the solution yellow. The mixture was
refluxed for 6 h and the solution became clear. The solution
was then extracted with CH2Cl2 (2 × 20 mL), washed with
saturated NaCl solution, dried, and concentrated to yield a
yellow oil (0.63 g, 89%), bp 138–140°C/7 Torr (lit. (23) bp
138–140°C/2 Torr).
(d, 1H, J = 3.9 Hz), 7.73 (m, 1H), 7.68 (m, 1H), 7.52
(d, 1H, J = 7.6 Hz), 7.45 (dd, 1H, J = 7.6, 3.8 Hz), 5.48
(s, 1H). Exact Mass calcd. for C11H8OS: 188.0288; found:
188.0281.
Synthesis of 7 by an alternative route, from
2-hydroxy-1-naphthaldehyde 9
A. 2-(tert-Butyldimethylsilylthio)-1-naphthaldehyde 10
To a solution of 2-hydroxy-1-naphthaldehyde (1.00 g,
5.81 mmol), in 16 mL of pyridine at 0°C, triflic anhydride
(1.09 mL, 6.45 mmol) was slowly added. Evolution of a
white gas occurred and the resulting mixture was stirred at
0°C for an additional 5 min. The mixture was then warmed
to room temperature and stirred for 24 h. Water (15 mL) was
added to the solution, which was extracted with diethyl ether
(2 × 15 mL), washed with H2O (15 mL), 10% aqueous HCl,
and then with saturated NaCl (15 mL). The organic layer
was dried and concentrated to obtain a brown, foamy solid
(1.32 g, 75%). Recrystallization from CH2Cl2–hexanes af-
1-Mercapto-2-naphthaldehyde 6
1-Naphthalenethiol (0.94 g, 5.87 mmol) was dissolved in
dry hexanes (50 mL) under argon, and TMEDA (2.20 mL,
14.67 mmol) was added to the mixture. The reaction was
cooled to 0°C and 1.6 M n-BuLi (9.17 mL, 14.67 mmol)
was added dropwise. The solution initially turned cloudy
white and eventually became yellow and clear. The mixture
was then stirred for 0.5 h at 0°C, then warmed to room tem-
perature before stirring for an additional 16 h. N-Formyl-
© 1999 NRC Canada

120
Can. J. Chem. Vol. 77, 1999
forded a beige solid (1.15 g, 65%). IR (KBr), ν: 3160, 2834,
2755, 1702, 1587, 856, 784; H NMR, δ: 10.81 (s, 1H),
8.45 (d, 1H, J = 6.3 Hz), 8.25–7.17 (m, 5H).
8,16-Imino-8H,16H-dinaphtho [1,2-b,f]-1,5-dithiocin 11
The same procedure outlined for compound 12 was used
for the formation of 11. Yellow crystals were obtained
(0.03 g, 92%) mp 168–170°C. IR (KBr), ν: 3033, 2953,
2846, 1529, 818. Exact Mass calcd. for C22H15NS2:
357.0646; found 357.0643.
1
Dry THF (25 mL) was saturated with H2S gas, and the re-
action vessel was then cooled to –78°C. The 1.6 M n-BuLi
(8.00 mL, 13.00 mmol) was added dropwise to the above so-
lution, which was allowed to warm to 0°C, with stirring for
0.5 h. The mixture was then recooled to –78°C and
TBDMS-Cl (1.68 g, 11.11 mmol) was added portionwise
with a spatula. The yellow mixture was warmed to room
temperature and was partitioned between pentane (50 mL)
and H2O (25 mL). The organic layer was extracted and
washed with H2O (20 mL), dried, and concentrated to afford
TBDMS-SH as a clear oil (83%). IR (film), ν: 2737, 2560;
1H NMR, δ: 0.97 (s, 9H),0.29 (s, 6H), 0.11 (s, 1H).
Potassium hydride (0.31 g, 7.69 mmol), was initially
washed with dry pentane (3 × 20 mL) and was placed in a
flask with 10 mL of pentane. The silanethiol above (1.13 g,
7.63 mmol) was added slowly to the reaction mixture at 0°C
and stirring was continued for 2 h. Solvent was removed and
a white solid was obtained (0.98 g, 69%). The salt was
recrystallized from toluene to yield white crystals of
TBDMS-SK (0.87 g, 61%).
8,16-Imino-8H,16H-dinaphtho [2,3-b,f]-1,5-dithiocin 13
The same procedure was used for the formation of 13.
Yellow crystals were obtained, recrystallized from methanol
(0.04 g, 96%), mp 170–172°C. IR (KBr), ν: 3197, 2953,
1590, 1495, 1492, 805. Exact Mass calcd. for C22H15NS2:
357.0646; found: 357.0640.
8,16-Imino-8H,16H-dinaphtho[2,1-b,f]-1,5-dioxocin 14a
A mixture of 2-hydroxy-1-naphthaldehyde (1.72 g,
10.00 mmol) and ammonium acetate in 15 mL of ethanol
was refluxed for 4.5 h, then cooled to room temperature.
The ethanol was partially evaporated and the yellow solid
was recrystallized to yield 14a (1.55 g, 95%), mp
241–243°C (lit. (15) mp 240–242°C). IR (KBr), ν: 3332,
1616, 955; 1H NMR, δ: 8.18 (d, 2H, J = 6.0 Hz), 7.72 (t, 4H,
J = 5.8 Hz), 7.59 (d, 2H, J = 6.0 Hz), 7.36 (d, 2H, J =
5.8 Hz), 7.05 (d, 2H, J = 5.8 Hz), 6.63 (d, 2H, J = 2.5 Hz),
3.00 (br s, 1H); 13C NMR, δ: 150.3s, 131.5s, 131.0d, 128.9s,
128.4d, 127.2d, 123.7d, 121.9d, 118.3d, 112.4s, 75.6d. Exact
Mass calcd. for C22H15NO2: 325.1101; found: 325.1093.
A solution of this salt (0.12 g, 0.66 mmol) in dry THF
(15 mL) was added to tetrakis(triphenylphosphine)palladium
(0) (0.06 g, 0.05 mmol) and the triflate obtained above
(0.20 g, 0.66 mmol) in toluene (20 mL). The brown solution
was refluxed for 5 h, after which it was partitioned between
H2O (25 mL) and ethyl acetate (25 mL). The organic layer
was washed with H2O (2 × 15 mL), dried, and concentrated
to afford a brown oil (0.14 g, 73%). Flash chromatography,
eluting with CH2Cl2 (Rf = 0.44), afforded 10 as a yellow oil
(0.10 g, 52%). IR (film), ν: 2990, 2946, 2856, 2725, 1722,
N-(Methoxycarbonyl)-2,8-dimethyl-6,12-imino-6H,12H-di
benzo[b,f]-1,5-dithiocin 15
The amine 2b (0.20 g, 0.70 mmol) was dissolved in ace-
tone (15 mL), then cesium carbonate (1.37 g, 4.20 mmol)
was added to the solution, which was stirred for 5 min. Slow
addition of methyl chloroformate (0.22 mL, 2.80 mmol) with
a syringe resulted in a red-coloured solution. The mixture
was refluxed for 16 h under argon. Removal of the Cs2CO3
by gravity filtration and evaporation of the acetone solution
yielded an orange oil. A solution of 4% NaOMe in methanol
was added to the oil and stirring was continued for 2 h. A
white precipitate was obtained (0.16 g, 67%), which was fil-
tered off and recrystallized from CH2Cl2–hexanes, mp
143–146°C. IR (KBr), ν: 3347, 2975, 2846, 1698, 1503, 731.
Exact Mass calcd. for C18H17NO2S2: 343.0700; found:
343.0702.
1
1597, 1517; H NMR, δ: 10.85 (s, 1H), 8.35 (d, 1H, J =
8.2 Hz), 7.98 (d, 1H, J = 7.1 Hz), 7.78 (dd, 1H, J = 8.1,
4.0 Hz), 7.60 (m, 1H), 7.41 (m, 1H), 7.17 (dd, 1H, J = 7.0,
3.9 Hz), 1.05 (s, 9H), 0.48 (s, 6H).
B. Deprotection of 10 to give 7
To a solution of the protected thiol 10 (0.53 g, 0.18 mmol)
in THF (10 mL) at 0°C, tetrabutylammonium fluoride (0.20 mL,
0.19 mmol) was added dropwise. The mixture was stirred
for 3 h, eventually turning a deep yellow colour. The reac-
tion mixture was washed with saturated NH4Cl (10 mL) and
extracted with CH2Cl2 (3 × 10 mL), dried, and concentrated
to afford a brown oil (0.30 g, 90%). Flash chromatography,
eluting with CH2Cl2 (Rf = 0.48), resulted in a yellow solid
(76% yield), mp 124–126°C. This product was identical
(mixture mp, IR, 1H NMR) with the 2-mercapto-1-naph-
thaldehyde 7 prepared as described above.
N-(1′-Phenylethyl)-2,8-dimethyl-6,12-imino-6H,12H-dibe
nzo[b,f]-1,5-dithiocin 16
To thiosalicylaldehyde 3b (0.11 g, 0.69 mmol) dissolved
in 20 mL of absolute ethanol and 1 mL of acetic acid, the
R-(+)-1-phenylethylamine (0.05 mL, 0.38 mmol) was added
dropwise. The solution turned an orange colour and was
then refluxed for 4.5 h. The mixture was washed with H2O
(10 mL), extracted with CH2Cl2 (3 × 15 mL), dried, and
concentrated to yield a brown oil (0.12 g, 86%). Flash chro-
matography, eluting with ethyl acetate – hexanes (1:1) (Rf =
0.57), gave a foamy beige solid (0.10 g, 77%), mp 81–83°C.
8,16-Imino-8H,16H-dinaphtho [2,1-b,f]-1,5-dithiocin 12
A mixture of the naphthaldehyde 7 (0.04 g, 0.20 mmol)
and ammonium acetate (0.02 g, 0.20 mmol) in absolute etha-
nol (15 mL) was refluxed for 3.5 h. The solution was cooled
and the ethanol was removed. The yellow solid was
recrystallized from methanol to give 12 (0.03 g, 94%), mp
160–163°C. IR (KBr), ν: 3356, 2952, 1583, 835, 806. Exact
Mass calcd. for C22H15NS2: 357.0646; found: 357.0647.
1
IR (KBr), ν: 3367, 2949, 1485; H NMR, δ: 7.39 (m, 4H),
6.92 (m, 7H), 5.53, 5.48 (2s, 2H), 4.17, 3.90 (2q, 1H, J =
7.8 Hz), 2.25 (s, 6H), 1.61, 1.55 (2d, 3H, J = 7.8 Hz); 13C
NMR, δ: 143.2s, 134.3s, 133.1s, 129.8d, 129.2d, 127.6d,
127.5d, 127.4s, 127.2d, 126.5d, 60.0d, 59.3d, 22.5q, 20.9q.
© 1999 NRC Canada

Still et al.
121
2. J. Rebek, Jr. Acc. Chem. Res. 23, 399 (1990).
Exact Mass calcd. for C24H23NS2: 389.1272; found:
389.1264.
3. (a) J. Tröger. J. Prakt. Chem. 36, 225 (1887); (b) M.A.
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N-(3′-Methylbutyl)-6,12-imino-6H,12H-dibenzo[b,f]-1,5-d
ithiocin 17a
A mixture of thiosalicylaldehyde 3a (0.12 g, 0.85 mmol),
L-leucine (0.06 g, 0.47 mmol), and absolute ethanol (30 mL)
was refluxed for 4.5 h. The clear yellow solution was cooled
to room temperature and the solvent was evaporated to yield
a yellow oil (0.09 g, 68%). Flash chromatography, eluting
with CH2Cl2 – hexanes (85:15) (Rf = 0.52), gave a yellow
oil (0.08 g, 60%). IR (film), ν: 3057, 2945, 2853, 830, 742;
1H NMR, δ: 7.28 (m, 2H), 7.0 (m, 6H), 5.41 (s, 2H), 2.98
(m, 1H), 1.62 (m, 4H), 0.91 (d, 6H, J = 7.5 Hz). Exact Mass
calcd. for C19H21NS2: 327.1115; found: 327.1112.
N-(2′-Hydroxyethyl)-6,12-imino-6H,12H-dibenzo[b,f]-1,5-
dithiocin 17b
A mixture of 3a (0.14 g, 1.03 mmol), L-serine methyl es-
ter hydrochloride (0.09 g, 0.57 mmol), and absolute ethanol
(15 mL) was refluxed for 4.5 h. The clear yellow solution
was cooled to room temperature and the solvent was evapo-
rated to yield a yellow-brown oil. This was dissolved in
CH2Cl2 (15 mL) and the organic layer was washed with sat-
urated NaHCO3 (15 mL), dried, and concentrated to afford a
yellow oil (0.14 g, 88%). Flash chromatography, eluting
with CH2Cl2–hexanes (85:15) (Rf = 0.57), gave white needle
crystals (0.11 g, 75%), mp 165–167°C. IR (film), ν : 3395,
1
2993, 1626, 1505, 806; H NMR, δ: 7.82 (dd, 4H, J = 7.8,
7.6 Hz), 7.32 (dt, 4H, J = 7.8, 7.7 Hz), 6.21 (s, 2H), 4.35 (m,
2H), 3.50 (m, 3H).
N-(1′-tert-Butyloxycarbonyl-3′-methylbutyl)-6,12-imino-6
H,12H-dibenzo[b,f]-1,5-dithiocin 17c
A mixture of 3a (0.22 g, 1.60 mmol), L-leucine tert-butyl
ester (0.19 g, 0.88 mmol), and absolute ethanol (15 mL) was
refluxed for 4.5 h. Work-up as for 17b, followed by flash
chromatography, eluting with CH2Cl2–hexanes (85:15) (Rf =
0.67), gave a yellow solid (0.24 g, 71%), mp 154–156°C. 1H
NMR, δ: 7.33 (m, 4H), 7.01 (m, 4H), 5.78, 5.70 (2s, 2H),
3.65 (t, 1H, J = 9.1 Hz), 1.82 (m, 1H), 1.64 (m, 2H), 1.20 (s,
9H), 0.90 (d, 6H, J = 9.4 Hz). Exact Mass calcd. for
C24H29NO2S2: 427.1639; found: 427.1644.
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Support of this work by a Natural Sciences and Engi-
neering Research Council of Canada research grant is grate-
fully acknowledged. One of us (F.D.T.) acknowledges the
award of an Ontario Graduate Scholarship.
1. (a) M. Harmata, C.L. Barnes, S.R. Karra, and S. Elahmad. J.
Am. Chem. Soc. 116, 8392 (1994); (b) S. Paliwal, S. Geib, and
C.S. Wilcox. J. Am. Chem. Soc. 116, 4497 (1994); (c) D. St.
C. Black, D.C. Craig, N. Kumar, and D.B. McConnell. Tetra-
hedron Lett. 37, 241 (1996); (d) K. Mitra and K.S. Gates. Tet-
rahedron Lett. 36, 1391 (1995); (e) B.G. Bag and U. Maitra.
Synth. Commun. 25, 1849 (1995).
TMEDA: N,N,N′,N′-tetramethylethylenediamine
TBAF: tetra-n-butylammonium fluoride
TBDMS: tert-butyldimethylsilyl
Tf:
Triflate: trifluoromethanesulfonate
DCC: dicyclohexylcarbodiimide
trifluoromethanesulfonyl
© 1999 NRC Canada