Stereochemistry and mechanistic insights in the [2t + 2i + 2i] annulations of thioketenes and imines

Article abstract of DOI:10.1039/c7ob02212c

Stereochemical models and mechanistic insights are proposed for [2^t + 2ⁱ + 2ⁱ] annulations of thioketenes and imines on the basis of experimental and computational investigations. In the [2^t + 2ⁱ + 2<

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Stereochemistry and mechanistic insights in the [2t + 2i + 2i]
annulations of thioketenes and imines
Wei He,†a Junpeng Zhuang,†a Hongguang Du,a Zhanhui Yang*a and Jiaxi Xu*a
Received 00th January 20xx,
Accepted 00th January 20xx
Stereochemical models and mechanistic insights are proposed for [2t + 2i + 2i] annulations of thioketenes and imines on
the basis of experimental and computational investigations. In the [2t + 2i + 2i] annulations involving cyclic imines, the
zwitterionic intermediates generated from monosubstituted thioketenes and the cyclic imine undergo a stepwise
nucleophilic endo-addition/Si-face attack pathway with a second imine molecule, giving initially (2,4)-cis-(4,5)-cis-[2t + 2i +
2i] annuladducts, which completely epimerize into the corresponding (2,4)-cis-(4,5)-trans-annuladducts under basic
reaction conditions. The annuloselectivity of thio-Staudinger cycloadditions is dependent on the substituents of both
thioketenes and imines. The reactivities and annuloselectivities of Staudinger, thio-Staudinger, and sulfa-Staudinger
intermediates are compared.
DOI: 10.1039/x0xx00000x
www.rsc.org/
imines,6,7 we now report the stereochemical and mechanistic
insights on the [2t + 2i + 2i] annulations, hoping to offer some
guidelines to chemists in organic and pharmaceutical fields.
Introduction
The annulation between thioketenes and imines is an important
route for constructing azacycles with thiolactam structural
motifs. However, the annulation can proceed via either [2t + 2i]
and
Annulations between thioketenes
imines
R2
R1
R2
R1
H
R2
R1
annulation between one
molecule
to produce four-membered β-thiolactams 3 1,2
+ 2i + 2i] annulation between one
hioketene molecule and two
mine molecules to yield six-membered 2,3,5,6-tetrahydro-
4(1H)-pyrimidinethione derivatives
(Scheme 1).1 Regarding
t
hioketene molecule
1
and one
i
mine
R3
R2
+
N
+
2
,
or [2t
C
H
N
N
R3
R3
S
S
1
N
R3
4
S
t
2
3
and
i
i
trans
[2t
cis
(±)-
(±)-
thioketene imine
+
2
4
]
i
i
[2t
]
+
+
2
2
the stereochemistry, the [2t + 2i] annulations generate two
stereocenters at C3 and C4 positions of the β-thiolactam ring.
The diastereoselectivity (cis- and trans-selectivity) has been well
studied by Schaumann’s,1 Sodo’s3 and our groups.4 Recently, we
proposed a practical model to explain and even to predict the
diastereoselectivity in the [2t + 2i] annulations by analysing the
steric difference of two thioketene-substituents.4 In [2t + 2i + 2i]
annulations, three stereocenters are generated at C2, C4, and
C5 positions of the 2,3,5,6-tetrahydro-4(1H)-pyrimidinethione
Two stereocenters
Well rationalized
Three stereocenters.
Not well studied.
Scheme 1. Annuloselectivity and stereochemistry in the
thioketene-imine annulations.
S
S
H
N
Cl
N
Cl
N
S
N
O
N
N
H
Antitumor
agents
Tuberculostatics
backbone (4, Scheme 1). However, their stereochemistry is
Figure 1. Representative bioactive structures with [2t + 2i + 2i]
annuladducts as backbones.
mysterious. The [2t + 2i + 2i] annuladducts are key structural
motifs in a variety of biologically active compounds (Fig. 1).5
Therefore, it is of significant importance to disclose their
stereochemistry, to shed light on the detailed mechanism, and
to propose a viable model to predict the stereochemistry. As an
extension of our mechanistic studies on the [2 + 2] and [2 + 2 +
2] annulations of heterocumulenes (ketenes and sulfenes) with
Results and discussion
Reactions of 3-aryl/alkyl-1,2,3-thiadiazoles and cyclic imine
The [2t + 2i + 2i] annuladducts contain three stereocenters
and show much more complex stereochemistry than the [2t + 2i]
annuladducts. Schaumann and co-workers observed the [2t + 2i
+ 2i] annuladducts several times when they reacted 3,4-
a. State Key Laboratory of Chemical Resource Engineering, Department of Organic
Chemistry, Faculty of Science, Beijing University of Chemical Technology, Beijing
100029, P. R. China. E-mail: zhyang@mail.buct.edu.cn (Z. Yang);
jxxu@mail.buct.edu.cn (J. X. Xu); Fax: +86 10 64435565
dihydroisoquiniline
(5) with thioketenes (1
),1 but their
stereochemistry was not assigned, and the mechanism was not
rationalized, either.1b,d,e In our previous studies on the ketene-
imine [2k + 2i + 2i] annulations6d,q and sulfene-imine [2s + 2i + 2i]
†These two authors contributed equally.
Electronic Supplementary Information (ESI) available: [Copies of 1H and 13C NMR,
spectra of products 3n, and 4a-m. NOE spectra of
4
, crystal data and structure of 4l
,
annulations,7b,d,e 3,4-dihydroisoquiniline (
5) was also found to
and computational details]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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3
favorably undergo the corresponding [2 + 2 + 2] annulations. while the C4 and C5 stereochemistry was decided by the J
View Article Online
Based on Schaumann’s1b,d,e and our previous work,4 we chose coupling constants between the adjacent protons [in general, J
DOI: 10.1039/C7OB02212C
3,4-dihydroisoquinoline (
different monosubstituted thioketenes
were generated in situ from 1,2,3-thiadiazoles
releasing a molecule of nitrogen under relatively simple 2i] annuladducts showed specific stereochemistry. For
conditions. arylthioketenes 1a 1e, regardless of the electron-donating (4a
and 4b) or electron-withdrawing groups (4d and 4e) on the aryl
5
) as a cyclic imine probe to react with = 0-4 Hz for the (4,5)-cis-products, J = 5-10 Hz for the (4,5)-trans-
. The thioketenes products]. The stereochemical results were further confirmed
through by the XRD analysis of product 4l (Fig. 2).§The obtained [2t + 2i +
1
1
6
-
Table 1. Substrate scope and stereochemistry in the [2t + 2i + 2i] rings, all the products possessed (2,4)-cis-(4,5)-trans-
annulationsa,b
configurations and were obtained in 26-52% yields. The
reaction of 4-trifluoromethylphenylthioketene (1f) only gave a
trace amount of [2t + 2i + 2i] annuladduct 4f, and its
N
]
R1
H
N
N
H
H
N
K
2CO3
R
S
5
stereochemistry was not determined. For alkylthioketenes 1g
1l including primary methyl, ethyl, pentyl, and
isobutylthioketenes 1g-j and secondary isopropyl and
cyclohexylthioketenes 1k,l), and electron-deficient
-
S
4
5
H
3
C
S
DMF,140 oC,3
6N1
R
[2t
i
i
h
+
+
2
2
2
H
(
)
6a-m
4a-m
1a-m
(
ethoxycarbonylthioketene (1m), the desired products were
isolated in 50-82% yields, and they all displayed the same (2,4)-
cis-(4,5)-trans-configurations. All the crude reaction mixtures
Me
6%
H
H
5%
H
H
H
H
N
Ph
6%
N
N
MeO
H
H
1
H
were submitted to H NMR analyses, and only (2,4)-cis-(4,5)-
N
S
4c
N
S
N
S
trans-products were observed in each of the reactions,
indicating excellent stereospecificity of the [2t + 2i + 2i]
annulations.
4a
,
52%
42%
,
4b
49%
,
F
3C
Cl
7%
I
H
H
N
H
H
N
H
H
N
7%
H
H
H
N
S
4f
N
S
N
S
trace
,
4e
46%
,
4d
26%
,
H
H
N
H
H
N
H
4%
H
N
4%
4%
Me
S
H
H
H
N
S
N
S
N
4g
53%
,
4h
4i
66%
,
70%
,
H
H
N
H
H
N
Figure 2. XRD structure of product 4l.
5%
H
H
4%
5%
N
H
H
3
H
N
S
One exception is the reaction of tert-butylthioketene (1n). In
this case, only [2t + 2i] annuladduct trans-3n was isolated in 69%
yield (Scheme 2).
N
S
N
S
4l
51%
,
4k
66%
,
4j
82%
,
H
H
N
N
K2CO3 DMF
,
H
H
5%
N
H
EtO2C
S
S
+
N
H
N
140 oC 3 h
C
N
H
S
5
S
1n
trans
69%
(±)-
3n
6n
4m
55%
,
Scheme 2. [2t + 2i] annulation between tert-butylthioketene (1n
and imine
)
aAll the reactions were performed on a 0.5-mmol scale. bIsolated yields
after column chromatography on silica gel.
5
.
Key intermediates in the [2t + 2i + 2i] annulations
The experimental results and stereochemical outcomes are
summarized in Table 1. The stereochemistry of the [2t + 2i + 2i]
annuladducts provides important clues to the mechanistic
rationale. The C2 and C4 stereochemistry was judged by the
NOE determination between the two protons on C2 and C4,
The [2t + 2i + 2i] annulations occur stepwise from thioketenes
1a-n and imine
5
(Scheme 3), and the intermediates are
. The exo addition of
proposed as zwitterionic intermediates
A
imine
5
to thioketenes 1a-n gives key intermediates A.4 When
R1 is the sterically bulky tert-butyl group, the corresponding
2 | J. Name., 2012, 00, 1-3
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t
intermediate An (R1 = Bu) conrotates directly to produce under basic conditions. Alternatively, when cyclic imine
5
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A
DOfI:r1o0m.103t9h/eC7OexBo022s1id2Ce
bicyclic trans-β-thiolactam trans-3n. Since cis-β-thiolactam cis- nucleophilically attacks intermediates
3n was not observed, the intermediate , which is conceivably through transition states TS1-exo, intermediates C-exo would
derived from isomerization of , could be eliminated in either be formed. They further undergo an intramolecular nucleophilic
[2t + 2i] or [2k + 2i + 2i] annulations. This has been demonstrated attack from the Re-face of the iminium moiety, giving rise to
in our recent work on the [2t + 2i] annulations.4 Similarly, in the (2,4)-trans-(4,5)-trans-annuladducts
. Thus, for the stepwise
B
A
8
Staudinger ketene-imine cycloaddition, the isomerization of the nucleophilic pathway, nucleophilic endo-addition/Si-face attack
enolate moiety does not occur.6 In most cases, probably pathway is possible.
because of the ring strain exerted by the cyclic iminium moiety
H
H
intermediates
Instead, intermediates
to yield (2,4)-cis-(4,5)-trans-[2t + 2i + 2i] annuladducts
4.
A
do not undergo conrotatory ring closure.
R1
N
A
react with a second molecule of imine
S
5
A
Nucleophilic
Nucleophilic
N
Diels-Alder
endo
-attack
exo
-attack
t +2i +
i
2
[2
]
H
N
H
H
N
conrotation
H
≠
≠
≠
H
≠
R1 tBu
=
N
S
S
Bn
N
N
3n
N
cis-
H
H
H
H
R1 tBu
=
H H
N
H
N
H
H
N
H
H
N
R1
R1
R1
R1
R1
H
N
H
H
H
N
R1
H
N
S
S
S
S
conrotation
5
exo
transition state
exo
exo
TS1-
endo
transition state
TS-
endo
TS1-
C
S
R1 tBu
=
TS-
endo
exo
S
attack
i
[2t
]
S
+
2
A
1a-n
trans-3n
i
t +2i +
N
2
[2
]
N
H
H
H
H
H
H
N
H
H
R1
H
N
H
R1
S
R1
S
R1
What is the detailed mechanism?
N
N
H
H
S
S
N
H
N
exo
H
N
C-
endo
R1
S
C-
Re-face
attack
H
Si-face
attack
Nucleophilic
attack
trans
trans-8
7
cis-
cis
(2,4)-
-(4,5)-
(2,4)- -(4,5)-
Not observed.
N
≠
Not observed.
≠
epimerization
4
trans-
cis
(2,4)- -(4,5)-
N
H
N
Scheme 3. Proposed key intermediates in the [2t + 2i + 2i]
annulations.
H
HH
H
R1
H
R1
H
H
N
R1
S
N
S
N
H
S
TS2-Re
TS2-Si
N
Proposed mechanisms and theoretical calculations for the [2t
+ 2i + 2i] annulations
4
trans-
cis
(2,4)- -(4,5)-
Scheme 4. Proposed mechanisms for the [2t + 2i + 2i]
annulations.
For the products 4a-4m listed in Table 1, two plausible
mechanistic and stereochemical explanations are depicted in
Scheme 4. The first explanation, an aza-Diels-Alder
cycloaddition mechanism, is based on our previous mechanistic
studies on the [2k + 2i + 2i] annulations of ketenes and imines.6q
To distinguish the mechanism for the formation of products
4,
theoretical calculations on the proposed possible
In
intermediates
endo-[4+2] cycloadditions with imine
cis-[2t + 2i + 2i] cycloadducts
, which would be converted to
(2,4)-trans-(4,5)-cis-annuladducts by epimerization at the C5
position (acidic -hydrogen of the thiocarbonyl group) under
basic conditions. However, concerted exo-[4+2] cycloadditions
might give (2,4)-trans-(4,5)-trans-cycloadducts , which could
not epimerize to (2,4)-cis-(4,5)-trans- at the C2 position. Thus,
endo-cycloaddition/C5-isomerization pathway is possible if
an
endo-cycloaddition/C5-isomerization
were envisioned to directly undergo concerted
to deliver (2,4)-cis-(4,5)-
pathway,
mechanisms were conducted at M06-2x/6-
A
311++g(d,p)//B3LYP/6-31g(d) level of theory. In the DFT
calculations of selected reactions, the transition states for both
endo- and exo-hetero-Diels-Alder processes cannot be found
(see ESI). Thus, the hetero-Diels-Alder cycloaddition proposals
might not be the most reasonable.
5
7
4
α
After excluding the hetero-Diels-Alder (HDA) cycloaddition
mechanisms, we turned our attention to the stepwise processes
8
4
between intermediates
A and imine 5 (Scheme 5). The
theoretical calculations on the stepwise processes were also
conducted. All the transition states of the endo-addition/Si-
attack and exo-addition/Re-attack pathways are located. All the
energies of transition states (TS1-endo) in the endo-addition/Si-
attack pathway are lower than the corresponding ones (TS1-exo
in the exo-addition/Re-attack, strongly supporting that the
endo-addition/Si-attack pathway is greatly favored over the
exo-addition/Re-attack one. In other words, only the endo-
addition/Si-attack pathway is preferred in the [2t + 2i + 2i]
intermediates
cycloaddition.
A and imine 5 undergo aza-Diels-Alder
The second possibility is a stepwise nucleophilic process.
Cyclic imine nucleophilically attacks intermediates from the
endo side through transition states TS1-endo, generating
intermediates C-endo The enethiolate of C-endo
intramolecularly attacks the iminium moiety from its Si-face,
affording (2,4)-cis-(4,5)-cis-annuladducts . (2,4)-cis-(4,5)-cis-
Annuladducts epimerize into (2,4)-cis-(4,5)-trans-products
5
A
)
.
7
7
4
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annulations. Our calculations also demonstrate that the intermediates for both endo-addition/Si-attacVkiewaAnrtidcle Oenxlione-
DOI: 10.1039/C7OB02212C
complete epimerization of (2,4)-cis-(4,5)-cis-
(4,5)-cis-
much lower than those of the former (Table 2).
By taking the reaction of intermediate Ag and imine
7
to (2,4)-trans- addition/Re-attack pathways are presented in Figure 2. The
4
is reliable, because the energies of the latter are activation energy of TS1-endo-g is 7.4 kcal/mol, while that of
the TS1-exo-g is 10.5 kcal/mol..
5
as an
example (Table 2, entry 2), the calculated transition states and
≠
≠
Si-face
attack
H
H
N
H
H
N
H
S
R1
S
R1
S
epimerization
K2CO3
H
R1
H
H
S
N
N
N
H
H
S
H
H
H
endo
-addition
N
N
N
N
R1
N
R1
5
H
H
-
H
R1
H
N
TS2-Si
endo
C-
endo
7
cis cis-
(±)-(2,4)- -(4,5)-
cis
TS1-
H
(±)-(2,4)-
4
trans-
(4,5)-
≠
≠
S
5
A
Re
attack
-face
H
H
N
R1
H
N
H
R1
S
exo
-addition
N
N
H
S
S
H
N
H
H
N
H
N
N
R1
R1
S
H
H
exo
exo
trans
trans-8
-(4,5)-
C-
TS1-
(±)-(2,4)-
TS2-Re
Scheme 5. Proposed stepwise mechanisms and stereochemical explanations for the [2t + 2i + 2i] annulations.
Table 2. Calculated Gibbs free energy change at 298 K (ΔG, in kcal/mol) at M06-2x/6-311++g(d,p)//B3LYP/6-31g(d) level of theory.
Entry
1
A
TS1-endo C-endo
TS2-Si
3.4
6.6
5.8
2.8
7
4
TS1-exo
9.64
10.5
10.4
8.2
C-exo TS2-Re
8
1
2
3
4
5
1c
1g
1k
1m
1n
Ac
Ag
Ak
Am
An
6.9
7.4
7.2
4.4
7.0
-17.4
-20.3
-20.0
-20.2
-18.6
-27.9
-31.7
-23.8
-33.0
-16.5
-32.9
-35.9
-33.5
-35.9
-29.9
-11.4
-13.5
-13.5
-12.3
-12.2
18.2
18.1
17.3
15.7
18.8
-17.0
-22.7
-14.3
-23.6
-10.3
7.8
10.3
∆
G gas
298K
kcal/mol
TS2-Re-g
exo-g
TS1-
TS1-endo-g
18.1
TS2-Si-g
6.6
10.5
7.4
0.0
0.0
-13.5
4g
trans-
cis
(2,4)- -(4,5)-
H
H
Me
N
-20.3
-22.7
S
-31.7
Ag
+
-35.9
exo-g
C-
N
8g
trans-
trans
(2,4)-
-(4,5)-
5
C-endo-g
7g
cis-
cis
(2,4)- -(4,5)-
exo
endo
addition
addition
Figure 2. The calculated energy surfaces for the reaction of thioketene Ag with imine
5 at the M06-2x/6-311++g(d,p)//B3LYP/6-
31g(d) level of theory using the gas phased optimized structures.
exo-Intermediates are usually expected to have a lower intermediates show higher energies than their corresponding
energy than the endo-ones, but the results of calculation given endo-counterparts. We believe that the sulfur atom of the
in Table 2 and Figure 1 show this is not the case. All the exo- thioxo group must play an important role. Our calculations
4 | J. Name., 2012, 00, 1-3
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reveal that there is a weak but favorable interaction between with imines are compared. The results are listed in Figure 3. All
View Article Online
DOI: 10.1039/C7OB02212C
the electron-rich enethiolate and the iminium ion within both three intermediates can undergo conrotatory ring closures to
intermediates C-endo and C-exo. For example, the distances give the corresponding four-membered products β-lactams, β-
between the sulfur and iminium within intermediates C-endo-g and thiolactams, and β-sultams, respectively.4,6,7 Regarding
C-exo-g are 1.93Å and 1.95 Å (see Figure 2 or supplementary reactions with imines, the thio-Staudinger and sulfa-Staudinger
information), respectively. Due to the weak interaction, the C-endo intermediates only take part in the stepwise nucleophilic [4+2]
intermediates exist in chair conformation, while the C-exo ones annulations.7b,d,e The Staudinger intermediates predominantly
in twist boat conformation. As a result, the intermediates C-endo undergo hetero-Diels-Alder cycloadditions, but in some special
are more stable than C-exo.
cases, the stepwise [4+2] annulations seem to be more
reasonable to explain the stereochemical outcomes.6q
Substituent-dependent annuloselectivity of thio-
Staudinger cycloadditions
Staudinger
intermediates
thio-Staudinger
intermediates
sulfa-Staudinger
intermediates
Based on previous1,2 and present work, the annuloselectivity
of the thio-Staudinger cycloadditions is summarized in Table 3.
Obviously, the annuloselectivity is dependent on the
substituents of both thioketenes and imines. The reactions of
monosubstituted alkylthioketenes, of which the substituent can
be primary, secondary, and tertiary alkyl groups, with N-alkyl
linear imines, follow the [2t + 2i] pathways (Entries 1-3, Table 3),
while the arylthioketenes give no reaction with linear imines
(Entry 4, Table 3). A variety of disubstituted thioketenes readily
react with N-alkyl linear imines to yield [2t + 2i] annuladducts
(Entry 5, Table 3). In the [2t + 2i] annulations, disubstituted
thioketenes show better reactivity than the monosubstituted
ones. However, the [2t + 2i] annulations between N-aryl linear
imines and thioketenes do not occur.
H
H
H
R1
H
R1
H
R1
H
R
R
R
N+
O
N+
N+
-O
-S
S
-O
R2
R2
R2
Conrotatory
ring closure
Yes
Yes
Yes
No
Yes
No
HDA
[4+2]
with imines
Yes a
stepwise [4+2]
with imines
Yes
Yes
a
cases.
in
Only
special
Figure 3. Reactivities of Staudinger, thio-Staudinger, and sulfa-
Staudinger intermediates.
Table 3. Substituent-dependent annuloselectivity of thio-
Staudinger cycloadditions
Conclusions
Thioketenes
1o alkyl
entry
1
imines
Cyclic
Linear imines
entry
[2t
[2t
[2t
]
i
[2t
+
]
]
i
i
i
+
2
By using cyclic imines as the probes, the stereochemistry and
mechanism for the [2t + 2i + 2i] annulations are experimentally
elucidated, and further supported by theoretical computations.
The zwitterionic intermediates generated from thioketenes and
imines undergo a stepwise nucleophilic endo-addition/Si-attack
pathway with a second molecule of imines, giving (2,4)-cis-(4,5)-
cis-[2t + 2i + 2i] annuladducts, which completely epimerize into
(2,4)-cis-(4,5)-trans-annuladducts in the presence of bases. The
annuloselectivity of the thio-Staudinger cycloadditions depends
on the substituents of thioketenes and imines. Generally, when
reacting with N-alkyl linear imines, monoalkyl and disubstituted
thioketenes prefer [2t + 2i] pathways, However, when reacting
with cyclic imines, except for tert-alkylthioketenes that favour
[2t + 2i] pathway, they prefer [2t + 2i + 2i] pathways. The
reactivities of Staudinger, thio-Staudinger, and sulfa-Staudinger
+
2
2
2
2
6
7
8
9
R
H
2o alkyl
+
+
+
+
i
i
2
2
3
4
]
[2t
3o alkyl
2
2
C
S
i
i
+
2
]
[2t
+
]
[2t
]
i
i
aryl
+
N. R.
2
R1 R2
[2t
&
]
i
i
+
+
2
2
i
R1 R2
H
≠
5
+
10
2
]
,
C
S
[2t
t
i
+
2
[2
]
=
N. R. No Reaction.
When reacting with cyclic imines, for example, 3,4-
dihydroisoquinoline (5), the monosubstituted thioketenes with
primary, secondary, and aryl groups all prefer [2k + 2i + 2i]
annulations (Entries 6, 7 and 9, Table 3), while only the
thioketenes with tertiary alkyl groups undergo [2t + 2i]
annulations (Entry 8, Table 3). Reactions between disubstituted intermediates are also compared. All three intermediates can
thioketenes and cyclic imines follow both [2t + 2i] and [2k + 2i +
undergo conrotatory ring closures to generate four-membered
ring products. When reacting with cyclic imines, the Staudinger
2i] pathways (Entry 10, Table 3).
intermediates prefer the hetero-Diels-Alder cycloadditions,
while the thio- and sulfa-Staudinger intermediates favour
stepwise nucleophilic additions.
Reactivities of Staudinger, thio-Staudinger, and sulfa-
Staudinger intermediates
The zwitterionic intermediates in the thio-Staudinger
cycloadditions (thio-Staudinger intermediates) are structurally
analogous to those in Staudinger cycloadditions (Staudinger
intermediates) and those in sulfa-Staudinger cycloadditions
(Sulfa-Staudinger intermediates). Their reactivities toward
conrotatory ring closure and [4+2] annulations/cycloadditions
Experimental
General Information
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N,N-Dimethylformamide was dried over magnesium sulfate 4-Pentyl-1,2,3-thiadiazole (6j)
View Article Online
overnight, and was freshly distilled at vacuum prior to use. Reddish-brown sticky oil. Yield: 370 mg, D1O6I%: 1.0R.1f0=390/C.57O(PBE02:E2A12C=
Melting points were obtained on a Yanaco MP-500 melting 10:1, v/v). 1H NMR (400 MHz, Chloroform-d) δ 8.15 (s, 1H), 3.14
1
point apparatus and are uncorrected. H and 13C NMR spectra (t, J = 7.7 Hz, 2H), 1.87 – 1.76 (m, 2H), 1.40 – 1.32 (m, 4H), 0.89
were recorded on a Bruker 400 MHz spectrometer in CDCl3 with (t, J = 6.4 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 164.3,
TMS as an internal standard and the chemical shifts (δ) are 131.2, 31.4, 29.4, 28.3, 22.5, 14.1. IR (film, KBr) v cm-1 3101,
reported in parts permillion (ppm). The one-dimention selected 2956, 2929, 2858, 1488, 1465, 1380, 1265, 1226, 1180, 1143,
NOE experiments were conducted on a Bruker 600 MHz 1076, 982, 886, 808, 781, 737, 704. ESI-HRMS [M + H]+ calcd for
spectrometer. The IR spectra (KBr pellets, v [cm-1]) were taken C7H13N2S+ m/z: 157.0794, found 157.0791.
on a Nicolet 370 FTIR spectrometer. HRMS measurements were
carried out on an Agilent LC/MS TOF mass spectrometer. TLC 4-Cyclohexyl-1,2,3-thiadiazole (6l)
o
analyses were performed on silica gel plates, and the plates White solid, mp. 52–54 C. Yield: 1.29 g, 51%. Rf = 0.6 (PE:EA =
were visualized with UV light. PE is the abbreviation for 10:1, v/v). 1H NMR (400 MHz, Chloroform-d) δ 8.12 (s, 1H), 3.26
petroleum ether (60
−
90 oC), and EA for ethyl acetate.
– 3.16 (m, 1H), 2.19 – 2.09 (m, 2H), 1.89 – 1.80 (m, 2H), 1.79 –
1.71 (m, 1H), 1.62 – 1.37 (m, 4H), 1.35 – 1.21 (m, 1H). 13C NMR
(101 MHz, Chloroform-d) δ 169.6, 129.8, 38.1, 33.5, 26.3, 26.0.
Theoretical calculation procedure
Theoretical calculations on the proposed possible mechanisms IR (film, KBr) v cm-1 3087, 2923, 2853, 1448, 1231, 1214, 1018,
were conducted by using Gaussian 09 D.01 program package. 973, 890, 830, 576. ESI-HRMS [M + H]+ calcd for C8H13N2S+ m/z:
The optimization of the minima and transition states were 169.0794, found 169.0794.
performed at M06-2x/6-311++g(d,p)//B3LYP/6-31g(d) level.
Frequency calculations were carried out on the optimized General Experimental Procedure for the [2t + 2i] and
structures at the same level of theory to verify if real minima or [2t + 2i + 2i] Annulations
transition states were obtained, and to produce zero-point
To a 15-mL heavy-wall reaction tube was sequentially added a
energies. Intrinsic reaction coordinate (IRC) calculations were
1,2,3-thiadiazole
6 (0.5 mmol), cyclic imine 5 (65.5 mg, 0.5
performed at the same level of theory to confirm that the
calculated transition states connect to the correct reactants and
products.
mmol), potassium carbonate (69 mg, 0.5 mmol), and dry DMF
(1.5 mL). The tube was immersed into a preheated oil-bath at
140 oC, and heated for 3 h. Upon cooling to room temperature,
the reaction mixture was diluted with ethyl acetate (10 mL) and
washed with brine (20 mL x 3). The organic phase was dried over
anhydrous sodium sulfate and concentrated under reduced
pressure. The residue was submitted to chromatography on
silica gel with PE and EA as eluent to afford pure [2t + 2i + 2i] and
General Experimental Procedure for the Syntheses of 1,2,3-
thiadiazoles (6a-n).
1,2,3-Thiadiazoles were prepared according to Mori’s and
Fujita’s procedures.12 To a 50-mL flask was sequentially added
ethyl hydrazinecarboxylate (1.56 g, 15 mmol, for 10a-h, 10m,
[2t + 2i] annuladducts
3 and 4, respectively.
10n) or p-toluenesulfonyl hydrazide (1.56 g, 15 mmol, for 10j-l),
ethanol (10 mL), ketones (15 mmol), and acetic acid (0.2 mL).
The resultant solution was refluxed for 3 h. Upon cooling to
room temperature, removal of ethanol gave white solids, which
were directly dissolved in 1,2-dichloroethane (20 mL), followed
by dropwise addition of thionyl chloride (5 mL). The resultant
solution was stirred at room temperature for 24 h. Washing
with saturated NaHCO3 solution (10 mL), drying over Na2SO4,
removal of the solvent under vacuum, and purification by
rel(4bR,5S,13bS)-5-(3-Methoxyphenyl)-4b,5,9,13b,15,16-
hexahydro-6H,8H-pyrimido[2,1-a:4,3-a']diisoquinoline-6-
thione (4a)
o
Colorless crystals, mp. 227–229 C. Yield: 55 mg, 52%. Rf = 0.4
(PE:EA = 10:1, v/v). 1H NMR (400 MHz, Chloroform-d) δ 7.59 (dd,
J = 5.6, 3.5 Hz, 1H), 7.37 – 7.24 (m, 4H), 7.20 – 7.10 (m, 2H), 7.02
– 6.93 (m, 1H), 6.91 – 6.83 (m, 2H), 6.80 – 6.76 (m, 1H), 6.40 (d,
J = 7.7 Hz, 1H), 6.15 (s, 1H), 5.42 – 5.11 (m, 1H), 4.75 (d, J = 9.3
Hz, 1H), 4.40 (d, J = 9.3 Hz, 1H), 3.92 (ddd, J = 13.2, 9.5, 3.5 Hz,
1H), 3.82 (s, 3H), 3.11 (ddd, J = 13.4, 9.5, 4.7 Hz, 1H), 3.05 – 2.89
(m, 2H), 2.78 – 2.62 (m, 3H). 13C NMR (101 MHz, Chloroform-d)
δ 201.0, 159.9, 144.4, 137.1, 136.5, 133.0, 132.3, 130.1, 129.2,
128.3, 127.7, 127.5, 127.5, 127.3, 125.5, 121.8, 115.7, 112.2,
77.7, 65.2, 60.5, 55.4, 48.0, 37.4, 28.7, 28.6. IR (film, KBr) v cm-1
2924, 2836, 1651, 1600, 1584, 1488, 1470, 1464, 1454, 1435,
1385, 1314, 1284, 1188, 1152, 1082, 1043, 908, 754, 728, 692.
ESI-HRMS [M + Na]+ calcd for C27H26N2NaOS+ m/z 449.1658,
found 449.1659.
chromatography on silica gel afforded 1,2,3-thiadiazoles
6.
Most of the products are known compounds and the analytical
data of known 1,2,3-thiadiazoles 6a-c,e-i,k,m,n are identical to
those reported.12
4-(4-Iodophenyl)-1,2,3-thiadiazole (6d)
White solid, mp. 174–176 oC. Yield: 3.02 g, 70%. Rf = 0.4 (PE:EA
1
= 10:1, v/v). H NMR (400 MHz, Chloroform-d) δ 8.66 (s, 1H),
7.85 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 8.5 Hz, 2H). 13C NMR (101
MHz, Chloroform-d) δ 162.0, 138.4, 130.4, 130.4, 129.1, 95.5. IR
(film, KBr) v cm-1 3088, 2954, 2920, 2849, 1655, 1648, 1638,
1561, 1508, 1459, 1450, 1398, 1377, 1261, 1223, 1184, 1105,
1060, 1042, 933, 896, 829, 801, 735. ESI-HRMS [M + H]+ calcd
for C8H6IN2S+ m/z: 288.9291, found 288.9291.
rel(4bR,5S,13bS)-5-(4-Methylphenyl)-4b,5,9,13b,15,16-
hexahydro-6H,8H-pyrimido[2,1-a:4,3-a']diisoquinoline-6-
thione (4b)
6 | J. Name., 2012, 00, 1-3
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o
Colorless crystals, mp. 231–233 C. Yield: 50 mg, 49%. Rf = 0.3 (s, 1H), 5.35 – 5.17 (m, 1H), 4.63 (d, J = 9.5 Hz, 1H), 4.30 (d, J =
View Article Online
1
(PE:EA = 10:1, v/v). H NMR (400 MHz, Chloroform-d) δ 7.62 – 9.5 Hz, 1H), 3.75 (ddd, J = 13.2, 9.8, 3.4 DHOz,I:110H.1),0339.0/C37O(dBd0d22,1J2C=
7.53 (m, 1H), 7.36 – 7.29 (m, 2H), 7.27 – 7.08 (m, 7H), 6.99 – 15.9, 9.7, 3.9 Hz, 1H), 2.97 – 2.80 (m, 2H), 2.73 – 2.54 (m, 3H).
6.92 (m, 1H), 6.36 (d, J = 7.8 Hz, 1H), 6.15 (s, 1H), 5.28 (ddd, J = 13C NMR (101 MHz, Chloroform-d) δ 200.5, 141.5, 137.1, 136.0,
13.1, 4.8, 3.8 Hz, 1H), 4.74 (d, J = 9.4 Hz, 1H), 4.36 (d, J = 9.4 Hz, 133.2, 133.1, 132.2, 130.8, 129.4, 129.2, 128.4, 127.6, 127.5,
1H), 3.89 (ddd, J = 13.1, 9.5, 3.4 Hz, 1H), 3.10 (ddd, J = 13.9, 9.7, 127.4, 127.3, 125.5, 77.9, 65.0, 59.4, 47.9, 37.3, 28.6, 28.5. IR
3.8 Hz, 1H), 3.04 – 2.87 (m, 2H), 2.81 – 2.58 (m, 3H), 2.38 (s, 3H). (film, KBr) v cm-1 3024, 2925, 2852, 1655, 1604, 1489, 1473,
13C NMR (101 MHz, Chloroform-d) δ 201.5, 140.0, 137.2, 136.9, 1438, 1384, 1352, 1338, 1305, 1285, 1226, 1180, 1151, 1131,
136.6, 133.0, 132.4, 129.8, 129.3, 129.2, 128.3, 127.7, 127.5, 1089, 1042, 1014, 910, 828, 791, 748, 640. ESI-HRMS [M + H]+
127.2, 125.5, 77.7, 65.1, 60.0, 48.0, 37.4, 28.7, 28.6, 21.4. IR calcd for C26H24ClN2S+ m/z: 431.1343, found 431.1346.
(film, KBr) v cm-1 3021, 2922, 2852, 1643, 1511, 1471, 1436,
1338, 1306, 1285, 1181, 1151, 1130, 1085, 1043, 912, 844, 789, rel(4bR,5S,13bS)-5-Methyl-4b,5,9,13b,15,16-hexahydro-
747, 646. ESI-HRMS [M + H]+ calcd for C27H27N2S+ m/z: 411.1889, 6H,8H-pyrimido[2,1-a:4,3-a']diisoquinoline-6-thione (4g)
found 411.1883.
Colorless crystals, mp. 160 oC. Yield: 44 mg, 53%. Rf = 0.5 (PE:EA
= 10:1, v/v). 1H NMR (400 MHz, Chloroform-d) δ 7.57 (dd, J = 5.7,
3.5 Hz, 1H), 7.34 – 7.27 (m, 2H), 7.28 – 7.15 (m, 4H), 7.14 – 7.06
(m, 1H), 5.72 (s, 1H), 4.82 (ddd, J = 13.2, 7.1, 3.9 Hz, 1H), 4.26 (d,
rel(4bR,5S,13bS)-5-Phenyl-4b,5,9,13b,15,16-hexahydro-
6H,8H-pyrimido[2,1-a:4,3-a']diisoquinoline-6-thione (4c)
o
Colorless crystals, mp. 199–202 C. Yield: 42 mg, 42%. Rf = 0.3 J = 7.7 Hz, 1H), 4.11 (ddd, J = 12.8, 8.1, 3.8 Hz, 1H), 3.35 (dq, J
(PE:EA = 10:1, v/v). 1H NMR (400 MHz, Chloroform-d) δ 7.58 (dd, =7.7, 7.3 Hz, 1H), 3.03 (ddd, J = 15.9, 8.0, 3.9 Hz, 1H), 2.99 – 2.84
J = 5.6, 3.6 Hz, 1H), 7.41 – 7.29 (m, 5H), 7.29 – 7.19 (m, 3H), 7.18 (m, 2H), 2.71 – 2.42 (m, 3H), 1.76 (d, J = 7.3 Hz, 3H). 13C NMR
– 7.09 (m, 2H), 6.98-6.90 (m, 1H), 6.30 (d, J = 7.7 Hz, 1H), 6.16 (101 MHz, Chloroform-d) δ 204.6, 137.5, 137.0, 133.3, 132.1,
(s, 1H), 5.30 (ddd, J = 13.2, 5.6, 4.0 Hz, 1H), 4.75 (d, J = 9.2 Hz, 129.3, 128.3, 128.1, 127.7, 127.5, 127.2, 126.8, 126.1, 76.4, 64.3,
1H), 4.40 (d, J = 9.2 Hz, 1H), 3.88 (ddd, J = 13.2, 9.5, 3.6 Hz, 1H), 49.9, 48.1, 37.6, 28.6, 28.5, 24.0. IR (film, KBr) v cm-1 3024, 2925,
3.10 (ddd, J = 16.0, 9.5, 4.0 Hz, 1H), 3.04 – 2.86 (m, 2H), 2.79 – 2852, 1660, 1644, 1471, 1441, 1385, 1371, 1353, 1340, 1311,
2.60 (m, 3H). 13C NMR (101 MHz, Chloroform-d) δ 201.2, 142.9, 1286, 1188, 1157, 1131, 1052, 954, 910, 772, 750, 735, 712, 654.
137.2, 136.4, 133.0, 132.2, 129.4, 129.3, 129.1, 128.4, 128.3, Elem. Anal. calcd. for C25H29N2S: C, 75.41; H, 6.63; N, 8.38; S,
127.7, 127.5, 127.4, 127.3, 125.5, 77.7, 65.1, 60.3, 47.9, 37.4, 9.58. Found: C, 75.54; H, 6.51; N, 8.34; S, 9.51.
28.6, 28.6. IR (film, KBr) v cm-1 3062, 2924, 2849, 1652, 1471,
1453, 1436, 1385, 1338, 1307, 1285, 1188, 1150, 1131, 1076, rel(4bR,5S,13bS)-5-Ethyl-4b,5,9,13b,15,16-hexahydro-6H,8H-
1042, 911, 751, 699, 663. ESI-HRMS [M + Na]+ calcd for pyrimido[2,1-a:4,3-a']diisoquinoline-6-thione (4h)
C26H24N2NaS+ m/z: 419.1552, found 419.1553.
Colorless crystals, mp. 159 – 161 oC. Yield: 63 mg, 70%. Rf = 0.5
(PE:EA = 10:1, v/v). 1H NMR (400 MHz, Chloroform-d) δ 7.59 (dd,
J = 5.5, 3.7 Hz, 1H), 7.34 – 7.26 (m, 2H), 7.27 – 7.15 (m, 4H), 7.13
– 7.07 (m, 1H), 5.72 (s, 1H), 4.70 (ddd, J = 13.2, 7.6, 4.0 Hz, 1H),
4.47 (d, J = 7.6 Hz, 1H), 4.20 (ddd, J = 13.2, 7.6, 4.0 Hz, 1H), 3.42
rel(4bR,5S,13bS)-5-(4-Iodophenyl)-4b,5,9,13b,15,16-
hexahydro-6H,8H-pyrimido[2,1-a:4,3-a']diisoquinoline-6-
thione (4d)
o
Colorless crystals, mp. 229–232 C. Yield: 35 mg, 26%. Rf = 0.3 (dt, J = 7.6, 5.1 Hz, 1H), 3.04 (ddd, J = 16.0, 7.6, 3.9 Hz, 1H), 3.01
(PE:EA = 10:1, v/v). H NMR (400 MHz, Chloroform-d) δ 7.68 – – 2.83 (m, 2H), 2.70 – 2.56 (m, 2H), 2.55 – 2.37 (m, 2H), 2.19 –
1
7.59 (m, 2H), 7.58 – 7.53 (m, 1H), 7.30 – 7.24 (m, 2H), 7.21-7.17 2.07 (m, 1H), 1.15 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz,
(m, 1H), 7.13 – 7.03 (m, 2H), 6.95 – 6.84 (m, 3H), 6.24 (d, J = 7.2 Chloroform-d) δ 203.3, 137.9, 137.0, 133.5, 132.3, 129.3, 128.2,
Hz, 1H), 6.09 (s, 1H), 5.34-5.25 (m, 1H), 4.66 (d, J = 9.4 Hz, 1H), 128.1, 127.6, 127.4, 127.1, 126.8, 126.1, 76.4, 60.4, 55.6, 48.2,
4.28 (d, J = 9.4 Hz, 1H), 3.74 (ddd, J = 13.3, 9.8, 3.5 Hz, 1H), 3.02 37.9, 29.0, 28.8, 28.6, 9.6. IR (film, KBr) v cm-1 3023, 2961, 2920,
(ddd, J = 14.6, 10.0, 4.2 Hz, 1H), 2.99 – 2.79 (m, 2H), 2.73 – 2.56 2849, 1723,1651, 1633, 1470, 1435, 1381, 1355, 1342, 1229,
(m, 3H). 13C NMR (101 MHz, Chloroform-d) δ 200.3, 142.6, 138.1, 1188, 1155, 1128, 1091, 1058, 1042, 949, 913, 802, 750, 695,
137.1, 136.0, 133.0, 132.1, 131.5, 129.4, 128.4, 128.4, 127.7, 646. ESI-HRMS [M + H]+ calcd for C22H25N2S+ m/z: 349.1733,
127.6, 127.5, 127.3, 125.5, 92.9, 77.8, 64.9, 59.7, 47.9, 37.4, found 349.1736.
28.5. IR (film, KBr) v cm-1 2923, 2852, 1660, 1652, 1645, 1482,
1446, 1385, 1306, 1285, 1224, 1152, 1132, 1061, 1043, 1007, rel(4bR,5S13bS)-5-Isobutyl-4b,5,9,13b,15,16-hexahydro-
910, 748. ESI-HRMS [M + Na]+ calcd for C26H23IN2NaS+ m/z: 6H,8H-pyrimido[2,1-a:4,3-a']diisoquinoline-6-thione (4i)
o
545.0519, found 545.0525.
Colorless crystals, mp. 144–145 C. Yield: 62 mg, 66%. Rf = 0.5
1
(PE:EA = 10:1, v/v). H NMR (400 MHz, Chloroform-d) δ 7.74 –
rel(4bR,5S,13bS)-5-(4-Chlorophenyl)-4b,5,9,13b,15,16-
hexahydro-6H,8H-pyrimido[2,1-a:4,3-a']diisoquinoline-6-
7.64 (m, 1H), 7.40 – 7.34 (m, 2H), 7.33 – 7.28 (m, 2H), 7.26 –
7.20 (m, 2H), 7.18 – 7.12 (m, 1H), 5.72 (s, 1H), 4.71 – 4.60 (m,
1H), 4.45 (d, J = 5.4 Hz, 1H), 4.12 (ddd, J = 13.5, 9.7, 3.7 Hz, 1H),
thione (4e)
o
Colorless crystals, mp. 224–226 C. Yield: 50 mg, 46%. Rf = 0.3 3.70 (dt, J = 9.7, 5.4 Hz, 1H), 3.14 – 3.05 (m, 1H), 3.04 – 2.92 (m,
(PE:EA = 10:1, v/v). 1H NMR (400 MHz, Chloroform-d) δ 7.51 (dd, 2H), 2.75 – 2.62 (m, 2H), 2.46 – 2.41 (m, 1H), 2.39 – 2.30 (m, 1H),
J = 5.6, 3.5 Hz, 1H), 7.33 – 7.21 (m, 4H), 7.20 – 7.16 (m, 1H), 7.14 1.96 (m, 2H), 1.14 (d, J = 6.4 Hz, 3H), 1.09 (d, J = 6.6 Hz, 3H). 13
C
– 7.01 (m, 4H), 6.92-6.85 (m, 1H), 6.20 (d, J = 7.7 Hz, 1H), 6.08 NMR (101 MHz, Chloroform-d) δ 203.8, 138.0, 136.9, 133.7,
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ARTICLE
Journal Name
132.1, 129.0, 128.2, 128.0, 127.5, 126.9, 126.5, 126.4, 75.4, 64.3, 1434, 1385, 1370, 1340, 1309, 1284, 1226, 1189, 1152, 1129,
View Article Online
DOI: 10.1039/C7OB02212C
55.8, 48.4, 48.3, 38.6, 29.0, 28.6, 25.1, 23.8, 22.2. IR (film, KBr) 1090, 1047, 945, 908, 798, 746, 731, 697, 660, 642. ESI-HRMS
v cm-1 3024, 2954, 2925, 2866, 1699, 1644, 1494, 1463, 1434, [M + H]+ calcd for C26H31N2S+ m/z: 403.2202, found 403.2204.
1384, 1366, 1341, 1281, 1188, 1153, 1130, 1091, 1057, 1043,
904, 794, 750, 729, 712. ESI-HRMS [M + H]+ calcd for C24H29N2S+ Ethyl rel(4bR,5R,13bS)-6-thioxo-4b,5,9,13b,15,16-hexahydro-
m/z: 377.2046, found 377.2066.
6H,8H-pyrimido[2,1-a:4,3-a']diisoquinoline-5-carboxylate
(
4m
)
o
Colorless crystals, mp. 169–172 C. Yield: 54 mg, 55%. Rf = 0.2
1
rel(4bR,5S,13bS)-5-Pentyl-4b,5,9,13b,15,16-hexahydro-
(PE:EA = 10:1, v/v). H NMR (400 MHz, Chloroform-d) δ 7.57 –
6H,8H-pyrimido[2,1-a:4,3-a']diisoquinoline-6-thione (4j)
7.49 (m, 1H), 7.35 – 7.27 (m, 2H), 7.25 – 7.08 (m, 4H), 7.06 –
o
Colorless crystals, mp. 144–146 C. Yield: 80 mg, 82%. Rf = 0.5 7.02 (m, 1H), 6.01 (s, 1H), 5.17 (ddd, J = 13.3, 5.8, 4.1 Hz, 1H),
1
(PE:EA = 10:1, v/v). H NMR (400 MHz, Chloroform-d) δ 7.72 – 4.89 (d, J = 8.6 Hz, 1H), 4.37 (d, J = 8.6 Hz, 1H), 4.34 (q, J = 7.1
7.62 (m, 1H), 7.41 – 7.33 (m, 2H), 7.34 – 7.22 (m, 4H), 7.20 – Hz, 2H), 3.91 (ddd, J = 13.2, 9.2, 3.8 Hz, 1H), 3.08 – 2.98 (m, 1H),
7.11 (m, 1H), 5.78 (s, 1H), 4.68 (ddd, J = 12.4, 7.7, 3.8 Hz, 1H), 2.98 – 2.86 (m, 2H), 2.73 – 2.57 (m, 2H), 2.53 – 2.43 (m, 1H),
4.54 (d, J = 7.4 Hz, 1H), 4.31 (ddd, J = 12.8, 7.4, 3.9 Hz, 1H), 3.56- 1.36 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ
3.48 (m, 1H), 3.16 – 3.01 (m, 1H), 3.04 – 2.90 (m, 2H), 2.77 – 193.5, 171.0, 136.8, 136.0, 133.3, 131.8, 129.3, 128.31, 128.28,
2.60 (m, 2H), 2.58 – 2.48 (m, 1H), 2.46 – 2.30 (m, 1H), 2.17 – 127.6, 127.53, 127.49, 126.8, 126.3, 77.1, 62.0, 61.0, 60.4, 47.1,
2.05 (m, 1H), 1.52 – 1.40 (m, 5H), 1.06 – 0.94 (m, 4H). 13C NMR 37.5, 28.6, 28.4, 14.2. IR (film, KBr) v cm-1 2926, 2848, 1726,
(101 MHz, Chloroform-d) δ 203.5, 137.9, 137.0, 133.5, 132.2, 1699, 1471, 1445, 1392, 1353, 1327, 1285, 1234, 1151, 1094,
129.2, 128.2, 128.0, 127.6, 127.4, 127.1, 126.8, 126.2, 76.2, 61.1, 1031, 938, 908, 752, 714, 642. ESI-HRMS [M + Na]+ calcd for
55.3, 48.1, 37.9, 36.4, 32.3, 28.8, 28.6, 25.0, 22.7, 14.3. IR (film, C23H24N2NaO2S+ m/z: 415.1451 found 415.1443.
KBr) v cm-1 2953, 2926, 2856, 1655, 1492, 1466, 1437, 1384,
1368, 1340, 1310, 1283, 1181, 1154, 1128, 1076, 1042, 1028, rel(1S,9bR)-1-(tert-Butyl)-1,4,5,9b-tetrahydro-2H-azeto[2,1-
950, 903, 750, 712, 683. ESI-HRMS [M + H]+ calcd for C25H30N2S a]isoquinoline-2-thione (3n)
m/z: 391.2202, found 391.2248.
Yellow-green sticky oil. Yield: 84 mg, 68%. Rf = 0.5 (PE:EA = 10:1,
v/v). H NMR (400 MHz, Chloroform-d) δ 7.43 – 6.88 (m, 4H),
1
rel(4bR,5S,13bS)-5-Isopropyl-4b,5,9,13b,15,16-hexahydro-
4.78 (d, J = 1.7 Hz, 1H), 4.28 – 4.19 (m, 1H), 3.46 – 3.36 (m, 1H),
3.24 – 3.12 (m, 1H), 2.90 – 2.80 (m, 1H), 2.80 (d, J = 1.7 Hz, 1H),
6H,8H-pyrimido[2,1-a:4,3-a']diisoquinoline-6-thione (4k)
o
Colorless crystals, mp. 166–168 C. Yield: 60 mg, 66%. Rf = 0.5 1.22 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 205.3, 135.4,
(PE:EA = 10:1, v/v). 1H NMR (400 MHz, Chloroform-d) δ 7.61 (dd, 133.8, 129.4, 127.6, 127.2, 125.6, 70.7, 58.6, 40.7, 31.8, 27.8,
J = 5.4, 3.8 Hz, 1H), 7.33 – 7.22 (m, 4H), 7.22 – 7.14 (m, 2H), 7.13 27.2. IR (film, KBr) v cm-1 2954, 2925, 2865, 1735, 1719, 1655,
– 7.06 (m, 1H), 5.69 (s, 1H), 4.53 (ddd, J = 13.5, 5.7, 4.3 Hz, 1H), 1560, 1474, 1459, 1448, 1437, 1426, 1396, 1365, 1350, 1286,
4.44 (d, J = 6.0 Hz, 1H), 4.15 (ddd, J = 13.4, 9.6, 3.7 Hz, 1H), 3.52 1239, 1192, 1141, 1101, 749. ESI-HRMS [M + H]+ calcd for
(dd, J = 6.0, 3.8 Hz, 1H), 3.04 (ddd, J = 15.8, 5.7, 3.8 Hz, 1H), 2.99 C15H20NS+ m/z: 246.1311, found 246.1317.
– 2.80 (m, 2H), 2.71 – 2.56 (m, 2H), 2.48 – 2.35 (m, 2H), 1.40 (d,
J = 6.8 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H). 13C NMR (101 MHz,
Chloroform-d) δ 201.6, 138.6, 137.0, 133.9, 132.4, 129.2, 128.2,
Acknowledgements
128.0, 127.44, 127.35, 127.0, 126.44, 126.36, 76.2, 63.1, 62.8,
48.4, 38.9, 35.1, 29.2, 28.7, 23.1, 18.3. IR (film, KBr) v cm-1 3026,
2957, 2926, 1651, 1605, 1493, 1463, 1454, 1432, 1385, 1367,
1307, 1284, 1253, 1186, 1152, 1129, 1090, 1068, 1054, 898, 748,
720, 697, 660. ESI-HRMS [M + H]+ calcd for C23H27N2S+ m/z:
363.1889, found 363.1887.
This work was supported by the National Natural Science
Foundation of China (no. 21602010 for Z. Yang) and (nos.
21372025 and 21172017 for J. X. Xu), the BUCT Fund for
Discipline Construction and Development (Project no. XK1533,
to Z. Yang), and the China Postdoctoral Science Foundation (no.
2016M600900, to Z. Yang). We thank Prof. Pingfan Li from
Beijing University of Chemical Technology for English polishing.
rel(4bR,5S,13bS)-5-Cyclohexyl-4b,5,9,13b,15,16-hexahydro-
6H,8H-pyrimido[2,1-a:4,3-a']diisoquinoline-6-thione (4l)
o
Colorless crystals, mp. 178–180 C. Yield: 51 mg, 51%. Rf = 0.5
Notes and references
(PE:EA = 10:1, v/v). 1H NMR (400 MHz, Chloroform-d) δ 7.61 (dd,
J = 5.4, 3.8 Hz, 1H), 7.34 – 7.28 (m, 3H), 7.26 – 7.20 (m, 1H), 7.21
– 7.13 (m, 2H), 7.11 – 7.06 (m, 1H), 5.71 (s, 1H), 4.64 – 4.55 (m,
1H), 4.49 (d, J = 6.0 Hz, 1H), 4.05 (ddd, J = 13.5, 9.8, 3.7 Hz, 1H),
3.50 (dd, J = 6.0, 3.2 Hz, 1H), 3.03 (ddd, J = 15.9, 5.4, 3.8 Hz, 1H),
2.98 – 2.85 (m, 2H), 2.68 – 2.58 (m, 2H), 2.42 – 2.32 (m, 1H),
§ Single crystals of 4l were recrystallized from a mixture of ethyl
acetate and petroleum ether mounted in inert oil and transferred
to the cold gas stream of the diffractometer. Crystal Data (CCDC
1571952). C26H30N2S, M =430.60, trigonal, a = 35.4337(15) Å, c =
9.6326(4) Å, U = 10473.9(8) Å3, T = 109.6, space group R-3 (no.
148), Z = 18, μ(Mo Kα) = 0.157, 8312 reflections measured, 4562
unique (Rint = 0.0234), which were used in all calculations. The
final wR(F2) was 0.1125 (all data).
2.08 – 1.77 (m, 6H), 1.77 – 1.62 (m, 1H), 1.37 – 1.17 (m, 4H). 13
C
NMR (101 MHz, Chloroform-d) δ 201.9, 138.7, 137.0, 134.0,
132.4, 129.1, 128.2, 128.0, 127.4, 127.3, 126.9, 126.5, 126.4,
76.1, 63.7, 62.7, 48.5, 45.7, 39.0, 33.0, 29.3, 29.0, 28.8, 27.4,
27.1, 26.2. IR (film, KBr) v cm-1 2923, 2850, 1682, 1494, 1463,
1
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Journal Name
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DOI: 10.1039/C7OB02212C
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DOI: 10.1039/C7OB02212C
Graphic Abstract
The mechanism and stereochemistry of [2t + 2i +2i] annulations between one thioketene molecule
and two imine molecules have been studied experimentally and theoretically.