Mechanistic study on the cleavage and reorganization of C(sp3)-H and C=N bonds in carbodiimides: Synthesis of 1,2-dihydrothiopyrimidines and 2,3-dihydropyrimidinthiones through four-component coupling

Article abstract of DOI:10.1002/chem.201301633

This study sheds light on the cleavage and reorganization of C(sp ³)-H and C=N bonds of carbodiimides in a three-component reaction of terminal alkynes, sulfur, and carbodiimides by a combination of methods including 1) isolation and X-ray analysis of six-membered-ring lithium species 2-S, 2) trapping of the oxygen-analogues (B-O and D-O) of both four-membered-ring intermediate B-S and ring-opening intermediate D-S, 3) deuterium labeling studies, and 4) theoretical studies. These results show that 1) the reaction rate-determining step is [2+2] cycloaddition, 2) the C=N bond cleavage takes place before C(sp³)-H bond cleavage, 3) the hydrogen attached to C6 in 2-S originates from the carbodiimide, and 4) three types of new aza-heterocycles, such as 1,2-dihydrothiopyrimidines, N-acyl 2,3-dihydropyrimidinthiones, and 1,2-dihydropyrimidinamino acids are constructed efficiently based on 2-S. All results strongly support the idea that the reaction proceeds through [2+2] cycloaddition/4π electrocyclic ring-opening/1,5-H shift/6π electrocyclic ring-closing as key steps. The research strategy on the synthesis, isolation, and reactivity investigation of important intermediates in metal-mediated reactions not only helps achieve an in-depth understanding of reaction mechanisms but also leads to the discovery of new synthetically useful reactions based on the important intermediates. Copyright

Full text of DOI:10.1002/chem.201301633

FULL PAPER
DOI: 10.1002/chem.201301633
3
À
Mechanistic Study on the Cleavage and Reorganization of C
(sp ) H and
C=N Bonds in Carbodiimides: Synthesis of 1,2-Dihydrothiopyrimidines and
2,3-Dihydropyrimidinthiones through Four-Component Coupling
Yang Wang,[a] Fei Zhao,[a] Yi Zhou,[a] Yue Chi,[a] Zitao Wang,[a]
Wen-Xiong Zhang,*[a, b] and Zhenfeng Xi[a]
Abstract: This study sheds light on the
cycloaddition, 2) the C=N bond cleav-
based on 2-S. All results strongly sup-
port the idea that the reaction proceeds
through [2+2] cycloaddition/4p electro-
cyclic ring-opening/1,5-H shift/6p elec-
trocyclic ring-closing as key steps. The
research strategy on the synthesis, iso-
lation, and reactivity investigation of
important intermediates in metal-medi-
ated reactions not only helps achieve
an in-depth understanding of reaction
mechanisms but also leads to the dis-
covery of new synthetically useful reac-
tions based on the important inter-
mediates.
3
3
À
À
cleavage and reorganization of C
G
age takes place before C
N
H and C=N bonds of carbodiimides in
a three-component reaction of terminal
alkynes, sulfur, and carbodiimides by a
combination of methods including
1) isolation and X-ray analysis of six-
membered-ring lithium species 2-S,
2) trapping of the oxygen-analogues
(B-O and D-O) of both four-mem-
bered-ring intermediate B-S and ring-
opening intermediate D-S, 3) deuteri-
um labeling studies, and 4) theoretical
studies. These results show that 1) the
reaction rate-determining step is [2+2]
cleavage, 3) the hydrogen attached to
C6 in 2-S originates from the carbodii-
mide, and 4) three types of new aza-
heterocycles, such as 1,2-dihydrothio-
pyrimidines, N-acyl 2,3-dihydropyrimi-
dinthiones, and 1,2-dihydropyrimidina-
mino acids are constructed efficiently
À
Keywords: C H activation · multi-
component reactions · reaction in-
termediates · reaction mechanisms ·
synthetic methods
Introduction
fragments into target molecules.[1–3] Carbodiimides have, for
a long time, been used as versatile reagents for organic syn-
thesis, pharmaceutical chemistry, and organometallic chem-
istry.[4–8] However, the cleavage and reorganization of chemi-
cal bonds in carbodiimide molecules has rarely been ex-
plored.
Cleavage and reorganization of chemical bonds are funda-
mental processes in synthetic organic chemistry and organo-
metallic chemistry. There are at least three great challenges
that need to be addressed to realize these two closely relat-
ed processes in a multicomponent reaction (MCR): 1) an
understanding of the cleavage process of chemical bonds,
2) trapping of the cleaved fragments by suitable compo-
nents, and 3) atom-economical incorporation of the cleaved
We previously reported an organolithium-promoted,
three-component reaction of terminal alkynes, sulfur, and
carbodiimides to afford 2,3-dihydropyrimidinthiones
1
(Scheme 1).[9] The most interesting feature of this reaction is
[a] Y. Wang, Dr. F. Zhao, Y. Zhou, Y. Chi, Dr. Z. Wang,
Prof. Dr. W.-X. Zhang, Prof. Dr. Z. Xi
Beijing National Laboratory
for Molecular Sciences (BNLMS)
Key Laboratory of Bioorganic Chemistry
and Molecular Engineering of Ministry of Education
College of Chemistry
Peking University
Beijing 100871 (P.R. China)
Fax : (+86)10-62751708
E-mail: wx_zhang@pku.edu.cn
[b] Prof. Dr. W.-X. Zhang
State Key Laboratory of Elemento-Organic Chemistry
Nankai University
Tianjin 300071 (P.R. China)
3
À
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301633.
Scheme 1. The unexpected bond cleavage and reorganization of C
H and C=N bonds of carbodiimides.
G
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3
À
that the selective cleavage of C
(sp ) H and C=N bonds is
lated intermediates led to the discovery of a one-pot, four-
component reaction (4CR), affording 1,2-dihydrothiopyrimi-
dines or N-acyl 2,3-dihydropyrimidinthiones. Further reac-
tions of 1,2-dihydrothiopyrimidines with amino acids pro-
vide a unique protocol for the synthesis of 1,2-dihydropyri-
midinamino acids that possess potential biological activities.
involved and integrated atom-economically into 1 through
an unknown pathway. For this unprecedented and syntheti-
cally useful transformation, we proposed two pathways
(Scheme 2). Pathway I might involve [2+2] cycloaddi-
Results and Discussion
1. Experimental support
Isolation and characterization of 2a-S and 2b-S: Results of
in situ variable-temperature NMR experiments (room tem-
perature to 808C) on the reaction of carbodiimides and lithi-
um alkynethiolates in [D8]tetrahydrofuran ([D8]THF) are as
follows: 1) No reaction took place between carbodiimide
and lithium alkynethiolate at room temperature; 2) When
the reaction temperature was increased from room tempera-
ture to 808C, only the starting materials and 2-S could be
observed; 3) When the reaction temperature was kept at
808C for 4 h, only 2-S could be observed. All these results
demonstrate that the rate-determining step of this reaction
might be the [2+2] cycloaddition reaction. Once B-S is
formed through [2+2] cycloaddition at higher temperatures,
the following transformations are very fast, delivering 2-S
through rearrangement. This is further supported by DFT
calculation results. Thus, because it is very difficult to direct-
ly isolate B-S, we attempted to isolate 2-S, which is one of
the key intermediates.
Scheme 2. Proposed pathways for 2-S.
From the nBuLi-promoted three-component reaction of
terminal alkynes, sulfur, and N,N’-diisopropylcarbodiimide
(iPrN=C=NiPr), we successfully isolated 2a-S and 2b-S in
high yields before quenching the reaction with water
(Scheme 3). X-ray analysis of 2b-S revealed a Li6S6 hexame-
tion,[10–12] 4p electrocyclic ring-opening,[13] 1,5-H shift,[14] and
6p electrocyclic ring-closing[15] to afford 2-S. Pathway II
might undergo [2+2] cycloaddition, intramolecular 1,4-H
shift, intramolecular ring-opening, and ring-closing proce-
dures. In these proposed processes, there were four interest-
3
À
ing features: 1) The key steps of C
(sp ) H and C=N bond
cleavage in a carbodiimide. Although the carbodiimide was
supposed to be cleaved into three fragments that were selec-
tively and atom-economically incorporated into 2-S, there
was no evidence to show that the C=N bond cleavage took
3
À
place before or after C
N
of the hydrogen attached to C6 in 2-S; 3) The rate-determin-
ing step of the three-component coupling; and 4) The impor-
tant intermediates, such as B-S with highly constrained
double bond, would receive much interest in the synthesis of
N-containing heterocycles. However, although two possible
pathways were proposed, there was no experimental or the-
oretical evidence available.
Scheme 3. Isolation of 2-S.
Given the importance of the issues mentioned above and
further synthetic applications of this multicomponent cou-
pling reaction for heterocycles, we carried out a detailed
mechanistic investigation both experimentally and theoreti-
cally. Experimental and computational results demonstrate
that the reaction process involves [2+2] cycloaddition/4p
electrocyclic ring-opening/1,5-H shift/6p electrocyclic ring-
closing as key steps. In addition, further application of iso-
ric aggregate in the solid state, in which two layers of chair
cyclohexane-like Li3S3 six-membered rings with alternating
Li and S atoms can be observed (Figure 1). Although oligo-
meric arrangements are common for lithium thiolates, to the
best of our knowledge, only one hexagonal prismatic Li6S6
example of a “paddle-wheel” arrangement has been report-
ed.[16] The isolated h3 S-C-N lithium species 2b-S was
quenched with water to give 1b (Scheme 3).
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Mechanistic Study on Carbodiimides
FULL PAPER
diisopropylamide (LDA) in THF at À788C for 1 h to pro-
vide the four-membered anionic intermediate B-O, which
was trapped with D2O and MeI. A site-selective reaction
took place, yielding the deuterated compound 4 and the me-
thylated compound 5, respectively. When warming the solu-
tion of B-O to room temperature for 1 h and then trapping
with water, the ring-opening product 6 was obtained in 97%
yield. When warming the solution of B-O to higher temper-
atures (40, 50, or 608C) and then trapping with water, mix-
tures of 6 and 7 were obtained. These results indicated that
the intermediate D-O was formed. It was found that D-O
could be completely transformed into 2-O when the temper-
ature was increased to 808C for 4 h. Compound 2-O was
trapped with water to yield 7 in 92% yield. The ring-closing
product 2-O was not observed when 6 was heated to high
temperatures. In contrast, the addition of LDA to 6 led to
the formation of 2-O. These results demonstrate that the
anion plays an important role in the 6p electrocyclic ring-
closing for the formation of 2-O. Although the azatrienes,
having one nitrogen atom, are well-known, diazatrienes,
such as 6, are a new type of conjugated compound. The
[2+2] cycloaddition/4p electrocyclic ring-opening provides a
novel route for the preparation of diazatrienes.
Figure 1. ORTEP drawing of 2b-S with 20% thermal ellipsoids. Hydro-
gen atoms are omitted for clarity.
Trapping of oxygen-analogues B-O, D-O, and 2-O: As men-
tioned above, the four-membered-ring intermediate B-S is
one of the key intermediates, but it is difficult to isolate.
Therefore, as an alternative, we tried to synthesize its
oxygen-analogue B-O, considering that oxygen and sulfur
atoms are in the same chalcogen group with very similar
properties. Thus, as given in Scheme 4, we synthesized the
oxygen-analogue precursor 3 through [2+2] cycloaddition of
2-phenylmalonic acid with N,N’-dicyclohexylcarbodiimide.[17]
We then carried out the base-promoted reaction of 3 at dif-
ferent temperatures. Compound 3 was treated with lithium
Deuterium labeling study on the origin of the hydrogen on
C6: Another important issue is the origin of the hydrogen
attached to C6 of the pyrimidine ring in 2-S. There are three
possible routes: 1) the terminal hydrogen of the terminal
alkyne, 2) the a-hydrogen adjoining the nitrogen atom of
the carbodiimide, and 3) water. As shown in Scheme 5, the
Scheme 5. Deuterium labeling studies.
terminal hydrogen of the terminal alkyne is deprotonated to
give the acetylide through the release of butane. Analysis of
the X-ray structure of the isolated 2b-S excluded the possi-
bility of H2O (Scheme 3 and Figure 1). To establish whether
3
À
or not the hydrogen originated from C
N
age of carbodiimide, as shown in Scheme 5, a three-compo-
nent coupling reaction of phenylethynyllithium, sulfur, and
deuterated N-phenyl-N’-cyclohexylcarbodiimide was per-
formed. After quenching the reaction with water, deuterated
2,3-dihydropyrimidinthione 1a-D was obtained in 76%
yield. The deuterium was incorporated exclusively at the C6
position of the product. Therefore, this study unambiguously
shows that the origin of the hydrogen attached to the C6 po-
sition is the a-hydrogen adjoining the nitrogen atom of the
carbodiimide.
Scheme 4. Trapping experiments of intermediates B-O, D-O, and 2-O.
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W.-X. Zhang et al.
Scheme 6. Calculated potential energy surfaces of pathway I.
2. Computational studies
ates ketenimine intermediate IM5. 1,5-H shift occurs via six-
membered-ring transition state TS4 (Figure 3, right). In TS4,
the atom distances of C3–H1 and C4–H1 are 1.323 and
1.379 ꢁ, respectively, which results in a reasonable energy
barrier (19.2 kcalmolÀ1) corresponding to the suitable con-
figuration. The final 6p-electrocyclic ring-closing step re-
quires an s-cis configuration between all C=C and C=N
double bonds. As a result, the configuration changes from
IM6 to IM6a before the 6p-electrocyclic ring-closing step
occurs with an energy barrier of 12.2 kcalmolÀ1. Formation
of IM7 is relatively favored (19.7 kcalmolÀ1 lower than IM4
and 18.9 kcalmolÀ1 lower than starting molecules, in Gibbs
free energy in solution). Optimized structures of TS5 and
the most stable configuration of the final product IM7a are
shown in Figure 4.
The experimental evidence described above include: 1) vari-
able–temperature NMR experiments indicating that the
rate-determining step might be the [2+2] cycloaddition step,
2) the X-ray structure of six-membered-ring lithium species
2-S, 3) trapping of the oxygen-analogues B-O and D-O, and
4) deuterium labeling studies confirming the origin of the
hydrogen attached to the C6 position. However, it was still
difficult to establish whether a 1,5-H shift or a 1,4-H shift
was involved and it was not clear why B-S could not be iso-
lated from the reaction. Thus, DFT calculations were per-
formed at the B3LYP/6-31+GACTHNUGRTENUNG(d,p) level.
The computational details of pathways I and II are dis-
cussed as follows. Previous reports have shown that both the
sulfur and b-carbon atoms in lithium alkynethiolate or lithi-
um thioketene, respectively, show nucleophilicity in nucleo-
philic reactions. In this calculation, the structure of TS1
clearly shows that nucleophilic attack of the b-carbon atom,
rather than the sulfur atom of IM1 to carbodiimide IM2
occurs during the first step. The energy barrier of this step is
29.1 kcalmolÀ1, which is the highest in the whole energy pro-
file, indicating that the first step (via TS1) is the rate-deter-
mining step. A second nucleophilic attack generates the
four-membered-ring intermediate IM4 (Scheme 6). The cal-
culated structures of the two transition states of this step-
wise [2+2] cycloaddition are shown in Figure 2.
Two possible reaction pathways are proposed starting
from IM4. In pathway I, a 4p-electrocyclic ring-opening
occurs first, followed by a sequential 1,5-H shift and 6p-elec-
trocyclic ring-closing step to generate the final product IM7
(Scheme 6). The 4p-electrocyclic ring-opening of IM4 gener-
Scheme 7. Calculated potential energy surfaces of pathway II.
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Mechanistic Study on Carbodiimides
FULL PAPER
Figure 2. Optimized structures of TS1 (top) and TS2 (bottom). Coordi-
nated THF is omitted for clarity. Selective atom distances (in ꢁ): TS1:
À
À
À
À
À
C2 C3 2.214, Li1 S1 3.310, Li1 N1 2.002; TS2: C1 N1 2.324, Li1 S1
À
3.393, Li1 N1 1.924.
In pathway II, intermediate IM9 is involved, the Gibbs
free energy of which is 44.3 kcalmolÀ1 higher than IM4
(Scheme 7). This result infers that either the transition state
involved in this transformation has very high energy or it
does not exist. The result also illustrates that the process
leading from IM4 to IM9 is extremely unfavored. Therefore,
on the basis of these calculations, we can conclude that
pathway II is not involved in the reaction mechanism.
From the computational results, we can conclude: 1) Path-
way I, involving [2+2] cycloaddition, 4p electrocyclic ring-
opening, 1,5-H shift, and 6p electrocyclic ring-closing, is a
favored route; 2) [2+2] cycloaddition is the rate-determining
Figure 3. Optimized structures of TS3 (top) and TS4 (bottom). Coordi-
nated THF is omitted for clarity. Selective atom distances (in ꢁ): TS3:
À
À
À
À
À
C3 N1 1.974, C3 N2 1.239, Li1 S1 2.316; TS4: C3 H1 1.323, C4 H1
1.379.
step, with an energy barrier of 29.1 kcalmolÀ1, which is the
highest energy barrier of the whole reaction pathway. This
means that, once B-S is formed at higher temperatures, the
following transformations to deliver 2-S through rearrange-
ment are fast. Thus it is difficult to directly obtain B-S from
this reaction system. As far as the energy surfaces from IM4
to IM7a are concerned, the 4p electrocyclic ring-opening is
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10647

W.-X. Zhang et al.
we have reported selective ring expansion of nitrogen-ana-
logue 2,4-diiminoazetidines at room temperature through
3
À
À
cleavage of C N and C
N
trogen-analogue intermediate could not be observed under
the lower temperatures because of the fast electrocyclic
ring-closing.[7a] The preliminary DFT calculations show simi-
lar energy surfaces to those of the sulfur analogues, with the
highest energy barrier of 21.8 kcalmolÀ1 for 4p electrocyclic
ring-opening and the lower energy barrier of 11.5 kcalmolÀ1
for 6p electrocyclic ring-closing (see the Supporting Infor-
mation), which is consistent with the experimental observa-
tion of fast electrocyclic ring-closing. In contrast, the pre-
liminary DFT calculations on the oxygen-analogues (B-O)
show that the 1,5-H shift is the rate-determining step, with
the highest energy barrier of 21.0 kcalmolÀ1 (see the Sup-
porting Information). Thus, it may be possible to obtain the
ring-opening intermediates at lower temperatures. We can
therefore conclude that the synthesis and reaction of the
oxygen-analogues (B-O) is an alternative avenue for investi-
gating the B-S system.
3. Application of the six-membered-ring intermediates 2-S
Preparation of 1,2-dihydrothiopyrimidines 8 through a new
À
C S bond formation: Isolated 2a-S was trapped with benzyl
bromide to give 1,2-dihydrothiopyrimidine 8a with a new
À
C S bond, in 99% yield [Eq. (1)]. X-ray structural analysis
of 8a revealed that the benzyl group is unambiguously
bonded to sulfur (Figure 5).
Figure 4. Optimized structures of TS5 (top) and IM7a (bottom). Coordi-
nated THF is omitted for clarity. Selective atom distances (in ꢁ): TS5:
À
À
À
À
À
C4 N2 2.072; IM7a: C1 N1 1.324, N1 C4 1.466, C4 N2 1.493, N2 C3
À
À
À
À
À
1.370, C2 C3, 1.363, C1 C2 1.462, C1 S1 1.754, Li1 S1 2.455, Li1 N1
1.987.
the critical step with the highest energy barrier (21.1 kcal
molÀ1). This means that, even if B-S was generated in situ
from the corresponding precursor, ring-opening intermedi-
ates such as C-S or D-S would be difficult to trap. Although
Figure 5. ORTEP drawing of 8a with 20% thermal ellipsoids. Hydrogen
atoms, except that on C2, are omitted for clarity.
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Mechanistic Study on Carbodiimides
FULL PAPER
Compound 8a could be easily obtained by one-pot, four-
component coupling of phenylethyne, sulfur, N,N’-diisopro-
pylcarbodiimide and benzyl bromide in high yield. Thus, var-
ious 1,2-dihydrothiopyrimidines 8 could be readily obtained
in the same manner by coupling terminal alkyne, elemental
sulfur, carbodiimide, and an electrophile (EX). Summarized
in Table 1 (entries 1–14) are representative results for the
formation of 8. In addition to benzyl bromide, methyl ido-
dide and allyl bromide could also act as suitable electro-
philes to furnish compounds 8a–d (entries 1–4). A wide
range of terminal alkynes including 1) aromatic terminal al-
kynes with either electron-withdrawing or electron-donating
substituents at the phenyl ring, 2) heteroaromatic alkynes,
and 3) aliphatic alkynes, could all afford the corresponding
1,2-dihydrothiopyrimidines 8e–n in good isolated yields (en-
tries 5–14).
Preparation of N-acyl 2,3-dihy-
dropyrimidinthiones 9 through
Table 1. Formation of 8 and 9.[a]
À
a new C N bond formation:
Representative results for the
formation of 9 through four-
component coupling of terminal
alkynes, elemental sulfur, car-
bodiimides, and acid chlorides
are summarized in Table 1 (en-
tries 15–19). The acyl group is
regioselectively connected to
R
R1
R2
R3
E–X
Product
Yield [%][b]
1,2-Dihydrothiopyrimidines 8
1
2
3
4
5
Me
Me
Me
Me
iPr
iPr
iPr
Cy
iPr
BnBr
MeI
8a
8b
8c
8d
8e
99
81
68
99
69
À
the nitrogen atom of the S=C
N unit.
Me
Pyrimidines or dihydropyri-
midines are extremely impor-
tant building blocks not only
because they are an integral
part of genetic materials but
also because they play critical
Me
-(CH2)5-
Me
MeI
MeI
Me
Me
roles
in
pharmaceutical
6
7
Me
Me
iPr
iPr
8 f
8g
64
89
fields.[18] Although the synthesis
of 3,4-dihydropyrimidinthiones
has been reported,[19] to the
best of our knowledge, there
are no reports on the synthesis
of 1,2-dihydrothiopyrimidine 8
or N-acyl 2,3-dihydropyrimidin-
thiones 9,[20] which are two
types of important dihydropyri-
midines with potential bioactiv-
ities.[19] A concise MCR method
starting from readily available
materials would provide an effi-
cient strategy for the construc-
tion of these N,S-containing
compounds.
Me
8
9
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
iPr
iPr
iPr
iPr
iPr
MeI
MeI
MeI
8h
8i
60
69
72
66
70
10
11
12
8j
8k
8l
13
14
Me
Me
Me
Me
iPr
iPr
MeI
MeI
8m
8n
67
61
N-Acyl 2,3-Dihydropyrimidinthiones 9
15
16
Me
Me
iPr
PhCOCl
PhCOCl
9a
9b
85
78
Further transformation of
8
[21]
À
through C S bond cleavage:
-(CH2)5-
Cy
When 8a was used to react with
3-aminopropanoic acid, 1,2-di-
hydropyrimidinamino acid 10a
was obtained in 90% yield
17
Me
Me
iPr
4-MeC6H4COCl
9c
75
18
19
Me
Me
Me
Me
iPr
iPr
4-MeC6H4COCl
PhCOCl
9d
9e
75
87
À
through C S bond cleavage
(Table 2). Both 4-aminobutano-
ic acid and 2-aminopropanoic
acid could be applied in this re-
action, affording 10b and 10c
[a] Reaction conditions (unless otherwise noted): terminal alkyne (1 mmol), carbodiimide (1 mmol), sulfur
(1 mmol), electrophile (1 mmol), THF (10 mL). [b] Isolated yield.
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W.-X. Zhang et al.
Table 2. Formation of 1,2-dihydropyrimidinamino acids 10.[a,b]
bonds, and are expected to receive increasing interest in the
synthesis of nitrogen-containing heterocycles. The oxygen-
analogue 6, which is a new type of diazatriene, is expected
to be a good starting material for the preparation of nitro-
gen-containing heterocycles and conjugated materials. The
research strategy, which involved a study on the synthesis,
isolation and reactivity of important intermediates in metal-
mediated reactions, not only helps gain an in-depth under-
standing of reaction mechanisms and but led to the discov-
ery of new synthetically useful reactions based on the impor-
tant intermediates.
Experimental Section
General methods: Unless otherwise noted, all starting materials were
commercially available and were used without further purification. Sol-
vents were purified by an Mbraun SPS-800 Solvent Purification System
and dried over fresh Na chips in the glovebox. nBuLi was obtained from
Acros. [D8]THF (all 99+ atom% D) was obtained from CIL and was
dried over fresh Na chips in the glovebox for NMR analysis. All reactions
were carried out under a dry and oxygen-free nitrogen atmosphere in
slight positive pressure by using Schlenk techniques or under a nitrogen
atmosphere in a Mikrouna Super (1220/750) Glovebox. The nitrogen in
the glovebox was constantly circulated through a copper/molecular sieve
catalyst unit. The oxygen and moisture concentrations in the glovebox at-
mosphere were monitored by an O2/H2O Combi-Analyzer to ensure both
[a] Reaction conditions (unless otherwise noted): 1,2-dihydrothiopyrimi-
dine (1 mmol), amino acid (1 mmol), EtOH (2 mL). [b] Isolated yield.
in 94 and 59% yield, respectively. Furthermore, n-propyl-
substituted 1,2-dihydrothiopyrimidines also acted as suitable
pyrimidine sources to generate the corresponding 10d in
69% yield.
Based on the skeleton possessing a pyrimidine ring and
an amino acid unit, 1,2-dihydropyrimidinamino acids 10
might show unique biological activity and good synthetic
utility.[22] More importantly, the synthesis of 1,2-dihydropyri-
midinamino acids, which is a new type of nitrogen-contain-
ing heterocyclic compound, has not been reported. Thus,
our method to synthesize well-defined 1,2-dihydropyrimidi-
namino acids should be of importance in both academia and
the pharmaceutical industry.
1
were always below 1 ppm. H and 13C NMR spectra were recorded with a
JEOL JNM-AL300 spectrometer (FT, 300 MHz for 1H; 75 MHz for 13C),
1
a Bruker ARX400 spectrometer (FT, 400 MHz for H; 100 MHz for 13C),
or a Bruker ARX500 spectrometer (FT, 500 MHz for 1H; 125 MHz for
13C) at RT, unless otherwise noted. Infrared spectra (IR) were recorded
with a Thermo Nicolet Avatar 330 FTIR spectrometer. High-resolution
mass spectra (HRMS) were recorded with a Bruker Apex IV FTMS
mass spectrometer by using ESI (electrospray ionization).
Isolation of intermediates 2a-S and 2b-S: In a 25 mL flask, nBuLi (1.6m
in pentane, 1 mmol) was added dropwise at À788C to a stirred solution
of terminal alkynes (1 mmol) in THF (10 mL). After stirring at À788C
for 0.5 h, sulfur (1 mmol, 32 mg) was added and the reaction mixture was
allowed to warm to RT. After 2 h, N,N’-diisopropylcarbodiimide
(1 mmol, 126 mg) was added and the reaction mixture was heated to
808C for 4 h. The solvent was removed under vacuum in a glovebox and
the residue was washed with diethyl ether (3 ꢂ10 mL). The h3 S-C-N lith-
ium species 2a-S and 2b-S, which were obtained as white powders, were
pure enough for NMR spectroscopic analysis and crystallization.
Compound 2a-S: Isolated yield: 89% (237 mg); yellow solid; 1H NMR
(300 MHz, [D8]THF): d=1.20 (d, J=6.0 Hz, 6H; CH3), 1.34 (s, 6H;
CH3), 3.44–3.52 (m, 1H; CH), 6.48 (s, 1H; CH), 6.91–6.95 (m, 1H; CH),
7.05–7.09 (m, 2H; CH), 7.55–7.57 ppm (m, 2H; CH); 13C NMR (75 MHz,
[D8]THF): d=24.08, 24.92, 47.43, 74.09, 115.53, 124.35, 127.08, 130.15,
134.48, 142.55, 182.17 ppm.
Conclusion
This study provides compelling experimental and computa-
tional evidence for the cleavage and reorganization of C-
3
À
N
promoted three-component coupling of terminal alkynes,
sulfur, and carbodiimides. The combined experimental and
theoretical studies strongly support the idea that the three-
component coupling proceeds through [2+2] cycloaddition/
4p electrocyclic ring-opening/1,5-H shift/6p electrocyclic
ring-closing as key steps. These results show that 1) the rate-
determining step is the [2+2] cycloaddition step; 2) C=N
Compound 2b-S: Isolated yield: 82% (190 mg); colorless solid; 1H NMR
(400 MHz, [D8]THF): d=0.91–0.96 (m, 3H; CH3), 1.22 (d, J=6.6 Hz,
6H; CH3), 1.34 (s, 6H; CH3), 1.54–1.60 (m, 2H; CH2), 2.39 (t, J=7.2 Hz,
2H; CH2), 3.53–3.66 (m, 1H; CH), 6.20 ppm (s, 1H; CH); 13C NMR
(100 MHz, [D8]THF): d=15.43, 25.30, 26.01, 28.16, 36.25, 48.17, 74.46,
114.46, 132.58, 185.97 ppm.
3
À
bond cleavage takes place before C
N
3) the hydrogen attached to C6 in 2-S originates from the a-
hydrogen adjoining the nitrogen atom of the carbodiimide;
4) further application of 2-S led to the discovery of a one-
pot, four-component reaction (4CR) of terminal alkynes, el-
emental sulfur, carbodiimides, and electrophiles, affording
1,2-dihydrothiopyrimidines or N-acyl 2,3-dihydropyrimidin-
thiones. The four-membered-ring intermediates B-S or B-O
are new types of azetine with highly constrained double
Trapping experiments of intermediates B-O, D-O and 2-O; The synthesis
of 3: In a 25 mL flask, 2-phenylmalonic acid (5 mmol, 900 mg) was added
in small portions to N,N’-dicyclohexylcarbodiimide (10 mmol, 2060 mg)
in dichloromethane (10 mL). After stirring at RT for 20 h, the resultant
precipitate was filtered off and the filtrate was concentrated in vacuo. To
the residue was added EtOH and the resultant precipitate was again fil-
tered off. The filtrate was concentrated under reduced pressure and the
10650
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 10643 – 10654

Mechanistic Study on Carbodiimides
FULL PAPER
residue was purified by recrystallization in EtOH to give 3. The data of
compound 3 is consistent with that reported.[17]
164.07 ppm; IR (film): n˜ =3207 (N-H), 3050 (C-H), 1640 (C=O), 1590
(C=N) cmÀ1; HRMS: m/z calcd for C21H29N2O: 325.2274 [M+H]+; found:
325.2275.
Compound 3: Isolated yield: 70% (227 mg); colorless solid; 1H NMR
(300 MHz, CDCl3, Me4Si): d=0.85–1.42 (m, 10H; CH2), 1.47–1.70 (m,
4H; CH2), 1.79–1.83 (m, 2H; CH2), 1.90–1.99 (m, 4H; CH2), 2.96–3.03
(m, 1H; CH), 3.64–3.72 (m, 1H; CH), 4.70 (s, 1H; CH), 7.22–7.36 ppm
(m, 5H; CH); 13C NMR (75 MHz, CDCl3, Me4Si): d=24.33, 24.51, 24.89,
25.07, 25.26, 30.06, 30.31, 33.78, 34.60, 51.65, 59.61, 62.00, 127.28, 127.84,
128.86, 132.05, 150.33, 167.87 ppm; HRMS: m/z calcd for C21H29N2O:
325.2274 [M+H]+; found: 325.2272.
Deuterium labeling studies: At À788C, sulfur (1 mmol, 32 mg) was
added to the THF (10 mL) solution of phenylethynyllithium, and the re-
action mixture was allowed to warm to RT. After 2 h, deuterated N-
phenyl-N’-cyclohexylcarbodiimide (1 mmol, 201 mg) was added and the
reaction mixture was heated to 808C for 4 h. The reaction was quenched
by addition of water at RT. The aqueous layer of the above quenched
mixture was extracted with CH2Cl2 and the combined organic layer was
washed successively with brine. Solvent was removed under reduced
pressure and the residue was purified by chromatography to give deuter-
ated 2,3-dihydropyrimidinthione 1a-D.
Compound 1a-D: Isolated yield: 76% (255 mg); yellow solid; 1H NMR
(500 MHz, CDCl3, Me4Si): d=1.15–1.75 (m, 8H; CH2), 2.39–2.43 (m, 2H;
CH2), 7.19–7.52 ppm (m, 10H + 1H; CH + NH); 13C NMR (125 MHz,
CDCl3, Me4Si): d=21.20, 24.46, 33.23, 73.60, 115.96, 126.58, 127.81,
Trapping experiments of intermediate B-O: In a 25 mL flask, LDA (1m
in THF, 1.1 mmol) was added dropwise at À788C to a stirred solution of
3 (1 mmol, 324 mg) in THF (10 mL). After stirring at À788C for 1 h,
D2O (1 mmol) was added dropwise at RT to a stirred solution of the
above reaction mixture. The solvent was removed under reduced pres-
sure, and the residue was purified by chromatography to give product 4.
Trapping experiments with MeI were carried out by the same method to
give product 5.
128.53, 128.74, 129.58, 129.83, 131.04, 137.64, 140.98 (t, JACTHNUTRGENUGN(C,D)=23.1 Hz),
187.40 ppm; IR (film): n˜ =1719 (C=O), 1598 (C=S) cmÀ1; HRMS: m/z
calcd for C21H22DN2S: 336.1639 [M+H]+; found: 336.1646.
Compound 4: Isolated yield: 95% (309 mg); yellow solid; m.p. 47.6–
48.48C; 1H NMR (300 MHz, CDCl3, Me4Si): d=0.81–0.95 (m, 2H; CH2),
1.12–1.27 (m, 6H; CH2), 1.50–1.98 (m, 12H; CH2), 2.94–3.04 (m, 1H;
CH), 3.62–3.73 (m, 1H; CH), 7.21–7.38 ppm (m, 5H; CH); 13C NMR
(75 MHz, CDCl3, Me4Si): d=24.36, 24.55, 24.92, 25.11, 25.30, 30.11, 30.36,
Synthesis of 1,2-dihydrothiopyrimidines 8a–n and N-acyl 2,3-dihydropyri-
midinthiones 9a–e: In a 25 mL flask, nBuLi (1.6m in pentane, 1 mmol)
was added dropwise at À788C to a stirred solution of terminal alkyne
(1 mmol) in THF (10 mL). After stirring at À788C for 0.5 h, sulfur
(1 mmol, 32 mg) was added and the reaction mixture was allowed to
warm to RT. After 2 h, carbodiimide (1 mmol) was added and the reac-
tion mixture was heated to 808C for 4 h. The reaction mixture was
quenched by addition of electrophile (1 mmol) at RT. The aqueous layer
of the above quenched mixture was extracted with CH2Cl2 and the com-
bined organic layer was washed successively with brine. Solvent was re-
moved under reduced pressure and the residue was purified by chroma-
tography to give 1,2-dihydrothiopyrimidines 8a–n or 2,3-dihydropyrimi-
dinthiones 9a–e.
33.83, 34.66, 51.76, 59.71, 61.81 (t, JACTHNUGTRNEUNG(C,D)=22.5 Hz), 127.47, 128.04,
129.07, 132.21, 150.53, 168.17 ppm; IR (film): n˜ =1738 (C=O), 1695 (C=
N) cmÀ1; HRMS: m/z calcd for C21H28DN2O: 326.2337 [M+H]+; found:
326.2336.
Compound 5: Isolated yield: 81% (277 mg); yellow solid; m.p. 58.3–
59.28C; 1H NMR (300 MHz, CDCl3, Me4Si): d=1.19–1.34 (m, 8H; CH2),
1.56–1.81 (m, 8H; CH2), 1.94–2.05 (m, 4H; CH2), 2.21 (s, 3H; CH3),
3.52–3.58 (m, 1H; CH), 3.64–3.69 (m, 1H; CH), 7.32–7.55 ppm (m, 5H;
CH); 13C NMR (75 MHz, CDCl3, Me4Si): d=13.03, 24.27, 24.45, 24.75,
24.96, 25.27, 30.08, 30.17, 33.83, 33.89, 51.89, 58.32, 71.40, 126.67, 128.57,
128.89, 132.66, 149.83, 168.69 ppm; IR (film): n˜ =1735 (C=O), 1689 (C=
N) cmÀ1; HRMS: m/z calcd for C22H31N2O: 339.2425 [M+H]+; found:
339.2421.
Compound 8a: Isolated yield: 99% (350 mg); yellow solid; m.p. 58.9–
59.88C; 1H NMR (400 MHz, CDCl3, Me4Si): d=1.17 (d, J=6.4 Hz, 6H;
CH3), 1.43 (s, 6H; CH3), 3.47–3.54 (m, 1H; CH), 4.09 (s, 2H; CH2), 6.46
(s, 1H; CH), 7.06–7.10 (m, 2H; CH), 7.12–7.20 (m, 6H; CH), 7.24–
7.26 ppm (m, 2H; CH); 13C NMR (100 MHz, CDCl3, Me4Si): d=24.03,
26.91, 33.50, 47.06, 75.58, 107.28, 125.85, 126.44, 127.92, 128.02, 128.90,
129.19, 136.54, 137.03, 139.04, 159.15 ppm. IR (film): n˜ =1618 (C=N)
Trapping experiments of intermediate D-O: In a 25 mL flask, LDA (1m
in THF, 1.1 mmol) was added dropwise at À788C to a stirred solution of
3 (1 mmol, 324 mg) in THF (10 mL). After stirring at À788C for 1 h, the
reaction mixture was allowed to warm to RT for 1 h. H2O (1 mmol) was
then added dropwise at RT to a stirred solution of the above reaction
mixture. The solvent was removed under reduced pressure and the resi-
due was purified by chromatography to give product 6.
cmÀ1 HRMS: m/z calcd for C22H27N2S: 351.1886 [M+H]+; found:
;
351.1889.
Compound 8b: Isolated yield: 81% (211 mg); yellow solid; m.p. 123.8–
124.88C; 1H NMR (300 MHz, CDCl3, Me4Si): d=1.44 (d, J=6.6 Hz, 6H;
CH3), 1.70 (s, 6H; CH3), 2.46 (s, 3H; CH3), 3.75–3.84 (m, 1H; CH), 6.73
(s, 1H; CH), 7.36–7.41 (m, 1H; CH), 7.43–7.49 ppm (m, 4H; CH);
13C NMR (75 MHz, CDCl3, Me4Si): d=12.26, 23.96, 26.70, 46.97, 75.37,
107.98, 125.99, 128.03, 129.03, 136.21, 137.28, 160.31 ppm; IR (film): n˜ =
1605 (C=N) cmÀ1; HRMS: m/z calcd for C16H23N2S: 275.1576 [M+H]+;
found: 275.1578.
Compound 6: Isolated yield: 97% (315 mg); yellow oil; m.p. 104.8–
105.68C; 1H NMR (300 MHz, CDCl3, Me4Si): d=0.98–1.16 (m, 4H;
CH2), 1.26–1.38 (m, 4H; CH2), 1.56–1.71 (m, 8H; CH2), 1.85–1.89 (m,
2H; CH2), 2.06–2.12 (m, 2H; CH2), 3.76–3.84 (m, 1H; CH), 5.07 (s, 1H;
CH), 6.85 (s, 1H; CH), 7.25–7.27 (m, 3H; CH), 7.33–7.37 ppm (m, 2H;
CH); 13C NMR (75 MHz, CDCl3, Me4Si): d=22.47, 22.48, 23.91, 24.85,
25.56, 26.29, 33.17, 47.58, 102.03, 126.44, 128.80, 129.93, 135.79, 139.03,
140.09, 168.57 ppm; IR (film): n˜ =1627 (br, C=N) cmÀ1; HRMS: m/z
calcd for C21H29N2O: 325.2274 [M+H]+; found: 325.2275.
Compound 8c: Isolated yield: 68% (204 mg); yellow oil; 1H NMR
(400 MHz, CDCl3, Me4Si): d=1.23 (d, J=6.8 Hz, 6H; CH3), 1.49 (s, 6H;
CH3), 3.54–3.57 (m, 1H; CH), 3.59 (d, J=7.0 Hz, 2H; CH2), 4.98–5.00
(m, 1H; CH2), 5.12–5.17 (m, 1H; CH2), 5.86–5.93 (m, 1H; CH), 6.53 (s,
1H; CH), 7.16–7.19 (m, 1H; CH), 7.25–7.30 ppm (m, 4H; CH);
13C NMR (100 MHz, CDCl3, Me4Si): d=24.02, 26.88, 32.25, 47.03, 75.51,
107.44, 116.50, 125.86, 127.92, 128.92, 134.78, 136.42, 137.07, 158.79 ppm;
Trapping experiments of intermediate 2-O: In a 25 mL flask, LDA (1m
in THF, 1.1 mmol) was added dropwise at À788C to a stirred solution of
3 (1 mmol, 324 mg) in THF (10 mL). After stirring at À788C for 1 h, the
reaction mixture was allowed to warm to RT for 1 h and then heated to
808C for 4 h. H2O (1 mmol) was then added dropwise at RT to a stirred
solution of the above reaction mixture. The solvent was removed under
reduced pressure and the residue was purified by chromatography to give
product 7.
IR (film): n˜ =1617 (C=N) cmÀ1
301.1738 [M+H]+; found: 301.1733.
; HRMS: m/z calcd for C18H25N2S:
Compound 8d: Isolated yield: 99% (351 mg); yellow solid; m.p. 136.7–
137.78C; 1H NMR (400 MHz, CDCl3, Me4Si): d=1.14–1.26 (m, 8H;
CH2), 1.43–1.57 (m, 4H; CH2), 1.64–1.83 (m, 4H; CH2), 1.92–2.02 (m,
2H; CH2), 2.15–2.18 (m, 2H; CH2), 2.32 (s, 3H; CH3), 3.11–3.17 (m, 1H;
CH), 6.54 (s, 1H; CH), 7.16–7.22 (m, 1H; CH), 7.26–7.30 ppm (m, 4H;
CH); 13C NMR (100 MHz, CDCl3, Me4Si): d=12.71, 22.21, 25.43, 26.13,
26.28, 35.05, 35.32, 54.67, 76.68, 106.87, 125.76, 127.96, 128.98, 137.18,
137.56, 159.14 ppm; IR (film): n˜ =1601 (C=N) cmÀ1; HRMS: m/z calcd
for C22H31N2S: 355.2208 [M+H]+; found: 355.2207.
Compound 7: Isolated yield: 92% (298 mg); colorless solid; m.p. 116.7–
117.28C; 1H NMR (300 MHz, CDCl3, Me4Si): d=1.06–1.17 (m, 4H;
CH2), 1.27–1.52 (m, 4H; CH2), 1.58–1.87 (m, 10H; CH2), 2.17–2.20 (m,
2H; CH2), 3.17–3.25 (m, 1H; CH), 5.97 (s, 1H; NH), 7.06 (s, 1H; CH),
7.10–7.15 (m, 1H; CH), 7.26–7.31 (m, 2H; CH), 7.52–7.54 ppm (m, 2H;
CH); 13C NMR (75 MHz, CDCl3, Me4Si): d=21.14, 24.48, 24.97, 25.94,
33.69, 34.68, 54.92, 74.03, 101.68, 124.69, 126.84, 127.79, 136.66, 141.92,
Chem. Eur. J. 2013, 19, 10643 – 10654
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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10651

W.-X. Zhang et al.
Compound 8e: Isolated yield: 69% (278 mg); yellow oil; 1H NMR
(400 MHz, CDCl3, Me4Si): d=1.24 (d, J=6.8 Hz, 6H; CH3), 1.49 (s, 6H;
CH3), 3.55–3.62 (m, 1H; CH), 3.78–3.82 (m, 5H; CH3, CH2), 4.99 (d, J=
10.0 Hz, 1H; CH2), 5.15 (d, J=17.0 Hz, 1H; CH2), 5.84–5.95 (m, 1H;
CH), 6.46 (s, 1H; CH), 6.84 (d, J=8.3 Hz, 2H; CH), 7.20 ppm (d, J=
8.3 Hz, 2H; CH); 13C NMR (100 MHz, CDCl3, Me4Si): d=24.05, 26.85,
32.29, 46.99, 55.17, 75.44, 107.01, 113.41, 116.50, 129.61, 130.74, 134.85,
135.94, 158.14, 159.24 ppm; IR (film): n˜ =1617 (C=N) cmÀ1; HRMS: m/z
calcd for C19H27N2OS: 331.1839 [M+H]+; found: 331.1836.
161.81 ppm; IR (film): n˜ =1635 (C=N) cmÀ1
C16H29N2S: 281.2041 [M+H]+; found: 281.2042.
;
HRMS: m/z calcd for
Compound 8m: Isolated yield: 67% (161 mg); yellow oil; 1H NMR
(400 MHz, CDCl3, Me4Si): d=0.89 (t, J=7.3 Hz, 3H; CH3), 1.20 (d, J=
6.6 Hz, 6H; CH3), 1.43 (s, 6H; CH3), 1.45–1.48 (m, 2H; CH), 2.10 (t, J=
7.4 Hz, 2H; CH2), 2.29 (s, 3H; CH3), 3.46–3.56 (m, 1H; CH), 6.19 ppm
(s, 1H; CH); 13C NMR (100 MHz, CDCl3, Me4Si): d=11.78, 13.74, 23.81,
23.96, 26.26, 31.28, 46.49, 74.79, 105.17, 133.99, 161.54 ppm; IR (film): n˜ =
1630 (C=N) cmÀ1; HRMS: m/z calcd for C13H25N2S: 241.1733 [M+H]+;
found: 241.1728.
Compound 8 f: Isolated yield: 64% (187 mg); yellow solid; m.p. 64.6–
65.38C; 1H NMR (400 MHz, CDCl3, Me4Si): d=1.13 (d, J=6.4 Hz, 3H;
CH3), 1.26 (d, J=6.7 Hz, 3H; CH3), 1.51 (s, 6H; CH3), 2.28 (s, 3H; CH3),
3.59–3.66 (m, 1H; CH), 6.57 (s, 1H; CH), 6.85–6.90 (m, 1H; CH), 6.99–
7.01 (m, 1H; CH), 7.06–7.08 (m, 1H; CH), 7.21–7.26 ppm (m, 1H; CH);
13C NMR (100 MHz, CDCl3, Me4Si): d=12.38, 24.05, 26.94, 47.22, 75.61,
106.79 (d, J=2.1 Hz), 112.48 (d, J=21.1 Hz), 115.41 (d, J=20.8 Hz),
124.01 (d, J=2.4 Hz), 129.25 (d, J=8.6 Hz), 136.61, 139.52 (d, J=8.1 Hz),
Compound 8n: Isolated yield: 61% (155 mg); yellow solid; m.p. 61.4–
62.38C; 1H NMR (400 MHz, CDCl3, Me4Si): d=0.91 (t, J=7.2 Hz, 3H;
CH3), 1.21 (d, J=6.7 Hz, 6H; CH3), 1.29–1.35 (m, 2H; CH), 1.38–1.46
(m, 8H; 2 ꢂCH3, CH2), 2.13 (t, J=7.4 Hz, 2H; CH2), 2.34 (s, 3H; CH3),
3.49–3.59 (m, 1H; CH), 6.24 ppm (s, 1H; CH); 13C NMR (100 MHz,
CDCl3, Me4Si): d=13.90, 22.21, 23.44, 24.03, 26.19, 28.91, 33.03, 46.70,
74.78, 105.59, 134.46, 161.98 ppm; IR (film): n˜ =1632 (C=N) cmÀ1
HRMS: m/z calcd for C14H27N2S: 255.1890 [M+H]+; found: 255.1885.
;
159.59, 162.55 ppm (d, J=243.5 Hz); IR (film): n˜ =1622 (C=N) cmÀ1
HRMS: m/z calcd for C19H22FN2S: 293.1489 [M+H]+; found: 293.1483.
;
Compound 9a: Isolated yield: 85% (310 mg); yellow oil; 1H NMR
(300 MHz, CDCl3, Me4Si): d=1.19 (d, J=6.7 Hz, 6H; CH3), 1.70 (s, 6H;
CH3), 3.87–4.00 (m, 1H; CH), 7.10 (s, 1H; CH), 7.22–7.35 (m, 6H; CH),
7.45–7.48 (m, 2H; CH), 8.03–8.06 ppm (m, 2H; CH); 13C NMR (75 MHz,
CDCl3, Me4Si): d=24.14, 26.75, 49.23, 63.77, 115.43, 126.38, 127.76,
128.01, 130.02, 130.25, 131.70, 136.82, 138.98, 144.94, 165.59, 176.35 ppm;
IR (film): n˜ =1739 (C=O), 1650 (C=S) cmÀ1; HRMS: m/z calcd for
C22H25N2OS: 365.1682 [M+H]+; found: 365.1677.
Compound 8g: Isolated yield: 89% (297 mg); yellow oil; 1H NMR
(400 MHz, CDCl3, Me4Si): d=1.26 (d, J=6.6 Hz, 6H; CH3), 1.50 (s, 6H;
CH3), 3.59–3.65 (m, 3H; CH2, CH), 5.02 (d, J=10.0 Hz, 1H; CH2), 5.17
(d, J=17.0 Hz, 1H; CH2), 5.85–5.95 (m, 1H; CH), 6.55 (s, 1H; CH),
7.14–7.21 ppm (m, 4H; CH); 13C NMR (100 MHz, CDCl3, Me4Si): d=
21.44, 27.06, 32.33, 47.29, 75.80, 106.17, 116.74, 125.80, 127.16, 128.61,
129.10, 133.74, 134.72, 136.96, 139.05, 158.26 ppm; IR (film): n˜ =1592 (C=
N) cmÀ1; HRMS: m/z calcd for C18H24ClN2S: 335.1349 [M+H]+; found:
335.1346.
Compound 9b: Isolated yield: 99% (347 mg); yellow solid; m.p. 207.9–
208.78C; 1H NMR (400 MHz, CDCl3, Me4Si): d=1.25–1.38 (m, 4H;
CH2), 1.52–1.56 (m, 2H; CH2), 1.59–1.62 (m, 2H; CH2), 1.66–1.68 (m,
2H; CH2), 1.81–1.89 (m, 6H; CH2), 1.96–1.99 (m, 2H; CH2), 2.47–2.50
(m, 2H; CH2), 3.60–3.66 (m, 1H; CH), 7.18 (s, 1H; CH), 7.26–7.44 (m,
6H; CH), 7.53–7.55 (m, 2H; CH), 8.11–8.13 ppm (m, 2H; CH);
13C NMR (100 MHz, CDCl3, Me4Si): d=22.30, 25.16, 25.52, 26.11, 34.54,
35.00, 57.05, 68.26, 115.94, 126.25, 127.68, 127.94, 129.98, 130.20, 131.49,
136.87, 138.93, 145.56, 165.15, 175.85 ppm; IR (film): n˜ =1715 (C=O),
1585 (C=S) cmÀ1; HRMS: m/z calcd for C28H33N2OS: 445.2308 [M+H]+;
found: 445.2304.
Compound 9c: Isolated yield: 75% (306 mg); yellow oil; 1H NMR
(300 MHz, CDCl3, Me4Si): d=1.38 (d, J=6.5 Hz, 6H; CH3), 1.78 (s, 6H;
CH3), 2.35 (s, 3H; CH3), 3.84 (s, 3H; CH3), 3.97–4.10 (m, 1H; CH), 6.89
(s, 1H; CH), 7.32–7.48 (m, 4H; CH), 7.91–8.00 (m, 4H; CH), 7.24–
7.26 ppm (m, 2H; CH); 13C NMR (75 MHz, CDCl3, Me4Si): d=21.19,
24.20, 26.75, 49.28, 55.21, 63.72, 112.17, 115.88, 122.46, 127.28, 127.98,
128.65, 130.99, 135.38, 136.74, 137.65, 140.38, 145.01, 165.42, 176.56 ppm;
IR (film): n˜ =1721 (C=O), 1594 (C=S) cmÀ1; HRMS: m/z calcd for
C24H29N2O2S: 409.1944 [M+H]+; found: 409.1951.
Compound 8h: Isolated yield: 60% (168 mg); yellow oil; 1H NMR
(400 MHz, CDCl3, Me4Si): d=1.26 (d, J=5.3 Hz, 6H; CH3), 1.50 (s, 6H;
CH3), 2.29 (s, 3H; CH3), 3.55–3.66 (m, 1H; CH), 6.59 (s, 1H; CH), 7.07–
7.08 (m, 2H; CH), 7.25–7.26 ppm (m, 1H; CH); 13C NMR (100 MHz,
CDCl3, Me4Si): d=12.42, 24.12, 27.00, 47.19, 75.50, 102.59, 120.49, 124.49,
128.86, 136.12, 128.90, 137.65 ppm; IR (film): n˜ =1623 (C=N) cmÀ1
HRMS: m/z calcd for C14H21N2S2: 281.1141 [M+H]+; found 281.1135.
;
Compound 8i: Isolated yield: 69% (210 mg); yellow oil; 1H NMR
(400 MHz, CDCl3, Me4Si): d=1.19 (d, J=6.7 Hz, 6H; CH3), 1.39 (s, 6H;
CH3), 1.55–1.66 (m, 4H; CH2), 2.06–2.11 (m, 4H; CH2), 3.49–3.56 (m,
3H; CH2, CH), 4.98 (d, J=9.9 Hz, 1H; CH2), 5.12–5.16 (m, 1H; CH2),
5.58 (s, 1H; CH), 5.64–5.92 (m, 1H; CH), 6.32 ppm (s, 1H; CH);
13C NMR (100 MHz, CDCl3, Me4Si): d=22.02, 23.02, 23.94, 25.43, 26.24,
29.52, 32.21, 46.73, 74.74, 110,66, 116.28, 125.65, 133.28, 133.59, 134.99,
159.56 ppm; IR (film): n˜ =1617 (C=N) cmÀ1
; HRMS: m/z calcd for
C18H29N2S: 305.2051 [M+H]+; found: 305.2046.
Compound 8j: Isolated yield: 72% (200 mg); yellow oil; 1H NMR
(300 MHz, CDCl3, Me4Si): d=1.22 (d, J=6.6 Hz, 6H; CH3), 1.43 (s, 6H;
CH3), 1.59–1.68 (m, 4H; CH2), 2.09–2.14 (m, 4H; CH2), 2.26 (s, 3H;
CH3), 3.50–3.63 (m, 1H; CH), 5.62 (s, 1H; CH), 6.36 ppm (s, 1H; CH);
13C NMR (75 MHz, CDCl3, Me4Si): d=12.18, 21.88, 22.87, 23.82, 25.29,
25.98, 29.32, 46.61, 74.49, 111.01, 125.64, 133.18, 133.44, 161.02 ppm; IR
(film): n˜ =1621 (C=N) cmÀ1; HRMS: m/z calcd for C16H27N2S: 279.1922
[M+H]+; found: 279.1920.
Compound 9d: Isolated yield: 75% (294 mg); yellow oil; 1H NMR
(400 MHz, CDCl3, Me4Si): d=1.42 (d, J=6.8 Hz, 6H; CH3), 1.76 (s, 6H;
CH3), 2.35–2.39 (m, 6H; CH3), 3.96–4.03 (m, 1H; CH), 7.15–7.22 (m,
5H; CH), 7.40–7.44 (m, 2H; CH), 8.01–8.03 ppm (m, 2H; CH);
13C NMR (100 MHz, CDCl3, Me4Si): d=21.13, 21.58, 24.23, 26.87, 49.14,
63.74, 115.13, 128.50, 128.68, 130.00, 130.05, 134.13, 135.82, 136.04, 142.03,
Compound 8k: Isolated yield: 66% (202 mg); yellow oil; 1H NMR
(400 MHz, CDCl3, Me4Si): d=1.02–1.13 (m, 2H; CH2), 1.19 (d, J=
6.6 Hz, 6H; CH3), 1.29–1.34 (m, 2H; CH2), 1.38 (s, 6H; CH3), 1.67–1.87
(m, 6H; CH2), 2.21–2.27 (m, 1H; CH), 3.49–3.56 (m, 1H; CH), 4.09 (d,
J=7.0 Hz, 2H; CH2), 5.03 (d, J=9.9 Hz, 1H; CH2), 5.19 (d, J=17.0 Hz,
1H; CH2), 5.87–5.98 (m, 1H; CH), 6.22 ppm (s, 1H; CH); 13C NMR
(100 MHz, CDCl3, Me4Si): d=23.99, 26.03, 26.29, 26.84, 32.10, 34.14,
36.66, 46.75, 74.63, 111.55, 116.46, 131.89, 135.07, 160.30 ppm; IR (film):
144.39, 164.96, 176.31 ppm; IR (film): n˜ =1736 (C=O), 1589 (C=S) cmÀ1
;
HRMS: m/z calcd for C24H29N2OS: 393.2020 [M+H]+; found: 393.2021.
Compound 9e: Isolated yield: 87% (320 mg); yellow oil; 1H NMR
(300 MHz, CDCl3, Me4Si): d=1.26–1.38 (m, 6H + 2H; 2 ꢂCH3 + CH2),
1.70–1.83 (m, 6H +1H; 2 ꢂCH3 + CH2), 2.19 (brs, 2H; CH2), 2.52 (brs,
2H; CH2), 3.89–4.00 (m, 1H; CH), 5.61 (s, 1H; CH), 7.01 (s, 1H; CH),
7.38–7.51 (m, 3H; CH), 8.16–8.27 ppm (m, 2H; CH); 13C NMR (75 MHz,
CDCl3, Me4Si): d=22.31, 23.09, 24.10, 25.56, 26.49, 48.83, 63.37, 70.49,
118.94, 124.94, 127.99, 129.88, 131.54, 137.14, 139.04, 143.45, 166.56,
175.85 ppm; IR (film): n˜ =1722 (C=O), 1592 (C=S) cmÀ1; HRMS: m/z
calcd for C22H29N2OS: 369.1995 [M+H]+; found: 369.1992.
n˜ =1637 (C=N) cmÀ1
; HRMS: m/z calcd for C18H31N2S: 307.2208
[M+H]+; found: 307.2205.
Compound 8l: Isolated yield: 70% (196 mg); yellow oil; 1H NMR
(300 MHz, CDCl3, Me4Si): d=1.04–1.08 (m, 2H; CH2), 1.20 (d, J=
6.6 Hz, 6H; CH3), 1.28–1.33 (m, 2H; CH2), 1.39 (s, 6H; CH3), 1.67–1.88
(m, 6H; CH2), 2.26–2.31 (m, 1H + 3H; CH + CH3), 3.50–3.59 (m, 1H;
CH), 6.23 ppm (s, 1H; CH); 13C NMR (75 MHz, CDCl3, Me4Si): d=
12.05, 23.89, 25.77, 26.16, 26.71, 33.96, 36.53, 46.63, 74.37, 111.95, 131.70,
Synthesis of 1,2-dihydropyrimidino acids: To a stirred solution of 8
(1 mmol) in EtOH (1 mL) was added amino acid (1 mmol), and the re-
sulting solution was heated to reflux overnight. After cooling to RT, the
reaction mixture was filtered and the filtrate was concentrated to dryness
10652
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 10643 – 10654

Mechanistic Study on Carbodiimides
FULL PAPER
under reduced pressure. The residue was purified by chromatography to
give products 10a–d.
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Compound 10a: Isolated yield: 90% (284 mg); yellow solid; m.p. 112.8–
113.58C; 1H NMR (500 MHz, D2O): d=1.30 (d, J=6.7 Hz, 6H; CH3),
1.71 (s, 6H; CH3), 2.44 (t, J=5.7 Hz, 2H; CH2), 3.49 (t, J=5.7 Hz, 2H;
CH2), 3.89–3.94 (m, 1H; CH), 7.31–7.33 (m, 3H; CH), 7.38–7.48 ppm (m,
3H; CH); 13C NMR (125 MHz, D2O): d=23.02, 24.61, 36.43, 38.73, 48.54,
71.84, 97.07, 127.67, 129.30, 129.51, 132.82, 145.33, 154.81, 179.30 ppm; IR
(film): n˜ =3268 (N-H) 1709 (C=O), 1638 (C=N) cmÀ1; HRMS: m/z calcd
for C18H26N3O2: 316.2019 [M+H]+; found: 316.2014.
[2] For sp3 C H bond activation, see: a) K. Godula, D. Sames, Science
À
2006, 312, 67; b) A. R. Dick, M. S. Sanford, Tetrahedron 2006, 62,
2439; c) H. Chen, S. Schlecht, T. C. Semple, J. F. Hartwig, Science
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Org. Lett. 2011, 13, 4562; b) Y. Kuninobu, T. Uesugi, A. Kawata, K.
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d) R. L. Zuckerman, S. W. Krska, R. G. Bergman, J. Am. Chem. Soc.
2000, 122, 751.
Compound 10b: Isolated yield: 94% (309 mg); yellow solid; m.p. 120.1–
120.98C; 1H NMR (500 MHz, D2O): d=1.34 (d, J=6.4 Hz, 6H; CH3),
1.77–1.82 (m, 6H + 2H; CH3 + CH2), 2.29 (t, J=6.1 Hz, 2H; CH2), 3.31
(t, J=6.8 Hz, 2H; CH2), 3.93–3.98 (m, 1H; CH), 7.33 (s, 1H; CH), 7.36–
7.53 ppm (m, 5H; CH); 13C NMR (125 MHz, D2O): d=23.08, 24.56,
24.73, 33.04, 40.83, 48.55, 72.19, 97.20, 127.83, 129.39, 129.73, 132.89,
145.18, 154.85, 181.01 ppm; IR (film): n˜ =3259 (N-H), 1712 (C=O), 1631
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Y. Liu, J. Org. Chem. 2007, 72, 6763; n) T.-G. Ong, J. S. OꢈBrien, I.
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(C=N) cmÀ1 HRMS: m/z calcd for C19H28N3O2: 330.2176 [M+H]+;
;
found: 330.2175.
Compound 10c: Isolated yield: 59% (186 mg); yellow solid; m.p. 99.7–
1
100.68C; H NMR (500 MHz, D2O): d=1.33–1.41 (m, 6H + 3H; 2 ꢂCH3
+ CH3), 1.77 (s, 6H; 2 ꢂCH3), 3.24–3.28 (m, 1H; CH), 3.48–3.53 (m, 1H;
CH), 6.98–7.07 (m, 3H; CH), 7.37–7.58 ppm (m, 3H; CH); 13C NMR
(500 MHz, D2O): d=23.02, 24.67, 24.72, 46.77, 52.33, 72.21, 115.43,
120.71, 127.76, 129.50, 130.04, 145.79, 155.46, 177.78 ppm; IR (film): n˜ =
3310 (N-H), 1710 (C=O), 1629 (C=N) cmÀ1
C18H26N3O2: 316.2019 [M+H]+; found: 316.2011.
; HRMS: m/z calcd for
Compound 10d: Isolated yield: 69% (194 mg); yellow solid; m.p. 95.7–
1
96.58C; H NMR (500 MHz, D2O): d=0.85 (t, J=7.3 Hz, 3H; CH3), 1.24
(d, J=6.6 Hz, 6H; CH3), 1.41 (q, J=7.3 Hz, 2H; CH2), 1.58 (s, 6H;
CH3), 2.11–2.16 (m, 2H; CH2), 2.47 (t, J=6.1 Hz, 2H; CH2), 3.50 (t, J=
6.1 Hz, 2H; CH2), 3.73–3.82 (m, 1H; CH), 7.08 ppm (s, 1H; CH);
13C NMR (125 MHz, D2O): d=12.56, 22.18, 23.00, 24.36, 27.81, 36.81,
38.58, 47.93, 71.37, 93.56, 144.97, 155.18, 179.54 ppm; IR (film): n˜ =3316
(N-H), 1701 (C=O), 1625 (C=N) cmÀ1
;
HRMS: m/z calcd for
C15H28N3O2: 282.2176 [M+H]+; found: 282.2174.
X-ray crystallographic studies: Single crystals of 2b-S that were suitable
for X-ray analysis were grown in diethyl ether/hexane at room tempera-
ture for 1 day. Single crystals of 8a that were suitable for X-ray analysis
were grown in CH2Cl2/hexane at room temperature for 1 day. Data col-
lections for 2b-S was performed at À1508C with a Rigaku RAXIS
RAPID IP diffractometer, using graphite-monochromated MoKa radia-
tion (l=0.71073 ꢁ). Data collection for 8a was performed at À1008C
with a Rigaku RAXIS RAPID IP diffractometer, using graphite-mono-
chromated MoKa radiation (l=0.71073 ꢁ). The determination of crystal
class and unit cell parameters was carried out by Rapid-AUTO (Rigaku
2000) program package for 2b-S and 8a. The raw frame data was proc-
essed by using Crystal Structure (Rigaku/MSC 2000) for 2b-S and 8a.
The structures of 2b-S and 8a were solved by the use of the SHELXTL
program. Refinement was performed on F2 anisotropically for all the
non-hydrogen atoms by the full-matrix least-squares method. The hydro-
gen atoms were placed at the calculated positions and were included in
the structure calculation without further refinement of the parameters.
Crystallographic data (excluding structure factors) have been deposited
with the Cambridge Crystallographic Data Centre as supplementary pub-
lication nos. CCDC-921536 (2b-S), and CCDC-921537 (8a). These data
can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
This work was supported by the Natural Science Foundation of China,
and the 973 Program (2011CB808600).
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www.chemeurj.org
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À
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Received: April 29, 2013
Published online: July 2, 2013
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