Synthesis of unexpected bifunctionalized thiazoles by nucleophilic attack on allenyl isothiocyanate

Article abstract of DOI:10.1002/ejoc.201301851

Treatment of allenyl isothiocyanate with a variety of nucleophiles leads to 5-methylthiazoles with a functional group at the 2-position. The same pattern of reactivity is also seen with N-aminophthalimide. In the presence of azide salt, hydrazoic acid, or N,N-disubstituted hydroxylamines, however, allenyl isothiocyanate is converted into bifunctionalized thiazoles. We explain the formation of these products by nucleophilic addition at the isothiocyanato moiety followed by ring closure and an N-N or N-O cleavage reaction to generate short-lived 2-imino-5-methylidenethiazole or 5-methylidenethiazol-2-one. Such intermediates are trapped by addition reactions to give the final heterocyclic compounds. In the case of N,N-disubstituted hydroxylamines, the primary addition products with allenyl isothiocyanate can be detected as unstable intermediates by IR and NMR spectroscopy.

Full text of DOI:10.1002/ejoc.201301851

Job/Unit: O31851
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Date: 17-03-14 16:58:33
Pages: 9
FULL PAPER
DOI: 10.1002/ejoc.201301851
Synthesis of Unexpected Bifunctionalized Thiazoles by Nucleophilic Attack on
Allenyl Isothiocyanate
Baker Jawabrah Al-Hourani,[a,b] Frank Richter,[a] Kai Vrobel,[a] Klaus Banert,*[a]
Marcus Korb,[c] Tobias Rüffer,[c] Bernhard Walfort,[c] and Heinrich Lang[c]
Dedicated to Professor Helmut Quast on the occasion of his 80th birthday
Keywords: Nitrogen heterocycles / Reaction mechanisms / Reactive intermediates / Allenes / Isothiocyanates
Treatment of allenyl isothiocyanate with a variety of nucleo-
philes leads to 5-methylthiazoles with a functional group at
the 2-position. The same pattern of reactivity is also seen
with N-aminophthalimide. In the presence of azide salt, hy-
drazoic acid, or N,N-disubstituted hydroxylamines, however,
allenyl isothiocyanate is converted into bifunctionalized thi-
azoles. We explain the formation of these products by nucleo-
philic addition at the isothiocyanato moiety followed by ring
closure and an N–N or N–O cleavage reaction to generate
short-lived 2-imino-5-methylidenethiazole or 5-methyl-
idenethiazol-2-one. Such intermediates are trapped by ad-
dition reactions to give the final heterocyclic compounds. In
the case of N,N-disubstituted hydroxylamines, the primary
addition products with allenyl isothiocyanate can be detected
as unstable intermediates by IR and NMR spectroscopy.
in its reactions with weak nucleophiles such as diphenyl-
amine[3a,3d] or neutral water in tetrahydrofuran,[3a,3e] which
led to thiazole products of type 4 even at room temperature.
Compounds 2 proved to be highly selective electrophilic
reagents, as shown by exposure to ambident nucleophiles,
for example, histamine or adenine.[4] Thus, the chemistry of
2 shows that allenyl isothiocyanates act predominantly as
valuable synthetic equivalents of synthons 5.[5]
Introduction
Thiazoles are well represented in a variety of biomo-
lecules, and they have diverse biological activities.[1] Most
commercially significant compounds of this type are fungi-
cides, drugs, or dyes. Consequently, diverse methods exist
for the synthesis of thiazoles.[2] Nevertheless, there is strong
demand to prepare such heterocycles by new methods and
so obtain, e.g., products with unknown substitution pat-
terns.
Recently, we reported the first synthesis of allenyl iso-
thiocyanates 2 by [3,3]-sigmatropic rearrangement of pro-
pargyl thiocyanates 1, which can be carried out in excellent
yields and on a large scale by using flash vacuum pyrolysis
(Scheme 1).[3] Highly reactive cumulenes 2 were treated with
carbon-, oxygen-, nitrogen-, phosphorus-, sulfur-, or
hydride-containing nucleophiles NuH to give thiazole deriv-
atives 3 and 4. The subsequent rearrangement 3Ǟ4 gave 4
as a single product.[3e] The unusual reactivity of 2 was seen
[a] Technische Universität Chemnitz, Organic Chemistry, Strasse
der Nationen 62,
Scheme 1. Generation of allenyl isothiocyanates 2 and their trans-
formation into thiazole derivatives 3 and 4.
09111 Chemnitz, Germany
E-mail: klaus.banert@chemie.tu-chemnitz.de
http://www.tu-chemnitz.de/chemie/org/index.html.en
[b] New address: American University of Madaba, Faculty of
Science,
In this paper, we describe the surprising reactions of all-
enyl isothiocyanate (2a) with lithium azide, hydrazoic acid,
or hydroxylamines with different substitution patterns. In
these cases, unexpected bifunctionalized thiazoles, which do
not fit into the simple structures 3 and 4, were obtained as
major products.
Madaba, Jordan
[c] Technische Universität Chemnitz, Institute of Chemistry,
Inorganic Chemistry,
09107 Chemnitz
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301851.
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K. Banert et al.
FULL PAPER
Results and Discussion
When we treated allenyl isothiocyanate (2a) with lithium
azide in methanol at room temperature, we did not detect
any trace of the expected product (i.e., 4a), which is
known[6] to equilibrate with bicyclic tetrazole 4aЈ
(Scheme 2). Instead, we observed liberation of dinitrogen
and, after workup, the formation of bifunctionalized thi-
azole 9 in 76% yield as well as known[3a,3d,7] methoxythi-
azole 4b in 24% yield. Compound 4a/4aЈ, which is easily
available by nitrosation of (5-methylthiazol-2-yl)hydraz-
ine,[6] was also treated with lithium azide in methanol. This
control experiment confirmed that compounds 4b and 9
were not formed from 4a/4aЈ under these conditions.
Figure 1. ORTEP diagram (50% ellipsoid probability) of the mo-
lecular structure of thiazole 8.
of the weak Nα–Nβ bond with liberation of dinitrogen leads
to 7 or the Nα-protonated intermediate. Finally, 1,6-ad-
dition of hydrazoic acid or methanol gives rise to aromatic
products 8 or 9, respectively. When 2a was treated with
hexadecyltributylphosphonium azide[12] in aprotic CDCl3 at
0 °C, we observed a rapid reaction with liberation of di-
nitrogen. However, we were not able to isolate any charac-
terizable product. Thus, we suppose that 7 is a short-lived
intermediate that must be trapped under protic conditions.
We assume that protonation of intermediate 6 at the CH2
position to form stable heterocycles 4a/4aЈ cannot compete
with the rapid cleavage to give dinitrogen. Thus, the weak
Nα–Nβ bond of azide 6 is responsible for the result that
products quite different from those shown in Scheme 1 are
generated. Consequently, it should be possible to use other
nucleophiles, such as hydrazines with weak N–N bonds or
hydroxylamines with cleavable N–O bonds, to obtain bi-
functionalized thiazoles analogous to 8 and 9.
When we treated cumulene 2a with hydrazine hydrate in
methanol, we did not get the expected thiazole derivative
(i.e., 4c) or any product that indicated that cleavage of the
hydrazine N–N bond had occurred (Scheme 3). A mixture
of thiosemicarbazide (11; 77% yield) and the surprising
imidazole-2-thione 10 (21%) was obtained instead. When
pure hydrazine was used instead of hydrazine hydrate, the
yields of the products changed only slightly. The structure
of heterocycle 10 was confirmed not only by elemental
Scheme 2. Reaction of allenyl isothiocyanate (2a) with lithium
1
analysis, IR, MS, H NMR, and 13C NMR spectroscopic
azide or hydrazoic acid.
data, but also by 15N NMR spectroscopic measurements.
Alkyl, aryl, and vinyl isothiocyanates are generally con- In a control experiment, we showed that known[13] com-
verted into 5-amino-substituted 1,2,3,4-thiatriazoles in the pound 4c is stable in the presence of hydrazine hydrate, and
presence of hydrazoic acid by addition at the C=N bond that it does not rearrange to the isomeric product 10 under
followed by ring closure,[8] whereas treatment with sodium such reaction conditions.
azide in protic solvents leads to the corresponding 1-substi-
We assumed that the N–N bond in N-aminophthalimide
tuted 5-mercaptotetrazoles.[9] When we treated 2a with an (12) may be weaker than that in hydrazine. Thus, products
excess of hydrazoic acid in chloroform at room temperature, resulting from cleavage of this bond should be accessible by
we obtained a single product 8 in 60% yield. Structural as- treatment of isothiocyanate 2a with nucleophile 12. How-
signment was based on IR and NMR spectroscopic data ever, treatment of 12 with a 1.5-fold excess of 2a in THF
and elemental analysis, and was further confirmed by sin- and methanol led to heterocycles 4d (12% yield) and 4e
gle-crystal X-ray diffraction analysis (Figure 1).[10,11]
(21%) after 24 h at room temperature. Obviously, the con-
A mechanism that explains the formation of the thiazoles version of 2a was slow, because increasing the reaction time
9 and 8 most probably includes initial attack of lithium az- to 48 h resulted in increased yields of 4d (29%) and 4e
ide or hydrazoic acid at the carbon atom of the N=C=S (45%). When a 2.3-fold excess of 2a was used together with
unit, and subsequent cyclization to generate anion 6 or the an extended reaction time of 48 h, the ratio of products 4d
corresponding Nα-protonated species. Thereafter, cleavage (22% yield) and 4e (57%) changed moderately. The struc-
2
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Synthesis of Bifunctionalized Thiazoles
cess of 2a was used, we obtained mixtures of 2-aminothi-
azoles 14 and bifunctionalized thiazoles 15. By using excess
13a or 13b, we exclusively obtained products 15a or 15b,
respectively. O-(Thiazol-2-yl)hydroxylamines 19 (see
Scheme 4), which correspond to product type 4, were not
detected in any case. For comparison, we prepared 14c
(43% yield), 14d (82%), and even the sterically hindered
tertiary amine N-(tert-butyl)-N-isopropyl-5-methylthiazol-
2-amine (14e; 80% yield) from 2a and the corresponding
secondary amines (i.e., 20c–20e). The synthesis of 2-amino-
thiazoles 14a,b by alternative methods has been described
Table 1. Reaction of 2a with 13a–13f in THF.
13
Hydroxylamine
Ratio
2a/13
Yields [%][a]
R1
R2
14
15
a
a
b
b
c
d
e
f
Me
Me
Et
Me
Me
Et
1.1:1
1:2
1.5:1
1:2
29
0
29
0
30
33
33
0[b]
58
55
55
79
40
35
0
Et
Et
–(CH2)5–
2:1
Scheme 3. Reaction of allenyl isothiocyanate (2a) with hydrazine
or N-aminophthalimide (12).
Bn
tBu
tBu
Bn
iPr
tBu
1.5:1
1.5:1
2:1
0[b]
ture of compound 4e was confirmed from its spectroscopic
[a] Isolated yields based on the substoichiometric starting com-
data as well as by single-crystal X-ray diffraction (Fig- pound (2a or 13) after separating 14 and 15 by chromatography.
ure 2).[11,14] The formation of this product via intermediate
[b] No reaction.
4d was surprising; we expected the less symmetrical thiazole
derivative 4f to be formed, but it was not detected. In the
case of other monosubstituted 2-aminothiazoles or the par-
ent compound itself, it is well known that the reaction with
2a starts with nucleophilic attack of the ring atom N-3, and
not the exocyclic amine functionality.[3e,4]
Figure 2. ORTEP diagram (55% ellipsoid probability) of thiazole
4e.
Finally, we treated allenyl isothiocyanate (2a) in THF
with hydroxylamine derivatives 13 (Table 1). When an ex- the formation of 14 and 15.
Scheme 4. Mechanism to explain the reaction of 2a with 13 and
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K. Banert et al.
FULL PAPER
in the literature.[15] The structures of products 15a–15d were demonstrated that the depicted NH–C=S tautomer is pre-
assigned on the basis of elemental analyses, HRMS data, dominant. When compounds 17 were stored in solution at
and especially their IR and NMR spectra. When the IR ambient temperature for approximately 24 h, or upon at-
and NMR spectra of these products were compared with tempted chromatography on silica gel, they isomerized to
those of the model compound 5-methylthiazol-2(3H)- give compounds 15. In this conversion, and also in the reac-
one,[3e,16] good agreement of the corresponding IR absorp- tion of 2a with an excess of 13 (see above), no signals of 14
tions originating from C=O (1645–1660 cm–1) and N–H were observed. Allenes 17 are the first open-chain interme-
units (3125–3171 cm–1) as well as similar δ values for the diates to be detected after treatment of cumulenes 2 with
13C NMR signals of C-2 (δ = 175.9–176.3 ppm), C-4 (δ = nucleophiles to generate thiazole derivatives.
116.3–118.9 ppm), and C-5 (δ = 116.4–120.6 ppm) were
When we treated 13 with excess 2a, mixtures of 14 and
seen. The 15N NMR spectrum of 15b revealed two signals 15 were formed. The product distribution formed in the re-
with the expected[16] chemical shifts [δ = –315.8 (NEt2) and action of 13b in particular was strongly dependent on the
–214.6 (NH–C=O) ppm]. The δ value of the upfield signal molar ratio of isothiocyanate to hydroxylamine. Thus, a
in particular is quite different from those of hydroxyl- twofold excess of 2a led exclusively to 2-aminothiazole 14b
amines, for example, 13b.[17] However, the value of (58% yield).
1J(15N,1H) could not be measured, probably owing to rapid
To explain the formation of heterocyclic products 14 and
exchange processes. We assume that the NH tautomer (thi- 15, the mechanism shown in Scheme 4 is suggested. After
azol-2(3H)-one) is the favored structure of 15 in solution. nucleophilic addition of 13 to the isothiocyanate moiety of
X-ray diffraction analysis proved the predominance of this 2a, intermediate 17 most probably cyclizes to give dipolar
tautomer also in the single crystal of 15c (Figure 3).[11,18]
species 18. Obviously, proton transfer (i.e., 18Ǟ19) cannot
compete with cleavage of 18 to give secondary amine 20
and highly reactive compound 21. The latter undergoes a
1,4-addition with 20 to give final product 15. If an excess
of 13 is used, 2a is rapidly and completely consumed, and
therefore production of 14 from 2a and 20 is not possible.
In the presence of excess 2a, however, 20 liberated from 18
also attacks 2a to give 14. A great excess of 2a (at least
2 equiv.) is able to completely transform in-situ-generated
trapping reagent 20 into 14. In this case, the interception
reaction (i.e., 20 + 21Ǟ15) is prevented.
We cannot completely exclude a direct rearrangement of
18 to give 15 without the formation of 21. But the corre-
sponding migration of the amino functionality seems to be
electronically unfavorable, and a synchronous process is im-
possible for geometrical reasons.
When an excess of 2a was treated with sterically hindered
hydroxylamines 13e[19] or 13f,[19] only the former nucleo-
phile was able to attack the isothiocyanate, and no reaction
occurred with 13f. Owing to its severe steric hindrance, the
liberated amine (i.e., 20e) obviously cannot trap short-lived
intermediate 21, but the reactivity of the amine is sufficient
to produce 14e in the presence of 2a (Table 1).
Figure 3. ORTEP diagram (25% ellipsoid probability) of the mo-
lecular structure of 15c. Only one atomic position of disordered
atoms is displayed.
We also treated isothiocyanate 2a with nucleophiles 13 in
CDCl3 to investigate the mechanism of formation of prod-
ucts 14 and 15. When 2a was treated with an excess of 13,
the conversion of the starting materials within about 15 min
at room temperature and the generation of intermediate 17
1
could be monitored by IR, H NMR, and 13C NMR spec-
troscopy (Scheme 4 and Table 2). The new functionalized
allenes 17 showed an IR absorption at ν = 1957–1964 cm–1,
˜
1
and the detection of a vicinal CH–NH coupling in the H
NMR spectra, for example, J = 9.8 Hz in the case of 17d,
3
Table 2. Reaction of 2a with 13a–13d, and 13f in CDCl3.
Conclusions
13
Hydroxylamine
Ratio
2a/13
Yields [%][a]
In summary, we have prepared several unexpected bi-
functionalized thiazole derivatives by treating allenyl iso-
thiocyanate (2a) with nucleophiles such as lithium azide or
hydroxylamines. The formation of these products can easily
be explained by mechanisms involving nucleophilic addition
to 2a and ring closure to generate thiazole intermediates.
These intermediates undergo cleavage reactions to give
highly unsaturated species 7 and 21. These then add meth-
anol, hydrazoic acid, or secondary amines to give thiazoles
with new substitution patterns. We assume that these new
synthetic methods can also be used with substituted allenyl
R1
R2
17[b]
14[c]
15[c]
a
a
b
b
b
c
d
f
Me
Me
Et
Et
Et
Me
Me
Et
Et
Et
1:2
2:1
1:2
1.5:2
2:1
1:2
100
100
86
0
62
0
35
58
0
84
21
60
41
0
51
61
0[e]
[d]
–
92
83
80
0[e]
–(CH2)5–
Bn
tBu
Bn
tBu
1:2
1:2
0
0[e]
[a] Yields based on the substoichiometric starting compound (2a
or 13) and 1H NMR standard after monitoring of the reaction.
[b] After about 15 min at room temperature. [c] After approxi-
mately 24 h at room temperature. [d] Not analyzed. [e] No reaction. isothiocyanates 2,[3] and possibly also with other nucleo-
4
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Synthesis of Bifunctionalized Thiazoles
n-hexane/THF, 6:4. The product was recrystallized from CH2Cl2/
philes with weak bonds, such as hydroperoxides or peroxy-
carboxylates.
n-hexane to give 8 (0.19 g, 60%) as yellow needles, m.p. 87–88 °C.
1
IR (neat): ν = 3410 (NH ), 2101 (N ), 1619, 1517 cm–1. H NMR
˜
2
3
(300 MHz, C6D6): δ = 3.49 (br. s, 2 H, CH2N3), 3.77 (br. s, 2 H,
NH2), 6.68 (t, 4J = 0.9 Hz, 1 H, 4-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 47.2 (t, CH2N3), 121.0 (s, C-5), 138.6 (d, C-4), 169.3
(s, C-2) ppm. C4H5N5S (155.20): calcd. C 30.96, H 3.25, N 45.13;
found C 31.15, H 3.48, N 44.99.
Experimental Section
Caution! Care must be taken in handling azides, which are explos-
ive. Neat azides in particular can lead to large explosions on fric-
tion, impact, or heating. Neat allene 2a can spontaneously poly-
merize in a highly exothermic reaction. Thus, larger amounts of
this substance should be handled in solution.
Reaction of 2a with Hydrazine Hydrate: Allene 2a (2.00 g,
20.6 mmol) was added dropwise to a stirred mixture of hydrazine
hydrate (80%; 50.0 mL, 1.03 mol) and methanol (50 mL) at 0 °C.
The mixture was stirred at room temperature for 24 h, then the
methanol and the excess hydrazine hydrate were removed by distil-
lation at 100 °C/26 mbar. The residue consisted of 10 (0.56 g, 21%)
and 11 (1.45 g, 77%). This mixture was treated with CH2Cl2 in a
Soxhlet apparatus for 3 d to give different fractions of the more
soluble 10. Compound 10 was then purified by recrystallization
from CHCl3. The less soluble compound 11 that remained in the
Soxhlet thimble was identical with commercially sourced 11, as
General Methods: Melting points were determined with a Pentakon
Dresden Boetius apparatus. FTIR spectra were recorded with a
Bruker IFS 28 FTIR spectrophotometer. Solutions in KBr cuvettes,
1
KBr pellets, or neat films were used for the IR measurements. H
NMR spectra were recorded with AC-200 (Bruker), Varian Gemini
2000, or Unity Inova 400 spectrometers operating at 200, 300, and
400 MHz, respectively. Using the same spectrometers, 13C NMR
spectroscopic data were recorded at 50, 75, and 100 MHz. NMR
signals were referenced to tetramethylsilane (TMS; δ = 0 ppm), or
to solvent signals and then recalculated relative to TMS. The multi-
plicities of 13C NMR signals were determined with the aid of
DEPT135 experiments. 15N NMR spectra were measured at 30.4
and 40.5 MHz, using MeNO2 as external standard (δ = 0 ppm).
MS and HRMS (ESI) spectra were recorded with an Applied
1
shown by H and 13C NMR spectroscopic data, m.p., and m.p. of
the corresponding mixture (no depression). When pure hydrazine
was used instead of hydrazine hydrate, the yields of 10 and 11
changed to 25 and 71%, respectively.
1-Amino-5-methylimidazole-2(3H)-thione (10): Colorless solid, m.p.
201 °C (decomp.). IR (CHCl ): ν = 3660, 3600, 3020 cm–1. 1H
˜
3
Biosystems Mariner 5229 mass spectrometer or
a Bruker
NMR (200 MHz, [D6]DMSO): δ = 2.05 (d, 4J = 1.2 Hz, 3 H, Me),
micrOTOF-QII spectrometer. MS (EI) spectra were conducted with
a Hewlett Packard 5988 A spectrometer. GC–MS (EI) was carried
out with a GC–MS-QP 5000 quadrupole mass spectrometer
(70 eV) from Shimadzu using helium as carrier gas. Elemental
analyses were carried out with a Vario EL elemental analyzer from
Elementar Analysensysteme GmbH Hanau, or with a Vario Micro
Cube from Elementar. TLC was carried out with Macherey–Nagel
Polygram SIL G/UV254 polyester sheets.
4
5.43 (s, 2 H, NH2), 6.55 (q, J = 1.2 Hz, 1 H, 4-H), 11.58 (br. s, 1
H, NH) ppm. 13C NMR (50 MHz, [D6]DMSO): δ = 9.4 (q, Me),
108.1 (d, C-4), 125.8 (s, C-5), 157.7 (s, C-2). 15N NMR (40.5 MHz,
1
1
[D6]DMSO): δ = –311.2 (t, J = 68 Hz, NH2), –222.4 (br. d, J ≈
90 Hz, N-3), –195.3 (s, N-1) ppm. MS (70 eV, EI): m/z (%) = 129
(100) [M]+, 86 (18), 71 (20). C4H7N3S (129.18): calcd. C 37.19, H
5.46, N 32.53, S 24.82; found C 37.24, H 5.74, N 32.36, S 24.77.
Reaction of 2a with N-Aminophthalimide (12): Allene 2a (10% in
dry THF; 222 mg, 2.30 mmol) was added to a solution of N-amino-
phthalimide (12; 161 mg, 1.00 mmol) in methanol (5 mL). The mix-
ture was stirred for 2 d at room temperature, then a white precipi-
tate of pure bisthiazole 4e was filtered off. The filtrate was concen-
trated in vacuo, and the reside was purified by flash chromatog-
raphy with Et2O/hexane, 1:1 to 3:1 to give first 4e (204 mg as total
amount, 0.57 mmol, 57%) and then 4d (56 mg, 0.22 mmol, 22%)
as colorless solids, which were recrystallized from CHCl3.
Reaction of 2a with Lithium Azide in Methanol: Freshly prepared
allene 2a[3c] (0.66 g, 6.8 mmol) was slowly added to a stirred solu-
tion of lithium azide (1.00 g, 20.4 mmol) in methanol (20 mL) at
0 °C. Liberation of a gas (N2) immediately occurred. The mixture
was stirred at room temperature for 2 d. Then the solvent was re-
moved in vacuo, and the residue was intensively extracted with
CH2Cl2. The organic layers were dried (MgSO4). The solvent was
removed in vacuo to give a mixture of 4b and 9 (0.96 g; 0.21 g
of 4b, 24%; 0.75 g of 9, 76%), which was analyzed by 1H NMR
spectroscopy. The compound 9 was separated and purified by subli-
mation at 60 °C/0.001 Torr.
2-(5-Methylthiazol-2-ylamino)isoindoline-1,3-dione (4d): Colorless
needles, m.p. 190 °C (decomp.). IR (KBr): ν = 2920, 1738 (C=O),
˜
1
4
1597 cm–1. H NMR (400 MHz, CDCl3): δ = 2.26 (d, J = 1.2 Hz,
3 H, Me), 6.80 (q, 4J = 1.2 Hz, 1 H, 4-H), 7.79 (dd, J = 5.6, 3.2 Hz,
2 H), 7.91 (dd, J = 5.6, 3.2 Hz, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 12.1 (q, Me), 123.9 (d), 124.1 (s, C-5), 130.1 (s), 133.3
(d, C-4), 134.6 (d), 165.4 (s, C-2), 168.0 (s, 2 C=O) ppm. HRMS
(ESI+): calcd. for C12H10N3O2S [M + H]+ 260.0494; found
260.0471; calcd. for C12H9N3O2SNa [M + Na]+ 282.0313; found
282.0283.
5-(Methoxymethyl)thiazol-2-ylamine (9): Colorless solid, m.p. 96–
1
97 °C. H NMR (200 MHz, CDCl3): δ = 3.32 (s, 3 H, OMe), 4.44
(br. s, 2 H, CH2), 5.38 (br. s, 2 H, NH2), 6.94 (br. s, 1 H, =CH)
ppm. 13C NMR (50 MHz, CDCl3): δ = 57.1 (q, OMe), 66.7 (t,
CH2), 127.2 (s, C-5), 137.9 (d, C-4), 169.2 (s, C-2) ppm. MS (70 eV,
EI): m/z (%) = 144 (23) [M]+, 113 (100), 86 (20), 45 (40). C5H8N2OS
(144.19): calcd. C 41.65, H 5.59, N 19.43; found C 41.49, H 5.67,
N 19.30.
5-(Azidomethyl)thiazol-2-ylamine (8): A dried solution of hydrazoic
acid in chloroform was prepared from sodium azide (6.50 g,
100 mmol) in water (20 mL) and chloroform (40 mL), by slow ad-
dition of concentrated sulfuric acid (96%; 4.93 g, 2.8 mL,
50.3 mmol) following a standard procedure.[20] Compound 2a (10%
solution in CHCl3; 0.200 g, 2.06 mmol) was added to this solution.
The mixture was stirred at room temperature for 3 d in the dark.
Then the excess hydrazoic acid and the solvent were removed in
vacuo, and the residue was purified by flash chromatography with
2-[Bis(5-methylthiazol-2-yl)amino]isoindoline-1,3-dione (4e): Yellow
crystals, m.p. 265 °C (decomp.). IR (KBr): ν = 3422 (NH), 3022,
˜
2919, 2857, 1761 (C=O), 1524 cm–1. 1H NMR (400 MHz, CDCl3):
4
4
δ = 2.35 (d, J = 1.2 Hz, 6 H, 2 Me), 7.00 (q, J = 1.2 Hz, 2 H, 2
4-H), 7.87 (dd, J = 5.6, 3.2 Hz, 2 H), 8.01 (dd, J = 5.6, 3.2 Hz, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 11.7 (q, 2 Me), 124.6
(d), 127.7 (s), 129.8 (s), 135.2 (d), 135.6 (d), 159.6 (s, C-2), 164.5
(s, 2 C=O) ppm. HRMS (ESI+): calcd. for C16H13N4O2S2 [M + H]
+ 357.0480; found 357.0443; calcd. for C16H12N4O2S2Na [M + Na]
Eur. J. Org. Chem. 0000, 0–0
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K. Banert et al.
FULL PAPER
379.0299; found 379.0262; calcd. for C16H12N4O2S2K [M + K]+
+
(0.190 g, 1.96 mmol) to give 14c (0.054 g, 0.296 mmol, 30%) and
15c (0.078 g, 0.390 mmol, 40%).
395.0039; found 394.9992.
2-(Piperidin-1-yl)-5-methylthiazole (14c): Colorless oil. IR (CCl ): ν
˜
Reaction of Allene 2a with N,N-Dimethylhydroxylamine (13a): 1-
Isothiocyanatopropa-1,2-diene (2a; 10% in dry THF; 445 mg,
4.58 mmol) was added dropwise under nitrogen to N,N-dimethyl-
hydroxylamine (13a)[21] (260 mg, 4.26 mmol) in dry THF (10 mL)
at –5 °C. After 1 h at –5 °C, the reaction mixture was stirred over-
night at room temperature. The solvent was removed under vac-
uum, and the crude products were separated by flash column
chromatography using first diethyl ether/n-hexane, 4:6 to give di-
methyl-(5-methyl-thiazole-2-yl)-amine (14a; 175 mg, 1.23 mmol,
29%), followed by elution with methanol/diethyl ether, 7:93 to give
4
= 2942, 1516, 1122 cm–1. H NMR (300 MHz, CDCl3): δ = 1.61–
1
4
1.67 (m, 6 H, 3Ј-H, 4Ј-H, 5Ј-H), 2.27 (d, J = 1.2 Hz, 3 H, Me-5),
3.38 (m, 4 H, 2Ј-H, 6Ј-H), 6.78 (q, 4J = 1.2 Hz, 1 H, 4-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 11.9 (q, Me-5), 24.1 (t, C-4Ј),
24.9 (t, C-3Ј, C-5Ј), 49.4 (t, C-2Ј, C-6Ј), 121.0 (s, C-5), 135.9 (d, C-
4), 171.0 (s, C-2) ppm. GC–MS: m/z (%) = 182 (52) [M]+, 153
(56), 126 (64), 99 (40), 72 (52), 41 (100). HRMS (ESI+) calcd. for
C9H15N2S [M + H]+ 183.0956; found 183.0997. C9H14N2S (182.29):
calcd. C 59.30, H 7.74, N 15.37; found C 59.59, H 7.16, N 15.48.
5-(dimethylaminomethyl)thiazol-2(3H)-one
(15a;
389 mg,
5-(Piperidin-1-ylmethyl)thiazol-2(3H)-one (15c): Colorless solid,
2.46 mmol, 58%). Compound 15a was recrystallized from diethyl
ether and n-hexane. Treatment of 2a with a twofold excess of 13a
was carried out similarly.
m.p. 136–138 °C. IR (CCl ): ν = 3138 (NH), 2936, 1659 (C=O),
˜
4
1097 cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.41 (m, 2 H, 4ЈЈ-H),
1.56 (m, 4 H, 3ЈЈ-H and 5ЈЈ-H), 2.38 (m, 4 H, 2ЈЈ-H and 6ЈЈ-H),
4
4
Dimethyl-(5-methylthiazol-2-yl)amine (14a): Colorless oil. 1H NMR
3.33 (d, J = 0.9 Hz, 2 H, 1Ј-H), 6.44 (t, J = 0.9 Hz, 1 H, 4-H),
9.87 (br. s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 24.0
(t, C-4ЈЈ), 25.6 (t, C-3ЈЈ, C-5ЈЈ), 53.8 (t, C-2ЈЈ, C-6ЈЈ), 56.4 (t, C-1Ј),
118.1 (d, C-4), 118.9 (s, C-5), 176.3 (s, C-2) ppm. MS (ESI+): m/z
= 199.08 [M + H]+. C9H14N2OS (198.29): calcd. C 54.52, H 7.12,
N 14.13, S 16.17; found C 54.45, H 6.83, N 13.91, S 16.81.
4
(300 MHz, CDCl3): δ = 2.23 (d, J = 1.2 Hz, 3 H, Me-5), 2.98 (s,
6 H, NMe2), 6.75 (q, 4J = 1.2 Hz, 1 H, 4-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 11.9 (q, Me-5), 40.0 (q, NMe2), 120.9 (s, C-
5), 136.3 (d, C-4), 170.4 (s, C-2) ppm. GC–MS: m/z (%) = 142 (47)
[M]+, 113 (89), 100 (30), 71 (54), 44 (100).
Reaction of Allene 2a with N,N-Dibenzylhydroxylamine (13d): Fol-
lowing the procedure described for the reaction of hydroxylamine
13a, N,N-dibenzylhydroxylamine (13d; 0.20 g, 0.94 mmol) was
treated with allene 2a (0.14 g, 1.44 mmol) to give 14d (0.09 g,
0.31 mmol, 33%) and 15d (0.10 g, 0.32 mmol, 35%).
5-(Dimethylaminomethyl)thiazol-2(3H)-one (15a): Colorless solid,
m.p. 105 °C. IR (CCl ): ν = 3125 (NH), 2997, 1645 (C=O) cm–1.
˜
4
1H NMR (400 MHz, CDCl3): δ = 2.24 (s, 6 H, NMe2), 3.29 (d, J
4
4
= 1.2 Hz, 2 H, NCH2), 6.46 (t, J = 1.2 Hz, 1 H, 4-H), 10.1 (br. s,
1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 44.7 (q, NMe2),
57.1 (t, NCH2), 118.0 (s, C-5), 119.3 (d, C-4), 176.1 (s, C-2) ppm.
HRMS (ESI+): calcd. for C6H11N2OS [M + H]+ 159.0592; found
159.0582; calcd. for C6H10N2NaOS [M + Na]+ 181.0412; found
181.0410.
2-Dibenzylamino-5-methylthiazole (14d): Colorless oil. IR (CCl ): ν
˜
4
= 3063, 2920, 1533, 1212 cm–1. H NMR (300 MHz, CDCl3): δ =
1
4
4
2.31 (d, J = 1.2 Hz, 3 H, Me-5), 4.64 (s, 4 H, 1Ј-H), 6.86 (q, J =
1.2 Hz, 1 H, 4-H), 7.25–7.37 (m, 10 H, 2 Ph) ppm. 13C NMR
(75 MHz, CDCl3): δ = 12.0 (q, Me-5), 53.3 (t, C-1Ј), 120.9 (s, C-
5), 127.4 (d), 127.6 (d), 128.6 (d), 136.1 (d, C-4), 136.8 (s), 170.3
(s, C-2) ppm. GC–MS: m/z (%) = 294 (2) [M]+, 203 (26), 91 (100),
65 (35). C18H18N2S (294.42): calcd. C 73.34, H 6.16, N 9.51, S
10.89; found C 73.11, H 5.96, N 9.36, S 11.07.
Reaction of Allene 2a with N,N-Diethylhydroxylamine (13b): Fol-
lowing the procedure described for the reaction with hydroxylamine
13a, N,N-diethylhydroxylamine (13b; 0.20 g, 2.25 mmol) was
treated with allene 2a (0.33 g, 3.37 mmol) to give 14b (0.11 g,
0.65 mmol, 29%) and 15b (0.21 g, 1.25 mmol, 55%). Treatment of
2a with a twofold excess of 13b was carried out similarly.
5-[(Dibenzylamino)methyl]thiazol-2(3H)-one (15d): Colorless solid,
m.p. 169–170 °C. IR (CCl ): ν = 3171 (NH), 1658 (C=O), 1493,
˜
4
Diethyl-(5-methylthiazol-2-yl)amine (14b): Colorless oil. IR (neat):
1120, 1097 cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.43 (s, 2 H,
1Ј-H), 3.59 (s, 4 H, 2 CH2Ph), 6.45 (s, 1 H, 4-H), 7.24–7.41 (m, 10
H, 2 Ph), 9.74 (br. s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3):
δ = 51.0 (t, C-1Ј), 57.3 (t), 117.5 (d, C-4), 120.4 (s, C-5), 127.1 (d),
128.3 (d), 128.7 (d), 138.7 (s), 175.9 (s, C-2) ppm. HRMS (ESI+):
calcd. for C18H19N2OS [M + H]+ 311.1218; found 311.1213.
1
ν = 2971, 1539, 1120 cm–1. H NMR (300 MHz, CDCl ): δ = 1.19
˜
3
(t, 3J = 7.0 Hz, 6 H, CH2Me), 2.61 (d, 4J = 1.2 Hz, 3 H, Me-5),
3
4
3.41 (q, J = 7.0 Hz, 4 H, CH2Me), 6.75 (q, J = 1.2 Hz, 1 H, 4-
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 11.8 (q, Me-5), 12.5 (q,
CH2Me), 45.0 (t, CH2), 119.6 (s, C-5), 136.0 (d, C-4), 168.8 (s, C-
2) ppm. GC–MS: m/z (%) = 170 (27) [M]+, 155 (18), 141 (41), 127
(100), 73 (32).
Reaction of Allene 2a with N-(tert-Butyl)-N-isopropylhydroxylamine
(13e): Following the procedure described for the reaction with hy-
droxylamine 13a, N-(tert-butyl)-N-isopropyl-hydroxylamine (13e;
0.200 g, 1.52 mmol) was treated with allene 2a (0.222 g, 2.29 mmol)
to give 14e (0.106 g, 0.499 mmol, 33%; for characterization data,
see below).
5-(Diethylaminomethyl)thiazol-2(3H)-one (15b): Colorless solid,
m.p. 80–82 °C. IR (CCl ): ν = 3148 (NH), 2972, 1659 (C=O),
˜
4
1
3
1096 cm–1. H NMR (300 MHz, CDCl3): δ = 1.02 (t, J = 7.2 Hz,
6 H, CH2Me), 2.55 (q, 3J = 7.2 Hz, 4 H, CH2Me), 3.46 (d, 4J =
1.2 Hz, 2 H, CH2 at C-5), 6.44 (t, 4J = 1.2 Hz, 1 H, 4-H), 9.49 (br.
s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 11.7 (q,
CH2Me), 46.3 (t, CH2Me), 50.7 (t, CH2 at C-5), 117.1 (d, C-4),
120.6 (s, C-5), 176.1 (s, C-2) ppm, assignments by C–H shift corre-
lation. 15N NMR (30.4 MHz, CDCl3): δ = –315.8 (s, NEt2), –214.6
(d, N-3) ppm. HRMS (ESI+): calcd. for C8H15N2OS [M + H]+
187.0900; found 187.0903. C8H14N2OS (186.28): calcd. C 51.58, H
7.58, N 15.04, S 17.21; found C 51.61, H 7.35, N 14.94, S 16.90.
2-(Piperidin-1-yl)-5-methylthiazole (14c) and 2-Dibenzylamino-5-
methylthiazole (14d): 1-Isothiocyanatopropa-1,2-diene (2a; 0.20 g,
2.06 mmol) in THF (2 mL) was added slowly at 0 °C to a solution
of piperidine (20c; 0.42 g, 4.93 mmol) or dibenzylamine (20d;
0.36 g, 4.92 mmol) and toluene-4-sulfonic acid monohydrate
(0.47 g, 2.47 mmol) in THF (4 mL) and water (2 mL). The mixture
was stirred for 3 d at room temperature, then water (10 mL) was
added, and the product was extracted with diethyl ether (3ϫ
10 mL). The organic layers were combined, dried with MgSO4, and
concentrated under reduced pressure. The residue was purified by
flash chromatography (diethyl ether/n-hexane, 2:8 and 3:8, respec-
Reaction of Allene 2a with N-Hydroxypiperidine (13c): Following
the procedure described for the reaction with hydroxylamine 13a,
piperidin-1-ol (13c; 0.100 g, 0.990 mmol) was treated with allene 2a
6
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Synthesis of Bifunctionalized Thiazoles
tively) to give 14c (0.16 g, 0.88 mmol, 43%) and 14d (0.50 g,
1.68 mmol, 82%) as colorless oils.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra of all new compounds,
and detailed crystallographic information.
N-(tert-Butyl)-N-isopropyl-5-methylthiazol-2-amine (14e): N-Iso-
propyl-tert-butylamine (20e; 115 mg, 1.00 mmol) was added to a
solution of allenyl isothiocyanate (2a; 146 mg, 1.50 mmol) in anhy-
drous THF (5 mL) at 0 °C. The mixture was stirred for 10 h at
room temperature, then the solvent was removed under reduced
pressure. The crude product was purified by flash chromatography
with Et2O/hexane, 1:20 to 1:15 to give 14e (169 mg, 0.80 mmol,
Acknowledgments
B. J. A.-H. thanks the Deutscher Akademischer Austauschdienst
(DAAD) for a PhD fellowship. The authors are indebted to Dr. A.
Ihle for assistance with the manuscript, and to Dr. S. Groth for
some control experiments. M. K. is grateful to the Fonds der
Chemischen Industrie for a PhD fellowship.
80%) as a colorless oil. IR (CCl ): ν = 2974, 2926, 2869, 1536 cm–1.
˜
4
1H NMR (400 MHz, CDCl3): δ = 1.13 (d, 3J = 7.0 Hz, 6 H,
CH(CH3)2), 1.30 [s, 9 H, C(CH3)3], 2.35 (s, 3 H, Me-5), 3.68 [sept,
3J = 7.0 Hz, 1 H, CH(CH3)2], 7.06 (s, 1 H, 4-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 12.5 (q, Me-5), 23.3 [q, CH(CH3)2], 28.9
[q, C(CH3)], 47.4 [d, CH(CH3)2], 57.0 [s, C(CH3)3], 129.3 (s, C-
5), 135.3 (d, C-4), 167.1 (s, C-2) ppm. HRMS (ESI+): calcd. for
C14H19N2S [M + H]+ 247.1269; found 247.1282; calcd. for
C14H18N2SNa [M + Na]+ 269.1088; found 269.1099.
[1] S. J. Kashyap, V. K. Garg, P. K. Sharma, N. Kumar, R. Dudhe,
J. K. Gupta, Med. Chem. Res. 2012, 21, 2123–2132.
[2] a) D. Kikelj, U. Urleb, in: Science of Synthesis vol. 11 (Ed.: E.
Schaumann), Thieme, Stuttgart, Germany, 2001, p. 627–833;
b) J. Liebscher, in: Houben–Weyl, 4th ed., vol. E 8b/II (Ed.: E.
Schaumann), Thieme, Stuttgart, Germany, 1994, p. 1–398; c)
A. Dondoni, P. Merino, in: Comprehensive Heterocyclic Chem-
istry II, vol. 3 (Eds.: A. R. Katritzky, C. W. Rees, E. F. V.
Scriven), Pergamon, Oxford, UK, 1994, p. 373–474.
[3] a) K. Banert, H. Hückstädt, K. Vrobel, Angew. Chem. Int. Ed.
Engl. 1992, 31, 90–92; Angew. Chem. 1992, 104, 72–74; b) K.
Banert, S. Groth, H. Hückstädt, K. Vrobel, Phosphorus Sulfur
Silicon Relat. Elem. 1994, 95–96, 323–324; c) K. Banert, S.
Groth, H. Hückstädt, J. Lehmann, J. Schlott, K. Vrobel, Syn-
thesis 2002, 1423–1433; d) K. Banert, B. Jawabrah Al-Hourani,
S. Groth, K. Vrobel, Synthesis 2005, 2920–2926; e) B. Jawab-
rah Al-Hourani, K. Banert, N. Gomaa, K. Vrobel, Tetrahedron
2008, 64, 5590–5597.
[4] B. Jawabrah Al-Hourani, K. Banert, T. Rüffer, B. Walfort, H.
Lang, Heterocycles 2008, 75, 2667–2679.
[5] a) K. Banert, Liebigs Ann./Recueil 1997, 2005–2018; b) K.
Banert, Targets Heterocycl. Systems 2000, 3, 1–32; c) K.
Banert, K. Fink, M. Hagedorn, F. Richter, ARKIVOC 2012,
3, 379–390.
[6] a) R. Faure, J.-P. Galy, E.-J. Vincent, J. Elguero, J. Heterocycl.
Chem. 1977, 14, 1299–1304; b) R. Faure, J.-P. Galy, E.-J. Vin-
cent, J. Elguero, Can. J. Chem. 1978, 56, 46–55.
[7] S. P. Cornwell, P. T. Kaye, A. G. Kent, G. D. Meakins, J. Chem.
Soc. Perkin Trans. 1 1981, 2340–2343.
Detection of Allene Intermediates 17a–17d and Thiazoles 15a–15d
in NMR and IR Monitoring Experiments: Hydroxylamines 13a–13d
(2 equiv.) were added to 1-isothiocyanatopropa-1,2-diene (2a; 10%
in dry CDCl3: 1 equiv.) at –5 °C. After 10, 13, 15, and 17 min,
1
respectively, H NMR and IR spectra showed no remaining allene
2a. The percentage yields were measured using naphthalene or
grease as standard, and found to be 100, 86, 83, and 80% for 17a,
17b, 17c, and 17d, respectively. After 24, 18, 20, and 21 h, respec-
tively, at room temperature, the reactions were completed to give
one major product in each case, i.e., thiazoles 15a–15d with yields
of 84, 60, 51, and 61%, respectively (grease was also used as a
standard). After 10–17 min as well as after 18–24 h, no signals of
14 could be observed. Experiments with 13a,b and excess amounts
of 2a, which led to detection of 14a,b, 15a,b, and 17a,b, were carried
out similarly.
O-Dimethylamino N-Propa-1,2-dienylthiocarbamate (17a): IR
1
(CDCl ): ν = 1962 (w, allene) cm–1. H NMR (400 MHz, CDCl ):
˜
3
3
4
δ = 2.80 (s, 6 H, NMe2), 5.36 (d, J = 6.4 Hz, 2 H, =CH2), 7.29 (t,
4J = 6.4 Hz, 1 H, =CH), 9.38 (br. s, 1 H, NH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 47.9 (q, NMe2), 86.6 (t, =CH2), 97.0 (d,
=CH), 184.5 (s, C=S), 202.8 (s, =C=) ppm.
O-Diethylamino N-Propa-1,2-dienylthiocarbamate (17b): IR
[8] a) E. Lieber, C. N. Pillai, R. P. Hites, Can. J. Chem. 1957, 35,
832–842; b) S. Hoff, A. P. Blok, Recl. Trav. Chim. Pays-Bas
1974, 93, 317–319.
1
(CDCl ): ν = 1964 (w, allene) cm–1. H NMR (300 MHz, CDCl ):
˜
3
3
3
3
δ = 1.08 (t, J = 7.2 Hz, 6 H, 2 Me), 2.95 (q, J = 7.2 Hz, 4 H, 2
4
4
[9] E. Lieber, J. Ramachandran, Can. J. Chem. 1959, 37, 101–109.
[10] Yellow, needle-like crystals of thiazole 8 were obtained by dif-
fusion-controlled addition of n-hexane into a dichloromethane
solution containing 8 at 25 °C. Crystal structure analysis: data
CH2), 5.33 (d, J = 6.6 Hz, 2 H, =CH2), 7.25 (t, J = 6.6 Hz, 1 H,
=CH), 9.42 (br. s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ
= 11.6 (q, 2 Me), 53.3 (t, 2 CH2), 86.5 (t, =CH2), 96.9 (d, =CH),
186.2 (s, C=S), 202.5 (s, =C=) ppm.
were collected at 298(2) K with Mo-Kα radiation (λ
=
O-Piperidin-1-yl N-Propa-1,2-dienylthiocarbamate (17c): IR
0.71073 Å) with a Bruker Smart CCD 1k diffractometer. Of
3888 collected reflections, 1191 reflections were independent
(Rint = 0.0460). The structure was solved by direct methods
and refined by full-matrix least-squares methods on F2 with
the SHELXTL-97 program package.[11] Crystal data for
C4H5N5S (8): M = 155.91 gmol–1, monoclinic, P21/c, a =
12.911(3), b = 5.4386(10), c = 10.732(2) Å, β = 113.164(3),
V = 692.8(2) Å3, Z = 4, ρc = 1.488 gcm–3, μ = 0.392 mm–1,
R1 = 0.0780 (all data), wR2 = 0.1178 (all data) and goodness-
of-fit on F2 is 1.027. Crystallographic data including bond
lengths, bond and torsion angles have been deposited with the
Cambridge Crystallographic Data Centre (CCDC-953514).
[11] a) G. M. Sheldrick, SHELXS-97, Program for Crystal Struc-
ture Solution, University of Göttingen, Germany, 1997; b)
G. M. Sheldrick, SHELXL-97, Program for Crystal Structure
Refinement, University of Göttingen, Germany, 1997.
1
(CDCl ): ν = 1960 (w, allene) cm–1. H NMR (300 MHz, CDCl ):
˜
3
3
δ = 1.22 (br. qt, J = 13.2, 3.0 Hz, 1 H), 1.62 (qd, J = 11.6, 3.8 Hz,
3 H), 1.83 (dm, J = 13.0 Hz, 2 H), 2.80 (dt, J = 11.0, 3.0 Hz, 2 H),
3.26 (br. dt, J = 9.9, 3.0 Hz, 2 H), 5.33 (d, 4J = 6.6 Hz, 2 H, =CH2),
7.24 (t, 4J = 6.6 Hz, 1 H, =CH), 9.46 (br. s, 1 H, NH) ppm. 13C
NMR (75 MHz, CDCl3): δ = 22.5 (t), 25.1 (t, 2 CH2), 56.8 (t, 2
CH2), 86.6 (t, =CH2), 96.9 (d, =CH), 184.5 (s, C=S), 202.6 (s, =C=)
ppm.
O-Dibenzylamino N-Propa-1,2-dienylthiocarbamate (17d): IR
1
(CDCl ): ν = 1957 (w, allene) cm–1. H NMR (300 MHz CDCl ):
˜
3
3
4
δ = 4.13 (s, 4 H, 2 CH2), 5.24 (d, J = 6.6 Hz, 2 H, =CH2), 6.84
3
4
(dt, J = 9.9, J = 6.6 Hz, 1 H, =CH), 7.32 (m, 10 H, 2 Ph), 8.72
(d, J = 9.3 Hz, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ =
3
62.7 (t, 2 CH2), 86.1 (t, =CH2), 96.6 (d, =CH), 128.2 (d), 128.6 (d),
129.5 (d), 134.3 (s), 184.5 (s, C=S), 202.3 (s, =C=) ppm.
[12] a) K. Banert, Chem. Ber. 1985, 118, 1564–1574; b) K. Banert,
Synthesis 2007, 3431–3446.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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K. Banert et al.
FULL PAPER
[13] H. Beyer, W. Lässig, E. Bulka, D. Behrens, Chem. Ber. 1954,
87, 1392–1401.
[18]
Colorless, plate-like crystals of 15c were obtained by diffusion-
controlled addition of n-hexane into a diethyl ether solution
containing 15c at 25 °C. Crystal structure analysis: data were
collected at 298(2) K with Mo-Kα radiation (λ = 0.71073 Å)
with a Bruker Smart CCD 1k diffractometer. Of 8368 collected
reflections, 1837 reflections were independent (Rint = 0.0396).
The structure was solved by direct methods and refined by full-
matrix least-squares methods on F2 with the SHELXTL-97
program package.[11] Crystal data for C9H14N2OS (15c): M =
[14] Yellow, cube-like crystals of thiazole 4e were obtained by evap-
oration of a chloroform solution containing 4e at 25 °C. Crys-
tal structure analysis: data were collected at 110.00(10) K with
Mo-Kα radiation (λ = 0.71073 Å) with an Oxford Gemini S
diffractometer. Of 6298 collected reflections, 3092 were inde-
pendent (Rint = 0.0247). The Structure was solved by direct
methods and refined by full-matrix least-squares methods on
F2 with the SHELXTL-97 program package.[11] Crystal data
for C16H12N4O2S2 (4e): M = 356.42 gmol–1, monoclinic,
P21/c, a = 14.6245(7), b = 11.2068(5), c = 9.9963(5) Å, β =
104.715(5), V = 1584.60(14) Å3, Z = 4, ρc = 1.494 gcm–3, μ =
0.353 mm–1, R1 = 0.0599 (all data), wR2 = 0.1341 (all data) and
goodness-of-fit on F2 is 1.033. Crystallographic data including
bond lengths, bond and torsion angles have been deposited
with the Cambridge Crystallographic Data Centre (CCDC-
975356).
198.28 gmol–1, monoclinic, P21/c,
5.4534(4), 12.6917(10) Å,
a
=
15.9889(13),
b
=
=
c
=
β
=
107.939(10), V
1052.84(14) Å3, Z = 4, ρc = 1.251 gcm–3, μ = 0.272 mm–1,
R1 = 0.0640 (all data), wR2 = 0.1171 (all data) and goodness-
of-fit on F2 is 1.054. Crystallographic data including bond
lengths, bond and torsion angles have been deposited with the
Cambridge Crystallographic Data Centre (CCDC-953515).
[19]
M. A. Schwartz, X. Hu, Tetrahedron Lett. 1992, 33, 1689–1692.
[20] J. v. Braun, Justus Liebigs Ann. Chem. 1931, 490, 100–179, see
[15] a) A. Dondoni, A. Medici, C. Venturoli, L. Forlani, V. Bertol-
asi, J. Org. Chem. 1980, 45, 621–626; b) A. Medici, P. Pedrini,
C. Venturoli, A. Dondoni, J. Org. Chem. 1981, 46, 2790–2793;
c) E. Ochiai, Y. Kashida, Yakugaku Zasshi 1942, 62, 97–105.
[16] S. P. Cornwell, P. T. Kaye, A. G. Kent, G. D. Meakins, J. Chem.
Soc. Perkin Trans. 1 1981, 2340–2343.
p. 125.
[21] We liberated 13a from its hydrochloride by using a procedure
with ammonia, see: N. W. Mitzel, B. A. Smart, S. Parsons,
H. E. Robertson, D. W. H. Rankin, J. Chem. Soc. Perkin Trans.
2 1996, 2727–2732.
Received: December 12, 2013
[17] M. Witanowski, L. Stefaniak, G. A. Webb, Annu. Rep. NMR
Spectrosc. 1986, 18, 1–761; see p. 99 and 312–315.
Published Online: ᭿
8
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O31851
/KAP1
Date: 17-03-14 16:58:33
Pages: 9
Synthesis of Bifunctionalized Thiazoles
Thiazole Synthesis
B. Jawabrah Al-Hourani, F. Richter,
K. Vrobel, K. Banert,* M. Korb, T. Rüffer,
B. Walfort, H. Lang .......................... 1–9
Synthesis of Unexpected Bifunctionalized
Thiazoles by Nucleophilic Attack on All-
enyl Isothiocyanate
Treatment of allenyl isothiocyanate with
hydroxylamines led to 5-aminomethylthi-
azol-2(3H)-ones. O-Amino N-allenylthio-
carbamates could be detected as intermedi-
ates. Thus, an addition–cyclization–cleav-
age–addition mechanism via the short-lived
5-methylidenethiazol-2(5H)-one is pro-
posed. The reaction of the isothiocyanate
with azide salt or hydrazoic acid gave com-
parable results.
Keywords: Nitrogen heterocycles / Reaction
mechanisms
/
Reactive intermediates
/
Allenes / Isothiocyanates
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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9