4,5-Dihydrothiazoline - A new protecting and activating group for generation of α-aminocarbanions of secondary amines

Article abstract of DOI:10.1080/00397910600941331

4,5-Dihydrothiazoline has been successfully used as a protecting and activating group for synthesis of various 1-substituted 1,2,3,4- tetrahydroisoquinolines via a lithiation-electrophillic substitution reaction sequence. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600941331

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4,5‐Dihydrothiazoline—A New Protecting
and Activating Group for Generation of
α‐Aminocarbanions of Secondary Amines
Kamal Nain Singh a , Paramjit Singh a & Amarjit Kaur a
a Department of Chemistry , Panjab University , Chandigarh, India
Published online: 23 Nov 2006.
To cite this article: Kamal Nain Singh , Paramjit Singh & Amarjit Kaur (2006) 4,5‐Dihydrothiazoline—A New
Protecting and Activating Group for Generation of α‐Aminocarbanions of Secondary Amines, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:22,
3339-3343, DOI: 10.1080/00397910600941331
To link to this article: http://dx.doi.org/10.1080/00397910600941331
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Synthetic Communicationsw, 36: 3339–3343, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600941331
4,5-Dihydrothiazoline—A New Protecting
and Activating Group for Generation of
a-Aminocarbanions of Secondary Amines
Kamal Nain Singh, Paramjit Singh, and Amarjit Kaur
Department of Chemistry, Panjab University, Chandigarh, India
Abstract: 4,5-Dihydrothiazoline has been successfully used as a protecting and acti-
vating group for synthesis of various 1-substituted 1,2,3,4-tetrahydroisoquinolines
via a lithiation–electrophillic substitution reaction sequence.
Keywords: a-Aminocarbanion, 4,5-dihydrothiazoline, protecting group, 1,2,3,4-
tetrahydroisoquinoline
a-Aminocarbanions are valuable intermediates in organic synthesis and have
been effectively used for carbon–carbon bond formation adjacent to the
nitrogen atom.[1] Generation of a-aminocarbanions from primary and
secondary amines is facilitated by covalent attachment of an activating
group to the nitrogen atom of the amine. The carbanion, formed after depro-
tonation, is then reacted with an appropriate electrophile and in the final step
the activating group is detached from the product. For activation of primary
amines isonitrile, a-(nitrosoamino)-alkyl ethers and tert-butyldiphenyl-
methylhydrazones have been used.[1] The activating groups used for the
secondary amines include nitrosoamines,[2] amides,[3] formamidines,[4] oxa-
zolines,[5] and carbamates[6] The Lewis acid complexation methodology
more recently has been developed for generation of a-aminocarbanions in
tertiary amines.[7]
Received in India April 27, 2006
Address correspondence to Kamal Nain Singh, Department of Chemistry, Panjab
University, Chandigarh, India. E-mail: kns@pu.ac.in
3339

3340
K. N. Singh, P. Singh, and A. Kaur
Although a number of functionalities have been used for a-activation
of secondary amines, some of them suffer from disadvantages, for example,
the carcinogenic nature of N-nitrosoamines[8] and harsh conditions required
for the removal of the activating group as in the case of N,N-diethyl
amides.[9] In this context we have explored the potential of 4,5-dihydrothiazo-
line as a protecting-cum-activating group for secondary amines. For this
study 1,2,3,4-tetrahydroisoquinoline was selected because the resulting
1-substituted 1,2,3,4-tetrahydroisoquinolines are abundant in plant products
and many exhibit interesting biological activities (Figure 1).[10]
Figure 1.
2-Mercaptothiazoline 1 was treated with methyl iodide in refluxing acetone
to afford 2-methyl-sulphanyl-4,5-dihydrothiazoline hydroiodide 2 as a pale
yellow solid, mp 114–1168C (lit.[11] mp 115–1178C), which was neutralized
with K2CO3 to furnish 3 as an oil. Reaction of 1,2,3,4-tetrahydroisoquinoline
with 2-methyl-sulphanyl-4,5-dihydrothiazolene 3, according to conditions
described by Bigg et al.,[12] furnished 2-(4,5-dihydro-thiazol-2-yl)-1,2,3,4-
tetrahydroisoquinoline 4 in 79% yield. In a model reaction, metallation of 4
was performed by using 1.2 equiv. of LDA in THF at –788C followed by
reaction with D2O. After workup, the 1H NMR spectrum of the crude product
indicated 92% deuterium incorporation at the C-1 position (6, E ¼ D).
Reaction of the intermediate 5 with different electrophiles afforded the C-1 sub-
stituted products 6. The protecting group was removed by the treatment with
hydrazine and acetic acid, according to conditions described by Meyers
et al.,[13] to generate the free amines 7 in high yields (Table 1).
These results clearly support the versatility of 4,5-dihydrothiazoline as an
activating group for a-functionalization of secondary amines and compare
favorably with those of oxazolines and formamidines reported by Gawley[5]
and Meyers.[4]

Generation of a-Aminocarbanions of Secondary Amines
3341
Table 1. Preparation of 1-substituted 1,2,3,4-tetrahydroisoquinolines 7
Yield
(%)a
Derivative/mp
(8C)
Entry Electrophile (Eþ)
7 (E ¼ )
1
CH3I
CH3
82
Picrate/
185–187
Lit.[14] mp 187
Oxalate/187
Lit.[15] mp 188
Oxalate/
2
3
BuI
n-C4H9
76
78
CH255CHCH2Br
CH255CHCH2-
167–168
Lit.[15] mp.169
Picrate/
167–168
4
5
C6H5CH2Br
Ph2CO
C6H5CH2-
72
70
58
Lit.[16] mp
166–167
Ph2(OH)C-
(CH2)4(OH)C-
Hydrochloride/
256–257
Lit.[17] mp.
259–260
6
7
(CH2)4C55O
Free base/
100–101
Lit.[18] mp 106
Hydrochloride/
195–197
3,4-(MeO)2C6H3CHO 3,4-(MeO)2C6H3C(OH)H- 68
Lit[19] mp.
198.5–200
Picrate/138–140
Lit.[15] mp
142–142.5
—
8
9
i-PrI
i-Pr-
62
65
PhSSPh
PhS
aYield refers to pure isolated sample characterized by relevant spectral data.
2-METHYL-SULPHANYL-4,5-DIHYDROTHIAZOLINE (3)
solution of 2-mercaptothiazoline (20 g, 168 mmol) and methyl
A
iodide (23.7 g, 10.4 ml, 168 mmol) in dry acetone (200 ml) was heated
under reflux for 3 h, cooled, filtered, and washed with acetone to give
2-methyl-sulphanyl-4,5-dihydrothiazoline hydroiodide 2 (41.0 g, 94%), mp
114–1168C (lit.[11] mp 115–1178C). A saturated aqueous solution of the
hydroiodide salt 2 (10 g, 62 mmol) was neutralized with solid potassium
carbonate and extracted with CH2Cl2 (4 ꢀ 20 mL). The combined organic
layer was washed with brine and dried over anhydrous sodium sulphate.
The solvent was removed under reduced pressure to give 3 (7.2 g, 88%) as
a viscous liquid.

3342
K. N. Singh, P. Singh, and A. Kaur
IR (Nujol): 1630 cm21 C55N; 1H NMR (300 MHz, CDCl3): d 2.1 (s, 3H,
SCH3), 2.4 (t, 2H, CH2N), 2.9 (t, 2H, CH2S).
2-(4,5-DIHYDRO-THIAZOL-2-YL)-1,2,3,4-
TETROHYDROISOQUINOLINE (4)
A solution of 2-methyl-sulphanyl-4,5-dihydrothiazoline 3 (5 g, 30 mmol) and
1,2,3,4-tetrahydroisoquinoline (4 g, 3.77 mL, 30 mmol) in ethanol (50 mL)
was heated under reflux for 10 h. The solvent was removed under reduced
pressure, and the residue, was distilled to give 4 (15.9 g, 79%), liquid, bp
140–448C/0.2 Torr. The compound solidified on standing and was recrystal-
lized from hexane/CH2Cl2 to afford an analytically pure sample (mp
54–568C).
IR (Nujol): 1615 cm21 C55N; 1H NMR (300 MHz, CDCl3): d 2.84–2.88
(t, 2H, ArCH2 CH2), 3.2–3.3 (t, 2H, SCH2), 3.67 (t, 2H, ArCH2CH2), 3.99–
4.02 (t, 2H, –CH55N–CH2), 4.63 (s, 2H, ArCH2N), 7.05–7.15 (m, 4H, ArH);
13C NMR (75 MHz, CDCl3): d 28.65, 34.75, 39.76, 46.32, 49.68, 59.78,
125.97, 126.21, 126.69, 126.79, 128.34, 128.85. 163.96; anal. calcd. for
C12H14N2S: C, 66.05; H, 6.42; N, 12.84. Found: C, 66.10; H, 6.38; N, 12.79.
1-BENZYL-1,2,3,4-TETRAHYDROISOQUINOLINE (TABLE 1,
ENTRY 4)
To a well-stirred solution of LDA [prepared from diisopropyl amine (0.27 g,
0.38 mL, 2.6 mmol) and n-BuLi (1.25 mL, 2.2 M, 2.6 mmol) in THF (5 mL)]
at 2788C, a solution of 4 (0.5 g, 2.2 mmol) in THF (3 mL) was added. The
dark-red-colored solution was stirred for 30 min followed by addition of
benzyl bromide (0.44 g, 0.30 mL, 2.6 mmol). The reaction mixture was
allowed to come to room temperature and quenched with 10% aqueous
NH4Cl solution. It was extracted with CH2Cl2 (4 ꢀ 15 mL), washed with
water and brine, and dried over anhydrous sodium sulphate. The solvent
was evaporated to furnish a crude material (0.66 g). It was taken up in
hydrazine hydrate (0.84 g, 0.82 mL, 16.8 mmol), glacial acetic acid (0.38 g,
0.36 mL, 6.3 mmol), and ethanol (20 mL). The reaction mixture was stirred
at 608C for 12 h. The solvent was evaporated and the residue partitioned
between water and CH2Cl2. The organic layer was washed with water and
brine and dried over sodium sulphate. The solvent was evaporated, and the
residue purified by the column chromatography over silica gel by eluting
with hexane/ethyl acetate (6:4) to give 7 (E55CH2C6H5, 0.31 g, 72%).
1
IR (CHCl3): 3400 cm21 (NH); H NMR (CDCl3): d 2.2 (br s, 1H, NH,
D2O exchangeable), 2.58–2.85 (m, 4H 2 ꢀ ArCH2), 3.03–3.21 (m, 2H,
ArCH2CH2), 4.11–4.16 (dd, 1H), 7.00–7.47 (m, 9H, ArH); 13C NMR
(CDCl3): d 29.58, 40.30, 41.62, 42.21, 56.85, 119.44, 125.36, 125.82,

Generation of a-Aminocarbanions of Secondary Amines
3343
126.10, 126.80, 126.98, 128.26, 128.44, 128.67, 129.00, 129.44, 134.88,
138.27, 138.62; MS, m/z (relative intensity): 224 (Mþ2 þ2, 0.8); 222 (2),
226 (3), 218 (1), 133 (12), 132 (100), 117 (10), 115 (5), 91 (10), 77 (6),
anal. calcd. for C22H20N4O7 (Picrate): C, 58:40; H, 4.46; N, 12.39. Found:
C, 58.23; H, 4.51; N, 12.36. Picrate derivative, mp 167–1688C, lit.[16] mp
166–1678C.
ACKNOWLEDGMENT
Financial support from CSIR, New Delhi, India, is gratefully acknowledged.
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