Modified asymmetric strecker reaction of aldehyde with secondary amine: A protocol for the synthesis of S-clopidogrel (an antiplatelet agent)

Article abstract of DOI:10.1021/jo300642z

A first approach for catalytic asymmetric Strecker reaction of aldehydes with a secondary amine in the presence of sodium fluoride using hydroquinine as chiral catalyst was developed. The catalytic system gave α-aminonitriles in excellent yields (up to 95

Full text of DOI:10.1021/jo300642z

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Note
Modified Asymmetric Strecker Reaction of Aldehyde with Secondary
amine: A Protocol for the Synthesis of S-Clopidogrel (an Antiplatelet agent)
Arghya Sadhukhan, S Saravanan, Noor-ul H. Khan,
Rukhsana I. Kureshy, Sayed H. R. Abdi, and Hari Chand Bajaj
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo300642z • Publication Date (Web): 26 Jul 2012
Downloaded from http://pubs.acs.org on July 26, 2012
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Modified Asymmetric Strecker Reaction of Aldehyde with
Secondary amine: A Protocol for the Synthesis of S-Clopidogrel (an
Antiplatelet agent)
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Arghya Sadhukhan, S. Saravanan, Noor-ul H. Khan,* Rukhsana I. Kureshy, Sayed
H. R. Abdi and Hari C. Bajaj
Discipline of Inorganic Materials and Catalysis, Central Salt and Marine Chemicals Research
Institute (CSMCRI), Council of Scientific & Industrial Research (CSIR), G. B. Marg,
Bhavnagar- 364 021, Gujarat, India. Fax: +91-0278-2566970; Tel: +91-0278-2566970;
E-mail: khan251293@yahoo.in.
ABSTRACT:
A first approach for catalytic asymmetric Strecker reaction of aldehydes with secondary amine in
the presence of sodium fluoride using hydroquinine as chiral catalyst was developed. The
catalytic system gave α-aminonitriles in excellent yields (up to 95%) and high
enantioselectivities (er up to 94:6). The efficacy of the chiral product was successfully fulfilled
in the improved synthesis of (S)-clopidogrel (an antiplatelet agent).
α-Aminonitriles1 are useful intermediates for the synthesis of pharmaceutically important chiral
amino acids2 and their derivatives, ligands, peptides and natural products.3 The enantioselective
addition of cyanide to imines (Strecker type reaction) to synthesize α-aminonitriles is well
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documented and are often catalyzed by enzymes,1b organo-catalyst4 and metal complexes.5 Yet,
the enantioselective addition of cyanide to iminium salt (in situ generated by the reaction of an
aldehyde with secondary amine) to synthesize α-aminonitrile derivatives is not reported, though
few reports are available in the literature6 for its racemic version. Harwood et al. have reported
diastereoselectve Strecker reaction of chiral iminium ion derived from (S)-5-phenylmorpholin-2-
one.7 In this reaction dry HCl was used as catalyst with CuCN as cyanide source which gave the
product with diastereomeric ratio (up to 15.4:1) which was most likely substrate driven. Herein,
we are reporting for the first time the synthesis of asymmetric α-aminonitriles by asymmetric
Strecker reaction of various iminium ions by using several chiral alkaloids as organocatalyst 1a-
1e in the presence of sodium fluoride. These iminium ions were generated in situ by the reaction
of various aldehydes with secondary amines viz., morpholine 2 and 4,5,6,7-tetrahydrothieno[3,2-
c]pyridine 3. The Strecker reaction with secondary amine 3 was studied for their use as precursor
to the drug clopidogrel. The choice of chiral alkaloids was based on their known prowess in
catalyzing asymmetric Strecker reaction.8 When we conducted the model reaction with
benzaldehyde and morpholine in the presence of quinine 1a (30 mol%) using TMSCN as a
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cyanide source in CH2Cl2 as solvent at -20 C for 16 h the product formed was in trace quantity
(Table 1, entry 1). On the addition of sodium fluoride (10 mol%) to the above reaction, there was
sizeable improvement in the product yield (89%) and enantioselectivity (er, 73:27) (entry 2)
under the same reaction condition. The consideration of NaF as an additive was based on strong
affinity of fluoride ion towards the silicon which was envisaged to facilitate the polarization of
Si-CN bond of TMSCN. In fact, when the above model reaction was conducted in the absence of
quinine, but in the presence of NaF, the product (racemic) formed in good yield (entry 3). Next,
we screened other related alkaloids 1b-1e for their catalytic ability towards the above model
Strecker reaction keeping other reaction parameters constant (entries 4-7). Among these
alkaloids, 1d was found to be better catalyst in terms of enantioselectivity (entry 6). A slow and
simultaneous addition of NaF and TMSCN (over a period of 3 h) to a stirred solution of
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benzaldehyde and morpholine in the presence of 1d in CH2Cl2 at -20 C significantly improved
the enantioselectivity of the product (entry 8) possibly by suppressing the background reaction
(responsible for the racemic product) caused by NaF. The same reaction when conducted at
further reduced temperature (-40 oC) gave the product in lower yield but with no improvement in
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the enantioselectivity (entry 9). Hence, -20 C was taken as preferred temperature to see the
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effect of solvent on this reaction (entries 10-12), however none of these (toluene, THF and
CH3CN) could match the performance of CH2Cl2 (entry 8). There is a possibility that source of
fluoride may influence the performance of Strecker reaction hence, the effect of various fluoride
salts e.g., LiF, NaF, KF, NH4F and (t-Bu)4NF was evaluated under the above optimized
condition (entries 13-16) where NaF was found to be most effective.
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Table 1. Screening of the catalysts for the catalytic modified asymmetric Strecker reactiona
with secondary amine
entry
catalyst
solvent
fluoride salt
yield (%)b
trace
89
erc
Nd
1
2
3
4
5
6
1a
1a
-
dichloromethane
dichloromethane
dichloromethane
dichloromethane
dichloromethane
dichloromethane
-
NaF
NaF
NaF
NaF
NaF
73:27
-
82
1b
1c
1d
82
66:34
70:30
82:18
85
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1e
1dd
1de
1d
1d
1d
1d
1d
1d
1d
dichloromethane
dichloromethane
dichloromethane
toluene
NaF
NaF
NaF
NaF
NaF
NaF
LiF
80
90
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76
88
85
80
92
85
92
54:46
94:6
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94:6
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86:14
89:11
80:20
80:20
70:30
75:25
88:12
tetrahydrofuran
acetonitrile
dichloromethane
dichloromethane
dichloromethane
dichloromethane
KF
NH4F
TBAF
aReagents and conditions: benzaldehyde (0.032 g, 0.3 mmol), morpholine (0.028 g, 0.32
mmol), catalyst (30 mol%), NaF (10 mol%), dichloromethane (0.8 mL) were taken and TMSCN
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b
(1.2 equiv.) was added over 3 h at -20 C (total reaction time 16 h). Isolated yield.
cDetermined by HPLC analysis on chiral OD column. dSolid NaF and TMSCN were
simultaneously added slowly over 3 h. eReaction was carried out at -40 oC.
The scope of the present Strecker protocol was extended to various substituted benzaldehydes,
naphthaldehyde, cyclohexylcarboxaldehyde and isovaleraldehyde with secondary amines 2 and 3
under the optimized condition (as entry 8 of Table 1) and the results are summarized in Scheme
1. The outcomes of these reactions however, do not suggest a trend indicating the effect of
electronic and steric properties of the substrates used herein. Among the various substrates used,
2-Cl-benzaldehyde with secondary amine 3 was of particular interest as its product gave
antiplatelet agent (S)-clopidogrel9 (er 78:22) in two steps10 (Scheme 2) against multistep
synthesis reported in the literature.9 It is worth mentioning here that the above optimized
protocol for the modified Strecker reaction of benzaldehyde with morpholine catalysed by
several organocatalysts like L-proline, L-Boc-phenylalanine, (S)-mandelic acid, L-
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diethyltartarate, (S)-BINOL, and tosylated (1S,2S)-1,2-diaminocyclohexane gave racemic
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product or with poor enantiomeric ratio (data are given in supporting information Table- 1S).
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Scheme 1. Scope of the catalytic modified asymmetric Strecker reaction with secondary
amine
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Scheme 2. Synthetic utility of the product: synthesis of (S)-Clopidogrel
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1
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In order to demonstrate the suggested influence of fluoride on TMSCN H, C and Si NMR
spectra of TMSCN in the presence of NaF were recorded in CDCl3 (Figure 1). All three methyl
group of TMSCN (spectrum a) that appeared as a singlet at 0.23 ppm in 1H NMR got downfield
shifted by 40.5 Hz on the addition of NaF (0.31 ppm, spectrum b). This phenomenon was also
seen in 13C NMR where methyl carbon signal of TMSCN at -1.25 ppm was downfield shifted (8
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Hz) to -1.23 ppm on the addition of NaF. However, more conclusive evidence was seen in Si
NMR, where a clear downfield shifting of Si signal of TMSCN from -11.10 ppm to 7.42 ppm
was observed on the addition of NaF (Figure 1). This shift also suggests that there is no
replacement of NC- of TMSCN with F-, as in the event of this the 29Si signal of (CH3)3SiF would
have appeared at 30 ppm.11 Consequently, it can be suggested that NaF is merely assisting in
polarising the Si-CN bond in order to facilitate the transfer of CN to the substrate iminium ion.
(c)
(d)
-11.0
7.27
(a)
(b)
0.23
0.31
0.4
0.3
0.2
0.1
0.0
-0.1
15
10
5
0
-5
-10
-15
-20
-25
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Figure 1. NMR comparison (a) H NMR of TMSCN; (b) TMSCN + NaF; (c) Si NMR of
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TMSCN + NaF; (d) Si NMR of TMSCN; (e) C NMR of TMSCN and (f) C NMR of
TMSCN+ NaF.
In conclusion, we have developed a straightforward catalytic protocol for the asymmetric
modified Strecker reaction of aldehydes with secondary amine to synthesize α–aminonitriles
with enantiomeric ratios (er) of up to 94:6. The present protocol also provides a new route for the
synthesis of S-Clopidogrel- an antiplatelet agent.12
EXPERIMENTAL SECTION
Typical procedure for asymmetric Strecker reaction of aldehyde with
secondary amine using benzaldehyde and morpholine as an example:
Caution! TMSCN must be used carefully in well-ventilated hood due to its high toxicity. A
mixture of benzaldehyde (0.032 g, 0.3 mmol), morpholine (0.028 g, 0.32 mmol) and catalyst 1d
(0.09 mmol) in CH2Cl2 (0.8 mL) was cooled to -20 0C, to which TMSCN (0.36 mmol) NaF (0.03
mmol) were added simultaneously over 3.5 h and the reaction mixture was allowed to stir for 16
h. After the reaction was completed, the reaction mass was filtered by passing through a pad of
celite and washed with water (3 x 15 mL) followed by brine and the organic layer was separated
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and dried with anhydrous Na2SO4. The solution was filtered, evaporated under reduced pressure
at ambient temperature and the α-aminonitrile product was purified by flash column
chromatography on silica gel (eluted with hexane: ethylacetate = 90:10). The enantiomeric ratio
of α-aminonitrile was determined by HPLC analysis.
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2-Morpholino-2-phenyl acetonitrile (4a).
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55 mg, 90% yield, white solid (amorphous); mp 70-72 C; H NMR (500 MHz, CDCl3): δ 7.53
(t, J = 5.0 Hz, 1H), 7.43-7.37 (m, 3H), 4.82 (s, 1H), 3.77-3.70 (m, 4H), 2.59 (t, J = 4.0 Hz, 4H);
13C NMR (125 MHz, CDCl3); δ 132.1, 129.3, 129.0, 128.2, 115.4, 66.9, 62.6, 50.2; [α]D30 = -28.2
(c = 0.035 in isopropanol); TOF–MS (ESI+); m/z calcd. for C12H14N2O (M+1) 203.11, Found
203.12; Anal. Calcd. For C12H14N2O: C, 71.26; H, 6.98; N, 13.85, O, 7.91. Found: C, 71.28; H,
6.95; N, 13.83, O, 7.90; HPLC (CHIRALPAK OD, i-PrOH/ Hexane = 10/90, Flow rate 0.8 mL/
min, λ = 254 nm): t (major) = 9.94 min, t (minor) = 10.79 min, er = 94:6.
2-Morpholino-2-(o-tolyl) acetonitrile (4b).
59 mg, 92% yield, viscous liquid; 1H NMR (500 MHz, CDCl3): δ 7.59 (d, J =10.0 Hz, 1H), 7.38-
7.36 (m, 1H), 7.34-7.29 (m, 2H), 4.93 (s, 1H), 3.77-3.72 (m, 4H), 2.66-2.63 (m, 4H), 2.48 (s,
3H); 13C NMR (125 MHz, CDCl3); δ 137.4, 131.2, 130.5, 129.2, 128.7, 125.9, 115.3, 66.7, 60.6,
49.7, 18.8; [α]D30 = -23.5 (c = 0.031 in isopropanol); TOF–MS (ESI+); m/z calcd. for C13H16N2O
(M+1) 217.13, Found 217.11; Anal. Calcd. For C13H16N2O: C, 72.19; H, 7.46; N, 12.95, O, 7.40.
Found: C, 72.18; H, 7.45; N, 12.96, O, 7.41;. HPLC (CHIRALPAK OD, i-PrOH/ Hexane =
10/90, Flow rate 0.6 mL/ min, λ = 254 nm): t (major) = 19.78 min, t (minor) = 22.58 min, er =
92:8.
2-(2-Fluorophenyl)-2-morpholino acetonitrile (4c).
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62 mg, 95% yield, viscous liquid; H NMR (500 MHz, CDCl3): δ 7.55-7.52 (m,1H), 7.43-7.39
(m, 1H), 7.22 (t, J = 10.5 Hz, 1H), 7.15 (t, J = 10.5 Hz, 1H), 5.03 (s, 1H), 3.72-3.68 (m, 4H),
2.62-2.60 (m, 4H); 13C NMR (125 MHz, CDCl3); δ 161.5, 159.5, 131.3, 130.2, 124.2, 119.9,
119.8, 116.2, 116.1, 114.8, 66.5, 56.2, 49.9; [α]D 30 = -31.1 (c = 0.032 in isopropanol); TOF–MS
(ESI+); m/z calcd. for C12H13FN2O (M+1) 221.10, Found: 221.11; Anal. Calcd. For
C12H13FN2O: C, 65.44; H, 5.95; N, 12.72, O, 7.26. Found: C, 65.43; H, 5.96; N, 12.70, O, 7.25;
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HPLC (CHIRALPAK AD, i-PrOH/ Hexane = 10/90, Flow rate 0.8 mL/ min, λ = 247 nm): t
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(major) = 17.88 min, t (minor) = 19.20 min, er = 92:8.
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2-Morpholino-(2-naphthalen-1-yl) acetonitrile (4d).
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68 mg, 90% yield, white solid (amorphous); mp 128-130 C; H NMR (500 MHz, CDCl3): δ
8.12 (t, J = 5.5 Hz, 1H), 7.91-7.86 (m, 2H), 7.52-7.49 (m, 2H), 7.05 (d, J = 5.0 Hz, 1H), 6.67 (d,
J = 5.0 Hz, 1H), 5.66 (s, 1H), 3.83 (d, J = 14.0 Hz, 1H), 3.66 (d, J = 10.5 Hz, 1H), 2.99 (t, J = 5.5
Hz, 2H); 13C NMR (125 MHz, CDCl3); δ 135.5, 132.4, 131.8, 130.3, 129.1, 128.6, 128.2, 127.8,
126.2, 125.1, 116.6, 68.1, 62.5, 51.3; [α]D30 = -41.0 (c = 0.032 in isopropanol); TOF–MS (ESI+);
m/z calcd. for C16H16N2O 252.13, Found: 252.11; Anal. Calcd. For C16H16N2O: C, 76.16; H,
6.39; N, 11.10, O, 6.34. Found: C, 76.18; H, 6.41; N, 11.09, O, 6.33; HPLC (CHIRALPAK OD,
i-PrOH/ Hexane = 10/90, Flow rate 0.8 mL/ min, λ = 247 nm): t (major) = 9.99 min, t (minor) =
8.96 min, er = 91.5:8.5.
2-Morpholino-2-(p-tolyl) acetonitrile (4e).
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58 mg, 90% yield, white solid (amorphous); mp 91-93 C; H NMR (500 MHz, CDCl3): δ 7.32
(d, J = 8.5 Hz, 2H), 7.12 (d, J = 10.0 Hz, 2H), 4.70 (s, 1H), 3.65-3.63 (m, 4H), 2.52-2.49 (m,
13
4H), 2.29 (s, 3H); C NMR (125 MHz, CDCl3); δ 140.4, 130.9, 129.3, 116.8, 68.1, 63.6, 51.3,
30
22.5; [α]D = +21.0 (c = 0.030 in isopropanol); TOF–MS (ESI+); m/z calcd. for C13H16N2O
(M+1) 217.13, Found: 217.12; Anal. Calcd. For C13H16N2O: C, 72.19; H, 7.46; N, 12.95, O,
7.40. Found: C, 72.15; H, 7.44; N, 12.96, O, 7.43; HPLC (CHIRALPAK OD, i-PrOH/ Hexane =
10/90, Flow rate 0.8 mL/ min, λ = 254 nm): t (major) = 7.73 min, t (minor) = 7.23 min, er =
79.5:20.5.
2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-phenylacetonitrile (4f).
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72 mg, 95% yield, white solid (amorphous); mp 84-86 C; H NMR (500 MHz, CDCl3): δ 7.60
(d, J = 9.0, Hz, 2H), 7.43-7.40 (m, 3H), 7.10 (d, J = 5.0 Hz, 1H), 6.71 (d, J = 5.0 Hz, 1H), 5.09
(s, 1H), 3.71 (d, J = 14.0Hz, 1H), 3.66 (d, J = 14.0, 1H), 2.97-2.88 (m, 4H); 13C NMR (125
MHz, CDCl3); δ 133.4, 130.5, 130.3, 129.3, 126.5, 124.6, 116.9, 63.7, 51.3, 49.1, 27.1; [α]D32 = +
33.4 (c = 0.030 in isopropanol); TOF–MS (ESI+); m/z calcd. for C15H14N2S 254.09, Found
254.10; Anal. Calcd. For C15H14N2S: C, 70.83; H, 5.55; N, 11.01, S, 12.61. Found: C, 70.85; H,
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5.54; N, 11.00, S, 12.64; HPLC (CHIRALPAK OD, i-PrOH/ Hexane = 10/90, Flow rate 0.8 mL/
min, λ = 247 nm): t (major) = 16.88 min, t (minor) = 12.06 min, er = 81:19.
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2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl) acetonitrile (4g).
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79 mg, 92% yield, white solid (amorphous); mp 123-125 C; 1H NMR (500 MHz, CDCl3): δ
7.66-7.61 (m, 1H), 7.39-7.29 (m, 3H), 6.62 (d, J = 12.5 Hz, 1H), 5.25 (s, 1H), 3.70 (d, J = 15.5
Hz, 1H), 3.55 (d, J = 15.5, 1H), 2.95-2.84 (m, 4H); 13C NMR (125 MHz, CDCl3); δ 134.6, 133.0,
132.5, 130.9, 130.6, 130.1, 126.9, 125.1, 123.1, 115.2, 59.3, 49.5, 47.8, 25.6; [α]D30 = +30.7 (c =
0.030 in isopropanol); TOF–MS (ESI+); m/z calcd. for C15H13ClN2S (M+1) 289.05, Found:
289.00; Anal. Calcd. For C15H13ClN2S: C, 62.38; H, 4.54; N, 9.70, S, 11.10. Found: C, 62.35; H,
4.56; N, 9.71, S, 11.13; HPLC (CHIRALPAK OD, i-PrOH/ Hexane = 10/90, Flow rate 0.8 mL/
min, λ = 247 nm): t (major) = 8.36 min, t (minor) = 7.76 min, er = 78:22.
2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-fluorophenyl) acetonitrile (4h).
1
75 mg, 92% yield, white solid (amorphous); mp 92-94 oC; H NMR (500 MHz, CDCl3): δ 7.62
(t, J = 7.5 Hz, 1H), 7.45-7.41 (m, 1H), 7.13 (t, J = 9.25 Hz, 1H), 7.09 (d, J = 5.5 Hz, 1H), 6.71
(d, J = 5.0 Hz, 1H), 5.28 (s, 1H), 3.77 (d, J = 14.0 Hz, 1H), 3.68 (d, J = 14.0 Hz, 1H), 3.02-2.96
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(m, 3H), 2.91- 2.86 (m, 1H); C NMR (125 MHz, CDCl3); δ 162.9, 160.9, 134.2, 133.9, 132.7,
30
131.5, 126.5, 125.6, 124.6, 117.5, 116.5, 57.3, 51.0, 49.3, 27.0; [α]D = -27.4 (c = 0.030 in
isopropanol); TOF–MS (ESI+); m/z calcd. for C15H13FN2S (M+1) 289.05, Found 289.00; Anal.
Calcd. For C15H13FN2S: C, 66.15; H, 4.81; N, 10.29, S, 11.77. Found: C, 66.11; H, 4.80; N,
10.25, S, 11.75; HPLC (CHIRALPAK OD, i-PrOH/ Hexane = 10/90, Flow rate 0.8 mL/ min, λ
= 247 nm): t (major) = 12.56 min, t (minor) = 11.65 min, er = 81.5:18.5.
2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(naphthalen-1-yl) acetonitrile (4i).
o
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84 mg, 93% yield, white solid (amorphous); mp 68-70 C; H NMR (500 MHz, CDCl3): δ 8.14
(t, J = 5.0 Hz, 1H), 7.92-7.87 (m, 3H), 7.54-7.50 (m, 3H), 7.07 (d, J = 5.0 Hz, 1H), 6.69 (d, J =
5.0 Hz, 1H), 5.67 (s, 1H), 3.85 (d, J = 14.0 Hz, 1H), 3.65 (d, J = 14.0 Hz, 1H), 3.00 ( t, J = 5.5
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Hz, 2H), 2.94-2.89 (m, 1H), 2.80-2.74 (m, 1H); C NMR (125 MHz, CDCl3); δ 135.5, 134.4,
134.1, 132.4, 131.7, 130.1, 129.7, 128.3, 127.7, 126.5, 126.2, 125.2, 124.5, 116.9, 62.1, 57.2,
48.9, 27.1; [α]D32 = -32.4 (c = 0.035 in isopropanol); TOF–MS (ESI+); m/z calcd. for C19H16N2S
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(M+1) 305.11, Found: 305.10; Anal. Calcd. For C19H16N2S: C, 74.97; H, 5.30; N, 9.20, S, 10.53.
Found: C, 74.94; H, 5.34; N, 9.18, S, 10.50; HPLC (CHIRALPAK OD, i-PrOH/ Hexane =
10/90, Flow rate 0.6 mL/ min, λ = 274 nm): t (major) = 8.50 min, t (minor) = 7.85 min, er =
80:20.
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2-cyclohexyl-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl) acetonitrile (4j).
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73 mg, 94% yield, yellowish white solid (amorphous); mp 80-82 C; H NMR (500 MHz,
CDCl3): δ 7.08 (d, J = 5.0 Hz, 1H), 6.72 (d, J = 5.0 Hz, 1H), 3.72 (d, J = 10.0 Hz, 1H), 3.55 (d, J
= 15.0, 1H), 3.32 (d, J = 10.0 Hz, 1H), 3.01-2.96 (m, 1H), 2.93-2.88 (m, 2H), 2.73-2.68 (m, 1H),
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2.00 (t, J = 15.0, 2H), 1.81-1.78 (m, 2H), 1.72-1.68 (m, 3H), 1.32-1.15 (m, 4H); C NMR (125
30
MHz, CDCl3); δ 135.1, 127.3, 125.3, 118.8, 52.1, 50.1, 40.1, 33.0, 32.0, 28.5, 27.8, 27.6; [α]D
=
+30.5 (c = 0.038 in isopropanol); TOF–MS (ESI+); m/z calcd. for C15H20N2S (M+1) 261.14,
Found 261.10; Anal. Calcd. For C15H20N2S: C, 69.19; H, 7.74; N, 10.76, S, 12.31. Found: C,
69.20; H, 7.71; N, 10.75, S, 12.34; HPLC (CHIRALPAK OD, i-PrOH/ Hexane = 10/90, Flow
rate 0.8 mL/ min, λ = 254 nm): t (major) = 9.80 min, t (minor) = 8.88 min, er = 88:12.
2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-methylpentanenitrile (4k).
1
63 mg, 91% yield viscous liquid; H NMR (500 MHz, CDCl3): δ 7.10 (d, J = 5.0 Hz, 1H), 6.74
(d, J = 5.5 Hz, 1H), 3.79 (d, J = 13.0 Hz, 1H), 3.75 (d, J = 7.5, 1H), 3.61 (d, J = 13.5 Hz, 1H),
3.04-2.87 (m, 3H), 2.78-2.73 (m, 1H), 1.88-1.84 (m, 1H), 1.76-1.72 (m, 2H), 0.97 (d, J = 2.5 Hz,
13
3H), 0.96 (d, J = 3 Hz, 3H); C NMR (125 MHz, CDCl3); δ 134.1, 126.5, 124.6, 118.7, 57.4,
51.1, 49.5, 41.3, 27.1, 26.2, 23.6; [α]D30 = +11.5 (c = 0.038 in isopropanol); TOF–MS (ESI+);
m/z calcd. for C13H18N2S (M+1) 235.12, Found 235.0; Anal. Calcd. For C13H18N2S: C, 66.62; H,
7.74; N, 11.95, S, 13.68. Found: C, 66.58; H, 7.69; N, 11.87, S, 13.61; HPLC (CHIRALPAK
OD, i-PrOH/ Hexane = 10/90, Flow rate 0.8 mL/ min, λ = 254 nm): t (major) = 18.02 min, t
(minor) = 13.46 min, er = 65:35.
Synthesis of 5 and 6: Compound 5 and 6 were synthesised from compound 4 according to the
procedure described in reference no. 10.
Characterization of 5; IR (cm-1): 3450, 2555, 1751.2, 1631.1, 1594.0, 1436.5, 1187.6, 880.3,
867.2, 845.8, 774.1; 1H NMR (200 MHz, D2O): δ 7.62 (d, J = 8.0, 1H), 7.62-7.48 (m, 3H), 7.28
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(d, J = 5.0, 1H), 6.7 (d, J = 5.0, 1H), 5.61 (s, 1H), 4.4-4.0 (m, 2H), 3.76 (s, 3 H), 3.65-3.79 (m, 2
H), 3.18 (s, 2 H). 13C NMR (125 MHz, CDCl3); δ 136.4, 132.6, 130.3, 130.2, 128.9, 126.2,
124.7, 122.5, 115.1, 58.1, 49.2, 47.6, 26.3.
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Optical rotation of compound 6: [α]D 30 = +32.1 (c = 0.038 in MeOH); Reported in literature [α]D
20 = +42.0 (c = 1 in MeOH). 9c
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Acknowledgment. We are thankful to DST and CSIR for financial assistance and Analytical
Division of the Institute especially Mr. Hitesh Bhatt for DEPT 135 NMR.
1
Supporting Information Available: H and 13C spectra, and HPLC chromatograms for
all compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
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