Allylation and cyanation of aza-aromatics activated by chloroformate and a catalytic amount of iodine

Article abstract of DOI:10.1016/j.tetlet.2005.03.127

Allyltrimethylsilane and trimethylsilyl cyanide undergo smooth addition to N-acylated quinolines in the presence of a catalytic amount of iodine to afford 2-allyl- and 2-cyano-1,2-dihydroquinoline derivatives, respectively in good yields with high chemo- and regioselectivity. A variety of functional groups such as alkyl, alkoxy, halo, and nitro functionalities are tolerated under the reaction conditions.

Full text of DOI:10.1016/j.tetlet.2005.03.127

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3489–3492
Allylation and cyanation of aza-aromatics activated by
chloroformate and a catalytic amount of iodine
q
*
J. S. Yadav, B. V. S. Reddy, M. Srinivas and K. Sathaiah
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 9 December 2004; revised 10 March 2005; accepted 17 March 2005
Available online 8 April 2005
Abstract—Allyltrimethylsilane and trimethylsilyl cyanide undergo smooth addition to N-acylated quinolines in the presence of a
catalytic amount of iodine to afford 2-allyl- and 2-cyano-1,2-dihydroquinoline derivatives, respectively in good yields with high
chemo- and regioselectivity. A variety of functional groups such as alkyl, alkoxy, halo, and nitro functionalities are tolerated under
the reaction conditions.
ꢀ
2005 Elsevier Ltd. All rights reserved.
Addition reactions of organometallic reagents to acti-
vated aza-aromatics, generated in situ by chlorofor-
mates or acyl chlorides, are of great importance in
organic synthesis, especially for the synthesis of biologi-
reagents, and require a stoichiometric amount or even
an excess of the Lewis acid to obtain reasonable reaction
rates and acceptable yields of products. Furthermore,
allylindium or allylmagnesium reagents are reported to
1
6
cally active alkaloids. Among the methods used, allyla-
tion and cyanation of activated aza-aromatics are
important methods for syntheses of quinoline and
produce a mixture of a- and c-allylated products. There
is still scope to develop a simple and efficient method for
the allylation and cyanation of N-acylated aza-aromat-
ics using less toxic and easily handled allylsilanes.
2
isoquinoline analogs. Organometallic reagents such as
allyltin, allylindium, and allylsilanes have been used
extensively to introduce allylic functionality into these
In continuation of our interest in catalytic applications
7
of elemental iodine for organic transformations, we re-
3
–5
nitrogen heterocycles. However, many of these meth-
ods involve the use of toxic tin compounds, expensive
port herein a mild and convenient method for the allyl-
ation of both activated quinolines and isoquinolines using
elemental iodine as catalyst. Initially, we attempted the
allylation of N-acylated quinoline 1, generated by ethyl
chloroformate, with allyltrimethylsilane 2 in the pres-
ence of 10 mol % of elemental iodine. The reaction went
to completion in 2.5 h and the product, 2-allyl-1,2-dihy-
droquinoline 3a was obtained in 85% yield (Scheme 1).
I2
+
N
Cl-
OEt
+
Si
CH Cl r.t
N
2
2,
O
1
O
OEt
2
3a
Scheme 1.
(
CH ) Si
R
3 3
I2
Cl-
OEt
+
+
2eq.
Si
N
R
N
CH Cl ,r.t
2
2
O
CO C H
2 2 5
1
2
4
Scheme 2.
Keywords: Aza-aromatics; Iodine catalysis; Allylation; Cyanation.
q
IICT Communication No. 050227.
Corresponding author. Tel.: +91 40 271 93030; fax: +91 40 27160512; e-mail: yadavpub@iict.res.in
*
0
040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.127

3490
J. S. Yadav et al. / Tetrahedron Letters 46 (2005) 3489–3492
Table 1. I
2
-Catalyzed allylation and cyanation of aza-aromatics activated by chloroformate
a
b
Entry
Quinolines
Product
Yield (%)
Time (h)
2.5
Refs.
4a
(a)
84
N
N
CO C H
2
2
5
3a
(
b)
N
CN
2
80
3.0
N
N
N
CO C H
2
5
3
b
(
CH ) Si
3
3
(
(
c)
75
82
2.5
3.0
4a
N
CO C H
2
2
5
4a
N
CO C H
d)
2
2
5
CN
3c
CH3
CH3
(
(
(
(
e)
N
80
2.5
3.0
4a
N
N
CO C H
2 2 5
3d
CH3
CN
CH3
f)
N
75
CO C H
2
2
5
3
e
H C
3
H C
3
g)
h)
N
812.5
72
N
CO C H
2
2
5
3
f
H C
3
H C
3
N
CN
3.5
N
CO C H
g
2 2
5
3
Br
Br
(
(
(
(
i)
N
70
67
79
65
2.5
3.5
3.5
2.5
4a
N
N
CO C H
2
2
5
3
h
Br
Br
j)
N
CN
CO C H
2
2
5
3i
MeO
MeO
NO2
k)
l)
N
4a
4a
N
CO C H
2 2 5
3j
(
CH ) Si
3 3
NO2
N
N
N
CO C H
2
2
5
4b
NO2
NO2
(
m)
n)
N
72
70
4.0
3.0
CO C H
5
2
2
CN
3
k
O N
2
O N
2
(
4a
N
N
CO C H
2
2
5
3
l
a
1
All products were characterized by H NMR, IR, and mass spectroscopy.
Isolated yields after purification.
b

J. S. Yadav et al. / Tetrahedron Letters 46 (2005) 3489–3492
3491
Similarly, several substituted quinolines reacted
smoothly with allyltrimethylsilane to produce the corre-
sponding 2-allyl-1,2-dihydroquinoline derivatives. In all
cases, the nucleophilic addition took place selectively at
the 2-position of the quinoline whereas 2- and 4-allyl-
ated products are formed when allyl Grignards are used.
Encouraged by the results obtained with quinolines, we
turned our attention to isoquinolines. Interestingly,
N-acylated isoquinolines underwent smooth addition
with 2 equiv of allyltrimethylsilane leading to the forma-
3. Hatano, B.; Haraguchi, Y.; Kozima, S.; Yamaguchi, R.
Chem. Lett. 1995, 1003.
4
. (a) Yamaguchi, R.; Nakayasu, T.; Hatano, B.; Nagura, T.;
Kozima, S.; Fujitha, K.-I. Tetrahedron 2001, 57, 109; (b)
Yamaguchi, R.; Mochizuki, K.; Kozima, S.; Takaya, H.
J. Chem. Soc., Chem. Commun. 1993, 981; (c) Haraguchi,
Y.; Kozima, S.; Yamaguchi, R. Tetrahedron: Asymmetry
1
996, 7, 443.
5
. (a) Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2000, 122, 6327; (b) Yamaguchi, R.;
Tanaka, M.; Matsuda, T.; Okano, T.; Nagura, T.; Fujitha,
K.-I. Tetrahedron Lett. 2002, 43, 8871.
4
a
tion of benzoisoquinuclidines as a 1:1 mixtures of
invertomers (4) (Scheme 2).
6
. (a) Lee, J. H.; Kweon, J. S.; Yoon, C. M. Tetrahedron Lett.
2002, 43, 5771; (b) Lee, S. H.; Park, Y. S.; Nam, M. H.;
Yoon, C. M. Org. Biomol. Chem. 2002, 43, 5771.
The mono-allylated products were not observed by
NMR. The formation of benzoisoquinuclidine from an
7
. (a) Yadav, J. S.; Reddy, B. V. S.; Hashim, S. R. J. Chem.
Soc., Perkin Trans. 1 2000, 3025; (b) Yadav, J. S.; Reddy, B.
V. S.; Sabitha, G.; Reddy, G. S. K. K. Synthesis 2000, 1532;
4
isoquinoline was consistent with the literature. Like all-
ylsilane, trimethylsilyl cyanide (TMSCN) also reacted
efficiently with N-acylated quinolinium and N-acylated
isoquinolinium ions to give 2-cyano-1,2-dihydroquino-
line and 1-cyano-1,2-dihydroisoquinoline derivatives,
respectively (Table 1, entries b, d, f, h, j, and m). In all
cases the reactions proceeded smoothly at ambient
temperature with high regioselectivities. No 4-substi-
tuted adduct normally formed by Grignard reagents
was obtained under these reaction conditions. The
(
c) Kumar, H. M. S.; Reddy, B. V. S.; Reddy, E. J.; Yadav,
J. S. Chem. Lett. 1999, 857; (d) Yadav, J. S.; Reddy, B. V. S.;
Rao, C. V.; Chand, P. K.; Prasad, A. R. Synlett 2001, 1638.
8. General procedure: To a solution of quinoline (1mmol), in
CH Cl (3 mL) was added ClCO Et (1.5 mmol) and the
2
2
2
mixture stirred at room temperature for 0.5 h. To the
reaction was added iodine (0.1mmol), and an allylic silane
(
1.2 mmol) under ice cooling and the reaction was stirred at
rt for the appropriate time (Table 1). The reaction mixture
was quenched with water (5 mL) and extracted with
dichloromethane (3 · 10 mL) the combined extracts were
washed with 15% solution of sodium thiosulfate, dried over
1
products were characterized by H NMR, IR, and mass
9
spectroscopy and by comparison with authentic
4
a
compounds. Dichloromethane is the solvent of choice.
This method is useful for the allylation of both electron-
rich and electron-deficient quinolines. The results of the
allylation and cyanation of both quinolines and isoquin-
2 4
anhydrous Na SO , and concentrated in vacuo. The
resulting product was purified by column chromatography
on silica gel (Merck, 100–200 mesh, ethyl acetate–hexane,
1:9) to afford pure product.
. Spectral data for selected products: 3b: Solid, mp 65–66 ꢁC.
IR (KBr): m 2982, 2240, 1712, 1489, 1376, 1293, 1260, 1129,
8
9
olines, are presented in Table 1. Although the reaction
was successful with a catalytic amount of TMSI, the
products were obtained in comparatively low yields
À1
1
1
034, 920, 764 cm ; H NMR (300 MHz, CDCl ): d 7.72
3
(
(
d, 1H, J = 8 Hz), 7.35 (t, 1H, J = 8 Hz), 7.15 (m, 2H), 6.7
d, 1H, J = 9 Hz), 6.1(d, 1H, J = 6.4 Hz), 6.0 (dd, 1H, J = 9,
(
50–65%) after longer reaction times (6–10 h). Thus,
the combination of allyltrimethylsilane and iodine is
better.
6
.4 Hz), 4.4–4.2 (m, 2H), 1.4 (t, 3H, J = 7.4 Hz); EIMS
+
Mass: m/z: 228 M , 184, 155, 129, 102, 77. Anal. Calcd for
: C, 68.41; H, 5.30; N, 12.27. Found: C, 68.85;
13 12 2 2
C H N O
In summary, we have described in efficient method for
the allylation and cyanation of quinolines and isoquinol-
ines activated by ethyl chloroformate using elemental
iodine as catalyst.
H, 5.28; N, 12.25. Compound 3c: Solid, mp 83–84 ꢁC. IR
(KBr): m 2959, 2239, 1712, 1639, 1455, 1376, 1335, 1293,
À1
1
1236, 1125, 1019, 898, 769 cm
CDCl ): d 7.33 (dt, 1H, J = 6.8, 2.6 Hz), 7.26 (m, 2H), 7.13
d, 1H, J = 6.8 Hz), 6.99 (d, 1H, J = 7.55 Hz), 6.31(s, 1H ),
; H NMR (300 MHz,
3
(
5
J = 6.7 Hz); EIMS Mass: m/z: 228 M , 202, 184, 156, 129,
.98 (d, 1H, J = 7.55 Hz), 4.4–4.3 (m, 2H), 1.37 (t, 3H,
+
Acknowledgements
102, 77. Anal. Calcd for C H N O : C, 68.41; H, 5.30; N,
2
1
3
12
2
1
2.27. Found: C, 68.65, H, 5.55, N, 12.34. Compound 3e:
S.K. thanks UGC, New Delhi for the award of a
Fellowship.
Solid, mp 79–80 ꢁC. IR (KBr): m 2930, 2240, 1702, 1377,
À1
1
1
324, 1251, 1029 cm ; H NMR (300 MHz, CDCl ): d 7.52
3
(
(
d, 1H, J = 8.1Hz), 7.25 (t, 1H, J = 8.1Hz), 7.1(m, 2H), 6.4
s, 1H), 5.7 (s, 1H), 4.45–4.20 (m, 2H), 2.1 (s, 3H), 1.4 (t, 3H,
+
J = 7.4 Hz); EIMS Mass: m/z: 242 M , 214, 198, 170, 157,
144, 116, 78, 43. Anal. Calcd for C H N O : C, 69.41; H,
References and notes
1
4
14
2
2
5
.82; N, 11.56. Found: C, 69.39; H, 5.62; N, 11.50.
1
. (a) Katritzky, A. R.; Rachwal, S.; Rachwal, S. Tetrahedron
996, 52, 15031; (b) Comins, D. L.; Sajan, P. J. Pyridines
and their benzo derivatives: reactivity at the ring. In
Comprehensive Heterocyclic Chemistry II; Katrizky, A. P.,
Rees, V. W., Scriven, E. F., Eds.; Pergamon: Oxford, 1996;
Vol. 5, pp 37–89.
Compound 3f: Liquid. IR (KBr): m 2980, 1703, 1497, 1396,
À1
1
1
1315, 1256, 1127, 1045, 916, 818, 763, 714 cm ; H NMR
(300 MHz, CDCl ): d 7.39 (br s, 1H), 7.0 (d, 1H, J = 7.5 Hz),
3
6.84 (s, 1H), 6.4 (d, 1H, J = 9 Hz), 5.99 (dd, 1H, J = 9.8,
6 Hz), 5.80–5.65 (m, 1H), 5.07–4.9 (m, 3H), 4.3–4.15 (m,
2H), 2.31(s, 3H), 2.2–2.06 (m, 2H), . 31 1(t, 3H,
+
2
. (a) Stout, D. M.; Meyers, A. I. Chem. Rev. 1982, 82, 223;
(
J = 6.77 Hz). EIMS Mass: m/z: 257 M , 217, 173, 145,
117, 90, 43. Anal. Calcd for C16H19NO : C, 74.68; H, 7.44;
2
b) Comins, D. L.; Zhang, Y.; Joseph, S. P. Org. Lett. 1999,
, 657; (c) Itoh, T.; Miyazaki, M.; Nagata, K.; Ohsawa, A.
1
N, 5.44. Found: C, 74.38; H, 7.03; N, 5.02. Compound 3g:
Solid, mp 122–123 ꢁC. IR (KBr): m 2930, 2240, 1702, 1377,
Tetrahedron 2000, 56, 4383; (d) Sieck, O.; Schaller, S.;
Grimme, S.; Liebscher, J. Synlett 2003, 337.
À1
1
1324, 1251, 1029 cm ; H NMR(300 MHz, CDCl ): d 7.54
3

3492
J. S. Yadav et al. / Tetrahedron Letters 46 (2005) 3489–3492
+
m/z: 308 (M +2), 306, 235, 233, 209, 207, 155, 154, 128, 127,
(d, 1H, J = 7.6 Hz), 7.12 (d, 1H, J = 8.4 Hz), 7.0 (br s, 1H),
6
1
3
1
.7 (d, 1H, J = 9.3 Hz), 6.1(d, 1H , J = 5.92 Hz), 5.98 (dd,
H, J = 9.3, 5.92), 4.42–4.28 (m, 2H), 2.37 (s, 3H), 1.39 (t,
11 2 2
101, 75, 51. Anal. Calcd for C13H N O Br: C, 50.84; H,
3.61; N, 9.12. Found: C, 50.66; H, 3.77; N, 9.22. Compound
3k: Solid, mp 93–94 ꢁC. IR (KBr): m 2970, 2930, 2251, 1708,
1518, 1343, 1301, 1043, 747 cm ; H NMR (300 MHz,
+
H, J = 6.77 Hz); EIMS Mass: m/z: 242 M , 198, 169, 143,
À1
1
15, 57, 43. Anal. Calcd for C14
H
14
2
N O
2
: C, 69.41; H, 5.82;
N, 11.56. Found: C, 69.42; H, 5.48; N, 11.32. Compound 3i:
Solid, mp 94–95 ꢁC. IR (KBr): m 2982, 2937, 2238, 1702,
3
CDCl ): d 8.06 (d, 1H, J = 9 Hz), 7.52 (br s, 1H), 7.41 (t, 1H,
J = 7.5 Hz), 7.12 (d, 1H, J = 8.3 Hz), 6.83 (d, 1H, J =
8.3 Hz), 6.41 (s, 1H), 4.4 (m, 2H), 1.4 (t, 3H, J = 7.4 Hz).
À1
1
571, 1487, 1373, 1322, 1251, 1038, 918, 756 cm ; H NMR
1
+
EIMS Mass: m/z: 273 M , 247, 174, 164, 146, 128, 116, 101,
(
300 MHz, CDCl
J = 6.77, 2.5 Hz), 7.32 (m, 2H), 7.03 (s, 1H), 6.16 (s, 1H),
.46–4.28 (m, 2H), 1.41 (t, 3H, J = 6.77 Hz). EIMS Mass:
3
): d 7.65 (d, 1H, J = 7.6 Hz), 7.36 (dt, 1H,
91, 75, 57, 43. Anal. Calcd for C H N O : C, 57.14; H,
1
3
11
3
4
4
4.06; N, 15.38. Found: C, 57.12; H, 4.11; N, 15.22.