An efficient one-pot synthesis of pyrrolines and tetrahydropyridines from their chloro-precursors via in situ aza-Wittig reaction

Article abstract of DOI:10.1016/j.tetlet.2005.04.054

A simple and efficient method for synthesizing pyrrolines and tetrahydropyridines via an intramolecular aza-Wittig reaction has been achieved by microwave irradiation of the corresponding chloro-alkane derivatives in the presence of tertiary phosphite and sodium azide. The in situ formation of the alkyl azides makes this a facile and safe method for aza-Wittig reactions.

Full text of DOI:10.1016/j.tetlet.2005.04.054

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4213–4217
An efficient one-pot synthesis of pyrrolines and
tetrahydropyridines from their chloro-precursors via
in situ aza-Wittig reaction
Pradeep N. D. Singh, Rodney F. Klima, Sivaramakrishnan Muthukrishnan,
Rajesh S. Murthy, Jagadis Sankaranarayanan, Heidi M. Stahlecker,
*
´
Bhavika Patel and Anna D. Gudmundsdottir
Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221-0172, USA
Received 24 March 2005; revised 8 April 2005; accepted 12 April 2005
Available online 29 April 2005
Abstract—A simple and efficient method for synthesizing pyrrolines and tetrahydropyridines via an intramolecular aza-Wittig reac-
tion has been achieved by microwave irradiation of the corresponding chloro-alkane derivatives in the presence of tertiary phosphite
and sodium azide. The in situ formation of the alkyl azides makes this a facile and safe method for aza-Wittig reactions.
Ó 2005 Elsevier Ltd. All rights reserved.
O
Pyrrolines and tetrahydropyridine derivatives are crucial
intermediates for synthesizing a large variety of func-
tionalized aza-heterocycles that have significant biologi-
cal and pharmacological activities.1 Aza-heterocyclo
derivatives are also valuable flavor compounds. For
example, heterocycles 1 and 2 are natural ingredients
of cooked rice and bread crust (Scheme 1).2 Compound
2 has been isolated from the leaves of Panadanus
amaryllifolius Roxb, which are used in Asia in the cook-
ing of everyday rice to provide a resemblance of the
scent of more luxurious fragrant Basmati rice.
Compound 1 has been identified as the major bread fla-
vor component that yields a strong cracker flavor in
freshly baked bread. Compound 2 has also been identi-
fied as one of the volatile fractions in the urine of tigers,
which they use for territorial and sexual statements.3
O
N
N
1
2
Scheme 1.
reactions of azido alkylketones.11 Of these methods the
aza-Wittig reaction is the least complicated, only requir-
ing the addition of tertiary phosphine to an organic
azide. The resulting iminophosphorane can then react
with a carbonyl group to form an imine (see Scheme
2).12
The introduction of combinatorial and robotized
parallel synthesis has led to a need for fast reactions
and efficient purification procedures.13 Thus, microwave
irradiation has become widespread since it requires
shorter reaction times, and generally gives high yields
Common approaches to synthesize simple aza-hetero-
cycles such as 2-phenylpyrrolines are (a) adding organo-
metallic reagents to N-vinyl lactams,4 lactim ethers,5 N-
(trimethyl silyl) lactams6 and x-halo nitriles,7 (b) radical
cyclization of sulphenyl imines,8 (c) acid-catalyzed rear-
rangement of tertiary azides,9 (d) palladium-catalyzed
oxidation of unsaturated amines10 and (e) aza-Wittig
O
O
N
∆
- R3P=O
(CR2)n-N3
R
R
(CR2)n-2
(CR2)n-N=PPh3
R3P
R
Keyword: Aza-Wittig reaction.
*
Corresponding author. Tel.: +1 513 556 3380; fax: +1 513 556
9239; e-mail: anna.gudmundsdottir@uc.edu
Scheme 2.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.054

4214
P. N. D. Singh et al. / Tetrahedron Letters 46 (2005) 4213–4217
poured into water to remove the triethylphosphate
N
N3
Microwave
N2
R
R
+
formed in the reaction, and then extracted with diethyl
ether. The organic layer was dried over MgSO4 and
the solvent removed under vacuum to yield an oil that
was purified on a short silica column eluted with 95:5
hexane: ethyl acetate to yield 2-phenylpyrroline 4a in
96% yield.
R
R
Scheme 3.
O
O
NaN3,DMSO
For comparison, we prepared 3a by the same procedure
but rather than aid the reaction by microwave irradia-
tion, we placed the test tube in boiling water and
followed the reaction with TLC. The reaction was not
completed until after 3 h of heating, verifying that the
microwave irradiation facilitates the reaction more
efficiently than conventional heating. Furthermore,
De Kimpe et al. have shown that this conversion
takes 14 h by stirring the reactant at room temp-
erature.20
N3
Cl
R
n
R
n
Microwave
5 - 12 min
n=2,3
Scheme 4.
and enhanced selectivity compared to conventional
heating.14 We have recently demonstrated that vinyl
alkyl azides can be activated with microwave irradiation
to form 2H-azidirines in high selectivity and yield (see
Scheme 3).15 We have shown also that b- and c-azido-
substituted arylketones are stable enough to be prepared
by briefly exposing the corresponding halo arylketones
and sodium azide to microwave irradiation in DMSO
(see Scheme 4).16 Hence, we set out to study the micro-
wave-assisted aza-Wittig reaction of alkyl azides, and
determine whether it is possible to combine the aza-Wit-
tig reaction and the preparation of the alkyl azide by
microwave irradiation of chloroketones in DMSO with
sodium azide and tertiary phosphite.
2-Phenylpyrrolines 4a–c were characterized from their
1H NMR, IR, and MS spectra, which were identical to
those in the literature.20,21 We characterized pyrrolines
4d–f from their 1H NMR, 13C NMR, IR, and mass
spectra.21
The isolated yields and reaction times for preparing
several 2-phenylpyrrolines are shown in Table 1. In all
instances the 2-phenylpyrrolines 4 are formed in good
yield after a reaction time of only 8–12 min. Thus there
is a noteworthy acceleration in the reaction rate com-
pared to conventional heating.
First, we prepared c-azidobutyrophenones 3 in Scheme
5 as we have previously reported,16 and investigated
their reactivity with triethylphosphite under microwave
irradiation. Since azide 3f has not been prepared previ-
We simplified further the preparation of 2-phenylpyrro-
lines 4a–f by microwave irradiation of the corresponding
c-chlorobutyrophenone, sodium azide and triethyl-
phosphite in DMSO (see Scheme 6).
ously, we characterized it from its H and 13C NMR
1
and IR spectra.17
In a typical experiment, c-azidobutyrophenone 3a
(180 mg, 1 mmol) was dissolved in DMSO (5 mL) in a
test tube and triethylphosphite (258 mg, 1.5 mmol)
added, and the resulting solution stirred. Since the
microwave oven cannot be fitted with a condenser to
prevent overheating,18 we followed the procedure of
Chan and co-workers,19 and ran the reaction in a water
bath inside the microwave oven. We placed the test tube
in a glass beaker containing water, and irradiated the
beaker with microwaves. The reaction was monitored
with TLC. After completion, the reaction mixture was
Table 1. Isolated yields for forming 2-phenylpyrroline
c-azidobutyrophenone 3
4 from
3
Microwave irradiation
Reaction time (min)
Isolated yields of 4 (%)
a
b
c
d
e
f
8
96
87
92
80
86
93
10
10
8
12
12
N
O
N
Y
O
(EtO) P
, DMSO
Y
3
N3
Y
X
, NaN , DMSO
(EtO)3P
3
Cl
Y
X
Microwave
X
Microwave
X
3a: Y = X = H
4a: Y = X = H
4a: Y = X = H
5a: Y = X = H
3b: Y = H, X = OMe
3c: Y = H, X = Br
3d: Y = H, X = OH
4b: Y = H, X = OMe
4c: Y = H, X = Br
4d: Y = H, X = OH
4e: Y = H, X = C(CH3)3
4b: Y = H, X = OMe
4c: Y = H, X = Br
4d: Y = H, X = OH
4e: Y = H, X = C(CH3)3
5b: Y = H, X = OMe
5c: Y = H, X = Br
5d: Y = H, X = OH
5e: Y = H, X = C(CH3)3
3e: Y = H, X = C(CH3)3
3f: Y = X = CH3
4f: Y = X = CH3
4f: Y = X = CH3
5f: Y = X = CH3
Scheme 5.
Scheme 6.

P. N. D. Singh et al. / Tetrahedron Letters 46 (2005) 4213–4217
4215
In a standard experiment, c-chlorobutyrophenone 5a
(182 mg, 1.0 mmol), sodium azide (100 mg, 1.5 mmol)
and triethylphosphite (250 mg, 1.5 mmol) were dissolved
in DMSO (5 mL) and the resulting solution stirred. The
reaction was carried out in a water bath inside the
microwave oven for 25 min. The reaction progress was
followed with TLC and when all the starting material
had reacted, the reaction mixture was poured into water
and extracted with diethyl ether. The organic layer was
dried over MgSO4 and the solvent removed under
vacuum to yield an oil, which was purified on a short
silica column eluted with 5% ethyl acetate in hexane to
give 2-phenylpyrroline 4a (130 mg, 0.93 mmol) in 95%
yield.
azides makes this a facile and safe method for aza-Wittig
reactions.
We were curious whether we could use this simple
approach to make azo-heterocyclic compounds from
aliphatic ketones, so we set out to prepare flavor com-
pound 1. We followed the method of De Kimpe et al.
and prepared 1 from 6 as shown in Scheme 7,23 but
rather than using conventional heating, we used micro-
wave irradiation to accelerate the formation of 10 and
11 (see Table 3). Thus we made compounds 10 and 11
in better yield and much shorter reaction times by using
microwave irradiation. We then modified the procedure
for forming 1 by doing in situ aza-Wittig reaction to
prepare 11 from 9 in one step. We obtained 11 in 98%
yield after 18 min of microwave irradiation.
The isolated yields and the reaction times for preparing
phenylpyrroline derivatives 4 from the microwave irra-
diation of c-chlorobutyrophenone are listed in Table 2.
In all cases yields are similar or better than for micro-
wave irradiation of the azidobutyrophenone 3 (see Table
1). Hence, 2-phenylpyrrolines can be prepared directly
just as easily from the corresponding c-chlorobutyro-
phenone, triethyphosphite and sodium azide, rather
than first preparing the analogous c-azidobutyrophen-
ones and then reacting the azido compounds with tri-
ethylphosphite. The in situ formation of the alkyl
Compounds 7–11 and 2 were characterized by their
IR and 1H NMR spectroscopy and the IR and 1H
NMR spectra fits with the literature.22,24–29
In conclusion, we have shown that substituted pyrro-
lines and tetrahydropyridines can be synthesized in a
simple one-pot approach from the corresponding
chloro-alkanes, tertiary phosphite and sodium azide by
flash heating with microwave irradiation. Thus micro-
wave assisted in situ aza-Wittig reactions are an efficient
and safe method to form pyrroline and tetrahydropyr-
idines derivatives in high purities, yields and short reac-
tion times.
Table 2. Isolated yields for forming 2-phenylpyrroline
c-chlorobutyrophenone 5
4 from
Chloride 5
Microwave irradiation
Reaction time (min)
Isolated yields of 4 (%)
Table 3. Isolated yields for forming 10 and 11 as shown in Scheme 7
Conventional heating22
Microwave irradiation
a
b
c
d
e
f
20
20
28
28
25
25
95
94
88
90
90
96
Yield (%)
Reaction
time (h)
Yield (%)
Reaction
time (min)
10
11
80
73
12–16
23–24
98
95
12
15
(CH3)2CHNH2
O
N
N
1. LDA,THF
TICl4
Cl
2. Cl(CH2)3Br
Diethyl Ether
MeO
OMe
MeO OMe
MeO OMe
6
7
8
(COOH)2(H2O)2
O
O
N
1
Ph3P
MWI
NaN3
Cl
HCl
N3
O
MWI
N
MeO OMe
10
MeO OMe
MeO
OMe
9
11
NaN3, Ph3P
MWI
N
O
1a
Scheme 7.

4216
P. N. D. Singh et al. / Tetrahedron Letters 46 (2005) 4213–4217
125.7, 129.1, 129.8, 134.6, 136.9, 142.7, 198.8 ppm. IR
(Neat): 1677, 2097 cmÀ1
Acknowledgments
.
18. We used a conventional microwave oven, 2450 MHz,
1100 W.
19. Law, M. C.; Wong, L.-Y.; Chan, T. H. Green Chem. 2002,
4, 328.
We thank the National Science Foundation (CAREER
Award #0093622) for supporting this work. H.M.S. also
gratefully acknowledges support from the NSF-REU
program at the University of Cincinnati (through Grant
No. CHE-0097726).
20. (a) Kemppainen, A. E.; Thomas, M. J.; Wagner, P. J.
J. Org. Chem. 1976, 41, 1294; (b) Cheng, S.-S.; Piantadosi,
C.; Irvin, J. L. J. Pharm. Sci. 1968, 57, 1910; (c) Koller,
W.; Schlack, P. Chem. Ber. 1963, 96, 93; (d) Burckhalter,
J. H.; Short, J. H. J. Org. Chem. 1958, 23, 1278.
21. The 1H NMR and IR of phenylpyrrolines 4a–f are as
References and notes
1
follows 4a: H NMR (CDCl3, 250 MHz) d 2.03 (m, 2H),
1. (a) Marayanoff, B. E.; McComsey, D. F.; Gardocki, J. F.;
Shank, R. P.; Costanzo, M. J.; Nortey, S. O.; Schneider,
C. R.; Setler, P. E. J. Med. Chem 1987, 30, 1433; (b)
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2. (a) De Kimpe, N.; Keppens, M. J. Agric. Food Chem.
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61, 8975; (c) Schieberle, P. J. Agric. Food Chem. 1995, 43,
2442; (d) Schieberle, P. J. Agric. Food. Chem. 1991, 39,
141; (e) Buttery, R. G.; Juliano, B. O.; Ling, L. Chem. Ind.
1983, 478.
3. Brahmachary, R. L.; Sarkar, M. P. Nature 1990, 344,
26.
4. (a) Coindet, C.; Comel, A.; Kirch, G. Tetrahedron Lett.
2001, 42, 6101; (b) Bielawski, J.; Brandange, S.; Lindbolm,
L. J. J. Heterocycl. Chem. 1978, 15, 97.
5. Zezza, C. A.; Smith, M. B.; Ross, B. A.; Arhin, A.;
Cronin, P. L. E. J. Org. Chem. 1984, 49, 4397.
6. Hua, D. H.; Miao, S. W.; Bharathi, S. N.; Katsushira, T.;
Bravo, A. A. J. Org. Chem. 1990, 55, 3682.
7. Fry, D. F.; Fowler, C. B.; Dieter, R. K. Synlett 1994, 836.
8. Boivin, J.; Fouquet, E.; Zard, S. Z. Tetrahedron Lett.
1990, 85.
9. Astier, A.; Plat, M. M. Tetrahedron Lett. 1978, 2051.
10. (a) Pugin, B.; Venanzi, L. M. J. Am. Chem. Soc. 1983, 105,
6877; (b) Fukuda, Y.; Matsubura, S.; Utimoto, K. J. Org.
Chem. 1991, 56, 5812.
11. Lambert, P. H.; Vaultier, M.; Carrie, R. J. Chem. Soc.,
Chem. Commun. 1982, 1224.
2.91 (m, 2H), 4.07 (m, 2H), 7.38 (m, 3H), 7.81 (m, 2H)
ppm. IR (KBr): 1622 cmÀ1; MS (70 eV, EI) 145 (M+).
Compound 4b: Crystalline solid mp: 76 °C (lit.18d 77–
78 °C). 1H NMR (CDCl3, 250 MHz) d 2.00 (quintet
7 Hz, 2H), 2.88 (t, 7 Hz, 2H), 3.82 (s, 3H), 4.02 (t, 7 Hz,
2H), 6.89 (d, 8 Hz 2H), 7.76 (d, 8 Hz, 2H) ppm. IR (KBr):
1614 cmÀ1. MS (70 eV, EI) m/e 175 (M+). Compound 4c:
Crystalline solid, mp: 83–84°C (lit.18b 87–88 °C), 1H NMR
(CDCl3, 250 MHz) d 2.05 (m, 2H), 2.92 (m, 2H), 4.05 (m,
2H), 7.55 (d, 7.5 Hz, 2H), 7.72 (d, 7.5 Hz 2H) ppm. IR
(KBr) 1622 cmÀ1. MS (70 eV, EI) e/m 225 (M+). Com-
pound 4d: Crystalline solid mp: 230–232 °C (lit.17c
234 °C). 1H NMR (250 MHz, CDCl3) d 2.08 (m, 2H),
3.01 (m, 2H), 3.96 (m, 2H), 6.81 (d, 8 Hz, 2H), 7.65 (broad
s, 1H), 7.69 (d, 8 Hz, 2H) ppm. 13C NMR (75 MHz,
CDCl3): d 23.1, 35.9, 60.8, 116.6, 130.0, 131.1, 162.6,m
176.5 ppm. IR (KBr): 3453, 2943, 2861, 1587, 1524,
1451 cmÀ1. MS (70 eV, EI) e/m 160 (M+). Compound
1
4e: H NMR (250 MHz, CDCl3) d 1.33 (s, 9H), 2.01 (m,
2H), 2.93 (m, 2H), 4.05 (m, 2H), 7.44 (d, 7.5 Hz, 2H), 7.79
(d, 7.5 Hz, 2H) ppm. 13C NMR (75 MHz, CDCl3): d 22.6,
31.2, 34.8, 34.9, 61.4, 125.3, 127.4, 131.8, 153.6,
173.1 ppm. IR (KBr): 1615 cmÀ1. MS (70 eV, EI) e/m
200 (M+À1). Compound 4f: Crystalline solid m.p. 64–
66°C, 1H NMR (CDCl3, 250 MHz) d 1.99 (m, 2H), 2.15 (s,
6H), 2.93 (m, 2H), 4.00 (t, 7 Hz, 2H), 7.13 (d, 8 Hz, 2H),
7.49 (d, 8 Hz, 2H), 7.66 (s, 1H) ppm; 13C NMR (75 MHz,
CDCl3): d 19.7, 19.7, 22.6, 34.8, 61.3, 125.2, 128.6, 129.6,
132.3, 136.6, 139.1, 173.3 ppm. IR (KBr): 1614 cmÀ1; MS
(70 eV, EI) 173 (M+).
12. (a) Staudinger, H.; Meyer, I. Helv. Chim. Acta 1919, 2,
635; (b) Gololobov, Y. G.; Zhmurova, I. N.; Kasukhin, L.
F. Tetrahedron 1981, 37, 437.
22. De Kimpe, N.; Tehrani, K. A.; Stevens, C.; De Cooman,
P. Tetrahedron 1997, 53, 3693.
23. (a) De Kimpe, N.; Stanoeve, E.; Boyeykens, M. Synthesis
1994, 4427; (b) De Kimpe, N.; Stevens, C. Tetrahedron
1995, 51, 2387.
13. Alterman, A.; Hallberg, At. J. Org. Chem. 2000, 65, 7984.
14. For some recent reviews see (a) Pillai, U. R.; Sahle-
Demessie, E.; Varma, R. S. J. Mater. Chem. 2002, 12,
3199; (b) Perreux, L.; Loupy, A. Tetrahedron 2001, 57,
9199; (c) Varma, R. S. Pure Appl. Chem. 2001, 73, 193; (d)
Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225; (e) Diaz-Ortiz, A.; de la
Hoz, A.; Langa, F. Green Chem. 2000, 2, 165; (f) Tanaka,
K.; Toda, F. Chem. Rev. 2000, 100, 1025; (g) Deshayes, S.;
Liagre, M.; Loupy, A.; Luche, J.-L.; Petit, A. Tetrahedron
1999, 55, 10851; (h) Varma, R. S. Green Chem. 1999, 1, 43;
(i) Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.;
Jacquault, P.; Mather, D. Synthesis 1998, 1213; (j)
Caddick, S. Tetrahedron 1995, 51, 10403.
24. Preparation of 7. A solution of 3,3-dimethoxy-2-butanone
(1.32 g, 10 mmol) and isopropyl amine (2.36 g, 40 mmol)
in dry diethyl ether (50 mL) in an icebath was stirred
vigorously under an N2 atmosphere. To this solution
was added dropwise solution of titanium(iv)chloride
(1.14 g, 60 mmol) in pentane (5 mL). The reaction mixture
was stirred for 30 min at room temperature and poured
into aqueous 0.5 N sodium hydroxide (50 mL) and
extracted three times with diethyl ether (30 mL). The
combined organic layers were dried with magnesium
sulfate, filtered and evaporated in vacuo to yield imine 7
(1.65 g, 9.5 mmol) in 95% yields. IR (neat): 2850,
´
15. Singh, P. N. D.; Carter, C. L.; Gudmundsdottir, A. D.
Tetrahedron Lett. 2003, 44, 6763.
1670 cmÀ1 1H NMR (250 MHz, CDCl3): 1.16 (d, 6 Hz,
.
6H), 1.88 (s, 3H), 1.41 (s, 3H), 3.26 (s, 6H), 3.75 (septet,
6 Hz, 1H) ppm.
16. Singh, P. N. D.; Muthukrishnan, S.; Murthy, R. S.;
Klima, R. F.; Mandel, S. M.; Hawk, M.; Yarbrough, N.;
´
Gudmundsdottir, A. D. Tetrahedron Lett. 2003, 44,
25. Preparation of 8. A solution of lithium diisopropylamide
(12 mmol) was prepared by addition of butyl lithium
(7.2 mL 1.65 M) in hexane to a solution of diisopropyl-
amine (1.31 g, 13 mmol) in dry tetrahydrofuran (20 mL) at
0°C under argon and magnetic stirring. To this solution,
was added drop-wise a solution of N-(3,3-dimethoxy-2-
9169.
17. Azide 3f: 1H NMR (250 MHz, CDCl3): d 1.99 (m, 2H),
2.31 (s, 6H), 3.01 (t, 7 Hz, 2H), 3.37 (t, 7 Hz, 2H), 7.19 (t,
8 Hz, 2H); 7.67 (t, 7.6 Hz, 2H), 7.73 (s, 1H) ppm. 13C
NMR (100 MHz, CDCl3): d 19.78, 20.0, 23.4, 35.0, 50.9,

P. N. D. Singh et al. / Tetrahedron Letters 46 (2005) 4213–4217
4217
1
butylidene)isopropylamine 7 (1.73 g, 10 mol) in dry tetra-
hydrofuran (2 mL). This mixture was stirred for 3 h at 0°C
and 1-bromo-3-chloropropane (1.83 g, 12 mmol) was
added drop-wise with a syringe. The resulting solution
was stirred for 20 h during which the mixture warmed to
ambient temperature. The reaction mixture was poured
into 0.05 N aqueous sodium hydroxide (100 mL) and
extracted three times with diethyl ether (50 mL). The
combined organic extracts were dried with magnesium
sulfate, filtered and evaporated under vacuum to yield 8
2100, 1733 cmÀ1. H NMR (CDCl3): 1.36 (s, 3H), 1.5–1.8
(m, 4H), 2.65 (t, 2H), 3.24 (s, 6H), 3.3 (m, 2H) ppm.
28. Preparation of 11. A solution of 10 (645 mg, 3.0 mol) and
triphenyl phosphine (786 mg, 3.0 mmol) in DMSO (5 mL)
was placed in a test tube and stirred. The test tube was
placed in a glass beaker containing water and irradiated
with microwaves. The reaction was monitored by tlc until
all the starting material had reacted (15 min). At the end
of the reaction the triphenylphosphine oxide was filtered
off and washed with cold diethyl ether (20 mL). The
diethyl ether solutions was evaporated under vacuum to
yield 11 (487 mg, 2.85 mmol, 95% yield). Alternatively,
sodium azide (296 mg, 4.6 mmol) and triphenyl phosphine
(1.21 g, 4.6 mmol) was added to 9 (636 mg, 3.04 mmol) in
DMSO and microwaved for 18 min. Diethyl ether (20 mL)
was added to the remaining oil and the resulting triphen-
ylphosphine oxide precipitated filter. The remaining
diethyl ether solution was evaporated under vacuum to
yield 11 (510 mg, 2.98 mmol, 98% yield). IR (neat): 2830,
1
(2.45 g, 9.8 mmol) in 98% yield. IR (neat): 1660 cmÀ1. H
NMR (250 MHz, CDCl3): 1.16 (d, 6 Hz, 6H), 1.40 (s, 3H),
3.20 (s, 6H), 1.5–1.7 (m, 2H), 1.8–2.0 (m, 2H), 2.2–2.5 (m,
2H), 3.57 (t, 6.5 Hz, 2H), 3.70 (septet, 6 Hz, 1H) ppm.
26. Preparation of 9: Oxalic acid dihydrate (970 mg,
7.2 mmol) dissolved in water (20 mL) was added to a
solution of iminoacetal 8 (1.19 g, 4.8 mmol) in dichloro-
methane (25 mL). The resulting mixture was refluxed for
1 h and extracted three times with dichloromethane. The
extract was dried with magnesium sulfate and evaporated
under vacuum to yield 9 as an oil (0.820 g, 3.9 mmol, 82%
1623 cmÀ1 1H NMR (CDCl3): 1.42 (s, 3H), 1.4–1.8 (m,
.
4H), 2.0–2.2 (m, 2H), 3.25 (s, 6H), 3.6–3.9 (m, 2H) ppm.
29. Preparation of 1. A solution of 11 (380 mg, 2.2 mol) in
dichloromethane (10 mL) and 2 N aqueous HCl acid
(11 mL, 2.2 mol) was stirred for 24 h. The reaction mixture
was made alkaline with 4 N sodium hydroxide. The
aqueous phase was extracted twice with dichloromethane
(20 mL). The combined organic extracts were dried over
magnesium sulfate, filtered and evaporated under vacuum
to yield the imine 1 and enamine 1a in 4:1 ratio (207 mg,
1.7 mmol, 75% yield). Compound 1a: IR (neat): 1630,
yield). IR (neat): 2835, 1730 cmÀ1 1H NMR (250 MHz,
.
CDCl3): 1.26 (s, 3H), 1.5–1.9 (m, 4H), 2.57 (t, 6 Hz, 2H),
3.18 (s, 6H), 3.52 (t, 6.5 Hz, 2H) ppm.
27. Preparation of 10: A solution of 9 (206 mg, 0.99 mmol)
and sodium azide (100 mg, 1.5 mmol) was dissolved in
DMSO (5 mL). The solution was stirred and the test tube
placed in a glass beaker containing water, and irradiated
with microwaves. The reaction was monitored by TLC
until all the starting material had reacted (12 min). At the
end water (20 mL) was added. The reaction mixture was
extracted with diethyl ether (50 mL), dried over magne-
sium sulfate and evaporated under vacuum to give 10
(209 mg, 0.97 mmol, 98% yield) as a clear oil. IR (neat):
1670 cmÀ1. H NMR (CDCl3): 2.2 (m, 4H), 2.38 (s, 3H)
5.64 (t, 4 Hz, 2H) ppm. Compound 1: IR (neat): 1700,
.
1660 cmÀ1 1H NMR (CDCl3): 1.4–2.0 (m, 4H), 2.3 (m,
2H), 2.37 (s, 3H) 3.5–4.0 (m, 2H) ppm.
1