Synthesis of functionalized pyrroles and 6,7-dihydro-1H-indol-4(5H)-ones by reaction of 1,3-dicarbonyl compounds with 2-azido-1,1-diethoxyethane

Article abstract of DOI:10.1016/j.tetlet.2006.01.121

The condensation of 1,3-dicarbonyl compounds with 2-azido-1,1- diethoxyethane and subsequent cyclization allowed an efficient synthesis of a variety of pyrroles and 6,7-dihydro-1H-indol-4(5H)-ones.

Full text of DOI:10.1016/j.tetlet.2006.01.121

Tetrahedron Letters 47 (2006) 2151–2154
Synthesis of functionalized pyrroles and
6,7-dihydro-1H-indol-4(5H)-ones by reaction of
1,3-dicarbonyl compounds with 2-azido-1,1-diethoxyethane
Esen Bellura,b and Peter Langera,c,
*
aInstitut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
bInstitut fu¨r Chemie und Biochemie, Universita¨t Greifswald, Soldmannstr. 16, 17487 Greifswald, Germany
cLeibniz-Institut fu¨r Organische Katalyse an der Universita¨t Rostock e. V. (IfOK), Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 16 December 2005; revised 19 January 2006; accepted 23 January 2006
Available online 10 February 2006
Abstract—The condensation of 1,3-dicarbonyl compounds with 2-azido-1,1-diethoxyethane and subsequent cyclization allowed an
efficient synthesis of a variety of pyrroles and 6,7-dihydro-1H-indol-4(5H)-ones.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Pyrroles and indoles occur in numerous pharmacologi-
OH OH
O
cally active natural and unnatural products. Functional-
ized pyrroles represent building blocks of natural
tetrapyrrole pigments, such as porphobilinogen or bili-
rubin, and of various other natural products and their
analogues.1,2 The pyrrole zomepirac possesses analgetic
and antiphlogistic activity and has found clinical appli-
cations.1 Substituted oligopyrroles are of interest in
the field of material sciences.1,2 In addition, pentasubsti-
tuted pyrroles have proven to be potent hypocholesterole-
mic agents through the inhibition of HMG-CoA
reductase—a key enzyme in the biosynthesis of choles-
terol.1i For example, atorvastatin (Fig. 1) is used today
in the clinic for the treatment of hyperlipidemias.1i
HN
N
HO
O
F
Figure 1. Hypolipidemic agent atorvastatin (Lipitorꢁ).
ized 2-alkylidenepyrrolidines and pyrroles by Lewis acid
catalyzed condensation of 2-azido-1,1-dimethoxyethane
with silyl enol ethers and 1,3-bis-silyl enol ethers and
subsequent intramolecular Staudinger-aza-Wittig reac-
tion.8 These syntheses rely on the initial formation of
a carbon–carbon bond and subsequent cyclization by
formation of the carbon–nitrogen bond. Herein, we
report the synthesis of pyrroles by application of the
opposite strategy: the intermolecular Staudinger-
aza-Wittig reaction of 2-azido-1,1-diethoxyethane with
1,3-dicarbonyl compounds afforded N-(2,2-diethoxy-
ethyl)-3-aminoalk-2-en-1-ones, which were subsequently
transformed into functionalized pyrroles and 6,7-dihy-
dro-1H-indol-4(5H)-ones. All reactions proceeded with
very good chemo- and regioselectivity under mild condi-
tions. The reaction of 2-azido-1,1-diethoxyethane with
1,3-dicarbonyl compounds complements analogous
reactions of 2-amino-1,1-dialkoxyethanes.9 Notably,
chemoselective transformations of 1,3-dicarbonyl
Although a variety of methods for the synthesis of
pyrroles are known,3,4 the development of alternative
and more selective strategies is of considerable impor-
tance. A versatile concept for the synthesis of pyrroles
relies on the application of the aza-Wittig reaction.5,6
Some years ago, we reported the synthesis of functional-
ized pyrroles based on reactions of a-azidoketones with
1,3-dicarbonyl dianions.7 2-Azido-1,1-dimethoxyethane
and 2-azido-1,1-diethoxyethane represent new and
interesting synthetic equivalents of aminoacetaldehyde.
Recently, we have reported the synthesis of functional-
Keywords: Pyrroles; Indoles; Azides; Cyclization; N-Heterocycles.
*
Corresponding author. Tel.: +49 381 4896410; fax: +49 381
4986412; e-mail: peter.langer@uni-rostock.de
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.121

2152
E. Bellur, P. Langer / Tetrahedron Letters 47 (2006) 2151–2154
compounds containing an additional electrophilic func-
tionality can be carried out (vide infra).
The application of method C gave 4l in 60% yield;
besides, a small amount of pyrrole 4l0 was isolated
(5%). The TFA-mediated cyclization of 3m, prepared
from benzoylacetone (1m), afforded the 3-benzoylpyr-
role 4m in 82% yield (method A).14 The use of Me3SiOTf
(0 ! 20 ꢂC, method B) and heating of a DMSO solution
of 3m (method C) also proved to be successful (Table 1).
Reflux of neither 3a nor 3m in other solvents such as,
THF, CH3CN, or 1,4-dioxane afforded the correspond-
ing pyrroles.
2-Azido-1,1-diethoxyethane (2) was prepared according
to the procedure reported for the synthesis of 2-azido-
1,1-dimethoxyethane.8,10 The aza-Wittig reaction of 2
with methyl acetoacetate (1a) afforded the enamine 3a
(Scheme 1 and Table 2). Related enamines, prepared
from 2-amino-1,1-dimethoxyethane, have been used
for the synthesis of isoquinolines.9b Optimal results were
obtained when the reaction was carried out using a small
excess of 2 (1.2 equiv) and of PPh3 (1.3 equiv) (THF,
reflux, 8 h).11–13 The transformation of 3a into the
desired pyrroles 4a required a thorough optimization
of the conditions (Table 1).14 Treatment of a CH2Cl2
solution of 3a, prepared from methyl acetoacetate (1a),
with TFA at 0 ! 20 ꢂC afforded 4a in 22% yield (method
A). The yield was increased to 35% by treatment of a
CH2Cl2 solution of 3a with Me3SiOTf at ꢀ78 ! 20 ꢂC
(method B). Heating of a DMSO solution of 3a at
150 ꢂC for 24 h afforded 4a in 40% yield (method C);
the pyrrole 4a0 was isolated as a side-product in 19%
yield. Methods C and B were successfully employed for
the synthesis of the ester substituted pyrroles 4b–c and
4d–k, respectively (Table 2).
The enamines 6a–d were prepared by reaction of 2 with
cyclohexane-1,3-diones 5a–d (Scheme 2 and Table 3).
Treatment of 6a–d with TFA afforded the 6,7-dihydro-
1H-indol-4(5H)-ones 7a–d in very good yields (method
A). Indole 7a was also prepared by application of
method C.15
In summary, we have reported a new and efficient
approach to a variety of pyrroles and 6,7-dihydro-
1H-indol-4(5H)-ones based on aza-Wittig reactions of
2-azido-1,1-diethoxyethane and subsequent cyclizations.
Table 2. Yields of condensation products (3) and pyrroles (4)
3, 4 R1
R2
% (3)a % (4)a Methodd
The reaction of 2 with acetylacetone (1l) afforded 4-(2,2-
diethoxyethylamino)pent-3-en-2-one (3l), which was
transformed into the pyrrole 4l (68%) by method A.
a
b
c
d
e
f
OMe
OEt
O(CH2)2OMe
OCH2CH@CH2
OMe
OEt
OEt
OEt
OEt
OEt
OEt
Me
H
H
H
H
Me
Et
nHex
nOct
nNon
nDec
86
89
89
90
82
75
84
86
91
91
40b
58
51
37
39
55
58
57
54
56
47
68
60c
82
C
C
C
B
B
B
B
B
B
B
B
A
C
A
OEt
N3
OEt
OEt
g
h
i
O
OEt
O
O
HN
2
R1
R1
R2
R2
j
i
k
l
(CH2)6Cl 83
H
1a-m
3a-m
98
97
H
N
R2
R1
ii
m
Ph
H
a Yields of isolated products.
b Besides, 4a0 was isolated in 19% yield.
c Besides, 4l0 was isolated in 5% yield.
d Method A: TFA, CH2Cl2; method B: Me3SiOTf (1.0 equiv), CH2Cl2;
method C: DMSO, 150 ꢂC.
O
4a-m
EtO
Scheme 1. Synthesis of 3a–m and 4a–m. Reagents and conditions: (i)
PPh3, THF, reflux, 8 h; (ii) see Tables 1 and 2. Method A: TFA
(10 equiv), CH2Cl2, 0 ! 20 ꢂC, 12 h; method B: Me3SiOTf (1 equiv),
CH2Cl2, ꢀ78 ! 20 ꢂC (for b-ketoesters) or 0 ! 20 ꢂC (for 1,3-
diketones), 12 h; method C: DMSO, 150 ꢂC, 24 h.
EtO
EtO
OMe
O
N
N
EtO
O
4l'
4a'
Table 1. Optimization for the synthesis of pyrroles 4a and 4m
Substrate
Solvent
t (h)
Conditions
Conversiona (%)
3a
3a
CH2Cl2
CH2Cl2
CH2Cl2
DMSO
CH2Cl2
CH2Cl2
DMSO
12
12
12
24
12
12
24
TFA, 20 ꢂC
Decomposition
TFA, 0 ! 20 ꢂC
22
35
40b
82
79
72
3a
3a
Me3SiOTf, ꢀ78 ! 20 ꢂC
150 ꢂC
3m
3m
3m
TFA, 0 ! 20 ꢂC
Me3SiOTf, 0 ! 20 ꢂC
150 ꢂC
a Yields of isolated products.
b Besides, 4a0 was formed, see Table 2 footnote.

E. Bellur, P. Langer / Tetrahedron Letters 47 (2006) 2151–2154
2153
J. R.; Krumpe, K.; Gupton, J. T.; Burnham, B. S.
Molecules 2004, 9, 135, and references cited therein.
2. Books for pyrrole syntheses: (a) Eicher, T.; Hauptmann, S.
Chemie der Heterocyclen; Thieme: Stuttgart, 1994, p 94;
(b) Sundberg, R. J. In Comprehensive Heterocyclic Chem-
istry; Bird, C. W., Cheeseman, G. W. H., Eds.; Pergamon
Press: Oxford, 1984; Vol. 4, p 331; (c) Gribble, G. W. In
Comprehensive Heterocyclic Chemistry II; Katritzky, A.
R., Rees, C. W., Scriven, E. F. V., Eds.; Elsevier: Oxford,
1996; Vol. 2, p 207; (d) Bean, G. P. In Pyrroles; Jones, R.
A., Ed.; Wiley: New York, 1990; p 105.
3. For pyrrole syntheses: (a) Huisgen, R. Angew. Chem., Int.
Ed. Engl. 1967, 2, 565; (b) Huisgen, R.; Gotthard, H.;
Bayer, H. O.; Scha¨fer, F. C. Chem. Ber. 1970, 103, 2611;
(c) Barnard, G. F.; Itoh, R.; Hohberger, L.; Shemin, D. J.
Biol. Chem. 1977, 252, 8965; (d) Chiu, P.-K.; Lui, K.-H.;
Maini, P. N.; Sammes, M. P. J. Chem. Soc., Chem.
Commun. 1987, 109; (e) Barton, D. H. R.; Kervagoret, J.;
Zard, S. Z. Tetrahedron 1990, 46, 7587; (f) Roskamp, E. J.;
Dragovich, P. S.; Hartung, J. B.; Pederson, S. F. J. Org.
Chem. 1989, 54, 4736; (g) Tang, J.; Verkade, J. G. J. Org.
Chem. 1994, 59, 7793; (h) De Kimpe, N.; Tehrani, K. A.;
Stevens, C.; De Cooman, P. Tetrahedron 1997, 53, 3693; (i)
OEt
OEt
OEt
OEt
O
HN
N3
2
R1
R2
R1
R2
O
O
i
5a-d
6a-d
HN
ii
R1
R2
O
7a-d
Scheme 2. Synthesis of 6,7-dihydro-1H-indol-4(5H)-ones 7a–d.
Reagents and conditions: (i) PPh3, THF, reflux, 8 h; (ii) method A:
TFA (10 equiv), CH2Cl2, 0 ! 20 ꢂC, 12 h; method C: DMSO, 150 ꢂC,
24 h.
Table 3. Yields of enamines 6 and 6,7-dihydro-1H-indol-4(5H)-ones 7
R1
R2
% (6)a
% (7)a
Method
´
Alberala, A.; Ortega, A. G.; Sadaba, M. L.; Snudo, C.
Tetrahedron 1999, 55, 6555.
6, 7
a
H
H
97
95
71
60
75
73
A
C
A
A
A
4. For other pyrrole syntheses: (a) Grigg, R.; Savic, V. Chem.
Commun. 2000, 873; (b) Trofimov, B. A.; Tarasova, O. A.;
Mikhaleva, A. I.; Kalinina, N. A.; Sinegovskaya, L. M.;
Henkelmann, J. Synthesis 2000, 11, 1585; (c) Almerico, A.
M.; Montalbano, A.; Diana, P.; Barraja, P.; Lauria, A.;
Cirrincione, G.; Dattolo, G. Arkivoc 2001, 129; (d)
Trofimov, B. A.; Markova, M. V.; Morozova, L. V.;
Mikhaleva, A. I. Arkivoc 2001, 24; (e) Nair, V.; Vinod, A.
U.; Rajesh, C. J. Org. Chem. 2001, 66, 4427; (f) Ranu, B.
C.; Hajra, A. Tetrahedron 2001, 57, 4767; (g) Lagu, B.;
Pan, M.; Wachter, M. P. Tetrahedron Lett. 2001, 42, 6027;
(h) Quiclet-Sire, B.; Wendeborn, F.; Zard, S. Z. Chem.
Commun. 2002, 2214; (i) Demir, A. S.; Akhmedov, I. M.;
b
c
d
Me
Me
Ph
Me
H
H
92
94
91
a Yields of isolated products.
The reactions of 2-azido-1,1-diethoxyethane with 1,3-
dicarbonyl compounds can be carried out under mild
conditions and complement analogous reactions of
2-amino-1,1-dialkoxyethanes.
¨
Sesenoglu, O Tetrahedron 2002, 58, 9793; (j) Yoshida, M.;
Kitamura, M.; Narasaka, K. Bull. Chem. Soc. Jpn. 2003,
76, 2003; (k) Knight, D. W.; Sharland, C. M. Synlett 2003,
2258; (l) Yu, M.; Pagenkopf, B. L. Org. Lett. 2003, 5,
5099; (m) Dhawan, R.; Arndtsen, B. A. J. Am. Chem. Soc.
2004, 126, 468; (n) Flo¨gel, O.; Reissig, H.-U. Synlett 2004,
895; (o) Song, Z.; Reiner, J.; Zhao, K. Tetrahedron Lett.
2004, 45, 3953; (p) Chien, T.-C.; Meade, E. A.; Hinkley, J.
M.; Townsend, L. B. Org. Lett. 2004, 6, 2857; (q)
Ramanathan, B.; Keith, A. J.; Armstrong, D.; Odom, A.
L. Org. Lett. 2004, 6, 2957; (r) Trofimov, B. A.; Zaitsev, A.
B.; Schmidt, E. Y.; Vasil’tsov, A. M.; Mikhaleva, A. I.;
Ushakov, I. A.; Vashchenko, A. V.; Zorina, N. V.
Tetrahedron Lett. 2004, 45, 3789; (s) Agarwal, S.; Kno¨lker,
H.-J. Org. Biomol. Chem. 2004, 2, 3060; (t) Dieltiens,
N.; Stevens, C. V.; De Vos, D.; Allaert, B.; Drozdzak, R.;
Verpoort, F. Tetrahedron Lett. 2004, 45, 8995; (u)
Dieltiens, N.; Stevens, C. V.; Allaert, B.; Verpoort, F.
Arkivoc 2005, 92; (v) Schmidt, E. Y.; Mikhaleva, A. I.;
Vasil’tsov, A. M.; Zaitsev, A. B.; Zorina, N. V. Arkivoc
2005, 11.
Acknowledgements
Financial support from the DAAD (scholarship for
E.B.), the BASF AG, and from the state of Mecklen-
burg-Vorpommern (Landesforschungsschwerpunkt ‘Neue
Wirkstoffe und Screeningverfahren’) is gratefully
acknowledged.
References and notes
1. For pyrrole natural products: (a) Falk, H. The Chemistry
of Linear Oligopyrroles and Bile Pigments; Springer: Wien,
1989, p 355; (b) Montforts, F.-P.; Schwartz, U. M. Angew.
Chem. 1985, 97, 767; Angew. Chem., Int. Ed. Engl. 1985,
24, 775; (c) Dutton, C. J.; Fookes, C. J. R.; Battersby, A.
R. J. Chem. Soc., Chem. Commun. 1983, 1237; (d) Stork,
G.; Nakahara, Y.; Nakahara, Y.; Greenlee, W. J. J. Am.
Chem. Soc. 1978, 100, 7775; (e) Stork, G.; Nakamura, E.
J. Am. Chem. Soc. 1983, 105, 5510; (f) Bickmeyer, U.;
Drechsler, C.; Ko¨ck, M.; Assmann, M. Toxicon 2004, 44,
5. Reviews of aza-Wittig reactions: (a) Eguchi, S.; Okano, T.;
Okawa, T. Rec. Res. Dev. Org. Chem. 1997, 337; Chem.
Abstr. 1999, 130, 252510; (b) Fresneda, P. M.; Molina, P.
Synlett 2004, 1; (c) Eguchi, S. Arkivoc 2005, 98.
45; (g) Lindel, T.; Breckle, G.; Hochgurtel, M.; Volk, C.;
¨
Grube, A.; Ko¨ck, M. Tetrahedron Lett. 2004, 45, 8149; (h)
Feldman, K. S. Arkivoc 2003, 179; (i) Holub, J. M.;
O’Toole-Colin, K.; Getzel, A.; Argenti, A.; Evans, M. A.;
Smith, D. C.; Dalglish, G. A.; Rifat, S.; Wilson, D. L.;
Taylor, B. M.; Miott, U.; Glersaye, J.; Lam, K. S.;
McCranor, B. J.; Berkowitz, J. D.; Miller, R. B.; Lukens,
6. (a) Montforts, F.-P.; Schwartz, U. M.; Mai, G. Liebigs
Ann. Chem. 1990, 1037; (b) Gusar, N. I. Russ. Chem. Rev.
1991, 60, 146; (c) Eguchi, S.; Matsushita, Y.; Yamashita,
K. Org. Prep. Proced. Int. 1992, 24, 211; (d) Eguchi, S.;
Okano, T. J. Synth. Org. Chem. Jpn. 1993, 51, 203; (e)
Molina, P.; Viliplana, M. J. Synthesis 1994, 1197; (f)

2154
E. Bellur, P. Langer / Tetrahedron Letters 47 (2006) 2151–2154
Wamhoff, H.; Richard, G.; Stoelben, S. Adv. Heterocycl.
Chem. 1995, 64, 159; (g) Ming-Wu, D.; Zhao-Jie, L. Chin.
J. Org. Chem. 2001, 21, 1.
3 · CH of Ph), 7.86 (m, 2H, 2 · CH of Ph), 11.42 (br s,
1H, NH). 13C NMR (CDCl3, 75 MHz): dC = 15.2 (2C),
19.5 (CH3), 46.3 (NCH2), 63.3 (2 · OCH2), 92.5 (CH@C),
101.1 (OCH), 126.7 (2C), 127.9 (2C), 130.2 (CH of Ph),
140.3 (C of Ph), 164.7 (N–C@CH), 187.8 (C@O). IR (neat,
7. Langer, P.; Freifeld, I. Chem. Commun. 2002, 2668.
8. Bellur, E.; Go¨rls, H.; Langer, P. J. Org. Chem. 2005, 70,
4751.
9. (a) Parr, R. W.; Reiss, J. A. Aust. J. Chem. 1984, 37, 389;
(b) Bridge, A. W.; Fenton, G.; Halley, F.; Hursthouse, M.
B.; Lehmann, C. W.; Lythgoe, D. J. J. Chem. Soc., Perkin
Trans. 1 1993, 22, 2761; (c) Kascheres, A.; Schumacher, H.
C.; Rodrigues, R. A. F. J. Heterocycl. Chem. 1997, 34,
757.
10. For related azides, see: (a) Bertschy, H.; Meunier, A.;
Neier, R. Angew. Chem. 1990, 102, 828; Angew. Chem.,
Int. Ed. Engl. 1990, 29, 777; (b) Carboni, B.; Vaultier, M.;
Carrie, R. Tetrahedron 1987, 43, 1799; (c) Chavan, S. P.;
Subbarao, Y. T. Tetrahedron Lett. 1999, 40, 5073.
11. CAUTION: The handling of low-molecular weight azides
is dangerous, due to their potentially explosive character.
Although, in our hands, neat 2 did not appear to be shock
sensitive, the compound should be handled with great
care. Neat azides must not be heated or distilled and all
reactions should be carried out on a small scale. The use of
a safety shield is highly recommended.
cmꢀ1): m ¼ 3060 (w), 2977 (m), 2930 (w), 2830 (w), 2883
~
(w), 1606 (s), 1550 (s), 1525 (m), 1483 (w), 1444 (m), 1378
(m), 1327 (s), 1294 (s), 1245 (m), 1172 (w), 1127 (s), 1065
(s), 1031 (m), 818 (w), 793 (w), 740 (m), 714 (w), 684 (w).
MS (EI, 70 eV): m/z (%) = 277 (M+, 7), 232 (6), 199 (7),
174 (7), 160 (2), 158 (6), 144 (1), 117 (1), 103 (100), 91 (14),
77 (17). HRMS (ESI): calcd for C16H23NO3 [M+]:
277.16779; found: 277.16803. Anal. Calcd for
C16H23NO3 (277.363): C 69.29, H 8.36, N 5.05. Found:
C 69.61, H 8.37, N 5.22.
14. Representative procedures for the synthesis of pyrroles (4):
Synthesis of (2-methyl-1H-pyrrol-3-yl)phenylmethanone
(4m): Method A: To a CH2Cl2-solution (3 mL) of 3m
(0.050 g, 0.18 mmol) was added TFA (0.14 mL, 1.8 mmol)
at 0 ꢂC. The reaction mixture was allowed to warm to
20 ꢂC during 12 h and was stirred for 4 h at 20 ꢂC. The
solvent was removed in vacuo and the residue was purified
by column chromatography (silica gel, n-hexane/
EtOAc = 50:1 ! 3:1) to give 4m as a yellowish solid
(0.027 g, 82%). Method B: To a CH2Cl2-solution (3 mL)
of 3m (0.050 g, 0.18 mmol) was added Me3SiOTf (0.050 g,
0.18 mmol) at 0 ꢂC. The reaction mixture was allowed to
warm to 20 ꢂC during 12 h and was stirred for 4 h at 20 ꢂC.
The solvent was removed in vacuo and the residue was
purified by column chromatography (silica gel, n-hexane/
EtOAc = 50:1 ! 1:1) to give 4m as a yellowish solid
(0.026 g, 79%). Method C: A DMSO solution (5 mL) of
3m (0.100 g, 0.36 mmol) was stirred at 150 ꢂC for 24 h.
After cooling to 20 ꢂC, water (10 mL) was added and the
mixture was extracted with diethylether (4 · 15 mL). The
combined organic extracts were dried (Na2SO4), filtered,
and the filtrate was concentrated in vacuo. The residue was
purified by column chromatography (silica gel, n-hexane/
EtOAc = 50:1 ! 1:1) to give 4m as a yellowish solid
12. Synthesis of 2-azido-1,1-diethoxyethane (2): Sodium azide
(19.5 g, 300.0 mmol) and potassium iodide (3.32 g,
20.0 mmol) were added to a solution of 2-bromo-1,1-
diethoxyethane (31 mL, 200.0 mmol) in DMSO (150 mL)
at 20 ꢂC. The reaction mixture was heated to 90 ꢂC and
stirred for 5 days at 90 ꢂC. After cooling to 20 ꢂC, water
(200 mL) and diethylether (200 mL) were added, the
organic layer was separated, and the aqueous layer was
repeatedly extracted with diethylether (4 · 200 mL). The
combined organic extracts were dried (Na2SO4), filtered,
and the filtrate was concentrated in vacuo. The azidoacetal
2 was isolated without further purification as a colorless
oil (30.63 g, 96%). For safety reasons, it is recommended
to carry out the reaction on a small scale (no decrement of
the yield was observed) and to use a safety shield. 1H
NMR (CDCl3, 300 MHz): d = 1.25 (t, J = 7.2 Hz, 6H,
2 · CH3), 3.25 (d, J = 5.4 Hz, 2H, CH2–N3), 3.54–3.64 (m,
2H, OCH2), 3.68–3.78 (m, 2H, OCH2), 4.61 (t, J = 5.4 Hz,
1H, OCH). 13C NMR (CDCl3, 75 MHz): dC = 15.0
(2 · CH3), 52.2 (CH2–N3), 62.7 (2 · OCH2), 101.21
1
(0.048 g, 72%). H NMR (CDCl3, 300 MHz): d = 2.54 (s,
3H, CH3), 6.40 (dd, J = 3.0, 2.7 Hz, 1H, CH), 6.55 (dd,
J = 3.0, 2.4 Hz, 1H, CH), 7.41–7.51 (m, 3H, 3 · CH of Ph),
7.78–7.81 (m, 2H, 2 · CH of Ph), 9.06 (br s, 1H, NH). 13
C
NMR (CDCl3, 75 MHz): dC = 13.7 (CH3), 112.5, 115.6
(CH), 119.6 (C), 128.0 (2C), 129.0 (2C), 131.1 (CH of Ph),
136.7 (C of Ph), 140.6 (C), 192.8 (C@O). In the NOESY
spectrum cross peaks were found for the protons NH with
CH3, NH with H-5, CH3 with H–ortho-C6H5 and H-4 with
H–ortho-C6H5, which confirm the given structure. 1H
NMR (CDCl3, 500.13 MHz): d = 8.94 (br s, 1H, NH), 7.78
(m, 2H, o-Ph), 7.49 (m, 1H, p-Ph), 7.42 (m, 2H, m-Ph), 6.54
(OCH). IR (neat, cmꢀ1): m ¼ 2980 (s), 2932 (m), 2884
~
(m), 2104 (s, N3), 1479 (w), 1446 (w), 1376 (w), 1348 (w),
1273 (s), 1233 (w), 1130 (s), 1067 (s), 946 (w), 921 (w), 844
(w). MS (EI, 70 eV): m/z (%) = 160 (M+, 100), 145 (31),
114 (17), 91 (24).
13. Typical procedure for the synthesis of enamines (3):
Synthesis of 3-(2,2-diethoxyethylamino)-1-phenylbut-2-en-
1-one (3m): To a THF solution (10 mL) of benzoylacetone
(0.200 g, 1.2 mmol) and 2-azido-1,1-diethoxyethane (2)
(0.236 g, 1.5 mmol) was added triphenylphosphine
(0.656 g, 2.5 mmol) at 20 ꢂC. The reaction mixture was
heated and stirred for 8 h at reflux. After cooling to 20 ꢂC,
the solvent was removed in vacuo and the residue was
purified by column chromatography (silica gel, n-hexane/
EtOAc = 100:1 ! 1:1) to give 3m as a yellowish oil
3
3
(t, 1H, J4,5 ꢁ J5,NH ꢁ 3.0 Hz, H-5), 6.39 (t, 1H,
4
3J4,5 ꢁ J4,NH ꢁ 3.0 Hz, H-4),2.53 (s, 3H, CH3). 13C
NMR (CDCl3, 125.8 MHz): d = 192.7 (CO), 140.6 (i-Ph),
136.7 (C–2), 131.1 (p-Ph), 129.0 (o-Ph), 128.0 (m-Ph), 119.6
(C–3), 112.5 (C–4), 115.6 (C–5), 13.7 (CH3). IR (KBr,
cmꢀ1): m ¼ 3232 (w), 2924 (w), 1608 (s), 1561 (m), 1446 (s),
~
1367 (m), 1340 (w), 1277 (m), 1212 (w), 1180 (w), 1148 (w),
1101 (w), 1075 (w), 1032 (w), 880 (m), 792 (m), 743 (w), 712
(s), 702 (s), 672 (w), 612 (w). MS (EI, 70 eV): m/z (%) = 185
(M+, 73), 170 (3), 107 (100), 80 (13), 77 (24). HRMS (ESI):
calcd for C12H11NO [M+]: 185.08406; found: 185.08483.
15. Bobbitt, J. M.; Kulkarni, C. L.; Dutta, C. P.; Kofod, H.;
Chiong, K. N. J. Org. Chem. 1978, 43, 3541.
1
(0.322 g, 97%). H NMR (CDCl3, 300 MHz): d = 1.25 (t,
J = 7.1 Hz, 6H, 2 · CH3), 2.10 (s, 3H, CH3), 3.46 (dd,
J = 6.4, 5.6 Hz, 2H, NCH2), 3.59 (dq, J = 9.3, 7.1 Hz, 2H,
OCH2), 3.76 (dq, J = 9.3, 7.1 Hz, 2H, OCH2), 4.59 (t,
J = 5.6 Hz, 1H, OCH), 5.68 (s, 1H, CH@C), 7.40 (m, 3H,