Facile preparation of N-protected 2-alkylidene-1,3-imidazolidines

Article abstract of DOI:10.1016/j.tetlet.2008.02.006

Stereoselective preparation of unsymmetrically protected 2-alkylidene-1,3-imidazolidines was achieved by the reaction of N,N′-protected ethylenediamine, bromopropynamide, and K₃PO₄ in hot DMF. When N-protected aminoethanol was used i

Full text of DOI:10.1016/j.tetlet.2008.02.006

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Tetrahedron Letters 49 (2008) 2298–2301
Facile preparation of N-protected 2-alkylidene-1,3-imidazolidines
Hiroyuki Naito, Takeshi Hata, Hirokazu Urabe *
Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259-B-59 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
Received 19 December 2007; revised 31 January 2008; accepted 4 February 2008
Available online 7 February 2008
Abstract
Stereoselective preparation of unsymmetrically protected 2-alkylidene-1,3-imidazolidines was achieved by the reaction of N,N0-
protected ethylenediamine, bromopropynamide, and K3PO4 in hot DMF. When N-protected aminoethanol was used in place of the
protected ethylenediamine, an oxazolidine derivative was produced.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Imidazolidine; Oxazolidine; Bromoacetylene; Sulfonamide
Alkylideneimidazolidines of structure 31 are conve-
PG1
N
NHPG1
niently prepared by the conjugate addition of 1,2-diamines
1 to bromopropiolic acid derivatives such as 2 as shown in
Scheme 1, while preventing the formation of the tautomeric
isomer 4.2 As the compounds represented by 3 have active
hydrogens on the nitrogen atoms, their N-protection is
often required to prevent complications in further synthetic
transformations.3 However, their efficient and full protec-
tion is rarely documented.4 A critical issue in selective pro-
tection is to discriminate between the two amine moieties
cis and trans to the carbonyl group. Here we report that
a suitably protected diamine 5 can be used instead of the
amine 1 itself for the direct preparation of the protected
+
Br
COX
NHPG2
N
COX
PG2
(7)
(5)
(6)
PG = Protective group
X = OR, NR2, etc.
Scheme 2.
imidazolidines 7, even for that of unsymmetrically pro-
tected ones, as formulated in Scheme 2. This method has
an additional advantage that the product is free from con-
tamination with its double-bond regioisomer, as shown in
Scheme 1.
In the above transformation, whether a bis-protected
diamine 5 shows sufficient nucleophilicity to the bromopro-
piolic acid derivative 6 appears to be a serious problem,
because protection of an amine usually decreases its nucleo-
philicity and also retards its reactivity as a result of steric
hindrance of the protective group(s). We were discouraged
by the fact that the reaction of N,N0-diacetyl-1,2-ethylene-
diamine (8) and ethyl bromopropiolate or N,N-diethyl-
bromopropynamide (9) (see Table 1, entry 1) did not give
the desired product. However, we soon realized the impor-
tance of the nature of the protecting group on the diamine
NH2
+
Br
CO2Me
NH2
(2)
(1)
H
N
N
+
N
H
N
H
CO2Me
CO2Me
(3)
(4)
Scheme 1.
*
Corresponding author. Tel./fax: +81 45 924 5849.
E-mail address: hurabe@bio.titech.ac.jp (H. Urabe).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.006

H. Naito et al. / Tetrahedron Letters 49 (2008) 2298–2301
2299
Table 1
Preparation of 2-alkylidene-1,3-imidazolidinesa
PG1
N
NHPG1
NHPG2
K3PO4 (2 equiv)
+
Br
CONR2
(1.1 equiv)
DMF, 70 ~ 100 ˚C
N
PG2
CONR2
Entry
Diamine
Bromopropynamide
Temperature (°C)
Period (h)
Product
Isolated yieldb (%)
NHPG
PG
N
NHPG
N
CONEt2
PG
1
2
3
4
5
6
PG = Ac (8)
Boc
(9)
100
100
100
100
100
100
7
7
7
7
0.5
7
PG = Ac
Boc
(0)
(5)
(19)
33
69
70
Br
9
CONEt2
Ms
9
Ms
Tf (10)
Ts (12)
Ts (12)
9
Tf (11)
Ts (13)
Ts (13)
9
9
Ts
N
7
12
12
100
7
7
(15)c
44
Br
Br
CO2Et
(14)
(16)
N
CO2Et
Ts
Ts
N
8
CONBn2
100
85d
N
CONR2
Ts
= NBn2 (19)
NR2
O
N
9
12
100
100
7
7
91
Br
Br
-N
(20)
(17)
(18)
O
N
10
12
82e
-N
O (21)
O
Ts
N
NHTs
11
9
70
0.5
68f
(22)
N
CONR2
(23)
NHBoc
Boc
NR2 = NEt2
12
13
22
16
17
70
70
0.5
5
NBn2 (24)
66
60
22
-N
-N
(25)
(26)
14
22
18
70
5
63
O
a
Abbreviations: DMF = N,N-dimethylformamide, Ac = acetyl, Boc = t-butyloxycarbonyl, Ms = methanesufonyl, Tf = trifluoromethanesulfonyl,
Ts = p-toluenesulfonyl (tosyl), Bn = benzyl.
b
Yields determined by 1H NMR are in parentheses.
For structural determination, see Ref. 5.
16 (2.0 equiv) was used.
18 (1.0 equiv) was used.
c
d
e
f
For the E stereochemistry of the olefin, see the text.
(entries 1–6) and we determined that bis-tosyl-protected
diamine 12 is the substrate of choice for the transformation
of Scheme 2 (entry 6).6 Other optimized reaction conditions
are the use of K3PO4 and DMF as the base and solvent,

2300
H. Naito et al. / Tetrahedron Letters 49 (2008) 2298–2301
respectively (see the equation in Table 1). A reaction period
as short as 0.5 h is satisfactory (cf. entries 5 and 6), but
longer times, up to 7 h, were generally used to ensure the
completion of the reaction. Bromopropynamide 9 is a
better acetylenic substrate than the corresponding ethyl
ester 14 (entry 7). With this combination of substrates
and reaction conditions, the desired product 13 was
obtained in 70% yield. Under similar reaction conditions,
other propynamides 16–18 afforded the desired products
19–21 in good yields (entries 8–10).7
Ts
N
K PO
3
4
NHTs
(2 equiv)
+
Br
CONEt
2
DMF, 110 °C
3 h
O
CONEt
2
OH
(34)
89%, single isomer
(33)
(9)
Scheme 4.
olefinic stereochemistry was assigned as Z by a NOESY
experiment.10
Although the tosyl protection of the diamine, such as in
12, proved to be essential for the success of the reaction, we
found that both tosyl groups in 12 are not necessary. Thus,
a mono-tosylated diamine having another protective group
still effected the desired reaction. For instance, Ts- and
Boc-protected diamine 22 afforded the desired product 23
in a satisfactory yield and, surprisingly, as a single stereo-
isomer (Table 1, entry 11). The stereochemistry of its olefin
moiety was assigned as E by a NOESY experiment that
showed the correlation between the vinyl proton and
ortho-protons of the Ts group. Similarly, unsymmetrical
imidazolidines 24–26 were prepared from the correspond-
ing bromoacetylenic amides 16–18 (entries 12–14).7,8
This reaction should proceed according to Scheme 3.
The sulfonamide moiety of 27, under any condition, takes
part in the first conjugate addition/elimination sequence to
produce b-(sulfonylamino)propynamide 28. The second
intramolecular addition of another amido group in 28
forms enolate 29–31, protonation of which most likely
determines the stereochemistry of the product to produce
sterically less hindered 32 (X = Boc).
In summary, 2-alkylidene-1,3-imidazolidines were con-
veniently prepared from suitably protected 1,2-diamines
and bromoproynamides. Further investigation of synthetic
applications of this reaction and its products is now under
way.
Acknowledgments
The authors are grateful to Kyowa Hakko Kogyo Co.,
Ltd for financial support. This work was also supported
in part by a Grant-in-Aid for Young scientists (Start-up)
(No. 18890069) to T.H. from Japan Society for the promo-
tion of science.
References and notes
1. For reviews on imidazolidines of structure 3, see: (a) Wang, M.;
Huang, Z. Prog. Nat. Sci. 2002, 12, 249–257; (b) Huang, Z.-T.; Wang,
M.-X. Heterocycles 1994, 37, 1233–1262. For reviews on imidazoli-
dines, see: (c) Huang, Z.-T.; Wang, M.-X. In The Chemistry of
Enamies; Rappoport, Z., Ed.; Wiley Interscience: London, 1994; pp
1303–1363; (d) Katritzky, A. R., Rees, C. W., Eds. Comprehensive
Heterocyclic Chemistry; Pergamon Press: Oxford, 1984; Vol. 5.
2. Tikhomirov, D. A.; Slyadevskaya, O. S.; Eremeev, A. V. Khim.
Geterotsikl. Soedin. 1991, 1205–1208; Chem. Heterocycl. Comp. 1991,
27, 966–969.
3. The parent 3 and its protected derivatives are a versatile building
block for the construction of five-membered diazacycles. For repre-
sentative synthetic applications, see: (a) Yu, C.-Y.; Yang, P.-H.;
Zhao, M.-X.; Huang, Z.-T. Synlett 2006, 1835–1840; (b) Jones, R. C.
F.; Patel, P.; Hirst, S. C.; Smallridge, M. J. Tetrahedron 1998, 54,
6191–6200; (c) Jones, R. C. F.; Turner, I.; Howard, K. J. Tetrahedron
Lett. 1993, 34, 6329–6332; (d) Jones, R. C. F.; Hirst, S. C. Tetrahedron
Lett. 1989, 30, 5361–5364; (e) Jones, R. C. F.; Hirst, S. C. Tetrahedron
Lett. 1989, 30, 5365–5368; (f) Jones, R. C. F.; Smallridge, M. J.
Tetrahedron Lett. 1988, 29, 5005–5008.
The reaction course shown in Scheme 3 suggests that the
second nucleophilic addition (i.e., from 28 to 29) might be
feasible with other heteroatom functional groups. This
expectation was realized when N-tosylated aminoalcohol
33 entered the reaction to produce oxazolidine derivative
34 in excellent yield as a single isomer (Scheme 4).9 Its
Ts
N
NHTs
CONR
2
K PO
3
4
Br
CONR
+
2
NHX
NX
(27)
(28)
X = Ts or Boc
4. For mono-protected form of 3, see: Ref. 3. For other preparations of
derivatives of 3, see: (a) Shubina, Y. V.; Tikhomirov, D. A.; Eremeev,
A. V. Khim. Geterotsikl. Soedin. 1985, 618–622; Chem. Heterocycl.
Comp. 1985, 21, 516–520; (b) Wang, H.-T.; Wang, X.-J.; Huang, Z.-T.
Chem. Ber. 1990, 123, 2141–2145; (c) Dannhardt, G.; Laufer, S.;
Ziereis, K. Arch. Pharm. 1988, 321, 429–430; (d) Huang, Z.-T.; Tzai,
L.-H. Chem. Ber. 1986, 119, 2208–2219; (e) Anderson, M. W.; Begley,
M. J.; Jones, R. C. F.; Saunders, J. J. Chem. Soc., Perkin Trans. 1
1984, 2599–2602. For mono-protection of relevant ketones, see: (g)
Wang, M.-X.; Wu, X.-D.; Wang, L.-B.; Huang, Z.-T. Synth.
Commun. 1995, 25, 343–349; (h) Wang, M.-X.; Huang, Z.-T. J.
Org. Chem. 1995, 60, 2807–2811; (i) Ren, Z.-X.; Li, Z.-J.; Huang,
Z.-T. Synth. Commun. 1998, 28, 4241–4247.
Ts
N
Ts
N
Ts
N
O
NR
O
2
N
X
N
X
N
X
NR
NR
2
2
O
(29)
(30)
(31)
Ts
N
Ts
N
E
(X = Boc)
CONR
+
2
H
N
X
N
X
CONR
2
5. For structural confirmation, product 15 was reduced with Dibal to
give allylic alcohol 35, which was consistent with the expected
structure by 1H NMR analysis.
(32)
none
Scheme 3.

H. Naito et al. / Tetrahedron Letters 49 (2008) 2298–2301
2301
fonyl)imidazolidin-2-ylidene]acetamide(23): To a solution of N-(t-
butyloxycarbonyl)-N0-(p-toluenesulfonyl)ethylenediamine (22) (62.9
mg, 0.200 mmol) and K3PO4 (84.9 mg, 0.400 mmol) in DMF
(2.0 mL) in an oil bath maintained at 70 °C was added N,N-
diethylbromopropynamide (9) (44.9 mg, 0.220 mmol) in DMF
(2.0 mL) under argon. The reaction mixture was stirred at the same
temperature for 0.5 h. After being cooled to room temperature, the
reaction mixture was diluted with water and extracted with ethyl
acetate. The combined organic layers were dried over Na2SO4 and
concentrated in vacuo to give a crude oil, which was chromato-
graphed on silica gel (hexane–ethyl acetate) to afford the title
δ 5.98 ppm (t)
δ 6.11 ppm
H
Ts
N
Ts
N
H
J
= 8.1 Hz
Dibal
CH2Cl2
-78 ºC → r.t.
H
H
N
Ts
N
Ts
δ 4.31 ppm
(br d)
CO2Et
HO
(35) 60%
(15)
6. In addition, N,N0-bis(o-nitrobenzenesulfonyl)ethylenediamine (di-Ns-
substituted 1) did not give the desired product in more than a trace
amount. Thus, acyl and sulfonyl derivatives of 1 having a less or more
acidic amide proton than that of 12 appear not to participate in this
conjugate addition.
compound (59.2 mg, 68%) as
a d 1.14 (t,
solid. 1H NMR
J = 7.2 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H), 1.36 (s, 9H), 2.41 (s, 3H),
3.32–3.72 (m, 8H), 6.04 (s, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.74 (d,
J = 8.4 Hz, 2H). NOESY experiments showed the correlation
between the peaks at d 6.04 ppm (vinyl H) and at d 7.74 ppm
(ortho-protons of the Ts group). Thus, the stereochemistry of the
olefin moiety was assigned to be E.13C NMR d 13.05, 14.07, 21.51,
27.96, 39.53, 42.47, 44.56, 45.38, 81.80, 92.36, 127.39, 129.92, 134.38,
139.99, 144.76, 150.40, 165.60. IR (Nujol) 3167, 2978, 2933, 2240,
1734 (C=O), 1653 (C=O), 1617, 1457, 1363, 1261, 1164, 1090, 953,
918, 848, 816 cmꢀ1. Anal. Calcd for C21H31N3O5S: C, 57.64; H, 7.14.
Found: C, 57.48; H, 6.76. Mp 44–48 °C.
7. Typical procedures for the preparation of 13 and 23 are as follows: N,N-
Diethyl-2-[1,3-di(p-toluenesulfonyl)imidazolidin-2-ylidene]acetamide
(13): To a solution of N,N0-di(p-toluenesulfonyl)ethylenediamine
(12) (73.7 mg, 0.200 mmol) and K3PO4 (84.9 mg, 0.400 mmol) in
DMF (2.0 mL) in an oil bath maintained at 100 °C was added N,N-
diethylbromopropynamide (9) (44.8 mg, 0.220 mmol) in DMF
(2.0 mL) under argon. The reaction mixture was stirred at the same
temperature for 7 h. After being cooled to room temperature, the
reaction mixture was diluted with water and extracted with ethyl
acetate. The combined organic layers were dried over Na2SO4 and
concentrated in vacuo to give a crude oil, which was chromato-
graphed on silica gel (hexane–ethyl acetate) to afford the title
8. For the deprotection of Ts and Boc groups, see: Greene, T. W.; Wuts,
P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New
York, 1991; pp 379–385, 387.
compound (68.5 mg, 70%) as
a d 1.12 (t,
solid. 1H NMR
9. For preparations and synthetic applications of 2-alkylidene-1,3-
oxazolidine derivatives, see: (a) Zhou, A.; Cao, L.; Li, H.; Liu, Z.;
Cho, H.; Henry, W. P.; Pittman, C. U., Jr. Tetrahedron 2006, 62,
4188–4200; (b) Huang, Z.-T.; Zhang, P.-C. Chem. Ber. 1989, 122,
2011–2016; (c) Kurth, M.; Decker, O. H. W.; Hope, H.; Yanuck, M.
D. J. Am. Chem. Soc. 1985, 107, 443–448. However, 2-alkylidene-1,3-
oxazolidines of the type 34 have not been included.
J = 7.2 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H), 2.40 (s, 3H), 2.41 (s, 3H),
3.27–3.45 (m, 8H), 6.28 (s, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.32 (d,
J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H).
13C NMR d 12.57, 13.87, 21.58 (2 peaks), 39.28, 42.26, 45.86, 46.50,
97.72, 127.39, 128.03, 129.79, 130.00, 134.36, 134.98, 138.69, 144.74,
145.07, 165.37. IR (Nujol) 2925, 2854, 1663 (C=O), 1623, 1598, 1365,
1338, 1320, 1261, 1164, 1138, 1087, 1046, 829 cmꢀ1. Anal. Calcd for
10. A correlation between the vinyl proton and ortho-protons of the tosyl
group was observed.
C
23H29N3O5S2: C, 56.19; H, 5.95. Found: C, 55.89; H, 6.14. Mp 103–
105 °C. (E)-N,N-Diethyl-[3-(tert-butyloxycarbonyl)-1-(p-toluenesul-