Thiourea-catalyzed nucleophilic addition of TMSCN and ketene silyl acetals to nitrones and aldehydes

Article abstract of DOI:10.1016/S0040-4039(03)00433-7

The effect of hydrogen bonding between nitrones and urea derivatives in the nucleophilic addition reaction was examined. Thioureas bearing an electron-withdrawing group on an aromatic ring, behave like Lewis acid to promote the addition of TMSCN and keten

Full text of DOI:10.1016/S0040-4039(03)00433-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2817–2821
Thiourea-catalyzed nucleophilic addition of TMSCN and ketene
silyl acetals to nitrones and aldehydes
Tomotaka Okino, Yasutaka Hoashi and Yoshiji Takemoto*
Department of Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501,
Japan
Received 3 February 2003; revised 13 February 2003; accepted 17 February 2003
Abstract—The effect of hydrogen bonding between nitrones and urea derivatives in the nucleophilic addition reaction was
examined. Thioureas bearing an electron-withdrawing group on an aromatic ring, behave like Lewis acid to promote the addition
of TMSCN and ketene silyl acatals to various nitrones and aldehydes. Presumed interaction between nitrones and thioureas was
supported by NMR experiments. © 2003 Elsevier Science Ltd. All rights reserved.
9
The invention and development of catalytic enantiose-
lective reactions are important research topics among
the most challenging and intensively studied frontiers in
organic synthesis. Thus far, many useful catalytic sys-
tems, most of which contain metallic ions in the active
site, have been developed. From the viewpoint of the
environmentally benign nature, easiness of handling,
and cost of the reaction process, metal-free organocata-
lysts recently attracted much attention to organic
vated. Similarly, it is reasonable to consider that two
NꢀH bonds of ureas would interact with the oxygen of
nitrone concurrently through the hydrogen-bonding
(Fig. 1). Herein, we report the thiourea-catalyzed nucleo-
philic addition of TMSCN and ketene silyl acetals to
nitrones and aldehydes.
1
0
To examine the catalytic potential of ureas, we ini-
tially carried out the reaction of 6-methyl-2,3,4,5-tetra-
hydropyridine N-oxide 1a and TMSCN (5 equiv.) in
the presence of 0.5 equiv. of ureas or thioureas in
1
–4
11
chemists and are intensively studied.
In addition,
different from metallic Lewis acids, these organocata-
lysts could be recovered and reused for a second reac-
tion. In contrast to the enantioselective reactions
CH Cl at −78°C (Table 1). Although even amide 3a
2
2
with only one NꢀH group accelerated the cyanation
reaction of 1a moderately, the reaction with urea 3b
bearing two NꢀH groups completed within 90 min to
give the desired product 2a in 77% yield (entries 1–3).
In addition, acidity of the NꢀH group should be
enhanced by changing urea 3b to thiourea 4a and
1
2
catalyzed by
L-proline, chiral Lewis bases, and phase-
3
transfer catalysts, there are a few reactions catalyzed
by urea derivatives as acid catalysts.
5
–7
Curran et al.
found that addition of ureas improved diastereoselec-
tivity of the radical-mediated allylation of cyclic a-sul-
5
fonyl halides. They also reported Claisen rearrange-
introducing an electron-withdrawing group (CF ) on
the aromatic rings. As expected, the reaction rate dra-
3
6
ment catalyzed by the same urea. Schreiner et al.
recently revealed that thioureas promoted Diels–Alder
reaction of N-crotonyloxazolidin-2-one with cyclopen-
tadiene and affected the diastereoselectivity of the prod-
matically increased when thioureas 4a–c were employed
7
ucts. However these effects on the stereoselectivity
were relatively small and the substrates employed were
limited. Then, with the aim of expanding the applicabil-
ity of ureas as an acid catalyst, we started to explore the
nucleophilic addition to nitrones and aldehydes cata-
8
lyzed by urea derivatives. Having the negatively
charged oxygen atom, nitrones are known to coordi-
nate effectively to the metallic Lewis acids to be acti-
*
Corresponding author. Tel.: +81-075-753-4528; fax: +81-075-753-
569; e-mail: takemoto@pharm.kyoto-u.ac.jp
4
Figure 1. Presumed activation mechanism of nitrones.
0
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00433-7

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T. Okino et al. / Tetrahedron Letters 44 (2003) 2817–2821
Table 1. Relationship between activity and structure of ureas derivatives
as the catalyst (entries 4–6). These results indicate that
positive correlation is observed between the acidity of
the NꢀH bond of thioureas and their catalytic activity,
and also, bidentate coordination of the ureas with 1a is
important for the catalytic activation. Among these
ureas, we selected thiourea 4c as the best catalyst for
the nucleophilic addition.
in the presence of 4c to give the product 2b bearing the
quaternary carbon center in good yield (entry 1). This
method could be applied to acyclic nitrones 1c and 1d.
The same treatment of 1c and 1d as 1b provided the
corresponding adducts 2c and 2d in 85–92% yields
(entries 2 and 3). In the case of entry 3, it is worthy to
note that only 1,2-adduct was obtained, while the con-
jugated nitrone 1d has two reactive sites (a- and g-posi-
tions). Finally, to investigate the effect of 4c on
The scope of the urea-catalyzed cyanation was demon-
strated by the reaction of nitrones 1b–e with TMSCN
catalyzed by thiourea 4c as shown in Table 2. The
cyanation of cyclic nitrone 1b was efficiently accelerated
1
2
diastereoselectivity of the cyanation, chiral nitrone 1e
was subjected to the reaction conditions (entry 4).
Unfortunately, although 4c shortened the reaction time
Table 2. Thiourea-catalyzed addition of TMSCN to various nitrones

T. Okino et al. / Tetrahedron Letters 44 (2003) 2817–2821
2819
effectively, improvement of the diastereoselectivity
syn/anti=42/58) was minimal.
tion of nitrone 1c by the hydrogen bonding with the
urea NꢀH in the manner of a Lewis acid and the
experimental data shown in Table 1.
(
As thiourea 4c was revealed to promote the cyanation
of nitrones, we next examined the reaction of nitrones
The benefit of ureas as organocatalyst is the easiness of
recycle and reuse. In the reaction of nitrone 1a with
TMSCN, thiourea 4c was recovered quantitatively and
no loss of activity was observed on using the recovered
thiourea (1st: 20 min, 76%; 2nd: 20 min, 86%).
13
with ketene silyl acetals 5a–c (Table 3). Reactions of
various nitrones with ketene silyl acetal 5a derived from
ethyl acetate were catalyzed by thiourea 4c, giving rise
to 1,2-isoxazolidin-5-ones 6a–c, and 6f in moderate to
1
4
good yields (entries 1–4). It should be noted that no
or negligible amounts of the desired adducts was
obtained without 4c in all cases. In addition, the reac-
tion of nitrone 1f with sterically hindered ketene silyl
acetals 5b and 5c proceeded smoothly to afford the
corresponding adducts 6g and 6h possessing tertiary
and quaternary carbon centers (entries 5 and 6). More-
over, reduction of the amount of 4c from 0.5 to 0.1
equiv. did not affect the reaction of the nitrone 1f with
Finally, we investigated the thiourea-catalyzed
Mukaiyama–aldol reaction of aldehydes 7a and 7b with
ketene silyl acetal (Eq. (1)). In the same manner as
described for nitrones, arylaldehydes 7a and 7b were
reacted with ketene silyl acetal 5a in the presence of 4c
(0.1 equiv.). Interestingly, benzaldehyde 7a gave the
desired product 8a in low yield, while the same reaction
of 7b bearing the methoxy groups at the ortho position
of the aromatic ring proceeded smoothly, resulting in
good chemical yield. At this stage, the reason is not
clear, but we now assume that both oxygens of the
carbonyl and methoxy groups of 7b might coordinate
to thiourea 6c to form a highly activated intermediate.
5c, giving the same result (entry 7).
Our assumption that ureas would activate nitrones by
the hydrogen-bonding was supported by NMR experi-
1
ments. H NMR titration of a solution of nitrone 1c in
CDCl with thiourea 4a resulted in a downfield shift of
3
the NꢁCꢀH of 1c and upfield shift of the NꢀH of 4a,
and these shifts were enhanced with increase of the
ratio of 6a/1c, respectively. In addition, downfield shift
(1)
13
of the NꢁCꢀH of 1c was also observed by C NMR of
1:1 mixture of 4a/1c. These results support the activa-
Table 3. Thiourea-catalyzed addition of ketene silyl acetals to various nitrones

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T. Okino et al. / Tetrahedron Letters 44 (2003) 2817–2821
In summary, thiourea-catalyzed nucleophilic addition
to various nitrones were developed. The reactions of
both TMSCN and ketene silyl acetal to nitrones were
greatly accelerated by the hydrogen bonding between
ureas and nitrones, and the Lewis acid-like activation
mechanism was supported by H and C NMR analy-
sis. Moreover, the urea employed could be recovered
quantitatively and the reuse of the catalyst 4c was also
demonstrated. Now we are engaged in an asymmetric
version of these reactions catalyzed by chiral thiourea
derivatives.
Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc.
2002, 124, 1172–1173; (e) Barrett, A. G. M.; Cook, A. S.;
Kamimura, A. Chem. Commun. 1998, 2533–2534; (f)
Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.;
Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219–
10220; (g) Enders, D.; Kallfass, U. Angew. Chem., Int.
Ed. 2002, 41, 1743–1745; (h) Kerr, M. S.; Read de Alaniz,
J.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298–10299.
5. Curran, D. P.; Kuo, L. H. J. Org. Chem. 1994, 59,
3259–3261.
1
13
6. Curran, D. P.; Kuo, L. H. Tetrahedron Lett. 1995, 37,
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7. Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217–
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Acknowledgements
8
. During our investigation, Jacobsen et al. reported asym-
metric catalytic addition to imines with HCN or ketene
silyl acetals. Very recently, Schreiner et al. also revealed
urea catalyzed 1,3-dipolar cycloaddition with nitrone but
the effect was small. See: (a) Vachal, P.; Jacobsen, E. N.
J. Am. Chem. Soc. 2002, 124, 10012–10014; (b) Wenzel,
A. G,; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124,
This research was supported by grants from the
NOVARTIS Foundation (Japan) for the promotion of
Science and Grant-in-Aid for Scientific Research (C)
from the Ministry of Education, Science, Sports, and
Culture, Japan.
12964–12965; (c) Wittkopp, A.; Schreiner, P. R. Chem.
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14. Experimental procedure: Under an argon atmosphere, to
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2
ml) was added 1-methoxy-2-methyl-1-(trimethylsily-
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cyclic compound. The reaction mixture was diluted with
CHCl and saturated NH Cl aq. The organic layer was
separated and the aqueous layer was extracted with
7
3
4
2
CHCl . The combined organic extracts was dried over
3
Na SO . Evaporation of solvents and purification of the
2
4
2
residual oil by column chromatography on silica gel
(ether/hexane=1/3) gave the desired product (24.8 mg,
80% yield) as white solid. An analytical sample was
4
prepared by recrystalization from hexane. Mp 96–97°C
1
(hexane); H NMR (500 MHz, CDCl ): l 7.26–7.23
3
(m, 2H), 7.18 (dd, J=3.9, 5.2 Hz, 1H), 7.09 (dd, J=3.9,

T. Okino et al. / Tetrahedron Letters 44 (2003) 2817–2821
2821
4
1
3
1
.3 Hz, 1H), 4.83 (br s, 1H), 3.61 (br s, 1H), 3.42 (br s,
ppm; IR (CHCl ): w 3030, 2980, 2940, 2876, 1773, 1112
3
−
1
+
+
H), 3.04 (br s, 1H), 2.89 (br s, 1H), 1.61 (s, 3H), 1.11 (s,
cm ; MS (EI ): 217 (M , 12), 131 (100). Anal. calcd for
: C, 71.87; H, 6.96; N, 6.45. Found: C, 72.06;
H, 7.11; N, 6.39%.
13
H) ppm; C NMR (126 MHz, CDCl ): l 181.2, 134.0,
C H15NO
13 2
3
31.0, 128.8, 127.4, 126.4, 70.0, 51.0, 45.2, 27.5, 25.6, 22.6