Thieme Chemistry Journal awardees - Where are they now? Dibutyltin dimethoxide catalyzed N-nitrosoaldol reaction of alkenyl trichloroacetate

Article abstract of DOI:10.1055/s-0028-1087815

Nitrosoaldol reaction between alkenyl trichloroacetates and nitrosobenzene has been achieved using dibutyltin dimethoxide as a catalyst, which is regenerated in the presence of methanol. The corresponding α-hydroxyamino ketones (N-adducts) have exclusivel

Full text of DOI:10.1055/s-0028-1087815

716
LETTER
Thieme Chemistry Journal Awardees – Where are They Now?
Dibutyltin Dimethoxide Catalyzed N-Nitrosoaldol Reaction
of Alkenyl Trichloroacetate
N
a
-Nitrosoaldol Re
k
actionof Alk
i
enyl
T
r
richloroa
a
cetate Yanagisawa,*a Youhei Izumi,b Satoshi Takeshitaa
Department of Chemistry, Graduate School of Science, Chiba University, Inage, Chiba 263-8522, Japan
Fax +81(43)2902789; E-mail: ayanagi@faculty.chiba-u.jp
Graduate School of Science and Technology, Chiba University, Inage, Chiba 263-8522, Japan
b
Received 22 September 2008
Abstract: Nitrosoaldol reaction between alkenyl trichloroacetates
and nitrosobenzene has been achieved using dibutyltin dimethoxide
as a catalyst, which is regenerated in the presence of methanol. The
corresponding a-hydroxyamino ketones (N-adducts) have exclu-
sively formed not only from cyclic alkenyl trichloroacetates but also
from acyclic ones.
Key words: tin catalyst, nitrosoaldol reaction, a-hydroxyamino ke-
tone, alkenyl trichloroacetate, nitrosobenzene
Nitrosoaldol reaction is one of the important C–N bond/ Akira Yanagisawa received his PhD from Nagoya University. He
became an Assistant Professor of Nagoya University and an Associa-
te Professor there. In 2001, he moved to Chiba University as a Full
Professor. His research interests focus on the development of new
synthetic methods using allylic organometallics such as allylic barium
C–O bond-forming reactions, which provides us with a-
hydroxyamino carbonyl compounds and/or a-aminooxy
carbonyl compounds.1–4 In 2002, Momiyama and Yama-
moto have reported that organotin enolates undergo addi-
reagents and asymmetric synthesis including BINAP·silver(I)-cataly-
tion reaction to nitrosoarenes without any catalyst and
yield a-hydroxyamino ketones exclusively.5 Furthermore,
an asymmetric version of this nitrosoaldol reaction has
been also achieved by the same group using BINAP·AgX
complexes as chiral catalysts.6 The a-amination reaction
of tin enolates is synthetically useful; however, it has a
disadvantage that a stoichiometric amount of environ-
mentally less benign organotin compound is essentially
required. We have previously shown that aldol reaction of
alkenyl trichloroacetates with aldehydes proceeds
smoothly under the influence of a catalytic amount of
Bu2Sn(OMe)2 and a stoichiometric amount of MeOH, in
which a tin enolate is catalytically generated in situ.7 We
envisioned that if a a-stannyloxy amino ketone, an initial
N-nitrosoaldol product, is protonated by MeOH and the
corresponding tin methoxide is regenerated efficiently,
the catalytic nitrosoaldol reaction might be possible to oc-
cur. This paper reports a Bu2Sn(OMe)2-catalyzed N-
nitrosoaldol reaction of alkenyl trichloroacetates with ni-
trosobenzene by the assistance of MeOH (Scheme 1).
zed asymmetric carbon–carbon bond-forming reactions and asymme-
tric protonations of metal enolates.
First of all, we attempted a reaction between 1-trichloro-
acetoxycyclohexene (2 equiv) and nitrosobenzene (1
equiv) in the presence of Bu2Sn(OMe)2 (0.2 equiv) and
MeOH (30 equiv) in THF at room temperature for one
hour. As a result, the corresponding a-hydroxyamino ke-
tone (N-adduct) was obtained in 76% yield without for-
mation of any byproducts including its dehydrated
product and an alternative a-aminooxy ketone (O-adduct)
as shown in entry 1 of Table 1. In order to gain more sat-
isfactory results, we then performed optimization of the
reaction conditions. Among the solvents tested, toluene
was found to give a higher yield under the similar reaction
conditions (entry 3). However, to our great surprise,
MeOH was the most effective solvent and indeed the de-
sired product was formed almost quantitatively notwith-
standing the possibility of protonation of an in situ
generating tin enolate with a large excess amount of
MeOH (entry 5). We further tested temperature effect on
the chemical yield of the reaction in MeOH and as a con-
sequence, both lower and higher temperatures caused de-
crease in the yield (entries 6 and 7).
OCOCCl3
R3
O
OH
N
Bu2Sn(OMe)2 (cat.)
MeOH, r.t.
+
PhN
O
R1
R1
Ph
R2 R3
R2
Then, we investigated catalytic activity of several organ-
otin(IV) compounds besides Bu2Sn(OMe)2 under the op-
timized reaction conditions (Table 2). Employment of
organotin methoxides instead of the organotin dimethox-
ide decreased the chemical yield (entries 2 and 3). Al-
Scheme 1 The Bu2Sn(OMe)2-catalyzed N-nitrosoaldol reaction
SYNLETT 2009, No. 5, pp 0716–0719
x
x.
x
x.
2
0
0
9
Advanced online publication: 16.02.2009
DOI: 10.1055/s-0028-1087815; Art ID: S08808ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
N-Nitrosoaldol Reaction of Alkenyl Trichloroacetate
717
Table 1 Solvent and Temperature Effects on Nitrosoaldol Reaction
derivative which afforded a low yield due to rapid proto-
nation of in situ generating tin enolate with MeOH (entry
2). However, the protonation was suppressed to a certain
extent when the reaction was performed in toluene as a
solvent (entry 3). In every case, no a-aminooxy ketone
was contaminated. In addition, other side reactions such
as double a-hydroxyamination were not observed at all,
which means that the reaction conditions are almost neu-
tral. Noteworthy was the fact that even a fully substituted
alkenyl trichloroacetate gave a targeted product in a near-
ly quantitative yield (entry 8).
of an Alkenyl Trichloroacetate of Cyclohexanone with Nitrosoben-
a
zene Catalyzed by Bu2Sn(OMe)2
OCOCCl3
O
OH
N
Bu2Sn(OMe)2 (0.2 equiv)
MeOH (30 equiv)
+
PhN
O
Ph
solvent, temp, 1 h
2 equiv
Entry
Solvent
THF
Temp (°C)
Yield (%)b
1
2
3
4
5
6
7
r.t.
r.t.
r.t.
r.t.
r.t.
0
76
55
86
52
98
92
79
DMF
Table 3 Bu2Sn(OMe)2-Catalyzed Nitrosoaldol Reaction of Various
Alkenyl Trichloroacetates with Nitrosobenzenea
toluene
CH2Cl2
MeOH
MeOH
MeOH
OCOCCl3
R3
O
OH
N
Bu2Sn(OMe)2 (0.2 equiv)
MeOH, r.t.
+
PhN
O
R1
R1
Ph
R2 R3
R2
2 equiv
Entry
Alkenyl trichloroacetate
Time (h)
1
Yield (%)b
98
40
a The reaction was performed using alkenyl trichloroacetate (2 equiv),
nitrosobenzene (1 equiv), Bu2Sn(OMe)2 (0.2 equiv), and MeOH (30
equiv) in a specified solvent at r.t. (entries 1–5), 0 °C (entry 6), or 40
°C (entry 7) for 1 h.
OCOCCl3
1
b Isolated yield.
OCOCCl3
OCOCl3
2
1
1
45
84
Table 2 Screening of Tin Catalysts in Nitrosoaldol Reaction of 1-
Trichloroacetoxy Cyclohexene with Nitrosobenzenea
OCOCCl3
O
OH
N
3c
Sn catalyst (0.2 equiv)
MeOH, r.t., 1 h
+
PhN
O
Ph
OCOCCl3
2 equiv
4
5
0.2
0.2
98
75
Entry
Tin catalyst
Bu2Sn(OMe)2
Bu3SnOMe
Me3SnOMec
Bu2SnO
Yield (%)b
1
2
3
4
98
41
20
55
OCOCCl3
OCOCCl3
OCOCCl3
6d
7d
1
77
88
a The reaction was carried out employing alkenyl trichloroacetate (2
equiv), nitrosobenzene (1 equiv), and tin catalyst (0.2 equiv) in MeOH
at r.t. for 1 h.
0.2
Ph
b Isolated yield.
OCOCCl3
c Prepared from Me3SnNMe2 and MeOH.
8
1
99
though dibutyltin oxide also indicated moderate activity
in the present nitrosoaldol reaction (entry 4), as a result,
Bu2Sn(OMe)2 was found to be a catalyst of choice (entry
1).
a The reaction was carried out using alkenyl trichloroacetate (2 equiv),
nitrosobenzene (1 equiv), and Bu2Sn(OMe)2 (0.2 equiv) in MeOH at
r.t.
b Isolated yield.
With the most promising tin catalyst at hand, we finally
carried out the a-amination of various ketone-derived al-
kenyl trichloroacetates with nitrosobenzene. The results
are summarized in Table 3. This catalytic reaction can be
applied not only to cyclic alkenyl esters but also to acyclic
ones and the corresponding a-hydroxyamino ketones
were obtained in high yield except for a cyclopentanone
c The reaction was performed in toluene in the presence of MeOH (30
equiv).
d A 1:4 mixture of E- and Z-isomers were used.
A probable catalytic mechanism for the present nitrosoal-
dol reaction is shown in Scheme 2. Initially,
Synlett 2009, No. 5, 716–719 © Thieme Stuttgart · New York

718
A. Yanagisawa et al.
LETTER
ence and Technology, Japan. We thank Prof. Takayoshi Arai at
Chiba University for helpful discussions.
Ph
N
O (5)
R1
O
OSnBu2(OMe)
OSnBu2(OMe)
R3
N
R1
Ph
R2 R3
R2
3
6
References and Notes
MeOCOCCl3
MeOH
(1) Reviews: (a) Merino, P.; Tejero, T. Angew. Chem. Int. Ed.
2004, 43, 2995. (b) Janey, J. M. Angew. Chem. Int. Ed.
2005, 44, 4292. (c) Yamamoto, H.; Momiyama, N. Chem.
Commun. 2005, 3514. (d) Yamamoto, H.; Kawasaki, M.
Bull. Chem. Soc. Jpn. 2007, 80, 595.
4
OCOCCl3
O
OH
N
R3
R1
Bu2Sn(OMe)2
R1
Ph
R2 R3
R2
2
(2) Nitrosoaldol reactions promoted by organocatalysts have
been extensively studied recently. For N-nitrosoaldol
reactions, see: (a) Momiyama, N.; Yamamoto, H. J. Am.
Chem. Soc. 2005, 127, 1080. (b) Guo, H.-M.; Cheng, L.;
Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Chem.
Commun. 2006, 429. (c) Kano, T.; Ueda, M.; Takai, J.;
Maruoka, K. J. Am. Chem. Soc. 2006, 128, 6046. (d) Kim,
S.-G.; Park, T.-H. Tetrahedron Lett. 2006, 47, 9067.
(e) López-Cantarero, J.; Cid, M. B.; Poulsen, T. B.; Bella,
M.; García Ruano, J. L.; Jørgensen, K. A. J. Org. Chem.
2007, 72, 7062. (f) Palomo, C.; Vera, S.; Velilla, I.; Mielgo,
A.; Gómez-Bengoa, E. Angew. Chem. Int. Ed. 2007, 46,
8054. For O-nitrosoaldol reactions, see: (g) Zhong, G.
Angew. Chem. Int. Ed. 2003, 42, 4247. (h) Brown, S. P.;
Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2003, 125, 10808. (i) Hayashi, Y.; Yamaguchi,
J.; Hibino, K.; Shoji, M. Tetrahedron Lett. 2003, 44, 8293.
(j) Bøgevig, A.; Sundén, H.; Córdova, A. Angew. Chem. Int.
Ed. 2004, 43, 1109. (k) Hayashi, Y.; Yamaguchi, J.;
Sumiya, T.; Shoji, M. Angew. Chem. Int. Ed. 2004, 43,
1112. (l) Zhong, G. Chem. Commun. 2004, 606.
1
7
Scheme 2 A plausible catalytic cycle
Bu2Sn(OMe)2 (1) reacts with alkenyl trichloroacetate 2 to
give tin enolate 3 and methyl trichloroacetate (4). Then
the resulting tin enolate 3 is allowed to add to nitrosoben-
zene (5), furnishing a tin alkoxide of a-hydroxyamino ke-
tone 6. Finally, methanolysis of the tin alkoxide 6
completes the catalytic cycle by regenerating the tin
dimethoxide 1 accompanied with the desired product 7.
In summary, we have achieved a Bu2Sn(OMe)2-catalyzed
nitrosoaldol reaction. The tin catalyst is effectively regen-
erated under the influence of methanol and various a-hy-
droxyamino ketones can be obtained in satisfactory yield.
The procedure is operationally simple and can be per-
formed using readily available chemicals under almost
neutral conditions.
(m) Momiyama, N.; Torii, H.; Saito, S.; Yamamoto, H.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5374. (n) Córdova,
A.; Sundén, H.; Bøgevig, A.; Johansson, M.; Himo, F.
Chem. Eur. J. 2004, 10, 3673. (o) Mathew, S. P.; Iwamura,
H.; Blackmond, D. G. Angew. Chem. Int. Ed. 2004, 43,
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(q) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Hibino, K.;
Shoji, M. J. Org. Chem. 2004, 69, 5966. (r) Hayashi, Y.;
Yamaguchi, J.; Hibino, K.; Sumiya, T.; Urushima, T.; Shoji,
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Typical Experimental Procedure for the Nitrosoaldol Reaction
– Synthesis of 2-(N-Phenylhydroxyamino)cyclohexanone (En-
try 1, Table 3)6b
1-Trichloroacetoxycyclohexene (1.0 mmol) and nitrosobenzene
(0.50 mmol) were dissolved in anhyd MeOH (3 mL) under argon at-
mosphere, and then dibutyltin dimethoxide (0.10 mmol) was added
to the resulting solution at r.t. After being stirred for 1 h at this tem-
perature, the mixture was treated with solid KF (ca. 1 g) and brine
(1 mL) at ambient temperature for 10 min. After separation of the
layers, the aqueous layer was extracted with EtOAc twice. The
combined organic layers were washed with brine, dried over
Na2SO4, and concentrated in vacuo after filtration. The residual
crude product was purified by column chromatography on SiO2
(neutral) to give 2-(N-phenylhydroxyamino)cyclohexanone (0.49
mmol, 98% yield).
TLC: Rf = 0.20 (hexane–EtOAc, 5:1). IR (neat): 3475, 2956, 2862,
1
1712, 1599, 1487, 1398 cm–1. H NMR (400 MHz, CDCl3): d =
1.61–1.75 (m, 2 H, CH2), 1.93–2.02 (m, 1 H, one proton of CH2),
2.05–2.16 (m, 3 H, CH2 and one proton of CH2), 2.35–2.45 (m, 1 H,
one proton of CH2), 2.51–2.58 (m, 1 H, one proton of CH2), 4.24
(dd, 1 H, J = 10.4, 7.5 Hz, CH), 6.18 (s, 1 H, OH), 6.95 (t, 1 H,
J = 7.4 Hz, arom.), 7.06 (d, 2 H, J = 7.7 Hz, arom.), 7.28 (t, 2 H,
J = 7.4 Hz, arom.). 13C NMR (100 MHz, CDCl3): d = 24.4, 27.3,
28.0, 42.1, 72.5, 116.0 (2 C), 121.7, 128.7 (2 C), 150.2, 209.7. The
above-mentioned spectral data indicated good agreement with re-
ported data.6b
(3) For O-nitrosoaldol reactions promoted by organocatalysts,
see: (a) Córdova, A.; Sundén, H.; Xu, Y.; Ibrahem, I.; Zou,
W.; Engqvist, M. Chem. Eur. J. 2006, 12, 5446.
(b) Kumarn, S.; Shaw, D. M.; Ley, S. V. Chem. Commun.
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Asymmetry 2006, 17, 1738. (d) Kim, S.-G.; Park, T.-H.;
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(g) Font, D.; Bastero, A.; Sayalero, S.; Jimeno, C.; Pericàs,
M. A. Org. Lett. 2007, 9, 1943. (h) Kotkar, S. P.;
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research
on Priority Areas ‘Advanced Molecular Transformations of Carbon
Resources’ from the Ministry of Education, Culture, Sports, Sci-
Synlett 2009, No. 5, 716–719 © Thieme Stuttgart · New York

LETTER
Suryavanshi, G. S.; Sudalai, A. Tetrahedron: Asymmetry
N-Nitrosoaldol Reaction of Alkenyl Trichloroacetate
719
(5) (a) Momiyama, N.; Yamamoto, H. Org. Lett. 2002, 4, 3579.
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(4) For related reactions of nitrosobenzene, see: (a)Yamamoto,
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(b) Yamamoto, Y.; Yamamoto, H. Angew. Chem. Int. Ed.
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