Aldol reactions of α-bromoalkyl phenyl ketones and aldehydes with tin(IV) iodide and tetrabutylammonium iodide

Article abstract of DOI:10.1055/s-2006-951550

Aldol reactions of α-bromoacetophenone and aldehydes in dichloromethane produced the corresponding E-α,β-unsaturated ketones at 25 °C with one equimolar amount of tin(IV) iodide, one equimolar amount of tetrabutylammonium iodide and one equimolar amount of N,N- diisopropylethylamine, and produced the corresponding β-hydroxy ketones at -80 °C with one equimolar amount of tin(IV) iodide and two equimolar amounts of tetrabutylammonium iodide. Using one equimolar amount of tin(IV) iodide and two equimolar amounts of tetrabutylammonium iodide at -80 °C in dichloromethane, α-bromopropiophenone reacted with aldehydes to afford the corresponding syn-α-methyl-β-hydroxy ketones selectively. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-951550

3346
LETTER
Aldol Reactions of a-Bromoalkyl Phenyl Ketones and Aldehydes with Tin(IV)
Iodide and Tetrabutylammonium Iodide
Aldol Reactions
w
o
ith SnI4and Ts
B
AI hiro Masuyama,* Masaru Ohtsuka, Ayako Kondo
Department of Chemistry, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo 102-8554, Japan
Fax +81(3)32383361; E-mail: y-masuya@sophia.ac.jp
Received 15 September 2006
lates.16 For example, in the carbonyl allylation, tri-
Abstract: Aldol reactions of a-bromoacetophenone and aldehydes
–
iodostannate(II) ion (SnI3 ), derived by the reduction of
in dichloromethane produced the corresponding E-a,b-unsaturated
SnI4 with I–,4,17 would cause nucleophilic substitutions in
ketones at 25 °C with one equimolar amount of tin(IV) iodide, one
2-propenyl chlorides to yield 2-propenyltriiodotins that
equimolar amount of tetrabutylammonium iodide and one equimo-
lar amount of N,N-diisopropylethylamine, and produced the corre- would function as allylic anions. We thus hoped that the
sponding b-hydroxy ketones at –80 °C with one equimolar amount
of tin(IV) iodide and two equimolar amounts of tetrabutylammoni-
um iodide. Using one equimolar amount of tin(IV) iodide and two
equimolar amounts of tetrabutylammonium iodide at –80 °C in
dichloromethane, a-bromopropiophenone reacted with aldehydes
to afford the corresponding syn-a-methyl-b-hydroxy ketones selec-
tively.
triiodostannate(II) ion would mediate the formation of tri-
iodotin enolates from a-bromo ketones to cause crossed
aldol reactions with aldehydes.
Ph
SnI4
R
Ph
R
Ph
Br
+
RCHO
+
TBAI
O
O
OH
O
Key words: aldol reactions, diastereoselectivity, tin, enones, b-hy-
droxyketones
1
2
3
Equation 1
The crossed aldol reaction is one of the most versatile syn- The aldol reaction of a-bromoacetophenone (1) and benz-
thetic tools for carbon–carbon bond formation, and many aldehyde with tin(IV) iodide and TBAI was investigated
convenient methods for generating metal enolates have under various conditions. The results are summarized in
been developed.1 a-Halo ketones such as a-bromoace- Table 1 (Equation 1, R = Ph). The addition of two
tophenone undergo reductive dehalogenation with low- equimolar amounts of TBAI to tin(IV) iodide caused the
valent metal reagents to yield the corresponding metal aldol condensation of 1 and benzaldehyde in dichloro-
enolates that are applied to crossed aldol reactions.2–15 We methane at 25 °C to produce an a,b-unsaturated ketone,
have found that a combo-reagent of tin(IV) iodide and tet- namely (E)-chalcone (2, R = Ph), selectively (entry 1).
rabutylammonium iodide (TBAI) can be applied to a car- The aldol condensation proceeded poorly with one
bonyl allylation with 2-propenyl chlorides and a carbonyl equimolar amount of TBAI. The use of one equimolar
propargylation and allenylation with 2-propynyl mesy- amount of TBAI and one equimolar amount of N,N-diiso-
Table 1 Aldol Reaction of 1 and Benzaldehydea
Entry
TBAI (mmol)
i-Pr2NEt (mmol)
Solvent
Temp (°C)
Time (h)
Yield (%)b
2
3
1
2
3
4
5
6
2.0
1.0
1.0
1.0
2.0
1.0
–
CH2Cl2
CH2Cl2
THF
25
48
48
48
67
48
48
57
68
67
38
–
–
1.0
1.0
1.0
–
25
–
25
–
DMF
25
–
CH2Cl2
CH2Cl2
–80
–80
52
51
1.0
25
a The reaction of 1 (1.1 mmol) and benzaldehyde (1.0 mmol) was carried out with tin(IV) iodide (1.0 mmol) in solvent (2 mL).
b Isolated yields.
SYNLETT 2006, No. 19, pp 3346–3348
0
1
.1
2
.2
0
0
6
Advanced online publication: 23.11.2006
DOI: 10.1055/s-2006-951550; Art ID: U10506ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Aldol Reactions with SnI4 and TBAI
3347
Ph
Br
propylethylamine as a base to tin(IV) iodide enhanced
the yield of 2 (R = Ph) (entry 2). The aldol reaction with
two equimolar amounts of TBAI at –80 °C selectively
afforded b-hydroxy ketone 3 (R = Ph) (entry 5), while
the aldol reaction with one equimolar amount of TBAI
and one equimolar amount of N,N-diisopropylethylamine
at –80 °C afforded a mixture of 2 (R = Ph) and 3 (R = Ph)
(entry 6). The aldol reaction did not occur without either
tin(IV) iodide or TBAI. Tin(II) iodide instead of tin(IV)
iodide under the same conditions as those of entry 1 did
not cause the aldol reaction.2,4,6
O
1
TBA+ –SnI3
TBAX
SnI4 TBAI
+
X = Br or I
A
TBA+ –SnI5
Ph
OSnXI2
TBAI
TBAI3
B
I2
The reaction conditions of entry 2 or entry 5 in Table 1
can be applied to various aldehydes to selectively prepare
the corresponding E-a,b-unsaturated ketones 2 or the
corresponding b-hydroxy ketones 3, respectively
(Equation 1, Table 2). The use of tetrahydrofuran as a
solvent at –80 °C facilitated the aldol reaction with 4-
chlorobenzaldehyde to enhance the yield of 2 together
with 3 (entry 8). The combo-reagent of SnI4 and TBAI did
not cause pinacol coupling of any aldehyde or 1 in the
reactions in Tables 1 and 2.
+
–
iPr2NHEt I3
R
Ph
RCHO
I2XSnO
O
C
+
–
iPr2NHEt I
H3O+
+
iPr2NEt
IXSn=O
R
Ph
R
Ph
A plausible mechanism for the aldol reaction of 1 with al-
dehydes is illustrated in Scheme 1. Tin(IV) iodide is first
reduced to triiodostannate(II) ion A with TBAI via the re-
ductive elimination of iodine from pentaiodostannate(IV)
ion. The stannate(II) ion A causes nucleophilic substitu-
O
OH
O
2
3
Scheme 1 A plausible mechanism for the aldol reaction of 1 with al-
dehydes
Table 2 Selective Preparation of E-a,b-Unsaturated Ketones 2 and
b-Hydroxy Ketones 3
tion in 1 to give triiodotin enolate B, which undergoes nu-
cleophilic addition to aldehydes to afford b-
triiodostannyloxy ketones C. N,N-Diisopropylethylamine
promotes b-elimination from C to produce E-a,b-unsatur-
ated ketones 2 together with IXSn=O and N-ethyl-N,N-
diisopropylammonium iodide. The N-ethyl-N,N-diisopro-
pylammonium iodide captures iodine by the reductive
elimination from pentaiodostannate(IV) ion. A second
TBAI performs a part of the capture of iodine in the aldol
reaction without N,N-diisopropylethylamine. In addition,
b-triiodostannyloxy ketones C formed at –80 °C can be
treated with acetic acid to produce b-hydroxy ketones 3.
Entry
R
Temp (°C)
Time (h) Yield (%)a
2
3
1
2
4-ClC6H4
4-MeOC6H4
4-MeC6H4
PhCH=CH
PhCHMe
C6H13
25
48
48
48
54
72
48
49
49
48
50
51
50
60
66
67
59
59
64
43
52
53
19
6
–
25
–
3
25
–
4
25
–
5
25
–
a-Bromopropiophenone (4) reacted with various alde-
hydes under the same conditions as those of entry 5 in
Table 1 to produce the corresponding syn-a-methyl-b-hy-
droxy ketones syn-5 selectively (Equation 2). The results
are summarized in Table 3. The syn diastereoselectivity
might be explained by the formation of Z enolate E from
a s*–p*-dominated Felkin–Anh model D18 followed by
the nucleophilic addition of E to aldehydes via a chair-
formed six-membered cyclic transition state F, as shown
in Scheme 2.
6
25
–
7
c-C6H11
25
–
8b
9
4-ClC6H4
4-MeOC6H4
4-MeC6H4
PhCH=CH
PhCHMe
C6H13
–80
–80
–80
–80
–80
–80
–80
55
47
53
63
43
44
31
10
11
12
13
14
3
–
–
–
SnI4
Ph
R
Ph
R
Ph
+
+
RCHO
Br
c-C6H11
–
TBAI
O
OH
syn-5
O
OH
O
a Isolated yields.
4
anti-5
b THF (3 mL) was used as a solvent, because 4-chlorobenzaldehyde
was hardly soluble in CH2Cl2 at –80 °C.
Equation 2
Synlett 2006, No. 19, 3346–3348 © Thieme Stuttgart · New York

3348
Y. Masuyama et al.
LETTER
Table 3 Selective Preparation of syn-a-Methyl-b-hydroxy Ketones
syn-5
mL) was added. The mixture was diluted with CH2Cl2 (100 mL) and
washed successively with aq NaHCO3 solution (20 mL), H2O (20
mL) and brine (20 mL). The CH2Cl2 extract was dried over anhyd
MgSO4. After evaporation of solvent, purification by column chro-
matography (silica gel, hexane–EtOAc, 5: 1) and then HPLC (Japan
Analytical Industry Co. Ltd., LC-908, JAIGEL-2H; CHCl3) afford-
ed b-hydroxy ketone 3 (0.12 g, 52%; R = Ph).
Entry
R
Temp (°C)
Time (h)
5, Yield (%)a
(syn/anti)b
1
2
3
4
5
6
Ph
–80
–80
–80
–80
–80
–80
47
48
49
50
69
68
41 (93:7)
43 (96:4)
45 (94:6)
50 (89:11)
32 (92:8)
30 (100:0)
4-MeC6H4
PhCH=CH
PhCH2CH2
C6H13
References and Notes
(1) In Comprehensive Organic Syntheses, Vol. 2; Trost, B. M.;
Fleming, I.; Heathcock, C. H., Eds.; Pergamon: Oxford,
1991, 99.
(2) Sn: (a) Harada, T.; Mukaiyama, T. Chem. Lett. 1982, 467.
(b) Chan, T. H.; Li, C. J.; Wei, Z. Y. J. Chem. Soc., Chem.
Commun. 1990, 505.
(3) CrCl2: Dubois, J.-E.; Axiotis, G.; Bertounesque, E.
Tetrahedron Lett. 1985, 26, 4371.
(4) CeI3, CeCl3–NaI or SnCl2: Fukuzawa, S.; Tsuruta, T.;
Fujinami, T.; Sakai, S. J. Chem. Soc., Perkin Trans. 1 1987,
1473.
c-C6H11
a Isolated yields.
b The isomer ratios were determined by 1H NMR analysis (JEOL
JNM-LA500); see ref.14
I3Sn–
Ph
H
(5) Et3B–Ph3SnH: Nozaki, K.; Oshima, K.; Utimoto, K. Bull.
Chem. Soc. Jpn. 1991, 64, 403.
(6) SnCl2/Na2SO3: Lin, R.; Yu, Y.; Zhang, Y. Synth. Commun.
1993, 23, 271.
Ph
–SnI3
SnI4
Br
Ph
SnX3
Br
O
Me
O
O
(7) SmI2: Aoyagi, Y.; Yoshimura, M.; Tsuda, M.; Tsuchibuchi,
T.; Kawamata, S.; Tateno, H.; Asano, K.; Nakamura, H.;
Obokata, M.; Ohta, A.; Kodama, Y. J. Chem. Soc., Perkin
Trans. 1 1995, 689.
SnI4
Z-enolate E
(X = Br or I)
4
D
RCHO
(8) Et2Zn, Et3B, Me3Al, EtMgBr: Aoki, Y.; Oshima, K.;
Utimoto, K. Chem. Lett. 1995, 463.
(9) Co(PMe3)4: Orsini, F. J. Org. Chem. 1997, 62, 1159.
(10) BiCl3–Al: Shen, Z.; Zhang, J.; Zou, H.; Yang, M.
Tetrahedron Lett. 1997, 38, 2733.
Ph
H
H3O+
R
X3SnO
Ph
R
Ph
SnX3
O
O
OH
O
R
O
(11) GaI3: Han, Y.; Huang, Y.-Z. Tetrahedron Lett. 1998, 39,
7751.
syn-5
F
(12) GeI2–K: Kagoshima, H.; Hashimoto, Y.; Oguro, D.; Saigo,
K. J. Org. Chem. 1998, 63, 691.
Scheme 2 Diastereoselective crossed aldol reaction
(13) Bu3SnSnBu3–Bu2Snl2: Shibata, I.; Kawasaki, M.; Yasuda,
M.; Baba, A. Chem. Lett. 1999, 689.
(14) TiCl2: Kagayama, A.; Igarashi, K.; Shiina, I.; Mukaiyama,
T. Bull. Chem. Soc. Jpn. 2000, 73, 2579.
(15) Bi–ZnF2: Lee, Y. J.; Chan, T. H. Can. J. Chem. 2003, 81,
1406.
(16) (a) Masuyama, Y.; Takeuchi, K.; Kurusu, Y. Tetrahedron
Lett. 2005, 46, 2861. (b) Masuyama, Y.; Yamazuki, R.;
Ohtsuka, M.; Kurusu, Y. Synlett 2006, 1750.
(17) Tsuritani, T.; Ito, S.; Shinokubo, H.; Oshima, K. J. Org.
Chem. 2000, 65, 5066.
(18) Since tin(II) iodide is not applicable for the aldol reactions
with 1 or 4, in contrast to the carbonyl allylation with 2-
propenyl chlorides and the carbonyl propargylation or
allenylation with 2-propynyl mesylates,16b,19 tin(IV) iodide
probably plays an important role in the aldol reactions. That
is to say, the coordination of tin(IV) to carbonyl oxygen of 1
or 4 should mediate the preparation of tin(IV) enolates from
1 and 4. Thus, we proposed that 4 was reduced to Z enolate
E via the s*–p*-dominated Felkin–Anh model D. For the
s*–p*-dominated Felkin–Anh model D, see: Atkinson, R. S.
Stereoselective Synthesis; Wiley: Chichester, 1995, 300.
(19) (a) Masuyma, Y. Recent Res. Dev. Org. Chem. 2000, 4, 373.
(b) Masuyama, Y.; Watabe, A.; Ito, A.; Kurusu, Y. Chem.
Commun. 2000, 2009.
Preparation of a,b-Unsaturated Ketones; Typical Procedure
(Table 1, Entry 2)
To a solution of tin(IV) iodide (0.63 g, 1.0 mmol) and a-bromoace-
tophenone (1; 0.22 g, 1.1 mmol) in CH2Cl2 (2 mL) were successive-
ly added TBAI (0.37 g, 1.0 mmol), benzaldehyde (0.11 g, 1.0
mmol) and N,N-diisopropylethylamine (0.13 g, 1.0 mmol) at 25 °C
under a nitrogen atmosphere. After stirring the mixture for 48 h, it
was diluted with CH2Cl2 (100 mL) and washed successively with aq
NH4Cl solution (20 mL), aq NaHCO3 solution (20 mL), H2O (20
mL) and brine (20 mL). The extract was dried over anhyd MgSO4.
After evaporation of solvent, purification by column chromatogra-
phy (silica gel, hexane–EtOAc, 7: 1) and then HPLC (Japan Analyt-
ical Industry Co. Ltd., LC-908, JAIGEL-2H, CHCl3) afforded (E)-
chalcone (2; 0.14 g, 68%; R = Ph).
Preparation of b-Hydroxy Ketones; Typical Procedure (Table
1, Entry 5)
To a solution of tin(IV) iodide (0.63 g, 1.0 mmol) and a-bromoace-
tophenone (1; 0.22 g, 1.1 mmol) in CH2Cl2 (2 mL) were successive-
ly added TBAI (0.74 g, 2.0 mmol) and benzaldehyde (0.11 g, 1.0
mmol) at –80 °C under a nitrogen atmosphere. After this mixture
was stirred for 48 h at –80 °C, Et2O (5 mL) containing AcOH (0.2
Synlett 2006, No. 19, 3346–3348 © Thieme Stuttgart · New York