Metal-free, one-pot, sequential protocol for transforming ,-epoxy ketones to -hydroxy ketones and -methylene ketones

Article abstract of DOI:10.1021/jo5025249

A new sequential, one-pot protocol for transforming 1,3-disubstituted 2,3-epoxy ketones to β;-hydroxy ketones and α-methylene ketones has been developed. Reaction of epoxy ketones with boron trifluoride etherate (BF₃·OEt₂) generates the cationic intermediates by regioselective epoxide ring opening and an acyl shift. Then, a treatment of these cations with 2-aryl-1,3-dimethylbenzimidazolines (DMBIH) results in formation of 1,2-disubstituted 3-hydroxy ketones. DMBIH serves as a hydride donor in the second step of this process. Finally, the β;-hydroxy ketones can be converted to 1,2-disubstituted 2-methylene ketones by treatment with methanesulfonic acid or a combination of methanesulfonyl chloride and triethylamine. Importantly, the sequential steps involved in formation of the α-methylene ketone products can be carried out in one pot.

Full text of DOI:10.1021/jo5025249

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Article
Metal-Free, One-Pot, Sequential Protocol for Transforming alpha,beta-
Epoxy Ketones to beta-Hydroxy Ketones and alpha-Methylene Ketones
Eietsu Hasegawa, Saki Arai, Eiji Tayama, and Hajime Iwamoto
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5025249 • Publication Date (Web): 06 Jan 2015
Downloaded from http://pubs.acs.org on January 12, 2015
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Metal-Free, One-Pot, Sequential Protocol for Transforming α,β-Epoxy Ketones
to β-Hydroxy Ketones and α-Methylene Ketones
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*
Eietsu Hasegawa, Saki Arai, Eiji Tayama, and Hajime Iwamoto
Department of Chemistry, Faculty of Science, Niigata University, Ikarashi-2 8050, Niigata
950-2181, Japan
ehase@chem.sc.niigata-u.ac.jp
ABSTRACT: A new sequential, one-pot protocol for transforming 1,3-disubstituted 2,3-epoxy
ketones to β-hydroxy ketones and α-methylene ketones has been developed. Reaction of epoxy
ketones with boron trifluoride etherate (BF •OEt ) generates the cationic intermediates by
3
2
regioselective epoxide ring opening and acyl shift. Then, a treatment of these cations with
2-aryl-1,3-dimethylbenzimidazolines (DMBIH) results in formation of 1,2-disubstituted 3-hydroxy
ketones. DMBIH serves as a hydride donor in the second step of this process. Finally, the
β-hydroxy ketones can be converted to 1,2-disubstituted 2-methyleneketones by treatment with
methane sulfonic acid or a combination of methane sulfonyl chloride and triethylamine. Importantly,
the sequential steps involved in formation of the α-methylene ketone products can be carried out in
one-pot.
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INTRODUCTION
2-Aryl-1,3-dimethylbenzimidazolines (DMBIHs) act as efficient hydride, hydrogen atom, and
1
2
electron donors (Scheme 1). For example, DMBIH derivatives donate hydride to carbocations
formed by Lewis acid complexation with certain Lewis basic substrates as well as cationic salts
3
derived from nitrogen heterocycles (path A). Recently, it was shown that DMBIHs donate hydride
4
to benzhydrylium ions more efficiently than do NADH analogues. In addition, hydrogen gas
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evolution from DMBIH derivatives takes place upon treatment with certain Brønsted-Lowry acids.
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7,8
In thermal or photochemical processes, DMBIHs can act as effective reducing reagents for
various organic functional groups. The DMBIH promoted reactions are initiated by hydrogen atom
abstraction (path B) or single electron transfer (SET) (path C). In the latter pathway, SET is
followed by either sequential proton and SET or by hydrogen atom transfer. Finally, DMBIH
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derivatives have been utilized recently in artificial photosynthesis systems as well as in organic
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semiconductor devices.
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Scheme 1. Pathways for oxidation of 2-aryl-1,3-dimethylbenzimidazoline (DMBIH)
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In previous studies, we have shown that photoinduced electron transfer (PET) reactions of
α,β-epoxy ketones in the presence of DMBIH derivatives produce β-hydroxy ketones. We have
7a,b,c,d,f,g
optimized this process to make it an efficient synthetic method (Scheme 2).
House and
others observed much earlier that boron trifluoride etherates such as BF •OEt promote
3
2
rearrangement reactions of α,β-epoxy ketones to form β-ketoaldehydes through a mechanistic
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pathway involving regioselective epoxide ring opening followed by an acyl shift.
Previous investigations have demonstrated that DMBIH is compatible with conditions employed in
processes promoted by several metal containing Lewis acids such as AlCl , ZnCl , SnCl , and
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FeCl3. To our knowledge, reactions in which BF •OEt and DMBIH are simultaneously utilized as
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reagents have not been explored. We reasoned that if these reagents would be compatible, isomeric
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β-hydroxy ketones, generated from α,β-epoxy ketones in the photochemical protocol, would be
formed in BF •OEt promoted reactions of epoxy ketones if the expected carbocation intermediate
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A (Scheme 2) is trapped by hydride transfer from DMBIH. In this event, the process would
represent a new, one-pot procedure for transforming α,β-epoxy ketones to β-hydroxy ketones. In
the effort described below, which was designed to explore this proposal, we investigated reactions
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of variously substituted α,β-epoxy ketones 1 in the presence of BF •OEt and DMBIH derivatives 2
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that form β-hydroxy ketones 3, and probed a one-pot method to convert α,β-epoxy ketones 1 to
α-methylene ketones 4 (eq 1).
Scheme 2. Photochemical and BF •OEt promoted transformations of α,β-epoxy ketones to
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isomeric β-hydroxy ketones
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RESULTS AND DISCUSSION
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2
In the initial phase of this effort, we observed that reaction of epoxy ketone 1a (R = R = Ph,
0.50 mmol) with DMBIH 2a (Ar = Ph) (1.5 equiv) in the presence of BF •OEt (1.1 equiv) in
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CH2Cl2 (1.5 mL) for 1 h leads to low yielding (17%) formation of the expected hydroxyl ketone 3a.
The procedure used for this process was modified in an attempt to uncover conditions that would
enable more efficient trapping of the putative, in situ formed carbocation intermediate by hydride
transfer from 2a. Consequently, 1a was first treated with BF •OEt for 30 min and the resulting
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mixture was treated with 2a for an additional 1 h (Table 1). By using this two-step, one-pot protocol,
3a was produced in a yield of 39% along with enone 4a and ketone 5a (entry 1). While increasing
the time of the hydride transfer reaction to 6 h at room temperature does not alter product yields
(entry 2), heating at ca. 40 ºC for 24 h leads to a significant decrease in the yield of 3a (4%) and a
corresponding increase in the yield of 4a (30%) (entry 3). In addition, use of slightly more than a
stoichiometric amount of BF3•OEt2 and an excess of 2a leads to a significantly improved yield of
3a (entries 6 and 8). Notably, the influence of heating for 24 h on the product yields in the reactions
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using these quantities of the Lewis acid and hydride donor is marginal (compare entries 7 and 6), an
observation that markedly contrasts with the effect of temperature when an excess of BF3•OEt2 is
used (compare entries 3 and 1). Finally, 3a is generated in slightly lower yields when less than
stoichiometric amounts of BF3•OEt2 are employed for this process (entries 9 and 10).
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The utilization of other hydride donors in this process was probed briefly. BF3•OEt2 promoted
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reaction of 1a, employing 2,6-dimethyl-3,5-pyridinedicarboxylate (Hantzsch ester) as the
reducing agent, was observed to generate 3a in 28% yield along with 4a (4%) and β-keto aldehyde
7a (17%). In contrast, hydrosilanes such as Ph3SiH and Et3SiH are not effective in promoting the
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formation of 3a. In these cases, H-NMR analysis of the reaction mixtures revealed that 7a is
produced in near quantitative yields. These observations are consistent with the expected order of
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hydride donating ability of Hantzsch esters and hydrosilanes versus DMBIH. This exploratory
study enabled us to define optimal conditions (1.1 equiv BF3•OEt2, 1.5 equiv 2a, room temperature,
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1.5 h) for the transformation of epoxy ketone 1a to hydroxy ketone 3a (entry 6 in Table 1).
a
Table 1. Sequential reactions of epoxy ketone 1a with BF •OEt and DMBIH 2a
3
2
BF •OEt
entry
1
yields (%)
2a
(eq vs 1a)
1.2
3
2
b
c
c
(eq vs 1a)
3a
39
4a
5a
1.5
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d
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2
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5
1
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0
a
c
b
1a (0.50 mmol), CH Cl (1.4–1.5 mL), room temp, 1.5 h reaction time. Isolated yield.
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1
d
e
Determined by using H NMR. After addition of 2a, 6 h at room temp. After addition of 2a, 24 h
at ca. 40 ºC.
The results of further studies reveal that treatment of β-keto aldehyde 7a with BF3•OEt2 and 2a
leads to formation of 3a, 4a, and 5a in yields that are similar to those obtained in the reaction of 1a
(eq 2). This observation demonstrates that BF coordination with the aldehyde oxygen in 7a is
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important in causing hydride transfer reduction by 2a. We also explored the use of NaBH to reduce
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7a (0.20 mmol, 2.0 mL MeOH, 2 h) (eq 3). When 1.0 equivalent of NaBH4 is used in this reaction,
the fully reduced diol 8a (33%) is formed along with small amounts of 3a (4%) and 6a (22%).
Utilization of lesser amounts of NaBH does not result in an improvement in the yield of 3a (0.5
4
equiv NaBH gives 11% of 3a and 49% of 6a at 88% conversion; and 0.25 equiv NaBH gives 3%
4
4
of 3a and 33% of 6a at 71% conversion).
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The effect of arene ring substituents in the DMBIHs 2 (Table 2) on the efficiencies of the
BF3•OEt2 induced reaction of epoxy ketone 1a was explored next. With the exception of 2f (Ar =
o-HOC6H4), most of the DMBIHs (1.5 equiv) explored in this study promoted the reduction step in
the reaction to produce 3a in good yields (>67%). In a manner that is consistent with the reaction
induced by 2a, a decrease in the amount of 2d (Ar = p-MeOC6H4) to 1.0 equiv causes the yield of
3a to drop to 56% concurrent with a corresponding increase in the yields of 4a (9%) and 5a (2%).
In addition, the reaction promoted by 2f (Ar = o-HOC6H4) forms 3a in a low yield and 7a in a
significant quantity (entry 6). In contrast, the regioisomer 2e (Ar = p-HOC6H4) is as effective as 2a
(entry 5) in promoting this reaction. It should also be noted that a reaction, using 2e for 24 h at
elevated temperature, produces 3a in 71%, which higher than that observed for the 2a induced
process (entry 7 in Table 1). While the yield difference of 3a between the reactions promoted by 2b
(Ar = p-ClC6H4) and 2c (Ar = o-ClC6H4) are small (entries 2 and 3), the efficiency of the reaction
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induced by 2e is much greater than that by 2f (entries 5 and 6). This observation suggests that a
steric effect of the ortho-arene substituent 2 is not significant. It has been reported that an
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intramolecular hydrogen bonding interaction exists between o-OH and the nitrogen lone pair in
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1,5a,18
2f.
It is possible that this specific interaction causes hydride transfer from 2f, which generates
+
the corresponding imidazolium ion (DMBI ), to be slow.
a
Table 2. Reactions of epoxy ketone 1a with BF •OEt and various DMBIHs 2
3
2
entry
2 (Ar)
yields (%)
5ac
1
b
c
3a
4a
d
2a (Ph)
74
67
68
69
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2
2b (p-ClC6H4)
2c (o-ClC6H4)
2d (p-MeOC6H4)
2e (p-HOC6H4)
2f (o-HOC6H4)
0
e
6
1
3
e
5
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4
e
3
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5
f
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0
6
a
1a (0.50 mmol), BF •OEt (1.1 equiv), 2 (1.5 equiv), CH2Cl2 (1.5 mL), room temp, 1.5 h reaction
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2
1
b
c
d
e
time. Isolated yield. Determined by using H NMR. Same as entry 6 in Table 1. Small amounts
f
of 1,2-diphenylethanone were obtained: ca. 1% for entry 3, trace for entry 4, ca. 5% for entry 5. 7a
(64%) was obtained.
In the final phase of this investigation, applications of the developed protocol to reactions of aryl
ring substituted epoxy ketones 1a-1h were probed (Table 3). In each case, the corresponding
hydroxyl ketone 3 is produced in modest to high yield (63-85%). Notably, the benzalacetone
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derived epoxy ketone 1i also participates this sequential reaction to form 3i (62%) as a major
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product (entry 9).
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a
Table 3. Reactions of various epoxy ketones 1 with BF3•OEt2 and DMBIH 2a
entry
R1
R2
yields (%)
1
b
c
c
3
4
5
d
Ph
Ph
Ph
p-MeOC6H4
p-MeC6H4
p-ClC6H4
1-Naph
Ph
74
85
69
1
2
5
1
1a
1b
1c
1d
1e
1f
1
2
2
5
e
Ph
3
e
f
f
f
Ph
4
65
66
trace
1
0
f
f
f
5
Ph
11
e
p-MeOC6H4
p-MeC6H4
p-ClC6H4
Me
63
66
68
62
3
4
0
6
e
Ph
1
3
0
1g
1h
1i
7
e
Ph
8
8
9
Ph
trace
a
1 (0.50 mmol), BF •OEt (1.1 equiv), 2a (1.5 equiv), CH Cl (1.5 mL), room temp, 1.5 h reaction
3
2
2
2
1
b
c
d
e
time. Isolated yield. Determined by using H NMR. Same as entry 6 in Table 1. Small amounts
f
of 6 were obtained: ca. 2% of 6c, ca. 11% of 6d, 3% of 6f, 2% of 6g, 4% of 6h. Average of two
independent experiments.
Plausible reaction pathways for the conversion of epoxy ketone 1 to the observed products 3, 4, 5
and 6 are displayed in Scheme 3. In this process, BF •OEt coordination to 1 promotes
3
2
regioselective epoxide ring opening of the intermediate 9 to form the cation 10, which then
undergoes an acyl shift to generate the BF coordinated keto-aldehyde 11 which is in equilibrium
3
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with 7. Hydride transfer from 2 to 11 subsequently gives alkoxy borinate 12, which is transformed
to hydroxyl ketone 3 by hydrolysis during work-up. One possible route for formation of unsaturated
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ketone 4 involves complexation of BF •OEt with 12 to give 13, which losses a proton to form the
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BF enolate 14. Enolate 14 could simply undergo concerted loss of BF3 and the borinic acid HOBF3
3
to produce 4 or a stepwise process through allyl cation 15 to form 4. Finally, hydride transfer
reaction between cation 15 and 2 would produce alkoxide 16, the precursor of 5. Compound 6 is
probably formed by retro-aldol type fragmentation of 12 via the enolate 17. These mechanistic
proposals are consistent with the observations that the use of larger quantities of BF •OEt leads to
3
2
an increased yield of 4 (see entries 1~ 3 in Table 1) while an increase in the amount of 2 enhances
formation of 3 (see entries 4~6 and 8 in Table 1).
Scheme 3. Plausible reaction pathways for transformation of epoxy ketones 1 to hydroxyl
ketones 3 and side products 4, 5 and 6
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Because α-methylene ketones are attractive synthetic building blocks, we have probed
conditions for transforming hydroxyl ketones 3 to unsaturated ketones 4. Two approaches,
involving Brønsted-Lowry acid and base promoted sequential sulfonylation-elimination, were
considered for this purpose. The results of exploratory studies demonstrated that an ideal acid
promoted process involves treatment of 3a (0.50 mmol) with MeSO H (1.0 equiv) in CH Cl (1.5
3
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mL) at ca. 40 ºC for 5 h. This reaction generates 4a in 74% yield along with a trace quantity of
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recovered 3a (upper path in Scheme 4). In addition, we found that MeSO Cl (1.3 equiv) and NEt3
2
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(6.1 equiv) is ideal for converting 3a (0.20 mmol, 0.6 mL CH Cl , ca. 40 ºC, 5 h) to 4a in a 88%
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yield (lower path in Scheme 4).
Scheme 4. Reactions of hydroxy ketone 3a with MeSO3H and MeSO3Cl-NEt
3
Scheme 5. One-pot transformation of epoxy ketone 1a to α-methylene ketone 4a
These results inspired us to develop conditions for one-pot sequential transformation of 1 to 4
(Scheme 5). On the basis of the proposed mechanism (Scheme 3), use of an excess of 2 (1.5 equiv)
could cause further reduction of 4 to generate 5 when an acid is present to promote water
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elimination in the final step. Furthermore, the reaction time (1 h) for the one-pot process was
4
5
6
7
elongated to ensure complete consumption of 2. Based on this reasoning, the one-pot reaction is
8
9
initiated by treatment of 1a (0.50 mmol) with BF •OEt (1.1 equiv) for 30 min, followed by
3
2
10
11
12
13
14
15
16
17
18
19
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21
22
23
24
25
26
27
28
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31
32
33
34
35
36
37
38
39
40
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
addition of 2a (1.1 equiv) and stirring for an additional 2 h. Finally, MeSO H (1.8 equiv) is added
3
and the resulting mixture is stirred at ca. 40 ºC for 5 h. Using this procedure (upper path in Scheme
5), 4a is produced in 48% yield along with small amounts of 5a (7%) and 6a (3%). Next, we carried
out the one-pot reaction using MeSO Cl and Et N to induce the final water elimination step (lower
2
3
path in Scheme 5). In this process, 1a is similarly treated with BF OEt followed by addition of 2a
3
2
(1.5 equiv) and stirring for 1 h. MeSO Cl (1.8 equiv) and Et N (3.0 equiv) are added followed by
2
3
heating for 1 h, further addition of Et N (3.0 equiv) and subsequent heating for an additional 2 h. In
3
this case, 4a is produced in low yield (27%) along with 6a (6%) and a significant amount of
25
recovered 3a (39%).
Eventually, a one-pot protocol was devised by performing a combination of the two methods
described above, in which sequential processes involving rearrangement, hydride transfer,
26
protonation and elimination proceed (Table 4). The yield (63%) of 4a (entry 2) is comparable
with the overall yield of 4a obtained using the stepwise procedure (65% derived from 74% for 1a to
3a and 88% of 3a to 4a). This one-pot sequential process was performed in other solvents using
MeCN, PhCH and PhCF (entries 3~5), and applied to other epoxy ketones 1 (entries 6~13). The
3
3
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aroyl substituted α-methylene ketones 4 were obtained in modest to good yields (53-70%, entries
6~9, and 12) except for the reactions of 1f and 1g affording 4f and 4g in less than 50% yields (entry
10 and 11). An acetyl substituted 4i was also obtained in low yield (entry 13). Since the yields of
the corresponding aldols 3f, 3g, and 3i were similar to those of other 3 (see Table 3), the relatively
low yields of 4f, 4g, and 4i might be attributed to the latter steps of one-pot transformation although
not confirmed yet.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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26
27
28
29
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a
Table 4. One-pot transformations of epoxy ketones 1 to methylene ketones 4
1
2
b
entry
solvent
CH Cl
1
R
R
yield of 4 [3] (%)
c
Ph
Ph
53 [4]
63 [3]
47 [7]
55 [1]
54 [4]
70 [5]
53 [~4]
55 [~8]
61 [~3]
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
1
2
2
CH Cl
2
3
Ph
Ph
2
2
Ph
Ph
Ph
MeCN
PhCH
4
Ph
3
PhCF
5
Ph
Ph
Ph
3
CH Cl
6
p-MeOC6H4
p-MeC6H4
p-ClC6H4
1-Naph
Ph
2
2
CH Cl
7
Ph
2
2
2
2
2
2
2
2
CH Cl
8
Ph
2
CH Cl
9
Ph
2
d
CH Cl
10
11
12
13
p-MeOC6H4
p-MeC6H4
p-ClC6H4
Me
34 [-]
2
d
CH Cl
Ph
1g
1h
1i
46 [-]
2
CH Cl
Ph
57 [~5]
45 [0]
2
CH Cl
Ph
2
a
1 (0.50 mmol), BF •OEt (1.1 equiv), 2a (1.1 equiv), MeSO H (1.8 equiv), MeSO Cl (1.3 equiv)
3
2
3
2
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4
b
1
and Et3N (6.0 equiv), solvent (1.5 mL). Yields of 4 were determined by using H NMR of the
c
d
mixtures containing 6 (0-5%). Numbers in brackets are yields of 3. MeSO Cl (1.8 equiv). 3 was
2
5
6
observed in the inseparable mixtures.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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CONCLUSION
In the studies described above, we demonstrated that the reagent system comprised of boron
trifluoride etherate and 1,3-dimethylbenzimidazolines is effective in transforming α,β−epoxy
ketones to β-hydroxy ketones. Methanesulfonic acid or methanesulfonyl chloride-triethylamine
promoted dehydration of the resulting hydroxyl ketones produce α-methylene ketones. Finally,
these consecutive chemical processes can be accomplished in one-pot. While these compounds can
15,20a-h
be prepared by other methods,
most of them require specific metal reagents which are in
contrast to our metal-free protocol. Because the starting epoxy ketones are readily prepared using
H O and NaOH promoted reactions of the corresponding α,β-unsaturated ketones, the new
2
2
protocol is a useful isomerization route for transforming 1,3-disubstituted 2,3−unsaturated ketones
to 1,2-disubstituted 2-methylene ketones, which are synthetically useful substances. The
applicability of this newly developed, metal free, mild synthetic method will be further explored.
EXPERIMENTAL SECTION
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General. NMR spectra were recorded using CDCl solutions with tetramethylsilane (Me Si) as an
3
4
4
5
6
7
8
1
13
internal standard at 270 MHz and 400 MHz for H NMR, and 100 MHz for C NMR. High
resolution mass spectra (HRMS) were recorded on a double-focusing mass spectrometer by using
electrospray ionization (ESI). Uncorrected melting points are reported. Column chromatography was
performed using silica gel. Preparative thin layer chromatography (TLC) was performed on 20 × 20
cm plates coated with silica gel. CH Cl was treated with H SO , water, 5 % NaOH, water, CaCl ,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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36
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2
2
2
4
2
and then distilled over CaH . MeCN was distilled over P O and subsequently distilled with
2
2 5
K CO . Other reagents and solvents were purchased and used without further purification.
2
3
7b,27
28
11b,13d
7b,27
α,β-Epoxy ketones 1a-1f,
1g, 1h,
and 1i,
which are known compounds, were
prepared by reactions of the corresponding α,β-enones with H2O2 and NaOH according to the
27a
2a,7b
3a
1
7e
literature procedures.
2-Aryl-1,3-dimethylbenziimidazolines (DMBIH) 2a,
2b, 2c, 2d,
7e
5c,7e
7e
2e, and 2f
are known and were prepared by using reported procedures. Known products
15
20
29
30
13f
31
1
3a-3i, 4a-4i, 5a-5h, 6a-6h, 7a and 8a, were characterized by comparison of their H
NMR data with those reported earlier. Spectral data were obtained for unknown compounds 3e, 3f,
3g, 3h, and 4e.
Reaction of α,β-epoxy ketones 1 with BF •OEt and DMBIH 2 (Table 1, 2, and 3). A typical
3
2
example (entry 6 in Table 1). To a N purged CH Cl (0.5 mL) solution containing 1a (112 mg,
2
2
2
0.50 mmol) was added BF •OEt (0.07 mL, 0.56 mmol). After stirring for 30 min, 2 (168.2 mg,
3
2
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0.75 mmol) dissolved in a N2 purged CH2Cl2 (1.0 mL) solution was added. The resulting mixture
4
5
6
7
was stirred under N2 at room temperature for 1 h, diluted with water, and extracted with Et O. The
2
8
9
extract was washed with water, brine and dried over anhydrous MgSO . A residue obtained by the
4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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43
44
45
46
47
48
49
50
51
52
53
54
55
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59
60
concentration of the extract in vacuo was subjected to column chromatography (EtOAc/n-Hexane =
1/5 and 2/1) giving 3a (84 mg, 0.37 mmol, 74%). Other products including 4a (1 mg, 0.006 mmol,
1%) and 5a (1 mg, 0.002 mmol, 1%) were separated by using TLC (AcOEt/n-hexane = 1/20).
Reactions of other 1 and 2 were performed in a similar manner. When isolations of minor products
1
were not performed, their yields were estimated by using H NMR.
1
3-Hydroxy-2-(1-naphthyl)-1-phenylpropan-1-one (3e). Pale yellow oil; H-NMR (400 MHz)
δ
8.37 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 7.2 Hz, 2H), 7.76 (d, J = 8.4 Hz, 1H),
7.68 (t, J = 7.6 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.41 (t, J = 7.2 Hz, 1H), 7.34-7.25 (m, 3H), 7.14
(d, J = 7.2 Hz, 1H), 5.52 (dd, J = 3.8 Hz, J = 8.6 Hz, 1H), 4.36 (dd, J = 8.8 Hz, J = 11.6 Hz, 1H),
13
3.96 (dd, J = 4.0 Hz, J = 11.6 Hz, 1H), 2.63 (broad s, 1H); C-NMR (100 MHz)
δ 200.6, 135.9,
134.3, 133.2, 132.0, 130.7, 129.3, 128.6, 128.5, 128.3, 127.1, 126.2, 126.0, 125.5, 122.3, 64.2, 51.9;
+
HRMS (ESI) m/z calcd for C H O (M+H) 277.1218, found 277.1223.
19 17
2
1
3-Hydroxy-1-(4-methoxyphenyl)- 2-phenylpropan-1-one (3f). Pale yellow oil; H-NMR (400
MHz)
δ 7.91 (d, J = 9.5 Hz, 2H), 7.33-7.20 (m, 5H), 6.83 (d, J = 9.7 Hz, 2H), 4.73 (dd, J = 4.8 Hz,
J = 8.4 Hz, 1H), 4.25 (dd, J = 9.8 Hz, J = 9.8 Hz, 1H), 3.90-3.77 (m, 3H), 2.59 (broad s, 1H);
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C-NMR (100 MHz)
δ
198.4, 163.5, 136.6, 131.2, 129.2, 129.1, 128.3, 127.4, 113.7, 65.2, 56.0,
+
55.4; HRMS (ESI) m/z calcd for C H O (M+H) 257.1172, found 257.1167.
16 16
3
8
9
3-Hydroxy-1-(4-methylphenyl)-2-phenylpropan-1-one (3g). White solid; mp 53.5-56.0 ℃;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
H-NMR (400 MHz)
δ 7.83 (d, J = 8.4 Hz, 2H), 7.33-7.20 (m, 5H), 7.16 (d, J = 8.0 Hz, 2H), 4.76
(dd, J = 4.8 Hz, J = 8.4 Hz, 1H), 4.26 (dd, J = 8.4 Hz, J = 11.6 Hz, 1H), 3.87 (dd, J = 4.8 Hz, J =
13
11.6 Hz, 1H), 2.34 (s, 3H), 2.14 (broad s, 1H); C-NMR (100 MHz)
δ 199.6, 144.2, 136.4, 133.7,
129.2, 129.1, 129.0, 128.4, 127.5, 65.2, 56.2, 21.6; HRMS (ESI) m/z calcd for C H O Na
16 16
2
+
[M+Na] 263.1043, found 263.1040.
1-(4-Chlorophenyl)-3-hydroxy-2-phenylpropan-1-one (3h). White solid; mp 79.0-82.0 ℃;
1
H-NMR (400 MHz)
δ 7.86 (d, J = 9.1 Hz, 2H), 7.36-7.22 (m, 7H), 4.72 (dd, J = 4.8 Hz, J = 8.4 Hz,
1H), 4.27 (dd, J = 8.6 Hz, J = 11.4 Hz, 1H), 3.87 (dd, J = 4.6 Hz, J = 11.4 Hz, 1H), 2.31 (broad s,
13
1H); C-NMR (100 MHz)
δ 198.7, 139.7, 135.9, 134.5, 130.3, 129.3, 128.9, 128.3, 127.8, 65.0,
35
+
37
56.5; HRMS (ESI) m/z calcd for C H
ClO (M+H) 261.0673, found 261.0677; C H
ClO
15 14
2
15 14 2
+
[(M+H) 263.0647, found 263.0644.
1
2-(1-Naphthyl)-1-phenyl-2-propen-1-one (4e). White solid; mp 83.0-85.0 ℃; H-NMR (400
MHz) 4 7.97 (d, J = 7.9 Hz, 2H), 7.89-7.81 (m, 3H), 7.53 (t, J = 7.6 Hz, 1H), 7.50-7.40 (m, 6H),
13
6.19 (s, 1H), 6.18 (s, 1H); C-NMR (100 MHz)
δ 195.6, 148.1, 137.1, 136.3, 133.6, 132.7, 131.2,
129.8, 128.8, 128.8, 128.5, 128.3, 127.3, 126.4, 125.8, 125.4, 125.1; HRMS (ESI) m/z calcd for
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+
C H O (M+H) 259.1117, found 259.1113.
19 15
4
5
6
7
Reaction
of
1a
with
BF •OEt
and
other
hydride
donors.
3
2
8
9
2,6-dimethyl-3,5-pyridinedicarboxylate (Hanztsch ester). The same reaction and work-up
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
procedures as those given in entry 6 of Table 1 were performed by using 1a (112 mg, 0.50 mmol)
,
BF •OEt (0.07 mL, 0.56 mmol), Hantzsch ester (190 mg, 0.75 mmol), CH Cl (1.5 mL). Then,
3
2
2
2
column chromatography (EtOAc / n-Hexane = 1/10 and 2/1) and TLC (EtOAc / n-Hexane = 1/5)
were performed. Due to the incomplete separation of 3a, the yield of 3a (0.14 mmol. 28%) was
1
determined by using H NMR with PH CH as an internal standard. The yields of 4a (0.018 mmol,
3
1
4%) and 7a (0.09 mmol, 17%) were determined on the basis of the H NMR signal intensities
relative to that of 3a in the crude product mixture.
Hydrosilanes (Ph3SiH, Et3SiH). Same reaction and work-up procedure as those reported in entry
6 of Table 1 were performed by using 1a (44.9 mg, 0.20 mmol), BF OEt (0.03 mL, 0.24 mmol),
3
2
1
Ph SiH (78.2 mg, 0.30 mmol), CH Cl (0.6 mL). H NMR of the product mixture indicated the
3
2
2
existence of 7a and Ph SiH without other marked signals. Reaction with Et3SiH was performed in a
3
similar manner.
Reaction of β-ketoaldehyde 7a with BF •OEt and DMBIH 2a (eq 2). Same reaction and
3
2
work-up procedure as those reported in entry 6 of Table 1 were performed by using 7a (112 mg,
0.50 mmol), BF •OEt (0.07 mL, 0.56 mmol), 2a (168 mg, 0.75 mmol), CH Cl (1.0 mL). Column
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5
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chromatography (EtOAc / n-Hexane = 1/10, 1/2 and 2/1) gave 3a (80 mg, 0.35 mmol, 71%).
Following TLC separation (AcOEt/n-hexane = 1/20) gave 4a (3 mg, 0.018 mmol. 3%) and 5a (2 mg,
0.009 mmol. 2%).
10
11
12
13
14
15
16
17
18
19
20
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22
23
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Reduction of β-ketoaldehyde 7a with NaBH (eq 3). To a N2 purged MeOH (2.0 mL)
4
solution containing 7a (45 mg, 0.20 mmol) was added NaBH (8 mg, 0.20 mmol). After stirring at
4
room temperature for 2 h, the mixture was concentrated, diluted with water, and extracted with
Et O. The extract was washed with water, brine and dried over anhydrous MgSO . The residue
2
4
obtained by concentration of the extract in vacuo was subjected to TLC (EtOAc/n-Hexane = 1/2)
giving 3a (2 mg, 0.008 mmol, 4%), 6a (9 mg, 0.04 mmol. 22%) and 8a (15 mg, 0.06 mmol. 33%).
Reactions of different quantities of NaBH were similarly performed.
4
Transformation of β-hydroxyl ketone 3a to α-methylene ketone 4a. A protocol using
MeSO H (upper path in Scheme 4). To a N purged CH Cl (1.5 mL) solution containing 3a (113.1
3
2
2
2
mg, 0.50 mmol) was added MeSO H (0.03 mL, 0.46 mmol), and the resulting mixture was stirred
3
under N at 40 ºC for 5 h. Then, saturated aqueous NaHCO was added, and the extraction with
2
3
Et O was conducted. The extract was washed with water, saturated aqueous NaHCO , brine and
2
3
dried over anhydrous MgSO . Column chromatography (Benzene) of the residue obtained by the
4
concentration of the extract in vacuo gave 4a (77 mg, 0.37 mmol, 74%).
A protocol using MeSO Cl and NEt (lower path in Scheme 4). To a N purged CH Cl (0.6 mL)
2
2
2
2
2
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solution containing 3a (45 mg, 0.20 mmol) placed in an ice bath was added MeSO Cl (0.02 mL,
2
4
5
6
7
0.26 mmol) and Et N (0.17 mL, 1.22 mmol), and the resulting mixture was stirred under N at 40
3
2
8
9
ºC for 5 h. The reaction mixture was diluted with water, and extracted with Et O. The extract was
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
washed with water, saturated aqueous NaHCO , brine and dried over anhydrous MgSO . Column
3
4
chromatography (benzene) of the residue obtained by the concentration of the extract in vacuo gave
4a (37 mg, 0.18 mol, 88%).
One-pot transformation of α,β-epoxy ketones 1 to α-methylene ketones 4. A protocol using
MeSO H (upper path in Scheme 5). To a N purged CH2Cl2 (0.5 mL) solution containing 1a (112
3
2
mg, 0.50 mmol) was BF •OEt (0.07 mL, 0.56 mmol). After stirred for 30 min, 2 (123 mg, 0.55
3
2
mmol) dissolved in a N purged CH2Cl2 (1.0 mL) was added. The resulting mixture was stirred
2
under N at room temperature for 2 h, followed by the addition of MeSO H (0.06 mL, 0.92 mmol).
2
3
After the mixture was stirred at 40 ºC for 5 h, same work-up as used for the reaction of 3a with
MeSO H was performed. TLC (EtOAc / n-Hexane = 1/20) of the residue obtained by the
3
concentration of the extract in vacuo gave the inseparable mixture of 4a and 5a, and that of 4a and
1
6a. The yield of each product was determined by H-NMR: 4a (0.24 mmol, 48%), 5a (0.035 mmol,
7%), and 6a (0.015 mmol, 3%).
A protocol using MeSO Cl-NEt (lower path in Scheme 5). To a N purged CH2Cl2 (0.5 mL)
2
3
2
solution containing 1a (112 mg, 0.50 mmol) was BF •OEt (0.07 mL, 0.56 mmol). After stirring for
3
2
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30 min, 2 (168 mg, 0.75 mmol) dissolved in a N purged CH2Cl2 (1.0 mL) was added. The resulting
2
4
5
6
7
mixture was stirred under N at room temperature for 1 h, and then MeSO Cl (0.07 mL, 0.90 mmol)
2
2
8
9
and Et N (0.21 mL, 1.51 mmol) were added in ice-bath. After stirring at 40 ºC for 1 h, MeSO Cl
2
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(0.07 mL, 0.90 mmol) and Et N (0.21 mL, 1.51 mmol) were added, and an additional heating at 40
3
ºC for 2 h was performed. The same work-up as used in the reaction of 3a with MeSO Cl and Et N
2
3
was performed. TLC (EtOAc / n-Hexane = 1/2) of the residue obtained by the concentration of the
extract in vacuo gave 3a (44 mg, 0.20 mmol, 39%) and the mixture of 4a and 6a. The yields of 4a
1
and 6a were determined by H-NMR: 4a (0.14 mmol, 27%) and 6a (0.14 mmol, 6%).
A sequential treatment using MeSO H and MeSO Cl with NEt (Table 4). A typical example
3
2
3
(entry 2 in Table 4). To a N2 purged CH2Cl2 (0.5 mL) solution containing 1a (112.1 mg, 0.50 mmol)
was BF •OEt (0.07 mL, 0.56 mmol). After stirring for 30 min, 2a (123 mg, 0.55 mmol) dissolved
3
2
in a N purged CH2Cl2 (1.0 mL) was added. The resulting mixture was stirred under N at room
2
2
temperature for 2 h, followed by the addition of MeSO3H (0.06 mL, 0.92 mmol). After the mixture
was stirred at 40 ºC for 1 h, MeSO3Cl (0.05 mL, 0.65 mmol) and Et3N (0.42 mL, 3.01 mmol) were
added in an ice-bath. Then, additional heating at 40 ºC for 4 h was performed. The same work-up as
used in the reaction of 3a with MeSO H was performed. TLC (EtOAc / n-Hexane = 1/2) of the
3
residue obtained by the concentration of the extract in vacuo gave 3a (4 mg, 0.016mmol, 3%) and
1
the mixture of 4a and 6a. The yields of 4a and 6a were determined by H-NMR: 4a (0.31mmol,
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2
3
63%) and 6a (0.018mmol, 4%).
4
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7
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ASSOCIATED CONTENT
Supporting Information
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H-NMR and C-NMR spectra of the products 3 and 4. This material is available free of charge
via the Internet at http://pubs.acs.org.
ACKNOWLEDGEMENTS
We thank Professor Masaki Kamata (Niigata University) and Associate-Professor Michael
Oelgemöller (James Cook University, Australia) for their useful comments.
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2
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(19) Other types of substrates such as 4-methyl-1-phenyl-2,3-epoxypentan-1-one,
3,4-epoxynonan-2-one did not undergo the expected rearrangement on the treatment with
8
9
BF •OEt .
Although
BF •OEt
2
promoted
rearrangement
of
3
2
3
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12k
3,5,5-trimethyl-2,3-epoxycyclohexan-1-one (isophorone epoxide) is known,
none of the
expected aldol was detected with the formation of the β-keto aldehyde (~25%) under the
optimized one-pot condition.
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Org. Chem., 1992, 57, 17 28. (b) Katritzky, A, R.; Toader, D.; Chassaing, C. J. Org. Chem.
–
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