Temperature-controlled Mukaiyama aldol reaction of cyclododecanone (CDD) with aromatic aldehydes promoted by TMSCl: Via the (TMS)3Si intermediate generated in situ

Article abstract of DOI:10.1039/c5nj02685g

An alternative method with temperature dependency for obtaining direct chemo-, regio- and diastereoselective monobenzylidene and β-hydroxy carbonyl derivatives has been developed. In the present work, an attempt has been made to synthesize a precursor con

Full text of DOI:10.1039/c5nj02685g

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Temperature-controlled Mukaiyama aldol reaction
of cyclododecanone (CDD) with aromatic
aldehydes promoted by TMSCl via the (TMS)3Si
intermediate generated in situ†
Cite this:DOI: 10.1039/c5nj02685g
Venkatesan Satheshab and Kulathu I. Sathiyanarayanan*a
An alternative method with temperature dependency for obtaining direct chemo-, regio- and diastereo-
selective monobenzylidene and b-hydroxy carbonyl derivatives has been developed. In the present
work, an attempt has been made to synthesize a precursor containing an organometallic compound,
trimethylsilyl chloride (TMSCl), and cyclododecanone (CDD). Unexpectedly, this precursor exhibited
temperature dependent chemoselective structures. At 35–40 1C, in situ formation of super silyl groups
(TTMSS) from trimethylsilyl chloride stabilized the positive charge on the a-corner (C) side (sterically
hindered side) of the CH2 group (1b) in zwitterionic CDD, leading to monobenzylidene derivatives
(enones). At ꢀ20 1C, interestingly, TMSCl stabilized silyl enol ethers, which in turn produced b-hydroxy
carbonyl derivatives (Mukaiyama aldol products) in the a-less hindered (S) side (sterically less hindered
side) of the CH2 group. When we tried the reaction with TTMSSH instead of TMSCl, we failed to get
either enones or aldol addition products. Tris(trimethylsilyl)silane (TTMSSH) stabilized the positive charge
on the a-less hindered (S) side of the CH2 group. In the present protocol, the formation of
monobenzylidene derivatives occurred in one step, whereas the methods available so far involved more
than three steps. From this, it is clear that temperature is the only factor that changes the course of the
reaction. In order to achieve diastereoselectivity in the Mukaiyama aldol reaction, sodium iodide was
added. In monobenzylidene derivatives, the E-isomer is predominant (97–99%), while in the case of
Mukaiyama aldol products, the anti-isomer is predominant (85–99%).
Received (in Montpellier, France)
1st October 2015,
Accepted 23rd February 2016
DOI: 10.1039/c5nj02685g
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and acyclic ketones.4a–d Wittig developed a direct aldol reaction
procedure using enolate intermediates in place of lithio deriva-
Introduction
Although aldol reactions are one of the most versatile tools for tives and some interesting applications were also developed by
creating new carbon–carbon bonds,1 their utility has several other chemists.4e For example, enol ether derivatives,5 enol
limitations because it is very difficult to control the course of ether/acetals,5 enol silyl ethers/TiCl4,4c Li–Me enol ethers,6a
the reaction.2 It has been known for a long time that silyl enol TiCl4-n-Bu4NI6b or with various catalysts,6c trimethylsilyl triflates7
ethers are useful intermediates in organic synthesis as well as have proven the usefulness of regio- and sometimes diastereo-
in the synthesis of natural products.3 In many aldol reactions, selective synthesis of aldol-type compounds. Unless some deliberate
even though the equilibrium is centered on the aldol anion, measures are taken for stereoselectivity, the enolate anions
the reaction could not be controlled, and many times undesir- with different metal cations do not undergo controlled aldol
able products were formed by self- or polycondensation.1b–d reactions. Finally, preformed lithium,8 aluminum,9 boron,10
Different methodologies have been devised to get chemo-, tin,11 and zirconium enolates,12a MeLi/TMS-enol ethers12b
regio- and diastereoselective aldol products using cyclic (5–8) and TiCl4–Bu3N-mediated aldol reactions12c have also received
much attention in relation to the stereochemical problems.
a Chemistry Division, School of Advanced Sciences, VIT University, Vellore-632014,
Tamilnadu, India. E-mail: sathiya_kuna@hotmail.com; Fax: +914162243092
b School of Chemical Sciences, National Institute of Scienc‘e Education and
Research (NISER), Institute of Physics Campus, Bhubaneswar-751005, Orissa,
India
† Electronic supplementary information (ESI) available: 1H NMR and 13C NMR
spectra of the newly synthesized compounds and mechanistic details. See DOI:
10.1039/c5nj02685g
Consequently, the preparation of enones usually requires more
than two steps,13 i.e. aldol addition followed by dehydration.14
The aldol addition is readily reversible15 and hence, to avoid
this, the Mukaiyama approach starting from the –OTMS of the
ketone16 has gained prominence.17 Silylation of the ketone
introduced another step and lowered the atom economy.18
Many new methodologies have been developed to get enones
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selectively by using preformed alkenyl trichloroacetates in the fascinating properties, full details of which are illustrated in
presence of dibutyltin dimethoxide in THF/CH3OH.19 The Scheme 1.
recent success of tris(trimethylsilyl)silyl-governed aldehyde
cross-aldol cascade reaction19d and syn 1,3-diol19e has led to
high diastereoselectivity. The ‘‘super silyl group’’ is superior
to the organotin and tributyltin groups in tuning the aldol
Results and discussion
reactions.19f,g The treatment of commercially available Cyclododecanone is known for its W shaped zwitterions in the
a-iodomercuric ketone with carbonyl compounds in the solution phase,24b and the organometallic reagent TTMSS
presence of enol silyl ether/Ni(CO)4 at 80 1C produced the (in situ generated from TMSCl) forms a bond with the keto
corresponding enones in lower yield.20 A freshly prepared group of CDD, since TMSCl is known for the homolytic bond
N-(1-cyclohexen-1-yl)morpholine reacted with benzaldehyde cleavage of Si–Cl linkage.27 The exploitation of this property for
in the presence of toluene under reflux conditions yielding the protonolysis of Si–O28 has been known for a long time, and
enones.21 Kreher and coworkers reported the monoarylidene the potential of the fluoro-mediated generation of nucleophiles
derivatives using 12 mol equiv of N,N-dimethylammonium has been demonstrated in regio-specific enolate formation.29
N0,N00 dimethylcarbamate (DIMCARB) as a catalyst to stabilize This work involved chloro-mediated enolate formation.
the aminal followed by the addition of aldehyde to get high N-heterocyclic carbenes were also demonstrated as catalysts for
selectivity of E and Z isomers.22 All the reaction procedures the formation of corresponding silyl enol ethers at 23 1C in THF
used only the small ring cyclic (5–8) and acyclic ketones.
regio-specifically.30 In symmetrical ketones TMSCl and tert-
In large ring ketones, certain catalysts do not work much butyldimethylsilyl (TBS) enol ethers were found to give pre-
efficiently.23 This prompted us to select CDD.23,24 We recently dominantly E isomers.31 Unsymmetrical and sterically hindered
reported25 a new series of unique aldol reactions of CDD, and ketones such as propiophenone,32 2-methylcyclohexanone33 and
we have tried to extend that method for the preparation of cyclododecanone34 afforded a mixture of E/Z-silyl enol ethers
monobenzylidene derivatives. We have been struggling to get mainly consisting of Z-isomers, and this selectivity also held true
an enone product using the one-pot strategy for the past 3 for the reaction with 3-pentanone.35 In the case of 3-pentanone,
years with various substituents on the benzaldehyde ring. a 5 mol% catalyst was required for the completion of the
There are a few types of synthetic approaches to get aldol reaction even after 3 days.
condensation and addition reaction products using the reac-
The reaction between cyclododecanone and parent benz-
tion of cyclododecanone with aliphatic aldehydes. This was aldehyde (2d) was examined with respect to a variety of acids,
reported five decades back, when Zakharkin et al.26a synthe- bases, metal salts and metal oxides as catalysts, and with
sized musk odored compounds involving more than three various solvents. In all the cases, products were not formed
steps. Paul et al.26b reacted 1 with ethylformate in the presence (Table 1, entries 1–11). However, NH4OAc initiated the reaction
of CH3ONa, which gave 2-hydroxymethylene cyclododecanone but the consumption of the starting materials at 70 1C in EtOH
in the first step. Then, this was treated with diethylamine was sluggish. It led to a mixture of products mainly consisting
to yield 2-N-dimethylaminomethylenecyclododecanone fol- of a macro acyclic Mannich product36 and a very small amount
lowed by treatment with alkyl magnesium halides 4 yielding of enones, as shown in Table 1, entries 12–14 (10–18%), and in
2-alkylidenocyclododecanone (3a–e) (Scheme 1) with pleasant Scheme 2. In some instances, HCl gas gave chemoselective
musk odor.26b
products37 of enones. But this method also did not work in our
We found that Mukaiyama aldol reaction using an organo- experiment even after passing HCl gas for a long time (Table 1,
silane reagent as a catalyst was the most suitable one for the entry 15). In our earlier work, the aldol addition reaction of
current study. Therefore, an alternative synthetic approach for cyclododecanone25 proceeded with strong bases such as NaOH,
the preparation of aldol condensation and addition products LiOH and KOH at ambient temperature (Table 1, entries 16 and 17).
was separately developed with temperature dependency in But the enones were not formed.
a one-pot manner. This aldol reaction showed a number of
Hence, two extreme reaction conditions using temperature
key factor for getting enones and aldol products
as
a
(Mukaiyama aldol products) are illustrated in Tables 2 and 3.
Chlorotrimethylsilane was used to get the chemo-, regio- and
stereocontrolled products in the case of both enone and aldol
products. Enone was formed upon treatment of CDD with
chlorotrimethylsilane in CH3CN at 35–40 1C with stirring for
18 hours and upon adding benzaldehyde 2d to the reaction
mixture (yield 83% with high diastereoselectivity (E/Z 4 99/1))
for 26 hours as shown in Table 1, entry 24. Aldol reactions of
cyclic or acyclic ketones with carbonyl compounds in the
presence of TMSCl/acid, ketone could give the silylation as well
as aldol addition products but not enones. But in the case of
CDD, the catalyst (in situ generation of TTMSS from TMSCl)
Scheme 1 Protocols for the chemo-, regio- and diastereoselective forma-
tion of CQC and C–C bonds.
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Table 1 Optimization of reaction conditionsa
Yield%g
Entry
Catalyst
Cat. load. mol%
Solvents
Temp. (1C)
T/h
3d
5d
1
2
3
4
5
6
7
8
ZnCl2
AcOH
10b
EtOH
EtOH
DCM
DCM
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
DCM
EtOH
EtOH
EtOH
MeOH
MeOH
MeOH
DCM
DCM
DCM
DCM
DCM
DCM
CH3CN
DCM
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
70
24
24
24
24
24
24
24
24
24
24
24
48
48
48
24
24
24
26
24
26
26
26
26
26
30
—
—
—
—
—
—
—
—
—
—
—
10
15
18
—
—
—
55
20
28
40
49
78
83
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
78
86
63d,e,f
—
—
—
10
FeCl3ꢁ6H2O
10c
CuI
10c
AlCl3
Al2O3
10
10
10
10
10
10
10
10
CoAlO4
NiAlO4
MgO
Zeolite-Y
FeCl3–SiO2
NH4OAc
NH4OAc
NH4OAc
HCl (gas)
KOH
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
20
30
70
70
Over 45 min gas has been passed
1
1
1 (eq.)
10
20
40
60
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
NaOH
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TTMSSH
—
2 (eq.)
2 (eq.)
2 (eq.)
—
81d,e
—
a
Unless otherwise noted, the reaction was carried out using various catalysts, CCD 1 (5 mmol) and parent benzaldehyde 2d (5 mmol), in different
b
c
d
solvents at different temperatures for 24–48 h. 10 mol% piperidine was used. N-Methylimidazole 10 mol% was used. The reaction was carried
e
f
out at ꢀ20 1C. Immediate addition (i.e. without preformed enolate) of the 2d mixture of the product (anti/syn: 50/50). 1 equivalent of NaI was
g
added. Isolated yield.
and aldolization with benzaldehyde with stirring at 0 1C did not
yield the desired aldol product.38b
The Mukaiyama aldol reaction was preformed with (cyclo-
dodecyloxy)trimethylsilane 1c (Table 3) (CDD/NaI equiv. molar
ratio) and benzaldehyde 2d as a model reaction, where TMSCl
was employed as the one of the reactants. This synthetic
protocol gave satisfactory results (5) when the reaction was
Scheme 2 Synthesis of enones from cyclododecanone and aldehydes
catalyzed by NH4OAc.
carried out with 2 equivalents of TMSCl/NaI under stirring
conditions for 8 hours at ꢀ20 1C. In some instances, immediate
addition (i.e. without preformed enolate) of 2d to CDD/TMSCl/NaI
played a major role, both in selectivity and yield, under the led to the mixture of products (1 : 1 anti/syn product). This problem
given reaction conditions (35–40 1C).
was specific when the amount of TMSCl was low (1 equiv.) as
Hence, using the optimum reaction conditions (Table 1, shown in Table 1, entry 18. The present reaction conditions
entry 24) we employed the Mukaiyama aldol reaction in the demonstrated that the control of the stereochemical course of
presence of sodium iodide38a at low temperature. NaI was the reaction by adding NaI was due to the formation of stable 1c.34
added to achieve the diastereoselectivity. We tried the same From these results, it is very clear that TMSCl/NaI/CH3CN (2 equiv.)
reaction with tris(trimethylsilyl)silane (TTMSSH) instead of played a crucial role in the Mukaiyama aldol addition reaction and
TMSCl (Table 1, entry 25) but the reaction did not proceed, that the reaction (Table 1, entry 24) was quite clean under the
and we failed to get either enones or aldol addition products optimum conditions described above.
due to the steric hindrance of cyclododecanone and bulkiness
We carried out the Mukaiyama aldol reaction under conven-
of the super silyl groups (TTMSSH). This is in line with the tional conditions, i.e. after the isolation of (cyclododecyloxy)-
report by Ramachandran et al., where enolization of tert-butyl trimethylsilane 1c or (cyclohex-1-en-1-yloxy)trimethylsilane which
2-phenylacetate with the bulky group of CHX2BOTf in CH2Cl2 reacted with benzaldehyde 2d in the presence of 2 equivalents of
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Table 2 Chemoselective synthesis of monobenzylidenecyclododeca-
none (enones) derivatives at room temperaturea
Table 2 (continued)
Entry R = alkyl or aryl
3
T/h Yield (%) E/Z (%)
Entry R = alkyl or aryl
3
T/h Yield (%) E/Z (%)
1
2
3
n-C2H5
n-C3H7
iso-C3H7
22
20
21
82
87
70
1/99
1/99
1/99
11
12
13
3-OH, 4-OCH3-C6H4
4-OCH3-C6H5
4-Br-C6H5
32
23
25
58
69
78
97/3
97/3
99/1
4
5
6
C6H5
26
24
28
83
87
65
99/1
99/1
99/1
2-CH3-C6H5
14
15
4-CN-C6H5
28
26
59
81
99/1
99/1
2-OCH3-C10H6
4-Cl-C6H5
7
8
9
2-Cl-C6H5
2-Br-C6H5
3-OH-C6H5
35
33
29
77
74
67
99/1
98/2
99/1
16
4-NO2-C6H5
32
30
73
53
99/1
99/1
17
3,4,5-Tri-OH-C6H2
a
Unless otherwise noted, all the reactions were carried out
with CDD 1 (5 mmol), benzaldehydes 2 (5 mmol) and TMSCl
(10 mmol) in 2 mL of dry CH3CN at 35–40 1C; the isolated yields
of all the compounds are given; chemoselectivity and the E/Z isomer
ratio were determined by 1H NMR. Compounds 3a–c have musk
odor.
10
2,4-Cl-C6H4
31
70
99/1
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Table 3 Anti and regio-selective Mukaiyama aldol reactions of cyclodo-
decanone with aldehydes using TMSCl as a catalyst at ꢀ20 1Ca
Scheme 3 Synthesis of Mukaiyama aldols or enones from isolated silyl
enol ethers of CDD and benzaldehyde.
Entry R = aryl
5
T/h Yield (%) Anti/syn (%)
We tried to prepare the tristrimethylsilylenol ether of cyclo-
dodecanone under similar conditions but we could not get the
expected intermediate.
1
2
3
4
C6H5
24 81
23 83
21 72
28 56
99/1
99/1
98/2
98/2
Monobenzylidene product formation
2-CH3-C6H5
2-Br-C6H5
2,4-Cl-C6H4
The versatility of the protocol was fully established by evaluat-
ing a variety of aldehydes as shown in Tables 2 and 3 respec-
tively. By employing cyclododecanone as the nucleophile, a
wide range of electron-donating and withdrawing substituents
on the aromatic ring were well tolerated. It afforded the desired
enone product 3 with moderate to good yield and high selec-
tivity (Table 2, 3a–3r, 53% to 87% yield, E/Z = 97/3 to 499).
The selectivity was reverse in the case of aliphatic aldehydes
such as propionaldehyde, isopropylaldehyde and n-butylaldehyde
(Z/E = 99%). In general, aromatic substituted aldehydes gave
higher yields than the aliphatic aldehydes. The formation
of enones was practically not possible using other ketones
(5–8 homologues and acyclic ketones), as 1b was not formed
(Fig. 2), which was formed under the present reaction condi-
tions. Using CDD, due to its dissimilar a and a0-CH2 groups, the
product formation was possible.
5
4-OCH3-C6H5
27 86
99/1
6
7
8
4-Br-C6H5
4-CN-C6H5
4-Cl-C6H5
22 82
34 63
22 80
99/1
85/15
98/2
Mukaiyama aldol products
As evident from Table 3, the product yield and the selectivity
depended on the benzaldehyde ring substituent and its bulkiness.
Unsubstituted benzaldehyde and 1-naphthaldehyde yielded only
anti-isomers predominately (499%) but the yield was decreased
for 2u (1-naphthaldehyde) when compared to 2d (benzaldehyde).
All the electron withdrawing and donating substituents at the
para position gave a relatively high yield (480%) and good
selectivity (499 anti-isomer) for compounds 5l, 5m, 5o, 5r, and 5t.
The yield and anti/syn ratio were decreased (63% and 85/15%)
in the case of 4-cyanobenzaldehyde 2n. On the other hand, ortho
substituted aldehydes gave moderate to good yield, and the anti-
product was obtained predominantly (Table 3, entries 2 and 3). In
contrast, di-substituted benzaldehydes gave low yield and less
selectivity (compounds 5j and 5s). We examined the reaction
using an excess of 2j (2,4-dichlorobenzaldehyde). In fact, 1.4 equiv.
of 2j gave a mixture of products mainly consisting of B81% aldol
products and B19% enones. On the other hand, excess of TMSCl
resulted in a mixture of anti and syn Mukaiyama aldol products
(50%) only.
9
4-C2H5-C6H5
29 79
38 59
99/1
10
11
2,4-Cl-C6H4
4-CH3-C6H5
89/11
23 87
26 66
99/1
99/1
12
C10H7
a
Unless otherwise noted, all the reactions were carried out with CDD 1
(5 mmol), aromatic benzaldehydes (5 mmol), NaI (5 mmol) and TMCl
(10 mmol) in 2 mL of dry CH3CN at ꢀ20 1C. Isolated yields of all the
derivatives are given. The anti/syn ratios were determined by the NMR
spectroscopic technique.
Plausible mechanism
Formation of enones. The enones were formed through
TMSCl and 1 equivalent of NaI or 2 equivalents of TMSCl in preformed 1-(trimethylsi1oxy)-1-cyclododecene at the a-corner
CH3CN stirring at room temperature or ꢀ20 1C yielding the (C) side of the CDD ring. Hence, we decided to isolate the
Mukaiyama aldol product in both the cases as shown in Scheme 3. 1-(trimethylsi1oxy)-1-cyclododecene, and for this, we carried
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out reaction in CDCl3 with CDD (5 mmol) and TMSCl (10 mmol) electrophilic silicon atom of TTMSS where an excess of chlorine
at 35–40 1C for 18 hours with stirring. After 18 hours, the crude atom acted as a counter anion (1b) as shown in Fig. 2. However,
mixture (CDCl3 portion) was analyzed by NMR spectroscopy. it was confirmed that the CDD existed as zwitterions. The
The NMR results revealed that 1-(trimethylsi1oxy)-1-cyclo- literature reports confirm that in the solution phase, cyclo-
dodecene had not been formed. It showed that the a-corner dodecanone was in the W-shape zwitterion state,24a,b which was
side of the CH2 group of the carbon atom containing hydrogen in mobile equilibrium with shifting of the positive charge
atoms was strongly affected, and also that variation in the between the C side of CH2, the carbon atom of CDD and the
splitting pattern occurred due to the coordination of electro- a-less hindered (S) side of CH2. TTMSS stabilized the positive
philic silicon to the C side of the CH2 group and also the TMSCl was charge on the C side of the CH2 group. At first, mechanistic
completely converted into an intermediate of tris(trimethylsilyl)- details of the 1b induced reactions were investigated to clarify
siloxy-CDD 1b (TTMSS-CDD). This discussion has been held the transfer of electrons from the silicon atom to the C side of
to be true since in 13C spectra also the C side of CH2 was shifted the CH2 group in CDD.
to about 2 ppm in the shielding region and CQO groups were
Hence, the removal of TTMSS was done by a simple workup.
shifted to about 2 ppm in the shielding region from the original The reaction mixture was diluted with hexane and the solvent
one (CDD) as shown in the ESI.† The above results supported was removed, and the obtained white solid was analyzed by
the formation of CDD-super silyl group intermediate 1b with- NMR. The results were compared with the original one (pure
out any doubt as shown in Fig. 1.
CDD). The 1H NMR spectrum of CDD showed different splitting
TTMSS stabilized the mobile equilibrium of CDD, and this patterns for the C side of CH2 and the a-less hindered (S) side of
might be due to the one electron-transfer mechanism.39 One CH2. Two specific pentets were obtained for these two CH2
electron transfer took place from Si-metal39b to the C side of the groups as shown in Fig. S1A (ESI†).25 Whereas in the case
CH2 group and the oxonium ion (Cꢁ ꢁ ꢁO) coordinated with an of CDD, it reacted with TMSCl (in situ generation of TTMSS).
Fig. 1 The reaction was carried out in CDCl3 and the NMR recorded in CDCl3. (a) Spectrum of commercially available TTMSSH. (b) Spectrum indicating
cyclododecanone. (c) Spectrum indicating the stabilization of the positive charge on the a-corner side of the CH2 group after the removal of silyl groups.
(d) Spectrum of in situ formation of TTMSS-CDD intermediate 1b. (e) Spectrum indicating the formation of TTMSS-CDD (1bb) from TTMSSH and this has
stabilized the positive charge on the a-less hindered side of the CH2 group. (f) Spectrum indicating the in situ formation of TTMSS-CDD from TMSCl after
the addition of benzaldehyde and it can generate a siloxocarbenium ion intermediate 1e. (g) Formation of TTMSS-CDD from TTMSSH and after the
addition of benzaldehyde it has not generated the siloxocarbenium ion aldol adducts (the full spectrum is given in the ESI†).
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silyl group (TTMSSH) and ring strain in the CDD ring. The
resulting attachment of TTMSSH to CDD in the a-less hindered
side prevented the attack of the carbonyl carbon of benz-
aldehyde toward the nucleophilic carbon as shown in Fig. 2.
Even though we tried to generate an in situ formation of
TTMSS-cyclohexanone from TMSCl in cyclohexanone under
the same reaction conditions, we failed to get the expected
product. Herein, CDD might act as a radical initiator.
Formation of Mukaiyama aldol products. Enol silyl ether (E)
was formed from the a-less hindered (S) side when the reaction
was carried out with CDD 1 (5 mmol), NaI (5 mmol) and TMSCl
(10 mmol) in dry acetonitrile with stirring for 8 hours at ꢀ20 1C
to give a corresponding 1-(trimethylsi1oxy)-1-cyclododecene
and this was well documented.34 The addition of benzaldehyde
produced an anti-aldol product with a diastereoselectivity of up
to 99% via the Mukaiyama aldol reaction. These are illustrated
in Fig. 1. This mechanism is similar to the one that we had
previously reported.25
Fig. 2 Plausible mechanistic pathway for the formation of enones and
Mukaiyama aldol reaction.
Conclusion
1
The H NMR spectrum showed one triplet (A) and one sextet
In summary, this is the first report of Mukaiyama aldol reaction
and aldol condensation involving CDD on a substantial scale,
employing ordinary laboratory equipment and readily available
starting materials. Various b-hydroxy carbonyl compounds and
a,b-unsaturated ketones with high chemo-, regio- and diastereo-
selectivity were obtained with fair to good yield. Temperature
was the only deciding factor, which played a crucial role. The
nucleophile attack from the a-corner (C) side led to enones,
while from the a-less hindered (S) side led to Mukaiyama aldol
products. The formation of a dehydrated product was due to the
absence of hydrogen bonding between –CQO and –OH groups
of the aldol adduct. This was because of the in situ formation of a
‘‘super silyl group’’ (TTMSS) from O–SiMe3 linkage in 1b on the
C side of the CH2 group in sterically congested CDD 1. Even
intermediate 1b was confirmed by reaction with TTMSSH and
CDD but this stabilized the positive charge on the a-less hindered
side of the CH2 group.
(B), clearly indicating that the shifting of the positive charge
was stabilized by TTMSS, and therefore we got a triplet in the C
side of the CH2 group (Fig. S1B, ESI†).
Next, we carried out the reaction between preformed 1b
and activated TTMSS-benzaldehyde 3d generating a siloxo-
carbenium ion intermediate 1d. The carbonyl group of benz-
aldehyde (2) approached the CDD from the C side of the CH2
group. TTMSS was released from 1d to the reaction medium to
give Tris(trimethylsilyl)silyl aldolate 1e (confirmed by 1H and
13C NMR shown in the ESI†) by the intramolecular transfer of
chloride anions (–Clꢀ) to the silicon atom. Hence, the inter-
molecular hydrogen bond formation between CQO and OH of
the aldol adduct was negligible due to backward pointing of OH
to the CQO group and bulkiness of the super silyl groups
(TTMSS), thereby preventing the aldol adduct formation in the
sterically congested CDD ring. Hence, we obtained a dehydrated
product which was formed by overcoming the H-bond forma-
tion. Therefore, we infer that the in situ formation of TTMSS
from TMSCl plays a major role in the formation of enones.
In situ formation of tris(trimethylsilyl)siloxy-cyclododecanone
1b (TTMSS-CDD) was confirmed by the formation of tris(trimethyl-
silyl)siloxy-cyclododecanone 1bb (TTMSS-CDD) from commercial
sources of tris(trimethylsilyl)silane (TTMSSH). The reaction
was simultaneously carried out using commercially available
Tris(trimethylsilyl)silane (TTMSSH) and cyclododecanone
under the same reaction conditions to confirm the formation
The present synthetic protocol is superior to other meth-
odologies already reported for CDD, because it proceeded in a
one-pot manner, and also because of the mildness of TMSCl
and high product selectivity. We believe that this will lead to an
increase in the scope and synthetic utility of silyl enol ethers of
CDD for creating new protocols.
General information
of the TTMSS-CDD (1b) intermediate. It clearly indicated that All chemicals were purchased from commercial sources and
TTMSS-CDD was formed, but the stabilization of the positive they were used without further purification unless otherwise
charge occurred in the a-less hindered side (1bb) instead of the specified. TLC –(thin layer chromatography) was performed on
a-corner side (1b), and this has been identified from 1H and13C a pre-coated silica gel on alumina plates using UV light to
NMR spectra. It showed that the marginal peak shifted from 1b visualize the course of reaction. Purification of the reaction
and the original one (CDD). After the addition of benzaldehyde mixture was carried out by chromatography on silica gel and
2, the expected product was not formed (either enone or aldol isolated yields after column chromatography are reported.
addition) and this could be due to the bulkiness of the super Melting points were determined using a microprocessor digital
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melting point apparatus, and they are uncorrected. IR spectra Illustrative procedure for the Mukaiyama aldol reaction (5)
were recorded in the range 4000–400 cmꢀ1 using a KBr pellet
In a dry two-necked RB flask with stopcock placed in an ice/NaCl
technique. 1H NMR and 13C NMR spectra were recorded at
mixture, equipped with a mechanical stirrer, 4 Å molecular sieves,
room temperature on a 400 MHz instrument using CDCl3 as the
2 mL of CH3CN, 10 mmol of trimethylsilyl chloride, 5 mmol of NaI
solvent with TMS as an internal standard. The following
abbreviations were used to designate chemical shift multi-
plicities: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet,
multiplet, br = broad. HRMS analysis was performed using a
double focusing electron impact method. Reactions involving
air- or moisture-sensitive compounds were conducted in appro-
sieves were removed through filtration. HCl solution (1 N, 4 mL)
priate shielded two neck round-bottomed flasks equipped
and 5 mmol of cyclododecanone were added. This mixture was
stirred at ꢀ20 1C for 8 hours. Aldehyde 2 (5 mmol) was added to
the preformed enol silyl ether over the period of 1 minute and
stirring was continued at ꢀ20 1C until the aldehydes were con-
sumed. This process was monitored by TLC. Then 4 Å molecular
was added to the reaction mixture and was stirred at ꢀ20 1C for
with magnetic stirring bars and placed in 4 Å molecular
sieves. CH3CN and DCM were distilled successively from P2O5
and K2CO3.
1–2 min. Saturated NaHCO3 aq solution (4 mL) and water (4 mL)
were added. Next, DCM (10 mL ꢂ 2) was added and the aqueous
layer was extracted with DCM. The organic layer was dried over
anhydrous Na2SO4 and the solvent was removed under vacuum to
give the crude residue, which was finally subjected to column
chromatography (hexane/ethylacetate). This produced the expected
product in moderate to good yield as indicated in Table 3.
Synthesis of 2-((2-bromophenyl)(hydroxy)methyl)cyclododec-
anone (5h).
Experimental section
Illustrative procedure for the preparation of the enone (3a–q)
4 Å molecular sieves, 2 mL of CH3CN, 10 mmol of trimethylsilyl
chloride and 5 mmol of cyclododecanone were placed in a dry,
two-necked RB flask with stopcock, equipped with a mechan-
ical stirrer. The mixture was stirred at room temperature for
18 hours. Aldehyde (5 mmol) was added to the preformed
intermediate over a period of 1 minute and stirring was
continued at 35–40 1C, until the aldehyde was consumed. This
The crude product was subjected to column chromatography on
process was monitored by TLC. Then 4 Å molecular sieves were
a silica gel (4: 1 n-hexane/ethylacetate) to afford the Mukaiyama
removed through filtration. HCl solution (1 N, 4 mL) was added
aldol product 5 h (1.32 g, 72%, dr = 98/2); Rf 0.7 (4 : 1 hexane :
to the reaction mixture and stirred at 35–40 1C for 1–2 min.
EtOAc); Mp: 136–138 1C; FT-IR (KBr) n = 3402.0 (OH), 3052.7,
Saturated NaHCO3 aq solution (4 mL) and water (4 mL) were
2929.7, 2852.7, 1685.1 (CQO), 1589.9, 821.0, 730.4, 599.6.
added. DCM (10 mL ꢂ 2) was added, and the aqueous layer was
extracted with DCM. The organic layer was dried over anhy-
drous Na2SO4 and the solvent was removed under vacuum to
give the crude residue, which was then subjected to column
chromatography (hexane/ethylacetate) to give the expected
product in moderate to good yield as indicated in Table 2.
Synthesis of (E)-1-(2-bromobenylidene)cyclododecanone (3h).
1H NMR (400 MHz, CDCl3): d = 7.57–7.55 (d, J = 8 Hz, 1H, CHAr);
7.45–7.43 (d, J = 8 Hz, 1H, CHAr); 7.36–7.33 (m, 1H, CHAr); 7.18–
7.15 (t, 14 Hz, 1H, CHAr); 5.24 (s, 1H, b-CHchiral), 3.22 (s, 2H,
CH2ali), 2.56–2.50 (dd, J = 15.2, 8.8 Hz, 1H, CH2ali); 2.33–2.27
(dd, J = 14, 4 Hz, 1H, CH2ali), 1.87–1.86 (d, J = 4 Hz, 1H, CH2ali
)
1.72 (bs, 1H, b-OH); 1.64 (bs, 1H CH2ali); 1.64–1.48 (bs, 1H,
CH2ali); 1.32 (bs, 14H, CH2ali). 13C NMR (100 MHz, CDCl3): d =
215.6 (CQO), 141.4, 132.9, 129.2, 128.0, 127.9, 122.6, 74.1
(b-CHchiral), 56.7 (a-CHchiral), 40.6 (a0-CH2), 28.0, 26.3, 25.6,
24.5, 24.4, 24.2, 23.8, 22.6, 21.7. HRMS (EI) m/z: calc. for
C19H27BrO2 366.1194 [M]+; found 366.1189.
The crude product was subjected to column chromatography on
a silica gel (n-hexane/EtOAc, 8/2) to afford the enone product 3 h
(1.29 g, 74% E/Z = 98/2), Rf 0.6 (n-hexane/EtOAc, 4/1); mp: 111–
113 1C; ref. 25 FT-IR (KBr) n = 3064.8, 2938.1, 2860.8, 1661.5
(CQO), 1464.8, 765.7, 742.3. 1H NMR (400 MHz, CDCl3): d =
7.56–7.54 (d, J = 8 Hz, 1H, CHAr); 7.33 (bs, 1H, CHvinylic); 7.27–
7.23 (t, J = 16 Hz, 1H, CHAr); 7.19–7.17 (d, J = 8 Hz, 1H, CHAr),
7.13–7.09 (t, J = 17.6 Hz, 1H, CHAr), 2.80–2.77 (t, J = 13.6 Hz, 2H,
CH2ali); 2.46–2.43 (t, J = 11.2 Hz, 2H, CH2ali); 1.81 (bs, 2H, CH2ali);
1.24–1.16 (m, 13H, CH2ali); 1.04 (bs, 2H, CH2ali). 13C NMR
(100 MHz, CDCl3): d = 205.6 (CQO), 142.8 (CQC ali-ring),
138.1, 136.6 (CQCvinylic), 132.6, 130.5, 129.4, 127.1, 124.0, 38.8
(a0-CH2), 26.6, 26.5, 25.4, 24.4, 24.2, 24.1, 24.0, 23.1, 22.6. HRMS
(EI) m/z: calc. for C19H25BrO 348.1089 [M]+; found 348.1086.
Acknowledgements
VS thanks VIT University, Tamilnadu, India, for providing
Research Associate fellowship. The FIST NMR facility at VIT is
greatly acknowledged. The authors thank the VIT management for
providing necessary facilities. VS thanks Dr V. Krishnan, NISER,
for giving an opportunity to do the postdoctoral research at his lab.
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