New methylene homologation method for cyclic ketones

Article abstract of DOI:10.1002/chem.201201346

Teaching new tricks to an old dog: By intercepting adducts between ketones and lithium trimethylsilyldiazomethane, a new Tiffeneau-Demjanov type methylene homologation could be realized in a single-step operation. Among proton sources and Lewis acids, silica gel was found to be the most effective reagent for the protonation of intermediates and their subsequent ring expansion (see scheme). Copyright

Full text of DOI:10.1002/chem.201201346

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DOI: 10.1002/chem.201201346
New Methylene Homologation Method for Cyclic Ketones
Huaqing Liu,[a] Chunrui Sun,[a] Nam-Kyu Lee,[a] Roger F. Henry,[b] and Daesung Lee*[a]
Ketones of carbocyclic and heterocyclic structures are piv-
otal for serving not only as a platform to develop new syn-
thetic methods but also as building blocks for the synthesis
of natural and medicinally important compounds.[1] One of
the transformations involving cyclic ketones is a one-carbon
insertion between the carbonyl carbon and its a-carbon
(methylene homologation). Various forms of methylene ho-
mologation methodology have been developed whereby
readily available ketone starting materials can be trans-
formed to the corresponding ring-expanded products.
Among these, the Tiffeneau–Demjanov reaction [Eq. (1)][2]
the similar reactivity of starting ketones and the homologat-
ed products.[4] On the other hand, the Tiffeneau–Demjanov
reaction, although it ensures the mono-homologation, re-
quires at least three steps to generate the key reactive inter-
mediates.[5] Only a few improved protocols that operate
under the Tiffeneau–Demjanov regime have emerged over
the years,[5,6] whereas extensive development of the Lewis
acid-catalyzed formation employing diazo compounds have
been made.[7]
To exploit the favorable features of both the Tiffeneau–
Demjanov and Lewis acid-catalyzed reactions, we envision
an alternative approach in which the weakly nucleophilic
diazo compound, such as trimethylsilyldiazomethane
(TMSD), will be activated to its lithiated form [LTMSD;
Eq. (3)]. This strongly nucleophilic reagent[8] should comple-
ment the low nucleophilicity of neutral diazomethane in the
Lewis acid-promoted approach, and thus would make its
substrate scope broader. Furthermore, in this anion-activat-
ed mode of reaction, the expected ring expansion would
occur only after protonation of the anionic adduct, whereby
a high fidelity of mono-homologation can be realized.
Herein we report an efficient single methylene homologa-
tion of a broad range of both symmetrical and asymmetrical
cyclic ketones by adding LTMSD followed by treatment
with silica gel as a mild proton source and promoter of ring
expansion.
and
a
Lewis-acid promoted diazomethane addition
[Eq. (2)][3] are two prototypes (Scheme 1). Each method has
its merits and shortcomings. The Lewis acid-catalyzed inser-
tion of diazo compounds, despite its favorable one-step op-
eration, sometimes renders multiple homologation due to
We commenced our investigation by examining the proto-
nation behavior of an anionic intermediate generated from
cyclohexanone derivative 1 and LTMSD (Scheme 2). In
light of the studies of Schçllkopf,[9] Magnus,[10] and Aggar-
wal[11] on related systems, we expected that two different
modes of protonation would occur for equilibrating species
Scheme 1. Methylene homologation by the Tiffeneau–Demjanov reac-
tion, a Lewis acid-catalyzed insertion of diazomethane, and addition of
LTMSD.
[a] H. Liu, C. Sun, N.-K. Lee, Prof. Dr. D. Lee
Department of Chemistry, University of Illinois at Chicago
845 West Taylor Street, Chicago, Illinois 60607 (USA)
Fax : (+1) 312-996-0431
E-mail: dsunglee@uic.edu
[b] Dr. R. F. Henry
Global Pharmaceutical Research and Development
Abbott Laboratories, 100 Abbott Park Road
Abbott Park, Illinois 60064-3500 (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201346.
Scheme 2. O- versus C-protonation and subsequent rearrangement.
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Table 1. Efficiency of ring expansion with various acids.
2 and 2’ depending on the nature of proton sources. Schçll-
kopf and Magnus showed that a selective O-protonation fol-
lowed by spontaneous rearrangement of the O-protonated
diazo compounds, providing epoxides related to 4 [Eq. (4)].
In contrast, Aggarwal observed a selective C-protonation
with methanol. Based on these observations, we predicted
that 2 and 2’ would undergo a selective C-protonation with
methanol to generate 5, which upon another protonation
with a stronger acid at the carbenic carbon would provide
ring-expanded product 6a [Eq. (5)].
To test this hypothesis, we screened various proton sour-
ces that have their pKa values ranging from 2.9
(ClCH2CO2H) to 16.5 (MeOH) to gain information about
their effects on the O- versus C-protonation and the subse-
quent ring expansion. From a series of experiments, a strong
correlation between the acidity of the proton sources and
the ratio of 4 and 6a has emerged (Figure 1). In general, the
formation of ring-expanded product 6a increases whereas
that of epoxide 4 decreases as the pKa value of the proton
source increases.[12]
Entry
Acid/conditions
Yield 4 [%][a]
Yield 6a [%][a]
1
2
3
4
5
6
7
8
9
H3CCO2H/CH2Cl2
F3CCO2H/CH2Cl2
Cl3CCO2H/CH2Cl2
HCl/aq THF
BF3·OEt2/CH2Cl2
SnCl4/CH2Cl2
27
0
63
37
49
45
27
47
47
78
84
trace
trace
0
trace
trace
3
TiCl4/CH2Cl2
Sm
ACHTUGNERTN(NUNG OTf)3/CH2Cl2
silica gel/THF
0
[a] Isolated yields; diazo compound 5 was generated by aqueous workup
and used without purification.
silica gel-promoted ring expansion (Table 2). Cyclohexanone
derivatives with a carbon- (1a–e) and heteroatom-based
(1 f) substituent at the C4 position (entry 1–6), piperidinones
1g–h (entries 7–8) and tetrahydropyranone 1i (entry 9) un-
derwent smooth ring-expansion to the corresponding seven-
membered ketones in respectable yields. Adamantanone 1j
also afforded the homologated product 6j in 85% yield
(entry 10). 3-Phenyl cyclobutanone 1k behaved similarly,
and provided the ring expanded product 3-phenyl cyclopen-
tanone 6k in 71% yield (entry 11).
Having established good methylene homologation with
symmetrical ketones, we next examined the selectivity for
unsymmetrical cyclic ketones containing substituent at the
a- and/or b-carbon (Table 3). Complete regioselectivity was
found for selected five to seven membered cyclic ketones.
Among five membered ketones, a-indanone 1l underwent
highly regioselective ring expansion, providing only b-tetra-
lone 6l in 67% yield (entry 1). This selectivity is in line with
the higher migratory aptitude of an aromatic carbon than
aliphatic carbon in a typical process developing cationic
characters along the reaction. On the other hand, two ste-
roids, estrone 1m and formestane 1n, afforded ring-expand-
ed homosteroid products, 6m and 6n, in 86 and 73% yield,
respectively, with exclusive migration of the less substituted
C16 methylene carbon over the more substituted C13 qua-
ternary carbon (entries 2 and 3). The identity of 6m and 6n
was further confirmed by their single crystal X-ray diffrac-
tion analysis.[14] For comparison to the homologation proto-
col developed by Kingbury,[7b] the two homosteroids 6m and
Figure 1. Relationship of the formation of epoxide and ring-expanded
ketone relative to the acidity of proton donors.
To further improve the efficiency for the formation of end
product 6a while minimizing epoxide 4, the ring expansion
behavior of isolated C-protonated diazo compound 5 was in-
vestigated. Assuming that a variety of Brønsted and Lewis
acids will potentially promote the rearrangement, we exam-
ined a set of readily available Brønsted and Lewis acids.
Most of these acids promote the desired ring expansion, but
their efficiency varies significantly (Table 1). Among the
acids examined, SmACHTUNGTRENNUNG(OTf)3 and silica gel stood out, yet silica
gel turned out to be the best reagent. With silica gel as a
proton source and a promoter for ring expansion, the high-
est yield of 6a was realized, and the formation of epoxide 4
was minimized. In a typical experiment, treatment of ketone
1 with LTMSD at À788C, followed by quenching with
MeOH and subsequent purification on silica gel afforded
ring expansion product 6a in 87% yield.[13]
Next, we explored the methylene homologation of a vari-
ety of symmetrical cyclic ketones by applying the protocol
involving MeOH quench at low temperature followed by
6n were homologated with catalytic ScACTHNUTRGENUG(N OTf)3, with 70 and
45% yield, respectively. As expected, a-tetralone 1o and a-
benzylidene cyclohexanone 1p provided the ring-expansion
products 6o and b-benzylidene cycloheptanone 6p with ex-
clusive sp2-carbon migration (entries 4 and 5). a,b-Epoxycy-
clohexanone derivative 1q also afforded single product 6q
through unsubstituted methylene migration (entry 6). a-Sub-
stituted cycloheptanone derivatives 1r and 1s also provided
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Methylene Homologation for Cyclic Ketones
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Table 2. Ring-expansion of symmetrical cyclohexa- and cyclobutanone
derivatives.
Table 3. Selective ring-expansion of unsymmetrical cyclic ketones.
Entry
Starting
ketone
Homologated
product
Yield
[%][a]
1
72
Entry
1
Starting
ketone
Homologated
product
Yield
[%][a]
2
3
86[b]
84
2
3
1b, R=H
1c, R=F
6b, R=H
6c, R=F
86
84
73[b]
4
5
6
1d, R=tBu
1e, R=CO2Et
1 f, R=NHBoc
6d, R=tBu
6e, R=CO2Et
6 f, R=NHBoc
86
84
64
4
5
6
78[b]
7
8
1g, R=CO2Bn
1h, R=Bn
6g, R=CO2Bn
6h, R=Bn
64
68
79
9
72
43
10
11
85
71
7
8
68
85
[a] Isolated yield; quenching the reaction with silica gel or loading the re-
action mixture on silica gel column gave identical results.
homologation products 6r and 6s with excellent selectivity
but an opposite migratory preference (entries 7 and 8). In
the former, the benzyl-substituted carbon migrated, but for
the latter the unsubstituted methylene migration occurred.
To gain further insight into the selectivity of ring expan-
sion for unsymmetrical cyclic ketones, substituted cyclohexa-
none derivatives 1t–z were examined (Table 4). a-Monosub-
stituted cyclohexanones showed varying degrees of selectivi-
ty, ranging from 13:1 to 1:2.3. The b-silyl substituent in 1z to
control the selectivity in the migration of a-carbons in a re-
lated reaction, such as Baeyer–Villiger reaction, is well-
known.[15] Due to a significant b-carbocation stabilizing
effect of the silyl group, we expected that migration of the
methylene near the silyl group should be more favorable to
generate 6z’. b-Silicon effects do exist, yet the preference
turned out to be only modest, affording 1:2.3 ratio of 6z/6z’.
At this point, it is not obvious what factors contribute
most to providing the observed selectivity trend for the ring
expansion of these cyclohexanone derivatives. Nevertheless,
the stereoselectivity for the addition of LTMSD to the car-
bonyl group should be an important factor. An equatorial
[a] Isolated yields. [b] 2.5 equiv LTMSD was used.
attack of LTMSD followed by protonation would lead to
two conformations, eq-syn and eq-anti, that lead to major
and minor products 6 and 6’, respectively (Scheme 3). Simi-
larly, an axial attack would lead to two conformations, ax-
syn and ax-anti, that also lead to the observed products.
Electronic effect should also play a certain role in addition
to the conformational and stereoelectronic effect[16] for the
selectivity, yet its contribution seems to be minimal. The
major product 6 should arise from the migration of the un-
substituted carbon via transition states TSeq-syn and TSax-syn as
opposed to seemingly more favorable transition states TSeq-
and TSax-anti even with cation-stabilizing R substituent
anti
(Table 4, entries 2–5). Therefore, we conclude that the ob-
served selectivity is mainly the consequence of conforma-
tional and stereoelectronic effects where the minimization
+
À À À À
of the syn-pentane-like interaction of N2 C C O SiMe3
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D. Lee et al.
Table 4. Ring expansion of unsymmetrical cyclohexanone derivatives.
tronic effect exerted by the silyl substituent at the
b-carbon (entry 7).
Entry
Starting
ketone
Homologated product
Yield
[%][a]
In conclusion, we have developed a new methyl-
ene homologation method employing unprecedent-
ed nucleophile activation strategy to generate the
pivotal adduct between diazo compounds and ke-
tones. In this study, we recognized strong dependen-
cy of O- versus C-protonation on the pKa values of
proton sources, and the discreet protonation event
controls the fate of the newly formed diazo com-
pounds. We found that silica gel is a very efficient
Brønsted acid and at the same time a Lewis acid to
promote the ring expansion. In contrast to an elec-
trophile activation method, in which the possibility
of multiple homologation exists, the nucleophile ac-
tivation strategy described in this study achieves
high fidelity mono-homologation independent of
substrate structures. Therefore, this new protocol
nicely complements Lewis acid-promoted ring ex-
pansion methods, and overcomes some of the limi-
tations associated with Lewis acid-promoted meth-
ylene homologation, which should be a viable alter-
native for synthetic chemists.
+
1
2
3
4
1t, R=Ph
1u, R=OMe
1v, R=Bn
6t
6u
6v
6w
13:1
2.4:1
1.6:1
0.8:1
6t’
6u’
6v’
6w’
83
52
75
68
1w, R=Me
5
1:1
98
6
7
1.3:1
1:2.3
72
63
[a] Isolated yields.
Experimental Section
Representative procedure for cyclic ketone homologation with
lithium trimethylsilyldiazomethane (LTMSD): Me3SiCHN2 (0.65 mL, 2m
in hexane) was added to a solution of nBuLi (0.56 mL, 2.5m in hexane)
in the anhydrous diethyl ether (5 mL) chilled to À788C. The mixture was
stirred at this temperature for 30 min, a cold solution of substrate ketones
(1 mmol) in THF (2 mL) was added dropwise and the solution was kept
at À788C for another 30 min. MeOH (2 mmol, 0.08 mL) in THF (2 mL)
was added and the dry-ice bath was removed. After being warmed to am-
bient temperature, the mixture was diluted with ether (20 mL), washed
with H2O and brine. The organic phase was treated with anhydrous
Na2SO4 and silica gel (2–4 g) for about 10 min. The solution was filtered
and concentrated under reduced pressure. The residue was chromato-
graphed on silica gel to provide the homologated ketone products.
Acknowledgements
We are grateful to the financial support from the National Science Foun-
dation (CHE 0955972) for this work. We appreciate the support from
Neuroscience Department of Abbott Laboratories for the equipment and
reagents used for this research.
Keywords: homologation
·
ketones
·
methylenes
·
Tiffeneau–Demjanov · trimethylsilyldiazomethane
Scheme 3. Rationale for the selectivity in ring expansion.
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Methylene Homologation for Cyclic Ketones
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Received: April 20, 2012
Published online: && &&, 0000
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D. Lee et al.
Homologation
H. Liu, C. Sun, N.-K. Lee, R. F. Henry,
D. Lee* ........................ &&&& — &&&&
New Methylene Homologation
Method for Cyclic Ketones
Teaching new tricks to an old dog: By
intercepting adducts between ketones
and lithium trimethylsilyldiazome-
thane, a new Tiffeneau–Demjanov
type methylene homologation could be
realized in a single-step operation.
Among proton sources and Lewis
acids, silica gel was found to be the
most effective reagent for the protona-
tion of intermediates and their subse-
quent ring expansion (see scheme).
&
6
&
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!