A Scalable Protocol for the Regioselective Alkylation of 2-Methylcyclohexane-1,3-dione with Unactivated sp3 Electrophiles

Article abstract of DOI:10.1055/s-0035-1560186

A method for the C-selective alkylation of 2-methylcyclohexane-1,3-dione with unactivated sp³ electrophiles is accomplished via alkylation and subsequent deprotection of the derived ketodimethyl hydrazones. The present method provides a high-yielding entry to dialkyl cycloalkanones that cannot be accessed via direct alkylation of 2-methylcyclohexane-1,3-dione. The title reaction may be useful in the scalable preparation of terpene and steroidal building blocks in the arena of natural product synthesis.

Full text of DOI:10.1055/s-0035-1560186

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2293–2295
letter
2293
R. J. Sharpe et al.
Letter
Synlett
A Scalable Protocol for the Regioselective Alkylation of 2-Methyl-
cyclohexane-1,3-dione with Unactivated sp3 Electrophiles
Robert J. Sharpe
Maribel Portillo
Robert A. Vélez
Jeffrey S. Johnson*
1) KH, THF
–78 to 0 °C then
Me2N
N
O
Me
Me
I
10 examples
up to 89% yield
complete
Me
O
Me
Me
2) Cu(OAc)2
THF–H2O (1:1), r.t.
Department of Chemistry, University of North Carolina at
Chapel Hill, Chapel Hill, NC 27599-3290, USA
jsj@unc.edu
C-selectivity
O
Me
11 g scale
10.34 g
76% (two steps)
single purification
Received: 20.07.2015
Accepted after revision: 12.08.2015
Published online: 21.08.2015
(a) alkylation of 1 with unactivated sp3 electrophiles
R
O
O
O
DOI: 10.1055/s-0035-1560186; Art ID: st-2015-r0564-l
Me
R
Me
Me
base, solvent
+
Abstract A method for the C-selective alkylation of 2-methylcyclohex-
ane-1,3-dione with unactivated sp3 electrophiles is accomplished via al-
kylation and subsequent deprotection of the derived ketodimethyl hy-
drazones. The present method provides a high-yielding entry to dialkyl
cycloalkanones that cannot be accessed via direct alkylation of 2-meth-
ylcyclohexane-1,3-dione. The title reaction may be useful in the scal-
able preparation of terpene and steroidal building blocks in the arena of
natural product synthesis.
R
O
O
O
X
minor
1
major
(b) alkylation of 1,3-cyclohexadienes (ref. 4)
1) t-BuLi, THF, –78 °C
then R2–X
HMPA (1 equiv)
O
OMe
R1
R2
C-selective
R1
Key words alkylation, regioselectivity, hydrazones, ketones, alkyl ha-
lides, steroids, terpenoids
2) HCl(aq.), acetone
O
OMe
3
2
The 2,2-dialkylcyclohexane-1,3-dione subunit has seen
widespread use as a building block in the preparation of
terpene and steroidal natural products.1 The preparation of
these compounds is often accomplished via the alkylation
of 2-methylcyclohexane-1,3-dione (1, Scheme 1) with acti-
vated sp3 electrophiles (e.g., MeI, H2C=CHCH2Br, BnBr, etc.)
or π-electrophiles (e.g. α,β–unsaturated carbonyls). While
alkylation with these electrophiles is efficient, the alkyla-
tion of 1 with unactivated sp3 electrophiles is a significant
challenge due to preferential O-alkylation in these cases,
limiting the effectiveness of this method in target-oriented
synthesis.2 While a number of methods directed toward C-
selective alkylation of 1 have been described,3 these meth-
ods have been primarily limited to activated alkyl electro-
philes. Piers and others have described preparation of 2,2-
dialkylcyclohexane-1,3-diones 3 via alkylation and hydro-
lysis of 1,5-dimethoxy-1,4-cyclohexadienes 2;4 however,
the stoichiometric requirements of t-BuLi and HMPA limit
scalability and practicality of this protocol.
(c) this work
1) KH, THF
Me2N
O
Me
N
–78 to 0 °C
then R–X
R
O
C-selective
Me
O
2) hydrolysis
5
4
Scheme 1 C-Selective alkylations of 2-alkylcyclohexane-1,3-diones
and their derivatives
As part of a research problem in our previously de-
scribed total synthesis of the indole diterpenoid paspaline,5
we required an efficient and scalable alkylation of 1 or its
derivatives. We were encouraged by the work of Enders and
co-workers,3d,6 which demonstrated C-selective alkylation
of cyclic ketohydrazones 4 with activated electrophiles
(MeI, HC≡CCH2Br, BnBr, EtO2CCH2Br) and EtI. We found that
ketohydrazone 4 gave exclusively C-alkylation even with
more hindered and functionalized electrophiles; subse-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2293–2295

2294
R. J. Sharpe et al.
Letter
Synlett
quent hydrolysis gave the desired diones 5. Herein, we de-
scribe this extension as a scalable protocol for the prepara-
tion of 2,2-dialkylcyclohexane-1,3-diones for use in the
arena of natural product synthesis.
THF]7 or upon treatment with Oxone in aqueous acetone.8
Employing these conditions, alkylation of 4 with 1-iodooc-
tane (entry 1) gave exclusively C-alkylation in 92% yield,
which upon hydrolysis, gave diketone 5a in 97% yield (89%,
two steps). Extending the carbon chain in the alkyl iodide
(entries 2 and 3) gave the same C-alkylation selectivity in
slightly decreased yields. Alkenyl halides (entries 4 and 5)
also performed well (78% and 92%, respectively), which
upon hydrolysis provided diketones 5d,e bearing valuable
functional handles. Alkylation of 4 with an iodide bearing a
protected hydroxyl group (entry 6) also underwent effi-
cient alkylation (73%, two steps), although the analogous
protected aminoiodide (entry 7) failed to react with 4 un-
der any conditions examined. Secondary alkyl halides (en-
try 8) also underwent alkylation with complete C-regiose-
lectivity, albeit in decreased yields (42%, two steps) to give
diketone 5h. Furthermore, alkyl bromides (entries 9–11)
also underwent C-selective alkylation. The alkyl bromide
bearing an electrophilic epoxide functionality (entry 11)
underwent alkylation (and not the undesired epoxide
opening) to give the corresponding diketone upon hydroly-
sis (52%, two steps).
To demonstrate the scalability of this protocol, the reac-
tion of ketohydrazone 4 with 5-iodo-2-methylpent-2-ene
was carried out on an 11.00 gram (65 mmol) scale with
complete C-alkylation selectivity (Scheme 2); the sequence
provided >10 grams (76% yield) of diketone 5d over two
steps. Notably, purification of the intermediate alkylated
hydrazone was omitted, enabling preparation of 5d requir-
ing only a single purification. Compound 5d is a critical in-
termediate in our previously described total synthesis of
paspaline.5
Table 1 Substrate Scope of the Alkylation/Hydrolysis of Ketohydra-
zone 4a
Me2N
O
N
Me
1) KH, THF, 0 °C
R
O
Me
O
then R–X, –78 °C to r.t.
2) hydrolysis
(method 1 or 2)
4
5
Entry
Alkyl halide
Product
Alkylation
Hydrolysis
method
yield (%)b
(yield, %)c
1
2
3
5a
5b
5c
92
81
90
1d (97)
1 (81)
1 (81)
Me
Me
I
I
I
7
9
11
Me
Me
I
I
4
5
5d
5e
78
92
1 (91)
1 (80)
Me
Me
TBSO
PhthN
6
7
5f
90
0
1 (81)
–
I
5g
I
Me
8
5h
5i
67
68
94
2e (63)
1 (78)
2 (80)
1) KH, THF
–78 to 0 °C then
Me
I
Me2N
Me
N
O
9
Me
Br
I
Me
Me
O
Me
EtO
Br
10
5j
Me
2) Cu(OAc)2
THF–H2O (1:1), r.t.
O
O
O
4
5d
10.34 g
Me
11 g scale
76% (two steps)
single purification
Me
11
5k
67
1 (77)
Br
Me
Scheme 2 Large-scale synthesis of dialkyldiketone 5d (10 g scale)
a Yields refer to isolated analytically pure products. Yields are reported as
averages of at least two experiments.
b Reactions were carried out with 1.0 mmol alkyl halide, 1.5 mmol 4, and
1.5 mmol of KH.
In summary, a practical and scalable alkylation of
2-methyl-1,3-cyclohexanediones using unactivated elec-
trophiles has been enabled via alkylation9 and deprotec-
tion10,11 of the corresponding ketohydrazones. The scalabili-
ty and applicability of this protocol has been demonstrated
via the 10 gram scale synthesis of diketone 5d. This meth-
odology may be useful to synthetic chemists in the prepara-
tion of ‘quaternized’ cyclohexane building blocks for natural
product synthesis.
c Reactions were carried out with 0.5 mmol of intermediate ketohydrazone.
d Method 1: Cu(OAc)2 (2.0 equiv), THF–H2O (1:1), r.t.
e Method 2: Oxone (4.0 equiv), acetone–H2O (1:3), r.t.
A screen of reaction conditions revealed the optimal
protocol: Deprotonation of ketohydrazone 4 with KH in
THF followed by addition of the electrophile provided ac-
cess to the intermediate dialkyl ketohydrazones in good
yields (Table 1). Hydrolysis of the intermediate alkylation
products was completed via Corey’s method [Cu(OAc)2, aq
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2293–2295

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R. J. Sharpe et al.
Letter
Synlett
Acknowledgment
mL). The suspension was transferred to a flame-dried, 10 mL
round-bottomed flask under an atmosphere of N2, and the sus-
pension was cooled to –78 °C. Hydrazone 4 (0.25 g, 1.50 mmol,
1.50 equiv) was dissolved in THF (1.0 mL) and added dropwise
to the KH suspension. The resulting solution was warmed to
0 °C and stirred 4.5 h. The reaction was recooled to –78 °C, and
1-iodooctane (0.18 mL, 1.00 mmol, 1.00 equiv) was added drop-
wise. The mixture was allowed to stir overnight, allowing the
reaction to slowly warm to r.t. as the dry ice bath evaporated.
After 14 h, the reaction was quenched via addition of sat. NH4Cl
aq (4.0 mL), and the mixture was partitioned in a separatory
funnel. The organic layer was separated, and the aqueous layer
was extracted with Et2O (3 × 10 mL). The combined organic
extracts were washed with brine (10 mL), dried with MgSO4
and concentrated in vacuo. The product was purified via flash
chromatography (hexanes–EtOAc, 80:20 to 70:30) to afford the
product ketohydrazone (0.25 g, 91% yield) as a yellow oil.
(10) Typical Procedure for Hydrazone Hydrolysis (Method 1)
A 10 mL round-bottomed flask was charged with Cu(OAc)2·H2O
(0.20 g, 1.00 mmol, 2.00 equiv) and H2O (3.3 mL), and the solu-
tion was allowed to stir until complete dissolution of
Cu(OAc)2·H2O was observed, typically 2 min. The intermediate
ketohydrazone derived from alkylation of 4 with 1-iodooctane
(0.14 g, 0.50 mmol, 1.00 equiv) was dissolved in THF (3.3 mL)
and added to the Cu(OAc)2·H2O solution. The resulting reaction
mixture was allowed to stir until complete conversion of the
starting material was observed by TLC analysis, typically 12 h.
The reaction mixture was concentrated on a rotary evaporator
to remove THF, and the remaining solution was quenched with
sat. NH4Cl aq (5 mL) and diluted with CH2Cl2 (5 mL). The
mixture was partitioned in a separatory funnel, the organic
layer was separated, and the aqueous layer was extracted with
CH2Cl2 (3 × 10 mL). The combined organic extracts were dried
with Na2SO4 and concentrated in vacuo. The product was puri-
fied via flash chromatography (hexanes–EtOAc, 90:10 to 80:20)
to afford diketone 5a (0.12 g, 99% yield) as a yellow oil.
(11) Typical Procedure for Hydrazone Hydrolysis (Method 2)
A 20 mL scintillation vial was charged with acetone (2.0 mL) and
Oxone (1.20 g, 2.00 mmol, 4.00 equiv) with magnetic stirring.
The intermediate ketohydrazone derived from alkylation of 4
with 2-iodopropane (0.11 g, 0.50 mmol, 1.00 equiv) was dis-
solved in acetone (0.7 mL) and transferred to the Oxone solution
at r.t., producing a white suspension. The resulting mixture was
stirred 2 h, whereupon the solution was concentrated on a
rotary evaporator to remove the acetone. The remaining solu-
tion was diluted with H2O (5 mL) and transferred to a separa-
tory funnel. The aqueous layer was extracted with EtOAc (2 × 7
mL) and CH2Cl2 (2 × 7 mL), and the combined organic extracts
were dried with MgSO4 and concentrated in vacuo. The product
was purified via flash chromatography (hexanes–EtOAc, 90:10
to 80:20) to afford diketone 5h (0.051 g, 65% yield) as a yellow
oil.
The project described was supported by Award No. R01 GM084927
from the National Institute of General Medical Sciences. R.J.S. ac-
knowledges an NSF Graduate Research Fellowship and ACS Division of
Organic Chemistry Graduate Fellowship. M.P. acknowledges a fellow-
ship from the McNair Undergraduate Scholars Program. R.A.V. ac-
knowledges support from the NSF REU program (CHE-1460874).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560186.
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References and Notes
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(9) Typical Procedure for Alkylation of 4
KH (30% dispersion in oil, 0.20 g, 1.50 mmol, 1.50 equiv) was
washed free of oil with PE and suspended in anhydrous THF (3.0
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2293–2295