Controllable Skeleton Rearrangement of 3-Substituted Cyclobutanones under Basic Conditions?

Article abstract of DOI:10.1002/cjoc.201900510

Divergent skeleton rearrangements of cyclobutanones under simply basic conditions have been described. The reaction pathway is controlled by the nature of Z group on 3-substituted cyclobutanones, leading to the formation of various lactones, lactams and a

Full text of DOI:10.1002/cjoc.201900510

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Accepted Article
Title: Controllable Skeleton Rearrangement of 3-Substituted Cyclobutanones under
Basic Conditions
Authors: Peng Yan, Qiang Zhou, Jun Chen, Ping Lu*
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DOI: 10.1002/cjoc.
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Controllable Skeleton Rearrangement of 3-Substituted Cyclobutanones
under Basic Conditions
Peng Yan, Qiang Zhou, Jun Chen, Ping Lu*
Research Center for Molecular Recognition and Synthesis, Department of Chemistry, Fudan University, 220 Handan Lu, Shanghai 200433, P. R. China.
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Divergent skeleton rearrangements of cyclobutanones under simply basic conditions have been described. The reaction pathway is
controlled by the nature of Z group on 3-substituted cyclobutanone, leading to the formation of various lactones, lactams and acids.
Preliminary results on enantioselective reaction were also reported.
Background and Originality Content
Scheme 1 Synthesis of bicycle[4.2.0]octane-2,8-dione
Four-membered carbon ring is not only an important motif in
natural products and pharmaceutically active compounds,[1] but
also an important building block in organic synthesis.[2] Due to
inherent high strain of four-membered carbocycles, significant
advances have been achieved in the field of carbon-carbon single
bond cleavage under the catalysis of transition-metal or
organocatalyst over the past decades.[3,4] However enolate
chemistry of cyclobutanone is less studied, arguably due to
instability of the corresponding enol metal intermediate.[5]
a.
Honda
stoichiometric chiral lithium amide
,
approach
n
A-1
-BuLi,
−
TESO
O
TESCl, THF, 100 o
C
Ph
N
H
Ph
ee
67%
92%
yield,
A-1
Ph
Ph
b. Our
intramolecular transacylation
,
plan
O
O
H
O
O
base
R
O
X
−
Z
Enantioselective desymmetric deprotonation of prochiral
ketone provided an efficient approach to synthesis of enantiomeric
enol ether using chiral lithium amide.[6] In the synthesis of lignin
lactones, Honda developed an elegant enantioselective
desymmetrization of 3-substituted cyclobutanone to access chiral
silyl enol ether (Scheme 1a).[7] The reaction of 3-phenyl
cyclobutanone provided the corresponding silyl enol ether in 67%
yield and 92% ee, using stoichiometric lithium (S,S’)-α,α’-
dimethyldibenzylamide (Li-A-1) as a base. Along with our continued
interests in functionalization of existing cyclobutane motif,[8] we
envisioned that desymmetrization reaction of readily available 3-
substituted cyclobutanones would offer an efficient approach to
access bicyclic intermediates via an intramolecular functional group
transfer process (Scheme 1b). These intermediates would be of
important use for the multistep synthesis. For instance, Weiler
developed a photo cycloaddition of dihydropyranone and allene to
access the bicyclo[4.2.0]octane-2,8-dione in the synthesis of
natural product lineatin.[9] However, this photocycloaddition
suffered poor regioselectivity (Scheme 1c). Herein we reported our
observations on the controllable skeleton rearrangement of
cyclobutanones via in-situ generated reactive bicyclic intermediate
under simply basic conditions.
X
O
Z
Me
lineatin
chiral base
enantioselective?
c.
Weiler
,
PCA
[2+2]
+
O
H
O
O
H
O
υ
h
O
+
O
Me
Me
regioselectivity
racemic
poor
Results and Discussion
We initiated our study with the reaction of carbamate 1a
.
Treatment of 1a with superstoichiometric KHMDS under
cryogenic conditions afforded expected transacylation
product trans-2a in the yield of 72% (Table 1, entry 1).
o
Interestingly, using substoichiometric KHMDS at 0 C led to
unexpected rearrangement product 3a in 6% yield, together
with uncharacterized mixture (entry 2). We envisioned that
the product 3a was generated from transacylation product 2a
via retro-Dieckmann condensation (vide infra). Encouraged by
these results, we further screened a series of base reagents
(see SI for more details). Gladly, using the combination of
catalytic amount of potassium phosphate and 18-crown-6 (0.2
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First author et al.
Report
cyclobutanones provided 4,4-disubstituted lactones uneventfully,
regardless of electronic properties of R group (cf. Me and CN). The
structure of 3m was further confirmed by single-crystal X-ray
diffraction analysis.[10] Cyclobutanones (1p-1s, X = CH2) were then
evaluated, and the reaction afforded corresponding
cyclopetanones (3p-3s) in 40-67% yield using K3PO4 as base at 110
equiv), the reaction of 1a in acetonitrile smoothly provided
rearrangement product 3a in 90% yield (entry 5). The
structures of products 2a and 3a were unambiguiously
determined by single-crystal X-ray diffraction analysis.[10]
Table 1. Reaction Optimization.a
oC
methoxycarbonyl)phenylcyclobutanones
in
toluene.
In
addition,
starting
from
(2-
the
O
(1t-1v),
O
O
CO2t-Bu
Ts
rearrangement reactions gave the corresponding 1-indanones (3t-
3v) in good yields (45-68%).
Base
NTs
H
+
N
CO2t-Bu
solvent, temp
H
H
CO2t-Bu
NHTs
Table 3. Substrate Scope of Cyclobutanones 4.a
1a
2a
3a
O
K3PO
18-crown-6
dioxane, 110 o
equiv)
4 (0.5
O
O
X
T (oC)
–78
yield (%)
2a, 72
3a, 6
R
entry
base, solvent
Z
X
C
Z
1
2
KHMDS (3 equiv), THF
KHMDS (0.2 equiv), THF
K3PO4 (1 equiv), CH3CN
K3PO4 (0.5 equiv), CH3CN
K3PO4 (0.2 equiv), CH3CN
R
=
=
X
Z
NTs, NPh, CH
OR'
4
O,
R,
2
5
O
–78 to 0
90
3
4b
5c
3a, 78
3a, 78
3a, 90
O
O
O
O
50
O
O
NTs
Ot-Bu
81%b
CH2
Ph
90
a1a (0.2 mmol) and base (0.2‒3 equiv) in THF or CH3CN at indicated
temperature, see SI for details. b18-crown-6 (0.5 equiv) was used. c18-
crown-6 (0.2 equiv) was used.
OR'
R'
OBn
O
O
O
O
47%c
5h
,
=
=
=
=
=
=
5a
5e
5f
5g
R' Me, 61%
R' Bn, 61%
R' CH2CF3 59%
,
R' t-Bu, 75%
R' Ph, 76%
R' i-Pr, 66%
,
,
,
,
,
5b
5c
,
b
5d
Table 2. Substrate Scope of Cyclobutanones 1.a
,
K3PO
O
equiv)
4 (0.2-1
a4 (0.2 mmol), K3PO4 (0.5 equiv), 18-crown-6 ether, dioxane, 110 oC, see SI
18-crown-6
O
90 oC to 110 o
C
X
Z
R
for more details. bNaH (1 equiv) in THF at 50 oC. cK3PO4 (1 equiv) in PhCH3.
X
=
=
X
Z
NTs, NPh, CH
O
O,
2
R
Z
3
OR', NR'R''
1
O
Cyclobutanones (4a-4h) with one-carbon homologation
were explored as well to test the substrate scope and the
results were summarized in Table 3. With substochiometric
O
O
O
O
O
O
NTs
NPh
OBn
O
O
R
R
R
H
H
K3PO4 (0.5 eq) as base, disubstituted δ-valerolactones (4a
and 4e 4f) could be obtained in 58-78% yield. For substrates
4d and 4g) with tert-butoxy group, stronger base sodium
-4c
Ot-Bu
OMe
O
OBn
OCH2CF3
-
O
O
O
O
b
=
=
3a
3b
R
R
3c R =H,
3e
,
R
3i
3j
65%
,
90%
Me, 85%
40%
51%
,
,
,
,
H,
=H,68%
(
b
3d
R
3f
R
=Me, 82%
=Me, 43%
,
,
3g R= Et,
69%
82%
,
hydride was required to afford lactone 5d and δ-lactam 5g in
higher yield. In addition, cyclohexanone 5h could be furnished
in 47% yield.
=
3h
R
Ph,
,
O
O
O
O
O
O
O
CH2
CH2
CH2
H
R
R
H
R
Scheme 2. More examples of cyclobutanones
N
Ph
OBn
OMe
OMe
O
OMe
45%
O
O
O
O
a
65%
58%b
40%b
=
=
=
=
=
R
H,
R
=Me, 68%
,
3k
R
3m
R
R
3p
R
R
3s
,
3t
,
,
,
,
,
O
H,85%
Me, 82%
H,
H,
Me, 67%
K3PO
4 (0.5
equiv)
C
O
b
CH C 90 o
=
=
Me, 66%
CN,
3l
R
3n
3q
3r
3u
3v
,
,
N,
3
OMe
b
=
=
=
3o
R
R
Ph,
R Ph,
84%
56%
52%
O
,
,
,
O
60%
yield
MeO2C
O
H
Me
Me
Me
Me
6
7
a1 (0.2 mmol), K3PO4 (0.2‒1 equiv), and 18-crown-6 in CH3CN, 90 oC, see SI
O
S
for more details. bPhCH3 as solvent at 110 oC.
b
NaH
equiv)
C
(1.0
,
O
THF 50 o
O
O
H
H
OMe
O
An array of cyclobutanones underwent efficient tandem
transacylation/retro-Dieckmann reactions to afford corresponding
lactams, lactones and cyclic ketones with substoichiometric to
stoichiometric K3PO4 as base (Table 2, 1a-1u). γ-Lactams 3a-3d
could be obtained in moderate to high yields (40-90%) from
cyclobutanones 1a-1d. Higher loading of K3PO4 (1 eq) and elevated
temperature were required in the cases of 1c and 1d. A series of γ-
butyrolactones (3e-3o) was also achieved in 51-85% yield using
catalytic amount of K3PO4. Among them, 3,3-disubstituted
OMe
OMe
S
H
S
O
8
9a
9b
,
3%
65%
,
yield
yield
c
O
O
Me
Cs2CO
equiv)
Me
Me
3 (0.5
THF reflux
Me
H
O
,
O
O
H
Me
OBn
O
OBn
OBn
O
H
Me
O
34%
O
10
11a
11b
17%
yield
,
,
yield
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Chin. J. Chem. 2019, 37, XXX－XXX
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Running title
Chin. J. Chem.
Furthermore, the reaction of cyclobutanone 6, bearing gem-
Scheme 4. More examples of cyclobutanones.
dimethyl group on the side chain, afforded lactone 7 in 60% yield as
a sole product (Scheme 2a). Carbonothiolate 8 gave the lactone
product 9a in 65% yield, together with dihydrofuran-2(3H)-thione
9b in 3% yield when treated with sodium hydride (Scheme 2b).
Meanwhile, cyclobutanone 10, bearing gem-dimethyl group on the
ring moiety, provided two mixtures, i.e., lactones 11a and 11b in 51%
combined yield with a 2:1 ratio (Scheme 2c).
a)
HO
O
KHMDS
(1.5
equiv)
C
−
THF, 78 o
F
O
O
F
O
40%
yield
O
O
O
F
OH
13a
O
F
F
O
KHMDS
equiv)
(3
−
12a
THF, 78 o
C
O
62%
yield
CO2H
Based on the above results, we proposed the following
14a
mechanism (Scheme 3): cyclobutanone
underwent intramolecular nucleophilic addition to afford
intermediate bicyclo[3.2.0]heptane-2,7-dione M-I
nucleophilic attack of Z anion to intermediate cyclobutanone
M-2 led to product
via a retro-Dieckmann process.[11]
1, treated with base,
HO
O
b)
KHMDS
equiv)
C
(1.5
−
THF, 78 o
F
O
O
F
O
O
;
a
F
46%
yield
O
O
OH
13b
KHMDS
THF,
then TMSCHN2
equiv)
(3
F
−
O
78 o
C
F
O
O
3
12b
However, in the cases of Z with poor leaving group ability (eg,
phenyl group), we assumed that intramolecular transacylation
and subsequent intramolecular nucleophilic attack of X anion
CO2Me
14b
47%
yield
over
two steps
c)
O
O
O
KHMDS
to cyclobutanone M-3 provided rearrangement product 3 [12]
.
H
O
equiv)
THF, 78 oC to
rt
(3
−
O
Ph
Ph
+
Treatment of substrates 1b and 1f under standard conditions
(0.4 equiv K3PO4 and 18-C-6) afforded the products 3b (76%)
and 3f (43%) without any dectable crossover products, thus
ruling out the possibility of intermolecular cyclobutanone
opening mode.
CO2tBu
HO
Ph
16a
54% NMR
15
16b
28% NMR
yield
yield
yield
19% isolation
34% isolation
yield
Furthermore, when substrate 17, bearing more hindered
diisopropylcarbamate, was treated with KHMDS, Haller-Bauer
reaction[14] product 18 was isolated without any detectable acyl
transfer reaction. After carefully screening the reaction conditions,
we found trace amount of water was crucial to reproduce this
reaction. When D2O (1.25 equiv) was added into the reaction
mixture, deuterated product 18-D was isolated in high yield with
100% D cooperated at Ca position (eq 1).
Scheme 3. Proposed Mechanism.
O
O
Z
O
O
a
−
X
X
Z
M-2
a
O
Z
base
O
Z
1
3
X
b
O
KHMDS, D O
1)
2
−
O
THF, 78 oC to
r.t.
M-1
O
Z
Z
TMSCHN
b
equiv)
2 (5.0
2)
O
O
72%
D
O
=
MeOH/PhCH3 1/3
0 oC to
r.t.
OMe
O
X
1)
(eq
a
X
O
NiPr2
NiPr2
M-3
74%
yield
D
100%
O
17
O
18-D
over
two steps
Inspired by Honda’s work,[7] we initiated enantioselective
reaction of cyclobutanone 1a using chiral metal amide (eq 2).
We envisioned that if Z was a good leaving group with poor
nucleophilicity, nucleophilic addition to the bicyclic product M-2
would be inhibited. The bicyclo[3.2.0]heptane-2,7-dione was an
important intermediate in many multiple-step syntheses. Along
with this line, we first studied the reaction of cyclobutanone 12 with
pentaflurophenyl group as a good leaving group. Interestingly,
treatment of 12a with 1.5 equivalents of KHMDS provided eight-
membered ring 13a in 40% yield (Scheme 4a). Instead the reaction
gave the acid 14a in 62% yield when 3 equivalents of KHMDS was
used. We assumed that bicyclic intermediate was formed in both
cases, however, due to inherent high reactivity, subsequent
reaction took place immediately.[13] The reaction of homologous
cyclobutanone 12b led to the similar results (Scheme 4b). The
structure of 13a and 13b were unambiguously determined by X-ray
diffraction analysis.[10] Gladly, we were able to isolate desired
bicyclic product 16a when cyclobutanone 15 with poor nucleophile
t-butoxy group was used (Scheme 4c). Of note, we isolated ring-
opening product 16b, indicating the instability of 16a during
isolation (cf. NMR and isolation yield).
Lithium (S,S’)-α,α’-dimethyldibenzylamide
cyclobutanone 1a at
78 oC to form chiral enol lithium
intermediate, which was subsequently transmetalation with
diethyl zinc to generate zinc enolate. After warming to
40 oC,
A deprotonated
‒
‒
we were able to isolate ketoester 2a in 43% yield, together
with unexpected migration byproduct S1 (28% yield, not
shown, see SI). Subsequent treatment of 2a with K3PO4
afforded lactam 3a in 59% yield and 66% ee.
A
(
Ph
)
Ph
N
K3PO
Li
equiv)
equiv)
C
O
N
4 (0.2
18-crown-6
−
THF, 78 o
C
O
(0.2
MeCN, 90 o
O
CO2t-Bu
−
then ZnEt2 40 o
,
C
Boc
NTs
Ts
3a
2)
(eq
NHTs
43%
yield
59%
66%
yield
ee
CO2t-Bu
1a
2a
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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First author et al.
Report
For recent reviews, see: (a) Seiser, T.; Saget, T.; Tran, D. N.; Cramer, N.
Cyclobutanes in Catalysis. Angew. Chem., Int. Ed. 2011, 50, 7740–7752.
(b) Wang, L.; Tang, Y. Asymmetric Ring ‐ Opening Reactions of
Donor‐Acceptor Cyclopropanes and Cyclobutanes. Isr. J. Chem. 2016,
56, 463–475. (c) Carreira, E. M.; Fessard, T. C. Four-Membered Ring-
Containing Spirocycles: Synthetic Strategies and Opportunities. Chem.
Rev. 2014, 114, 8257–8322. (d) Mack D. J.; Njardarson, J. T. Recent
Advances in the Metal-Catalyzed Ring Expansions of Three- and Four-
Membered Rings. ACS Catal. 2013, 3, 272–286.
Conclusions
In conclusion, we reported here divergent skeleton
rearrangements of cyclobutanones under simply basic
conditions. Various products could be furnished, tunable by
functional group Z and different basic conditions. Preliminary
enantioselective reaction was also studied using chiral metal
amide.
For selected reviews, see: (a) Funk, R. L.; Vollhardt, K. P. C. Thermal,
Photochemical, and Transition-Metal Mediated Routes to Steroids by
Intramolecular Diels–Alder Reactions of o-Xylylenes (o-
Quinodimethanes). Chem. Soc. Rev. 1980, 9, 41–61. (b) Michellys, P.-
Y.; Pellissier, H.; Santelli, M. Cycloadditions of ortho-Quinodimethanes
Derived from Benzocyclobutenes in Organic Synthesis. Org. Prep. Proc.
Int. 1996, 28, 545–608. (c) Chen, P.-H.; Billett, B. A.; Tsukamoto, T.;
Dong, G. “Cut and Sew” Transformations via Transition-Metal-
Catalyzed Carbon–Carbon Bond Activation. ACS Catal. 2017, 7, 1340–
1360. (d) Murakami, M.; Ishida, N. Potential of Metal-Catalyzed C–C
Single Bond Cleavage for Organic Synthesis. J. Am. Chem. Soc. 2016,
138, 13759–13769. (e) Fumagalli, G.; Stanton, S.; Bower, J. F. Recent
Methodologies That Exploit C–C Single-Bond Cleavage of Strained Ring
Systems by Transition Metal Complexes. Chem. Rev. 2017, 117, 9404–
9432.
For recent examples, see: (a) Deng, L.; Fu, Y.; Lee, S. Y.; Wang, C.; Liu,
P.; Dong, G. Kinetic Resolution via Rh-Catalyzed C–C Activation of
Cyclobutanones at Room Temperature. J. Am. Chem. Soc. 2019, 141,
16260–16265. (b) Ambler, B. R.; Turnbull, B. W. H.; Suravarapu, S. R.;
Uteuliyev, M. M.; Huynh, N. O; Krische, M. J. Enantioselective
Ruthenium-Catalyzed Benzocyclobutenone–Ketol Cycloaddition:
Merging C–C Bond Activation and Transfer Hydrogenative Coupling for
Type II Polyketide Construction. J. Am. Chem. Soc. 2018, 140, 9091–
9094. (c) Zhao, H.; Fan, X.; Yu, J.; Zhu, C. Silver-Catalyzed Ring-
Opening Strategy for the Synthesis of β- and γ-Fluorinated Ketones. J.
Am. Chem. Soc. 2015, 137, 3490–3493 (d) Zhang, K.; Chang, L.; An, Q.;
Wang, X.; Zuo, Z. Dehydroxymethylation of Alcohols Enabled by
Cerium Photocatalysis. J. Am. Chem. Soc. 2019, 141, 10556–10564. (e)
Yu, X.-Y.; Chen, J.-R.; Wang, P.-Z.; Yang, M.-N.; Liang, D.; Xiao, W.-J. A
Visible‐Light‐Driven Iminyl Radical‐Mediated C−C Single Bond
Cleavage/Radical Addition Cascade of Oxime Esters. Angew. Chem., Int.
Ed. 2018, 57, 738–743. (f) Zhao, J.-F.; Duan, X.-H.; Gu, Y.-R.; Gao. P.;
Guo, L.-N. Iron-Catalyzed Decarboxylative Olefination of Cycloketone
Oxime Esters with α,β-Unsaturated Carboxylic Acids via C–C Bond
Cleavage. Org. Lett. 2018, 20, 4614–4617. (g) Souillart, L.; Cramer, N.
Regiodivergent Cyclobutanone Cleavage: Switching Selectivity with
Different Lewis Acids. Chem. Eur. J. 2015, 21, 1863–1867.
Experimental
General Procedure I. An oven-dried screw tube was
charged with K3PO4 (0.2 to 1.0 equiv), 18-crown-6 (0.2 to 1.0
equiv). Then appropriate cyclobutanone (0.2 mmol) was
added via syringe in 4 mL of solvent. The reaction mixture was
stirred for several hours at appropriate temperature till
completion (monitored by TLC). The reaction mixture was then
filtered through a pad of celite, concentrated under vacuum,
and the residue was purified by column chromatography on
silica gel to afford the pure product.
General Procedure II. To an oven-dried Schlenk tube was
added KHMDS and THF (1 mL) under Ar, followed by the
introduction of substrate (0.4 mmol) in THF via a syringe at –
o
o
78 C. The resulting mixture was stirred at –78 C for several
hours before quenched with 5 mL of a saturated aqueous
solution of NH4Cl and 5 mL of H2O. The mixture was extracted
with ethyl acetate, and the combined organic phase was
washed with brine, dried over Na2SO4, concentrated, and the
residue was purified by column chromatography on silica gel
to afford the title product.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Acknowledgement
This work was supported by National Natural Science
Foundation of China (21772024, 21921003), 1000-Youth Talents
Program and Fudan University (for the start-up grant). We thank
Prof. H.-Y. Fang for assistance with X-ray crystallography.
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Running title
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(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
CCDC 1958087 (3a) 1958088 (2a), 1958089 (13a), 1958090 (13b) and
1958104 (3m). See Supporting Information for details.
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Chin. J. Chem. 2019, 37, XXX－XXX
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First author et al.
Report
Entry for the Table of Contents
HO
O
O
KHMDS
K PO
eq)
C
eq)
C
(1.5
4 (0.2
Page No.
3
−
THF, 78 o
CH3CN, 90 o
O
O
O
=
=
Z
Z
OMe
O
40%
yield
Controllable Skeleton Rearrangement of
3-Substituted Cyclobutanones under
Basic Conditions
82%
yield
O
=
OH
Z
OC6F5
COOMe
KHMDS/D2O
−
KHMDS
THF, 78 o
C
O
eq)
(3
C
O
O
O
−
THF, 78 o
D
then TMSCHN2
Ni-Pr2
Z
OMe
O
62%
OH
74%
yield
yield
O
Ni-Pr2
D
O
O
A divergent skeleton rearrangement of cyclobutanones under simply basic conditions have been
described. The reaction pathway is controlled by the nature of Z group on 3-substituted
cyclobutanone, leading to the formation of various lactones and lactams and acids. Preliminary
results on enantioselective reaction were also reported..
Peng Yan, Qiang Zhou, Jun Chen, Ping Lu*
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© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.