Catalytic Cyclopropanol Ring Opening for Divergent Syntheses of γ-Butyrolactones and δ-Ketoesters Containing All-Carbon Quaternary Centers

Article abstract of DOI:10.1021/acscatal.8b00711

Catalytic ring opening cross coupling reactions of strained cyclopropanols have been useful for the syntheses of various β-substituted carbonyl products. Among these ring opening cross coupling reactions, the formation of α,β-unsaturated enone byproducts often competes with the desired cross coupling processes and has been a challenging synthetic problem to be addressed. Herein, we describe our efforts in developing divergent syntheses of a wide range of γ-butyrolactones and δ-ketoesters containing all-carbon quaternary centers via copper-catalyzed cyclopropanol ring opening cross couplings with 2-bromo-2,2-dialkyl esters. Our mechanistic studies reveal that unlike the previously reported cases, the formation of α,β-unsaturated enone intermediates is actually essential for the γ-butyrolactone synthesis and also contributes to the formation of the δ-ketoester product. The γ-butyrolactone synthesis is proposed to go through an intermolecular radical conjugate addition to the in situ generated α,β-unsaturated enone followed by an intramolecular radical cyclization to the ester carbonyl double bond. The reactions are effective to build all-carbon quaternary centers and have broad substrate scope.

Full text of DOI:10.1021/acscatal.8b00711

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Article
Catalytic Cyclopropanol Ring Opening for Divergent Syntheses of #-
Butyrolactones and #-Ketoesters Containing All-Carbon Quaternary Centers
Zhishi Ye, XINPEI CAI, Jiawei Li, and Mingji Dai
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00711 • Publication Date (Web): 11 May 2018
Downloaded from http://pubs.acs.org on May 11, 2018
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Page 1 of 9
ACS Catalysis
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Catalytic Cyclopropanol Ring Opening for Divergent Syntheses of γ-
Butyrolactones and δ-Ketoesters Containing All-Carbon Quaternary
Centers
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Zhishi Ye,† Xinpei Cai,† Jiawei Li, and Mingji Dai*
Department of Chemistry, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, West Lafayette,
IN 47907, United States.
† Contributed equally.
Supporting Information Placeholder
ABSTRACT: Catalytic ring opening cross coupling reactions of strained cyclopropanols have been useful for the syntheses of
various βꢀsubstituted carbonyl products. Among these ring opening cross coupling reactions, the formation of α,βꢀunsaturated
enone byproducts often competes with the desired cross coupling processes and has been a challenging synthetic problem to be
addressed. Herein, we describe our efforts in developing divergent syntheses of a wide range of γꢀbutyrolactones and δꢀketoesters
containing allꢀcarbon quaternary centers via copperꢀcatalyzed cyclopropanol ring opening cross couplings with 2ꢀbromoꢀ2,2ꢀdialkyl
esters. Our mechanistic studies reveal that unlike the previously reported cases, the formation of α,βꢀunsaturated enone intermediꢀ
ates is actually essential for the γꢀbutyrolactone synthesis and also contributes to the formation of the δꢀketoester product. The γꢀ
butyrolactone synthesis is proposed to go through an intermolecular radical conjugate addition to the in situ generated α,βꢀ
unsaturated enone followed by an intramolecular radical cyclization to the ester carbonyl double bond. The reactions are effective
to build allꢀcarbon quaternary centers and have broad substrate scope.
KEYWORDS: cyclopropanol, copper catalysis, ring opening, γ-butyrolactone, δ-ketoester, α,β-unsaturated enone, quaternary
carbon
INTRODUCTION
elimination process in palladiumꢀcatalyzed cyclopropanol ring
opening cross couplings.7
Cyclopropanols, readily available from the Kulinkovich
protocol or the SimmonsꢀSmith reaction, are prone to undergo
various ring expansion1 and ring opening2 reactions due to the
intrinsic strain in the threeꢀmembered ring system. For examꢀ
ple, cyclopropanol ring opening cross coupling reactions proꢀ
moted by various transition metal catalysts3 or single electron
transferring (SET) oxidants4 have been utilized to synthesize a
wide range of βꢀsubstituted ketone products including those
embedded in complex natural products and lifeꢀsaving drug
molecules (Figure 1A). In general, these processes go through
either a metalloꢀhomoenolate (2) or a βꢀalkyl radical intermeꢀ
diate (3) and substituents including aryl, alkyl, alkynyl,
alkenyl, acyl, halogen, nitrile, azide, amine, and others can be
installed at the βꢀcarbon (cf. 4). In these ring opening cross
coupling processes, transition metal such as palladiumꢀ
promoted βꢀH elimination5 of the metalloꢀhomoenolate 2 and
over oxidation6 of the βꢀalkyl radical intermediate 3 are two
serious competing reaction pathways that can result in the
formation of α,βꢀunsaturated enone byproducts (5). Many
efforts have been invested to avoid these side reaction pathꢀ
ways and prevent the formation of the enone byproducts. For
example, various ligands have been used to suppress the βꢀH
To address the issues of α,βꢀunsaturated enone byproduct
formation, we have developed a series of copperꢀcatalyzed
cyclopropanol ring opening cross coupling reactions such as
trifluoromethylation, trifluoromethylthiolation, amination, and
(fluoro)alkylation (Figure 1B).8 The use of copper catalysts
helps to reduce the formation of the enone products in these
oxidative ring opening cross couplings because copper cataꢀ
lysts are less prone to βꢀH elimination in comparison to pallaꢀ
dium catalysts. We also developed a novel palladiumꢀ
catalyzed cyclopropanol ring opening carbonylation to syntheꢀ
size oxaspirolactions9 as well as manganeseꢀmediated oxidaꢀ
tive cyclopropanol ring opening tandem radical cyclizations to
synthesize Nꢀheterocycles.10 In the carbonylation chemistry,
the βꢀH elimination process is reduced because carbon monoxꢀ
ide can occupy the empty orbitals on the palladium center
which are required for βꢀH elimination. In the manganeseꢀ
mediated oxidative cyclopropanol ring opening radical cycliꢀ
zations, highly reactive radical acceptors such as isonitriles
and electronꢀdeficient double bonds were used to trap the βꢀ
alkyl radical intermediate generated in situ before over oxidaꢀ
tion or dimerization occurs.
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ACS Catalysis
In our continuing interest of developing copperꢀcatalyzed
Page 2 of 9
formation of γꢀbutyrolactone 12 was very exciting because this
process not only built a CꢀC bond with an allꢀcarbon quaterꢀ
nary center, but also a CꢀO bond to form a γꢀbutyrolactone. At
this stage, we speculated that the formation of 12 might be a
continued copperꢀcatalyzed formal CꢀH oxidative lactonizaꢀ
tion13 after the formation of 13, which was eventually proved
not to be the case as we continued our investigation. Nevertheꢀ
less, this interesting observation as well as the importance of
γꢀbutyrolactones in natural products and other bioactive moleꢀ
cules14 prompted us to establish a general procedure to enable
efficient access of γꢀbutyrolactone products from readily
available cyclopropanols and αꢀbromoesters directly. Our
continuing reaction condition optimization revealed that the
addition of 1.0 equiv. of KI dramatically increased the yield
for the formation of 12 (63%) and 13 (10%, entry 2). After
evaluating different bases, copper catalysts, and ligands, we
learned that (i) K2CO3 was superior to other bases such as
KHCO3, Na2CO3, NaHCO3, and Cs2CO3; (2) Cu(OTf)2 was
more effective than CuI, CuCl2, and CuBr; (3) Phen was better
than other nitrogenꢀbased chelating ligands (L1-6) we exꢀ
plored. Slightly increase the amount of 11 to 4.5 equiv. was
able to enhance the formation of 12 in 82% yield (80% isolatꢀ
ed yield) and reduce the formation of 13 to 6% yield (entry
16). The need for an excess amount of 11 is because it serves
as both the cross coupling partner and the terminal oxidant in
the lactonization process. During these investigations, we also
learned that switch base from K2CO3 to KOAc (entry 17) proꢀ
duced 13 as the major product in 64% yield with 9% of 12.
This observation offered an opportunity to develop a divergent
approach to produce either 12 or 13 as the dominant product
as needed. We then switched to organic bases and discovered
that the yield of 13 could be improved to 71% with diisopropꢀ
ylamine (iPr2NH, entry 18). After a quick evaluation of several
copper catalysts and ligands and reducing the amount of 11 to
3.0 equiv., product 13 was produced in 78% yield (73% isolatꢀ
ed yield, entry 25) with 12% yield of 12 by using a combinaꢀ
tion of CuCl (0.1 equiv.) and L5 (0.2 equiv.). Further decreasꢀ
ing the amount to 11 to 2.0 equiv. only slightly reduced the
yield of 13 to 75% (entry 26). Products 12 and 13 can be sepaꢀ
rated readily by flash column chromatography on silica gel.
1
cyclopropanol ring opening cross coupling reactions, we wonꢀ
dered the possibility of building allꢀcarbon quaternary centers
via cyclopropanol ring opening alkylꢀalkyl cross couplings
with 2ꢀbromoꢀ2,2ꢀdialkylesters (Figure 1C). Allꢀcarbon quaꢀ
ternary centers, while prevalently exist in many functional
molecules including bioactive natural products, smallꢀ
molecule therapeutics, and agrochemicals, still present a chalꢀ
lenge for synthetic chemists.11 Alkylꢀalkyl cross coupling reacꢀ
tions to build allꢀcarbon quaternary centers are rare and variꢀ
ous side reaction pathways can compete with the desired couꢀ
pling. By finely tuning the reaction conditions, we not only
realized the desired cross coupling reaction to synthesize δꢀ
ketoesters (cf. 9) containing allꢀcarbon quaternary centers, but
also discovered a novel γꢀbutyrolactone synthesis (cf. 8) via a
tandem sequence of CꢀC bond cleavage followed by CꢀC and
CꢀO formations. Our mechanistic studies indicate that unlike
the previously reported cross coupling reactions which occur
via a metalloꢀhomoenolate (2) or a βꢀalkyl radical intermediate
(3), the formation of γꢀbutyrolactones is likely to go through
the α,βꢀunsaturated enone intermediate (cf. 5) derived from
the corresponding cyclopropanol start material followed by
copperꢀcatalyzed conjugate addition and oxidative lactone
formation. Herein, we report the details of our research efforts.
2
3
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5
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A. General cyclopropanol ring opening cross couplings
O
X
O
M
O
Pd, Ag, Cu, Rh etc
or oxidant
X-Y
.
or
R
R
R
HO
R
R
2
3
4
1
O
side reaction
5
B. Our previous work
Cu(I)/Cu(II) cat.
X-Y
O
CF3/SCF3/NR2/Alkyl
HO
R
R
R
1
6
C. This work
Cu(I)/Cu(II) cat.
O
O
O
O
or
R
O
OR’
Br
CO2R’
HO
R
1
all-carbon
quaternary center
7
8
9
O
R
5
Figure 1. Prior arts and this work.
RESULTS
Reaction Condition Optimization
Our investigation started with 1ꢀphenylꢀ1ꢀcyclopropanol 10
and methyl 2ꢀbromoꢀ2,2ꢀdimethyl acetate 11 (Table 1). Upon
the treatment of 10 (0.2 mmol) and 11 (0.8 mmol) with CuI
(0.1 equiv.) as catalyst, phenanthroline (Phen, 0.2 equiv.) as
ligand, and K2CO3 (2.0 equiv.) as base in MeCN at 80 °C for
12 h, the reaction conditions we established for our previous
cyclopropanol ring opening fluoroalkylation process,8c surprisꢀ
ingly, γꢀbutyrolactone 12 was obtained as the main product in
27% yield with only a trace amount of cross coupling product
13 we were expecting. The structure of 12 was unambiguously
confirmed by xꢀray crystallography analysis.12 The unexpected
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ACS Catalysis
O
O
O
O
O
Cu(OTf)2 (10 mol %)
Phen (20 mol %)
Br
conditions
O
Br
O
CO2Me/R’
O
+
OMe
Ph
+
O
1
R
+
Ph
OMe
O
HO
Ph
10
0.2 mmol
Me Me
11
0.8 mmol
HO
R
Me Me
K2CO3 (2 equiv.), KI (2.0 equiv.)
MeCN, 80 °C, 10-12 h
Me
2
12
13
Me
3
4
5
6
7
8
9
O
entry reaction conditions (equiv.)
yield 12a
13a
O
O
O
O
1
2
CuI (0.1), Phen (0.2), K2CO3 (2.0), MeCN, 80 °C
27%
63%
47%
48%
31%
34%
56%
53%
74%
51%
40%
27%
12%
64%
23%
trace
10%
16%
14%
15%
16%
8%
Me
Me
Me
Me
CuI (0.1), Phen (0.2), K2CO3 (2.0), KI (1.0), MeCN, 80 °C
CuI (0.1), Phen (0.2), KHCO3 (2.0), KI (1.0), MeCN, 80 °C
CuI (0.1), Phen (0.2), Na2CO3 (2.0), KI (1.0), MeCN, 80 °C
CuI (0.1), Phen (0.2), NaHCO3 (2.0), KI (1.0), MeCN, 80 °C
CuI (0.1), Phen (0.2), Cs2CO3 (2.0), KI (1.0), MeCN, 80 °C
CuCl2 (0.1), Phen (0.2), K2CO3 (2.0), KI (1.0), MeCN, 80 °C
CuBr (0.1), Phen (0.2), K2CO3 (2.0), KI (1.0), MeCN, 80 °C
3
F
12: 80%
14: 77%
x-ray of 12
4
5
O
O
O
O
O
O
O
O
O
6
7
Me
Me
Me
Me
8
12%
Me
Me
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
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9
Cu(OTf)2 (0.1), Phen (0.2), K2CO3 (2.0), KI (2.0), MeCN, 80 °C
Cu(OTf)2 (0.1), L1 (0.2), K2CO3 (2.0), KI (1.0), MeCN, 80 °C
Cu(OTf)2 (0.1), L2 (0.2), K2CO3 (2.0), KI (1.0), MeCN, 80 °C
Cu(OTf)2 (0.1), L3 (0.2), K2CO3 (2.0), KI (1.0), MeCN, 80 °C
Cu(OTf)2 (0.1), L4 (0.2), K2CO3 (2.0), KI (1.0), MeCN, 80 °C
Cu(OTf)2 (0.1), L5 (0.2), K2CO3 (2.0), KI (1.0), MeCN, 80 °C
Cu(OTf)2 (0.1), L6 (0.2), K2CO3 (2.0), KI (1.0), MeCN, 80 °C
6%
5%
I
F3C
BnO
15: 60%
16: 29%
17: 87%
10
11
12
13
14
15
5%
O
O
O
O
O
O
O
O
O
10%
12%
10%
11%
6%
Me
Me
Me
Me
Me
Me
Me
TsO
N
MeO
20: 70%
18: 85%
19: 41%
Ts
16b Cu(OTf)2 (0.1), Phen (0.2), K2CO3 (2.0), KI (2.0), MeCN, 80 °C
82%(80%)
O
O
17
18
19
20
21
22
23
24
25c
CuI (0.1), Phen (0.2), KOAc (2.0), KI (1.0), MeCN, 80 °C
CuI (0.1), Phen (0.2), iPr2NH (2.0), KI (1.0), MeCN, 80 °C
CuCl (0.1), Phen (0.2), iPr2NH (2.0), KI (1.0), MeCN, 80 °C
CuCl2 (0.1), Phen (0.2), iPr2NH (2.0), KI (1.0), MeCN, 80 °C
CuBr (0.1), Phen (0.2), iPr2NH (2.0), KI (1.0), MeCN, 80 °C
Cu(OTf)2 (0.1), Phen (0.2), iPr2NH (2.0), KI (1.0), MeCN, 80 °C
CuCl (0.1), L1 (0.2), iPr2NH (2.0), KI (1.0), MeCN, 80 °C
CuCl (0.1), L5 (0.2), iPr2NH (2.0), KI (1.0), MeCN, 80 °C
CuCl (0.1), L5 (0.2), iPr2NH (2.0), KI (1.0), MeCN, 80 °C
9%
15%
15%
17%
17%
14%
13%
14%
64%
71%
75%
69%
68%
6%
O
O
O
O
O
O
O
Me
Me
Me
Me
Me
O
Me
N
21: 77%
22: 61%
23: 62%
64%
77%
O
O
O
O
O
O
O
O
O
12% 78%(73%)
8% 75%
Me
Me
24: 91%
Me
Me
Me
Me
26d
CuCl (0.1), L5 (0.2), iPr2NH (2.0), KI (1.0), MeCN, 80 °C
N
N
N
Ts
26: 60%
Ts
Boc
25: 68%
aYield by NMR with trimethoxybenzene as internal reference and isolated yield in parenthesis;
12 h reaction time; b4.5 equiv. 11; c3.0 equiv. 11; d2.0 equiv. 11.
Ph
Ph
R
O
O
O
O
O
O
O
O
O
R
R
N
N
N
N
N
N
N
N
Me
Me
S
L1 (R = H)
L2 (R = Me)
Me
Me
R
L3
R
R
Phen (R = H)
L4 (R = Me)
L5 (R = H)
L6 (R = Me)
BnO
BnO
27: 41%
29: 56%
28: 69% (R’ = Et)
Table 1. Reaction condition optimization.
O
O
O
O
O
O
Substrate Scope
Me
Me
CO2Et
Me
With a divergent strategy established to access either the γꢀ
butyrolactone or δꢀketoester products, the substrate scope
study of both transformations was subsequently conducted
(Table 2 and Table 3). For the syntheses of γꢀbutyrolactones,
the reaction has a broad substrate scope and tolerates a variety
of functional groups. A wide range of 1ꢀarylcyclopropanol
substrates underwent the desired cross coupling and lactonizaꢀ
tion to afford the corresponding γꢀbutyrolactone products.
Functional groups such as ketone, lactone, fluoride (14), ioꢀ
dide (15), benzyl ether (17), tosylate (19), sulfonamide (20)
and carbamate (25) are well tolerated. Heteroaromatics includꢀ
ing pyrrole (22), furan (23), indole (24, 25), and thiophene
(27) are compatible as well. In general, substrates with an
electronꢀneutral or electronꢀrich aryl group gave higher reacꢀ
tion yield than electronꢀdeficient ones (cf. 16). 1ꢀ
Alkylcyclopropanol is effective as well, but it requires an all
carbon quaternary center at the αꢀposition of the newly formed
ketone (30). For the case of 31, a mixture of diastereomers
(1.2:1) was obtained.
BnO
30: 43%
31: 80% (dr: 1.2:1; R’ = Et)
Table 2. Substrate scope for the γꢀbutyrolactone synthesis.
The substrate scope for the synthesis of δꢀketoester is even
broader than the γꢀbutyrolactone synthesis (Table 3). In addiꢀ
tion to 1ꢀarylcyclopropanol and 1ꢀheteroarylcyclopropanol
substrates (with reaction condition A), which worked well for
the γꢀbutyrolactone synthesis, various 1ꢀalkyl substituted cyꢀ
clopropanols are effective substrates as well (cf. 48, 56ꢀ63).
For the latter, a modified reaction condition was used (reaction
condition B), in which KI was removed and Phen was used to
replace L5. Remote olefin (62) or conjugated enones (54 and
55) are tolerated. For the case of 55, no electrocyclic cyclobuꢀ
tene ring opening product was observed. In addition to haloꢀ
gens, alkyl ethers, carbamates, and sulfonamides, more labile
functional groups such as TBSꢀether (55 and 60), benzoate
(59), and free alcohol (63) are compatible under the relatively
mild reactions.
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ACS Catalysis
considered as an undesired side reaction pathway in the previꢀ
Page 4 of 9
A. CuCl (10 mol %), L5 (20 mol %)
iPr2NH (2.0 equiv.) KI (1.0 equiv.)
MeCN, 80 °C, 10-12 h
O
O
O
Br
CO2R’
1
2
3
4
5
6
7
8
+
ously reported transition metalꢀcatalyzed cyclopropanol ring
opening cross coupling reactions. Recently, Lei and coꢀ
workers reported an interesting nickelꢀcatalyzed radical type
addition of αꢀbromoesters to styrenes and α,βꢀunsaturated
enones to form γꢀbutyrolactones.15 Inspired by their discovery,
we treated α,βꢀunsaturated enone 64 with αꢀbromoester 11
under the γꢀbutyrolactone formation conditions and γꢀ
butyrolactone product 18 was produced in 70% yield (Eq. 2).
This result supports that the formation of 18 is from enone 64,
not from δꢀketoester 36. We then treated a mixture of 64 and
11 with the two standard cross coupling reaction conditions
for the δꢀketoester synthesis (Table 3). The formation of both
18 and 36 were observed, but the yield for 36 was low and a
significant amount of γꢀbutyrolactone product 18 was proꢀ
duced (Eq. 3). The product distribution is different from the
results we obtained in Table 3, where 36 was produced as the
major product. These observations indicate that the enone
pathway only partially contributes to the formation of δꢀ
ketoester 36 and the direct ring opening cross coupling beꢀ
tween 66 and 11 without going through the enone intermediate
is still the major pathway. This notion was corroborated by the
reaction of enone 65 with 11 under the standard δꢀketoester
formation condition B (Eq. 4), from which only 14% of the
desired product 57 was obtained, significantly lower than the
direct cross coupling result (57%, Table 3).
R
OR’
HO
R
B. CuCl (10 mol %), Phen (20 mol %)
iPr2NH (2.0 equiv.)
3.0 equiv. (A)
4.0 equiv. (B)
MeCN, 80 °C, 10-12 h
O
O
O
O
O
OMe
OMe
OMe
Me Me
Me Me
Me Me
F
I
13: 73%
32: 77%
33: 64%
O
O
O
O
O
O
OMe
OMe
OMe
OMe
OMe
Me Me
34: 87%
Me Me
35: 74%
Me Me
36: 69%
9
F3C
BnO
MeO
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
O
O
O
O
O
O
OMe
O
OMe
Me Me
Me Me
Me Me
Me
TsO
N
Ph
37: 64%
38: 71%
39: 85%
Ts
O
O
O
O
O
OMe
OMe
Me Me
Me Me
Me Me
O
N
N
Ts
N
40: 73%
41: 71%
42: 82%
O
O
O
O
O
O
OMe
OMe
OMe
OEt
OMe
Me Me
43: 79%
Me Me
Me Me
45: 43%
S
N
Ts
O
Boc
44: 80%
O
O
O
O
O
O
Ph
OMe
OEt
OEt
Me Me
46: 87%
47: 77%
48: 44% (B)
We then probed the controlling factors for the enone forꢀ
mation. We first treated cyclopropanol 66 with stoichiometric
amount of Cu(OTf)2/Phen with K2CO3 as base (Eq. 5). Ethyl
ketone 67, a cyclopropanol ring opening protonation product,
was produced along with dimeric product 68 and other unidenꢀ
tifiable products, but enone 64 was not one of them. We then
added KI to the reaction mixture (Eq. 6). In this case, we did
observe the formation of enone 64 in 28% yield together with
18% of dimer 68 and 30% of recovered 66. This result indiꢀ
cates that KI is facilitating the formation of the enone intermeꢀ
diate, presumably via βꢀiodoketone intermediate 69 followed
by a baseꢀpromoted elimination. K2CO3 was then removed
from the reaction system (Eq. 7). Without the base, after 1 h
reaction, 69 was detected as the major product (30ꢀ40% yield
based on crude NMR analysis) in the reaction mixture and it
underwent rapid elimination on silica gel column to give
enone 64. Additionally, when cyclopropanol 66 was treated
with stoichiometric amount of CuCl/Phen without base and KI
(Eq. 8), most of 66 could be recovered with 18% of 67 and
16% of 68, but no enone 64 formation. The involvement of βꢀ
iodoketone intermediate 69 was further confirmed by the fact
that γꢀbutyrolactone product 18 was obtained after subjecting
69 to the reaction conditions of Cu(OTf)2/Phen with K2CO3 in
MeCN at 80 °C (Eq. 9).
O
O
O
O
O
OEt
OEt
N
N
49: 85%
50: 80%
51: 63%
Boc
Ts
O
O
O
O
O
O
OEt
Ph
OMe
OMe
Me
Ph
Me Me
54: 29%
Ph
Ph
52: 94%
53: 43%
O
O
O
O
Ph
O
O
TBSO
OPh
Ph
OMe
OMe
OMe
Me Me
56: 60% (B)
Me Me
55: 57%
Me Me
57: 54% (B)
O
O
OBz
O
O
OTBS
O
O
OMe
OMe
OMe
Me Me
Me Me
Me Me
60: 42% (B)
58: 59% (B)
59: 46% (B)
OH
O
O
O
O
O
8
O
OMe
OMe
Me Me
63: 53% (B)
Me Me
Me Me
61: 51% (B)
62: 39% (B)
F
Table 3. Substrate scope for the δꢀketoester synthesis.
Mechanistic Studies
To provide insights about the reaction mechanisms of these
two divergent synthetic transformations, a series of experiꢀ
ments were conducted (Figure 2). We initially speculated that
the formation of the γꢀbutyrolactone product (cf. 18) might be
derived from the corresponding cyclopropanol ring opening
cross coupling product (cf. 36) via a formal αꢀCꢀH oxidative
lactonization process; therefore, we treated purified 36 with
the standard reaction conditions for the γꢀbutyrolactone synꢀ
thesis (Eq. 1). However, we didn’t observe the formation of γꢀ
butyrolactone 18 and recovered 36 in 95% yield, which indiꢀ
cates that 18 was not derived from 36. Another possibility for
the formation of 18 might be from an α,βꢀunsaturated enone
(cf. 64), while the α,βꢀunsaturated enone formation is often
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Eq. 1
O
O
O
Our further investigation showed that both the direct cross
Cu(OTf)2 (10 mol %)
Phen (20 mol %)
O
O
1
2
3
4
5
6
7
8
OMe
+
coupling pathway and γꢀbutyrolactone formation pathway are
inhibited by TEMPO (Eq. 10). In this case, enone 64 was proꢀ
duced in 75% yield. TEMPO may interfere with the βꢀalkyl
radical intermediate generated from 66 or the αꢀalkyl radical
(cf. F, Figure 3) derived from 11. The former could still result
in enone 64 via a subsequent baseꢀpromoted elimination of the
βꢀTEMPOꢀketone intermediate. Copperꢀcatalyzed αꢀalkyl
radical formation from αꢀbromoester such as 11 has been
commonly proposed and widely used in organic synthesis16
and polymer synthesis.17 We then prepared allyl αꢀbromoester
70 to probe this process and were expecting that the αꢀradical
could be intercepted by the intramolecularly tethered double
bond via a 5ꢀexo-trig cyclization process. Interestingly, under
the standard γꢀbutyrolactone synthesis conditions, desired γꢀ
butyrolactone 18 was formed 54% yield along with δꢀketoester
71 in 15% yield (Eq. 11). When 70 was subjected to the standꢀ
ard δꢀketoester synthesis conditions (Eq. 11), 71 was obtained
in 71% yield with a trace amount of 64 and dimer 72 detected.
The observation of 72 suggests the αꢀradical formation, but
the αꢀradical reacts faster with enone 64 generated in situ or
the copperꢀhomoenolate derived from 66 to provide desired
product 18 or 71 as the dominant ones. The involvement of
copperꢀhomoenolate was supported by the formation of prodꢀ
uct 74 from cyclopropanol 73 which contains an intramolecuꢀ
larly tethered olefin for a potential 6ꢀexoꢀtrig radical cyclizaꢀ
tion. Since the yield of 74 is low (20%) and the reaction is
quite complex, the formation of a βꢀalkyl radical (cf. B, Figure
3) cannot be completely eliminated.
11
K2CO3 (2 equiv.)
KI (2.0 equiv.)
MeCN, 80 °C, 10 h MeO
Me Me
Me
(3.0 equiv.)
MeO
Me
36
18
(not formed)
95% of 36 recovered
Eq. 2
Cu(OTf)2 (10 mol %)
Phen (20 mol %)
O
+
18
70%
11
(3.0 equiv.)
K2CO3 (2 equiv.), KI (2.0 equiv.)
MeCN, 80 °C,11 h
64
MeO
A. CuCl (10 mol %), L5 (20 mol %)
iPr2NH (2.0 equiv.), KI (1.0 equiv.)
Eq. 3
11
64
+
+
9
18
36
(A. 3.0 equiv.)
(B. 4.0 equiv.)
B. CuCl (10 mol %), Phen (20 mol %)
iPr2NH (2.0 equiv.)
A: 18%
B: 28%
A: 20%
B: 19%
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
MeCN, 80 °C, 13 h
Eq. 4
CuCl (10 mol %)
Phen (20 mol %)
O
O
O
11
+
Ph
OMe
Ph
(4.0 equiv.)
iPr2NH (2.0 equiv.)
Me Me
MeCN, 80 °C, 13 h
57
14%a
65
Eq. 5
O
O
O
OH
Cu(OTf)2 (100 mol %)
Phen (200 mol %)
Me
+
K2CO3 (2.0 equiv.)
MeCN
68
13%a
67
MeO
MeO
66
13%a
80 °C, 5 h
OMe
MeO
Eq. 6
O
OH
Cu(OTf)2 (100 mol %)
Phen (200 mol %)
66
30%a
recovered
68
+
+
18%a
K2CO3 (2.0 equiv.)
KI (2.0 equiv.)
MeCN, 80 °C, 8 h
64
MeO
MeO
66
28%a
O
Cu(OTf)2 (100 mol %)
Phen (200 mol %)
Eq. 7
I
66
KI (2.0 equiv.)
MeCN, 80 °C, 1 h
MeO
69
Based on the above experimental results, a plausible reacꢀ
tion mechanism was proposed in Figure 3 by using 10 and 11
as model substrates. The catalytic cycle is expected to start
with a CuII species derived from Cu(OTf)2 or oxidation of
CuCl by 11. Ligand exchange with cyclopropanol 10 would
generate alkoxide intermediate A, which would undergo a ring
opening process to provide βꢀalkyl radical B (potentially stabiꢀ
lized by the resulting CuI) or copperꢀhomoenolate C. B/C
could then react with KI to form βꢀiodoketone D. Base
(K2CO3 or iPr2NH)ꢀpromoted elimination would convert D to
enone E. The latter would react with radical intermediate F
derived from the reaction of CuI with 11 to form a new radical
intermediate H. At this stage, the involvement of copperꢀ
enolate G cannot be ruled out. Intermediate H would then
undergo two possible pathways to form carbocation intermeꢀ
diate K, then to product 12 after the loss of a methyl group.
The first pathway would involve an addition of the αꢀradical
of H to the ester carbonyl πꢀbond to form a new carbonꢀ
centered radical I which is stabilized by the two adjacent oxyꢀ
gen atoms. This electron rich radical would be readily oxiꢀ
dized to carbocation K by CuII in the reaction system. The
other pathway would involve a CuIIꢀmediated oxidation of
radical intermediate H to carbocation J. Nucleophilic attack of
the newly formed carbocation by the carbonyl group of the
ester would give rise to K. While plausible, the oxidation of
radical H to J with a carbocation right next to an electronꢀ
withdrawing ketone would require much higher energy than
the radial cyclization pathway.15 Additionally, radical H could
be quenched by a hydrogen abstraction process to provide δꢀ
ketoester product 13, but this is not the major pathway for the
formation of 13. Under the δꢀketoester formation conditions,
the majority of the δꢀketoester is likely to be obtained via a
direct cross coupling reaction between B/C and F/G.
30-40%a
CuCl (100 mol %)
Phen (200 mol %)
Eq. 8
Eq. 9
Eq. 10
66
66
~50%
recovered
67
18%
+
68
16%
+
MeCN, 80 °C, 7 h
Cu(OTf)2 (10 mol %)
Phen (20 mol %)
18
76%
11
(3.0 equiv.)
69
66
+
K2CO3 (2.0 equiv.)
MeCN, 80 °C, 13 h
O
Cu(OTf)2 (10 mol %)
Phen (20 mol %)
11
(4.5 equiv.)
+
+
18/36
(not formed)
K2CO3 (2 equiv.), KI (2.0 equiv.)
MeCN, 80 °C
MeO
64
TEMPO (5.0 equiv.), 11 h
75%
O
O
O
O
Cu(OTf)2 (10 mol %)
Phen (20 mol %)
Eq. 11
Eq. 12
Eq. 13
Br
18
54%
+
O
+
66
K2CO3 (2 equiv.)
KI (2.0 equiv.)
MeCN, 80 °C, 11 h
Me Me
Me Me
MeO
71
15%
70
(4.5 equiv.)
Me
CuCl (10 mol %)
Me
O
O
L5 (20 mol %)
+
+
64
trace
+
71
66
70
O
iPr2NH (2.0 equiv.)
KI (1.0 equiv.)
O
71%
Me
(3.0 equiv.)
Me
72
MeCN, 80 °C, 11 h
trace
CuCl (10 mol %)
Phen (20 mol %)
OMe
O
11
+
O
HO
iPr2NH (2.0 equiv.)
MeCN, 80 °C, 13 h
(4.0 equiv.)
Me Me
73
74
20%
Figure 2. Mechanistic studies. aYield based on H NMR analꢀ
ysis with 1,3,5ꢀtrimethoxybenzene as internal reference.
1
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Page 6 of 9
O
O
1
OH
iPr2NH
O
2
3
4
5
6
7
8
9
Ph
OMe
Ph
CuI
.
O
OMe
13
Me Me
LnCuII
10
Me Me
.
F
Ph
O
LnCuII
or
O
H
OMe
CuII
Me Me
O
OMe
Me Me
G
Ph
E
O
OCuII
O
11
O
O
.
Ph
OMe
Ph
LnCuI
Ph
O
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
Ph
I
A
D
I
Me
Me
J
OMe
K2CO3
or iPr2NH
Me Me
O
LnCuII
CuI
CuII
O
O
O
Ph
.
OMe
Me
or
KI
Ph
Ph
K
B
C
O
Me
O
O
Ph
X
F/G
13
Me
Me
12
Figure 3. Proposed reaction mechanism for the formation of 12 and 13.
with brine, dried over anhydrous MgSO4, filtered and concentratꢀ
ed under reduced pressure. The resulting residue was purified by
flash chromatography with hexane and ethyl acetate as eluents to
provide the desired δꢀketoester product. Condition B: L5 was
replaced with Phen and KI was removed from the reaction sysꢀ
tem. The rest remains the same as described in condition A.
CONCLUSIONS
In summary, we have developed two divergent copperꢀ
catalyzed cyclopropanol ring opening reactions to form either
δꢀketoesters or γꢀbutyrolactones. The reaction conditions are
mild and tolerate a wide range of functional groups. Our
mechanistic studies revealed an unprecedented reaction mechꢀ
anism involving the formation of enone intermediate, which is
often considered as one of the main byproducts in many cyꢀ
clopropanol ring opening reactions. This novel reaction mechꢀ
anism is expected to guide the development of new cycloproꢀ
panol ring opening reactions and to provide mechanistic inꢀ
sights about some of the existing transition metal catalyzed
cyclopropanol ring opening reactions.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information including experimental procedures
and compound characterization is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.xxxxx.
AUTHOR INFORMATION
Corresponding Author
mjdai@purdue.edu
EXPERIMENTAL
γ-Butyrolactone synthesis procedure:
† Z.Y. and X.C. contributed equally.
A mixture of the cyclopropanol substrate (0.2 mmol), 2ꢀbromoꢀ
2,2ꢀdialkylester (0.9 mmol), Cu(OTf)2 (7.2 mg, 0.02 mmol), Phen
(7.2 mg, 0.04 mmol), K2CO3 (55.2 mg, 0.4 mmol), and KI (66.4
mg, 0.4 mmol) was dissolved in MeCN (2 mL) and stirred at 80
°C for 10ꢀ12 h. The reaction was quenched with saturated aqueꢀ
ous NH4Cl solution and extracted with CH2Cl2 (30 mL) for three
times. The combined organic extract was then washed with brine,
dried over anhydrous MgSO4, filtered and concentrated under
reduced pressure. The resulting residue was purified by flash
chromatography with hexane and ethyl acetate as eluents to proꢀ
vide the desired γꢀbutyrolactone product.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was financially supported by NSF CAREER Award
1553820 and the ACS petroleum research foundation (PRF No.
54896ꢀDNI1). We thank the NIH P30CA023168 for supporting
shared NMR resources to Purdue Center for Cancer Research.
The XRD data is collected on a new single crystal Xꢀray diffracꢀ
tometer supported by the NSF through the Major Research Inꢀ
strumentation Program under Grant No. CHE 1625543. M.D.
thanks Eli Lilly for an unrestricted grant support via the Eli Lilly
Grantee Award. We thank Kristen E. Gettys for some initial inꢀ
vestigation of this project.
δ-Ketoester synthesis procedure:
Condition A: A mixture of the cyclopropanol substrate (0.2
mmol), 2ꢀbromoꢀ2,2ꢀdialkylester (0.6 mmol), CuCl (2.0 mg, 0.02
mmol), L5 (13.2 mg, 0.04 mmol), iPr2NH (56ꢀL, 0.4 mmol), and
KI (33.2 mg, 0.2 mmol) was dissolved in MeCN (2 mL) and
stirred at 80 °C for 10ꢀ12 h. The reaction was quenched with satuꢀ
rated aqueous NH4Cl solution and extracted with CH2Cl2 (30 mL)
for three times. The combined organic extract was then washed
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OR’
CO2R’
δ-ketoesters
35 examples
γ-butyrolactones
20 examples
Divergent syntheses
Building all-carbon quaternary centers
Novel machanism via enone intermediate
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