α-Alkylidene-γ-butyrolactone Formation via Bi(OTf)3-Catalyzed, Dehydrative, Ring-Opening Cyclizations of Cyclopropyl Carbinols: Understanding Substituent Effects and Predicting E/Z Selectivity

Article abstract of DOI:10.1021/acs.joc.7b01706

A Bi(OTf)₃-catalyzed ring-opening cyclization of (hetero)aryl cyclopropyl carbinols to form α-alkylidene-γ-butyrolactones (ABLs) is reported. This transformation represents different chemoselectivity from previous reports that demonstrated formation of (hetero)aryl-fused cyclohexa-1,3-dienes upon acid-promoted cyclopropyl carbinol ring opening. ABLs are obtained in up to 89% yield with a general preference for the E-isomers. Mechanistically, Bi(OTf)₃ serves as a stable and easy to handle precursor to TfOH. TfOH then catalyzes the formation of cyclopropyl carbinyl cations, which undergo ring opening, intramolecular trapping by the neighboring ester group, subsequent hydrolysis, and loss of methanol resulting in the formation of the ABLs. The nature and relative positioning of the substituents on both the carbinol and the cyclopropane determine both chemo- and stereoselective outcomes. Carbinol substituents determine the extent of cyclopropyl carbinyl cation formation. The cyclopropane donor substituents determine the overall reaction chemoselectivity. Weakly stabilizing or electron-poor donor groups provide better yields of the ABL products. In contrast, copious amounts of competing products are observed with highly stabilizing cyclopropane donor substituents. Finally, a predictive model for E/Z selectivity was developed using DFT calculations.

Full text of DOI:10.1021/acs.joc.7b01706

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Article
#-Alkylidene-#-butyrolactone Formation via Bi(OTf)3-Catalyzed,
Dehydrative, Ring-Opening Cyclizations of Cyclopropyl Carbinols:
Understanding Substituent Effects and Predicting E/Z Selectivity
Matthew J. Sandridge, Brett D. McLarney, Corey W Williams, and Stefan France
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01706 • Publication Date (Web): 06 Sep 2017
Downloaded from http://pubs.acs.org on September 7, 2017
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α-Alkylidene-γ-butyrolactone Formation via Bi(OTf) -Catalyzed, Dehydrative, Ring-
Opening Cyclizations of Cyclopropyl Carbinols: Understanding Substituent Effects and
Predicting E/Z Selectivity
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a
a
a
a,b,
Matthew J. Sandridge , Brett D. McLarney , Corey W. Williams , and Stefan France *
a
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia,
3
0332, United States
b
Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta,
Georgia 30332, United States
stefan.france@chemistry.gatech.edu
Abstract
3
A Bi(OTf) -catalyzed ring-opening cyclization of (hetero)aryl cyclopropyl carbinols to form α-
alkylidene-γ-butyrolactones (ABLs) is reported. This transformation represents different
chemoselectivity from previous reports that demonstrated formation of (hetero)aryl-fused
cyclohexa-1,3-dienes upon acid-promoted cyclopropyl carbinol ring opening. ABLs are obtained
3
in up to 89% yield with a general preference for the E-isomers. Mechanistically, Bi(OTf) serves
as a stable and easy to handle precursor to TfOH. TfOH then catalyzes the formation of
cyclopropyl carbinyl cations, which undergo ring opening, intramolecular trapping by the
neighboring ester group, subsequent hydrolysis, and loss of methanol resulting in the formation
of the ABLs. The nature and relative positioning of the substituents on both the carbinol and the
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cyclopropane determine both chemo- and stereoselective outcomes. Carbinol substituents
determine the extent of cyclopropyl carbinyl cation formation. The cyclopropane donor
substituents determine the overall reaction chemoselectivity. Weakly stabilizing or electron-poor
donor groups provide better yields of the ABL products. In contrast, copious amounts of
competing products are observed with highly stabilizing cyclopropane donor substituents.
Finally, a predictive model for E/Z-selectivity was developed using DFT calculations.
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R2
OMe
R2
R2
HO R2
O
R2
O
OMe
O
O
Bi(OTf)3
5-20 mol %)
(
R1
R1
R1
OMe
R4
O
R4
R1
R1
OMe
R4
O
4
Å MS
R5
R5
R5
R3
R3
R5
R5
R3
CH Cl2
R3
2
R4
R4
R3
23 ˚C
1
9 examples
up to 89% yield
up to >99:1 E:Z
INTRODUCTION
The α-alkylidene-γ-butyrolactone (ABL) framework represents an important structural
motif to both organic and medicinal chemists (Figure 1). It is found in a vast collection of natural
products and potential therapeutics with significant biological activities including anticancer,
1
anti-inflammatory, antibacterial, antifungal, and antiviral. ABLs are also useful building blocks
2
for chemical synthesis due to their facile derivatizations. It was estimated that by 2009 there
were more than 5000 identified ABL natural products along with another 9000 synthetic
3
analogues. Synthesis of the ABL framework is an ongoing endeavor for the synthetic
community. As such, several extensive reviews have been published highlighting the diverse
1
,3,4
approaches that can be taken toward the scaffold.
The general synthetic approaches to the
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ABL core have been classified into the following types: alkylidenation of γ-butyrolactones,
6
various lactonization approaches,
tandem (or sequential) intramolecular C-H
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insertion/olefination, the Dreiding-Schmidt organometallic approach, cross methathesis
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between α-methylene-γ-butyrolactones and olefins, intramolecular enyne metathesis reactions,
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Pd-catalyzed cross-couplings,
Diels-Alder and retro-Diels-Alder reactions,
radical
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cyclizations, and Baeyer-Villiger reactions on cyclobutanones. Despite the abundant literature,
the diversity within the ABLs has made the pursuit of strategic ABL targets and the development
of methodologies to access them persistently meaningful endeavors in the synthetic
1
5
community.
O
O
R2
O
O
HO
HO
Me
Me
O
H
H
O
R1
Me
O
Me
Me
RO C
2
O
H
R5
R4
R3
O
OH
O
α-alkylidene-γ-
butyrolactone phellinsin A (R = H)
OH
curcumanolide A
maximileolide
O
(ABL)
pharbilignanol D (R = Et)
Me
O
O
O
O
O
O
O
O
Me
O
Me
Me
Me
O
Me
O
O
O
Me
isolinderalacton
heteroplexisolide E
fraxinellone
savinin
O
Figure 1. Examples of ABL frameworks in target molecules
Over the past 10 years, our lab has explored a variety of intra- and intermolecular ring-
opening cyclizations of small, strained ring systems (e.g., cyclopropanes, cyclopropenes,
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alkylidene cyclopropanes, and cyclobutanes). In one pertinent example, we disclosed a
calcium-catalyzed, dehydrative, ring-opening cyclization of (hetero)aryl cyclopropyl carbinols to
1
7
form (hetero)aryl-fused cyclohexa-1,3-dienes. Interestingly, we found that when cyclopropyl
carbinol 4a was subjected to the reaction conditions, 14% yield of α-alkylidene-γ-butyrolactone
6a was obtained in addition to the expected dihydronaphthalenes 5a and 5aʹ (Scheme 1). Product
6
a was unexpected, as no mention of α-alkylidene-γ-butyrolactone formation had been reported
1
8
in the previous literature for the transformation.
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Scheme 1. Ca(II)-catalyzed ring-opening cyclization of cyclopropyl carbinols
O
O
Ca(NTf2)2 MeO
1 mol %)
Bu NPF
OMe
OMe
(
+
OH
O
4
6
MeO
MeO
O
MeO
MeO
(1 mol %)
OMe
Ph
Ph
OMe Ph
5a (76%)
5a' (9%)
0
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1
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4
5
6
7
8
9
0
4 Å MS
1,2-DCE
4
a
O
84 ˚C
Ph
MeO
MeO
6a (14%)
While ABLs have been generated from the reactions of vinyl cyclopropanes with
substituted benzaldehydes in the presence of DABCO, no examples of their synthesis from
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cyclopropyl carbinols have been reported. Intrigued by the formation of 6a, we were
particularly interested in discerning the factors that govern the chemoselectivity of the reaction
(
formation of 5 and/or 6) and how they could be rationalized in terms of substituent effects. We
envisioned that this knowledge would contribute to determining the conditions for selective ABL
formation, establishing cyclopropyl carbinols 4 as a useful common precursor to multiple
different, yet desirable, core structures. This type of approach represents one of the hallmarks of
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3
diversity-oriented synthesis. Toward that end, we disclose our studies on the Bi(OTf) -calyzed,
ring-opening cyclization of cyclopropyl carbinols 4 to form ABLs 6 and show how the
dehydrative, ring-opening cyclization is dependent upon the electronic nature of the substituents
on both the carbinol and the cyclopropane ring (Scheme 2).
3
Scheme 2. Bi(OTf) -catalyzed ring-opening cyclization of cyclopropyl carbinols
HO R5
R4
O
cat.
Bi(OTf)3
R5
O
R5
OMe
O
O
R5
R4
6
R4
O
OMe
R
R4
OMe
R
R2
2
2
R3
R2
R1
R3
R3
R3
R1
R1
R1
4
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RESULTS AND DISCUSSION
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Synthesis of Carbinols 4. Carbinols 4a-4v, 4x, and 4y were prepared using a three-step
sequence from the corresponding β-ketoesters 1. Diazo transfer followed by Rh(II)-catalyzed
3
cyclopropanation with various olefins gave donor-acceptor (D-A) cyclopropanes 3. LiEt BH
reduction generated secondary (2˚) carbinols 4a-4v. Tertiary (3˚) carbinols 4x and 4y were
obtained upon addition of methyl or phenyl lithium to the D-A cyclopropane, respectively
(Scheme 3).
Scheme 3. D-A Cyclopropane Approach to Cyclopropyl Carbinols 4a-4v, 4x, and 4y
O
H
HO
R1
1
NEt3
CH CN
) TsN3
LiEt BH
3
OMe
2
THF
up to 90%
R
3
O
O
R4
R3
4a-4v
O
O
up to 98%
R1
R3
OMe
R
R1
2
OMe
2) Rh esp
R2
4 O
2
2
R1
3
HO
R1
R
1
4
R Li
R4
OMe
2
R3
THF
up to 90%
R
R4
R3
CH Cl
2
2
up to 92%
4x/4y
OH
O
4a R = H
4b R = 4-Me
c R = 4-OMe
4d R = 4-Cl
OH O
MeO
MeO
MeO
MeO
OMe
OMe
4
Cl
R
4
4
4
e R = 4-Br
f R = 3-Br
g R = 2-Br
Br
OH
4
h
OH
O
OH
O
O
MeO
MeO
MeO
MeO
MeO
OMe
OMe
Me
OMe
R
MeO
R
4
i R = 2-Np
4k R = Ph
4l R = 3-thienyl
4m
4j R = 2-furyl
OH
O
OH O
OH
O
MeO
MeO
OMe
OMe
Ph
MeO
R
OMe
Ph
4n
4o R = 4-OMe
p R = H
4q R = 4-Cl
r R = 3-Cl
OMe 4s
4
4
OH
O
OH
O
OH O
R
MeO
MeO
O
OMe
Ph
R
OMe
Ph
OMe
Ph
4
t
4u R = Et
4v R = i-Pr
4x R = Me
4y R = Ph
ꢀ
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For the preparation of trialkyl 3˚ carbinol 4w, the previously discussed sequence failed to
provide the desired product. Instead, 4w was synthesized using Nishii’s Reformatsky approach
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(
Scheme 4). 1,1-Dibromocyclopropane 10w (prepared from the reaction of styrene with CHBr
aq. NaOH, and catalytic BnEt NBr) was treated with n-BuLi and quenched with dry ice (CO ).
Following workup, the crude acid was converted to the ester 11w using K CO and MeI in 46%
3
,
3
2
2
3
yield over the two steps. Lastly, formation of the Reformatsky reagent and reaction with 3-
pentanone gave carbinol 4w. In all cases, the carbinols are prepared and used as mixtures of
diastereomers.
Scheme 4. Reformatsky Approach to Carbinol 4w
1
) n-BuLi
then CO2
O
Zn
then
OH
O
Br
Br
Ph
Br
Me
OMe
R
OMe
Ph
2
Me
Me
Me
2
) K CO
R3
2
3
R1
O
MeI
1
0w
11w
4w
4
6%
59%
(
prepared in
one step
from styrene)
(over two
steps)
ꢀ
ꢀ
1
7
Reaction Optimization. Given the benchmark formation of ABL 6a in the previous report
(Scheme 1), carbinol 4a was logically chosen as the model system for reaction optimization
Table 1). In the previous work, similar to when no catalyst was present (entry 1), no reaction
was observed with Zn(OTf) Al(OTf) Cu(OTf) [Cu(OTf)] •PhMe, Yb(OTf)
Ni(ClO •6H O, La(OTf) , Y(OTf) , or Dy(OTf)
(
2
,
3
,
2
,
2
3
,
4
)
2
2
3
3
3
. Also, stoichiometric amounts of Lewis acid
17,18
do not afford ABL products and only dihydronaphthalenes 5 are generated.
As discussed in
Scheme 1, the calcium complex (Ca(NTf , n-Bu NPF ) (1 mol %) gave ABL 6a in 14% yield
2
)
2
4
6
along with 85% of 5a/5a’ (entry 2). This result was obtained in 1,2-DCE at reflux since the Ca-
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catalyzed reaction did not occur at room temperature in CH
employing In(OTf) , Sc(OTf) , or Ga(OTf) as catalysts each proceeded at room temperature in
CH Cl . In(OTf) at 15 mol % loading produced 39% yield of ABL 6a and 45% of 5a (entry 3).
Sc(OTf) (15 mol %) provided a similar product profile as 6a was formed in 35% yield along
with 49% of 5a (entry 4). A modest 27% yield of 6a was obtained with 5 mol % of Ga(OTf)
along with 5a as an intractable mixture (entry 5). InCl (10 mol %) gave a 52% combined yield
of 5a/5a’ and no ABL product (entry 6). GaCl (10 mol %) led to formation of 67% yield of 5
2 2
Cl . In contrast, the reactions of 4a
3
3
3
2
2
3
10
11
12
13
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3
3
3
3
along with an intractable mixture containing a minor amount of 6a (entry 7).
Table 1. Reaction Optimization
R1
MeO
O
CO2Me
MeO
MeO
O
OH
R2 Ph
acid
X mol %) 5a (R =OMe; R = H)
Ph
MeO
MeO
CO2Me
Ph
1
2
(
6a
1
2
5
a' (R =H; R = OMe)
solvent
0.1 M)
4 Å MS
temp
O
(
MeO
4
a
OMe
OH
MeO
Ph
7
a
entrya
acid (mol %)
None
time (h)
24.0
% yield 5/6b
0/0
solvent (T ˚C)
CH Cl (23)
1c
2
2
2
Ca(NTf2)2 (1)
1,2-DCE (84)
0.5
85/14
n-Bu4NPF6 (1)
In(OTf)3 (15)
Sc(OTf)3 (15)
3
CH2Cl2 (23)
CH2Cl2 (23)
2.5
1.0
45/39
49/35
4
d
5
6e
Ga(OTf)3 (5)
InCl3 (10)
CH2Cl2 (23)
CH2Cl2 (23)
CH2Cl2 (23)
CH2Cl2 (23)
2
.5
24.0
4.0
.0
-- /27
52/--
67/--f
7
GaCl3 (10)
2
d
8
Bi(OTf)3 (5)
1
-- /62
9e
10e,g
BiBr3 (5)
2 2
CH Cl (23)
24.0
24.0
0.5
18/0
0/0
Bi(NO ) •5H O (5)
3 2
2
CH2Cl2 (23)
CH2Cl2 (23)
CH Cl (23)
d
11
TfOH (15)
TsOH (20)
-- /61
1
2e
3c
2
2
24.0
24.0
24.0
7/38
0/0
1
TFA (20)
2 2
CH Cl (23)
1
4c
[pyrH][OTf] (15)
CH Cl (23)
2
2
0/0
Bi(OTf)3 (10)
,5-di-t-BuPyr (30)
5c
CH Cl (23)
24.0
0/0
1
2
2
2
1
1
1
6h
7
Bi(OTf)3 (5)
Bi(OTf)3 (5)
Bi(OTf)3 (5)
CH2Cl2 (23)
1,2-DCE (84)
CH2Cl2 (40)
1.0
--d/60i
0.5
1.0
39/55
49/36
8
1
9
Bi(OTf)3 (5)
Bi(OTf)3 (10)
Bi(OTf)3 (2)
CH2Cl2 (0)
CH2Cl2 (23)
CH2Cl2 (23)
3.0
-- /58
d
20
1e
1.0
28/55
20/--
ꢀ
2
24.0
ꢀ
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a
Reactions were performed with 1 equiv. of cyclopropyl carbinol 4a, indicated mol % of Lewis
acid in indicated solvent (0.1 M) at indicated temperature (T) in the presence of 4 Å mol sieves.
b
c
d
Ratios determined after product isolation. No reaction. Starting material 4a recovered.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
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5
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3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
e
Complex mixture containing 5. Reaction did not go to completion and starting material 4a was
f
g
recovered. Complex, inseparable mixture containing 6a. Isolated 12% of acyclic hydroxylated
h
i
product 7a. Reaction performed without 4 Å mol sieves. Complex, inseparable mixture.
1
Product yield based on H NMR using dimethyl terephthalate as an internal standard.
In searching for effective catalysts for carbinol activation, we were intrigued by Bi(III)
salts. Due to their synthetic utility, low toxicity, and low cost, Bi(III) salts are attractive reagents
2
2
for the practicing organic chemist. Over the past 15 years, a variety of Bi(III) compounds have
been used in organic reactions as organobismuth reagents or as catalysts. They have been shown
to be effective catalysts for etherification, allylation, cyanation, cycloaddition, and a host of
2
3
protection/deprotection reactions. Given this versatilty, we screened three Bi(III) salts in the
reaction: Bi(OTf) , BiBr , and Bi(NO •5H O. Bi(OTf) provided ABL 6a in 62% yield as a
single diastereomer (entry 8). A small amount of 5a was also formed as an inseparable, complex
mixture. In contrast, the reactions employing BiBr and Bi(NO •5H O did not to go to
completion after 24 h and failed to provide any ABL product (entries 9 and 10). In the case of
3
3
2
)
3
2
3
2
)
3
2
3
BiBr
3
, 18% of dihydronaphthalene 5a was formed, whereas 12% of hydroxylated product 7a was
24,25
2 3 2
identified using Bi(NO ) •5H O.
Due to the effectiveness of Bi(OTf) in catalyzing the transformation relative to the other
3
Bi(III) salts, we hypothesized that Bi(OTf) is serving as a precursor to TfOH, which is generated
3
in situ and behaves as the active catalytic species. This behavior of Bi(OTf) has precedent and is
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most commonly observed in esterification reactions. Moreover, the poor performance of all of
the non-triflate-containing Lewis acids seem to support the importance of TfOH. To probe this
hypothesis, 4a was subjected to TfOH (15 mol %) at room temperature (entry 11). Product 6a
was isolated in 61% yield along with an intractable mixture containing 5a, which is comparable
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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35
36
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44
45
46
47
48
49
50
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53
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60
to the outcome with Bi(OTf) (62% yield, entry 6). TfOH also outperformed other Bronsted
3
acids (TsOH and TFA) that were examined (entries 12 and 13). When 15 mol % of pre-formed
pyridinium triflate was used as the catalyst, only trace product was generated (entry 14). Finally,
when a reaction was run using Bi(OTf) (10 mol %) with 30 mol % of added 2,6-di-t-butyl
3
pyridine, no reaction occurred (entry 15). Based on these controls, we are confident that Bi(OTf)3
is serving as a surrogate for TfOH. The Bi(OTf) presumably reacts with the carbinol
3
3 2 3 2
stoichiometrically, as BiBr and Bi(NO ) •5H O did, but is immediately hydrolyzed to generate
the TfOH, which proceeds to catalyze the reaction. Moreover, Bi(OTf) performed better than
3
the other metal triflates studied due to both its ability to form TfOH more readily and its unique
27
Lewis acidity. This is important, as the extent of Lewis acid coordination to the ester carbonyl
seems to correlate with dihydronaphthalene formation (aryl trapping) versus ABL formation
(
ester trapping). Ultimately, due its superb ease of handling compared to TfOH, Bi(OTf) was
3
chosen as the preferable catalyst for the remaining studies.
In the previous report, 4 Å molecular sieves were included in the reaction mixture in
order to sequester the generated water and prevent unwanted side reactions and Lewis acid
deactivation. For ABL formation, the desired reaction pathway requires an equivalent of water in
the hydrolysis step of the mechanism, releasing methanol. To determine if the 4 Å molecular
sieves were a hindrance or boon for ABL formation, the reaction was performed without the
addition of 4 Å molecular sieves for comparison (entry 16). Although the reaction provided 60%
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1
1
1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
NMR yield of ABL 6a, it resulted in a highly complex mixture, preventing the isolation of pure
product. It is likely that the 4 Å molecular sieves help to control the amount of water in the flask,
2
8
resulting in less side reactions. Further attempts to improve the yields by changing catalyst
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
loading, solvent, or temperature were unsuccessful (entries 17-21). Thus, the optimized reaction
conditions chosen for ABL formation were Bi(OTf)
in CH Cl at room temperature.
3
(5 mol %) with added 4 Å molecular sieves
2
2
E/Z Determination. With ABL 6a isolated as a single diastereomer, we sought to determine the
absolute configuration. We predicted an E configuration based on the allylic coupling constants;
however, initial attempts using NOE and 2D NMR techniques failed to conclusively elucidate
the configuration. In order to conclusively determine the configuration of 6a, crystals were
grown and the X-Ray crystal structure was obtained (Figure 2). ꢀ This confirmed our initial
suspicion that 6a was indeed the E-isomer.
Figure 2. Crystal Structure of 6a drawn at the 50% probability level.
3
Proposed Mechanism. Mechanistically, we propose that Bi(OTf) first reacts with cyclopropyl
carbinol 4 to form cyclopropyl carbinyl carbocation I (Scheme 5). In this initial reaction,
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Bi(OTf)
3
3
is converted to O=Bi(OTf) and TfOH is generated. With Bi(OTf) consumed, TfOH
catalyzes the transformation of remaining 4 to carbocation I. At this stage, the reaction can
proceed through two different pathways to afford products 5 and/or 6. In the path towards
product 6, cyclopropyl carbinyl carbocation I undergoes ring opening to form homoallylic
carbinyl cation transition state TS1. Intramolecular trapping of the cation in TS1 by the pendant
10
11
12
13
14
15
16
17
18
19
20
21
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23
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27
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57
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59
60
2
9
ester would then form oxonium intermediate II. Hydrolysis of II results in the loss of methanol,
1
2
furnishing ABL 6 (pathway a). If R or R is a π-donating substituent (aryl or alkenyl group),
Friedel-Crafts-type π-attack on an alternative ring opened transition state (TS2) would generate
the (hetero)aryl-fused cyclohexa-1,3-diene 5 (pathway b). It is also likely that if hydrolysis is
slow, intermediate II could go back towards intermediate I and proceed towards product 5. To
fully understand the nature of this chemodivergence, substituent effects on both the cyclopropane
and carbinol were studied.
Scheme 5. Proposed Mechanism for the Bi(OTf)
3
-Catalyzed Dehydrative, Ring-Opening
Cyclization
OH
O
R2
R1
R2
R2
R2 OMe
OMe
O
OMe
R4
R1
R1
Hydrolysis
R1
O
R4
O
4
- H O
O
R3
2
pathway (a)
HOTf
R4
II
3 R4
R
TS1
R3
6
R3
R2
Bi(OTf)3
O
R1
OMe
R4
I
R3
R2 OMe
O
O=Bi(OTf)
R2
OMe
Friedel-Crafts
O
R1
=
R3
pathway (b)
TS2
R4
R3 R4
5
Exploration of Substrate Scope and Substituents Effects. Toward exploring the scope of the
reaction, the effects of changing the cyclopropane substituents were probed (Table 2). First,
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2
2
2
2
2
2
2
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3
3
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
various aryl substituents were studied to identify any electronic effects. Interestingly, a clear
trend emerged. Slightly electron-poor aryl rings favored ABL formation, whereas electron-rich
ones favored the formation of cyclohexa-1,3-diene products 5 . For instance, changing from the
phenyl in 4a to the more electron-rich tolyl or 4-methoxyphenyl (as in 4b and 4c) afforded 23%
yield of ABL 6b (as a 3:1 E:Z mixture of diastereomers) in the case of 4b, whereas no ABL was
detected with 4c (entries 2 and 3). In each case, dihydronaphthalenes 5b and 5c were
respectively isolated with 49% and 67% yield. In contrast, when the phenyl ring was substituted
with a chlorine or bromine, the reaction proceeded efficiently to the ABL product. ABL 6d was
isolated as the E-diastereomer in 81% yield from 4-chlorophenyl-substituted cyclopropane 4d
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
entry 4). Similarly, the 4-bromophenyl-, 3-bromophenyl-, and 2-bromophenyl-substituted
cyclopropanes (4e-4g) each provided their respective ABL products (6e-6g) in 87%, 89%, and
2% yield as single E-diastereomers, indicating minimal positional electronic effects (entries 5-
7
7). To further probe this trend, cyclopropane 4h (bearing a 2-bromo-4-chlorophenyl substituent)
was used. The reaction failed to reach completion under the standard conditions; however, at a
higher loading (20 mol %) of Bi(OTf)
diastereomer (entry 8).
3
, ABL 6h was obtained in 78% yield as the E-
Table 2.ꢀProbing the Effects of the Cyclopropane Donor Group(s).
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entrya
Carbinol 4
ABL 6
yield (%)b
E:Zc
O
MeO
MeO
OH
O
O
MeO
MeO
OMe
R
R
1d
2d
3
4
4a (R = H)
6a
6b
62
23
>99:1
3:1e
4b (R = 4-Me)
4c (R = 4-MeO)
4d (R = 4-Cl)
4e (R = 4-Br)
4f (R = 3-Br)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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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
f
--
--
6
6
c
d
81
87
89
>99:1
>99:1
>99:1
5
6e
6
6
6
f
7
4g (R = 2-Br)
72
>99:1
g
O
OH
O
MeO
MeO
O
8g
OMe
78
>99:1
Cl MeO
Br
MeO
Br
4
h
6h
Cl
O
OH
O
MeO
MeO
MeO
MeO
O
OMe
R
R
9
4i (R = 2-Np)
6i
6j
24
--h
>99:1
--
1
0
4j (R = 2-furyl)
OH
O
O
MeO
MeO
MeO
MeO
OMe
Me
O
Me
R
R
1
1
4k (R = Ph)
4l (R = 3-thienyl)
38
>99:1
--
6
k
i
12
6l
--
OH
O
O
MeO
MeO
MeO
MeO
OMe
OMe
O
--j
1
1
3
4
34
4
m
6m
6n
OH
O
O
MeO
MeO
MeO
MeO
O
43k
1:1
4n
ꢀ
a
3
Reactions were performed with cyclopropyl carbinol 4 (1 equiv) and Bi(OTf) (10 mol %) in
b
CH
2
Cl
2
(0.1 M) at 23 ˚C in the presence of 4 Å mol sieves. Isolated yield after column
c
1
d
chromatography. E/Z ratios determined by H NMR on the crude mixture. Reaction performed
e
1
with 5 mol % Bi(OTf)
3
. E/Z ratio determined by combination of isolated yield of (E)-6b and H
f
NMR yield of impure (Z)-6b using dimethyl terephthalate as an internal standard. Only
g
h
3
dihydronaphthalene product 5c formed. Reaction performed with 20 mol % Bi(OTf) .
i
j
Intractable mixture. No desired product formed. Isolated as a 5:1 mixture of unassigned
k
diastereomers. Isolated as a 12:1 mixture of 6n and an elimination product 8n. Product yield
1
based on H NMR using dimethyl terephthalate as an internal standard.
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1
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
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4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
Other aryl (and heteroaryl) substituents were also studied. With the electron-rich 2-
naphthyl substituted derivative 4i, ABL 6i was obtained in 24% yield as the E-diastereomer in
addition to 51% of dihydronaphthalene 5i (entry 9). Next, given its presence in various ABL
natural products, a furyl substituent was employed. Unfortunately, an intractable mixture was
formed from the 2-furyl substrate 4j (entry 10). This outcome is most likely due to acid-mediated
furan degradation/polymerization pathways.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The reaction proved amenable to certain geminally-substituted cyclopropanes. The gem-
methyl phenyl cyclopropane 4k gave its ABL product 6k in 38% yield as the single E-
diastereomer with dihydronaphthalene 5k also present in an inseparable mixture (entry 11).
Conversely, no ABL product was formed from the gem-methyl 3-thienyl cyclopropane 4l, (entry
10
1
2); instead, acyclic elimination products 8l were obtained in 46% yield (Figure 3). These
products presumably arise from cyclic oxonium II as undesired E1-type elimination outpaces
hydrolysis. Indanyl cyclopropane 4m gave 34% yield of the desired ABL 6m along with 43% of
similar elimination products 8m (entry 13). Finally, the gem-dialkyl-substituted, spirocyclic
cyclopropane 4n afforded ABL 6n in 43% NMR yield as a 12:1 mixture of ABL isomers to
elimination product 8n (entry 14).
O
O
O
MeO
MeO
MeO
MeO
OMe
OMe
MeO
MeO
OMe
8l
8m
8n
S
Figure 3. Undesired Elimination Products 8
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The carbinol substituent was next changed from the 3,4-dimethoxyphenyl group to other
(hetero)aryl and alkyl groups to similarly probe electronic effects (Table 3). The 4-
methoxyphenyl carbinol 4o gave the desired ABL 6o in 73% yield as a 7:1 E:Z mixture (entry 1).
Phenyl carbinol 4p afforded ABL product 6p in 65% yield as a 1:1 E:Z mixture (entry 2). 4-
Chlorophenyl carbinol 4q generated a complex mixture that contained 35% NMR yield of ABL
10
11
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13
14
15
16
17
18
19
20
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22
23
24
25
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27
28
29
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32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
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50
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59
60
6
q as a 1:1 mixture of diastereomers (entry 3). An intractable mixture was obtained with 3-
chlorophenyl carbinol 4r (entry 4). Using the 3,5-dimethoxyphenyl substrate 4s also resulted in a
complex mixture of products, containing ABL product 6s in 26% yield as a 1:1 mixture of
diastereomers by NMR (entry 5). ABL 6t was obtained as the single E-diastereomer in 48%
yield from benzofuranyl carbinol 4t (entry 6).
Table 3. Probing the Effects of the Carbinol Substituent(s)
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2
2
2
2
2
2
2
3
3
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3
3
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3
3
3
3
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4
4
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4
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5
5
5
5
5
5
5
5
5
5
6
entrya
yield (%)b
E:Zc
Carbinol 4
ABL 6
OH
O
O
OMe
Ph
O
R
R
Ph
1
2
3
4
4o (R = 4-MeO)
4p (R = H)
4q (R = 4-Cl)
4r (R = 3-Cl)
6o
73
60
7:1d
1:1
1:1
--
6p
6q
6r
e
35
f
--
OH
O
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MeO
MeO
OMe
Ph
O
5
6
26e
1:1
Ph
MeO
MeO
4s
6s
OH
O
O
O
O
OMe
Ph
O
48
>99:1
Ph
4
4
t
6t
OH
O
O
Me
Me
Me
Me
OMe
Ph
O
7
8
--g
--
--
6u
u
Ph
OH
O
O
OMe
Ph
O
--g
Me
Me
Ph
4
v
6v
OH
O
Me
O
Me
OMe
Ph
Me
Me
O
27e
9
--
4
w
6w
Ph
R
O
OH O
R
MeO
MeO
MeO
MeO
O
OMe
Ph
Ph
10h
11
4x (R = Me)
4y (R = Ph)
6x
6y
54
41
>99:1
i
--
a
3
Reactions were performed with cyclopropyl carbinol 4 (1 equiv) and Bi(OTf) (10 mol %) in
b
CH
2
Cl
2
(0.1 M) at 23 ˚C in the presence of 4 Å mol sieves. Isolated yield after column
c
1
d
chromatography. E/Z ratios determined by H NMR on the crude mixture. E/Z ratios
e
1
determined from yields of isolated E and Z-isomers. Yield based on H NMR using dimethyl
f
g
terephthalate as an internal standard. Intractable mixture. No reaction. Starting material
h
i
recovered. Reaction performed with 5 mol % Bi(OTf)
3
.
Isolated as a 3:1 mixture of
unassigned diastereomers.
When 2˚ dialkyl carbinols (as in 4u and 4v) were employed, no reaction occurred and
starting materials were recovered (entries 7 and 8). In contrast, the trialkyl 3˚ carbinol 4w does
react to give ABL 6w, albeit as a complex mixture with a low 27% yield by NMR (entry 9). As
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expected, tertiary benzylic carbinols similarly undergo the ring-opening cyclization to form ABL
products. For instance, in the case of 4x (bearing methyl and aryl carbinol substituents), ABL 6x
was formed in 54% yield as a single diastereomer (entry 10). For the diaryl-substituted carbinol
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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45
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4
y, ABL 6y was obtained in 41% yield as a 3:1 diastereomeric mixture (entry 11). While it is
assumed that the E-isomer is the major product in both cases, it was impossible to
1
unambiguously assign the major and minor isomers using H NMR due to the absence of the
allylic coupling. In both cases, dihydronaphthalene products were also observed (5% of 5x; 36%
of 5y).
The outcomes from the exploration of substrate scope aligned well with the proposed
mechanism and also highlighted that substituent effects were critical in determining product
outcomes through comparative stabilization of intermediates and/or transition states. For instance,
since the carbinol substituents serve to stabilize cyclopropyl carbinyl cation I, the carbinols must
be sufficiently activated to promote the reaction. While electron-rich aryl substituents are well-
tolerated, electron-poor ones give substantially lowered yields, loss of E/Z selectivity, or
increased unwanted side reactions. Similary, secondary (and by default, primary) carbinols are
not amenable to the reaction as the cyclopropyl carbinyl cations do not form. For aryl
cyclopropyl carbinols, the ABL formation pathway (ester trapping and hydrolysis) directly
competes with the Friedel-Crafts pathway with substituent electronic effects determining product
outcomes. Electron-rich aryl substituents on the cyclopropane result in predominantly Friedel-
Crafts products while more electron-poor aryl donor substituents give preferential ABL
formation. It is plausible that the extent of ester involvement in stabilizing the acyclic
carbocationic transition state may facilitate cyclopropane ring opening and, ultimately, determine
the chemoselectivity.
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6
3
Revisiting TfOH as the Catalyst. Despite the fact that Bi(OTf) was chosen as the optimum
catalyst for the transformation in the optimization studies (due to ease of handling and overall
performance), TfOH also presented itself as a viable option as a catalyst. To probe potential
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3
differences between TfOH and Bi(OTf) as catalysts, four moderately active substrates with
varying E/Z selectivities were submitted to optimized catalytic TfOH conditions (Table 4). As
previously mentioned, the reaction outcomes were almost identical for the formation of ABL 6a
3
(entry 1). For spirocyclic ABL 6n, Bi(OTf) afforded a higher yield than TfOH (43% vs. 30%,
entry 2), whereas the reverse was observed for ABL 6p (60% vs. 73% yield). In both cases, the
same 1:1 E:Z selectivity was obtained. In contrast, a dramatic selectivity difference occurred
3
with benzofuranyl ABL 6t (entry 4). While Bi(OTf) gave a >99:1 E:Z ratio with a modest 48%
yield, TfOH provided a much higher yield (69%) but with a severely reduced 5:1 E:Z ratio. From
this subset of reactions, it seems that there are some difference between the catalysts, which may
arise from the amount of TfOH readily available to catalyze the reaction or the potential for
interactions with the Lewis acidic Bi(OTf)
than the other in terms of product yields, but Bi(OTf)
outcomes of ABL 6t. This, along with the experimental precautions necessary for TfOH use,
suggests Bi(OTf) as the catalyst of choice for this transformation; however, TfOH remains a
strongly viable catalyst for the transformation should Bi(OTf) be unavailable for use.
3
. Neither set of conditions was consistently better
3
may provide more selectivity based on the
3
3
3
Table 4. Comparison of Bi(OTf) vs. TfOH Catalysis
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entrya
Bi(OTf)3a
(10 mol %)
TfOHb
(15 mol %)
ABL 6
O
MeO
62% isolated yieldc
99:1 E:Zd
61% isolated yieldc
>99:1 E:Zd
1
O
>
MeO
6
a
n
Ph
O
MeO
43% NMR yielde
1:1 E:Zd
30% NMR yielde
1:1 E:Zd
O
2
3
4
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MeO
6
O
6
1
0% isolated yieldc
:1 E:Zd
73% NMR yielde
1:1 E:Zd
O
6p
Ph
O
O
8% isolated yieldc
99:1 E:Zd
69% NMR yielde
5:1 E:Zd
4
>
O
Ph
6
t
a
3
Reactions were performed with cyclopropyl carbinol 4 (1 equiv) and Bi(OTf) (10 mol %) in
b
CH
2
Cl
2
(0.1 M) at 23 ˚C in the presence of 4 Å mol sieves. Reactions were performed with
cyclopropyl carbinol 4 (1 equiv) and TfOH (15 mol %) in CH
2
Cl
2
(0.1 M) at 23 ˚C in the
c
d
presence of 4 Å mol sieves. Isolated yield after column chromatography.
E/Z ratios
1
e
1
determined by H NMR on the crude mixture. NMR yield based on H NMR using dimethyl
terephthalate as an internal standard.
E/Z Selectivity. With a handle on trends for ABL vs. cyclohexadiene chemodivergence, the
origins of E/Z selectivity were the next subject to be explored. While most substrates were
completely E-selective, a handful offered either no selectivity or reduced diastereomeric ratios.
In hopes of understanding these outliers, DFT calculations were employed to examine the
cyclopropane opening transition states between intermediates I and II, derived from both the 3,4-
dimethoxy phenyl substituted carbinol 4a (high selectivity) and the phenyl carbinol 4p (low
selectivity, Figure 4). The transformation generally agreed with our proposed mechanistic
transformation between I and II, going through a homoallylic cation partially stabilized through
an approaching ester. Consistent with the experimentally observed selectivities, the computations
‡
revealed a ∆∆G = 3.9 kcal/mol – in favor of E isomer formation – for the 3,4-dimethoxy phenyl
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6
‡
carbinyl cation I-a. Meanwhile, ∆∆G = 1.3 kcal/mol for I-p, which displayed no E/Z selectivity
under the optimized reaction conditions.
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0
A.
B.
OMe
O
OMe
O
MeO
MeO
2.83/2.86 Å (E/Z)
2.98/2.98 Å (E/Z)
8
8.2
.7/
Ph
Ph
TS1-a
4.5/
4.3
TS1-p
Z
E
Z
E
4.8/
∆∆G‡E/Z = 3.9 kcal/mol
∆∆G‡E/Z = 1.3 kcal/mol
E/Zexperimental = 1:1
4
.8
3.2/
2.6
E/Zexperimental = 99:1
0
.0
1
.42 Å
0
.0
β CO2Me
α
1.40 Å
-3.8/
OMe
O
1.73 Å
-7.4/
-8.2
-3.9
MeO
MeO
γ
OMe
O
Z
E
β CO2Me
Z
MeO
MeO
Ph
α
1.45 Å
I-p
1
.65 Å
γ
Ph
-9.7/
-9.9
Ph
-13.4/
-13.9
1
.47 Å
I-a
Ph
II-a
E
II-p
Reaction coordinate
Reaction coordinate
Figure 4. Cyclopropane opening reaction coordinates for I-a (A) and I-p (B) given in both Gibbs
free energy and enthalpy. Relevant geometries reflect a relatively late transition state from I-a to
II-a.
The more exothermic ring opening for I-p suggests an earlier transition state and thus
begs the application of Hammond’s postulate to rationalize observed selectivities. Indeed, not
only is the transformation more exothermic for I-p, but the cyclopropane C
β
-C bond in I-p is
γ
weakened compared to that in I-a, 1.73 Å vs. 1.65 Å respectively. In this light, the C
β
-C bond
γ
must undergo more elongation to reach the transition state from I-a, prompting a later and more
selective transition compared to that from I-p.
Here, the difference in cyclopropane lability arises from the different electron donating
potentials of the phenyl rings. Methoxy substitutions at the 3 and 4 positions increase
stabilization of the benzylic cation at C . With less electron donating potential on the
α
unsubstituted phenyl ring, I-p compensates by elongating the C
β
-C bond and delocalizing some
γ
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of the positive charge onto the benzylic C
γ
position. This phenomenon is reflected not only in the
elongation of C
β
-C
γ
but also in the shortening of the Ph-C bond (1.47 Å in I-a vs. 1.45 Å in I-p).
γ
+
Atomic partial charges (δ ) reflect these geometric changes by displaying a shift of positive
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charge accumulation from C
α
to C
γ
as the C
β
-C length increases.
γ
Hypothetically, the cyclopropane could be polarized via substitution on the second
phenyl ring as well. For example, comparing I-a and I-b we see that 4-methyl substitution is
responsible for elongating C
β
-C by 0.02 Å in the ground state (Figure 5A); a concomitant drop in
γ
E/Z selectivity from 99:1 to 3:1 is observed in the synthetic experiments. Holding sterics
constant and examining this trend across structures I-a, I-b, I-d to I-h, I-o, I-p, I-q, and I-s
1
suggests that, as a corollary to Hammond’s postulate, electron donating groups at Ph and
2
electron withdrawing groups at Ph enhance E/Z selectivity by strengthening the C
β
-C
γ
bond in
the ground state carbinyl cation I (Figure 5B).
A.
+
1.23
d+ = +1.34
+1.37
b
a
1.73 Å
1
.67 Å
1
.65 Å
g
I-a
I-b
I-p
d+ = +0.80
+0.95
+1.08
B.
1:1
E/Z = 99:1
7:1 3:1
α
β
β CO Me
CO Me
2
2
Ph1
Ph1
α
γ
γ
Ph2
Ph2
I-h
I-g
I-f
I-o I-b
I-q
I-p
I-s
I-a
I-d
I-e
C -C =
1.60 Å
1.64 Å
1.68 Å
1.72 Å
1.74 Å
β
γ
1
2
Figure 5. (A) Substitution on either Ph or Ph can effect elongation of the C
β
-C bond. (B) A
γ
spectrum of C
β
-C bond lengths highlights the correlation between observed E/Z selectivities and
γ
cyclopropane lability.
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Through comparing the experimental results to DFT calculations, the selectivities can be
reasonably rationalized by applying Hammond’s postulate to the transition from I to II through
TS1. Moreover, the E/Z selectivity and the polarization (as measured by bond length) of the
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cyclopropyl C
β
-C in the ground state carbinyl cation I can then be correlated. This approach
γ
provides an easily accessible calculation (C
β
-C bond length in intermediate I) as the basis for
γ
predicting the E/Z selectivity in ABL formation.
ꢀ
Conclusions. In summary, we have disclosed the Bi(OTf)
of (hetero)aryl cyclopropyl carbinols to form functionalized α-alkylidene-γ-butyrolactones
ABLs). The overall transformation marks different chemoselectivity than observed in previous
reports for the acid-promoted reactions of (hetero)aryl cyclopropyl carbinols. Bi(OTf) likely
3
-catalyzed ring-opening cyclizations
(
3
serves as a stable and user-friendly precursor to TfOH, which proceeds to catalyze the reaction.
The resulting ABLs are formed in up to 89% yield, with generally high E-diastereoselectivity.
Substituent effects play a major role in the determination of reaction chemoselectivity, with
cyclopropyl carbinol substituents directly influencing cyclopropane ring-opening. The
cyclopropane donor substituents directly influence the overall reaction chemoselectivity, with
weakly stabilizing or electron-poor substituents providing better yields of the ABL products. In
contrast, highly stabilizing cyclopropane donor substituents give copious amounts of competing
products including, most importantly, (hetero)aryl-fused cyclohexa-1,3-diene products 5. Using
DFT calculations, a predictive model was developed that correlates E/Z selectivity with the C
β
-C
γ
bond length in the ground state cyclopropyl carbinyl cation. The ester plays an important role in
stabilizing the transient acyclic homoallylic cation formed upon ring opening or, possibly, in
facilitating cyclopropane ring opening by anchimeric assistance. Overall, we now have a better
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understanding of how different substituents can influence product outcomes through their
interactions with intermediate I and ring-opening transition states in our proposed mechanism.
Future efforts with enantiopure cyclopropyl carbinols will serve to better explore the hypothesis
of ester involvement while enabling access to chiral ABLs. Future work will also focus on
specific target synthesis and applying the trends we learned towards targets for both products 5
and 6.
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EXPERIMENTAL SECTION
General Information. Chromatographic purification was performed as flash chromatography
with Silicycle SiliaFlash P60 silica gel (40-63µm) or preparative thin-layer chromatography
(prep-TLC) using silica gel F254 (1000 µm) plates and solvents indicated as eluent with 0.1-0.5
bar pressure. For quantitative flash chromatography, technical grades solvents were utilized.
Analytical thin-layer chromatography (TLC) was performed on Silicycle SiliaPlate TLC silica
gel F254 (250 µm) TLC glass plates. Visualization was accomplished with UV light.
Infrared (IR) spectra were obtained using ATR on an IRAffinity-1S FTIR from
Shimadzu. The IR bands are characterized as broad (br), weak (w), medium (m), and strong (s).
1
13
Proton and carbon nuclear magnetic resonance spectra ( H NMR and C NMR) were recorded
on a Varian Mercury Vx 300 MHz spectrometer or a Bruker 500 MHz spectrometer with solvent
1
13
resonances as the internal standard ( H NMR: CDCl
3
at 7.26 ppm; C NMR: CDCl
3
at 77.0
1
ppm). H NMR data are reported as follows: chemical shift (ppm), multiplicity (s = singlet, d =
doublet, dd = doublet of doublets, dt = doublet of triplets, ddd = doublet of doublet of doublets, t
=
triplet, m = multiplet, br = broad), coupling constants (Hz), and integration. High resolution
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6
mass spectrometry (HRMS) measurements were obtained either through EI on a Micromass
AutoSpec M [forward geometry (EBE) three sector tandem MS] or through ESI on a Thermo
Orbitrap XL. The accurate mass analyses run in EI mode were at a mass resolution of 10,000 and
were calibrated using PFK (perfluorokerosene) as an internal standard. The accurate mass
analyses run in ESI mode were at a mass resolution of 30,000 using the calibration mixture
supplied by Thermo. Uncorrected melting points were measured with a digital melting point
apparatus (DigiMelt MPA 160).
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Computational Method. All calculations were performed using the Gaussian 09 package at the
30,31
M06L/6-31g(d,p) level of theory.
Gaussian’s default solvation model, the Polarizable
Continuum Model implemented via integral equation formalism (IEF-PCM), was employed to
3
2-34
simulate a dichloromethane solvent.
Transition state calculations were verified to have only
one imaginary vibrational frequency.
Synthesis of β-keto Esters 1.
General Procedure: A dry round-bottom flask was charged with a stir bar, and sodium hydride
(2.8 equiv) was added under nitrogen atmosphere. Dimethyl carbonate (2.0 equiv) was then
added with toluene, and the reaction was stirred and heated to reflux. A solution of the aryl
ketone (1.0 equiv.) in toluene was added drop-wise over 30 min using a syringe pump for an
overall reaction concentration of 1.0 M. The reaction was monitored by TLC until complete
conversion of the aryl ketone was observed. After the evolution of hydrogen gas, the reaction
was allowed to cool to room temperature, and acetic acid (6 mL) was added drop-wise to the
reaction mixture. Ice-cold water was added to dissolve any solid that formed, and then the
solution was diluted with EtOAc. The organic layer was extracted with EtOAc three times, dried
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over Na
2
SO
4
, and filtered through a celite plug. The combined organic layers were concentrated
under reduced pressure and purified by flash chromatography on silica gel using EtOAc/Hexanes
as the mobile phase.
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Methyl 3-(4-chlorophenyl)-3-oxopropanoate (1q): Prepared following the general procedure
using sodium hydride (60 % dispersion in mineral oil, 3.60 g, 90.6 mmol), dimethyl carbonate
(99% pure, 5.5 mL, 64.7 mmol) and 1-(4-chlorophenyl)ethan-1-one (5.00 g; 32.3 mmol) in
toluene (32.3 mL) over 30 min. After work up and purification, (20% EtOAc/Hexanes, R
f
=
0
.50), compound 1q was afforded as a thick orange oil (6.67 g, 97% yield). Characterizations
3
5
were consistent with previously reported literature.
Methyl 3-(3-chlorophenyl)-3-oxopropanoate (1r): Prepared following the general procedure
using sodium hydride (60 % dispersion in mineral oil, 3.60 g, 90.6 mmol), dimethyl carbonate
(99% pure, 5.5 mL, 64.7 mmol) and 1-(4-chlorophenyl)ethan-1-one (5.00 g; 32.3 mmol) in
toluene (32.3 mL) over 30 min. After work up and purification, (20% EtOAc/Hexanes, R
f
=
0.52), compound 1r was afforded as a orange oil (6.62 g, 96% yield). Characterizations were
35
consistent with previously reported literature.
Synthesis of Diazo Compounds 2.
General Procedure: A 1M solution in CH
to a dry flask charged with a stir bar under nitrogen. Et
was allowed to stir for 5 min. TsN (1.2 equiv) was then added in one shot and stirred at room
temperature until completion. The reaction was monitored by TLC until complete conversion of
3
CN of the starting β-keto ester (1.0 equiv) was added
3
N (1.2 equiv) was added in one shot and
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the β-keto ester was observed. Upon completion, the reaction was concentrated under reduced
2 2 2
pressure and TsNH was recrystallized and filtered out using cold CH Cl . The filtrate was then
concentrated under reduced pressure and purified by flash chromatography on silica gel using
EtOAc/Hexanes as the mobile phase.
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Methyl 2-diazo-3-(3,4-dimethoxyphenyl)-3-oxopropanoate (2a) was synthesized as previously
1
7
reported.
Methyl 3-(4-chlorophenyl)-2-diazo-3-oxopropanoate (2q): The general procedure was followed
using compound 1q (4.35 g, 20.5 mmol) in acetonitrile (18.3 mL), Et N (99% pure, 2.22 g, 21.9
mmol), and TsN (85% pure, 4.68 g, 23.7 mmol) over 18 h. After work up and purification, (20%
EtOAc/Hexanes, R = 0.40), compound 2q was afforded as a yellow solid (4.39 g, 90% yield).
Characterizations were consistent with previously reported literature.
3
3
f
3
6
Methyl 3-(3-chlorophenyl)-2-diazo-3-oxopropanoate (2r): The general procedure was followed
using compound 1r (3.07 g, 14.4 mmol) in acetonitrile (14.4 mL), Et N (99% pure, 1.56 g, 15.4
mmol), and TsN (85% pure, 3.25 g, 16.7 mmol) over 18 h. After work up and purification, (20%
EtOAc/Hexanes, R = 0.33), compound 2r was afforded as a yellow solid (3.33 g, 97% yield).
3
3
f
o
1
[
m.p. = 53-54 C] H NMR (300 MHz, CDCl
3
) δ =ꢀ7.61 - 7.58 (m, 1 H), 7.52 - 7.46 (m, 2 H),
1
3
7
1
.39 - 7.32 (m, 1 H), 3.79 (s, 3 H) C NMR (75 MHz, CDCl ) δ = 185.4, 161.0, 138.4, 134.0,
3
-
1
32.1, 129.1, 128.3, 126.4, 52.4 IR: 2955 (w), 2852 (w), 2133 (s), 1722 (s), 1628 (m) cm .
+
HRMS (EI) m/z: [M] Calcd. for C10
H
7
ClN
2
O
3
238.0145; Found 238.0140.
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Synthesis of styrene derivatives.
General Procedure: A general Wittig procedure was followed. Methyltriphenylphosphonium
iodide (5.0 g, 12.4 mmol) was added to a clean, dry round bottom flask under nitrogen charged
with a stir bar. Dry THF (100 mL) was added and the reaction was cooled to 0 °C with stirring.
n-BuLi (4.8 mL of 2.5 M solution in hexanes, 12.0 mmol) was added dropwise and allowed to
stir for 15 min. Aldehyde (10.7 mmol in 7 mL THF) was added over 1 min. After another 15 min
of stirring at 0 °C, the reaction was allowed to warm to room temperature and stir for another 2 h.
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2 4
The reaction was quenched with water, extracted 3 times with EtOAc, dried using Na SO ,
passed through a celite plug, concentrated under reduced pressure, and columned on silica gel
using hexane as the mobile phase.
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-Bromostyrene (9a): Prepared using the general procedure using 3-bromobenzaldehyde (2.0 g,
10.7 mmol) as the aldehyde. After workup and purification, compound 9a was obtained as a
colorless oil (1.51 g, 77%). Characterizations were consistent with previously reported
3
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literature.
2
-Bromostyrene (9b): Prepared using the general procedure using 2-bromobenzaldehyde (2.0 g,
0.7 mmol) as the aldehyde. After workup and purification, compound 9b was obtained as a
1
colorless oil (1.47 g, 75%). Characterizations were consistent with previously reported
37
literature.
2
-Bromo-5-chlorostyrene (9c): Prepared using the general procedure using 2-bromo-5-
chlorobenzaldehyde (2.35 g, 10.7 mmol) as the aldehyde. After workup and purification,
2
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Synthesis of Cyclopropanes 3.
2 2
General Procedure: A dry flask was charged with a stir bar, Rh esp (0.2 mol%), and half the
necessary dry CH
2
Cl
2
for the reaction under nitrogen. The alkene (2.0 equiv) was then added in
˚
one shot and the reaction was cooled to 0 C. The diazo (1.0 equiv) was dissolved in the other
˚
portion of CH
2
Cl
2
necessary to make a 0.1 M solution, cooled to 0 C, and added to the reaction
˚
vessel over 1 min. The reaction stirred at 0 C for 15 min, and then was allowed to warm to room
temperature and stir until completion. The reaction was monitored by TLC until complete
conversion of the diazo was observed. Upon completion, the reaction was quenched with
2 2 2 4
thiourea (aq), extracted with CH Cl three times, dried using Na SO , and filtered through celite.
The combined organic layers were concentrated under reduced pressure and purified by flash
chromatography on silica gel using EtOAc/Hexanes as the mobile phase.
Methyl 2-(3-bromophenyl)-1-(3,4-dimethoxybenzoyl)cyclopropane-1-carboxylate (3f): Prepared
following the general procedure using compound 9a (180 mg, 1.0 mmol), Rh
2 2
esp (96% pure,
1
.4 mg, 0.0018 mmol), and compound 2a (179 mg, 0.68 mmol) in CH Cl (6.8 mL) over 4 h.
2
2
After work up and purification, (20% EtOAc/Hexane, R
f
= 0.35), compound 3f was afforded as
1
an off-white oil (59.3 mg, 21% yield). Diastereomeric Ratio: 25:1). H NMR (300 MHz, CDCl
3
)
δ = 7.56 (dd, J = 2.1, 8.4 Hz, 1 H), 7.49 (d, J = 1.9 Hz, 1 H), 7.48 - 7.44 (m, 1 H), 7.39 - 7.33 (m,
H), 7.25 - 7.12 (m, 2 H), 6.88 (d, J = 8.5 Hz, 1 H), 3.94 (s, 3 H), 3.93 (s, 3 H), 3.45 (t, J = 8.5
1
1
3
Hz, 1 H), 3.32 (s, 3 H), 2.37 (dd, J = 5.0, 8.1 Hz, 1 H), 1.63 (dd, J = 5.1, 9.0 Hz, 1 H) C NMR
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(
75 MHz, CDCl
3
) δ = 192.1, 168.9, 153.3, 149.1, 137.4, 132.1, 130.3, 129.6, 129.4, 127.6, 123.0,
122.1, 110.5, 110.1, 56.0, 55.9, 52.4, 41.9, 29.4, 19.3 IR: 2936 (w), 2839 (w), 1732 (m), 1670
-1
+
5
(m) cm . HRMS (EI) m/z: [M] Calcd. for C20H19BrO 418.0416; Found 418.0420.
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Methyl 2-(2-bromophenyl)-1-(3,4-dimethoxybenzoyl)cyclopropane-1-carboxylate (3g): Prepared
following the general procedure using compound 9b (1.10 g, 6.01 mmol), Rh esp (96% pure,
.9 mg, 0.076 mmol), and compound 2a (1.0 g, 3.78 mmol) in CH Cl (38 mL) over 1 h. After
2
2
5
2
2
work up and purification, (30% EtOAc/Hexane, R
f
= 0.35), compound 3g was afforded as a
1
colorless oil (309.2 mg, 20% yield). Diastereomeric Ratio: (15:1). H NMR (300 MHz, CDCl
3
)
δ = 7.58 - 7.51 (m, 3 H), 7.31 - 7.22 (m, 2 H), 7.16 - 7.08 (m, 1 H), 6.90 - 6.84 (m, 1 H), 3.94 (s,
H), 3.93 (s, 3 H), 3.64 (t, J = 8.5 Hz, 1 H), 3.30 (s, 3 H), 2.46 (dd, J = 4.9, 8.1 Hz, 1 H), 1.67
3
1
3
(dd, J = 4.9, 8.9 Hz, 1 H) C NMR (75 MHz, CDCl
3
) δ = 192.0, 169.2, 153.1, 149.0, 134.9,
1
32.5, 130.3, 129.7, 128.8, 126.8, 126.2, 122.8, 110.6, 109.9, 56.0, 55.9, 52.3, 41.3, 31.3, 20.2
-
1
+
IR: 2947 (w), 2839 (w), 1728 (m), 1670 (m) cm . HRMS (EI) m/z: [M] Calcd. for C20H19BrO
5
418.0416; Found 418.0411.
Methyl 2-(2-bromo-5-chlorophenyl)-1-(3,4-dimethoxybenzoyl)cyclopropane-1-carboxylate (3h):
Prepared following the general procedure using compound 9c (0.935 g, 4.3 mmol), Rh esp
96% pure, 5.9 mg, 0.0076 mmol), and compound 2a (1.0 g, 3.78 mmol) in CH Cl (37.8 mL)
2
2
(
2
2
over 18 h. After work up and purification, (30% EtOAc/Hexane, R
f
= 0.37), compound 3h was
1
afforded as a colorless oil (270.4 mg, 16% yield). Diastereomeric Ratio: (15:1). H NMR (300
MHz, CDCl
3
) δ = 7.56 - 7.44 (m, 3 H), 7.24 (d, J = 2.5 Hz, 1 H), 7.11 (dd, J = 2.5, 8.5 Hz, 1 H),
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.91 - 6.85 (m, 1 H), 3.95 (s, 3 H), 3.93 (s, 3 H), 3.57 (t, J = 8.5 Hz, 1 H), 3.37 - 3.34 (m, 3 H),
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