Copper-catalyzed chan-lam cyclopropylation of phenols and azaheterocycles

Article abstract of DOI:10.1021/acs.joc.7b03100

Small molecules containing cyclopropane-heteroatom linkages are commonly needed in medicinal chemistry campaigns yet are problematic to prepare using existing methods. To address this issue, a scalable Chan-Lam cyclopropylation reaction using potassium cyclopropyl trifluoroborate has been developed. With phenol nucleophiles, the reaction effects O-cyclopropylation, whereas with 2-pyridones, 2-hydroxybenzimidazoles, and 2-aminopyridines the reaction brings about N-cyclopropylation. The transformation is catalyzed by Cu(OAc)₂ and 1,10-phenanthroline and employs 1 atm of O₂ as the terminal oxidant. This method is operationally convenient to perform and provides a simple, strategic disconnection toward the synthesis of cyclopropyl aryl ethers and cyclopropyl amine derivatives bearing an array of functional groups.

Full text of DOI:10.1021/acs.joc.7b03100

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Featured Article
Copper-Catalyzed Chan–Lam Cyclopropylation
of Phenols and Azaheterocycles
Joseph Derosa, Miriam L. O'Duill, Matthew Holcomb, Mark N. Boulous, Ryan L.
Patman, Fen Wang, Michelle Tran-Dubé, Indrawan McAlpine, and Keary M. Engle
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03100 • Publication Date (Web): 02 Mar 2018
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The Journal of Organic Chemistry
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CopperꢀCatalyzed Chan–Lam Cyclopropylation of
Phenols and Azaheterocycles
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Joseph Derosa‡†, Miriam L. O’Duill‡†, Matthew Holcomb†, Mark N. Boulous†, Ryan L. Patman§, Fen
Wang§, Michelle Tran-Dubé§, Indrawan McAlpine§,* Keary M. Engle†*
†Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla,
California 92037, United States
§ Pfizer Oncology Medicinal Chemistry, 10770 Science Center Drive, San Diego, California 92121,
United States
* indrawan.mcalpine@pfizer.com; keary@scripps.edu
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
Abstract. Small molecules containing cyclopropane–heteroatom linkages are commonly needed in
medicinal chemistry campaigns, yet are problematic to prepare using existing methods. To address this
issue, a scalable Chan–Lam cyclopropylation reaction using potassium cyclopropyl trifluoroborate has
been developed. With phenol nucleophiles, the reaction effects Oꢀcyclopropylation, whereas with 2ꢀ
pyridones, 2ꢀhydroxybenzimidazoles, and 2ꢀaminopyridines the reaction brings about Nꢀ
cyclopropylation. The transformation is catalyzed by Cu(OAc)2 and 1,10ꢀphenanthroline and employs 1
atm O2 as the terminal oxidant. This method is operationally convenient to perform and provides a
simple, strategic disconnection toward the synthesis of cyclopropyl aryl ethers and cyclopropyl amine
derivatives bearing an array of functional groups.
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Introduction. Cyclopropyl groups are prevalent in drug molecules and bioactive compounds,1 with 8 of
the top 200 bestꢀselling therapeutics from last year containing a cyclopropyl moiety.2 As such, methods
for introducing these substituents are of significant interest in both academia and the pharmaceutical
industry. The goal of the present study was to expand the synthetic toolkit for appending cyclopropyl
groups to phenols and azaꢀheterocycles.
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Medicinal Chemistry Considerations. The rationale for incorporating cyclopropyl substituents in the
context of medicinal chemistry merits a brief introduction. Sound decisionꢀmaking in drug discovery
campaigns is often guided by disciplined optimization of lipophilic efficiency (LipE), a metric that is
used to capture the efficiency of a compound’s potency as a function of its lipophilicity.3 Increasing the
lipophilicity of a compound or series in the absence of other changes can often result in higher metabolic
clearance and thus higher dosing requirements to achieve sufficient efficacy. Therefore, from a practical
standpoint, judicious use of lipophilic groups is advised and the metabolic consequences of their
incorporation should be considered in parallel to any observed potency gain.
To interrogate the metabolic stability of the cyclopropyl functionality within the context of drugꢀlike
molecules, we performed a pairwise analysis of matched molecular pairs (MMPs) for a series of
cyclopropylꢀtoꢀalkyl group transforms using the Pfizer database and tools developed by our
computational ADME group.5 For this analysis, we focused on mining MMPs for transforms of interest
that contained clearance endpoints from Pfizer’s highꢀthroughput human liver microsome (HLM) assay.
Figure 1 summarizes the transforms that were examined and the corresponding statistics; for each
transformation, the percentages of cases that fall into each of three categories (decrease, no change, or
increase) are represented by the colorꢀcoded pie chart, and the numerical values represent the
corresponding mean change with the associated confidence interval. The data show that, on average,
cyclopropyl ringꢀopening transforms (iꢀPr, 2a and nꢀPr, 2b) along with ring expansion transforms
(cyclobutyl, 2c and cyclopentyl, 2d) result in an increase in HLM clearance.5 It is important to point out
the intrinsic variability in the HLM assay, as illustrated by the relatively wide confidence intervals
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observed. Nevertheless, general trends are useful to analyze, and these increases in microsomal
clearance can be rationalized as a result of increasing lipophilicity across the aforementioned
transformations.6 To demonstrate this point, we evaluated the transform of cyclopropyl 1 (clogP ~1.6) to
ethyl 2e (clogP ~1.7), having approximately equal lipophilic contributions, and found no meaningful
change in clearance for 82% of the 1752 MMPs with HLM data. Therefore, it is not surprising that
methylꢀbearing MMPs 2f (clogP Me~1.1) show a 30% increase in microsomal stability, and thus
represent the only transform examined with a clear metabolic advantage to cyclopropyl substitution.
Improving metabolic stability in a series is a common medicinal chemistry objective in order to improve
pharmacokinetic properties.7 In light of this analysis, new methodologies to introduce the cyclopropyl
motif are warranted and believed to be of broad interest due to the privileged nature of this functionality.
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Figure 1. Transformations examined to probe trends in microsomal stability. For each transform, the
number of total matched molecular pairs (MMPs) with human liver microsome (HLM) unbound
intrinsic clearance (CLint,u) is provided below the individual pie chart, along with the total number of
MMPs in the Pfizer data base in parentheses. The percentages of MMPs with HLM Clint,u data that fall
into each of three categories (decrease, no change, or increase) are represented by the colorꢀcoded pie
chart, where increase and decrease are defined by a ±20% change. The numerical value immediately
beneath each pie chart represents the mean change in HLM Clint corresponding with that transform.
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N
N
O
H
OH
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N
N
O
O2N
O
CF3
N
O
O
Cl
antitubercular agent9a
Huntington's Disease therapeutic9b
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O
Cl
O
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HO
O
N
O
N
N
H
O
CF3
Me
OMe
antidepressant9d
antibacterial agent9c
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F
O
O
F
CF3
F
F
H
N
OH
F
N
O
F
O
O
O
F
antiarthritic agent9e
cardiovascular disease therapeutic9f
Figure 2. Representative bioactive compounds bearing cyclopropylaryl ethers.9
While methodology to access cyclopropyl amines has been vigorously pursued in recent years,8
cyclopropyl ethers have received less attention. Nevertheless, small molecules containing cyclopropyl
aryl ethers have a range of biological activities across several different medical indications (Figure 2).9
Despite their utility, current methods for their synthesis remain limited and sometimes incompatible
with structurally complex, heteroatomꢀrich substrates. This gap in synthetic methodology motivated the
present study.
Results and Discussion. In terms of synthetic strategy, the most prudent retrosynthetic
disconnection of a cyclopropyl aryl ether is of the O–cꢀPr bond to give the corresponding phenol and a
cyclopropyl source. The alternative disconnection of the Ar–O bond is complicated by the fact that
cyclopropanol readily rearranges to form propanal.10 Indeed, this retrosynthetic logic underlies all
existing methods (Scheme 1).11–13 In one approach, a multiꢀstep sequence consisting of Oꢀalkylation
with a 1,2ꢀdihaloethane electrophile, baseꢀmediated E2 elimination, and Simmons–Smith
cyclopropanation11 is used. While this route provides access to the desired compounds, it requires at
least three steps, uses reagents with poor functional group compatibility, and can be lowꢀyielding
(Scheme 1a).11b A second approach is the reaction between a cyclopropyl halide electrophile and a
phenoxide nucleophile in a Williamson ether synthesis (Scheme 1b).12 Unfortunately, cyclopropyl
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halides are poor electrophiles in SN2 reactions and can undergo competitive E2 elimination. Thus, high
temperatures (typically ≥150 °C) are required to enable addition of the aryloxide into the corresponding
in situ formed cyclopropene. Under these forcing conditions, functional group compatibility can be
limited and formation of undesired allylꢀcontaining byproducts is sometimes observed. A third strategy
was reported in 1999 by Hollingworth and coworkers. This method exploits a sulfurꢀstabilized
carbocation in a modified SN1 reaction to form the key O–C(cyclopropyl) bond. Subsequent
oxidation/reduction then excises the sulfide (Scheme 1c).13 While inventive, this route nonetheless
suffers from limited phenol substrate scope due to the difficulty of the SN1 step with electronꢀpoor
phenols and requires subsequent oxidation/reduction steps that are incompatible with many functional
groups.
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A. Haloalkylation/E2 elimination/Simmons–Smith
C. Modified SN1 reaction
OH
1. CH2BrCH2Cl, K2CO3
2. t-BuOK
O
OH
O
I
1. Ag2CO3,
SPh
R
R
R
R
2. Oxone®, Al2O3
3. Na(Hg)
3. CH2I2, ZnEt2
B. Williamson ether synthesis
D. This work: Chan–Lam O-Cyclopropylation
Br
cat. CuII
OH
O
OH
O
BF3K
(excess)
cat. phen
R
R
R
1atm O2
R
base, 150–200 °C
• one-step • mild conditions • high FG tolerance
• scalable • OH/NH nucleophiles
Scheme 1. Comparisons of different methods for Oꢀcyclopropylation of phenols.11–13
The limitations of these existing methods prompted us to consider an alternative, whereby a
phenol could react with a nucleophilic cyclopropyl source in an oxidative coupling reaction. We
envisioned that a reaction of this type would avoid the aforementioned complications with cyclopropyl
halide electrophiles and would not require any additional concession steps. Herein, we describe the
realization of this idea and report a new method for generating cyclopropyl aryl ethers using Chan–Lamꢀ
type coupling.14 While the initial focus was on phenols, it was later found that this protocol is also
efficient for Nꢀcyclopropylation with select azaꢀheterocycles (vide infra).
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Reaction Optimization. At the outset, we took inspiration from recent reports on Chan–Lam
Nꢀcyclopropylation for the preparation of cyclopropylamine derivatives.8 Of particular importance for
our investigation, Mudryk and coworkers reported that Nꢀcyclopropyl 4ꢀnitrobenzenesulfonamide
(pKa(DMSO) 13.9 for NsNH2)15 underwent Chan–Lam coupling with cyclopropyl boronic acid,8d
lending credence to the notion that phenols (pKa(DMSO) = 10–19) would be of an appropriate acidity
and would be sufficiently nucleophilic to be competent reaction partners. This approach was further
motivated by other recent reports on Chan–Lam O- and Nꢀalkylation using alkyl boronates/boronic
acids.16–18 To the best of our knowledge, there is only one example in which a phenol has been reported
to react with a cyclopropylboronic acid in the presence of a copper promoter. In a 2010 patent, Cacatian
and coworkers report a single reaction proceeding in 13% yield using 1 equivalent of Cu(OAc)2 and 2
equivalents of bipyridine.19
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Table 1. Optimization of reaction conditions for Oꢀcyclopropylation of phenols.a
OH
O
+
BF3K
solvent, 70 ˚C, 12 h
1 atm O2 (balloon)
3a
4
5a
Entry
Ligand
Base (2 equiv)
Solvent
Yield (%)b
CuI/II (10 mol%)
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
DCE/H2O (2:1)
toluene/H2O (2:1)
MeCN/H2O (2:1)
toluene/H2O (2:1)
toluene/H2O (2:1)
toluene/H2O (2:1)
toluene/H2O (2:1)
1
2
3
4
5
20% pyridine
20% pyridine
20% pyridine
20% pyridine
20% pyridine
---
---
24
35
21
0
---
---
---
Cu(OAc)2
KOAc
K2CO3
K2CO3
K2CO3
41
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
6
7
8
20% pyridine
---
47
0
toluene/H2O (1:1)
toluene/H2O (3:1)
20% pyridine
43
Cu(OAc)2
K2CO3
9
20% pyridine
36
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
K2CO3
K2CO3
K2CO3
toluene/H2O (2:1)
toluene/H2O (2:1)
toluene/H2O (2:1)
10
11c
10% bipy
10% bipy
10% phen
71
49
84
12
Cu(HCO2)2
K2CO3
toluene/H2O (2:1)
13
10% phen
82
Cu(OTf)2
CuI
K2CO3
K2CO3
toluene/H2O (2:1)
toluene/H2O (2:1)
14
15
10% phen
10% phen
63
56
CuBr
K2CO3
toluene/H2O (2:1)
16
10% phen
56
a
phen = 1,10ꢀphenanthroline, bipy = 2,2’ꢀbipyridine. Reaction conditions (unless otherwise
specified): 3a (0.3 mmol), 4 (0.9 mmol), solvent, 1 atm O2 (balloon), 12 h, 70 °C. b 1H NMR yield using
dibromomethane as internal standard. c Reaction run under air instead of an O2 balloon.
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Based on these earlier precedents, we began our reaction optimization efforts using cyclopropyl
1
2
boronic acid as the coupling partner in the presence of catalytic quantities of copper(II) salts. While we
did observe product formation under these conditions, we soon turned to the more stable potassium
trifluoroborate salt due to inconsistent results with cyclopropyl boronic acid, which we believe stems
from its decomposition during reaction setup (evidenced by a visible yellowing of the typically white
solid).20 To our delight, the use of potassium cyclopropyl trifluoroborate nearly doubled the yield and
improved reproducibility. Using 1 atm O2 as the terminal oxidant, we were pleased to find that the
reaction led to consistent product formation with only 10% Cu(OAc)2 (Table 1). Interestingly, the use of
bidentate ligands dramatically improved the efficiency of the reaction, with 1,10ꢀphenanthroline
ultimately providing the highest yield (entries 10 and 12). The optimal solvent mixture was found to be
3:1 toluene:H2O. We believe that water is necessary for solubilizing the reaction components and
promoting transmetalation by facilitating formation of the mixed boronate species via hydrolysis.21
Various bases were screened (entries 5–6), and K2CO3 proved to be optimal. It was found that the
reaction vessel must be purged with an O2 balloon and left under an atmosphere of O2 for the duration of
the reaction to achieve optimal yields.22 With 95% N2/ 5% O2 gas mixtures, the reaction only delivered
trace product (<5%) after 3 hours. Other oxidants, such as ditertbutylperoxide, did not give the desired
product in appreciable yield (<5%). Simply running the reaction open to air or purging the reaction
vessel with O2 and sealing it resulted in reduced yields (entry 11). The reaction proceeded with good to
high yields over a large variety of copper(II) species. Notably, copper(II) formate (Cu(HCO2)2), a
copper(II) species that is seldom used in Chan–Lam coupling was found to be nearly as effective as the
optimal catalyst, Cu(OAc)2. Copper(I) salts also provided the desired product in moderate yield (entries
15 and 16). Ultimately, Cu(OAc)2 was used for subsequent studies because of its efficiency in the
reaction and its widespread availability. 23
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Substrate Scope. Having optimized the reaction conditions, we next examined the scope of
phenol nucleophiles (Table 2). Phenols with diverse functional groups, differing electronic properties,
and varied substitution patterns were tested. In most cases, the desired product was obtained in moderate
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to high yield (5a–r). Phenols containing one or more electronꢀdonating substituents at the ortho-, meta-,
or para- position on the aromatic ring were generally highꢀyielding, with the reaction tolerating ethers,
thioethers, and alkyl groups (5a–5g). Substitution at the ortho-position led to diminished yields, likely
due to steric hindrance (5d). Furthermore, the reaction proceeds smoothly in the presence of halide
substituents (5h–k), which presents the opportunity to diversify the products via subsequent crossꢀ
coupling. The introduction of strong electronꢀwithdrawing groups at either the meta- or para-positions
led to lower yields, requiring higher catalyst loading (5l–o). Moreover, in these cases, competitive
formation of the undesired Oꢀallylated byproduct was observed. We postulate that this is due to the
attenuated nucleophilicity of the corresponding electronꢀpoor phenoxides, which could potentially
reduce the affinity of the substrate for the Cu(II) center and/or raise the activation energy for the C–O
reductive elimination step. Although the yields are generally lower for electronꢀpoor phenols, it is
important to note that the reaction is nevertheless compatible with a wide variety of functional groups
that one might encounter in medicinal chemistry, such as esters, nitriles, halogens, and nitro groups,
providing preparatively useful quantities of the product in all of these cases. Notably, methyl ester does
not hydrolyze under the reaction conditions and gives the desired cyclopropylated product (5l). We were
pleased to observe that the reaction proceeded to a modest extent in the presence of various heterocycles
(5p–r), including those that could potentially bind to copper.
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Table 2. Substrate scope of phenol Oꢀcyclopropylation.a
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10 mol% Cu(OAc)2
10 mol% phen
1
2
3
2 equiv K2CO3
OH
O
R
+
BF3K
R
toluene/H2O
70 oC, O2 (balloon), 12 h
4 (3 equiv)
3
5
4
5
6
7
Me
Me
O
t-Bu
O
O
O
t-Bu
t-Bu
5c (42%)
5a
8
5b (72%)
5d (46%)
0.3 mmol (84%)
6.0 mmol (81%)
9
O
O
O
MeO
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
F
MeS
BnO
5e (60%)
5f (63%)
5g (56%)
5h (50%)
O
O
O
O
MeO
Cl
Br
I
O
5i (53%)
5j (54%)
5k (60%)
5l (34%)
O
O2N
O
NC
O
NC
5m (27%)c
5n (30%)c
5o (28%)c
NBoc
O
O
O
N
S
5p (31%)d
5q (42%)
5r (61%)
a
b
All reactions were run on 0.3 mmol scale unless noted otherwise. Percentages correspond to
isolated yields. c 25 mol% Cu(OAc)2, 12.5 mol% phen. d 25 mol% Cu(OAc)2, 25 mol% phen.
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We also established that the reaction could be performed on larger scale. In particular, 6 mmol of
our standard substrate, pꢀphenyl phenol (3a), yielded 81% (>1 gram) of the desired cyclopropylated
product 5a.
These reaction conditions are not generally effective in promoting Nꢀcyclopropylation of
nitrogen nucleophiles; for example, unprotected, NꢀBoc, and N-Ac anilines were unreactive under these
conditions. Nevertheless, extensive screening of potential reaction partners revealed three classes of azaꢀ
heterocycles, 2ꢀpyridones,24 2ꢀaminopyridines,25 and 2ꢀhydroxybenzimidazoles, are reactive substrates
using this method (Table 3). Interestingly, subjecting simple 2ꢀhydroxybenzimidazole to the reaction
conditions resulted in bisꢀN,N’ꢀcyclopropylation in high yield (8a). Although 2ꢀhydroxpyridine itself
reacted smoothly to form product 9b, other derivatives were cyclopropylated in lower yields (9a–g).
2ꢀAminopyridine derivatives were also reactive; in this case, the exoꢀcyclic nitrogen proved to be the
more reactive position (10a–c). In compound 10c the amide is preferentially functionalized over the free
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phenol, likely due to the two electronꢀwithdrawing carbonyl substituents, which are expected to
attenuate reactivity.
1
2
3
4
5
Table 3. Substrate scope of azaheterocycle Nꢀcyclopropylation.a
6
7
8
9
X
X
R
O
R
OH
N
N
6 (X = O, NH)
25 mol% Cu(OAc)2
12.5 mol% phen
2 equiv K2CO3
8
or
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R
R
R
BF3K
R
+
or
N
N
N
O
N
XH
toluene/H2O
(3 equiv)
70 °C, O2 (balloon), 12 h
9
10
7 (X = O, NR')
Me
X
O
N
N
N
O
O
O
N
N
O
N
8a (70%)b,c
8b (76%)
8c (X = H) (86%)
8d (X = Cl) (70%)
9a (74%)
Me
X
N
O
Me
N
O
N
O
N
O
9b (87%)
9c (71%)
9d (X = F) (63%)
9e (X = Cl) (66%)
9f (61%)d
Me
NBoc
N
N
O
O
O
Me
N
N
N
N
N
Me
NH
Me
N
O
OH
9g (59%)d
10a (89%)
10b (33%)
10c (64%)d
a
All reactions were run on a 0.3–0.6 mmol scale. Percentages correspond to isolated yields.
b 13% of the monoꢀcyclopropylated product (8a’) was also isolated. With 10% Cu(OAc)2 and 10%
phen under otherwise identical conditions: 49% 8a (bis), 15% 8a’ (mono). The connectivity of 8a’ was
confirmed by singleꢀcrystal Xꢀray diffraction (see SI). d 25 mol% Cu(OAc)2, 25 mol% phen.
c
Conclusion. In summary, we have developed a Chan–Lam protocol for Oꢀcyclopropylation of
phenols and Nꢀcyclopropylation of select azaheterocycles. The reaction uses a simple copper(II)
precatalyst with 1 atm O2 as the terminal oxidant and allows for a range of structurally and functionally
diverse nucleophiles to be smoothly coupled with potassium cyclopropyl trifluoroborates in good to high
yields. A broad range of functional groups, including halides, ethers, esters, heterocycles, and nitro
groups were tolerated. Compared to existing synthetic methods, this approach has several advantages. It
is operationally convenient to perform, uses commercially available reagents, employs an inexpensive
copper(II) catalyst, has high levels of functional group tolerance, and gives minimal byproduct formation
in most cases. We envision that this reaction will find immediate use in medicinal chemistry laboratories
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The Journal of Organic Chemistry
as a tool for lateꢀstage installation of cyclopropyl groups. Additionally, in the long term, it could
potentially be adapted for use on larger scale in earlyꢀ or lateꢀstage development.
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5
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7
8
Experimental Section.
9
General Information. Unless otherwise noted, all materials were used as received from commercial
sources without further purification. Consistently high yields were obtained with potassium
cyclopropyltrifluoroborate purchased from Boron Molecular. Batches from other suppliers sometimes
afforded lower yields; we therefore recommend calibrating the reaction using the 4ꢀphenylphenol
substrate and purifying the trifluoroborate salt via soxhlet extraction if yields are lower than expected.
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1H and C spectra were recorded on Bruker DRXꢀ500 and AVꢀ600. Spectra were internally referenced
to SiMe4 or solvent signals. The following abbreviations (or combinations thereof) were used to explain
multiplicities: b = broad, s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet. Highꢀ
resolution mass spectra (HRMS) were recorded on an Agilent ESIꢀTOF (LC/MSD TOF); compounds
that could not be ionized under these conditions were measured on an Agilent 5973 Inert GCꢀMS mass
spectrometer. Compounds with no mass spec data reported in this manuscript could not be ionized on
either of these machines. Of the compounds that could not be ionized, five representative examples were
further analyzed by elemental analysis. Melting points were measured on a MELꢀTEMP II (Laboratory
Devices, USA) apparatus and are uncorrected
General Procedure for O- and N-Cyclopropylation of Phenols and Azaheterocycles: To a 5ꢀmL
scintillation vial equipped with a Teflonꢀcoated magnetic stir bar were added the phenol substrate (0.3
mmol), cyclopropyl potassium trifluoroborate (133.2 mg, 0.9 mmol), Cu(OAc)2, 1,10ꢀphenanthroline,
and K2CO3 (83.0 mg, 0.6 mmol). The vial was charged with toluene (0.5 mL) and water (0.15 mL) and
sealed with a septum cap. Caution! Because the reaction involves heating an organic solvent under O2,
a blast shield should be used at all times, particularly in large-scale experiments. After the indicated
reaction time, the reaction vessel should be allowed to cool to room temperature behind the blast shield
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prior to workup. The septum was pierced with a 21G needle connected to an O2 balloon. The septum
cap was partially unscrewed to purge the vial for 5 seconds and then resealed by tightening the cap. The
reaction was stirred under O2 (balloon) at 70 °C for 12 h, after which it was quenched with sat. NH4Cl
(aq.) and extracted with EtOAc. The combined organics were dried over MgSO4, filtered and
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8
9
1
concentrated in vacuo. H NMR yields were determined by integration of the cyclopropyl product peak
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relative to 1.0 equiv dibromomethane as internal standard. Crude products were then purified by silica
flash column chromatography. The optimal catalyst/ligand loading was found to vary depending on the
substrate employed:
• General Procedure A (typical phenol substrates):
Cu(OAc)2 (5.4 mg, 10 mol %), 1,10ꢀphenanthroline (5.4 mg, 10 mol %)
• General Procedure B (electronꢀpoor phenols and azaheterocycles):
Cu(OAc)2 (13.6 mg, 25 mol%), 1,10ꢀphenanthroline (6.8 mg, 12.5 mol%)
• General Procedure C (Pfizer examples, more valuable substrates)
Cu(OAc)2 (13.6 mg, 25 mol%), 1,10ꢀphenanthroline (13.5 mg, 25 mol%)
Characterization of New Compounds:
Data for Oꢀcyclopropyl aryl ether products 5a–5r and Nꢀcyclopropylated azaheretocycle products 8a–
8d, 9a–9g, 10a–10c as well as starting material S4 are included below. Original NMR spectra can be
found in the supporting information. Analytical data for compounds S1–S3 have been reported
elsewhere.
4-Cyclopropoxy-1,1'-biphenyl (5a): The title compound was prepared from 4ꢀphenylphenol (54 mg,
0.3 mmol) according to General Procedure A. Purification by silica gel chromatography with 10:1
hexanes:EtOAc as the eluent gave the product as a white solid (52.9 mg, 84% yield). mp = 109–110 ºC;
1H NMR (500 MHz, CDCl3) δ 7.65–7.49 (m, 4H), 7.42 (t, J = 7.7 Hz, 2H), 7.33–7.28 (m, 1H), 7.12 (d,
13
J = 8.7 Hz, 1H), 3.81–3.75 (m, 1H), 0.81 (d, J = 4.5 Hz, 4H); C NMR (150 MHz, CDCl3) δ 128.9,
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128.2, 126.9, 115.4, 51.0, 6.4. EA calc’d for C15H14O: C, 85.68%; H, 6.71%, found: C, 85.31%; H,
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2
3
6.81%.
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6
7
8
9
1-(tert-Butyl)-4-cyclopropoxybenzene (5b): The title compound was prepared from 4ꢀ(tertꢀ
butyl)phenol (45 mg, 0.3 mmol) according to general procedure A. Purification by silica gel
chromatography with 10:1 hexanes:EtOAc as the eluent gave the product as a yellow oil (41.0 mg, 72%
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yield). H NMR (500 MHz, CDCl3) δ 7.30 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 3.71 (dq, J =
13
5.9, 4.4 Hz, 1H), 1.30 (s, 9H), 0.76 (d, J = 4.1 Hz, 4H); C NMR (150 MHz, CDCl3) δ 157.0, 144.0,
126.5, 114.8, 100.0, 51.1, 34.5, 32.0, 6.6; GC/MS (EI) m/z calcd for C13H18O [M]+ 190.1358, found
190.
1,3-Di-tert-butyl-5-cyclopropoxybenzene (5c): The title compound was prepared from 3,5ꢀdiꢀtertꢀ
butylphenol (61.8 mg, 0.3 mmol) according to General Procedure A. Purification by silica gel
chromatography with 10:1 hexanes:EtOAc as the eluent gave the product as a colorless oil (30.9 mg,
42% yield). 1H NMR (500 MHz, CDCl3) δ 7.04 (t, J = 1.7 Hz, 1H), 6.92 (d, J = 1.6 Hz, 2H), 3.79–3.60
13
(m, 1H), 1.32 (s, 18H), 0.77 (d, J = 6.4, 3.6, 1.6 Hz, 4H); C NMR (150 MHz, CDCl3) δ 158.6, 152.2,
115.3, 109.4, 50.6, 35.1, 31.6, 6.3; GC/MS (EI) m/z calcd for C17H26O [M]+ 246.1984, found 246.
2-Cyclopropoxy-1,4-dimethylbenzene (5d): The title compound was prepared from 2,5ꢀ
dimethylphenol (36.6 mg, 0.3 mmol) according to General Procedure A. Purification by silica gel
chromatography with 10:1 hexanes:EtOAc as the eluent gave the product as a yellow oil (22.3 mg, 46%
1
yield). H NMR (500 MHz, CDCl3) δ 7.03–6.93 (m, 2H), 6.69 (dt, J = 7.4, 1.2 Hz, 1H), 3.79–3.64 (m,
13
1H), 2.35 (s, 3H), 2.13 (s, 3H), 0.88–0.64 (m, 4H); C NMR (150 MHz, CDCl3) δ 157.3, 136.8, 130.7,
123.7, 121.4, 113.4, 50.9, 21.9, 16.1, 6.7.
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(4-Cyclopropoxyphenyl)(methyl)sulfane (5e): The title compound was prepared from 4ꢀ
(methylthio)phenol (42 mg, 0.3 mmol) according to General Procedure A. Purification by silica gel
chromatography with 10:1 hexanes:EtOAc as the eluent gave the product as a yellow solid (32.4 mg,
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2
3
4
5
6
7
8
1
60% yield). mp = 52–55 ºC; H NMR (500 MHz, CDCl3) δ 7.28 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8
9
Hz, 2H), 3.75–3.67 (m, 1H), 2.44 (s, 3H), 0.76 (d, J = 3.0 Hz, 4H); 13C NMR (150 MHz, CDCl3) δ
157.9, 130.4, 129.5, 116.1, 51.3, 18.4, 6.6. EA calc’d for C10H12OS: C, 66.63%; H, 6.71%, found: C,
66.98%; H, 7.11%.
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1-(Benzyloxy)-4-cyclopropoxybenzene (5f): The title compound was prepared from 4ꢀ
(benzyloxy)phenol (60 mg, 0.3 mmol) according to General Procedure A. Purification by silica gel
chromatography with 10:1 hexanes:EtOAc as the eluent gave the product as an offꢀwhite solid (45.0 mg,
63% yield). mp = 77–79 ºC; 1H NMR (500 MHz, CDCl3) δ 7.41 (d, J = 7.6 Hz, 2H), 7.36 (t, J = 7.5 Hz,
2H), 7.31 (d, J = 7.2 Hz, 1H), 6.96 (d, J = 9.2 Hz, 2H), 6.89 (d, J = 8.2 Hz, 2H), 5.00 (s, 2H), 3.66 (dt, J
= 5.5, 2.4 Hz, 1H), 0.73 (d, J = 3.2 Hz, 4H); 13C NMR (150 MHz, CDCl3) δ 153.6, 153.6, 137.7, 129.0,
128.3, 127.9, 116.1, 116.1, 116.1, 100.0, 71.1, 51.5, 6.6. EA calc’d for C16H16O2: C, 79.97%; H, 6.71%,
found: C, 79.76%; H, 6.34%.
1-Cyclopropoxy-3-methoxybenzene (5g): The title compound was prepared from 3ꢀmethoxyphenol
(37.2 mg, 0.3 mmol) according to General Procedure A. Purification by silica gel chromatography with
1
10:1 hexanes:EtOAc as the eluent gave the product as a colorless oil (27.5 mg, 56% yield). H NMR
(500 MHz, CDCl3) δ 7.18 (t, J = 8.2 Hz, 1H), 6.67 (ddd, J = 8.1, 2.3, 0.8 Hz, 1H), 6.62 (t, J = 2.4 Hz,
1H), 6.53 (ddd, J = 8.2, 2.4, 0.8 Hz, 1H), 3.79 (d, J = 0.5 Hz, 3H), 3.75–3.69 (m, 1H), 0.77 (d, J = 4.5
13
Hz, 4H); C NMR (150 MHz, CDCl3) δ 130.2, 107.8, 106.8, 101.8, 55.7, 51.2, 6.6; GC/MS (EI) m/z
calcd for C10H12O2 [M]+ 164.0837, found 164.
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3
1-Cyclopropoxy-4-fluorobenzene (5h): The title compound was prepared from 4ꢀfluorophenol (33.6
4
5
mg, 0.3 mmol) according to General Procedure A. Purification by silica gel chromatography with 10:1
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7
8
1
hexanes:EtOAc as the eluent gave the product as a yellow oil (22.6 mg, 50% yield). H NMR (500
9
MHz, CDCl3) δ 7.08–6.87 (m, 4H), 3.80–3.56 (m, 1H), 0.84–0.67 (m, 4H); 13C NMR (150 MHz,
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CDCl3) δ 116.2, 116.1, 116.0, 51.6, 30.1, 6.6.
1-Chloro-4-cyclopropoxybenzene (5i): The title compound was prepared from 4ꢀchlorophenol (38.4
mg, 0.3 mmol) according to General Procedure A. Purification by silica gel chromatography with 10:1
1
hexanes:EtOAc as the eluent gave the product as an orange oil (26.7 mg, 53% yield). H NMR (500
MHz, CDCl3) δ 7.32 (dd, J = 10.7, 5.9 Hz, 2H), 7.06 (t, J = 8.3 Hz, 2H), 3.79 (tt, J = 5.9, 2.9 Hz, 1H),
0.85 (d, J = 5.3 Hz, 4H); 13C NMR (150 MHz, CDCl3) δ 129.6, 127.3, 126.2, 116.6, 51.5, 6.6.
1-Bromo-4-cyclopropoxybenzene (5j): The title compound was prepared from 4ꢀbromophenol (51.9
mg, 0.3 mmol) according to General Procedure A. Purification by silica gel chromatography with 10:1
1
hexanes:EtOAc as the eluent gave the product as a yellow oil (34.5 mg, 54% yield). H NMR (500
MHz, CDCl3) δ 7.37 (d, J = 7.1 Hz, 2H), 6.92 (d, J = 7.1 Hz, 2H), 3.70 (dd, J = 6.0, 3.4 Hz, 1H), 0.77
(ddt, J = 5.4, 3.4, 1.9 Hz, 4H), 13C NMR (150 MHz, CDCl3) δ 132.6, 117.2, 113.6, 51.4, 30.1, 6.6;
GC/MS (EI) m/z calcd for C9H9OBr [M]+ 211.9837, found 212.
1-Iodo-4-cyclopropoxybenzene (5k): The title compound was prepared from 4ꢀiodophenol (66.0 mg,
0.3 mmol) according to General Procedure A. Purification by silica gel chromatography with 10:1
hexanes:EtOAc as the eluent gave the product as an orange solid (46.6 mg, 60% yield). mp = 49–50 ºC;
1H NMR (500 MHz, CDCl3) δ 7.69–7.56 (d, 2H), 6.99–6.81 (d, 2H), 3.78 (m, J = 6.1, 2.8 Hz, 1H), 0.85
13
(m, J = 7.5, 2.8 Hz, 4H); C NMR (150 MHz, CDCl3) δ 159.0, 138.3, 117.6, 83.2, 51.1, 6.3; GC/MS
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(EI) m/z calcd for C9H9OI [M]+ 259.9698, found 260. EA calc’d for C9H9OI: C, 41.56%; H, 3.49%,
1
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3
found: C, 41.37%; H, 3.14%.
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Methyl 4-cyclopropoxybenzoate (5l): The title compound was prepared from methyl 4ꢀ
hydroxybenzoate (45.6 mg, 0.3 mmol) according to General Procedure A. Purification by silica gel
chromatography with 10:1 hexanes:EtOAc as the eluent gave the product as a yellow oil (19.6 mg, 34%
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yield). H NMR (500 MHz, CDCl3) δ 7.98 (d, J = 8.9 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 3.88 (s, 2H),
13
3.78 (m, J = 6.1, 3.2 Hz, 1H), 0.97–0.65 (d, 4H); C NMR (150 MHz, CDCl3) δ 167.3, 163.2, 131.9,
123.3, 115.1, 52.3, 51.6, 6.7.
4-(Cyclopropyloxy)benzonitrile (5m): The title compound was prepared from 4ꢀcyanophenol (35.6
mg, 0.3 mmol) according to General Procedure B. The standard reaction conditions afforded an
inseparable mixture of the desired Oꢀcyclopropylated product, as well as Oꢀallylated product S1. After
aqueous workup, the mixture was redissolved in H2O (0.8 mL) and acetone (6.2 mL), and treated with
OsO4 (2.5 wt% in iꢀPrOH, 0.15 mL, 0.015 mmol, 5 mol%) and NMO (53 mg, 0.45 mmol, 1.5 equiv).
The reaction was stirred at rt, after which it was quenched with aqueous sodium bisulfite, extracted with
EtOAc, dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica flash column
chromatography (eluent: 2% EtOAc/Hex to 5% EtOAc/Hex) afforded the title compound as a colorless
oil (13.0 mg, 27% yield). 1H NMR (500 MHz, CDCl3) δ 7.60–7.56 (m, 2H), 7.12–7.07 (m, 2H), 3.78 (tt,
J = 6.0, 3.0 Hz, 1H), 0.85–0.81 (m, 2H), 0.82–0.78 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 162.6,
134.0, 119.4, 116.0, 104.4, 51.5, 6.4.
4-(Allyloxy)benzonitrile (S1):26 1H NMR (500 MHz, CDCl3) δ 7.63–7.55 (m, 2H), 6.99–6.94 (m, 2H),
6.03 (ddd, J = 22.5, 10.6, 5.3 Hz, 1H), 5.48–5.38 (m, 1H), 5.36–5.28 (m, 1H), 4.59 (dt, J = 5.3, 1.6 Hz,
2H).
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3-(Cyclopropyloxy)benzonitrile (5n): The title compound was prepared from 3ꢀcyanophenol (35.6 mg,
0.3 mmol) according to General Procedure B. The standard reaction conditions afforded an inseparable
mixture of the desired Oꢀcyclopropylated product, as well as Oꢀallylated product S2. After aqueous
workup, the mixture was redissolved in H2O (0.8 mL) and acetone (6.2 mL), and treated with OsO4 (2.5
wt% in iꢀPrOH, 0.15 mL, 0.015 mmol, 5 mol%) and NMO (53 mg, 0.45 mmol, 1.5 equiv). The reaction
was stirred at rt, after which it was quenched with aqueous sodium bisulfite, extracted with EtOAc,
dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica flash column
chromatography (eluent: 2% EtOAc/Hex to 5% EtOAc/Hex) afforded the title compound as a colorless
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oil (14.1 mg, 30% yield). H NMR (500 MHz, CDCl3) δ 7.37 (t, J = 8.0 Hz, 1H), 7.34–7.32 (m, 1H),
7.27–7.23 (m, 2H), 3.75 (tt, J = 6.0, 3.0 Hz, 1H), 0.85–0.81 (m, 2H), 0.81–0.78 (m, 2H); 13C NMR (150
MHz, CDCl3) δ 159.3, 130.4, 124.9, 120.5, 118.9, 118.1, 113.2, 51.4, 6.4.
2-(Allyloxy)benzonitrile (S2):27 1H NMR (500 MHz, CDCl3) 7.19–7.14 (m, 3H), 6.88 (d, J = 8.8 Hz,
1H), 6.81 (d, J = 8.3 Hz, 2H), 5.99–6.06 (m, 1H), 5.42 (d, J = 17.7, 1H), 5.33 (d, J = 10.7 Hz, 1H), 4.56
(d, J = 5.3 Hz, 2H).
1-(Cyclopropyloxy)-3-nitrobenzene (5o): The title compound was prepared from 3ꢀnitrophenol (41.7
mg, 0.3 mmol) according to General Procedure B. The standard reaction conditions afforded an
inseparable mixture of the desired Oꢀcyclopropylated product, as well as Oꢀallylated product S3. After
aqueous workup, the mixture was redissolved in H2O (0.8 mL) and acetone (6.2 mL), and treated with
OsO4 (2.5 wt% in iꢀPrOH, 0.15 mL, 0.015 mmol, 5 mol%) and NMO (53 mg, 0.45 mmol, 1.5 equiv).
The reaction was stirred at rt, after which it was quenched with aqueous sodium bisulfite, extracted with
EtOAc, dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica flash column
chromatography (eluent: 2% EtOAc/Hex to 10% EtOAc/Hex) afforded the title compound as a yellow
1
oil (14.8 mg, 28% yield). H NMR (500 MHz, CDCl3) δ 7.92 (t, J = 2.3 Hz, 1H), 7.86–7.81 (m, 1H),
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7.42 (t, J = 8.2 Hz, 1H), 7.34–7.30 (m, 1H), 3.82 (tt, J = 6.2, 2.9 Hz, 1H), 0.89–0.84 (m, 2H), 0.84–0.79
(m, 2H); 13C NMR (150 MHz, CDCl3) δ 160.0, 149.5, 130.2, 122.3, 116.4, 109.9, 51.9, 6.7.
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1-(Allyloxy)-3-nitrobenzene (S3):28 1H NMR (600 MHz, CDCl3) δ 7.25–7.80 (m, 4H), 6.11–5.99 (m,
1H), 5.45 (dd, J = 17.2, 1.5 Hz, 1H), 5.37–5.32 (m, 1H), 4.63 (dt, J = 5.3, 1.5 Hz, 2H).
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tert-butyl-8-cyclopropoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (5p): The title compound was
prepared from tertꢀbutylꢀ8ꢀhydroxyꢀ3,4ꢀdihydroisoquinolineꢀ2(1H)ꢀcarboxylate (74.8 mg, 0.300 mmol)
according to General Procedure C. Purification was performed using flash column chromatography (12g
SiO2, Isco, 100% Hept. to 10% EtOAc) to afford the title compound as a colorless oil (27.0 mg, 31%
yield). 1H NMR (600 MHz, CDCl3) δ 7.19–7.12 (m, 1 H) 7.08 (d, J = 8.07 Hz, 1 H) 6.77 (br d, J = 7.34
Hz, 1 H) 4.45 (br s, 2 H) 3.80–3.72 (m, 1H) 3.64 (br t, J = 5.69 Hz, 2 H) 2.82 (br t, J = 5.50 Hz, 2 H)
1.52 (s, 9 H) 0.78 (br d, J = 3.48 Hz, 4 H); 13C NMR (150 MHz, CDCl3) δ 155.48 (br s, 1C), 154.99 (br
s, 1C), 135.85 (br s, 1C), 126.57, 122.49 (br s, 1C), 121.08 (br s, 1C), 109.62, 79.55, 50.76, 41.53 (br s,
1C), 40.97–40.39 (m, 1C), 29.00 (br s, 1C), 28.49 (s, 3C), 6.20 (br s, 2C); HRMS (ESIꢀTOF) m/z calcd
for C17H23NO3 [M+Na]+ = 312.1570, found 312.1551.
+
2-(4-cyclopropoxyphenyl)pyridine (5q): The title compound was prepared from 4ꢀ(pyridinꢀ2ꢀ
yl)phenol (51.3 mg, 0.3 mmol) according to General Procedure A. Purification by silica gel
chromatography with 10:1 hexanes:EtOAc as the eluent gave the product as an offꢀwhite solid (26.6 mg,
1
42% yield). mp = 82–84 ºC; H NMR (500 MHz, CDCl3) δ 8.66 (d, J = 4.8 Hz, 1H), 7.97–7.93 (m,
2H), 7.71 (dd, J = 23.5, 7.8 Hz, 2H), 7.22–7.11 (m, 3H), 3.80 (t, J = 4.6 Hz, 1H), 0.87–0.74 (m, 4H);
13C NMR (150 MHz, CDCl3) δ 160.1, 157.1, 149.3, 137.1, 132.1, 128.3, 121.6, 120.1, 115.4, 51.1, 6.4;
HRMS (ESIꢀTOF) m/z calcd for C14H14NO [M+H]+ 212.1070, found 212.1064.
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2-(4-Cyclopropoxyphenyl)thiophene (5r): The title compound was prepared from 4ꢀ(thiophenꢀ2ꢀ
yl)phenol (52 mg, 0.3 mmol) according to General Procedure A. Purification by silica gel
chromatography with 10:1 hexanes:EtOAc as the eluent gave the product as an offꢀwhite solid (39.5 mg,
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61% yield). mp = 88–89 ºC; H NMR (500 MHz, CDCl3) δ 7.71–7.53 (m, 2H), 7.32–7.24 (m, 2H),
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7.27–7.03 (m, 3H), 3.94–3.76 (m, 1H), 0.88 (d, J = 5.1 Hz, 4H); 13C NMR (150 MHz, CDCl3) δ 159.0,
144.8, 128.3, 128.0, 127.5, 124.3, 122.5, 115.8, 51.3, 6.7; GC/MS (EI) m/z calcd for C13H12OS [M]+
216.0609, found 216. EA calc’d for C13H12OS: C, 72.19%; H, 5.59%, found: C, 72.31%; H, 6.00%.
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1,3-Dicyclopropyl-1,3-dihydro-2H-benzimidazol-2-one (8a): The title compound was prepared from
2ꢀhydroxybenzimidazole (40.2 mg, 0.3 mmol) according to General Procedure B. Purification by silica
flash column chromatography (eluent: 5% EtOAc/Hexane to 20% EtOAc/Hexane) afforded the title
compound as a white solid (31.8 mg, 49% yield), along with separable monoꢀcyclopropylated product
8a’. mp = 92–94 °C; 1H NMR (500 MHz, CDCl3) δ 7.21–7.13 (m, 2H), 7.12–7.04 (m, 2H), 2.83 (tt, J =
7.0, 3.7 Hz, 2H), 1.11–1.05 (m, 4H), 0.99 (ddd, J = 8.0, 5.4, 3.8 Hz, 4H); 13C NMR (150 MHz, CDCl3)
δ 155.0, 130.1, 121.2, 108.4, 22.5, 6.0; HRMS (ESIꢀTOF) m/z calcd for C13H15N2O [M+H]+ 215.1184,
found 215.1180.
1-Cyclopropyl-1H-benzimidazol-2-ol (8a’): The title compound was prepared according to the
procedure described above for 8a and was isolated as a white solid (7.7 mg, 15% yield). mp = 184–
1
188 °C; H NMR (CDCl3, 500 MHz) δ 10.03 (brs, 1H, OH), 7.23–7.19 (m, 1H), 7.14–7.04 (m, 3H),
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2.91 (tt, J = 7.0, 3.6 Hz, 1H), 1.18–1.09 (m, 2H), 1.08–1.02 (m, 2H); C NMR (CDCl3, 150 MHz) δ
156.1, 131.5, 127.6, 121.7, 121.4, 109.5, 108.9, 22.4, 6.2; HRMS (ESIꢀTOF) m/z calcd for C10H11N2O
[M+H]+ 175.0871, found 175.0876; X-ray (singleꢀcrystal): Colorless block crystals of Xꢀray diffraction
quality were obtained by slow evaporation of a solution of 8a’ in CDCl3 (CCDC 1584673).29
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1-Cyclopropyl-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (8b): The title compound was prepared
from 1ꢀmethylꢀ1,3ꢀdihydroꢀ2Hꢀbenzimidazolꢀ2ꢀone (44.5 mg, 0.3 mmol) according to General
Procedure B. Purification by silica flash column chromatography (eluent: 10% EtOAc/Hex) afforded the
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title compound as a white solid (43.0 mg, 76% yield). mp = 84–86 °C; H NMR (500 MHz, CDCl3) δ
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7.20–7.15 (m, 1H), 7.10–7.05 (m, 2H), 6.95–6.90 (m, 1H), 3.36 (s, 3H), 2.86 (tt, J = 7.1, 3.7 Hz, 1H),
1.11–1.06 (m, 2H), 1.02–0.97 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 154.8, 130.3, 129.8, 121.3,
121.1, 108.5, 107.2, 27.0, 22.6, 6.1; HRMS (ESIꢀTOF) m/z calcd for C11H13N2O [M+H]+ 189.1028,
found 189.1022.
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3-Cyclopropylbenzo[d]oxazol-2(3H)-one (8c):
The title compound was prepared from
2ꢀhydroxybenzoxazolinone (40.5 mg, 0.3 mmol) according to General Procedure B. Purification by
silica flash column chromatography (eluent: 5 % EtOAc/Hex to 10% EtOAc/Hex) afforded the title
compound as a white solid (45.3 mg, 86% yield). mp = 62–63 °C; 1H NMR (500 MHz, CDCl3) δ 7.21–
7.13 (m, 3H), 7.12–7.08 (m, 1H), 2.92 (tt, J = 7.0, 3.6 Hz, 1H), 1.15–1.08 (m, 2H), 1.08–1.02 (m, 2H);
13C NMR (150 MHz, CDCl3) δ 154.4, 142.3, 132.0, 123.8, 122.5, 109.9, 109.2, 23.3, 6.0; HRMS (ESIꢀ
TOF) m/z calcd for C9H9N2O2 [M+H]+ 177.0659, found 177.0659.
6-Chloro-3-cyclopropyl-1,3-benzoxazol-2(3H)-one (8d): The title compound was prepared from
6ꢀchlorobenzoxazolꢀ2(3H)ꢀone (50.9 mg, 0.3 mmol) according to General Procedure B. Purification by
silica flash column chromatography (eluent: 10% EtOAc/Hex to 20% EtOAc/Hex) afforded the title
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compound as an orange solid (44.3 mg, 70% yield). mp 110–112 °C; H NMR (500 MHz, CDCl3) δ
7.18–7.12 (m, 2H), 7.08–7.03 (m, 1H), 2.90 (tt, J = 7.0, 3.6 Hz, 1H), 1.15–1.07 (m, 2H), 1.05–0.98 (m,
2H); 13C NMR (125 MHz, CDCl3) δ 154.0, 142.6, 130.8, 128.1, 123.9, 110.8, 109.7, 23.4, 6.0; GC/MS
(EI) m/z calcd for C10H8ClNO2 [M]+ 209.0244, found 209.
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1-Cyclopropylquinolin-2(1H)-one (9a): The title compound was prepared from 2ꢀhydroxyquinoline
(43.5 mg, 0.3 mmol) according to General Procedure B. Purification by silica flash column
chromatography (eluent: 30% EtOAc/Hex to 50% EtOAc/Hex) afforded the title compound as a yellow
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oil (41.0 mg, 74% yield). H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 9.5 Hz,
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1H), 7.55–7.45 (m, 2H), 7.18 (t, J = 7.5 Hz, 1H), 6.59 (d, J = 9.4 Hz, 1H), 2.93 (tt, J = 7.7, 4.1 Hz, 1H),
1.39–1.30 (m, 2H), 0.93–0.85 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 163.8, 141.1, 139.1, 130.0,
128.6, 122.5, 122.2, 121.0, 115.6, 26.2, 10.5; HRMS (ESIꢀTOF) m/z calcd for C12H12NO [M+H]+
186.0913, found 186.0914.
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1-Cyclopropylpyridin-2-one (9b): The title compound was prepared from 2ꢀhydroxypyridine (47.6 mg,
0.5 mmol) according to General Procedure B. Purification by silica flash column chromatography
(eluent: 2% MeOH/DCM to 5% MeOH/DCM), followed by preparative TLC (eluent: 5% MeOH/DCM)
afforded the title compound as a yellow oil (24.8 mg, 37% yield). The connectivity (i.e., Nꢀ versus Oꢀ
cyclopropylation) was confirmed by NOESY analysis and by the diagnostic carbonyl signal at 164.3
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ppm in the C NMR spectrum. H NMR (500 MHz, CDCl3) δ 8.63–8.57 (m, 2H), 7.87–7.83 (m, 1H),
7.44 (tt, J = 6.8, 1.2 Hz, 1H), 4.64 (tt, J = 7.7, 3.6 Hz, 1H), 2.47–2.42 (m, 2H), 2.19–2.15 (m, 2H);
13C NMR (125 MHz, CDCl3) δ 164.3, 139.0, 136.9, 120.9, 105.7, 32.3, 6.8; HRMS (ESIꢀTOF) m/z
calcd for C8H10NO [M+H]+ 136.0757, found 136.0757.
1-Cyclopropyl-4-methylpyridin-2-one (9c): The title compound was prepared from 2ꢀhydroxyꢀ4ꢀ
methylpyridine (32.7 mg, 0.3 mmol) according to General Procedure B. Purification by silica flash
column chromatography (eluent: DCM to 2% MeOH/DCM) afforded the title compound as a paleꢀ
1
yellow oil (31.9 mg, 71% yield). H NMR (500 MHz, CDCl3) δ 7.11 (d, J = 7.1 Hz, 1H), 6.29 (s, 1H),
5.92 (dd, J = 7.1, 1.9 Hz, 1H), 3.24 (tt, J = 7.6, 4.2 Hz, 1H), 2.10 (s, 3H), 1.09–1.01 (m, 2H), 0.82–0.75
(m, 2H); 13C NMR (125 MHz, CDCl3) δ 164.2, 150.6, 135.8, 119.2, 108.2, 31.8, 21.2, 6.7; HRMS
(ESIꢀTOF) m/z calcd for C9H12NO [M+H]+ 150.0913, found 150.0912.
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1-Cyclopropyl-5-fluoropyridin-2-one (9d): The title compound was prepared from 2ꢀhydroxyꢀ5ꢀ
fluoropyridine (33.9 mg, 0.3 mmol) according to General Procedure B. Purification by silica flash
column chromatography (eluent: DCM to 2% MeOH/DCM) afforded the title compound as a paleꢀ
yellow oil (29.0 mg, 63% yield). 1H NMR (500 MHz, CDCl3) δ 7.25–7.19 (m, 1H), 7.17 (t, J = 3.9 Hz,
1H), 6.48 (dd, J = 10.0, 5.4 Hz, 1H), 3.30 (tt, J = 7.7, 4.3 Hz, 1H), 1.14–1.09 (m, 2H), 0.86–0.81 (m,
2H); 13C NMR (125 MHz, CDCl3) δ 162.3, 147.1 (d, J = 231 Hz), 131.0 (d, J = 24 Hz), 122.3 (d, J = 37
Hz), 121.5 (d, J = 7 Hz), 32.7, 7.1; 19F NMR (CDCl3, 376 MHz, CDCl3) δ −149.35; HRMS (ESIꢀTOF)
m/z calcd for C8H9FNO [M+H]+ 154.0663, found 154.0663.
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1-Cyclopropyl-5-chloropyridin-2-one (9e): The title compound was prepared from 2ꢀhydroxyꢀ5ꢀ
chloropyridine (38.9 mg, 0.3 mmol) according to General Procedure B. Purification by silica flash
column chromatography (eluent: DCM to 2% MeOH/DCM), followed by preparative TLC (eluent: 2%
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MeOH/DCM) afforded the title compound as a yellow oil (33.8 mg, 66% yield). H NMR (500 MHz,
CDCl3) δ 7.30 (d, J = 2.8 Hz, 1H), 7.21 (dd, J = 9.7, 2.9 Hz, 1H), 6.48 (d, J = 9.7 Hz, 1H), 3.28 (tt, J =
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7.6, 4.2 Hz, 1H), 1.15–1.09 (m, 2H), 0.86–0.82 (m, 2H); C NMR (151 MHz, CDCl3) δ 162.7, 140.1,
134.7, 121.8, 112.0, 32.9, 31.1, 7.1; HRMS (ESIꢀTOF) m/z calcd for C8H9ClNO [M+H]+ 170.0367,
found 170.0367.
1-Cyclopropyl-6-methylpyridin-2(1H)-one (9f): The title compound was prepared from
6ꢀmethylpyridinꢀ2(1H)ꢀone (32.7 mg, 0.300 mmol) according to General Procedure C. Purification was
performed using flash column chromatography (12 g SiO2, Isco, 100% Hept. to 10% MeOH/EtOAc) to
1
afford the title compound as a paleꢀyellow gum (27.5 mg, 61% yield). H NMR (400MHz, CDCl3) δ
7.15 (dd, J = 9.2, 6.7 Hz, 1H), 6.39 (d, J = 9.2 Hz, 1H), 5.97 (d, J = 6.7 Hz, 1H), 2.83 (tt, J = 7.1, 4.2
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Hz, 1H), 2.46 (s, 3H), 1.31–1.23 (m, 2H), 0.92–0.85 (m, 2H); C NMR (100 MHz, CDCl3) δ 165.24,
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148.59, 138.60, 118.44, 106.83, 28.08, 20.53, 10.33 (s, 2C); HRMS (ESIꢀTOF) m/z calcd for C9H11NO+
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[M+H]+ 150.0913, found 150.0915.
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tert-Butyl-7-cyclopropyl-8-oxo-3,4,7,8-tetrahydro-2,7-naphthyridine-2(1H)-carboxylate (9g): The
title compound was prepared from tertꢀbutylꢀ8ꢀoxoꢀ3,4,7,8ꢀtetrahydroꢀ2,7ꢀnaphthyridineꢀ2(1H)ꢀ
carboxylate (75.1 mg, 0.300 mmol) according to General Procedure C. Purification was performed using
flash column chromatography (12g SiO2, Isco, 100% Hept. to 10% MeOH/EtOAc) to afford the title
compound as a paleꢀyellow gum (55.4 mg, 63% yield). 1H NMR (600 MHz, CDCl3) δ 7.12 (br d, J=6.97
Hz, 1 H) 5.95 (br d, J = 6.97 Hz, 1 H) 4.39 (s, 2 H) 3.61 (br t, J = 5.59 Hz, 2 H) 3.34 (dt, J = 7.24, 3.53
Hz, 1 H) 2.64–2.56 (m, 2 H) 1.50 (d, J = 1.10 Hz, 9 H) 1.12 (br d, J = 7.15 Hz, 2 H) 0.83–0.88 (m, 2 H);
13C NMR (150MHz, CDCl3) δ = 162.04, 154.95 (br s, 1C), 144.63 (br s, 1C), 133.18, 123.98 (br s, 1C),
106.95 (br s, 1C), 79.95 (br s, 1C), 42.28 (br s, 1C), 39.47 (br s, 1C), 31.77, 28.52, 28.47 (s, 3C), 6.56
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(s, 2C); HRMS (ESIꢀTOF) m/z calcd for C16H22N2O3 [M+H]+ = 291.1703, found 291.1707.
+
N-Cyclopropyl-N-(pyridin-2-yl)acetamide (10a): The title compound was prepared from
2ꢀacetamidopyridine (40.8 mg, 0.3 mmol) according to General Procedure B. Purification by silica flash
column chromatography (eluent: 1% MeOH/DCM) afforded the title compound as a brown oil (47.0
mg, 89% yield). 1H NMR (500 MHz, CDCl3) δ 8.45 (d, J = 4.7 Hz, 1H), 7.68 (td, J = 7.7, 2.0 Hz, 1H),
7.21–7.10 (m, 2H), 3.11 (tt, J = 7.2, 3.8 Hz, 1H), 2.16 (s, 3H), 0.95–0.84 (m, 2H), 0.60–0.46 (m, 2H);
13C NMR (150 MHz, CDCl3) δ 172.8, 155.3, 148.8, 137.8, 122.2, 121.8, 30.5, 23.6, 9.2; HRMS (ESIꢀ
TOF) m/z calcd for C10H13N2O [M+H]+ 177.1022, found 177.1021.
N-Cyclopropylpyrazin-2-amine (10b): The title compound was prepared from 2ꢀaminopyrimidine
(28.5 mg, 0.3 mmol) according to General Procedure B. Purification by silica flash column
chromatography (eluent: 1–2% MeOH/DCM) afforded the title compound as a paleꢀyellow solid (13.2
1
mg, 33% yield). mp = 82–85 °C; H NMR (600 MHz, CDCl3) δ 8.34 (s, 2H), 6.58 (t, J = 4.8 Hz, 1H),
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5.67 (brs, 1H, –NH), 2.77 (dddd, J = 9.2, 7.1, 3.6, 2.1 Hz, 1H), 0.89–0.80 (m, 2H), 0.59–0.52 (m, 2H);
13C NMR(150 MHz, CDCl3) δ 163.4, 158.2, 111.2, 111.2, 23.9, 7.5, 7.5; HRMS (ESIꢀTOF) m/z calcd
for C7H10N3 [M+H]+ 136.0869, found 136.0871.
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5-Hydroxy-N1,N1-dimethyl-N3-(5-methylpyridin-2-yl)isophthalamide (S4): The title compounds was
prepared in a similar method as a previously published Pfizer patent (white solid).30 mp = 202–205 °C;
1H NMR (400 MHz, DMSOꢀd6) δ 10.64 (s, 1H), 9.97 (s, 1H), 8.21 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H),
7.65 (dd, J = 2.0, 8.5 Hz, 1H), 7.47 (s, 1H), 7.43–7.36 (m, 1H), 6.93 (dd, J = 1.3, 2.1 Hz, 1H), 2.98 (br s,
3H), 2.93 (br s, 3H), 2.28 (s, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ 169.9, 165.6, 157.8, 150.4, 148.2,
138.9, 138.4, 136.1, 129.3, 117.5, 117.2, 116.2, 114.9, 35.2, 17.8 (carbon signal suspected under solvent
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peak); HRMS (ESIꢀTOF) m/z calcd for C16H17N3O3 [M+H]+ 300.1343, found 300.1345.
+
N1-Cyclopropyl-5-hydroxy-N3,N3-dimethyl-N1-(5-methylpyridin-2-yl)isophthalamide (10c): The
title compound was prepared from 5ꢀhydroxyꢀN1,N1ꢀdimethylꢀN3ꢀ(5ꢀmethylpyridinꢀ2ꢀyl)isophthalamide
(S4) (180 mg, 0.6 mmol) according to General Procedure C. Purification by ISCO (0–100%
EtOAc/Heptanes, then 10% MeOH/EtOAc) afforded the title compound as a light tan foam (130 mg,
64%). Structure elucidated by HMBC. 1H NMR (400 MHz, DMSOꢀd6) δ 9.80 (s, 1 H), 8.26–8.08 (m, 1
H), 7.57 (ddd, J = 8.07, 2.45, 0.61 Hz, 1 H), 7.16 (d, J = 8.07 Hz, 1 H), 6.81 (dd, J = 2.32, 1.47 Hz, 1
H), 6.65 (dd, J = 2.38, 1.41 Hz, 1 H), 6.60 (t, J = 1.41 Hz, 1 H), 3.10 (tt, J = 7.21, 3.73 Hz, 1 H), 2.90
(br s, 3 H), 2.62 (br s, 3 H), 2.23 (s, 3 H), 0.81–0.69 (m, 2 H), 0.63–0.52 (m, 2 H); 13C NMR (100 MHz,
DMSOꢀd6) δ 171.1, 169.6, 157.3, 153.5, 149.1, 139.0, 138.9, 137.7, 132.0, 122.5, 116.9, 115.9, 115.30,
39.0, 35.0, 31.4, 17.7, 8.3; HRMS (ESIꢀTOF) m/z calcd for C19H21N3O3 [M+H]+ 340.1656, found
+
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Author contributions. ‡These authors contributed equally.
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Acknowledgements. This work was financially supported by the National Institutes of Health
(1R35GM125052), The Scripps Research Institute (TSRI), and Pfizer, Inc. We gratefully acknowledge
the NSF for a Graduate Research Fellowship (NSF/DGEꢀ1346837, J.D.) and the DAAD for a
postdoctoral fellowship (M.L.O.). We further thank Dr. DeeꢀHua Huang for assistance with NMR
spectroscopy; Dr. Milan Gembicky and Dr. Arnold L. Rheingold for Xꢀray structure determination; and
Dr. Gregory Kauffman, Dr. Eugene Rui, and Dr. Klaus Dress for helpful discussion regarding the MMP
analysis.
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Supporting Information Available. Photographic depiction of reaction setup, matched molecular pair
(MMP) data, Xꢀray crystallographic data, and 1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
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