Palladium(II)-Catalyzed highly enantioselective C-H arylation of cyclopropylmethylamines

Article abstract of DOI:10.1021/ja512529e

C-H arylation via a Pd(II)/Pd(IV) catalytic cycle has been one of the most extensively studied C-H activation reactions since the 1990s. Despite the rapid development of this reaction in the past two decades, an enantioselective version has not been reported to date. Herein, we report a Pd(II)-catalyzed highly enantioselective (up to 99.5% ee) arylation of cyclopropyl C-H bonds with aryl iodides using mono-N-protected amino acid (MPAA) ligands, providing a new route for the preparation of chiral cis-aryl-cyclopropylmethylamines. The enantiocontrol is also shown to override the diastereoselectivity of chiral substrates.

Full text of DOI:10.1021/ja512529e

Subscriber access provided by ERCIYES UNIV
Article
Palladium(II)-Catalyzed Highly Enantioselective
C–H Arylation of Cyclopropylmethylamines
Kelvin S. L. Chan, Haiyan Fu, and Jin-Quan Yu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja512529e • Publication Date (Web): 12 Jan 2015
Downloaded from http://pubs.acs.org on January 13, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 14
Journal of the American Chemical Society
1
2
3
Palladium(II)-catalyzed Highly Enantioselective C–H
4
5
6
7
Arylation of Cyclopropylmethylamines
8
9
Kelvin S. L. Chan, Hai-Yan Fu, Jin-Quan Yu*
*Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla,
California 92037, United States;
10
11
12
13
14
15
16
17
18
19
20
yu200@scripps.edu
Abstract. C–H arylation via a Pd(II)/Pd(IV) catalytic cycle is one of the most extensively studied C–H
activation reactions since the 1990s. Despite the rapid development of this reaction in the past two
decades, an enantioselective version has not been reported to date. Herein, we report a Pd(II)-catalyzed
highly enantioselective (up to 99.5% ee) arylation of cyclopropyl C–H bonds with aryl iodides using
mono-protected amino acid (MPAA) ligands, providing a new route for the preparation of chiral cis-
aryl-cyclopropylmethylamines. The enantiocontrol is also shown to override the diastereoselectivity of
chiral substrates.
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1. Introduction
Although Pd-catalyzed enantioselective activation of prochiral C–H bonds has been
demonstrated with both Pd(0)1,2 and Pd(II)3–9 catalysts, achieving high levels of reactivity and
enantioselectivity using different classes of substrates in these reactions remain a significant challenge.
Previously, we demonstrated that Pd(II) complexes coordinated to a chiral mono-N-protected amino
acid (MPAA) ligand catalyze both C(sp2)–H4–7 and C(sp3)–H4a,8,9,10 activation, leading to a range of
enantioselective carbon–carbon, carbon–oxygen, and carbon–halogen bond forming reactions.
However, despite Pd(II)/Pd(IV) arylation being one of the most studied C–H activation reactions since
the 1990s,11 an enantioselective version has not been demonstrated to date.
1
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 14
The use of MPAA ligands to accelerate or enable Pd(II)-catalyzed C–H functionalization
reactions is crucial for controlling and achieving high enantioselectivities. In 2011, our lab reported a
MPAA ligand-catalyzed enantioselective cross coupling cyclopropyl C–H activation reaction via
Pd(II)/Pd(0) catalysis.8 This report provided early examples of enantioselective coupling reactions, but
the scope was limited to carboxylic acid-derived substrates and was not compatible with -hydrogens.
The yields and enantioselectivity (up to 93%) remain to be substantially improved. More recently, we
have also reported enantioselective C(sp2)–H iodination of benzylamine substrates,7 but no examples of
enantioselective cyclopropyl or other C(sp3)–H bonds in amines have yet been reported. Compared to
the extensive development of -C–H functionalizations of aliphatic acids using weakly coordinating
directing groups,8–10 C–H functionalization of alkyl amines via weak coordination has been
demonstrated with only a single example,7 highlighting the challenge of developing enantioselective C–
H activation reactions of alkyl amines.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In addition to the aforementioned fundamental challenges, the widespread presence of
cyclopropyl moieties in drug and agrochemical molecules provided further motivation for us to develop
enantioselective arylation of cyclopropyl C–H bonds in cyclopropylmethylamines (Fig. 1).12 Notably,
synthesis of chiral cis-aryl-cyclopropylmethylamines remains a significant challenge.13
Figure 1. Drugs containing cyclopropylmethylamine moieties
Herein, we report a Pd(II)-catalyzed enantioselective arylation of cyclopropyl C–H bonds of
triflyl-protected cyclopropylmethylamines using a chiral MPAA ligand, demonstrating the first example
of C–H arylation via Pd(II)/Pd(IV) catalysis. Both yields (up to 99%) and enantiomeric excesses (up to
99.5%) are superior to prior reports of enantioselective C–H activation reactions involving various
2
ACS Paragon Plus Environment

Page 3 of 14
Journal of the American Chemical Society
modes of catalysis. The observed exclusive mono-selectivity is also a highly desirable feature in C–H
arylation reactions. This reaction allows for the rapid generation of two chiral centers in a single step,
yielding a single cis-functionalized enantiomer from a prochiral substrate, and provides a new route for
the synthesis of enantiopure cis-aryl-cyclopropylmethylamines. Remarkably, the chiral MPAA ligand
can also override the innate diastereoselectivity of chiral substrates, thus providing a method to
construct four different diastereomers, each with three chiral centers.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2. Results and Discussion
Following our recent success in using triflyl-protected amines as a weak coordinating directing
group for C(sp3)–H activation,10 we first focused on the reaction of 1 with para-iodotoluene in the
presence of acetyl-N-protected amino acids (Table 1, entries 1 to 5). We found that bulky substituents
on the amino acid side chain improved the ees without affecting the yields (entries 1 to 5). Linear
substituents (n-alkyl) did not perform as well as branched chains. We then explored the protecting
groups on the amino group. Formyl protection performed poorly (entry 6). Increasing bulk did not
improve either reactivity or selectivity (entries 7 and 8). The electron-withdrawing trifluoroacetyl group
substantially improved the ee to 94.2% (entry 9). Carbamates are most effective for this reaction,
affording both high yields, and excellent ees (entries 11 to 15), with Boc-protected valine reaching the
highest ee of 98.8% (entry 12). Notably, the high enantioselectivities are obtained in spite of the
relatively high reaction temperature (80 ºC).
Table 1. Screening of ligandsa, b
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 14
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aExperiments were performed with 1 (0.2 mmol), p-iodotoluene (0.6 mmol), Pd(OAc)2 (0.02 mmol), Ag2CO3
(0.4 mmol), sodium trifluoroacetate (0.1 mmol), ligand (0.04 mmol) in t-BuOH (1 mL) for 18 hours at 80 ºC under air.
bYields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard.
With the optimized reaction conditions in hand, we explored the enantioselective arylation
reaction of various substrates with para-iodotoluene in the presence of Boc-L-Val-OH (Table 2). The
unsubstituted cyclopropylmethylamine 1 gave a single mono-arylated product 1a in good yield, and
excellent ee of 98.8%. The observed exclusive mono-selectivity is rare with C–H arylation reactions
using aryl iodides. Excellent mass balance was retained with unreacted starting material fully recovered.
In the presence of competing terminal methyl C(sp3)–H bonds, benzylic C(sp3)–H bonds, and aryl
C(sp2)–H bonds (substrates 2 to 4), the regio-selectivity for the cyclopropyl C(sp3)–H bonds remained
exclusive. Although the yield was significantly lower for 4a, mass balance remained excellent and
unreacted starting material was fully recovered. To explore this anomaly further, we subjected substrate
5, an electron-deficient analog of substrate 4, to the same reaction conditions. To our delight, nearly
4
ACS Paragon Plus Environment

Page 5 of 14
Journal of the American Chemical Society
quantitative yield of the desired product in 98.9% ee was obtained. We hypothesized that the electron-
rich ꢀ-ring in 4 or 4a could interfere with the active catalyst, but the electronegative F atoms in the rings
in 5 or 5a reduced the electron density in the rings so that the reaction could proceed. The TBS-
1
2
3
4
5
6
7
8
protected 1,3-amino alcohol derivative 6
-
9
amino acid 7 was compatible with the reaction conditions, and in spite of lower yields, the excellent ee
of 98.7% was obtained. The lowered yield of 7a could be due to possible competing coordination modes
of the ester moiety, which may prevent the Pd center from approaching the C–H bond.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Substrate scope for the enantioselective arylation of cyclopropylmethylaminesa, b
aExperiments were performed with substrate (0.2 mmol), p-iodotoluene (0.6 mmol), Pd(OAc)2 (0.02 mmol),
Ag2CO3 (0.4 mmol), sodium trifluoroacetate (0.1 mmol), Boc-L-Val-OH (0.04 mmol) in t-BuOH (1 mL) for 18 hours
at 80 ºC under air. bIsolated yields. cSubstrate 2 was run at 0.179 mmol scale. dSubstrate 4 was run at 0.25 mmol scale.
Table 3. Scope of aryl iodide reagents for the enantioselective arylation of
cyclopropylmethylaminesa,b
5
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 14
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aExperiments were performed with 1 (0.2 mmol), aryl iodide (0.6 mmol), Pd(OAc)2 (0.02 mmol), Ag2CO3 (0.4
mmol), sodium trifluoroacetate (0.1 mmol), Boc-L-Val-OH (0.04 mmol) in t-BuOH (1 mL) for 18 hours at 80 ºC under
air. bIsolated yields.
In order to derive diversified chiral cyclopropanes from simple cyclopropylmethylamine 1, it is
crucial that a wide range of aryl iodides can be used as coupling partners. We were delighted to find that
a wide range of electron-donating and electron-withdrawing substituents in para-, meta-, and ortho-
positions on the aryl iodides are compatible affording good to excellent yields (Table 3). In all but one
example, the enantioselectivity is higher than 98% ee. Electron-donating substituents at the para-
position of the aryl iodide appeared to lower the yield slightly (products 1d–1e), but did not
compromise the ee of the reaction. The highest ee of >99.5% was obtained in the reaction with 1-iodo-
6
ACS Paragon Plus Environment

Page 7 of 14
Journal of the American Chemical Society
3,4-methylenedioxybenzene affording 1e. Electron-withdrawing substituents such as ester, acetyl,
cyano, nitro, and trifluoromethyl groups at the para-position gave good yields and excellent ees (1f–j).
Aryl iodides containing halogens at the para-positions performed well (1k–n), with yields ranging from
81% to quantitative yields. Both electron-donating (1o), and electron-withdrawing substituents such as
ester, acetyl, nitro, and 3,5-di(trifluoromethyl) (1p–s) at the meta-position afforded good to excellent
yields and ees. Although the ortho-fluoro substituent afforded the lowest yield of 38% and lowest ee of
95.3%, we were particularly delighted to find that aryl iodide containing an ortho-ester substituent is an
excellent coupling partner (95% yield, 98.8% ee). At this stage of development, heterocyclic iodides are
incompatible with the reaction (see Supporting Information).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 4. Overriding the diastereoselectivitya,b
aExperiments were performed with 8 (0.2 mmol), p-iodotoluene (0.6 mmol), Pd(OAc)2 (0.02 mmol), Ag2CO3
(0.4 mmol), sodium trifluoroacetate (0.1 mmol), ligand (0.04 mmol) in t-BuOH (1 mL) for 18 hours at 80 ºC under air.
bIsolated yields reported are combined yields of diastereomers. Relative stereoconfiguration is reported.
The excellent enantiocontrol of this ligand prompted us to test whether we can override substrate-
controlled diastereoselectivity in substrates containing a chiral center, thereby providing access to all
four possible diastereomers. When we subjected the cyclopropylglycine (S)-8 to the optimized
conditions with Boc-L-Val-OH (Table 4 entry 1), a >20:1 diastereomeric ratio (dr) favoring product 9a
was obtained. To discern whether the observed stereoselectivity was controlled by the substrate or
ligand, we performed a series of control experiments. The use of achiral Boc-Gly-OH (entry 2) resulted
in a drastic decrease of stereoselectivity, suggesting that substrate control is not responsible for the
7
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 14
observed high selectivity. The use of Boc-D-Val-OH afforded a >20:1 dr favoring the other
diastereomer 9b (entry 3), suggesting that the external chiral ligand is overriding substrate control of
stereoselectivity. These results indicate that the careful choice of ligands allow access to all four
diastereomers in high dr >20:1. It is therefore possible to enantioselectively arylate racemic 8 to give
two diastereomers which can be separated by chromatography or recrystallization. The diminished yield
is probably caused by the -ester group coordinating to the Pd-center and hindering the reaction
turnover.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To test the scalability of the reaction, we proceeded to run a gram-scale reaction of the simple
cyclopropylmethylamine 1 with methyl-2-iodobenzoate (Scheme 1a). Scaled by 25 times to 5 mmol, the
reaction proceeded as expected, affording 89% isolated yield and excellent ee (98.6% ee). The
triflamide could also be removed in a two-step reaction to yield the free amine in excellent yields
(Scheme 1b). For simplicity in product isolation, we decided to trap the free amine with benzoyl
chloride, and the reaction yielded 91% over three-steps with unchanged ee.
Scheme 1. Scale up and deprotection of triflamide
Based on the extensive studies of Pd(II)-catalyzed C–H arylation with aryl iodides via
Pd(II)/Pd(IV) redox chemistry,11 a catalytic cycle is proposed for the enantioselective C–H arylation of
cyclopropylmethylamines (Fig. 2a). Cleavage of the C–H bond generates palladacycle 12. Oxidative
addition of Ar–I onto the palladacycle affords Pd(IV) complex 13. Subsequently, reductive elimination
occurs from the high-energy intermediate to give product R–Ar and Pd(II) complex 14. Silver salt
scavenges the iodide anion from 14 to regenerate the active catalyst 11 thus closing the catalytic cycle.
8
ACS Paragon Plus Environment

Page 9 of 14
Journal of the American Chemical Society
The silver salt is also known to promote the oxidative addition of Ar–I as well as the reductive
elimination by interacting with the iodide. Although the Pd(IV) intermediate in this type of arylation has
not been isolated, the reaction of the Pd(II) palladacycle with Ar–I to give the arylated product has been
rigorously demonstrated by Daugulis, which is consistent with a Pd(II)/Pd(IV) instead of a Pd(0)/Pd(II)
catalytic cycle.14 A closely related Pd(II)/Pd(III) catalytic cycle15 is also unlikely in this case because
the bisdentate coordination of the MPAA to Pd(II) does not permit the dimerization via the bridging
carboxylate.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In comparison to our previous Pd(II)/MPAA-catalyzed C–H arylation via a Pd(II)/Pd(0)
catalytic cycle (Fig. 2b),8 each step in this reaction except for the C–H cleavage is fundamentally
different. The lack of trace reaction in the absence of a silver salt rules out the possibility of involving a
Pd(II)/Pd(0) catalytic cycle (see Supporting Information), because one catalytic turnover would be
observed otherwise.8 In addition, a Pd(II)/Pd(0) catalytic cycle for C–H arylation with aryl iodides has
never been conceived or experimentally supported in the literature. On the other hand, a Pd(0)/Pd(II)
catalytic cycle for an intermolecular C(sp3)–H arylation16 is conceivable. However, this redox chemistry
is known to be incompatible with silver salts.16,17 In addition, the commonly used Pd(0) catalysts such
as allylpalladium(II) chloride dimer, bis(dibenzylideneacetone)palladium(0), and tris(dibenzylidene
acetone)dipalladium(0) are not reactive under the standard conditions in our exploratory studies. While
we do not have concrete evidence in support of a Pd(II)/Pd(IV) catalytic cycle at this stage, the reaction
pathway depicted in Fig. 2a provides the best explanation for the experimental data.
9
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 14
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. Catalytic cycles possible with the Pd(II)/MPAA system
3. Conclusion
In summary, Pd(II)-catalyzed highly enantioselective arylation of cyclopropylmethylamines
with aryl iodides has been achieved using Pd(II)-MPAA catalysts in excellent yields and ees. This
reaction represents the first example of enantioselective C–H arylation through a Pd(II)/Pd(IV) catalytic
manifold. In light of the lack of efficient methods for the preparation of chiral cis-aryl-
cyclopropylmethylamines, this transformation is a valuable addition to the tool box for making chiral
cyclopropanes.
4. Experimental Section
General
Precedure
for
the
Enantioselective
C(sp3)–H
Activation
of
Cyclopropylmethylamines (Table 2). A 50 mL sealed tube was charged with the starting material (0.2
mmol), aryl iodide (0.6 mmol), Pd(OAc)2 (4.5 mg, 0.02 mmol), Boc-L-Val-OH (8.7 mg, 0.04 mmol),
sodium trifluoroacetate (13.6 mg, 0.1 mmol), Ag2CO3 (110.3 mg, 0.4 mmol), and t-BuOH (1 mL, 0.2
M). The reaction mixture was then stirred at 80 °C for 18 h. After being allowed to cool to room
temperature, the mixture was diluted with a 1:1 mixture of hexanes:ethyl acetate, and filtered through a
10
ACS Paragon Plus Environment

Page 11 of 14
Journal of the American Chemical Society
pad of celite. The filtrate was concentrated in vacuo, and the resulting mixture purified by column
chromatography using an eluent of hexanes: ethyl acetate.
1
2
3
4
5
6
7
8
9
Acknowledgements. We gratefully acknowledge The Scripps Research Institute and the National
Institutes of Health (NIGMS, 2R01GM084019) for financial support. K.S.L.C. thanks the Agency for
Science, Technology and Research (A*STAR) Singapore for a predoctoral fellowship. H.Y.F. is a
visiting scholar sponsored by Sichuan University, People's Republic of China.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Supporting Information Available. Detailed experimental procedures, characterization of new
compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) For intramolecular examples of enantioselective Pd(0)-catalyzed C(sp3)–H activation, see: (a)
Nakanishi, M.; Katayev, D.; Besnard, C.; Kündig, E. P. Angew. Chem., Int. Ed. 2011, 50, 7438. (b)
Anas, S.; Cordi, A.; Kagan, H. B. Chem. Commun. 2011, 47, 11483. (c) Martin, N.; Pierre, C.; Davi,
M.; Jazzar, R.; Baudoin, O. Chem.—Eur. J. 2012, 18, 4480. (d) Saget, T.; Lemouzy, S. J.; Cramer, N.
Angew. Chem., Int. Ed. 2012, 51, 2238. (e) Nakanishi, M.; Katayev, D.; Besnard, C.; Kündig, E. P.
Chimia 2012, 66, 241.
(2) For an intermolecular example of enantioselective Pd(0)-catalyzed C(sp3)–H activation, see:
Renaudat, A.; Jean-Gérard, L.; Jazzar, R.; Kefalidis, C. E.; Clot, E.; Baudoin, O. Angew. Chem., Int. Ed.
2010, 49, 7261.
(3) For an example of Pd-catalyzed atropselective arylation, see: Yamaguchi, K.; Yamaguchi, J.; Studer,
A.; Itami, K. Chem. Sci. 2012, 3, 2165.
(4) For intermolecular examples of enantioselective Pd(II)/MPAA-catalyzed C(sp2)–H activation and
subsequent coupling with organoboron reagents, see: (a) Shi, B.-F.; Maugel, N.; Zhang, Y.-H.; Yu, J.-Q.
11
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 12 of 14
Angew. Chem., Int. Ed. 2008, 47, 4882. (b) Gao, D.-W.; Shi, Y.-C.; Gu, Q.; Zhao, Z.-L.; You, S.-L. J.
Am. Chem. Soc. 2013, 135, 86.
1
2
3
4
5
6
7
8
9
(5) For intermolecular examples of enantioselective Pd(II)/MPAA-catalyzed C(sp2)–H activation and
subsequent olefination, see: (a) Shi, B.-F.; Zhang, Y.-H.; Lam, J. K.; Wang, D.-H.; Yu, J.-Q. J. Am.
Chem. Soc. 2009, 132, 460. (b) Pi, C.; Li, Y.; Cui, X.; Zhang, H.; Han, Y.; Wu, Y. Chem. Sci. 2013, 4,
2675.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(6) For an intermolecular example of enantioselective Pd(II)/MPAA-catalyzed C(sp2)–H activation and
subsequent oxidation, see: Cheng, X.-F.; Li, Y.; Su, Y.-M.; Yin, F.; Wang, J.-Y.; Sheng, J.; Vora, H. U.;
Wang, X.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 1236.
(7) For an intermolecular example of enantioselective Pd(II)/MPAA-catalyzed C(sp2)–H activation and
subsequent iodination, see: Chu, L.; Wang, X.-C.; Moore, C. E.; Rheingold, A. L.; Yu, J.-Q. J. Am.
Chem. Soc. 2013, 135, 16344.
(8) For an intermolecular example of enantioselective Pd(II)/MPAA-catalyzed cyclopropyl C–H
activation and subsequent coupling with organoboron reagents, see: Wasa, M.; Engle, K. M.; Lin, D.
W.; Yoo, E. J.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 19598.
(9) For an intermolecular example of enantioselective Pd(II)-catalyzed cyclobutyl C(sp3)–H activation
and subsequent coupling with organoboron reagents, using a MPAA analog (mono-protected amino-O-
methylhydroxamic acid) ligand, see: Xiao, K.-J.; Lin, D. W.; Miura, M.; Zhu, R.-Y.; Gong, W.; Wasa,
M.; Yu, J.-Q. J. Am. Chem. Soc. 2014, 136, 8138.
(10) For an example of Pd(II)/MPAA-catalyzed C(sp3)–H activation, see: Chan, K. S. L.; Wasa, M.;
Chu, L.; Laforteza, B. N.; Miura, M.; Yu, J.-Q. Nat. Chem. 2014, 6, 146.
(11) For examples of Pd(II)/Pd(IV) C–H arylation, see: (a) Dyker, G. Angew. Chem., Int. Ed. 1994, 33,
103. (b) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154. (c) Sehnal,
P.; Taylor, R. J. K.; Fairlamb, I. J. S. Chem. Rev. 2010, 110, 824.
(12) For reviews of transition metal-mediated transformations for the synthesis of enantiopure
cyclopropanes, see: (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic
12
ACS Paragon Plus Environment

Page 13 of 14
Journal of the American Chemical Society
Synthesis with Diazo Compounds: From Cyclopropanes to Ylides; Wiley: New York, 1998. (b) Lebel,
H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 977. (c) Davies, H. M. L.;
Antoulinakis, E. G. Org. React. 2001, 57, 1. (d) Denmark, S. E.; Beutner, G. In Cycloaddition Reactions
in Organic Synthesis; Kobayashi, S., Jørgensen, K. A., Eds.; Wiley-VCH: Weinheim, Germany, 2002;
pp 85 ff.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(13) For asymmetric synthesis of cyclopropanes, see (a) Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998,
98, 911. (b) Doyle, M. P.; Protopopova, M. N. Tetrahedron 1998, 54, 7919. (c) Davies, H. M. L.;
Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861. (d) Lou, Y.; Horikawa, M.; Kloster, R. A.; Hawryluk,
N. A.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 8916. (e) Zhu, S.; Cui, X.; Zhang, X. P. Eur. J. Inorg.
Chem. 2012, 430.
(14) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc., 2010, 132, 3965.
(15) Powers, D. C.; Lee, E.; Ariafard, A.; Sanford, M. S.; Yates, B. F.; Canty, A. J.; Ritter T. J. Am.
Chem. Soc., 2012, 134, 12002.
(16) Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 9886.
(17) He, J.; Wasa, M.; Chan, K. S. L.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 3387.
13
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 14 of 14
1
2
3
TOC Graphic
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
14
ACS Paragon Plus Environment