Asymmetric Intermolecular Heck Reaction of Propargylic Acetates and Cycloalkenes to Access Fused Cyclobutenes

Article abstract of DOI:10.1002/anie.201708435

An asymmetric Heck annulation of propargylic acetates with several types of cyclic olefins affords highly strained cyclobutenes in high enantioselectivity.

Full text of DOI:10.1002/anie.201708435

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Accepted Article
Title: Asymmetric Intermolecular Heck Reaction of Propargylic
Acetates and Cycloalkenes to Access Fused Cyclobutenes
Authors: Jianrong Steve Zhou, Zhiwei Jiao, and Qi Shi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201708435
Angew. Chem. 10.1002/ange.201708435
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10.1002/anie.201708435
Angewandte Chemie International Edition
COMMUNICATION
Asymmetric Intermolecular Heck Reaction of Propargylic
Acetates and Cycloalkenes to Access Fused Cyclobutenes
*
Zhiwei Jiao, Qi Shi, and Jianrong Steve Zhou
Abstract: Asymmetric Heck cyclization of propargylic acetates with
several types of cyclic olefins affords highly strained cyclobutenes in
high enantioselectivity.
and donating alkynes via polar pathways.[14] The example
reported by Narasaka et al. used a stoichiometric amount of a
titanium-TADDOL reagent (Figure 1a).[15] Recently, Ishihara,
Feng and others also disclosed enantioselective processes
using olefins and alkynes of inverse electronic properties (see
Figure 1b).[16] Some late metal catalysts have been known to
promote formation of cyclobutenes,[17] including those involving a
key step of reductive coupling of olefins and alkynes.[18] However,
asymmetric examples based on reductive coupling are rare and
are restricted to reactive olefins such as norbornene.[19] A recent
example by Cramer et al. is shown in Figure 1c.[20]
Asymmetric Heck reaction of aryl or alkenyl electrophiles has
been extensively developed and also successfully applied in
synthesis of bioactive complex molecules.[1-3] In efforts to use
other types of carbon electrophiles in these reactions, we and
Sigman group have reported asymmetric benzylation[4] and
alkynylation[5] of alkenes. As a logical extension, we now
disclose results on asymmetric Heck cyclization of propargylic
electrophiles,[6] which affords highly strained cyclobutenes in
good ee values (Figure 1d).[6-8]
Me
OAc
Pd(dba)2 5 mol%
ligand 7.5 mol%
Me
H
Me
KOAc 1.2 equiv
1:1 i-PrOH/EtCN
50 oC, 24 h
O
O
Ph
H
1a
2a (3x)
(a) [2+2] cycloaddition of electron-deficient alkenes and thioalkynes
Ph
3a
O
O
Ph
OH
OH
Ph Ph
O
O
Ph
TiCl2(Oi-Pr)2 + TADDOL
MeO2C
Me
Ph
O
O
Me Me
N
O
O
MeO2C
Me
N
110 mol%
O
O
O
Me
N
N
SMe
98% ee
(Narasaka, 1992)
N
N
N
N
SMe
R
R
R
R
TADDOL
R
R
L3 R = Ph 45% ee, 5% yield
L4 R = t-Bu 3% ee, 11% yield
L5 R = Bn 30% ee, 9% yield
L6 R = Ph 7% ee, 21% yield
L7 R = t-Bu 3% ee, 13% yield
L8 R = Bn 8% ee, 83% yield
L1 R = H 91% yield
L2 R = Me 21% yield
(b) [2+2] cycloaddition of silyl enol ethers and ynones
O
Ph
Zn(NTf2)2 + ligand
5 mol%
OTBS
TBSO
O
Ph
N
N
O
H
O
O
H
H
O
O
H
O
O
O
O
O
HN
Ar
(Feng, 2016)
NH
Ar
N
Ph
Ph
N
N
H
N
N
N
ligand
H
H
H
94% ee
H
Ar = 2,6-i-Pr2C6H3
Ph
Ph
L9 99% ee, 2% yield
L10 90% ee, 64% yield
L11 36% ee, 51% yield
(c) [2+2] cycloaddition of reactive norbornene and ynoates
Ph
H
O
-
+
O
N
O
N
CO2Me
Ph
PF6
O
Ru complex
5 mol%
CO2Me
Ph
R
N
N
N
N
Ph
Ru
Bn
Bn
t-Bu
H
H
(Cramer, 2017)
H
(MeCN)3
L12 30% ee, 12% yield
L13 R = H 22% ee, 91% yield
L14 R = CF3 31% ee, 48% yield
L15 3% ee, 61% yield
93% ee
Ru complex
Scheme 1. Ligand effect of a model Heck cyclization.
(d) Heck cyclization of propargylic acetates
Me
H
H
H
O
H
O
In a test reaction of 3-phenylpropargyl acetate 1a and 2,3-
dihydrofuran 2a, initially we found that a palladium catalyst of
2,2´-bipyridine L1 efficiently promoted this process to give
racemic cyclobutene 3a in good yield (Scheme 1). Inspired by
this finding, we next explored other nitrogen-based chelators.
Among them, a bisoxazoline L10[21] bearing rigid indanyl side
group delivered 3a in 64% yield and 90% ee to our gratification.
Other chiral diphosphines, e.g., binap and segphos and Pfaltz-
type oxazoline-phosphines didn’t catalyze this transformation.
With regard to other reaction parameters, acetate was the best
leaving group among other esters and carbonates. Stronger
bases, e.g., K2CO3 and Et3N, inhibited the desired reactivity,
however. We used a 1:1 isopropanol and propionitrile as the
reaction solvent, because the ee was slightly better than in
isopropanol. For a substrate similar to 1a but devoid of gem-
dimethyl groups, no reaction occurred.
R
OAc
R
cat. Pd 5 mol%
(this work)
N
N
X
H
Ph
X
H
>90% ee
Ph
(X = CH2, O, NBoc)
ligand:
bisoxazoline
over 40 examples
Figure 1. Examples of catalytic asymmetric synthesis of cyclobutenes.
Cyclobutenes contain a high degree of ring strain,[9] which
presents as a challenge in stereoselective synthesis.[10] They
were also used as spring-loaded intermediates to access other
four-membered ring compounds[11] and 1,3-dienes after ring
opening.[12] These strained rings are also present as key motifs
in some bioactive compounds.[13] [2+2] cycloaddition of
unsaturated olefins and alkynes is common reaction of choice to
prepare cyclobutenes owing to atom economy and favorable
energetics. A few Lewis acidic metal catalysts were reported to
promote asymmetric [2+2] cycloaddition of electron-poor olefins
The Pd catalyst of L10 was successfully applied to reactions
of 2,3-dihydrofuran (Scheme 2). Both electron-deficient and rich
3-aryl rings were well tolerated on 3-arylpropargylic acetates. In
cases that resulted in moderate yields, a side reaction, addition
of isopropanol to 2,3-dihydrofuran was observed, which was
catalyzed by acetic acid as produced in the Heck pathway.
Unfortunately, reactions of 3-alkylpropargylic acetates afforded
the products in low yields. The propargyl electrophile with a
[*]
Dr. Z. Jiao, Ms. Q. Shi, Prof. Dr. J. S. Zhou
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University, Singapore 637371
E-mail: jrzhou@ntu.edu.sg
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201708435
Angewandte Chemie International Edition
COMMUNICATION
gem-cyclopentyl group also reacted smoothly (3m). However, a
similar substrate with a cyclohexyl ring failed to react due to
steric reason in a chair conformation where the alkynyl group
preferentially occupies an axial position. Notably, the fused
cyclobutenes prepared from 2,3-dihydrofuran, once purified and
stored in neat form, tend to polymerize over hours to days.
yield, but in good ee, along with a noncyclized isomer 5a. 3-
Arylpropargylic acetates of different electronic properties on aryl
rings also reacted efficiently with cyclopentene. Furthermore, no
insertion occurred with cyclohexene, which is known to be a
challenging substrate in cationic Heck pathways.
Why didn't 2,3-dihydrofuran 2a and 2,3-dihydropyrrole 2b
undergo produce noncyclized isomers of type 5? We reason that
during β hydride elimination leading to the noncyclized isomers,
partial positive charge develops on the β carbon of cycloalkyl
group, which is destabilized by the electron-withdrawing
inductive effect of heteroatoms (O and N) in the transition state.
Moreover, in a reaction of 1a and an acyclic alkene, 1-butyl
vinyl ether, a catalyst formed by Pd(dba)2 and bipy led to simple
Heck reaction at the alpha carbon of the vinyl group and resulted
in two E/Z isomers of trienes after further allene isomerization,
while no cyclized isomer was detected (see the Supporting
Information). A combination of Pd(dba)2 and L10 was almost
inactive with <5% product.
Me
OAc
Me
Me
(a)
Pd(dba)2 5 mol%
ligand L10 7.5 mol%
Me
H
Me
C
+
KOAc (1.2 equiv)
H
Ph
Ph
We then studied the reaction of 1a and N-Boc-2,3-
dihydropyrrole 2b, which afforded product 3n in 19% yield and
20% ee, in the presence of Pd(dba)2/L10 and KOAc in
isopropanol; a side reaction of 2b and isopropanol consumed
the remaining material of 2b. After additional optimization, the
use of Pd(dba)2 and pseudoantipodal ligand L9 afforded 3n in
48% yield and 90% ee in the presence of (-)-sparteine (Scheme
2c); In the absence of L9, a background reaction in the presence
of (-)-sparteine furnished 3n in 43% yield, but merely 2% ee.
Additionally, replacement of (-)-sparteine with achiral TMEDA
under similar conditions of Scheme 2c led to formation of 50%
yield of 3n in 50% ee. Thus in this reaction, chiral ligand L9
accelerated palladium-catalyzed asymmetric bond formation, in
competition with the diamine-catalyzed nonselective process.
H
Ar
1a (Ar = Ph) 2c (5x)
1:1 i-PrOH/EtCN
4a
96% ee, 57% yield
(ratio of 2 isomers 2.2:1)
5a
60 o
C
64% ee, 26% yield
(b) Other cyclobutene products
Ar =
O
O
OMe
OMe
4b 96% ee
52% yield
ratio 2.9:1
4c 96% ee
60% yield
ratio 3.3:1
4d 96% ee
63% yield
ratio 3.4:1
4e 94% ee
51% yield
ratio 2.8:1
OMe
COPh
S
F
4i 88% ee
4h 89% ee
43% yield
ratio 1.2:1
with 10% Pd
4g 94% ee
55% yield
ratio 1.7:1
4f 92% ee
54% yield
ratio 2:1
67% yield
ratio 3.1:1
with 10% Pd
Scheme 3. Asymmetric Heck cyclization with cyclopentene.
Me
OAc
Pd(dba)2
ligand L10 7.5 mol%
5 mol%
Me
Ph
Me
Me
Me
OAc
Pd(dba)2 5 mol%
(a)
H
KOAc (1.2 equiv)
i-PrOH, 50 o
ligand L10 7.5 mol% Me
+
6a 93% ee, 89% yield
+
C
(a)
Ar
1a (Ar = Ph) 2d (3x)
i-PrO
with 1% Pd
92% ee, 56% yield
O
O
KOAc (1.2 equiv)
1:1 i-PrOH/EtCN
50 oC, 24 h
O
Ar
H
Ar
1a
(Ar = Ph)
(b) Products from other 3-aryl-1,1-dimethylpropargyl acetates and 2d
3a 90% ee, 64% yield
2a (3x)
OMe
O
O
(b) Products from other 3-arylpropargylic acetates
Ar =
OMe
6d 96% ee
MeO
6c 90% ee
6b 95% ee
68% yield
6e 96% ee
76% yield
3d Y = t-Bu 88% ee, 62% yield
3e Y = OMe 90% ee, 71% yield
6f 96% ee
85% yield
71% yield
65% yield
Ar =
3f Y = F
3g Y = Cl
91% ee, 61% yield
88% ee, 67% yield
Y
Y
F
C(O)Ph
3b Y = H
91% ee, 69% yield
3c Y = MeO 89% ee, 70% yield
C(O)Ph
Ph
S
6j 90% ee
76% yield
6i 95% ee
92% yield
6h 92% ee
62% yield
6g 94% ee
51% yield
OMe
O
O
(c) Products from other propargylic acetates and norbornene
MeO
Me
Et
3j 91% ee, 63% yield
3h 90% ee, 66% yield
3i 86% ee, 58% yield
Ph
Ph
Ph
Ph
6m 89% ee
Ph
H
F
6k 89% ee
6n 77% ee
6l 88% ee
84% yield
81% yield
98% yield
75% yield
S
Ph
O
Me
Ph
H
Me
Et
Et
OAc
Me
Ph
3k 86% ee, 56% yield
3l 90% ee, 41% yield
3m 87% ee, 58% yield
same conditions
as in (a)
(d)
+
Ph
6o 91% ee
Pd(dba)2 10 mol%
ligand L9 15 mol%
H
Ph
1r (racemate)
91% yield
ratio 2.4:1
Me
6p 99% ee
2d
1a
+
+
(c)
i-PrO
N
N
Boc
N
(-)-sparteine (1.2 equiv)
Boc
2b (3x)
Ph
H
Boc
(e) Products from other bicyclic olefins
i-PrOH, 90 oC, 24 h
3n 90% ee, 48% yield
Me
Ph
OH
OH
Me
Me
Me
Me
Scheme 2. Asymmetric Heck reaction of 2,3-dihydrofuran and N-Boc-
O
2,3-dihydropyrrole.
Ph
Ph
2-naph
O
Ph
N
O
Me
Me
Me
O
Next, we attempted reactions of cyclopentene, which is less
reactive than electron-rich olefins 2a and 2b in the cationic Heck
reactions (Scheme 3). Product 4a was obtained in moderate
6q 89% ee
49% yield
6r 90% ee
71% yield
6u 94% ee
63% yield
6s 87% ee
89% yield
6t 93% ee
64% yield
Scheme 4. Asymmetric Heck cyclization of bicyclic alkenes.
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10.1002/anie.201708435
Angewandte Chemie International Edition
COMMUNICATION
Strained norbornene is known to be reactive towards metal-
catalyzed insertion. Furthermore, they lack syn β hydrogen to
eliminate after insertion. Consequently, Heck reaction of 1a
efficiently delivered product 6a in an excellent yield and good ee
(Scheme 4). Moreover, propargylic acetates tolerated
cyclopentyl (6k), cycloheptyl (6l) and 3-pentyl groups (6m) on
C1 position. Notably, racemic 1r carrying sec-butyl group led to
two isomers 6o and 6p, depending on the direction of β
hydrogen elimination. Interestingly, norbornadiene and
benzofused norbornene also reacted smoothly to give products
6q and 6u, and the reaction was compatible with diol (6r), acetal
(6s) and succinic imide groups (6t).
by rare 4-exo-dig cyclization[25] of the allene fragment and β
hydrogen elimination. A simple quadrant model based on C2-
symmetric bisoxazoline L10 predicts that the allenyl complex
inserts to the cycloolefin in the unhindered top-right quadrant of
the chiral pocket and thus sets the carbon configurations in the
final product.
N
Me
N
Me
OAc
N
N
Me
Me
Me
cat.
Pd/L10
Pd
Pd
O
Me
H
C
C
O
Ph
allenyl complex
1a
O
H
Ph
Ph
alkyl complex
H
O
H
O
N
N
N
N
H
Me
Pd
H
Me
H
H
[(N-N)PdH]+
The strained cyclobutenes readily underwent Diels-Alder
cycloaddition with a maleimide to give fused carbocycles 7a, 7c,
7d and 7g (Scheme 5). By single-crystal X-ray diffraction of 7a
and 7g we unambiguously assigned the absolute configuration
as shown. Moreover, the 1-propeneyl groups on cyclobutenes
were cleaved via Sharpless dihydroxylation and subsequent
NaIO4 oxidation to give ketones 7b, 7e and 7f.[22] In all cases, no
erosion of the ee from cyclobutenes was detected.
L10
Me
O
β hydride
elimination
Ph
H
O
3a 90% ee
Ph
H
(quadrant presentation)
Scheme 6. A plausible catalytic cycle
In conclusion, the first catalytic enantioselective Heck
cyclization of propargylic acetates results in highly strained,
fused cyclobutenes. The compounds cannot be made from other
reactions.
Furthermore, the cyclobutenes underwent smoothly Pd-
catalyzed annulation with o-iodophenyl acetate[23] and Pd/tri-t-
butylphosphine catalyzed transfer hydrogenation,[24] both of
which occurred regioselectively at terminal 1-propenyl groups to
give 7h and 7i. No other regioisomers were detected in the
crude mixture.
Acknowledgements
We thank Singapore Ministry of Education Academic Research
Fund (MOE2014-T1-001-021; MOE2015-T1-001-166) for
financial support.
Me
O
Me
Me
H
H
H
H
H
Me
O
H
(b)
Ph
(a)
Keywords: palladium catalysis • Heck reaction • strained small
O
N
Ph
Ph
H
Ph
H
O
rings • cyclobutene • propargylic electrophiles
O
7b 73% yield
Br
7a 85% yield (X-ray)
[1] Reviews: a) O. Loiseleur, M. Hayashi, N. Schmees, A. Pfaltz, Synthesis
1997, 1338; b) A. B. Dounay, L. E. Overman, Chem. Rev. 2003, 103,
2945; c) M. Shibasaki, E. M. Vogl, T. Ohshima, Adv. Synth. Catal. 2004,
346, 1533; d) D. McCartney, P. J. Guiry, Chem. Soc. Rev. 2011, 40,
5122.
[2] Examples: a) E. W. Werner, T.-S. Mei, A. J. Burckle, M. S. Sigman,
Science 2012, 338, 1455; b) B. J. Stokes, A. J. Bischoff, M. S. Sigman,
Chem. Sci. 2014, 5, 2336; c) L. Xu, M. J. Hilton, X. Zhang, P.-O. Norrby,
Y.-D. Wu, M. S. Sigman, O. Wiest, J. Am. Chem. Soc. 2014, 136, 1960;
d) H. H. Patel, M. S. Sigman, J. Am. Chem. Soc. 2015, 137, 3462; e) Z.-
M. Chen, M. J. Hilton, M. S. Sigman, J. Am. Chem. Soc. 2016, 138,
11461; f) C. M. Avila, J. S. Patel, Y. Reddi, M. Saito, H. M. Nelson, H. P.
Shunatona, M. S. Sigman, R. B. Sunoj, F. D. Toste, Angew. Chem. 2017,
129, 5900; Angew. Chem. Int. Ed. 2017, 56, 5806.
Me
Ar
R
R
O
O
R
(b)
(a)
N
Ar
Ar
Ar
H
H
H
H
H
H
O
H
H
Br
7e Ar, R = Ph 85% yield
7f Ar = 3-MeOPh, R = Me
82% yield
7c Ar = Ph 88% yield
7d Ar = 4-BzPh 83% yield
Me
Me
O
Ph
(a)
O
N
O
Ph
H
N
H
H
Me
O
N
O
H
Me
Br
O
7g 83% yield (X-ray)
6t
[3] Examples: a) W.-Q. Wu, Q. Peng, D.-X. Dong, X.-L. Hou, Y.-D. Wu, J.
Am. Chem. Soc. 2008, 130, 9717; b) J. Hu, H. Hirao, Y. Li, J. Zhou,
Angew. Chem. 2013, 125, 8838; Angew. Chem. Int. Ed. 2013, 52, 8676;
c) J. Hu, Y. Lu, Y. Li, J. Zhou, Chem. Commun. 2013, 49, 9425; d) C.
Wu, J. Zhou, J. Am. Chem. Soc. 2014, 136, 650; e) G. M. Borrajo-
Calleja, V. Bizet, T. Burgi, C. Mazet, Chem. Sci. 2015, 6, 4807; f) C. C.
Oliveira, A. Pfaltz, C. R. D. Correia, Angew. Chem. 2015, 127, 14242;
Angew. Chem. Int. Ed. 2015, 54, 14036; g) Q.-S. Zhang, S.-L. Wan, D.
Chen, C.-H. Ding, X.-L. Hou, Chem. Commun. 2015, 51, 12235.
[4] Z. Yang, J. Zhou, J. Am. Chem. Soc. 2012, 134, 11833.
(a) N-(4-Bromophenyl)maleimide in xylenes.
(b) AD-mix-β and MeSO2NH2; NaIO4
Me
O
Me
Me
Pd(dba)2 5 mol%
DPPE 6 mol%
Pd(OAc)2 5 mol%
t-Bu3P HBF4 10 mol%
Me
Ar
Ar
Ph
Ag2CO3 3 equiv
HCO2H 5 equiv
THF, rt
1,4-dioxane/H2
O
7i Ar = p-anisyl
~90% yield
7h 65% yield
dr 1.3:1
OAc
I
[5] Z.-M. Chen, C. S. Nervig, R. J. DeLuca, M. S. Sigman, Angew. Chem.
2017, 129, 6751; Angew. Chem. Int. Ed. 2017, 56, 6651.
Scheme 5. Derivatiztion of fused cyclobutenes.
[6] Review on Pd-catalyzed cyclization processes: T. Vlaar, E. Ruijter, R. V.
A. Orru, Adv. Synth. Catal. 2011, 353, 809.
We believe that after oxidative addition, the presence of
gem-dimethyl groups in the propargyl electrophile favors the η1-
allenyl form, instead of tertiary carbon bonded η1- or η3-
propargyl complexes (Scheme 6). Moreover, the cationic η3-
propargyl complex is electrophilic which cannot participate in the
oelfin-insertion process. A plausible pathway thus involves the
insertion of η1-allenyl complex to a bound cycloolefin, followed
[7] Examples of Heck cyclization of propargylic electrophiles to form
cyclopropanes: a) R. Grigg, R. Rasul, J. Redpath, D. Wilson,
Tetrahedron Lett. 1996, 37, 4609; b) W. Oppolzer, A. Pimm, B.
Stammen, W. E. Hume, Helv. Chim. Acta 1997, 80, 623; c) V. Bagutski,
N. Moszner, F. Zeuner, U. K. Fischer, A. de Meijere, Adv. Synth. Catal.
2006, 348, 2133. Example of Heck cyclization of vinyl triflates that
generated methylcyclobutanes: d) A. Innitzer, L. Brecker, J. Mulzer, Org.
Lett. 2007, 9, 4431.
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10.1002/anie.201708435
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COMMUNICATION
[8] Other examples of Pd-catalyzed propargyl/allenyl insertion of olefins: a)
T. Mandai, M. Ogawa, H. Yamaoki, T. Nakata, H. Murayama, M.
Kawada, J. Tsuji, Tetrahedron Lett. 1991, 32, 3397; b) X. Lian, S. Ma,
Angew. Chem. 2008, 120, 8379; Angew. Chem. Int. Ed. 2008, 47, 8255;
c) W. Shu, G. Jia, S. Ma, Angew. Chem. 2009, 121, 2826; Angew. Chem.
Int. Ed. 2009, 48, 2788; d) J. Ye, S. Ma, Angew. Chem. 2013, 125,
11009; Angew. Chem. Int. Ed. 2013, 52, 10809.
Chem. 2016, 128, 6630; Angew. Chem. Int. Ed. 2016, 55, 6520; g) M. E.
de Orbe, L. Amenós, M. S. Kirillova, Y. Wang, V. López-Carrillo, F.
Maseras, A. M. Echavarren, J. Am. Chem. Soc. 2017, 139, 10302; h) C.
García-Morales, B. Ranieri, I. Escofet, L. López-Suarez, C. Obradors, A.
I. Konovalov, A. M. Echavarren, J. Am. Chem. Soc. 2017, DOI:
10.1021/jacs.7b07651.
[18] Recent examples of low-valent late metal-catalyzed reductive coupling of
alkenes and alkynes to access racemic cyclobutenes via: a) B. M. Trost,
M. Yanai, K. Hoogsteen, J. Am. Chem. Soc. 1993, 115, 5294; b) D.-J.
Huang, D. K. Rayabarapu, L.-P. Li, T. Sambaiah, C.-H. Cheng, Chem.-
Eur. J. 2000, 6, 3706; c) R. W. Jordan, W. Tam, Org. Lett. 2000, 2, 3031;
d) J. Treutwein, G. Hilt, Angew. Chem. 2008, 120, 6916; Angew. Chem.
Int. Ed. 2008, 47, 6811; e) G. Hilt, A. Paul, J. Treutwein, Org. Lett. 2010,
12, 1536; f) Y. Li, X. Liu, H. Jiang, B. Liu, Z. Chen, P. Zhou, Angew.
Chem. 2011, 123, 6465; Angew. Chem. Int. Ed. 2011, 50, 6341; h) A.
Nishimura, M. Ohashi, S. Ogoshi, J. Am. Chem. Soc. 2012, 134, 15692;
g) K. Sakai, T. Kochi, F. Kakiuchi, Org. Lett. 2013, 15, 1024; i) A.
Nishimura, E. Tamai, M. Ohashi, S. Ogoshi, Chem.-Eur. J. 2014, 20,
6613.
[19] a) T. Shibata, K. Takami, A. Kawachi, Org. Lett. 2006, 8, 1343; b) B.-M.
Fan, X.-J. Li, F.-Z. Peng, H.-B. Zhang, A. S. C. Chan, Z.-H. Shao, Org.
Lett. 2010, 12, 304.
[20] a) D. Kossler, N. Cramer, Chem. Sci. 2017, 8, 1862; b) D. Kossler, F. G.
Perrin, A. A. Suleymanov, G. Kiefer, R. Scopelliti, K. Severin, N. Cramer,
Angew. Chem. 2017,129, 11648; Angew. Chem. Int. Ed. 2017, 56,
11490.
[21] a) I. W. Davies, C. H. Senanayake, R. D. Larsen, T. R. Verhoeven, P. J.
Reider, Tetrahedron Lett. 1996, 37, 813; b) D. M. Barnes, J. Ji, M. G.
Fickes, M. A. Fitzgerald, S. A. King, H. E. Morton, F. A. Plagge, M.
Preskill, S. H. Wagaw, S. J. Wittenberger, J. Zhang, J. Am. Chem. Soc.
2002, 124, 13097.
[22] K. B. Sharpless, W. Amberg, Y. L. Bennani, G. A. Crispino, J. Hartung, K.
S. Jeong, H. L. Kwong, K. Morikawa, Z. M. Wang, J. Org. Chem. 1992,
57, 2768.
[23] R. V. Rozhkov, R. C. Larock, Org. Lett. 2003, 5, 797.
[24] J. M. Brunel, Synlett 2007, 330.
[25] B. Salem, J. Suffert, Angew. Chem. 2004,116, 2886; Angew. Chem. Int.
Ed. 2004, 43, 2826.
[9] P. S. Lee, S. Sakai, P. Hörstermann, W. R. Roth, E. A. Kallel, K. N. Houk,
J. Am. Chem. Soc. 2003, 125, 5839.
[10] Review: Y. Xu, M. L. Conner, M. K. Brown, Angew. Chem. 2015, 127,
12086; Angew. Chem. Int. Ed. 2015, 54, 11918.
[11] Reviews: a) N. Gauvry, C. Lescop, F. Huet, Eur. J. Org. Chem. 2006,
2006, 5207; b) A. Misale, S. Niyomchon, N. Maulide, Acc. Chem. Res.
2016, 49, 2444.
[12] a) M. R. Wilson, R. E. Taylor, Angew. Chem. 2013, 125, 4170; Angew.
Chem. Int. Ed. 2013, 52, 4078; b) P. Nava, Y. Carissan, Phys. Chem.
Chem. Phys. 2014, 16, 16196; c) B. A. Boon, A. G. Green, P. Liu, K. N.
Houk, C. A. Merlic, J. Org. Chem. 2017, 82, 4613.
[13] Examples: a) N. González, J. Rodríguez, R. G. Kerr, C. Jiménez, J. Org.
Chem. 2002, 67, 5117; b) V. M. Dembitsky, J. Nat. Med. 2008, 62, 1.
[14] Recent examples: a) H. Ito, M. Hasegawa, Y. Takenaka, T. Kobayashi,
K. Iguchi, J. Am. Chem. Soc. 2004, 126, 4520; b) C. Schotes, A.
Mezzetti, Angew. Chem. 2011, 123, 3128; Angew. Chem. Int. Ed. 2011,
50, 3072; c) K. Enomoto, H. Oyama, M. Nakada, Chem.-Eur. J. 2015, 21,
2798; d) L. Shen, K. Zhao, K. Doitomi, R. Ganguly, Y.-X. Li, Z.-L. Shen,
H. Hirao, T.-P. Loh, J. Am. Chem. Soc. 2017, 139,
10.1021/jacs.7b07997.
[15] K. Narasaka, Y. Hayashi, H. Shimadzu, S. Niihata, J. Am. Chem. Soc.
1992, 114, 8869.
[16] a) K. Ishihara, M. Fushimi, J. Am. Chem. Soc. 2008, 130, 7532; b) T.
Kang, S. Ge, L. Lin, Y. Lu, X. Liu, X. Feng, Angew. Chem. 2016, 128,
5631; Angew. Chem. Int. Ed. 2016, 55, 5541; c) C. Schotes, R. Bigler, A.
Mezzetti, Synthesis 2012, 44, 513.
[17] Recent examples of metal-catalyzed synthesis of racemic cyclobutenes:
a) R. F. Sweis, M. P. Schramm, S. A. Kozmin, J. Am. Chem. Soc. 2004,
126, 7442. A. Fürstner, P. W. Davies, T. Gress, J. Am. Chem. Soc. 2005,
127, 8244; b) M. Shi, L.-P. Liu, J. Tang, J. Am. Chem. Soc. 2006, 128,
7430; c) A. Masarwa, A. Furstner, I. Marek, Chem. Commun. 2009,
5760; d) V. López-Carrillo, A. M. Echavarren, J. Am. Chem. Soc. 2010,
132, 9292; e) Y. Qiu, B. Yang, C. Zhu, J.-E. Bäckvall, J. Am. Chem. Soc.
2016, 138, 13846; f) Y. Qiu, B. Yang, C. Zhu, J.-E. Bäckvall, Angew.
This article is protected by copyright. All rights reserved.

10.1002/anie.201708435
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
asymmetric Heck annulation
Intermolecular
Heck reaction of
propargylic
Zhiwei Jiao, Qi Shi, and Jianrong Steve Zhou *
Me
H
H
R
OAc
R
Pd catalyst
X
Page No. – Page No.
R
X
acetates and
cyclic olefins led
to highly
strained
cyclobutenes
R
>90% ee
(X = CH2, O, NBoc)
Asymmetric Intermolecular Heck Reaction of
Propargylic Acetates and Cycloalkenes to Access Fused
Cyclobutenes
H
O
H
O
N
N
H
H
supporting
ligand
This article is protected by copyright. All rights reserved.