Asymmetric Synthesis of Alkylzincs by Rhodium-Catalyzed Enantioselective Arylative Cyclization of 1,6-Enynes with Arylzincs

Article abstract of DOI:10.1002/anie.202008770

A chiral diene-rhodium complex was found to catalyze the reaction of 1,6-enynes with ArZnCl to give high yields of 2-(alkylidene)cyclopentylmethylzincs with high enantioselectivity (95–99 % ee). The enantioenriched alkylzincs were readily converted in a one-pot approach into a wide variety of functionalized products by taking advantage of their unique reactivity. The catalytic cylcle involves arylrhodation of alkyne, intramolecular alkenylrhodation of alkene, and transmetalation of the alkyl-rhodium intermediate into alkylzinc.

Full text of DOI:10.1002/anie.202008770

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Accepted Article
Title: Asymmetric Synthesis of Alkylzincs by Rhodium-Catalyzed
Enantioselective Arylative Cyclization of 1,6-Enynes with
Arylzincs
Authors: Jiahua Chen and Tamio Hayashi
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10.1002/anie.202008770
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Asymmetric Synthesis of Alkylzincs by Rhodium-Catalyzed
Enantioselective Arylative Cyclization of 1,6-Enynes with
Arylzincs
Jiahua Chen[b] and Tamio Hayashi*[a,b]
Abstract: A chiral diene–rhodium complex was found to catalyze the
reaction of 1,6-enynes with ArZnCl to give high yields of 2-
(alkylidene)cyclopentylmethylzincs with high enantioselectivity (95–
99% ee). The enantioenriched alkylzincs were readily converted in
one-pot into a wide variety of functionalized products by taking
advantages of their unique reactivity. The catalytic cylcle involves
arylrhodation of alkyne, intramolecular alkenylrhodation of alkene,
and transmetalation of the alkyl-rhodium intermediate into alkylzinc.
yield of cyclopentane derivative 5a together with a minor amount
of side product 6a (5a/6a = 20/1). The deuterium was found at
one of the two methyl groups in 5a and at ortho position to the
alkenyl group on the phenyl ring in 6a. With bisphosphine ligand,
binap, the reaction was slower and the 5a/6a selectivity was
lower. The results on the deuterium quenching studies clearly
demonstrate that alkylzinc 3a and arylzinc 4a were produced by
the Rh-catalyzed arylzincation of 1a. Based on the reaction
pathways reported for Rh-catalyzed arylation of alkynes[6,7,12]
and cyclization reactions,[9a–c] addition of an aryl–Rh
intermediate to alkyne in 1a followed by addition of the resulting
alkenyl–Rh A to alkene generates the alkyl–Rh intermediate B.
Transmetalation between B and ZnCl2[10] produces alkylzinc 3a
and a Cl–Rh species, the latter undergoing the reaction with
ArZnCl regenerating aryl-Rh species. When the regiochemistry
at the arylrhodation of alkyne is opposite, the alkenyl–Rh
intermediate C cannot participate in the intramolecular addition
to alkene. Instead, 1,4-Rh shift takes place from alkenyl to the
phenyl ring,[12,13] and transmetalation of aryl–Rh species D with
ZnCl2 produces arylzinc 4a.[10]
Organozincs are organometallic reagents conveniently used for
organic synthesis because of their unique features covering both
high functional group compatibility and high reactivity towards
electrophiles in the presence of metal catalysts at the same
time.[1] As such, enantioenriched chiral alkylzincs are very useful
for the synthesis of functionalized chiral molecules including
biologically active compounds.[1] They have been obtained
mainly from enantioenriched alkyl halides by insertion of zinc
metal or halide-zinc exchange, or from other alkylmetals by
transmetalation.[1,2] Catalytic enantioselective carbozincation of
alkenes would be one of the promising methods of synthesizing
chiral alkylzincs (Scheme 1a), but, unfortunately, this type of
asymmetric reaction has not been well developed[3] except for
the addition to cyclopropene derivatives[4] and electron deficient
alkenes.[5] On the other hand, Murakami[6] and we[7]
independently reported rhodium-catalyzed arylative cyclization
of a malonate-tethered 1,6-enyne with ArB(OH)2 producing a
bicyclo[2.2.1]heptanone derivative. The catalytic cycle involves
an alkyl-Rh species which is formed by carborhodation of
alkene[8,9] and attacks ester carbonyl to result in the formation of
ketone (Scheme 1b). If the ArB(OH)2 is replaced by ArZnX and
the transmetalation with ZnX2 takes place for the alkyl-Rh
intermediate, the overall reaction would be a new type of
catalytic carbozincation giving alkylzinc product. During our
studies on the arylzincation of carbon–carbon multiple
bonds,[3,10] we found that the catalytic asymmetric carbozincation
giving chiral alkylzincs shown in Scheme 1b is realized in the
presence of a chiral diene/Rh catalyst and zinc chloride.
a) Catalytic asymmetric carbozincation producing chiral alkylzincs
[ML*]
catalyst
R1
R2
R3
R4
R
ZnX
R3
Reported only for cyclopropenes
and electron deficient alkenes
*
R—ZnX
+
R1
R2 R4
b) Arylative cyclization by Hayashi (2005) and its asymmetric reaction by Murakami (2005)
R1
Ar
R1
[Rh]
(catalyst)
RO2C
RO2C
RO2C
R1
R2
+ ArB(OH)2
R2
ArZnX + ZnCl2
O
R1
Ar
Ar–[Rh]
RO–[Rh]
R1
this work
Ar
Ar
RO2C
RO2C
[Rh]
R2
R2
RO2C
RO2C
RO2C
RO2C
transmetalaton
R2
[Rh]
XZn
ZnX2
X–[Rh]
Scheme 1. Catalytic asymmetric carbozincation producing chiral alkylzincs.
As shown in Scheme 2, 1,6-enyne 1a was allowed to react
[11]
with 4-MeOC6H4ZnCl (2a) and ZnCl2
in the presence of 5
mol% of a chiral diene/Rh catalyst, [RhCl(L1*)]2, at 30 °C for 1 h,
and the reaction mixture was quenched with DOAc to give 88%
[a] Prof. Dr. T. Hayashi
Department of Chemistry, National Tsing-Hua University
Hsinchu 30013, Taiwan
E-mail: hayashi@mx.nthu.edu.tw
[b] J. Chen, Prof. Dr. T. Hayashi
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
21 Nanyang Link, Singapore 637371 (Singapore)
Scheme 2. Rhodium-catalyzed asymmetric arylative cyclization producing
alkylzincs.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.202008770
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COMMUNICATION
also catalyzed the reaction, but the yields and/or the selectivity
are lower (entries 6 and 7). The reaction did not take place with
bulky DTBMsegphos[22] (entry 8). The presence of ZnCl2 is
necessary for the reaction to proceed efficiently, which is
probably because ZnCl2 participates in the catalytic cycle at the
transmetalation step giving the final alkylzinc product[10] (See
Scheme 2). While the high yield (91%) of 7aa was obtained
under standard conditions with 0.5 equiv of ZnCl2 (entry 1), the
reaction was slower in the absence of excess ZnCl2 (entry 9),
and a large excess of ZnCl2 retarded the reaction (entry 11).
The % ee of 7aa was kept high (99% ee) irrespective of the
amount of ZnCl2 (entries 1 and 9–11). The use of ArZnBr/ZnBr2
instead of ArZnCl/ZnCl2 did not affect the enantioselectivity or
7aa/8aa selectivity, although the yield was somewhat lower
(entry 12). A prolonged reaction time (24 h) did not cause a
significant change, demonstrating that the alkylzinc product 3a is
stable under the present reaction conditions (entry 13). The
30 °C is the reaction temperature of choice. At lower
temperature (0 °C) the reaction is much slower, although the
7aa/8aa selectivity is slightly higher (entry 14).
Table 1. Catalytic asymmetric arylative cyclization of enyne 1a with 4-
methoxyphenylzinc chloride (2a).[a]
Entry Variations from standard
conditions (shown above)
Yield (%)[b] % ee[c] of Ratio[d] of
of 7aa
7aa
7aa:8aa
1
2
3
none
91
70
85
99 (S)
96 (S)
98 (S)
20:1
14:1
10:1
[RhCl(L2*)]2
[RhCl(L3*)]2
4
5
6
7
8
[RhCl(coe)2]2 + (R,R)-Ph-bod
[RhCl(coe)2]2 + (S,S)-Fc-tfb
[RhCl(coe)2]2 + (R)-binap
12
62
35
63
<5
94 (S)
91 (S)
99 (S)
98 (S)
—
5:1
50:1
10:1
4:1
[RhCl(coe)2]2 + (R)-segphos
[RhCl(coe)2]2 + (R)-DTBMsegphos
—
9
ZnCl2 (0.0 equiv)
44
88
68
75
84
24
76
99 (S)
99 (S)
99 (S)
99 (S)
99 (S)
99 (S)
99 (S)
20:1
20:1
20:1
20:1
20:1
22:1
17:1
10 ZnCl2 (0.1 equiv)
11 ZnCl2 (1.0 equiv)
12 ArZnBr + ZnBr2 (0.5 eq)
13 24 h instead of 1 h
14 0 °C instead of 30 °C
15 60 °C instead of 30 °C
[a] Reaction conditions: Enyne 1a (0.20 mmol), ArZnCl (2a) (0.30 mmol),
ZnCl2 (0.10 mmol), and Rh catalyst (5 mol% of Rh) in THF (2.0 mL) at 30 °C
for 1 h. To the reaction mixture was added CuCN•2LiCl (0.36 mmol) and
subsequently benzoyl chloride (0.36 mmol). For the details, see text and
Supporting Information. [b] Isolated yield. [c] The % ee was determined by
HPLC on a chiral stationary phase column. [d] The ratio of 7aa:8aa was
determined by 1H NMR of the crude reaction mixture.
Although the alkylzinc product 3a itself is not very reactive
toward electrophiles other than proton, the Cu-mediated
acylation[1,2,14] developed by Knochel proceeded well to give a
high yield of the benzoylation product 7aa which is readily
analyzed for its enantiomeric purity. Thus, the reaction mixture
resulting from arylzincation of 1a, which contains 3a, was treated
first with CuCN and then with PhCOCl to give phenyl ketone 7aa
in 91% yield with 99% ee (reaction scheme in Table 1). Some of
the results obtained at optimization of the reaction conditions for
higher yield and enantioselectivity in the reaction of enyne 1a
with ArZnCl 2a are shown in Table 1. The chiral diene ligand
L1*,[15,16] which bears a bulky ester group, was found to be most
effective in both the chemo- and enantioselectivities (entry 1).
Other chiral diene ligands, L2*,[17] L3*,[18] Ph-bod,[19] and Fc-
tfb,[20] are less effective giving the product 7aa in a lower yield or
with lower 7aa/8aa selectivity and/or enantioselectivity (entries
2–5). Rhodium complexes with binap[21] and segphos[22] ligands
Scheme 3. Asymmetric arylation/cyclization producing alkylzincs catalyzed by
[RhCl(L1*)]2.[a]
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10.1002/anie.202008770
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[RhCl(diene*)]2
(5 mol% Rh)
The conditions using chiral diene ligand L1* optimized for the
reaction of 1a with 2a (entry 1 in Table 1) were applied to
several other 1,6-enynes 1 and arylzincs 2 (Scheme 3). The
results are summarized in Scheme 3. The arylzinc reagents
substituted with MeO group at meta and ortho positions gave
high yields of the corresponding phenyl ketones, 7ab and 7ac,
respectively, although the enantioselectivity is slightly lower than
7aa where the MeO substitution is at para position. The aryl
groups bearing Me (7ad), Ph (7ae), CF3 (7af), F (7ag), and
SiMe3 (7ah), at para-position were all successfully introduced
into the products with high enantioselectivity (96–99% ee). For
those zinc reagents whose reactions are slow, the reaction
temperature was increased to 60 °C. Reactions of disubstituted
phenylzincs and 2-naphthylzinc proceeded well to give the
arylative cyclization products 7ai, 7aj and 7ak of high % ee.
As a substituent R1 at the alkyne terminus of 1,6-enyne 1,
primary alkyl and cyclopropyl groups are tolerable to give the
corresponding products 7ba, 7ca, and 7da with high % ee.
Aromatic groups as R1 at the alkyne terminus cause the
opposite regiochemistry at the arylrhodation of alkyne,[10a] and
hence the target alkylzincs were not formed. The 1,6-enyne
substrate 1e bearing trimethylsilyl group as R1 gave the target
product 7ea with high ee albeit in a lower yield. The asymmetric
arylative cyclization took place without serious problems for
those 1,6-enyne substrates where the R2 groups at 2-position of
the alkene moiety are primary alkyls (7fa and 7ga), a secondary
alkyl (7ha), and a benzyl (7ia). Dimethyl and dibenzyl ethers at
the carbon connecting propargyl and allyl groups underwent the
arylative cyclization well (7ja, 7ka, and 7la), the yields and
selectivity being as high as the t-butyl esters. The absolute
1. CuCN•2LiCl
2. PhCOCl
*
t-BuO2C
t-BuO2C
t-BuO2C
t-BuO2C
Ar t-BuO2C
+
Ar
(1)
t-BuO2C
ZnCl2 (0.5 eq)
THF, 60 °C, 48 h
1n
+
*
H
COPh
COPh
7na
9
ArZnCl (2a) (1.5 eq)
[RhCl(L1*)]2: 20% yield, 94% ee, 7na:9 = 8:1
[RhCl(L3*)]2: 63% yield, 99% ee, 7na:9 = >30:1
Ar =
OMe
Rh/Fc-tfb: 7na: 13% yield, 99% ee, 7na:9 = 1:2.8
9: 39% yield, 88% ee
H
H
H–[Rh]
[Rh]
Z
Z
Ar
[Rh]
Z
Z
Ar
Z
Z
Ar
Z
Z
Ar
Z
Z
Ar
H
H–[Rh]
[Rh]
E
F
In addition to the benzoylation shown in Scheme 3, the
enantioenriched alkylzinc 3a was readily functionalized in one-
pot by reaction with various types of electrophiles (Scheme 4).
Thus, the copper-mediated reaction reported by Knochel[1,2,13]
covers acylation (giving 11), allylation (12 and 13), allenylation
(14 and 15), alkynylation (16), coupling with alkyl and alkenyl
halides (17 and 18), conjugate addition (19), and stannylation
(20). Palladium-catalyzed cross-coupling of alkylzinc 3a with aryl
bromides giving 21a and 21b was also successful.[24] Treatment
of 3a with benzoquinone resulted in the oxidative cyclization
giving tricyclic product 22. It should be noted that all the
reactions shown in Scheme 4 are one-pot reactions and the
yields are based on enyne 1a employed. The enantiomeric
purities were all kept 99% as expected. As one example of
transformation of the products obtained in Scheme 4, the
synthesis of [4.3.0]bicyclic enone 24 is shown in equation 2.
[RhCl(L1*)]2
Z
Z
Z
Z
Ar
Z
Z
Ar
(5 mol% Rh)
CuCN•2LiCl
+ ArZnCl (2a)
ZnCl2 (0.5 eq)
THF, 30 °C, 1 h
CuLn
ZnCl
1a
3a: 99% ee
10
Z = CO2t-Bu
electrophiles (E)
configuration and
Z geometry of the double bond was
Ar =
OMe
determined by X-ray crystal analysis of 7ka. The yield of 7ma
was low (31%) in the reaction of methyl ester in place of t-butyl
ester. It is because a bicyclo[2.2.1]heptanone derivative is
formed as a side product by the intramolecular attack of alkyl-
rhodium intermediate B to the ester carbonyl[6,7] (Scheme 1b).
The reaction of 1n, which has an unsubstituted allyl group as
the alkene moiety, gave us some information on the stability and
reactivity of the alkylrhodium intermediate bearing a -hydrogen
(eq 1). High enantioselectivity (99% ee) and selective formation
of the target product 7na were observed in the reaction with the
diene ligand L3*. With ligand L1*, which is used for other 1,6-
enynes, the yield of 7na was lower and the olefin isomer 9 was
formed as a minor product. It is remarkable that the use of Fc-tfb
ligand gave the olefin isomer 9 as a main product (7na/9 = 1/2.8)
and that high % ee was observed in 9 (88% ee) as well as in
7na (99% ee). The product 9 should be formed through
Z
Z
Ar
Z
Z
Ar
COt-Bu
Z
Z
Ar
Z
Z
Ar
•
CO2Me
14: 83%, 99% ee
E = BrCH2C CH
11: 74%, 99% ee
E = t-BuCOCl
12: 85%
E = CH2=C(Me)CH2Br
13: 88%, 99% ee
E = CH2=C(CO2Me)CH2Br
Z
Z
Ar
Z
Z
Ar
Z
Z
Ar
Z
Z
Ar
•
OMe
17: 70%, 99% ee
E = BrCH2OMe
16: 70%
E = BrC CPh
15: 77%, 99% ee
E = BrCH2C CMe
Ph
O
18: 87%, 99% ee
E = I
O
Z
Z
Ar
Z
Z
Ar
SnMe3
O
20: 86%, 99% ee
E = ClSnMe3
19: 71%, 99% ee
E = CH2=CHCOMe
Pd/Sphos
(5 mol%)
Z
Z
Ar
Z
Z
Ar
Z
Z
benzoquinone
OMe
isomerization of homoallylic Rh intermediate
E to allylic
ZnCl
Br
R
3a: 99% ee
intermediate F, before transmetalation giving the corresponding
homoallylic or allylic zinc species. It is most likely that the
isomerization proceeds through several steps consisting of -
hydrogen elimination, migration of hydrido-rhodium to the other
double bond, hydrorhodation, and allylic 1,3-shift. The high % ee
of the isomerized product 9 may indicate that the hydrido-
rhodium does not move from one coordination site to the other
during those steps for isomerization.[23]
22: 68%, 99% ee
R
21a (R = CN): 81%, 99% ee
21b (R = COMe): 74%, 99% ee
[a] Yields are based on the amount of 1a.
Scheme 4. Functionalization of the alkylzinc 3a (99% ee) obtained by the Rh-
catalyzed asymmetric arylation/cyclization.[a]
O
O
1) O3
KOH
t-BuO2C
t-BuO2C
Ar
t-BuO2C
t-BuO2C
t-BuO2C
t-BuO2C
(2)
O
t-BuOH
2) PPh3
12
(R)-23: 61%
24: 54%, 98% ee
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Acknowledgements
This work was supported by funding from Nanyang Techno-
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Keywords: enantioenriched alkylzinc • asymmetric
carbometalation • chiral diene ligand • rhodium catalyst
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10.1002/anie.202008770
Angewandte Chemie International Edition
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Fei Xue and Tamio Hayashi*
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Asymmetric Synthesis of Alkylzincs
by Rhodium-Catalyzed
Enantioselective Arylative Cyclization
of 1,6-Enynes with Arylzincs
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Jiahua Chen and Tamio Hayashi*
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Asymmetric Synthesis of Alkylzincs
by Rhodium-Catalyzed
Enantioselective Arylative Cyclization
of 1,6-Enynes with Arylzincs
A chiral diene–rhodium complex was found to catalyze the reaction of 1,6-enynes
with ArZnCl to give high yields of 2-(alkylidene)cyclopentylmethylzincs with high
enantioselectivity (95–99% ee). The enantioenriched alkylzincs were readily
converted in one-pot into a wide variety of functionalized products by taking
advantages of their unique reactivity.
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