Chromium(II)-Catalyzed Diastereoselective and Chemoselective Csp2-Csp3 Cross-Couplings Using Organomagnesium Reagents

Article abstract of DOI:10.1021/jacs.9b08586

A simple protocol for performing chromium-catalyzed highly diastereoselective alkylations of arylmagnesium halides with cyclohexyl iodides at ambient temperature has been developed. Furthermore, this ligand-free CrCl₂ enables efficient electrophilic alkenylations of primary, secondary, and tetiary alkylmagnesium halides with readily available alkenyl acetates. Moreover, this chemoselective C-C coupling reaction with stereodefined alkenyl acetates proceeds in a stereoretentive fashion. A wide range of functional groups on alkyl iodides and alkenyl acetates are well tolerated, thus furnishing functionalized Csp²-Csp³ coupling products in good yields and high diastereoselectivity. Detailed mechanistic studies suggest that the in situ generated low-valent chromium(I) species might be the active catalyst for these Csp²-Csp³ cross-couplings.

Full text of DOI:10.1021/jacs.9b08586

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Article
Chromium(II)-Catalyzed Diastereoselective and Chemoselective
Csp2#Csp3 Cross-Couplings Using Organomagnesium Reagents
Jie Li, Qianyi Ren, Xinyi Cheng, Konstantin Karaghiosoff, and Paul Knochel
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b08586 • Publication Date (Web): 21 Oct 2019
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Chromium(II)-Catalyzed Diastereoselective and Chemoselective
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Csp2‒Csp3 Cross-Couplings Using Organomagnesium Reagents
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Jie Li,* Qianyi Ren, Xinyi Cheng, Konstantin Karaghiosoff, and Paul Knochel*
Department Chemie, Ludwig-Maximilians-Universitӓt München, Butenandtstr. 5-13, Haus F, 81377 Munich, Germa-
ny.
ABSTRACT:
A simple protocol for performing chromium-catalyzed highly diastereoselective alkylations of
arylmagnesium halides with cyclohexyl iodides at ambient temperature has been developed. Furthermore, this ligand-free
CrCl2 enables efficient electrophilic alkenylations of primary, secondary and tetiary alkylmagnesium halides with readily
available alkenyl acetates. Moreover, this chemoselective C‒C coupling reaction with stereodefined alkenyl acetates pro-
ceeds in a stereoretentive fashion. A wide range of functional groups on alkyl iodides and alkenyl acetates are well tolerat-
ed, thus furnishing functionalized Csp2‒Csp3 coupling products in good yields and high diastereoselectivity. Detailed
mechanistic studies suggest that the in situ generated low-valent chromium(I) species might be the active catalyst for
these Csp2‒Csp3 cross-couplings.
INTRODUCTION
zinc reagents with secondary alkyl iodides or bromides
has been reported using Fe,[13] Co[14] or Ni catalysts.[15]
Transition-metal-catalyzed cross-couplings between Csp2-
centers and Csp3-centers are important for the elabora-
tion of complex organic molecules.[1,2] Whereas palladi-
um- and nickel-catalysts are very useful, other first-row
transition-metals,[2] such as Fe[3] or Co[4] have also found
numerous applications. These metal-catalysts are espe-
cially important due to their low toxicity, low price and
abundance. Recently, low-valent chromium salts have
attracted considerable attention due to their natural
abundance[5] and lower toxicity compared to iron.[6] We
have shown that low-valent chromium-catalyzed cross-
couplings between (hetero)aryl halides and aryl-[7] or al-
kyl-magnesium halides[8] proceeds very efficiently
(Scheme 1a). Furthermore, Zeng also illustrated the chela-
tion-assisted chromium-catalyzed aryl C‒O or C‒N bonds
activation with Grignard reagents (Scheme 1b).[9]
Since Hiyama pioneered the stoichimetric chromium-
mediated diastereoselective addition of allylic electro-
philes to aldehydes,[10] an enantioselective 1,2-
difunctionalization of 1,3-butadiene by chromium/cobalt-
catalysis and stereoselectivie allylation of aldehydes by
dual photoredox/chromium catalysis were recently re-
ported by Zhang[11] and Glorius.[12] Despite these remarka-
ble advances, chromium-catalyzed diastereoselective and
chemoselective Csp2‒Csp3 cross-couplings still have un-
fortunately thus far not been reported. The performance
of diastereoselective cross-couplings catalyzed with tran-
sition metals of alkyl-, aryl- and alkynyl-magnesium or
While
the
related
transition-metal-catalyzed
diastereoselective cross-couplings between alkenyl or
(hetero)aryl iodides and alkyl-zinc or magnesium rea-
gents largely rely on the use of Pd (Scheme 1c).[16] As a
result, we have studied the chromium-catalyzed
diastereoselective cross coupling between aryl Grignard
reagents and functionalized alkyl halides (Scheme 1d).
On the other hand, easily accessible phenol and enol
derivatives have been utilized as environmental friendly
electrophiles (halide-free) for 3d transition-metal-
catalyzed cross-couplings with organometallic reagents
using iron- and nickel-catalysis, as were reported by Shi,[17]
Garg,[18] Fürstner,[19] Martin[20] and others.[21] However,
utilization of these more atom-economical and stable
alkenyl acetates was rarely reported. Early reductive
cross-couplings of vinylic acetates with aryl halides were
developed by Gosmini, albeit with a limited substrate
scope.[22] Thereafter, Ackermann has used alkenyl acetates
for performing cobalt-catalyzed C‒H activation of
indoles.[23] The cross-couplings between alkenyl acetates
and organometallic reagents were only recently reported
by Jacobi von Wangelin and us using iron-[24] and cobalt-
catalysis.[25] Also, the iron-catalyzed stereoselective cross-
coupling using related enol carbamates and Grignard rea-
gents was only recently described by Frantz.[26] Hence, we
report herein a ligand-free chromium(II)-catalyzed cross-
couplings between various functionalized alkenyl acetates
and primary, secondary and tertiary alkylmagnesium hal-
ides under remarkably mild reaction conditions. It is
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noteworthy that the chromium-catalyzed alkenylation
3a‒3f in 64‒91% yield, albeit 3d was obtained with a lower
diastereoselectivity. Moreover, TBS-protected iodohydrin
with stereodefined alkenyl acetates occurred in
stereoretentive fashion (Scheme 1e).
a
2d was also investigated and delivered the arylated
products 3g‒3i' with good diastereoselctivity. The more
synthetically useful amino-substituted cyclohexyl iodides
2e‒2f were identified as suitable substrates for the
diastereoselective cross-couplings with functionalized
arylmagnesium reagents, thereby providing the
corresponding products 3j‒3n in 54‒78% yield. Coupling
of Grignard reagents with 1,3-disubstituted cyclohexyl
iodides 2g‒2j gave the cyclohexane derivatives 3o‒3r in
63‒89% yields. Remarkably, different steroid derivatives,
such as cholesteryl and epiandrosterone iodides 2k‒2m,
led to arylated steroids 3s‒3u in 53‒75% (dr > 97:3) yield.
It is noteworthy that a deuterated cholesteryl iodide 2n
Scheme 1. Low-valent chromium-catalyzed cross-
couplings with Grignard reagents.
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underwent
the
arylation
with
(3-
methoxyphenyl)magnesium bromide 1d to afford the
desired product 3v with a slightly decreased yield.
Additionally, this Cr(II)-catalyzed cross-coupling was
further applicable to functionalized secondary and
primary iodides 2n‒2q to provide the corresponding
arylated products 3w‒3z in moderate yields.
Table 1. Diastereoselective chromium(II)-catalyzed
Csp2‒Csp3 cross-coupling.[a]
entry
[Cr] (mol %)
CrCl2
CrCl2
CrCl2
CrCl2
CrCl2
CrCl2
CrCl2
CrCl2
--
ligand
yield (%)[b]
16 (dr: 92:8)
70 (dr: 96:4)
14 (dr: 96:4)
17 (dr: 93:7)
91 (dr: 97:3)
88 (dr: 96:4)[c]
60 (dr: 96:4)[d]
66 (dr: 96:4)[e]
0
1
dtbbpy (10 mol %)
2
3
4
5
6
7
8
9
TMEDA (20 mol %)
RESULTS AND DISCUSSION
IPr•HCl (10 mol %)
dppbz (10 mol %)
We initiated our studies by testing different reaction
conditions for the envisioned chromium-catalyzed
diastereoselective Csp2‒Csp3 cross-coupling between
arylmagnesium reagents (1a) and 1,4-disubstituted
cyclohexyl iodide (2a). Among various ligands (Table 1,
--
--
--
--
--
entries 1‒4), TMEDA gave
a
good yield and
diastereoselectivity of desired product 3a (70%, dr: 96:4).
It is worth noting that omission of ligand led to a further
yield of 3a increase to 91%, with high diastereoselectivity
(dr: 97:3; entry 5). Similar results were observed when
using as low as 5 mol % of CrCl2 (entry 6). Further, per-
forming the reaction at 0 °C or switching the ratio of the
starting materials resulted in significantly reduced yields
(entries 7‒8). Obviously, no reaction was observed in the
absence of CrCl2 (entry 9).
[a] 1a (0.45 mmol, 1.5 equiv), 2a (0.3 mmol, 1.0 equiv), CrCl2
(10 mol %), THF, 0~23 °C, 16 h. [b] Isolated Yield, dr value
was determined by GC analysis. [c] CrCl2 (5 mol %). [d] 0 °C,
16 h. [e] 1a (0.3 mmol, 1.0 equiv), 2a (0.45 mmol, 1.5 equiv), 12
h. dtbbpy
=
4,4'-di-tert-butyl-2,2'-bipyridine; TMEDA
=
N,N,N',N'-tetramethylethylenediamine; IPr•HCl
=
1,3-Bis-
(2,6-diisopropylphenyl)imidazolinium chloride; dppbz = 1,2-
Bis(diphenylphosphino)benzene.
Scheme 2. Substrate scope of the chromium(II)-
catalyzed diastereoselective arylation.
Thereafter, the optimized ligand-free chromium(II)
catalyst was probed in a range of coupling reactions of
various arylmagnesium halides 1 with functionalized
cyclohexyl iodides
2 (Scheme 2). 1,4-Disubstituted
cyclohexyl iodides 2a‒2c bearing phenyl, cyclohexyl, tert-
butyl or methyl groups reacted smoothly with different
arylmagnesium halides, furnishing the desired products
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olefination of alkylmagesium reagents (4a) with 4-
acetoxy-2-chromenone (5a) through C‒O bond cleavage.
Among a set of representative ligands and additives, the
alkylated product 6a was obtained in 21‒60% yields (Ta-
ble 2, entries 1‒5). However, 5.0 mol % CrCl2 increased the
yield of 6a to 68% (entries 6) at 23 °C. No reaction was
observed in the absence of chromium salts (entry 7). Re-
placement of CrCl2 by using CrCl3 or other typically tran-
sition-metal catalysts, such as FeCl3, CoCl2, NiCl2, or
Pd(OAc)2 resulted in significantly reduced yields (entries
8‒12). It is worth noting that related electrophiles, such as
tosylate (5b), triflate (5c), carbamate (5d), as well as
isobutyrate (5e), were also tested and led to inferior re-
sults (entries 13‒16). Performing the reaction at 40 °C or in
the presence of 10 mol % of CrCl2 did not increase the
yield of product 6a (entries 17‒18).
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Table 2. Optimization for chromium(II)-catalyzed
alkylation of 5 with cyclohexylmagnesium chloride
(4a) through C‒O bond cleavage.[a]
entry
1
modified conditions
bpy (10 mol %) as ligand
TMEDA (20 mol %) as ligand
IMesHCl (10 mol %) as ligand
TMSCl (2.0 equiv)
NMP (2.0 equiv)
yield (%)[b]
21
19
2
3
15
4
44
60
68[c]
0
5
6
none
7
without CrCl2
8
CrCl3 instead of CrCl2
FeCl3 instead of CrCl2
CoCl2 instead of CrCl2
NiCl2 instead of CrCl2
Pd(OAc)2 instead of CrCl2
5b instead of 5a
28
53
9
10
11
37
24
26
trace
17
12
13
14
15
16
17
18
5c instead of 5a
5d instead of 5a
50
49
54
66
5e instead of 5a
under 40 °C
CrCl2 (10 mol %)
[a] c-HexMgCl (4a, 0.45 mmol, 1.5 equiv), 5a (0.3 mmol, 1.0
equiv), CrCl2 (5.0 mol %), THF, 0 °C, 16 h. [b] Isolated Yield.
[c] c-HexMgCl (0.45 mmol, 1.5 equiv), CrCl2 (5.0 mol %),
23 °C, 16 h. bpy = 2,2'-bipyridine; IMesHCl = 1,3-bis(1,3,5-
trimethylphenyl)imidazolium chloride.
[a]
After standard procedure, the residue was treated with
TBAF (2.0 equiv) in CH2Cl2 (2.0 mL), 23 °C, 24 h.
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In consideration of the high catalytic activity of this ro-
bust chromium(II) catalyst, we have further optimized
the reaction conditions for the chromium-catalyzed
Scheme 3. Substrate scope of the chromium(II)-
catalyzed alkylation of alkenyl acetates of type 5.
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as
solvent
(56‒59%).
Importantly,
secondary
alkylmagnesium reagents proved to be viable nucleo-
philes as well, successfully participating in the
alkenylation to produce the desired products 6s‒6v. We
also found that tBuMgCl could be utilized for an
alkenylation. A moderate yield of 6w was obtained under
our standard conditions. Interestingly, a two step reaction
sequence consisting of the chromium-catalyzed electro-
philic alkenylation, along with a nucleophilic addi-
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tion/elimination
neopentylmagnesium bromide as the nucleophile, yield-
ing the bis-alkylated product 6x in 42% yield.
occurred,
when
using
Scheme 4. Chromium(II)-catalyzed stereoselective
alkenylation with stereodefined alkenyl acetates of
type 7.
[a] CrCl2 (10 mol %) was used in CPMe (CPMe = cyclopentyl
methyl ether).
With the optimized chromium(II)-catalyst in hand, we
have investigated the cross-coupling of various alkenyl
acetates with alkylmagnesium halides (Scheme 3). All
alkylmagnesium reagents were prepared from the corre-
sponding alkyl bromides by Mg insertion in the presence
of LiCl.[27] Notably, the 4-acetoxy-2-chromenone reacted
smoothly with various primary alkylmagnesium deriva-
tives leading to the alkylated chromenones 6b‒6f in
56‒76% yields. Similarly, indenyl acetate, naphthalenyl
acetate and chromenyl acetate underwent the desired
cross-coupling reactions through C‒O bond cleavage with
functionalized Grignard reagents affording the corre-
sponding products 6g‒6o in moderate to good yields.
Among a set of alkylmagnesium derivatives, MeMgCl de-
livered the methylation product 6k with high catalytic
efficacy in 96% yield. Moreover, this cross-coupling was
extended to acetoxycyclohexenylcarboxylate (5i) and
acetoxycycloheptenylcarboxylate (5j). We were delighted
to observe that the alkylated products 6p‒6r were
smoothly generated, while better isolated yields were ob-
tained when employing CPMe (cyclopentyl methyl ether)
[a] CrCl2 (10 mol %) was used in CPMe.
Thereafter, we further extended the substrate scope to
well-stereodefined acyclic acetates of type 7 under other-
wise identical reaction conditions (Scheme 4). Remarka-
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bly, the chromium(II)-catalyzed electrophilic alkenylation
was performed and delivered the alkylated steroid deriva-
tive 10 in 81% yield (Scheme 5c).
using (Z)-alkenyl acetates 7 occurred in a stereoretentive
mode. Indeed, no isomers of the desired functionalized
olefins were observed by 1H-NMR spectroscopy after puri-
fication of the reaction mixtures. Aryl acrylates bearing
different valuable electrophilic substituents, such as fluo-
ro-, chloro-, bromo-, methoxy-, as well as alkenyl-, ether-
substitutents on the alkylmagnesium reagents were well
tolerated under our standard conditions, thereby deliver-
ing the corresponding (E)-olefins 8a‒8m as the sole
MECHANISM STUDIES
Scheme 6. Mechanistic studies for chromium-
catalyzed diastereoselective arylation of functional-
ized iodides.
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products.
Beyond
that,
(Z)-diastereomers
of
tetrasubstituted acrylates 8n‒8r were also efficiently ob-
tained through chromium(II)-catalyzed alkenylations
between (Z)-alkenyl acetates and synthetic useful
alkylmagnesium derivatives in good yields. It is notewor-
thy that the (E)-alkenyl acetates also delivered the
stereoretentive products, which highlighted the unique
versatility and stereoselectivity of this chromium(II)-
catalysis, albeit the products were obtained in rather
modest yields (see Scheme S10 in the Supporting Infor-
mation for more details).
Scheme 5. Comparison experiments of regio-control
between chromium- and iron-catalysis.
Furthermore, the results of comparison experiments
between chromium(II)- and iron(III)-catalysis with (Z)-
alkenyl acetate and (Z)-alkenyl carbamate highlighted the
unique stereoselectivity of our current approach, since
the chromium-catalyst delivered (Z)-8s as the single
product (Scheme 5a), while the iron-catalyst (FeCl3) pro-
vided a isomeric mixture of 8s (Z:E = 1:1; Scheme 5b).[26]
To illustrate the synthetic potency of this ligand-free
chromium(II)-catalyzed alkylation protocol,
a cross-
We performed detailed experiments to unravel the re-
action mode of action. In this context, intermolecular
competition experiments between the differently substi-
tuted arylmagnesium reagents (1k vs 1e) showed that
coupling reaction between alkylmagnesium and pharma-
cologically relevant compound of estrone derivative (9)[25]
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electron-rich aryl groups react preferentially (Scheme 6a).
On the other hand, in order to reveal the function of
This Cr(II)-catalyzed diastereoselective cross-coupling
was inhibited by employing of stoichimetric quantities of
TEMPO. Radical-clock experiment using 6-iodo-1-hexene
2s as reaction partner was also performed and both ring-
closed product 3as and linear product 3as' were detected
(Scheme 6b). These results indicate that this cross-
coupling may proceed by a single electron transfer (SET)
process. Based on the previous mechanistic insights, an in
situ low-valent Cr(0) was proposed as the catalytically
active species.[9b] Therefore, we performed experiments of
CrCl2 (1.0 equiv) with excess of ArMgBr (1k or 1c) under
typical reaction conditions for 30 min. The reactions fur-
nished the corresponding homo-product (11a or 11b) in a
near 0.5 equiv ratio to that of CrCl2. These results support
the formation of a Cr(I)-intermediate according to the
stoichiometry shown in scheme 6c. Furthermore, we
treated the CrCl2 (0.03 mmol) with two equivalent of 3-
FC6H4MgBr (1c, 0.06 mmol) at 23 °C for 30 min to form a
tentative Cr(I)-species, followed by addition of the alkyl
iodide 2a (0.3 mmol) and another 0.45 mmol of 1c. The
desired product 3c was obtained in 84% yield (Scheme
6d). These findings indicated that the in situ generated
low-valent chromium(I)-species might be the active cata-
lyst.
CrCl2 in the cross-couplings between alkyl Grignard rea-
gents and alkenyl acetates, a series of kinetic experiments
using 10 mol % of CrCl2, Sc(OTf)3 or CrCl2-COD as the
metal complex were performed (Scheme 7). The trans-
formation between n-hexylmagnesium bromide 4t and
acetate (Z)-7h occurred successful under standard condi-
tions A, up to 90% conversion of the desired product (Z)-
8s was detected by GC analysis after 100 min. However, 10
mol % of Sc(OTf)3 only gave a sharp decreased conversion
of 30%. Interestingly, different to the homogeneous catal-
ysis of iron,[24] using COD (2.0 equiv ) as the π-acceptor
ligand of CrCl2 resulted in a minor alteration of catalytic
activity, which suggested that π-hydrocarbons could not
coordinate to chromium species.[28]
Additionally, upon radical-clock experiment with sub-
strate (E)-7j bearing a vinyl substituent, the stereoreten-
tive product (Z)-8t was generated in 23% yield, while the
ring-closing/cross-coupling compound 8t' was not de-
tected (Scheme 8a). With these findings, we propose this
alkenylation undergoes a non-radical process. Similarly,
we further performed the experiments to examine the
catalytic activity of the in situ generated low-valent
chromium species. A mixture of CrCl2 (0.03 mmol) and
two equivalent of n-hexMgBr (4t) or MeMgCl (4j) was
stirred at 23 °C for 30 min and the low-valent chromium
intermediate was generated (see Scheme S8 in the Sup-
porting Information for more details). Substrate 7f (0.3
mmol) and n-hexMgBr or MeMgCl (0.45 mmol) were sub-
sequently added to the in situ generated chromium spe-
cies solution and the reactions were continued for an-
other 16 h. The corresponding products 8j and 8u were
afforded in 61‒64% yields.[28] These experimental results
show again that the in situ formed low-valent chromium
species enables the following C‒O bond functionalization
(Scheme 8b).[9] To further illustrate the effect of ester
group, intermolecular competition experiments between
the substrates (Z)-7k and (E)-7k were performed. A sig-
nificant ratio (90:10) of 8v and 8w was detected by GC
analysis, which verified the crucial importance of the es-
ter directing group (Scheme 8c, see Scheme S9 in the
Supporting Information for more details).
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Scheme 7. Kinetic experiments with different Lewis
acids.
A
B
C
100
80
60
40
20
0
Given our mechanistic studies and previous mechanis-
tic insights,[9] we propose the catalytic cycle involves an
initial coordination of low-valent chromium species D
and alkenyl acetate 7. A subsequent C‒O bond cleavage of
E
forms the intermediate F, which undergoes
0
20
40
60
time [min]
80
100
transmetalation with alkyl Grignard reagent 4 to generate
the key intermediate G. Finally, reductive elimination
liberates the desired Csp2‒Csp3 coupling product 8 and
regenerates the catalytically active chromium species
(Scheme 8d).
Based on our mechanistic studies, we propose a catalyt-
ic cycle for this chromium-catalyzed diastereoselective
cross-coupling reaction (Scheme 6e). The reaction might
start with the in situ formed Cr(I)-species (A), which re-
duces alkyl iodies (2) by SET and forms intermediate B,
then followed by transmetalation with ArMgX (1) and
reductive elimination deliver the desired product 3 and
regenerate the active chromium(I)-catalyst.
Scheme 8. Mechanistic studies for chromium-
catalyzed alkenylation through C‒O bond cleavage.
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tivity, as compared to other activated esters, such as
triflates, tosylates, carbamates and isopropylates. Notable
features of this method are an unique stereoselectivity,
less toxic and ligand-free chromium(II)-catalysis, user-
and environmental-friendly reaction conditions, as well as
an ample substrate scope and good functional group tol-
erance. The high-yielding preparation of arylated and
alkylated steroids shows the potential of these methods
for applications in medicinal chemistry. Detailed mecha-
nistic studies demonstrated the in situ formed low-valent
chromium-species might be the catalytically active cata-
lyst.
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ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
General remarks, optimization tables, additional experiments,
representative procedures, X-ray of 3c, characterization data
of 3, 6, 8‒10 and NMR spectra (PDF)
CCDC 1945146 contain the supplementary crystallographic
data for this paper. This data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by containing The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, U.K.; fax:+44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
E-mail: jjackli@jiangnan.edu.cn.
E-mail: paul.knochel@cup.uni-muenchen.de.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the Deutsche Forschungsgemeinschaft (DFG), the
National Natural Science Foundation of China (Grant No.
21602083) and Natural Science Foundation of Jiangsu Prov-
ince (Grant No. BK20160160) for financial support.
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