Synthesis of Homoallylic Alcohols with Acyclic Quaternary Centers through CoIII-Catalyzed Three-Component C?H Bond Addition to Internally Substituted Dienes and Carbonyls

Article abstract of DOI:10.1002/anie.201906633

An efficient Co^III-catalyzed three-component strategy to prepare homoallylic alcohols containing acyclic quaternary centers is disclosed. This transformation enables the introduction of two C?C σ bonds through C?H bond activation and sequential addition to internally substituted dienes and a wide range of aldehydes and activated ketones. Isoprene and other internally monosubstituted dienes are effective inputs, with the reaction proceeding with high diastereoselectivity for those substrate combinations that result in more than one stereogenic center. Moreover, the opposite relative stereochemistry can be achieved by employing 1,2-disubstituted dienes. A mechanism for the transformation is proposed based upon the relative stereochemistry of the products and studies with isotopically labeled starting materials.

Full text of DOI:10.1002/anie.201906633

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Accepted Article
Title: Synthesis of Homoallylic Alcohols with Acyclic Quaternary
Centers via CoIII-Catalyzed Three-Component C–H Bond
Addition to Internally Substituted Dienes and Carbonyls
Authors: Jonathan Anthony Ellman, Sun Dongbang, and Zican Chen
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201906633
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Synthesis of Homoallylic Alcohols with Acyclic Quaternary
III
Centers via Co -Catalyzed Three-Component C–H Bond Addition
to Internally Substituted Dienes and Carbonyls
†
†
*
Sun Dongbang, Zican Shen, and Jonathan A. Ellman
III
Abstract: An efficient Co -catalyzed three-component strategy to
prepare homoallylic alcohols containing acyclic quaternary centers is
disclosed. This transformation enables introduction of two C–C σ
bonds via C–H bond activation and sequential addition to internally
substituted dienes and a wide range of aldehydes and activated
ketones. Isoprene and other internally monosubstituted dienes are
effective inputs, with the reaction proceeding with high
diastereoselectivity for those substrate combinations that result in
more than one stereogenic center. Moreover, the opposite relative
stereochemistry can be achieved by employing 1,2-disubstituted
dienes. A mechanism for the transformation is proposed based upon
the relative stereochemistry of the products and studies with
isotopically labeled starting materials.
Transition metal-catalyzed C–H bond functionalization has
become an effective strategy to access synthetically useful
structural motifs.[1] While remarkable progress has been made for
two-component C–H bond additions to diverse coupling partners,
the sequential addition of C–H bonds across two different
coupling partners to access complex motifs has only recently
begun to be developed.[2,3] Recently, our lab reported the CoIII-
catalyzed C–H bond addition to dienes and aldehydes [Figure 1,
Eq. (1)].[2c,4] In this approach, two new C–C σ bonds are formed
Figure 1. Transition metal-catalyzed three-component addition for the synthesis
of homoallylic alcohols.
Herein, we describe a three-component strategy to access
homoallylic alcohols containing acyclic quaternary centers via
III
Co -catalyzed C–H bond activation and sequential addition to
internally substituted dienes and aldehydes or activated ketones
[Figure 1, Eq. (2-4)]. For isoprene, secondary alcohol products are
obtained by reactions of a variety of C–H bond substrates with
both activated and unactivated alkyl and aryl aldehydes [Eq. (2)].
In addition, the first examples of three-component coupling with
III
in a regio- and stereoselective manner as dictated by a Co -allyl
chair-like transition state. To expand upon this work, we have
focused on internally substituted dienes to introduce acyclic
quaternary centers, which are synthetically challenging motifs to
[
5,6]
[7]
access due to their congested nature.
Recently Zhao et al.
activated ketones provide tertiary alcohols that incorporate
III
reported the first Rh -catalyzed three-component C–H bond
contiguous tetrasubstituted carbons [Eq. (2)]. Upon extending the
three-component reaction to internally monosubstituted dienes
other than isoprene, two stereogenic centers are introduced with
high diastereoselectivity [Eq. (3)].[ Moreover, the opposite
relative stereochemistry of the methyl and hydroxyl groups on the
two vicinal stereogenic carbon centers can be obtained by
employing previously unexplored 1,2-disubstituted dienes [Eq.
addition to a range of monosubstituted dienes and aldehydes [Eq.
(
1)].[2a] Although two examples of additions of internally
5]
substituted dienes were included, these reactions proceeded in
modest yields and were demonstrated only for the highly activated
aldehyde ethyl glyoxylate.
(4)]. The catalytic cycle, which is supported by studies with
isotope labeled starting materials, provides a rationale for the
disparate stereochemical outcomes for the two different diene
substitution patterns [Eqs (3) and (4)].
An extensive evaluation of different reaction conditions was
conducted for the three-component coupling of phenyl pyrazole
[
*]
S. Dongbang, Z. Shen, Prof. Dr. J. A. Ellman
Department of Chemistry
Yale University
1
a, isoprene 2a and isovaleraldehyde 3a (Table 1; see
Supplementary Table S1). The use of [Cp*Co(C )][B(C
6
H
6
6 5 4 2
F ) ]
,[8]
2
25 Prospect St., New Haven, CT 06520 (USA)
previously developed in our lab, was found to be crucial, with
E-mail: jonathan.ellman@yale.edu
CoIII
RhIII
other preformed catalysts, such as
[Cp*Co(C )][PF ][SbF and
6
Cp*Rh(MeCN) ][SbF ]2, resulting in little to no conversion. A
and
†These authors contributed equally
6
H
6
4 2
] ,
[Cp*Rh(MeCN)
2
6 2
]
[
2
Supporting information for this article is given via a link at the end of
the document.
catalytic amount of AcOH was found to be beneficial as opposed
to LiOAc[ or PivOH,[9] which have been used as additives for
2f]
III
other Co -catalyzed C–H bond addition reactions. Concentration
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was shown to have a critical role in this transformation, with 0.4 M
leading to much lower conversion than 1.0 M.[2c,d,f] Heating at
Table 1. C–H bond functionalization with isoprene and aldehydes/ketones.
5
0 °C was chosen as the standard conditions for isoprene addition,
but 70 °C was found to be necessary for some dienes and/or
carbonyl compounds bearing bulkier substituents (vide infra). In
addition, while dioxane was selected for the standard reaction
conditions, DCE and toluene were also effective solvents, and
toluene was in fact superior to dioxane for some sterically
hindered coupling partners (vide infra).
Having determined the optimal reaction conditions, we next
explored the scope for isoprene addition (Table 1). First, alkyl
aldehydes were investigated (4a-4b), including those displaying
benzyl ether (4c), terminal alkene (4d), and primary alkyl chloride
(
4e) functionality. The reaction is sensitive to sterics, with α-
branched cyclopropanecarboxaldehyde requiring an elevated
0 °C reaction temperature and toluene as solvent to provide
7
homoallylic alcohol 4f in 62% yield. Not surprisingly, the more
sterically hindered α,α-dibranched pivaldehyde gave only a trace
amount of product (data not shown). A series of aryl aldehydes
were next examined. Benzaldehyde (4g), along with derivatives
with electron-deficient groups at the ortho, meta, or para-positions
(4h-4k) all coupled in high yields. Acidic m-hydroxybenzaldehyde
(4l) and the moderately electron-rich p-tolualdehyde (4m) coupled
in 50% and 62% yields, respectively. The presence of a basic
pyridyl nitrogen did not impede the reaction, with homoallylic
alcohol 4n obtained in excellent yield.
Along with alkyl and aromatic aldehydes, the first examples of
three-component coupling of more challenging ketones
proceeded to give homoallylic tertiary alcohols 4o-4v that
incorporate contiguous tetrasubstituted carbons (Table 1).
Electron-deficient isatin and N-methylisatin furnished tertiary
alcohols 4o and 4p, respectively, in moderate yields. Chloro-
substituted isatin and N-methylisatin also afforded the alcohols 4q
and 4r in comparable yields, respectively. The highly strained
cyclic ketone 3-oxetanone also displayed good reactivity,
providing tertiary alcohol 4s in good yield. Additionally, N-
carboxybenzyl (Cbz)-protected 3-azetidinone afforded tertiary
alcohols 4t and 4u in >90% yields. Reaction with the indantrione
furnished 4v, albeit in moderate yield. We also investigated the
coupling of unactivated ketones such as acetone and
acetophenone, but three-component coupling products were not
obtained.
[
a] Conditions: 0.2 mmol of 1, 0.8 mmol of 2, 0.6 mmol of 3. Isolated yields of
products after purification by chromatography are reported. [b] Reactions
performed in toluene at 70 ⁰ C.
A number of different C–H bond substrates were also
investigated. A methyl substituent at either the ortho (4t) or meta
(4u and 4w) position prevented bis-functionalization for phenyl
pyrazole substrates. Additionally, 2-phenylpyridine served as an
excellent C–H bond substrate, furnishing product 4x in near-
quantitative yield. C–H bond substrates with amide directing
groups were also effective as demonstrated for secondary N-
isopropyl (4y) and N-methyl (4z) benzamides as well as for
tertiary pyrrolidine benzamide (4aa-4ac). Lastly, homoallylic
alcohol 4ad was prepared by C–H functionalization of N-
methyldihydroisoquinolin-2-one.
A series of internally substituted dienes 5 were next explored
for preparing homoallylic alcohols 6 with stereogenic quaternary
carbons (Table 2). Three-component addition to 3-
methyleneoctene and acetaldehyde provided alcohol 6a in 62%
yield and with >20:1 dr. The relative stereochemistry of 6a was
confirmed by X-ray crystallographic determination of its 3,5-
dinitrobenzoylated derivative, confirming
a syn-relationship
[
10]
between the methyl and hydroxyl groups. C–H bond substrates
with both pyrazole and pyridine directing groups were effective for
coupling with benzyloxyacetaldehyde to give alcohols 6b and 6c
with high diastereoselectivities and 66% and 51% yields,
respectively. Benzaldehyde derivatives with electron-withdrawing
groups at the para position afforded the corresponding products
6
d-6f in moderate yields. m-Bromobenzaldehyde was also an
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COMMUNICATION
Table 3. C–H bond functionalization with 1,2-disubstituted dienes.
effective coupling partner to give alcohol 6g that incorporates a
site for further elaboration. Contiguous tetrasubstituted carbons
could also be introduced as demonstrated by coupling the
activated ketone 1-Cbz-3-azetidinone to give alcohol 6h in good
yield. More sterically demanding substituents on the diene were
investigated as well. The isobutyl substituted diene coupled with
2
-benzyloxyacetaldehyde to give the homoallylic alcohol 6i with
good diastereoselectivity. In contrast, reaction with acetaldehyde
provided product 6j in modest yield and with lower
diastereoselectivity. The aryl substituted diene, 2-phenyl-1,3-
butadiene, also furnished product 6k, albeit in low yield and with
poor diastereoselectivity.
Table 2. C–H bond functionalization with internally monosubstituted dienes and
aldehydes/ketones.
[
a] Conditions: 0.2 mmol of 1, 0.4 mmol of 7, 0.6 mmol of 3. Isolated yields of
products after purification by chromatography are reported.
A
series of experiments were conducted to obtain
mechanistic information using isotopically labeled starting
materials. When 2-(phenyl-D )pyridine was subjected to the
standard reaction conditions with isoprene and 4-
5
2
formylbenzoate as the coupling partners, an 18% conversion to
the three-component coupling product was observed after a 30
min reaction time. Under these conditions, 58% of the C–H bond
substrate was recovered and showed extensive H/D exchange at
the ortho positions (Figure 2a). These results establish that the
C–H activation step is reversible.
[
a] Conditions: 0.2 mmol of 1, 0.4 mmol of 5, 0.6 mmol of 3. Isolated yields of
products after purification by chromatography are reported. [b] Reactions
performed at 70 ⁰C for 40 h.
When the terminally dideuterated isoprene 2-d
2
was
subjected to the standard reaction conditions, deuterium
migration was observed on two different sites in the product 4u-
d (Figure 2b). Only one out of the two methyl groups in 4u-d
2 2
Next, we extended the scope to 1,2-disubstituted 1,3-dienes
(Table 3), which provide the opposite relative stereochemistry
7
incorporated a significant amount of deuterium. Additionally, the
ortho position of the aromatic ring incorporated 30% deuterium
likely due to reversible C–H activation. The product incorporated
for the methyl and hydroxyl groups on the two contiguous
stereogenic centers as compared to internally monosubstituted
dienes
methylpentadiene and acetaldehyde gave alcohol 8a in 49% yield
and with high diastereoselectivity (>20:1 dr). The relative
stereochemistry was confirmed by X-ray crystallographic
5 (Table 2). Three-component coupling with 3-
1
.65 out of the two deuteriums present in 2-d
2
. Presumably, some
III
deuterium loss occurs from Co –hydride intermediate C (Figure
3) during the catalytic cycle (vide infra).
[
10]
determination of its 3,5-dintrobenzoylated derivative, showing
that the methyl and the hydroxyl groups are in an anti-relationship.
Three-component coupling for C–H bond substrates with the
pyridyl directing group provided moderate to excellent yields and
good diastereoselectivity for alkyl, aromatic and heteroaromatic
aldehydes (8b-8f). Finally, when the diene with R2 = Et was
employed, both aryl (8g) and alkyl (8h) aldehydes gave
homoallylic products that incorporated a propyl substituent at the
quaternary carbon center.
A mechanism is proposed based upon the studies with
isotope labeled starting materials, the stereochemistry observed
for the products, and prior mechanistic studies for three-
[2c]
component coupling of butadiene (Figure 3). In the presence of
III
the Co -catalyst, a reversible ortho C–H bond activation of
substrate 1 via concerted metalation deprotonation generates 5-
[11]
membered metallocycle A. Alkene coordination and migratory
3
[2c]
insertion of the diene affords the η -Co-allyl species B. Syn β-
hydride elimination provides species C, with the syn coplanar
hydrogen H
undergoes reversible hydride reinsertion of H
position of the diene, as evidenced by deuterium incorporation at
the C-4 position (Figure 2b). Parallel reactions of 2 and 2-d
a
incorporated as the Co hydride. This intermediate
a
into the C-4
2
proceeded at the same rate, establishing that neither the β-
hydride elimination nor reinsertion is a rate limiting step (See
Supplementary Information VI). Diastereoselective addition of
intermediate D to aldehyde 3 through the chair-like transition state
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shown in E provides the observed relative stereochemistry in the
Both X-ray structural characterization of the products and
mechanistic experiments support the proposed mechanism.
final product for both the internally monosubstituted (Table 2) and
1,2-disubstituted (Table 3) dienes. Release of product F upon
protonolysis regenerates the cobalt catalyst.
Acknowledgements
This work was supported by the NIH (R35GM122473). We gratefully
acknowledge Dr. Brandon Mercado (Yale University) for solving the crystal
structures reported in this manuscript. Helpful input provided by Jeffrey Boerth
and Soham Maity is greatly appreciated.
Keywords: C–H activation • homogeneous catalysis • multicomponent
reactions • cobalt • diastereoselectivity
[
1]
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[
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4]
A three-component approach initiated by Pd-catalyzed C-I oxidative
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III
Selected reviews on Co -catalyzed C–H bond functionalization: (a) O.
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Figure 3. Proposed mechanism for the three-component transformation.
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III
In summary, a Co -catalyzed C–H bond addition to form
secondary and tertiary homoallylic alcohols containing quaternary
carbons has been developed. The sequential C–H bond addition
to internally substituted dienes and carbonyls shows broad scope,
including not only alkyl and aryl aldehydes but also the first
examples of additions to activated ketones for the formation of
tertiary homoallylic alcohols. Additionally, this robust
transformation proceeds with high diastereoselectivity for various
internally monosubstituted dienes. Notably, with the first
application of 1,2-disubstituted dienes, the opposite relative
stereochemistry of the two stereogenic centers can be achieved.
2
014, 516, 181-191.
[
6]
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COMMUNICATION
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CDC1917393 (3,5-dinitrobenzoylated derivative of 6a) and
CDC1917394 (3,5-dinitrobenzoylated derivative of 8a) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre. See SI for additional details.
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†
†
Sun Dongbang, Zican Shen, and
Jonathan A. Ellman*
Page No. – Page No.
Synthesis of Homoallylic Alcohols
with Acyclic Quaternary Centers via
III
Co -Catalyzed Three-Component C–H
III
An efficient Co -catalyzed three-component synthesis of homoallylic alcohols
Bond Addition to Internally
Substituted Dienes and Carbonyls
containing acyclic quaternary centers is disclosed. This highly diastereoselective
approach introduces two C–C σ bonds via C–H bond activation and sequential
addition to internally substituted dienes and a wide range of aldehydes or activated
ketones.
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