Highly Selective Palladium-Catalyzed Hydroborylative Carbocyclization of Bisallenes to Seven-Membered Rings

Article abstract of DOI:10.1021/jacs.8b08708

A highly selective palladium-catalyzed hydroborylative carbocyclization of bisallenes to afford seven-membered rings has been established. This ring-closing coupling reaction showed good functional group compatibility with high chemo- and regioselectivity, as seven-membered ring3was the only product obtained. The extensive use of different linkers, including nitrogen, oxygen, malononitrile, and malonate, showed a broad substrate scope for this approach. A one-pot cascade reaction was realized by trapping the primary allylboron compound with an aldehyde, affording a diastereomerically pure alcohol and a quaternary carbon center by formation of a new C-C bond. A comprehensive mechanistic DFT investigation is also presented. The calculations suggest that the reaction proceeds via a concerted hydropalladation pathway from a Pd(0)-olefin complex rather than via a pathway involving a defined palladium hydride species. The reaction was significantly accelerated by the coordination of the pendant olefin, as well as the introduction of suitable substituents in the bridge, due to the Thorpe-Ingold effect.

Full text of DOI:10.1021/jacs.8b08708

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Article
Highly Selective Palladium-Catalyzed Hydroborylative
Carbocyclization of Bisallenes to Seven-Membered Rings
Can Zhu, Bin Yang, Binh Khanh Mai, Sara Palazzotto, Youai Qiu, Arnar
Gudmundsson, Alexander Ricke, Fahmi Himo, and Jan-E. Bäckvall
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b08708 • Publication Date (Web): 03 Oct 2018
Downloaded from http://pubs.acs.org on October 3, 2018
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Highly Selective Palladium-Catalyzed Hydroborylative
Carbocyclization of Bisallenes to Seven-Membered Rings
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Can Zhu+,* Bin Yang+, Binh Khanh Mai, Sara Palazzotto, Youai Qiu, Arnar Gudmundsson,
Alexander Ricke, Fahmi Himo,* and JanꢀE. Bäckvall*
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Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SEꢀ106 91
Stockholm, Sweden.
Corresponding Authors:
*jeb@organ.su.se (Prof. JanꢀE. Bäckvall)
*fahmi.himo@su.se (Prof. Fahmi Himo)
*zhucaner@gmail.com (Dr. Can Zhu)
[+]These authors contributed equally to this work.
Abstract
A highly selective palladiumꢀcatalyzed hydroborylative carbocyclization of bisallenes to
afford sevenꢀmembered rings has been established. This ringꢀclosing coupling reaction
showed good functional group compatibility with high chemoꢀ and regioselectivity, as sevenꢀ
membered ring 3 was the only product obtained. The extensive use of different linkers,
including nitrogen, oxygen, malononitrile, and malonate, showed a broad substrate scope for
this approach. A oneꢀpot cascade reaction was realized by trapping the primary allylboron
compound with an aldehyde, affording a diastereomerically pure alcohol and a quaternary
carbon center by formation of a new CꢀC bond. A comprehensive mechanistic DFT
investigation is also presented. The calculations suggest that the reaction proceeds via a
concerted hydropalladation pathway from Pd(0)ꢀolefin complex rather than via a pathway
involving a defined palladium hydride species. The reaction was significantly accelerated by
the coordination of the pending olefin, as well as the introduction of suitable substituents in
the bridge, due to the ThorpeꢀIngold effect.
Keywords: sevenꢀmembered rings • bisallene • palladium • hydroborylative carbocyclization
• aldehyde • DFT calculations
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I. Introduction
Organoboranes are a class of highly useful compounds in organic synthesis, owing to the fact
that they are fundamental building blocks for complex molecules.1,2 They have found wide
applications in various carbonꢀcarbon (C–C) bondꢀforming reactions, in particular in Suzuki
crossꢀcoupling reactions as lateꢀstage steps in synthetic chemistry.3ꢀ6 The direct hydroboration
of unsaturated compounds (e.g. alkenes and alkynes) with boranes provides a direct and
efficient approach to organoboranes, given the fact that these starting materials are readily
accessible compounds (Scheme 1a).7 However, the reaction outcome of this chemistry is
mostly limited to the antiꢀMarkovnikov selectivity and synꢀaddition product(s).
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In recent years a significant progress in the development of novel methodologies involving
organoboranes has occurred, in particular on methods catalyzed by transition metals. This is
exemplified by recent reviews on Suzuki–Miyaura coupling3 and organoboron compounds
involved in photocatalysis.8 Important methods to prepare organoboranes that have received
much attention include catalytic hydroboration, where regioꢀ and stereoselectivity are
controlled by the transition metal catalyst system (Scheme 1b).9 The metal hydride ([M]−H) is
considered as the active species that promotes the hydroboration reaction. However, in this
case the functionalꢀgroup tolerance will be challenging, since many groups may react with the
metal hydride. On the other hand, the construction of mediumꢀsized rings has attracted
increasing attention, owing to their broad occurrence as the core structure in various natural
products and pharmacologically active substances.10 Due to their unfavorable transannular
interactions, the synthesis of mediumꢀsized rings is still challenging.11 Therefore, the direct
hydroborylative carbocyclization of unsaturated compounds would be an efficient and
powerful strategy to realize both the construction of mediumꢀsized rings and the introduction
of boron functionality in a oneꢀstep manner (Scheme 1c).
Bisallenes are a class of compounds bearing two allene moieties, which have been
demonstrated as powerful building blocks in organic chemistry.12,13 In 2005, Ma et al.
reported a highly efficient and selective Rh(I)ꢀcatalyzed approach to steroid scaffolds from
bisallenes, which showed the unique character of bisallenes in organic synthesis.13g
Herein, we disclose our recent observations on the highly selective palladiumꢀcatalyzed
hydroborylative carbocyclization of bisallenes to sevenꢀmembered rings (Scheme 1d).14
A
oneꢀpot cascade reaction was also developed by trapping of the primary allylboron product by
an aldehyde leading to an alcohol. The key challenge was to identify a suitable catalyst
system, which works nicely in both the carbocyclization and the hydroboration reaction, and
the control of the involved regioꢀ and stereoselectivity.15 DFT calculations provide important
information concerning the mechanism of the reaction and suggest that the formal hydroꢀ
palladation step of the allene does not involve a defined palladium hydride.
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Scheme 1. Previous studies and this work.
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M = metal. HB = Hydroboration. B2pin2 = Bis(pinacolato)diboron.
II. Results and Discussion
II.A. Development of Pd-catalyzed hydroborylative carbocyclization of bisallenes
Based on the concept shown in Scheme 1c and 1d, we initially chose bisallene 1a as the
standard substrate to investigate the reactivity in this hydroborylative carbocyclization. When
the reaction of 1a with HBpin (1.3 equiv) was run in toluene in the presence of Pd(OAc)2 (5
o
mol%), no product was detected after 3 h at 50 C, and 1a was recovered in 94% yield. To
our delight, when B2pin2 (1.3 equiv) together with MeOH (1.0 equiv) were used in place of
the active borane (HBpin), the sevenꢀmembered carbocycle 3a was generated in 56% yield
(Scheme 2). Surprisingly, the proposed isomers of typeꢀA and typeꢀB (Scheme 1d) were not
formed during the reaction, showing the high selectivity of this approach. Finally, the
formation of 3a was not detected when HBpin and MeOBpin were employed together.16
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Scheme 2. Initial Attempt.
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aYield was determined by 1H NMR analysis with anisole as the internal standard. bMeOH (1.0
c
equiv) and B2pin2 (1.3 equiv) were used. HBpin (1.1 equiv) and MeOBpin (1.1 equiv) were
used with THF as the solvent. HB = Hydroboration.
We next turned to optimizing the reaction conditions using bisallene 1a as the standard
o
substrate. Under the initial reaction conditions at 50 C, 3a was detected in 56% yield (Table
o
1, entry 1). Changing the temperature to 40 or 60 C did not improve the outcome of the
reaction, but rather led to a slight decrease in yield in both cases (Table 1, entries 2ꢀ3). To our
delight, the use of AcOH in place of MeOH as the proton source improved the yield of the
sevenꢀmembered carbocycle 3a to 67%, with much less side products detected (Table 1, entry
4). Solvent screening revealed that THF was the best solvent, in which carbocycle 3a was
produced in 70% yield (Table 1, entries 5ꢀ7). Moreover, when the amount of AcOH was kept
at 1.2 equiv with 1.1 equiv of B2pin2, the yield of 3a was improved further to 75% yield
(Table 1, entries 8ꢀ13). Sevenꢀmembered carbocycle 3a was obtained as the only isomer,
without any formation of typeꢀA or typeꢀB products (see Scheme 1d). Therefore, the
optimized reaction conditions for additional studies were defined as Pd(OAc)2 (5 mol%),
B2pin2 (1.1 equiv), and AcOH (1.2 equiv) in THF at 50 oC (Table 1, entry 12).
Under the optimal reaction conditions, we next studied the scope of bisallenes in the
reaction (Scheme 3). Meꢀ or Bnꢀsubstituted bisallene (1b or 1c) could also be employed to
afford product 3b and 3c in 65% and 70% yield, respectively. Bisallene 1d, bearing two
remote olefins also worked well to produce 3d in 55% yield. The remote olefin group
survived during the reaction, showing the high selectivity of this approach. Moreover, ester as
functional group was also compatible with the reaction conditions as shown by the formation
of 3e in 72% yield. Furthermore, a series of secondary substituents were investigated as well:
i
when R is Pr, cyclopentyl or cyclohexyl, the reaction afforded 3f-h in good yields with
excellent selectivities.
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Table 1. Optimization of the Reaction Conditionsa.
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Entry
Proton source
(equiv)
B2pin2
(equiv)
1.3
Solvent
Yield of 3a (%)b
1
MeOH (1.0)
toluene
toluene
toluene
toluene
THF
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2c
3d
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MeOH (1.0)
MeOH (1.0)
AcOH (1.0)
AcOH (1.0)
AcOH (1.0)
AcOH (1.0)
AcOH (1.0)
AcOH (1.0)
AcOH (1.0)
AcOH (0.9)
AcOH (1.2)
AcOH (1.3)
1.3
1.3
1.3
1.3
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1.3
1.2
1.1
1.0
1.1
1.1
1.1
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6e
dioxane
DCE
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trace
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THF
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THF
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THF
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THF
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THF
75 (73)
72
THF
aUnless otherwise noted the reaction was conducted in the indicated solvent (1 mL) with
1a (0.2 mmol), B2pin2 (2), and proton source in the presence of Pd(OAc)2 (5 mol%) at 50
oC for 3 h. Yield determined by H NMR analysis using anisole as the internal standard.
b
1
c
o
d
The number in parentheses is the isolated yield. The reaction was run at 60 C. The
reaction was run at 40 oC. e1a was recovered in 10% yield.
Next, we turned to investigating the effect of the linker connecting the two allene moieties.
Bisallene 1i without the olefin in the bridge was therefore prepared. The reaction of 1i under
standard conditions was very slow and gave only 20% yield of 3i after 3 h reaction time.
However, 1i could be cyclized to 3i in 74% yield on prolongation of the reaction time to 30 h.
Interestingly, the reactions of bisallenes 1j (X = NTs) and 1k (X = O) under the standard
reaction conditions (3 h) gave the hydroborylated products 3j (76%) and 3k (70%),
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respectively, as the only product. Bisallene bearing the malononitrile (1l) or malonate (1m or
1o) moiety in the bridge produced the corresponding products 3l, 3m, and 3o in 87, 90, and 90%
yield, respectively. When dicyclopentyl and diphenylꢀsubstituted bisallenes (1n and 1p) were
employed, the sevenꢀmembered carbocycles 3n and 3p were obtained in 91 and 65% yield,
respectively. However, when bisallene 1q bearing a tetrasubstituted allene moiety was
employed, the corresponding product 3q was not formed, but direct hydroboration of one
allene moiety was observed as the formation of 4 in 44% yield.17 Also a bisallene with R = H
and R = IPr with X=NTs failed to give any product 3 (see Supporting Information p. S20 for
bisallene 1r). It is noteworthy that products with sevenꢀmembered rings were the only
products obtained under these reaction conditions.18
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Scheme 3. Substrate Scope.
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Finally, gramꢀscale synthesis of sevenꢀmembered carbocycle 3a was realized from bisallene
1a, which is readily obtained from commercially available compounds via a threeꢀstep
synthesis without any chromatographyꢀpurification (Scheme 4).19
Scheme 4. Gramꢀscale synthesis of 3a.
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Allylation of aldehydes using allyboron compounds has been developed as a powerful
method for diastereoselective formation of alcohols.20 The high diastereoselectivity is the
result of a sixꢀmembered transition state (ZimmermanꢀTraxler transition state). Since an
allylboron unit is formed in products 3 (Scheme 3), we investigated whether these products
could be trapped by an aldehyde, which should lead to diastereoselective formation of
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Scheme 5. Oneꢀpot cascade reaction of bisallene with B2pin2 and an aldehyde.
b
c
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aFor 8d: t2 = 44 h. For 8f: t1 = 4 h. For 8i: the reaction temperature was increased to 60 C
after the addition of the aldehyde.
alcohols with a quaternary carbon in the βꢀposition. After completion of the reaction of
bisallene 1a to give allylboron product 3a under standard conditions (without removal of the
solvent), pꢀbromobenzaldehyde was added to the reaction mixture and the reaction was stirred
for another 20 h at 50 oC. Workup of this oneꢀpot cascade reaction afforded the corresponding
alcohol 8a as a single diastereomer in 61% yield (Scheme 5).21 pꢀChoro and pꢀfluoro
benzaldehyde also proved to be compatible with the reaction conditions, and 8b and 8c were
obtained in 65 and 62% yield, respectively. Electronꢀrich benzaldehydes, such as pꢀ
anisaldehyde and butyraldehyde could be employed as shown by the formation of 8d and 8e
in 61 and 56% yield, respectively. The reaction of bisallene 1b with two methyl groups
afforded the corresponding product 8f in 54% yield. Finally, the employment of bisallenes
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with oxygen or malonate in the bridge also worked nicely, as shown by the formation of 8g-i
in 52ꢀ64% yields. Control experiments showed that catalytic amount of acid is essential for
the allylation reaction of aldehydes with allyboron compounds (for details, see the Supporting
Information). The oneꢀpot reaction described in Scheme 5 provides a new quaternary carbon
center by forming a new CꢀC bond, which should have potential applications in synthetic
chemistry.22
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II.B. Kinetic Isotope Effect
To gain a deeper insight into this Pdꢀcatalyzed hydroborylative carbocyclization, the compeꢀ
titive kinetic isotope effect (KIE) was determined from the reaction of a 1:1 mixture of HOAc
o
and acetic acidꢀd4 at 50 C for 5 min (Eq. 1, Scheme 6). The product ratio 3a/3a-d measured
was 4.05:1, while the conversion of the reaction was 20%. From these ratios the competitive
KIE was determined to be kH/kD = 4.7 (for details, see the Supporting Information (SI)).
Furthermore, parallel kinetic experiments using HOAc and acetic acidꢀd4 provided a parallel
KIE (kH/kD, from the early stage of the reaction) value of 4.4 (for details, see the Supporting
Information). These results indicate that the proton transfer from acetic acid to palladium or
the allene occurs during the rateꢀdetermining step. Based on the competitive KIE, this step
also has to be the first irreversible step.
Scheme 6. Kinetic isotope effect.
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II.C. Computational Investigations
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Density functional theory (DFT) calculations, using substrate 1a as a representative case,
were carried out to gain further insight into the mechanism of the hydroborylative
carbocyclization reaction (see Supporting Information for the computational protocol). On the
basis of these calculations the mechanism shown in Scheme 7 is proposed.
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The calculations first show that the Pd(0) active catalyst, Int-0, can be easily formed from
the Pd(OAc)2 precatalyst.23 The details of this activation step, involving substrate
coordination and transmetalation with B2pin2, are given in Figure S5 in the Supporting
Information. Without the coordination of substrate 1a, the activation barrier for the formation
of Pd(0) is calculated to be 5.6 kcal/mol higher than TS-2Pre (see Figure S5 in SI for
optimized structures). This result clearly shows that the coordination of substrate 1a facilitates
for the formation of Pd(0) active catalyst. Interestingly, in Int-0, both of the allene moieties
and also the olefin linker coordinate to the metal ion (see Figure 1). Structures of other
coordination modes of Pd(0) with bisallene 1a are also optimized, which are calculated to be
higher in energy than Int-0 (see Figure S6 in SI for details). A structure in which an AcOH,
the alkene, and only one of the allenes bind to Pd(0) could also be located. However, this
structure was found to be 2.8 kcal/mol higher in energy than Int-0 and it is therefore not
included in Scheme 7.
Scheme 7. Reaction mechanism for the palladiumꢀcatalyzed hydroborylative carbocyclization
proposed on the basis of current DFT calculations.
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In general, the expected route to reach the vinylpalladium intermediate Int-1 from Int-0 is
through a Pdꢀhydride species from protonation of Pd(0) that can then undergo
hydropalladation.24 However, the calculations show that this mechanism is associated with
very high energies. The Pd(II)ꢀhydride intermediate is calculated to be 19.9 kcal/mol higher in
energy than Int-0, and the barrier for the formal oxidative addition of the acetic acid to Pd(0)
leading to the Pd(II)ꢀhydride is calculated to be 33.7 kcal/mol (see Figure S7 in SI for details).
Instead, the calculations indicate that Int-1 is reached from Int-0 in a single step, in which the
proton of the acetic acid transfers to the terminal carbon of the allene.25 At the transition state
(TS-1, Figure 1), the distances to the transferring hydrogen atom from acetate oxygen atom
and terminal carbon atom are 1.41 and 1.36 Å, respectively. Interestingly, the distance
between the transferring hydrogen atom and Pd is 2.07 Å, which is too long for a palladium
hydride. In TS-1, the second allene moiety loses its coordination to the metal (Figure 1). The
barrier for this reaction is calculated to be as low as 14.3 kcal/mol (Figure 2), which is
considerably lower than the pathway involving a palladium hydride intermediate. The low
barrier can be rationalized considering the fact that in the Pd(0) complex, the strong backꢀ
donation makes the olefin electronꢀrich and therefore prone to be protonated. These results are
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consistent with recent calculations on the palladiumꢀcatalyzed cycloisomerization of
enynamide, in which a similar mechanism was obtained for this step.25 Here, it should be
mentioned that another conformer of TS-1 was also located in which the allene moiety rather
than the alkene linker coordinates to the Pd, leading directly to Int-2. However, this
conformation was found to be 3.7 kcal/mol higher than TS-1 (see Figure S11 in SI for
optimized structure).
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For the carbocyclization to take place, the coordination to Pd in Int-1 has to change from the
olefin linker to the allene moiety. This ligand change gives vinylꢀallene palladium
intermediate Int-2, which is 2.2 kcal/mol higher in energy than Int-1. Carbocyclization via
TS-2 then occurs to generate the sevenꢀmembered ring σꢀallylpalladium intermediate, Int-3.
The barrier for the carbocyclization is calculated to be 15.5 kcal/mol relative to Int-1 (Figure
2). The carbocyclization step is followed by a rearrangement to produce a more stable πꢀ
allylpalladium intermediate, Int-4. The activation energy of this step is calculated to be 5.9
kcal/mol relative to Int-3, and the πꢀallylpalladium intermediate Int-4 is 12.9 kcal/mol lower
in energy than σꢀallylpalladium complex Int-3, i.e. ꢀ37.4 kcal/mol relative to Int-0.
Subsequent transmetalation from Int-4 occurs to produce Int-6. This transmetalation consists
of two steps: a nucleophilic attack (TS-4) and a BꢀB bond cleavage (TS-5). The energies of
TS-4 and TS-5 are calculated to be +10.9 and +15.3 kcal/mol relative to Int-4, respectively.
At Int-6, an agostic interaction between the C–H bond of the nPr substituent and the Pd ion is
observed. It is interesting to note that transmetalation directly from Int-3 was also considered
and found to have an overall barrier of 16.8 kcal/mol (see Figure S8 in SI for details). This
barrier is much higher than the barrier (via TS-3) leading to πꢀallyl complex Int-4.
The last step of the reaction is the reductive elimination of Int-6 to generate Int-7. The
barrier of this step is also low, amounting to 10.6 kcal/mol. Finally, to close the catalytic
cycle, a ligand exchange can take place, releasing product 3a and binding a new bisallene
substrate (1a).
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Figure 1. Optimized structures of stationary points for the palladiumꢀcatalyzed
hydroborylative carbocyclization. For clarity, the methyl groups on the Bpin ligands are
omitted in all structures except Int-7. Bond distances are in Å.
The calculations show that the overall cycle is exergonic by as much as 76.5 kcal/mol. As
seen from the full free energy profile given in Figure 2, the reactions proceeding via TS-1,
TS-2, and TS-5 have quite similar energy barriers of 14.3, 15.5 and 15.3 kcal/mol,
respectively. It is therefore not possible on the basis of only the calculations to single out
which one of these steps that is rateꢀdetermining. However, for substrate 1a, the KIE
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measurements discussed above (Scheme 6) clearly show that TS-1 is the rateꢀdetermining
step, which indicates that the energy of this TS is somewhat underestimated compared to the
other two TSs in the calculations. The fact that there are three transition states associated with
barriers that are close in energy is indeed a very interesting finding, because it indicates that
even small alterations of the substrate (e.g. the use of a different linker or different
substituents) can lead to a change in the nature of the rateꢀdetermining step.
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Figure 2. Calculated free energy profile (kcal/mol) for the palladiumꢀcatalyzed
hydroborylative carbocyclization.
Here it is important to mention that we also explored the possibility that the sevenꢀ
membered ring product A in Scheme 1d could be formed from Int-6. This requires a
rearrangement of Int-6 to the other σꢀallyl, Int-6’ (see Figure S9 in SI). The barrier for
reductive elimination from Int-6’ via transition state TS-6’ is calculated to be 18 kcal/mol,
and Int-6’ is 6.3 kcal/mol higher than Int-6, which makes the overall barrier from Int-6 to be
24.3 kcal/mol. The latter barrier is 13.7 kcal/mol higher in energy than the barrier via TS-6
(see Figure S9 in SI for details). This result is consistent with the fact that product A could not
be observed experimentally. Furthermore, we also considered the formation of the sixꢀ
membered ring product B (see Scheme 1d) from Int-2 via carbocyclization transition state
(TS-3’). The energy of this transition state was calculated to be 4.3 kcal/mol higher than TS-2,
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which is also consistent with the experimental data that no product B was found in this
reaction (see Figure S10 in SI).
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Finally, we have also studied the influence of the bisallene linker on the energy profile by
considering the reactions of substrates 1m (with C(CO2Me)2 linker) and 1i (with CH2 linker
and also iPr substituent instead of nPr). The obtained energy graphs are given in Figure 3.
Experimentally, the overall reaction of 1i was observed to be about one order of magnitude
slower than the reactions of 1a and 1m, which were equally fast (Scheme 3).
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Figure 3. Calculated free energy profiles (kcal/mol) for the palladiumꢀcatalyzed
hydroborylative carbocyclization of substrates 1m and 1i.
As seen from Figure 3, substrates 1i and 1m follow the same reaction mechanism as 1a
(Figure 2), with essentially the same energy profiles. Some interesting differences can,
however, be observed, in particular in the energies of the initial step. Since the olefin linker is
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absent in 1i and 1m, intermediate Int-1 cannot be formed for these substrates, and therefore
TS-1 results directly in Int-2 (the optimized structures for Int-0, TS-1, and Int-2 for substrates
1i and 1m are shown in Figure 4). The energy of this intermediate is significantly higher for
1i and 1m compared to 1a (+2.3 and ꢀ1.1 kcal/mol for 1i and 1m, respectively, compared to ꢀ
9.2 kcal/mol for 1a). The lack of coordination of the linker also leads to that the barrier of the
second step via TS-2, becomes lower for 1i and 1m compared to 1a (8.8 and 5.9 kcal/mol,
respectively vs. 15.5 kcal/mol). In addition, the ThorpeꢀIngold effect, present for 1m but not
1i, contributes further to the lowering of the energy of TS-2 for 1m.
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It is interesting to mention that at the hydropalladation TS-1m, the ester C=O bond in 1m can
coordinate to the Pd (analogously to the olefin linker in TS-1 for 1a). However, this
conformation is calculated to be 7.4 kcal/mol higher than TS-1m (see Figure S11 in SI for
optimized structure).
Figure 4. Optimized structures of initial step for substrates 1i and 1m.
III. Conclusions
In conclusion, we have developed an efficient palladiumꢀcatalyzed carbocyclizationꢀ
borylation of bisallenes to sevenꢀmembered rings in good to excellent yields (up to 91%
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yield). The reaction is highly selective as shown by the exclusive formation of one isomer of
the sevenꢀmembered ring product from bisallenes. In addition to the olefin unit, different
substituents including nitrogen, oxygen, malononitrile, and malonate in the bridge also
resulted in a fast hydroborylative carbocyclization. The introduction of suitable substituents in
the bridge, including nitrogen, oxygen, malononitrile, and malonate also favored such
transformations due to the ThorpeꢀIngold effect. A oneꢀpot cascade reaction was realized by
addition of an aldehyde to the in situꢀformed allylboron product, providing diasteroselective
formation of sevenꢀmembered ring alcohols bearing a new quaternary carbon center.
The detailed mechanism of the carbocyclizationꢀborylation was investigated by means of
DFT calculations, which revealed that the initial step takes place via a concerted
hydropalladation. The more expected oxidative addition of the acetic acid leading to an
intermediate Pd(II)ꢀhydride was found to be associated with much higher energy barriers.
These results might at first sight seem somewhat counterintuitive. However, the low barrier
for the concerted protonation mechanism can be understood in terms of the Pd(0) providing a
strong backꢀdonation that makes the olefin electronꢀrich and therefore prone to be protonated.
Similar results were obtained by Anderson and coꢀworkers for the palladiumꢀcatalyzed
cycloisomerization of enynamide.26
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Finally, due to the success of our approach in the selective synthesis of sevenꢀmembered
rings bearing a boron functionality, this method will be highly attractive in synthetic
chemistry. Further studies on the scope and asymmetric variants of the new reactions are
currently underway in our laboratory.
Acknowledgements
Financial support from the Swedish Research Council (2016ꢀ03897, 2018ꢀ00830), the
Berzelii Center EXSELENT, and the Knut and Alice Wallenberg Foundation is gratefully
acknowledged.
Supporting Information
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Experimental procedures and compound characterization data, including the H/13C NMR
spectra, computational details, additional figures of intermediates and transition states,
absolute energies and energy corrections, and Cartesian coordinates of optimized structures.
8
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References
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(14) For reviews on sevenꢀmembered rings, see: (a) Nguyen, T. V.; Hartmann, J. M.; Enders,
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(16) For the detailed comparative experiments using different reagent(s) for the
hydroboration of bisallenes, see the Supporting Information. One reviewer suggested
that bis(pinacolato)diboron (B2pin2) may react with acetic acid to give HꢀB(pin) and
AcOꢀB(pin). The reactions of B2pin2 with acetic acid in THF at 50 °C in the absence or
presence of Pd(OAc)2 did not give of any new boron species and B2pin2 was recovered
in 96% and 100%, respectively (see Supporting Information).
(17) When bisallene 1q bearing a tetrasubstituted allene moiety was employed under the
standard reaction conditions, the direct hydroboration of one allene moiety was
observed as the formation of 4 in 44% yield. The corresponding product 3q was not
detected.
1
(18) Crude H NMR spectrum for the reaction forming 3l is also provided to show the
involved selectivity of the reaction. For details, see the Supporting Information.
(19) For details, see the Supporting Information.
(20) (a) Hoffman, R. W. Pure Appl. Chem. 1988, 60, 123. (b) Yus, M.; GonzálezꢀGómez, J.
C.; Foubelo, F. Chem. Rev. 2011, 111, 7774.
(21) The relative configuration of compounds 8 was determined by the NMR studies of 8f
(for details, see the Supporting Information).
Furthermore, the possible transitionꢀstates (TS) were described as follows. Therefore,
TS-A would be favored for the reaction towards alcohols (8). For a relative example,
see: Deng, H.ꢀP.; Eriksson, L.; Szabó, K. J. Chem. Commun. 2014, 50, 9207.
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(22) Attempts to obtain an asymmetric version in the oneꢀpot reaction led only to 15% ee in
the best case using a chiral phosphoric acid (For details, see the Supporting
Information). Catalytic asymmetric allylation of aldehydes using fully substituted
allylboron compounds has not been reported. For selected reviews on the relative
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ACS Paragon Plus Environment