Double C(sp3)-H bond functionalization mediated by sequential hydride shift/cyclization process: Diastereoselective construction of polyheterocycles

Article abstract of DOI:10.1021/ja412706d

Described herein are two novel types of double C(sp³)-H bond functionalizations triggered by a sequential hydride shift/cyclization process: (1) construction of a bicyclo[3.2.2]nonane skeleton by a [1,6]- and [1,5]-hydride shift sequence and (2) sequential [1,4]- and [1,5]-hydride shift mediated construction of a linear tricyclic skeleton.

Full text of DOI:10.1021/ja412706d

Communication
pubs.acs.org/JACS
Double C(sp3)−H Bond Functionalization Mediated by Sequential
Hydride Shift/Cyclization Process: Diastereoselective Construction of
Polyheterocycles
Keiji Mori,† Kazuki Kurihara,† Shinnosuke Yabe,‡ Masahiro Yamanaka,‡ and Takahiko Akiyama*,†
†Department of Chemistry, Faculty of Science, Gakushuin University, Mejiro, Toshima-ku, Tokyo 171-8588, Japan
‡Department of Chemistry and Research Center for Smart Molecules, Faculty of Science, Rikkyo University, 3-34-1 Nishi-ikebukuro,
Toshima-ku, Tokyo 171-8501, Japan
S
* Supporting Information
ABSTRACT: Described herein are two novel types of
double C(sp3)−H bond functionalizations triggered by a
sequential hydride shift/cyclization process: (1) construc-
tion of a bicyclo[3.2.2]nonane skeleton by a [1,6]- and
[1,5]-hydride shift sequence and (2) sequential [1,4]- and
[1,5]-hydride shift mediated construction of a linear
tricyclic skeleton.
he development of methodology for the direct function-
T
alization of relatively unreactive C−H bonds has become a
major topic of research interest.1 Recently, the C(sp3)−H bond
functionalization by a hydride shift/cyclization process, namely,
the “internal redox process,” has attracted much attention for its
unique features (Scheme 1).2 The key feature of this trans-
Figure 1. Sequential hydride shift processes.
the reaction course ([1,4]- or [1,6]-hydride shift) is completely
controlled by the electrophilic moiety of the substrate. A
substrate with a trans-α,β-unsaturated trifluoroacetyl group (R1 =
H) affords a bicyclo[3.2.2]nonane skeleton by a sequential [1,6]-
and [1,5]-hydride shift process (type I). On the other hand, a
[1,4]- and [1,5]-hydride shift occurred successively in a substrate
with a benzyl group at the position α to a trifluoroacetyl group
(type II). Theoretical studies have revealed that the resonance
stabilization in the benzylidene carbonyl moiety and the steric
repulsion of the α-substituent (R1) are the key to changing the
reaction course.
Scheme 1. C(sp3)−H Functionalization by Internal Redox
Process
To develop the desired sequential hydride shift/cyclization
system, we selected benzylamine derivative B because of the
potent hydride shift ability of the α-H of the N-atom (Figure 2).4
The main challenge is twofold: (1) control of the two potentially
competitive hydride shift processes ([1,4]-hydride shift vs [1,6]-
hydride shift) and (2) selection of the appropriate electron-
withdrawing group (EWG) that would trigger the second [1,5]-
hydride shift. We were plagued by the latter issue because most of
the internal redox reactions reported so far involve a 1,4-
formation is the [1,5]-hydride shift of the C(sp3)−H bond α to
the heteroatom. Subsequent 6-endo cyclization to a cationic
species affords heterocycle 2.3
Because of the potential synthetic utility, several groups
including ours have developed new types of transformations and
constructed useful skeletons.4−8 However, in contrast to the
dramatic advances in the process involving a [1,5]-hydride shift,
the processes involving [1,4]- and [1,6]-hydride shifts, which
would also offer various synthetically useful skeletons, have not
been well investigated.9,10 Furthermore, the sequential utilization
of a [1,n]-hydride shift process (n = 4, 5, 6) is also a promising
approach to construct complex polyheterocycles. Nevertheless,
to the best of our knowledge, there is no precedent for the
sequential hydride shift triggered double C(sp3)−H bond
functionalization.
Figure 2. Two challenges in the reaction of benzylamine derivatives.
We wish to report herein two types of double C(sp3)−H bond
functionalizations mediated by a sequential hydride shift/
cyclization process (Figure 1). The interesting feature is that
Received: December 18, 2013
Published: February 24, 2014
© 2014 American Chemical Society
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Figure 3. Two types of sequential hydride shift mediated double
C(sp3)−H bond functionalizations.
Figure 5. Substrate scope of sequential hydride shift processes.
The substrate scope of the two sequential hydride shift
reactions is illustrated in Figure 5. As regards the [1,6]-[1,5]-
sequential hydride shift process, bicyclo[3.2.2]nonane deriva-
tives 4b−f with electron-donating groups (methyl, methoxy) and
an electron-withdrawing group (fluoro) were obtained in good
chemical yields (up to 96%). Naphthyl-type product 4g was
obtained in excellent chemical yield (94%). The hydride shift
occurred exclusively on the benzyl group in the presence of an
isopropyl group to furnish 4h in 30% yield. The acyclic nature of
the N,N-dialkylamine moiety is important for the sequential
hydride shift process; i.e., an isoquinoline-type substrate 3i
afforded only 7-membered ring adduct 4i (single hydride shift
adduct) due to the restriction of the conformational mobility
required for the second hydride shift process by the ring structure
of the isoquinoline moiety. Furthermore, the use of at least one
benzyl group on nitrogen was crucial in this reaction: no
appreciable adduct was obtained from N,N-diallyl analogue 3j.
The [1,4]-[1,5]-sequential hydride shift process has proven
amenable to a range of substrates bearing a benzyl moiety,14
affording tricyclic compounds (6b−d) in good to excellent
chemical yields (79−90%, Figure 4). Naphthyl product 6e was
also obtained as a single diastereomer, albeit in low chemical
yield (40%).15 Interestingly, the second hydride shift ([1,5]-
hydride shift) occurred exclusively on an isopropyl group in
preference to a benzyl group (6f, 64%), whereas benzylic
hydrogen migrated exclusively in the above sequential reaction.
In this case as well, the presence of a benzyl group on nitrogen
was essential and diallyl amine derivative 6g was not obtained.
To elucidate the major factor controlling the reaction course,
DFT calculations for the first hydride shift were carried out
(Figures 6 and 7). The transition states (TSs) of the [1,4]-
hydride shift (TS1) and the [1,6]-hydride shift (TS2) were
compared using the protonated chemical models for 3a (TSa),
5a (TSd), 7 (TSb), and 8 (TSc). Increasing the bulkiness of the
α-substituent (R1) induced the reversal of the relative stability of
TSs, in good agreement with the experimental results (Figure 6).
TS1a (R1 = H) was 2.7 kcal/mol less stable than TS2a. In
contrast, TS1d with a sterically demanding benzyl group at the α-
Figure 4. Effect of α-substituent of α,β-unsaturated trifluoroacetyl
group.
reduction type hydride shift, and the 1,2-reduction type reaction
is rare.11 Model experiments revealed that the trifluoroacetyl
group had excellent reactivity for the 1,2-reduction type internal
redox process compared to aldehyde and methyl ketone (not
shown, see Supporting Information (SI)).
Based on the above discussion and our previous studies of
internal redox processes,7 we selected a N,N-dibenzylbenzyl-
amine derivative with a trans-α,β-unsaturated trifluoroacetyl
group as the substrate (Figure 3).12 We found that the key initial
hydride shift process ([1,4]- or [1,6]-hydride shift) was
completely controlled by tuning the electrophilic moiety
(selection of the α-substituent of the trifluoroacetyl group).
When substrate 3a with a simple trans-α,β-unsaturated trifluoro-
acetyl group was subjected to the reaction conditions (5 mol %
Yb(OTf)3, toluene, reflux, 48 h), bicyclo[3.2.2]nonane-type
compound 4aa ([1,6]-hydride shift involved adduct) was
obtained as the sole product (90%) and no appreciable 4ab
([1,4]-hydride shift involved adduct) was observed. In sharp
contrast, α-benzyl substrate 5a underwent another sequential
hydride shift process ([1,4]- and [1,5]-hydride shift) smoothly to
furnish linear tricyclic compound 6ab in excellent chemical yield
(86%). Another interesting feature is that the three contiguous
stereogenic centers in 4aa and 6ab were completely controlled,
and the relative stereochemistries of each product were
ambiguously established by X-ray analysis.13
Investigation of the electrophilic moiety revealed that the
bulkiness of the α-substituent of the trifluoroacetyl group was the
key to controlling the reaction course (Figure 4). Subjection of
substrate 7, bearing a methyl group at the α-position, to the
optimum reaction conditions furnished bicyclo[3.2.2]nonane
derivative 9a in slight preference to linear tricyclic compound 9b
(93%, 9a:9b = 64:36). The [1,4]-hydride shift involving adduct
10b prevailed in substrate 8 with an α-ethyl group (73%, 10a:10b
= 39:61). The structures and relative stereochemistries of 9a and
9b were determined by X-ray analysis.
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Figure 6. Relative energy differences (kcal/mol in parentheses) between
TS1 and TS2 in series a (R1 = H), b (R1 = Me), c (R1 = Et), and d (R1 =
Bn).
Figure 8. Rationalization of stereoselective formation of 4 and 6.
Luo5g and Reinhoudt’s early investigation.4a Luo suggested that
the hydride shift process is the rate-determining step and
subsequent cyclization occurred rapidly after the process
according to the computational study. The primary kinetic
isotope effects (kH/kD) of those two reactions (3.0 for [1,6]-
hydride shift process, 2.6 for [1,4]-hydride shift process) also
support this mechanism.16−18 In addition, Reinhoudt’s work4a
and an enantioselective version of these types of processes
developed by us7f and Luo5f revealed the highly stereoselective
nature of the internal redox process; i.e., the stereochemistry of
the starting material was mostly transferred to the newly formed
stereogenic center of the product. Based on this information, the
stereoselectivity in both processes is explained as follows (Figure
8): the cyclization to the iminium cation, which was generated by
the [1,6]- or [1,4]-hydride shift, by enolate species occurred from
the same face of the transferred hydrogen to afford trans-E and
cis-H, respectively. The severe steric repulsion between the CF3
moiety and the adjacent substituent (Ph or Bn group) would
control the direction of the trifluoroacetyl group, leading to the
highly stereoselective [1,5]-hydride shift (reduction of trifluor-
oacetyl group). As a result, the corresponding adducts (4 and 6)
were obtained with excellent stereoselectivities.
In summary, we have developed two types of double C(sp3)−
H bond functionalizations triggered by a sequential hydride
shift/cyclization process. The interesting feature here is that
simply changing the electrophilic moiety altered the reaction
course. Theoretical studies revealed that the resonance
stabilization in the benzylidene carbonyl moiety and the steric
repulsion of the α-substituent (R1) are the key to changing the
reaction course. Further investigation of the hydride shift/
cyclization sequence, particularly concerning the successive
hydride shift system, is underway in our laboratory.
Figure 7. 3D structures of TS1 and TS2 in series a (R1 = H), b (R1 =
Me), and d (R1 = Bn). Bond lengths are shown in Å.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, analytical and spectroscopic data for
new compounds, and copies of NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
position was 1.4 kcal/mol more stable than TS2d. Relatively
small energy differences between TS1 and TS2 were obtained in
series b (R1 = Me) and c (R1 = Et).
S
The relative orientations between the olefin portion and the
phenyl moiety are nearly orthogonal in TS1 and parallel in TS2
(Figure 7). TS2a is energetically more favored than TS1a mainly
due to the resonance-stabilized structure in the benzylidene
moiety (Ca−Cb−Cc−Cd). The steric repulsion between the α-
methyl and phenyl groups would cause the deformation of the
resonance-stabilized structure, thereby leading to a decrease in
the energy difference between TS1b and TS2b. The sterically
demanding benzyl group at the α-position would induce a large
steric repulsion with the phenyl group (shown in purple curves in
Figure 7) to overwhelmingly destabilize TS2d rather than TS1d.
The relative stereoselectivity in each sequential process could
be well rationalized based on the results of a theoretical study by
AUTHOR INFORMATION
Corresponding Author
takahiko.akiyama@gakushuin.ac.jp
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Transformationby
Organocatalysis” from the Ministry of Education, Culture,
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(7) For the internal redox reaction developed by our group, see:
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Sports, Science and Technology, Japan, and a Grant-in-Aid for
Scientific Research from the Japan Society for the Promotion of
Science.
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