Site-Selective 1,1-Difunctionalization of Unactivated Alkenes Enabled by Cationic Palladium Catalysis

Article abstract of DOI:10.1021/jacs.9b04142

A palladium(II)-catalyzed 1,1-difunctionalization of unactivated terminal and internal alkenes via addition of two nucleophiles was developed using a cationic palladium(II) complex. The palladacycle generated in situ as a result of a regioselective addition of a nucleophile to the alkene can readily undergo regioselective β-hydride elimination and migratory insertion with a cationic palladium catalyst. The resulting η ³-π-allyl palladium(II) complex is the key intermediate that reacts with a second nucleophile to furnish the desired 1,1-difunctionalization of the alkene. Under the optimized reaction conditions, a wide range of indoles and anilines add to alkene units of 3-butenoic or 4-pentenoic acid derivatives to afford the synthetically useful γ,γ-or ?,?-difunctionalized products with excellent regiocontrol. Furthermore, by employing internal hydroxyl or acid groups and external carbon nucleophiles, this transformation enables unsymmetric 1,1-difunctionalization to forge challenging and important oxo quaternary carbon centers. Combining experiments and DFT calculations on the mechanism of the reaction is investigated in detail.

Full text of DOI:10.1021/jacs.9b04142

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Article
Site-Selective 1,1-Difunctionalization of Unactivated
Alkenes Enabled by Cationic Palladium Catalysis
Jinwon Jeon, Ho Ryu, Changseok Lee, Dasol Cho, Mu-Hyun Baik, and Sungwoo Hong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b04142 • Publication Date (Web): 31 May 2019
Downloaded from http://pubs.acs.org on May 31, 2019
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Site-Selective 1,1-Difunctionalization of Unactivated Alkenes
Enabled by Cationic Palladium Catalysis
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Jinwon Jeon, Ho Ryu, Changseok Lee, Dasol Cho, Mu-Hyun Baik,* and Sungwoo Hong*
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Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Korea
Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon, 34141, Korea
Supporting Information Placeholder
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ABSTRACT: A palladium(II)-catalyzed 1,1-difunctionalization of unactivated terminal and internal alkenes via addition of two
nucleophiles was developed using a cationic palladium(II) complex. The palladacycle generated in situ as a result of a
regioselective addition of a nucleophile to the alkene can readily undergo regioselective β-hydride elimination and migratory
insertion with a cationic palladium catalyst. The resulting η3-π-allyl palladium(II) complex is the key intermediate that reacts with
a second nucleophile to furnish the desired 1,1-difunctionalization of the alkene. Under the optimized reaction conditions, a wide
range of indoles and anilines add to alkene units of 3-butenoic or 4-pentenoic acid derivatives to afford the synthetically useful
γ,γ- or δ,δ-difunctionalized products with excellent regiocontrol. Furthermore, by employing internal hydroxyl or acid groups
and external carbon nucleophiles, this transformation enables unsymmetric 1,1-difunctionalization to forge challenging and
important oxo quaternary carbon centers. Combining experiments and DFT calculations on the mechanism of the reaction is
investigated in detail.
INTRODUCTION
Palladium-catalyzed difunctionalization1 of alkenes is a powerful synthetic tool for rapidly accessing structural motifs
found in a variety of valuable building blocks of pharmaceuticals and natural products.2 Through alkene polarization by π-Lewis
acid activation of a transition metal, two functional groups could be installed across a double bond in an atom-economical
fashion.3 Difunctionalization of alkenes catalyzed by high-valent palladium4 species was extensively explored by Michael,5
Muñiz,6 Sanford,7 Liu8 and Stahl.9 A strategy that uses special tethering has been widely used for the regioselective
functionalization of unactivated alkenes. In particular, preorganized directing groups often allow a favorable substrate binding to
the catalyst, which enables intramolecular reactions with high reactivity and regioselectivity.10 Recently, a series of palladium(II)-
catalyzed β,γ-vicinal difunctionalizations of unactivated alkenes11 was described by the Engle12 utilizing an amide-linked
aminoquinoline (AQ) directing group for the regioselective addition to a Pd(II)-bound alkene. The palladacycle generated in this
process is thought to undergo either protodepalladation or oxidative addition with electrophiles. Bidentate directing groups13 used
in this transformation guide the regioselective installation of nucleophiles, wherein the conformational rigidity of the directing
group is believed to suppress competing β-hydride (β-H) elimination reaction, allowing the alkylpalladium species to be
intercepted by a proton source to give a hydrofunctionalized product.14 In contrast to the remarkable advances in 1,2-vicinal
difunctionalization, a similar strategy for 1,1-geminal difunctionalization of unactivated alkenes by two nucleophiles has
remained elusive to date,15-19 despite being tremendously attractive from synthetic perspectives. Sanford reported the 1,1-aryl
halogenation of alkenes using arylstannanes,15 and Sigman16 and Toste17 have described Pd-catalyzed 1,1-diarylation and 1,1-
arylborylation of alkenes. Recently, Brown also reported the 1,1-arylboration of α-methyl vinyl arenes.18 In these examples,
prefunctionalization of the aryl source as boronic acids or aryldiazonium salts are required for successful arylation. Moreover,
these reactions were applied only to terminal alkenes limiting the overall synthetic flexibility. Finally, the formation of quaternary
carbon centers has thus far remained out of reach.
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Scheme 1. State-of-Art Strategies for Pd-Catalyzed Alkene Difunctionalization.
a) 1,1-Arylchlorination of terminal alkene (Sanford)
4
5
Ph
Pd(II)
R
CuCl2
Ph-SnBu3
R
Cl
6
7
8
9
b) 1,1-Diarylation and arylborylation of terminal alkene (Sigman, Toste)
O
E
O
Pd(0)
Ar-N2BF4
E-X
OR
Ar
OR
CAPT cat
E = Ar' or Bpin
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c) Site selective difunctionalization of unactivated alkene
O
Nu
O
Nu
R
O
Pd(II)
Nu-H
(Engle)
1,2-
DG
X
R
DG
Pd DG
H
R
X = H+ or E+
regioselective
-H-elimination
[Pd]+
This work
Nu
R
Nu
Nu
Nu
Nu
O
O
O
1,1-
1,1-
DG
R
H
H
DG
DG
Pd
H
R = Nu
Drawing inspiration from the aforementioned studies, we wondered if a synthetically useful regioselective 1,1-
difunctionalization of nonconjugated alkenes could be developed via addition of two nucleophiles. We envisioned a strategy that
takes advantage of β-H elimination from the palladacycle complex to regenerate an olefin moiety, which sets the stage for a
second nucleopalladation. Such an approach has not been successful to date, largely because of the conformational rigidity of the
stable palladium-bound bidentate directing group, suggesting that the structural flexibility should be increased to enable β-H
elimination.14a,14b,20 The Engle group observed the formation of a 1,1-difunctionalized product using a 4-pentenoic-acid-derived
substrate probably generated from a less stable six-membered palladacycle, although a mixture of hydrofunctionalized and 1,1-
difunctionalized products was obtained in 45% and 30% yield respectively.14b As depicted in Figure 1, we imagined that a cationic
Pd(II)-bound bidentate directing group21 might enable β-H elimination of the palladacycle complex and subsequent olefin
insertion,16c,22 which would present a new opportunity for a second nucleophile to form the 1,1-difunctionalized product. Herein,
we report the discovery of a new catalytic platform by strategic use of a cationic palladium species to enable the 1,1-
difunctionalization of unactivated alkenes at either the γ- or δ- position, which is suitable and applicable to both terminal and
internal alkene substrates. Moreover, this new protocol is highly effective in unsymmetric 1,1-difunctionalization of alkenes
bearing tethered hydroxyl or carboxylic acid groups, which promotes regioselective palladation for the rapid buildup of molecular
complexity with oxo quaternary carbon centers under mild reaction conditions.
cationic
Pd
bidentate
DG
O
O
O
H
N
N
N
N
PdII
PdII
N
PdII
-H elimination
high 1,1-regioselectivity
& reactivity
low regioselectivity
& reactivity
no -H elimination
Figure 1. Design plan for cationic Pd(II)-catalyzed 1,1-difunctionalization of alkenes via addition of two nucleophiles.
RESULTS AND DISCUSSION
First, we set out to develop a general method that invokes β-H elimination of a palladacycle intermediate and
successfully enables 1,1-difunctionalization of unactivated alkenes. The feasibility of the proposed process was investigated using
the 3-butenoic acid derivative 1a bearing an 8-aminoquinoline (AQ) directing group as the model substrate and methylindole 2a
as the coupling partner (Table 1). In the presence of 10 mol % Pd(OAc)2 as the catalyst, only mono-indolylated product 3a’ could
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be observed in 18% yield (entry 1). The addition of AgOAc did not promote the desired reaction and resulted in minimal yield
(entry 2). Switching AgOAc to AgOH produced a higher yield of 37% of the mono-indolylated product 3a’ but failed to give
detectable quantities of the 1,1-difunctionalized product 3a (entry 3). Remarkably, the addition of AgBF4 was critical for the
success of the 1,1-difunctionalization process to afford the corresponding product 3a in 70% yield, with minimal formation of
3a’ (3a/3a’ = 25:1) (entry 4). Various metal salt sources were screened, and copper salts were also reactive under these conditions,
although they afforded a diminished product yield of 67% of 3a (see the Table S2 for details). We continued our optimization
efforts by evaluating the effect of counteranions, and AgSbF6 displayed the best activity, yielding the desired product 3a in 82%
yield (entry 6). Among the solvents screened, acetonitrile was most efficient for this reaction. Interestingly, further optimization
revealed that the addition of benzoquinone (BQ) accelerated the overall reaction rate, and the reaction was completed within 7
hours (entry 9). Finally, we found that by reducing the AgSbF6 loading to 10 mol%, the reaction performs comparably well and
that 3a was generated in 80% yield, albeit requiring a longer reaction time (entry 10). As expected, control experiments confirmed
that the Pd-catalyst was required for this reaction (entry 11).
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Table1. Optimization of Reaction Conditions.a
N
O
Pd(OAc)2
additive
O
N
O
N
AQ
N
H
50 C, O2
AQ
N
3a'
N
(AQ)
1a
2a
3a
Entry
1
additive (mol %)
-
solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCE
yield (3a/3a’, %)b
0 / 18
2
AgOAc (50)
AcOH (50)
0 / 3
3
0 / 37
4
AgBF4 (50)
AgPF6 (50)
AgSbF6 (50)
AgSbF6 (50)
AgSbF6 (50)
AgSbF6 (50), BQ (10)
AgSbF6 (10)
AgSbF6 (50)
AgSbF6 (50)
70 / <3
53 / <3
82 / <3
18 / 56
38 / 17
81 / <3
80 / <3
0 / 0
5
6
7
8
DMF
9c
10d
11e
12f
MeCN
MeCN
MeCN
MeCN
40 / <2
aReaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), Pd(OAc)2 (10 mol %), additive and solvent (0.3 mL) at 50 ⚬C for 48 h in
capped test tube under O2 condition. bYields were determined by 1H NMR. cThe reaction was conducted for 7 h. dThe reaction
was conducted for 72 h. eNo Pd(OAc)2. fThe reaction was conducted under an air atmosphere. BQ = 1,4-Benzoquinone.
With these optimized reaction conditions in hand, we next investigated the substrate scope with respect to both β,γ-
alkene substrates 1 and coupling partners 2. As summarized in Table 2, indoles containing various functional groups were
successfully engaged and afforded γ,γ-difunctionalized products. The reaction with N–H free indole (3b) also afforded the
corresponding products. We were pleased to observe that indoles bearing different substitution patterns such as methyl (3g, 3j),
methoxy (3c), fluoro (3d, 3k), chloro (3e, 3l), bromo (3f, 3m), trifluoromethyl (3h) or trifluoromethoxy (3i) groups reacted well
to afford the desired products under the optimized reaction conditions. In particular, chloro and bromo groups were intact under
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the standard reaction conditions to provide products 3e, 3l, 3f, and 3m, respectively, thus enabling further synthetic
functionalizations. In addition, the scope could be expanded to azaindole by increasing the amount of Ag additive (50 mol%),
which afforded the corresponding product 3n. Various aniline derivatives were competent nucleophiles as well, allowing the
formation of 3o, 3p, and 3q. Similarly, alkene substrates bearing various substituents at the α-position, as exemplified by methyl,
isopropyl, and benzyl groups, also readily participated in the reaction and provided the desired products 3r, 3s, 3t, and 3u. Notably,
exploration of alkene scope demonstrated that not only terminal alkenes, but also internal alkenes could be well accommodated
in this protocol to construct quaternary carbon centers (3v, 3w, 3x, and 3y), which would be otherwise difficult to synthesize The
utility of the present method was further broadened by reaction with cyclic alkene substrates such as cyclopentene or cyclohexene
motifs, which provided the products 3z and 3aa. When two different external nucleophiles (2a and 2b) were used, a mixture of
products (3a, 27% / 3af, 37% / 3b, 6%) was obtained (see the Scheme S19 for details).
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Table 2. Substrate Scope of Nucleophiles and β,γ-Alkenes.a,b
O
Pd(OAc)2 (10 mol%)
AgSbF6 (10 mol%)
O
R3
R3
Nu
N
NuH
AQ
H
MeCN, O2, 50 
C
Nu
R1 R2
R1 R2
N
2
(AQ)
1
3
H
N
N
N
N
O
O
O
O
AQ
AQ
AQ
R
AQ
MeO
OMe
R
N
N
N
N
H
3a
3b
, 70%
, 80%
3c
3d
3e
, 81%
, R = F,
76%c
74%d
50%d
71%d
71%d,e
50%d
, R = Cl,
, R = Br,
N
3f
O
N
N
O
O
3g
, R = Me,
, R = CF3,
, R = OCF3,
N
AQ
AQ
AQ
R
3h
3i
N
N
N
N
R
72%d
71%d
65%d
3k
, R = F,
R = Cl,
e
3j
, 64%
3n
, 53%
3l
,
3m
, R = Br,
N
N
N
O
O
O
O
N
O
AQ
AQ
AQ
AQ
O
N
N
N
N
3p, 44%
e
e
3o
, 37%
3r
3q
, 51%
, 53%
O
O
N
N
O
O
AQ
AQ
R
AQ
AQ
R
N
N
N
N
N
N
, R = Me, 79%e
, R = Me,
82%
56%
3z
, 59%
3aa
, 60%
3s
3t
3v
i
78%
3w
3x
, R = Pr,
, R = Bn,
71%e
3u
, R = C3H6-NPhth, 63%
, R = Bn,
e
3y
, R = C H -CO Me,
70%
3
6
2
aReaction conditions: 1 (0.2 mmol), 2 (0.6 mmol), Pd(OAc)2 (10 mol%), AgSbF6 (10 mol%) in MeCN (0.3 mL) for 18-72 h in
capped test tube under O2 condition. bYields of the isolated products. c1,4-Benzoquinone (10 mol%) was added at 60 ⚬C. dPd (10
mol%), AgSbF6 (10 mol%), 1,4-benzoquinone (20 mol%) were added at 60 ⚬C. eAgSbF6 (0.10 mmol) was used.
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To further explore the scope of the reaction, we next sought to extend this concept from β,γ-alkenes to γ,δ-alkenes. A
brief optimization revealed that room temperature was sufficient to conduct δ,δ-difunctionalization via formation of larger 6-
membered palladacycles. Under slightly modified conditions, the indole scope for γ,δ-alkenes 4 was similar to that observed for
β,γ-alkenes 1, as illustrated in Table 3. Alkene substrates bearing α- or β-substituents reacted well, affording the corresponding
products 5e, 5f, and 5g. Importantly, internal alkenes also exhibit moderate to good reactivity, demonstrating the ability of this
method to forge quaternary carbon centers at the δ-position (5h, 5i, and 5j). Interestingly, we observed that allyl-alcohol-derived
substrates bearing an AQ carbamate group underwent this transformation to afford δ,δ-difunctionalized products 5k and 5l.
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Table 3. Substrate Scope of Nucleophiles and γ,δ-Alkenes.a,b
R3
O
Nu R3
R4
O
Pd(OAc)2 (10 mol%)
AgSbF6 (50 mol%)
R4
N
H
NuH
Nu
AQ
NH
R1 R2
N
R1 R2
2
MeCN, O2, rt
4
5
(AQ)
N
NH
N
Cl
MeO
O
O
O
O
AQ
AQ
HN
N
AQ
AQ
HN
N
Cl
d
OMe
N
5a
, 79%
5b
, 73%
5c
5d
, 61%
, 83%
N
N
N
O
O
O
O
AQ
AQ
AQ
AQ
N
N
N
N
R
c
c
5g
, 88%
5f
, 54%
89%c
58%d
5e
, 79%
O
5h
, R = Me,
5i
, R = C2H5Ph,
N
N
AQ
O
O
O
AQ
O
AQ
N
N
N
N
c
d
d
5j
, 48%
5k
, 36%
5l
, 34%
aReaction conditions: 4 (0.2 mmol), 2 (0.6 mmol), Pd(OAc)2 (10 mol%), AgSbF6 (50 mol%) in MeCN (0.3 mL) for 24-72 h in
capped test tube under O2 condition. bYields of the isolated products. c1,4-Benzoquinone (10 mol%) was added. dPd(10 mol%),
1,4-benzoquinone (20 mol%) were added.
Unlike the conventional difunctionalization approach using a nucleophile and electrophile set, installation of two
different nucleophiles at the same position of the unactivated alkene has been rarely studied.23 We speculated that the use of an
internal hydroxyl nucleophile might enable regioselective palladium-catalyzed intramolecular C–O bond formation,24 wherein
the subsequent addition of external nucleophiles would provide the opportunity to rapidly generate a variety of cyclic ether
scaffolds with oxo quaternary carbon centers. To apply the designed strategy, substrate 6a containing the pendant alcohol on the
olefin chain was selected as a model substrate. Gratifyingly, we observed that the desired product 7a was formed in 55% yield
with only minimal formation of the bisindolylated side product (<3%) under the standard reaction conditions (see the Table S3
for details). This result indicates that the rate of intramolecular reaction of the hydroxyl group is faster than that of the
intermolecular reaction of the indole nucleophile. Using the standard conditions, we next examined the scope of this
transformation, demonstrating that both 5-membered and 6-membered cyclic ethers could be constructed with various indoles
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(7a-7g). Importantly, the scope could be expanded to the quaternary lactone structures (7h, 7i, 7j) by employing internal
carboxylic acid as nucleophiles. The reaction was also compatible with the internal phenol nucleophile (7k). Beyond β,γ-
unsaturated alkenyl alcohols, γ,δ-alkene substrates could be used in this transformation to afford the corresponding products (7l,
7m, 7n).
Table 4. Substrate Scope of Unsymmetric Nucleophiles.a,b
8
9
R1
Pd(OAc)2 (10 mol%)
AgSbF6 (10 mol%)
R1
N
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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25
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30
31
32
33
34
35
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37
38
39
40
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50
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58
59
60
R2
N
O
N
H
n
MeCN/PhMe (1:9)
60 C, air
AQ
N
n
OH
R2
O
2
6
(AQ)
X
7
X
X = H2 or O
N
O
NH
NH
N
MeO
AQ
O
O
O
O
AQ
AQ
AQ
O
O
7c
O
7a
7b
7d
, 58%
, 55%
N
, 47%
, 56%
N
O
NH
NH
O
F
O
O
MeO
O
AQ
AQ
AQ
AQ
O
O
O
O
c
7g
, 46%
7f
7h
, 56%
, 56%
NH
7e
, 58%
N
NH
O
O
MeO
O
O
O
AQ
AQ
AQ
AQ
AQ
O
O
O
N
O
7j
O
d
c
7l
c
, 53%
, 56%
7k
, 36%
7i
, 54%
O
O
O
O
AQ
OMe
HN
HN
d
d
7m
, 50%
7n
, 36%
aReaction conditions: 6 (0.1 mmol), 2 (0.15 mmol), Pd(OAc)2 (10 mol%), AgSbF6 (10 mol%) in MeCN/PhMe (1:9, 1.0 mL) at
60 C for 48-72 h in capped test tube under an air atmosphere. Yields of the isolated products. MeCN (1.0 mL) was used as
solvent at 80 ⚬C. d1,4-Benzoquinone (20 mol%) was added.
⚬
b
c
To demonstrate the efficiency of this Pd(II)-catalyzed alkene 1,1-difunctionalization method, we subsequently
performed the reaction with alkene substrate 1a, and N-methylindole (2a), on the 2.0 mmol scale, and the reaction performance
was consistent with that of smaller-scale reactions. After 1,1-difunctionalization, the 8-aminoquinoline directing group was then
conveniently removed via hydrolysis (see the Scheme S10 and S11 for details).
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Figure 2. Computed energy profile of Pd(II)-catalyzed γ-mono-functionalization of the unactivated alkene with N-methylindole.
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Details of the isomerization are presented in the Supporting information (see the Figure S5).
We next carried out density functional theory (DFT) calculations to propose a plausible mechanism25 that unifies and
conceptualizes the experimental findings. Figure 2 shows the computed energy profile of the Pd(II)-catalyzed γ-mono-
functionalization of the unactivated alkene with N-methylindole. The catalytic cycle proceeds via an outer-sphere mechanism to
afford γ-functionalized intermediate A7o. As indicated by entry 6-8 in Table 1, acetonitrile can stabilize the cationic species
whereas DCE and DMF likely facilitate the addition of an anionic ligand to the Pd(II) center26 rendering the overall charge of the
–
catalyst to become neutral. Moreover, a weakly coordinating anion SbF6 stabilizes the cationic Pd(II) complexes.27 These
observations are consistent with a catalytic cycle that starts with the cationic Pd(II) complex A3 where the Pd(II) center binds the
terminal alkene bearing the AQ directing group. As anticipated, the reaction proceeds via nucleopalladation where N-
methylindole acts as a nucleophile and attacks the γ-position of the terminal alkene, traversing the transition state A3-TS with a
barrier of 24.7 kcal/mol to give rise to 5-membered palladacycle intermediate A4. From the A4, the C3-proton of the substituted
N-methylindole is shifted to the nitrogen of the amide group, generating γ-mono-indolylated 5-membered ring intermediate A5.
The intramolecular deprotonation renders the directing group hemilabile as the amide moiety becomes protonated and thus is
converted from an X-type ligand to an L-type ligand. Intermediate A5o, which is readily obtained by isomerization from the A5,
can β-hydride eliminate with an activation barrier of 19.0 kcal/mol, resulting in the Pd–H intermediate A6o. Intermediate A6o
readily isomerizes to the intermediate A6q, and migratory insertion of the alkene into the Pd–hydride bond can take place. As the
ring strain is released and the η3-π-allyl interaction is obtained, the highly stabilized η3-π-allyl Pd(II) intermediate A7o is
generated.
Our calculations can be used to more precisely probe why the cationic nature of the Pd-catalyst is so important for
catalysis. More specifically, it is the difference between adding a strongly coordinating solvent such as acetonitrile to the fourth
coordination site, which will render the Pd(II) complex cationic. If the charge of the Pd(II) complex is neutralized by a strongly
coordinating anionic ligand, such as an amide, the structural flexibility of the catalyst is reduced significantly, as will be shown
below. In the cationic Pd-catalyst, the directing group becomes hemilabile and allows for significant deviations from the ground
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state geometry. To test the feasibility of these various coordination geometries, we selected substrate 1ae bearing the MeAQ
directing group in the absence of a free N–H bond that strongly coordinates with Pd(II). Experimentally the γ,γ-difunctionalized
product was observed selectively in 13% yield. As illustrated in Scheme 2, two coordination modes can be envisioned, and our
calculations suggest that A5o is the most stable intermediate among the isomers. Adopting the O-binding motif creates a
conjugated π-system with the amide group parallelized with the AQ moiety (see the Figure S5 for details).
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Scheme 2. Possible Binding Modes of MeAQ Directing Group
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O
N-binding
mode
Me
N
PdII
N
N
N
O
standard
condition
O
N
MeAQ
N
Me
1ae
N
N
(MeAQ)
3ae
13%
,
MeAQ
O
PdII
O-binding
mode
N
Scheme 3. Deuterium Labeling Experiments
a) Deuterium migration experiment
81% D
N
D
O
O
standard
condition
N
D
N
AQ
N
H
D
N
D
d2-4a
2a
D
72%
migration
(AQ)
d -5a
, 78%
2
b) Crossover experiment
H
O
N
N
H
AQ
standard
condition
O
O
4e
2a
AQ
AQ
N
N
D
D
O
6 equiv
D
D
AQ
5e
, 71%
d2-4a
d -5a
, 74%
2
no crossover
N
c) KIE experiment
standard
condition
O
H/D
H/D
O
2a
3 equiv
AQ
AQ
N
H/D
H/D
5a 2-5a
d
/
4a d -4a
/
2
KH/KD = 1.1
To probe whether an alkylpalladium(II) species can undergo β-H elimination during the reaction, we conducted
deuterium-labeling experiments by subjecting substrate d2-4a (81% deuterium content) to the standard reaction conditions
(Scheme 3). This deuterium experiment illustrated that one of the deuterium atoms migrated to the γ-position of the carbonyl
group, supporting a mechanism that invokes β-H elimination.3a,16a,28 Furthermore, crossover experiment was performed with 4e
and d2-4a as substrates, and only products 5e and d2-5a were observed from 4e and d2-4a, respectively, indicating that the
coordinated alkene does not dissociate prior to olefin insertion into the Pd–H species.3a,16a We have conducted the kinetic isotope
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effect (KIE) experiment with 4a and d2-4a as substrates, in which the KH/KD ratio was found to be 1.1, which indicates that the
β-hydride elimination/migratory insertion steps are not involved in a turnover-limiting step in a significant way.
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Figure 3. Comparison of a) cationic and b) neutral pathways of β-H elimination & migratory insertion step and the electronic
structures of the transition states: c) A5o-TS, d) A6q-TS, e) D1-TS and f) D2-TS. Nonessential hydrogen atoms are omitted for
clarity. The unit of free energy in parentheses is kcal/mol.
Figure 3 shows the comparison of activation barriers of β-H elimination and migratory insertion steps using a cationic
and a neutral Pd-catalyst. The step barrier of the β-H elimination ~19 kcal/mol regardless of the charge of the catalyst. But the
transition state of the migratory insertion using the neutral catalyst, D2-TS, is located at 40.2 kcal/mol, whereas the corresponding
transition state for the cationic catalyst, A6q-TS, is found at 18.3 kcal/mol. The reason for this notable difference is that a penalty
derived from breaking the coordination between the Pd(II) center and the nitrogen of the anionic amide ligand is significant,
whereas the cationic catalyst can easily accommodate this insertion by loosening the Pd-acetonitrile bonding with little energetic
penalty.
Scheme 4. Possible Pathways for γ,γ-Difunctionalization (Nucleopalladation vs. Migratory Insertion)
H
N
N
PdLn
O
reductive
N
O
elimination
AQ
nucleo-
palladation
AQ
N
H
PdLn
O
N
nucleopalladation
pathway
AQ
migratory
insertion
N
3a
-allyl
formation
N
nucleophilic
addition
N
H
O
O
PdLn
AQ
AQ
N
PdLn
Pd-H migratory insertion
pathway
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Scheme 5. Control Experiments Using Monodentate Directing Group
3
4
O
N
N
O
standard
condition
DG
N
5
O
O
DG
6
7
8
9
DG
DG
N
N
N
N
C
B
A
not detected
-nucleopalladation
DG
migratory
insertion
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X
A
B
C
:
nucleopalladation
-H elimination
:
H
LnPd
N
O
O
N
45% : 29% : 0
42% : 37% : 0
DG
H
DG
N
H
PdLn
OMe
B'
A'
Next, we questioned whether the mechanism of the second nucleophilic attack could proceed via nucleopalladation or
via migratory insertion of the alkene into the Pd–H species (Scheme 4). To account for the insertion mode of the second
nucleophile, we attempted to expose the substrate bearing the aniline monodentate directing group to the optimized reaction
conditions and took note of the connectivity of the products (Scheme 5). Notably, a mixture of γ,γ- and β,β-difunctionalized
products A and B (1.7 : 1 ratio) was obtained without the formation of β,γ-difunctionalized product C. Similar results were
observed when an analogous experiment with ester groups was carried out. As expected, the lack of selectivity confirms the
importance of the bidentate directing group for the first regioselective nucleophilic attack on the alkene by forming the
palladacycle. After the nucleopalladation, a mixture of the resulting β- or γ-functionalized alkylpalladium(II) species are likely
to undergo β-H elimination to afford two isomeric olefin products A’ and B’. If nucleopalladation of B’ with indole were operative,
one would expect the indole to be installed at the γ-position to afford β,γ-difunctionalized product C. However, we only observed
1,1-difunctionalized products, which could potentially be due to the involvement of a stable π-allyl Pd(II) complex via migratory
insertion into the Pd–H species.16b,16c,29 Considering this control experimental result, we proposed that after the first
nucleopalladation, β-H elimination and migratory insertion of the alkene into the Pd–H species proceed for the formation of the
η3-π-allyl Pd(II) complex, which reacts with a second nucleophile to provide the 1,1-difunctionalized product.
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Figure 4. a) Computed energy profile of Pd-catalyst exchange step and SN2 reaction. The electronic structures of the transition
states: b) A8-TS and c) A7a-TS. Nonessential hydrogen atoms are omitted for clarity.
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8
Along with the control experiments, additional DFT calculations were conducted to complete a plausible mechanism.
Figure 4 compares two possible reaction pathways that begin with the η3-π-allyl Pd(II) intermediate A7o. One pathway starts
with isomerization to the A7o, which gives a slightly less stable intermediate A8 at –5.3 kcal/mol followed by the reduction of
the Pd(II) center, passing through the transition state A8-TS at 10.7 kcal/mol to afford the Pd(0) complex A9. Next, the Pd(II)/(0)
exchange takes place as an irreversible process since the Pd(0) is rapidly consumed to regenerate Pd(II)OAc2 using dioxygen and
two equivalents of acetic acids.30 On the other hand, the opposite pathway via SN2 reaction at γ-position of the A7a is initiated
with a calculated barrier of A7a-TS located at 24.1 kcal/mol, which is too high to be mechanistically acceptable under the
experimental conditions.
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Figure 5. Computed energy profile of the Pd(II)-catalyzed γ-di-functionalization of the unactivated alkene with N-methylindole.
Our calculations unveiled that the dicationic reaction pathway, which starts from intermediate A10 is the only reasonable
–
reaction pathway that affords the desired product. The computed reaction profile suggests that a weakly-coordinating anion SbF6
is necessary to stabilize the dicationic potential surface in solution. Figure 5 shows the second indolylation of the substrate. From
the A10, N–H deprotonation takes place with a negligible barrier of 2.6 kcal/mol. The resting state A12 of the second cycle
consists of palladium(II) catalyst and cationic indolyl substrate. At the intermediate A12, the N-methylindole attacks electrophilic
γ-position to afford γ-di-functionalized intermediate via outer-sphere nucleophilic addition of the transition state A12-TS at 9.4
kcal/mol. The nucleophilic addition of the second indole takes place with a moderate barrier of 15.2 kcal/mol. Subsequently, the
oxygen of the intra- amide deprotonates indolyl proton to generate the iminol intermediate A14. Finally, isomerization from A14
gives rise to thermodynamically stable product A15.
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Scheme 6. Proposed Catalytic Cycle
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4
5
6
7
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9
Substrate
O
O
Pd
[Pd(OAc)]+
Product
O
N
Nucleo-
palladation
2
N
HO
N
Pd
N
A3
+
O
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N
Pd
H
N
Nu
N
N
Pd
N
A14
A5
Nucleophilic
addition
Hydride
elimination
Dicationic
pathway
Nu
+
O
AQ
2
N
N
O
Pd
H
N
Pd
Cationic
pathway
A12
A6o
+
N
AQ
+
AQ
[Pd0] / [PdII]
exchange
O
O
Pd
Migratory
insertion
Pd
N
N
[PdII]
Reduction
A9
Nu = N-Me-indole
A7o
Based on the aforementioned results and computational studies, a plausible catalytic cycle is shown in Scheme 6.
Initially, palladium(II) binds to the olefin and directing group, which facilitates π-Lewis acid activation. Subsequently, a carbon
nucleophile, such as N-methylindole, attacks the alkene to generate the alkylpalladium(II) intermediate A5.14b After the initial
addition of a nucleophile to the γ-carbon, the in situ generated stable 5-membered palladacycle A5 can undergo regioselective
β-H elimination and subsequent migratory insertion under cationic palladium catalytic system to form η3-π-allyl Pd(II)
intermediate A7o. Next, N-methylindole attacks the electrophilic γ-position to afford the γ,γ-difunctionalized product via outer-
sphere nucleophilic addition.
CONCLUSIONS
In summary, we have developed a catalytic method for the 1,1-difunctionalization of simple alkenes using a cationic
Pd(II) complex. Key to the development of this method was the identification of AgSbF6 in the presence of a Pd-catalyst to enable
a regioselective β-H elimination of the palladacycle and subsequent migratory insertion. Under the cationic Pd(II) catalytic system,
the addition of two nucleophiles could be achieved as a strategy for alkene 1,1-difunctionalization. This work represents the first
example of installation of two nucleophiles at the same position of the unactivated terminal and internal alkenes, allowing for
nearly exclusive formation of the synthetically useful γ,γ- or δ,δ-difunctionalized products. Furthermore, by employing internal
hydroxy groups and external carbon nucleophiles, this methodology enables unsymmetric 1,1-difunctionalization to forge
previously challenging and important oxo quaternary carbon centers. Combined experiments and DFT calculations clarified the
origin of the reactivity and catalytic cycle for achieving alkene 1,1-difunctionalization.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publication website at DOI: xx.xx/jacs.xxxx.
Experimental procedures, characterization data, and copies of NMR spectra for all products. Computed energy components, Cartesian
coordinates, vibrational frequencies of all of the DFT-optimized structures.
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AUTHOR INFORMATION
Corresponding Author
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*E-mail: hongorg@kaist.ac.kr
*E-mail: mbaik2805@kaist.ac.kr
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ORCID
Ho Ryu: 0000-0001-8450-991X
Mu-Hyun Baik: 0000-0002-8832-8187
Sungwoo Hong: 0000-0001-9371-1730
NOTES
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research was supported financially by Institute for Basic Science (IBS-R10-A1 and IBS-R10-A2).
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(12) (a) Liu, Z.; Zeng, T.; Yang, K. S.; Engle, K. M. β,γ-Vicinal Dicarbofunctionalization of Alkenyl Carbonyl Compounds via Directed
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Z.; Ni, H.-Q.; Zeng, T.; Engle, K. M. Catalytic Carbo- and Aminoboration of Alkenyl Carbonyl Compounds via Five- and Six-
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(13) For selected examples of regioselective functionalization using bidentate directing group, see: (a) Rouquet, G.; Chatani, N. Catalytic
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(b) Aihara, Y.; Chatani, N. Nickel-Catalyzed Direct Arylation of C(sp3)–H Bonds in Aliphatic Amides via Bidentate-Chelation
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Deng, Z.; Wang, H.; He, G.; Peng, Q.; Chen, G. Pd(0)-Catalyzed Bidentate Auxiliary Directed Enantioselective Benzylic C–H
Arylation of 3-Arylpropanamides Using the BINOL Phosphoramidite Ligand. ACS Catal. 2018, 8, 11502. (e) Yan, S.-Y.; Han, Y.-
Q.; Yao, Q.-J.; Nie, X.-L.; Liu, L.; Shi, B.-F. Palladium(II)-Catalyzed Enantioselective Arylation of Unbiased Methylene C(sp3)–H
Bonds Enabled by a 2-Pyridinylisopropyl Auxiliary and Chiral Phosphoric Acids. Angew. Chem. Int. Ed. 2018, 57, 9093. (f) Han, Y.-
Q.; Ding, Y.; Zhou, T.; Yan, S.-Y.; Song, H.; Shi, B.-F. Pd(II)-Catalyzed Enantioselective Alkynylation of Unbiased Methylene
C(sp3)–H Bonds Using 3,3’-Fluorinated-BINOL as a Chiral Ligand. J. Am. Chem. Soc. 2019, 141, 4558.
(14) (a) Gurak, J. A., Jr.; Yang, K. S.; Liu, Z.; Engle, K. M. Directed, Regiocontrolled Hydroamination of Unactivated Alkenes via
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Regioselective Hydrocarbofunctionalization of Unactivated Alkenes with Diverse C–H Nucleophiles. J. Am. Chem. Soc. 2016, 138,
14705. (c) Nimmagadda, S. K.; Liu, M.; Karunananda, M. K.; Gao, D.-W.; Apolinar, O.; Chen, J. S.; Liu, P.; Engle, K. M. Catalytic,
Enantioselective α-Alkylation of Azlactones with Nonconjugated Alkenes by Directed Nucleopalladation. Angew. Chem. Int. Ed.
2019, 58, 3923.
(15) (a) Kalyani, D.; Sanford, M. S. Oxidatively Intercepting Heck Intermediates: Pd-Catalyzed 1,2- and 1,1-Arylhalogenation of Alkenes.
J. Am. Chem. Soc. 2008, 130, 2150. (b) Satterfield, A. D.; Kubota, A.; Sanford, M. S. Palladium-Catalyzed 1,1-Aryloxygenation of
Terminal Olefins. Org. Lett. 2011, 13, 1076.
(16) (a) Urkalan, K. B.; Sigman, M. S. Palladium-Catalyzed Oxidative Intermolecular Difunctionalization of Terminal Alkenes with
Organostannanes and Molecular Oxygen. Angew. Chem. Int. Ed. 2009, 48, 3146. (b) Saini, V.; Sigman, M. S. Palladium-Catalyzed
1,1-Difunctionalization of Ethylene. J. Am. Chem. Soc. 2012, 134, 11372. (c) Yamamoto, E.; Hilton, M. J.; Orlandi, M.; Saini, V.;
Toste, F. D.; Sigman, M. S. Development and Analysis of a Pd(0)-Catalyzed Enantioselective 1,1-Diarylation of Acrylates Enabled
by Chiral Anion Phase Transfer. J. Am. Chem. Soc. 2016, 138, 15877.
(17) (a) He, Y.; Yang, Z.; Thornbury, R. T.; Toste, F. D. Palladium-Catalyzed Enantioselective 1,1-Fluoroarylation of Aminoalkenes. J.
Am. Chem. Soc. 2015, 137, 12207. (b) Nelson, H. M.; Williams, B. D.; Miró, J.; Toste, F. D. Enantioselective 1,1-Arylborylation of
Alkenes: Merging Chiral Anion Phase Transfer with Pd Catalysis. J. Am. Chem. Soc. 2015, 137, 3213.
(18) Bergmann, A. M.; Dorn, S. K.; Smith, K. B.; Logan, K. M.; Brown, M. K. Catalyst‐Controlled 1,2‐ and 1,1‐Arylboration of α‐Alkyl
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Diborylalkanes from Terminal Alkenes. Nat. Commun. 2017, 8, 345.
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Bonds. J. Am. Chem. Soc. 2010, 132, 3965.
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(21) For selected example of cationic palladium catalysis, see: Deb, A.; Hazra, A.; Peng, Q.; Paton, R. S.; Maiti, D. Detailed Mechanistic
Studies on Palladium-Catalyzed Selective C–H Olefination with Aliphatic Alkenes: A Significant Influence of Proton Shuttling. J.
Am. Chem. Soc. 2017, 139, 763.
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(22) For selected recent examples of chain walking using Pd catalysis, see: (a) Werner, E. W.; Mei, T.-S.; Burckle, A. J.; Sigman, M. S.
Enantioselective Heck Arylations of Acyclic Alkenyl Alcohols Using a Redox-Relay Strategy. Science 2012, 338, 1455. (b) Larionov,
E.; Lin, L.; Guénée, L.; Mazet, C. Scope and Mechanism in Palladium-Catalyzed Isomerizations of Highly Substituted Allylic,
Homoallylic, and Alkenyl Alcohols. J. Am. Chem. Soc. 2014, 136, 16882. (c) Mei, T.-S.; Patel, H. H.; Sigman, M. S. Enantioselective
Construction of Remote Quaternary Stereocentres. Nature 2014, 508, 340. (d) Zhang, C.; Santiago, C. B.; Crawford, J. M.; Sigman,
M. S. Enantioselective Dehydrogenative Heck Arylations of Trisubstituted Alkenes with Indoles to Construct Quaternary
Stereocenters. J. Am. Chem. Soc. 2015, 137, 15668. (e) Vasseur, A.; Bruffaerts, J.; Marek, I. Remote Functionalization through Alkene
Isomerization. Nat. Chem. 2016, 8, 209. (f) Singh, S.; Bruffaerts, J.; Vasseur, A.; Marek, I. A Unique Pd-Catalysed Heck Arylation
as a Remote Trigger for Cyclopropane Selective Ring-Opening. Nat. Commun. 2017, 8, 14200.
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(23) For selected examples of installing nucleophiles in activated position, see: (a) Kong, W.; Cui, J.; Yu, Y.; Chen, G.; Fu, C.; Ma, S.
PtCl4-Catalyzed Cyclization Reaction of β-Allenols in the Presence of Indoles. Org. Lett. 2009, 11, 1213. (b) Niu, T.; Huang, L.; Wu,
T.; Zhang, Y. FeCl3-Promoted Alkylation of Indoles by Enamides. Org. Biomol. Chem. 2011, 9, 273. (c) Young, P. C.; Hadfield, M.
S.; Arrowsmith, L.; Macleod, K. M.; Mudd, R. J.; Jordan-Hore, J. A.; Lee, A.-L. Divergent Outcomes of Gold(I)-Catalyzed Indole
Additions to 3,3-Disubstituted Cyclopropenes. Org. Lett. 2012, 14, 898. (d) Shaaban, S.; Roller, A.; Maulide, N. Visible-Light, Metal-
Free α-Amino C(sp3)–H Activation through 1,5-Hydrogen Migration: A Concise Method for the Preparation of Bis(indolyl)alkanes.
Eur. J. Org. Chem. 2015, 2015, 7643.
(24) (a) Hay, M. B.; Wolfe, J. P. Palladium-Catalyzed Synthesis of 2,1'-Disubstituted Tetrahydrofurans from γ-Hydroxy Internal Alkenes.
Evidence for Alkene Insertion into a Pd–O Bond and Stereochemical Scrambling via β-Hydride Elimination. J. Am. Chem. Soc. 2005,
127, 16468. (b) Zhang, Y. J.; Wang, F.; Zhang, W. Chelation-Induced Axially Chiral Palladium Complex System with Tetraoxazoline
Ligands for Highly Enantioselective Wacker-Type Cyclization. J. Org. Chem. 2007, 72, 9208. (c) Kim, Y.; Kim, S.-T.; Kang, D.;
Sohn, T.-I.; Jang, E.; Baik, M.-H.; Hong, S. Stereoselective Construction of Sterically Hindered Oxaspirocycles via Chiral Bidentate
Directing Group-Mediated C(sp3)–O Bond Formation. Chem. Sci. 2018, 9, 1473.
(25) For selected examples of work that combine calculations with experiments to understand the mechanisms of the Pd-catalyzed
reactions, see: (a) Mekareeya, A.; Walker, P. R.; Couce-Rios, A.; Campbell, C. D.; Steven, A.; Paton, R. S.; Anderson, E. A.
Mechanistic Insight into Palladium-Catalyzed Cycloisomerization: A Combined Experimental and Theoretical Study. J. Am. Chem.
Soc. 2017, 139, 10104. (b) Chen, G.; Gong, W.; Zhuang, Z.; Andrä, M. S.; Chen, Y.-Q.; Hong, X.; Yang, Y.-F.; Liu, T.; Houk, K. N.;
Yu, J.-Q. Ligand-Accelerated Enantioselective Methylene C(sp3)–H Bond Activation. Science 2016, 353, 1023. (c) Yang, Y.-F.; Chen,
G.; Hong, X.; Yu, J.-Q.; Houk, K. N. The Origins of Dramatic Differences in Five-Membered vs Six-Membered Chelation of Pd(II)
on Efficiency of C(sp3)–H Bond Activation. J. Am. Chem. Soc. 2017, 139, 8514. (d) Yang, Y.-F.; Hong, X.; Yu, J.-Q.; Houk, K. N.
Experimental–Computational Synergy for Selective Pd(II)-Catalyzed C–H Activation of Aryl and Alkyl Groups. Acc. Chem. Res.
2017, 50, 2853. (e) Yang, Y.; Mustard, T. J. L.; Cheong, P. H.‐Y.; Buchwald, S. L. Palladium‐Catalyzed Completely Linear‐Selective
Negishi Cross‐Coupling of Allylzinc Halides with Aryl and Vinyl Electrophiles. Angew. Chem. Int. Ed. 2013, 52, 14098.
(26) Díaz-Torres, R.; Alvarez, S. Coordinating Ability of Anions and Solvents towards Transition Metals and Lanthanides. Dalton Trans.
2011, 40, 10742.
(27) Strauss, S. H. The Search for Larger and More Weakly Coordinating Anions. Chem. Rev. 1993, 93, 927.
(28) Liao, L.; Jana, R.; Urkalan, K. B.; Sigman, M. S. A Palladium-Catalyzed Three-Component Cross-Coupling of Conjugated Dienes
or Terminal Alkenes with Vinyl Triflates and Boronic Acids. J. Am. Chem. Soc. 2011, 133, 5784.
(29) (a) Shu, W.; Jia, G.; Ma, S. Palladium-Catalyzed Three-Component Cascade Cyclization Reaction of Bisallenes with Propargylic
Carbonates and Organoboronic Acids: Efficient Construction of cis-Fused Bicyclo[4.3.0]nonenes. Angew. Chem. Int. Ed. 2009, 48,
2788. (b) Park, S.; Malcolmson, S. J. Development and Mechanistic Investigations of Enantioselective Pd-Catalyzed Intermolecular
Hydroaminations of Internal Dienes. ACS Catal. 2018, 8, 8468.
(30) Gligorich, K. M.; Sigman, M. S. Mechanistic Questions about the Reaction of Molecular Oxygen with Palladium in Oxidase Catalysis.
Angew. Chem. Int. Ed. 2006, 45, 6612.
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site-selective 1,1-difunctionalization C–H, O–H nucleophile
regioselective -H-elimination quaternary carbon center
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