Full text of DOI:10.1021/acscatal.7b03744

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Article
Pd-Catalyzed Asymmetric Cyclopropanation Reaction of Acyclic
Amides with Allyl and Polyenyl Carbonates. Experimental and
Computational Studies for the Origin of Cyclopropane Formation
Jian-Qiang Huang, Wei Liu, Bao Hui Zheng, Xiu Yan Liu, Zhen
Yang, Chang-Hua Ding, Hao Li, Qian Peng, and Xue-Long Hou
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b03744 • Publication Date (Web): 22 Jan 2018
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Pd-Catalyzed Asymmetric Cyclopropanation Reaction of Acyclic Amides with
Allyl and Polyenyl Carbonates. Experimental and Computational Studies for
the Origin of Cyclopropane Formation
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†
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†1
† 1
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1,5
JianꢀQiang Huang, Wei Liu, BaoꢀHui Zheng, Xiu Yan Liu, Zhen Yang, ChangꢀHua
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1
2,3
1,4
Ding,* Hao Li, Qian Peng,* and XueꢀLong Hou*
1
State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
2
Road, Shanghai 200032, China. State Key Laboratory of ElementoꢀOrganic Chemistry, College
3
of Chemistry, Nankai University, Tianjin 300071, China. Collaborative Innovation Center of
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Chemical Science and Engineering (Tianjin), Tianjin 300071, China. Shanghai–Hong Kong
Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, Chinese
5
Academy of Sciences, Shanghai 200032, China. University of Chinese Academy of Sciences,
Beijing, China
3
KEYWORDS: palladium catalysis, cyclopropanation, selectivity, enantioselectivity, (η ꢀ
phenylallyl)Pd complex, DFT studies
ABSTRACT: Cyclopropanes with three chiral centers were afforded in good to high yields with
dr ratio of 4ꢀ23:1 and ee of 83ꢀ99% in the reaction of acyclic amides with monosubstituted allyl
carbonates as well as polyenyl carbonates under the Pdꢀcatalysis in the presence of (Sphos,R)ꢀ
SIOCPhox L1 as the ligand, while allylic alkylated products were provided only if (Rphos,R)ꢀ
SIOCPhox L2 was the ligand. The amide group of product was easily reduced to hydroxymethyl
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group in high yield. The active reaction intermediate was determined and transition states for
cyclopropanation and allylation were calculated. The origin of cyclopropane formation was
investigated by experiments, NMR studies, Xꢀray analysis of allylꢀPdꢀligand complexes and
DFT calculations.
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INTRODUCTION
Cyclopropanes have widely been presented as the key subunit in many natural products and
biologically active compounds, as well as used also as the important building block in organic
1
2ꢀ5
synthesis. Many efficient protocols have been developed to prepare cyclopropane compounds.
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3
4
However the cyclopropanation reactions involving carbenes, carbenoids, and ylides
intermediates are among the most important approaches. Pioneering work of Hegedus, the
palladiumꢀmediated cyclopropanation via attack of a nucleophile to the central carbon of allyl
ligand of a πꢀallylpalladium chloride, revealed a new way to synthesize cyclopropanes (Scheme
6
1
a). Since then, many researches have focused on the formation of cyclopropane via the Pdꢀ
mediated reaction of allyl substrates and nucleophiles. Hoffmann confirmed the attack of
nucleophile on the central carbon of allyl ligand of πꢀallylpalladium complex by isolation of the
7
reaction intermediate formed by the nucleophilic attack on a πꢀallylpalladium complex.
Bäckvall showed that nucleophile favored to attack the terminal carbon of πꢀallylpalladium
complex using a Pdꢀcatalyst with phosphine as ligand while central carbonꢀattacked product was
8
given when nitrogen ligand was used. Musco and Santi reported a catalytic version of the
cyclopropanation reaction using 1,1'ꢀbis(diphenylphosphino)ferrocene (DPPF) as ligand to
9
produce allylation/cyclopropanation products in a ratio of 1.5ꢀ6.5:1. Satake realized
cyclopropanation using a neutral Pdꢀcatalyst, asymmetric catalytic version of the reaction was
also provided though the allylation/cyclopropanation ratio as well as the ee values were rather
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lower. Breakthrough appeared when Hayashi and coworkers reported their elegant works on
the Pdꢀcatalyzed cyclopropanation with excellent stereoselectivity, and mechanism studies
demonstrated that the electronic property of the phosphine ligand has great impact on the
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reaction. Though significant progress has been made, the types of allyl reagents and
nucleophiles suitable for the Pdꢀcatalyzed cyclopropanation were very limited. No successful
examples have appeared regarding the highly enantioselective transition metalꢀcatalyzed
cyclopropanation with allyl reagents so far. In addition, the factors controlling the selectivities of
the cyclopropanation/allylation (c/a selectivity) are far from understanding. To develop the
transition metalꢀcatalyzed asymmetric cyclopropanation in high enantioselectivity as well as to
understand the reaction mechanism in depth are great challenges.
Scheme 1. Allylation vs cyclopropanation in PdꢀCatalyzed reaction of allyl reagent with
nucleophile
We have studied the palladiumꢀcatalyzed asymmetric allylic substitution reaction for
1
2
years, During the course, we found that the nucleophile could attack the Cꢀ2 of the allyl moiety
of Pdꢀcomplex and reported a highly diastereoꢀ and enantioꢀselective Pdꢀcatalyzed
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13a
cyclopropanation of acyclic amides with substituted allyl carbonates as a communication.
Further studies revealed why the nucleophile attacks the Cꢀ2 of the allyl substrate and provided
an insight to understand the reaction mechanism by the Xꢀray diffraction analysis of single
crystals of the reaction intermediates, the Pdꢀligandꢀallyl complexes, as well as DFT
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calculations (Scheme 1b). Based upon the understanding of the reaction course, polyenyl
carbonates were applied to this Pdꢀcatalyzed cyclopropanation as well, which afforded the highly
functionalized vinylcyclopropanes bearing three continuous chiral centers. Their synthesis via
15
asymmetric and catalytic way is scarce. In this article, we report this Pdꢀcatalyzed asymmetric
cyclopropanation and related mechanism studies in detail.
RESULTS AND DISCUSSION
Pd-Catalyzed Cyclopropanation with Allyl and Polyenyl Carbonates. We have studied
1
3a
the reaction of acyclic amides 1 with monosubstituted allyl carbonates 2 under Pdꢀcatalysis,
and found that cyclopropanes 3 were afforded in good yields with high enantioselectivity by
using (Sphos,R)ꢀSIOCPhox L1 as the ligand while allylic alkylation products 4a and 5a were
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3a
obtained by employing (Rphos,R)ꢀSIOCPhox L2 as the ligand (eq 1). The investigation of the
+
ꢀ
impact of reaction parameters on the reaction revealed that the presence of both Li and Cl ions
is important for the selectivity of cyclopropanation/allylic alkylation (c/a selectivity) and
diastereoselectivity of cyclopropanation (for details, see our preliminary report, ref. 13a).
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During the experimental and theoretical studies on the origin of cyclopropane formation in
this reaction, it was found from the Xꢀray analysis of single crystals of the Pdꢀallyl complex 1
(CP1) with (Sphos,R)ꢀSIOCPhox L1 as ligand and the Pdꢀallyl complex 2 (CP2) using (Rphos,R)ꢀ
SIOCPhox L2 as ligand respectively that the conjugation between the phenyl ring and the allyl
ligand is better in CP1 than in CP2 (vide infra). DFT calculations suggested that better
conjugation should lower the energy of LUMO of the central carbon of πꢀallylpalladium
complex and facilitates the attack on it by nucleophile in the reaction using L1 as the ligand (vide
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c,16
infra).
This findings inspired us to explore other allyl substrates having the substituent
conjugated with allyl subunit for the cyclopropanation. Thus, three allyl substrates 6ꢀ8 bearing
cyano, methoxy and phenyl ethynyl group respectively, were tested (eq. 2). However, no desired
cyclopropanation occurred but the decomposition of compounds 6ꢀ8 was observed.
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Then dienyl carbonate 9a was tested because the alkene group may have better conjugation
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ability with allyl group. Pleasingly, the reaction proceeded smoothly with 2.5 mol% of [Pd(η ꢀ
C H )Cl] and 5 mol % of L1 in THF. The cyclopropane 10a and allylated products 11a and 12a
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were obtained in 90% yield, with cyclopropanation/allylation ratio being 81/19, dr being 10.5/1
and ee of 10a being 97% (entry 1, Table 1). Thus, the impact of other reaction parameters on the
cyclopropanation was studied (Table 1). Similar with that we found before, LiCl was the best
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2,13a
additive (entry 1).
When NaCl was applied as additive, both the yield and the ratio of c/a
selectivity decreased although the enantioselectivity remained excellent (entry 2). The use of NaI
led to very low c/a ratio and diastereoselectivity (entry 3). The reaction was severely retarded in
the presence of LiI (entry 4). The absence of additive resulted in a reduced yield, while the dr
and the ee values still kept excellent (entry 5). Temperature has great influence on the reaction,
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3a
which differs with that we observed before: lower temperature enabled reaction to be sluggish
and higher temperature also gave inferior results (entries 6ꢀ8 vs. entry 1). The evaluation of the
solvent effect on the reaction revealed that the solvents such as CH CN, DCE, DMSO, and DMF
3
gave poorer results (data not shown in table).
Table 1. Impact of Reaction Parameters on the Pdꢀcatalyzed Cyclopropanation of Amide 1a with
a
Dienyl Carbonate 9a
b
c
c
d
entry additive yield 10a/11a+12a dr
ee
1
LiCl 90% 81/19 10.5/1 97%
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NaCl
NaI
LiI
67%
85%
trace
66%
trace
68%
50%
70/30
31/69
ꢀꢀ
9.1/1 96%
4.5/1 ꢀꢀ
ꢀꢀ
10.4/1 97%
ꢀꢀ ꢀꢀ
ꢀꢀ
ꢀꢀ
74/26
ꢀꢀ
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9
0
e
e
e
LiCl
LiCl
LiCl
70/30
22/78
9.0/1 ꢀꢀ
6.4/1 ꢀꢀ
a
3
Molar ratio of 1a/9a/[Pd(η ꢀC H )Cl)] /L1/additive/LiHMDS = 100/115/2.5/5/100/120.
Isolated yield. Determined by GC. Determined by chiral HPLC. Reaction temperature for
entries 6, 7, and 8 is 10, 30, and 45 C respectively.
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2
b
c
d
e
o
The substrate scope of the reaction was investigated under the optimized reaction conditions
and the results are compiled in Table 2. In general, the reaction proceeded smoothly to afford
cyclopropanes 16 in high diastereoselectivity (4.1–19.9:1) and excellent enantioselectivity (93–
9
8%). The length of the alkyl chain of the amide 1 exerted little influences on the
enantioselectivity of the reaction, while the c/a ratio and diastereoselectivity decreased when the
alkyl chain was lengthened (entries 2 and 3 vs 1). For aryl substituted dienyl carbonates 9, both
electronꢀdonating and withdrawing groups of the phenyl ring were well tolerated (entries 4ꢀ8).
The use of dienyl 9 with a furyl substituent led to the cyclopropane with 97% ee (entry 9).
Remarkably, the alkyl substituted dienyls 9j and 9l were also suitable substrates for the
cyclopropanation with excellent diastereoꢀ and enantioselectivities and in moderate cyclopropane
yields (entries 10 and 12). It is noteworthy that the reaction worked well for the gemꢀ
disubstituted dienyl 9k, providing the cyclopropane in high c/a ratio, with diastereoselectivity
being 19.9/1 and enantioselectivity being 98% (entry 11).
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Table 2. Substrate Scope for the Pdꢀcatalyzed Cyclopropanation of Amides 1 with Dienyl
a
Carbonates 9
0
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2
3
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8
9
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3
4
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7
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b
c
c
d
entry
R , R , R
yield (%)
90
10/11+12
81/19
dr
ee (%)
1
2
3
4
5
6
7
8
9
a, Me, Ph, H
10.5/1
6.3/1
7.1/1
8.4/1
12.4/1
6.5/1
97
b, Et, Ph, H
83
74/26
73/27
67/33
70/30
77/23
69/31
74/26
68/32
55/45
94/6
97
96
95
>99
95
93
97
97
97
98
c, nPr, Ph, H
74
d, Me, 4ꢀFC H , H
72
6
4
e, Me, 4ꢀMeOC H , H
78
6
4
f, Me, 4ꢀBrC H , H
80
6
4
e
g, Me, 3ꢀBrC H , H
80
4.1/1
6
4
h, Me, 2ꢀnaphthyl, H
i, Me, 2ꢀfuryl, H
j, Me, Me, H
91
17.6/1
8.3/1
85
10
11
12
88
9.5/1
k, Me, Ph, Me
l, Me, ꢀC H ꢀ
83
19.9/1
14.3/1
e
70
61/39
98
5
10
a
3
b
Molar ratio of 1/9/[Pd(η ꢀC H )Cl] /L1/LiCl/LiHMDS = 100/115/2.5/5/100/120. Isolated
3
5
2
c
d
e
1
yield. Determined by GC. Determined by chiral HPLC. Determined by H NMR.
The absolute configuration of cyclopropanes 10g was determined to be (S,R,S) via the Xꢀray
diffraction analysis of its single crystal (Fig 1).
To demonstrate the potential utility of the methodology, the amide group of cyclopropane
1
0a was reduced to alcohol 13 with well retention of the diastereoꢀ and enantioselectivities (eq
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3
). The reaction on larger scale also proceeded well. Treatment of 770 mg of 1a (3.4 mmol)
3
with 900.0 mg of 9a (4.1 mmol) using 0.8 mol% of [Pd(η ꢀC H )Cl)] and 1.6 mol% of (Sphos,R)ꢀ
3
5
2
L1 afforded 1.0 g of the mixtures of 10a, 11a, and 12a (80% yield). Recrystallization afforded
.72 g of cyclopropane 10a (57% yield) with 99% ee (eq 4).
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O
Br
NPh2
10g
Figure 1. ORTEP Diagram of Xꢀray diffraction analysis of cyclopropane 10g.
O
LiAlH4
(3)
OH
Ph
Ph
NPh2
°
THF, 0 C
13
10a
9
>
2% yield
99% ee
>99% ee
O
NPh2
[Pd(η3-C H )Cl] (0.8 mol%)
O
1a
3
5
2
(
770 mg, 3.4 mmol)
+
(
Sphos,R)-L1 (1.6 mol%)
Ph
NPh2
(4)
LiHMDS, LiCl
THF, 20 °C
10a
Ph
OCO Me
2
9a
(900 mg, 4.1 mmol)
7
20 mg, 57% yield, 99% ee
(after recrystalization)
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Determination of the active reaction intermediate The above experimental results and our
previous studies demonstrated clearly that c/a selectivity was switched when diastereomeric
1
2e,h,13
ligands, (Sphos,R)ꢀSIOCPhox L1 or (Rphos,R)ꢀSIOCPhox L2, was used (eq. 1).
Noting that
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both ligands L1 and L2 have the same coordination atoms and backbone except that the
configuration on the phosphine atom is (S) or (R) respectively. To uncover the factors
influencing the c/a selectivity, great efforts have been made to define the active reaction
intermediates. After trial and error, two crystals of complex 1 (CP1) and complex 2 (CP2) were
3
acquired by the reaction of [(η ꢀphenylallyl)PdCl] and AgOTf with (Sphos,R)ꢀSIOCPhox L1 and
2
(
Rphos,R)ꢀSIOCPhox L2, respectively. Based on the square planar of Pd(II) complex, the position
of coordination atoms P and C3 is used to define trans/cis, P and C3 located at the same side
being cis while the definition of endo/exo is depended on the relative orientation of binol subunit
1
8
and Ph substituent on allyl group. The Xꢀray analysis of CP1 and CP2 showed that both of
3
1
them were defined as transꢀexo configuration according to above definition (Fig. 2). P NMR
spectrum of CP1 displayed four peaks at 131.6, 130.1, 124.8, 123.1 in a ratio of 0.51:1:0.24:0.24
(
See Fig S1, Supporting Information (SI)), which should be related to the isomers with PꢀC3
1
trans or cis mode in exoꢀ or endoꢀconfiguration (Fig. 3A). H NMR with Nuclear Overhauser
effect (NOE) (Figure S2, SI) as well as DFT calculations recognized transꢀexo and transꢀendo
19
isomers in PꢀC3 trans mode were in a ratio of 66:34 (Fig. 3B). Based on above results and the
determined absolute configuration of the major reaction product, cyclopropane 10g (Fig. 1), the
PꢀC3 transꢀexo isomer could be assigned as the active intermediate (Fig. 3B).
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CP1
CP2
Figure 2.ORTEP diagram and selected data of Xꢀray diffraction analysis of CP1 and CP2.
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Figure 3.Determination of active reaction intermediates. (A) Four possible isomers of CP1
3
31
with exoꢀ and endoꢀconfigurations of (η ꢀphenylallyl)PdL with our observed experimental P
3
1
NMR and predicted theoretical P NMR. (B) Calculated H3ꢀH distances and experimental
1
1
H, H NOESY of CP1.
The transꢀexo isomer as active intermediate was further confirmed by the reaction of amide
1
a with CP1 crystal in a molar ratio of 1:1, which afforded 25% yield of products in a ratio of
3
a/4a+5a being 83/17 with 10.3/1 dr and 95% ee for 3a (Fig. 4A, b), consistent with that in
13a
regioꢀ/diastereoꢀ/enantioꢀ selectivities using the catalytic amount of Pd/L1 (Figure 4A, a).
ꢀ
ꢀ
Lower yield should be caused by the different counter ion in above reactions (TfO vs Cl ion).
1
3a
Controlled experiments showed that when 110 mol% of AgOTf was added to the reaction,
2
0% yields of products were produced with similar selectivities (3a/4a+5a being 82/18, dr ratio
being 11/1 and ee being 95% for 3a) (Fig. 4A, c vs a and b). These results suggest that the active
ꢀ
transꢀexo intermediate was favored in the presence of counter ion Cl possibly accelerated by the
2
0
πꢀσꢀπ rearrangement, which was supported by our DFT calculations on thermodynamic
3
ꢀ
stability of complexes [(η ꢀphenylallyl)PdL] with Cl coordination. The transꢀexo intermediate is
the most stable complex among all the calculated πꢀ or σꢀintermediates. The calculated energy
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ꢀ
difference between transꢀendo and transꢀexo intermediates increase to 2.7 kcal/mol under the Cl
ꢀ
coordination in Figure 4, while it is only 0.7 kcal/mol without Cl ion shown in Figure 3B. The
results indicate the active πꢀcomplex with transꢀexo configuration tends to be dominated via πꢀσꢀ
ꢀ
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π rearrangement in the presence of Cl ion. The similar trend could be found in minor cisꢀisomer
as well.
Figure 4. (A) Controlled experiment for active intermediate. (B) Calculated thermodynamic
ꢀ
stability of πꢀσꢀπ rearrangement for CP1 with Cl involved, energy shown in free energy in
kcal/mol including CPCM solvent correction (See SI also)
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Origin of cyclopropane formation. Closely inspecting the crystal structures of CP1 and
CP2 (Fig. 2B), the notable difference is the orientation of binol subunit. Due to distinct
configuration of P atoms, the orientation of binol subunit in CP1 is away from its allyl group,
while that in CP2 appears toward allyl group. This orientation difference led to the great changes
in bond lengths and bite angles. The bond length of PdꢀC43 in both complexes is longer than Pdꢀ
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C41 due to stronger transꢀeffect of P compared to N. However, the difference of bond length
between PdꢀC41 and PdꢀC43 in CP2 is larger than that in CP1, suggesting that terminal carbon
(C43) in CP2 should be more easily attacked by nucleophiles. The structure of CP1 exhibits the
relative smaller angles for P1ꢀPdꢀN1 and C41ꢀC42ꢀC43, and more single bond character of CꢀC
bonds of πꢀallyl subunit. All these structural information indicates that the allylꢀPd subunit in
CP1 forms a closer palladacyclobutane structure than that in CP2. Therefore, these crystal
observations suggest that the nucleophile tends to attack the central carbon of allyl subunit of
(η3ꢀphenylallyl)PdL in CP1 while attacking the terminal carbon was favoured in CP2.
The property of nucleophile is also an important factor to influence the reaction regarding
1
3b
the reactivity as well as the selectivities. In order to understand how it affects the reaction, a
series of reactions were performed using different kind of carboxylic acid derivatives as
nucleophiles (Scheme 2). When the amide 14 with one methyl group instead of Ph group on
nitrogen was used in the reaction, 31% yield of cyclopropane 15 with low selectivity was
provided. Sluggish reaction occurred if amide 16 with two methyl groups on nitrogen was
employed. No cyclopropanation products were observed using pyrrolyl substituent derivatives
1
8, ketone 19, or thioamide 20. The reaction of methyl isobutyrate 21 could afford cyclopropane
22 in 41% yield, c/a ratio being 1/1.2, and ee of 22 being 17% (Scheme 2). These results could
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be ascribed to the different stability of the corresponding carbanions. DFT calculations reveal the
HOMO energies of carbanions are highly correlated with their reactivity (vide infra).
1
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Scheme 2. The Pdꢀcatalyzed reaction of different nucleophiles with allyl reagent 2a
The results of Scheme 2 indicated that the property of nucleophile singnificantly influences
the selectivity of the reaction. For more insights into c/a selectivity, DFT calculations were
carried out to locate transition states (TSs) in the nucleophilic attacking step. As shown in Fig. 5,
TS1 and TS2 are responsible for cyclopropanation and allylic alkylation, respectively. TS1 with
good staggered conformation (59.0°) is 1.7 kcal/mol more stable than TS2 with eclipsed
conformation, suggesting cyclopropane should be major product together with minor allylation
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product. Close inspection of both transition states, the bulky NPh group of the nucleophile 1a
2
prefers to avoid the major steric repulsion with substituent Ph group of the allyl group, as
depicted in the Newman projections. From contrasting TSs for CP2, because of the orientation
of binol subunit toward allyl group, the relative TS largely favoured to attack the terminal carbon,
indicating the overwhelming allylated product should be observed (∆∆G=6.5 kcal/mol for
transition states leading to favorable allylation products, see Fig S4 (SI) for structures). These
calculated selectivities are consistent with experimental observation. The TS1 energy of
cyclopropanation from CP1 (transꢀexo isomer) appears 3.7ꢀ6.4 kcal/mol more stable in free
energy than that from other isomers, which evidently supports again our assignment of the active
intermediate (vide supra) (more unstable TSs were shown in Fig S3, SI).
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CP1:
TS1 0.0 kcal/mol
TS2 1.7 kcal/mol
torsion angle
18.2°
.5°
9.7°
bite angle
∠
C -C -C -C
2
3
4
PdL2
2
5
TS2CP1
90.0°
N
P
4
5
TS1CP1
85.4°
88.2°
Pd
6
5
Ph
1
3
CP1(calc.)
Figure 5. The 3D structures, Newman projections and relative energies of transition states.
TS1 and TS2 are responsible for cyclopropanation and allylic alkylation, respectively. The
energies were shown in ꢁꢁG free energy at level of M06/6ꢀ31G(d)/Lanl2DZ//6ꢀ
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11+G(d,p)/Lanl2DZ with CPCM solvent model correction in THF. Atom colors: Liꢀpurple, Pꢀ
orange, Oꢀred, Nꢀblue, Cꢀgrey, Hꢀwhite.
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It is worthwhile to note that there is a relationship between the torsion angle (C2ꢀC3ꢀC4ꢀC5,
Fig 5) and the c/a selectivity. The torsion angles reflect the dihedral angle of two planes of allyl
subunit and phenyl rings, observed in crystal structures (Fig 2, 4.7° for CP1 and 14.0° for CP2)
and calculated TS1 for CP1 (table of Fig. 5). The complex with smaller torsion angle gave rise
to better c/a selectivity. Obviously, smaller torsion angle means better conjugative effect between
allyl subunit and phenyl ring, which would stabilize CP1 as well as TS1 and favor the
cyclopropanation. Additionally, our calculated orbital populations of ally subunit in Fig. 6B also
reveal a conjugative effect between phenyl substituent and allyl group could stabilize LUMO of
CP1+Li complex. The orbital overlap is clearly illustrated at the 0.02 isoꢀvalue level in CP1+Li
complex, but not clearly shown in CP2+Li, which suggest that the conjugative effect plays an
important role in controlling c/a selectivity. These results demonstrate why the presence of aryl
substituent on allyl reagents is important in Pdꢀmediated/catalyzed cyclopropanation and explain
7
c
also the so called “aryl effect” proposed by Hoffmann. Based upon these understandings, the
allyl substrates were also successfully extended from aryl allyl reagents 2 to polyenyl reagents 9
(vide supra).
To further investigate the factors operating the reaction, natural population analysis (NPA)
charges and LUMOs of πꢀallyl Pdꢀcomplexes as well as HOMOs of nucleophiles have been
analysed by DFT calculations (Fig. 6). It could be found that the tiny positive charges were
shown at the central carbon in CP1 and terminal carbons in CP2 (Fig. 6A), though the changes
of the computed NPA charges at the πꢀallyl carbon atoms are so small (lower than 0.05) and
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could not be evaluated in details. The LUMO of CP1+Li shows a large orbital coefficient on
middle of allyl part comparing to that of CP2+Li and the energy of LUMO in CP1+Li is lower
than that in CP2+Li, suggesting that CP1+Li with more stable LUMO is more likely to react
ꢀ
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with HOMO of Nu and thus to form cyclopropane product (Fig. 6B). Calculated energy
sequence of nucleophiles’ HOMOs follows 1a>21>19>18>20, which is clearly associated with
their reactivity of cyclopropanation (Scheme 2). As the frontier orbital dependency and the
negligible charge difference, we could conclude the central carbon attacking would be largely
22
controlled by orbitals. Higher energy of nucleophile’s HOMO and lower energy of πꢀallyl’s
LUMO would decrease the energy gap between them which may kinetically facilitate the
formation of cyclopropane.
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Figure 6. NPA Charges and frontier orbitals of electronic structures. (A) Charges in Natural
Population Analysis (NPA); (B) Frontier orbitals for HOMOs of nucleophiles and LUMOs of πꢀ
allyls (isoꢀvalue=0.02), Orbital energies are in ev.
3
We noted that the orbital populations of (η ꢀphenylallyl)Pdꢀligand partially located on ligand
area (Fig. 6B), indicating that the ligand could contribute to those LUMOs, while smaller bite
angle of metal with coordination atoms could stabilize TS1 for cyclopropanation (Fig. 5, table)
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and be observed in CP1 (Fig. 2B). It seems that ligand bite angle also plays a role in the
2
2
nucleophilic attack at the central carbon to form cyclopropanes. When the angle of our newly
designed NHCꢀPy/Pd/allyl catalysts, CP3 and CP4, increases from 77.8° to 88.0° determined by
Xꢀray analysis, the cyclopropanation ratio dropped from 78% to 28% in Pdꢀcatalyzed
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13b
cyclopropanation (eq 5). The data from Xꢀray analysis of crystal structures, including CP1,
CP4, TMEDAꢀPdꢀallyl, and controlling experimental results afford some supports for this
2
3
deduction. The findings regarding the relationship between biteꢀangle and c/a selectivity
24
provide us some useful information on designing new catalyst system.
Conclusions
In conclusion, we realized highly enantioselective cyclopropanation under Pdꢀcatalysis in
the reaction of aryl substituted allyl and polyenyl carbonates with acyclic amides. The factors
controlling c/a selectivity were investigated through experiments, Xꢀray diffraction analysis of
two palladiumꢀligandꢀallyl complexes (CP1 and CP2), as well as DFT calculations. It revealed
that the reaction should be under orbital control, and the characters of both nucleophile and Pdꢀ
ally complex with ligand (active intermediate) including bond lengths and bite angles are
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important. Conjugative effect between allyl subunit and the substituent on it as well as bite angle
1
2
of L ꢀPdꢀL are also important factors to influence c/a selectivity of the reaction. All these
information will be great helpful in design of new catalyst and extension of new type of allyl
substrate and nucleophile of the reaction.
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0
ASSOCIATED CONTENT
Supporting Information
Detailed experimental procedures, analysis data, Computational methods and structure details,
NMR and HPLC spectra of products, cif files of complex 1 (CP1), complex 2 (CP2), complex 3
(CP3), complex 4 (CP4), and 10g. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*XꢀL. Hou: eꢀmail, xlhou@sioc.ac.cn, tel, 86ꢀ21ꢀ54925144.
*
*
C.ꢀH. Ding: eꢀmail, dingch@sioc.ac.cn.
Q. Peng: eꢀmail, qpeng@nankai.edu.cn.
Notes
†
These authors contributed equally.
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
Financial supported by National Natural Science Foundation of China (NSFC) (21532010,
1472214, 21372242, 21421091, 21702109), the Strategic Priority Research Program of the
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Chinese Academy of Sciences (XDB20030100), “1000ꢀTalent Youth Plan” of China, the
European Community (FP7ꢀPEOPLEꢀ2012ꢀIIF under grant agreement 912364, the CSAꢀtrust
grant, the NSFC and the Research Grants Council of Hong Kong Joint Research Scheme
(21361162001), the Chinese Academy of Sciences, Nankai University, the Technology
Commission of Shanghai Municipality, and the Croucher Foundation of Hong Kong.
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