Tertiary amine-catalyzed (3+3) annulations of δ-acetoxy allenoates: Substrate scope, synthetic application and mechanistic insight

Article abstract of DOI:10.1016/j.tet.2017.04.058

Herein is reported the formal (3?+?3) annulations of δ-acetoxy allenoates with 1C,3O-bisnucleophiles by using 6’-deoxy-6’-perfluorobenzamido-quinine (5g) as the catalyst, providing rapid access to 4H-pyrans with excellent enantioselectivity. The reaction

Full text of DOI:10.1016/j.tet.2017.04.058

Accepted Manuscript
Tertiary amine-catalyzed (3+3) annulations of δ-acetoxy allenoates: Substrate scope,
synthetic application and mechanistic insight
Chunjie Ni, Weiping Zhou, Xiaofeng Tong
PII:
S0040-4020(17)30449-0
10.1016/j.tet.2017.04.058
TET 28659
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 March 2017
Revised Date: 19 April 2017
Accepted Date: 22 April 2017
Please cite this article as: Ni C, Zhou W, Tong X, Tertiary amine-catalyzed (3+3) annulations of δ-
acetoxy allenoates: Substrate scope, synthetic application and mechanistic insight, Tetrahedron (2017),
doi: 10.1016/j.tet.2017.04.058.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
Tertiary amine-catalyzed (3+3) annulations
of δ-acetoxy allenoates: substrate scope,
synthetic application and mechanistic insight
Leave this area blank for abstract info.
Chunjie Ni, Weiping Zhou and Xiaofeng Tong
Key Laboratory for Advanced Materials, East China University of Science and Technology

ACCEPTED MANUSCRIPT
Graphical Abstract
Tertiary amine-catalyzed (3+3) annulations
of δ-acetoxy allenoates: substrate scope,
synthetic application and mechanistic insight
Leave this area blank for abstract info.
Chunjie Ni, Weiping Zhou and Xiaofeng Tong
Key Laboratory for Advanced Materials, East China University of Science and Technology

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Tertiary amine-catalyzed (3+3) annulations of δ-acetoxy allenoates: substrate scope,
synthetic application and mechanistic insight
a,b
Chunjie Nia, Weiping Zhoua and Xiaofeng Tong
a Key Laboratory for Advanced Materials, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China
b Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, School of Petrochemical Engineering, Changzhou University, 1 Gehu Road,
Changzhou, 213164, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Herein is reported the formal (3+3) annulations of δ-acetoxy allenoates with 1C,3O-
bisnucleophiles by using 6’-deoxy-6’-perfluorobenzamido-quinine (5g) as the catalyst,
providing rapid access to 4H-pyrans with excellent enantioselectivity. The reaction features
wide substrate scope and mild reaction conditions. The utility of this method is demonstrated in
highly stereoselective synthesis of the core of calyxin I. Mechanistic experiments suggest the
involvement of 3-ammonium-2,4-dienoate intermediate BN. This type of cationic intermediate
arises from an addition-elimination process between allenoate substrate and amine catalyst, and
is stable enough for isolation and characterization. Mechanistic studies also disclose the crucial
role of amide NH of 5g, which is able to not only activate allenoate to facilitate the formation of
BN, but enhance the electrophilicity of δC of BN for nucleophilic attack.
Available online
Keywords:
Allenoate
Bisnucleophile
Amine catalysis
(3+3) Annulation
4H-pyran
2009 Elsevier Ltd. All rights reserved
.
1. INTRODUCTION
Perhaps the invention or identification of generic activation
mode is one of most important impetus for all branches of
catalysis, which provides an extremely valuable platform for
designing new reactions.1 As is the case, highly reactive
zwitterionic intermediate has come to be the cornerstone for the
Lewis-base-catalyzed annulations of allenoates since the
pioneering report2 of Lu’s (3+2) cycloaddition.3 In general,
phosphonium/carbanion or ammonium/carbanion pair is
generated via 1,4-addition of Lewis base catalyst (tertiary
phosphine or amine) to allenoate substrate. There are substantial
efforts on the development4 of zwitterion variants and discovery5
of their new chemical behaviors. These studies elegantly
illustrate the crucial role of zwitterionic intermediates on the
annulations of allenoates with C=X electrophiles (X = C, N, O).
This type of reaction mode attributes to the preferential carbanion
addition reactivity of zwitterionic intermediate, thereby
excluding the participation of a nucleophile as the other
annulation partner.6 The Lewis-base-catalyzed annulation of
allenoate with nucleophile has thus far been elusive.
Scheme 1. Lewis Base-Catalyzed Annulations of Allenoates
via Cationic Intermediate (E = -CO2R)
In 2010, we reported the phosphine-catalyzed (4+1)
annulations of β’-acetoxy allenoate 1 with 1C,3O-bisnucleohiles
(Scheme 1a).7 Cationic intermediate AP is proposed to be
involved via an alternative addition-elimination process (Scheme
new type of annulation. In subsequent developments, Lu and Fu
elegantly demonstrated that a wide range of nucleophiles could
be applicable to this type of (4+1) annulation even in asymmetric
fashion (Scheme 1a),8 and we developed the (3+3) annulations of
allenoate 1 with 1C,3O-bisnucleophiles under amine catalysis via
1a) and its intrinsic bis-electrophilic reactivity is the pivot for this
———
Corresponding author. Tel.: +86-13671833759; e-mail: txf@cczu.edu.cn

2
Tetrahedron
ACCEPTED MANUSCRIPT
cationic intermediate AN (Scheme 1b)9. A major advance has
reaction became sluggish and no improvement of ee value was
also been made toward the (3+3) annulation of δ-acetoxy
allenoate 2 with 1,3-dicarbonyl compound by using phosphine
catalyst (Scheme 1c).10 In this case, the formation of cationic
intermediate BP with bis-electrophilicity via a similar addition-
elimination process is also supposed to be a pivot for the success
of the (3+3) annulation. Therefore, the cationic intermediate is
emerging as a new activation mode for the Lewis-base-catalyzed
annulation of allenoate.
observed when reaction temperature was further decreased to -20
oC (Table 1, entry 5). Surprisingly, significant decrease in yield
was observed when 5d bearing HNTs group was employed as the
catalyst (Table 1, entry 6). These results inspired us to
hypothesize that both of enantioselectivity and efficiency might
interrelate with the donating ability of H-bond of the catalyst.
Accordingly, we paid close attention to catalysts 5e-5g (Table 1,
entries 7-9). Their H-bond donor was optimized by subtly tuning
the electronic property of benzoyl moiety. Investigation of these
three catalysts rapidly disclosed that catalyst 5g with a
perfluorobenzamido group (HNCOC6F5) afforded 4aa in 94%
yield and 99% ee (Table 1, entry 9).
Nonetheless, this activation mode is still in infancy and
warrants further study. The extension of its synthetic potential
and collection of the mechanistic insights thus become important
goals. Herein, we report the amine-catalyzed formal (3+3)
annulations of δ-acetoxy allenoate 2 with 1C,3O-bisnucleophiles,
which provide facile access to 4H-pyrans (Scheme 1d).11
Alternatively, cationic intermediate BN is involved, which is
capable of engaging in (3+3) annulations with a wide range of
1C,3O-bisnucleophiles. In addition, the asymmetric version can
be readily achieved by using a quinine-based bifunctional
catalyst. These two features are beneficial for the modular
synthesis of enantioenriched pyran compounds. More
importantly, this reaction provides an ideal platform for
mechanistic study and we have gained insights into the key
cationic intermediate, the catalytic cycle as well as the
bifunctionality of catalyst.
Table 1. Reaction Optimizationa
2. Results and Discussion
2.1. Screening and scope. At the outset of this study, we were
cognizant that intermediate BN is susceptible to the O-nucleophile
addition at its βC site on the base of the amine-catalyzed (4+2)
annulation of 2 with salicylal derivative.12 To simplify the issues
related to chemoselectivity, benzoyl acetonitrile 3a, a compound
without enol form in toluene, was thus chosen as the 1C,3O-
bisnucleophile for reaction discovery.
aReactions were conducted in 3 mL toluene in 0.2 mmol scale.
Isolated yield was reported. The ee value was determined by
HPLC analysis.
As expected, the opposite enantiomeric product (R)-4aa was
obtained with 83% ee when pseudo enantiomer 5g’ was used as
the catalyst under the otherwise identical conditions (Eq 2).
When the reaction of 2a and 3a was conducted in toluene in
the presence of DABCO (20 mol%) and K2CO3 (1.2 equiv), 4H-
pyran 4aa was isolated in the yield of as high as 96% (Eq 1).
Notably, this (3+3) annulation is quite distinct from the
phosphine-catalyzed reaction of 2a and 3a which led to 2H-pyran
product (Scheme 1c).10 These results indicate the different
catalytic behaviors between amine and phosphine catalysts.13
Then, the substrate scope of the asymmetric (3+3)
annulations of allenoates 2 and 3-oxo-nitriles 3 was examined.
Generally, various 3-aryl-3-oxopropanenitriles, including phenyl
groups with either electron-donating (-Me, -OMe) or electron-
withdrawing (-halide, -NO2) substituent and naphthalene, reacted
well with 2a, affording the corresponding products 4aa-4al with
excellent ee (Table 2, entries 1-12). The yields of 4ah-4ak with
an ortho-substituted phenyl ring dropped to the moderate level
likely due to the steric hindrance (Table 1, entries 8-11). Nitriles
3m-3o with a heteroaryl group, such as furan, thiophene as well
as pyridine, also worked well under these reaction conditions,
giving products 4am-4ao in good yields and with excellent
enantioselectivity (Table 1, entries 13-15). Additionally, 3-alkyl-
3-oxopropanenitriles 3p-3s were compatible and excellent
reaction performances were still achieved (Table 1, entries 16-
19). Then, we briefly investigated the scope of allenaote partner.
A variety of allenates 2 with different type of substituent at δ-
position, including aromatic ring, alkene and alkyl group, were
After verification of the amine-catalyzed (3+3) annulation of
2a and 3a, we turned our attention to the development of the
asymmetric version. To achieve this goal, we had recourse to the
cinchona alkaloids due to their privileged chiral scaffold and
readily structural modification.14 We were surprised to find that
quinine-derived 5a was completely inactive and 2a was
recovered in 95% yield (Table 1, entry 1). This failure might be
due to both of the sterically congested tertiary amine center and
relatively lower activity of γ-substituted allenoate. Delightedly,
4aa was obtained in 35% yield and 54% ee when catalyst 5b with
a free phenolic hydroxyl group was used (Table 1, entry 2).
These results clearly pointed out the crucial role of the H-bond
donor of amine catalyst. Therefore, catalyst 5c bearing a stronger
H-bond donor (HNBz) was tested, which indeed increased the
yield and enantioselectivity to 86% and 60%, respectively (Table
o
1, entry 3). Lowering the reaction temperature to 0 C furnished
4aa in 95% yield and 85% ee (Table 1, entry 4). However, the

3
applicable to the reaction (Table 1, entries 20-26). However, the
latter two cases gave moderate yield, despite with excellent
enantioselectivity. Finally, product 4jo was obtained in 90%
yield and 96% ee, whose structure was established on the X-ray
crystallographic analysis.15 Thus, its absolute configuration was
assigned to be S and other products were determined by analogy.
suitable substrates and similar level of reaction performances
ACCEPTED MANUSCRIPT
were observed. Although a regioselectivity issue arose from non-
symmetric 1,3-dicarconyl compound 6g, the two products 7ag
and 7ag’ were separable. Notably, β-carbonyl esters 6h and 6i
also reacted well with allenoate 2a, delivering 7ah and 7ai with
excellent ee, respectively. Compatibility of 1,3-dicarbonyl
substrate was further demonstrated by the reactions of lactone 6j
with allenoates 2a and 2u. Interestingly, the reaction of 2a with
chiral racemic substrate 6k exhibited slight discrimination on the
remote chiral center, affording products 7ak and 7ak’. The two
diastereoisomers could be easily separated by flash
chromatography. The stereochemistry of minor product 7ak’ was
assigned to be anti on the basis of X-ray analysis.15 Although
acyclic 3-oxo-amide was proven to be inert under the standard
conditions, piperidine-2,4-dione 6l was able to react with 2a,
affording 7al in 73% yield and 94% ee.
Table 2. Substrate Scope of (3+3) Annulations of
Allenoates 2 and 3-Oxo-nitriles 3a
entry
4 (R1, R2)
4aa (Ph, Ph)
yield/ee (%)
94
1
2
3
99
99
91
93
98
96
98
93
97
99
97
97
97
98
96
93
93
94
96
97
99
98
95
96
98
97
98
96
4ab (Ph, 4-Me-C6H4)
4ac (Ph, 4-OMe-C6H4)
99
90
97
99
87
90
88
77
55
42
82
76
77
82
83
97
85
75
90
96
94
93
99
52
44
46
90
4
4ad (Ph, 4-F-C6H4)
4ae (Ph, 4-Cl-C6H4)
4af (Ph, 4-Br-C6H4)
4ag (Ph, 4-I-C6H4)
4ah (Ph, 2-Me-C6H4)
4ai (Ph, 2-OMe-C6H4)
4aj (Ph, 2-I-C6H4)
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
4ak (Ph, 2-NO2-C6H4)
4al (Ph, 2-naphthyl)
4am (Ph, 2-furan)
4an (Ph, 2-thiophene)
4ao (Ph, 2-pyridin)
4ap (Ph, Me)
4aq (Ph, n-C5H11)
4ar (Ph, CH2CH2Ph)
4as (Ph, CH2OBn)
4ba (4-Cl-C6H4, Ph)
4ca (2-Br-C6H4, Ph)
4da (1-naphthyl, Ph)
4ea (2-furan, Ph)
4fa (2-thiophene, Ph)
4ga (2-propen, Ph)
4ho [(CH2)2Ph, 2-pyridin]
4io (Cy, 2-pyridin)
4jo (3-Br-C6H5, 2-pyridin)
aReactions were conducted in 0.2 mmol scale in toluene (3.0
mL). Isolated yield was reported. The ee value was determined
by chiral HPLC analysis.
To further assess the generality of this process, these
conditions were applied to the (3+3) annulations of allenaotes 2
with 1,3-dicarbonyl compounds (Scheme 2). It was delighted to
find that cyclohexane-1,3-dione 6a was able to engage in the
(3+3) annulations with various allenoates, as illustrated by the
isolation of products 7aa, 7ha and 7ka-7ta in mediate to good
yields and with excellent enantioselectivity. 5-Substituted
cyclohexane-1,3-diones 6b and 6c exhibited similar activity as
6a. Tolerance of medium cycle was demonstrated by the
conversion of cycloheptane-1,3-dione 6d to 7ad. Additionally,
acyclic 1,3-dicarconyl compounds 6e and 6f was found to be
Scheme 2. Substrate Scope of (3+3) Annulations of
Allenoates 2 and 1,3-Dicrbonyl Compounds 6
Moreover, moderate level of kinetic resolution of α-sulfinyl
ketone 6m was observed in its reaction with allenaoate 2a (eq 3).
In addition to 1,3-dicarbonyl compounds, 2-indanone 8a, a less
acidic substrate (pKa = 16.9 in DMSO), smoothly reacted with

4
Tetrahedron
ACCEPTED MANUSCRIPT
2a, affording product 9aa in 63% yield and with 84% ee (eq 4).
development of an efficient approach to calyxin I analogues
Notably, 2-coumaranone 8b was also a suitable substrate,
delivering 9ab in 72% yields and with 91% ee (eq 4). These
results implied the strong electrophilicity preference of δ-position
of intermediate BN towards C-nucleophile.
would be useful for the structure−activity relationship studies.19
Thus, the reaction of 2r and 6h was conducted in 5 mmol scale
under the standard conditions, which afforded 1.83 gram of 4H-
pyran 7rh with 92% ee. The treatment of 7rh with catalytic
hydrogenation led to pyran 13 as a single isomer. After
deprotection of MOMO group, compound 14 was obtained via
lactonization with the help of TFA. While the configuration of
C3 is opposite to that of calyxin I, the epimerization was readily
achieved via simple isomerization/lactone opening and re-
lactonization processes, giving compound 16 in very high yield
and enantioselectivity (Scheme 4).
Ph
5g
20 mol%
2a
+
(4)
O
1.2 equiv K2CO3
toluene, 0 oC, 48 h
X
E
X
O
8a
: X = CH2
8b
: X = O
9aa
9ab
: 63% yield, 84% ee
: 72% yield, 91% ee
2.2. Synthetic transformations. Once the practicable and
mild approach to prepare the multi-substituted 4H-pyrans was
established, we were interested in their applications in the
synthesis of enantioenriched complex scaffolds. In addition to
their prevalence in biologically active compounds and natural
products, 4H-pyrans are a valuable synthon for the construction
of complex molecule.16
Scheme 4. Synthetic Application of Product 7rh
2.3. Mechanistic consideration. We next sought to gain
mechanistic insights into the amine-catalyzed (3+3) annulation of
δ-acetoxy allenoate 2. As outlined in Scheme 5, there are at least
two possible pathways for this reaction.
Scheme 3. Synthetic Transformation of Product 7ra
Upon the treatment of catalytic amount of PTSA, 7ra was
readily converted into 2,8-dioxabicclo [3.3.1]nonane 10 (Scheme
3). This structural unit is found in a variety of natural products
with a wide range of biological activity.17 Intriguingly, when
compound 10 was treated with catalytic amount of PTSA (10
mol%) in refluxing DCM, a tandem sequence, consisting of four
steps, smoothly occurred to give compound 11 in nearly
quantitative
yield.
Moreover,
highly
stereoselective
hydrogenation of 11 was achieved to afford compound 12 as a
single isomer with 95% ee (Scheme 3).
To further demonstrate the synthetic utility of this (3+3)
annulation, we targeted compound 16, a tricyclic core of calyxin
I (Scheme 4). This natural product has attractive bioactivities but
no total synthesis has been reported to date.18 We believe that the
Scheme 5. The Proposed Mechanism.

5
These two share cationic intermediate BN, which arises from
the process of addition of amine catalyst and elimination of
acetate group. The first (path a) involves initial addition of
nucleophile 3 to δ-position of BN to yield intermediate C, which
is converted into intermediate D via proton shift. Then, oxa-
Michael addition and subsequent 1,2-elimination of amine
catalyst lead to compound 17. Product 4 would be finally
produced via isomerization (path a). The second (path b) involves
direct formation of intermediate E via addition of 3 to BN, which
is followed by 1,2-elimination of amine catalyst to generate
allenoate 18. With the assistance of a base, intramolecular oxa-
Michael addition occurs in 6-trig-endo manner to give 4H-pyran
4, thus furnishing a formal (3+3) annulation (path b).
Surprisingly, the use of 5g merely led to zwitterion 23 in 9%
ACCEPTED MANUSCRIPT
yield (Scheme 7b). Increasing the loading of 5g to 100 mol%
significantly improved the yield of 23 to 78%. Solution of 23 in
CDCl3 exhibits a characteristic peak of H-bond at 13.7 ppm. The
distinct reactivity of compound 21 may attribute to its
structurally stable enol form. In the corresponding intermediate
E’, the enol (purple marked) is capable of quenching the
carbanion to shut down the 1,2-elimation of amine catalyst, thus
preventing the reaction sequence of (3+3) annulation. As a result,
compound 23 was instead formed, which would be stabilized by
H-bonding between amide NH and the resultant enolate (Scheme
7b). As expected, decomposition of compound 23 produced
(3+3) annulation product 22 with 99% ee albeit in 5% yield after
7 d (Scheme 7c).
Scheme 6. Control Experiments
We then interrogated path a in more detail (Scheme 6).
Notably, compound 17’, an analogue of intermediate 17
postulated in this pathway, was authentically prepared via our
previous synthetic route.20 However, we found that compound
17’ was unable to be converted into 4H-pyran 4aa’ under the
standard conditions (Scheme 6a), thus providing strong evidence
against path a. Moreover, when the reaction of 3a-D (95% D)
and 2a was conducted under the standard conditions, product
4aa-D was obtained with no incorporation of deuterium into γ-
position but with 12% D at α-position (Scheme 6b). Apparently,
no observation of deuterium at γ-position implies the absence of
C with a carbanion located at the γC center. The observation of
deuterium at α-position is consistent with path b, wherein either
proton shift in intermediate E or Michael addition of allenoate 18
is responsible for the deuterium incorporation. To further confirm
the feasibility of path b, we designed a control experiment to
probe the accessibility and reactivity of compound 18, a key
intermediate in path b. After several attempts, we were delighted
to obtain compound 19, an analogue of 18, via the 5g-catalyzed
reaction of 2a with dimethyl malonate (Scheme 6c). Due to the
less activity of dimethyl malonate, an elevated reaction
Scheme 7. The Reaction of 2n and 21
After establishing the catalytic cycle, we then turned our
attention to cationic intermediate BN (Scheme 8). The success of
this (3+3) annulation was strongly dependent on the formation of
BN as it plays a crucial role on the interaction with bis-
nucleophile.
o
temperature (30 C) was required. Remarkably, this reaction still
maintained good enantioselectivity. Moreover, upon the
treatment of catalytic amount of aqueous KOH (20 mol%),
compound 19 was converted into 4H-pyran 20 in high yield
(Scheme 6c). These results clearly indicate that allenoate 18
would be a viable intermediate for the formal (3+3) annulation.
Scheme 8. Stoichiometric Investigations
Luckily, despite the requirement of a long reaction time (96
h), simple mixing of equal molar allenoate 2a and DABCO in
toluene enabled the isolation of adduct 24 in 90% yield (Scheme
8a). Interestingly, compound 24 can be isolated via flash
chromatography and stored at bench for one week without any
observable decomposition. NOESY experiment confirmed the
trans-configuration of the two alkenes, indicating no interaction
Some unusual and intriguing observations were made in the
case of bisnucleophile 21 (Scheme 7), which unveiled some
information related to intermediate E. Indeed, compound 21
reacted well with allenoate 2n in the presence of DABCO,
affording annulation product 22 in 97% yield (Scheme 7a).

6
Tetrahedron
ACCEPTED MANUSCRIPT
between ester and ammonium in BN. In order to validate the
3. Conclusion
catalytic activity of 24, an experimental test was conducted by
using the reaction of 2a and 3a in the presence of 24 (20 mol%)
under the otherwise identical conditions, which led to 4aa in 89%
yield. It is, to the best of our knowledge, the first isolated active
intermediate in the amine-catalyzed annulations of allenoates.21
Surprisingly, no any new peaks was observed even after 7 days
when the analogous reaction of 2n and 5g was probed in an NMR
tube using toluene-d8 (Scheme 8b). In contrast, a new species
(found 872.2113) was observed when this reaction was
monitored by ESI-HRMS, which is assigned to the cationic
moiety of adduct 25 (cal. 872.2117) (Scheme 8b). As compared
to the 5g-catalyzed reactions in term of timescale, the
stoichiometric reaction of 2n and 5g should have finished, at
least, no more than 48 h. This paradox inspired us to postulate
that the reaction of 2n and 5g is reversible and the equilibrium is
much more favorable for the starting materials.
In summary, we have developed the 5g-catalyzed formal (3+3)
annulation of δ-acetoxy allenoate 2 with 1C,3O-bisnucleophile,
which provides a facile access to 4H-pyran with excellent
enantioselectivity. This method is distinguished by the mild
reaction conditions and wide substrate scope. Mechanistic
investigations point out the involvement of cationic intermediate,
3-ammonium-2,4-dienoate, which presents a new activation
mode for the Lewis-base-catalyzed annulation of allenoate. The
key cationic intermediate has been isolated and characterized,
which sheds light on the catalytic cycle. Furthermore, the crucial
roles of amide NH of 5g as H-bond donor have been elucidated,
which not only facilitate the formation of cationic intermediate
but also enhance the electrophilicty of δC of BN. We anticipate
that the findings in this work will foster further exploration of the
Lewis-base-catalyzed annulation of allenoate via cationic
intermediate.
4. Experimental section
4.1 General methods
Unless otherwise noted, all reagents were obtained
1
commercially and used without further purification. H and 13C
spectra are recorded on the Bruker AVANCE spectrometer,
1
operating at 400 MHz (300 MHz or 500 MHz) for H NMR and
100 MHz (75 MHz or 125 MHz) for 13C NMR. Mass spectra
were in general recorded on an AMD 402/3 or a HP 5989A mass
selective detector. HPLC analysis was performed on Waters
equipment using Daicel Chiralpak AS-H, OJ-H, OZ-H, AD-H, IC
and OD-H column. Optical rotations were measured on a
Autopol IV-T polarimeter. Column chromatography was
performed with silica gel (200-300 mesh ASTM).
4.2 General Procedure
To a 25 mL flask was added catalysts 5g (0.04 mmol, 23.7
mg), K2CO3 (0.24 mmol, 33.2 mg), 3 or 6 or 8 (0.24 mmol) and
toluene (1.5 mL). After the mixture was stirred at 0 C for five
Scheme 9. The Reversible Reaction of 2l and 5g
o
The postulation could be confirmed by the reaction of
racemic 2n with 20 mol% 5g (Scheme 9a). Indeed, 97% yield of
2n was recovered with 15% ee and 17% ee for its two
diastereomers, respectively. More instructive evidences came
from the reaction of 2n with CD3CO2D under otherwise identical
conditions (Scheme 9b). The use of 5g (20 mol%) enabled the
isolation of 2n-D with 30% AcO-group exchange. However, this
event did not happen in the presence of either DABCO or 5a.
minutes, a solution of 2 (0.20 mmol) in toluene (1.5 mL) was
slowly added. The reaction was stirred at 0 C for 48 h. After
that, the solvent was removed and the residue was directly
subjected to silica gel column chromatography (petroleum
ether/ethyl acetate as eluent) to give (3+3) annulation product.
o
Acknowledgements
This work is supported by the National Natural Science
Foundation of China (No. 21472042), the Jiangsu Province
Funds for Distinguished Young Scientists (BK20160005) and
Qing-Lan Project. We are also grateful to Advanced Catalysis
and Green Manufacturing Collaborative Innovation Center,
Changzhou University for financial support.
References
(1) MacMillan, D. W. C. Nature 2008, 455, 304.
(2) (a) Xu, Z.; Lu, X. Tetrahedron Lett. 1997, 38, 3461. (b) Xu,
Z.; Lu, X. J. Org. Chem. 1998, 63, 5031.
Scheme 10. The Roles of Amide NH of Catalyst 5g
These results also demonstrated the unique roles of amide
NH group of catalyst 5g (Scheme 10). The amide NH would
interact with allenoate 2 via H-bonding, which not only activates
allenoate but also enables the sterically congested quinuclidine to
attack in a pseudo-intramolecular manner, thus facilitating the
formation of cationic intermediate BN. This may be the
underlying reason for the high activity of catalyst 5g. Moreover,
the H-bonding would be also able to enhance the electrophilicity
of δC of BN significantly. The enhancement eventually makes the
attack of AcO- operative, which accounts for the reversible
reaction of 2n and 5g.
(3) For selected reviews, see: (a) Lu, X.; Zhang, C.; Xu, Z. Acc.
Chem. Res. 2001, 34, 535. (b) Methot, J. L.; Roush, W. R. Adv.
Synth. Catal. 2004, 346, 1035. (c) Lu, X.; Du, Y.; Lu, C. Pure
Appl. Chem. 2005, 77, 1985. (d) Cowen, B. J.; Miller, S. J. Chem.
Soc. Rev. 2009, 38, 3102. (e) Ye, L.-W.; Zhou, J.; Tang, Y. Chem.
Soc. Rev. 2008, 37, 1140. (f) Denmark, S. E.; Beutner, G. L.
Angew. Chem. Int. Ed. 2008, 47, 1560. (g) Fan, Y. C.; Kwon, O.
Chem. Commun. 2013, 49, 11588. (h) Xiao, Y.; Sun, Z.; Guo, H.;
Kwon, O. Beilstein J. Org. Chem. 2014, 10, 2089. (i) Wei, Y.;
Shi, M. Acc. Chem. Res. 2010, 43, 1005. (j) Wang, S.-X.; Han, X.
Y.; Zhong, F. R.; Wang, Y. Q.; Lu, Y. Synlett 2011, 2766. (k)

7
Wang, Z.; Xu, X.; Kwon, O. Chem. Soc. Rev. 2014, 43, 2927. (l)
Zhao, Q.-Y.; Lian, Z.; Wei, Y.; Shi, M. Chem. Commun. 2012,
48, 1724.
(15) The crystallographic coordinates of 4jo, 7ak’, 11 and 14
ACCEPTED MANUSCRIPT
have been deposited with the deposition numbers CCDC
1533837-1533840, respectively. These data can be obtained free
of charge from the Cambridge Crystallographic Data Centre, at
deposit@ccdc.cam.ac.uk.
(16) (a) Faulkner, D. J. Nat. Prod. Rep. 2000, 17, 7. (b) Yeung,
K.-S.; Paterson, I. Chem. Rev. 2005, 105, 4237. (c) Kang, E. J.;
Lee, E. Chem. Rev. 2005, 105, 4348. (d) Inoue, M. Chem. Rev.
2005, 105, 4379. (e) Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem.
Rev. 2005, 105, 4406. (f) Nakata, T. Chem. Rev. 2005, 105, 4314.
(g) Liu, R. H.; Zhang, W. D.; Gu, Z. B.; Zhang, C.; Su, J.; Xu, X.
K. Nat. Prod. Res. 2006, 20, 866. (h) Larghi, E. L.; Kaufman, T.
S. Synthesis 2006, 187. (i) Gunatilaka, A. A. L. J. Nat. Prod.
2006, 69, 509.
(17) (a) Reddy, G. M.; Sridhar, P. R. Org. Biomol. Chem. 2014,
12, 8408. (b) Sharma, P. K.; Romanczyk Jr., L. J.; Kondaveti, L.;
Reddy, B.; Arumugasamy, J.; Lombardy, R.; Gou, Y.; Schroeter,
H. Org. Lett. 2015, 17, 2306. (c) Ganguly, N. C.; Roy, S.;
Mondal, P. RSC Adv. 2014, 4, 42078. (d) Ito, Y.; Ohmori, K.;
Suzuki, K. Angew. Chem., Int. Ed. 2014, 53, 10129. (e) Yang, Z.;
He, Y.; Toste, F. D. J. Am. Chem. Soc. 2016, 138, 9775.
(18) (a) Gewali, M. B.; Tezuka, Y.; Banskota, A. H.; Ali, M. S.;
Saiki, I.; Dong, H.; Kadota, S. Org. Lett. 1999, 1, 1733. (b) Ali,
M. S.; Banskota, A. H.; Tezuka, Y.; Saiki, I.; Kadota, S. Biol.
Pharm. Bull. 2001, 24, 525.
(19) (a) Ackrill, T. D.; Sparkes, H. A.; Willis, C. L. Org. Lett.
2015, 17, 3884. (b) Yang, X.-F.; Wang, M.; Zhang, Y.; Li, C.-J.
Synlett 2005, 1912. (d) Reddy, B. V. S.; Reddy, M. R.; Reddy, S.
G.; Sridhar, B.; Kumar, S. K. Eur. J. Org. Chem. 2015, 2015,
3103. (d) Cakir, S. P.; Stokes, S.; Sygula, A.; Mead, K. T. J. Org.
Chem. 2009, 74, 7529.
(4) For selected examples, see: (a) Zhu, X.-F.; Lan, J.; Kwon, O.
J. Am. Chem. Soc. 2003, 125, 4716. (b) Tran, Y. S.; Kwon, O. J.
Am. Chem. Soc. 2007, 129, 12632. (c) Meng, X.; Huang, Y.;
Zhao, H.; Xie, P.; Ma, J.; Chen, R. Org. Lett. 2009, 11, 991. (d)
Zheng, J.; Huang, Y.; Li, Z. Org. Lett. 2013, 15, 5064. (e) Li, E.;
Huang, Y.; Liang, L.; Xie, P. Org. Lett. 2013, 15, 3138. (f) Li, E.;
Jia, P.; Liang, L.; Huang, Y. ACS Catal. 2014, 4, 600. (g)
Gicquel, M.; Gomez, C.; Retailleau, P.; Voituriez, A.; Marinetti,
A. Org. Lett. 2013, 15, 4002.
(5) For selected examples, see: (a) Zhao, G.-L.; Shi, Y.-L.; Shi,
M. Org. Lett. 2005, 7, 4527. (b) Guan, X.-Y.; Wei, Y.; Shi, M.
Org. Lett. 2010, 12, 5024. (c) Sun, Y.-W.; Guan, X.-Y.; Shi, M.
Org. Lett. 2010, 12, 5664. (d) Zhao, G.-L.; Huang, J.-W.; Shi, M.
Org. Lett. 2003, 5, 4737. (e) Yao, W.; Dou, X.; Lu, Y. J. Am.
Chem. Soc. 2015, 137, 54. (f) Takizawa, S.; Kishi, K.; Yoshida,
Y.; Mader, S.; Arteaga, F. A.; Lee, S.; Hoshino, M.; Rueping, M.;
Fujita, M.; Sasai, H. Angew. Chem., Int. Ed. 2015, 54, 15511. (g)
Guo, H.; Xu, Q.; Kwon, O. J. Am. Chem. Soc. 2009, 131, 6318.
(h) Sankar, M. G.; Garcia-Castro, M.; Golz, C.; Strohmann, C.;
Kumar, K. Angew. Chem., Int. Ed. 2016, 55, 9709. (i) Meng, W.;
Zhao, H.-T.; Nie, J.; Zheng, Y.; Fu, A.; Ma, J.-A. Chem. Sci.
2012, 3, 3053. (j) Xu, S.; Zhou, L.; Ma, R.; Song, H.; He, Z. Org.
Lett. 2010, 12, 544. (k) Tian, J.; He, Z. Chem. Commun. 2013, 49,
2058.
(6) Alternatively, the carbanion of zwitterionic intermediate is
capable of serving as a base to initiate umpolung γ-addition. (a)
Trost, B. M.; Li, C.- J. J. Am. Chem. Soc. 1994, 116, 3167. (b) Lu,
C.; Lu, X. Org. Lett. 2002, 4, 4677. (c) Liu, B.; Davis, R.; Joshi,
B.; Reynolds, D. W. J. Org. Chem. 2002, 67, 4595.
(20) (a) Wang, X.; Fang, T.; Tong, X. Angew. Chem., Int. Ed.
2011, 50, 5361. (b) Ashtekar, K. D.; Staples, R. J.; Borhan, B.
Org. Lett. 2011, 13, 5732.
(7) Zhang, Q.; Yang, L.; Tong, X. J. Am. Chem. Soc. 2010, 132,
2550.
(8) (a) Han, X.; Yao, W.; Wang, T.; Tan, Y. R.; Yan, Z.;
Kwiatkowski, J.; Lu, Y. Angew. Chem., Int. Ed. 2014, 53, 5643.
(b) Ziegler, D. T.; Riesgo, L.; Ikeda, T.; Fujiwara, Y.; Fu, G. C.
Angew. Chem., Int. Ed. 2014, 53, 13183. (c) Kramer, S.; Fu. G. C.
J. Am. Chem. Soc. 2015, 137, 3803.
(21) (a) Liu, H.; Zhang, Q.; Wang, L.; Tong, X. Chem. Eur. J.
2010, 16, 1968. (b) Zhu, X.-F.; Henry, C. E.; Kwon, O. J. Am.
Chem. Soc. 2007, 129, 6722.
(9) (a) Li, C.; Zhang, Q.; Tong, X. Chem. Commun. 2010, 46,
7828. (b) Li, K.; Hu, J.; Liu, H.; Tong, X. Chem. Commun. 2012,
48, 2900. (c) Gu, Y.; Hu, P.; Ni, C.; Tong, X. J. Am. Chem. Soc.
2015, 137, 6400.
(10) Hu, J.; Dong, W.; Wu, X.-Y.; Tong, X. Org. Lett. 2012, 14,
5530.
(11) For preliminary results, see: Zhou, W.; Ni, C.; Chen, J.;
Wang, D.; Tong, X. Org. Lett. 2017, 19, 1890.
(12) Gu, Y.; Li, F.; Hu, P.; Liao, D.; Tong, X. Org. Lett. 2015, 17,
1106.
(13) The different catalytic behavior between of tertiary
phosphine and amine has been cearly elucidated by Miller and
co-workers: Evans, C. A.; Miller, S. J. J. Am. Chem. Soc. 2003,
125, 12394.
(14) For reviews, see: (a) Yoon, T. P.; Jacobsen, E. N. Science
2003, 299, 1691. (b) Privileged Chiral Ligands and Catalysts;
Zhou, Q.-L., Ed.; Wiley-VCH: Weinheim, Germany, 2011. (c)
Morrill, L. C.; Smith, A. D. Chem. Soc. Rev. 2014, 43, 6214. (d)
France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. Rev.
2003, 103, 2985. (e) Masson, G.; Housseman, C.; Zhu, J. Angew.
Chem., Int. Ed. 2007, 46, 4614. (f) Tian, S.-K.; Chen, Y.; Hang,
J.; Tang, L.; McDaid, P.; Deng, L. Acc. Chem. Res. 2004, 37, 621.
(g) Stegbauer, L.; Sladojevich, F.; Dixon, D. J. Chem. Sci. 2012,
3, 942. (h) Marcelli, T.; van Maarseveen, J. H.; Hiemstra, H.
Angew. Chem., Int. Ed. 2006, 45, 7496. (i) Marcelli, T.; Hiemstra,
H. Synthesis 2010, 1229.