Rh-Catalyzed Chemoselective [4 + 1] Cycloaddition Reaction toward Diverse 4-Methyleneprolines

Article abstract of DOI:10.1021/acs.joc.9b01466

An efficient synthesis of 4-methyleneproline derivatives has been developed through an Rh-catalyzed [4 + 1] cycloaddition strategy using 3-methyleneazetidines and diazo compounds. The reaction proceeds under very mild conditions with a high degree of chemoselectivity, and competing experiments revealed that it is the preferred reaction, dominant over the C-H insertion, O-H insertion, and olefin cyclopropanation reactions which are commonly observed in Rh carbene chemistry. This method can incorporate the proline ester scaffold in pharmaceuticals and natural products. The intramolecular version of the reaction effectively provides proline-fused small to medium-sized tricyclic heterocycles. Gram-scale reactions, one-time addition of diazo compounds, and a minimum catalyst loading of 0.1 mol %, proceeded smoothly, implying their practicality.

Full text of DOI:10.1021/acs.joc.9b01466

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Article
Rh-Catalyzed Chemoselective [4+1] Cycloaddition
Reaction towards Diverse 4-Methyleneprolines
Wangshui Cai, Junxian Wu, Haowei Zhang, Hitesh B Jalani, Guigen Li, and Hongjian Lu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01466 • Publication Date (Web): 06 Aug 2019
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Rh-Catalyzed Chemoselective [4+1] Cycloaddition
Reaction towards Diverse 4-Methyleneprolines
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Wangshui Cai,† Junxian Wu,† Haowei Zhang,† Hitesh B. Jalani,†,‡ Guigen
Li*,†,δ and Hongjian Lu*,†
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† Institute of Chemistry & BioMedical Sciences, Nanjing University, Nanjing
210023, China
‡ Smart BioPharm, 310-Pilotplant, Incheon Techno-Park, 12-Gaetbeol-ro, Yeonsu-gu,
Incheon 21999 & Yonsei University, College of Pharmacy, 85-Songdogwahak-ro,
Incheon 21983, South Korea
δ Department of Chemistry and Biochemistry, Texas Tech University, Lubbock,
Texas 79409-1061, United States
Email: guigenli@nju.edu.cn; hongjianlu@nju.edu.cn
R4HC
N2
R4HC
Intramolecular
up to 0.1 mol %
Rh2(OAc)4
Intermolecular
up to 0.1 mol %
Rh2(OAc)4
O
O
R2
R3
COOR1
O
R2
N
O
R1
R2
N
R3
1 one-time protocol
one-time protocol
n
R
R3
N
R4
link for intramolecular
2R = H, Ar, COR3
n = 4 to 8
ABSTRACT: An efficient synthesis of 4-methyleneproline derivatives has been
developed through an Rh-catalyzed [4+1] cycloaddition strategy using
3-methyleneazetidines and diazo compounds. The reaction proceeds under very mild
conditions with a high degree of chemoselectivity and competing experiments
revealed that it is the preferred reaction, dominant over the C−H insertion, O−H
insertion and olefin cyclopropanation reactions which are commonly observed in Rh
carbene chemistry. This method can incorporate the proline ester scaffold in
pharmaceuticals and natural products. Intramolecular version of the reaction
effectively provides proline-fused small to medium sized tricyclic heterocycles. Gram
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scale reactions wherein one-time addition of diazo compounds and a minimum
catalyst loading of 0.1 mol%, proceeded smoothly, implying its practicality.
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Introduction
Introduction of rigid amino acid residues into native peptides often helps to
overcome the peptides’ shortcomings in pharmacology, by means of low
bioavailability, enzymatic instability or lack of selectivity towards specific receptors.
This evidently results in restricted conformational freedom, often is a defense against
the consequences of proteolytic degradation and thereby, can lead to improved
selectivity or potency.1 Because of the conformational rigidity of pyrrolidine
structures and the hinge-like behavior displayed at peptide bonds, proline analogues
play a unique role in the formation of secondary structures, which affect the overall
biological outcome of peptides.2 Application of proline analogues has enormous
potential in drug discovery, which continuously fuels their synthetic endeavor.
4-Methyleneproline is a rare, naturally occurring racemic amino acid isolated from the
seeds of the loquat tree fruits, and the plants of the Raphiolepis indica and Afzelia
bella families,3 is a key fragment in some natural products (Figure 1A). Moreover,
olefin functionalization of 4-methyleneproline is a known procedure for the synthesis
of different 4-substituted-prolines,4 which are important scaffolds found in natural
products, drugs and peptides.5 However, the methods for the synthesis of
4-methyleneproline and its analogues are poorly developed, and to date, are mostly
limited to the use of the Wittig reaction of 4-oxoproline derivatives (Path a, Figure
1B).6 Although much more efficient than other strategies incorporating intramolecular
ring formations of complex linear substrates (Path b, Figure 1B),7 cycloaddition
strategies have not been explored well and are primarily based on [3+2] reactions
which has a narrow substrates scope (Path c, Figure 1B).8
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A
. Selected examples of natural products containing 4-methyleneproline moiety
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HO
COO
H
N
N
N
COOH
H
N
HO
O
N
NH2
NH
O
H
N
9
O
H
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NHCOR
lucentamycins A,C,D
4-methyleneproline
Me
excelsinidine
O
AcO
H
O
CO2H
S
S
Me
OH
N
N
N
S
N
S
HOOC
H
H
OAc
O
CO2H
N
Me
OAc
O
O
H
isodomoic acid H (cis-olefin)
isodomoic acid G (trans-olefin)
acetylapoaranotin
Gliotoxin
B. Synthetic methods towards 4-methyleneprolines
O
COOR
X
X
Path c[8]
Path a[6]
HN
[3+2] cyclization
Wittig
COOR
PG
N
PG
R4
2R
1ROOC
COOH
N
Path b[7]
N2
Path d
N 3R
H
complex linear
substrates
[4+1] expansion
ring formations
This work
Link for intramolecular
Figure 1. Synthetic Methods for 4-Methyleneproline Analogues
The exocyclic C=C bond can assist in breaking intrinsically strained rings due to its
ability in stabilizing formed ions or radicals, and transfer to products which can be
further functionalized. Therefore, strained rings containing an exocyclic double bond,
such as vinylcyclopropanes,9 methylenecyclopropanes,10 vinylaziridines11 and
methyleneaziridines12 are reactive in various chemical transformations. Taking the
12
advantage of high reactivity of methyleneaziridines
and combining with the
cycloaddition strategies to access interesting heterocycles,13,14 Schomaker and
co-workers recently reported an cycloaddition protocol of methyleneaziridines into
methyleneazetidines. In this reaction, new C−C and C−N bonds were constructed
efficiently with adjacent functionalized stereocenters.15 The substrates scope in this
reaction was found to be limited to carbamate-derived bicyclic methyleneaziridines
which resulted in the restricted applications of the protocol and thereby prevented the
intramolecular reaction to achieve more complex products. Homologous to
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methyleneaziridines, 3-methyleneazetidines are easily prepared and stable,16 however,
very few reports on their transformations towards N-heterocycles have appeared.17
Inspired by the possibility of interesting cycloaddition strategies,14,18 and our earlier
work on the synthesis of fused pyridines/quinolines from 3-methyleneaazetidines,19
we report herein a general method for the synthesis of 4-methyleneproline derivatives,
proceeding through Rh-catalyzed [4+1] cycloaddition of 3-methyleneazetidines with
diazo compounds (Path d, Figure 1B).
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Results and Discussion
Our investigation commenced with the reaction between 3-methyleneazetidine (1a)
and phenyl diazoacetate (2a) in the presence of a metal catalyst (Scheme 1).20 Firstly,
different Rh catalysts were screened and found that Rh2(OAc)4 was the optimal
(entries 1-5). Other types of metal catalysts were then tested, the desired product 3aa
was achieved in 36% yield by using Cu(acac)2 catalyst under the reflux conditions.
After screening catalyst loading (entries 10-12) and solvent (entries 13-16), the
optimal condition was achieved (entry 12). The catalyst loading can be as low as 0.5
mol % without reducing the efficiency, however, in order to set up the reactions easily,
2 mol % catalyst loading was used when exploring the scope of the substrates (entry
1).
Scheme 1. Optimization of the Reaction Conditions
Ph
EtOOC
N2
catalyst
N
+
MeO
N
solvent, rt
Ph
COOEt
MeO
1a
2a
3aa
Entry catalyst (mol %)
solvent
DCM
DCM
time (h) yield (%)
1
Rh2(OAc)4 (2)
2
94a
2
Rh2 (TFA)4 (2)
2
84b
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3
[Rh(cod)Cl]2 (2)
[Cp*RhCl2]2 (2)
Rh2(esp)2 (2)
Ph3PAuCl (5)
AgOAc (5)
DCM
DCM
DCM
DCM
DCM
DCM
toluene
DCM
DCM
DCM
toluene
Et2O
2
2
2
2
2
2
8
1
4
12
4
4
4
4
8b
4
trace
72b
trace
trace
trace
36b
85a
5
6
10
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7
8
AgSbF6 (5)
9d
10
11
12
13
14
15
16
Cu(acac)2 (5)
Rh2(OAc)4 (5)
Rh2(OAc)4 (1)
Rh2(OAc)4 (0.5)
Rh2(OAc)4 (1)
Rh2(OAc)4 (1)
Rh2(OAc)4 (1)
Rh2(OAc)4 (1)
94a
95a
28b
55b
70b
68b
THF
MeCN
a Reactions were performed with 3-methyleneazetidine 1a (0.2 mmol) and diazo ester
2a (0.24 mmol) under Ar. The solution of diazo ester 2a should be dropwise added
during 1h. b isolated yield. c 3-methyleneazetidine 1a was recovered after the reaction.
d the reaction temperature was set to reflux.
The ester functionality in diazo compounds with sterically different groups was
tolerated well (Scheme 2), and the sterically hindered groups produced the desired
products, albeit with moderate yields (3aa-3ad). The reactions of both electron-rich
and electron-poor aryl diazoacetates were successful (3ae-3ag). Halogen substitution
on the aryl rings was tolerated well (3ah-3ai) and can provide an opportunity for
further transformations. Thiophene and naphthalene tethered diazo esters provided
desired 3aj-3ak in good yields. When the phenyl group of 2a was replaced by styrene,
3al was formed in high yield with no regio- or chemo-selectivity issues. As a
representative example of acceptor/acceptor diazo compounds, diethyl
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2-diazomalonate was successfully employed (3am). Ethyl diazoacetate also worked
well, producing N-phenyl-4- methyleneproline (3an). With 2-diazo-1-phenylethanone,
the pyrrolidine (3ao) was formed in moedrate yield.
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Scheme 2. Scope of Diazo Compound 2a, b
R
Rh2(OAc)4 (2 mol %)
DCM, rt, 3 h
R
+
N2
N
N
COR'
3aa 3ao
COR'
2a 2o
PMP
PMP
1a
-
-
Me
C6H5
CO2
C6H5
C6H5
CO2Et
N
N
N
CO2Me
PMP
PMP
PMP
iPr
[c]
3ab
3ac
, 96%
, 52% (dr = 1/1)
3aa
, 94%, 95%
C6H5
4-MeOC6H4
CO2Et
PMP
3ae
4-CF3C6H4
CO2Et
4-NO2C6H4
CO2Et
t
N
N
N
N
CO2 Bu
PMP
3ad
PMP
PMP
3ag
, 94%
3af
, 49%
, 89%
, 76%
S
4-FC6H4
CO2Et
4-BrC6H4
CO2Et
N
N
N
CO2Et
PMP
N
CO2Et
PMP
PMP
PMP
3ak
3ah,
3ai
3aj
73%
Ph
, 85%
, 95%
, 83%
H
H
CO2Et
N
N
N
N
CO2Et
, 81%
CO2Et
CO2Et
COPh
PMP
3al
PMP
3am
, 86%
PMP
3an
, 51%
PMP
3ao
[d]
[d]
[d]
, 54%
a
Standard Conditions: 1 (0.2 mmol), Rh2(OAc)4 (2 mol %), DCM (1 mL), 2
b
(0.24 mmol) in DCM (0.5 mL) was added dropwise over 1 h, then rt for 2 h.
Isolated yield. c 0.5 mol% Rh2(OAc)4. d Reflux in DCM .
After demonstrating the general scope of the diazo compounds, the scope of the
substrates with respect to the 3-methyleneazetidines was then explored (Scheme 3).
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Azetidines whose terminal carbon of the methylene group is substituted by
electron-rich or electron-deficient phenyl or alkyl groups were examined to determine
their influence on the reaction. They all reacted well (3ba-3ga). The N-phenyl group,
unsubstituted or with a meta- or para-substituent led to the corresponding proline
esters in good yields (3ha-3la). An N-heteroaryl group such as benzothiazole reduced
the efficiency (3ma), but the N-benzyl-3-methyleneazetidine provided 3nf in good
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Scheme 3. Scope of 3-Methyleneazetidine 1a, b
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CHR2
N
CHR2
N
COOEt
Standard conditions
Ar
+
N2
CO2Et
Ar
,
1R 3ba-3na
R1
1b-1q
2a 2f or 2n
9
CHEt
CHPh
N
CH(4-NO2C6H4)
Ph
CH(4-MeOC6H4)
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Ph
N
Ph
CO2Et
4-CF3C6H4
CO2Et
PMP
N
CO2Et
N
CO2Et
PMP
3ea
, 66% (1/1.6)
PMP
3ba
Ph
, 70% (1/1.8)
3cf
3da
, 78% (1/1.1)
, 86% (1/1)
CHiPr
CH(cyclopropanyl )
Ph
CHPh
CHPh
4-CF3C6H4
CO2Et
Ph
4-CF3C6H4
CO2Et
N
N
N
N
CO2Et
CO2Et
PMP
3ff
Ph
Ph
Ph
3hf
3ga
3ha
, 76% (1/1)
, 84% (1/1)
, 92% (1/1)
, 75% (1/1)
CHPh
CHPh
CHPh
CHPh
Ph
Ph
Ph
Ph
N
N
N
N
CO2Et
CO2Et
CO2Et
CO2Et
4-NO2C6H4
3-MeC6H4
3,5-DiMeC6H3
3-BrC6H4
3ia
3ja
3ka
3la,
, 76% (1/1)
, 75% (1/1)
, 68% (1/1)
61% (1/1)
CHPh
CHPh
N
Ph
Ph
Ph
4-CF3C6H4
Ph
N
CO2Et
CO2Et
N
N
CO2Et
CO2Me
N
S
PMP
PMP
4-MeC6H4
3nf
3on
, 54% (1/1)
3ob
3ma
, 65%
, 91% (1/1)
(1/1)
, 34% (1/1.7)
Me
O
Ph
EtOOC
Ph
4-CF3C6H4
EtO2C
N
CHiPr
CO2Et
N
N
Ph
4pf
, 64%
5qa
, 36%
PMP
not observed
a
b
Standard conditions, see note a in Scheme 2. Isolated yield, the ratio of
Z/E olefin isomers in the parentheses.
yield. Since the 4-conjugated-dienyl proline is also a key fragment of natural products
as shown in Figure 1, 1o was applied and the desired 4-conjugated-dienyl proline
esters (3on, 3ob) were obtained with good to excellent yields. In case of an N-phenyl
group with an ortho-methyl group, C(sp2)−H alkylation in the para-position was
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observed as a major pathway instead of cycloaddition reaction (4pf), suggesting that
steric hindrance near the nitrogen atom can influence the reaction. When the
methylene group was replaced with an oxygen atom, the C(sp3)−H alkylation was
obtained (5qa). The reaction failed to provide the desired product when
N-phenylazetidine was the substrate. These results clearly indicate that the presence of
the exocyclic double bond in azetidine is critical. When the exocyclic double bond is
absent, competitive side reactions predominate over the cycloaddition pathway.
Several experiments were carried out in order to understand the reaction
mechanism (Figure 2). The competitive reactions between two 3-methyleneazetidines
with different N-substituents were conducted, and showed that an electron-rich
N-substituted group could accelerate the reaction (Figure 2A). 3-Methyleneazetidine
with two deuteriums on the terminal carbon of the methylene (D2-1a) was reacted and
gave product D2-3aa with deuteriums remaining in the methylene group and some
deuteriums appearing in the pyrrolidine ring (Figure 2B). No shift of deuterium was
observed using the deuterium labeled compound D6-1b (D6-3ba). These results
suggest that the reaction may proceed through a stepwise reaction mechanism. When
applying a commercially available chiral catalyst Rh2(S-DOSP)4, no enantioselectivity
was observed (Figure 2C). Rh-carbene is known to participate in O−H insertion21 and
olefin cyclopropanation22, and we employed benzyl alcohol or styrene as an additive
to test the chemoselectivity of this reaction (Figure 2D). It was found that 3aa is still
formed predominantly and neither O−H insertion nor olefin cyclopropanation was
observed, suggesting that cycloaddition has a high degree of chemoselectivity and is
preferred over other reactions of Rh carbenes. Based on previous reports15 and our
own investigation, we propose a possible transformation via a two pathways
mechanism (Figure 2E). Rh-bound carbene is attacked by the azetidine nitrogen with
the release of Rh to form an ylide (A). The formation of A over competing C−H
insertion, alkene cyclopropanation or O−H insertion is supported by the known
reactivity of the nitrogen with electrophiles.20 Subsequently, A is transformed into
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3aa via direct 1, 2-migration (path I), or ring opening with zwitterionic species
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followed by ring closure (path II).
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A) Competitive reactions
2a
2a
(0.5 equiv)
(0.5 equiv)
1a
1n
1a
1i
+
+
3aa
15%
3na
28%
3aa
27%
3ia
8%
Standard
Standard
Conditions
Conditions
B) Deuterated experiments
Ph
PMP
Ph
PMP
N
PMP
CO2Et
CO2Et
PMPN
N
N
2a
2a
22%)
D(
Standard
22%)
D(
Standard
Conditions
Conditions
D
D
D
D
D
C6D5
1b
C6D5
3ba
D6-
D
93%
66%
(84%)(84%)
1a
(60%) (60%)
3aa
D6-
D2-
D2-
C) Attempts for asymmetric reaction
D) With additional reactants
Standard
Standard
Conditions
Conditions
3aa
1a
2a
3aa
+
1a
2a
+
Rh2(S-DOSP)4
92% yield, 0% ee
BnOH (1.0 equiv)
PhCH=CH2 (1.0 equiv)
79%
76%
Rh2(S-PTAD)4 0% yield
E) Proposed mechanistic rationale
path I
Ph
[Rh]
Ph
PMP N
COOEt
EtOOC
Ph
COOEt
-[Rh]
path II
stepwise
3aa
PMP N
PMP
N
A
Competition with O-H and C-H insertion
and olefin cyclopropantion
Figure 2. Control Experiments and Proposed Mechanism
The high chemoselectivity observed in this reaction, further tempted us to apply
this strategy to the late stage, predictable functionalization of natural products and
pharmaceutical compounds (Figure 3A). Although benzyl aryldiazoacetates are
known to undergo β-lactone formation through Rh-catalyzed intramolecular C−H
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alkylation of weak benzylic C−H bonds,23 the benzyl aryldiazoacetate derivative (2p)
selectively underwent an intermolecular Rh-catalyzed [4+1] reaction in the presence
of 3-methyleneazetidine, providing the Adapalene derivative (3ap) in good yield.
Similarly, the estrone-derived 3-benzylidineazetidine was converted to the
corresponding proline ester derivative (3sa) without being affected by weak benzylic
C−H bonds. A very interesting spiro-carbapenem compound (3aq) was achieved in
moderate yield, such structurally diverse carbapenam analog could be useful in
structural activity relation studies for better activity and ADME properties. Next, we
examined the chemoselectivity in the intramolecular reaction as it allows the
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construction
of
fused
rings
(Figure
3B).
In
the
reaction
of
N-phenyl-3-methyleneazetidine (6a) with an o-substituted diazo ester function in its
N-phenyl ring, the common intramolecular 1, 5-C−H alkylation was not observed, but
instead, the intramolecular [4+1] reaction led efficiently to a tricyclic N-heterocycle
(7a), with a newly formed strained azetidine between benzene and proline ester.
Inclusion of extra carbons may result in a larger ring attached directly to the
pyrrolidine or proline ring. In this context, a 5-membered ketone ring or 6- to
8-membered ester ring incorporating pyrrolidine were achieved with good yields
(7b-7e).
Functional group transformations of these newly synthesized structures were then
carried out (Figure 3C). Palladium-catalyzed selective reduction of 3aa provided
4-methylproline ester (8aa) in high yield. Olefinic cyclopropanation of 3aa produced
the corresponding difluoro-substituted spiro-cyclopropane derivative (9aa) as a single
isomer. The ester group was selectively reduced to a hydroxymethylene group (10aa).
In chloroform, this compound (10aa) converted spontaneously to a bridged
morpholine-like compound (11aa), a structural unit found in a number of
pharmaceuticals and natural products.24 A practical application of this method was
also tested with gram scale reactions (Figure 3D), in which both inter- and
intra-molecular reactions worked well with 0.1 mol % of catalyst loading and adding
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the diazo compound in one portion instead of in a dropwise manner.
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A) Drug or natural derivatives
O
CO2Bn
O
8
9
H
H
O
S
H
N
N
Ph
H
O
PMP
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11
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PMP
N
O
EtO2C
PhCF3p-
N
Adapalene
derivative
3ap
, 86%
Estrone
Carbapenem
derivative
derivative
3sa
, 75%
3aq
, 47% (dr > 20/1)
Ph
B) Intramolecular reactions
N2
R4HC
R4HC
2R
3R
COR1
R2
Rh2(OAc)4 (2 mol%)
DCM, rt, 3 h
COR1
R2
O
R1
or
N
R3
N
R3
N
n
R4
6
7
Ph
Ph
CHPh
CHPh
Ph
N2
N2
N2
O
O
CHPh
O
O
O
N
N
N2
O
O
Ph
N
CO2Me
N
CHPh
N
CHPh
N2
6a
6b
CHPh
6c
CHPh
6d
6e
CHPh
N
CHPh
N
CHPh
N
Ph
Ph
Ph
Ph
O
CO2Me
O
O
O
N
N
O
6
5
7
O
8
O
7a,
7b
, 79% (1/1.3)
7c
, 75% (1/1.2)
7d,
7e
83% (1/1.4)
81% (1/1.5)
, 61%, (1/1.2)
C) Transformations of product 3aa
Ph
Ph
(c) LiAlH4 , THF
87%
(a) H2, Pd/C, MeOH
92%
N
CH2OH
N
CO2Me
PMP
10aa
PMP
8aa
(dr = 1/1)
3aa
F
O
F
(c) LiAlH4 , THF
(d) CHCl3
72%
(b)TMSCF3, NaI,
THF, 65 0C
73%
Ph
N
Ph
PMP 11aa
N
CO2Me
PMP
(one isomer)
9aa
D) Inter- and Intra-molecular gram-scale reactions
CHPh
Rh2(OAc)4
1a
Rh2(OAc)4
(0.1 mol%)
(0.1 mol%
)
N
C6H5
6e
+
DCM, rt, 24 h.
One-time protocol
N
DCM, rt, 24 h.
One-time protocol
CO2Et
Ph
2a
PMP
3aa
O
7e
(1/1.2)
, 53%
O
2.19 g,
95%
0.242 g
Figure 3. Applications and Large Scale Reactions
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Conclusions
In summary, we have described a versatile and highly chemoselective and
regioselective Rh-catalyzed [4+1] cycloaddition strategy incorporating
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3-methyleneazetidines and diazo compounds, leading to the synthesis of diverse
4-methyleneprolines. Competitive experiments revealed the [4+1] cycloaddition
reaction is predominant over C−H insertion, O−H insertion and olefin
cyclopropanation which are common transformations in Rh carbene chemistry,
indicating the robustness of this method. Subsequently, intramolecular reaction was
well explored, and allowed the formation of various tricyclic fused small to moderate
N-heterocycles, which are otherwise difficult to produce by conventional methods,
showing the significant contribution of the present protocol towards diverse structural
features. This protocol allows the modifications of drug substances and natural
products analogs incorporating 4-methyleneproline systems as a result of post
synthetic functional group transformation. Additionally, the gram scale reactions
worked well using 0.1 mol % catalyst with the addition of diazo compounds in one
portion. We expect this work will support a better understanding and exploitation of
the reaction of 3-methyleneazetidines.
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Experimental Section
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General. The reactions were carried out under Argon atmosphere. Commercially available
reagents were used without further purification. 1H NMR spectra were recorded on a NMR
instrument operated at 400 MHz. Chemical shifts are reported in ppm from tetramethylsilane with
the solvent resonance as the internal standard (CDCl3: δ 7.26 ppm, CD3OD: δ 3.31 ppm,
CD3SOCD3: δ 2.50 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, d
= doublet, t = triplet, q = quartet, br = broad, m = multiplet or unresolved), coupling constants
(Hz), and integration. 13C {H} NMR spectra were recorded on a NMR instrument operated at 100
MHz with complete proton decoupling. Infrared spectra were recorded from thin films of pure
samples. Mass and HRMS spectra were measured in EI or ESI mode and the mass analyzer type
used for the HRMS was TOF. Flash column chromatography was performed on silica gel.
General methods for preparation of substrates 1 are according literature.19 Compounds 1a,
1c, 1d, 1e, 1f, 1i, 1l, 1n, 1o and 1q are new compounds. Compounds 1b, 1g, 1h, 1j, 1k, 1m and
1p are known compounds and the corresponding NMR dates are consistent with literature
reports.19
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1-(4-Methoxyphenyl)-3ethyleneazetidine (1a): Rf = 0.3 (EA : PE = 1 : 10), yellow solid, yield:
0.54 g, 31%, mp: 50.3-51.8 oC. 1H NMR (400 MHz, CDCl3) δ 6.86 (d, J = 8.9 Hz, 2H), 6.49 (d, J
= 8.9 Hz, 2H), 5.01 (t, J = 2.4 Hz, 2H), 4.43 (s, 4H), 3.79 (s, 3H). 13C {H} NMR (101 MHz,
CDCl3) δ 152.3, 146.1, 139.8, 114.6, 113.2, 105.7, 61.6, 55.8. IR (film): 3028, 2899, 1625, 1453,
1120, 1121, 747, 691cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H14NO 176.1070;
Found 176.1074.
3-Benzylidene-1-(4-methoxyphenyl)azetidine (1b): Rf = 0.2 (EA : PE = 1 : 10), yellow solid,
yield: 1.56 g, 62%. 1H NMR (400 MHz, CDCl3) δ 7.35 (t, J = 7.6 Hz, 2H), 7.23 (t, J = 7.4 Hz, 1H),
7.16 (d, J = 7.7 Hz, 2H), 6.89 – 6.84 (m, 2H), 6.56 – 6.51 (m, 2H), 6.28 (p, J = 2.3 Hz, 1H), 4.77
(q, J = 2.8 Hz, 2H), 4.58 (q, J = 2.6 Hz, 2H), 3.78 (s,3H).
3-(4-Methoxybenzylidene)-1-(4-methoxyphenyl)azetidine (1c): Rf = 0.2 (EA : PE = 1 : 10),
yellow solid, yield: 1.53 g, 62%. 1H NMR (400 MHz, CDCl3) δ 7.12 (m, 2H), 6.89 (m, 4H), 6.55
(m, 2H), 6.24 (t, J = 2.3 Hz, 1H), 4.77 (d, J = 2.9 Hz, 2H), 4.59 (d, J = 2.8 Hz, 2H), 3.84 (s, 3H),
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3.80 (s, 3H). 13C {H} NMR (101 MHz, CDCl3) δ 153.5, 141.4, 136.6, 133.3, 128.6, 127.2, 120.7,
5
6
116.4, 115.4, 113.3, 62.8, 62.8, 55.9. IR (film): 3057, 2894, 1605, 1450, 1180, 1120, 741, 686
7
8
9
cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H19NO 282.1489; Found 282.1491.
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3-(4-Nitrobenzylidene)-1-phenylazetidine (1d): Rf = 0.2 (EA : PE = 1 : 5), yellow solid, yield:
2.02 g, 76%, mp: 102.5-103.9 oC. 1H NMR (400 MHz, CDCl3) δ 8.18 (m, 2H), 7.40 (m, 2H), 7.30
(t, J = 7.5 Hz, 1H), 7.19 (m, 2H), 6.46 (m, 2H), 6.43 (m, 1H), 4.98 (q, J = 3.1 Hz, 2H), 4.80 (q, J =
2.9 Hz, 2H). 13C {H} NMR (101 MHz, CDCl3) δ 153.8, 138.1, 135.8, 129.2, 128.8, 127.4, 127.2,
126.2, 122.8, 109.7, 60.8, 60.7. IR (film): 3048, 2891, 1615, 1452, 1181, 1121, 742, 686 cm-1;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H15N2O2 267.1128; Found 267.1130.
1-(4-Methoxyphenyl)-3-propylideneazetidine (1e): Rf = 0.5 (EA : PE = 1 : 20), yellow solid,
1
yield: 1.24 g, 61%. H NMR (400 MHz, CDCl3) δ 6.85 (d, J = 8.9 Hz, 2H), 6.48 (d, J = 8.8 Hz,
2H), 5.31 (td, J = 7.2, 2.3 Hz, 1H), 4.40 (ddd, J = 15.4, 2.8, 1.4 Hz, 4H), 3.78 (s, 3H), 1.98 (ddd, J
= 8.8, 5.1, 1.4 Hz, 2H), 1.02 (t, J = 7.5 Hz, 3H). 13C {H} NMR (101 MHz, CDCl3) δ 152.1, 146.2,
128.9, 122.8, 114.7, 113.1, 60.9, 59.8, 55.8, 22.0, 13.9. IR (film): 3032, 2889, 1635, 1452, 1181,
1121, 742, 686 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H18NO 204.1383; Found
204.1385.
1-(4-Methoxyphenyl)-3-(2-methylpropylidene)azetidine (1f): Rf = 0.3 (EA : PE = 1 : 10),
yellow solid, yield: 1.00 g, 46%. 1H NMR (400 MHz, CDCl3) δ 6.85 (d, J = 8.8 Hz, 2H), 6.47 (d,
J = 8.9 Hz, 2H), 5.18 (dt, J = 8.6, 2.3 Hz, 1H), 4.44 (q, J = 2.5 Hz, 2H), 4.37 (t, J = 2.4 Hz, 2H),
3.78 (s, 3H), 2.38 – 2.24 (m, 1H), 1.01 (d, J = 6.7 Hz, 6H). 13C {H} NMR (101 MHz, CDCl3) δ
152.1, 146.2, 128.2, 127.3, 114.6, 113.0, 60.9, 59.9, 55.8, 28.6, 22.6. IR (film): 3049, 2901, 1605,
1461, 1175, 1103, 749, 695 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H20NO 218.1539;
Found 218.1541. 3-(Cyclopropylmethylene)-1-phenylazetidine (1g): Rf = 0.4 (EA : PE = 1 : 10),
1
yellow solid, yield: 1.24 g, 67%. H NMR (400 MHz, CDCl3) δ 7.27 (td, J = 7.3, 2.1 Hz, 2H),
6.78 (t, J = 7.3 Hz, 1H), 6.59 – 6.49 (m, 2H), 4.84 (dt, J = 9.3, 2.3 Hz, 1H), 4.58 (q, J = 2.6 Hz,
2H), 4.45 (q, J = 2.4 Hz, 2H), 1.36 – 1.23 (m, 1H), 0.81 – 0.71 (m, 2H), 0.41 (dt, J = 6.5, 4.5 Hz,
2H).
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1-([1,1'-Biphenyl]-4-yl)-3-benzylideneazetidine (1h): Rf = 0.4 (EA : PE = 1 : 10), yellow solid,
yield: 1.69 g, 78%, mp: 61.7-62.9 oC. 1H NMR (400 MHz, CDCl3) δ 7.61 (m, 4H), 7.44 (m, 4H),
7.37 – 7.28 (m, 2H), 7.27 – 7.20 (m, 2H), 6.73 – 6.64 (m, 2H), 6.36 (m, 1H), 4.91 (q, J = 2.9 Hz,
2H), 4.72 (q, J = 2.7 Hz, 2H).
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3-Benzylidene-1-(4-nitrophenyl)azetidine (1i): Rf = 0.2 (EA : PE = 1 : 5), yellow solid,
yield:1.94 g, 73%. 1H NMR (400 MHz, CDCl3) δ 8.19 (m, 2H), 7.40 (t, J = 7.5 Hz, 2H), 7.30 (m,
1H), 7.20 (m, 2H), 6.46 (m, 2H), 6.40 (m, 1H), 4.98 (q, J = 3.1 Hz, 2H), 4.80 (q, J = 2.9 Hz, 2H).
13C {H} NMR (101 MHz, CDCl3) δ 153.8, 138.1, 135.8, 129.2, 128.8, 127.4, 127.2, 126.1, 122.8,
109.7, 60.8, 60.6. IR (film): 3048, 2891, 1615, 1452, 1181, 1121, 742, 686 cm-1; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C16H15N2O2 267.1128; Found 267.1132.
3-Benzylidene-1-(m-tolyl)azetidine (1j): Rf = 0.2 (EA : PE = 1 : 5), yellow solid, yield: 1.57 g,
67%, mp: 66.6-67.9 oC. 1H NMR (400 MHz, CDCl3) δ 7.41 (m, 2H), 7.30 (m, 1H), 7.26 – 7.18
(m, 3H), 6.68 (m, 1H), 6.44 (m, 2H), 6.34 (m, 1H), 4.86 (q, J = 2.9 Hz, 2H), 4.67 (q, J = 2.7 Hz,
2H), 2.40 (s, 3H).
3-Benzylidene-1-(3,5-dimethylphenyl) azetidine (1k): Rf = 0.4 (EA : PE = 1 : 10), yellow solid,
yield: 1.89 g, 76%, mp: 71.8-72.9 oC. 1H NMR (400 MHz, CDCl3) δ 7.39 (m, 2H), 7.30 – 7.24 (m,
1H), 7.21 (m, 2H), 6.50 (s, 1H), 6.32 (m, 1H), 6.25 (s, 2H), 4.84 (d, J = 2.7 Hz, 2H), 4.64 (d, J =
2.6 Hz, 2H), 2.34 (s, 6H).
3-Benzylidene-1-(3-bromophenyl)azetidine (1l): Rf = 0.5 (EA : PE = 1 : 20), yellow solid, yield:
2.11 g, 70%, the ratio of Z/E olefin isomers 1/3. 1H NMR (400 MHz, CDCl3) δ 7.39 (t, J = 7.5 Hz,
2H), 7.28 (d, J = 6.3 Hz, 1H), 7.19 (d, J = 7.6 Hz, 2H), 7.13 (t, J = 7.9 Hz, 1H), 6.99 (t, J = 7.9 Hz,
0.25H), 6.92 (dd, J = 7.8, 1.8 Hz, 1H), 6.71 (d, J = 2.1 Hz, 0.75H), 6.49 (ddd, J = 14.9, 8.1, 2.3 Hz,
1H), 6.34 (p, J = 2.3 Hz, 1H), 4.83 (q, J = 3.1 Hz, 2H), 4.64 (q, J = 2.9 Hz, 2H). 13C {H} NMR
(101 MHz, CDCl3) δ 152.0, 136.3, 131.8, 131.8, 130.4, 130.3, 128.7, 127.1, 127.0, 126.4, 123.1,
121.7, 121.7, 120.6, 120.4, 114.7, 111.0, 110.4, 61.4, 61.3. IR (film): 3049, 2908, 1615, 1467,
1303, 1200, 771, 691 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H15BrN 300.0382;
Found 300.0385.
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4-(3-Benzylideneazetidin-1-yl)benzo[d]thiazole (1m): Rf = 0.3 (EA : PE = 1 : 5), yellow solid,
yield:0.58 g, 21%. 1H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 7.40 (m, 2H), 7.37 – 7.31 (m, 2H),
7.27 (m, 3H), 6.52 (m, 1H), 6.35 (t, J = 2.4 Hz, 1H), 5.27 (q, J = 3.0 Hz, 2H), 5.02 (q, J = 2.8 Hz,
2H).
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3-Benzylidene-1-(4-methylbenzyl)azetidine (1n): Rf = 0.3 (EA : PE = 1 : 5), yellow solid, yield:
2.38 g, 95%. 1H NMR (400 MHz, CDCl3) δ 7.29 (m, 5H), 7.18 (d, J = 7.8 Hz, 2H), 7.11 (m, 2H),
6.19 (t, J = 2.4 Hz, 1H), 4.23 (q, J = 2.7 Hz, 1H), 4.07 (q, J = 2.4 Hz, 2H), 3.80 (s, 2H), 2.38 (s,
3H). 13C {H} NMR (101 MHz, CDCl3) δ 138.1, 137.2, 136.9, 136.7, 135.3, 129.2, 128.4, 127.1,
126.4, 120.7, 65.1, 63.2, 63.1, 21.1. IR (film): 3030, 2913, 1624, 1454, 1219, 1171, 756, 687 cm-1;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H20N 250.1590; Found 250.1594.
(Z/E)-1-(4-Methoxyphenyl)-3-(3-phenylallylidene)azetidine (1o): Rf = 0.3 (EA : PE = 1 : 20),
yellow solid, yield: 1.5 g, 54%, mp: 127.9-128.5 oC. 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J =
7.7 Hz, 2H), 7.35 (t, J = 7.5 Hz, 2H), 7.28 (d, J = 1.1 Hz, 1H), 7.25 (t, J = 7.3 Hz, 1H), 6.88 (m,
2H), 6.66 (dd, J = 15.6, 10.7 Hz, 1H), 6.51 (m, 2H), 4.63 (d, J = 3.1 Hz, 2H), 4.53 (s, 2H), 3.79 (d,
J = 1.2 Hz, 3H). 13C {H} NMR (101 MHz, CDCl3) δ 152.4, 145.9, 137.3, 134.6, 131.2, 128.6,
127.5, 126.2, 124.1, 121.2, 114.7, 113.1, 61.2, 60.4, 55.8. IR (film): 3028, 2915, 1625, 1454, 1219,
1171, 756, 687 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H20NO 278.1539; Found
278.1543.
3-(2-Methylpropylidene)-1-(o-tolyl)azetidine (1p): Rf = 0.3 (EA : PE = 1 : 20), yellow oil, yield:
1
1.13 g, 48%. H NMR (400 MHz, CDCl3) δ 7.21 – 7.13 (m, 1H), 7.14 – 7.07 (m, 1H), 6.81 (m,
1H), 6.57 (m, 1H), 5.20 (dt, J = 8.7, 2.2 Hz, 1H), 4.57 (q, J = 2.4 Hz, 2H), 4.50 (q, J = 2.3 Hz, 2H),
2.34 (dq, J = 8.8, 6.8 Hz, 1H), 2.29 (s, 3H), 1.05 (d, J = 6.7 Hz, 6H).
1-(4-Methoxyphenyl)azetidin-3-one (1q): Rf = 0.4 (EA : PE = 1 : 5), yellow solid, yield: 1.52 g,
1
86%. H NMR (400 MHz, CDCl3) δ 6.91 (d, J = 8.9 Hz, 2H), 6.59 (d, J = 8.9 Hz, 2H), 4.64 (s,
4H), 3.80 (s, 3H). 13C {H} NMR (101 MHz, CDCl3) δ 198.0, 153.1, 144.3, 114.8, 114.5, 73.8,
55.7. IR (film): 3042, 2978, 1710, 1645, 1478, 1246, cm-1; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C10H12NO2 178.0863; Found 178.0866.
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1-Phenylazetidine (1r): Rf = 0.4 (EA : PE = 1 : 50), pale yellow solid, yield: 1.23 g, 92%. H
NMR (400 MHz, CDCl3) δ 7.30 (m, 2H), 6.77 (t, J = 7.3 Hz, 1H), 6.48 (m, 2H), 3.91 (t, J = 7.2
Hz, 4H), 2.39 (p, J = 7.2 Hz, 2H). 13C {H} NMR (101 MHz, CDCl3) δ 152.3, 128.9, 117.3, 111.3,
52.4, 17.0. IR (film): 3029, 2898, 1645, 1465, 1109, 789, 687 cm-1; HRMS (ESI-TOF) m/z: [M +
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H]+
Calcd
for
C9H12N
134.0964;
Found
134.0966.
(8R,9S,13S,14S)-3-(3-Benzylideneazetidin-1-yl)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydr
o-17H-cyclopenta[a]phenanthren-17-one (1s): Rf = 0.4 (EA : PE = 1: 10), pale yellow solid,
yield: 3.66 g, 92%, mp: 150.9-151.8 oC, the ratio of Z/E is 1/1. 1H NMR (400 MHz, CDCl3) δ 7.37
(t, J = 7.5 Hz, 2H), 7.24 (dd, J = 12.0, 7.8 Hz, 2H), 7.19 (d, J = 7.6 Hz, 2H), 6.44 (dd, J = 8.3, 2.5
Hz, 1H), 6.38 – 6.22 (m, 2H), 4.82 (q, J = 2.9 Hz, 2H), 4.62 (q, J = 2.7 Hz, 2H), 2.94 (dd, J = 10.1,
6.3 Hz, 2H), 2.53 (dd, J = 18.8, 8.5 Hz, 1H), 2.43 (d, J = 9.9 Hz, 1H), 2.28 (s, 1H), 2.23 – 1.94 (m,
4H), 1.56 (d, J = 23.2 Hz, 6H), 0.93 (s, 3H). 13C {H} NMR (101 MHz, CDCl3) δ 149.3, 137.1,
136.5, 133.0, 129.3, 128.6, 127.1, 126.7, 126.0, 121.1, 112.2, 110.0, 61.7, 61.6, 50.4, 48.0, 44.0,
38.5, 35.9, 31.6, 29.7, 26.6, 25.9, 21.6, 13.8. IR (film): 3044, 2936, 1680, 1635, 1452, 1181, 1040,
741, 686 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C28H32NO 398.2478; Found 398.2472.
1-(4-Methoxyphenyl)-3-(methylene-d2)azetidine (D2-1a): Rf = 0.3 (EA : PE = 1 : 10), yellow
solid, yield: 0.55 g, 31%. 1H NMR (400 MHz, CDCl3) δ 6.86 (d, J = 8.9 Hz, 2H), 6.49 (d, J = 8.9
Hz, 2H), 5.01 (t, J = 2.4 Hz, 0.32H), 4.43 (s, 4H), 3.79 (s, 3H). 13C {H} NMR (101 MHz, CDCl3)
δ 152.3, 146.1, 139.8, 114.7, 113.2, 105.8, 61.6, 55.9. IR (film): 3028, 2899, 1625, 1453, 1120,
1121, 747, 691cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H12D2NO 178.1195; Found
178.1198.
3-(Hepta-2,4,6-triyn-1-ylidene-d6)-1-(4-methoxyphenyl)azetidine (D6-1b): Rf = 0.3 (EA : PE =
1 : 10), yellow solid, yield: 2.01 g, 78%. 1H NMR (400 MHz, CDCl3) δ 6.91 (d, J = 8.3 Hz, 2H),
13
6.57 (d, J = 8.4 Hz, 2H), 4.81 (t, J = 3.0 Hz, 2H), 4.62 (t, J = 3.0 Hz, 2H), 3.82 (s, 3H). C {H}
NMR (101 MHz, CDCl3) δ 153.5, 141.4, 136.6, 133.2, 128.6, 127.2, 126.8, 121.7, 120.7, 116.4,
115.4, 113.3, 62.8, 62.8, 55.9. IR (film): 3047, 2924, 1605, 1450, 1180, 1040, 741, 686 cm-1;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H12D6NO 258.1760; Found 258.1764.
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Methods for preparation of diazo compounds 2 are according to the literature. Diazo
compounds 2 are known compounds and the NMR dates of diazo compounds 2 are consistent with
literature reports. 25 Compounds 2m and 2n are commercially available.
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Ethyl 2-Diazo-2-phenylacetate (2a): Rf = 0.7 (EA : PE = 1 : 20), pale yellow oil, yield: 1.53 g,
81%. 1H NMR (400 MHz, CDCl3) δ 7.55 – 7.48 (m, 2H), 7.41 (t, J = 7.9 Hz, 2H), 7.25 – 7.15 (m,
1H), 4.36 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H).
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Methyl 2-Diazo-2-phenylacetate (2b): Rf = 0.7 (EA : PE = 1 : 20), pale yellow oil, yield: 1.41 g,
80%.1H NMR (400 MHz, CDCl3) δ 7.54 – 7.48 (m, 2H), 7.41 (dd, J = 8.5, 7.3 Hz, 2H), 7.25 –
7.17 (m, 1H), 3.90 (s, 3H).
(1S, 2R, 5S)-2-Isopropyl-5-methylcyclohexyl 2-diazo-2-phenylacetate (2c): Rf = 0.5 (EA : PE =
1
1 : 20), pale yellow oil, yield: 2.68 g, 89%. H NMR (400 MHz, CDCl3) δ 7.58 – 7.46 (m, 2H),
7.46 – 7.34 (m, 2H), 7.25 – 7.15 (m, 1H), 4.90 (td, J = 10.9, 4.4 Hz, 1H), 2.14 (dtd, J = 12.0, 4.0,
1.7 Hz, 1H), 1.94 (pd, J = 7.0, 2.8 Hz, 1H), 1.80 – 1.66 (m, 2H), 1.62 – 1.52 (m, 2H), 1.46 (ddt, J
= 10.9, 9.2, 3.1 Hz, 1H), 1.20 – 1.04 (m, 2H), 0.94 (dd, J = 6.8, 5.3 Hz, 6H), 0.83 (d, J = 6.9 Hz,
3H).
Tertbutyl 2-diazo-2-phenylacetate (2d): Rf = 0.7 (EA : PE = 1 : 20), pale yellow oil, yield: 1.33
g, 61%. 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.25 (m, 5H), 1.58 (s, 9H).
Ethyl 2-diazo-2-(4-methoxyphenyl)acetate (2e): Rf = 0.4 (EA : PE = 1 : 20), pale yellow oil,
yield:1.83 g, 83%. 1H NMR (400 MHz, CDCl3) δ 7.52 – 7.33 (m, 2H), 7.08 – 6.83 (m, 2H), 4.34
(q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H).
Ethyl 2-Diazo-2-(4-(trifluoromethyl)phenyl)acetate (2f): Rf = 0.8 (EA : PE = 1 : 20), pale
1
yellow oil, yield: 2.35 g, 91%. H NMR (400 MHz, CDCl3) δ 7.63 (s, 4H), 4.38 (q, J = 7.1 Hz,
2H), 1.38 (t, J = 7.1 Hz, 3H).
Ethyl 2-diazo-2-(4-nitrophenyl)acetate (2g): Rf = 0.4 (EA : PE = 1 : 5), pale yellow solid, yield:
2.01 g, 84 %. δ 8.01 (s, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.7 Hz,
1H), 7.49− 7.38 (m, 2H), 4.37 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H).Ethyl
2-Diazo-2-(4-fluorophenyl)acetate (2h): Rf = 0.7 (EA : PE = 1 : 20), pale yellow oil, yield: 1.89
1
g, 91%. H NMR (400 MHz, CDCl3) δ 7.47 (dd, J = 8.7, 5.1 Hz, 2H), 7.11 (t, J = 8.6 Hz, 2H),
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4.35 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H).
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Ethyl 2-(4-Bromophenyl)-2-diazoacetate (2i): Rf = 0.7 (EA : PE = 1 : 20), pale yellow oil, yield:
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8
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2.21 g, 82%. H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H),
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4.36 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H).
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Ethyl 2-Diazo-2-(thiophen-2-yl)acetate (2j): Rf = 0.7 (EA : PE = 1 : 20), pale yellow oil, yield:
1.49 g, 76%. 1H NMR (400 MHz, CDCl3) δ 7.27 – 7.18 (m, 1H), 6.98 (d, J = 6.4 Hz, 2H), 4.28 –
4.15 (m, 2H), 1.30 (dd, J = 8.0, 6.5 Hz, 3H).
Ethyl 2-Diazo-2-(naphthalen-2-yl)acetate (2k): Rf = 0.6 (EA : PE = 1 : 20), pale yellow oil,
1
yield: 1.49 g, 76%. H NMR (400 MHz, CDCl3) δ (ppm) 8.26-8.23 (m, 2H), 7.70-7.67 (m, 2H),
4.36-4.31 (q,
J
=
7.5 Hz, 2H), 1.36-1.32 (t,
J
=
7.5 Hz, 3H).Ethyl
(E)-2-Diazo-4-phenylbut-3-enoate (2l): Rf = 0.6 (EA : PE = 1 : 20), pale yellow oil, yield: 1.43 g,
1
66%. H NMR (400 MHz, CDCl3) δ 7.40 – 7.31 (m, 4H), 7.25 – 7.19 (m, 1H), 6.51 (d, J = 16.3
Hz, 1H), 6.22 (d, J = 16.3 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H).
2-Diazo-1-phenylethan-1-one (2o): Rf = 0.5 (EA : PE = 1 : 20), pale yellow oil, yield: 1.00 g,
57%. 1H NMR (400 MHz, CDCl3) δ 7.83 – 7.74 (m, 2H), 7.60 – 7.53 (m, 1H), 7.51 – 7.44 (m, 2H),
5.93 (s, 1H).
(6-(3-((1R,
3S,
5R
7R)-Adamantan-2-yl)-4-methoxyphenyl)naphthalen-2-yl)methyl
2-diazo-2-phenylacetate (2p): Rf = 0.5 (EA : PE = 1 : 10), pale yellow oil, yield: 385 mg, 71%.
1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 1.6 Hz, 1H), 7.87 (dd, J = 12.2, 8.5 Hz, 2H), 7.79 –
7.74 (m, 2H), 7.61 (d, J = 2.4 Hz, 1H), 7.55 (dd, J = 8.4, 2.3 Hz, 1H), 7.45 (d, J = 1.7 Hz, 1H),
7.37 – 7.32 (m, 5H), 7.02 (d, J = 8.4 Hz, 1H), 3.93 (s, 3H), 3.74 (d, J = 4.0 Hz, 2H), 2.22 (d, J =
2.9 Hz, 6H), 2.13 (t, J = 3.3 Hz, 3H), 1.83 (d, J = 3.0 Hz, 6H).
Benzyl (2S)-6-Diazo-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate (2q):
1
Rf = 0.3 (EA : PE = 1 : 10), pale yellow oil, yield: 2.16 g, 68%. H NMR (400 MHz, CDCl3) δ
7.38 (dd, J = 22.5, 8.1 Hz, 5H), 6.17 (d, J = 3.3 Hz, 1H), 5.19 (s, 2H), 4.39 (d, J = 3.4 Hz, 1H),
1.57 (d, J = 3.4 Hz, 3H), 1.32 (d, J = 3.3 Hz, 3H).
Methods for preparation of substrates 6.
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Methyl 2-(2-(3-Benzylideneazetidin-1-yl)phenyl)-2-diazoacetate (6a): the method as follows:
Rf = 0.3 (EA : PE = 1 : 10), pale yellow solid, yield: 352 mg, 55%. 1H NMR (400 MHz, CDCl3) δ
7.76 (m, 1H), 7.40 (m, 3H), 7.26 (m, 1H), 7.17 (m, 2H), 6.83 (t, J = 7.5 Hz, 1H), 6.67 (d, J = 8.4
Hz, 1H), 6.28 (p, J = 2.4 Hz, 1H), 4.87 (d, J = 3.0 Hz, 2H), 4.68 (d, J = 2.8 Hz, 2H), 3.95 (s, 3H).
13C {H} NMR (101 MHz, CDCl3) δ 167.8, 150.5, 136.4, 132.5, 132.4, 131.6, 128.7, 127.2, 126.8,
120.9, 117.3, 115.6, 114.4, 63.1, 62.9, 52.0. IR (film): 3028, 2894, 2234, 1680, 1605, 1450, 1180,
1040, 741, 686 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H18N3O2 320.1394; Found
320.1394.
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To a two-necked flask 2-(2-bromophenyl)acetic acid (2.13 g, 10 mmol) and MeOH (80 mL), DMF
o
(0.2 mL) were added under N2 atmosphere. (COCl)2 (1.3 mL, 15 mmol) was added at 0 C, then
the mixture was stirred at room temperature overnight. The mixture was evaporated and give the
crude product methyl 2-(2-bromophenyl)acetate.
To a 100 mL schlenk tube methyl 2-(2-bromophenyl)acetate (2.28 g, 10 mmol) and
3-benzylidene-1-chloro-1-azetidine (2.17 g, 12 mmol), Pd2dba3 (460 mg, 0.5 mmol), RuPhos (466
mg, 1 mmol), dioxane (50 mL), Cs2CO3 (8.12 g, 25 mmol) were added under N2 atmosphere. Then
o
the mixture was stirred at 100 C with oil bath overnight. The mixture was evaporated and
purification by column chromatography with petroleum ether and ethyl acetate to give the product
methyl 2-(2-(3-benzylideneazetidin-1-yl)phenyl)acetate. (2.11 g, 72%), Rf = 0.4 (EA : PE = 1 :
10).
To a two-necked flask methyl 2-(2-(3-benzylideneazetidin-1-yl)phenyl)acetate (586 mg, 2 mmol)
and P-ABSA (720 mg, 3 mmol), THF (20 mL) was added under N2 atmosphere. DBU (456 mg, 3
o
mmol) were added to the mixture dropwise at 0 C. Then warmed the temperature to room
temperature and stirred for overnight. The mixture was evaporated and purification by column
chromatography with petroleum ether and ethyl acetate to give the product 6a (350 mg, 55%).
1-(2-(3-Benzylideneazetidin-1-yl)phenyl)-2-diazo-2-phenylethen-1-one (6b): The method of
synthesizing 6b with 1-(2-bromophenyl)-2-phenylethan-1-one is the same as 6a. Rf = 0.3 (EA : PE
= 1 : 10), pale yellow solid, yield: 527 mg, 72%. 1H NMR (400 MHz, CDCl3) δ 7.61 (ddd, J =
15.2, 7.4, 1.8 Hz, 4H), 7.44 (dt, J = 18.0, 7.6 Hz, 4H), 7.37 – 7.28 (m, 2H), 7.27 – 7.20 (m, 2H),
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6.73 – 6.64 (m, 2H), 6.36 (p, J = 2.3 Hz, 1H), 4.91 (q, J = 2.9 Hz, 2H), 4.72 (q, J = 2.7 Hz, 2H).
13C {H} NMR (101 MHz, CDCl3) δ 169.9, 149.6, 146.7, 140.1, 139.9, 138.9, 134.4, 133.5, 129.6,
129.4, 129.0, 128.8, 128.4, 127.8, 127.7, 127.4, 127.2, 125.6, 75.1. IR (film): 3026, 2898, 2232,
1683, 1605, 1450, 1180, 1040, 741, 686 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C24H20N3O 366.1601; Found 366.1604.
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To a two-necked flask 2-bromobenzoic acid (2.01 g, 10 mmol) and DCM (80 mL), DMF (0.2 mL)
was added under N2 atmosphere. (COCl)2 (1.2 mg, 15 mmol) were added at 0 oC, then the mixture
was stirred at room temperature overnight. The mixture was evaporated and give the crude
product 2-bromobenzoyl chloride.
To a solution of bis[2-(N,N-dimethylaminoethyl)]ether (1 mL, 5.2 mmol) in THF (16 mL) was
added BnMgBr (2.60 mL, 5.2 mmol, 2 M solution in THF) at 0 oC. The mixture was stirred at 0-5
oC for 30 min. This mixture was slowly added to a solution of 2-bromobenzoyl chloride (538 mg,
o
o
2.0 mmol) at -60 C for 15 min, and the resulting mixture was stirred at -60 C for 10 min. The
mixture was then quenched with aqueous ammonium chloride. After extraction of the mixture
with EtOAc, the extract was dried over MgSO4 and concentrated. The residue was purified by
chromatography on silica gel to give 1-(2-bromophenyl)-2-phenylethan-1-one (409 mg, 75%), Rf
= 0.5 (EA : PE = 1 : 20).
2-(3-Benzylideneazetidin-1-yl)phenyl 2-Diazo-2-phenylacetate (6c): The method of
synthesizing 6c with 2-bromophenyl 2-phenylacetate is the same as 6a. Rf = 0.3 (EA : PE = 1 : 10),
1
pale yellow solid, yield: 634 mg, 83%. H NMR (400 MHz, CDCl3) δ 7.38 (t, J = 7.6 Hz, 2H),
7.36 – 7.27 (m, 6H), 7.20 (dd, J = 7.1, 5.5 Hz, 3H), 7.08 (dd, J = 7.5, 1.5 Hz, 1H), 6.84 (t, J = 7.4
Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 6.31 (t, J = 2.4 Hz, 1H), 4.88 (t, J = 2.8 Hz, 2H), 4.71 (t, J = 2.7
Hz, 2H). 13C {H} NMR (101 MHz, CDCl3) δ 169.9, 149.7, 147.7, 140.2, 139.1, 134.0, 132.2,
130.8, 129.3, 128.7, 128.7, 128.3, 128.3, 128.0, 127.5, 127.1, 127.0, 125.5, 77.3, 77.0. IR (film):
3039, 2899, 2233, 1698, 1603, 1452, 1181, 1040, 741, 686 cm-1; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C24H20N3O2 382.1550; Found 382.1554.
To a two-necked flask 2-bromophenol (1.73 g, 10 mmol) and DCM (80 mL), NEt3 (2.8 mL, 20
mmol) were added under N2 atmosphere. BnCOCl (4.4 mL, 15 mmol) was added at 0 oC, then the
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mixture was stirred at room temperature overnight. The mixture was evaporated and purification
by column chromatography with petroleum ether and ethyl acetate to give the product
2-bromophenyl 2-phenylacetate (2.62 g, 90%). Rf = 0.4 (EA : PE = 1 : 4)
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2-(3-Benzylideneazetidin-1-yl)benzyl 2-Diazo-2-phenylacetate (6d): The method of
synthesizing 6d with 2-bromobenzyl 2-phenylacetate is the same as 6a. Rf = 0.4 (EA : PE = 1 : 4),
pale yellow solid, yield: 584 mg, 74%. 1H NMR (400 MHz, CDCl3) δ 7.53 (m, 2H), 7.37 (m, 6H),
7.21 (m, 4H), 6.88 (td, J = 7.4, 1.1 Hz, 1H), 6.67 (m, 1H), 6.32 (t, J = 2.3 Hz, 1H), 5.36 (s, 2H),
4.98 (q, J = 2.9 Hz, 2H), 4.79 (q, J = 2.6 Hz, 2H). 13C {H} NMR (101 MHz, CDCl3) δ 165.1,
149.6, 136.4, 132.5, 132.1, 129.5, 128.9, 128.6, 127.1, 126.8, 125.9, 125.4, 124.0, 121.5, 120.9,
119.0, 113.6, 64.0, 62.9, 62.7. IR (film): 3041, 2902, 2230, 1698, 1603, 1452, 1181, 1040, 741,
686 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C25H21N3O2 396.1707; Found 396.1711.
To a two-necked flask (2-bromophenyl)methanol (1.87 g, 10 mmol) and DCM (80 mL), NEt3 (2.8
mL, 20 mmol) were added under N2 atmosphere. BnCOCl (4.4 mL, 15 mmol) was added at 0 oC,
then the mixture was stirred at room temperature overnight. The mixture was evaporated and
purification by column chromatography with petroleum ether and ethyl acetate to give the product
2-bromobenzyl 2-phenylacetate (2.83 g, 93%). Rf = 0.3 (EA : PE = 1 : 5)
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2-(3-Benzylideneazetidin-1-yl)phenethyl 2-Diazo-2-phenylacetate (6e): The method of
synthesizing 6e is the same as 6d. Rf = 0.4 (EA : PE = 1 : 4), pale yellow solid, yield: 558 mg, 68%.
1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7 .4 Hz, 2H), 7.38 (qd, J = 9.4, 8.5, 4.5 Hz, 5H), 7.23
(dd, J = 15.9, 7.8 Hz, 5H), 6.88 (td, J = 7.4, 1.1 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 6.33 (dd, J =
4.9, 2.6 Hz, 1H), 4.93 (t, J = 2.9 Hz, 2H), 4.75 (q, J = 2.6 Hz, 2H), 4.56 (t, J = 7.3 Hz, 2H), 3.07 (t,
J = 7.3 Hz, 2H). 13C {H} NMR (101 MHz, CDCl3) δ 165.2, 149.0, 136.5, 132.8, 131.4, 129.3,
128.9, 128.6, 127.5, 127.3, 127.2, 126.8, 125.7, 125.5, 124.0, 120.7, 119.7, 113.8, 64.0, 62.4, 62.1,
32.1. IR (film): 3041, 2902, 2230, 1698, 1603, 1452, 1181, 1040, 741, 686 cm-1; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C26H24N3O2 410.1863; Found 410.1866.
General methods for preparation of products 3: To a schlenk flask 3-methyleneazetidine (0.2
mmol) and Rh2(OAc)4 (1.8 mg, 2 mol%), DCM (1 mL) were added under N2 atmosphere. diazo
ester (0.24 mmol) dissolved in DCM (0.5 mL) was added at room temperature, then stirred for 2 h.
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the reaction was evaporated and the residue was purification by column chromatography with
petroleum ether and ethyl acetate to give the corresponding products.
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Ethyl 1-(4-Methoxyphenyl)-4-methylene-2-phenylpyrrolidine-2-carboxylate (3aa): Rf = 0.4
(EA : PE = 1 : 10), pale yellow oil, yield: 64 mg, 94%. 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J =
7.9 Hz, 2H), 7.30 (t, J = 7.5 Hz, 2H), 7.24 (t, J = 7.1 Hz, 1H), 6.69 (d, J = 9.1 Hz, 2H), 6.43 (d, J
= 9.1 Hz, 2H), 5.04 (s, 1H), 4.91 (s, 1H), 4.36 (d, J = 12.8 Hz, 1H), 4.23 (d, J = 12.4 Hz, 1H), 4.17
– 4.03 (m, 2H), 3.70 (s, 3H), 3.45 (d, J = 15.6 Hz, 1H), 2.87 (dd, J = 15.6, 1.8 Hz, 1H), 1.02 (t, J =
7.1 Hz, 3H). 13C {H} NMR (101 MHz, CDCl3) δ 173.7, 151.7, 143.2, 141.1, 140.5, 128.0, 127.4,
127.1, 115.3, 114.2, 106.5, 73.7, 61.3, 55.9, 55.6, 51.0, 14.1. IR (film): 3043, 2912, 1670, 1633,
1452, 1181, 1040, 741, 686 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H24NO3
338.1751; Found 338.1753.
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Methyl 1-(4-Methoxyphenyl)-4-methylene-2-phnylpyrrolidine-2-carboxylate (3ab): Rf = 0.5
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(EA : PE = 1 : 10), pale yellow oil, yield: 63 mg, 96%. H NMR (400 MHz, CD3OD) δ 7.48 –
7.42 (m, 2H), 7.31 – 7.21 (m, 3H), 6.70 – 6.63 (m, 2H), 6.45 – 6.38 (m, 2H), 5.08 – 5.04 (m, 1H),
4.94 – 4.92 (m, 1H), 4.37 (dd, J = 12.9, 1.4 Hz, 1H), 4.22 (d, J = 12.1 Hz, 1H), 3.68 (d, J = 5.5 Hz,
3H), 3.61 (s, 3H), 3.47 (d, J = 15.5 Hz, 1H), 2.86 (dd, J = 15.5, 1.8 Hz, 1H). 13C {H} NMR (101
MHz, CD3OD) δ 174.4, 151.8, 143.2, 140.8, 140.2, 127.4, 127.1, 126.7, 114.7, 113.7, 105.5, 73.5,
55.2, 54.6, 51.3, 50.6. IR (film): 3041, 2913, 1675, 1637, 1459, 1181, 1040, 741, 686 cm-1; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C20H22NO3 324.1594; Found 324.1591.
(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl-1-(4-methoxyphenyl)-4-methylene-2-phenylpyrr
olidine-2-carboxylate (3ac): Rf = 0.4 (EA : PE = 1 : 5), orange oil, yield 47 mg, 52%, The ratio
1
of Z/E is 1/1. H NMR (400 MHz, CD3OD) δ 7.56 – 7.49 (m, 2H), 7.33 – 7.24 (m, 3H), 6.71 –
6.65 (m, 2H), 6.43 (t, J = 9.1 Hz, 2H), 5.08 (d, J = 2.0 Hz, 1H), 4.94 (t, J = 2.2 Hz, 1H), 4.67 –
4.53 (m, 1H), 4.43 (dd, J = 12.9, 1.9 Hz, 1H), 4.19 (ddd, J = 13.0, 8.0, 2.2 Hz, 1H), 3.68 (d, J =
2.6 Hz, 3H), 3.42 (dd, J = 15.7, 12.6 Hz, 1H), 2.85 (ddd, J = 15.8, 4.2, 2.1 Hz, 1H), 1.71 – 1.40 (m,
4H), 1.04 – 0.95 (m, 2H), 0.93 (d, J = 6.6 Hz, 2H), 0.86 (d, J = 7.0 Hz, 3H), 0.76 (t, J = 6.9 Hz,
3H), 0.59 (d, J = 7.0 Hz, 2H), 0.35 (d, J = 6.9 Hz, 2H). 13C {H} NMR (101 MHz, CD3OD) δ 173.8,
173.5, 152.0, 151.8, 143.5, 141.3, 141.2, 140.7, 140.6, 127.5, 127.4, 127.1, 127.0, 126.6, 126.6,
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115.3, 114.9, 113.8, 113.6, 105.3, 105.3, 75.0, 75.0, 73.8, 73.4, 55.8, 54.7, 54.6, 48.2, 48.0, 47.8,
47.6, 47.4, 47.1, 46.9, 40.2, 40.0, 33.8, 33.8, 31.2, 31.0, 25.7, 24.3, 22.5, 22.2, 21.0, 20.9, 20.0,
19.8, 14.79, 14.3. IR (film): 3013, 2932, 1675, 1637, 1459, 1181, 1040, 741, 686 cm-1; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C29H38NO3 448.2847; Found 448.2848.
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Tertbutyl-1-(4-methoxyphenyl)-4-methylene-2-phenylpyrrolidine-2-carboxylate (3ad): Rf =
0.3 (EA : PE = 1 : 10), orange oil, yield: 36 mg, 49%. 1H NMR (400 MHz, CD3OD) δ 7.48 (dd, J
= 5.3, 3.3 Hz, 2H), 7.29 – 7.24 (m, 2H), 7.23 – 7.18 (m, 1H), 6.66 (d, J = 9.2 Hz, 2H), 6.44 (d, J =
9.1 Hz, 2H), 5.08 – 5.02 (m, 1H), 4.94 – 4.89 (m, 1H), 4.40 – 4.31 (m, 1H), 4.15 (d, J = 12.7 Hz,
1H), 3.66 (s, 3H), 3.40 (d, J = 15.6 Hz, 1H), 2.79 (dd, J = 15.7, 1.9 Hz, 1H), 1.24 (s, 9H). 13C {H}
NMR (101 MHz, CD3OD) δ 172.7, 151.8, 143.7, 141.4, 140.8, 127.3, 127.1, 126.5, 115.1, 113.5,
105.0, 81.3, 74.0, 55.7, 54.6, 50.6, 26.6. IR (film): 3042, 2914, 1676, 1638, 1452, 1181, 1040, 741,
686 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C23H28NO3 366.2064; Found 366.2058.
Ethyl 1,2-Bis(4-methoxyphenyl)-4-methylenepyrrolidine-2-carboxylate (3ae): Rf = 0.5 (EA :
1
PE = 1 : 5), pale yellow oil, yield: 66 mg, 89%. H NMR (400 MHz, CD3OD) δ 7.35 (d, J = 8.8
Hz, 2H), 6.79 (d, J = 8.9 Hz, 2H), 6.64 (d, J = 9.1 Hz, 2H), 6.40 (d, J = 9.1 Hz, 2H), 5.03 (s, 1H),
4.89 (s, 1H), 4.32 (d, J = 12.9 Hz, 1H), 4.17 (d, J = 12.8 Hz, 1H), 4.04 (q, J = 7.1 Hz, 2H), 3.73 (s,
3H), 3.64 (s, 3H), 3.39 (d, J = 15.4 Hz, 1H), 2.79 (dd, J = 15.5, 1.3 Hz, 1H), 1.00 (t, J = 7.1 Hz,
3H). 13C {H} NMR (101 MHz, CD3OD) δ 174.0, 158.6, 151.7, 143.5, 140.5, 132.8, 128.3, 114.9,
113.6, 112.8, 105.3, 73.1, 60.8, 55.3, 54.6, 54.2, 50.6, 12.9. IR (film): 3042, 2911, 1675, 1633,
1452, 1181, 1040, 741, 686 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H26NO4
368.1856; Found 368.1850.
Ethyl
1-(4-Methoxyphenyl)-4-methylene-2-(4-(trifluoromethyl)phenyl)pyrroledine-2-carboxylate
1
(3af): Rf = 0.5 (EA : PE = 1 : 10), pale yellow oil, yield: 62 mg, 76%. H NMR (400 MHz,
CD3OD) δ 7.67 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 9.1 Hz, 2H), 6.40 (d, J =
9.1 Hz, 2H), 5.07 (s, 1H), 4.92 (s, 1H), 4.38 (d, J = 12.7 Hz, 1H), 4.24 (d, J = 12.7 Hz, 1H), 4.07
(q, J = 7.1 Hz, 2H), 3.65 (s, 3H), 3.49 (d, J = 15.6 Hz, 1H), 2.82 (dd, J = 15.6, 1.3 Hz, 1H), 0.99 (t,
J = 7.1 Hz, 3H). 13C {H} NMR (101 MHz, CD3OD) δ 173.3, 152.1, 145.6, 142.9, 140.0, 128.8 (q,
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J = 31.8 Hz), 128.0, 125.7 (q, J = 269.5 Hz), 124.3 (q, J = 3.8 Hz), 114.8, 113.9, 105.8, 73.2, 61.1,
55.5, 54.6, 50.2, 12.9. 19F NMR (376 MHz, CD3OD) δ -63.89. IR (film): 3040, 2910, 1670, 1630,
1450, 1181, 1040, 741, 686 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H22F3NO3
406.1625; Found 406.1621.
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Ethyl 1-(4-Methoxyphenyl)-4-methylene-2-(4-nitrophenyl)pyrrolidine-2-carboxylate (3ag):
Rf = 0.2 (EA : PE = 1 : 5), yellow solid, yield: 72 mg, 94%. 1H NMR (400 MHz, CD3OD) δ 8.19
(d, J = 8.9 Hz, 2H), 7.77 (d, J = 8.9 Hz, 2H), 6.73 (d, J = 9.1 Hz, 2H), 6.42 (d, J = 9.1 Hz, 2H),
5.11 (s, 1H), 4.96 (s, 1H), 4.43 (d, J = 12.7 Hz, 1H), 4.28 (d, J = 12.9 Hz, 1H), 4.11 (q, J = 7.1 Hz,
2H), 3.69 (s, 3H), 3.54 (d, J = 15.6 Hz, 1H), 2.86 (d, J = 15.7 Hz, 1H), 1.02 (t, J = 7.1 Hz, 3H).
13C {H} NMR (101 MHz, CD3OD) δ 174.5, 153.7, 150.2, 148.4, 144.1, 141.3, 130.1, 123.9, 116.2,
115.4, 107.4, 74.6, 62.6, 56.9, 56.0, 51.4, 14.3. IR (film): 3044, 2915, 1676, 1637, 1458, 1189,
1040, 741, 686 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H23N2O5 383.1601; Found
383.1599.
Ethyl 2-(4-Fluorophenyl)-1-(4-methoxyphenyl)-4-methylenepyrrolidine-2-carboxylate (3ah):
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Rf = 0.4 (EA : PE = 1 : 10), pale yellow oil, yield: 52 mg, 73%. H NMR (400 MHz, CD3OD) δ
7.47 (dd, J = 8.8, 5.5 Hz, 2H), 6.99 (t, J = 8.8 Hz, 2H), 6.67 (d, J = 9.1 Hz, 2H), 6.40 (d, J = 9.1
Hz, 2H), 5.05 (s, 1H), 4.91 (s, 1H), 4.34 (d, J = 12.8 Hz, 1H), 4.21 (d, J = 12.8 Hz, 1H), 4.05 (q, J
= 7.1 Hz, 2H), 3.66 (s, 3H), 3.43 (d, J = 15.5 Hz, 1H), 2.80 (d, J = 15.5 Hz, 1H), 0.99 (t, J = 7.1
Hz, 3H). 13C {H} NMR (101 MHz, CD3OD) δ 173.7, 161.8 (d, J = 243.1 Hz), 151.9, 143.2, 140.2,
136.9 (d, J = 3.2 Hz), 129.2 (d, J =7.9 Hz), 114.8, 114.0 (d, J = 21.5 Hz), 113.7, 105.6, 73.0, 60.9,
55.4, 54.6, 50.5, 12.9. 19F NMR (376 MHz, CD3OD) δ -118.22. IR (film): 3049, 2918, 1677, 1636,
1455, 1184, 1043, 741, 686 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H23FNO3
356.1656; Found 356.1655.
Ethyl 2-(4-Bromophenyl)-1-(4-methoxyphenyl)-4-methylenepyrrolidine-2-carboxylate (3ai):
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Rf = 0.3 (EA : PE = 1 : 10), pale yellow oil, yield: 71 mg, 85%. H NMR (400 MHz, CD3CD) δ
7.43-7.35 (m, 4H), 6.67 (d, J = 9.1 Hz, 2H), 6.39 (d, J = 9.1 Hz, 2H), 5.05 (s, 1H), 4.91 (s, 1H),
4.35 (d, J = 12.8 Hz, 1H), 4.21 (d, J = 12.9 Hz, 1H), 4.05 (q, J = 7.1 Hz, 2H), 3.65 (s, 3H), 3.43 (d,
J = 15.6 Hz, 1H), 2.79 (dd, J = 15.6, 1.2 Hz, 1H), 0.99 (t, J = 7.1 Hz, 3H). 13C {H} NMR (101
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MHz, CD3OD) δ 173.5, 152.0, 143.0, 140.4, 140.1, 130.4, 129.3, 120.5, 114.8, 113.8, 105.7, 73.0,
61.0, 5.4, 54.6, 50.3, 12.9. IR (film): 3043, 2912, 1670, 1633, 1452, 1181, 1040, 741, 686 cm-1;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H23BrNO3 416.0856; Found 416.0850.
Ethyl 1-(4-Methoxyphenyl)-4-methylene-2-(thiophen-2-yl)pyrrolidine-2-carboxylate (3aj): Rf
= 0.2 (EA : PE = 1 : 10), pale yellow oil, yield: 66 mg, 95%. 1H NMR (400 MHz, CD3OD) δ 7.24
(d, J = 5.1 Hz, 1H), 7.16 (d, J = 3.5 Hz, 1H), 6.89 (dd, J = 4.9, 3.8 Hz, 1H), 6.66 (d, J = 9.1 Hz,
2H), 6.43 (d, J = 9.1 Hz, 2H), 5.09 (s, 1H), 4.95 (s, 1H), 4.37 (d, J = 12.9 Hz, 1H), 4.17 (d, J =
12.8 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.64 (s, 3H), 3.28 (d, J = 14.9 Hz, 1H), 2.92 (dd, J = 15.7,
1.3 Hz, 1H), 1.04 (t, J = 7.1 Hz, 3H). 13C {H} NMR (101 MHz, CD3OD) δ 173.5, 152.0, 146.0,
142.8, 140.1, 125.9, 124.9, 124.9, 114.8, 113.6, 106.1, 71.0, 61.2, 55.4, 54.6, 51.4, 12.9. IR (film):
3043, 2912, 1670, 1633, 1452, 1181, 1040, 741, 686 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C19H22NO3S 344.1315; Found 344.1311.
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Ethyl 1-(4-Methoxyphenyl)-4-methylene-2-(naphthalen-1-yl)pyrrolidine-2-carboxylate (3ak):
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Rf = 0.3 (EA : PE = 1 : 10), white solid, yield: 65 mg, 83%. H NMR (400 MHz, d6-DMSO) δ
7.99 – 7.94 (m, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.75 – 7.70 (m, 1H), 7.54 – 7.49 (m, 2H), 7.45 (d, J
= 6.9 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 6.71 (d, J = 8.9 Hz, 2H), 6.62 (d, J = 9.0 Hz, 2H), 5.06 (s,
1H), 4.87 (s, 1H), 4.26 (s, 2H), 4.04 – 3.89 (m, 3H), 3.63 (s, 3H), 3.04 (d, J = 15.7 Hz, 1H), 0.86 (t,
J = 7.0 Hz, 3H). 13C {H} NMR (101 MHz, d6-DMSO) δ 172.2, 152.2, 143.6, 140.1, 136.7, 134.6,
130.8, 129.3, 129.1, 127.7, 126.6, 125.8, 125.5, 125.0, 116.1, 114.3, 107.3, 75.2, 62.9, 61.4, 55.5,
48.5, 14.2. IR (film): 3042, 2915, 1678, 1633, 1456, 1189, 1040, 741, 686 cm-1; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C25H26NO3 388.1907; Found 388.1904.
(E)-Ethyl-1-(4-methoxyphenyl)-4-methylene-2-styrylpyrrolidine-2-carboxylate (3al): Rf = 0.5
(EA : PE = 1 : 10), pale yellow oil, yield: 59 mg, 81%. 1H NMR (400 MHz, CD3OD) δ 7.30 (d, J
= 7.2 Hz, 2H), 7.25 (t, J = 7.5 Hz, 2H), 7.17 (t, J = 7.1 Hz, 1H), 6.88 (d, J = 16.1 Hz, 1H), 6.74 (d,
J = 9.1 Hz, 2H), 6.51 (d, J = 9.1 Hz, 2H), 6.38 (d, J = 16.1 Hz, 1H), 5.10 (s, 1H), 4.99 (s, 1H),
4.30 (d, J = 12.1 Hz, 1H), 4.21 (d, J = 13.0 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.67 (s, 3H), 3.14 (d,
J = 15.4 Hz, 1H), 2.83 (dd, J = 15.5, 1.5 Hz, 1H), 1.06 (t, J = 7.1 Hz, 3H). 13C {H} NMR (101
MHz, CD3OD) δ 174.8, 151.8, 142.9, 140.1, 136.8, 129.5, 128.3, 128.2, 127.2, 126.1, 114.5, 113.9,
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106.1, 71.1, 61.0, 55.6, 54.6, 12.9. IR (film): 3023, 2952, 1680, 1633, 1462, 1181, 1040, 741, 686
cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C23H26NO3 364.1907; Found 364.1904.
Diethyl 1-(4-Methoxyphenyl)-4-methylenepyrrolidine-2,2-dicarboxylate (3am): Rf = 0.3 (EA :
PE = 1 : 5), pale yellow oil, yield: 58 mg, 86%. 1H NMR (400 MHz, d6-DMSO) δ 6.78 (d, J = 9.0
Hz, 2H), 6.60 (d, J = 9.1 Hz, 2H), 5.07 (dt, J = 8.0, 2.1 Hz, 2H), 4.12 (q, J = 7.1 Hz, 4H), 4.05 (d, J
= 1.8 Hz, 2H), 3.67 (s, 3H), 3.19 (t, J = 1.8 Hz, 2H), 1.11 (t, J = 7.1 Hz, 6H). 13C {H} NMR (101
MHz, d6-DMSO) δ 169.9, 160.7, 152.4, 142.4, 139.8, 115.9, 114.3, 107.5, 73.9, 61.8, 61.5, 55.6,
55.2, 44.4, 14.6, 14.2. IR (film): 3043, 2912, 1670, 1633, 1452, 1181, 1040, 741, 686 cm-1; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C18H24NO5 334.1649; Found 334.1651.
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Ethyl 1-(4-Methoxyphenyl)-4-methylenepyrrolidine-2-carboxylate (3an): Rf = 0.2 (EA : PE =
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1 : 10), pale yellow oil, yield: 27 mg, 51%. H NMR (400 MHz, CD3OD) δ 6.80 (d, J = 9.0 Hz,
2H), 6.53 (d, J = 9.0 Hz, 2H), 5.08 (s, 1H), 5.05 (s, 1H), 4.49 – 4.41 (m, 1H), 4.09 (qd, J = 7.0, 2.3
Hz, 2H), 4.03 (q, J = 9.0 Hz, 2H), 3.70 (s, 3H), 3.12 (dd, J = 15.8, 9.2 Hz, 1H), 2.68 (d, J = 16.1
Hz, 1H), 1.16 (t, J = 7.1 Hz, 3H). 13C {H} NMR (101 MHz, CD3OD) δ 174.3, 151.9, 144.7, 141.1,
114.4, 112.9, 105.8, 60.7, 60.5, 54.7, 52.8, 36.4, 13.1. IR (film): 3042, 2915, 1674, 1636, 1452,
1181, 1040, 741, 686 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H20NO3 262.1438;
Found 262.1440.
(1-(4-Methoxyphenyl)-4-methylenepyrrolidin-2-yl)(phenyl)methenone (3ao): Rf = 0.3 (EA :
1
PE = 1 : 10), yellow oil, yield: 31 mg, 54%. H NMR (400 MHz, CD3OD) δ 8.08 (d, J = 7.4 Hz,
2H), 7.67 (d, J = 7.6 Hz, 1H), 7.56 (t, J = 7.7 Hz, 2H), 6.77 (d, J = 8.9 Hz, 2H), 6.47 (d, J = 8.7 Hz,
2H), 5.54 (dd, J = 9.9, 2.7 Hz, 1H), 5.12 (d, J = 2.8 Hz, 1H), 5.02 (t, J = 2.2 Hz, 1H), 4.20 – 4.12
(m, 2H), 3.69 (s, 3H), 3.34 (d, J = 1.6 Hz, 1H), 2.64 (d, J = 15.9 Hz, 1H). 13C {H} NMR (101
MHz, CD3OD) δ 201.1, 151.6, 144.5, 141.2, 134.8, 133.4, 128.6, 128.0, 114.4, 112.8, 106.3, 63.1,
54.7, 53.5, 36.7. IR (film): 3043, 2912, 1670, 1633, 1452, 1181, 1040, 741, 686 cm-1; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C19H20NO2 294.1489; Found 294.1492.
Ethyl
1-(4-Methoxyphenyl)-4-(methylene-d2)-2-phenylpyrrolidine-2-carboxylate-3,3-d2
(D2-3aa): Rf = 0.3 (EA : PE = 1 : 10), yellow oil, yield: 63 mg, 93%. 1H NMR (400 MHz, CD3OD)
δ 7.51 – 7.45 (m, 2H), 7.32 – 7.21 (m, 3H), 6.71 – 6.65 (m, 2H), 6.47 – 6.40 (m, 2H), 5.06 (dd, J =
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5.7, 2.0 Hz, 0.4H), 4.93 (d, J = 2.2 Hz, 0.4H), 4.38 (d, J = 13.2 Hz, 1H), 4.22 (d, J = 13.0 Hz, 1H),
4.09 (qd, J = 7.1, 1.0 Hz, 2H), 3.68 (s, 3H), 3.50 – 3.43 (m, 0.78H), 2.85 (dd, J = 15.6, 1.7 Hz,
0.78H), 1.03 (t, J = 7.1 Hz, 3H). 13C {H} NMR (101 MHz, CD3OD) δ 173.8, 151.8, 141.0, 140.4,
129.4, 128.7, 127.4, 127.1, 126.6, 114.9, 113.6, 73.5, 60.8, 55.4, 54.6, 50.5, 12.9. IR (film): 3043,
2912, 1670, 1633, 1452, 1181, 1040, 741, 686 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C21H20D4NO3 342.2002; Found 342.2004.
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Ethyl 4-(Hepta-2,4,6-triyn-1-ylidene-d6)-1,2-diphenylpyrrolidine-2-carboxylate (D6-3ba): Rf
1
= 0.4 (EA : PE = 1 : 10), yellow oil, yield: 51 mg, 66%. The ratio of Z/E is 1/1. H NMR (400
MHz, CDCl3) δ 7.63 – 7.52 (m, 2H), 7.36 – 7.27 (m, 3H), 6.78 – 6.71 (m, 2H), 6.53 (t, J = 9.0 Hz,
2H), 4.70 (dd, J = 29.8, 13.5 Hz, 1H), 4.54 – 4.42 (m, 1H), 4.18 – 4.04 (m, 2H), 3.74 (d, J = 2.2
Hz, 3H), 3.73 – 3.60 (m, 1H), 3.15 (ddd, J = 16.3, 14.2, 2.3 Hz, 1H), 1.03 (dt, J = 11.4, 7.1 Hz,
3H). 13C {H} NMR (101 MHz, CDCl3) δ 173.7, 173.5, 151.8, 151.7, 141.3, 140.8, 140.5, 140.4,
136.9, 136.3, 136.2, 128.1, 128.0, 127.2, 127.1, 115.6, 115.3, 114.0, 74.1, 72.0, 61.2, 61.1, 58.0,
55.5, 54.3, 52.7, 48.6, 14.1, 14.0. IR (film): 3049, 2918, 1677, 1636, 1455, 1184, 1040, 741, 686
cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C27H22D6NO3 420.2440; Found 420.2442.
Ethyl (Z/E)-4-Benzylidene-1-(4-methoxyphenyl)-2-phenylpyrrolidine-2-carboxylate (3ba): Rf
1
= 0.3 (EA : PE = 1 : 10), orange oil, yield: 58 mg, 70%. The ratio of Z/E is 0.64/0.36. H NMR
(400 MHz, CDCl3) δ 7.60 – 7.52 (m, 2H), 7.44 – 7.40 (m, 1H), 7.36 – 7.26 (m, 6H), 7.25 – 7.20
(m, 1H), 6.77 – 6.70 (m, 2H), 6.56 – 6.52 (m, 2H), 6.51 (d, J = 2.3 Hz, 0.36H), 6.35 (t, J = 2.3 Hz,
0.64H), 4.74 (d, J = 13.7 Hz, 0.64H), 4.66 (d, J = 13.3 Hz, 0.36H), 4.55 – 4.42 (m, 1H), 4.17 –
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4.05 (m, 2H), 3.79 – 3.62 (m, 4H), 3.21 – 3.07 (m, 1H), 1.02 (dt, J = 11.5, 7.1 Hz, 3H). C {H}
NMR (101 MHz, CDCl3) δ 173.7, 173.4, 151.7, 140.8, 140.4, 137.2, 136.4, 136.3, 128.5, 128.4,
128.3, 128.2, 128.1, 128.0, 127.3, 127.1, 127.0, 126.7, 126.6, 122.0, 121.5, 115.6, 115.3, 114.0,
77.3, 77.0, 76.7, 74.1, 72.0, 61.2, 58.1, 55.5, 54.3, 52.7, 48.6, 14.0. IR (film): 3043, 2912, 1670,
1633, 1452, 1181, 1040, 741, 686 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C27H28NO3
414.2064; Found 414.2068.
(Z/E)4-(4-Methoxybenzylidene)-1-(4-methoxyphenyl)-2-(4-(trifluoromethyl)phenyl)pyrrolidi
ne-2-carboxylate (3cf): Rf = 0.2 (EA : PE = 1 : 5), orange oil, yield: 88 mg, 86%. The ratio of Z/E
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