Phosphine-Catalyzed (4+1) Annulation: Rearrangement of Allenylic Carbamates to 3-Pyrrolines through Phosphonium Diene Intermediates

Article abstract of DOI:10.1002/cctc.202000626

We have developed a phosphine-catalyzed (4+1) annulative rearrangement for the preparation of 3-pyrrolines from allenylic carbamates via phosphonium diene intermediates. We employed this methodology to synthesize an array of 1,3-disubstituted- and 1,2,3-t

Full text of DOI:10.1002/cctc.202000626

The European Society Journal for Catalysis
Supported by
Accepted Article
Title: Phosphine-Catalyzed (4+1) Annulation: Rearrangement of
Allenylic Carbamates to 3-Pyrrolines Through Phosphonium
Diene Intermediates
Authors: Ohyun Kwon, Brian Blank, and Ian Andrews
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To be cited as: ChemCatChem 10.1002/cctc.202000626
Link to VoR: https://doi.org/10.1002/cctc.202000626
01/2020

10.1002/cctc.202000626
ChemCatChem
FULL PAPER
Phosphine-Catalyzed (4+1) Annulation: Rearrangement of
Allenylic Carbamates to 3-Pyrrolines through Phosphonium
Diene Intermediates
Brian R. Blank,[a] Ian P. Andrews,[a] and Ohyun Kwon*[a]
[a]
Dr. B. R. Blank, Dr. I. P. Andrews, Prof. O. Kwon
Department of Chemistry and Biochemistry
University of California, Los Angeles
607 Charles E. Young Drive East, Los Angeles, California, 90095-1569
Group Homepage: https://www.thekwonlab.net/
E-mail: ohyun@chem.ucla.edu
Supporting information for this article is given via a link at the end of the document.
Abstract: We have developed
a
phosphine-catalyzed (4+1)
Tertiary phosphines have emerged as excellent nucleophilic
catalysts over the last two decades, enabling the rapid and facile
construction of multifarious carbocyclic and heterocyclic
systems.[3] For example, Lu’s phosphine-catalyzed (3+2)
reaction between allenoates and N-sulfonyl imines produces
1,2,3-trisubstituted-3-pyrrolines in high yield when simply using
catalytic PPh3 (as the only reagent) at room temperature.[4,5] This
reaction has since been modified to facilitate the synthesis of
1,2,3,5-tetrasubstituted-3-pyrrolines[6] and the production of
enantiomerically enriched 3-pyrrolines.[7] As pyrrolines can be
transformed quickly to pyrrolidines[8] through reduction or to
pyrroles[4b] and pyrrolidinones[9] through oxidation, a diverse
array of five-membered nitrogen heterocycles is readily
accessible from this class of compounds. As such, one might
expect the allene–imine (3+2) annulation to be widely used in
the total synthesis of natural products. It has, however, been
limited thus far to imines bereft of an a-proton,[10] with only two
exceptions,[6h,7g] even though access to 2-alkyl-substituted 3-
pyrrolines would greatly expand the range of natural products
that could be assembled through phosphine catalysis.[11]
Over the last few years, several approaches have been
designed to circumvent this limitation of Lu’s reaction and allow
the construction of 2-alkyl-substituted 3-pyrrolines.[12] With these
variations, phosphine-catalyzed annulations of imines appear
ideally suited for the synthesis of pyrrolizidine alkaloids.
Nevertheless, there has been only one attempt to construct a
member of this class of natural products.[13] This paucity of
examples suggests the need for additional methodological
advances toward 2-alkyl-substituted 3-pyrrolines that can be
successfully applied to natural product synthesis.
annulative rearrangement for the preparation of 3-pyrrolines from
allenylic carbamates via phosphonium diene intermediates. We
employed this methodology to synthesize an array of 1,3-
disubstituted- and 1,2,3-trisubstituted-3-pyrrolines, including the
often-difficult-to-prepare 2-alkyl variants. A mechanistic investigation
employing allenylic acetates and mononucleophiles unexpectedly
unveiled that
a phosphine-catalyzed (4+1) reaction for the
construction of cyclopentene products, previously reported by Tong,
might not occur through a phosphonium diene, as had been
proposed, but rather through multiple mechanisms working in
concert. Consequently, our phosphine-catalyzed rearrangement is
most likely the first transformation to involve the unequivocal
formation of a phosphonium diene intermediate along the reaction
pathway. To demonstrate the synthetic utility of this newly developed
reaction, we have completed concise formal syntheses of the
pyrrolizidine alkaloids (±)-trachelanthamidine and (±)-supinidine.
Introduction
Pyrrolizidine alkaloids are compounds that have attracted the
interest of medicinal chemists for several decades because of
their interesting biological activities, including antitumor activity,
hepatotoxicity, carcinogenicity, and mutagenicity (Figure 1).[1,2b]
Synthetic chemists have also been interested in these
compounds because their compact and often highly oxygenated
structures are challenging testing grounds for new synthetic
methodologies.[2]
As an alternative to the (3+2) annulations, we envisioned a
phosphine-catalyzed annulative rearrangement of allenylic
carbamates 1, proceeding through intermediate phosphonium
dienes 2, to provide 3-pyrrolines 3 (Scheme 1). The first
example of a similar reactive species was disclosed when Tong
N
N
H
H
OH
OH
(–)-Trachelanthamidine
(–)-Supinidine
proposed the formation of phosphonium diene
intermediate in the phosphine-catalyzed (4+1) annulation
between allenylic acetate and carbon-centered
bisnucleophile, to yield cyclopentene 6.[14–17] Additionally, Tong
reported a single example whereby a nitrogen (bis)nucleophile
was used instead to deliver a 1,3-disubstituted 3-pyrroline in a
modest yield of 22%.[14] This aspect of Tong’s work was
elaborated upon by Fu to allow for the preparation of
enantioenriched 1,3,5-trisubstituted-3-pyrrolines.[16] In contrast to
5 as an
4
a
N
N
OH
HO
H
H
OH
OH
OH
OH
(–)-Rosmarinecine
(–)-Crotanecine
Figure 1. Representative pyrrolizidine alkaloids.
1
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10.1002/cctc.202000626
ChemCatChem
FULL PAPER
Table 1. Optimization of the phosphine-catalyzed (4+1) reaction.[a]
Tong’s and Fu’s approaches, we anticipated that our annulative
rearrangement of allenylic carbamates 1 would expand the
substrate scope of 3-pyrrolines that could be obtained through
phosphine-catalyzed (4+1) reactions by allowing for the
preparation of 1,2,3-trisubstituted-3-pyrrolines. Furthermore, to
illustrate its synthetic value, we have applied our new
methodology to syntheses of the pyrrolizidine alkaloids (±)-
trachelanthamidine and (±)-supinidine (vide infra).
Ts
N
R
•
OCONHTs
CO2Et
catalyst
R
solvent
concentration
rt
CO2Et
3a R = H
3b R = Me
1a R = H
1b R = Me
entry
R
catalyst
solvent
concentration
[M]
yield[b]
[%]
19
47
69
17
33
trace
55
55
14
66
51
1[c]
2
3
4
5
6
7
8
9
H
H
H
PPh3
PPh3
PPh3
PPh3
PMePh2
PMe3
PEt3
PBu3
PCy3
PBu3
PBu3
PBu3
CH2Cl2
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
0.035
0.035
0.035
0.035
0.035
0.035
0.035
0.035
0.035
0.018
0.007
0.018
This work:
Me
Me
Me
Me
Me
Me
Me
Me
Me
OCONHTs
CO2Et
CO2
Ts
N
R1
TsNH
R1
R1
PR3
CO2Et
PR3
•
CO2Et
PR3
1
2
3
10
11
12[d]
R = Ph or Bu
R1 = H, alkyl, phenyl
74
[a] Reactions were performed by adding a solution of 1 (0.14 mmol, 1.0 equiv)
in solvent (4 mL) over 24 h to a solution of phosphine (0.14 mmol, 1.0 equiv) in
solvent (4 mL), followed by stirring for an additional 4 h. [b] All yields reported
are isolated yields. [c] Allenylic carbamate 1a was added to the phosphine in
one portion. [d] The solvent was deaerated by bubbling with Ar for 1.5 h.
Previous work by Tong:
OAc
O
O
O
CO2Bn
CN
CN
CN
CO2Bn
PPh3
Ph
Ph
Ph
•
PPh3
Cs2CO3
CO2Bn
PPh3
To further improve the yield of the reaction, we then explored
a variety of sulfonamides in an attempt to influence the outcome
of the reaction by altering the electronics of the nucleophile.
Thus, we prepared four additional allenylic carbamates, 1ba–bd,
by reacting allenylic alcohol 7b with various sulfonyl isocyanates
(Table 2).[21] When employed in the (4+1) reaction, p-
nitrobenzenesulfonyl–substituted carbamate 1ba resulted in 3ba
being formed in the lowest yield, 37%, presumably because of
the weak nucleophilicity of its sulfonamide anion (entry 1). Use
of the less electron-poor m-trifluoromethylbenzenesulfonyl
variant 1bb resulted in an improved yield of 3bb (45%, entry 2).
Using a simple benzenesulfonyl group increased the yield of 3bc
to 58% (entry 3). The previously obtained 74% yield for the
product, 3b, from the electron-rich p-tosyl variant 1b was likely
due to its anion’s relatively high nucleophilicity (entry 4).
Nevertheless, when using an even more electron-rich p-
methoxybenzenesulfonyl group, the yield of 3bd decreased
slightly to 72%, presumably because of the lower acidity of its
sulfonamide (entry 5). As a result, we continued with our initial
choice, p-tosyl–substituted carbamates, for further study.
4
5
6
Scheme 1. Phosphine-catalyzed (4+1) reactions.
Results and Discussion
We tested our idea by reacting allenylic carbamate 1a with
PPh3, obtaining 3-pyrroline 3a in 19% yield (Table 1, entry 1).[18]
Addition of 1a over 24 h increased the yield to 47% (entry 2),
presumably by minimizing undesired decomposition of the
substrate.[19] After exploring the effects of the catalyst, the
solvent, and the addition time of 1a, and whether the addition of
a combination of external p-toluenesulfonamide and base would
be beneficial, we determined that the optimal conditions for this
transformation involved adding 1a over 24 h to a solution of
PPh3 in CH3CN (entry 3).[20] With the optimized conditions for the
transformation of allenylic carbamate 1a determined, we
employed allenylic carbamate 1b in the reaction, but obtained 3-
pyrroline 3b in only 17% yield (entry 4). Slightly increasing the
nucleophilicity of the catalyst, by using PMePh2, increased the
yield to 33% (entry 5). The application of the more nucleophilic
PMe3 resulted, however, in only a trace of product and mainly
decomposition of allenylic carbamate 1b (entry 6). Employing
PEt3 and PBu3 as catalysts resulted in a dramatic increase in
yield to 55% in both cases (entries 7–8). In contrast, the use of
PCy3 yielded 3-pyrroline 3b in only 14%, presumably a result of
the greater steric bulk of this catalyst (entry 9). Next, we further
optimized this transformation by exploring the effects of solvent
and concentration.[20] Decreasing the concentration from 0.035
to 0.018 M increased the yield to 66% (entry 10). Lowering the
concentration even further to 0.007 M proved detrimental, as the
yield decreased to 51% (entry 11). We found that deaerating the
solvent was beneficial, resulting in an increase in the yield of
desired 3-pyrroline 3b to 74% (entry 12). To summarize, the final
reaction protocol was determined to involve addition of 1b over
Table 2. Phosphine-catalyzed (4+1) reactions employing various sulfonamide
nucleophiles.[a–c]
R1
R1
R2
R2
R2
O
O
R1
S NCO
O
OH
S
HN
PBu3
O
CO2Et
O S O
N
O
O
•
CH3CN
0.018 M
rt, 28 h
CH2Cl2
0 ˚C to rt
1.5 h
CO2Et
•
CO2Et
7b
entry
1b, 1ba–bd
3b, 3ba–bd
R1
R2
carbamate
yield 1
[%]
99
3-pyrroline
yield 3
[%]
37
1
2
3
4
5
NO2
H
H
Me
OMe
H
CF3
H
H
H
1ba
1bb
1bc
1b
3ba
3bb
3bc
3b
79[d]
99
45
58
74
72
94
96
1bd
3bd
24
h to a solution of PBu3 in deaerated CH3CN at a
[a] Pertaining to the first step: The isocyanate (1.05 equiv) was added to 7 in
dry CH2Cl2 (0.4 M) at 0 °C, and stirred for 1 h, and then the solution was
concentration of 0.018 M.
2
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10.1002/cctc.202000626
ChemCatChem
FULL PAPER
stirred at room temp for 0.5 h. [b] In regards to the phosphine-catalyzed step:
Reactions were performed by adding a solution of 1 (0.14 mmol, 1.0 equiv) in
CH3CN (4 mL) over 24 h to a solution of PBu3 (0.14 mmol, 1.0 equiv) in
CH3CN (4 mL), followed by stirring for an additional 4 h. The solvents
employed in these reactions were deaerated by bubbling with Ar for 1.5 h. [c]
All yields reported are isolated yields. [d] Yield based on recovered starting
material; isolated yield: 22%.
Ts
OH
N
5
6
7
88
86
88
28
7e
3e
•
CO2Et
CO2Et
Ts
N
37
OH
7f
3f
CO2Et
•
CO2Et
To explore the substrate scope of the (4+1) reaction, we
prepared an array of allenylic carbamates 1 from their respective
allenylic alcohols 7 (Table 3). We used a Morita–Baylis–Hillman
(MBH) reaction between ethyl 2,3-butadienoate and
paraformaldehyde or acetaldehyde in the presence of 3-
hydroxyquinuclidine to prepare allenylic alcohols 7a and 7b in 66
and 79% yield, respectively.[20,22] This approach failed, however,
to provide useful yields of more-elaborate allenylic alcohols.
Ts
N
30
OH
7g
CO2Et
3g
CO2Et
•
Ts
N
Ph
•
OH
7h
CO2Et
8
88
89
72
72
92
95
66
52
52
48
56
55
Ph
3h
CO2Et
Thus, we exploited either
a
tin(II)- or indium-mediated
Ts
N
OH
7i
allenylation of aldehydes to synthesize allenylic alcohols 7c–
m.[20,23] Subsequently, we converted allenylic alcohols 7a–m to
allenylic carbamates 1a–m, in good to excellent yields, through
reactions with tosyl isocyanate (Table 3).
9
3i
•
CO2Et
CO2Et
Ts
N
Ph
OH
Ph
10
11[e]
12
13
7j
The newly prepared substrates were then subjected to the
optimized reaction conditions to deliver 3-pyrrolines 3c–m
(Table 3). Allenylic carbamates containing nonfunctionalized
linear alkyl chains of various lengths produced their respective
3-pyrrolines 3b–d in moderate to good yields (entries 2–4).
Substrates with cycloalkyl groups of various sizes produced
pyrrolines 3e–g, albeit with lower reaction efficiencies (entries 5–
7). Thus, there appears to be a correlation between the steric
bulk at the b¢-carbon and the reaction efficiency. The presence
of a phenyl ring or unsaturation within the substituent was well
tolerated in the reaction, with pyrrolines 3h–j being produced in
moderate to good yields (entries 8–10). The reaction was also
accepting of siloxy and ester functionalities, with the respective
pyrrolines 3k–m being produced in moderate to good yields
(entries 11–13). Notably, the latter two compounds served as
direct precursors for syntheses of pyrrolizidine alkaloids (vide
infra).
•
CO2Et
3j
CO2Et
Ts
N
OH
TBSO
7k
OTBS
•
CO2Et
3k
CO2Et
Ts
EtO2C
OH
7l
CO2Et
N
CO2Et
•
3l
CO2Et
Ts
N
EtO2C
OH
7m
CO2Et
3m
•
CO2t-Bu
CO2t-Bu
[a] Pertaining to the first step: The isocyanate (1.05 equiv) was added to 7 in
dry CH2Cl2 (0.4 M) at 0 °C, and stirred for 1 h, and then the solution was
stirred at room temp for 0.5 h. [b] In regards to the phosphine-catalyzed step:
Reactions were performed by adding a solution of 1 (0.14 mmol, 1.0 equiv) in
CH3CN (4 mL) over 24 h to a solution of PBu3 (0.14 mmol, 1.0 equiv) in
CH3CN (4 mL), followed by stirring for an additional 4 h. The solvents
employed in these reactions were deaerated by bubbling with Ar for 1.5 h. [c]
All yields reported are isolated yields. [d] PPh3 was used as the catalyst. [e]
Solvent was not deaerated for this reaction.
Table 3. Synthesis of allenylic carbamates 1 and 3-pyrrolines 3.[a–c]
Ts
R2
•
R2
•
OH
OCONHTs
βʹ
PBu3
TsNCO
N
R2
CH3CN
0.018 M
rt, 28 h
CH2Cl2
0 ˚C to rt
1.5 h
CO2R1
CO2R
1
α
CO2R1
γ
We surmised that the mechanism of this transformation
involved initial displacement of the carbamate by the phosphine,
thereby decomposing 1 into phosphonium diene 2, CO2, and
toluenesulfonamide anion 8, which then served as the
nucleophile in the reaction to construct 3-pyrrolines 3 (Scheme
7a–m
entry
1a–m
3a–m
allenylic alcohol
yield of 1
3-pyrroline
yield of 3
[%]
[%]
69
Ts
N
OH
1[d,e]
92
94
84
69
7a
3a
CO2Et
2). There arises
a point of contention, however, when
•
CO2Et
considering how the reaction progresses from phosphonium
diene 2 to 3-pyrroline 3, because it seems feasible that 8 could
potentially add to either the b¢- or the g-carbon of phosphonium
diene 2.[24–26]
Ts
N
OH
2
3
4
74
62
55
7b
3b
•
CO2Et
CO2Et
Ts
N
OH
7c
3c
•
CO2Et
8
Ts
H
CO2Et
N
A
B
Ts
N
CO2
Ts
N
R1
•
OH
OCONHTs
CO2Et
R1
?
R1
CO2Et
PR3
7d
•
CO2Et
3d
CO2Et
R3P
CO2Et
1
3
2
3
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10.1002/cctc.202000626
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FULL PAPER
Scheme 2. Conversion of allenylic carbamate 1 to phosphonium diene 2 and
3-pyrroline 3.
Table 5. Investigation of reactions between allenylic acetate 9 and 10b.[a,b]
O
O
OAc
O
CO2Et
CO2Et
H
OAc
•
O
10b
CO2Et
9
CO2Et
Regarding Tong’s (4+1) reaction, it was proposed that the
nucleophile initially added to the g-carbon of the suggested
intermediate 5 (Scheme 1), with the argument that the electron-
withdrawing effect of a triphenylphosphonium moiety is stronger
than that of a carboxylate group.[14] While this scenario is not
unreasonable, we felt that experimental evidence to support this
hypothesis was lacking. In addition, contrary to this mechanism,
Tong later published a reaction between allenylic acetate 4 and
butyl toluenesulfonamide in the presence of 20 mol% PPh3 that
produced an allenoate analogous to 12a (see Table 4) in 76%
yield.[27] Consequently, we wished to perform an in-depth
investigation of the reactions of an allenylic acetate with
nitrogen- and carbon-centered nucleophiles capable of
undergoing only monoaddition to the proposed phosphonium
diene 2. As such, if the mononucleophile were to add to the g-
carbon first, a phosphorus ylide would be generated. After
protonation of the ylide a second nucleophile could potentially
conditions
PhH, rt
O
O
O
•
O
9
11b
12b
13b
entry PPh3
Cs2CO3
NaOAc
[mol%]
yield
11b
[%]
0
8
0
0
0
0
0
yield
12b
[%]
42
74
34
0
34
0
0
yield
yield
[mol%] [mol%]
13b[c]
[%]
19
0
9
[%]
0
0
9
0
7
0
100
1
2
3
4
5
6
7
20
–
130
130
–
–
–
–
–
–
20
110
20
110
–
19
23
18
24
0
–
130
130
130
–
–
[a] Reactions were performed by adding a solution of 9 (0.190 mmol, 1.0
equiv) in dry benzene (2.8 mL) over 1 h to a solution of 10b (1.2 equiv) in dry
benzene (2.8 mL) containing the following reagents, if required, for the
reactions listed in the specific entries above: PPh3 (either 0.2 or 1.1 equiv),
Cs2CO3 (1.3 equiv), or NaOAc (1.3 equiv). Once the addition was complete,
the mixture was stirred for another 5–5.5 h. [b] All yields reported are isolated
yields. [c] Allylic acetate 13b was isolated as a mixture of isomers, with the E-
to-Z ratio ranging between 1.05:1 and 1.18:1.
add to the b¢-carbon and deliver
a trisubstituted olefin.
Conversely, initial addition to the b¢-carbon would lead to the
formation of an allenoate, such as 12a, upon elimination of the
phosphine.
Table 6. Investigation of reactions between allenylic acetate 9 and 10c.[a,b]
O
OAc
CN
CN
CO2Et
CO2Et
H
OAc
•
Ph
O
10c
CO2Et
CO2Et
9
Mechanistic Investigation
CN
O
Ph
NC
O
conditions
PhH, rt
Ph
•
Ph
13c
Our mechanistic investigation into the (4+1) reaction began by
employing allenylic acetate 9 in a series of reactions (Table 4)
with benzyl toluenesulfonamide (10a). To determine whether a
carbon mononucleophile would exhibit similar reactivity to 10a,
we then performed a series of reactions employing 3-methyl-2,4-
pentanedione (10b) as the pronucleophile (Table 5). We also
9
11c
12c
yield
12c
[%]
26
44
7
entry
PPh3
[mol%]
Cs2CO3
[mol%]
yield
yield
13c
[%]
0
yield
9
[%]
5
2
11c
[%]
18
28
0
1
2
3
4
20
–
20
130
130
–
0
0
2
0
employed
a second carbon monopronucleophile, benzoyl
110
–
0
0
20[c]
propionitrile (10c), in the reactions to determine whether this pair
of carbon nucleophiles would demonstrate similar reactivities
(Table 6).
[a] Reactions were performed by adding a solution of 9 (0.190 mmol, 1.0
equiv) in dry benzene (2.8 mL) over 1 h to a solution of 10c (1.2 equiv) in dry
benzene (2.8 mL) containing the following reagents, if required, for the
reaction listed in the specific entries above: PPh3 (either 0.2 or 1.1 equiv) or
Cs2CO3 (1.3 equiv). Once the addition was complete, the mixture was stirred
for another 8.5, 29, 72, and 9 h for entries 1–4, respectively. [b] All yields
reported are isolated yields. [c] Allylic acetate 13c was isolated as a mixture of
isomers, with an E-to-Z ratio of 1.08:1.
Table 4. Investigation of reactions between allenylic acetate 9 and 10a.[a,b]
OAc
Bn
Ts
OAc
•
BnNHTs
10a
CO2Et
N
CO2Et
H
CO2Et
CO2Et
9
Ts
N
conditions
CH3CN, rt
•
Subjecting monopronucleophiles 10a and 10b to the standard
reaction conditions employed by Tong (20 mol% PPh3 and 130
mol% Cs2CO3 in CH3CN) resulted in the generation of three
different products: diene 11, allenoate 12, and allylic acetate 13.
The product distributions for the reactions employing either
pronucleophile 10a or 10b in the presence of both PPh3 and
Cs2CO3 were vastly different from each other (Tables 4 and 5,
entry 1). We suspected that diene 11a was produced through an
SN2¢ addition of the sulfonamide anion of 10a to allenylic acetate
9. In contrast, allenoate 12b was likely formed through either
direct SN2 displacement of the acetate of 9 by the enolate of 10b
or b¢-addition of the enolate to phosphonium diene 2 (vide infra).
Allylic acetate 13b was, however, likely formed through either g-
umpolung addition of the enolate of 10b to allenylic acetate 9 or
sequential g-addition of the enolate of 10b and b¢-addition of
acetate onto phosphonium diene 2. Importantly, we did not
Bn
N
Bn
Ts
13a
9
11a
12a
yield
11a
[%]
77
81
0
entry
PPh3
Cs2CO3
[mol%]
NaOAc
[mol%]
yield
12a
[%]
0
0
20
0
19
0
yield
13a[c]
[%]
0
0
15
14
14
0
yield
9
[mol%]
[%]
1
2
3
4
5
6
20
–
20
110
20
–
130
130
–
–
–
–
–
–
–
130
0
0
6
0
0
0
0
6
–
130
100
[a] Reactions were performed by adding a solution of 9 (0.190 mmol, 1.0
equiv) in dry CH3CN (2.8 mL) over 6 h to a solution of 10a (1.2 equiv) in dry
CH3CN (2.8 mL) containing the following reagents, if required for the reactions
listed in the specific entries above: PPh3 (either 0.2 or 1.1 equiv), Cs2CO3 (1.3
equiv), or NaOAc (1.3 equiv). Once the addition was complete, the mixture
was stirred for another 1–1.5 h. [b] All yields reported are isolated yields. [c]
Allylic acetate 13a was isolated as a mixture of isomers, with the Z-to-E ratio
ranging between 1.11:1 and 1.19:1.
observe formation of
a
trisubstituted olefin in which the
4
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10.1002/cctc.202000626
ChemCatChem
FULL PAPER
nucleophile had added to both the b¢- and g-carbons. Based on
Tong’s proposal that the nucleophile should add first to the g-
carbon of the phosphonium diene, we would have expected to
observe this product if the phosphonium diene did indeed form
during the reaction. Thus, it is unlikely for 13b to have formed by
way of a phosphonium diene, because an excess of the more
nucleophilic enolate of 10b was present during the reaction,
relative to the amount of possible acetate ion (when considering
the slow addition of 9), so we should have observed the
aforementioned trisubstituted olefin, rather than allylic acetate
13b that we actually obtained. It seems unlikely that the acetate
ion would outcompete the carbon-centered nucleophile for
addition to the b¢-carbon. For these reasons, we believe that 13b
was delivered through a well-established phosphine-catalyzed g-
umpolung addition.[25,26]
Performing the reaction in the absence of PPh3 verified our
hypothesis that the sulfonamide anion of 10a underwent SN2¢
addition to allenylic acetate 9 to generate diene 11a (Table 4,
entry 2). Employing pronucleophile 10b in an analogous reaction
revealed that production of allenoate 12b most likely occurred by
way of simple SN2 displacement of the acetate of allenylic
acetate 9 by the enolate of 10b (Table 5, entry 2). More
importantly, this result implies that it is not necessary to pass
through phosphonium diene 2 en route to allenoate 12b. With
the assumption that phosphonium diene 2 is not likely to be
generated in the reactions represented in entry 1 of Tables 4
and 5, the difference in reactivity between the nitrogen- and
carbon-centered nucleophiles in the presence of both PPh3 and
Cs2CO3 can still be explained by considering the involvement of
PPh3. When 10a was employed, its anion presumably reacted
with allenylic acetate 9 in an SN2¢ manner to form 11a faster than
PPh3 could add through conjugate addition, thereby inhibiting
the production of allylic acetate 13a. Conversely, compared with
the rate of reaction of the anion of 10a, the enolate of 10b likely
underwent SN2 displacement of the acetate at a slower rate,
allowing conjugate addition of PPh3 to allenylic acetate 9,
leading to formation of allylic acetate 13b.
allylic acetates 13a,b (Tables 4 and 5, entry 3). When we used
10c, the only isolated product was allenoate 12c (Table 6, entry
3). Thus, because we observed these products from these
reactions, we questioned whether it was indeed possible to
afford such outcomes by way of a phosphonium diene in the
absence of Cs2CO3 (vide infra). When we subjected 9 and each
of the three pronucleophiles 10a–c to excess PPh3, the only
product generated was the respective allylic acetate 13a–c
(Tables 4–6, entry 4). It is possible that allenoates 12a–c were
produced during these reactions, but were subsequently
consumed by the excess of PPh3 present.[28] Overall, it appears
that allenylic acetate 9 and both nitrogen- and carbon-based
nucleophiles reacted in a similar manner when exposed solely to
PPh3 in the absence of Cs2CO3.
To rationalize the construction of products 12 and 13 in the
absence of Cs2CO3, we returned to the question of the
plausibility of a phosphonium diene intermediate leading to the
formation of 12 and 13. Generation of this intermediate would
result in the liberation of acetate into the reaction mixture. As
such, we were interested in probing whether acetate was acting
as the base in the reaction en route to constructing allenoates
12 and allylic acetates 13. Thus, we performed a series of
reactions of 9 with 10a or 10b in the presence of PPh3 and
excess NaOAc (Table 4, entry 5; Table 5, entries 5 and 6). If
NaOAc was indeed capable of serving as the base in this
reaction, the product distribution should have more closely
resembled that observed in the presence of Cs2CO3. Our results
were, however, nearly identical to those observed in the
absence of NaOAc (Table 4, entry 3; Table 5, entries 3 and 4).
Subsequently, we conducted two experiments of 9 with 10a or
10b in the presence of NaOAc alone; no reaction occurred in
either case (Table 4, entry 6; Table 5, entry 7). From these
findings, we conclude that the acetate ion did not act as a base
during any of these reactions. Most importantly, taken together,
our results indicate that it is extremely unlikely that the
phosphonium diene was generated during these reactions. As
discussed earlier, in the absence of an external base, the
phosphonium diene would not undergo a reaction with the
pronucleophile and, thus, no products would form. Because we
have demonstrated that nothing else could serve as the base in
the absence of Cs2CO3, it would be reasonable to expect that
these reactions would not afford any products at all. We did,
however, observe product formation, making it clear that the
phosphonium diene did not form during these reactions.
Ultimately, our findings suggest that, in the absence of an
appropriate external base, phosphonium dienolate 14,
generated upon Michael addition of PPh3 to allenylic acetate 9,
must fulfill the role of a Brønsted base (vide infra) and facilitate
the formation of 12 and 13.[29]
Next, we tested a second carbon pronucleophile, 10c, in the
reactions to determine whether it would demonstrate reactivity
similar to that of 10b (Table 6, entries 1 and 2). Unexpectedly,
we found that the reactivity of 10c was similar in certain aspects
to that of both pronucleophiles 10a and 10b, with both diene 11c
and allenoate 12c being produced from the reactions. In analogy
to our discussion above, this outcome implies that the enolate of
10c reacted faster than PPh3 with allenylic acetate 9 (Table 6,
entry 1). Unlike the enolate of 10b, however, the enolate of 10c
readily took part in both SN2 and SN2¢ reactions with allenylic
acetate 9, with the SN2 pathway being the slightly favored mode
of reactivity.
We then turned our attention to performing the reactions in the
absence of Cs2CO3. In these scenarios, we suspected that if the
phosphonium diene were indeed generated, there would be no
means to deliver any product. These reactions rely on the fact
that Cs2CO3 must first deprotonate the pronucleophiles to deliver
the active nucleophiles for the reactions. In the absence of an
external base, the phosphonium diene would not undergo a
reaction with the pronucleophile and, thus, no products would
form. In this case, we would expect the phosphonium diene
simply to undergo polymerization. Nevertheless, when we
employed PPh3 as the sole catalyst in reactions using
pronucleophiles 10a and 10b, we isolated allenoates 12a,b and
With this realization, we propose that a potential pathway
toward allenoates 12a–c, in the absence of an external base,
proceeds through phosphonium dienolate 14, as displayed in
Scheme 3.[30] The monopronucleophiles 10a–c are subsequently
deprotonated by 14, yielding phosphonium 15. At this point, the
newly formed anion of the nucleophile 10 undergoes an SN2
reaction at the acetate of 15 to produce phosphonium 16.
Deprotonation of the a-carbon of 16 generates new
phosphonium dienolate 17, which then eliminates PPh3 to
produce allenoate 12.
5
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10.1002/cctc.202000626
ChemCatChem
FULL PAPER
OAc
O
OAc
CN
Nu
Ph
•
CO2Et
•
9
CO2Bn
•
H
A
CO2Et
4
10
H
Nu
OAc
CO2Et
CO2Bn
6
12
PPh3
OAc
O
PPh3
CN
Ph3P
CO2Bn
Ph
Ph3P
18
14
O
O
Ph3P
Ph
CO2Bn
Cs2CO3
24
Nu
CN
CN
Ph
Ph
Nu
19
O
Ph3P
CO2Et
OAc
CO2Et
CN
OAc
CO2Bn
17
Nu
O
Ph3P
O
Ph3P
15
Ph
Ph
20
NC
H
Ph3P
CO2Bn
CO2Et
NC
Ph3P
H
23
B
B
OAc
16
OAc
Ph3P
CO2Bn
Ph3P
CO2Bn
22
21
Scheme 3. Mechanistic rationale for the formation of allenoate 12 from
allenylic acetate 9 in the absence of Cs2CO3.
Scheme 4. Plausible mechanism for Tong’s (4+1) reaction.
While our proposed mechanisms are more consistent with the
observed product distributions, we cannot unequivocally exclude
An alternative pathway can be proposed, beginning in the
same manner as just discussed. The pathways diverge,
however, upon construction of phosphonium 20. Instead of
adding to the b¢-carbon, the reaction could proceed initially via g-
umpolung addition of the nucleophile to phosphonium 20,
generating phosphorus ylide 25 (Scheme 5). Following proton
transfer, the anion of intermediate 26 undergoes an
intramolecular SN2 reaction, displacing the acetate to form
phosphonium 27. Cyclopentene 6 would then be produced
following deprotonation of the a-carbon of 27 and subsequent
elimination of PPh3 from 24.
the possibility of phosphonium diene
2
as
a
reactive
intermediate in the formation of allenoates 12a–c and allylic
acetates 13a–c. A route proceeding through phosphonium diene
2 is, however, possible only if it employs phosphonium 15 as
well; otherwise, there would be no means of introducing the
nucleophile to the reaction in the absence of an external base.
Therefore, instead of suggesting that 12 and 13 are produced
through a complex system of mechanisms employing multiple
reactive intermediates working in tandem, we feel it is best to
propose a much simpler mechanism for this process, involving
phosphonium 15 as a common intermediate, and not requiring
formation of phosphonium diene 2.[31]
O
CN
Ph
OAc
CO2Bn
6
•
CO2Bn
O
4
Proposed Mechanism for Tong’s (4+1) Reaction
CN
PPh3
Ph
Based on the data obtained from our investigations employing
the various monopronucleophiles, it is likely that the mechanism
proposed by Tong for the phosphine-catalyzed (4+1) reaction of
allenylic acetate 4 does not adequately describe the actual
events. The most important observation is that this reaction does
not have to pass through phosphonium diene 5 en route to the
formation of cyclopentene 6. Rather, the data we have obtained
suggest a series of alternative mechanisms working in concert to
produce 6. Scheme 4 presents the first plausible mechanism,
based on our findings. The addition of PPh3 to allenylic acetate 4
generates phosphonium dienolate 18, which then undergoes
protonation to yield phosphonium 20. At this point, the enolate of
19 could displace the acetate, yielding intermediate 21.
Following deprotonation of 21, zwitterionic intermediate 22
undergoes intramolecular g-umpolung cyclization to produce
phosphorus ylide 23, which subsequently undergoes proton
transfer to 24 and then elimination of PPh3 to yield cyclopentene
6.[32]
Ph3P
CN
CO2Bn
O
24
CN
Ph
O
OAc
Ph
Ph3P
CO2Bn
27
20
O
O
CO2Bn
OAc
Ph
Ph3P
H
Ph
CN
CN
B
OAc
OAc
Ph3P
CO2Bn
Ph3P
CO2Bn
25
26
Scheme 5. Plausible alternative mechanism for Tong’s (4+1) reaction.
A
third potential mechanism can also be proposed.
Considering that benzoyl acetonitrile (19) would likely be
converted almost completely to its enolate in the presence of
excess Cs2CO3, as was the case in Tong’s reaction, addition of
allenylic acetate 4 to the mixture would mostly result in
conversion to allenoate 28 through an SN2 displacement of the
acetate of 4 (Scheme 6). Allenoate 28 then undergoes a
phosphine-catalyzed intramolecular g-umpolung cyclization that
begins with addition of PPh3 to 28, generating phosphonium
dienolate 29.[32] Following subsequent proton transfer,
intermediate 22 is obtained, ultimately producing cyclopentene 6
6
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10.1002/cctc.202000626
ChemCatChem
FULL PAPER
as shown in Scheme 4.
Annulative Rearrangement
OAc
Based on the knowledge gathered from the studies conducted
with monopronucleophiles 10a–c, it is now apparent that our
(4+1) reaction likely begins with addition of phosphine to
CO2Bn
O
O
O
•
Ph
Ph
CN
CN
H
PPh3
PPh3
NC
NC
Ph
•
allenylic carbamate
1 to form phosphonium dienolate 33
4
6
O
(Scheme 8). This intermediate subsequently undergoes b-
elimination of the carbamate, generating phosphonium diene 2,
toluenesulfonamide anion 8, and CO2. At this point, we return to
our initially posed question: To which carbon of phosphonium
diene 2 does the anion 8 add to first? As unveiled from our
investigation into the reactions between allenylic acetate 9 and
monopronucleophiles 10a–c, a phosphonium diene is not likely
to be generated from 9. Accordingly, we were unable to
elucidate the initial site of attack of the sulfonamide anion 8 on
phosphonium diene 2. While we cannot conclusively state that
addition to the g-carbon did not occur first, we believe that 8 was
most likely to add to the b¢-carbon of phosphonium diene 2. This
mode of addition would be consistent with the lower reaction
efficiency observed upon increasing the steric bulk of the alkyl
substituent. Following addition to the b¢-carbon, phosphonium
dienolate 34 would be obtained. Notably, this intermediate could
potentially eliminate the phosphine to generate allenoate 35,
instead of undergoing proton transfer to generate the next
intermediate in the catalytic cycle. Importantly, we have
previously disclosed an intramolecular g-umpolung cyclization of
compounds similar to 35 that produce 3-pyrrolines 3 following
exposure to catalytic PPh3.[18] Such facile conversion of 35 to 3
serves to provide support that 8 adds to the b¢-carbon of
phosphonium diene 2. From 34, the conversion to 3-pyrroline 3
occurs through proton transfer to construct zwitterion 36,
intramolecular g-umpolung cyclization to yield phosphorus ylide
37, proton transfer to form 38, and subsequent elimination of the
phosphine.
Cs2CO3
SN2
CO2Bn
Ph
19
Ph3P
CO2Bn
Ph3P
CO2Bn
28
29
22
Scheme 6. Alternative pathway for the production of intermediate 22.
Because the major products obtained when Cs2CO3 was
employed in the reactions with the carbon-centered
monopronucleophiles 10b,c were allenoates 12b,c, it is likely
that the predominant pathway in operation during Tong’s
reaction involves the intramolecular g-umpolung cyclization
presented in either Scheme 4 or 6. This argument is further
supported by the fact that when catalytic PPh3 was employed in
the reactions, the formation of the b¢-addition products was
favored over those produced by g-umpolung addition. The route
presented in Scheme 5 cannot be discounted completely, but it
is likely that it constitutes only a minor pathway, if it all.
To obtain further evidence to support our proposed
mechanism, we ran a reaction between allenylic acetate 9 and
benzoyl acetonitrile (19) in the presence of Cs2CO3 (Scheme 7);
we isolated allenoate 30, 4H-pyran 31, and 2H-pyran 32 in
yields of 19, 27, and 12%, respectively.[33] Allenoate 30 was
likely formed via an SN2 reaction of the enolate of 19 with
allenylic acetate 9. The presence of this product is important; it
provides evidence for the mechanism proposed in Scheme 6 as
being the primary reaction pathway for the (4+1) annulation. It is
also notable that 4H-pyran 31 was likely produced from
allenoate 30 through an intramolecular oxa-Michael addition.[34]
In contrast, 2H-pyran 32 probably arose from an SN2¢ addition of
the enolate of 19 to allenylic acetate 9 and subsequent
intramolecular oxa-Michael addition to the b¢-carbon.[34] As such,
the total yield of products constructed via the SN2 pathway was
46%, whereas the yield obtained from the SN2¢ pathway was
only 12%. This observation ultimately suggests that the
mechanism presented in Scheme 6 is the major pathway for the
formation of cyclopentene 6 from allenylic acetate 4, and more
accurately depicts what is transpiring during Tong’s phosphine-
catalyzed (4+1) reaction.
Ts
N
R1
R1
OCONHTs
Ts
N
CO2Et
3
•
CO2Et
1
R1
PR3
O
O
R3P
CO2Et
Ts
N
NHTs
38
R1
R1
R3P
CO2Et
CO2
33
37
R3P
CO2Et
Ts
N
R1
CN
TsNH
8
R1
R3P
CO2Et
8
NH
2
19
Ph
O
Ts
Ts
HN
OAc
R3P
CO2Et
O
R1
R1
CO2Et
Cs2CO3
(1.3 equiv)
CO2Et
36
CN
H
NC
Ph
CO2Et NC
Ph
CO2Et
Ph
•
•
R3P
R3P
CO2Et
34
PhH
rt, 20 h
O
O
2
CO2Et
– PR3
+ PR3
NHTs
9
30
31
32
19%
27%
12%
R = Ph or Bu
R1
R1 = H, alkyl, cycloalkyl,
or aryl
Scheme 7. Reaction between allenylic acetate 9 and 19 in the presence of
•
CO2Et
Cs2CO3.
35
Scheme 8. Proposed mechanism for our phosphine-catalyzed (4+1) reaction.
Proposed Mechanism for our Phosphine-Catalyzed
7
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10.1002/cctc.202000626
ChemCatChem
FULL PAPER
CO2Et
CO2Et
We also considered an alternative mechanism that produces
8 through direct SN2 displacement of the carbamate or addition
to the carbonyl by the phosphine. In an attempt to evaluate this
alternative pathway, we subjected benzyl tosyl carbamate (39)
to both catalytic and stoichiometric PPh3 (Scheme 9). If PPh3
were able to facilitate the displacement of the carbamate or
Ts
1. 15% TFA, CH2Cl2
rt, 3 h, 95%
Ts
N
Mg (50 equiv)
N
MeOH
sonication
3.5 h
2. ClCO2Et, Et3N,
THF, 0 ˚C, 1 h
3. NaBH4, MeOH
– 78 ˚C, 1.5 h
CO2t-Bu
HO
72%
3m
41
73% over two steps
addition to the carbonyl, it would generate
a
benzyl
O
phosphonium or benzyloxycarbonyl phosphonium species and
sulfonamide anion 8. From this point, 8 might undergo a
subsequent SN2 reaction to generate benzyl toluenesulfonamide
(10a). Much to our delight, we observed no reaction between
PPh3 and 39, suggesting that the sulfonamide anion 8 was not
generated through an SN2 displacement of the carbamate from 1
by PPh3. Consequently, our transformation in Scheme 8 must
proceed by way of an SN2¢ reaction, generating phosphonium
diene 2 and toluenesulfonamide anion 8. As such, this reaction
is the first example of a phosphine-catalyzed transformation that
proceeds unequivocally through a phosphonium diene as a
reactive intermediate. We conclude that the reaction developed
by Tong is unlikely to proceed through phosphonium diene 5,
whereas our reaction clearly must proceed through
phosphonium diene 2 to arrive at 3-pyrrolines 3.
[Ref. 37]
N
N
OH
OH
42
(±)-Supinidine
Scheme 11. Formal synthesis of (±)-supinidine.
Conclusion
We have developed a novel phosphine-catalyzed (4+1)
annulative rearrangement of allenylic carbamates 1 to form 3-
pyrrolines 3. This reaction was employed to prepare an array of
1,3-disubstituted and 1,2,3-trisubstituted 3-pyrrolines in
moderate to good yields, focusing on the 2-alkyl-substituted
variants that have traditionally been difficult to synthesize
through phosphine catalysis. This reaction appears to begin with
stepwise displacement of the carbamate by the phosphine,
generating phosphonium diene 2, CO2, and toluenesulfonamide
anion 8, which then adds to the b¢-carbon of the phosphonium
diene, followed by intramolecular g-umpolung cyclization to form
3-pyrroline 3. To discern experimentally which carbon of
phosphonium diene 2 underwent addition of the sulfonamide
anion, we investigated the reactions of allenylic acetate 4 with
several mononucleophiles. The results from this study revealed,
unexpectedly, that Tong’s phosphine-catalyzed (4+1) reaction to
construct cyclopentenes is unlikely to proceed—as had been
proposed—through a phosphonium diene, but rather appears to
employ multiple mechanisms working in parallel. Of these
mechanisms, we propose that the major pathway along which
Tong’s reaction is likely to travel is a phosphine-catalyzed
intramolecular g-umpolung cyclization. Consequently, our newly
developed (4+1) reaction is the first example of a phosphine-
catalyzed reaction that must pass unequivocally through a
phosphonium diene intermediate. Additionally, our newly
developed methodology was applied to concise formal
syntheses of the pyrrolizidine natural products (±)-
trachelanthamidine and (±)-supinidine.
PPh3
O
(20 or 100 mol%)
O
NHTs
No Reaction
CH3CN
rt, 24 h
39
Scheme 9. Reaction of benzyl tosyl carbamate (39) with PPh3.
Application in Total Synthesis
We demonstrate the synthetic utility of this phosphine-
catalyzed (4+1) reaction through syntheses of the pyrrolizidine
alkaloids (±)-trachelanthamidine (Scheme 10) and (±)-supinidine
(Scheme 11). A formal synthesis of (±)-trachelanthamidine was
achieved by treating pyrroline 3l with Mg in MeOH—effecting
detosylation, lactamization, diastereoselective 1,4-reduction of
the a,b-unsaturated ester, and transesterification—to yield the
lactam 40 in 86% yield.[35,36]
Our formal synthesis of (±)-supinidine commenced with the
trifluoroacetic acid–mediated removal of the tert-butyl group from
pyrroline 3m in 95% yield. We then converted the resulting free
carboxylic acid to the mixed anhydride, which was reduced with
NaBH4 to deliver the allylic alcohol 41 in 73% yield over the two
steps. Detosylation using Mg in MeOH and concomitant in situ
lactamization gave the lactam 42 in 72% yield, thereby
completing a formal synthesis of (±)-supinidine in four steps from
pyrroline 3m in 50% overall yield.[37]
CO2Et
O
Ts
Experimental Section
N
[Ref. 35]
Mg (25 equiv)
N
N
H
MeOH
sonication
4.5 h
H
General Information. All reactions were performed under an Ar
atmosphere with dry solvents in oven-dried round-bottom flasks
containing Teflon coated stirrer bars, unless otherwise noted. CH2Cl2,
CH3CN, and Et3N were freshly distilled from CaH2; tetrahydrofuran (THF),
Et2O, toluene, and benzene were distilled from Na/benzophenone. All
other reagents were obtained commercially and used without further
purification, unless otherwise stated. Reactions were monitored using
thin layer chromatography (TLC), performed on 0.25-mm SiliCycle Glass-
Backed Extra-Hard-Layer, 60-Å silica gel plates (TLG-R10011B-323) and
MeO2C
CO2Et
OH
86%
3l
40
(±)-Trachelanthamidine
Scheme 10. Formal synthesis of (±)-trachelanthamidine.
8
This article is protected by copyright. All rights reserved.

10.1002/cctc.202000626
ChemCatChem
FULL PAPER
visualized under UV light or through permanganate and iodine staining.
Flash column chromatography was performed using SiliCycle SiliaFlash®
P60 (230–400 mesh, R12030B) and compressed air. IR spectra were
recorded using either a Thermo Nicolet Avatar 370 FT-IR spectrometer
tert-Butyl 4-bromo-2-butynoate (S7). Methanesulfonyl chloride (6.20
mL, 79.8 mmol) was added dropwise to a solution of S6 (11.3 g, 72.6
mmol) and dry Et3N (11.0 mL, 76.2 mmol) in dry CH2Cl2 (400 mL) that
was cooled to 0 °C in an ice-water bath. The solution was then stirred at
0 °C for 1 h, at which point distilled water (200 mL) was added. The
separated organic phase was washed sequentially with 2 M HCl (3 ´ 250
mL), saturated aqueous NaHCO3 (2 ´ 250 mL), and brine (250 mL), dried
(Na2SO4), filtered, and concentrated under reduced pressure to yield the
crude propargylic mesylate (16.3 g). This material was subjected to the
subsequent reaction without further purification. A solution of the crude
propargylic mesylate in freshly distilled acetone (20 mL) was added to a
solution of anhydrous lithium bromide (reagent stored in a glove box,
23.0 g, 26.5 mmol) in freshly distilled acetone (460 mL). The mixture was
heated under reflux for 1.75 h and then cooled to room temperature. The
suspension was filtered through Celite using a glass fritted funnel. The
filter cake was washed thoroughly with acetone and then the resulting
solution was concentrated under reduced pressure. The residue was
partitioned between distilled water (300 mL) and hexanes (200 mL). The
aqueous phase was extracted with hexanes (2 ´ 200 mL); the combined
organic phases were dried (Na2SO4), filtered, and concentrated under
reduced pressure. The crude material was purified through flash column
chromatography (100% hexanes to 10% EtOAc/hexanes) to yield S7
(12.6 g, 80% over two steps) as a light-yellow oil. IR (n, cm–1) 3006, 2982,
2971, 2941, 1738, 1708, 1369, 1278, 1256, 1216, 1152, 1082, 840, 751,
712; 1H NMR (300 MHz, CDCl3) d (ppm) 3.94 (s, 2H), 1.50 (s, 9H); 13C
NMR (75.5 MHz, CDCl3) d (ppm) 151.7, 84.0, 78.9, 78.4, 27.8, 11.9; MS
(GCMS) calcd for C4H3BrO2 [M – t-Bu]+ m/z 161.9, found 161.9.
or
a JASCO FT/IR-4100 spectrometer with an ATR-PRO 450-S
accessory. NMR spectra were recorded using Bruker ARX-500, DRX-500,
AV-500, or AV-300 instruments calibrated to CH(D)Cl3 as an internal
reference (7.26 and 77.00 ppm for 1H and 13C NMR spectra,
respectively). Data for 1H NMR spectra are reported in terms of chemical
shift (δ, ppm), multiplicity, coupling constant (Hz), and integration. Data
for 13C NMR spectra are reported in terms of chemical shift (δ, ppm), with
multiplicity and coupling constants in the case of C–F coupling. The
following abbreviations are used to denote multiplicities: s = singlet; d =
doublet; dd = doublet of doublets; dt = doublet of triplets; dq = doublet of
quartets; ddd = doublet of doublet of doublets; t = triplet; td = triplet of
doublets; tt = triplet of triplets; q = quartet; qd = quartet of doublets; quin
= quintet; sex = sextet; m = multiplet. Mass spectra were recorded using
an Applied Biosystems Voyager-DE STR MALDI-TOF spectrometer
operated in a reflector mode, under positive polarity. The matrix was 2,5-
dihydroxybenzoic acid, which was also employed as an internal calibrant.
Data were analyzed using the instrument software. One compound’s
mass was determined using an Agilent 6890-5975 GC-MS instrument;
the sample was dissolved in CHCl3. Some samples were also
characterized in an Agilent ESI mass spectrometer, with the data
analyzed using the instrument’s software.
Starting Materials. Ethyl 4-bromo-2-butynoate (S4) was prepared
following literature procedures;[38] the synthetic route to S4 is presented
in Scheme S1.[20] tert-Butyl 4-bromo-2-butynoate (S7) was prepared in a
Ethyl 4-oxobutanoate (S8). This compound was prepared using a
known methodology that had not yet been applied to the synthesis of
S8.[42] Tri-n-butyltin hydride (2.30 mL, 8.40 mmol) was added dropwise
over 5 min to a solution of ethyl succinyl chloride (1.14 mL, 8.00 mmol) in
freshly distilled N-methylpyrrolidinone (8 mL) cooled to 0 °C in an ice-
water bath. The mixture was stirred for 30 min at 0 °C and then it was
removed from the bath and warmed to room temperature. Once removed
from the ice bath, the mixture was stirred for 45 min, at which point the
manner
similar
to
S4
(Scheme
S2).[20,39]
4-(tert-
Butyldimethylsilyloxy)butanal[40] and 4-pentynal[41] were prepared
following literature procedures.
tert-Butyl 4-hydroxy-2-butynoate (S6). 3,4-Dihydro-2H-pyran (14.9 mL,
160 mmol) and propargyl alcohol (S1; 8.65 mL, 145 mmol) were placed
in an oven-dried round-bottom flask containing a magnetic stirrer bar and
then cooled to 0 °C using an ice-water bath. p-Toluenesulfonic acid
(0.276 g, 1.45 mmol) was added to the mixture, which was then stirred at
0 °C for 10 min. The solution was then removed from the bath and
warmed to room temperature. After stirring for 2 h at room temperature,
dry THF (230 mL) was added and then the solution was cooled to –78 °C.
n-BuLi (1.6 M solution in hexanes, 99.7 mL, 160 mmol) was slowly added
and then the mixture was stirred for 1.5 h at –78 °C. A solution of di-tert-
butyl dicarbonate (39.5 g, 181 mmol) in dry THF (35 mL) was slowly
added (in 20 mL portions) to the mixture over a period of 20 min. The
mixture was stirred at –78 °C for 1 h before being removed from the
cooling bath and placed in an ice-water bath (0 °C), in which it was
stirred for 30 min. The reaction was quenched through the addition of
saturated aqueous NH4Cl (450 mL). The separated aqueous layer was
extracted with EtOAc (3 ´ 150 mL) and then the combined organic layers
were washed with brine (100 mL), dried (Na2SO4), filtered, and
concentrated to yield crude S5 (43.3 g). This material was subjected to
the subsequent reaction without further purification. The crude product
was dissolved in absolute EtOH (570 mL) and then pyridinium p-
toluenesulfonate (3.72 g, 14.5 mmol) was added. The mixture was
heated to 55 °C and stirred at that temperature for 2 h. After this time, the
reaction was quenched through the addition of saturated aqueous
NaHCO3 (500 mL) and then the mixture was concentrated under reduced
pressure to remove the EtOH. The aqueous slurry was extracted with
Et2O (5 ´ 100 mL). The combined organic phases were washed with
brine, dried (Na2SO4), and concentrated under reduced pressure. The
residue was purified through flash column chromatography (100%
hexanes to 5% EtOAc/hexanes to 10% EtOAc/hexanes, and finally 15%
EtOAc/hexanes) to yield S6 (18.7 g, 82% over the three steps) as an oil.
The spectral data were in agreement with those previously published in
the literature.[39]
reaction
was
determined, using TLC (staining
with 2,4-
dinitrophenylhydrazine produced a yellow spot to reveal the presence of
the aldehyde), to be complete. Distilled water (20 mL) and EtOAc (40
mL) were added and the aqueous phase was extracted with EtOAc (3 ´
40 mL). The combined organic phases were washed with saturated
aqueous NH4Cl (3 ´ 40 mL) to ensure removal of NMP. The organic
phase was subsequently washed with brine (20 mL), dried (Na2SO4),
filtered, and concentrated under reduced pressure. The residue was
distilled under reduced pressure (head temperature: 100–110 °C; bath
temperature: 150 °C) to yield S8 (0.602 g, 69%) as a colorless oil. The
spectral data were in agreement with those previously published.[43]
p-Methoxybenzenesulfonyl isocyanate (S9). Prepared by following a
literature procedure for a similar compound.[21a] A solution of triphosgene
(5.88 g, 19.8 mmol) in dry 1,2-dichlorobenzene (30 mL) was added over
4.5 h, via syringe pump, to a solution of p-methoxybenzenesulfonamide
(11.0 g, 58.8 mmol) and isopropyl isocyanate (0.550 mL, 5.60 mmol) in
dry 1,2-dichlorobenzene (30 mL) at 150 °C. The mixture was then heated
at 180 °C for 2 h before being removed from the oil bath and cooled to
room temperature, with stirring for 12 h. The solvent and isopropyl
isocyanate were distilled off under
3 mmHg of pressure (bath
temperature: 155 °C; head temperature: 120 °C). The remaining thick
black liquid was then further distilled under 3 mmHg of pressure (bath
temperature: 200 °C; head temperature: 160–165 °C) to yield S9 (7.09 g,
57%) as a clear liquid. Upon cooling, the product solidified in the form of
a low-melting white solid, which was stored under Ar at –20 °C. The
spectral data were in agreement with those previously reported.[44]
p-Nitrobenzenesulfonyl isocyanate (S10). Prepared in an analogous
manner to that presented above for S9, with n-butyl isocyanate employed
instead of isopropyl isocyanate. A mixture of p-nitrobenzenesulfonamide
(5.50 g, 27.2 mmol) and n-butyl isocyanate (1.21 mL, 10.9 mmol) in dry
9
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10.1002/cctc.202000626
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FULL PAPER
1,2-dichlorobenzene (25 mL) was heated under reflux until the solution
became clear-yellow. A solution of triphosgene (3.30 g, 11.1 mmol) in dry
1,2-dichlorobenzene (20 mL) was added to this solution over 3.5 h, via
syringe pump, and then the mixture was heated under reflux for another
2 h. At this point, the mixture was removed from the oil bath and cooled
to room temperature, with stirring for 12 h. The solvent and n-butyl
isocyanate were then distilled off under reduced pressure. The remaining
thick black liquid was subjected to Kugelrohr distillation to yield S10 as a
light-yellow solid (0.316 g, 5%), which was stored under Ar at –20 °C.
The spectral data were in agreement with those previously reported.[45]
6.28 mmol) and NaI (0.942 g, 6.28 mmol) were added sequentially, each
in one portion, to a solution of ethyl 4-bromo-2-butynoate (S4, 1.00 g,
5.24 mmol) in N,N´-dimethylpropyleneurea (DMPU; 8 mL). The flask was
wrapped in aluminum foil and the hood light turned off to protect the
reaction from light. After stirring at room temperature for 7–8 h, the
mixture was cooled to
0 °C in an ice-water bath. A solution of
propionaldehyde (0.300 mL, 4.19 mmol) in DMPU (4 mL) was added
over 15 min. The mixture was stirred at 0 °C for another 2 h and then
removed from the ice bath, warmed to room temperature, and stirred for
18–24 h at room temperature while still wrapped in aluminum foil. At this
point, the mixture was cooled to 0 °C in an ice-water bath and diluted
with Et2O (15 mL); the reaction was quenched through the addition of
saturated aqueous NH4Cl (15 mL). The separated aqueous phase was
extracted with Et2O (4 x 15 mL). The combined organic phases were
washed with brine (15 mL), dried (Na2SO4), filtered, and concentrated
under reduced pressure. The residue was purified through flash column
chromatography (5–10% EtOAc/hexanes) to yield 7c (373 mg, 52%) as a
light-yellow oil. IR (n, cm–1) 3435, 2978, 2937, 1964, 1708, 1262, 1067;
1H NMR (400 MHz, CDCl3) δ 5.22 (d, J = 1.8 Hz, 2H), 4.31 (br s, 1H),
4.20 (q, J = 7.1 Hz, 2H), 3.04 (br s, 1H), 1.65 (quin, J = 7.2 Hz, 2H), 1.26
(t, J = 7.1 Hz, 3H), 0.93 (t, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ
212.4, 167.1, 102.9, 80.5, 70.7, 61.2, 28.3, 14.2, 10.2; MS (MALDI) calcd
for C9H14O3Na [M + Na]+ m/z 193.08, found 193.09.
Synthesis of Allenylic Alcohols 7. Allenylic alcohols 7a and 7b were
synthesized through an organocatalytic MBH reaction between ethyl 2,3-
butadienoate (S11) and either paraformaldehyde or acetaldehyde in the
presence of 3-hydroxyquinuclidine (reaction optimization studies for 7a
are presented in the SI).[20] Allenylic alcohols 7c–7g and 7i–7m were
prepared from a tin(II)-mediated allenylation of propargyl bromides to
aldehydes.[23a] Allenylic alcohol 7h was prepared according to the
procedure described in the literature.[23b]
Ethyl 2-(hydroxymethyl)-2,3-butadienoate (7a).[46] Paraformaldehyde
(2.82 g, 89.2 mmol) was placed under vacuum in a flask and then
immersed in an oil bath at 55 °C for 1 h to remove water. After cooling to
room temperature, THF (50 mL) was added and then the flask was
placed in an ice/NaCl bath at –15 °C. A solution of 3-hydroxyquinuclidine
(472 mg, 3.57 mmol) in THF (25 mL) was added dropwise over 5 min to
Ethyl 2-(1-hydroxybutyl)-2,3-butadienoate (7d). This compound was
prepared as described above for 7c, except that butyraldehyde was
employed as a reactant. A light-yellow oil was isolated in 55% yield. All
spectral data were in agreement with those previously published.[23b]
the suspension of paraformaldehyde.
A
solution of ethyl 2,3-
butadienoate[47] (S11, 2.01 g, 17.90 mmol) in THF (25 mL) was added
dropwise to the suspension of paraformaldehyde and 3-
hydroxyquinuclidine over 5 min. The mixture was stirred at –15 °C for 1 h,
at which point the flask was removed from the bath and warmed to room
temperature while stirring for 3.75 h. Saturated aqueous NH4Cl (50 mL)
was added and then the aqueous phase was extracted with EtOAc (3 ´
50 mL). The combined organic extracts were washed with brine (50 mL),
dried (Na2SO4), filtered, and concentrated under reduced pressure. The
residue was purified through flash column chromatography (15%
EtOAc/hexanes) to yield 7a (1.67 g, 66% yield) as a thick, slightly yellow,
oil. All spectral data were in agreement with those previously
published.[23b]
Ethyl 2-[cyclopropyl(hydroxy)methyl]-2,3-butadienoate (7e).[18] This
compound was prepared as described above for 7c, except that
cyclopropanecarboxaldehyde was employed as a reactant. A light-yellow
oil was isolated in 65% yield. IR (n, cm–1) 3465, 2986, 1963, 1710, 1256,
1208; 1H NMR (500 MHz, CDCl3) δ 5.25 (d, J = 1.9, 2H), 4.23 (q, J = 7.2,
2H), 3.73 (d, J = 7.9 Hz, 1H), 3.12 (d, J = 3.4 Hz, 1H), 1.28 (t, J = 7.2 Hz,
3H), 1.18–1.10 (m, 1H), 0.63–0.56 (m, 1H), 0.52–0.40 (m, 2H), 0.27–0.21
(m, 1H); 13C NMR (125 MHz, CDCl3) δ 212.7, 167.0, 102.9, 80.2, 73.7,
15.8, 14.0, 3.5, 2.6; MS (MALDI) calcd for C10H14O3Na [M + Na]+ m/z
205.08, found 205.08.
Ethyl 2-(1-hydroxyethyl)-2,3-butadienoate (7b).[18,48] Ethyl 2,3-
butadienoate[47] (S11, 2.03 g, 18.1 mmol) was added dropwise over 5
min to a solution of 3-hyoxyquinuclidine (460 mg, 3.55 mmol) in dry Et2O
(10 mL) that was cooled at –15 °C in an ice/NaCl bath. Acetaldehyde
(2.00 mL, 35.8 mmol) was then added dropwise over 1 min to this chilled
solution [note: the bottle of acetaldehyde had been cooled at –78 °C and
kept under Ar prior to use, to ensure that the compound remained as a
liquid]. The mixture was stirred at –15 °C for 50 min, at which point the
reaction was deemed to be complete (TLC). Saturated aqueous NH4Cl
(10 mL) was added and then the aqueous phase was extracted with
EtOAc (3 ´ 10 mL). The combined organic phases were washed with
H2O (10 mL) and brine (10 mL), dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue was purified through
flash column chromatography (10% EtOAc/hexanes) to yield 7b (2.20 g,
79% yield) as a thick, slightly yellow, oil. IR (n, cm–1) 3433, 2982, 2935,
2907, 1966, 1708, 1266, 1059; 1H NMR (300 MHz, CDCl3) δ 5.19 (d, J =
2.2 Hz, 2H), 4.62–4.51 (m, 1H), 4.17 (d, J = 7.1 Hz, 1H), 4.12 (d, J = 7.1
Hz, 1H), 3.30 (d, J = 4.0 Hz, 1H), 1.25 (d, J = 6.4 Hz, 3H), 1.21 (t, J = 7.1
Hz, 3H); 13C NMR (75.5 MHz, CDCl3) δ 212.0, 167.1, 104.3, 80.8, 64.7,
61.1, 21.0, 14.1; MS (MALDI) calcd for C8H12O3Na [M + Na]+ m/z 179.07,
found 179.04.
Ethyl 2-[cyclopentyl(hydroxy)methyl]-2,3-butadienoate (7f).[18] This
compound was prepared as described above for 7c, except that
cyclopentanecarboxaldehyde was employed as a reactant. Isolated in
62% yield, as a light-yellow oil. IR (n, cm–1) 3479, 2955, 2869, 1964,
1704, 1255, 1071, 1030; 1H NMR (500 MHz, CDCl3) δ 5.19 (s, 2H), 4.18
(q, J = 7.1 Hz, 2H), 3.19 (br s, 1H), 2.17 (sex, J = 8.1 Hz, 1H), 1.88–1.76
(m, 1H), 1.67–1.41 (m, 7H), 1.25 (t, J = 4.8 Hz, 3H), 1.18–1.10 (m, 1H);
13C NMR (125 MHz, CDCl3) δ 212.9, 167.1, 102.6, 80.0, 74.1, 61.1, 44.2,
29.44, 29.11, 25.6, 25.5, 14.0; MS (MALDI) calcd for C12H18O3Na [M +
Na]+ m/z 233.12, found 233.12.
Ethyl 2-[cyclohexyl(hydroxy)methyl]-2,3-butadienoate (7g).[18] This
compound was prepared as described above for 7c, except that
cyclohexanecarboxaldehyde was employed as a reactant. A light-yellow
oil was isolated in 80% yield. IR (n, cm–1) 3478, 2982, 2927, 2852, 1964,
1710, 1255, 1067; 1H NMR (500 MHz, CDCl3) δ 5.19 (d, J = 1.0 Hz, 2H),
4.19 (q, J = 7.1 Hz, 2H), 2.96 (br s, 1H), 1.97 (d, J = 12.8 Hz, 1H), 1.76–
1.54 (m, 6H), 1.26 (t, J = 7.1 Hz, 3H), 1.22–1.09 (m, 3H), 1.02–0.93 (m,
2H); 13C NMR (125 MHz, CDCl3) δ 212.8, 166.9, 101.5, 79.8, 74.7, 61.0,
42.5, 29.7, 28.4, 26.3, 25.9, 25.7, 14.0; MS (MALDI) calcd for
C13H20O3Na [M + Na]+ m/z 247.13, found 247.12.
Ethyl 2-(1-hydroxy-4-pentynyl)-2,3-butadienoate (7i). This compound
was prepared as described above for 7c, except that 4-pentynal[41] was
employed as a reactant. A thick light-yellow oil was isolated in 29% yield.
IR (n, cm–1) 3604–3334, 3289, 3063, 2981, 2961, 2929, 2117, 1963,
1939, 1699, 1367, 1268, 1102, 1070, 1050, 852; 1H NMR (300 MHz,
CDCl3) d (ppm) 5.27 (d, J = 2.0 Hz, 2H), 4.61–4.51 (m, 1H), 4.23 (q, J =
General Procedure for the Preparation of Allenylic Alcohols 7c–7g
and 7i–7m. Allenylic alcohols 7d–7g and 7i–7m were prepared
according to the procedure described below for allenylic alcohol 7c.
Ethyl 2-(1-hydroxypropyl)-2,3-butadienoate (7c).[18] Prepared using a
slight modification of the procedure reported by Ma.[23a] SnCl2 (1.19 g,
10
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10.1002/cctc.202000626
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FULL PAPER
7.1 Hz, 2H), 3.11 (d, J = 5.2 Hz, 1H), 2.35 (td, J = 7.2, 2.6 Hz, 2H), 1.95
(t, J = 2.7 Hz, 1H), 1.86 (q, J = 7.0 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H); 13C
NMR (75.5 MHz, CDCl3) d (ppm) 212.1, 166.9, 102.6, 83.6, 80.9, 686,
67.7, 61.3, 33.7, 14.9, 14.1; MS (MALDI) calcd for C11H14O3Na [M + Na]+
m/z 217.08, found 217.07.
as a white crystalline solid. M.p. 111–114 °C; IR (n, cm–1) 3224, 2985,
1966, 1752, 1711, 1448, 1160; 1H NMR (300 MHz, CDCl3) δ 8.26 (s, 1H),
7.90 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 5.18 (t, J = 2.1 Hz, 2H),
4.76 (t, J = 2.1 Hz, 2H), 4.16 (q, J = 7.1 Hz, 2H), 2.42 (s, 1H), 1.22 (t, J =
7.1 Hz, 3H): 13C NMR (75 MHz, CDCl3) δ 214.6, 165.1, 150.2, 145.0,
135.5, 129.6, 128.5, 96.3, 81.0, 62.9, 61.5, 21.7, 14.1; MS (MALDI) calcd
for C15H17NO6SNa [M + Na]+ m/z 362.07, found: 362.06.
Ethyl
2-(1-hydroxy-3-phenylpropyl)-2,3-butadienoate
(7j).
This
compound was prepared as described above for 7c, except that
hydrocinnamaldehyde was employed as a reactant. A thick light-yellow
oil was isolated in 67% yield. IR (n, cm–1) 3609–3293, 3059, 3023, 2982,
2928, 1962, 1933, 1703, 1495, 1456, 1391, 1366, 1259, 1097, 1067; 1H
NMR (300 MHz, CDCl3) d (ppm) 7.31–7.26 (m, 2H), 7.22–7.16 (m, 3H),
5.27 (d, J = 2.0 Hz, 2H), 4.50–4.39 (m, 1H), 4.24 (q, J = 7.1 Hz, 2H),
2.89–2.80 (m, 1H), 2.76–2.66 (m, 1H), 2.02–1.93 (m, 2H), 1.29 (t, J = 7.1
Hz, 3H); 13C NMR (75.5 MHz, CDCl3) d (ppm) 212.2, 167.1, 141.7, 128.4,
128.3, 125.8, 102.9, 80.8, 68.4, 61.2, 36.7, 31.9, 14.1; MS (MALDI) calcd
for C15H18O3Na [M + Na]+ m/z 269.12, found 269.12.
Ethyl 2-[1-(tosylcarbamoyloxy)ethyl]-2,3-butadienoate (1b).[18] p-
Toluenesulfonyl isocyanate (0.430 mL, 2.70 mmol) was added dropwise
to a solution of allenylic alcohol 7b (0.400 g, 2.56 mmol) in dry CH2Cl2
(6.4 mL), cooled at 0 °C in an ice-water bath. The mixture was stirred for
1 h at 0 °C, at which point it was removed from the bath and warmed to
room temperature. After 30 min, the mixture was concentrated under
reduced pressure and the residue purified through flash column
chromatography (5–20% EtOAc/hexanes) to yield 1b (0.846 g, 94%
yield) as a thick colorless oil. IR (n, cm–1) 3232, 2988, 1967, 1750, 1717,
1450, 1357, 1286, 1224, 1162; 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J =
8.4 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 5.53–5.48 (m, 1H), 5.20 (dd, J =
14.7, 2.1 Hz, 1H), 5.15 (dd, J = 14.6, 2.1 Hz, 1H), 4.04 (q, J = 7.1 Hz, 2H),
2.35 (s, 3H), 1.28 (d, J = 6.5 Hz, 3H), 1.11 (t, J = 7.1 Hz); 13C NMR (125
MHz, CDCl3) δ 212.8, 164.7, 149.8, 144.7, 135.6, 129.3, 128.2, 101.8,
82.2, 69.4, 61.2, 60.4, 21.4, 18.9, 14.0, 13.8; MS (MALDI) calcd for
C16H19NO6SNa [M + Na]+ m/z 376.08, found 376.04.
Ethyl 2-[1-hydroxy-4-(tert-butyldimethylsilyloxy)butyl]-2,3-butadienoate
(7k). This compound was prepared as described above for 7c, except
that 4-(tert-butyldimethylsilyloxy)butanal[40] was employed as a reactant.
A thick light-yellow oil was isolated in 44% yield. IR (n, cm–1) 3580–3253,
2953, 2923, 2889, 2858, 1965, 1939, 1711, 1255, 1097, 1061, 832; 1H
NMR (300 MHz, CDCl3) d (ppm) 5.25 (d, J = 1.9 Hz, 2H), 4.5–4.39 (br s,
1H), 4.22 (q, J = 7.1 Hz, 2H), 3.67–3.63 (m, 2H), 3.65 (td, J = 5.8, 1.3 Hz,
1H), 1.78–1.58 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H), 0.88 (s, 9H), 0.05 (s,
6H); 13C NMR (75.5 MHz, CDCl3) d (ppm) 212.4, 166.9, 103.3, 80.6, 68.9,
63.0, 61.1, 32.2, 29.0, 25.8, 18.2, 14.1, –5.4; MS (MALDI) calcd for
C16H30O4SiNa [M + Na]+ m/z 337.18, found 337.17.
Ethyl
2-[1-(tosylcarbamoyloxy)propyl]-2,3-butadienoate
(1c).[18]
Isolated in 84% yield as a thick colorless oil. IR (n, cm–1) 3231, 2981,
2938, 1970, 1750, 1717, 1447, 1162; 1H NMR (500 MHz, CDCl3) δ 7.89
(d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 5.38–5.35 (m, 1H), 5.20, (dd,
J = 14.6, 1.9 Hz, 1H), 5.15 (dd, J = 14.6, 2.0 Hz, 1H), 4.11 (q, J = 7.1,
2H), 2.42 (s, 3H), 1.79–1.63 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H), 0.82 (t, J =
7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 213.0, 164.7, 149.7, 144.8,
135.6, 129.4, 128.3, 100.6, 81.7, 74.2, 61.2, 26.3, 21.5, 13.9, 9.3. MS
(MALDI) calcd for C17H21NO6SNa [M + Na]+ m/z 390.41, found 390.21.
Diethyl 3-hydroxy-2-vinylidenehexanedioate (7l). This compound was
prepared as described above for 7c, except that ethyl 4-oxobutanoate
(S8) was employed as a reactant. A thick light-yellow oil was isolated in
61% yield. IR (n, cm–1) 3644–3248, 2984, 2935, 2905, 1965, 1940, 1737,
1709, 1367, 1253, 1176, 1070; 1H NMR (300 MHz, CDCl3) d (ppm) 5.26
(d, J = 2.0 Hz, 2H), 4.49–4.38 (br s, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.10 (q,
J = 7.1 Hz, 2H), 3.24–3.14 (br s, 1H), 2.54–2.36 (m, 2H), 2.01–1.88 (m,
2H), 1.26 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H); 13C NMR (75.5 MHz,
CDCl3) d (ppm) 212.1, 173.5, 166.8, 102.7, 81.0, 68.2, 61.2, 60.3, 30.5,
30.1, 14.1, 14.1; MS (MALDI) calcd for C12H18O5Na [M + Na]+ m/z 265.11,
found 265.11.
Ethyl 2-[1-(tosylcarbamoyloxy)butyl]-2,3-butadienoate (1d). Isolated in
69% yield as a thick light-yellow oil. IR (n, cm–1) 3432–3088, 2962, 2934,
2873, 1965, 1933, 1751, 1709, 1598, 1496, 1446, 1349, 1284, 1255,
1218, 1160, 1091, 885, 862; 1H NMR (300 MHz, CDCl3) d (ppm) 7.89 (d,
J = 8.3 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 5.47–5.39 (m, 1H), 5.23 (dd, J =
14.5, 1.8 Hz, 1H), 5.16 (dd, J = 14.5, 1.9 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H),
2.43 (s, 3H), 1.71–1.61 (m, 2H), 1.29–1.18 (m, 5H), 0.85 (t, J = 7.3 Hz,
3H); 13C NMR (75.5 MHz, CDCl3) d (ppm) 213.0, 164.7, 149.7, 144.8,
135.6, 129.4, 128.3, 101.0, 81.8, 73.0, 61.2, 35.3, 21.5, 18.3, 14.0, 13.5;
MS (MALDI) calcd for C18H23NO6SNa [M + Na]+ m/z 404.11, found
404.11.
1-tert-Butyl 6-ethyl 3-hydroxy-2-vinylidenehexanedioate (7m). This
compound was prepared as described above for 7c, except that tert-butyl
4-bromo-2-butynoate (S7) and ethyl 4-oxobutanoate (S8) were employed
as the reactants. A thick light-yellow oil was isolated in 72% yield. IR (n,
cm–1) 3585–3318, 2981, 2935, 1963, 1941, 1734, 1702, 1367, 1296,
1249, 1168, 846; 1H NMR (300 MHz, CDCl3) d (ppm) 5.19 (d, J = 2.0 Hz,
2H), 4.44–4.38 (m, 1H), 4.13 ppm (q, J = 7.1 Hz, 2H), 3.19 (d, J = 5.7 Hz,
1H), 2.56–2.38 (m, 2H), 2.0–1.92 (m, 2H), 1.48 (s, 9H), 1.25 (t, J = 7.1
Hz, 3H); 13C NMR (75.5 MHz, CDCl3) d (ppm) 211.9, 173.5, 166.1, 103.8,
81.8, 80.4, 68.3, 60.3, 30.5, 30.2, 27.9, 14.1; MS (MALDI) calcd for
C14H22O5Na [M + Na]+ m/z 293.14, found 293.14.
Ethyl
2-[cyclopropyl(tosylcarbamoyloxy)methyl]-2,3-butadienoate
(1e).[18] Isolated in 88% yield as a thick oil. IR (n, cm–1) 3230, 2985, 1964,
1715, 1448, 1353, 1161; 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.2 Hz,
2H), 7.28 (d, J = 8.2 Hz, 2H), 5.27 (dd, J = 14.6, 1.4 Hz, 1H), 5.23 (dd, J
= 14.6, 1.3 Hz, 1H), 4.88 (d, J = 9.0 Hz, 1H), 4.07 (q, J = 7.1 Hz, 2H),
2.40 (s, 3H), 1.28–1.21 (m, 1H), 1.15 (t, J = 7.1 Hz, 3H), 0.52–0.40 (m,
3H), 0.32–0.28 (m, 1H); 13C NMR (100.6 MHz, CDCl3) δ 213.7, 164.7,
150.0, 144.6, 135.7, 129.3, 128.2, 100.9, 81.6, 77.2, 61.2, 60.4, 21.5,
14.0, 13.9, 3.9, 2.9; MS (MALDI) calcd for C18H21NO6SNa [M + Na]+ m/z
402.10, found: 402.11.
Allenylic carbamates 1. Allenylic carbamates 1a and 1bb were
prepared according to the procedures described below, while allenylic
carbamates 1b–m, 1ba, 1bc, and 1bd were prepared according to the
procedure described for 1b.
Ethyl
2-[cyclopentyl(tosylcarbamoyloxy)methyl]-2,3-butadienoate
Ethyl 2-[(tosylcarbamoyloxy)methyl]-2,3-butadienoate (1a).[18] p-
Toluenesulfonyl isocyanate (0.590 mL, 3.71 mmol) was added dropwise
quickly to a solution of allenylic alcohol 7a (0.500 g, 3.52 mmol) in dry
CH2Cl2 (8.8 mL) at room temperature. The mixture was stirred for 1.5 h at
room temperature and then concentrated under reduced pressure. The
residue was purified through flash column chromatography (10–30%
EtOAc/hexanes) to yield 1a (1.10 g, 92% yield) as a thick oil that
solidified into a white crystalline solid upon standing in the freezer (–
20 °C). This compound could also be recrystallized from EtOAc/hexanes
(1f).[18] Isolated in 86% yield as a thick oil. IR (n, cm–1) 3229, 2958, 2868,
1964, 1750, 1701, 1447, 1162; 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J =
8.1 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 5.32 (dt, J = 8.1, 1.4 Hz, 1H), 5.19
(dd, J =14.6, 1.5 Hz, 1H), 5.13 (dd, J = 14.5, 1.5 Hz, 1H), 4.09 (q, J = 7.1
Hz, 2H), 2.40 (s, 3H), 2.25 (sex, J = 8.0 Hz, 1H), 1.61–1.34 (m, 6H),
1.26–1.14 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
213.7, 164.9, 150.0, 144.6, 135.7, 129.3, 128.2, 100.8, 81.5, 76.4, 61.1,
42.8, 28.6, 28.3, 25.2, 25.2, 21.5, 13.9; MS (MALDI) calcd for
C20H25NO6SNa [M + Na]+ m/z 430.13, found: 429.95.
11
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10.1002/cctc.202000626
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164.5, 149.9, 144.7, 135.7, 129.4, 128.2, 100.5, 82.2, 72.0, 61.3, 60.6,
29.8, 28.4, 21.5, 14.1, 14.0; MS (ESI) calcd for C20H25NO8SNa [M + Na]+
m/z 462.12, found 462.0.
Ethyl
2-[cyclohexyl(tosylcarbamoyloxy)methyl]-2,3-butadienoate
(1g).[18] Isolated in 88% yield as a thick oil. IR (n, cm–1) 3231, 2929, 2854,
1718, 1448, 1161, 1091; 1H NMR (500 MHz, CDCl3) δ 7.90 (d, J = 8.4 Hz,
2H), 7.32 (d, J = 8.2 Hz, 2H), 5.23 (dt, J = 7.0, 1.6 Hz, 1H), 5.19 (dd, J =
14.5, 1.3 Hz, 1H), 5.13 (dd, J = 14.5, 1.6 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H),
2.43 (s, 3H), 1.73–1.58 (m, 4H), 1.53 (d, J = 11.9 Hz, 2H), 1.22 (t, J = 7.1
Hz, 3H), 1.19–1.03 (m, 3H), 1.00–0.82 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 213.5, 164.9, 149.9, 144.9, 135.7, 129.5, 128.4, 99.9, 81.5,
77.3, 61.3, 40.8, 29.0, 27.7, 26.1, 25.8, 25.7, 21.7, 14.1; MS (MALDI)
calcd for C21H27NO6SNa [M + Na]+ m/z 444.15, found: 444.16.
1-tert-Butyl 6-ethyl 3-(tosylcarbamoyloxy)-2-vinylidenehexanedioate
(1m). Isolated in 95% yield as a thick light-yellow oil. IR (n, cm–1) 2981,
2933, 1967, 1732, 1704, 1443, 1367, 1288, 1220, 1153, 1089, 847; 1H
NMR (500 MHz, CDCl3) d (ppm) 7.88 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.1
Hz, 2H), 5.43–5.40 (m, 1H), 5.17 (dd, J = 14.4, 2.0 Hz, 1H), 5.11 (dd, J =
14.4, 2.2 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 2.41 (s, 3H), 2.25 (t, J = 7.7
Hz, 2H), 2.07–1.95 (m, 2H), 1.38 (s, 9H), 1.21 (t, J = 7.1 Hz, 3H); 13C
NMR (125.8 MHz, CDCl3) d (ppm) 212.5, 172.6, 163.6, 149.6, 144.8,
135.6, 129.5, 128.3, 101.8, 81.9, 81.9, 72.1, 60.6, 29.9, 28.4, 27.8, 21.5,
14.1; MS (ESI) calcd for C22H29NO8SNa [M + Na]+ m/z 490.15, found
490.0.
Ethyl 2-[phenyl(tosylcarbamoyloxy)methyl]-2,3-butadienoate (1h).
Isolated in 88% yield as a white form. IR (n, cm–1) 3226, 2985, 2922,
1967, 1750, 1706, 1598, 1496, 1443, 1345, 1259, 1222, 1185, 1155,
1089, 869; 1H NMR (300 MHz, CDCl3) d (ppm) 7.88 (dt, J = 8.6, 1.8 Hz,
2H), 7.31–7.26 (m, 7H), 6.44 (t, J = 2.4 Hz, 1H), 5.24 (dd, J = 14.7, 2.3
Hz, 1H), 5.19 (dd, J = 14.7, 2.4 Hz, 1H), 4.17–4.02 (m, 2H), 2.43 (s, 3H),
1.17 (t, J = 7.1 Hz, 3H); 13C NMR (75.5 MHz, CDCl3) d (ppm) 213.1,
164.4, 149.2, 145.0, 136.7, 135.4, 129.5, 128.7, 128.4, 128.3, 127.2,
102.0, 82.6, 74.3, 61.4, 21.6, 14.0; MS (MALDI) calcd for C21H21NO6SNa
[M + Na]+ m/z 438.10, found 438.09.
Ethyl 2-[1-(4-nitrophenylsulfonylcarbamoyloxy)ethyl]-2,3-butadienoate
(1ba). This compound was prepared as described above for 1b, except
that p-nitrobenzenesulfonyl isocyanate (S10) was employed as
a
)
reactant. A thick light-yellow oil was isolated in 99% yield. IR (n, cm–1
3210, 3002, 2970, 2943, 1967, 1739, 1722, 1531, 1437, 1365, 1352,
1159, 1059, 912, 854; 1H NMR (500 MHz, CDCl3) d (ppm) 8.37 (d, J =
8.9 Hz, 2H), 8.23 (d, J = 8.9 Hz, 2H), 5.62–5.56 (m, 1H), 5.34 (dd, J =
14.7, 1.9 Hz, 1H), 5.30 (dd, J = 14.7, 1.9 Hz, 1H), 4.18–4.06 (m, 2H),
1.37 (d, J = 6.5 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H); 13C NMR (125.8 MHz,
CDCl3) d (ppm) 213.2, 164.8, 150.7, 149.4, 144.0, 129.8, 124.1, 101.4,
82.3, 70.5, 61.4, 18.8, 14.0; MS (ESI) calcd for C15H17N2O8S [M + H]+
m/z 385.1, found 385.0.
Ethyl
2-[1-(tosylcarbamoyloxy)-4-pentynyl]-2,3-butadienoate
(1i).
Isolated in 89% yield as a thick light-yellow oil. IR (n, cm–1) 3447–3066,
2987, 2928, 1962, 1936, 1752, 1707, 1595, 1447, 1351, 1276, 1226,
1162, 1085, 862; 1H NMR (300 MHz, CDCl3) d (ppm) 7.89 (d, J = 8.3 Hz,
2H), 7.32 (d, J = 8.0 Hz, 2H), 5.54–5.46 (m, 1H), 5.23 (dd, J = 14.7, 1.8
Hz, 1H), 5.16 (dd, J = 14.7, 2.0 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 2.43 (s,
3H), 2.17–2.08 (m, 2H), 2.04–1.87 (m, 3H), 1.21 (t, J = 7.1 Hz, 3H); 13C
NMR (75.5 MHz, CDCl3) d (ppm) 212.8, 164.5, 149.6, 144.9, 135.5,
129.5, 128.3, 100.4, 82.4, 82.2, 72.1, 69.1, 61.3, 32.1, 21.6, 14.6, 14.0;
MS (MALDI) calcd for C19H21NO6SNa [M + Na]+ m/z 414.10, found
414.10.
Ethyl 2-[1-(phenylsulfonylcarbamoyloxy)ethyl]-2,3-butadienoate (1bc).
This compound was prepared as described above for 1b, except that
benzenesulfonyl isocyanate was employed as a reactant. A thick light-
yellow oil was isolated in 99% yield. IR (n, cm–1) 3219, 2989, 2970, 2940,
1967, 1741, 1717, 1449, 1364, 1276, 1259, 1217, 1156, 1090, 1060, 911,
845; 1H NMR (300 MHz, CDCl3) d (ppm) 8.05–7.99 (m, 2H), 7.66–7.59
(m, 1H), 7.56–7.48 (m, 2H), 5.62–5.51 (m, 1H), 5.27 (dd, J = 14.6, 2.1 Hz,
1H), 5.20 (dd, J = 14.6, 2.1 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 1.34 (d, J =
6.5 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H); 13C NMR (75.5 MHz, CDCl3) d (ppm)
212.8, 164.7, 149.6, 138.5, 133.7, 128.8, 128.2, 101.8, 82.2, 69.7, 61.2,
18.9, 13.9; MS (ESI) calcd for C15H18NO6S [M + H]+ m/z 340.1, found
340.0.
Ethyl 2-[1-(tosylcarbamoyloxy-3-phenylpropyl]-2,3-butadienoate (1j).
Isolated in 72% yield as a thick light-yellow oil. IR (n, cm–1) 3366–3107,
3064, 3024, 2988, 2924, 1964, 1932, 1752, 1707, 1599, 1444, 1355,
1287, 1217, 1167, 1088, 1017, 860; 1H NMR (300 MHz, CDCl3) d (ppm)
7.92 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 7.27–7.21 (m, 2H),
7.20–7.13 (m, 1H), 7.11–7.05 (m, 2H), 5.52–5.45 (m, 1H), 5.23 (dd, J =
14.6, 1.8 Hz, 1H), 5.17 (dd, J = 14.6, 1.9 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H),
2.56 (t, J = 7.9 Hz, 2H), 2.42 (s, 3H), 2.13–1.93 (m, 2H), 1.21 (t, J = 7.1
Hz, 3H); 13C NMR (75.5 MHz, CDCl3) d (ppm) 213.0, 164.6, 149.6, 144.9,
140.7, 135.6, 129.5, 128.3, 128.3, 128.2, 126.0, 100.8, 82.0, 72.8, 61.3,
34.9, 31.4, 21.6, 14.0; MS (MALDI) calcd for C23H25NO6SNa [M + Na]+
m/z 466.13, found 466.13.
Ethyl
2-[1-(4-methoxyphenylsulfonylcarbamoyloxy)ethyl]-2,3-
butadienoate (1bd). This compound was prepared as described above
for 1b, except that p-methoxybenzenesulfonyl isocyanate (S9) was
employed as a reactant. A thick light-yellow oil was isolated in 96% yield.
IR (n, cm–1) 3160, 3072, 2979, 1967, 1703, 1597, 1579, 1499, 1466,
1443, 1418, 1362, 1342, 1305, 1265, 1160, 1061, 1023, 846; 1H NMR
(500 MHz, CDCl3) d (ppm) 7.95 (d, J = 8.9 Hz, 2H), 6.97 (d, J = 8.9 Hz,
2H), 5.59–5.52 (m, 1H), 5.28 (dd, J = 14.6, 1.9 Hz, 1H), 5.24 (dd, J =
14.6, 1.9 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 1.35 (d, J = 6.5
Hz, 3H), 1.9 (t, J = 7.1 Hz, 3H); 13C NMR (125.8 MHz, CDCl3) d (ppm)
212.9, 164.7, 163.8, 149.7, 130.6, 130.0, 114.0, 102.0, 82.2, 69.6, 61.3,
55.6, 19.0, 14.0; MS (MALDI) calcd for C16H19NO7SNa [M + Na]+ m/z
392.08, found 392.07.
Ethyl 2-[1-(tosylcarbamoyloxy)-4-(tert-butyldimethylsilyloxy)butyl]-2,3-
butadienoate (1k). Isolated in 72% yield as a thick light-yellow oil. IR (n,
cm–1) 3223, 2953, 2925, 2858, 1963, 1934, 1752, 1718, 1443, 1360,
1258, 1219, 1162, 1091, 839; 1H NMR (300 MHz, CDCl3) d (ppm) 7.89 (d,
J = 8.3 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 5.48–5.40 (m, 1H), 5.22 (dd, J =
14.6, 1.7 Hz, 1H), 5.16 (dd, J = 14.6, 1.9 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H),
3.60–3.49 (m, 2H), 2.42 (s, 3H), 1.88–1.64 (m, 2H), 1.51–1.38 (m, 2H),
1.20 (t, J = 7.1 Hz, 3H), 0.85 (s, 9H), 0.00 (s, 6H); 13C NMR (75.5 MHz,
CDCl3) d (ppm) 213.0, 164.7, 149.7, 144.8, 135.6, 129.4, 128.3, 100.9,
81.9, 73.0, 62.3, 61.2, 29.7, 28.2, 25.8, 21.5, 18.2, 14.0, –5.4; MS
(MALDI) calcd for C24H37NO7SSiNa [M + Na]+ m/z 534.20, found 534.20.
Ethyl
2-{1-[3-(trifluoromethyl)phenylsulfonylcarbamoyloxy]ethyl}-2,3-
butadienoate (1bb). This compound was prepared following a literature
procedure to generate sulfonyl isocyanates in situ.[21b] A solution of (3-
trifluoromethylphenyl)tributyltin[49]
(0.587
g,
1.35
mmol)
and
Diethyl 3-(tosylcarbamoyloxy)-2-vinylidenehexanedioate (1l). Isolated
in 92% yield as a thick light-yellow oil. IR (n, cm–1) 2988, 2970, 2940,
1967, 1737, 1722, 1444, 1365, 1257, 1217, 1156, 858; 1H NMR (300
MHz, CDCl3) d (ppm) 7.89 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H),
5.48–5.43 (m, 1H), 5.24 (dd, J = 14.6, 1.8 Hz, 1H), 5.17 (dd, J = 14.6, 2.0
Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 2.44 (s, 3H),
2.28 (t, J = 7.7 Hz, 2H), 2.13–1.98 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H), 1.21
(t, J = 7.1 Hz, 3H); 13C NMR (75.5 MHz, CDCl3) d (ppm) 212.7, 172.6,
chlorosulfonyl isocyanate (0.120 mL, 1.35 mmol) in freshly distilled
chlorobenzene (2 mL) was heated under reflux for 15.5 h. The flask was
removed from the oil bath, cooled to room temperature, and
subsequently to 0 °C in an ice-water bath. Allenylic alcohol 7b (0.200 g,
1.28 mmol) was added dropwise to the cooled mixture. Because of a
solubility problem, dry CH2Cl2 (2 mL) was added after 10 min. The
mixture was then stirred at 0 °C for 30 min, removed from the ice bath,
and stirred at room temperature for another 30 min. The reaction was
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quenched by adding distilled water (20 mL) and diluted by adding CH2Cl2
(20 mL). The separated organic phase was washed with distilled water (3
´ 20 mL); the aqueous phase was extracted with CH2Cl2 (2 x 20 mL).
The combined organic phases were washed with brine (20 mL), dried
(Na2SO4), and concentrated under reduced pressure. The residue, as a
solution in chlorobenzene, was purified through flash column
chromatography (100% hexanes to wash away chlorobenzene, then 5–
20% EtOAc/hexanes) to yield 1bb (114 mg, 22% isolated; 145 mg of 7b
was re-isolated, giving a yield of 1bb of 79% based on this recovered
starting material) as a thick, slightly yellow, oil. IR (n, cm–1) 3224, 2989,
1968, 1934, 1751, 1712, 1440, 1363, 1326, 1281, 1160, 1131, 1103,
1068, 913, 845; 1H NMR (300 MHz, CDCl3) d (ppm) 8.31–8.22 (m, 2H),
8.18–8.02 (br s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H),
5.64–5.54 (m, 1H), 5.31 (dd, J = 14.8, 2.1 Hz, 1H), 5.26 (dd, J = 14.8, 2.2
Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 1.36 (d, J = 6.5 Hz, 3H), 1.19 (t, J = 7.1
Hz, 3H); 13C NMR (75.5 MHz, CDCl3) d (ppm) 213.1, 164.7, 149.4, 139.7,
131.8, 131.6 (q, JC–F = 33.7 Hz), 130.4 (q, JC–F = 3.4 Hz), 129.8, 125.4 (q,
JC–F = 3.9 Hz), 123.1 (q, JC–F = 273.0 Hz), 101.6, 82.2, 70.3, 61.4, 18.8,
14.0; MS (ESI) calcd for C16H17F3NO6S [M + H]+ m/z 408.1, found 408.0.
(d, J = 8.2 Hz, 2H), 6.59–6.57 (m, 1H), 4.81–4.79 (m, 1H), 4.24–4.22 (m,
2H), 4.19–4.13 (m, 2H), 2.41 (s, 3H), 2.08–2.00 (m, 1H), 1.94–1.87 (m,
1H), 1.25 (t, J = 7.1 Hz, 3H), 0.83 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 162.1, 143, 136.2, 134.6, 134.3, 129.7, 127.2, 66.6, 60.7, 55.3,
26.6, 21.4, 14.0, 7.4; MS (MALDI) calcd for C16H21NO4SNa [M + Na]+ m/z
346.11, found: 346.13.
Ethyl 2-propyl-1-tosyl-2,5-dihydropyrrole-3-carboxylate (3d). Isolated
in 55% yield as a thick light-yellow oil. IR (n, cm–1) 2959, 2932, 2872,
1715, 1645, 1598, 1494, 1458, 1342, 1262, 1243, 1160, 1085, 1044,
1017, 816; 1H NMR (500 MHz, CDCl3) d (ppm) 7.70 (d, J = 8.3 Hz, 2H),
7.29 (d, J = 8.0 Hz, 2H), 6.53 (dd, J = 3.8, 2.1 Hz, 1H), 4.82–4.76 (m, 1H),
4.26–4.20 (m, 2H), 4.20–4.11 (m, 2H), 2.41 (s, 3H), 1.97–1.88 (m, 1H),
1.86–1.78 (m, 1H), 1.44–1.35 (m, 1H), 1.30–1.18 (m, 4H), 0.89 (t, J = 7.4
Hz, 3H); 13C NMR (125.8 MHz, CDCl3) d (ppm) 162.3, 143.6, 136.0,
135.1, 134.7, 129.8, 127.3, 66.1, 60.8, 55.2, 36.1, 21.5, 16.9, 14.1, 14.0;
MS (MALDI) calcd for C17H24NO4S [M + H]+ m/z 338.14, found 338.14.
Ethyl 2-cyclopropyl-1-tosyl-2,5-dihydropyrrole-3-carboxylate (3e).[18]
Isolated in 28% yield as a thick oil. IR (n, cm–1) 3078, 2979, 2916, 2852,
1717, 1346, 1261, 1163; 1H NMR (300 MHz, CDCl3) δ 7.68 (d, J = 8.3 Hz,
2H), 7.27 (d, J = 8.3 Hz, 2H), 6.52–6.50 (m, 1H), 4.54 (t, J = 5.2 Hz, 1H),
4.28–4.12 (m, 4H), 2.40 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.12–1.01 (m,
1H), 0.81–0.71 (m, 1H), 0.60–0.37 (m, 3H); 13C NMR (125 MHz, CDCl3)
δ 162.4, 143.5, 136.5, 135.5, 135.0, 129.6, 127.3, 28.3, 60.7, 54.9, 21.4,
16.0, 14.1, 3.4, 2.4; MS (GCMS) calcd for C17H21NO4S [M]+ m/z 335.1,
found 335.1.
3-Pyrrolines 3a–m and 3ba–bd. 3-Pyrroline 3a was prepared according
to the procedure described below for 3a, while 3-pyrrolines 3b–m and
3ba–bd were synthesized according to the procedure described for 3b.
Ethyl 1-tosyl-2,5-dihydropyrrole-3-carboxylate (3a).
A solution of
allenylic carbamate 1a (50.0 mg, 0.147 mmol) in dry CH3CN (2 mL) was
added to a solution of PPh3 (38.6 mg, 0.147 mmol) in dry CH3CN (2 mL)
over 24 h via syringe pump. To prevent evaporation of the solvent, the
needle was fastened to the syringe by wrapping the joint with Teflon tape
and Parafilm. Once the addition was complete, the mixture was stirred for
another 4 h. At this point, the solvent was evaporated under reduced
pressure. The crude reaction mixture was purified through flash column
chromatography (10% EtOAc/hexanes) to yield 3a (29.9 mg, 69%) as a
thick colorless oil. The spectral data were in agreement with those
previously reported in the literature.[50]
Ethyl 2-cyclopentyl-1-tosyl-2,5-dihydropyrrole-3-carboxylate (3f).[18]
Isolated in 37% yield as a thick oil. IR (n, cm–1) 2955, 2870, 1717, 1345,
1257, 1163, 1091; 1H NMR (500 MHz, CDCl3) δ 7.67 (d, J = 8.3 Hz, 2H),
7.25 (d, J = 7.6 Hz, 2H), 6.45–6.40 (m, 1H), 4.92 (t, J = 4.1 Hz, 1H), 4.21
(dd, J = 18.4, 2.6 Hz, 1H), 4.18–4.09 (m, 3H), 2.39 (s, 3H), 2.31–2.24 (m,
1H), 1.74–1.66 (m, 3H), 1.63–1.45 (m, 4H), 1.33–1.26 (m, 1H), 1.24 (t, J
= 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 162.5, 143.5, 136.4, 135.9,
134.4, 129.6, 127.4, 68.5, 60.6, 55.7, 45.0, 28.5, 27.4, 25.0, 24.4, 21.4,
14.0; MS (MALDI) calcd for C19H25NO4SNa [M + Na]+ m/z 386.14, found
386.17.
Ethyl 2-methyl-1-tosyl-2,5-dihydropyrrole-3-carboxylate (3b).[18] Argon
(g) was bubbled through dry CH3CN for 1.5 h to prepare a deaerated
stock of solvent. In a second flask, a solution of allenylic carbamate 1b
(50.0 mg, 0.142 mmol) in CH3CN (5–6 mL) was also deaerated by
bubbling Ar through it for 1.5 h. A third oven-dried round-bottom flask
containing a magnetic stirrer bar was then fitted with a rubber septum,
which was covered with Teflon tape and Parafilm. This flask was placed
under vacuum for 5 min and then backfilled with Ar; this process was
repeated twice. To this flask was added the deaerated CH3CN (4 mL),
followed by tri-n-butylphosphine (0.035 mL, 0.1415 mmol). The solution
of deaerated carbamate in CH3CN was then removed from its flask using
a syringe; the flask was rinsed with stock CH3CN (usually ca. 2 mL). The
flask was rinsed with more deaerated CH3CN until the syringe contained
4 mL of solution within it. The syringe was then placed in a syringe pump
and the carbamate solution was added to the solution of phosphine over
24 h at room temperature. To prevent evaporation of the solvent, the
needle was fastened to the syringe by wrapping the joint with Teflon tape
and Parafilm. Upon completion of the addition, the mixture was stirred at
Ethyl 2-cyclohexyl-1-tosyl-2,5-dihydropyrrole-3-carboxylate (3g).[18]
Isolated in 30% yield as a thick oil. IR (n, cm–1) 2985, 2928, 2854, 1717,
1449, 1373, 1345, 1256, 1164; 1H NMR (500 MHz, CDCl3) δ 7.66 (d, J =
8.2 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.46–6.45 (m, 1H), 4.70 (t, J = 3.4,
1H), 4.20 (dd, J = 18.4, 2.7 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 4.07 (ddd, J
= 18.4, 4.3, 1.7 Hz, 1H), 2.39 (s, 3H), 1.81–1.68 (m, 4H), 1.66–1.56 (m,
2H), 1.41 (dq, J = 12.5, 3.1 Hz, 1H), 1.23 (t, J = 7.1 Hz, 3H), 1.26–1.01
(m, 4H); 13C NMR (125 MHz, CDCl3) δ 162.6, 143.6, 136.5, 135.2, 134.4,
129.6, 127.4, 71.0, 60.7, 55.9, 42.9, 30.1, 27.2, 26.4, 26.3, 26.2, 21.5,
14.0; MS (MALDI) calcd for C20H27NO4SNa [M + Na]+ m/z 400.16, found
400.16.
Ethyl 2-phenyl-1-tosyl-2,5-dihydropyrrole-3-carboxylate (3h). Isolated
in 66% yield as a thick oil. The spectral data were in agreement with
those previously reported in the literature.[50]
room temperature for another
4 h. At this point, the solvent was
Ethyl
2-(but-3-ynyl)-1-tosyl-2,5-dihydropyrrole-3-carboxylate
(3i).
evaporated under reduced pressure. The residue was purified through
flash column chromatography (10% EtOAc/hexanes) to yield 3b (32.3 mg,
74%) as a thick colorless oil. IR (n, cm–1) 2985, 2926, 2862, 1717, 1347,
1267, 1164; 1H NMR (500 MHz, CDCl3) δ 7.11 (d, J = 8.1 Hz, 2H), 7.30
(d, J = 7.9 Hz, 2H), 6.53 (s, 1H), 4.78–4.67 (m, 1H), 4.41–4.26 (m, 1H),
4.26–4.12 (m, 3H), 2.41 (s, 3H), 1.53 (t, J = 6.3 Hz, 3H), 1.26 (t, J = 7.1
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 162.1, 143.5, 136.5, 135.1, 134.6,
129.7, 127.3, 62.0, 60.7, 54.4, 22.1, 21.4, 14.0; MS (MALDI) calcd for
C15H19NO4SNa [M + Na]+ m/z 332.09, found: 332.16.
Isolated in 52% yield as a thick light-yellow oil. IR (n, cm–1) 3282, 2979,
2924, 2868, 1715, 1681, 1644, 1597, 1446, 1375, 1341, 1267, 1244,
1161, 1091, 1052, 816; 1H NMR (300 MHz, CDCl3) d (ppm) 7.70 (d, J =
8.3 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 6.56 (dd, J = 3.8, 2.0 Hz, 1H), 4.84–
4.76 (m, 1H), 4.33–4.21 (m, 2H), 4.17 (q, J = 7.1 Hz, 2H), 2.41 (s, 3H),
2.38–2.07 (m, 4H), 1.91 (t, J = 2.4 Hz, 1H), 1.26 (t, J = 7.1 Hz, 3H); 13C
NMR (75.5 MHz, CDCl3) d (ppm) 162.0, 143.9, 136.6, 134.5, 134.2,
129.9, 127.4, 84.0, 68.6, 65.3, 60.9, 55.3, 32.9, 21.5, 14.1, 13.4; MS
(MALDI) calcd for C18H22NO4S [M + H]+ m/z 348.13, found 348.12.
Ethyl 2-ethyl-1-tosyl-2,5-dihydropyrrole-3-carboxylate (3c).[18] Isolated
in 62% yield as a thick oil. IR (n, cm–1) 2972, 1718, 1347, 1249, 1164,
1083, 1040; 1H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 8.2 Hz, 2H), 7.29
Ethyl
2-phenethyl-1-tosyl-2,5-dihydropyrrole-3-carboxylate
(3j).
Isolated in 52% yield as a thick light-yellow oil. IR (n, cm–1) 3028, 2979,
2936, 2929, 2861, 1716, 1692, 1647, 1598, 1495, 1455, 1345, 1265,
13
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10.1002/cctc.202000626
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1243, 1162, 1092, 1051, 815; 1H NMR (500 MHz, CDCl3) d (ppm) 7.72 (d,
J = 8.2 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.27–7.23 (m, 2H), 7.18–7.13
(m, 3H), 6.57 (dd, J = 3.6, 1.9 Hz, 1H), 4.89–4.82 (m, 1H), 4.32–4.24 (m,
2H), 4.20–4.10 (m, 2H), 2.77–2.67 (m, 1H), 2.59–2.51 (m, 1H), 2.42 (s,
3H), 2.37–2.28 (m, 1H), 2.24–2.15 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H); 13C
NMR (125.8 MHz, CDCl3) d (ppm) 162.1, 143.8, 141.7, 136.4, 134.7,
134.6, 129.9, 128.5, 128.2, 127.4, 125.7, 65.8, 60.9, 55.4, 35.4, 30.0,
21.5, 14.1; MS (MALDI) calcd for C22H26NO4S [M + H]+ m/z 400.16,
found 400.16.
NMR (125.8 MHz, CDCl3) d (ppm) 162.0, 139.2, 136.7, 134.9, 131.9 (q,
JC–F = 33.5 Hz), 130.4, 130.1, 129.5 (q, JC–F = 3.6 Hz), 124.3 (q, JC–F
=
3.7 Hz), 123.2 (q, JC–F = 272.9 Hz), 62.4, 61.0, 54.5, 22.0, 14.1; MS (ESI)
calcd for C15H17F3NO4S [M + H]+ m/z 364.1, found 364.0.
Ethyl
2-Methyl-1-(phenylsulfonyl)-2,5-dihydropyrrole-3-carboxylate
(3bc). Isolated in 58% yield as a thick light-yellow oil. IR (n, cm–1) 2982,
2934, 2872, 1714, 1644, 1586, 1560, 1446, 1375, 1343, 1265, 1242,
1163, 1092, 1067, 843, 755; 1H NMR (500 MHz, CDCl3) d (ppm) 7.85–
7.81 (m, 2H), 7.59 (tt, J = 7.5, 1.5 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 6.54
(dd, J = 3.7, 1.9 Hz, 1H), 4.76–4.69 (m, 1H), 4.31 (ddd, J = 17.4, 5.4, 2.0
Hz, 1H), 4.22 (dt, J = 17.5, 2.5 Hz, 1H), 4.19–4.12 (m, 2H), 1.54 (d, J =
6.4 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR (125.8 MHz, CDCl3) d
(ppm) 162.2, 137.7, 136.6, 135.1, 132.8, 129.2, 127.3, 62.2, 60.8, 54.5,
22.1, 14.1; MS (ESI) calcd for C14H18NO4S [M + H]+ m/z 296.1, found
296.0.
Ethyl 2-[3-(tert-butyldimethylsilyloxy)propyl]-1-tosyl-2,5-dihydropyrrole-
3-carboxylate (3k). The same procedure was followed as described
above for 3b, except that the solvent and carbamate were not deaerated
prior to the reaction. A thick light-yellow oil was isolated in 48% yield. IR
(n, cm–1) 2953, 2928, 2856, 1718, 1647, 1598, 1553, 1494, 1463, 1349,
1257, 1163, 1090, 834; 1H NMR (500 MHz, CDCl3) d (ppm) 7.70 (d, J =
8.3 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 6.55 (dd, J = 3.6, 2.0 Hz, 1H), 4.87–
4.79 (m, 1H), 4.27–4.18 (m, 2H), 4.15 (qd, J = 7.1, 1.0 Hz, 2H), 3.65–
3.59 (m, 1H), 3.58–3.52 (m, 1H), 2.41 (s, 3H), 2.02–1.88 (m, 2H), 1.64–
1.56 (m, 1H), 1.47–1.38 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H), 0.88 (s, 9H),
0.03 (s, 3H), 0.03 (s, 3H); 13C NMR (125.8 MHz, CDCl3) d (ppm) 162.1,
143.7, 136.2, 134.9, 134.7, 129.8, 127.4, 65.9, 63.0, 60.8, 55.2, 30.2,
26.9, 25.9, 21.5, 18.3, 14.1, –5.3, –5.3; MS (MALDI) calcd for
C23H37NO5SSiNa [M + Na]+ m/z 490.21, found 490.21.
Ethyl
1-(4-methoxyphenylsulfonyl)-2-methyl-2,5-dihydropyrrole-3-
carboxylate (3bd). Isolated in 72% yield as a thick light-yellow oil. IR (n,
cm–1) 2981, 2935, 2873, 1715, 1647, 1595, 1577, 1497, 1460, 1376,
1342, 1305, 1259, 1093, 1064, 1021, 835, 804; 1H NMR (500 MHz,
CDCl3) d (ppm) 7.76 (dt, J = 9.5, 2.5 Hz, 2H), 6.97 (dt, J = 9.5, 2.5 Hz,
2H), 6.53 (dd, J = 3.8, 2.0 Hz, 1H), 4.71–4.64 (m, 1H), 4.28 (ddd, J =
17.5, 5.4, 2.0 Hz, 1H), 4.18 (dt, J = 17.4, 2.4 Hz, 1H), 4.19–4.11 (m, 2H),
3.85 (s, 3H), 1.53 (d, J = 6.3 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR
(125.8 MHz, CDCl3) d (ppm) 163.0, 162.2, 136.6, 135.3, 129.4, 129.3,
114.4, 62.1, 60.8, 55.6, 54.5, 22.2, 14.1; MS (ESI) calcd for C15H20NO5S
[M + H]+ m/z 326.1, found 326.1.
Ethyl
2-(3-ethoxy-3-oxopropyl)-1-tosyl-2,5-dihydropyrrole-3-
carboxylate (3l). Isolated in 56% yield as a thick light-yellow oil. IR (n,
cm–1) 2981, 2927, 2868, 1715, 1652, 1644, 1598, 1448, 1344, 1262,
1244, 1161, 1091, 816; 1H NMR (300 MHz, CDCl3) d (ppm) 7.69 (d, J =
8.3 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 6.54 (dd, J = 3.5, 1.9 Hz, 1H), 4.86–
4.78 (m, 1H), 4.24–4.18 (m, 2H), 4.18–4.05 (m, 4H), 2.44–2.29 (m, 6H),
2.25–2.10 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H); 13C
NMR (75.5 MHz, CDCl3) d (ppm) 173.2, 161.9, 143.8, 136.6, 134.4,
134.1, 129.8, 127.3, 65.2, 60.9, 60.3, 55.1, 29.1, 29.0, 21.4 14.1, 14.0;
MS (ESI) calcd for C19H26NO6S [M + H]+ m/z 396.1, found 396.2.
Synthesis Performed for the Mechanistic Investigation
Allenylic Acetate 9
Ethyl 2-(ethanoyloxymethyl)-2,3-butadienoate (9). 2,6-Lutidine (265 µL,
2.28 mmol) was added dropwise to a solution of allenylic alcohol 7a
(0.200 g, 1.41 mmol) in dry CH2Cl2 (10 mL) at 0 °C (ice-water bath) and
then the solution was stirred at 0 °C for 5 min. At this point, acetyl
chloride (225 µL, 3.10 mmol) was added dropwise to the stirred solution.
After stirring at 0 °C for 1 h, the mixture was removed from the ice bath
and warmed to room temperature, where it was stirred for an additional
17 h. The reaction was quenched by adding 2 M HCl (10 mL) to remove
excess 2,6-lutidine from the mixture. The layers were then separated and
the aqueous phase was extracted with CH2Cl2 (2 ´ 5 mL) and then with
Et2O (3 ´ 5 mL). Each set of organic layers was washed with brine (10
mL). The combined organic phases were dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue was purified through
flash column chromatography (0–10% EtOAc/hexanes) to yield 9 (219
mg, 85%) as a colorless oil. IR (n, cm–1) 2888, 1969, 1942, 1742, 1709,
1447, 1368, 1264, 1219, 1126, 1044, 1024, 857; 1H NMR (300 MHz,
CDCl3) δ 5.25 (t, J = 2.2 Hz, 2H), 4.73 (t, J = 2.2 Hz, 2H), 4.18 (q, J = 7.1,
2H), 2.02 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H); 13C NMR (75.5 MHz, CDCl3) δ
214.4, 170.3, 165.1, 96.8, 80.3, 61.2, 60.8, 20.7, 14.1; MS (MALDI) calcd
for C9H12O4Na [M + Na]+ m/z 207.06, found 207.05.
tert-Butyl
2-(3-ethoxy-3-oxopropyl)-1-tosyl-2,5-dihydropyrrole-3-
carboxylate (3m). Isolated in 55% yield as a thick light-yellow oil. IR (n,
cm–1) 2982, 2924, 2862, 1732, 1713, 1655, 1596, 1456, 1373, 1342,
1285, 1245, 1159, 1094; 1H NMR (300 MHz, CDCl3) d (ppm) 7.68 (d, J =
8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 6.44 (dd, J = 3.6, 2.0 Hz, 1H), 4.81–
4.74 (m, 1H), 4.24–4.15 (m, 2H), 4.10 (q, J = 7.1 Hz, 2H), 2.40 (s, 3H),
2.39–2.27 (m, 3H), 2.22–2.07 (m, 1H), 1.44 (s, 9H), 1.24 (t, J = 7.1 Hz,
3H); 13C NMR (75.5 MHz, CDCl3) d (ppm) 173.2, 161.2, 143.7, 135.9,
135.7, 134.2, 129.8, 127.4, 81.7, 65.2, 60.3, 54.9, 29.1, 29.0, 27.9, 21.4,
14.1; MS (MALDI) calcd for C21H29NO6SNa [M + Na]+ m/z 446.16, found
446.19.
Ethyl
2-methyl-1-(4-nitrophenylsulfonyl)-2,5-dihydropyrrole-3-
carboxylate (3ba). Isolated in 37% yield as a thick light-yellow oil. IR (n,
cm–1) 3107, 2983, 2934, 2872, 1715, 1647, 1606, 1529, 1457, 1400,
1348, 1308, 1266, 1243, 1164, 1092, 1072, 856; 1H NMR (500 MHz,
CDCl3) d (ppm) 8.37 (dt, J = 9.1, 2.1 Hz, 2H), 8.03 (dt, J = 9.1, 2.1 Hz,
2H), 6.57 (dd, J = 3.8, 1.9 Hz, 1H), 4.77–4.69 (m, 1H), 4.36 (ddd, J =
17.3, 5.4, 2.0 Hz, 1H), 4.24 (dt, J = 17.3, 2.3 Hz, 1H), 4.22–4.13 (m, 2H),
1.55 (d, J = 6.3 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13C NMR (125.8 MHz,
CDCl3) d (ppm) 161.8, 150.2, 143.7, 136.7, 134.6, 128.4, 124.5, 62.5,
61.1, 54.6, 22.0, 14.1; MS (ESI) calcd for C14H17N2O6S [M + H]+ m/z
341.1, found 341.0.
Reactions Between Allenylic Acetate 9 and Monopronucleophiles
10a–c
General Procedure for the Reactions of Allenylic Acetate 9 with
Benzyl Toluenesulfonamide 10a. An oven-dried round-bottom flask
containing
a magnetic stirrer bar was charged with N-benzyl-4-
Ethyl 2-Methyl-1-[3-(trifluoromethyl)phenylsulfonyl]-2,5-dihydropyrrole-
3-carboxylate (3bb). Isolated in 45% yield as a thick light-yellow oil. IR (n,
cm–1) 3082, 2930, 1714, 1642, 1606, 1542, 1489, 1461, 1428, 1349,
1322, 1308, 1271, 1245, 1165, 1117, 1066, 814; 1H NMR (500 MHz,
CDCl3) d (ppm) 8.10 (s, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.85 (d, J = 7.8 Hz,
1H), 7.68 (d, J = 7.9 Hz, 1H), 6.57 (dd, J = 3.8, 2.0 Hz, 1H), 4.78–4.71 (m,
1H), 4.34 (ddd, J = 17.3, 5.4, 2.0 Hz, 1H), 4.23 (dt, J = 17.4, 2.4 Hz, 1H),
4.21–4.13 (m, 2H), 1.55 (d, J = 6.4 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13C
methylbenzenesulfonamide[51] (10a, 1.2 equiv) and then the following
reagents were added, if required, for the reactions listed in the specific
entries of Table 4: PPh3 (either 0.2 or 1.1 equiv), Cs2CO3 (1.3 equiv), or
NaOAc (1.3 equiv); followed by dry CH3CN (2.8 mL). A solution of
allenylic acetate 9 (0.190 mmol, 1.0 equiv) in dry CH3CN (2.8 mL) was
added over 6 h via syringe pump. Once the addition was complete, the
mixture was stirred for another 1–1.5 h. At this point the solvent was
evaporated under reduced pressure. The residue was purified through
14
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10.1002/cctc.202000626
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FULL PAPER
flash column chromatography (0–30% EtOAc/hexanes) to yield the
products displayed in Table 4. Diene 11a eluted from the column when
the eluent was between 7.5 and 10% EtOAc/hexanes. Allenoate 12a
eluted between 10 and 15% EtOAc/hexanes. Lastly, allylic acetate 13a
eluted during elution with 30% EtOAc/hexanes. The characterization data
of the products 11a, 12a, and 13a are provided below.
468.15, found 468.12.
General Procedure for Reactions of Allenylic Acetate 9 with 10b
or 10c. An oven-dried round-bottom flask containing a magnetic stirrer
bar was charged with the following reagents, if required, for the reaction
listed as a specific entry in either Table 5 or 6: PPh3 (either 0.2 or 1.1
equiv), Cs2CO3 (1.3 equiv), or NaOAc (1.3 equiv); followed by dry
benzene (2.8 mL) and the respective monopronucleophile [1.2 equiv of
freshly distilled material of either 3-methyl-2,4-pentanedione (10b) or
benzoyl propionitrile (10c)[52]]. A solution of allenylic acetate 9 (0.190
mmol, 1.0 equiv) in dry benzene (2.8 mL) was then added over 1 h via a
syringe pump. Once the addition was complete, the mixture was stirred
for another 5–5.5 h (true only for 10b; when 10c was used, the reaction
times were 8.5, 29, 72, and 9 h for entries 1–4, respectively). At this point
the solvent was evaporated under reduced pressure. The residue was
purified through flash column chromatography (0–25% EtOAc/hexanes)
to yield the products displayed in Tables 5 and 6. Diene 11b or 11c
eluted from the column when the eluent was between 5 and 7.5%
EtOAc/hexanes. Allenoate 12b or 12c eluted between 10 and 15%
EtOAc/hexanes. Lastly, allylic acetate 13b or 13c eluted during the 25%
EtOAc/hexanes portion. Characterization data for products 11b/c, 12b/c,
and 13b/c are provided below.
General information regarding characterization of allylic acetates 13a–
c: Allylic acetates 13a–c were isolated from the reactions as mixtures of
(E) and (Z) isomers, where the isomeric ratios ranging between 1.11:1
and 1.19:1 (Z:E) for 13a (see Table 4, entries 3–5), between 1.05:1 and
1.18:1 (E:Z) for 13b (see Table 5, entries 1 and 3–6), and 1.08:1 (E:Z) for
13c (see Table 6, entry 4) (see below for the syntheses of allylic acetates
13b,c). For characterization purposes, the compounds were separated
using preparatory TLC (silica gel). Each isomer was fully characterized
and the data are presented below. The structures of the (E) and (Z)
isomers of 13b were assigned based on NOE experiments (these data
are located within the section of the SI containing the 1H and 13C
spectra).19 The (E) isomer is referred to herein as allylic acetate 13ba,
while the (Z) isomer is known as allylic acetate 13bb. The isomers of
allylic acetates 13a,c were then assigned based on analogy to the
isomers of allylic acetate 13b, with the (E) isomers referred to as allylic
acetates 13aa and 13ca, respectively, and the (Z) isomers are known as
allylic acetates 13ab and 13cb, respectively.
Ethyl 4-ethanoyl-4-methyl-2,3-dimethylene-5-oxohexanoate (11b).
Isolated as a thin film. IR (n, cm–1) 2983, 2957, 2925, 2852, 1718, 1704,
1553, 1542, 1458, 1355, 1320, 1232, 1208, 1144, 1091; 1H NMR (500
MHz, CDCl3) δ 6.29 (d, J = 1.5 Hz, 1H), 5.72 (d, J = 1.5 Hz, 1H), 5.50 (s,
1H), 5.18 (s, 1H), 4.17 (q, J = 7.2 Hz, 2H), 2.24 (s, 6H), 1.38 (s, 3H), 1.27
(t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 206.5, 165.8, 145.0,
141.3, 128.7, 122.0, 70.0, 61.4, 26.8, 19.0, 14.0; MS (MALDI) calcd for
C13H18O4Na [M + Na]+ m/z 261.11, found 261.13.
Ethyl
3-(N-benzyl-4-methylphenylsulfonamido)-2-methylene-3-
butenoate (11a). Isolated as a colorless thin film. IR (n, cm–1) 3033, 2995,
2970, 2925, 1739, 1704, 1626, 1586, 1473, 1455, 1360, 1345, 1232,
1165, 1141, 1092, 1022, 920; 1H NMR (300 MHz, CDCl3) δ 7.71 (dt, J =
8.4, 1.8 Hz, 2H), 7.33–7.23 (m, 7H), 6.09 (s, 1H), 5.81 (d, J = 0.8 Hz, 1H),
5.62 (s, 1H), 4.86 (s, 1H), 4.52 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 2.43 (s,
3H), 1.27 (t, J = 7.1 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ 165.7,
143.6, 140.7, 138.0, 135.8, 135.5, 129.5, 129.2, 128.4, 128.0, 127.9,
127.9, 118.0, 61.0, 54.1, 21.6, 14.1; MS (MALDI) calcd for
C21H23NO4SNa [M + Na]+ m/z 408.12, found 408.10.
Ethyl 4-ethanoyl-4-methyl-5-oxo-2-vinylidenehexanoate (12b). Isolated
as a colorless oil. IR (n, cm–1) 2985, 2935, 1966, 1943, 1698, 1447, 1424,
1359, 1259, 1214, 1116, 1068, 857; 1H NMR (300 MHz, CDCl3) δ 5.10 (t,
J = 2.4 Hz, 2H), 4.16 (q, J = 7.1, 2H), 2.87 (t, J = 2.4 Hz, 2H), 2.12 (s,
6H), 1.31 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H); 13C NMR (75.5 MHz, CDCl3) δ
214.6, 206.3, 166.9, 95.7, 79.9, 66.5, 61.4, 31.6, 26.7, 17.7, 14.2; MS
(MALDI) calcd for C13H18O4Na [M + Na]+ m/z 261.11, found 261.09.
Ethyl
2-[(N-benzyl-4-methylphenylsulfonamido)methyl]-2,3-
butadienoate (12a). Isolated as a colorless thin film. IR (n, cm–1) 2925,
2854, 1967, 1706, 1453, 1338, 1258, 1157, 1092, 1055, 912; 1H NMR
(300 MHz, CDCl3) δ 7.72 (dt, J = 8.2, 1.9 Hz, 2H), 7.33–7.21 (m, 7H),
5.01 (t, J = 2.9 Hz, 2H), 4.43 (s, 2H), 4.08 (q, J = 7.1, 2H), 4.04 (t, J = 2.8
Hz, 2H), 2.43 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H); 13C NMR (75.5 MHz,
CDCl3) δ 214.2, 165.8, 143.2, 137.8, 136.1, 129.6, 128.5, 127.8, 127.3,
97.1, 81.0, 61.2, 51.9, 45.4, 21.5, 14.1; MS (MALDI) calcd for
C21H23NO4SNa [M + Na]+ m/z 408.12, found 408.13.
(E)-Ethyl
5-ethanoyl-2-(ethanoyloxymethyl)-5-methyl-6-oxohept-2-
enoate (13ba). Isolated as a thin film. IR (n, cm–1) 2979, 2960, 2921,
2851, 1710, 1698, 1552, 1462, 1362, 1247, 1223, 1175, 1095, 1070,
1026, 964; 1H NMR (500 MHz, CDCl3) δ 6.77 (t, J = 7.6 Hz, 1H), 4.85 (s,
2H), 4.21 (q, J = 7.1 Hz, 2H), 2.85 (d, J = 7.7 Hz, 2H), 2.13 (s, 6H), 2.04
(s, 3H), 1.37 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 205.9, 170.7, 165.8, 142.2, 130.3, 66.0, 61.1, 57.8, 33.1, 26.5, 20.9,
18.4, 14.2; MS (MALDI) calcd for C15H22O6Na [M + Na]+ m/z 321.13,
found 321.14.
(E)-Ethyl
4-(N-benzyl-4-methylphenylsulfonamido)-2-
(ethanoyloxymethyl)but-2-enoate (13aa). Isolated as a thin film. IR (n,
cm–1) 2979, 2958, 2924, 2852, 1738, 1715, 1457, 1341, 1243, 1160,
1093, 1028, 935, 737; 1H NMR (500 MHz, CDCl3) δ 7.76–7.72 (m, 2H),
7.35 (d, J = 8.0 Hz, 2H), 7.31–7.27 (m, 3H), 7.25–7.23 (m, 2H), 6.61 (t, J
= 6.7 Hz, 1H), 4.56 (s, 2H), 4.32 (s, 2H), 4.14 (q, J = 7.1 Hz, 2H), 3.99 (d,
J = 6.7 Hz, 2H), 2.45 (s, 3H), 1.96 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 170.6, 165.3, 143.8, 142.7, 136.4, 135.3,
130.0, 128.7, 128.7, 128.6, 128.2, 127.3, 61.1, 57.5, 52.2, 45.2, 21.6,
20.8, 14.1; MS (MALDI) calcd for C23H27NO6SNa [M + Na]+ m/z 468.15,
found 468.10.
(Z)-Ethyl
5-ethanoyl-2-(ethanoyloxymethyl)-5-methyl-6-oxohept-2-
enoate (13bb). Isolated as a thin film. IR (n, cm–1) 2957, 2924, 2852,
1716, 1701, 1555, 1463, 1389, 1246, 1183, 1095, 1028; 1H NMR (300
MHz, CDCl3) δ 6.05 (tt, J = 7.4, 1.0 Hz, 1H), 4.71 (d, J = 1.0 Hz, 2H),
4.24 (q, J = 7.1 Hz, 2H), 3.15 (d, J = 7.4 Hz, 2H), 2.14 (s, 6H), 2.05 (s,
3H), 1.37 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
206.7, 170.5, 165.5, 141.3, 129.7, 66.0, 65.1, 60.8, 33.4, 26.6, 20.9, 18.5,
14.2; MS (MALDI) calcd for C15H22O6Na [M + Na]+ m/z 321.13, found
321.17.
(Z)-Ethyl
4-(N-benzyl-4-methylphenylsulfonamido)-2-
(ethanoyloxymethyl)but-2-enoate (13ab). Isolated as a thin film. IR (n,
cm–1) 2979, 2959, 2925, 2852, 1747, 1714, 1457, 1339, 1243, 1224,
1161, 1095, 1043, 1028, 740; 1H NMR (500 MHz, CDCl3) δ 7.75–7.70 (m,
2H), 7.36–7.32 (m, 2H), 7.31–7.26 (m, 4H), 7.25–7.23 (m, 1H), 5.99 (t, J
= 5.7 Hz, 1H), 4.50 (d, J = 1.0 Hz, 2H), 4.29 (s, 2H), 4.25 (d, J = 5.8 Hz,
2H), 4.11 (q, J = 7.2 Hz, 2H), 2.45 (s, 3H), 2.00 (s, 3H), 1.20 (t, J = 7.1
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 170.3, 164.9, 143.7, 143.6, 136.3,
135.7, 129.9, 128.7, 128.6, 128.0, 127.4, 127.3, 63.8, 60.8, 52.9, 47.2,
21.6, 20.9, 14.1; MS (MALDI) calcd for C23H27NO6SNa [M + Na]+ m/z
Ethyl
4-cyano-4-methyl-2,3-dimethylene-5-oxo-5-phenylpentanoate
(11c). Isolated as a thin film. IR (n, cm–1) 2956, 2923, 2851, 2240, 1716,
1694, 1597, 1555, 1449, 1385, 1373, 1316, 1287, 1229, 1134, 1105,
1024, 959; 1H NMR (500 MHz, CDCl3) δ 8.13–8.09 (m, 2H), 7.62–7.56
(m, 1H), 7.49–7.43 (m, 2H), 6.42 (d, J = 1.2 Hz, 1H), 5.69 (d, J = 1.2 Hz,
1H), 5.52 (s, 1H), 5.42 (s, 1H), 4.27–4.12 (m, 2H), 1.90 (s, 3H), 1.25 (t, J
= 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 191.0, 165.4, 142.7, 139.4,
133.9, 133.8, 130.8, 129.9, 128.4, 121.3, 120.3, 61.6, 51.5, 25.3, 14.0;
15
This article is protected by copyright. All rights reserved.

10.1002/cctc.202000626
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FULL PAPER
MS (MALDI) calcd for C17H17NO3Na [M + Na]+ m/z 306.11, found 306.10.
7.1 Hz, 2H), 3.28 (d, J = 1.3 Hz, 2H), 2.38 (apparent t, J = 1.3 Hz, 3H),
1.32 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 166.2, 159.6,
159.3, 131.3, 130.8, 128.6, 127.5, 101.5, 85.1, 60.8, 24.6, 18.5, 14.3; MS
(MALDI) calcd for C16H15NO3Na [M + Na]+ m/z 292.10, found 292.06.
Ethyl 4-cyano-4-methyl-5-oxo-5-phenyl-2-vinylidenepentanoate (12c).
Isolated as a colorless oil. IR (n, cm–1) 3065, 2986, 2925, 2851, 1965,
1938, 1709, 1689, 1597, 1448, 1367, 1304, 1258, 1221, 1080, 972, 860;
1H NMR (500 MHz, CDCl3) δ 8.17–8.13 (m, 2H), 7.64–7.58 (m, 1H),
7.53–7.48 (m, 2H), 5.24 (dt, J = 14.3, 2.7 Hz, 1H), 5.17 (dt, J = 14.3, 2.7
Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.26 (dt, J = 15.1, 3.0 Hz, 1H), 2.80 (dt,
J = 15.1, 2.4 Hz, 1H), 1.76 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 214.8, 193.6, 166.4, 134.2, 133.8, 129.4, 128.7, 121.4,
95.5, 81.9, 61.6, 45.6, 36.0, 24.4, 14.2; MS (MALDI) calcd for
C17H17NO3Na [M + Na]+ m/z 306.11, found 306.08.
Ethyl
5-cyano-4-methyl-6-phenyl-2H-pyran-3-carboxylate
(32).
Isolated as a thin film. IR (n, cm–1) 2957, 2924, 2852, 2212, 1710, 1692,
1632, 1545, 1491, 1447, 1394, 1337, 1289, 1251, 1176, 1058; 1H NMR
(500 MHz, CDCl3) δ 7.94–7.90 (m, 2H), 7.58–7.53 (m, 1H), 7.51–7.46 (m,
2H), 5.04 (d, J = 1.2 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 2.51 (apparent t, J
= 1.2 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
169.8, 164.3, 142.7, 132.7, 130.6, 129.5, 128.7, 110.7, 92.2, 67.3, 60.8,
17.3, 14.3; MS (MALDI) calcd for C16H15NO3Na [M + Na]+ m/z 292.10,
found 292.06.
(E)-Ethyl
5-cyano-2-(ethanoyloxymethyl)-5-methyl-6-oxo-6-
phenylhex-2-enoate (13ca). Isolated as a thin film. IR (n, cm–1) 2958,
2924, 2852, 2238, 1736, 1716, 1690, 1552, 1487, 1448, 1384, 1371,
1241, 1173, 1160, 1092, 1081, 1027; 1H NMR (500 MHz, CDCl3) δ 8.17–
8.13 (m, 2H), 7.66–7.61 (m, 1H), 7.55–7.50 (m, 2H), 7.02 (dd, J = 8.0,
7.4 Hz, 1H), 4.92 (d, J = 12.1 Hz, 1H), 4.87 (d, J = 12.1 Hz, 1H), 4.24 (q,
J = 7.1 Hz, 2H), 3.19 (dd, J = 15.2, 7.2 Hz, 1H), 2.91 (dd, J = 15.1, 8.1 Hz,
1H), 2.05 (s, 3H), 1.76 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 192.8, 170.7, 165.6, 139.9, 134.2, 133.5, 131.7, 129.4,
128.9, 120.9, 61.3, 57.8, 45.1, 36.6, 24.3, 20.9, 14.2; MS (MALDI) calcd
for C19H21NO5Na [M + Na]+ m/z 366.13, found 366.12.
Reactions Between Benzyl Tosyl Carbamate 39 and PPh3. PPh3
(0.2 or 1.0 equiv) was added to a solution of benzyl tosyl carbamate[54]
(39; 0.350 mmol, 1.0 equiv) in dry CH3CN (10 mL) and then the mixture
was stirred at room temperature while monitoring using both TLC and 1
H
NMR spectroscopy. After 24 h, it was determined that no reaction had
occurred. A 1H NMR spectrum of the crude product isolated at this time
revealed a very clean mixture of only 39 and PPh3. Furthermore, the 31P
NMR spectrum of this crude sample featured only one signal, that of
PPh3, indicating that there was no other form of phosphine present. As
such, it was determined that that no reaction had occurred.
(Z)-Ethyl 5-cyano-2-(ethanoyloxymethyl)-5-methyl-6-oxo-6-phenylhex-
2-enoate (13cb). Isolated as a thin film. IR (n, cm–1) 2958, 2921, 2851,
2260, 1745, 1716, 1690, 1648, 1553, 1490, 1457, 1450, 1377, 1234,
1179, 1096, 1027; 1H NMR (500 MHz, CDCl3) δ 8.17–8.14 (m, 2H), 7.66–
7.61 (m, 1H), 7.54–7.49 (m, 2H), 6.30–6.26 (m, 1H), 4.79 (dd, J = 13.1,
0.8 Hz, 1H), 4.75 (dd, J = 13.1, 0.8 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.41
(dd, J = 15.7, 6.7 Hz, 1H), 3.30 (dd, J = 15.7, 8.0 Hz, 1H), 2.07 (s, 3H),
1.73 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 193.2,
170.4, 165.1, 138.3, 134.0, 133.8, 131.2, 129.4, 128.8, 121.2, 64.5, 61.0,
45.4, 36.8, 23.8, 20.9, 14.2; MS (MALDI) calcd for C19H21NO5Na [M +
Na]+ m/z 366.13, found 366.14.
Formal Synthesis of (±)-Trachelanthamidine[35]
Methyl 5-oxohexahydropyrrolizine-1-carboxylate (40). A suspension of
pyrroline 3l (25.0 mg, 0.0630 mmol) and freshly crushed (using a
hammer) Mg turnings (38.4 mg, 1.58 mmol) in dry MeOH (3.2 mL) under
a balloon of Ar was subjected sonication for 4.25 h. The reaction was
stopped by diluting the mixture with CH2Cl2 (50 mL) and adding saturated
aqueous NH4Cl (30 mL). The separated organic phase was further
washed with saturated aqueous NH4Cl (3 ´ 30 mL). The initial aqueous
layer was extracted with CH2Cl2 (3 ´ 15 mL). The combined organic
phases were washed with brine (20 mL), dried (Na2SO4), and
concentrated under reduced pressure. The residue was purified through
Reaction Between Allenylic Acetate 9 and Benzoyl Acetonitrile
19.[53] A solution of allenylic acetate 9 (35.0 mg, 0.190 mmol) in dry
benzene (2.8 mL) was added over 1 h via a syringe pump to a
suspension of Cs2CO3 (80.5 mg, 0.247 mmol) and benzoyl acetonitrile
(19; 33.1 mg, 0.228 mmol) in dry benzene (2.8 mL). Once the addition
was complete, the mixture was stirred for an additional 19 h. The reaction
was then quenched by adding saturated aqueous NH4Cl (5 mL). The
separated aqueous phase was extracted with Et2O (3 ´ 5 mL). The
combined organic phases were washed with brine (10 mL), dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
residue was purified through flash column chromatography (0–15%
EtOAc/hexanes) to yield allenoate 30 (9.8 mg, 19%) and a co-eluted
mixture of 4H-pyran 31 and 2H-pyran 32. To fully separate 31 from 32,
the mixture was subjected to preparatory TLC to yield 4H-pyran 31 (13.8
mg, 27%) and 2H-pyran 32 (5.9 mg, 12%).
flash column chromatography
(100% hexanes
to 50–80%
EtOAc/hexanes to 100% EtOAc; to visualize the product, the TLC plates
were stained in an I2 chamber) to yield 40 (10 mg, 86% yield) as a light-
yellow oil. The spectroscopic data were in agreement with those
previously reported in the literature.[55]
Formal Synthesis of (±)-Supinidine
2-(3-Ethoxy-3-oxopropyl)-1-tosyl-2,5-dihydropyrrole-3-carboxylic acid
(S12). Trifluoroacetic acid (0.63 mL) was added to a solution of pyrroline
3m (53 mg, 0.13 mmol) in dry CH2Cl2 (3.6 mL) and then the mixture was
stirred at room temperature for 3 h. At this point, the solvent was
evaporated and the residue purified through flash column
chromatography (10–30% EtOAc/hexanes then 30% EtOAc/hexanes
containing 1% AcOH) to yield S12 (43.7 mg, 95% yield) as a colorless
thin film. IR (n, cm–1) 3624–3028, 2980, 2927, 1717, 1704, 1643, 1598,
1452, 1398, 1377, 1343, 1268, 1233, 1160, 1092, 1067, 1039, 817; 1H
NMR (500 MHz, CDCl3) d (ppm) 8.66–7.86 (br s, 1H), 7.67 (d, J = 8.2 Hz,
2H), 7.29 (d, J = 8.1 Hz, 2H), 6.63 (s, 1H), 4.82–4.77 (br s, 1H), 4.28–
4.17 (m, 2H), 4.09 (q, J = 7.1 Hz, 2H), 2.49–2.29 (m, 6H), 2.19–2.10 (m,
1H), 1.23 (t, J = 7.1 Hz, 3H); 13C NMR (125.8 MHz, CDCl3) d (ppm) 173.8,
166.5, 144.1, 139.2, 134.1, 134.0, 130.0, 127.4, 65.0, 60.7, 55.4, 29.1,
29.0, 21.6, 14.1; MS (MALDI) calcd for C17H21NO6SNa [M + Na]+ m/z
390.10, found 390.09.
Ethyl 4-cyano-5-oxo-5-phenyl-2-vinylidenepentanoate (30). Isolated as
a colorless oil. IR (n, cm–1) 2982, 2958, 2922, 2851, 2209, 1967, 1733,
1671, 1625, 1446, 1354, 1270, 1251, 1168, 1027, 863, 769; 1H NMR
(500 MHz, CDCl3) δ 7.80–7.75 (m, 2H), 7.49–7.42 (m, 3H), 4.98 (d, J =
2.1 Hz, 1H), 4.55 (d, J = 2.1 Hz, 1H), 4.23 (qd, J = 7.1, 1.8 Hz, 2H), 3.59
(dd, J = 5.8, 5.0 Hz, 1H), 2.93 (dd, J = 16.4, 4.8 Hz, 1H), 2.76 (dd, J =
16.4, 6.0 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
169.6, 162.4, 151.0, 131.7, 131.0, 128.5, 127.8, 119.2, 97.0, 82.2, 61.9,
40.9, 26.6, 14.1; MS (MALDI) calcd for C16H15NO3SNa [M + Na]+ m/z
292.10, found 292.08.
Ethyl 3-[3-(hydroxymethyl)-1-tosyl-2,5-dihydropyrrol-2-yl]propanoate
(41). An oven-dried conical vial containing a magnetic spin vane was
charged with carboxylic acid S12 (21 mg, 0.057 mmol) and dry THF (500
µL) and then the solution was cooled to 0 °C in an ice-water bath. Et3N
(16 µL, 0.11 mmol) and ethyl chloroformate (97%, 8.0 µL, 0.081 mmol)
Ethyl
5-cyano-2-methyl-6-phenyl-4H-pyran-3-carboxylate
(31).
Isolated as thin film. IR (n, cm–1) 2954, 2919, 2850, 2210, 1715, 1672,
1631, 1447, 1382, 1368, 1245, 1211, 1173, 1154, 1078, 770; 1H NMR
(500 MHz, CDCl3) δ 7.79–7.75 (m, 2H), 7.51–7.43 (m, 3H), 4.23 (q, J =
16
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10.1002/cctc.202000626
ChemCatChem
FULL PAPER
and 32, and copies of 1H and 13C NMR spectra for all new
compounds (PDF).
were added dropwise sequentially to the cooled solution. The ice bath
was removed and the solution stirred at room temperature for 1.2 h. The
mixture was filtered through a short pad of Celite, which was then
washed thoroughly with EtOAc. The filtrate was concentrated under
reduced pressure and azeotropic removal of water was performed using
benzene. The crude material was then dissolved in dry MeOH (1 mL) and
transferred to a new oven-dried conical vial containing a magnetic spin
vane. After the solution had been cooled to –78 °C, NaBH4 (6.0 mg, 0.14
mmol) was added and then the mixture was stirred for 30 min at that
temperature. A second portion of NaBH4 (6.0 mg, 0.14 mmol) was added
and then the reaction was stirred for a further 1 h at –78 °C. The reaction
was quenched through the addition of saturated aqueous NH4Cl (2 mL)
and then the mixture was slowly warmed to room temperature. The
mixture was diluted with EtOAc (20 mL) and then another portion of
saturated aqueous NH4Cl (10 mL) was added. The separated aqueous
phase was extracted with EtOAc (3 ´ 30 mL). The combined organic
phases were washed with brine (30 mL), dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue was purified through
flash column chromatography (0–60% EtOAc/hexanes) to yield 41 (14.7
mg, 73% yield) as a thin film. IR (n, cm–1) 3666–3194, 2981, 2927, 2870,
1727, 1598, 1494, 1448, 1396, 1377, 1337, 1305, 1288, 1259, 1157,
1093, 1036, 814; 1H NMR (500 MHz, CDCl3) d (ppm) 7.68 (d, J = 8.3 Hz,
2H), 7.28 (d, J = 8.2 Hz, 2H), 5.53–5.49 (m, 1H), 4.61–4.56 (m, 1H), 4.11
(q, J = 7.1 Hz, 2H), 4.15–4.00 (m, 4H), 2.55–2.47 (m, 1H), 2.40 (s, 3H),
2.37–2.27 (m, 2H), 1.97–1.88 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H); 13C NMR
(125.8 MHz, CDCl3) d (ppm) 174.0, 143.7, 141.6, 134.3, 129.8, 127.4,
120.8, 65.7, 60.6, 59.0, 55.1, 28.6, 28.6, 21.5, 14.2; MS (ESI) calcd for
C17H24NO5S [M + H]+ m/z 354.1, found 354.1.
Acknowledgements
This material is based upon studies supported by the NIH (GM
071779) and the NSF under equipment grant no. CHE-1048804.
Keywords: phosphine-catalysis • phosphonium diene • 3-
pyrroline
•
pyrrolizidine alkaloid
•
(4+1) annulative
rearrangement
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7-(Hydroxymethyl)-5,7a-dihydropyrrolizin-3(2H)-one
(42).[37]
A
suspension of allylic alcohol 41 (14 mg, 0.040 mmol) and freshly crushed
(using a hammer) Mg turnings (25 mg, 1.03 mmol) in dry MeOH (2 mL)
under a balloon of Ar was subjected to sonication for 1.5 h. At this point,
a second portion of freshly crushed Mg turnings (25 mg, 1.03 mmol) was
added to the mixture, which was sonicated for another 2 h (at this point,
all the Mg had dissolved). The reaction was then stopped by diluting the
mixture with CH2Cl2 (50 mL) and adding saturated aqueous NH4Cl (30
mL). The separated organic phase was washed with saturated aqueous
NH4Cl (3 ´ 30 mL). The initial aqueous phase was extracted with CH2Cl2
(3 ´ 15 mL). The combined organic phases were then washed with brine
(20 mL), dried (Na2SO4), and concentrated under reduced pressure. The
residue was purified through flash column chromatography in a Pasteur
pipette (100% hexanes to 50% EtOAc/hexanes to 100% EtOAc to 10–
50% MeOH/EtOAc; to visualize the product, the TLC plates were stained
in an I2 chamber or stained with KMnO4) to yield 42 (4.4 mg, 72% yield)
as a light-yellow oil. IR (n, cm–1) 3556–3095, 2979, 2917, 2865, 1672,
1643, 1529, 1461, 1406, 1328, 1307, 1281, 1222, 1169, 1054, 1010,
834; 1H NMR (300 MHz, CDCl3) d (ppm) 5.74 (dd, J = 3.6, 2.1 Hz, 1H),
4.75–4.63 (m, 1H), 4.46–4.35 (doublet of multiplets, J = 15.7 Hz, 1H),
4.32–4.26 (m, 2H), 3.78–3.67 (doublet of multiplets, J = 15.9 Hz, 1H),
2.80–2.65 (m, 1H), 2.49–2.29 (m, 2H), 1.98–1.81 (m, 1H); 13C NMR (75.5
MHz, CDCl3) d (ppm) 177.9, 143.6, 122.9, 67.3, 59.0, 49.5, 33.9, 29.2;
MS (MALDI) calcd for C8H12NO2 [M + H]+ m/z 154.09, found 154.08.
Supporting Information
Catalysis, Vol.
2 (Eds.: E. Vedejs, S. E. Denmark), Wiley-VCH,
Weinheim, 2016, pp. 715–804; ff) Y. Xiao, H. Guo, O. Kwon,
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Supporting information for this article can be found under
http://dx.doi.org/10.1002/cctc____. This material is available free
of charge via the internet at the website provided. The
supporting information includes: synthetic routes to propargyl
bromides S4 and S7, reaction optimization for the syntheses of
allenylic alcohol 7a and 3-pyrrolines 3a–b, deuterium labeling
studies, proposed mechanisms for the formation of pyrans 31
17
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10.1002/cctc.202000626
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FULL PAPER
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and subsequent (3+2) annulation with N-sulfonyl alkylimines in total
18
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10.1002/cctc.202000626
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FULL PAPER
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19
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10.1002/cctc.202000626
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elimination of the phosphine. As we have demonstrated, however, the
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mechanism presented in Scheme 3 is likely in operation for the reaction
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[31] Deuterium labeling studies employing allenylic acetate
9 and
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20
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FULL PAPER
Entry for the Table of Contents
N
(±)-Trachelanthamidine
PBu3
OCONHTs
or
Ts
N
CO2
TsNH
H
CO2R1
PPh3
R2
R2
R2
OH
•
CH3CN
rt
CO2R1
N
CO2R1
R3P
PR3
(±)-Supinidine
R1 = Et, t-Bu
R2 = H, alkyl, cycloalkyl, phenyl
OH
From allenes to pyrrolizidines: A phosphine-catalyzed (4+1) annulative rearrangement of allenylic carbamates yields 1,3-
disubstituted- and 1,2,3-trisubstituted-3-pyrrolines, including difficult-to-prepare 2-alkyl variants, via phosphonium diene intermediates.
This new methodology has been employed as the key step in concise formal syntheses of the pyrrolizidine alkaloids (±)-
trachelanthamidine and (±)-supinidine.
21
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