Phosphine-catalyzed [3 + 2] cycloaddition of sulfamate-derived cyclic imines with allenoate: Synthesis of sulfamate-fused dihydropyrroles

Article abstract of DOI:10.1021/jo401107v

Ph₃P-catalyzed [3 + 2] cycloaddition reaction of sulfamate-derived cyclic imines with allenoate has been developed, affording sulfamate-fused dihydropyrroles under very mild conditions in high yields. Using amino acid-based bifunctional phosphi

Full text of DOI:10.1021/jo401107v

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Article
Phosphine-catalyzed [3+2] Cycloaddition of Sulfamate-derived Cyclic
Imines with Allenoate: Synthesis of Sulfamate-fused Dihydropyrroles
Hao Yu, Lei Zhang, Zhilin Yang, Zhen Li, Yan Zhao, Yumei Xiao, and Hongchao Guo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo401107v • Publication Date (Web): 29 Jul 2013
Downloaded from http://pubs.acs.org on July 30, 2013
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Phosphine-catalyzed [3+2] Cycloaddition of
Sulfamate-derived Cyclic Imines with Allenoate:
Synthesis of Sulfamate-fused Dihydropyrroles
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Hao Yu, Lei Zhang, Zhilin Yang, Zhen Li, Yan Zhao, Yumei Xiao, and Hongchao Guo*
Department of Applied Chemistry, China Agricultural University, Beijing 100193, P. R. China
EꢀMail: hchguo@cau.edu.cn
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RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
Abstract: Ph3Pꢀcatalyzed [3+2] cycloaddition reaction of sulfamateꢀderived cyclic imines with
allenoate has been developed, affording sulfamateꢀfused dihydropyrroles under very mild conditions in
high yields. Using amino acidꢀbased bifunctional phosphine as chiral catalyst, its asymmetric variant
provided the corresponding products in good yields with moderate to excellent enantiomeric excesses
(up to 91%yield and up to 98%ee). Subsequent transformations of the heterocyclic products gave
various pharmaceutically attractive compounds.
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INTRODUCTION
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In the past twenty years, nucleophilic phosphineꢀcatalyzed cycloaddition reactions have been
developed as a reliable and powerful tool for the synthesis of carboꢀ and heterocycles from readily
available starting materials.1 In the presence of phosphine, electrophilicꢀdeficient imine is one of most
often used electrophilicꢀcoupling reagents since the pioneering contribution from Lu and coworkers.2 In
the presence of phosphine, imines could undergo [3+2],2b, 2c, 3 [4+2],4 [4+1],5 and [2+2+2]6 annulation
with various activated substrates including allenes, allylic carbonates, alkynyl ketones, 3ꢀalkylnoates,
and conjugated dienes to give all kinds of nitrogenꢀcontaining heterocycles.7 The enantioselective [3+2]
and [4+2] cycloaddition reactions have also been achieved.3c–3e, 3h, 3j, 3m, 3o, 4c, 4e Certain reactions have
successfully been applied to drug discovery8 and total synthesis of natural products.9 Although the
imines have extensively been applied in the phosphineꢀcatalyzed reactions, cyclic imines have received
minimal attention. Only two examples described phosphineꢀcatalyzed [2+2],10a [3+2],10a and [4+2]10b
cycloaddition reactions of cyclic ketimines with allenoates, which afforded sultamꢀfused azetidines,
dihydropyrroles and tetrahydropyridine. To the best of our knowledge, the application of sulfamateꢀ
derived cyclic aldimines in phosphineꢀcatalyzed cycloadditions remains unexplored. The sulfamate
moiety could bring very appealing properties to the compounds incorporating it, leading to specific
biological activities such as antibiotic, antiꢀviral, antimetastatic, antiꢀconvulsant, antiꢀcancer, antiꢀ
obesity, antiꢀarthritis, antiꢀosteoporosis, inhibiting hyperlipidemia and atherosclerosis activity, and has
widely been exploited in the drug design of various pharmacological agents.11 Therefore, developing
new reactions for the synthesis of sulfamateꢀfused molecules is highly desirable. The reactions
employing the sulfamateꢀderived cyclic aldimines (1 in Scheme 1) as the substrates, which are readily
accessible and stable compounds,12 can provide rapid and concise access to biologically active
compounds containing sulfamate moiety, but received very limited attention. In 1987, Tripathi et al
reported the reaction of sulfamateꢀderived cyclic aldimines with 1,3ꢀdiphenylnitiolimine to synthesize
heterocycles.13 In 2009, Du Bois and coworkers studied CꢀH hydroxylation with cyclic aldimines like 1
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as the catalyst.14 Then Lam et al presented enantioselective Rhodiumꢀcatalyzed nucleophilic
alkenylation of 1 with alkenylboron reagents15a and allylation of 1 with allylboron reagents in 2012.15b
Most recently, Xu et al reported Rhꢀcatalyzed asymmetric arylations of 1 using new and simple
sulfinamideꢀbased branched olefin ligands.16 Inspired by our continuing interest in exploring phosphineꢀ
catalyzed cycloaddition,17 we anticipated to develop the cycloaddition of 1 with allenoates with
phosphine as the catalyst (Scheme 1). Herein we disclose our results on phosphineꢀcatalyzed [3+2]
cycloaddition reaction of sulfamateꢀderived cyclic imines with allenoates and its asymmetric variant for
the synthesis of sulfamateꢀfused dihydropyrroles.
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Scheme 1. Phosphine-catalyzed Annulation of Sulfamate-derived cyclic imines with Allenoates
RESULTS AND DISCUSSION
In initial screening, the benzol[e][1,2,3]oxathiazine 2,2ꢀdioxide (1a) was treated with ethyl butaꢀ
2,3ꢀdienoate (2a) in dichloromethane at room temperature in the presence of 20 mol% PPh3. The
reaction proceeded smoothly and could complete within 7 hours. Gratifyingly, a new product 3a was
isolated in 97%yield. Its structure was established to be a [3+2] cycloaddition product by NMR spectra
(Table 1, entry 1). A subsequent screening of solvents indicated that a wide range of solvents such as
THF, toluene, CH3OH and CH3CN are compatible for catalysis, providing the desired product in
moderate to excellent yield (entries 2–5). In particular, when the reaction was carried out in toluene, the
best 99% yield was obtained (Table 1, entry 3). Next, several typical phosphines such as PBu3, PMe3,
and PMePh2 were tested in the reaction of 1a with ethyl butaꢀ2,3ꢀdienoate (2a) using toluene as the
solvent at room temperature. The strong nucleophile PBu3 and PMe3 only led to trace of [3+2]
cycloaddition product with most of the starting material 1a left (entries 6–7). The relative weaker
nucleophile PMePh2 could give 72% yield (entry 8). When the catalyst loading of PPh3 was decreased to
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10 and 5 mol% respectively, the cycloaddition reaction still proceeded efficiently nearly without
deterioration of the yield, albeit in longer reaction time (entries 9–10).
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Table 1. Optimization of the Reaction Conditions for Phosphine-catalyzed [3+2] Cycloaddition of
Cyclic Imine (1a) with Allenoate (2a)a
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entry
1
phosphine
PPh3
X
solvent
CH2Cl2
time (h)
6
yield (%)b
97
20
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3
PPh3
PPh3
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10
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THF
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99
toluene
CH3OH
CH3CN
toluene
toluene
toluene
toluene
toluene
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PPh3
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PPh3
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64
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PBu3
PMe3
PMePh2
PPh3
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trace
trace
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12
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97
10
PPh3
95
a All reactions were carried out with 0.125 mmol of 1a and 0.15 mmol of 2a in 2 mL of solvent, unless
otherwise indicated. b Isolated yields, unless otherwise indicated.
With the optimized reaction conditions in hand, the substrate scope of the [3+2] cycloaddition
reaction was examined (Table 2). With 20 mol% of PPh3 as the catalyst, the [3+2] cycloadition
reactions of various sulfamateꢀderived cyclic imines 1 with ethyl allenoate 2a were performed in toluene
at room temperature for 6h to provide the sulfamateꢀfused 3,10bꢀdihydrobenzo[e]pyrrolo[1,2ꢀ
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c][1,2,3]oxathiazineꢀ1ꢀcarboxylate 5,5ꢀdioxide derivatives (3aa–3pa) in moderate to excellent yields
(Table 2, entries 1–16)). The reactions were tolerant of a wide range of cyclic imines with electronꢀ
donating groups (Me, MeO, tꢀBu) and electronꢀwithdrawing groups (F, Cl, Br). Strangely, in contrast to
other cyclic imines, the imine 1g with 6ꢀBr substituent only gave the product 3ga in 56% yield (entry 7).
Two special substrates 1o and 1p also worked very well to afford the corresponding product 3oa and
3pa in 88% yield and 77% yield respectively (entries 15–16). The variation of allenoates was also
tested. Tuning the ester moieties in allenoates had little influence on the reactivity of the reaction.
Several allenoates with iꢀPr, tꢀBu, cyclohexyl, Ph and Bn group in ester moiety (2b–2f) smoothly
underwent the [3+2] cycloaddition reaction to give the corresponding sulfamateꢀfused dihydropyrroles
(3ab–3af) in 86–92% yield (entries 17–21).
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Table 2. Substrate Scope for Phosphine-catalyzed [3+2] Cycloaddition of Sulfamate-derived
Cyclic Imines (1) with Allenoates (2) a
entry R1 in 1
R2 in 2
Et (2a)
product
yield (%)b
99
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H (1a)
3aa
6ꢀMe (1b)
6ꢀOMe (1c)
6ꢀtꢀBu (1d)
6ꢀF (1e)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
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3ba
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6ꢀCl (1f)
6ꢀBr (1g)
7ꢀMeO (1h)
3ga
3ha
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7ꢀCl (1i)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
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98
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3ia
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7ꢀBr (1j)
3ja
8ꢀMe (1k)
8ꢀOMe (1l)
8ꢀtꢀBu (1m)
8ꢀCl (1n)
3ka
3la
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3ma
3na
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Et (2a)
Et (2a)
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3pa
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H (1a)
H (1a)
H (1a)
H (1a)
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3ae
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tꢀBu (2c)
cyclohexyl (2d)
Ph (2e)
Bn (2f)
a All reactions were carried out with 0.125 mmol of 1 and 0.15 mmol of 2 in 2 mL of toluene, unless
otherwise indicated. b Isolated yields, unless otherwise indicated.
Phosphineꢀcatalyzed asymmetric annulations of allenoates with electronꢀdeficient olefins and imines
provide a concise and efficient access to enantiomerically enriched carboꢀ and heterocycles, which are
useful building blocks for the synthesis of natural products and biologically active compounds.
Therefore, phosphineꢀcatalyzed enantioselective annulations have attracted much attention, and
numerous reactions have successfully been accomplished in recent years.1l, 1m In the research on
enantioselective [3+2] cycloaddition of imine with allenoate, Jacobsen used thiourea based chiral
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phosphine3h and Lu employed the dipeptide based chiral phosphine,3o respectively, accomplishing
excellent enantioselectivity in the [3+2] cycloaddition of diphenylphosphinoyl imines with allenoates.
However, chiral phosphine promoted asymmetric [3+2] cycloadditions of Nꢀtosyl imines with allenes,
generally affording functionalized 3ꢀpyrrolines with moderate enantioselectivity.3c–3e, 3j Particularly, the
enantioselective annulations of cyclic imines with allenoates were still unexplored. In this context, we
investigated asymmetric variant of phosphineꢀcatalyzed [3+2] cycloaddition of sulfamateꢀderived cyclic
imines with allenoate. Since amino acid and thioureaꢀbased bifunctional chiral phosphines have
demonstrated excellent enantioselective catalytic capability,1l bifunctional chiral phosphines (P1-P10)
were prepared and screened (Table 3). In the initial exploration, the [3+2] cycloaddition of the cyclic
imine 1a and ethyl allenoates 2 was selected as a model reaction (Table 3). To our delight, 10 mol% of
the thioureaꢀbased bifunctional chiral phosphine P1 catalyzed the model reaction to produce the desired
product in 86% yield with 38% ee (Table 3, entry 1). Subsequent examination of the phosphines P2–P6,
which possess similar chiral backbone to P1, did not give better results (entries 2–6). Thus, the amino
acidꢀbased phosphine P7 was tested,3m which displayed excellent enantioselectivity in [3+2]
cycloaddition reaction of allenoates with dual activated olefins, the encouraging result (70%yield and
45%ee) was obtained (entry 7). In the hope of getting more encouraging results, the catalysts P8-P10
were designed by the combination of the major functional moieties of the catalysts 4 and 5 and prepared
by reported procedure,3h, 3m their catalytic results were disappointing (entries 8–10). In this situation, the
amino acidꢀbased phosphine P7, which afforded the highest 45% ee at present, was chosen to make
further conditions optimization by tuning the ester moieties in allenoates. The screening results
indicated the benzyl ester proved to be superior to other esters in the allenoate structures, and the yield
and ee of the cycloaddition product could be improved to 91% and 90% respectively (entries 11–14).
The absolute configuration was assigned as R by using Xꢀray crystallography of the homologous chiral
sulfamateꢀfused dihydropyrrole 3kf obtained from the [3+2] annulation of 8ꢀmethyl substituted cyclic
imine (1k) with benzyl allenoate 2f.
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Table 3: Screening of Reaction Conditions of Asymmetric [3+2] Cycloaddition of Sulfamate-
derived Cyclic Imines (1a) with Allenoates (2)a
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entry phosphine
R
time (h)
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48
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18
2
product
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3ab
3ac
yield (%)b
86
ee(%)c
38
1
2
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
iꢀPr (2b)
tꢀBu (2c)
Cy (2d)
Bn (2f)
P1
P2
P3
P4
P5
P6
P7
P8
P9
P10
P7
P7
P7
P7
93
27
3
4d
74
4
90
ND
ND
ꢀ8
5
94
6
92
7
70
45
8
12
12
36
2
74
24
9
86
22
10
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12
13
14
96
26
83
50
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6
85
83
87
73
3ad
3af
2
91
90
a Reaction conditions: 1a (0.1 mmol), 2 (0.12 mmol), and the catalyst (0.01 mmol) in toluene (1.0 mL)
b
c
at room temperature. Yield of isolated product. The ee values were determined by HPLC analysis
using a chiral stationary phase. d 20 mol% of phosphine was used.
Under the optimized reaction conditions established, using the phosphine P7 as the catalyst, the
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substrate scope of enantioselective [3+2] cycloaddition of benzyl allenoate (2f) with cyclic imines was
examined (Table 4). A significant site effect and electronic effect of the substituent at Ar group was
observed. The substrates with the electronꢀdonating substituents at 8ꢀposition of cyclic imines carried
out the reaction to give the corresponding products (3kf, 3lf, 3qf) in 92 – 98% ee, while the substrate
with electronꢀwithdrawing substituent at 8ꢀposition of cyclic imine afforded the product 3rf in 52% ee.
Those substrates with various substituents in other positions of cyclic imines, irrespective of the
electronic nature of the substituents, were converted to the corresponding cycloaddition products (3hf,
3jf, 3cf, 3gf, 3pf) with 31 – 53% ee in good yields. The exact reason of the poor enantioselectivities is
still under exploring.
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Table 4. Asymmetric [3+2] Cycloaddition of Benzyl Allenoate (2f) with Cyclic Imines (1)a, b, c
a Reaction conditions: 1 (0.1 mmol), 2 (0.12 mmol), and the catalyst (0.01 mmol) in toluene (1.0 mL) at
b
c
room temperature. Isolated yield. The ee values were determined by HPLC analysis using a chiral
stationary phase.
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Based on Lu’s proposal2a and recent mechanistic studies,18 a plausible mechanism for [3+2]
cycloaddition and transition state model for enantioselective catalysis are presented in Scheme 2. Upon
conjugate addition of PPh3 to the allenoate 2, the zwitterion A is formed. It attacks cyclic imine 1 to
give the intermediate B, which sequentially undergoes intramolecular addition reaction to give the
intermediate C. The βꢀphosphonium ester D formed from C via a [1,2]ꢀproton shift carries out a βꢀ
elimination to regenerate the catalyst, affording the final tricyclic product 3. The imines 1 are highly
active and might react with A quickly enough to prohibit the transformation of A to the delocalized
structure A', ensuring excellent regioselectivity to give the sole product 3. As shown by the transition
state model3h, 3o in Scheme 2, the hydrogenꢀbonding interaction and PꢀO interaction might adapt the
flexible chiral bone of the catalyst to adopt a conformation favoring the Reꢀface attack of the imine, and
the Siꢀface was blocked by the steric hindrance from the catalyst.
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Scheme 2. Proposed Mechanism and Transition State Model
To evaluate the synthetic potential of this catalytic system, the gramꢀscale preparation of the
cycloaddition adduct was investigated. The reaction of 1 mmol of the starting material (1a) proceeded
smoothly, delivering the corresponding sulfamateꢀfused dihydropyrrole derivative 3aa without any loss
in reactivity (Scheme 3). The dihydropyrrole derivatives can be readily converted into various
interesting compounds (Scheme 3). First, treatment of 3aa with LiAlH4 at reflux followed by Boc2O
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afforded the Bocꢀprotected dihydropyrrole 4. Next, the sulfamateꢀfused dihydropyrrole 3aa was treated
with Bu4NF in THF at room temperature, leading to desulfonylated aromatized product 5.19 This
procedure provides a convenient and efficient access to pyrrole derivatives. More interestingly, a
coumarin fused with pyrrole 6 was obtained by treatment of the cycloadduct 3aa with tꢀBuOK in
DMSO at room temperature.20 The Cycloadduct 3aa could also be hydrolyzed using LiOH, providing
the carboxylic acid 7. Subsequent amidation of 7 with LꢀPhenylalanine under TBTU/DIPEA conditions
gave a LꢀPhenylalanine amide derivative 8, which could be potential inhibitor of protein
prenyltransferases including GGTaes I and RabGGTase.21 Finally, the treatment of 3af with Mg power
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in THF and CH3OH specifically reduced the double bond,22 while concomitant transesterification
resulted in displacement of benzyl with methyl group, thus affording sulfamateꢀfused tetrahydropyrrole
9.
Scheme 3. Gram-scale Synthesis of Dihydropyrrole Derivative and Further Transformations
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CONCLUSION
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In summary, we have described a novel Ph3Pꢀcatalyzed [3+2] cycloaddition of various sulfamateꢀ
derived cyclic imines with allenoates under mild reaction conditions to give the 3,10bꢀ
dihydrobenzo[e]pyrrolo[1,2ꢀc][1,2,3]oxathiazineꢀ1ꢀcarboxylate 5,5ꢀdioxide derivatives in high yields.
By using amino acidꢀbased bifunctional phosphine as chiral catalyst, asymmetric variant of the [3+2]
cycloaddition has also been developed, leading to chiral sulfamateꢀfused dihydropyrroles in good yields
with moderate to excellent enantiomeric excesses. This reaction could be performed in gram scale and is
a practical protocol. Subsequent transformations provided a concise access to various heterocycles and
pharmaceutically attractive compounds.
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EXPERIMENTAL SECTION
General Methods. Unless otherwise indicated, all compounds and reagents were purchased from
commercial suppliers and purified by standard techniques. Reactions were monitored through thinꢀlayer
chromatography (TLC) on silica gel–precoated glass plates. Chromatograms were visualized by
fluorescence quenching under UV light at 254 nm. Flash column chromatography was performed using
flash silica gel (200–300 mesh). IR spectra were recorded with an FTꢀIR spectrophotometer and are
1
reported as cm−1. H and 13C NMR spectra were recorded on a NMR instrument. HRMS analyses were
carried out on an electrospray ionization (ESI) apparatus using timeꢀofꢀflight (TOF) mass spectrometry.
Xꢀray crystallographic data were collected using a diffractometer equipped with a lowꢀtemperature
apparatus operated at 100K.
General Procedures for Synthesis of Sulfamate-derived Cyclic Imines 1.
Some cyclic slufamateꢀderived cyclic imines were prepared from the corresponding substituted
salicylaldehydes following reported procedures16 and others were prepared from corresponding
substituted phenols by the following procedures.16, 23, 24
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The Journal of Organic Chemistry
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Typical procedure for the Preparation of Salicylaldehyde Derivative23
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Parafomaldehyde (2.1 g, 67.5 mmol) was added to a mixture of the phenolic derivative (10 mmol),
anhydrous MgCl2 (1.43 g, 15 mmol) and Et3N (5.3 mL, 37.5 mmol) in THF (50 mL), and the mixture
was heated to reflux for 24 h or until complete consumption of the starting material as determined by
TLC. After the reaction mixture was cooled to room temperature, the reaction was quenched with 1M
HCl and the product was extracted with EtOAc (50 mL x 3). The organic layers were combined, washed
with saturated brine, dried (Na2SO4) and filtered. All volatiles were removed under reduced pressure and
the product was isolated by flash chromatography (petroleum ether / EtOAc) on silica gel. The products
were confirmed by NMR comparison to reported data.
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Typical Procedure for the Preparation of Sulfamate-derived Cyclic Imines16, 23
Anhydrous formic acid (40.0 mmol, 1.85 g, 1.5 mL) was added dropwise to neat chlorosulfonyl
isocyanate (40.0 mmol, 5.66 g, 3.5 mL) at 0 °C with rapid stirring. Vigorous gas evolution was observed
during the addition process. The resulting viscous suspension was stirred at room temperature until gas
evolution ceased (1–2h). The result colorless solid was used in the following step immediately.
To a solution of salicylaldehyde (1.83 g, 15.0 mmol) in DMA (100 mL) at room temperature was
carefully added freshly prepared ClSO2NH2 (4.62 g, 40.0 mmol) in small portions and the resulting
solution was stirred for 18 h. The reaction was quenched carefully with iceꢀcold H2O (100 mL) and the
mixture was transferred to a separating funnel containing CH2Cl2 (200 mL). The aqueous layer was
separated and extracted with CH2Cl2 (3 x 50 mL), and the combined organic layers were washed with
saturated NaHCO3 solution (100 mL), dried (MgSO4), filtered through a short pad of silica using
CH2Cl2 as eluent and concentrated in vacuo. The residue was heated to 180 °C under vacuum to remove
volatile impurities to leave 1. The products were confirmed by NMR comparison to reported data.
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General Procedure for the [3 + 2] Cycloaddition Reaction of Cyclic Imines with Allenoates
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Under a nitrogen atmosphere, to a stirred solution of cyclic imines 1 (0.125 mmol, 1.0 equiv) and
catalyst PPh3 (0.025 mmol, 20 mol%) in toluene (2 mL) was added 2,3ꢀbutadienoate 1 (0.15 mmol, 1.2
equiv) via a syringe in one portion. Then the reaction solution was vigorously stirred at room
temperature and monitored by TLC. After the reaction was complete, the mixture was directly purified
by column chromatography on silica gel (petroleum ether / EtOAc as the eluent) to furnish the
corresponding product.
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3aa. White solid (36.5 mg, 99% yield). Mp: 84 – 86 °C. 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J = 7.7
Hz, 1H), 7.35 – 7.27 (m, 1H), 7.17 (td, J = 1.2, 7.7 Hz, 1H), 7.03 (dd, J = 1.2, 7.7 Hz, 1H), 6.91 – 6.80
(m, 1H), 6.13 (d, J = 3.4 Hz, 1H), 4.52 – 4.39 (m, 2H), 4.33 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H).
13C NMR (75 MHz, CDCl3) δ 162.3, 149.8, 137.3, 135.4, 129.4, 127.3, 125.9, 120.8, 119.2, 66.6, 61.6,
55.9, 14.1. IR (film) νmax 1738, 1722, 1404, 1373, 1230, 1208, 1175, 885, 763, 634, 570, 528 cm–1.
HRMS (ESI) calcd for C13H14NO5S+ [M + H]+ 296.0587, found 296.0579.
1
3ba. White solid (37.8 mg, 98% yield). Mp: 86 – 89 °C. H NMR (300 MHz, CDCl3) δ 7.45 (s, 1H),
7.09 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.90 – 6.87 (m, 1H), 6.08 (d, J = 2.8 Hz, 1H), 4.54 –
4.23 (m, 4H), 2.29 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 162.4, 147.7, 137.3,
135.8, 135.6, 130.0, 127.5, 120.3, 118.9, 66.6, 61.5, 55.9, 20.9, 14.1. IR (film) νmax 1721, 1405, 1374,
1350, 1255, 1231, 1209, 1186, 1132, 1111, 842, 660, 626, 595 cm–1. HRMS (ESI) calcd for
C14H16NO5S+ [M + H]+ 310.0744, found 310.0736.
3ca. White solid (38.5 mg, 95%yield). Mp: 159 – 161 °C. 1H NMR (300 MHz, CDCl3) δ 7.55 (d, J = 8.8
Hz, 1H), 6.86 – 6.81 (m, 1H), 6.73 (dd, J = 2.6, 8.8 Hz, 1H), 6.55 (d, J = 2.6 Hz, 1H), 6.06 (d, J = 3.1
Hz, 1H), 4.50 – 4.38 (m, 2H), 4.33 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ 162.4, 160.2, 150.6, 136.9, 135.8, 128.1, 112.64, 112.60, 104.1, 66.3, 61.5, 55.9,
55.6, 14.1. IR (film) νmax 1716, 1493, 1403, 1258, 1207, 1178, 1132, 842, 411 cm–1. HRMS (ESI) calcd
for C14H16NO6S+ [M + H]+ 326.0693, found 326.0685.
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3da. White solid (43.0 mg, 98%yield). Mp: 127 – 128 °C. H NMR (300 MHz, CDCl3) δ 7.70 (d, J =
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2.0 Hz, 1H), 7.30 (dd, J = 2.0, 8.7 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 6.86 – 6.81 (m, 1H) , 6.13 (d, J =
4
5
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3.1 Hz, 1H), 4.50 – 4.19 (m, 4H), 1.36 (t, J = 7.1 Hz, 3H), 1.26 (s, 9H). C NMR (75 MHz, CDCl3) δ
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8
162.5, 149.1, 147.5, 137.1, 135.6, 126.4, 124.2, 119.9, 118.6, 66.9, 61.6, 55.9, 34.6, 31.2, 14.2. IR (film)
9
ν
max 1719, 1406, 1254, 1195, 1179, 1122, 1100, 846, 779 cm–1. HRMS (ESI) calcd for C17H22NO5S+ [M
+ H]+ 352.1213, found 352.1206.
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3ea. White solid (28.7 mg, 75% yield). Mp: 124 – 125 °C. H NMR (300 MHz, CDCl3) δ 7.51 – 7.44
(m, 1H), 7.06 – 6.97 (m, 2H), 6.91 – 6.88 (m, 1H), 6.09 (s, 1H), 4.50 – 4.40 (m, 2H), 4.40 – 4.29 (m,
13
2H), 1.37 (t, J = 7.1 Hz, 3H). C NMR (75 MHz, CDCl3) δ162.2, 159.6 (d, J CꢀF=245.8 Hz), 145.8 (d,
4J CꢀF = 2.7 Hz), 137.8, 135.0, 122.4 (d, 1J CꢀF = 7.7 Hz), 120.7 (d, 3J CꢀF = 8.4 Hz), 116.5 (d, 2J CꢀF = 23.9
2
4
Hz), 114.2 (d, J
= 26.0 Hz), 66.6 (d, J
= 1.6 Hz), 61.8, 56.0, 14.1. IR (film) νmax 1717, 1485,
CꢀF
CꢀF
1408, 1258, 1209, 1167, 1099, 843, 661, 421, 411 cm–1. HRMS (ESI) calcd for C13H13FNO5S+ [M + H]+
314.0493, found 314.0483.
3fa. White solid (36.3 mg, 88%yield). Mp: 163 – 164 °C. 1H NMR (300 MHz, CDCl3) δ 7.65 (d, J = 8.5
Hz, 1H), 7.15 (dd, J = 2.1, 8.5 Hz, 1H), 7.06 (d, J = 2.1 Hz, 1H), 6.92 – 6.80 (m, 1H), 6.10 (d, J = 1.2
13
Hz, 1H), 4.51 – 4.38 (m, 2H), 4.33 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). C NMR (75 MHz,
CDCl3) δ 162.1, 148.4, 137.8, 135.0, 131.2, 129.6, 127.5, 122.3, 120.6, 66.4, 61.8, 56.0, 14.1. IR (film)
νmax 1718, 1482, 1406, 1253, 1206, 1192, 1179, 1130, 1086, 922, 907, 774, 609, 568 cm–1. HRMS (ESI)
calcd for C13H13ClNO5S+ [M + H]+ 330.0197, found 330.0197.
1
3ga. White solid (26.0 mg, 56% yield). Mp: 128 – 130 °C. H NMR (300 MHz, CDCl3) δ 7.87 (d, J =
2.0 Hz, 1H), 7.42 (dd, J = 2.0, 8.7 Hz, 1H), 6.99 – 6.87 (m, 2H), 6.09 (s, 1H), 4.50 – 4.27 (m, 4H), 1.39
(t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 162.1, 149.0, 137.9, 135.0, 132.5, 130.4, 122.7, 120.9,
118.6, 66.3, 61.8, 56.0, 14.1. IR (film) νmax 1715, 1472, 1409, 1262, 1210, 1193, 1169, 1132, 1111, 879,
823, 774, 642, 588 cm–1. HRMS (ESI) calcd for C13H13BrNO5S+ [M + H]+ 373.9692, found 373.9683.
1
3ha. White solid (35.8 mg, 89% yield). Mp: 134 – 135 °C. H NMR (300 MHz, CDCl3) δ 7.26 – 7.22
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(m, 1H), 6.96 (d, J = 9.0 Hz, 1H), 6.89 – 6.77 (m, 2H), 6.08 (d, J = 3.5 Hz, 1H), 4.50 – 4.38 (m, 2H),
4.33 (q, J = 7.1 Hz, 2H), 3.75 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H).13C NMR (75 MHz, CDCl3) δ 162.5,
157.1, 143.4, 137.5, 135.3, 121.5, 120.1, 115.5, 111.6, 66.8, 61.6, 56.0, 55.6, 14.1. IR (film) νmax 1714,
1625, 1505, 1399, 1375, 1348, 1258, 1232, 1204, 1129, 1095, 1051, 956, 797, 784, 620 cm–1. HRMS
(ESI) calcd for C14H16NO6S+ [M + H]+ 326.0693, found 326.0693.
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3ia. White solid (38.0 mg, 92% yield). Mp: 170 – 173 °C. H NMR (300 MHz, CDCl3) δ 7.65 (d, J =
8.5 Hz, 1H), 7.15 (dd, J = 2.1, 8.5 Hz, 1H), 7.05 (d, J = 2.1 Hz, 1H), 6.89 – 6.83 (m, 1H), 6.12 – 6.06
13
(m, 1H), 4.51 – 4.39 (m, 2H), 4.33 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). C NMR (75 MHz,
CDCl3) δ 162.2, 150.3, 137.5, 135.2, 134.8, 128.6, 126.2, 119.5, 119.4, 66.4, 61.7, 56.0, 14.1. IR (film)
νmax 1715, 1408, 1251, 1210, 1195, 1170, 1113, 826, 777, 647, 612, 592, 552, 533, 498 cm–1. HRMS
(ESI) calcd for C13H13ClNO5S+ [M + H]+ 330.0197, found 330.0193.
1
3ja. White solid (36.4 mg, 79% yield). Mp: 125 – 127 °C. H NMR (300 MHz, CDCl3) δ 7.59 (d, J =
8.5 Hz, 1H), 7.30 (dd, J = 2.0, 8.5 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 6.90 – 6.81 (m, 1H), 6.10 – 6.03 (m,
1H), 4.55 – 4.40 (m, 2H), 4.33 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3)
δ 162.2, 150.3, 137.5, 135.1, 129.2, 128.8, 122.39, 122.36, 119.9, 66.5, 61.7, 56.0, 14.1. IR (film) νmax
1717, 1478, 1409, 1251, 1206, 1191, 1179, 1132, 1120, 1082, 897, 773, cm–1. HRMS (ESI) calcd for
C13H13BrNO5S+ [M + H]+ 373.9692, found 373.9685.
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3ka. White solid (35.5 mg, 92% yield). Mp: 123 – 125 °C. H NMR (300 MHz, CDCl3) δ 7.47 (d, J =
7.7 Hz, 1H), 7.15 (d, J = 7.7 Hz, 1H), 7.05 (t, J = 7.7 Hz, 1H), 6.86 – 6.79 (m, 1H), 6.12 (d, J = 3.6 Hz,
1H), 4.52 – 4.39 (m, 2H), 4.33 (q, J = 7.1 Hz, 2H), 2.29 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H). 13C NMR (75
MHz, CDCl3) δ 162.4, 148.3, 137.1, 135.7, 130.9, 128.5, 125.2, 124.7, 120.5, 66.7, 61.5, 56.0, 15.6,
14.1. IR (film) νmax 1719, 1404, 1374, 1252, 1232, 1205, 1159, 1131, 1079, 869, 768, 615, 587, 553 cm–
1. HRMS (ESI) calcd for C14H16NO5S+ [M + H]+ 310.0744, found 310.0739.
3la. White solid (40.0 mg, 98% yield). Mp: 137 – 139 °C. 1H NMR (300 MHz, CDCl3) δ 7.20 (d, J = 7.7
Hz, 1H), 7.09 (t, J = 7.7 Hz, 1H), 6.95 – 6.76 (m, 2H), 6.13 (d, J = 2.3 Hz, 1H), 4.54 – 4.39 (m, 2H),
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4.33 (q, J = 7.1 Hz, 2H), 3.87 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H). C NMR (75 MHz, CDCl3) δ 162.3,
149.0, 139.5, 137.3, 135.5, 125.6, 121.8, 118.2, 112.0, 66.7, 61.5, 56.2, 56.0, 14.1. IR (film) νmax 1717,
1479, 1403, 1275, 1256, 1204, 1163, 1131, 1091, 1066, 867, 763, 605, 555 cm–1. HRMS (ESI) calcd for
C14H16NO6S+ [M + H]+ 326.0693, found 326.0688.
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3ma. White solid (37.1 mg, 85% yield). Mp: 132 – 135 °C. H NMR (300 MHz, CDCl3) δ 7.57 – 7.49
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(m, 1H), 7.31 (dd, J = 1.1, 7.9 Hz, 1H), 7.09 (t, J = 7.9 Hz, 1H), 6.88 – 6.81 (m, 1H), 6.13 (d, J = 4.2 Hz,
1H), 4.57 – 4.36 (m, 2H), 4.32 (q, J = 7.1 Hz, 2H), 1.41 (s, 9H), 1.34 (t, J = 7.1 Hz, 3H). 13C NMR (75
MHz, CDCl3) δ 162.4, 149.2, 140.4, 137.2, 135.8, 127.0, 125.34, 125.30, 121.4, 67.0, 61.5, 56.3, 35.0,
30.0, 14.1. IR (film) νmax 1719, 1405, 1199, 1128, 870, 775, 606, 420, 412, 405 cm–1. HRMS (ESI) calcd
for C17H22NO5S+ [M + H]+ 352.1213, found 352.1207.
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3na. White solid (35.6 mg, 86% yield). Mp: 169 – 170 °C. H NMR (300 MHz, CDCl3) δ 7.64 – 7.58
(m, 1H), 7.42 – 7.35 (m, 1H), 7.10 (t, J = 8.0 Hz, 1H), 6.90 – 6.84 (m, 1H), 6.14 (d, J = 3.9 Hz, 1H),
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4.56 – 4.38 (m, 2H), 4.33 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). C NMR (75 MHz, CDCl3) δ
162.2, 145.9, 137.5, 135.2, 130.2, 125.9, 125.7, 124.1, 122.7, 66.8, 61.7, 56.1, 14.1. IR (film) νmax 1717,
1410, 1256, 1201, 1132, 858, 769, 671, 403 cm–1. HRMS (ESI) calcd for C13H13ClNO5S+ [M + H]+
330.0197, found 330.0191.
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3oa. White solid (38.0 mg, 88% yield). Mp: 153 – 155 °C. H NMR (300 MHz, CDCl3) δ 8.27 – 8.17
(m, 1H), 7.84 – 7.76 (m, 2H), 7.54 – 7.43 (m, 2H), 7.15 (d, J = 8.9 Hz, 1H), 6.72 (d, J = 4.4 Hz, 1H),
6.59 – 6.51 (m, 1H), 4.70 – 4.56 (m, 1H), 4.46 – 4.34 (m, 1H), 4.11 (q, J = 7.1 Hz, 2H), 1.13 (t, J = 7.1
13
Hz, 3H). C NMR (75 MHz, CDCl3) δ 162.4, 147.9, 145.6, 144.3, 137.3, 135.6, 113.2, 106.0, 102.0,
100.7, 66.6, 61.6, 56.0, 14.1. IR (film) νmax 1721, 1404, 1253, 1215, 1193, 1082, 871, 818, 650, 621 cm–
1. HRMS (ESI) calcd for C17H16NO5S+ [M + H]+ 346.0744, found 346.0739.
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3pa. White solid (32.8 mg, 77% yield). Mp: 176 – 178 °C. H NMR (300 MHz, CDCl3) δ 7.13 (s, 1H),
6.85 (s, 1H), 6.52 (s, 1H), 6.05 – 5.91 (m, 3H), 4.53 – 4.22 (m, 4H), 1.36 (t, J = 7.1 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ 162.2, 145.9, 137.5, 135.2, 130.2, 125.9, 125.7, 124.1, 122.7, 66.8, 61.7, 56.1, 14.1.
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IR (film) νmax 1715, 1484, 1404, 1249, 1205, 1141, 1087, 1037, 859, 820, 749, 620, 561 cm–1. HRMS
(ESI) calcd for C14H14NO7S+ [M + H]+ 340.0485, found 340.0481.
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3ab. White solid (33.1 mg, 86% yield). Mp: 102 – 104 °C. H NMR (300 MHz, CDCl3) δ 7.67 (d, J =
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8
9
7.8 Hz, 1H), 7.35 – 7.27 (m, 1H), 7.23 – 7.11 (m, 1H), 7.07 – 7.00 (m, 1H), 6.83 (s, 1H), 6.13 (d, J = 2.8
Hz, 1H), 5.33 – 5.06 (m, 1H), 4.55 – 4.24 (m, 2H), 1.45 – 1.26 (m, 6H ). 13C NMR (75 MHz, CDCl3) δ
161.9, 149.9, 137.0, 135.9, 129.4, 127.3, 125.9, 120.8, 119.2, 69.4, 66.6, 55.9, 21.8, 21.7. IR (film) νmax
1713, 1405, 1374, 1257, 1208, 1193, 1175, 1133, 1103, 1074, 1057, 884, 862, 825, 770, 634, 570 cm–1.
HRMS (ESI) calcd for C14H15NO5SNa+ [M + Na]+ 332.0563, found 332.0565.
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3ac. White solid (37.1 mg, 92% yield). Mp: 120 – 122 °C. H NMR (300 MHz, CDCl3) δ 7.70 – 7.64
(m, 1H), 7.34 – 7.27 (m, 1H), 7.17 (td, J = 1.2, 8.0 Hz, 1H), 7.03 (dd, J = 1.2, 8.0 Hz, 1H), 6.75 – 6.72
(m, 1H), 6.09 (d, J = 3.2 Hz, 1H), 4.50 – 4.28 (m, 2H), 1.56 (s, 9H). 13C NMR (75 MHz, CDCl3) δ
161.8, 149.9, 137.0, 136.0, 129.4, 127.3, 125.9, 120.8, 119.2, 74.3, 66.6, 55.9, 31.5, 31.5, 25.2, 23.7,
23.6, 0.97. IR (film) νmax 1738, 1439, 1376, 1280, 1228, 1217, 1130, 749, 733, 694, 682, 623, 560, 528,
463, 436 cm–1. HRMS (ESI) calcd for C15H17NO5SNa+ [M + Na]+ 346.0720, found 346.0716.
1
3ad. White solid (38.3 mg, 88% yield). Mp: 122 – 125 °C. H NMR (300 MHz, CDCl3) δ 7.67 (d, J =
7.7 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.16 (t, J = 7.7 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.84 (s, 1H),
6.14 (s, 1H), 5.06 – 4.84 (m, 1H), 4.52 – 4.28 (m, 2H), 2.04 – 1.19 (m, 11H). 13C NMR (75 MHz,
CDCl3) δ 161.7, 149.9, 137.0, 136.2, 129.4, 127.2, 125.9, 121.0, 119.2, 82.7, 66.6, 55.9, 28.1. IR (film)
νmax 1710, 1405, 1257, 1208, 1193, 1173, 1129, 1103, 884, 861, 772, 633, 569 cm–1. HRMS (ESI) calcd
for C17H19NO5SNa+ [M + Na]+ 372.0876, found 372.0877.
1
3ae. White solid (37.7 mg, 88% yield). Mp: 153 – 156 °C. H NMR (300 MHz, CDCl3) δ 7.73 (d, J =
8.0 Hz, 1H), 7.49 – 7.40 (m, 2H), 7.36 – 7.27 (m, 2H), 7.22 – 7.11 (m, 4H), 7.07 (dd, J = 1.2, 8.0 Hz,
13
1H), 6.23 (d, J = 3.7 Hz, 1H), 4.63 – 4.43 (m, 2H). C NMR (75 MHz, CDCl3) δ 160.9, 150.1, 150.0,
139.6, 134.9, 129.7, 129.6, 127.4, 126.4, 126.1, 121.3, 120.7, 119.4, 66.7, 56.2. IR (film) νmax 1736,
1488, 1404, 1356, 1235, 1208, 1192, 1175, 1118, 1102, 1050, 885, 772, 741, 635, 564 cm–1. HRMS
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(ESI) calcd for C17H14NO5S+ [M + H]+ 344.0587, found 344.0582.
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3af. White solid (40.8 mg, 92% yield). Mp: 122 – 124 °C. 1H NMR (300 MHz, CDCl3) δ 7.62 – 7.56 (m,
1H), 7.37 (s, 5H), 7.30 – 7.22 (m, 1H), 7.13 – 7.05 (m, 1H), 7.00 (dd, J = 0.8, 8.2 Hz, 1H), 6.89 – 6.84
(m, 1H), 6.12 (d, J = 3.7 Hz, 1H), 5.30 (AB q, ΔδAB = 0.10 ppm, JAB = 12.0 Hz, 2H ), 4.48 – 4.29 (m,
9
2H). 13C NMR (75 MHz, CDCl3) δ 162.1, 149.8, 137.9, 135.1, 135.0, 129.4, 128.7, 128.6, 128.39,
128.36, 127.3, 125.9, 120.6, 119.2, 67.2, 66.6, 55.9. IR (film) νmax 1716, 1453, 1403, 1350, 1249, 1208,
1193, 1174, 1126, 1103, 1058, 884, 863, 763, 699, 635 cm–1. HRMS (ESI) calcd for C18H15NO5SNa+
[M + Na]+ 380.0563, found 380.0561.
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Preparation of Bifunctional Chiral Phosphines
The chiral phosphines were prepared according to the procedure of Jacobsen3h and Zhao3m.
The NMR data of P8: 1H NMR (300 MHz, CDCl3) δ 7.56 – 6.97 (m, 20H), 7.01 (br s, 1H), 6.58 (br s,
1H), 5.67 (s, 1H), 4.89 – 4.40 (m, 4H), 2.35 – 2.07 (m, 2H), 1.76 (s, 1H), 1.34 (d, J = 6.7 Hz,3H), 1.29 –
0.95 (m,1H), 0.84 (d, J = 6.5 Hz, 3H), 0.76 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 174.3,
162.3, 138.6, 138.4, 136.2, 135.8, 133.4, 133.1, 132.7, 132.4, 128.9, 128.7, 128.5, 128.45, 128.40,
128.36, 127.9, 127.8, 127.5, 127.2, 56.1, 55.9, 50.1, 48.2, 31.0, 30.8, 25.0, 19.2, 15.1, 11.6.
General Procedure for Asymmetric [3+2] Cycloaddition Reaction of Cyclic Imines with Benzyl 2,
3-Butadienoate
Under a nitrogen atmosphere, to a stirred solution of cyclic imines 1 (0.1 mmol, 1.0 equiv) and
catalyst P7 (0.01 mmol, 0.1 equiv) in toluene (1 mL) was added benzyl 2, 3ꢀbutadienoate 2f (0.12
mmol, 1.2 equiv) via a syringe in one portion. Then the reaction solution was vigorously stirred at room
temperature and monitored by TLC. After the reaction was complete, the mixture was directly purified
by column chromatography on silica gel (petroleum ether / EtOAc as the eluent) to furnish the
corresponding product.
1
3af. White solid (32.6 mg, 91% yield). [α]20D= + 11.2 (c 0.44, CHCl3). Mp: 122 – 124 °C. H NMR
(300 MHz, CDCl3) δ 7.62 – 7.56 (m, 1H), 7.37 (s, 5H), 7.30 – 7.22 (m, 1H), 7.13 – 7.05 (m, 1H), 7.00
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(dd, J = 0.8, 8.2 Hz, 1H), 6.89 – 6.84 (m, 1H), 6.12 (d, J = 3.7 Hz, 1H), 5.30 (AB q, ΔδAB = 0.10 ppm,
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JAB = 12.0 Hz, 2H ), 4.48 – 4.29 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 162.1, 149.8, 137.9, 135.1,
135.0, 129.4, 128.7, 128.6, 128.39, 128.36, 127.3, 125.9, 120.6, 119.2, 67.2, 66.6, 55.9. IR (film) νmax
1716, 1453, 1403, 1350, 1249, 1208, 1193, 1174, 1126, 1103, 1058, 884, 863, 763, 699, 635 cm–1.
HRMS (ESI) calcd for C18H15NO5SNa+ [M + Na]+ 380.0563, found 380.0561. HPLC analysis: 90% ee
(Chiralcel ADꢀH: 5:95 isopropanol / hexane, 1mL/min, 254 nm, tR1= 21.219 min, tR2 = 30.699 min.).
3kf. White solid (30.1 mg, 82% yield). [α]20D= + 8.5 (c 0.52, CHCl3). Mp: 134 – 136 °C. 1H NMR (300
MHz, CDCl3) δ 7.43 – 7.32 (m, 6H), 7.16 – 7.09 (m, 1H), 6.97 (t, J = 7.7 Hz, 1H), 6.89 – 6.80 (m, 1H),
6.12 (d, J = 3.9 Hz, 1H), 5.29 (AB q, ΔδAB = 0.09 ppm, JAB = 12.0 Hz, 2H), 4.51 – 4.30 (m, 2H), 2.27
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(s, 3H). 13C NMR (75 MHz, CDCl3) δ 162.1, 148.2, 137.7, 135.3, 135.0, 130.8, 128.7, 128.6, 128.5,
128.4, 125.2, 124.6, 120.4, 67.2, 66.7, 56.0, 15.5. IR (film) νmax 1719, 1463, 1404, 1350, 1250, 1205,
1159, 1128, 1077, 1056, 869, 765, 732, 699, 689, 664, 615, 582, 556 cm–1. HRMS (ESI) calcd for
C19H17NO5SNa+ [M + Na]+ 394.0720, found 394.0717. HPLC analysis: 93% ee (Chiralcel ADꢀH: 15:85
isopropanol / hexane, 1 mL/min, 254 nm, tR1= 9.911 min, tR2 = 12.521 min).
1
3lf. White solid (28.4 mg, 74% yield). [α]20 = + 6.9 (c 1.32, CHCl3). Mp: 177 – 179 °C. H NMR (300
D
MHz, CDCl3) δ 7.44 – 7.31 (m, 5H), 7.16 – 7.11 (m, 1H), 7.02 (t, J = 8.1 Hz, 1H), 6.89 – 6.84 (m, 2H),
6.13 (d, J = 4.0 Hz, 1H), 5.30 (AB q, ΔδAB = 0.08 ppm, JAB = 12.0 Hz, 2H), 4.56 – 4.27 (m, 2H), 3.86
(s, 3H). 13C NMR (75 MHz, CDCl3) δ 162.1, 149.0, 139.4, 137.8, 135.2, 135.0, 128.7, 128.6, 128.4,
125.6, 121.6, 118.2, 111.9, 67.2, 66.7, 56.2, 56.0. IR (film) νmax 1719, 1478, 1403, 1276, 1259, 1205,
1163, 1128, 1091, 1064, 867, 761, 731, 700, 606, 555 cm–1. HRMS (ESI) calcd for C19H17NO6NaS+ [M
+ Na]+ 410.0669, found 410.0670. HPLC analysis: 98% ee (Chiralcel ADꢀH: 15:85 isopropanol /
hexane, 1 mL/min, 254 nm, tR1= 22.696 min, tR2 = 38.312 min).
3qf. White solid (36.8 mg, 87% yield). [α]20D= + 5.6 (c 0.40, CHCl3). Mp: 137 – 140 °C. 1H NMR (300
MHz, CDCl3) δ 7.45 – 7.31 (m, 5H), 7.12 (m, 1H), 6.99 (t, J = 8.1 Hz, 1H), 6.89 – 6.81 (m, 1H), 6.12
(d, J = 4.1 Hz, 1H), 5.29 (AB q, ΔδAB = 0.10 ppm, JAB = 12.0 Hz, 2H) , 4.50 – 4.29 (m, 1H), 4.05 (q,
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13
J = 7.1 Hz, 1H), 1.43 (t, J = 7.1 Hz, 1H). C NMR (75 MHz, CDCl3) δ 161.9, 146.6, 138.1, 134.9,
134.8, 133.3, 128.7, 128.4, 126.44, 126.37, 122.6, 112.8, 67.3, 66.8, 56.1. IR (film) νmax 1719, 1470,
1404, 1276, 1260, 1205, 1171, 1128, 1086, 1061, 867, 762, 732, 606, 557, cm–1. HRMS (ESI) calcd for
C20H19NO6SNa+ [M + Na]+ 424.0825, found 424.0822. HPLC analysis: 92% ee (Chiralcel ADꢀH: 15:85
isopropanol / hexane, 1 mL/min, 254 nm, tR1= 16.075 min, tR2 = 29.580 min).
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3rf. White solid (36.3 mg, 84% yield). Mp: 123 – 126 °C. H NMR (300 MHz, CDCl3) δ 7.58 (d, J =
8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.37 (s, 5H), 6.96 (t, J = 8.0 Hz, 1H), 6.90 – 6.87 (m, 1H), 6.12 (d,
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J = 3.8 Hz, 1H), 5.29 (AB q, ΔδAB = 0.11 ppm, JAB = 12.0 Hz, 2H) , 4.52 – 4.32 (m, 2H). C NMR
(75 MHz, CDCl3) δ 161.9, 146.6, 138.1, 134.9, 134.8, 133.3, 128.7, 128.4, 126.44, 126.37, 122.6, 112.8,
67.3, 66.8, 56.1. IR (film) νmax 1718, 1625, 1504, 1402, 1253, 1204, 1127, 1105, 1054, 955, 793, 744,
701, 619, 579 cm–1. HRMS (ESI) calcd for C18H14BrNO5SNa+ [M + Na]+ 457.9668, found 457.9671.
HPLC analysis: 52% ee (Chiralcel ADꢀH: 15:85 isopropanol / hexane, 1 mL/min, 254 nm, tR1= 15.989
min, tR2 = 21.563 min).
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3hf. White solid (32.3 mg, 84% yield). Mp: 127 – 129 °C. H NMR (300 MHz, CDCl3) δ 7.48 (d, J =
8.8 Hz, 1H), 7.40 – 7.35 (m, 5H), 6.89 – 6.80 (m, 1H), 6.64 (dd, J = 2.6, 8.8 Hz, 1H), 6.52 (d, J = 2.6 Hz,
1H), 6.05 (d, J = 3.1 Hz, 1H), 5.29 (AB q, ΔδAB = 0.10 ppm, JAB = 12.0 Hz, 2H), 4.47 – 4.29 (m, 2H),
3.75 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 162.1, 160.1, 150.5, 137.5, 135.4, 135.0, 128.65, 128.60,
128.4, 128.0, 112.6, 112.4, 103.9, 67.1, 66.2, 55.9, 55.5. IR (film) νmax 1718, 1625, 1504, 1402, 1253,
1204, 1127, 1105, 1054, 955, 862, 793, 744, 700, 619, 579 cm–1. HRMS (ESI) calcd for
C19H17NO6SNa+ [M + Na]+ 410.0669, found 410.0672. HPLC analysis: 34% ee (Chiralcel ODꢀH: 15:85
isopropanol / hexane, 1 mL/min, 254 nm, tR1= 20.814 min, tR2 =25.570min).
3jf. White solid (35.5 mg, 82% yield). Mp: 125 – 127 °C. 1H NMR (300 MHz, CDCl3) δ 7.50 (d, J = 8.3
Hz, 1H), 7.38 (s, 5H), 7.24 – 7.16 (m,2H), 6.94 – 6.82 (m, 1H), 6.07 (s, 1H), 5.30 (AB q, ΔδAB = 0.11
ppm, JAB = 12.0 Hz, 2H ), 4.53 – 4.33 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 162.0, 150.2, 138.1,
134.85, 134.78, 129.1, 128.7, 128.4, 122.4, 122.3, 119.7, 67.4, 66.5, 56.0. IR (film) νmax 1718, 1402,
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1249, 1206, 1191, 1179, 1129, 1081, 899, 779, 768, 733, 699, 606, 556 cm–1. HRMS (ESI) calcd for
C18H14BrNO5SNa+ [M + Na]+ 457.9668, found 457.9667. HPLC analysis: 32% ee (Chiralcel ADꢀH:
15:85 isopropanol / hexane, 1 mL/min, 254 nm, tR1= 14.037 min, tR2 = 17.575 min).
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3gf. White solid (33.5 mg, 77% yield). Mp: 152 – 154 °C. 1H NMR (300 MHz, CDCl3) δ 7.46 – 7.34 (m,
6H), 7.03 – 6.97 (m, 1H), 6.93 – 6.90 (m, 1H), 6.12 – 6.06 (m, 1H), 5.31 (AB q, ΔδAB = 0.08 ppm,
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JAB = 12.0 Hz, 2H), 4.49 – 4.32 (m, 2H). C NMR (75 MHz, CDCl3) δ 162.0, 161.2, 157.9, 145.74,
145.70, 138.3, 134.8, 134.7, 128.8, 128.5, 122.3, 122.2, 120.8, 120.7, 116.7, 116.3, 114.4, 114.0, 67.5,
66.6, 66.5, 56.0. IR (film) νmax 1717, 1485, 1407, 1258, 1208, 1168, 1150, 1127, 1099, 1061, 913, 843,
801, 770, 749, 699, 661, 630, 601, 538 cm–1. HRMS (ESI) calcd for C18H14BrNO5SNa+ [M + Na]+
457.9668, found 457.9666. HPLC analysis: 56% ee (Chiralcel ADꢀH: 15:85 isopropanol / hexane, 1
mL/min, 254 nm, tR1= 17,143 min, tR2 = 25.250 min).
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3pf. White solid (25.6 mg, 64% yield). Mp: 112 – 114 °C. H NMR (300 MHz, CDCl3) δ 7.38 (s, 5H),
7.09 (s, 1H), 6.87 (s, 1H), 6.50 (s, 1H), 5.99 (d, J = 3.6 Hz, 1H), 5.94 (s, 2H), 5.28 (AB q, ΔδAB
=
0.08 ppm, JAB = 12.0 Hz, 2H), 4.46 – 4.28 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 162.1, 147.9, 145.6,
144.2, 137.9, 135.2, 134.9, 128.7, 128.6, 128.4, 113.0, 105.9, 102.0, 100.6, 67.3, 66.6, 56.0. IR (film)
νmax 1717, 1504, 1483, 1404, 1249, 1205, 1140, 1087, 1037, 861, 814, 748, 702, 620, 560 cm–1. HRMS
(ESI) calcd for C19H15NO7SNa+ [M + Na]+ 424.0461, found 424.0460. HPLC analysis: 31% ee
(Chiralcel ADꢀH: 15:85 isopropanol:hexane, 1 mL/min, 254 nm, tR1= 24.568 min, tR2 = 30.788 min).
General Procedure for the Scale-up Reaction.
Under an N2 atmosphere, to a stirred solution of cyclic imines 1a (10 mmol, 1.0 equiv) and catalyst
PPh3 (2 mmol, 0.2 equiv) in toluene (100 mL) was added ethyl 2, 3ꢀbutadienoate 1a (12 mmol, 1.2
equiv) via a syringe in one portion. Then the reaction solution was vigorously stirred at room
temperature and monitored by TLC. After the reaction was complete, the mixture was directly purified
by column chromatography on silica gel (10:1 petroleum ether / EtOAc) to furnish the corresponding
product 3a (2.9 g ) as a white solid (98% yield).
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General Procedure for the Synthesis of 4
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To a solution of 3aa (75 mg, 0.26 mmol) in THF (0.5 mL) at room temperature was added LiAlH4
(2.0 M in THF, 0.39 mL, 0.78 mmol) dropwise over 2 min. The mixture was heated at 60 °C for 2 h,
cooled naturally to room temperature, and then to 0 °C with an ice bath. The reaction was quenched
carefully with EtOAc (1 mL) followed by EtOH (1 mL) and H2O (1 mL). To the resulting white turbid
mixture was added Boc2O (170 mg, 0.78 mmol) in one portion and the mixture was stirred at room
temperature for 1 h. The reaction was diluted with EtOAc (20 mL) and acidified with 2 M HCl until the
aqueous layer became clear. The aqueous layer was separated and extracted with EtOAc (2 x 20 mL).
The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. Purification of
the residue by column chromatography (1:1 petroleum ether / EtOAc) gave 4 (15 mg, 21% yield) as a
semisolid. 1H NMR (300 MHz, CDCl3) δ 7.20 – 6.83 (m, 4H), 6.58 (br s, 1H), 4.27 (s, 2H), 3.73 (br s,
1H), 3.20 (d, J = 6.6 Hz, 2H), 2.34 (t, J = 6.6 Hz, 2H), 1.40 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 156.6,
153.3, 129.6, 128.6, 123.9, 120.2, 115.9, 79.8, 66.4, 39.1, 29.8, 28.4. IR (film) νmax 3450, 2956, 2919,
2851, 750 cm–1. HRMS (ESI) calcd for C16H21NO4Na+ [M + Na]+ 314.1363, found 314.1361.
General Procedure for the Synthesis of 5
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To a solution of 3aa (90 mg, 0.3 mmol) in THF (1 mL) was added a solution of Bu4NF in THF (1M,
0.9mL, 3 equiv). The mixture was then stirred at room temperature overnight. Methanol (2 mL) was
added, and the mixture was concentrated under reduced pressure. The residue was diluted with ethyl
acetate and washed with saturated NaHCO3, and the aqueous layer was extracted twice with ethyl
acetate. The combined organic phase was washed with brine, dried (Na2SO4), and concentrated. The
residue was purified by column chromatography on silica gel (4:1 petroleum ether / EtOAc) to afford 5
(21 mg, 30% yield) as a white solid. Mp: 159 – 161 °C. 1H NMR (300 MHz, CDCl3) δ 8.57 (br s, 1H),
8.38 (br s, 1H), 7.35 – 7.27 (m, 1H), 7.23 (dd, J = 1.4, 7.7 Hz, 1H), 7.13 – 7.07 (m, 1H), 6.97 (td, J = 1.4,
7.7 Hz, 1H), 6.82 – 6.77 (m, 1H), 6.74 – 6.70 (m, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H).
13C NMR (75 MHz, CDCl3) δ 168.2, 154.8, 133.9, 130.4, 130.0, 121.8, 121.2, 120.0, 118.7, 113.4,
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111.5, 61.0, 14.2. IR (film) νmax 3302, 2956, 2919, 2851, 1658, 1463, 741 cm–1. HRMS (ESI) calcd for
C13H13NO3Na+ [M + Na]+ 254.0788, found 254.0788.
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General Procedure for the Synthesis of 6
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tꢀBuOK (112 mg, 1.0 mmol) and 3aa (90 mg, 0.3 mmol) was dissolved in DMSO (10 mL). The
mixture was stirred at room temperature and monitored by TLC. After the starting material consumed,
the reaction was quenched by addition of water and the mixture was extracted with Et2O. The combined
organic extracts were evaporated and the residue was purified through silica gel (1:1 petroleum ether /
EtOAc with 0.5% Et3N) to give the desired product 6 (20 mg, 36% yield) as a white solid. Mp: >250 °C.
1H NMR (300 MHz, DMSOꢀd6) δ 12.63 (br s, 1H), 8.07 – 8.01 (m, 1H), 7.49 – 7.35 (m, 3H), 7.34 –
7.31 (m, 1H), 6.71 – 6.68 (m, 1H). 13C NMR (75 MHz, DMSOꢀd6) δ 158.7, 151.6, 135.5, 129.1, 124.5,
124.3, 121.7, 117.3, 114.3, 108.6, 107.3. IR (film) νmax 3418, 1651, 1049, 1026, 1002, 826, 765, 631
cm–1. HRMS (ESI) calcd for C11H7NO2Na+ [M + Na]+ 208.0369, found 208.0357.
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General Procedure for the Synthesis of 8
6 mL of 1N LiOH in H2O were added to the mixture of 3aa (90 mg, 0.3 mmol) in THF (6 mL) and
EtOH (6 mL). The mixture was stirred at room temperature for 1 h, acidified with 2N HCl at 0 °C, and
extracted with EtOAc. The combined organic extracts were dried (Na2SO4) and concentrated under
reduced pressure to give crude product 7, which was used in the following step without further
purification.
To a mixture of carboxylic acid 7, LꢀPhenylalanine (85 mg, 0.45 mmol) and HBTU (210 mg, 0.6
mmol) in CH2Cl2 (5 mL) was added freshly distilled DIPEA (0.2 mL, 1.2 mmol) . The resulting mixture
was stirred under N2 at room temperature for 24 h. The mixture was diluted with CH2Cl2 (5 mL),
washed with aqueous solution of HCl (1M, 3 × 5 mL,), NaHCO3 (5 mL) and dried over Na2SO4. After
filtering Na2SO4 off, the solution was concentrated to give the crude product, which was further purified
using flash chromatography (1:1 petroleum ether / EtOAc ) to give 8 as a white solid (95.6 mg, 74.5%
yield). Mp: 171 – 173 °C. 1H NMR (300 MHz, CDCl3) δ 7.37 – 7.06 (m, 1H), 7.02 – 6.95 (m, 1H), 6.67
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– 6.49 (m, 1H), 5.55 (d, J = 6.2 Hz, 1H), 4.11 – 3.98 (m, 1H), 3.96 – 3.87 (m, 1H), 3.79 (s, 1H), 3.22 –
3.17 (m, 1H), 3.15 – 3.07 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 171.7, 169.2, 149.4, 135.6, 129.3,
129.2, 129.0, 128.7, 127.2, 127.1, 126.2, 123.1, 118.8, 61.0, 58.51, 58.48, 53.0, 52.5, 37.8. IR (film)
νmax 1744, 1662, 1530, 1453, 1402, 1262, 1207, 1172, 1103, 1032, 824, 802, 761, 702, 561 cm–1. HRMS
(ESI) calcd for C21H20N2O6SNa+ [M + Na]+ 451.0934, found 451.0934.
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General Procedure for the Synthesis of 9
A mixture of the cyclic imine 3af (107 mg. 0.3 mmol) and Mg powder (10 equiv) in MeOH (5 mL)
and THF (5 mL) was stirred for 12 h at room temperature. Then, the saturated NH4Cl aqueous solution
was added to the reaction mixture. The resulting mixture was extracted with CH2Cl2, and the combined
organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was
purified by silica gel chromatography (1:1 petroleum ether / EtOAc ) to afford the product 9 as a white
solid (70 mg, 82% yield). Mp: 78 – 80 °C. 1H NMR (300 MHz, CDCl3) δ 7.35 – 7.18 (m, 1H), 7.01 (d, J
= 8.1 Hz, 1H), 5.50 (d, J = 3.6 Hz, 1H), 3.84 (s, 1H), 3.77 – 3.64 (m, 1H), 3.51 – 3.40 (m, 1H), 3.39 –
13
3.30 (m, 1H), 2.46 – 2.31 (m, 1H), 2.26 – 2.12 (m, 1H). C NMR (75 MHz, CDCl3) δ 171.9, 150.3,
129.4, 126.8, 126.0, 121.7, 118.9, 64.6, 52.8, 52.2, 49.6, 27.1. IR (film) νmax 1736, 1452, 1398, 1199,
1172, 1104, 878, 816, 761, 616, 554 cm–1. HRMS (ESI) calcd for C12H13NO5SNa+ [M + Na]+ 306.0407,
found 306.0405.
ASSOCIATED CONTENT
Supporting Information
1H and 13C NMR spectra of all compounds, HPLC data of 3af, 3kf, 3lf, 3qf, 3rf, 3hf, 3jf, 3cf, 3gf and
3pf, and crystallographic data (CIF) of 3kf. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
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*H.G.: hchguo@cau.edu.cn
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
This study was supported by the National Natural Science Foundation of China (No. 21172253), the
Program for New Century Excellent Talents in University (No. NCETꢀ11ꢀ0481), the National Scientific
and Technology Supporting Program of China (No. 2011BAE06B05ꢀ5), the National S&T Pillar
Program of China (2012BAK25B03), Chinese Universities Scientific Fund (No. 2013QJ002 and
2013RC023), and Nutrichem Company.
REFERENCES
(1) For selected representative reviews on phosphineꢀpromoted cycloaddition, see: (a) Lu, X.; Zhang,
C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. (b) Methot, J. L.; Roush, W. R. Adv. Synth. Catal.
2004, 346, 1035. (c) Lu, X.; Du, Y.; Lu, C. Pure Appl. Chem. 2005, 77, 1985. (d) Nair, V.;
Menon, R. S.; Sreekanth, A. R.; Abhilash, N.; Biju, A. T. Acc. Chem. Res. 2006, 39, 520. (e) Ye,
L.ꢀW.; Zhou, J.; Tang, Y. Chem. Soc. Rev. 2008, 37, 1140. (f) Denmark, S. E.; Beutner, G. L.
Angew. Chem., Int. Ed. 2008, 47, 1560. (g) Aroyan, C. E.; Dermenci, A.; Miller, S. J. Tetrahedron
2009, 65, 4069. (h) Cowen, B. J.; Miller, S. J. Chem. Soc. Rev. 2009, 38, 3102. (i) Marinetti, A.;
Voituriez, A. Synlett 2010, 174. (j) Kolesinska, B. Cent. Eur. J. Chem. 2010, 1147. (k) Wei, Y.;
Shi, M. Acc. Chem. Res. 2010, 43, 1005. (l) Wang, S.ꢀX.; Han, X. Y.; Zhong, F. R.; Wang, Y. Q.;
Lu, Y. X. Synlett 2011, 2766. (m) Zhao, Q.ꢀY.; Lian, Z.; Wei, Y.; Shi, M. Chem. Commun. 2012,
48, 1724. (n) Yu, S.; Ma, S. Angew. Chem., Int. Ed. 2012, 51, 3074.
(2) (a) Zhang, C. M.; Lu, X. Y. J. Org. Chem. 1995, 60, 2906. (b) Xu, Z. R.; Lu, X. Y. Tetrahedron.
Lett. 1997, 38, 3461. (c) Xu, Z. R.; Lu, X. Y. J. Org. Chem. 1998, 63, 5031.
(3) For example of [3+2] annulation, see: (a) Zhu, X. F.; Henry, C. E.; Kwon, O. Tetrahedron 2005,
26
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61, 6276. (b) Zhao, G. L.; Shi, M. J. Org. Chem. 2005, 70, 9975. (c) Jean, L.; Marinetti, A.
Tetrahedron. Lett. 2006, 47, 2141. (d) Scherer, A.; Gladysz, J. A. Tetrahedron. Lett. 2006, 47,
6335. (e) FleuryꢀBregeot, N.; Jean, L.; Retailleau, P.; Marinetti, A. Tetrahedron 2007, 63, 11920.
(f) Zhang, B.; He, Z.; Xu, S.; Wu, G.; He, Z. Tetrahedron 2008, 64, 9471. (g) Meng, L.ꢀG.; Cai,
P.; Guo, Q.; Xue, S. J. Org. Chem. 2008, 73, 8491. (h) Fang, Y.ꢀQ.; Jacobsen, E. N. J. Am. Chem.
Soc. 2008, 130, 5660. (i) Zheng, S.; Lu, X. Org. Lett. 2008, 10, 4481. (j) Pinto, N.; Fleuryꢀ
Bregeot, N.; Marinetti, A. Eur. J. Org. Chem. 2009, 146. (k) Guan, X.ꢀY.; Shi, M. J. Org. Chem.
2009, 74, 1977. (l) Schuler, M.; Duvvuru, D.; Retailleau, P.; Betzer, J.ꢀF.; Marinetti, A. Org. Lett.
2009, 11, 4406. (m) Xiao, H.; Chai, Z.; Zheng, C.ꢀW.; Yang, Y.ꢀQ.; Liu, W.; Zhang, J.ꢀK.; Zhao,
G. Angew. Chem, Int. Ed. 2010, 49, 4467. (n) Duvvuru, D.; Betzer, J.ꢀF.; Retailleau, P.; Frison,
G.; Marinetti, A. Adv. Synth. Catal. 2011, 353, 483. (o) Han, X. Y.; Zhong, F. R.; Wang, Y. Q.;
Lu, Y. X. Angew. Chem., Int. Ed. 2012, 51, 767.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
(4) For examples of [4+2] annulation, see: (a) Zhu, X. F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003,
125, 4716. (b) Zhao, G. L.; Shi, M. Org. Biomol. Chem. 2005, 3, 3686. (c) Wurz, R. P.; Fu, G. C.
J. Am. Chem. Soc. 2005, 127, 12234. (d) Lu, K.; Kwon, O. Org. Synth. 2009, 86, 212. (e) Xiao,
H.; Chai, Z.; Wang, H.ꢀF.; Wang, X.ꢀW.; Cao, D.ꢀD.; Liu, W.; Lu, Y.ꢀP.; Yang, Y.ꢀQ.; Zhao, G.
Chem. Eur. J. 2011, 17, 10562.
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(5) Tian, J.; Zhou, R.; Sun, H.; Song, H.; He, Z. J. Org. Chem. 2011, 76, 2374.
(6) Liu, H.; Zhang, Q.; Wang, L.; Tong, X. Chem. Commun. 2010, 46, 312.
(7) For an example of phosphineꢀcatalyzed other annulation, see: Ma, G.ꢀN.; Wang, F.ꢀJ.; Gao, J.;
Shi, M. Chem. Commun. 2008, 4998.
(8) (a) Castellano, S.; Fiji, H. D. G.; Kinderman, S. S.; Watanabe, M.; De Leon, P.; Tamanoi, F.;
Kwon, O. J. Am. Chem. Soc. 2007, 129, 5843. (b) Watanabe, M.; Fiji, H. D. G.; Guo, L.; Chan, L.;
Kinderman, S. S.; Slamon, D. J.; Kwon, O.; Tamanoi, F. J. Biol. Chem. 2008, 283, 9571. (c) Lu,
J.; Chan, L.; Fiji, H. D. G.; Dahl, R.; Kwon, O.; Tamanoi, F. Mol. Cancer Ther. 2009, 8, 1218. (d)
27
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Choi, J.; Mouillesseaux, K.; Wang, Z.; Fiji, H. D. G.; Kinderman, S. S.; Otto, G. W.; Geisler, R.;
Kwon, O.; Chen, J.ꢀN.Development 2011, 138, 1173. (e) Wang, Z.; Castellano, S.; Kinderman, S.
S.; Argueta, C. E.; Beshir, A. B.; Fenteany, G.; Kwon, O. Chem. Eur. J. 2011, 17, 649. (f) Cruz.
D.; Wang, Z.; Kibbie, J.; Modlin, R.; Kwon, O. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 6769.
(9) (a) Tran, Y. S.; Kwon, O. Org. Lett. 2005, 7, 4289. (b) Sampath, M.; Lee, P.ꢀY. B.; Loh, T.ꢀP.
Chem. Sci. 2011, 2, 1988. (c) Andrews, I. P.; Kwon, O. Chem. Sci. 2012, 3, 2510.
(10) (a) Chen, X.ꢀY.; Lin, R.ꢀC.; Ye, S. Chem. Commun. 2012, 48, 1317. (b) Chen, X.ꢀY.; Ye, S. Eur.
J. Org. Chem. 2012, 5723.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(11) For some reviews, see: (a) Winum, J.ꢀY.; Scozzafava, A.; Montero, J.ꢀL.; Supuran, C. T. Med.
Res. Rev. 2005, 25, 186. (b) Winum, J.ꢀY.; Scozzafava, A.; Montero, J.ꢀL.; Supuran, C. T. Expert
Opin. Ther. Patents 2006, 16, 27. (c) Woo, L. W. L.; Purohit, A.; Potter, B. V. L. Mol. Cell.
Endocrinol. 2011, 340, 175. (d) Williams, S. J. Expert Opin. Ther. Patents 2013, 23, 79.
(12) Kamal, A.; Sattur, P. B. Synthesis. 1981, 272.
(13) Tripathi, M.; Dhar, D. N. Indian. J. Chem. B. 1987, 26, 888.
(14) Litvinas, N. D.; Brodsky, B. H.; Du Bois, J. Angew. Chem., Int. Ed. 2009, 48, 4513.
(15) (a) Luo, Y.; Carnell, A. J.; Lam, H. W. Angew. Chem., Int. Ed. 2012, 51, 6762. (b) Luo,
Hepburn, H. B.; Chotsaeng, N.; Lam, H. W. Angew. Chem., Int. Ed. 2012, 51, 8309.
(16) Wang, H.; Jiang, T.; Xu, M.ꢀH. J. Am. Chem. Soc. 2013, 135, 971.
Y.;
(17) (a) Na, R.; Jing, C.; Xu, Q.; Jiang, H.; Wu, X.; Shi, J.; Zhong, J.; Wang, M.; Benitez, D.;
Tkatchouk, E.; Goddard, W. A., III; Guo, H.; Kwon, O. J. Am. Chem. Soc. 2011, 133, 13337. (b)
Jing, C.; Na, R.; Wang, B.; Liu, H.; Zhang, L.; Liu, J.; Wang, M.; Zhong, J.; Kwon, O.; Guo, H.
Adv. Synth. Catal. 2012, 354, 1023. (c) Liu, J.; Liu, H.; Na, R.; Wang, G.; Li, Z.; Yu, H.; Wang,
M.; Zhong, J.; Guo, H. Chem. Lett. 2012, 41, 218. For other cycloaddition reactions from our
group, see: (d) Na, R.; Liu, H.; Li, Z.; Wang, B.; Liu, J.; Wang, M.ꢀA.; Wang, M.; Zhong, J.; Guo,
H. Tetrahedron 2012, 68, 2349. (e) Wu, X.; Na, R.; Liu, H.; Liu, J.; Wang, M.; Zhong, J.; Guo, H.
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Tetrahedron Lett. 2012, 53, 342. (f) Zhang, L.; Jing, C.; Liu, H.; Wang, B.; Li, Z.; Jiang, H.; Yu,
H.; Guo, H. Synthesis 2013, 45, 53.
1
2
3
4
5
6
7
8
(18) a) Xia, Y. Z.; Liang, Y.; Chen, Y. Y.; Wang, M.; Jiao, L.; Huang, F.; Liu, S.; Li, Y. H.; Yu, Z. X.
J. Am. Chem. Soc. 2007, 129, 3470. b) Dudding, T.; Kwon, O.; Mercier, E. Org. Lett. 2006, 8,
3643. c) Mercier, E.; Fonovic, B.; Henry, C.; Kwon, O.; Dudding, T. Tetrahedron. Lett. 2007, 48,
3617. d) Liang, Y.; Liu, S.; Xia, Y. Z.; Li, Y. H.; Yu, Z. X. Chem. Eur. J. 2008, 14, 4361.
(19) Weinreb, S. M.; Demko, D. M.; Lessen, T. A.; Demers, J. P. Tetrahedron. Lett. 1986, 27, 2099.
(20) Xu, T.; Mu, X.; Peng, H.; Liu, G. Angew. Chem., Int. Ed. 2011, 50, 8176.
(21) Kwon, O.; Tamanoi, F.; Fiji, H.; Watanabe, M. PCT Int.Appl. WO 2010014054 A1 20100204,
2010.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(22) Nakamura, S.; Maeno, Y.; Ohara, M.; Yamamura, A.; Funahashi, Y.; Shibata, N. Org. Lett. 2012,
14, 2960.
(23) Phan, D. H. T.; Kim, B.; Dong, V. M. J. Am. Chem. Soc. 2009, 131, 15608.
(24) Wang, Y.ꢀQ.; Yu, C.ꢀB.; Wang, D.ꢀW.; Wang, X.ꢀB.; Zhou, Y.ꢀG. Org. Lett. 2008, 10, 2071.
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