Intramolecular Imino-ene Reaction of Azirines: Regioselectivity

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Intramolecular Imino-ene Reaction of Azirines: Regioselectivity, Diastereoselectivity and Computational Insights Mei-Hua Shen, Hong-Yu Qu, Ping Dai, Hao Zhou, TaiShang Liu, Xiaoguang Bao, Defeng Xu, and Hua-Dong Xu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00087 • Publication Date (Web): 27 Feb 2019 Downloaded from http://pubs.acs.org on March 5, 2019

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The Journal of Organic Chemistry

Intramolecular Imino-ene Reaction of Azirines: Regioselectivity, Diastereoselectivity and Computational Insights Mei-Hua Shen,*, Ɨ Hong-Yu Qu,Ɨ Ping Dai,ⱡ Hao Zhou,Ɨ Tai-Shang Liu,Ɨ Xiaoguang Bao,*, ⱡ Defeng Xu,Ɨ and Hua-Dong XuƗ ƗJiangsu

Key Laboratory of Advanced Catalytic Materials & Technology, School of Pharmaceutical Engineering & Life Science, Changzhou University, Changzhou 213164, P. R. China . ⱡCollege

of Chemistry, Chemical Engineering and Materials Science, Soochow University, 199 Ren-Ai Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China. Supporting Information Placeholder HN

H

RN Ph trans cis/ trans 1/0 1/0

NR R Bn Ar

N

H

Ph

Me R': Ph

R' N

RN

R': Me

N Z-exo

Ph

HN NR

Me trans R cis/ trans 1/0, >10/1 Bn, Ts 1/1-2/1 Ar 1.5/1, 1.8/1 Boc, Cbz HN

H RN

‡

Me

E-exo G‡ (kcal/mol) 2.8 f or R = Bn 1.9 f or R = Ph

H

RN NR

RN N

Z-endo G‡ (kcal/mol) 19.3 f or R = Bn 19.0 f or R = Ph

HN

Ph cis

‡

N Me E-endo

Me cis

NR

ABSTRACT: Intramolecular imino-ene reaction of 2H-aziridine has been studied experimentally and computationally, demonstrating that: 1) the concerted process takes place regioselectively on the alkene E-CH group; 2) the geometry of the N-linker impacts the reaction activation energy and diastereoselectivity significantly, with pyramidal alkyl amine as the linkage, exclusive cis-product is achieved; 3) when the reaction has to occur with the Z-CH group, the cisdiastereoselectivity is solely observed regardless the nature fo the N-linkage.

INTRODUCTION Imino-ene reaction provides an efficient means for coupling of easily attainable imines with simple alkenes bearing allyl hydrogen through a C-C bond formation, giving rise to synthetically important homoallylic amines.1 Remarkably, the product stereochemistry is usually precisely predictable because of the concerted pericyclic nature of ene reactions that proceed with highly ordered transition-states. Notwithstanding significant advances in catalytic asymmetric protocols2 as well as elegant applications in synthesis3 have been made, almost no significant breakthrough has been reported in the last 20 years in this field and this ene reaction is still very limited largely due to the large energies of activation that necessitates high temperatures. We envisioned that a strain-activated imine such as 2Hazirine4 should be a good enophile and could readily participate in concerted ene reaction with appropriate alkenes to give NH-aziridines, a class of useful but not easily accessible N-heterocycles.5 Along with this direction, we6 have recently developed a powerful intramolecular vinyl azide fragmentation/imino-ene cascade that provides an efficient strategy for the

synthesis of otherwise difficultly accessible spiro NH aziridines.7 Therein, the enophilic 2H-azirines were generated from the in situ decomposition of related vinyl azides which in turn, were conveniently obtained from corresponding terminal alkynes.4c, 8

RESULTS AND DISCUSSION In the course of our research, it was further found this intramolecular ene process is extremely sensitive to the seemingly innocent N-substituents with respect to the diastereoselectivity (cis/trans ratio). This intriguing phenomenon was prominently observed with prenyl vinyl azides 1 and summarized in Table 1. Thermal decomposition in hot toluene (100 oC) for 8 h converts vinyl azides 1 into corresponding transient intermediates azirines 2, which cyclize to spiro aziridines 3 promptly via an intramolecular imino-ene process. 2a, derived from alkyl amine 1a (R = Bn), holds a pyramidal conformation at the N-center and was transformed into spiro aziridine cis-3a solely in a single isomeric form (74% yield, Table 1 entry 1); under the same conditions, substrate 1b (R = Ts), with a flattened pyramidal NTs linker, reacted to give a ˃10/1 mixture of diastereomers favoring the cis-spiro aziridine cis-3b in a total 61% yield (Table 1 entry 2);

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Protection of the N connectivity with favorite Boc and Cbz groups furnished planar vinyl azides 1c and 1d, and unexpectedly, the fragmentation-ene relay gave rise to correspondent 1.5/1 and 1.8/1 cis/trans isomeric mixtures of aziridines 3c and 3d in 86% and 70% yields respectively (Table 1 entries 3 and 4). A dramatic drop of the diastereoselectivity to 1.5/1 cis/trans was also observed with planar N-Ph substrate 1e (Table 1 entry 5). These data collectively demonstrate that the stereoselectivety of this intramolecular ene reaction is extremely sensitive to the substrate geometry. At current stage, the exact reason accounting for the correlation of diastereoselectivity to the geometry of substrates keeps elusive, but might reflect a pronounced steric impact of N-substituents on the imino-ene transition states in terms of activation energy difference between cis- and trans- configurations. Table 1. N-substituent impact on the reactiona RN N3

solvent

RN

H N

heating 8h

1

N 2

H N

+ RN

RN

trans-3

cis-3

entry

1 (R)

Geometry at the N-tether

Yield (%)b

cis/trans ratio

1

1a (Bn)

pyramidal

74

cis only

2

1b (Ts)

flat pyramidal

61

> 10/1

3

1c (Boc)

planar

86

1.5/1c

4

1d (Cbz)

planar

70

1.8/1d

5

1e (Ph)

planar

75

1.5/1d

aReaction conditions: 1 (0.3 mmol), toluene (1 mL), 100 oC, 8 h. bIsolated yield. cWeight ratio. dNMR ratio.

Studies on the solvent effects shown that eventhough the reaction can happen in most solvents giving low diastereoselectivity, aprotic nonpolar solvents provided better outcomes; and toluene was chosen as the medium for future studies due to its satisfactory performance with respect to both yield and diastereoseletivity (see Table SI1). Next, a series of N-aryl N-prenyl vinyl azides 1f-n bearing substituents of divergent electronic properties on the phenyl ring were made and submitted to the reaction to investigate the electronic impact on this intramolecular imino-ene reaction. The results are tabulated in Table 2 and no significant relevance between the yield and electronic property of the N-phenyl group can be found; on the other hand, a distinct correlation of electronic property to the diastereoselectivity does appear there. Along with the decline in electron donating ability of para-substitution from the most electronic rich 1f to the most deficient 1m, the cis/trans ratio dropped gradually from 2.0/1 to 1/1 whereas the yields fell into a narrow range of 75-86% without any prominent trend (Table 2 entries 1-8). Additionally, 1n, with a 3-OMe phenyl group, gave rise to spiro aziridine 3n in 83% yield with a 1.5/1 cis/trans ratio (Entry 9). It seems that the more electron deficient of the substitution on the phenyl ring, the

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greater the electron density at N atom will donate to the phenyl ring and consequently results in a more planar conformation and decreased cis-selectivity, which is in line with the trend found in Table 1. Table 2. The electronic effect of N-Aryl groupa toluene

ArN N3

ArN

ArN

NH

100 oC cis-3f-n

1f-n

NH

+ trans-3f-n

Entry

1 (Ar)

product, yieldb

cis/transc

1

1f (4-OMe-Ph)

3f, 77%

2.0/1

2

1g (4-Me-Ph)

3g, 81%

1.8/1

3

1h (4-Br-Ph)

3h, 78%

1.5/1

4

1i (4-Cl-Ph)

3i, 85%

1.4/1

5

1j (4-F-Ph)

3j, 84%

1.6/1

6

1k (4-CO2Et-Ph)

3k, 81%

1.2/1

7

1l (4-CN-Ph)

3l, 86%

1.2/1

8

1m (4-NO2-Ph)

3m, 75%

1.0/1

9

1n (3-OMe-Ph)

3n, 83%

1.5/1

aReaction conditions: 1 (0.3 mmol), toluene (1 mL), 100 oC, sealed tube, 8 h. bIsolated yield. cDetermined by 1H NMR.

More substrates with different alkenyl moieties as ene donors were also examined and the results are listed in Table 3. N-benzyl-(E)-crotyl vinyl azide 4a with only a trans-CH3 underwent the vinyl azide fragmentation/intramolecular aza-ene relay smoothly to achieve spiro aziridine cis-5a (75% yield) exclusively; its N-phenyl counterpart 4b accomplished the ene product 5b as an approximate 1/2 cis/trans mixture in 61% yield. Similarly, the NBn/NPh pair 4c/4d derived from Zgeraniol exhibited an analogous manner to form single isomer N-benzylated cis-5c from the former and a 1/1 cis/trans isomeric mixture of N-phenylated 5d from the latter. Evidently, it was only the E-CH3 but not the Z–CH2 that participated in the pericyclic ene process to give terminal alkene group. Accordingly, a 0.8/1 cis/trans mixture of spiro aziridines 5e was obtained in 84% yield from the reaction of E-geraniol derived N-phenylated 4e, and again only the E-CH2 was involved in the ene reaction. The Bn/Ph pair of 4f/4g consisting of an exocyclic alkene were transformed to cis-5f and a 3.7/1 diastereomeric mixture of cis-/trans-5g respectively. With NTs substrate 4h, a 20/1 cis/trans selectivity and a moderate yield of 67% (entry 8) was obtained which was in line with previous observation for N-tosylated 1b (Table 1 entry 2). Interestingly, the reaction of N-benzylated 4i bearing a vinyl iodine group resulted in a messy mixture, while with its N-Ph congener 4j, on the contrary, a clean reaction was realized, affording spiro aziridine 5j in 74% yield as a 4/1 cis/trans mixture. This remarkable disparity between these two reactions can surely attribute to the presence of basicity vulnerable vinyl iodine, which might be destroyed by tertiary benzyl amine in high temperature but nicely tolerated the less basic tertiary aniline. With


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equal efficiency, N-benzyl 4k carrying only Z-CH3 was transformed to cis-spiro aziridine cis-5k with exclusive diastereoselectivity; interestingly, its N-phenyl congener 4l didn’t give, as expected, an isomeric mixture of spiro aziridines, but a single diastereomer cis-5l in 78% yield. For cyclohexene 4m, which also has only Z-CH2 available for the ene-process, tricyclic aziridine cis-5m was obtained in 81% yield as a single diatereoisomer. Table 3. The substrate scope of the vinyl azide fragmentation/intramolecular aza-ene cascadea Product,yieldb (cis/ trans)c

Entry, substrate

Product,yieldb (cis/ trans)c

Entry, substrate

4k-4m rendered us to draw the following conclusion: the current intramolecular imino-ene reaction of in situ generated azirine occurs exclusively at the E-CH group, and if there is no E-CH available, the reaction will alternately proceed at the Z-CH group. Table 4. The reaction of deuterated substratesa Product,yieldb (cis/ trans)c

Entry, substrate 1, f or 6a 2, f or 6b

CD3

D3C

CD2

CD3

RN

N3 R: Bn, 6a R: Ph, 6b

NH RN 7a, 70% (cis only) 7b, 77% (1.4/1)

Product,yieldb (cis/ trans)c

Entry, substrate CD3

4,

D3C

CH3

PhN N3

6d

NH PhN 7d, 80% (1.5/1)

7,

1,

H N

BnN N3 4a

BnN 5a, 75% (cis only)

2, N3 4b

N3

3, H N

4c

2

H

H N

PhN 4d

2

H

H N

Me

N3

PhN

2H

4e

6,

N3

4l

H N

N3 4f

BnN 5f, 83% (cis only)

Ph H N PhN 5l, 78% (cis only) H Ph N

12,

BnN

H N

Ph

PhN

PhN 5e, 84% (0.8/1)

Ph

BnN 5k, 79% (cis only)

4k Me

11, H N

N3

RN messy for 4i 5j, 78% (4/1)

Ph

BnN

PhN 5d, 79% (1/1)

5,

I

N3 4i: NBn 4j: NPh 10,

N3

TsN 5h, 67% (20/1)

RN

BnN 5c, 79% (cis only)

4,

4h

I

9,

BnN

H N

N3

PhN N3 4m

CD3

3,

NH H 5m, 81% (cis only)

aReaction

conditions: 4 (0.3 mmol), toluene (1 mL), 100 oC, sealed tube, 8 h. bIsolated yield. cDetermined by 1H NMR.

In order to collect more information about this reaction, deuterated vinyl azides 6a-e were prepared and submitted to the thermal conditions (Table 4). With both methyl groups deuterated, 6a and 6b were converted to corresponding deuterated aziridines 7a and 7b in virtually the same yields and diastereoselectivities when compared with their hydrogenated counterparts 1a and 1e, indicating that deuteration on the ene-donor imposes negligible impact on the reaction outcomes. With substrates 6c and 6d, their Z-CD3 was conserved completely in correlated products (7c and 7d) after the reaction. On the other hand, with 6e, the intramolecular imino-ene process took place only at the E-CD3 to produce 7e, leaving the Z-CH3 group untouched. These data together with those previously observed for 4c-e and

D3C

N3 6c

CH3

5,

CH3

BnN

PhN 5g, 89% (3.7/1)

TsN

PhN 5b, 61% (1/2)

N3

4g

8,

H N

PhN

H N

PhN

H3C

CD2

CD3

PhN NH BnN 7c, 72% (cis only)

N3 6e

NH PhN 7e, 76% (1.3/1)

aReaction

conditions: 6 (0.3 mmol), toluene (1 mL), 100 oC, sealed tube, 8 h. bIsolated yield. cDetermined by 1H NMR.

As shown in Figure 1, there are four plausible transition states for this concerted intramolecular ene reaction that define the product’s configuration. When the E-CH group involves in the concerted process, the methylene group in the azirine ring can point either inward (exo) or outward (endo) to develop transition state E-exo (I) or E-endo (II) and then to generate trans or cis spiro aziridine product accordingly (Figure 1 left). Similarly, if the ene reaction occurs at cis-CH group, there are also two transition-state candidates, namely Z-exo (III) and Z-endo (IV) corresponding to cis- and trans-product. The experimental results indicate that II (R=Bn, Ts) is arguably the only operating transition state for Nbenzylated and N-tosylated substrates, whereas their NPh relatives transformed into trans- and cis-products via I (R=Ph) and II (R=Ph) competivily. In cases that III and IV have to be the only possible transition states (right), the pathway via III wins out thoroughly in the route competition regardless the type of NR group (NPh vs NBn). RN

H N R'

E-exo (I)

H N R' E-endo (II)

trans

cis

RN

H R' Z-exo (III)

RN

N

cis

H

RN

N R' Z-endo (IV)

trans

Figure 1. Plausible transition states for the imino-ene reactions

Computational studies1c, 9 were carried out to understand the regio- and diastereoselectivity of the imino-ene reactions.10 For the N-benzyl intermediate 2a, there are four optimized transition states shown as TS1TS2 in Figure 2a and TS3-TS4 in Figure 2b, which relate to the hypothesized transition states I, II, III and IV (R, R’: Bn, Me). Transition states TS1 and TS2, developed from the E-CH3 (Ca), are lower in energy than those (TS3 and



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were examined and shown as TS5 and TS6 in Figure SI1. The predicted energy barriers of analogous ene process that give the cis- and trans-products are 24.4 and 26.3 kcal/mol, respectively. Although the formation of the cisproduct is still more favorable than the trans one, the energy difference between TS5 and TS6 reduces to only 1.9 kcal/mol, much smaller than that between TS1 and TS2, which is consistent with the reduced cis/trans ratio observed for 3e.

TS4) from Z-CH3 (Cb). Moreover, the predicted activation energy for TS2 is 25.7 kcal/mol, ca. 3 kcal/mol lower than that for its exo-counterpart TS1, leading to the exclusive observation of cis-3a. Structural examination on TS1 indicates that the approaching of the methylene group of the azirine ring toward the Z-CH3 (Cb) might result in considerable steric hindrance and consequently energy enhancement in this transition state, whereas such steric effect is absent in TS2. For the N-aryl intermediate 2e, transition states of type I and II (R = Ph) involving the E-CH3 as hydrogen donor a

b

49.5 G(kcal/mol)

28.5

C2

C2

TS1

N1 C1

25.7 TS2

1.6 6

C

1.92 Cb

1.20

Ca

Cb 1.6 7

1.21 Ca

BnN N NH

-19.9 cis-3a

1.22

Ca

1.5 5

Cb

Ca

1.22

TS3

Cb Ca

BnN NH

Cb

TS4 0.0 2a

BnN -19.6 trans-3a

1.93

1.82

TS3

Cb Ca

BnN

1.5 7

30.6

C3

TS2

TS1 0.0 2a

N1

C1 3

1.80

TS4

G(kcal/mol)

BnN

N NH

-19.9 cis-3a

BnN -19.6 trans-3a

NH

Figure 2. Energy profiles for the intramolecular imino-ene reactions of 2a

The ene processes for the formation of 5k and 5l from vinyl azides 4k and 4l were also examined through computational calculations. In each case, only a Z-CH3 is available for the pericyclic reaction, and the exo (III)/endo (IV) transition-state pairs for 4k and 4l are shown as TS7/TS8 and TS9/TS10 respectively (see Figure SI2). The energy divergence within the two exo/endo couples are both as huge as ca. 19 kcal/mol which render the formation of trans ene-products impossible for both N-benzylated 4k and N-arylated 4l. The significantly higher energy barrier for the formation of trans-product is due to the substantial steric hindrance between the methylene group of the azirine ring and the Z-methyl group in both endo transition states (the distance of H1…H2 is only 1.94 Å in TS8 and 1.93 Å in TS10). Overall, the theoretic calculation results fully match our experimental outcomes and provide insightful understanding for the intramolecular imino-ene reaction of azirine.

CONCLUSION In conclusion, the intramolecular imino-ene reaction of 2H-aziridine has been investigated with emphasis on the regio- and diastereochemistry experimentally and computationally. It is found that the temperature impact little on the reaction with respect of both yield and stereoseletivity, whereas the topological structure of the N-linker correlate closely to the diastereoselectivity, namely the more flat the linker is , the lower cis/trans product ratio is obtained. It is also established that the ECH is exclusively preferred than its cis congener via

experiments and theoretic calculations, and when the ene reaction proceeds on the Z-CH group, only the cisdiastereomer could be observed.

EXPERIMENTAL SECTION General Information. All reactions were carried out under nitrogen or argon with anhydrous solvents in ovendried glassware, unless otherwise noted. All reagents were commercially obtained and, where appropriate, purified prior to use. Analytical thin layer chromatography (TLC) was performed on 0.25 mm extra hard silica gel plates with UV254 fluorescent indicator and/or by exposure to phosphormolybdic acid/cerium (IV) sulfate/ninhydrine followed by brief heating with a heat gun. Liquid chromatography (flash chromatography) was performed on 60Å (40 – 60 µm) mesh silica gel (SiO2). NMR spectra were recorded using Bruker AV-300 / AV-400 / AV500 spectrometers. The data are reported as follows: chemical shift in ppm from internal tetramethylsilane on the δ scale, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, dd = doublet of doublets, dt = doublet of triplets, td = triplet of doublets), coupling constants (Hz) and integration. High resolution mass spectra were acquired on an agilent 6230 TOF spectrometer (ESI) and were obtained by peak matching. Vinyl azides 1, 4 and 6 were preparation according to the reported procedures. 8 Typical procedure for the vinyl azide fragmentation/intramolecular aza-ene cascade (with


Page 5 of 12 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 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


3a as an example): A stirred soultion of 1a (100 mg , 0.39 mmol) in dry toluene (1 mL) under N2 was heated to 100 oC (oil bath) for 8 h. After cooling to room temperature, volatiles were removed in vacuum and the residue was purified by column chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1) to give cis-3a (66 mg, 74% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.35 – 7.25 (m, 4H), 7.26 – 7.19 (m, 1H), 4.86 – 4.74 (m, 1H), 4.62 (d, J = 2.1 Hz, 1H), 3.61 (q, J = 12.8 Hz, 2H), 3.02 – 2.88 (m, 2H), 2.72 (d, J = 9.6 Hz, 1H), 2.66 – 2.55 (m, 2H), 1.76 (s, 3H), 1.74 (s, 1H), 1.64 (s, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 143.0, 138.7, 128.8, 128.3, 127.1, 114.6, 61.5, 60.7, 58.5, 50.0, 41.6, 31.3, 20.5. HRMS (ESI) m/z Calculated for C15H21N2+ [M + H]+ 229.1699, found 229.1703. 6 7-(Prop-1-en-2-yl)-5-tosyl-1,5-diazaspiro[2.4]heptane (3b). According to the typical procedure, 1b (100 mg, 0.31 mmol) was converted into cis-3b and trans-3b. Purification via flash chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1) afford the inseparable mixture of two isomers. The area of one alkenyl-H peak in cis isomer was compared with that in trans isomer to derive a 1H NMR ratio of cis/trans > 10 : 1. cis-3b (56 mg, 61% yield): yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H), 4.86 (s, 1H), 4.63 (s, 1H), 3.59 (dd, J = 10.0, 7.8 Hz, 1H), 3.37 (d, J = 10.4 Hz, 1H), 3.26 (dd, J = 10.0, 7.2 Hz, 1H), 3.19 (d, J = 10.3 Hz, 1H), 2.84 (t, J = 7.6 Hz, 1H), 2.43 (s, 4H), 1.70 (s, 1H), 1.65 (s, 1H), 1.63 (s, 3H), 0.85 (br, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 143.8, 140.7, 132.7, 129.7, 127.8, 115.7, 54.0, 51.6, 49.0, 41.5, 30.3, 21.6, 20.9. HRMS (ESI) m/z Calculated for C15H21N2O2S+ [M + H]+ 293.1318, found 293.1327. 6 tert-Butyl 7-(prop-1-en-2-yl)-1,5-diazaspiro[2.4]heptane5-carboxylate (3c). According to the typical procedure, 1c (100 mg, 0.38 mmol) was converted into cis-3c and trans3c. Isolation by flash chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1) gave the ratio cis/trans = 1.5/1. cis-3c (47 mg, 52% yield): yellow oil. 1H NMR(400 MHz, CDCl3) δ 4.83 (s, 1H), 4.71 (s, 1H), 3.77 – 3.47 (m, 3H), 3.29 (d, J = 11.6 Hz, 1H), 2.61 (t, J = 6.6 Hz, 1H), 1.88 – 1.68 (m, 5H), 1.44 (s, 9H). 13C{1H} NMR (75 MHz,CDCl3) δ 154.3, 142.2, 113.4, 79.5, 52.5, 50.6, 49.3, 42.6, 28.5, 25.8, 20.7. HRMS (ESI) m/z Calculated for C13H23N2O2+ [M + H]+ 239.1754, found 239.1759. trans-3c (31 mg, 34% yield): yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.94 (s, 1H), 4.74 (s, 1H), 3.75 – 3.69 (m, 1H), 3.57 – 3.37 (m, 3H), 2.90 – 2.70 (m, 1H), 1.83 – 1.76 (m, 5H), 1.45 (s, 9H), 0.42 (br, 1H). 13C{1H} NMR (75 MHz, CDCl ) δ 154.3, 141.7, 114.6, 79.5, 52.3, 3 49.7, 48.4, 41.7, 30.1, 28.5, 21.7. HRMS (ESI) m/z Calculated for C13H23N2O2+ [M + H]+ 239.1754, found 239.1758. 6 Benzyl 7-(prop-1-en-2-yl)-1,5-diazaspiro[2.4]heptane-5carboxylate (3d). According to the typical procedure, 1d (100 mg, 0.33 mmol) was converted into cis-3d and trans3d. 1H NMR of the reaction solution was taken and the area of one alkenyl-H peak in cis isomer was compared with that in trans isomer to derive a 1H NMR ratio of cis/trans = 1.8/1. cis-3d (63 mg, 70 % yield): yellow oil. Purified by flash chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1). 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.28 (m, 5H), 5.13 (s, 2H), 4.94 (d, J = 5.2 Hz, 1H), 4.74 (d, J =

6.7 Hz, 1H), 3.80 (dd, J = 11.3, 8.0 Hz, 1H), 3.63 – 3.53 (m, 2H), 3.47 (d, J = 11.3 Hz, 1H), 2.84 (t, J = 7.5 Hz, 1H), 1.80 – 1.75 (m, 5H),0.45 (br, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 154.7, 141.2, 136.7, 128.5, 127.9, 114.9, 66.9, 52.4, 49.7, 49.1, 48.3, 42.7, 29.9, 21.7. HRMS (ESI) m/z Calculated for C16H21N2O2+ [M + H]+ 273.1598, found 273.1593. trans-3d can not be obtained in pure form. 6 5-Phenyl-7-(prop-1-en-2-yl)-1,5-diazaspiro[2.4]heptane (3e). According to the typical procedure, 1e (100 mg, 0.41 mmol) was converted into cis-3e and trans-3e. 1H NMR of the reaction solution was taken and the area of one alkenyl-H peak in cis isomer was compared with that in trans isomer to derive a 1H NMR ratio of cis/trans = 1.5/1. cis-3e (40 mg, 45 % yield): yellow oil. Purified by flash chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1). 1H NMR (400 MHz, CDCl ) δ 7.25 (t, J = 7.8 Hz, 2H), 6.72 3 (t, J = 7.3 Hz, 1H), 6.58 (d, J = 8.0 Hz, 2H), 4.91 (s, 1H), 4.77 (s, 1H), 3.69 (t, J = 8.7 Hz, 1H), 3.53 – 3.37 (m, 3H), 2.97 (t, J = 6.6 Hz, 1H), 1.87 (s, 2H), 1.78 (s, 3H), 0.49(br, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 147.7, 143.2, 129.2, 116.5, 114.4, 112.0, 54.9, 52.0, 49.8, 42.0, 31.8, 20.9. HRMS (ESI) m/z Calculated for C14H19N2+ [M + H]+ 215.1543, found 215.1543. trans-3e (27 mg, 30 % yield): yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.29 – 7.20 (m, 2H), 6.72 (t, J = 7.3 Hz, 1H), 6.57 (d, J = 8.1 Hz, 2H), 4.83 (s, 1H), 4.75 (s, 1H), 3.74 (dd, J = 9.5, 7.9 Hz, 1H), 3.56 (d, J = 10.0 Hz, 1H), 3.44 (dd, J = 9.5, 5.6 Hz, 1H), 3.32 (d, J = 9.8 Hz, 1H), 2.90  2.80 (m, 1H), 1.89 (s, 1H), 1.86 (s, 1H),1.76 (s, 3H), 0.71(br, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 147.7, 143.0, 129.2, 116.5, 113.5, 112.0, 55.3, 51.6, 51.2, 42.9, 29.0, 20.4. HRMS (ESI) m/z Calculated for C14H19N2+ [M + H]+ 215.1543, found 215.1543. 5-(4-Methoxyphenyl)-7-(prop-1-en-2-yl)-1,5-diazaspiro [2.4]heptane (3f). According to the typical procedure, 1f (100 mg, 0.41 mmol) was converted into cis-3f and trans3f. 1H NMR of the reaction solution was taken and the area of one alkenyl-H peak in cis isomer was compared with that in trans isomer to derive a 1H NMR ratio of cis/trans = 2.0/1. cis-3f (51 mg, 59 % yield): yellow oil. Purified by flash chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1). 1H NMR (300 MHz, CDCl3) δ 6.86 (d, J = 9.0 Hz, 2H), 6.55 (d, J = 9.0 Hz, 2H), 4.90 (s, 1H), 4.76 (s, 1H), 3.76 (s, 3H), 3.63 (dd, J = 9.3, 7.9 Hz, 1H), 3.43 – 3.31 (m, 3H), 3.04  2.94 (m, 1H), 1.85 (br, 2H), 1.79 (s, 3H), 0.47 (br, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 151.6, 143.3, 142.8, 115.0, 114.5, 113.2, 55.9, 55.8, 52.8, 50.0, 42.0, 31.9, 20.7. HRMS (ESI) m/z Calculated for C15H21N2O+ [M + H]+ 245.1648, found 245.1652. trans-3f (25 mg, 28 % yield): yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.86 (d, J = 9.0 Hz, 2H), 6.55 (d, J = 9.0 Hz, 2H), 4.84 - 4.78 (m, 1H), 4.75 (s, 1H), 3.76 (s, 3H), 3.69 (dd, J = 9.2, 8.0 Hz, 1H), 3.48 (d, J = 9.4 Hz, 1H), 3.36 (dd, J = 9.3, 5.9 Hz, 1H), 3.29 (d, J = 9.6 Hz, 1H), 2.92 – 2.83 (m, 1H), 1.80 (s, 1H), 1.78 (s, 1H), 1.76 (s, 3H), 0.58 (br, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 151.6, 143.1, 142.8, 115.0, 113.5, 113.2, 56.3, 55.9, 52.5, 51.4, 43.0, 29.2, 20.2. HRMS (ESI) m/z Calculated for C15H21N2O+ [M + H]+ 245.1648, found 245.1652. 7-(Prop-1-en-2-yl)-5-p-tolyl-1,5-diazaspiro[2.4]heptane (3g). According to the typical procedure, 1g (125 mg, 0.49 mmol) was converted into cis-3g and trans-3g. 1H NMR



of the reaction solution was taken and the area of one alkenyl-H peak in cis isomer was compared with that in trans isomer to derive a 1H NMR ratio of cis/trans = 1.8/1. cis-3g (58 mg, 52 % yield): yellow oil. Purified by flash chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1). 1H NMR (400 MHz, CDCl ) δ 7.05 (d, J = 8.2 Hz, 2H), 6.51 3 (d, J = 8.4 Hz, 2H), 4.90 (s, 1H), 4.75 (s, 1H), 3.66 (dd, J = 9.5, 7.8 Hz, 1H), 3.43 (dd, J = 9.5, 5.3 Hz, 1H), 3.39 (d, J = 3.2 Hz, 2H), 2.96 (dd, J = 7.8, 5.3 Hz, 1H), 2.25 (s, 3H), 1.87 (s, 1H), 1.86 (s, 1H), 1.78 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 145.7, 143.3, 129.7, 125.7, 114.4, 112.2, 55.2, 52.3, 49.9, 41.9, 31.9, 20.7, 20.3. HRMS (ESI) m/z Calculated for C15H21N2+ [M + H]+ 229.1699, found 229.1703. trans-3g (32 mg, 29 % yield): yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.05 (d, J = 8.3 Hz, 2H), 6.50 (d, J = 8.5 Hz, 2H), 4.81 (s, 1H), 4.74 (s, 1H), 3.70 (dd, J = 9.4, 7.8 Hz, 1H), 3.61 – 3.46 (m, 1H), 3.39 (dd, J = 9.4, 5.7 Hz, 1H), 3.33  3.24 (m, 1H), 2.84 (t, J = 6.7 Hz, 1H), 2.25 (s, 3H), 1.85 (br, 2H), 1.75 (s, 3H), 0.86 (br, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 145.8, 143.2, 129.7, 125.7, 113.4, 112.2, 55.8, 52.1, 51.4, 43.0, 29.1, 20.3, 20.2. HRMS (ESI) m/z Calculated for C15H21N2+ [M + H]+ 229.1699, found 229.1702. 5-(4-Bromophenyl)-7-(prop-1-en-2-yl)-1,5-diazaspiro [2.4]heptane (3h). According to the typical procedure, 1h (100 mg, 0.31 mmol) was converted into cis-3h and trans3h. 1H NMR of the reaction solution was taken and the area of one alkenyl-H peak in cis isomer was compared with that in trans isomer to derive a 1H NMR ratio of cis/trans = 1.5/1. cis-3h (43 mg, 47 % yield): yellow oil. Purified by flash chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1). 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 9.0 Hz, 2H), 6.41 (d, J = 9.0 Hz, 2H), 4.98 – 4.85 (m, 1H), 4.82 – 4.70 (m, 1H), 3.63 (dd, J = 9.7, 7.8 Hz, 1H), 3.42 (dd, J = 9.7, 5.5 Hz, 1H), 3.36 (s, 2H), 3.04 – 2.88 (m, 1H), 1.86 (br, 2H), 1.76 (s, 3H), 0.50 (br, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 146.5, 142.7, 131.8, 113.5, 108.4, 100.0, 54.9, 52.1, 49.7, 42.0, 31.5, 21.0. HRMS (ESI) m/z Calculated for C14H18BrN2+ [M + H]+ 293.0648, found 293.0643. trans-3h (28 mg, 31 % yield): yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.9 Hz, 2H), 6.41 (d, J = 8.9 Hz, 2H), 4.86  4.79 (m, 1H), 4.74 (s, 1H), 3.68 (dd, J = 9.5, 7.8 Hz, 1H), 3.58 – 3.43 (m, 1H), 3.39 (dd, J = 9.6, 5.5 Hz, 1H), 3.25 (d, J = 9.9 Hz, 1H), 2.82 (t, J = 6.6 Hz, 1H), 1.86 (br, 2H), 1.74 (s, 3H). 13C NMR{1H} (75 MHz, CDCl3) δ 146.5, 142.7, 131.8, 113.7, 113.5, 108.4, 55.2, 51.7, 51.1, 42.9, 28.9, 20.4. HRMS (ESI) m/z Calculated for C14H18BrN2+ [M + H]+ 293.0648, found 293.0645. 6 5-(4-Chlorophenyl)-7-(prop-1-en-2-yl)-1,5-diazaspiro[2.4] heptane (3i). According to the typical procedure, 1i (145 mg, 0.52 mmol) was converted into cis-3i and trans-3i. 1H NMR of the reaction solution was taken and the area of one alkenyl-H peak in cis isomer was compared with that in trans isomer to derive a 1H NMR ratio of cis/trans = 1.4/1. cis-3i (65 mg, 50 % yield): yellow oil. Purified by flash chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1). 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 8.8 Hz, 2H), 6.46 (d, J = 8.8 Hz, 2H), 4.83 (s, 1H), 4.74 (s, 1H), 3.69 (dd, J = 9.5, 7.8 Hz, 1H), 3.51 (d, J = 8.7 Hz, 1H), 3.39 (dd, J = 9.5, 5.6 Hz, 1H), 3.26 (d, J = 9.9 Hz, 1H), 2.89  2.71 (m,

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1H), 1.87 (br, 2H), 1.74 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 146.2, 142.7, 129.0, 121.4, 113.6, 113.0, 55.4, 51.8, 51.2, 42.9, 28.9, 20.4. HRMS (ESI) m/z Calculated for C14H18ClN2+ [M + H]+ 249.1153, found 249.1153. trans-3i (46 mg, 35 % yield): yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 8.9 Hz, 2H), 6.46 (d, J = 8.9 Hz, 2H), 4.92 (s, 1H), 4.76 (s, 1H), 3.65 (dd, J = 9.6, 7.8 Hz, 1H), 3.43 (dd, J = 9.6, 5.5 Hz, 1H), 3.38 (s, 2H), 3.05  2.88 (m, 1H), 1.87 (s, 2H), 1.77 (s, 3H), 0.50 (br, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 146.1, 142.7, 129.0, 121.3, 114.6, 113.0, 54.9, 52.1, 49.7, 41.9, 31.6, 21.0. HRMS (ESI) m/z Calculated for C14H18ClN2+ [M + H]+ 249.1153, found 249.1153. 5-(4-Fluorophenyl)-7-(prop-1-en-2-yl)-1,5-diazaspiro[2.4] heptane (3j). According to the typical procedure, 1j (130 mg, 0.50 mmol) was converted into cis-3j and trans-3j. 1H NMR of the reaction solution was taken and the area of one alkenyl-H peak in cis isomer was compared with that in trans isomer to derive a 1H NMR ratio of cis/trans = 1.6/1. cis-3j (60 mg, 52 % yield): yellow oil. Purified by flash chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1). 1H NMR (400 MHz, CDCl3) δ 7.0  6.85 (m, 2H), 6.56  6.40 (m, 2H), 4.91 (s, 1H), 4.76 (s, 1H), 3.63 (dd, J = 9.4, 7.9 Hz, 1H), 3.41 (dd, J = 9.5, 5.5 Hz, 1H), 3.36 (s, 2H), 2.98 (t, J = 6.7 Hz, 1H), 1.86 (s, 2H), 1.77 (s, 3H), 0.48(br, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 155.4 (d, 1JCF = 233.3 Hz), 144.4 (d, 4JCF = 1.5 Hz), 142.9, 115.6 (d, 2JCF = 21.8 Hz), 114.6, 112.6 (d, 3JCF = 7.5 Hz), 55.4, 52.6, 49.8, 42.0, 31.7, 20.8. HRMS (ESI) m/z Calculated for C14H18FN2+ [M + H]+ 233.1449, found 233.1452. trans-3j (38 mg, 32 % yield): yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.00 – 6.89 (m, 2H), 6.55  6.43 (m, 2H), 4.83 (s, 1H), 4.74 (s, 1H), 3.69 (t, J = 8.6 Hz, 1H), 3.57  3.41 (m, 1H), 3.44  3.33 (m, 1H), 3.32  3.18 (m, 1H), 2.94  2.78 (m, 1H), 1.86 (s, 2H), 1.75 (s, 3H). 13C{1H} NMR (75 MHz, CDCl ) δ 155.4 (d, 1J 3 CF = 233.3 Hz), 144.4 (d, 4JCF = 0.8 Hz), 115.6 (d, 2JCF = 21.8 Hz), 113.6, 112.6 (d, 3JCF = 6.8 Hz), 55.9, 52.2, 51.3, 42.9, 29.1, 20.3. HRMS (ESI) m/z Calculated for C14H18FN2+ [M + H]+ 233.1449, found 233.1452. Ethyl 4-(7-(prop-1-en-2-yl)-1,5-diazaspiro[2.4]heptan-5yl)benzoate (3k). According to the typical procedure, 1k (120 mg, 0.38 mmol) was converted into cis-3k and trans3k. 1H NMR of the reaction solution was taken and the area of one alkenyl-H peak in cis isomer was compared with that in trans isomer to derive a 1H NMR ratio of cis/trans = 1.2/1. cis-3k (48 mg, 44 % yield): yellow oil. Purified by flash chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1). 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.8 Hz, 2H), 6.52 (d, J = 8.9 Hz, 2H), 4.97 (s, 1H), 4.81 (s, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.77 (dd, J = 10.0, 7.9 Hz, 1H), 3.56 (dd, J = 10.0, 5.7 Hz, 1H), 3.49 (s, 2H), 3.01 (br, 1H), 1.90 (br, 2H), 1.80 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H), 0.54 (br, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 167.0, 150.4, 142.2, 131.3, 117.7, 114.8, 110.8, 60.2, 54.4, 51.7, 49.3, 41.9, 31.2, 21.3, 14.5. HRMS (ESI) m/z Calculated for C17H23N2O2+ [M + H]+ 287.1754, found 287.1754. trans-3k (40 mg, 37 % yield): yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.5 Hz, 2H), 6.53 (d, J = 8.5 Hz, 2H),4.88 (s, 1H), 4.78 (s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.83 (dd, J = 9.9, 7.8 Hz, 1H), 3.75  3.60 (m, 1H), 3.56 (dd, J = 9.9, 5.4 Hz, 1H), 3.47  3.30 (m, 1H),


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2.86 (br, 1H), 1.93 (s, 2H), 1.78 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 166.0, 149.3, 141.3, 130.3, 116.7, 112.7, 109.7, 59.2, 53.7, 50.3, 49.8, 41.7, 27.7, 19.5, 13.5. HRMS (ESI) m/z Calculated for C17H23N2O2+ [M + H]+ 287.1754, found 287.1758. 4-(7-(Prop-1-en-2-yl)-1,5-diazaspiro[2.4]heptan-5yl)benzonitrile (3l). According to the typical procedure, 1l (100 mg, 0.37 mmol) was converted into cis-3l and trans3l. 1H NMR of the reaction solution was taken and the area of one alkenyl-H peak in cis isomer was compared with that in trans isomer to derive a 1H NMR ratio of cis/trans = 1.2/1. cis-3l (42 mg, 47 % yield): yellow oil. Purified by flash chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1). 1H NMR (300 MHz, CDCl3) δ 7.40 (d, J = 8.9 Hz, 2H), 6.44 (d, J = 8.9 Hz, 2H), 4.92(s, 1H), 4.74 (s, 1H), 3.67 (dd, J = 10.1, 7.9 Hz, 1H), 3.46 (dd, J = 10.0, 5.8 Hz, 1H), 3.40 (s, 2H), 2.95 (t, J = 6.3 Hz, 1H), 1.85 (s, 1H), 1.82 (s, 1H), 1.71 (s, 3H), 0.50 (br, 1H). 13C{1H} NMR (75 MHz,CDCl3) δ 149.6, 141.8, 133.5, 120.7, 115.0, 111.6, 97.8, 54.3, 51.6, 49.1, 41.8, 31.0, 21.4. HRMS (ESI) m/z Calculated for C15H18N3+ [M + H]+ 240.1495, found 240.1499. trans-3l (35 mg, 39 % yield): yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J =8.6 Hz, 2H), 6.49 (d, J = 8.6 Hz, 2H), 4.86 (s, 1H), 4.75 (s, 1H), 3.79 – 3.75 (m, 1H), 3.67  3.55 (m, 1H), 3.50 (dd, J = 10.0, 5.4 Hz, 1H), 3.37 – 3.20 (m, 1H), 2.82 (t, J = 6.6 Hz, 1H), 1.91 (s, 2H), 1.75 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 149.6, 133.6, 120.7, 113.9, 111.6, 97.8, 54.5, 51.2, 50.7, 42.7, 28.7, 20.6. HRMS (ESI) m/z Calculated for C15H18N3+ [M + H]+ 240.1495, found 240.1499. 6 5-(4-Nitrophenyl)-7-(prop-1-en-2-yl)-1,5-diazaspiro[2.4] heptane (3m). According to the typical procedure, 1m (105 mg, 0.37 mmol) was converted into cis-3m and trans-3m. 1H NMR of the reaction solution was taken and the area of one alkenyl-H peak in cis isomer was compared with that in trans isomer to derive a 1H NMR ratio of cis/trans = 1.0/1. cis-3m (36 mg, 38 % yield): yellow solid. Purified by flash chromatography (silica gel; PE : EtOAc : Et3N = 50 : 50 : 1). 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 9.3 Hz, 2H), 6.47 (d, J = 9.2Hz, 2H), 5.00 (s, 1H), 4.82 (s, 1H), 3.80 (dd, J = 10.3, 8.0 Hz, 1H), 3.65 – 3.44 (m, 3H), 3.05 (br, 1H), 1.92 (br, 2H), 1.78 (s, 3H), 0.56 (br, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 151.4, 141.4, 126.3, 115.2, 110.5, 110.3, 54.6, 51.9, 48.9, 41.9, 30.6, 21.6. HRMS (ESI) m/z Calculated for C14H18N3O2+ [M + H]+ 260.1394, found 260.1399. trans-3m (35 mg, 37 % yield): yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 9.3 Hz, 2H), 6.48 (d, J = 9.3 Hz, 2H), 4.89 (s, 1H), 4.77 (s, 1H), 3.85 (dd, J = 10.3, 7.8 Hz, 1H), 3.73  3.63 (m, 1H), 3.58 (dd, J = 10.3, 5.4 Hz, 1H), 3.47  3.35 (m, 1H), 3.34  3.24 (m, 1H), 2.84 (s, 1H), 1.94 (br, 2H), 1.76 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 151.4, 141.9, 137.3, 126.3, 114.0, 110.5, 54.7, 51.5, 50.6, 42.7, 28.6, 20.7. HRMS (ESI) m/z Calculated for C14H18N3O2+ [M + H]+ 260.1394, found 260.1400. 5-(3-Methoxyphenyl)-1-methyl-7-(prop-1-en-2-yl)-1,5diazaspiro[2.4]heptane (3n). According to the typical procedure, 1n (130 mg, 0.48 mmol) was converted into cis-3n and trans-3n. 1H NMR of the reaction solution was taken and the area of one alkenyl-H peak in cis isomer was compared with that in trans isomer to derive a 1H

NMR ratio of cis/trans = 1.5/1. cis-3n (58 mg, 50 % yield): yellow oil. Purified by flash chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1). 1H NMR (300 MHz, CDCl3) δ 7.16 (t, J = 8.1 Hz, 1H), 6.36  4.26 (m, 1H), 6.24  61.6 (m, 1H), 6.12 (t, J = 2.4 Hz, 1H), 4.92 (t, J = 1.6 Hz, 1H), 4.77 (s, 1H), 3.80 (s, 3H), 3.68 (dd, J = 9.7, 7.8 Hz, 1H), 3.47 (dd, J = 9.7, 5.2 Hz, 1H), 3.43  3.40 (m, 2H), 2.96 (dd, J = 7.8, 5.2 Hz, 1H), 1.88 (s, 2H), 1.78 (s, 3H), 0.49 (br, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 160.7, 148.9, 143.1, 129.9, 114.4, 105.1, 101.5, 98.3, 55.1, 54.9, 52.0, 49.7, 41.9, 31.8, 20.9. HRMS (ESI) m/z Calculated for C15H21N2O+ [M + H]+ 245.1648, found 245.1652. trans-3n (35 mg, 39 % yield): yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.14 (t, J = 8.1 Hz, 1H), 6.29 (dd, J = 8.1, 2.3 Hz, 1H), 6.19 (dd, J = 8.2, 2.2 Hz, 1H), 6.13  6.04 (m, 1H), 4.82 (s, 1H), 4.74 (s, 1H), 3.79 (s, 3H), 3.72 (dd, J = 9.5, 7.9 Hz, 1H), 3.63  3.47 (m, 1H), 3.43 (dd, J = 9.5, 5.6 Hz, 1H), 3.35  3.23 (m, 1H), 2.83 (t, J = 6.9 Hz, 1H), 1.85 (br, 2H), 1.74 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 160.7, 148.9, 142.8, 129.9, 113.5, 105.1, 101.5, 98.3, 55.3, 55.1, 51.6, 51.1, 42.8, 29.0, 20.4. HRMS (ESI) m/z Calculated for C15H21N2O+ [M + H]+ 245.1648, found 245.1651. cis-5-Benzyl-7-vinyl-1,5-diazaspiro[2.4]heptane (cis-5a). According to the typical procedure, 4a (100 mg, 0.41 mmol) was converted into 5a (cis only, 66 mg, 75% yield). Yellow oil. Purified by flash chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1). 1H NMR (400 MHz, CDCl3) δ 7.33 – 7.23 (m, 5H), 5.68 – 5.59 (m, 1H), 5.07 (dd, J = 10.2, 1.8 Hz, 1H), 4.96 (dd, J = 17.1, 1.7 Hz, 1H), 3.62 (s, 2H), 3.06 (dd, J = 9.1, 7.2 Hz, 1H), 2.97  2.86 (m, 1H), 2.83 (d, J = 9.8 Hz, 1H), 2.54 (d, J = 9.7 Hz, 1H), 2.45 (t, J = 8.6 Hz, 1H), 1.76 (s, 1H), 1.65 (s, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 137.4, 134.6, 127.9, 127.3, 126.1, 117.2, 60.0, 59.6, 59.3, 46.0, 41.1, 28.7. HRMS (ESI) m/z Calculated for C14H19N2+[M + H]+ 215.1543, found 215.1545. 6 Phenyl-7-vinyl-1,5-diazaspiro[2.4]heptane (5b). According to the typical procedure, 4b (116 mg, 0.51 mmol) was converted into cis-5b and trans-5b. 1H NMR of the reaction solution was taken and the area of one alkenyl-H peak in cis isomer was compared with that in trans isomer to derive a 1H NMR ratio of cis/trans = 1/2. cis-5b (21 mg, 21 % yield): yellow oil. Purified by flash chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1). 1H NMR (400 MHz, CDCl ) δ 7.30 – 7.18 (m, 2H), 6.70 (t, J 3 = 7.3 Hz, 1H), 6.55 (d, J = 8.1 Hz, 2H), 5.80  5.58 (m, 1H), 5.27 – 5.11 (m, 2H), 3.70 (t, J = 8.4 Hz, 1H), 3.66  3.55 (m, 1H), 3.37 (t, J = 8.5 Hz, 1H), 3.30  3.18 (m, 1H), 3.14  2.98 (m, 1H), 1.89 (s, 1H), 1.81 (s, 1H), 0.50 (br, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.6, 133.8, 129.2, 119.4, 116.3, 111.7, 55.0, 52.7, 46.0, 42.8, 26.8. HRMS (ESI) m/z Calculated for C13H17N2+ [M + H]+ 201.1386, found 201.1387. trans-5b (41 mg, 40 % yield): yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.28  7.20 (m, 2H), 6.71 (t, J = 7.3 Hz, 1H), 6.55 (d, J = 8.1 Hz, 2H), 5.73  5.57 (m, 1H), 5.15 (s, 1H), 5.11 (d, J = 7.6 Hz, 1H), 3.74 (dd, J = 9.2, 7.5 Hz, 1H), 3.47 (d, J = 9.3 Hz, 1H), 3.42 – 3.28 (m, 2H), 3.00  2.86 (m, 1H), 1.93 (s, 1H), 1.73 (s, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.5, 134.6, 129.2, 118.5, 116.3, 111.6, 54.3, 52.8, 47.2, 43.3, 28.6. HRMS (ESI)



m/z Calculated for C13H17N2+ [M + H]+ 201.1386, found 201.1387. cis-5-Benzyl-7-(6-methylhepta-1,5-dien-2-yl)-1,5diazaspiro[2.4]heptane (cis-5c). According to the typical procedure, 4c (100 mg, 0.31 mmol) was converted into 5c (cis only, 72 mg, 79% yield). Yellow oil. Purified by flash chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1). 1H NMR (400 MHz, CDCl ) δ 7.40 – 7.24 (m, 5H), 5.15 – 3 5.11 (m, 1H), 4.93 (s, J = 1.7 Hz, 1H), 4.80 (s, 1H), 3.67 – 3.60 (m, 2H), 3.08 – 3.01 (m, 2H), 2.84 – 2.80 (m, 1H), 2.63 – 2.58 (m, 2H), 2.15 – 2.10 (m, 2H), 2.08 – 2.00 (m, 2H), 1.80 – 1.75 (m, 1H), 1.71 – 1.69 (m, 4H), 1.67 (s, 1H) 1.63 (s, 3H), 0.40 (br, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 138.6, 132.1, 128.88, 128.85, 128.3, 127.1, 123.8, 110.2, 61.7, 60.7, 59.6, 49.6, 41.9, 34.4, 31.5, 26.5, 25.7, 17.8. HRMS (ESI) m/z Calculated for C20H29N2+ [M + H]+ 297.2325, found 297.2332. 6 7-(6-Methylhepta-1,5-dien-2-yl)-5-phenyl-1,5-diazaspiro [2.4]heptane (5d). According to the typical procedure, 4d (100 mg, 0.32 mmol) was converted into cis-5d and trans5d. 1H NMR of the reaction solution was taken and the area of one alkenyl-H peak in cis isomer was compared with that in trans isomer to derive a 1H NMR ratio of cis/trans = 1.0/1. cis-5d (35 mg, 38 % yield): yellow oil. Purified by flash chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1). 1H NMR (400 MHz, CDCl3) δ 7.33-7.21 (m, 3H), 6.74 (t, J = 7.3Hz, 1H), 6.59 (d, J = 8.0 Hz,2H), 5.11 (t, J = 6.9 Hz, 1H), 5.05 (s, 1H), 4.93 (s, 1H), 3.71 (dd, J = 9.4, 7.8 Hz, 1H), 3.53  3.37 (m, 3H), 3.09 (br, 1H), 2.23  2.00 (m, 4H), 1.82  1.74 (br, 2H), 1.93  1.83 (br, 2H), 1.72  1.69 (br,3H), 1.64  1.61 (br,3H), 0.56 (br, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.6, 132.2, 129.2, 123.5, 116.5, 116.4, 112.1, 111.9, 55.1, 52.7, 48.7, 42.1, 35.1, 30.3, 26.4, 25.7, 17.8. HRMS (ESI) m/z Calculated for C19H27N2+ [M + H]+ 283.2169, found 283.2170. trans-5d (37 mg, 40 % yield): yellow oil. 1H NMR (400 MHz, CDCl ) δ 7.38 – 7.19 (m, 2H), 6.75 (t, J 3 = 7.3 Hz, 1H), 6.59 (d, J = 8.1 Hz, 2H), 5.18 – 5.05 (m, 1H), 4.92 (s, 1H), 4.88 (s, 1H), 3.76 (dd, J = 9.4, 7.7 Hz, 1H), 3.60 (d, J = 9.8 Hz, 1H), 3.48 (dd, J = 9.4, 5.7 Hz, 1H), 3.33 (d, J = 9.9 Hz, 1H), 2.94  2.78 (m, 1H), 2.25-2.01 (m, 4H), 1.92 (s, 1H), 1.89 (s, 1H), 1.71 (br, 3H), 1.64 (br, 3H), 0.84 (br, 1H). 13C{1H} NMR (75 MHz, CDCl ) δ 147.6, 146.9, 132.1, 129.2, 3 123.6, 116.4, 111.9, 110.2, 55.3, 52.0, 50.6, 43.2, 34.0, 29.1, 26.5, 25.7, 17.8. HRMS (ESI) m/z Calculated for C19H27N2+ [M + H]+ 283.2169, found 283.2173. 7-(6-Methylhepta-2,5-dien-2-yl)-5-phenyl-1,5-diazaspiro [2.4]heptane (5e). According to the typical procedure, 4e (100 mg, 0.32 mmol) was converted into cis-5e and trans5e. (No further identification of the E or Z double bond was made). 1H NMR of the reaction solution was taken and the area of one alkenyl-H peak in cis isomer was compared with that in trans isomer to derive a 1H NMR ratio of cis/trans = 0.8/1. cis-5e (34 mg, 37 % yield): yellow oil. Purified by flash chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1). 1H NMR (300 MHz, CDCl3) δ 7.20 – 7.14 (m, 2H), 6.70  6.60 (m, 1H), 6.56 – 6.47 (m, 2H), 5.15  5.07 (m, 1H), 5.05  4.96 (m, 1H), 3.59 (dd, J = 9.7, 8.2 Hz, 1H), 3.42 – 3.33 (m, 3H), 2.86 (dd, J = 8.1, 5.4 Hz, 1H), 2.65 (t, J = 7.3 Hz, 2H), 1.77 (br, 2H), 1.65  1.53 (m,

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10H), 0.35 (br, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.7, 132.3, 129.19, 129.17, 122.4, 116.5, 112.1, 111.9, 55.12, 55.05, 52.0, 51.4, 42.0, 27.0, 25.7, 17.8, 14.3. HRMS (ESI) m/z Calculated for C19H27N2+ [M + H]+ 283.2169, found 283.2169. trans-5e (43 mg, 47 % yield): yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.28 – 7.23 (m, 2H), 6.71 (t, J = 7.2 Hz, 1H), 6.57 (d, J = 8.0 Hz, 2H), 5.19 (t, J = 7.2 Hz, 1H), 5.06 (t, J = 7.2 Hz, 1H), 3.69 (t, J = 8.9 Hz, 1H), 3.51-3.33 (m, 3H), 2.86 (t, J = 7.5 Hz, 1H), 2.69 (t, J = 7.2 Hz, 2H), 1.82 (s, 1H), 1.77 (s, 1H), 1.69 (s, 3H), 1.65 (s, 3H), 1.62 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 147.8, 132.1, 131.6, 129.2, 127.9, 122.4, 116.5, 112.1, 55.4, 52.5, 51.6, 42.8, 29.9, 27.0, 25.7, 17.8, 14.0. HRMS (ESI) m/z Calculated for C19H27N2+ [M + H]+ 283.2169, found 283.2170. cis-5-Benzyl-7-cyclohexenyl-1,5-diazaspiro[2.4]heptane (cis-5f). According to the typical procedure, 4f (100 mg, 0.34 mmol) was converted into 5f (cis only, 75 mg, 83% yield). Yellow oil. Purified by flash chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1). 1H NMR (400 MHz, CDCl3) δ 7.33 – 7.22 (m, 5H), 5.36 (s, 1H), 3.59 (s, 2H), 2.90 – 2.88 (m, 2H), 2.72 (d, J = 9.6 Hz, 1H), 2.57 – 2.52 (m, 2H), 1.98 – 1.95 (m, 4H), 1.70 – 1.68 (m, 2H), 1.66 – 1.57 (m, 2H), 1.56 – 1.45 (m, 2H), 0.22 (br, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 138.7, 134.8, 128.9, 128.3, 127.0, 126.5, 61.6, 60.8, 58.0, 50.4, 41.7, 31.4, 26.6, 25.3, 22.8, 22.4. HRMS (ESI) m/z Calculated for C18H25N2+ [M + H]+ 269.2012, found 269.2016. 6 7-Cyclohexenyl-5-phenyl-1,5-diazaspiro[2.4]heptane (5g). According to the typical procedure, 4g (50 mg, 0.18 mmol) was converted into cis-5g and trans-5g. 1H NMR of the reaction solution was taken and the area of one alkenyl-H peak in cis isomer was compared with that in trans isomer to derive a 1H NMR ratio of cis/trans = 3.7/1. cis-5g (32 mg, 71 % yield): yellow oil. Purified by flash chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1). 1H NMR (300 MHz, CDCl ) δ 7.32 – 7.15 (m, 2H), 6.77 – 3 6.65 (m, 1H), 6.63 – 6.48 (m, 2H), 5.56 – 5.41 (m, 1H), 3.65 (dd, J = 9.6, 8.0 Hz, 1H), 3.44 (dd, J = 9.6, 5.6 Hz, 1H), 3.39 (s, 2H), 2.87 (t, J = 6.9 Hz, 1H), 2.09 – 1.94 (m, 4H), 1.83 (s, 2H), 1.67 – 1.50 (m, 4H), 0.44 (br, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.7, 135.3, 129.2, 126.0, 116.4, 112.0, 55.0, 51.9, 50.1, 42.1, 31.7, 26.8, 25.3, 22.7, 22.3. HRMS (ESI) m/z Calculated for C17H23N2+ [M + H]+ 255.1856, found 255.1856. trans-5g (9 mg, 20 % yield): yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.29 – 7.22 (m, 2H), 6.78 – 6.64 (m, 1H), 6.63 – 6.48 (m, 2H), 5.48 (s, 1H), 3.78 – 3.63 (m, 1H), 3.51 – 3.31 (m, 3H), 2.80 (t, J = 7.3 Hz, 1H), 2.10  1.90 (m, 4H), 1.80 (s, 1H), 1.73 – 1.45 (m, 5H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.8, 134.7, 129.2, 125.1, 116.4, 111.9, 68.0, 55.3, 51.2, 42.9, 29.4, 26.3, 25.2, 22.7, 22.4. HRMS (ESI) m/z Calculated for C17H23N2+ [M + H]+ 255.1856, found 255.1856. 7-Cyclopentenyl-5-tosyl-1,5-diazaspiro[2.4]heptane (5h). According to the typical procedure, 4h (100 mg, 0.29 mmol) was converted into cis-5h and trans-5h. 1H NMR of the reaction solution was taken and the area of one alkenyl-H peak in cis isomer was compared with that in trans isomer to derive a 1H NMR ratio of cis/trans > 20/1. cis-5h (62 mg, 67% yield): yellow oil. Purified by flash chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1).


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1H

NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 5.39 (s, 1H), 3.62 – 3.58 (m, 1H), 3.37 (d, J = 10.4 Hz, 1H), 3.25  3.11 (m, 2H), 3.07  2.95 (m, 1H), 2.41 (s, 3H), 2.27  2.18 (m, 2H), 2.12  2.05 (m, 2H), 1.80 – 1.71 (m, 2H), 1.68 – 1.57 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 143.7, 138.8, 133.1, 130.0, 129.7, 127.7, 53.9, 51.9, 43.6, 41.9, 34.0, 32.2, 29.5, 23.1, 21.6. HRMS (ESI) m/z Calculated for C17H23N2O2S+ [M + H]+ 319.1475, found 319.1477. 6 7-(1-Iodovinyl)-5-phenyl-1,5-diazaspiro[2.4]heptane (5j). According to the typical procedure, 4j (145 mg, 0.41 mmol) was converted into cis-5j and trans-5j. 1H NMR of the reaction solution was taken and the area of one alkenyl-H peak in cis isomer was compared with that in trans isomer to derive a 1H NMR ratio of cis/trans = 4/1. cis-5j (84 mg, 63 % yield): yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.33 – 7.18 (m, 2H), 6.74 (t, J = 7.3 Hz, 1H), 6.66 – 6.51 (m, 2H), 6.27 (s, 1H), 5.97 (s, 1H), 3.73 (dd, J = 9.8, 7.5 Hz, 1H), 3.64 – 3.51 (m, 2H), 3.46 – 3.25 (m, 1H), 3.12 (br, 1H), 1.99 (br, 1H), 1.85 (brs, 1H), 0.88 (br, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.3, 129.2, 116.8, 112.1, 111.6, 54.5, 54.4, 54.2, 42.3, 31.9. HRMS (ESI) m/z Calculated for C13H16IN2+ [M + H]+ 327.0353, found 327.0356. trans-5j (21 mg, 15 % yield): yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.32  7.24 (m, 2H), 6.78 (t, J = 7.3 Hz, 1H), 6.62 (d, J = 8.0 Hz, 2H), 6.22 (s, 1H), 5.88 (d, J = 1.6 Hz, 1H), 3.81 (dd, J = 9.8, 7.8 Hz, 1H), 3.74 (d, J = 10.0 Hz, 1H), 3.53 (dd, J = 9.8, 5.0 Hz, 1H), 3.30 (d, J = 9.9 Hz, 1H), 2.94 (dd, J = 7.7, 5.0 Hz, 1H), 2.20 (s, 1H), 2.07 (s, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.4, 129.3, 128.0, 117.0, 112.3, 55.7, 55.4, 54.6, 43.4, 28.9. HRMS (ESI) m/z Calculated for C13H16IN2+ [M + H]+ 327.0353, found 327.0355. cis-5-Benzyl-7-(1-phenylvinyl)-1,5-diazaspiro[2.4]heptane (cis-5k). According to the typical procedure, 4k (100 mg, 0.31 mmol) was converted into 5k (cis only, 72 mg, 79% yield). Yellow oil. Purified by flash chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1). 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.26 (m, 10H), 5.47 (s, 1H), 5.20 (s, 1H), 3.69 – 3.64 (m, 3H), 3.16 (dd, J = 9.2, 7.4 Hz, 1H), 2.95 (d, J = 9.7 Hz, 1H), 2.74 (d, J = 9.8 Hz, 1H), 2.69 (t, J = 9.0 Hz, 1H), 1.77 (s, 1H), 1.66 (s, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 146.2, 141.0, 138.6, 128.8, 128.4, 128.3, 127.8, 127.1, 126.7, 116.7, 61.7, 60.7, 60.4, 47.2, 42.8, 31.2. HRMS (ESI) m/z Calculated for C20H23N2 +[M + H]+ 291.1856, found 291.1856. 6

cis-5-Phenyl-7-(1-phenylvinyl)-1,5-diazaspiro[2.4]heptane (cis-5l). According to the typical procedure, 4l (100 mg, 0.33 mmol) was converted into 5l (cis only, 71 mg, 78% yield). yellow oil. Purified by flash chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1). 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.32 (m, 5H), 7.28 – 7.25 (m, 2H), 6.74 (t, J = 7.3 Hz, 1H), 6.59 (d, J = 8.2 Hz, 2H), 5.58 (s, 1H), 5.30 (s, 1H), 3.83 (t, J = 8.2 Hz, 1H), 3.73 (br, 1H), 3.62  3.54 (m, 2H), 3.45 (d, J = 9.7 Hz, 1H), 1.78 (s, 1H), 1.71 (s, 1H), 0.63 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 147.7, 145.2, 141.3, 129.3, 128.7, 128.0, 126.5, 116.4, 116.1, 111.8, 55.1, 53.2, 46.3, 42.8, 29.1. HRMS (ESI) m/z Calculated for C19H21N2+ [M + H]+ 277.1699, found 277.1701. 6

cis-1'-Phenyl-1',2',3a',6',7',7a'-hexahydrospiro[aziridine2,3'-indole] (cis-5m). According to the typical procedure, 4m (100 mg, 0.39 mmol) was converted into 5m (cis only, 72 mg, 81% yield). Yellow oil. Purified by flash chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1). 1H NMR (400 MHz, CDCl ) δ 7.26 – 7.22 (m, 2H), 6.67 (t, J 3 = 7.4 Hz, 1H), 6.58 (d, J = 8.1 Hz, 2H), 6.11 – 6.06 (m, 1H), 5.34 – 5.30 (m, 1H), 4.01 – 3.86 (m, 1H), 3.66 (d, J = 9.9 Hz, 1H), 3.16 (d, J = 9.9 Hz, 1H), 3.10 (br, 1H), 2.26 – 2.25 (m, 1H), 2.23 – 2.13 (m, 2H), 1.89 (s, 1H), 1.83 (s, 1H), 1.54 – 1.46 (m, 1H), 0.66 (br, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 146.6, 134.5, 129.4, 120.3, 115.5, 111.1, 57.4, 54.4, 42.1, 40.8, 24.20, 24.18, 23.0. HRMS (ESI) m/z Calculated for C15H19N2+ [M + H]+ 227.1543, found 227.1544. 6 Deuterated product cis-7a. According to the typical procedure, 6a (27 mg, 0.1 mmol) was converted into 7a (cis only, 17 mg, 70 % yield). Yellow oil. Purified by flash chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1). 1H NMR (400 MHz, CDCl ) δ 7.40 – 7.20 (m, 5H), 3.61 (q, J 3 = 12.8 Hz, 2H), 3.04 – 2.84 (m, 2H), 2.73 (d, J = 9.6 Hz, 1H), 2.67 – 2.51 (m, 2H), 1.74 (s, 1H), 1.64 (s, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 142.7, 138.7, 128.8, 128.3, 127.1, 61.5, 60.7, 58.4, 49.9, 41.6, 31.3. Deuterated product 7b. According to the typical procedure, 6b (60 mg, 0.24 mmol) was converted into cis7b and trans-7b. 1H NMR of the reaction solution was taken and the area of one alkenyl-H peak in cis isomer was compared with that in trans isomer to derive a 1H NMR ratio of cis/trans = 1.4/1. cis-7b (24 mg, 45 % yield): yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.25 (t, J = 7.7 Hz, 2H), 6.72 (t, J = 7.3 Hz, 1H), 6.58 (d, J = 8.0 Hz, 2H), 3.69 (dd, J = 9.6, 7.8 Hz, 1H), 3.52 – 3.34 (m, 3H), 3.04 – 2.90 (m, 1H), 1.87 (s, 2H), 0.49 (br, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.6, 142.8, 129.2, 116.5, 112.0, 54.8, 52.0, 49.7, 41.9, 31.8. trans-7b (17 mg, 32 % yield): yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 7.7 Hz, 2H), 6.72 (t, J = 7.3 Hz, 1H), 6.57 (d, J = 8.0 Hz, 2H), 3.73 (dd, J = 9.5, 7.8 Hz, 1H), 3.55 (br, 1H), 3.44 (dd, J = 9.5, 5.7 Hz, 1H), 3.32 (br, 1H), 2.84 (t, J = 6.9 Hz, 1H), 1.86 (s, 2H), 0.32 (br, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.6, 142.8, 129.2, 116.5, 112.0, 55.3, 51.6, 51.0, 42.9, 29.0. Deuterated product cis-7c. According to the typical procedure, 6c (70 mg, 0.24 mmol) was converted into 7c (cis only, 45 mg, 72 % yield). Yellow oil. Purified by flash chromatography (silica gel; PE : EtOAc : Et3N = 75 : 25 : 1). 1H NMR (400 MHz, CDCl ) δ 7.38 – 7.27 (m, 5H), 4.80 (d, J 3 = 2.3 Hz, 1H), 4.63 (d, J = 2.2 Hz, 1H), 3.61 (q, J = 12.8 Hz, 2H), 3.06 – 2.87 (m, 2H), 2.73 (d, J = 9.6 Hz, 1H), 2.69 – 2.51 (m, 2H), 2.21 (d, J = 3.2 Hz, 1H), 1.75 (s, 1H), 1.65 (s, 1H). 13C{1H} NMR (75 MHz, CDCl ) δ 143.0, 138.7, 128.8, 128.3, 3 127.1, 114.6, 61.5, 60.7, 58.4, 50.0, 41.6, 31.3. Deuterated product 7d. According to the typical procedure, 6d (90 mg, 0.37 mmol) was converted into cis7d and trans-7d. 1H NMR of the reaction solution was taken and the area of one alkenyl-H peak in cis isomer was compared with that in trans isomer to derive a 1H NMR ratio of cis/trans = 1.5/1. cis-7d (39 mg, 49 % yield): yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.31 – 7.17 (m, 2H),



6.79 – 6.65 (m, 1H), 6.64 – 6.51 (m, 2H), 4.91 (d, J = 1.9 Hz, 1H), 4.77 (d, J = 1.9 Hz, 1H), 3.69 (dd, J = 9.6, 7.8 Hz, 1H), 3.47 (dd, J = 9.7, 5.2 Hz, 1H), 3.43 (s, 2H), 2.97 (dd, J = 7.8, 5.3 Hz, 1H), 1.88 (s, 2H), 0.51 (br, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.6, 143.0, 129.2, 116.5, 114.4, 112.0, 54.8, 52.0, 49.7, 41.9, 31.8. HRMS (ESI) m/z Calculated for C14H16D3N2+ [M + H]+ 218.1731, found 218.1732. trans-7d (25 mg, 31 % yield): yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.32 – 7.18 (m, 2H), 6.79 – 6.67 (m, 1H), 6.63 – 6.51 (m, 2H), 4.83 (d, J = 1.9 Hz, 1H), 4.75 (d, J = 1.5 Hz, 1H), 3.74 (dd, J = 9.5, 7.9 Hz, 1H), 3.55 (d, J = 9.9 Hz, 1H), 3.44 (dd, J = 9.5, 5.7 Hz, 1H), 3.32 (d, J = 9.8 Hz, 1H), 2.85 (dd, J = 7.8, 5.7 Hz, 1H), 1.89 (s, 1H), 1.86 (s, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.6, 130.4, 129.2, 116.5, 113.5, 112.0, 55.3, 51.6, 51.1, 42.9, 29.0. HRMS (ESI) m/z Calculated for C14H16D3N2+ [M + H]+ 218.1731, found 218.1729. Deuterated product 7e. According to the typical procedure, 6e (80 mg, 0.33 mmol) was converted into cis7e and trans-7e. 1H NMR of the reaction solution was taken and the area of one alkenyl-H peak in cis isomer was compared with that in trans isomer to derive a 1H NMR ratio of cis/trans = 1.5/1. cis-7e (32 mg, 45 % yield): yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.33 – 7.09 (m, 2H), 6.78 – 6.66 (m, 1H), 6.62 – 6.49 (m, 2H), 3.69 (dd, J = 9.6, 7.8 Hz, 1H), 3.53 – 3.36 (m, 3H), 2.97 (dd, J = 7.8, 5.3 Hz, 1H), 1.88 (s, 2H), 1.78 (s, 2H), 0.50 (br, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.6, 142.9, 129.2, 116.5, 112.0, 54.8, 52.0, 49.7, 41.9, 31.8, 20.8. trans-7e (22 mg, 31 % yield): yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.30 – 7.19 (m, 2H), 6.78 – 6.66 (m, 1H), 6.65  6.53 (m, 2H), 3.74 (dd, J = 9.5, 7.9 Hz, 1H), 3.56 (d, J = 10.0 Hz, 1H), 3.45 (dd, J = 9.5, 5.7 Hz, 1H), 3.32 (d, J = 9.9 Hz, 1H), 2.86 (dd, J = 7.8, 5.6 Hz, 1H), 1.90 (s, 1H), 1.87 (s, 1H),1.76 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.6, 143.9, 129.2, 116.5, 112.0, 55.3, 51.6, 51.0, 42.9, 29.0, 20.3. Computational methods. All the computations were carried out using ωB97XD density functional method11, which contains long-range exchange and empirical dispersion corrections. The 6-31G(d) basis set12 was used for all atoms in the geometry optimizations. Vibrational frequency was calculated to characterize stationary points as local minima or transition states which have been checked by intrinsic reaction coordinate (IRC)13. To consider the solvation effect in toluene, the single-point energy computations were performed using the SMD model14 at the optimized gas-phase geometries. On the basis of the optimized geometries, the ωB97XD functional with larger basis set 6-311++G(d,p) were utilized for single-point energy calculations on stationary points. The Gibbs energy of solvation was determined by adding the solvation single-point energy and the gas-phase thermal correction to the Gibbs energy obtained from the vibrational frequencies. All calculations were performed with the Gaussian 09 suite of programs15. The 3D structures of the studied species were shown using the CYLView software. 16

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ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: . Preparation and characterization of vinyl azides 1, 4 and 6 , studies of solvent effects, computational studies and NMR spectra of compounds (PDF)

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. *E-mail: [email protected].

Author Contributions The manuscript was written through contributions of all authors. / All authors have given approval to the final version of the manuscript. / ‡These authors contributed equally. (match statement to author names with a symbol)

Notes

Any additional relevant notes should be placed here.

ACKNOWLEDGMENT We thank the National Natural Science Foundation of China (NSFC 21672027 and 21642004), QingLan Project of Jiangsu Province (2016), and Six-Talent-Peaks Program of Jiangsu (2016) for financial support. This work was also supported by High-Level Entrepreneurial Talent Team of Jiangsu Province (2017-37).

REFERENCES (1) (a) Borzilleri, R. M.; Weinreb, S. M. Imino Ene Reactions in Organic Synthesis. Synthesis 1995, 1995, 347360. (b) Terada, M. Ene Reactions; Georg Thieme Verlag, 2011. (c) Zhang, Y.; Zhu, Y.; Zheng, L.; Zhuo, L.-G.; Yang, F.; Dang, Q.; Yu, Z.-X.; Bai, X. On-Demand Selection of the Reaction Path from Imino Diels-Alder to Ene-Type Cyclization: Synthesis of Epiminopyrimido[4,5-b]azepines. Eur. J. Org. Chem. 2014, 2014, 660-669. (d) Han, B.; Xiao, Y.-C.; Yao, Y.; Chen, Y.-C. Lewis Acid Catalyzed Intramolecular Direct Ene Reaction of Indoles. Angew. Chem. Int. Ed. 2010, 49, 10189-10191. (e) Oliver, L. H.; Puls, L. A.; Tobey, S. L. Bronsted Acid Promoted Imino-Ene Reactions. Tetrahedron Lett. 2008, 49, 4636-4639. (f) Pandey, M. K.; Bisai, A.; Pandey, A.; Singh, V. K. Imino-Ene Reaction of N-tosyl Arylaldimines with α-Methylstyrene: Application in the Synthesis of Important Amines. Tetrahedron Lett. 2005, 46, 5039-5041. (g) Yamanaka, M.; Nishida, A.; Nakagawa, M. Imino Ene Reaction Catalyzed by Ytterbium(III) Triflate and TMSCl or TMSOTf. J. Org. Chem. 2003, 68, 3112-3120. (h) Laschat, S.; Grehl, M. Diastereoselective Synthesis of Amino-Substituted Indolizidines and Quinolizidines by the Intramolecular Hetero-Ene Reaction of Prolinal Imine and 2-Piperidine Carbaldimine. 1994, 33, 458-461. (2) (a) Drury, W. J.; Ferraris, D.; Cox, C.; Young, B.; Lectka,


Page 11 of 12 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 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


T. A Novel Synthesis of α-Amino Acid Derivatives through Catalytic, Enantioselective Ene Reactions of α-Imino Esters. J. Am. Chem. Soc. 1998, 120, 11006-11007. (b) Momiyama, N.; Okamoto, H.; Kikuchi, J.; Korenaga, T.; Terada, M. Perfluorinated Aryls in the Design of Chiral Brønsted Acid Catalysts: Catalysis of Enantioselective [4 + 2] Cycloadditions and Ene Reactions of Imines with Alkenes by Chiral Mono-Phosphoric Acids with Perfluoroaryls. ACS Catalysis 2016, 6, 1198-1204. (c) Caplan, N. A.; Hancock, F. E.; Bulman Page, P. C.; Hutchings, G. J. Heterogeneous Enantioselective Catalyzed Carbonyl- and Imino-Ene Reactions using Copper Bis(Oxazoline) Zeolite Y. 2004, 43, 1685-1688. (3) (a) Borzilleri, R. M.; Weinreb, S. M.; Parvez, M. Total Synthesis of the Unusual Marine Alkaloid (-)-Papuamine Utilizing a Novel Imino Ene Reaction. J. Am. Chem. Soc. 1995, 117, 10905-10913. (b) Jin, J.; Weinreb, S. M. Application of a Stereospecific Intramolecular Allenylsilane Imino Ene Reaction to Enantioselective Total Synthesis of the 5,11-Methanomorphanthridine Class of Amaryllidaceae Alkaloids. J. Am. Chem. Soc. 1997, 119, 5773-5784. (4) (a) Gilchrist, T. L. Activated 2H-azirines as Dienophiles and Electrophiles. Aldrichim. Acta 2001, 34, 51-55. (b) Zhou, H.; Shen, M.-H.; Xu, H.-D. Evolution of the Aza-DielsAlder Reaction of 2H-Azirines. Synlett 2016, 27, 2171-2177. (c) Xu, H.-D.; Zhou, H.; Pan, Y.-P.; Ren, X.-T.; Wu, H.; Han, M.; Han, R.-Z.; Shen, M.-H. Stereoselective Synthesis of Polycycles Containing an Aziridine Group: Intramolecular aza-Diels-Alder Reactions of Unactivated 2H-Azirines with Unactivated Dienes. Angew. Chem., Int. Ed. 2016, 55, 2540-2544. (5) (a) Sabir, S.; Kumar, G.; Jat, J. L. Unprotected Aziridines: A Synthetic Overview. Asian J. Org. Chem. 2017, 6, 782-793. (b) Ma, Z.; Zhou, Z.; Kurti, L. Direct and Stereospecific Synthesis of N-H and N-Alkyl Aziridines from Unactivated Olefins Using Hydroxylamine-O-Sulfonic Acids. Angew. Chem., Int. Ed. 2017, 56, 9886-9890. (c) Jat, J. L.; Paudyal, M. P.; Gao, H.; Xu, Q.-L.; Yousufuddin, M.; Devarajan, D.; Ess, D. H.; Kuerti, L.; Falck, J. R. Direct Stereospecific Synthesis of Unprotected N-H and N-Me Aziridines from Olefins. Science 2014, 343, 61-65. (6) Liu, T.-S.; Zhou, H.; Chen, P.; Huang, X.-R.; Bao, L.-Q.; Zhuang, C.-L.; Xu, Q.-S.; Shen, M.-H.; Xu, H.-D. Intramolecular Imino-ene Reaction of 2H-azirines with Alkenes: Rapid Construction of Spiro NH Aziridines from Vinyl Azides. Org. Lett. 2018, 20, 3156-3160. (7) (a) Zhu, M.; Hu, L.; Chen, N.; Du, D.-M.; Xu, J. Synthesis of NH-aziridines from vicinal amino alcohols via the Wenker reaction. Scope and limitation. Lett. Org. Chem. 2008, 5, 212-217. (b) Quast, H.; Aldenkortt, S.; Freudenreich, B.; Schaefer, P.; Hagedorn, M.; Lehmann, J.; Banert, K. Synthesis, Configuration, and 15N NMR Spectra of Iminoaziridines. Synthons Equivalent to Three Components of the Ugi Reaction. J. Org. Chem. 2007, 72, 1659-1666. (c) Morton, D.; Pearson, D.; Field, R. A.; Stockman, R. A. Direct Synthesis of Chiral Aziridines from

N-tert-butyl-sulfinylketimines. Chem. Commun. 2006, 0, 1833-1835. (d) Ling, Y.-z.; Li, J.-s.; Kato, K.; Liu, Y.; Wang, X.; Klus, G. T.; Marat, K.; Nnane, I. P.; Brodie, A. M. H. Synthesis and in vitro Activity of Some Epimeric 20αHydroxy, 20-Oxime and Aziridine Pregnene Derivatives as Inhibitors of Human 17α-Hydroxylase/C17,20-lyase and 5α-Reductase. Bioorg. Med. Chem. 1998, 6, 1683-1693. (e) Morrow, D. F.; Butler, M. E.; Huang, E. C. Y. The Synthesis of 17β-Amino-17-isoprogesterone. J. Org. Chem. 1965, 30, 579-587. (f) Morrow, D. F.; Butler, M. E. Stereoselectivity in the Neber Rearrangement-synthesis of a Steroidal Spiroazirine. J. Heterocycl. Chem. 1964, 1, 53-54. (g) Zhou, J.; Ding, C.; Shen, Q. Oridonin Analogs, Compositions, and Methods Related Thereto. Patent WO2017062436, 2017. (h) Chen, H.-J.; Degoey, D. A.; Kalthod, V.; Krueger, A.; Randolph, J. T.; Wagner, R. Anti-Viral Compounds. Patent WO2016134050, 2016. (8) Liu, Z.; Liao, P.; Bi, X. General Silver-Catalyzed Hydroazidation of Terminal Alkynes by Combining TMS-N3 and H2O: Synthesis of Vinyl Azides. Org. Lett. 2014, 16, 3668-3671. (9) For previous computational studies on imino-ene reactions, please see: (a) 1c. (b) Yang, Q.; Liu, Y.; Zhang, W. A Theoretical Study of Imine-ene Reaction Influencing Factors. Org. Biomol. Chem. 2011, 9, 6343. (c) Thomas, B. E.; Houk, K. N. Tuning exo/endo Stereoselectivity in Ene Reactions. J. Am. Chem. Soc. 1993, 115, 790. (10) See SI for computational details. (11) Chai, J.-D.; Head-Gordon, M. Long-range Corrected Hybrid Density Functionals with Damped Atom–atom Dispersion Corrections. Phys. Chem. Chem. Phys. 2008, 10, 6615-6620. (12) Hariharan, P. C.; Pople, J. A. J. T. c. a. The Influence of Polarization Functions on Molecular Orbital Hydrogenation Energies. Theoret. Chim. Acta 1973, 28, 213-222. (13) (a) Fukui, K. Formulation of the Reaction Coordinate. J. Phys. Chem. 1970, 74, 4161-4163. (b) Fukui, K. The Path of Chemical Reactions - the IRC Approach. Acc. Chem. Res. 1981, 14, 363-368. (14) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions. J. Phys. Chem. B 2009, 113, 6378-6396. (15) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;



Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J.; Gaussian 09, Revision C.01; Gaussian, Inc.: Wallingford, CT, 2010. (16) Legault, C. Y. CYLview, 1.0 b; Université de

Sherbrooke: Sherbrooke, http://www.Cylview.org.


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