Mn(III)-mediated formal [3+3]-annulation of vinyl azides and cyclopropanols: A divergent synthesis of azaheterocycles

Article abstract of DOI:10.1021/ja200879w

Mn(III)-mediated formal [3+3]-annulation has been developed using readily available vinyl azides and cyclopropanols with a wide range of substituents. Vinyl azides were successfully applied as a three-atom unit including one nitrogen to prepare pyridines and σ-lactams by the reactions with monocyclic cyclopropanols as well as to construct 2-azabicyclo[3.3.1] and 2-azabicyclo[4.3.1] frameworks with bicyclic cyclopropanols, bicyclo[3.1.0]hexan-1-ols, and bicyclo[4.1.0]heptan-1-ols. These reactions were initiated by a radical addition of β-carbonyl radicals, generated by the one-electron oxidation of cyclopropanols with Mn(III), to vinyl azides to give iminyl radicals, which cyclized with the intramolecular carbonyl groups. In addition, application of the present methodology to a synthesis of the quaternary indole alkaloid, melinonine-E, was accomplished.

Full text of DOI:10.1021/ja200879w

Supporting Information
Mn(III)-Mediated Formal [3+3]-Annulation of Vinyl Azides and Cyclopropanols: A
Divergent Synthesis of Azaheterocycles
Yi-Feng Wang, Kah Kah Toh, Eileen Pei Jian Ng, and Shunsuke Chiba*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637371, Singapore
E-mail: shunsuke@ntu.edu.sg
1
2
3
4
.
.
.
.
General
SI-2
SI-2
SI-3
SI-3
SI-3
SI-5
SI-8
Safety issues in handling azido compounds
Synthesis of vinyl azides 1
Synthesis of cyclopropanols 2, 5, 8 and 16
Synthesis of 4-vinylbicyclo[3.1.0]hexan-1-ol (8c)
Synthesis of 4-((tert-Butyldiphenylsilyloxy)methyl)bicyclo[3.1.0]hexan-1-ol (8h)
Synthesis of other cyclopropanols
4
.1.
4
.2
4
.3.
5
.
Mn(III)-mediated/catalyzed formation of pyridines 3 from vinyl azides 1 and
cyclopropanols 2
SI-8
6
.
.
One-pot synthesis of δ-lactams 7 from vinyl azides 1 and 1-ethoxycyclopropanol (5) SI-18
Mn(acac) -catalyzed 2-azabicyclo[3.3.1]non-2-en-1-ol derivatives 9 formation
7
3
from vinyl azides 1 and bicyclo[3.1.0]hexan-1-ols 8
SI-20
8.
One-pot synthesis of 2-azabicyclo[3.3.1]nonanes 11 from vinyl azides 1 and
bicyclo[3.1.0]hexan-1-ols 8
SI-27
SI-30
SI-30
SI-30
SI-31
SI-31
9
.
Transformations of 2-azabicyclo[3.3.1]non-2-en-1-yl acetate 12
Synthesis of 2-azabicyclo[3.3.1]non-2-en-1-yl acetate 12
Synthesis of (1R*,5S*)-3-phenyl-2-azabicyclo[3.3.1]non-2-ene (13)
Synthesis of (1R*,5S*)-1-methyl-3-phenyl-2-azabicyclo[3.3.1]non-2-ene (14)
Synthesis of (1R*,5S*)-1-allyl-3-phenyl-2-azabicyclo[3.3.1]non-2-ene (15)
One-pot synthesis of 7-azabicyclo[4.3.1]decane derivatives 21from vinyl azides 1
and bicyclo[4.1.0]heptan-1-ols 16
9
9
9
9
.1.
.2.
.3.
.4.
10.
SI-32
SI-35
SI-35
SI-36
SI-38
SI-39
SI-40
SI-42
11.
Synthesis of (±)-melinonine-E (22)
1
1.1. Mn(acac)
1.2. Synthesis of cyclic imine 23
1.3. Synthesis of cyclic N-H amines 25 and 26
1.4. Synthesis of (±)-melinonine-E (22)
2. References
3
-mediated synthesis of 2-azabicyclo[3.3.1]non-2-en-1-ols 9jh
1
1
1
1
1
13
Appendix: H and C NMR spectra for new compounds
SI-1

1
. General
1
1
H NMR (300 MHz) spectra were recorded on a Bruker Avance 300 apparatus, H NMR (400
1
MHz) spectra on a Bruker Avance 400 in CDCl
3
[using CDCl
3
(for H, δ = 7.26) as internal
1
3
standard] unless otherwise mentioned.
C NMR (75 MHz) spectra were recorded on a Bruker
Avance 300, C NMR (100 MHz) spectra on a Bruker Avance 400 spectrometers in CDCl [using
(for C, δ = 77.00) as internal standard] unless otherwise mentioned. The following
1
3
3
1
3
CDCl
3
abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet,
br = broad. IR spectra were recorded on a Shimadzu IR Prestige-21 FT-IR Spectrometer.
High-resolution mass spectra were obtained with a Q-Tof Premier LC HR mass spectrometer.
Melting points are uncorrected and were recorded on a Buchi B-54 melting point apparatus. Flash
column chromatographs were performed using Silicycle 60 silica gel or Florisil® adsortbent
(
100-200 mesh) and distilled eluting solvents. Ethanol (EtOH) was distilled from sodium under
and stored over MS 4A. Tetrahydrofuran (THF) and diethyl ether (Et O) when used as
solvents for the reactions, were distilled from sodium and benzophenone under N
N,N-dimethylformamide (DMF) was distilled from CaH under N and stored over MS 4A.
Toluene and dichloromethane (CH Cl ) were dried by passing over a column of activated alumina
A-2, Purify) followed by a column of Q-5 scavenger (Engelhard). 1,2-Dichloroethane were
N
2
2
2
.
2
2
2
2
(
distilled from CaH
2
and stored over molecular sieve 4A (MS 4A). Acetonitrile (MeCN) was
was used purified by reprecipitation of
commercially available one (Aldrich) from benzene-hexane.
4 3
distilled from P O10 and stored over MS 4A. Mn(acac)
1
,2
2. Safety issues in handling of azido compounds
2
.1. Sodium azide (NaN
Sodium azide is toxic (LD50 oral = 27 mg/kg for rats) and can be absorbed through skin.
Appropriate golves are necessary when using it. It decomposes explosively upon heating to above
75 °C. Sodium azide are relatively safe especially in aqueous solution, unless acidified to form
HN , which is volatile and highly toxic.
3
)
2
3
2.2. Organic azides
Organic azides are potentially explosive substances that can decompose with the slight input of
energy from external sources (heat, light, pressure, etc). When desiging the organic azides used
for the project, we keep in mind the following equation. It is noted that this equation takes into
account all nitrogen atoms in the organic azide, not just those in the azido group.
NC + NO
>
3
(N: number of the atom)
NN
SI-2

All organic azides prepared in this work are satisfied with the equation above except for 1a and
k, and they are enough stable to be stored under –20 ºC at leatst for 6 months. Vinyl azides 1a
1
and 1k are known compounds and were carefully synthesized by following reported procedures.
We have never experienced a safety problem with these materials.
3. Synthesis of vinyl azides 1
3
4
5
4
5
4
5
5
5
6
7
8
3
9
Vinyl azides 1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i, 1j, 1k, 1l, 1m, and 1n are known
compounds and were prepared according to reported literatures.
4. Synthesis of cyclopropanols 2, 5, 8 and 16
4
.1. Synthesis of 4-vinylbicyclo[3.1.0]hexan-1-ol (8c):
1
0
To a solution of silyl enol ether A (1.95 g, 10.7 mmol) and diethyl zinc (15.3 mL, 15.3 mmol,
.0 M in hexane) in Et O (10 mL) was added dropwise a solution of diiodomethane (1.22 mL, 15.3
O (10 mL) over 1 h at 0 °C. The reaction was heated at reflux for 3 h to give a cloudy
1
2
mmol) in Et
2
solution which was allowed to cooled and then quenched by the dropwise addition of pyridine (2.0
mL). The resulting suspension was filtered through a celitepad, the precipitate was washed
thoroughly with Et
15 mL) followed by addition of K
room temperature and then quenched by adding pH 9 ammonium buffer, and the organic materials
were extracted with ethyl acetate. The organic lay was washed with brine, and drid over MgSO
2
O. After evaporation of solvents, the crude materials were dissolved in MeOH
(
2
CO (0.14 g, 1.1 mmol). The reaction was stirred for 30 min at
3
4
.
After evaporation of solvent, resulting crude materials were purified by flash column
chromatography (silica gel; hexane : ethyl acetate = 85 : 15) to give 8c (1.11 g, 8.9 mmol, 84%
yield from silyl enol ether A) as a colorless liquid as an inseparable mixture of diastereomers (ca.
1
13
4
: 1 for cyclopropanation) and H and C NMR are described for the major product.
-
1 1
IR (KBr) 3588, 2950, 1636, 907 cm ; H NMR (400 MHz, CDCl
3
) δ 0.66 (1H, dd, J = 4.8, 4.8 Hz),
0
.90-0.95 (1H, m), 1.29-1.50 (3H, m), 1.92-2.00 (3H, m), 2.43 (1H, dd, J = 7.2, 7.6 Hz), 4.90-5.07
1
3
(
2H, m), 5.93 (1H, ddd, J = 7.2, 10.4, 17.6 Hz); C NMR (100 MHz, CDCl
3
) δ 15.5, 27.5, 28.5,
+
8
31.2, 42.7, 64.5, 112.6, 142.5; ESIHRMS: Found: m/z 125.0964. Calcd for C H13O: (M+H)
125.0966.
4
-Isopropylbicyclo[3.1.0]hexan-1-ol (8b):
SI-3

Cyclopropanol 8b was prepared from the corresponding silyl enol ether following the same
procedure as 8c. An inseparable mixture of diastereomers (ca. 4 : 1 for cyclopropanation) was
1
13
obtained; H and C NMR are described for the major product.
-
1 1
Yield: 35%. Colorless liquid; IR (NaCl) 3374, 2957 cm ; H NMR (400 MHz, CDCl
3
) δ 0.53 (1H,
dd, J = 4.8, 4.8 Hz), 0.89-0.93 (7H, m), 1.19-1.27 (2H, m), 1.50-1.66 (3H, m), 1.84-1.95 (2H, m),
1
3
2
6
.21 (1H, s br); C NMR (100 MHz, CDCl
3
) δ 16.7, 20.38, 20.45, 24.8, 27.9, 31.9, 32.8, 46.7,
+
5.0; ESIHRMS: Found: m/z 163.1099. Calcd for C
9
H
16ONa: (M+Na) 163.1099.
4
-Allylbicyclo[3.1.0]hexan-1-ol (8d):
Cyclopropanol 8d was prepared from the corresponding silyl enol ether following the same
procedure as 8c. An inseparable mixture of diastereomers (ca. 4 : 1 for cyclopropanation) was
1
13
obtained; H and C NMR are described for the major product.
Yield: 21%. Colorless liquid; IR (NaCl) 3300, 2997, 1641, 1231cm ; H NMR (300 MHz, CDCl
-
1 1
3
)
δ 0.61 (1H, dd, J = 4.4, 5.2 Hz), 0.87-0.90 (1H, m), 1.22-1.30 (2H, m), 1.42 (1H, dd, J = 7.8, 13.5
Hz), 1.83 (1H, dd, J = 7.2, 13.5 Hz), 1.89-2.00 (3H, m), 2.05-2.17 (2H, m), 5.01-5.06 (2H, m),
1
3
5
1
.75-5.85 (1H, m); C NMR (75 MHz, CDCl
3
) δ 15.9, 26.3, 29.2, 31.2, 39.1, 39.8, 64.4, 115.7,
+
37.4; ESIHRMS: Found: m/z 139.1121. Calcd for C
9
H
15O: (M+H) 139.1123.
4-Phenylbicyclo[4.1.0]heptan-1-ol (16b):
Cyclopropanol 16b was prepared from the corresponding silyl enol ether following the same
procedure as 8c. Only single diastereoisomer was obtained.
Yield: 80%. White solid; mp 55-57 °C; IR (NaCl) 3420, 3082, 3067, 3017, 2932, 1603, 1493, 1180
-
1 1
cm ; H NMR (300 MHz, CDCl
.10 (1H, ddd, J = 4.8, 11.7, 12.3 Hz), 1.22-1.33 (2H, m), 1.64-1.73 (2H, m), 1.93 (1H, ddd, J = 5.1,
1.7, 12.3 Hz), 2.14 (1H, br), 2.25-2.30 (1H, m), 2.66 (1H, dd, J = 4.8, 10.8 Hz), 7.17-7.21 (1H, m),
3
) δ 0.51 (1H, dd, J = 5.7, 6.0 Hz), 0.98 (1H, dd, J = 5.4, 11.1 Hz),
1
1
7
1
1
3
.27-7.34 (4H, m); C NMR (75 MHz, CDCl
3
) δ 19.5, 20.7, 26.3, 31.4. 32.5, 44.3, 55.9, 125.8,
+
27.3, 128.4, 148.1; ESIHRMS: Found: m/z 211.1091. Calcd for C13
H
16ONa: (M+Na) 211.1099.
SI-4

5
-Allylbicyclo[4.1.0]heptan-1-ol (16c):
Cyclopropanol 16c was prepared from the corresponding silyl enol ether following the same
procedure as 8c. An inseparable mixture of diastereomers was obtained (diastereoselectivity is not
1
13
determined); H and C NMR are described for the major product.
Yield: 20%. Colourless liquid; IR (NaCl) 3343, 3075, 3003, 2926, 2857, 1639, 1512, 1209 cm ; H
NMR (300 MHz, CDCl ) δ 0.35 (1H, dd, J = 3.3, 3.6 Hz), 0.86-0.99 (4H, m), 1.41-1.54 (2H, m),
-
1 1
3
1
3
1
.62-1.68 (1H, m), 1.73-1.83 (2H, m), 2.14-2.23 (3H, m), 5.00-5.09 (2H, m), 5.76-5.90 (1H, m); C
NMR (75 MHz, CDCl
3
) δ 19.2, 21.0, 24.8, 29.9. 31.7, 37.4, 42.3, 56.1, 115.8, 137.2; ESIHRMS:
+
Found: m/z 175.1095. Calcd for C10
H
16ONa: (M+Na) 175.1099.
4-Phenylbicyclo[4.1.0]heptan-1-ol (16d):
Cyclopropanol 16d was prepared from the corresponding silyl enol ether following the same
procedure as 8c. An inseparable mixture of diastereomers (ca. 5 : 1 for cyclopropanation, needed to
1
13
be confirmed again) was obtained; H and C NMR are described for the major product.
Yield: 94%. White solid; mp 62-79 °C; IR (NaCl) 3522. 3061, 3026, 2926, 2853, 1697, 1601, 1236
-
1 1
3
cm ; H NMR (300 MHz, CDCl ) δ 0.45 (1H, dd, J = 5.7, 5.7 Hz), 0.91 (1H, dd, J = 5.4, 10.5 Hz),
1
3
1
.22-1.67 (4H, m), 1.87-2.13 (3H, m), 2.27-2.54 (2H, m), 7.11-7.31 (5H, m); C NMR (75 MHz,
CDCl
3
) δ 18.8, 21.5, 29.4, 31.3. 32.4, 36.9, 54.1, 125.9, 126.9, 128.3, 146.4; ESIHRMS: Found: m/z
+
211.1097. Calcd for C13
H
16ONa: (M+Na) 211.1099.
11
6
6
11
11
11
11
12
Cyclopropanols 2a, 2b, 2c, 2e, 2m, 8a, 16a, and 16e are known compounds and were
prepared by the same method as 8c from the corresponding enol silyl ethers.
4.2. 4-((tert-Butyldiphenylsilyloxy)methyl)bicyclo[3.1.0]hexan-1-ol (8h):
SI-5

4
-((Methoxymethoxy)methyl)bicyclo[3.1.0]hexan-1-yl acetate (B):
6
To a solution of cyclopropanol 8f (2.28 g, 13.3 mmol, ca. 2.3:1 diastereoisomeric mixture), Et
3
N
(2.77 mL, 19.9 mmol), DMAP (162.0 mg, 1.33 mmol) in CH
2
Cl
2
2
(80 mL) was added Ac O (1.50
mL, 15.9 mmol). After 1 h, the reaction was diluted with CH
2
Cl
2
and water, and the aqueous layer
was extracted twice with CH
MgSO , and concentrated. Purification of the crude product by flash column chromatography (silica
gel; hexane : ethyl acetate = 90 : 10) afforded B (2.67 g, 12.5 mmol) in 94% yield as an inseparable
2 2
Cl . The combined organic layers were washed with brine, dried over
4
1
13
mixture of diastereomers (ca. 2.3 : 1); and H and C NMR are described for the major product.
-
1 1
Colorless liquid; IR (KBr) 2985, 1740, 1150, 1045 cm ; H NMR (400 MHz, CDCl
3
) δ 0.83-0.88
(1H, m), 0.93-0.96 (1H, m), 1.30-1.38 (1H, m), 1.48 (1H, dd, J = 4.8, 9.6 Hz), 1.60 (1H, dd, J = 9.2,
1
7
2
3.6 Hz), 1.99 (3H, s), 2.03-2.10 (2H, m), 2.17 (1H, dd, J = 8.4, 12.0), 3.37 (3H, s), 3.50 (1H, dd, J =
13
.6, 9.6 Hz), 3.56 (1H, dd, J = 7.2, 9.6 Hz), 4.65 (2H, s); C NMR (100 MHz, CDCl ) δ 14.4, 21.2,
3
4.1, 24.8, 28.0, 39.6, 55.2, 66.2, 70.5, 96.5, 171.2; ESIHRMS: Found: m/z 215.1281. Calcd for
+
C
11
H
19
O
4
: (M+H) 215.1283.
4
-(Hydroxymethyl)bicyclo[3.1.0]hexan-1-yl acetate (C):
A solution of intermediate B (1.81 g, 8.44 mmol, ca. 2.3:1 diastereoisomeric mixture) and lithium
tetrafluoroborate (7.1 g, 76 mmol) in 120 mL of CH
3
CN and 6 mL of H
2
O was heated at 75 ºC for
1
8 h. The reaction was then quenched with saturated aqueous NH
4
Cl solution in ice bath and
SI-6

extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over
MgSO , and concentrated. The product was isolated by flash column chromatography (silica gel;
4
hexane : ethyl acetate = 70 : 30) in 90% yield (0.971 g, 7.58 mmol). The resulted diastereoisomers
1
could be partially separated, the yield mentioned above was the combined yield of two isomers. H
1
3
and C NMR are described for the major product. The two isomers (ca. 2.3:1) were used together
for the next reaction.
-
1 1
Colorless liquid; IR (KBr) 3412, 2951, 1741, 1043 cm ; H NMR (400 MHz, CDCl
3
) δ 0.74 (1H, dd,
J = 4.8, 6.0 Hz), 0.96 (1H, ddd, J = 2.0, 6.0, 9.6 Hz), 1.33-1.43 (1H, m), 1.51 (1H, dd, J = 4.4, 9.6 Hz),
1
.74 (1H, dd, J = 9.2, 13.6 Hz), 1.98-2.05 (2H, m), 2.03 (3H, s), 2.23-2.26 (1H, m), 3.20 (1H, dd, J =
13
2.8, 9.6 Hz), 3.63 (1H, ddd, J = 4.8, 9.6, 10.8 Hz), 3.80 (1H, ddd, J = 2.8, 3.6, 10.8 Hz), ; C NMR
(
100 MHz, CDCl
3
) δ 14.0, 21.3, 24.5, 26.3, 29.4, 42.2, 66.9, 67.4, 172.0; ESIHRMS: Found: m/z
+
1
71.1020. Calcd for C
9 15 3
H O : (M+H) 171.1021.
4
-((tert-Butyldiphenylsilyloxy)methyl)bicyclo[3.1.0]hexan-1-yl acetate (D):
3
To a solution of alcohol C (2.36 g, 13.9 mmol, ca. 2.3:1 diastereoisomeric mixture), Et N (3.90
mL, 27.8 mmol), DMAP (170.0 mg, 1.39 mmol) in CH
tert-butyldiphenylsilyl chloride (5.40 mL, 20.8 mmol). After 12 h, the reaction was diluted with
CH Cl and water, the aqueous layer was extracted twice with CH Cl . The combined organic layers
were washed with brine, dried over MgSO and concentrated. Purification of the crude product by
flash column chromatography (silica gel; hexane : ethyl acetate = 95 : 5) afforded D (5.46 g, 13.4
2
Cl
2
(80 mL) was added
2
2
2
2
4
1
13
mmol) in 96% yield as an inseparable mixture of diastereomers (ca. 2.3 : 1); H and C NMR are
described for the major product.
-
1 1
Colorless liquid; IR (KBr) 3070, 1744, 1471, 1427, 1361, 1240, 1113 cm ; H NMR (400 MHz,
CDCl ) δ 0.86-0.92 (1H, m), 0.94-0.98 (1H, m), 1.07 (9H, s), 1.26-1.32 (1H, m), 1.48 (1H, dd, J =
.8, 8.4 Hz), 1.64 (1H, dd, J = 9.2, 14.0 Hz), 1.88-1.94 (1H, m), 2.00 (3H, s), 2.02-2.07 (1H, m),
.16-2.23 (1H, m), 3.61 (1H, dd, J = 7.6, 9.6 Hz), 3.68 (1H, dd, J = 7.2, 9.6 Hz), 7.37-7.43 (6H, m),
3
4
2
7
6
1
3
.68-7.69 (4H, m); C NMR (100 MHz, CDCl ) δ 14.4, 19.3, 21.2, 23.9, 24.4, 26.8, 28.4, 41.9,
3
6.3, 66.5, 127.6, 129.5, 133.9, 135.6, 171.3; ESIHRMS: Found: m/z 409.2194. Calcd for
+
C
25
H
33
O
3
Si: (M+H) 409.2199.
4
-((tert-Butyldiphenylsilyloxy)methyl)bicyclo[3.1.0]hexan-1-ol (8h):
SI-7

To a solution of acetate D (5.41 g, 13.2 mmol, ca. 2.3:1 diastereoisomeric mixture) in MeOH (60
mL) was added K CO (180.0 mg, 1.33 mmol). The reaction was stirred for 1 h at room
temperature and then quenched by adding pH 9 ammonium buffer, and the organic materials were
extracted with ethyl acetate. The organic lay was washed with brine and dried over MgSO
2
3
4
.
After evaporation of solvent, resulting crude materials were purified by flash column
chromatography (silica gel; hexane : ethyl acetate = 80 : 20) to give cyclopropanol 8h (4.60 g, 12.5
1
13
mmol) in 95% yield as an inseparable mixture of diastereomers (ca. 2.3 : 1); H and C NMR are
described for the major product.
-
1
1
Viscous liquid; IR (KBr) 3342, 3089, 1602, 1497, 1456, 1267, 1236, 1099 cm ; H NMR (400
MHz, CDCl ) δ 0.62 (1H, dd, J = 3.6, 4.4 Hz), 0.89-0.90 (1H, m), 1.10 (9H, s), 1.22-1.32 (2H, m),
.57-1.61 (1H, m), 1.75 (1H, s br), 1.87-1.99 (2H, m), 2.04-2.08 (1H, m), 3.59-3.61 (2H, m),
3
1
7
3
1
3
.40-7.46 (6H, m), 7.69-7.72 (4H, m); C NMR (100 MHz, CDCl ) δ 15.5, 19.3, 23.8, 26.6, 26.9,
1.5, 42.3, 64.1, 66.9, 127.6, 129.6, 133.9, 135.61, 135.64; ESIHRMS: Found: m/z 389.1919. Calcd
3
+
for C23
H
30
O
2
SiNa: (M+H) 389.1913.
4
.4. Synthesis of other cyclopropanols
1
3
14
15
16
17
18
19
20
21
22
6
6
6
23
Cyclopropanols 2d, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2n, 5, chiral 8a, 8e, 8f, and 8g
are known compounds and were prepared according to literatures.
5
. Mn(acac)
3
-mediated/catalyzed formation of pyridines 3 from vinyl azides 1 and
6
cyclopropanols 2
Typical procedure using Conditions A (stoichiometric reaction):
To a solution of α-azidostyrene (1a) (43.5 mg, 0.30 mmol) and 1-phenylcyclopropanol (2a) (60.6
3
mg, 0.45 mmol) in MeOH (3.0 mL) was added Mn(acac) (179.8 mg, 0.51 mmol) at room
temperature under nitrogen atmosphere. After 5 min, AcOH (34 μL, 0.60 mmol) was added and the
reaction mixture was stirred for 1 h at the same temperature. The reaction mixture was quenched
with pH 9 ammonium buffer and then extracted twice with ethyl acetate. The combined organic
extracts were washed with brine, dried over MgSO
4
, and concentrated. Purification of the crude
product by flash column chromatography (silica gel; hexane : ethyl acetate = 98 : 2) afforded 3aa
(58.0 mg, 0.25 mmol) in 84% yield as a pale yellow solid.
SI-8

Typical procedure using Conditions B (catalytic reaction):
To a solution of α-azidostyrene (1a) (43.6 mg, 0.30 mmol) and 1-phenylcyclopropanol (2a) (48.4
3
mg, 0.36 mmol) in MeOH (3.0 mL) was added Mn(acac) (10.6 mg, 0.03 mmol) at room
temperature under nitrogen atmosphere. After 5 min, HCl (0.20 mL, 0.60 mmol, 3.0 M in MeOH)
was added and the nitrogen balloon was then replaced by oxygen balloon. The reaction mixture was
heated at 40 ºC for 1 h and quenched with pH 9 ammonium buffer, and then extracted twice with
4
ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO , and
concentrated. Purification of the crude product by flash column chromatography (silica gel;
hexane : ethyl acetate = 98 : 2) afforded 3aa (55.6 mg, 0.24 mmol) in 80% yield as a pale yellow
solid.
2
4
2,6-Diphenylpyridine (3aa):
1
H NMR (400 MHz, CDCl
3
) δ 7.41-7.44 (2H, m), 7.45-7.52 (4H, m), 7.70 (2H, d, J = 7.4 Hz), 7.83
1
3
(
1H, t, J = 7.6 Hz), 8.15-8.17 (4H, m); C NMR (100 MHz, CDCl ) δ 118.6, 127.0, 128.7, 129.0,
3
137.5, 139.5, 156.8.
6
2
-Phenyl-6-p-tolylpyridine (3ba):
N
Me
Total reaction time for Conditions A: 0.5 h.
1
H NMR (400 MHz, CDCl
3
) δ 2.43 (3H, s), 7.30 (2H, d, J = 8.0 Hz), 7.43 (1H, t, J = 7.2 Hz), 7.50
(
2H, dd, J = 7.2, 7.6 Hz), 7.68 (2H, d, J = 7.6 Hz), 7.80 (1H, dd, J = 7.6, 8.0 Hz), 8.06 (2H, d, J =
1
3
8
1
3
.0 Hz), 8.15-8.17 (2H, m); C NMR (100 MHz, CDCl ) δ 21.3, 118.4 (overlapped), 126.9, 127.0,
28.7, 128.9, 129.4, 136. 8, 137.4, 139.0, 139.6, 156.7, 156.9.
6
2
-(2-Methoxyphenyl)-6-phenylpyridine (3ca):
SI-9

Total reaction time for Conditions A: 0.5 h. Total reaction time for Conditions B: 1 h.
1
H NMR (400 MHz, CDCl
3
) δ 3.90 (3H, s), 7.03 (1H, d, J = 8.0 Hz), 7.14 (1H, t, J = 7.6 Hz),
7
8
.38-7.43 (2H, m), 7.49 (2H, dd, J = 7.6, 7.6 Hz), 7.67 (1H, d, J = 8.0 Hz), 7.78 (1H, dd, J = 7.6,
1
3
.0 Hz), 7.85 (1H, d, J = 7.6 Hz), 8.03 (1H, d, J = 7.6 Hz), 8.12 (2H, d, J = 7.6 Hz); C NMR (100
) δ 55.6, 111.4, 118.3, 121.0, 123.5, 126.9, 128.6, 128.7, 129.2, 129.9, 131.5, 136.3,
39.7, 155.4, 156.7, 157.2.
MHz, CDCl
3
1
25
2
-(4-Methoxyphenyl)-6-phenylpyridine (3da):
Total reaction time for Conditions A: 0.5 h.
1
H NMR (400 MHz, CDCl
3
) δ 3.88 (3H, s), 7.03 (2H, d, J = 8.0 Hz), 7.43 (1H, t, J = 7.2 Hz), 7.51
(
2H, dd, J = 7.2, 8.0 Hz), 7.64 (2H, d, J = 8.0 Hz), 7.82 (1H, dd, J = 8.0, 8.0 Hz), 8.11-8.15 (4H,
1
3
m); C NMR (100 MHz, CDCl ) δ 55.3, 114.0, 117.8, 117.9, 126.9, 128.2, 128.6, 128.8, 132.1,
3
137.3, 139.6, 156.4, 156.6, 160.4.
2
6
2
-(2-Bromophenyl)-6-phenylpyridine (3ea):
Br
N
Total reaction time for Conditions A: 1 h.
1
H NMR (400 MHz, CDCl
3
) δ 7.25-7.29 (2H, m), 7.41-7.50 (3H, m), 7.55 (1H, d, J = 7.6 Hz), 7.65
(
1H, d, J = 7.6 Hz), 7.70 (1H, d, J = 7.6 Hz), 7.73 (1H, d, J = 7.6 Hz), 7.83 (1H, dd, J = 7.6, 7.6 Hz),
1
3
8
.09 (2H, d, J = 7.6 Hz); C NMR (100 MHz, CDCl
3
) δ 119.1, 121.9, 122.9, 127.1, 127.5, 128.7,
129.0, 129.6, 131.7, 133.4, 136.6, 139.3, 141.4, 157.0, 158.0.
2
7
2
-(4-Bromophenyl)-6-phenylpyridine (3fa):
Total reaction time for Conditions A: 0.5 h.
SI-10

1
H NMR (400 MHz, CDCl
3
) δ 7.44 (1H, t, J = 7.2 Hz), 7.51 (2H, dd, J = 7.2, 7.6 Hz), 7.62 (2H, d, J
=
8.4 Hz), 7.67 (1H, d, J = 7.6 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.82 (1H, dd, J = 7.6, 8.0 Hz), 8.04
1
3
(
3
2H, d, J = 8.4 Hz), 8.13 (1H, d, J = 7.6 Hz); C NMR (100 MHz, CDCl ) δ 118.3, 118.9, 123.4,
126.9, 128.5, 128.7, 129.1, 131.8, 137.6, 138.3, 139.2, 155.6, 157.0.
6
Methyl 4-(6-phenylpyridin-2-yl)benzoate (3ga):
Total reaction time for Conditions A: 0.5 h.
1
H NMR (400 MHz, CDCl
3
) δ 3.96 (3H, s), 7.45 (1H, t, J = 7.2 Hz), 7.52 (2H, dd, J = 7.2, 7.6 Hz),
7
.74 (2H, d, J = 8.0 Hz), 7.85 (1H, dd, J = 7.6, 8.0 Hz), 8.14-8.18 (4H, m), 8.23 (2H, d, J = 8.0 Hz);
1
3
C NMR (100 MHz, CDCl ) δ 52.2, 119.1, 119.4, 126.9, 127.0, 128.7, 129.1, 130.0, 130.3, 137.6,
3
139.2, 143.6, 155.5, 157.1, 167.0.
6
2
-(Naphthalen-2-yl)-6-phenylpyridine (3ha):
Total reaction time for Conditions A: 0.5 h. Total reaction time for Conditions B: 1 h.
1
H NMR (400 MHz, CDCl
3
) δ 7.46 (1H, t, J = 7.2 Hz), 7.52-7.56 (4H, m), 7.72-7.74 (1H, m),
7
.85-7.87 (2H, m), 7.89-7.91 (1H, m), 7.99 (2H, dd, J = 7.6, 8.0 Hz), 8.21(2H, d, J = 7.6 Hz), 8.34
1
3
(
1H, d, J = 8.8 Hz), 8.63 (1H, s); C NMR (100 MHz, CDCl
3
) δ 118.7, 118.9, 124.8, 126.2, 126.3,
126.5, 127.0, 127.7, 128.3, 128.72, 128.74, 129.0, 133.5, 133.7, 136.8, 137.5, 139.5, 156.7, 157.0.
6
2-Phenyl-6-(1-tosyl-1H-pyrrol-2-yl)pyridine (3ia):
Total reaction time for Conditions A: 1 h.
1
H NMR (400 MHz, CDCl ) δ 2.32 (3Η, s), 6.37 (1H, dd, J = 3.2, 3.2 Hz), 6.48 (1H, dd, J = 2.0, 3.2
3
Hz), 7.05 (2H, d, J = 8.4 Hz), 7.40-7.42 (3H, m), 7.44 (1H, d, J = 7.6 Hz), 7.47 (1H, dd, J = 2.0, 3.2
Hz), 7.52 (2H, d, J = 8.4 Hz), 7.66 (1H, d, J = 8.0 Hz), 7.75 (1H, d, J = 7.6 Hz), 7.79-7.81 (2H, m);
1
3
C NMR (100 MHz, CDCl ) δ 21.5, 111.8, 116.4, 119.5, 123.8, 124.6, 127.2 (overlapped), 128.4,
3
128.7, 129.5, 135.5, 136.3, 136.5, 139.1, 144.4, 150.7, 156.5.
SI-11

6
2
-(6-Phenylpyridin-2-yl)-1-tosyl-1H-indole (3ja):
Total reaction time for Conditions A: 1 h.
1
H NMR (400 MHz, CDCl
3
) δ 2.26 (3Η, s), 6.88 (1H, s), 7.03 (2H, d, J = 8.4 Hz), 7.25 (1H, t, J =
7
8
.6 Hz), 7.36 (1H, dd, J = 7.2, 8.4 Hz), 7.40-7.50 (4H, m), 7.61 (2H, d, J = 8.4 Hz), 7.76 (1H, d, J =
1
3
.0 Hz), 7.83 (1H, dd, J = 7.6, 7.6 Hz), 8.00 (2H, d, J = 7.2 Hz), 8.21 (1H, d, J = 8.4 Hz); C NMR
) δ 21.5, 114.3, 116.0, 119.8, 121.3, 124.1, 124.4, 125.1, 127.1, 127.2, 128.6,
28.9, 129.3, 130.2, 134.8, 136.2, 137.9, 139.2, 141.2, 144.4, 151.3, 156.4.
(100 MHz, CDCl
3
1
2
8
Ethyl 6-phenylpicolinate (3ka):
Total reaction time for Conditions A: 8 h.
1
H NMR (400 MHz, CDCl ) δ 1.46 (3H, t, J = 7.6 Hz), 4.49 (2H, q, J = 7.6 Hz), 7.43 (1H, t, J = 7.2
3
1
3
Hz), 7.49 (2H, dd, J = 6.8, 7.2 Hz), 7.88-7.91 (2H, m), 8.03-8.08 (3H, m); C NMR (100 MHz,
CDCl ) δ 14.3, 61.8, 123.2, 123.4, 127.2, 128.8, 129.4, 137.6, 138.5, 148.3, 157.6, 165.5.
3
2
-(2-Bromophenyl)-6-phenylpyridine (3ab):
Total reaction time for Conditions A: 1 h.
This compound is identical to compound 3ea.
2
-(4-Bromophenyl)-6-phenylpyridine (3ac):
Total reaction time for Conditions A: 0.5 h. Total reaction time for Conditions B: 1 h.
This compound is identical to compound 3fa.
SI-12

25
2-(Biphenyl-4-yl)-6-phenylpyridine (3ad):
N
Total reaction time for Conditions A: 9 h.
1
H NMR (400 MHz, CDCl
3
) δ 7.39 (1H, d, J = 7.6 Hz), 7.44-7.55 (5H, m), 7.68-7.76 (6H, m), 7.84
1
3
(
1H, dd, J = 7.6, 8.0 Hz), 8.19 (2H, d, J = 7.6 Hz), 8.26 (2H, d, J = 8.0 Hz); C NMR (100 MHz,
CDCl
3
) δ 118.5, 118.6, 127.0, 127.1, 127.35, 127.39, 127.5, 128.7, 128.8, 129.0, 137.5, 138.4,
139.5, 140.7, 141.7, 156.4, 156.9.
6
2-Phenethyl-6-phenylpyridine (3ae):
N
Total reaction time for Conditions A: 0.5 h. Total reaction time for Conditions B: 1 h.
1
H NMR (400 MHz, CDCl
3
) δ 3.17 (4H, s, overlapped), 7.02 (1H, d, J = 7.6 Hz), 7.17-7.30 (5H, m),
7
7
1
.40 (1H, t, J = 7.2 Hz), 7.48 (2H, dd, J = 7.2, 7.6 Hz), 7.54 (1H, d, J = 8.0 Hz), 7.62 (1H, dd, J =
1
3
.6, 8.0 Hz), 8.01 (2H, d, J = 8.0 Hz); C NMR (100 MHz, CDCl ) δ 35.7, 40.1, 117.9, 121.2,
3
25.8, 127.0, 128.3, 128.5, 128.6, 128.7, 136.8, 139.7, 141.8, 156.8, 161.0.
6
2-Cyclopropyl-6-phenylpyridine (3af):
Total reaction time for Conditions A: 0.5 h. Total reaction time for Conditions B: 30 h.
1
H NMR (400 MHz, CDCl ) δ 0.98-1.02 (2H, m), 1.13-1.17 (2H, m), 2.06-2.13 (1H, m), 7.07 (1H,
3
d, J = 8.0 Hz), 7.38 (1H, t, J = 7.6 Hz), 7.45 (2H, dd, J = 7.6, 8.0 Hz), 7.49 (1H, d, J = 7.6 Hz), 7.59
1
3
(
1H, dd, J = 7.6, 8.0 Hz), 8.01 (2H, d, J = 8.0 Hz); C NMR (100 MHz, CDCl
19.6, 126.8, 128.5, 128.7, 136.4, 139.7, 156.3, 162.4.
3
) δ 9.9, 17.2, 116.9,
1
6
2-Cyclobutyl-6-phenylpyridine (3ag):
SI-13

Total reaction time for Conditions A: 0.5 h. Total reaction time for Conditions B: 2 h.
1
H NMR (400 MHz, CDCl
3
) δ 1.92-2.00 (1H, m), 2.03-2.15 (1H, m), 2.37-2.50 (4H, m), 3.71-3.79
(
1H, m), 7.11 (1H, d, J = 7.6 Hz), 7.41 (1H, t, J = 7.2 Hz), 7.48 (2H, dd, J = 7.2, 7.6 Hz), 7.54 (1H,
1
3
d, J = 7.6 Hz), 7.67 (1H, dd, J = 7.6, 7.6 Hz), 8.01 (2H, d, J = 7.6 Hz); C NMR (100 MHz,
CDCl
3
) δ 18.3, 28.5, 42.3, 117.5, 119.3, 126.9, 128.59, 128.63, 136.7, 139.8, 156.4, 164.5.
6
2-(1-Benzylpiperidin-2-yl)-6-phenylpyridine (3ah):
Total reaction time for Conditions A: 0.5 h. Total reaction time for Conditions B: 2 h.
1
H NMR (400 MHz, CDCl ) δ 1.39-1.49 (1H, m), 1.56-1.65 (3H, m), 1.82 (1H, d, J = 12.4 Hz),
3
1
7
7
8
1
.96-2.06 (2H, m), 3.00-3.03 (2H, m), 3.50 (1H, dd, J = 2.4, 11.2 Hz), 3.76 (1H, d, J = 13.6 Hz),
.21 (1H, t, J = 6.8 Hz), 7.25-7.32 (4H, m), 7.40 (1H, t, J = 7.6 Hz), 7.47 (2H, dd, J = 7.6, 7.6 Hz),
.56 (1H, d, J = 7.6 Hz), 7.61 (1H, d, J = 7.6 Hz), 7.73 (1H, dd, J = 7.6, 7.6 Hz), 8.00 (2H, d, J =
1
3
.0 Hz); C NMR (100 MHz, CDCl
3
) δ 24.8, 25.9, 35.5, 53.1, 60.1, 70.7, 118.8, 119.6, 126.6,
27.0, 128.0, 128.64 (overlapped), 128.67, 137.3, 139.5, 139.8, 156.5, 165.2.
2
9
(
E)-2-Phenyl-6-styrylpyridine (3ai):
N
Total reaction time for Conditions A: 4 h. Total reaction time for Conditions B: 2 h.
1
H NMR (400 MHz, CDCl ) δ 7.25 (1H, d, J = 16.0 Hz), 7.32 (2H, dd, J = 7.2, 7.6 Hz), 7.39 (2H,
3
dd, J = 7.6, 7.6 Hz), 7.44 (1H, d, J = 7.6 Hz), 7.48-7.52 (2H, m), 7.59-7.63 (3H, m), 7.73 (1H, dd, J
1
3
=
7.6, 8.0 Hz), 7.78 (1H, d, J = 16.0 Hz), 8.09 (2H, d, J = 7.6 Hz); C NMR (100 MHz, CDCl
3
)
δ 118.9, 120.4, 127.0, 127.1, 128.2, 128.3, 128.7 (overlapped), 128.9, 132.8, 136.8, 137.2, 139.6,
155.3, 157.1.
6
2-Phenyl-6-(phenylethynyl)pyridine (3aj):
N
Total reaction time for Conditions A: 5 h. Total reaction time for Conditions B: 2 h.
-
1 1
3
IR (KBr) 3016, 2228, 1598, 1562, 1491, 1442, 1213, 1167, 1027 cm ; H NMR (400 MHz, CDCl )
SI-14

δ 7.37-7.39 (3H, m), 7.43 (1H, t, J = 7.2 Hz), 7.47 -7.50 (3H, m), 7.62-7.65 (2H, m), 7.68 (1H, d, J
1
3
=
7.6 Hz), 7.75 (1H, dd, J = 7.6, 8.0 Hz), 8.00 (2H, d, J = 7.6 Hz); C NMR (100 MHz, CDCl
δ 88.9, 89.1, 119.8, 122.4, 125.7, 127.2, 128.3, 128.7, 128.9, 129.2, 132.1, 136.8, 138.9, 143.3,
58.0.
3
)
1
6
Methyl 6-phenylpicolinate (3ak):
Total reaction time for Conditions A: 10 h.
IR (KBr) 3011, 1736, 1582, 1554, 1492, 1435, 1242, 1137, 1027; H NMR (400 MHz, CDCl
1
3
)
1
3
δ 4.03 (3H, s), 7.43-7.51 (3H, m), 7.91 (2H, d, J = 8.0 Hz), 8.04-7.08 (3H, m); C NMR (100 MHz,
CDCl
3
) δ 52.8, 123.3, 123.7, 127.2, 128.8, 129.4, 137.7, 138.5, 148.0, 157.7, 166.0.
6
3
Typical procedure of Mn(pic) -mediated pyridine formation:
To a solution of (E)-(1-azidoprop-1-enyl)benzene (1m) (48.0 mg, 0.30 mmol) and
-phenylcyclopropanol (2a) (60.7 mg, 0.45 mmol) in MeOH (3.0 mL) was added AcOH (35 μL,
1
0
7
.60 mmol) and Mn(pic)
h. The reaction mixture was quenched with pH 9 ammonium buffer and then extracted twice with
, and
3
(215.9 mg, 0.51 mmol), and the reaction mixture was stirred at 40 ºC for
ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO
4
concentrated. Purification of the crude product by flash column chromatography (silica gel;
hexane : ethyl acetate = 98 : 2) afforded 3ma (33.0 mg, 0.14 mmol) in 45% yield.
3
0
3
-Methyl-2,6-diphenylpyridine (3ma):
1
Reaction time: 7 h. H NMR (400 MHz, CDCl
3
) δ 2.41 (3H, s), 7.38 -7.49 (6H, m), 7.64 -7.66 (4H,
) δ 19.9, 118.7, 126.8, 127.9, 128.1,
28.56, 128.6, 129.19, 129.25, 139.3, 139.4, 140.9, 154.5, 158.1.
1
3
m), 8.06 (2H, d, J = 7.6 Hz); C NMR (100 MHz, CDCl
3
1
SI-15

6
Ethyl 3,6-diphenylpicolinate (3la):
1
Reaction time: 11 h. H NMR (400 MHz, CDCl
3
) δ 1.08 (3H, t, J = 7.2 Hz), 4.22 (2H, q, J = 7.2
Hz), 7.40-7.51 (8H, m), 7.82 (1H, d, J = 8.0 Hz), 7.88 (1H, d, J = 8.0 Hz), 8.09 (2H, d, J = 7.6 Hz);
1
3
C NMR (100 MHz, CDCl ) δ 13.7, 61.5, 121.5, 127.1, 128.0, 128.3, 128.5, 128.8, 129.4, 134.9,
3
138.08, 138.12, 138.80, 149.5, 155.9, 167.4.
6
2-Phenyl-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (3na):
N
1
Reaction time: 8 h. H NMR (400 MHz, CDCl
3
) δ 1.41 (4Η, m), 1.73 (2H, m), 1.84 (2H, m), 2.80
(
2H, t, J = 6.2 Hz), 3.05 (2H, t, J = 6.2 Hz), 7.37 (1H, t, J = 7.2 Hz), 7.43-7.49 (4H, m), 7.98 (2H, d,
1
3
J = 7.6 Hz); C NMR (100 MHz, CDCl
3
) δ 25.9, 26.1, 30.8, 31.6, 32.2, 34.9, 118.3, 126.8, 128.3,
128.6, 134.6, 137.2, 140.0, 154.9, 160.9.
6
2-(Dimethyl(phenyl)silyl)-6-phenylpyridine (3al):
N
SiMe Ph
2
The reaction was performed in the absence of AcOH. Reaction time: 24 h. Flash column
chromatography was using Florisil® adsorbent (100-200 mesh) by hexane/ethyl acetate (99 : 1) as
eluent.
1
H NMR (400 MHz, CDCl ) δ 0.66 (6H, s), 7.37 -7.38 (4H, m), 7.42 (1H, d, J = 7.2 Hz), 7.48 (2H,
3
13
dd, J = 7.2, 7.6 Hz), 7.61 (1H, dd, J = 7.2, 7.6 Hz), 7.65-7.67 (3H, m), 8.11 (2H, d, J = 7.6 Hz); C
NMR (100 MHz, CDCl ) δ -3.0, 119.3, 126.9, 127.8, 127.9, 128.6, 128.7, 129.1, 134.3, 134.6,
37.7, 139.8, 156.6, 166.3.
3
1
3
1
4
-Methyl-2,6-diphenylpyridine (3am):
SI-16

1
Reaction time: 2 h. H NMR (400 MHz, CDCl ) δ 2.49 (3H, s), 7.42 (2H, t, J = 7.4 Hz), 7.49-7.54
3
1
3
(
6H, m), 8.11 (4H, d, J = 7.4 Hz); C NMR (100 MHz, CDCl
3
) δ 21.4, 119.7, 127.0, 128.6, 128.8,
139.6, 148.3, 156.8.
6
(
(2R*,3R*)-3-Methyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)(phenyl)methanone (4am):
1
H NMR (400 MHz, CDCl ) δ 1.24 (3H, d, J = 7.2 Hz), 2.70 (1H, dd, J = 5.2, 17.2 Hz), 2.89 - 2.96
3
(
1H, m), 3.32 (1H, ddd, J = 1.6, 8.4, 17.2 Hz), 5.39 (1H, d, J = 4.0 Hz), 7.38 - 7.44 (3H, m), 7.51
(
2H, dd, J = 7.6, 7.6 Hz), 7.60 (1H, t, J = 7.2 Hz), 7.87 (2H, d, J = 7.2 Hz), 8.21 (2H, d, J = 7.6 Hz);
1
3
C NMR (100 MHz, CDCl
34.2, 136.2, 174.8, 197.7.
3
) δ 20.4, 34.1, 43.4, 84.3, 127.9, 128.4, 128.5, 129.2, 130.8, 133.2,
1
3
2
2,4,6-Triphenylpyridine (3an):
1
Reaction time: 6 h. H NMR (400 MHz, CDCl
3
) δ 7.44-7.56 (9H, m), 7.76 (2H, d, J = 7.6 Hz), 7.91
1
3
(
2H, s), 8.21 (4H, d, J = 8.0 Hz); C NMR (100 MHz, CDCl
3
) δ 117.1, 127.1, 127.2, 128.7, 128.97,
129.04, 129.1, 139.1, 139.6, 150.2, 157.5.
6
(
(2R*,3S*)-3,5-Diphenyl-3,4-dihydro-2H-pyrrol-2-yl)(phenyl)methanone (4an):
1
H NMR (400 MHz, CDCl
3
) δ 3.24 (1H, ddd, J = 1.2, 5.2, 17.2 Hz), 3.67 (1H, ddd, J = 2.4, 9.6,
17.2 Hz), 4.10 (1H, ddd, J = 4.8, 5.2, 9.6 Hz), 5.86 (1H, ddd, J = 1.2, 2.4, 4.8 Hz), 7.22 - 7.25 (3H,
SI-17

m), 7.30 - 7.34 (2H, m), 7.40 - 7.49 (5H, m), 7.57 (1H, tt, J = 1.2, 7.2 Hz), 7.91 (2H, dd, J = 1.2, 7.6
1
3
Hz), 8.15 (2H, dd, J = 1.2, 7.2 Hz); C NMR (100 MHz, CDCl
3
) δ 44.4, 44.7, 85.7, 126.8, 127.1,
128.1, 128.5 (overlapped), 128.9, 129.4, 131.0, 133.3, 133.8, 135.9, 144.4, 174.3, 196.8.
6
. One-pot synthesis of δ-lactams 7 from vinyl azides 1 and 1-ethoxycyclopropanol (5)
Typical procedure:
To a solution of α-azidostyrene (1a) (44.2 mg, 0.305 mmol) in ethanol (3 mL) was added
3
1-ethoxycyclopropanol (5) (37.3 mg, 0.365 mmol) and Mn(acac) (10.8 mg, 0.031 mmol) at room
temperature. NaBH (23.0 mg, 0.609 mmol) was added at 0 °C to the mixture as soon as the Mn(III)
4
decolourized. The mixture was then stirred at room temperature for 2 h. The resulting mixture was
quenched with water (5 mL) and extracted with dichloromethane (30 mL x 3). The organic extract
4
was washed with brine and dried with MgSO . The volatile materials were removed in vacuo and
the resulting crude residue was purified by flash column chromatography (silica gel; ethyl acetate:
diethyl ether: methanol = 50: 47.5: 2.5), affording δ-lactam 7a (45.5 mg, 0.259 mmol) in 85% yield.
3
3
6-Phenylpiperidin-2-one (7a):
1
3
H NMR (300 MHz, CDCl ) δ 1.62–1.96 (3H, m), 2.07–2.14 (1H, m), 2.37–2.54 (2H, m), 4.55 (1H,
1
3
3
dd, J = 4.3, 8.8 Hz), 5.83 (1H, br), 7.28–7.40 (5H, m); C NMR (75 MHz, CDCl ) δ 19.7, 31.3,
32.2, 57.8, 126.1, 128.0, 128.9, 142.5, 172.3.
6
-(4-Bromophenyl)piperidin-2-one (7b):
SI-18

O
N
H
Br
-
1 1
Colourless crystal; mp 158-160 °C; IR (NaCl) 3183, 2938, 2884, 1651, 1479, 590 cm ; H NMR
(
300 MHz, CDCl ) δ 1.64–1.97 (3H, m), 2.06–2.12 (1H, m), 2.36–2.55 (2H, m), 4.53 (1H, dd, J =
3
1
3
4
.5, 8.7 Hz), 5.81 (1H, s br), 7.18 (2H, d, J = 8.4 Hz), 7.50 (2H, d, J = 8.4 Hz); C NMR (75 MHz,
CDCl
3
) δ 19.5, 31.2, 32.1, 57.2, 121.8, 127.8, 132.0, 141.5, 172.2; ESIHRMS: Found: m/z 254.0172.
+
Calcd for C11
H
13NOBr: (M+H) 254.0181.
Methyl 4-(6-oxopiperidin-2-yl)benzoate (7c):
-
1 1
Colourless crystal; mp 174–176 °C; IR (NaCl) 3391, 2953, 2878, 1720, 1659, 1613 cm ; H NMR
(
300 MHz, CDCl
3
) δ 1.67–2.04 (3H, m), 2.09–2.16 (1H, m), 2.38–2.56 (2H, m), 3.92 (3H, s), 4.63
1
3
(
1H, dd, J = 4.8, 8.7 Hz), 5.95 (1H, s br), 7.37 (2H, d, J = 8.4 Hz), 8.04 (2H, d, J = 8.4 Hz); C
NMR (75 MHz, CDCl
3
) δ 19.5, 31.3, 31.9, 52.2, 57.5, 126.1, 129.9, 130.2, 147.5, 166.6, 172.3;
+
ESIHRMS: Found: m/z 234.1126. Calcd for C13
H
16NO
3
: (M+H) 234.1130.
6-p-Tolylpiperidin-2-one (7d):
-
1 1
Colourless crystal; mp 142–144 °C; IR (NaCl) 3192, 2951, 2876, 1651, 1514 cm ; H NMR (300
MHz, CDCl ) δ 1.59–1.71 (1H, m), 1.74–1.82 (1H, m), 1.84–1.97 (1H, m), 2.04-2.11 (1H, m), 2.35
3
1
3
(
(
3H, s), 2.38-2.56 (2H, m), 4.51 (1H, dd, J = 4.5, 8.7 Hz), 5.87 (1H, br), 7.18 (4H, m); C NMR
75 MHz, CDCl
3
) δ 19.7, 21.0, 31.2, 32.2, 57.6, 126.0, 129.5, 137.7, 139.5, 172.3; ESIHRMS:
+
Found: m/z 190.1230. Calcd for C12
H
16NO: (M+H) 190.1232.
3
3
6
-(4-Methoxyphenyl)piperidin-2-one (7e):
1
3
H NMR (300 MHz, CDCl ) δ 1.59-1.71 (1H, m), 1.72-1.98 (2H, m), 2.05-2.10 (1H, m), 2.35-2.54
(2H, m), 3.81 (3H, s), 4.49 (1H, dd, J = 4.5, 9.2 Hz), 5.82 (1H, br), 6.89 (2H, d, J = 8.7 Hz), 7.21
SI-19

1
3
(
3
2H, d, J = 8.6 Hz); C NMR (75 MHz, CDCl ) δ 20.0, 31.5, 32.5, 55.5, 57.6, 114.4, 127.5, 134.8,
159.5, 172.5.
3
7. Mn(acac) -catalyzed formation of 2-azabicyclo[3.3.1]non-2-en-1-ol derivatives 9 from vinyl
azides 1 and bicyclo[3.1.0]hexan-1-ols 8
Typical procedure:
3
To a solution of α-azidostyrene (1a) (1.45 g, 10.0 mmol) and Mn(acac) (0.35 g, 1.0 mmol) in
MeOH (100 mL) was added a solution of bicyclo[3.1.0]hexan-1-ol (8a) (1.18 g, 12.0 mmol) in
MeOH (30 mL) via a syring pump over 4 h. The reaction mixture was qunched with pH 9
ammonium buffer and then extracted twice with ethyl acetate. The combined organic extracts were
4
washed with brine, dried over MgSO and concentrated. Purification of the crude product by flash
column chromatography (silica gel; hexane : ethyl acetate = 60 : 40) afforded 9aa (1.87 g, 8.7 mmol)
in 87% yield.
6
(1S*,5S*)-3-Phenyl-2-azabicyclo[3.3.1]non-2-en-1-ol (9aa):
1
H NMR (400 MHz, CDCl
3
) δ 1.18-1.30 (1H, m), 1.47–1.69 (5H, m), 1.81-1.84 (1H, m), 1.90 (1H,
endo), 2.50-2.52 (1H, m, C H), 2.61 (1H, s br,
exo), 7.38-7.41 (3H, m), 7.84 (2H, dd, J = 1.6, 7.2 Hz); C
) δ 19.3, 27.9, 31.9, 33.4, 36.1, 37.6, 84.0 (C ), 126.4, 128.2, 130.0, 138.5,
dd, J = 2.8, 12.0 Hz), 2.42 (1H, d, J = 18.8 Hz, C
OH), 2.83 (1H, dd, J = 6.8, 18.8 Hz, C
NMR (100 MHz, CDCl
65.7 (C ).
The reaction of vinyl azide 1a (50.4 mg, 0.347 mmol) with chiral bicyclo[3.1.0]hexan-1-ol (9a)
85% ee, 40.9 mg, 0.417 mmol) using 5 mol % Mn(acac) afforded racemic 9aa (62.5 mg, 0.290
4
H
5
13
4
H
3
1
1
3
(
3
6
mmol) in 84% yield.
(
1S*,5S*)-3-p-Tolyl-2-azabicyclo[3.3.1]non-2-en-1-ol (9ba):
SI-20

9
OH
2
1
N
8
3
4
5
6
Me
H
7
-
1 1
White solid; mp 122-123 °C; IR (NaCl) 3404, 2931, 1707, 1609, 1416, 1452 cm ; H NMR (300
MHz, CDCl ) δ 1.15-1.30 (1H, m), 1.45-1.68 (5H, m), 1.81–1.86 (1H, m), 1.88 (1H, dd, J = 3.2,
6.4 Hz), 2.37 (3H, s), 2.41 (1H, d, J = 18.6 Hz, C endo), 2.48-2.50 (1H, m, C H), 2.80 (1H, dd, J
6.9, 18.6 Hz, C exo), 2.87 (1H, s br, OH), 7.19 (2H, d, J = 8.0 Hz), 7.73 (2H, d, J = 8.0 Hz); C
NMR (75 MHz, CDCl
40.2, 165.3 (C ); ESIHRMS: Found: m/z 230.1550. Calcd for C15
3
1
4
H
5
1
3
=
4
H
3
) δ 19.3, 21.3, 28.0, 32.0, 33.4, 36.2, 37.7, 84.0 (C
1
), 126.4, 128.9, 135.9,
+
1
3
H
20NO: (M+H) 230.1545.
(
1S*, 5S*)-3-(2-Methoxyphenyl)-2-azabicyclo[3.3.1]non-2-en-1-ol (9ca):
-
1 1
White solid; mp 124-125 °C; IR (NaCl) 3422, 2928, 1624, 1602, 1420, 1246, 1130 cm ; H NMR
(
400 MHz, CDCl
1H, d, J = 19.2 Hz, C
exo), 3.84 (3H, s), 6.91 (1H, d, J = 8.0 Hz), 6.98 (1H, dd, J = 7.2, 7.6 Hz), 7.32 (1H, d, J =
3
) δ 1.50-1.77 (6H, m), 1.82–1.85 (1H, m), 1.89 (1H, dd, J = 2.8, 12.4 Hz), 2.42
(
4
H
endo), 2.43 (1H, m, C H), 2.70 (1H, s br, OH), 2.77 (1H, dd, J = 6.8, 19.2
5
4
Hz, C H
1
3
7
3
2
3
.6 Hz) 7.34 (1H, dd, J = 7.2, 8.0 Hz); C NMR (100 MHz, CDCl ) δ 19.2, 28.3, 31.9, 35.9, 36.6,
7.8, 55.5, 83.9 (C
1
), 111.1, 120.8, 128.8, 130.0, 130.4, 156.7, 169.9 (C
3
); ESIHRMS: Found: m/z
+
46.1493. Calcd for C15
H
20NO
2
: (M+H) 246.1494.
(
1S*, 5S*)-3-(4-Methoxyphenyl)-2-azabicyclo[3.3.1]non-2-en-1-ol (9da):
-
1 1
White solid; mp 120-121 °C; IR (NaCl) 3421, 2932, 1624, 1574, 1452, 1244, 1119 cm ; H NMR
400 MHz, CDCl ) δ 1.20-1.27 (1H, m), 1.46–1.67 (5H, m), 1.80-1.83 (1H, m), 1.88 (1H, d, J =
2.4 Hz), 2.39 (1H, d, J = 18.8 Hz, C endo), 2.49 (1H, m, C H), 2.73 (1H, s br, OH), 2.79 (1H, dd,
J = 6.8, 18.8 Hz, C exo), 3.84 (3H, s), 6.90 (2H, d, J = 8.4 Hz), 7.80 (2H, d, J = 8.4 Hz); C NMR
100 MHz, CDCl ) δ 19.4, 28.1, 32.0, 33.1, 36.3, 37.7, 55.3, 84.0 (C
64.6 (C ); ESIHRMS: Found: m/z 246.1495. Calcd for C15
(
3
1
4
H
5
1
3
4
H
(
3
1
), 113.5, 128.0, 131.2, 161.2,
+
1
3
H
20NO
2
: (M+H) 246.1494.
(
1S*,5S*)-3-(2-Bromophenyl)-2-azabicyclo[3.3.1]non-2-en-1-ol (9ea):
SI-21

-
1 1
White solid; mp 145-146 °C; IR (NaCl) 3420, 2924, 1707, 1647, 1138, 1120 cm ; H NMR (300
MHz, CDCl ) δ 1.63-1.75 (6H, m), 1.86-1.91 (2H, m), 2.34 (1H, d, J = 19.6 Hz, C
1H, m, C H), 2.69 (1H, dd, J = 6.6, 19.6 Hz, C exo), 2.77 (1H, s br, OH), 7.21 (1H, ddd, J = 1.8,
.5, 7.8 Hz), 7.27 (1H, dd, J = 1.8, 7.2 Hz), 7.34 (1H, dd, J = 7.2, 7.5 Hz), 7.57 (1H, d, J = 7.8 Hz);
3
4
Hendo), 2.38-2.46
(
5
4
H
7
1
3
C NMR (75 MHz, CDCl
3
) δ 19.3, 28.0, 31.6, 35.9, 36.8, 37.4, 83.9 (C
1
), 119.9, 127.6, 128.9,
+
1
3
29.7, 133.1, 141.9, 170.1 (C ); ESIHRMS: Found: m/z 294.0492. Calcd for C14H17NOBr: (M+H)
294.0494.
(
1S*,5S*)-3-(4-Bromophenyl)-2-azabicyclo[3.3.1]non-2-en-1-ol (9fa):
-
1 1
White solid; mp 149-150 °C; IR (NaCl) 3582, 2928, 1711, 1628, 1586, 1215 cm ; H NMR (300
MHz, CDCl ) δ 1.13-1.25 (1H, m), 1.50–1.68 (5H, m), 1.80-1.83 (1H, m), 1.89 (1H, dd, J = 1.6,
1.6 Hz), 2.36 (1H, d, J = 18.8 Hz, C endo), 2.51-2.52 (1H, m, C H), 2.72 (1H, s br, OH), 2.78 (1H,
dd, J = 7.2, 18.8 Hz, C exo), 7.52 (1H, d, J = 8.4 Hz), 7.72 (1H, d, J = 8.4 Hz); C NMR (100
MHz, CDCl ) δ 19.3, 28.0, 31.9, 33.2, 36.0, 37.6, 84.2 (C
ESIHRMS: Found: m/z 294.0490. Calcd for C14
3
1
4
H
5
1
3
4
H
3
1
), 124.6, 128.1, 131.4, 137.3, 164.4 (C
3
);
+
H
17NOBr: (M+H) 294.0494.
Methyl 4-((1S*,5S*)-1-hydroxy-2-azabicyclo[3.3.1]non-2-en-3-yl)benzoate (9ga):
-
1 1
Pale yellow solid; mp 142-143 °C; IR (NaCl) 3580, 2930, 1719, 1630, 1568, 1215 cm ; H NMR
300 MHz, CDCl ) δ 1.17−1.26 (1Η, m), 1.47-1.70 (5H, m), 1.81–1.86 (1H, m), 1.90 (1H, d, J = 3.0,
2.0 Hz), 2.41 (1H, d, J = 18.9 Hz, C endo), 2.52-2.54 (1H, m, C H), 2.70 (1H, s br, OH), 2.83 (1H,
dd, J = 6.9, 18.9 Hz, C exo), 3.93 (3H, s), 7.88 (2H, d, J = 8.4 Hz), 8.05 (2H, d, J = 8.4 Hz); C
NMR (75 MHz, CDCl
(
3
1
4
H
5
1
3
4
H
3
) δ 19.3, 28.0, 31.9, 33.5, 36.0, 37.6, 52.2, 84.3 (C
1
), 126.4, 129.5, 131.3,
+
1
42.5, 164.8 (C
3
3
), 166.7; ESIHRMS: Found: m/z 274.1445. Calcd for C16H20NO : (M+H)
274.1443.
6
(
1S*,5S*)-3-(1-Tosyl-1H-pyrrol-2-yl)-2-azabicyclo[3.3.1]non-2-en-1-ol (9ia):
SI-22

9
OH
2
1
N
8
3
4
5
6
N
Ts
H
7
1
H NMR (400 MHz, CDCl
3
) δ 1.30-1.44 (2H, m), 1.51–1.66 (5H, m), 1.74 (1H, dd, J = 3.2, 12.0
endo), 2.37-2.39 (1H, m, C H), 2.39 (3H, s),
exo), 6.29 (1H, dd, J = 3.2, 3.6 Hz), 6.51 (1H, dd, J = 1.6, 3.2 Hz),
Hz), 2.61 (1H, s br, OH), 2.18 (1H, d, J = 18.8 Hz, C
4
H
5
2
.75 (1H, dd, J = 6.8, 18.8 Hz, C
4
H
1
3
7
.28 (2H, d, J = 8.0 Hz), 7.51 (1H, dd, J = 1.6, 3.6 Hz), 7.73 (2H, d, J = 8.0 Hz); C NMR (100
MHz, CDCl
3
) δ 19.2, 21.6, 28.0, 31.6, 35.2, 35.9, 37.5, 84.0 (C
).
1
), 111.0, 116.4, 126.2, 126.9, 129.4,
134.2, 138.0, 144.2, 159.0 (C
3
6
(
1S*,5S*)-3-(1-Tosyl-1H-indol-2-yl)-2-azabicyclo[3.3.1]non-2-en-1-ol (9ja):
9
OH
2
1
N
8
3
4
5
6
N
Ts
H
7
1
H NMR (400 MHz, CDCl
9.2 Hz, C endo), 2.48-2.52 (1H, m, C
exo), 6.73 (1H, s), 7.12 (2H, d, J = 8.0 Hz), 7.21 (1H, dd, J = 8.0, 8.0 Hz), 7.33 (1H, dd, J = 8.0,
3
) δ 1.50-1.71 (5H, m), 1.87–1.96 (3H, m), 2.27 (3H, s), 2.39 (1H, d, J =
1
4
H
5
H), 2.90 (1H, s br, OH), 3.11 (1H, dd, J = 6.8, 19.2 Hz,
4
C H
1
3
8
.4 Hz), 7.43 (1H, d, J = 8.0 Hz), 7.67 (2H, d, J = 8.0 Hz), 8.10 (1H, d, J = 8.4 Hz); C NMR (100
MHz, CDCl
3
) δ 19.1, 21.5, 28.1, 31.8, 35.6, 37.7, 37.8, 84.2 (C
).
1
), 113.0, 115.7, 121.5, 124.3, 125.5,
127.1, 129.5, 130.1, 134.1, 137.5, 140.5, 144.8, 164.5 (C
3
6
(
1S*,4*R,5S*)-4-Methyl-3-phenyl-2-azabicyclo[3.3.1]non-2-en-1-ol (9ma):
9
OH
1
2
Me
3
N
8
Ph
4
5
H
6
7
H
An inseparable mixture (exo : endo = 85 : 15). A pure exo isomer was obtained by
1
13
recrystallization from ethyl acetate/hexane; H and C NMR are described for the exo isomer.
1
Colorless crystal (CCDC-735783); H NMR (400 MHz, CDCl
3
) δ 1.09 (3H, d, J = 7.2 Hz, C
H), 2.66 (1H, q, J = 7.2 Hz, C H), 2.73 (1H,
s br, OH), 7.38-7.40 (3H, m), 7.68-7.71 (2H, m); C NMR (100 MHz, CDCl ) δ 19.7, 19.9, 31.9,
2.1, 36.1, 36.6, 37.6, 84.6 (C ), 127.0, 128.4, 129.5, 138.8, 171.1 (C ).
4 3
CH ),
1
.25–1.32 (1H, m), 1.49–1.78 (7H, m), 2.11 (1H, m, C
5
4
1
3
3
3
1
3
(
1S*,5S*,6S*)-6-Isopropyl-3-phenyl-2-azabicyclo[3.3.1]non-2-en-1-ol (9ab):
SI-23

An inseparable mixture (exo : endo = 85 : 15). A pure exo isomer was obtained by
1
13
recrystallization from ethyl acetate/hexane; H and C NMR are described for the exo isomer.
-
1 1
Colorless crystal; mp 142-143 °C; IR (NaCl) 3581, 3016, 1708, 1630, 1533, 1215, 1109 cm ; H
NMR (400 MHz, CDCl ) δ 0.96 (3H, d, J = 6.4 Hz, C CH(CH ), 0.98 (3H, d, J = 6.4 Hz,
CH(CH ), 1.02-1.05 (1H, m), 1.27 -1.31 (1H, m), 1.47-1.51 (1H, m), 1.61-1.89 (4H, m), 1.99
1H, dd, J = 2.4, 12.4 Hz), 2.39 (1H, d, J = 19.2 Hz, C endo), 2.56 (1H, m, C H), 2.83 (1H, s br,
OH), 2.95 (1H, dd, J = 7.2, 19.2 Hz, C exo), 7.28-7.43 (3H, m), 7.84 (2H, dd, J = 2.4, 8.0 Hz); C
NMR (100 MHz, CDCl ) δ 20.9, 21.0, 21.9, 26.2, 29.3, 31.2, 33.2, 35.3, 46.8, 84.1 (C
3
6
3 2
)
C
6
3 2
)
(
4
H
5
13
4
H
3
1
), 126.4,
+
1
28.3, 130.0, 138.6, 165.2 (C
3
); ESIHRMS: Found: m/z 258.1857. Calcd for C17H24NO: (M+H)
258.1858.
6
(
1S*,5S*,6R*)-3-Phenyl-6-vinyl-2-azabicyclo[3.3.1]non-2-en-1-ol (9ac):
An inseparable mixture (exo : endo = 83 : 17). A pure exo isomer was obtained by
1
13
recrystallization from ethyl acetate/hexane; H and C NMR are described for the exo isomer.
1
Colorless crystal (CCDC-735784); H NMR (400 MHz, CDCl
3
) δ 1.42-1.51 (1H, m), 1.62-1.68 (3H,
m), 1.87 (1H, ddd, J = 4.4, 12.8, 13.6 Hz), 2.07 (1H, dd, J = 2.8, 12.4 Hz), 2.27 (1H, m), 2.44 (1H,
4
m), 2.48 (1H, d, J = 18.8 Hz, C endo), 2.64 (1H, s br, OH), 2.95 (1H, dd, J = 7.2, 18.8 Hz, C Hexo),
4
H
5
.13-5.17 (2H, m, C
6
CH=CH
2
), 5.99 (1H, ddd, J = 6.0, 10.8, 17.0 Hz, C
6
CH=CH
2
), 7.39-7.43 (3H,
1
3
m), 7.84 (2H, d, J = 8.0 Hz); C NMR (100 MHz, CDCl
3
) δ 22.9, 31.3, 33.2, 33.3, 34.7, 42.5, 84.2
(
1 3
C ), 114.8, 126.4, 128.3, 130.1, 138.5, 140.4, 164.9 (C ).
(
1S*,5S*,6S*)-6-Allyl-3-phenyl-2-azabicyclo[3.3.1]non-2-en-1-yl acetate (9ad’):
2 2
Compound 9ad (86% NMR yield by using Cl CHCHCl as internal standard) was prepared
according to the same procedure as 9aa from vinyl azide 1a (43.8 mg, 0.30 mmol) and
SI-24

cyclopropanol 9d (50.2 mg, 0.36 mmol) by using Mn(acac)
However, compound 9ad itself was too unstable to be isolated. Therefore, the crude product 9ad
71.1 mg, 0.28 mmol) was then treated with Ac O (0.30 mL, 2.79 mmol), DMAP (4.0 mg, 0.03
mmol), and Et N (80 µL, 0.56 mmol) in CH Cl (1.0 mL) at room temperature for 8 h. After that,
the reaction was diluted with CH Cl and water, the aqueous layer was extracted twice with CH Cl
The combined organic layers were washed with brine, dried over MgSO and concentrated.
Purification of the crude product by flash column chromatography (silica gel; hexane : ethyl acetate
90 : 10) afforded 9ad’ (60.2 mg, 0.20 mmol) in 67% yield (from 1a).
3
(11.6 mg, 0.03 mmol) as a catalyst.
(
2
3
2
2
2
2
2
2
.
4
=
1
13
An inseparable mixture (exo : endo = 86 : 14); H and C NMR are described for the exo isomer.
-
1 1
Yellow liquid; IR (NaCl) 3561, 2932, 1730, 1634, 1447, 1252 cm ; H NMR (400 MHz, CDCl
δ 1.44-1.48 (2H, m), 1.61-1.63 (1H, m), 1.75-1.78 (1H, m), 2.09 (3H, s, C OCOCH ), 2.20-2.33
6H, m), 2.46 (1H, d, J = 18.8 Hz, C endo), 2.95 (1H, dd, J = 6.4, 18.8 Hz, C exo), 5.00-5.09 (2H,
m, C CH CH=CH ), 5.70-5.80 (1H, m, C CH CH=CH ), 7.37-7.38 (3H, m), 7.80 (2H, m);
NMR (100 MHz, CDCl ) δ 21.9, 22.8, 28.0, 29.1, 31.8, 35.4, 36.2, 39.0, 93.8 (C ), 116.2, 126.6,
3
)
1
3
(
4
H
4
H
1
3
6
2
2
6
2
2
C
3
1
1
28.2, 130.0, 137.2, 138.6, 165.6 (C
3
), 170.0 (C
1
OCOCH
3
); ESIHRMS: Found: m/z 298.1805.
+
Calcd for C19
H
24NO : (M+H) 298.1807.
2
6
(
1S*,5S*,6R*)-3,6-Diphenyl-2-azabicyclo[3.3.1]non-2-en-1-ol (9ae):
9
OH
2
1
8
N
3
Ph
Ph
5
6
H
4
H
7
An inseparable mixture (exo : endo = 94 : 6). A pure exo isomer was obtained by
1
13
recrystallization from ethyl acetate/hexane; H and C NMR are described for the exo isomer.
1
Colorless crystal (CCDC-735785); H NMR (400 MHz, CDCl
3
) δ 1.44-1.48 (1H, m), 1.64-1.73 (1H,
m), 1.81-1.86 (1H, m), 1.90 (1H, dd, J = 7.2 Hz), 2.04 (1H, ddd, J = 4.4, 13.2, 13.6 Hz), 2.13-2.17
1H, m), 2.68 (1H, d, J = 18.8 Hz, C endo), 2.82 (1H, s br, OH), 2.87-2.91 (2H, m, C H and C H),
exo), 7.23 (1H, t, J = 7.2 Hz), 7.35 (2H, dd, J = 7.2, 8.0 Hz),
(
4
H
5
6
3
7
8
4
.08 (1H, dd, J = 7.2, 18.8 Hz, C H
1
3
.41-7.45 (5H, m), 7.89 (2H, m); C NMR (100 MHz, CDCl
3
) δ 22.0, 30.8, 34.0, 34.4, 35.1, 43.0,
).
4.1 (C ), 125.9, 126.5, 127.2, 128.33, 128.35, 130.2, 138.5, 143.3, 164.7 (C
1
3
6
(
1S*,5S*,6S*)-6-((Methoxymethoxy)methyl)-3-phenyl-2-azabicyclo[3.3.1]non-2-en-1-ol (9af):
1
13
An inseparable mixture (exo : endo = 85 : 15); H and C NMR are described for the exo
isomer.
SI-25

1
H NMR (400 MHz, CDCl
1H, m), 1.94-1.97 (1H, m), 2.42 (1H, d, J = 18.8 Hz, C
7.2, 18.8 Hz, C exo), 3.52 (3H, s, C CH OCH OCH ), 3.52 (1H, dd, J = 7.6, 9.2 Hz, C
.62 (1H, dd, J = 8.4, 9.2 Hz, C CHH’O), 4.08 (1H, s br, OH), 4.63 (2H, s, C CH OCH
.37-7.40 (3H, m), 7.79 (2H, dd, J = 1.6, 8.0 Hz); C NMR (100 MHz, CDCl ) δ 20.8, 29.1, 31.2,
3.1, 35.1, 39.2, 55.1, 68.3, 84.0 (C ), 96.4 (C CH OCH OCH ), 126.4, 128.2, 130.1, 138.3, 165.6
).
3
) δ 1.33-1.42 (1H, m), 1.50-1.56 (2H, m), 1.69-1.78 (2H, m), 1.82-1.91
endo), 2.51 (1H, m, C H), 2.92 (1H, dd, J
CHH’O),
OCH ),
(
4
H
5
=
4
H
6
2
2
3
6
3
7
3
6
6
2
2
3
1
3
3
1
6
2
2
3
(
C
3
(
1R*,5S*,7S*)-3,7-Diphenyl-2-azabicyclo[3.3.1]non-2-en-1-ol (9ag):
3
4
-1 1
Colorless crystal (CCDC-809896); mp 162-163 °C; IR (NaCl) 3446, 2924, 1631 cm ; H NMR
400 MHz, CDCl ) δ 1.73-1.78 (2H, m), 1.84-1.91 (2H, m), 2.02 (1H, dd, J = 3.0, 12.2 Hz),
.08-2.13 (1H, m), 2.54-2.66 (3H, m), 2.85 (1H, s br, OH), 3.93 (1H, dd, J = 6.8, 18.8 Hz, C
.17-7.20 (3H, m), 7.28-7.30 (2H, m), 7.43-7.46 (3H, m), 7.88-7.91 (2H, dd, J = 2.0, 7.6 Hz); C
) δ 28.1, 33.6, 35.8, 37.5, 39.9, 45.0, 84.3 (C ), 126.3, 126.5, 127.0, 128.35,
28.43, 130.3, 138.4, 144.6, 165.6 (C ); ESIHRMS: Found: m/z 292.1704. Calcd for C20
(
3
2
7
4
Hexo),
1
3
NMR (100 MHz, CDCl
3
1
1
3
H
22NO:
+
(
M+H) 292.1701.
(
3S*,5R*)-3-(2-Oxo-2-phenylethyl)-5-phenylcyclohexanone (10ag):
O
1
2
6
O
Ph
3
5 Ph
4
1
13
1
1
The structure of 10ag was determined by H and C NMR, H- H COSY, HMBC, and HMQC
spectra. The stereochemistry was deduced by NOESY correlation analysis.
o
-1
1
White solid; mp 87-88 C; IR (NaCl) 3026, 2955, 1713, 1682 cm ; H NMR (400 MHz,
CDCl ) δ 1.70 (1H, ddd, J = 12.0, 12.0, 13.0 Hz, C ax), 2.23-2.29 (2H, m, C eq), 2.52
1H, dd, J = 13.5, 14.0 Hz, C ax), 2.60-2.68 (3H, m, C H and C CH ), 3.02-3.14 (3H, m, C H and
eq), 7.24-7.27 (3H, m), 7.35 (2H, dd, J = 7.5, 7.5 Hz), 7.50 (2H, dd, J = 7.5, 7.5 Hz), 7.60
3
4
H
6 4
Heq and C H
(
6
H
3
3
2
5
2 ax
C H H
1
3
(
(
1H, t, J = 7.5 Hz), 7.95-7.97 (2H, d, J = 7.5 Hz); C NMR (100 MHz, CDCl
3
3
) δ 34.1 (C ), 39.4
C
4
), 43.3 (C
36.8, 143.8, 198.1, 209.4 (C
93.1542.
5
), 45.1 (C
2
), 47.2 (C
6
), 48.5 (C
3
CH
2
), 126.5, 126.8, 128.0, 128.69, 128.70, 133.3,
+
1
2
1
); ESIHRMS: Found: m/z 293.1547. Calcd for C20H21O: (M+H)
SI-26

8. One-pot synthesis of 2-azabicyclo[3.3.1]nonanes 11 from vinyl azides 1 and
bicyclo[3.1.0]hexan-1-ols 8
Typical procedure:
3
To a solution of α-azidostyrene (1a) (44.2 mg, 0.305 mmol) and Mn(acac) (10.6 mg, 0.030
mmol) in MeOH (2 mL) was added a solution of bicyclo[3.1.0]hexan-1-ol (8a) (35.9 mg, 0.365
mmol) in methanol (1 mL) via a syring pump over 1 h. Sodium cyanoborohydride (57.4 mg, 0.913
mmol) followed by HCl (0.30 mL, 0.913 mmol, 3.0 N in MeOH) was added to the mixture and
stirred for 2 h at room temperature. The reaction was then quenched by addition of saturated
aqueous sodium bicarbonate solution. The aqueous layer was extracted twice with CH
combined organic layers were washed with brine, dried over MgSO and concentrated. Purification
of the crude product by flash column chromatography (aluminum oxide, pH = 10; CH Cl : MeOH
99: 1) afforded 12aa (43.0 mg, 0.21 mmol) in 70% yield.
2 2
Cl , and the
4
2
2
=
6
(
1R*,3R*,5S*)-3-phenyl-2-azabicyclo[3.3.1]nonane (11aa):
1
H NMR (400 MHz, CDCl
H), 7.24 (1H, t, J = 7.2 Hz), 7.32 (2H, dd, J = 7.2, 7.6 Hz), 7.46 (2H, d, J = 7.6
Hz); C NMR (100 MHz, CDCl ) δ 15.7, 25.0, 28.8, 33.2, 34.7, 37.9, 46.5, 52.6, 126.8, 126.9, 128.2,
46.2.
3
1
) δ 1.26-1.63 (8H, m), 2.07-2.29 (4H, m), 3.47 (1H, m, C H), 4.14 (1H,
dd, J = 4.4, 12.4 Hz, C
3
13
3
1
(1R*,3R*,5S*)-3-p-Tolyl-2-azabicyclo[3.3.1]nonane (11ba):
SI-27

-
1 1
White solid; mp 102-104 °C; IR (NaCl) 3340, 3019, 2930, 1514, 1456 cm ; H NMR (400 MHz,
CDCl ) δ 1.24-1.27 (1H, m) 1.36-1.58 (7H, m), 2.08-2.23 (4H, m), 2.33 (3H, s), 3.45 (1H, m, C H),
.10 (1H, dd, J = 4.8, 12.8 Hz, C H), 7.13 (2H, d, J = 8.0 Hz), 7.34 (2H, d, J = 8.0 Hz); C NMR
3
1
1
3
4
3
(
100 MHz, CDCl
3
) δ 15.7, 21.1, 25.0, 28.8, 33.3, 34.7, 37.9, 46.6, 52.3, 126.8, 128.9, 136.4, 143.2;
+
ESIHRMS: Found: m/z 216.1751. Calcd for C15
H
22N: (M+H) 216.1752.
(
1R*,3R*,5S*)-3-(4-Methoxyphenyl)-2-azabicyclo[3.3.1]nonane (11da):
-
1 1
Colourless crystal; mp 51-53 °C; IR (NaCl) 3390, 3015, 2932, 1611, 1512, 1244 cm ; H NMR
(
300 MHz, CDCl
3
) δ 1.23-1.60 (8H, m), 2.01-2.28 (4H, m), 3.44 (1H, m, C
1
H), 3.79 (3H, s), 4.08
1
3
(1H, dd, J = 4.5, 12.3 Hz, C
3
H), 6.85 (2H, d, J = 8.7 Hz), 7.37 (2H, d, J = 8.7 Hz); C NMR (75
MHz, CDCl
3
) δ 15.7, 25.0, 28.7, 33.3, 34.7, 37.9, 46.6, 51.9, 55.2, 113.6, 127.9, 138.4, 158.5;
+
ESIHRMS: Found: m/z 232.1704. Calcd for C15
H
22NO: (M+H) 232.1701.
(
1R*,3R*,5S*)-3-(4-Bromophenyl)-2-azabicyclo[3.3.1]nonane (11fa):
-
1 1
White solid; mp 93-95 °C; IR (NaCl) 3333, 3017, 2928, 1487 cm ; H NMR (300 MHz, CDCl
3
) δ
H),
) δ 15.7, 25.0, 28.8,
1
7
3
.25-1.60 (8H, m), 2.01-2.25 (4H, m), 3.44 (1H, m, C
1
H), 4.09 (1H, dd, J = 4.8, 12.6 Hz, C
3
1
3
.33 (2H, d, J = 8.4 Hz), 7.42 (2H, d, J = 8.4 Hz); C NMR (75 MHz, CDCl
3
3.2, 34.7, 38.1, 46.4, 52.1, 120.4, 128.7, 131.3, 145.5; ESIHRMS: Found: m/z 280.0696. Calcd for
+
C
14
H
19NBr: (M+H) 280.0701.
(
1R*, 3R*, 5S*, 6S*)-6-Isopropyl-3-phenyl-2-azabicyclo[3.3.1]nonane (11ab):
9
H H 2
H
1
N
8
7
Ph
3
5
H
4
H
6
1
13
An inseparable mixture (exo : endo = 82 : 18). H and C NMR are described for the exo isomer.
-
1 1
White solid; mp 69-77 °C; IR (NaCl) 3349, 3022, 2940, 1634, 1366, 1136 cm ; H NMR (400 MHz,
CDCl ) δ 0.90 (3H, d, J = 6.8 Hz, C CH(CH ), 0.96 (3H, d, J = 6.8 Hz, C CH(CH ), 1.37-1.67
7H, m), 1.81-1.86 (1H, m), 1.97-2.00 (1H, m), 2.16-2.22 (2H, m), 2.35-2.40 (1H, m), 3.41 (1H, m,
3
6
3
)
2
6
3 2
)
(
C
1 3
H), 4.21 (1H, dd, J = 4.8, 12.8 Hz, C H), 7.23 (1H, t, J = 7.2 Hz), 7.32 (2H, dd, J = 7.2, 7.6 Hz),
1
3
3
7.46 (2H, d, J = 7.6 Hz); C NMR (100 MHz, CDCl ) δ 17.2, 21.3, 22.4, 23.1, 26.0, 26.5, 30.7,
SI-28

3
9.7, 46.5, 47.9, 53.1, 126.9, 127.0, 128.3, 146.1; ESIHRMS: Found: m/z 244.2067. Calcd for
+
C
17
H
26N: (M+H) 244.2065.
(
1R*, 3R*, 5S*, 6R*)-6-Vinyl-3-phenyl-2-azabicyclo[3.3.1]nonane (11ac):
9
H H 2
H
1
N
8
7
Ph
3
5
H
4
H
6
1
13
An inseparable mixture (exo : endo = 81 : 19). H and C NMR are described for the exo isomer.
-
1 1
Yellow liquid; IR (NaCl) 3348, 3024, 2930, 1636, 1603, 1574 cm ; H NMR (300 MHz, CDCl
3
) δ
H), 4.21 (1H, d, J = 4.6,
CH=CH ), 7.21-7.34 (3H, m),
) δ 19.1, 23.3, 30.4, 30.7, 39.6, 43.9, 46.4, 53.0,
1
1
7
.42-1.64 (6H, m), 1.99-2.27 (4H, m), 2.54-2.56 (1H, m), 3.44 (1H. m, C
2.3 Hz, C H), 5.05-5.15 (2H, m, C CH=CH ), 5.98-6.09 (1H, m, C
.46 (2H, d, J = 7.0 Hz); C NMR (75 MHz, CDCl
1
3
6
2
6
2
1
3
3
1
13.8, 126.90, 126.93, 128.3, 142.0, 146.1; ESIHRMS: Found: m/z 228.1750. Calcd for C16
H
22N:
+
(
M+H) 228.1752.
(
1R*, 3R*, 5S*, 6S*)-6-Allyl-3-phenyl-2-azabicyclo[3.3.1]nonane (11ad):
9
H H 2
H
1
N
8
7
Ph
3
5
H
4
H
6
1
13
An inseparable mixture (exo : endo = 81 : 19). H and C NMR are described for the exo isomer.
-
1 1
White solid; mp 60-62 °C; IR (NaCl) 3341, 3073, 2924, 1638, 1601, 1557, 1489 cm ; H NMR
300 MHz, CDCl ) δ 1.40-1.52 (5H, m), 1.78-1.88 (2H, m), 1.92-2.02 (2H, m), 2.15-2.26 (2H, m),
.40-2.51 (1H, m), 3.43 (1H, m, C H), 4.22 (1H, dd, J = 4.8, 12.3 Hz, C H), 4.92-5.05 (2H, m,
CH CH=CH ), 5.69-5.86 (1H, m, C CH CH=CH ), 7.23 (1H, t, J = 7.2 Hz), 7.32 (2H, dd, J = 7.2,
.5 Hz), 7.46 (2H, d, J = 7.5 Hz); C NMR (100 MHz, CDCl ) δ 18.8, 22.7, 29.1, 29.9, 36.1, 39.8,
(
3
2
1
3
C
6
2
2
6
2
2
1
3
7
4
3
0.2, 46.4, 53.0, 115.2, 126.90, 126.92, 128.2, 138.4, 145.8; ESIHRMS: Found: m/z 242.1913.
+
Calcd for C17
H
24N: (M+H) 242.1909.
(
1R*, 3R*, 5S*, 6R*)-6-Phenyl-3-phenyl-2-azabicyclo[3.3.1]nonane (11ae):
9
H H 2
H
1
N
8
7
Ph
3
Ph
5
H
4
H
6
1
13
An inseparable mixture (exo : endo = 90 : 10). H and C NMR are described for the exo isomer.
-
1
1
Yellow liquid; IR (NaCl) 3356, 3024, 2932, 1601, 1568 cm ; H NMR (300 MHz, CDCl
3
) δ
1
2
.33-1.38 (1H, m), 1.62-1.78 (2H, m), 1.96-2.01 (4H, m), 2.31-2.41 (1H, m), 2.47-2.51 (1H, m),
.70-2.83 (2H, m), 3.53 (1H, m, C
1
3
H), 4.26 (1H, dd, J = 4.5, 12.3 Hz, C H), 7.17-7.37 (6H, m),
SI-29

1
3
7
3
.44 (2H, d, J = 7.5 Hz), 7.51 (2H, d, J = 7.2 Hz); C NMR (75 MHz, CDCl ) δ 18.3, 22.8, 31.5,
3
2.0, 40.1, 44.7, 46.3, 53.2, 125.4, 127.0 (overlapped), 127.8, 128.0, 128.3, 145.3, 146.0;
+
ESIHRMS: Found: m/z 278.1911. Calcd for C20
H
24N: (M+H) 278.1909.
6
9. Transformations of 2-azabicyclo[3.3.1]non-2-en-1-yl acetate 12
6
9.1 Synthesis of 2-azabicyclo[3.3.1]non-2-en-1-yl acetate 12
To a solution of compound 9aa (1.00 g, 4.7 mmol), Et
.47 mmol) in CH Cl (10 mL) was added Ac O (3.55 mL, 37.6 mmol). After 4 h, the reaction was
Cl and water, the aqueous layer was extracted twice with CH Cl . The combined
organic layers were washed with brine, dried over MgSO and concentrated. Purification of the crude
product by flash column chromatography (silica gel; hexane : ethyl acetate = 90 : 10) afforded 12
3
N (1.31 mL, 9.4 mmol), DMAP (57.2 mg,
0
2
2
2
diluted with CH
2
2
2
2
4
(1.04 g, 4.04 mmol) in 86% yield.
1
3
H NMR (400 MHz, CDCl ) δ 1.30-1.38 (1H, m), 1.53-1.61 (3H, m), 1.93-2.04 (2H, m), 2.10 (3H, s,
C
1
OCOCH
exo), 7.36-7.39 (3H, m), 7.81 (2H, d, J = 8.0 Hz); C NMR (100 MHz, CDCl
3
), 2.14 (1H, dd, J = 2.8, 12.0 Hz), 2.39-2.51 (3H, m), 2.84 (1H, dd, J = 6.4, 18.8 Hz,
13
C
4
H
3
) δ 18.7, 22.8, 28.1,
OCOCH ).
32.0, 33.3, 33.5, 34.2, 93.8 (C
1
), 126.6, 128.2, 130.0, 138.7, 166.2 (C
3
), 169.9 (C
1
3
6
9
.2 Synthesis of (1R*,5S*)-3-phenyl-2-azabicyclo[3.3.1]non-2-ene (13)
TiCl
solution of acetate 12 (52.6 mg, 0.20 mmol) in CH
at room temperature for 3 h. The mixture was poured into saturated aqueous NaHCO
with CH Cl . The combined organic extracts were washed with brine, dried over MgSO
4
4
(0.30 mL, 0.3 mmol, 1.0 M in CH
2
Cl
2
) and Et
Cl (2.0 mL), and the resulting mixture was stirred
and extracted
and
3
SiH (65 μL, 0.41 mmol) were added to a
2
2
3
2
2
concentrated. The resuting residue was chromatographed (silica gel; hexane : ethyl acetate = 70 : 30)
to give 3-phenyl-2-azabicyclo[3.3.1]non-2-ene (13) (36.5 mg, 0.183 mmol) in 90% yield.
1
H NMR (400 MHz, CDCl ) δ 1.30-1.39 (1H, m), 1.44-1.48 (1H, m), 1.58-1.76 (5H, m), 1.93-1.96
3
4 4
(1H, m), 2.27 (1H, m), 2.49 (1H, d, J = 18.8 Hz, C Hendo), 2.89 (1H, dd, J = 7.2, 18.8 Hz, C Hexo),
SI-30