Studies on the aza-Claisen rearrangement of 7 to 9-membered vinylazacycles

Article abstract of DOI:10.3987/COM-16-13432

A systematic study on the amide enolate-induced aza-Claisen rearrangement (ACR) of 7 to 9-membered vinylazacycles has been carried out, resulting in an efficient synthetic method to prepare 11 to 13-membered macrolactams. Key feature includes introduction of electron-donating substituents at α-position of the amide substrates possessing 7 to 9-membered vinylazacycles to facilitate amide enolate-induced ACR. In addition, substituent effects on ACR has been discussed based on the experimental results. We believe this study would provide experimental evidences for the substituent effects and envision for the synthetic application of ACR-induced ring expansion.

Full text of DOI:10.3987/COM-16-13432

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HETEROCYCLES, Vol. 92, No. 5, 2016
HETEROCYCLES, Vol. 92, No. 5, 2016, pp. 886 - 899. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 6th February, 2016, Accepted, 9th March, 2016, Published online, 24th March, 2016
DOI: 10.3987/COM-16-13432
STUDIES ON THE AZA-CLAISEN REARRANGEMENT OF 7 TO
9
-MEMBERED VINYLAZACYCLES
Seok-Ho Kim,1,† Won-Il Lee,2,† Seon-Mi Kim, Jae-Kyung Jung, Jaebong
2
3
2
2
4,
2,
Jang, Jaehoon Sim, Jong-Wha Jung, * and Young-Ger Suh *
1
College of Pharmacy, Institute of Pharmaceutical Sciences, CHA University,
2
Pocheon 487-010, Korea College of Pharmacy, Seoul National University, Seoul
1
51-742, Korea; E-mail: ygsuh@snu.ac.kr 3 College of Pharmacy, Chungbuk
4
National University, Cheongju 362-763, Korea College of Pharmacy, Research
Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu
41566, Korea; E-mail: jungj@knu.ac.kr
Abstract – A systematic study on the amide enolate-induced aza-Claisen
rearrangement (ACR) of 7 to 9-membered vinylazacycles has been carried out,
resulting in an efficient synthetic method to prepare 11 to 13-membered
macrolactams. Key feature includes introduction of electron-donating substituents
at D-position of the amide substrates possessing 7 to 9-membered vinylazacycles
to facilitate amide enolate-induced ACR. In addition, substituent effects on ACR
has been discussed based on the experimental results. We believe this study would
provide experimental evidences for the substituent effects and envision for the
synthetic application of ACR-induced ring expansion.
INTRODUCTION
1
Medium- and macrolactams as well as related azacyclic compounds find widespread applications in the
2
field of pharmaceutical research and the natural product synthesis. Thus, the development of an efficient
synthetic route to gain an access toward such ring systems has been a challenge. In an effort to expand the
3
synthetic potential of the amide enolate-induced aza-Claisen rearrangement (ACR), we have been
interested in the syntheses of 11 to 13-memberd lactams from the corresponding 7 to 9-memberd
precursors. This strategy share the defining characteristic of rapidly generating the medium-sized lactams
starting from easily accessible 2-vinylazacycles (e.g. 1b-d) with a pioneering lactam ring expansion
†
These authors equally contributed to this work.

HETEROCYCLES, Vol. 92, No. 5, 2016
887
strategy that has been focused on the 3, 5, and 6-membered precursors.4,5 Furthermore, highly reliable
6
stereochemical outcome of [3,3]-sigmatropic rearrangement due to the highly ordered transition state as
well as advantages in entropic and enthalpic sense, promise an efficient chiral transfer to the
ring-expanded lactams.3
Our research program has been focused on the synthesis of bioactive natural product via ACR, and we
have reported a unique approach of lactam ring expansion for the synthesis of functionalized
3
macrolactams. Our previous studies involved the stereoselective lactam ring expansion and its
applications. For instance, ACR of enol ethers has been reported as an intramolecular aldol equivalent,
and utilized in several natural product synthesis programs.3b-d ACR of simple vinylazacycles, which has
also been utilized in natural product synthesis, however, was only limited to deliver 10-membered lactam
from the 6-membered azacycles.3e-f Thus, studies in the lactam ring expansion via ACR using medium- to
macro-sized azacycles with a various functional groups are still in need to expand its synthetic utility of
the strategy. Herewith, we report a systematic study for the preparation of the 11 to 13-memberd lactams
from the 2-vinylazacycles via anionic ACR promoted by an introduction of electron-donating substituents
at D-position of the amide substrate (Figure 1).
Figure 1. Strategies in ACR of 7 to 9-Membered Vinylazacycles
RESULTS AND DISCUSSION
Our study commenced with the preparation of the requisite 8 and 9-membered azacycles as ACR
precursors. As shown in Scheme 1, the Boc-protected lactam 4 were subjected to the Tebbe condition
o
7,8
(
Tebbe reagent, THF, 0 C) to afford the enamines, which were then converted to the primary alcohols

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HETEROCYCLES, Vol. 92, No. 5, 2016
5
by hydroboration in moderate yields. PDC oxidation of the alcohol 5 followed by Wittig reaction of the
resulting aldehyde provided 6 in acceptable yields. Finally, Boc-deprotection of 6 and subsequent
acylation with the various acid derivatives afforded the 2-vinyl amide 1c and 1d, requisite precursors of
ACR.
O
(
)n
( )n
OH
Boc
d, e
( )n
b, c
N
N
N
R'
Boc
3c : n = 3, R' = H
d : n = 4
5
6
a
4
: R' = Boc
f, g
( )n
1
ca : n = 3, R = Me
1cb : n = 3, R = OMe
cc : n = 3, R = NH2
1da : n = 4, R = Me
1db : n = 4, R = OMe
1dc : n = 4, R = NH2
N
R
1
O
a
o
Reagents and conditions: (a) LHMDS, Boc O, THF, -78 C, 93% for 4c, 95% for 4d;
2
o
o
(
b) Tebbe reagent, THF, 0 C; (c) BH
steps), 60% for 5d (2 steps); (d) PDC, CH
2% for 6c (2 steps), 63% for 6d (2 steps); (f) TFA, CH
DMAP, CH Cl , propionic anhydride for R = Me, or methoxyacetyl chloride for R =
OMe; Et N, DEPC, DMF, N-Boc-Gly-OH, then TFA, CH
3-99% (2-3 steps).
3
-THF complex, THF, 0 C to rt, 54% for 5c (2
o
2
Cl
2
; (e) Ph PMeI, n-BuLi, THF, -78 C to rt,
3
o
7
2
Cl
2
, 0 C to rt; (g) Et N,
3
2
2
o
3
2
Cl
2
, 0 C to rt for R = NH
2
,
5
Scheme 1. Preparation of 8 and 9-Membered Vinylazacyclesa
For the synthesis of 7-membered azacyclic substrate, however, it was not successful to obtain the
9
corresponding product in analogous to Scheme 1. After an extensive efforts for the functionalization of
the D position of nitrogen, Beak’s formylation protocol11 was successfully employed after extensive
10
efforts (Scheme 2).
a
CHO
b
N
N
N
Boc
Boc
Boc
8
9
7
1
ba : R = Me
c, d
1bb OMe
N
R
1bc
1bd
NH2
H
O
a
o
Reagents and coditions: (a) s-BuLi, TMEDA, DMF, ether, -40 C, 65%; (b) Ph
3
PMeI,
N, DMAP, CH Cl
propionic anhydride for R = Me, acetic anhydride for R = H, or methoxyacetyl
o
o
n-BuLi, THF, -78 C to rt, 70%; (c) TFA, CH
2
Cl
2
, 0 C to rt; (g) Et
3
2
2
,
o
chloride for R = OMe; Et
3
N, DEPC, DMF, N-Boc-Gly-OH, then TFA, CH
2
Cl , 0 C to
2
rt for R = NH
2
, 69-98% (2-3 steps).
Scheme 2. Preparation of 7-Membered Vinylazacyclea

HETEROCYCLES, Vol. 92, No. 5, 2016
889
To this end, treatment of the Boc-protected azepine 7 with s-BuLi and subsequent formylation of the
resulting metallated amine with DMF provided the desired aldehyde 8. The aldehyde 8 was converted
into the vinyl substituted 7-membered azacycle 1b through a three-step sequence of Wittig olefination,
deprotection of Boc group and acylation of the resulting amine by analogy to the synthesis of 1c and 1d.
Table 1. ACR of 2-Vinylazacyclesa
Entry
2-Vinylazacycle (1)
n
2
2
2
2
3
3
3
4
4
4
R
Yield (%)b
1
2
3
4
5
6
7
8
9
1ba
1bb
1bc
1bd
1ca
1cb
1cc
Me
69
75
82
31
89
56
30
84
49
31
OMe
NH
H
2
Me
OMe
NH
2
1da
1db
1dc
Me
OMe
1
0
NH
2
a
b
Reaction condition: LHMDS, toluene, reflux. Isolated yields after SiO
2
chromatography.
With the desired 2-vinylazacycles 1 in hand, the objective ACR was attempted under the previously
3
established reaction condition (LHMDS, toluene, reflux). The result was summarized in Table 1. As
expected, ACR of all substrates proceeded smoothly to afford the ring-expanded lactams 2 in moderate to
high yields except for the acetylated vinylazacycles. The introduction of D-alkyl group or D-heteroatom
facilitated ACR, and ACR of 1bb and 1bc were more efficient compared to the ACR of 1ba and 1bd in
terms of both higher yield and shorter reaction time (69%, 1.5 h for entry 1 vs. 75-82%, 15 min for entry
2, 3). Considering factors affecting related [3,3]-sigmatropic rearrangements such as in Cope and Claisen
rearrangement as well as other variants,12 ACR induced ring expansion of azacycles containing

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HETEROCYCLES, Vol. 92, No. 5, 2016
electron-donating groups at D-position of the amide substrates are expected to have advantages in
promoting ACR of azacycles as in the case of enol ethers. Previous studies also supported these trends in
3
amide-enolate induced ACR involved in lactam ring expansion. Especially, ACR of simple vinyl
substituted 6-membered azacycles was found to be promoted by the introduction of electron-donating
3
a,3e-f
substituents at D-position.
The electronic effects of D-alkyl group or D-heteroatom shown in Table 1
might be understood by thermodynamic perturbation among the transition states (t.s.1 and t.s.2),12a
whereas ACR-induced ring expansion might be promoted by anion effect as in the case of oxy-Cope
rearrangement.12b-c In other words, weak forces including H-bonding, steric, electronic, and conjugation
effects may affect the equilibrium between the transition states,12a and the anion effect introduced by the
substitution of D-alkyl group or D-heteroatom seems to be one of the predominant factors for the
acceleration of ACR. The remarkable anion effect in Cope rearrangement were widely used and discussed
in synthetic applications since the oxy-Cope rearrangement reported,12b-c and the promotion of
ACR-induced ring expansion in this study might also be attributed to the anion effect as well. The effects
1
2d-e
of D-heteroatom might also be interpreted with chelation-promoted or dianionic ACR (not shown.).
For the ACR of 8 and 9-membered precursors, the corresponding substrates possessing D-heteroatom
showed a somewhat different trend in terms of yield compared to the corresponding ACR of the
corresponding 7-membered precursors (entry 5-10), and the reason is not clear at present. Nonetheless, it
seems clear that the introduction of D-substituents facilitated ACR compared to the ACR of
non-substituted acetamides in which the reaction of 1cb, 1cc, 1db, and 1dc completed faster than the
ACR of 1ca and 1da in terms of the disappearance of corresponding substrates as in the case of ACR of
7-membered precursors. The (E)-stereochemistry of olefin in the ring expanded lactams is defined by
coupling constant of ~15 Hz between two olefinic protons. The preference for (E)-olefin over (Z) might
be contributed by the highly ordered chair-like transition state and exclusive formation of amide
(Z)-enolate as proposed in Table 1.
CONCLUSION
In summary, a systematic study on the ACR of 7 to 9-membered azacycles have been carried out,
resulting in the efficient synthetic method to prepare the 11 to 13-membered lactams having internal
(
E)-olefins which has been synthetically inaccessible by the conventional methods.13 Introduction of
3
b-d
D-substituents facilitated ACR-induced ring expansion as in the case of enol ethers.
We believe this
study would provide experimental evidences and insights on the synthesis of natural products such as
alkaloids and macrolactam antibiotics as well as bioactive small molecules via ACR-induced ring
expansion.

HETEROCYCLES, Vol. 92, No. 5, 2016
891
EXPERIMENTAL
Unless otherwise noted, all starting materials and solvents were used as obtained from commercial
suppliers without further purification. Organic solvents used in this study were dried over appropriate
drying agents and distilled prior to use. Thin layer chromatography was carried out using Merck silica gel
6
2
1
0 F254 plates, and flash chromatography was performed using Merck silica gel 60 (0.040-0.063 mm,
1
30-400 mesh). NMR spectra were recorded in deuterated solvents on a Bruker 500 (500 MHz for H;
13
1
13
25 MHz for C), JEOL JNM-GCX 400 (400 MHz for H; 100 MHz for C), or JEOL JNM-LA 300
1
13
1
13
(
300 MHz for H; 75 MHz for C) spectrometer. H- and C-NMR chemical shifts are reported in parts
per million (ppm) relative to TMS, with the residual solvent peak used as an internal reference. Infrared
spectra were recorded on a Perkin-Elmer 1710 FT-IR spectrometer. Low-resolution electrospray
ionization (ESI) mass spectra were obtained with Finnigan LCQ mass spectrometer. Low and
high-resolution fast atom bombardment (FAB) and electron impact (EI) mass spectra were obtained with
JEOL JMS-700 instrument.
tert-Butyl 2-(hydroxymethyl)azocane-1-carboxylate (5c): Tebbe reagent (1M in THF, 17.3 mL, 17.3
o
mmol) was added to a solution of 4c (3.58g, 15.8 mmol) in THF (60 mL) at 0 C. After stirring for 5 h,
the reaction mixture was diluted with Et
2
O, and quenched with MeOH. The suspension was filtered
O. Volatiles were
through a short plug of celite, and the filtrate was decanted with n-hexane and Et
2
removed under the reduced pressure, and the residue containing tert-butyl 2-methyleneazocane-
1
1
-carboxylate was used without further purification: H-NMR (CDCl
3
, 300 MHz) δ 4.94 (s, 1H), 4.80 (s,
1H), 3.56 (t, 2H, J = 5.5 Hz), 1.92-1.89 (m, 2H), 1.14-0.72 (m, 17H).
To a solution of tert-butyl 2-methyleneazocane-1-carboxylate above in THF (30 mL), a solution of borane
o
(1M BH
3
·THF, 15.7 mL, 15.7 mmol) was added at 0 C. After stirring for 9 h at rt, the solution was
o
diluted with Et
2
O, and then, 6N-NaOH (72 mL) and 30% H
2
O
2
(72 mL) were added at 0 C. The mixture
was stirred for 5 h, and filtered with a short plug of celite. The filtrate was washed with water and brine,
and dried over MgSO . Volatiles were removed under the reduced pressure, and the residue was purified
chromatography (40% EtOAc in n-hexane) to provide 5c as a colorless oil (2.07 g, 54% for 2
, 300 MHz) δ 4.07-2.94 (m, 7H), 1.81-1.24 (m, 17H).
4
with SiO
2
1
steps): H-NMR (CDCl
3
tert-Butyl 2-vinylazocane-1-carboxylate (6c): PDC (473 mg, 1.26 mmol) was added to a solution of
o
alcohol 5c (200 mg, 0.823 mmol) in CH
diluted with Et
the reduced pressure, and the residue was purified by SiO
2
Cl
2
(20 mL) at 0 C. After stirring for 9 h at rt, the mixture was
2
O, and filtered through a short plug of celite. Volatiles in the filtrate was removed under
2
chromatography (15% EtOAc in n-hexane) to
1
provide tert-butyl 2-formylazocane-1-carboxylate as a colorless oil (159 mg, 80%); H-NMR (CDCl
3
,
3
00 MHz) δ 9.54 (d, J = 12.2 Hz, 1H), 4.24 and 3.50 (m, 1H), 3.80 (m, 1H), 3.21 (m, 1H), 2.04-1.18 (m,

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HETEROCYCLES, Vol. 92, No. 5, 2016
19H).
A solution of n-BuLi (1.6 M in hexane, 0.915 mL, 1.46 mmol) was added to the solution of
o
methyltriphenylphosphonium iodide (650 mg, 1.60 mmol) in THF (10 mL) at -78 C. After stirring for 2
o
h, tert-butyl 2-formylazocane-1-carboxylate (324 mg, 1.34 mmol) in THF (5 mL) was added at -78 C,
and the temperature was slowly elevated to rt. After stirring for 9 h, the reaction was quenched with
aqueous NH
4
Cl solution. The organic phase was washed with water and brine, and dried over MgSO
4
.
Volatiles were removed under the reduced pressure, and the residue was purified with SiO
2
1
chromatography (10% EtOAc in n-hexane) to provide 6c as a colorless oil (285 mg, 89%); H-NMR
(
CDCl , 300 MHz) δ 5.63 (ddd, 1H, J = 17.2, 10.4, 4.2 Hz), 4.96-4.85 (m, 2H), 4.54 and 4.30 (m, 1H),
3
1
3
2
.82 (m, 1H), 1.91-1.41 (m, 19H); C-NMR (CDCl
3
, 100 MHz) δ 155.7, 155.2, 138.7, 138.4, 113.1, 78.9,
7
8.8, 58.0, 56.7, 42.1, 41.7, 29.0, 28.4, 27.8, 26.9, 26.6, 26.6, 26.5, 26.1, 26.0, 25.9, 24.5, 24.1; FT-IR
-1
+
+
+
(
thin film, neat) Qmax 2928, 1693, 1475, 1403 cm ; MS (ESI ) m/z 240 (M+H ), 262 (M+Na ).
-(2-Vinylazocan-1-yl)propan-1-one (1ca): TFA (0.426 mL, 5.54 mmol) was added to a solution of 6c
133 mg, 0.556 mmol) in CH Cl (5 mL), and the solution was stirred for 2 h at rt. Volatiles were
1
(
2
2
removed under the reduced pressure, and the residue was re-dissolved in CH
2
Cl (5 mL). DMAP (3.40
2
o
mg, 0.0279 mmol) and Et
3
N (1.54 mL, 11.1 mmol) were added at 0 C, and propionic anhydride (0.213
mL, 1.67 mmol) was added subsequently. After stirring for 3 h, water was added. The mixture was
extracted with CH Cl , and the organic phase was dried over MgSO . Volatiles were removed under the
chromatography (33% EtOAc in n-hexane) to
, 300 MHz) δ 5.67 (m, 1H), 5.06-4.89 (m,
2
2
4
reduced pressure, and the residue was purified with SiO
2
1
provide 1ca as a yellow oil (107 mg, 99%): H-NMR (CDCl
3
2H), 3.85 (m, 1H), 3.46 (m, 1H), 3.16 (m, 1H), 2.73 (m, 1H), 2.34 (m, 1H), 2.03-0.75 (m, 13H);
13C-NMR (CDCl
, 100 MHz) δ 177.4, 174.0, 138.1, 138.0, 114.2, 113.7, 59.6, 55.5, 42.5, 41.8, 29.5, 28.9,
3
1
3
2
1
9
7.7, 27.1, 26.7, 26.6, 26.0, 25.9, 24.5, 23.9, 9.7, 9.5; C-NMR (CDCl
3
, 100 MHz) δ 174.4, 174.0, 138.1,
38.0, 114.2, 113.7, 59.6, 55.5, 42.5, 41.8, 29.5, 28.9, 27.7, 27.1, 26.7, 26.6, 26.0, 25.9, 24.5, 23.9, 9.7,
-1
+
+
.5; FT-IR (thin film, neat) Qmax 2930, 1734, 1642, 1417 cm ; MS (ESI ) m/z 196 (M+H ), 218.1
(
M+Na+).
-Methoxy-1-(2-vinylazocan-1-yl)ethan-1-one (1cb): 1cb was synthesized by analogy to the synthesis
of 1ca except for using methoxyacetyl chloride instead of propionic anhydride; Yield 90%, a yellow oil;
1H-NMR (CDCl
, 300 MHz) δ 5.46 (ddd, 1H, J = 14.1, 10.5, 3.9 Hz), 4.86-4.70 (m, 2H), 3.85 (m, 1H),
.21 (m, 1H), 2.86 (m, 1H), 2.53 (m, 1H), 3.22 (s, 3H), 1.66-0.55 (m, 10H); C-NMR (CDCl
δ 169.2, 167.7, 139.6, 137.9, 137.7, 126.6, 114.4, 76.1, 71.6, 71.1, 69.5, 69.3, 60.5, 59.4, 59.3, 59.2, 58.6,
2
3
13
3
3
, 100 MHz)
5
7.1, 56.0, 29.2, 28.9, 27.6, 26.9, 26.6, 26.2, 25.9, 25.7, 24.5, 24.1; FT-IR (thin film, neat) Qmax 1633,
-1
+
+
1
417 cm ; MS (EI ) m/z 211 (M ).

HETEROCYCLES, Vol. 92, No. 5, 2016
893
2
-Amino-1-(2-vinylazocan-1-yl)ethan-1-one (1cc): TFA (0.209 mL, 2.73 mmol) was added to a solution
of 6c (65 mg, 0.273 mmol) in CH Cl (3 mL), and the solution was stirred for 2 h at rt. Volatiles were
removed under the reduced pressure, and the residue was re-dissolved in DMF (2 mL). DEPC (0.055 mL,
.362 mmol), and Et N (0.761 mL, 5.46 mmol) were added to a solution of N-Boc-glycine (57 mg, 0.327
2
2
0
3
mmol) in DMF (2 mL) in a separate flask, the resulting solution was added to the solution of
Boc-deprotected amine after 30 min. The solution was stirred for 4 h at rt, and water was added. The
mixture was extracted with CH
2
Cl
2
, and the organic phase was dried over MgSO
4
. Volatiles were
removed under the reduced pressure, and the residue was purified with SiO
2
chromatography (50%
EtOAc in 1:1 solution of n-hexane and CH
2
Cl
2
) to provide tert-butyl (2-oxo-2-(2-vinylazocan-
1
1
5
-yl)ethyl)carbamate (102 mg, 89%) as a yellow oil; H-NMR (CDCl
3
, 300 MHz) δ 5.67 (m, 1H),
.08-4.91 (m, 2H), 3.90 (m, 1H), 3.43 (m, 1H), 3.12 (m, 1H), 2.82 (m, 1H), 1.97-1.16 (m, 19H);
, 125 MHz) δ 169.1, 168.4, 155.8, 137.5, 137.2, 79.5, 58.9, 56.7, 42.6, 42.4, 42.3, 29.3,
13C-NMR (CDCl
3
+
+
2
8.6, 28.4, 27.9, 27.1, 26.7, 26.2, 25.9, 24.5, 24.1; MS (EI ) m/z 296 (M ).
o
To a solution of the amide above (81 mg, 0.274 mmol) in CH
2
Cl
solution was added, and the mixture was
, and volatiles
2
(5mL), TFA was added at 0 C (0.210
mL, 2.37 mmol). After stirring for 2 h at rt, aqueous NaHCO
3
extracted several times with CH
2
Cl
2
. The combined organic phases were dried over MgSO
4
were removed under the reduced pressure. The resulting amine 1cc was used as a substrate for
aza-Claisen rearrangement without further purification.
tert-Butyl 2-oxoazonane-1-carboxylate (4d): 9-Membered lactam 4d was synthesized by analogy to the
synthesis of 8-membered lactam 4c except for using 2-azacyclononanone instead of 2-azacycloheptanone;
1
Yield 91%, a colorless oil; H-NMR (CDCl
3
, 300 MHz) δ 3.78 (t, 2H, J = 6.3 Hz), 2.87-2.83 (m, 2H),
1.83-1.75 (m, 2H), 1.69-1.61 (m, 2H), 1.51 (s, 9H), 1.52-1.25 (m, 6H).
tert-Butyl 2-(hydroxymethyl)azonane-1-carboxylate (5d): 9-Membered azacycle 5d was synthesized
by analogy to the synthesis of 8-membered azacycle 5c except for using 9-membered lactam 4d instead of
1
8
4
2
3
-membered lactam 4c for tert-butyl 2-methyleneazonane-1-carboxylate, H-NMR (CDCl
3
, 300 MHz) δ
.87 (s, 1H), 4.77 (s, 1H), 3.60 (t, 2H, J = 5.9 Hz), 2.47-2.33 (m, 2H), 1.73-1.23 (m, 19H); for tert-butyl
1
-(hydroxymethyl)azonane-1-carboxylate (5d), yield 60% for 2 steps, a colorless oil; H-NMR (CDCl
3
,
00 MHz) δ 4.47-3.07 (m, 5H), 1.67-1.15 (m, 21H).
tert-Butyl 2-vinyl-1-azonanecarboxylate (6d): 9-Membered azacycle 6d was synthesized by analogy to
the synthesis of 8-membered azacycle 6c except for using 9-membered alcohol 5d instead of 8-membered
1
alcohol 5d for, tert-butyl 2-formylazonane-1-carboxylate, H-NMR (CDCl
3
, 300 MHz) δ 9.50 (d, 1H, J =
1
6
1
0.0 Hz), 4.08-3.01 (m, 3H), 2.13-1.37 (m, 21H); for tert-butyl 2-vinyl-1-azonanecarboxylate (6d), yield
1
0% for 2 steps, oil; H-NMR (CDCl
3
, 300 MHz) δ 5.72 (m, 1H), 5.05-4.97 (m, 2H), 4.68 and 4.36 (m,
1
3
H), 3.37 (m, 1H), 2.80 (m, 1H), 1.83-1.27 (m, 12H), 1.48 and 1.46 (s, 9H); C-NMR (CDCl
3
, 100 MHz)

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HETEROCYCLES, Vol. 92, No. 5, 2016
δ 156.3, 155.8, 138.7, 138.6, 113.9, 113.8, 79.0, 60.1, 58.7, 57.4, 44.2, 43.3, 29.5, 28.3, 28.3, 28.0, 27.1,
6.8, 26.7, 25.5, 25.2, 24.0, 23.7, 23.5, 20.8, 14.0; FT-IR (thin film, neat) Qmax 2924, 1692, 1455, 1403
2
-1
+
+
+
cm ; MS (ESI ) m/z 254 (M+H ), 276 (M+Na ).
-(2-Vinylazonan-1-yl)propan-1-one (1da): 9-Membered vinylazacycle 1da was synthesized by
1
analogy to the synthesis of 8-membered vinylazacycle 1ca using 9-membered azacycle 6d instead of
1
8
-membered azacycle 6c. Yield 99%, a colorless oil; H-NMR (CDCl
3
, 300 MHz) δ 5.66 (ddd, 1H, J =
1
3
1
7.3, 10.5, 3.9 Hz), 5.08-4.92 (m, 2H); 4.22-2.33 (m, 5H), 1.88-1.05 (m, 15H); C-NMR (CDCl , 100
3
MHz) δ 175.3, 174.7, 138.2, 137.9, 114.8, 114.2, 60.2, 60.0, 44.7, 43.8, 29.2, 28.3, 28.0, 27.7, 27.0, 26.9,
-1
2
6.8, 26.5, 25.7, 24.9, 23.4, 23.0, 9.5, 9.3; FT-IR (thin film, neat) Qmax 2923, 1734, 1643, 1416 cm ; MS
+
+
+
(
ESI ) m/z 210 (M+H ), 232 (M+Na ).
2-Methoxy-1-(2-vinylazonan-1-yl)ethan-1-one (1db): 9-Membered vinylazacycle 1db was synthesized
by analogy to the synthesis of 8-membered vinylazacycle 1cb using 9-membered azacylcle 6d instead of
1
8
1
1
1
-membered azacycle 6c: Yield 85%; a colorless oil; H-NMR (CDCl
3
, 300 MHz) δ 5.66 (ddd, 1H, J =
7.3, 10.5, 3.9 Hz), 5.09-4.94 (m, 2H), 4.16 (m, 1H), 3.73 (m, 1H), 3.39 (m, 1H), 3.01 (m, 1H), 2.69 (m,
13
H), 3.44 (s, 3H), 2.11-0.76 (m, 12H); C-NMR (CDCl
3
, 100 MHz) δ 170.2, 169.9, 150.5, 138.1, 115.2,
14.9, 71.9, 71.3, 69.2, 62.3, 59.3, 51.9, 43.7, 29.7, 29.0, 27.9, 26.7, 26.2, 25.8, 24.8, 23.8, 23.4; MS
+
+
(
ESI ) m/z 226 (M+H ).
-Amino-1-(2-vinylazonan-1-yl)ethan-1-one (1dc): 9-Membered vinylazacycle 1dc was synthesized by
analogy to the synthesis of 8-membered vinylazacycle 1cc using 9-membered azacylcle 6d instead of
2
8
-membered azacycle 6c. For tert-butyl (2-oxo-2-(2-vinylazonan-1-yl)ethyl)carbamate; Yield 88%, a
1
yellow oil; H-NMR (CDCl
3
, 500 MHz) δ 5.74-5.61 (m, 2H), 5.07 (m, 1H), 4.97 (d, 1H, J = 17.3 Hz),
1
3
4
.08-3.78 (m, 3H), 3.38, 3.09 and 2.74 (m, 1H), 1.93-1.36 (m, 12H), 1.43 (s, 9H); C-NMR (CDCl
3
, 125
MHz) δ 169.7, 168.9, 155.8, 155.7, 137.8, 137.3, 115.5, 115.1, 79.4, 59.4, 44.2, 42.9, 29.3, 28.4, 27.9,
+
+
2
7.2, 26.7, 26.0, 25.1, 23.6, 23.3; MS (ESI ) m/z 310 (M+H ).
tert-Butyl 2-formyl-1-azepanecarboxylate (8): Formylazapane 8 was synthesized according to the
1
1
literature. Briefly, N-Boc-azapane 7 was treated with s-BuLi in the presence of TMEDA in Et
2
O at low
1
temperature, and then formylated by the addition of DMF: Yield 40%, oil; H-NMR (CDCl
3
, 300 MHz) δ
9
.55 (d, 1H, J = 4.1 Hz), 4.36 and 4.02 (dd, 1H, J = 11.1, 6.3 Hz), 3.7 and 3.65 (m, 1H), 3.28 and 2.99
+
+
(
dd, 1H, J = 14.6, 9.8 Hz), 2.21 (m, 1H), 1.80-1.24 (m, 7H), 1.45 (s, 9H); MS (EI ) m/z 228 (M+H ).
tert-Butyl 2-vinyl-1-azepanecarboxylate (9): 7-Membered azacycle 9 was synthesized by analogy to the
synthesis of 8-membered azacycle 6c except for using 7-membered formylazacycle 8 instead of
1
8
3
-membered formylazacycle, tert-butyl 2-formylazocane-1-carboxylate: Yield 66%, oil; H-NMR (CDCl
3
,
00 MHz) δ 5.71 (m, 1H), 5.01-4.93 (m, 2H), 4.57 and 4.36 (m, 1H), 3.83 and 3.66 (m, 1H), 2.65 (dd, 1H,
1
3
J = 14.1, 11.4 Hz), 2.04 (m, 1H), 1.79-1.20 (m, 7H), 1.45 and 1.36 (s, 9H); C-NMR (CDCl , 100 MHz)
3

HETEROCYCLES, Vol. 92, No. 5, 2016
895
δ 155.5, 155.4, 138.2, 137.9, 112.5, 112.5, 78.8, 78.7, 77.1, 57.6, 56.2, 42.0, 41.4, 33.6, 33.3, 29.4, 29.4,
-
1
+
+
2
2
1
8.3, 28.2, 25.0, 24.6; FT-IR (thin film, neat) Qmax 2927, 1692, 1408 cm ; MS (ESI ) m/z 226 (M+H ),
48 (M+Na+).
-(2-Vinylazepan-1-yl)propan-1-one (1ba): 7-Membered vinylazacycle 1ba was synthesized by
analogy to the synthesis of 8-membered vinylazacycle 1cb using 7-membered azacylcle 9 instead of
1
8
1
2
-membered azacycle 6c; Yield 78% for 2 steps; a colorless oil; H-NMR (CDCl
3
, 300 MHz) δ 5.71 (ddd,
H, J = 17.0, 10.4, 4.1 Hz), 5.07-4.91 (dd, 2H, J = 19.9, 10.4 Hz), 4.18 (m, 1H), 3.56 and 2.95 (m, 1H),
1
3
.56 (m, 1H), 2.49-2.01 (m, 3H), 1.85-1.19 (m, 7H), 1.12 (t, 3H, J = 7.4 Hz); C-NMR (CDCl , 100
3
MHz) δ 174.1, 174.0, 136.9, 136.8, 113.2, 112.7, 58.6, 54.8, 42.3, 40.7, 33.8, 32.2, 29.6, 29.1, 28.8, 27.9,
-1
+
+
2
6.9, 25.9, 25.8, 24.5, 24.1, 9.2, 9.1; FT-IR (thin film, neat) Qmax 1644, 1417 cm ; MS (EI ) m/z 181 (M ).
2-Methoxy-1-(2-vinylazepan-1-yl)ethan-1-one (1bb): 7-Membered vinylazacycle 1bb was synthesized
by analogy to the synthesis of 8-membered vinylazacycle 1cb using 7-membered azacylcle 9 instead of
1
8
1
-membered azacycle 6c; Yield 98% for 2 steps; a colorless oil; H-NMR (CDCl
3
, 300 MHz) δ 5.67 (ddd,
H, J = 17.0, 10.2, 4.1 Hz), 5.04-4.91 (dd, 2H, J = 17.0, 10.5 Hz), 4.19-3.84 (m, 4H), 3.38 (s, 3H), 2.91
1
3
and 2.57 (dd, 1H, J = 12.2, 12.1 Hz), 2.07 (m, 1H), 1.78-1.18 (m, 7H); C-NMR (CDCl
3
, 100 MHz) δ
69.0, 167.7, 139.6, 137.4, 126.6, 113.8, 113.6, 71.3, 71.2, 69.5, 69.4, 60.5, 59.3, 59.2, 59.1, 57.9, 57.2,
5.5, 42.0, 41.1, 34.2, 32.5, 30.4, 29.7, 29.4, 28.4, 24.9, 24.7; FT-IR (thin film, neat) Qmax 1650, 1428,
1
5
1
2
-1
+
+
122 cm ; MS (EI ) m/z 197 (M ).
-Amino-1-(2-vinylazepan-1-yl)ethan-1-one (1bc): 7-Membered vinylazacycle 1bc was synthesized by
analogy to the synthesis of 8-membered vinylazacycle 1cc using 7-membered azacylcle 9 instead of
-membered azacycle 6c. For tert-butyl (2-oxo-2-(2-vinylazepan-1-yl)ethyl)carbamate, a yellow oil;
1H-NMR (CDCl
, 300 MHz) δ 5.65 (ddd, 1H, J = 21.4, 10.5, 6.1 Hz), 5.51 (bs, H), 5.05-4.89 (dd, 2H, J =
7.0, 10.5 Hz), 4.14 and 3.44 (m, 1H), 3.96 (m, 1H), 3.72 (m, 1H), 2.95 and 2.62 (dd, 1H, J = 13.3, 12.1
8
3
1
1
3
Hz), 2.10 (m, 1H), 1.76-1.17 (m, 8H), 1.38 (m, 9H); C-NMR (CDCl
3
, 100 MHz) δ 168.5, 168.3, 155.9,
1
2
1
55.8, 137.0, 136.7, 114.3, 113.8, 79.5, 79.4, 58.3, 56.2, 42.4, 42.3, 42.1, 41.6, 34.3, 32.7, 30.1, 29.6, 29.3,
-1
+
+
8.5, 28.4, 25.0, 24.7; FT-IR (thin film, neat) Qmax 3417, 3329, 1714, 1650 cm ; MS (EI ) m/z 282 (M ).
-(2-Vinylazepan-1-yl)ethan-1-one (1bd): 7-Membered vinylazacycle 1bd was synthesized by analogy
to the synthesis of 7-Membered vinylazacycle 1ba except for using acetic anhydride instead of propionic
1
anhydride; Yield 69% for 2 steps; a colorless oil; H-NMR (CDCl
3
, 300 MHz) δ 5.72 (ddd, 1H, J = 17.0,
1
0.5, 4.4 Hz), 5.01 (dd, 2H, J = 20.4, 10.4 Hz), 4.16 (m, 1H), 3.60 and 3.03 (m, 1H), 2.58 (m, 1H), 2.09
1
3
(
s, 3H), 2.14-1.20 (m, 8H); C-NMR (CDCl
3
, 125 MHz) δ 171.0, 170.7, 137.5, 137.3, 113.8, 113.3, 60.2,
5
1
5.1, 43.7, 41.0, 34.5, 32.8, 29.9, 29.7, 29.4, 28.5, 25.1, 24.6, 21.7, 21.6; FT-IR (thin film, neat) Qmax 1633,
-1
+
+
417 cm ; MS (EI ) m/z 167 (M ).

896
HETEROCYCLES, Vol. 92, No. 5, 2016
Typical Procedure of the Aza-Claisen Rearrangement for the Preparation of Lactam (2).
E)-3-Methylazacycloundec-5-en-2-one (2ba): To a solution of 1ba (36.2 mg, 0.2 mmol) in refluxing
toluene (2 mL) was added dropwise LHMDS (1.0 M solution in hexane, 0.4 mL, 0.4 mmol). The
resulting mixture was refluxed for 1.5 h, and cooled to rt, then quenched with NH Cl (aq). The resulting
(
4
mixture was extracted with EtOAc. Volatiles removed under reduced pressure, and the residue was
purified by flash column chromatography on silica gel (40% EtOAc in hexane) to afford the compound
1
2
ba (25.0 mg, 69%) as a white solid; H-NMR (CDCl
3
, 300 MHz) δ 5.47 (bs, 1H), 5.38-5.34 (m, 2H),
3.66 (m, 1H), 2.64 (m, 1H), 2.24-2.13 (m, 4H), 1.75 (m, 1H), 1.58-1.44 (m, 4H), 1.15-1.11 (m, 2H), 1.14
1
3
(
d, 3H, J = 6.1 Hz); C-NMR (CDCl
3
, 75 MHz) δ 176.1, 132.2, 128.3, 42.1, 39.5, 39.1, 33.8, 28.8, 25.4,
-1
+
2
2.6, 16.6; FT-IR (thin film, neat) Qmax 3261, 1643, 1556 cm ; HRMS (FAB ) calculated for C11H20NO
+
(
M+H ) 182.1546, found 182.1548.
1
(
E)-3-Methoxyazacycloundec-5-en-2-one (2bb): a white solid; H-NMR (CDCl
3
, 300 MHz) δ 6.49 (bs,
1
5
1
H), 5.40-5.34 (m, 2H), 3.78-3.73 (m, 2H), 3.39 (s, 3H), 2.67-2.53 (m, 4H), 1.83 (m, 1H), 1.60-1.46 (m,
-1 13
H), 1.11 (m, 1H); FT-IR (thin film, neat) Qmax 3294, 1650, 1106 cm ; C-NMR (CDCl , 100 MHz) δ
3
+
72.2, 133.8, 124.6, 82.4, 57.8, 39.1, 35.3, 33.8, 28.7, 25.4, 22.5; HRMS (FAB ) calculated for
+
C
11
H20NO
2
(M+H ) 198.1494, found 198.1492.
1
(
E)-3-Aminoazacycloundec-5-en-2-one (2bc): a dark yellow oil; H-NMR (CD
3
OD, 300 MHz) δ 6.97
(bs, 1H), 5.44-5.38 (m, 2H), 3.30 (m, 1H), 2.92 (m, 1H), 2.50 (m, 1H), 2.49 (m, 1H), 2.15 (m, 1H), 2.09
-1
(
m, 1H), 1.89 (m, 1H), 1.40-1.15 (m, 6H); FT-IR (thin film, neat) Qmax 3286, 2852, 1647 cm ; HRMS
+
+
(
FAB ) calculated for C10
H
19
N
2
O (M+H ) 183.1497, found 183.1501.
1
(
E)-Azacycloundec-5-en-2-one (2bd): a white solid; H-NMR (CDCl
3
, 300 MHz) δ 5.39 (bs, 1H), 5.33
(m, 1H), 5.24 (m, 1H), 3.09-3.06 (m, 2H), 2.29-2.26 (m, 2H), 2.08-2.05 (m, 2H), 2.00-1.96 (m, 2H),
1
3
1
2
1
.46-1.18 (m, 6H); C-NMR (CDCl , 100 MHz) δ 174.1, 132.9, 128.4, 40.6, 34.0, 30.4, 29.7, 29.0, 25.6,
3
-1
+
+
2.7; FT-IR (thin film, neat) Qmax 3296, 1645 cm ; HRMS (FAB ) calculated for C10H18NO (M+H )
68.1388, found 168.1389.
1
(
E)-3-Methylazacyclododec-5-en-2-one (2ca): a white solid; H-NMR (CD
3
OD, 300 MHz) δ 7.69 (bs,
1
2
1
1
H), 5.37 (m, 1H), 5.20 (ddd, 1H, J = 15.4, 10.2, 3.2 Hz), 3.75 (m, 1H), 2.73 (m, 1H), 2.35 (m, 1H),
1
3
.11-1.92 (m, 4H), 1.67-1.34 (m, 8H), 1.08 (d, 3H, J = 6.6 Hz); C-NMR (CDCl
3
, 100 MHz) δ 175.4,
32.4, 128.0, 43.0, 38.7, 36.3, 30.2, 26.5, 25.0, 23.8, 21.0, 17.4; FT-IR (thin film, neat) Qmax 3286, 2932,
-1
+
+
638, 1556 cm ; HRMS (FAB ) calculated for C12
H
22NO (M+H ) 196.1702, found 196.1706.
1
(
E)-3-Methoxyazacyclododec-5-en-2-one (2cb): a white solid; H-NMR (CD
3
OD, 300 MHz) δ 7.67 (bs,
1
H), 5.41 (ddd, 1H, J = 15.1, 5.9, 9.2 Hz), 5.26 (ddd, 1H, J = 15.6, 5.3, 8.5 Hz), 3.75 (m, 1H), 3.56 (m,
H), 3.37 (s, 3H), 3.03 (m, 1H), 2.49 (m, 1H), 2.37 (m, 1H), 2.09-2.01 (m, 2H), 1.66-1.11 (m, 8H);
1

HETEROCYCLES, Vol. 92, No. 5, 2016
897
13C-NMR (CDCl
FT-IR (thin film, neat) Qmax 3307, 2913, 1641 cm ; HRMS (FAB ) calculated for C12
12.1651, found 212.1650.
E)-3-Aminoazacyclododec-5-en-2-one (2cc): a yellow sticky oil; H-NMR (CD
, 100 MHz) δ 171.1, 133.8, 124.0, 82.3, 57.6, 35.7, 34.4, 30.4, 26.4, 24.9, 23.8, 20.9;
3
-1
+
22NO
(M+H+)
H
2
2
1
(
(
(
3
OD, 300 MHz) δ 5.39
ddd, 1H, J = 15.1, 9.5, 4.6 Hz), 5.25 (ddd, 1H, J = 15.1, 9.3, 4.9 Hz), 3.60 (m, 1H), 2.93 (m, 1H), 2.38
+
N
O (M+H+)
m, 1H), 2.20-1.97 (m, 4H), 1.66-0.91 (m, 8H); HRMS (FAB ) calculated for C11
H
21
2
1
97.1654, found 197.1659.
1
(
E)-3-Methylazacyclotridec-5-en-2-one (2da): a white solid; H-NMR (CD
3
OD, 300 MHz) δ 7.99 (bs,
1
1
4
H), 5.53-5.34 (m, 2H), 3.55 (m, 1H), 2.72 (m, 1H), 2.40 (m, 1H), 2.21 (m, 1H), 2.13-1.97 (m, 3H),
1
3
.67-1.15 (m, 10H), 1.09-1.07 (d, 3H, J = 6.2 Hz); C-NMR (CDCl
3
, 100 MHz) δ 175.7, 133.0, 128.1,
2.2, 39.4, 37.3, 31.3, 27.3, 26.8, 26.6, 26.1, 25.4, 18.4; FT-IR (thin film, neat) Qmax 3301, 2928, 1642, 1549
-1
+
+
cm ; HRMS (FAB ) calculated for C13
H
24NO (M+H ) 210.1858, found 210.1857.
1
(
E)-3-Methoxyazacyclotridec-5-en-2-one (2db): a white solid; H-NMR (CD
3
OD, 300 MHz) δ 7.98 (bs,
1
1
3
H), 5.57-5.39 (m, 2H), 3.73 (m, 1H), 3.45 (m, 1H), 3.39 (s, 3H), 2.98 (m, 1H), 2.78 (m, 1H), 2.44 (m,
1
3
H), 2.06-2.00 (m, 2H), 1.66-1.17 (m, 10H); C-NMR (CDCl
3
, 100 MHz) δ 171.5, 134.9, 81.6, 57.4,
-1
9.2, 33.2, 31.2, 27.3, 27.0, 26.8, 26.2, 25.7; FT-IR (thin film, neat) Qmax 3325, 2917, 1646 cm ; HRMS
+
+
(
FAB ) calculated for C13
H24NO
2
(M+H ) 226.1807, found 210.1815.
1
(
E)-3-Aminoazacyclotridec-5-en-2-one (2dc): a dark yellow oil; H-NMR (CD
3
OD, 300 MHz) δ
5
1
.57-5.36 (m, 2H), 3.49 (m, 1H), 3.33 (m, 1H), 2.89 (m, 1H), 2.37-2.22 (m, 2H), 2.07-2.03 (m, 2H),
+
+
.59-1.31 (m, 10H); HRMS (FAB ) calculated for C12
H
23
N O (M+H ) 211.1810, found 211.1816.
2
ACKNOWLEDGEMENTS
This research was supported by Basic Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2013R1A1A1007632) and by
Kyungpook National University Research Fund, 2013 (2014).
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1

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HETEROCYCLES, Vol. 92, No. 5, 2016
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4
5
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Chattopadhyay, and B. Sinha, Synthesis, 2009, 2117; (c) T. Tsunoda and S. Ito, J. Synth. Org. Chem.
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(a) E. D. Edstrom, J. Am. Chem. Soc., 1991, 113, 6690; (b) E. Vedejs and M. Gingras, J. Am. Chem.
Soc., 1994, 116, 579; (c) M. Diederich and U. Nubbemeyer, Angew. Chem., Int. Ed. Engl., 1995, 34,
1
026; (d) U. M. Lindstro and P. Somfi, J. Am. Chem. Soc., 1997, 119, 8385; (e) A. Sudau and U.
Nubbemeyer, Angew. Chem. Int. Ed., 1998, 37, 1140; (f) See also ref. 1.
6
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(a) A. M. Martin Castro, Chem. Rev., 2004, 104, 2939; (b) H. Ito and T. Taguchi, Chem. Soc. Rev.,
1
999, 28, 43; (b) M. Hiersemann and L. Abraham, Eur. J. Org. Chem., 2002, 1461; (c) Y. H. Chai, S.
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7.
8.
9.
Other synthetic approaches involving Stille coupling of the corresponding enol phosphate followed
by chemoselective reduction of the resulting enamine were also investigated with little success.
(a) F. N. Tebbe, G. W. Parshall, and G. S. Reddy, J. Am. Chem. Soc., 1978, 100, 3611; (b) S. H. Pine,
R. Zahler, D. A. Evans, and R. H. Grubbs, J. Am. Chem. Soc., 1980, 102, 3270.
The major byproduct of the Tebbe reaction in the 7-membered lactam 4b was olefin-isomerized
product 10.
1
0. Pd(0)-Catalyzed allylic cyclization of 11 gave the desired vinyl-substituted product 12 in satisfactory
yield; however, selective debenzylation in the presence of olefin proved to be of problem.
Bn
OAc
Pd(PPh3)4
N
H
Et N, MeCN
3
N
Bn
11
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(
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3. Conventional ring-closing reaction of amides via metathesis generates medium- to macrolactams
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