Electronic and steric effects on the intramolecular Schmidt reaction of alkyl azides with secondary benzyl alcohols

Article abstract of DOI:10.1016/j.tet.2013.11.098

The intramolecular Schmidt reaction of simple azido secondary benzyl alcohols has been realized for the first time. Investigation of the electronic and steric effects of the substrates on the product outcome was conducted. Unique intramolecular Schmidt rearrangements were observed with the formation of a cinnamaldehyde derivative and aryl aldehydes, respectively. Using this protocol, an efficient synthesis of dihydrobenzotriazine derivatives was achieved. Moreover, a practical approach to 2-aryl-1-pyrrolines was also accessed.

Full text of DOI:10.1016/j.tet.2013.11.098

Tetrahedron 70 (2014) 643e649
Contents lists available at ScienceDirect
Tetrahedron
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Electronic and steric effects on the intramolecular Schmidt reaction
of alkyl azides with secondary benzyl alcohols
*
Xiaowei Sun, Chengzhe Gao, Fan Zhang, Zhuang Song, Lingyi Kong, Xiaoan Wen ,
*
Hongbin Sun
State Key Laboratory of Natural Medicines and Center of Drug Discovery, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 October 2013
Received in revised form 22 November 2013
Accepted 28 November 2013
Available online 4 December 2013
The intramolecular Schmidt reaction of simple azido secondary benzyl alcohols has been realized for the
first time. Investigation of the electronic and steric effects of the substrates on the product outcome was
conducted. Unique intramolecular Schmidt rearrangements were observed with the formation of a cin-
namaldehyde derivative and aryl aldehydes, respectively. Using this protocol, an efficient synthesis of
dihydrobenzotriazine derivatives was achieved. Moreover, a practical approach to 2-aryl-1-pyrrolines
was also accessed.
Keywords:
Intramolecular Schmidt reaction
Alkyl azide
Ó 2013 Elsevier Ltd. All rights reserved.
Secondary benzyl alcohol
Dihydrobenzotriazine
1. Introduction
Particularly, we address the substituent effects of the phenyl ring
and the tether lengths of the azido alkyl chains on the product
Two decades ago, the intramolecular Schmidt reaction of alkyl
outcome. Detailed mechanistic analysis is also presented herein.
azides with ketones and tertiary carbocations was first reported by
1,2
ꢀ
Aube and Pearson independently. Since then, a considerable
2. Results and discussion
amount of research has been conducted on the optimizations of the
reaction conditions,3 the applications in the synthesis of complex
nitrogen-containing heterocycles,4 and expanding the substrate
scope.5 Nevertheless, detailed studies are still warranted to address
the steric and electronic effects of the substrates on these reac-
tions.5b,j,m,p For example, Molina et al. showed that the azido
benzylic carbocations with the tether length of four-carbon be-
tween the azido group and the phenyl group could readily undergo
intramolecular Schmidt reaction to give five-membered cyclic
imines.5c However, their attempts to make six-membered cyclic
imines via Schmidt reaction of the azido benzylic carbocations with
the tether length of five-carbon failed, without giving any expla-
nation. On the other hand, although a variety of substrates have
been explored in generating various electron-deficient systems for
azide rearrangements,5h surprisingly, there is so far no report on
intramolecular Schmidt reactions based on simple azido secondary
benzyl alcohols.5k,6
As shown in Scheme 1, upon treatment of azido alcohols 1 with
trifluoroacetic acid (TFA) at 0 ꢀC, room temperature or 40 ꢀC,
products 2e6 were formed via paths iev, respectively, depending
on the length of azido alkyl chains and the electronic properties of
the substituents at the phenyl ring. To test how the steric and
electronic factors affected the product outcome, 19 substrates were
examined (Table 1).
For azido alcohols 1 without substituents at the phenyl ring and
with tether lengths of three-carbon (1a), five-carbon (1l), or six-
carbon (1p), trifluoroacetic esters 2a, 2l, and 2p were obtained as
the major products (entries 1, 12, and 16) together with recovered
starting materials, respectively. In contrast, for azido alcohol 1e
with tether length of four-carbon, five-membered cyclic imine 4e
was obtained as the major product (entry 5). This discrepancy
might be due to that, given the instability of benzylic carbocations 7
without substitution at the phenyl ring, the steric difficulties in
forming cyclic aminodiazonium ions 8 from 7 gave rise to the for-
mation of trifluoroacetic esters 2a, 2l, and 2p, respectively (Scheme
1, path i). For example, the strain of the four-membered cyclic in-
termediate 8 derived from 1a might be so strong that, before its
formation, an intermolecular nucleophilic trapping of 7 by TFA
This paper describes our study results on intramolecular
Schmidt reaction of alkyl azides with secondary benzyl alcohols.
* Corresponding authors. Tel./fax: þ86 25 83271198; e-mail addresses: wxagj@
126.com (X. Wen), hbsun2000@yahoo.com (H. Sun).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.098

644
X. Sun et al. / Tetrahedron 70 (2014) 643e649
n
with different alkyl chain lengths were examined. Except for 1m
R1
R2
allowing for the formation of ester 2m (entry 13), treatment of 1b,
1f, and 1q with TFA at room temperature or at 40 ꢀC all resulted in
the recovery of the staring materials (entries 2, 6, 17), implying that
electron-withdrawing groups disabled the generation of the cor-
responding benzylic carbocations 7.
By contrast, azido alcohols 1 with electron-donating sub-
stituents at the phenyl ring were more susceptible to the Schmidt
rearrangements (Scheme 1, paths ii, iii, iv), leading to different
types of products 3e5. This demonstrates that electron-donating
groups promote the formation of stabilized benzylic carbocations
7 or O-methylated quinone methide cation 70 (R2¼OCH3), thus
allowing for the formation of aminodiazonium ions 8 as the pre-
cursors to Schmidt reactions. The product profile still depends on
the alkyl chain lengths and the electronic properties of the sub-
stituents (entries 3, 4, 7e11, 14, 15, 18, 19). The possible mechanisms
are discussed as below.
N
N
O
R1
R2
N
H
H
N
6
5
path iv
path v
n
O
H
H
H
R1
R2
R1
R2
R1
R2
path ii
path iii
N
N
N
H
8
3
4
n
n
R1
R1
N
N
N
N
N
N
R2
O
7'
7
(R2=OCH3)
Scheme 2 elucidates the plausible mechanism for the forma-
tion of 3,4-dimethoxycinnamaldehyde 3d from 1d with tether
length of three-carbon. We envisioned that, upon protonation of
the benzylic hydroxyl group, the p-methoxy function in 1d should
play a key role as the secondary driving force through electron
delocalization, leading to the quinone methide cation 7d0 as the
first in situ generated species,7 instead of benzylic carbocation 7d.
In comparison with 7d, 7d0 is so stable that the unfavored four-
membered cyclic intermediate 8d could be formed. The strain in
8d favors a nonbenzylic hydride shift to the cyclic N atom with loss
of nitrogen, leading to carbocation 9. After a series of electron
transfer and proton transfer steps, hydrolysis of aldimine ion 14
results in 3d. On the other hand, an alternative mechanism in-
volving decomposition of a cinnamyl azide under acidic condi-
tions cannot be excluded,8 even though the generation of this
cinnamyl azide in the presence of the p-methoxy function is
questionable. To our knowledge, this is the first example for an
intramolecular Schmidt reaction affording a cinnamaldehyde
derivative as the major product.5k
TFA
path i
O
O
CF3
OH
R1
R2
N3
R1
R2
N3
n
n
1
2
Scheme 1. Reactions of azido alcohols 1 with TFA.
Table 1
Product outcome of the reactions of azido alcohols 1 with TFAa
Entry
Azido alcohol
n
R1
R2
Product
Yieldb (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
0
0
0
0
1
1
1
1
1
1
1
2
2
2
2
3
3
3
3
H
H
H
OCH3
H
H
H
H
H
H
CF3
OCH3
OCH3
H
CF3
CH3
Ph
OCH3
OCH3
OCH3
H
2a
44
dc
dd
31
56
dc
75
58
74
65
63
37
58
54
61
55
dc
52
73f
dc
dd
3d
4e
dc
4g
4h
4i
4j
4k
2l
2m
5n
5o
2p
dc
5n
6s/5of
9
10
11
12
13
14
15
16
17
18
19
OCH3
Re
H
H
H
OCH3
H
H
H
OCH3
CF3
H+
OCH3
OCH3
H
CF3
OCH3
OCH3
OH
O
O
O
O
-H2O
N
N
O
O
N3
N
N
N
N
7d
7d'
1d
a
Reaction temperature: rt for 1a, 1e, 1g, 1h, 1l, and 1p; 0 ꢀC for 1c, 1d, 1iek, 1n,
H
H
1o, 1r, 1s; 40 ꢀC for 1b, 1f, 1m, and 1q.
H
H
O
O
O
path ii
N
b
N
Isolated yields.
Starting materials recovered.
The reaction was complex and no products could be identified.
c
N2
-N2
H
O
d
9
8d
e
R¼O(CH2)3OCH3.
f
6s/5o¼6.3:1.
H
NH
NH
O
O
O
N
H
O
O
H
H
H
H
occurred, leading to ester 2a as the major product. In addition, the
longer tether lengths in 7 derived from 1l and 1p might delay and
disfavor the azido attack at the benzylic carbocations so that esters
2l and 2p became the dominant products, respectively. This well
explains why Molina et al. failed to make six-membered cyclic
imines via intramolecular Schmidt reaction.5c
O
10
12
11
- H+
NH2
H
NH
O
O
H+
H
O
14
O
13
On the other hand, despite the instability of carbocation 7 de-
rived from 1e, the favored kinetics of five-membered ring forma-
tion readily gave rise to the corresponding aminodiazonium ion 8,
further leading to cyclic imine 4e via benzylic hydride migration to
the cyclic N atom with loss of nitrogen (Scheme 1, path iii).5c
To test the effect of electron-withdrawing substituents of the
phenyl ring on the product profile, azido alcohols 1b, 1f, 1m, and 1q
hydrolysis
O
O
H
O
3d
Scheme 2. Mechanism of formation of 3d from 1d.

X. Sun et al. / Tetrahedron 70 (2014) 643e649
645
H+
As mentioned above with 1e, the Schmidt reactions of the azido
OH
alcohols with tether length of four-carbon afforded 2-aryl-1-
pyrrolines 4 (entries 7e11). The putative mechanism for these re-
actions is similar to that proposed by Molina.5c
O
O
O
O
N3
3
O
O
-H2O
N
N
N
N
N
N
7s'
1s
7s
With further increasing in the tether length by one or two car-
bons, an alternative rearrangement pathway occurred, leading to
aryl aldehydes 5 (Scheme 1, path iv) (entries 14, 15, 18, 19). A rep-
resentative mechanism elucidation is shown in Scheme 3. Amino-
diazonium ion 8n derived from 1n has four possible conformations
AeD, among which conformer C with both the aromatic group and
N2 cation group in equatorial positions should be more stable than
A, B, and D. According to CurtineHammett principle, although the
interconversion of A to B and C to D could be very fast, the energy
barrier for Schmidt rearrangement transition states of A and D
might be much higher than that for B and C, thus leading to the
dominance of path iv rearrangement products. Therefore, anti-
periplanar 1,2-migration of the pinkened CeC bond in B or C to the
cyclic N atom occurs with loss of nitrogen, leading to carbocation
15, and then aldimine ion 16. Hydrolysis of 16 afforded 4-
methoxybenzaldehyde 5n. This is the first example for such
a transformation, and again explains why the corresponding six-
membered cyclic imines could not be obtained via benzylic hy-
dride shift-mediated Schmidt rearrangement.5c
O
N
N
N
O
8s
path v
path iv
-N2
H
H
O
O
O
O
N
N
N
N
18
H
17
- H+
O
O
N
O
O
N
N
19
O
N
hydrolysis
6s
(63%)
O
H
O
5o
(10%)
Ar
Scheme 4. Mechanism of formation of 6s from 1s.
N
H
N2
A
O
O
OH
O
1. TFA
2. aq. NaHCO3
1n
O
O
Ar
N3
N2
N
20
H
H
B
H
N
N
path iv
N
O
O
O
O
O
O
- N2
O
H
N
N
H
15
O
O
O
O
O
N
N
N
+
8n
N2
N
Ar
N
21
C
H
22
(11%)
(84%)
Scheme 5. Reaction of aliskiren intermediate 20 with TFA.
O
16
H
hydrolysis
N
21 in a good yield (84%), while cyclic imine 22 was isolated as
a minor product (11%). In contrast to the reaction of 1k carrying the
same aryl moiety with 20, where cyclic imine 4k is the major
product (entry 11), the lactone moiety and the isopropyl group near
the benzylic carbon in 20 seem to disfavor the Schmidt rear-
rangement. The configuration of the benzylic carbon of 21 was
confirmed by the ROESY spectrum. 3,4-Dihydrobenzotriazine 21
represents an interesting novel scaffold for the development of
renin inhibitors as antihypertensive agents that is a part of our
ongoing program.12
Ar
N2
O
D
H
O
5n
Scheme 3. Mechanism of formation of 5n from 1n.
Interestingly, for azido alcohol 1s with tether length of six-
carbon and 3,4-dimethoxy substituents, 3,4-dihydrobenzotriazine
6s was obtained as the major product (63%), together with alde-
hyde 5o as a minor product (10%) (entry 19). The formation of 6s
can be attributed to the enhanced nucleophilicity of the phenyl ring
by the 3-methoxy function via electron resonance, toward the
aminodiazonium group in 8s (Scheme 4, path v, blue arrows).9 This
approach is more favored over the Schmidt rearrangement of 8s
allowing for the production of aldehyde 5o (Scheme 4, path iv, pink
arrows). We therefore have developed a novel approach to 3,4-
dihydrobenzotriazines with potential pharmaceutical and agricul-
tural utility.10
3. Conclusion
In conclusion, we have carried out the intramolecular Schmidt
reactions of simple azido secondary benzyl alcohols. The sub-
stitution profile of the phenyl ring and the tether lengths of the
azido alkyl chains had profound effects on the product outcome.
Unique intramolecular Schmidt rearrangements led to the
formation of a cinnamaldehyde derivative and aryl aldehydes,
respectively. An efficient synthesis of 3,4-dihydrobenzotriazine
derivatives has been realized and would provide novel scaffolds
for pharmaceutical purpose. Moreover, a practical synthesis of 2-
aryl-1-pyrrolines has also been developed. Further studies are
To further illustrate the utility of the above methodology, azido
alcohol 20, an important intermediate in the synthesis of aliskiren
derivatives as renin inhibitors,11 was examined (Scheme 5). Thus,
treatment of 20 with TFA at 0 ꢀC afforded 3,4-dihydrobenzotriazine

646
X. Sun et al. / Tetrahedron 70 (2014) 643e649
underway to explore the generality of these reactions and their
applications in heterocyclic synthesis.
143.3. ESI-MS m/z 533.3 [2MꢁH]ꢁ. HRMS calcd for C32H33N6O2
[2MꢁH]ꢁ m/z 533.2665, found 533.2670.
4.2.6. 4-Azido-1-(4-methoxyphenyl)butan-1-ol (1i). Brown oil,
4. Experimental section
4.1. General information
0.30 g (46% yield). 1H NMR (300 MHz, CDCl3)
d 1.50e1.60 (m, 1H),
1.65e1.80 (m, 3H), 1.99 (s, 1H), 3.25e3.40 (m, 2H), 3.80 (s, 3H),
4.60e4.70 (m, 1H), 6.85e7.00 (m, 2H), 7.20e7.30 (m, 2H). 13C NMR
(75 MHz, CDCl3)
d 25.4, 35.9, 51.4, 55.3, 73.7, 114.0, 127.0, 136.5,
Low- and high-resolution mass spectra (LRMS and HRMS)
were recorded in electron impact mode. The mass analyzer type
used for the HRMS measurements is TOF. Reactions were moni-
tored by TLC on silica gel 60 F254 plates (Qingdao Ocean Chemical
Company, China). Column chromatography was carried out on
silica gel (200e300 mesh, Qingdao Ocean Chemical Company,
China).
159.2. ESI-MS m/z 244.1 [MþNa]þ. HRMS calcd for C11H15N3O2Na
[MþNa]þ m/z 244.1056, found 244.1061.
4.2.7. 4-Azido-1-(4-methoxy-3-(3-methoxypropoxy)phenyl)butan-
1-ol (1k). Brown oil, 0.46 g (52% yield). 1H NMR (300 MHz, CDCl3)
d
1.50e1.70 (m,1H),1.72e2.00 (m, 4H), 2.05e2.20 (m, 2H), 3.25e3.33
(m, 2H), 3.36 (s, 3H), 3.59 (t, 2H, J¼6.1 Hz), 3.86 (s, 3H), 4.13 (t, 2H,
J¼6.5 Hz), 4.60e4.66 (m,1H), 6.82e6.90 (m, 2H), 6.94 (s,1H).13C NMR
4.2. Procedure for the preparation of 1
(75 MHz, CDCl3)d24.9, 29.0, 35.4, 50.9, 55.6, 58.1, 65.6, 68.8, 73.4,110.4,
111.1,117.7,136.6,148.2,148.5. ESI-MS m/z 332.2 [MþNa]þ. HRMScalcd
4.2.1. 3-Azido-1-phenylpropan-1-ol (1a). To a solution of iodo-
benzene (5.77 g, 28.3 mmol) in anhydrous THF (60 mL) was added
a 1.0 M solution of i-PrMgCl in anhydrous THF (28.3 mL, 28.3 mmol)
over 20 min at ꢁ25 ꢀC, and the resulting mixture was stirred for 1 h
at ꢁ25 ꢀC. After cooling to ꢁ75 ꢀC, a solution of 3-azidopropanal
(1.3 g, 13.0 mmol) in anhydrous THF (23 mL) was added dropwise
over 20 min. After stirring for 1 h at ꢁ75 ꢀC, the reaction mixture
was quenched by saturated aqueous NH4Cl. The mixture was
extracted with EtOAc. The combined extract was washed with
brine, dried over anhydrous sodium sulfate, filtered and concen-
trated in vacuo. The crude product was purified by column chro-
matography (petroleum ether/ethyl acetate, 20:1 to 9:1) to give
a brown oil, 1.20 g (52% yield). 1H NMR (300 MHz, CDCl3)
for C15H23N3O4Na [MþNa]þ m/z 332.1586, found 332.1589.
4.2.8. 5-Azido-1-phenylpentan-1-ol (1l). Brown oil, 1.41 g (44%
yield). 1H NMR (500 MHz, CDCl3)
d 1.33e1.42 (m, 1H), 1.47e1.55 (m,
1H), 1.58e1.65 (m, 2H), 1.70e1.76 (m, 1H), 1.79e1.85 (m, 1H), 2.00
(br s, 1H), 3.20e3.30 (m, 2H), 4.63e4.70 (m, 1H), 7.20e7.40 (m, 5H).
13C NMR (125 MHz, CDCl3)
d 23.0, 28.7, 38.4, 51.3, 74.3, 125.8, 127.6,
128.5, 144.6. ESI-MS m/z 228.1 [MþNa]þ. HRMS calcd for
C
11H15N3ONa [MþNa]þ m/z 228.1107, found 228.1109.
4.2.9. 5-Azido-1-(4-methoxyphenyl)pentan-1-ol (1n). Brown oil,
1.20 g (43% yield). 1H NMR (300 MHz, CDCl3)
1.25e1.37 (m, 1H),
d
1.40e1.53 (m, 1H), 1.55e1.65 (m, 2H), 1.67e1.74 (m, 1H), 1.75e1.84
(m,1H), 1.87 (br s, 1H), 3.24 (t, 2H, J¼6.8 Hz), 3.80 (s, 3H), 4.60 (t,1H,
J¼6.6 Hz), 6.87 (d, 2H, J¼8.5 Hz), 7.25 (d, 2H, J¼8.4 Hz). 13C NMR
d
1.90e2.10 (m, 2H), 2.14 (s, 1H), 3.33e3.53 (m, 2H), 4.80e4.84 (m,
1H), 7.25e7.40 (m, 5H). 13C NMR (75 MHz, CDCl3)
d 37.3, 47.9, 71.3,
125.2, 127.4, 128.2, 143.3.
(75 MHz, CDCl3) d 23.1, 28.7, 38.3, 51.3, 55.3, 74.0, 113.9, 127.1, 136.7,
Following the procedure described for the preparation of 1a,
compounds 1c, 1e, 1g, 1h, 1i, 1k, 1l, 1n, 1o, 1p, 1r, and 20 were
prepared.
159.1. ESI-MS m/z 258.1 [MþNa]þ. HRMS calcd for C12H17N3O2Na
[MþNa]þ m/z 258.1218, found 258.1220.
4.2.10. 5-Azido-1-(3,4-dimethoxyphenyl)pentan-1-ol (1o). Brown
4.2.2. 3-Azido-1-(4-methoxyphenyl)propan-1-ol (1c). Brown oil,
oil, 0.91 g (53% yield). 1H NMR (500 MHz, CDCl3)
d 1.32e1.41 (m,
0.92 g (30% yield). 1H NMR (300 MHz, CDCl3)
d
1.57e2.20 (m, 3H),
1H), 1.45e1.55 (m, 1H), 1.58e1.65 (m, 2H), 1.67e1.75 (m, 1H),
1.79e1.85 (m, 2H), 3.25 (t, 2H, J¼6.8 Hz), 3.87 (s, 3H), 3.89 (s, 3H),
4.61 (t, 1H, J¼6.3 Hz), 6.82e6.87 (m, 2H), 6.90 (s, 1H). 13C NMR
3.30e3.50 (m, 2H), 3.81 (s, 3H), 4.70e4.80 (m, 1H), 6.85e7.00 (m,
2H), 7.25e7.30 (m, 2H). 13C NMR (75 MHz, CDCl3)
d 37.3, 48.0,
54.8, 71.0, 113.6, 126.5, 135.4, 158.7. ESI-MS m/z 206.1 [MꢁH]ꢁ.
(125 MHz, CDCl3) d 23.1, 28.7, 38.4, 51.3, 55.9, 56.0, 74.3, 109.0, 111.1,
HRMS calcd for
206.0933.
C
10H12N3O2 [MꢁH]ꢁ m/z 206.0930, found
118.1, 137.3, 148.6, 149.2. ESI-MS m/z 288.1 [MþNa]þ. HRMS calcd
for C13H19N3O3Na [MþNa]þ m/z 288.1324, found 288.1327.
4.2.3. 4-Azido-1-phenylbutan-1-ol (1e). Brown oil, 0.50 g (20%
yield). 1H NMR (300 MHz, CDCl3)
1.55e1.67 (m, 1H), 1.69e1.92 (m,
3H), 2.04 (br s, 1H), 3.29 (t, 2H, J¼5.7 Hz), 4.65e4.75 (m, 1H),
4.2.11. 6-Azido-1-phenylhexan-1-ol (1p). Brown oil, 1.40 g (45%
d
yield). 1H NMR (300 MHz, CDCl3)
d 1.20e1.50 (m, 4H), 1.50e1.65 (m,
2H), 1.66e1.83 (m, 2H), 1.98 (br s, 1H), 3.22 (t, 2H, J¼6.8 Hz), 4.65 (t,
7.25e7.40 (m, 5H). 13C NMR (75 MHz, CDCl3)
d
25.3, 35.9, 51.3, 74.0,
1H, J¼6 Hz), 7.24e7.38 (m, 5H). 13C NMR (75 MHz, CDCl3)
d 24.8,
125.7, 127.7, 128.5, 144.3. ESI-MS m/z 381.2 [2MꢁH]ꢁ. HRMS calcd
26.1, 28.3, 38.3, 50.8, 74.0, 125.4, 127.1, 128.0, 144.2. ESI-MS m/z
242.1 [MþNa]þ. HRMS calcd for C12H17N3ONa [MþNa]þ m/z
242.1264, found 242.1263.
for C20H25N6O2 [2MꢁH]ꢁ m/z 381.2039, found 381.2043.
4.2.4. 4-Azido-1-p-tolylbutan-1-ol (1g). Brown oil, 0.82 g (31%
yield). 1H NMR (300 MHz, CDCl3)
d
1.50e1.87 (m, 4H),1.96 (br s,1H),
4.2.12. 6-Azido-1-(4-methoxyphenyl)hexan-1-ol (1r). Brown oil,
2.34(s, 3H), 3.23e3.30 (m, 1H), 3.50e3.60 (m, 1H), 4.60e4.70 (m,
1.89 g (49% yield). 1H NMR (500 MHz, CDCl3)
d 1.23e1.33 (m, 1H),
1H), 7.10e7.25 (m, 4H). 13C NMR (75 MHz, CDCl3)
d
21.1, 25.4, 35.9,
1.35e1.47 (m, 3H), 1.55e1.63 (m, 2H), 1.65e1.71 (m, 1H), 1.74e1.80
(m, 1H),1.87 (br s, 1H), 3.23 (t, 2H, J¼6.9 Hz), 3.80 (s, 3H), 4.61 (t, 1H,
J¼5.1 Hz), 6.88 (d, 2H, J¼8.5 Hz), 7.25 (d, 2H, J¼8.4 Hz). 13C NMR
51.4, 73.8, 125.7, 129.2, 137.4, 141.4. ESI-MS m/z 228.1 [MþNa]þ.
HRMS calcd for
228.1098.
C
11H15N3ONa [MþNa]þ m/z 228.1107, found
(125 MHz, CDCl3) d 25.4, 26.6, 28.7, 38.7, 51.4, 55.3, 74.1, 113.9, 127.1,
136.9, 159.1. ESI-MS m/z 272.1 [MþNa]þ. HRMS calcd for
4.2.5. 4-Azido-1-(biphenyl-4-yl)butan-1-ol (1h). Brown oil, 0.75 g
(34% yield). 1H NMR (300 MHz, CDCl3)
1.55e1.70 (m, 1H),
C
13H19N3O2Na [MþNa]þ m/z 272.1375, found 272.1381.
d
1.72e2.00 (m, 4H), 3.31 (t, 2H, J¼5.8 Hz), 4.70e4.80 (m, 1H),
4.2.13. (3S,5S)-5-((1S,3S)-1-Azido-3-(hydroxy(4-methoxy-
3-(3-methoxypropoxy)phenyl)methyl)-4-methylpentyl)-3-
isopropyldihydrofuran-2(3H)-one (20).11 Brown oil, 1.02 g (61%
7.20e7.49 (m, 5H), 7.50e7.60 (m, 4H). 13C NMR (75 MHz, CDCl3)
d
25.3, 36.0, 51.4, 73.8, 126.2, 127.0, 127.2, 127.3, 128.8, 137.9, 140.7,

X. Sun et al. / Tetrahedron 70 (2014) 643e649
647
yield). 1H NMR (300 MHz, CDCl3)
d
0.78e2.65 (m, 23H), 3.34 (s, 3H),
7.60 (d, 2H, J¼8.0 Hz). 13C NMR (125 MHz, CDCl3)
d
25.1, 26.6, 28.7,
3.58(t, 2H, J¼6.0 Hz), 3.61e3.64 (m, 0.53H), 3.84 (s, 3H), 4.00e4.04
(m, 0.47H), 4.10 (t, J¼6.0 Hz, 2H), 4.32e4.39 (m, 1H), 4.45 (d, 0.47H,
J¼8.6 Hz), 4.58 (d, 0.53H, J¼8.2 Hz), 6.80e6.95 (m, 3H). ESI-MS m/z
500.2 [MþNa]þ.
39.0, 51.3, 73.8, 123.1, 125.3, 125.3, 125.4, 125.4, 126.1, 129.6, 129.9,
148.7. ESI-MS m/z 545.2 [2MꢁHꢁN2]ꢁ. HRMS calcd for
C
26H31N4O2F6 [2MꢁHꢁN2]ꢁ m/z 545.2351, found 545.2358.
4.2.20. 6-Azido-1-(3,4-dimethoxyphenyl)hexan-1-ol (1s). Brown oil,
1.47 g (37% yield). 1H NMR (300 MHz, CDCl3)
1.40e1.50 (m, 4H),
4.2.14. 3-Azido-1-(4-(trifluoromethyl)phenyl)propan-1-ol (1b). To
d
a
solution of 1-bromo-4-(trifluoromethyl)benzene (7.3 g,
1.51e1.90 (m, 5H), 3.23 (t, 2H, J¼6.8 Hz), 3.86 (s, 3H), 3.88 (s, 3H),
32.6 mmol) in anhydrous THF (90 mL) was added a 2.5 M solution
of n-BuLi in hexane (13.04 mL, 32.6 mmol) over 20 min at ꢁ65 ꢀC,
and the resulting mixture was stirred for 1 h. Then, a solution of 3-
azidopropanal (1.487 g, 15.0 mmol) in anhydrous THF (40 mL) was
added dropwise to the mixture over 20 min. After stirring for 1 h
at ꢁ65 ꢀC, the reaction mixture was quenched by saturated
aqueous NH4Cl. The mixture was extracted with EtOAc. The
combined extract was washed with brine, dried over anhydrous
sodium sulfate, filtered and concentrated in vacuo. The crude
product was purified by column chromatography (petroleum
ether/ethyl acetate, 10:1 to 3:1) to give a colorless oil, 1.73 g (47%
4.60 (t, 1H, J¼6.1 Hz), 6.80e6.95 (m, 3H). 13C NMR (75 MHz, CDCl3)
d
24.9, 26.1, 28.3, 38.3, 50.9, 55.3, 55.4, 74.0, 108.3, 110.9, 118.1, 137.3,
148.0, 148.7. ESI-MS m/z 302.1 [MþNa]þ. HRMS calcd for
C
14H21N3O3Na [MþNa]þ m/z 302.1475, found 302.1476.
4.3. Procedure for the reaction of 1 with trifluoroacetic acid
(TFA)
4.3.1. Reaction of 1a with TFA. To a solution of 1a (100 mg,
0.56 mmol) in dry CH2Cl2 (7.6 mL) was added dropwise TFA
(0.28 mL, 3.36 mmol) at room temperature. The resulting mixture
was kept at this temperature for 48 h. Then, a solution of aqueous
saturated NaHCO3 (7.9 mL) was added dropwise to the mixture at
0 ꢀC and the resulting mixture was stirred at room temperature for
10 min. The mixture was extracted with CH2Cl2. The combined
extract was washed with brine, dried over anhydrous sodium sul-
fate, filtered, and concentrated in vacuo. The crude product was
purified by column chromatography (petroleum ether/ethyl ace-
tate, 100:1 to 5:1) to give 3-azido-1-phenylpropyl 2,2,2-
trifluoroacetate (2a) as a colorless oil, 68 mg (44% yield). 1H NMR
yield). 1H NMR (300 MHz, CDCl3)
d 1.90e2.10 (m, 2H), 2.40 (br s,
1H), 3.30e3.46 (m, 1H), 3.47e3.60 (m, 1H), 4.85e4.95 (m, 1H), 7.47
(d, 2H, J¼8.0 Hz), 7.63 (d, 2H, J¼8.0 Hz). 13C NMR (75 MHz, CDCl3)
d
37.7, 48.1, 71.0, 122.1, 125.3, 125.3, 125.4, 125.5, 125.8, 126.6,
129.6, 130.0, 147.7. ESI-MS m/z 244.1 [MꢁH]ꢁ. HRMS calcd for
C
10H9N3F3O [MꢁH]ꢁ m/z 244.0698, found 244.0701.
Following the procedure described for the preparation of 1b,
compounds 1d, 1f, 1j, 1m, 1q, and 1s were prepared.
4.2.15. 3-Azido-1-(3,4-dimethoxyphenyl)propan-1-ol (1d). Brown
(300 MHz, CDCl3)
d 2.05e2.20 (m, 1H), 2.25e2.50 (m, 1H),
oil, 1.87 g (39% yield). 1H NMR (300 MHz, CDCl3)
d 1.80e2.10 (m,
3.20e3.50 (m, 2H), 5.95e6.05 (m, 1H), 7.25e7.50 (m, 5H). 13C NMR
2H), 2.35 (br s, 1H), 3.25e3.37 (m, 1H), 3.38e3.42 (m, 1H), 3.84 (s,
(75 MHz, CDCl3) d 37.7, 48.2, 71.7, 125.6, 127.8, 128.6, 143.8. ESI-MS
3H), 3.85 (s, 3H), 4.70e4.80 (m, 1H), 6.70e6.90 (m, 3H). 13C NMR
m/z 292.3 [MþH2OþH]þ. HRMS calcd for C11H13N3O3F3
(75 MHz, CDCl3)
d 37.8, 48.4, 55.8, 55.9, 71.5, 108.8, 111.1, 118.0,
[MþH2OþH]þ m/z 292.0909, found 292.0911.
136.5, 148.6, 149.2. ESI-MS m/z 260.1 [MþNa]þ. HRMS calcd for
C
11H15N3O3Na [MþNa]þ m/z 260.1011, found 260.1013.
4.3.2. Reaction of 1e with TFA. Following the procedure described
for the reaction of 1a with TFA, 5-phenyl-3,4-dihydro-2H-pyrrole
(4e) was obtained as a white solid, 24 mg (56% yield). 1H NMR
4.2.16. 4-Azido-1-(4-(trifluoromethyl)phenyl)butan-1-ol
(1f). Brown oil, 0.71 g (31% yield). 1H NMR (300 MHz, CDCl3)
(300 MHz, CDCl3)
d
1.95e2.10 (m, 2H), 2.95 (t, 2H, J¼8.0 Hz), 4.07 (t,
d
1.50e1.72 (m, 1H), 1.75e1.95 (m, 3H), 2.08 (br s, 1H), 3.31 (t, 2H,
2H, J¼7.2 Hz), 7.40e7.50 (m, 3H), 7.80e7.90 (m, 2H). 13C NMR
J¼6.0 Hz), 4.78 (t, 1H, J¼6.0 Hz), 7.45 (d, 2H, J¼8.0 Hz), 7.61 (d, 2H,
(75 MHz, CDCl3) d 22.6, 34.9, 61.4, 127.6, 128.4, 130.3, 134.4, 173.2.
J¼8.0 Hz). 13C NMR (75 MHz, CDCl3)
d
28.5, 36.1, 44.7, 73.1, 122.2,
ESI-MS m/z 146.1 [MþH]þ. HRMS calcd for C10H12N [MþH]þ m/z
125.3, 125.3, 125.4, 125.5, 126.0, 126.2, 128.1, 129.4, 162.4. ESI-MS m/
146.0970, found 146.0972.
z
258.1 [MꢁH]ꢁ. HRMS calcd for C11H11N3F3O [MꢁH]ꢁ m/z
258.0854, found 258.0856.
4.3.3. Reaction of 1g with TFA. Following the procedure described
for the reaction of 1a with TFA, 5-p-tolyl-3,4-dihydro-2H-pyrrole
(4g) was obtained as a light yellow solid, 58 mg (75% yield). 1H NMR
4.2.17. 4-Azido-1-(3,4-dimethoxyphenyl)butan-1-ol (1j). Brown oil,
1.14 g (26% yield). 1H NMR (500 MHz, CDCl3)
d
1.57e1.65 (m, 1H),
(300 MHz, CDCl3) d 1.95e2.10 (m, 2H), 2.37 (s, 3H), 2.85e2.95 (m,
1.71e1.91 (m, 4H), 3.25e3.35 (m, 2H), 3.87 (s, 3H), 3.89 (s, 3H),
2H), 4.04 (t, 2H, J¼7.3 Hz), 7.15e7.30 (d, 2H, J¼8.1 Hz), 7.72 (d, 2H,
4.60e4.68 (m, 1H), 6.80e6.87 (m, 2H), 6.90 (s, 1H). 13C NMR
J¼8.1 Hz). 13C NMR (75 MHz, CDCl3)
d 21.4, 22.6, 34.8, 61.4, 127.5,
(125 MHz, CDCl3)
d
25.4, 36.0, 51.4, 55.9, 56.0, 74.0, 109.0, 111.2,
129.1, 131.9, 140.4, 173.1. ESI-MS m/z 160.1 [MþH]þ. HRMS calcd for
118.1, 137.1, 148.7, 149.2. ESI-MS m/z 274.1 [MþNa]þ. HRMS calcd for
C
11H14N [MþH]þ m/z 160.1121, found 160.1120.
C
12H17N3O3Na [MþNa]þ m/z 274.1168, found 274.1170.
4.3.4. Reaction of 1h with TFA. Following the procedure described
for the reaction of 1a with TFA, 5-(biphenyl-4-yl)-3,4-dihydro-2H-
4.2.18. 5-Azido-1-(4-(trifluoromethyl)phenyl)pentan-1-ol
(1m). Brown oil, 1.25 g (35% yield). 1H NMR (500 MHz, CDCl3)
pyrrole (4h) was obtained as a white solid, 24 mg (58% yield). 1
H
d
1.30e1.43 (m, 1H), 1.45e1.55 (m, 1H), 1.57e1.65 (m, 2H), 1.69e1.82
NMR (300 MHz, CDCl3)
(t, 2H, J¼7.3 Hz), 7.20e7.50 (m, 3H), 7.55e7.70 (m, 4H), 7.85e7.95
(m, 2H). 13C NMR (75 MHz, CDCl3)
22.7, 34.9, 61.6, 127.0, 127.6,
128.0, 128.8, 133.5, 137.9, 140.3, 142.9, 172.9. ESI-MS m/z 222.1
[MþH]þ. HRMS calcd for C16H16N [MþH]þ m/z 222.1283, found
222.1285.
d 1.95e2.15 (m, 2H), 2.93e3.03 (m, 2H), 4.09
(m, 2H), 2.13 (br s, 1H), 3.27 (t, 2H, J¼6.8 Hz), 4.70e4.77 (m, 1H),
7.44 (d, 2H, J¼8.0 Hz), 7.62 (d, 2H, J¼8.0 Hz). 13C NMR (125 MHz,
d
CDCl3)
d
22.8, 28.6, 38.5, 51.2, 73.7, 122.3, 125.3, 125.4, 125.4, 125.5,
126.0,129.6, 130.2,148.5. ESI-MS m/z 274.1 [MþH]þ. HRMS calcd for
C
12H15N3OF3 [MþH]þ m/z 274.1167, found 274.1171.
4.2.19. 6-Azido-1-(4-(trifluoromethyl)phenyl)hexan-1-ol
(1q). Brown oil, 1.15 g (30% yield). 1H NMR (500 MHz, CDCl3)
4.3.5. Reaction of 1i with TFA. Following the procedure described
for the reaction of 1a with TFA except that the reaction temperature
was 0 ꢀC, 5-(4-methoxyphenyl)-3,4-dihydro-2H-pyrrole (4i) was
obtained as a white solid, 28 mg (74% yield). 1H NMR (300 MHz,
d
1.30e1.50 (m, 4H), 1.55e1.65 (m, 2H), 1.68e1.80 (m, 2H), 1.98 (br s,
1H), 3.24 (t, 2H, J¼6.8 Hz), 4.70e4.77 (m, 1H), 7.45 (d, 2H, J¼8.0 Hz),

648
X. Sun et al. / Tetrahedron 70 (2014) 643e649
CDCl3)
d
1.95e2.10 (m, 2H), 2.92 (t, 2H, J¼8.1 Hz), 3.84 (s, 3H), 4.04
130.1, 149.6, 154.5, 190.7. ESI-MS m/z 167.1 [MþH]þ. HRMS calcd for
C9H11O3 [MþH]þ m/z 167.0708, found 167.0710.
(t, 2H, J¼7.3 Hz), 6.92 (d, 2H, J¼8.7 Hz), 7.81 (d, 2H, J¼8.7 Hz). 13
C
NMR (75 MHz, CDCl3)
d 22.7, 34.9, 55.3, 61.1, 113.8, 127.2, 129.3,
161.5, 172.8. ESI-MS m/z 176.1 [MþH]þ. HRMS calcd for C11H14NO
4.3.12. Reaction of 1p with TFA. Following the procedure described
for the reaction of 1a with TFA, 6-azido-1-phenylhexyl 2,2,2-
trifluoroacetate (2p) was obtained as a colorless oil, 161 mg (55%
[MþH]þ m/z 176.1075, found 176.1077.
4.3.6. Reaction of 1j with TFA. Following the procedure described
for the reaction of 1a with TFA except that the reaction temperature
was 0 ꢀC, 5-(3,4-dimethoxyphenyl)-3,4-dihydro-2H-pyrrole (4j)
was obtained as a white solid, 85 mg (65% yield). 1H NMR (500 MHz,
yield). 1H NMR (300 MHz, CDCl3)
d 1.30e1.50 (m, 4H), 1.50e1.65 (m,
2H), 1.80e2.00 (m, 1H), 2.02e2.15 (m, 1H), 3.24 (t, 2H, J¼6.8 Hz),
5.85 (t, 1H, J¼6.4 Hz), 7.24e7.42 (m, 5H). 13C NMR (75 MHz, CDCl3)
d
24.3, 25.8, 28.1, 35.2, 50.7, 80.2, 126.0, 128.3, 128.4, 137.5. ESI-MS
CDCl3)
d
1.95e2.10 (m, 2H), 2.96 (t, 2H, J¼8.1 Hz), 3.91 (s, 3H), 3.94
m/z 174.1 [MꢁN2ꢁC2O2F3]þ. HRMS calcd for C12H16
N
(s, 3H), 4.05 (t, 2H, J¼7.3 Hz), 6.86 (d, 1H, J¼8.3 Hz), 7.27 (dd, 1H,
[MꢁN2ꢁC2O2F3]þ m/z 174.1283, found 174.1286.
J¼2.3, 8.9 Hz), 7.63 (s, 1H). 13C NMR (125 MHz, CDCl3)
d 22.6, 34.8,
55.9, 56.0, 60.7, 109.9, 110.3, 121.9, 127.2, 149.1, 151.6, 173.3. ESI-MS
m/z 206.1 [MþH]þ. HRMS calcd for C12H16NO2 [MþH]þ m/z
206.1181, found 206.1183.
4.3.13. Reaction of 1r with TFA. Following the procedure described
for the reaction of 1a with TFA except that the reaction temperature
was 0 ꢀC, 4-methoxybenzaldehyde (5n) was obtained as a light
yellow oil, 63 mg (52% yield).
4.3.7. Reaction of 1k with TFA. Following the procedure described
for the reaction of 1a with TFA except that the reaction temperature
4.3.14. Reaction of 1s with TFA. Following the procedure described
for the reaction of 1a with TFA except that the reaction temperature
was
[1,2,3]triazino[1,6-a]azepine (6s) was obtained as a brown oil,
88 mg (63% yield). In addition, 3,4-dimethoxybenzaldehyde (5o)
was obtained as a light yellow solid, 11 mg (10% yield). For 6s: 1H
was
dihydro-2H-pyrrole (4k) was obtained as a white solid, 38 mg
(63% yield). 1H NMR (500 MHz, CDCl3)
2.00e2.15 (m, 4H), 2.97 (t,
0
ꢀC, 5-(4-methoxy-3-(3-methoxypropoxy)phenyl)-3,4-
0
ꢀC, 2,3-dimethoxy-8,9,10,11,12,12a-hexahydrobenzo[4,5]
d
2H, J¼5.0 Hz), 3.34 (s, 3H), 3.57 (t, 2H, J¼5.0 Hz), 3.90 (s, 3H), 4.06 (t,
2H, J¼6.7 Hz), 4.19 (t, 2H, J¼6.4 Hz), 6.87 (d, 1H, J¼8.2 Hz), 7.32 (d,
1H, J¼8.0 Hz), 7.65 (s, 1H). 13C NMR (125 MHz, CDCl3)
d
22.4, 29.5,
NMR (300 MHz, CDCl3) d 1.41e1.63 (m, 3H), 1.65e1.80 (m, 4H),
34.8, 56.0, 58.6, 60.3, 66.3, 69.3, 110.7, 111.6, 122.0,172.6. ESI-MS m/z
264.2 [MþH]þ. HRMS calcd for C15H22NO3 [MþH]þ m/z 264.1600,
found 264.1602.
2.05e2.15 (m, 1H), 3.47e3.56 (m, 1H), 3.84 (s, 3H), 3.87 (s, 3H),
4.16e4.25 (m, 1H), 4.41 (m, 1H), 6.37 (s, 1H), 6.98 (s, 1H). 13C NMR
(75 MHz, CDCl3)
d 25.9, 26.6, 28.8, 37.2, 54.5, 54.8, 56.0, 56.1, 106.5,
107.4, 114.9, 132.1, 148.9, 150.0. ESI-MS m/z 262.1 [MþH]þ. HRMS
4.3.8. Reaction of 1l with TFA. Following the procedure described
for the reaction of 1a with TFA, 5-azido-1-phenylpentyl 2,2,2-
trifluoroacetate (2l) was obtained as a colorless oil, 96 mg (37%
calcd for C14H20N3O2 [MþH]þ m/z 262.1556, found 262.1559.
4.3.15. Reaction of 20 with TFA. Following the procedure described
for the reaction of 1a with TFA except that the reaction temperature
yield). 1H NMR (500 MHz, CDCl3)
d 1.40e1.75 (m, 2H), 1.81e1.90 (m,
2H), 2.05e2.18 (m, 1H), 2.20e2.35 (m, 1H), 3.48 (t, 2H, J¼6.7 Hz),
was
0
ꢀC, (3S,5S)-3-isopropyl-5-((1S,3S,10bR)-1-isopropyl-8-
6.05e6.15 (m, 1H), 7.40e7.70 (m, 5H). 13C NMR (125 MHz, CDCl3)
methoxy-9-(3-methoxypropoxy)-1,2,3,10b-tetrahydrobenzo[e]pyr-
rolo[1,2-c][1,2,3]triazin-3-yl)dihydrofuran-2(3H)-one (21) was ob-
tained as a colorless oil, 122 mg (84% yield). In addition, (3S,5S)-3-
isopropyl-5-((2S,4S)-4-isopropyl-5-(4-methoxy-3-(3-
d
22.5, 28.4, 35.3, 51.0, 80.5, 126.4, 128.8, 128.9, 130.0, 137.8. ESI-MS
m/z 160.1 [MꢁN2ꢁC2O2F3]þ. HRMS calcd for C11H14
N
[MꢁN2ꢁC2O2F3]þ m/z 160.1126, found 160.1128.
methoxypropoxy)phenyl)-3,4-dihydro-2H-pyrrol-2-yl)dihy-
4.3.9. Reaction of 1m with TFA. Following the procedure described
for the reaction of 1a with TFA except that the reaction temper-
ature was 40 ꢀC, 5-azido-1-(4-(trifluoromethyl)phenyl)pentyl
2,2,2-trifluoroacetate (2m) was obtained as a colorless oil, 264 mg
drofuran-2(3H)-one (22) was obtained as a colorless oil, 15 mg (11%
25
yield). For 21: [
CDCl3)
a
]
ꢁ111.2 (c 0.30, CH3OH). 1H NMR (500 MHz,
D
d
0.86 (d, 3H, J¼5.0 Hz), 0.91 (d, 3H, J¼5.0 Hz), 0.95 (d, 3H,
J¼5.0 Hz), 1.06 (d, 3H, J¼5.0 Hz), 1.95e2.15 (m, 7H), 2.20e2.27 (m,
1H), 2.33e2.43 (m, 1H), 2.45e2.55 (m, 1H), 3.35 (s, 3H), 3.57 (t, 2H,
J¼5.0 Hz), 3.89 (s, 3H), 3.91 (d, 1H, J¼12.7 Hz), 4.14 (t, 2H, J¼5.0 Hz),
(58% yield). 1H NMR (300 MHz, CDCl3)
d 1.30e1.70 (m, 4H),
1.89e2.00 (m, 1H), 2.03e2.10 (m, 1H), 3.30 (t, 2H, J¼6.6 Hz),
5.90e5.94 (m, 1H), 7.49 (d, 2H, J¼8.1 Hz), 7.68 (d, 2H, J¼8.1 Hz). 13
C
4.25e4.30 (m, 1H), 4.81e4.86 (m, 1H), 6.61 (s, 1H), 7.10 (s, 1H). 13
C
NMR (75 MHz, CDCl3)
d
22.4, 28.3, 35.3, 50.9, 79.5, 125.8, 125.9,
NMR (125 MHz, CDCl3) d 17.3, 18.1, 20.3, 22.3, 24.7, 27.5, 44.8, 44.9,
125.9, 126.0, 126.7, 141.7. ESI-MS m/z 228.1 [MꢁN2ꢁC2O2F3]þ.
HRMS calcd for C12H13NF3 [MꢁN2ꢁC2O2F3]þ m/z 228.1000, found
228.1003.
55.3, 56.1, 58.8, 61.2, 66.2, 69.0, 79.0, 106.1, 108.4, 117.0, 134.3, 149.1,
150.3,178.6. ESI-MS m/z 460.2 [MþH]þ. HRMS calcd for C25H38N3O5
[MþH]þ m/z 460.2811, found 460.2814. For 22: [
a
]
D
¼32.0 (c 0.13,
25
CH3OH). 1H NMR (300 MHz, CDCl3)
d
0.63 (d, 2H, J¼6.8 Hz),
4.3.10. Reaction of 1n with TFA. Following the procedure described
for the reaction of 1a with TFA except that the reaction temperature
was 0 ꢀC, 4-methoxybenzaldehyde (5n) was obtained as a light
0.90e1.15 (m,10H),1.55e1.65 (m,1H),1.85e2.05 (m, 2H), 2.05e2.25
(m, 5H), 2.35e2.45 (m, 1H), 2.70e2.90 (m, 1H), 3.34 (s, 3H), 3.57 (t,
2H, J¼6.1 Hz), 3.89 (s, 3H), 4.10e4.25 (m, 3H), 4.60e4.70 (m, 1H),
6.84 (d, 1H, J¼8.3 Hz), 7.20e7.30 (m, 1H), 7.44e7.47 (m, 1H). 13C
yellow oil, 63 mg (54% yield). 1H NMR (300 MHz, CDCl3)
d 3.89 (s,
3H), 7.01 (d, 2H, J¼8.6 Hz), 7.84 (d, 2H, J¼8.6 Hz), 9.89 (s, 1H). 13
C
NMR (75 MHz, CDCl3) d 16.2, 18.2, 20.6, 21.7, 25.6, 26.7, 28.6, 29.4,
NMR (75 MHz, CDCl3)
d
55.5, 114.2, 129.9, 131.9, 164.5, 190.7. ESI-MS
29.5, 45.6, 54.1, 56.0, 58.7, 66.1, 69.3, 75.7, 80.0, 101.4, 109.6, 110.7,
112.3, 112.4, 121.7, 175.4. ESI-MS m/z 454.3 [MþNa]þ. HRMS calcd
for C25H37NO5Na [MþNa]þ m/z 454.2569, found 454.2573.
m/z 137.1 [MþH]þ. HRMS calcd for C8H9O2 [MþH]þ m/z 137.0603,
found 137.0606.
4.3.11. Reaction of 1o with TFA. Following the procedure described
for the reaction of 1a with TFA except that the reaction temperature
was 0 ꢀC, 3,4-dimethoxybenzaldehyde (5o) was obtained as a light
4.3.16. Reaction of 1d with TFA. To a stirred solution of 1d (130 mg,
0.55 mmol) in dry CH2Cl2 (6 mL) was added dropwise TFA (0.25 mL,
3.3 mmol) at 0 ꢀC. The resulting mixture was kept at this temper-
ature for 1 h. The mixture was then warmed to room temperature
and stirred for 11 h. A solution of aqueous saturated NaHCO3 (3 mL)
was added dropwise to the mixture at 0 ꢀC and the resulting
yellow solid,100 mg (61% yield). 1H NMR (500 MHz, CDCl3)
d
3.91 (s,
3H), 3.93 (s, 3H), 6.95 (d, 2H, J¼8.2 Hz), 7.43 (d, 2H, J¼8.2 Hz), 9.82
(s, 1H). 13C NMR (125 MHz, CDCl3)
55.9, 56.1, 109.0, 110.4, 126.7,
d

X. Sun et al. / Tetrahedron 70 (2014) 643e649
649
ꢀ
3. Motiwala, H. F.; Fehl, C.; Li, S. W.; Hirt, E.; Porubsky, P.; Aube, J. J. Am. Chem. Soc.
2013, 135, 9000e9009.
mixture was stirred at room temperature for 10 min. Then, the
mixture was extracted with CH2Cl2 (3ꢂ10 mL). The combined ex-
tract was washed with brine, dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo. The crude product was purified
by column chromatography (petroleum ether/ethyl acetate 10:1) to
give (E)-3-(3,4-dimethoxyphenyl)acrylaldehyde 3d as a yellow
4. (a) Pearson, W. H.; Gallagher, B. M. Tetrahedron 1996, 52, 12039e12048; (b)
Iyengar, R.; Schildknegt, K.; Aube, J. Org. Lett. 2000, 2, 1625e1627; (c) Smith, B.
T.; Wendt, J. A.; Aube, J. Org. Lett. 2002, 4, 2577e2579; (d) Wrobleski, A.; Sa-
hasrabudhe, K.; Aube, J. J. Am. Chem. Soc. 2004, 126, 5475e5481; (e) Kapat, A.;
Nyfeler, E.; Giuffredi, G. T.; Renaud, P. J. Am. Chem. Soc. 2009, 131, 17746e17747;
(f) Liu, R. Z.; Gutierrez, O.; Tantillo, D. J.; Aube, J. J. Am. Chem. Soc. 2012, 134,
ꢀ
ꢀ
ꢀ
ꢀ
solid, 32 mg (31% yield). 1H NMR (300 MHz, CDCl3)
d 3.92 (s, 3H),
6528e6531.
5. (a) Pearson, W. H.; Walavalkar, R.; Schkeryantz, J. M.; Fang, W. K.; Blickensdorf,
J. D. J. Am. Chem. Soc. 1993, 115, 10183e10194; (b) Milligan, G. L.; Mossman, C. J.;
Aube, J. J. Am. Chem. Soc. 1995, 117, 10449e10459; (c) Molina, P.; Alcantara, J.;
Lopez-Leonardo, C. Synlett 1995, 363e364; (d) Mossman, C. J.; Aube, J. Tetra-
hedron 1996, 52, 3403e3408; (e) Desai, P.; Schildknegt, K.; Agrios, K. A.;
Mossman, C.; Milligan, G. L.; Aube, J. J. Am. Chem. Soc. 2000, 122, 7226e7232; (f)
Reddy, P. G.; Varghese, B.; Baskaran, S. Org. Lett. 2003, 5, 583e585; (g) Gorin, D.
J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260e11261; (h) Lang, S.;
Murphy, J. A. Chem. Soc. Rev. 2006, 35, 146e156; (i) Lertpibulpanya, D.; Marsden,
3.93 (s, 3H), 6.60 (dd, 1H, J¼7.7, 15.8 Hz), 6.89 (d, 1H, J¼8.3 Hz), 7.08
(d, 1H, J¼1.8 Hz), 7.15 (dd, 1H, J¼3.0, 9 Hz), 7.41 (d, 1H, J¼15.8 Hz),
ꢀ
ꢀ
9.66 (d, 1H, J¼7.7 Hz). 13C NMR (75 MHz, CDCl3)
d
55.9, 56.0, 109.9,
ꢀ
ꢀ
111.1, 123.4, 126.7, 126.9, 149.3, 151.9, 152.8, 193.5. ESI-MS m/z 193.1
[MþH]þ. HRMS calcd for C11H13O3 [MþH]þ m/z 193.0865, found
193.0867.
ꢀ
For the reactions of 1b, 1f, and 1q with TFA, following the pro-
cedure described for the reaction of 1a with TFA except that the
reaction temperature was 40 ꢀC, the starting materials were re-
covered, respectively. For the reaction of 1c with TFA at 0 ꢀC, the
product was unstable and decomposed.
ꢀ
S. P. Org. Biomol. Chem. 2006, 4, 3498e3504; (j) Lee, H. L.; Aube, J. Tetrahedron
2007, 63, 9007e9015; (k) Hayashi, K.; Tanimoto, H.; Zhang, H.; Morimoto, T.;
Nishiyama, Y.; Kakiuchi, K. Org. Lett. 2012, 14, 5728e5731 In this letter, there are
two examples involved in azido secondary benzyl alcohols, however, each has
an allylic hydroxyl group playing a key role for the reaction to occur; (l) Gu, P.
M.; Kang, X. Y.; Sun, J.; Wang, B. J.; Yi, M.; Li, X. Q.; Xue, P.; Li, R. Org. Lett. 2012,
14, 5796e5799; (m) Pearson, W. H.; Walavalkar, R. Tetrahedron 2001, 57,
ꢀ
5081e5089; (n) Katz, C. E.; Aube, J. J. Am. Chem. Soc. 2003, 125, 13948e13949;
(o) Yao, L.; Aube, J. J. Am. Chem. Soc. 2007, 129, 2766e2767; (p) Gutierrez, O.;
Acknowledgements
ꢀ
ꢀ
Aube, J.; Tantillo, D. J. J. Org. Chem. 2012, 77, 640e647.
This work was supported by the ‘111 Project’ from the Ministry
of Education of China, the State Administration of Foreign Expert
Affairs of China (No. 111-2-07) and program for Changjiang Scholars
and Innovative Research Team in University (IRT1193).
6. (a) Sahasrabudhe, K.; Gracias, V.; Furness, K.; Smith, B. T.; Katz, C. E.; Reddy, D.
S.; Aube, J. J. Am. Chem. Soc. 2003, 125, 7914e7922; (b) Pearson, W. H.; Fang, W.
ꢀ
K. J. Org. Chem. 1995, 60, 4960e4961.
€
7. Dehn, R.; Katsuyama, Y.; Weber, A.; Gerth, K.; Jansen, R.; Steinmetz, H.; Hofle,
G.; Muller, R.; Kirschning, A. Angew. Chem., Int. Ed. 2011, 50, 3882e3887.
8. Szostak, M.; Yao, L.; Aube, J. Org. Lett. 2009, 11, 4386e4389.
€
ꢀ
9. (a) Pearson et al. reported the production of dihydrotriazines via intra-
molecular cyclization of azides with indolylalkyl and allylic cations: Pearson,
W. H.; Fang, W. K.; Kampf, J. W. J. Org. Chem. 1994, 59, 2682e2684; (b) Reddy, D.
Supplementary data
1H NMR and 13C NMR copies of all new compounds. Supple-
mentary data associated with this article can be found in the online
version, at http://dx.doi.org/10.1016/j.tet.2013.11.098.
ꢀ
S.; Judd, W. R.; Aube, J. Org. Lett. 2003, 5, 3899e3902.
10. Reingruber, R.; Vanderheiden, S.; Muller, T.; Nieger, M.; Es-Sayed, M.; Braese, S.
€
Tetrahedron Lett. 2009, 50, 3439e3442 and references therein.
€
11. (a) Maibaum, J.; Stutz, S.; Goschke, R.; Rigollier, P.; Yamaguchi, Y.; Cumin, F.;
Rahuel, J.; Baum, H. P.; Cohen, N. C.; Schnell, C. R.; Fuhrer, W.; Gruetter, M. G.;
€
Schilling, W.; Wood, J. M. J. Med. Chem. 2007, 50, 4832e4844; (b) Goschke, R.;
References and notes
Herold, P.; Rigollier, P.; Maibaum, J. K. U.S. Patent 5,606,078, 1997.
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