AgOTf-catalyzed one-pot reaction of 2-alkynylbenzaldehyde, amine, and sodium borohydride

Article abstract of DOI:10.1016/j.tetlet.2008.02.143

One-pot reactions of 2-alkynylbenzaldehydes, amines, and sodium borohydride catalyzed by AgOTf under mild conditions provide a facile protocol for the concise synthesis of 1,2-dihydroisoquinoline derivatives.

Full text of DOI:10.1016/j.tetlet.2008.02.143

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2752–2755
AgOTf-catalyzed one-pot reaction of 2-alkynylbenzaldehyde,
amine, and sodium borohydride
Qiuping Ding a,c, Xingxin Yu a, Jie Wu a,b,
*
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
c Analytical Centre for Physics and Chemistry, Jiangxi Normal University, 437 West Beijing Road, Nanchang 330027, China
Received 3 December 2007; revised 22 February 2008; accepted 26 February 2008
Available online 29 February 2008
Abstract
One-pot reactions of 2-alkynylbenzaldehydes, amines, and sodium borohydride catalyzed by AgOTf under mild conditions provide a
facile protocol for the concise synthesis of 1,2-dihydroisoquinoline derivatives.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: 2-Alkynylbenzaldehydes; Amine; 1,2-Dihydroisoquinoline; Silver triflate; Sodium borohydride
As a privileged scaffold, 1,2-dihydroisoquinoline is
found in many natural products and pharmaceuticals that
exhibit remarkable biological activities.1,2 Significant effort
continues to be given to the development of new 1,2-di-
hydroisoquinoline-based structures and new methods for
their construction.3–6 Recently, metal-catalyzed 6-endo-
mode cyclization of 2-(1-alkynyl)arylaldimine is reported
as a powerful synthetic tool for the synthesis of isoquino-
lines and 1,2-dihydroisoquinolines.3,4 Among these, vari-
ous nucleophiles, such as alkynes, allylstannanes, silyl
enol ethers, and active methylene compounds, have been
employed in the Lewis acid catalyzed reaction of 2-(1-alkyn-
yl)arylaldimine, leading to 1,2-dihydroisoquinoline deriva-
tives.3 Takemoto also investigated the cyclization of 2-(1-
alkynyl)arylaldimine accompanied by hydride reduction
of the iminium intermediate using various reducing
agents.3a It was found that the use of Et3SiH was not effec-
tive for this purpose in the presence of different Lewis acid
catalysts, and the desired cyclic adduct could be obtained
in 80% yield by the reaction of 2-(1-alkynyl)arylaldimine
1 with 2 equiv of Hantzsch ester7 in the presence of
AuCl(PPh3)/AgNTf2 catalyst (10 mol %) (Scheme 1).8
However, in this reaction, expensive Hantzsch ester and
catalyst with high catalytic loading has to be utilized in
order to obtain a respectable yield. Moreover, the starting
material 2-alkynylarylaldimine 1 should be prepared in
advance via condensation of the corresponding aldehyde
and amine. Thus, it is highly desired to develop more effec-
tive and practical synthetic methodology using reducing
agent for 1,2-dihydroisoquinoline formation. Recently,
we described that the functionalized 1,2-dihydroisoquino-
lines could be formed via multi-component reactions of
Ph
AuCl(PPh3) (10 mol %)
AgNTf2 (10 mol %)
Ph
N
Hantzsch ester
(CH2Cl)2, r.t.
N
PMP
PMP
80% yield
1
EtO2C
Me
CO2Et
Me
N
H
Hantzsch ester
*
Corresponding author. Tel.: +86 21 5566 4619; fax: +86 21 6510 2412.
Scheme 1.
E-mail address: jie_wu@fudan.edu.cn (J. Wu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.143

Q. Ding et al. / Tetrahedron Letters 49 (2008) 2752–2755
2753
2-(1-alkynyl)benzaldehydes, amines, and diethyl phosphite
or organozinc reagents.9 Prompted by these results, we
envisioned that one-pot cyclization of 2-(1-alkynyl)benz-
aldehydes, in the presence of amines and reducing agent
may be possible via hydride reduction, as reported herein.
The reaction was initially studied with 2-alkynylbenzal-
dehydes 2a, which was selected as suitable substrate for
reaction development. We found that, in the presence of
silver triflate as catalyst and sodium borohydride as the
hydride source, the reaction of 2-alkynylbenzaldehydes 2a
with p-anisidine 3a in EtOH afforded the desired product
4a in 56% yield (Table 1, entry 1). Following an extensive
investigation, we observed that the result could be dramati-
cally improved in the presence of proline as additive (88%
yield, Table 1, entry 2). Inferior results were displayed
when other Lewis acids were employed in the reaction.
For instance, only 34% yield of product 4a accompanied
with 48% of product 5a was obtained when CuI was used
as the catalyst (Table 1, entry 3). Similar results were gen-
erated while other Lewis acids such as Cu(OTf)2, Zn(OTf)2,
In(OTf)3, Dy(OTf)3, and FeCl3 were utilized in the reaction
(Table 1, entries 4–8). These results indicated that AgOTf is
the most efficient catalyst for this kind of transformation
and only product 4a was detected in the reaction. Further
screening revealed that ethanol is the solvent of choice.
Other solvents such as dichlorometahne, DCE, and MeCN
gave unsatisfactory results (Table 1, entries 9–11). Lower
yield was obtained when pyrrolidine or acetic acid was used
as additive instead of proline (Table 1, entries 12 and 13).
Similar yield was observed when the catalytic amount of
AgOTf was reduced to 2–5 mol % (Table 1, entries 14
and 15). However, the reaction was retarded when
0.1 mol % of AgOTf was employed in the reaction (data
not shown in Table 1). AgOTf is demonstrated crucial
for the reaction. Without AgOTf, only 13% yield of prod-
uct 4a was obtained in the presence of proline (Table 1,
entry 16), while product 5a was generated in the absence
of proline (62% yield, Table 1, entry 17). Increasing
amount of proline could not improve the result (76% yield,
Table 1, entry 18). Slightly lower yield of desired 4a was
observed without the addition of molecular sieves (78%
yield, Table 1, entry 19).
To explore the scope of the reaction, a set of substrates
were subjected to the reaction under optimized conditions
˚
(AgOTf (2–5 mol %), proline (10 mol %), 4 A MS, ethanol,
room temperature), and the results are summarized in
Table 2. Complete conversion and moderate to good iso-
lated yields were observed for most of cases utilized. For
the reactions of 2-alkynylbenzaldehydes 2a with anilines,
better results were obtained when anilines with electron-
donating groups attached on the aromatic ring were
employed. For example, 2-alkynylbenzaldehyde 2a reacted
with 2-methoxybenzeneamine 3c leading to the correspond-
ing product 4c in 80% yield (Table 2, entry 3), while 56%
yield of product 4f was afforded when 4-chlorobenzene-
amine 3f was used in the reaction (Table 2, entry 6).
Table 1
Screening conditions for the reaction of alkynylbenzaldehydes 2a,
p-anisidine 3a with sodium borohydride
PMP
N
NH2
1. Lewis acid (cat.)
additive (10 mol %)
4A MS, solvent, r.t.
CHO
Ph
4a
5a
+
+
2. NaBH4
one-pot
PMP
N
H
Ph
OMe
2a
3a
Table 2
Ph
AgOTf-Catalyzed one-pot reactions of 2-alkynylbenzaldehydes 2, amines
3, and sodium borohydride10
Entry
Lewis acid
Additive
Solvent
Yielda (%)
4a
5a
1. AgOTf (2-5 mol %)
proline (10 mol %)
4A MS, EtOH, r.t.
R2
R1
CHO
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18b
19c
a
AgOTf (10 mol %)
AgOTf (10 mol %)
CuI (10 mol %)
—
Proline
Proline
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CH2Cl2
(CH2Cl)2
MeCN
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
56
88
34
36
18
11
23
18
43
47
59
56
62
88
87
13
—
76
78
—
—
48
16
42
16
37
42
—
—
—
—
—
—
—
—
62
—
—
N
R2 NH2
+
2. NaBH4
R1
4
2
3
Cu(OTf)2 (10 mol %)
Zn(OTf)2 (10 mol %)
In(OTf)3 (10 mol %)
Dy(OTf)3 (10 mol %)
FeCl3 (10 mol %)
AgOTf (10 mol %)
AgOTf (10 mol %)
AgOTf (10 mol %)
AgOTf (10 mol %)
AgOTf (10 mol %)
AgOTf (5 mol %)
AgOTf (2 mol %)
—
Proline
Proline
Proline
Proline
Proline
Proline
Proline
Proline
Pyrrolidine
AcOH
Proline
Proline
Proline
—
Entry
R1
R2
Product
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
a
C6H5 (2a)
C6H5 (2a)
C6H5 (2a)
C6H5 (2a)
C6H5 (2a)
C6H5 (2a)
C6H5 (2a)
C6H5 (2a)
C6H5 (2a)
C6H5 (2a)
C6H5 (2a)
4-MeOC6H4 (3a)
3-MeOC6H4 (3b)
2-MeOC6H4 (3c)
4-MeC6H4 (3d)
C6H5 (3e)
4-ClC6H4 (3f)
4-FC6H4 (3g)
3-NO2C6H4 (3h)
3-CF3C6H4 (3i)
C6H5CH2 (3j)
n-Hexyl (3k)
4a
4b
4c
4d
4e
4f
88
75
80
80
96
56
60
73
4g
4h
4i
67
4j
Trace
Trace
90
—
4k
4l
AgOTf (10 mol %)
AgOTf (10 mol %)
Proline
Proline
4-MeOC6H4 (2b)
4-MeOC6H4 (2b)
4-MeOC6H4 (2b)
Cyclopropyl (2c)
4-MeOC6H4 (3a)
C6H5 (3e)
4-FC6H4 (3g)
4-MeOC6H4 (3a)
4m
4n
4o
73
94
Isolated yield based on 2-alkynylbenzaldehydes 2a.
In the presence of 30 mol % of proline.
Without molecular sieves.
b
c
Trace
Isolated yield based on 2-alkynylbenzaldehydes 2.

2754
Q. Ding et al. / Tetrahedron Letters 49 (2008) 2752–2755
Beshore, D. C.; Hartman, G. D.; Dinsmore, C. J. J. Med. Chem. 2006,
O
1. AgOTf (5 mol %)
proline (10 mol %)
4A MS, EtOH, r.t.
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NH2
CH3
+
No reaction
2. NaBH4
MeO
Ph
6
3a
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Scheme 2.
Although anilines worked well in this reaction, only a trace
amount of product was observed when aliphatic amines,
such as benzylamine and n-hexylamine, were utilized in
the reactions of 2-alkynylbenzaldehyde 2a (Table 2, entries
10 and 11). The R1 attached on the alkynyl group is also
important in this kind of transformation. When 4-
methoxyphenyl group was used as the replacement of
phenyl group in substrate 2, good yields were generated
despite p-anisidine 3a or 4-fluorobenzeneamine 3g was
employed in the reaction (Table 2, entries 12 and 14). How-
ever, to our surprise, only a trace amount of product was
detected when R1 was changed to cyclopropyl group due
to the stability of the product (Table 2, entry 15). Formyl
group in substrate 2 is crucial in this reaction. When formyl
group was replaced by acetyl group (Scheme 2), no reaction
occurred at all which was presumably due to the instability
of formed imine in situ.
In summary, we have described AgOTf-catalyzed one-
pot reactions of 2-alkynylbenzaldehydes, amines, and
sodium borohydride under mild conditions, which provide
a facile and efficient protocol to facilitate the concise syn-
thesis of 1,2-dihydroisoquinoline derivatives. We believe
that this method provides an excellent complement to the
1,2-dihydroisoquinoline synthesis. The advantages of this
method include the use of inexpensive reagent and catalyst
under mild conditions, and experimentally operational
ease.
Acknowledgments
We thank Dr. Renhua Fan for his invaluable advice
during the course of this research. Financial support from
the National Natural Science Foundation of China
(20772018), Shanghai Pujiang Program, and Program for
New Century Excellent Talents in University (NCET-07-
0208) is gratefully acknowledged.
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2008.02.143.
References and notes
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NaBH4 (2.0 equiv) was added and the reaction mixture was stirred for
another 5 min. The reaction solvent was evaporated and the residue
was purified on silica gel to afford the corresponding product 4.
Selected example: 2-(4-Methoxyphenyl)-3-phenyl-1,2-dihydroisoquin-
oline (4a), colorless liquid, 88% yield; 1H NMR (400 MHz, CDCl3) d
3.63 (s, 3H), 4.86 (s, 2H), 6.49 (s, 1H), 6.61 (d, J = 8.8 Hz, 2H), 6.79
(d, J = 8.8 Hz, 2H), 6.97 (d, J = 7.3 Hz, 1H), 7.10 (dt, J = 2.0, 7.3 Hz,
1H), 7.16–7.23 (m, 5H), 7.49 (d, J = 6.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d 55.2, 56.0, 110.6, 113.8, 123.4, 123.9, 124.8,
126.1, 127.2, 127.8, 127.9, 128.1, 128.5, 133.7, 137.2, 140.5, 144.2,
154.6. IR (film): 3047, 2924, 1601, 1508, 1452, 1383, 1244, 1035,
763 cmÀ1; HRMS calcd for C22H19NO: 313.1467; found, 313.1475.
10. General procedure:
A
solution of 2-alkynyl benzaldehyde
2
(0.30 mmol, 1.0 equiv), amine
3
(0.30 mmol, 1.0 equiv), AgOTf
(2–5 mol %), proline (10 mol %), 4A MS (30 mg) in C2H5OH
(3.0 mL) was stirred at room temperature under N2 for 8 h, then