Synthesis of naphthalene amino esters and arylnaphthalene lactone lignans through tandem reactions of 2-alkynylbenzonitriles

Article abstract of DOI:10.1039/c4cc01738b

Tandem reaction of 2-alkynylbenzonitriles with a Reformatsky reagent turned out to be a novel and efficient approach toward 1-aminonaphthalene-2- carboxylates. Interestingly, with 2-(3-hydroxyprop-1-ynyl)benzonitriles as the substrates, a more sophisticat

Full text of DOI:10.1039/c4cc01738b

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Synthesis of naphthalene amino esters and
arylnaphthalene lactone lignans through tandem
reactions of 2-alkynylbenzonitriles†
Cite this: Chem. Commun., 2014,
50, 5641
Received 7th March 2014,
Accepted 2nd April 2014
Yan He, Xinying Zhang and Xuesen Fan*
DOI: 10.1039/c4cc01738b
www.rsc.org/chemcomm
Tandem reaction of 2-alkynylbenzonitriles with a Reformatsky elaboration of these versatile intermediates have emerged as
reagent turned out to be a novel and efficient approach toward powerful tools in the preparation of a plethora of compounds.
1-aminonaphthalene-2-carboxylates. Interestingly, with 2-(3-hydroxy- Inspired by these pioneering achievements, we envisioned a new
prop-1-ynyl)benzonitriles as the substrates, a more sophisticated cascade synthesis of 1-aminonaphthalene-2-carboxylates via a cascade
process occurred to give 9-aminonaphtho[2,3-c]furan-1(3H)-ones procedure combining a zinc-mediated Blaise reaction of 2-alkynyl-
in good yields. By using this tandem reaction as a key step, a concise benzonitriles and subsequent intramolecular cyclization of the
and versatile synthetic strategy for the total synthesis of aryl- in situ formed enamine intermediates (Scheme 1).
naphthalene lactone lignans has been developed.
Thus, 2-(phenylethynyl)benzonitrile (1a) was prepared via
Sonogashira coupling of 2-bromobenzonitrile with ethynyl benzene
Functionalized naphthalenes, frequently found in natural products, and then treated with ethyl 2-bromoacetate (2, 1 equiv.) and zinc
pharmaceuticals and electronic materials,1,2 were traditionally synthe- powder (1 equiv.) in THF at 80 1C for 2 h. To our delight, the reaction
sized by stepwise introduction of required functional groups onto the gave the desired ethyl 1-amino-2-naphthoate (3a) in a yield of 45%
naphthalene core via electrophilic substitutions.3 However, the applic- (Table 1, entry 1). To optimize the reaction conditions, CH3CN, DCE
ability of this strategy is compromised owing to the limited availability and DMF were studied as alternative solvents. It turned out that
of suitable naphthalene substrates and the difficulty in controlling they were less effective than THF in mediating this cascade process
the regio-selectivity. To circumvent these limitations, synthesis of (entries 2–4). Next, the effect of the quantity of 2 and zinc was investi-
substituted naphthalenes from readily available benzene precursors gated (entries 5–8). Promisingly, when 2 equiv. of 2 and 3 equiv. of
turned out to be an attractive alternative.4–6 Following this strategy, an zinc were used, the yield of 3a raised to 75% and the time period for a
efficient synthesis of 1-amino-2-naphthalene carboxylic acids via complete conversion shortened to 0.5 h (entry 7). Nevertheless,
reacting 2-(a-lithioalkyl) benzonitriles with a,b-unsaturated carboxyl- a further increase in the quantity of 2 and zinc did not improve the
ates or nitriles has been developed by Kobayashi.7 More recently, reaction obviously (entry 8). It was also found that when the reaction
Sudalai revealed a novel preparation of naphthalene amino esters was run at lower temperatures, the yield of 3a decreased dramatically
through CuCN-mediated one-pot cyclization of 4-(2-bromo phenyl)- (entries 9 and 10). It was noted herein that the intermediate amino-
2-butenoates.8 While these elegant processes are generally efficient ester as shown in Scheme 1 was not obtained or observed.
and reliable, a motivation to develop more practical and convenient
With the optimized conditions (Table 1, entry 7), a range of
approaches carried out under mild conditions still strongly persists. 2-alkynylbenzonitriles (1) were screened to probe the scope of this
Recently, zinc enolates have found broad applications due to reaction. The results listed in Table 2 showed that all the substrates
their versatile reactivity and excellent functional group tolerance.9 reacted smoothly with ethyl 2-bromoacetate (2) and zinc to furnish
As demonstrated by Lee,10 Johnson11 and others, addition of a the corresponding 1-aminonaphthalene-2-carboxylates (3) in good to
Reformatsky reagent onto a carbonyl or a cyano group to form excellent yields and various functional groups were well tolerable. It
new enolates or a zinc bromide complex of b-enamino ester and was noted that while the X unit in 1 could be hydrogen, methoxy,
fluoro or chloro, substrates with a fluoro or a chloro group (1j–1m)
School of Chemistry and Chemical Engineering, School of Environment,
Collaborative Innovation Centre of Henan Province for Green Manufacturing of
Fine Chemicals, Henan Key Laboratory for Environmental Pollution Control,
Henan Normal University, Xinxiang, Henan 453007, P. R. China.
E-mail: xuesen.fan@htu.cn
† Electronic supplementary information (ESI) available: Experimental procedures,
characterisation data and NMR spectra. See DOI: 10.1039/c4cc01738b
Scheme 1 Proposed synthesis of functionalized naphthalene.
Chem. Commun., 2014, 50, 5641--5643 | 5641
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Table 1 Optimization studies for the formation of 3aa
Table 2 Scope of the reaction leading to 3a
Yieldb (%)
Entry Substrates (1)
Products (3)
Yieldb (%)
75
Entry
2 (eq.)
Zinc (eq.)
T (1C)
Solvent
t (h)
1
2
3
4
5
6
7
8
9
10
1
1
1
1
1
1
2
3
2
2
1
1
1
1
2
3
3
4
3
3
80
80
80
80
80
80
80
80
r.t.
60
THF
CH3CN
DCE
DMF
THF
THF
THF
THF
THF
THF
2
2
2
2
1
1
0.5
0.5
2
45
20
15
Trace
50
56
75
76
Trace
55
1
2
73
2
3
4
5
6
69
71
77
75
a
b
Reaction conditions: 1a (0.5 mmol), solvent (2 mL). Isolated yield.
gave relatively higher yields. As for the scope of R1, it could be not
only an aryl unit (1a–1f, 1i–1m), but also a hydrogen (1g) or an
alkyl (1h) group. These results indicate that this synthetic method
is suitable for the preparation of naphthalene with diverse sub-
stitution patterns. It was notable that in all cases only the 6-endo
pathway was observed and the 5-exo-dig product was not found.
In further exploration of the scope of substrates, we postulated that
if 2-(3-hydroxyprop-1-ynyl)benzonitrile (4a) was used to replace 1a,
the in situ formed 1-amino-3-(hydroxylmethyl)-2-naphthoate (A) via
Blaise reaction of 4a may simultaneously undergo lactonization to give
9-amino naphtho[2,3-c]furan-1(3H)-one (5a, Scheme 2).12
7
68
Indeed, treatment of 4a with 2 and zinc in THF at 80 1C afforded
5a in a yield of 70%. Further studies showed that this cascade
process was suitable for a wide range of substrates possessing
either EWG or EDG (X) on the benzene moiety. In addition, both
alkyl (Table 3, entries 6 and 7) and phenyl (entries 8–10) substituted
3-hydroxyprop-1-ynyl units participated in this tandem reaction as
smoothly as that without a substituent (entries 1–5) to afford the
corresponding products with good efficiency, and this thus results
in a simple and general synthetic protocol toward naphtho-
[2,3-c]furan-1(3H)-ones.13
It is well known that arylnaphthalene lactone lignans are plant
derived natural products with a wide range of valuable medicinal
properties and therefore have been of continued interest in drug
discovery.14 It is also noticed that 9-amino naphtho[2,3-c]furan-
1(3H)-one (5) has the same naphthalene lactone scaffold as that
in arylnaphthalene lactone lignans and the amino group embedded
in 5 is actually a convenient intermediary for the introduction of an
aryl unit. On the basis of these observations, we were then interested
in developing a new strategy for the total synthesis of arylnaphthalene
lactone natural products by using the synthetic protocol developed
above as a key step. Thus, 6-(3-hydroxyprop-1-ynyl)benzo[d][1,3]-
dioxole-5-carbonitrile (4k) was reacted with 2 and zinc to afford
9-amino-6,7-methylenedioxynaphtho[2,3-c]furan-1(3H)-one (5k).
Treatment of 5k with aqueous solution of hydrochloric acid and
sodium nitrite followed by addition of potassium iodide gave
9-iodo-6,7-methylenedioxynaphtho[2,3-c]furan-1(3H)-one (6). Suzuki
8
65
68
84
83
9
10
11
12
86
88
13
a
Reaction conditions: 1 mmol of 1, 2 mmol of 2, 3 mmol of zinc, 3 mL
b
of THF, 80 1C, 0.5 h. Isolated yield.
Scheme 2 Proposed one-pot formation of 5a from 4a.
coupling of 6 with the commercially available benzo[d][1,3]dioxol- another member of the arylnaphthalene lactone family, chinensin.
5-yl boronic acid (7a) afforded taiwanin C (Scheme 3). Similarly, Given the broad scope of 4 and 7, this concise and versatile strategy
coupling of 6 with 3,4-dimethoxyphenyl boronic acid (7b) afforded should be able to provide numerous arylnaphthalene lactone
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Table 3 Scope of the reaction leading to 5a
In summary, we have revealed efficient and convenient syntheses
of 1-aminonaphthalene-2-carboxylates and 9-amino naphtho[2,3-c]-
furan-1(3H)-ones via Blaise reaction of 2-alkynylbenzonitriles
followed by 6-p cyclization and lactonization. More interestingly,
9-aminonaphtho[2,3-c]furan-1(3H)-ones were found to be con-
venient intermediates to arylnaphthalene lactone lignans. As a
result, a concise and versatile strategy for the total synthesis of
naturally occurring arylnaphthalene lactones, chinensin and
taiwanin C was developed. Studies to find more applications of
zinc mediated cascade reactions are currently underway in our
lab and the results will be reported in due course.
Entry
1
Substrates (4)
Products (5)
Yieldb (%)
70
2
3
4
5
62
77
75
78
We are grateful to the National Natural Science Foundation of
China (21172057, 21272058), RFDP (20114104110005), PCSIRT
(IRT1061) and 2012IRTSTHN006 for financial support.
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72
66
82
74
88
10
a
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b
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lignans with diverse substitution patterns, which is extremely
important for drug discovery in which a large number of related
compounds with diverse functional groups are needed for
biological activity screening.
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Chem. Commun., 2014, 50, 5641--5643 | 5643