Gold(I)-catalyzed tandem reactions initiated by hydroamination of alkynyl carbamates: Application to the synthesis of nitidine

Article abstract of DOI:10.1021/jo901906b

(Chemical Equation Presented) As a convenient and direct synthesis of 1,2-dihydroisoquinolines, the gold(I)-catalyzed intramolecular hydroamination of (2-alkynyl)benzyl carbamates has been developed. The reaction with cationic gold(I) complex [AuCl(PPh₃)/AgNTf₂] proceeded at room temperature, giving the desired 6-endo adducts. The addition of alcohol efficiently promoted the reaction, and the amount of the catalyst could be reduced to 1 mol %. However, the alkynes bearing either an electron-deficient aryl group or an alkyl group resulted in predominant production of 5-exo adducts. In such cases, use of a bulky gold catalyst, AuCl[(o-biPh)( ^tBu)₂P]Cl/AgNTf₂, improved the regioselectivity, giving the 6-endo adducts in better yields. Furthermore, the hydroamination of alkynyl carbamates bearing an acetal or enone was successfully applied to the concise synthesis of tetracyclic heterocycles such as nitidine via the single catalyst-mediated tandem cyclization which consists of a condensation or a Michael addition of the resulting enecarbamates.

Full text of DOI:10.1021/jo901906b

pubs.acs.org/joc
Gold(I)-Catalyzed Tandem Reactions Initiated by Hydroamination
of Alkynyl Carbamates: Application to the Synthesis of Nitidine
Taro Enomoto,† Anne-Lise Girard,† Yoshizumi Yasui,‡ and Yoshiji Takemoto*,†
†Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501,
Japan and ‡World Premier International Research Center, Advanced Institute for Materials Research,
Tohoku University, Aoba, Sendai 980-8578, Japan
takemoto@pharm.kyoto-u.ac.jp
Received September 3, 2009
As a convenient and direct synthesis of 1,2-dihydroisoquinolines, the gold(I)-catalyzed intra-
molecular hydroamination of (2-alkynyl)benzyl carbamates has been developed. The reaction with
cationic gold(I) complex [AuCl(PPh3)/AgNTf2] proceeded at room temperature, giving the desired
6-endo adducts. The addition of alcohol efficiently promoted the reaction, and the amount of the
catalyst could be reduced to 1 mol %. However, the alkynes bearing either an electron-deficient aryl
group or an alkyl group resulted in predominant production of 5-exo adducts. In such cases, use of
a bulky gold catalyst, AuCl[(o-biPh)(tBu)2P]Cl/AgNTf2, improved the regioselectivity, giving the
6-endo adducts in better yields. Furthermore, the hydroamination of alkynyl carbamates bearing an
acetal or enone was successfully applied to the concise synthesis of tetracyclic heterocycles such as
nitidine via the single catalyst-mediated tandem cyclization which consists of a condensation or
a Michael addition of the resulting enecarbamates.
Introduction
tetrahydroisoquinolines2 as well as to discover a series of
cascade reactions for diversity-oriented synthesis with an
aim of construction of tetrahydroisoquinoline-based small
molecular libraries.3 Among the isoquinoline derivatives, we
focused on benzo[c]phenanthridine alkaloids,4 such as niti-
dine and fagaronine (Figure 1), because these compounds
are considered as promising antitumor drug candidates due
to their strong antitumor activity by the inhibition of DNA
topoisomerase I.5 Although a number of elegant synthesis of
the 1,2-dihydroisoquinolines have been developed,6 there are
yet a few convenient methods for 3-substituted and 4-sub-
stituted 1,2-dihydroisoquinolines.7Recently, transition-
metal-catalyzed 6-endo-mode cyclizations of 2-(1-alkynyl)-
arylaldimines were discovered as a powerful synthetic tool
Both isoqinolines and hydroisoquinolines are found in
many biologically active natural products and pharma-
ceutically relevant compounds, and they play a key role in
their activities.1 Their structural novelty and diverse bio-
logical activities stimulate many synthetic chemists to devel-
op efficient synthetic methods for highly functionalized
*To whom correspondence should be addressed. Fax: þ81-75-753-4569.
(1) (a) Bentley, K. W. The Isoquinoline Alkaloids; Harwood Academic:
Australia, 1998; Vol. 1. (b) Kaneda, T.; Takeuchi, Y.; Matsui, H.; Shimizu, K.;
Urakawa, N.; Nakajyo, S. J. Pharmacol. Sci. 2005, 98, 275. (c) Trotter, B. W.;
Nanda, K. K.; Kett, N. R.; Regan, C. P.; Lynch, J. J.; Stump, G. L.; Kiss, L.; Wang,
J.; Spencer, R. H.; Kane, S. A.; White, R. B.; Zhang, R.; Anderson, K. D.;
Liverton, N. J.; McIntyre, C. J.; Beshore, D. C.; Hartman, G. D.; Dinsmore, C. J.
J. Med. Chem. 2006, 49, 6954. (d) Marchand, C.; Antony, S.; Kohn, K. W.;
Cushman, M.; Ioanoviciu, A.; Staker, B. L.; Burgin, A. B.; Stewart, L.; Pommier,
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54, 9875. (b) Nakanishi, T.; Suzuki, M. Org. Lett. 1999, 1, 985. (c) Harayama,
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9158 J. Org. Chem. 2009, 74, 9158–9164
Published on Web 11/12/2009
DOI: 10.1021/jo901906b
r
2009 American Chemical Society

Enomoto et al.
JOCArticle
operational simplicity and assemble efficiency.11 We envi-
saged that 1,2-dihydroisoquinoline scaffolds can be used as
templates for the tandem reaction discovery. As outlined in
Scheme 1, treatment of alkynyl carbamates A with a carbo-
philic Lewis acid12 provides the desired dihydroisoquinoline
C via cycloisomerization. If the resultant product C, bearing
an enecarbamate moiety, possesses an another reactive site
such as ketone, acetal, or electron-deficient double bond in
the molecule, the subsequent cyclization of C would occur to
give the polycyclic hydroisoquinoline alkaloids F. We have
already reported the synthesis of several 1,2-dihydroisoqui-
nolines through cycloisomerization and nucleophilic addi-
tion of 2-(alkynyl)phenylaldimines in the presence of an
alkynophilic metal catalyst (Ni, In, or Au) and a proper
nucleophile.13 Furthermore, we recently described the gold-
catalyzed intramolecular hydroamination of 2-(alkynyl)-
benzyl carbamates as a general approach toward the synth-
esis of 2,3-disubstituted 1,2-dihydroisoquinolines.14
FIGURE 1. Structure of some benzo[c]phenanthridine alkaloids.
Herein, we describe the full detail of a scope and limitation
of gold(I)-catalyzed cycloisomerization15 of 2-(alkynyl)-
benzyl carbamates together with an extension of the tandem
reaction to alkynyl carbamates bearing appropriate func-
tional groups for the synthesis of benzo[c]phenanthridine
alkaloids.
of such isoquinolines and 1,2-dihydroisoquinolines and also
successfully applied to the total synthesis of natural pro-
ducts.8 In contrast to these results, there are few reports on
the synthesis of 3-substituted 1,2-dihydroisoquinolines
through intramolecular hydroamination9 of alkynylbenzy-
lamine derivatives.10
On the other hand, the development of tandem reactions
for the efficient construction of complex molecules is also an
important goal of organic syrnthesis from the viewpoints of
Results and Discussion
Lewis Acid-Catalyzed Intramolecular Hydroamination of
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benzylamine 1a16 in the presence of several Lewis acid
catalysts. The reaction of 1a was carried out with 10 mol
% of group 10 or 11 metal salts in 1,2-dichloroethane (1,2-
DCE) (Table 1). First trials with PdCl2(PhCN)2, Cu(OTf)2,
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TABLE 1. Optimization of Catalysts for Hydroamination of 1aa
yieldb (%)
entry
catalyst
AgNTf2
PtCl2
Au(2-PyCO2)Cl2
AuCl(PPh3)
AuCl(PPh3)/AgNTf2
AuCl(PPh3)/AgNTf2
AuCl(PPh3)/AgNTf2
AuCl(PPh3)/AgNTf2
AuCl(PPh3)/AgNTf2
AuCl(PPh3)/AgNTf2
AuCl(PPh3)/AgNTf2
AuCl(PPh3)/AgNTf2
mol %
additive (5 equiv)
temp (°C)
time (h)
2a
1a
1
2
3
4
5
6
7
8
9
10
10
10
10
10
1
1
1
1
1
70
70
rt
70
rt
rt
rt
rt
rt
rt
rt
rt
24
24
24
24
1
48
24
24
2
7
46
30
N.R.
75
53
54
51
81
83
77
79
67
50
28
16
30
AcOH
CF3CH2OH
MeOH
10
11
12
EtOH
iPrOH
2
4
9
1
1
tBuOH
aReactions were carried out with N-Boc-benzylamine 1a and additive (5 equiv) in the presence of several Lewis acids (1-10 mol %) at rt to 70 °C.
bIsolated yield.
room temperature to give 2a in 75% yield (entries 4 and 5).
Encouraged by this result, we next examined the amount of
the catalyst in the presence of several additives. The amount
of the cationic gold complex was reduced to 1 mol %,
resulting in incomplete consumption of 1a (entry 6). Un-
expectedly, the addition of 5 equiv of EtOH or MeOH to the
reaction mixture dramatically accelerated the Au(I)-cata-
lyzed cyclization to give the desired product 2a in good yield
within 2 h. However, such effect became weaker in the cases
of iPrOH and tBuOH. Furthermore, AcOH or CF3CH2OH
had no effect on the reaction rate (entries 7-12). Relatively
stronger protic acids such as CF3SO3H or AcOH are known
to accelerate gold-catalyzed hydroamination as well as other
gold-catalyzed reactions.20 In contrast to these results, less
acidic and less bulky alcohols showed a striking effect in this
reaction.
SCHEME 1. Lewis Acid Catalyzed Tandem Cyclization of A
Having established the optimized reaction conditions, we
applied this method to a variety of substrates 1b-m bearing
different R1 and R2 substituents for the synthesis of various
1,2-dihydroisoquinolines (Table 2). All reactions were car-
ried out in 1,2-DCE at room temperature in the presence of
the cationic gold catalyst (1 mol %) and EtOH (5 equiv). As a
result, not only Boc but also Cbz, p-methoxyphenyl (PMP),
and Ms groups can be used as a protecting group (R1) of the
benzylamine derivatives 1b-d, giving the corresponding
cyclized adducts 2b-d in 81-83% yields (entries 1-3). In
addition, the substituent (R2) of the alkynyl group signifi-
cantly affected on the chemical yield of 2 and the 6-endo/5-
exo selectivity by changing electron density on the triple
bond (entries 4-12). The substrates 1e-h bearing an aryl
group with the electron-donating groups such as methyl,
hydroxymethyl, methoxy, and chloride generally furnished
the desired 6-endo adducts in good yields, while 5 mol %
of the catalyst was required to complete the reaction of
and AgNTf2 did not give any good results, providing
the desired product 2a in up to 7% yield (entry 1). When
PtCl215c,17 or Au(2-PyCO2)Cl218 was used as the catalyst, 2a
was obtained in moderate yield (entries 2 and 3). Although
AuCl(PPh3) itself did not catalyze the cyclization of 1a at all,
a cationic gold(I) complex, generated from AuCl(PPh3)
and AgNTf2,19 efficiently promoted the reaction even at
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(b) Istrate, F. M.; Gagosz, F. Org. Lett. 2007, 9, 3181. Recently, we reported
that the catalyst, generated from AuCl(PPh)3 and AgNTf2, promotes the
6-endo cyclization of N-Boc-propargylamines. See: Miyabe, H; Sami, Y.;
Naito, T.; Takemoto, Y. Heterocycles 2007, 73, 187.
(19) (a) Mezailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133.
(20) (a) Mizushima, E.; Sato, K.; Hayashi, T.; Tanaka, M. Angew. Chem.,
Int. Ed. 2002, 41, 4563. (b) Mizushima, E.; Hayashi, T.; Tanaka, M. Org.
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Lett. 2003, 5, 3349. (c) Piera, J.; Krumlinde, P.; Strubing, D.; Backvall, J.-E.
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JOCArticle
TABLE 2. Au(I)-Catalyzed Hydroamination of 2-Alkynylbenzyla-
mines 1b-m
SCHEME 2. Intermolecular Trapping of 5-exo Adducts
entry substrate R1
R2
time (h) product yielda (%)
1
2
3
4
5
6
7b
8
9
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1l
1a
1m
1j
Cbz Ph
PMP Ph
Ms Ph
Boc 3,5-Me2C6H3
Boc 4-ClC6H4
Boc 4-HOCH2C6H4
Boc 4-MeOC6H4
Boc 4-NCC6H4
Boc tBu
4
0.5
7
2
2
3
2
24
24
2
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2l
2a
2m
2j
83
82
81
87
71
79
87
N.R.
N.R.
0
SCHEME 3. Gold(I)-Catalyzed Tandem Cyclization
10
11
12
Boc
H
Boc nPr
6
Boc 4-MeOCOC6H4 24
28
20 (15)c
13d
14d
15d
16d,e
Boc nPr
Boc Ph
0.2
0.5
98
91
Boc 4-MeOCOC6H4 24
Boc tBu
37 (6)c
48
32 (61)c
aIsolated yield. b5 mol % of the Au(I) catalyst was used. cValues in
parentheses are yields of recovered starting materials. dReactions were
carried out without EtOH, and AuCl[(o-biPh)(tBu)2P] (1 mol %) was
used instead of AuCl(PPh3). eThe reaction was heated at 50 °C.
carbamate 1h which has a 4-OMe substituent. In contrast,
the current reaction revealed to be not effective for the 6-endo
cyclization of the substrates 1i-m bearing either an electron-
deficient aryl group or an alkyl group. Indeed, the reaction of
1i and1j did not take place at all and only recovered the
starting material, but the same treatment of 1k resulted in a
complex mixture of products. Moreover, subjection of al-
kyne 1l and ester 1m to the same reaction conditions afforded
the dihydroisoquinolines 2l and 2m in 28 and 20% yields,
respectively, together with a mixture of unidentified com-
pounds. To improve the regioselectivity, a bulkier gold(I)
catalyst was examined (entries 13-15). The reaction
(1 mol %)
15i,21
of 1l with AuCl[(o-biPh)(tBu)2P]/AgNTf2
not only enhanced the reaction rate but also increased the
chemical yield to 98%. Interestingly, the same treatment
of 1a and 1m led to somewhat different results. Although 1a
provided the desired product 2a in better yield (91%) (entry
10 in Table 1), the 6-endo adduct 2m was obtained in
only 37% yield. Even with the bulky gold(I) catalyst, the
6-endo cyclization of electron-deficient arylalkynes took
place sluggishly.
We presumed these unidentified compounds might be the
corresponding 5-exo adducts, but unfortunately, we could
not isolate these products. We then undertook the intermo-
lecular trapping experiment of the presumed 5-exo adducts
with N-methylmaleimide in order to identify these side
products10b (Scheme 2). For this purpose, pentynyl carba-
mate 1l was selected as a suitable substrate for the 5-exo
cyclization. In fact, the reaction of 1l with the gold catalyst
(1 mol %) afforded the 6-endo adduct 2l in only 28% yield
(Table 2, entry 11). However, when the same reaction was
carried out with 1.1 equiv of N-methylmaleimide, new
product 4l was obtained in 68% yield along with 27% yield
of 2l. The relative configuration of 4l shown in Scheme 2 was
determined by the NOESY experiment. The Diels-Alder
adduct 4l was probably formed via the 5-exo cyclization of 1l,
subsequent isomerization of 5-exo adduct 3l to labile iso-
indole intermediate G, and Diels-Alder type cycloaddition
with maleimide. On the basis of these results, the low yields of
dihydroisoquinolines 2k-m is obviously attributed to the
predominant occurrence of the 5-exo cyclization of 1k-m.
We proved that the substitution of the R2 group to either an
alkyl or an electron-deficient aryl group promoted the 5-exo
cyclization to give the corresponding isoindole derivatives
which could not be isolated due to their instability.
ꢀ
(21) (a) Nieto-Oberhuber, C.; Lopez, S.; Echavarren, A. M. J. Am. Chem.
Soc. 2005, 127, 6178.
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SCHEME 4. Total Synthesis of Nitidine
The Au(I)-Mediated Tandem Reaction of Alkynyl
Carbamates Bearing Several Electrophiles. In order to
apply the intramolecular hydroamination into tandem
reaction8c,d,15t,u,x,22 for the synthesis of polycyclic com-
pounds, we planned to utilize high nucleophilic activity of
enecarbamates,23 which can be easily synthesized by the
Au(I)-catalyzed intramolecular hydroamination with var-
ious electrophiles (Scheme 3). We initially examined the
tandem reaction of aldehyde 5, because the gold catalyst
would be expected to activate both C-C triple bond and
formyl group. However, instead of the carbamate, aldehyde
exclusively attacked the triple bond in a 6-endo mode to give
bicyclic acetal 6 as the single product.24 To suppress the
nucleophilic addition by the formyl group, cyclic acetal 7 and
dimethyl acetal 9 were prepared and their reactivity was
examined. When we carried out the reaction with acetal 7 in
the presence of methanol, a complex mixture was obtained
due to the acetal-exchange reaction. Therefore, in the case
of 7, methanol was not added to the reaction mixture. Con-
sequently, both compounds 7 and 9 underwent the tandem
reaction of the 6-endo hydroamination and aldol condensa-
tion to give the desired tetracyclic adducts 8 and 10 with 32%
and 54% yields, respectively. Under these conditions, the
corresponding hydroamination adducts were not observed
as a reaction intermediate, probably because the second
cyclization with the acetal might be much faster than the
first hydroamination. Furthermore, it was revealed that R,β-
unsaturated ketone could be used as an electrophile for the
second cyclization.22 Indeed, the enone 11 underwent the
tandem cyclization efficiently to give the ketone 12 in 80%
yield. However, during this reaction, a dihydroisoquinoline
intermediate was observed on TLC due to slower reaction
rate of the subsequent Michael addition than that of the first
step. Then, the reaction required a long reaction time (6 h) to
complete the tandem cyclization. In contrast, the tandem
reaction of enoate 13 did not occur due to the insufficient
electrophilicity of the enoate as a Michael acceptor, provid-
ing the corresponding hydroisoquinoline 14 in 85% yield.
Application of the Tandem Reaction to Formal Total
Synthesis of Nitidine. Since the gold(I)-catalyzed hydroami-
nation of alkynylbenzyl carbamate 9 bearing the acetal
moiety efficiently provided the tetracyclic compound 10,
our attention was next directed toward the total synthesis
of polycyclic natural products such as nitidine by using this
tandem reaction. The requisite N-Boc-alkynylbenzylamine
20 for the tandem reaction was prepared from aldehyde 1525
and benzylamine derivative 17 (Scheme 4). Successive treat-
ment of 15 with K2CO3 in methanol and Wittig reagent
(Ph3PdCHOMe) provided the desired arylethyne 16 in 89%
yield. The aryl iodide 18 was synthesized from 17 in good
yield by trifluoroacetylation with CF3CO2Et and the sub-
sequent iodination with I2 and HIO3. The Pd-catalyzed
Sonogashira reaction of 16 and 18 proceeded smoothly,
and the requisite acetal 20 was synthesized by the acetaliza-
tion, hydrolysis, and N-Boc protection of the resulting
acetamide 19 without any troubles. We next investigated
the tandem cyclization under the optimized conditions
(22) (a) Arcadi, A.; Bianchi, G.; Chiarini, M.; D’Anniballe, G.; Marinelli,
F. Synlett 2004, 944. (b) Alfonsi, M.; Arcadi, A.; Aschi, M.; Bianchi, G.;
Marinelli, F. J. Org. Chem. 2005, 70, 2265. (c) Li, Z.; Shi, Z.; He, C. J.
Organomet. Chem. 2005, 690, 5049. (d) Arcadi, A.; Alfonsi, M.; Bianchi, G.;
D’Anniballe, G.; Marinelli, F. Adv. Synth. Catal. 2006, 348, 331. (e)
Ambrogio, I.; Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F. Synlett
2007, 1775. (f) Skouta, R.; Li, C.-J. Synlett 2007, 1759.
(23) (a) Cossey, K. N.; Funk, R. L. J. Am. Chem. Soc. 2004, 126, 12216.
(b) Matsubara, R.; Nakamura, Y.; Kobayashi, S. Angew. Chem., Int. Ed.
2004, 43, 1679. (c) Terada, M.; Machioka, K.; Sorimachi, K. Angew. Chem.,
Int. Ed. 2006, 45, 2254. (d) Matsubara, R.; Kawai, N.; Kobayashi, S. Angew.
Chem., Int. Ed. 2006, 45, 3814. (e) Matsubara, R.; Kobayashi, S. Angew.
Chem., Int. Ed. 2006, 45, 7993. (f) Nilson, M. G.; Funk, R. L. Org. Lett. 2006,
8, 3833. (g) Terada, M.; Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 292. (h)
Harrison, T. J.; Patrick, B. O.; Dake, G. R. Org. Lett. 2007, 9, 367. (i) Fuwa,
H.; Sasaki, M. Org. Biomol. Chem. 2007, 5, 1849. (j) Matsubara, R.;
Kobayashi, S. Acc. Chem. Res. 2008, 41, 292. (k) Sivaguru, J.; Solomon,
M. R.; Poon, T.; Jockusch, S.; Bosio, S. G.; Adam, W.; Turro, N. J. Acc.
Chem. Res. 2008, 41, 387. (l) Carbery, D. T. Org. Biomol. Chem. 2008, 6, 3455.
(24) (a) Asao, N.; Nogami, T.; Takahashi, K.; Yamamoto, Y. J. Am.
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Chem. Soc. 2002, 124, 764. (b) Barluenga, J.; Vazquez-Villa, H.; Ballesteros,
A.; Gonzalez, J. M. J. Am. Chem. Soc. 2003, 125, 9028. (c) Zhu, J.; Germain,
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A. R.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2004, 43, 1239. (d) Yue, D.; Ca,
N. D.; Larock, R. C. Org. Lett. 2004, 6, 1581. (e) Yao, X.; Li, C.-J. Org. Lett.
2006, 8, 1953. (f) Godet, T.; Vaxelaire, C.; Michel, C.; Milet, A.; Belmont, P.
Chem.;Eur. J. 2007, 13, 5632.
(25) (a) Grotjahn, D. B.; Vollhardt, K. P. C. Synthesis 1993, 579.
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9162 J. Org. Chem. Vol. 74, No. 23, 2009

Enomoto et al.
JOCArticle
SCHEME 5. Reaction Mechanism of the Au(I)-Catalyzed Tandem Cyclization
TABLE 3. Au(I)-Catalyzed Tandem Cyclization of 20
aromatization of the resulting unstable compound M
would take place to give the corresponding 5,6-dihydro-
benzo[c]phenanthridine 22 in good yield. Finally, the re-
duction of 22 with LiAlH4 furnished dihydronitidine as
the single product, which was identical to the reported
compound by comparing their spectral data with an
authentic sample.26 Since dihydronitidine had been already
converted into nitidine by two steps, we achieved a formal
total synthesis of nitidine.
yieldb (%)
entry catalysta Au(I) (mol %) MeOH (equiv)
21
20
22
1
2
3
4
5
A
A
A
B
B
3
3
5
5
5
5
0
5
0
5
74
19
88
47
98
53
10
50
trace
aKey: (A) AuCl(PPh3)/AgNTf2, rt, 24 h; (B) AuCl[(o-biPh)(tBu)2P]/
AgNTf2, rt, 24 h. bIsolated yield.
Conclusion
(Table 3). In contrast to the one-carbon homologue 9, the
tandem reaction of 20 proceeded slowly even with 3 mol % of
the gold complex AuCl(PPh3)/AgNTf2 to afford dihydroi-
soquinoline 21 and the desired policyclic product 22 in 20%
and 74% yields, respectively (entry 1). No addition of
methanol to the reaction resulted in deceleration of both
the hydroamination and condensation, and further increas-
ing the catalytic amount of the catalyst did not improve the
chemical yields dramatically (entries 2 and 3). After screen-
ing various catalysts, sufficient improvement was achieved
by using the bulkier gold(I) catalyst, AuCl[(o-biPh)(tBu)2-
P]Cl/AgNTf2. In this case, the addition of methanol pro-
moted the second condensation reaction to give the desired
product 22 in 98% yield (entries 4 and 5).
The reaction mechanism of the tandem cyclization of 20
is shown in Scheme 5. Since the dihydroisoquinoline 21 was
always observed on TLC during the reaction, 21 would be a
reaction intermediate, which was obtained regioselectively
by the Au(I)-catalyzed intramolecular hydroamination of
20 via H. The subsequent activation of the acetal moiety of
21 by the same Au(I)-catalyst promoted the intramolecular
Mukaiyama-type aldol condensation with the enecar-
bamate moiety via I to J to afford labile 5,6,11,12-
tetrahydrobenzo[c]phenanthridine M. Since subjection of
the isolated 21 to the cyclization conditions of 20 provided
the same product 22 in 58% yield along with the starting
material 21 (33%), another mechanism in which the alke-
nylgold moiety of H directly acts as a nucleophile for the
Mukaiyama-type aldol condensation via K to L cannot
be excluded to provide M. In any event, the oxidative
We have demonstrated that the nitrogen atom of
(2-alkynyl)benzylamines acts as a reactive nucleophile in
the Au(I)-catalyzed hydroamination, irrespective of the sub-
stituents on the nitrogen atom. The Au(I) catalysts such as
AuCl(PPh3)/AgNTf2 or AuCl[(o-biPh)(tBu)2P]Cl/AgNTf2
are efficient carbophilic Lewis acids for the 6-endo cycliza-
tion. Furthermore, the resulting N-Boc-1,2-dihydroisoqui-
nolines were revealed to be versatile synthetic intermediates
for the further C-C bond formation at C4 position. The
tandem cyclization of alkynyl carbamates bearing an acetal
or enone was successfully applied to the concise synthesis
of tetracyclic heterocycles such as dihydronitidine via the
single catalyst-mediated tandem reaction which consists
of a condensation or a Michael addition of the resulting
enecarbamates.
Experimental Section
Typical Procedure for the Gold(I)-Catalyzed 6-Endo Hydro-
amination. To a solution of alkynyl carbamate 1a (309 mg,
1.00 mmol) in 1,2-dichloroethane (2.0 mL) was added a mixture
of AuCl(PPh3) (4.9 mg, 0.0099 mmol), AgNTf2 (3.8 mg, 0.0098
mmol), EtOH (293 μL, 5.02 mmol), and 1,2-dichloroethane
(1.0 mL) at room temperature. After the mixture was stirred
for 2 h, a saturated aqueous NaHCO3 solution was added, and
the resulting mixture was extracted with CHCl3. The combined
organic extracts were washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by
(26) Hanaoka, M.; Yamagishi, H.; Marutani, M.; Mukai, C. Chem.
Pharm. Bull. 1987, 35, 2348.
J. Org. Chem. Vol. 74, No. 23, 2009 9163

Enomoto et al.
JOCArticle
silica gel column chromatography (hexane/AcOEt = 25/1) to
afford 2a (256 mg, 83%) as colorless crystals.
1,2-dichloroethane (2.0 mL) was added a mixture of AuCl-
(PPh3) (5.0 mg, 0.010 mmol), AgNTf2 (4.0 mg, 0.010 mmol),
EtOH (292 μL, 5.00 mmol), and 1,2-dichloroethane (1.0 mL) at
room temperature. After the mixture was stirred for 3 h, a
saturated aqueous NaHCO3 solution was added, and the resul-
tant mixture was extracted with CHCl3. The combined organic
extracts were washed with brine, dried over Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by silica gel
column chromatography (hexane/AcOEt = 25/1 to 4/1) to
afford 2l (74 mg, 27%) as a pale yellow oil and 4l (262 mg,
68%) as a colorless oil.
tert-Butyl 3-Phenylisoquinoline-2(1H)-carboxylate (2a). Mp:
105-106 °C. 1H NMR (500 MHz, CDCl3): δ 7.48 (d, 2H, J =
7.3 Hz), 7.36 (dd, 2H, J = 7.3, 7.1 Hz), 7.30 (t, 1H, J = 7.1 Hz),
7.27-7.18 (m, 4H), 6.42 (s, 1H), 4.89 (s, 2H), 1.05 (s, 9H). 13
C
NMR (126 MHz, CDCl3): δ 153.0, 140.6, 139.0, 132.7, 132.0,
128.1, 127.7, 127.5, 127.2, 126.3, 125.1, 125.0, 115.2, 81.0, 47.5,
27.6. IR (CHCl3) ν 3011, 1693 cm-1. MS (FABþ): m/z 307 [M]þ
(100), 251 (96), 206 (53). Anal. Calcd for C20H21NO2: C, 78.15;
H, 6.89; N, 4.56. Found: C, 78.23; H, 7.07; N, 4.48.
Synthesis of 22 by the Gold(I)-Catalyzed Tandem Cyclization
(Table 3, Entry 5). To a solution of alkynyl carbamate 20
(69.8 mg, 0.140 mmol) in 1,2-dichloroethane (0.2 mL) was added
a mixture of AuCl[(o-biPh)(tBu)2P] (3.7 mg, 0.0070 mmol),
AgNTf2 (2.7 mg, 0.0070 mmol), MeOH (28 μL, 0.70 mmol),
and 1,2-dichloroethane (0.27 mL) at room temperature. After
being stirred for 24 h, saturated aqueous NaHCO3 was added,
and the resultant mixture was extracted with CHCl3. The
combined organic extracts were washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by silica gel column chromatography (hexane/
AcOEt = 4/1) to afford 22 (59.9 mg, 98%) as a white powder.
tert-Butyl 2,3-Dimethoxy[1,3]benzodioxolo[5,6-c]phenanthridine-
12(13H)-carboxylate (22). Mp: 183-184 °C. 1H NMR (500 MHz,
CDCl3): δ 7.65 (d, 1H, J = 8.6 Hz), 7.57 (d, 1H, J = 8.6 Hz), 7.34
(s, 1H), 7.25 (s, 1H), 7.09 (s, 1H), 6.84 (s, 1H), 6.03 (br s, 2H), 5.31
(br s, 1H), 4.14 (d, 1H, J = 15.1 Hz), 3.98 (s, 3H), 3.94 (s, 3H), 1.28
(s, 9H). 13C NMR (126 MHz, CDCl3): δ 154.1, 148.68, 148.66,
147.8, 147.3, 133.0, 130.2, 128.0, 126.7, 125.5, 125.3, 119.8, 108.9,
107.1, 103.8, 101.7, 101.1, 81.0, 56.1, 56.0, 47.4, 28.1 (one carbon
peak was missing due to overlapping). IR (ATR) ν 2935, 2859, 1716
cm-1. MS (FABþ): m/z 435 [M]þ (38), 379 (75), 334 (100). HRMS
(FABþ): calcd for C25H25NO6 [M]þ 435.1682, found 435.1685.
Experimental Procedure for the Intermolecular Trapping of
5-Exo Adduct. To a solution of alkynyl carbamate 1l (274 mg,
1.00 mmol) and N-methylmaleimide (123 mg, 1.11 mmol) in
tert-Butyl (3aR*,4S*,9R*,9aS*)-4-Butyl-2-methyl-1,3-dioxo-
2,3,3a,4,9,9a-hexahydro-1H-4,9- epiminobenzo[f]isoindole-10-
carboxylate (4l). 1H NMR (500 MHz, CDCl3): δ 7.26-7.18
(m, 3H), 7.11 (d, 1H, J = 6.5 Hz), 5.48 (d, 1H, J = 5.4 Hz), 3.74
(dd, 1H, J = 8.1, 5.4 Hz), 3.41 (d, 1H, J = 8.1 Hz), 2.76-2.69
(m, 1H), 2.67-2.60 (m, 1H), 2.23 (s, 3H), 1.65-1.57 (m, 2H),
1.54-1.45 (m, 2H), 1.47 (s, 9H), 0.97 (t, 3H, J = 7.0 Hz). 13C
NMR (126 MHz, CDCl3): δ 174.7, 174.6, 154.3, 141.7, 138.5,
127.7, 127.6, 121.4, 120.6, 81.4, 75.5, 63.3, 51.7, 49.1, 29.1, 28.2,
26.9, 23.8, 23.1, 14.1. IR (ATR) ν 3022, 2960, 2872, 1779, 1703,
1699 cm-1. MS (FABþ): m/z 385 [M þ H]þ (22), 329 (100), 285
(73), 268 (45). HRMS (FABþ): calcd for C22H28N2O4 [M]þ
384.2049, found 384.2047.
Acknowledgment. This work was supported in part by
a Grant-in-Aid for Scientific Research (B) (Y.T.) and
“Targeted Proteins Research Program” from the Ministry
of Education, Culture, Sports, Science and Technology of
Japan. A.G. thanks the JSPS for a Postdoctoral Fellowship.
Supporting Information Available: Experimental pro-
cedure and characterization data for all obtained compounds
and 1H and 13C NMR spectra of all obtained compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
9164 J. Org. Chem. Vol. 74, No. 23, 2009