Access to 1,2-dihydroisoquinolines through gold-catalyzed formal [4+2] cycloaddition

Article abstract of DOI:10.1002/chem.201403290

A new synthetic route to the privileged 1,2-dihydroisoquinolines is reported. This method, which relies on a gold-catalyzed formal [4+2] cycloaddition between ynamides and imines, provides a new retrosynthetic disconnection of the 1,2-dihydroisoquinoline core by installing the 1,8a C-C and 2,3 C-N bonds in one step. Both aldimines and ketimines can be used as substrates. In addition, one example of dihydrofuropyridine synthesis is also demonstrated. Heterocycles: A new synthetic route to the privileged 1,2-dihydroisoquinolines is reported. This method, which relies on a gold-catalyzed formal [4+2] cycloaddition between ynamides and imines, provides a new retrosynthetic disconnection of the 1,2-dihydroisoquinoline core by installing the 1,8a C-C and 2,3 C-N bonds in one step. Both aldimines and ketimines can be used as substrates. In addition, one example of dihydrofuropyridine synthesis is also demonstrated (see scheme).

Full text of DOI:10.1002/chem.201403290

DOI: 10.1002/chem.201403290
Communication
&
Synthetic Methods
Access to 1,2-Dihydroisoquinolines through Gold-Catalyzed
Formal [4+2] Cycloaddition
Zhuo Xin, Søren Kramer,* Jacob Overgaard, and Troels Skrydstrup*[a]
Abstract: A new synthetic route to the privileged 1,2-di-
hydroisoquinolines is reported. This method, which relies
on a gold-catalyzed formal [4+2] cycloaddition between
ynamides and imines, provides a new retrosynthetic dis-
connection of the 1,2-dihydroisoquinoline core by instal-
ling the 1,8a CÀC and 2,3 CÀN bonds in one step. Both al-
dimines and ketimines can be used as substrates. In addi-
tion, one example of dihydrofuropyridine synthesis is also
demonstrated.
The 1,2-dihydroisoquinoline core represents a privileged struc-
Scheme 1. New retrosynthetic disconnection of the 1,2-dihydroisoquinoline
core. EWG=electron-withdrawing group.
ture encountered in many natural products, as well as mole-
cules exhibiting promising bioactivities. Hence, the synthesis of
this motif has been of high interest for the organic-synthesis
community.[1] In general, two different approaches to these
structural targets have been developed: a) functionalization of
the parent isoquinoline or b) de novo synthesis of the 1,2-dihy-
droisoquinoline. Significant progress has been made for the
first approach, in which either the C1 and C2 substituents
were introduced through a Reissert-type reaction, or alterna-
tively the parent isoquinoline can be reduced selectively to the
1,2-dihydroisoquinoline.[2] These strategies inherently require
that the desired substituents are already present on the parent
isoquinoline. Therefore, a de novo approach might provide
easier access to more diversely functionalized heterocycles. In
general, the de novo synthesis of functionalized 1,2-dihydroiso-
quinolines is limited to variations of the transition-metal-cata-
lyzed 6-endo cyclization of ortho-alkynylaryl aldimines either as
the substrate or made in situ from the aldehyde (Scheme 1,
Eq. (1)); however, other strategies including the Larock dihy-
droisoquinoline synthesis have also been developed.[3,4] Inter-
estingly, there is no existing method for de novo synthesis of
1,2-dihydroisoquinolines installing the 1,8a CÀC bond and 2,3
CÀN bond in one step (Scheme 1, Eq. (3). The successful devel-
opment of such a formal [4+2] cycloaddition would therefore
add significantly to the arsenal of disconnections for 1,2-dihy-
droisoquinolines.
Over the last decade, the tremendous potential of homoge-
neous gold catalysis has been investigated, and new reactivi-
ties are still being discovered.[5] Inspired by the gold-catalyzed
[4+2] cycloadditions between alkenes and ynamides devel-
oped by Liu et al., we envisaged the possibility to develop the
first method for the above-mentioned disconnection of the
1,2-dihydroisoquinoline core as a mean for the synthesis of
highly substituted 1,2-dihydroisoquinolines.[6,7] While not only
providing a new route to this important heterocycle, the pro-
posed strategy would also display complete atom economy
with no pre-functionalization of the aryl moiety necessary.
A few examples of interception of gold–carbene intermedi-
ates with imines followed by cyclization have been published
including a new synthesis of dihydro-g-carbolines.[8] However,
no direct [4+2] cycloadditions between 1,3-enynes and imines
have been reported.[9]
In 2011, we reported the dimerization of ynamides and iso-
lated the products arising from a formal [4+2] cycloaddition
between the triple bond of one ynamide with the alkynylaryl
moiety of another ynamide.[10b] As part of our continued inter-
est in ynamides and gold catalysis, we decided to use
ynamides as substrates for the proposed transformation.[10,11]
Our initial investigations were encouraging as 5 mol%
IPrAuNTf2 (IPr=1,3-bis(diisopropyl phenyl) imidazole-2-ylidene)
in 1,2-dichloroethane (DCE) at 608C led to clean conversion to
the desired dihydroisoquinoline 3a, which could be isolated in
a satisfactory yield of 96% (Table 1, entry 1). The structure of
3a was confirmed by X-ray analysis as depicted in Figure 1. At
[a] Z. Xin, Dr. S. Kramer, Dr. J. Overgaard, Prof. Dr. T. Skrydstrup
Center for Insoluble Protein Structures, Department of Chemistry
Interdisciplinary Nanoscience Center, Aarhus University
Langelandsgade 140, 8000 Aarhus C (Denmark)
Fax: (+45)861-961-99
E-mail: ts@chem.au.dk
kramer@chem.au.dk
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403290.
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was observed favoring the 8-methoxy product 3e. With only
one methoxy group, bromides and chlorides were also tolerat-
ed, although a slight decrease in the yield was observed for 3 f
and g. This corresponds with the less nucleophilic character of
the aryl moiety of these ynamides. Other functional groups
than halides were tolerated including cyano, methoxy, amide,
ester, ether, alkyne, and acetal groups as illustrated with the
products 3h–k. Employing a mesyl instead of the alkoxycar-
bonyl group as the electron-withdrawing substituent did not
affect the reaction outcome (3l). Furthermore, when the reac-
tion was performed with ketimines instead of aldimines, the
products were again obtained in a high yields, as shown with
Table 1. Optimization of the 1,2-dihydroisoquinoline synthesis.
Entry
Catalyst
T [8C]
Yield [%][a]
1
2
3
4
5
6
7
IPrAuNTf2
IPrAuNTf2
(Ph3P)AuNTf2
PicAuCl2
AgNTf2
60
RT
60
60
60
60
60
100 (96)
60
100
93
0
0
0
HNTf2
none
1
[a] Determined by H NMR spectroscopy of the crude reaction mixture by
using 1,3,5-trimethoxybenzene as internal standard. Isolated yield after
column chromatography in parenthesis.
Figure 1. X-ray structure of 3a.
room temperature, lower conversion and yield was obtained
(Table 1, entry 2). The use of Gagosz’ catalyst, (Ph3P)AuNTf2,
also led to clean conversion to 3a (Table 1, entry 3); however,
for ynamides with less electron-rich aryls, IPrAuNTf2 provided
slightly higher yields and this catalyst was therefore chosen for
the investigation of the substrate scope.[12] Examining the
gold(III) catalyst, PicAuCl2 (Pic=picolinato), a small drop in
yield was observed compared to the two gold(I) catalysts
(Table 1, entry 4). Both AgNTf2 and HNTf2 were completely inef-
fective as catalysts for the formal [4+2] cycloaddition (Table 1,
entries 5 and 6), and no product formation was observed in
the absence of a catalyst (Table 1, entry 7).
With the optimized reaction conditions established, we start-
ed investigating the substrate scope with N-aryl imines
(Scheme 2). Halogen substituents (F, Cl, Br) in different posi-
tions of the substrates still led to high yields of the desired
products when two methoxy groups were present on the
ynamide 3b–d. For the ynamide with only one methoxy
group, there was no erosion in yield, and good regioselectivity
Scheme 2. Substrate scope for the 1,2-dihydroisoquinoline synthesis with N-
aryl imines. The yields given are for the isolated product. [a] The reaction
was performed at 808C.
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fied as the aza-enyne metathesis products 4a and 5, which are
the typical products when Brønsted acid catalysis is applied to
these substrates.[13] However, in our case, the ratio of product
to byproducts was unchanged in the presence of stoichiomet-
ric amounts of NaHCO3, indicating that these products are
more likely formed by gold catalysis instead of Brønsted acid
catalysis under our reaction conditions.[14] Interestingly, when
the electron-donating groups were removed from the aromatic
ring of the ynamide, and an N-alkyl imine was employed, by-
product 4 could be obtained in excellent yield after a simple
optimization (Scheme 4b). The yield of the product was the
same as that with the addition of stoichiometric amounts of
NaHCO3. This result further proves that the reaction is indeed
catalyzed by gold instead of a Brønsted acid.
A mechanistic proposal for the formal [4+2] cycloadditions
leading to 1,2-dihydroisoquinolines is shown in Scheme 5. Acti-
vation of the triple bond in the ynamide by the gold catalyst
would be followed by addition of the imine through nitrogen.
Scheme 3. Substrate scope for the 1,2-dihydroisoquinoline synthesis with N-
alkyl imines. The yields given are for the isolated product. PMB=para-me-
thoxybenzyl. [a] The reaction was performed with 1% (PPh3)AuNTf2.
3m and n. Both dialkyl and arylalkyl imines gave the desired
1,2-dihydroisoquinoline with quaternary centers.
Next, we turned our attention to N-alkyl imines (Scheme 3).
For these substrates, (Ph3P)AuNTf2 turned out to be the superi-
or catalyst, but otherwise the reaction conditions remained un-
changed. We were pleased to see that the nitrogen substitu-
ents, such as methyl (3o), allyl (3p), para-methoxybenzyl (3q),
and benzyl (3r), as well as an alkyl ether on a two-carbon
linker (3s), were well tolerated.
For the unsubstituted phenyl ring in the terminal position of
the ynamide, byproduct formation was observed along with
the desired product (Scheme 4a). The byproducts were identi-
Scheme 5. Proposed mechanism for dihydroisoquinoline and byproduct for-
mation.
Two possible pathways for the generated iminium intermedi-
ate can then be envisioned. The direct trapping of the iminium
species by the aromatic ring would give the dihydroisoquino-
line core with only a deprotonation and protodeauration nec-
essary to generate the final product (path 1). Alternatively, in
analogy to the mechanism for the two different reactions be-
tween alkenes and alkynes reported by Liu et al. and Shin
et al., the formation of a gold carbene and an aziridine can be
proposed (path 2).[6,14] Although this intermediate might also
be on the path to the dihydroisoquinolines, it can explain the
byproduct formation through a 1,2-migration to the gold car-
bene. Elimination of the gold fragment would lead to a dihy-
droazete, which can open in a 4p electrocyclic ring opening
generating the byproducts.
Scheme 4. a) Reaction products with a less nucleophilic aromatic ring. b) Re-
action of ynamides without electron-rich groups in the aromatic ring with
N-alkyl imines. The yields given are for the isolated products. PMB=p-me-
thoxybenzyl.
Finally, to further expand the synthetic utility of the formal
[4+2] cycloaddition, an ynamide with a furan in the terminal
position was subjected to the optimized reaction conditions
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Scheme 6. Extension to dihydrofuropyridine synthesis.
(Scheme 6). This led directly to the corresponding dihydrofuro-
pyridine 3u in a high yield.
In summary, we have developed the first method for the si-
multaneous formation of the 1,8a CÀC bond and 2,3 CÀN
bond of 1,2-dihydroisoquinolines thereby adding a new dis-
connection to this important heterocycle. This de novo meth-
odology displays good functional-group tolerance and works
well for both aldimines and ketimines, as well as both N-aryl
imines and N-alkyl imines. Furthermore, one example of the ex-
tension to the synthesis of a dihydrofuropyridine was demon-
strated.
Experimental Section
Synthesis of 3-(6,8-dimethoxy-1,2-diphenyl-1,2-dihydroiso-
quinolin-3-yl)oxazolidin-2-one (3a, Scheme 2)
To a vial (4 mL) in an argon-filled glovebox were added IPrAuNTf2
(5 mol%, 0.01 mmol, 8.7 mg), ynamide (2a, 0.21 mmol, 51.9 mg,
1.05 equiv), and imine (1a, 0.20 mmol, 36.2 mg, 1.00 equiv) fol-
lowed by DCE (0.8 mL). The vial was sealed, and the reaction mix-
ture was stirred 22 h at 608C outside the glovebox. The reaction
mixture was allowed to cool to RT and then concentrated in vacuo.
The crude oil was purified by flash chromatography (1% Et2O in
CH2Cl2) giving the 1,2-dihydroisoquinoline 3a in a 96% yield
1
(82.0 mg). H NMR (400 MHz, CDCl3): d=7.35–7.21 (m, 9H), 7.08 (t,
J=7.2 Hz, 1H), 6.48 (d, J=2.4 Hz, 1H), 6.42 (s, 1H), 6.35 (d, J=
2.4 Hz, 1H), 6.21 (s, 1H), 4.15 (q, J=8.4 Hz, 1H), 4.05 (q, J=8.4 Hz,
1H), 3.83 (s, 3H), 3.69 (s, 3H), 3.48 ppm (t, J=8.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=160.3, 156.4, 155.8, 146.0, 142.4, 134.5, 133.7,
129.7 (2C), 128.2 (2C), 127.5, 127.0 (2C), 123.7, 121.0 (2C), 111.7,
106.3, 101.2, 97.1, 61.9, 61.5, 55.54, 55.50, 44.8 ppm. HRMS:
C26H24N2O4: calcd 429.1809 [M+H+]; found: 429.1813.
Acknowledgements
We thank the Danish National Research Foundation (Grant
number DNRF59), the Danish Council for Independent Re-
search, the Carlsberg Foundation, and Aarhus University for
generous financial support of this work. The China Scholarship
Council is thanked for a CGSP scholarship to Z. X.
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Keywords: cycloaddition · homogeneous catalysis · gold ·
heterocycles · ynamides
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Received: April 28, 2014
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COMMUNICATION
&
Synthetic Methods
Z. Xin, S. Kramer,* J. Overgaard,
T. Skrydstrup*
&& – &&
Heterocycles: A new synthetic route to
the privileged 1,2-dihydroisoquinolines
is reported. This method, which relies
on a gold-catalyzed formal [4+2] cyclo-
addition between ynamides and imines,
provides a new retrosynthetic discon-
nection of the 1,2-dihydroisoquinoline
core by installing the 1,8a CÀC and 2,3
CÀN bonds in one step. Both aldimines
and ketimines can be used as sub-
strates. In addition, one example of
dihydrofuropyridine synthesis is also
demonstrated (see scheme).
Access to 1,2-Dihydroisoquinolines
through Gold-Catalyzed Formal [4+2]
Cycloaddition
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!