Copper-Catalyzed Cascade Reaction via Intramolecular Hydroamination Cyclization of Homopropargylic Amines and Intermolecular Povarov Reaction with Imines

Article abstract of DOI:10.1021/acs.orglett.6b00804

A new one-pot cascade reaction of homopropargylic amines with simple imines is developed in the presence of Cu(OTf)₂ and affords a series of hexahydro-1H-pyrrolo[3,2-c]quinoline derivatives in good to high yields. This reaction proceeds through

Full text of DOI:10.1021/acs.orglett.6b00804

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Cascade Reaction via Intramolecular
Hydroamination Cyclization of Homopropargylic Amines and
Intermolecular Povarov Reaction with Imines
Hongkai Wang, Chan Wang, Kaimeng Huang, Lingyan Liu,* Weixing Chang, and Jing Li*
†
†
†
,†
†
,†,‡
†
State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
‡
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Weijin Road #94, Nankai District, Tianjin 300071,
China
*
S Supporting Information
ABSTRACT: A new one-pot cascade reaction of homopropargylic amines with simple imines is developed in the presence of
Cu(OTf) and affords a series of hexahydro-1H-pyrrolo[3,2-c]quinoline derivatives in good to high yields. This reaction proceeds
2
through an intramolecular hydroamination cyclization of homopropargylic amine to generate a highly reactive dihydropyrrole
intermediate in situ. It subsequently reacts with imine via an intermolecular inverse-electron-demand aza-Diels−Alder reaction
and a 1,3-H shift to give the fused pyrroloquinoline structures, forming two new C−C bonds and one C−N bond and one N−H
bond.
omopropargylic amine is a β-amino alkyne that contains
Scheme 1. Possible Reactions of Homopropargylic Amines
H
two functional groups, an amino group and a triple bond.
Taking full advantage of these two functional groups at the
same time results in an elegant reaction: metal-catalyzed
intramolecular 5-endo-dig cyclization of homopropargylic
amines for the synthesis of five-membered N-containing
1
heterocyclic compounds. This cyclization usually involves the
formation of a sp C−M bond, and trapping of this sp C−M
bond by a proton occurs in most cases. Recently, some
2
2
2
2
examples of exploration of this sp C−M bond to generate a
3
C−C bond have been reported. For example, we have
developed a tandem reaction of homopropargylic amine 1 to
construct a series of multisubstituted pyrrole derivatives 3 by
4
reacting it with aryl iodides 2 (Scheme 1, a). As a part of our
continuous program aimed at exploring the diverse reactivity of
homopropargylic amine in organic synthesis, we envisioned
that the cyclization of homopropargylic amines in the presence
of triple bond activators will produce a highly reactive
dihydropyrrole, an enamine, which might be further applied
to other transformations. Therefore, the typical Povarov
reaction, an inverse-electron-demand aza-Diels−Alder reaction
formed in situ, which may act as electron-rich olefin
dienophile. To our delight, the cascade hydroamination
cyclization−Povarov reaction was expectedly realized between
homopropargylic amine 1 and imine 4 in the presence of
5
(IEDDA reaction) between 2-azadienes and electron-rich
Received: March 19, 2016
olefins, was chosen to investigate the reactivity of enamine
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00804
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
copper triflate (Scheme 1, b). Through this strategy, an arsenal
of pyrroloquinoline derivatives 5 can be facilely and highly
efficiently constructed in one pot, which would offer a new
avenue to fabricate substituted nitrogen-containing fused
polyheterocyclic compounds. The hexahydropyrrolo[3,2-c]-
quinoline motif is a unique nitrogen-containing heterocycle.
It can be found in the alkaloids of Martinella iquitosensis, such as
martinellic acid (6a) and martinelline (6b), which exhibit
Table 1. Screening of Catalysts in the Cascade Reaction of
Homopropargylic Amine and Imine
a
6
interesting biological activity (Figure 1). Additionally, it is
c
dr (endo/
total yield
(%)
b
entry
catalyst
exo)
1
2
3
4
5
6
7
8
9
PPh AuCl/AgNTf2
3
PtCl2
Cu(OTf)2
62:38
58:42
92
82
Fe(OTf)3
Zn(OTf)2
Hg(OTf)2
CuCl
63:37
56:44
79
86
TfOH (10 mol %)
PhCOOH (10 mol %)
Figure 1. Natural products from the roots of the Amazonian plant
Martinella iquitosensis.
1
0
Cu(OTf) (5 mol %),
2
PhCOOH (10 mol %)
a
Reaction conditions: 1a (0.24 mmol, 1.2 equiv), 4a (0.2 mmol, 1.0
worth noting that this reaction renders several distinguishing
features: (1) a fused tricyclic pyrroloquinoline, which has one
more nitrogen-containing heterocycle than that of elegant
Povarov reaction of imine and electron-rich olefin, is generated
in this reaction, and (2) the cyclic enamine formed in situ
without a special protecting group, an unstable dihydropyrrole
which is difficult to prepare in advance, is suggested to be
reactive in the Povarov reaction, as it expands previous limited
equiv), 5 mol % of catalyst, and MeOH (2 mL) were sequentially
added into a tube. The reaction was carried out under the given
reaction conditions, and the products were subsequently detected by
b
TLC. The diastereomeric ratios were determined on the basis of
c
NMR analysis of the crude products. Isolated yield.
With the optimal reaction conditions in hand, various
homopropargylic amines and imines were then investigated to
diversify the general pyrroloquinoline (Table 2). Remarkably,
all substrates were competent in this cascade reaction and
produced multiaryl-substituted pyrroloquinoline derivatives in
good or high yields. For instance, regarding the 4-methylphenyl
7
N-protected (N-Ts, N-Boc, or N-Cbz) dihydropyrroles.
This interesting cascade sequence intrigued us and prompted
us to investigate the reaction parameters in greater detail to
evaluate their impact on the outcome of the reaction. The
homopropargylic amine (1a) and imine (4a) were selected as
model substrates. π-Acidic metal catalysts, Au/Ag and PtCl2,
were first employed to catalyze this reaction. However, the
starting material remained untouched in these two cases (Table
1
or 4-methoxyphenyl (R ) homopropargylic amine substrates 1a
2
2
(R = H) and 1c (R = Me), both electron-rich and electron-
deficient substituents on two different aryl rings of imines (4a−
e) could be smoothly converted to the desired products (Table
2, entries 1−5 and 7−9). For the nonsubstituted phenyl
homopropargylic amine (1e), only the imines with electron-
donating substituents could react smoothly and give the fused
pyrroloquinolines (entries 11−13). In the case of homopro-
pargylic amines bearing 4-F (1d) and 4-Br substituents (1f), the
reactions delivered the corresponding products in good yields
under the optimal reaction conditions with imine 4a,
respectively (Table 2, entries 10 and 14). Interestingly, when
1
, entries 1 and 2). Copper(II) trifluoromethanesulfonate,
Cu(OTf) was then used as a metal catalyst in the reaction of
2,
homopropargylic amine and imine. Gratifyingly, this reaction
gave high total yields of pyrroloquinoline 5 and 5′ (endo- and
exo-) in MeOH at 50 °C (entry 3). The absolute configuration
of exo-5′aa was unambiguously determined by a single-crystal
8
X-ray diffraction (Figure S1). Other metal triflates, such as
Fe(OTf) , were screened, but no obvious improved result was
3
1
2
obtained (entry 4). In the presence of Zn(OTf) or Hg(OTf) ,
R = H, R = 4-HOCH CH , namely 1g, the amine could also
2
2
2 2
no reaction occurred (entries 5 and 6). Using CuCl, this
reaction could also proceed smoothly in MeOH at 50 °C and
deliver the corresponding pyrroloquinoline in good total yields
react with imines 4a and 4i, which even bears heteroaryl group,
to efficiently produce the target compounds (entries 15 and
16). Unfortunately, when using the imines with aryl group
(entry 7). In addition, the protic acid catalysts were also
bearing electron-withdrawing substituents (4-NO , 4i and 4-Br,
2
examined. However, both TfOH and PhCOOH have no effect
on this reaction (entries 8 and 9). When PhCOOH was
4j) on the N terminal, only trace of target compounds were
obtained by H NMR with most materials left (entries 17−18).
1
combined with Cu(OTf) , the reaction gave a result similar to
Additionally, no reaction occurred in three cases, such as
employing ketimine 4k or homopropargylic amines 1h or 1i
with internal alkyne (entries 19−21). The reason may be
ascribed to the low activity and steric hindrance of ketimine 4k
and the large steric hindrance and electron effect of internal
alkynes 1h and 1i. Notably, most reactions of homopropargylic
amines and imines afforded diastereoisomers with endo- and
exo-configured pyrroloquinolines. In particular, the imines 4e
2
that using only Cu(OTf) (entry 10). On the basis of these
2
outcomes, Cu(OTf) was considered as the optimal catalyst.
2
Other experimental parameters, such as solvent, the ratio of
homopropargylic amine 1a and imine 4a, and the amount of
catalyst as well as the system concentration, were then
examined as shown in Tables S1−S3. It was found that the
optimal reaction conditions were a 1.2:1 ratio of 1a/4a, 5 mol
3
3
%
of Cu(OTf) , 0.1 M MeOH, 50 °C, in air.
and 4f with 2-BrC H (Ar ) and 3-CN C H (Ar ) gave a single
2
6
4
6
4
B
DOI: 10.1021/acs.orglett.6b00804
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Scope of Homopropargylic Amines and Imines
a
Reaction conditions: 1 (0.24 mmol, 1.2 equiv), 4 (0.2 mmol, 1.0 equiv), 5 mol % of Cu(OTf) , and MeOH (2 mL) were sequentially added into a
2
b
tube. The reaction was carried out at 50 °C in the air for 5−6 h, and the products were subsequently detected by TLC. The diastereomeric ratios
were determined based upon NMR analysis of the crude products. Isolated yield. Using ketimine derived from 4-bromoacetophenone. The
substrates were homopropagylic amines with internal alkyne.
c
d
e
endo- and exo-product in moderate yields, respectively (entries
and 9). Moreover, due to three new stereocenters formed in
render the intermediate D, followed by a 1,3-H shift to give the
final product pyrroloquinoline 5ea (Scheme 2).
5
the products, some endo- or exo-configurational pyrroloquino-
lines have additional diastereoisomers. All products were
racemic.
With the scope of this method established, the reaction
mechanism was considered. The key intermediate is the
formation of dihydropyrrole intermediate. A possible mecha-
nism was proposed as shown in Scheme 2. The dihydropyrrole
C was generated via a typical intramolecular hydroamination
cyclization of terminal alkyne activated by Cu(OTf)2.
Subsequently, the formed unstable enamine attacked the
In summary, we have established a simple, rapid, and high-
yielding synthesis of diverse polyaryl-substituted
hexahydropyrrolo[3,2-c]quinolines from simple homopropar-
gylic amines and imines. Two main diastereomers, endo- and
exo-, were obtained with the formation of five σ-bonds (C−
N(1), C−H(1), C−C(2), N−H(1)) and three new stereogenic
centers in a one-pot, sequential transformation. It should be
noted that the highly reactive dihydropyrrole was formed in situ
through intramolecular hydroamination cyclization of the
homopropargylic amine and then subtly used as a dienophile
in a subsequent Povarov reaction with imine. This strategy
imine 4a, which was activated by Lewis acid Cu(OTf) , to
2
C
DOI: 10.1021/acs.orglett.6b00804
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Possible Cascade Reaction Mechanism of
Homopropargylic Amine and Imine
REFERENCES
■
(
1) For selected reviews on cyclization of alkynes containing
compounds, see: (a) Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011,
1
2
11, 6513. (b) Godoi, B.; Schumacher, R. F.; Zeni, G. Chem. Rev.
011, 111, 2937.
(2) (a) Wang, X.; Yao, Z.; Dong, S.; Wei, F.; Wang, H.; Xu, Z. Org.
Lett. 2013, 15, 2234. (b) Shu, C.; Liu, M.-Q.; Wang, S.-S.; Li, L.; Ye,
L.-W. J. Org. Chem. 2013, 78, 3292. (c) Agarwal, S.; Passler, U.;
Knolker, H.-J. ARKIVOC 2013, 6. (d) Egi, M.; Azechi, K.; Akai, S. Org.
Lett. 2009, 11, 5002. (e) Hiroya, K.; Matsumoto, S.; Ashikawa, M.;
Ogiwara, K.; Sakamoto, T. Org. Lett. 2006, 8, 5349. (f) Hayes, S. J.;
Knight, D. W.; O’Halloran, M.; Pickering, S. R. Synlett 2008, 2008,
2
188. (g) Knight, D. W.; Sharland, C. M. Synlett 2004, 119. (h) Van
Esseveldt, B. C. J.; Vervoort, P. W. H.; van Delft, F. L.; Rutjes, P. J. T.
J. Org. Chem. 2005, 70, 1791.
(3) (a) Yao, B.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2012, 51,
5
170. (b) Rauniyar, V.; Wang, Z. J.; Burks, H. E.; Toste, F. D. J. Am.
Chem. Soc. 2011, 133, 8486. (c) Liu, F.; Qian, D.; Li, L.; Zhao, X.;
Zhang, J. Angew. Chem., Int. Ed. 2010, 49, 6669. (d) Fujino, D.;
Yorimitsu, H.; Osuka, A. Org. Lett. 2012, 14, 2914. (e) Yao, T.; Zhang,
X.; Larock, R. C. J. Org. Chem. 2005, 70, 7679. (f) Yao, T.; Zhang, X.;
Larock, R. C. J. Am. Chem. Soc. 2004, 126, 11164.
(
4) Wang, C.; Huang, K. M.; Wang, J. Y.; Wang, H. K.; Liu, L. Y.;
Chang, W. X.; Li, J. Adv. Synth. Catal. 2015, 357, 2795.
5) (a) Ma, Y.; Qian, C.; Xie, M.; Sun, J. J. Org. Chem. 1999, 64,
ue, J. P.; Bonnet-Delpon, D. J. Org.
(
6
462−6427. (b) Crousse, B.; Beg
́ ́
Chem. 2000, 65, 5009. (c) Kudale, A. A.; Kendall, J.; Miller, D. O. J.
Org. Chem. 2008, 73, 8437. (d) Ramesh, S.; Nagarajan, R. J. Org. Chem.
expands previous limited N-protected dihypyrroles in the
Povarov reaction and provides a new route for the synthesis of
diverse pyrroloquinoline derivatives. We believe that this
intramolecular hydroamination cyclization of alkyne constitutes
a particularly striking example of a one-pot reaction for the
rapid assembly of molecular complexity, which should prove
highly valuable in the context of the diversity-oriented
synthesis. Our ongoing studies focus on an asymmetric variant
and its extension toward the synthesis of other heterocyclic
scaffolds.
2
013, 78, 545. (e) Lin, W. C.; Yang, D. Y. Org. Lett. 2013, 15, 4862.
(f) Huang, Y.; Qiu, C.; Li, Z.; Feng, W.; Gan, H.; Liu, J.; Guo, K. ACS
Sustainable Chem. Eng. 2016, 4, 47.
(6) (a) Witherup, K. M.; Ransom, R. W.; Graham, A. C.; Bernard, A.
M.; Salvatore, M. J.; Lumma, W. C.; Anderson, P. S.; Pitzenberger, S.
M.; Varga, S. L. J. Am. Chem. Soc. 1995, 117, 6682. (b) Malassene, R.;
Sanchez-Bajo, L.; Toupet, L.; Hurvois, J. P.; Moinet, C. Synlett 2002,
2
002, 1500.
(7) (a) Batey, R. A.; Simoncic, P. D.; Lin, D.; Smyj, R. P.; Lough, A. J.
Chem. Commun. 1999, 651. (b) Liu, H.; Dagousset, G.; Masson, G.;
Retailleau, P.; Zhu, J. P. J. Am. Chem. Soc. 2009, 131, 4598.
(
1
c) Dagousset, G.; Drouet, F.; Masson, G.; Zhu, J. P. Org. Lett. 2009,
1, 5546−5549. (d) Wang, C.; Han, Z. Y.; Luo, H. W.; Gong, L. Z.
Org. Lett. 2010, 12, 2266. (e) Vicente-García, E.; Catti, F.; Ramon, R.;
ASSOCIATED CONTENT
Supporting Information
■
*
S
́
Lavilla, R. Org. Lett. 2010, 12, 860. (f) Dagousset, G.; Zhu, J. P.;
Masson, G. J. Am. Chem. Soc. 2011, 133, 14804.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00804.
(
8) Crystal data for the compound 5′aa: C H N , MW) 430.58,
31
30
2
triclinic, P-1; final R indices [I > 2σ(I)], R1 = 0.0448, wR2 = 0.1318, R
indices (all data), R1 = 0.0637, wR2 = 0.1449, a = 10.116(2) Å, b =
Procedures for the synthesis of homopropargylic amines
and cascade reaction; NMR and HR-MS spectra of all
pyrroloquinoline derivatives (PDF)
Characterization data (PDF)
X-ray data of compound exo-5′aa (CIF)
3
1
0.554(2) Å, c = 11.501(2) Å, V = 1172.5(4) Å , T = 113 (2) K, Z = 2.
Reflections collected/unique: 11808/5502 [R(int) 0.0285], number of
observations [I > 2σ(I)] 5502, parameters) 300, goodness-of-fit on F2)
1
.005. Supplementary crystallographic data have been deposited at the
Cambridge Crystallographic Data Centre, CCDC 1441746.
AUTHOR INFORMATION
Corresponding Authors
■
*
E-mail: liulingyan@nankai.edu.cn.
E-mail: lijing@nankai.edu.cn.
*
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (Grant No. 21372120) for this
work. We also acknowledge support from the Collaborative
Innovation Center of Chemical Science and Engineering
(Tianjin).
D
DOI: 10.1021/acs.orglett.6b00804
Org. Lett. XXXX, XXX, XXX−XXX