Enantioselective Palladium-Catalyzed Heck-Heck Cascade Reactions: Ready Access to the Tetracyclic Core of Lycorane Alkaloids

Article abstract of DOI:10.1002/adsc.201500431

A rapid and efficient access to a wide variety of enantiomerically enriched C-11b substituted lycorane analogues can be achieved via a catalytic asymmetric Heck-Heck 6-exo/6-endo cascade reaction in the presence of (R)-BINAP.

Full text of DOI:10.1002/adsc.201500431

FULL PAPERS
DOI: 10.1002/adsc.201500431
Enantioselective Palladium-Catalyzed Heck–Heck Cascade
Reactions: Ready Access to the Tetracyclic Core of Lycorane
Alkaloids
Estibaliz Coya,a Nuria Sotomayor,a and Esther Letea,*
a
Departamento de Química Orgµnica II, Facultad de Ciencia y Tecnología, Universidad del País Vasco/Euskal Herriko
Unibertsitatea (UPV/EHU), Apdo. 644. 48080 Bilbao, Spain
Fax: (+34)-94-601-2748; e-mail: esther.lete@ehu.es
Received: April 30, 2015; Revised: July 10, 2015; Published online: September 11, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500431.
Abstract: A rapid and efficient access to a wide vari- asymmetric Heck–Heck 6-exo/6-endo cascade reac-
ety of enantiomerically enriched C-11b substituted tion in the presence of (R)-BINAP.
lycorane analogues can be achieved via a catalytic
Keywords: alkaloids; asymmetric catalysis; domino
reactions; Heck reaction; palladium
Introduction
dride transfer, thus favoring the second ring closure,[8]
or by changing the chiral ligands.[9] Naphthoyl halides
Catalytic asymmetric transition metal-catalyzed cas- can also be used in this process instead of the corre-
cade reactions represent one of the most powerful sponding triflates.[10]
and efficient methods for the rapid assembly of bio-
On the other hand, we had previously reported[11]
logically active and complex chiral molecules from that the intramolecular palladium-catalyzed reaction
simple substrates.[1] Particularly, the enantioselective of 2-alkenyl-substituted N-(o-iodobenzyl)pyrroles can
intramolecular Heck reaction[2] has emerged as an ex- be directed to the alkene (Heck reaction), avoiding
cellent tool for the construction of polycyclic frame- the direct arylation on the pyrrole nucleus by choos-
works generating tertiary and quaternary stereocen- ing the appropriate catalytic system, regardless of the
ters[3] through palladium-catalyzed polyene cycliza- nature of the substituent on the alkene, obtaining ex-
tions.[4] In this strategy, the s-arylpalladium intermedi- cellent yields of pyrrolo[1,2-b]isoquinolines. The pro-
ate resulting from the migratory insertion of the aryl- cedure has also been applied to the selective synthesis
palladium to the alkene, would be trapped by an of medium-sized rings and to (hetero)fused indolizine
adequately positioned internal alkene, allowing the systems.[12] With these precedents in mind, we decided
sequential formation of two or more rings in one step. to apply the enantioselective palladium-catalyzed
Related cascade reactions have also been developed, polyene cyclization to the construction of the structur-
where b-hydride elimination is avoided by an anion al core of the Lycorine class of Amaryllidaceae alka-
capture event.[5] In this context, Overman reported in loids (Figure 1).[13]
1989 the first example of an enantioselective palladi-
These naturally occurring natural products and
um-catalyzed polyene cyclization of trienyl triflates their derivatives exhibit a broad spectrum of pharma-
for the construction of spirocyclic trienones.[6] The po- cological properties,[14] including anticancer,[15] antivi-
tential of this type of asymmetric cascade reactions ral,[16] antiparasitic,[17] and anti-inflammatory activi-
for the construction of polycyclic frameworks has ties,[18] as well as being phytotoxic in herbicide bioas-
been shown by Keay in his total synthesis of the says.[19] Because of their unique tetracyclic structure
marine natural product, (+)-Xestoquinone.[7] Al- and their bioactive properties, Lycorane-type alka-
though the cyclization of dialkenylfurans with a naph- loids have attracted numerous synthetic studies.[20]
thoyl triflate using (S)-BINAP as the chiral ligand led However, relatively few approaches to the asymmet-
to moderate enantiomeric excesses, the procedure ric synthesis of these alkaloids have been reported so
was later improved either by tuning the experimental far.[21]
conditions (base, solvent) in order to inhibit the hy-
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Enantioselective Palladium-Catalyzed Heck–Heck Cascade Reactions
Table 1. Optimization of the cascade cyclization of 1a with
(R)-BINAP.
Entry Base
T
Time
[h]
Solvent Yield
[%]
ee[a]
[%]
1
2
3
4
5
6
7
8
Et3N
Et3N
PMP
808C 72
1108C 72
808C 72
DMF
DMF
DMF
DMF
THF
dioxane 19
CH3CN 33
CH3CN 75
CH3CN 10
CH3CN 43
CH3CN 46
CH3CN 76
CH3CN 65
EtOH 11
CH3CN 82
17
3
7
8
13
63
29
<5
30
nd
62
67
67
nd
63
58
63
63
68
66
Cy2NMe 808C 72
Et3N
Et3N
Et3N
reflux 72
808C 72
reflux 72
reflux 24
408C 72
reflux 48
reflux 24
reflux 48
PMP
PMP
9
10
11
12
13
14
PMP[b]
PMP[c]
PMP[d]
Figure 1. Lycorine class of Amaryllidaceae alkaloids.
CyNMe2 reflux 30
PMP
reflux 48
reflux 48
15[e] PMP
[a]
Determined by chiral stationary phase HPLC (Chiralcel
OZ3 2% hexane/i-PrOH).
3 equiv.
Ag3PO4 (2 equiv.) was added.
1 equiv.
[b]
[c]
[d]
[e]
Pd(dba)2 was used.
could isolate only small amounts (8%) of 2a. We de-
cided to optimize the reaction conditions in the asym-
metric version, and we chose (R)-BINAP as ligand
(Table 1, Scheme 1). Although only a low yield of 2a
could be obtained, the enantioselectivity of the reac-
Figure 2. A 6-exo Mizoroki–Heck reaction to generate the
quaternary stereocenter.
For this work, 2,3-dialkenylpyrroles 1 were selected tion was promising, obtaining 63% ee using Et3N as
to attempt the catalytic asymmetric polyene cycliza- base. The use of different bases, such as PMP, has
tion. A shown on Figure 2, a 6-exo Mizoroki–Heck re- been shown to minimize competing hydride transfer,
action would generate the quaternary stereocenter, increasing the yield of the cyclized product.[8] Howev-
giving rise to the s-alkylpalladium intermediate that er, an increase of the temperature (entry 2) or the use
would undergo a 6-endo insertion to give the tetracy- of different bases (entries 3 and 4) resulted in a loss
clic framework of Lycorane alkaloids.[22]
of enantioselection. Different solvents were tested,
and acetonitrile and dioxane increased the enantiose-
lectivity to 67% and 62%, respectively, although the
yields continued to be poor (entries 6 and 7). The
best results were achieved when PMP was used as
Results and Discussion
We started studying the cascade reaction with 1a[23] base in acetonitrile, obtaining a good yield of 2a
(Scheme 1). We first performed the reaction in a race- (72%) in 24 h, with moderate ee (66%) (entry 8). A
mic fashion employing Pd(OAc)2 (5 mol%) as cata- decrease of the temperature to 408C caused a com-
lyst, PPh3 (14 mol%) as ligand in DMF at 808C. A plete loss of the yield and the enantioselectivity
mixture of products was obtained from which we (entry 9). An increase of the amount of the base or
the addition of silver salts[10] did not improve the re-
sults (entries 10 and 11). The use of less PMP
(entry 11) or Cy2NMe resulted in longer reaction
times to obtain similar levels of enantioselection and
yield. The change of the solvent to ethanol[9c] resulted
in a loss of yield (11%), although with the same level
of enantioselection (entry 14). Finally, the change of
the catalyst to Pd(dba)2 (entry 15) did not improve
significantly the results, requiring a longer reaction
Scheme 1. Polyene cyclization of 1a.
time.
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Estibaliz Coya et al.
Table 2. Cyclization of 1a using ligands L1–6.
We have previously demonstrated the need to use
catalytic systems that follow the “classical” neutral
Pd(0)/Pd(II) mechanism to promote the intramolecu-
lar alkenylation of iodinated N-(arylalkyl)pyrroles, as
the electrophilic palladium(II) species favor the direct
arylation reaction.[11,12] However, in this case, although
conditions that may direct the reaction towards a cat-
ionic type of mechanism have been used, it is note-
worthy that in all cases the Heck–Heck reaction was
the only process observed, we did not detect the for-
mation of any product from a direct arylation on the
pyrrole nucleus.
We next carried out a further optimization of the
reaction using different phosphane ligands L1–L6
(Table 2, Scheme 2). We selected both bidentate and
monodentate phosphanes, which would show different
electronic and steric properties. However, under the
previously optimized conditions [Pd(OAc)2, PMP,
CH3CN, reflux] the use of a modified BINAP, such as
Xyl-BINAP (L1)[9b] did not improve the results ob-
tained with BINAP (entry 1), neither did the rest of
the ligands (entries 2–4, 8, 17).
Entry L
Base
Time
[h]
Solvent Yield
[%]
ee[a]
[%]
1
2
3
4
5
6
7
8
L1 PMP
L2 PMP
L3 PMP
L4 PMP
L4 PMP
L4 PMP
L5 PMP
L5 Et3N
L5 Et3N
L5 Et3N
L5 Et3N
L5 Et3N
L5 Et3N
31[d]
24[d]
31[d]
31[d]
48[d]
24[d]
72[d]
24[d]
48[e]
72[f]
72[e]
72[d]
72[f]
CH3CN 54
CH3CN 70
CH3CN 18
CH3CN 75
55
11
34
49
40
57
55
28
41
53
56
57
46
37
30
54
11
toluene
EtOH 33
THF 43
CH3CN 44
5
9
DMF
DMF
73
59
10
11
12
13
14
15
16
17
dioxane 18
THF
THF
DMF
DMF
CHCl3
69
24
34
75
8
L5[b] Cy2NMe 9[e]
L5[b] Cy2NMe[c] 48[e]
L5[b] Cy2NMe[c] 72[d]
L6 PMP
24[d]
CH3CN 65
[a]
Determined by chiral stationary phase HPLC (Chiralcel
OZ3 2% hexane/i-PrOH).
[b]
[c]
[d]
[e]
[f]
20 mol%.
3 equiv.
Reflux.
808C.
A further optimization of the reaction conditions
(solvent, base) was carried out also with SEGPHOS
(L4) and phosphoramidite L5, but lower yields were
obtained with solvents such as toluene, ethanol or di-
oxane, with no improvement of the enantioselectivity.
Thus, (R)-BINAP was selected as the most efficient
phosphane ligand.
408C.
The reaction could also be applied to the non-sub-
Once the best reaction conditions had been select- stituted benzene ring (2b), or to a fluoro-substituted
ed, we studied the scope of the reaction using differ- derivative (2n), but a low yield and enantioselectivity
ent substitution patterns in the arene. As can be seen were obtained when a strong acceptor, such as a nitro
from the examples depicted on Scheme 3, the reaction
tolerates different substitution patterns on the ben-
zene ring.
Thus, 9,10-dioxygenated compounds (Scheme 3, 2c,
2i–k) were obtained with consistently good yield, and
maintaining the level of enantioselection. The nature
of the oxygen substituent (Me, Bn or substituted
benzyl derivatives) had no relevant impact in the re-
action performance. Mono-alkoxylated (2d, 2h) or
8,9-dimethoxylated (2e) derivatives were also success-
fully obtained. Substitution ortho to the iodine atom,
however, resulted in a complete loss of both yield and
enantioselectivity (2f, 2g), in contrast with previously
reported results.[7b] On the other hand, it has also
been reported that, in this type of reactions, substitu-
tion on the alkene may have an important impact on
the enantioselectivity. Thus, the presence of a substitu-
ent on the furan double bond or a group ortho to the
triflate results in a significant increase in the ee in the
palladium-catalyzed polyene cyclizations of 3,4-di-
alkenylfurans with benzoyl triflates.[7b] Unfortunately,
in our case substitution in the a or b-positions of the
pyrrole C-3 alkene completely precluded cycliza-
tion.[24]
Scheme 2. Ligand optimization for the cyclization of 1a.
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Enantioselective Palladium-Catalyzed Heck–Heck Cascade Reactions
Scheme 4. Catalytic hydrogenation of 2a.
with (S)-BINAP, obtaining the same level of enantio-
selection for the opposite enantiomer (see the Sup-
porting Information). Although the enantioselectivi-
ties obtained were in most cases moderate, the optical
purity could be significantly improved after a single
crystallization, as shown for 2k (90% ee after crystalli-
zation from Et2O). The absolute configuration was
unambiguously assigned by single crystal X-ray analy-
sis of 2k as R (see the Supporting Information).[26]
The configurations of 2a–p were assigned assuming
a uniform mechanism.
Finally, it has been shown that the double bond can
be reduced by catalytic hydrogenation (Scheme 4).
Thus, 2a was hydrogenated at 30 psi affording 3a in
moderate yield (55%).
Conclusions
The Lycorane tetracyclic framework of the Amarylli-
daceae alkaloids can be efficiently accessed through
a palladium-catalyzed Heck–Heck cascade reaction.
Thus, N-benzyl-2,3-dialkenylpyrroles undergo sequen-
tial 6-exo/6-endo cyclizations to yield enantiomerically
enriched (11bR)-substituted pyrrolophenanthridines.
The choice of the base and solvent (PMP; CH3CN) is
crucial to lead the sequence to completion, avoiding
hydride transfer. (R)-BINAP has been shown to be
the most efficient chiral phosphane ligand. The reac-
tion can be extended to various substitution patterns
on the aromatic ring, and also to heteroaromatic
rings. This procedure allows a rapid and efficient
access to a wide variety of enantiomerically enriched
C-11b substituted lycorane analogues.
Scheme 3. Extension of the methodology. Synthesis of (R)-
pyrrolophenanthridines 2b–n and (S)-heterofused analogues
2o–p. The ees were determined by chiral stationary phase
HPLC (Chiralcel OD3).
Experimental Section
group, is present (2m). In this case, only a 28% yield
could be obtained, using an additional 10% mol of
the catalyst and an extended reaction time.[25]
The procedure could also be extended to heteroar-
omatic analogues. In these cases the corresponding
bromide 1o and iodide 1p were prepared,[23] and sub-
mitted to the same reaction conditions. It is notewor-
thy that the quinoline-fused derivative 2o was ob-
tained in low yield, using 20% catalyst and under an
extended reaction time, but with an excellent ee
Pd(0)-Catalyzed Cyclization of 1a–p. Synthesis of
Pyrrolophenanthridines and Heterofused Analogues
2a–p; General Procedure
To a solution of the corresponding 2,3-dialkenylpyrrole 1a–p
(1 mmol) in anhydrous CH3CN (15 mL) under an argon at-
mosphere, (R)-BINAP (0.28 mmol), PMP (2 mmol) and
Pd(OAc)2 (0.10 mmol) were added. The mixture was heated
under reflux for 24 h.[27] Then the reaction mixture was dilut-
ed with AcOEt (50 mL), washed with saturated NH4Cl (1”
(99%). In this case, the reaction was also carried out 30 mL) and H2O (2”30 mL). The combined organic extracts
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Estibaliz Coya et al.
were dried (Na2SO4), and concentrated under vacuum. Flash
column chromatography (silica gel, hexane/AcOEt) afford-
ed the pyrrolophenanthridines 2a–n and analogues 2o–p.
(R)-9,10-Dimethoxy-11b-methyl-7,11b-dihydro-1H-pyrro-
lo[3,2,1-de]phenanthridine (2a) (Table 1, entry 8): Prepared
from pyrrole 1a (160 mg, 0.38 mmol), (R)-BINAP (68 mg,
0.11 mmol), PMP (0.14 mL, 0.76 mmol) and Pd(OAc)2
(9.0 mg, 0.04 mmol). The reaction mixture was heated under
reflux for 24 h. After work-up, flash column chromatogra-
phy (silica gel, hexane/AcOEt 8:2) afforded 2a as an oil;
yield: 80 mg (75%). IR (ATR): n=1511 cmÀ1 (C=C);
1H NMR (300 MHz, CDCl3): d=1.28 (s, 3H, CH3), 2.56–
2.82 (m, 2H, 2”H-1), 3.89 (s, 3H, OCH3), 3.92 (s, 3H,
OCH3), 5.01 (d, J=15.4 Hz, 1H, H-7a), 5.04 (d, J=15.4 Hz,
1H, H-7b), 5.52–5.70 (m, 1H, H-2), 6.10 (d, J=2.6 Hz, 1H,
H-4), 6.49 (dd, J=9.4, 3.1 Hz, 1H, H-3), 6.61 (d, J=2.6 Hz,
1H, H-5), 6.72 (s, 1H, H-11), 6.86 (s, 1H, H-8); 13C NMR
(75.5 MHz, CDCl3): d=27.4 (CH3), 34.1 (C-11b), 37.1 (C-1),
47.0 (C-7), 56.4 (2”OCH3), 105.7 (C-4), 107.8 (C-11), 109.9
(C-8), 113.4 (C-3a), 117.0 (C-5), 117.8 (C-2), 122.9 (C-11a),
123.1 (C-3), 132.0 (C-3a1), 135.6 (C-7a), 147.3 (C-9), 148.8
(C-10); MS (CI): m/z (rel. intensity)=282 (MH+, 100), 281
(M+, 67), 267 (22), 266 (78); HR-MS (CI): m/z=282.1489,
calcd. for C18H20NO2 [MH]+: 282.1494. [a]2D0: +22.7 (c=0.32,
CH2Cl2). The enantiomeric excess was determined by HPLC
to be 67%, [Chiralcel OZ3, hexane/isopropyl alcohol 98:2,
0.8 mLminÀ1, tr (minor)=15.3 min (16.66%), tr (major)=
15.9 min (83.34%)].
(R)-11b-Methyl-7,11b-dihydro-1H-pyrrolo[3,2,1-de]phen-
anthridine (2b): Prepared from pyrrole 1b (66.4 mg,
0.19 mmol), (R)-BINAP (33.2 mg, 0.053 mmol), PMP
(0.07 mL, 0.38 mmol) and Pd(OAc)2 (4.3 mg, 0.019 mmol).
The reaction mixture was heated under reflux for 48 h.
After work-up, flash column chromatography (silica gel,
hexane/AcOEt 9.8:0.2) afforded 2b as an oil; yield: 16 mg
(38%). IR (ATR): n=1562 cmÀ1 (C=C); 1H NMR
(300 MHz, CDCl3): d=1.31 (s, 3H, CH3), 2.64–2.77 (m, 2H,
2”H-1), 5.07 (d, J=15.7 Hz, 1H, H-7a), 5.14 (d, J=15.7 Hz,
1H, H-7b), 5.53–5.67 (m, 1H, H-2), 6.13 (d, J=2.7 Hz, 1H,
H-4), 6.50 (dd, J=9.4, 3.3 Hz, 1H, H-3), 6.63 (d, J=2.7 Hz,
1H, H-5),7.15–7.48 (m, 4H, H-8, H-9, H-10, H-11; 13C NMR
(75.5 MHz, CDCl3): d=27.0 (CH3), 33.9 (C-11b), 37.2 (C-1),
47.1 (C-7), 105.3 (C-4), 113.8 (C-3a), 117.1 (C-5), 118.0 (C-
2), 123.1 (C-3), 124.7 (C-11), 126.1 (C-10), 126.3 (C-9), 128.0
(C-8), 130.1 (C-3a1), 131.9 (C-7a), 143.5 (C-11a); MS (CI):
m/z (rel. intensity)=222 (MH+, 99), 221 (M+, 79) 207 (20),
206 (100), 204 (17). HR-MS (CI): m/z=222.1287, calcd. for
C16H16N [MH]+: 222.1283. [a]D20: +84.4 (c=0.8, CH2Cl2). The
enantiomeric excess was determined by HPLC to be 72%,
(d, J=15.5 Hz, 1H, H-7b), 5.54–5.68 (m, 1H, H-2), 5.97 (s,
2H, OCH2O), 6.12 (d, J=2.6 Hz, 1H, H-4), 6.49 (dd, J=9.4,
3.0 Hz, 1H, H-3), 6.61 (d, J=2.6 Hz, 1H, H-5), 6.69 (s, 1H,
H-8), 6.86 (s, 1H, H-11); 13C NMR (75.5 MHz, CDCl3): d=
26.9 (CH3), 33.9 (C-11b), 37.4 (C-1), 47.1 (C-7), 101.2
(OCH2O), 105.0 (C-11), 105.3 (C-4), 106.4 (C-8), 113.5 (C-
3a), 117.0 (C-5), 117.9 (C-2), 123.1 (C-3), 124.0 (C-11a),
131.1 (C-3a1), 137.1 (C-7a), 145.8 (C-10), 147.3 (C-9); MS
(CI): m/z (%)=266 (MH+, 99), 265 (M+, 90), 251 (23), 250
(100), 220 (11); HR-MS (CI): m/z=266.1150, calcd. for
C17H16NO2 [MH]+: 266.1181; [a]20: +47.3 (c=1.39, CH2Cl2).
The enantiomeric excess was deDtermined by HPLC to be
65% [Chiralcel OD3, hexane/isopropyl alcohol 98:2,
0.8 mLminÀ1, tr (major)=15.2 min (82.74%), tr (minor)=
19.0 min (17.26%)].
(R)-9-Methoxy-11b-methyl-7,11b-dihydro-1H-pyrro-
lo[3,2,1-de]phenanthridine (2d): Prepared from pyrrole 1d
(62.0 mg, 0.16 mmol), (R)-BINAP (28.5 mg, 0.045 mmol),
PMP (0.06 mL, 0.32 mmol) and Pd(OAc)2 (3.7 mg,
0.016 mmol). The reaction mixture was heated under reflux
for 48 h. After work-up, flash column chromatography
(silica gel, hexane/AcOEt 9:1) afforded 2d as an oil; yield:
25 mg (62%). IR (ATR): n=1497 cmÀ1 (C=C); 1H NMR
(300 MHz, CDCl3): d=1.28 (s, 3H, CH3), 2.58–2.93 (m, 2H,
2”H-1), 3.83 (s, 3H, OCH3), 5.02 (d, J=15.7 Hz, 1H, H-
7a), 5.11 (d, J=15.7 Hz, 1H, H-7b), 5.53–5.67 (m, 1H, H-2),
6.11 (d, J=2.6 Hz, 1H, H-4), 6.49 (dd, J=9.4, 3.1 Hz, 1H,
H-3), 6.61 (d, J=2.6 Hz, 1H, H-5), 6.77 (d, J=2.3 Hz, 1H,
H-8), 6.90 (dd, J=8.6, 2.3 Hz, 1H, H-10), 7.30 (d, J=8.6 Hz,
1H, H-11); 13C NMR (75.5 MHz, CDCl3): d=27.2 (CH3),
33.3 (C-11b), 37.4 (C-1), 47.3 (C-7), 55.3 (OCH3), 105.3 (C-
4), 111.6 (C-10), 113.5 (C-8), 113.6 (C-3a), 117.0 (C-5), 118.0
(C-2), 123.1 (C-3), 125.7 (C-11) 132.1 (C-11a), 132.7 (C-3a1),
135.7 (C-7a), 157.6 (C-9); MS (CI): m/z (rel. intensity)=252
(MH+, 74), 251 (M+, 61), 237 (21), 236 (100); HR-MS (CI):
m/z=252.1376, calcd. for C17H18NO [MH]+: 252.1388; [a]20:
+54.8 (c=0.79, CH2Cl2). The enantiomeric excess was dDe-
termined by HPLC to be 68%, [Chiralcel OD3, hexane/iso-
propyl alcohol 90:10, 0.8 mLminÀ1, tr (major)=7.04 min
(83.94%), tr (minor)=8.03 min (16.06%)].
(R)-8,9-Dimethoxy-11b-methyl-7,11b-dihydro-1H-pyrro-
lo[3,2,1-de]phenanthridine (2e): Prepared from pyrrole 1e
(75.4 mg, 0.18 mmol), (R)-BINAP (34.4 mg, 0.055 mmol),
PMP (0.07 mL, 0.36 mmol) and Pd(OAc)2 (4.2 mg,
0.018 mmol). The reaction mixture was heated under reflux
for 30 h. After work up, flash column chromatography
(silica gel, hexane/AcOEt 9:1) afforded 2e as an oil; yield:
25.9 mg (51%). IR (ATR): n=1490 cmÀ1 (C=C); 1H NMR
(300 MHz, CDCl3): d=1.28 (s, 3H, CH3), 2.52–2.91 (m, 2H,
2”H-1), 3.89 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 4.88 (d,
J=16.6 Hz, 1H, H-7a), 5.38 (d, J=16.6 Hz, 1H, H-7b), 5.59
(ddd, J=9.4, 6.0, 2.5 Hz, 1H, H-2), 6.12 (d, J=2.7 Hz, 1H,
H-4), 6.43–6.53 (m, 1H, H-3), 6.65 11 (d, J=2.7 Hz, 1H, H-
5), 6.93 (d, J=8.5 Hz, 1H, H-10), 7.07 (d, J=8.5 Hz, 1H, H-
11); 13C NMR (75.5 MHz, CDCl3): d=24.5 (CH3), 33.4 (C-
11b), 37.4 (C-1), 42.1 (C-7), 55.9 (OCH3), 60.4 (OCH3),
105.3 (C-4), 111.9 (C-10), 113.5 (C-3a), 117.4 (C-11), 117.9
(C-3), 119.8 (C-5), 123.0 (C-2), 125.2 (C-7a), 132.0 (C-3a1),
136.7 (C-11a), 145.1 (C-9), 150.4 (C-8); MS (CI): m/z (rel.
intensity)=282 (MH+, 79), 266 (100), 250 (5), 235 (8); HR-
MS (CI): m/z=282.1482, calcd. for C18H20NO2 [MH]+:
282.1494; [a]2D0: À51.67 (c=0.95, CH2Cl2). The enantiomeric
[Chiralcel
OD3,
hexane/isopropyl
alcohol
98:08,
0.8 mLminÀ1, tr (major)=9.33 min (86.09%), tr (minor)=
10.18 min (13.91%)].
(R)-9,10-Methylenedioxy-11b-methyl-7,11b-dihydro-1H-
pyrrolo[3,2,1-de]phenanthridine (2c): Prepared from pyrrole
1c (81 mg, 0.20 mmol), (R)-BINAP (35.9 mg, 0.057 mmol),
PMP (0.07 mL, 0.40 mmol) and Pd(OAc)2 (4.7 mg,
0.02 mmol). The reaction mixture was heated under reflux
for 48 h. After work up, flash column chromatography
(silica gel, hexane/AcOEt 9.5:0.5) afforded 2c as an oil;
yield: 31.7 mg (60%). IR (ATR): n=1482 cmÀ1 (C=C);
1H NMR (300 MHz, CDCl3): d=1.27 (s, 3H, CH3), 2.57–
2.82 (m, 2H, 2”H-1), 4.98 (d, J=15.5 Hz, 1H, H-7a), 5.01
3210
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Adv. Synth. Catal. 2015, 357, 3206 – 3214

FULL PAPERS
Enantioselective Palladium-Catalyzed Heck–Heck Cascade Reactions
excess was determined by HPLC to be 63%, [Chiralcel
OD3, hexane/isopropyl alcohol 98:02, 0.8 mLminÀ1, tr
17 mg (65%). IR (ATR): n=1500 cmÀ1 (C=C); 1H NMR
(300 MHz, CDCl3): d=1.30 (s, 3H, CH3), 2.52–2.93 (m, 2H,
2”H-1), 5.01 (d, J=15.8 Hz, 1H, H-7a), 5.06–5.14 (m, 3H,
H-7b, CH2Ph), 5.57–5.65 (m, 1H, H-2), 6.12 (d, J=2.7 Hz,
1H, H-4), 6.49 (dd, J=9.3, 3.3 Hz, 1H, H-3), 6.61 (d, J=
2.7 Hz, 1H, H-5), 6.86 (d, J=2.7 Hz, 1H, H-8), 6.97 (dd, J=
8.6, 2.7 Hz, 1H, H-10), 7.28–7.53 (m, 6H, H-1, CH2Ph);
13C NMR (75.5 MHz, CDCl3): d=27.2 (CH3), 33.3 (C-11b),
37.4 (C-1), 47.3 (C-7), 70.2 (CH2Ph), 105.3 (C-4), 112.7 (C-
10), 113.6 (C-3a), 114.4 (C-8), 117.0 (C-5), 118.0 (C-2), 123.1
(C-3), 125.8 (C-11), 127.4 (C-2’arom, C-6’arom), 128.0 (C-
4’arom), 128.6 (C-3’, C-5’arom), 132.2 (C-11a), 136.0 (C-3a1),
136.9 (C-7a, C-1’arom), 156.9 (C-9); MS (CI): m/z (rel. in-
tensity)=328 (MH+, 100), 327 (M+, 56), 314 (13), 313 (34),
312 (74), 221 (9); HR-MS (CI): m/z=328.1693, calcd. for
C23H22NO [MH]+: 328.1701; [a]D20: +23.23 (c=0.83, CH2Cl2).
The enantiomeric excess was determined by HPLC to be
69%, [Chiralcel OD3, hexane/isopropyl alcohol 98:02,
0.8 mLminÀ1, tr (major)=19.7 min (84.47%), tr (minor)=
27.6 min (15.53%)].
(R)-9-Benzyloxy-10-methoxy-11b-methyl-7,11b-dihydro-
1H-pyrrolo[3,2,1-de]phenanthridine (2i): Prepared from pyr-
role 1i (93.7 mg, 0.19 mmol), (R)-BINAP (33.6 mg,
0.053 mmol), PMP (0.07 mL, 0.38 mmol) and Pd(OAc)2
(4.3 mg, 0.019 mmol). The reaction mixture was heated
under reflux for 48 h. After work-up, flash column chroma-
tography (silica gel, hexane/AcOEt 8:2) afforded 2i as an
oil; yield: 46 mg (68%). IR (ATR): n=1510 cmÀ1 (C=C);
1H NMR (300 MHz, CDCl3): d=1.29 (s, 3H, CH3), 2.58–
2.89 (m, 2H, 2”H-1), 3.94 (s, 3H, OCH3) 4.90 (d, J=
15.4 Hz, 1H, H-7a), 5.01 (d, J=15.4 Hz, 1H, H-7b), 5.16 (s,
2H, CH2Ph), 5.60 (ddd, J=9.4, 5.9, 2.6 Hz, 1H, H-2), 6.11
(d, J=2.7 Hz, 1H, H-4), 6.50 (dd, J=9.4, 3.1 Hz, 1H, H-3),
6.59 (d, J=2.7 Hz, 1H, H-5), 6.75 (s, 1H, H-11), 7.26–7.56
(m, 6H, H-8, CH2Ph); 13C NMR (75.5 MHz, CDCl3): d=
26.9 (CH3), 33.7 (C-11b), 37.3 (C-1), 46.6 (C-7), 56.2
(OCH3), 71.4 (CH2Ph), 105.2 (C-4), 108.4 (C-11), 112.3 (C-
8), 113.5 (C-3a), 117.0 (C-5), 117.8 (C-3), 121.6 (C-2), 127.3
(C-2’arom, C-6’arom), 127.9 (C-4’arom), 128.5 (C-3’arom, C-
5’arom), 131.9 (C-3a1), 135.3 (C-11a), 136.4 (C-7a), 137.0 (C-
1’arom), 146.4 (C-10), 149.4 (C-9); MS (CI): m/z (rel. inten-
sity)=358 (MH+, 99), 357 (M+, 85), 343 (25), 342 (100), 286
(29), 266 (14), 251 (12); HR-MS (CI): m/z=358.1793, calcd.
for C24H24NO2 [MH]+: 358.1807; [a]2D0: +40.13 (c=0.66,
CH2Cl2). The enantiomeric excess was determined by HPLC
to be 71%, [Chiralcel OD3, hexane/isopropyl alcohol 90:10,
0.8 mLminÀ1, tr (minor)=15.19 min (85.44%), tr (minor)=
17.47 min (14.56%)].
(major)=10.1 min
(81.28%),
tr
(minor)=10.9 min
(18.72%)].
(R)-9,11-Dimethoxy-11b-methyl-7,11b-dihydro-1H-pyrro-
lo[3,2,1-de]phenanthridine (2f): Prepared from pyrrole 1f
(61.7 mg, 0.15 mmol), (R)-BINAP (26.3 mg, 0.042 mmol),
PMP (0.06 mL, 0.30 mmol) and Pd(OAc)2 (3.4 mg,
0.015 mmol). The reaction mixture was heated under reflux
for 48 h. After work-up, flash column chromatography
(silica gel, hexane/AcOEt 9:1) afforded 2e as an oil; yield:
23.3 mg (55%). IR (ATR): n=1457 cmÀ1 (C=C); 1H NMR
(300 MHz, CDCl3): d=1.33 (s, 3H, CH3), 2.43–2.63 (m, 1H,
H-1a), 3.44 (dd, J=17.0, 6.3 Hz, 1H, H-1b), 3.82 (s, 3H,
OCH3), 3.86 (s, 3H, OCH3), 5.05 (s, 2H, 2”H-7), 5.52–5.68
(m, 1H, H-2), 6.12 (d, J=2.6 Hz, 1H, H-4), 6.35 (d, J=
2.4 Hz, 1H, H-10), 6.42–6.54 (m, 2H, H-3, H-5), 6.60 (d, J=
2.4 Hz, 1H, H-8); 13C NMR (75.5 MHz, CDCl3): d=23.3
(CH3), 34.2 (C-11b), 37.0 (C-1), 47.3 (C-7), 55.2 (OCH3),
55.3 (OCH3), 98.4 (C-10), 102.4 (C-4), 105.3 (C-8), 114.0 (C-
3a), 116.5 (C-5), 119.9 (C-2), 122.5 (C-3), 123.4 (C-11a),
132.7 (C-3a1), 135.3 (C-7a), 158.8 (C-11), 159.6 (C-9). MS
(CI): (rel. intensity)=282 (MH+, 73), 281 (M+, 55), 267 (22),
266 (100). HR-MS (CI): m/z=282.1481, calcd. for
C18H20NO2 [MH]+ : 282.1494; found:. [a]2D0: + 7.29 (c=0.87,
CH2Cl2). The enantiomeric excess was determined by HPLC
to be 7%, [Chiralcel OD3, hexane/isopropyl alcohol 90:10,
0.8 mLminÀ1, tr (major)=7.40 min (53.52%), tr (minor)=
8.39 min (46.48%)].
(R)-9,10,11-Trimethoxy-11b-methyl-7,11b-dihydro-1H-pyr-
rolo[3,2,1-de]phenanthridine (2g): Prepared from pyrrole 1g
(66.2 mg, 0.15 mmol), (R)-BINAP (27.9 mg, 0.045 mmol),
PMP (0.06 mL, 0.30 mmol) and Pd(OAc)2 (3.5 mg,
0.015 mmol). The reaction mixture was heated under reflux
for 48 h. After work-up, flash column chromatography
(silica gel, hexane/AcOEt 9:1) afforded 2g as an oil; yield:
6 mg (13%). IR (ATR): n=1451 cmÀ1 (C=C); 1H NMR
(300 MHz, CDCl3): d=1.33 (s, 3H, CH3), 2.61 (dd, J=16.8,
6.3 Hz, 1H, H-1a), 3.38 (dd, J=16.8, 6.3 Hz, 1H, H-1b), 3.87
(s, 6H, 2”OCH3), 3.97 (s, 3H, OCH3), 5.00 (s, 2H, 2”H-7),
5.58 (ddd, J=9.1, 6.2, 2.3 Hz, 1H, H-2), 6.11 (d, J=2.7 Hz,
1H, H-4), 6.46 (dd, J=9.4, 3.0 Hz, 1H, H-3), 6.51 (s, 1H, H-
8), 6.59 (d, J=2.7 Hz, 1H, H-5); 13C NMR (75.5 MHz,
CDCl3): d=24.7 (CH3), 34.8 (C-11b), 37.3 (C-1), 47.1 (C-7),
55.9 (OCH3), 60.6 (OCH3), 60.7 (OCH3), 105.0 (C-4), 105.3
(C-8), 114.0 (C-3a), 116.6 (C-5), 119.5 (C-2), 122.5 (C-11a),
126.8 (C-3), 128.4 (C-3a1), 132.1 (C-7a), 141.9 (C-10), 151.9
(C-11), 153.1 (C-9); MS (CI): m/z (rel. intensity)=312 (88,
MH+), 311 (M+, 66), 310 (9), 297 (23), 296 (100), 281 (6),
280 (7), 265 (6); HR-MS (CI): m/z=312.1590, calcd. for
C19H22NO3 [MH]+: 312.1600; [a]D20: À5.84 (c=0.94, CH2Cl2).
The enantiomeric excess was determined by HPLC to be
30%, [Chiralcel OD3, hexane/isopropyl alcohol 98:02,
0.8 mLminÀ1, tr (minor)=12.5 min (35.20%), tr (major)=
15.6 min (64.80%)].
(R)-9,10-Bis(benzyloxy)-11b-methyl-7,11b-dihydro-1H-
pyrrolo[3,2,1-de]phenanthridine (2j): Prepared from pyrrole
1j (75.5 mg, 0.13 mmol), (R)-BINAP (23.5 mg, 0.037 mmol),
PMP (0.05 mL, 0.26 mmol) and Pd(OAc)2 (3.1 mg,
0.014 mmol). The reaction mixture was heated under reflux
for 48 h. After work-up, flash column chromatography
(silica gel, hexane/AcOEt 9.5:0.5) afforded 2j as an oil;
yield: 27 mg (48%). IR (ATR): n=1510 cmÀ1 (C=C);
1H NMR (300 MHz, CDCl3): d=1.23 (s, 3H, CH3), 2.48–
2.75 (m, 2H, 2”H-1), 4.91 (d, J=15.5 Hz, 1H, H-7a), 5.01
(d, J=15.5 Hz, 1H, H-7b), 5.17 (s, 2H, CH2Ph), 5.20 (s, 2H,
CH2Ph), 5.52–5.63 (m, 1H, H-2), 6.10 (d, J=2.7 Hz, 1H, H-
4), 6.47 (dd, J=9.5, 3.0 Hz, 1H, H-3), 6.58 (d, J=2.7 Hz,
1H, H-5), 6.80 (s, 1H, H-11), 6.93 (s, 1H, H-8), 7.29–7.59
(R)-9-Benzyloxy-11b-methyl-7,11b-dihydro-1H-pyrro-
lo[3,2,1-de]phenanthridine (2h): Prepared from pyrrole 1h
(38.2 mg, 0.08 mmol), (R)-BINAP (14.6 mg, 0.023 mmol),
PMP (0.03 mL, 0.16 mmol) and Pd(OAc)2 (2.0 mg,
0.009 mmol). The reaction mixture was heated under reflux
for 48 h. After work-up, flash column chromatography
(silica gel, hexane/AcOEt 9:1) afforded 2h as an oil; yield:
Adv. Synth. Catal. 2015, 357, 3206 – 3214
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3211

FULL PAPERS
Estibaliz Coya et al.
(m, 10H, 2”CH2Ph); 13C NMR (75.5 MHz, CDCl3): d=26.9
(CH3), 33.7 (C-11b), 37.3 (C-1), 46.7 (C-7), 77.6 (CH2Ph),
77.8 (CH2Ph), 105.2 (C-4), 112.3 (C-11), 113.2 (C-8), 113.5
(C-3a), 117.1 (C-5), 117.9 (C-2), 123.1 (C-3), 124.0 (C-11a),
127.3 (C-2’arom, C-6’arom), 127.5 (C-2’’arom, C-6’’arom),
127.9 (C-4’arom, C-4’’arom), 128.4 (C-3’arom, C-5’arom),
128.5 (C-3’’arom, C-5’’arom), 132.1 (C-3a1), 136.6 (C-7a),
137.2 (C-1’arom, C-1’’arom), 147.3 (C-9), 148.5 (C-10); MS
(CI): m/z (rel. intensity)=434 (MH+, 100), 433 (M+, 55),
419 (23), 418 (74), 343 (9), 342 (6), 327 (6), 208 (9); HR-MS
(CI): m/z=434.2109, calcd. for C30H28NO2 [MH]+: 434.2120;
[a]2D0: +17.39 (c=1.01, CH2Cl2). The enantiomeric excess
was determined by HPLC to be 66%, [Chiralcel OD3,
hexane/isopropyl alcohol 90:10, 0.8 mLminÀ1, tr (major)=
14.93 min (82.80%), tr (minor)=21.70 min (17.20%)].
(R)-10-Methoxy-11b-methyl-9-[(3-nitrobenzyl)oxy]-7,11b-
dihydro-1H-pyrrolo[3,2,1-de]phenanthridine (2k): Prepared
from pyrrole 1k (45.5 mg, 0.08 mmol), (R)-BINAP (14.9 mg,
0.024 mmol), PMP (0.03 mL, 0.17 mmol) and Pd(OAc)2
(2.0 mg, 0.009 mmol). The reaction mixture was heated
under reflux for 48 h. After work-up, flash column chroma-
tography (silica gel, hexane/AcOEt 9.5:0.5) afforded 2k as
an oil; yield: 19 mg (56%). IR (ATR): n=1530 cmÀ1 (C=C);
1H NMR (300 MHz, CDCl3): d=1.28 (s, 3H, CH3), 2.58–
2.91 (m, 2H, 2”H-1), 3.95 (s, 3H, OCH3), 4.91 (d, J=
15.5 Hz, 1H, H-7a), 5.02 (d, J=15.5 Hz, 1H, H-7b), 5.22 (s,
2H, CH2Ph), 5.55–5.63 (m, 1H, H-2), 6.10 (d, J=2.7 Hz,
1H, H-4), 6.48 (dd, J=9.4, 3.1 Hz, 1H, H-3), 6.59 (d, J=
2.7 Hz, 1H, H-5), 6.75 (s, 1H, H-11), 6.91 (s, 1H, H-8), 7.56–
7.75 (m, 1H, H-5’arom), 7.75–7.82 (m, 1H, H-6’arom), 8.18
(dd, J=8.4, 2.3 Hz, 1H, H4’arom), 8.36 (broad s, 1H, H-
2’arom); 13C NMR (75.5 MHz, CDCl3): d=26.9 (CH3), 33.7
(C-11b), 37.3 (C-1), 46.6 (C-7), 56.2 (OCH3), 70.5 (CH2Ph),
105.3 (C-4), 108.4 (C-11), 113.0 (C-8), 113.6 (C-3a), 117.1
(C-3), 117.8 (C-5), 122.2 (C-4’arom), 122.9 (C-2’arom), 123.1
(C-2), 123.1 (C-5’arom), 129.6 (C-6’arom), 131.8 (C-11a),
133.1 (C-3a1), 137.5 (C-7a), 139.3 (C-1’arom), 145.7 (C-10),
148.5 (C-3’arom), 149.6 (C-9); MS (CI): m/z (rel. intensi-
ty)=403 (MH+, 100), 402 (M+, 27),387 (40), 373 (27), 372
(18), 357 (12) 251 (18), 250 (11); HR-MS (CI): m/z=
403.1641, calcd. for C24H23N2O4 [MH]+: 403.1658; [a]D20:
+49.6 (c=0.83, CH2Cl2). The enantiomeric excess was de-
termined by HPLC to be 61%, [Chiralcel OD3, hexane/iso-
propyl alcohol 90:10, 0.8 mLminÀ1, tr (major)=26.4 min
(80.30%), tr (minor)=29.7 min (19.70%)].
46.6 (C-7), 55.2 (OCH3), 56.2 (OCH3), 71.2 (CH2Ph), 105.3
(C-4), 108.4 (C-11), 112.3 (C-4’arom), 112.7 (C-2’arom),
113.4 (C-8), 113.5 (C-3a), 117.0 (C-6’arom), 117.8 (C-3),
119.4 (C-5), 123.0 (C-3a1), 123.1 (C-5’arom), 129.6 (C-2),
131.9 (C-7a), 136.5 (C-1’arom), 138.7 (C-11a), 146.4 (C-10),
149.4 (C-9), 159.9 (C-3’arom); MS (CI): m/z (rel. intensi-
ty)=388 (MH+, 100), 387 (M+, 60), 373 (19), 372 (63), 267
(6), 251 (9); HR-MS (CI): m/z=388.1920, calcd. for
C25H26NO3 [MH]+: 388.1913; [a]D20: +65.2 (c=1.14, CH2Cl2).
The enantiomeric excess was determined by HPLC to be
61%, [Chiralcel OD3, hexane/isopropyl alcohol 90:10,
0.8 mLminÀ1, tr (major)=21.2 min (80.64%), tr (minor)=
23.9 min (19.36%)].
(R)-11b-Methyl-9-nitro-7,11b-dihydro-1H-pyrrolo[3,2,1-
de]phenanthridine (2m): Prepared from pyrrole 1m
(65.3 mg, 0.16 mmol), (R)-BINAP (28.9 mg, 0.046 mmol),
PMP (0.06 mL, 0.32 mmol) and Pd(OAc)2 (3.8 mg,
0.016 mmol). The reaction mixture was heated under reflux
for 48 h. Then, Pd(OAc)2 (7.6 mg, 0.034 mmol) and (R)-
BINAP (57.8 mg, 0.093 mmol) were added and heated to
reflux for another 24 h. After work-up, flash column chro-
matography (silica gel, hexane/AcOEt 9:1) afforded 2m as
an oil; yield: 2.4 mg (<10%). IR (ATR): n=1522 (N=O),
1
1343 (NO2) cmÀ1; H NMR (300 MHz, CDCl3): d=1.32 (s,
3H, CH3), 2.61–2.96 (m, 2H, 2”H-1), 5.19 (s, 2H, 2 ” H-7),
5.61 (ddd, J=9.4, 5.9, 2.4 Hz, 1H, H-2), 6.14 (d, J=2.7 Hz,
1H, H-4), 6.50 (dd, J=9.4, 3.2 Hz, 1H, H-3), 6.66 (d, J=
2.7 Hz, 1H, H-5), 7.56 (d, J=8.6 Hz, 1H, H-11), 8.15 (dd,
J=2.4 Hz, 1H, H-8), 8.21 (m, J=8.6, 2.4 Hz, 1H, H-10);
13C NMR (75.5 MHz, CDCl3): d=26.9 (CH3), 34.7 (C-11b),
36.9 (C-1), 46.9 (C-7), 106.1 (C-4), 114.3 (C-3a), 117.5 (C-10,
C-3), 121.7 (C-5), 123.1 (C-8), 123.2 (C-11), 125.9 (C-2),
130.2 (C-3a1), 132.6(C-7a), 146.0 (C-9), 150.9 (C-11a); MS
(CI): m/z (rel. intensity)=267 (MH+, 36), 266 (M+, 8), 265
(14), 251 (14), 238 (19), 237 (100), 236 (53), 222 (17), 221
(78); HR-MS (CI): m/z=267.1134, calcd. for C16H15N2O2
[MH]+: 267.1134; The enantiomeric excess was determined
by HPLC to be 28%, [Chiralcel OD3, hexane/isopropyl al-
cohol 98:02, 0.8 mLminÀ1, tr (major)=23.18 min (63.95%), tr
(minor)=34.64 min (36.05%)].
(R)-9-Fluoro-11b-methyl-7,11b-dihydro-1H-pyrrolo[3,2,1-
de]phenanthridine (2n): Prepared from pyrrole 1n (41.6 mg,
0.11 mmol), (R)-BINAP (19.7 mg, 0.031 mmol), PMP
(0.04 mL, 0.22 mmol) and Pd(OAc)2 (2.6 mg, 0.011 mmol).
The reaction mixture was heated under reflux for 48 h.
After work-up, flash column chromatography (silica gel,
hexane/AcOEt 9.5:0.5) afforded 2n as an oil; yield: 13.3 mg
(50%). IR (ATR): n=1490 cmÀ1 (C=C); 1H NMR
(300 MHz, CDCl3):d=1.28 (s, 3H, CH3), 2.91–2.60 (m, 2H,
H-1), 5.03 (d, J=15.5 Hz, 1H, H-7a), 5.11 (d, J=15.5 Hz,
1H, H-7b), 5.69–5.55 (m, 1H, H-2), 6.12 (d, J=2.6 Hz, 1H,
H-4), 6.49 (dd, J=9.4, 3.2 Hz, 1H, H-3), 6.62 (d, J=2.6 Hz,
(R)-10-Methoxy-9-[(3-methoxybenzyl)oxy]-11b-methyl-
7,11b-dihydro-1H-pyrrolo[3,2,1-de]phenanthridine (2l): Pre-
pared from pyrrole 1l (44.9 mg, 0.09 mmol), (R)-BINAP
(15.2 mg, 0.024 mmol), PMP (0.03 mL, 0.18 mmol) and
Pd(OAc)2 (2.0 mg, 0.009 mmol). The reaction mixture was
heated under reflux for 48 h. After work-up, flash column
chromatography (silica gel, hexane/AcOEt 9:1) afforded 2l
as an oil; yield: 23 mg (72%). IR (ATR): n=1511 cmÀ1 (C= 1H, H-5), 6.94 (dd, J=9.2, 2.7 Hz, 1H, H-8), 7.04 (td, J=
C); 1H NMR (300 MHz, CDCl3): d=1.29 (s, 3H, CH3),
2.56–2.91 (m, 2H, 2”H-1), 3.82 (s, 3H, OCH3), 3.92 (s, 3H,
OCH3), 4.89 (d, J=15.4 Hz, 1H, H-7a), 5.01 (d, J=15.4 Hz,
1H, H-7b), 5.14 (s, 2H, CH2Ph), 5.52–5.62 (m, 1H, H-2),
6.10 (d, J=2.7 Hz, 1H, H-4), 6.49 (dd, J=9.4, 3.1 Hz, 1H,
H-3), 6.58 (d, J=2.7 Hz, 1H, H-5), 6.74 (s, 1H, H-11), 6.84–
6.93 (m, 2H, H-8, H-4’arom), 6.98–7.09 (m, 2H, H-2’arom,
H-6’arom), 7.30 (t, J=8.1 Hz, 1H, H-5’arom); 13C NMR
(75.5 MHz, CDCl3): d=26.9 (CH3), 33.7 (C-11b), 37.3 (C-1),
8.5, 2.7 Hz, 1H, H-10), 7.35 (dd, J=8.5, 5.6 Hz, 1H, H-11);
13C NMR (75.5 MHz, CDCl3): d=27.1 (CH3), 33.7 (C-11b),
37.4 (C-1), 46.9 (C-7), 105.6 (C-4), 113.06 (d, J=21.8 Hz, C-
10), 113.8 (C-3a), 114.9 (d, J=21.2 Hz, C-8), 117.1 (C-3),
117.9 (C-5), 123.0 (C-2), 126.4 (d, J=8.3 Hz, C-11), 131.7
(C-11a), 132.9 (d, J=7.1 Hz, C-7a), 139.3 (C-3a1), 160.7 (d,
J=274.5 Hz, C-9); 19F NMR (282.2 MHz, CDCl3): d=
À116.7; MS (CI): m/z (rel. intensity)=240 (MH+, 100), 239
(M+, 67), 225 (13), 224 (55), 220 (17); HR-MS (CI): m/z=
3212
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Enantioselective Palladium-Catalyzed Heck–Heck Cascade Reactions
240.1182, calcd. for C16H15FN [MH]+: 240.1189; [a]D20: +37.2
(c=0.50, CH2Cl2). The enantiomeric excess was determined
by HPLC to be 64%, [Chiralcel OD3, hexane/isopropyl al-
cohol 98:02, 0.8 mLminÀ1, tr (major)=8.00 min (81.76%), tr
(minor)=9.46 min (18.24%)].
through a Celite pad and concentrated. The oil crude was
purified by flash column chromatography (silica gel, hexane/
AcOEt 8:2) to give 3 as an oil; yield: 34 mg (55%). IR
1
(ATR): n=1511 cmÀ1 (C=C); H NMR (300 MHz, CDCl3):
d=1.41 (s, 3H, CH3), 1.77–1.92 (m, 1H, H-1a), 2.05–2.20
(m, 2H, 2 ” H-2), 2.32–2.41 (m, 1H, H-1b), 2.44–2.58 (m,
1H, H-3a), 2.66–2.74 (m, 1H, H-3b), 3.90 (s, 3H, OCH3),
3.94 (s, 3H, OCH3), 4.91 (d, J=15.0 Hz, 1H, H-7a), 5.08 (d,
J=15.0 Hz, 1H, H-7b), 5.99 (d, J=2.4 Hz, 1H, H-4), 6.68
(d, J=2.5 Hz, 1H, H-5), 6.76 (s, 1H, H-8), 6.94 (s, 1H, H-
11); 13C NMR (75.5 MHz, CDCl3): d=20.5 (C-2), 22.4 (C-3),
28.8 (CH3), 34.9 (C-1), 35.1 (C-11b), 47.4 (C-7), 56.1 (2”
OCH3), 106.3 (C-4), 107.4 (C-11), 109.8 (C-8), 113.6 (C-3a),
117.7 (C-5), 125.3 (C-7a), 131.7 (C-3a1), 137.8 (C-11a), 146.8
(C-9), 148.4 (C-10); MS (CI): m/z (rel. intensity)=284
(MH+, 100), 283 (M+, 59), 282 (23), 269 (27), 268 (96); HR-
MS (CI): m/z=284.1631, calcd. for C18H22NO2 [MH]+:
284.1651; [a]2D0: À55.73 (c=1.14, CH2Cl2). The enantiomeric
excess was determined by HPLC to be 60% [Chiralcel OD3,
98% hexane/isopropyl alcohol, 0.8 mLminÀ1, tr (minor)=
22.1 min (20%), tr (major)=24.8 min (80%)].
(S)-13b-Methyl-7,13b-dihydro-1H-benzo[b]indolo[1,7-gh]
[1,6]naphthyridine (2o): Prepared from pyrrole 1o (53.1 mg,
0.15 mmol), (R)-BINAP (39.4 mg, 0.063 mmol), PMP
(0.06 mL, 0.30 mmol) and Pd(OAc)2 (5.2 mg, 0.023 mmol).
The reaction mixture was heated under reflux for 6 days.
After work-up, flash column chromatography (silica gel,
hexane/AcOEt 9:1) afforded 2o as an oil; yield: 4.4 mg
(11%). IR (ATR): n=1460 cmÀ1 (C=C); 1H NMR
(300 MHz, CDCl3): d=1.42 (s, 3H, CH3), 2.88–3.20 (m, 2H,
2”H-1), 5.25 (d, J=15.7 Hz, 1H, H-7a), 5.35 (d, J=15.7 Hz,
1H, H-7b), 5.68–5.73 (m, 1H, H-2), 6.14 (d, J=2.7 Hz, 1H,
H-4), 6.48 (dd, J=9.5, 3.4 Hz, 1H, H-3), 6.67 (d, J=2.7 Hz,
1H, H5), 7.49–7.56 (m, 1H, H-10), 7.67–7.75 (m, 1H, H-11),
7.79 (d, J=8.1H, 1H, H-12), 8.00 (s, 1H, H-8), 8.11 (d, J=
8.1 Hz, 1H, H-9); 13C NMR (75.5 MHz, CDCl3): d=25.4
(CH3), 35.9 (C-13b), 37.4 (C-1), 47.0 (C-7), 105.8 (C-4),
114.7 (C-3a), 117.1 (C-3), 119.1 (C-5), 122.2 (C-10), 124.1
(C-8a), 126.3 (C-9), 127.2 (C-12), 129.1 (C-11), 129.2 (C-
3a1), 129.3 (C-8), 131.8 (C-7a), 133.2 (C-2), 147.6 (C12a),
162.1 (C13a); MS (CI): m/z (rel. intensity)=273 (MH+,
100), 272 (M+, 33), 258 (32), 257 (93); HR-MS (CI): m/z=
273.1374, calcd. for C19H17N2 [MH]+: 273.1392; The enantio-
meric excess was determined by HPLC to be 99%, [Chiral-
cel OD3, hexane/isopropyl alcohol 98:02, 0.8 mLminÀ1, tr
Acknowledgements
The Ministerio de Economía y Competitividad (CTQ2013-
41229-P), Gobierno Vasco (IT-623-13) and Universidad del
País Vasco/Euskal Herriko Unibertsitatea UPV/EHU
(UFI11/22, PPM12/03) are gratefully acknowledged for their
financial support. We also thank Gobierno Vasco for a grant
(E.C.). Technical and human support provided by Servicios
Generales de Investigación SGIker (UPV/EHU, MINECO,
GV/EJ, ERDF and ESF) is also acknowledged.
(major)=9.51 min
(99.37%),
tr
(minor)=11.90 min
(0.63%)].
The reaction was repeated under the same conditions, but
using (S)-BINAP a ligand, obtaining (R)-2o; [a]2D0: À338 (c=
0.79, CH2Cl2) The enantiomeric excess was determined by
HPLC to be 99%, [Chiralcel OD3, hexane/isopropyl alcohol
98:02, 0.8 mLminÀ1, tr (major)=9.56 min (0.44%), tr
(minor)=11.85 min (99.56%)].
(S)-10b-Methyl-7,10b-dihydro-1H-pyrrolo[3,2,1-ij]thie-
no[3,2-c]quinoline (2p): Prepared from pyrrole 1o (32.8 mg,
0.09 mmol), (R)-BINAP (16.1 mg, 0.026 mmol), PMP
(0.03 mL, 0.18 mmol) and Pd(OAc)2 (2.1 mg, 0.009 mmol).
The reaction mixture was heated under reflux for 48 h.
After work-up, flash column chromatography (silica gel,
hexane/AcOEt 9.5:0.5) afforded 2p as an oil; yield: 9.4 mg
(46%). This compound could not be completely character-
ized because it decomposed. 1H NMR (300 MHz, CDCl3):
d=1.39 (s, 3H, CH3), 2.53–2.73 (m, 2H, 2”H-1), 5.02 (d,
J=15.7 Hz, 1H, H-7a), 5.10 (d, J=15.7 Hz, 1H, H-7b),
5.58–5.63 (m, 1H, H-2), 6.13 (d, J=2.7 Hz, 1H, H-4), 6.45–
6.54 (m, 1H, H-3), 6.63 (d, J=2.7 Hz, 1H, H-5), 6.88 (d, J=
5.1 Hz, 1H, H-8), 7.22 (d, J=5.1 Hz, 1H, H-9); MS (CI): m/
z (rel. intensity)=228 (MH+, 100), 227 (M+, 50), 226 (6),
213 (7), 212 (23); HR-MS (CI): m/z=228.0841, calcd. for
C14H14NS [MH]+: 228.0847; The enantiomeric excess was de-
termined by HPLC to be 66%, [Chiralcel OD3, hexane/iso-
propyl alcohol 99.5:0.5, 0.3 mLminÀ1, tr (minor)=16.08 min
(16.96%), tr (major)=19.58 min (83.04%)].
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asc.wiley-vch.de
3213

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3214
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Adv. Synth. Catal. 2015, 357, 3206 – 3214