Enamides and enesulfonamides as nucleophiles: Formation of complex ring systems through a platinum(II)-catalyzed addition/Friedel-Crafts pathway

Article abstract of DOI:10.1021/jo901512m

(Chemical Equation Presented) Cyclic enamine derivatives (enesulfonamides and enamides) tethered to an 1-arylalkynyl fragment undergo a platinum(II)-catalyzed tandem alkyne addition/Friedel-Crafts ring closure to formnitrogen-containing polycyclic structures.Regioselectivity in the initial addition of the enesulfonamide or enamide nucleophile to the platinum(II)-alkyne complex is important. Electron-rich arenes and heterocycles led to the formation of products resulting from an initial 6-endo cyclization. Twenty-three examples of this process are presented.

Full text of DOI:10.1021/jo901512m

pubs.acs.org/joc
Enamides and Enesulfonamides as Nucleophiles: Formation of Complex
Ring Systems through a Platinum(II)-Catalyzed Addition/
Friedel-Crafts Pathway
Jennifer A. Kozak, Jennifer M. Dodd, Tyler J. Harrison, Katherine J. Jardine,
Brian O. Patrick,† and Gregory R. Dake*
Department of Chemistry, 2036 Main Mall, University of British Columbia, Vancouver, BC,
Canada V6T 1Z1. Manager, University of British Columbia X-ray Analysis Facility. Inquiries regarding the
analysis of the X-ray crystallography should be directed to Dr. Patrick.
†
gdake@chem.ubc.ca
Received July 14, 2009
Cyclic enamine derivatives (enesulfonamides and enamides) tethered to an 1-arylalkynyl fragment undergo
a platinum(II)-catalyzed tandem alkyne addition/Friedel-Crafts ring closure to form nitrogen-containing
polycyclic structures. Regioselectivity in the initial addition of the enesulfonamide or enamide nucleophile to
the platinum(II)-alkyne complex is important. Electron-rich arenes and heterocycles led to the formation
of products resulting from an initial 6-endo cyclization. Twenty-three examples of this process are presented.
Introduction
that utilize the π-nucleophilicity of enamine derivatives.5
The enamine nitrogen in most instances is derivatized using
an electron-withdrawing group such as an amide (forming
an N-acylenamine or enamide), carbamate (N-carbamoylena-
mine or enecarbamate), or sulfonyl group (N-sulfonylenamine
or enesulfonamide) to improve stability and enable isolation
and purification (Figure 1).6 These enamide, enecarbamate,
or enesulfonamide functional groups have most been used
most often as precursors to electrophilic reactive species such as
N-acylazacarbenium ions.7 The latent nucleophilic behavior
The complexity and diversity of nitrogen-containing ring
systems within alkaloids make them inspiring targets for the
synthetic organic chemistry community.1 Alkaloids often
have significant interest for chemical biology studies as well.2
Indeed, the biological potency of nitrogen-containing mole-
cules is a main interest of the pharmaceutical industry.3
Consequently, the development of methods to generate ring
systems that contain nitrogen for applications to either
natural product synthesis or non-natural compound con-
struction is a useful aim.4
(5) (a) Harrison, T. J.; Dake, G. R. Org. Lett. 2004, 6, 5023–5026.
(b) Harrison, T. J.; Patrick, B. O.; Dake, G. R. Org. Lett. 2007, 9, 367–370.
(c) Kozak, J. A.; Dake, G. R. Angew. Chem., Int. Ed. 2008, 47, 4221–4223.
(6) For a review of the chemistry of enamides and related derivatives:
Carbery, D. R. Org. Biomol. Chem. 2008, 6, 3455–3460.
As part of our research direction involved in this topic, we
have been interested in developing metal-catalyzed reactions
(1) (a) Kobayashi, J.; Kubota, T. Nat. Prod. Rep. 2009, 26, 936–962.
(b) Hirasawa, Y.; Kobayashi, J.; Morita, H. Heterocycles 2009, 77, 679–729.
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Prod. Rep. 2004, 21, 752–772. (e) O’Hagan, D. Nat. Prod. Rep. 2000, 5, 435–446.
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Quinn-Beattie, M. L.; Farnsworth, N. R. Phytother. Res. 2001, 15, 183–205.
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2007, 63, 5341–5378. (c) Naito, T. Chem. Pharm. Bull. 2008, 56, 1367–1383.
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Batey, R. A. Tetrahedron 2005, 61, 1221–1244. (b) Padwa, A.; Lee, H. I.;
Rashatasakhon, P.; Rose, M. J. Org. Chem. 2004, 69, 8209–8218. (c) David,
M.; Dhimane, H.; Vanucci-Bacque, C.; Lhommet, G. Heterocycles 2001, 55,
941–949. (d) Leroy, C.; Dupas, G.; Bourguigon, J.; Queguiner, G. Tetra-
hedron 1994, 50, 13135–13144. (e) Flynn, G. A.; Giroux, E. L.; Dage, R. C.
J. Am. Chem. Soc. 1987, 109, 7914–7915. (f) Cassayre, J.; Quiclet-Sire, B.;
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J. Y.; Lee, Y. S.; Chung, B. Y.; Park, H. Tetrahedron 1997, 53, 2449–2458.
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992. (i) Hurley, P. B.; Dake, G. R. J. Org. Chem. 2008, 73, 4131–4138.
(j) Dake, G. R.; Fenster, M. D. B.; Hurley, P. B. J. Org. Chem. 2004, 69,
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DOI: 10.1021/jo901512m
r
Published on Web 08/18/2009
J. Org. Chem. 2009, 74, 6929–6935 6929
2009 American Chemical Society

Kozak et al.
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SCHEME 1. Spiroannulations at the β-Carbon of Enesulfona-
mides
FIGURE 1. Enamine derivatives.
of these enamine derivatives also has been recognized and used,
especially within the past decade.8 The use of these compounds
as π-nucleophiles within reactions activated by metal catalysis
has been studied to a much lesser extent.5,9-11
We have been interested in developing reactions that
utilize the latent nucleophilicity of these enamine deriva-
tives within the context of “electrophilic” metal-catalyzed
processes, specifically those that involve platinum(II), gold-
(I), or silver(I) salts.12 An example of such a process is a
spiroannulation forming quaternary carbon centers at the
3-position of enamine derivatives (Scheme 1, path a).5b
Interestingly, modification of the substrate structure by
the addition of a phenyl ring to the alkyne terminus led to
an alternative reactivity profile. In this instance, both the
latent nucleophilic and electrophilic character of the
SCHEME 2. Formation of Regioisomeric Products
(8) (a) Shono, T.; Matsumura, Y.; Tsubata, K.; Sugihara, S.; Yamane,
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391–396. (c) Angle, S. R.; Frutos, R. P. J. Chem. Soc., Chem. Commun.
1993, 171–173. (d) de Faria, A. R.; Salvador, E. L.; Correia, C. R. D. J. Org.
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B. T. J. Org. Chem. 2004, 69, 1704–1715. (f) Cossey, K. N.; Funk, R. L.
J. Am. Chem. Soc. 2004, 126, 12216–12217. (g) Suga, S.; Nishida, T.;
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Kobayashi, S. Angew. Chem., Int. Ed. 2004, 43, 1679–1681. (e) Kiyohara, H.;
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(10) For examples of reactions of enamides and their structural relatives
in metal-catalyzed reactions where the double bond does not behave formally
as a nucleophile, see: (a) Wu, X. Y.; Nilsson, P.; Larhed, M. J. Org. Chem.
2005, 70, 346–349. (b) Andappan, M. M. S.; Nilsson, P.; von Schenck, H.;
Larhed, M. J. Org. Chem. 2004, 69, 5212–5218. (c) Mo, J.; Xu, L.; Xiao, J. J.
Am. Chem. Soc. 2005, 127, 751–760. (d) Bennasar, M. L.; Roca, T.; Monerris,
M.; Garcia-Diaz, D. J. Org. Chem. 2006, 71, 7028–7034. (e) Toumi, M.;
Couty, F.; Evano, G. Angew. Chem., Int. Ed. 2007, 46, 572–575. (f) Toumi,
M.; Couty, F.; Evano, G. J. Org. Chem. 2008, 73, 1270–1281. (g) Katz, J. D.;
enesulfonamide was observed (Scheme 1, path b). Pre-
sumably, an interaction between the 1-aryl-substituted
alkyne in 2 with the Pt(II) salt led to a tandem addition of
the enesulfonamide to the (putative) metal-alkyne com-
plex followed by a Friedel-Crafts/Pictet-Spengler-type
ring closure to generate tetracycle 3N5b as the major pro-
duct within a roughly 4:1 mixture of constitutional isomers.
As indicated in the text above, two products were
observed in the reaction of 2 with platinum(II) chloride.
These compounds arose from differing regiochemical
modes of addition of the enesulfonamide to the alkyne
within 2 (Scheme 2). Formation of an intermediary plati-
num-alkyne π-complex a activates the alkyne for addition
by the nucleophilic enesulfonamide. Addition of the nu-
cleophile to the alkyne complex could occur in a 5-exo
fashion to form intermediate b. Alternatively, addition
could take place through a 6-endo manifold to produce
intermediate c. Each of these intermediates could then
undergo a Friedel-Crafts (Pictet-Spengler)-type ring
€
Overman, L, E. Tetrahedron 2004, 60, 9559–9568. (h) Lindstrom, S.;
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(11) For examples of combining enamine catalysis (used as a nucleophile)
and cationic gold(I) catalysis, see: Binder, J. T.; Crone, B.; Haug, T. T.;
Menz, H.; Kirsch, S. F. Org. Lett. 2008, 10, 1025-1028.
€
(12) For reviews surveying the reactions of platinum salts, see: (a) Furstner,
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A. R.; Lee, S. J.; Gagne, M. R. Angew. Chem., Int. Ed. 2007, 46, 4042–59.
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(13) The suffixes “N” and “X” used in the numbering system in this paper
are derived as follows: products that are formed through an initial 6-endo
addition of the enamine derivative to the alkyne complex are given the suffix
“N”, while products that derive from an initial 5-exo cyclization are given the
suffix “X”.
ꢀ
~
Jimenez-Nꢀunez, E.; Echavarren, A. M. Chem.;Eur. J. 2006, 12, 5916–5923.
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FIGURE 2. Substrates used in this study.
closure and proto-demetalation to generate the observed
products 3X or 3N, respectively.13,14
arene or heteroaromatic systems installed as the 1-alkynyl
substituent were examined. It is important to note that
during the course of these investigations, Zhai and co-work-
ers used our reported platinum(II)-catalyzed cyclization as
the basis to build a molecule that incorporated the tetracyclic
ring system within nakadomarin. The cyclization substrate
in that case featured a five-membered enecarbamate tethered
via a sulfonamide linker to a 3-alkynylfuran.15 Our studies of
this platinum(II)-catalyzed cyclization chemistry are pre-
sented in this report.
On the basis of Scheme 2, it was reasonable to predict that
manipulation of the electronic properties of the alkyne, and
therefore the electronics of an intermediary alkyne-platinum
π-complex, could affect the regioselectivity of this platinum(II)-
catalyzed cyclization reaction. For example, an electron-donat-
ing substituent on the arene ring could add electron density
through resonance to one of the carbons of the alkyne, render-
ing that alkyne carbon less electrophilic. To that end, it was
demonstrated that substituents at the 4-position of the aryl ring
attached to the alkyne could be modified in order to adjust the
ratio of products in this process (eq 1). An electron-donating
substituent (R = OMe) within 4 favored the formation of
isomer 6N in a 19:1 ratio. An electron-withdrawing substituent
(R=CF3) in 5 altered the ratio roughly 5-fold in the opposite
direction relative to the standard (R=H) process, generating
7N and 7X as a 1:1 mixture of constitutional isomers.
Results and Discussion
Substrate Preparation. The structures of the substrates used
in this study are shown in Figure 2. In our experience, six-
membered enamine derivatives display a reasonable balance
between synthetic accessibility, stability, and reactivity com-
pared to those enamine derivatives within five- or seven-mem-
bered rings. As the most regioselective reaction in our previous
study had an arene ring with a p-methoxy (electron-donating)
group, we determined to largely study substrates having elec-
tron-rich arene or heterocyclic ring systems. A generalized
synthesis of these substrates is shown in Scheme 3. The methods
are patterned from those previously reported by our group.5b
The key step in the substrate construction was a Sonogashira
coupling process that was used to form the C-C bond between
the alkyne and arene ring.16 The full details of the synthesis of
each substrate are presented in the Supporting Information.17
Cyclization Experiments. It is important to note that the
products of these cyclization experiments are inseparable.
The product ratios were determined by inspection of the 1H
NMR spectrum of unpurified reaction mixtures. The char-
acteristic data for a typical NMR analysis are presented in
Figure 3. In this example, the diagnostic signals for the
product mixtures 3X/3N and 6X/6N are the signals due to
alkenyl protons HN1 or HX1 and the benzylic protons HN2 or
HX2. The structures of 3X/3N were established using X-ray
crystallography.18 The products resulting from an initial
The relatively high regioselectivity within the reaction of
4 with platinum(II) chloride encouraged us to more fully
explore this transformation. Specifically, other electron-rich
(14) For other examples of “coinage-metal”-catalyzed reactions that are
sequenced with a Friedel-Crafts reaction, see: (a) Nieto-Oberhuber, C.;
ꢀ
Lopez, S.; Echavarren, A. M. J. Am. Chem. Soc. 2005, 127, 6178–6179. (b)
Nieto-Oberhuber, C.; Perez-Galan, P.; Herrero-Gomez, E.; Lauterbach, T.;
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guez, C.; Lopez, S.; Bour, C.; Rosellon, A.; Cardenas, D. J.; Echavar-
ren, A. M. J. Am. Chem. Soc. 2008, 130, 269–279. (c) Toullec, P. Y.; Genin,
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(15) Deng, H.; Yang, X.; Tong, Z.; Li, Z.; Zhai, H. Org. Lett. 2008, 10,
1791–1793.
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(16) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874–922.
(17) References that are cited in the Supporting Information: (a) Li, M.;
^
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Chem.;Eur. J. 2001, 7, 4378–4385.
P.; Michelet, V. Adv. Synth. Catal. 2008, 350, 2401–2408. (e) Leseurre, L.;
^
Chao, C.-M.; Seki, T.; Genin, E.; Toullec, P. Y.; Genet, J.-P.; Michelet, V.
Tetrahedron 2009, 65, 1911–1918. (f) Odabachian, Y.; Gagosz, F. Adv. Synth.
Catal. 2009, 351, 379–386. (g) Gourdet, B.; Lam, H. W. J. Am. Chem. Soc.
2009, 131, 3802–3803. (h) For an early example, see: Snider, B. B.; Kwon, T.
J. Org. Chem. 1992, 57, 2399–2410.
(18) Please see the Supporting Information for details regarding the
X-ray structure. Compound sets 3N/3X and 36N/36X contain both
isomers in the unit cell. Atoms within the minor isomer are displayed in
the CIF.
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SCHEME 3. Substrate Preparation
FIGURE 3. Diagnostic signals in sample 1H NMR analysis of 3N/
3X and 6N/6X.
electivity of the addition reaction.20 Its use did not result in
any useful trends; generally, the cyclizations were less regio-
selective for the 6-endo cyclization isomer (entries 10, 17, and
21). Substrates having electron-donating p-methoxy groups
typically reacted to favor the 6-endo isomer in a synthetically
useful ratio (entries 11, 16, and 17). Alternative catalyst
systems were briefly examined in the cyclizations of 12.
Gold(I) systems ranged from inactive to overly destructive
(entries 12-14). The addition of S-Phos to a platinum(II)-
based catalyst system substantially decreased the reactivity
(entry 15).21 Lastly, electron-withdrawing substituents on
the arene ring such as -Br, -OTs, or -CF3 groups lowered
the reactivity of the substrates and decreased the regioselec-
tivity of the process (entries 18-21). The structure of the
product of 5-exo cyclization from the reaction of 16 under
these conditions was supported using X-ray crystallography.
As expected, the aryl bromide substituent within
14 was compatible with the reaction conditions involving
Pt(II), highlighting the orthogonal nature between Pt(II)-
and Pd(0)-based catalytic cycles (entry 18).
The results from Table 1 indicated that the reaction
proceeded most effectively with substrates that were ap-
pended to electron-rich aromatic rings. A set of substrates
derived from veratrole (1,2-dimethoxybenzene) were conse-
quently examined (Scheme 4). Enesulfonamide 17 reacted
with platinum chloride to produce 37N/37X in a 20:1 ratio, as
established by NMR spectroscopy, in a 61% yield (entry 1).
Although in principle two sites are available for the second
step of this process involving electrophilic aromatic substitu-
tion, the more sterically hindered potential product was not
observed. Generally, the reactions of enamides are higher
yielding. The reaction of enamide 18 proceeded in 98% yield
using platinum chloride as a 10:1 mixture of products
(entry 2). Enamide 39N, the product of the reaction of
19 with platinum(II), was also characterized using X-ray
crystallography. As observed previously, the utilization of
platinum bromide (10 mol %) to catalyze the reaction of 19
offered little practical advantage (entry 4).
6-endo cyclization (e.g., 3N and 6N, in these examples) had a
triplet between δ 5.50 and 6.00 with a characteristically small
coupling constant (J ≈ 3.5 Hz) in the 1H NMR spectra. In the
case of 3N and 6N, these signals are at δ 5.96 and δ 5.83,
respectively. Those isomers resulting from an initial 5-exo
cyclization had alkenyl protons that resonated further down-
field in the 1H NMR spectrum. The signals are at δ 6.15 and
δ 6.11 for 3X and 6X, respectively. The protons labeled HN2
1
also gave rise to useful signals for interpretation in the H
NMR spectrum. The signals from products of initial 6-endo
cyclization were consistently upfield compared to the signals
from products of initial 5-exo cyclization.
A set of substrates that had para substitution on the aryl
ring were initially evaluated (eq 2 and Table 1). Unless
otherwise noted, substrates were subjected to 10 mol % of
the platinum catalyst in toluene at 110 °C. Less reactive
substrates required heating at 130 °C to achieve reasonable
cyclization rates (entries 18, 20, and 21). Results from the
earlier study are included in Table 1 for completeness (entries
1-3). Two alternative catalyst systems were attempted for
the cyclization of 4. Running the reaction under a CO
atmosphere19 inhibited the reaction as a slow conversion
only led to the isolation of a 38% yield of a 3:2 mixture of 4
and 6N/6X (entry 4). Alternatively, catalysis using a cationic
gold(I) system (PPh3AuCl, AgSbF6, 10 mol % each) resulted
in a 30% yield of 6N (entry 5). These and some later
experiments (entries 12 and 13) established that Pt(II) sys-
tems were superior for this reaction. The enesulfonamide 8
within a five-membered ring cyclized effectively to generate
largely the “6-endo” cyclization product 28N in 62% yield
(entry 6). Ene tert-butyl carbamate 9 was briefly studied. The
best conditions for the reaction of 9 involved 20 mol %
loading of platinum(II) chloride at 60 °C for 48 h to obtain
48% of 29N (entry 7). Further reaction optimization for 9
was not successful. Happily, though, enamides 10-13 re-
acted effectively and generally followed the same regiochem-
ical trend as the enesulfonamides. Substrates having phenyl-
substituted alkynes cyclized to form products having a
modest ratio favoring the 6-endo product (entries 8, 9 and
10). We were interested to test whether the use of platinum-
(II) bromide as the catalyst would optimally alter the regios-
Unlike 17, enesulfonamide 20 contains a symmetrically sub-
stituted dimethoxylated arene ring attached to the alkyne. A
comparison of the results of the reaction of 17 and 20 to
€
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platinum(II) catalysis can be used to evaluate the relative
importance of the para substituent on the regioselectivity of
the addition of the enesulfonamide to the alkyne. The result in eq
3 (69%, 8:1) compared to that in Scheme 3 (61%, 20:1) suggests
that the electron donation from the substituent para to the
alkyne within the substrate is a significant contributor. Not too
surprisingly, these results suggest that the electronic polar-
ization of the alkyne is more important relative to the
nucleophilicity of the arene ring in the subsequent Friedel--
Crafts reaction.
Heterocyclic Arenes. We were interested in incorporating
heteroaromatic components within these platinum(II)-cata-
lyzed cyclization processes to increase the structural com-
plexity of the products. Unfortunately, these experiments
revealed some limitations of scope for this metal-catalyzed
process. As an example, compound 21 has its alkyne sub-
stituted with a N-methylindole substituent at the 3-position
of the indole. Pentacycle 41N is produced in low yield (17%)
when 21 is heated with platinum(II) chloride in toluene. The
majority of the reaction mixture is noncharacterizable de-
composition.
TABLE 1. Evaluation of Substrates Having Para-Substituted Arene Rings
entry substrate
X
R1
R2
n
products yielda (%) ratiob
1
2
2
4
5
4
4
8
9
10
11
11
12
12
12
12
12
13
13
14
15
16
16
H, H Ts
H, H Ts
H, H Ts
H, H Ts
H, H Ts
H, H Ts
H
OCH3
CF3
OCH3
OCH3
OCH3
1
1
1
1
1
0
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
3N:3X
6N:6X
7N:7X
6N:6X
6N:6X
78
65
67
4:1
19:1
1:1
3
4c
see text nd
30 >25:1
5d
6
28N:28X 62
29N:29X 48
30N:30X 98
31N:31X 77
31N:31X 61
32N:32X 79
32N:32X NR
32N:32X 41
32N:32X dec
32N:32X 11
33N:33X 79
33N:33X 88
34N:34X 66
35N:35X 68
36N:36X 52
36N:36X 46
25:1
>25:1
10:1
4:1
1.5:1
7:1
nd
3:1
nd
nd
18:1
9:1
2:1
2:1
1:2
1:1.6
7e
H, H Boc OCH3
8
9
O
O
O
O
O
O
O
O
O
O
O
O
O
O
CH3
Bn
Bn
H
H
H
10f
11
12g
13h
14i
15j
16
17e
18
19
20
21e
CH3 OCH3
CH3 OCH3
CH3 OCH3
CH3 OCH3
CH3 OCH3
Bn OCH3
Bn OCH3
CH3 Br
Compounds 22-24 each have a furan ring (attached at
C-2 of the furan) appended to its alkyne. These cyclization
reactions proceed in low to moderate yield (eq 5). As an
example, enesulfonamide 22 reacts to produce tetracycle 42N
in 37% yield. Although, or perhaps because, the overall
isolated yield is low, the minor regioisomer in these cycliza-
tions was only detected to a very small extent or not at all. In
contrast, enamide 24 reacted to generate tetracyclic products
44N/44X in 51% yield as a 7:1 ratio of isomers.
CH3 OTs
CH3 CF3
CH3 CF3
aIsolated yields. NR = no reaction; dec=decomposition. bRatio was
determined by inspection of 1H NMR spectrum of product mixture.
nd = not determined. cReaction was carried out using PtCl2 under a CO
atmosphere. dReaction was carried out using PPh3AuCl (10 mol %) and
e
AgSbF6 (10 mol %) at 60 °C. Reaction was carried out using PtCl2
f
(20 mol %) at 60 °C for 48 h. Reaction was carried out using PtBr2
(10 mol %). gReaction was carried out using AuCl, PPh3, and AgSbF6
(5 mol % each) at 60 °C. hReaction was carried out using PPh3AuCl and
i
AgSbF6 (5 mol % each) at 80 °C. Reaction was carried out using
S-PhosAuCl and AgSbF6 (5 mol % each) at 60 °C. jReaction was carried
out using PtCl2 (10 mol %) and S-Phos (15 mol %).
SCHEME 4. Cyclization of Veratrole Derivatives
Replacement of the furan moiety with an indole fragment
gave better results (eq 6). The treatment of enesulfonamide
25 with platinum(II) catalysis generated 45N/45X as a 20:1
mixture of isomers in 36% yield. The low yield for this
process was attributed to the unfunctionalized nitrogen on
the indole ring since its N-methylated analogue 26 cyclized to
form a similar ratio in 77% yield. Enamide 27 could be
reacted in an analogous manner to produce 47N/47X in 80%
yield as a 20:1 mixture of isomers. The unusual ring skeleta of
J. Org. Chem. Vol. 74, No. 18, 2009 6933

Kozak et al.
JOCFeatured Article
46N and 47N could have use as structural mimics of indole
alkaloids.
for 12 h. The reaction mixture was cooled to rt and directly
purified by column chromatography on triethylamine-washed
silica gel (8:1 to 5:1 hexanes/ethyl acetate) to afford 26 mg (65%)
of a 19:1 mixture of 6N and 6X as a colorless film which
solidified into a white solid upon storage in the freezer. The
solid was recrystallized from diethyl ether. Mp: 121-123 °C. IR
(film): 2938, 1608, 1484, 1154 cm-1 1H NMR (400 MHz,
.
CDCl3): δ 7.81 (d, J=8.3 Hz, 2H), 7.35 (d, J=8.3 Hz, 2H),
7.25 (d, J=8.3 Hz, 1H), 6.76 (dd, J=8.3, 2.2 Hz, 1H), 6.60 (s,
1H), 5.83 (t, J=3.6 Hz, 1H), 4.89 (s, 1H), 3.91 (d, J=14.0 Hz,
1H), 3.71 (s, 3H), 2.91 (td, J=12.6, 2.2 Hz, 1H), 2.44 (s, 3H),
2.17-2.10 (m, 2H), 1.79-1.53 (m, 4H), 1.50-1.16 (m, 4H).
Additional peaks associated with the minor isomer 6X: δ 6.90 (d,
J=8.3 Hz, 1H), 6.67 (dd, J=8.3, 2.6 Hz, 1H), 6.55 (s, 1H), 6.11
(s, 1H), 5.17 (s, 1H), 3.61 (s, 3H). 13C NMR (100 MHz, CDCl3)
for the major isomer 6N: δ 159.9, 143.3, 143.0, 142.1, 138.9,
132.6, 129.6, 127.0, 121.7, 116.9, 114.8, 108.3, 66.2, 55.4, 44.5,
41.7, 29.1, 28.9, 24.5, 21.5, 20.8, 18.1. HRMS (ESI): calcd for
C24H28NO332S (M þ H)þ 410.1790, found 410.1784.
Concluding Remarks
These results demonstrate a potential utility for these
platinum(II)-catalyzed addition-Friedel-Crafts processes
to generate nitrogen-containing ring fragments with reason-
able structural complexity. The understanding of the direc-
tion and magnitude of the regioselectivity of the derivatized
enamine nucleophile to the metal complexed alkyne is critical
as, in our hands at least, the products of these cyclizations are
inseparable. The electronic properties of the 1-arylalkyne
could be adjusted by modification of either the substituents
on the arene ring or the arene ring itself. Substrates having
electron-rich aromatic systems react in a predictable manner
to produce useful ratios of the product isomer that results
from an initial 6-endo cyclization. Some heteroaromatic
systems (e.g., furans and unsubstituted indoles) do not
appear to be compatible with the reaction conditions at this
current stage of reaction development. Future work in-
cludes: (a) the modification of the metal catalyst in order
to generate products with some level of enantiopurity, (b) a
study in which the putative azacarbenium ion intermediate is
reacted with different internal or external nucleophiles (e.g.,
heteroatoms or allylsilanes), and (c) the synthetic processing
of these reaction products to generate compounds of interest
in natural product synthesis or biological studies. Efforts
toward these ends are ongoing in our laboratory.
Tetracycles 33N and 33X. A solution of 68 mg of enamide 13
(0.19 mmol) and 5.0 mg of platinum(II) chloride (0.019 mmol) in
0.5 mL of toluene was stirred in a sealed tube at 110 °C for 16 h.
The reaction mixture was cooled to rt and directly purified by
column chromatography on triethylamine-washed silica gel (5:1
to 1:1 hexanes:ethyl acetate) to afford 54 mg (79%) of an 18:1
mixture of 33N and 33X as a white foam. IR (film): 2938, 1642,
732, 648 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.32-7.25 (m,
6H), 6.77 (dd, J=8.2, 2.0 Hz, 1H), 6.46 (d, J=1.6 Hz, 1H), 5.78
(t, J=3.7 Hz, 1H), 5.34 (d, J=14.5 Hz, 1H), 4.50 (d, J=14.5 Hz,
1H), 4.39 (s, 1H), 3.68 (s, 3H), 2.39-2.32 (m, 1H), 2.27-2.20 (m,
1H), 2.18-2.11 (m, 1H), 2.05-1.93 (m, 2H), 1.78-1.63 (m, 4H),
1.32-1.25 (m, 1H). Additional peaks associated with the minor
isomer 33X: δ 6.97 (d, J=8.2 Hz, 1H), 6.16 (s, 1H), 5.95 (d, J=
14.1 Hz, 1H), 4.26 (s, 1H), 3.82 (s, 3H). 13C NMR (100 MHz,
CDCl3) for the major isomer 33N: δ 173.2, 161.1, 145.7, 144.5,
138.8, 133.7, 129.8, 129.7, 128.7, 122.0, 116.7, 115.8, 108.8, 70.5,
56.5, 52.0, 47.3, 34.4, 33.6, 32.1, 25.2, 19.0. HRMS (ESI): calcd
for C24H25NO2Na (M þ Na)þ 382.1783, found 382.1771.
Tetracycles 38N and 38X. A solution of 34 mg of enamide 18
(0.11 mmol) and 2.8 mg of platinum(II) chloride (0.011 mmol) in
0.5 mL of toluene was stirred in a sealed tube at 110 °C for 16 h.
The reaction mixture was cooled to rt and directly purified by
column chromatography on triethylamine washed silica gel (1:1
hexanes/ethyl acetate) to afford 33 mg (98%) of a 10:1 mixture
of 38N and 38X as an off-white solid. Mp: 132-134 °C. IR
Experimental Section
1
(neat): 2964, 1642, 731 cm-1. H NMR (400 MHz, CDCl3): δ
Tetracycles 28N and 28X. A solution of 0.025 g of enesulfo-
namide 8 (0.69 mmol) and 1.8 mg of platinum(II) chloride
(0.0069 mmol) in 0.5 mL of toluene was stirred in a sealed tube
at 110 °C for 16 h. The reaction mixture was cooled to rt and
directly purified by column chromatography on triethylamine-
washed silica gel (6:1 hexanes/ethyl acetate) to afford 0.017 g
(62%) of a 25:1 mixture of 28N and 28X as a white crystalline
solid. Mp: 162 °C dec. IR (film): 2937, 1343, 1162, 735 cm-1. 1H
NMR (400 MHz, CDCl3): δ 7.82 (d, J=8.2 Hz, 2H), 7.37-7.35
(m, 1H), 7.36 (d, J=7.8 Hz, 2H), 7.25 (d, J=8.6 Hz, 1H), 6.84
(dd, J=8.6, 2.3 Hz, 1H), 5.83 (t, J=3.5 Hz, 1H), 4.61 (s, 1H),
3.87 (s, 3H), 3.56-3.52 (m, 1H), 3.28-3.21 (m, 1H), 2.47 (s, 3H),
2.21-2.02 (m, 2H), 1.86-1.74 (m, 2H), 1.66-1.40 (m, 2H), 1.04
(m, 1H), 0.90 (m, 1H). Additional peaks associated with the
minor isomer 28X: δ 6.10 (s, 1H), 4.79 (s, 1H). 13C NMR (100 MHz,
CDCl3) for the major isomer 28N: δ 160.6, 144.5, 143.8, 141.2,
134.4, 131.5, 129.9, 128.1, 121.4, 117.0, 116.6, 110.2, 72.9, 55.8,
53.2, 49.0, 34.8, 29.0, 24.5, 21.8, 19.3. HRMS (EI): calcd for
C23H25O3NS (M)þ 395.1555, found 395.1552.
6.87 (s, 1H), 6.76 (s, 1H), 5.82 (br s, 1H), 4.33 (s, 1H), 3.89 (s,
3H), 3.86 (s, 3H), 3.33 (s, 3H), 2.37-2.22 (m, 3H), 2.14-2.03 (m,
2H), 1.90-1.83 (m, 2H), 1.77-1.71 (m, 2H), 1.62-1.52 (m, 1H).
Additional peaks associated with the minor isomer 38X: δ 6.60
(s, 2H), 6.15 (br s, 1H), 3.25 (s, 3H), 2.80 (s, 2H). 13C NMR (100
MHz, CDCl3) for the major isomer 38N: δ 172.6, 150.7, 150.6,
144.8, 136.4, 133.2, 116.9, 107.2, 104.0, 73.8, 57.1, 57.0, 47.0,
37.9, 32.8, 31.3, 30.6, 25.2, 18.9. HRMS (ESI): calcd for
C19H23NO3Na (M þ Na)þ 336.1576, found 336.1570.
Tetracycle 42N. A solution of 17 mg of enesulfonamide 22
(0.048 mmol) and 1.3 mg of platinum(II) chloride (0.0048 mmol)
in 0.5 mL of toluene was stirred in a sealed tube at 110 °C for 16 h.
The reaction mixture was cooled to rt and directly purified by
column chromatography on triethylamine-washed silica gel (5:1
hexanes/ethyl acetate) to afford 6.4 mg (37%) of the title com-
pound 42N as a clear, colorless oil. IR (film): 2930, 1344, 1164
cm-1. 1H NMR(400MHz, CDCl3):δ7.78 (d, J=8.2 Hz, 2H), 7.34
(d, J=8.6 Hz, 2H), 7.32 (d, J=2.0 Hz, 1H), 6.43 (d, J=2.0 Hz, 1H),
5.63 (t, J=3.7 Hz, 1H), 4.43 (s, 1H), 3.55-3.50 (m, 1H), 3.24 (q, J=
8.6 Hz, 1H), 2.46 (s, 3H), 2.27-2.18 (m, 1H), 2.13-2.03 (m, 1H),
2.00-1.96 (m, 2H), 1.74-1.64 (m, 1H), 1.37-1.21 (m, 3H). 13C
NMR (100 MHz, CDCl3): δ 156.9, 146.9, 143.7, 135.0, 133.1,
Tetracycles 6N and 6X. A solution of 40 mg of enesulfona-
mide 4 (0.098 mmol) and 2.7 mg of platinum(II) chloride (0.010
mmol) in 1 mL of toluene was stirred in a sealed tube at 110 °C
6934 J. Org. Chem. Vol. 74, No. 18, 2009

Kozak et al.
JOCFeatured Article
129.8, 129.3, 127.9, 114.4, 109.5, 77.4, 66.2, 58.1, 48.3, 35.5, 30.0,
23.8, 21.8, 18.8. HRMS (EI): calcd for C20H21O3NS (M)þ
355.1242, found 355.1244.
138.2, 129.8, 127.2, 124.1, 121.8, 119.9, 119.5, 117.8, 116.4,
109.4, 62.2, 49.3, 42.0, 31.3, 31.0, 29.8, 24.6, 21.7, 21.3, 18.0.
HRMS (ESI): calcd for C26H29N2O232S (M þ H)þ 433.1950,
found 433.1960.
Tetracycle 46N. A solution of 0.025 g of enesulfonamide 26
(0.058 mmol) and 1.5 mg of platinum(II) chloride (7.0 μmol) in
1.0 mL of toluene was stirred in a sealed tube at 130 °C for 16 h.
The reaction mixture was cooled to rt and directly purified by
column chromatography on triethylamine-washed silica gel (1:1
to 1:2 hexanes/dichloromethane to dichloromethane to 98:2
dichloromethane/ethyl ether) to afford 17 mg (78%) of the title
compound 46N as a colorless film. IR (film): 2934, 1458, 1331,
Acknowledgment. We thank the University of British
Columbia, the Natural Science and Engineering Research
Council (NSERC) of Canada, and the Canada Foundation
for Innovation (CFI) for financial support of our programs.
T.J.H. thanks NSERC for PGS A and PGS B graduate
fellowships. J.A.K. thanks NSERC for PGS M and PGS D
graduate fellowships.
1
1166, 1150 cm-1. H NMR (400 MHz, CDCl3): δ 7.84 (d, J=
8.2 Hz, 2H), 7.34 (d, J=7.5 Hz, 2H), 7.24 (d, J=8.2 Hz, 1H),
7.18-7.13 (m, 2H), 6.98 (t, J=7.2 Hz, 1H), 5.80 (t, J=3.8 Hz,
1H), 5.14 (s, 1H), 3.96-3.88 (m, 1H), 3.78 (s, 3H), 3.04 (dd, J=
10.9, 2.7 Hz, 1H), 2.47 (s, 3H), 2.33-2.12 (m, 2H), 1.89-1.80 (m,
2H), 1.74-1.66 (m, 2H), 1.66-1.45 (m, 3H), 1.38-1.29 (m, 1H).
13C NMR (100 MHz, CDCl3): δ 143.8, 143.0, 142.1, 139.3,
Supporting Information Available: Experimental proce-
dures and characterization data for all previously unreported
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 18, 2009 6935