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Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 1
CHAPTER 1
Aryne Annulations in the Synthesis of Nitrogen Heterocycles
1.1 INTRODUCTION
As organic chemistry nears the eve of its third century, the fundamental concerns of
a modern synthetic chemist remain startlingly similar to those facing Friedrich Wöhler in
the 1820s.1 Namely, planning a series of transformations in an order that imparts
efficiency, selectivity, and reactivity over the course of a total synthesis. Countless
innovations in instrumentation and methodology have helped the synthetic community
better address those criteria through improved understanding of specific transformations.
Application of these developments to chemical synthesis has created both tactical
breakthroughs2 and incremental improvements3 on existing methodologies4 to construct
all manner of structural motifs. With new target molecules reported every day, the
developmental challenges confronting the community are not diminishing; they are being
brought into sharper focus.5,6 Historically, perhaps no class of molecules has inspired
synthetic creativity or a sense of its futility as deeply as the alkaloids (Figure 1.1).7
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 2
Figure 1.1. Alkaloids of classical and contemporary significance
N MeN
OO
MeOAc S
OO
NHMeO
HO
H
HOOMe
Me
OH
Ecteinascidin 743 (6)Yondelis !
• antitumor antibiotic •
N
HO
MeO
NH
Quinine (5)
• anti-malarial •
N
N
OO
H
H
H
H
Strychnine (4)
• poison •
NH
Me
Coniine (1)
• poison •
Tropinone (2)
• stimulant •
O OHHO
HN
Me
Morphine (3)
• analgesic •
NMe
O
This nitrogen-containing family of more than 12,000 natural products includes
molecules of a breathtaking expanse of structural diversity.8 Moreover, their
exceptionally broad range of biological activity has woven them so tightly with humanity
that this group includes compounds that have been used for the breadth of human history.
Their impact on the synthetic community has been enormous. From the first total
synthesis of the poison coniine (1) by Ladenburg9 in 1886 to the current clinical trials for
ecteinascidin-743 (6) as a potent anticancer agent,10 chemists have conceived of
persistently inventive ways to synthesize these target molecules to maximize efficiency,
enhance selectivity, and moderate reactivity. In the following chapter, we will briefly
overview some of these strategies before detailing the synthesis of heterocycles using
aryne intermediates. Because the synthetic efforts in pursuit of various members of this
family have been extensively detailed elsewhere, our focus will be on benzannulated,
polycyclic nitrogen-containing heterocycles.7
1.2 ALKALOIDS AND THE SYNTHESIS OF NITROGEN HETEROCYCLES
The only defining structural feature of any alkaloid is a nitrogen atom set in a
particular carbon framework. Many of the alkaloids contain complex polycyclic core
structures that are in large part responsible for their potent and highly specific biological
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 3
activity. Consequently, any approach to these molecules will inevitably encounter the
challenge of nitrogen heterocycle synthesis. Despite of the structural diversity of
alkaloids, the fundamental structural components found in these molecules are limited in
variety. These motifs can be broadly divided into monocyclic N-heterocycles (Figure
1.2) and benzannulated bicyclic systems (Figure 1.3).
Figure 1.2. Simple, monocyclic nitrogen-containing heterocyclic structures
NHHN
O
imidazolines
OHN
O
oxazolidinones
NHHN
O
hydantoinsO
NHNHHN
O
urazolesO
OHN
imidazolines
N
2-H-azirines
HN
3-pyrrolines
HN
2-pyrrolines
N
1-pyrrolines
HN
maleimides
OO
ON
2-isoxazolines
O N
2-oxazolines
O N
3-oxazolines
HN N
2-imidazolines
HNN
pyrazolines
HN
pyrroles
NHN
imidazoles
NHN
pyrazoles
NN
HN
1,2,3-triazoles
NH
NN
1,2,4-triazoles
N NN
HN
tetrazoles
R
NHHN
imidazol-2-ones
O
NN
imidazol-5-ones
O
NHO
2-oxazolones
O
NO
oxazoles
NO
isoxazoles
NS
thiazoles
NNO
1,3,4-oxadiazoles
N
NO
1,2,4-oxadiazoles
NNS
1,3,4-thiadiazoles
N
pyridines
NH
dihydropyridines
NH
2-pyridones
O N
N
pyrimidines
N
N
N
1,3,5-triazines
HN
pyrrolidines
HN NH
2-imidazolidines
NH
piperidines
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 4
Figure 1.3. Fundamental benzannulated nitrogen-containing heterocycles
N NH
indolines
NH
indoles
NH
oxindoles
O
N NH
azaindoles
NH
isoindolesindolizines
N
indolizinones
O
NH
carbazoles
N
quinolines
N
isoquinolines
NH
tetrahydro-quinolines
NH
tetrahydro-isoquinolines
NH
1,2-dihydro-quinolines
N
3,4-dihydro-isoquinolines
N N
naphthyridines
N
N
quinazolines
N
N
quinoxalines
NH
2-quinolones
NH
isoquinolones
O
O NH
4-quinolones
O
NH
N
indazoles
NH
N
benzimidazoles
NH
NN
benzotriazoles
NH
HN
benzimidazolones
ON
O
benzoxazoles
NO
benzisoxazoles
N
S
benzothiazoles
The presence of an arene in an aromatic, bicyclic heterocycle severely limits the
synthetic approaches available to these molecules. While methods do exist to construct
an aryl ring directly from non-aromatic precursors on a heterocycle,11,12 the most direct
and efficient approaches to these structures rely upon formation of the nitrogen-bearing
ring at a late stage. Thus, these benzannulated heterocycles require a detailed
understanding of reactivity to properly activate aromatic systems for bond formation.
The most effective way to generate reactivity from an unactivated aryl ring is to
promote the formation of a Lewis acidic intermediate capable of undergoing electrophilic
aromatic substitution. Many approaches, including the classic Bischler–Möhlau13 and
Pictet–Spengler14 reactions, have been developed to synthesize indoles and isoquinolines,
respectively, through this reaction pathway (Scheme 1.1). In chapter 2, we present a
detailed analysis of classical synthetic approaches to indoles and isoquinolines, so the
summary that follows will include lesser-known approaches.
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 5
Scheme 1.1. Benzannulated heterocycles by electrophilic aromatic substitution
7 8
Bischler–Möhlau (1881)
NH
R
R'O
NH
R
R'HO
NH
R–H2O
R'H3O+
9
SEAr
N
OMe
OMeN
OMe
N
HCl SEAr
–MeOH
Pomeranz–Fritsch (1893)
10 11 12
There are numerous variations upon this general theme, as used in Poupon’s
synthesis of PK11195 analogue 17 (Scheme 1.2). 15 The approach uses an interesting
Ritter reaction where allyl arene 14 and aryl nitrile 13 are coupled to form an
intermediate nitrilium species (15). The nitrilum is attacked by the arene, and cyclizes to
furnish 3,4-dihydroisoquinoline 16, which is subsequently advanced to the target
molecule. The low yield of this process shows that even electron-rich aromatic systems
do not provide predictable reactivity in such transformations.
Scheme 1.2. Ritter reaction in Poupon’s synthesis of isoquinoline 17
PK11195 analogue (17)
CN
MeOOMe
OMe OO
54% HBF4
Et2O23 °C
N
OO
Me
OMeOMe
OMe SEArN
MeO
O
MeOOMe
OMe
N
CO2HO
O
MeOOMe
OMe
Ritter Reaction
(17% yield)
Poupon (2004)
13 14 15 16
Mestroni was able to use a similar electrophilic aromatic substitution approach
to generate phenanthroline ligands (22, Scheme 1.3).16 By using a Doebner–Miller
quinoline synthesis,17 enal 19 and nitroaniline 18 are condensed to form α,β-unsaturated
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 6
iminium 20. Cyclization of this intermediate generates the quinoline (21), which is
advanced to the chiral ligand (22).
Scheme 1.3. Chiral phenanthroline ligands (22) through Doebner–Miller quinoline synthesis
NO2
NH2
O
H
MeMe
As2O5
85% aq H3PO4120 °C
NO2
N
Me
Me
HH NO2
N
Me
Me
HDoebner–Miller
QuinolineSynthesis
(24% yield)
NN
Me
Me
Me
Me
Phenanthroline Ligand (22)
18 19 20 21
Mestroni (1990)
Not all approaches to heterocycle synthesis use electrophilic aromatic substitution
to create bonds. More recently, there have been several reports that use transition metal
catalysis to regioselectively form substituted heterocycles.18 By taking advantage of this
characteristic, Fu has been able to develop an efficient synthesis of substituted
quinazolines (27) through an Ullman-type coupling of ortho-bromo benzylamine 23 and
amide 24 (Scheme 1.4).19
Scheme 1.4. Ullman-type couplings to generate quinazolines (27)
NH2
BrR1
H2N
O
R2
CuI (10 mol%)2 eq K2CO3
O2i-PrOH110 °C
NH2
CuR1
BrNH
OR2
NH
R1
NH2
R2
O N
NR1
R2
– H2O
(37–87% yield)
23 24 25 26 quinazolines (27)Ullman-Type Coupling
R1 = -H, -ORR2 = -aryl
Fu (2010)
Benzannulated nitrogen heterocycle synthesis can proceed through other
mechanisms, but the above general strategies dominate heterocycle synthesis.
Prefunctionalization of the aromatic ring with electron-rich (e.g., Pictet–Spengler),
halogen (e.g., Ullman couplings), or nitrogen (e.g., Doebner–Miller) substituents is a
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 7
prerequisite for these cyclization methodologies to proceed. As a consequence, there are
limitations to how efficient these processes are, and to the variety of known and unknown
benzannulated heterocyclic motifs that are accessible by these pathways. To address
these potential pitfalls, an alternative strategy using highly reactive aryne intermediates
has been developed to complement these more common approaches.
1.3 ARYNE ANNULATIONS IN THE SYNTHESIS OF NITROGEN
HETEROCYCLES
1.3.1 A Brief Introduction to Arynes
Benzyne (28), or 1,2-dehydrobenzene, is a six-membered aromatic ring
containing a highly strained alkyne (Scheme 1.5). Due to the ring strain imparted on the
alkyne, benzyne is a highly reactive species and often acts as an electrophile in chemical
transformations. Aromatic molecules containing this strained triple bond are more
generally known as arynes, and bear similar reactivity to the prototypical benzyne.
Historically, the specific structural notion of an aryne reactive intermediate—and the
term “benzyne” itself—come from seminal work by Roberts, wherein an amination
reaction using isotopically labeled unsubstituted chlorobenzene-1-14C (29), proceeded to
give a mixture of labeled isomers, of aniline-1-14C (31) and aniline-2-14C (32) in 43%
yield.20 This mixture suggested the existence of a symmetrical intermediate into which
the amide could add to form the observed product mixture.21
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 8
Scheme 1.5. Benzyne (28), and Roberts’ seminal structural proof
Benzyne (XX)
KNH2
NH3
(43% yield)XX
Cl
= 14C
NH2
NH2
XXXX
+NH2
XX
Roberts (1953)
Since Roberts used the deprotonative method for benzyne generation, many more
ways have been developed to form the strained aryne triple bond. More recently, mild
methods for aryne generation have led an expansion in the application of this
intermediate to synthetic organic efforts (Scheme 1.6). As a result more than 75 reported
natural product syntheses have utilized aryne reactive intermediates,22 with countless
more reports of synthetic methodologies complementing the growing body of literature
on the subject (Scheme 1.7).23 In the survey that follows, we elected to focus exclusively
on arynes that are used to form benzannulated N-heterocyclic molecules. For ease of
organization, we have categorized these methodologies into intra- and intermolecular
reactions, and subdivided both groups based upon the bonds formed with the aryne itself.
When applicable, we have placed these reactions in the context of broader synthetic
efforts, but we will not discuss that work in any greater detail.
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 9
Scheme 1.6. The many roads to benzyne24
F
Li
F
MgBr
N2
CO2SO2
NN
X
X1
X2
NN
N
NH2
TMS
OTf
I
TMS
Ph
X
OTf
Bu4NFstrong base
Pb(OAc)2
heat
n-BuLiBu4NF
0 °C
Mg orRMgX
0 °C
–20 °C
OTf
Benzyne(28)
Scheme 1.7. Some representative reactions using benzyne
O
OMeOMe
OMeMeO
O
BrMg
[2+2]cycloadditions
[4+2]cycloadditions
nucleophilicadditions
!-bond insertionreactions
metal-catalyzedreactions
multicomponentreactions
Benzyne
Pd(PPh3)4CO2MeO
O
CO2Me
t-BuNC
R R
Nt-Bu
R
R
1.3.2 Heterocycle Synthesis via Intramolecular Aryne Annulation
1.3.2.1 Carbon–Nitrogen Bond-Forming Reactions
The application of arynes to any synthetic effort must exploit the highly reactive
intermediate under controlled circumstances. Strategies using intramolecular amide
attack upon arynes to form heterocyclic structures are appealing because they combine an
understood nucleophile (the amide) and a potent, internal electrophile (the aryne).
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 10
Interestingly, many of the initial reports of these reactions occur exclusively in the
context of natural product total synthesis. Over time, as more mild conditions were
developed to generate arynes, these reactive intermediates began to see more application
in broader synthetic methodologies.
The first application of an aryne annulation strategy occurred en route to
Kametani’s 1967 total synthesis of cryptausoline, wherein tetrahydroisoquinoline 33 is
deprotonated and undergoes addition to the aryne (34) generated from the pendant aryl
chloride (Scheme 1.8).25 Subsequent protonation of the resultant aryl anion affords the
indolinoisoquinoline ring system. Von Angerer used a very similar 5-exo cyclization to
construct several different indoloisoquinolines (38) from 1-benzyl
tetrahydroisoquinolines (36) two decades later for the use in artificial, biologically active
structures.26
Scheme 1.8. Indoloisoquinolines by aryne annulation
NH
MeO
BnO
Cl
NaNH2
NH3 (l), THF–40 °C
(77% yield)
N
MeO
BnOOR
OR
Indolinoisioquinolines — Synthesis of Cryptausoline — Kametani (1967)
Indoloisoquinolines — von Angerer (1990)
NH
R2MeO
R1 HBr
R3
R4
NaH
DMSO25 °C, 15 h
(46–55% yield)
36
NNa
R2MeO
R1
R3
R4
N
R2MeO
R1
R3
R4
37 38
35
O
O
33
N
MeO
BnO
34
oxygen
Iwao used an aminocyclization in a different manner, by generating 4,5-indolyne
(40) from a chlorinated tryptamine derivative (39) to ultimately build a tricyclic
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 11
intermediate (41) that he subsequently advanced to several makaluvamines (Scheme
1.9).27
Scheme 1.9. Iwao aminocyclization with indolyne (40)
NMeO
Cl
NH2
LICA
THF, 0 °C
(75–78% yield)NMeO
HN
NMeO
NH2
40
4-aminoindoles — Synthesis of Makaluvamine A — Iwao (1998)
R R R4139
45
Tokuyama was able to obtain similar reactivity by using magnesium to generate
the aryne from an aryl bromide (42, Scheme 1.10).28 By this method, the Boc-protected
amine was successfully cyclized onto the aryne (43), yielding an arylmagnesium
intermediate (44). Next, cupric iodide and a palladium catalyst were added with
iodoanisole, which, upon warming, was cross-coupled with the organomagnesium
intermediate (44) to provide an advanced indoline intermediate 45 for the synthesis of
dictyodendrin A.
Scheme 1.10. Indoline formation with tandem cross-coupling
Br
Br
OMe
OMe
BocHNMg(TMP)2•2LiBr
THF, –78 ! 0 °C
Br
OMe
OMe
BocNCuI, –78 °C;
4-iodoanisolePd(PPh3)4
–78 ! 23 °C
(93% yield)
Br
OMeNBoc
MeO
OMe4542 43
Indolines — Synthesis of Dictyodendrins A–E — Tokuyama (2010)
Br
OMeNBoc
MeO
Mg(TMP)
44
Biehl has recently been able to adopt a new direction in these intramolecular
aryne aminocyclization methods (Scheme 1.11).29 By using the low-temperature
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 12
conditions with tert-butyllithium, alkylated 2-bromo thiophenol derivatives (46) bearing
pendant amines can undergo a ring closure to generate thiazyl heterocylces (47) in a
variety of sizes. In a more limited case, Kurth has developed a solid-suppoted synthesis
of similar benzannulated heterocycles (50) by using bulky alkoxide bases to form arynes
(49) from nitroarenes (48).30
Scheme 1.11. Sulfur and oxygen containing nitrogen heterocycles by internal aryne annulation
Benzothiazines, benzothiazepines, benzothiazocines — Biehl (2004)S
NH2R nBr
RNH
Sn
46a–c 47a–c
47a, n = 1, (87–89% yield)47b, n = 2, (85–95% yield)47c, n = 3, (64–92% yield)
Tetrahydroquinoxalines, benzoxazines, benzothiazines — Kurth (2005)
HFX
H2N
O2NNHAlloc
HN
O
LiOt-Bu
THF:DMF25 °C, 24 h
X
O2NNHAlloc
HN
O
NHX
O2NNHAlloc
HN
O
NH
48a–c 49a–c 50a–c
50a, X = NH, (69% yield)50b, X = O, (82–91% yield)50c, X = S, (88% yield)
R R R
t-BuLi
THF–100 ! 20 °C
1.3.2.2 Carbon–Carbon Bond-Forming Reactions
Typically, C–N bond formations through intramolecular addition to arynes led to
very similar products and possessed similar reactivity. Conversely, closing heterocyclic
structures by forming a new carbon-carbon bond can proceed through a nucleophilic
addition or, as an alternative strategy, a cycloaddition pathway.
In one of the earliest reports of heterocycle formation, the C–C bond was created
by nucleophilic addition to the aryne. Semmelhack was able to complete his synthesis of
the cephalotaxus alkaloids (53) by trapping an aryne intermediate (52) generated from
aryl chloride (51) with a pendant enolate to close the benzazepine and form a new C–C
bond (Scheme 1.12).31 Kametani was similarly able to exploit a 3,4-dihydroisoquinoline
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 13
bearing a C(1)-exo-methylene substituent (54).32 Following aryne generation,
intermediate 55 was cyclized by intramolecular nucleophilic addition to the triple bond,
forming the isoquinolone component of the xylopinine core (56).
Scheme 1.12. Cyclization by intramolecular enamine and enolate attack
56
N O
MeO
MeOBr
OMeMeO
NaNH2
NH3(l), –40 °C
(15% yield)
N O
MeO
MeO
OMeOMe
N
MeO
MeO
OMeOMe
O
54 55
1
Isoquinolones — Synthesis of Xylopinine — Kametani (1977)
O
O Cl
N
OOMe
KCPh3
DME, 50 °C
(13–16% yield)
O
ON
OOMe
H
51 Cephalotaxinone (53)
Benzazepines — Synthesis of Cephalotaxinone — Semmelhack (1972)
O
O
N
OOMe
52
Following these initial reports, there were efforts to use stabilized anions to
perform similar reactions. Jaques had limited success in developing a synthesis of both
tetrahydroisoquinolines (59) and isoindoles (62) from aryl chlorides 57 and 60,
respectively through a general intramolecular addition of stabilized carbanions (58 and
61) to arynes (Scheme 1.13).33 In 1997, Couture reported a synthesis of cepharanones A
and B, wherein the aryne generated from aryl bromide 63 can undergo 5-exo cyclization
(64) through addition of the phosphine oxide-stabilized anion.34 Interestingly, a second
deprotonation adjacent to the phosphine oxide (65) is followed by addition of a
benzaldehyde derivative (66) to form the benzylidene isoxindole product (67) by a
tandem aryne annulation/olefination sequence.
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 14
Scheme 1.13. Ring closure by intramolecular stabilized enolate attack of arynes
NPMB
Br
O
PO
Ph Ph
KHMDS
THF–78 ! –30 °C
NPMB
O
PO Ph
Ph
NPMB
O
PO Ph
Ph
O
H
I
THF, –30 °C
(71–74% yield)
NPMB
O
I64 65
Isoxindoles — Synthesis of Cepharanones A + B — Couture (1997)
60
Tetrahydroisoquinolines — Jaques (1977)
NMe
Cl
CN
Cl
NMe
CN
57
K/NH3(l)
–78 °C
(50% yield)
K/NH3(l)
–78 °C
(89% yield)
N
N Me
MeCN
CN
59
62
R1
63
R1R1 R1
61
NMe
CN
NMe
CN
58
Isoindoles — Jaques (1977)
67
66
A more direct approach to the intramolecular anionic C–C bond formation using
arynes was reported by Barluenga, who was able to develop an approach to 3,4-
disubstituted indoles (71) by low-temperature lithiation (Scheme 1.14).35 In his
examples, ortho-fluoro anilines with pendant 2-bromo-allyl fragments (e.g., 68) generate
aryne intermediates (69) upon treatment with tert-butyllithium that close to form indole-
3-methylidenes (70) with a C(4) anion, which, upon warming, are quenched with various
electrophiles to form the products (71). Notably, the reaction proceeds selectively,
generating the aryne by elimination of the aryl fluoride while simultaneously performing
a lithium-halogen exchange to form the vinyl anion (69).
Scheme 1.14. Barluenga indole synthesis by lithiation/annulation
E+
–78 ! –20 °C
(46–75% yield)
Indoles — Barluenga (2002)
N
F
R
Br
t-BuLi
THF–100 ! –40 °C N
R
68 69
N
Me
R
E
71
NR
70
4
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 15
A common, but much less obvious nucleophile for these intramolecular
cyclizations is another aryl ring, acting through an electrophilic aromatic substitution
reaction (Scheme 1.15). Kessar first reported such a reaction in the conversion of aryl
bromide 72 to fused isoquinoline intermediate 74 in his total synthesis of chelerythrine
chloride.36 The proposed mechanism for the ring closure involves amine-assisted
intramolecular addition to the aryne (73) by the aminonaphthyl functional group.
Oxidation in the next step furnishes the observed isoquinoline product. At the same time,
Stermitz reported a nearly identical approach to the naphthoisoquinoline core (77) of
fagaronine chloride through an aryne intermediate (76) generated from aryl bromide 75.37
Sanz was recently able to extend a variation of Barluenga’s indole synthesis (vide supra)
to complete the total synthesis of N-methylcrinasiadine (81). In this work, aryne
generation and lithiation of the aryl bromide (78) are followed by cyclization of the aryl
anion onto the reactive triple bond (79→80) and proton quench of the resulting
intermediate with an equivalent of methanol.38
Scheme 1.15. Forming biaryl linkages by arene addition to aryne intermediates
NH
O
O
OMeMeO
BrKNH2
NH3 (l) NH
O
O
OMeMeO
MnO2
CHCl3
(80% yield,2 steps)
N
O
O
OMeMeO
72 73 74
Isoquinolines — Synthesis of Chelerythrine Chloride — Kessar (1974)
NHMeO
Br NaNH2
NH3(l)air oxidation
(24% yield)75
MeOOMe
Oi-Pr
NMeO
77
MeOOMe
Oi-Pr
Isoquinolines — Fagaronine Chloride — Stermitz (1974)
NMeO
76
MeOOMe
Oi-Pr
Phenanthridinones — Synthesis of N-methylcrinasiadine — Sanz (2007)
N
F
Me
78
Brt-BuLi
THF–100 ! 20 °C
NMe80
OO
OO
MeOH–78 ! –20 °C
–then–air
(65% yield) NMe
N-methylcrinasiadine (81)
OO
H
ONMe79
OO
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 16
Groups targeting more complex polycyclic structures with heterocycles at their
core have also exploited the impressive reactivity of arynes to build complexity through
multiple C–C bond formations in a single step. In particular, Castedo pioneered a method
for benzisoxindole (82) synthesis by a [4 + 2] cycloaddition approach in his synthesis of
aristolactam (84, Scheme 1.16).39 The aryne (83), in this case, reacts by a formal
cycloaddition process through enamine-assisted dearomatization of the pendant aryl ring,
which forms the natural product (84). More than a decade later, en route to
eupolauramine, Couture used a related reaction (85→86) to form a benzisoxindoles
bearing a fused pyridyl ring (87).40
Scheme 1.16. Intramolecular [4 + 2] cycloadditions
82
MeO
MeO Br
O
NH
OMe
LDA
THF, 0 °C
(35% yield)
MeO
MeO
O
N
OMe
MeO
MeONH
O
83 Aristolactam (84)
MeO
Benzisoxindoles — Synthesis of Aristolactam — Castedo (1989)
Benzisoxindoles — Synthesis of Eupolauramine — Couture (2001)
85
N
NO
H
N
NHO
Br
LTMP
–30 °C
(30% yield)
8786
N
NHO
[4 + 2]
[4 + 2]
1.3.3 Heterocycle Synthesis via Intermolecular Aryne Annulation
1.3.3.1 Carbon–Carbon Bond-Forming Reactions
Synthesizing heterocycles by intermolecular aryne annulation allows a different
approach than the intramolecular variants. The majority of the reported efforts in this
reaction manifold involve formal cycloadditions, which offers a convergent alternative to
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 17
the largely nucleophile/electrophile strategies that we have reviewed thus far.
Accordingly, chemists have designed reactions that allow the functionalization of both
carbon atoms of a benzyne intermediate with a single reaction partner. Intermolecular
methods for aryne annulation, however, must act on both ends of the aryne bond, as they
are not tethered to the arene in the first place. Such methods underscore the benefits of a
convergent approach to heterocycle synthesis, where multiple, substituted components
can be united, forming multiple new bonds in a single operation.
Castedo reported the first method for intermolecular nitrogen heterocycle
synthesis with aryne reactive intermediates in 1986 (Scheme 1.17).41 In this
development, pyrroloisoquinolines (87) were coupled with benzyne (28) generated from
diazonium carboxylate aryne precursor 88 through the imidate tautomer (89). A
cycloaddition reaction between these intermediates and a subsequent chelotropic
extrusion of carbon monoxide furnishes the isoquinolone product (90). Later, Rigby
reported a synthesis of 2-quinolones (95) by the [4 + 2] cycloaddition of cyclohexenyl
isocyanate 91 with the substituted aryne (94) produced from the lead-mediated
decomposition of 1-aminobenzotriazole derivative 92.42
Scheme 1.17. Quinolones and isoquinolones through early intermolecular aryne annulations
93
94
O
O
NC
O
Pb(OAc)4
CH2Cl2
MeO
MeO NN
N
NH2
O
O
HN
O
O
O
NC
OOMe
OMe
91 92 95
OMe
OMe
2-Quinolones — Rigby (1991)
N
O
O
MeO
MeO
Isoquinolones — Castedo (1986)
87
Me
88
CO2
N2
cat. TCA
DME, reflux
(52% yield)
N
MeO
MeOO
Me
90
N
O
O
MeO
MeO
89
Me28
[4 + 2]
– CO
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 18
Not all approaches to heterocycles by aryne annulation use neutral intermediates
for cycloadditions. Work with multicomponent synthesis has yielded an excellent
general reaction partner for use with arynes, the 1,3-dipole. In the context of heterocycle
synthesis, that dipole is often an activated pyridinium salt resulting from pyridine
addition to an electrophile (Scheme 1.18). Matsumoto reported the first example of such
a reaction with benzyne, wherein a pyridinium malononitrile (96) reacts with benzyne
formed from phenyl diazonium carboxylate (88), to form pyridoisoindoline 97 in modest
yields.43 Interestingly, the product can form a second dipole (98) and react with another
equivalent of benzyne to form the unique pentacyclic aromatic compound 99. In 2008,
Xu disclosed a three-component reaction with bromoacetophenone derivatives (101),
pyridines (102) and arynes generated in situ from ortho-silyl aryl triflate 100.44 Again, a
dipolar pyridinium intermediate is formed (101) that reacts with the aryne to create
substituted pyridoisoindoles (105).
Scheme 1.18. Approaches to pyridoisoindoles through a pyridinium dipolar addition (96 and 103)
Pyridoisoindolines — Matsumoto (1996)
N
CNNC
9688
CO2
N2
acetone CHCl3
refluxN
CNCN
N
Pyridoisoindoles — Xu (2008)
OBr
N
R3
TMS
OTf
100
R1
101 102
CsF
MeCN, 80 °C2 h
(36–60% yield)
N
O
R2
R3
R1
R2
105
99(11% yield)
97(20% yield)
NO
R2
104103
R3
R1
N
CN
– HCN
98
– HCN
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 19
Yoshida has explored three-component processes with different reaction partners
to obtain similar structures to the pyridoisoindoles (Scheme 1.19).45 By combining
arynes arising from silyl aryl triflates (100) with isocyanides (106) and aryl tosyl
aldimines (107), an iminoisoindole product is formed (108). This combination of arynes
and isocyanides has become very fruitful for heterocycle synthesis via aryne annulation,
as demonstrated by Huang in 2009, when arynes, alkynes (110), and alkyl isocyanides
(109) participated in a four-component coupling that furnished highly substituted
isoquinoline products (111).46
Scheme 1.19. Approaches to heterocycles through an isocyanide multi-component reactions
TMS
OTf
100
R1 NR2 R3H
109 110
CsF
MeCN:PhMe 40 °C, 12 h
(55–79% yield)
C N
R2
R1
R1
Isoquinolines — Huang (2009)
111
Iminoisoindoles — Yoshida (2004)
TMS
OTf
100
R1NTs
N
R1
KF18-Crown-6
THF25 °C, 24 h
(35–68% yield)
R2
106
C N R2
R3
H
NTs
107
R3
108
2 equivR3
In further multicomponent reactions, Wang reported the synthesis of
phenanthridines (114) by the union of arynes, anilines (112) and aryl aldehydes (113,
Scheme 1.20).47 Masked within the larger phenanthridine cores are substituted
isoquinoline products.
Scheme 1.20. Phenanthridines by aryne three-component reactions
N2
CO2
88
NH2
R2
OR3
112 113
DCE 80 °C2 h
(31–95% yield)
N
R3
R2
Phenanthridines — Wang (2006)
114
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 20
In addition to the strategies of multicomponent synthesis, dipolar addition, and
cycloaddition, some new approaches to structures of higher complexity have been
reported. For instance, Hsung has published a method to construct tricyclic piperidyl ring
systems (118) through an aryne intermediate (Scheme 1.21).48 In this example, a formal
[2 + 2] cycloaddition reaction between vinyl enamine 115 and the aryne formed from
silyl aryl triflate 100 produces benzocyclobutenyl intermediate 116. This rapidly
undergoes a 4π electrocyclic ring opening to reveal the ortho-quinone dimethide 117, that
reacts with the pendant olefin through a [4 + 2] cycloaddition, forming the core of the
product (118). While not technically a benzannulated bicycle, the piperidine formed
within tricycle 118 could not be formed without the direct participation of the aryne
intermediate during the course of the reaction cascade.
Scheme 1.21. Formal [2 + 2]/retro-4π/[4 + 2] cascade
Azatricycles — Hsung (2009)
TMS
OTf
100
R1
TsN
115
CsF
dioxane110 °C, 24 h
(51–87% yield)
N
H
HTs
NTs
N
H
Ts
116 117
4! [4+2]
118
H
While palladium participation aryne annulation reactions is relatively rare, Zhang
reported an intramolecular, palladium-mediated method to form indolophenanthridines
(Scheme 1.22).49 The palladium-phosphine catalyst performs an oxidative addition into
the aryl bromide (120), and adds across an aryne equivalent to generate aryl palladium
intermediate 121. Ring closure results from carbopalladation of the palladium to forge
the C–C bond between the arene and the indole, yielding the product (122).
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 21
Scheme 1.22. Pd-catalyzed cascade cyclization to form indolophenanthridines Indolophenanthridines — Zhang (2007)
N Br
119
TMS
OTf
CsFPd2(dba)3 (2.5 mol%)
dppp (5 mol%)
1:1 MeCN:toluene110 °C
(72–87% yield)
N
R1R1
120 122
N
R1
121
PdL2
cascade
cyclization
1.3.3.2 Carbon–Nitrogen Bond-Forming Reactions
In the intramolecular aryne annulation reactions, carbon–nitrogen bond formation
was effectively limited to nucleophilic attack of the aryne by an amine. In the
intermolecular reactions, however, the cyclizations reactions are much more diverse in
their mechanisms. These various pathways are borne out in the numerous ways to
generate substituted indole substructures.
In 2010, Wang reported a direct synthesis of 2-carboxyl indoles (125) from the
reaction between benzyne and azidoacrylates (123, Scheme 1.23).50 Interestingly, this
reaction requires triphenylphosphine to proceed, suggesting that a Staudinger-like
reduction of the azide precedes coupling of the aminoacrylate and the aryne through
azaphosphonium zwitterion 124. This past year, Greaney examined the reaction of tosyl
hydrazones (126) and arynes, and found that indole products result (128).51 This
transformation presumably proceeds through aryl hydrazide 127 via the Fischer
mechanism for indole formation, mediated by the boron trifluoride Lewis acid additive.
Scheme 1.23. Direct indole synthesis by aryne annulation
TMS
OTf
100
R1
Indoles — Greaney (2011)
R2
NTsHN
R3
126
NH
R2
R3
R1
128
CsF
MeCN25 °C, 12 h
then BF3•OEt2
(51–80% yield)
Indoles — Wang (2010)
TMS
OTf
100
R1CO2EtN3
R2
123
CsFPPh3
MeCN:PhMe 50 °C, 5 h, air
(64–89% yield)
NH
CO2Et
R2
R1
125
R1
NPPh3
CO2Et
R2
124
R1N
NH
Ts
R2
R3
127
[3,3]
– NH3
BF3•OEt2
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 22
A number of approaches have been reported for the construction of indole
derivatives (Scheme 1.24). In 2007, Yamamoto showed that diazo compounds (129)
undergo a 1,3-dipolar cycloaddition with arynes to generate indazoles (130).52
Interestingly, the reaction is highly dependent upon aryne stoichiometry; additional
equivalents produce the N-arylated indazole. That same year, Larock developed a
synthesis of isatins (132) by condensation of arynes with N-aryl methyl oxamide (131).53
In a separate effort, Larock coupled tosyl hydrazones (133) and arynes to find that, when
heated, these proceed smoothly to the desired diaza product (130). Interestingly, this
reaction does not stop at the putative aryl hydrazide (127) invoked by Greaney in the
aforementioned indole synthesis (126→128).54
Scheme 1.24. Indole derivative synthesis through heterocyclization with arynes
TMS
OTfR1
R2 H
NTsHN
100 133
CsFEt3NBn+Cl–
THF, 70 °C24 h
(55–84% yield)
R1
130
NH
N
R2
Indazoles — Larock/Shi (2011)
Indazoles — Yamamoto (2007)TMS
OTf
100
R1 R2
H
N2
129
NN
R2
R1
130R3
KF18-Crown-6
THF25 °C, 24 h
(54–90% yield)
1.0 equiv 100, R3 = H
2.0 equiv 100, R3 = R1
TMS
OTf
100
R1 MeO
O
Isatins — Larock (2007)
NH
O CsF
MeCN 25 °C, 24 h
(51–90% yield)
131
N
O
OR2 R1
R1132
Larock’s interest in indole synthesis55 was later extended to carbazole (136)
formation through a two-step, one-pot, palladium-mediated aryne annulation (Scheme
1.25).56 This reaction begins with 2-iodoaniline (139) addition to the aryne (from 100) to
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 23
form diarylamine 135. Palladium catalyst insertion into the aryl iodide precedes C–H
functionalization and closes the 5-membered ring, yielding the carbazole (136).
Scheme 1.25. Two-step, one-pot Pd-catalyzed carbazole synthesis
Benzocarbazolines — Greaney (2009)F
137
Br NMe
138
Mg0
THF
(22% yield)
NMe
H
H
140
NMe
139
Greaney conceived of an approach to benzocarbazolines (140) by reaction of N-
methyl pyrrole (138) with two equivalents of the aryne generated from ortho-fluoro
bromobenzene (137, Scheme 1.26).57 In this transformation, initial [4 + 2] cycloaddition
of benzyne with 138 is followed by a second N-arylation reaction to generate the
ammonium tricyclic intermediate 139. Next, a [3, 3]-sigmatropic shift occurs, forming
the indoline ring system of the observed benzocarbazoline (140).
Scheme 1.26. Pyrrole and aryne coupling + rearrangement to form benzocarbazolines
Benzocarbazolines – Greaney (2009)F
137
Br NMe
138
Mg0
THF
(22% yield)
NMe
H
H
140
NMe
139
Larock58 and Ramtohul59 concomitantly reported very similar reactions in 2009,
wherein 1-H-indole-2-carboxylates (125) react with arynes to form indoloindolones (141,
Scheme 1.27). This condensation reaction is effective across a wide substrate scope.
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 24
Scheme 1.27. Aryne reaction with indoles to form indoloindolones
TMS
OTf
100
R1
Me4N+F–
THF, 25 °C1–2 h
(53–90% yield)
CsFCs2CO3
DME 90 °C, 24 h
(39–94% yield)
Indoloindolones — Larock and Ramtohul (2009)
NH
R3
R2
125
O
OR N
R3
R2
141
O
R1
LarockOR = OMe
RamtohulOR = OEt
Intermolecular aryne annulations have focused on a broader range of substrates
than indoles and indole derivatives. In 2002, Pawlas designed a synthesis of
phenanthridines (114) from the reaction aryl nitriles (143) and two equivalents the
reactant aryne through the activated nitrilium zwitterions 144 (Scheme 1.28).60 Zhu was
able to use an aryne annulation to complete the same molecules while maintaining an
alternative approach from functionalized oximes (145).61 The role of palladium in the
reaction is not clear, but it might assist in N–O bond cleavage after the hetero Diels–
Alder reaction to form the core of the product (114).
Scheme 1.28. Phenanthridines by direct arylation
NO
C6F5 O
TMS
OTf
100
R1
R3R2
145
[Pd(allyl)Cl]2 (2.5 mol%)P(o-tolyl)3 (5 mol%)
CsFMS4Å
H3C(CH2)2CN120 °C, 24 h
(41–67% yield)
NR2
R3
R1
114
Phenanthridines — Zhu (2008)
FCN
R2
142 143
t-BuLi
THF–50!25 °C
(26–43% yield)
N
R2
114
Phenanthridines — Pawlas (2002)
N
R3
R2
146
H
O
O
C6F5
R1
N
R2
144
[4 + 2]
28
– C6F5CO2H
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 25
In an exceptional display of aryne reactivity, Kunai was able to form
benzoxazinones (148) by reaction of aryl aldimines (147) with arynes and gaseous carbon
dioxide (Scheme 1.29).62
Scheme 1.29. CO2 incorporation to form benzoxazinones
Benzoxazinones — Kunai (2006)
TMS
OTf
100
R1 H
NR3
147
R2
CO2 (1 atm)KF
18-Crown-6
THF0 °C, 5–18 h
(49–82% yield)
O
N
O
R1
R2
148
R3
Interestingly, ortho-acyl- (149)63 and ortho-acrolyl anilines (150)64 effectively
react with arynes generated from ortho-silyl aryl triflates (100), yielding variously
substituted acridines (150 and 152) as products (Scheme 1.30). Huang and Larock have
independently demonstrated this reactivity.
Scheme 1.30. Acridines by aryne annulation of ortho-substituted anilines
Acridines — Larock (2011)
TMS
OTf
100
R1
NH2
O
R3
151
TBAT
DME 25 °C, 24 h
(52–96% yield)
N
R3
R1R2
152
Acridines — Huang/Zhang (2010)
TMS
OTf
100
R1
NH2
R2
149
R3
O CsF
THF66 °C, 36 h
(47–54% yield)
NH
R1
R2 R3
O
150
The widespread application of azide-alkyne cycloaddition chemistry, has led to
the use of arynes as activated partners for this reaction, as demonstrated by Chen
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 26
(Scheme 1.31).65,66 In this account, naphthylyne is generated from silyl iodonium triflate
153, and forms the triazole analog (155) through a standard 1,3-dipolar cycloaddition
with benzyl azide 154.
Scheme 1.31. Naphthotriazoles through aryne-azide coupling
Naphthotriazoles — Chen (2011)
Si(OH)Me2
I(Ph)Otf R2
N3 KF18-Crown-6
CH2Cl225 °C, 24 h
(51–78% yield)
NN
N
R2
153 154 155
Interestingly, Yoshida reported different kind of reactivity than what is often seen
in these heterocyclization reactions, in his account of benzodiazopine (157) synthesis
(Scheme 1.32).67 In this case, the heterocyclic products were formed by an aryne C–N
bond insertion reaction between the urea carbonyl and one of its nitrogen subsitutents
(156). While aryne C–N bond insertion is known,68 this marks its only application in
heterocycle formation to date.
Scheme 1.32. Yoshida’s C–N insertion for benzodiazepine synthesis
Benzodiazepines and Benzodiazocines — Yoshida (2002)
TMS
OTf
100
R1NN
O
Me Me
156
CsF
THF66 °C, 36 h
(47–54% yield)n
R1
N
N
Me
O Me
n
157a, n = 1, benzodiazepines157b, n = 2, benzodiazocines
157
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 27
1.3.3.3 Carbon–X Bond-Forming Reactions
One of the relatively uninvestigated aspects of aryne annulation chemistry is the
ability to form entirely novel heterocyclic ring systems that include second heteroatom
partners. A few leading efforts have reported truly unique heterocycles using arynes.
The interesting bridged tetracyclic product (159) of ortho-alkynyl aryl oxime
(158) reaction with an equivalent of aryne reported by Wu touches upon potentially new
structures available for investigation by aryne annulation reactions (Scheme 1.33).69
Scheme 1.33. Aryne C–O bond formation to form bridged tetracycle 159
2-oxa-6-aza-bicyclo[3.2.2.]nona-6,8-dienes — Wu (2011)
TMS
OTf
100
R1TBAF
THF50 °C, 10 h
(42–84% yield)
NOH
R3
HR2
OR2
R1
NR3
158 159
Biehl has used derivatives of seleno- (260)70 and thiourea (163)71 starting
materials to form unprecedented structures with completely unknown properties (Scheme
1.34). Interestingly, formation of the benzothiazines (164) produced by cyclization of
benzyne with the thiourea derivatives (163) can be controlled by fluoride stoichiometry to
such an extent that isothiazine (165) products can actually be favored.
Scheme 1.34. Biehl’s syntheses of benzoselenazines, benzothiazines, and isothiazines
Benzoselenazines — Biehl (2004)
TMS
OTf
100
R1
NR3R2
Se N
NMe2160
R1N
Se NR3
R2
161
CsF
MeCN25 °C, 10 h
–then–NaBH4
(49–85% yield)
TMS
I(Ph)OTf
162
R1N
R3R2
S N
NMe2163
TBAF
CH2Cl20 °C, 1 h
(33–79% yield)
R1 R1N
SN
S
N R3R2
NR3
R2
Benzothiazines and Isothiazines — Biehl (2005)
164 165
1.5 equiv TBAF, 164 is product4.0 equiv TBAF, 165 is product
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 28
Finally, Orenes very recently suggested that phosphorus might be a competent
agent to incorporate into aryne annulation pathways (Scheme 1.35).72 When vinyl
phosphazenes (166) are reacted with arynes, interesting benzazaphosphorinium triflate
salts (167) result.
Scheme 1.35. P–N heterocycles by aryne annulation of phosphazenes
Benzazaphosphorinium Triflates — Orenes (2011)
Ph2PN
R3
R4TMS
OTf
100
R1
N
Ph2P
R4
R3
R2
166
OTf
R2
R1CsF
MeCN 25 °C, 24 h
(57–95% yield)167
These completely novel products of aryne annulation suggest that, as chemistry
continues to evolve into targeted synthesis more carefully designed molecules, aryne
annulations will continue to have a place in pushing innovation in the field.
1.4 CONCLUDING REMARKS
The prevalence of nitrogen-containing heterocyclic systems in natural products
has led to a number of inventive methods to generate highly complex structures.
Reactions using arynes as intermediates for the synthesis of benzannulated heterocycles
are appealing alternatives to the prevalent strategies that rely on transition metal catalysis
and electophilic aromatic substitution. Because of their highly reactive nature, aryne
annulation is a complementary strategy to these known approaches, allowing chemists to
access challenging heterocyclic motifs through intra- and intermolecular C–C and C–N
bond formations. Reactions with arynes allow the functionalization of two adjacent
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 29
positions on an aromatic ring, a property that makes them exceedingly amenable to
convergent synthetic procedures. Moreover, the propensity of benzyne to participate in
multicomponent reactions, and transformations with generally inert, unique reaction
intermediates combine to make these appealing agents for the synthesis of novel
heterocyclic structures.
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 30
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Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 32
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