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
HO
Me HO OH N OMe
O NH
N MeO HO Me
H N O
H
HO OAc OS H
N Me N Me
H H H N Me
H MeO
N
O O N
O Me H O
N
O OH
Coniine (1) Tropinone (2) Morphine (3) Strychnine (4) Quinine (5) Ecteinascidin 743 (6)
Yondelis !
• poison • • stimulant • • analgesic • • poison • • anti-malarial • • antitumor antibiotic •

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

H H H H
N O N O N N N
N

2-H-azirines pyrroles maleimides 3-pyrrolines 2-pyrrolines 1-pyrrolines

O O O O
H
N
HN N N HN NH HN NH HN NH HN N
N
O
pyrrolidines imidazoles imidazol-5-ones imidazol-2-ones hydantoins imidazolines 2-imidazolines
O
N N
HN NH O N O HN S N O NH

2-imidazolidines oxazoles isoxazoles pyrazoles thiazoles 2-oxazolones

O O
H
N N O
N O N O N HN O O HN HN NH
NH
O
pyrazolines 2-oxazolines 3-oxazolines oxazolidinones 2-isoxazolines imidazolines urazoles
H
R N
N N N N
HN N N O N O S N
N N
NH N N N

1,2,3-triazoles 1,2,4-triazoles 1,3,4-oxadiazoles 1,2,4-oxadiazoles 1,3,4-thiadiazoles tetrazoles

N N N

N N O N N N N
H H H
pyridines 2-pyridones dihydropyridines piperidines pyrimidines 1,3,5-triazines
Chapter 1 – Aryne Annulations in the Synthesis of Nitrogen Heterocycles 4
Figure 1.3. Fundamental benzannulated nitrogen-containing heterocycles

O NH
N N
N N N N
H H H H
indoles oxindoles indolizines indolizinones carbazoles indolines isoindoles
N H
N O O S
N O N
N
N N N N N N
H H H H
indazoles benzimidazoles azaindoles benzimidazolones benzoxazoles benzisoxazoles benzothiazoles
O

N
N
N
N N N O N N N
H H H H H
1,2-dihydro- tetrahydro-
benzotriazoles quinolines 2-quinolones 4-quinolones quinolines quinolines isoquinolines
O
N
NH N
N NH
N N N N
3,4-dihydro- tetrahydro-
isoquinolones isoquinolines isoquinolines naphthyridines quinazolines quinoxalines

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

Bischler–Möhlau (1881)
HO R'
O R' R'
H3O+ –H2O
R R
N R SEAr N N
H H H
7 8 9
Pomeranz–Fritsch (1893)
Me
OMe O

OMe HCl SEAr

N N N
–MeOH
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

Poupon (2004) CO2H

Me O
Me O
CN N
N O
N O
54% HBF4 OMe SEAr

Et2O
MeO OMe 23 °C (17% yield)
O OMe MeO OMe
OMe O O MeO OMe
OMe OMe
O OMe
13 14 15 16 PK11195 analogue (17)
Ritter Reaction

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

Mestroni (1990) Me
NO2 H NO2
N H Doebner– N H
NO2 Me O As2O5 Miller Me
N Me
NH2 Me Me Me
H 85% aq H3PO4 Quinoline N
120 °C Synthesis
Me Me Phenanthroline Me
(24% yield) Ligand (22)
18 19 20 21

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)

Fu (2010) NH2
CuI (10 mol%)
O 2 eq K2CO3 – H2O
NH2
R1
NH2 O N R1 = -H, -OR
R1 R1 R1
H2N R2 O2 (37–87% yield) R2 = -aryl
Br i-PrOH Cu NH N R2 N R2
H
110 °C Br O
R2
23 24 25 26 quinazolines (27)
Ullman-Type Coupling

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)

Roberts (1953)

Cl NH2
KNH2
NH2 +
NH3
NH2
(43% yield)
XX XX XX XX
= 14C

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
24
Scheme 1.6. The many roads to benzyne

N2

F N
CO2 N
S
MgBr O2

0 °C heat 0 °C
N
F
N
N
–20 °C Pb(OAc)2
Li NH2

Benzyne
strong base Bu4NF
(28)
X TMS

OTf
Mg or Bu4NF
RMgX n-BuLi Ph
X1
I
X OTf
X2
TMS
OTf

Scheme 1.7. Some representative reactions using benzyne

nucleophilic [4+2]
additions cycloadditions

O
O

BrMg

Nt-Bu MeO OMe

OMe
multicomponent t-BuNC [2+2]
R OMe
reactions cycloadditions
R R
Benzyne
R

O
Pd(PPh3)4
CO2Me

CO2Me

!-bond insertion metal-catalyzed

reactions reactions

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

Indolinoisioquinolines — Synthesis of Cryptausoline — Kametani (1967)

MeO MeO MeO

NaNH2
NH N N OR
BnO BnO BnO
NH3 (l), THF
O –40 °C
OR
(77% yield)
O Cl
33 34 35
Indoloisoquinolines — von Angerer (1990)

MeO R2 MeO R2 MeO R2

NH NaH NNa oxygen

N
R1 H R1 R1
DMSO
Br 25 °C, 15 h R3

(46–55% yield)
R4
R3 R3
36 R4 37 R4 38

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)

4-aminoindoles — Synthesis of Makaluvamine A — Iwao (1998)

NH2
NH2
Cl HN

LICA
5 4
N THF, 0 °C N
MeO N MeO
MeO
R (75–78% yield) R
39 40 R 41

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

Indolines — Synthesis of Dictyodendrins A–E — Tokuyama (2010)

MeO MeO
OMe OMe

Br Br

Br Mg(TMP)2•2LiBr Br CuI, –78 °C;

BocHN BocN 4-iodoanisole
THF, –78 ! 0 °C N N
OMe Pd(PPh3)4 OMe
Boc Boc
Mg(TMP) –78 ! 23 °C
Br OMe OMe
(93% yield)

42 43 44 45
OMe

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 S
NH2 t-BuLi
R n R n 47a, n = 1, (87–89% yield)
Br
THF
N
47b, n = 2, (85–95% yield)
–100 ! 20 °C H 47c, n = 3, (64–92% yield)
46a–c 47a–c
Tetrahydroquinoxalines, benzoxazines, benzothiazines — Kurth (2005)
R R R

H2N H NH NH
X F LiOt-Bu X X
50a, X = NH, (69% yield)
NHAlloc THF:DMF NHAlloc NHAlloc
50b, X = O, (82–91% yield)
O2N 25 °C, 24 h O2 N O2 N 50c, X = S, (88% yield)
H H H
N N N

48a–c O 49a–c O 50a–c O

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
32
bearing a C(1)-exo-methylene substituent (54). 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

Benzazepines — Synthesis of Cephalotaxinone — Semmelhack (1972)

KCPh3 O
O N O N N
DME, 50 °C O
H
O Cl (13–16% yield) O
OMe OMe O
O O
OMe
51 52 Cephalotaxinone (53)
Isoquinolones — Synthesis of Xylopinine — Kametani (1977)

MeO MeO MeO

NaNH2
N O
1 N O N O MeO
MeO NH3(l), –40 °C MeO
Br
(15% yield)

MeO OMe OMe

56 OMe
54 OMe 55 OMe

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

Tetrahydroisoquinolines — Jaques (1977)

Cl

K/NH3(l)
N –78 °C N N
Me Me Me
CN (50% yield) CN CN

57 58 59
Isoindoles — Jaques (1977)
Cl
Me K/NH3(l) Me
N N
N Me
–78 °C
CN CN
(89% yield) CN
60 61 62
H
Isoxindoles — Synthesis of Cepharanones A + B — Couture (1997)
O O
O O O
I R1
KHMDS R1 R1 66 NPMB
NPMB NPMB NPMB
R1
O THF THF, –30 °C
Br P –78 ! –30 °C P Ph P Ph
Ph Ph O O (71–74% yield)
Ph Ph
I
63 64 65 67

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

Indoles — Barluenga (2002)

E Me
4
F t-BuLi E+

Br THF –78 ! –20 °C

N –100 ! –40 °C N N N
R R R (46–75% yield) R
68 69 70 71
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

Isoquinolines — Synthesis of Chelerythrine Chloride — Kessar (1974)
O O O
Br
O KNH2 O MnO2 O

NH NH3 (l) NH CHCl3 N

MeO MeO MeO
OMe OMe (80% yield, OMe
2 steps)
72 73 74

Isoquinolines — Fagaronine Chloride — Stermitz (1974)

Oi-Pr Oi-Pr Oi-Pr

Br NaNH2
MeO MeO MeO
OMe OMe OMe
NH3(l)
NH air oxidation N N
MeO MeO MeO
75 (24% yield) 76 77

Phenanthridinones — Synthesis of N-methylcrinasiadine — Sanz (2007)

O O O
F O O O
Br MeOH H
t-BuLi –78 ! –20 °C
N THF –then–
Me –100 ! 20 °C air
O N N N O
(65% yield)
O Me Me Me
78 79 80 N-methylcrinasiadine (81)
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

Benzisoxindoles — Synthesis of Aristolactam — Castedo (1989)

O O
MeO [4 + 2] MeO O
MeO LDA N
NH
THF, 0 °C NH
MeO Br MeO MeO
(35% yield)

MeO
OMe OMe
82 83 Aristolactam (84)

Benzisoxindoles — Synthesis of Eupolauramine — Couture (2001)

N N
N

LTMP
[4 + 2]

O –30 °C O
O
NH (30% yield) NH
N
H
Br

85 86 87

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
Isoquinolones — Castedo (1986)

MeO MeO MeO

CO2 cat. TCA [4 + 2]
N N N O
MeO O MeO O MeO
DME, reflux – CO
N2
Me (52% yield) Me Me
O O
28
87 88 89 90

2-Quinolones — Rigby (1991)

O
C O O
N C OMe
N OMe
MeO N HN
O Pb(OAc)4
N O
OMe O
N OMe
O MeO CH2Cl2 94
NH2 O
O
91 92 93 95
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)

CO2 acetone
CHCl3 – HCN
N N N N
N2 reflux CN – HCN
NC CN CN
CN
88 96 97 98 99
(20% yield) (11% yield)

Pyridoisoindoles — Xu (2008) R2

R3
O O
O R3
N
TMS Br CsF
R1 R1 N
MeCN, 80 °C R2
OTf R2 N 2h

(36–60% yield) R3
R1
100 101 102 103 104 105
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

Iminoisoindoles — Yoshida (2004)

R2
TMS NTs KF N
18-Crown-6
R1 C N R2
H R1 NTs
OTf R3 THF
25 °C, 24 h

100 106 107 (35–68% yield) 108

R3
Isoquinolines — Huang (2009)
R2
TMS CsF
C N
R1 R2 N H R3 R1
MeCN:PhMe
OTf 40 °C, 12 h
2 equiv (55–79% yield) R3 R1
100 109 110 111

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

Phenanthridines — Wang (2006) R3

NH2
N2
N
O
R3 DCE
CO2 80 °C
R2 2h
88 112 113 114 R2
(31–95% yield)
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)

H Ts
Ts Ts N
N N H
TMS CsF N 4! Ts [4+2]
R1 H H
dioxane
OTf 110 °C, 24 h

(51–87% yield)
100 115 116 117 118

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)
R1 CsF R1 R1
Pd2(dba)3 (2.5 mol%)
TMS dppp (5 mol%) cascade
N N N
Br
1:1 MeCN:toluene cyclization
OTf 110 °C PdL2

(72–87% yield)
119 120 121 122

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

Indoles — Wang (2010)
R2
CsF R2
TMS N3 CO2Et PPh3
R1 R1 R1 CO2Et
MeCN:PhMe N
OTf R2 50 °C, 5 h, air N CO2Et
H
PPh3
(64–89% yield)
100 123 124 125

Indoles — Greaney (2011)

Ts
BF3•OEt2 R3
TMS N
TsHN CsF NH [3,3]
R1 N R1
R1 R2
OTf R3 MeCN R2 – NH3
R2 25 °C, 12 h N
R3 H
then BF3•OEt2
100 126 127 128
(51–80% yield)
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

Indazoles — Yamamoto (2007)

R2
TMS N2 KF
18-Crown-6 1.0 equiv 100, R3 = H
R1 R2
R1 N
OTf H THF N
25 °C, 24 h 2.0 equiv 100, R3 =
R3 R1
100 129 (54–90% yield) 130

Isatins — Larock (2007) O

O CsF
TMS R2 R1 O
MeO MeCN N
R1 N 25 °C, 24 h
H
OTf O
(51–90% yield)

100 131 132

R1

Indazoles — Larock/Shi (2011)

CsF R2
TMS TsHN Et3NBn+Cl–
N
R1 R1 N
THF, 70 °C
OTf R2 H N
24 h H

100 133 (55–84% yield) 130

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 Me H
N Mg0 Me
Br
N
THF N H
Me
(22% yield)
137 138 139 140

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 Me H
N Mg0 Me
Br
N
THF N H
Me
(22% yield)
137 138 139 140

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

Indoloindolones — Larock and Ramtohul (2009) CsF

Cs2CO3

DME
Larock 90 °C, 24 h
OR = OMe R3
R3 (39–94% yield)
TMS O
R2 O
R2
R1 N
N OR
OTf H Ramtohul
OR = OEt
100 125 Me4N+F– 141
R1
THF, 25 °C
1–2 h

(53–90% yield)

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

Phenanthridines — Pawlas (2002)

R2 R2
F
CN t-BuLi 28
N
R2 THF N [4 + 2]
–50!25 °C

(26–43% yield)

142 143 144 114

Phenanthridines — Zhu (2008) R1

C6F5 O R1
H
O [Pd(allyl)Cl]2 (2.5 mol%) O
TMS N P(o-tolyl)3 (5 mol%) R2 – C6F5CO2H
N
R1 O C6F5 R2
CsF N
OTf R2 R3 MS4Å
H3C(CH2)2CN
120 °C, 24 h
R3
100 145 (41–67% yield) 146 114 R3
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)

CO2 (1 atm)
NR3 KF R3
TMS R2
18-Crown-6 N
R1 H
R2 THF R1
OTf 0 °C, 5–18 h O

(49–82% yield) O
100 147 148

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 — Huang/Zhang (2010) O

R2 R3 R3
R2
TMS
O CsF
R1 R1
THF
OTf NH2 66 °C, 36 h N
H
(47–54% yield)
100 149 150

Acridines — Larock (2011)

O R3
TMS
R3 TBAT
R1 R2 R1
DME
OTf NH2 25 °C, 24 h N

(52–96% yield)
100 151 152

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
65,66
(Scheme 1.31). 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)

R2
N3
KF
Si(OH)Me2 18-Crown-6 N
N
CH2Cl2 N
I(Ph)Otf R2 25 °C, 24 h

(51–78% yield)
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)

O
Me
TMS O N
CsF 157a, n = 1, benzodiazepines
R1 Me Me R1
N N THF 157b, n = 2, benzodiazocines
OTf 66 °C, 36 h N n
n
Me
(47–54% yield)
100 156 157
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)
OH
N R1
TMS R3
TBAF
R1 H N
R2
R2 THF
OTf 50 °C, 10 h O

R3 (42–84% yield)
100 158 159

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)

R3
R2 R3 Se N
TMS N CsF R2
R1
R1 MeCN N
Se N
OTf 25 °C, 10 h
–then–
NMe2 NaBH4
100 160 161
(49–85% yield)

Benzothiazines and Isothiazines — Biehl (2005)

R3
R2 R3 S N S
TMS N TBAF R2 1.5 equiv TBAF, 164 is product
R1 R1 N 4.0 equiv TBAF, 165 is product
R1 N
S N CH2Cl2
I(Ph)OTf 0 °C, 1 h N R3
NMe2 R2
(33–79% yield)
162 163 164 165
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)

OTf
R3 Ph2
TMS P R3
R4 CsF
R1 Ph2P
R1
OTf N MeCN
25 °C, 24 h N R4
R2
(57–95% yield)
100 166 167

R2

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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