Recent Applications of Benzynes and Indolynes in Organic Synthesis

Report
Recent Applications of Benzynes and
Indolynes in Organic Synthesis
Trevor Mogg
Nov.10, 2011
Outline

Part I - Benzyne







Importance
Discovery
Properties
Preparation
Selected Reactions
Total Synthesis
Part II – Indolyne

Reactivity and Applications
2
Importance of Benzynes








Benzynes unique, highly reactive intermediate
Useful to create molecules
Traditional methods of preparation use harsh conditions or
dangerous precursors
High reactivity requires careful selection of reaction
conditions, substrate
Mild method of preparation allows more flexibility
Over last decade, new reactions of benzynes developed
Mild method of preparation extended to generate
heteroaromatic indolynes
Useful for preparing biologically active molecules
3
Discovery

First Evidence by Roberts (1953)
= 14C

via
Trapping by Wittig (1956)
Roberts et al, JACS, 75, 3290 (1953).
G. Wittig and L.Pohmer, Chem. Ber., 89, 1334 (1956).
4
Benzynes




Belong to family of intermediates known as arynes
Di-radical, aromatic, highly reactive species
Properly called didehydrobenzenes – ortho, meta, para
Two non-bonding orbitals outside ring, perpendicular to p
system, two electrons between them
ortho
Roberto Sanz, Org. Prep. Proced. Int., 40 (3), 215-291 (2008).
Sander et al, Angew Chem. Int. Ed., 2003, p502.
meta
para
5
Ortho-Benzyne



Reduced overlap of orbitals gives weak p bond
Better described as strained alkyne
Low-lying LUMO – Electrophilic


Readily undergoes pericyclic reactions, nucleophilic addition
Reacts with nucleophiles not normally reactive towards alkynes
K.N. Houk et al, Tet. Lett., 35, 3237 (1979). Sander et al, Angew Chem. Int. Ed., 2003, p502. Roberto Sanz, Org. Prep. Proced. Int.,
40 (3), 215-291 (2008). http://www.bama.ua.edu/~blacksto/CH435_CH531/home.html. Accessed Oct.20, 2011
6
Preparing Benzyne
Roberto Sanz, Org. Prep. Proced. Int., 40 (3), 215-291 (2008).
7
Less Common Methods
Cation
Fragmentation
-2 N2
Radicals
Zwitterion
*EXPLOSIVE*
L. Friedman et al, Org.Synth., 48, 12 (1968). Jones, J.Org.Chem. ,1971, p1536.
R.W. Franck et al, JACS, 1968, p.5814. Rees et al, J. Chem. Soc., 1969, p742.
8
Aryl Anions

Ortho-metalation/elimination

Metal-halogen exchange/elimination

Fluoride induced elimination

Milder base than above methods, better functional group tolerance
Durst et al, Org. Lett.,Vol. 1, No.12, 1973 (1999). Suzuki et al, Tet. Lett., Vol.32, No.46, 6735 (1991).
Kobayashi et al, Chem. Lett., 1211 (1983).
9
TMS Triflate



Available from Aldrich – $176 for 5 grams
Several published methods of preparation
One example uses 2-bromophenol as starting material
92%
Kobayashi et al, Chem. Lett., 1211 (1983).
Guitian et al, Synthesis, 2002, p.1454.
80%
65%
10
Regioselectivity

Controlled by Steric and Electronic Effects
Roberto Sanz, Org. Prep. Proced. Int., 40 (3), 215-291 (2008).
K. Suzuki, Tet. Lett., 1991, Vol.32, p6735.
11
Selected Reactions of Benzyne


Nucleophilic Addition
Pericyclic Reactions





[2+2]
[3+2]
[4+2]
Ene
Palladium Catalyzed Reactions
12
Nucleophilic Addition
53%
Buchwald et al, J.Org.Chem., 2000, p5334.
Barrett et al, JACS, 2006, Vol. 128, p14042
65%
13
Nucleophilic Addition
Hiyama et al, Angew. Chem. Int. Ed., 2002, p.3247.
66%
Greaney et al, Angew. Chem. Int. Ed., 2009, p5199.
65%
14
Acyl Alkylation of Benzyne

Insertion of Benzyne into C-C bond
+
42%
53%
Via
Stoltz et al, JACS, 2005, p5341.
15
Acyl Alkylation of Benzyne

Improved selectivity by removal of a-substituent
90%

Ring Expansion
50%
Stoltz et al, JACS, 2005, p5341.
16
Pericyclic Reactions



Benzyne low lying LUMO; readily undergoes pericyclic
Cyclic dienes locked in flat s-cis conformation give [4+2] (e.g.
furan, cyclopentadiene)
Some substrates undergo competing [4+2], [2+2], and ene
processes
Waali, J. Org. Chem., 1975, p1355. Huisgen, Tet. Lett., 1963, p1017.
Crews, J. Org. Chem., 1973, p522. Braun, J. Org. Chem., 1970, p1208.
17
[2+2] Additions
Liebeskind et al, J.Org.Chem., 1989, p1435.
44%
Hsung et al, Org. Lett., 2009, p.3666.
95%
18
[3+2] Additions
+
Larock et al, J.Org.Chem., 2010, p7381
58%
R = CH2CO2Et,
Aryl, Cinnamyl
Larock et al, Org. Lett., 2008, p2409.
19
[4+2] Additions
K. Suzuki et al, JACS, Vol.114, No.9, p.3568 (1992).
+
Olofson et al, J.Org.Chem., 1992, p.7122.
68%
20
Intramolecular [4+2] and Ene Additions
Danheiser et al, Org.Lett., 2005, p3917.
Lautens et al, JACS, 2011, Vol.133, p.14200.
21
[4+2] - Dihydronapthalenes
+
R
Yield
H
84%
Br
80%
CO2Et
85%
CH3
0%
48%
er > 19:1
First Enantioselective Aryne Diels Alder Reaction
Lautens et al, JACS, 2005, Vol. 127 p15028.
22
Palladium Catalyzed Cyclizations
Yamamoto et al, Angew. Chem. Int. Ed., 2000, p173.
Phenanthrene
69%
+ 5eq.
Larock et al, J. Org. Chem., 2008, p6679.
Fluoren-9-one
75%
23
Palladium p-Allyl Reactions
R1 = aryl, allenyl,
alkynyl
Cheng et al, Org Lett, 2005, p2921.
Cheng et al, Org. Lett., 2004, p2821.
Cheng et al, Synthesis, 2005, p1693.
Cheng et al, Angew Chem. Int. Ed, 2009, p391.
Yields 66-93%
R2 = aryl, alkyl
Yields 59-92%
24
Outline

Part I - Benzyne







Importance
Discovery
Properties
Preparation
Selected Reactions
Total Synthesis
Part II – Indolyne

Reactivity and Applications
25
Total Synthesis: (-)–Quinocarcin





Isolated from Streptomyces melunovinuceus
Antitumor, antibiotic properties
Brian Stoltz’s Group, California Institute of Technology
Shortest total synthesis to date (11 steps)
Formed by formal [4+2] annulation of benzyne
(-) - Quinocarcin
Stoltz et al, JACS, 2008, vol.130, p17270.
Zhu, JACS, 2008, Vol.130, p7148.
26
Enamide Synthesis
74%, 2 steps
93%
Stoltz et al, JACS, 2003 p.15000. Stoltz et al, JACS, 2008, p17270. Karmas et al, JACS, 1952 p1580.
69%
27
[4+2] Annulation
60%
Stoltz et al, JACS, 2008, vol.130, p1558. Stoltz et al, JACS, 2008, vol.130, p17270.
28
Completion of (-)-Quinocarcin
99%
80%
(-)-Quinocarcin
81%, 2 steps
Stoltz et al, JACS, 2008, vol.130, p17270.
29
Outline

Part I - Benzyne







Importance
Discovery
Properties
Preparation
Selected Reactions
Total Synthesis
Part II – Indolyne

Reactivity and Applications
30
Part II: Indolynes
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A heteroaromatic aryne
First indolyne from Igolen and co-workers in1967; nothing in
literature until 2007
Keith Buszek and co-workers prepared and trapped three
indolynes with furan
Useful to synthesize compounds containing indole rings ->
biologically active compounds
Further studies by Buszek and Garg Labs
4,5-Indolyne
5,6-Indolyne
6,7-Indolyne
Reinecke, Tetrahedron, 1982, p427. Buszek et al, Org.Lett., 2007, Vol.9, No.21, p.4135
Igolen et al, Comptes Rendus des Seances de l’Academie des Sciences, Serie C: Sciences Chimique,Vol. 265, Iss.2, p.110, 1967.
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Indole TMS Triflate

To study reactivity of 4,5-Indolyne, TMS Triflate was prepared
88%
Garg et al, JACS, 2010, vol.132, p17933.
Garg et al, Org. Lett., 2009, Vol.11, No.4, p1007.
32
Indolyne Reactivity Patterns
Nucleophile
K. Houk, N. Garg et al, JACS, 2010, Vol.132, p.1267.
C5
:
C4
12.5 :
1
3
:
1
3.3
:
1
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Unsymmetrical Aryne Distortions



Pre-distorted ring gives C5 larger internal angle, orbital has electropositive
“p” character
C4 smaller internal angle, orbital has more electronegative “s” character
Attack occurs at flat, electropositive end, relieves ring distortion
Aniline Addition
C5
C5
C4
C3a
C4
C3a
C3a
K. Houk, N. Garg et al, JACS, 2010, Vol.132, p1267.
34
Regioselectivity Reversal

4,5-Indolyne with Br atom, reversed selectivity
C4
C5
Garg et al, JACS, 2011, Vol.133, p.3832.
C5
C4
35
Indolactam V




Activator of protein kinase C
Synthesis by Neil Garg’s Group
Demonstrates reversal of normal indolyne selectivity by
introducing Br atom
C-N bond formed by nucleophilic attack
Indolactam V
Garg et al, JACS, 2011, Vol.133, 3822.
36
Indolyne Addition
62% (<5% other regioisomer)
Garg et al, JACS, 2011, Vol.133, 3822.
K.Houk, N.Garg et al, JACS, 2010, vol.132, p17933.
37
Completion of Indolactam V
Yield Not Given
3:1 Mixture of
Diastereomers
Indolactam V
Garg et al, JACS, 2011, Vol.133, 3822.
Nakatsuka et al, Agric. Biol. Chem., 1989, vol.53, p2257.
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(-)-N-methylwelwitindolinone C Isothiocyanate





Isolated from blue-green algae Hapalosiphon welwitschii and
Westiella intricata in 1994
Reverses P-glycoprotein mediated multiple drug resistance to
variety of anticancer drugs in human cancer cell lines
Promising for treating drug-resistant tumors
First total synthesis of this compound by Neil Garg’s Group
Intramolecular cyclization via nucleophilic attack on indolyne
(-)-N-methylwelwitindolinone C Isothiocyanate
Garg et al, JACS, 2011, Vol.133 (40), p15797.
Moore et al, JACS, 1994, Vol.116, p9935.
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Retrosynthesis
Indolyne Cyclization
Garg et al, JACS, 2011, Vol.133 (40), p15797.
40
Indole Substitution
S-Carvone
Garg et al, JACS, 2011, Vol.133 (40), p15797.
Natsume et al, Chem. Pharm. Bull., 1994, Vol.42, p1393. Wang et al, Synlett., 2003, p.2377.
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Indolyne Cyclization
+
46%
2.5
Garg et al, JACS, 2011, Vol.133 (40), p15797.
:
1
42
Nitrene Insertion
Garg et al, JACS, 2011, Vol.133 (40), p15797.
43
Completion of Target
(-)-N-methylwelwitindolinone C Isothiocyanate
Garg et al, JACS, 2011, Vol.133 (40), p15797.
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Summary
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Benzyne readily undergoes nucleophilic, pericyclic, palladium
catalyzed reactions
Mild conditions allows greater variety of substrates to be used,
new reactions
Benzyne has been used to complete total synthesis of (-)Quinocarcin
Regioselectivity of Indolyne explained through models
Reversal of Indolyne regioselectivity demonstrated through
synthesis of Indolactam V
Indolyne has been used to complete first total synthesis of Nmethylwelwitindolinone C isothiocyanate
45
Acknowledgements

Dr. Tony Durst
Durst Lab Members


Chemaphor Members
46
EXTRA SLIDES

Prep of starting material in N-Methylwelwetindolinone C
Isothiocyanate Synthesis
47
Indolynes

Prepared three indolynes
Buszek et al, Org.Lett., 2007, Vol.9, No.21, p.4135
48
TMS Triflate
Guitian et al, JACS, 1999, p5827.
49
Bromoindole TMS Triflate Synthesis
Garg et al, JACS, 2011, Vol.133, 3822.
Garg et al, JACS, 2010, vol.132, p17933.
50
Pd Cat. Cycle
Cheng Suzuki
Cheng Stille Alkyne
51
Pd Catalytic Cycle
Cheng, Stille Allene coupling
Cheng Copper Pd coupling
52
Pd Cat. Cycle
Larock cat. cycle
53
Pd Cat Cycle
Yamamoto cat. cycle
54
Reagents
Comins Reagent
dba
Dibenzylidene acetone
Bathophenanthroline
dppf
1,1’-bisdiphenylphosphinoferrocene
dppp
1,3-bis(diphenylphosphino)propane
dppb
Bis(diphenylphosphino)butane
55
Reagents
IBX
2-iodoxybenzoic acid
Dess Martin
HMDS
56

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