Baran Lab GM
10/1/11
"Flatland": Logic and Methods in the Synthesis of Benzenoids
Introduction
Steven McKerrall
Synthesis of Benzenoids: Substitution versus Synthesis
-Scope: -The synthesis and substitution chemistry of simple and
complex benzenoid aromatics
-Logic in the synthesis of complex polycyclic benzenoids
Rn
R1
R2
-Not covered: Heterocyclic aromatics, Polymer chemistry, etc.
-See Also:
Directed Metalation (Krawczuk, 2008)
Atropselective Biaryl Synthesis (Gulder, 2008)
Direct sp3-sp2 Coupling (Lin, 04)
The key choice in the retrosynthesis of a benzenoid is whether to use
substitution chemistry or synthesis to prepare the substituted aromatic
General Guidelines:
In the synthesis of simple to moderately substituted benzene
derivatives (<4 substituents), venerable substitution methods are
generally used
Background:
-Benzene was first isolated by Michael Faraday in 1825
-1:1 Hydrogen to carbon ratio and unusual chemistry was
perplexing to chemists who proposed a variety of possible
polycyclic and/or polyene structures
MeO
HCl, CO
AuCl3
MeO
MeO
CHO Br
2
MeO
MeO
CHO
MeO
Br
Polyalkyl substituted benzenes can be challenging to prepare by
substitution methods and often need to be synthesized
Claus
(1867)
Dewar
(1867)
Ladenburg
(1869)
Thiele
(1899)
Kekule
(1865)
-The structure of benzene was firmly established with X-Ray
crystallography by Kathleen Lonsdale in 1929
HO
-Benzenoids are ubiquitous and found in all classes of natural products,
pharmaceuticals, materials, etc.
O
O
OH
OH
H
N
Alkyl or Aryl fused benzene rings are efficiently synthesized via a
variety of methods
Most substituted naphthalenes are more easily synthesized than
substituted
Fused polycyclic aromatics can be synthesized in a highly
convergent manner
HO
OH
O
Tetrangomycin
Rm
X
HO
X
Rm
+
Salbutamol
Rn
Rn
X
X
1
Baran Lab GM
10/1/11
"Flatland": Logic and Methods in the Synthesis of Benzenoids
Substitution Methods on Benzenes
Selectivity can even be governed by reagents and conditions
Electrophillic Substitution
EDG
EDG
NBS, NIS, Br2
EDG
NBS, NCS
Br2
E
E+
+
MeO
E
OH
-Sterics favor para but mixtures are usually seen
-Polysubstitution is common
EWG
EWG
E
E
DG
MeO
DG
DG
Li
RLi
In systems with multiple electronic factors selectivity is very common
R
R
OMe
Nuc
LG
Nuc
Br2
EWG
EWG
OMe
OHC
OH
-Generally requires one or more electron withdrawing groups on the arene
-Intramolecular case proceeds under much milder conditions
OHC
OMe
OH
O
Br2
OH
OMe
CHO
HO
CHO
Br2
MeO
Br
CHO
O
NH2
HO
OMe
O
O
CONH2
NaOH
Br2
HO
CHO
R
Nucleophillic Substitution
Highly substituted benzenes give highly selective reactions, but the
selectivity is largely empirical
MeO
E
E
DG=SO2R, SOR, CONR2, CONHR, CO2H, MOM, OAr, CN, etc.
E=RCHO, RCOR', RX, CO2, TMSCl, Ac2O, RNCO, X2
OMe
I2, Br2
OMe
OH
See: Directed Metalation: A Survival Guide (Krawczuk, 2008)
In general selective, reduced polysubstitution
MeO
MeO
Br2/tBuNH2
Electrophillic substitution methods are mose useful (selective) on
systems containing a number of electronically active groups
Directed Metalation
+
Br2
Steven McKerrall
OH
O
then H2O H N
2
Name?
63% overall
Org. Syn., 2007, 84, 325
2
Baran Lab GM
10/1/11
"Flatland": Logic and Methods in the Synthesis of Benzenoids
Preparation of o-Silyl T rif lates
Nucleophillic Substitution (cont.)
F
O2N
OiPr
OR2
HO
R1
O
DMF
86%
OiPr
Prepared in 50% overall yield
6 steps from simple aromatic
compounds
OMe
3 Steps 84%
OR2
R1=NO2, R2=iPr
R1=R2=H
Plagiochin D
1.42
CO2-
OH
1.44
N2
R
CN
Li
Nuc
CN
CN
Computed Bond Lengths
Chem. Soc. Special Publ., 1958, 100
R
R
T et. Lett., 2000, 41, 8401
OMe
F
OMe
BuLi
MgCl
OTBDPS
MgCl
TMS
N
N
O
O
X
OMe
N
I
ArI
OMe
65%
OMe
OMe
N
NH2
E
E+
1.22
+
N
N
TMS
Substitutions on arynes
Benzyne can be generated from several different starting materials
N
OMe
HMDS
then BuLi
OTf
MeO
OH then Tf 2O MeO
42%
overall
Stoltz, Org. Lett., 2010, 12, 1224
MeO
OMe
NH2
66% from the
phenol
Br
Li
The significant distortion
inherent arynes makes them
highly powerful electrophiles
TMS
TMS
Nuc1.37
OTf
DBU
then PhNTf 2
Nuc
Benzyne Substitution
CO2H
O
OMe
NBS
MeO
Eur. J. Org. Chem., 2011, 3165-3170
NHiPr
Garg, J. Org. Chem., 2009, 74, 8842
K2CO3
MeO
O
i. TBSOTf
NHiPr
O
ii. TMEDA, BuLi
iii. TMSCl
O
Steven McKerrall
OMe
4 Steps
J. Am. Chem Soc.,
2006, 128, 14042
O
X
OMe
O
O
ent-Clavilactone B O
OMe OH
OTBDPS
3
Baran Lab GM
10/1/11
"Flatland": Logic and Methods in the Synthesis of Benzenoids
Steven McKerrall
OH
Benzyne Substitution (cont.)
O
O
TMS R
1
O
OR2
TMS
BnO
Various cyclic
and acyclic
ketoesters work
R1
OMe
MeO
+
J. Am. Chem Soc., 1974, 96, 4207
Cross Coupling Reactions
X
O
OMe
O
MeO
MeO
RO
OH
O
OMe
OMe 1) NaOMe, air
CO2Me
2) H2, Pd/C
40%
HO
OH
O
Stoltz, Org. Lett., 2010, 12, 1224
R
C
R-M
Rn
X=Cl, Br, I, OTf, OPO(OR)2, etc.
C=Pd, Cu, Ni, Fe
M=B(OR)2, SnR3, Si, ZnX
Mixture
OBn O
Ph
62%
Rn
BnO
O
+
53%
Only observed product
Unsymmetrical
Benzyne
MeO
NH2Ar
Mechanism?
CO2Et
MeO
MeO
OR
51%
NAr
OEt
OMe
(-)-Curvularin
Benzyne Ene, underappreciated reactivity
OMe O
O
OLi
Li+
O
CsF
OTf
O
J. Org. Chem., 1992, 57, 2485
O
OMe
HO
Org. Lett., 2010, 12, 1612
2
Stoltz, J. Am. Chem. Soc., 2005, 127, 5340
TMS
OTf O
CO2R2
CO2R2
2) H2, Pd/C
18%
50-90% yield
OCs
R1
O
1) CsF
O
+
CO2R2
O
O
R1
CsF
OTf
Cs
OBn
Unnamed isolate
from Cercospora
-Useful for modular syntheses
-Useful for substituted biary compounds
-Not generally useful when one coupling
partner is simple (phenyl, tolyl, etc)
-When plannaing it can be compared with
some substitution methods (benzyne)
-Simple or easily accessable aromatics can be
incorporated in synthesis
4
Baran Lab GM
10/1/11
"Flatland": Logic and Methods in the Synthesis of Benzenoids
Synthesis of Isolated Benzene Rings
Dehydro-Diels-Alder Reaction
R2
[2+2+2] Cycloaddition
R
cat. M
R2
R
Pd(PPh3)4
R
+
R
R
R
J. Am. Chem. Soc., 1996, 118, 4218
J. Org. Chem., 1998, 63, 7022
R
BINAP
57-92%
RO2C
Org. Lett., 2003, 5, 4697
CO2R
1) CpCo(CO)2
O
Si iPr 2) TBAF
40-60%
O
R1
R2
O
(PrOi)2B
R3 CpRuCl(cod) O
R1 Pd(PCy3)
HO
B
ArI
HO
R4
R2
R3 or R4=H
R4
R2
R3
R4
R2
Pd(OAc)2
PCy3
CO
J. Am. Chem. Soc., 2005, 127, 9625
R3
O
Ph
OH
Ph
Ph
1) Grubbs II
2) [RhCl(cod)]2
85%
Ar
OiPr
Grubbs II
92%
J. Am. Chem. Soc., 2005, 127, 10470
While the reaction is efficient, the synthesis of RCM substrates is not trivial
OH
R1
R1
OH
Z olefin is the
major bottleneck
Org. Lett., 2004, 6, 1519
R2
R4
Metathesis
Ph
iPr
R4
J. Am. Chem. Soc., 1999, 121, 6391
OH
R1
R3
24-99%
R
R4
OH
R2
Pd(PPh3)4
R4
R3
CO2R
iPr iPr
O Si
R1
R2
R2
Regioselectivity is achieved by using one coupling partner that is
significantly less reactive in the initial cyclometalation
OH
R1
R1
CO2R [Rh(cod)2]BF4
+
R1
R2
In most cases the intermolecular trimerization is
problematic and mixtures of regioisomers is common
2
R1
30-100%
R1
R
R
Steven McKerrall
O
Ph
HO
Ph
Ph
R1
O
X
+
O
R4
R2
R3
Chem. Eur. J., 2008, 14, 9706
5
Baran Lab GM
10/1/11
"Flatland": Logic and Methods in the Synthesis of Benzenoids
Metathesis (cont.)
N2BF4
O
OH
Ph Pd(OAc)2
+
60%
CO2Et
H
Ph
Ar
O
I2, MeOH
R5
R6
R8
R7
R4
Grubbs I or II
then SiO2
R1
87-99%
OH
N
O
R3
R1
85-90%
Ph
R5
R2
R4
R3
NMe2
57-96%
OH
Above
H
96%
2) Acetone,
NaOMe
80%
R2
Tol
Ph
OH
2 Suzuki Couplings
T et. Lett., 1990, 31, 481
19% Yield
Br
O
Tol
Ph
versus
OH
CO2R
O
R1
O
O
OMe
CO2R
Br
Tol
O
O
Ph
N
H
$14/g
R1
R1
Tol
Stahl, Science, 2011, 333, 209
R3I
O
R2
CO2R
20% TsOH
O2, 10%
1) NaOH
R1 I , MeOH
2
R3
R4
R3
Tol
O
Hagemann's
Ester Derivatives
R2
5% Pd(TFA)2
R6
Oxidation of Cyclohexenones
R2
R5
R7
Synthesis of cis olefin is challenging, only tenable systems are fused
at R4 and R5
R3
R1
R2
R5
C6H5
Tet. Lett., 2000, 41, 1913
R3
R2
Ar
O
O
R4 HO R
3
CO2Et
33%
C6H5
Ar
Chem. Eur. J., 2008, 14, 9706
OMe
HO
OMe
H
HO
O
Steven McKerrall
RO2C
TMSO
OMe
OH
R2
Synthesis and chemistry of Hagemann's Ester: Tet., 2010, 66, 2775
-Synthesis of highly substituted cyclohexenones is very well known
-Extremely useful for polyalkyl phenols and anisoles
-Oxidative aromatization to phenols is also possible with I2/tBuOH or Pd/C
Ph
OTMS
OTMSO
TiCl4
CO2Me
66%
J. Am. Chem. Soc., 1980, 102, 3534
See Also: Poly(B-carbonyl)s (Michaudel, 2011)
6
Baran Lab GM
10/1/11
"Flatland": Logic and Methods in the Synthesis of Benzenoids
Phthalide Annulations
Misc. Other Methods
Danheiser Annulation Preview
O
3 Steps
O
O
O
O
TBSO
CHO
Steven McKerrall
O
Base
+
+
OAc
OMe
X
Name Reaction?
O
MOMO
Mechanism?
OH
CO2H
76%
O
OMOM
MeO
X
X
X
X=CN, SO2Ph, SPh,
J. Am. Chem. Soc., 1986, 108, 806
Synthesis of Phthalide coupling partners
Naphthalenes and higher order fused polyaromatics
CHO
R
Substitution of Naphthalenes
R
MeO
CHBr2
R
R
O
R
O
CO2Me
O
OMe
CH(OEt)2
CO2Et
R
Br
R
R
N
CO2Me
O
82%
MeO
J. Org. Chem., 1996, 61, 2885
O
O
SO2Ph
OH
O
OMe
MeO
R
CONEt2
o-Quinodimethanes
OMe
CN
CHO
Br
-Electrophillic Substitution, Directed Metalation, SnAr, etc can
be used to prepare moderately functionalized Naphthalenes
-Chemistry is very similar to that of benzenes
-In most cases naphthalenes bearing 4 or more substituents
are synthesized because of regiochemical issues
MeO
O
O
O
O
MeO
O
OH
4 Steps
Mycophenolic Acid
O
O
OTBS
O
O
PhH,
MeO
CO2Et
MeO
Br
O
O
A wide variety of starting materials can be used to quickly synthesize
Phthalide donors, allowing for the facile synthesis of highly
substituted donors via previously discussed methods
Chem. Rev., 2007, 107, 1892
7
Baran Lab GM
10/1/11
"Flatland": Logic and Methods in the Synthesis of Benzenoids
Modif ied Hauser Reactions
Phthalide Annulations (cont.)
Hauser annulations are extremely useful for the convergent
synthesis of oxygenated poly aromatics
OMe
1) LDA, -78
O
O
O MeO
2) NaOEt, -78 to RT
3) BBr3
+ O
HN
60%
OMe
O
NC
R
OMe
R2
CO2R
R4
O
Fredericamycin A
O
O
R4
R1
R1
R1
R4
-CO2
R3
70-80%
OJ. Org. Chem., 1992, 57, 5911
R2
NR
R3
MeO
MeO
CO2R
R2
O
LTB
then DDQ,
O
83%
O
Mechanism?
Chem. Comm., 1996, 1181
R3
heat
41-70%
In addition to being powerful electrophiles arynes are
very powerful dieneophiles
R
O
R3
Chem. Comm., 1998, 2741
OH
SO2Ph
O
Base
S
R4
O
O
OH
Benzyne Cycloadditions
O
HN
+
+ Ph
R2
O
R1
OMe
HO O
O
O
HO
O
O
O
O
Bach, J. Am. Chem. Soc., 1994, 116, 9921
O
Steven McKerrall
Br
LDA
O
MeO
MeO
NR2
NR
NR2
MeO
NHR2
MeO
Unlikely Acceptor
Br
Br
R1
Br
Tet. Lett., 1996, 37, 6797
BuLi
R1
R1
60%
T et. Lett., 1992, 33, 6883
Br
O
O
Me
O
MeO
CN
H
Me
1) LDA
2) Bu3SnH, AIBN
MeO
15% overall
O
OMOM
Me
H
Me
O
Favelanone
MOMO
R1
R2
BrH
+ O
R3
NC
Tetrahedron, 2003, 59, 3201
O
R1
R2
LiTMP
43%
R3
O
Mumbaistatin
8
Baran Lab GM
10/1/11
"Flatland": Logic and Methods in the Synthesis of Benzenoids
Br
O
Br
O
R1
Si
O
O
OTMS
2) KOH; HCl
34%
R2
Br
O
O
1) 3 eq n-BuLi 85%
Si
Steven McKerrall
1) Br2
2) TrN3
66%
NaNH2
then PhBr
42%
Br
OTIPS
OH
HO
OH
O
OH
O
2 Steps
OH
H
R1
R2
O
OH
Vineomycinone B2
Methyl Ester
O
CO2Me
Martin, J. Am. Chem. Soc., 2006, 128, 13696
R2
+
R4
X
R3
heat
OTIPS
Salvilenone
R1
R4
X
R3
33-92%
HO
Br
2) TBAF
3) DDQ
43%
OH
O
1) MeLi; BuLi;
Acetone; HCl
O
O
OH
Danheiser Benzannulation and Related Reactions
R1
hv
62%
Danheiser, J. Am. Chem. Soc., 1994, 116, 9471
O
N2
Br
Normal alkynes can be used in both inter and intramolecular cases
O
hv, DCM
R2
Danheiser, J. Org. Chem., 1984, 49, 1672
OH
60%
N2
Ph
Ph
-Lack of general methods for many heterosubstituted
alkynes is a significant drawback
-Cyclobutenones are non-trivial to synthesize
R1
C
O
Padwa, Tet. Lett., 1991, 32, 5923
It is likely a diradical mechanism in these cases
N2
, then Pd/C
R3
EtO
R2
R2
R3
OH
O
O
R4
Key intermediate is also available from a photochemical Wolff Rearrangement
Danheiser, J. Am. Chem. Soc., 1990, 112, 3093
26%
OH
N
N
N
EtO
OH
N
Cribrostatin 6
Martin, Angew. Chem. Int. Ed., 2009, 48, 2569
9
Baran Lab GM
10/1/11
"Flatland": Logic and Methods in the Synthesis of Benzenoids
CO2H
O
ClCO2Et/TEA
5 Steps
Dehydro-Diels-Alder
CO2Et
90%
CO2Et
Steven McKerrall
CO2Et
O
OH
CO2Et
OH
CO2Et
HO
Ph
Steps
Chem. Ber., 1907, 40, 3847
O
CO2Et
Synlett, 1998, 1252
(+)-Curcuphenol
-Reaction can be done inter or intramolecularly (tether)
-In general the yields and regioselectivities are modest
O
Acid Mediated Ring Closures
Ph
O
NH2OH HCl
O
130 C, 4d
quant.
Mechanism?
O
Ph
2)
R
R1
R2
TMS
R 160 C
Barluenga, Chem. Eur. J., 2006, 12, 5790
R
R3
R
R2
O
R1
52-78%
[2+2+2] Cycloaddition
R2
OTBS
R2
CpCo(CO)2
76-93%
OR1
OR1
O
OPiv
O
R2
O
X
AgSbF6
R1
R2
R
CyN
Synthesis, 2004, 761
R
Mechanism is complex, involves isomerization versus
reopening/reclosing of the initial intermediate
O
R3
TMS
TEA
160 C
74-89%
54-74%
1) IPy2BF4
O
O
CyN
PhMe
CyN
T et. Lett., 1999, 40, 7457
Ph
R
TMS
O
Ph
X
O
R1
Toste, J. Am. Chem. Soc., 2006, 128, 7436
R2
steps
51-94%
R2
Ag(Py)2MnO4
48-62%
R1=Me, R2=H
R1=Me, R2=OH
R1=H, R2=OH
Angucyclinone Antibiotics
OR1 O
OR1 O
Chem. Eur. J., 2010, 16, 8805
10
Baran Lab GM
10/1/11
"Flatland": Logic and Methods in the Synthesis of Benzenoids
Steven McKerrall
Chromium Carbene
Cl
O
Cl
OMe
nPr
nPr
Cr(CO)5
+
DCM, 55 C
MeN
then DDQ
80%
OMe
OMe
O
O
J. Org. Chem., 2005, 70, 3745
OMe
OMe
HO
1) hv
2) TBAF
61%
MeN
OMe
O
OTBDPS
OMe
HO
(-)-curcuquinone
Steps
Selected Total Syntheses
Bismurrayaquinone A (R. Thompson)
O
OH
OMe Conjugate
O
O
Me
OH
3 Steps Br
nPr
N
Me
N
H
Bismurrayaquinone A
8 Steps, 14% overall
MeO
6 Steps
Me
Cl O OMe
HO
nPr
+
OTBDPS
OTBS
+
PtBr4
MeN
55%
O
O
Cl
1) hv
2) TBAF, 54%
O2
OH
O
O
OMe
MeN
TIPSO
Br
O
nPr
OH
HO
Friedel-Crafts
O
OMe
43%
HO
O
N2
OMe
99% ee
ACIEE, 2011, 50, 1
Kibdelone C (J. Porco)
OMe
Me
O
Fused Dan Shen Diterpenoid Quinones (R. Danheiser)
Br
O
OMe OH
Kibdelone C
62%
O
OH
O
Angew. Chem. Int. Ed., 2011, 50, 2511 Cl
J. Am. Chem. Soc., 2011, 133, 9952
O
O
Addition
MeO
H
OMe
1) PIDA, MeOH
LDA, CuCl2
OMe
H
2) Me2Zn
63%
Cu(OTf)2
MeO OMe
OMe
chiral L
MeO OMe
99% ee
40-47%
1) BF3 Et2O 78%
2) Br2
H
N
OH
OH
O
O
O
MeO
HO
OMe
OTBDPS
-Cryptotanshinone
-Tanshinone IIA ( 1,2
J. Org. Chem., 1995, 60, 8341
Neocryptotanshinone
8 Steps 23% Overall
11
Baran Lab GM
10/1/11
"Flatland": Logic and Methods in the Synthesis of Benzenoids
Steven McKerrall
Further Reading
General:
T et., 2003, 59, 7
Chem. Rev., 2000, 100, 2901
o-Quinonedimethanes:
Chem. Rev., 1999, 99, 3199
T et., 2001, 57, 625
Electrocyclization:
Chem. Eur. J., 2007, 13, 6782
Arynes:
T et., 2003, 59, 701
Chem. Rev., 1962, 62, 81
Metathesis:
Chem. Rev., 2009, 109, 3743
Dehydro-Diels-Alder
Chem. Rev., 2008, 108, 2051
Hauser Annulation
Chem. Rev., 2007, 107, 1892
Oxidative Aromatization
Molecules, 2009, 14, 5308
12