Formal aromatic C-H insertion for stereoselective isoquinolinone synthesis and studies on mechanistic insights into the C-C bond formation

Article abstract of DOI:10.1021/jo9011255

(Chemical Equation Presented) Formal aromatic C-H insertion of rhodium(II) carbenoid was intensively investigated to develop a new methodology and probe its mechanism. Contrasting with the previously proposed direct C-H insertion, the mechanism was revealed to be electrophilic aromatic substitution, which was supported by substituent effects on the aromatic ring and a secondary deuterium kinetic isotope effect. Various isoquinolinones were synthesized intramolecularly via six-membered ring formation with high regioand diastereoselectivity, while averting the common Buchner-type reaction. Intermolecularly, dirhodium catalyzed formal aromatic C-H insertion on electron-rich aromatics was also achieved.

Full text of DOI:10.1021/jo9011255

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Formal Aromatic C-H Insertion for Stereoselective Isoquinolinone
Synthesis and Studies on Mechanistic Insights into the C-C Bond
Formation
Chan Pil Park,† Advait Nagle,‡ Cheol Hwan Yoon,† Chiliu Chen,‡ and
Kyung Woon Jung*,†
†Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California,
Los Angeles, California 90089-1661, and ‡Department of Chemistry, University of South Florida, Tampa,
Florida 33620
kwjung@usc.edu
Received June 3, 2009
Formal aromatic C-H insertion of rhodium(II) carbenoid was intensively investigated to develop a
new methodology and probe its mechanism. Contrasting with the previously proposed direct C-H
insertion, the mechanism was revealed to be electrophilic aromatic substitution, which was supported
by substituent effects on the aromatic ring and a secondary deuterium kinetic isotope effect. Various
isoquinolinones were synthesized intramolecularly via six-membered ring formation with high regio-
and diastereoselectivity, while averting the common Buchner-type reaction. Intermolecularly,
dirhodium catalyzed formal aromatic C-H insertion on electron-rich aromatics was also achieved.
Introduction
devoted to the construction of their skeletons by using
different methods.3 Dirhodium(II)-catalyzed C-H insertion
of carbenoid compounds has been a powerful and versatile
method in synthetic organic chemistry over the past few
decades.4 Recently, much attention has been extended to
aromatic C-H insertion systems. Several successful exam-
ples of five-membered ring formation without disrupting
aromatic resonance have been reported (eq 1).5 However, in
reports for the construction of a six-membered ring, such
as isoquinolinone, formation of a 7,5-bicyclic structure
via cyclopropanation on the aromatic ring was also
observed (eq 2).6 Although isoquinolinone formation with
Isoquinolinones constitute an important class as synthons
in the synthesis of many alkaloids1 as well as chiral ligands
for transition metal catalysts.2 Isoquinolinones bearing a
stereogenic center at the C1 position are an extensively
studied topic, since they can be used as starting materials
in the total synthesis of erysotramidine, peyoruvic acid, and
many other compounds. Consequently, much effort has been
(1) (a) Bentley, K. W. The Isoquinoline Alkaloids; Hardwood Academic:
Amsterdam, The Netherlands, 1998; Vol. 1. (b) Bently, K. W. Nat. Prod. Rep.
2001, 18, 148. (c) Michael, J. P. Nat. Prod. Rep. 2002, 19, 742. (d) Hansch, C. P.;
Sammes, G.; Taylor, J. B. Comprehensive Medicinal Chemistry; Pergamon
Press: Oxford, UK, 1990. (e) Scott, J. D.; Williams, R. M. Chem. Rev. 2002,
102, 1669.
(2) (a) Durola, F.; Sauvage, J. P.; Wenger, O. S. Chem. Commun. 2006,
€
171. (b) Sweetman, B. A.; Muller-Bunz, H.; Guiry, P. J. Tetrahedron Lett.
2005, 46, 4643.
(3) (a) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. 2004, 104,
3341. (b) Asao, N.; Yudha, S. S.; Nogami, T.; Yamamoto, Y. Angew. Chem.,
Int. Ed. 2005, 44, 5526. (c) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc.
2004, 126, 10558. (d) Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc.
2006, 128, 1086. (e) Rose, M. D.; Cassidy, M. P.; Rashatasakhon, P.; Padwa, A.
J. Org. Chem. 2007, 72, 538. 21. (f) Garcia, E.; Arrasate, S.; Lete, E.; Sotomayor,
N. J. Org. Chem. 2005, 70, 10368. (g) Tambar, U. K.; Ebner, D. C.; Stoltz, B. M.
J. Am. Chem. Soc. 2006, 128, 11752. (h) Zhang, F.; Simpkins, N. S.; Wilson, C.
Tetrahedron Lett. 2007, 48, 5942. (i) Chaumonte, M.; Piccardi, R.; Baudoin, O.
Angew. Chem., Int. Ed. 2009, 48, 179.
(4) (a) Padwa, A.; Austin, D. J. Angew. Chem., Int. Ed. 1994, 33, 1797. (b)
Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998, 98, 911. (c) Gois, P. M. P.;
Afonso, C. A. M. Eur. J. Org. Chem. 2004, 3773. (d) Merlic, C. A.; Zechman,
A. L. Synthesis 2003, 8, 1137. (e) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern
Catalytic Methods for Organic Synthesis with Diazo Compounds; John Wiley
and Sons: New York, 1998.
(5) (a) Padwa, A.; Austin, D. J.; Price, A. T.; Semones, M. A.; Doyle,
M. P.; Protopopova, M. N.; Winchester, W. R.; Tran, A. J. Am. Chem. Soc.
1993, 115, 8669. (b) Tsutsui, H.; Yamaguchi, Y.; Kitagaki, S.; Nakamura, S.;
Anada, M.; Hashimoto, S. Tetrahedron: Asymmetry. 2003, 14, 817.
(c) Hashimoto, S.; Watanabe, N.; Ikegami, S. J. Chem. Soc., Chem. Commun.
1992, 1508. (d) Candeias, N. R.; Gois, P. M. P.; Afonso, C. A. M. J. Org. Chem.
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DOI: 10.1021/jo9011255
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J. Org. Chem. 2009, 74, 6231–6236 6231
2009 American Chemical Society

Park et al.
JOCArticle
diazoacetamides and protic acid has been reported, the
reaction was only applicable to limited substrates and was
not regioselective.7 Variation of the dirhodium(II) ligand
system and the R-substituent of the diazo compounds can
significantly influence the steric effect and electron density at
the rhodium carbenoid center, which in turn has a profound
effect on the diastereo- and regioselectivities of the reaction.
Therefore, the dirhodium(II) framework has been subjected to
ligand exchange with a large number of bridging ligands, and
various substituents at the R-position have been examined.8
TABLE 1. R-Substituent Effect on Rh(II)-Catalyzed Reactionsa
productsc
7,5-bicyclic
entry
Z (R-Substituent)
6,6-bicyclic
1
2
3
H (3)
85% (10)
65% (11)
66% (12)
MeCO (4)
MeO2C (5)
PhO2S (1)
(EtO)2OP (6)
12% (7)
15% (8)
93% (2)
86% (9)
4
5b
aReaction conditions: diazoacetamides (1.0 mmol), Rh2(pfb)4 (5 mol %),
benzene (10 mL), 60 °C, 5 h. bReaction time was 12 h, cIsolated yields.
propose a plausible reaction mechanism, suggesting that this
reaction does not resemble direct C-H activation (σ-bond
metathesis) such as that of aliphatic C-H insertion.
Previously this has been the subject of considerable specula-
tion, due to the lack of experimental data to support the
reaction mechanisms.5,10 Therefore, our newly developed
protocols can provide a valuable tool to complement the
existing methods, as well as provide mechanistic insight.
Recently, we reported dirhodium(II)-catalyzed intramo-
lecular C-H insertion of diazoacetamides to afford γ-lac-
tams with high regio- and diastereoselectivities and its
application to the total syntheses of rolipram, lactacystin,
and kainic acid.9 We also found that the regio- and chemo-
selectivity of C-H insertion can be controlled by changing
the R-substituent of the carbenoids to an R-(phenyl-
sulfonyl)diazoacetamide group. This encouraged us to inves-
tigate an aromatic C-H insertion system, and surprisingly,
it was determined that the aromatic R-(phenylsulfonyl)-
diazoacetamide compound (1) was exclusively converted to
isoquinolinone analogue (2) by six-membered dirhodium-
catalyzed formal aromatic C-H insertion (eq 3).
Results and Discussion
r-Substituent Effect on the Rh(II)-Catalyzed Aromatic
Reaction. We examined formal aromatic C-H insertion
reactions of diazoacetamides with different R-substituents
such as diazoacetamide 3, acetodiazoacetamide 4, and
(methoxycarbonyl)diazoacetamide 5 (Table 1). We em-
ployed the cyclic N,O-acetonide substrate to reduce the
“degree of freedom” for the rotation of various bonds by
forming an N,O-acetal.9b The geminal dimethyl structure in
the N,O-acetal would encounter a steric repulsion with the
bulky rhodium(II) carbenoid, thus forcing the aromatic ring
to be located proximal to the reactive carbenoid center. This
would thereby increase the rate of reaction as well as avoid the
formation of undesired side products.11 The formal aromatic
C-H insertion product for diazoacetamide 3 was not de-
tected. Isoquinolinone products were obtained as minor
products for carbenoids 4 and 5 and the major products of
the reactions were cycloheptapyrrolones 10, 11, and 12. The
major products were formed via ring expansion of the cyclo-
propanated intermediate as the Buchner reaction.6
Herein, we report a dirhodium-catalyzed formal aromatic
C-H insertion for 6,6-bicyclic ring construction and also
(6) (a) Merlic, C. A.; Zechman, A. L.; Miller, M. M. J. Am. Chem. Soc.
2001, 123, 11101. (b) Wee, A. G. H.; Duncan, S. C. Tetrahedron Lett. 2002,
43, 6173. (c) Kane, J. L.; Shea, K. M.; Crombie, A. L.; Danheiser, R. L. Org.
Lett. 2001, 3, 1081. (d) Doyle, M. P.; Protopopova, M. N.; Peterson, C. S.;
Vitale, J. P.; Mckervey, M. A.; Garcia, C. F. J. Am. Chem. Soc. 1996, 118, 7865.
(e) Yang, M.; Webb, T. R.; Livant, P. J. Org. Chem. 2001, 66, 4945.
(f) Sugimura, T.; Im, C. Y.; Sato, Y.; Okuyama, T. Tetrahedron 2007, 63, 4027.
(7) Rishton, G. M.; Schwartz, M. A. Tetrahedron Lett. 1988, 29, 2643.
(8) (a) Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861.
(b) Wee, A. G. H.; Liu, B.; Zhang, L. J. Org. Chem. 1992, 57, 4404. (c)
Moody, C. J.; Miah, S.; Slawin, A. M. Z.; Mansfield, D. J.; Richards, I. C.
Tetrahedron 1998, 54, 9689. (d) Prein, M.; Manley, P. J.; Padwa, A.
Tetrahedron 1997, 53, 7777. (e) Davies, H. M. L.; Jin, Q.; Ren, P.;
Kovalenvsky, A. Y. J. Org. Chem. 2002, 67, 4165. (f ) Davies, H. M. L.;
Coleman, M. G.; Ventura, D. L. Org. Lett. 2007, 9, 4971.
(9) (a) Yoon, C. H.; Jaworotko, M. J.; Moulton, B.; Jung, K. W. Org.
Lett. 2001, 3, 3539. (b) Yoon, C. H.; Flanigan, D. L.; Chong, B. D.; Jung, K.
W. J. Org. Chem. 2002, 67, 6582. (c) Yoon, C. H.; Nagle, A.; Chen, C. L.;
Gandhi, D.; Jung, K. W. Org. Lett. 2003, 5, 2259. (d) Flanigan, D. L.; Yoon,
C. H.; Jung, K. W. Tetrahedron. Lett. 2005, 46, 143. (e) Yoon, C. H.;
Flanigan, D. L.; Yoo, K. S.; Jung, K. W. Eur. J. Org. Chem. 2007, 37. (f )
Jung, Y. C.; Yoon, C. H.; Turos, E.; Yoo, K. S.; Jung, K. W. J. Org. Chem.
2007, 72, 10114.
Analogous to our approach toward aliphatic C-H inser-
tion, we postulated that a bulky “relatively electron-rich”
carbenoid as a R-substituent would enable a thermo-
dynamically controlled reaction pathway, while averting
(10) (a) Taber, D. F.; Ruckle, R. E. Jr. J. Am. Chem. Soc. 1986, 108, 7686.
(b) Doyle, M. P.; Westrum, L. J.; Wolthuis, W. N. E.; See, M. M.; Boone,
W. P.; Bagheri, V.; Pearson, M. M. J. Am. Chem. Soc. 1993, 115, 958.
(11) For the leading references to a comformational study of N-acylox-
azolidines, see: (a) Porter, N. A.; Bruhnke, J. D.; Wu, W, X.; Rosenstein,
I. J.; Breyer, R. A. J. Am. Chem. Soc. 1991, 113, 7788. (b) Kanemasa, S.;
Onimura, K. Tetrahedron 1992, 48, 8631.
(12) For the leading references to other studies with R-diazo-R-phenyl-
sulfonyl compounds see: (a) Wee, A. G. H.; Slobodian, J. J. Org. Chem. 1996,
61, 2897. (b) Padwa, A.; Straub, C. S. Org. Lett. 1999, 1, 83. (c) Moody, C. J.;
Davies, M. J. J. Chem. Soc., Perkin Trans. 1 1991, 9. (d) Monteiro, H. J.
Tetrahedron Lett. 1987, 28, 3459. (e) Takeda, H.; Nakada, M. Tetrahedron:
Asymmetry 2006, 17, 2896.
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Park et al.
JOCArticle
cycloheptapyrrolone formation via an intramolecular Buch-
ner reaction.6 We selected phenylsulfonyl12 and ethoxyphos-
phoryl13 groups as the candidates for the reactions. As
illustrated in entries 4 and 5, R-(phenylsulfonyl)dia-
zoacetamide 1 was exclusively converted to formal aromatic
C-H insertion product 2 without the formation of any
appreciable side products, such as cycloheptapyrrolone.
Although the reaction proceeded more slowly, diethylphos-
phate carbenoid 6 also afforded the formation of isoquino-
linone 9 in 86% yield. Diazoacetamides 1 and 6, which
included a more bulky and less electron-withdrawing
R-substituent than carbonyl substituents, gave high chemo-
selectivity for formal aromatic C-H activation as the intra-
molecular C-H insertion reaction.4c In addition to the
reaction being chemoselective, this ring closure was highly
diastereoselective, where the stereochemistry of isoquinoli-
none 2 at the C7 position was inductively generated by the
defined chirality at the C14 position (Figure 1). (S)-Diazo-
acetamide 1 gave the (1S,4R)-isoquinolinone 2 exclusively.
Optimization of Reaction Conditions. As shown in Table 2,
we screened various solvents and temperatures to optimize
the conditions of the formal aromatic C-H insertion. Di-
azoacetamide (1) was subjected to formal C-H aromatic
insertion reaction in CH2Cl2, giving rise to a larger amount
of isoquinolinone product 2 under reflux condition than
room temperature (entries 1 and 2). The insertion reactions
in 1,2-dichloroethane and benzene as solvent were complete
in excellent yields after 5 h and the increase in yield was
attributed to the higher boiling point of these solvents
compared with that of dichloromethane (entries 3 and 4).
However, although increasing the temperature accelerated
the reaction rate, it also accelerated decomposition of the
diazoacetamides to desulfonated products along with other
side products (entry 5). The use of Rh2(OAc)4 instead of
Rh2(pfb)4 also gave the formal insertion product exclusively
in lower yields over a longer period of time (entry 6). We also
tested this carbon-carbon bond forming reaction under
different catalytic conditions (entries 7 and 8). Under protic
acid-catalyzed condition of electrophilic aromatic substitu-
tion, the generation of isoquinolinone products was insig-
nificant. This outcome confirmed that the Rh(II) catalysts
played a pivotal role in the reaction and the uncomplexed
ligands had minimal effect on the reaction.7
FIGURE 1. Structure of isoquinolinone 2. H atoms, except those
on C7 and C14, are omitted for clarity.
electrophilic aromatic substitution.14 That is, the site of C-C
bond formation for 13 and 15 was mismatched with the
π-electron density for an ortho-, para-directing methoxy
group in electrophilic aromatic substitution. Additionally,
invoking an electrophilic aromatic substitution mechanism
is consistent with a five-membered aromatic reaction of
diazoacetamides as a favorable reaction pathway when the
ortho-position of the aromatic ring is highly activated for
electrophilic aromatic substitution, due to the amide nitro-
gen.15 The failure of six-membered cyclization to occur for
the 2,4-dimethoxyphenyl compound 16 was due to the steric
repulsion between the -OCH3 group and the bulky rhodium
carbenoid (entry 4).
We also evaluated aromatic compounds 18, 19, and 20
containing a deactivating -CF3 group. The isoquinolinone
formation was successful for only p-trifluoromethylphenyl
diazoacetamide 20, which was also consistent with electro-
philic aromatic substitution (electron-withdrawing and
meta-directing in the substitution) (entry 8). Even though
the diazoacetamide 18 was well matched for the construction
of isoquinolinone product based on the electrophilic aro-
matic substitution mechanism, the bulky -CF3 group
blocked the approach of the rhodium carbenoid. Next,
m-fluorophenyl diazoacetamide compound 21 and p-fluoro-
phenyl compound 22 were subjected to the formal aromatic
C-H insertion (entries 9 and 10) to evaluate the feasibility of
a reaction involving aromatic compounds containing halo-
gen functionality. As postulated, diazoacetamide compound
21 gave an increased conversion of isoquinolinone product
29 for the reason that halide groups are deactivating and
ortho- and para-directing in electrophilic aromatic substitu-
tion. Even though the N,O-acetal moiety of diazoacetamides is
a weakly electron-donating alkyl group, it did not effect a
large influence on site selectivity of the aromatic substitution.
Effect of the Aromatic Substituents. Having established
optimized conditions, the effect of various aryl substituents
on the aromatic ring such as electron-releasing group, elec-
tron-withdrawing group, or halide were examined for the
feasibility of the methodology, as shown in Table 3. First, we
found that diazoacetamides with methoxyphenyl groups 13,
14, and 15 exhibited vastly different reactivities. In the cases
of o-methoxyphenyl compound 13 and p-methoxyphenyl
compound 15, formal C-H insertion reactions proceeded
more slowly, leading to predominant formation of side
products. On the contrary, m-methoxyphenyl compound
14 afforded the desired isoquinolinone product 24 in excel-
lent yield. These results can suggest the reaction occurs by an
(13) For the leading references to other studies with R-diazo-R-alkoxy-
phosphoryl compounds see: (a) Davis, F. A.; Bowen, K. A.; Xu, H.;
Velvadapu, V. Tetrahedron 2008, 64, 4174. (b) Davis, F. A.; Zhang, J.;
Qiu, H.; Wu, Y. Org. Lett. 2008, 10, 1433. (c) Zhang, W.; Romo, D. J. Org.
Chem. 2007, 72, 8939. (d) Xu, C.; Zhang, Y.; Yuan, C. Eur. J. Org. Chem.
2004, 10, 2253.
(14) Which is more commonly invoked for the activation of C-H bonds
by highly electrophilic late transition metal systems. (a) Stahl, S. S.; Labinger,
J. A.; Bercaw, J. E. Angew. Chem., Int. Ed. 1998, 37, 2180. (b) Zhou, C. X.;
Larock, R. C. J. Org. Chem. 2006, 71, 3551.
(15) Doyle, M. P.; Shanklin, M. S.; Pho, H. Q.; Mahapatro, S. N. J. Org.
Chem. 1988, 53, 1017.
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TABLE 2. Optimization of Rh(II)-Catalyzed Formal Aromatic C-H Insertion Reactionsa
entry
catalyst
Rh2(pfb)4 (5 mol %)
Rh2(pfb)4 (5 mol %)
Rh2(pfb)4 (5 mol %)
Rh2(pfb)4 (5 mol %)
Rh2(pfb)4 (5 mol %)
Rh2(OAc)4 (5 mol %)
TFA (10 mol %)b
Rh2(OAc)4 (5 mol %) TFA (5 mol %)
solvent
CH2Cl2
CH2Cl2
CH2ClCH2Cl2
benzene
Benzene
BENZENE
benzene
benzene
temp (°C)
time (h)
yield (%)c
1
2
3
4
5
6
7
8
rt
72
10
5
5
2
24
10
5
78
88
87
93
69
67
25
58
reflux
60
60
70
60
reflux
60
aReaction conditions: diazoacetamide (1.0 mmol) and solvent (10 mL). bTFA: trifluoroacetic acid. cIsolated yields.
TABLE 3. Effect of Aromatic Substituentsa
SCHEME 1. Deuterium Transfer in the Rhodium-Catalyzed Rea-
ction of Diazoacetamide-d5 31
entry
diazoacetamide
time (h)
productb
that of the formal C-H insertion reaction of undeuterated
diazoacetamide compound 1. This result implied that the
C-H or C-D bond breaking process would not be included
in the overall rate-determining step.
1
2
3
4
5
6
7
8
9
10
13 (R1=OMe, R2, R3, R4=H)
14 (R2=OMe, R1, R3, R4=H)
15 (R3=OMe, R1, R2, R4=H)
16 (R1, R4=OMe, R2, R3=H)
17 (R2, R3=OMe, R1, R4=H)
18 (R1=CF3, R2, R3, R4=H)
19 (R2=CF3, R1, R3, R4=H)
20 (R3=CF3, R1, R2, R4=H)
21 (R2=F, R1, R3, R4=H)
22 (R3=F, R1, R2, R4=H)
48
2
23 (18%)
24 (96%)
25 (10%)
N. R.
26 (86%)
N.R.
27 (10%)
28 (96%)
29 (82%)
30 (25%)
48
48
48
48
48
24
24
48
Therefore, to understand the kinetic difference between
C-H and C-D, we studied an intramolecular competition
reaction using monodeuterated compound 33. As repre-
sented in Scheme 2, we estimated the kinetic isotope effect
with diazoacetamide-d1 33, which was prepared from
20-hydroxyacetophenone.18 The ratio of deuterated isoqui-
nolinone products 34 and 35 was 46.1%/53.9% and the
calculated kinetic isotope effect value for the reaction was
0.855 (kH/kD < 1). Because primary isotope effects are
expected for direct C-H activation reaction (σ-bond
metathesis), not observing a primary isotope effect could
rule out a direct C-H activation pathway, such as an alipha-
tic C-H insertion. The observation of the inverse SDKIE
value is consistent with a sp2- to sp3-hybridization change
during the addition of a rhodium carbenoid to the sp2-center
of the aromatic ring to form a σ-complex adduct as the rate-
determining step.19 This inverse effect would warrant elec-
trophilic aromatic substitution over direct aromatic C-H
insertion without ambiguity.
aReaction conditions: diazoacetamides (1.0 mmol), Rh2(pfb)4 (5 mol %),
benzene (10 mL). bIsolated yields.
The reaction site was predominantly influenced by other
substituents, such as -OCH3, -CF3, and -F.
Secondary Deuterium Kinetic Isotope Effect (SDKIE) for
Dirhodium(II)-Catalyzed Formal Aromatic C-H Insertion;
Electrophilic Aromatic Substitution. To clarify the mechan-
ism of dirhodium(II)-catalyzed C-C bond formation via
formal C-H insertion, we examined the reaction with deut-
erated diazoacetamide-d5 31 in the presence of Rh2(pfb)4 at
60 °C. As an expected reaction pathway, a diazoacetamide-d5
31 study was conducted to confirm a 1,2-hydrogen shift as a
result of formal aromatic C-H insertion and then deuterated
isoquinolinone 32 was exclusively produced (Scheme 1).16,17
The reaction rate of this catalysis was found to be the same as
Mechanistic Study Dependent on the r-Substituent of
Diazoacetamides. On the basis of these experimental results,
we would like to suggest a plausible mechanism for Rh(II)-
catalyzed formal C-H insertion to produce stereoselective
isoquinolinone as follows (Scheme 3): In the first step,
diazoacetamide 1 interacted with dirhodium catalyst to
(16) (a) Hoye, T. R.; Dinsmore, C. J. Tetrahedron Lett. 1991, 32, 3755. (b)
Davies, H. M. L.; Saikali, E.; Clark, T. J.; Chee, E. H. Tetrahedron Lett. 1990,
31, 6299.
(17) Although we confirmed the deuterated product 32 through crude
NMR data, the transferred deuterium was lost after column chromatogra-
phy (see the Supporting Information for NMR spectra). Therefore, the
deuterated product 32 would be the kinetically favored one via the proposed
transition state before H/D exchange or equilibration (e.g., silica column).
Besides, we could not observe the other diastereomer during the reaction.
(18) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett.
1986, 27, 5541.
(19) (a) Griffin, G. W.; Horn, K. A. J. Am. Chem. Soc. 1987, 109, 4919. (b)
Kang, M. J.; Song, W. J.; Han, A. R.; Choi, Y. S.; Jang, H. G.; Nam, W. W.
J. Org. Chem. 2007, 72, 6301.
6234 J. Org. Chem. Vol. 74, No. 16, 2009

Park et al.
JOCArticle
SCHEME 2. SDKIE for Rh(II)-Catalyzed C-C Bond Formation
SCHEME 3. Plausible Mechanism for Rh(II)-Catalyzed Aromatic Reactions
generate the rhodium carbenoid 36 irreversibly.20 We believe
that the six-membered ring in the transition state would
prefer adopting a boat-like configuration, unlike a chair-like
configuration commonly observed with aliphatic sub-
strates.21 The amide functionality and aromatic region im-
pose the restrictions of planarity on those regions of the
molecule, allowing only the boat-like configuration
(Figure 1) for attack by the aromatic π-electron to the
rhodium carbenoid carbon. Aromaticity was restored via
syn periplanar rhodium-facilitated hydrogen transfer from
the aromatic carbon to the former carbenoid carbon. In the
case of smaller R-substituents, cyclopropanation would be
the favorable pathway because of the more reactive nature of
carbenoids, as well as low steric effects. Intermediate 39
generated as a result of cyclopropanation would rearrange
to generate cycloheptatriene products. The proposed me-
chanism was supported by kinetic isotope studies, as well as
by the fact that no 7,5-bicyclic ring products were observed in
the case of bulky and electron-rich carbenoids.
SCHEME 4. Intermolecular Aromatic Substitution of Rhodium-
(II) Carbenoids
of aromatic resonance was reported. Encouraged by our
results in the intramolecular system, we attempted inter-
molecular aromatic substitution using bulky electron-rich
carbenoids, as shown in Scheme 4.
Reactions of benzene and R-(phenylsulfonyl)diazo-
acetester 41 took place smoothly to provide the desired
compound 42 in 55% yield. Surprisingly, the reaction with
anisole afforded an 85% yield of the para-substituted pro-
duct 43, because the methoxy group is the ortho-, para-
directing group in electrophilic aromatic substitution. As
anticipated, however, the reaction of trifluoromethylben-
zene, substituted with an electron-deficient group, was not
detected even at higher reaction temperature. These observa-
tions further validate our hypothesis that an electrophilic
aromatic substitution is accelerated with the electron-
rich aromatic system. The intermolecular reaction did not
Intermolecular Formal Aromatic C-H Insertion of
r-(Phenylsulfonyl)diazoacetester while Averting the Common
Buchner Reaction. In the intermolecular reaction of rhodium
carbenoids with aromatic substrates, only few examples were
developed22 or the Buchner reaction pathway with breaking
(20) Wang, F. M.; Wang, J.; Hengge, A. C.; Wu, W. Org. Lett. 2007, 9,
1663 and references cited therein.
(21) Taber, D. F.; You, K. K.; Rheingold, A. L. J. Am. Chem. Soc. 1996,
118, 547.
(22) (a) Davies, H. M. L.; Smith, H. D.; Hu, B.; Klenzak, S. M.; Hegner,
F. J. J. Org. Chem. 1992, 57, 6900. (b) Davies, H. M. L.; Jung, Q. Org. Lett.
2004, 6, 1769.
J. Org. Chem. Vol. 74, No. 16, 2009 6235

Park et al.
JOCArticle
provide higher yield than the intramolecular reaction, since
there was not an induced steric effect, such as N,O-acetal
formation in the intramolecular reaction. However, based on
our knowledge, this is the first example of rhodium-catalyzed
intermolecular formal aromatic C-H insertion. Currently in
progress are further studies focusing on intermolecular
cross-coupling reactions with various diazocarbenoids, and
their successful results will be reported in due course.
δ 157.66, 137.15, 134.98, 134.48, 130.92, 129.66, 129.20,
128.99, 128.28, 125.46, 123.94, 95.71, 74.51, 68.17, 58.14,
25.04, 23.22. MS (EI) m/z (%) 342 ([M - 15]þ, 4), 215 (100),
201 (33), 130 (71); HRMS-ESI (m/z) [M þ Hþ] calcd. for
C19H20NO4S 358.1108, found 358.1115
10:. Syn: 1H NMR (250 MHz, CDCl3) δ 6.45-6.41 (m, 2H),
6.16-6.15 (m, 1H), 6.07 (d, J=2.0 Hz, 1H), 5.32 (d, J=9.6 Hz,
1H), 4.85 (ABX, J = 6.2, 9.6 Hz, 1H), 4.09 (ABX, J=6.2, 7.8 Hz,
1H), 3.32 (s, 1H), 3.27 (ABX, J=7.8, 9.2 Hz, 1H), 1.71 (s, 3H),
1.49 (s, 3H); 70%. Anti: 1H NMR (250 MHz, CDCl3) δ 6.47-
6.45 (m, 2H), 6.14-6.12 (m, 1H), 6.05 (d, J = 2.0 Hz, 1H), 5.33
(d, J=9.6 Hz, 1H), 4.77 (ABX, J=6.2, 9.6 Hz, 1H), 4.15 (ABX,
J=6.2, 7.8 Hz, 1H), 3.52 (ABX, J=7.8, 9.2 Hz, 1H), 3.20 (s, 1H),
1.73 (s, 3H), 1.48 (s, 3H); 30%
Conclusion
We have developed a protocol for the preparation of
various isoquinolinones via a dirhodium(II)-catalyzed for-
mal aromatic C-H insertion of six-membered systems that
avoids the common Buchner reaction. The reactions occ-
urred via an electrophilic aromatic substitution pathway
rather than σ-bond metathesis, as indicated by an inverse
secondary deuterium kinetic isotope effect. Six-membered-
ring formations were successfully achieved by the use of steri-
cally bulky and electron-rich carbenoids, including a phe-
nylsulfonyl group or an ethoxyphosphoryl group. In addi-
tion, we have extended the scope of this methodology by
including an intermolecular formal aromatic C-H insertion
reaction, which has never been reported previously.
General Procedure for the Intermolecular Electrophilic Aro-
matic Substitution of Diazoacetamide 41. A 50-mL two-necked
flask equipped with a condenser was completely dried with a
heat gun under flowing N2. After the flask was cooled to room
temperature, Rh2(pfb)4 (0.10 mmol) and 41 (0.51 g, 2.00 mmol)
were added under a gentle stream of nitrogen. Anisole (20 mL)
was added, and the mixture was stirred at 60 °C under a N2
atmosphere. After complete consumption of the diazoacetamide
41, solvent was removed in vacuo. The insertion product 43
1
(85%) was isolated by silica gel column chromatography. H
NMR (250 MHz, CDCl3) δ 7.65-7.57 (m, 3H), 7.47-7.40 (m,
2H), 7.30-7.24 (m, 2H), 6.84-6.79 (m, 2H), 5.04 (s, 1H), 4.26-
4.12 (m, 2H), 3.79 (s, 3H), 1.21 (t, J=7.3 Hz, 3H); 13C NMR
(62.5 MHz, CDCl3) δ 164.95, 160.61, 136.46, 133.98, 131.50,
129.85, 128.47, 119.57, 113.92, 74.60, 62.35, 55.26, 13.82. MS
(EI) m/z(%) 344 ([M]þ, 12), 193 (100), 165 (53), 109 (42);
HRMS-ESI (m/z) [M þ Hþ] calcd for C17H19O5S 335.0948,
found 335.0952
Experimental Section
General Procedure for the Intramolecular Electrophilic Aro-
matic Substitution of Diazoacetamides 1 and 3. A 50-mL two-
necked flask equipped with a condenser was completely dried
with a heat gun under flowing N2. After the flask was cooled to
room temperature, Rh2(pfb)4 (0.05 mmol) and diazoacetamide
(1.0 mmol) were added under a gentle stream of nitrogen.
Benzene (10 mL) was added, and the mixture was stirred at
60 °C under a N2 atmosphere. After complete consumption of
the diazoacetamide, benzene was evaporated. The insertion
product was isolated by silica gel column chromatography.
2:. 1H NMR (250 MHz, CDCl3) δ 7.85-7.81 (m, 2H), 7.73-
7.67 (m, 1H), 7.58-7.52 (m, 2H), 7.47-7.34 (m, 3H), 7.07 (d, J=
7.3 Hz, 1H), 5.06 (ABX, J = 6.3, 10.3 Hz, 1H), 4.92 (s, 1H), 4.60
(ABX, J=6.3, 8.4 Hz, 1H), 3.80 (ABX, J=8.5, 10.3 Hz, 1H),
1.69 (s, 3H), 1.52 (s, 3H); 13C NMR (62.5 MHz, CDCl3)
Acknowledgment. We acknowledge generous financial
support from the National Institute of General Medical
Sciences of the National Institute of Health (RO1 GM
62767 and GM 71495).
Supporting Information Available: Experimental details for
the preparation of compounds and NMR spectra of these
compounds, and crystallographic information for compounds
10. This material is available free of charge via the Internet at
http://pubs.acs.org.
6236 J. Org. Chem. Vol. 74, No. 16, 2009