Steric modulation of chiral biaryl diamines via Pd-catalyzed directed C-H arylation

Article abstract of DOI:10.1021/jo802632v

Palladium-catalyzed directed arylation of 2,2 -diacetamidobiaryls with aryl iodides provides efficient access to chiral ortho-substituted biaryl diamines. Aryl iodides with para-and meta-substituents are tolerated. Deprotection of the acetyl groups under

Full text of DOI:10.1021/jo802632v

CHART 1. Common Biaryl Diamine Structures (DABN )
2,2′-Diamino-1,1′-binaphthyl)
Steric Modulation of Chiral Biaryl Diamines via
Pd-Catalyzed Directed C-H Arylation
Christopher C. Scarborough, Richard I. McDonald,
Caroline Hartmann, Graham T. Sazama, Ana Bergant, and
Shannon S. Stahl*
Department of Chemistry, UniVersity of WisconsinsMadison,
Madison, Wisconsin 53706
to addition reactions.9-19 Derivatives of these diamines have
been employed as ligands for transition-metal catalysts and
directly as nonmetal-based catalysts, for example, as chiral
nucleophilic catalysts. In several cases, enantioselectivities of
reactions with DABN and H8-DABN-based catalysts (cf. Chart
1) can be increased substantially by introducing substituents in
the 3- and 3′-positions of the aromatic rings (i.e., ortho to the
amino groups).6a,14b,17-19 Here, we describe a Pd-catalyzed
C-H arylation method that provides efficient access to ortho-
functionalized biaryl diamine derivatives.
stahl@chem.wisc.edu
ReceiVed December 2, 2008
Recent studies in our laboratory have employed biphenyl
diamines as a scaffold for the development of axially chiral,
seven-membered N-heterocyclic carbenes (A).20 In the course
of this work, we sought access to derivatives with bulky
substituents in the 3- and 3′-positions of biphenyl diamine
derivative 1 (Chart 1). Existing methods for the introduction of
substituents in these positions are based on Suzuki-Miyaura
coupling and require preparation of the corresponding haloge-
nated biaryl diamines.6a,14b,17-19The synthetic inefficiency and
low selectivity that we encountered with the halogenation
Palladium-catalyzed directed arylation of 2,2′-diacetami-
dobiaryls with aryl iodides provides efficient access to chiral
ortho-substituted biaryl diamines. Aryl iodides with para-
and meta-substituents are tolerated. Deprotection of the acetyl
groups under basic conditions furnishes the free diamines,
which should find broad utility in asymmetric catalysis.
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alkenes: (a) Wood, M. C.; Leitch, D. C.; Yeung, C. S.; Kozak, J. A.; Schafer,
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2007, 72, 10291–10293. (b) Korostylev, A.; Tararov, V. I.; Fischer, C.; Monsees,
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10.1021/jo802632v CCC: $40.75
Published on Web 02/16/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2613–2615 2613

TABLE 1. Scope of ortho-Arylation of 4a
SCHEME 1. Synthetic Sequence for Bis-ortho-Arylation of
Biphenyl Diamine 1
procedures prompted us to consider alternative strategies for
ortho-functionalization of biphenyl diamines.
Several methods have been reported recently for arylation
of aromatic C-H bonds, directed by an adjacent functional
group.21 Daugulis and Zaitsev, for example, have shown that
anilides undergo arylation selectively in the ortho position(s)
with aryl iodides in the presence of stoichiometric AgOAc and
catalytic Pd(OAc)2 in trifluoroacetic acid.21a,22 These methods
are attractive because they employ aryl iodides, which are
more readily available than the diaryliodonium salts21c and
trialkoxylarylsilanes21d employed in other C-H arylation
methods. We first attempted a Daugulis-Zaitsev (DZ) coupling
reaction with iodobenzene and 2,2′-diacetylaminobiphenyl (2).23
This reaction was successful and afforded the quaterphenyl-
diamine 3 in 70% isolated yield (eq 1). Extension of this
reactivity to chiral biaryldiamines was also successful. The N,N′-
diacetyl derivative of diamine 1 is a highly effective substrate
for this reaction (Scheme 1); the C-H arylation product 5a is
obtained in essentially quantitative yield from the DZ coupling
reaction (Scheme 1). Removal of the acetyl directing groups
under basic conditions (1:1 EtOH/50% KOH(aq) in a stainless
steel pressure vessel, 150 °C, 48 h) affords the quaterphenyl
diamine 6 in very good overall yield.
a Substrate (1.0 mmol), ArI (5.0 mmol), Pd(OAc)2 (0.15 mmol),
AgOAc (2.2 mmol), 3 mL of CF3CO2H, reflux, 6 h. b 20% Pd(OAc)2,
3.0 equiv of AgOAc, 14 h.
the reactions proceed in good-to-excellent yields (entries 1-3,
5, and 6). Limitations include strongly electron-withdrawing
groups and the presence of ortho-substitution in the aryl iodide
(entries 4 and 7). The presence of meta-substituents is tolerated,
although somewhat more forcing conditions were required in
these reactions (20% Pd loading, 3.0 equiv of AgOAc, 14 h,
entries 5 and 6).
Both the DZ coupling and amide hydrolysis conditions require
rather high temperatures, and it was unclear if these conditions
could lead to epimerization of the atropisomeric biaryls.
Enantiomerically resolved (S)-1 (>99% ee) was subjected to
the diacetylation, DZ coupling, and hydrolysis conditions in
Scheme 1. The expected quaterphenyl diamine (S)-5a was
obtained in 94% overall yield, and chiral HPLC analysis
demonstrated that the product retained >99% ee (eq 2).
Therefore, these conditions are well suited for the preparation
of enantiomerically resolved diamines.
In order to probe the scope of the DZ coupling conditions
for the synthesis of ortho-arylated biphenyldiamines, we
examined other iodoarene substrates (Table 1). A number of
(21) See, for example: (a) Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int.
Ed. 2005, 44, 4046–4048. (b) Shabashov, D.; Daugulis, O. J. Org. Chem. 2007,
72, 7720–7725. (c) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S.
J. Am. Chem. Soc. 2005, 127, 7330–7331. (d) Yang, S.; Li, B.; Wan, X.; Shi, Z.
J. Am. Chem. Soc. 2007, 129, 6066–6067.
(22) For an earlier demonstration of related reactivity with alkyl iodides and
stoichiometric Pd, see: Tremont, S. J.; Rahman, H. U. J. Am. Chem. Soc. 1984,
106, 5759–5760.
We have briefly investigated whether the methods described
here can be applied to other common biaryl diamines. DABN
is an attractive biaryl diamine substrate because the resolved
enantiomers are commercially available. Pd-catalyzed ortho
arylation of N,N′-diacetyl-DABN with PhI was successful, and
(23) Zhang, S.; Zhang, D.; Liebeskind, L. S. J. Org. Chem. 1997, 62, 2312–
2313.
2614 J. Org. Chem. Vol. 74, No. 6, 2009

4 (296 mg, 1.0 mmol), Pd(OAc)2 (34 mg, 0.15 mmol), AgOAc
(384 mg, 2.3 mmol), and PhI (560 µL, 5.0 mmol) were dissolved
in 3 mL of trifluoroacetic acid. A reflux condenser was attached,
and the reaction was heated to a vigorous reflux for 6 h. After the
mixture was cooled to room temperature, 10 mL of toluene was
added to the dark mixture, which was then filtered over Celite, and
the solvent removed under vacuum. The mixture was purified by
flash chromatography with silica gel (gradient, 1:1 Et2O/toluene to
pure Et2O, Rf ) 0.29 in 1:1 Et2O/toluene) to afford 446 mg of off-
the desired diamine 7 was obtained in 86% yield following
removal of the acetyl groups (eq 3).24 The partially hydrogenated
DABN derivative H8-DABN25 also undergoes effective aryla-
tion: DZ coupling of the N,N′-diacetyl derivative of H8-DABN
with PhI, followed by amide hydrolysis, afforded quaterphe-
nyldiamine 8 in nearly quantitative yield (eq 4).17-19
1
white powder: 99.6% yield; H NMR (300 MHz, CDCl3, δ) 1.60
(s, 6H), 1.94 (s, 6H), 7.26-7.40 (m, 14H); 13C NMR (75 MHz,
CDCl3, δ) 20.1, 23.0, 127.3, 128.4, 128.8, 129.4, 129.8, 132.8,
138.8, 140.2; HRMS m/z (ESI) calcd [MH]+ ) 449.2224, measured
449.2242 (∆ ) 4.0 ppm).
General Procedure for the Deacetylation of 2,2′-Diacet-
amidobiaryls. A representative example is given for the synthesis
of 6. Compound 5a (1.19 g, 2.65 mmol) was added to 100 mL of
a 1:1 mixture of EtOH and 50% KOH(aq) in a stainless steel Parr
bomb. The bomb was sealed and heated to 150 °C (based on an
internal temperature probe) for 48 h. After the mixture was cooled
to room temperature, 100 mL saturated NH4Cl(aq) was added to the
suspension, which was then extracted 2× with CH2Cl2. The
combined CH2Cl2 solutions were dried over MgSO4 and filtered,
and the solvent was removed in vacuo to afford 905 mg of pure 6
(94% yield) without further purification: 1H NMR (300 MHz,
CDCl3, δ) 2.04 (s, 6H), 3.67 (br. s, 4H), 6.79 (dd, J ) 7.5, 0.3 Hz,
2H), 7.07 (d, J ) 7.8 Hz, 2H), 7.30 (tt, J ) 7.5, 1.5 Hz, 2H),
7.39-7.44 (m, 4H), 7.46-7.50 (m, 4H); 13C NMR (75 MHz,
CDCl3, δ) 19.9, 120.1, 122.7, 125.5, 127.1, 128.9, 129.4, 129.7,
In conclusion, we have developed a simple and efficient three-
step procedure for the installation of o-aryl groups onto 2,2′-
diaminobiaryls. This procedure takes advantage of the Daugulis-
Zaitsev coupling method for amide-directed arylation of aromatic
C-H bonds. The incorporation of bulky ortho-substituents onto
BINOL has had dramatic beneficial effects in asymmetric
catalysis.26 We anticipate the methods described here will
provide the basis for similar advances in asymmetric reactions
with biaryl diamine-derived catalysts.
137.3, 140.2, 141.5; (S)-6: [R]25 -81.4 (c 8.9, CH2Cl2); HRMS
D
m/z (ESI) calcd [MH]+ ) 365.2013, measured 365.2027 (∆ ) 3.8
ppm).
Acknowledgment. We thank Sigma-Aldrich and Amgen for
resolving (()-2,2′-diamino-6,6′-dimethylbiphenyl (1). This work
was supported by the NIH (R01 GM67163) and a UW-Madison
Draper Technology Innovation Fund Grant. C.C.S. is grateful
to the ACS Division of Organic Chemistry for a graduate
research fellowship.
Experimental Section
General Procedure for the Daugulis-Zaitsev Coupling. A
representative example is given for the synthesis of 5a. Bisamide
(24) The DABN substrate appears to be more reactive and susceptible to
side reactions. Efforts to perform reactions with aryl iodides other than PhI
typically resulted in lower yields. For example, DZ coupling of N,N′-diacetyl-
DABN with 1-iodo-3,5-dimethylbenzene proceeded in 46% yield with complete
consumption of starting material (cf. entry 5, Table 1).
(25) Partial hydrogenation of DABN to form H8-DABN can be achieved
without loss of enantiopurity.
(26) (a) Akiyama, T.; Itoh, J.; Fuchibe, K. AdV. Synth. Catal. 2006, 348,
999–1010. (b) Pihko, P. M. Lett. Org. Chem. 2005, 2, 398–403. (c) Chen, Y.;
Yekta, S.; Yudin, A. K. Chem. ReV. 2003, 103, 3155–3211.
Supporting Information Available: Procedure for the
synthesis of 4, characterization data and NMR spectra for all
new compounds, as well as chiral HPLC data for 6. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO802632V
J. Org. Chem. Vol. 74, No. 6, 2009 2615