7-Chloroquinoline: a versatile intermediate for the synthesis of 7-substituted quinolines

Article abstract of DOI:10.1016/j.tetlet.2009.06.077

A practical synthesis of 7-mono-substituted quinolines has been achieved. Selective reduction of the inexpensive commercial reagent 4,7-dichloroquinoline affords 7-chloroquinoline, which has been converted into more complex 7-mono-substituted quinolines through a series of Pd-catalyzed cross coupling reactions. These studies include the first examples of Suzuki reactions for the preparation of 7-mono-substituted quinolines as well as the first application of the Sonagashira reaction for the synthesis of 7-substituted quinolines. This strategy has been extended to the preparation of 2,7-di-substituted quinolines.

Full text of DOI:10.1016/j.tetlet.2009.06.077

Tetrahedron Letters 50 (2009) 4989–4993
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
7-Chloroquinoline: a versatile intermediate for the synthesis
of 7-substituted quinolines
*
Joshua J. Hirner, Michael J. Zacuto
Department of Process Research, Merck and Co., Inc., PO Box 2000, Rahway, NJ 07065, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical synthesis of 7-mono-substituted quinolines has been achieved. Selective reduction of the
inexpensive commercial reagent 4,7-dichloroquinoline affords 7-chloroquinoline, which has been con-
verted into more complex 7-mono-substituted quinolines through a series of Pd-catalyzed cross coupling
reactions. These studies include the first examples of Suzuki reactions for the preparation of 7-mono-
substituted quinolines as well as the first application of the Sonagashira reaction for the synthesis of
7-substituted quinolines. This strategy has been extended to the preparation of 2,7-di-substituted
quinolines.
Received 10 April 2009
Revised 12 June 2009
Accepted 15 June 2009
Available online 18 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Quinolines with mono-substitution at the 7-position are impor-
tant structural moieties for numerous medicinal applications,
including but not limited to cancer treatment1 and antibiotics.2
Therefore a synthesis of these compounds that is practical, concise
and selective would be valuable. Broadly defined, the strategies
that have been reported to date are categorized as methods that
either (a) manipulate functionality appended to a commercially
available quinoline core, or (b) construct the quinoline ring system
from aniline precursors. With regards to 7-mono-substituted quin-
olines, the most common tactic employs the former procedure; a
multi-step process that utilizes quinoline-7-carboxaldehyde (1)
or derivatives thereof.3 In this scenario 1 is usually derived from
the SeO2-mediated oxidation of 7-methylquinoline (2)4 (Scheme
1). One limitation to this approach is the high expense and low
availability (on scale) of 1 and 2. Examples of the latter strategy
include the classical Skraup5 and Doebner–Miller6 reactions.
Unfortunately, these reactions suffer from poor regioselectivity,7
leading to a mixture of the desired 7-substituted quinoline and
the 5-substituted regioisomer. A number of regioselective transi-
tion metal-mediated annulation reactions with anilines have been
disclosed,8 but none have lent themselves to the preparation of
7-mono-substituted quinolines.
Recently, the use of Pd-catalyzed cross coupling reactions with
7-haloquinolines has advanced the potential of the ‘quinoline func-
tionalization’ approach.9 With no commercial availability of these
substrates, however, this methodology ultimately relies on unse-
lective Skraup annulation chemistry in order to obtain the halo-
quinoline. Nonetheless, this strategy holds much promise. Most
work in this area has focused on the use of 7-iodo and 7-trifluo-
romethane sulfonyl derivatives of highly substituted quinolines,
while relatively little attention has been paid to the reactivity of
7-chloroquinolines. The reported examples using aryl chlorides
R
O
N
N
Me
N
2
H
1
HO
OH
CHO
(Doebner-Miller)
or
+
OH
(Skraup)
R
N
R
NH2
(+ 5-isomer)
Scheme 1.
* Corresponding author. Tel.: +1 732 594 0363; fax: +1 732 594 5170.
E-mail address: michael_zacuto@merck.com (M.J. Zacuto).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.077

4990
J. J. Hirner, M. J. Zacuto / Tetrahedron Letters 50 (2009) 4989–4993
Cl
N
Pd-catalyzed
cross coupling
selective
reduction
Cl
R
N
Cl
N
4
3
Scheme 2.
concern a single substrate–commercially available 7-chloroquin-
aldine10–and focus heavily on the borylation of this reagent with
bis(pinacolato)diboron. Consequently, the use of 7-chloroquino-
lines as direct coupling partners is largely unexplored, and the
application of this strategy to the synthesis of 7-mono-substituted
quinolines has not been reported to date. In this Letter, we describe
a practical and selective preparation of 7-chloroquinoline and
demonstrate its broad utility in cross coupling reactions as part
in the crude reaction mixture by HPLC analysis. Aside from the
over-reduction byproduct quinoline (5%), the only significant
impurity was 7-chloro-4-hydroxy-quinoline (7) (8%), which ap-
pears to result from a reaction between 3 and water in the reaction
solution or in the quench (Fig. 1).15 Fortunately, these impurities
could be removed by column chromatography.
Having achieved an effective method to prepare 4, we turned
our attention towards the proposed Pd-catalyzed cross coupling
reactions for the synthesis of more complex 7-substituted quino-
lines. Our investigations into Suzuki couplings (Table 2)16 revealed
that 4 exhibited reactivity patterns typical of aromatic chlorides.
The use of PPh3 as a ligand for the coupling with phenylboronic
acid provided the desired quinoline in modest yield (entry 1).
The use of ligands known to activate aromatic chlorides towards
oxidative addition afforded improved reactivity.17 The catalyst
combination of Pd(OAc)2 and a water-soluble version of the SPhos
ligand18 promoted an efficient reaction between 4 and an electron-
rich boronic acid (entry 2), but only a modest yield in combination
with an electron-deficient cross coupling partner (entry 3). The
catalyst combination of Pd(OAc)2 and XPhos, in combination with
K3PO4 as the base, enabled the successful Suzuki reaction between
4 and both ortho-substituted (entry 5) and electron-deficient (en-
try 6) boronic acids. These conditions also resulted in a marked
increase in yield in the reaction with phenylboronic acid (entry
4), highlighting the potential for the Suzuki reaction between 4
and a wide variety of boronic acids.
of
quinolines.
We envisioned the use of 7-chloroquinoline as a direct coupling
a concise synthesis of more complex 7-mono-substituted
partner (i.e., the electrophile) in Pd-catalyzed cross coupling reac-
tions. The practicality of this approach relied upon the commercial
availability of 4,7-dichloroquinoline (3) as an inexpensive reagent
that could allow easy access to 7-chloroquinoline (4), provided that
a selective reduction could be performed (Scheme 2). While the
selective functionalization of the 4-chloro moiety of 3 has been re-
ported in the course of Pd-catalyzed cross couplings,11 the chemo-
selective reduction of 3 to 4 is, to the best of our knowledge,
unknown.
Our efforts focused on transfer hydrogenation conditions as a
means to control the stoichiometry of reducing agent (Table 1).
The use of Pd/C and NH4CO2H in MeOH invariably led to over-
reduction, as evidenced by the detection of quinoline (5) by HPLC
analysis (entries 1–3).12 Homogeneous catalysis using Pd(PPh3)4
and Et3SiH afforded high selectivity but only moderate conversion
(entry 4). The use of Pd(II) sources, whereby the active Pd(0) spe-
cies would be generated in situ, was then investigated. We focused
on Pd(PPh3)2Cl2 due to its low cost and ease of handling. Initial
experiments revealed high selectivity for the desired compound
413 without any detection of over-reduction (entries 5–7). After
further optimization, we discovered that the use of 1.4 equivalents
of Et3SiH in MeCN at 70 °C resulted in an optimal balance of con-
version and chemoselectivity (entry 8), affording 7-chloroquino-
line (4) in 85% isolated yield. Although other catalyst
complexes14 derived from Pd(II) pre-catalysts were screened, none
offered an improvement over Pd(PPh3)2Cl2 in terms of conversion
and selectivity. Importantly, 4-chloroquinoline (6) is not detected
In addition to the Suzuki reaction, we also investigated other
Pd-catalyzed cross coupling reactions as a means to diversify
substitution at the 7-position of the quinoline ring. The Sonagashira
Cl
OH
N
N
Cl
6
7
(not observed)
Figure 1.
Table 1
Cl
+
N
Cl
N
Cl
N
5
4
3
Entry
Catalyst (mol %)
Reducing agent (equiv)
Solvent
Time (h), temp.
Ratioa (4:5)
Conversiona (%)
1
2
3
4
5
6
7
8
Pd/C (5)
Pd/C (5)
Pd/C (5)
Pd(PPh3)4 (1)
Pd(PPh3)2Cl2 (2)
Pd(PPh3)2Cl2 (2)
Pd(PPh3)2Cl2 (2)
Pd(PPh3)2Cl2 (1)
NH4CO2H (1.3)
NH4CO2H (1.1)
NH4CO2H (2.2)
Et3SiH (1.4)
NH4CO2H (1.3)
Et3SiH (1.6)
MeOH
MeOH
MeOH
MeCN
MeOH
DMF
1 h, reflux
21 h, 25 °C
20 h, 25 °C
24 h, 70 °C
20 h, 25 °C
16 h, 25 °C
18 h, 25 °C
18 h, 70 °C
2:1
6:1
1:7
1:0
3:5:1
1:0
1:0
90
58
99
75
99
62
50
92
Et3SiH (1.6)
Et3SiH (1.4)
MeCN
MeCN
21:1
a
Determined by HPLC analysis (see Ref. 12).

J. J. Hirner, M. J. Zacuto / Tetrahedron Letters 50 (2009) 4989–4993
4991
Table 2
1 mol% Pd(OAc)2
+ ArB(OH)2
ligand
Cl
N
Ar
N
conditions
4
Entry
1
Ligand (mol %)
PPh3 (4)
ArB(OH)2
Conditionsa
Product
Yield (%)
44
B(OH)2
A
A
A
B
B
B
N
5
MeO
MeO
B(OH)2
B(OH)2
MeO
MeO
N
2
3
4
5
SPhosb (2)
SPhosb (2)
XPhos (2)
XPhos (2)
XPhos (2)
87
48
83
77
94
6
OMe
OMe
N
F3C
7
F3C
B(OH)2
N
N
B(OH)2
Me
8
Me
B(OH)2
6
N
F
9
F
a
Conditions A: 3 N aq Na2CO3, PhMe/IPA, 80 °C B: 2 N aq K3PO4, PhMe, 70 °C.
Water-soluble SPhos.
b
reaction with 7-chloroquinolines is unprecedented, and the reactiv-
ity of 4 towards alkynes proved more challenging than in the Suzuki
coupling. The initial use of Pd(OAc)2/XPhos and Na2CO3 in toluene
did furnish the desired product, albeit in low yield (Table 3, entry
1). After screening various pre-catalyst/XPhos combinations with
different solvents and bases, we discovered that the use of
Pd(MeCN)2Cl2 and Cs2CO3 in acetonitrile afforded the alkyne
coupling products in good yield (entries 2 and 3).19
As an entryinto carbonyl-relatedquinolinederivatives, we inves-
tigated the cyanation of 4. The use of 0.6 equiv of Zn(CN)2 and the
catalyst system composed of 2 mol % [(allyl)PdCl]2 and 4 mol %
XPhos afforded 7-cyanoquinoline (13) in 79% yield (Eq. 1):20
form the dihydroquinoline 14 in 90% yield. No evidence of me-
tal–halogen exchange was observed by HPLC or NMR.21 This
intermediate was readily oxidized to quinoline 15 in 85% yield
(Eq. 2):22
n-BuLi
KMnO4
Acetone, 0 oC
85%
4
MTBE, -78 o
C
Cl
N
H
Cl
N
95%
15
14
Me
Me
ð2Þ
2 mol% [(allyl)PdCl]2
4 mol% XPhos
DMAc, 120 oC
In a similar manner, isopropenylMgCl underwent 1,2-addition
+ Zn(CN)2
to 3 to smoothly afford an 8:1 mixture of dihydroquinoline 16
and quinoline 17 (believed to be derived from the air oxidation
of 16) in 80% combined yield (Eq. 3).23 When the mixture of 16
and 17 was not isolated but was instead subjected to DDQ-medi-
ated oxidation, 17 was isolated in 55% yield over the two steps.
As a proof of concept for the synthesis of 2,7-di-substituted quino-
lines, 17 was elaborated to quinoline 18 via a Suzuki reaction (Eq.
4).24
NC
N
Cl
N
79%
13
4
ð1Þ
7-Chloroquinoline also proved useful for the synthesis of
quinolines with substitution at both the 2- and the 7-positions.
As a demonstration of this aptitude, n-BuLi was added to 4 to

4992
J. J. Hirner, M. J. Zacuto / Tetrahedron Letters 50 (2009) 4989–4993
Table 3
conditions
A or B
+
R
N
Cl
N
R
Entry
1
Conditionsa
A
Product
Yield (%)
39
R
EtO2C
Ethyl-5-hexynoate (1.1 equiv)
Phenylacetylene (1.3 equiv)
N
10
N
2
B
57
11
BocHN
3
N-(Boc)-5-pentyneamine (1.3 equiv)
B
68
N
12
a
Conditions A: 2 mol % Pd(OAc)2, 4 mol % XPhos, 2.5 equiv, Na2CO3, 1 M in PhMe 90 °C 22 h. Conditions B: 3 mol % Pd(MeCN)2Cl2, 6 mol% XPhos, 1.5 equiv, Cs2CO3, 0.2 M in
MeCN 75 °C, 16–22 h.
2. (a) Altmann, K.-H.; Bold, G.; Caravatti, G.; Flörsheimer, A.; Guagnano, V.;
Wartmann, M. Bioorg. Med. Chem. Lett. 2007, 10, 2765; (b) Nomura, T.; Iwaki, T.;
Narukawa, Y.; Uotani, K.; Hori, T.; Miwa, H. Bioorg. Med. Chem. 2008, 14, 3697.
3. For example, see: Plobeck, N.; Delorme, D.; Wei, Z.-L.; Yang, H.; Zhou, F.;
Schwarz, P.; Gawell, L.; Gagnon, H.; Pelcman, B.; Schmidt, R.; Yi Yue, S. Y.;
Walpole, C.; Brown, W.; Zhou, E.; Labarre, M.; Payza, K.; St-Onge, S.; Kamassah,
A.; Morin, P.-E.; Projean, D.; Ducharme, J.; Roberts, E. J. Med. Chem. 2000, 43,
3878. Additional examples are found in Refs. 1,2.
Me
MgCl
4
+
Cl
N
Cl
N
THF, rt.
80%
H
Me
Me
17
16
(8:1)
4. Rodunov, V. M.; Berkengein, M. A. J. Gen. Chem. USSR 1945, 16, 330.
5. Manske, R. H. F.; Kulka, M. Org. React. 1953, 7, 59.
ð3Þ
6. For a recent use of a Doebner–Miller variant, see: Cho, C. K.; Lee, N. Y.; Choi, H.-
J.; Kim, T.-J.; Shim, S. C. J. Heterocycl. Chem. 2003, 40, 929.
7. For an exception, in the preparation of 7-hydroxyquinoline, see: Cameron, M.;
Hoerrner, R. S.; McNamara, J. M.; Figus, M.; Thomas, S. Org. Proc. Res. Dev. 2006,
10, 149.
8. For a limited set of recent examples, see: (a) Movassaghi, M.; Hill, M. D. J. Am.
Chem. Soc. 2006, 128, 4592; (b) Sandelier, M. J.; DeShong, P. Org. Lett. 2007, 9,
3209; (c) Korivi, R. P.; Cheng, C.-H. J. Org. Chem. 2006, 71, 7079.
9. The only known example of this strategy for the synthesis of mono-7-
substituted quinolines used 7-bromoquinoline, as documented in Ref. 2a. For
application to more highly substituted 7-halo- and 7-trifloxyquinolines, see:
(a) Boschelli, D. H.; Wu, B.; Ye, F.; Wang, Y.; Golas, J. M.; Lucas, J.; Boschelli, F. J.
Med. Chem. 2006, 49, 7868; (b) Barrios Sosa, A. C.; Boschelli, D. H.; Wu, B.;
Wang, Y.; Golas, J. M. Bioorg. Med. Chem. Lett. 2005, 15, 1743; (c) Wu, B.; Barrios
Sosa, A. C.; Boschelli, D. H.; Boschelli, F.; Honores, E. E.; Golas, J. M.; Powell, D.
W.; Wang, Y. D. Bioorg. Med. Chem. Lett. 2006, 16, 3993; (d) Berger, D.; Dutia,
M.; Powell, D.; Wissner, A.; DeMorin, F.; Raifeld, Y.; Weber, J.; Boschelli, F.
Bioorg. Med. Chem. Lett. 2002, 12, 2989; (e) Kulkarni, S. S.; Newman, A. H. Bioorg.
Med. Chem. Lett. 2007, 10, 2987.
10. Limited to Suzuki reactions: see: (a) Kulkarni, S. S.; Hauck Newman, A. Bioorg.
Med. Chem. Lett. 2007, 17, 2987; (b) Milbank, J. B. J.; Knauer, C. S.; Augelli-
Szafran, C. E.; Sakkab-Tan, A. T.; Lin, K. K.; Yamagata, K.; Hoffman, J. K.; Zhuang,
N.; Thomas, J.; Galatsis, P.; Wendt, J. A.; Mickelson, J. W.; Schwarz, R. D.; Kin
ora, J. J.; Lotarski, S. M.; Stakich, K.; Gillespie, K. K.; Lam, W. W.; Mutlib, A. E.
Bioorg. Med. Chem. Lett. 2007, 17, 4415.
Me
(4-F-C6H4)B(OH)2
1.
MgCl
THF, rt. 5h
1 mol% Pd(OAc)2
2 mol% XPhos
4
2.
Cl
N
2N K3PO4
DDQ,
PhMe, rt. 1h
58%
PhMe, 70 o
C
Me
17
55%
N
Me
18
F
ð4Þ
In summary, we have developed a practical synthesis of 7-chlo-
roquinoline via a chemoselective reduction of 4,7-dichloroquino-
line. The utility of 7-chloroquinoline for the synthesis of more
complex 7-mono-substituted quinolines has been demonstrated
through a series of Suzuki and Sonagashira couplings, as well as
a cyanation reaction. The versatility of 7-chloroquinoline as a syn-
thetic intermediate has been further expanded to the preparation
of 2,7-di-substituted quinolines.
11. (a) Maerten, E.; Hassouna, F.; Couve-Bonnaire, S.; Mortreux, A.; Carpentier, J.-
F.; Castanet, Y. Synlett 2003, 1874; (b) Najiba, D.; Carpentier, J.-F.; Castanet, Y.;
Biot, C.; Brocard, J.; Mortreux, A. Tetrahedron Lett. 1999, 40, 3719.
12. The ratio of 4:5 was determined using HPLC by comparison of the area under
the curve for each compound in the reaction mixture. This ratio was then
corrected with the extinction coefficient of each component as determined
from independently prepared samples of known concentration. Conversion
values were calculated as the ratio of (4+5):3, with correction by the extinction
coefficient as above.
References and notes
13. NMR data for 4: 1H NMR (400 MHz, CDCl3) d 8.93 (dd, J1 = 1.6 Hz, J2 = 4.3 Hz,
1H), 8.20–8.16 (m, 1H), 8.15 (d, J = 2.0 Hz, 1H), 7.54 (dd, J1 = 2.0 Hz, J2 = 8.8 Hz,
1H), 7.44 (dd, J1 = 4.4 Hz, J2 = 8.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 151.6,
148.9, 136.1, 135.5, 129.3, 128.7, 127.9, 126.9, 122.5; HRMS for C9H7ClN calc’d
[M+H] = 164.0267, found 164.0300.
1. (a) Kaneko, T.; Romero, K.; Li, B.; Buzon, R. Bioorg. Med. Chem. Lett. 2007, 17,
5049; (b) Mulvihill, M. J.; Ji, Q.-S.; Coate, H. R.; Cooke, A.; Dong, H.; Feng, L.;
Foreman, K.; Rosenfeld-Franklin, M.; Honda, A.; Mak, G.; Mulvihill, K. M.; Nigro,
A. I.; O’Connor, M.; Pirrit, C.; Steinig, A. G.; Siu, K.; Stolz, K. M.; Sun, Y.; Tavares,
P. A. R.; Yao, Y.; Gibson, N. W. Bioorg. Med. Chem. 2008, 16, 1359.

J. J. Hirner, M. J. Zacuto / Tetrahedron Letters 50 (2009) 4989–4993
4993
14. PdCl2 + ligands, including numerous triarylphosphines, SPhos and XPhos.
Although Pd(0) complexes were active catalysts (entries 1–4), we focused on
P(II) species due to their relative ease of handling in air.
15. This assertion is based on the observation that heating a mixture of 3 and HCl
(1 equiv) in 9:1 MeCN:H2O at 70 °C for 18 h resulted in the formation of 7 (15%
yield at 15% conversion of 3). This experiment models the reaction conditions
whereupon the Et3SiCl byproduct of the reduction creates acidic conditions for
any adventitious water. For relevant observations see: (a) Illuminati, G.;
Gilman, H. J. Am. Chem. Soc. 1950, 72, 4288 and (b) Cutler, R.A..; Surrey, A.. J. Am.
Chem. Soc. 1950, 72, 3394.
3H), 7.46–7.32 (m, 4H); for 11: (400 MHz, CDCl3) d 8.97–8.91 (m, 1H), 8.30 (s,
1H), 8.10 (s, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.77 (dd, J1 = 2.3 Hz, J2 = 8.2 Hz, 1H),
7.70–7.55 (m, 3H), 7.46–7.32 (m, 4H); for 12: (400 MHz, CD3CN) d 8.86 (dd,
J1 = 1.7 Hz, J2 = 4.3 Hz, 1H), 8.23–8.18 (m, 1H), 8.03 (s, 1H), 7.82 (d, J = 8.4 Hz,
1H), 7.50 (dd, J1 = 1.7 Hz, J2 = 8.4 Hz, 1H), 7.41 (dd, J1 = 4.3 Hz, J2 = 8.4 Hz, 1H),
5.36 (br s, 1H), 3.17 (dt, J1 = J2 = 7.0 Hz,, 2H), 2.46 (dd, J1 = J2 = 7.0 Hz, 2H), 1.74
(tt, J1 = J2 = 7.4 Hz, 2H), 1.37 (s, 9H).
20. 1H NMR (400 MHz, CDCl3) d 9.06 (dd, J1 = 1.7 Hz, J2 = 4.3 Hz, 1H), 8.50 (s, 1H),
8.23 (dd, J1 = 1.7 Hz, J2 = 8.6 Hz, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.72 (dd,
J1 = 1.7 Hz, J2 = 8.4 Hz, 1H), 7.56 (dd, J1 = 4.3 Hz, J2 = 8.4 Hz, 1H); 13C NMR
(125 MHz, CDCl3) d 152.3, 147.1, 136.0, 135.5, 130.3, 129.3, 127.3, 123.6, 118.4,
113.0.
16. 1H NMR data (400 MHz, CDCl3) for 5: d 8.96 (dd, J1 = 1.6 Hz, J2 = 4.3 Hz, 1H),
8.38–8.33 (m, 1H), 8.20 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.84 (dd,
J1 = 1.8 Hz, J2 = 8.4 Hz, 1H), 7.78 (dd, J1 = 1.4 Hz, J2 = 7.4 Hz, 2H), 7.52 (dd,
J1 = J2 = 7.4 Hz, 2H), 7.45–7.39 (m, 2H); for 6: d 8.96 (dd, J1 = 1.6 Hz, J2 = 4.3 Hz,
1H), 8.33–8.30 (m, 1H), 8.20 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.824
(dd, J1 = 1.7 Hz, J2 = 8.3 Hz, 1H), 7.42 (dd, J1 = 4.3 Hz, J2 = 8.3 Hz, 2H), 6.98 (s,
2H), 3.98 (s, 6H), 3.94 (s, 3H); for 7: d 9.00 (dd, J1 = 1.7 Hz, J2 = 4.3 Hz, 1H), 8.38–
8.34 (m, 1H), 8.24–8.21 (m, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.90–7.85 (m, 2H), 7.83
(dd, J1 = 1.7 Hz, J2 = 8.3 Hz, 1H), 7.80–7.75 (m, 2H), 7.46 (dd, J1 = 4.3 Hz,
J2 = 8.6 Hz, 1H); for 8: d 9.00–8.97 (m, 1H), 8.24 (d, J = 8.3 Hz, 1H), 8.10 (s,
1H), 7.90 (dd, J1 = 1.6 Hz, J2 = 8.4 Hz, 1H), 7.59 (dd, J1 = 1.6 Hz, J2 = 8.4 Hz, 1H),
7.48–7.43 (m, 1H), 7.40–7.30 (m, 4H), 2.37 (s, 3H); for 9: d 8.96 (dd, J1 = 1.7 Hz,
J2 = 4.3 Hz, 1H), 8.31–8.28 (m, 1H), 8.20 (dd, J1 = 1.2 Hz, J2 = 8.4 Hz, 1H), 7.90 (d,
J = 8.4 Hz, 1H), 7.79 (dd, J1 = 1.8 Hz, J2 = 8.4 Hz, 1H), 7.76–7.70 (m, 2H), 7.42 (dd,
J1 = 4.3 Hz, J2 = 8.4 Hz, 1H), 7.24–7.17 (m, 2H).
21. A small amount of 15 was observed as an impurity in the crude reaction
mixture, presumably arising from air oxidation of 14. 1H NMR data for 14:
(400 MHz, CDCl3) d 6.72 (d, J = 7.9 Hz, 1H), 6.50 (dd, J1 = 2.0 Hz, J2 = 7.9 Hz, 1H),
6.36 (d, J = 2.0 Hz, 1H), 6.26 (dd, J1 = 1.3 Hz, J2 = 10.0 Hz, 1H), 5.55 (dd,
J1 = 3.9 Hz, J2 = 10.0 Hz, 1H), 4.29–4.20 (m, 1H), 3.81 (br s, 1H), 1.65–1.51 (m,
2H), 1.42–1.30 (m, 2H), 0.92 (t, J = 7.0 Hz, 3H).
22. 1H NMR data for 15: (400 MHz, CDCl3)
d 8.07–8.02 (m, 2H), 7.71 (d,
J = 8.6 Hz, 1H), 7.44 (dd, J1 = 2.0 Hz, J2 = 8.6 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H),
2.79 (t, J = 8.1 Hz, 2H), 1.84–1.77 (m, 2H), 1.49–1.41 (m, 2H), 0.98 (t,
J = 7.4 Hz, 3H).
23. Interestingly, iPrMgCl was unreactive under these conditions. PhMgCl
underwent a similar 1,2-addition as described in Eq. 3.
24. 1H NMR for 17: (400 MHz, CDCl3) d 8.08 (d, J = 2.1 Hz, 1H), 7.99 (d, J = 8.7 Hz,
1H), 7.64 (d, J = 8.7 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.40 (dd, J1 = 2.1 Hz,
J2 = 8.7 Hz, 1H), 5.95–5.91 (m, 1H), 5.52–5.49 (m, 1H), 2.35–2.32 (m, 3H); for
18: (400 MHz, CDCl3) d 8.12 (d, J = 8.7 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.78–
7.67 (m, 4H), 7.23–7.16 (m, 2H), 5.97–5.94 (m, 1H), 5.54–5.50 (m, 1H), 2.41–
2.38 (m, 3H).
17. Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121,
9550.
18. Anderson, K. W.; Buchwald, S. L. Angew. Chem., Int. Ed. 2005, 44, 6173.
19. 1H NMR data for 10: (400 MHz, CDCl3) d 8.97–8.91 (m, 1H), 8.30 (s, 1H), 8.10 (s,
1H), 8.12 (d, J = 8.2 Hz, 1H), 7.77 (dd, J1 = 2.3 Hz, J2 = 8.2 Hz, 1H), 7.70–7.55 (m,