Palladium(II)-Catalyzed Annulation of Alkynes with 2-(Cyanomethyl)phenylboronates Leading to 3,4-Disubstituted 2-Naphthalenamines

Article abstract of DOI:10.1021/acs.joc.5b02378

1,2-Bis(diphenylphosphino)ethane (dppe)-ligated palladium(II) complexes catalyze the annulation of internal alkynes with 2-(cyanomethyl)phenylboronates to provide 3,4-disubstituted-2-naphthalenamines in good yields. The annulation reaction proceeds under mild and neutral conditions and requires methanol as an essential solvent. In addition to symmetrical alkynes, unsymmetrical alkynes substituted by aryl, alkyl, and alkynyl groups participate in the annulation to afford the corresponding 2-naphthalenamines with electron-withdrawing sp²- and sp-carbons preferentially located at the C-3 position. Substituents including an alkyl or alkoxy group on the cyanomethyl moiety and a halogen atom on the benzene ring in the boronates are compatible with the reaction conditions. The annulation proceeds through the transmetalation of the palladium(II) complexes with the boronates and alkyne insertion followed by nucleophilic addition of the generated alkenylpalladium(II) species to the intramolecular cyano group. Stoichiometric reactions revealed that the methanol solvent was effective for both transmetalation and catalyst regeneration.

Full text of DOI:10.1021/acs.joc.5b02378

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Featured Article
Palladium(II)-Catalyzed Annulation of Alkynes
with 2-(Cyanomethyl)phenylboronates Leading
to 3,4-Disubstituted 2-Naphthaleneamines
Hirokazu Tsukamoto, Taishi Ikeda, and Takayuki Doi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02378 • Publication Date (Web): 25 Nov 2015
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The Journal of Organic Chemistry
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Palladium(II)ꢀCatalyzed Annulation of Alkynes with
2ꢀ(Cyanomethyl)phenylboronates Leading to 3,4ꢀ
Disubstituted 2ꢀNaphthalenamines
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Hirokazu Tsukamoto,* Taishi Ikeda and Takayuki Doi
Graduate School of Pharmaceutical Sciences, Tohoku University, Aramakiꢀaza aoba 6ꢀ3, Aobaꢀku,
Sendai 980ꢀ8578, Japan
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
TOC
ABSTRACT
1,2ꢀBis(diphenylphosphino)ethane (dppe)ꢀligated palladium(II) complexes catalyze the annulation
of internal alkynes with 2ꢀ(cyanomethyl)phenylboronates to provide 3,4ꢀdisubstitutedꢀ2ꢀ
naphthalenamines in good yields. The annulation reaction proceeds under mild and neutral
conditions and requires methanol as an essential solvent. In addition to symmetrical alkynes,
unsymmetrical ones substituted by aryl, alkyl, and alkynyl groups participate in the annulation to
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afford the corresponding 2ꢀnaphthalenamines with electronꢀwithdrawing sp2ꢀ and spꢀcarbons
preferentially located at the Cꢀ3 position. Substituents including an alkyl or alkoxy group on the
cyanomethyl moiety and a halogen atom on the benzene ring in the boronates are compatible with
the reaction conditions. The annulation proceeds through the transmetalation of the palladium(II)
complexes with the boronates and alkyne insertion followed by nucleophilic addition of the
generated alkenylpalladium(II) species to the intramolecular cyano group. Stoichiometric reactions
revealed that the methanol solvent was effective for both transmetalation and catalyst regeneration.
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INTRODUCTION
Naphthalenamines and their derivatives are an important class of compounds due to their
biological activity1, which includes emetic, spasmolytic, and antimicrobacterial activity; they are
also known for their utility as starting materials for azo dyes.2 Moreover, their homoꢀ and heteroꢀ
dimers [i.e., 1,1′ꢀbinaphthylꢀ2,2′ꢀamines (BINAMs)] have recently received considerable attention as
axially chiral ligands, organocatalysts, and reagents.3 The introduction of substituents in the 3ꢀ and
3′ꢀpositions of BINAM can improve the enantioselectivities of reactions; however, these syntheses
are not trivial in comparison with those of the corresponding alcohols (BINOLs) and phosphines
(BINAPs).4, 5 Unsubstituted and substituted BINAMs can be synthesized by the oxidative coupling
of the parent 2ꢀnaphthalenamines.6, 7 Some conventional methods including the Bucherer reaction of
naphthols,8 the Curtius rearrangement of naphthoic acids,9 the Beckmann rearrangement of
acetonaphthone oximes,10 and transformation of tetralone derivatives can synthesize 2ꢀ
naphthalenamines.11 However, the poor availability of the starting bicyclic compounds (especially
multiꢀsubstituted ones) and harsh reaction conditions render them neither practical nor applicable to
substrates, including a wide variety of functional groups. There is still a need to develop an efficient
method to prepare substituted 2ꢀnaphthalenamines.
A decade ago, Larock developed a method for synthesizing 2ꢀnaphthalenamines 5 based on the
annulation of alkyne 1 with 2ꢀiodophenylacetonitrile (2) (Scheme 1, clockwise cycle on the left).12
The reaction is thought to proceed through the oxidative addition of 2 to in situꢀgenerated
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palladium(0), alkyne insertion between the arylꢀpalladium bond in 3, and nucleophilic addition of
alkenylpalladium(II) 4 to the proximal nitrile followed by aromatization. An additional step (i.e.,
reduction of the (amido)palladium(II) complex formed in the final step of the catalytic cycle with
triethylamine) is also essential to regenerate palladium(0). The annulation reaction offers relatively
mild reaction conditions and provides a wide variety of 3,4ꢀdisubstitutedꢀ2ꢀnaphthalenamines 5.
However, the method still requires a high reaction temperature (100 °C), long reaction time (48 h),
and excess alkyne (3 equiv) along with additives. Moreover, the reluctant reduction step sometimes
causes oxidation of the annulation products with an alkyl substituent at Cꢀ3 along with the
incorporation of the iminium salt formed by the oxidation of triethylamine into the products.
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Scheme 1. Annulation of internal alkyne 1 with 2ꢀiodoꢀ and 2ꢀboronoꢀphenylacetonitriles 2 and 6
Previously, we reported the palladium(II)ꢀcatalyzed annulation of internal alkynes with 2ꢀ
(methoxycarbonyl)phenylboronic acid (7) and 2ꢀ[(methoxycarbonyl)methyl]phenylboronate 8,
leading to 2,3ꢀdisubstituted 1Hꢀindenones 9 and 3,4ꢀdisubstituted 2ꢀnaphthols 10, respectively
(Scheme 2).13 The annulation proceeds through arylꢀpalladium(II) intermediates generated by
transmetalation between the arylboron reagents and palladium(II) catalyst and requires no redox
step. In contrast to the successful Larock’s annulation of diphenylacetylene (1a) with oꢀ
iodobenzonitrile, leading to indenone 9a,12a, 14 the substitution of the methoxycarbonyl group in
boronic acid 7 by a cyano group caused a significant decrease in the yield of 9a (Scheme 3).13–15 The
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result makes us hesitant to test the homologue 2ꢀ(cyanomethyl)phenylboronate 6 for the preparation
of 2ꢀnaphthalenamines 5 (Scheme 1, counterꢀclockwise cycle on the right), although there are
several reports on palladiumꢀcatalyzed reactions with nitrile electrophiles.16ꢀ20 Furthermore, similar
dppeꢀligated cationic palladium(II) catalysts were reported to promote the hydroamination of 1a
with aromatic amines.21 Herein, we have reported the successful synthesis of palladium(II)ꢀcatalyzed
3,4ꢀdisubstituted 2ꢀnaphthalenamines 5 based on the annulation of internal alkynes 1 with
commercially available22 or readily accessible boronate 6.
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Scheme 2. Pd(II)ꢀcatalyzed annulation of 1 with orthoꢀesterꢀcontaining
phenylboron reagents 7 and 8
Scheme 3. Unsuccessful Pd(II)ꢀcatalyzed annulation of 1a with 2ꢀcyanophenylboronic acid (12)
RESULTS AND DISCUSSION
Reaction Optimization and Substrate Scope. In contrast to the ineffective annulation with 2ꢀ
cyanophenylboronic acid (12), the reaction of 1a with 1.2 equiv of 2ꢀ(cyanomethyl)phenylboronate
6A under 5 mol% Pd(OCOCF3)2(dppe)23 (11a, dppe = 1,2ꢀbis(diphenylphosphino)ethane) catalyst in
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methanol upon heating at 80 °C for 3 h led to the formation of 3,4ꢀdiphenylꢀ2ꢀnaphthalenamine (5a)
in high yield (Table 1, entry 1). As with the previously reported synthesis of 2ꢀnaphthols,13 methanol
turned out to be the best solvent for the annulation, and aprotic solvents were much less effective
(entries 1 vs. 2–5). The protic solvent should play an important role in the annulation. It is
noteworthy that the hydroamination of 1a with in situꢀformed 5a did not take place under the
reaction conditions.21 Reducing the reaction temperature to 65 °C did not affect the yield of 5a (entry
6), while a lower catalyst loading of 11a gave 5a in much poorer yield (entries 6 vs. 7). In contrast,
the amount of cationic palladium(II) complex 11b24 can be reduced to 2 mol% without a significant
decrease in product yield (entries 8 and 9).
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Table 1. Optimization of Pd(II)ꢀcatalyzed annulation of 1a with 6A
entry
catalyst
X
5
5
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5
2
solvent
MeOH
temp (°C) time (h) yield (%)
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9
Pd(OCOCF3)2(dppe) (11a)
80
80
80
80
80
65
65
65
65
3
24
24
12
12
4
88
10
6
DMF
11a
acetone
CH3CN
1,4ꢀdioxane
MeOH
11a
5
11a
<2
89
57
99
94
11a
11a
MeOH
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2
11a
[Pd(PhCN)2(dppe)](BF4)2 (11b)
11b
MeOH
MeOH
6
With readily available catalyst 11a, the annulation reactions using various alkynes 1b–q were
examined (Table 2). Symmetrical diarylacetylenes 1b and 1c with electronꢀdonating or electronꢀ
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withdrawing substituents at the paraꢀpositions were converted into 3,4ꢀdiarylꢀ2ꢀnaphthalenamines
5b and 5c, respectively, in high yields (entries 1 and 2). While the yield of the annulation product 5d
obtained from orthoꢀsubstituted diarylacetylene 1d was comparable to those of 5b and 5c (entry 3),
the use of di(heteroaryl)alkyne 1e resulted in slightly lower yield of 5e (entry 4). The annulation of
both acyclic and cyclic symmetrical dialkylꢀsubstituted alkynes 1f and 1g afforded 3,4ꢀdialkylꢀ2ꢀ
naphthalenamines 5f and 5g, respectively, without any oxidation of the products14a (entries 5 and 6).
Protected 1,4ꢀbutanediol 1h also participated in the annulation to give naphthalenamine 5h in
moderate yield (entry 7). 2ꢀAlkylꢀsubstituted 1ꢀphenylacetylenes 1i–k underwent the annulations
with 6A to provide 4ꢀalkylꢀ3ꢀphenylꢀ2ꢀnaphthalenamines 5i–k together with a small amount of 3ꢀ
alkylꢀ4ꢀphenylꢀ2ꢀnaphthalenamines 5i–k′ as a separable mixture (entries 8–11). The regioselectivity
observed in the annulation of 1ꢀphenylꢀ1ꢀpropyne (1i) with 6A is similar to that of the palladium(II)ꢀ
catalyzed annulation with 7, leading to indenone 9.13 The secondary and tertiary alkyl groups in 1j
and 1k lower the selectivity, preferring 3ꢀphenylꢀ2ꢀnaphthalenamines (entries 9, 10 vs. 8). The
tertiary alcohol in 1l was compatible with the annulation conditions and competed with the phenyl
group for the 3ꢀposition of the naphthalenamines to give 5l and 5l′ in nearly equal amounts (entry
11). The annulation of 2ꢀpropynes 1m and 1n substituted by either primary or secondary alkyl
groups furnished a mixture of two possible 2ꢀnaphthalenamines; the quantity of the formed 4ꢀmethyl
substituted one was slightly more than that of the formed 3ꢀmethyl substituted one (entries 12 and
13). As in entries 10 and 11, the sterically similar tertꢀbutyl and 2ꢀhydroxypropanꢀ2ꢀyl groups in 1o
and 1p guided the annulation in a different way and were preferentially incorporated in the Cꢀ4 and
Cꢀ3 positions of the products, respectively (entries 14 and 15). It is worth noting that the
regioselectivity of our annulation using 1,3ꢀdiyne 1q is opposite to that of Larock’s annulation with
2ꢀiodophenylacetonitrile 2, leading to the exclusive formation of 5q′ (entry 16).12, 14 Unfortunately,
the annulation reactions of alkynyl esters, alkynylsilanes, and terminal alkynes were unsuccessful.
The structures of naphthalenamines prepared by our reactions with unsymmetrical alkynes 1i–q
were determined by NOESY correlation between the proton at Cꢀ5 and the protons of the substituent
at Cꢀ4 in 2ꢀaminonaphthanlenes 5i–q and 5i–q′ (see Supporting Information).
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Table 2. Annulation of symmetrical and unsymmetrical alkynes 1b–q with 6Aa
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entry
1
alkyne 1
product 5
yield (%)
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5i: 73
5i′: 15
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5j: 70
5j′: 27
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5k: 33
5k′: 12
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5l: 36
5l′: 33
11
5m: 40
5m′: 33
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13
5n: 50
5n′: 33
5o: 22
5o′: 41
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5p: 50
5p′: 23
5q: 77
5q′: 3
a Reaction conditions: 1b–q (1 equiv), 6A (1.2 equiv) and Pd(OCOCF3)2(dppe) (5 mol%), MeOH
(0.4 M for 1b–q), 65 °C, 4 h.
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The effects of substituents in the boronate 6 on the annulation of 1a were also examined. Methyl
substitution on the cyanomethyl moiety in 6 did not hamper the annulation, which gave 1ꢀmethylꢀ
3,4ꢀdiphenylꢀ2ꢀnaphthalenamine (5B) in 80% yield (Table 3, entry 1). The annulations of 1a with
benzylꢀ and acetylꢀprotected cyanohydrins 6C and 6D afforded 2ꢀaminoꢀ1ꢀnaphthyl benzyl ether 5C
and 2ꢀacetamidoꢀ1ꢀnaphthol 5D′ in excellent yields, respectively (entries 2, 3). The latter product
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5D′ resulted from the annulation followed by O–N acyl migration instead of oxazole formation12b
.
Electronꢀdonating methoxy groups and electronꢀwithdrawing halogen atoms on the benzene ring in 6
did not affect the reactions, which gave 5E–G in high yields (entries 4–6). The compatibility of
halogen atoms in the palladium(II)ꢀcatalyzed reaction allows the further transformation of the
halogenꢀcontaining products under palladium(0) catalysis.
Table 3. Annulation of 1a with boronates 6B–Ga
entry
1b
boronate 6
product 5
yield (%)
80
2b
91
3b
4c
5c
92
81
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6c
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a
Reaction conditions: 1a (1 equiv), 6 (2 equiv for 6B–D, 1.2 equiv for 6E–G) and
7
8
Pd(OCOCF3)2(dppe) (5 mol%), MeOH (0.4 M for 1a), 65 °C. b Reaction for 24 h. c Reaction for 4 h.
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Reaction Mechanism. A plausible reaction mechanism is shown in Scheme 4. Methanol is an
essential solvent for the annulation and converts catalyst 11a into the corresponding methoxoꢀ
complex 1325 along with trifluoroacetic acid, the former of which should be favorable for
transmetalation with arylboronate 6 to give arylꢀpalladium(II) species 14.26 The migratory insertion
of coordinated alkyne 1 between the arylꢀpalladium bond in 15 is accelerated and guided by the
substituent with electronꢀwithdrawing sp2ꢀ and spꢀcarbons or a 1ꢀhydroxyalkyl group27 as R2. The
nucleophilic addition of alkenylꢀpalladium 16 to the proximal nitrile followed by the aromatization
of 17 and solvolysis of amido complex 18 form naphthalenamine 5, as well as catalyst 13. Hence,
the protic solvent would participate in the formation of (methoxo)palladium 13 not only from 11a
but also from 18.
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Scheme 4. Plausible reaction mechanism for the annulation
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To verify the actual role of methanol in the catalytic cycle, the stoichiometric reactions shown in
Scheme 5 were investigated. First, the solvent effect on the transmetalation reaction between dppeꢀ
ligated palladium 11a and arylboronate 6A in the presence of triphenylphosphine to stabilize the
1
complex28 was examined by H and 31P NMR experiments. Among the tested deuterium solvents
(i.e., chloroformꢀd, acetonitrileꢀd3, acetoneꢀd6, and methanolꢀd4) only methanolꢀd4 allowed the
formation of palladium(II) complex 20a after heating the mixture at 65 °C for 24 h.29 The 31P signals
exhibited at 47.3 ppm (dd, J = 26, 362 Hz), 38.9 ppm (dd, J = 26, 26 Hz), and 18.1 ppm (dd, J = 26,
362 Hz) were identical to those of an authentic sample synthesized according to Miyaura’s
procedure28 from silver trifluoroacetete, dppe, and bis(triphenylphosphine) complex 19a, which was
prepared
by
the
oxidative
addition
of
2ꢀiodophenylacetonitrile
(2)
to
tetrakis(triphenylphosphine)palladium(0).29 Similarly, the formation of lower homologue 20b was
also observed after heating a mixture of 11a, oꢀcyanophenylboronic acid (12), and
triphenylphosphine in methanolꢀd4 under the same conditions.
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Next, the stoichiometric annulation between diphenylacetylene (1a) and dppeꢀligated
arylpalladium complex 20a was explored (Scheme 5). The annulation reaction of 20a proceeded in
acetonitrile, acetone, and 1,4ꢀdioxane as well as in methanol, indicating that neither alkyne insertion
nor nucleophillic addition to the adjacent nitrile in the catalytic cycle was affected by the solvent.
The similar phenomena were also observed in the absence of the triphenylphosphine ligand (vide
infra, Scheme 6. The yields of 5a based on arylpalladium iodide 23a were constant without regard to
the solvents, i.e., methanol and acetonitrile). Even in the presence of excess 1a, hydroamination
products 21 and 22 were not observed. In contrast, methanol was much less effective than other
solvents in the annulation of lower homologue 20b, leading to indenone 9a. The incompatibility of
this step with methanol as solvent accounts for the inefficient annulation of 1a with 12.
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The Journal of Organic Chemistry
Scheme 5. Preparation of arylpalladiums 20a, b via transmetalation of 11a with 6A and 12 and
their annulation with 1a
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Finally, the solvent effect on the annulation between 1a and 6E in the presence of a catalytic
amount of cationic dppeꢀligated arylpalladium 15 (Scheme 4) generated in situ from arylpalladium
iodide 23a and silver trifluoroacetate was investigated to obtain insights into the catalyst
regeneration step (Scheme 6). The palladium complex 23a was easily prepared by the oxidative
addition of 2ꢀiodophenylacetonitrile (2) to the in situꢀgenerated palladium(0)ꢀdppe complex upon
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heating in 1,4ꢀdioxane.31 While naphthalenamine 5a derived from catalyst 23a was obtained in
comparable yields in methanol and acetonitrile, the yield of 5E from boronate 6E dramatically
depended on the solvent (76% in methanol vs. 6% in acetonitrile). These contrasting results
demonstrate that methanol is essential for the turnover (i.e., solvolysis) of amidopalladium 18
(Scheme 4).
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Scheme 6. Preparation of 23a and its catalytic use for the annulation between 1a and 6E
CONCLUSIONS
In summary, we have developed a new preparative method for 3,4ꢀdisubstitutedꢀ2ꢀ
naphthalenamines based on the palladium(II)ꢀcatalyzed annulation of internal alkynes with 2ꢀ
(cyanomethyl)phenylboronates. Compared with the palladium(0)ꢀcatalyzed reaction with (2ꢀ
iodophenyl)acetonitrile, our naphthalenamine synthesis has the advantages of relatively low reagent
consumption, lower reaction temperature, shorter reaction time, and wider substrate scope.12
Moreover, our redoxꢀfree system did not cause product oxidation, which was sometimes observed in
the former reaction. Investigations of annulations with functionalized phenylboronic acids leading to
other carboꢀ and heterocycles and their asymmetric processes are underway in this laboratory.
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The Journal of Organic Chemistry
EXPERIMENTAL SECTION
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General Techniques. All commercially available reagents and anhydrous solvents including 1,4ꢀ
dioxane, acetone, tetrahydrofuran (THF), dichloromethane, and benzene were purchased and used
without further purification. Anhydrous methanol (MeOH) was obtained by distillation from
magnesium. Anhydrous N, Nꢀdimethylformamide (DMF) and acetonitrile were obtained by
distillation from calcium hydride. All reactions were monitored by thin layer chromatography (TLC)
performed on 0.25 mm silica gel glassplates (60 F254) using UV light and ethanolic pꢀanisaldehydeꢀ
sulfuric acid, ethanolic molybdatophosphoric acid, aqueous cerium sulfateꢀhexaammonium
heptamolybdateꢀsulfuric acid, or aqueous potassium permanganateꢀpotassium carbonateꢀsodium
hydroxide solutions as visualizing agents. Flash column chromatography was carried out with silica
gel (spherical, neutral, 63ꢀ210 ꢀm grade). Purifications of 2ꢀnaphthalenamines were performed on
0.75 mm PLC plates and 0.5 mm NH2 silica gel 60 F254 Plates. Yields refer to chromatographically
and spectroscopically homogenous materials. Melting points were measured on a melting point
apparatus and were uncorrected. Only the strongest and/or structurally important absorptions of
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1
infrared (IR) spectra are reported in reciprocal centimeters (cmꢀ1). H NMR spectra (400 MHz and
600 MHz), 13C{1H}NMR spectra (100 MHz and 151 MHz), 31P{1H}NMR spectra (243 MHz), and
19F NMR spectra (564 MHz) were recorded in the indicated solvent. Chemical shifts (δ) are reported
in delta (δ) units, parts per million (ppm). Chemical shifts for 1H NMR spectra are given relative to
signals for internal tetramethylsilane (0 ppm) or residual nondeuterated solvents, i.e., chloroform
(7.26 ppm), acetone (2.04 ppm), acetonitrile (1.93 ppm), and methanol (3.30 ppm). Chemical shifts
for 13C NMR spectra are given relative to the signal for chloroformꢀd (77.0 ppm). Chemical shifts
for 31P NMR spectra are given relative to the signal for external 85% phosphoric acid (0 ppm).
Chemical shifts for 19F NMR spectra are given relative to the signal for external fluorobenzene (–
113.8 ppm32 in acetoneꢀd6). Multiplicities are reported by the following abbreviations: s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), dd (double doublet), dt (double triplet), br–s (broad
singlet). Coupling constants (J) are represented in hertz (Hz). 1H and 13C NMR chemical shifts were
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assigned using a combination of COSY, NOESY, HMQC, and HMBC. Low and highꢀresolution
mass spectra were measured on TOFꢀMS with EI, FAB, or ESI probe.
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Materials. All internal alkynes are literatureꢀknown. Internal alkynes 1a, 1f, 1i, 1m, 1n, 1o, 1p
and 1q were purchased. Arylacetylenes 1b,33 1c,34 1d,35 1e,36 1j,37 1k,38 and 1l39 were prepared by
Sonogashira reaction between the parent iodoarene and alkyne. Dialkyl acetylenes 1g40 and 1h41
were prepared according to the literature procedures. Catalysts 11a23 and 11b24 were prepared
according to the literature procedures. Transꢀ[Pd{C6H4(CN)ꢀ2}Br(PPh3)2] (19b)42 was prepared
according to the literature procedure.
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Preparation of 2ꢀ(cyanomethyl)phenylboronic acid pinacol ester: The boronates 6A–E were
prepared by borylation of the parent iodides according to the literature procedure.43 The starting
iodides
except
for
2ꢀ(benzyloxy)ꢀ2ꢀ(2ꢀiodophenyl)acetonitrile
and
2ꢀ(5ꢀbromoꢀ2ꢀ
iodophenyl)acetonitrile were prepared according to the literature procedures.44
2ꢀ(Benzyloxy)ꢀ2ꢀ(2ꢀiodophenyl)acetonitrile: To a solution of 2ꢀiodobenzaldehyde45 (1.08 g, 4.65
mmol) in benzyloxytrimethylsilane (1.86 g, 10.3 mmol) was added iron(III) chloride (15.1 mg, 93.1
o
µmol) at 0 °C.46 After being stirred at 0 C for 2 h, the mixture was treated with trimethylsilyl
cyanide (0.70 mL, 5.6 mmol). The resulting mixture was stirred at 0 °C for 4 h and then partitioned
between CH2Cl2 and phosphate buffer (pH 7). The aqueous layer was extracted with CH2Cl2 twice.
The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo.
The residue was purified by silica gel chromatography eluting with 20% EtOAc/hexane to yield the
title compound (619 mg, 1.77 mmol, 38%) as a pale yellow oil.
Rf=0.55 (25% EtOAc/hexane). IR ν (neat, cmꢀ1): 3032, 2870, 1456, 1066, 1015, 753, 698. 1HꢀNMR
(400 MHz, CDCl3): δ 7.87 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.73–7.34 (m, 6H), 7.11
(dd, J = 8.0, 7.2 Hz, 1H), 5.45 (s, 1H), 4.88 (d, J = 11.2 Hz, 1H), 4.74 (d, J = 11.2 Hz, 1H). 13Cꢀ
NMR (100 MHz, CDCl3): δ 140.0, 136.1, 135.5, 131.4, 129.2, 128.9, 128.7, 128.6, 128.65, 128.62,
116.8, 98.1, 73.9, 72.6. LRMS (EI) m/z (relative intensity) 349 [M]+ (46), 243 (57), 242 (27), 116
(63), 92 (92), 91 (100). HRMS (EI, [M]+): calcd for C15H12INO, 348.9964; found 348.9953.
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The Journal of Organic Chemistry
2ꢀ(5ꢀBromoꢀ2ꢀiodophenyl)acetonitrile: To a solution of 5ꢀbromoꢀ2ꢀiodobenzoic acid (981 mg,
3.00 mmol) in anhydrous THF (6.0 mL) was added boraneꢀtetrahydrofuran complex (1 M, 9.0 mL,
9.0 mmol) at room temperature. After being refluxed for 2 h with stirring, the resulting mixture was
cooled to 0 °C, cautiously treated with MeOH, and concentrated in vacuo. To a solution of the crude
alcohol (960 mg) in anhydrous DCM (7.5 mL) were added anhydrous DMF (0.36 mL, 4.7 mmol)
and thionyl chloride (0.44 mL, 6.0 mmol) successively at 0 °C. The mixture was stirred at room
temperature for 1 h, and then treated with saturated aqueous NaHCO3. The aqueous layer was
extracted with Et2O twice. The combined organic layers were washed with brine, dried over MgSO4,
and concentrated in vacuo. To a solution of the crude chloride (972 mg) in anhydrous DMF (9.0 mL)
was added potassium cyanide (586 mg, 9.00 mmol) at room temperature. The mixture was stirred at
50 °C for 1 h, and then treated with water. The aqueous layer was extracted with EtOAc twice. The
combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The
residue was purified by silica gel chromatography eluting with 20% EtOAc/hexane to yield the title
compound (476 mg, 1.48 mmol, 49% over three steps) as a colorless oil.
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Rf=0.53 (25% EtOAc/hexane). IR ν (neat, cmꢀ1): 2925, 2243, 1457, 1398, 1012, 819. HꢀNMR (400
MHz, CDCl3): δ 7.72 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.19 (dd, J = 8.6, 2.0 Hz, 1H),
3.79 (2H, s). 13CꢀNMR (100 MHz, CDCl3): δ 140.9, 135.2, 133.1, 132.0, 123.2, 116.5, 96.8, 29.7.
LRMS (EI) m/z (relative intensity) 323 [M+2]+ (98), 321 [M]+ (100), 242 (18), 196 (27), 194 (27),
169 (17), 167 (17). HRMS (EI, [M]+): calcd for C8H5NBrI, 320.8650; found 320.8641.
General procedure for the preparation of 2ꢀ(cyanomethyl)phenylboronic acid pinacol ester:
To
a
mixture of 2ꢀ(2ꢀiodophenyl)acetonitrile (1 equiv), triethylamine (3 equiv), 2ꢀ
(dicyclohexylphosphino)biphenyl (4 mol%) and palladium diacetate (2 mol%) in anhydrous 1,4ꢀ
dioxane (0.4 M for 2ꢀ(2ꢀiodophenyl)acetonitrile) was added pinacolborane (4 equiv) at room
o
temperature. After being stirred at 80 C for 30 min, the resulting mixture was cooled to room
temperature and cautiously treated with saturated aqueous NH4Cl. The aqueous layer was extracted
with EtOAc twice. The combined organic layers were washed with brine, dried over MgSO4, and
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concentrated in vacuo. The product was purified by silica gel chromatography eluting with 20%
EtOAc/hexane, unless otherwise noted.
Page 18 of 41
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2ꢀ(2ꢀ(4,4,5,5ꢀTetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)phenyl)acetonitrile
(6A)43a:
Synthesis
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according to the general procedure from 2ꢀ(2ꢀiodophenyl)acetonitrile44a (2.98 g, 12.3 mmol). Yield
85% (2.56 g, 10.5 mmol), dark orange oil. All the analytical data were in good agreement with
values reported in the literature.43a
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2ꢀ(2ꢀ(4,4,5,5ꢀTetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)phenyl)propanenitrile (6B):
Synthesis
according to the general procedure from 2ꢀ(2ꢀiodophenyl)propionitrile44b (377 mg, 1.47 mmol).
Yield 96% (362 mg, 1.41 mmol), dark orange oil. Rf=0.60 (25% EtOAc/hexane). IR (neat, cmꢀ1):
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2980, 2241, 1601, 1349, 1145, 859, 660 cmꢀ1. HꢀNMR (400 MHz, CDCl3): δ 7.86 (d, J = 7.2 Hz,
1H), 7.59 (d, J = 7.6 Hz, 1H), 7.49 (dd, J = 7.6, 7.6 Hz, 1H), 7.49 (dd, J = 7.6, 7.6 Hz, 1H), 7.31
(dd, J = 7.2, 7.6 Hz, 1H), 4.90 (q, J = 7.2 Hz, 1H), 1.58 (d, J = 7.2 Hz, 3H), 1.35 (s, 6H), 1.34 (s,
6H). 13CꢀNMR (100 MHz, CDCl3): δ 144.1, 136.9, 132.0, 127.1, 126.6, 122.8, 84.0, 29.8, 24.9, 24.7,
22.6. LRMS (EI) m/z (relative intensity) 257 [M]+ (37), 242 (13), 199 (73), 198 (40), 157 (100), 131
(36). HRMS (EI, [M]+):calcd for C15H20BNO2, 257.1587; found 257.1578.
2ꢀ(Benzyloxy)ꢀ2ꢀ(2ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)phenyl)acetonitrile (6C):
Synthesis according to the general procedure from 2ꢀ(benzyloxy)ꢀ2ꢀ(2ꢀiodophenyl)acetonitrile (221
mg, 0.632 mmol). Yield 49% (109 mg, 0.312 mmol), dark orange oil. Rf=0.59 (25% EtOAc/hexane).
1
IR ν (neat, cmꢀ1): 2979, 1728, 1350, 1068, 698. HꢀNMR (400 MHz, CDCl3): δ 7.87 (d, J = 7.2 Hz,
1H), 7.79 (d, J = 7.8 Hz, 1H), 7.54 (dd, J = 7.8, 6.4 Hz, 1H), 7.42–7.31 (m, 6H), 6.15 (1H, s), 4.85
(d, J = 11.2 Hz, 1H), 4.72 (d, J = 11.2 Hz, 1H), 1.31 (s, 6H), 1.28 (s, 6H). 13CꢀNMR (100 MHz,
CDCl3): δ 139.7, 136.5, 136.4, 131.8, 128.8, 128.5, 128.3, 128.2, 127.2, 118.3, 84.2, 72.1, 68.4, 24.9,
24.8. HRMS (FAB, [MꢀCN]+): calcd for C20H24BO3, 323.1819; found 323.1813.
Cyano(2ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)phenyl)methyl acetate (6D): Synthesis
according to the general procedure from 2ꢀ(acetyloxy)ꢀ2ꢀ(2ꢀiodophenyl)acetonitrile14a (246 mg,
0.817 mmol). Yield 67% (164 mg, 0.545 mmol), dark orange oil. Rf=0.51 (25% EtOAc/hexane). IR
(neat, cmꢀ1): 2980, 1760, 1349, 1025, 658 cmꢀ1. 1HꢀNMR (400 MHz, CDCl3): δ 7.92 (d, J = 6.4 Hz,
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The Journal of Organic Chemistry
1H), 7.76 (d, J = 7.6 Hz, 1H), 7.55 (dd, J = 7.6, 7.2 Hz, 1H), 7.45 (dd, J = 6.4, 7.2 Hz, 1H), 7.13 (s,
1H), 2.14 (s, 3H), 1.35 (s, 6H), 1.33 (s, 6H). 13CꢀNMR (100 MHz, CDCl3): δ 168.7, 137.4, 136.8,
131.9, 129.4, 127.7, 116.9, 84.4, 62.4, 24.84, 24.76, 20.5. LRMS (EI) m/z (relative intensity) 301
[M]+ (12), 243 (50), 200 (38), 185 (46), 143 (100), 142 (34). HRMS (EI, [M]+): calcd for
C16H20BNO4, 301.1485; found 301.1491.
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2ꢀ(4,5ꢀDimethoxyꢀ2ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)phenyl)acetonitrile (6E):
Synthesis according to the general procedure from 2ꢀ(2ꢀiodoꢀ4,5ꢀdimethoxyphenyl)acetonitrile44c
(606 mg, 2.00 mmol). The product was purified by silica gel chromatography eluting with 40%
EtOAc/hexane. Yield 87% (527 mg, 1.74 mmol), white solid. Rf=0.31 (25% EtOAc/hexane). Mp:
1
132–135 °C. IR ν (compression cell, cmꢀ1): 2932, 2362, 1373, 1162, 668. HꢀNMR (400 MHz,
CDCl3): δ 7.32 (s, 1H), 6.94 (s, 1H), 4.09 (s, 2H), 3.94 (s, 3H), 3.93 (s, 3H), 1.35 (s, 12H). 13CꢀNMR
(100 MHz, CDCl3): δ 151.6, 147.9, 130.4, 119.2, 118.6, 111.8, 83.9, 56.0, 55.9, 24.9, 23.0. LRMS
(EI) m/z (relative intensity) 303 [M]+ (66), 302 (17), 245 (12), 203 (100), 202 (28), 177 (25). HRMS
(EI, [M]+): calcd for C16H22BNO4, 303.1642; found 303.1653.
2ꢀ(4ꢀChloroꢀ2ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)phenyl)acetonitrile (6F):
Synthesis according to the general procedure from 2ꢀ(4ꢀchloroꢀ2ꢀiodophenyl)acetonitrile44d (601 mg,
2.17 mmol). Yield 72% (437 mg, 1.57 mmol), grey solid. Rf=0.56 (25% EtOAc/hexane). Mp: 93–
1
96 °C. IR ν (compression cell, cmꢀ1): 2981, 2245, 1486, 1343, 1141, 869. HꢀNMR (400 MHz,
CDCl3): δ 7.84 (d, J = 2.4 Hz, 1H), 7.43 (dd, J = 2.4, 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 4.05 (s,
2H), 1.36 (s, 12H). 13CꢀNMR (100 MHz, CDCl3): δ 136.5, 135.0, 133.7, 131.6, 130.0, 118.4, 84.5,
24.8, 23.0. LRMS (EI) m/z (relative intensity) 277 [M]+ (76), 237 (32), 219 (88), 178 (46), 176
(100), 151 (44). HRMS (EI, [M]+): calcd for C14H17BClNO2, 277.1041; found 277.1046.
2ꢀ(5ꢀBromoꢀ2ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)phenyl)acetonitrile (6G):
Synthesis according to the general procedure from 2ꢀ(5ꢀbromoꢀ2ꢀiodophenyl)acetonitrile (179 mg,
0.556 mmol). Yield 45% (80.1 mg, 0.249 mmol), brown oil. Rf=0.56 (25% EtOAc/hexane). IR ν
1
(neat, cmꢀ1): 2989, 2245, 1586, 1347, 1150, 1059, 825. HꢀNMR (400 MHz, CDCl3): δ 7.72 (d, J =
8.0 Hz, 1H), 7.61 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 4.06 (s, 2H), 1.35 (s, 12H). 13CꢀNMR (100
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MHz, CDCl3): δ 136.8, 136.6, 131.8, 128.5, 127.2, 118.9, 84.1, 24.9, 23.6. LRMS (EI) m/z (relative
intensity) 323 [M+2]+ (69), 321 [M]+ (69), 280 (64), 265 (74), 263 (80), 223 (100), 221 (91). HRMS
(EI, [M]+): calcd for C14H17O2NBrB, 321.0536; found 321.0521.
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General procedure for the optimization of Pd(II)ꢀcatalyzed annulation of 1a with 6A (Table
1): To a test tube containing diphenylacetylene (1a, 0.10 mmol, 1 equiv), 2ꢀ(2ꢀ(4,4,5,5ꢀtetramethylꢀ
1,3,2ꢀdioxaborolanꢀ2ꢀyl)phenyl)acetonitrile (6A, 0.12 mmol, 1.2 equiv), and catalysts
(Pd(OCOCF3)2(dppe) (11a) for entries 1–7 and [Pd(PhCN)2(dppe)](BF4)2 (11b) for entries 8 and 9, 5
or 2 µmol, 5 or 2 mol%) was added the solvent shown in Table 1 (0.5 mL). The resulting mixture
was sealed with a screw cap, stirred under the reaction conditions shown in Table 1, cooled to room
temperature, and then concentrated in vacuo. The residue was purified by preparative TLC eluting
with 2% EtOAc/toluene to yield 3,4ꢀdiphenylꢀ2ꢀnaphthylamine (5a) as a yellow solid.
entry 1: Yield 88% (27.0 mg, 91.4 µmol) from 1a (18.6 mg, 104 µmol), 6A (28.0 mg, 115 µmol),
11a (3.7 mg, 5.1 µmol), and MeOH (0.5 mL).
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entry 2: Yield 10% (3.1 mg, 10 µmol) from 1a (18.6 mg, 104 µmol), 6A (28.4 mg, 117 µmol),
11a (4.0 mg, 5.5 µmol), and DMF (0.5 mL).
entry 3: Yield 6% (1.7 mg, 5.8 µmol) from 1a (17.8 mg, 99.9 µmol), 6A (29.4 mg, 121 µmol),
11a (4.0 mg, 5.5 µmol), and acetone (0.5 mL).
entry 4: Yield 5% (1.4 mg, 4.7 µmol) from 1a (18.6 mg, 104 µmol), 6A (28.0 mg, 115 µmol), 11a
(3.9 mg, 5.3 µmol), and CH3CN (0.5 mL).
entry 5: Yield <2% (<0.7 mg, 2 µmol) from 1a (18.2 mg, 102 µmol), 6A (28.4 mg, 117 µmol),
11a (3.7 mg, 5.1 µmol), and 1,4ꢀdioxane (0.5 mL).
entry 6: Yield 89% (26.9 mg, 91.1 µmol) from 1a (18.3 mg, 103 µmol), 6A (28.6 mg, 118 µmol),
11a (3.6 mg, 4.9 µmol), and MeOH (0.5 mL).
entry 7: Yield 57% (17.8 mg, 60.3 µmol) from 1a (18.9 mg, 106 µmol), 6A (29.4 mg, 121 µmol),
11a (1.5 mg, 2.1 µmol), and MeOH (0.5 mL).
entry 8: Yield 99% (29.2 mg, 98.9 µmol) from 1a (17.8 mg, 99.9 µmol), 6A (28.8 mg, 118 µmol),
11b (4.5 mg, 5.1 µmol), and MeOH (0.5 mL).
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entry 9: Yield 94% (28.5 mg, 96.5 µmol) from 1a (18.2 mg, 102 µmol), 6A (29.6 mg, 122 µmol),
11b (1.9 mg, 2.1 µmol), and MeOH (0.5 mL).
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3,4ꢀDiphenylnaphthalenꢀ2ꢀamine (5a)12a: Rf=0.43 (2% EtOAc/toluene). Mp: 164–165 °C. IR ν
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(compression cell, cmꢀ1): 3466, 3373, 1619, 1344, 749. HꢀNMR (400 MHz, CDCl3): δ 7.65 (d, J =
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8.5 Hz, 1H), 7.38–7.34 (m, 2H), 7.24–7.09 (m, 13H), 3.47 (br–s, 2H). 13CꢀNMR (100 MHz, CDCl3):
δ 142.2, 139.8, 139.1, 137.5, 134.4, 130.9, 130.6, 129.9, 128.3, 127.4, 127.3, 126.94, 126.91, 126.4,
126.1, 125.6, 122.5, 108.4. HRMS (ESI, [M+H]+): calcd for C22H18N, 296.1434; found 296.1425.
General procedure for the Pd(II)ꢀcatalyzed annulation of 1b–q with 6A (Table 2): To a test
tube containing internal alkyne 1b–q (1 equiv), 6A (1.2 equiv) and 11a (5 mol%) was added
anhydrous MeOH (0.2 M for 1). The resulting mixture was sealed with a screw cap, stirred at 65 °C
for 4 h, cooled to room temperature, and then concentrated in vacuo. The residue was purified by
preparative TLC eluting with 2% EtOAc/toluene, unless otherwise noted, to yield 3,4ꢀdisubstituted
2ꢀnaphthylamine 5b–q and 5i–q′.
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3,4ꢀBis(4ꢀmethoxyphenyl)naphthalenꢀ2ꢀamine (5b)14a (entry 1): Yield 70% (19.0 mg, 53.5
µmol) from 1b (18.1 mg, 76.0 µmol), 6A (22.2 mg, 91.1 µmol), and 11a (2.8 mg, 3.8 µmol). White
solid. Rf=0.27 (2% EtOAc/toluene). Mp: 184–185 °C. IR ν (compression cell, cmꢀ1): 3378, 2931,
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2359, 1609, 1515, 1245, 1031, 751. HꢀNMR (400 MHz, CDCl3): δ 7.64 (d, J = 8.1 Hz, 1H), 7.40
(d, J = 8.6 Hz, 1H), 7.35 (dd, J = 8.1, 6.8 Hz, 1H), 7.12–7.09 (m, 2H), 7.05–7.00 (m, 4H), 6.79–6.75
(m, 4H), 3.78 (s, 3H), 3.76 (s, 3H). 13CꢀNMR (100 MHz, CDCl3): δ 158.3, 157.9, 142.7, 139.7,
134.3, 131.9, 131.65, 131.58, 129.8, 127.7, 127.0, 126.0, 125.5, 122.3, 113.8, 113.0, 108.0, 55.1.
LRMS (EI) m/z (relative intensity) 355 [M]+ (100), 324 (3), 280 (3), 252 (3), 239 (2), 177 (5).
HRMS (EI, [M]+): calcd for C24H21NO2, 355.1572; found 355.1574.
3,4ꢀBis(4ꢀacetylphenyl)naphthalenꢀ2ꢀamine (5c) (entry 2): Yield 74% (13.6 mg, 35.8 µmol)
from 1c (12.7 mg, 48.4 µmol), 6A (14.0 mg, 58.1 µmol), and 11a (1.8 mg, 2.4 µmol) through
preparative TLC eluting with 33% EtOAc/toluene. Pale yellow solid. Rf=0.17 (10% EtOAc/toluene).
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Mp: 167–168 °C. IR ν (compression cell, cmꢀ1): 3473, 3369, 1684, 1606, 1267, 752. HꢀNMR (400
MHz, CDCl3): δ 7.84–7.69 (m, 4H), 7.68 (d, J = 8.3 Hz, 1H), 7.40 (dd, J = 7.0, 8.0 Hz, 1H), 7.28–
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7.18 (m, 5H), 7.18 (s, 1H), 7.14 (dd, J = 8.3, 7.0 Hz, 1H), 3.71 (br–s, 2H), 2.57 (s, 3H), 2.56 (s, 3H).
13CꢀNMR (100 MHz, CDCl3): δ 197.8, 197.6, 144.1, 142.5, 141.7, 138.4, 135.8, 135.5, 134.6, 131.1,
130.9, 128.53, 128.47, 127.7, 126.7, 126.6, 126.4, 125.8, 122.9, 109.1, 26.5. HRMS (ESI, [M+H]+):
calcd for C26H22NO2, 380.1645; found 380.1642.
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3,4ꢀBis(2ꢀmethylphenyl)naphthalenꢀ2ꢀamine (5d) (entry 3): Yield 70% (22.6 mg, 69.9 µmol)
from 1d (20.5 mg, 99.4 µmol), 6A (30.7 mg, 126 µmol), and 11a (3.9 mg, 5.3 µmol). Pale yellow
solid. Rf=0.43 (2% EtOAc/toluene). Mp: 183–188 °C. IR ν (compression cell, cmꢀ1): 3485, 3383,
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3066, 3009, 2927, 1605, 1491, 1457, 1439, 1343, 1193, 841, 745. HꢀNMR (400 MHz, CDCl3): δ
7.68 (d, J = 8.3 Hz, 1H), 7.36 (dd, J = 7.8, 6.8 Hz, 1H), 7.13–7.03 (m, 11H), 3.64 (br–s, 2H), 2.10
(s, 3H), 1.91 (s, 3H). 13CꢀNMR (100 MHz, CDCl3): δ 142.6, 139.0, 138.0, 136.8, 136.5, 136.1,
134.3, 132.04, 132.03, 130.0, 129.5, 129.4, 127.4, 127.1, 126.9, 126.7, 126.0, 125.6, 125.3, 124.5,
122.4, 107.8, 20.0, 19.3. LRMS (EI) m/z (relative intensity) 323 [M]+ (100), 308 (11), 291 (3), 232
(5), 215 (3). HRMS (EI, [M]+): calcd for C24H21N, 323.1674; found 323.1663.
3,4ꢀDi(thiophenꢀ3ꢀyl)naphthalenꢀ2ꢀamine (5e) (entry 4): Yield 51% (15.3 mg, 49.8 µmol) from
1e (18.6 mg, 97.8 µmol), 6A (30.1 mg, 124 µmol), and 11a (4.1 mg, 5.6 µmol) through preparative
TLC eluting with 17% EtOAc/hexane. Pale yellow solid. Rf=0.36 (2% EtOAc/toluene). Mp: 130–
136 °C. IR ν (compression cell, cmꢀ1): 3367, 3102, 1617, 1567, 1499, 1443, 1336, 1256, 1196, 838,
666. 1HꢀNMR (400 MHz, CDCl3): δ 7.63 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.37 (dd, J =
8.3, 6.8 Hz, 1H), 7.24 (dd, J = 4.9, 2.9 Hz, 1H), 7.21 (dd, J = 4.9, 2.9 Hz, 1H), 7.14 (dd, J = 8.3, 6.8
Hz, 1H), 7.11 (s, 1H), 7.04 (dd, J = 2.9, 1.0 Hz, 1H), 6.96 (dd, J = 2.9, 1.0 Hz, 1H), 6.87 (dd, J =
4.9, 1.0 Hz, 1H), 6.85 (dd, J = 4.9, 1.0 Hz, 1H), 3.87 (br–s, 2H). 13CꢀNMR (100 MHz, CDCl3): δ
142.7, 139.1, 137.5, 135.5, 134.4, 130.2, 129.4, 127.4, 126.7, 126.3, 125.6, 125.4, 125.3, 124.3,
124.24, 124.19, 122.6, 108.4. LRMS (EI) m/z (relative intensity) 307 [M]+ (100), 274 (21), 273 (22),
262 (7), 260 (5), 258 (7), 241 (5). HRMS (EI, [M]+): calcd for C18H13NS2, 307.0489; found
307.0475.
3,4ꢀDipropylnaphthalenꢀ2ꢀamine (5f) (entry 5): Yield 71% (28.0 mg, 123 µmol) from 1f (19.1
mg, 173 µmol), 6A (50.6 mg, 208 µmol), and 11a (6.3 mg, 8.7 µmol). Brown oil. Rf=0.42 (2%
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EtOAc/toluene). IR ν (neat, cmꢀ1): 3468, 3378, 2957, 1627, 1456, 1348, 742. HꢀNMR (400 MHz,
CDCl3): δ 7.87 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.31–7.21 (m, 2H), 6.90 (s, 1H), 3.78
(br–s, 2H), 3.01 (t, J = 8.3 Hz, 2H), 2.69 (t, J = 8.3 Hz, 2H), 1.70–1.59 (m, 4H), 1.12–1.06 (m, 6H).
13CꢀNMR (100 MHz, CDCl3): δ 142.9, 137.1, 133.7, 127.6, 127.0, 126.2, 125.0, 124.1, 122.3, 108.4,
31.0, 30.2, 24.4, 22.7, 14.75, 14.70. HRMS (ESI, [M+H]+): calcd for C16H22N, 228.1747; found
228.1739.
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7,8,9,10,11,12,13,14,15,16ꢀDecahydrocyclododeca[a]naphthalenꢀ6ꢀamine (5g) (entry 6): Yield
51% (21.5 mg, 76.4 µmol) from 1g (24.7 mg, 150 µmol), 6A (43.8 mg, 180 µmol), and 11a (5.5 mg,
7.5 µmol). Brown oil. Rf=0.40 (2% EtOAc/toluene). IR ν (neat, cmꢀ1): 3471, 3380, 2926, 1625,
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1443, 756. HꢀNMR (400 MHz, CDCl3): δ 7.91 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.30
(dd, J = 8.1, 6.8 Hz, 1H), 7.23 (dd, J = 8.3, 6.8 Hz, 1H), 6.93 (s, 1H), 3.86 (br–s, 2H), 3.15 (t, J =
8.4 Hz, 2H), 2.84 (m, 2H), 1.80–1.51 (m, 16H). 13CꢀNMR (100 MHz, CDCl3): δ 143.3, 137.5, 133.7,
127.9, 127.4, 126.2, 125.0, 124.5, 122.3, 108.3, 28.9, 28.2, 28.1, 27.2, 27.0, 26.9, 26.8, 26.3, 22.3,
22.2. HRMS (ESI, [M+H]+): calcd for C20H28N, 282.2216; found 282.2212.
3,4ꢀBis((methoxymethoxy)methyl)naphthalenꢀ2ꢀamine (5h) (entry 7): Yield 50% (21.7 mg,
74.5 µmol) from 1h (26.0 mg, 149 µmol), 6A (43.6 mg, 179 µmol), and 11a (5.5 mg, 7.5 µmol)
through preparative TLC eluting with 40% EtOAc/toluene. Brown oil. Rf=0.11 (10%
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EtOAc/toluene). IR ν (neat, cmꢀ1): 3447, 3366, 2886, 1634, 1149, 1097, 1028. HꢀNMR (400 MHz,
CDCl3): δ 8.09 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.37 (dd, J = 8.0, 6.8 Hz, 1H), 7.30
(dd, J = 8.4, 6.8 Hz, 1H), 7.07 (s, 1H), 5.14 (s, 2H), 4.96 (s, 2H), 4.73 (s, 2H), 4.68 (s, 2H), 4.35
(br–s, 2H), 3.47 (s, 3H), 3.44 (s, 3H). 13CꢀNMR (100 MHz, CDCl3): δ 144.3, 135.0, 133.1, 127.2,
126.3, 126.2, 125.3, 124.5, 123.2, 111.3, 95.7, 95.0, 62.3, 61.8, 55.64, 55.60. LRMS (EI) m/z
(relative intensity) 291 [M]+ (100), 261 (11), 184 (40), 169 (41), 156 (27). HRMS (EI, [M]+): calcd
for C16H21NO4, 291.1471; found 291.1466.
4ꢀMethylꢀ3ꢀphenylnaphthalenꢀ2ꢀamine (5i) and 3ꢀmethylꢀ4ꢀphenylnaphthalenꢀ2ꢀamine (5i′)
(entry 8): 4ꢀMethylꢀ3ꢀphenylnaphthalenꢀ2ꢀamine (5i as a fasterꢀmoving component; 38.5 mg, 73%)
and 3ꢀmethylꢀ4ꢀphenylnaphthalenꢀ2ꢀamine (5i′ as a slowerꢀmoving component; 7.6 mg, 15%) were
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obtained from 1i (26.1 mg, 225 µmol), 6A (58.9 mg, 242 µmol), and 11a (7.3 mg, 10.0 µmol)
through preparative TLC eluting with 20% EtOAc/hexane twice. 4ꢀMethylꢀ3ꢀphenylnaphthalenꢀ2ꢀ
amine (5i)12a: Brown solid. Rf=0.43 (2% EtOAc/toluene). Mp: 95–99 °C. IR ν (compression cell,
cmꢀ1): 3474, 3380, 3056, 2363, 1624, 760. 1HꢀNMR (400 MHz, CDCl3): δ 7.91 (dd,, J = 8.0, 1.2 Hz,
1H), 7.61 (dd, J = 8.0, 1.2 Hz, 1H), 7.52–7.48 (m, 2H), 7.43–7.36 (m, 1H), 7.35–7.31 (m, 2H),
7.30–7.27 (m, 2H), 6.99 (s, 1H), 3.75 (br–s, 2H), 2.35 (3H, s). 13CꢀNMR (100 MHz, CDCl3): δ
142.4, 138.5, 134.3, 132.8, 130.0, 129.0, 128.2, 127.5, 127.2, 126.1, 125.9, 124.5, 122.4, 106.8,
16.4. HRMS (ESI, [M+H]+): calcd for C17H16N, 234.1277; found 234.1270. 3ꢀMethylꢀ4ꢀ
phenylnaphthalenꢀ2ꢀamine (5i′): Brown solid. Rf=0.36 (2% EtOAc/toluene). Mp: 121–125 °C. IR
ν (compression cell, cmꢀ1): 3441, 3355, 3053, 1629, 1495, 1440, 1344, 748, 702, 620. 1HꢀNMR (600
MHz, CDCl3): δ 7.61 (d, J = 8.3 Hz, 1H), 7.48 (dd, J = 7.2, 7.7 Hz, 2H), 7.42 (t, J = 7.2 Hz, 1H),
7.30 (dd, J = 8.3, 6.8 Hz, 1H), 7.25 (d, J = 7.7 Hz, 2H), 7.20 (d, J = 8.2 Hz, 1H), 7.09–7.06 (m, 2H),
3.83 (br–s, 2H), 2.05 (s, 3H). 13CꢀNMR (151 MHz, CDCl3): δ 143.2, 140.1, 139.6, 133.3, 130.2,
128.3, 127.8, 127.0, 126.5, 125.4, 125.3, 123.2, 122.3, 108.4, 15.2. HRMS (ESI, [M+H]+): calcd for
C17H16N, 234.1277; found 234.1273.
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4ꢀIsopropylꢀ3ꢀphenylnaphthalenꢀ2ꢀamine (5j) and 3ꢀisopropylꢀ4ꢀphenylnaphthalenꢀ2ꢀamine
(5j′) (entry 9): 3ꢀIsopropylꢀ4ꢀphenylnaphthalenꢀ2ꢀamine (5j′ as a fasterꢀmoving component; 14.4
mg, 27%) and 4ꢀisopropylꢀ3ꢀphenylnaphthalenꢀ2ꢀamine (5j as a slowerꢀmoving component; 38.0 mg,
70%) were obtained from 1j (29.9 mg, 207 µmol), 6A (58.2 mg, 239 µmol), and 11a (7.7 mg, 10.5
µmol). 4ꢀIsopropylꢀ3ꢀphenylnaphthalenꢀ2ꢀamine (5j): Brown solid. Rf=0.45 (2% EtOAc/toluene).
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Mp: 129–138 °C. IR ν (compression cell, cmꢀ1): 3488, 3391, 2960, 1622, 1440, 1336, 756, 709. Hꢀ
NMR (600 MHz, CDCl3): δ 8.20 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.49 (dd, J = 7.6, 7.6
Hz, 2H), 7.41 (t, J = 7.6 Hz, 1H), 7.34 (dd, J = 7.9, 7.0 Hz, 1H), 7.26 (d, J = 7.6 Hz, 2H), 7.22 (dd,
J = 8.1, 7.0 Hz, 1H), 6.96 (s, 1H), 3.49 (br–s, 2H), 3.23 (m, 1H), 1.43 (m, 6H). 13CꢀNMR (151 MHz,
CDCl3): δ 142.6, 142.3, 140.8, 139.2, 135.5, 129.2, 128.2, 127.4, 126.9, 125.4, 125.1, 122.3, 121.4,
110.9, 87.6, 22.3, 20.4. HRMS (ESI, [M+H]+): calcd for C19H20N, 262.1590; found 262.1583. 3ꢀ
Isopropylꢀ4ꢀphenylnaphthalenꢀ2ꢀamine (5j′): Brown solid. Rf=0.48 (2% EtOAc/toluene). Mp:
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128–133 °C. IR ν (compression cell, cmꢀ1): 3495, 3382, 2973, 1618, 1565, 1489, 1437, 1339, 745,
698. 1HꢀNMR (600 MHz, CDCl3): δ 7.57 (d, J = 8.2 Hz, 1H), 7.47 (dd, J = 7.2, 7.2 Hz, 2H), 7.42 (t,
J = 7.2 Hz, 1H), 7.29–7.24 (m, 3H), 7.04 (m, 3H), 3.99 (br–s, 1H), 3.18 (quint, J = 4.8 Hz, 1H),
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1.30 (d, J = 4.8 Hz, 6H). CꢀNMR (151 MHz, CDCl3): δ 143.6, 140.8, 139.3, 133.1, 132.2, 129.9,
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128.2, 128.0, 127.0, 126.9, 125.4, 125.1, 122.3, 110.8, 30.2, 20.3. HRMS (ESI, [M+H]+): calcd for
C19H20N, 262.1590; found 262.1584.
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4ꢀ(tertꢀButyl)ꢀ3ꢀphenylnaphthalenꢀ2ꢀamine (5k) and 3ꢀ(tertꢀbutyl)ꢀ4ꢀphenylnaphthalenꢀ2ꢀ
amine (5k′) (entry 10): 3ꢀ(tertꢀButyl)ꢀ4ꢀphenylnaphthalenꢀ2ꢀamine (5k′ as a fasterꢀmoving
component; 6.4 mg, 12%) and 4ꢀ(tertꢀbutyl)ꢀ3ꢀphenylnaphthalenꢀ2ꢀamine (5k as a slowerꢀmoving
component; 18.0 mg, 33%) were obtained from 1k (31.5 mg, 199 µmol), 6A (59.4 mg, 244 µmol),
and 11a (7.8 mg, 10.7 µmol). 4ꢀ(tertꢀButyl)ꢀ3ꢀphenylnaphthalenꢀ2ꢀamine (5k): Red solid. Rf=0.41
(2% EtOAc/toluene). Mp: 143–152 °C. IR ν (compression cell, cmꢀ1): 3504, 3391, 2960, 1621, 1331,
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756, 705. HꢀNMR (600 MHz, CDCl3): δ 8.39 (d, J = 8.9 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.43–
7.36 (m, 3H), 7.33–7.27 (m, 3H), 7.22–7.19 (m, 1H), 6.96 (s, 1H), 3.40 (br–s, 2H), 1.39 (s, 9H). 13Cꢀ
NMR (151 MHz, CDCl3): δ 144.1, 142.9, 141.2, 135.8, 130.8, 130.0, 128.7, 128.3, 127.2, 127.0,
126.9, 124.9, 120.5, 108.3, 38.6, 35.0. HRMS (ESI, [M+H]+): calcd for C20H22N, 276.1747; found
276.1744. 3ꢀ(tertꢀButyl)ꢀ4ꢀphenylnaphthalenꢀ2ꢀamine (5k′)14a: All the analytical data were in
good agreement with values reported in the literature.14a
2ꢀ(3ꢀAminoꢀ2ꢀphenylnaphthalenꢀ1ꢀyl)propanꢀ2ꢀol (5l) and 2ꢀ(3ꢀaminoꢀ1ꢀphenylnaphthalenꢀ
2ꢀyl)propanꢀ2ꢀol (5l′) (entry 11): 2ꢀ(3ꢀAminoꢀ2ꢀphenylnaphthalenꢀ1ꢀyl)propanꢀ2ꢀol (5l as a fasterꢀ
moving component; 19.9 mg, 36%) and 2ꢀ(3ꢀaminoꢀ1ꢀphenylnaphthalenꢀ2ꢀyl)propanꢀ2ꢀol (5l′ as a
slowerꢀmoving component; 18.0 mg, 33%) were obtained from 1l (31.6 mg, 197 µmol), 6A (59.6
mg, 245 µmol), and 11a (8.0 mg, 10.9 µmol) through preparative TLC eluting with 12.5%
EtOAc/toluene twice. 2ꢀ(3ꢀAminoꢀ2ꢀphenylnaphthalenꢀ1ꢀyl)propanꢀ2ꢀol (5l): Brown solid.
Rf=0.37 (10% EtOAc/toluene). Mp: 187–193 °C. IR ν (compression cell, cmꢀ1): 3327, 2927, 2364,
1623, 1429, 705. 1HꢀNMR (600 MHz, CDCl3): δ 8.60 (d, J = 8.9 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H),
7.46 (dd, J = 7.6, 7.6 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.35 (dd, J = 7.9, 7.2 Hz, 1H), 7.26–7.22 (m,
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3H), 7.01 (s, 1H), 3.45 (br–s, 2H), 1.63 (s, 6H). 13CꢀNMR (151 MHz, CDCl3): δ 142.7, 142.6, 140.7,
135.7, 129.7, 128.9, 128.6, 128.4, 127.4, 126.7, 125.7, 125.4, 121.5, 109.2, 76.1, 33.7. HRMS (ESI,
[M+H]+): calcd for C19H19NO, 278.1539; found 278.1532. 2ꢀ(3ꢀAminoꢀ1ꢀphenylnaphthalenꢀ2ꢀ
yl)propanꢀ2ꢀol (5l′): Brown solid. Rf=0.26 (10% EtOAc/toluene). Mp: 166–173 °C. IR ν
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(compression cell, cmꢀ1): 3355, 2971, 1620, 1337, 1141, 756. HꢀNMR (600 MHz, CDCl3): δ 7.52
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(d, J = 8.3 Hz, 1H), 7.40–7.38 (m, 3H), 7.28 (dd, J = 8.3, 7.2 Hz, 1H), 7.20–7.19 (m, 2H), 7.04 (s,
1H), 6.99 (dd, J = 7.2, 8.6 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 4.21 (br–s, 2H), 1.34 (s, 6H). 13Cꢀ
NMR (151 MHz, CDCl3): δ 144.6, 141.6, 137.6, 133.3, 132.0, 130.7, 128.4, 127.7, 127.4, 127.1,
126.0, 124.7, 122.1, 112.2, 76.6, 31.8. HRMS (ESI, [M+H]+): calcd for C19H19NO, 278.1539; found
278.1531.
3ꢀButylꢀ4ꢀmethylnaphthalenꢀ2ꢀamine (5m) and 4ꢀbutylꢀ3ꢀmethylnaphthalenꢀ2ꢀamine (5m′)
(entry 12): 3ꢀButylꢀ4ꢀmethylnaphthalenꢀ2ꢀamine (5m as a fasterꢀmoving component; 18.2 mg, 40%)
and 4ꢀbutylꢀ3ꢀmethylnaphthalenꢀ2ꢀamine (5m′ as a slowerꢀmoving component; 15.0 mg, 33%) were
obtained from 1m (20.5 mg, 213 µmol), 6A (58.0 mg, 238 µmol), and 11a (7.0 mg, 9.6 µmol). 3ꢀ
Butylꢀ4ꢀmethylnaphthalenꢀ2ꢀamine (5m): Red oil. Rf=0.42 (2% EtOAc/toluene). IR ν (neat, cmꢀ1):
3474, 3374, 2955, 1627, 1506, 1462, 1446, 742. 1HꢀNMR (600 MHz, CDCl3): δ 7.89 (d, J = 8.4 Hz,
1H), 7.55 (d, J = 8.1 Hz, 1H), 7.31 (dd, J = 8.1, 6.9 Hz, 1H), 7.24 (dd, J = 8.4, 6.9 Hz, 1H), 6.92 (s,
1H), 3.52 (br–s, 2H), 2.75 (t, J = 8.1 Hz, 2H), 2.61 (s, 3H), 1.58–1.46 (m, 4H), 0.99 (t, J = 7.2 Hz,
3H). 13CꢀNMR (151 MHz, CDCl3): δ 142.8, 133.3, 132.1, 128.2, 127.8, 126.1, 125.1, 124.1, 122.3,
108.1, 31.2, 28.0, 23.2, 14.7, 14.0. HRMS (ESI, [M+H]+): calcd for C15H20N, 214.1590; found
214.1585. 4ꢀButylꢀ3ꢀmethylnaphthalenꢀ2ꢀamine (5m′): Red oil. Rf=0.33 (2% EtOAc/toluene). IR
ν (neat, cmꢀ1): 3466, 3377, 2955, 1628, 1509, 1444, 742. 1HꢀNMR (600 MHz, CDCl3): δ 7.89 (d, J =
8.3 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.30 (dd, J = 8.3, 6.7 Hz, 1H), 7.24 (dd, J = 8.3, 6.7 Hz, 1H),
6.93 (s, 1H), 3.78 (br–s, 2H), 3.07 (t, J = 8.1 Hz, 2H), 2.30 (s, 3H), 1.62–1.48 (m, 4H), 0.99 (t, J =
7.2 Hz, 3H). 13CꢀNMR (151 MHz, CDCl3): δ 143.3, 137.2, 133.6, 126.9, 126.3, 124.9, 122.8, 122.3,
107.7, 32.5, 28.7, 213.2, 14.0, 13.5. HRMS (ESI, [M+H]+): calcd for C15H20N, 214.1590; found
214.1586.
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3ꢀIsopropylꢀ4ꢀmethylnaphthalenꢀ2ꢀamine (5n) and 4ꢀisopropylꢀ3ꢀmethylnaphthalenꢀ2ꢀamine
(5n′) (entry 13): 3ꢀIsopropylꢀ4ꢀmethylnaphthalenꢀ2ꢀamine (5n as a fasterꢀmoving component; 18.4
mg, 50%) and 4ꢀisopropylꢀ3ꢀmethylnaphthalenꢀ2ꢀamine (5n′ as a slowerꢀmoving component; 12.1
mg, 33%) were obtained from 1n (15.2 mg, 185 µmol), 6A (58.9 mg, 242 µmol), and 11a (7.2 mg,
9.9 µmol). 3ꢀIsopropylꢀ4ꢀmethylnaphthalenꢀ2ꢀamine (5n): Brown oil. Rf=0.40 (2%
EtOAc/toluene). IR ν (neat, cmꢀ1): 3489, 3435, 2978, 1694, 1331, 731. 1HꢀNMR (600 MHz, CDCl3):
δ 7.92 (d, J = 8.3 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.30 (dd, J = 7.6, 7.2 Hz, 1H), 7.24 (dd, J = 8.3,
7.2 Hz, 1H), 6.89 (1H, s), 3.85 (br–s, 2H), 3.72 (m, 1H), 2.66 (s, 3H), 1.45 (d, J = 7.2 Hz, 6H). 13Cꢀ
NMR (151 MHz, CDCl3): δ 143.4, 133.3, 132.8, 131.9, 128.2, 125.9, 125.2, 124.2, 122.4, 109.7,
28.2, 20.6, 15.5. HRMS (ESI, [M+H]+): calcd for C14H18N, 200.1434; found 200.1430. 4ꢀIsopropylꢀ
3ꢀmethylnaphthalenꢀ2ꢀamine (5n′): Brown oil. Rf=0.32 (2% EtOAc/toluene). IR ν (neat, cmꢀ1):
3479, 3373, 2927, 1626, 1445, 1239, 743. 1HꢀNMR (600 MHz, CDCl3): δ 8.12 (m, 1H), 7.57 (d, J =
8.1 Hz, 1H), 7.29 (dd, J = 7.2, 8.1 Hz, 1H), 7.21 (dd, J = 7.2, 7.6 Hz, 1H), 6.94 (s, 1H), 3.99 (m,
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1H), 3.74 (br–s, 2H), 2.36 (s, 3H), 1.53 (d, J = 6.8 Hz, 6H). CꢀNMR (151 MHz, CDCl3): δ 143.5,
142.3, 134.1, 126.7, 124.7, 123.0, 121.8, 108.4, 29.2, 21.9, 14.4. HRMS (ESI, [M+H]+): calcd for
C14H18N, 200.1434; found 200.1432.
3ꢀ(tertꢀButyl)ꢀ4ꢀmethylnaphthalenꢀ2ꢀamine (5o) and 4ꢀ(tertꢀButyl)ꢀ3ꢀmethylnaphthalenꢀ2ꢀ
amine (5o′) (entry 14): 3ꢀ(tertꢀButyl)ꢀ4ꢀmethylnaphthalenꢀ2ꢀamine (5o as a fasterꢀmoving
component; 8.5 mg, 22%) and 4ꢀ(tertꢀbutyl)ꢀ3ꢀmethylnaphthalenꢀ2ꢀamine (5o′ as a slowerꢀmoving
component; 16.1 mg, 41%) were obtained from 1o (17.8 mg, 185 µmol), 6A (59.4 mg, 244 µmol),
and 11a (7.5 mg, 10.3 µmol). 3ꢀ(tertꢀButyl)ꢀ4ꢀmethylnaphthalenꢀ2ꢀamine (5o)12a: All the
analytical data were in good agreement with values reported in the literature.12a 4ꢀ(tertꢀButyl)ꢀ3ꢀ
methylnaphthalenꢀ2ꢀamine (5o′): Red oil. Rf=0.32 (2% EtOAc/toluene). IR ν (neat, cmꢀ1): 3495,
3364, 2962, 1579, 1356, 754. 1HꢀNMR (600 MHz, CDCl3): δ 8.24 (d, J = 8.8 Hz, 1H), 7.52 (d, J =
8.3 Hz, 1H), 7.23 (dd, J = 8.3, 8.1 Hz, 1H), 7.11 (dd, J = 8.8, 8.1 Hz, 1H), 6.88 (s, 1H), 3.74 (br–s,
2H), 2.44 (s, 3H), 1.71 (s, 9H). 13CꢀNMR (151 MHz, CDCl3): δ 145.7, 144.0, 134.3, 128.0, 127.0,
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126.4, 124.8, 124.0, 120.1, 108.6, 38.8, 34.2, 18.4. HRMS (ESI, [M+H]+): calcd for C15H20N,
214.1590; found 214.1590.
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2ꢀ(3ꢀAminoꢀ1ꢀmethylnaphthalenꢀ2ꢀyl)propanꢀ2ꢀol (5p) and 2ꢀ(3ꢀaminoꢀ2ꢀmethylnaphthalenꢀ
1ꢀyl)propanꢀ2ꢀol (5p′) (entry 15): 2ꢀ(3ꢀAminoꢀ1ꢀmethylnaphthalenꢀ2ꢀyl)propanꢀ2ꢀol (5p as a
fasterꢀmoving component; 22.8 mg, 50%) and 2ꢀ(3ꢀaminoꢀ2ꢀmethylnaphthalenꢀ1ꢀyl)propanꢀ2ꢀol
(5p′ as a slowerꢀmoving component; 10.5 mg, 23%) were obtained from 1p (20.5 mg, 209 µmol),
6A (60.1 mg, 247 µmol), and 11a (7.0 mg, 9.6 µmol) through preparative TLC eluting with 33%
EtOAc/toluene twice and 50% EtOAc/hexane twice. 2ꢀ(3ꢀAminoꢀ1ꢀmethylnaphthalenꢀ2ꢀ
yl)propanꢀ2ꢀol (5p): Brown solid. Rf=0.17 (10% EtOAc/toluene). Mp: 90–95 °C. IR ν (compression
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cell, cmꢀ1): 3374, 2974, 2361, 1623, 1366, 751. HꢀNMR (600 MHz, CDCl3): δ 7.91 (d, J = 8.4 Hz,
1H), 7.49 (d, J = 7.9 Hz, 1H), 7.32 (dd, J = 7.9, 7.2 Hz, 1H), 7.23 (dd, J = 8.4, 7.2 Hz, 1H), 6.85 (s,
1H), 4.36 (br–s, 2H), 2.69 (s, 3H), 1.84 (s, 6H). 13CꢀNMR (151 MHz, CDCl3): δ 143.9, 134.2, 133.1,
131.6, 128.7, 125.7, 125.6, 124.2, 122.6, 111.6, 76.8, 31.3, 19.1. HRMS (ESI, [M+H]+): calcd for
C14H18NO, 216.1383; found 216.1380. 2ꢀ(3ꢀAminoꢀ2ꢀmethylnaphthalenꢀ1ꢀyl)propanꢀ2ꢀol (5p′):
Brown solid. Rf=0.10 (10% EtOAc/toluene). Mp: 109–113 °C. IR ν (compression cell, cmꢀ1): 3406,
2360, 1623, 1456, 748. 1HꢀNMR (600 MHz, CDCl3): δ 8.46 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.1 Hz,
1H), 7.26 (dd, J = 8.1, 7.2 Hz, 1H), 7.15 (dd, J = 8.4, 7.2 Hz, 1H), 6.93 (s, 1H), 3.77 (br–s, 2H),
2.46 (s, 3H), 1.93 (s, 6H). 13CꢀNMR (151 MHz, CDCl3): δ 143.92, 143.88, 134.3, 126.9, 126.35,
126.26, 124.5, 123.9, 121.0, 109.3, 76.2, 32.5, 17.6. HRMS (ESI, [M+H]+): calcd for C14H18NO,
216.1383; found 216.1378.
4ꢀ(tertꢀButyl)ꢀ3ꢀ(3,3ꢀdimethylbutꢀ1ꢀynꢀ1ꢀyl)naphthalenꢀ2ꢀamine (5q) and 3ꢀ(tertꢀbutyl)ꢀ4ꢀ(3,3ꢀ
dimethylbutꢀ1ꢀynꢀ1ꢀyl)naphthalenꢀ2ꢀamine (5q′) (entry 16): 4ꢀ(tertꢀButyl)ꢀ3ꢀ(3,3ꢀdimethylbutꢀ1ꢀ
ynꢀ1ꢀyl)naphthalenꢀ2ꢀamine (5q as a fasterꢀmoving component; 42.9 mg, 77%) and 4ꢀ(tertꢀbutyl)ꢀ3ꢀ
(3,3ꢀdimethylbutꢀ1ꢀynꢀ1ꢀyl)naphthalenꢀ2ꢀamine (5q′ as a slowerꢀmoving component; 1.7 mg, 3%)
were obtained from 1q (32.3 mg, 199 µmol), 6A (61.0 mg, 251 µmol), and 11a (7.7 mg, 10.5 µmol).
4ꢀ(tertꢀButyl)ꢀ3ꢀ(3,3ꢀdimethylbutꢀ1ꢀynꢀ1ꢀyl)naphthalenꢀ2ꢀamine (5q): Red solid. Rf=0.51 (2%
EtOAc/toluene). Mp: 66–70 °C. IR ν (compression cell, cmꢀ1): 3481, 3382, 2967, 2360, 1622, 1262,
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749. 1HꢀNMR (600 MHz, CDCl3): δ 8.35 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.26 (dd, J =
7.7, 7.0 Hz, 1H), 7.13 (dd, J = 8.8, 7.0 Hz, 1H), 6.93 (1H, s), 4.56–4.36 (2H, br–s), 1.84 (9H, s),
1.38 (9H, s). 13CꢀNMR (151 MHz, CDCl3): δ 148.2, 144.3, 135.5, 127.9, 127.0, 126.2, 125.3, 120.7,
110.6, 110.4, 107.3, 77.9, 38.9, 34.2, 30.6, 28.8. HRMS (ESI, [M+H]+): calcd for C20H26N,
280.2060; found 280.2056. 3ꢀ(tertꢀButyl)ꢀ4ꢀ(3,3ꢀdimethylbutꢀ1ꢀynꢀ1ꢀyl)naphthalenꢀ2ꢀamine
(5q′): All the analytical data were in good agreement with values reported in the literature.14a
General procedure for the Pd(II)ꢀcatalyzed annulation of 1a with 6B–G (Table 3): To a test
tube containing internal alkyne 1a (1 equiv), 6 (2 equiv for 6B–D, 1.2 equiv for 6E–G) and 11a (5
mol%) was added anhydrous MeOH (0.2 M for 1a). The resulting mixture was sealed with a screw
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cap, stirred at 65 C for the time shown in Table 3, cooled to room temperature, and then
concentrated in vacuo. The residue was purified by preparative TLC eluting with 2% EtOAc/toluene,
unless otherwise noted, to yield 3,4ꢀdiphenylꢀ2ꢀnaphthylamine 5B–G.
1ꢀMethylꢀ3,4ꢀdiphenylnaphthalenꢀ2ꢀamine (5B) (entry 1): Yield 81% (37.4 mg, 121 µmol)
from 1a (26.5 mg, 149 µmol), 6B (76.6 mg, 298 µmol), and 11a (5.4 mg, 7.4 µmol). Brown solid.
Rf=0.49 (2% EtOAc/toluene). Mp: 179–180 °C. IR ν (compression cell, cmꢀ1): 3397, 3062, 1605,
1379, 1028, 752. 1HꢀNMR (600 MHz, CDCl3): δ 7.97 (d, J = 8.9 Hz, 1H), 7.45 (dd, J = 8.9, 6.8 Hz,
1H), 7.42 (d, J = 8.2 Hz, 1H), 7.24–7.09 (m, 11H), 3.77 (br–s, 2H), 2.53 (s, 3H). 13CꢀNMR (151
MHz, CDCl3): δ 139.6, 139.5, 138.1, 137.7, 132.9, 131.0, 130.6, 129.8, 128.3, 127.6, 127.4, 126.9,
126.3, 126.0, 122.2, 122.0, 112.2, 12.2. HRMS (ESI, [M+H]+): calcd for C23H20N, 310.1590; found
310.1578.
1ꢀ(Benzyloxy)ꢀ3,4ꢀdiphenylnaphthalenꢀ2ꢀamine (5C) (entry 2): Yield 91% (42.9 mg, 107
µmol) from 1a (21.0 mg, 118 µmol), 6C (82.1 mg, 236 µmol), and 11a (4.3 mg, 5.9 µmol). Brown
solid. Rf=0.62 (2% EtOAc/toluene). Mp: 150–151 °C. IR ν (compression cell, cmꢀ1): 3062, 2362,
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2342, 1605, 1361, 757, 700. HꢀNMR (600 MHz, CDCl3): δ 8.07 (d, J = 8.6 Hz, 1H), 7.62 (d, J =
7.6 Hz, 1H), 7.47–7.43 (m, 4H), 7.39 (t, J = 7.4 Hz, 1H), 7.25–7.11 (m, 12H), 5.12 (s, 2H), 3.88 (br–
s, 2H). 13CꢀNMR (151 MHz, CDCl3): δ 139.1, 137.8, 137.4, 135.7, 134.6, 131.2, 130.53, 130.45,
128.7, 128.3, 128.1, 127.9, 127.4, 127.3, 127.0, 126.4, 126.1, 122.5, 119.9, 74.0. LRMS (EI) m/z
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