C–H Bond Functionalization of 1,4-Benzoquinone by Silver-Mediated Regioselective Phosphination and Amination Reactions

Article abstract of DOI:10.1002/ejoc.201700109

The one-pot synthesis of 2,5-bis(diarylphosphoryl)-3,6-bis(arylamino)cyclohexa-2,5-diene-1,4-diones has been achieved by Ag^I-mediated full C–H functionalization of 1,4-benzoquinone (BQ) through regioselective dual phosphination and amination reactions. BQ, diarylphosphine oxides [SPOs, Ar₂PH(=O)], and imines reacted to give the products under mild conditions. 1,4-Naphthoquinone (NQ) could also be used instead of BQ. When aniline was used instead of the corresponding imine, a lower yield of the desired product was obtained. In the absence of Ag₂CO₃, hydrophosphinylation of the imine by the SPO occurred as a competitive side-reaction. Ag^I plays versatile roles in this reaction, as a mediator for facilitating the consecutive additions of Ar₂P(=O)^– and aniline to the related β-carbon atoms of BQ, as an oxidant of hydroquinone (HQ) intermediates to form the substituted BQ counterpart, and as an inhibitor of the hydrophosphinylation side-reaction of the imine by the SPO. The X-ray crystal structures of several new products have been determined. A reaction mechanism is also proposed based on the experimental results.

Full text of DOI:10.1002/ejoc.201700109

A Journal of
Accepted Article
Title: The C-H Bond Functionalization of 1,4-Benzoquinone by Silver-
mediated Regioselective Phosphination and Amination Reactions
Authors: FUNG-E HONG, Yu-Chang Chang, and Pin-Ting Yuan
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10.1002/ejoc.201700109
European Journal of Organic Chemistry
FULL PAPER
The C-H Bond Functionalization of 1,4-Benzoquinone by Silver-
mediated Regioselective Phosphination and Amination Reactions
Yu-Chang Chang,[a] Pin-Ting Yuan,[a] and Fung-E Hong*[a]
Abstract: The one-pot synthesis of 2,5-bis(diarylphosphoryl)-3,6-
bis(arylamino)cyclohexa-2,5-diene-1,4-dione has been achieved from
Ag(I)-mediated fully C-H functionalization of 1,4-benzoquinone (BQ)
via regioselectively dual phosphination and amination reactions. The
BQ, diarylphosphine oxide (SPO, Ar2PH(=O)), and imine were reacted
under mild conditions. The 1,4-naphthoquinone (NQ) could also be
used to replace BQ. When aniline was used instead of its
corresponding imine, lower yield of the desired product was obtained.
Without the presence of Ag2CO3, hydrophosphinylation of imine by
SPO occurs as the competitive side reaction. Ag(I) plays versatile
roles here, such as a mediator for facilitating the consecutive additions
of Ar2P(=O)- and aniline on the related -carbon atoms of BQ, oxidant
for hydroquinone (HQ) intermediates to form the substituted BQ
counterparts, and inhibitor of the hydrophosphinylation of imine by
SPO as side reaction. X-ray crystal structures of several new products
were determined. A reaction mechanism is also proposed based on
the experimental results.
steric and electronic properties of substituted BQ co-ligands have
been shown to have direct influence on the site-selectivity in
palladium-catalyzed oxidative C-H activations.[11]
Figure 1. BQ derivatives equipped with CBQ-P or CBQ-N bonds.
Over the past few decades significant development on the
subject of C-P bond formation employing transition-metal
catalyzed and silver-mediated oxidative reactions has attracted
much attention.[12] H-phosphinates, and H-phosphonates are of
the two frequently used substrates for constructing C-P bonds in
palladium-catalyzed reactions.[13] Compared with transition-metal
free Michaelis-Becker (1897, (RO)2P(O)-H as substrate)[14] and
Michaelis-Arbuzov (1900s, P(OR)3)[15] reactions, Hirao reaction is
regarded as the seminar work, which employed Pd(0)-catalyzed
cross-coupling reaction (1980, (RO)2P(O)-H) for making C-P
bonds.[16] While recent studies focused on the coupling between
unsaturated (C=C or CC) or aromatic C-H and -P(O)H unit,[13]
the use of BQ as C-H source has long been on the focus.[17] On
the other hand, C-N bond formation employing BQ or NQ as
reactant through Michael-type nucleophilic addition has also been
reported.[8,18] However, to the best of our knowledge, there is no
example that addresses the formations of C-P and C-N bonds on
BQ or NQ in one-pot reaction as demonstrated in this work.
Secondary phosphine oxides (SPOs: R2P(O)-H) have been
proven to be effective pre-ligands in palladium-catalyzed cross-
coupling reactions.[19] It might act as an authentic phosphine
ligand through tautomerization to phosphinus acid (PA: R2P-OH)
in the presence of TM salts. Inspired by the enthralling Pd(II)-
catalyzed oxidative cross-coupling reactions as shown in Scheme
1a[11,20] and 1b,[21] we initially sought nitrogen-directing imine as a
potential alternative of 2-phenylpyridine for constructing C-P
bonds with SPO (Scheme 1c). Unexpectedly, the anticipated
formation of Cimine-Ar-PSPO bond via Cimine-Ar-H bond activation was
not observed (Scheme 1d) despite the analogous Pd(II)-catalyzed
C-P bond formation using N-directing (E)-azoarenes has been
recently reported.[22]
Introduction
Quinones are remarkable building blocks which could be found in
molecules of natural products,[1] antitumor drugs,[2] reactants for
flame retardation materials,[3] electroactive ligands for valence-
tautomeric metal-ligand systems,[4]-spacer for electronic
interactions between redox-active metal terminus,[5] and catalysts
of various oxidation reactions.[6] For example, the 1,4-
benzoquinone (BQ), one of the redox-active simple quinones,[7]
can be employed to synthesize new phosphate, halogen-free
flame retardant of DOPO-HQ where a CHQ-P bond is formed
(Figure 1a, HQ: hydroquinone).[3] While the CBQ-N bond
containing 2-amino-1,4-napthoquinone derivatives are natural
product antibiotics (Figure 1b),[8] the 2,5-bis(amino)benzo-1,4-
quinone is a bis-OBQ,N-bi-dentate -conjugated bridging ligand
capable of linking two redox-active metal fragments to exhibit
interesting electrochemical, magnetic and optical properties
(Figure 1c).[9] Among quinones, BQ is also a multi-functional
additive in palladium-catalyzed reactions.[10] Namely, BQ
stabilizes coordinatively unsaturated active species, promotes the
rate of reductive elimination, and oxidizes reduced transition-
metal center in a catalytic cycle. Interestingly, the concentration,
[a]
Department of Chemistry, National Chung Hsing University,
Taichung 40227, Taiwan
E-mail: fehong@dragon.nchu.edu.tw
Several elegant synthetic protocols for C-H functionalization
of BQ that giving rise to CBQ-halogen[23] or CBQ-CAr[24] bonds have
been nicely established. To our knowledge, we report for the first
time an intriguing fully substituted 2,5-phosphinated and 3,6-
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201700109
European Journal of Organic Chemistry
FULL PAPER
aminated BQ (3aa) that could be obtained in a regioselective
manner without pre-functionalization of the starting materials
using similar reaction conditions to the Pd(II)-catalyzed reactions
(Scheme 1a-1b). As demonstrated, the cross-dehydrogenative
coupling (CDC)[13e] and dual CBQ-H/PSPO-H and CBQ-H/Naniline-H
functionalizations of BQ can be carried out in one-pot cascade
reaction with good yields under optimized mild conditions. Three
major components, Pd(II), Ag(I), and BQ, were typically regarded
as catalyst, oxidant, and additive in Pd(II)-catalyzed oxidative
reactions for C-H activations;[10b] nevertheless, they turned out to
act as additive, mediator/oxidant, and reactant as demonstrated
in this study (Scheme 1d). Moreover, one of the specific functions
of Ag2CO3 has been proven to effectively inhibit the
hydrophosphinylation of imine by SPO (2).[25] Several crystal
structures related to the fully substituted products 3 or N3 have
been well resolved by X-ray diffraction methods.
attributed to the increase of hydrolysis rate of imine (1a in this
case) to aniline. Besides, the proton released from 2a could also
play a role in acid-catalyzed imine hydrolysis. However, the yield
of 3aa is reduced when H2O was added more than one molar
equivalent,[27] which suggests that too fast hydrolysis rate of imine
will negatively affect the formation of the target compound.
Moreover, the formation of excess aniline can be coordinated to
Ag(I) cation, and eventually leads to inactive Ag(I) complex(es).
Entries 6-9 show that the optimal reaction time is 15 hours, and
entries 6 and 10-13 illustrate that toluene is the best solvent
among DCM, THF, DMF, and H2O. Degassed toluene was found
crucial to the reaction yield since SPO can be oxidized to R2P(O)-
OH in the presence of dissolved oxygen.
The fact that the yield of 3aa appears to be
stoichiometrically proportional to the amounts of added Pd(OAc)2
(entries 6 and 14-16 in Table 1) is noteworthy. The yields of 3aa
were 76%, 66%, 61%, and 57% for the addition of 20 mol-%, 10
mol-%, 5 mol-% and null of Pd(OAc)2, respectively. Initially, this
observation seemingly contradicts to the idea that large excess
amount of R2P(O)-H substrates would hinder the formation of C-
P coupling product in the Pd(II)-catalyzed reaction (Scheme
1b).[21] As known, a relatively stable SPO-coordinated Pd(II)-
complex could be easily obtained from the reaction of R2P(O)-H
with Pd(OAc)2.[28] However, in this reaction, Pd(OAc)2 is regarded
as a beneficial additive rather than the major catalytic agent
(entries 6 and 14-16). When 10 mol-% of SPO-coordinating [µ2-
ClPd(PPh2-OH)(PPh2O)]2 (Pd-I) was employed as additive, the
yield of 3b is similar to the case without the addition of Pd(OAc)2
(entry 17 vs. 16). This observation demonstrates that SPO-
coordinated Pd-I is ineffective for the reaction, which is indeed
consistent with the results of Yu et al. (i.e. Pd-SPO complex is an
inactive catalyst for C-P bond formation).[21] In addition, 10 mol-%
of two palladacycles, [µ2-(OAc)(2-C,N-1a)Pd]2 (Pd-II) and [µ2-
Cl(2-C,N-1a)Pd]2 (Pd-III), were employed as additives (entries
18-19), respectively. However, no discernible difference in yield
of 3aa was obtained (entries 17-19). Moreover, using 20 mol-% of
Pd(cod)Cl2 yielded 3aa in matching yield to that without the
presence of Pd(OAc)2 (c.f. entries 20 and 16). Although Pd(TFA)2
has been reported as an excellent catalyst for CAr-CBQ coupling
reactions,[25] it is, obviously, not a competitive Pd(II) additive here
in this type of reaction. The X-ray structure of 3aa confirms the
formation of fully substituted product through 2,5-phosphinations
and 3,6-aminations (Figure 2a). There are two intramolecular
hydrogen bonds between O3…H1A (1.925 Å) and O4…H2A (1.772
Å).
Scheme 1. Pd(II)-catalyzed C-C or C-P bond formation with 1,4-benzoquinone
employed as co-catalyst (1a,11a 1b21) or substrate in this work (1d).
Results and Discussion
Our efforts towards optimizing the reaction conditions were shown
in Table 1-3. The distinct reactivity of BQ is achieved using (E)-
N,1-diphenylmethanimine (1a) as substrate. As known, imine is a
common N-directing substrate used in transition-metal catalyzed
C-H activation.[26] However, in the presence of diphenylphosphine
oxide (2a), no ortho-C-H on phenyl groups of 2a was activated but
the formation of 3aa (Table 1). The yield of 3aa was improved with
the increase of temperature, reaching maximum of 62% at 60 oC
(entries 1-5). Addition of trace amount of water (1 equiv.) also
helps promoting the yield of 3aa to 76% (entry 6). This could be
Figure 2. Crystal structures of (a) product 3aa and (b) N3ab. Hydrogen
atoms except the N-H protons are omitted for clarity.
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10.1002/ejoc.201700109
European Journal of Organic Chemistry
FULL PAPER
Recently, Larrosa[29] and Sanford[30] had independently come to
the same conclusion that Ag(I) is capable of activating electron-
deficient arene C-H bond through a concerted metalation-
deprotonation (CMD) mechanism[31] when appropriate base such
as CO32-, OAc-, or OPiv- is the counterion in silver salt. Although
the capacity of Ag(I) to oxidize HQ intermediates to the
corresponding BQ derivatives is known, other roles played by it
have not yet revealed in this reaction.
Table 1. Optimizing the reaction conditions for the formation of 3aa.[a]
En-
try
Additives
(mol-%)
Temp.
(oC)
H2O
(equiv.)
Time
(h)
Solvent
Yield
(%)[b]
Table 2. Exploring the optimal oxidant for the synthesis of 3aa.[a]
1
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (10)
Pd(OAc)2 (5)
Pd(OAc)2 (0)
Pd-I (10)
100
80
60
40
r.t.
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
0
0
0
0
0
1
1
1
1
1
1
1
-
15
15
15
15
15
15
6
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCM
32
56
62
38
21
76
48
64
70
51
55
33
36
66
61
57
50
51
47
53
39
Entry
Oxidant (equiv.)
Isolated Yield (%)
2
1[b]
2
Ag2CO3 (0)
Ag2CO3 (5)
Ag2O (4)
-
[c]
3
34
35
37
9
4
3
5
4
Ag(OAc) (8)
AgF (8)
6
5
7
[c]
6
AgBF4 (8)
Cu(OAc)2 (8)
-
8
12
24
15
15
15
15
15
15
15
15
15
15
15
15
[c]
7
-
9
[a] Reaction conditions: 2 equiv. of 1a, 2 equiv. of 2a, 1 equiv. of BQ, oxidant
(n equiv.), 1 equiv. of H2O, 2mL of degassed solvent, reacted at 60 oC for 15
hours. [b] 20 mol-% of Pd(OAc)2 was loaded. [c] Not detected.
10
11
12
13
14
15
16
17
18
19
20
21
THF
DMF
When aniline instead of 1a was used as substrate in the
reaction carried out at the optimized conditions, the yield of 3aa
dropped significantly from 76% to 36% (entry 1, Table 3). This
could be associated with the formation of inactive Ag(I)-aniline
complex(es) under excess amount of aniline. The yield of 3aa
could also be drastically attenuated to 18% when the reaction was
carried out in air (entry 2). By contrast, it has been reported
elsewhere for a related reaction that phosphinyl radical (R2P(O))
was presumably generated while it was carried out with SPO in
air and thereby enhanced the yields of products.[32]
H2O
1
1
1
1
1
1
1
1
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Pd-II (10)
Pd-III (10)
Pd(cod)Cl2 (20)
Pd(TFA)2 (20)
Table 3. Refining the optimized reaction conditions for synthesizing 3aa.[a]
Entry
Reaction Conditions (equiv.)
Isolated Yield (%)
[a] Reaction conditions: 2 equiv. of 1a, 2 equiv. of 2a, 1 equiv. of BQ, 4 equiv.
of Ag2CO3, 2mL of degassed solvent. [b] Isolated yields.
1
2
3
4
5
6
NH2Ph (2)
in air
36
18
52
56
57
91
TEMPO (2)
TEMPO (4)
TEMPO (4)[b]
1a (3), 2a (3)[c]
The results from the variations of the amount of Ag2CO3 and
the usages of different Ag(I) sources and Cu(OAc)2 as oxidants in
the reaction are compiled in Table 2. Clearly, Ag2CO3 is
indispensable for the synthesis of 3aa despite 20 mol-% of
Pd(OAc)2 additive was employed (entry 1, Table 2). The yield of
3aa decreased to 34% when 5 equiv. of Ag2CO3 was used (entry
2). The employments of 4 equiv. of Ag2O and 8 equiv. of Ag(OAc)
gave rise to the comparable yields of 3aa (entries 3-4). In the
presence of Ag(OAc), 7% of acetanilide was isolated, indicating
the existence of aniline in the reaction system. Oxidants such as
AgF, AgBF4 and Cu(OAc)2 are ineffective here (entries 6-8).
[a] Reaction conditions: 2 equiv. of 1a, 2 equiv. of 2a, 1 equiv. of BQ, n equiv.
of oxidant, 20 mol-% of Pd(OAc)2 as additive, 1 equiv. of H2O, 2mL of
degassed toluene, reacted at 60 oC for 15 hours. [b] No Pd(OAc)2 additive
was employed.
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At the first glance, the yield of 3aa is seemingly to be
influenced negatively by the addition of 2 to 4 equiv. of TEMPO
(entry 6 in Table 1 vs. entries 3-4 in Table 3). However, it was
found that the yields of 3aa were not much in difference in the
absence of Pd(OAc)2 with 4 equiv. of TEMPO (57%, entry 5 in
Table 3) or in the presence of Pd(OAc)2 with 2 or 4 equiv. of
TEMPO (52% or 56%, entries 3-4 in Table 3). Here, TMEPO
appears to diminish the positive effect brought by Pd(OAc)2 in
terms of the yield of 3aa. Based on these observations, a
previously speculated free radical mechanism is unlikely for this
type of reactions.[33] To our delight, the yield of 3aa could be
increased up to 91% when 3 equiv. of 1a and 1b were employed
(entry 6 in Table 3).
After carefully screening the relevant variables, the
optimized conditions for the synthesis of 3aa are listed as follows:
3 equiv. 1a, 3 equiv. 2a, 1 equiv. BQ, 4 equiv. Ag2CO3, 20 mol-%
Pd(OAc)2, 2 mL degassed toluene, 1 equiv. H2O, under nitrogen
atmosphere and reacted at 60 oC for 15 hours. With the optimized
conditions, the influences on the yields of 3 caused by the steric
and electronic effects of various SPOs and imines were further
evaluated (Figure 3). Note that the abbreviations for products 3s
are given based on the uses of imines and SPOs: 3(amino
group)(phosphine oxide). For example, the product 3ab stands for
the employments of (E)-N,1-diphenylmethanimine (1a) and di-p-
tolylphosphine oxide (2b). The yield of 3ab (77%) is moderately
reduced, compared to that of 3aa (91%), by using di-p-
tolylphosphine oxide (2b), equipped with electron-donating
methyl group on the para-position of phenyl substituent, as SPO
source. Neither bulky di-tert-butylphosphine oxide (2c) nor
diphenyl H-phosphonate (2d) gave the anticipated product of 3ac
or 3ad. The ineffectiveness of substrates of 2c and 2d may be
attributed to much slower tautomerization rates, from SPO to PA,
than that of 2a (i.e. the order of initial tautomerization rates of
SPOs: Ph2P(O)H > (PhO)2P(O)H >> tBu2P(O)H).[34]
Figure 3. Fully functionalization of BQ with various SPO and imine derivatives.
The 2 equiv. of imine and SPO were used when NQ was employed. Note that
the abbreviations for the products are given based on the rules: the first alphabet
stands for the employed imine, the second for the SPO, while N for NQ.
Several imine derivatives Ph-CH=N-Ar (Ar: 4-tert-
butylphenyl (1b), 4-methoxyphenyl (1c), 2-fluorophenyl (1e), 3-
fluorophenyl (1f), 4-fluorophenyl (1g), 4-(trifluoromethyl)phenyl
Preliminary mechanistic studies concerning the water-
assisted reactivity between SPO and imine w/wo the presence of
BQ or Ag2CO3 were carried out under the optimized reaction
conditions (Scheme 2). The hydrophosphinylation product A via
1,2-addition of the C=N bond of imine 1a by R2P(O)-H 2a was
obtained from the control reaction in 2 mL toluene reacted at 60
oC for 2.5 hours. The isolated yield of A was 88% (entry 1 in
Scheme 2). While BQ was loaded into the previous control
reaction, 79% yield of A was isolated (entry 2). Moreover, the
byproduct of 2-phosphoryl hydroquinone (HQ) B was also
detected through 1,4-addition of BQ by SPO 2a (31P NMR yield in
(1h); and
(E)-N-tert-butyl-1-phenylmethanimine (1d)) were
employed as substrates as well. The presence of electron-
donating group (EDG) on the para-position of -Ar or electron-
withdrawing group (EWG) on the meta-position of -Ar has less
impact on the yields of 3 (3ba, 3ca and 3fa in Figure 3b). However,
the functionalization of EWG on the ortho- or para-position of -Ph
on imine resulted in slightly reduction in yields (3ea, 3ga, 3ha in
Figure 3b and 3cb in Figure 3c). The production of 3 is not very
sensitive to the electronic effect caused by imine, but it could be
drastically influenced by the steric effect of imine in the production
of 3da. Notably, the fully C-H functionalization of BQ is also
applicable to NQ, giving rise to the 2-phosphination and 3-
amination products with moderate yields (N3aa: 44% and N3ab:
44% in Figure 3c). The crystal structure of N3ab is shown in
Figure 2b. The well-resolved crystal structures for 3ba, 3ca, 3fa
and 3ga are shown in the Supporting Information.
-
DMSO-d6: c.a. 20%),[33b] implying that P(O)R2 is the first
nucleophile that attaching BQ. Compared to the control reaction,
the yield of A (22%) was greatly reduced at the presence of 4
equiv. of Ag2CO3 (entry 3, Scheme 2). It is presumed that Ag(I) is
of crucial importance in the reaction not only acting as an
indispensable oxidant but also as a handy reagent to avoid
hydrophosphinylation of C=N bond of imine by SPO.
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10.1002/ejoc.201700109
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HQ was not mentioned, Han’s work indeed implies a stepwise-
substitution mechanism on BQ in the title reaction. Therefore, the
nucleophilic attack of aniline on the 3-position of III to form
-
intermediate IV could be expected albeit P(O)Ph2 could be a
better nucleophile than aniline. The aniline derivatives are
believed to be formed from the acid-catalyzed hydrolysis of their
corresponding imines. The regioselectivity of 2-phosphination and
3-amination on BQ (III) could be originated from large steric
repulsion between two neighboring -P(O)Ph2 substituents when
functionalized on the 2- and 3-positions of BQ.
Scheme 2. Preliminary mechanistic studies for fully functionalization of BQ. [a]
Yields were estimated based on the amount of imine.
Subsequently, 2,3-substituted intermediate V could be
2-
obtained from IV through deprotonation by the assistance of CO3
and further oxidation by two Ag(I) cations which are coordinated
by one of the oxygen atoms of IV. Based on our DFT calculations,
the C6 contributes more -type 2p atomic orbital than C5 to the
LUMO of V,[39] which is again consistent with the previously
reported computational predictions for donor- or acceptor-
functionalized BQ substituent.[38] Thus, the succeeding C-H
functionalization through nucleophilic attack of aniline on the C6-
position of V might be anticipated. Eventually, the fully substituted
product could be obtained from repeating the previous elementary
steps. Although the role played by Pd(OAc)2 is not clear, it might
act as a mild Lewis acid towards the coordination of N- or P-
substituted intermediates. Thereby, the electrophility of those
moderate substituted BQ intermediates is increased. As reported
in entries 6, 14-16 in Table 1, the yield of 3aa is proportional to
the amounts of Pd species loaded into the reaction flasks.
Although Ag(I)-P(O)Ph2 might be formed in reaction,[35] the
adduct was speculated to be readily fragmented to R2P(O) and
zero-valent Ag(0). Herein, the formation of BQ-Ag(I)-O-PPh2 (I)
adduct is thereby proposed in the presence of a redox-active
moiety such as BQ (Scheme 3). In addition, the attenuation of the
hydrophosphinylation in production allows the generation of some
more amount of aniline through proton-assisted hydrolysis of
imine.[36] When A was employed as reagent to replace both SPO
and imine in the title reaction (Scheme 1d), no targeted product
of fully substituted BQ (3aa) was observed by judging from both
1H and 31P NMR spectra of the reaction mixture.
A proposed mechanism is thereby shown and illustrated as
follows (Scheme 3). Firstly, the two lone-pair electrons of oxygen
atom(s) in BQ could coordinate to two Ag(I) ions,[37] and grants
-
BQ a better electrophile for P(O)Ph2 which is presumably
released from the adduct BQ-Ag(I)-O-PPh2 (I). After the formation
of intermediate II, the deprotonation process takes place by the
assistance of CO3 and then two electrons transfer from the
Conclusions
2-
intermediate to two Ag(I) ions, giving rise to the P-
monosubstituted BQ III along with two equivalents of Ag(0)
species. Based on the quantum-mechanical calculations pursued
by Houk,[38] the subsequent nucleophilic addition of aniline
presumably prefers to take place at the 3-position of III because
an electron-withdrawing group such as -P(O)Ph2 has been
functionalized on the 2-position of BQ. In addition, the 31P NMR
peak at 34 ppm is always observed in the quenched reaction
In conclusion, a new reactivity of BQ has been revealed when N-
directing imines (1) and SPOs (2) are employed as substrates and
20 mol-% Pd(OAc)2 as additive in the Ag(I)-mediated reaction.
The reaction is proposed to undergo a series of 1,4-addition and
oxidation reactions that eventually giving rise to fully C-H
functionalized BQ products. When compared with the previously
reported Pd(II)-catalyzed oxidative C-P bond formation analogue,
the reagents of Pd(II), Ag(I) and BQ are acting as catalyst, oxidant,
and additive (as promoter) as demonstrated in this work (c.f.
Scheme 1b & 1d). Under similar reaction conditions, the role
played by BQ is no longer an additive but a reactant for 2,5-
phosphinations and 3,6-aminations. This newly found one-pot
reactivity is originated from the replacement of 2-phenylpyridine
(Scheme 1b) with N-directing imine (Scheme 1d). The
employments of imine and SPO in Ag(I)-mediated reactions leads
to the hydrolysis of imine to a well-suited nucleophile, aniline.
Several substituted imines, SPOs, and even NQ were also
mixtures,
indicating
the
formation
of
A
through
hydrophosphinylation between SPO and imine.
successfully employed and yielded similar reactivities.
A
mechanism for this Ag(I)-mediated CDC-type (dual C-H/P-H and
C-H/N-H) and multi-components reaction is tentatively proposed.
Most importantly, these results serve as a reminder that BQ can
be an active reactant, besides oxidant, when suitable
nucleophiles can be generated in a potentially Pd(II)-catalyzed
oxidative reaction where Ag(I) is an oxidant. In view of the various
applications of BQ (or HQ) derivatives containing the CBQ/HQ-P or
Scheme 3. Preliminary mechanistic studies for fully functionalization of BQ.
Recently, Han et al. demonstrated that the reaction of BQ
and diphenylphosphine oxide yielded 98% of P-monosubstituted
HQ (B) with no mention of the potential production of 2,5-
disubstituted HQ.[33b] Although the formation of higher substituted
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10.1002/ejoc.201700109
European Journal of Organic Chemistry
FULL PAPER
recrystallization process while a small amount of red crystals of Pd-III were
also attained. The yield of Pd-III was 86% (0.106 g, 0.166 mmol).
CBQ-N bonds shown in Figure 1, the newly synthesized and highly
substituted BQ and NQ products might have versitle applications.
‡ Spectroscopic data for Pd-III:
Experimental Section
1H NMR (400 MHz, CDCl3, δ/ppm): δ = 9.17-9.15 (d, J= 7.6 Hz, 2H), 8.02-
7.97 (d, J= 19.6 Hz, 2H), 7.97-7.78 (d, J = 7.6 Hz, 2H), 7.61-7.48 (m, 4H),
7.46-7.30 (m, 8H), 7.06 (s, 2H); 13C NMR (150 MHz, CDCl3, δ/ppm): δ =
171.1 (s, NCH), 151.3 (s, NAr), 133.8 (s, CAr), 131.8 (s, Ar), 131.7 (s, Ar),
129.3 (s, Ar), 128.8 (s, Ar), 128.2 (s, Ar), 123.9 (s, Ar); Element Anal.
Calcd. for C26H20Cl2N2Pd2: N, 4.35 %; C, 48.48 %; H, 3.13 %. Found: N,
4.50 %; C, 48.50 %; H, 3.07 %; HR-MS (EI, M+, m/z): Calcd. for
C26H20Cl2N2Pd2+ [M+]: 641.9073. Found: 641.9063.
1
General: Routine H NMR spectra were recorded at 399.756 MHz. The
chemical shifts are reported in ppm relative to internal standards TMS ( =
0.0 ppm). 31P and 13C NMR spectra were recorded at 161.835 and 100.529
MHz, respectively. The chemical shifts for the former and the latter are
reported in ppm relative to external standards H3PO4 (δ = 0.0 ppm) and
CHCl3 (δ = 77 ppm), respectively. Mass spectra were recorded on GC-MS-
MS or LC-MS spectrometer. Electron ionization-high resolution mass
spectra (EI-HRMS) were recorded on a mass spectrometer with magnetic
sector analyzers. Electrospray ionization-high resolution mass spectra
(ESI-HRMS) were recorded on a mass spectrometer with LTQ-Orbitrap
Preparation of imine derivatives of 1a-1c and 1e-1h: Into a 100 mL
round-bottomed flask with a magnetic stir bar were placed benzaldehyde
(1.02 mL, 10 mmol), aniline (0.91 mL, 10 mmol), and then 10 mL of
deionized water. The solution was stirred at room temperature for 12 hours.
Subsequently, brine was added to the crude mixture, and it was extracted
with ethyl acetate for three times. The combined organic layer was then
dried with anhydrous MgSO4. Lastly, the concentrated organic layer was
purified by flash column chromatography to yield the desired pale-yellow
product 1a (1.75 g, 9.69 mmol, 97%).
mass analyzers. All reactions were carried out under
a nitrogen
atmosphere using standard Schlenk techniques or in a nitrogen-flushed
glove box. Freshly distilled and degassed solvents were used. All
processes of separations of the tetra-substituted BQ products were
performed by column chromatography. For palladium complexes I, II, and
III, purifications were done by recrystallization. All chemicals purchased
from venders were directly used without further purification unless
otherwise stated.
Similar procedures were applied to the preparations of 1b, 1c, and 1e-1h.
The corresponding starting materials, 4-tert-butylaniline (1.59 mL, 10
mmol), 4-methoxyaniline (1.23 g, 10 mmol), 2-fluoroaniline (0.96 mL, 10
mmol), 3-fluoroaniline (0.96 mL, 10 mmol), 4-fluoroaniline (0.96 mL, 10
mmol), and 4-(trifluoromethyl)aniline (1.25 mL, 10 mmol) were used. The
corresponding yields of purified 1b (pale-yellow solids), 1c (brown solids),
1e (pale-yellow solids), 1f (yellow liquid), 1g (pale-green solids), and 1h
(white solids) are 95% (2.37g, 9.51 mmol), 92% (1.94g, 9.17 mmol), 71%
(1.42g, 7.11 mmol), 99% (1.97g, 9.90 mmol), 94% (1.87g, 9.40 mmol), and
X-ray Crystallographic Studies: Suitable crystals for X-ray analysis for
respective 3aa, 3ba, 3ca, 3fa, 3ga, N3ab, Pd-III (red crystals) and Pd-III
(yellow crystals), were obtained through the liquid-liquid diffusion method
in binary solvent system of n-hexane and DCM. Suitable crystals were
immersed with FOMBLIN®Y under a N2 atmosphere and mounted on a
diffractometer employing graphitemonochromated Mo Kα radiation (λ =
0.710 73 Å). Intensity data were collected with 
and reduction were performed with the CrysAlisPro software,[40] and the
absorptions were corrected by the SCALE3 ABSPACK multiscan
method.[41] The space group determination was based on a check of the
Laue symmetry and systematic absences, and was confirmed using the
structure solution. The structure was solved by direct methods using a
SHELXTL package.[42] All non-H atoms were located from successive
Fourier maps and hydrogen atoms were refined using a riding model.
Anisotropic thermal parameters were used for all non-H atoms, and fixed
isotropic parameters were used for H atoms.[43] Crystallographic data with
the CCDC numbers of 1497618, 1497619, 1497620, 1497621, 1497622,
1497623, 1497624 and 1497625 for 3aa, 3ba, 3ca, 3fa, 3ga, N3ab, Pd-III
(red crystals) and Pd-III (yellow crystals), respectively. These data are
provided free of charge by The Cambridge Crystallographic Data Centre.
95%
(2.37g,
9.51
mmol),
respectively.
(E)-N-tert-butyl-1-
phenylmethanimine (1d) was purchased from Sigma-Aldich.
‡ Spectroscopic data for compound 1a: 1H NMR (400 MHz, CDCl3, δ/ppm):
δ = 8.47 (s, 1H), 7.92-7.90 (d, J = 7.2 Hz, 2H), 7.49-7.48 (t, J = 4 Hz, 3H),
7.42-7.39 (d, J = 15.2 Hz, 2H), 7.24-7.21 (t, J = 12.4 Hz, 3H).
‡ Spectroscopic data for compound 1b: 1H NMR (400 MHz, CDCl3, δ/ppm):
δ = 8.45 (s, 1H), 7.89-7.86 (d, J = 9.6 Hz, 2H), 7.43-7.39 (m, 5H), 7.18-
7.16 (d, J = 8.8 Hz, 2H), 1.33 (s, 9H).
‡ Spectroscopic data for compound 1c: 1H NMR (400 MHz, CDCl3, δ/ppm):
δ = 8.49 (s, 1H), 7.90-7.88 (d, J= 9.2 Hz, 2H), 7.47-7.45 (t, J= 8.0 Hz, 3H),
7.25-7.23 (d, J = 8.8 Hz, 2H), 6.95-6.93 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H).
Preparation of palladium complexes Pd-III: Note that the [µ2-
ClPd(PPh2-OH)(PPh2O)]2 (Pd-I),[44] [µ2-(OAc)(2-C,N-1a)Pd]2 (Pd-II),[45]
and [µ2-Cl(2-C,N-1a)Pd]2 (Pd-III)[46] were all synthesized based on their
respective literature. The synthesis of Pd-III is presented because two
crystal structures belonging to different space groups were obtained, and
their structures were determined by X-ray diffraction methods. Into a 100
mL round-bottomed flask with stir bar was placed Pd(MeCN)2Cl2 (0.100 g,
0.386 mmol), 1a (0.069 g, 0.386 mmol), and NaOAc (0.063 g, 0.772 mmol).
Then, 10 mL of freshly distilled CH2Cl2 was added into the mixtures. The
solution was stirred at room temperature for 18 hours. Subsequently, brine
was added to the crude mixture, and the mixture was extracted with ethyl
acetate from a separatory funnel for three times. The combined organic
layer was dried with anhydrous MgSO4 then filtered with celite. The
solution was concentrated under vacuum, and yellow solids were obtained.
The solids were dissolved in CH2Cl2 and n-hexane, and two layers will form.
The yellow crystals of Pd-III were obtained as the major product from the
‡ Spectroscopic data for compound 1e: 1H NMR (400 MHz, CDCl3, δ/ppm):
δ = 8.53 (s, 1H), 7.95-7.92 (d, J= 9.6 Hz, 2H), 7.50-7.48 (t, J= 7.2 Hz, 3H),
7.17-7.14 (m, 4H).
‡ Spectroscopic data for compound 1f: 1H NMR (400 MHz, CDCl3, δ/ppm):
δ = 8.42 (s, 1H), 7.96-7.94 (d, J = 9.2 Hz, 2H), 7.53-7.49 (t, J = 16.8 Hz,
3H), 7.37-7.35 (t, J = 8.4 Hz, 1H), 7.05-6.96 (m, 3H).
‡ Spectroscopic data for compound 1g: 1H NMR (400 MHz, CDCl3, δ/ppm):
δ = 8.45 (s, 1H), 7.91-7.89 (d, J = 9.6 Hz, 2H), 7.50-7.47 (t, J = 14.0 Hz,
3H), 7.23-7.19 (d, J = 14.0 Hz, 2H), 7.11-7.07 (d, J = 17.2 Hz, 2H).
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10.1002/ejoc.201700109
European Journal of Organic Chemistry
FULL PAPER
‡ Spectroscopic data for compound 1h: 1H NMR (400 MHz, CDCl3, δ/ppm):
δ = 8.18 (s, 1H), 7.67-7.65 (d, J = 9.2 Hz, 2H), 7.41-7.38 (d, J = 8.4 Hz,
2H) , 7.28-7.23 (m, 3H), 7.01-6.99 (t, J = 8.4 Hz, 2H).
(s, Ar), 123.6 (s, Ar), 97.8 (d, J = 101.9 Hz, CP); 31P NMR (162 MHz, CDCl3,
δ/ppm): δ = 38.9; Element Anal. Calcd for C42H32N2O4P2: N, 4.06 %; C,
73.04%; H, 4.67%; O, 9.27%. Found: N, 4.00%; C, 72.89%; H, 5.02 %; O,
+
9.48%; HR-MS (EI) m/z Calcd for C42H32N2O4P2 [M]+: 690.1837. Found:
690.1841.
Preparation of diphenylphosphine oxide 2a: Into a 100 mL round-
bottomed flask with stir bar was placed chlorodiphenylphosphine (0.61 mL,
3.0 mmol) and then 12 mL of freshly distilled THF. Next, 1 mL of deionized
water was slowly added into the flask. The solution was stirred at room
temperature for 30 minutes, aiming at the hydrolysis of
chlorodiphenylphosphine. The triethylamine (7.0 mL, 15 mmol) in 5 mL
THF was then slowly added into the reaction mixture. The solution was
reacted for another 1 hour, and white precipitates of HCl·NEt3 were
observed. Subsequently, brine was added to the crude mixture, and it was
extracted with ethyl acetate from a separatory funnel for three times. The
combined organic layer was then dried with anhydrous MgSO4. Lastly, the
concentrated organic layer was purified by column chromatography to
yield the desired white solids of diphenylphosphine oxide 2a (0.44g, 2.17
mmol, 72%). Note that the di-p-tolylphosphine oxide 2b and diphenyl H-
phosphonate 2d were purchased from Alfa Aesar and TCI, respectively.
‡ Spectroscopic data for 3ab: 1H NMR (400 MHz, CDCl3, δ/ppm): δ =
12.51(s, 2H), 7.73-7.68(dd, J= 12.8, 12.8 Hz, 8H), 7.26-7.24(d, J= 8.0 Hz,
8H), 7.04-7.02(t, J= 7.6 Hz, 2H), 6.98-6.94(d, J= 15.2 Hz, 4H), 6.50-6.48(d,
J = 8.0 Hz, 4H), 2.43(s, 12H); 13C NMR (100 MHz, CDCl3, δ/ppm): δ =
177.4 (s, CO), 159.6 (s, CN), 142.4 (d, J = 2.6 Hz, Ar), 139.0(s, Ar), 132.1
(d, J = 11.5 Hz, Ar), 129.7 (d, J = 111.4 Hz, Ar), 128.9 (d, J = 13.4 Hz, Ar),
128.4 (s, Ar), 125.4 (s, Ar), 123.5 (s, Ar), 98.2 (d, J = 101.4 Hz, CP), 21.6
(s, CH3); 31P NMR (162 MHz, CDCl3, δ/ppm): δ = 38.8; Element Anal.
Calcd for C46H40N2O4P2: N, 3.75%; C, 73.98%; H, 5.40%. Found: N,
+
3.73%; C, 71.90%; H, 5.40%; HR-MS (EI) m/z Calcd for C46H40N2O4P2
[M]+: 746.2463. Found: 746.2466.
‡ Spectroscopic data for 3ba: 1H NMR (400 MHz, CDCl3, δ/ppm): δ =
12.44(s, 2H), 7.86-7.81(dd, J= 12.8, 12.8 Hz, 8H), 7.60-7.57(t, J= 14.8 Hz,
4H), 7.48-7.44(m, 8H), 6.97-6.95(d, J = 8.8 Hz, 4H), 6.52-6.50(d, J = 8.4
Hz, 4H), 1.27(s, 18H); 13C NMR (100 MHz, CDCl3, δ/ppm): δ = 177.4 (s,
CO), 160.2 (s, CN), 148.4 (s, Ar), 136.2 (s, Ar), 133.0 (s, Ar), 132.3 (d, J =
11.1 Hz, Ar), 131.9 (s, Ar), 128.3 (d, J = 12.6 Hz, Ar), 125.6 (s, Ar), 123.0
(s, Ar), 118.9 (s, Ar), 97.6 (d, J = 101.9 Hz, CP), 34.4 (s, tBu), 31.2 (s, tBu);
31P NMR (162 MHz, CDCl3, δ/ppm): δ = 38.9; Element Anal. Calcd for
C50H48N2O4P2: N, 3.49 %; C, 74.80 %; H, 6.03 %. Found: N, 3.52 %; C,
74.69 %; H, 5.78 %; HR-MS (ESI) m/z Calcd for [C50H48N2O4P2 + H]+ [M +
H]+: 803.3162. Found: 803.3143.
‡ Spectroscopic data for 2a: 1H NMR (400 MHz, CDCl3, δ/ppm): δ = 8.56
(d, JP-H = 483.7 Hz, 1H), 7.72-7.66 (dd, J = 8.0, 8.0 Hz, 4H), 7.57-7.54 (t, J
= 14.8 Hz, 2H), 7.50-7.46 (m, 4H); 31P NMR (162 MHz, CDCl3, δ/ppm): δ
= 22.02 (d, JP-H = 483.7 Hz).
General procedure for fully C-H functionalization of 1,4-
benzoquinone or 1,4-Napphthoquinone by dual regioselective
phosphination and amination reactions:
BQ as reactant:
‡ Spectroscopic data for 3ca: 1H NMR (400 MHz, CDCl3, δ/ppm): δ =
12.49(s, 2H), 7.87-7.82(dd, J= 12.8, 12.8 Hz, 8H), 7.60-7.56(t, J= 14.4 Hz,
4H), 7.49-7.45(m, 8H), 6.55-6.53(d, J = 8.8 Hz, 4H), 6.50-6.48(d, J = 9.2
Hz, 4H), 3.75(s, 6H); 13C NMR (100 MHz, CDCl3, δ/ppm): δ = 177.2 (s,
CO), 159.6 (s, CN), 157.3 (s, Ar), 132.9 (d, J = 124.1 Hz, Ar), 132.2 (d, J
= 11.1 Hz, Ar), 131.9 (s, Ar), 128.3 (d, J = 13.0 Hz, Ar), 124.6 (s, Ar), 113.8
(s, Ar), 96.8 (d, J = 102.5 Hz, CP), 55.3 (s, OCH3); 31P NMR (162 MHz,
CDCl3, δ/ppm): δ = 39.2; Element Anal. Calcd. for C44H36N2O6P2: N,
3.73 %; C, 70.40 %; H, 4.83 %. Found: N, 3.55 %; C, 70.06 %; H, 4.72 %;
HR-MS (ESI) m/z Calcd for [C44H36N2O6P2 + H]+ [M + H]+: 751.2121.
Found: 751.2101.
Into a 20 mL Schlenk tube with a magnetic stir bar was placed
diphenylphosphine oxide (130.41 mg, 0.65 mmol,
3 equiv), N-
Benzylideneaniline (116.89 mg, 0.65 mmol, 3 equiv), Pd(OAc)2 (9.6 mg,
0.048 mmol, 20 mol-%), benzoquinone (23.7 mg, 0.22 mmol, 1 equiv),
Ag2CO3 (237.2 mg, 0.86 mmol, 4 equiv). The Schlenk tube was then
evacuated and backfilled with nitrogen three times. Next, 2 mL of
degassed toluene was slowly added into the flask, and 4 μL of deionized
water (1 equiv.) was added with micropipette under the nitrogen
atmosphere. The solution was stirred at 60 oC for 15 hours. After the
solution was cooled to room temperature, 5 mL CH2Cl2 was added into the
flask. The solution was filtered over celite, dried with anhydrous MgSO4,
and concentrated under vacuum. Subsequently, the reaction mixture was
purified by column chromatography on silica gel using hexane/EtOAc = 4/1
to yield the dark-red solids of 3aa (134.4 mg, 0.19 mmol, 91%).
‡ Spectroscopic data for 3da: 1H NMR (400 MHz, CDCl3, δ/ppm): δ =
11.32(s, 2H), 7.87-7.82(dd, J = 132, 12.8 Hz, 8H), 7.52-7.49(m, 4H), 7.49-
7.42(m, 8H), 1.12(s, 18H); 13C NMR (100 MHz, CDCl3, δ/ppm): δ = 177.9
(s, CO), 163.8 (s, CN), 133.5 (d, J = 108.8 Hz, Ar), 132.2 (d, J = 11.1 Hz,
Ar), 131.6 (d, J = 3.1 Hz, Ar), 128.0 (d, J = 13.0 Hz, Ar), 93.4 (d, J = 107.6
Hz, CP), 56.5 (s, tBu), 29.9 (s, tBu); 31P NMR (162 MHz, CDCl3, δ/ppm): δ
= 40.0; Element Anal. Calcd. for C38H40N2O4P2: N, 4.31 %; C, 70.14 %; H,
6.20 %. Found: N, 4.19 %; C, 69.13 %; H, 6.27 %; HR-MS (EI) m/z Calcd
for C38H40N2O4P2+ [M ]+: 650.2463. Found: 650.2470.
The same protocol and was applied to other imines and SPOs substrates.
The isolated yields for fully substituted BQ products were dark-red solids
of 3ab (124.0 mg, 0.17 mmol, 77%), dark-red solids of 3ba (151.8 mg, 0.19
mmol, 88%), dark-red solids of 3ca (141.7 mg, 0.19 mmol, 88%), orange
solids of 3da (25.1 mg, 0.04 mmol, 18%), dark-red solids of 3ea (118.9 mg,
0.16 mmol, 76%), dark-red solids of 3fa (131.4 mg, 0.18 mmol, 84%), dark-
red solids of 3ga (116.4 mg, 0.16 mmol, 75%), dark-red solids of 3ha
(118.9 mg, 0.14 mmol, 67%), and dark-red solids of 3cb (151.4 mg, 0.19
mmol, 87%). All the products were purified by column chromatography on
silica gel using hexane/EtOAc = 4/1 solvent system.
‡ Spectroscopic data for 3ea: 1H NMR (400 MHz, CDCl3, δ/ppm): δ =
12.33(s, 2H), 7.84-7.78(dd, J= 12.8, 12.8 Hz, 8H), 7.58-7.55(t, J= 14.8 Hz,
4H), 7.48-7.43(m, 8H), 7.05-7.03(m, 2H), 6.89-6.88(m, 4H), 6.72-6.67(m,
2H); 13C NMR (100 MHz, CDCl3, δ/ppm): δ = 177.7 (s, CO), 159.4 (s, CN),
156.5 (d, J = 248.4 Hz, FAr), 132.3 (d, J = 109.1 Hz, Ar), 132.1 (d, J = 11.4
Hz, Ar), 132.0 (d, J = 2.6 Hz, Ar), 131.8 (d, J = 10.4 Hz, Ar), 128.5 (d, J =
13.8 Hz, Ar), 128.2 (d, J = 13.4 Hz, Ar), 127.8 (d, J = 12.3 Hz, Ar), 127.0
(d, J = 7.6 Hz, Ar), 125.1 (s, Ar), 124.1 (d, J = 3.8 Hz, Ar), 121.3 (d, J = 4.5
Hz, Ar), 116.1 (s, Ar), 115.6 (d, J = 19.8 Hz, Ar), 97.8 (d, J = 101.8 Hz,
CP); 31P NMR (162 MHz, CDCl3, δ/ppm): δ = 39.6; Element Anal. Calcd.
for C42H30F2N2O4P2: N, 3.86 %; C, 69.42 %; H, 4.16 %. Found: N, 3.96 %;
‡ Spectroscopic data for 3aa: 1H NMR (400 MHz, CDCl3, δ/ppm): δ =
12.54(s, 2H), 7.86-7.81 (dd, J= 13.2, 12. 8Hz, 8H), 7.60-7.58 (t, J= 7.6 Hz,
4H), 7.57-7.45 (m, 8H), 7.07-7.03 (t, J= 14.4 Hz, 2H), 7.01-6.97 (t, J= 14.8
Hz, 4H), 6.64-6.62 (d, J= 7.6 Hz, 4H); 13C NMR (100 MHz, CDCl3, δ/ppm):
δ = 177.4 (s, CO), 159.8 (s, CN), 138.9(s, Ar), 132.8 (d, J = 109.4 Hz, Ar),
132.2 (d, J = 11.5 Hz, Ar), 128.6 (s, Ar), 128.3 (d, J = 13.0 Hz, Ar), 125.6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700109
European Journal of Organic Chemistry
FULL PAPER
C, 69.69 %; H, 4.23 %. HR-MS (EI) m/z Calcd for C42H30F2N2O4P2+ [M]+:
726.1649. Found: 726.1640.
solution was cooled to room temperature, 5 mL CH2Cl2 was added into the
flask. The solution was filtered over celite, dried with anhydrous MgSO4,
and concentrated under vacuum. Subsequently, the reaction mixture was
purified by column chromatography on silica gel using hexane/EtOAc = 3/1
to yield the dark-red solids of N3aa (85.6 mg, 0.19 mmol, 44%).
‡ Spectroscopic data for 3fa: 1H NMR (400 MHz, CDCl3, δ/ppm): δ =
12.60(s, 2H), 7.86-7.81(dd, J= 12.8, 12.8 Hz, 8H), 7.61-7.57(t, J= 14.4 Hz,
4H), 7.51-7.46(m, 8H), 6.70-6.94(m, 2H), 6.81-6.77(m, 2H), 6.48-6.43(t, J
= 20.0 Hz, 2H); 13C NMR (100 MHz, CDCl3, δ/ppm): δ = 177.3 (s, CO),
163.6 (d, J = 246.9 Hz, FAr), 159.2 (s, CN), 140.5 (d, J = 10.3 Hz, Ar),
132.3 (d, J = 109.1 Hz, Ar), 132.2 (d, J = 1.9 Hz, Ar), 132.0 (d, J = 11.1 Hz,
Ar), 129.8 (d, J = 9.1 Hz, Ar), 128.4 (d, J = 13.0 Hz, Ar), 119.6 (d, J = 3.0
Hz, Ar), 112.9 (d, J = 21.4 Hz, Ar), 111.3 (d, J = 23.6 Hz, Ar), 98.8 (d, J =
101.0 Hz, CP); 31P NMR (162 MHz, CDCl3, δ/ppm): δ = 38.9; Element
Anal. Calcd. for C42H30F2N2O4P2: N, 3.86 %; C, 69.42 %; H, 4.16 %.
Found: N, 3.88 %; C, 69.36 %; H, 4.22 %; HR-MS (EI) m/z Calcd for
C42H30F2N2O4P2+ [M]+: 726.1649. Found: 726.1642.
The same protocol was applied to the reaction by using imine 1a and SPO
2b as substrates. The isolated yields for fully substituted product N3ab
was in dark-red solids of (90.2 mg, 0.19 mmol, 44%, hexane/EtOAc = 3/1).
‡ Spectroscopic data for N3aa: 1H NMR (400 MHz, CDCl3, δ/ppm): δ =
12.66 (s, 1H), 7.98-7.92 (dd, J = 13.6, 13.2 Hz, 5H), 7.89-7.87 (d, J = 7.6
Hz, 1H), 7.69-7.66 (t, J = 14.8 Hz, 1H), 7.62-7.54 (m, 3H), 7.52-7.49 (m,
4H), 7.38-7.34 (t, J = 15.6 Hz, 2H), 7.27-7.23 (t, J = 14.4 Hz, 1H), 7.14-
7.12 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3, δ/ppm): δ = 181.9 (d,
J = 5.7 Hz, CO), 181.3 (d, J = 10.4 Hz, CO), 157.3 (s, CN), 140.1 (s, Ar),
134.6 (s, Ar), 133.2 (d, J = 109.5 Hz, Ar), 132.6 (s, Ar), 132.2 (s, Ar), 132.0
(d, J = 11.1 Hz, Ar), 131.9 (s, Ar), 129.0 (s, Ar), 128.4 (d, J = 13.0 Hz, Ar),
126.5 (s, Ar), 126.0 (s, Ar), 125.9 (d, J = 1.9 Hz, Ar), 124.2 (s, Ar), 102.7
(d, J = 101.1 Hz, CP); 31P NMR (162 MHz, CDCl3, δ/ppm): δ = 40.4;
Element Anal. Calcd. for C28H20NO3P: N, 3.12 %; C, 74.83 %; H, 4.49 %.
Found: N, 3.02 %; C, 75.56 %; H, 5.16 %; HR-MS (EI) m/z Calcd for
C28H20NO3P+ [M]+: 449.1181. Found: 449.1172.
‡ Spectroscopic data for 3ga: 1H NMR (400 MHz, CDCl3, δ/ppm): δ =
12.48(s, 2H), 7.85-7.80(dd, J = 8.4, 12.0 Hz, 8H), 7.62-7.58(t, J = 16.0 Hz,
4H), 7.51-7.44(m, 8H), 6.70-6.65(t, J= 16.8 Hz, 4H), 6.60-6.57(m, 4H); 13
C
NMR (100 MHz, CDCl3, δ/ppm): δ = 177.3 (s, CO), 161.6 (d, J = 246.1 Hz,
FAr), 159.7 (s, CN), 134.8 (d, J = 3.1 Hz, Ar), 132.6 (d, J = 109.1 Hz, Ar),
132.1 (d, J = 11.5 Hz, Ar), 128.3 (d, J = 13.0 Hz, Ar), 125.2 (d, J = 8.3 Hz,
Ar), 115.6 (d, J = 22.8 Hz, Ar), 97.6 (d, J = 101.9 Hz, CP); 31P NMR (162
MHz, CDCl3, δ/ppm): δ = 39.2; Element Anal. Calcd. for C42H30F2N2O4P2:
N, 3.86 %; C, 69.42 %; H, 4.16 %. Found: N, 3.76 %; C, 64.70 %; H,
‡ Spectroscopic data for N3ab: 1H NMR (400 MHz, CDCl3, δ/ppm): δ =
12.69 (s, 1H), 7.96-7.94 (d, J = 8.0 Hz, 1H), 7.89-7.80 (m, 5H), 7.69-7.65
(t, J = 15.2 Hz, 1H), 7.62-7.58 (t, J = 14.8 Hz, 1H), 7.37-7.33 (t, J = 16.0
Hz, 2H), 7.31-7.29 (m, 4H), 7.26-7.23 (t, J = 14.4 Hz, 1H), 7.13-7.11 (d, J
= 8.0 Hz, 1H), 2.41 (s, 6H); 13C NMR (100 MHz, CDCl3, δ/ppm): δ = 181.9
(d, J = 5.7 Hz, CO), 181.3 (d, J = 9.8 Hz, CO), 157.1 (s, CN), 142.4 (s, Ar),
140.3 (s, Ar), 134.5 (s, Ar), 132.7 (d, J = 6.9 Hz, Ar), 132.5 (s, Ar), 132.3
(s, Ar), 132.0 (d, J = 11.3 Hz, Ar), 130.0 (d, J = 111.9 Hz, Ar), 129.1 (s, Ar),
129.0 (d, J = 8.3 Hz, Ar), 126.4 (s, Ar), 126.0 (s, Ar), 124.2 (s, Ar), 103.2
(d, J = 100.9 Hz, CP); 31P NMR (162 MHz, CDCl3, δ/ppm): δ = 40.3;
Element Anal. Calcd. for C30H24NO3P: N, 2.93 %; C, 75.46 %; H, 5.07 %.
Found: N, 3.02 %; C, 75.56 %; H, 5.16 %; HR-MS (EI) m/z Calcd for
C30H24NO3P+ [M]+: 477.1494. Found: 477.1485.
+
4.53 %; HR-MS (EI) m/z Calcd for C42H30F2N2O4P2 [M]+: 726.1649.
Found: 726.1642.
‡ Spectroscopic data for 3ha: 1H NMR (400 MHz, CDCl3, δ/ppm): δ =
12.57(s, 2H), 7.86-7.81(dd, J= 12.8, 12.8 Hz, 8H), 7.65-7.61(t, J= 15.2 Hz,
4H), 7.52-7.48(m, 8H), 7.24-7.22(d, J = 8.0 Hz, 4H), 6.71-6.69(d, J = 8.0
Hz, 4H); 13C NMR (100 MHz, CDCl3, δ/ppm): δ = 177.5 (s, CO), 159.7 (s,
CN), 142.0 (s, Ar), 132.4 (d, J = 2.7 Hz, Ar), 132.3 (d, J = 109.2 Hz, Ar),
132.2 (d, J = 11.1 Hz, Ar), 128.5 (d, J = 13.0 Hz, Ar), 127.6 (d, J = 32.9 Hz,
Ar), 125.9 (d, J = 3.4 Hz, Ar), 125.2 (d, J = 272.0 Hz, Ar), 123.8 (s, Ar),
99.5 (d, J = 99.5 Hz, CP); 31P NMR (162 MHz, CDCl3, δ/ppm): δ = 38.6;
Element Anal. Calcd. for C44H30F6N2O4P2: N, 3.39 %; C, 63.93 %; H,
3.66 %. Found: N, 3.41 %; C, 64.08 %; H, 3.82 %; HR-MS (ESI) m/z Calcd
for [C44H30F6N2O4P2 + H]+ [M + H]+: 827.1658. Found: 827.1632.
General procedure for preliminary mechanistic studies: A mixture of
N-Benzylideneaniline (117 mg, 0.645 mmol), diphenylphosphine oxide
(130 mg, 0.645 mmol), deionized water (4 μL, 0.215 mmol) in degased
toluene (2 mL) with 1,4-benzoquinone (23 mg, 0.215 mmol) (optional), and
Ag2CO3 (237 mg, 0.86 mmol) (optional) under nitrogen in a Teflon-sealed
tube was stirred at 60℃ for 2.5 h. The mixture was filtered over celite and
concentrated under vacuum. The residue was purified by silica gel
chromatography with dichloromethane/ethyl acetate = 8/1 to afford the
product as a white solid. The formation of B was confirmed by comparison
with the 1H and 31P NMR spectra reported by Han et al.[33b]
‡ Spectroscopic data for 3cb: 1H NMR (400 MHz, CDCl3, δ/ppm): δ =
12.46(s, 2H), 7.74-7.69(dd, J= 12.4, 12.8 Hz, 8H), 7.27-7.26(d, J= 4.8 Hz,
8H), 6.55-6.53(d, J= 8.4 Hz, 4H), 6.48-6.46(d, J= 8.8 Hz, 4H), 3.75(s, 6H) ,
2.44(s, 12H); 13C NMR (100 MHz, CDCl3, δ/ppm): δ = 177.4 (s, CO), 159.5
(s, CN), 157.2 (s, Ar), 142.3 (s, Ar), 132.2 (d, J = 11.5 Hz, Ar), 131.9 (s,
Ar), 129.9 (s, Ar), 128.9 (d, J = 13.4 Hz, Ar), 124.6 (s, Ar), 113.7 (s, Ar),
97.8 (d, J = 101.4 Hz, CP), 55.2 (s, OCH3), 21.7 (s, CH3); 31P NMR (162
MHz, CDCl3, δ/ppm): δ = 39.1; Element Anal. Calcd. for C48H44N2O6P2: N,
3.47 %; C, 71.46 %; H, 5.50 %. Found: N, 3.40 %; C, 69.63 %; H, 5.52 %;
HR-MS (ESI) m/z Calcd for [C48H44N2O6P2 + H]+ [M + H]+: 807.2747.
Found: 807.2724.
‡ Spectroscopic data for compound A: 1H NMR (400 MHz, CDCl3, δ/ppm):
δ = 7.85-7.90 (m, 2H; P(O)-Ph), 7.50-7.60 (m, 1H; P(O)-Ph), 7.47-7.50 (m,
2H; P(O)-Ph), 7.37-7.41 (m, 3H; P(O)-Ph), 7.25-7.30 (m, 2H; P(O)-Ph),
7.1-7.25 (m, 8H; Ar), 6.67 (t, J = 14 Hz ,1H; CH), 6.59-6.62 (m, 2H; Ar),
5.18 (d, J = 12 Hz,1H; NH); 13C NMR (150 MHz, CDCl3, δ/ppm): δ =
146.098, 146.020, 135.018 (d, J=2.0 Hz), 132.288 (d, J=2.6 Hz), 131.931
(d, J=2.6 Hz), 131.669 , 131.612, 130.433, 129.173, 128.820 , 128.744,
128.347 (d, J=4,5 Hz), 128.157, 128.136, 128.056, 127.623 (d, J=2.9 Hz),
118.361, 113,912, 57.329(d, J=75.1 Hz); 31P NMR (162 MHz, CDCl3,
δ/ppm): δ = 33.9; Element Anal. Calcd for C25H22NOP: C, 78.31; H, 5.78;
N, 3.65. Found: C, 78.25; H, 5.78; N, 3.79; HR-MS (EI) m/z Calcd for
C25H22NOP+ [M+]: 383.1439. Found: 383.1434.
NQ as reactant:
Into a 20 mL Schlenk tube with a magnetic stir bar was placed
diphenylphosphine oxide (173.88 mg, 0.86 mmol,
2
equiv),N-
Benzylideneaniline (155.86 mg, 0.86 mmol, 2 equiv),Pd(OAc)2 (19.2 mg,
0.086 mmol, 20 mol-%)), Naphthoquinone (68.0 mg, 0.43 mmol, 1 equiv),
Ag2CO3 (237.2 mg, 0.86 mmol, 2 equiv). The Schlenk tube was then
evacuated and backfilled with nitrogen three times. Next, 2 mL of
degassed toluene was slowly added into the flask, and 4 μL of deionized
water (1 equiv.) was added with micropipette under the nitrogen
atmosphere. The solution was stirred at 60 oC for 15 hours. After the
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10.1002/ejoc.201700109
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Computational Methods: All calculations were done with Gaussian 09.[47]
Incorporated in the process of geometry optimizations. Geometry
optimization for 2-(diphenylphosphoryl)-3-(phenylamino)- cyclohexa-2,5-
diene-1,4-dione (intermediate V in Scheme 3) was performed with the
hybrid functional B3LYP in conjugation with the 6-31+G(d) basis set.
Vibrational frequencies were calculated to confirm whether the optimized
structure is a local minimum (Nimag = 0) or transition state (Nimag = 1). In
addition, the orbital analysis was done to identify the atomic orbital
contributions to LUMO of intermediate V (Gaussian keyword: pop=(orbitals,
threshorbitals=3)).
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Acknowledgements
The authors thank the Ministry of Science and Technology of the
ROC (MOST 104-2119-M-005-004) for financial support and the
National Center for High-performance Computing (NCHC) for
computer time and facilities.
Keywords: C-H functionalization • quinone • phosphination •
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Quinone Functionalization
Yu-Chang Chang, Pin-Ting Yuan, and
Fung-E Hong*[a]
Page No. – Page No.
The C-H Bond Functionalization of
1,4-Benzoquinone by Silver-mediated
Regioselective Phosphination and
Amination Reactions
“Like reactions, unlike reactivities” - Imine, a nitrogen-directing substrate in TM-
catalyzed C-H activations, turns out to be the precursor of aniline in the presence of
Ar2P(O)-H and Ag2CO3. Thus, fully functionalized 1,4-benzoquinones via
unprecedented dual and regioselective C-P and C-N bond formations are obtained
in the Ag(I)-mediated one-pot reactions.
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