Thiourea-Catalyzed Cross-Dehydrogenative Coupling of C(sp3)–H with Diethyl Phosphite

Article abstract of DOI:10.1002/ejoc.201600801

The efficient thiourea-catalyzed cross-dehydrogenative coupling of C(sp³)–H with diethyl phosphite by using tert-butyl peroxide as a terminal oxidant was explored. This protocol further expands the application scope of H-bond donors and also pr

Full text of DOI:10.1002/ejoc.201600801

A Journal of
Accepted Article
Title: Thiourea-Catalyzed Cross-Dehydrogenative Coupling of sp3 C-H with Diethyl
Phosphite
Authors: Kai Gu; Zhiguo Zhang; Zongbi Bao; Huabin Xing; Qiwei Yang; Qilong Ren
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European Journal of Organic Chemistry
10.1002/ejoc.201600801
COMMUNICATION
Thiourea-Catalyzed Cross-Dehydrogenative Coupling of sp3 C-H
with Diethyl Phosphite
Kai Gu, Zhiguo Zhang,* Zongbi Bao, Huabin Xing, Qiwei Yang, and Qilong Ren
We report for the first time an efficient thiourea-catalzyed cross-
dehydrogenative coupling of sp3 C-H with diethyl phosphite
using tert-butyl peroxide as a terminal oxidant. This protocol
not only further expands the application scope of H-bond
donors but also provides a facile access to biologically relevant
α-amino phosphonic derivatives.
α-Aminophosphonates and their corresponding α-amino-
phosphonic acids serve as isosteric or bio-isosteric analogues to
natural and unnatural amino acids and have thus found wide
applications in biological and pharmacological realm, such as
antibacterial and antifungal agents, proteolytic enzyme inhibitors,
haptens for catalytic antibodies, etc.[1] Therefore, this class of
compounds has received considerable attention and resulted in
intense efforts directed toward the development of suitable
synthetic methodologies for their preparation.[2] Among others,
the addition of phosphites to imines catalyzed by Lewis acids is
probably the most general and direct approach to α-
aminophosphonates.[3] Recently, one-pot operation with
a
carbonyl compound, amine, and dialkyl phosphite in the
presence of transition metals have also been reported.[4] In view
of today’s environmental consciousness, there is still a need to
develop efficient and atom economic methodologies.[5]
Pioneered by the studies of Murahashi[6] and Li[7], the direct
activation of sp3-hybridized carbon-hydrogen (C-H) bonds
Scheme 1. T1-catalyzed reactions
(thio)urea-based catalysts reported, N,N-bis[3,5-bis(trifluoro-
methyl)phenyl]thiourea developed by Schreiner’s group
(abbreviated here as T1) has stood to be a privileged catalyst in
promoting chemical transformations (Scheme 1a) via double
hydrogen-bonding interactions.[11] The combination of T1 and
tert-butyl hydroperoxide (TBHP) has also been reported to be an
effective catalytic system for the oxidation of sulfides to the
corresponding sulfoxides (Scheme 1b).[12] The rationale behind
resembles much likely CuBr/TBHP oxidative system. Taking all
these together, we envisaged that the use of T1/TBHP, which
are environmentally friendly, readily available, and easy to
handle, would be a superior alternative system to those with
transition metal catalysts. Herein, we present our preliminary
experimental results, in which the C-P bond can be efficiently
constructed between N-phenyltetrahydro-isoquinoline and
diethyl phosphite in the presence of T1 as catalyst and TBHP as
the terminal oxidant.
adjacent
to
tertiary
amines,
in
particular
N-aryl
tetrahydroisoquinolines, has seen an explosion of interest. The
phosphonation of N-aryl tetrahydroisoquinolines with phosphite
employing oxidative cross-dehydrogenative coupling (CDC)
method represents one of the most popular methods for the
construction of α-aminophosphonates. Currently, these reactions
are often dominated by using transition-metals as catalyst or
visible light mediated photocatalysis.[8] Recently, several metal
free molecules[9] such as Eosin Y[9a], DDQ[9b, c], I2[9d], Rose
[9j]
Bengal[9e], AcOH[9f], BODIPY[9i], CBr4 has started to play a
significant role in promoting this transformation. As part of our
ongoing interest in noncovalent organocatalysis, we have
developed a series of reactions using thiourea derviatives as
catalyst, owing largely to their ability to activate the substrates
and stabilize partially developing negative charges in the
transition states through double hydrogen-bonding.[10] Among
We focused our initial studies on the oxidative coupling
reaction of N-phenyltetrahydroisoquinoline with diethyl phosphite
under a similar reaction conditions reported by Li and co-
workers[7a, b] using T1 instead of CuBr as the catalyst. To our
delight, the desired coupling product was obtained in 79%
isolated yield (Table 1, entry 1). For comparison, the reaction in
the absence of T1, only trace amount of product was acquired,
suggesting the critical role of T1 for this transformation (Table 1,
entry 9). Encouraged by these results, we continued to
investigate the solvent effects on reaction outcomes. The
reaction in most of solvents proceeds smoothly to furnish the
[a]
Kai Gu, Zhiguo Zhang,* Zongbi Bao, Huabin Xing, Qiwei Yang, and
Qilong Ren
Key Laboratory of Biomass Chemical Engineering of Ministry of
Education, College of Chemical and Biological Engineering
Zhejiang University
Zheda Road 38, Hangzhou 310027, China.
E-mail: zhiguo.zhang@zju.edu.cn
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))

European Journal of Organic Chemistry
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COMMUNICATION
Table 1. Survey of different solvents.
Table 2. Survey of reaction parameters.
Entry[a]
Solvent
Yield [%][b]
Entry[a]
2 [equiv.]
TBHP [equiv.] T1 [mol%]
Yield [%][b]
1
CH2Cl2
CH3OH
THF
79
1
1
2
4
3
3
3
3
3
3
3
3
3
3
3
3
3
3
1
2
4
3
3
3
3
3
3
3
3
20
20
20
20
20
20
5
52
57
73
58
60
79
56
62
75
80
81
59
83
84
2
68
2
3
56
3
4
EtOAc
Acetone
CH3CN
Toluene
DMF
49
4
5
72
5
6
80
6
7
76
7
8
76
8
10
15
20
25
20
20
20
9[c]
10[c]
CH2Cl2
CH3OH
trace
39
9
10
11
12[c]
13[d]
14[e]
[a] Reaction conditions: amine 1a (0.2 mmol), diethyl phosphite 2 (3.0 equiv.),
T1 (20 mol%), solvent (600 μL), TBHP (0.6 mmol, 5.5 M in decane), 35 oC, 24
h. [b] Isolated yield. [c] without T1.
product in moderate to high yields (Table 1, entries 1-2, 5-8), in
which CH3CN gives the highest yield. The reaction performed in
THF and ethyl acetate results in inferior results (Table 1, entries
3-4), probably due to the competitive hydrogen bonding
interaction between solvent and T1. It is worth noting that a
moderate yield was also obtained in the protic solvent methanol
(Table 1, entry 2). To further clarify this unusual phenomenon,
the reaction was performed in methanol without T1, a 39% yield
of the desired product was obtained, underlining the beneficial
effect of the hydrogen bonding interaction between methanol
and TBHP (Table 1, entry 10).
Using CH3CN as a superior solvent, we further examined
other reaction parameters including substrate/substrate ratios,
temperature, and catalyst loadings (Table 2). We found that the
yield of product can be improved as the ratio of diethyl phosphite
or TBHP increases (Table 2, entries 1-6), but no continuously
beneficial effect was observed when a larger excess more than
4.0 equivalents of them was used. 20 mol% of catalyst loading
with T1 seems optimal for giving the product in good yield and
reasonable reaction time (Table 2, entry 10). A slightly increased
temperature (Table 2, entries 10 and 12-14) was essential for a
short reaction time and a good isolated yield.
[a] Reaction conditions: amine 1a (0.2 mmol), CH3CN (600 μL), 35 oC, 24 h.
[b] Isolated yield. [c] room temperature, 48 h. [d] 50 oC, 12 h. [e] 70 oC, 6 h.
yield was obtained for the product (3i), probably owing to the
strong interaction of nitro group with T1. It is worthy of pointing
out that considerably inert N,N,4-trimethylaniline 1k was also
eligible for this procedure, albeit with a low isolated yield
(Scheme 2, 3k).
Based on the mechanism reported before,[13] a plausible
mechanism for the present reaction system was proposed and
Under the optimized reaction conditions, various N-
aryltetrahydroisoquinoline derivatives were examined for the
generality of this protocol, and the results were summarized in
Scheme 2. Substrates bearing both electron-donating (Scheme
2, 3e-3h) and weak electron-withdrawing groups (Scheme 2, 3b-
3d) on N-aryl were well tolerated, giving the corresponding
product in high yields (75-89%). Substrates with o-, m-, and p-
substituted methoxyl group afforded the corresponding products
in good to excellent yields (Scheme 2, 3f-3h). Only moderate
Scheme 3.
reaction.
A plausible mechanism of thiourea-catalyzed cross-coupling

European Journal of Organic Chemistry
10.1002/ejoc.201600801
COMMUNICATION
Scheme 2. Substrate generality.[a,b]
other hand, a slightly inferior result was observed for the
reaction between 4 and 2 without T1, suggesting that T1 may
also facilitate the substitution of tert-butyl peroxyl group with
diethylphosphite via H-bond activation (Scheme 4d).
In summary, we have developed a new catalyst system to
form C-P bond under mild reaction conditions through CDC
reactions between diethyl phosphite and various tertiary
arylamines, by using thiourea T1 as the catalyst and TBHP as a
terminal oxidant. N-aryltetrahydroisoquinolines bearing either
electron withdrawing or electron donating groups are well
tolerated with this method, giving the corresponding α-amino
phosphonic derivatives in good yields. The present method not
only further expands the application of T1, but also paves a new
avenue for thiourea-based organocatalysts. Further studies on
using this catalystic system to construct C-C bond and its
detailed mechanism investigations are under way in our
laboratory and will be reported in due course.
Experimental Section
Diethyl phosphonate 2 (0.6 mmol) and TBHP (0.6 mmol, 5.5 M in
decane) were successively added to
a mixture of N-aryl-1,2,3,4-
tetrahydroisoquinolines 1 (0.2 mmol) and N,N-bis[3,5-bis-(trifluoromethyl)
phenyl]thiourea T1 (20 mol%, 20 mg) in MeCN (600 μL). Then the
reaction mixture was stirred at 50 oC for 12 hours. After the reaction was
completed monitoring by TLC analysis under UV, the reaction mixture
was directed purified by column chromatography on silica gel with a
mixture of n-hexane and ethyl acetate as the eluent (hexane/ethyl
acetate = 2:1) to afford the desired coupling products 3.
[a] Reaction conditions: amine 1 (0.2 mmol), diethyl phosphite 2 (3.0 equiv.),
T1 (20 mol%), CH3CN (600 μL), TBHP (0.6 mmol, 5.5 M in decane), 12 h. [b]
Isolated yield.
Acknowledgements
depicted in Scheme 3. Namely, T1 facilitates the formation of
reactive intermediate 4 via hydrogen bonding interaction with
TBHP. The intermediate 4, aided by hydrogen bonding of T1,
was subsequently intercepted with diethylphosphite to generate
the corresponding product. This proposed mechanism was
further testified by means of experimental methods, in which the
possible reactive intermediate 4 was successfully isolated under
the same reaction conditions without the addition of
diethylphosphite (Scheme 4a). In contrast, in the absence of T1,
only trace amount of 4 was observed, emphasizing the crucial
role of T1 in promoting the cross-dehydrogenative coupling of N-
aryl-tetrahydroisoquinoline 1 with TBHP (Scheme 4b). When the
isolated intermediate 4 was used as the substrate, the reaction
with diethylphosphite proceeded well in the presence of T1 as
catalyst, affording the product in 89% yield (Scheme 4c). On the
We are grateful for financial support from the National Nature
Science foundation of China (21376212, 21436010), the
Fundamental Research Funds for the Central Universities
(2016FZA4019) and the Natural Science Foundation of Zhejiang
Province, China (LY13B060001).
Keywords: C-P coupling • organocatalysis • C-H activation •
cross-dehydrogenative coupling • thiourea
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European Journal of Organic Chemistry
10.1002/ejoc.201600801
COMMUNICATION
COMMUNICATION
This study report for the first time an
Kai Gu, Zhiguo Zhang,* Zongbi Bao,
efficient
organocatalytic
cross-
Huabin Xing, Qiwei Yang, and Qilong
Ren
dehydrogenative coupling of sp3 C-H
with diethyl phosphite using thiourea
based catalyst and tert-butyl peroxide
as a terminal oxidant.
Page No. – Page No.
Thiourea-catalyzed cross-
dehydrogenative coupling of sp3 C-H
with diethyl phosphite