Trifluoromethylthiolation of diazo compounds through copper carbene migratory insertion

Article abstract of DOI:10.1002/ejoc.201402105

A strategy to introduce the SCF₃ group through the Cu ^I-promoted reaction of diazo compounds with the nucleophilic AgSCF₃ trifluoromethylthiolation reagent was developed. Various diazo compounds were smoothly converted under mild conditions to form the C(sp ³)-SCF₃ bond. Mechanistically, migratory insertion of SCF₃-bearing Cu carbene intermediates is involved in this transformation. Copyright

Full text of DOI:10.1002/ejoc.201402105

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402105
Trifluoromethylthiolation of Diazo Compounds through Copper Carbene
Migratory Insertion
Xi Wang,[a] Yujing Zhou,[a] Guojing Ji,[a,b] Guojiao Wu,[a] Ming Li,[b] Yan Zhang,[a] and
Jianbo Wang*[a]
Keywords: Diazo compounds / Carbenes / Fluorine / Migratory insertion
A strategy to introduce the SCF3 group through the CuI-pro- mild conditions to form the C(sp3)–SCF3 bond. Mechan-
moted reaction of diazo compounds with the nucleophilic
AgSCF3 trifluoromethylthiolation reagent was developed.
Various diazo compounds were smoothly converted under
istically, migratory insertion of SCF3-bearing Cu carbene in-
termediates is involved in this transformation.
Introduction
Fluorine-containing molecules are valuable in many
fields, ranging from agrochemicals and pharmaceuticals to
materials science, because introduction of a fluorine or
fluorinated functional group into organic moieties will lead
to profound changes in their physical and chemical proper-
ties, as well as their bioactivity.[1] The trifluoromethylthio
group (–SCF3), privileged in the family of fluorinated func-
tional groups as a result of its unique properties that in-
clude a strong electron-withdrawing inductive effect and ad-
mirable lipophilicity (πR = +1.44), has become an impor-
tant structural element of pharmaceutical and agrochemical
agents.[2] However, SCF3-bearing molecules do not exist in
nature. It is therefore significant to develop general and
practical methods to introduce a SCF3 group onto organic
moieties.
Scheme 1. Retrosynthetic analysis for trifluoromethylthiolation.
Apparently, a more reasonable route to the SCF3-bearing
moiety is the direct incorporation of the SCF3 group by
The trifluoromethylthiolated compounds are tradition- using trifluoromethylthiolation reagents. In this context, a
ally synthesized by the Swarts-type reaction, which involves common approach involves the reaction of nucleophiles
exhaustive photochemical chlorination of the CH3 group, with electrophilic trifluoromethylthiolation reagents such as
followed by Cl/F exchange with anhydrous HF (Scheme 1, CF3SCl,[5] RRЈNSCF3,[6] hypervalent iodine(III) reagents
a). The harsh conditions in the Swarts-type reaction limit (“SCF3+”),[7] and trifluoromethanesulfonyl hypervalent
the diversity of functional groups in the substrates.[3] To iodonium ylides[8] or the reaction of electrophiles with nu-
–
solve such a problem, many milder methods have been ex- cleophilic trifluoromethylthiolation reagents (“SCF3 ”,
plored. A widely practiced strategy is the trifluoromethyl- Scheme 1, c).[9] More recently, efforts have been directed
ation of RSX sulfides, such as RSK,[4a] RSCl,[4b–4d] towards transition-metal-catalyzed or -mediated cross-cou-
RSSR,[4e–4l] RSH,[4m,4n] and RSCN[4o] (Scheme 1, b).
pling reactions of aryl iodides[10a,10b] and bromides[10c] and
diazonium salts[10d,10e] with “SCF3” sources and towards
[a] Beijing National Laboratory of Molecular Sciences (BNLMS) direct C–H trifluoromethylthiolation.[11] Moreover, a dis-
and Key Laboratory of Bioorganic Chemistry and Molecular
tinct method is the trifluoromethylthiolation of electron-
Engineering of Ministry of Education, College of Chemistry,
rich π systems on the basis of a SCF3 radical process.[12]
Peking University,
Beijing 100871, P. R. China
In addition to these strategies, aryl-SCF3 and alkynyl-
SCF3 can also be accessed through the reaction of the cor-
responding aryl boronic acids or terminal alkynes, respec-
tively, with elemental sulfur and TMSCF3 (Scheme 1, d).[13]
Although remarkable advances in trifluoromethylthiol-
ation have been made, most of the methods so far devel-
E-mail: wangjb@pku.edu.cn
http://www.chem.pku.edu.cn/physicalorganic/home.htm
[b] College of Chemistry and Molecular Engineering, Qingdao
University of Science and Technology,
Qingdao 266042, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402105.
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X. Wang, Y. Zhou, G. Ji, G. Wu, M. Li, Y. Zhang, J. Wang
SHORT COMMUNICATION
oped are encumbered by at least one of the following limita- Table 1. Optimization of the trifluoromethylthiolation conditions.[a]
tions: high reaction temperature, limited substrate scope, ex-
pensive and/or toxic reagents, costly catalysts/ligands, and
cumbersome preparation of the starting materials or reagents.
In contrast, we and others have recently explored a set
Entry 1a/2
Additive (equiv.)
Addition time
[h]
T
[°C]
Yield[b]
[%]
of transition-metal-catalyzed and -mediated cross-coupling
reactions with diazo compounds as coupling partners.[14,15]
The key step in these reactions is metal carbene migratory
insertion, and the migratory groups include aryl, vinyl,
allyl, alkynyl, propargyl, acyl, and allenyl groups
(Scheme 2). Recently, Hu and co-workers explored this type
of coupling reaction for trifluoromethylation and gem-di-
fluoroolefination.[16] In connection to our interest in metal-
carbene-based coupling reactions, we report herein a novel
strategy for the construction of C(sp3)–SCF3 bonds through
the direct conversion of the diazo group into the SCF3
group.
1
2
3
4
5
6
7
1:1
1:1
1:1
1:1
1:1
1:1
1:1
none
none
0
1
1
1
1
1
5
5
5
5
5
5
5
5
5
0
0
0
0
0
0
0
0
–25
–25
–25
–25
–25
–25
–25
trace
10
42
40
45
CuCl (1.0)
CuBr (1.0)
CuI (1.0)
CuI (0.2)
CuI (1.0)
19
53
64
68
8
1.5:1 CuI (1.0)
9
1.5:1 CuI (1.0)
10
11
12
13
1.5:1 CuI (1.0), H2O (1.0)
1.5:1 CuI (1.0), H2O (1.5)
1.5:1 CuI (1.0), MeOH (1.0)
1.5:1 CuI (1.0), iPrOH (1.0)
84 (83)[c]
73
71
74
50
10
14[d] 1.5:1 none
15
1.5:1 H2O (1.0)
[a] Reaction conditions: A solution of 1a in MeCN (1 mL) was
added dropwise to a mixture of 2 (0.3 mmol) and the additive in
MeCN (0.5 mL) over the indicated time at low temperature. The
reaction mixture was stirred for another 2 h at this temperature and
then warmed up to r.t. Stirring was continued for another 3 h at
r.t. Upon completion of the reaction, saturated aqueous NH4Cl
(3 mL) was added. [b] The yield is based on 19F NMR spectroscopy
analysis by using PhCF3 as an internal standard. [c] The yield in
parentheses refers to the yield of the isolated product. [d] CuSCF3
was used instead of AgSCF3.
Scheme 2. Trifluoromethylthiolation through metal carbenes.
Results and Discussion
To implement this plan, we initially examined trifluoro-
methylthiolation by treatment of methyl α-diazophenylacet- of proton, such as MeOH and iPrOH (Table 1, entries 11–
ate (1a) with AgSCF3 (2) at 0 °C in MeCN. However, only a 13). If CuSCF3 was used in the reaction instead of AgSCF3,
trace amount of desired product 3a was observed (Table 1, product 3a was obtained in a decreased yield, which was
entry 1). The yield was improved to 10% if 1a was added indicative of its moderate reactivity in this reaction (Table 1,
dropwise to a solution of 2 in MeCN over a period of 1 h entry 14). However, a control experiment conducted in the
(Table 1, entry 2). We surmised that the failure to obtain absence of CuI demonstrated that a copper promoter was
the trifluoromethylthiolated product in decent yield could necessary (Table 1, entry 15).
be ascribed to the low efficiency of AgSCF3 on decomposi-
With the optimal reaction conditions (Table 1, entry 10)
tion of the diazo compound. Thus, we conceived that the identified, this novel trifluoromethylthiolation method was
employment of a copper salt as an additive might lead to applied to structurally diverse diazo compounds 1a–v
an increase in the efficiency of the reaction. After screening (Table 2).
copper species, we identified that the addition of 1.0 equiv.
Generally, α-diazoarylacetates bearing either electron-
CuI to the reaction mixture afforded the coupling product donating or electron-withdrawing groups underwent the
in 45% yield on the basis of 19F NMR spectroscopy analy- transformation smoothly to afford corresponding SCF3-
sis (Table 1, entries 3–5). However, reducing the amount of bearing products 3b–g in moderate to good yields. Methyl
CuI to 20 mol-% led to a diminished yield (Table 1, en- α-diazo(1-naphthyl) acetate and allyl α-diazophenylacetate
try 6).
proved to be suitable substrates, and they gave rise to tri-
If 1a was added more slowly, we observed an increase in fluoromethylthiolated compounds 3h and 3i, respectively.
the yield of product 3a from 45 to 53% (Table 1, entry 7). For TMS-substituted α-diazo esters and ethyl α-diazoacet-
The data show that performing the reaction with a 1.5:1 ate, the yields of 3j and 3k were determined on the basis
ratio of 1a/2 at a lower temperature offered a further im- of 19F NMR spectroscopy owing to the volatility of the
provement in the conversion and yield (Table 1, entries 8 products.
and 9). We speculated that the proton source would have
It is noteworthy that alkyl-substituted 3l and methyl-sub-
a significant effect on the transformation. To our delight, stituted 3m could also be accessed through this strategy,
1.0 equiv. H2O facilitated the protonation, and expected albeit in relatively lower yield, and a small amount of alk-
product 3a was isolated in 83% yield (Table 1, entry 10). ene byproducts was generated through the competitive 1,2-
However, the yields of 3a were appreciably diminished with H shift of the Cu carbene intermediate (see below). The α-
the use of an excess amount of H2O or with other sources diazo ketones exhibited reactivity similar to that of the α-
2
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Trifluoromethylthiolation of Diazo Compounds
Table 2. Optimization of the trifluoromethylthiolation conditions.[a]
This novel method was also applied to diaryl diazometh-
anes 1r–v. In these cases, the efficiency of the reaction
seemed to depend on the substituents on the aromatic ring.
The conversion of diaryl diazomethane substrates bearing
electron-withdrawing substituents on the aromatic ring gen-
erally resulted in good yield (i.e., 3s and 3t). In contrast, for
substrates bearing electron-donating groups on the aro-
matic ring, the reaction was sluggish and afforded di-
minished yields (i.e., 3u and 3v).
A possible mechanism is proposed as shown in Scheme 3.
Treatment of AgSCF3 with CuI leads to the in situ genera-
tion of the more reactive CuSCF3 species with the forma-
tion of AgI as a precipitate (see the Supporting Information
for details).[9a] Decomposition of diazo compound 1m by
CuSCF3 forms SCF3-containing Cu carbene A as the key
intermediate. Subsequently, migratory insertion occurs to
generate Cu species B, protonation of which affords tri-
fluoromethylthiolated product 3m. From CuI carbene inter-
mediate A, a competing 1,2-hydride shift occurs to give side
product methyl acrylate C.
Scheme 3. Mechanistic rationale.
Conclusions
In summary, we demonstrated a novel cross-coupling re-
action of various diazo compounds with the nucleophilic
AgSCF3 trifluoromethylthiolation reagent under mild con-
ditions. The reaction involves the formation of a CuI carb-
ene, migratory insertion of the carbene carbon to the Cu–
SCF3 bond, and finally protonation. The conversion is a
valuable complement to the previously established trifluor-
omethylthiolation methods. In-depth mechanistic studies of
the reaction and further exploration of novel methods
based on the migratory insertion of transition-metal carb-
ene intermediates will be the focus of future efforts in our
laboratories.
[a] Reaction conditions: A solution of 1a–v (0.45 mmol, 1.5 equiv.)
in MeCN (1 mL) was added dropwise to a mixture of 2 (0.3 mmol)
and H2O (1.0 equiv.) in MeCN (0.5 mL) over a period of 5 h at
–25 °C. The reaction mixture was stirred for another 2 h at –25 °C
and then warmed up to r.t. The stirring was continued for another
3 h at r.t. Upon completion of the reaction, saturated aqueous
NH4Cl (3 mL) was added. The yields refer to isolated products if
not otherwise noted. [b] The yield of isolated 3g is based on 1g.
See the Supporting Information for details. [c] The yield is based
on 19F NMR spectroscopy analysis by using PhCF3 as the internal
standard.
Experimental Section
Typical Procedure for the Trifluoromethylthiolation of Diazo Com-
pounds through Cu Carbene Migratory Insertion: An oven-dried
Schlenk tube equipped with a magnetic stir bar was charged with
CuI (57 mg, 0.30 mmol, 1.0 equiv.) and AgSCF3 (2; 63 mg,
0.30 mmol, 1.0 equiv.), sealed with a septum, and degassed by alter-
nating vacuum evacuation and nitrogen backfill (three times) be-
fore MeCN (0.5 mL) was added. H2O (6 mg, 0.30 mmol, 1.0 equiv.)
was added by microsyringe to the resulting suspension, which was
precooled to –25 °C (dry ice/o-xylene bath). Then, a solution of 2-
diazo ester analogues (i.e., 3n–p). Notably, the trifluoro-
methylthiolation of 1-phenyl-2,2,2-trifluorodiazoethane was
successfully achieved, and 3q was produced in 70% yield.
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X. Wang, Y. Zhou, G. Ji, G. Wu, M. Li, Y. Zhang, J. Wang
SHORT COMMUNICATION
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Received: February 19, 2014
Published Online: ᭿
4
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Trifluoromethylthiolation of Diazo Compounds
Trifluoromethylthiolation
X. Wang, Y. Zhou, G. Ji, G. Wu, M. Li,
Y. Zhang, J. Wang* .......................... 1–5
Trifluoromethylthiolation of Diazo Com-
pounds through Copper Carbene Mi-
gratory Insertion
A strategy to introduce the SCF3 group
through the CuI-promoted reaction of di-
azo compounds with the nucleophilic
AgSCF3 trifluoromethylthiolation reagent
is developed. Various diazo compounds are
smoothly converted under mild conditions
to form the C(sp3)–SCF3 bond. Migratory
insertion of SCF3-bearing CuI carbene in-
termediates is proposed as the key step in
this transformation.
Keywords: Diazo compounds / Carbenes /
Fluorine / Migratory insertion
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