Palladium-Catalyzed Formylation of Arylzinc Reagents with S-Phenyl Thioformate

Article abstract of DOI:10.1021/acs.orglett.7b00447

The first example of palladium-catalyzed direct formylation of arylzinc reagents using S-phenyl thioformate is reported. The reaction proceeded under mild conditions, allowing high functional group tolerance. In addition, the developed formylation method

Full text of DOI:10.1021/acs.orglett.7b00447

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Formylation of Arylzinc Reagents with S‑Phenyl
Thioformate
Ryosuke Haraguchi,* Sho-go Tanazawa, Naoya Tokunaga, and Shin-ichi Fukuzawa*
Department of Applied Chemistry, Institute of Science and Engineering, Chuo University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo
112-8551, Japan
*
S Supporting Information
ABSTRACT: The first example of palladium-catalyzed direct
formylation of arylzinc reagents using S-phenyl thioformate is
reported. The reaction proceeded under mild conditions,
allowing high functional group tolerance. In addition, the
developed formylation method was used to prepare deuterated
and 13C-labeled aryl aldehydes from isotope-labeled S-phenyl
thioformates. Moreover, this procedure was applied to an
alkenylzinc halide, affording the corresponding enal.
romatic aldehydes are versatile building blocks for various
C−C bond formation reactions. Among numerous
functionalized aldehydes, which are otherwise difficult to
synthesize by the aforementioned conventional methods.
1
A
aldehyde synthesis methods, the highest synthetic efficiency is
achieved by the direct introduction of a formyl group into
aromatic rings. Electrophilic formylation of aromatics is ideally
suited for this purpose, avoiding prefunctionalization prior to
Scheme 1. Formylation of Arylzinc Reagents by Cross-
Coupling Reaction with S-Phenyl Thioformate
2
formyl group incorporation. However, the corresponding
substrate scope is limited to electron-rich aromatic compounds;
moreover, their functional group tolerance is low. Function-
alized aldehydes can be obtained by transition-metal-catalyzed
3
formylation, particularly by palladium-catalyzed reductive
4
S-Aryl thioformates 2 have previously been prepared by other
formylation of aryl halides with CO gas. Although this method
11
4l
research groups and utilized for O-formylation of carboxylic
has been applied on an industrial scale, the use of gaseous CO
hampers the utilization of such procedures by synthetic
chemists working in the laboratory. Recently, some reagents
have been developed as C1 sources, presenting an alternative to
11a
acids in the field of biochemistry. However, the correspond-
ing C-formylation of organometallic reagents has received less
attention. To achieve this transformation, we explored
palladium-catalyzed formylation of organozinc reagents with
S-aryl thioformates. First, we screened a range of electronically
and sterically diverse S-aryl thioformates in the formylation of
organozinc reagent 1a prepared from 4-iodobenzonitrile with
Zn and LiCl (type A reagent). As shown in Scheme 2,
treatment of 1a with S-phenyl thioformate (2a) at 0 °C for 30
min in toluene/THF afforded the formylated product in 32%
yield. Although the use of S-aryl thioformate 2b, bearing an
electron-withdrawing group did not result in a marked change,
the presence of an electron-donating group reduced the yield
(2c), and only traces of the product were observed for sterically
demanding 2d and 2e. Alkylthiol-derived thioformate 2f gave
the product in 32% yield. Considering the greater availability of
5
the toxic CO gas. Aryl aldehydes have mostly been synthesized
by formylation of organolithium and organomagnesium
reagents with formic acid or its derivatives due to the user-
6
friendly handling of these reagents. However, such methods
suffer from low functional group tolerance because of their high
nucleophilicity. Therefore, new methods for the synthesis of
highly functionalized aldehydes under mild reaction conditions
are still required.
Organozinc reagents are regarded as versatile C-nucleophiles
due to their excellent functional group tolerance and chemo-
7
selectivity. They have exhibited enhanced synthetic value
owing to their utilization in transition-metal-catalyzed cross-
8
,9
coupling reactions. For instance, the use of thioesters as
2
a compared to that of 2b and 2f, we identified the former as
an appropriate formylating reagent for this reaction and further
investigated the reaction condition optimization.
After extensive experimentation (see the Supporting
Information for details), formylation of 1a with 2a afforded
coupling partners affords highly functionalized ketones under
9
mild reaction conditions (Fukuyama coupling). Even though
significant progress has been made in organozinc chemistry,
direct formylation of organozinc reagents remains undeveloped
10
because of the lack of appropriate formylating agents. Herein,
we utilized S-phenyl thioformate as a versatile formylating agent
for palladium-catalyzed formylation of arylzincs (Scheme 1).
This reaction proceeded under mild conditions to afford highly
Received: February 14, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00447
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Pd-Catalyzed Formylation of Organozinc Reagent
With the optimized reaction conditions in hand, we next
investigated the scope of arylzinc reagents (Scheme 3), initially
a,b
1
a with 2: Effect of Different S-Substituents
a,b
Scheme 3. Substrate Scope of Arylzinc Reagents
a
Standard conditions: 1a (0.22 mmol), 2 (0.20 mmol), PdCl (PPh )
3 2
2
(
24 μmol), toluene (2.0 mL), THF (0.4 mL) at 0 °C for 30 min.
b
1
Determined by H NMR analysis of the crude reaction mixture using
dibromomethane as the internal standard.
3
a in 96% yield under the following optimized reaction
conditions: Pd(OAc) (2.0 mol %) and P(2-furyl) (1.4 mol %)
2
3
in toluene/THF = 5/1 (v/v) at 0 °C for 30 min (Table 1, entry
Table 1. Optimization of the Reaction Conditions for the
a
Pd-Catalyzed Formylation of 1a with 2a
b
entry
variation from the standard conditions
yield (%)
1
2
3
4
5
6
7
8
9
none
96
trace
14
24
20
12
3
no Pd(OAc)2
no P(2-furyl)3
PPh , instead of P(2-furyl)
3
3
PCy , instead of P(2-furyl)
3
3
BINAP, instead of P(2-furyl)3
dppf, instead of P(2-furyl)3
P(2-furyl) (1.0 mol %)
47
55
45
39
25
42
3
P(2-furyl) (2.0 mol %)
3
1
1
1
1
0
1
2
3
P(2-furyl) (4.0 mol %)
a
3
Standard conditions: 1 (0.22 mmol), 2a (0.20 mmol), Pd(OAc) (4.0
2
P(2-furyl) (8.0 mol %)
3
μmol), P(2-furyl) (2.8 μmol), toluene (2.0 mL), THF (0.4 mL) at 0
3
b
c
d
THF as a sole solvent
°
C, for 30 min. Isolated yields. Reagent type = A. Reagent type = B.
e
f g h
at 25 °C
At 0 °C for 2 h. At−20 °C for 15 h. At 0 °C for 15 h. The starting
material was protected by a TMS group, which was removed after
workup.
a
Standard conditions: 1a (0.22 mmol), 2a (0.20 mmol), Pd(OAc)2
4.0 μmol), P(2-furyl) (2.8 μmol), toluene (2.0 mL), THF (0.4 mL)
(
3
b
1
at 0 °C for 30 min. Determined by H NMR analysis of the crude
reaction mixture using dibromomethane as the internal standard.
focusing on the synthesis of functionalized aldehydes bearing
electrophilic functional groups that are not tolerated in the
conventional formylation of organolithium or organomagne-
sium reagents. For example, arylzinc reagents containing cyano,
ethoxycarbonyl, and N,N-diisopropylamide moieties were
formylated in good yields to afford 3a−c. Arylzinc reagents
with halogen functional groups underwent smooth formylation
to give product 3d−g without any functional group loss.
Electron-rich arylzinc reagents (3i−p,s were prepared from the
1
). No formylation took place in the absence of Pd(OAc)2
(entry 2), and a poor yield was obtained in the absence of P(2-
furyl) (entry 3). As shown in entries 4−7, the use of mono-
3
and bidentate phosphines instead of P(2-furyl) resulted in
3
lower yields.
Notably, the amount of P(2-furyl) played a key role in this
3
formylation, with deviations from the optimal value of 1.4 mol
%
causing significantly deteriorated yields (entries 1 and 8−11).
corresponding ArMgBr with equimolar of ZnCl : type B
2
This result is interesting because Fukuyama coupling usually
requires more than 1 equiv of the phosphine ligand relative to
palladium, although the exact reason behind the dramatic effect
of the phosphine amount in the present reaction is not well
understood. Conducting formylation in pure THF decreased
the product yield to only 25% (entry 12). The increase of
reaction temperature also reduced the yield (entry 13).
reagent) could also be utilized in the reaction (3h−k). 4-
Hydroxybenzaldehyde (3j) was synthesized from a TMS-
protected precursor, and deprotection was performed after
quenching with aqueous NH Cl. Substituents in the 2-position
4
did not cause steric inhibition, furnishing the desired products
in moderate to good yields (3l−n). Polyaromatic and
heteroaromatic aldehydes could also be synthesized by
B
DOI: 10.1021/acs.orglett.7b00447
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
formylation (3o−s). The result of a gram-scale synthesis of 3e
to CO utilization, and further studies on extending its scope are
currently underway in our laboratories.
(
1.21 g, 82%) showed the practicality of the present reaction
Scheme 4).
(
ASSOCIATED CONTENT
■
Scheme 4. Gram-Scale Synthesis
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00447.
Detailed experimental procedures and compound char-
acterization data (PDF)
Further applications concerning the incorporation of isotope-
AUTHOR INFORMATION
Corresponding Authors
■
labeled formyl groups are shown in Schemes 5 and 6. 2a-d and
1
Scheme 5. Synthesis of the Deuterated Aldehyde
*E-mail: ryo1229@kc.chuo-u.ac.jp.
*
E-mail: orgsynth@kc.chuo-u.ac.jp.
ORCID
Ryosuke Haraguchi: 0000-0001-6703-8036
Notes
The authors declare no competing financial interest.
Scheme 6. Synthesis of the 13C-Labeled Compound
REFERENCES
■
(
1) (a) Rom
̈
pp Chemie Lexikon; Falbe, J., Regitz, M., Eds.; Thieme:
ller, E. Methoden der Organischen Chemie
Stuttgart, 1995. (b) Mu
̈
(Houben-Weyl); Thieme: Stuttgart, 1954, Bd. VII, Teil 1. (c) Ferguson,
L. N. Chem. Rev. 1946, 38, 227. (d) Larock, R. C. Comprehensive
Organic Transformation: A Guide to Functional Group Preparation, 2nd
ed.; Wiley-VCH: New York, 1999. (e) Tokuyama, H.; Yokoshima, S.;
Lin, S.-C.; Li, L.; Fukuyama, T. Synthesis 2002, 2002, 1121.
1
3
2
a- C were readily prepared from commercially available
(
2) (a) Aldabbagh, F. Compr. Org. Funct. Group Transform. II 2005, 3,
9. (b) Crawford, L. P.; Richardson, S. K. Gen. Synth. Methods 1994,
16, 37. (c) Wynberg, H. Chem. Rev. 1960, 60, 169. (d) Fetter, J.;
Bertha, F.; Poszavacz, L.; Simig, G. J. Heterocycl. Chem. 2005, 42, 137.
isotope-labeled formic acids. The reaction of 2a-d with 1a
under optimized reaction conditions afforded 3a-d (99 atom D
), as confirmed by H NMR analysis. Moreover, isotope-
labeled 4-bromostyrene 4- C was readily obtained by C-
formylation of arylzinc reagent 1e and a subsequent
methylenation reaction. The prepared compounds are
versatile building blocks for the synthesis of isotope-labeled
molecules.
As shown in Scheme 7, this method could also be applied to
an alkenylzinc reagent. In the presence of Pd(OAc) (10 mol
1
9
1
1
%
́
́
1
3
13
(e) Meth-Cohn, O.; Stanforth, S. P. Comp. Org. Syn 1991, 2, 777.
(f) Kantlehner, W. Eur. J. Org. Chem. 2003, 2003, 2530. (g) Chen, J.;
Liu, B.; Liu, D.; Liu, S.; Cheng, J. Adv. Synth. Catal. 2012, 354, 2438.
1
2
(h) Li, L.-T.; Huang, J.; Li, H.-Y.; Wen, L.-J.; Wang, P.; Wang, B.
Chem. Commun. 2012, 48, 5187. (i) Fei, H.; Yu, J.; Jiang, Y.; Guo, H.;
Cheng, J. Org. Biomol. Chem. 2013, 11, 7092. (j) Li, X.; Gu, X.; Li, Y.;
Li, P. ACS Catal. 2014, 4, 1897. (k) Lu, L.; Xiong, Q.; Guo, S.; He, T.;
Xu, F.; Gong, J.; Zhu, Z.; Cai, H. Tetrahedron 2015, 71, 3637.
2
(
3) (a) Wu, W.; Su, W. J. Am. Chem. Soc. 2011, 133, 11924.
Scheme 7. Formylation of Alkenylzinc Reagent 5
(
b) Serrano, J. L.; Perez, J.; García, L.; Sanchez, G.; García, J.; Tyagi,
K.; Kapdi, A. RSC Adv. 2012, 2, 12237. (c) Huang, H.; Li, X.; Yu, C.;
́
́
Zhang, Y.; Mariano, P. S.; Wang, W. Angew. Chem., Int. Ed. 2017, 56,
1
3
500. (d) Xiang, S.; Chen, H.; Liu, Q. Tetrahedron Lett. 2016, 57,
870.
(
4) (a) Schoenberg, A.; Heck, R. F. J. Am. Chem. Soc. 1974, 96, 7761.
b) Baillargeon, V. P.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 452.
c) Kikukawa, K.; Totoki, T.; Wada, F.; Matsuda, T. J. Organomet.
(
(
Chem. 1984, 270, 283. (d) Ben-David, Y.; Portnoy, M.; Milstein, D. J.
Chem. Soc., Chem. Commun. 1989, 1816. (e) Cai, M.-Z.; Zhao, H.;
Zhou, J.; Song, C.-S. Synth. Commun. 2002, 32, 923. (f) Pri-Bar, I.;
Buchman, O. J. Org. Chem. 1984, 49, 4009. (g) Misumi, Y.; Ishii, Y.;
Hidai, M. Organometallics 1995, 14, 1770. (h) Kotsuki, H.; Datta, P.
K.; Suenaga, H. Synthesis 1996, 1996, 470. (i) Mutin, R.; Lucas, C.;
Thivolle-Cazat, J.; Dufaud, V.; Dany, F.; Basset, J. M. J. Chem. Soc.,
Chem. Commun. 1988, 896. (j) Klaus, S.; Neumann, H.; Zapf, A.;
%
), PPh (20 mol %), and ZnBr (1.0 equiv), the reaction of
3 2
alkenylzinc reagent 5 with 2a proceeded with the retention of
configuration, furnishing the corresponding enal compound.
Although the yield of the above reaction needs to be improved,
this result suggests the possibility of further expanding the
substrate scope of the present formylation.
In summary, we have demonstrated the first example of
palladium-catalyzed direct formylation of arylzinc reagents with
S-phenyl thioformate under mild reaction conditions to afford
functionalized aldehydes bearing cyano, ester, amide, chloride,
and bromide groups. The use of isotope-labeled formylating
reagents allowed the introduction of isotope-labeled formyl
groups. Thus, the developed method provides a safe alternative
Stru
̈ ̈
bing, D.; Hubner, S.; Almena, J.; Riermeier, T.; Groβ, P.; Sarich,
M.; Krahnert, W.-R.; Rossen, K.; Beller, M. Angew. Chem., Int. Ed.
2
2
006, 45, 154. (k) Ashfield, L.; Barnard, C. F. J. Org. Process Res. Dev.
007, 11, 39. (l) Sergeev, A. G.; Spannenberg, A.; Beller, M. J. Am.
Chem. Soc. 2008, 130, 15549. (m) Singh, A. S.; Bhanage, B. M.;
Nagarkar, J. M. Tetrahedron Lett. 2011, 52, 2383. (n) Neumann, H.;
Kadyrov, R.; Wu, X.-F.; Beller, M. Chem. - Asian J. 2012, 7, 2213.
C
DOI: 10.1021/acs.orglett.7b00447
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
5) (a) Cacchi, S.; Fabrizi, G.; Goggiamani, A. J. Comb. Chem. 2004,
T.; Utimoto, K.; Oshima, K.; Matsubara, S. J. Am. Chem. Soc. 2010,
132, 17452. (c) Nishida, Y.; Hosokawa, N.; Murai, M.; Takai, K. J. Am.
Chem. Soc. 2015, 137, 114.
6, 692. (b) Ueda, T.; Konishi, H.; Manabe, K. Angew. Chem., Int. Ed.
2
013, 52, 8611. (c) Korsager, S.; Taaning, R. H.; Lindhardt, A. T.;
Skrydstrup, T. J. Org. Chem. 2013, 78, 6112. (d) Jiang, X.; Wang, J.-M.;
Zhang, Y.; Chen, Z.; Zhu, Y.-M.; Ji, S.-J. Org. Lett. 2014, 16, 3492.
(
(
e) Qi, X.; Li, C.-L.; Wu, X.-F. Chem. - Eur. J. 2016, 22, 5835.
f) Natte, K.; Dumrath, A.; Neumann, H.; Beller, M. Angew. Chem., Int.
Ed. 2014, 53, 10090. (g) Yu, B.; Zhao, Y.; Zhang, H.; Xu, J.; Hao, L.;
Gao, X.; Liu, Z. Chem. Commun. 2014, 50, 2330. (h) Kumar, S.;
Verma, S.; Jain, S. L. Tetrahedron Lett. 2015, 56, 2430. (i) Iranpoor, N.;
Firouzabadi, H.; Etemadi-Davan, E.; Rostami, A.; Rajabi Moghadam,
K. Appl. Organomet. Chem. 2015, 29, 719. (j) Christensen, S. H.;
Olsen, E. P. K.; Rosenbaum, J.; Madsen, R. Org. Biomol. Chem. 2015,
1
(
8
1
1
3, 938.
6) (a) Olah, G. A.; Ohannesian, L.; Arvanaghi, M. Chem. Rev. 1987,
7, 671. (b) Olah, G. A.; Arvanaghi, M. Angew. Chem., Int. Ed. Engl.
981, 20, 878. (c) Meyers, A. I.; Comins, D. L. Tetrahedron Lett. 1978,
9, 5179. (d) Sato, F.; Oguro, K.; Watanabe, H.; Sato, M. Tetrahedron
Lett. 1980, 21, 2869.
7) (a) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117.
b) Knochel, P.; Almena Perea, J. J.; Jones, P. Tetrahedron 1998, 54,
275. (c) Knochel, P.; Leuser, H.; Gong, L.-Z.; Perrone, S.; Kneisel, F.
(
(
8
F. In Handbook of Functionalized Organometallics; Knochel, P., Ed.;
Wiley-VCH: Weinheim, 2005; Vol. 1, p 251. (d) Knochel, P.; Leuser,
H.; Gong, L.-Z.; Perrone, S.; Kneisel, F. F. The Chemistry of Organozinc
Compounds; Rappoport, Z., Marek, I., Eds.; Wiley: Chichester, 2006; p
2
87. (e) Knochel, P.; Millot, N.; Rodriguez, A. L.; Tucker, C. E. Org.
React. 2001, 58, 417.
8) (a) Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42,
821. (b) House, H. O.; Ghali, N. I.; Haack, J. L.; VanDerveer, D. J.
Org. Chem. 1980, 45, 1807. (c) Herrmann, W. A.; Bohm, V. P. W.;
(
1
̈
Reisinger, C.-P. J. Organomet. Chem. 1999, 576, 23. (d) Saeki, T.;
Takashima, Y.; Tamao, K. Synlett 2005, 1771. (e) Ohashi, M.;
Kambara, T.; Hatanaka, T.; Saijo, H.; Doi, R.; Ogoshi, S. J. Am. Chem.
Soc. 2011, 133, 3256. (f) Li, B.-J.; Li, Y.-Z.; Lu, X.-Y.; Liu, J.; Guan, B.-
T.; Shi, Z.-J. Angew. Chem., Int. Ed. 2008, 47, 10124. (g) Wang, C.;
Ozaki, T.; Takita, R.; Uchiyama, M. Chem. - Eur. J. 2012, 18, 3482.
(
(
h) Xie, L.-G.; Wang, Z.-X. Angew. Chem., Int. Ed. 2011, 50, 4901.
i) Srogl, J.; Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1997,
119, 12376. (j) Otsuka, S.; Fujino, D.; Murakami, K.; Yorimitsu, H.;
Osuka, A. Chem. - Eur. J. 2014, 20, 13146. (k) Huang, C.-Y. D.; Doyle,
A. G. J. Am. Chem. Soc. 2012, 134, 9541. (l) Bercot, E. A.; Rovis, T. J.
Am. Chem. Soc. 2002, 124, 174. (m) Shi, S.; Szostak, M. Org. Lett.
2
016, 18, 5872. (n) Zhang, Y.; Rovis, T. J. Am. Chem. Soc. 2004, 126,
15964. (o) Zhao, Y.; Wang, H.; Hou, X.; Hu, Y.; Lei, A.; Zhang, H.;
Zhu, L. J. Am. Chem. Soc. 2006, 128, 15048. (p) Jin, L.; Zhao, Y.; Zhu,
L.; Zhang, H.; Lei, A. Adv. Synth. Catal. 2009, 351, 630. (q) Cahiez, G.;
Foulgoc, L.; Moyeux, A. Angew. Chem., Int. Ed. 2009, 48, 2969.
(
r) Chen, M.; Zheng, X.; Li, W.; He, J.; Lei, A. J. Am. Chem. Soc. 2010,
132, 4101. (s) Jin, C.; Gu, L.; Yuan, M. Catal. Sci. Technol. 2015, 5,
4341. (t) Norinder, J.; Matsumoto, A.; Yoshikai, N.; Nakamura, E. J.
Am. Chem. Soc. 2008, 130, 5858. (u) Tobisu, M.; Hyodo, I.; Chatani,
N. J. Am. Chem. Soc. 2009, 131, 12070. (v) Ilies, L.; Okabe, J.;
Yoshikai, N.; Nakamura, E. Org. Lett. 2010, 12, 2838.
(
9) (a) Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T.
Tetrahedron Lett. 1998, 39, 3189. (b) Fukuyama, T.; Tokuyama, H.
Aldrichimica Acta 2004, 37, 87.
(
10) For acetal-protected formylation of organozinc reagents, see:
Katritzky, A. R.; Odens, H. H.; Voronkov, M. V. J. Org. Chem. 2000,
5, 1886.
11) (a) Jonsson, S.; Ricagno, S.; Lindqvist, Y.; Richards, N. G. J. J.
Biol. Chem. 2004, 279, 36003. (b) Henke, A.; Srogl, J. J. Org. Chem.
6
(
2
008, 73, 7783. (c) Sprecher, M.; Nov, E. Synth. Commun. 1992, 22,
2949. (d) Smith, R. A. J.; Keng, G. S. Tetrahedron Lett. 1978, 19, 675.
(
(
e) Murthy, R. S.; Bio, M.; You, Y. Tetrahedron Lett. 2009, 50, 1041.
f) Amin, R.; Ardeshir, K.; Heidar Ali, A.-N.; Zahra, T.-R. Chin. J.
Catal. 2011, 32, 60.
12) (a) Matsubara, S.; Sugihara, M.; Utimoto, K. Synlett 1998, 1998,
13. (b) Sada, M.; Komagawa, S.; Uchiyama, M.; Kobata, M.; Mizuno,
(
3
D
DOI: 10.1021/acs.orglett.7b00447
Org. Lett. XXXX, XXX, XXX−XXX