N, N-diisopropylformamidine (DIFA) protection of anilines in metalation reactions

Article abstract of DOI:10.1055/s-0030-1259058

A novel N,N-diisopropylformamidine (DIFA) protecting group for anilines was studied. Metalation is often metal-directed by this weakly coordinating and bulky group, making it complementary to ortho-metalation directed by tert-butylcarbamate and pivaloylam

Full text of DOI:10.1055/s-0030-1259058

LETTER
3039
N,N-Diisopropylformamidine (DIFA) Protection of Anilines in Metalation
Reactions
N
,
N
-Diisoprop
a
ylformami
u
l
on of
A
niline
E. Zhichkin,* Sergiy G. Krasutsky, Ravi Krishnamoorthy
Medicinal Chemistry Department, AMRI, 26 Corporate Circle, P.O. Box 15098, Albany, NY 12212, USA
Fax +1(518)5122079; E-mail: paul.zhichkin@verizon.net
Received 20 September 2010
NHBoc, and NSi groups in DOM reactions, and show ex-
amples of its deprotection and practical use.
Abstract: A novel N,N-diisopropylformamidine (DIFA) protecting
group for anilines was studied. Metalation is often metal-directed
by this weakly coordinating and bulky group, making it comple-
mentary to ortho-metalation directed by tert-butylcarbamate and
pivaloylamide groups and to regular electrophilic reactions of
anilines. Importantly, DIFA is removed under nucleophilic condi-
tions and is stable toward acids, thus being orthogonal to tert-butyl-
carbamate, N-tert-butylamide, and other acid-labile protecting
groups.
DMFA and DIFA derivatives 2a–f were prepared via the
reaction of anilines 1 with the corresponding Vilsmeier
reagents (Table 1). A one-pot bis-protection of amino-
benzoic acids 3 was carried out as described earlier, using
two equivalents of the corresponding Vilsmeier reagent7
to provide, after the subsequent reaction with tert-butyl-
amine fully protected derivatives 4 (Table 1).
Key words: protecting groups, regioselectivity, metalation, form-
amidine
Table 1 Protection with DMFA and DIFA
X
X
R2NCHO, (COCl)2
Directed ortho-metalation (DOM) reactions are popular
and valuable synthetic tools. Aromatic amines protected
as pivaloylamides (NHPv) or tert-butylcarbamates
(NHBoc) are among the most well-researched ortho-
directing groups.1 However, to the best of our knowledge,
no other protecting groups for anilines, with the exception
of silyl groups (NSi),2 have been systematically studied in
DOM reactions.
NH2
N
1
NR2
2
CONHt-Bu
CO2H
1. 2 i-Pr2NCHO, (COCl)2
Y
Y
2. t-BuNH2
There were two reasons why we undertook the explora-
tion of alternative protecting groups for anilines. First, the
strong ortho-orienting character of NHPv and NHBoc
groups may be undesirable in some cases; for example, it
may lead to mixtures of regioisomers when other strong
ortho-directing groups are present.3 Second, the ability to
vary regioselectivity of lithiations with a simple change of
the protecting group, that is, regiochemical redirection,1,2
is very useful synthetically.
N
NH2
3
Ni-Pr2
4
Product
2a
R
Substituents
4-Br
Yield (%)
Me
i-Pr
Me
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
79
95
88
86
89
91
87
89
72
61
2b
4-Br
2c
3-OMe
3-OMe
2-OMe
4-NHBoc
One of the options we considered was the N,N-dimethyl-
formamidine (DMFA) protecting group,4 which is known
to ortho-direct metal–halogen exchange in polyhalogenat-
ed arenes.5 However, it is also known that the N-methyl
groups in DMFA and the N-alkyl groups in many other
N,N-dialkylformamidines are themselves prone to metala-
tion with various organolithium reagents.6 Addressing
this concern, a novel N,N-diisopropylformamidine
(DIFA) protecting group for aromatic amines, recently in-
troduced by us,7 has the advantage of greater stability than
DMFA and, likely, much lower CH acidity. In this letter,
we further compare the DMFA and DIFA groups, present
the DIFA group as a useful alternative to the NHPv,
2d
2e
2f
4a
3-CONHt-Bu, Y = CH
2-CONHt-Bu, Y = CH
4-CONHt-Bu, Y = CH
4-CONHt-Bu, Y = N
4b
4c
4d
According to the literature, the DMFA group is stable to-
ward Grignard reagents.5,8 A single reference suggests
that it is also stable toward n-BuLi at –78 °C.9 Our first
step was to establish the relative stability of DMFA- and
DIFA-protected aryllithium species. Compounds 2a and
SYNLETT 2010, No. 20, pp 3039–3044
Advanced online publication: 19.11.2010
DOI: 10.1055/s-0030-1259058; Art ID: S06310ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
0

3040
P. E. Zhichkin et al.
LETTER
2b were treated with t-BuLi at –70 °C, and decomposition ever, 2d remained unchanged, while 2c decomposed, even
of the resulting anions was monitored at progressively though the in situ quench with triisopropyl borate, often
higher temperature.10 The DMFA-protected anion was successful in the case of unstable anions,12 was used. At-
significantly less stable than the DIFA-protected ana- tempted lithiations of 2c with n-BuLi in diethyl ether or
logue. The half-life of 4-DIFA phenyllithium derived THF (entries 2, 3) gave mixtures of unchanged 2c, depro-
from 2b was 8 hours at 20 °C in 0.5 M solution in THF– tection (1c) and decomposition products. In the face of
pentane,11 while the half-life of 4-DMFA phenyllithium these disappointing results, further work with DMFA
derived from 2a was only 15 minutes at –30 °C.
analogues was stopped.
Under standard metalation conditions, the instability of In contrast to DMFA derivative 2c, DIFA analogue 2d
the DMFA group is even more pronounced. LTMP was could be selectively metalated between the two substitu-
able to deprotonate neither DMFA-protected m-anisidine ents with n-BuLi, albeit in a low yield (entries 5 and 6),
2c nor its DIFA analogue 2d (Table 2, entries 1, 4). How- mostly due to a low conversion. Applying a stronger co-
Table 2 Metalation of meta-Substituted DIFA Derivatives13
O
t-Bu
E
HO
X
E
X
N
X
N
t-Bu
O
1. DOM
2. E+
1. DOM
2. E+
X = CONHt-Bu
X = CONHt-Bu
E = CHO
OH
N
N
E = CHO
N
N
NR2
Ni-Pr2
N
Ni-Pr2
Ni-Pr2
2c R = Me
2d, 4a R = i-Pr
5
7
Ni-Pr2
6
8
Entry Compd X
Base (equiv),a conditions
E+
E
Ratio (5/6 or 7/8)b Product, yield (%)
1
2
2c
2c
2c
2d
2d
2d
2d
2d
2d
2d
2d
2d
2d
2d
4a
4a
4a
4a
4a
4a
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
LTMP (2), THF, –70 °C to 0 °C, 0.5 h
n-BuLi (2), Et2O, –40 °C, 1 h
n-BuLi (2), THF, –75 °C, 2 h
LTMP (2), THF, 0 °C, 2 h
B(Oi-Pr)3
C2F4Br2
C2F4Br2
I2
B(OH)2
–
none, –
Br
–
none, –
3
Br
–
none, –
4
I
–
none, –
5
n-BuLi (1.3), Et2O, 0 °C, 6 h
n-BuLi (1.3), THF, 0 °C, 1 h
t-BuLi (1.3), Et2O, –10 °C, 2 h
t-BuLi (1.3), Et2O, –10 °C, 2 h
t-BuLi (1.3), Et2O, –10 °C, 2 h
C2F4Br2
C2F4Br2
C2F4Br2
C2H4Br2
I2
Br
>100:1
50:1
40:1
–
5a, 28b
6
Br
5a, 41b
8
Br
5a, 59c
9
Br
5a, 1b
10
11
12
13
14
15
16
17
18
19
20
21
I
40:1
1.3:1
1.4:1
13:1
7:1
5b, 52c
s-BuLi (2), TMEDA (2), THF, –75 °C, 2 h CO2
CO2H
CHO
CHO
CHO
CHO
Br
5c, 20;b 6c, 15b
5d, 30;c 6d, 27c
5d, 17;b 6d, 1.3b
5d, 39;b 6d, 6b
5d, 49c
s-BuLi (1.4), TMEDA, Et2O, –50 °C, 1 h
s-BuLi (1.5), PMDTA, Et2O, –55 °C, 1 h
s-BuLi (1.5), PMDTA, Et2O, –45 °C, 2 h
s-BuLi (3), PMDTA, Et2O, –42 °C, 2 h
DMF
DMF
DMF
DMF
C2F4Br2
DMF
DMF
DMF
DMF
DMF
17:1
4:1
CONHt-Bu n-BuLi (2.5), THF, –25 °C to –10 °C, 1 h
CONHt-Bu n-BuLi (2.4), Et2O, 0 °C, 1.5–2.5 h
CONHt-Bu t-BuLi (2.4), Et2O, –12 °C, 0.6 h
5e, 52;b 6e, 13b
7, 30–33c
7, 43c
CHO
CHO
CHO
CHO
CHO
4:1
15:1
5:1
CONHt-Bu t-BuLi (2.4), Et2O, –12 °C, 1.5 h
7, 38c
CONHt-Bu s-BuLi (2.3), TMEDA, Et2O, –55 °C, 1 h
CONHt-Bu s-BuLi (2.3), PMDTA, Et2O, –55 °C, 1 h
1:4.5
1:7
7, 13;c 8, 69c
8, 50c
a If different from 1 equiv.
b Estimated from LC-MS and/or NMR of crude mixtures.
c Isolated yield. Purity > 95% (HPLC area method and 1H NMR).
Synlett 2010, No. 20, 3039–3044 © Thieme Stuttgart · New York

LETTER
N,N-Diisopropylformamidine Protection of Anilines
3041
ordinating base (t-BuLi) increased the conversion. The conditions broadly similar to the ones applied to the pro-
subsequent quench with electrophiles afforded corre- tected m-anisidine 2d.
sponding bromo- and iodo-derivatives in moderate-to-
good yields (entries 8, 10). Interestingly, 1,2-dibromo-
ethane (C2H4Br2), a brominating reagent most frequently
used in such a quench, gave almost no desired product
(entry 9). It appears that more reactive and more expen-
sive 1,2-dibromotetrafluoroethane (C2F4Br2) is mandato-
ry in this case (entries 8 and 9).
As with 2d, metalation of 4a with n-BuLi and t-BuLi was
directed predominantly between the two substituents, af-
fording, after a quench with electrophiles, compounds 5 or
7 in a low-to-moderate yield (entries 16–19).
Switching the base to s-BuLi/TMEDA reversed selectivi-
ty, and the easily separable by flash chromatography iso-
mer 8 was isolated in a good yield (entry 20). Unlike the
Unlike the selective metalation observed with n-BuLi and
examples with anisidine 2d (entries 13–15), s-BuLi/PM-
t-BuLi, comparable amounts of the isomeric products (en-
DTA further shifted the metalation into the position far-
thest from the large DIFA substituent (further towards 8;
see entry 21). However, despite the increased selectivity,
the amounts of side products and unreacted 4a were high-
er with PMDTA, affording a lower isolated yield of 8 (en-
try 21).
tries 11, 12) were obtained with a strong complexed base,
s-BuLi/TMEDA. This result indicates that the coordinat-
ing ability of DIFA is responsible for much of its ortho-
orienting effect. To our surprise, a more hindered com-
plexed base, s-BuLi/N,N,N¢,N¢¢,N¢¢-pentamethyldiethyle-
netriamine (PMDTA), increased the share of metalation
This result is illustrative of the concept of optional site se-
ortho to the large DIFA substituent from 1.4:1 to 13:1
lectivity,1,2,16 according to which n-BuLi or t-BuLi prefer-
(compare entries 12 and 13). s-BuLi/PMDTA appeared to
entially abstract a proton at the position ortho to the
behave as a weaker base than s-BuLi/TMEDA both kinet-
coordinating substituent (in our case, DIFA group). On
ically (slower reaction, 96% conversion in entry 12 vs.
the other hand, organolithiums complexed with chelating
38% conversion in entry 13) and thermodynamically
amines abstract the most acidic and the least hindered pro-
(metalation appeared to stop at 58% conversion in entry
ton.
14). The literature is equivocal on this issue.14 To make
the s-BuLi/PMDTA lithiation practical a large excess of s-
BuLi had to be used (entry 15).
Metalation of less acidic o-anisidine-derived analogue 2e
was low-yielding even with activated bases. The depro-
tection to o-anisidine (1e) predominated with TMEDA-
containing bases (Table 3, entries 1 and 2), while forma-
tion of other byproducts was the main direction with
LICKOR base (entry 3).
To the best of our knowledge, DOM of aminobenzoic ac-
ids and their derivatives is entirely without a precedent.15
Hence, we were very happy to observe the metalation of
protected 3-aminobenzamide 4a (entries 16–21) under
Table 3 Metalation of ortho-Substituted DIFA Derivatives13
OH
1. s-BuLi
E
TMEDA
X = CONHt-Bu
N
t-Bu
2. E+
E = CHO
X
X
O
N
N
N
Ni-Pr2
Ni-Pr2
Ni-Pr2
10
9
9a X = OMe, E = Br
9b X = OMe, E = PhCHOH
9c X = OMe, E = CHO
9d X = CONHt-Bu, E = PhCHOH
Entry
Compd
2e
Base (equiv),a conditions
E+
Product, yield (%)
9a, 10b
1
2
3
4
5
6
7
n-BuLi (2), TMEDA (2), Et2O, 0 °C, 0.25 h
C2F4Br2
PhCHO
DMF
2e
t-BuLi (1.5), TMEDA (1.5), Et2O, –35 °C, 1 h
n-BuLi (3), KOt-Bu (3), THF, –75 °C, 1 h
s-BuLi (2.2), TMEDA, Et2O, –50 °C, 1 h
s-BuLi (2.3), TMEDA, Et2O, –55 °C, 1 h
s-BuLi (2.2), TMEDA, THF, –75 °C, 1 h
s-BuLi (2.2), TMEDA, Et2O, –40 °C, 1 h
9b, 12c
2e
9c, 19c
4b
PhCHO
DMF
9d, 65c
4b
10, 64c
4b
PhCHO
PhCHO
9d, 32b
4b
9d, 31c
a If different from 1 equiv.
b Estimated from LC-MS and/or NMR of crude mixtures.
c Isolated yield. Purity > 95% (HPLC area method and 1H NMR).
Synlett 2010, No. 20, 3039–3044 © Thieme Stuttgart · New York

3042
P. E. Zhichkin et al.
LETTER
The standard reaction conditions used with the protected (a mixture of t-BuMgCl and 2 LTMP) was successful (en-
meta-benzamide 4a (s-BuLi, TMEDA, Et2O) also worked tries 3, 4). As above, a single regioisomer directed by the
well for the ortho analogue 4b (entries 4 and 5). It is im- CONHt-Bu group was formed.
portant to keep the reaction temperature between –60 and
The relative strength of the ortho-directing ability of
–50 °C because metalation is too slow at lower tempera-
NHBoc and DIFA groups is illustrated by DOM reactions
ture (conversion 54% in entry 6), while 4b is prone to
of differentially protected 4-phenylenediamine 2f. Meta-
deprotection to tert-butylanthranylamide at higher tem-
lation with t-BuLi in diethyl ether gives a mixture, in
perature (20% of deprotection in entry 7). Notably, for all
which the ortho-NHBoc regioisomer 12c predominates
(entry 5, 4:1 ratio). The reaction can be made synthetically
useful by employing s-BuLi/TMEDA (entry 7). Higher
temperature, more base and longer time were needed for
of the ortho-substituted DIFA derivatives lithiation oc-
curred exclusively next to the stronger directing group X
(OMe or CONHt-Bu).17
Metalation of the protected 4-aminobenzamide 4c was carbamate 2f (entry 6, conversion 7%; entry 7, conversion
also successful, although a somewhat higher temperature 75%) as compared with tert-butylamide analogue 4c (en-
and longer time were required to drive it to completion try 1, conversion 96%). Metalation ortho to the DIFA
(Table 4, entry 1). Metalation of the 6-aminonicotinamide group was observed only as a minor side reaction (entry
derivative 4d with t-BuLi proceeded in low yield because 7). Excess TMEDA increased the regioselectivity of the
of competing ring addition reactions (entry 2); however, reaction; however, the isolated yield did not increase (en-
metalation with the magnesiate base ‘LiMgt-BuTMP2’18 try 8) because the conversion was also lower (65%). This
Table 4 Metalation of para-Substituted DIFA Derivatives13
NHBoc
E
X
N
Ni-Pr2
Y
1. DOM
2. E+
11d E = I
11e E = CHO
N
t-Bu
O
X
N
Ni-Pr2
E
HO
X = CONHt-Bu
Y
Y
E = CHO
N
N
Ni-Pr2
12
Ni-Pr2
13a Y = CH
13b Y = N
12a X = CONHt-Bu, Y = N, E = Br
12b X = CONHt-Bu, Y = N, E = I
12c X = NHBoc, Y = CH, E = I
12d X = NHBoc, Y = CH, E = CHO
Entry
Compd
4c
Base (equiv),a conditions
E+
Product, yield (%)
13a, 84c
1
2
3
4
5
6
7
8
s-BuLi (2.3), TMEDA, Et2O, –45 °C, 1.5 h
t-BuLi (2.4), THF, –70 °C, 1.5 h
DMF
C2F4Br2
I2
4d
4d
4d
2f
12a, 10b
LiMgt-BuTMP2 (1.5), THF, 0 °C, 0.5 h
LiMgt-BuTMP2 (1.5), THF, 0 °C, 0.5 h
t-BuLi (2.5), Et2O, –14 °C, 1.5 h
12b, 73c
DMF
I2
13b, 73c
11c, 8;b 12c, 32b
12d, 2b
2f
s-BuLi (2.3), TMEDA, Et2O, –55 °C, 1 h
s-BuLi (3), TMEDA, Et2O, –37 °C, 3 h
s-BuLi (3), TMEDA (3), Et2O, –33 °C, 3 h
DMF
DMF
DMF
2f
11d 8;d 12d 46c,e
12d 47c,f
2f
a If different from 1 equiv.
b Estimated from LC-MS and/or NMR of crude mixtures.
c Isolated yield. Purity > 95% (HPLC area method and 1H NMR).
d Isolated yield. Purity = 83% (HPLC area method).
e Ratio 11/12 = 1:4 in crude reaction mixture.
f Ratio 11/12 = 1:17 in crude reaction mixture.
Synlett 2010, No. 20, 3039–3044 © Thieme Stuttgart · New York

LETTER
N,N-Diisopropylformamidine Protection of Anilines
3043
result is consistent with the literature, which notes that ex- moved by nucleophilic DMEDA, thus being orthogonal to
cess TMEDA may either decrease14 or increase14 metala- many acid-labile protecting groups.
tion rates.
To illustrate the practical use of DIFA-protected deriva-
Supporting Information for this article is available online at
tives, bromide 5a was converted into 15, a precursor of a
potent corticotrophin-releasing factor receptor antago-
nist,19 via a Suzuki reaction followed by deprotection with
N,N¢-dimethylethylenediamine (DMEDA; Scheme 1).
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
detailed experimental procedures and spectra for isolated com-
pounds 2a–f, 4a–d, 5a,b,d, 6d, 7, 8, 9b,c, 10, 11d, 12b,d, 13a,b,
and 14–17.
B(OH)2
References and Notes
(1) (a) Chevallier, F.; Mongin, F. Chem. Soc. Rev. 2008, 37,
595. (b) Schlosser, M.; Mongin, F. Chem. Soc. Rev. 2007,
36, 1161. (c) Majewski, M.; Snieckus, V. Science of
Synthesis, Vol. 8a; Thieme: Stuttgart, 2006, 5.
Cl
Cl
OMe
Br
N
MeO
MeO
DMEDA
71%
Cl
62%
(d) Schlosser, M. Angew. Chem. Int. Ed. 2005, 44, 376.
(e) Anctil, E. J.-G.; Snieckus, V. Metal-Catalyzed Cross-
Coupling Reactions, 2nd ed., Vol. 2; Wiley-VCH:
Weinheim, 2004, 761.
NH2
N
Ni-Pr2
Ni-Pr2
5a
14
15
(2) (a) Takagishi, S.; Katsoulos, G.; Schlosser, M. Synlett 1992,
360. (b) Baston, E.; Maggi, R.; Friedrich, K.; Schlosser, M.
Eur. J. Org. Chem. 2001, 3985. (c) Leroux, F.; Castagnetti,
E.; Schlosser, M. J. Org. Chem. 2003, 68, 4693.
(3) For example, see: (a) Schlecker, W.; Huth, A.; Ottow, E.
J. Org. Chem. 1995, 60, 8414. (b) Carroll, W.; Zhang, X.
Tetrahedron Lett. 1997, 38, 2637.
(4) For the background on N,N-dimethylformamidine
protection, see: (a) Hanaya, T.; Toyota, H.; Yamamoto, H.
Synlett 2006, 2075. (b) Saneyoshi, H.; Seio, K.; Sekine, M.
J. Org. Chem. 2005, 70, 10453. (c) Hikishima, S.;
Minakawa, N.; Kuramoto, K.; Fujisawa, Y.; Ogawa, M.;
Matsuda, A. Angew. Chem. Int. Ed. 2005, 44, 596.
(d) Gudmundsson, K. J.; Johns, B. A. Org. Lett. 2003, 5,
1369. (e) Wuts, P. G. M.; Greene, T. W. Greene’s Protective
Groups in Organic Synthesis, 4th ed.; Wiley-Interscience:
Hoboken, 2007, 830.
Scheme 1 Practical use of DIFA protection
The two synthetically important properties of the DIFA
group are its stability under acidic conditions and its abil-
ity to be deprotected by nucleophilic DMEDA. This opens
a multitude of possibilities for the orthogonal protection
with acid-sensitive groups and for the following selective
deprotection. For example, tert-butylamide in compound
7 can be selectively hydrolyzed to 16 under acidic condi-
tions while DIFA stays unchanged (Scheme 2). On the
other hand, DIFA can be selectively deprotected to 17
with DMEDA without disturbing tert-butylamide and the
masked aldehyde group (Scheme 2).
(5) Varchi, G.; Jensen, A. E.; Dohle, W.; Ricci, A.; Cahiez, G.;
Knochel, P. Synlett 2001, 477.
O
O
(6) Review: Meyers, A. Aldrichimica Acta 1985, 18, 59.
(7) Zhichkin, P.; Peterson, L.; Beer, C.; Rennells, M. J. Org.
Chem. 2008, 73, 8954.
(8) (a) Yang, X.; Knochel, P. Synthesis 2006, 2618.
(b) Staubitz, A.; Dohle, W.; Knochel, P. Synthesis 2003,
233. (c) Lindsay, D. M.; Dohle, W.; Jensen, A. E.; Kopp, F.;
Knochel, P. Org. Lett. 2002, 4, 1819.
OH
t-Bu
O
C, 18 h
l, 90 °
N
N
aq HC
6 M
• HCl
Ni-Pr2
50%
OH
DM
16
ED
A, EtO
N
H, 110 °
C, 24 h
t-Bu
O
(9) Gall, M.; McCall, J. M.; TenBrink, R. E.; VonVoigtlander,
P. F.; Mohrland, J. S. J. Med. Chem. 1988, 31, 1816.
(10) An aliquot of the reaction mixture was quenched with 5%
AcOH in H2O, and the HPLC areas of des-Br 2a or des-Br
2b were compared with those for decomposition products.
(11) The anion of 2b obtained using n-BuLi had a half-life of only
1 h at –30 °C due to its reaction with 1-bromobutane, a side
product of the metal–halogen exchange. After warming to
r.t., N¢-(4-butylphenyl)-N,N-diisopropylformamidine could
be isolated in 90% yield (see Supporting Information for
details).
(12) Li, W.; Nelson, D. P.; Jensen, M. S.; Hoerrner, R. S.; Cai, D.;
Larsen, R. D.; Reider, P. J. J. Org. Chem. 2002, 67, 5394.
(13) See Supporting Information for detailed procedures.
(14) (a) In THF PhLi/PMDTA is more reactive than PhLi/
TMEDA, see: Reich, H. J.; Green, D. P.; Medina, M. A.;
Goldenberg, W. S.; Gudmundson, B.; Dykstra, R. R.;
Phillips, N. H. J. Am. Chem. Soc. 1998, 120, 7201. (b) In
Et2O s-BuLi/PMDTA is less reactive than s-BuLi/TMEDA,
Ni-Pr2
N
7
OH
NH2
17
Scheme 2 Selective deprotections of DIFA and CONHt-Bu groups
In conclusion, the use of a novel N,N-diisopropylform-
amidine (DIFA) protecting group for aromatic amines in
directed ortho-metalation reactions was established.
DIFA is a large group with only weak ortho-orienting
properties. In many cases, it is meta directing. This allows
changing the usual ortho-directing regiochemistry ob-
served with NHBoc/NHPv groups via a simple change of
the amine protecting group to DIFA. The other important
property of DIFA is that it is stable to acids and can be re-
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P. E. Zhichkin et al.
LETTER
see: McGrath, M. J.; Bilke, J. L.; O’Brien, P. Chem.
Commun. 2006, 2607. (c) In hydrocarbons, LDA/PMDTA
is less reactive than LDA/TMEDA, see: Remenar, J. F.;
Collum, D. B. J. Am. Chem. Soc. 1998, 120, 4081.
(17) Confirmed through NOE experiments with 9b and 9c (see
Supporting Information).
(18) Inspired by LiMgBuTMP2 base, see: Hawad, H.; Bayh, O.;
Hoarau, C.; Trécourt, F.; Quéguiner, G.; Marsais, F.
Tetrahedron 2008, 64, 3236.
(19) Huang, C. Q.; Wilcoxen, K.; McCarthy, J. R.; Haddach, M.;
Webb, T. R.; Gu, J.; Xie, Y.-F.; Grigoriadis, D. E.; Chen, C.
Bioorg. Med. Chem. Lett. 2003, 13, 3375.
(15) No literature on DOM of derivatives of aminobenzoic acids
could be found, and only two papers (see ref. 3) dealt with
the lithiation of derivatives of aminoheteroarylcarboxylic
acids.
(16) Maggi, R.; Schlosser, M. J. Org. Chem. 1996, 61, 5430.
Synlett 2010, No. 20, 3039–3044 © Thieme Stuttgart · New York

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